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Full text of ' UNIVERSITY OF IILINOIS LIBRARY AT U ^.NA-CHAMPAIGN Digitized by the Internet Archive in 2012 with funding from University of Illinois Urbana-Champaign SEMINAR TOPICS I Semester 1979-80 X- — ^ Generation and Synthetic Utility of Carbanions Stabilized by Divalent Sulfur Peter Becker r The Design, Synthesis, and Biology of Intercalating Agents David W. Robertson J HERTZBERG - NEW METHOD, INC. EAST VANDALIA ROAD, JACKSONVILLE, ILL. 62650 Q_, - TITUE NO.

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B ]• ACCOUNT NO.: NRTK« LOT AND TICKET NO.13 22 5>79~82*PT ♦ 1 Q* 547*IG»L 5^- R' I 2 T. C=SCH 2 Li Ll y + 1 R = Ph Y 3 2 R = Me - A Reaction of a-lithiosulfides with a variety of electrophiles gives the expected products in good yield; j2.j. 2^ with carbon dioxide gives 2-methylthioacetic acid. Methylenation of ketones 10 has been performed with 1>and 1_ along with higher homologs has been used in the synthesis of epoxides.

11 Homologation of trialkyl boranes 12 has been effected with 2^, as well as the synthesis of terminal alkynes from carboxylic acids. 13 Trost has formed cyclobutanones 14 and cyclopentenes 15 from adducts of phenylthiocyclopropyl lithium with ketones. Allyl and benzyl sulfides are more readily metallated, and even the dianions of allyl and benzyl thiol 16 have been reported. Trialkyl borane complexes 17 and complexation with heteroatoms 18 have been used to direct a-alkylation of ambident allyl anion J3.

However, the copper reagent gives predominantly y- alky la t ion. 19 Reported syntheses of terpenes, 20 jasmonoids 21 and prostaglandin F 2 22 employed species J3. Cecropia juvenile hormones have been made via dihydrothiapyrans. 23 Alkylation followed by sigmatropic rearrangement has proven useful. 24 Metallated vinyl sulfides serve as acyl anion equivalents and have been prepared by addition of organometallic reagents to acetylenic sulfides and thioketenes and transmetallation.

25 Direct proton abstraction is the or most widely used route and there have been a number of recent examples. D Metallation of 1,3-dien-l-yl sulfides has also been reported. 27 Higher homologs have been metallated in the a-position.

28 Derivatives of thiols such as thioimidates, dithiocarbonates and thio- esters have been deprotonated on the sulfur-bearing carbon and are thought to be dipole stabilized 4_. 29 Mono and dithiocarbamates also have been deprotonated. 30 The above compounds are generally limited to the methyl and allyl cases; however, a-lithioisopropyl 2,4,6-triisopropylthio- benzoate has been formed in good yield. 31 -2- BIBLIOGRAPHY 1. Gillman and F. Soc, 71, 4062 (1949). Chen., 31, 4097 (1966) 3.

Peterson, ibid., 32, 1717 (1967). Bryson, Tetrahedron Lett., 1961 (1977). Mendoza and D. Chem., 44, 1352 (1979). Screttas and M. Micha-Screttas, ibid., 44, 713 (1979); T. Daniewski and R.

Weisenfeld, Tetrahedron Lett., 4665 (1978). Damonc, and A. Krief, ibid., 1617 (1975); D.

Meyer, and A. Chem., 846 (1977). Peterson, Organomet.

Rev., A 2, 295 (1972). Pichat and J. Beaucourt, J. Com., 10, 103 (1974). Kurata, Tetrahedron Lett., 737 (1972); T.

Shono, et al., ibid., 2807 (1978); R. Sowerby and R. Soc, 94, 4758 (1972). Shanklin, e_t al., J. Soc, 95_, 3429 (1973); W. Pirkle and P. Chem., 43, 3803 (1978); W.

Pirkle and P. Rinaldi, ibid., 44, 1025 (1979).

Nigishi, et al., J. Chem., 40, 814 (1975). Yokomatsu, and S. Shibuya, ibid., 43, 4366 (1978). Trost, et al., J.

Soc, 99, 3080,3088 (1977); B. Chem., 43, 2938 (1978); B. Vladchick, Synthesis, 821 (1978). Soc, 98, 248 (1976). Seebach and K.-H.

Geiss, Angew. Chem., 86^, 202 (1974); M.

Pohmakotr, K.-H. Geiss, and D. Seebach, Chem.

Ber., 112, 1420 (1979). Yatagai, and K. Commun., 157 (1979). Hayashi, and T.

Mukaiyama, Chem. Lett., 259 (1972). Oshima, et al., Bull. J., 48, 1567 (1975). Chem., 43, 4915 (1978); M.

Matsuki, and S. Ito, Tetrahedron Lett., 1121 (1976); J. Biellmann and J. Ducep, ibid., 3707 (1969); E. E Van Tamelen, et al., J. Soc, 94, 8228 (1972). Biellmann and D.

Schirlin, Syn. Coram., 8, 409 (1978). Noyori, Tetrahedron Lett., 311 (1970). Sotter and R. Soc, 95_, 4444 (1973). Thiaclaisen, L.

Brandsma, and H. Verkraijsse, Rec Trav. Pays-Bas, 9^, 319 (1974); K. Yamamoto, and H. Soc, 95, 4446 (1973). Evans, ibid., 100, 2242 (1978).

GrSbel and D. Seebach, Synthesis, 357 (1977) and references cited in section 5.1. Cookson and P. Commun., 990 (1976) and 821,822 (1978).

Everhardus, H. Eeuwhorst, and L. Commun., 801 (1977); R. Grafing and L. Brandsma, Synthesis, 578 (1978); R.

Everhardus, R. Grafing and L. Brandsma, Rec Trav. Pays-Bas, 97, 69 (1978). Muthukrishman and M. Schlosser, Helv. Acta, _59, 13 (1976); J.

Chem., 44, 303 (1979). Rev., _78, 275 (1978) and references cited in section IV. Sakurai, and T.

Lett., 1483 (1977); T. Mimura, and A. Ari-Izumi, Tetrahedron Lett., 2425 (1977) and references cited therein.

Becker, unpublished results. -3- THE DESIGN, SYNTHESIS, AND BIOLOGY OF DNA INTERCALATING AGENTS Reported by David W. Robertson September 27, 1979 Intercalation is the noncovalent insertion of planar aromatic mole- cules between two successive base pairs of double-helical DNA. Since Lerman's classic delineation of intercalation 1 over two decades ago, many antitumor agents, mutagens, carcinogens, and teratogens have been found to exert their effects through intercalative binding to DNA. Because of the biological and clinical importance of intercalation, molecular biologists, oncologists, and chemists have intensively investigated the nature of this phenomenon. In this paper the evidence adduced for intercalation will be surveyed, and the design, synthesis, and biological applications of DNA intercalating agents will be examined.

Structural Requirements for Intercalation. Ethidium bromide (1), a phenanthridinium trypanocide, and proflavin (2), a powerful frameshift mutagen, are archetypical intercalators (Figure 1).

Both inhibit DNA and RNA synthesis 2 and are two of the more widely studied intercalators. As these two examples indicate, molecules which intercalate are planar aromatic molecules; large deviations from molecular planarity in the form of bulky substituents such as in 2,7-di-t-butylproflavin 3 prevent intercalation. In addition to the endo- cyclic nitrogens which most high-affinity intercalators possess, many inter- calators also contain exocyclic amine groups.

These, if positioned properly, result in enhanced binding affinity. ^ Figure 1 9 10 12 H 2 N 3 'NH 2 proflavin (2) ethidium bromide (1) Methods by Which Intercalation and the Resultant DNA Deformations are Studied. In the normal DNA duplex, the adjacent parallel base pairs are in van der Waals contact with one another. A planar molecule is accommodated in the helix by a local unwinding of the deoxyribose backbone; this separates the base pairs sufficiently to allow the insertion of the intercalator while still maintaining the integrity of the interbase Watson-Crick hydrogen bonding.

The DNA-intercalator complex is stabilized by many physical processes; hydrophobic interactions, electronic interactions between the -rr- clouds of the intercalator and DNA bases, and hydrogen bonding have all been shown to contribute to the stabilization of the complex. Because intercala- tive interactions perturb the physical and chemical characteristics of both the DNA and the intercalator, a number of physicochemical probes can be used to examine the interaction of an intercalator with DNA. Fluorescence and Visible Spectroscopy. Upon intercalation of ethidium bromide into DNA, hypochromic and bathochromic shifts are produced in the visible spectrum of ethidium.

5 When the intercalator is treated with -4- increasing concentrations of DNA, the absorbance spectrum of the drug shifts progressively towards a limit which represents the spectrum of the drug when fully intercalated (Figure 2). The curves pass through a well-defined isosbestic point, indicating that two forms of the drug, free and bound, are contributing to the absorbance.

Figure 2 ^V 1 1 free fully complexed 400 450 500 550 600 Wavelength (nm) From a combination of the visible spectrum and a Scatchard plot, the association constant and number of binding sites in the DNA can be estimated. For ethidium bromide the approximate association constant is 5 x 10 M~, with up to one ethidium per two base pairs being bound. The nonlinearity of the Scatchard plots 5 and many other lines of evidence indicate that two types of binding are possible. After the high-affinity intercalative sites are exhausted, more positively charged ethidium molecules can interact with the negatively charged phosphates of the DNA. At a ratio of one drug per nucleo- tide residue, an electrostatically neutral complex precipitates. 5 When ethidium is complexed with DNA there is a dramatic increase in the fluorescence of the intercalator 6 (Figure 3).

The most plausible explanation for the fluorescence enhancement is the immersion of the ethidium into a hydrophobic region of the nucleic acid upon intercalation. This reduces the rate of excited state-solvent proton transfer, and increases the fluorescence lifetime by a factor of 12. 7 Figure 3 1000 Fluorescence intensity 500 300 400 500 600 A (nm) NMR Spectroscopy. Numerous X H- and 31 P-NMR experiments have been con- ducted on mixtures of complementary oligonucleotides and intercalators.

8 ~ 10 When 9-aminoacridine in D 2 is titrated with increasing concentrations of dGpC, the nonexchangeable protons experience a linear upfield shift until a 1:2 acridine-dinucleotide stoichiometry is reached 11 (Figure A). This suggests the formation of a minihelix with the acridine sandwiched betwef n -5- Figure 4 59 i r i i — r— — r— 60 si - 2^ 6.1 •* o>' ' I' a - • 0.5 ppm (H-l, H-10) relative to the corresponding protons in uncomplexed ethidium. 12 Calculated values for the upfield shifts based upon the atomic diamagnetic anisotropy and ring current contributions compare favorably with the experimentally determined values. Circular Dichroism and X-Ray Studies.

When ethidium is mixed with 7—9 double-helical DNA, circular dichroism is induced in the nonchiral ethidium. R Various dichroism studies have indicated that the plane of the inter calator is approximately parallel to the planes of the adjacent base pairs. Complexes of intercalators and complementary oligonucleotides can some- times be crystallized, allowing the direct visualization of inter calative binding in a miniature double helix.

13 All the X-ray studies confirm the postulates which were based on spectroscopic data. Intercalation, because of the necessary local unwinding of the helix, results in a lengthening and stiffening of the DNA molecule. This causes the intercalated DNA to become more rod-like than its pristine counterpart; as a consequence the intrinsic viscosity of DNA solutions is increased. 1 Because the additional length due to an intercalator is approxi- mately the same as that of an additional base pair and most intercalators are of less molecular weight than a base pair, the average molecular weight per unit length of the DNA decreases; this results in a decrease of the sedimentation coefficient. 1 A unique method of studying intercalation is the interaction of the intercalating agent with covalently closed, supercoiled DNA. These DNAs display large changes in their supercoiling as a result of local intercalative helix unwinding.

' 5 As increasing concentrations of intercalator are added, the right-handed supercoiling decreases until open circles are obtained. Additional intercalating agent results in more unwinding until torsional strains produce left-handed supercoils (Figure 5). The progress of the titra- Figure 5 ->^ right-handed left-handed -6- tion is most conveniently monitored by changes in the sedimentation coeffi- cient of the DNA (Figure 6). All known intercalating agents remove and reverse the supercoils of closed circular duplex DNA. Figure 6 right-handed supercoils left-handed supercoils open circles 0.02 0.06 0.1 drug molecules bound per nucleotide Intercalative Photoaf f inity Labelling Reagents.

Intercalators such as ethidium bromide have been widely used to probe numerous biological structures such as tRNA, 5S-RNA, and chromatin; they have also been of great utility in studies of biological processes such as DNA replication and transcription, and the mechanism of frameshift mutagenesis. 16 One of the major disadvantages of using noncovalently attached intercalators in the study of biological structures and processes is that during the time of a biological or physical assay the intercalators can move from site to site. 17 In in vivo studies, cell fractionation techniques can rearrange concentration gradients and drug distributions among subcellular compartments. 18 This problem can be circum- vented by the use of intercalating agents which can be covalently attached to the DNA or juxtaposed proteins. Photoaf f inity labelling is a technique which permits this covalent attachment. At least two different types of intercalative photoaf f inity labels have been developed: the furocoumarins (Figure 7) and azide analogs of ethidium and acridine. Figure 7 psoralin (3) angelicin (A) The furocoumarins are a group of naturally occurring and synthetic compounds which manifest interesting photobiological effects such as skin They have been used therapeutically since antiquity; the sensitization, 19 fruit and seed extracts used by the ancient Egyptians to treat vitiligo contained furocoumarins.

20 A more recent medicinal application is the photochemo therapy of psoriasis and other skin diseases 19 The mechanism by which furocoumarins exert their photobiological effects is photoreaction with DNA; a linear relationship normally exists between the -7- biological effects and the extent of photoreaction. 2 1 In the absence of electromagnetic excitation there is no disruption of cellular processes. Furocoumarins intercalate into DNA and form cyclobutane adducts with the pyrimidine bases in DNA when the complex is irradiated with 365 nm light. *^ The linear furocoumarins, the psoralens (Figure 7), are capable of forming either monofunctional or difunctional adducts with DNA. The difunctional adducts are due to the reaction of both the 3,4 and 4', 5* double bonds with pyrimidine bases in each strand of duplex DNA. This crosslinks the DNA strands and prevents them from becoming separated even under conditions which normally denature DNA.

The crosslinking has been demonstrated by denaturation-renaturation kinetics 22 and by electron microscope studies. 23 Cole has shown that the inhibition of certain bacterial functions by psoralin is approximately equal to the rate of formation of a single psoralen cross- link per DNA molecule. 24 Numerous derivatives of psoralen have been prepared in order to optimize their DNA interaction characteristics.

Hearst and Rapoport reported 2 - 5 that 4'-aminomethyl-4,5 l,8-trimethylpsoralen is the best derivative for photo- reaction with DNA. It can bind to DNA to the extent of one drug molecule per five base pairs with a 65% photoattachment efficiency. The angular furocoumarins, the angelicins (Figure 7), form only mono- functional adducts and have a low ability to produce photosensitized effects.^ The angelicins, however, may be the furocoumarins of choice if inhibition of DNA or RNA synthesis is the only desired biological effect.

Crosslinking is a very severe type of damage to a cell's genome and often leads to undesirable results. 9-Azidoacridine, another type of intercalative photoaffinity label, was prepared to help elucidate the mechanism of 9-aminoacridine ' s frameshift mutagenicity.

26 Surprisingly, 9-azidoacridine is not a frameshift mutagen; it is a base pair substitution mutagen with or without photolytic activa- tion. Placing the azide moiety at other positions on 9-aminoacridine would perhaps yield a photoaffinity label which still maintains the frameshift mutagenicity of the parent compound. A more suitable photoaffinity label for the frameshift mutagen studies is the fluorescent intercalator 8-azidoethidium bromide. 7 >18 >27 Structure- activity relationships of various phenanthridinium analogs of ethidium bromide indicated that the 8-amino group could be modified with little change in its interaction with DNA. 4 This was found to be true with 8-azido ethidium bromide. In the dark, 8-azidoethidium bromide and ethidium bromide are competitive inhibitors in DNA binding studies and cause similar pertur- bations in the hydrodynamic properties of native DNA.

The azide analog binds strongly to DNA (K a =2-3xl0 5 M _1 ), and can be photoattached to DNA with efficiencies approaching 75%. 27 Unlike 9-azidoacridine, 8-azidoethidium bromide behaves as a frameshift mutagen both before and after covalent attachment to DNA.

Antibiotic Intercalators. Many naturally occurring antibiotics have been shown to exert their effects through intercalative binding to DNA. The actinomycins, 28 ' 29 quinomycins, 30 and triostlns 31 all intercalate into DNA with very high affinity.

The two most heavily studied intercalators are actinomycin D (5, Figure 8) and echinomycin (60, a member of the quinomycin antibiotic family. Both of these compounds differ from pre- viously mentioned intercalators in that they have peptide moieties, and -8- after incercalation of the chromophore, these peptides lie in the minor groove of the DNA. Through their hydrogen bonding and hydrophobic inter- actions with various components of the helix, the peptides enhance the binding affinity of the intercalators to the DNA and contribute some degree of sequence specificity. Figure 8 '1 C— NH, II 2 actinomycin D (5) HoC / CH.

P 3 f 3 W S» 'V- C— N— CH C— N— CH— C— N— CH— C— N— CH— C J I CH, I ' II H,CH N SCH 3 / CH 2 CH, H H / y Z— CH— N C— CH— N— C— CH— N— C— CH— N— C— r^ S I l H CH CH 3 / CH, CH- *^. CH, echinomycin (6) Actinomycin D is a widely used intercalative biochemical tool which inhibits DNA-dependent RNA polymerase by inhibiting the elongation of nascent RNA chains. 28 The antibiotic preferentially binds to G-C rich regions of DNA; guanine-free DNAs bind the compound poorly if at all. Furthermore, the molecule is able to distinguish between DNAs which have different nucleotide sequences adjacent to the G and C nucleotides. For instance, a marked effect of the nucleotide sequence on binding was seen by comparing poly d(T-A-C)-poly d(G-T-A) with poly d(A-T-C)-poly d(G-A-T). The former polynucleotide binds actinomycin whereas the latter does not. 29 Echinomycin is a member of the quinoxaline antibiotics, a family of metabolites produced by Streptomycetes.

It is 4-5 times more potent than actinomycin in inhibiting RNA synthesis. 30 The importance of the peptides in the intercalation process is made apparent by the observation that quinoxaline-2-carboxamide (_7 in Figure 8) displays no propensity for inter- calation. 30 This finding and structure-activity relationships 31 indicate that the intact octapeptide backbone is necessary for high-affinity inter- action with DNA; breaking the lactone linkages of the thioacetal cross- bridge obliterates intercalation. Echinomycin is unique in that both quinoxaline rings can intercalate simultaneously into DNA. The helix unwinding angle is 1.82 times that of ethidium and the molar quantity of echinomycin required to unwind supercoiled -9- DNA to uncoiled circles is one-half the amount of ethidium required. 30 The antibiotic lengthens the helix 6.

3 A per molecule bound, whereas a mono- functional intercalator lengthens the helix by 3. 32 NMR studies, 33 model building, 33 and semiempirical potential energy calculations 3 3 » 31+ for echinomycin indicate that in solution the two quinoxa- line chromophores are held in a syn orientation by the octapeptide lactone; this results in a rigid, tweezer-like molecular conformation. The rings are almost parallel to each other and are separated by a distance of 10.2 X, which is the exact value required to accommodate two stacked base pairs between them. 34 Synthetic Polyintercalators.

DNA is the only pharmacological receptor which has been defined to atomic resolution. This, theoretically, should allow the design and synthesis of agents which possess optimal DNA inter- action characteristics. Following Nature's model, echinomycin, polyinter- calators have been synthesized in order to obtain intercalators with the highest possible affinity for DNA; provided entropic and steric factors are not unfavorable, the binding affinity should increase with each additional intercalating subunit. 35 In addition, the possibility exists that these synthetic polyintercalators will exhibit some degree of sequence specificity in their interaction with DNA, a phenomenon lacking with most monointer- calators. The bulk of the synthetic and biological work in the area has been on dimeric intercalators which have been prepared by linking monomeric intercalators with straight-chain paraffins or polyamines (polyamines are natural constituents of many forms of life, and because of their polycationic nature they bind tightly to nucleic acids). 36 Ethidium 35 and its methyl analog me thidium, 37 ~ 39 acridines, 1 * 0- ^ 2 quinal- dines, 43 caffeine, ^^ anthracyclines, 37 and ellipticines 1 * 5 have all been used to prepare homodimeric intercalators. In addition, an acridine-ethidium heterodimer has been reported.

35 By standard methodology Dervan and Becker have synthesized 38 a p_-carboxy- methidium dimer using the polyamine spermine as the connecting chain. The pro- uct, bis (me thidium) spermine (8, Fig. 9), was shown to remove and reverse the supercoils of PM2 DNA, and the molecule possesses an unwinding angle 1.5- fold greater than that of ethidium. Since previous studies have shown that substitution of a methyl for the ethyl group or addition of a p_-carboxyl group to ethidium has little effect on the unwinding angle, the value for the dimer may reflect equal contributions from mono- and bisintercalated species. From fluorescence and stoichiometry of binding studies the workers concluded that the dimer does bisintercalate and has a binding affinity at least 1,000 times that of ethidium. 39 Kuhlmann e_t al. Have synthesized 37 a m-carboxyme thidium and dimerized it by amide linkage to 1,5-diaminopentane.

The dimer (9 in Figure 9) exhibits intramolecular stacking of the two chromophores. From spectro- scopic and hydrodynamic studies it was shown to be a bisintercalator with a much higher affinity for DNA than ethidium. Despite its high affinity for DNA, it is a poorer inhibitor of nucleic acid synthesis in L1210 cells than ethidium. This may be related to a low cellular or nuclear uptake owing to the compound's double positive charge. An ethidium homodimer (10, Figure 9) and an acridine-ethidium hetero- dimer ( 11 ) were synthesized 35 by linking the monomers via the phenanthri- dinium's quaternary nitrogen. By a combination of NMR and fluorescent spectroscopy and ring current calculations, the compounds were found to -10- Figure 9 H,N y-NH 2 h 2 n7/ C— NH(CH,)cNHC II 2 5 II (CH 2 ) 3 NH2 CH 2~ 10 v + 11 (CH 2 ) n 12 exist in a temperature- and pH-dependent equilibrium between folded and unfolded conformations (Figure 10).

These compounds do not bisintercalate. 6 Figure 10 Much of the study of bisintercalators has involved acridine homodimers, Various bis(9-acridyl)polyamines have been prepared, and a homologous series of diacridines connected by the amino groups of the diamines NH 2 (CH 2 ) n NH 2 (where n = 2, 3,4,6,8, 10,12,14,16,18) has been synthesized 40 ( 12 in Figure 9). In the latter compounds, bifunctional intercalation occurs when six methylene units separate the acridines. The diacridines of shorter chain length are monofunctional intercalators. The activity of the homologous series against P-388 tumor cells in mice was then determined. Maximal activity is attained when the chain length is six carbons; longer connecting chains are increasingly toxic to the host (Figure ll). 40 Spermine diacridine at low concentrations inhi- bits RNA polymerase by preferentially inhibiting chain initiation, 48 in marked contrast to actinomycin D which inhibits chain elongation.

28 -11- Figure 11 200 - S 120 - CO 0) u EH 160 - 8 10 12 14 16 18 Chain length - number of carbons Whitlock and Chen have synthesized 1 * 1 * a series of caffeine dimers linked by rigid diyne chains. This decreases the amount of self-association of the two chromophores which was seen with the ethidium dimers. Since the self- association must be disrupted for intercalation to occur, 35 bifunctional intercalators should possibly be constructed with rigid connecting chains in order to optimize the free energy of DNA binding. Despite the large amount of work which has been reported to date, many aspects of intercalation are still enigmatic. The number of base pairs affected by intercalation, the differential effect of inter- calation on the recognition of nucleic acids by various proteins, and the correlation between biological activity and the structure of the inter- calative complex are still unknown. The answers to these and other ques- tions concerning intercalation await the synthesis and physicochemical characterization of many other intercalating agents and is a goal which will require the union of synthetic organic chemistry and molecular biology. BIBLIOGRAPHY 4.

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-13- MODIFICATION OF OLEFINS WITH ORGANOSELENIUM REAGENTS Reported by Larry D. Boardman October 4, 1979 In 1970 Jones, Mundy, and Whitehouse observed that selenoxides underwent clean syn elimination to form olefins. With this fact at hand Sharpless 2 - and Reich' opened the door to modern or gano selenium chemistry in 1973 with the conversion of epoxides to allylic alcohols and the prepa- ration of a,3-unsaturated ketones and esters, respectively, via organo- selenium intermediates.

Organoselenium methodology has since undergone a remarkable growth and diversification and now occupies an important position in the field of organic synthesis. 4 This report reviews the elaboration of olefinic substrates by organoselenium reagents, an area that recently has increasingly attracted the attention of the investigative community.

A wide variety of organoselenium reagents has been prepared, and selenofunctionalization of organic molecules has been refined to a high degree. Como Hackear Medidor De Luz Digital Cfe. A large number of important synthetic transformations can be achieved by taking advantage of the properties of organic selenium com- pounds. As expected, the chemistry of selenium parallels that of sulfur to a certain extent; however, the differences between the two elements often allow specific conversions to be accomplished in circumstances under which the analogous sulfur reaction might proceed only with diffi- culty or not at all.

Opera Mini 7 Free Download For Blackberry Curve 8520. The unique properties of selenium also manifest themselves in reactions that have no counterpart in sulfur chemistry. Reich 1 * in his recent review draws attention to some of the key differ- ences between the chemistries of sulfur and selenium and emphasizes organoselenium transformations that capitalize upon these differences. At the heart of organoselenium chemistry is the selenoxide elimina- tion (Eq. Introduction of an arylseleno moiety followed by oxidation and elimination of the corresponding aryl selenenic acid has been developed and refined to the point that it is now a standard means of introducing [0] (1) unsaturation into organic molecules. Oxidation has been accomplished with a number of reagents: l+a sodium periodate, peracids, hydrogen peroxide, ozone, and more recently tert- butyl hydroperoxide.

6 Thermal elimination of sulfoxides is also known; however, pyro lysis at 50° to 110° is required whereas aryl selenoxides decompose cleanly under neutral conditions at room temperature. The elimination is stereospecif ically syn and, in general, (E) -olefins are obtained where possible. The regiochemistry of the frag- mentation is also predictable, the ease of hydrogen abstraction following the order allylic ^propargylic >benzylic ^methyl >methylene » methine. Elimination is generally away from an electronegative substituent £ to the selenoxide function, the above order notwithstanding (Eq. -14- Addition of Aryl Selenenlc Acid Derivatives, ArSeX.

The first additions of selenenic acid derivatives to alkenes were reported in 1958 by Holze and Jenny; 7 however, the harsh reaction conditions and difficultly prepared starting materials detracted from the synthetic utility of their approach. More useful was the discovery by Clive 8 in 1974 that benzene- selenenyl bromide reacts with alkenes in the presence of silver trifluoro- acetate to give B-trif luoroacetoxy selenides.

Mild hydrolysis with aqueous sodium bicarbonate afforded the corresponding 0-hydroxy selenides in excellent yield (Eq. PhSeBr 9>Ag0 2 CCF 3 cc s xSePh NaHCO. T,oSePh H 2 ->2 CCF 3 (2) Experiments with cyclic olefins gave exclusively products arising from anti addition suggesting the intermediacy of the seleniranium ion 1^ which is then captured by an external nucleophile (Eq. This species is not without analogy (e.g., cyclic halonium, mercurinium, and sulfonium cc SePh CF 3 C0 2 ' 2 CCF 3;;sePh s+eph _ j;;;seph 0^ cr ci ^s.

SePh ^ SePh CI~CT + CI' J H PhSe ^ SePh a^^/h + /3^Zh H I CI 4 OEt * 2. NaIOz, R x OEt O^S [3f3] o'W R3 R3 (6) 5 d -16- 3-Hydroxy selenides are potentially important intermediates; in addition to ally lie alcohols, they can be converted into simple alcohols, epoxides, olefins, bromohydrins, phenylseleno ketones, and vinyl selenides.

17 The synthetic potential of these transformations is apparent; the prepara- tion of (±)-crinamine and related compounds by Isobe and co-workers 3 is but one example. Phenyl vinyl selenides can also be prepared directly from olefins by the addition of benzeneselenenyl bromide to terminal double bonds followed by dehydrohalogenation as described by Raucher. 13 Proper choice of reac- tion conditions permits control of both the regio- and stereochemistry of the elimination.

* 3 » 2t * Once prepared, these compounds can be subjected to further transformations. Vinyl and allyl bromides can be obtained simply and in good yield. 25 Vinyl selenides can also be employed as + CH=CH~ synthons; 26 reaction with an alkyllithium yields a phenylseleno stabilized carbanion which may be trapped by an appropriate electrophile (Eq.

Selenoxide elimination affords the (E_) -olefin in good yield. Li RT i CH 2 =CHSePh — — >RCH 2 CHSePh I (7) H N„ „/ E E [0] I / C=C X H 2: ->SePh Raney Ni V (8) Many other transformations of this general type are possible. Bicyclic ethers 35 can be prepared from the appropriate olefinic alcohols, and the synthesis of ring-fused tetrahydrofurans 36 is particularly important in view of the widespread occurrence of this ring system among natural products. Nicolaou, for example, has applied this methodology to the preparation of several prostacyclin isomers and analogs, ' 38 and Lysenko and co-workers have exploited the process in their synthesis of muscarine analogs. 39 In another example, Petrzilka 40 obtained the phenylseleno acetal 9^ from the cyclization of J3.

Selenoxide fragmentation and spontaneous Claisen rearrangement afforded (±)-phoracanthrolide J ( 10a in Eq. O H PhSeBr ->PhSe 1. A (9) MeO MeO (10) Precocene-I and nitrogen heterocycles can be prepared by cyclofunctionalization of olefinic urethanes (Eq. ^ NH C0 2 Et ->SePh ->H (11) Carbon-carbon bond formation has also been recently achieved in this manner, dive 1 * 2 obtained the substituted hydrindan 11 by the reaction of benzeneselenenyl chloride with 1,5-cyclononadiene in acetic acid (Eq. Hydrolysis of the acetyl group followed by reduction of the benzeneseleneno function by triphenyltin hydride 1 * 3 afforded the alcohol _12 in 61% overall yield. PhSeCl AcOH OAc '>k^V 2. H 2 0, K 2 C0 3 ■>Ph 3 SnH, A SePh 11 OH (12) 12 Cyclofunctionalization also holds potential for selective protection- deprotection operations; Nicolaou 33 has observed that reversion can be accomplished by treatment of the cyclized compounds with sodium in liquid ammonia (Eq.

C0 2 H Na/ >liq. NH 3 (13) SePh Epoxidation. Another important modification of olefins mediated by organoselenium compounds is epoxidation.

The process was initially observed as a side reaction in certain selenoxide eliminations. 4 ~ -19- Grieco, 45 for example, noted a product composition as a function of the number of equivalents of oxidizing agent employed when carrying out the selenoxide fragmentation of 13 (Eq.

H 2 2: 93% 18% (14) 0% 30% Once eliminated, benzeneselenenic acid, as observed by Sharpless, 2 may be further oxidized to benzeneseleninic acid. Grieco 45 postulated oxidation of this species to benzeneperoxyseleninic acid in the presence of excess hydrogen peroxide (Eq.

15) and proposed this as the active H 2 PhSeOH H2 ° 2 >PhSeOH H 2 2 PhSe0 2 H + H 2 u PhSef + H 2 I OH (15) reagent responsible for the epoxidation. As benzeneseleninic acid is regenerated in the reaction, the overall process is catalytic with respect to the selenium reagent. Appropriate conditions for avoiding this oxidation when desired have been designed by Reich 47 while Hori and Sharpless 6 have developed useful synthetic procedures for the epoxida- tion of olefins with arylperoxyseleninic acids. Dichloromethane was found to be the best solvent and o-nitrophenylseleninic acid, 14, and 2,4- dinitrophenylseleninic acid, 15, the most effective catalysts (Eq.

R,-^VseOH Ri 14 ->CH 2 C1 L 14 Rx-NOa, R 2 =H 15 R r = R 2 =N0 2 90% (16) Unlike carboxylic peracids and alkyl hydroperoxides in the presence of vanadium or molybdenum catalysts, little or no regioselectivity is observed in the epoxidation of allylic dieneols with arylperoxyseleninic acids. -20- In summary, many important transformations are possible through the action of organoselenium reagents on olefins. Addition of aryl selenenic acid derivatives to double bonds provides a convenient route to several important synthetic intermediates, and, although the methodology is still young, cyclofunctionalization and epoxidation may provide important new answers to old problems. BIBLIOGRAPHY 1. Mundy, and R.

Whitehouse, J. Commun., 86 (1970). Sharpless and R. Soc, 95, 2697 (1973). Reich, and J. Soc, 95, 5813 (1973). For recent reviews of organoselenium chemistry, see (a) D.

Clive, Tetrahedron, 34, 1049 (1978); (b) H. Reich, 'Organo- selenium Oxidations', in 'Oxidation in Organic Chemistry', Part C, W. Trahanovsky, Ed., Academic Press, New York, N.Y., 1978; (c) H. Reich, Accts. Res., JL2, 22 (1979). Cohen, and P.

Synth., in press, and references cited therein. Sharpless, J. Chem., 43, 1689 (1978).

Acta, 41, 593 (1958). Commun., 100 (1974). Schmid and D. Garratt, Tetrahedron Lett., 3991 (1975). Chem., 39, 428 (1974). Garratt and G. Chem., j42, 1776 (1977).

Sharpless and R. Chem., 39, 428 (1974). Chem., 42, 2950 (1977). Liotta and G. Zima, Tetrahedron Lett., 4977 (1978).

Garratt and G. Chem., 5_2, 3599 (1974).

Garratt, Can. Chem., 5_6, 2184 (1978).

Krief, and L. Hevesi, Tetrahedron Lett., 3967 (1978) and references cited therein. Baudat and M.

Petrzilka, Helv. Acta, 62, 1406 (1979). Murai, and N.

Commun., 293 (1975). Toshimitsu, S. Uemura, and M. Commun., 166 (1977) 21. Boulanger, T.

Schleis, S and S. Chem., 4j3, 4388 (1978). Pitteloud and M. Petrzilka, Helv. Tsuda, Tetrahdedron Lett., 2331 (1976).

Hansen, and M. Chem., 43, 4885 (1978). Raucher, Tetrahedron Lett., 3909 (1977). Raucher and G. Chem., 4-3, 4252 (1978).

Raucher, Tetrahedron Lett., 2261 (1978). Takahashi, H. Nagashima, and J. Tsuji, Tetrahedron Lett., 799 (1978). Kuwajima and M. Shimizu, Tetrahedron Lett., 1277 (1978). Takeda, and I.

Kuwajima, Tetrahedron Lett., 419 (1979) 31. Chittattu, N. Commun., 725 (1977). Campos and N. Petragnani, Chem. Ber., 93, 317 (1960). Sipio, and J.

Soc, 101, 3884 (1979). Le, 62, 1319 (1979). Chittattu, J. Commun., 484 (1977). Nicolaou and Z.

Lysenko, Tetrahedron Lett., 1257 (1977). Chittattu, and C. Chem., 5_5, 3894 (1977). Nicolaou and W. Commun., 331 (1977). Barnette, and R.

Soc, 100, 2567 (1978). Ricciardi, J.

Joullie, Tetrahedron Lett., 2679 (1978). Petrzilka, Helv. Acta, 61, 3075 (1978). Commun., 379 (1978).

Chittattu, and C. Commun., 441 (1978). Chittattu, and C. Commun., 41 (1978). Nemoto, and K. Fukumoto, Heterocycles, _6, 1365 (1977). Nishizawa, J.

Chem., 42, 2034 (1977). Peake, Synthesis, 299 (1978).

Wollowitz, J. Wendelborn, J. Chem., 43, 1697 (1978). -22- SYNTHETIC METHODS FOR THE PREPARATION OF STERICALLY HINDERED OLEFINS 1 Reported by Ronald S. Michalak October 22, 1979 Introduction. Conventional synthetic routes to olefins are seriously affected by steric hindrance. Although the Wittig reaction is frequently used for the preparation of disubstituted olefins, yields decrease for tri- substituted olefins and are generally very low for tetrasubstituted olefins.

2 Photochemical pinacol coupling of aromatic carbonyl compounds is reversible; consequently, yields of products decrease as steric hindrance increases. Elimination reactions provide another important route to olefins. However, previously developed methods are plagued by inaccessability of inter- mediates as substitution increases. 7 This paper will discuss some of the more recently developed methods for the preparation of olefins which have special application to highly substituted and sterically hindered olefins.

Chemists are interested in hindered alkenes because as the double bond of an olefin becomes more hindered, it is less accessible to electrophiles. Also, the steric hindrance which is introduced by bulky substituents can cause a weakening of the double bond, which is manifested in abnormally long bond lengths and less interaction between the orbitals in the it bond. Olefins via Titanium Based Reagents. Several transition metal-based reagents 2 (for example, W, 4 Mg, b and Al 6 ) have been reported to couple aryl and diaryl ketones, but fail to couple dialkyl ketones due to their higher reduction potentials.

Reductive coupling of carbonyl compounds by some of these reagents was discussed in a previous departmental seminar. Presently, the transition metal based reagent used most frequently is TiCla/LiAlHi, which was reported by McMurray and Fleming in 1974 12 (Eq. 2 R 2 C=0 4T1Cl3 >RaC-CR, (1) 2LAH R= aryl, alkyl The reaction generally proceeds in high yields for symmetrical olefins. Unsymmetrical dialkyl ketones are expected to give mixtures of the three possible products unless one of the ketones is in excess.

When acetone is used in excess, good yields of unsymmetrical olefins have been realized 8 (Table 1). When the diaryl ketones, benzophenone and fluorenone, are coupled with dialkyl ketones, unsymmetrical olefins are obtained in good yield (Table 2).

Reductive Coupling Between Acetone and Other Ketones (Acetone/Ketone = 4/1) with TiCl 3 /Li Ketone + Acetone Products Yield (% ) Adamantanone Isopropylideneadaraantanone 63 Adamantylideneadamantanone 12 Acetophenone 2-Methyl-3-phenyl-2-butene 65 2,3-Diphenyl-2-butene 16 Benzophenone l,l-Diphenyl-2-methylpropene 94 Tetraphenylethylene trace Cycloheptanone Isopropylidenecycloheptanone 50 Cycloheptylidenecycloheptanone 26 -23- Table 2. Reductive Coupling Between Diaryl Ketones and Other Ketones (Ratio of Ketones 1:1) with TiCl 3 /Li Ketones Benzophenone + Cyclohexanone Fluorenone + Cycloheptanone Fluorenone + Acetophenone Products Yield (%) 78 19 77 17 70 15 Since the reduction potential of these diary lketones is 1.0-1.5 V less negative (a change in reduction potential of 1.0 V corresponds to a free energy change of 23 kcal/mole) than the dialkyl ketones, one would expect an anion radical 9 coupling mechanism to effect predominantly symmetrical coupling. This mechanism is similar to that proposed for the reductive coupling of carbonyl compounds by other metals such as Al, Zn, and Mg. 2 An alternative mechanism assumes the initially formed anion-radical is reduced further to a dianion, which undergoes nucleo- philic addition to the dialkyl ketone.

8 The second reduction potential of benzophenone and fluorenone is less negative than the first reduction potential of the dialkyl ketones. The evidence against a radical-anion mechanism in the case of diary 1-dialkyl couplings does not exclude an anion radical mechanism in the case of dialkyl couplings, where reduction potentials may be too high for the formation of dianions. 2 Through a series of experiments, McMurray has ascertained that the reduction of the intermediate pinacol occurs on the active surface of a titanium particle in a heterogenous process. Olefins 1^~A nave been synthesized by the use of titanium-based reagents. 12,36 1» R: 4, R.

Me H -24- Olefins via Reduction of vic-Dinitro Compounds. A promising new method for the preparation of highly substituted olefins involves the coupling of nitro compounds to vicinal dinitro compounds (Eq. 13 Treatment with a mild reducing agent (for example, Na 2 S, Ca/Hg, or NaS(J)) then yields the olefin. Unsymmetrical olefins can be prepared by employing an a-a dinitro compound in Eq. Use of the milder reducing agent Ca/Hg (2) K I + R x /N0 2 C _ R^ Li + 6 ^>R N0 2 N0 a R Na 2 S or R^ /R R R R^ N0 2 5 S NaStt) I X=Br, N0 2 R = aryl, a lkyl amalgam allows the synthesis of olefins with ester, cyano, keto, and ether functionalities. The synthesis of bifluroenylidene via reduction of the vic-dinitro intermediate with SnCl 2 has been reported. 15 The prepa- ration of a, 0-unsaturated nitriles or esters has been accomplished by the reaction of an anion of a-cyanosulfones or a-ethoxy carbonylsulfones with a,a-dinitro compounds (Eq.

15 R,.N0 2 ArS0 2.R R^ ^ R „ Q R. X R% X C— C^ -2**I_» >= C ' (3) R/ X N0 2 l/ Na + R / ^X r/ ^X 8 X = CN, C0 2 Et N0 2 S0 2 Ar 9 The mechanism proposed for these couplings involves radical-anion intermediates and it is not expected that this method will provide very highly hindered alkenes, because many crowded radicals, such as triisopropyl- tert- butyl, di-, and tri- tert -butylmethyl radicals ( 10, 11, and 1_2, respec- tively) are resistant to dimerization and decay by other paths. However, this approach may prove superior to pinacol coupling when functional groups sensitive to reduction are present. IPr 3 tBu 2 CH tBu 3 C 10 11 12 Decarboxylative Dehydration of 3-Hydroxy Acids. A method which has been used to synthesize cycloalkylidenecycloalkanes involves the reaction of a carboxylate dianion 1_3 with a cycloalkanone to yield a 3-hydroxy acid.

17 The 3-hydroxy acids can be cyclized to the 3-lactones which lose C0 2 upon thermolysis to form the olefins. Elimination to the olefin may also occur without formation of a 3-lactone by reaction of 1_4 with a solution of DMF»acetal 18 (N,N-dimethyl formamide dimethyl acetal). -25- 13 -i2' — CO 2 2Li + + (.CH,)^ N CF 3 CF« x~* h — 17 — — 18 19 One method for preparing thiadiazolines is to form the azine first with hydrazine.

Allowing the azine to react with H 2 S provides the 1,3,4- thiadiazolidines, which are oxidized with Pb(OAc) ^C=N— N=C N „ R' R'/ X R v -H 2 S IN N R = aryl, alkyl 20 r' R 21 Pb(OAc)* or (Et0 2 CN=NC0 2 Et) R * / R ' } ' N=N.>- H M / t-Bu S / t-Bu 29 PhLi ether ■>100% (5) In the case of dicyclohexylepisulf ide _30, the sulfur atom adopts the pseudoaxial position. 24 Olefins _31 through 3522,29-32 h ave been synthesized via thiadiaxo lines. OBz 30 N=N 32 OBz 31 34 35 In the search for new antibacterial cephalosporins, the addition of diazoethane and 2-diazopropane to 36^ produced the 4-alkylidene-2- azetidinones 31_ and J38 after desulfurization 37 (Eq. -28- 36 S Me J-»y^ CO,Me 1) ^C=N 2 Me Me 2) Ph 3 P ->R' = phthalimide R'l / C(Me)R CO 2 Me (6) 37 R = H 38 R = Me The reaction of isomeric sulfines with diazo compounds proceedes in a stereospecific manner.

Unfortunately, the thiadiazoline-1-oxides generally do not give the episulf oxides upon thermolysis, but undergo retro-cycloaddition to starting materials, 28 A desire to extend the scope of this method prompted Barton to examine A -1, 3,4, -selenadiazolines as precursors to hindered olefins. 33 Since the radius of the selenium atom is larger than that of sulfur, the hindered carbon centers would be held farther apart in a selenadiazoline than in a thiadiazoline.

Previously unknown saturated monomeric seleno- ketones were prepared and reacted more readily with diazo compounds than the analogous thiones. Attempts to prepare tetra- tert- butylethylene by this method failed, and in fact more highly hindered olefins could not be prepared via selenadiazolines.

It is interesting to examine the steric limitations of these methods. The synthesis of tetra- tert- butyl ethylene has not yet been reported. The attempted synthesis of olefins 39 22 and 4j3 30 via thia- diazolines gave exchange products J32_ and J33, indicating formation of the intermediate thiadiazoline which underwent cycloreversion faster than elimination of nitrogen. McMurray's method has failed to produce olefins 27, 41, 42, or tetra- tert- butyl ethylene; however, _27 was synthesized in 68% yield via thiadiazolines.

33 The phenyl rings in _27 are twisted out of the plane by 61° and 59°. When the meta positions are linked together as in olefin 4_3, the phenyl rings might be forced to adopt a more planar conifguration. The attempted synthesis of 4^3 via thiadiazolines failed.

35 fc 39 40 42 Physical and Chemical Properties. The X-ray crystallographic structures of crowded olefins 4, 38 24, 39 3_2, 40 ^33, 30 and W* 1 have been reported. Among this group the olefins which has the largest double bond twist is 44^ with a twist angle of 40°. Tetra- tert- butylethylene has been calculated to have a double bond torsion angle of 75°. ^ 2 The thermo- chromic behavior of bianthrones is postulated to occur via metastable intermediates which are torsionally strained at the C=C bond.^ 8 -29- 45 Bromium ions have long been postulated as intermediates in the electrophilic addition of bromine to olefins.

The first example of an isolable, stable bromonium perbromide, 4_5, was obtained by the bromination of ^.^ A stable 1, 2-dioxetane was isolated from the reaction of ^ and 1 2. 49 Tetraneopentylethylene is stable to Br 2 /CCl To L' £->Weak Field T_ Strong Field Ipso facto, the yield of cage products should be increased in the presence of a magnetic field. As the applied field increases, however, a decrease in the cage product yield should begin because the field can more effectively promote the S-T transition due to the Ag effect (Figure 4). Bjj is the field strength at which the magnetic effect is half its maximum value (vide infra). With the advent of high speed computers, many excellent, quantitative treatments of these effects have appeared.

14 Briefly, to treat these systems, a statistically based model of diffusion is inserted into an -39- analytical expression of the initial energetics of the species, exchange interactions, and reaction rates. The diffusion model developed by Noyes 15 is coupled with the stochastic Liouville equation. 16 An expansion series of this relationship provides solutions with an accuracy of the order of a percent. Magnetic Field Effects on Radical Ions.

Recent advances in nanosecond laser spectroscopy has allowed the direct observation of magnetic field effects within the lifetime of the radical ion pair. 8 ~ 20 These time resolved experiments have shown that magnetic field phenomena can serve as sensitive probes of the energetics of many photochemical and chemi- luminescence reactions.

Direct effects on product distribution have also l ft? L been demonstrated. ' Time-dependent field effects on geminate recombination in polar solvents have been extensively studied. 18-20 The fluorescence quenching of an aromatic acceptor (A) in its excited singlet state, by an appropriate donor (D), leads to a singlet radical ion pair. 22 A general mechanism is presented in Scheme I. Internal conversion to the singlet ground state may occur, but because of its large exothermicity in polar solvents, 23 ' 24 the reaction is expected to be slow.

This has been shown recently for the pyrene (1_) + N,N-dimethylaniline (2) system. 18 The singlet phased radical ion pair may then annihilate in the solvent cage to yield the excited singlet state of the aromatic hydrocarbon which may fluoresce.

If inter- Scheme I 'a* + 'D J A + 'D l ( 2 A. 2 D+) HFI ^ 3 ( 2 A. 2 DT+) Cage Cage Fluores- cence 3 A* + 3 A* Delayed fluorescence 2 A- + 2 D+ Bulk Solvent system crossing to the triplet occurs rapidly from the radical ion pair (due to hyperf ine interactions available -HFI), the triplet excited state of A can be formed (Scheme I). Delayed fluorescence may now occur if encounters another 3 A* (Eq. 'A* 3 A* + 3 A* >*A* + A >light (3) Weller e_t al. Generated singlet phased radical ion pairs via rapid photoinduced electron transfer. 10 ' 18 For the system pyrene (1) + 3,5- dimethoxy-N,N-dimethylaniline (3), recombination from the radical ions is energetically allowed to the triplet excited state but not the singlet excited state (Scheme II).

-40- Scheme II 1 ( 2 r t. 1 -) — >3 ( 2 r. 2 3+) i 4 *1 + x 3 3 1* + *3 The recombination can be followed spectroscopically as delayed fluorescence due to triplet-triplet annihilation of 3 1* + 3 1* on the nanosecond time scale. The system has been resolved into a fast geminate (^10 ns) and a slow homogeneous (^1000 ns) process. The fast geminate recombination entails initial separation of the radical ions and then fast re-encounter still within the solvent cage. This process is strongly influenced by the solvent medium. 18 The less viscous the solvent, the more likely the radical ions may encounter members of other pairs and recombine.

In the slow homogeneous phase of the reaction, higher triplet to singlet ratios are observed compared to the fast phase. Random spin alignment in the slow phase accounts for this observation; 75% of the encounters are in the triplet state while 25% are in the singlet state. In the fast phase of the reaction, triplet products are also observed. 10 ' 12 Since the radical ion pairs are generated from singlet precursors, a spin flip must occur in order to observe triplet products. The rapid change of the electron spin multiplicity can be induced by hyperfine interactions with the nuclear spin.

2i+ The existence of the hyperfine mechanism in radical pairs has been demonstrated in many systems by electron and nuclear spin polarization in ESR and CIDNP spectra. 6 ^ Magnetic field effects at the nanosecond time scale, however, premit the most direct evidence for this mechanism. Since a magnetic field lifts the degeneracy of the T and T+ states, the S -» T+ transition probability is reduced. This results in a lowering of the overall singlet to triplet transition probability and hence of the triplet yield. Weller, e_t al., observed an 80% decrease in the yield of fast triplet products at fields up to 500 G compared to its zero field value.

This observation supports their conclusion that formation of fast triplet products occurs via hyperfine interactions in the radical pair. Further evidence for the importance of hyperfine interactions was presented by Werner, Staerk, and Weller. 18 Theoretical and experimental studies have shown that the field strength at which the magnetic effect takes half its maximum value (Bj^), (see Figure 4), for geminate triplet yield, is nearly independent of the diffusion, recombination rate, and spin motion of radical pairs in solution.

25-28 Changes in Bu arise solely from changes in the hyperfine coupling constants of the radical pair. 3 Werner, et al., utilized this fact by replacing their donor dimethyl- aniline GO with dimethoxy-dimethylaniline (3). Due to the electron donating effect of the methoxy groups in _3, the coupling constant of the nitrogen is smaller than in 2. This should lead to a smaller B^ for the l/_3 system. A Bij of 55 G is found for the 1/2, system. As expected, the value for the 1/3 system is lower, 632 = 45 0.

The second half of Equation 2 can be modified to include changes from differing isotopic compositions. The hyperfine coupling effect then becomes: -41- 1 2 hyper fine 2l EAjS^Ii + EA i S 2 I-; effect i J (4) where A= 4Tr/3g3g n 3 n P anc * Si and S 2 denote different isotopic interaction of two unpaired electrons with the nuclear moments I of radicals 1 and 2. 4, we can expect a change in Bj^ when the isotopic composition is changed. Werner has found this to be true. When proceeding from _l/2_ to l.-dio/2-dii the B^ value is reduced by a factor of 2.

A quantitative theory of this effect is presented by Haberkorn. 14c Experimental data is also presented. Bube, Haberkorn, and Michel-Beyerle 20 examined the mag- netic field effect upon deuteration of anthracene (4) with _N,N-diethyl- aniline (5) as donor in acetonitrile. Table 1 presents the pertinent values for the different nuclei.

Table 1 H I A h 5.585 75±3G (C^Hio) 1 0.857 62±3G (CiJ) 10 ) As a result, the half-width field, B^, decreased by vL7% for the deuterated species. H 3 cr^ CH 3 N, N-Dimethylaniline 2 H s C0 »■ 'V OCH, •N- H 3 C CH 3 3, 5-Dlmethoxy- dimethylaniline 3 Anthracene 4 HsCj C 2 Hs N,N-Diethylaniline 5 Fluor enone 6 Such isotope effects confirm the role of the hyperfine mechanism in spin-selective radical ion reactions. Recently, these effects have been used for isotope enrichment. An increase in the 13 C/ 12 C ratio has been observed in the photolysis of aromatic ketones and peroxides.

31 Spin-state dependence of recombination of radical ions formed initially in the triplet state show predictable results analogous to the singlet phased systems. I2 Electron transfer from DABCO (diazabicyclo- octane) to triplet f luorenone (J3), results in the triplet phased radical ion pair, 33 (Scheme III): 32 -42- Scheme III 3 F ^^.(V.^^ V W t. L^ i F + 2 D V + 2 D+ F and D represent fluorenone and DABCO, respectively; k eT and k es are the rate constants for cage escape of the triplet and singlet phased radical pairs to uncorrelated radical ions in the bulk solvent; k s is the rate constant for intersystem crossing, and k^ is the rate constant for electron transfer to give the ground state species. In this report, temperature, polarity, and viscosity effects are studied by noting changes in the radical ion UV absorption in a magnetic field.

Schulten, e_t al_., 26 >27 and Schomburg, e_t a_l., 33 found that high temperature, high polarity, and low viscosity all favored cage escape in the radical ion pair. Perisamy and Linschitz 31 confirm this past work and extend it to the triplet fluorenone/DABCO system. They show that the cage escaped radical ion yield decreases strongly in a temperature region where the solvent viscos- ity rises sharply. In the same temperature region, a weak field raises the yield, indicating a decrease in k s. Such a field effect is expected if hyperfine coupling induces the spin flip in the geminate pair. Light Generating Reactions. Chemiluminescent reactions via electron transfer have recently received considerable attention from the chemical and biochemical communities.

3 ^ Faulkner, et al., have done extensive work on charged ions generated electrochemically in solution. 35 When anthracene (4) radical cations and anions, A+ and A', generated by electrolysis at a single microelectrode, diffuse together, electron transfer occurs.

This leads to 3 A* + A. Two such excited triplet molecules may encounter each other.

Annihilation generates the excited singlet anthracene molecule. 36 The excited singlet molecule may now relax to the ground state and emit a photon in the process.

The appearance of light by this redox mechanism is referred to as electrogenerated chemiluminescence (ECL). The process can be summarized as: reduction: A + e~ oxidation: A - e~ electron transfer: A - + A >3 A* + A triplet-triplet annihilation: 3 A* + 3 A* >*A* + J A fluorescence: *A* >A + light Scheme IV The magnetic field effect arises in the triplet-triplet annihilation step (TTA). When two triplets encounter each other, the overall spin state may be singlet, or quintet (±2, ±1,0). The overall singlet phased pair can go on to produce the excited singlet state (and singlet ground state) of anthracene upon their first encounter. If, however, they are in the over- all quintet state, their encounter will be unproductive.

They may, however, rephase into the overall singlet under the influence of different hyper- fine interactions (similar to two doublets, cf. Second paragraph of this ■43- paper). Fluorescence is now permitted. In the presence of a magnetic field, this rephasing is inhibited since the five quintet orientations are no longer degenrate. In this way the field will inhibit the fluores- cence yield. Numerous experimental observations of this effect have been reported.

36 * 37 However, a reversal of this effect was noted upon the addition of doublets (radical ions). These results suggest a competition between quenching by doublets and TTA. 35 ' 38 The mechanism in Scheme IV can now be modified: Scheme V *Ac*. A I*-->3 Ac * +: D 2 R+ °r 2 ^ >i Ac + 2 R (±) + 3 Ac* *Ac* >light + *Ac where Ac and D represent an appropriate acceptor and donor, respectively: R is a radical ion, generated in situ, that can intercept the triplet before it annihilates (the fluorescence yield is then reduced). If it is energetically feasible, the excited singlet state of the emitting species may be formed directly from the electron transfer step. 39 Faulkner has labelled this mechanism the S-route while triplet-triplet annihilation is the T-route.

This leads to a delineation of the magnetic field effects in ECL. For an energy sufficient system, S-route, we expect to see no magnetic field effect while for an energy deficient system, T-route, we expect an increase in the fluorescence yield in a magnetic field. We can expect no effect for S-route systems presumably because intersystem crossing to the triplet phased radical ion pair is slow compared to formation of A* by electron transfer. This delineation has been verified experimentally 34 ° and theoretically.

1 * This interpretation of ECL has unfortunately exposed some inconsis- tencies in the theory of ECL or magnetic field effects. Faulkner and Morris, 40 ' 41 have examined various systems to determine the generality of the S-route and T-route systems. The fluoranthene (7) and tri- p_-tolylamine (8) system was found to be the archetypical T-route Fluoranthene 7 example. They found a linear relationship between ECL intensity and radical ion annihilation, and a magnetic field enhanced fluorescence. The thianthrene (9)/2,5-diphenyl-l,3,4-oxadiazole ( 10 ) system was knovm to be an energy sufficient system. 42 It shows no magnetic field effect -44- yet exhibited T-route kinetics.

Morris* 40 introduces the Marcus theory of electron transfer 43 as an explanation for the anomolous kinetic data. No satisfactory theory can explain the lack of a magnetic field effect. 8, 2419 (1978). Miehel-Beyerle, H. Kruger, and R.

Haberkorn, Chem. Physics, 42, 441 (1979). Haberkorn, M. Miehel-Beyerle, J. Soc, 9J3, 5993 (1978). Turro and M.-F. Soc., 101, 3701 (1979).

Leonhardt and A. NF _29, 277 (1961). Phys., 43, 2654 (1965); R. Marcus, ibid., 52, 2803 (1970). Van Duyne and S. Fischer, Chem. Phys., _5, 183 (1974).

Brocklehurst, J. Faraday Trans.

2, 12^, 1869 (1976); B. Brocklehurst, Chem. Lett., 28, 357 (1974). Schulten and K.

Phys., 66, 4616 (1977). Schulten, and K. Phys., 67^, 646 (1977).

Phys., 71, 1878 (1979); K. Schulten and I. Epstein, ibid., 71, 309 (1979).

Soc, 89, 5172 (1967). Belchenko, Yu. Molin, and A.

Rezvukhin, Chem. Lett., 48, 89 (1977). Perisamy and H. Linschitz, Chem.

Lett., 64^, 281 (1979). Linschitz, J. Photochem., 6_, 355 (1977).

Schomburg, H. Weller, and H. Werner, Chem. Letts., 56, 399 (1978). For general reviews, see: (a) G.

Schuster, Accts. Res., 12 (1979), in press; (b) L. Faulkner, 'Bioluminescence and Chemi- luminescence', Vol.

57 in the series 'Methods in Enzymology', M. DeLuca, ed., Academic Press, New York, 1978; (c) N. Turro, 'Modern Molecular Photochemistry', Benjamin/ Cummings, California, 1978, p. Faulkner and A.

Bard, Electroanal. 10, 1 (1977).

For instance, see: Ref. 34b and references cited therein. Faulkner and A.

Soc, 21, 6495 (1969); L. Faulkner and A. Bard, ibid., 21, 6497 (1969). Tachikawa and A.

Soc, 95_, 1672 (1973). Tachikawa and A. Letts., 26^, 568 (1974); H. Tachikawa and A. Bard, ibid., 26, 10 (1974). Tachikawa and A. Letts., 26, 246 (1974); R.

Bezman and L. Soc, 94, 6324 (1972); and ref. 34a with references cited therein 40.

Morris, Ph.D. Thesis, University of Illinois, 1978. Faulkner and D. Soc, £3, 2097 (1971); L. Faulkner and D.

Freed, ibid., 93, 3565 (1971); L. Faulkner and D. Freed, ibid., 94, 4790 (1972); L. Faulkner and D. Freed, ibid., 6331 (1972).

Michael and L. Soc, 99, 7754 (1977).

Phys., 43, 679 (1965). -46- SYNTHETIC APPROACHES TO BIOTIN Reported by Jack Muskopf November 12, 1979 The vitamin biotin has been of interest to biologists, nutritionists, and chemists for over eighty years. Recent disclosures of the importance of biotin in animal health and nutrition have fostered a renewed interest on the part of organic chemists to develop novel and more efficient syn- theses of the vitamin.

Currently, the. Only viable method for producing useful quantities of biotin is by chemical synthesis. This review will describe briefly the chemistry of biotin and will survey, in more detail, recent stereospecif ic syntheses. Isolation and Identification. In 1935, KJJgl 1 reported the isolation of small amounts of a crystalline compound from egg yolk which promoted the growth of yeast.

This compound, named biotin, was later found by Gybrgy 3 to be the same factor which cured and prevented the 'egg-white' syndrome in rats. 1 * The structure of biotin was elucidated in 1942 by du Vigneaud and co-workers, who based their conclusions on chemical transformations of the natural product. ' 6 In 1943, Folkers 7 » 8 reported the first total synthesis of (+) -biotin (vide infra ) which confirmed the earlier structural assign- ment. The relative configuration at the three contiguous assymetric centers in biotin was determined in 1956 by X-ray crystallographic analy- sis. 93 Later X-ray studies established the absolute configuration shown in 1.9b (+) -Biotin (1) Biochemistry. Since the discovery that acetyl-CoA carboxylase con- tains the vitamin as a prosthetic group, 10 biotin has been shown to be a co-factor for a number of carboxylases, transcarboxylases and decarboxyl- ases.

1 These enzymes require devalent metal ions, such as magnesium or manganese, and, in addition, the carboxylases are ATP-dependent and utilize bicarbonate as the source of C0 2. An understanding of the mode of action of biotin in carboxylase systems has been gained through model reactions, identification of inter- mediates, isotope exchange experiments, and investigation of the kinetics.

11 * 12 For example, the enzyme acetyl-CoA carboxylase consists of three separate proteins: biotin carboxylase, carboxyl transferase, and the biotin-con- taining carboxyl carrier protein (CCP). 13 Biotin, covalently attached as an amide through an e-amino lysine residue of the CCP, migrates from the active site on biotin carboxylase to the active site on carboxyl transfer- ase. The reactive group of the CCP-bound biotin is the ureido-l'-N.

4 The overall process for the carboxylation of acetyl-CoA by acetyl-CoA carboxylase is shown in Eq. -47- CCP x.y ^ CCP II CH3CSC0A AS.

HN NCO V A - CCP A HN NH A- 0CCH 2 CSCoA (1) [Biotin carboxylase] [Carboxyl transferase] Biosynthesis. The biosynthesis of biotin from pimelic acid (2) has been studied and four of the five enzymatic steps have been resolved (Eq. 15 Pimelyl-CoA (3), synthesized f rom 1_ by pimelyl-CoA synthetase in a reaction requiring Mg(II), CoASH and ATP, is condensed with L-alanine to form 4 in a step catalyzed by an enzyme requiring pyridoxal 5' -phos- phate (PLP) as a coenzyme. Reductive amination of amino ketone 4_ affords diamine 5_, a reaction catalyzed by an aminotransferase which requires both PLP as a coenzyme and J3-adenoxyl-L-methionine (SAM) as the amine donor. Dethiobiotin (6) is formed from 5 in a reaction requiring ATP, C0 2, Mg(II) and dethiobiotin synthetase.

± NH 2 CH 3 CHC0 2 H R— CH 2 C0 2 H - 2 COASH *S ->R— CH 2 C0SCoA PLP NH ^ V 7 C0 2 + COASH CR. CH 2 — R NH 2 NH 2 ATP ADP SAM PLP ■9>+ p i HN NH (2) ch 3 ^R 5 A r,&? / _ — >W C0 2 CH 3 R (, ^ R= (CH 2 ) t C0 2 H I The conversion of h_ to biotin is poorly understood at present and has been the subject of a recent report by Parry. 16 Results from the incor- poration of isotopically labeled dethiobiotin into Aspergillus niger led to the conclusion that the introduction of sulfur takes place with the loss of one hydrogen at C-2 and C-5. The stereochemistry of hydrogen loss from C-2 of dethiobiotin and the order of functionalization of C-5 and C-2 have not been determined. Total Synthesis of Biotin.

Biotin has been the synthetic goal of many groups both in industrial and academic settings. Although this review is primarily concerned with the recent syntheses of biotin, a brief survey of the earlier approaches has been included for comparison. Folkers and co-workers were the first to prepare synthetic samples of biotin, thereby confirming the structure of natural biotin. In a series of articles they described a nonstereospecif ic synthesis of (±)- biotin from L-cystine and chloroacetic acid via the key intermediate _7.

8 » 17 The resolution of (±) -biotin from the racemic mixture was achieved in 64% yield by crystallization of the l,(+)-arginine salt. 17d -48- In 1945 Grussner and co-workers reported a non-stereospecif ic prepara- tion of (±)-biotin in low yield. 18 The substituted tetrahydrothiophene 8^ originally prepared by von Schmid, 19 was converted to the diester 9_ in four steps (Eq.

The important steps in the pathway from 9 to (±)- biotin were Curtius rearrangement of the corresponding diazide to give 10 and addition of the fifth carbon to the sidechain using cyanide displace- ment of an alkyl bromide. Intermediates prepared after 9_ were not purified and any unwanted diastereomers formed were removed by crystallization. Ch 3 o 2 c o S^ (CH 2 ) t 0CH 3 8 A steps 30% CH 3 2 C C0 2 CH 3 * M ■ S S (CH 2 ) 4 0CH, 3 steps Et0 2 CNH HNC0 2 Et 3 (CH 2 ) t 0CH s 5 steps 0.3% from 9 -^ (±)-biotin 10 (3) About this same time Baker and co-workers 20 reported a synthesis of (±)-biotin that required no fractional cyrstallizations in order to sepa- rate diastereomers. From pimelic acid, they prepared the trans triacid 1_1 with the stereochemistry at C-2 unspecified (Eq. The trans urea acid 12, available from 11 by selective Curtius rearrangement, was epimerized and cyclized to the cis uracil L3 by reaction with sodium acetate in acetic anhydride. Reaction of the anilide of 1_3 with hydrazine followed by conversion to the azide led to the rearranged product 14_. Hydrolysis of 1_4 and reaction with phosgene completed the synthesis of (±)-biotin in an overall yield of 1.7% from pimelic acid.

C0 2 H C0 2 H M ^ S ' (CH 2 KC0 2 H 3 steps. 36%'^ 11 HNCNH4) S (CH 2 )=0 PhHNC, s (CH 2 )i.C0 2 H 13 N NH 3 steps V — J ( X s S X (CH 2 ) fc CNH (4) The need for a more practical synthesis of (±)-biotin led Cheney and Piening to develop a synthetic route to the tetradehydrobiotin L5. 21a At the time the authors did not report any method for the reduction of 15_ to the all- cis (±)-biotin, although a later patent Jl^ describes the hydrogenation of 1_5 in unspec- ified yield at 200°C and 2700 psi using a molybdenum trisulf ide-alumina gel catalyst. 21 ' 3 ' (CH 2 KC0 2 H NH w 15 -49- An industrial preparation patented in 1950 by Goldberg and Sternbach 22 originates from meso-diaminosuccinic acid, 16.* which corresponds to the cis- structure of the two nitrogens in biotin. Resolution of an inter- mediate sulfonium salt as a d-camphorsulfonate permitted direct production of (+)- and (-)-biotin. H 2 N NHa H Y ' H iin.r C0 2 H H0 2 C 16 In recent years there has been an increase in the use of readily available carbohydrates as starting materials for the total synthesis of many different types of natural products. 23 In 1975 Ohrui and Emoto reported a stereospecif ic synthesis of (+)-biotin from the bis isopropyl- idene mannofuranose 17 (Eq.

2lf The three chiral centers present in (+) -biotin are already present in 17. The aldehyde 1_8, prepared in 3 steps from 1_7, was condensed with excess methyl A-triphenylphosphoranylidene-2- butenoate, and the resulting diene ester was hydrolyzed after hydrogena- tion and subsequently reduced with sodium borohydride to give the diol 19. The reaction of the dimesylate of 19_ with sodium sulfide afforded a tetra- hydrothiophene derivative which was hydrolyzed with 92% formic acid to diol 20.

Preparation of the all -cis diazide 21_ was accomplished by Sft2 displacement of the dimesylate of ^0 with sodium azide. Catalytic reduc- tion followed by hydrolysis and reaction with phosgene gave (+) -biotin. 17 CHO 3 steps -^ 80% 4 steps 70% CH 3 2 C OH >C0 2 CH 3 2 ste P s >( + )-blotin (6) 30% A stereospecif ic synthesis of (+)-biotin was achieved by Confalone and co-workers at Hoffmann-La Roche from the amino acid _L(+) -cysteine ( 22 in Eq. 26 The reactive functionality in 22 was blocked by condensation with benzaldehyde and methyl chloroformate to give thiazoline 2_3. Selec- tive reduction with diborane followed by Collins oxidation gave the alde- hyde 24^ which afforded the vinyl alcohol 25_ upon reaction with vinyl magne- sium bromide. This compound underwent Claisen rearrangement to trans olefin 26. Bromination of 2b_ with pyridinium hydrobromide perbromide in methanol gave bromo carbamate TJ_ in 47% yield which was hydrolyzed quantitatively to the amine hydrobromide 28.

22 23^ R = -C0 2 H 24 R = -CHO 25 R = -CHOH k (61% from 22) ^ SH S^ X S-^ 26 RNH ->C0 2 CH 3 (Equation 7) (CH 2 ) 2 C0 2 CH, 27 R = -C0 2 CH s 28 R = H«HBr Heating bromo amine hydrobromide 28^ in acetic acid set up an equilib- rium between 28^ and J30 via the aziridine _29_. Bromo amine _30 cyclized to the crystalline trans bromo lactam 31 in quantitative yield (Eq.

28 H 1 1 ~ V s>S fCH 2 ) 2 C0 2 CH 3 29 Br O/s C0 2 CH 3 30 31 (8) Unfortunately, bromo lactam 31 gave only poor yields of the desired cis azide. Hydrogenation of the azide and hydrolysis of the lactam, followed by reaction with phosgene, produced the methyl ester of (+)- bisnorbiotin. The addition of two carbons to the sidechain was performed in the manner of Goldberg and Sternbach. 22 In a recent communication, Field reported a synthesis of (+)-biotin from methyl 6-oxohexanoate ( 32 ) which gives the vitamin in 7.2% overall yield.

27 Its success depended upon both the easy resolution of inter- mediate nitro acid _3_3 or nitro ketone J7_ and the virtually stereospecif ic catalytic hydrogenation of 39. Nitro acid 33 was prepared from _32 by -51- condensation with nitromethane, dehydration with magnesium sulfate, and addition of thioglycolic acid (Eq. Fractional crystallization of the (+)-a-methylbenzylamine salt 34 in ethyl acetate gave the (S) enantiomer of 33 as required for the synthesis of (+)-biotin. Conversion of _34 to the dicyclohexyl amine salt j$5_ and esterif ication with phenol furnished the phenyl ester J36. Cyclization of J36^ to nitro ketone 31_ was effected by reaction with (-)-a-methylbenzylamine in ethyl acetate. Catalytic hydro- genation, followed by reaction with potassium cyanate and alkaline hydroly- sis provided the bicyclic urea 38^ which was acetylated and dehydrated to 39.

Hydrogenation and hydrolysis of 39 afforded (+)-biotin. CH0-(CH 2 KC0 2 CH 3 32 NH RO _ NO + - RHO NO 2 75% T>C0 2 CH, C0 2 CH 3 33 R = H 34 R = MBA-a-(+)H' 1 35 R = HDCA + 36 R= A 26% from 32 I HN^NH 38 C0 2 CH LAH 90% 2 steps 50% 42 (10) >(±)-biotln 43 44 -52- A total synthesis of (±)-biotin reported by Marquet and co-workers 29 took advantage of the high stereoselectivity of the alkylation of chiral sulfoxides. Bory and Marquet had previously shown that methylation of the anions of six-membered cyclic sulfoxides occurred exclusively trans to the S ->bond.

U They assumed correctly that this empirical rule would also be true for f ive-membered cyclic sulfoxides. The starting material was meso-dibromosuccinic acid ( 45 ) and, in the manner of Goldberg and Steinbach, they prepared the diacid 4j>which was converted to the tetrahydrothiophene 47 in three steps (Eq. The sulfide 47 was oxidized to the sulfoxide 48 with the S ->bond cis to the hydrogens at C-3 and C-4 by reaction with sodium metaperiodate in aqueous mehanol.

The lithio derivative of 48 was alkylated smoothly with tert- butyl 5-iodopentanoate. Reduction of the product with titanium(III) chloride gave the benzylated derivative 4j? Which was hydrolyzed to (±)-biotin. Br Br H.t.J f.H C0 2 H C0 2 H 45 R^ / ^ H»i«y — ('H 2 steps 76% L>48 »-A «s- 4 steps H >«'y ('H 86% H.i. C0 2 H C0 2 H 46 R = CH 2 Ph R^ / ^R N N^ ■-vV' ' (ID Hit' 1; l'H 50% (CH 2 ) fc C0 2 -f- 7>(±)-biotin S H 49 Marx and co-workers 31 focused on the formation of ring system j>4_ and its reduction to 55_ as a means of in functionality about the tetrahydrothiophene ring of bio dinitro sulfide _52_, formed in good yield from the conju 2-nitroethanethiol ( 51 ) to methyl 7-nitro-6-heptenoate the thionofuroxan _54_ under dehydrating conditions. Bis is presumably an intermediate in the cyclization.

The was reduced to ene diamide 55 by activated zinc in dime the thienofuroxan troducing the tin (Eq. The gate addition of ( 50 ), furnished -nitrile oxide 53 thienofuroxan 54 thoxy ethane- tri- (CH 2 ) h C0 2 CH 3 o 2 n- 50 51 80% ->n 52 (CHjKCOaCHs S^.(CH 2 )„C0 2 CH 3 fT N N I 4 53 • _(CH 2 KC0 2 CH 3 o 40% ->54 CF 3 C0NH HNC0CF 3 CF 3 0C C0CF 3 (12) I I HN NH >77% C0 2 CH 3 ♦ a 55 S ' ^(CH 2 ) fc C0 2 Me 56 -53- fluoroacetic acid which afforded the cis urethane 56_ by catalytic hydrogena- tion. (±)-Biotin was obtained from 56_ by hydrolysis and reaction with phosgene. Confalone and co-workers have reported a stereospecific synthesis of (±)-biotin which incorporates an efficient reduction of the thiophene derivative 6J3_ producing the requisite all -cis conformation at C-2, C-3 and C-4 in the precursor 61_ (Eq. 32 Thiophene _58_ was prepared by reaction of the oxime of ketone 57 a with hydrogen chloride.

Cyclization to the mixed imido anhydride _59_ afforded protection of the sidechain carboxyl group prior to Curtius rearrangement in methanol. The mixed diurethan 6^0 was hydrogenated at 50 °C and 1800 psi with 10% palladium on carbon as catalyst to the all -cis acid j61. The need for phosgene was obviated because hydrolysis of 61_ in aqueous barium hydroxide furnished (±)-biotin directly. The overall yield of biotin from 57 was 37%. C0 2 Et COaCHj U COjH NH a S (CH 2 )*C0 2 CH s 57 3 steps 95% 3 steps 80% >HNCOjMe HNCO a Et C0 2 C0 2 Et S (CH 2 ) 6 C0 2 H 58 2 steps ^ 87% HNC0 2 Me HNC0 2 Et s (CH 2 ) fc C0 2 H 60 95% ^ h (CH 2 )C0 2 H 61 59 (13) Another approach to (±) -biotin developed by the Confalone group involves the stereospecific hydrogenation of 2, 5-dihydro thiophene 63_ to the all -cis tetrahydro thiophene 6^4 (Eq. 33 The acid 62^ obtained from ketone 5_7 in 83% yield after six steps, underwent Curtius rearrangement to the imido urethane 6J3 which was hydrogenated to 64^ by the same conditions used in the previous synthesis. Hydrolysis of 64_ afforded (±) -biotin in 39% yield from 57.

C0 2 H HNAc HNC0 2 Me 57 6 steps ^ 83% 3 steps s ' '(CH 2 KC0*£^ 62 Me0 2 CNH HNC0 2 Et 85% (CH 2 )„C0N o 64 HNC0 2 Et (CH 2 KC0N o 63 (14) A synthesis of (±) -biotin developed by Zavylov and co-workers con- cluded with the hydrogenation of the thiophene 66^ to (±) -biotin in poor yield (Eq. 35 Bromo imidazolone 65 was prepared according to the -54- literature method of Dushinsky and Dolan.

34 Reaction of 65_ with potassium thioacetate followed by alkaline hydrolysis afforded 66_ which was reduced to (±)-biotin in 10% yield by reaction with triethylsilane in trifluoro- acetic acid. O o A I * C * f Ac 2 steps. HN?H,C0 2 Et BrCH Tvr->yj (is) 6 s (CH,) t CO,H 65 66 In summary, a number of efficient and stereospecif ic syntheses of biotin have been reported since 1975. Novel reactions have been used in many cases to introduce the requisite asymmetry at C-2, C-3 and C-4. In addition, several of the recent approaches have the potential of being exploited industrially. BIBLIOGRAPHY 1. Ber., 68, 16 (1935).

Wilders, Cellule, 18, 313 (1901). Melville and V. Du Vigneaud, Science, 92^, 609 (1941). Boas, Biochem.

J., 21, 712 (1927). Hofmann and V. Du Vigneaud, J. Chem., 146, 487 (1942). For a review on the chemistry of biotin known prior to 1943 see: D. Melville, Vitamins and Hormones, 2_>29 (1944).

Mozingo and K. Folkers, Science, 97_, 447 (1943). Easton, and K. Soc, J57, 2096 (1945). Traub, Nature, 649 (1956); (b) J. Trotter and J.

Hamilton, Biochemistry, 5_, 713 (1966). Gibson, Biochem. Acta, 41, 122 (1960).

For a complete review and references see: J. Enzymol., 35, 321 (1971). For brief reviews on the mechanism of carboxylation reactions see: (a) H. Wood, Trends in Biochemical Science, 1_, 4 (1976); (b) D. McCormick, Nutrit. Rev., J33, 97 (1975). Chem., 249, 6633 (1974).

Fenselau, and M. Lane, ibid., 249, 6646 (1974). For reviews on the biosynthesis of biotin see: (a) M. Eisenberg, Adv. Enzymol., _38, 317 (1973); (b) Y. Applied Microbiol., 22, 145 (1977). Soc, 98^, 4024 (1976); (b) G.

Gaudry, and A. Marquet, Biochimie., 59, 119 (1977).

Wilson, and K. Soc, 66^, 1756 (1944); (b) S. Wilson, and K. Folkers, ibid., 66, 1757 (1944); (c) S. Harris, -55- R. Folkers, ibid., 66, 1800 (1944); (d) S.

Anderson, and K. Folkers, ibid., 67, 2100 (1945). Grlissner, J.

Bourquin, and 0. Von Schnider, Helv.

Acta, 28, 510, 517, 528 (1945). Von Schmid, ibid., 27, 127 (1944). Bernstein, S. Safir, and Y. Chem., 12, 167 (1947); (b) B. McEwen, and S.

Bernstein, ibid., 12, 174 (1947); (c) B. Bernstein, S. Dorfman, And Y. Subbarow, ibid., 12, 186 (1947). Cheney and J. Soc, 67_, 731 (1945); (b) L. Cheney and J.

Piening, Chem. Abst., 44, 6440 (1950). Goldberg and L. Sternbach, Chem. Abst., 45, 184, 185, 186, 187 (1951).

Hanessian, Ace. Res., 12, 159 (1979).

Emoto, Tetrahedron Lett., 2765 (1975). Kawano, and M. Matsui, Carbohydrate Res., 57, C31 (1977). Confalone, G. Pizzalota, E. Baggiolini, D. Lollar, and M.

Uskokovic, J. Soc, 9_7, 5936 (1975); (b) P. Confalone, G. Pizzalota, E.

Baggiolini, D. Lollar, and M. Uskokovic, ibid., 99, 7020 (1977). Vasilevskis, J. Gualtieri, S. Hutchings, R. Bizzarro, and G.

Soc, 100, 7423 (1978). Confalone, E.

Pizzolato, and M. Uskokovic, J. Soc, 100, 629 (1978); (b) P. Confalone, G.

Pizzolato, D. Confalone, and M. Uskokovic, J.

Soc, in press. Lavielle, and A. Marquet, Tetrahedron Lett., 827 (1975); (b) S. Lavielle, and A.

Soc, 100, 1558 (1978); (c) A. Marquet, Pure Appl. Chem., 49, 183 (1977). Marquet, Tetrahedron Lett., 4155 (1973).

Reisdorff, R. Sandmeir, and S. Soc, 99, 6754 (1977).

Confalone, G. Pizzolato, and M. Uskokovic, Helv. Acta, _59, 1005 (1976); (b) P. Confalone, G.

Pizzolato, and M. Uskokovic, J. Chem., 42, 135 (1977). Confalone, G.

Pizzolato, and M. Uskokovic,' J.

Chem., 42, 1630 (1977). Duschinisky and L. Soc, 70, 657 (1948). Rodionova, M. Kondrateva, S.

Zavyalov, and V. Filippov, Bull. Sci., 19, 606 (1970); (b) S. Zheleznaya, A.

Pavlova, and N. Rodionova, ibid., 22, 1641 (1973); (c) S.

Rodionova, L. Zheleznaya, G. Bolestova, V. Parnes, and D. Kursanov, ibid., 24, 1533 (1975). -56- S TABLE HEXACOORDINATE ORGANOPHOSPHORUS COMPOUNDS Reported by Stephen D.

Harper November 15, 1979 The ability of phosphorus to expand its octet has permitted the synthesis and characterization of stable compounds in which six atoms are bonded directly to a negatively charged phosphorus. This abstract shall review the chemistry of all such hexacoordinate species except those con- taining halogen ligands or possessing a zwitterionic structure. 1 Several synthetic routes to hexacoordinate phosphorus compounds have been developed. One common approach involves the reaction of a penta- coordinate species with an alcohol, phenol, 3 >6 >8_1 3 or amine 14 in the presence of base or with a metallosubstituted biphenyl. 15 The phosphorane may have one or more leaving groups, in which case more than one ligand is added to the phosphorus. An example of this synthetic approach appears in Figure 1. Phosphorane 1_ reacts with one equivalent of catechol to yield the hexacoordinate species 2_.

The dimethylamine liberated from the phos- phorane serves as the base in this reaction and is incorporated as the counter ion in the product. Figure 1 C v X + lo) N(CH 3 ): 1 25°C quant. O- / e H 2 N(CH 3 ); Phosphoryl chlorides react with catechols in the presence of tertiary amines to yield tris(o-arylenedioxy) phosphate anions.

' Hexacoordinate compounds containing hydrogen directly attached to phosphorus are obtained upon reaction of (R0) 2 PR' species with catechols and tertiary amines. ° Many of the first hexacoordinate organophosphorus compounds to be isolated were formed in the reaction of bis (2, 2 '-biphenylene)phosphonium iodides with either 2,2 '-dilithiobiphenyls 2 1_214 or arylenediolates. 25 Figure 2 illustrates a reaction of this type.

25 Figure 2 - © I© + c§x OLi OLi THF, 25'C 96%;>-,© Li © -57- Other less extensively exploited routes to P(VI) species have also been described. 26-28 The structures of two hexacoordinate phosphorus compounds have been determined by X-ray crystallography.

9 ' 30 Only small deviations from an octahedral geometry were noted. These two compounds exhibit 31 P NMR chemical shifts considerably upfield from 85% H 3 P0 A due to shielding of the negatively charged hypervalent phosphorus. This property has been very useful in determining whether other isolated species are also hexa- coordinate.

The octahedral geometry about phosphorus creates a chiral center if the ligands are bidentate or non-equivalent. Hellwinkel separated the two enantiomers (_5_ and 6) of bis(2,2'-biphenylene)phosphonium tris(2,2'- biphenylene) phosphate via their methyl brucinium salts.

21 Circular di- chroism and electron absorption spectra were used to determine the absolute configuration. 31 Optically active a-hydroxy acids react with phosphoranes to yield diastereomeric mixtures of P(VI) species.

1 * The optically pure diastereomers epimerize in solution. ' 33 Other aspects of hexacoordinate phosphorus stereochemistry have also been examined. 1 1 ' 23 >2t+ ' 31+ 5 A Hexacoordinate phosphorus compounds display a wide range of stabili- ties. Bis(2, 2 '-biphenylene)phosphonium tris) 2, 2 '-biphenylene) phosphate is stable in boiling water 15 and does not exchange labelled phosphorus between the counter ions up to 130°C. 35 In general, the structural features of the ligands which enhance the stability of phosphoranes also increase the stability of P(VI) compounds.

Bidentate ligands provide greater stability than do monodentate ligands. Hexaphenoxy 1 2 and hexamethoxy 7 phosphate anions have been observed by NMR, but have not been isolated. Five- membered rings are more readily introduced than are six-membered rings. »' BIBLIOGRAPHY An early, comprehensive review of hexacoordinate organophosphorus compounds, includng those bearing halogen ligands, has been published: D. Hellwinkel, 'Organic Phosphorus Compounds', Vol.

Kosolapoff and L. Maier, ed., Wiley, New York, NY, 1972, Chapter 5B. A recent leading reference on zwitterionic species is: C. Garrigues, M. Koenig, and A.

Munoz, Tetrahedron, _35, 1825 (1979). Powell, and D. Commun., 1070 (1971). Bernard and R. C, 279, 883 (1974). Koenig, and R. Fr., 909 (1975).

Chem., 437, 53 (1977). Schmidpeter and J. Weinmaier, Chem. Ber., Ill, 2086 (1978). Denney, and C.-F. Soc, 96, 7269 (1974).

Bernard, and C. C, 276, 297 (1973).

Prasad, and J. Soc, 96, 7269 (1974). Bernard and R.

Burgada, Phosphorus, _5_, 285 (1975). Hellwinkel and W. Krapp, ibid., 6_, 91 (1976). Lerman and F.

Westheimer, J. Soc, 9_8, 179 (1976).

Schmidpeter, T. Von Criegern, W. Sheldrick, and D. Schomburg, Tetrahedron Lett., 2857 (1978). Von Criegern and A.

Schmidpeter, Z. B, _34, 762 (1979). Hellwinkel, Chem.

Ber., ^8, 576 (1965). Yoshida, and E. Yoshii, Tetrahedron Lett., 1075 (1974). Gallagher, A.

Gence, and M. Commun., 321 (1976).

Wieber and K. Foroughi, Angew. Engl., 12, 419 (1973); (b) M. Foroughi, and H.

Klingl, Chem. Ber., 107, 639 (1974). Terent'eva, and A.

USSR, 45, 2292 (1975). Boisdon, and J. C, 275, 295 (1972). Hellwinkel, Chem.

Ber., 99, 3628 (1966). Hellwinkel, ibid., 9j?, 3642 (1966). Hellwinkel, ibid., _99, 3660 (1966). Hellwinkel and H.-J. Wilfinger, Phosphorus, 2, 87 (1972). Hellwinkel and H.-J.

Wilfinger, Chem. Ber., 103, 1056 (1970). Soc, 85_, 4050 (1963); (b) H. Allcock, ibid., 86, 2591 (1964). Luderer, and H. Pays- Bas, 91, 836 (1972).

Houalla, and R. Commun., 182 (1974). Allcock and E. Commun., 676 (1972); (b) H. Allcock and E. Soc, 95, 3154 (1973).

Marecek, and V. Prasad, Phosphorus Sulfur,.5, 323 (1979). Hellwinkel and S.

B, 640 (1970). Dalton, 570 (1977). Munoz, and R. Soc Perkin II, 955 (1976). Munoz, and R. Perkin II, 40 (1979).

Hellwinkel, Chem. Ber., 99, 3668 (1966). -59- VANADIUM- AND MOLYBDENUM- CATALYZED EPOXIDATIONS OF OLEFINS WITH ALKYL HYDROPEROXIDES Reported by John R. Hurst November 19, 1979 The epoxidation of olefins with alkyl hydroperoxides in the presence of certain transition metals is well-known. 1 Metals which are likely to be active catalysts must meet three criteria: they must be relatively small, highly charged atoms with at least some low-lying vacant d-orbitals; they must be stable under strongly oxidizing conditions; and they must be labile to substitution.

2 Of the few metals that meet these requirements, V 1 ' 5 and Mo +5 have received the majority of attention. V -1 ' 5 and Mo +6 are almost always generated in situ by addition of VO(acetylacetonate) 2 or MO(C0) 6, and subsequent oxidation. This review deals with the development of olefin epoxidations employing alkyl hydroperoxides and these two metals. Simple Olefins. In 1968, Gould, Hiatt, and Irwin 2 reported an exten- sive study on the epoxidation of cyclohexene with VO(acetylacetonate) 2 (V0(acac) 2 ) and tert- butyl hydroperoxide (TBHP), as a model for simple olefins.

Their study shows the reaction rate to be linearly dependent on both the catalyst and olefin concentrations. The concentration of the TBHP, however, has a non-linear effect on the rate. At low peroxide concentrations the rate is apparently first order in peroxide, but at higher concentration it approaches a limiting value which is proportional to the catalyst concentration. The data are in good agreement with Eq. 1, which is based on the assumption that a 1:1 complex of the peroxide and the catalyst is responsible for the oxidation. Mvio ratS = (1/([P]K) + 1) (1) where [V] = initial concentration of catalyst [P] = peroxide concentration K = association constant of the complex k=a proportionality constant A plot of rate/[P] vs. Rate was linear and gave values for k and K at different temperatures.

An Arrhenius plot gave the activation parameters AH* =12. 7 ±.4 kcal/mol, and AS* = -19.9 ± 1.9 eu. Added tert- butyl alcohol inhibited the reaction drastically, and the authors speculated that the alcohol was forming one or more inactive complexes with the vanadium. The kinetic data of the inhibited reaction are well modeled by Eq.

K[Vl rate = (2) l/CfPlKCKifAj+Ki' [A] 2 + 1)) +1 where [A] = concentration of alcohol K^ = association constant for VA K^' = association constant for VA 2 -60- Th e association constants were determined to be K^ = 119 M -1 and K^' = 2.1X10 1 * M~ 2. Most importantly, their data indicate that 1 molecule each of peroxide, catalyst, and olefin are involved in the transition state. Since a ter-molecular transition state is unlikely, the transition state probably involves the olefin and a peroxide-catalyst complex. Linden and Farona 3 have reported that improved yields in the epoxida- tion of some simple olefins result when the vanadium catalyst is incorpo- rated on an insoluble polymer. For example, the oxidation of cyclohexene to its oxide with the polymer-bound catalyst occurs in 74% yield (on peroxide consumed) at 80°C, whereas the homogenous catalyst affords only 10-12% of the epoxide. Sharpless e_t al.^ have found that addition of small amounts of anhydrous disodium hydrogen phosphate (Na 2 HP0i.) reduces the amount of diols formed by ring opening of the epoxides, and thus improves the yield.

Peroxomolybdenum Compounds as Possible Intermediates. The discovery by Mimoun, de Roch, and Sajus b that 1_ and similar peroxomolybdenum com- pounds stoichiometrically epoxidize olefins led them to speculate that a similar compound was involved in the molybdenum-catalyzed oxidation with TBHP. 0^ I HMPA (HMPA = hexamethylphosphoramide) Chong and Sharpless 7 have investigated the possibility of such an intermediate but were unable to isolate any peroxomolybdenum compounds such as 1 when HMPA was added at different stages of the reaction. They performed an 18 labeling experiment which demonstrated that a compound such as 1_ is not involved in the epoxidation. Since the oxo-oxygen of the catalyst readily exchanges with H 2 18 0, these workers carried out the epoxidation in the presence of labeled water, and the results in Scheme I TBHP Scheme I dioxane, H 2 0' ■>VO(acac) 25°C, 12 2 h no label H— 0- no label + TBHP dioxane, H 2 Mo(C0) 6 115°C, 1 day no label H-0*— f- 74Z Incorporation H— 0- same as above H-0 68% incorporation -61- were obtained. The two mechanisms which would be likely to produce the peroxo species (Scheme 2 7 ) both would lead to the incorporation of labeled oxygen in the reaction products. The first involves oxo-oxygen incorpora- tion in the peroxy linkage, and the second involves incorporation in the tert- butyl alcohol.

Although incorporation of 18 into the tert- butyl alcohol occurred in the Mo(Co) 6 -catalyzed reaction, tert -butyl alcohol itself was shown to exchange extensively under the conditions of the reaction. Since the oxo-oxygen is not involved in the epoxidation, the alkyl peroxide must be directly involved in the epoxidation step. An assumption inherent in this conclusion is that the molybdenum and vanadium- catalyzed oxidations have similar mechanisms. This may not be the case since the reactivity of some olefins is significantly different with the two catalysts. Scheme 2 M + „/ -o-f-;=± i_oV H - B '* l + H ~°'T H / ^ M-U/' °'h H-O-M + h' o—o-l— =* o-Ui N f' oH- — >r->m^ + h-o*— I- K „/ n / H 2 0* ^ Dienes and Substituted Olefins. Sheng and Zajacek 8 have reported the epoxidation of a number of dienes and substituted olefins. The reactivity of non-conjugated dienes is similar to that of mono-olef ins, in that the reactivity increases with increasing substitution.

For example, oxidation of 1,4-hexadiene gives predominantly the internal epoxide. The ratio of internal epoxide to external epoxide was 11:1 from the oxidation of cis- 1,4-hexadiene wiht cumene hydroperoxide and Mo(C0) 6, and the ratio from the trans isomer was 6:1. For conjugated dienes the reactivity is dimin- ished slightly, but the preference for reaction at the more substituted site is retained. Thus, isoprene is epoxidized 4 times faster at the more substituted double bond than at the less substituted one with TBHP and Mo(C0) 6. Epoxidation of allylic compounds, such as allylic ethers and halides, is slower and less efficient than that of the non-conjugated dienes, probably owing to the inductive properties of the electronegative allylic substituent. For example, epoxidation of allyl ethyl ether pro- ceeded in only 77% yield, while the mono-epoxide of cis- 1,4-hexadiene was obtained in 90% yield.

A ratio of olefin to hydroperoxide greater than 2:1 increased the yields of the epoxides of the allylic compounds. Allylic alcohols, on the other hand, displayed a significantly different pattern of reactivity. This special reactivity has been the object of much interest. Epoxidation of Allylic Alcohols. With other olefinic compounds, the molybdenum catalyst gave higher yields than the vanadium catalyst, but the reverse was true for allylic alcohols.

8 The vanadium-catalyzed epoxidation of allyl alcohol is much faster than that of simple olefins, and the reaction could even be carried out with an excess of hydroperoxide, in contrast to other allylic compounds. This exceptional reactivity has been attributed to a complexation of the alcohol with the activated catalyst. -62- Chong and Sharpless 7 have suggested some possible transition states for the metal-catalyzed epoxidation, which are shown in Scheme 3. Complexa- tion with the allylic alcohol is geometrically impossible in 2^ and J3, whereas 4- and 5^ seem to be ideally situated for the complexation.

For this reason, they suggest that the peroxide is coordinated to the vanadium at the oxygen furthest from the alkyl group. Scheme 3 H o B °CII II— 'A, >C M sp>°- R £) Sharpless and Michaelson 9 have demonstrated that the increased reac- tivity of allylic alcohols can be utilized to effect selective oxidations which might be difficult to realize with other reagents. Some examples are shown in Table 1. Table 1% Yield OH VO(acac): TBHP 98 VO(acac) 2 TBHP ^ 95 VO(acaca) TBHP >95 a OH Mo (CO) 6 TBHP ->98 The reaction of the homo-allyl alcohol 6^ is also faster than cyclohexene, and, furthermore, is stereospecif ic. The rate acceleration can be seen in Table 2. 9 -63- Table 2 tert-Butyl iydroperoxide Olefin Perbenzoic acid Mo(C0) 6 VO(acac) 2 rel. Race% cis rel.

Rate 1% cis rel. Rate 1% cis Cyclohexene 1 - Cyclohex-2-enol.55 92 4.5 98 >200 98 Cyclohex-3-enol.42 60 11 98 10 98 In the epoxidation of cis- cycloalk-2-enols, Dehnel and Whitman 10 and Itoh, Jitsukawa, Kaneda, and Teranishi 11 have reported that the V0(acac) 2 - catalyzed epoxidations display higher cis selectivity than those of per- acids. Most notably, the vanadium-catalyzed reaction gives cis stereo- chemistry for cis- cycloalkenols with 6-9 members, while the peracid oxida- tion shifts from cis preference with 6-membered rings to a trans preference with 8- and 9-membered rings.

10 ' 11 The conformationally fixed cis- and trans- 5- tert- butylcylohex-2-enols were epoxidized with the vanadium catalyst. 1U >1 1 The pseudo-axial alcohol underwent epoxidation 34 times faster 10 and with greater cis-stereoselectivity 1 1 than the pseudo-equatorial isomer. Oxidation of the alcohol to an unsaturated ketone becomes the dominant reaction of the pseudo-equatorial case. 10 ' 11 In contrast, the peracid oxidation showed higher selectivity in the pseudo-equatorial case. 11 Accordingly, Teranishi et_ al_. Suggested that the preferred transition state geometry for the peracid oxidation is similar to that of the pseudo-equatorial alcohol, while the transition state geometry for the vanadium-catalyzed reaction is similar to the pseudo-axial alcohol.

Teranishi et al. 11 have also reported the epoxidation of some cyclic trans-allylic alcohols, and the vanadium- catalyzed oxidation retained its preference for cis stereoselectivity. A notable exception is 1R*,2R*- cyclooct-2-enol, which gives the trans epoxy alcohol.

In the oxidation of some acyclic allylic alcohols, Rossiter, Verhoeven, and Sharpless 12 have demonstrated that the vanadium and molybdenum catalysts offer improved stereoselectivity over peracids (Table 3). 12 (continued on next page) -64- Table 3.

Yields of Erythro Epoxy Alcohol Formed by Various Methods MCBPA + Mo +6 /TBHP* V +5 /TBHP* R OH 39 58 80 (typical) 2 R OH 8 59 84 98 (typical) JT 36 38 71 OH 9 ( 5 16 29 10 ^OH 5 5 14 1 11 MCPBA = m-chloroperbenzoic acid ft TBHP = tert-butyl hydroperoxide Furthermore, the pattern of reactivity is dependent on the olefin substi- tution. To account for the effect of substitution on the relative yields of the threo and erythro isomers, they have suggested optimal double bond- alcohol dihedral angles for the epoxidations with V0(acac) 2 and tert- butyl hydroperoxide, and m-chloroperbenzoic acid (Table 4). 12 For V+ 5 / tert- butyl hydroperoxide For peracids Table 4. Optimal Partial Geometries for Epoxidation For threo For erythro V V.^50°.^50° ^^j4^ b H-, =^o OC(Ph); 5% HC10„ ^ THF, 0°C, 1.5 h 17 33% The enhanced reactivity of allylic alcohols and the likelihood that they are coordinated to the catalyst during epoxidation led some researchers to investigate the possibility that asymmetric induction might be achieved by using a catalyst with a chiral ligand. Michaelson, Palermo, and Sharpless* 5 employed chiral hydroxamic acids as the ligand.

Although molybdenum complexes gave poor results ( j^O OH 3% // ■„■ -N Ph 95% (80% e.e.) Ph F 3 C 18 It is evident that vanadium- and molybdenum-catalyzed epoxidations with alkyl hydroperoxides can be useful in synthesis. For many cases the reaction proceeds with greater chemo- and stereoselectivity and in better yield than epoxidation with peroxy acids. BIBLIOGRAPHY 1.

Hiatt in 'Oxidation', Vol. Augustine and D.

Trecker, ed., Marcel Dekker, New York, N.Y., 1971, Chapter 3. Hiatt, and K. Soc, 90, 4573 (1968). Linden and M. Farona, Inorg. Chem., lb_, 3176 (1977). Michaelson, L.

Sharpless, unpublished results from reference 5. Sharpless and T. Verhoeven, Aldrichemica Acta, in press.

Seree de Roch, and L. Sajus, Tetrahedron, ^6_, 37 (1970). Sharpless, J. Chem., 42, 1587 (1977). Chem., 35, 1839 (1970). Sharpless and R. Michaelson, J.

Soc, 95, 6136 (1973). Dehnel and G.

Perkin I, 953 (1979). Jitsukawa, K. Kaneda, and S. Soc, 101, 159 (1979). Verhoeven, and K.

Sharpless, Tetrahedron Lett., in press. Sharpless, R. Michaelson, and J. Soc, 96_, 5255 (1974). Van Tamelen and J.

McCormick, J. Soc, ^2, 737 (1970).

Michaelson, R. Palermo, and K. Sharpless, J. Soc, 99, 1990 (1977). Oshima and K. Sharpless, unpublished results from reference 5 17. Wiering, and H.

Wynberg, Tetrahedron Lett., 1831 (1976). -68- DETECTION AND CHARACTERIZATION OF CERTAIN CARBON DIRADICALS VIA ESR AND CIDNP Reported by G. Slocum November 26, 1979 Carbon diradicals have been proposed as reactive intermediates in chemical reactions for some time.

The past decade has seen the development of electron spin resonance (ESR) and chemically induced dynamic nuclear polarization (CIDNP) as probes for examining these short-lived inter- mediates. This report will deal with the application of these two tech- niques to the study of certain diradicals in which the two radical sites are on carbons separated by a carbon chain. The basic principles of the application of ESR to organic radicals are presented in a monograph by Wertz and Bolton.

1 In a diradical, in which the radical sites are separated by a long saturated chain, the un- paired electrons will not be coupled to each other and the ESR spectrum observed will be that of two isolated carbon monoradicals. In most diradicals, however, there is considerable interaction, either through bond or through space, and spectra of triplet species are observed. ESR spectra of triplets are generally obtained by generating the diradical in a rigid matrix which serves to isolate the triplet species, inhibiting intermolecular reaction. This method increases the lifetime of the diradical intermediate and allows a measurable steady state concentration to exist. While well-resolved ESR spectra of several diradicals have been obtained, the properties of diradicals at the low temperatures usually used in matrix formation may differ significantly from those in solution phase at normal temperatures.

The simplest carbon diradical is the 1, 3-diradical, trimethylene, which has been proposed 2 as an intermediate in the stereoisomerization of cyclopropane. Although the extremely short lifetime of this diradical has prevented the observation of its ESR spectrum, the spectra of related 1, 3-diradicals have been recorded. Closs 3 has reported the spectrum of the diradical produced by the photolysis of 2, 3-diazabicyclo [2. L]heptene-2, _1, in a cyclohexane matrix at 5.5K.

The splitting pattern in the spectrum matched that predicted for a triplet species randomly oriented in a rigid matrix. The D value from the spectrum was d =0.084 cm -1 and the E value was e =0.002 cm -1. These are in reasonable agreement with the D and E values predicted for a diradical with specified geometry, represented by structure 2. The D and E values are a measure of the distance between and orientation of the two radical sites. In order to exclude the possibility that the spectrum arose from a diradical derived from the bicyclic compound, 1_, by cleavage of a single C-N bond, Closs examined the spectrum of the di- radical from _l-d 8. The narrowing of the lines in the ESR spectrum was attributed to the lower hyperfine coupling of deuterium, and eliminated the possibility of coupling with nitrogen nuclei.

The spectrum persisted down to 1.3K, suggesting that diradical 2 has a triplet ground state. O // -69- Photolysis of tricyclic azo compound _3 at 77K produced an ESR spectrum attributed 4 to diradical h_. This spectrum also exhibited the splitting pattern expected for a randomly oriented triplet species in a rigid matrix. The D and E values obtained in the spectrum were in reasonable agreement with those expected for the proposed structure. A 1,3-diradical of theoretical interest is trimethyleneme thane, _5.

Dowd 5 reviewed the literature of the ESR of 5^ in 1972. Berson 6 has discussed the chemistry of ethano-bridged trimethylene methane analogs, 6_, and cites some of the more recent ESR results. Both trimethylene- methane and its bridge analog exhibit triplet spectra. Irradiation of a single crystal of 3-methylenecyclobutanone, _7>at 77K i- n an ESR spec- trometer produced a spectrum consisting of a doublet of septets, consis- tent with a triplet species regularly oriented in a rigid matrix with six equivalent protons. R, R V Considerable effort has been expended to establish that the spectrum arises from a ground state triplet, in agreement with theoretical predic- tions, rather than from a low-lying, thermally populated triplet.

One approach used to distinguish these two alternatives is to study the relationship of the intensity of the ESR signal as a function of tempera- ture. The Curie law predicts that the intensity of the ESR signal for a ground state triplet will be inversely proportional to the absolute tem- perature. A study 8 of the temperature- intensity data from the irradiation of methylenecyclobutanone, 1_, in a methylcyclohexane glass over the range of 20 to 80K indicated that trimethylenemethane was indeed a ground state triplet. The temperature dependence of the intensity of the ESR spectra of the bridged analogs 9 led to the conclusion that they, too, have triplet ground states. -70- Th is method must be used with care, however.

Another diradical pre- dicted to have a triplet ground state is 1,8-naphthoquinodime thane, 8. The temperature dependence of the intensities of the ESR spectra of diradicals JS, 10, and 1_2 have been studied. 10-12 The ESR intensities for these radicals were not found to vary inversely over certain ranges. Instead those intensities were found to vary according to the following equation: I = [ (exp - AE/RT) / (1 + 3exp - AE/RT) ] /T In this equation, I is the intensity, T is the absolute temperature, and AE is the energy difference between a singlet ground state and a low lying triplet state. Analyses of the different temperature-intensity data predict AE between singlet ground states and triplet excited states of _8. 10, and 12_ of 40 cal/mol, 200 cal/mol, and 640 cal/mol, respectively.

Later reports 13 of a simple inverse dependence between temperature and intensity over a broader range led to the conclusion that diradicals 8^, 10, and 1_2 either had triplet ground states or triplet states lying only a few cal/mol above the ground state. Platz 14 reported the ESR spectrum of a triplet species resulting from the photolysis of the diazo compound 14_.

The spectrum was identical with the spectrum of 8^. Temperature-intensity data in this report support a ground state triplet. N==N 14 12 13 17 Closs 15 ' 16 reported ESR spectra for diradicals 1_5 and 1_6, produced by photolysis of pyrazoline 1_7 in a pentane-isopentane glass at 77K. A D value of 0.1069 for 15 (R = CN) is indicative of contribution tc the structure of 15_ from resonance contributors a. The D valuf- of di- radical 16_, however, was consistent with the formal 1, 5-diradicaJ struc- ture shown. -71- The difference in the properties of diradicals in matrix-isolated conditions and solution phase is illustrated in a report 17 that photolysis of three to seven carbon cycloalkanones in an adamantane matrix over the range 123 to 296K did not produce any species with a triplet or diradical ESR spectrum. The observation of CIDNP signals from the photolysis of cycloheptanone, however, implicates a diradical intermediate as is generally proposed in the Norrish I photocleavage of this cycloalkanone.

Thus, CIDNP appears to be the method of choice for the investigation of some diradicals in solution. There are two mechanisms by which a CIDNP 18 effect may be produced in the reaction of a diradical intermediate.

The first mechanism is essen- tially the radical pair mechanism proposed independently by K.aptein 1 ^ and Closs in 1969. A diradical is formed either in the pure singlet or pure triplet state with the electron spins coupled. As the distance between the carbons is increased, the exchange coupling falls toward zero, and the singlet state becomes nearly degenerate with the triplet state. This allows mixing of the states through either a difference of g factors for the two electrons or for a difference in hyperfine interactions. If there is hyperfine splitting by a nucleus having a spin of +1/2. Or -1/2, the rephasing frequency for the electrons will differ for th'e two nuclear spin states. As a consequence, the singlet will be enriched in one nuclear spin state and the triplet will be enriched in the other.

If the diradical now undergoes two competing reactions, one of which requires the diradical to be in its singlet state, such as recombination or disproportionation, the other of which is spin independent, there will be spin selection. The nuclear spin state favored in the singlet will predominate the singlet derived product. Similarly, the enrichment of the other nuclear spin state in the triplet will be carried over into the spin- independent pro- ducts.

If the reaction is performed in the cavity of an NMR spectrometer, the spectrum will show enhanced absorption or emission for the lines in the spectrum corresponding to the protons the spins of which effected the singlet triplet mixing. 'Radical pair mechanism' will be used to refer to this mechanism. The other mechanism, proposed subsequently by Closs, 1 will be called the 'diradical mechanism' because it was developed to account for CIDNP effects unique to diradicals. When the singlet state, S, and the triplet state, T (M=0), are not degenerate due to residual exchange coupling, J, a degeneracy of one of the other triplet states, T+ (M=±l), may be imposed by adjusting the magnetic field, H, such that g3H. In this equation, g is the g-factor for the electron, 3 is the Bohr mag- netron for the electron, and is the mean value of 2J. This allows mixing of the singlet state with either of the T + or T_ states with which it is degenerate.

Since the total spin angular momentum must be conserved, an electronic spin flip must be accompanied by a nuclear spin flip. There- fore, when a T+ state of a diradical is depopulated by crossing to S and is followed by self reaction, there is a depopulation of one nuclear spin state. This process gives rise to a non-equilibrium spin population in the products, which manifests itself as enhanced absorption or emission in the NMR spectrum. This mechanism does not require a competing reaction for spin selection, as does the radical pair mechanism. CIDNP effects produced by the diradical mechanism will be either solely enhanced absorp- -72- tion or emission in all of the peaks, rather than the mixed enhanced absorption-emission characteristic of the radical pair mechanism. CIDNP was first observed from diradical products by Kaptein 22 in the thermolysis of spiro diperoxide, JL8. Kaptein was able to account for the CIDNP effects observed in the NMR signals of the product 1-decene in terms of the radical pair mechanism and Scheme I.

Here the reaction pathway to 'other products' provides the competing reaction for spin selection. The spectrum exhibited an emission-absorption multiplet effect. Kaptein 23 later reported polarization in the signal for cyclodecane when the thermoly- sis was carried out in a low magnetic field.

He was able to make qualita- tive observation on the S - T+ splitting and the effect of solvent on that splitting from the field dependence of the signal enhancement. Scheme I 0—0 j •>-CHaCCH^aCHa* >I (CH a ) i. Several ' 2 vun 2^ a^n 2 - zr ^n 2;io steps i „.„„„,„.

Other products The diradical mechanism is operative in the photochemical ring cleavage of cycloalkanones. Closs irradiated a series of cycloalkanones, 19 in Scheme II, in chloroform under the influence of both high field 2 ** and a series of low fields. 25 He observed emission in the signals for the a and 3 protons on the cycloalkanones, _19_, and in the olefinic and alde- hyde protons of the unsaturated aldehyde, 2^). From the intensities of the CIDNP signals from cycloheptanone ( 18, n = 2) and the corresponding unsatu- rated aldehyde, Closs calculated a ratio of forward to reverse reaction of 0.33. Scheme II Q (CH 2 ) n 19 hv ^ 0C(CH 2 ) n+3 CH 2.

>CH 2 =CH(CH 2 ) n+2 CH0 'v 20 From the field dependence of the maximum intensity of emission from the aldehyde peaks for the different cycloalkanones, Closs deduced the So - T_ splittings. He also calculated the life times of the diradicals from the width of the curves of the intensity vs. The field strength plot (Figure 1).

Kaptein's 26 investigation of the 13 C CIDNP observed in cycloalkanone photolysis confirmed the splittings estimated by Closs, since the same magnetic field dependence of the maximum enhancement was ■73- obtained. The broadening of the curves which Closs attributed to the relationship of the diradical lifetime to the splitting through the uncertainty principle, Kaptein assigned more reasonably to the hyperfine 1 3, interaction on the basis of larger broadening with the C CIDNP than in J H CIDNP consistent with the larger 1 3 C hyperfine coupling constant. Figure 1 Int H ( Kaptein 27 reported that the photolysis of cycloalkanones in the presence of a radical scavenger produces a change from the diradical mechanism to the radical pair mechanism, provided scavenging can compete with electron spin relaxation. At low fields the diradical mechanism predominates and only emission is observed. At higher fields the radical pair mechanism becomes favored and enhanced absorption is observed. The field strength at which the polarization changes is dependent on the scavenger concentration and the diradical chain length. From the magnetic field dependence of the signals observed on photolysis of cycloalkanones in the presence of 2-methyl-2-propane- thiol, Kaptein calculated a scavenging rate constant of 5 x 10 7 M -1 s _1 for the thiol.

One of the major problems in CIDNP is in the assignment of reliable enhancement factors. A technique was recently reported which could improve this situation. Sagdeev 8 and co-workers observed CIDNP signals produced during the photolysis of cyclododecanone by spin echo NNR. They calculated an enhancement factor of over 10 6 from the intensity of the CIDNP signals and the light absorbed in one pulse. The polarization qunatum yield, i.e., the probability of a nuclear spin flip after the absorption of a photon, calculated from this enhancement factor was 0.3. Theoretically, CIDNP signals arising from the diradical mechanism may be observed from products of diradicals of any length by adjusting the magnetic field such that gBH =.

Practically, however, the exchange coupling in 1,3-, 1,4- and 1,5- diradicals is large enough that a very high magnetic field would be -74- required to impose degeneracy on the S -T- pair. Closs 3 has reported preliminary results of CIDNP arising from a 1, 3-diradical. Although experimental details were not given, the degeneracy of the S -T+ states appears to be fortuitous in this case. Development of very high field NMR spectrometers promises to expand the range of diradical intermediates which may be investigated by CIDNP. BIBLIOGRAPHY 1. Bolton, 'Electron Spin Resonance: Elementary Theory and Practical Application', McGraw-Hill, New York, 1972. Rabinovitch, E.

Schlag, and K. Phys., 28, 504 (1958). Bachwalter and G.

Soc, 97^, 3857 (1975). Evnir, and R. Soc, 91, 784 (1969). Res.,,5, 242 (1972). Berson, Accts. Res., 11, 446 (1978).

Soc, jH), 2715 (1968). Soc, 98, 5726 (1976). Porter, and J. Soc, 9j8, 5725 (1976).

Soc, 98, 2551 (1976). Burnett, and J. Soc, £9, 1972 (1977). Dewey, and J. Soc, 100, 1629 (1978). Burnett, and R. Soc, 101, 2218 (1979).

Soc, 101, 3398 (1979). Soc, 9JL, 2168 (1969). Kaplan, and V.

Soc, 89, 3376 (1967). Photochem., 9_, 312 (1978).

For reviews of CIDNP see: G. Closs, 'Chemically Induced Dynamic Nuclear Polarization', in Adv.

Res., 7_, 157 (1974), and A. Lepley and G. Closs, 'Chemically Induced Magnetic Polarization', Wiley-Interscience, New York, 1973. Kaptein and L.

Oosterhoff, Chem. Lett., b_, 195, 214 (1969).

Soc, 91, 4529 (1969); (b) G. Closs, ibid., 91, 4552 (1969); (c) G. Trifunac, ibid., 91, 4554 (1969); (d) G.

Trifunac, ibid., 92, 2183, 2186 (1970). Closs, 'Chemically Induced Dynamic Nuclear Polarization', in Adv. Res., 7_>157, p. Frater-Schroder, and L. Oosterhoff, Chem.

Lett., 12, 16 (1971). Van Leeuwen, and R. Lett., 41, 264 (1976). Doubleday, J.

Soc, 94, 9248 (1972). Doubleday, J. Soc, 9^5, 2735 (1973). De Kanter, R.

Sagdeev, and R. Kaptein, Chem.

Lett., 58, 334 (1978). De Kanter and R.

Kaptein, Chem. Lett., 58, 340 (1978) 28. Grishin, and R. Sagdeev, Chem. Lett., 55, 174 (1978). -76- ENZYMIC CATALYSIS IN ORGANIC SYNTHESES Reported by Venkatesalu Bakthavachalam November 29, 1979 Should organic chemists meddle in biochemistry? You might well answer this question in the negative if you read the article entitled 'The explanation of the secret of alcoholic fermentation' published in 1839.

* Clearly things have changed since the days of Liebig and Wbhler. The establishment of primary metabolic pathways, the isolation of many of the enzymes involved, and the understanding of the physical organic chemistry related to the mechanism of enzymic catalysis has lead to a number of bridges between the territory of biochemistry and organic chem- istry. One aspect of this bridging, at least in the future, will perhaps be the use of enzymes in organic syntheses.

The utilization of micro- organisms to bring about structural transformations in the fields of steroids and antibiotics 2 paved the way for the current investigations with isolated enzyme systems. The major values of enzymes in organic syntheses are their regio- and stereospecif icity and the simple procedures normally required for the isolation of products. There are enzymes known which catalyze most of the common organic reactions such as oxidatioft- reduction, condensation, addition, decarboxylation, deamination, and halogenation. 3 Even though enzymes are ordained by nature to catalyze specific reactions at specific sites, there exists a large number of enzymes which show a broad spectrum of substrate activity.

The advent of insolubilized and immobilized enzymes has enhanced the efficiency and stability of the enzymes and their general utility to wider applications in organic chemistry. The purpose of this abstract is to survey those cell-free enzyme systems which have been utilized to synthesize organic compounds in preparative quantities and to examine the steps taken to over- come the practical difficulties posed by the enzymic reactions. Practical Aspects of Enzymes as Synthetic Catalysts. Common criteria for choosing a reagent are its cost, availability, stability for storage, and, of course, its suitability for the reaction in question. It would be a tedious job for chemists to isolate enzymes in a pure state, but fortunately the range of commercially purified enzymes is rapidly widening.

11 Many of these preparations require only mild refrigeration to guarantee months of service. Even crude preparations obtained by breaking open the cells of the source organism often possess adequate activity. In order for an enzyme to be active, the protein should be in its active conformation. As would be expected, these molecules of high molecular weight have limited stability.

With most enzymes, the range of stability reflects the fact that they have evolved to function in a pre- dominantly aqueous environment at around 37 °C. Accordingly, it is necessary to handle them under similarly mild conditions, so that the activity may be maintained.

However, such an aqueous medium is a poor solvent for many organic compounds. Nevertheless, many enzymes tolerate significant quanti- ties of organic solvents mixed with water; e.g., the stereospecif ic reduc- tion of benzaldehydes to benzyl alcohols by Battersby 5 was carried out in a 5% organic solvent-phosphate buffer medium with high dilution and excellent yields were obtained given sufficient time. Similarly, it has been shown recently that a- chymo trypsin retains its L-enantiomeric preference to a significant extent in aqueous solutions to which moderate (up to 40%) pro- portions of organic solvents, such as 2-propanol, dioxane or dimethylsul- f oxide, have been added. 6 Special cases are known in which reactions are run in predominantly organic media. 7 Recently a novel approach to prepara- -77- tive enzymatic synthesis using a biphasic 'vrater-water-'CrnnrCscible organic solvent' system has been demonstrated with the chymotrypsin catalyzed synthesis of N-acetyl-L-tryptophan ethyl ester.

8 Since enzymes are expensive, it would be desirable to recycle them in many runs of a reaction. The technique of immobilizing enzymes makes this practical.

Various techniques for immobilization of enzymes are well documented in recent reviews. 9 However, it is worth mentioning the elegant work done by Whitesides. 10 A new general chemical immobilization procedure was used based upon the peptide coupling agents, N-hydroxysuccinimidoyl esters (Scheme I); the choice of reagents allows greater control of the chemical and physical properties of the immobilized enzymes, which were protected from inactivation during the immobilization by the addition of substrate and/or coenzyme to the reaction mixture. This method has been successfully employed to immobilize several synthetically useful enzymes.

Scheme I NH S o o =^ ^0 N Azobisisobutyroni.tr ile O^N^O ^ 1. NH 2 CH 2 CH 2 NHCH 2 I H 2 NCH 2 CH 2 — NHCH 2 2.

Enz-NH 2 Requirement for Coenzyme and Coenzyme Recycling. The requirement of coenzymes in many biosynthetic reactions places important restrictions on the use of these reactions for preparative scale syntheses.

Although certain coenzymes act as true catalysts (that is, they are regenerated unchanged at the conclusion of reactions in which they are involved), others are involved as stoichiometric reagents. All of these coenzymes are expen- sive; estimated costs in $ per mole are ATP, 2,500; NAD +, 2,500; NADH, 18,000; NADP+, 60,000; NADPH, 250,000. This has been recognized for many years and some progress has been made by using only catalytic quantities of the appropriate coenzyme in conjunction with a system capable of con- tinuously regenerating it in its active form. 1 Recently, more refined methods of coenzyme recycling have been reported. Redox reactions catalyzed by alcohol dehydrogenases consume nicotinamide coenzyme in stoichiometric amounts (Eq. -78- C=0 + NAD(P)H + CH(OH) + NAD(P) (1) Jones and co-workers 12 employed H- transfer reactions between 1,4-dihydro- pyridines and NAD +, and pyridinium salts and NADH (Eq.

2) for an efficient nicotinamide coenzyme regeneration during enzyme catalyzed carbonyl-reduc- tion and hydroxyl-oxidation reactions. II II •N I R + NAD + Y s Is is usually difficult to oxidize electron-deficient heterocyclic compounds, but enzymes have developed useful reactivities. Xanthine oxidase catalyzed the oxidation of many heterocyclic compounds not closely related to xanthine, its natural substrate, and it has been described as omnivorous. Purines and pteridines are oxidized to the corresponding hydroxy compounds normally at the electron-deficient positions. 35 Similarly, N-methylnicotin- amide can be oxidized to the 6-oxo derivative.

36 Recently, xanthine oxidase has been used for the preparation of lin- benzoxanthosine ( 10 ) and 7-(p-X- phenyl)pteridine diones ( 11 ) (next page). 38 Xanthine oxidase has also been shown to oxidize crotonaldehyde in a variety of organic solvents at rates qq less than a tenth of the rate in homogeneous aqueous solutions. 03 -82- H R= (3-D-ribofuranose 10 X=H, 0CH 3, Br, NOj, CN 11 Neidleman 40 has reported some unusual halogenations catalyzed by the enzyme chloroperoxidase. Electron rich molecules are halogenated by the enzyme in the presence of hydrogen peroxide and an alkali metal halide.

The electrophilic halogenating agent generated by the enzyme attacks the most electron rich positions by substitutions, as in thiazole 1_2 or by addition, as in the steroid 13. II N-x, (a) II N ~- CH3-C-NH— CH3-C-NH— 13 (a): Chloroperoxidase, KBr, H 2 2 Enzymes Catalyzing Hydrolysis Reactions. Hydrolytic enzymes in their usual function have three possible applications in syntheses. First, they can provide extremely mild methods of removing protecting groups, such as amides and esters. For example, the esterase from orange peel selectively hydrolyzes acetate esters from a range of substrates including the sensitive 0-lactam antibiotics (Scheme VII).

1 * 1 Scheme VII II RCNH P^ Orange peel » CH 2 0C0Me esterase COOH CH 2 0H COOH A second contribution of hydrolases is selective protection when enzymes are used for deprotection. Selective ester hydrolysis by chymotrypsin and its use in nucleotide synthesis has been demonstrated. 2 The third application of hydrolytic enzymes is their use in resolution and in determination of absolute configurations.

3 -83- Phosphorylating Enzymes. Large scale enzymatic phosphorylation of glucose, creatine and glycerol has been reported by Whitesides. ^ The general utility of his method is exemplified by the fact that recoverable, chemically immobilized enzymes were used in each case with coenzyme recycling. Other Enzymes. There are a few other enzymes which have been employed in certain instances of syntheses. Perhaps the most outstanding is Khorana's synthesis of a gene. 115 He used chemically synthesized poly- nucleotides as substrates and joined them together, using polynucleotide kinase and ligase, to give a complete gene.

Rose 1 * 6 took advantage of the indiscriminate nature of aldolase to prepare a number of hexose epoxides from dihydroxyacetones and a variety of aldehydes. Most published work pertaining to hydrogenation and dehydrogenation of carbon-carbon bonds refers to steroids.

1 * Battersby 48 used the enzyme 6-aminolaevulinate dehydratase to prepare 3 C-labeled samples of phorphobilinogen ( 14 ) in high yield. C0 2 H.co 2 h C0 2 H 6-aminolaevulinate ^ dehydratase This highly reactive pyrrole is notoriously difficult to synthesize chemically and the expense involved in 13 C-labeling made an alternative route essential. In all of the above examples one enzyme is used to catalyze a single chemical step. This contrasts with the biological situation where usually a group of several enzymes catalyze multiple transformations.

This feature of enzymic catalysis has thus far only been exploited to a very limited extent in synthetic chemistry. A successful project of this type, recently reported, is the d_e novo synthesis of the decapeptide antibiotic gramici- din S from its constituent amino acids using reactors containing several immobilized enzymes.

From the above examples, it is clear that the use of enzymes in organic syntheses is still a developing science. Experimental procedures for enzyme isolation, stabilization, and immobilization are sufficiently advanced that it is now practical for organic chemists to consider catalysis by cell-free enzymes as an integral, if relatively unexploited, technique in intermediate and large scale syntheses. Having higher selectivity than chemical means and being more amenable to control and modification than fermentation, enzymic synthesis holds promise in a number of areas of fine chemical synthesis, particularly in areas relevant to biologically active compounds. T08T9 stoujxtI 'BUBqjfl Xa^sjuiaqo jo imauiriJBdaQ saouaxos x BD T mat lO 1° '[ooipg SJOUTXII JO ^TSjaATUQ I aaisaraas '08-6/16T siovHisav Hvwiwas diwoho -84- BIBLIOGRAPHY 1. Anon., Annalen der pharmacie, 2j^, 100 (1939).

Rosazza, 'Applications of Biochemical Systems in Organic Chemistry', J. Perlman, eds., Wiley, New York, N.Y., 1976, pp. Fonken and R. Johnson, 'Chemical Oxidations with Microorganisms', Marcel Dekker, New York, 1972. For a general description of enzymic reactions see M.

Webb, 'The Enzymes', 2nd ed., Longmans, London, 1964; 'Methods in Enzymology', Academic Press, London and New York, Vols. 1-28; 'The Enzymes', P. Boyer, ed., Academic Press, London and New York, Vols. 1-8, 1967-74.

For a list of enzymes and commercial sources see, 'Applications of Biochemical Systems in Organic Chemistry', J. Perlman, eds., Wiley, New York, NY, 1976, part 1, pp. Battersby, J. Staunton, and H. Wiltshire, J.

Soc, Perkin I, 1156 (1975). Chem., 5_7, 2245 (1979).

Ramakrishnan, J. Soc, 27, 260 (1950); G. Ramakrishnan, ibid., 28, 271, 333, 471 (1951). Martinex, and L. Berezin, Biotech. Bioeng., 9_, 1351 (1977).

Mosbach, 'Applications of Biochemical Systems in Organic Chemistry', J. Perlman, eds., Wiley, New York, N.Y., 1976, part II, pp. Suckling, Chem. Rev., 6, 215 (1977). Adalskinsson, and G. Whitesides, J. Soc, 100, 302 (1978).

Beck, 'Applications of Biochemical Systems in Organic Chemistry', J. Perlman, eds., Wiley, New York, N.Y., 1976, part I, pp. Taylor and J.

Soc, 98^, 5689 (1976); J. Chem., 54, 2974 (1976). Chem., 54, 2969 (1976). Van Osselar, G. Lepoivre, and F.

Alderweiveldt, J. Soc, Perkin II, 1181 (1978). Whitesides, e_t al., 'Enzyme Engineering', K. Wingard, ed., Plenum Press, New York, N.Y., Vol. II, 1974, pp.

Baughn, and G. Whitesides, J. Soc, 99, 2366 (1977).

Haynie, and G. Whitesides, J. Chem., 44, 864 (1979) and references cited therein. Rios-Mercadillo, and G. Whitesides, J.

Soc, 101, 5829 (1979). Suckling and K.

Suckling, Chem. Rev., ^» 3 87 (1974); (b) 'Applications of Biochemical Systems in Organic Chemistry', J. Perlman, eds., Wiley, New York, N.Y., Vol. I and II, 1976. Stuart, Heterocycles, 5_, 701 (1976). Battersby and J. Staunton, Tetrahedron, 30, 1707 (1974).

Krishnamoorthy, J. Soc, 94, 7159 (1972). Bentley, 'Molecular Asymmetry in Biology', Academic Press, New York, 1970, Vol. Battersby, J. Staunton, and H. Wiltshire, J.

Soc, Perkin I, 1162 (1975). Soc, 99_, 556 (1976); J. Chem., 57, 1025 (1979). Goodbrand and J. Commun., 469 (1977). Soc, 99, 1025 (1977); J. Goodbrand, Can.

Chem.,,55, 2685 (1977). Soc, 98, 8476 (1976). Davies and J. Soc, 101, 5405 (1979). Hulthy, and J. Retey, Nature, 221, 1213 (1969). Holmes-Siedle, and B.

Stark, 'Peroxidase', Butterworths, London, 1964; 'Oxidative Coupling of Phenols', W. Taylor and A. Battersby, eds., Marcel Dekker, Inc., New York, N.Y., 1967; Reference 21. Aoyagi, and M. Matsuo, Tetrahedron Lett., 2363 (1969) 34. Holland and B.

Saunders, Tetrahedron, 2]_, 2851 (1971). Horecker and L.

Heppel, Methods Enzmol., 2, 483 (1955); D. Valerino and J. McCormack, Biochim. Acta., 184, 154 (1969). Greenlee and P. Chem., 239, 1090 (1964). Keyser and N.

Chem., 44, 2989 (1979). Van der Plas and F. Miiller, Rec Trav. (paysbas), 98^, 224 (1979). Dastoli and S. Biophy., 118, 163 (1967).

Neidleman, A. Cohen, and L. Dean, Biotech. Bioeng., 11, 1227 (1969) and references cited therein. Abraham, and G. Newton, Biochem.

J., 81, 591 (1961). Taunton Rigby, J. Chem., J38, 977 (1973). Reference 20(b), pp.

133-191 and 403-478. Reference 17; Y.

Whitesides, J. Chem., 42, 4165 (1977); 0. Aldalsteinsson and G. Whitesides, J. Soc, 100, 304 (1978); V.

Rios-Mercadillo and G. Whitesides, J. Soc, 101, 5829 (1979). Caruthers, N. Rajbhandary, J. Van de Sande, H.

Weber, and T. Yamada, Nature, 227, 27 (1970). O'Connell, and K. Chem., 248, 2214 (1973).

Reference 20(a). Battersby, E. Commun., 442 (1973).

Montgomery, C. Sanford, and I.

Soc, 168th ACS National Meeting, Micr. -86- REGIOSELECTIVITY IN THE REACTIONS OF HETERO-SUBSTITUTED ALLYLIC CARBANIONS Reported by Dale Kempf December 3, 1979 Tbe question of regioselectivity in the reactions of electrophiles with 1-substituted allylic carbanions (Eq. 1) to form a and y products is M+ E — i* 4- E + >a-attack y-attack (1) of both theoretical and synthetic interest.

The ratio of a- to y-attack is profoundly dependent on a variety of factors, including substituent atom, metal ion, solvation, type of electrophile, and steric effects. The intent of this review is to compile experimental data and discuss various explanations for the observed regioselectivity.

The discussion will deal primarily with allyl carbanions bearing a single heteroatom substituent at the 1-position. 1 Those to be included are carbanions in which X=SR, S', OR, NR 2, CI, Br, SiR 3, SeR and BR 2; and M=Li, Mg, Cu, Zn, and Cd. Although the reactions of allylic carbanions having two or more such substituents are not covered, the factors affecting regio- selectivity in these anions are probably similar.

The generation of 1-heterosubstituted allylic anions is normally accomplished by removal of the a-proton of a 3-substituted propene with n-butyl or sec- butyllithium, often in conjunction with tetramethylethylenediamine (TMEDA) or hexamethylphosphoric triamide (HMPA). Lithium dialkylamides have also been employed. C Kow and Rathke have reported the y-deprotonation of vinyldialkylboranes to generate the allylic species. Finally, chloro-substituted allylic anions are most efficiently prepared by transmetalation of 3-chloroallyltriphenyllead with n-butyllithium. 9 » 10 The preparative metalations have normally been performed in tetrahydrofuran (THF) at -65°C or lower owing to the high reactivity of both the alkyllithium base and the resulting allylic carbanion. These conditions, with lithium as the metal, are the basis on which comparison of factors governing regioselectivity in electrophilic attack are to be made. Mechanisms of Electrophilic Attack.

The initial problem in describing the mechanism of attack on substituted allyl anions is that the structures of the organometallic species are not well described. Ab initio calcula- tions on allyllithium 1 1 have indicated that the cation is symmetrically placed above the planar anion. Substituents undoubtedly perturb this geometry, and, as with alkyl-substituted allyl organometallics, 12 there is presumably a rapid equilibrium between a- and y-substituted structures (Eq. Mixtures of a and y have been postulated to result from a M ^ M -87- variety of competitive pathways: (1) Direct attack (either Sg2 or Sjr2 ' ) on the two isomers of Eq. 2 could lead to mixtures, depending on the relative rates of reaction with electrophiles.

12 (2) Alkylation of cisoid (1_) and transoid (2) allylphenylether anions, which are not in rapid equilibrium, M - - - OPh has been postulated by Schlosser and co-workers 13 to produce y and a prod- ucts, respectively. (3) Competing Sg2 and Se2' mechanisms with a common organometallic species (Eq. 3) has also been suggested to account for mix- tures of products. 12 ' 1 ^ (4) Addition to carbonyl compounds, which often (3) S E 2 ' X, shows selectivity opposite that of alkylation, has been rationalized by formation of an 'ate' complex followed by cycloaddition through a six- membered transition state (Eq. 12 ' 11+ Evidence against this mechanism in alkyl-substituted allyl anions has been presented, however.' Lt+ ° M ■^ ' >^ I (4) (5) Another proposed competing reaction involves one-electron transfer to give a caged radical pair which then collapses to yield one of the observed products.

Lt+a >10c (6) Finally, with activated halides, halogen-metal exchange could occur to form an allyl halide and new organometallic reagent, and coupling could then occur. A further mechanistic consideration is the question of kinetic vs. Thermodynamic control. Renger and Seebach 2 have reported that addition of carbanions from allyl nitrosamines to ketones is reversible and that regio- selectivity can be explained in this way.

The same phenomenon has been observed in the reaction of alkyl-substituted allyl organometallics with with ketones 15 and in the electrophilic capture of 1,1-dichloroallyllithium with several inorganic reagents. 1 ' 3 Reversible alkylation has never been observed, however, and addition to ketones has been found to be irrevers- ible in several allylic systems. 10 ^ 5 ' 16 It is doubtful, therefore, that the regiochemistry of most hetero-substituted allyl carbanions can be explained in this manner.

-88- Unfortunately, most studies in this area have dealt simply with product ratios, and few attempts to characterize the allyl organometallic species have been made. Systematic comparisons of product ratios, however, can provide useful information and possibly reveal reactivity trends. In accordance with the proposed mechanisms, different substituents, metal ions, solvents and electrophiles will profoundly affect these a:y product ratios. Effects of Substituents on the Regioselectivity. The 1-substituted allylic carbanions for which the most information is available are those derived from allyl sulfides (X=SR). 18 Various substituents on sulfur have been employed, including phenyl 19 and vinyl 20 as well as saturated alkyl groups.

Anions 3 21 and 4^ 22 resulting from metalation of the cor- PhS _3: R = H 4: R=CH 3 responding dihydrothiopyrans, have al metalated sulfides with primary alkyl 2:1 and 10:1 mixtures of a and y prod definite preference for a-attack. 19 ' 2 ketones, however, shows high y -select hindered carbanion 5_. Seebach and reversing the preference for ot-alkyla mercaptan yields a dianion (Eq. 5) wh so been prepared. Reaction of the halides generally leads to between ucts, respectively, indicating a Reaction with aldehydes and ivity 19-22 except in the sterically co-workers 2 have succeeded in tion. Double deprotonation of allyl ich can be trapped initially at SH E n-BuLi TMEDA THF >-i2- 1.

RX >+ SR ' B= (5) SR carbon and subsequently alkylated at sulfur. With the dianion, the opposite regiochemistry of alkylation and condensation with carbonyl com- pounds is eliminated, and both alkyl halides and carbonyl electrophiles show a preference for y-attack, with a:y ratios between 1:2 and 1:5.

Several examples of carbanions from allyl ethers have appeared. Evans and co-workers 25 have reported 54-89% y-selectivity in the reaction of 6^ with 1-iodohexane. Still and McDonald 26 improved the y-preference Li+ Et 3 Si Et 3 SiO OLi 6: R=t-Bu, Ph, Et, OTHP for primary alkyl halides to 78% by use of triethyl- (7) and dimethyl-n- butylsilyl ethers. With cyclohexanone, a-selectivity is normally encoun- ■89- tered. Or gano lithium 1_ yields 71% of the a-product while the trimethyl- silyl ether exhibits 95% a-selectivity, 26 Reaction of b_ with cyclo- hexanone shows a-preference with R= t-Bu, Ph, but y-preference with R = Me, Et.

It appears, however, that in most cases, alkoxyallyl carbanions undergo preferable y-attack on alkyl halides and addition of the a-carbon to carbonyl compounds, behavior opposite that of allyl sulfide anions. Interestingly, the organolithium 8^ is in equilibrium with 7^ 26a, 2 7 an( j ^ as been trapped with highly reactive electrophiles.

A similar rearrangement is found 8 with anions from allyl phosphates and phosphordiamides, the products of which can be further deprotonated to dianionic species. N-Substituted allylic carbanions have been generated from a variety of compounds. The anions 9-11, derived from N-allyl-N-methylaniline, 17 >2g N-allylpyrrolidine 30 and N-allylcarbazole, 31 respectively, react with primary halides and chlorotrimethylsilane with >93% y-selectivity. As with Li + or K + 10 S- and O-substituted anions, addition to aldehydes and ketones is radically different, and both 9_ and 10 exhibit only a slight a-selectivity (50-60%) with these electrophiles. 2 ^*' 30 In addition to amines, N-substituted allyl carbanions have been formed from N-allyl-N-me thy 1-bis (dime thylamino)phos- phoramide, 32 N-allyl amide anions, 3 allylnitrosamines 2 and an allyl urea, giving 12-L5, respectively. Both 12 and 1_3 alkylate exclusively at the Li' (Me 2 N) 2 PN' I Me 12 Li 13 NO 14 11 y-position. The nitrosamine anion, however, undergoes regiospecific alkylation at the a-carbon.

2 The lithio carbanion 15 has not been alkylated, There have been few cases of allylic carbanions substituted by halogen. Recently, Wenkert and co-workers 4 have reported a dimerization of allyl chloride and allyl bromide, with the allylic anion as a probable inter- mediate (Eq. Allyl bromide yields only the a-product while allyl chloride gives an 8:1 a:y ratio, both in low yield. Mauze has generated the 1-chloro-l-methylallyl anion by lithium-lead exchange, which is stable at -90° and can be trapped exclusively at the a-position with unhindered -90- 0.5 eq. LiN[CH(CH 3 ) 2 ] 2 >^ ^ ^ + ^^- ^CHC1 (6) ■78' X ketones and aldehydes. A-Attack on both alkyl halides and carbonyl com- pounds is in marked contrast to the previous £[-, N-, or O-substituted carbanions, although only a limited amount of data on haloallyl anions is available.

Seyferth and co-workers 10,c have shown that addition of 1,1-dichloroallyllithium to carbonyl compounds can be selectively a or y, depending on the electrophile. Anions derived from allylsilanes were first reported by Corriu and co-workers. 33 Again, as with halo-substituted anions, selectivity for both ketones and alkyl halides appears to be similar, although the data are limited in this case as well. Benzophenone, chlorotrimethylsilane, and methyl iodide react at the y-position of anion _16_, 33a >b anc j 17 condenses with other ketones and aldehydes exclusively at the y-position. ** Li_+ PhaSr^^'^ 16 17 The y-silation of 18 has recently been employed by Corriu as a key step in the preparation of asymmetric disilacyclopentanes. Reich 5 has generated allyl organometallics stabilized by the phenyl- seleno group. Alkylation of _19 produces ca.

80% of the a-product, while a 15:85 a:y ratio is obtained with acetophenone. From the limited data (Sia) 2 B^ ^ ^R 20: R = alkyl available, the behavior of phenylseleno allyl carbanions appears to parallel that of allylthio anions. 5 Kow and Rathke 6 have reported that boron-stabilized anions ( 20 ) react with water and methyl iodide predomi- nantly at the a-carbon, but reaction with chlorotrimethylsilane and acetone occurs mainly at the y-position.

Steric factors are cited as an explanation for this difference; consequently, little is known regarding the effect of dialkylboron substitution on the regioselectivity. Most explanations of substituent effects upon regioselectivity involve donor or acceptor abilities of the substituent group. Still and McDonald 26 have suggested that alkylation and protonation occur at the site of higher electron density and that carbonyl compounds react by a cyclic mechanism. Donor groups (OR, NR 2, alkyl) create a greater charge density at the y- carbon while acceptor groups (SR, BR 2 ) create a greater charge density at the a-carbon. 26 ' To test this proposal further, this reviewer has performed MIND0/3 calculations on several model 1-substituted allyl anions. -91- Tables 1 and 2 list the calculated charge densities and the coefficients of the highest occupied molecular orbital for the carbon and substituent atoms of each of these models. A greater charge density is found at the y-carbon in each case.

Or- Alkylation of allyl sulfide anions is consistent, however, with the larger HOMO coefficient at the or-carbon. When X = OR or Table 1. Calculated Charge Densities for 1-Substltuted Allyl Anions Substituent Charge X = y-Carbon B-Carbon or-Carbon Substituent X X = SCH 3 non- -planar.4381 +.1972.2352.2673 X = 0CH 3.5155 +.1890.1768.3821 X=NH 2.4936 +.2251.3656.1261 X= S'.6243 +.1201.0798 -1.0373 X= CI.4858 +.1920.2026.3594 X= SiH 3.4416 +.2338.4167 +.1804 Table 2. Calculated HOMO Coefficients for 1-Substituted Allyl Anions Substituent Coe f ficient X = Y-Carbon 8-Carbon or-Carbon Substituent X X= SCH 3 non- -planar.65055.00359 +.68898.01248 X = 0CH 3.68927 +.07208 +.68226.22442 x = m 2.68907 +.02127 +.70132.01732 X*= S' +.66181.22080.61176 +.37284 X = C1 +.68320.03014.70199 +.19884 X=SiH 3 +.66642 +.03836.69729.10030 or NR 2, the a and y-coef f icients are very nearly the same, providing no basis for selectivity. The greater charge density at the y-carbon, there- fore, appears to be the important factor in the transition state and y- alkylation is observed. When X=C1, ar-alkylation is predicted because of the greater HOMO coefficient at that carbon, while the thioallyl dianion (X=S~) would be expected to alkylate mainly at the y-carbon on the basis of both the HOMO coefficients and the charge densities.

Both of these predictions correspond to the observed behavior. With allylsilyl anions, however, the predictions break down and y-alkylation is observed, possibly owing to overriding steric effects. The coefficients of the HOMO may explain the observation by Ahlbrecht 17 that increasing the donor ability of the dialkylamino group of aminoallyl anions unexpectedly decreased the preference for y-attack, although no quantitative data are available. Additions to carbonyl compounds appear to depend more on the position of the metal than on orbital coefficients, and a cyclic mechanism appears to be reasonable in cases where the selectivity is opposite to that observed in alkylation. Seebach and co-workers have postulated 2 ^ a structure such as 211^ for dilithiated allylmercaptan to explain the absence of trans products.

In 21, the cyclic mechanism would not be expected, and addition to carbonyl compounds would be predicted by both charge density and HOMO coefficients to parallel alkylation at the y-position, which is the observed preference. Li.Li 21 -92- Effects of Metals on Regioselectivlty. Metals other than lithium often alter the regioselectivity of hetero-substituted allyl carbanions. Seebach and co-workers 36 have found that addition of MgBr 2 to the allyl- mercaptan dianion reverses the selectivity of reaction with cyclopentanone from 65% y to 95% a. Addition of MgBr 2 to the anion of an allylmethyl- piperidinyl urea ( 15 ) resulted in almost exclusive y-attack with both alkyl halides and carbonyl compounds. 7 In contrast, Corriu and co-workers, 33b found similar regioselectivity with the lithium and Grignard reagents of allyl silanes.

Recently, the lithio derivative of an allylsilane in con- junction with MgBr 2 has been observed to react with different selectivity than the corresponding Grignard reagent. 37 This phenomenon raises ques- tions about the role of the metals in the reaction and has not yet been sufficiently studied. The addition of Cul to anion 22, followed by alkylation with allylic halides has been reported by Yamamoto and co-workers 38 to exhibit specific Y-attack on the nucleophile and Sft[2?

Attack on the halide. Reaction with acetone yields predominantly the or-product; therefore, selectivity opposite to that of the lithio / reagent is observed.

Upon low-temperature / reaction of 22^ with benzyl bromide, a moder- ate yield of bibenzyl was obtained, a possible 22 indication of a radical mechanism. 38 a-Selectivity of >95% has been observed in reactions of ketones with zinc derivatives of allyl ethers 25 ' 39 and allyl amines 30 and the cadmium derivatives of allyl sulfides. 40 Both metals promote selective y-condensa- tion of allylsilyl anions with acetophenone, 3 and zinc has been found to give greater selectivity than cadmium in allyl ether carbanions.

1 Only with sulfides is the regioselectivity reversed; in the other examples, zinc and cadmium simply enhance the selectivity observed with the lithio derivatives. Effects of Solvation. The regioselectivity is also dependent upon the solvating ability of the solvent and/or additives. Tetrahydrofuran has been found to enhance the a- and y-selectivity of allyl sulfides 13 and amines, 17 respectively, in comparison to hydrocarbon solvents. 1,4-Diazabicyclo [2,2,2] octane (DABCO) and TMEDA enhance the y-selectivity in the reaction of acetone with the anion from an allyl sulfide, 16 although TMEDA has also been reported to reduce the y-selectivity with heptanal. 19C In both cases, the effects were small.

HMPA, a better solvating agent, is also quite unpredict- able, and both increased and decreased selectivities have been observed. 16 * 24b, 26b Presumably, highly solvating agents cause dissociation of the ion pairs to solvent-separated ion pairs or free ions. The Se2' and cyclic mecha- nisms should not be favored, and the regioselectivity should be governed by charge densities and orbital interactions. Biellmann and co-workers 16 found that a phenylthio-substituted carbanion in the presence of a highly solvating diamino polyether reacted with acetone at the a-position and with alkyl halides randomly at both a- and y-positions. This behavior is consistent with solvent-separated or free ions. Ahlbrecht 17 has examined the UV spectra of alkali allyldialkylamines in media of various solvating abilities and detected three different anionic species.

Effect of the Electrophile on Regioselectivity. The effect of different carbonyl compounds on the regiochemistry in reactions of 1,1- dichloroallyllithium has been studied by Seyferth and co-workers. 10b >c -93- Generally, ketones and aldehydes with electron-donating substituents afforded a-products, and those with electron-withdrawing groups, y-products. This behavior was explained by characterizing the a- and y-carbons as the soft and hard centers of the ambident nucleophile, respectively.

However, MINDO/3 calculations on the dichloroallyl anion 35 indicate a greater charge density at the a-carbon, making it the harder center. ^ 2 The results can still be rationalized, however, by competing cyclic and Sg2-like mechanisms. Hard-soft effects have been observed in alkylations of allyl sulfide carbanions. Torii and co-workers 1 have found that the anion (3) derived from A 3 -dihydrothiopyran gives a:y ratios of 53:1, 11:1 and 2.4:1 upon reaction with n-butyl chloride, bromide and iodide, respectively. Similar behavior in 1, 1-disubstituted allylic anions has been rationalized in terms of hard-soft interactions. 143 Controlling the Regiochemistry. Synthetic chemists, in efforts to achieve higher regioselectivity, have developed several methods of control in which the normal factors affecting the regiochemistry appear to be outweighed.

Evans and Andrews 10 and Mukaiyama have reported greater or- selectivity with anions from heteroaromatic-substituted allyl sulfides and ethers than normally observed. Intramolecular chelation of the lithium to the heteroaromatic ring (Eq. 7) is presumed to be responsible for this effect, Anions from allylthio- a and dithiocarbamates, 8 b,c and dithiocarbonate tosylhydrazones 80 exhibit the same high a-selectivity with both alkyl halides and carbonyl compounds. The kinetically favored a-alkylation of allylnitrosamine anions 2 could also be a result of intramolecular complexa- tion. A Li:B ->->a (7) Li A second method controlling the regiochemistry, recently reported by Yamamoto and co-workers, 145 involves prior formation of a y 'ate' complex by reaction of an allylthio carbanion with a trialkyl borane.

Subsequent reaction with electrophiles followed by oxidation affords a-products almost exclusively. Still 146 has reported the intramolecular alkylation of an allyl ether carbanion to form a vinyl oxetane (Eq.

Only a-attack is observed because of the geometric requirements for nucleophilic attack, in spite of the formation of the more highly strained product. S-BuLi TMEDA >',- Li+ ->H: H OH (8) As illustrated in this review, the factors influencing the regio- selectivity in the reactions of hetero-substituted allylic carbanions are quite varied and complex. Generalizations can be made in most cases, however, and the application of molecular orbital theory will hopefully bring more order and predictability to the matter. •94- BIBLIOGRAPHY 1. For reviews which include allyl organometallics, see (a) S. Martin, Synthesis, 633 (1979); (b) G. Courtois and L.

Organometal, Chem., j69, 1 (1974); (c) D. Andrews, Accts. Res., 7_, 147 (1974); (d) H. House, 'Modern Synthetic Reactions', 2nd ed., W. Benjamin, Menlo Park, Calif., 1972, Chapter 9. Renger and D.

Seebach, Chem. Ber., 110, 2334 (1977). Tischler and M. Tischler, Tetrahedron Lett., 3407 (1978). Dynak, and C. Swindell, Synth.

Commun.,% 11 (1979). Chem., 40, 2570 (1975). Soc, 95, 2715 (1973).

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Ari-Izumi, Tetrahedron Lett., 2425 (1977); (b) T. Shiono, and M. Okawara, ibid., 3625 (1974); (c) T. Hayashi, ibid., 339 (1974); (d) T. Mikami, Chem, Lett., 469 (1979). Chem., 170, 265 (1979).

Murphy, and R. Woodruff, (a) J. Chem., 141, 71 (1977); (b) J. Soc, 96, 5011 (1974); (c) D. Murphy, and B.

Soc, 99, 5317 (1977). Binkley, and J. Chem., 150, 1 (1978). Chem., 91, 123 (1975), and references cited therein. Muthukrishnan, and M. Schlosser, Helv. Acta, 57, 2261 (1974).

Rautenstrauch, Helv. Acta, 57, 496 (1974); (b) G. Courtois and L. Chem., S9_, 1 (1974). Siklosi, and E. Soc, 100, 2134 (1978), and references cited therein.

Biellmann, S. Vicens, Tetrahedron Lett., 2665 (1974). Ahlbrecht, Chimia, 391 (1977). For a review of a-thiocarbanions, see B. Grobel and D.

Seebach, Synthesis, 357 (1977). Biellmann and J.

Ducep, Tetrahedron Lett., 5629 (1968); and Tetrahedron, 2]_ y 5861 (1971); (b) K. Matsui, Tetrahedron, 30, 715 (1974); (c) J. Biellmann and D.

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Tomotaki, Chem. Lett., 1541 (1974). Stotter and R.

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Tetrahedron Lett., 2115 (1976). -96- MODERN METHODS FOR THE DEOXYGENATION OF ALCOHOLS Reported by William Stevenson * December 6, 1979 The alcohol functionality is one of the most important and ubiquitous in organic chemistry, occurring throughout the range of aliphatics, aromatics, and an enormous number of natural products. In many areas of synthetic chemistry deoxygenation reactions become necessary to effect the formal conversion R-OH — >R-H without altering other functionalities present in the molecule.

Understandably the development of efficient methods for the deoxygenation of alcohols has been the subject of much current interest in the field of organic chemistry, and considerable research in synthetic methodology has been directed towards this end. For the purposes of this review, reactions are classified by mechanistic type under one of the following headings - 1) hydride transfer, 2) hydrogenation or hydrogenolysis, 3) dissolving metal, 4) radical chain, or 5) photo- chemical. The scope of the seminar includes both aliphatic alcohols and phenols; the deoxygenation of activated cases (e.j*. Allylic, benzylic) will not be discussed in detail, although references are given for these transformations.

Furthermore, deoxygenation methods which involve initial oxidation of alcohols to ketones or aldehydes followed by carbonyl removal (e.j*. By Clemmensen or Wolf f-Kishner reductions) will not be included in this review, although such methods are often useful for primary and secondary alcohols. Throughout, emphasis will center on the more modern and most efficient methods of deoxygenation. Deoxygenation by Hydride Transfer. Metal hydrides such as lithium aluminum hydride have frequently been used for deoxygenation of alcohols after initial conversion to the corresponding sulfonate or halide. The scope of this procedure has generally been limited to primary alcohols; secondary and tertiary derivatives react poorly and give rise to large amounts of elimination products. A >3a A major disadvantage is the high reactivity of metal hydrides toward other functional groups.

4 The scope of metal hydride deoxygenations has been significantly extended by the recent development of lithium triethylborohydride (Super Hydride) 3 and copper hydrides such as LiCuHR. 5 Relatively hindered primary alcohols and many secondary alcohols may be reduced by lithium triethyl- borohydride in good yield with far fewer elimination products. A The copper hydride reagents have been less extensively studied but show indications of similar utility and are also effective in the reduction of aromatic and vinyl halides ' (Table 1). Other reducing agents of interest include borohydride 'ate' complexes which reduce tertiary and activated halides selectively 6 and lithium aluminum hydride in the presence of transition metals which has been shown effective in reducing alkyl and aromatic halides. Undesirable reduction of functionalities is a common problem in metal hydride procedures. The general order of reactivity of the most commonly used reagents is as follows - LiAlH^, >NaBH 6 alkyl halides, sulfonates, and imminium salts are the only groups reduced. A particularly good one-pot reduction of alcohols involving in situ generation of the -97- Table 1.

Metal Hydride Reductions 33 ' 5a >5c Substrate Cyclohexyltosylate Cyclohexyltosylate Cycloheptyltosylate CH 3 (CH 2 ) 3 -C(CH 3 ) 2 CH 2 -OTs Cyclohexyltosylate endo- 2-Norbornylmesylate exo- 2-Norbornylmesylate Reagent LiAlH,, LiBHEt 3 LiBHEt 3 LiBHEt 3 LiCuHBu [Cul + LiAlH(0CH 3 ) 3 ] [Cul + LiAlH(OCH 3 ) 3 ] Products% Yield 3 Cyclohexane 54 Cyclohexene 25 Cyclohexanol 19 Cyclohexane 80 Cyclohexene 20 Cycloheptane 100 CH 3 (CH 2 ) 3 C(CH 3 ) 3 81 Cyclohexane 80 Norbornane 99 Norbornane 75 Determined by gas chromatography iodide is described by Hutchins et al. 7b This reaction is most useful for relatively unhindered primary alcohols, 4-methyl,4-hydroxymethylcyclo- hexene being reduced in only 58% yield. Alcohols which form relatively stable carbonium ions may be deoxyge- nated directly in acidic media by hydride transfer reagents. 8 Examples of such systems include NaBHi,/CF 3 C00H, R 3 Si-H/BF 3, and (Ph 3 P) aPtRiRa/Ha/CFaCOOH, Yields are often excellent for allylic and benzylic cases but are not as good for tertiary alcohols. Other methods of deoxygenation give improved yields for those allylic alcohols especially prone towards rearrangement. Hydrogenation and Hydrogeno lysis Reactions. Dehydration of alcohols followed by hydrogenation is a standard method of deoxygenation.

This method is most effective with tertiary alcohols which are easily dehydrated. The necessity of an acid catalyst and the possibility of molecular rearrangement are the major disadvantages of this method.

And in this as in all deoxgenations involving hydrogenation, the presence of other functional groups capable of reduction may render the procedure undesirable. Derivatization of alcohols followed by hydrogenolysis has been developed using several procedures and has been most commonly applied to phenols 10 (Scheme I, Table 2). Conversion of phenols to mercaptans via the O-aryldialkylthiocarbamates (Eq. 1) and subsequent hydrogenolysis is a very general method, proceeding in fair yield even for the hindered 2, 3, 5, 6-tetramethylphenol.

10a This method is, however, limited to those molecules which can withstand the rather severe pyrolysis temperatures necessary in the rearrangement step. Hydrogenolysis of phenyltetrazolyl ethers (2) is a milder method which is compatible with ketone and aldehyde groups 10 ' 3 (Eq. The conversion is generally more successful with relatively unhindered alcohols and allows selective deoxygenation in some cases.

10c Deoxygena- tion via the isourea derivatives 3 has been demonstrated for aliphatic -98- Scheme I. Deoxygenation by Hydrogenolysis (CH 3 ) 2 NCSC1 ^, s (130-300°)^ Ar-OH —: ^-=—;>Ar-0CSN(CH 3 ) 2 — — — ' >NaH, DMF A Ar-SC0N(CH 3 ) 2 ° H >Ar-SH ^^ >Ar-H // N K 2 C0 3 ^ // N Ar-OH + Cl-^ — - >Ar-O-/ / / Ph Ph Ar-H + 0=^ j Ph H 2 /Pd ->(1) (2) ^ N_R? H /VA R-OH + R'-NCN-R' >R-O-C — 2/ >R-H ^NHR' (3) Ar-0-S0 3 CH 3 H * /Pd ^ Ar-H:B (4) Ar-OH + PhNR 2 »S0 3 ■>Ar-0S0 3 HNR 2 Ph KOH >+ Ar-0S0 3 ~K RaNi/KOH or RaNiH 2 /H 2 >Ar-H (5) alcohols 10 ^ and phenols 10e »h (Eq. Yields are generally good to excellent; however, the reaction is sensitive to steric hindrance, and rearrangement occurs in some cases (i.e. Hydrogenolysis of sulfonate esters 4_ is also effective for many phenols but requires conditions which reduce aldehydes 10 (Eq. Reduction of the aryl sulfate 5^ shown in Eq. 5 also proceeds in generally good yield and has the advantage of alternate cleavage conditions.

°§ -99- Table 2. Deoxygenation by Hydrogenolysis Substrate Product Equation% Yield 2-Naphthol Naphthalene 1 75 it n 2 60 ii ii 3 92 ii ti A 91 ii ii 5 55 4-Methoxyphenol Anisole 2 80 ii ii 3 69 a ii ii 5 72 2,3,4,6-Tetra- 2,3,5,6-Tetra- methylphenol methylbenzene Yield determined by gas chromatography; all other values are for pure isolated product Dissolving Metal Reactions. The most generally useful reaction of this class are those which involve cleavage of a phosphate ester.

This reaction has been known since 1955, lla but its usefulness in deoxygenation was first shown by Ireland et al. 11 ' 5 using the N,N,N',N_'-tetramethylphos- phordiamidate and diethylphosphate esters (Eq. Yields are generally good for deoxygenation of alcohols, phenols, and enolates 11 (Table 3). 0H ((OM-yoCl R _JU, (CH3),), 'w., R - H (6) n-BuLi THF Recently, treatment of alcohols with N,N-dimethylphosphoramidic dichloride followed by addition of dimethylamine has been found to be a particularly good way to derivatize hindered alcohols. 11 Several other alcohol derivatives have been cleaved by dissolving metals to effect deoxygenation; use of N,N-dimethylsulfamoyl derivatives has been found particularly valuable for secondary positions at which Sjq2 processes are hindered.

12 Cleavage of carboxyl esters gives selective deoxygenation of tertiary and hindered secondary esters. 13 Zinc reduction of primary and secondary tosylates or mesylates (via in situ formation of the iodide) has been reported to give excellent yields of the hydrocarbons, 4 and the reduction of thioesters 15 and 2,4-diaminophenylethers 16 has been used on occasion. Allylic and benzylic alcohols may often be directly deoxygenated in high yield by dissolving metals. 17 A common limitation of dissolving metal reactions is the relatively harsh conditions necessary for ester cleavage. Functionalities not compatible with the reaction conditions include aryl aldehydes, aryl esters and aryl chlorides. However, isolated esters, enolizable ketones, ethers, and isolated alkenes are usually compatible.

Reduction of aromatics may also occur if the molecule has a high affinity for electrons (e.g. Nitro- -100- Table 3. Dissolving Metal Reductions 1 lc >d >12 >l 3 1-Napthol 2, 6-Dime thy lphenol 2-Allyl-4-me thy lphenol 3- Ace ty lphenol RO:h 3 NHC0 2 CH 3 33, 4, 4-Trimethyl-5a- cholestan-3a-ol Derivative Cleavage Cond.% Yield -PO-fOEt) 2 Ti/THF 74 -P0-(0Et) 2 K/NH 3 92 a -P0-(0Et) 2 Li/NH 3 77 -P0-(0Et) 2 Na/NH 3 52 -S0 2 N(CH 3 ) 2 -COR Na/NH; Na/HMPA 65 >95 Yield determined by gas chromatography; all other yields are for pure isolated deoxygenated products. Phenol, naphthalene), but this problem may be minimized by adding 'electron mops' such as sodium benzoate immediately prior to quenching 110 or by using highly activated titanium in place of a group 1A metal. Llc * It should be noted that titanium is not a true dissolving metal as reduction is thought to occur on the surface of the metal and not in solution.

Radical Chain Reactions. Barton and co-workers have developed a deoxygenation procedure which involves derivatization of alcohols to 0- alkyl thioesters followed by reduction with tributyltin hydride 18 (Eq. The reduction step is specific for secondary groups and is quite effective for the deoxygenation of hindered secondary alcohols. It is desirable + + R-OH + R, -C=N(CH 3 ) 2 >R-0-C=N(CH 3 ) 2 CI R' Jkl^ R _o-C-R' Bu3SnH >R-H II S (7) to keep the concentration of the tin hydride as low as possible in order to favor fragmentation of the radical intermediate 6^ over hydrogen abstraction (Scheme II). -101- Scheme II R' R-O-C-R' Bu3Sn * >R-O-C. II I U3 / I S-SnBu 3 SSnB R-H CH3I V H3CO 0CH; Bu 3 SnH >HO H3CO— >H3CO 0CH; H3CSOCO— ^^]_.

H,co-^7A H3CO 1) Cr +2 2) 'OH ->0CH- CH 3 H 3 C0-^->^ H3CO OCH 3 Tributyltin hydride is also an excellent dehalogenating agent, thus providing a method of deoxygenation by initial conversion of alcohols to halides.^ Allylic, benzylic, and other alcohols which form relatively stable radicals may be deoxygenated by reduction of their carboxylic 19 esters. Trialkylsilanes have also been shown to be effective deoxygenating agents of primary and secondary alcohols via the corresponding chloro- formates. 20 This procedure is compatible with carbonyl functions, 2- pentanone being obtained in 69% yield from the chloroformate CH 3 C0(CH 2 >7 0C0C1. -102- Photochemical Deoxygenations. Photochemical cleavage of esters has been reported as a general method for deoxygenation of aliphatic alcohols.

21 Yields are generally good, even for hindered secondary and tertiary alcohols, and the reaction conditions are compatible with alkene, alcohol, ether, acid, and acetal groups —ketones and halogens are reduced. Selectivity among di- and tri-esters is low, and multiple deoxygenation frequently occurs in this case. As a result of the recent advances in synthetic method- ology the organic chemist now has available a wide range of procedures for the deoxygenation of alcohols.

Perhaps the greatest advances have been made in the reduction of rather hindered secondary alcohols and of phenols, systems for which no general method has traditionally been available. Quite hindered secondary alcohols may be efficiently deoxygenated by dissolving metals, radical processes and photochemical cleavage, while some of the more modern hydride reagents (Super Hydride) are also effective in many cases.

Phenols may be most generally deoxygenated by one of the hydrogenolysis reactions, though dissolving metals are successful if the substrate does not have a great affinity for electrons. No doubt the area of alcohol deoxygenation will continue to advance both in scope of application and efficiency of reduction. BIBLIOGRAPHY 1.

Scheer and E. Soc, 7]_, 1820 (1955); (b) K.

Wiberg and J. Pfeiffer, ibid., 92., 553 (1970); (c) E. Chem., _43, 1263 (1978). Koegh, and D. Koharshi, Tetrahedron Lett., 3495 (1969); (b) H. Vanderslice, and A.

Chem., 34, 3923 (1969); (c) R. Hutchins and others, ibid., 43, 2259 (1978). Krishnamurthy and H.

Chem., 41, 3064 (1976); (b) R. Holden and M. Matturro, ibid., 42, 2166 (1977). House, 'Modern Synthetic Reactions', 2nd ed., W. Benjamin, Inc., Menlo Park, Calif., 1972. Rossy, and S. Soc, 95_, 6452 (1973); (b) T.

Yoshida and E. Commun., 762 (1974); (c) S. Bates, and P. Georghiou, J.

Soc, 96, 3686 (1974); (d) E. Ashby, Tetrahedron Lett., 3695 (1977) 6. Murahashi and I. Soc, 97, 2558 (1975).

Kandasamy, C. Maryanoff, D. Masilamani, and B. Maryanoff, J. Chem., 42, 82 (1977); (b) R. Maryanoff, and C.

Commun., 1097 (1971). Bayer, and H. Chem., 29, 121 (1964); (b) Y. Fujimoto and N. Ikekawa, Chem.

Bull., 24, 825 (1976); (c) G. Gribble and R. Leese, Synthesis, 173 (1977); (d) M. Kalinskin, Z. Shaapuni, and D. Kursanov, Doklady Chem., 219, 888 (1974); (e) M.

Addington, M. Orfanapoulos and J. Fry, Tetrahedron Lett., 2955 (1976). Chem., 34, 3667 (1969). Newman and H. Karnes, ibid., 3980 (1966); (b) W.

Musliner and J. Gates, Jr., J. Soc, 88, 4271 (1966); (c) H. Maat, Rec Trav. Pays-Bas, 95, 43 (1976); (d) E. Vowinkel and I. Buthe, -103- Chem.

Ber., 107, 1353 (1974); (e) E. Vowinkel and C. Wolff, ibid., 107, 907 (1974); (f) K.

Clauss and H. Jensen, Angew. Chem., 85, 981 (1973); (g) W. Traitler, and K. Perkin I, 169 (1975); (h) E. Vowinkel and H. Ber., 107, 1213 (1974).

Kenner and N. Soc, 522 (1955); (b) R. Muchmore, and Hengartner, J. Soc, 94, 5098 (1972); (c) R. Chem., 38, 2314 (1973); (d) S. Watters, ibid., 43, 4797 (1978); (e) S. Watters, ibid., 43, 2715 (1978); (f) H.-J.

Chem., 55_, 3797 (1977). Tsuchiya and others, Tetrahedron Lett., 3365 (1978). Johkhardar, J. McGhie, and S.

Commun., 68 (1978); (b) H. Deshayes and J. Pete, ibid., 567 (1978).

Fujimoto and T. Tatsumo, Tetrahedron Lett., 3325 (1976).

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Zabriskie, J. Chem., 29, 3124 (1964). Minnella, and S. Chem., 40, 3151 (1975). Barton and S. Perkin I, 1575 (1975); (b) D. Barton and R.

Subramanian, ibid., 1718 (1977). Lee, Tetrahedron Lett., 4351 (1968).

Billingham, R. Jackson, and F. Commun., 344 (1977). Portella, and D. Scholler, ibid., 439 (1975); (b) H.

Portella, Tetrahedron Lett., 2019 (1976); (c) P. Collins and V. Munasinghe, J. Commun., 927 (1977); (d) J. Portella, Synthesis, 774 (1977). -104- ENANTIOMERICALLY UNUSUAL BIOMOLECULES Reported by Anthony W.

Czarnik December 10, 1979 A high degree of optical asymmetry has been known to exist in com- pounds of biological origin nearly since the inception of plane-polarized light. 1 Virtually every major class of biomolecules exhibits enantiomerism to varying extents.

Sugars, amino acids, and phospholipids exist almost exclusively as one stereoisomer, while terpenoids, alkaloids, and other natural products will somewhat more frequently occur as several isomers. Interest in the enantiomerically unusual forms of these biomolecules (Figure 1) has recently become acute owing largely to their anticipated resistance to enzymatic degradation in living systems. Enantiomeric Forms of Some Common Biomolecules C0 2 H H 2 N»-C-^H CH 3 Hi C0 2 H C-*iNH 2 CH 3 L-alanine D-alanine CH 2 0H CH 2 0H HO CH 2 0H •C-*H CH 2 0© (R) -a-gly cerol phosphate CH 2 0H H •»► C -^OH CH 2 0(?) (S) -a-glycerol phosphate The reason that one of two enantiomers of a chiral compound should predominate in a biological system is by no means obvious. Many investiga- tions have been reported to test various theories concerning stereochemical evolution.

Asymmetric syntheses and decompositions using circularly polarized light are known. ' 3 The interaction of racemic 2-butanol with asymmetric inorganic crystals of quartz leads to enantioselective dehydra- tion of the chiral alcohol. In addition, a number of L-amino acids have been reported to bind preferentially to L-quartz 5 and to bentonite, a colloidal hydrated aluminum silicate. 6 The spontaneous resolution of some racemates has been observed to occur on crystallization 3, and the implications to stereochemical evolution have been discussed.

3 Efforts have also been made to correlate the now well-known asymmetry of (3-decay 7 to the induction of asymmetry in biomolecules. ' The successful enantio- -105- selective decomposition of amino acids exposed to 3-sources (e.g. - 90 Sr) has been reported; 1 >1 1 however, some controversy over the 3-decay mechanism for the origin of optical activity exists. 12 The preponderance of biologically-derived carbohydrates exist as the D-isomer, so termed because of their relationship to D-glyceraldehyde.

While the enantiomeric L- forms of D-glucose and D-ribose have never been found in nature, L-rhamnose and L-arabinose occur in plants, L_-fucose in blood, and L_-galactose in snails. In addition, several bacterial anti- biotics originating from the genus Streptomyces contain L_-sugars. 13 Recently, the synthesis of L-sucrose, the enantiomer of common table sugar, has been accomplished by Szarek and Jones from L-arabinose. The finding that L_-sucrose is sweet (unlike L-glucose 1 '^ which is salty 38 ) makes it potentially useful as a non-nutritive sweetner.

The twenty or so common amino acids found in living systems exist mainly as the L- enantiomer. The isomeric D- amino acids are found in the cell walls of gram-positive bacteria and in over 25 naturally occurring antibiotics, including penicillin. 13 An enzyme, alanine racemase, has been found in some bacteria which catalyzes the conversion of L— alanine to D-alanine. 16 The concept that these D- amino acid-containing peptides are resistant to protease hydrolysis has been the motivation behind the synthesis of enantio- and retroenantio-peptides (Figure 2).

17 The enantiomers of oxytocin, 18 bradykinin, ^ angiotensin, 20 eledoisin, 21 and MSH-pentapeptide 22 have been synthesized. All were found to be biologically inactive with respect to the parent peptide. Some Isomers of MSH-Pentapeptide Natural MSH-pentapeptide: L-His-L-Phe-L-Arg-L-Try-Gly Enantio-MSH-pentapeptide: D-His-D-Phe-D-Arg-D-Try-Gly Retroenantio-MSH-Pentapeptide: Gly-D-Try-D-Arg-D-Phe-D-His The retroenantiomer of a peptide results by both inverting each chiral center and reversing the sequence direction of a linear chain of amino acids.

In 1969, Shemyakin et al. Suggested that retroenantiomers of biologically active peptides should themselves show activity owing to their close topological similarity to the parent peptides. 23 Both retro- enantio-Gly » -gramicidin S and retroenantio-antamanid 5 have been synthesized and do show activity comparable to their natural counterparts. Ft However, the retroenantiomers of bradykinin, D MSH-pentapeptide, tuftsin, ° somatostatin analogues, g desamino-gastrin C-terminal tetrapeptide, 28 and lutenizing hormone releasing factor 30 subsequently have been reported to be inactive. The basic premise of close topological similarity has been reinvestigated, and recently Freidinger and Veber have reported that there are innate differences in sidechain topology between a retroenantiomer and its parent peptide based on computer models of cyclic peptides. 31 -106- Phospholipids are chiral biomolecules derived by enzymatic phos- phorylation of glycerol, an achiral precursor. The a-glycerol phosphate which results has the (R) -configuration as shown by ^C- incorporation experiments 32 The interactions of (R)- and (S)-diacylphospholipids with cholesterol, a common membrane constituent, have been studied by pressure- area measurements 33 and by ^-NMR 3 ^ of the resulting lipid vesicles.

This latter study indicates a stereospecific interaction between the hydrogen bond accepting carbonyl group of the lipid and the hydrogen bond donating hydroxyl group of cholesterol. In addition, initial findings by Arnett and co-workers also show clear differences between samples of (R)-and (R,j3)-diacylphospholipids by 31 P-NMR, ^-NMR, and differential scanning calorimetry.

35 Natural products such as terpenoids or alkaloids often occur as a single enantiomer; yet, it is not uncommon to observe diastereomerism or enantiomerism within a series of compounds. An interesting example is found in the Strychnos alkaloid series (Figure 3) in which the presence of both (+)- and (-)-akuammicine raised difficult biosynthetic questions: e.g., did a separate pathway exist for each enantiomer? In 1973, Scott and Yeh resolved this problem by showing that dihydro-(+)- and (-)- akuammicine could be reversibly interconverted in vitro under simple thermal conditions and proposed a mechanism which accounted for the observed inversion at the three chiral centers of interest. Enantiomers in the Strychnos alkaloid series 35 C0 2 CH 3 (-) -akuammicine 1 H y KJ v/ H H C0 2 CH 3 (+) -akuammicine BIBLIOGRAPHY 1. Alworth in 'Stereochemistry and its Application to Biochemistry', Wiley-Inter science, New York, 1972, p. Buchardt, Angew.

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