Simpkins, Nigel S.

English

CHIMIA

ILMAC 99: RETROSPECTIVE/COST CHEMISTRY SYMPOSIUM 53CHIMIA 2000 54, No. 112glycero-3-phosphocholine) and similar compounds with differ-ent alkyl chains and head groups. The corresponding liposomesconsist of a membrane with a hydrophobic core that is able tobind hydrophobic compounds, such as hydrophobic amino acidderivatives and peptides, as well as lipophilic condensing agents(Figure).We have been able to bind the barely water-soluble condensingagentEEDQ (2-ethoxy-l-ethoxycarbonyl-l ,2-dihydroquinoline)to POPC liposomes. When these liposomes were exposed to alibrary of tryptophan-containing dipeptides such as H-Asp- Trp-OH, H-Trp-Trp-OH, H-Glu-Trp-OH, H-Gly-Trp-OH, only H-Trp-Trp-OH was bound to the liposomes and therefore oligomer-ized with significant yields (i. e. out of the theoretically possible16 tetrapeptides, H-Trp-Trp-Trp-Trp-OH makes about 70% ofall tetrapeptides formed) [8]. The other peptides are too hy-drophilic and were not selected. With this type of selection,tryptophan oligomers can be formed. The products of such anoligomerization become more hydrophobic with increasing lengthand remain attached to the liposomal matrix. We have thereforetwo selection steps, one arising from the choice of the monomer,and one from the possibility of polymerizing water-insolublecompounds on the liposome membrane.As an alternative to the use of a hydrophobic condensing agent,we have carried out direct polymerization of N-carboxy anhy-dride (NCA) amino acids, such as NCA-Trp. Also in this case, wecould obtain long oligomers (up to a polymerization degree of29), which cannot be obtained by aqueous polymerization meth-ods in the absence of liposomes [8].The selectivity and specificity of the liposome membrane can bechanged and regulated by the type of lipidic surfactants (i.e.addition of ionic co-surfactants). For example, the positivelychargedDDAB (didodecyldimethylammonium bromide) formsstable mixed liposomes with POPe. This lipidic bilayer can nowalso attract negatively charged amino acid derivatives - forexample NCA-glutamic acid - and induce polymerization.The possibility of obtaining co-oligopeptides made out of hydro-phobic and ionic amino acids in the same molecule is the nextchallenge. As a matter of fact, we have been able to condense thedipeptide H-His- Trp-OH to the corresponding hexapeptide.Recognizing the catalytic character of the imidazole group, thismay open up ways to construct simple, catalytically activepolypeptides.[I] S.L. Miller, Science 1953, 117, 528.[2] S.L. Miller, H.C. Urey, Science 1959, 130, 245.[3] D. Yoet, J.G. Yoet, 'Biochemistry', 2nd ed., John Wiley & Sons, Inc.,New York, 1995.[4] B. Alberts, D. Bray, J. Lewis, M. Raff, K. Roberts, J.D. Watson,'Molecular Biology of the Cell', 3rd ed., Garland Publishing, Inc, NewYork, 1994.[5] N.A. Campbell, J.B. Reece, L.G. Mitchell, 'Biology', 5th ed., Addison-Wesley, Menlo Park, California, 1999.[6] D. W. Deamer, in 'The Molecular Origins of Life: Assembling Pieces ofthe Puzzle', Ed. A. Brack, Cambridge University Press, 1998, p. 189.[7] J. Or6, in 'Early Life on Earth: Nobel Symposium No. 84', Ed. S.Bengtson, Columbia University Press, New York, 1994, p. 48.[8] M. Blocher, D. Liu, P. Walde, P.L. Luisi, Macromolecules 1999, 32,7332.Chimia 54 (2000) 53-54© Neue Schweizerische Chemische GesellschattISSN 0009-4293Enantioselective Proton Transfer Chemistry:Asymmetric Synthesis with Chiral Lithium AmideBasesNigel S. Simpkins*Keywords: Asymmetric synthesis' COST· Lithium amide bases· Proton transferEnantioselective proton transfer chemistry has been relativelyunderdeveloped, considering the potential power and broadapplicability of this approach [1]. Notable early contributions inthis area include the enantioselective protonation of enolates byDuhamel and Plaquevent [2], and the asymmetric rearrangementof cyclohexene oxide by reaction with a chirallithium amide,described by Whitesell and Feldman [3].We have devoted a substantial part of our research effort to thedevelopment of desymmetrisation reactions using chirallithiumamide bases, including 1and 2, and have helped to establish thisapproach as a tool for asymmetric synthesis. Much of this'Correspondence: Prof. N.S. SimpkinsSchool of ChemistryThe University of NottinghamUniversity ParkNottingham NG7 2RD, UKTel.: +44 115951 3533Fax: +44 115951 3564E-Mail: nigel.simpkins@nottingham.ac.ukchemistry involves the reaction of acyclic (orpolycyclic) prochiralketone with a chirallithium amide base in a process that involvesthe base selecting between enantiotopic hydrogens. For exam-ple, the use of base 1allows the conversion of ketone 3 into theenol silane 4, and the azabicyclic ketone 5 into the aldol product6, both in high enantiomeric excess (Scheme 1).This type of transformation has obvious applications in targetsynthesis. For example we have prepared the unique alkaloidtoxin anatoxin-a 7 (the unnatural enantiomer) by this method [4],as well as a protected form of thymine polyoxin C 8 [5]. Currentactivities in this area involve the development of a strategy for thesynthesis of functionalised intermediates possessing the [5-8-5]framework found in natural products such as the ophiobolins andfussicoccins, e.g. conversion of ketone 9 into the complexintermediate 10, as shown in Scheme 2 [6].In addition to applications in the area of enol ate chemistry, chirallithium amides have also been used to generate reactive anions,in non-racemic form, from a considerable range of non-ketonicsubstrates. Examples include the enantioselective synthesis ofILMAC 99: RETROSPECTIVE/COST CHEMISTRY SYMPOSIUM 53CHIMIA 2000 54, No. 112glycero-3-phosphocholine) and similar compounds with differ-ent alkyl chains and head groups. The corresponding liposomesconsist of a membrane with a hydrophobic core that is able tobind hydrophobic compounds, such as hydrophobic amino acidderivatives and peptides, as well as lipophilic condensing agents(Figure).We have been able to bind the barely water-soluble condensingagentEEDQ (2-ethoxy-l-ethoxycarbonyl-l ,2-dihydroquinoline)to POPC liposomes. When these liposomes were exposed to alibrary of tryptophan-containing dipeptides such as H-Asp-Trp-OH, H-Trp-Trp-OH, H-Glu-Trp-OH, H-Gly-Trp-OH, only H-Trp-Trp-OH was bound to the liposomes and therefore oligomer-ized with significant yields (i. e. out of the theoretically possible16 tetrapeptides, H-Trp-Trp-Trp-Trp-OH makes about 70% ofall tetrapeptides formed) [8]. The other peptides are too hy-drophilic and were not selected. With this type of selection,tryptophan oligomers can be formed. The products of such anoligomerization become more hydrophobic with increasing lengthand remain attached to the liposomal matrix. We have thereforetwo selection steps, one arising from the choice of the monomer,and one from the possibility of polymerizing water-insolublecompounds on the liposome membrane.As an alternative to the use of a hydrophobic condensing agent,we have carried out direct polymerization of N-carboxy anhy-dride (NCA) amino acids, such asNCA-Trp. Also in this case, wecould obtain long oligomers (up to a polymerization degree of29), which cannot be obtained by aqueous polymerization meth-ods in the absence of liposomes [8].The selectivity and specificity of the liposome membrane can bechanged and regulated by the type of lipidic surfactants (i.e.addition of ionic co-surfactants). For example, the positivelychargedDDAB (didodecyldimethylammonium bromide) formsstable mixed liposomes with POPe. This lipidic bilayer can nowalso attract negatively charged amino acid derivatives - forexample NCA-glutamic acid - and induce polymerization.The possibility of obtaining co-oligopeptides made out of hydro-phobic and ionic amino acids in the same molecule is the nextchallenge. As a matter of fact, we have been able to condense thedipeptide H-His- Trp-OH to the corresponding hexapeptide.Recognizing the catalytic character of the imidazole group, thismay open up ways to construct simple, catalytically activepolypeptides.[I] S.L. Miller, Science 1953, 117, 528.[2] S.L. Miller, H.C. Urey, Science 1959, 130, 245.[3] D. Yoet, J.G. Yoet, 'Biochemistry', 2nd ed., John Wiley & Sons, Inc.,New York, 1995.[4] B. Alberts, D. Bray, J. Lewis, M. Raff, K. Roberts, J.D. Watson,'Molecular Biology of the Cell', 3rd ed., Garland Publishing, Inc, NewYork, 1994.[5] N.A. Campbell, J.B. Reece, L.G. Mitchell, 'Biology', 5th ed., Addison-Wesley, Menlo Park, California, 1999.[6] D.W. Deamer, in 'The Molecular Origins of Life: Assembling Pieces ofthe Puzzle', Ed. A. Brack, Cambridge University Press, 1998, p. 189.[7] J. Or6, in 'Early Life on Earth: Nobel Symposium No. 84', Ed. S.Bengtson, Columbia University Press, New York, 1994, p. 48.[8] M. Blocher, D. Liu, P. Walde, P.L. Luisi, Macromolecules 1999, 32,7332.Chimia 54 (2000) 53-54© Neue Schweizerische Chemische GesellschattISSN 0009-4293Enantioselective Proton Transfer Chemistry:Asymmetric Synthesis with Chiral Lithium AmideBasesNigel S. Simpkins*Keywords: Asymmetric synthesis' COST· Lithium amide bases· Proton transferEnantioselective proton transfer chemistry has been relativelyunderdeveloped, considering the potential power and broadapplicability of this approach [1]. Notable early contributions inthis area include the enantioselective protonation of enolates byDuhamel and Plaquevent [2], and the asymmetric rearrangementof cyclohexene oxide by reaction with a chirallithium amide,described by Whitesell and Feldman [3].We have devoted a substantial part of our research effort to thedevelopment of desymmetrisation reactions using chirallithiumamide bases, including 1and 2, and have helped to establish thisapproach as a tool for asymmetric synthesis. Much of this'Correspondence: Prof. N.S. SimpkinsSchool of ChemistryThe University of NottinghamUniversity ParkNottingham NG7 2RD, UKTel.: +44 115951 3533Fax: +44 115951 3564E-Mail: nigel.simpkins@nottingham.ac.ukchemistry involves the reaction of acyclic (orpolycyclic) prochiralketone with a chirallithium amide base in a process that involvesthe base selecting between enantiotopic hydrogens. For exam-ple, the use of base 1allows the conversion of ketone 3 into theenol silane 4, and the azabicyclic ketone 5 into the aldol product6, both in high enantiomeric excess (Scheme 1).This type of transformation has obvious applications in targetsynthesis. For example we have prepared the unique alkaloidtoxin anatoxin-a 7 (the unnatural enantiomer) by this method [4],as well as a protected form of thymine polyoxin C 8 [5]. Currentactivities in this area involve the development of a strategy for thesynthesis of functionalised intermediates possessing the [5-8-5]framework found in natural products such as the ophiobolins andfussicoccins, e.g. conversion of ketone 9 into the complexintermediate 10, as shown in Scheme 2 [6].In addition to applications in the area of enol ate chemistry, chirallithium amides have also been used to generate reactive anions,in non-racemic form, from a considerable range of non-ketonicsubstrates. Examples include the enantioselective synthesis ofILMAC 99: RETROSPECTIVE/COST CHEMISTRY SYMPOSIUM 54CHIMIA 2000, 54, No. 1/2Scheme 1 Scheme 3H~~-"'~~ uptoca.900loeeIBU/~ -----oLiCI, Me3SiCIca. -lOOoC,o"t):~M~PhPh Ph, h frN N-""\PhLI liph~ oup to ca. 95% ee1618Ph Ph7-)-< ..-"N N'.. \Ph LI LI PhTHF, -78°C, BnBr17 80% (95% eelMeo2c~co'MeI: .Bn ---..Bn1978% (>98% eelsulfoxides [7], tricarbonyl(1}6-arene)chromium complexes [8]and phosphine oxides [9,10], as represented by the chiral prod-ucts 11-15. In each case the product originates from a chiral basereaction of a symmetrical substrate which serves to introduce thehighlighted substituent.Our present activities, aimed at further extending the applica-tions of chiral lithium amides, are focussed on developingdesymmetrisation reactions of polyfunctional substrates. Exam-ples include the conversion of imide 16 into the silylated deriv-2.2 equiv. Fe(NO,)3 [I] Forthe mostrecentreviewofchirallithium amidebasechemistry,seeP. O'Brien, J. Chern. Soc., Perkin Trans. /1998, 1439.[2] L. Duhamel, J-C. Plaquevent,J. Arn. Chern. Soc. 1978, 100,7415.[3] J.K. Whitesell, S.W. Feldman, J. Org. Chern. 1980,45, 755.[4] N.J. Newcombe, N.S. Simpkins, J. Chern. Soc., Chem. Cornrnun.1995,831.[5] D.M. Gethin,N.S. Simpkins, Tetrahedron 1997, 53,14417.[6] AJ. Blake,A.J.Highton,T.N.Majid,N.S.Simpkins,Org. Lett. 1999,1,787.[7] a) A.J. Blake, S.M.Westaway,N.S. Simpkins,Synlett 1997, 919; b)R. Armer,M.J. Beg]ey,P.J.Cox,A Persad,N.S. Simpkins,J. Chel1l.Soc., Perkin Trans. ] 1993, 3099.[8] a) A. Ariffin, A.J. B]ake, R.A Ewin, W.-S. Li, N.S. Simpkins, J.Chel1l.Soc., Perkin Trans.] 1999,3177; b)D.A. Price,N.S.Simpkins,A.M. MacLeod,A.P. Watt, J. Org. Chel1l. 1994,59,1961.[9] S.C. Hume, N.S. Simpkins,J. Org. Chern. 1998.63,912.[10] D.A. Price,N.S. Simpkins,Tetrahedron Lett. 1995, 36, 6]35.[11] D.J. Adams, N.S. Simpkins, T.J.N. Smith, Chem. COI1lI1lUI1.998,1605.[I2] N.J. Go]dspink,N.S. Simpkins,M. Beckmann, Synlett 1999, ]292.ative 17 [11], and the alkylation reactions of piperidine diester 18to give products of general structure 19 [12] (Scheme 3). This lastexample is notable for the extremely good levels of both diaster-eo- and enantiocontrol observed, and opens up an interesting newavenue for the synthesis of enantiomerically pure piperidines andcyclic amino acids.In summary, chiral lithium amide base chemistry continues todevelop apace, and we expect to see many more applications ofthese reagents in organic synthesis over the years to come.(79%)10 (X = H, SPh)55-72%(i) LOA, Me3SiCI(ii) El"ln, CH.I.PhSeSO,TolAIBN, benzene9(83%)(X = H, CI, SPh)65-75%~~~6---(i) trichloroacetoneTFP, NaH(ii) ZnlCulMeOH, benzeneOMF +eilherA - cyclohexadieneB·NCSC - PhSSPh(R = butenyl)R-y,'°;yRUScheme 2gSitSuPh2 OMe~O..tS] QrEl : ....,~ 0 og:lPh"" P ""Ph:::-.... '." .~1+ 'SiMe3 " -:,. Ph" 0'Cr(COh "'Cr(COh01160% ee 12 90% ee 13 99% ee 1470% ee 15 ca. 90% ee

Enantioselective Proton Transfer Chemistry: Asymmetric Synthesis with Chiral Lithium Amide Bases

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Enantioselective Proton Transfer Chemistry: Asymmetric Synthesis with Chiral Lithium Amide Bases

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