Asymmetric Phase Transfer Catalysis for the Production of Non-proteinogenic a-Amino Acids: Application of C2-Symmetric Chiral 1,1’-Binaphthyl-derived Quaternary Ammonium Bromides Masaya Ikunaka, Ph. D. Principal of Technology Development Fine Chemicals Division Fine Chemicals Department, Nagase & Co., Ltd. Keiji Maruoka, Ph.D. Professor Department of Chemistry Graduate School of Science, Kyoto University 東北大学 農学部 化学工学概論（2009 年 12 月） 1 学んでほしいこと（Lessons that you will learn） What looks ordinary in the lab is out of the ordinary in the plant. （学術論文では当たり前に書かれていることが，工業的には実施できないことがあ る） Be skeptical about any premise. （実験や考察の前提がいつも正しいとは限らない．状況が変われば，前提も変化す る） Discovery consists of seeing what everybody has seen and thinking what nobody has thought. Albert von Szent-Györgyi (1893–1986) （同じ現象でも見る人が変われば，違う考察と違う結論が導かれる） 2 The Ballad of East and West Rudyard Kipling (1865–1936) Oh, East is East, and West is West, and never the twain (two) shall meet, Till Earth and Sky stand presently at God’s great Judgment Seat; But there is neither East nor West, Border, Nor Breed, nor Birth, When two strong men stand face to face, though they come from the ends of the earth! 3 Oil is Oil, and Salt is Salt, But the two can engage in reaction, When a phase transfer catalyst comes into play, although they stay apart in different phases! Phase transfer catalyst Organic phase Organic phase Inorganic phase Inorganic phase 4 C2-Symmetric chiral 1,1’-binaphthyl-derived quaternary ammonium salts Ar Ar F N+ Br - Ar = N+ F F R N R3 H R5 O OR4 Q* Organic phase N Br OR4 N R R + K OH - - 3 R3 1 R + H2O K Br - N + - R1 R5 OR4 R2 O K OR4 3 R1 R2 O R2 Br - + - Ar Ar 2 Br O Q* + Interface R1 Aqueous phase Ikunaka, M.; Maruoka, K. In Asymmetric Catalysis on Industrial Scale, 2nd ed.; Wiley-VCH: Weinheim, in press. 5 a-Amino acids and their derived drug candidates O O Br N N OH Cl NH2 O F Cl + H 3N TsO Asymmetric phase transfer catalysis (PTC) - - + H3N CO2Et H CO2 O H H O + N EtO2C F O H CO2H - NH3 6 Starks’ Extraction Mechanism Aliquat® 336 (CH2)7Me + Me(CH2)7 N Me Cl - (CH2)7Me C7H15 NaCN + Cl + C8H17-Cl + Q CN C7H15 H2O - C8H17-CN + CN + Q Cl - Organic phase Aqueous phase + Na Cl - Anion partitioning + + Q CN - + Na CN - Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195. + + Q Cl - 7 Makosza’s Interfacial Mechanism + PhCH2NEt3 Cl Ph CN + Et - Et Cl Ph 50% aq NaOH H H Ph CN Cl CN + Organic phase Q Cl - N Q - Ph + Ph C CN Lipophilic ion pair Ph C - N Na+ Ph C Interface - N Q + - Na OH H2O + Na Cl - + Aqueous phase Makosza, M.; Serafinowa, B. Rocz. Chem. 1965, 39, 1223. 8 The first efficient asymmetric phase transfer catalyst Cl O Cl HO (10 mol%) N MeO N Me 50% aq NaOH toluene 20 C, 18 h (95% yield) Cl Cl Cl MeO 92% ee Br - H N-[(4-trifluoromethyl) benzyl]cinchoninium bromide CF3 Cl O + 1) AlCl3 PhMe, 45 C 2) ClCH2CO2Et NaI, K2CO3 PhMe, reflux 3) aq NaOH PhMe, reflux O Cl O O HO Uricosuric (+)-indacrinone (MK-0197) Dolling, U.-H.; Davis P; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446. 9 The first successful asymmetric phase-transfer-catalytic alkylation of benzophenone imine of tert-butyl glycinate O Ph Br + N Cl Ot-Bu Ph HO Cl N CH2Cl2 25 C 50% aq NaOH 15 h (95% yield) N Ph N H Ph N-Benzylcinchoninium chloride O Ph N Ot-Bu Ph H (R) 64% ee + (10 mol%) O Ph - Filtrate (R) > 99% ee Crystals (R) 8% ee Ot-Bu H Cl Recrystallization from n-hexane Cl O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. 10 The active form of catalyst O Ph Ph O Ph Br N N Ot-Bu Ph 50% aq NaOH CH2Cl2, 25 C Ph Ot-Bu H Ph Ph O N N - Br HO N + 61% ee N 60% ee + N Rapid N- and O-alkylation N HO Ph Br - Ph 60% ee O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507. 11 N-Anthracenylmethyl-dihydrocinchonidinium chloride O Ph N Cl Ot-Bu Ph - N + Ph Cl + N Br OH O N rt, 18 h toluene N (10 mol%) 50% aq KOH The least uncatalyzed alkylation in the use of aq KOH Active form of the catalyst generated in situ N Ph O O Ph + Ot-Bu H Ph H3O (85%) H2N OH H Ph Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595. 94% ee 12 Blockage of the second alkylation by the benzophenone imine O Ph N N Ph O Ph Ot-Bu Ph H H O Ph Ph OEt H H pKa 18.7 (DMSO) - Cl OEt H Me pKa 22.8 (DMSO) Ot-Bu Ot-Bu N N Ph H O Ph N Ot-Bu N + O Na - + O Na H Cl O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. 13 Cinchona alkaloids in pseudoenantiomeric forms N-Benzylcinchonidium chloride N-Benzylcinchoninium chloride H + + Ph OH Ph HO - N Cl N - Cl H N N (10% mol) O Ph N Ph Ot-Bu 50% aq NaOH CH2Cl2 N Ph 20 C, 12 h + Br Cl O Ph 82% yield O Ot-Bu H H3O + H 2N OH H (S) 62% ee Cl O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. Cl 14 O-Allyl-N-anthracenylmethyl-cinchonidinium bromide O Ph N + N CH2Cl2 (87% yield) CsOH•H2O O Ph O (10 mol%) Br -78 C, 23 h N Ph N Ot-Bu Ph Ph Br - Ot-Bu H Ph Use of solid base to minimize the possibility of water in the organic phase (CH2Cl2) to apply lower temp (-60 to -78 C) than are possible with 50% aq KOH 94% ee Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. 15 Cinchonidinium-induced enantioface selectivity O Ph CsOH Ph N N - O Q* Ot-Bu Ph Q* Br Ot-Bu CsBr + - Br Ph H2O + Chiral ammonium E-enolate The quinoline ring of the cinchonidinium moiety blocks the re (front) face of the E-enolate. - N + Q* + - E Br Br O N Attack of the electrophile (E+) takes place at the si (rear) face of the E-enolate. • Corey, E. J.; et al. J. Am. Chem. Soc. 1997, 119, 12414. • Lygo, B.; et al. Acc. Chem. Res. 2004, 37, 518. O Ph N Ot-Bu Ph H E 16 Cinchonidine-derived ammonium salts O Ph X N - N + R1 O R2 Ph 10 mol% Ot-Bu + Ph Br O Ph base solvent N temp time Ph N O’Donnell (1989) R1 = CH2Ph R2 = H (O-alkylation in situ) X = Cl Lygo (1997) R1 = Anthracenylmethyl R2 = H (O-alkylation in situ) X = Cl Corey (1997) R1 = Anthracenylmethyl R2 = CH2CH=CH2 X = Br Ot-Bu H Ph 20 C 12 h 82% yield 62% ee (4-Cl-C6H4CH2Br) 50% aq KOH toluene rt 18 h 85% yield 94% ee (after C- and Ndeprotection) CsOH•H2O CH2Cl2 -78 C 23 h 87% yield 94% ee 50% aq NaOH CH2Cl2 17 Asymmetric alkylation of N,C-protected alanine by the use of O’Donnell’s catalyst Cl R Br (1.1 equiv) O N Ot-Bu O N CH2Cl2 25 C, 18 h Mixed solid base (10 mol%) Ot-Bu R K2CO3/KOH (R) (10 equiv each) Cl HO N N Cl H - 44% ee 80% yield + Ph N-Benzylcinchoninium bromide R= 48% ee 87% yield Cl 36% ee 78% yield O’Donnell, M. J.; Wu, S. Tetrahedron: Asymmetry 1992, 3, 591. 18 Asymmetric alkylation of N,C-protected alanine by the use of Lygo’s catalyst Cl R Br (1.2 equiv) O N Cl (S) O N toluene rt, 30 min Ot-Bu Mixed solid base KOH fused with K2CO3 Ot-Bu R AcOH, THF-H2O (O-alkylation in situ ) O H2N (10 mol%) Ot-Bu R N + 87% ee 95% yield Br OH - R= N N-Anthracenylmethyldihydrocinchonidinium chloride 77% ee 72% yield Cl Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671. 19 Asymmetric alkylation of N,C-protected alanine by the use of Jew and Park’s catalyst R Br (5 equiv) O O N N Ot-Bu Ot-Bu toluene -35 C R RbOH (10 mol%) (5.0 equiv) Br (S) - N 1N HCl, THF, rt O H2N + Ot-Bu R O N F F F O-Allyl-N-(2,3,4-trifluorobenzyl)dihydrocinchonidinium chloride 95% ee 91% yield R= 85% ee 87% yield Jew, S-s.; et al. J. Org. Chem. 2003, 68, 4514. 20 a-Benzylalanine tert-butyl ester O R1 Br Ph N Ot-Bu O R1 solvent base temp N * + H3O Ot-Bu Ph Ot-Bu Ph R1 = 4-C6H4 Lygo (1999) R1 = 4-C6H4 R2 = Anthracenylmethyl R3 = H (O-Benzylation in situ) X = Cl toluene K2CO3/KOH rt 87% ee (S) 95% yield Jew & Park (2003) R1 = 2-Naphthyl R2 = 2,3,4-Trifluorobenzyl R3 = Ally X = Br toluene RbOH -35 C 95% ee (S) 91% yield Ph HO N X H2N * CH2Cl2 44% ee (R) K2CO3/KOH 80% yield rt (Schiff base) H N O + O’Donnell (1992) - + N R2 3 OR N Br 21 Cinchona alkaloid-derived chiral phase transfer catalysts Q* R2 - + X N R X - N + R4 OR5 N H O Q* Ot-Bu 3 R1 R4 - + X Br O R2 N * R3 R4 = Reactive alkyl (benzyl, allyl, etc.) Ot-Bu R1 R4 Catalyst loading of 10 mol% R1 = H (a-alkyl glycine) Benzophenone imine (R2 = R3 = Ph) for monoalkylation with little racemization Cinchonidinium rt (aq KOH) to -78 C (solid CsOH•H2O) R5O N N - X + R4 Cinchoninium R1 = Me (a-alkyl alanine) Aromatic aldehyde imine (R2 = 4-Cl-C6H4, 2-naphthyl; R3 = H) Solid base: rt (K2CO3/KOH) to -35 C (RbOH) 22 Denagliptin tosylate, a dipeptidyl IV (DPP-IV) inhibitor O BocHN CONH2 OH + HN p-TsOH F F F O C3H7 P O O T3P = Patterson, D. E.; et al. Org. Process Res. Dev. 2009, 13, 900. C3H7 P O O P O C3H7 1) T3P, i-Pr2NEt AcOEt, 50 C 2) T3P, 78 C 3) p-TsOH, i-PrOH 70 C 4) ReX (iPrOH/H2O) (78%) CN O H2N N p-TsOH DPP-IV inhibitor for the treatment of type 2 diabetes that increases the levels of active GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide), both of which play important roles in regulating blood glucose level F F F Denagliptin tosylate 23 Cinchonidine-derived phase transfer catalyst O Ph N Br (10 mol%) Ot-Bu Ph CH2Cl2 (5 vol) 45% aq KOH (10 equiv) O Br cooling time F 0 C - N + N (1.5 equiv) O Ph N Ph F F Ot-Bu F (S)/(R) (80:20) Crystallization (AcOEt/heptane) scale cooling time (S)/(R) yield Small 5 – 10 min 99 : 1 55% large (kg) 30 – 60 min 50 : 50 65% Patterson, D. E.; et al. Org. Process Res. Dev. 2007, 11, 624. 24 Decomposition of the catalyst in the absence of electrophile Br N - Hofmann degradation + O H N 45% aq KOH CH2Cl2 O N CO2t-Bu N N Ph Ph Alkylation O-Deallylation N N + CO2t-Bu N O N N Ph HO Ph Patterson, D. E.; et al. Org. Process Res. Dev. 2007, 11, 624. 25 Optimized procedures for the use of the cinchonidine-derived phase transfer catalyst F F (1.5 equiv) Br Ph N Br CO2t-Bu O - N + Ph CH2Cl2 (5 vol) N 0 C 10 mol% 0–5 C 0–5 C 15–30 min 5h Ph 45% aq KOH (10 equiv) N CO2t-Bu (S)/(R) (80:20) Ph > 99% ee (56%) after crystallization (AcOEt/heptane) F F Patterson, D. E.; et al. Org. Process Res. Dev. 2007, 11, 624. 26 Issues to be addressed in up-scaling the asymmetric phase-transfer-catalytic synthesis of a-amino acids 2 R 3 N R3 H 1 O Q* 4 OR 1 R 4 + R5 + X - 2 Base N * X Water-immiscible organic solvent O R2 R 3 OR4 R1 R 5 Chiral quaternary ammonium salt catalyst should be base-proof and exhibit supreme enantioselectivity even at its extremely low loadings (« 1 mol%). Aqueous base should always be substituted for solid base, such as CsOH•H2O, that is more expensive and difficult to handle on scale. Aromatic aldehyde imine (R3 = H) can be employed even when R1 = H since it is much easier to prepare than benzophenone imine (R2 = R3 = Ph). Amino acid esters should be produced that are easier to manipulate in the ensuing steps than the corresponding tert-butyl ones. 27 BIRT-377, LFA-1 antagonist O Br O Br N N Cl H2N O Cl OR R = Et, Me N-Aryl-substituted hydantoin identified as a potent inhibitor of the interaction between ICAM-1 (intercellular adhesion molecule-1) and LFA-1 (lymphocyte functionassociated antigen-1) nominated for a preclinical candidate in the treatment of inflammatory and immune disorders at Boehringer Ingelheim Pharmaceuticals Inc. Yee, N. K. Org. Lett. 2000, 2, 2781. 28 (R)-a-(4-Bromobenzyl)alanine esters Seebach’s self-regeneration of stereocenters1 O O H Br BnO N H BnO CO2H Cbz-L-Ala N O H Ph O Organocatalytic asymmetric amination2 Br BnO2C BnO2C N N + CO2R R = Et, Me N N H H2N N + HN N (15 mol%) CHO 1. Kapadia, S. R.; et al. J. Org. Chem. 2001, 66, 1903. 2. Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867. 29 Self-regeneration of stereocenters CO2H BnO O PhC(OMe)2 ZnCl2, SOCl2 NH THF 0 C, 4 h (76%) O BnO H O N Br O Ph Br Cbz-L-Ala cis/trans (25:1) O Br BnO N O O H Ph KN(SiMe3)2 THF -27 C (1 h) to rt (1 h) (75%) 1. 30% HBr, AcOH rt, 20 h 2. HCl (g), EtOH 70 C, 34 h (87%) Br H2 N CO2Et > 99% ee 66% overall yield from Cbz-L-Ala over 4 steps Kapadia, S. R.; et al. J. Org. Chem. 2001, 66, 1903. 30 3-(4-Bromophenyl)-2-methylpropanal CHO + N CO2 CHO - H2N LiAlH4, AlCl3 THF CHO + 65 C, 11 h (85%) rt, 48 h (80%) Br Br OH Br (COCl)2, Et3N DMSO CH2Cl2 -60 C, 5 min (95%) CHO Br (65% overall yield) Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867. 31 Organocatalytic asymmetric amination O N H 1. N H HN N (15 mol%) + Br N N CO2Bn CO2Bn N O MeCN rt, 3 h H HN N CO2Bn CO2Bn 2. Recrystallization from AcOEt/hexane (3:7) (71%) Br N N N BnO2C N > 99% ee N N H N CO2Bn Br Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867. 32 (R)-a-(4-Bromobenzyl)alanine methyl ester HN OHC N CO2Bn CO2Bn 2. Me3SiCHN2 (2 M in hexane) PhMe/MeOH (2:1) rt, 10 min (99%) Br HN MeO2C 1. NaClO2, NaH2PO4 2-methyl-2-butene t-BuOH/H2O (5:1) 4 C, 12 h (86%) N COCF3 CO2Bn SmI2 (0.1 M in THF) MeOH MeO2C HN CO2Bn (CF3CO)2O Py rt, 48 h (99%) Br H N MeO2C NH2 CO2Bn HBr, AcOH rt, 24 h (99%) rt, 30 min (98%) Br Br N MeO2C CO2Bn Br 38% overall yield from 4-Br-C6H4CHO over 9 steps Barbas, III, C. F.; Chowadari, N. S. Org. Lett. 2005, 7, 867. 33 Asymmetric phase-transfer-catalytic alkylation Br Br H N CO2Et F F MeO N CO2Et PhMe, 0 C,10 h Cl CsOH•H2O (5 equiv) aq Citric acid (0.5 M) THF, rt Cl MeO (1.5 equiv) Br F Br (1 mol%) MeO H2 N N+ MeO CO2Et 90% ee F Br - MeO MeO F (S) F 2-step overall yield of 86% • Self-regeneration of chiral centers: 66% (4 steps) • Organocatalytic asymmetric amination: 38% (9 steps) K. Maruoka, et al. Tetrahedron Lett. 2005, 46, 8555. 34 Issues to be addressed in up-scaling the asymmetric phase-transfer-catalytic synthesis of a-amino acids 2 R 3 N R3 H 1 O Q* 4 OR 1 R 4 + R5 + X - 2 Base N * X Water-immiscible organic solvent O R2 R 3 OR4 R1 R 5 Chiral quaternary ammonium salt catalyst should be base-proof and exhibit supreme enantioselectivity even at its extremely low loadings (« 1 mol%). Aqueous base should always be substituted for solid base, such as CsOH•H2O, that is more expensive and difficult to handle on scale. Aromatic aldehyde imine (R3 = H) can be employed even when R1 = H since it is much easier to prepare than benzophenone imine (R2 = R3 = Ph). Amino acid esters should be produced that are easier to manipulate in the ensuing steps than the corresponding tert-butyl ones. 35 Maruoka Catalysts® 3 R2 N H O 4 4 OR toluene + 5 R X 2 1 R 48% aq KOH O R2 N OR4 R1 R5 1 Ar Ar F N Ar Ar = + Br - F N + Br - F Ar C2-Symmetric chiral 1,1’-binaphthyl-derived quaternary ammonium bromides work wonders in the enantioselective synthesis of a-amino acids by asymmetric alkylation 36 Maruoka Catalysts® offer solutions 3 R2 N H O 4 4 OR R1 1 Maruoka CatalystTM + R5 X 2 48% aq KOH toluene O R2 N OR4 R1 R5 The catalyst, being invulnerable to the basic conditions applied, shows excellent performance in both reactivity (TON) and enantioselectivity such that 0.1–0.5 mol% of it suffices to obtain alkylated products of high enantiomeric purity in good yield. Easy-to-handle and inexpensive aq KOH solution can be used irrespective of substrates used, whether R1 is H or not. Easy-to-prepare aromatic aldehyde imine of glycinate (R1 = H) can undergo mono-alkylation with high enantioselectivity. Methyl and ethyl esters of N-protected a-amino acid (R4 = Me, Et) of high ee can be produced in good yield, which are easier to manipulate than the corresponding tert-butyl esters. 37 a-Amino acids and their derived drug candidates O O Br N N OH Cl NH2 O F Cl + H 3N TsO Asymmetric phase transfer catalysis (PTC) - - + H3N CO2Et H CO2 O H H O + N EtO2C F O H CO2H - NH3 38 (S)-N-Acetylindoline-2-carboxylic acid esters, intermediates for potent angiotensin converting enzyme (ACE) inhibitors H H EtO2C H H N N H O Vincent, N.; et al. Tetrahedron Lett. 1982, 23, 1677. H CO2H Peridolpril CO2R N H Ac H N EtO2C O Carba-analog of peridolpril H R = Me, t-Bu H CO2H CO2R H NHAc Br Stanton, J. L.; et al. J. Med. Chem. 1983, 26, 1277. 1. Buchwald, S. L.; et al. J. Am. Chem. Soc. 1997, 119, 8451. 2. Maruoka, K.; et al. J. Am. Chem. Soc. 2003, 125, 5139. 39 Asymmetric hydrogenation of eneamide CO2Me Br + rt 2.5 h CO2R H NHAc Br - NHAc (1.1 equiv) Br Et Et P P Et (S,S)-Et-DUPHOS (0.1 mol%) Et Pd2(DBA)3 (10 mol% Pd) P(o-tolyl)3 (20 mol%) CO2Me N Cs2CO3, PhMe 100 C, 15 h (98%) Ac O 99% ee 2-step overall yield of 80% CO2Me + 100 C, 2.5 h (84%) NHAc [(COD)Rh ]OTf (0.1 mol%) MeOH H2 (30 psig) (95%) I Pd(OAc)2, Et3N DBA = Ph H 99% ee Ph Buchwald, S. L.; et al. J. Am. Chem. Soc. 1997, 119, 8451. 40 N-Spiro-C2-symmetric bis-1,1’-binaphthyl-derived chiral ammonium bromide O Ph N Ar F Ot-Bu Ph 1 mol% Br Ar PhMe/50% aq KOH (1:3) 0 C, 24 h under Ar F Ar = N H - F (R,R) AcHN Ot-Bu Ph Br O O Br + (1.2 equiv) Br Ph N 1. 1 M aq citric acid THF, rt, 3 h 2. AcCl, Et3N, CH2Cl2 0 C, 0.5 h Ot-Bu H 99% ee Br 86% overall yield over 3 steps Maruoka, K.; et al. J. Am. Chem. Soc. 2003, 125, 5139. 41 Alkylation of protected Gly using N-Spiro-C2-symmetric chiral ammonium bromide of bis-1,1’-binaphthyl structure O Ph Ar F N Ot-Bu Ph N+ R-X (1.2 equiv) PhMe/50% aq KOH (1:3) 0 C under Ar O Ph N Ph Br - F Ar = F Ar (S, S) Ot-Bu H R Ph 1 mol% 99% ee 90% (12 h) 0.5 mol% 99% ee 85% (36 h) Br R -X 1 mol% 99% ee 80% (24 h) Br 0.2 mol% 99% ee 72% (48 h) I (5 equiv) -15 C sat aq CsOH 1 mol% Maruoka, K. et al. J. Am. Chem. Soc. 2003, 125, 5139. 98% ee 89% (10 h) 42 Alkylation of protected a-alkyl a-amino acids using N-Spiro-C2symmetric chiral ammonium bromide of bis-1,1’-binaphthyl structure 4-Cl-Ph N CO2t-Bu F R1 (0.25 M) PhMe/CsOH•H2O (5 equiv) R2-X (1.2 equiv) 0 C under Ar 4-Cl-Ph Ar N CO2t-Bu Ar Br F Ar = N+ 1 mol% F - (S, S) 4-Cl-Ph = 4-Cl-C6H4- R1 R2 R1 = Me 0.5 M aq citric acid THF H2N R2-X CO2t-Bu Ph Br 85% (0.5 h) 98% ee R1 = Me I (5 equiv) 71% (0.3 h) 99% ee R1 = CH2CH(Me)2 Br 70% (1 h) 93% ee R1 R2 Maruoka, K. et al. J. Am. Chem. Soc. 2000, 122, 5228. 43 Sequential double alkylation using N-spiro-C2-symmetric chiral ammonium bromide of bis-1,1’-binaphthyl structure 4-Cl-Ph N Ar CO2t-Bu F 4-Cl-Ph = 4-Cl-C6H4(0.25 M) PhMe 1. (1 equiv) CsOH•H2O - 10 C (5 equiv) 2 2. R -X (1.2 equiv) under Ar 0 C R1-X 4-Cl-Ph N Br F (S, S) R2-X R1-X Br R1 R2 0.5 M aq citric acid THF - Ar CO2t-Bu (3.5 h) H2N F Ar = N+ 1 mol% Ph Br (0.5 h) 98% ee (R) 80% CO2t-Bu R1 R2 Ph (2 h) Br Br (0.3 h) Maruoka, K. et al. J. Am. Chem. Soc. 2000, 122, 5228. 92% ee (S) 74% 44 Alkylation of simple esters of Gly benzophenone imine O Ph Ar N Ph R1-X (1.2 equiv) PhMe/50% aq KOH (1:3) 0 C under Ar 1 mol% N Ar (S, S) Br F Br OR H R1 R1-X F Ar = N+ - O Ph Ph F OR Ph I (5 equiv) sat aq CsOH - 15 C Br R = Me 82% (3 h) 97% ee R = Et 96% (2 h) 98% ee 99% (2 h) 97% ee Maruoka, K. et al. Tetrahedron Lett. 2004, 45, 1675. 75% (3 h) 93% ee 45 Alkylation of simple esters of Ala 4-Cl-benzaldehyde imine O 4-Cl-Ph Ar N F OR R1-X (1.2 equiv) PhMe/CsOH•H2O (5 equiv) -20 C, 3–5 h under Ar F Ar = N+ 1 mol% F - Br Ar (S, S) O N 4-Cl-Ph OR Br 4-Cl-Ph = 4-Cl-C6H4- R1 R1-X 1 M HCl THF O H2N R Ph Br R = Me 81% 85% ee R = Et 82% 98% ee OR 1 Ph Maruoka, K. et al. Tetrahedron Lett. 2004, 45, 1675. 89% 88% ee Br 80% 82% ee 46 Manipulations of the ethyl functionalities Ph N Ph CO2Et H 40% MeNH2 in MeOH a-Np = a-Np O BocHN rt, 8 h (98%) 97% ee 1. 1 M HCl/THF, rt, 2 h BocHN 2. (Boc)2O, sat aq NaHCO3 THF, rt, 30 min (quant) CO2Et H a-Np NHMe H a-Np DIBAL-H PhMe 97% ee O BocHN -78 C, 2 h (95%) H H a-Np 97% ee O H2N CO2Et Ph 98% ee (Boc)2O, NaHCO3 BocHN THF, rt, 12h (97%) CO2Et Ph DIBAL-H BocHN PhMe -78 C, 2 h (81%) Maruoka, K. et al. Tetrahedron Lett. 2004, 45, 1675. H Ph 98% ee 47 N-Protection of Gly esters for monoalkylation Ph NH + - O + Cl H3N N OR Ph NH4 Cl (81%) Ph O H2N Ph - Ph N OR N H MgBr OR Ph + MeOH O Ph CH2Cl2 H O OR * Ph R1 Ar O PhMgBr Et2O Ph C N H2O O Ar N Ar OR N H O * OR R1 1. O’Donnell, M.; Polt, R. T. J. Org. Chem. 1982, 47, 2663. 2. Pickard, P. L.; Tolbert, T. L. Org. Syntheses; Wiley-VCH: New York, 1973; Coll. Vol. V, pp 520-522. 48 Intermediacy of mono-alkylation product in the sequential asymmetric double alkylation Cl 1. R1-X (1 equiv) - 10 C N CO2t-Bu PhMe CsOH•H2O (5 equiv) under Ar Ar N+ Br - Cl N CO2t-Bu 1 mol% H R1 2. R2-X (1.2 equiv) 0 C Ar F (S, S) F Ar = Cl N F CO2t-Bu R1 R2 Maruoka, K. et al. J. Am. Chem. Soc. 2000, 122, 5228. 49 Intermediacy of mono-alkylation product in the sequential asymmetric double alkylation Cl 1. R1-X (1 equiv) - 10 C N CO2t-Bu PhMe CsOH•H2O (5 equiv) under Ar Ar Cl N N+ Br - F F Ar = H R1 2. R2-X (1.2 equiv) 0 C Ar (S, S) 1 mol% CO2t-Bu F Maruoka, K. et al. J. Am. Chem. Soc. 2000, 122, 5228. Cl N CO2t-Bu R1 R2 50 Mono-alkylation of 4-chlorobenzaldehyde imine of glycine t-butyl ester Cl 1 mol% N Ar CO2t-Bu F (0.15 M) R-X (1.2 equiv) N + F Ar = PhMe/50% aq KOH (3:1) 0 C under Ar Ar Cl N Br - F (R,R) CO2t-Bu R-X H R Ph Br Br I (10 equiv) 1 M HCl THF 0 C, 0.5 h H2N CO2t-Bu H R 2h 99% 98% ee 2h 84% 92% ee 5h 93% 99% ee Maruoka, K. et al. Tetrahedron: Asymmetry 2006, 17, 603. 51 Enantiofacial differentiation of the prochiral enolate R5 X can approach only the re (front) face of the (E)-enolate (S,S)-BBN F F + N F F R3 R1 N (E)-Enolate R2 F - O OR4 R3 R1 F R2 R5 OR4 N (R) O The two 3,4,5-F3-C6H2 groups create a chiral molecular pocket shielding the si (rear) face of the (E)-enolate 1. Maruoka, K.; et al. J. Am. Chem. Soc. 1999, 121, 6519. 2. Maruoka, K.; et al. J. Am. Chem. Soc. 2003, 125, 5139. 52 C2-Symmetric mono-1,1’-binaphthyl-derived chiral ammonium bromide Ar Ar F N + Br - N F Ar = + Br - F Ar Ar (S)-MBN (S,S)-BBN Ph Ph N Br (1.2 equiv) CO2t-Bu 50% aq KOH/PhMe (1:1) 0 C Ph (S)-MBN (S,S)-BBN Ph N Ph H CO2t-Bu Ph 0.05 mol% 2h 98% yield 99% ee 0.01 mol% 9h 92% yield 98% ee 0.05 mol% 24 h 22% yield 85% ee Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549. 53 The less lipophilic catalyst can enter the interface more easily Ar Ar F N+ Br Ar = - F N+ Br - F Ar Q* (S)-MBN - + Ar Br (S,S)-BBN The Makosza interfacial mechanism R 2 N R3 H R5 O OR4 Q* Organic phase Br - + O R2 N Br R R1 R5 R1 OR4 R2 N R + K OH - - 3 R R1 K Br - N + + H2O OR4 R2 O K - OR4 3 O Q* 3 Interface + R1 Aqueous phase Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549. 54 Powerful chiral phase transfer catalyst F At least 20 times more active than the N-spiro-bis-binaphthyl-derived catalyst F F N + Br Effective in the asymmetric alkylation of 4-chlorobenzaldehyde imine of Ala esters - (Angew. Chem. Int. Ed. 2005, 44, 1549) Effective in the asymmetric alkylation of 4-chlorobenzaldehyde imine of Gly esters F (Tetrahedron: Asymmetry 2006, 17, 603.) F (S)-MBN F Ar N CO2t-Bu Ar = 4-Cl-C6H4 Ar N CO2t-Bu (R) (1 mol%) PhMe/50% aq KOH 0 C, 2 h under Ar (S) (0.05 mol%) CsOH•H2O (5 equiv) PhMe, -20 C, 1 h H2N H2N CO2t-Bu Ph 98% ee (63%) CO2t-Bu 98% ee (95%) 55 ortho-Magnesiation for the catalyst synthesis CO2H CO2H Mg(TMP)2 THF 1) SOCl2 CO2i-Pr 0 C–rt CO2i-Pr 2) i-PrOH Py (94%) TMP = Br MgTMP CO2i-Pr CO2i-Pr N Br2 CO2i-Pr -78 C–rt (89%) CO2i-Pr MgTMP 1. Maruoka, K.; et al. J. Org. Chem. 2003, 68, 4576. 2. Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549. Br 56 Suzuki-Miyaura cross coupling for the catalyst synthesis Br CO2i-Pr CO2i-Pr Br Ar ArB(OH)2 Pd(OAc)2 PPh3 CO2i-Pr F CO2i-Pr K2CO3 DMF, 90 C (94%) Ar Ar = F F 1) LiAlH4 THF 0 C–rt 2) PBr3 THF 0 C–rt (91%) Ar Ar Br Br Ar Bu2NH MeCN + N reflux (89%) Br - Ar 1. Maruoka, K.; et al. J. Org. Chem. 2003, 68, 4576. 2. Maruoka, K.; et al. Angew. Chem. Int. Ed. 2005, 44, 1549. 57 Exquisite compounds derived from (S)-allylglycine OH N-Acylimminium ion cyclization Iodolactonization O H N CO2H H2N Boc CO2H H R1 Heck reaction N H OR2 O Rh-catalyzed hydroformylation Ar H Boc N H CO2t-Bu N CO2Me Boc 1. Rutjes, F. P. J. T.; et al. Org. Biol. Chem. 2005, 3, 3435. 2. Rutjes, F. P. J. T.; et al. J. Chem. Soc. Perkin Trans. I 2000, 4197. 58 Synthetic plan for (S)-allylglycine ester - O + Cl H3N - X H3N F 4 OR OR4 F R4 t-Bu Base F Base•HCl N+ Br O - H2N O H2N Ar O + OR4 F OR4 F (R)-MBN O F Ar HX H2O O H2O O O Ar N aq KOH/PhMe OR 4 Aromatic aldehyde imine Ar N OR4 Br 59 Production of ethyl (S)-allylglycinate on scale Cl - + H3N CO2Et PhMe Ph O (1.0 equiv) - + TsO H3N CO2Et H Et3N (1.0 equiv) H2O Aq layer Et3N•HCl 99.6% ee (70% yield) PhMe layer ReX from EtOH/AcOEt Ph N CO2Et (94%) • 48% aq KOH (2.5 equiv) • (R)-MBN (0.1 mol%) • Br (1.1 equiv) TsOH•H2O (1.1 equiv)/AcOE 5 C, 6 h (94%) Ph N CO2Et H 92.3% ee 60 Asymmetric phase transfer catalysts of a C2-symmetric chiral 1,1’-binaphthyl type O 3 BBN: effective at not more than 1 mol%. Ar MBN: effective at not more than 0.5 mol%. MBN is at least 20 times more active than BBN. N 4 OR4 H H R4 t-Bu O Mono-alkylation is possible with aromatic aldehyde imine of glycinate Ar Esters other than t-butyl ones are tolerated N 4 OR4 H R1 Ar Ar F N+ Br - Ar = N+ F Br - F Ar (S,S)-BBN Ar (S)-MBN 61 Chiral analog of FTY720 O HO Novartis Pharmaceutical Corporation H2N Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164. Sphingosine kinase FTY720 (Fingolimod) 7 HO (S)-FTY720-phosphate 7 in vivo O (HO)2P HO H2N HO O H2N Immunomodulator acting via sphingosine 1-phosphate (S 1 P) receptor agonism The first S 1 P receptor modulator being evaluated in a phase-III clinical study Potential therapeutic agent to treat autoimmune diseases such as multiple sclerosis 62 Enantioselective synthesis of a-alkyl alanine derivative O Chiral analog of FTY720 HO H2N O RO2C H2N Diastereoselective alkylation using Schölkopf chiral template Asymmetric alkylation using chiral phase transfer catalyst O N OMe + MeO I (S)-MBN + N N CO2t-Bu n-BuLi Cl Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164. 63 Synthesis of 2-(2-propoxynaphth-6-yl)ethyl iodide n-PrI K2CO3 HO Br O O O + acetone 59 C, 48 h (95%) Br Pd(OAc)2 (1 mol%) K3PO4 (3.5 equiv) PhMe O OEt LiBH4, THF 65 C, 4 h (80%) 90 C (2 h) 100 C (2 h) (80%) I2 (1.5 equiv) Ph3P (1.3 equiv) O OH imidazole (1.5 equiv) THF, rt, 0.25 h (90%) Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164. O OEt (1.3 equiv) P(t-Bu)2 (2 mol%) O I 64 Research synthesis using Schölkopf’s chiral template O O I HO H2N N MeO OMe n-BuLi/hexane THF, -70 C (71%) N LiAlH4, THF (60%) Diastereoselectivity: 90–95% O MeO2C Elimination of HI N MeO O OMe N H2N TFA (20 equiv) MeCN, H2O (59%) Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164. 65 Asymmetric phase-transfer-catalytic alkylation Et3N MgSO4 Ar N CO2t-Bu MeOH (94%) (S)-MBN (1.3 mol%) CsOH•H2O (5 equiv) 0 C, 10 h Ar + O - + Cl H3N CO2t-Bu Ar = 4-Cl-C6H4 O (S)-MBN F (1.3 equiv) F I F PhMe/t-BuOMe (17:1) N+ Br - O F t-BuO2C F N Ar 96% ee Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164. F 66 Deprotection and reduction O 1. 6 M HCl/i-PrOH, H2O (68%) 2. slurrying in EtOH/PhMe (82%) t-BuO2C N O HO2C Cl - + Cl H3N > 99% ee 56% overall yield from protected Ala O LiAlH4 (4 equiv) HO H2N THF, 56 C, 4–5 h (79%) Prasad, R.; et al. Org. Process Res. Dev. 2008, 12, 1164. 67 The last issue to be addressed: asymmetric phase-transfercatalytic alkylation of protected alanine using liquid base Ar N PhMe/t-BuOMe (17:1) CO2t-Bu O I 0 C (S)-MBN O t-BuO2C N Ar = 4-Cl-C6H4 Ar CsOH•H2O Less costly Easier to handle 2 aq KOH Cl Cl PhMe R5-X + N t-Bu N F H R4 + O OR4 F F Br F - F F O R4 O N R5 68 (R)-a-(4-Fluorobenzyl)alanine F F Br Phase-transfer-catalytic asymmetric benzylation of N- and C-protected alanine using liquid base phase + CO2 F Cl Kinetic resolution with Lipase L (Amano) 100% by weight of enzyme 5 days at rt F S N CO2Et - H 3N H2N N AcHN CO2H F AcHN CO2H Boehringer Ingelheim Pharmaceuticals, Inc. Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61, 7398. 69 (±)-2-(Acetylamino)-2-methyl3-(3-fluorophenyl)-propionic acid ethyl ester - + 1. Et3N, H2O rt, 0.5 h H Cl H3N CO2Et F rt, 48 h t-Bu N H t-Bu 2. t-BuCHO MgSO4 CH2Cl2 rt, 20 h 1 N HCl CO2Et KOt-Bu (1 M/THF) toluene N CO2Et F (90%) Br -3 C 2h Ac2O, Py rt, 20 h F - + Cl H3N Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61, 7398. CO2Et (93%) F AcHN CO2Et (70%) 70 (S)-2-(Acetylamino)-2-methyl-3-(3-fluorophenyl)propionic acid 100% by weight of Lipase L (Amano) t-BuOH F AcHN phosphate buffer pH 6.5 (2 N KOH) rt, 5d CO2Et 5-step overall yield of 59% from (±)-Ala-OEt•HCl pH 8.8 (2 N NaOH) F Extraction with AcOEt pH 7.0 (2 N HCl) F AcHN Concentration to dryness AcHN CO2H (S)-Acid > 95.6% ee (37%) CO2Et (R)-Ester > 99.9% ee (47%) SiO2 Chromatog 22% from (±)-Ala-OEt•HCl Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61, 7398. 71 Production of (R)-4-fluorobenzylalanine on scale Cl - + H3N CO2Et H O (1.0 equiv) Ar PhMe 99.7% ee Ar = 4-Cl-C6H4 + H3N - CO2 F Et3N (1.1 equiv) H2O (63% overall yield) Aq layer PhMe layer Ar N Et3N•HCl Isoelectric precipitation (pH 5.9) (87%) aq KOH (Et ester hydrolysis) CO2Et (85%) H aq HCl (imine hydrolysis) (93%) • 48% aq KOH (4.7 equiv) • (S)-MBN (0.1 mol%) • F (1.0 equiv) Br Ar 8 C 6h (93%) N CO2Et F 87% ee 72 Scalable asymmetric PTC for the production of a-amino acids F F R2 F N + F (S)-MBN F O H 4 OR R1 Br F N - R5 X PhMe O R2 N 48% aq KOH (S)-MBN OR4 R1 R5 With C2-symmetric chiral mono-1,1’-binaphthyl derived quaternary ammonium bromide, MBN, (1) 0.1–0.5 mol% of it suffices to drive the reaction to completion with high enantioselectivity; (2) Any chiral centers, including quaternary ones, can be built enantioselectively under liquid-liquid biphasic conditions using aq KOH; (3) benzaldehyde imine of Gly esters (R1 = H, R2 = Ph) can undergo enantioselective mono-alkylation without incident; (4) esters simpler than tert-butyl ones (R4 = Me, Et) can be used without compromising enantioselectivity or yield. 73 Conformationally constrained b-methyl-a-amino acids Introduction of a b-methyl group can restrict conformational freedom around the side chain in c space O O OH OH NH2 NH2 anti-(2S, 3S) Component of bottromycin, a peptidic antibiotic produced by Streptomyces bottropensis syn-(2S, 3R) Component of sst4-selective somatostatin (SRIF) agonist Bull. Chem. Soc. Jpn. 1976, 49, 1081. J. Med. Chem. 2003, 46, 5587. O * * O - + F NH3 74 Double enantioselection by chiral quaternary ammonium ion Selection of a chiral center of racemic bromide (S)-MBN Selection of a prochiral enolate enantioface F O - R3 N F R2 4 OR N F F + F F si-face Ar H Ar (S) 2 Ar 3 H H Br R6 Br (R) CO2t-Bu R2 N R3 anti-(2R,3R) Br SN2 Ar 2 CO2t-Bu N R2 3 syn-(2R,3S) R3 75 Double enantioselection by C2-symmetric chiral phase transfer catalyst Ot-Bu O H 2 Br F (2 equiv) (S)-MBN (0.5 mol%) PhMe 50% aq KOH 3 N NH2 F Ph Ph anti-(2R,3R): 99% ee anti/syn (81:19): 73% yield 1 M aq HCl EtOH 0 C, 3 h Q* + - O Ot-Bu Br H F CO2t-Bu SN2 N + Ph (S) CO2t-Bu Ph si (front) face F N Ph Ph 76 Production of anti-(2R,3R)-b-methyl-4-fluorophenylalanine on scale F F O Ph N F H Br (1.5 equiv) OEt F (S)-MBN PhMe, (S)-MBN (0.1 mol%) 48% aq KOH (5 equiv) 5 C, 6.5 h N F O OEt 1. aq HCl (80%) 2. K2CO3 Br - F F N F + O Ph OEt O 2 O 3 - 1. aq NaOH 2. aq HCl (46%) F + F NH3 anti/syn (99:1) anti-(2R,3R): > 99% ee NH2 anti/syn (94.5:5.5) anti-(2R,3R): 99% ee 77 Streamlined production of chiral a-amino acids on scale Aromatic aldehyde imine formation (toluene) R2 N Direct use of the toluene solution without isolating the imine formed Asymmetric phase-transfer-catalytic alkylation H CO2R4 R1 (toluene/48% aq KOH) Liquid/liquid biphasic mixture R2 R5 N CO2R4 * R1 Phase separation and extraction Facile isolation of N- and C-protected a-amino acid products R6 CO2R4 * * R1 N R2 Manipulations with N- or C-protecting groups R5 7 R HN Purification by (re)crystallization * R1 CO2R8 4 CO R 2 * R6 R1 7 R HN * Isoelectric precipitation: free a-amino acids Formation of crystalline salts: N-acyl a-amino acids or a-amino esters 78 Conclusion What looks ordinary in the lab is out of the ordinary in the plant. Be skeptical about any premise. Discovery consists of seeing what everybody has seen and thinking what nobody has thought. Albert von Szent-Györgyi (1893–1986) 79 Thank you 80
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