Synthesis of p-Amino Acids

Additionally, p-amino acids possess the ability to form p-peptide analogues to a-peptides. These secondary structures are highly stable against cleavage of proteolytic 

The structures of possible products containing p-amino acids as intermediates. 

In the last few years several approaches to the enz3unatic synthesis of enantio-pure p-amino acids were pursued [6, 95]. Starting from N-acetylated ethyl esters, lipases [92], aminomutases [96, 97], acylases [98], moncxtxygenases [99], and ami-dases [100] were used for the synthesis of p-amino acids. 

Due to benefits like the wide substrate scope and their role in the biodegradation process of p-amino acids by microbes, the focus for the synthesis of optically pure p-amino acids has been relied recently on transaminases. 

The advantage of the kinetic resolution of p-amino acids is the shift of the equilibrium toward the product side, due to the spontaneous decarboxylation of tire p-keto acid by-product. For the synthesis of D-amino-N-butyric acid with an co-transaminase from Alcaligenes denitrificans and pyruvate as amino acceptor, conversion yields of 53% and 99% ee were obtained [52]. The kinetic resolution of racemic p-phenyla-lanine catalyzed by the co-transanrinase from Burkholderia phytoflrmans was examined recently [101]. 

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The approach of the alkylation of 5,6-diphenyltetrahydro-l,4-oxazin-2-one enolates (Equation 55) has the additional benefit that it could be extended to the synthesis of P-amino acids <2001JA3472> and y- or 5-amino acids <1998T10419>, as was shown in Scheme 22. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

Juaristi, E., Ed. "Enantioselective Synthesis of p-Amino Acids" Wiley-VCH New York, 1997. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Juaristi E (ed) (1997) Enantioselective synthesis of p-amino acids. VCH, Weinheim... 

Palomo C, Aizpurua JM, Ganboa I (1997) In Juaristi E (ed) Enantioselective synthesis of P-amino acids. Wiley-VCH, New York, p 279... 

Carbohydrate-derived homoallylamines have been demonstrated as being useful chiral synthons for the stereoselective synthesis of P-amino acids. With allyltribu-tylstannane or allyltrimethylsilane as the nucleophiles, glycosyl imines form homoallylamines with high efficiency [29-31]. Promoted by SnCl4, the nucleophile al-lyltributylstannane attacks from the stoically less hindered side. 

J. L. Matthews, C. Braun, C. Guibourdenche, M. Overhand, D. Seebach, Preparation of Enantiopure P-Amino Acids from a-Amino Acids Using the Amdt-Eistert Homologation , in Enantioselective Synthesis of P-Amino Acids , Chapter 5, (Ed. E. Juaristi), Wiley-VCH, New York, 1997, 105- 126. 

Cardillo, G. Tomasini, C. Asymmetric Synthesis of P-Amino Acids and a-Substituted P-Amino Acids, Chem. Soc. Rev. 1996, 25, 117-128. 

Yamamoto, Y Asao, N. Tsukada, N. Asymmetric Synthesis of P-Amino Acids and P-Lactam Derivatives via Conjugate Addition of Metal Amides, AiJv. Asym. Syruh., Vol. 3, Hassner, A., Ed. JAI Press, Stamford, CT, 1998. 

Kunz, H, Schanzenbach, D, Carbohydrates as chiral templates stereoselective synthesis of p-amino acids, Angew. Chem. Int. Ed., 28, 1068-1069, 1989. 

Enders, D., Bettray, W., Schankat, J., Wiedemann, J. Diastereo- and enantioselective synthesis of P-amino acids via SAMP hydrazones and hetero Michael addition using TMS-SAMP as a chiral equivalent of ammonia. Enantioselective Synthesis of/T-Amino Acids 1997,187-210. 

Juaristi, E., Garcia-Barradas, O. Asymmetric addition of amines to a, 3-unsaturated esters and nitriles in the enantioselective synthesis of P-amino acids. Enantioselective Synthesis of. beta.-Amino Acids 1997, 139-149. 

Lubell, W. D., Kitamura, M., Noyori, R. Enantioselective synthesis of P-amino acids based on BINAP-ruthenium(ll) catalyzed hydrogenation. Tetrahedron Asymmetry 1991, 2, 543-554. 

Derivatives from fi-Lactams Update in Enantioselective Synthesis of p-Amino Acids, 2" edition, E. Juaristi, V. A. Soloshonok, Eds John Wiley Sons, Hohoken, NJ, 2005 Chp. 20, p477. 

E. Juaristi, Enantioselective Synthesis of P-Amino Acids, Wiley-VHC, New York, 1997. 

Reactions using highly acidic active methylene compounds (pATa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer6 and Harada7 have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aprotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of p-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce (3-phenylalanine (88) in high yield (equation 14).82 This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

Juaristi, E. Garcia-Barradas, O. In Enantioselective Synthesis of P-Amino Acids, Juaristi, E. Ed. Wiley-VHC, New York, 1997. pp. 139-150. 

Al-salen complex, the addition of hydrazoic acid to mixed imides in which one of the acyl groups is a,p-unsaturated, excellent enantioselectivity results. Thus, this process is very valuable for the synthesis of p-amino acids. 

Sibi, M.P. and Itoh, K. (2007) Organocatalysis in conjugate amine additions. Synthesis of P-amino acid derivatives. Journal of the American Chemical Society, 129, 8064—8065. 

Asymmetric synthesis of P-amino acid esters. The chiral diazaborolidine 1 (16,155) also effects diastereo- and enantioselective reactions of (S)-r-butyl thiopro-ponoate (2) with N-benzyl or N-allyl aldimines 3 to form j3-amino acid esters 4, precursors to chiral irons-pAactams (5) in 90-99% ee. 

Parallel to the above approach efficient synthesis of P-amino acid derivatives by the use of Sn(II) enolates and a-aminoesters have been carried out by Japanese workers [90]. The most recent asymmetric synthesis of a (-h)-6-epi PS-5 carbapenem building block through this methodology (Scheme 33), involved... 

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