Enantiopure p-amino acids

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. 

Matthews, J. L., Braun, C., Guibourdenche, C., Overhand, M., Seebach, D. Preparation of enantiopure P-amino acids from a-amino acids using the Arndt-Eistert homoiogation. Enantiosel. Synth. /3-Amino Acids 1997,105-126. 

Asymmetric 1,3-DC of ynolates with a nitrone derived from Gamer s aldehyde afforded 5-isoxazolidinones in good yields and with high diastereoselectivity. The adducts were alkylated and converted to enantiopure P-amino acids, P-lactams and y-lactams <05TA2821>. 

The chiral l,4-oxazepin-7-one 166, prepared in turn from (i )-phenylglycinol 164 via 165, served as a key intermediate in the preparation of a variety of enantiopure P-amino acids <05TL8203>. The oxazepinone 166 could be selectively alkylated alpha to the ester group, then the double bond reduced diastereoselectively and the reduced oxazepinone then hydrolytically ring opened to the P-amino acids in good overall yields. 

Liljeblad, A. and Kanerva, L.T. (2006) Biocatalysis as a profound tool in the preparation of highly enantiopure P-amino acids. Tetrahedron, 62 (25), 5831-5854. 

Currently, resolution of racemates is a valuable strategy for the production of enantiopure P-amino acids [26]. The classical method of resolving amino acids is through transformation of the racemate into diastereomeric salts via complexation of the carboxylic acids with a chiral base, usually followed by multistep fractional recrystallization [25]. An alternative method is to resolve the enantiomers by applying the high stereoselectivity of enzymes, and there are a number of suitable biocatalysts available. 

Biocatalytic Preparation of Enantiopure P-Amino Acids 14.2.2.1 Lipases and Aminoacyiases... 

Kanerva, L.T., Csomos, P., Sundholm, O., Bernath, G., and Fiilop, F. (1996) Approach to highly enantiopure P-amino acid esters by using lipase catalysis in organic media. Tetrahedron Asymmetry, 7, 1705-1716. 

Exploration of the synthetic routes to sitagliptin reveals how catalytic asymmetric hydrogenation of unprotected p-enamides to enantiopure p-amino acid amides was discovered. First, we consider the whole synthetic route to the key precursor 13 (Scheme 4.1). 

Considering the growing importance of p-amino acids as building blocks for peptid-omimetics and bioactive compoimds, there is the need for new synthesis strategies for their production in enantiopure p-amino acids. As shown in Scheme 29.11, the amino group of p-amino acids is attached to the p-carbon atom compared to a-amino acids. There are p -, p -, and p -substituted amino acids classified by the position and number of their residues [79,80,88]. 

Enantiopure bis-P-amino acids can be prepared from chiral bis-sulfinimines.37 Bis-sulfinimine (Ss,Ss)-160 and the sodium enolate of methyl acetate react to give 161 as a diastereomeric mixture. The major isomer (5s,/ ,Ss,/ )-161 can be isolated by preparative reverse-phase HPLC in 46% yield. Hydrolysis of (Ss,/ ,Ss,/ )-161 gave bis-P-amino ester (/ ,/ )-162 in >97% ee and 86% yield.37... 

Biotransformations of hve-membered alicyclic trani-A-protected-amino nitriles proceeded faster than in case of six-membered compounds. The products of the trani-A-protected-amino nitriles (amides and acids) were formed preferentially than the products of the c A-counterparts (only amides). Enantioselectivities were strongly dependent on the structure the trani-hve-membered substrates gave exclusively amides with excellent optical purity (94-99%), in contrast to the tran -six-membered substrates resulted in the formation of the acid with excellent enantiopurity (87-99%). The corresponding c A-compounds yielded much lower enantiomeric excesses. Nitrile precursor of a-methylene-P-amino acids was analogously investigated (Winkler et al., 2005) (Table 17.13). 

Ma, D.Y, Wang, D.X., Zheng, Q.Y, et al. 2006. Nitrile biotransformations for the practical synthesis of highly enantiopure azido carboxylic acids and amides, click to functionalized chiral triazoles and chiral P-amino acids. Tetrahedron Asymmetry, 17 2366-76. 

S. Abele, D. Seebach, Preparation of Achiral and of Enantiopure Geminally Disubstituted p-Amino Acids for P-Peptide Synthesis , Eur. J. Org. Chem. 2000, 1 - 15. 

Isoxazolines 54, prepared by stereoselective 1,3-DC of nitrile oxides and enantiopure allylic alcohols, were converted into p-amino acids 56 eind 58 by nucleophilic addition to the C=N bond followed by reductive cleavage of the N-0 bond and oxidative cleavage of the diol moiety. The facial selectivity in the nucleophilic addition was dictated by the C-5 substituent in either a directed (hydride addition) or a sterically (Grignard reagents addition) controlled manner <03JA6846>. 

Preparation of Enantiopure a-Substituted p-Amino Acids. In preliminary studies, racemic 2-rerr-hutyl-perhydropyrimidinone, rac-4, was alkylated with high di-astereoselectivity via its corresponding enolate (eq 5). The high stereoselectivity encountered in the reaction of rac-4-Li with various electrophiles was ascribed to steric hindrance generated by the axial disposition of the tert-butyl group at C(2), which directs approach to the electrophile from the enolate face opposite to this group. 

These observations paved the road for the development of a new method for the asymmetric synthesis of a-substituted p-amino acids. Thus, an efficient protocol for the preparation of enantiopure pyrimidinone (S)—4 was developed (vide supra, eq 1 ). 

The Nicholas reaction was used to synthesize the p-lactam precursor of thienamycin in the laboratory of P.A. Jacobi and thereby accomplish its formal total synthesis. The necessary p-amino acid was prepared by the condensation of a boron enolate (derived from an acylated oxazolidinone) with the cobalt complex of an enantiopure propargylic ether. The resulting adduct was oxidized with ceric ammonium nitrate (CAN) to remove the cobalt protecting group from the triple bond, and the product was obtained with a 17 1 anti.syn selectivity and in good yield. 

Mapp et al. have reported a versatile and efficient synthesis of substituted P-amino acids (P-AA) through diastereoselective nucleophilic addition to enantiopure isoxazolines 40. In the C=N reduction with LiAlILt in THF, the proximal hydroxymethyl substituent directed the hydride approach to the same side as the C-5 ring substituent, affording the amino diol 41 with high diastereoselectivity. In contrast, carbon nucleophiles were sterically driven and preferentially added on the opposite isoxazoline face. The facial selectivity was complete with... 

Although at present this chemoenzymatic method might not seem as versatile as the original hydantoinase process, the results on dihydropyrimidinases indicate a clear opportunity for the production of enantioenriched or enantiopure and P -amino acids by kinetic resolution ivhen the enantioselectivity of the enzyme is very high. Thus, further research is needed to find (or create) new enzymes with higher enantioselectivity. 

R. erythropolis A4, Rhodococcus sp. R312, and R. erythropolis NCIMB 11540 were used in the hydrolysis of five- and six-membered ahcyclic trans-aminonitriles (Figure 11.6), which are the precursors of cyclic p-amino acids. The enzymes discriminated between the trans- and cis-isomers, the transformation of the former proceeding slowly or stopping at the amide stage. Moreover, hydrolysis of the latter resulted in excellent enantiopurity of the trans-amino acids or amides [38]. 

Nitriles may be converted to amino acids by nitrilases, which catalyze a two-step nitrile hydrolysis reaction, and can provide p -amino acids in high enantiopurity. The same reaction can be catalyzed by a combination of nitrile hydratase and... 

Gyarmati, Z.C., Liljeblad, A., Argay, G., Kalman, A., Bernath, G., and Kanerva, L.T. (2004) Chemoenzymatic preparation of enantiopure homoadamantyl P-amino acid and P-lactam derivatives. Adv. Synth. Catal, 346, 566-572. 

The Backvall group reported the DKR of p-amino acids using CAL-A and Ru or Pd catalyst (Scheme 5.38) [61]. CAL-A was immobilized in the functionalized meso-cellular form (MCF) to improve its stability and enantioselectivity. The DKR with Pd catalyst and the MCF-immobilized CAL-A provided (S)-products, with better yields and higher enantiopurities (Chart 5.34). Our group explored the DKR of p-amino acids for preparing Ihe products of opposite configuration with PSL and Pd/ AIO(OH) (Scheme 5.39) [62]. As PSL was not thermally stable, the PSL-catalyzed resolution and Pd-catalyzed racemization were performed alternatively at two different temperatures (RT and 70 °C) to give (R)-product with 90% yield and >99% ee (Scheme 5.39). 

The variations and combinations of cascade design involving these core biocatalysts are vast. In addition, biocatalysts with complementary activities continue to be uncovered. For example, ammonia lyases and aminomutases have been demonstrated to be viable biocatalysts for the synthesis of enantiopure a- and p- amino acids... 

Hydrogenation of -substituted ( )-p-(acylamino)acrylates catalyzed by the BINAP-Ru es P-amino acid derivatives with high enantiopurities (Scheme 1.9) [8S]. The Z double-bond isomers that have an intramolecular hydrogen bond between amide and ester groups are more reactive but are hydrogenated with poor enantioselectivity. The sodium or triethylammonium salts of the unsaturated acid are hydrogenated in water containing a sulfonated p-Ibl-MeO-BIPHEP-Ru ditrifluoroacetate complex with an S/C of KKX)-10,000 and an up to 99% optical... 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

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