Enantioselective synthesis using amino acids

A regio-, diastereo- and enantioselective synthesis of amino acids was reported by Takemoto and coworkers. The glycine equivalent ethyl diphenylimino glycinate was used as pronucleophile (Scheme 9.14), while the Hgand was a bidentate chiral phosphite, and 3-arylaUyl diethyl phosphates were employed as allylic substrates [39, 46]. 

An enantioselective synthesis of amino acids has been examined using chiral nonracemic a-imino esters (36) derived from (S)-l-phenylethylamine and (-)-l-cyclohexylethylamine (equation 9, Table 9). Allyl-magnesium, -copper and -titanium reagents react at both the imine and ester carbon atoms of (36), a result of the molecule s ambient electrophilicity. The addition of allyl-, methallyl- and prenyl-9-BBN and -ZnBr to a-imino ester (36), however, generates amines (38) and (39). While the absolute stereochemistry of (38) and (39 R = Ph) has been determined (entries 1-4, Table 9), that of the cyclohexyl-ethylamine-derived products has not (entries 5-8, Table 9). 

Enzymatic methods offer in principle the possibility of a direct enantioselective synthesis of amino acids. Enzymes are often used for separation of racemic mixtures, as examplified in the case of methionine. Although racemic methionine is adequate for the animal feed sector, other applications require the enan-tiomerically pure (L)-form. For the resolution, (L)-acylases from Aspergillus sp. are often used, since they can accept a broad spectrum of substrates, are highly active, and very stable under the production conditions. [62]... 

Wulff, G. Vietmeier, J. Enz me-analog built polymers. 26. Enantioselective synthesis of amino acids using pol5mers possessing chiral cavities obtained by an imprinting procedure with template molecules. Makromol. Chem. 1989,190, 1727-1735. 

Amino acids can be synthesized in racemic form by several methods, including alkylation of diethyl acetamidomalonate and reductive amination of an a-keto acid. Alternatively, an enantioselective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

Wittig and Wittig-like reactions are frequently used for C2-elongation of a-amino aldehydes. For example, (carbethoxymethyl)triphenylphosphorane 14 was recently used in preparation of the intermediate 15 for enantioselective synthesis of (+)-alIokainic acid [28] (Scheme 6). A similar method was used in the synthesis of the amino hexose, IV-acetyl-L-tolyposamine [29]. 

The synthesis of amino acid esters can be carried out enantioselectively when optically active EBTHI zirconaaziridines are used. After diastereomeric zir-conaaziridines are generated and allowed to equilibrate (recall Scheme 3), the stereochemistry of the chiral carbon center in the insertion product is determined by competition between the rate constants kSSR and ksss for the epimerization of zirconaaziridine diastereomers and the rate constants [EC] and ks[EC] for ethylene carbonate (EC) insertion (Eq. 31) [43]. When kR[EC] and ks[EC] are much greater than kSSR and ksss> the product ratio reflects the equilibrium ratio as shown in Eq. 32. However, the opposite limit, where epimerization is much faster than insertion, is a Curtin-Hammett kinetic situation [65] where the product ratio is given by Eq. 33. 

Reaction of lithiodithianes with acyl chlorides, esters or nitriles leads to the fOTination 1,2-dicarbonyl compounds in which one of the carbonyl groups is protected as the thioacetal. d76043j44 Optically active amino ketones of type (69) are inepared via acylation of dithiane with an oxazoline-protected (5)-serine methyl ester (Scheme 41). Optically active (5)-2-alkoxy-l-(l,3-dithian-2-yl)-l-propanones were prepaid by the reaction of the corresponding methyl (5)-lactate with 2-lithio-l,3-enantioselective synthesis of (-)-trachelanthic acid. Enantioselective synthesis of L-glyceraldehyde involves the acylation of a dithiane glycolic acid derivative followed by bikers yeast mediated reduction. ... 

Takatori, K., Tanaka, K., Matsuoka, K., Morishita, K., and Kajiwara, M., An enantioselective synthesis of (-)-nonactic acid and (+)-8-cy -nonactic acid using microbial reduction, Synlett, 159, 1997. Ornstein, P.L., Bleisch, T.J., Arnold, M.B., Wright, R.A., Johnson, B.G., and Schoepp, D.D., 2-Substituted (2SJ )-2-amino-2-(15 J, 2SR)-2-carboxycycloprop-l-yl)glycmes as potent and selective antagonists of group II metabotropic glutamate receptors. Part 1. Effects of alkyl, arylalkyl, and diarylalkyl substitution, 7. Med. Chem., 41, 346, 1998. 

The use of chiral complexes gives rise to enantioselectivity of carbon—carbon bond formation and this phenomenon has also been applied to resolution and enantioselective deuteration of amino acids. Both the kinetic acidity of the a-methylene protons and the enantioselectivity of bond formation are greatly enhanced by the formation of chiral complexes (32) and (33) of imines derived from the amino acid and salicylaldehyde or pyridoxal respectively. Similar use has been made of imine complexes (34) derived from pyruvic acid and the amino acid. > Very recently, an asymmetric synthesis of threonine has been achieved using the chiral imine complex (35). ... 

An enantioselective a-indoline amino acid protocol was also described using glycinyl imines but with varying loss of enantiomeric purity [40]. More recently, synthetic attempts towards the indole alkaloid ambiguine G, as seen in the synthesis of 49, have also utilized this chemistry [41]. 

Viswanathan R, Prabhakaran EN, Plotkin MA, Johnston JN (2003) Free radical-mediated aryl amination and its use in a convergent 3-1-2 strategy for enantioselective indoline alpha-amino acid synthesis. J Am Chem Soc 125 163-168... 

Several methods are used for the synthesis of amino acids. A mqjor problem with any synthesis is preparing enantiopure products. Most of the syntheses shown here give racemic amino acids, but methods are known that produce amino acids highly enriched in one enantiomer (see Chapter 9). Enantioselective synthetic methods will not be discussed. A method used quite often to obtain an enantiopure amino acid prepares the racemic compound, followed by isolation of the 1-amino acid by resolution, as described in Chapter 9, Section 9.8. 

A variety of reaction types have been used for the synthesis of amino acids in this chapter and the ones preceding it. Many reactions do not fit into a single category, as did the reactions in section 5.1. Those reactions that proceed with good diastereo-selectivity or with reasonable enantioselectivity are collected into this section. 

---