Chiral pool amino acids

Part II - Asymmetric Syntheses from the Chiral Pool Amino Acids... 

Organic chemists speak of a chiral pool, which comprises those naturally occurring compounds that are readily available as a single enantiomer and capable of being used as starting materials for the enantioselective synthesis of other chiral molecules. Amino acids are well represented in the chiral pool. All except glycine have at least one chirality center and, although L-amino acids are more abundant and less expensive than their D-enantiomers, both are available. 

The general syntheses of alkenes (p. 28 — 44) and 1,2-dihydroxy compounds (p. 50—54 and 123 — 132) are not repeated here. But there is an important chiral pool" for chiral 1,2-disubstituted compounds, namely a-amino acids. 

Optically active five- or six-membered cyclic A -acyliminium ions of this type are generated from the a-inethoxy derivatives, easily obtainable through anodic methoxylation of intermediates that are prepared via ex-chiral-pool syntheses from certain natural amino acids. Reaction of 5-substituted five-membered cyclic A -acyliminium ions with various nucleophiles leads to the predominant formation of cw-products with moderate selectivity. The trans-selective reaction with alkyl copper reagents appears to be an exception. 

Despite of the disadvantage, that at least one symmetrical dimer is formed as a major side product, mixed Kolbe electrolysis has turned out to be a powerful synthetic method. It enables the efficient synthesis of rare fatty acids, pheromones, chiral building blocks or non proteinogenic amino acids. The starting compounds are either accessible from the large pool of fatty acids or can be easily prepared via the potent methodologies for the construction of carboxylic acids. 

Dutton reported on the synthesis of an e-caprolactam analog of an anthelmintic cyclic peptide. The a-hydroxy-e-caprolactam 44 was generated in an ex chiral pool synthesis staring from malic acid. The a-hydroxy carboxylic acid unit was protected as a dioxolanone in 43. The protective group served simultaneously as the reactive function during cyclization lactam 44 formation succeeded by ring opening of the dioxolanone 43 by the nucleophilic attack of the amino function, Eq. (8) [14]. 

In the rearrangement of divinylaziridines 289, the participation of a boat-like transition state 290 explained the stereochemical outcome of the reactions to give the azepinones 291 in 73 to 85% yield. The divinylaziridines 289 were synthesized via ex-chiral pool sequences starting from optically active a-amino acids. Table 16, Eq. (26) [55]. 

One of the fundamental operations in organic synthesis remains the stereoselective reduction of carbonyl groups1241. In a process related to that reported by Hosomi et u/.[25], using hydrosilanes as the stoichiometric oxidant and amino acid anions as the catalytic source of chirality, a variety of ketones were reduced in good to excellent yield and with good stereoselectivity1261. This process reduces the amount of chiral catalyst needed and utilizes catalysts from the chiral pool that can be used directly in their commercially available form. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

Chiral effector ligands can be a variety of molecules, including amino acids. The chiral alcohol products of the chiral-transfer reactions in Fig. 11.4 cycle back into these reactions by subsequent tomplexation with the pool of diisopropyl zinc. 

One purpose of our work is to mimic the chiral environment of the enzymes. Therefore, we thought it a reasonable goal to supply chiral models for the active sites of metalloenzymes. This was achieved before by Alsfasser et al. 113) or Vahrenkamp et al. 114) via amino acids that have been incorporated into the ligand systems. Modification of Tp ligands by chiral pyrazoles derived from the chiral pool is another way to chiral W,W,iV tripod ligands and has been achieved before by W. B. Tolman and coworkers (115). Thus, first we focused on the synthesis of a racemic mixture of a chiral NJtl,0 scorpionate... 

The use of chiral oxazolines as ligands for catalytic asymmetric synthesis is undoubtedly the most important development in oxazohne chemistry. Compared with other ligands, oxazolines offer the advantage of being easily accessible from chiral amino alcohols that are, in turn, readily available from a chiral pool of amino acids. There have been numerous reports on this exciting use of oxazolines during the last 10 years. Many of the ligands studied to date contain at least two oxazoline units. The synthesis and reactions of bis(oxazohnes) are discussed in detail in Chapter 9 the discussions in this section are limited to mononuclear oxazolines. 

The most widely applicable method of optical resolution utilizes a chiral auxiliary, which is taken from either the chiral pool 14 (carbohydrates, terpenes, amino acids etc.) or obtained by previous optical resolution. The auxiliary A, in an optically pure form, combines with the racemic substrate S to form two diastereomers p and n, respectively. 

Despite its efficiency in numerous cases optical resolution is by no means a trivial operation. In each case the optimum method has to be found by laborious trial and error procedures the optical purity of the material has to be secured and its absolute configuration has to be established before the compound can be used in a synthetic sequence. These drawbacks of optical resolution led chemists to start their syntheses from optically active natural products (the so-called chiral carbon pool ). A variety of suitable ex-chiral-pool compounds including carbohydrates, amino acids, hydroxy acids, and terpenoids are shown. 

Amino acids have been used in ex-chiral-pool syntheses far less frequently. The most popular starting material is serine (available in both configurations), due to the differentiable functional groups at the termini. L-Serine (1) may be converted into a variety of (R)-amino acids 5 by straightforward manipulations12. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Since the stereochemical changes in each reaction of the sequence are known, a particular amino acid starting material (R or S) will give a particular configuration in the product. In this strategy of asymmetric synthesis, all or part of die final molecular skeleton is derived from the chiral precursor. While simple, diis strategy is limited by the size of the chiral pool and by the types of reactions which occur stereospecifically at tetrahedral centers. 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

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