A-hydroxyesters

Various racemic secondary alcohols with different substituents, eg, a-hydroxyester (60), are resolved by PFL neatly quantitatively (75). The effect of adjacent unsatuiation on enzyme-catalyzed kinetic resolutions was thoroughly studied for a series of aHyUc (61), propargyUc (62), and phenyl-substituted 2-aIkanols (76,77). Excellent selectivity was observed for (E)-aHyhc alcohols whereas (Z)-isomers showed poor selectivity (76). 

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

Enanlioselectivc hydrogenation of a-kelocsiers Pt/C, Pl/Al,0, a-hydroxyesters Chiral intermediates... 

Since the advent of the one step procedure for the preparation of various substituted thenaldehydes (44), the majority of the necessary starting materials were readily available. Consequently, the Reformatsky reaction was studied with these compounds. With the a-bromoesters the reaction was successfully carried out with four of the thenaldehydes and 2-acetothienone. The nature of the product seemed to depend on the degree of branching of the bromoester. In only one case, where ethyl bromoacetate was used, was a hydroxyester obtained. However, when the carbon atom adjacent to the carbethoxy group was substituted, the product usually contained a hydroxyl group. The dehydration by means of aqueous oxalic acid resulted in a nearly quantitative conversion to the unsaturated esters. 

Scheme 166 Desoxygenation of a-hydroxyesters via reduction of the methanesulfonates with diphenyidiselenide as mediator.

If a hydroxyester function is incorporated into a potential chelating system then the ability even of a labile metal ion to catalyze the hydrolysis can be assessed. The 8-hydroxyquinoline 17 and 2,2 -phenanthroline 18 frameworks have proved popular for this purpose. 

Dihydrofuranones can be generated by Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates. The resulting intramolecular Dieckmann condensation yields substituted furanone rings (Scheme 82) (57HCA1157). 

A very useful method for generating 3 (2H)- dihydrofuranones is based on the Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates (Scheme 82). The intermediate anion attacks the adjacent ester moiety via a Dieckmann condensation reaction to produce a substituted furanone ring which usually bears useful functionality. Overall yields of 45-60% have been obtained for this reaction. 

Phosphonopyruvate systems were the first candidates submitted to reductive amination. Because of the presence of the ester group, the a-ketoester carbonyl is less reactive than traditional oxoalkylphosphonates, and yields of isolated amino-esters never exceeded 55 %. The reaction is run at pH 7 in ethanol and it is general for ammonia and primary amines. Steric hindrance represents the second limiting factor since a-substituted or thiono-phosphonopyruvates react sluggishly thus secondary amines cannot be introduced. When the reductive amination process is effected the exclusive by-product is the a-hydroxyester which arises by reduction of the carbonyl group (7j-8). 

A few years previously, the same research group reported a one-pot condensation of three components (methylphenylglyoxylate (MPG), aniline, and aromatic aldehyde), promoted by a TiCl3/pyridine system under anhydrous conditions, for the diasteroselective synthesis of P-amino-a-hydroxyesters (Equation 14.24) [32]. 

Scheme 2.32 Formation of optically active a-hydroxyesters by reaction of acid chlorides with benzoylquinidine acting a catalytic chiral nucleophile, followed by [4+2]-cycloaddition with o-chloroanil.

The methodology was developed using a series of a-hydroxyhydrazones 48a-d (Scheme 13) prepared from the corresponding a-hydroxyesters by standard transformations. These were converted to a series of 16 silyl ethers (49Da-d, 49Ea-d, 49E a-d, 49Fa-d) by reaction with the appropriate chlorosilanes. 

The activated zinc will also react rapidly with a-chloroesters in THF. However, the yields are not nearly as high and generally are in the 65% range. In this particular case, the yields of the a-hydroxyester are very dependent on the anion of the zinc salt used to generate the zinc metal and can range down to as little as 5%. 

Similar results have come from studies of the DEBS 1-i-TE system in vitro [53]. When DEBS 1 -I- TE was incubated with appropriate precursors in the absence of the reducing agent NADPH the keto 27 and the pyrone 28 analogues of the triketide lactone were obtained (Scheme 13) [53,54]. This latter result resembles the similar formation of a pyrone product by the animal PAS and the 6-methyl-salicylic acid PKS under similar conditions [55]. Clearly, the /Tketoester intermediates can be transferred from one module to the next without further processing, even in modules which are geared to the production of a hydroxyester intermediate. 

The reduction of 2-acyl- 1,3-oxathianes such as 3.96 (X = S) or of 2-acyl-3-oxa-N-benzylpiperidines 3.96 (X = NCH2Ph) can also take place with or without chelation control [El, EFl, EH2, KEl, KF4]. In cases of chelation control, the oxygen atom of the heterocycle participates in the chelation process (Figure 3.32). When the reaction is carried out with Li(5-Bu)3BH in the presence of Lil as an additive, the reduction occurs under chelation control. However, when using two equivalents of DIBAH, each of them coordinates to a one basic site, and no chelation takes place. The use of these chiral auxiliaries allows the synthesis of nonracemic a-hydroxyaldehydes or a-hydroxyesters with a high enantiomeric excess [NNl, S3]. 

The asymmetric insertion of a-diazoesters into the O—H bond of water provides an extremely simple approach for the synthesis of chiral a-hydroxyesters in an efficient and atom-economical way. The challenges of asymmetric O—H insertion of water are mainly attributed to two considerations first, the active metal carbene intermediates are generally sensitive to water and secondly, the small molecular structure of water makes chiral discrimination quite difficult. Zhou and co-workers discovered a highly enantioselective O—H insertion of water catalyzed by chiral spiro Cu [112] and Fe catalysts [111]. Under mild conditions, both Cu andFe complexes of ligand (S, 5,5)-23a... 

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