A-Hydroxy carboxylic esters

Ojima (43) used the same DIOPRh catalyst earlier to add Et2SiH2, PhMeSiH2, Ph2SiH2 and a-naph-PhSiH2 to a-ketoesters to synthesize optically active a-hydroxy carboxylate esters. With diethyl- or phenyl-methylsilane and propyl pyuvate, a double hydrosilation occurred to chiefly make a cyclic product with double asymmetry. 

In these synthesis, the optically active (R)-cyanohydrin is transformed into the corresponding a-hydroxy carboxylic ester and the hydroxyl funchon is achvated by sulfonylahon. The treatment of the corresponding intermediate with tetra-hydrothieno[3,2-c]pyridine stereoselectively yields the (S)-configured clopidogrel (Scheme 10.23). In the second case, a mutant of the recombinant almond (Pmnus amigdalus) (R)-oxynitrilase isoenzyme 5 catalyzes the formation of enantiopure (R)-2-hydroxy-4-phenylbutyronitrile [54]. Reaction of the sulfonylated hydroxyester derivative with the corresponding dipeptide leads to the formation of enalapril or lisinopril (Scheme 10.24). 

Acylation of chiral alcohols The pyridinium triflates and tetrafluoroborates are useful reagents for delivery of acyl groups to chiral secondary alcohols such as a-hydroxy carboxylic esters. 

Binder, J., and Zbiral, E., A new procedure for homologation of carbonyl compounds to a-hydroxy-carboxylic esters by means of diethyl (trimethylsilylethoxymethyl)phosphonate. Tetrahedron Lett., 27, 5829, 1986. 

Corey s auxiliary reagent 10 is also applied in order to obtain a f/-2-bromo-3-hydroxy-carboxylic esters in enantiomeric purities of 91-98%. The a-bromo esters thus obtained are useful intermediates for the preparation of a-unsubstituted /Miydroxy esters as well as for 2-amino-3-hydroxy- and 3-amino-2-hydroxycarboxylates64a b. 

D-a-Hydroxy carboxylic acids.1 These optically active acids can be prepared by a Sn2 reaction between the t-butyl esters of L-2-halo carboxylic acids and cesium p-nitrobenzoate, which proceeds with complete inversion. 

Diazocycloalkanones with five- to twelve-membered rings can be synthesized by the present procedure in good yields (Table I).4 Diazo transfer with deformylation can also be used for the preparation of bicyclic a-diazo ketones.10,11 A related procedure involving reaction of the sodium salt of an a-(hydroxy methylene)-ketone with p-toluenesulfonyl azide in ethanol has been applied to the synthesis of diazoalkyl ketones, a-diazo aldehydes, and a-diazo carboxylic esters.12... 

The biotechnological synthesis of lactones has reached a high standard. Besides microbial production, lactones can also be enzymatically produced. For instance, a lipase-catalysed intramolecular transesterification of 4-hydroxy-carboxylic esters leads enantioselectively (ee>80%) to (S)-y-lactones the chain length may vary from C5 to Cl 1 [13]. y-Butyrolactone can be produced in that way with lipase from Mucor miehei [30]. 

Asymmetric synthesis of fi-hydroxy carboxylic estersEsters of 1 in the presence of f-butylmagnesium bromide as base react with aldehydes and ketones to form optically active a-sulfinyl-jS-hydroxy carboxylic esters, which are desulfurized by aluminum amalgam in aqueous THF (equation I). Chemical yields are 75% of... 

Aldol condensation of a-amino silyl ketene acetals (l).10 2-Dibenzylami-noketene trimethylsilyl acetals (1) react with aldehydes premixed with TiCl4 to give a-amino-p-hydroxy carboxylic esters (2) with moderate to high syn-selectivity. Surprisingly, TiCl4-catalyzed reaction of 1 with a chiral a-alkoxy aldehyde proceeds with low asymmetric induction. 

In general, the method of enzymatic cyanohydrin synthesis promises to be of considerable value in asymmetric synthesis because of the synthetic potential offered by the rich chemistry of enantiomerically pure cyanohydrins, including their stereoselective conversion into other classes of compounds such as a-hydroxy carboxylic acids or respective esters, w c-diols, / -aminoalcohols, aziridins, a-azido(amino/fluoro)nitriles, and acyloins [501, 516]. 

Aldol condensation.2 Theenolateofl reacts with aldehydes to form preferentially cn7hm-f/-methyl-a,/f-di hydroxy carboxylic esters (equation I). The O-MEM ether of methyl lactate shows similar erythro-selectivity (ca. 6 1). In contrast, the anion of... 

Computational efforts to describe the conformational preferences of (R,R)-tartaric acid and its derivatives - mainly for isolated molecules - were made recently [18-25]. The conformations of these molecules also attracted attention from experimental chemists [22-40]. (/ ,/ [-tartaric acid and its dimethyl diester were observed in crystals, in conformations with extended carbon chain and planar a-hydroxy-carboxylic moieties (T.v.v and Tas for the acid and the ester, respectively) [25-28] (see Figure 2). The predominance ofthe T-structure was also shown by studies of optical rotation [31], vibrational circular dichroism (VCD) [23], Raman optical activity [32, 35], and nuclear magnetic resonance (NMR) [22, 33, 34]. The results of ab-initio and semiempirical calculations indicated that for the isolated molecules the Tsv and T as conformers were those of lowest energy [22, 21, 23, 25]. It should be noted, however, that early interpretations of NMR and VCD studies indicated that for the dimethyl diester of (/ ,/ [-tartaric acid the G+ conformation is favored [36-38]. 

Fig. 13.40. Alkylation of an ester enolate for the preparation of an a-hydroxycarboxylic acid (for the preparation of enantiomerically pure a-hydroxy carboxylic acid through alkylation of an enantiomerically pure ester enolate cf. Figure 13.41). The initially formed benzyl ester B contains two benzylic C—0 bonds, which can be cleaved by means of hydrogenolysis.

Dioxathiolan-4-one 2-oxides (50) decompose rapidly in the presence of water and mineral acids to form a-hydroxy carboxylic acids, the detailed mechanism of hydrolysis being unknown. Nucleophilic attack on (50) by alcohols occurs at the acyl carbon atom and, with elimination of sulfur dioxide, gives a-hydroxy carboxylic acid esters (76CRV747). In a similar fashion to (50), l,2,3-oxadithiolan-5-one 2-oxides react rapidly with water to yield the parent a-mercaptocarboxylic acids (77MI43301). 

Ng [2,3] prepared bioerodible copoly(ortho esters) consisting of the Step 2 product with monomethyl polyethylene glycol ether termini and 1,4-cyclohex-anedimethanol and either an a-hydroxy carboxylic acid, (II), or A -methyl-di-ethanol amine (III), for use as bioerodible matrices for the sustained release of biologically active agents. Other dioxalane bioerodible analogues were prepared by Ng [4] in an earlier investigation. 

Enantiomerically enriched a- and P-hydroxy carboxylic esters are valuable reagents for optical resolution and are important intermediates in the preparation of pharmaceuticals and agrochemicals [18,19], Esters of mandelic acid are used as precursors... 

Stereoselective addition of a dithiane anion to chiral 2-metiiyl-3-trimethylsUyl-3-butenal combined with the stereoselective addition of a Grignard reagent to the chiral a-alkoxy ketone affords a practical method for the construction of a, y-dimethyl-a,p-dihydroxy compounds, useful intermediates for the synthesis of erythronolides (Scheme 33). -Hydroxy carboxylic esters were synthesized by the addition of ethyl 1,3-dithiolanyl-2-carboxylate enolate to a chiral aldehyde, followed by desulfurization. ... 

In the benzil-benzilic acid rearrangement, an a-diketone is treated with a base to give the sodium salt of an a-hydroxy carboxylic acid. In the Favorskii rearrangement, an a-halogenoketone is treated with an alkoxide anion to give the a-alkyl ester. This reaction may also be used to effect a ring contraction. 

Alkylation of fahydroxy carboxylic esters (8, 258). Dianions of / -hydroxy carboxylic esters (LDA, —50° to —20°) are alkylated stereoselectively to give mainly f/irao-compounds (equation I). The alkylation of dianions of a-mono-... 

---