Chiral monoesters

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

The enantioselective enzyme (pig liver esterase)-catalyzed hydrolysis of a prostereogenic diester, such as dimethyl we.vo-4-oxocyclopentane-l,2-dicarboxylate, to give the chiral monoester 357,58 (for configurational assignment, see p441) or the enantioselective monoacylation of a prostereogenic diol. 

Asymmetric ring opening of achiral monocyclic, bicyclic and tricyclic anhydrides under formation of the corresponding chiral monoesters can be accomplished in high yield with modest enantioselectivity with methanol in the presence of less than stoichiometric amounts of cinchona alkaloids in toluene or diethyl ether (Table 9)91 94. As expected the use of cinchonine A or quinidine C, and of cinchonidine B or quinine D gives opposite enantiomers. Recrystallization of the monoesters and lactones affords material of considerably higher enantiomeric purity (Table 9, entries 15, 16, 21, and 23). 

Numerous meso-configured or otherwise prochiral substrates, preferentially containing enantiotopic methoxycarbonyl groups, have been converted by a pig liver esterase- or lipase-catalyzed enantioselective hydrolysis in water to chiral monoesters (see Sect. 11.1.1.1.1., Tables 11.1-1 to 11.1-4 and Sect. 11.1.1.1.5, Tables 11.1-10 to 11.1-12). In nearly all cases investigated thus far the pig liver esterase-catalyzed hydrolysis of the substrate diester S terminates at the stage of the enantiomeric monoesters P and ent-P. In this case, where the products P and ent-P are not transformed further, the irreversible enantiotopos-differentiation may be described by the process depicted in Scheme 11.1-10167 691. 

Chiral monoesters, obtained either from a prochiral diol or diester, may be converted by a suitable series of chemoselective transformation to either enantiomer of a given target compound (enantiodivergent synthesis) (Scheme 11.1-13)110 40l... 

On the other hand, when the substrate is a diacetate, the resulting monoester is less polar and thus usually undergoes further cleavage in a second step to yield an achiral diol [29]. However, since the second step is usually slower, the chiral monoester can be trapped in fair yield if the reaction is carefully monitored. 

Similarly, the two chemically identical groups X, positioned on carbon atoms of opposite (/ ,5)-configuration in a weso-substrate, can react at different rates in a hydrolase-catalyzed reaction (Scheme 2.4). So, the optically inactive meso-substrate is transformed into an optically active product due to the transformation of one of the reactive groups from X into Y along with the destruction of the plane of symmetry within the substrate. Numerous open-chain or cyclic c/s-weso-diesters have been transformed into chiral monoesters by this technique [30]. Again, for dicarboxylates the reaction usually stops after the first step at the carboxylate monoester stage, whereas two hydrolytic steps are usually observed with diacetoxy esters [31]. The theoretical yield of chiral product from single-step reactions based on an enantioface or enantiotopos differentiation or a desymmetrization of meso-compounds is always 100%. 

As depicted in Scheme 2.25, a,a-disubstituted malonic diesters can be selectively transformed by PLE or a-chymotrypsin to give the corresponding chiral monoesters [212, 213]. 

Cyclic meso-cis-Aio s were asymmetrically acylated quite efficiently to give the respective chiral monoester by a PSL [185], Whereas a slow reaction rate was observed in a reversible reaction using ethyl acetate as acyl donor, the reaction was about ten times faster when vinyl acetate was employed. 

The chiral monoester, (1 S,21 )-2-(methoxycarbonyl)cyclohex-4-ene-l-carboxylic add 24a (Figure 11.6 ) is a key intermediate for the synthesis of a potential drug candidate 27 for the modulation of chemokine receptor 2 (CCR2) activity useful in treatment of rheumatoid arthritis [67-69]. Both the (lS,2k)-monoester 24a and its enantiomer (lk,2S)-monoester 24b were obtained by resolving the... 

Scheme 6.11 Enantioselective ling opening of meso anhydrides affords chiral monoesters of valuable dicarboxylic acids in excellent enantioselectivity using the sulfoneunide catalyst 77...

This first chemoenzymatic synthesis [48] is not included m Fig. 1 but can be considered as a preparation of A-ring synthons in general in the steroid field, and particularly in area of vitamin D (Scheme 9). The stereo control of the quaternary chiral carbon center is one of the important subjects in asymmetrical synthesis. This issue prompted research on the use of chiral monoester 197, which can be obtained in multihundred gram scale by the pig liver esterase (PLE)-mediated hydrolysis of the corresponding symmetrical diester 196 [49]. Thus, an efficient methodology was developed for the preparation of chiral cyclohexene derivatives from cw-diester 196, using PLE in a biphasic system using phosphate buffer and acetone, to afford the chiral half-ester 197. Scheme 9 shows the efficient... 

To introduce the methyl group at C-1, the chiral monoester 197 was treated with LDA and methyl iodide to afford die methylated monoester 198. In a separate experiment, the chiral monc ster 197 was transformed to the terr-butyl monc ster and was reacted with LDA and Mel in the same manner as for 197 to obtain the methylated product 201. The conversion of these monoesters 198 and W1 to the bicyclic y-lactone derivatives was examined. Reaction of the monoester 198 with LiBHj and methanol resulted in the reduction of the methoxycaibonyl group, and the subsequent treatment of the crude hydroxy acid with p-toluenesulfonic acid (TsOH) afforded the y-lactone 199. On the other hand, reduction of the carboxyl group of 198 and acid treatment of the hydroxy ester afforded the isomeric 7-lactone 200. The chiral monoester 201 was similarly converted to the enantiomeric 7-lactones 202 and 203. 

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