Esters, a-hydroxy synthesis

The ubiquitous sulphur-stabilized carbanion has been used in a general a-hydroxy ester synthesis as well as a general route to esters (Scheme 35), " the modification to the standard 1,3-dithiane being a change in oxidation level by the addition of a 2-methylthio group. 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

Effenberger and coworkers have utilized the tolerance of methyl ketones by the recombinant enzyme to develop an alternative synthesis of tetronic acids and their amino derivatives, as shown in Figure 5.18. Treatment of O-acyl cyanohydrins with lithium disilazide resulted in base-induced ring closure to amino tetronic acid derivatives. Alternatively, the cyanohydrins could be converted to a-hydroxy esters prior to acylation, and the same base-induced cyclization then led to tetronic acid derivatives [89]. 

The first derivatives of the 4(5/f)-oxazolone ring system 1 were prepared almost 90 years ago when Traube and Ascher described the synthesis of 2-amino-4(5H)-oxazolones (pseudohydantoins) 2 via condensation of guanidine with a-hydroxy esters (Scheme 6.1). This is quite remarkable in that it was 36 years later before Sheehan and Izzo prepared the hrst example of a simple 2-aryl analogue via... 

Reactions using catecholborane proceed smoothly in toluene (Scheme 16) (40). The utility of catalytic hydroboration of ketones has been demonstrated by the efficient enantioselective synthesis of a series of biologically active compounds (41). Scheme 17 shows some compounds prepared by using this method. Enantioselective reduction of trichloro-methyl ketones is a general route to a-amino acids and a-hydroxy esters it also allows ready synthesis of a precursor to the carbonic anhy-drase inhibitor MK-0417 (42). 

Scheme 35 Synthesis of 1-Oxoethylene Peptides by Alkylation with an a-Hydroxy Ester 47 ...

A full account5 describes the enantioselective carbonyl-ene reaction of glyoxylate esters catalyzed by a binaphthol-derived chiral titanium complex that is potentially useful for the asymmetric synthesis of a-hydroxy esters of biological and synthetic importance.6 The present procedure is applicable to a variety of 1,1-disubstituted olefins to provide ene products in extremely high enantiomeric purity by the judicious choice of the dichloro or dibromo chiral catalyst (see Table). In certain glyoxylate-ene reactions involving removal of a methyl hydrogen, the dichloro catalyst... 

Racemic resolution of a-hydroxy esters was achieved with Pseudomonas cepacia lipase (PCL) and a ruthenium catalyst (for a list, see Figure 18.13) as well as 4-chlorophenyl acetate as an acyl donor in cyclohexane, with high yields and excellent enantiomeric excesses (Huerta, 2000) (Figure 18.14). Combining dynamic kinetic resolution with an aldol reaction yielded jS-hydroxy ester derivatives in very high enantiomeric excesses (< 99% e.e.) in a one-pot synthesis (Huerta, 2001). 

The p-amino-a-hydroxy esters have been converted to diamino acids [88, 89] and related compounds like the nitrogen-substituted azetidinone shown in Scheme 13, a key structure in the synthesis of the commercially available antibiotic loracarbef [90] by substitution of the alcohol moiety with an azide. Several approaches have been used to achieve this transformation. Mesylation of the alcohol followed by substitution with sodium or trimethylsilyl azide provided cis-diamino acids [88,89]. trans-Diamino acids were obtained by ring opening of the aziridine [88] or by inversion of the alcohol bearing carbon followed by substitution under Mitsunobo conditions [90]. 

A general synthesis of a-hydroxy esters is based on 2-ethylthio-l,3-benzodithiole which serves as a methoxycarbonyl anion equivalent. Thus reaction of the lithium compound (216) with ketones followed by treatment with mercury perchlorate in methanol leads to the formation of a-hydroxy acid derivatives (217) (81SC209). 

Another lithiated trithioformate, such as the intermediate 498, has been used for the synthesis of a-hydroxy esters by reaction with aldehydes and final deprotection, as mentioned for compound 497735. The aldehyde 520 has been transformed into the hydroxy ester 521, a key intermediate for the preparation of peptidyl a-keto esters746 (Scheme 139). 

This is an example of a tetronate synthesis from an a-hydroxy ester and ylide 11. Equipment... 

The products can be converted into chiral cyanohydrins or a-hydroxy esters by oxidation and -elimination of the chiral side chain (equatjon 1). Alternatively, the cyano group can be reduced (BH,-THF) prior to oxidation and (i-elimination for a synthesis of ehiral 3-amino seeondary alcohols. 

A key step in the asymmetric synthesis of the angiotensin converting enzyme inhibitor, benazepril HCl 32, was the reduction of the ketoester 28 with baker s yeast to afford the chiral a-hydroxy ester 29 in high chemical yield and ee. Formation of the benz[i]azepinone 31 directly from 29 proceeded in 42% yield (without racemization at C-3) or in 74% yield in two steps via 30, again with no racemization <03TA2239>. 

Oxidation of the dienolate of (17) with (+)-( ) affords a-hydroxy ester (18), a key intermediate in the enantioselective synthesis of the antibiotic echinosporin (eq 19) whereas oxidation of enolates derived from 1,3-dioxin vinylogous ester (19) gives rise to both a - and y-hydroxylation depending on the reaction conditions (eq 20). With (+)-( ) the lithium enolate of (19) gives primarily the a -hydroxylation product (20), while the sodium enolate gives )/-hydroxylation product (21). Only low levels of asymmetric induction (ca. 16% ee) are found in these oxidations. Birch reduction products are also asymmetrically hydroxylated in situ by (+)-( ) (eq 21). ... 

An alternative strategy for achieving asymmetric control may be by covalent attachment of a chiral auxiliary to the carbenoid. This strategy has so far met with rather limited success in cyclopropanation reactions (see eq. (3) for a similar palladium-catalyzed reaction). However, the use of a-hydroxy esters as chiral auxiliaries with stabilized rhodium(II) vinylcarbenoids allowed entry into both series of enantiomeric vinylcyclopropanes with predictable stereochemistry. Optical yields are fair to excellent [14] and the outcome of the reaction was rationalized on the basis of interactions between the carbonyl oxygen of the chiral auxiliary and the carbenoid carbon. The strategy led to an efficient synthesis of optically active hydroxy vitamin D3 ring A [28]. 

Addition to C=0. Hydrates of a-ketoaldehydes react selectively at the aldehyde group with allylsilanes under the influence of YbfOTfjj at room temperature. The allylation of aldehydes with allylstannanes is accelerated by benzoic acid." Another method for the synthesis of homoallylic alcohols is by the ene reaction, thus y,6-unsaturated a-hydroxy esters are obtained from glyoxylic esters at room temperature in a catalyzed process. ... 

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