Reduction of 3-ketoesters

Many enantioselective catalysts have been developed for reduction of functional groups, particularly ketones. BINAP complexes of Ru(II)C12 or Ru(II)Br2 give good enantioselectivity in reduction of (3-ketoesters.49 This catalyst system has been shown to be subject to acid catalysis.50 Thus in the presence of 0.1 mol % HC1, reduction proceeds smoothly at 40 psi of H2 at 40° C. 

Stereoselective reductions of (3-ketoesters are of great importance in the biosynthesis of antibiotics and other biologically-active compounds. 

Asymmetrical reduction of ketones to alcohols66 can be done in a number of ways. Reductions with microorganisms67 were described in Chap. 9. By choosing appropriate microbes both R and S isomers were obtained. The inclusion of dimethylsulfide in a reduction of /3-ketoesters with Baker s yeast raised the enantioselectivity from 94 to 98%.68... 

The diphosphine on the left was used with a rhodium catalyst and hydrogen to reduce the dehydroamino acid derivatives. The same reduction could also be carried out with sugar-derived phosphinites, the product being obtained in 97-99% ee.84 The diphosphine on the right, or better its counterpart, in which isopropyl has replaced methyl, was used with a ruthenium catalyst and hydrogen or 2-propanol in the reductions of /3-ketoesters. 1-Acetyl-naphthalene was reduced with a ruthenium catalyst using the ligand on the left with 2-propanol (10.38) in more 99% yield and 97% ee. 

Azerad R, Buisson D (1992) Stereocontrolled reduction of 3-ketoesters with Geotrichum... 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

Quallich and Woodall described the first asymmetric synthesis utilizing a catalytic enantioselective reduction of the ketoester 35 with (S)-terahydro-l-methyl-3,3-diphenyl-lH,3W-pyrrolo[l,2-c][l,3.2]oxazaborole (CBS) to give the desired hydroxyester 36 (90% ee). After mesylation, Sn2 displacement with a higher-order cuprate derived from copper cyanide gave the diaryl r-butyl ester 37 with good chirality transfer. Intramolecular Friedel-Crafts cyclization gave the tetralone 31 in 90% ee (Scheme 7). ... 

An important step in the asymmetric synthesis of the angiotensin-converting enzyme inhibitor, benazepril HC1 132, was the reduction of the ketoester 128 (obtained from 127 by condensation with diethyl oxalate) with baker s yeast to give the chiral cr-hydroxy ester 129 in high yield and ee (Scheme 17). Direct formation of the 1//-1-benzazepin-2-one 131 from 129 proceeded in 42% yield (without racemization at C-3) or in 74% yield in two steps via 130, again with no racemization <2003TA2239>. 

The reduction of yff-ketoesters to aldols is one of the most important applications of Ru(II)-BlNAP catalysts [7]. As a special bonus, the chirally labile C2 stereogenic center can be exploited in a dynamic kinetic resolution such that racemic reactants yield only one of the four conceivable stereoisomers in high diastereomeric and enantiomeric excess. This strategy has been extended to the reduction of -ketophosphonates 10. The 3-hydroxyphosphonic acids 7 which are accessible by this route constitute promising starting materials for the synthesis of peptide analog and antibiotics [8]. 

The reduction of p-ketoesters such as 3.128 or p-ketoamides such as 3.129 by Zn(BH4)2 is extremely stereoselective in favor of the syn p-hydroxy isomer, while KBH4 or n-Bu4NBH4 in EtOH or, better, K(j-Bu)3BH, lead selectively to the anti... 

Finally, the introduction of additives may allow the stereoselectivity of the reductions to increase. Thus the addition of ZnCl, to Zn(BH4)2 or the coordination of the carbonyl group by a bulky Lewis acid such as diisobutylaluminum 2,6-di-r-Bu-4-methylphenolate (BHT) induces high and opposite stereoselectivities from chiral P-ketoesters 3.135 (Figure 3.46). In the first case, chelation is strengthened, and the reduction involves a cyclic transition state. In the second case, chelation is disfavored, and the other isomer is formed [TDl]. Chelation may also be promoted in reductions of P-ketoesters or amides by addition of TiCl4 [SG2] or MnCl2 in catalytic amounts [FOl]. 

Other prochiral units that can be trapped in rings are enolates. One famous application is the alkylation of [3-hydroxy acid derivatives available from the chiral pool (chapter 23), by asymmetric aldol reactions (chapter 27) and by asymmetric reduction of P-keto-esters either by catalytic hydrogenation (chapter 26) or by enzymes (chapter 29). Frater found that the alcohol 55, from the baker s yeast reduction of the ketoester 54, formed the enolate 56 held in shape by chelation. Alkylation occurred on the top face.8 This is not so much because the OH is down in 55 as that the methyl group is down in 56. 

The reaction is extended [3] to the reduction of a-ketoesters, another class of ketones, possessing powerful electron-withdrawing ester group. The reduction of a-ketoesters with 40% excess of neat Alpine-Borane proceeds rapidly at 25 °C (Eq. 26.4 Table 26.9) [3,4b]. 

Heterocycles may also be carbonylated, to give either ring-expanded heterocycles, or ring-opened products. These include epoxides (Scheme 4.29), aziridines (Scheme 4.30), ° oxetanes (Scheme 4.31) and azetidines (Scheme 4.32). The cobalt-catalysed carbonylation of epoxides provides a short route to (3-hydroxyesters 4.73 (Scheme 4.29). These useful synthetic building blocks are often obtained in enan-tiomerically enriched form by the asymmetric reduction of P-ketoesters. As many epoxides are readily available in very high e.e., the carbonylation chemistry provides a useful alternative route. 

The double reduction of jff-ketoester methoxymethyl enol ethers (88) is reported by an American school o high-yield method for the hydro-genolysis of the /S-carbonyl function treatment with lithium in ammonia causes reduction of the conjugated double bond, elimination of methoxy-methanol, and further reduction to give the saturated ester (89). This procedure is equally effective on the corresponding /3-ketoacids. ... 

The influence of additives present in an enzymatic enantioselective reduction is illustrated in the next example [51]. In general, the use of microbial reducing systems provides efficient access to optically pure hydroxy compounds. One such system is the reduction of P-ketoesters to P-hydroxyesters with baker s yeast, which serve as versatile building blocks in organic synthesis. However, control of the configuration of the product can often not be accomphshed sufficiently (Scheme 3.29). 

A more concise route to chiral amines would be direct synthesis from the ketone via direct asymmetric reductive amination. This has been developed successfully for the conversion of (3-ketoesters to chiral (3-amino acid esters and demonstrated in the manufacture of sitagliptin, a DPP-IV inhibitor for... 

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

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