Reductions of P-Ketoesters

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. 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

Reduction of p-ketoesters in aqueous ethanolic sulphuric acid leads to removal of both functional groups and the formation of a hydrocarbon. This reaction which was discovered in 1907 [117] and recognised in 1912 [118] as involving a skeletal rearrangement is now termed the Tafel rearrangement. Conversions of the type 26 into 27 occur in 30 - 60 % yields [118,119] and the hydrocarbon is easily separated... 

CJ Sih, BN Zhou, AS Gopalan, WR Shieh, CS Chen, G Girdaukas, F vanMiddles-worth. Enantioselective reduction of P-ketoesters by Baker s yeast. Ann NY Acad Sci 434 186-193, 1984. 

RN Patel, CG McNamee, A Banerjee, JM Howell, RS Robison, LJ Szarka. Stereoselective reduction of P-ketoesters by Geotrichum candidum. Enzyme Microb Technol 14 731-738, 1992. 

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]. 

Orlistat (32 tetrahydrolipstatin, Xenical ) is a potent inhibitor of pancreatic lipase [23] which has been launched for the treatment of obesity in 1998. Large amounts of 32 required for clinical development were obtained using a route based on the enantioselective reduction of P-ketoester 29 to provide P-hydroxyester R)-30 followed by diastereoselective elaboration strategies (via (S,S,i )-31, Scheme 6)... 

Christen M, Crout DHG (1987) Enzymatic reduction of P-ketoesters using unmobilized yeast. In Moody GW, Baker PB (eds) Bioreactors and Biotransformatimts. Elsevier, London,p 213... 

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 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). 

In yeast, the reduction of P-ketoesters is carried out by dehydrogenase complexes that can individually afford either the (l)- or the (d)configuration (36e). Therefore inhibition of the (L)cnzyme will provide (D)-products and vice versa. Nakamura et al. [52] reported that addition of allyl alcohol or a,P-unsaturated carbonyls resulted in the formation of (D)-hydroxyesters 137, thereby inhibiting the (L)-enzyme. To shift the product formation toward the t-side 138 a-halo esters can be used. Thus, the best results were obtained with a-chloroacetates. In this way, the additive serves as a switch between the formation of the enantiomeric P-hydroxy esters 137 and 138. 

Although the reduction of P-ketoesters 1 with BH3 py/TiCU was studied in different solvents (CH2CI2, THF, and Et20) dichloromethane proved to be the best solvent of ehoiee since the use of THF or Et20 led to the complete loss of dia-stereoseleetivity. 

The dramatic change of the stereoselectivity with the Lewis acid observed in the reductions of P-ketoesters 1, could be rationalized on the basis of the different chelating ability of the metals involved in the process. In this case, there are major differences between TiCU and CeCb whereas TiCU is a strong chelating agent, CeCh is not. 

Besides wild-type strains, more recently the use of recombinant whole cells has gained increasing popularity for application in asymmetric ketone reduction. When overexpressing the ADFi only, in situ cofactor recycling based on a "substrate-coupled approach" represents a favorite approach as demonstrated in an early contribution by the Itoh group [86] utilizing a recombinant ADH from a Corynebacterium overexpressed in E. coli. This concept has been also applied by Daicel researchers in the presence of an E. coli catalyst with recombinant ADH from Candida parapsilosis. This biocatalyst catalyzes the reduction of p-ketoester 28 at a 36.6 g/1 substrate loading and fimiished the alcohol (R)-29 in 95.2% yield and with 99%ee (Scheme 23.12) [87]. 

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