Enantioselective diketo ester

In the consecutive hydrogenation of />,<5-diketo esters (Table 21.16), selection of the chiral ligand can determine the sense of diastereoselection, and the 3,5-syn dihydroxy product was formed predominantly upon use of a Ru-(S)-amino-phosphinephosphinite-((S)-AMPP) catalyst, although the enantioselectivity of the syn-product is poor (Table 21.16, entry 7) [103a]. Syn 3,5-diol formation... 

Highly enantioselective reduction of ethyl 6-benzyloxy-3,5-dioxohexanoate by ADH of Acinetohacter calcoaceticus has been reported (97 to >99% ee) [6]. Regi-oselectivity was not encountered, however, as was the case in the reduction of a variety of 3,5-dioxohexanoates A with baker s yeast [7]. The application of isolated enzymes in an anticipated regio- and enantioselective reduction of diketo esters A seemed most promising to us. 

The enzyme recLBADH is the first catalyst that has been found to allow the highly regio- and enantioselective synthesis of 5-hydroxy-P-keto esters by reduction of the respective diketo esters. This enzymatic reaction is of enormous preparative value. The substrates are readily available by acylation of P-keto ester bisenolates and the reaction only requires a simple batch technique which is easy to scale up. Reduction of the chlorinated compound la has been performed routinely on a 75 g scale in our laboratory (8 L fed batch), yielding (S)-2a in an isolated yield of 84% [10]. 

In summary, it has been shown that the enzyme-catalyzed regio- and enantioselective reduction of 3,5-diketo esters can be performed advantageously on a preparative scale giving access to enantiopure (R)- and (S)-3,5-... 

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

Substituted 1,3-diols are valuable intermediates in the synthesis of drugs and natural products [18]. Starting from the regio- and enantioselective enzymatic reduction of diketo esters described above, various methods to obtain enantio-merically pure 3,5-dihydroxy esters were developed. 

Scheme 2.2.7.11 Chiral building blocks evolved from diketo ester la via regio- and enantioselective enzymatic reduction.

A few years later, a new process for the (R)-HPB ester was reported by Solvias in collaboration with Ciba SC (see Figure 2.11). Claisen condensation of cheap acetophenone and diethyl oxalate was carried out, followed by chemo- and enantioselective hydrogenation of the resulting diketo ester and hydrogenolysis to the HPB ester [30]. Even though the 2,4-dioxo ester was a new substrate type, it took only a few months to develop, scale up, and implement the new process. The following aspects were the key to success (i) the low price of the diketo ester prepared via Claisen... 

Route D Synthesis and Enantioselective Hydrogenation of Diketo Ester 6,... 

Hiyama et al. have reported an enantioselective synthesis of p-hydroxy 5-lactones as simplified analogs of compactin and mevinolin [47] (Scheme 10). The p,5-diketo ester 54 derived from Taber s chiral alcohol 57 was subjected to a stereoselective reduction with sodium borohydride in the presence of Et2BOMe to afford a syn diol, which upon saponification and then heating in dry toluene led to the chiral lactone 56. 

The hydrogenation of 2,4-diketo acid derivatives to the corresponding 2-hydroxy compounds with cinchona-modified Pt catalysts as depicted in Figure 2.4 can be carried out with chemoselectivities more than 99% and enantioselectivities up to 87% (R) and 68% (S), respectively [30a]. Enrichment to more than 98% ee was possible for several substrates by recrystallization, giving rise to an efficient technical synthesis of (R)-2-hydroxy-4-phenyl butyric acid ethyl ester [30b], a building block for several ACE (angiotensin-converting enzyme) inhibitors, as well as some enantio-merically enriched a-hydroxy and a-amino acid esters (see below) [30c]. 

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