Chemoenzymatic Approach to Enantiomerically Pure (R)‐3‐Hydroxy‐3‐methyl‐4‐pentenoic Acid Ester and Its Application to a Formal Total Synthesis of Taurospongin A

Abstract

(R)-3-Hydroxy-3-methyl-5-hexanoic acid p-methoxybenzyl ester 1b was prepared by carbonchain elongation on both termini of the starting material, (R)-3-benzyloxy-2-methylpropane-1,2-diol 2a, which was prepared by an over-expressed Bacillus subtilis epoxide hydrolase-catalyzed enantioselective hydrolysis of the racemic 1-benzyloxymethyl-1-methyloxirane 3. One of the key steps of the requisite transformation was the Rhodococcus rhodochrous NBRC 15564-mediated hydrolysis of a cyano group to a carboxyl group under neutral conditions, to exclude any racemization of the intermediate and/or product. The enantiomerically pure form of (R)-1b was applied to a new formal total synthesis of taurospongin A.

Epoxide Hydrolases and their Application in Organic Synthesis

“…Enantiopure (R)-3-benzyloxy-2-methylpropane-1,2-diol was the starting material for the synthesis of (R)-bicalutamide, a synthetic antiandrogen [6]. The same (R)-diol was used as the starting material for the bio-assisted synthesis of the intermediate (R)-3-hydroxy-3-methyl-5-hexanoic acid p-methoxybenzyl ester, which was then used in the synthesis of taurospongin A [153], a natural product inhibiting DNA poly merase β and HIV reverse transcriptase.…”

“…Enantiopure (R)-3-benzyloxy-2-methylpropane-1,2diol was the starting material for the synthesis of (R)-Bicalutamide, a synthetic antiandrogen (Fujino et al, 2007). The same (R)-diol was used as the starting material for the bio-assisted synthesis of the intermediate (R)-3-hydroxy-3-methyl-5-hexanoic acid p-methoxybenzyl ester, which was then used in the synthesis of Taurospongin A (Fujino et al, 2008), a natural product inhibiting DNA polymerase β and HIV reverse transcriptase. Note:In several papers it was mentioned that the biohydrolysis led to a diol with an inverted absolute configuration when compared to the configuration of the reacting epoxide, the reason being a switch in the Cahn-Ingold-Prelog (CIP) priority and not an inversion at the stereogenic center.…”

Preparation and Applications of 4-Methoxybenzyl Esters in Organic Synthesis

“…For example, Fujino and Sugai showed that deprotonation of the carboxylic acid with potassium hydroxide followed by trapping with PMBCl is effective for obtaining PMB ester 6 , which was used in an approach to obtain the enantiomerically pure ( R )-3-hydroxy-3-methyl-4-pentenoic acid PMB ester. 8 The silver salts of carboxylates have also been alkylated with PMBCl to synthesize the PMB esters of amino acids. 9 This method reportedly provided higher yields of the esters with several amino acid substrates and avoided racemization, providing materials that are useful for custom peptide synthesis.…”

“…For example, Fujino and co-workers used a PMB ester as a protecting group in their formal total synthesis of taurospongin A ( 94 ) (Scheme 26). 8 Hydrogenation of PMB ester 92 with Pd(OH) 2 followed by re-protection of the carboxylic acid with an allyl group afforded ester 93 in 76% yield in two steps. The reduction of alkenes is typically competitive in these transformations, as observed in the reduction of the alkene of compound 92 .…”

Synthesis of Taurospongin A

“…Assignment of the stereochemistry in the natural product was supported by a synthesis of the enantiomer of the C(1−10) core in which the C(3) stereogenic center was imported as ( R )-mevalonolactone and the C(7,9) diol was created without stereocontrol. In subsequent synthetic work, , the C(3) and C(7,9) centers were treated as essentially separate stereochemical problems. Ley’s total synthesis , differs in this respect by the use of π-allyltricarbonyl lactone complexes to direct stereoselective delivery of hydride (to generate the syn- C(7,9) diol) or methyl (to generate the C(3) center).…”