Synthesis of Isoaminile Mediated by Enzymes

Abstract

A lipase-mediated synthesis of all four enantiomers of isoaminile is reported. The key issues of the paper are: (i) enantioselective acetylation of allylic alcohol (E)-(±)-5 to give (E,S)-5 (ee = 92%) and (E,R)-6 (ee >99%); (ii) Claisen-Johnson rearrangement of R and S enantiomers of 5 to generate the quaternary benzylic stereocenter; (iii) chromatographic separation of aldehyde diastereoisomers; (iv) X-ray structure of aldehyde (2R,4R)-10; (v) unpredicted formation of lactone 12 during the hydrolysis of 11.Isoaminile 1 (Figure 1) is an antitussive agent, discovered by Hoechst and widely used as therapeutic agent. 1 The molecule contains two stereogenic centres: one centre is a quaternary carbon at the benzylic position and the second at C(4) position bears an amine group. The isoaminile-cyclamate salt is commercialized in racemic form as tablets or syrup under the trade name Peracon ® . Figure 1Our interest in this and related compounds relies on the presence of a benzylic stereogenic center. Indeed, during the last years we have been involved in the development of a general synthetic methodology that allows the enantioselective generation of either tertiary or quaternary benzylic carbons. This synthetic route consists of the Claisen rearrangement of optically pure allylic alcohols, which can be easily prepared by enzymatic asymmetric esterification (Scheme 1). 2 Certainly, the generation of benzyl stereogenic centres remains a chemical delicacy of modern organic synthesis, and so far, most of the strategies that have been reported in the literature are mainly based on transition metal asymmetric catalysts. 3 However, the advantages of using a methodology based on the enzymatic resolution of allylic alcohols are: (i) acetylation occurs always with excellent ee on a large variety of substrates; (ii) enzyme is commercially available and can be reused several times without loss of efficiency; (iii) the reaction does not require any special set up, which is usually a tedious and time consuming operation; (iv) laboratory equipment and the synthetic skills needed are of standard level. Indeed, we have successfully employed this methodology for the preparation of several different targets such as a drug, 2a,b a natural product, 2d a solving agent 2c and a fragrance. 2e Scheme 1 Key: (a) Enzymatic resolution of allylic alcohols; (b) hydrolysis of acetyl derivative; (c) Claisen rearrangement to give either the quaternary or the tertiary benzylic stereocenter.To the best of our knowledge neither enantioselective synthesis nor resolutions of isoaminile have been described. Herein, we report the first preparation of all four stereoisomers of 1 in enantimerically pure form.The synthesis of the racemic allylic alcohols (E)-(±)-5 and (Z)-(±)-5 is outlined in Scheme 2. Horner-Emmons olefination of ketone 2 with the diethoxylphosphoryl ethylacetate 3, using NaH as base, gave an almost 1:1 mixture of the configurational isomers (E)-4 and (Z)-4, in a yield of ca. 80%. 4,5 The two isomers were easily separated by column chromatogra...

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