Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

Abstract

SummaryAn investigation on the stereoselective cascade sulfa-Michael/aldol reaction of nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitrostyrenes affording the heterocyclic products in good yields and moderate stereoselectivities.

Recent Progress in Organocatalytic Asymmetric Domino Transformations

“…[198] Thea uthors also established ap arallelr elationship between the diastereoselective ratios andc omputed thermodynamic stability of the different diastereomers of tetrahydrothiophenes 516 in toluene. [198] Thesea uthors also achieved ad omino double Michael reactionb etween a-cyano-a,b-unsaturated ketones 518 and tert-butyl trans-4-mercapto-2-butenoate (trans-519a,R 3 = t-Bu) using the same amine thiourea catalyst 517,w hich led to the formation of tetrahydrothiophenes 520 in good yields ands tereoselectivities (Scheme 137, left equation).…”

“…[198] Thea uthors also established ap arallelr elationship between the diastereoselective ratios andc omputed thermodynamic stability of the different diastereomers of tetrahydrothiophenes 516 in toluene. [198] Thesea uthors also achieved ad omino double Michael reactionb etween a-cyano-a,b-unsaturated ketones 518 and tert-butyl trans-4-mercapto-2-butenoate (trans-519a,R 3 = t-Bu) using the same amine thiourea catalyst 517,w hich led to the formation of tetrahydrothiophenes 520 in good yields ands tereoselectivities (Scheme 137, left equation). [199] Thea uthors proposed ad ynamic kinetic resolution (DKR)p athwayt hat involvedadomino sulfa-Michael/retro-Michael/Michael reactiont oa ccount for the experimental results,s uch as the isolation of racemicM ichaela dduct 521 and its successful transformation to the diastereoenriched final product 520 under the reaction conditions.…”

Organocatalytic Asymmetric Synthesis of Tetrahydrothiophenes and Tetrahydrothiopyrans

“…The authors observed a dynamic kinetic resolution process that played a role in the high enantioselectivity in the reaction. In the next year, Xu et al employed 1,4-dithiane-2,5-diol (38), the dimer of mercaptoacetaldehyde (39), for the synthesis of enantiopure tetrahydrothiophenes (Scheme 11). [30] For this purpose, chalcones 40 were used as Michael acceptors, and 41, a bifunctional quinine-derived squaramide, was found to be the most efficient catalyst.…”

“…The authors explained the stereochemical outcome of the reaction as shown in Scheme 12. Here also, the thiol of mercaptoacetaldehyde (39) is activated by the tertiary amino group, and the squaramide activation of the carbonyl group of the chalcone leads the Michael addition to take place through intermediate A from the Re-face to generate intermediate B.…”

“…The stereochemical outcome of the reaction was explained in terms of a plausible transition state (Scheme 14). [31] The Michael acceptor 43 is presumably activated by the hydrogen atoms of the squaramide, and the tertiary amine enhances the nucleophilicity of mercaptoacetaldehyde (39). As shown in the intermediates C, Si-facial Michael reaction takes place on the activated olefin system, followed by intramolecular aldol reaction of intermediates D on the Re-face of the aldehyde.…”