Stereodivergent Organocatalytic Intramolecular Michael Addition/Lactonization for the Asymmetric Synthesis of Substituted Dihydrobenzofurans and Tetrahydrofurans

Abstract

A stereodivergent asymmetric Lewis base catalyzed Michael addition/lactonization of enone acids into substituted dihydrobenzofuran and tetrahydrofuran derivatives is reported. Commercially available (S)-(−)-tetramisole hydrochloride gives products with high syn diastereoselectivity in excellent enantioselectivity (up to 99:1 d.r.syn/anti, 99 % eesyn), whereas using a cinchona alkaloid derived catalyst gives the corresponding anti-diastereoisomers as the major product (up to 10:90 d.r.syn/anti, 99 % eeanti).

Catalytic Strategies for Diastereodivergent Synthesis

“…Smith disclosed that either syn ‐ or anti ‐2,3‐substituted THF and dihydrobenzofuran derivatives 44 with two stereocenters could be obtained by applying ( S )‐(−)‐tetramisole hydrochloride 43 and OTMS‐quinidine 41 as catalysts, respectively, to catalyze the asymmetric intramolecular oxy‐Michael addition/lactonization of enone acids, following a nucleophilic ring‐opening reaction (Scheme ) . The diastereoinversion was rationalized with the pre‐transition‐states presented in Scheme .…”

Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies

“… 22 Related intramolecular Michael addition-lactonisation cascades from enone-acid substrates have been used to generate simple heterocyclic products such as THFs and pyrrolidines with excellent enantioselectivity. 23 Building upon this previous work, the application of this strategy to construct the highly desirable pyrrolizine core in a catalytic enantioselective fashion starting from pyrrole-derived enone acid substrates such as 5 is investigated ( Fig. 3 ).…”

Organocatalytic Asymmetric Synthesis of Highly Substituted Tetrahydrofurans and Tetrahydropyrans via Double Michael Addition Strategy

“…As a consequence, a variety of approaches were developed for the stereoselective synthesis of tetrahydrofuran, and tetarhydropyran, derivatives. Despite significant efforts for the synthesis of chiral 2‐substituted tetrahydrofurans– including elegant cycloetherification approach by Matsubara, Scheidt and Zhao (Scheme ),– catalytic asymmetric synthesis of highly substituted tetrahydrofurans– is still a challenging task and only few organocatalytic methods are known. List and co‐workers reported excellent methods for the synthesis of mainly disubstituted furans using vinylogous Prins as well as by intramolecular carbonyl‐ene reactions –.…”