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 ).

Keywords: Michael addition; asymmetric catalysis; cinchona alkaloid; isothiourea; organocatalysis; oxygen heterocycles; stereodivergent.

Scheme 1

Intramolecular Michael addition/lactonization for the synthesis of syn-2,3-dihydrobenzofurans catalyzed by a) cinchona alkaloid derivative 2;[6a] b) (S)-(−)-tetramisole hydrochloride 5.[9j] c) Proposed stereodivergent synthesis of 2,3-dihydrobenzofuran, 2,3-THF, and 3,4-THF derivatives.

Scheme 2

Unsuccessful intramolecular Michael addition/lactonization for the synthesis of anti-2,3-THFs.

Scheme 3

a) Proposed mechanism for Lewis-base (LB*)-catalyzed Michael addition/lactonization of activated enone acids into 2,3-dihydrobenzofurans. b) Proposed pretransition state assembly by using (S)-(−)-tetramisole hydrochloride 5 as catalyst. c) Proposed pretransition state assembly by using OTMS-quinidine 19 catalyst.