Asymmetric Net Cycloaddition for Access to Diverse Substituted 1,5-Benzothiazepines

In
this study, the isothiourea-catalyzed enantioselective formal
[4+3] cycloaddition of various α,β-unsaturated carboxylic
acid derivatives with 2-aminothiophenols was developed. Mechanistic
studies suggested that the reaction proceeds via a reversible sulfa-Michael
addition to α,β-unsaturated acylammonium intermediates,
followed by the enantioselective formation of a seven-membered ring,
enabling the facile and divergent synthesis of optically active 2-
and 3-substituted 1,5-benzothiazepines. This process was demonstrated
to be highly versatile, affording the corresponding products in excellent
regioselectivities and high enantioselectivities. Furthermore, this
method enabled the synthesis of chiral 2,3-disubstituted 1,5-benzothiazepines
in high regio-, enantio-, and diastereoselectivities. Hence, this
protocol can be applied for the construction of a library of useful
pharmaceutical candidates.