Enantioselective Organocatalytic Double Michael Addition Reactions

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070581y.html

From Prof. Wei Wang's group at the University of New Mexico, Albuquerque, NM

The method presented in this paper recently published in Org Lett ASAP detailed the using of chiral organo catalyst in performing domino double Michael additions to form chiral tetrahydrothiophene derivatives.

The reaction seemed to be quite simple to conduct. First, several catalysts (I-IV) were screened for reactivity in the representative reaction using enal 1a. However, the reaction only proceeded and stopped after the first Michael addition to give aldehyde 3. The authors reasoned that the steric hindrance of the benzene ring in the thiophenol framework perhaps prevented the second addition of the enamine intermediate to the ester.

Therefore, the thiol reacting partner was switched to thiol ester 4 and the reaction was screened again with all four organocatalysts and the results are summarized below.

This time, the reaction worked very well with catalysts I-III, while catalyst IV did not give any desired product. The reactions between 1a and 4 were found to be extremely efficient both in terms of yields and selectivities. After optimal conditions were found, the several substrates were screened for scope of the reaction and the results are summarized in Table 2.

The reactions were found to telerate well in a variety of substrates 1, whether it be electron-rich (entries 8 and 9) or electron-deficient aromatic rings (entries 2-7), or both (entry 10). In 2-substituted aromatic rings (entries 3, 7, and 9), the reaction also tolerated well with steric hindrance. Entry 11 demonstrated the tolerance of the reaction with heteroaromatic. Entry 12 showed that extended conjugation in aromatic ring also worked well, as well as with alkyl-substituted enal (entry 13).

A nice method, which can be used to build complex tetrahydrothiophene derivatives quickly with good to excellent yields and excellent enantio- and diastereoselectivities.