Angewandte
Chemie
DOI: 10.1002/anie.201004534
Asymmetric Synthesis
Organocatalytic Asymmetric Sulfa-Michael/Michael Addition
Reactions: A Strategy for the Synthesis of Highly Substituted
Chromans with a Quaternary Stereocenter**
Xu-Fan Wang, Qiu-Lin Hua, Ying Cheng, Xiao-Lei An, Qing-Qing Yang, Jia-Rong Chen,* and
Wen-Jing Xiao*
Chromans form the core of numerous natural products and
synthetic analogues displaying a broad and interesting range
of biological activities.[1] In particular, the chiral chroman
skeleton plays an important role in various therapeutic
areas.[1d] For example, (À)-siccanin, isolated from the culture
broth of Heleminthosposium siccans, exhibited potent anti-
fungal activity against the pathogentic fungi Trichophyton
interdigitale, Trichophyton asteroids, Epidermophyton, and
Mycosporum (Figure 1).[2] Rubioncolin B belongs to a class of
methods for the construction of chromans remain largely
unexplored.[10]
The search for new efficient and highly enantioselective
approaches to complex molecular architectures, especially
those with multiple stereogenic carbon atoms and quaternary
stereocenters, continues to be a substantial challenge in both
academic and industrial domains.[11] In this context, the
organocatalytic cascade reaction has recently emerged as a
powerful tool to facilitate a rapid increase in molecular
complexity and diversity from simple and readily available
starting materials by reducing the steps of manual operation
as well as the generation of waste.[12] Of the catalytic strategies
developed for enantioselective cascade transformations,
bifunctional organocatalysts bearing both hydrogen-bond
donors and basic functional groups have formed a focal
point of attention in recent years.[13] Recently, our laboratory
implemented a novel formal inter-[4+1]/intra-[3+2] cycliza-
tion cascade of cycloadditions of sulfur ylides with nitroolefin
enoates to construct densely functionalized chromans
[Eq. (1)].[14] Notwithstanding the fascinating results, the
Figure 1. Examples of highly substituted biologically active chroman
derivatives.
unusual naphthohydroquinones that are administered in
traditional Chinese and Ayurvedic medicine,[3] and Gamma
secretase inhibitor is a candidate for use in Alzheimerꢀs
disease.[4] Therefore, these complex polycyclic frameworks
have become targets of interest in the organic synthetic
community. Recently, a number of catalytic asymmetric
methodologies using Lewis acids or transition-metal com-
plexes have been developed for the synthesis of this privileged
structural motif, including asymmetric epoxidation,[5] oxida-
tive cyclization,[6] allylic alkylation,[7] enyne cyclization,[8] and
others.[9] Despite these advances, organocatalytic asymmetric
development of an enantioselective version of this consec-
utive reaction remains extremely desirable. Therefore we
describe herein an alternative bifunctional organocatalyst for
the sulfa-Michael/Michael addition[15] reaction of thiols with
nitroolefin enoates to afford polyfunctionalized chroman
derivatives in a highly stereoselective manner [Eq. (2)]. The
notable features of this procedure include: 1) the generation
of three consecutive stereogenic carbon centers including one
quaternary stereocenter with high enantioselectivity (up to
96% ee) and excellent diastereoselectivity (> 95:5 d.r.), 2) no
reaction reversibility, which is usually found with hetero
nucleophiles,[16] 3) the cascade reaction adducts are the core
structural feature of the Gamma secretase inhibitor, and
[*] X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An, Q.-Q. Yang, Dr. J.-R. Chen,
Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax: (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
[**] We are grateful to the National Science Foundation of China
(20872043) and the Program for Changjiang Scholars and Innova-
tive Research Team in University (IRT0953) for supporting this
research.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 8379 –8383
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8379