Angewandte
Chemie
DOI: 10.1002/anie.201204274
Asymmetric Catalysis
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Organocatalytic Asymmetric Direct Csp3 H Functionalization of
Ethers: A Highly Efficient Approach to Chiral Spiroethers**
Zhi-Wei Jiao, Shu-Yu Zhang, Chuan He, Yong-Qiang Tu,* Shao-Hua Wang, Fu-Min Zhang,
Yong-Qiang Zhang, and Hui Li
The asymmetric synthesis of chiral spiroethers, which are
present in numerous bioactive natural products (Figure 1)
enantioselective reaction of ethers are scarce. In 2005, Sames
and co-workers. reported that Sc(OTf)3 or BF3·Et2O could
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initiate a direct functionalization of Csp3 H bonds of cyclic
ethers 1 to give racemic spiroethers 2’ (Scheme 1). This
Figure 1. Natural products containing a spiroether moiety.
and pharmaceuticals,[1] is an important endeavor in organic
synthesis. Tremendous efforts have been made during the past
few years toward developing methods for the synthesis of
spiroethers,[2] although of the methods developed, many
involve multiple steps and only a few are enantioselective.[2d–i]
Therefore, the development of methods that are highly
efficient, catalytic, and enantioselective is still required.
The direct and selective functionalization of inactive
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Scheme 1. Asymmetric funtionalization of Csp3 H bonds for preparing
enantiopure spiroethers. LA=Lewis acid.
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Csp3 H bonds is not only a significant and actively studied
subject in fundamental organic chemistry,[3] it is also becom-
ing a practical method for organic synthesis because of its
atom- and step economy.[4] Among the reported transforma-
tions, intramolecular redox processes for the direct function-
transformation proceeds through a tandem 1,5-hydride trans-
fer/cyclization redox process.[5b] These results suggested that
an asymmetric catalytic variant should be possible, a process
that would involve the conversion of a racemic mixture of
a cyclic ether into enantiomerically enriched spiroether.
Organocatalysis has emerged as an important method in
organic chemistry and it has been used to effect many
enantioselective transformations.[8] To accomplish the above
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alization of Csp3 H bonds that are a to heteroatoms are
important for the synthesis of structurally diverse amine and
ether derivatives.[5] Furthermore, since the pioneering work of
Kim and co-workers,[6] there have many good results reported
in the area of intramolecular redox processes for the direct
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enantioselective Csp3 H functionalization at positions a to
nitrogen atoms.[7] However, examples of the corresponding
enantioselective C H bond functionalization, we envisioned
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that the formation of an iminium ion through the reaction
between a cyclic ether containing an a,b-unsaturated alde-
hyde group (1) and a chiral organocatalyst (R1NHR2) would
initiate a 1,5-hydride shift and that the resulting enamine and
oxocarbenium moieties would react to give chiral spiroether
2’’ (Scheme 1). Herein, we present our success toward this
goal.
Our investigation started with the use of tetrahydrofuran
1a, which contains both an a,b-unsaturated aldehyde and
a diethylmalonate moiety, as the model substrate for identi-
fying a suitable catalytic system. We envisioned that the
presence of strong acid would be required to ensure that the
iminium ion would be of sufficient electrophility for facilitat-
ing the transfer of the a-hydrogen atom from the THF moiety
of 1a. Thus the combination of a catalytic amount of
(+)-camphorsulphonic acid (CSA) and a proline-derived
[*] Z.-W. Jiao, Dr. S.-Y. Zhang, Prof. Y.-Q. Tu, Prof. S.-H. Wang,
Prof. F.-M. Zhang, Dr. Y.-Q. Zhang, H. Li
State Key Laboratory of Applied Organic Chemistry and
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou 730000 (P.R. China)
Prof. C. He
Department of Chemistry, University of Chicago
929 East 57th Street, Chicago, IL 60637 (USA)
[**] This work was supported by the NSFC (Nos. 21072085,
20921120404, 21102061, and 20972059), MOST (“973” Program,
No. 2010CB833203), Key National S&T Program “Major New Drug
Development” of the Ministry of Health of China (2012ZX09201101-
003), and MOE (“111” Program and scholarship award for excellent
doctoral student, No. 86007).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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