Biphenyl-Derived Phosphepines as Chiral Nucleophilic Catalysts: Enantioselective [4+1] Annulations To Form Functionalized Cyclopentenes†
Daniel T. Ziegler
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorLorena Riesgo
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
Search for more papers by this authorTakuya Ikeda
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorYuji Fujiwara
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
Search for more papers by this authorCorresponding Author
Prof. Gregory C. Fu
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)Search for more papers by this authorDaniel T. Ziegler
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorLorena Riesgo
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
Search for more papers by this authorTakuya Ikeda
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Search for more papers by this authorYuji Fujiwara
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
Search for more papers by this authorCorresponding Author
Prof. Gregory C. Fu
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA)Search for more papers by this authorSupport has been provided by the National Institutes of Health (National Institute of General Medical Sciences: R01-GM57034), EMD Serono (fellowship support for D.T.Z.), the Spanish MICINN (fellowship support for L.R.), Daiichi Sankyo Co., Ltd (fellowship support for T.I.), and Dainippon Sumitomo Pharma Co., Ltd. (fellowship support for Y.F.). We thank Trixia Buscagan, Dr. Søren Kramer, Dr. Allen Oliver (University of Notre Dame), Dr. Nathan D. Schley, Dr. Michael K. Takase, Dr. David VanderVelde, Dr. Scott C. Virgil, and Dr. Ashraf Wilsily for assistance and for helpful discussions.
Abstract
Because of the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. Introduced herein is a new family of chiral nucleophilic catalysts, biphenyl-derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation. A range of one-carbon coupling partners can be employed, thereby generating cyclopentenes which bear a fully substituted stereocenter [either all-carbon or heteroatom-substituted (sulfur and phosphorus)]. Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four-carbon coupling partner is not the turnover-limiting step of the catalytic cycle.
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- 23Although we have not yet pursued systematic studies of 3,3′-substituted biphenyl-derived phosphepines, our investigations of binaphthyl-based phosphepines suggest that the substituted aromatic groups in the 3- and 3′-positions may play a significant role in enhancing enantioselectivity.
- 24Exposure of (R)-3 and (R)-4 (as solids) to air for 21 days led to essentially no phosphine oxide (<5 %) according to 31P NMR spectroscopy. Exposure of toluene solutions to air for 8 days led to about 10 % oxidation of (R)-3 and about 55 % oxidation of (R)-4.
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- 27Under our standard reaction conditions, n-hexylsulfonylacetonitrile undergoes this [4+1] annulation in 78 % ee and 94 % yield (determined by 1H NMR spectroscopy with the aid of an internal standard).
- 28Notes:
- 28aThe minor diastereomer is formed in 28 % ee;
- 28bWe have not yet examined the impact of the choice of ester on the ee, d.r., and yield.
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