A convergent fragment coupling strategy to access quaternary stereogenic centers

Creators: Kerkovius, Jeff K.; Wong, Alice R.; Mak, Victor W.; Reisman, Sarah E.¹

1. California Institute of Technology

Abstract

The formation of quaternary stereogenic centers via convergent fragment coupling is a longstanding challenge in organic synthesis. Here, we report a strategy for the formation of quaternary stereogenic centers in polycyclic systems based upon the semi-pinacol reaction. In the key transformation, two fragments of a similar size and complexity are joined by a 1,2-addition of an alkenyl lithium to an epoxy ketone, and the resulting epoxy silyl ether undergoes a semi-pinacol rearrangement catalyzed by N-(trimethylsilyl)bis(trifluoromethanesulfonyl)imide (TMSNTf2) or trimethylsilyl trifluoromethanesulfonate (TMSOTf). Polycyclic scaffolds were generated in high yields and the reaction conditions tolerated a variety of functional groups including esters, silyl ethers, enol ethers, and aryl triflates. This method provides a useful strategy for the synthesis of complex polycyclic natural product-like scaffolds with quaternary stereogenic centers from simplified fragments.

Additional Information

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. All publication charges for this article have been paid for by the Royal Society of Chemistry. The California Institute of Technology Center for Catalysis and Chemical Synthesis is gratefully acknowledged for access to analytical equipment. We thank the Dow Next Generation Educator Funds and Instrumentation Grants for their support of the NMR facility at Caltech and the X-ray Crystallography Facility in the Beckman Institute at Caltech. Dr Mona Shahgholi at the Multi-User Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering is acknowledged for their help in acquisition of HRMS data with instrumentation purchased by funds from DOW Next Generation Instrumentation and the NSF CRIF program (CCEC.DOWINSTR-1-GRANT.DOWINSTR). Dr M. Takase and L. Henling are acknowledged for acquiring the X-ray diffraction data. Funding: Fellowship support was provided by the Natural Sciences and Engineering Research Council (NSERC) of Canada (PGS-D fellowship to J. K. K., grant PGSD3-532535-2019), and the NSF (DGE-1144469 to A. R. W. and V. W. M). S. E. R. acknowledges financial support from the NIH (R35GM118191). Author contributions. Project conceptualization: A. R. W., V. W. M., and S. E. R. Funding acquisition: S. E. R. Experimental design and investigation: J. K. K., A. R. W., V. W. M., and S. E. R. Manuscript writing and editing: J. K. K. and S. E. R. Data availability. Experimental procedures and characterization data (¹H and ¹³C NMR) for all new compounds are provided in the ESI. There are no conflicts to declare.

Attached Files

Published - SC-014-D2SC07023E.pdf

Supplemental Material - d2sc07023e1.pdf

Files

SC-014-D2SC07023E.pdf

Files (3.1 MB)

Name	Size	Download all
SC-014-D2SC07023E.pdf md5:64921baf2b34c1eb44fd294344948f44	784.5 kB	Preview Download
d2sc07023e1.pdf md5:480d5f63c444a1bb07ef87cbcaeaae54	2.3 MB	Preview Download

Additional details

	All versions	This version
Views	0	0
Downloads	0	0
Data volume	0 Bytes	0 Bytes