Anion Relay Chemistry: Access to the Type II ARC Reaction Manifold through a Fundamentally Different Reaction Pathway Exploiting 1‐Oxa‐2‐silacyclopentanes and Related Congeners

Abstract

Type I and II anion relay chemistry (ARC) [1] exploiting [1,n]-Brook rearrangements [2] (Scheme 1A and B, respectively), comprise an effective set of synthetic tactics that unite multiple components, in a single reaction flask, that permits rapid access to architecturally diverse polyketide and alkaloid molecular arrays. [2] To extend the ARC concept, we recently designed, synthesized and evaluated a number of new bifunctional linchpins for the type II process, [3] and then demonstrated their utility both in natural product [4] and diversity oriented synthesis (DOS). [5] During the development of the type II multicomponent process, we became intrigued with the possibility of accessing the type II ARC reaction manifold through a fundamentally different pathway employing 1-oxa-2-silacyclopentanes and related congeners (cf. 2, Scheme 2).Based on the structural resemblance of 1-oxa-2-silacyclopentene 2 to the proposed ARC silicon ate intermediate 4, we envisioned that addition of a nucleophile (MeLi) might provide access to the type II reaction products. We were of course cognizant of the elegant observation of Mosher and Brook, [6] that in the [1,2]-Brook rearrangement, charge transfer from the initially derived oxyanion to carbon proceeds through a silicon ate intermediate. [7] However to achieve success with the type II ARC protocol, we learned early on that a change in temperature, solvent polarity, and/or metal ion additive was required to trigger the [1,4]-Brook rearrangement after initial addition of a nucleophile. The presumed silicon ate intermediate [7] then furnishes the reactive anion 5, capable of alkylation, [3d] or in the presence of a palladium catalyst, cross-coupling. [3d,f, 8] By arriving at the silicon ate intermediate through a different pathway (cf. 2→4), we anticipated that the use of such "triggers" might not be required to arrive at 5. That is, access to the pentacoordinate silicon ate species 4, followed by conversion and capture of the resultant anion 5 might only require addition of methyllithium in a compatible solvent (Scheme 2).The synthetic utility of 1-oxa-2-silacyclopentanes and related congeners has been widely recognized by other laboratories. Ito [9] and Woerpel [10] exploited the Tamao-Fleming ** Financial support was provided by the NIH through Grant GM-29028. We thank Drs P. J. Carroll and R. Kohli at the University of Pennsylvania for assistance in obtaining X-ray diffraction and high resolution mass spectra, respectively.