A Highly Chemo-, Regio-, and Stereoselective Metallacycle-Mediated Annulation Between a Conjugated Enyne and an Ene-Diyne.

Glenn Christopher Micalizio,John Arthur Joule,Zacharay A. Shalit

doi:10.24820/ark.5550190.p010.487

Glenn Christopher Micalizio, John Arthur Joule

Open Access

https://doi.org/10.24820/ark.5550190.p010.487

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Abstract

Alkoxide-directed metal-centered intermolecular [2+2+2] annulation is shown to chemo-, regio-, and stereoselectively engage two polyunsaturated substrate in productive cyclization chemistry. This annulation process is unique in the field, revealing that it is possible to selectively engage three of five π-systems residing in the coupling partners in initial [2+2+2] reaction, and demonstrating that one of the two remaining π-systems (the TMS-alkyne) can ultimately serve to simply generate a new metallacyclopentene of great potential value in additional metallacycle-mediated coupling chemistry.

Highlights

While many of these advances have been demonstrated to be of great value in complex molecule or natural product synthesis,[14] it is typically the case that intermolecular versions of this type of organometallic chemistry are rather restricted in scope, and of limited value in stereoselective synthesis, including natural product synthesis.[14]
We have reported over thirty distinct and highly selective coupling reactions between a variety of unsymmetrically substituted unsaturated systems, and have demonstrated the utility of these reactions in total synthesis and function-oriented synthesis[15] of representative members of diverse families of natural products.[16,17,18,19,20,21,22,23,24,25,26,27]
Initial chemoselective activation of the commercially available enyne by the action of Ti(Oi-Pr)[4] and n-BuLi, followed by addition of the lithium alkoxide of ene-diyne as a solution in PhMe, and quenching of the reaction with aqueous NaHCO3, resulted in the formation of the cross-conjugated triene-containing hydrindane 14, isolated in 51% yield as a single regio- and stereoisomer – no evidence was found for the formation of any other isomer of this coupled product, nor was evidence found for the presence of the TMS-alkyne containing product 15.32

Summary

Introduction

Since the pioneering work of Professor Vollhardt that revealed the great value of metal-centered [2+2+2] annulation chemistry for accessing stereodefined carbo- and heterocyclic targets, this area of organometallic chemistry has grown to occupy a unique role in organic synthesis (Figure 1A).[1,2,3,4,5] These reactions that may be considered to be inspired by the foundation of chemistry first established by Reppe,[6] and later developed by luminaries in the field, often embrace organometallic intermediates of relevance for [2+2+2] annulation as a means to realize a large swathe of complex and diverse bond-forming reactions.[7,8,9,10,11,12,13] While many of these advances have been demonstrated to be of great value in complex molecule or natural product synthesis,[14] it is typically the case that intermolecular versions of this type of organometallic chemistry are rather restricted in scope, and of limited value in stereoselective synthesis, including natural product synthesis.[14].

Results

Conclusion