Abstract
In this Personal Account, we will give an overview of the room temperature O-directed free radical hydrostannation reaction of propargylically-oxygenated dialkyl acetylenes with Ph3 SnH and catalytic Et3 B/O2 in PhMe. We will show how this excellent reaction evolved, and how it has since been used to stereoselectively construct the complex trisubstituted olefin regions of three synthetically challenging natural product targets: (+)-pumiliotoxin B, (-)-(3R)-inthomycin C, and (+)-acutiphycin. Throughout this Account, we will pay special attention to highlighting important facets of the I-SnPh3 exchange processes that have so far been used in the various different steric settings that we have addressed, and we will document the range of cross coupling protocols that have critically underpinned the first successful applications of this method in complex natural product total synthesis. Last, but not least, we will comment on various aspects of the O-directed free radical hydrostannation mechanism that have been published by ourselves, and others, and we will discuss all of the factors that can contribute to the observed stereo-and regio-chemical outcomes. We will also challenge and refute the recent non-directed stannylvinyl cation mechanism put forward by Organ, Oderinde and Froese for our reaction, and we will show how it cannot be operating in these exclusively free radical hydrostannations.
Highlights
Introduction and Historical BackgroundThe first example of an O-directed free radical hydrostannation of a monoalkyl acetylene can be found in the 1975 report of Corey and Wollenberg in JOC,[1] who demonstrated that the propargyl THP-ether 1 underwent a highly stereo- and regio-selective hydrostannation reaction to give the (Z)-configured vinylstannane 2, almost exclusivelyChem
The very fact that the b-addition/ tandem vinyl radical cyclisation product 298 could be trapped out and detected in the reactions that were conducted at low substrate and stannane concentration, provided the first solid evidence needed to demonstrate how the intermediary b-alkyl-b-stannylvinyl radicals must typically be inherently unstable and rapidly eliminate under normal O-directed free radical hydrostannation conditions, since b-addition products are generally only seldom observed as very minor reaction constituents in our hydrostannation reactions. We suggest that this inherent instability of b-alkyl-btriphenylstannylvinyl radical intermediates of structure 300 is reflective of the significant combined A1,2/A1,3-strain that they experience in various rotamers and invertomers that are being generated, a strain that will only be further exacerbated by strong internal OÀSn coordination continuing after the O
Our mechanism (Scheme 73) recognises that the intermediary a-stannylvinyl radicals that will form will rapidly invert between the (E)- and (Z)-isomeric forms and essentially have bent structures, with the most heavily populated invertomer being the (Z)-isomer 434, due to the significant A1,3-strain that will be present in its (E)-configured counterpart 438, as was first proposed by us in 2005.[29,23] We suggest that Hatom abstraction will occur preferentially from the (Z)-vinyl radical in the manner shown due to transition state offering the least hindered pathway for approach by the bulky Ph3SnH
Summary
The first example of an O-directed free radical hydrostannation of a monoalkyl acetylene can be found in the 1975 report of Corey and Wollenberg in JOC,[1] who demonstrated that the propargyl THP-ether 1 underwent a highly stereo- and regio-selective hydrostannation reaction to give the (Z)-configured vinylstannane 2, almost exclusively. Of Et3B/O2 as the initiator (Scheme 10) Their contributions to the area of Odirected free radical hydrostannation can only be regarded as outstanding, since their reports are, for the most part, very well documented and, in the case of the former three teams, they provided the first hard physical evidence (Xray crystallography and NMR) for the existence of a coordinative interaction between the tin grouping and the ballylic OH in the products, which was strongly suggestive of the propargylic hydroxyl likely directing the observed regioand stereo-chemical outcomes, which some would consider extraordinary and unusual. Et3B/O2 alkyl acetylene hydrostannations that the Organ team report using our method (Scheme 25), they observe very high levels of regio- and (Z/E)-stereo-selectivity alongside good yields of product, as one would naturally expect given the typically excellent performance, high fidelity, and remarkable efficiency of our reaction and method (vide infra). The alternative in Scheme 33 looks the more 41 reasonable
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