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. 2010 Apr 16;75(8):2681-701.
doi: 10.1021/jo1002455.

Ladder polyether synthesis via epoxide-opening cascades directed by a disappearing trimethylsilyl group

Timothy P Heffron  1 , Graham L Simpson, Estibaliz Merino, Timothy F Jamison
Affiliations

Ladder polyether synthesis via epoxide-opening cascades directed by a disappearing trimethylsilyl group

Timothy P Heffron et al. J Org Chem. .

Abstract

Epoxide-opening cascades offer the potential to construct complex polyether natural products expeditiously and in a manner that emulates the biogenesis proposed for these compounds. Herein we provide a full account of our development of a strategy that addresses several important challenges of such cascades. The centerpiece of the method is a trimethylsilyl (SiMe(3)) group that serves several purposes and leaves no trace of itself by the time the cascade has come to an end. The main function of the SiMe(3) group is to dictate the regioselectivity of epoxide opening. This strategy is the only general method of effecting endo-selective cascades under basic conditions.

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Figures

Figure 1
Figure 1
Representative examples of polyethers containing the characteristic trans-syn topography.
Figure 2
Figure 2
Chelation-directed cascades (Murai).
Figure 3
Figure 3
Cascades directed by methyl groups at each nascent ring junction (McDonald).
Figure 4
Figure 4
McDonald’s cascade synthesis of a polyoxepane that contains two ring junctions without directing groups.
Figure 5
Figure 5
The SiMe3 group resides in a pseudo-axial position in the transition state in the cyclization of an epoxysilane.
Figure 6
Figure 6
Cyclizations of epoxysilanes in which SiMe3 would occupy a pseudo-equatorial position in the proposed transition state (Schaumann and coworkers).
Figure 7
Figure 7
Convergent strategy of polyene synthesis utilizing a four-stage, one-pot reaction.
Figure 8
Figure 8
HMBC analysis used to distinguish between two potential products of cascade.
Figure 9
Figure 9
One conformation of 35 cannot lead to the desired cyclization product.
Figure 10
Figure 10
Possible sequences of steps in cascades leading to the formation of bisfuran 37.
Figure 11
Figure 11
Proposed mechanism for the formation. of spiroketal 42
Figure 12
Figure 12
Suggested mechanism for the cascade formation of bispyran 53.
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Scheme 21
See this image and copyright information in PMC

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