Gallenkamp, D.; Fürstner, A. J. Am. Chem. Soc., 2011, 133, 9232–9235.
A few months back two papers focusing on selective macrocyclization appeared in JACS. In general, small rings (e.g. 5- and 6-membered) can be formed without complication, but as ring size increases, things can get dicey. Oligomerization can be problematic in larger rings since you’re paying more of an entropic toll to cyclize. In addition, unless there’s a bias for either the E or Z isomer, you generally end up with a mixture (this of course isn’t a problem with small rings). To make things even more complicated, many macrocyclic natural products contain more than one olefin, which increases the potentially formed products even more.
Damian Young and coworkers at the Broad Institute were studying macrocylization reactions for diversity oriented synthesis. Young’s group introduced a silicon atom on one of the terminal olefins in their macrocyclization precursors and observed high selectivity for macrocyclization and for the E-silyl macrocycle in particular. The resulting trisubstituted olefinic products are presumably too hindered to re-enter the catalytic cycle, trapping the kinetic product. Importantly, Young and coworkers found that the less hindered catalyst shown below was needed for the highest yields, and the –Si(OEt)2Me group stood out as the best of several silyl groups screened.
Though silyl substitution isn’t necessarily desired in target compounds, vinyl silanes can serve as versatile intermediates. Young simply protodesilylated them to make the Z-alkene, but they can also potentially serve as handles for further functionalization by cross coupling reactions.
Fürstner and coworkers showcased additional benefits of the vinyl silicon substituent. In their recent paper, they used the silyl group as both a protecting and stereochemical directing group for conjugated dienes. The bulky silyl group renders its olefin unreactive and also directs the newly formed olefin to the less hindered geometry. In their new synthesis of lactimidomycin, the Fürstner group used a trisubstituted vinyl silane as part of a tetraene macrocyclization precursor. They then used the hindered Dorta catalyst shown below to react selectively with the terminal olefins to produce their target macrocycle in good yield. The silyl group was cleaved in high yield with TBAF to provide the E, Z-conjugated diene present in the natural product.
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