Some limitations of an approach to the assembly of bryostatins by ring-closing metathesis

Abstract

Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1-C16 and C17-C27 fragments. However, studies of the formation of the C16-C17 double-bond by RCM were not successful and complex mixtures of products were obtained. To provide an insight into factors that may be involved in hindering RCM in this system, a slightly simplified C1-C16 acid and modified C17-C25 alcohols were prepared and their use for the synthesis of analogues of bryostatins was investigated. Although only low yields were obtained, it appeared that macrolides analogous to the bryostatins can be prepared by RCM, using the Grubbs II catalyst, if the precursors lack the two methyl groups at C18. RCM was not observed, however, for substrates in which these methyl groups were present.

Recent Advances in Total Synthesis via Metathesis Reactions

“…Having ascribed the importance of steric hindrance, imposed by the presence of the gem-dimethyl system at the allylic position, as the reason for these disappointing results, in 2017 Thomas and co-workers studied the RCM reaction in model systems of the bryostatins in which the gem-dimethyl group was removed (Scheme 11). 96 In their study, the RCM reaction of model compound 132 by exposure to the Grubbs II catalyst (4) furnished the macrocyclic compound 133, albeit in a poor 17% yield (Scheme 11). These results are an indication of the serious hurdles that this class of systems presents for the metathesis reaction.…”