Trimethylene Methane Dianion Equivalent for the Asymmetric Consecutive Allylation of Aldehydes: Applications to Prins-Driven Macrocyclizations for the Synthesis of Bryostatin 1 and Analogues

Abstract

We report a one-step (one-flask) generation and reaction of a bifunctional allylating reagent, a trimethylene methane dianion equivalent, that provides a route for the asymmetric 2-(trimethylsilylmethyl) allylation of aldehydes. The product of the first aldehyde allylation process is then set to engage in a second separate aldehyde allylation, providing an improved Prins macrocyclization strategy both for the scalable synthesis of bryostatin 1 and for the total synthesis of a new potent bryostatin analogue.

Exploring a Non-Comfort Zone: Central Chirality-Generating Macrocyclizations

“…This efficient ringclosing strategy was recently used to prepare more than 20 C-13modified bryostatin analogues for evaluation as protein kinase C modulators (Scheme 7). 21 Several tested analogues were found to display good clinical potential for enhancing antigen-targeted immunotherapies. The development of a novel bifunctional trichlorosilane reagent 22 not only improved their previous route for the A-ring fragment but also provided access to a structurally more simplified des-A-ring analogue 40, which retains excellent affinity for several protein kinase C isoforms as compared to the parent natural product.…”