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

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.

Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues.

Tigilanol tiglate is a natural product diterpenoid in clinical trials for the treatment of a broad range of cancers. Its unprecedented protein kinase C isoform selectivity make it and its analogues exceptional leads for PKC-related clinical indications, which include human immunodeficiency virus and AIDS eradication, antigen-enhanced cancer immunotherapy, Alzheimer's disease and multiple sclerosis. Currently, the only source of tigilanol tiglate is a rain forest tree, Fontainea picrosperma, whose limited number and restricted distribution (northeastern Australia) has prompted consideration of designed tree plantations to address supply needs. Here we report a practical laboratory synthesis of tigilanol tiglate that proceeds in 12 steps (12% overall yield, >80% average yield per step) and can be used to sustainably supply tigilanol tiglate and its analogues, the latter otherwise inaccessible from the natural source. The success of this synthesis is based on a unique strategy for the installation of an oxidation pattern common to many biologically active tiglianes, daphnanes and their analogues.

Function-Oriented Synthesis: Design, Synthesis, and Evaluation of Highly Simplified Bryostatin Analogues.

Using a function-oriented synthesis strategy, we designed, synthesized, and evaluated the simplest bryostatin 1 analogues reported to date, in which bryostatin's A- and B-rings are replaced by a glutarate linker. These analogues, one without and one with a C26-methyl group, exhibit remarkably different protein kinase C (PKC) isoform affinities. The former exhibited bryostatin-like binding to several PKC isoforms with Ki's < 5 nM, while the latter exhibited PKC affinities that were up to ∼180-fold less potent. The analogue with bryostatin-like PKC affinities also exhibited bryostatin-like PKC translocation kinetics in vitro, indicating rapid cell permeation and engagement of its PKC target. This study exemplifies the power of function-oriented synthesis in reducing structural complexity by activity-informed design, thus enhancing synthetic accessibility, while still maintaining function (biological activity), collectively providing new leads for addressing the growing list of therapeutic indications exhibited by PKC modulators.