| Description |
Generally, β,γ-unsaturated carbonyls are thermodynamically less stable than their corresponding α,β-unsaturated isomers. An investigation of SmI2-mediated deconjugation of α,β-unsaturated esters to provide β,γ-unsaturated esters is described herein. Under almost neutral conditions, α,β-unsaturated esters bearing good leaving groups at the γ-position were reductively deconjugated into β,γ-unsaturated esters in excellent yields at low temperature. The newly formed double bonds slightly favored E-geometry, whereas α,β-unsaturated esters bearing poor leaving groups afforded both deconjugated products and saturated products. Bryostatin 1, a macrocyclic lactone isolated from the bryozoan Bugula neritina, has attracted great attention from the scientific community since its structure was identified by Pettit in 1982. Clinical development of bryostatin 1 has been ongoing since 1990. To date, bryostatin 1 has been the subject for various cancers, HIV and Alzheimer’s disease in more than 80 human clinical trials. All the unique bioactivities of bryostatin 1 are closely related to its ability to modulate protein kinase C isozymes (PKCs), which are the key players in cell proliferation and death. Clarifying the structure-activity relationship (SAR) of bryostatin 1 promises extraordinary benefits to our understanding of the detailed mechanism of PKC activation and regulation. The work described herein focuses on the preparation of the C-27 des-methyl bryostatin analogue and its biological evaluation. A convergent and efficient route that involved extension of our pyran-annulation and catalytic asymmetric allylation (CAA) methodologies was developed and successfully delivered the target analogue. Upon addition of a catalytic amount of pyridine, the pyran-annulation reaction was more effective and consistent in terms of its yields. The des-methyl analogue demonstrated that the C-27 had no effect on the binding affinity to PKCs and the biological properties of the molecule. This discovery may facilitate future analogue syntheses. In order to investigate the role of the C-9 hemiketal hydroxyl group in the biological profile of bryostatin 1, a synthetic route was designed to prepare an analogue with the hemiketal alcohol. In this route, SmI2-mediated reductive cyclization was attempted to construct the hydroxypyran A-ring. Unfortunately, a side reaction occurring on the C-ring of the analogue prevented the desired cyclization. Without the cyclized A-ring, an unexpected analogue was finally obtained, which had an expanded macrolactone with a fused C-ring. |
