Development of Iminium-Activation Technologies and the Total Synthesis of (+)-Frondosin B

Citation

Lee, Sandra (2008) Development of Iminium-Activation Technologies and the Total Synthesis of (+)-Frondosin B. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/83M6-7R38. https://resolver.caltech.edu/CaltechETD:etd-08132007-171008

Abstract

The enantioselective imidazolidinone-catalyzed epoxidation of α,β-unsaturated aldehydes has been accomplished via a novel 1,4-heteroconjugate addition reaction using hypervalent iodine reagents. Development of an “internal syringe pump” protocol for the slow release of iodosobenzene from an iminoiodinane source provides high levels of reaction efficiency and enantiomeric control in the asymmetric epoxidation of electron-deficient olefins. Fundamental to our studies were ¹⁵N NMR experiments that elucidated the oxidation pathways that lead to catalyst depletion, thereby providing a mechanistic rational for the utilization of iminoiodinanes, which circumvent these catalyst depletion pathways.

We further established iminium catalysis as a valuable strategy for asymmetric synthesis in an organocatalytic addition of trifluoro(organo)borates and boronic acids to α,β-unsaturated aldehydes. Inspired by the Petasis reaction and guided by rational mechanistic considerations, we discovered a new mode of reactivity for organoboronates and a metal-free “coupling” procedure for enantioselective C–C bond construction. From a practical standpoint, this methodology stands to benefit from the structural diversity and wide commercial availability of several hundred organoboron reagents accessible to organic chemists. Furthermore, the low toxicity and the air and moisture stability of potassium organotrifluoroborates reagents make this powerful new organocatalytic process operationally trivial.

A five-step total synthesis of (+)-frondosin B highlights the stereoselective construction of a natural product target using an organocatalytic conjugate addition of a trilfluoro(organoboronate) reagent. This key step unambiguously established the absolute configuration of the frondosin B to be the (R)-enantiomer and led to the reassignment of naturally occurring frondosin B, thus resolving an existing discrepancy in the literature. To date, this work represents the most effective synthesis of frondosin B, which is accessible in only five steps and in a 32% overall yield.

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