Synthetic Strategies for the Total Synthesis of Acutumine Alkaloids and the Development of Radical Deoxychlorination Reactions

Author: Grünenfelder, Denise Christine

Year: 2019

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Stoltz, Brian M.; Reisman, Sarah E.; Peters, Jonas C.; Tirrell, David A.

Option: Chemistry

DOI: 10.7907/FS86-HB55

Abstract

The acutumine alkaloids are a family of architecturally complex propellane natural products with promising medicinal properties. Herein, we disclose the continued development of a synthetic strategy toward the asymmetric total synthesis of acutumine alkaloids. The spirocyclic scaffold was synthesized in two new series, which follow our successful access to the dechloroacutumine core in 2013. Central to the synthetic design is the retro-aldol/Dieckmann cyclization of a cyclobutyl lactone to install the spirocycle. The key cyclobutane intermediate is obtained via a photo-mediated [2+2]-cycloaddition of a furanyl dihydroindolone, which is accessible via a stereoselective 1,2-addition/reductive cyclization sequence of a benzoquinone-derived imine. Installation of the dimethoxyenone motif is accomplished via a late-stage elimination of a dimethoxyketal, which furnished the requisite vinylogous ester after methylation. Overall, these efforts have culminated in the synthesis of the complete carbocyclic core and oxidation pattern of the natural product (–)-acutuminine, with a C10 neopentyl alcohol in place of the neopentyl chloride.

Ten of the known acutumine alkaloids contain a neopentyl chloride; this motif provided underlying motivation for the development of novel radical deoxychlorination reactions, including the chlorination of cesium oxalates. This reaction allows access to hindered 2° and 3° alkyl chlorides, provides complementary reactivity to standard heterolytic conditions, and is performed under mild conditions using visible light and ethyl trichloroacetate as a Cl• source. Application to deoxybromination and deoxyfluorination is also demonstrated, showcasing the versatility of the discovered halogenation. This method should find broad utility in the deoxyhalogenation of hindered alcohols, particularly in the pharmaceutical industry where selective installation of fluorides is a common challenge.

Files