Development of Tandem Chemical Processes for the Synthesis of Bioactive Natural Products.

polyenes;steroids;tandem chemical processes;Chemistry;Science;Chemistry

Cichowicz, Nathan R.Matzger, Adam J. ;

University of Michigan

关键词: polyenes;    steroids;    tandem chemical processes;    Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/113527/nrcich_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The discovery of new reagents and the development of new tandem chemical processes, which permit access to bioactive natural products and therapeutic agents, is an area of great interest.Described herein is the development of two new tandem chemical processes:the synthesis of conjugated polyenes utilizing designed sulfonylphosphonate reagents and the stereoselective rapid assembly of steroid skeletons via a Michael-aldol-aldol cascade. Chapter 1 provides an overview of polyenes including their importance in medicine and materials science and synthetic advancements.Discussed is synthetic methods and strategies employed in polyene synthesis including the historically employed linear installation approach and recent advancements using iterative cross-coupling. Chapter 2 describes the development of sulfonylphosphonate reagents for the synthesis of unsymmetrical all trans-polyenes.Selective metalation of sulfonylphosphonate results in sufficiently stable carbanions that undergo chemoselective Julia-Kocienski condensation with aldehydes to provide (E)-allylic phosphonates in good yields and selectivities (16 examples, up to 85% yield, and up to >95:5 E:Z).The subsequent Horner-Wadsworth-Emmons condensation with aldehydes is used to synthesize various unsymmetrical trans-dienes, trienes, and tetraenes.This methodology was utilized in the concise synthesis (5 linear steps, 6 total steps) of a naturally occurring fluorescent probe, β-parinaric acid.Chapter 3 provides an overview of cardiotonic steroids including their structure, biologi-cal activity, and historical importance.The chapter focuses on synthetic strategies including semi-synthetic and synthetic methods and highlights the inherent challenges that prevent appre-ciable quantities of cardiotonic steroids to be synthesized. Chapter 4 describes a rapid conceptually new asymmetric approach to functionalized oxygenated steroid cores.Developed is the unprecedented chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reaction of cyclic ketoesters and enones to install challenging vicinal quaternary and tertiary stereocenters (8 examples, up to 95% yield, up to >20:1 dr, and up to 96% ee).These products subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural (3 examples, up to 59% yield, up to >20:1 dr, and up to 92% ee) or unnatural (6 examples, up to 86% yield, >20:1 dr, and up to 99% ee)steroid skeletons.