Over the past two decades, the field of N-heterocyclic carbene (NHC) organocatalysis has distinctively enabled the construction of enantioenriched heterocycles, and the power of cascade and one-pot processes has led to an ever-increasing level of synthetic efficiency in the assembly of complex architectures. Here these tools are employed in concise, enantioselective syntheses of two corynanthe alkaloid classes: the yohimbines and corynantheines. Key transformations include a highly enantio- and diastereoselective NHC-catalyzed annulation and an amidation/N-acyliminium ion cyclization sequence to construct the tetracyclic Corynanthe alkaloid core in two operations. Following selective reduction of the lactam, this tetracyclic intermediate served as a point of divergence to access these two alkaloid classes. A novel reductive homologation of the unsymmetrical diester was followed by ring closure, methanolysis, and diastereoselective reduction to yield rauwolscine. Alternatively, the less sterically hindered ester of the same tetracycle could be deoxygenated with excellent regiocontrol using a two-step protocol, thereby facilitating access to the corynantheine-type skeleton. The key tetracyclic lactam could also be selectively manipulated to allow access to all four possible diastereomeric arrangements of the corynanthe stereotriad. When combined with the ability to access either enantiomer of the NHC annulation product, this work provides a powerful platform to access related analogs concisely for biological evaluation.

Creator

• Miller, Eric Robert

DOI

• https://doi.org/10.21985/n2-2bbp-8c18

Subject

• Organic chemistry

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15460
• etdadmin_upload_794579

Keyword

• Organocatalysis
• Corynanthe alkaloids
• Total synthesis
• Divergent synthesis

Date created

• 2021-01-01

Resource type

• Dissertation

Rights statement

• In Copyright