Eric R. Ashley

A Highly Efficient Asymmetric Synthesis of Vernakalant

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.

Selective functionalization of complex heterocycles via an automated strong base screening platform

Knochel–Hauser bases, derived from 2,2,6,6-tetramethylpiperidinyl (TMP) metal amides, offer exceptional selectivity and functional group tolerance in the regioselective metalation of arenes and heteroarenes. The selectivity, stability and yield of these reactions are highly dependent on the nature of the base, additive and deprotonation temperature. We have developed and validated an automated micro-scale high throughput experimentation (HTE) approach to rapidly optimize base and temperature matrices. We describe the application of this approach to the regioselective functionalization of a variety of complex heterocycles and extension to the preparation of organometallic reagents for transition metal catalyzed cross-coupling screens.

Chapter 13 - A Dipolar Cycloaddition Strategy for the Synthesis of 3,8-Diazabicyclo[3.2.1]Octane Tetrahydroisoquinoline Antitumor Antibiotics: The Total Synthesis of (−)-Lemonomycin

Abstract At the beginning of the Stoltz research group in 2000, we envisioned a novel strategy for the synthesis of 3,8-diazabicyclo[3.2.1]octane tetrahydroisoquinoline antitumor antibiotics, comprising an asymmetric dipolar cycloaddition, an iodoenamide cross-coupling reaction, a substrate-directed diastereoselective enamide reduction, and an alkoxyacetaldehyde Pictet-Spengler cyclization. This chapter describes the development and execution of this strategy toward the total synthesis of (-)-lemonomycin, including the numerous challenges of unexpected reactivity, selectivity, and chemical instability we faced and the tactics we used to overcome these challenges. These studies culminated with the first successful total synthesis of (-)-lemonomycin on October 5th, 2003, a date fondly remembered within the group as “lemonomycin day”.

New reactions and processes for the efficient synthesis of a HCV NS5b prodrug

Herein we describe the route scouting and process development efforts toward a green and sustainable synthesis of the HCV NS5b cyclic prodrug nucleoside (CPN) 1. Through the discovery and development of a crystallization-induced dynamic resolution and a novel chemo- and stereo-selective phosphorylation reaction, we eliminated costly chromatographies and protecting group manipulations utilized in the initial approaches to this compound and implemented a highly streamlined and sustainable approach to the target molecule. We demonstrate how these improvements impact the PMI of the API on the kilogram scale and compare our work to the PMI of APIs of similar complexity.

Development of a stereoselective and scalable process for the preparation of a methylcyclobutanol-pyridyl ether

The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed.