Meeting Challenges in Asymmetric Synthesis

Industry and academia advance novel approaches for achieving enanioselectivity.
Sep 02, 2012
Volume 36, Issue 9

Patricia Van Arnum
Chiral chemistry plays a significant role in the development of pharmaceutical intermediates and APIs, and as such, advances in asymmetric synthesis are of value to pharmaceutical companies. Researchers in academia and industry continue to develop new routes for achieving desired enantioselectivity. Some recent approaches include a more efficient route to prostaglandins, a biocatalytic route for making a key intermediate in the production of boceprevir, the API in Merck & Co.'s Victrelis, and a bifunctional catalyst derived from BINOL ligands for producing highly enantioselective bromolactonizations of unsaturated carboxylic acids.

Assessing the market

The global market for chiral technology, inclusive of applications in pharmaceuticals, is expected to show moderate growth during the next five years. The global chiral technology market was worth nearly $5.3 billion in 2011, according to a recent analysis by BCC Research. This market is expected to increase at a compound annual growth rate (CAGR) of 6.5% from 2011 to 2016 and will approach $7.2 billion by the end of the forecast period. Chiral synthesis products accounted for the majority of the chiral technology market in 2010, with an 80.0% share (i.e., $3.9 billion in revenues). This market segment was estimated at $4.2 billion in 2011 and is exepected to be $5.7 billion by 2016, a five-year CAGR of 6.4%, according to BCC. The chiral analysis market was valued at $785.7 million in 2010 and grew to $839.4 million in 2011. This market is projected to reach nearly $1.1 billion by 2016, a CAGR of 5.8% over the five-year period, according to BCC.

A better route to prostaglandins

Researchers at the University of Bristol in England recently reported on an improved method for making prostaglandins, natural, hormone-like chemicals that have pharmaceutical applications. The prostaglandin analog latanoprost, which is used to treat glaucoma and ocular hypertension, is a well-known prostaglandin. It is the active ingredient in Pfizer's Xalatan, which generated 2011 sales of $1.25 billion; the patent for the drug expired in 2011 (1).

Due to prostaglandins' biological activity, but difficulty in synthesizing them, strategies for better synthetic routes for prostaglandins are an active area of research. For example, the current synthesis of latanoprost requires 20 steps and uses the methodology and strategy developed by E.J. Corey, winner of the 1990 Nobel Prize in Chemistry, according to an Aug. 15, 2012, University of Bristol press release.

The University of Bristol researchers reported on a synthesis of prostaglandin PGF, which relies on the use of an organocatalyst, a small organic molecule, to catalyze a key step in the process, which produced high levels of control of relative and absolute stereochemistry and fewer steps, according to the university press release and recent article detailing the research (2). The new process uses a new disconnection that enabled the researchers to complete the synthesis in only seven steps, according to the university release. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step with enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups (1). The route to the bicyclic enal is important for a more efficient and potentially cost-effective route but also serves as a basis for examining related chemical structures of prostaglandin analogs (1, 2).

"Despite the long syntheses and the resulting huge effort that is required for the preparation of these molecules, they are still used in the clinic because of their important biological activity, said Varinder K. Aggarwal, professor in the School of Chemistry, University of Bristol, in the university release. "Being able to make complex pharmaceuticals in a shorter number of steps and, therefore, more effectively, would mean that many more people could be treated for the same cost."

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