Achieving Enantioselectivity - Pharmaceutical Technology

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Achieving Enantioselectivity
Carbon–hydrogen functionalization, ketone α-alkylation, and biocatalysis are some recent advances in asymmetric synthesis.

Pharmaceutical Technology
Volume 9, Issue 32, pp. 60-64

Asymmetric Diels–Alder reactions

Eric Jacobsen, professor of the Department of Chemistry at Harvard University, recently reported on transannular reactions for achieving desired enantioselectivity. Specifically, Jacobsen reported on a catalytic transannular asymmetric Diels–Alder (TADA) reaction for producing polycyclic products in high enantiomeric excess. The catalyst system (derivatives of oxazaborolidine-based Lewis-acid compounds) were used to alter the diastereoselectivity of cyclizations with substrates containing chiral centers. The catalytic enantioselective TADA was used as the key step in synthesizing sesquiterpene 11, 12-diacetoxydrimane. This route may also provide a general approach to the polycyclic carbon framework shared by other terpene natural products (6).


BASF (Ludwigshafen, Germany) is using a class of enzymes, enoate reductases, for the industrial production of chiral intermediates. The asymmetric reaction catalyzed by the enoate reductases can take place at low temperatures and standard pressures, according to a company press release. BASF and researchers at the University of Graz recently reported on using three cloned enoate reductases (12-oxophytodienoate reductase isoenzymes [OPR1 and OPR3] from Lycopersicon esculentu and YqjM from Bacillus subtilis) in the asymmetric bioreduction of activated alkenes. According to the research, the biocatalysts were able to reduce α, β-unsaturated aldehydes, ketones, maleimides, and nitroalkenes with absolute chemoselectivity (with reduction of only the conjugated carbon–carbon double bond) with enantioselectivity > 99% ee (7).

Codexis (Redwood City, CA) is ausing ketoreductases to produce chiral secondary alcohols. Chiral secondary alcohols are commonly produced using boron-based reducing agents or chemocatalysis. Although a biocatalytic route could improve reaction conditions, ketoreductases have had drawbacks, including narrow substrate-specificity, low activity, poor in-process stability, inadequate stereoselectivity, and productivity-limiting product inhibition. To resolve these problems, Codexis launched ketoreductase biocatalyst panels that consist of 180 variants of one wild-type ketoreductase that are pre-evolved for in-process thermal and solvent stability. The variants are arrayed on microtiter plates for screening to find the desired activity on a new ketone substrate and to obtain amino-acid sequence versus activity data for further evolution if needed (8). The company launched the panels in 2007.

Figure 1: Biocatalysis offers an improved route for producing a chiral intermediate used in the synthesis of montelukast (pictured), the active ingredient in Merck Singulair. (FIGURE IS COURTESY OF US FOOD AND DRUG ADMINISTRATION.)
Codexis developed an improved route to (S,E)-2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-hydroxypropyl)-benzoate (MLK-III), a chiral intermediate used in the synthesis of the anti-asthama drug "Singulair" (montelukast sodium) (see Figure 1) using biocatalysis. In the traditional approach, the ketone reduction to this chiral alcohol requires at least 1.8 equivalents of the reductant (–)-β-chlorodiisopinocampheylborane ((–)-DIP-Cl) in tetrahydrofuran at –20 to –25 C. After quenching, an extraction removes spent borate salt waste. The reduction produces the S-alcohol in 97% ee and requires crystallization to give 99.5% ee in 87% yield (8).


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