Lipases resolution

An excellent example for an enzymatic resolution process is reported for production of Pregabalin. This drug was approved by the US Food and Drug Administration (FDA) in 2004 against neurophatic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Several different routes have been developed based on asymmetric hydrogenation, crystallization and biocatalytic resolutions [16-20]. The most powerful and currently applied process is based on a lipase resolution, shown in Figure 14.3. This process is one of the very few... 

Two methods have been developed to provide enantiomerically enriched cycloadducts using the chromium-mediated [6 + 2]- and [6 + 4]-cycloadditions one involving a chiral resolution and the other involving the attachment of a chiral auxiliary to the triene. The lipase resolution method provides access to either enantiomer of the chromium complex, albeit with moderate enantiomeric excesses (Scheme 34).119 The [6 + 4]- and [6 + 2]-reactions of chiral substrates such as 116 which are available by the attachment of a removable chiral auxiliary (R ) to the triene moiety are highly diastereoselective (Equation (17)).120... 

Scheme 1.34 Lipase resolution of a key intermediate in the synthetic route to an androgen receptor antagonist. TBME tert-butyl methyl ether...

Lipase Resolution of (R)-isomer and (S)-isomer of 2-hydroxy octanoic acid in phosphate buffer/iso-octane [72]... 

Three processes have been developed for L-(-)-menthol, which has three asymmetric centers (i) separation of diastereomeric salt pairs (ii) homogeneous catalysis with Rh-BINAP and (iii) lipase resolution of menthol benzoates. 

The use of 0.75 mol% Yb(fod)3 (27) at 50 °C offered more reproducible results (Scheme 6). A diastereomeric mixture (65 35) of cis-11 to trans-11 was isolated in 60-65% yields as racemic materials. This process, however, required an oxidation (TEMPO, NaOCl) followed by NaBH4 reduction, protection as acetate derivative and lipase resolution (PS-C, amino-I) to afford the bis-THF alcohol in 97-98% ee and 28-35% yields. 

Researchers at Tibotec patented a synthesis of racemic bis-THF alcohol ll.33 This synthesis used the multicomponent reaction developed by Ghosh and co-workers.34 As shown in Scheme 7, multicomponent reaction of dihydrofuran 12 and glyoxalate 28 provided 29 in 70-92% yield by GC. Reduction of 29 by NaBH4 gave 30 in 76% yield, which underwent an acid-catalyzed cyclization to give ( )-ll. This was subjected to a three-step process that included a TEMPO oxidation, NaBH4 reduction, and lipase resolution to provide optically active bis-THF (-)-ll. 

A patented synthesis by Doan et al. at GlaxoSmithKline used a Patemo-Buchi photochemical reaction to obtain acetal 33 in 96% yield, as shown in Scheme 8.35 Hydrogenation followed by acid-catalyzed cyclization resulted in a diastereomeric mixture of bis-THF alcohol ( )-ll. Formation of acetate 15, followed by lipase resolution resulted in the formation of the acetyl bis-THF, which was subsequently deprotected to afford the desired product (-)-ll in 98% ee.35... 

The double dynamic system comprised 24 chiral aminonitrile intermediates, carrying different substituents on the aromatic moiety and the /V-position, and was subsequently challenged by the lipase-mediated amidation resolution process. Not only H-XMR spectroscopy was used to follow the reactions HPLC, through the integration of preparative Zorbax and chiral OD-H columns, was used to confirm the product formations and to analyze the enantioselectivities. According to both analyses, the results indicated that only /V-methyl aminonitriles, produced from methylamine A, were transformed by the lipase resolution process. The major product was found to be amide 33A, derived from its corresponding intermediate 32A. The other products were amides 36A and 30A. 

Diltiazem Lipase Resolution will be achieved by preferential hydrolysis of starting racemic p-methoxy-phenylglycidate [70]... 

Organic Lipase Resolution of chiral alcohols and amides... 

Although the lipase resolution results looked promising, direct enantioselective 1,2-reduction of the enone would be much more efficient if appropriate conditions could be found. It was known that Corey s oxazaborolidine (CBS) catalyst would reduce 2-bromo-cyclopent-2-enone with high enantioselectivity (34) due to the large bromine atom being located alpha to the ketone. It was uncertain if 22 would reduce with enantioselectivity since the iodine atom was one atom further removed from the ketone. After an extensive effort at this reduction, our best conditions gave a 90% yield of enantioenriched 24 (3 1 S R) using 5 mol % (R) 5-methyl CBS catalyst.(i5)... 

As in the case of sec-alcohols, ruthenium complex has also been investigated as a catalyst in the racemization of primary amines. In fact, Shvo s complex 2 (Figure 14.3) was employed by the Backvall s group as the catalyst of the racemization of amines under transfer hydrogenation conditions [105]. However, temperatures up to 110 °C were required for amine racemization, incompatible with the lipase resolution, and furthermore, side products were formed in the medimn and a hydrogen source was needed. To avoid these drawbacks, the racemization at high temperature was carried out after a first lipase-catalyzed KR, followed by a second KR process, and a hydrogen source such as 2,4-dimethylpentan-3-ol was employed. 

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