Chemoenzymatic protocols

SCHEME 6.18. Chemoenzymatic protocol for the continuous flow synthesis of epoxides. 

Yu H, Chokhawala HA, Huang S, Chen X. One-pot three-enzyme chemoenzymatic approach to the synthesis of sialosides containing natural and non-natural functionalities. Nature Protocols 2006 1 2485-2492. 

Although initially prepared and evaluated as a racemate, the NMDA antagonist activity was likely to reside primarily in a single enantiomer. The stereoselective nature of the NDMA receptor is well established, albeit not completely understood. Consequently, several attempts have been undertaken to develop synthetic protocols that would allow preparation of optically active compounds. Early reports of preparation of optically active co-amino-o-carboxyalkylphosphonic acids describe the preparation of (.S )-A P-3 from an optically active amino nitrile prepared by reaction of diethyl 1-formylphosphonate with hydrogen cyanide and (5)-(-)-a-methylbenzylamine. Acid hydrolysis, enrichment of the diastereomers by fractional recrystaUization, and debenzylation lead to the isolation of (.S )-A P-3 in 86% enantiomeric excess. " Recently reported procedures, which use chemoenzymatic processes, offer a more convenient and mild approach for the production of optically pure aminophosphonic acids. Enzymatic hydrolysis of amides using penicillinacylase (EC... 

So far, the most efficient protocols for the chemoenzymatic large-scale (multigram) syntheses of GDP-Fuc and analogs, starting from commercially available fucose, have recently been published by Baisch and Ohrlein [163], In this seven-step synthesis, the crucial last step is the enzymatic deprotection of the triacetylated fucose moiety with acetylesterase from orange peel (Fig. 9). 

Transition metal catalysed prenylation. There is a new one-step N-tert-prenylation of indole developed by Baran and co-workers [42] which still outcom-petes the chemoenzymatic approach (Scheme 5). Isobutene (21) as prenyl source is reacted with side-chain Fmoc-protected tryptophan methyl ester 20 in the presence of catalytic amounts of Pd(OAc)2 and superstoichiometric amounts of Ag(I) trifluoroacetate and Cu(II) acetate. The protocol also requires the presence of oxygen. After about 1 day at 35°C, the N-tert-prenylated indole is obtained in a yield of about 60%. The mechanism has not been elucidated, but may involve a 7i-allyl-Pd(II) complex which is coordinated by the indole nitrogen or by C3. In the latter case, a Pd-Claisen rearrangement of a 3-palladated indole would follow. Ag (I) functions as reoxidant of Pd(0). 

The substrate scope of the DKR protocol above was extended to include a wide range of primary amines [89]. Functional groups tolerated include fluorine, bromine, nitrile, nitrate, and trifluoromethyl. Aliphatic amines and more sterically hindered substrates were also obtained in high yields and ee values. The method was found applicable with both isopropenyl acetate and dibenzyl carbonate as acyl donors. For 18 different substrates, the corresponding enantiomericafly pure products were obtained in high to excellent yields (70-95%) and with high to excellent ee values (93 to >99%). The chemoenzymatic DKR protocol was also applied to the synthesis of norsertraline, from readily available 1,2,3,4-tetrahydro-l-naphthyl-amine. Norsertraline is cmrently in clinical trials for the treatment of central nervous system (CNS) disorders. 

The chemoenzymatic DKR protocol combines the enzyme-catalyzed resolution of a racemic substrate with the in situ racemization of the less reactive enantiomer, thus, producing optically active products in up to quantitative yield. This is a significant improvement with respect to the maximum yield of 50% obtained in classic kinetic resolution (KR). However, certain requirements have to be fulfilled to achieve an efficient DKR 1) The substrate must racemize at least as fast as the subsequent enzymatic reaction (2) no product racemization has to occur under the reaction conditions and (3) the enzymatic reaction must be both irreversible and highly stereoselective. Given that the racemization rate is higher than the resolution rate, the aizyme... 

Alkyl and aryl [ C]nitriles can be hydrolyzed by chemical or chemoenzymatic methods to labeled amides and carboxylic acids following routine protocols. Since alkali metal [ C]-cyanides are stable, nonvolatile and easy to handle reagents, the latter transformation can be regarded as an alternative to [ C]carboxylation of organolithium or organomagnesium precursors (Chapter 5, Section 5.1), in cases where the requisite organometallic species are unviable or the use of gaseous C02 has to be avoided for experimental or radiation protection reasons. 

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