Microbial synthesis of chiral intermediates for β‐3‐receptor agonists

Abstract

Chiral intermediates were prepared by biocatalytic processes for the chemical synthesis of β-3-receptor agonists. These include: (i) the microbial reduction of 4-benzyloxy-3-methanesulfonylamino-2′-bromoacetophenone 1 to the corresponding (R)-alcohol 2 by Spingomonas paucimobilis SC 16113. In the biotransformation process, a reaction yield of >85% and an optical purity of 99.5% were obtained for the desired (R)-alcohol 2; (ii) the enzymatic resolution of racemic α-methyl phenylalanine amide, 3, and α-methyl-4-hydroxyphenylalanine amide, 5, by amidase from Mycobacterium neoaurum ATCC 25795 to prepare the corresponding (S)-amino acids 4 and 6. Reaction yields of 49.9 and 49 M% (theoretical maximum yield 50 M%) and optical purities of 99 and 94% were obtained for the desired (S)-amino acids 4 and 6, respectively; (iii) the asymmetric hydrolysis of methyl-(4-methoxyphenyl)-propanedioic acid, ethyl diester, 7, to the corresponding (S)-monoester 8 by pig liver esterase. A reaction yield of 96 M% and an optical purity of 96% were obtained for (S)-monoester 8 when reactions were carried out in a biphasic system containing 10% ethanol at 10°C.Much attention is currently focused on the interaction of small molecules with biological macromolecules. The search for selective enzyme inhibitors and receptor agonists or antagonists is one of the keys for target-oriented research in the pharmaceutical industry. Increasing understanding of the mechanism of drug interaction on a molecular level has led to growing awareness of the importance of chirality as the key to the efficacy of many drug products. It is now known that in many cases only one stereoisomer of a drug substance is required for efficacy; the other stereoisomer is either inactive or exhibits considerably reduced acitivity. Pharmaceutical companies are aware that, where the switch from racemate drug substance to enantiomerically pure compound is feasible, new drugs should be homochiral to avoid the possibility of side effects caused by an undesirable stereoisomer. There is the opportunity to double the use of an industrial process by obtaining a separate patent on the use of a single stereoisomer as a more efficient drug. The physical advantages of enantiomers over racemates may confer processing and formulation advantages, as well as lower doses.The advantages of microbial or enzyme-catalyzed reactions over chemical reactions are that they are stereoselective and can be carried out at ambient temperature and atmospheric pressure. These minimize problems of isomerization, racemization, epimerization, and rearrangement, which generally occur during chemical processes. Biocatalytic processes are usually carried out in aqueous solution. This avoids the use of solvent and other environmentally harmful chemicals used in the chemical processes. Furthermore, microbial cells or enzymes derived from biocatalysis can be immobilized and reused for many cycles. Recently, a number of review articles (1-9) have been published on the use of enzymes in organic synthesis.β-Adrenocepto...

Chiral Drugs and the Associated Asymmetric Synthesis

“…The reaction yields and ee of 74 were dependent upon the solvent used. High ee values (>91%) were obtained with methanol, ethanol, and toluene as a cosolvent; ethanol gave the highest reaction yield (96.7%) and ee (96%) (Patel et al, 1998).…”

Biocatalytic Synthesis of Chiral Pharmaceutical Intermediates

“…Consequently, several research groups are engaged in developing selective b3 agonists for the treatment of gastrointestinal disorders, type II diabetes, and obesity (74,75). Three different biocatalytic approaches for synthesis of chiral intermediates required for the total synthesis of b3 receptor agonists 80 [Scheme 16A] have been investigated (76).…”

“…These are available via the enzymatic resolution of racemic a-methyl phenylalanine amide 85 and a-methyl-4-methoxyphenylalanine amide 86, respectively, by an amidase from Mycobacterium neoaurum ATCC 25795 (76). Wet cells (m/V=10 %) completed reaction of amide 85 in 75 min with a yield of x=48 % (theoretical max.…”

“…The enantioselective enzymatic hydrolysis of diester 88 to the desired acid ester 87 by pig liver esterase (76) has been demonstrated. In various organic solvents the reaction yields and e.e.…”

Enzymatic synthesis of chiral intermediates for pharmaceuticals

“…Three different biocatalytic syntheses of chiral intermediates required for the total synthesis of b3 receptor agonists 19 (Fig. 6A) have been investigated [19].…”