1. Nickel-Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin
Shana Sudhakaran, et al. Chem Asian J. 2022 Jan 3;17(1):e202101208. doi: 10.1002/asia.202101208. Epub 2021 Dec 6.
Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug (R)-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75-92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with (R)- and (S)-1-phenylethylamines, the partially enantioenriched (R)- and (S)-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided >99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee, and has been reproduced in multiple batches.
2. Efficient Preparation of (S)-N-Boc-3-Hydroxylpiperidine Through Bioreduction by a Thermostable Aldo-KetoReductase
Mengyan He, Shuo Zhou, Maolin Cui, Xiaolu Jin, Dunyue Lai, Shuangling Zhang, Zhiguo Wang, Zhenming Chen Appl Biochem Biotechnol. 2017 Apr;181(4):1304-1313. doi: 10.1007/s12010-016-2285-3. Epub 2016 Nov 16.
(S)-N-Boc-3-hydroxypiperidine ((S)-NBHP) is a key pharmaceutical intermediate and the chiral source in synthesizing Imbruvica, which is a newly approved drug in lymphoma therapy by targeting Bruton's tyrosine kinase (BTK). Current chemical synthesis of (S)-NBHP suffered from the need of noble metal catalyst and low yield. The single reported bioconversion of (S)-NBHP was achieved by using recombinant ketoreductase, but enzyme sequence was kept confidential and the catalytic process suffered from the thermodeactivation and substrate inhibition. In the current study, we presented a thermostable aldo-keto reductase (AKR)-AKR-43-which showed high activity toward N-Boc-3-piperidone (NBP) to produce (S)-NBHP, high enantioselectivity, and no substrate inhibition. The molecular simulations demonstrated the structural rationale for the enantioselectivity of AKR-43 toward NBP and supported the classic ordered two-step catalytic mechanism. The catalytic process was achieved by using glucose dehydrogenase (GDH) for cofactor recycling, and the optimal reaction conditions were determined to be 30 °C and pH 7.5. Within a reaction time of 16 h, the 16 % substrate concentration (w/w), over 99 % ee and under 3.5 % of enzyme loading (w/w) characterized a high efficiency process with promising industrial values.
3. Synthesis of 1-Boc-3-fluoroazetidine-3-carboxylic acid
Eva Van Hende, Guido Verniest, Frederik Deroose, Jan-Willem Thuring, Gregor Macdonald, Norbert De Kimpe J Org Chem. 2009 Mar 6;74(5):2250-3. doi: 10.1021/jo802791r.
Synthetic strategies toward 3-fluoroazetidine-3-carboxylic acid, a new cyclic fluorinated beta-amino acid with high potential as building block in medicinal chemistry, were evaluated. The successful pathway includes the bromofluorination of N-(diphenylmethylidene)-2-(4-methoxyphenoxymethyl)-2-propenylamine, yielding 1-diphenylmethyl-3-hydroxymethyl-3-fluoroazetidine after reduction of the imino bond, ring closure, and removal of the 4-methoxybenzyl group. Changing the N-protecting group to a Boc-group allows further oxidation to 1-Boc-3-fluoroazetidine-3-carboxylic acid, a new fluorinated heterocyclic amino acid.
