Nickel‐Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin

Abstract

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.

Highly Selective C–N and C–S Dual Functionalization of 1,3-Dicarbonyl Derivatives Using TBHP as an Oxidant

“…12 The cyclization of 3d using 50% sulfuric acid gave corresponding thiazolinone (18c). Products 18a−18c were confirmed by 1 H , 13 The Journal of Organic Chemistry…”

“…Gratifyingly, TBHP proved the most effective oxidant with an impressive yield of 3a (Table 1, entry 7). Reducing the loading of The observed E-selective product (3a) was well characterized by 1 H NMR, 13 C, and DEPT. Subsequently, we began implementing our standard condition on various substrates to access their synthetic applicability.…”

“…Recently, our research group explored the utilization of betaketo esters as a substrate in sitagliptin drug development. 13 Going through the literature survey of the application of β-keto ester compounds, we observed that there are no reports on metal-, photocatalyst-and electrosynthesis-free methods for the synthesis of 3-amino-2-thiocyanato-α,β-unsaturated carbonyl compounds in a single step. So, we thought to develop a new method for the direct synthesis of 3-amino-2-thiocyanatoα, β-carbonyl compounds using the benzylic-β-keto ester (1a) as a substrate.…”

“…Melting points were determined using the Buchi B-540 melting point apparatus and uncorrected. 1 H, 13 C NMR, and DEPT 135 spectra were recorded on a Bruker Avance NMR spectrometer operating at 200 or 400 MHz for 1 H NMR and 50 or 100 MHz for 13 C NMR at room temperature using CDCl 3 as a solvent. The chemical shifts (δ) are reported in ppm, and coupling constants (J) are given in Hz.…”

Development of Construction of Chiral C—X Bonds through Nickel Catalyzed Asymmetric Hydrogenation★

“…值得强调的是, 作者利用标准底物进行了克级 规模的氢化反应和高催化剂催化转化数(TON)实验, 使 用 0.02 mol%催化剂用量时, 以 63%分离产率和＞99% ee 值得到氢化产物, TON 高达 3350, 充分显示出该催化 体系的高效性. 随后在 2021 年, Punji 等 [33] 报道了一例 镍催化不对称氢化烯胺的研究, 以高收率和优异的对映 选择性得到抗糖尿病药物西他列汀关键中间体(图 15). 2008 年, Hamada 课题组 [34] 利用过渡金属镍催化体 系, 以动态动力学拆分的方式成功地实现了 α-氨基-β-羧酸酯盐酸盐的不对称氢化反应, 有效合成了一系列高 非对映选择性和对映选择性手性 β-羟基-α-氨基酯类化 合物.…”