Synthesis of (−)‐(R)‐Sitagliptin by Rh^I‐Catalyzed Asymmetric Hydroamination

Abstract

Scheme 1. Industrial process for the synthesis of (R)-(À )-Sitagliptin (1) developed by DSM and Codexis.

Rhodium-Catalyzed Allylic Addition as an Atom-Efficient Approach in Total Synthesis

“…The protected allylic amine was transformed into aldehyde 152 by Wacker oxidation. The final steps consisted of oxidation to the corresponding carboxylic acid, amide coupling with the amine 153 , and Boc deprotection to give ( R )-Sitagliptin as its phosphate salt on the gram scale in 34% overall yield (Scheme B) …”

“…To synthesize natural products such as Quercus lactones (1,2), 1 Helicascolides A−C (3−5), 17 Epothilone D (6), 18 Homolargazole (7), 19 Thailandepsin B (8) and derivatives, 20 Clavosolide A (9), 21 Vermiculine (10), 22 Centrolobine (11), 4 Rosuvastatin (12), 23 and Pitavastatin (13), 23 For the synthesis of Angustureine (14), 24 Cuspareine (15), 24 25 Abacavir (24), 3 Glucokinase activators (25), 14i and Chaetominine (26), 14j the C−N bond formation was recognized as the key step.…”

“…For the synthesis of Angustureine ( 14 ), Cuspareine ( 15 ), Cermizine C ( 16 ), Senepodine G ( 17 ), Homoproline ( 18 ), Pipecolinol ( 19 ), Coniceine ( 20 ), Coniine ( 21 ), Ruxolitinib ( 22 ), Sitagliptin ( 23 ), Abacavir ( 24 ), Glucokinase activators ( 25 ), and Chaetominine ( 26 ), the C–N bond formation was recognized as the key step.…”

Molybdenum-Catalyzed Regio- and Enantioselective Amination of Allylic Carbonates: Total Synthesis of (S)-Clopidogrel

“…Encouragingly, our protocol is comparable in terms of its cost effectiveness, wide substrate scope, simple and mild conditions, and the applicability of the late-stage N -alkylation of complex drug molecules. Further follow-up product transformation led us to develop the first asymmetric total synthesis of ( S )-clopidogrel (Plavix); demonstrating the synthetic importance and adaptability of the current protocol . To the best of our knowledge, chiral Schiff base metal catalysts for the asymmetric amination of allylic carbonates have not been reported thus far …”

Rhodium-catalyzed diastereoselective synthesis of highly substituted morpholines from nitrogen-tethered allenols

“…In this context, rhodium/ligand catalyst systems have found wide applications in inter- and intramolecular reactions as well as the synthesis of natural and bioactive products. 3 In this context, cyclization of terminal and internal allenols for the asymmetric synthesis of tetrahydropyrans is developed by our group. 3 a…”