Enantioselective Synthesis of 3,3-Difluoropyrrolidin-4-ol, a Valuable Building Block in Medicinal Chemistry

Abstract

In this paper, we report for the first time two enantioselective routes to 4,4-difluoropyrrolidin-3-ol, a valuable building block in medicinal chemistry. In the first route, we took advantage of the C2 symmetry of (3R,4R)-3,4-dihydroxypyrrolidine in which the desired chirality was derived from the chiral pool (l-(+)-tartaric acid). In the second route, we efficiently assembled the pyrrolidine ring in the presence of a gem-difluoro moiety to avoid using potentially hazardous deoxofluorinating reagents and subsequently introduced the chirality by a stereoselective iridium-diamine-catalyzed asymmetric transfer hydrogenation reaction.

Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model

“…Synthesis of these compounds proceeded through reaction of 5-halothiophene 26 or 27 with cyclic amines under S N Ar or Buchwald amination conditions to provide 28a and related analogues 28b – i or with pyridone boronate to provide 29 . While the amines used were commercially available, in related work we developed and recently reported an enantioselective synthesis of 3,3-difluoropyrrolidin-4-ol, as well as RCM-mediated synthesis of the dihydropyridones 30a , b . , Intermediates 30a , b were reacted with 2-thienylzinc bromide under Negishi conditions to provide thiophenes 31a , b . Subsequent chlorosulfonylation and coupling with 24 produced dihydropyridones 32a , b .…”

“…23 While the amines used were commercially available, in related work we developed and recently reported an enantioselective synthesis of 3,3-difluoropyrrolidin-4-ol, as well as RCM-mediated synthesis of the dihydropyridones 30a,b. 24,25 Intermediates 30a,b were reacted with 2-thienylzinc bromide under Negishi conditions to provide thiophenes 31a,b. Subsequent chlorosulfonylation and coupling with 24 produced dihydropyridones 32a,b.…”

“…The filtrate was evaporated under reduced pressure to yield the title compound 22 (1.70 g, 7.1 mmol, 52%) as a yellow solid. 1 7-Amino-6-fluoro-2H-isoquinolin-1-one (24). To a solution of 23 (100 g, 0.48 mol, 1 equiv) in methanol (1500 mL) was added carefully wetted palladium (20 g, 0.18 mol, 0.38 equiv).…”

Synthesis of Chiral Tertiary α,α‐Difluoromethyl Carbinols by Cu‐Catalyzed Asymmetric Propargylation

“…However, the difluoromethylation agents are generally limited by the obligatory presence of an electron‐withdrawing substituent (e.g., sulfone, carbonyl, CN, etc.). So far, there is only one documented example of catalytic asymmetric synthesis in this respect, with a single α,α‐difluoromethyl carbinol (1‐benzyl‐3,3‐difluoro‐4‐hydroxypyrrolidin‐2‐one, 98 % ee ) being obtained through an Ir‐catalyzed asymmetric transfer hydrogenation of the corresponding α,α‐difluoroketone hydrate (Scheme B) . Accordingly, the synthesis of optically active tertiary difluoromethyl carbinols with diversified substituents at the CF 2 terminus remains an unaddressed challenge.…”

Synthesis of gem-Difluorinated Hydroxypyrrolidines

“…gem -Difluorinated pyrrolidines have been considered as valuable building blocks and as target compounds in medicinal research. They are typically synthesized either from acyclic precursors or by deoxofluorination reaction from corresponding ketones .…”