Development of a Kilogram-Scale Synthesis of cis-LC15-0133 Tartrate, a Potent Dipeptidyl Peptidase IV Inhibitor

Abstract

(4S)-N-Boc-4-fluoro-l-proline methyl ester (4) was prepared from the following sequence of reactions: esterification of trans-4-hydroxy-l-proline (2), Boc protection, and fluorination by DAST. Reaction of 4 with lithiated oxadiazole provided oxadiazolyl ketone 7. Deprotection of the Boc group of 7 and subsequent coupling with bromoacetyl bromide gave bromide 9. Coupling reaction of 9 with excess oxazolidine 16 provided coupled product 17. Unexpectedly, the stereogenic center of 17 was completely epimerized to a virtually 1:1 mixture of cis- and trans-17 at this stage. After the deprotection of the N,O-methylene acetal group of 17 using aqueous ammonium chloride, crystallization induced dynamic resolution (CIDR) of cis- and trans-mixture of LC15-0133 (1) in the course of tartrate salt formation provided cis-LC15-0133 (1a) tartrate salt in 83% yield (>98% de).

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…4-Hydroxy-L-proline derivative, cis-LC15-0133, was identified as a potent dipeptidyl peptidase IV (DPP-IV) inhibitor by researchers at LG (Scheme 15). [65] Unexpectedly, this development candidate readily epimerized under neutral or basic conditions, forming a 1:1 mixture of cis/trans stereoisomers. As depicted by structure 35, it was presumed that epimerization was facilitated by proximity of the internal amine base.…”

“…4‐Hydroxy‐L‐proline derivative, cis ‐LC15‐0133, was identified as a potent dipeptidyl peptidase IV (DPP‐IV) inhibitor by researchers at LG (Scheme 15). [65] …”

Approaches to Obtaining Fluorinated α-Amino Acids

“…This approach allowed the generation of the (2S,4R)-4fluoroproline derivative (2S,4R)-286, starting from cis-4hydroxy-L-proline ((2S,4R)-286 not shown, Scheme 61). 185 Another approach reported by Hamacher et al involved the generation of unprotected (2S,4S)-4-fluoroproline also starting with 4-hydroxy-L-prolines. Treatment of the (2S,4R) or (2S,4S)isomer of hydroxyproline with HFA led to the conversion to the corresponding 1,3-oxazolidinones.…”

Diastereodivergent Synthesis of Chiral 4-Fluoropyrrolidines (exo and exo′) Based on the Cu(II)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition

“…Furthermore, synthesis of optically pure pyrrolidines with four contiguous stereogenic centers bearing a quaternary stereogenic center at C4 is still a challenging task due to the requisite use of less reactive and sterically crowded α,β-disubstituted dipolarophiles (Scheme a) . With this background and in view of the importance of 4-fluorinated pyrrolidine derivatives in pharmaceutical and biological research (Figure ), albeit a paucity of general synthetic tactics, we here investigate the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides and α-fluoro-α,β-unsaturated arylketones . Accordingly, under the Cu­(II)/( S )-tol-BINAP catalysis, the exo -pyrrolidine derivatives bearing a fluorinated quaternary stereogenic center at C4 were obtained.…”