Enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine: the key to an efficient and practical synthesis of a glucokinase activator.
A short and practical synthesis of glucokinase activator 1 was achieved utilizing a convergent strategy involving S(N)Ar coupling of activated aryl fluoride 11 with hydroxypyridine 9. The key to the success of the synthesis was the development of a novel method for enantioselective formation of alpha-arylpyrrolidines during the course of the project. In this method, (-)-sparteine-mediated enantioselective lithiation of N-Boc-pyrrolidine was followed by in situ transmetalation to zinc and Pd-catalyzed coupling with aryl bromide 3, proceeding in 92% ee. This transformation allowed the preparation of compound 1 in a 31% overall yield over six steps.
Klapars
Artis
A
Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA. artis_klapars@merck.com
Campos
Kevin R
KR
Waldman
Jacob H
JH
Zewge
Daniel
D
Dormer
Peter G
PG
Chen
Cheng-yi
CY
D020536:Enzyme Activators / Q000138:chemical synthesis*; D005941:Glucokinase / Q000378:metabolism*; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*
D020536:Enzyme Activators; C531441:N-Boc-pyrrolidine; D011759:Pyrrolidines; D010165:Palladium; D005941:Glucokinase