TY - JOUR

T1 - Total Synthesis of Δ 12-Prostaglandin J 3

T2 - Evolution of Synthetic Strategies to a Streamlined Process

AU - Nicolaou, K. C.

AU - Pulukuri, Kiran Kumar

AU - Yu, Ruocheng

AU - Rigol, Stephan

AU - Heretsch, Philipp

AU - Grove, Charles I.

AU - Hale, Christopher R. H.

AU - ElMarrouni, Abdelatif

N1 - Publisher Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2016/6/13

Y1 - 2016/6/13

N2 - The total synthesis of Δ 12-prostaglandin J 3(Δ 12-PGJ 3, 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji–Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C−H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ 12-PGJ 3and designed analogues for further biological and pharmacological studies.

AB - The total synthesis of Δ 12-prostaglandin J 3(Δ 12-PGJ 3, 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji–Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C−H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ 12-PGJ 3and designed analogues for further biological and pharmacological studies.

KW - antitumor agent

KW - asymmetric catalysis

KW - chiral auxiliary

KW - prostaglandin

KW - total synthesis

UR - http://www.scopus.com/inward/record.url?scp=84970003913&partnerID=8YFLogxK

U2 - 10.1002/chem.201601449

DO - 10.1002/chem.201601449

M3 - Article

VL - 22

SP - 8559

EP - 8570

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

SN - 0947-6539

IS - 25

ER -