Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor.
A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA). keith.fandrick@boehringer-ingelheim.com.
Keith R
KR
Fandrick
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Wenjie
W
Li
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Yongda
Y
Zhang
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Wenjun
W
Tang
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Joe
J
Gao
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Sonia
S
Rodriguez
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Nitinchandra D
ND
Patel
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Diana C
DC
Reeves
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Jiang-Ping
JP
Wu
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Sanjit
S
Sanyal
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Nina
N
Gonnella
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Bo
B
Qu
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Nizar
N
Haddad
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Jon C
JC
Lorenz
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Kanwar
K
Sidhu
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
June
J
Wang
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Shengli
S
Ma
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Nelu
N
Grinberg
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Heewon
H
Lee
Research and Development, Boehringer Ingelheim (Canada) Ltd. 2100 Cunard Street, Laval, Québec H7S 2G5 (Canada).
Youla
Y
Tsantrizos
Research and Development, Boehringer Ingelheim (Canada) Ltd. 2100 Cunard Street, Laval, Québec H7S 2G5 (Canada).
Marc-André
MA
Poupart
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Carl A
CA
Busacca
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Nathan K
NK
Yee
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Bruce Z
BZ
Lu
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877-0368 (USA).
Chris H
CH
Senanayake
D000215:Acylation; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D006678:HIV / Q000201:enzymology*; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry
D019428:HIV Integrase Inhibitors; D008024:Ligands; D013449:Sulfonamides; D003300:Copper; D019427:HIV Integrase
Suzuki couplings; acylation; asymmetric synthesis; phosphine ligands; tert-butylation