Structure determination of chiral sulfoxide in diastereomeric bicalutamide derivatives.
We report on the synthesis and investigation of two diastereomers (5a and 5b) of a new bicalutamide analog with an asymmetric carbon atom and a chiral sulfoxide group. These bicalutamide analogs are novel androgen receptor antagonists with biological activities that depend significantly on the configuration of their stereogenic centers. We determined the absolute configuration at the SO center by combining X-ray and NMR measurements with quantum chemical calculations. Since 5a and 5b failed to yield satisfactory crystals for X-ray crystal structure determination, analogs 6a and 6b differing in only one remote functional group relative to the chiral sulfoxide were synthesized, which yielded satisfactory crystals. X-ray structure determination of 6a and 6b provided the absolute configuration at the chiral sulfoxide. Since the structural difference between 5 and 6 is remote from the chiral sulfoxide, the structural assignment was extended from the diastereomers of 6 to those of 5 provisionally. These assignments were verified with the help of measured and DFT-calculated proton and carbon NMR chemical shifts.
Li
Wei
W
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Hwang
Dong Jin
DJ
Cremer
Dieter
D
Joo
Hyun
H
Kraka
Elfi
E
Kim
Juhyun
J
Ross
Charles R
CR
Nguyen
Viet Q
VQ
Dalton
James T
JT
Miller
Duane D
DD
D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D009570:Nitriles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011789:Quantum Theory; D011944:Receptors, Androgen / Q000378:metabolism; D012451:Safrole / Q000031:analogs & derivatives* / Q000737:chemistry; D013237:Stereoisomerism; D014105:Tosyl Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D059002:Androgen Receptor Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D012451:Safrole; C005746:sulfoxide