Total synthesis of SR 121463 A, a highly potent and selective vasopressin v(2) receptor antagonist.
SR 121463 A, 1, is a promising nonpeptide prototype for potent and selective antagonism of the vasopressin V(2) receptor subtype and, thus, a candidate for control of the clinically debilitating condition of hyponatremia and its associated syndromes. In the present work, we present a novel and stereoselective synthesis that stems from the preparation of three key intermediates: the substituted benzenesulfonyl chloride 2, the N-protected oxindole 3, and protected dibromide 4. The synthesis of 1 has been achieved in good overall yield, each step proceeding in greater than 80% yield. In addition, intermediate 2 and the syn isomer of 1 were prepared with complete control of stereochemistry. The latter reduction appears to proceed by lithium cation mediated chelation control. Molecular mechanics calculations with the MM3* and MMFF force fields underscore geometric and energetic aspects of the reaction.
Venkatesan
H
H
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA. hvenkate@prius.jnj.com
Davis
M C
MC
Altas
Y
Y
Snyder
J P
JP
Liotta
D C
DC
D065092:Antidiuretic Hormone Receptor Antagonists; D008401:Gas Chromatography-Mass Spectrometry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009025:Morpholines / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D013141:Spiro Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism
D065092:Antidiuretic Hormone Receptor Antagonists; D007202:Indicators and Reagents; D009025:Morpholines; D013141:Spiro Compounds; C103281:satavaptan