Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (S,R,R,R)-Nebivolol

The first enantioselective total synthesis of the antihypertensive agent ( S, R, R, R )-nebivolol ( 3 ) is described. The synthesis includes the efficient (EBTHI)Zr-catalyzed kinetic resolutions of cycloheptenyl styrenyl ethers 8 and 16, which are subsequently treated with 4 mol % Mo(CHCMe 2 Ph)(N(2,6-( i -Pr) 2 C 6 H 3 ))(OCMe(CF 3 ) 2 ) 2 to afford chiral nonracemic 2-substituted chromenes ( R, R )- 9 and ( S, R )- 17 . Since the present retrosynthetic analysis dissects the molecule into two chromene fragments, both the ( R ) and ( S ) antipodes of (EBTHI)Zr catalyst are required. Accordingly, Buchwald's efficient resolution process is used to resolve rac -(EBTHI)ZrCl 2 (from catalytic hydrogenation of commercially available rac -(EBI)ZrCl 2 ), such that the two requisite transition metal chiral catalysts are obtained by a single process. Other noteworthy features of the synthesis include a highly efficient, regio- and stereoselective Pd-catalyzed opening of cyclic allylic epoxide 7 with diaryloxystannane 15 and a photochemical modification of the C2 chromane side chain (e.g., 10 → 11 ).