No abstract

The first stereocontrolled synthesis of the C(1)-C(13) fragment of cytotoxic macrolides dolabelides is reported. The C(3), C(7), C(9) and C(11) hydroxyl-bearing stereocenters were installed using ruthenium-mediated asymmetric hydrogenation reactions of the adequate b-keto esters and b-hydroxy ketone.Dolabelides A and B were isolated in 1995 from Japanese sea hare Dolabella auricularia. Two other similar marine macrolides dolabelides C and D were isolated from the same source in 1997 (Scheme 1). 1,2 These macrolides exhibit cytotoxicity against HeLa-S 3 cells with IC 50 values of 6.3, 1.3, 1.9 and 1.5 mg/mL, respectively. The dolabelides contain a 22-or 24-membered ring, including eleven stereogenic centers. Eight of them are hydroxyl or acetyl functions. Those challenging molecules and especially their syn-and anti-1,3-diol sequences constitute an excellent target for our ongoing program on the use of ruthenium-mediated asymmetric hydrogenation for the preparation of biologically relevant natural products. [3][4][5] Moreover, this would allow us to valorize the SYNPHOS ® ligand, a chiral atropisomeric diphosphine recently developed by our group. 6