OSW Saponins: Facile Synthesis toward a New Type of Structures with Potent Antitumor Activities

OSW saponins, featuring a 16β,17α-dihydroxycholest-22-one aglycon and an acylated β-d-xylopyranosyl-(1→3)-α-l-arabinopyranosyl residue attached to the 16-hydroxyl group, have recently
been discovered from a group of lily plants, which show potent antitumor activities with a novel
mechanism of action. This paper describes an aldol approach to the stereoselective construction of
the 16α,17α-dihydroxycholest-22-one structure from 16α-hydroxy-5-androsten-17-ones and propionates. Elaboration of the aldol adducts toward OSW-1, involving installation of the isoamyl ketone
side chain, inversion of the 16-hydroxyl configuration, and selective protection of the C22-oxy
function, has been explored and accomplished. In particular, the present route was found convenient
for the synthesis of OSW saponin analogues with a C22-ester side chain. Thus, the 23-oxa-analogue
of OSW-1 (40) was prepared starting from the industrial dehydroisoandrosterone (1) in a linear
eight-step sequence and in 26% overall yield. Analogues with a variety of modified side chains
were prepared, via aldol condensation with propionates of varying length, thiopropionate, and
acetate (for preparation of 68−75) or via aminolysis of the 22,16-lactone 26 (for preparation of the
23-N-analogues). Cross metathesis (CM) reaction was also found feasible for modification at the
final stage from C22-allyl ester 70. Valuable structure−activity relationships (SAR), together with
the practical synthetic approach, have thus been provided to set a new stage for further studies on
this new type of antitumor structures.