Stereospecific synthesis of antitumor active thioether PAF analogs

A novel stereospecific synthesis of antitumor active thioether analogs of platelet‐activating factor (PAF) is reported. The synthesis is based upon: i) the use of D ‐serine to provide the chiral center for the construction of the optically active phospholipid molecule; ii) development of the sn ‐1‐thioalkyl function via thioacetate displacement of methanesulfonate‐activated primary hydroxyl group followed by alkylation of the sn ‐1‐thiolate function; and iii) introduction of the phosphocholine moiety through the 2‐chloro‐2‐oxo‐1,3,2‐dioxaphospholane/trimethylamine sequence. The entire scheme relies on the use of a single protecting group. The synthetic thioether phospholipid 1‐ S ‐hexadecyl‐2‐ N ‐acetamidodeoxy‐ sn ‐glycero‐3‐phosphocholine has been shown to be a potent antitumor active phospholipid, exhibiting tumor cytotoxicity against a lymphoblastoid lymphoma (Li‐A) cell line and a malignant histiocytic (DHL‐4) cell line of human origin at the same level of potency as ET‐18‐OMe and 1‐ O ‐octadecyl‐2‐ N ‐acetamidodeoxy‐ sn ‐glycero‐3‐phosphocholine. The synthetic method described has a great deal of flexibility, providing a convenient general route to a wide range of thioether PAF analogs.