Total synthesis of antitumor Goniothalamus styryllactones

Abstract

Synthesis of eight enantiopure styryllactones has been achieved from a common precursor: ethyl (2 S, 3 S, 4 R)-4-( t-butyldimethylsilyloxy)-2,3-isopropylidenedioxy-4-phenylbutanoate 16, prepared in five steps and 65 % yield from ( R)-mandelic acid. Key elements for the synthesis of goniofufurone 3, goniopypyrone 4, goniobutenolides A and B ( 5, 6) and 7- epi-goniofufurone 7 were the introduction of the Z-acrylate moiety by a Julia coupling between 16 or its epimer in benzylic position and methyl 3-phenylsulfonyl orthopropionate 11 followed by a highly diastereoselective reduction of the resulting β-keto sulfone which sets up the last of the four contiguous asymmetric center. In the case of styryllactones 4 and 7, prior to the Julia coupling, the benzyl sterocenter of 16 was efficiently inverted by a Mitsunobu reaction. Goniodiol 1 and 9-deoxygoniopypyrone 2 were synthesized via an efficient coupling between the primary triflate derived from the common intermediate 16 or its epimer and Ghosez's sulfone 11 followed by lactonization and PhSO 2H elimination. Goniodiol 1 has been efficiently converted to another styryllactone: isogoniothalamin epoxide 41. Addition of the Ghosez's sulfone to an epoxide derived from the enantiomer of 16 allowed a short synthesis of 8- epi-9-deoxygoniopypyrone 8, thereby establishing that its structure is the following: (1 R, 5 R, 7 S, 8 S) -8-hydroxy -7-phenyl-2,6- dioxabicyclo[3.3.1] nonan-3-one.