Total Synthesis of the Annonaceous Acetogenins Asiminocin and Asiminecin by a Bidirectional Approach

Abstract

A total synthesis of the Annonaceous acetogenins asiminocin and asiminecin is described. The approach is bidirectional starting from the (S,S)-tartrate derived dialdehyde 7 and the (R)-α-OSEM stannane 6. Addition of 6 to 7 in the presence of InCl3 afforded the bis-adduct, anti-diol 8. The derived tosylate 9 was converted to the bis-tetrahydrofuran core unit 10 upon treatment with TBAF. Selective silylation of one of the two equivalent terminal diol groupings led to the OTBS ether alcohol 11. Oxidation to aldehyde 12 and then InCl3-promoted addition of the (S)-allylic stannane 14 gave the anti adduct 15. Removal of the OH group by reduction of the tosylate 16 with LiBEt3H yielded the SEM ether 17. Hydrogenation of the three double bonds of 17 followed by cleavage of the terminal silyl ether and oxidation afforded aldehyde 20. Conversion to the vinylic iodide 21 followed by Pd(0)-catalyzed coupling with the (S)-alkynyl butenolide 24 gave the asiminocin derivative 25. Selective hydrogenation of the enyne moiety with diimide and cleavage of the SEM protecting groups completed the synthesis of asiminocin (27). Asiminecin (41) was prepared starting from aldehyde 12 and the OTBS allylic stannane 28. Addition of the latter to the former in the presence of InCl3 afforded the anti adduct 29 which was protected as the SEM ether 30. Hydrogenation followed by OTBS cleavage with TBAF and selective silylation of the primary alcohol with TBSCl and Et3N−DMAP led to the secondary alcohol 33. Tosylation and hydrogenolysis with LiEt3BH removed the C30 OTs group affording the SEM ether 35. The remaining steps were carried out along the lines described for asiminocin via the vinyl iodide 38 which was coupled with acetylenic butenolide 24 to afford enyne 39. Selective reduction with diimide and SEM cleavage completed the synthesis.