Total synthesis of the HDAC inhibitor (+)-(R)-trichostatin A via O-directed dialkylacetylene free radical hydrostannation with Ph3SnH/Et3B. The unusual inhibitory effect of a proximal α-OPv group on the course of a vinyl iodide Stille cross-coupling

Abstract

In this paper, a new asymmetric total synthesis of optically pure (+)-trichostatin A (1a) is described via a route that utilises a Marshall chiral allenylzinc addition between 9 and 4-dimethylaminobenzaldehyde (10) and an O-depivaloylation at its early stages. O-Directed free radical hydrostannation of the resulting propargylic alcohol 15 with Ph₃SnH/cat. Et₃B/O₂ in PhMe at rt thereafter provided the (Z)-α-triphenylstannylvinyltin 16 in 80–89% yield, with complete stereocontrol and very high α : β regioselectivity (25 : 1). A stereoretentive I–Sn exchange reaction between 16 and I₂ (1.4 equiv.) in CH₂Cl₂ (−78 °C to rt, 1 h) subsequently secured the vinyl iodide 18 in 84–96% yield. The latter was transformed into the enal 4 by successive TPAP/NMO (Ley–Griffith) oxidation and a high yielding (80%) Stille reaction between the α-iodo enal 20 and Me₄Sn, catalysed by Pd(PPh₃)₄ in DMF at 60 °C, under the Baldwin–Lee conditions, which use CsF and CuI as promoters. A Wittig reaction between 4 and Ph₃PCHCO₂Et (5), saponification, and DDQ oxidation next afforded (+)-trichostatic acid (22). Helquist's ethyl chloroformate mixed-anhydride/TBSONH₂ coupling procedure (ref. ) thereafter secured (+)-trichostatin A (1a) in good yield. This new total synthesis of 1a is the first-ever successful application of the O-directed dialkylacetylene free radical hydrostannation with Ph₃SnH/cat. Et₃B/O₂ in a dialkylaniline N-containing disubstituted alkynol system, and it now provides a convenient means of accessing many novel trichostatin analogues for future biological screening.