Stereoselective Total Synthesis of Tubulysin V

Abstract

The total synthesis of tubulysin V was accomplished in 1.0% overall yield with linear 13 steps. Our synthetic strategy featured the following two reactions. One is zinc-mediated aza-Barbier reaction of (R)-N-tert-butanesulfinyl imine 8 with β-ester group functionalized allylic bromide 9 to afford the chiral homo-allylic amine (7); the other is to employ the methodology of aqueous indium-mediated aza-Barbier reaction previously developed by our group, giving the chiral homo-allylic amine 13 with high efficiency.

Muscarine, imidazole, oxazole and thiazole alkaloids

“…Given the limited availability from natural sources and attractive anti-mitotic activity, much attention has been paid to the synthesis of tubulysins and their analogues. The stereoselective total synthesis of tubulysin U 429 and its C4 epimer, 319 as well as tubulysin V 430, 320 has been achieved based on different methodologies. Diverse derivation strategies, such as N-terminal modication, 321 replacement of thiazole by a triaole 322 or phenyl group, 323 cyclization of the middle Tuv residue, 324 and application of the cyclic photolabile protecting group, 325 have been elaborated for improved biological stability and easier preparation.…”

Synthetic Approaches Towards Tubulysins and Derivatives Thereof

“…In 2004, also in patents, Dömling et al described a straightforward synthesis of an N-protected tubuvalineprecursor based on a modified Passerini protocol (Scheme 2) [27,28]. This approach was used in the synthesis of tubuvaline U and V as well [29,30]. In this case Schöllkopf isocyanide (9), accessible in one step from glycine isocyanide [31], reacting with Boc-protected homovaline aldehyde (7) and thioacetic acid (8) as an acid component.…”

Diastereocontrol in Radical Addition to β-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O-Benzyltubulysin V Benzyl Ester

“… 40 Most Tuv syntheses begin with precursors having the C13 chiral amine already established from various valine derivatives and their homologues. Asymmetric induction at C13 has been accomplished by kinetic resolution of racemic aza-Michael or Mannich adducts, 33 , 41 hydride reduction, 30 and additions of various C -nucleophiles (enolate, 42 organomagnesium, 43 and allylindium reagents 44 ) to imines. A nitrone cycloaddition approach established both C11 and C13 stereogenic centers.…”