Total Synthesis of Tubulysin U and V

Structure–activity and High‐content Imaging Analyses of Novel Tubulysins

“…In parallel to the biological studies, recent synthetic activity toward the tubulysins has been remarkable. After two segment preparations were reported by Friestad and Wipf in 2004 (18,19), Dömling and co‐workers synthesized stereoisomers of tubulysins U and V in 2006 (20,21), and Ellman and co‐workers published the first total synthesis of tubulysin D (22). Concomitantly with Zanda and co‐workers’ report of a scalable synthesis of tubulysins U and V (23), we published the synthesis of N 14 ‐desacetoxytubulysin H (WZY‐III‐63C) in 20 steps and 2.1% overall yield from commercially available building blocks (24,25).…”

Synthesis and Biological Evaluation of Pretubulysin and Derivatives

“…1:1) as a yellow oil. Methyl (2S,4R)-4-Amino-2-methyl-5-phenylpentanoate, Hydrochloride (15): [21] As described in the literature, [8a] the menthyl ester 14 (334 mg, 0.750 mmol) was deprotected and converted into the methyl ester 15 (138 mg, 0.535 mmol, 71 %).…”

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.…”

“…Also in patents, researchers at Morphochem described a related approach based on an auxiliary-controlled C-Ccoupling (Scheme 14) [27,28]. In the same year, Dömling and Wessjohann et al described a synthesis via an asymmetric aziridine ring opening using pseudoephedrine derived propionamide 85 (Scheme 18) [29]. Unfortunately, this approach generated the undesired configuration of the methyl group at the -position (87) [50].…”

“…Shortly thereafter the authors presented another approach, based on Enders' SAMP auxiliary [51]. With derivative, which were both incorporated into tubulysin derivatives [52].…”