Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly

Abstract

A concise and modular total synthesis of the highly potent N 14 -desacetoxytubulysin H ( 1 ) has been accomplished in 18 steps in an overall yield of up to 30%. Our work highlights the complexity–augmenting and route-shortening power of diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple and step economy but will also stimulate major advances in the development of new tubulysin analogues.

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

“…The low diastereoselectivity observed in the Ugi‐4CR step was similarly experienced in many previous total syntheses which utilised isocyanide‐based multicomponent reactions (IMCRs), [32–36] where notable exceptions were when cyclic imines were used [37, 38] . Consequently, several groups have reported the use of chiral phosphoric acids (CPAs) to induce enantioselectivity for IMCRs [39–42] .…”

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

“…X-ray crystallography analysis of 15 a was used to determine its absolute stereochemistry, which corresponded to the stereochemistry of hemiasterlin (Scheme 3 b). [50] The low diastereoselectivity observed in the Ugi-4CR step was similarly experienced in many previous total syntheses which utilised isocyanide-based multicomponent reactions (IMCRs), [32][33][34][35][36] where notable exceptions were when cyclic imines were used. [37,38] Consequently, several groups have reported the use of chiral phosphoric acids (CPAs) to induce enantioselectivity for IMCRs.…”

The 100 facets of the Passerini reaction

“…Very recently Dömling optimized a diastereoselective Passerini reaction on a well-defined combination of 3 chiral reagents, which was aimed at the total synthesis of N 14 -desacetoxytubulysin H ( Scheme 50 ) reported in detail in chapter 5. 107 …”

“…Recently, Dömling reported the highly convergent total synthesis of N 14 -desacetoxytubulysin H 263 employing a diastereoselective Passerini reaction applied in the PADAM protocol ( Scheme 63 ). 107 The three components needed in the MCR could be prepared on a multi-gram scale from commercially available amino acids. The isocyanide 257 was prepared in three steps from l -cysteine methyl ester by trityl protection and the classical formamide/dehydration protocol; the aldehyde 258 derived from Fmoc l -valine by the Arndt–Eistert homologation reaction and oxidation/reduction steps and the acid 259 was obtained by coupling Cbz d -pipecolic acid and l -isoleucine methyl ester and final hydrolysis of the ester.…”