Total Synthesis of Tubulysins U and V

Abstract

Meeting the challenge: A reliable and modular reaction sequence has been developed for the synthesis of the challenging tubulysin framework. This route allows preparation of hundreds of milligrams of the stereochemically pure tetrapeptides (see picture), which are produced in small amounts by two different species of myxobacteria. Thus, full biological evaluation of the tubulysins and their analogues is now a real possibility.

Total Synthesis of Tubulysin U and V

“…This approach gave the correct diastereomer of the common intermediate 15 in four steps (Scheme 2 B). [2] In the meantime the syntheses by the groups of Ellman [3] and Zanda [4] also emanated, and comparison of the specific rotation values of 14 and epi-14 with those reported by Zanda and co-workers confirmed our findings. It appears that NMR spectroscopy is not ideal to determine the stereochemistry of Tup.…”

“…The previously reported diastereomers also have been updated with the corrected names, stereochemical descriptors, and formulas. Finally, in Table 1, column 1, G should read H. We thank Prof. G. Höfle and Dr. F. Sasse for the biological evaluation of the tubulysins, Prof. M. Zanda for providing reference spectra prior to publication of his manuscript [4] to additionally verify the correct diastereomers, and Dr. Simon Dörner and Gisela Schmidt (IPB) for experimental support. We apologize for any inconvenience caused by our misassignment.…”

Total Synthesis and Cytotoxicity Evaluation of an Oxazole Analogue of Tubulysin U

“…The next step was the synthesis of the other nonproteinogenic amino acid fragment. We have previously reported the scalable synthesis of Tup starting from L-phenylalaninol, 9 which was reasonably efficient but required a rather laborious separation of two epimers of Tup, involving the formation and chromatographic purification of the (-)-menthol esters followed by further manipulations of the protecting groups. We therefore decided to develop an improved synthesis of orthogonally protected and stereopure Tup (Scheme 4).…”

“…9 One-pot reaction involving Boc-carbamate, benzene sulfinic acid sodium salt, and isobutyraldehyde in MeOH-H 2 O afforded the bamino sulfone 12. Enolisation of 4b using NaH followed by the addition of the amino sulfone 12 to the oxazole enolate solution gave the b-amino ketone 13 (81%) as a racemic mixture.…”

Graphisches Inhaltsverzeichnis: Angew. Chem. 14/2007

“…Sechs Calix [4]arenmoleküle bilden mithilfe von Wasserstoffbrücken eine große, hexamere, ringförmige Struktur (siehe Bild; Br gelb, O rot, C grau, H weiß). Das Donut-Gebilde hat im festen Zustand eine bemerkenswerte strukturelle ¾hnlichkeit mit Cucurbit[6]uril und kann deshalb als ein nichtkovalentes Analogon gesehen werden.…”