Total Synthesis of Tubulysin U and V

Abstract

Tubulysins (1) are compounds of extraordinary potency, rapidly degrading the tubulin cytoskeleton, with tubulysin D being the most active tubulin-modifier known so far.[1, 2] The tubulysins were first described by Höfle, Reichenbach, and co-workers in 2000. [3,4] Several representatives are active with GI 50 values (growth inhibition of 50 %) in the low picomolar range against the NCI-60 cancer cell-line panel, and some are highly antiangiogenic.[5] Semisynthetic tubulysins, derived from isolated material, show promising in vivo anticancer properties and are candidates for antibody conjugates. Thus, tubulysins are attractive leads as novel anticancer agents. [5] However, so far, tubulysins can only be produced by a fermentation process that yields less than 10 mg L À1 by several rather tedious chromatographic purification steps. Thus, and

Total Synthesis and Biological Evaluation of Tubulysin U, Tubulysin V, and Their Analogues

“…We were gratified to find that treatment of tripeptide 15 with the ( S )-CBS or ( R )-CBS reagent in the presence of BH 3 •DMS almost exclusively afforded the reduced tripeptides 16 and 17 , respectively (Schemes 3 and 4). The stereochemical outcome of these reactions was supported by the following: 1) the 1 H NMR spectrum of 4 matched that of tubulysin V as previously reported, 5a and 2) the findings of Zanda and co-workers who reported that the ( S )-CBS reagent with BH 3 •DMS reacted nearly exclusively from the si face of the ketone of a racemic Tuv intermediate to give the alcohol products possessing the natural configuration as established by X-ray crystallography. 5a The 1 H NMR spectrum of the immediate tetrapeptide benzyl ester precursor of tubulysin V was identical to the minor diastereomer 14 , enabling us to assign the stereochemistry of the purified diastereomers 14 .…”

“…Interestingly, purification of tubulysin V by reverse-phase HPLC under the conditions reported by Dömling and co-workers 5b using MeOH as the mobile phase resulted in isolation of the methyl ester to a significant extent (38%). Using acetonitrile as the mobile phase smoothly afforded the natural product in an analytically pure form.…”

“…The total synthesis of tubulysins D, 4 U and V, 5 and numerous analogs 6 has allowed for determination of structure–activity relationship (SAR) studies for these natural products. In a report by Wipf and co-workers, it was established that the Mep residue at the N-terminus of the tubulysins could be replaced with the acyclic amino acid N -methylsarcosine.…”

Synthesis of a Cyclic Analogue of Tuv N-Methyl Tubulysin

“…D-Mep (8) and L-Ile-OMe (10) were synthesized in parallel. Reductive amination using formaldehyde and commercially available pipecolic acid (7) proceeded smoothly to give D-Mep (8) in a quantitative yield, and the esterification of L-Ile (9) in methanol afforded L-Ile-OMe (10) in a good yield (75%) as well. D-Mep (8) and L-Ile-OMe (10) were then coupled together.…”

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

“…The Ugi-4CR is not specifically prone to asymmetric induction, but at least some auxiliaries are known to result in preferential formation of a diastereoisomer [33–34]. Therefore, the isonitrile 4b was synthesized from menthyl anthranilate.…”