Total Synthesis of Tubulysins U and V

Sani, Monica; Fossati, Giacomo; Huguenot, Florent; Zanda, Matteo

doi:10.1002/ange.200604557

Cited by 27 publications

(7 citation statements)

References 21 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[4b, [7][8][9][10][11][12] However, only a few synthetic methods adaptable to analogue synthesis have been explored, probably due to the lack of stereoselectivity or efficiency for the syntheses of Tuv and Tup. [11] We have recently developed an efficient method for the synthesis of Tuv featuring the stereoselective 1,3-dipolar cycloaddition of a nitrone derived from d-gulose with N-acryloyl camphor sultam as well as a synthetic method for Tup by employing a stereoselective aldol reaction followed by Barton deoxygenation.…”

Section: Introductionmentioning

confidence: 99%

Total Syntheses of Tubulysins

Shibue¹,

Hirai

Okamoto

et al. 2010

Chemistry A European J

View full text Add to dashboard Cite

The total syntheses of tetrapeptides tubulysins D (1 b), U (1 c), and V (1 d), which are potent tubulin polymerization inhibitors, are described. The synthesis of Tuv (2), an unusual amino acid constituent of tubulysins, includes an 1,3-dipolar cycloaddition reaction of chiral nitrone D-6 derived from D-gulose with N-acryloyl camphor sultam (-)-9 employing the double asymmetric induction, whereas the synthesis of Tup (20), another unusual amino acid, involves a stereoselective Evans aldol reaction of (Z)-boron enolate generated from (S)-4-isopropyl-3-propionyl-2-oxazolidinone with N-protected phenylalaninal and a subsequent Barton deoxygenation protocol. We accomplished the total syntheses of tubulysins U (1 c) and V (1 d) by using these methodologies, in which the isoxazolidine ring was used as the effective protective group for γ-amido alcohol functionality. Furthermore, to understand the structure-activity relationship of tubulysins, we synthesized tubulysin D (1 b) and cyclo-tubulysin D (1 e) from 2-Me and 20, and ent-tubulysin D (ent-1 d) from ent-2-Me and ent-20, respectively. The preliminary results regarding their biological activities are also reported.

show abstract

Section: Introductionmentioning

confidence: 99%

Total Syntheses of Tubulysins

Shibue¹,

Hirai

Okamoto

et al. 2010

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…11,12 The replacement of this group with N-alkyl substituents (methyl, benzyl, cyclopropylmethyl) resulted in analogues that remained anticancer activity in nanomolar range [13][14][15][16] and are at least double more active than those replaced with a hydrogen atom. 16,17 In addition, the chemical modifications at the Mep and Tup positions were well tolerated. Recently, syntheses of simplified tubulysin analogues have focused mainly on the chemical modification of the N-and C-terminal amino acids and the N,O-acetal moiety.…”

Section: Letter Synlettmentioning

confidence: 99%

“…Our synthetic strategy of the -amino acid Tup (Scheme1) was carried out as described by the previous work of Kazmaier 18,19 and Zanda 17,20 or Wipf 21 with modified protocols. According to these synthetic routes, methyl ester 1 was either reduced to aldehyde with diisobutylaluminium hydride (DIBAL-H) at -78 °C18 or converted into alcohol, which utilized a large amount of NaBH4 (10 equiv) at 60 °C, and subsequent oxidation with Dess-Martin periodinane or TEMPO/NaOCl oxidation.…”

Section: Letter Synlettmentioning

confidence: 99%

Design, Synthesis, and Cytotoxic Activity of New Tubulysin Analogues

Tran

Trần

et al. 2021

Synlett

View full text Add to dashboard Cite

Synthesis of tubulysin analogues, containing an N-methyl substituent on tubuvaline-amide together with the replacement of either the hydrophobic N-terminal N-methyl pipecolic acid (Mep) or at both N- and C- terminal peptides with available heteroaromatic acids and an unsaturated tubuphenylalanine moiety, respectively, were described. The in vitro cytotoxic activity by SRB assay on five cancer cell lines for sixteen tubulysins was evaluated. Among them, five analogues exhibited strong cytotoxic activities against five human cancer cell lines, including human breast carcinoma (MCF7), human colorectal adenocarcinoma (HT-29), HL-60, SW-480, human lung adenocarcinoma (A459). Interestingly, one analogue showed the strongest cytotoxicity on all five tested cell lines even much higher toxicity than the reference compound ellipticine.

show abstract

“…Thus they are exciting targets for total synthesis in several laboratories around the world. 14 Our laboratory 15 and the Zanda group 16 disclosed the first total synthesis of tubulysin U and V, Ellman described the first total synthesis of Tubulysin D 17a and later N-methyl tubulysins. 17b,c Later onwards several modifications on tubulysins and their total synthesis have been well documented.…”

Section: Figure 1 Retrosynthesis Of Tubulysinsmentioning

confidence: 99%

Concise Total Synthesis of N¹⁴-Desacetoxytubulysin H

Vishwanatha¹,

Giepmans²,

Dömling³

2020

Preprint

View full text Add to dashboard Cite

Access to analogues within the highly cytotoxic natural product family of tubulysins has previously required lengthy routes involving multiple functional group manipulations that is costly and time intensive on scale. A concise and modular total synthesis of the highly potent N¹⁴-desacetoxytubulysin H has been accomplished in a short sequence from commercially available building blocks. Our work highlights the complexity augmenting and route shortening power of multicomponent reaction (MCR) as well as the role of catalysts in controlling diastereoselectivity. Our operationally simple and s tep economical total synthesis can be easily performed on gram scale without compromising the yield.

show abstract

Total Synthesis of Tubulysins U and V

Cited by 27 publications

References 21 publications

Total Syntheses of Tubulysins

Total Syntheses of Tubulysins

Design, Synthesis, and Cytotoxic Activity of New Tubulysin Analogues

Concise Total Synthesis of N¹⁴-Desacetoxytubulysin H

Contact Info

Product

Resources

About