Toward Tubulysin: Gram-Scale Synthesis of Tubuvaline-Tubuphenylalanine Fragment

Chandrasekhar, Srivari; Mahipal, Bodugam; Kavitha, Mitta

doi:10.1021/jo9015503

Cited by 52 publications

(20 citation statements)

References 35 publications

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“…[4b, 7-12] 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. [13] We describe herein efficient total syntheses of tubulysins U (1 c), V (1 d), and D (1 b) by using the above methodologies.…”

Section: Introductionmentioning

confidence: 99%

Total Syntheses of Tubulysins

Shibue¹,

Hirai

Okamoto

et al. 2010

Chemistry A European J

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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.

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Section: Introductionmentioning

confidence: 99%

Total Syntheses of Tubulysins

Shibue¹,

Hirai

Okamoto

et al. 2010

Chemistry A European J

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“…Treatment of 14 with I 2 and imidazole and subsequently with t BuOK generated the olefinic compound 15. 12 The latter was treated with RuCl 3 and NaIO 4 and the resulting aldehyde with PhMgBr to produce alcohol 16 and its diastereoisomer in a 95:5 ratio. 13 The major product 16 was separated and then treated with LiAlH 4 to afford (+)-sedamine 3 with a melting point of 56-58°C (lit.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective total synthesis of the piperidine alkaloids, (+)-coniine, (+)-pseudoconhydrine, and (+)-sedamine through a common intermediate

Satyalakshmi

Suneel

Shinde

et al. 2011

Tetrahedron: Asymmetry

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“…5a (13) (1.00 mmol scale, 158 mg, 83%); 5b (14) (0.215 mmol scale, 28 mg, 70%); 5c (15) (0.200 mmol scale, 13 mg, 38%); 5d (16) (0.120 mmol scale, 3.8 mg, 25% (56% NMR)); 5e (17) (0.139 mmol scale, 12 mg, 49%); 5f (18) (0.116 mmol scale, 8.3 mg, 50% (64% NMR)); 5g (2a) (0.156 mmol scale, 30 mg, 74%); 6a (19) (0.255 mmol scale, 41 mg, 78%); 6c (20) (0.192 mmol scale, 23 mg, 62%); 6e (21) (0.238 mmol scale, 27 mg, 62%); 6f (21) (0.217 mmol scale, 20 mg, 58% (78% NMR)); 7a (19) (0.246 mmol scale, 44 mg, 87%); 7b (2b) (0.179 mmol scale, 25 mg, 69%); 7c (2b) (0.122 mmol scale, 13 mg, 54%); 7d (2b) (0.135 mmol scale, 7.5 mg, 39% (67% NMR)); 7e (2b) (0.168 mmol scale, 23 mg, 75%); 7f (2b) (0.141 mmol scale, 12 mg, 53% (70% NMR)); 7g (2b) (0.204 mmol scale, 46 mg, 81%).…”

Section: Experimental Sectionmentioning

confidence: 99%

Boron Carboxylate Catalysis of Homoallylboration

et al. 2014

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Boron tris(trifluoroacetate) is identified as the first effective catalyst for the homoallyl- and homocrotylboration of aldehydes by cyclopropylcarbinylboronates. NMR spectroscopic studies and theoretical calculations of key intermediates and transition states both suggest that a ligand-exchange mechanism, akin to our previously reported PhBCl2-promoted homoallylations, is operative. Our experimental and theoretical results also suggest that the catalytic activity of boron tris(trifluoroacetate) might originate from more facile catalytic turnover of the trifluoroacetate ligands (in agreement with DFT calculations) or from a lower propensity for formation of off-pathway reservoir intermediates (as observed by 1H NMR). This work shows that carboxylates are viable catalytic ligands for homoallyl- and homocrotylations of carbonyl compounds and opens the door to the development of catalytic asymmetric versions of this transformation.

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Toward Tubulysin: Gram-Scale Synthesis of Tubuvaline-Tubuphenylalanine Fragment

Abstract: A practical and stereoselective synthesis of the tubuvaline-tubuphenylalanine (Tuv-Tup) fragment of tubulysin is achieved involving the opening of aziridine, crucial MacMillan alpha-hydroxylation on both fragments, and an epoxide-opening reaction.

Cited by 52 publications

References 35 publications

Total Syntheses of Tubulysins

Total Syntheses of Tubulysins

Stereoselective total synthesis of the piperidine alkaloids, (+)-coniine, (+)-pseudoconhydrine, and (+)-sedamine through a common intermediate

Boron Carboxylate Catalysis of Homoallylboration

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