Improved efficiency and selectivity in peptide synthesis: Use of triethylsilane as a carbocation scavenger in deprotection of t-butyl esters and t-butoxycarbonyl-protected sites

Mehta, Anita; Jaouhari, Rabih; Benson, T. J.; Douglas, Kenneth T.

doi:10.1016/s0040-4039(00)79116-7

Cited by 124 publications

(100 citation statements)

References 11 publications

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“…Palladium black catalyzed hydrogenolysis of 87a-b simultaneously removed the benzyl carbamate, the benzyl ester, and the benzyl ether, and reduced the ethynyl group to the requisite ethyl group to afford the linear precursors, which underwent macrolactamization to provide macrocycles 88a-b in moderate yield in two steps. Cleavage of the Boc carbamate and tert-butyl ester by TFA in the presence of triethylsilane 70 completed the total syntheses of ustiloxin D (4) 71 and ustiloxin F (5). 51 The longest linear sequence of this second generation approach was 15 steps.…”

Section: Total Synthesis Of Ustiloxins D and F And Three C-6 Analoguesmentioning

confidence: 99%

Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Evans

et al. 2008

J. Am. Chem. Soc.

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Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an S N Ar reaction. An nOe study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R, 10S)-epi-ustiloxin analogues) were prepared via the second generation route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization. Antimitotic agentsAntimitotic agents have long been of interest to scientists and physicians, even before their precise mechanism of action could be articulated. Most of these compounds interfere with microtubule assembly and functions thus resulting in mitotic arrest of eukaryotic cells. There are a number of natural and synthetic compounds that interfere with tubulin function to inhibit the formation of microtubules. 1 Such antimitotic agents exhibit a broad range of biological activities and can be used for medicinal and agrochemical purposes, acting as anticancer, antifungal, or anthelmintic agents. Moreover, tubulin binding compounds are valuable for understanding basic mechanisms involved in the dynamics of the microtubule network. 2 Mitotic arrest is of importance in cancer chemotherapy, since tubulin is an established chemotherapeutic target. In addition to the widely used vinca alkaloids and taxoids, many other antimitotic agents are currently in clinical or preclinical development. 3 Newer potential targets NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that may cause mitotic arrest are in development as well. Although cancer chemotherapy is a very important goal being extensively investigated, the mechanism of action of the naturally occurring peptides that inhibit tubulin polymerization remains a challenging problem. Attempts to establish a relationship among the tubulin binding peptides have only had limited success. [4][5][6][7][8] As a result, the mechanism of action of peptidic antimitotic agents is not completely elucidated and deserves further investigation. UstiloxinsThe first peptide shown to interact with tubulin was phomopsin A (Error! Reference source not found.). [9][10][11][12][13] Since then, a number of peptides and depsipeptides were found to disrupt cellular microtubules. These compo...

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Section: Total Synthesis Of Ustiloxins D and F And Three C-6 Analoguesmentioning

confidence: 99%

Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Evans

et al. 2008

J. Am. Chem. Soc.

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“…The synthesis of l-prolinethioamide 5a involved the coupling of N-Boc-l-proline [10] (2) with aniline [7b] followed by the reaction with the Lawessons reagent [11] (Scheme 1). After removal of the Boc group [12] the desired catalyst 5a was obtained in a good yield, but unfortunately it was not optically pure (ee 26%). We found that the racemisation took place during the formation of 4a.…”

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confidence: 99%

L‐Prolinethioamides – Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

Gryko

Lipiński

2005

Adv Synth Catal

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Received Aldol reaction / Asymmetric organocatalysis / Water / Solvent-free reactions / Prolinethioamides ABSTRACT Organocatalysts 1, derived from L-Pro and (1S,2R)-cis-1-aminoindan-2-ol or (R)-1-aminoindane, are evaluated as promoters in the direct asymmetric aldol reaction between ketones and aromatic aldehydes in the presence of water and under solvent-free reaction conditions. L-Prolinethioamides 1c and 1d exhibited higher enantioselectivity than the corresponding prolinamides 1a and 1b in the model aldol reaction between cyclohexanone with 4-nitrobenzaldehyde in the presence of 4-nitrobenzoic acid as cocatalyst. In particular, L-prolinethioamide 1d (5 mol%), derived from L-Pro and (R)-1-aminoindane, is shown as the most efficient organocatalyst studied promoting the direct aldol reaction of cycloalkyl, alkyl, and α-functionalized ketones with aromatic aldehydes in the presence of water and under solvent-free reaction conditions employing only 2 equiv. of nucleophile. Generally, anti-aldol products are obtained in high yields and excellent diastereo-and enantioselectivities (up to >98/2 anti/syn, up to 98% ee). Solvent-free conditions give slightly higher dr and ee than using water as solvent. In addition, organocatalyst 1d can be easily recovered by extractive work-up and reused. Prolinethioamide 1d (5 mol%) in combination with 4-NO 2 C 6 H 4 CO 2 H (5 mol%) is also a very effective organocatalytic system for the asymmetric solvent-free intramolecular Hajos-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to other reported catalysts in organic solvents.

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“…Thus, the diazoketones Fmoc-Glu(OtBu)-CHN 2 (5) [18] and Fmoc-Lys-(Boc)-CHN 2 (6) [18] were subjected to the conditions of the Wolff rearrangement with allyl alcohol and N-methylmorpholine (NMM) [20] to give the corresponding allyl esters 7 and 8 in good yields of 67 and 77 %, respectively (Scheme 2). Cleavage of the Boc and the tBu protecting groups of both derivatives was accomplished with TFA and TIPS in CH 2 Cl 2 [21] and the special protected amino acid derivatives Fmoc-b 3 -hGlu-OAll (9) and Fmoc-b 3 hLys-OAll (10) were obtained in 91 % and almost quantitative yield, respectively.…”

Section: Resultsmentioning

confidence: 99%

Cyclic β‐Tetra‐ and Pentapeptides: Synthesis through On‐Resin Cyclization and Conformational Studies by X‐Ray, NMR and CD Spectroscopy and Theoretical Calculations

Büttner¹,

Norgren²,

Zhang³

et al. 2005

Chemistry A European J

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The solution-phase synthesis of the simplest cyclic beta-tetrapeptide, cyclo(beta-Ala)4 (4), as well as the solid-phase syntheses through side chain anchoring and on-resin cyclization of the cyclic beta3-tetrapeptide cyclo(-beta3hPhe-beta3hLeu-beta3hLys-beta3hGln-) (14) and the first cyclic beta3-pentapeptide cyclo(-beta3hVal-beta3hPhe-beta3hLeu-beta3hLys-beta3hLys-) (19) are reported. Extensive computational as well as spectroscopic studies, including X-ray and NMR spectroscopy, were undertaken to determine the preferred conformations of these unnatural oligomers in solution and in the solid state. cyclo(beta-Ala)4 (4) with no chiral side chains is shown to exist as a mixture of rapidly interchanging conformers in solution, whereas inclusion of chiral side chains in the cyclo-beta3-tetrapeptide causes stabilization of one dominating conformer. The cyclic beta3-pentapeptide on the other hand shows larger conformational freedom. The X-ray structure of achiral cyclo(beta-Ala)4 (4) displays a Ci-symmetrical 16-membered ring with adjacent C=O and N-H atoms pointing pair wise up and down with respect to the ring plane. CD spectroscopic examinations of all cyclic beta-peptides were undertaken and revealed results valuable as starting point for further structural investigations of these entities.

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Improved efficiency and selectivity in peptide synthesis: Use of triethylsilane as a carbocation scavenger in deprotection of t-butyl esters and t-butoxycarbonyl-protected sites

Cited by 124 publications

References 11 publications

Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

L‐Prolinethioamides – Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

Cyclic β‐Tetra‐ and Pentapeptides: Synthesis through On‐Resin Cyclization and Conformational Studies by X‐Ray, NMR and CD Spectroscopy and Theoretical Calculations

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