Total Synthesis of Cyclotheonamide B, a Facile Route towards Analogues

Bastiaans, H. M. M.

doi:10.1016/00404-0399(50)11539-

Cited by 16 publications

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“…All analogues have been tested and found to have excellent inhibitory properties. The total chemical synthesis of these compounds has been achieved, and significant structural data obtained from nuclear magnetic resonance (NMR) studies [164,165], which has enabled SAR studies to be carried out, particularly against thrombin. Studies screening natural products from blue-green algae have also led to the discovery of a number of interesting serine protease inhibitors.…”

Section: Natural Product Inhibitors Of Serine Proteasesmentioning

confidence: 99%

Strategies for the inhibition of serine proteases

Walker¹,

Lynas²

2001

CMLS, Cell. Mol. Life Sci.

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Serine proteases have been shown to play a multifarious role in health and disease. As a result, there has been considerable interest in the design and development of synthetic inhibitors of these enzymes. In view of their diverse roles in biological processing events, one of the great challenges in such endeavours has been the need to produce compounds with exquisite selectivity. Inhibitor design has been broadly guided by the use of either peptide- or heterocyclic-based compounds, designed to exploit the known substrate specificity characteristics of individual enzymes. This review describes the thinking and strategies employed in such efforts.

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Section: Natural Product Inhibitors Of Serine Proteasesmentioning

confidence: 99%

Strategies for the inhibition of serine proteases

Walker¹,

Lynas²

2001

CMLS, Cell. Mol. Life Sci.

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“…Other unsaturated amino acid couplings, such as those involving β,γ-unsaturated or vinylogous amino acids, will not be covered since methods for their incorporation do not deviate significantly from standard protocols. The reader is referred to work of Schreiber et al and to recent syntheses of the cyclotheonamides for examples of vinylogous amino acid incorporation. − This review covers material published through 1996.…”

Section: Introductionmentioning

confidence: 99%

Chemical Synthesis of Natural Product Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides

1997

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“…The cyclotheonamides A and B ( 1a , b , Figure ) are cyclic pentapeptides from the marine sponge Theonella swinhoei , isolated and characterized as late as 1990. One might wonder why these metabolites have attracted so much attention: as much as 16 papers on isolation and characterization, synthetic aspects, enzyme inhibition, X-ray data, and conformational analysis have appeared in the literature since 1990. − The answer to this question lies in the unique structure as well as in the biological activity of these two closely related natural products. They are true peptide-mimics consisting of five amino acids, viz.…”

Section: Introductionmentioning

confidence: 99%

Flexible and Convergent Total Synthesis of Cyclotheonamide B

Bastiaans¹,

Baan²,

Ottenheijm³

1997

J. Org. Chem.

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A convergent approach using two key intermediates, segment A [a l-proline-l-α-hydroxy-β-homoarginine-d-phenylalanine (Pro-hArg-d-Phe) tripeptide] and segment B [a vinylogous l-tyrosine-l-2,3-diaminopropanoic acid (vTyr-Dpr) dipeptide], was developed for the synthesis of cyclotheonamide B (Scheme ). The starting compound for the preparation of the hArg moiety 7, the predominant part of segment A, was N α-(benzyloxycarbonyl)-N ω,N ω‘-bis(tert-butyloxycarbonyl)-l-arginine methyl ester (15, Scheme 2), which was converted into the aldehyde 16 and subsequently homologated using [tris(methylthio)methyl]lithium as a carboxylic acid anion equivalent. Coupling with properly protected Pro and d-Phe derivatives gave smoothly the desired Pro-hArg-d-Phe tripeptide derivative 24. The key feature of segment B, i.e., the l-tyrosine-derived α,β-unsaturated γ-amino acid 4, was prepared by a Wadsworth−Emmons olefination of the aldehyde 29 (Scheme 3) derived from N-(tert-butyloxycarbonyl), O-tert-butyl-l-tyrosine methyl ester (28). Selective N-(tert-butyloxycarbonyl) removal in the presence of the aryl tert-butyl ether present in the fully protected segment B, i.e., 32, was achieved by treatment with trimethylsilyl triflate/2,6-lutidine to give vTyr-Dpr dipeptide derivative 34 in quantitative yield. Coupling of the key intermediates 24 and 34 using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) afforded the protected linear pentapeptide 35 in high yield (Scheme 4). Treatment of 35 with Pd(PPh3)4/morpholine resulted in simultaneous removal of the C-terminal allyl group and the N-terminal allyloxycarbonyl group to yield 36. Ring closure was effected under dilution conditions by treatment with TBTU/1-hydroxybenzotriazole/4-(dimethylamino)pyridine and gave the protected cyclopentapeptide 37 in 61% yield. Oxidation of the hydroxyl group with Dess−Martin periodinane (24 h, 40 °C) in the presence of tert-butyl alcohol gave 38, which was then subjected to O,N-deprotection with trifluoroacetic acid/thioanisole. Subsequent HPLC purification afforded cyclotheonamide B in an overall yield of 1.8% in 17 steps.

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Total Synthesis of Cyclotheonamide B, a Facile Route towards Analogues

Cited by 16 publications

References 0 publications

Strategies for the inhibition of serine proteases

Strategies for the inhibition of serine proteases

Chemical Synthesis of Natural Product Peptides: Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides

Flexible and Convergent Total Synthesis of Cyclotheonamide B

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