129033-05-2Relevant articles and documents
Flexible and convergent total synthesis of cyclotheonamide B
Bastiaans, Harold M.M.,Van der Baan, Juul L.,Ottenheijm, Harry C.J.
, p. 3880 - 3889 (2007/10/03)
A convergent approach using two key intermediates, segment A [a L-proline-L-α-hydroxy-β-homoarginine-D-phenylalamine (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. 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-ar ginine methyl ester (15), 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 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. 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.
Macrocyclic peptide inhibitors of serine proteases. Convergent total synthesis of cyclotheonamides A and B via a late-stage primary amine intermediate. Study of thrombin inhibition under diverse conditions
Maryanoff, Bruce E.,Greco, Michael N.,Zhang, Han-Cheng,Andrade-Gordon, Patricia,Kauffman, Jack A.,Nicolaou,Liu, Aijun,Brungs, Peter H.
, p. 1225 - 1239 (2007/10/02)
Cyclotheonamide A (CtA, 1), a cyclic pentapeptide isolated from the marine sponge Theonella sp., is an inhibitor of serine proteases such as α-thrombin and trypsin. We describe, in detail, our total synthesis of CtA by a convergent [3 + 2] fragment-conden
Synthese von Cyclotheonamid B und Derivaten
Deng, Jingen,Hamada, Yasumasa,Shioiri, Takayuki,Matsunaga, Shigeki,Fusetani, Nobuhiro
, p. 1811 - 1813 (2007/10/02)
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