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.
A new synthesis of cyclotheonamide B via guanidination of ornithine
Deng, Jingen,Hamada, Yasumasa,Shioiri, Takayuki
, p. 2261 - 2264 (2007/10/03)
A macrocyclic thrombin inhibitor, cyclotheonamide B (1, R = Ac) was synthesized via a new approach: guanidination of the ornithine-containing macrocyclic peptide (2). In comparison of various coupling reagents, pentafluorophenyl diphenylphosphinate (FDPP) gave the macrocyclic peptide (2) in good yield, and the configuration of the amino acid residue has been revealed to be important for the macrolactamization.
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
Total synthesis of cyclotheonamide B, a facile route towards analogues
Bastiaans, Harold M. M.,Van Der Baan, Juul L.,Ottenheijm, Harry C. J.
, p. 5963 - 5966 (2007/10/02)
A flexible, convergent synthesis of cyclotheonamide B (1b) was developed, starting from the constituent amino acids, using conventional benzyl-, t-butyl- and allyl-based protecting groups. By modification of the key intermediates, this approach allows the preparation of cyclotheonamide analogues.
