198482-00-7Relevant articles and documents
Design, synthesis, and biological evaluation of fluorinated analogues of salicylihalamide
Sugimoto, Yoshinori,Konoki, Keiichi,Murata, Michio,Matsushita, Masafumi,Kanazawa, Hiroshi,Oishi, Tohru
experimental part, p. 798 - 806 (2009/11/30)
Salicylihalamide A (SA), a benzolactone enamide compound, possesses potent cytotoxicity against human tumor cell lines. SA is a selective inhibitor of mammalian vacuolar type H+-ATPase (V-ATPase), and is distinct from previously known V-ATPase
Total synthesis of salicylihalamides A and B
Herb, Christian,Bayer, Alexander,Maier, Martin E.
, p. 5649 - 5660 (2007/10/03)
The paper illustrates two efficient routes to macrolactone 19 containing a 3-(para-methoxybenzyloxy)propyl side chain at C-15. The chiral center at C-15 was introduced by a Noyori reduction of keto ester 5. The intermediate common to both routes, aldehyde 8, was prepared from keto ester 5. The subsequent chain extension utilized Evans aldol reactions. The first route leads to the alkene 14, which was used, after hydroboration, for a Suzuki cross-coupling reaction with vinyl iodide 15. The derived seco acid 18 was converted into the macrolactone 19 by a Mitsunobu lactonization by using immobilized triphenylphosphine. Alternatively, an aldol reaction of 8 with the 4-pentenoyl derivative 20 was used to prepare alkene 26. This building block led to ester 28, which could also be converted into macrolactone 19 by the classical ring-closing metathesis. After conversion of the C-15 side chain to the corresponding aldehyde, the enamide was introduced through hemiaminal formation and formal elimination of water. Separation of the double-bond isomers and removal of the silyl protecting groups provided salicylihalamides A (E)-1 and B (Z)-1.
Total synthesis and initial structure - Function analysis of the potent V-ATPase inhibitors salicylihalamide A and related compounds
Wu, Yusheng,Liao, Xibin,Wang, Ruifang,Xie, Xiao-Song,De Brabander, Jef K.
, p. 3245 - 3253 (2007/10/03)
Salicylihalamide A is the first member of a growing class of macrocyclic salicylate natural products that induce a variety of interesting phenotypes in cultured mammalian cells. Salicylihalamide A was reported to be a unique and highly differential cytotoxin and a potent inhibitor of the mammalian vacuolar (H+)ATPase. The total synthesis of both enantiomers of salicylihalamide A, a revision of the absolute configuration assigned to the natural product, and extensive structure-function studies with synthetic salicylihalamide variants are reported. These studies were possible only due to a highly efficient synthetic strategy that features (1) a remarkably E-selective ring-closing olefin metathesis to construct the 12-membered benzolactone skeleton 29, (2) a mild stereocontrolled elaboration to E-alkenyl isocyanate 41, and (3) addition of carbon, oxygen, and sulfur nucleophiles to isocyanate 41 to obtain salicylihalamide A and congeners. We demonstrate for the first time that salicylihalamide A is a potent inhibitor of fully purified reconstituted V-ATPase from bovine brain, and have identified several similarly potent side chain modified derivatives, including salicylihalamide dimers 43-45. In combination, these studies have laid the foundation for ongoing studies aimed at a comprehensive understanding of salicylihalamide's mode-of-action, of potential relevance to the development of lead compounds for the treatment of osteoporosis and cancer.
Total synthesis of (-)-salicylihalamide A and related congeners
Smith III, Amos B,Zheng, Junying
, p. 6455 - 6471 (2007/10/03)
A concise, highly efficient total synthesis of (-)-salicylihalamide A (1), a novel marine sponge metabolite, has been achieved. Key features of the synthetic strategy include a highly E-selective ring-closing metathesis to construct the 12-membered salicylihalamide A macrocycle and a practical method for installation of the labile ene-hepta-(Z,Z)-dienamide side chain involving N-acylation of enecabarmate 5, the latter derived from the corresponding α,β-unsaturated carboxylic acid 28 via acyl azide formation and thermal Curtius rearrangement. Two structurally simplified analogs (3 and 4) were also prepared which displayed significant, but attenuated cell growth inhibitory activity against several human tumor cell lines.
Enantioselective total synthesis of salicylihalamides A and B
Labrecque, Denis,Charron, Sylvie,Rej, Rabindra,Blais, Charles,Lamothe, Serge
, p. 2645 - 2648 (2007/10/03)
We have devised a total synthesis of (12R,13S,15R) salicylihalamides A and B, which allowed revision of the absolute stereochemistry of the natural compounds. The same strategy was then applied to the preparation of naturally occurring salicylihalamides.
Total synthesis of (-)-salicylihalamide.
Fuerstner,Dierkes,Thiel,Blanda
, p. 5286 - 5298 (2007/10/03)
A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of beta-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl2]2. NEt3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The EIZ ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl2-mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.
Total synthesis of (-)-salicylihalamide A.
Snider,Song
, p. 1817 - 1820 (2007/10/03)
[see structure]. A 16-step synthesis of the novel cytotoxin salicylihalamide A (1E) has been achieved in 3.3% overall yield using ring closing metathesis to generate the macrolide and addition of (1Z,3Z)-hexadienylcuprate (2), which was generated in situ from ethylcuprate and acetylene, to alkenyl isocyanate 3 to form the side chain.
A first generation total synthesis of (+)-salicylihalamide A
Smith III,Zheng
, p. 1019 - 1023 (2007/10/03)
An efficient total synthesis of (+)-salicylihalamide (1) is described. The synthetic strategy features a highly E-selective ring-closing metathesis to construct the 12-membered salicylihalamide A macrocycle and a practical method for installation of the labile ene-hepta-(Z,Z)-dienamide side chain, which relies on a Curtius rearrangement to forge the C18-N bond with subsequent N-acylation.
Synthesis and initial structure--activity relationships of modified salicylihalamides.
Wu,Seguil,De Brabander
, p. 4241 - 4244 (2007/10/03)
[reaction:see text] The first stereoselective total synthesis of the potent antitumor compound (-)-salicylihalamide A is presented. The practicality of our approach provides for high material throughput and is highlighted by the rapid construction of a variety of modified congeners. Initial structure-activity relationships are derived from growth inhibition experiments with a human melanoma cancer cell line.
Revision of the absolute configuration of salicylihalamide A through asymmetric total synthesis
Wu, Yusheng,Esser, Lothar,De Brabander, Jef K.
, p. 4308 - 4310 (2007/10/03)
A highly E-selective ring-closing metathesis is the key to building the macrocyclic salicylate core of (+)-salicylihalamide A (1). The synthesis results in a reassignment of the absolute configuration of natural (-)-salicylihalamide A (2), a structurally
