- Synthesis and structure-activity studies of the V-ATPase inhibitor saliphenylhalamide (SaliPhe) and simplified analogs
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An efficient total synthesis of the potent V-ATPase inhibitor saliphenylhalamide (SaliPhe), a synthetic variant of the natural product salicylihalamide A (SaliA), has been accomplished aimed at facilitating the development of SaliPhe as an anticancer and antiviral agent. This new approach enabled facile access to derivatives for structure-activity relationship studies, leading to simplified analogs that maintain SaliPhe's biological properties. These studies will provide a solid foundation for the continued evaluation of SaliPhe and analogs as potential anticancer and antiviral agents.
- Garcia-Rodriguez, Jose,Mendiratta, Saurabh,White, Michael A.,Xie, Xiao-Song,De Brabander, Jef K.
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p. 4393 - 4398
(2015/10/12)
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- The scent of bacteria: Headspace analysis for the discovery of natural products
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Volatile compounds released by 50 bacterial strains, 45 of them actinobacteria in addition to three chloroflexi and two myxobacteria, have been collected by use of a closed-loop stripping apparatus, and the obtained headspace extracts have been analyzed by GC-MS. Excluding terpenes that have recently been published elsewhere, 254 compounds from all kinds of compound classes have been identified. For unambiguous compound identification several reference compounds have been synthesized. Among the detected volatiles 12 new natural products have been found, in addition to mellein, which was released by Saccharopolyspora erythraea. The iterative PKS for this compound has recently been identified by in vitro experiments, but mellein production in S. erythraea has never been reported before. These examples demonstrate that headspace analysis is an important tool for the discovery of natural products that may be overlooked using conventional techniques. The method is also useful for feeding experiments with isotopically labeled precursors and was applied to investigate the biosynthesis of the unusual nitrogen compound 1-nitro-2-methylpropane, which arises from valine. Furthermore, several streptomycetes emitted compounds that were previously recognized as insect pheromones, thus questioning if bacterial symbionts are involved in insect communication.
- Citron, Christian A.,Rabe, Patrick,Dickschat, Jeroen S.
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p. 1765 - 1776
(2013/01/15)
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- Formal Total Synthesis of (+)-Salicylihalamides A and B: A Combined Chiral Pool and RCM Strategy
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The formal total synthesis of the (+)-salicylihalamides A and B is detailed, utilizing a chiral pool approach to generate the three stereogenic centers and a ring-closing metathesis (RCM) for the formation of the macrocyclic ring structure. Starting from a known glucose-derived alcohol, the formal total synthesis was achieved in an efficient 13-step protocol in 26% overall yield. It was found that substitution at the remote phenolic group significantly influenced the ratio of the E-and Z-double bond products in the RCM step. The introduction of phenol protecting groups provided E-isomers preferentially and also enhanced the rates of the RCM reactions.
- Yang, KyoungLang,Blackman, Burchelle,Diederich, Wibke,Flaherty, Patrick T.,Mossman, Craig J.,Roy, Subho,Ahn, Yu Mi,Georg, Gunda I.
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p. 10030 - 10039
(2007/10/03)
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- Short and efficient chiral pool and RCM approach towards the synthesis of the macrocyclic core of the salicylihalamides
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The macrolactone core structure of the salicylihalamides was prepared from diacetone-D-Glucose and via a ring-closing metathesis reaction.
- Georg,Yu Mi Ahn,Blackman,Farokhi,Flaherty,Mossman,Roy,Yang
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p. 255 - 256
(2007/10/03)
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- Total synthesis of (-)-salicylihalamide.
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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.
- Fuerstner,Dierkes,Thiel,Blanda
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p. 5286 - 5298
(2007/10/03)
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- Total synthesis of (-)-salicylihalamide A.
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[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.
- Snider,Song
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p. 1817 - 1820
(2007/10/03)
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- Asymmetric synthesis of the fully functional macrolide core of salicylihalamide: remote control of olefin geometry during RCM.
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A catalysis-based approach to the core region 24 of the antitumor agents salicylihalamides A and B is reported. Key steps are two asymmetric hydrogenations of beta-keto esters 13 and 16 catalyzed by [(R)-BINAP.RuCl(2)](2).NEt(3) and an RCM-based macrocyclization effected by the NHC-containing ruthenium carbene 21. The stereochemical outcome of the latter reaction is controlled by remote substituents on the phenolic OH group of the cyclization precursor 23.
- Fuerstner,Thiel,Blanda
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p. 3731 - 3734
(2007/10/03)
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