- Toward Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis
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The iterative homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by Hoppe-Beak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (-)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative homologations were conducted on commercially available p-MeOC6H4CH2Bpin to build up the core of the molecule before the C-B bond was converted into the desired C-N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative homologations were conducted on p-MeOC6H4Bpin with only four intermediate purifications before oxidation of the C-B bond to the desired alcohol. The stereocontrolled and efficient syntheses of these complex molecules highlight the power of iterative chemical synthesis using boronic esters. (Chemical Equation Presented).
- Balieu, Sebastien,Hallett, Gayle E.,Burns, Matthew,Bootwicha, Teerawut,Studley, John,Aggarwal, Varinder K.
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p. 4398 - 4403
(2015/04/14)
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- Synthesis and biological activity of kalkitoxin and its analogues
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Total syntheses of kalkitoxin, isolated from the Caribbean Lyngbya majuscula, and its analogues, 3-epi-, 7-epi-, 8-epi-, 10-epi-, 10-nor-, and 16-nor-kalkitoxin, were achieved via oxazolidinone-based diastereoselective 1,4-addition reaction of a methyl group and efficient TiCl4-mediated thiazoline ring formation as the key steps. The biological activities of synthetic kalkitoxin and its analogues were evaluated with brine shrimp.
- Umezawa, Taiki,Sueda, Manabu,Kamura, Takao,Kawahara, Teppei,Han, Xuerong,Okino, Tatsufumi,Matsuda, Fuyuhiko
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p. 357 - 370
(2012/02/15)
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- An expeditious total synthesis of kalkitoxins: Determination of the absolute stereostructure of natural kalkitoxin
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Kalkitoxin, a potent neurotoxin isolated from the marine cyanobacteria Lyngbya majuscula, and its congeners (1-7) were efficiently synthesized utilizing Hruby's diastereoselective 1,4-addition and the Wipf's oxazoline-thiazoline conversion as key steps. T
- Yokokawa, Fumiaki,Asano, Toshinobu,Okino, Tatsufumi,Gerwick, William H.,Shioiri, Takayuki
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p. 6859 - 6880
(2007/10/03)
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- Total synthesis and biological evaluation of (+)-kalkitoxin, a cytotoxic metabolite of the cyanobacterium Lyngbya majuscula
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(+)-Kalkitoxin, a metabolite of the marine cyanobacterium Lyngbya majuscula, was synthesized from (R)-2-methylbutyric acid, (R)-cysteine, and (3S, 4S, 6S)-3,4,6-trimethyl-8-(methylamino)octanoic acid. A key step in the synthesis was installation of the anti,anti methyl stereotriad by means of a tandem asymmetric conjugate addition of an organocopper species to an α,β-unsaturated N-acyl oxazolidin-2-one followed in situ by α-methylation of the resultant enolate. The thiazoline portion of kalkitoxin was assembled by titanium tetrachloride catalyzed cyclization of a vinyl substituted amido thiol.
- White, James D.,Xu, Qing,Lee, Chang-Sun,Valeriote, Frederick A.
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p. 2092 - 2102
(2007/10/03)
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- Total synthesis of (+)-kalkitoxin
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The neurotoxic lipopeptide (+)-kalkitoxin was synthesized by a route which employed asymmetric organocopper conjugate addition followed by in situ enolate alkylation to install the anti,anti-1,2,4-trimethyl relationship of the toxin; the synthesis of kalkitoxin required sixteen steps and proceeded in 3% overall yield.
- White, James D.,Lee, Chang-Sun,Xu, Qing
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p. 2012 - 2013
(2007/10/03)
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