CH3Li/TiCl4: A non-basic and highly selective grignard analogue

Reetz, Manfred T.; Kyung, Suk‐Hun; Hüllmann, Michael

doi:10.1016/s0040-4020(01)90582-4

Cited by 69 publications

(14 citation statements)

References 35 publications

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“…Methylation conditions described by Reetz et al provided an improved synthetic route that generated both mono- and gem -dimethyl nitrothiophene triggers from aldehyde 7 in good yield. 50 Mono- methyl trigger 9 was synthesized through methylation of aldehyde 7 with methyllithium and titanium tetrachloride. 50 Oxidation with Dess-Martin periodinane (DMP) generated ketone 10 in high yield, and further methylation of ketone 10 furnished the gem -dimethyl trigger 11 (Scheme 2).…”

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“…50 Mono- methyl trigger 9 was synthesized through methylation of aldehyde 7 with methyllithium and titanium tetrachloride. 50 Oxidation with Dess-Martin periodinane (DMP) generated ketone 10 in high yield, and further methylation of ketone 10 furnished the gem -dimethyl trigger 11 (Scheme 2). 50,51 Further investigation determined that trimethyl aluminum was a more effective methylation agent for the conversion of aldehyde 7 and ketone 10 to their corresponding mono- and gem- triggers 9 and 11 , respectively, in comparison to the methyllithium/titanium tetrachloride method (see Supplementary data).…”

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confidence: 99%

“…37,49 The synthetic route reported by Reetz and co-workers was utilized for the synthesis of the nitrobenzyl triggers 16 and 18 (Scheme S2, Supplementary data). 50 …”

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confidence: 99%

“…51,54,64 Despite several attempts directed towards methylation of the nitroimidazole ketone, the gem -dimethyl nitroimidazole trigger was not successfully synthesized in our hands (Scheme S5, Supplementary data). 50,51,55–63 …”

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Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia

Winn

Shi

Carlson

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50 = 1.0 μM). In fact, the majority of the BAPCs (seven of the eleven analogs) were not inhibitors of tubulin polymerization (IC50 > 20 μM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin.

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“…37,49 The synthetic route reported by Reetz and co-workers was utilized for the synthesis of the nitrobenzyl triggers 16 and 18 (Scheme S2, Supplementary data). 50 …”

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confidence: 99%

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confidence: 99%

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Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia

Winn

Shi

Carlson

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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“…Oxophilic organometallWe have recently established that silyloxy Cope re-ics were used for this purpose to avoid nucleophilic attack arrangements of chiral syn-aldols proceed very rapidly in at the very reactive conjugate double bonds of the Cope products that would occur using Grignard reagents and cu- [a] Institut für Organische Chemie der Georg-August-Universität Göttingen, prates. Thus, CH 3 TiCl 3 addition [19] to 2d (R 1 , R 2 ϭ CH 3 )…”

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confidence: 99%