Synthesis of homochiral tris-indanyl molecular rods

Kjeldsen, Niels Due; Funder, Erik Daa; Gothelf, Kurt V.

doi:10.1039/c4ob00011k

Cited by 5 publications

(6 citation statements)

References 29 publications

(60 reference statements)

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“…As an alternative to the use of a vinylmetal in the epoxide opening reaction, we then investigated the reaction of lithiated alkyne 27 and epoxide 28 in the presence of BF3•Et2O in THF. 50 In the event, the corresponding homopropargylic alcohol was obtained in excellent yield (83%). Hydroalumination of the latter with LAH after aqueous work-up delivered the desired E olefin as a single stereoisomer, albeit with concomitant loss of the TBDPS protecting group.…”

Section: Resultsmentioning

confidence: 95%

“…In addition, the C(20) stereocenter could be established with high selectivity, employing a putative (S)-BINOL-based amide transfer reagent that we have recently developed. As the only exception, 5-desmethyl-(-)-dactylolide(50) could not be converted into the corresponding zampanolide analog 4, which has remained elusive in this study. Likewise, a macrolactonization-based approach had to be developed to access 50, as the required -oxo -keto phosphonate precursor 41 for an HWE-based macrocyclization could not be obtained in this case by oxidation of the corresponding diol 40.C(13)-Desmethylene-(-)-zampanolide (3) proved to be an equally potent inhibitor of cancer cell growth as (-)-zampanolide (1) across a panel of 6 tumor cell lines.…”

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confidence: 71%

“…63 While the reaction was slow and took up to five days to reach >90% conversion, no isomerization of the Z-double bond occurred under the modified Pinnick conditions and seco acid 42 was isolated in 74% overall yield (based on the preceding diol). Gratifyingly, treatment of seco acid 42 with 2,4,6-trichlorobenzoic acid, Et3N and DMAP 51 led to smooth macrolactonization (69% yield); simultaneous cleavage of the two PMB-ether groups with DDQ followed by DMP oxidation of the resulting diol then furnished 5-desmethyl-13-desmethylene-(-)-dactylolide (50) in 39% overall yield for the three-step sequence from seco acid 42. Unfortunately, all attempts to convert 50 into 13-desmethylene-5-desmethyl-(−)-zampanolide (4) by applying our stereoselective aza-aldol reaction protocol 23 proved to be futile.…”

Section: Macrolactonization Approachmentioning

confidence: 99%

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Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(−)-Zampanolide Analogs

Brütsch

Cotter

Lucena‐Agell

et al. 2023

Preprint

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We have prepared a series of partially reduced or demethylated analogs of the natural microtubule stabilizer (−)-zampanolide and we have assessed their antiproliferative activity, their microtubule-binding affinity and their effects on the cellular microtubule network and on cell cycle progression. For reasons of synthetic efficiency, these analogs were derived from 13-desmethylene-(-)-zampanolide, which we had previously shown to be an equally potent cancer cell growth inhibitor as the natural product. The synthesis of all compounds was based on a unified strategy that included final formation of the macrobicyclic core by an intramolecular HWE reaction and a stereoselective aza-aldol reaction to establish the C(20) stereocenter as the key steps. All structural modifications investigated led to reduced cellular activity and lower microtubule-binding affinity compared to the parent 13-desmethylene-(–)-zampanolide, which may be ascribed to increased conformational flexibility due to the formal reduction of double bonds or the removal of the C(17)-methyl group. Notwithstanding this general trend, the cellular potency of 2,3-dihydro-13-desmethylene zampanolide as the most potent analog identified remained within a 9-fold range of that of 13-desmethylene-(–)-zampanolide (for 5 out of 6 cell lines). Notably, while the formal reduction of the C=C double bond of the enone system that is required for the covalent attachment of (−)-zampanolide to beta-tubulin caused a drop in antiproliferative activity of several hundred fold, the compound does bind to microtubules and shows the typical cellular hallmarks of a microtubule-stabilizing agent.

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Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 71%

Section: Macrolactonization Approachmentioning

confidence: 99%

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Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(−)-Zampanolide Analogs

Brütsch

Cotter

Lucena‐Agell

et al. 2023

Preprint

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“…As an alternative to the use of a vinylmetal in the epoxide opening reaction, we then investigated the reaction of lithiated alkyne 27 and epoxide 28 in the presence of BF 3 ⋅Et 2 O in THF [50] . In the event, the corresponding homopropargylic alcohol was obtained in excellent yield (83 %).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure‐Activity Relationship Studies of C(13)‐Desmethylene‐(−)‐Zampanolide Analogs

Brütsch

Cotter

Lucena‐Agell

et al. 2023

Chemistry A European J

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We describe the synthesis and biochemical and cellular profiling of five partially reduced or demethylated analogs of the marine macrolide (−)‐zampanolide (ZMP). These analogs were derived from 13‐desmethylene‐(−)‐zampanolide (DM‐ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67–95 % yield) and a stereoselective aza‐aldol reaction with an (S)‐BINOL‐derived sorbamide transfer complex, to establish the C(20) stereocenter (24–71 % yield). As the sole exception, for the 5‐desmethyl macrocycle, ring‐closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. All modifications led to reduced cellular activity and lowered microtubule‐binding affinity compared to DM‐ZMP, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC50 values for cancer cell growth inhibition varied between 5 and 133 nM, compared to 1–12 nM for DM‐ZMP. Reduction of the enone double bond led to a several hundred‐fold loss in growth inhibition. The cellular potency of 2,3‐dihydro‐13‐desmethylene zampanolide, as the most potent analog identified, remained within a ninefold range of that of DM‐ZMP.

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“…1 In the deprotection of silyl ethers, fluoridebased reagents such as TBAF, NH 4 F and py/HF are often used. 2 Other reagents are proton acids such as p-TsOH 3 or AcOH, 4 Lewis acids such as ICl 5 or ZrCl 4 , 6 or bases such as CsCO 3 7 or i-Bu 2 AlH. 8 However, due to the basicity associated with TBAF, side product ethers from the Williamson reaction are formed in rather large amounts in the desilylation of halidecontaining substrates.…”

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confidence: 99%

From organocatalysed desilylations to high-yielding benzylidenations of electron-deficient benzaldehydes

Niu

Xing

2017

Journal of Chemical Research

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A new type of organoprecatalyst (MeSCH2Cl/KI) for desilylation and benzylidenation reactions has been designed. Both reactions are user friendly and high yielding (71–>99%) and have fast reaction rates. The desilylation of iodo silyl ethers was achieved with no sequential etherification side reactions like those seen for reactions when using TBAF. In the application of the catalytic system to a 6-TBDMS ether of a glucoside, glucoside benzylidenations using electron-deficient benzaldehydes were achieved in 87% yield compared with the previously reported yields of 69–77%. Altogether, 14 benzylidenation reactions were realised using silyloxy alcohols and electron-deficient benzaldehydes instead of their activated acetal forms. In terms of reaction rates and yields, the order of the benzylidenations is p-fluorobenzaldehyde > benzaldehyde > p-anisaldehyde, and a possible mechanism is discussed. These experiments have preliminarily differentiated this cost-effective catalytic system from the classic Lewis acids.

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Synthesis of homochiral tris-indanyl molecular rods

Cited by 5 publications

References 29 publications

Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(−)-Zampanolide Analogs

Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(−)-Zampanolide Analogs

Synthesis and Structure‐Activity Relationship Studies of C(13)‐Desmethylene‐(−)‐Zampanolide Analogs

From organocatalysed desilylations to high-yielding benzylidenations of electron-deficient benzaldehydes

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