Systematic Construction of a Monotetrahydrofuran‐Ring Library in Annonaceous Acetogenins by Asymmetric Alkynylation and Stereodivergent Tetrahydrofuran‐Ring Formation.

Kojima, Naoto; Maezaki, Naoyoshi; Tominaga, Hiroaki; Asai, Mikito; Yanai, Minori; Tanaka, Tetsuaki

doi:10.1002/chin.200404223

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“…Results from model alkynylations reactions [40], showed that optimum yields in the alkynylation step, using standard conditions, was achieved when the O-protecting group (OP 1 ) was a MOM moiety (89%. >94% de).…”

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confidence: 98%

Asymmetric Alkynylation Reactions of Aldehydes Using a Zn(OTf)2-Chiral Ligand-Base System

Tyrrell¹

2009

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Optically active propargylic alcohols serve as an important building block in asymmetric synthesis. The customised synthesis of chiral ligands and transition metal activators as catalysts, to effect asymmetric alkynylation reactions, continue to feature in the literature. This review article focuses upon the use of Zn(OTf) 2 , in conjunction with 2-point chiral ligands, for effecting asymmetric alkynylation reactions to aldehydes.

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Section: Fig (5)mentioning

confidence: 98%

Asymmetric Alkynylation Reactions of Aldehydes Using a Zn(OTf)2-Chiral Ligand-Base System

Tyrrell¹

2009

COC

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“…Compounds 5.1 and 5.4 were prepared from 3.2 and 3.1 , via 4.2 and 4.1 , respectively, in four easy steps, including mesylation, Sharpless asymmetric dihydroxylation with AD-mix-β, Williamson-type etherification and monobenzoylation. Compounds 5.1 and 5.4 were oxidized using Swern reaction, and the resulting aldehydes, 6.1 and 6.4 , were alkynylated with 1-decyne using Carreira’s enantioselective alkynylation to give both threo and erythro products. The alkynylated products were hydrogenated over Pd−C, and the resulting saturated compounds 7.1 a , b and 7.4 a , b were converted to alcohols 8.1 a , b and 8.4 a , b .…”

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Alteration of the Bis-tetrahydrofuran Core Stereochemistries in Asimicin Can Affect the Cytotoxicity

et al. 2008

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A systematic analysis using ten synthetic asimicin stereoisomers revealed that the stereochemistry of the bis-tetrahydrofuran core, including the tetrahydrofuran rings and the adjacent hydroxy functions, had significant effect on its cytotoxicity. Our findings set to rest the highly controversial perception that the stereochemistry of the tetrahydrofuran core has little effect on the activity, which is not true for its cytotoxic effect, and also reinforces the previous conclusion that asimicin is a highly potent anticancer compound.Annonaceous adjacent bis-tetrahydrofuran (bis-THF) acetogenins, asimicin (1.1a) and bullatacin (1.1b), are highly potent cytotoxic molecules. 1 Reportedly, they are several orders of magnitude more cytotoxic than doxorubicin, in particular against multidrug resistant cell lines. Although the exact mechanism of action remains unknown, these compounds are believed to display anticancer activity by inhibiting the mitochondrial enzyme, Complex I, inducing the expression of pro-apoptopic genes, and arresting cells in multiple phases, including G1 and G2/M. 2 Based on a comparison among various acetogenins and their analogs, it has been shown that the THF core, including both the THF ring and the neighboring free hydroxyl functions, are crucial structural elements for their strong Complex I inhibitory effect and high anticancer activitiy. 3 Yet, stereochemistry of the THF core is believed to have little effect on the activity of an acetogenin. 1 This would imply that all sixty-four stereoisomeric asimicins (1.1-1.16)(a-d) with dissimilar stereo-chemistry in the bis-THF core (Figure 1), would have identical anticancer activity. This is an unlikely assumption from a historic perspective of medicinal chemistry. Though one could cite the famous example of bullatacin being more than a billion times more potent than asimicin and trilobacin (1.13a) in MCF-7 cells, in spite of the fact that these molecules differ from one other at only one stereogenic center in the THF core, 4 the results could not be corroborated in later studies. 5 Therefore, we prepared several asimicin stereo-isomers, including 1.1(a-d) and 1.4(a-d), and using these compounds as well as the previously described asimicin stereoisomers, 1.6a and 1.8a ,6 we determined both their anticancer activities and the Complex I inhibitory effects. Based on the results of these studies, we report here that both the cytotoxic activity, and to a lesser extent the Complex I inhibitory effect of acetogenins, do indeed depend upon the stereochemistry of 1 To whom correspondence should be addressed. Phone: (858) 784-8512. Fax: (858) 784-8732. E-mail: E-mail: subhash@scripps.edu. Supporting Information Available: Typical experimental procedure, analytical and biological data, and copies of 1 H and 13 C NMR spectra for selected compounds (45 pages). This material is available free of charge via the internet at (http://pubs.acs.org). NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the THF core. In ...

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Systematic Construction of a Monotetrahydrofuran‐Ring Library in Annonaceous Acetogenins by Asymmetric Alkynylation and Stereodivergent Tetrahydrofuran‐Ring Formation.

Abstract: Formation. -(KOJIMA, N.; MAEZAKI, N.; TOMINAGA, H.; ASAI, M.; YANAI, M.; TANAKA, T.; Chem. Eur. J. 9 (2003) 20, 4980-4990; Grad. Sch. Pharm. Sci., Osaka Univ., Suita, Osaka 565, Japan; Eng.) -Adam 04-223

Cited by 2 publications

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Asymmetric Alkynylation Reactions of Aldehydes Using a Zn(OTf)2-Chiral Ligand-Base System

Asymmetric Alkynylation Reactions of Aldehydes Using a Zn(OTf)2-Chiral Ligand-Base System

Alteration of the Bis-tetrahydrofuran Core Stereochemistries in Asimicin Can Affect the Cytotoxicity

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Systematic Construction of a Monotetrahydrofuran‐Ring Library in Annonaceous Acetogenins by Asymmetric Alkynylation and Stereodivergent Tetrahydrofuran‐Ring Formation.

Abstract: Formation. -(KOJIMA, N.; MAEZAKI*, N.; TOMINAGA, H.; ASAI, M.; YANAI, M.; TANAKA*, T.; Chem. Eur. J. 9 (2003) 20, 4980-4990; Grad. Sch. Pharm. Sci., Osaka Univ., Suita, Osaka 565, Japan; Eng.) -Adam 04-223

Cited by 2 publications

References 1 publication

Asymmetric Alkynylation Reactions of Aldehydes Using a Zn(OTf)2-Chiral Ligand-Base System

Asymmetric Alkynylation Reactions of Aldehydes Using a Zn(OTf)2-Chiral Ligand-Base System

Alteration of the Bis-tetrahydrofuran Core Stereochemistries in Asimicin Can Affect the Cytotoxicity

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Abstract: Formation. -(KOJIMA, N.; MAEZAKI, N.; TOMINAGA, H.; ASAI, M.; YANAI, M.; TANAKA, T.; Chem. Eur. J. 9 (2003) 20, 4980-4990; Grad. Sch. Pharm. Sci., Osaka Univ., Suita, Osaka 565, Japan; Eng.) -Adam 04-223