Total Synthesis of Apoptolidin:  Completion of the Synthesis and Analogue Synthesis and Evaluation

Nicolaou, K. C.; Li, Yiwei; Sugita, Kazuyuki; Monenschein, Holger; Guntupalli, Prasuna; Mitchell, Helen J.; Fylaktakidou, Konstantina C.; Vourloumis, Dionisios; Giannakakou, Paraskevi; O′Brate, Aurora

doi:10.1021/ja030496v

Cited by 102 publications

(49 citation statements)

References 21 publications

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“…Syntheses of apoptolidinone A, the aglycone of 1, were reported by the groups of Sulikowsky [143], Crimmins [144], Nicolaou [138][139][140], and Koert [141,142]. In addition, several studies on the synthesis of fragments of apoptolidinones have been reported [137,[145][146][147][148][149][150][151][152][153][154][155].…”

Section: Methodsmentioning

confidence: 94%

“…Successful total synthesis of 1 has been achieved by the groups of Nicolaou [138][139][140] and Koert [141,142]. Syntheses of apoptolidinone A, the aglycone of 1, were reported by the groups of Sulikowsky [143], Crimmins [144], Nicolaou [138][139][140], and Koert [141,142].…”

Section: Methodsmentioning

confidence: 99%

“…Another key intermediate in the total synthesis of apoptolidin A is the Nicolaou's C 1 -C 11 fragment 69 [140]. We have developed an expeditious synthesis of 69 that requires the isolation of only three synthetic intermediates (Scheme 9) [163] and is based on our one-pot, four-component synthesis of sulfones.…”

Section: Methodsmentioning

confidence: 99%

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Use of sultines in the asymmetric synthesis of polypropionate antibiotics

Vogel

Turks

Bouchez

et al. 2008

Pure and Applied Chemistry

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At low temperature and in the presence of an acid catalyst, SO 2 adds to 1,3-dienes equilibrating with the corresponding 3,6-dihydro-1,2-oxathiin-2-oxides (sultines). These compounds are unstable above -60°C and equilibrate with the more stable 2,5-dihydrothiophene 1,1-dioxides (sulfolenes). The hetero-Diels-Alder additions of SO 2 are suprafacial and follow the Alder endo rule. The sultines derived from 1-oxy-substituted and 1,3-dioxydisubstituted 1,3-dienes cannot be observed at -100°C but are believed to be formed faster than the corresponding sulfolenes. In the presence of acid catalysts, the 6-oxy-substituted sultines equilibrate with zwitterionic species that react with electron-rich alkenes such as enoxysilanes and allylsilanes, generating β,γ-unsaturated silyl sulfinates that can be desilylated and desulfinylated to generate polypropionate fragments containing up to three contiguous stereogenic centers and an (E)-alkene unit. Alternatively, the silyl sulfinates can be reacted with electrophiles to generate polyfunctional sulfones (one-pot, four-component synthesis of sulfones), or oxidized into sulfonyl chlorides and reacted with amines, then realizing a one-pot, four-component synthesis of polyfunctional sulfonamides. Using enantiomerically enriched dienes such as 1-[(R)-or 1-(S)-phenylethyloxy]-2-methyl-(E,E)-penta-1,3-dien-3-yl isobutyrate, derived from inexpensive (R)-or (S)-1-phenylethanol, enantiomerically enriched stereotriads are obtained in one-pot operations. The latter are ready for further chain elongation. This has permitted the development of expeditious total asymmetric syntheses of important natural products of biological interest such as the baconipyrones, rifamycin S, and apoptolidin A.

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Section: Methodsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Use of sultines in the asymmetric synthesis of polypropionate antibiotics

Vogel

Turks

Bouchez

et al. 2008

Pure and Applied Chemistry

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“…Die in jüngster Zeit zunehmend beobachtete Resistenz von Bakterien verleiht der Antibiotika-Forschung allerdings besondere Dringlichkeit. Wer konnte in diese Thematik besser einführen als C. Walsh (Harvard Medical School), der durch Monographien [1] und jüngst als Herausgeber eines ganzen Heftes der Chemical Reviews [2] [4] und Koert [5] (Apoptolidin) sowie Crimmins (Apoptolidinon) [6] synthetisiert worden war, erforderte das ganze Spektrum der modernen stereoselektiven Synthesechemie. Die Synthese umfasste nur 14 Stufen in der längsten linearen Sequenz.…”

unclassified

Nicht nur Antibiotika!

Krohn

2006

Angewandte Chemie

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“…Implementation of this "top down" strategy in our laboratory has thus far led to a higher yielding isolation procedure, to the identification of isoapoptolidin (4), 7 an isomer of apoptolidin that forms during isolation and assay, and to the synthesis and biological evaluation of numerous semi-synthetic analogs 8 which have uncovered new aspects of its mode of action. In the course of these studies we have also identified several new apoptolidins.…”

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confidence: 99%

Apoptolidins B and C: Isolation, Structure Determination, and Biological Activity.

2005

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Apoptolidin (1) is a promising new therapeutic lead that exhibits remarkable selectivity against cancer cells relative to normal cells. We report the isolation, characterization, solution structure, stability, and biological activity of two new members of this family: apoptolidins B (2) and C (3). These new agents are found to have antiproliferative activity on par with or better than apoptolidin itself in an assay with H292 lung cancer cells.Apoptolidin (1) is a structurally novel macrocyclic lactone that exhibits remarkably selective activity against certain cancer cells. First isolated from the soil bacteria Nocardiopsis sp. in 1997 by Seto and co-workers, 1 apoptolidin was shown by NMR to possess a highly unsaturated 20-membered ring core with hydropyranyl appendages attached at positions C-9 and C-19. 2 Of special significance in current efforts to achieve greater selectivity in cancer chemotherapy, apoptolidin shows no cytotoxicity against normal cells even at high concentrations (>1 mM) but induces apoptosis in E1A-transformed rat glia cells at nanomolar concentrations. 1 In studies at the National Cancer Institute, apoptolidin was found to be in the top 0.1% of the most selective agents screened in the NCI-60 cell line assay. 3a By comparison to activity profiles of other compounds in this assay and through independent studies, apoptolidin was proposed to operate through inhibition of mitochondrial F 0 F 1 -ATPase. 3 wenderp@stanford.edu. Supporting Information Available Procedure for the H292 growth inhibition assay, HPLC methods for purification, and spectroscopic data for 2 and 3, including 1 H NMR, 13 C NMR, COSY, TOCSY, HMQC, HMBC, ROE distance restraints, IR, and HRMS is available free of charge via Internet at http://pubs.acs.org. The promising therapeutic potential of apoptolidin and its exceptional selectivity have stimulated efforts to identify the structural basis for its activity and its mode of action. While total synthesis studies are making important progress toward these goals, 4,5,6 the ready availability of apoptolidin from its source organism (109 mg/L of fermentation medium) offers facile access to apoptolidin as well as to various derivatives through semi-synthesis. NIH Public AccessImplementation of this "top down" strategy in our laboratory has thus far led to a higher yielding isolation procedure, to the identification of isoapoptolidin (4), 7 an isomer of apoptolidin that forms during isolation and assay, and to the synthesis and biological evaluation of numerous semi-synthetic analogs 8 which have uncovered new aspects of its mode of action. In the course of these studies we have also identified several new apoptolidins. We describe herein the isolation, structural characterization, stability, solution structure, and biological evaluation of two new members of this family: apoptolidin B (2) and apoptolidin C (3).During our efforts to obtain apoptolidin A (1) (the "A" appended to differentiate members of this now expanding family) through fermentation of Nocardiopsis sp.,...

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Total Synthesis of Apoptolidin: Completion of the Synthesis and Analogue Synthesis and Evaluation

Cited by 102 publications

References 21 publications

Use of sultines in the asymmetric synthesis of polypropionate antibiotics

Use of sultines in the asymmetric synthesis of polypropionate antibiotics

Nicht nur Antibiotika!

Apoptolidins B and C: Isolation, Structure Determination, and Biological Activity.

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