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Volumn 118, Issue 45, 1996, Pages 11054-11080

Syntheses of discodermolides useful for investigating microtubule binding and stabilization

Author keywords

[No Author keywords available]

Indexed keywords

DISCODERMOLIDE; DISCODERMOLIDE DERIVATIVE; IMMUNOSUPPRESSIVE AGENT; UNCLASSIFIED DRUG;

EID: 0029860912     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja961374o     Document Type: Article
Times cited : (174)

References (98)
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    • We have reported an initial communication of the total synthesis of (-)-discodermolide. Total synthesis of the (-)-enantiomer has also been reported
    • (a) Nerenberg, J. B.; Hung. D. T.; Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621. We have reported an initial communication of the total synthesis of (-)-discodermolide. Total synthesis of the (-)-enantiomer has also been reported
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    • note
    • 5a we arbitrarily chose to start with (R)-(-)-3-(hydroxymethyl)propionate, which resulted in the synthesis of the unnatural enantiomer. While the stereochemistry drawn in Schemes 1-9 corresponds to that of the natural enantiomer, the compounds depicted in Schemes 1,2, and 4-9 were initially characterized as the enantiomers of those drawn.
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    • The relative stereochemistry was confirmed by NOE experiments.
    • The relative stereochemistry was confirmed by NOE experiments.
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    • An alternative synthesis of the ketone fragment begins with a different homoallylic diastereomer.
    • An alternative synthesis of the ketone fragment begins with a different homoallylic diastereomer.
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    • note
    • 2, dibutylboron triflate and Hunig's base, and lithium 2,2,6,6-tetramethylpiperidide (LiTMP).
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    • Subsequent assignment of analogous substrates from this alkylation reaction now suggest that the stereochemical outcome is opposite of that predicted by the chelated transition state model.
    • Subsequent assignment of analogous substrates from this alkylation reaction now suggest that the stereochemical outcome is opposite of that predicted by the chelated transition state model.
  • 39
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    • By analogy to other similar substrates that have now been rigorously assigned, the major epimer corresponds to the desired 1,3-syn-alcohol.
    • By analogy to other similar substrates that have now been rigorously assigned, the major epimer corresponds to the desired 1,3-syn-alcohol.
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    • note
    • Changing counterions to cerium, magnesium, boron, and potassium, or adding HMPA or TMEDA to the reaction medium did not have any effect on the addition. The feasibility of a lithium vinyl anion addition to the Weinreb amide or aldehyde was also investigated. The vinyl iodide corresponding to 16 was synthesized by the addition of (iodomethylene)-triphenylphosphorane to the common aldehyde leading to 16. Metallation using tBuLi, however, resulted in decomposition of the substrate.
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    • note
    • Attempted addition of the acetylide to Mel also resulted in recovery of starting material. It is now presumed that the terminal acetylene with its branched substitution pattern on the other side behaves quite sterically large, perhaps causing the difficulty in addition. Its sterically demanding behavior is confirmed by the CBS reduction of ynone 23, in which the acetylene functionality behaves as the larger group in the directed reduction.
  • 50
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    • The assignment of these alcohols is done by correlation to similar substrates that have been rigorously assigned (vide infra).
    • The assignment of these alcohols is done by correlation to similar substrates that have been rigorously assigned (vide infra).
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    • Other reduction conditions tried were activated zinc with KCN, Cu/ Ag, copper hydride, trimethylstannylcopper, or tantalum/zinc.
    • Other reduction conditions tried were activated zinc with KCN, Cu/ Ag, copper hydride, trimethylstannylcopper, or tantalum/zinc.
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    • Ph.D. Thesis, Harvard University
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    • The C17 stereocenter in this and other related substrates was assigned by treating the alcohol with anhydrous DDQ and performing NOE studies on the resulting benzylidene acetal.
    • The C17 stereocenter in this and other related substrates was assigned by treating the alcohol with anhydrous DDQ and performing NOE studies on the resulting benzylidene acetal.
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    • (b) Toshima, K..; Tatsuta, K.; Kinoshita, T. Bull. Chem. Soc. Jpn. 1988, 61, 2369. This protecting group was chosen after the TBS ether was shown to be stable to all deprotection conditions and the TES ether was shown to be too labile to survive the subsequent Jones oxidation conditions.
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    • Epimerization during the alkylation reaction was ruled out by resubjection of the alkylated product 27a to the reaction conditions without any change in starting material ratios.
    • Epimerization during the alkylation reaction was ruled out by resubjection of the alkylated product 27a to the reaction conditions without any change in starting material ratios.
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    • For examples of the importance of the β-alkoxy group in the stereochemical course of addition to aldehydes, see: (a) Keck, G. E.; Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847.
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    • This boronate was synthesized by heating 5-hexyn-1-ol pivalate with 1.5 equiv of catecholborane overnight at 80 °C. After removal in vacuo of excess catecholborane, the product was sublimed at 160 °C, 0.5 mmHg. Miyaura, N.; Suginome, H.; Suzuki, A Tetrahedron 1983, 39(20) 3271.
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    • The main side products recovered were lactols that were a mixture of stereoisomers at C2. This was presumably a result of some elimination to the pyran that was observed by mass spectrometry and nmr, to which water added on silica gel.
    • The main side products recovered were lactols that were a mixture of stereoisomers at C2. This was presumably a result of some elimination to the pyran that was observed by mass spectrometry and nmr, to which water added on silica gel.


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