Total Synthesis of Halichondrin C

Yamamoto, Akihiko; Ueda, Atsushi; Brémond, Paul; Tiseni, Paolo S.; Kishi, Yoshito

doi:10.1021/ja2108307

Cited by 61 publications

(24 citation statements)

References 27 publications

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“…88 Other family members of the halichondrin family could also be accessed by incorporating variant building blocks into a similar synthetic sequence. 100 This efficient and modular synthesis enabled Kishi and coworkers to discover that half of halichondrin B, the portion that contains the macrocycle, is nearly equipotent as an anticancer agent to the exceptionally potent natural product. A close variant of this iterative synthesis was successfully scaled up by chemists at Eisai to produce enough of this portion of the molecule, dubbed Eribulin, to enable its clinical utlization.…”

Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

Towards the generalized iterative synthesis of small molecules

2018

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Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the customized approach currently used to synthesize this class of chemical matter. In contrast, the “building block approach”, i.e., generalized iterative assembly of interchangeable parts, has now proven to be a highly efficient and flexible way to construct things ranging all the way from skyscrapers to macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that improve access to specific classes of small molecules. There has also been substantial recent progress toward the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes, and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small molecule synthesis may be within reach.

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Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

Towards the generalized iterative synthesis of small molecules

2018

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“…Consideration of the mechanisms for conversion of 3 to 7 and 11 to 14 accounted for the novel rearrangements (Figure ). They were triggered by the instability of the highly oxygenated epoxide intermediates that initially form (i.e., I and V ), especially in light of the acidity of the medium . The epoxidation, which follows a “majority rules” model, appears to have been highly diastereoselective because we were only able to detect and isolate one product from each reaction.…”

Section: Figurementioning

confidence: 98%

“…They weret riggered by the instability of the highly oxygenated epoxide intermediates that initially form (i.e., I and V), [3,24] especially in light of the acidity of the medium. [25,26] The epoxidation,w hich follows a" majority rules" model, [27] appears to have been highly diastereoselective because we were only able to detect and isolate one product from each reaction. Following epoxidation, ac ascade of steps including oxocarbenium ion formation and attack by nucleophiles occurred en route to both 7 and 14.W hereas V opened to oxocarbenium ion VI and was trapped by the hydroxyl group of the erstwhile hemiketal, the pathwayf ollowed by epoxide I was more complex.…”

mentioning

confidence: 99%

Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation

Lorenc

Saurí

Moser³

et al. 2015

ChemistryOpen

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Spiroketals organize small molecule structures into well-defined, three-dimensional configurations that make them good ligands of proteins. We recently discovered a tandem cycloisomerization–dimerization reaction of alkynyl hemiketals that delivered polycyclic, enol-ether-containing spiroketals. Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them “inside out”. Due to the high level of substitution on the carbon skeletons of the substrates and products, characterization resorted to X-ray crystallography and advanced computation and NMR techniques to solve the structures of representative compounds. In particular, a new proton-detected ADEQUATE NMR experiment (1,1-HD-ADEQUATE) enabled the unequivocal assignment of the carbon skeleton of one of the new compounds. Solution of the structures of the representative compounds allowed for the assignment of product structures for the other compounds in two separate series. Both the rearrangement and the methods used for structural determination of the products are valuable tools for the preparation of characterization of new small molecule compounds.

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“…Halichondrin C was also synthesized ( 13 + 14→23 ). In this series, an additional step was required to remove the allyl group at C12, which was uneventfully achieved with the method used in the previous synthesis . Synthetic halichondrin C and its C38 epimer were isolated in yields of 55 % and 11 %, respectively.…”

Section: Methodsmentioning

confidence: 99%

Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel‐Mediated One‐Pot Ketone Synthesis as the Final Coupling Reaction

Yahata

et al. 2017

Angew Chem Int Ed

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Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni-mediated one-pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80-90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]-spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrin B; 150 mg of halichondrin B (68 % overall yield) were obtained from 200 mg of the right-half precursor.

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Total Synthesis of Halichondrin C

Cited by 61 publications

References 27 publications

Towards the generalized iterative synthesis of small molecules

Towards the generalized iterative synthesis of small molecules

Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation

Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel‐Mediated One‐Pot Ketone Synthesis as the Final Coupling Reaction

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