Organic Letters
Letter
Vishwakarma, R.;Kumar, S. Synth. Commun. 2010, 41, 177. (c)George, J.
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(7) Xue/Li and Winne also reported comparable (4 + 3) cycloaddition
approaches in theirsyntheses of frondosin Band 5-epi-liphagal, utilizing a
presumed benzofuranyl cationic species as their three-atom component.
See refs 4i and 4j.
In summary, we were pleased that our efforts not only
culminated in the total syntheses of frondosin B and liphagal but
also provided important insights into unsaturated Pt-carbene
catalysis.The(4+3)cycloadditionchemistrywaseasilyapplicable
to the synthesis of frondosin B, and our finding that
phosphoramidite ligands improve the carbene-based cyclo-
additionsuggests future opportunities incatalytic reaction design.
The analogous cycloaddition was unsuccessful in the liphagal
context, but gratifyingly the enol interception strategy we
developed provided a fruitful solution. We anticipate that the
studies herein may prove beneficial to the inclusion of these
methods in future synthetic strategies toward complex molecules.
Further studies of α,β-unsaturated Pt carbenes are ongoing, and
their results will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
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S
TheSupportingInformationisavailablefreeofchargeontheACS
Experimental procedures, compound characterization data
(8) Tang also reported the competency of two less nucleophilic dienes:
cyclopentadiene and cyclohexadiene. See ref 6b.
(9)(a) Townsend, C. A.;Bloom, L. M. TetrahedronLett. 1981, 22, 3923.
(b) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1.
(10) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
́
(11)Ether10was synthesizedbystandard alkylationusing3-butyn-2-ol
(12) Tanis, S. P.; Abdallah, Y. M. Synth. Commun. 1986, 16, 251.
(13) A similar observation of differential bond migrations was made by
Iwasawa. See ref 6c.
AUTHOR INFORMATION
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Corresponding Author
ORCID
(14) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
(15) (a) The intermediacy of a furanyl cation via benzofuran formation
followed by ether ionization was ruled out as a mechanistic pathway. The
benzofuranyl Bn ether from intramolecular hydroalkoxylation of 3a was
unreactive under the catalytic conditions. (b) Although the phosphor-
amiditeligandischiral,enantioinductioninthecycloadditionwasmodest
(<15% ee).
(16) Benzofuran 13 was isolated as a 2.5:1 mixture of conjugated olefin
isomers. These isomerscan bepurifiedafterdemethylation. Seerefs 4a, g,
j.
Present Addresses
†Department of Chemistry, Colorado State University, Fort
Collins, Colorado 80523, United States.
‡Department of Medicine, Stanford University, Stanford,
California 94305, United States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The National Institutes of Health (NIGMS, R01GM110560) is
gratefully acknowledged.
(17) Liron, F.; Fontana, F.; Zirimwabagabo, J.-O.; Prestat, G.; Rajabi, J.;
La Rosa, C.; Poli, G. Org. Lett. 2009, 11, 4378.
(18) Winne, J. M.; Catak, S.; Waroquier, M.; Van Speybroeck, V. Angew.
Chem., Int. Ed. 2011, 50, 11990.
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(19) Both Tang and Iwasawa discuss mechanistic considerations of the
α,β-unsaturated carbene-based (4 + 3) cycloaddition. Multiple possible
pathways are suggested, many of which implicate an asynchronous
pathway, whose reactivity would be facilitated by the use of siloxydienes.
See refs 6b, c.
(20)Analternativepossibilityisthattheelectron-richareneisactingasa
competingnucleophile,leadingtocomplexoligomerizationofphenol3b.
(21) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
(22) In our experience, carbene interception will occur at lower
temperatureranges(23−50°C)formorereactivenucleophiles(e.g.,enol
ethers), while less reactive nucleophiles (e.g., electron-neutral dienes)
tend to require more elevated temperatures (80−100 °C) for efficient
reaction times.
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