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A Comprehensive History of Arynes in Natural Product Total Synthesis

Tadross, Pamela M. and Stoltz, Brian M. (2012) A Comprehensive History of Arynes in Natural Product Total Synthesis. Chemical Reviews, 112 (6). pp. 3550-3577. ISSN 0009-2665. https://resolver.caltech.edu/CaltechAUTHORS:20120712-093347151

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Abstract

Within 14 years of the seminal experiments of J. D. Roberts leading to the first proposal of the structure of benzyne (1), synthetic organic chemists recognized the potential to exploit this highly reactive intermediate (and its substituted variants) in the total synthesis of natural products. More specifically, it was recognized that arynes offered the strategic advantage of rapidly functionalizing an aromatic ring by forming multiple carbon− carbon or carbon−heteroatom bonds in a single operation, often in a regioselective manner. Initially, the scope of synthetic applications was somewhat limited by the harsh conditions required to produce the aryne species. Many of these methods required strong bases, such as n-BuLi, or high temperatures (Scheme 1). However, with the development of milder methods for the generation of arynes came increased interest in employing them in the synthesis of more complex polycyclic systems. Most recently, the use of o-silyl aryl triflates as aryne precursors has allowed generation of the reactive intermediate under almost neutral conditions. To date, over 75 individual natural products have been prepared using arynes to generate key synthetic intermediates. Herein are recounted the reports of total syntheses that utilize arynes in ways that build complexity or introduce motifs essential to the completion of their targets. The methods by which the authors featured in this review accomplish this task reflect the versatility of arynes as reactive intermediates for synthesis (Scheme 2). For the purposes of organization, the syntheses are divided into subgroups on the basis of the type of aryne transformation: (i) nucleophilic additions or multicomponent reactions, (ii) σ-bond insertion reactions, (iii) [4 + 2]- and [2 + 2]-cycloaddition strategies, and (iv) metal-catalyzed aryne reactions.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/cr200478hDOIArticle
https://doi.org/10.1021/acs.chemrev.8b00367DOICorrection
ORCID:
AuthorORCID
Stoltz, Brian M.0000-0001-9837-1528
Additional Information:© 2012 American Chemical Society. Received: December 22, 2011; Published: March 23, 2012. The authors thank Abbott, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Sigma−Aldrich, Teva, and Caltech for financial support and Dr. Kevin Allan, Dr. Kun-Liang (Phil) Wu, and Mr. Christopher Haley for editorial assistance.
Errata:The authors would like provide clarification regarding the early contributions to structural elucidation of the benzyne intermediate. Although Roberts and co-workers provided the first experimental evidence of the aryne structure in 1953 (Roberts, J. D.; Simmons, H. E., Jr.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem. Soc. 1953, 75, 3290), we would be remiss to not acknowledge that this structure was first proposed by Wittig in 1942 (Wittig, G.Naturwissenschaften 1942, 30, 696). In this report, Wittig proposes both the zwitterion and aryne structures as potential intermediates, favoring the zwitterion to explain the observed reactivity. Ultimately, the seminal ^(14)C-labeling experiments by Roberts and co-workers provided the first evidence of the aryne structure of benzyne that is accepted today. We regret if the introductory statement of this review was misleading to the readers. It has also been brought to our attention that the literature reference for Scheme 70 has been omitted from the manuscript. The total synthesis of pseudopterosin A and E aglycon was reported by Buszek and Bixby in the following reference: Buszek, K. R.; Bixby, D. L. Tetrahedron Lett. 1995, 36, 9129–9132.
Funders:
Funding AgencyGrant Number
AbbottUNSPECIFIED
AmgenUNSPECIFIED
Boehringer IngelheimUNSPECIFIED
Bristol-Myers SquibbUNSPECIFIED
MerckUNSPECIFIED
Sigma-AldrichUNSPECIFIED
TevaUNSPECIFIED
CaltechUNSPECIFIED
Issue or Number:6
Record Number:CaltechAUTHORS:20120712-093347151
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120712-093347151
Official Citation:A Comprehensive History of Arynes in Natural Product Total Synthesis Pamela M. Tadross and Brian M. Stoltz Chemical Reviews 2012 112 (6), 3550-3577
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:32375
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:12 Jul 2012 18:20
Last Modified:03 Oct 2019 04:00

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