We have recently uncovered a novel, intramolecular, tandem benzyne-forming/trapping process in which a 1,3-diyne cycloadds to a monoyne to produce an annulated benzenoid. We call the benzyne-forming stage a hexa-dehydro Diels-Alder (HDDA) reaction and the overall process an HDDA cascade. We show many exciting and highly efficient examples that serve to demonstrate the considerable versatility and power of this transformation. This thermal reaction proceeds in a catalyst- and reagent-free manner and is highly convergent and atom economical. It allows access to highly complex benzyne intermediates that would be difficult, if not impossible, to prepare by any conventional benzyne synthesis. This discovery will lead to a major impact through a fundamentally new body of research-a rare opportunity in contemporary synthetic chemistry. A very large portion (>70%) of top-selling drugs contain a benzenoid ring. In nearly half of these, the arene is fused to one or more additional rings (often heterocyclic in nature), comprising a polycyclic unit. Only a few strategies for de novo synthesis of benzenoids exist, and none is highly general. The HDDA cascade strategy is amenable to the synthesis of a wide array of pharmaceutically relevant, benzo-fused heterocycles. We have organized the project under two Aims, which parallel the benzyne-forming (Stage I) and -trapping (Stage II) events.
Sub Aims a) and b) in each further segregate the studies into the categories of intra- vs. inter- molecular reactions, respectively. This research will lead to two categories of significant outcomes: (1) Enabling technology for synthesis of drug-like molecules, encompassing new paradigms valuable in both drug discovery and drug manufacturing (process) activities, will have emerged;(2) New fundamental insights and understanding of benzyne reactivity and altogether new reaction classes will have emerged. The HDDA-cascade process represents virtually unexplored territory. This research will allow chemists to think about, plan, and perform arene synthesis in new ways.

Public Health Relevance

Through this project we will delineate a new strategy that has broad implications on the ways that many drug-like molecules can be synthesized. We will do this by capitalizing on our recently discovered ability to synthesize aromatic compounds in a very atypical fashion that is highly complementary to traditional methods. These types of substructural units are present in ca. 70% of all pharmaceutical agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM065597-09A1
Application #
8514165
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2002-03-01
Project End
2017-05-31
Budget Start
2013-06-05
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$270,079
Indirect Cost
$80,079
Name
University of Minnesota Twin Cities
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zhang, Juntian; Niu, Dawen; Brinker, Vincent A et al. (2016) The Phenol-Ene Reaction: Biaryl Synthesis via Trapping Reactions between HDDA-Generated Benzynes and Phenolics. Org Lett 18:5596-5599
Wang, Tao; Hoye, Thomas R (2016) Hexadehydro-Diels-Alder (HDDA)-Enabled Carbazolyne Chemistry: Single Step, de Novo Construction of the Pyranocarbazole Core of Alkaloids of the Murraya koenigii (Curry Tree) Family. J Am Chem Soc :
Xu, Feng; Xiao, Xiao; Hoye, Thomas R (2016) Reactions of HDDA-Derived Benzynes with Perylenes: Rapid Construction of Polycyclic Aromatic Compounds. Org Lett 18:5636-5639
Chen, Junhua; Palani, Vignesh; Hoye, Thomas R (2016) Reactions of HDDA-Derived Benzynes with Sulfides: Mechanism, Modes, and Three-Component Reactions. J Am Chem Soc 138:4318-21
Xu, Feng; Hershey, Kyle W; Holmes, Russell J et al. (2016) Blue-Emitting Arylalkynyl Naphthalene Derivatives via a Hexadehydro-Diels-Alder Cascade Reaction. J Am Chem Soc 138:12739-12742
Wang, Tao; Niu, Dawen; Hoye, Thomas R (2016) The Hexadehydro-Diels-Alder Cycloisomerization Reaction Proceeds by a Stepwise Mechanism. J Am Chem Soc 138:7832-5
Wang, Teng; Naredla, Rajasekhar Reddy; Thompson, Severin K et al. (2016) The pentadehydro-Diels-Alder reaction. Nature 532:484-8
Marell, Daniel J; Furan, Lawrence R; Woods, Brian P et al. (2015) Mechanism of the Intramolecular Hexadehydro-Diels-Alder Reaction. J Org Chem 80:11744-54
Pogula, Vedamayee D; Wang, Tao; Hoye, Thomas R (2015) Intramolecular [4 + 2] trapping of a hexadehydro-Diels-Alder (HDDA) benzyne by tethered arenes. Org Lett 17:856-9
Nguyen, Quang Luu; Baire, Beeraiah; Hoye, Thomas R (2015) Competition between classical and hexadehydro-Diels-Alder (HDDA) reactions of HDDA triynes with furan. Tetrahedron Lett 56:3265-3267

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