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
Woods, Brian P; Baire, Beeraiah; Hoye, Thomas R (2014) Rates of hexadehydro-Diels-Alder (HDDA) cyclizations: impact of the linker structure. Org Lett 16:4578-81
Niu, Dawen; Hoye, Thomas R (2014) The aromatic ene reaction. Nat Chem 6:34-40
Willoughby, Patrick H; Niu, Dawen; Wang, Tao et al. (2014) Mechanism of the reactions of alcohols with o-benzynes. J Am Chem Soc 136:13657-65
Chen, Junhua; Baire, Beeraiah; Hoye, Thomas R (2014) CYCLOADDITION REACTIONS OF AZIDE, FURAN, AND PYRROLE UNITS WITH BENZYNES GENERATED BY THE HEXADEHYDRO-DIELS-ALDER (HDDA) REACTION. Heterocycles 88:1191-1200
Niu, Dawen; Wang, Tao; Woods, Brian P et al. (2014) Dichlorination of (hexadehydro-Diels-Alder generated) benzynes and a protocol for interrogating the kinetic order of bimolecular aryne trapping reactions. Org Lett 16:254-7
Marell, Daniel J; Emond, Susanna J; Kulshrestha, Aman et al. (2014) Analysis of seven-membered lactones by computational NMR methods: proton NMR chemical shift data are more discriminating than carbon. J Org Chem 79:752-8
Hoye, Thomas R; Baire, Beeraiah; Wang, Tao (2014) Tactics for Probing Aryne Reactivity: Mechanistic Studies of Silicon-oxygen Bond Cleavage During the Trapping of (HDDA-generated) Benzynes by Silyl Ethers. Chem Sci 5:545-550
Niu, Dawen; Willoughby, Patrick H; Woods, Brian P et al. (2013) Alkane desaturation by concerted double hydrogen atom transfer to benzyne. Nature 501:531-4
Baire, Beeraiah; Niu, Dawen; Willoughby, Patrick H et al. (2013) Synthesis of complex benzenoids via the intermediate generation of o-benzynes through the hexadehydro-Diels-Alder reaction. Nat Protoc 8:501-8
Izgu, Enver Cagri; Burns, Aaron C; Hoye, Thomas R (2011) Access to functionalized steroid side chains via modified Julia olefination. Org Lett 13:703-5

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