Natural products continue to provide stimulation for the development of creative, interesting, or valuable new chemistry. In this application we propose studies that stem from consideration of the structures or properties of selected natural products that have anticancer properties.
In Aim I new methods for the determination of the structure of natural compounds will be developed. The work will primarily address stereochemical issues-specifically, the relative configuration of unknown stereocenters. A major goal will be to develop computational methods that can routinely and reliably be used to deduce stereostructures by guiding proper interpretation of NMR data.
In Aim II a new methodology, which has the potential to be broadly applicable in natural product synthesis, will be developed. Namely, relay cross (olefin) metathesis (RelayCM) will be developed. This will allow for efficient (i.e., non-statistical) cross coupling of two different alkenes, even when the two are used in an equimolar ratio. Plans for application of this strategy to accomplish a key convergent cross coupling are presented in the context of a proposed total synthesis of lyngbyaloside B (II). A polyol-acylketene macrolactonization reaction is also showcased in this synthesis.
In Aim III the studies related to the biosynthesis of five target compounds will be studied. These are ottelione a (IIIa), salinosporamide A (IIIb), the putative polyenyne biosynthetic precursor to the 9-membered enediyne family (IIIc), uncialamycin (IIId), and okiloactomycin (IIIe). These include compounds with considerable biological relevance to human cancers, including one (IIIb) that is currently in two Phase I clinical trials. Mechanistic considerations, in the light of unprecedented structural features within this group of natural compounds, have led us to propose non-conventional core strategies for the synthesis of each. More specifically, the role of (chemical) spontaneity in biosynthesis drives much of that thinking. In brief, we hypothesize that many natural products undergo their final assembly by non-enzymatic, 'purely chemical'reaction cascades that occur spontaneously under the ambient conditions of the producing organism. Where true, capitalizing on this natural spontaneous event will lead to substantially more efficient chemical synthesis than would otherwise be the case. The driving hypotheses to be tested are: An ambient temperature Cope rearrangement is the key step in the biosynthesis of IIIa. The 2-lactone IIIb is biosynthesized by a spontaneous intramolecular ketene cycloaddition. The polyenyne IIIc is formed by a remarkable and spontaneous cationic cyclization of a highly unsaturated allenyldiynol. The enediyne IIId is formed by spontaneous ring opening of an o-aminoaryloxirane and cyclization of the resultant quinone methide imine. Unique reactivity pairing induces an unusual Diels- Alder reaction leading to IIIe.

Public Health Relevance

Chemical compounds produced by organisms (i.e., natural products) are an invaluable resource. The origin of nearly half of all FDA-approved and U.S.-marketed pharmaceuticals can be traced to a natural product lead. This is also the case for chemotherapeutic agents used to treat human cancers.* Thus, the development of improved methods and strategies i) for the chemical synthesis of natural products, ii) for increasing our understanding of the pathways by which natural products are produced in nature, and iii) for the determination of the structures of new natural products-the titled objectives of this project-is essential if we are to capture the full value of the contents of nature's chemical treasure chest. * Among the currently approved drugs used in cancer chemotherapy, each of the following either is a natural product itself or is directly derived from one: actinomycin, bleomycin, doxorubicin/daunorubicin/darubici/valrubicin (from daunomycin), etoposide/teniposide (from podophyllotoxin), irinotecan/topotecan (from camptothecin), mitomycin, mylotarg (from calicheamicin), streptozotocin, taxol (and docetaxel), vincristine, and vinblastine. Many more are in various stages of clinical trial. Newman and Cragg report (J. Nat. Prod. 2007, 70, 461- 477) that over 75% of new chemical entity anticancer drugs submitted to the FDA between 1981-2006 "were either natural products per se or were based thereon, or mimicked natural products in one form or another."

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076497-14
Application #
8447572
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fu, Yali
Project Start
1998-08-11
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$262,270
Indirect Cost
$88,581
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
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
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; Hoye, Thomas R (2014) The aromatic ene reaction. Nat Chem 6:34-40
Wohl, Adam R; Michel, Andrew R; Kalscheuer, Stephen et al. (2014) Silicate esters of paclitaxel and docetaxel: synthesis, hydrophobicity, hydrolytic stability, cytotoxicity, and prodrug potential. J Med Chem 57:2368-79
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
Hoye, Thomas R; Ayyad, Seif-Eldin N; Beckord, Hollie J et al. (2013) New diarylheptanoids and a hydroxylated ottelione from Ottelia alismoides. Nat Prod Commun 8:351-8
Niu, Dawen; Hoye, Thomas R (2012) A concise total synthesis of (ýý)- and (-)-okilactomycin D. Org Lett 14:828-31
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
Hoye, Thomas R; Jeon, Junha; Tennakoon, Manomi A (2011) Allylmalonate as an activator subunit for the initiation of relay ring-closing metathesis reactions. Angew Chem Int Ed Engl 50:2141-3

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