Bunce Research Summary
Dr. Richard A. Bunce
Room 412 Physical Sciences
Much of our research has involved the exploration of tandem reaction methodology for the efficient preparation of heterocycles as potential drug compounds. Tandem reactions have gained considerable recognition in organic synthesis over the past 25 years. These processes link together several chemical transformations in a single reaction vessel, thus minimizing the number of laboratory operations needed and the amount of chemical waste generated during a synthesis. In a typical tandem process, an initial transformation generates an intermediate that can react sequentially with one or more functional groups present in the same molecule. Since the steps that occur after the initiating reaction are usually intramolecular, many of the problems associated with steric hindrance and chemoselectivity are minimized. Some examples of this synthetic strategy from our work include a reduction-reductive amination,1,2 a Michael-SNAr reaction,3,4 an SNAr-Michael reaction,5 a reduction-cycloaromatization-Friedel-Crafts reaction,6 an addition-elimination-SNAr reaction7,8 and an imine addition-SNAr reaction.9 We have also reported new conditions for the preparation of mono- and disubstituted 2,3-dihydro-4(1H)-quinazolinones from 2-nitro- and 2-amino-benzamide.10
More recently, much of our effort has been directed towards the development of two new medicinal agents. The first is a benzothiopyran-based anticancer drug currently entering phase 1 trials.11,12 The second is a family of 2,4-diaminopyrimidine-based antibiotics, which are active against Bacillus anthracis and Staphalococcus aureus.13,14 Work is focused on generating more active derivatives of these agents15 as well as elucidating their mechanisms of action.16,17,18
1. Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi, S. V. "Diastereoselective synthesis of substituted tetrahydroquinoline-4-carboxylic esters by a tandem reduction-reductive amination reaction," J. Org. Chem. 2001, 66, 2822-2827.
2. Bunce, R. A.; Schammerhorn, J. E.; Slaughter, L. M. "Catalyst and pressure dependent reductive cyclizations for the synthesis of hexahydropyrrolo[1,2-a]quinoline-5-carboxylic esters," J. Heterocyclic Chem. 2006, 43, 1505-1511.
3. Bunce, R. A.; Nago, T. "1-Alkyl-2,3-dihydro-4(1H)-quinolinones by a tandem Michael-SNAr annulation reaction," J. Heterocyclic Chem. 2009, 46, 623-628.
4. Bunce R. A.; Squires, S. T.; Nammalwar, B. "1-Alkyl- and (±)-1,2-dialkyl-2,3-dihydro-1,8-naphthyridine-4(1H)-ones by a tandem SNAr-Michael addition reactions," J. Org. Chem. 2013, 78, 2144-2148.
5. Bunce, R. A.; Lee, E. J. "Ester- and ketone-substituted (±)-1-alkyl-6-nitro-1,2,3,4-tetrahydroquinolines by a tandem SNAr-Michael reaction," J. Heterocyclic Chem. 2010, 47, 1176-1182.
6. Bunce, R. A.; Nammalwar, B. "1,2,3,9-Tetrahydro-4H-carbazol-4-one and 8,9-di-hydropyrido[1,2-a]indol-6(7H)-one from 1H-indole-2-butanoic acid," J. Heterocyclic Chem. 2009, 46, 172-177.
7. Bunce, R. A.; Lee, E. J.; Grant, M. T. "Ethyl 1,4-dihydro-4-oxo-3-quinoline-carboxylates by a tandem addition-elimination-SNAr reaction," J. Heterocyclic Chem. 2011, 48, 620-625.
8. Bunce, R. A.; Nammalwar, B. "Ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylates by a tandem addition-elimination-SNAr reaction," J. Heterocyclic Chem., 2012, 49, 658-663.
9. Bunce, R. A.; Schammerhorn, J. E. "Substituted 4-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate esters by a tandem imine addition-SNAr reaction" J. Heterocyclic Chem. 2013, 50, 373-380.
10. Bunce, R. A.; Nammalwar, B. "New conditions for synthesis of (±)-2-monosubstituted and (±)-2,2-disubstituted 2,3-dihydro-4(1H)-quinazolinones from 2-nitro- and 2-amino-benzamide," J. Heterocyclic Chem. 2011, 48, 991-997.
11. Nammalwar, B.; Bunce, R. A.; Benbrook, D. M.; Lu, T.; Li, H.; Chen, Y.; Berlin, K. D. "Synthesis of N-[3,4-dihydro-4-(hydroxymethyl)-2,2,4-trimethyl-2H-1-benzo-thiopyran-6-yl]-N'-(4-nitrophenyl)thiourea, a major metabolite of N-(3,4-dihydro-2,2,4,4-tetramethyl-2H-1-benzothiopyran-6-yl)-N'-(4-nitrophenyl)thiourea, Phosphorus Sulfur Silicon and the Related Elements 2011, 186, 189-204.
12. Nammalwar, B.; Berlin, K. D.; Bunce, R. A. "SHetA2—A mini-review of a promising anticancer drug," JSM Chem. 2013, 1, 1005.
13. Bourne, C. R.; Bunce, R. A.; Bourne, P. C.; Berlin, K. D.; Barrow, E. W.; Barrow, W. W. "Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity," Antimicrob. Agents Chemother. 2009, 53, 3065-3073.
14. Bourne, C. R.; Barrow, E. W.; Bunce, R. A.; Bourne, P. C.; Berlin, K. D.; Barrow, W. W. "Inhibition of antibiotic resistant Staphylococcus aureus by the broad‐spectrum dihydrofolate reductase inhibitor RAB1," Antimicrob. Agents Chemother. 2010, 54, 3825-3833.
15. Nammalwar, B.; Bunce, R. A.; Berlin, K. D.; Bourne, C. R.; Bourne, P. C.; Barrow, E.W.; Barrow,, W. W. "Synthesis and biological activity of substituted 2,4-diaminopyrimidines that inhibit Bacillus anthracis" Eur. J. Med. Chem. 2012, 52, 387-396.
16. Bourne, C. R.; Wakeham, N.; Bunce, R. A.; Berlin, K. D.; Barrow, W. W. "Classifying compound mechanism of action for linking whole cell phenotypes to molecular targets," J. Mol. Recognit. 2012, 25, 216-223.
17. Nammalwar, B.; Bourne, C. R.; Bunce, R. A.; Wakeham, N.; Bourne, P. C.; Ramnarayan, K.; Mylvaganam, S.; Berlin, K. D.; Barrow, E. W.; Barrow, W. W. "Inhibition of bacterial dihydrofolate reductase by 6-alkyl-2,4-diaminopyrimidines," ChemMedChem 2012, 7, 1474-1482.
18. Bourne, C. R.; Wakeham, N.; Nammalwar, B.; Tseitin, V.; Bourne, P. C.; Barrow, E. W.; Ramnarayan, K.; Bunce, R. A.; Berlin, K. D., Barrow, W. W. "Structure-activity relationship guides enantiomeric preference among potent inhibitors of B. anthracis dihydrofolate reductase," Biochem Biophys Acta, 2013, 1834, 46-52.