Natural products inspired drug discovery
A novel and highly efficient diazo–OH insertion/Conia-ene cascade reaction of readily available homopropargylic acids and alcohols with diazo carbonyl compounds is described. The cascade reaction involves a synergistic Rh/Ag/Au catalyst cocktail and proceeds instantly with a variety of substituted diazo compounds and acids/alcohols to provide functionalized γ-butyrolactones, and tetrahydrofurans with complete regio- and stereo-selectivity. The unprecedented rate-enhancement, complete stereoselectivity, and the enabling of new Conia-ene cyclizations suggest a concerted [4+1]-cycloaddition reaction pathway under synergistic (Rh/Ag/Au)-catalysis conditions.
17. Hunter, A. C.; Schlitzer, S. C.; Sharma, I. “Synergistic Diazo–OH Insertion/Conia-Ene Cascade Catalysis for the Stereoselective Synthesis of γ-Butyrolactones and tetrahydrofurans” Chem. Eur. J. 2016. 22(45), 16062–16065. Link To Article
Prior to Independent Career
18. Chinthapally, K.; Massaro, N.; Sharma, I. “Rhodium Carbenoid Initiated O–H Insertion/Aldol/Oxy-Cope Cascade for the Stereoselective Synthesis of Functionalized Oxacycles” Org. Lett. 2016., 18 (24), 6340–6343.
20. Hunter, A.C.; Schlitzer, S.C.; Stevens, J.C.; Almutwalli, B.; Sharma, I. “A Convergent Approach to Diverse Spiroethers through Stereoselective Trapping of Rhodium Carbenoids with Gold Activated Alkynols" J. Org. Chem. 2018. DOI: 10.1021/acs.joc.7b03196.
21) Hunter, A. C.; Almutwalli, B.; Bain, A.; Sharma, I. "Diazo N–H Insertion/Conia-ene Cascade for the Stereoselective Synthesis of Functionalized Pyrrolidines” 2018 (Submitted).
A novel diazo-cascade approach has been developed for the synthesis of 9-membered oxacycles utilizing readily accessible β-hydroxy vinyl ketones and vinyl diazo esters. The Rh(II)-catalyzed cascade reaction begins with carbene-OH insertion followed by an intramolecular aldol cyclization to provide a substituted tetrahydrofuan intermediate that undergoes an oxy-Cope rearrangement to provide functionalized 9-membered oxacycles with complete stereoselectivity.
A convergent approach for the stereoselective synthesis of diverse spiroethers is described. The reaction involves stereoselective trapping of diazo-derived rhodium carbenoids with gold-activated alkynols for the installation of spiro cores. The reaction has proven general with a range of readily accessible homopropargylic alcohols and diazo carbonyls to provide functionalized spiroether cores of bioactive scaffolds such as spirobarbiturates, spirooxindoles and pseurotin natural products.
19. Chinthapally, K.; Massaro, N.; Padgett, H.L.; Sharma, I. “A Serendipitous Cascade of Rhodium Vinylcarbenoids with Aminochalcones for the Synthesis of Functionalized Quinolines” Chem. Comm. 2017, 53, 12205–12208. DOI: 10.1039/C7CC07181G – Link to Article
22) Hunter, A. C.; Chinthapally, K.; Steven, J. C.; Sharma, I. "Revisiting Baldwin Rules in sp2-CH Activation/Conia-ene Cascade for the Stereoselective Synthesis of Spirocarbocycles” 2018 (Submitted).
Cover Page Description:
The cover picture shows O–H insertion reactions of carboxylic acids into highly stabilized acceptor/acceptor diazo compounds. Rh2(esp)2 acts as an effective catalyst for the decomposition of these stable diazos to form a reactive rhodium-carbenoid. The carboxylic acid comes into contact with the reactive rhodium-carbenoid and undergoes and O- insertion action to release the Rh-catalyst. Rh2(esp)2 now completes its catalytic cycle and gets ready for participating in the decomposition of another diazo molecule.
Contributed 6 chapters to the Electronic Encyclopedia of Reagents for Organic Synthesis Book
i) 3-Hydroxy-2-[(2,4,6 trimethoxyphenyl)methyl]thio]benzaldehyde, CAS: 901126-79-2.
ii) 3-Nitro-2-pyridinesulfenyl chloride, CAS: 68206-45-1.
iii) 5-Ethyl-2-methylpyridine borane, CAS: 1014979-56-6.
iv) Lithium trimethylsilanethiolate, CAS: 2006-10-4.
v) Tetrabutylammonium Difluorotriphenylstannate, CAS: 139353-88-1.
vi) 1-[3-(Diphenylphosphino)-propanoyl]-2,5-pyrrolidindione, CAS: 170278-50-9.
14. Ji, C.; Sharma, I.; Pratihar, D.; Hudson, L. L.; Maura, D.; Guney, T.; Rahme, L. G.; Pesci, E. C.; Coleman, J. P.; Tan, D. S. “Designed small-molecule inhibitors of the anthranilyl-CoA synthetase PqsA block quinolone biosynthesis in Pseudomonas aeruginosa” ACS Chem. Biol. 2016, DOI: 10.1021/acschembio.6b00575
13. Matarlo, J. S.; Evans, E. C.; Sharma, I.; Lavaud, L. J.; Ngo, S. C.; Shek, R.; Rajashankar, K. R.; French, J. B.; Tan, D. S.; Tonge, P. J. “Mechanism of MenE Inhibition by Acyl-Adenylate Analogues and Discovery of Novel Antibacterial Agents” Biochemistry 2015, 54, 6514.
12. Sharma, I.; Wurst, J.; Tan, D. S. “ Solvent-Dependent Divergent Functions of Sc(OTf)3 in Stereoselective Epoxide-Opening Spiroketalizations” Org. Lett. 2014, 16, 2474.
11. In collaboration with Dr. Susruta Majumdar (Pasternak Lab, MSKCC), Váradi, A.; Palmer, T. C.; Notis, P. R.; Redel-Traub, G. N.; Afonin, D.; Subrath, J. J.; Pasternak, G. W.; Hu, C.; Sharma, I.; Majumdar, S.; “Three-Component Coupling Approach for the Synthesis of Diverse Heterocycles Utilizing Reactive Nitrilium Trapping” Org. Lett. 2014, 16, 1668–1671.
10. Sharma, I.; Tan, D. S. News and Views “Drug Discovery Diversifying Complexity” Nature Chemistry 2013, 5, 157.
9. Lu, X.; Zhou, R.; Sharma, I.; Li, X.; Kumar, G.; Swaminathan, S.; Tonge, P. J.; Tan, D. S. “Stable Analogues of OSB-AMP: Potent Inhibitors of MenE, the o-Succinylbenzoate-CoA Synthetase from Bacterial Menaquinone Biosynthesis” ChemBioChem. 2012, 13, 129.
8. Sharma, I.; Bohe, L.; Crich D. “Influence of Protecting Groups on the Anomeric Equilibrium; Case of the 4,6-O-Benzylidene Acetal in the Mannopyranose Series” Carbohydr. Res. 2012, 357, 126.
7. Sharma, I.; Crich D. “Direct Fmoc-Chemistry-Based Solid Phase Synthesis of Peptidyl Thioesters” J. Org. Chem. 2011, 76, 6518.
6. Aubry, S.; Sasaki, K.; Sharma, I.; Crich, D. "Influence of protecting groups on the reactivity and selectivity of glycosylation: Chemistry of the 4,6-O-benzylidene protected mannopyranosyl donors and related species" Topics Curr. Chem. 2011, 301, 141.
5. Crich, D.; Sharma, I. “Influence of the O3 Protecting Group on Stereoselectivity in the Preparation of C-Mannopyranosides with 4,6-O-Benzylidene Protected Donors” J. Org. Chem. 2010, 75, 8383.
4. Crich, D.; Sharma, I. “Triblock Peptide and Peptide Thioester Synthesis with Reactivity- Differentiated Sulfonamides and Peptidyl Thioacids” Angew. Chem. Int. Ed. 2009, 48, 7591.
3. Crich, D.; Sharma, I. "Epimerization-Free Block Synthesis of Peptides from Thioacids and Amines with Sanger’s and Mukaiyama’s Reagents” Angew. Chem. Int. Ed. 2009, 48, 2355.
2. Crich, D.; Sharma, I. “Is Donor-Acceptor Hydrogen Bonding Necessary for 4,6-O-Benzylidene Directed β-Mannopyranosylation. Stereoselective Synthesis of β-C-Mannopyranosides and α-CGlucopyaronosides” Org. Lett.2008, 10, 4731.
1. Mal, D.; Ray, S.; Sharma, I. "Direct Access to 1,4-Dihydroxyanthraquinones: The Hauser Annulation Reexamined with p-Quinones” J. Org. Chem. 2007, 72, 4981.
A serendipitous five-step cascade of rhodium vinylcarbenoids with aminochalcones enables a unique synthetic approach to highly functionalized tri- and tetra-cyclic quinolines. The cascade reaction begins with the insertion of aminochalcone nitrogen into rhodium vinylcarbenoids followed by an intramolecular aldol cyclization to provide a substituted indoline intermediate that undergoes an oxy-Cope rearrangement to provide 9-membered azacycle, which then rearranges to the functionalized quinoline through an intramolecular aldol/dehydration sequence. With catalyst loading as low as 0.1 mol %, the cascade reaction has proven general with a range of aminochalcones and vinylcarbenoids.
23) Massaro, N. P.; Stevens, J. C.; Chatterji, A.; Sharma, I. “Utilizing Ketoacids in Rhodium Carbenoid Initiated Cascade for the Synthesis of Diverse Lactones” 2018 (Submitted)
Rh2(esp)2 has been identified as a highly efficient catalyst for O–H insertion of carboxylic acids into acceptor/acceptor diazo compounds. The insertion reaction proceeds in CH2Cl2 within minutes at room temperature in excellent yields and accommodates carboxylic acids having varying functionalities including amino acids, free alcoholic and phenolic O–H, indole N–H, alkenes, alkynes, and substituted aromatics. In addition, the reaction tolerates a broad range of stable diazo compounds carrying diverse functional groups
15. Hunter, A. C.; Chinthapally, K.; Sharma, I. "Rh2(esp)2: An Efficient Catalyst for O-H Insertion Reactions of Carboxylic Acids into Acceptor/Acceptor Diazo Compounds" Eur. J. Org. Chem. 2016, 2260–2263
16. In Collaboration with Professor Lakshmi Devi (Mount Sinai, New York) and Joseph Parello (Vanderbilt University); Gupta, A.; Gomes, I.; Bobeck, E. N.; Fakira, A. K.; Massaro, N. P.; Sharma, I.; Cave, A.; Hamm, H. E.; Parello, J.; Devi, L. A. “Collybolide is a Novel Biased Agonist of κ-Opioid Receptors with Potent Antipruritic Activity” Proc. Natl. Acad. Sci. (PNAS), USA. 2016, 113(21), 6041–6046. DOI:10.1073/pnas.1521825113. Link To Article
In recent years, the κ-opioid receptor (κOR) has become an attractive therapeutic target for the treatment of a number of disorders including depression, visceral pain, and drug addiction. A search for natural products with novel scaffolds targeting κOR has been intensive. Here, we report the discovery of a natural product (Colly) from the fungus Collybia maculata as a novel scaffold that contains a furyl-δ-lactone core structure similar to that of Salvinorin A, another natural product isolated from the mint Salvia divinorum. We show that Colly functions as a κOR agonist with antinociceptive and antipruritic activity. Interestingly, Colly exhibits biased agonistic activity, suggesting that it could be used as a backbone for the generation of novel therapeutics targeting κOR with reduced side effects.