Natural products inspired drug discovery

Abstract

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.

Book Chapters
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.

Independent Career

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.



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.

Link to Article

Abstract

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. Chem2016, 2260–2263

Abstract

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.

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

Abstract

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.​

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.