Research in Organic Chemistry

 

Minehan Group

 

 

 

From left: Armen Nazarian, Annie Smith, Ryan Shaktah, Elroma David, David Shabazi, Joshua Manlutac, Christina Voskanian, Jason Lee,

 Fred Farrar, Milena Balazy, Brendon Mirand, Kevin Ng, Alejandra Fausto, Sayuri Pacheco, Omar Nunez, Bianca Chavez, Ligia Zelaya, Benjamin Azmon, Thomas Minehan, Karen Vo

 

      Research in the Minehan group is primarily focused on the total synthesis of natural products and the development of new synthetic methods for carbon-carbon bond-formation, with an emphasis on the use of environmentally friendly reagents and solvent systems. Inspiration for the development of these methods comes from the complex structures of naturally occurring substances of medicinal and pharmaceutical import. We are currently pursuing four main lines of investigation:

 

1.        The [3,3]-sigmatropic rearrangement of aliphatic allyl-alkynyl ethers is a relatively unexplored reaction in organic synthesis. Allyl-alkynyl ethers may be generated from allyl-1,1-dichlorovinyl ethers by treatment with excess n-BuLi at low temperatures; however, subjecting allyl-dichlorovinyl ethers to these conditions, followed by quenching with an alcohol, leads to rearranged products in the form of gamma, delta-unsaturated esters. Sigmatropic rearrangement is occurring rapidly and stereospecifically at low temperatures in this process. Mechanistic investigations of this reaction are underway; the proposed ketene intermediate holds great synthetic promise, since it may be intercepted by a wide variety of nucleophiles to form an array of carbonyl compounds in a single step. We have recently developed milder methods for the preparation of alkynyl ethers and have successfully applied these methods in the rearrangement process. Currently we are investigating the synthesis and sigmatropic rearrangement propensity of allyl alkynyl amines.

         

 

         

 

 

[2+2] Cycloaddition Reactivity of Alkynyl Ether-Derived Ketenes

 

 

2.          Allylindium reagents, generated in-situ from allyl halides and indium metal, react with carbonyl compounds in water to form products containing a new carbon-carbon bond. We have prepared a series of silyl-substituted allylindium reagents that allow multiple carbon-carbon bonds to be formed in a single step in aqueous media upon reaction with appropriate electrophiles. Such reagents may be employed in an environmentally benign preparation of substituted pyrans and 7- and 8-membered carbocycles, which are at the core of a variety of biologically-important natural products. Allylic substitution reactions are important and powerful methods for carbon-carbon bond-formation. Environmentally benign organoindium reagents participate in transition-metal catalyzed cross-coupling reactions and allylic substitution reactions.

We have reported that 1-acetoxy-2,7- and 2,8-enynes undergo a palladium-catalyzed cyclization / substitution reaction in the presence of organoindium reagents to form substituted 5- and 6-membered carbo- and heterocycles. We envision that this process may be extended to the stereoselective synthesis of fused 6-5 ring systems found in many natural products

 

         

 

3.          C-aryl glycosides are an important class of naturally occurring compounds with unique chemical and biological properties. Possessing a carbon-carbon bond between aromatic and carbohydrate moieties, these substances are endowed with remarkable stability toward acid and enzymatic hydrolysis; this affords them sufficient intracellular lifetime to allow trafficking to the nucleus, where they bind DNA to form stable complexes. Indeed, numerous members of the glycosyl arene family have been show to possess antibacterial, antitumor, and antifungal activities. We have embarked on a program directed toward the total synthesis of members of this family of natural products, and have developed new methods for their synthesis. In particular, we have recently reported an indium allylation/organoindium cross coupling route to 2-deoxy C-aryl ribofuranosides and pyranosides. Furthermore, we have accomplished the total syntheses of aspalathin, nothofagin, indole-3-acetonitrile-4-methoxy-2-C-beta-D-glucopyranoside, polycarcin V, 3,3-di-O-methylardimerin, hortonones A-C, and subamolides D and E.

 

         

 

 

 

4.          We are also assessing the binding affinity and sequence selectivity of C-aryl glycosides for duplex nucleic acids using fluorescence and ultraviolet spectroscopies. Polycarcin V, which has an association constant for calf-thymus DNA of 1.7(0.1) x 106M-1, has been found to bind AT-rich DNA with an order of magnitude greater binding affinity than GC-rich DNA. In order to further explore the principles of carbohydrate-DNA molecular recognition, we are currently investigating the preparation bis-C-glycoside derivatives of intercalating chromophores that place carbohydrate moieties in both the major and minor grooves of DNA.

 

 

 

 

 

 

Students in the Minehan group gain practical experience in the synthesis, purification, and spectroscopic characterization of organic molecules. Some examples of the useful skills obtained are:

1.    Techniques for running reactions under inert atmosphere

2.     Purification of compounds by column chromatography and radial chromatography

3.    Analysis of reactions by thin-layer chromatography and GC-MS

4.    Structure elucidation of synthetic compounds using one- and two-dimensional NMR spectroscopy

5.    Characterization of synthetic compounds by LC-MS, IR, and UV spectroscopies

6.    Evaluation and quantitation of small molecule-macromolecule binding interactions by UV, CD, and fluorescence spectroscopy

 

Useful website for beginning laboratory students: Synthetic organic laboratory techniques

 

NSF-Funded Research Descriptive Video

 

NSF Progress Report

 

 

Research Funding

 

National Science Foundation

 

National Institutes of Health

 

American Chemical Society Petroleum Research Fund

 

Henry Dreyfus Teacher Scholar Award

 

Research Corporation

 

CSUN Competition for Research, Scholarship and Creative Activity Award

 

Selected Recent Publications:

 

 

1.                      Dimeric and Trimeric Derivatives of the Azinomycin B Chromophore show Enhanced DNA Binding Milena Balazy, Alejandra Fausto, Christina Voskanian, Bianca Chavez, Harmanpreet Panesar, and Thomas Minehan Org. Biomol.   
         Chem. 2017, in press
.

 

2.                      A Protecting Group-Free Synthesis of Hortonones A-C from the Inhoffen-Lythgoe Diol Stambulyan, H. ; Minehan, T.G.  Org. Biomol. Chem 2016, 14, 8728-8731

 

3.                      A Single-Flask Synthesis of Morita-Baylis-Hillman Adducts from Ethoxyacetylene and Carbonyl Compounds: Synthesis of Subamolides D and E Ng, K.; Minehan, T.G. Org. Lett. 2016, 18, 4028-4031.

 

4.                      Tandem Bond-Forming Reactions of 1-Alkynyl Ethers Minehan, T. G. Acc. Chem. Res. 2016, 49, 1168-1181.

 

5.                      A single-flask synthesis of alpha-alkylidene and alpha-benzylidene lactones from ethoxyacetylene, epoxides/oxetanes, and carbonyl compounds. Ng, K.; Tran, V.; Minehan, T.G. Tetrahedron Lett. 2016, 57, 415-419.

 

6.                      Synthesis and DNA binding profile of N-mono- and N,N-disubstituted indolo[3,2-b]carbazoles Panesar, H.; Solano, J.; Minehan, T. G. Org. Biomol Chem 2015, 13, 2879-2883.

 

7.           Total Synthesis of the Antitumor Natural Product Polycarcin V and Evaluation of Its DNA Binding Profile Cai, X.; Ng, K.; Panesar, H.; Moon, S.-J.; Paredes, M.; Ishida, K.; Hertweck, C.; Minehan, T.G. Org. Lett. 2014, 16, 6588-6591.

 

8.           Synthesis of 3,3-Di-O-Methyl Ardimerin and Exploration of Its DNA Binding Properties Mavlan, M.; Ng, K.; Panesar, H.; Yepremyan, A.; Minehan, T.G. Org. Lett, 2014, 16, 2212-2215.

 

9.           Low Temperature n-Butyllithium-Induced [3,3]-Sigmatropic Rearrangement/Electrophile Trapping Reactions of Allyl-1,1-Dichlorovinyl Ethers. Synthesis of b-, g-, and d-Lactones Christopher, A.; Brandes, D.; Kelly, S.; Minehan, T.G. Org. Biomol. Chem. 2013, 11, 7658-7661.

 

10.         Anti-Peroxyl Radical Quality and Antibacterial Properties of Rooibos Infusions and Their Pure Glycosylated Polyphenolic Constituents Simpson, M.J.; Hjelmqvist, D.; Lopez-Alcaron, C.; Karamehmedovic, N.; Minehan, T.G.; Yepremyan, B.; Salehani, B.; Lissi, E.; Joubert, E.; Udekwu, K.I. Alcaron, E.I. Molecules 2013, 18, 11264-11280.

  

11.         Lewis Acid Catalyzed Catalyzed Intramolecular Condensation of Ynol Ether-Acetals. Synthesis of Alkoxycycloalkene Carboxylates Tran, V.; Minehan, T.G. Org. Lett. 2012, 14, 6100-6103.

 

    12.         Total Synthesis of Indole-3-Acetonitrile-4-Methoxy-2-C-b-D-Glucopyranoside. Proposal for Structural Revision of the Natural Product Yepremyan, A.; Minehan, T.G. Org. Biomol. Chem. 2012, 10, 5194-5196.

 

13.                  Intramolecular [2+2] cycloaddition reactions of alkynyl ether-derived ketenes. A convenient synthesis of donor-acceptor cyclobutanes Tran, V.; Minehan, T.G. Org Lett. 2011, 13, 6588-6591.

 

14.                  [3,3]-Sigmatropic Rearrangement/5-Exo-Dig Cyclization Reactions of Benzyl Alkynyl Ethers: Synthesis of Substituted 2-Indanones and Indenes Tudjarian, A.A.; Minehan, T.G. J. Org. Chem. 2011, 76, 3576-3581.

 

 

15.                  Indium-Mediated Allylation of Aldehydes, Ketones, and Sulfonimines with 2-(Alkoxy)allyl bromides Dhanjee, H.; Minehan, T.G. Tetrahedron Lett. 2010, 51, 5609-5612.

 

16.                  Concise Total Syntheses of Aspalathin and Nothfagin Yepremyan, A.; Salehani, B.; Minehan, T.G. Organic Letters 2010, 12, 1580-1583.

 

    17.         A Sequential Indium-Mediated Aldehyde Allylation/Palladium-Catalyzed Cross-Coupling Reaction in the Synthesis of 2-Deoxy-β-C-Aryl Glycosides Moral, J.A.; Moon, S.-J.; Rodriguez-Torres, S.; Minehan, T.G. Organic Letters, 2009, 11, 3734-3737.

 

    18.         Synthesis of Alkynyl Ethers and Low-Temperature Sigmatropic Rearrangement of Allyl and Benzyl Alkynyl Ethers. Juan R. Sosa, Armen A. Tudjarian, and Thomas G. Minehan. Org. Lett. 2008, 10, 5091-5094.

 

    19.         Palladium-Catalyzed Reactions of Arylindium Reagents Prepared Directly from Aryl Iodides and Indium Metal. Vardan Papoian and Thomas Minehan. J. Org. Chem. 2008, 73, 7376-7379.

 

    20.         An Environmentally Benign Synthesis of cis-2,6-Disubstituted Tetrahydropyrans via Indium-Mediated Tandem Allylation / Prins Cyclization Reaction. Minh Pham, Amir Allatabakhsh, and Thomas Minehan. J. Org. Chem. 2008, 73, 741-744.

 

    21.         Synthesis of Oxa-Bridged 7- and 8-Membered Rings Via Indium-Mediated Annulation of 1,4- and 1,5-Dicarbonyl Compounds with 3-Iodo-2-[(trimethylsilyl)methyl]propene. Amir Allatabakhsh, Minh Pham, and Thomas Minehan. Heterocycles 2007, 72, 115-122.

 

22.          Palladium-Catalyzed Reactions of Acetoxyenynes with Triorganoindium Reagents. John T. Meza, Raffi A. Terzian and Thomas Minehan. Tetrahedron Lett. 2006, 47, 8905-8910.

 

   23.          Low-Temperature n-Butyllithium-Induced Rearrangement of Allyl 1,1-Dichlorovinyl Ethers. Aaron Christopher, Dahniel Brandes, Stephen Kelly, and Thomas Minehan. Org. Lett., 2006, 8, 451-454.

 

 

 


 

Armen Nazarian and Sayuri Pacheco at the ACS National Meeting in San Francisco, April 2017

 

 


Sayuri Pacheco at the Sigma Xi International Research Conference, Atlanta, Georgia, November, 2016

 


 

Kevin Ng at the 2017 ACS National Meeting in San Francisco, April 2017

 


Ligia Zelaya at the 2017 ACS National Meeting in San Francisco

 



Alejandra Fausto and Bianca Chavez at the 2017 CSUNposium

 

T. Minehan: Personal