Research in Organic Chemistry

Minehan Group

Back From left: Ashley Salvador, Daljeet Kaur, Michael Khoury, Mikayla Patterson, Donald Eli Trujillo, Aren Mirzakhanian, Jose Salvatierra, Fred Farrar, Karen Melendez

Edward Brian Huseman, Kapil Luthra; Front From Left Natalie Silberberg, Vanessa Medina, Philip Chung, James Nguyen

Research in the Minehan group is primarily focused in three areas: 1. The total synthesis of biologically active natural products; 2. The development of new synthetic methods for carbon-carbon bond-formation, with an emphasis on advancing the utility of ynol ethers or ynolates as synthetic intermediates; 3. The development of sequence-specific major–groove binding small molecules for the regulation of gene expression. 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.

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, subamolides D and E, alvaradoins E and F, uveoside and 10-epi-uveoside, conioidine A, sootepdienone, jambolanins C and I, and gibberodione.

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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. Recently we have discovered that derivatives of the triarylmethane dye crystal violet are non-intercalating major-groove binding molecules which display a preference for associating with non-alternating AT tracts of B^* form DNA due their steric bulk. Further studies looking at shape-selective binding of these molecules are currently underway.

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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