Friday May 4th – Presentations

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Investigation Of Z/E Configurational Isomerization In Dicyanorhodanine-Functionalized Oligothiophenes

Lei Li,1 Asmerom O. Weldeab,1 Cory T. Kornman,1 and Ronald K. Castellano1

1 Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL 32611-7200, USA

08:30 AM
Organic Chemistry

Oligothiophenes functionalized with the dicyanorhodanine acceptor have been widely used as electron donor materials in organic solar cells, where they have led to state-of-the-art device performance. Surprisingly, there are no reports in this literature that has considered potential configurational isomerization (Z to E) within the acceptor portion that could potentially alter electronics, conformational preferences, or molecular packing. Reported here is the preliminary investigation of Z/E configurational isomerization in a homologous series of oligothiophenes terminated with the dicyanorhodanine group. The structures of the two configurational isomers were first confirmed by 2D NMR (gHMBC and EXSIDE), and their gas-phase stabilities were studied through DFT calculation. The origin of the isomerization and the consequences of the structural change on optical properties have been explored. By varying the π-conjugation length, solubilizing groups, solvent, and photon source, some of the factors that influence the Z/E configurational isomerization have been identified. The kinetics of the processes and consequences of the isomerization on thin film processing and structure are currently being evaluated.

Iodine catalyzed diazo activation to access radical reactivity

Chiyu Wei, Pan Li, Xiaodong Shi*

Univerisity of South Florida

08:50 AM
Organic Chemistry

An unprecedented iodine catalyzed diazo activation is disclosed herein under either photo- or thermal-initiated conditions. The mechanistic studies revealed the formation of an iodo-substituted alkyl radical as the key intermediate, which represents a novel approach to enable diazo radical reactivity. This metal-free diazo-activation strategy was successfully applied to olefin cyclopropanation with excellent yields. A further extension to substituted pyrrole synthesis under thermal-initiated conditions demonstrates the unique reactivity using this method over typical metal-catalyzed conditions.

Development of the reductive enyne Cope rearrangement

Sarah K. Scott, Katherine E. White and Alexander J. Grenning

Department of Chemistry, University of Florida, Gainesville FL 32611-7200, USA

09:10 AM
Organic Chemistry

Although the enyne Cope rearrangement has been known for several decades, it has not seen applications in synthetic chemistry due to low yields and product instability. However, through the implementation of a reductive variant, this reaction is now being exploited to access functionalized allenyl malonates, which can be further manipulated to generate a range of carbocyclic frameworks commonly found in natural products. This work not only demonstrates the first potential application of the enyne Cope rearrangement in the synthesis of natural products and their analogs, but also provides significant insight into overcoming the challenges previously associated with the transformation.

NSF 101: The Process of Preparing, Submitting, and Reviewing Proposals for The National Science Foundation

Tarek Sammakia

National Science Foundation and the University of Colorado

09:30 AM
Organic Chemistry

The process of preparing, submitting, and reviewing proposals for Chemistry Division of The National Science Foundation (NSF) will be described. This talk is geared at those in early stages of their careers and will provide some basic advice about the process of obtaining funding from the NSF.

Green Methods for the Synthesis of Anti-Cancer Resveratrol Analogues

Daniel H. Paull

Florida Gulf Coast University

10:15 AM
Organic Chemistry

Resveratrol analogues have been widely tested in all kinds of aging-related disorders in the last decade, and their use has only increased because of successes in several diverse areas, including anti-inflammatory, cardioprotective, and anti-cancer. Likewise, we need an ever-expanding library of synthetic methods for their production, especially ones that are easy, quick, efficient, and clean. These green principles guide our method development, and we have three distinct methods to present.

The products we synthesize are tested against various breast cancer cell lines, and we have found several that are active against, and induce metastasis-inhibiting morphological changes in, triple-negative breast cancer cell lines. We are currently designing and synthesizing a second, more focused set of compounds for testing. This application will be presented along with the advantages of each green method for these syntheses.

Synthesis and Biological Evaluation of Spirastrellolide A analogues

Jagadeesh Nagendra Manda, Barry B. Butler Jr, and Aaron Aponick

University of Florida

10:45 AM
Organic Chemistry

Spirastrellolide A is a marine macrolide first isolated by the Anderson group from the Caribbean marine sponge Spirastrella coccinea in 2003. Due to its novel antimitotic potency (IC50 = 100 ng/mL) and selective inhibition of protein phosphatase 2A (IC50 = 1 nM), Spirastrellolide A is potentially a lead compound for anti-cancer therapeutics. However, further evaluation of its biological potency was hindered by inadequate supplies. This issue could be circumvented by developing structurally simplified analogues of Spirastrellolide A that could retain the biological activity. A convergent synthesis of southern hemisphere of spirastrellolide A which involved two key intermediates including a tetrahydropyran and a [6,6]-spiroketal was designed. Two gold-catalyzed cyclization methods developed in our group were employed in the synthesis, namely 1) Gold-catalyzed dehydrative cyclization of monoallylic diols for the synthesis of the tetrahydropyran, and 2) Regioselective gold-catalyzed spiroketalization for the efficient generation of the [6,6]-spiroketal. Progress towards the synthesis of Spirastrellolide A analogues will be presented.

Catalytic Activation of Diazonium and Diazo Compounds: New Chemistry from Unexpected Results

Xiaodong Shi

Department of Chemistry, University of South Florida

11:05 AM
Organic Chemistry

Activation and transformations of organic compounds is the main goal for organic chemists.  Various activation strategy might give different intermediate, leading to distinct transformations. Dazonium and diazo compounds were active motifs containing two nitrogen atoms.  Releasing of nitrogen gas is an entropic gaining and irreversible process which makes dazonium and diazo compounds wildly used in organic synthesis.

By utilizing gold catalyst, our group developed a diazoester decomposition forming a carbophilic carbocation for Friedel–Crafts alkylation.  With this result, we further wanted to merge photoredox and gold catalyst together to activate diazonium salt.  Surprisingly, photoredox catalyst was not necessary in the transformation, which suggested that gold catalyst itself could also serve as a redox catalyst between Au(I) and Au (III).  Unexpectedly, we developed iodide activation of diazo compounds to form iodocaboradical.

Precise Formation of concise G-Octamer for Construction of Noncovalent and Covalent “Molecular Cube” with enhanced stability

Ying He, Yanbin Zhang, Xiaodong Shi

University of South Florida

04:00 PM
Organic Chemistry

Both non-covalent and covalent “molecular cube” was constructed through self-assembly of designated guanosine derivatives, which were characterized by X-ray, NMR and MS.  The key design was the analysis of the key steric factors that control G-quartet stacking.  With the introduction of 8-aryl and sterically hindered protecting group on ribose, interdigitation of sugar between G-quartet layers was prevented successfully and a concise, discrete self-assembled guanosine octamer was achieved with enhanced stability and unique property on Rb+ recognition.

Unleashing bacterial biosynthetic pathways to expand diketopiperazine chemical diversity

Amy L. Lane

University of North Florida

04:20 PM
Organic Chemistry

Natural products with 2,5-diketopiperazine (DKP) scaffolds offer a broad range of bioactivities and chemical structures. The functional and structural diversity of these cyclodipeptides arises via enzyme-catalyzed construction from a variety of amino acids as well as tailoring of DKP cores. For many years, nonribosomal peptide synthetases (NRPSs) were the only enzymes recognized as catalysts for DKP assembly. Cyclodipeptide synthases (CDPSs), employing two aminoacyl-tRNAs as substrates for DKP assembly, were first reported in 2009. Aminoacyl-tRNAs are uncommon players in natural product assembly, making CDPSs intriguing members of Nature’s biosynthetic repertoire. Biochemical and bioinformatics analyses support that CDPSs are found from at least six bacterial phyla and some animals, yet biosynthetic pathways with CDPSs remain understudied relative to pathways featuring NRPSs or other common biosynthetic enzymes.  Through studies of bacterial pathways that include CDPSs, my group has unveiled novel biosynthetic capabilities and developed tools for the engineered biosynthesis of DKPs. This presentation will highlight our strategies for the characterization of these pathways to discover uniquely functionalized DKPs and our development of a platform for the CDPS-catalyzed assembly of novel DKPs from unnatural aminoacyl-tRNA precursors. Our results establish the catalytic promise of CDPSs beyond natural cellular aminoacyl-tRNAs, and showcase the utility of biosynthetic strategies for expanding the breadth of chemical space provided natural products.

Development of a practical synthesis of THC and CBD enabling access to novel analogs

Zachary Shultz, James Leahy

University of South Florida, Department of Chemistry

04:50 PM
Organic Chemistry

Medicinal use of the cannabis plant dates back to 2700 BC in ancient China. We now have an understanding of the chemical profile of these plants and what molecules are responsible for their observed therapeutic effects. Δ9 Tetrahydrocannabinol (THC) and cannabidiol (CBD) have been identified as the main cannabinoids that contribute to the myriad of effects such as anti-parasitic, antibacterial, analgesic and anti-anxiety effects. It has been recently discovered that these natural derived cannabinoids may play a role in Alzheimer’s disease by disrupting the formation of β-amyloid plaques. Our interest is to probe the therapeutic potential of this class of compounds and to this end we developed a practical modular synthesis of the cannabinoids. A chemoenzymatic approach to access a chiral building block used to control the stereochemistry found in the cannabinoids was successfully employed. This route allows for a scalable and efficient platform for analog development of both natural and unnatural cannabinoid isomers.

Standardizing Complex Terpenoid Synthesis

Alexander J. Grenning

University of Florida

05:45 PM
Organic Chemistry

Complex terpenoid natural product synthesis is challenged by scalability, reproducibility, and efficiency (time and yield). My lab aims to develop a chemical strategy to standardize complex cycloheptane synthesis from malonic acid derivatives, ketones/aldehydes, and two different allylic electrophiles. The strategy to be developed is comprised of an operationally simple sequence (2 – 5 steps) to couple the starting materials together yielding the key advanced scaffolds for target (and target-analog) synthesis.1-3

Much like how cross-coupling standardized how biaryl-targets are prepared, we hope to revolutionize how cycloheptane-targets are accessed via standardization. Our route allows for facile recognition of starting materials (retrosynthesis) and efficient synthesis of complex targets. This overall goal also requires significant methodological advancement in the realms of allylic alkylation, [3,3] sigmatropic rearrangements, and malonic acid functional group interconversion.

At the FAME 2018 meeting, I will present an overview of this approach and key recent findings related to new metholodgy and our progress towards various terpenoid natural products.

Representative published work:

(1) Lahtigui, O.; Emmetiere, F.; Zhang, W.; Toledo-Roy, S.; Jirmo, L.; Hershberger, J.; Macho, J.; and Grenning, A. J. “Assembly of Terpenoid Cores by a Simple, Tunable Strategy.” Angew. Chem. Int. Ed. 2016, 55, 15792 –15796.

(2) Fereyduni, E.; Grenning, A. J.; “Factors Governing and Application of the Cope Rearrangement of 3,3-Dicyano-1,5-dienes and Related Studies.” Org. Lett. 2017, 19, 4130.

(3) Scott, S.; Grenning, A. J.; “An Enyne Cope Rearrangement Enables Polycycloalkane Synthesis from Abundant Starting Materials by a Simple Strategy.” Angew. Chem. Int. Ed. 2017, 56, 8125

Ring Distortion of Vincamine Leads to Intriguing Biological Discoveries

Verrill M. Norwood IV and Robert W. Huigens III

Department of Medicinal Chemistry; Center for Natural Products, Drug Discovery and Development (CNPD3); College of Pharmacy, University of Florida

06:15 PM
Organic Chemistry

Despite the rich history of natural products as sources of bioactive molecules, the 1990s saw a paradigm shift away from natural products and toward the screening of collections of synthetic compounds (i.e. High-Throughput Screening (HTS)). This shift is due to many factors, including the increasing difficulty of identifying new natural products, the ease of sp2-sp2 coupling reactions, and the rise of combinatorial and parallel synthesis methodology used to rapidly generate large compound libraries. Consequently, current drug screening libraries are highly populated with flat (e.g. sp2 hybridized) molecules. These screening libraries have been effective at targeting protein targets with flat binding pockets (e.g. protein kinases), but ineffective against more complex biological targets (e.g. protein-protein interactions). An indole-based ring distortion approach was used to address this current lack of complexity. Commercially available indole containing natural products (NPs) are used to create diverse screening libraries. Herein we report this indole-based method executed on the NP vincamine to yield a library of >100 highly complex small molecules, which are being screened for biological activities. Progress related to both the chemistry and biology of vincamine ring distorted compounds will be presented at this talk.

Photoassisted synthesis of complex molecular motifs

James H. Frederich

Florida State University

06:35 PM
Organic Chemistry

The strategic use of photochemical reactions in chemical synthesis offers a powerful avenue to build complexity. Herein, we report our recent efforts to harness photoinduced ring-opening reactions of pyridazine N-oxides to access natural product frameworks.