Research Overview
The focus of our research program is to discover new organic reactivity leading to the development of synthesis methods. Many of these new reactions are then applied to the synthesis of compounds of medicinal interest with emphasis on neuroprotection. Most projects involve the development of new leaving groups, nucleophilic catalysts, and allenyl carbonyl chemistry.
New Reactions of Allenes and Alkynes
We have long been interested in the unique reactivity of allenyl silanes ( J. Am. Chem. Soc. 2009, 131, 4196). Recently we took advantage of the organosilicon substituent on this class of allenes to selectively produce all-carbon quaternary centers (including via SNAr) or allene dicarbinols under mild conditions ( ChemComm 2017, 53, 5125).
Organometallic auxiliaries have also been used in our group to produce chiral allenal building blocks in moderate to good enantiomeric excesses (
Org. Lett.
2016, 18, 1230). Normally, conjugated alkynyl aldehydes do not isomerize to their thermodynamically less stable allene isomers. However, with a manganese auxiliary in place to promote allene formation, asymmetric protonation of cumulenolate intermediates was realized using a variety of cinchonidinium salts in a weakly basic biphasic reaction system. Optimal results were realized using a novel cinchonidinium geranyl derivative with its C-9 hydroxyl group playing a crucial role in enantioselectivity. The manganese traceless auxiliary also magnifies the axial chirality of the allene moiety, allowing for highly diastereoselective additions to the aldehyde carbonyl and subsequent access to an array of 2,3-allenols. Using this strategy, a nitrile substituted 2,3-allenol was prepared and efficiently converted to Hagen’s gland lactone (
Org. Lett.
2015, 17, 900).
Propargyl systems have also long attracted our attention ( Angew. Chem. Int. Ed. 2011, 50, 8338). Recently, we have developed a versatile approach to isoxazolines and pyrazolines by the cyclization of alkyne substrates using tetrabutylammonium fluoride (TBAF), which engages in a cation-π interaction with the carbon-carbon triple bond ( ChemComm 2016, 52, 2311). These diheteroatom cycles were produced under mild reaction conditions and with broad product scope. A vinyl anion intermediate is produced under unusually mild conditions, which we have trapped in situ as part of a tandem cyclization/aldehyde addition sequence ( Org. Lett. 2017, 19, 3695).
Biological Applications of Compounds Produced from Allenes
We have exploited the unique reactivity of allyl esters to efficiently produce bridged bicyclic systems ( J. Org. Chem. 2014, 79, 9402). Using this chemistry, we have designed a molecular scaffold that can be thought of as a resveratrol monomer; we have termed these compounds resveramorphs. Their structures possess much of the functional group characteristics of resveratrol but in a non-planar molecular arrangement. Working together with the Dawson-Scully Group here at FAU, we have found that these novel compounds protect neurotransmission from hydrogen peroxide-induced oxidative stress. Our findings demonstrate that, at a subnanomolar level, one analog, resveramorph 1, protects synaptic transmission from acute oxidative stress at the Drosophila neuromuscular junction ( ACS Chem Neuroscience). These results position resveramorphs as potential lead compounds in the development of new drugs for neurodegenerative diseases, prompting us to submit a patent application (#62642627).
New Leaving Groups and Nucleophilic Catalysts
One of the longest running projects in the Lepore Group has been the development of new approaches to nucleophilic substitution reactions to facilitate the production of PET probes. Initially our efforts focused on the development of novel leaving groups (
Tetrahedron
2007, 63, 5103) that we have termed Nucleophile Assisting Leaving Groups or NALGs (
Angew. Chem. Int. Ed.
2008, 47, 7511 and
J. Fluor. Chem.
2014, 158, 48). More recently, we have created new bifunctional phase transfer agents capable of promoting rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in molecular imaging with positron emission tomography (PET). The hydrolysis-resistant aryl silicon fragment is promising as a convenient synthon for labeling potential PET radiotracers (
J. Org. Chem. 2017, 82, 2329).
