1,2,3-Triazoles as versatile directing group for selective sp2 and sp3 C–H activation
Chiyu Wei, Xiaohan Ye, and Xiaodong Shi*
The Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, Florida 33620, United States
Selective C-H functionalization was achieved with designated 1,2,3-triazole acid auxiliary groups under Pd-catalyzed C–H activation conditions. Both sp2 and sp3 C–H bonds were effectively activated, giving the desired products in good yields. This result revealed several successful examples for for C-H amination, acetoxylation, alkynylation, and olefination using 1,2,3-triazole ligands.
Facile Synthesis of Highly Functionalized Tricycloalkanes via Enyne Cope Rearrangement
Sarah K. Scott and Alexander J. Grenning
Department of Chemistry, University of Florida, Gainesville FL 32611-7200, USA
Terpenoid natural products and their derivatives are often targets of organic synthesis due to their promising biological activity and intriguing structural complexity. Moreover, efficient access to natural product derivatives is important for application in the drug discovery process. The work presented offers a short and simple route (four steps, three unique reactions) to access linearly fused 6/7/5 tricyclic ring systems, which represent a large class of terpenoid tricyclic natural products (dolestane, abeo-taxane, etc.). Furthermore, this work exploits the use of a rare 1,5-enyne Cope rearrangement which has previously found no application in natural product synthesis.
Enantioselective Tsuji allylation of Enol Acetates
Ji Liu, Sourabh Mishra, Aaron Aponick
University of Florida
The convenient construction of all-carbon quaternary chiral centers which are ubiquitous in natural products
is a major challenge in organic synthesis. Enantioselective allylation to form α-quaternary ketones has recently
become an efficient tool targeting this challenge. A new method of enantioselective intermolecular deacylative
allylation from easily available enol acetates has been developed. In this process, enol acetates act as
prenucleophiles as well as an activators of allylic alcohols via simple transesterification which allows for direct use of
allyl alcohols. Various allylic alcohols and enol acetates have been demonstrated to give excellent enantioselectivity
and yields. The method of this development will be presented.
Modular entry to the fusicoccane nucleus via a photoinduced pericyclic reaction cascade
Anna E. Salvati, James A. Law, Josue Liriano, and James H. Frederich
Florida State University
The fusicoccanes are a group of diterpenes that have attracted considerable attention for their capacity to stabilize protein-protein interactions. Herein, we describe a unified strategy to prepare this family of natural products, and a range of synthetic variants, in a practical fashion. This chemistry provides a uniquely flexible synthetic platform to explore the rich biological activity of this chemotype.
Solution phase synthesis of teixobactin
University of Central Florida
The globally ever-increasing antimicrobial resistance has become a serious threat to human health and it demands immediate attention to develop novel therapeutic agents. Recently, a novel cyclic depsipeptide antibiotic, teixobactin, has been discovered through screening of uncultured bacteria. Teixobactin exhibits excellent activities against an array of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE) and Mycobacterium tuberculosis.
We have reported a solid-phase peptide synthesis (SPPS) based approach for the preparation of teixobactin and its analogues. In the reported route, both fragments were produced by SPPS, and coupled by a serine ligation. Further medicinal development requires large scale synthesis of the parent molecule and straightforward methods to access various analogues. To address these challenges, our laboratory initiated an exploration of second generation, homogenous approach to the scalable synthesis of the depsipeptide. In the second generation synthesis, we retained the original disconnection at Ser7 position to allow maximum convergence, which also provided a convenient handle for analogue synthesis. The cyclic peptide synthesis commenced from Ala residue. After C-terminal was masked by an allyl group, D-Thr was attached followed by Ser/Cys. The subsequent ester formation was much smoother compared to SPPS and the unnatural amino acid (AA), enduracididine, was the last AA incorporated into the fragment. By this synthetic sequence, a highly convergent synthesis of the cyclic fragment was achieved in good yield.
The linear peptide D-N-Me-Phe1 to Ile6 was prepared by HATU coupling of 2 tripeptides. Permutation of various AAs gives direct access to different analogues. In the first generation approach, the C-terminal salicylaldehyde ester was produced by ozonolysis, but this condition was not compatible with reducing side chain functional groups, e.g. Cys. We used an alternative masking strategy to gain the access to such C-terminal group in the presence of reducing side chain
INVESTIGATION OF THE ORTHO-PYRIDINONE METHIDE REACTIVITY OF VITAMIN B6
Gregory R. Boyce
Florida Gulf Coast University
Our laboratory is dedicated to the development of new reactions for the synthesis of complex biologically active targets. This presentation will describe our progress in exploring the ortho-pyridinone methide reactivity of vitamers of vitamin B6. While ortho-quinone methide reactivity that has been well-studied; the analogous reactivity with 3-pyridinols has received little attention. Two vitamers of vitamin B6, pyridoxine and pyridoxal, serve as inexpensive, non-toxic, and readily available 3-pyridinols from which we can investigate this reactivity. Additionally, functionalization of these vitamers is of interest due to the broad range of biological activity (anti-SARS, anti-HIV, anti-diabetic, gram-negative antibiotic) displayed by their derivatives. We have utilized ortho-pyridinone methide reactivity to generate novel ether, amino, furopyridine and tricyclic derivatives with high regioselectivity. The scope, limitations, mechanistic insights, and reactivity trends for these operationally-simple methodologies will be presented. Efforts to utilize these specific derivatives as water-triggered pro-substances to deliver molecules of importance will also be discussed.
Gold Redox Catalysis with Diazonium Salts
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA
Gold redox catalysis has received far less attention compared to the well established regime of carbophilic Au(I) Lewis acid catalysis. This can be attributed to the high oxidation potential between Au(I) and Au(III), which creates a reliance on strong oxidants such as selectfluor or hypervalent iodine.
The discovery of photo-assisted diazonium activation toward gold(I) oxidation greatly extended the scope of gold redox catalysis by avoiding the use of a strong oxidant. Some practical issues that limit the application of this new type of chemistry are the relative low efficiency (long reaction time and low conversion) and the strict reaction condition control that is necessary (degassing and inert reaction environment). Herein, an alternative photo-free condition has been developed through base induced diazonium activation.
We have reported a Gold-catalyzed cross-coupling strategy using aryldiazonium salts as the oxidant. By forming an alkynyl or aryl gold complex in situ, oxidation of AuI to AuIII with diazonium salt, sp2-sp2 and sp-sp2 cross coupling was achieved. By using this strategy, Gold-catalyzed C-heteroatom (C–X) coupling reactions are also evaluated. By accelerating the reaction rate to outcompete C–C homo-coupling or diazonium dediazoniation, gold-catalyzed Sandmeyer reactions were achieved with different nucleophiles, forming C–Br, C–S and C–P bonds in high yields and selectivity.
In combination with Na2CO3 and diazonium salts, a Au(III) intermediate could be generated. The efficient activation of various substrates including alkyne, alkene, allene and cyclopropanol wcould then be achieved. A rapid Au(III) reductive elimination allows access to C-C coupling products in good to excellent yields. Challenging substrates such as cyclopropanol and electron rich/neutral allenes, which could not be activated under the photo condition (<5% yield), could be activated to subsequently yield the desired coupling products in good to excellent yield.