Iodine(III)-Mediated Cyclization of Unsaturated O-Alkyl Hydroxamates: Silyl-Assisted Access to α-Vinyl & α-(2-Silylvinyl) Lactams
Wardrop, D. J.; Yermolina, M. V.; Bowen, E. G. Synthesis 2012, 14, 1199-1207.

Synthesis 2012
Abstract: The embodiment of lactams rings within a wealth of physiologically active natural products and pharmaceutical agents ensures that the development of synthetic methods, which facilitate the preparation of these saturated N-heterocycles is of critical importance. Herein we report the development of a versatile method for the synthesis of 4 to 8-membered α-vinyl and α-(2-silylvinyl) lactams involving the iodine(III)-mediated oxidative cyclization of unsaturated O-alkyl hydroxamates which encompass an allylsilane. Importantly, the outcome of this transformation can be effectively controlled through variation of the substitution pattern at the silicon center. While allyltrimethylsilanes undergo ring closure with desilylation to form α-vinyl lactams, the corresponding triisopropyl and triphenylsilanes cyclize without loss of the larger silyl group to form E-vinylsilanes with excellent stereoselectivity. From a mechanistic standpoint, we believe that this reaction proceeds via concerted alkene addition of a singlet nitrenium ion (or its equivalent) to form a bicyclic N-acyl-N-alkoxyaziridinium ion, which undergoes eliminative ring opening
DOI: 10.1055/s-0031-1290750 pdficon_large

Dehydrative Fragmentation of 5-Hydroxyalkyl-1H-tetrazoles:
A Mild Route to Alkylidenecarbenes

Wardrop, D. J.; Komenda, J. Org. Lett. 2012, 14, 1548-1551.

Abstract: The development of a mild, base-free method for the generation of alkylidenecarbenes is reported. Treatment of 5-hydroxyalkyl-1H-tetrazoles with carbodiimides generates products arising from the 1,2-rearrangement or [1,5]-C-H bond insertion of a putative alkylidenecarbene. Formation of this divalent intermediate is proposed to occur by way of a tetraazafulvene, which undergoes extrusion of two moles of dinitrogen. Details of this methodology, its application to the synthesis of combretastatin A-4 and an improved route to 5-hydroxyalkyl-1H-tetrazoles are described.
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Methods for Direct Alkene Diamination, Old & New
de Jong, S.; Nosal, D. G.; Wardrop, D. J. Tetrahedron 2012, 68,

Tetrahedron Report
Abstract: The 1,2-diamine moiety is a ubiquitous structural motif present in a wealth of natural products, including non-proteinogenic amino acids and numerous alkaloids, as well as in pharmaceutical agents, chiral ligands and organic reagents. The biological activity associated with many of these systems and their chemical utility in general has ensured that the development of methods for their preparation is of critical importance. While a wide range of strategies for the preparation of 1,2-diamines have been established, the diamination of alkenes offers a particularly direct and efficient means of accessing these systems. The purpose of this review is to provide an overview of all methods of direct alkene diamination, metal-mediated or otherwise.

Nitrenium Ion-Mediated Alkene Bis-Cyclofunctionalization:
Total Synthesis of (-)-Swainsonine

Wardrop, D. J.; Bowen, E. G. Org. Lett. 2011, 13, 2376-2379.

Org. Lett 2011 Swainsonine
Abstract: The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-D-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an gamma,delta-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.
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Diastereoselective Nitrenium Ion-Mediated Cyclofunctionalization: Total Synthesis of (+)-Castanospermine
Bowen, E. G.; Wardrop, D. J. Org. Lett. 2010, 12, 5330-5333.

Org. Lett 2010 Castanospermine
Abstract: The asymmetric total synthesis of the alpha-glucosidase inhibitor (+)-castanospermine is reported. The central theme in our approach to this polyhydroxylated alkaloid is the simultaneous generation of the piperidine ring and the C-1/8a erythro stereodiad through the diastereoselective, oxamidation of an unsaturated O-alkyl hydroxamate. This process is believed to proceed sequentially via singlet acylnitrenium and aziridinium ion intermediates.
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Discovery, Synthesis, and Biological Evaluation of a Novel Group of Selective Inhibitors of Filoviral Entry
Yermolina, M. V.; Wang, J.; M., C.; Rong, L. L.; Wardrop, D. J. J. Med. Chem. 2011, 54, 765–781.

J Med Chem 2010
Abstract: Herein, we report the development of an anti-filoviral screening system, based on a pseudotyping strategy, and its application in the discovery of a novel group of small molecules that selectively inhibit the Ebola and Marburg glycoprotein (GP)-mediated infection of human cells. Using Ebola Zaire GP-pseudotyped HIV particles bearing a luciferase reporter gene and 293T cells, a library of 237 small molecules was screened for inhibition of GP-mediated viral entry. From this assay, lead compound 8a was identified as a selective inhibitor of filoviral entry with an IC50 of 30 μM. In order to analyze functional group requirements for efficacy, a structure-activity relationship analysis of this 3,5-disubstituted isoxazole was then conducted with 56 isoxazole and triazole derivatives prepared using “click” chemistry. This study revealed that while the isoxazole ring can be replaced by a triazole system, the 5-(diethylamino)acetamido substituent found in 8a is required for inhibition of viral-cell entry. Variation of the 3-aryl substituent provided a number of more potent anti-viral agents with IC50 values ranging to 2.5 μM. Lead compound 8a and three of its derivatives were also found to block the Marburg glycoprotein (GP)-mediated infection of human cells.
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Our work on filoviral inhibitors was the subject of an article entitled Nipped in the Bud: Small Molecules May Inhibit Ebola Cell Entry in Future Virology in Future Virology 2011, 6, 27. pdficon_large

Intramolecular Oxamidation of Unsaturated O-Alkyl Hydroxamates: A Remarkably Versatile Entry to Hydroxy Lactams
Wardrop, D. J.; Bowen, E. G.; Forslund, R. E.; Sussman, A. D.; Weerasekera, S. L. J. Am. Chem. Soc. 2010, 132, 1188-1189.

JACS 2010 Oxiamidation
Abstract: The development of a versatile method for the preparation of five- to eight-membered hydroxy lactams that involves the iodine(III)-mediated oxamidation of unsaturated O-alkyl hydroxamates is described. This transformation, which is believed to proceed through the intermediacy of singlet nitrenium and bicyclic N-acyl-N-alkoxyaziridinium ions, is both stereospecific and highly regioselective in most of the 22 cases examined.
DOI: doi: 10.1021/ja9069997 pdficon_large

Article Featured of the Cover of the 03-03-2010 Issue of the Journal of the American Chemical Society.

Synthesis and Biological Activity of Naturally Occurring Alpha-Glucosidase Inhibitors
Wardrop, D. J.; Waidyarachchi, S. L. Nat. Prod. Rep. 2010, 27, 1431-1468.

NPR 2010
Abstract: In addition to their clinical importance in the treatment of type II diabetes, α-glucosidase inhibitors have attracted considerable attention from the synthetic community because of their profound effect on an array of cellular processes, including N-linked glycoprotein processing and maturation, oligosaccharide metabolism, and cell-cell and cell-virus recognition. Over the past decade, a number of structurally-novel naturally occurring α-glucosidase inhibitors which do not conform to the classical iminosugar mold have been identified, including zwitterionic thiosugars and marine organosulfates. While these natural products are important leads in the development of new classes of glucosidase inhibitors, they have also attracted considerable attention as synthetic targets in of themselves. This article reviews the recent literature concerning the synthesis of these emerging natural product families as well as the preparation of those polyhydroxylated alkaloids more traditionally associated with anti-α-glucosidase activity. The literature from 2005 to end 2009 is reviewed, with 176 references cited.


Total Synthesis of the α-Glucosidase Inhibitors Schulzeine A, B, and C and a Structural Revision of Schulzeine A.
Bowen, E. G.; Wardrop, D. J. J. Am. Chem. Soc. 2009, 131, 6062-6063.

JACS 2009 Schulzeine
Abstract: The enantioselective total synthesis of the potent alpha-glucosidase inhibitors schulzeine A, B, and C and a revision of the proposed C20' configuration of schulzeine A are reported. The central feature of our convergent route to this family of novel marine natural products is the preparation of the common benzo[a]quinolizidine subunit through a substrate-controlled, diastereoselective Pictet-Spengler cyclocondensation.
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Reduction of Solid-Supported Olefins and Alkynes
Dickson, D. P.; Toh, C.; Lunda, M.; Yermolina, M. V.; Wardrop, D. J.; Landrie, C. L. J. Org. Chem. 2009, 74, 9535-9538.

Abstract: The reduction of carbon-carbon multiple bonds in alkynes and olefins supported on a polystyrene resin has been investigated. Homogeneous catalysis by titanocene reagents is effective for the stereoselective preparation of cis-olefins from diarylacetylenes, while the use of copper(I) hydride reagents is effective for the reduction of unsaturated ketones.
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Total Synthesis of (±)-Agelastatin A, A Potent Inhibitor of Osteopontin-Mediated Neoplastic Transformations
Dickson, D. P.; Wardrop, D. J. Org. Lett. 2009, 11, 1341-1344.

Pasted Graphic
Abstract: A stereoselective synthesis of agelastatin A, a potent cytotoxin and inhibitor of osteopontin (OPN)-mediated neoplastic transformations, has been accomplished in 14 steps (12 operations) with an approximate overall yield of 8%. Notable features of this route include the direct manner in which the pyrroloketopiperazine A-ring of the target is generated and the efficient employment of a trichloroacetamide, introduced through Overman rearrangement, as a protecting group, pendant nucleophile, and latent urea.
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Total Synthesis of (±)-Magnofargesin
Wardrop, D. J.; Fritz, J. Org. Lett. 2006, 8, 3659-3662.

Pasted Graphic 1
Abstract: A convenient method for the preparation of 2,5-dihydrofurans by using the chemistry of alkynyl(phenyl)iodonium salts is reported. Treatment of 3-alkoxy-1-alkynyl(phenyl)iodonium triflates with sodium benzenesulfinate generates an alkylidenecarbene, which undergoes [1,5]-C-H insertion to form 2-substituted 4-benzenesulfonyl-2,5-dihydrofurans in reasonable yield. These cyclic vinyl sulfones are functionalized in such a way as to make them useful starting materials for the preparation of lignans. The application of this methodology to the first total synthesis of (±)-magnofargesin is disclosed.
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Nitrenium Ion Azaspirocyclization−Spirodienone Cleavage: A New Synthetic Strategy for the Stereocontrolled Preparation of Highly Substituted Lactams and N-Hydroxy Lactams
Wardrop, D. J.; Burge, M. S. J. Org. Chem. 2005, 70, 10271-10284.

JOC 2006 Dienone Cleavage
Abstract: Although 1,4-cyclohexadienes 2, obtained through the Birch reduction of arenes 1, have found widespread use as masked β-oxo carbonyl synthons 3, the possibility that 2,5-cyclohexadienones 5 might also be employed to the same end has been overlooked despite their ready availability. As part of our ongoing investigation of the synthetic chemistry of nitrenium ions, we have developed a novel and efficient strategy for the stereoselective preparation of di- and trisubstituted azetidinone, pyrrolidinone, and piperidinone derivatives, which features the ozonolytic cleavage of azaspirocyclic 2,5-cyclohexadienones 12. For example, ozonolysis of spirodienone 12c in CH2Cl2 and reductive workup with dimethyl sulfide generated unstable β-formyl ester 21, whereas cleavage in MeOH followed by reduction with thiourea led to hemiacetal 22. While both 21 and 22 partially decompose upon exposure to silica gel, they can be trapped in situ, with a variety of weakly basic nucleophiles, to usefully substituted products. The requisite spirodienone substrates are readily accessible through the nitrenium ion cyclization of alkyl ω-arylhydroxamates 10, which proceeds with moderate to high diastereoselectivity.
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