Duncan J. Wardrop

Intramolecular Oxamidation of Unsaturated O-Alkyl Hydroxamates: A Remarkably Versatile Entry to Hydroxy Lactams

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.

Synthesis and biological activity of naturally occurring α-glucosidase inhibitors

Covering: 2005 to the end of 2009 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. 176 references are cited.

Total Synthesis of (±)-Agelastatin A, A Potent Inhibitor of Osteopontin–Mediated Neoplastic Transformations

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.

Alkylidenecarbene insertion at anomeric CH bonds. Synthesis of 3-deoxy-d-arabino-2-heptulosonic acid (DAH) and 3-deoxy-d-manno-2-octulosonic acid (KDO)

Abstract A novel method for the homologation of glycals to the corresponding 3-deoxy-2-ulosonic acids, based on the [1,5]-CH bond insertion of alkylidenecarbenes, is presented. The application of this approach is illustrated through the synthesis of 3-deoxy- d - arabino -2-heptulosonic acid (DAH) and 3-deoxy- d - manno -2-octulosonic acid (KDO).

Diastereoselective nitrenium ion-mediated cyclofunctionalization: Total synthesis of (+)-castanospermine

The asymmetric total synthesis of the α-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.

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

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 γ,δ-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.

π-face selective azaspirocyclization of ω-(methoxyphenyl)-N-methoxyalkylamides

A novel method for the stereoselective preparation of 1-azaspiranes is described. Treatment of α- and β-substituted 3-(methoxyphenyl)-N-methoxypropionamides 1 with phenyliodine(III) bis(trifluoroacetate) initiates efficient azaspirocyclization, via a putative N-acylnitrenium ion intermediate, to provide cyclohexa-2,5 and 2,4-dienone spirolactams 8 and 11 with good π-facial selectivity. Furthermore, a preliminary study indicates that this strategy is also amenable to the preparation of 1-azaspiro[5.5]undeca-2,5-dienones.

Synthesis of (′)-7-episordidin

Abstract The stereoselective synthesis of (±)-7-episordidin, an aggregation pheromone from the male banana weevil, Cosmopolites sordidus Germar, is reported. The key step of this work is a regioselective rhodium(II)-catalyzed diazocarbonyl C H insertion reaction that simultaneously generates three of the natural products four stereocenters. The work reported herein also represents a formal synthesis of sordidin.

Dehydrative fragmentation of 5-hydroxyalkyl-1H-tetrazoles: a mild route to alkylidenecarbenes.

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 2 mol 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.

Template-directed CH activation: development and application to the total synthesis of 7-episordidin

Abstract The development of a template-directed CH activation strategy and its application to the diastereoselective synthesis of (±)-7-episordidin, an aggregation pheromone from the male banana weevil, Cosmopolites sordidus Germar, is reported. The key step of the synthetic route is a regioselective rhodium(II)-catalyzed diazocarbonyl CH activation reaction that simultaneously generates three of the four stereocenters present in the natural product.