N-Morpholinomethyl-5-lithiotetrazole: A Reagent for the One-Pot Synthesis of 5-(1-Hydroxyalkyl)tetrazoles.

An efficient, one-pot method for the preparation of 5-(1-hydroxyalkyl)tetrazoles is reported. N-Morpholinomethyl-5-lithiotetrazole, generated by the deprotonation of 4-(N-tetrazolylmethyl)morpholine with LiHMDS, undergoes addition to ketones and aldehydes (both aromatic and aliphatic) to form 5-(1-hydroxyalkyl)tetrazoles in a high yield, after acidic workup. The reported protocol displays a broad substrate scope and functional group tolerance, avoids the use of cyanide- or azide-based reagents, and provides access to sterically congested and unsaturated tetrazoles, which are difficult to access by other means.

2-Arylidene Hydrazinecarbodithioates as Potent, Selective Inhibitors of Cystathionine γ-Lyase (CSE).

Hydrogen sulfide is produced from l-cysteine by the action of both cystathionine γ-lyase (CSE) and cystathionine ß-synthase (CBS) and increasingly has been found to play a profound regulatory role in a range of physiological processes. Mounting evidence suggests that upregulation of hydrogen sulfide biosynthesis occurs in several disease states, including rheumatoid arthritis, hypertension, ischemic injury, and sleep-disordered breathing. In addition to being critical tools in our understanding of hydrogen sulfide biology, inhibitors of CSE hold therapeutic potential for the treatment of diseases in which increased levels of this gasotransmitter play a role. We describe the discovery and development of a novel series of potent CSE inhibitors that show increased activity over the benchmark inhibitor and, importantly, display high selectivity for CSE versus CBS.

Oxamidation of Unsaturated O-Alkyl Hydroxamates: Synthesis of the Madangamine Diazatricylic (ABC Rings) Skeleton.

A novel approach to the diazatricyclic madangamine ABC ring system and the synthesis of an advanced, differentially protected intermediate for the synthesis of madangamine D is reported. Central to the success of this approach is the iodine(III)-mediated intramolecular oxamidation of an unsaturated O-methyl hydroxamate, a π-N+-type cyclization which proceeds in high yield and with complete regioselectivity to generate the 2-azabicyclo[3.3.1]nonane (morphan) system encompassing rings A and C.

Inhibition of influenza H7 hemagglutinin-mediated entry.

The recent outbreak of H7N9 influenza in China is of high concern to public health. H7 hemagglutinin (HA) plays a critical role in influenza entry and thus HA presents an attractive target for antivirals. Previous studies have suggested that the small molecule tert-butyl hydroquinone (TBHQ) inhibits the entry of influenza H3 HA by binding to the stem loop of HA and stabilizing the neutral pH conformation of HA, thereby disrupting the membrane fusion step. Based on amino acid sequence, structure and immunogenicity, H7 is a related Group 2 HA. In this work we show, using a pseudovirus entry assay, that TBHQ inhibits H7 HA-mediated entry, as well as H3 HA-mediated entry, with an IC50 ~ 6 µM. Using NMR, we show that TBHQ binds to the H7 stem loop region. STD NMR experiments indicate that the aromatic ring of TBHQ makes extensive contact with the H7 HA surface. Limited proteolysis experiments indicate that TBHQ inhibits influenza entry by stabilizing the H7 HA neutral pH conformation. Together, this work suggests that the stem loop region of H7 HA is an attractive target for therapeutic intervention and that TBHQ, which is a widely used food preservative, is a promising lead compound.

Methods for direct alkene diamination, new & old.

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.

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.

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.

Discovery, synthesis, and biological evaluation of a novel group of selective inhibitors of filoviral entry.

Herein, we report the development of an antifiloviral 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 IC(50) of 30 µM. 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 antiviral agents with IC(50) 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.

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.

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.

Reduction of solid-supported olefins and alkynes.

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 alpha,beta-unsaturated ketones.

Total synthesis of the alpha-glucosidase inhibitors schulzeine A, B, and C and a structural revision of schulzeine A.

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.

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.

Quinocarmycin analog DX-52-1 inhibits cell migration and targets radixin, disrupting interactions of radixin with actin and CD44.

In the course of screening for new small-molecule modulators of cell motility, we discovered that quinocarmycin (also known as quinocarcin) analog DX-52-1 is an inhibitor of epithelial cell migration. While it has been assumed that the main target of DX-52-1 is DNA, we identified and confirmed radixin as the relevant molecular target of DX-52-1 in the cell. Radixin is a member of the ezrin/radixin/moesin family of membrane-actin cytoskeleton linker proteins that also participate in signal transduction pathways. DX-52-1 binds specifically and covalently to the C-terminal region of radixin, which contains the domain that interacts with actin filaments. Overexpression of radixin in cells abrogates their sensitivity to DX-52-1's antimigratory activity. Small interfering RNA-mediated silencing of radixin expression reduces the rate of cell migration. Finally, we found that DX-52-1 disrupts radixin's ability to interact with both actin and the cell adhesion molecule CD44.

Total synthesis of (+/-)-magnofargesin.

[reaction: see text] 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.

Nitrenium ion azaspirocyclization-spirodienone cleavage: a new synthetic strategy for the stereocontrolled preparation of highly substituted lactams and N-hydroxy lactams.

[reaction: see text] Although 1,4-cyclohexadienes 2, obtained through the Birch reduction of arenes 1, have found widespread use as masked beta-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 beta-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 omega-arylhydroxamates 10, which proceeds with moderate to high diastereoselectivity.

A formal synthesis of (+)-lactacystin.

A synthetic route to the neurotrophic agent (+)-lactacystin has been developed utilizing a base-promoted intramolecular alkylidenecarbene C-H insertion as the key transformation.

Total synthesis of polycavernoside A, a lethal toxin of the red alga Polycavernosa tsudai.

[structure: see text] Two approaches to the synthesis of the aglycon 120 of polycavernoside A (1) were developed, only one of which was completed. The successful "second-generation" route assembled the aglycon seco acids 102 and 106 via Nozaki-Hiyama-Kishi coupling of aldehyde 70, prepared from methyl (S)-3-hydroxy-2-methylpropionate (72) and (S)-pantolactone (73), with vinyl bromide 71. The latter was obtained from a sequence which commenced from the silyl ether 24 of 3-hydroxypropionaldehyde and entailed cyclization of (Z)-zeta-hydroxy-alpha,beta-unsaturated ester 82. Regioselective Yamaguchi lactonization of trihydroxycarboxylic acids 102 and 106 and subsequent functional-group adjustments led to macrolactone 120, to which the fucopyranosylxylopyranoside moiety was attached. Stille coupling of the glycosidated aglycon 128 with dienylstannane 129 furnished polycavernoside A in a synthesis for which the longest linear sequence was 25 steps. The overall yield to lactone 120 was 4.7%.

Total synthesis of (-)-dysibetaine via a nitrenium ion cyclization-dienone cleavage strategy.

The diastereoselective total synthesis of the marine natural product (-)-dysibetaine is reported. The key steps in this venture are i) a diastereoselective nitrenium ion spirocyclization, which serves to generate the pyrrolidinone ring and quaternary stereocenter of the target, and ii) use of the 2-methoxycyclohexa-2,5-dienone ring formed during cyclization as a masked 2-amino-1,3-dicarbonyl synthon.