An intramolecular [2 + 3] cycloaddition route to fused 5-heterosubstituted tetrazoles.

[reaction: see text] Fused 5-heterotetrazole ring systems are synthesized in high yield via intramolecular [2 + 3] cycloadditions of organic azides and heteroatom-substituted nitriles. Cyanates, thiocyanates, and cyanamides are all competent dipolarophiles for this reaction. A variety of scaffolds are tolerated when the new enclosed ring is five- or six-membered.

Preparation of 5-substituted 1H-tetrazoles from nitriles in water.

The addition of sodium azide to nitriles to give 1H-tetrazoles is shown to proceed readily in water with zinc salts as catalysts. The scope of the reaction is quite broad; a variety of aromatic nitriles, activated and unactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction.

2,6-Dichloro-9-thiabicyclo[3.3.1]nonane: a privileged, bivalent scaffold for the display of nucleophilic components.

The title compound, the condensation product of sulfur dichloride and 1,5-cyclooctadiene, is a reliable acceptor of a wide variety of heteroatom nucleophiles, sometimes in reversible fashion. Optical resolution of the core structure has been achieved and preserved in succeeding transformations. The high reactivity and reliable stereochemical control afforded by this system illustrates the power of neighboring-group participation by the sulfur center.

A simple method for the preparation of N-sulfonylsulfilimines from sulfides.

While excellent methods exist for the oxidation of sulfides to sulfoxides R1R2S-->R1R2SO, the azaversion of this atom transfer redox process, i.e., R1R2S-->R1R2S=N-SO2R3, has been less reliable. In sulfilimine synthesis, sulfoxide has been an inevitable byproduct in all cases to date, and the yields of sulfilimine have varied widely. A nearly ideal procedure for the sulfide to sulfonyl sulfilimine transformation is described. Almost quantitative yields are achieved from a diverse set of sulfides and a broad range of the readily available sulfonyl nitrenoid sources known as chloramine salts (R3SO2NClNa), essentially by simply stirring them together in acetonitrile.

The copper-mediated cross-coupling of phenylboronic acids and N-hydroxyphthalimide at room temperature: synthesis of aryloxyamines.

[figure: see text] A novel route to aryloxyamines via the copper-mediated cross-coupling of N-hydroxyphthalimide and phenylboronic acids is reported. The reaction is mediated by selected copper(I) and (II) salts in the presence of pyridine and is tolerant of several functional groups on the phenylboronic acid. The phthallmide group is removed using hydrazine to afford the corresponding aryloxyamine.

Applications of aziridinium ions. Selective syntheses of alpha, beta-diamino esters, alpha-sulfanyl-beta-amino esters, beta-lactams, and 1,5-benzodiazepin-2-one.

A variety of nucleophiles, including amines, thiolates, and alkoxides, were employed to open the aziridinium ions Az. The latter are opened stereospecifically and regioselectively at the C-3 position by a wide range of amines, and thiolate nucleophiles attack predominately at the C-2 position. Poor regioselectivities (ca. 1:1) were observed using nucleophiles derived from phenols, carboxylic acids, and imides. Base-mediated ring closure of the aziridinium opening products, from primary amines, gave beta-lactams and a 1, 5-benzodiazepin-2-one in high yields.

Primary amides. A general nitrogen source for catalytic asymmetric aminohydroxylation of olefins.

N-Bromo,N-lithio salts of primary carboxamides have been shown to be efficient nitrogen sources for catalytic asymmetric aminohydroxylation of olefins, behaving much like the parent N-bromoacetamide in these reactions. alpha-Chloro-N-bromoacetamide is a particularly interesting nitrogen source, as it is functionalized for further reaction, including easy deprotection by treatment with thiourea.

Tert-butylsulfonamide. A new nitrogen source for catalytic aminohydroxylation and aziridination of olefins.

[reaction: see text] The N-chloramine salt of tert-butylsulfonamide has been shown to be an efficient nitrogen source and the terminal oxidant for catalytic aminohydroxylation and aziridination of olefins, resembling closely Chloramine-T by its behavior in these catalytic reactions. The sulfonyl-nitrogen bond in the product or its derivatives is easily cleaved under mild acidic conditions, allowing for facile liberation of the amino group.

Applications of aziridinium ions. Selective syntheses of beta-aryl-alpha,beta-diamino esters.

[formula: see text] alpha,beta-Diamino esters are readily prepared through stereospecific and regioselective opening of an aziridinium ion intermediate with a variety of amines. The aziridinium ion is generated from the epoxide in two steps.

Catalytic asymmetric aminohydroxylation with amino-substituted heterocycles as nitrogen sources.

The suprafacial, vicinal addition of a heterocyclic moiety and a hydroxyl group is achieved by the osmium-catalyzed asymmetric aminohydroxylation (AA) of olefins with amino-substituted heterocycles as the nitrogen sources. Amino alcohols are obtained in up to 97 % yield and with up to 99 % ee when a ligand derived from dihydroquinidine (DHQD-L) is used [Eq. (1); R(i) indicates the remaining portion of the heterocycle (Het); H2 O is the O source]. The AA can now be considered as a means to directly introduce complex, biologically relevant substructures to hydrocarbon backbones.

Catalytic asymmetric aminohydroxylation provides a short taxol side-chain synthesis.

The p-toluenesulfonamide derivate of the C-13 side-chain of taxol was prepared on a one third mole scale in a single step from methyl cinnamate. The process employed is catalytic asymmetric aminohydroxylation (catalytic AA). In the present case, there is no work-up other than filtration of the pure product which is insoluble in the reaction mixture. The sulfonamide protecting group is removed by acidic hydrolysis.

Transformations of hydroxy cyclic sulfates: stereospecific conversion into 2,3,5-trisubstituted tetrahydrofurans.

1,2-Cyclic sulfates have been prepared from O-protected ricinoleate and ricinelaidate esters. Upon deprotection of the 12-hydroxy moiety, the resulting 12-hydroxy-9,10-cyclic sulfates underwent stereospecific cyclization to the corresponding 2,3,5-trisubstituted tetrahydrofurans. The cyclization occurs by backside attack of the hydroxy oxygen on the distal carbon of the 1,2-cyclic sulfate, with inversion at that center.

Selective perhydroxylation of squalene: taming the arithmetic demon.

Osmium-catalyzed asymmetric dihydroxylation, which produces 1,2-diols of high enantiopurity from prochiral olefins, is an example of the synthetic catalysts that have been developed that rival enzymes in their efficiency and high enantioselectivity. Although the asymmetric dihydroxylation catalyst lacks an enzyme's ability to effectively distinguish among the subtly different olefinic sites in a polyolefin such as squalene, this very inability permits it to bring about the "exhaustive" polyhydroxylation of squalene to give a dodecahydroxy derivative. Twelve chemical and stereochemical events proceed in tandem with a remarkable average yield of 98 percent per step, giving 1 out of the 36 possible stereoisomers in (0.98)12 = 78.9 percent overall yield.

Effect of isomers of swainsonine on glycosidase activity and glycoprotein processing.

The chemical synthesis of swainsonine [(1S,2R,8R,8 alpha R)-trihydroxyindolizidine] from trans-1,4-dichloro-2-butene was previously described [Adams, C. E., Walker, F. J., & Sharpless, K. B. (1985) J. Org. Chem. 50, 420-424]. A modification of that synthesis provided two other isomers, referred to here as "Glc-swainsonine" [(1S,2S,8R,8 alpha R)-trihydroxyindolizidine] and "Ido-swainsonine" [(1S,2S,8S,8 alpha R)-trihydroxyindolizidine]. To determine whether these new compounds had biological activity, they were compared to swainsonine as inhibitors of a number of commercially available glycosidases. While swainsonine is a potent inhibitor of jack bean alpha-mannosidase but does not inhibit other glycosidases, its two isomers were inactive on alpha-mannosidase but did inhibit other enzymes. Thus, Glc-swainsonine was an inhibitor of the fungal alpha-glucosidase amyloglucosidase, and this inhibition was of a competitive nature (Ki = 5 X 10(-5) M) with respect to the substrate p-nitrophenyl alpha-D-glucopyranoside. This alkaloid also inhibited beta-glucosidase, but much less effectively than alpha-glucosidase. On the other hand, Ido-swainsonine was more effective toward beta-glucosidase than toward alpha-glucosidase, and this inhibition was also of a competitive nature. None of these inhibitors were effective against beta-mannosidase or alpha- or beta-galactosidase. Glc-swainsonine was also tested against the glycoprotein processing glycosidases. Surprisingly, in this respect, the alkaloid was like swainsonine in that it inhibited mannosidase II but had no effect or only slight effect on glucosidase I, glucosidase II, and mannosidase I. Glc-swainsonine also inhibited glycoprotein processing in cell culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Total synthesis of the L-hexoses.

Enantiomerically pure polyhydroxylated natural products are synthesized by using a reiterative two-carbon extension cycle consisting of four steps. The generality and efficiency of this methodology are demonstrated in the total synthesis of all eight L-hexoses.