Design of 1,2-dioxines with anti-Candida activity: aromatic substituted 1,2-dioxines

In an ongoing effort to rationally design new antimicrobials, 47 new 1,2-dioxines have been synthesised. Broad antifungal structure-activity relationships governing aromatically substituted epoxy-1,2-dioxines 2 and 3 and their parent 1,2-dioxines 1 were assessed primarily against the pathogenic yeast, Candida albicans, with haemolytic activity of selected examples also reported.     

N-heterocyclic carbene catalyzed reaction of enals and 1,2-dicarbonyl compounds: stereoselective synthesis of spiro gamma-butyrolactones

[reaction: see text]. Nucleophilic heterocyclic carbene (NHC) catalyzed annulation of enals and cyclic 1,2-dicarbonyl compounds, opening a route to gamma-spirolactones, has been observed for the first time. The strategy works well with isatins, leading to spiroannulated oxindole derivatives. It is conceivable that the spiroannulation protocol reported herein will be applicable to the synthesis of important natural products that are endowed with a spiro gamma-butyrolactone motif, especially oxindoles and norsesquiterpenoids.     

An improved synthesis of cyclopropanes from stabilized phosphonates and 1,2-dioxines

Addition of stabilized Horner-Wadsworth-Emmons (HWE) phosphonates to substituted 1,2-dioxines leads to diastereomerically pure di- and trisubstituted cyclopropanes in high yields and represents a viable alternative to ylides in the cyclopropanation reaction involving 1,2-dioxines. While yields are comparable, reaction times with these stabilized phosphonates were accelerated and the diastereoselectivity for this cyclopropanation reaction was significantly greater than for the previously reported examples employing ylides.     

Ammonium-directed dihydroxylation: metal-free synthesis of the diastereoisomers of 3-aminocyclohexane-1,2-diol

The ammonium-directed, metal-free oxidation of 3-(N,N-dibenzylamino)cyclohex-1-ene with mCPBA in the presence of either trichloroacetic acid or tosic acid has been used as the key step to facilitate the synthesis of all the diastereoisomers of 3-aminocyclohexane-1,2-diol, in >98% de in each case.     

CuI/glycerol mediated stereoselective synthesis of 1,2-bis-chalcogen alkenes from terminal alkynes: synthesis of new antioxidants

(E)-1,2-Bis-chalcogen alkenes were stereoselectively prepared in good yields by the addition of diorganyl dichalcogenides to terminal alkynes using CuI/Zn/glycerol as a recyclable catalytic system. The antioxidant activity in vitro of four (E)-1,2-bis-chalcogen alkenes synthesized was evaluated and (E)-1,2-bis-(4-methoxyphenylselanyl)styrene 3b presented excellent activity. The catalytic system used in the synthesis was recovered and used directly up to 5 cycles without loss of activity.     

One-pot stereoselective synthesis of 1,2-amino alcohol derivatives

Common β-hydroxy amino acids (such as threonine) can be readily transformed into 1,2-amino alcohols with excellent stereoselectivity. This one-pot decarboxylation-alkylation process allows the replacement of the carboxyl group by alkyl, allyl, or aryl groups, generally in high yields. A variation of the process (decarboxylation-Diels-Alder) allows the formation of bi- and polycyclic systems, which are useful precursors of alkaloid cores or iminosugars.     

Chemo- and stereoselective monobenzoylation of 1,2-diols catalyzed by organotin compounds

A new facile method for monoacylation of diols has been developed. A variety of cyclic and acyclic diols, in particular 1,2-diols, were selectively monobenzoylated in good yields by the reaction with benzoyl chloride in the presence of a catalytic amount of dimethyltin dichloride and inorganic bases such as potassium carbonate. Furthermore, the method was successfully applied to a kinetic resolution of racemic 1-phenyl-1,2-ethanediol using a chiral organotin catalyst. The ee was dependent on the kind of base, water as an additive, and the reaction temperature.     

Highly stereoselective synthesis of aristeromycin through dihydroxylation of 4-aryl-1-azido-2-cyclopentenes

Dihydroxylation of 4-aryl-1-azido-2-cyclopentenes 6, in which an aryl group is used as a synthetic equivalent of CH(2)OH, was studied to improve the low to moderate stereoselectivity previously reported for cyclopentenes 3 possessing CH(2)X and nitrogen atom-containing groups. 2-Furyl, Ph, and p-MeOC(6)H(4) groups were chosen as the aryl groups. Compounds 6a-c possessing such aryl groups were prepared by CuCN-catalyzed reaction between 2-cyclopentene-1,4-diol monoacetate 9 and the corresponding Grignard reagents followed by substitution of the hydroxyl group with (PhO)(2)P(=O)N(3). The desired diols 7a-c were obtained with higher selectivities of >7:1 when dihydroxylation of 6a-c was carried out at 0 degrees C with OsO(4) (catalyst) and NMO in a mixed solvent of MeCN, THF, t-BuOH, and H(2)O. Among them, the furyl compound recorded the highest selectivity of 14:1. The furyl and azido groups on diol 7a were converted into hydroymethyl and adeninyl groups, respectively, to produce acetonide 2, which upon hydrolysis affords aristeromycin 1.     

A stereoselective entry into functionalized 1,2-diamines by zinc-mediated homologation of alpha-aminoacids

A general, stereoselective synthesis of 4,5-disubstituted imidazolidines-2-ones from alpha-aminoacids has been developed: the key steps are a Blaise reaction of bromoacetate on alpha-aminonitriles and further reduction. Although reduction with sodium cyanoborohydride afforded a mixture of cis and trans isomers 6a-e with moderate to good stereoselectivity, reduction with sodium in liquid ammonia gave the trans isomers 8a-e with complete stereoselectivity. Acidic hydrolysis of the urea gave 4-amino-pyrrolidinones, which can be precursors to beta,gamma-diaminoacids or 3-aminopyrrolidines.     

Intramolecular reactions of hydroperoxides and oxetanes: stereoselective synthesis of 1,2-dioxolanes and 1,2-dioxanes

[reactions: see text] The 5-exo openings of oxetanes by hydroperoxides proceed rapidly and stereospecifically to furnish 1,2-dioxolanes. The corresponding 6-exo cyclizations are slower and proceed with moderate stereoselectivity. In the case of hydroperoxy acetals, 5-exo nucleophilic transfer of alkoxide competes effectively with 6-exo attack by the hydroperoxide.     

Acid catalyzed stereoselective rearrangement and dimerization of flavenes: synthesis of dependensin

Appropriately substituted flavenes undergo stereoselective rearrangement and dimerization when treated with methanolic hydrochloric acid to give benzopyranobenzopyrans. A rationale for the rearrangement is proposed. This synthetic methodology has been used for a high yield synthesis of the natural product dependensin.     

A stereoselective synthesis of 1,2-diols from α-hydroxyaldehydes

The addition of lithium acetylides to (20R)-20-hydroxypregnane-22-carboxaldehydes in the absence and in the presence of BF₃ afforded predominantly 20R,22R- or 20R,22s-diols, respectively, characteristic of ecdysones.     

A novel stereoselective synthesis of 1,2-trans-thioaldoses

A mild and one-pot protocol for the efficient and stereoselective synthesis of 1,2-trans-aldosyl mercaptans is presented.     

A regio- and stereoselective synthesis of 1,2-disubstituted vinylsilanes

The alkylcopper reagents prepared from RMgBr and CuBr react with trimethylsilylacetylene to give regio- and stereo-selectivity 1-trimethylsilyl-1(Z)-alkenylcopper adducts. Hydrolysis affords 1-trimethylsilyl-1(E)-alkenes exclusively. Alkylation, acylation, halogenation, and stannylation proceed stereoselectively to afford synthetically useful intermediates. Homopropargylation of alkyl 1-trimethylsilyl-1(Z)-alkenylcuprates provided better yield than that of the original vinylcopper reagents.     

Ozonolysis of bicyclic 1,2-dioxines: initial scope and mechanistic insights

The ozonolysis of bicyclic 1,2-dioxines was investigated using a variety of 1,4-disubstituted 1,2-dioxines along with a 1,3-dialkyl and steroidal example, with yields ranging from moderate to excellent. Two different pathways were observed upon reaction of the 1,4-disubstituted 1,2-dioxines with ozone; one pathway saw the "expected" results, that is, cleavage of the olefinic moiety with generation of 1,4-dicarbonyl 1,2-dioxines, while the other pathway revealed a previously unobserved rearrangement involving cleavage of the peroxide linkage along with loss of either CO or CO(2). Several unsymmetrical ozonolyses were also performed to further investigate the origins of this rearrangement, and initial mechanistic insights into the fragmentation pathways are discussed.     

Highly stereoselective cyclopropanation of glycals with cyclic diazoamides: a facile synthesis of spirooxindolyl sugar derivatives

Rhodium(II) acetate catalyzed intermolecular cyclopropanation of glycals with cyclic carbenoids generated from 3-diazo-2-oxindole has been achieved to produce a novel series of spirooxindolyl sugar derivatives in good yields under mild experimental conditions.     

Alkylated sugar amino acids: a new entry toward highly functionalized dipeptide isosters

[reaction: see text] Novel highly functionalized dipeptide isosters are synthesized via a diastereoselective alkyl/arylation protocol of a glucose-derived (R)-tert-butanesulfinylimine. One of these novel sugar amino acid derivatives, a D-Ala-Ser/Thr isostere, was applied in a peptide synthesis protocol to afford a cyclic tetramer.     

Propargyl 1,2-orthoesters as glycosyl donors: stereoselective synthesis of 1,2-trans glycosides and disaccharides

Propargyl 1,2-orthoesters are identified as glycosyl donors. Various glycosides and disaccharides were synthesized in a stereoselective manner using AuBr₃ as the promoter. AuBr₃ may activate the alkyne resulting in the formation of a 1,2-dioxolenium ion and also behaves as a Lewis acid to facilitate the attack of the glycosyl acceptor. The versatility of the protocol was demonstrated using a panel of aglycones comprising aliphatic, alicyclic, steroidal and sugar alcohols.     

1,2-dioxines as masked cis gamma-hydroxy enones and their versatility in the synthesis of highly substituted gamma-lactones

Addition of highly stabilized ester nucleophiles to 1,2-dioxines affords good to high yields of gamma-lactones with high diastereoselectivity. Heterolytic or homolytic cleavage of the 1,2-dioxines under appropriate conditions generates the key reactive cis gamma-hydroxy enones, which ultimately afford the observed gamma-lactones. Diastereoselectivity is installed as a result of anti 1,4-addition by the ester enolate to the cis enones followed by intramolecular cyclization. The reaction is tolerant of a range of substitution patterns on the 1,2-dioxine while a broad range of esters are also accommodated. In addition to the synthesis of racemic gamma-lactones, highly enantioenriched gamma-lactones can also be synthesized when chiral cobalt(II) catalysts are employed for the initial homolytic ring-opening of the 1,2-dioxine.