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Natural products with interesting biological properties and structural diversity have often served as valuable lead drug candidates for the treatment of human diseases. Salacinol, a naturally occurring alpha-glucosidase inhibitor, was shown to be one of the active principles of the aqueous extract of a medicinal plant that has been prescribed traditionally as an Ayurvedic treatment for type II diabetes. Salacinol contains an intriguing zwitterionic sulfonium-sulfate structure that comprises a 1,4-anhydro-4-thio-D-arabinitol core and a polyhydroxylated acyclic chain. Due to the unique structural features and its potential to become a lead drug candidate in the treatment of type II diabetes, a great deal of attention has been focused on salacinol and its analogues. Since the isolation of salacinol, several papers describing various synthetic routes to salacinol and its analogues have appeared in the literature. This review is aimed at highlighting the synthetic aspects of salacinol and related compounds as well as their structure-activity relationship studies.

Direct catalytic asymmetric Mannich-type reaction of a trichloromethyl ketone as a propionate equivalent donor is described. A new lanthanum aryloxide−iPr-pybox + lithium aryloxide combined catalys...

N-Protected beta-amino aldehydes have been prepared starting from imines through a sequence involving a Zn-mediated direct alkynylation followed by a Ru-catalyzed anti-Markovnikov alkyne hydration. The rate and the efficiency of the latter reaction are enhanced by the use of microwave irradiation. The possibility to carry out a one-pot Ru-catalyzed hydration/oxidation process from a terminal alkyne to a carboxylic acid was demonstrated, which provided direct access to a N-protected beta-amino acid from the corresponding terminal alkyne.

The superacid-catalyzed reactions of N-acyliminium ion salts have been studied. The new conversions are remarkably similar to the Nazarov reaction and dicationic superelectrophilic species are thought to be involved. Experimental studies show that the cyclizations may be used to prepare varied heterocyclic products, while theoretical studies show that formation of the superelectrophiles can lead to very favorable reaction energetics.

L-Pipecolinic acid derived Lewis basic N-formamide 5e has been developed as a first highly effective catalyst for the asymmetric reduction of aromatic and aliphatic ketones as well as aromatic and aliphatic ketimines in good to high enantioselectivity.

N-(1H)-Tetrazole sulfoximines are readily available by addition of sodium azide to the corresponding N-cyano derivatives in the presence of ZnBr2. The use of these N-(1H)-tetrazoles as intermediates in the synthesis of other N-heterocyclic sulfoximines is demonstrated.

A series of binaphthalene-fused azepinium salts has been generated and used as organocatalysts in the asymmetric epoxidation of unfunctionalized alkenes, giving rise to ees of up to 84%.

Thia−Fries rearrangement of BINOL perfluoroalkylsulfonates affords readily derivatized novel mono- and disulfone ligands in just two steps from enantiomerically pure BINOL. These electron-demanding BINOLs have been successfully applied as catalysts for indium-mediated allylation of N-acylhydrazones. A general and highly enantioselective catalytic process is described, in which the presence of two perfluoroalkylsulfone (SO2RF) groups is shown to be crucial for activity and selectivity. The allylation process affords the corresponding homoallylic amines up to 99% yield and 99% ee.

Chiral amines play a pivotal role in fine chemical and natural product syntheses and the design of novel materials.

Dirhodium(II) salts efficiently catalyze the three-component assembly reaction of an imine, diazoacetonitrile (DAN), and an activated alkynyl coupling partner to form substituted 1,2-diarylpyrroles in moderate to good yields. The transition-metal-catalyzed decomposition of the diazo compound in the presence of the imine presumably generates a transient azomethine ylide that undergoes cycloaddition with dipolarophiles in a highly convergent manner.

[reaction: see text] The first successful catalytic oxidation procedure for the chemoselective conversion of imines to nitrones is reported. The reaction is general, high yielding, and user and environmentally friendly, and furnishes a solution to the yet unanswered issue of regioselective access to nitrones by oxidation of nitrogen derivatives.

The first example of catalytic enantioselective Mannich-type reactions of simple ketoimines is described. The optimized conditions for aromatic ketoimines include the use of CuOAc−DTBM−SEGPHOS as the catalyst (10 mol %) and (EtO)2Si(OAc)2 as the trapping reagent (1 equiv) of the intermediate copper amide (generated via the addition of a copper enolate to the imine). The trapping reagent significantly facilitated the catalyst turnover. Excellent enantioselectivity was produced from a range of aromatic ketoimines, including heteroaromatic and ethyl-substituted ketoimines. The optimized conditions for aliphatic ketoimines include the use of CuOAc−4-tBu−cyclohexyl−DuPHOS as the catalyst and (EtO)3SiF as the trapping reagent. When aliphatic substrates were used, the enantioselectivity was in the 77−81% ee range. The products were converted to β,β-disubstituted amino acids, which are a very important class of chiral building blocks for natural product synthesis, pharmaceuticals, and conformationally regulated a...

Treatment of novel chiral N-sulfinyl alpha-chloro ketimines with Grignard reagents resulted in the synthesis of chiral N-(1-substituted cyclopropyl)-tert-butanesulfinamides in acceptable to good yields and diastereoselectivity via 1,3-dehydrohalogenation and subsequent addition of the Grignard reagent to the intermediate cyclopropylideneamine. Only in the case of allylmagnesium chloride did the reaction lead to aziridines in high yield. Further deprotection toward N-unprotected 1-substituted cyclopropylamines was established, and the absolute configuration was determined. [reaction: see text].

For the efficient synthesis of divergent nitrogen-containing compounds of pharmaceutical and agricultural importance, the development of efficient, complementary, and new synthetic methodologies is essential. One of the key subjects is how to introduce nitrogen atoms in to organic molecules. This review summaries our recent efforts on this issue, focusing on the use of carbamates, acylhydrazines, and ammonia as nitrogen sources.

[Structure: see text] Various alkenes were prepared from phenyl sulfides in a one-pot manner at room temperature by converting them to the corresponding S-aminosulfonium salts with O-mesitylenesulfonylhydroxylamine, followed by treatment with potassium carbonate. Alkenes were formed by cis-elimination of in situ generated phenyl sulfilimines.

Asymmetric radical addition of ethers to enantiopure aromatic N-p-toluenesulfinyl aldimines has been achieved. The requisite radicals were generated by dimethylzinc-air. Lewis acid activation of the N-p-toluenesulfinyl aldimines followed by radical addition gives a mixture of sulfinamide and sulfonamide products. Subsequent treatment of the mixture with dry m-CPBA affords the sulfonamide product in enantiomerically enriched form. [reaction: see text]

A concise total asymmetric synthesis of the tetrahydronaphthridine alkaloid (−)-normalindine has been accomplished via the addition of a laterally metallated 4-methyl-3-cyanopyridine to a sulfinimine (N-sulfinyl imine) as the key step.

The reaction of alkene-tethered alpha-ketocarboxylic acid derivatives with monosubstituted hydrazines allows highly substituted cis-cyclopentapyrazolidine ring systems to be constructed rapidly. Successful cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids accelerate these reactions. alpha-Methoxy-alpha,beta-unsaturated esters are suitable alkene components, as are alkenes having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon. alpha-Ketoesters, alpha-ketoamides, and alpha-ketothioesters can be employed. Various hydrazines substituted with N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers interconvert under the reaction conditions.

[Structure: see text] A highly enantioselective synthesis of alpha-dehydroaminoacids with a stereogenic center in the gamma position through copper-catalyzed asymmetric conjugate addition of diethylzinc to alpha,beta-unsaturated imines using a TADDOL-derived phosphoramidite complex is reported.

Trialkyl phosphites were evaluated for addition reactions to alpha,beta-unsaturated imines. An acidic medium is required to allow consecutive 1,4- and 1,2-addition to occur. In this manner, 3-phosphonyl-1-aminophosphonates, phosphonic acid analogues of glutamate, are obtained in good yields (32-90%). The reaction is mainly influenced by the steric bulk of the nitrogen substituent: less steric N-substituents lead to better yields of the tandem adducts.

A variety of substituted iminocoumarins are prepared in good to excellent yields via a copper-catalyzed multicomponenet reaction of sulfonyl azides, terminal alkynes, and salicylaldehydes or o-hydroxylacetophenones. The method is general, mild, versatile, and efficient. A plausible mechanism for the domino process is proposed.

Double diastereoselective acetate aldol reactions using the N-acetyl thiazolidinethione-based chiral auxiliaries 1 and 2 and chiral aldehydes are described. Aldehydes that bear alpha-alkyl stereocenters exhibit moderate levels of double diastereoselection, while those that bear alpha- or beta-alkoxy substitution exhibit little to no double diastereoselection. In all cases studied, the stereoselectivity of the reaction is dictated by the reagent, not the substrate.

Highly substituted pyrrolidines are prepared by formal cycloaddition of imines to a metal-stabilised ‘Nicholas’ dipole derived from an alkyne–cyclopropane dicobalt complex.

3,3-Dichloro-1-azaallylic anions, generated by deprotonation of alpha,alpha-dichloroketimines 10 with lithium diisopropylamide, reacted with N-sulfonylaldimines 7 to produce the Mannich-type products N-[2,2-dichloro-3-(N-alkylimino)-1,3-diarylpropyl]benzenesulfonamides 11. The latter stable compounds were hydrolyzed at the imino functionality to afford N-[2,2-dichloro-3-oxo-1,3-diarylpropyl]benzenesulfonamides 12 in excellent yields. N-[2,2-Dichloro-3-(N-alkylimino)-1,3-diarylpropyl]benzenesulfonamides 11 were cyclized to cis-3-aryl-2-chloro-2-imidoylaziridines 19 in 81-99% yield with high diastereoselectivity, representing a novel and readily available class of stable 2-chloroaziridines. Finally, a highly stereoselective entry to 2-(aminomethyl)-2-chloroaziridines 27 (70-98% yield; de95-99) was worked out from the reaction of cis-3-aryl-2-chloro-2-imidoylaziridines 19 and sodium cyanoborohydride in the presence of acetic acid. The latter 2-(aminomethyl)aziridines 27 represent stereochemically defined small azaheterocyclic rings which were scarcely reported in the literature.

金沢大学医薬保健研究域薬学系, N-Carbobenzyloxy (Cbz) ketimines were prepared conveniently from N-Cbz amines by oxidation with N-tert-butylbenzenesulfinimidoyl chloride. © The Royal Society of Chemistry 2006.

A general catalytic allylation of simple ketoimines was developed using 1 mol % of CuF.3PPh(3) as catalyst, 1.5 mol % of La(O(i)Pr)(3) as the cocatalyst, and stable and nontoxic allylboronic acid pinacol ester as the nucleophile. This reaction constituted a good template for developing the first catalytic enantioselective allylation of ketoimines. In this case, using LiO(i)Pr as the cocatalyst produced higher enantioselectivity and reactivity than La(O(i)Pr)(3). Thus, using the CuF-cyclopentyl-DuPHOS complex (10 mol %) and LiO(i)Pr (30 mol %) in the presence of (t)BuOH (1 equiv) produced high enantioselectivity up to 93% ee from a range of aromatic ketoimines. Mechanistic studies indicated that LiO(i)Pr accelerates the reaction by increasing the concentration of an active nucleophile, allylcopper.

In this communication, we report an asymmetric Friedel−Crafts reaction of indoles with imines catalyzed by a bifunctional cinchona alkaloid catalyst. This is the first efficient organocatalytic asymmetric Friedel−Crafts reaction of indoles with imines. This reaction is operationally simple and, unprecedentedly, affords high enantioselectivity for a wide range of indoles and both aryl and alkyl imines. This establishes a direct, convergent, and versatile approach to optically active 3-indolyl methanamines, a structural motif embedded in numerous indole alkaloids and synthetic indole derivatives.

Palladium and rhodium catalyzed the addition of H-phosphine oxides to isocyanides to selectively generate alpha-iminophosphine oxides and bisphosphinoylaminomethanes, respectively.

This review describes recent developments in the use of dialkylzincs in radical reactions. In most of the processes reported therein, dialkylzincs act simultaneously as sources of alkyl radicals, as Lewis acids, and as chain transfer agents. A parallel is drawn with the behaviour of trialkylboranes in similar reactions.

A palladium-catalyzed one-step synthesis of imidazoles from imines and acid chlorides is described. A plausible mechanism for this multicomponent reaction is provided, which explains the selective incorporation of two different imines into the final product with perfect regiocontrol. Overall, this catalytic process provides a modular method to prepare imidazoles directly from building blocks that are all either commercially available or readily generated.

Enantiopure diarylmethanols and diarylmethylamines are important intermediates for the synthesis of pharmaceutically relevant products with antihistaminic, antiarrhythmic, diuretic, antidepressive, laxative, local-anesthetic and anticholinergic properties. Furthermore, they have been used as precursors for 1,1-diarylalkyl moieties, which occur in other antidepressants as well as in antimuscarinics and endothelin antagonists. In this critical review catalytic strategies towards enantioenriched diarylmethanols and diarylmethylamines are discussed, including methods for asymmetric carbon-carbon bond formations by aryl transfer reactions to aldehydes and arylimines, respectively, and enantioselective reductions of diarylketones.

A highly enantioselective Mannich reaction between malonate esters and N-Boc and N-Cbz aldimines, catalysed by a bifunctional cinchonine derivative, has been developed; extension of this methodology to encompass the use of 2-substituted-1,3-dicarbonyl nucleophiles allows the formation of adjacent stereocentres, one of which is quaternary, in high relative and absolute stereocontrol.

We describe a general synthetic strategy for the preparation of a series of macrocyclic chiral manganese(III) salen complexes. The developed reaction pathway allows the modulation of the different key groups, namely, the chiral diimine, the bulky substituents in positions 3 and 3', and the linker used in the macrocyclization of the Schiff base. The different complexes presented here illustrate these readily available structural variations. The catalytic properties of the catalysts (5 mol %) were improved for the asymmetric epoxidation of 2,2'-dimethylchromene with NaOCl or H2O2 as oxygen atom donor. A large range of enantiomeric excesses was obtained (ee values from 30% to 96%), depending on the features and the stability of the complexes. The most efficient catalyst, in terms of stereoinduction (ee value = 96%), contains a diiminocyclohexyl moiety, ethyl groups in positions 3 and 3', and a short polyether junction arm.

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with hydrazine to give selectively 6-amino-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones 5. Compounds 5 were further transformed to iminophosphoranes 6 by reaction with triphenylphosphine, hexachloroethane and triethylamine. A tandem aza-Wittig reaction of iminophosphorane 6 with isocyanate or acyl chloride generated previously unreported 3,5-dihydro-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a]pyrimidin-9-ones 10 or 12 in satisfactory yield. X-ray structure analysis of 10 g verified the proposed structure and the reaction selectivity.

The aza-Henry reaction of imines with nitromethane was promoted by cinchona alkaloids and modified cinchona bases to give optically active β-nitroamines. Various N-protected imines were examined as substrates. N-Boc, N-Cbz, and N-Fmoc protected imines gave the best results in terms of chemical yields and enantioselectivities. After a careful screening of a series of chiral bases, very good enantioselectivities up to 94% ee were obtained using a cinchona-based thiourea organocatalyst under the optimized reaction conditions.

Rapid synthesis of quinoline-4-carboxylic acid derivatives has been achieved by reaction of 2-methoxy acrylates or acrylamides with N-arylbenzaldimines in acetonitrile under InCl3 catalysis and microwave irradiation. Isolated yields up to 57% within 3 min have been obtained. The Lewis acid and the microwave activation appeared as crucial parameters for the reaction. The role of indium chloride and ytterbium triflate was specified using 13C NMR data and model theoretical studies.

An equimolar reaction of 2-diazo-1, 2-diarylethanones with N-(2-thienylidene)imines affords 1-substituted-3, 3-diaryl-4-(2-thienyl)-2-azetidinones in excellent yields. The products have been characterized on the basis of satisfactory analytical and spectral (IR, 1H and 13C NMR, MS) data. The mechanism of formation of the products is shown. The antimicrobial activity of the compounds against some Gram(+) and Gram(-) bacteria, and fungi is reported.

Cinchona alkaloids catalyze the enantioselective Mannich reaction of beta-keto esters with acyl aryl imines. The reaction requires 10 mol % of cinchonine or cinchonidine. The reaction products are obtained in good yields (81-99%), high enantioselectivities (80-96% ee), and in diastereoselectivities that range from 1:1 to95:5. The cinchonine-catalyzed reaction provides access to highly functionalized building blocks used in the asymmetric synthesis of a dihydropyrimidone and beta-amino alcohol.

A catalytic asymmetric method for the chemical synthesis of alkaloids containing the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (1) moiety is reported and verified by the enantioselective total synthesis of (+)-minfiensine (4). The central step in this total synthesis is the sequential catalytic asymmetric Heck−N-acyliminium ion cyclization of dienyl carbamate triflate 10, prepared in six steps from 1,2-cyclohexanedione, to give enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole (12) in 75% yield. Iminoethano-9H-carbazole 12 is transformed in six steps to dienyl iodide 17, which undergoes diastereoselective intramolecular Heck cyclization to form pentacyclic intermediate 18. In eight additional steps, this latter intermediate is transformed to (+)-minfiensine (4).

A copper-catalyzed cross-coupling of organotin reagents with imines and acid chlorides is reported. The reaction proceeds efficiently with a range of vinyl-, alkyl-, aryl- and heteroaryl-substituted organostannanes as well as a diverse set of imines of non-enolizable aldehydes. Use of chloroformates also allows for the formation of N-protected alpha-substituted amines. This chemistry has been applied to the synthesis of isoquinoline alkaloid derivatives through the activation of cyclic imines.

Imines have been reduced to amines in high yield, and with excellent chemoselectivity, by catalytic hydrogenation in a continuous flow-reactor, utilising an electrochemically-generated hydrogen source to produce a mixed hydrogen-liquid flow stream.

This review outlines the synthesis of covalent conjugates of oligonucleotides and their analogues that are obtained by reactions of carbonyl compounds with various nucleophiles such as primary amines, N-alkoxyamines, hydrazines, and hydrazides. The products linked by imino, oxime, hydrazone, or thiazolidine groups are shown to be useful intermediates for a wide range of chemical biology applications. Methods for their preparation, isolation, purification, and analysis are highlighted, and the comparative stabilities of the respective linkages are evaluated. The relative merits of incorporation of a carbonyl group, particularly an aldehyde group, into either the oligonucleotide or the ligand parts are considered. Examples of harnessing of aldehyde-nucleophile coupling for the labeling of nucleic acids are given, as well as their conjugation to various biomolecules (e.g. peptides and small molecule ligands), site-specific cross-linking of oligonucleotides to nucleic acid-binding proteins, assembly of multibranched supramolecular structures, and immobilization on functionalized surfaces. Future perspectives of bioconjugation and complex molecular engineering via carbonyl group addition-elimination reactions in nucleic acids chemistry are discussed.

Trifluoromethylated nitrogen-containing molecules have been shown to have important biological effects and their synthesis is in the focus of the pharmaceutical industry. In the last few years, simple nitrogen derivatives of fluoral, i.e. imines, acetals and oxazolidines, have emerged as powerful building blocks to synthesize these target molecules and relevant precursors. This review summarizes the chemistry of these "N-derivatives of fluoral", with special highlight on the syntheses of peptidomimetic units (amino alcohols, amino acids...) and heterocycles (piperidines, beta-lactams...).

This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol. The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain. The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity.