Organocatalytic enantioselective formal synthesis of bromopyrrole alkaloids via aza-Michael addition

An unprecedented organocatalytic enantioselective formal synthesis of bromopyrrole alkaloid natural products is reported. An organocatalytic aza-Michael addition using pyrroles as the N-centered nucleophile is utilized as the enantioselective step to construct the nitrogen-substituted stereogenic carbon center in bromopyrrole alkaloids in good yield and excellent enantioselectivity. The aza-Michael product is converted via lactamization using a Staudinger-type reductive cyclization to the key intermediate, which was previously used in the total synthesis of bromopyrrole alkaloid natural products.     

Total synthesis of the 2,6-disubstituted piperidine alkaloid (−)-andrachcinidine

The total synthesis of the 2,6-disubstituted piperidine alkaloid (?)-andrachcinidine is reported using Keck’s asymmetric allylation, Sharpless epoxidation, nucleophilic substitution, and intramolecular aza-Michael addition as the key steps.     

Regiospecific synthesis of 2,6-bis-indazol-1-ylpyridines from 2,6-bis-hydrazinopyridine

The synthesis of 2,6-bis-hydrazonopyridines from 2,6-bis-hydrazinopyridine and the conversion of these bis-hydrazones into 2,6-bis-indazol-1-ylpyridines were studied. The conversion of bis-haloarylhydrazones to bis-indazoles was systematically optimized using iron and copper mediated reactions and various bases and ligands. By varying solvent, base, transition metal, and ligand, a novel regiospecific route to the 2,6-bis-indazol-1-ylpyridine class of ligands was developed.     

Organocatalytic enantioselective synthesis of quinolizidine alkaloids (+)-myrtine, (−)-lupinine, and (+)-epiepiquinamide

The organocatalytic synthesis of quinolizidine alkaloids (+)-myrtine, (−)-lupinine, and (+)-epiepiquinamide is described. It involved, as the key step, an enantioselective intramolecular aza-Michael reaction (IMAMR) catalyzed by Jørgensen catalyst I, affording the common precursor with high enantioselectivity. This compound was subsequently transformed into the three alkaloids in a highly diastereoselective manner.     

Target-oriented multifunctional organocatalysis for enantioselective synthesis of bicyclo[3.3.1]nona-2,6-dien-9-ones. A formal asymmetric synthesis of huperzine A

A target-oriented highly enantioselective multifunctional organocatalytic approach has been developed to construct the bicycle-[3.3.1]nona-2,6-dien-9-one core of (?)-huperzine A for the first time, with up to 95% ee in the gram-scale procedure. The newly established methodology is also eligible to synthesize a variety of bicyclo[3.3.1]nona-2,6-dien-9-ones in high enantiopurities, and thus is useful for the future development of novel huperzine A analogs with medicinal interests.     

Enantioselective organocatalytic intramolecular aza-Michael reaction: a concise synthesis of (+)-sedamine, (+)-allosedamine, and (+)-coniine

The intramolecular aza-Michael reaction of carbamates bearing remote alpha,beta-unsaturated aldehydes under organocatalytic conditions took place with good yields and excellent ee's when J?rgensen catalyst IV was used in the process, giving rise to the enantioselective formation of several five- and six-membered heterocycles. The developed methodology was applied to the synthesis of three piperidine alkaloids.     

Organocatalytic asymmetric aza-Michael reaction: enantioselective addition of O-benzylhydroxylamine to chalcones

A novel organocatalytic approach for aza-Michael reaction of chalcones using commercial and non-expensive O-benzylhydroxylamine and a readily available organocatalyst is provided. The use of this simple protocol results in β-keto hydroxylamines in up to 60% ee, thus extending the generality of the catalytic enantioselective aza-Michael reaction.     

Stereoselective synthesis of fluorinated 2,3-dihydroquinolin-4(1H)-ones via a one-pot multistep transformation

A new organocatalytic one-pot multistep transformation via Knoevenagel condensation/aza-Michael addition/electrophilic fluorination has been developed. Simple starting materials were used under mild conditions to construct fluorinated 2,3-dihydroquinolin-4(1H)-one derivatives in good to high yields (up to 98%) and diastereoselectivities (dr up to 99/1).     

A Synthetic and Stereochemical Study of 2,6-Diaroyl-3,5-Diaryl-4-Ethyltetrahydro-1,4-Thiazine-1,1-Dioxides

Double aza-Michael addition of ethylamine over 2,2'-sulfonylbis(1,3-diarylprop-2-en-1-ones) gave the previously unknown title compounds in moderate yields. The decreased yields of the title compounds compared to 2,6-diaroyl-3,5-diaryltetrahydro-1,4-thiazine-1,1-dioxides or the corresponding 4-methyl derivatives is explained on the basis of steric size of the nucleophile. The structure and stereochemistry of the thianes have been deduced from elemental analyses and spectroscopic data.     

An organocatalytic cascade approach toward polysubstituted quinolines and chiral 1,4-dihydroquinolines-unanticipated effect of N-protecting groups

A matter of protection: The outcome of a divergent organocatalytic aza-Michael/aldol cascade process toward quinolines and 1,4-dihydroquinolines depends on the choice of the N-protecting group (see scheme; TEA = triethylamine, TMS = trimethylsilyl). Use of an electron-donating sulfonyl group results in an unanticipated aza-Michael/aldol/aromatization cascade to give polysubstituted quinolines (right). In contrast, chiral 1,4-dihydroquinolines are obtained with an electron-withdrawing sulfonyl group (left).     

Organocatalytic enantioselective aza-Michael reaction of nitrogen heterocycles and alpha,beta-unsaturated aldehydes

The asymmetric organocatalytic aza-Michael reaction of several nitrogen heterocycles and alpha,beta-unsaturated aldehydes has been studied in detail; under the optimised conditions, the conjugate addition products have been obtained in high to excellent enantioselectivities.     

Synthesis and reactions of 6-chloro-2,2,6-trimethyl- and 2,6-dichloro-2,6-dimethyl-1-oxa-2,6-disilacyclohexanes

6-Chloro-2,2,6-trimethyl- and 2,6-dichloro-2,6-dimethyl-1-oxa-2,6-disilacyclohexanes have been synthesized. Their behavior in alcoholysis, amination, acetoxylation, and reduction reactions has been studied.     

Synthesis and reactions of 6-chloro-2,2,6-trimethyl- and 2,6-dichloro-2,6-dimethyl-1-oxa-2,6-disilacyclohexanes

6-Chloro-2,2,6-trimethyl- and 2,6-dichloro-2,6-dimethyl-1-oxa-2,6-disilacyclohexanes have been synthesized. Their behavior in alcoholysis, amination, acetoxylation, and reduction reactions has been studied.     

2,6-Diazaspiro[3.3]heptanes: synthesis and application in Pd-catalyzed aryl amination reactions

A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of N-Boc- N'-aryl-2,6-diazaspiro[3.3]heptanes.     

Stereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates

Diastereoselective synthesis of cis-2,6-disubstituted piperidines from 1,2-cyclic sulfamidates is described. Regioselective ring-opening reactions of 1,2-cyclic sulfamidates derived from L-phenylalanine, alanine, valine, norvaline with the ketal protected acetylide with a phenyl substituent proceed smoothly to form the N-sulfamate intermediates which on acidic hydrolysis give alkynylated amines with the ketal group intact. Hydrogenation of the alkynylated amines, debenzylation, ketal deprotection, subsequent cyclization (of aminoketones) and stereoselective hydrogenation of the cyclic iminium ion intermediates afford the corresponding cis-2,6-disubstituted piperidines in high diastereoselectivity (98%?≥?d.e.) with good chemical yields (68–86%). The present approach provides a novel route for the stereoselective synthesis of cis-2,6-disubstituted piperidines.     

An efficient synthesis of 2-substituted 6-methylpurine bases and nucleosides by Fe- or Pd-catalyzed cross-coupling reactions of 2,6-dichloropurines

Fe-catalyzed cross-coupling reactions of 9-substituted or protected 2,6-dichloropurines with 1 equiv of methylmagnesium chloride gave regioselectively 2-chloro-6-methylpurines in good yields. The same reactions with 3 equiv of methylmagnesium chloride or Pd-catalyzed reactions with trimethylaluminum afforded 2,6-dimethylpurines. The 2-chloro-6-methylpurines underwent another coupling with phenylboronic acid to give 6-methyl-2-phenylpurines. All reactions were perfomed for Bn- and THP-protected purine bases as well as for acyl-protected ribosides and 2-deoxyribosides. After deprotection, free purine bases and nucleosides were obtained.     

Solvent-free double aza-Michael under ultrasound irradiation: diastereoselective sequential one-pot synthesis of pyrrolidine Lobelia alkaloids analogues

Novel 2,5-meso-pyrrolidines have been straightforwardly synthesized from readily available symmetrical double Michael acceptors. The key step rested on an aza-Michael addition of primary alkylamines to bis-enones. Competitive Rauhut-Currier and aza-Michael reactions have been highlighted in protic solvent. Ultrasound activation associated with solvent-free conditions led to the expected pyrrolidines in quantitative yields and excellent stereoselectivities. The optimized conditions have been extended to the sonochemical synthesis of pyrrolidine Lobelia alkaloids analogues in short sequences.     

Application of 2,6-diazidopurine derivatives in the synthesis of thiopurine nucleosides

2,6-Diazidopurine derivatives undergo double azide–alkyne 1,3-dipolar cycloaddition (CuAAC) reactions to give 2,6-bis-(triazolyl)purine analogs, which undergo selective nucleophilic aromatic substitution with various thiols at C(6). This synthetic sequence produces nucleoside analogs with 6-alkyl/arylthio-2-(4-alkyl/aryl-1H-1,2,3-triazol-1-yl)purine bases. In contrast, glycosylated 2,6-diazidopurines exhibit reasonable C(2) selectivity in nucleophilic aromatic substitution with thiols. This permits the synthesis of 2-alkylthio-6-azido-purine derivatives, which after CuAAC provide the corresponding 2-alkylthio-6-triazolyl-purine analogs. The latter are also susceptible to nucleophilic aromatic substitution with amines at C(6). The above mentioned compounds are useful molecular platforms in terms of medicinal chemistry.     

Highly efficient two-step selective synthesis of 2,6-dimethylnaphthalene

2,6-Dimethylnaphthalene (2,6-DMN), a key raw material for poly(ethylene naphthalate) (PEN), was selectively synthesized via a two-step process in an overall 66% yield from commercially available 4-bromotoluene and 3-methyl-3-buten-1-ol. The ligand-free Heck reaction of the starting materials produced γ-(p-tolyl)-substituted aldehyde that was cyclized with an acid to give 2,6-DMN after in situ oxidation. No other isomers of 2,6-DMN were found.     

Parallel synthesis of 4-amino-2,6-dialkylamino-pyridines

In this Letter a fast and useful parallel synthesis approach to 4-amino-2,6-dialkylamino-pyridines is described starting from commercially available 2,6-difluoro-3,5-dichloro-pyridine. Both symmetrical and unsymmetrical derivatives have been synthesized respectively in two or three steps in good yields. The method described is mild, adaptable to combinatorial purposes and applicable to a variety of amines.