Synthesis of 1,2,3,4-tetrahydropyrido- [2,3-<Emphasis Type="Italic">b</Emphasis>]pyrazine-2,3-dione derivatives with a chiral substituent at the nitrogen atom

The sequence of steps including nucleophilic substitution of the chlorine atom in 2-chloro-3-nitropyridine by esters of optically active phenylalanine, reduction of the nitro group, acylation with ethyl oxalyl chloride, and intramolecular cyclization, leads to the synthesis of derivatives of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-2,3-dione with a chiral substituent at the nitrogen atom. It was established that, depending on the conditions of carrying out the cyclization, the parallel formation of derivatives of imidazo[4,5-b]pyridine is possible. Conditions were found for selectively carrying out the cyclization under with only structures of pyrazines or imidazole condensed with pyridine were formed. Dedicated to Academician J. Stradins in connection with his 75th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 237-243, February, 2009.     

An alternative approach towards novel heterocycle-fused 1,4-diazepin-2-ones by an aromatic amidation protocol

The synthesis of new 1,4-diazepin-2-one derivatives starting from glycine or alanine aminoacids is presented. The key cyclization step includes the PIFA mediated formation of N-acylnitrenium ions and their subsequent intramolecular trapping by an (hetero)aromatic ring. The so-promoted aromatic amidation process takes place without loss of enantiomeric purity when optically pure methoxyamide precursors are employed.     

Highly enantioselective hydrogenation of exocyclic double bond of N-tosyloxazolidinones catalyzed by a neutral rhodium complex and its synthetic applications

A highly enantioselective synthesis of optically active N-tosyl-4-alkyl-1,3-oxazolidin-2-ones based on the asymmetric hydrogenation of the trisubstituted exocyclic double bond of N-tosyl-4-alkylidene-1,3-oxazolidin-2-ones under the catalysis of neutral [Rh(COD)Cl]₂ (COD=1,5-cyclooctadiene) and (S)-(+)-DTBM-SEGPHOS was developed. The utility of this highly enantioselective reaction was exemplified by the synthesis of optically active amino acids, amino alcohols, and piperidine derivatives.     

Regioselective synthesis of pyrrolin-3-ones and 2,3,4,5-tetrahydro[1,3]-oxazines from N-vinylic amidines

Achiral and optically active N-vinylic amidines are obtained by simple addition of amidines to acetylenic esters. Thermal intramolecular cyclization of these substrates containing a carboxylate group in position 3 gives pyrrolin-3-ones. The enaminone character of these compounds towards propargyl bromide, diethyl azodicarboxylate, diethyl acetylenedicarboxylate, ethyl propiolate and phenyl isocyanate is studied and functionalized pyrrolin-3-one derivatives are obtained. The reaction of the pyrrolinones prepared with diethyl ketomalonate leads to new 1,3-oxazine derivatives.     

Oxyoxazolidinone as an auxiliary for heterocyclic synthesis. Enantioselective formation of N-unprotected 2-pyrrolidones from selenocarboxylate and allylamines via radical cyclization

Optically active N-unprotected 2-pyrrolidones were prepared in a highly stereoselective manner through radical cyclization reaction of oxyoxazolidinone. Asymmetric induction from the oxyoxazolidinone ring system was generally high and oxazabicyclo[3.3.0]octanones were obtained in good yields. Treatment of the bicyclic compounds with TBAF resulted in the one-step cleavage of C-O and C-N bond, directly giving secondary 2-pyrrolidones in good yields along with recovery of chiral mandelic acid without loss of optical purity. The use of the present procedure gave optically active 4,5-disubstituted N-unprotected 2-pyrrolidone derivatives trans selectively.     

A new synthesis of enantiomerically pure α- and β-amino acid derivatives using aziridinyl anions

Optically active sulfinylaziridines having a 4-methoxyphenyl group on their nitrogen atom were synthesized from optically active 1-chloroalkyl p-tolyl sulfoxide and an imine derived from benzaldehyde and p-anisidine stereoselectively in good overall yields. The sulfinylaziridines were treated with ethylmagnesium bromide or tert-butyllithium to afford aziridinylmagnesiums or aziridinyllithiums, respectively, in quantitative yields. Cross-coupling of the aziridinylmagnesiums with iodoalkanes in the presence of Cu(I) iodide gave tri-substituted aziridines in high yields from which enantiomerically pure β,β-disubstituted β-amino acid derivatives were synthesized. A β-amino acid derivative having deuterium at the stereogenic center was also realized by this method. On the other hand, from the aziridinyllithium, enantiomerically pure quaternary phenylalanine and quaternary aspartic acid derivatives were synthesized.     

Studies on palladium-catalyzed enantioselective cyclization of 3,4-allenylic hydrazines with organic halides

A convenient route to optically active pyrazolidine derivatives from Pd(0)/(R,R)-Bn-BOX-catalyzed enantioselective cyclization of 3,4-allenylic hydrazines in the presence of organic halides has been developed, the ee value is 75-84%. The absolute configuration of the products was determined by the conversion of one of the products to a known product prepared in this group. The reaction may proceed via the oxidative addition, intermolecular carbometallation of the allene moiety forming a π-allylic palladium intermediate, and the intramolecular enantioselective allylation.     

Synthesis of nitrogen heterocycle-fused 1,2,4-benzothiadiazine-1,1-dioxide, quinazolinone, and pyrrolidinone derivatives with a guanidine joint via sequential aza-Wittig reaction/intramolecular NH-addition cyclization/nucleophilic substitution ring closure methodology, using functionalyzed carbodiimides as key intermediates

We achieved efficient synthesis of imidazo- and pyrimido[1,2-b]benzo-1,2,4-thiadiazine-1,1-dioxides by the tandem aza-Wittig reaction/intramolecular NH-nucleophilic addition/NH-nucleophilic substitution cyclization methodology, involving sulfonamide ester-containing carbodiimides as the key intermediates. Similarly, imidazo[2,1-b]quinazolinones, imidazo[1,2-a]pyrimidinediones, and imidazo[1,2-a]imidazolidinediones were also synthesized through the aza-Wittig reaction-tandem cyclization strategy. When homochiral (l)-alanine methyl ester was incorporated as a building block into the corresponding iminophosphorane starting materials, we obtained optically active imidazo[1,2-b]benzo-1,2,4-thiadiazine and imidazo[2,1-b]quinazolinone derivatives without any racemization through the one-pot tandem methodology.     

SmI2-induced reductive cyclization of optically active β-alkoxyvinyl sulfoxides with aldehyde

SmI₂-induced reductive cyclization of optically active (E)- and (Z)-β-alkoxyvinyl sulfoxides with aldehyde was developed for the construction of several stereoisomers of tetrahydropyran derivatives.     

Regioselective synthesis of flavone derivatives via DMAP-catalyzed cyclization of o-alkynoylphenols

A catalytic amount of DMAP promoted cyclization of o-alkynoylphenols via a 6-endo cyclization mode leading to flavone derivatives in high yields without forming 5-exo cyclized aurone derivatives. Utilizing this method, methoxy substituted flavone and alkyl substituted γ-benzopyranone derivatives were synthesized.     

Palladium-catalyzed synthesis of novel optically active tryptophan analogues

[reaction: see text] Both unsaturated proline derivatives and optically active tryptophan analogues have been obtained via Pd-catalyzed cyclization of aniline-containing acetylenic amino acids. The side chain length of the cyclization precursor determines which one of the two possible products will be formed.     

6-endo Versus 5-exo radical cyclization: streamlined syntheses of carbahexopyranoses and derivatives by 6-endo-trig radical cyclization

Three factors that can direct 6-endo radical cyclization over 5-exo ring closure: substitution at C-5, vinyl radical cyclization and ring strain, have been considered in the context of the preparation of carbapyranoses from carbohydrate derivatives. As a result, alkyl radicals in substrates containing a strain inducing 2,3-O-isopropylidene ring, and vinyl radical in non-strained compounds undergo a completely regioselective 6-endo-trig ring closure leading to carbasugar derivatives.     

Rhodium-catalyzed reductive cyclization of 1,6-enynes and stereoselective synthesis of the putative structure of lucentamycin A and its stereoisomers

A Rh-catalyzed diastereoselective reductive cyclization, mediated by hydrogen, of optically active 1,6-enynes using chiral BINAP was successfully applied to the total synthesis of four stereoisomers of the proposed structure of lucentamycin A. In order to synthesize two of these four stereoisomers, we successfully constructed chiral proline derivatives bearing cis-carbon substituents at C2 and C3 positions based on Krische’s methodology, which has very rarely been reported. Anti-proliferative activities on HCT-116 cell line and NMR data of these four stereoisomers were compared with those of naturally occurring lucentamycine A. The results show that the proposed structure of lucentamycin A needs revision.     

Bioinspired polyene cyclization promoted by intermolecular chiral acetal-SnCl4 or chiral N-acetal-TiCl4: investigation of the mechanism and identification of the key intermediates

New strategies using chiral acetal or chiral mixed-acetal in the presence of Lewis acids (SnCl4 or TiCl4) to promote polyene cyclization reaction are described. Acetal-promoted and mixed-acetal-promoted polyene cyclization products are very versatile and can easily be converted into various optically active tricyclic and tetracyclic terpenoids. One of the derivatives of the cyclization products was obtained up to 96% ee after a single recrystallization. In addition, an oxocarbenium intermediate was found to be responsible for the good asymmetric selectivity for this type of reaction.     

Stereo- and regiocontrol in ene-dimerisation and trimerisation of 1-trimethylsilyl-3-phenylcyclopropene

1-Trimethylsilyl-3-phenylcyclopropene and its 2D-analog undergo a highly stereocontrolled ene-reaction to give a single dimer. Further reaction leads to one or more trimers derived through two ene-reactions. The dimer formed easily undergoes cycloaddition with active dienes and nitrile oxides while the trimers do not react under the same conditions. The first enantioselective example of an ene-reaction of cyclopropene derivatives using optically active 1-trimethylsilyl-3S-phenylcyclopropene is also discussed.     

Stereoselective 5-exo-trig radical cyclization in the enantioselective synthesis of Pregabalin

A practical stereoselective 5-exo-trig radical cyclization procedure was developed in order to prepare enantiomerically pure GABA derivative precursors (4-alkyl-pyrrolidin-2-ones). This procedure allows much more rapid access to optically pure GABA derivatives, such as the powerful antiepileptic agent (S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregabaline).     

Synthesis and separation of substituted cyclopropane carboxylic acid amide isomers

The phase-transfer-catalyzed cyclization of optically active malonic acid allylic ester amides yields bicyclic cyclopropane carboxamide lactone derivatives. The two diastereomers obtained could be separated in some cases by simple column chromatography yielding the pure isomers.     

Diastereoselective reduction of enantiopure N-p-toluenesulfinyl ketimines derived from pyridyl ketones

DIBAL reduction of enantiopure N-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones bearing an additional substituent on the 6-position of the pyridine ring afforded the related N-p-toluenesulfinyl amines with high yields and diastereoselectivities. The results of a number experiments exploring the conversion of a optically active 1-substituted N-toluenesulfinyl 1-(6-bromopyridin-2-yl)methylamine in a number of more complex pyridine derivatives with maintenance of the toluenesulfinyl group N-protecting group is also reported.     

Radical cyclization of exo-methylene furanose derivatives: an expedient approach to the synthesis of chiral tricyclic nucleosides and benzannulated oxepine derivatives

Tributyltin radical mediated cyclization of the glucose derived exo-methylene furanose derivatives 5a-c led to the highly functionalized cis-fused bicyclic ethers 6a-c. The product could subsequently be transformed to the optically active tricyclic nucleoside analogue 8 or oxepine derivative 9.     

An efficient double 1,2-addition reaction of 2,3-allenoates with allyl magnesium chloride

In this paper, it was reported that double 1,2-addition reaction of 2,3-allenoates with allyl magnesium chloride at room temperature in the absence of any transition metal catalyst provides an efficient method for the synthesis of tertiary alpha-allenols. The optically active allenol could be prepared from the reaction of the optically active 2,3-allenoate without obvious racemization of the axial chirality. Under different reaction conditions, cyclization reactions of alpha-allenol 2i prepared have been studied for the synthesis of different 2,5-dihydrofuran derivatives.