An expedient domino three-component [3+2]-cycloaddition/annulation protocol: regio- and stereoselective assembly of novel polycyclic hybrid heterocycles with five contiguous stereocentres

A novel three-component strategy for the efficient synthesis of unprecedented polycyclic hybrid heterocycles comprising fused, bridged, and spiro rings with five contiguous stereocentres in a regio- and stereoselective manner is described. This transformation proceeds via 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of sarcosine/thiazolidine-4-carboxylic acid and acenaphthoquinone to a series of 2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones and concomitant annulation through an intramolecular aldol-type reaction.     

A new route to thiopyran S,S-dioxide derivatives via an overall ring-enlargement protocol from 3-nitrothiophene

(1E,3Z)-1-Aryl-4-methanesulfonyl-2-nitro-1,3-butadienes (8), derived from the initial ring-opening of 3-nitrothiophene (5), have been found to undergo a facile base-induced cyclization leading to thiopyran S,S-dioxides (9), thus furnishing a further example of effective ring-enlargement from 5- to 6-membered sulfur heterocycles. Compounds 9 are obtained as single racemic mixtures in satisfactory yields; they still contain a nitrovinylic moiety, which can be exploited for further modifications targeted to new derivatives endowed with either synthetic or pharmacological potentialities e.g., in the field of L-type Ca²⁺-channel blockers.     

Synthesis and Stereochemistry of (1S,3S,4S,7R11R)-3-(4-Nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,04,11]undecane

The reaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with glutaraldehyde has been studied. It has been established on the basis of AM1 and PM3 calculations and ¹H NMR spectra recorded in the presence of the shift reagent Eu(fod)₃ that (1S,3S,4S,7R,11R)-3-(4-nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,0^4,11]undecane is formed as the result of the reaction.     

One-pot synthesis of aza-Morita-Baylis-Hillman adducts from α-oxo ketene-S,S-acetals, arylaldehydes and nitriles

Promoted by TiCl₄, a series of α-(1,3-dithiolan-2-ylidene)-β-amino carbonyl derivatives--the aza-Morita-Baylis-Hillman adducts, have been synthesized from α-oxo cyclic ketene-S,S-acetals, arylaldehydes, and nitriles in good to excellent yields. A mechanism involving sequential Morita-Baylis-Hillman and Ritter reactions for this novel one-pot, three-component reaction is described.     

Synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone

Radical-mediated opening of a chiral trisubstituted epoxy alcohol using cp₂TiCl furnished the ‘2-methyl-1,3-diol’ moiety with the desired stereochemistry, which led to a total synthesis of (3R,4S,5S,9S)-3,5,9-trihydroxy-4-methylundecanoic acid δ-lactone 1.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

TiCl4 mediated Michael addition reactions of α-cyanoketene-S,S-acetals with enones

Titanium tetrachloride promoted Michael addition reactions of α-cyanoketene-S,S-acetals 1 with enones 2 have been developed. The polyfunctionalized 2-[1,3]dithiolan-2-ylidene-3-substituted-5-oxo-5-substituted-pentanenitriles 3 were obtained in good to high yields and the corresponding mechanism was also described.     

Synthesis and odor of optically active trans-2,2,6-trimethylcyclohexyl methyl ketones and their related compounds

The synthesis characterized by cationic olefin cyclizations accomplished using ketone enol esters and odor of novel (1R,6S)- and (1S,6R)-2,2,6-trimethylcyclohexyl methyl ketones (5) are described. The stereoselective syntheses of (E)-(1R,6S)- and (E)-(1S,6R)-1-(2,2,6-trimethylcyclohexyl)-2-buten-1-one (6) and (1R,6S)-ethyl 2,2,6-trimethylcyclohexylcarboxylate (7), useful raw materials for flavor and fragrance, starting from the (1R,6S)- and (1S,6R)-5 are also described.     

Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-Villiger lactonization of ketones 4a-i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a-i. A new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).     

Asymmetric synthesis of (−)-(S,S)-homaline

The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)₃-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date.     

Synthesis of α-conhydrine

A synthesis of α-conhydrine has been achieved from trans-(2S,4R)-4-hydroxyproline via diastereoselective Grignard addition, regioselective Baeyer-Villiger reaction, and ring-closing metathesis as the key steps.     

A novel effective electrophile: β-trifluoroacetylketene diphenyldithioacetal S,S-tetroxide

A synthesis of a novel electrophilic reagent--β-trifluoroacetylketene diphenyldithioacetal S,S-tetroxide 3 is described. The reaction of 3 with various electron-rich aromatics such as 1,3-dimethoxybenzene, 2-methylthiophene, N-methylpyrrole, and 2-methylindole was investigated. In the course of these reactions an unusual migration of a phenylsulfonyl group takes place. An easy and ready for scale-up procedure for the synthesis of previously unknown β-aryl, α-phenylsulphonyl substituted α,β-unsaturated trifluoromethyl ketones is reported.     

Synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles en route to murrapanine analogue

A three-step procedure has been developed for the synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles. TBAF was proved to be an effective reagent for dehydrobromination and carbomethoxy deprotection in one step to give 3-[2-(1,3-butadienyl)]-1H-indoles from the corresponding bromo-derivatives. Suitably substituted indolyl-1,3-butadiene has been successfully applied to prepare murrapanine analogue via Diels-Alder reaction.     

Synthesis of isomeric 2-oxazolidinones from (1<Emphasis Type="Italic">R</Emphasis>,2<Emphasis Type="Italic">R</Emphasis>)-and (1<Emphasis Type="Italic">S</Emphasis>,2<Emphasis Type="Italic">S</Emphasis>)-2-amino-1-(4-nitrophenyl)-1,3-propanediols

A synthesis is reported for (4R,5R)-and (4S,5S)-4-hydroxymethyl-5-(4-nitrophenyl)oxazolidin-2-ones and (1′R,4R)-and (1′S,4S)-4-[hydroxy(4-nitrophenyl)methyl]oxazolidin-2-ones from (1R,2R)-and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediols. The effect of the experimental conditions on the formation of these compounds was studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1562–1570, October, 2007.     

Synthesis of DMJ analogs with seven- and eight-membered iminocyclitols

A straightforward synthesis of new hydroxy azepane and azocane with an additional hydroxymethyl side arm (1-deoxymannojirimycin, DMJ analogs) has been achieved from trans-(2S,4R)-4-hydroxyproline via Grignard addition, ring-closing metathesis, and stereoselective osmylation as the key steps.     

Novel intramolecular cyclization of 2-(buta-1,3-dienyl)-3-methylpyrazines and 3-(buta-1,3-dienyl)-4-methyl-1,2,5-oxadiazoles into 5H-cycloheptapyrazines and 4H-cyclohepta-1,2,5-oxadiazoles

2-(Buta-1,3-dienyl)-3-methylpyrazines (5) and 3-(buta-1,3-dienyl)-4-methyl-1,2,5-oxadiazoles (10) were synthesized starting from base-induced reaction of 2,3-dimethylpyrazine or 3,4-dimethyl-1,2,5-oxadiazole with α,β-unsaturated carbonyls. The thus obtained heteroaromatics bearing a butadienyl moiety and a methyl at the adjacent position underwent intramolecular cyclization by the action of LDA to give the corresponding heteroaromatics fused with a seven-membered ring [7 (8)] and [11 (12)] in moderate to high yields.     

The fragmentation reaction of 16R-bromopregnane-3S,20S-diol

16R-Bromopregnane-3S,20S-diol reacted with potassium t-butoxide to afford androst-16-en-3S-ol in a moderate yield via fragmentation reaction. The latter is a key intermediate for the synthesis of 5α-androst-16-en-3-one, as boar sex pheromone, and other steroidal drugs. In addition, 16R,20S-epoxypregnane-3S-ol was also obtained as a major product by changing the reaction solvent.     

Transformations of (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates into pyridine and pyrrole derivatives

New, highly functionalised (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates proved to be useful and versatile reagents in the formation of highly substituted pyridine, N-aminopyridine, pyrrole and pyrido[3,4-c]pyridazine derivatives. The formation of the particular type heterocyclic system is dependent on the starting (1E,3E)-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate. By an appropriate choice of different ester groups it is possible to drive the reactions towards the formation of either pyridine or pyrrole derivatives.     

6,8-Dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione: new heterocyclizations based on SN-methodology. Unexpected formation of the first iso-π-electronic analogue of the still unknown dibenzo[a,o]pycene

N₍₂₎-Oxide and 3-amino derivatives of 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione have been shown to react with primary alkylamines in the presence of an oxidant to produce condensed imidazolines or imidazoles. Both conversions based on S_N^H-strategy represent a new approach to imidazoline-(imidazole-)ring annulation. Heterocyclic analogues of the still unknown dibenzo[a,o]pycene were obtained as a by-products of the above transformations upon using of cyclohexylamine.     

Novel generation and ring closure of 1,3-thiaza-1,3-butadiene S-oxides through thermal cycloreversion of 6H-1,3,5-oxathiazine S-oxides

Heating of 6H-1,3,5-oxathiazine S-oxides efficiently afforded 1,2,4-oxathiazoles through the mechanism involving thermal cycloreversion of the substrates and the subsequent ring closure of the intermediary 1,3-thiaza-1,3-butadiene S-oxides.