Synthesis of new chiral N-arylsulfonyl-1,3-oxazolidin-2-ones from α-amino acids

A variety of new chiral N-arylsulfonyl-1,3-oxazolidin-2-ones were prepared in three steps starting from (d)- and (l)-amino acid. N-Arylsulfonyl amino alcohols, derived from amino acids, were carbonylated with the bis-(trichloromethyl) carbonate (BTC), in the presence of triethylamine, to provide optically pure N-phenylsulfonyloxazolidin-2-ones 3a–f, N-naphthylsulfonyloxazolidin-2-ones 3g–j and N-tosylsulfonyloxazolidin-2-ones 3k–p in good yields.     

Nucleophile-mediated ring expansion of 4-chloromethyl- and 4-mesyloxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-ones to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones: effect of the leaving group and the substituent at C6

A five-step synthesis of 4-chloromethyl- and 4-mesyloxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-ones has been developed. The reaction of N-[(2-benzoyloxy-1-tosyl)ethyl]urea with sodium enolates of α-tosylketones followed by cyclization-dehydration, and debenzoylation gave 4-hydroxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-ones, which were transformed into the 4-chloromethyl- or 4-mesyloxymethyl-derivatives. Treatment of the latter with nucleophilic reagents, such as sodium cyanide, sodium diethyl malonate, sodium thiophenolate, or potassium phthalimide, afforded the corresponding 4,7-disubstituted 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones as a result of ring expansion. The effect of the leaving group and the substitution at the position C6 on the reactivity of the pyrimidines is discussed.     

Phosphine oxide-Sc(OTf)<Subscript>3</Subscript> catalyzed enantioselective bromoaminocyclization of <Emphasis Type="Italic">tri</Emphasis>-substituted allyl <Emphasis Type="Italic">N</Emphasis>-tosylcarbamates

Phosphine oxide-Sc(OTf)₃ catalyzed regio- and enantioselective bromoaminocyclization of tri-substituted allyl N-tosylcarbamates is described. A wide variety of optically active tertiary 5-bromo-1,3-oxazinan-2-ones can be obtained with high regio-and enantioselectivity.     

N-Tosylaziridine, a new substrate for chemical fixation of carbon dioxide via ring expansion reaction under atmospheric pressure

N-Tosylaziridine was found to be a useful substrate for cycloaddition reaction with carbon dioxide. The reaction was successfully catalyzed by lithium bromide under atmospheric pressure to give the corresponding five-membered cyclic urethane, N-tosyl-1,3-oxazolidin-2-one, selectively. It was found that electron-donating nature of the substituent at 2-position of N-tosylaziridine accelerated the reaction, and this tendency allowed us to estimate the reaction mechanism.     

General approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones via nucleophile-mediated ring expansion of tetrahydropyrimidines

A general six-step approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones has been developed. The key step involves a ring expansion reaction of 4-mesyloxymethyl- or 4-tosyloxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-one mediated by nucleophilic reagents.     

Efficient synthesis of functionalized spiro-2,5-dihydro-1,2-λ-oxaphospholes

The reaction of ethyl propiolate with triphenylphosphine (Ph₃P) in the presence of N-alkylisatins led to ethyl 2,2,2-triphenyl-2,5-dihydro-1,2-λ⁵-oxaphosphole-4-carboxylate-spiro-1-alkyl-1,3-dihydro-2H-indol-2-ones in good yield. The reaction of dialkyl acetylenedicarboxylates with Ph₃P in the presence of N-alkylisatins led to dialkyl 2,2,2-triphenyl-2,5-dihydro-1,2-λ⁵-oxaphosphole-3,4-dicarboxylate-spiro-1-alkyl-1,3-dihydro-2H-indol-2-ones and alkyl 4-(alkoxy)-5-oxo-2,5-dihydro-3-furancarboxylate-spiro-1-alkyl-1,3-dihydro-2H-indol-2-ones.     

Synthesis of 4,5,6,7-tetrahydrobenzoxazol-2-ones by a highly regioselective Diels-Alder cycloaddition of exo-oxazolidin-2-one dienes with chalcones

The synthesis of novel of 4,5,6,7-tetrahydrobenzoxazol-2-ones is herein reported. They were obtained in moderate to good yields by a highly regio- and stereoselective Diels-Alder cycloaddition of N-substituted exo-oxazolidin-2-one dienes with chalcones or bis-chalcones as dienophiles.     

Synthesis of optically active 1,3-dioxin-4-one derivatives having a hydroxymethyl group at the 2-position and their use for regio-, diastereo-, and enantioselective synthesis of substituted cyclobutanols

A new method for preparing optically active 1,3-dioxin-4-one derivatives is presented. A series of prochiral 2,2-bis(hydroxymethyl)-1,3-dioxin-4-ones was synthesized by [4+2]cycloaddition of acylketene to protected 1,3-dihydroxy-2-propanone derivatives followed by deprotection of the hydroxyl groups. Desymmetrization of the prochiral dioxinones by lipase-catalyzed monoacetylation afforded optically active 2-(hydroxymethyl)dioxinones. Intramolecular photo[2+2]cycloaddition of ω-alkenyl esters of these alcohols provided an efficient method for regio-, diastereo-, and enantioselective synthesis of cyclobutanols.     

Stereoselective synthesis of 4-hydroxymethyl-1,3-oxazolidin-2-one derivatives from novel 2-hydroxymethylaziridines

A stereoselective and simple method for the synthesis of trans-2-hydroxymethyl-N-alkyl-1,3-oxazolidin-2-ones is described. The synthesis involved the reduction of trans-aziridine-2-carboxylates with LiAlH₄, followed by a ring opening and a cyclization reaction in the presence of methyl chloroformate to afford the target trans-oxazolidinones in completely regio- and stereoselective process. A plausible reaction mechanism has been proposed involving an S_N1 pathway and a detailed computational study of this mechanistic process has been carried out using theoretical calculations.     

Enantioselective Addition of a 2‐Alkoxycarbonyl‐1,3‐dithiane to Imines Catalyzed by a Bis(guanidino)iminophosphorane Organosuperbase

A chiral bis(guanidino)iminophosphorane catalyzes enantioselective addition reactions of a 1,3‐dithiane derivative as a pronucleophile. The chiral uncharged organosuperbase facilitates the addition of benzyloxycarbonyl‐1,3‐dithiane to aromatic N‐Boc‐protected imines to provide optically active α‐amino‐1,3‐dithiane derivatives, which are valuable versatile building blocks in organic synthesis.     

Application of modular nucleophilic glycine equivalents for truly practical asymmetric synthesis of β-substituted pyroglutamic acids

A new series of achiral glycine equivalents have been evaluated with respect to their synthetic utility for the production of β-substituted pyroglutamic acid derivatives. Among them, the piperidine-derived complex was found to be a superior glycine derivative for the Michael additions with various (R)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones representing a general and practical synthesis of sterically constrained β-substituted pyroglutamic acids. In particular, application of complex allowed for the first time preparation of the corresponding isopropyl derivatives thus increasing the synthetic efficiency and expanding generality these Michael addition reactions.     

An efficient,one-pot,three-component procedure for the synthesis of chiral spirooxindolopyrrolizidines via catalytic highly enantioselective 1,3-dipolar cycloaddition

The catalytic, highly regio-, diastereo-, and enantioselective synthesis of a small library of chiral spirooxindolopyrrolizidines via a three-component 1,3-dipolar cycloaddition reaction of azomethine ylides, derived from isatin, with electron-deficient dipolarophiles, 3-(2-alkenoyl)-1,3-oxazolidin-2-ones, is described. A chiral copper(II) complex of cyclohexane-1,2-bis(arylmethyleneamine) catalyzed this process at room temperature. The reaction mechanism is discussed on the basis of the assignment of the absolute configuration of the cycloadducts.     

Synthesis of stereo-defined α-trifluoromethyl (Tfm)-malic units

Aldol reactions of titanium enolates of N-acyl-1,3-oxazolidin-2-ones with ethyl trifluoropyruvate occurred with low to good stereoselectivity depending on the steric properties of the N-acyl group. Attempts to transform the resulting aldols into peptidomimetics incorporating stereo-defined α-trifluoromethyl (Tfm)-malic units are described.     

Formation of 2-halomethylene-4-cyclopentene-1,3-diones and/or 2-halo-1,4-benzoquinones via ring-expansion of 4-ethynyl-4-hydroxy-2,3-substituted-2-cyclobuten-1-ones. Total synthesis of methyl linderone

An in-depth study of the reactions of 4-(ethynyl)-4-hydroxy-2,3-substituted-2-cyclobuten-1-ones with N-bromo- or N-iodosuccinimide, affording in most cases 2-halomethylene-4-cyclopentene-1,3-dione, is described. This reaction was used in a short total synthesis of methyl linderone.     

Synthesis and characterization of chiral mono N-heterocyclic carbene-substituted rhodium complexes and their catalytic properties in hydrosilylation reactions

Different chiral mono-substituted N-heterocyclic carbene complexes of rhodium were prepared, starting from [Rh(COD)Cl]₂ (COD = cyclooctadiene) by addition of free N-heterocyclic carbenes (NHC), or an in-situ deprotonation of the corresponding iminium salt. All new complexes were characterized by spectroscopy methods. In addition, the structures of chloro(η⁴-1,5-cyclooctadiene)(1,3-di-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl] imidazolin-2-ylidene)rhodium(I) (5a), chloro(η⁴-1,5-cyclooctadiene)(1,3-di-[(1R,2S,5R)-2-isopropyl-5-menthylcyclohex-1-yl]imidazol-2-ylidene)rhodium(I) (5b) and chloro(η⁴-1,5-cyclooctadiene)(1,3-di-[(2R,4S,5S)-2-methyl-4-phenyl-1,3-dioxacyclohex-5-yl]imidazolin-2-ylidene)rhodium(I) (5i) were analyzed by DFT-calculations. The enantioselective hydrosilylation of acetophenone, ethylpyruvate and n-propylpyruvate with diphenylsilane and hydrolysis was carried out with chiral C₂-symmetrical mono-substituted N-heterocyclic carbene rhodium complexes giving for the first time an enantioselective excess of up to 74% ee in the case of the n-propylpyruvate.     

Heteroaromatic annulation studies on 2-[bis(methylthio)methylene]-1,3-indanedione: efficient routes to indenofused heterocycles

2-[Bis(methylthio)methylene]-1,3-indanedione has been shown to be a useful three carbon 1,3-dielectrophilic synthon for the highly efficient regiospecific synthesis of a variety of indenofused five- and six-membered heterocycles via heteroaromatic annulation. The methodology has been further elaborated to the corresponding N,S-acetals leading to amino substituted heterocycles, thus providing further point of diversity in the newly synthesized heterocyclic frameworks. Further, the facile access to cytotoxic indeno[2,1-c]quinolin-7-ones and the novel polycyclic heteroaromatics demonstrates the versatility of heteroaromatic annulation protocol via α-oxoketene-S,S-acetal in generating novel biologically important polycyclic heteroaromatics.     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Stereoselective synthesis of 3,4-disubstituted pyroglutamates by ring transformation of 5-ylidene-1,3-dioxan-4-ones with N-(diphenylmethylene)-glycinate

N-(Diphenylmethylene)-glycinate gives stereoselective conjugate addition to readily available (E) and (Z)-5-ylidene-1,3-dioxan-4-ones. Hydrolytic cleavage of the imine functionality of the resulting Michael-adducts causes ring transformation to new, optically active 3,4-disubstituted pyroglutamates.     

Molecular geometry and optical activity of N-nitroso-2,2,6,6-tetramethylpiperidines generated by spontaneous crystallization and inclusion complexation with optically active diols

Three sterically strained N-nitrosamines and their inclusion complexes with optically active diols (TADDOLs) were obtained and their solid state crystal structures are described. Owing to the formation of N-nitroso-4-hydroxy-2,2,6,6-tetramethylpiperidine 2 as spontaneously resolvable conglomerate crystals (space group P3₂) its solid state CD was measured. The crystal structures of the inclusion complexes revealed that in all cases the guest nitrosamines assume chiral conformations as seen by their chiroptical spectra. The optically active nitrosamines are configurationally labile and rapidly racemize in solution. The solid state structures revealed that in order to avoid an allylic 1,3-strain [A^(1,3)], caused by an interaction of the nitrosamino group with the methyl substituents, the piperidine ring in 1 and 2 assumes a chair conformation significantly flattened at the amino nitrogen whereas in the 4-oxo derivative 3 the piperidine ring assumes a twist-boat conformation.     

A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction

The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na₂S₂O₄ in dioxane/water at reflux.