Electronic structure and aromaticity of planar singlet π-electron monocyclic π2 carbenes

Induced -electron ring currents and relative diamagnetic susceptibilities of planar singlet -electron monocyclic ² carbenes are calculated in the coupled variant of perturbation theory in the CNO method. It is shown that the parity theorem holds for charged planar ² and ² carbenes formally generated by the detachment of a proton or a hydride ion from alternant hydrocarbons. This leads, in such carbenes, to the same energies of singlet-singlet and singlet-triplet transitions, electric polarizabilities, conjugation energies, -electron ring currents, diamagnetic susceptibilities and current contributions to chemical shifts, whereas the charge contributions to the latter are of opposite signs.Donbas State Academy of Building and Architecture, 1 Derzhavina St., 339023 Makeevka, Donetsk Region, Ukraine. Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 32, No. 3, pp. 157–162, May–June, 1996. Original article submitted December 5, 1994.     

Induced ring currents and aromaticity of planar singlet π-electronic monocyclic carbenes

The induced -electronic ring currents and the relative diamagnetic susceptibilities of planar singlet -electronic monocycic carbenes with the general formula C_nH_2n–1(n = 3–10) were calculated within the framework of a linked variant of perturbation theory using the PPP method; this permitted their inclusion in the general aromaticity-antiaromaticity scale of organic compounds. It was shown that these carbenes can act as intermediates in a number of thermal rearrangements.Translated from Teoreticheskaya i Éksperimental'yana Khimiya, Vol. 29, No. 1, pp. 4–48, January–February, 1993.     

Diastereoselective and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides

A diastereo- and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides has been designed by the strategy of the 1,3-dipolar cycloaddition reaction of a Vasella-type nitrone. The reaction leads to (1′R)- and (1′S)-4′-aza analogues of 2′,3′-dideoxythimidine and fluorouridine, in enantiomerically pure forms.     

Microbial deracemization of α-substituted carboxylic acids: control of the reaction path

A novel approach to preparing optically active α-substituted carboxylic acids using the whole cells of Nocardia diaphanozonaria JCM 3208 is described. When 2-phenylthiopropanoic acid and 2-methyl-3-phenylpropanoic acid were subjected to the reaction under aerobic conditions, the oxidation reaction proceeded preferentially rather than deracemization of these substrates. Herein, we report the design of reaction conditions to increase the deracemization activity in preference to oxidation reactions. In addition, we have successfully detected a metabolic intermediate in the reaction mixture of 2-methyl-3-phenylpropanoic acid, which indicates that the deracemization is a competitive reaction against the β-oxidation pathway of fatty acid metabolism.     

Synthesis of 4′-substituted 2′-deoxy-4′-thiocytidines and its evaluation for antineoplastic and antiviral activities

4′-Azido- (7), 4′-C-fluoromethyl- (8) 4′-C-ethynyl- (9) and 4′-C-cyano- (10) 2′-deoxy-4′-thiocytidines have been synthesized. In this study, it was found that the isolated yield of 4′-thiouracil nucleoside 13 in a Lewis acid-promoted Vorbrüggen-type glycosidation utilizing 12 was better than that of the electrophilic glycosidation reaction between silylated uracil and 11. This improved result prompted us to perform the glycosidation utilizing 36 and 43 for the synthesis of 37 and 44. Introduction of the azido group was carried out by nucleophilic substitution in the 4′-benzoyloxy derivative 22a. On the other hand, 9 and 10 were synthesized by way of the chemical manipulation of the hydroxymethyl group at the 4′-position of 46.Evaluation of the antineoplastic activity of 2 and 7–10 against human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines revealed that 4′-azido- (7) and 4′-C-fluoromethyl- (8) derivatives exhibited cytotoxic activity whereas no cytotoxicity was observed in the 4′-C-ethynyl- (9) and 4′-C-cyano- (10) derivatives as well as the parent compound 2. Compound 7 was also found to possess promising antiviral activity against VZV and HSV-1 without any cytotoxity against HEL host cells. It is noteworthy that 7 exhibited potent inhibitory activities against the thymidine kinase-deficient (TK^?) mutant of VZV and HSV-1.     

Practical synthesis of 1′-substituted Tubercidin C-nucleoside analogs

Several 1′-substituted analogs of Tubercidin C-nucleosides were prepared using a highly convergent synthesis. Good to high diastereoselectivity was achieved using a variety of nucleophiles targeting the 1′-position. The source for this stereoselectivity is herein proposed. It is thought to be attributed to a temperature-dependent chelation of the incoming nucleophile to either the 2′- or 3′-benzyloxy ether of the ribose core.     

Reaction of 2-formyl-1,3-cyclanediones with N,N′-substituted 1,1-diamino-2-nitroethylenes

Reaction of 2-formyldimedone and 2-formyl-1,3-indanedione with 1,1-di(2-hydroxyethylamino)- and 1,1-di(4-morpholyl)-2-nitroethylenes produces 2-[3,3-di(2-hydroxyethylamino)-2-nitroprop-2-en-1-ylidene]- and 2-[3,3-di(4-morpholyl)-2-nitroprop-2-en-1-ylidene]-5,5-dimethyl-1,3-cyclohexanediones and the 1,3-indanediones, respectively. The reaction of the same 2-formyl-1,3-cyclanediones with 2-nitromethyleneimidazolidine yields 8,8-dimethyl-4-nitro-6-oxo-1,2,3,6,7,8-hexahydroimidazo[1,2-a]quinoline and 4-nitro-6-oxo-1,2-dihydro-6H-imidazo[1,2-c]-4-azafluorene.Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lanet.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 330–333, March, 1999.     

The rate of cyclization of 2′- and 4′-substituted diphenylamine-2-carboxylic acids in sulfuric acid as a function of the electronic properties of substituents

The kinetic regularities of cyclization of 2′- and 4′-substituted diphenylamine-2-carboxylic acids in sulfuric acid were determined. The rate of cyclization of diphenylamine-2-carboxylic acids is linearly dependent on the nature of substituents in the meta-position relative to the reaction site in accordance with the two-parameter Hammett equation.     

Diastereoselective aminocarbonylation of a steroidal iodoalkene with 2,2′-diamino-1,1′-binaphthalene in palladium-catalysed reactions

A palladium-catalysed aminocarbonylation of a steroidal iodoalkene (17-iodo-5α-androst-16-ene) model compound with 2,2′-diamino-1,1′-binaphthalene as an N-nucleophile was carried out. The combination of a steroidal skeleton possessing central elements of chirality and a binaphthyl moiety with axial chirality was carried out resulting in a novel type of steroidal carboxamides. The binaphthalene—steroid conjugates are potential 5α-reductase inhibitors. Both epimers of the monocarboxamide and those of the dicarboxamide, formed with moderate diastereoselectivity, were isolated and fully characterised.     

Synthesis of Optically Active trans-2-Aminocyclopropanecarboxylic Esters

The research on optical alicyclic β-amino acids has recently attracted increasingly attention due to their significant pharmacological properties endowed by rigid frameworks, stable conformation1. Numerous biologically active peptides, β-lactams and some other natural products2 contain optical alicyclic β-amino acids. Cyclopropyl-modified alanines have been proved to be useful intermediates in medicine synthesis because of their rigid framework and reactive functional groups (amino and carb…     

Synthesis of 1′-substituted 4′,4′-dimethyl-6′-methoxy-4′H-spiro[cyclohexane-1,3′-isoquinolines]

The reaction of 1-(4-methoxyphenyl)-1-(1-methylcyclohexyl)ethanol with nitriles in concentrated sulfuric acid afforded 1′-substituted 6′-methoxy-4′,4′-dimethyl-4′H-spiro[cyclohexane-1,3′-isoquinolines] as a result of consecutive Wagner-Meerwein rearrangement and Ritter reaction.     

Diastereoselective synthesis of highly functionalized β2,2,3-substituted amino acids from 4-substituted-1,3-oxazinan-6-ones

1,3-Oxazinan-6-ones were used to generate substituted β^2,2,3-substituted amino acid derivatives. The enolates of 1,3-oxazinan-6-ones were trans-selectively intercepted with electrophiles. This alkylation was subsequently optimized for a one-pot dialkylation to form 5,5-disubstituted oxazinanones. The initial 5-monomethylated compounds could be enolized and then diastereoselectively intercepted with different electrophiles to form differentially 5,5-disubstituted products. The 5,5-dialkylated oxazinanones were then transformed to N-methyl β^2,2,3-substituted amino acids by reductive cleavage. Hydrolysis or solvolysis of the oxazinanones afforded β^2,2,3-substituted amino acids or esters, respectively. The chemistry thus provides access to a range of symmetrical and stereopure β^2,2,3-substituted amino acids and further establishes 1,3-oxazinan-6-ones as useful intermediates.     

Experimental and theoretical investigations of absolute stereochemistry and chiroptical properties of enantiopure 2,2′-substituted 9,9′-bianthryls

The absolute stereochemistry of axially chiral 2,2′-X₂-9,9′-bianthryls (X=COOH, COOMe, and Cl) was determined by X-ray analysis of the (+)-quinidine salt of the diacid to be (M)-(−) or (P)-(+). The M isomers of these compounds showed specific rotations of −115, −123, and −32, respectively, in acetone. The circular dichroism (CD) as well as UV spectra of the two M isomers (X=COOMe and Cl) were investigated with the aid of theoretical calculations by the time-dependent DFT (TDDFT) method. The calculations reasonably reproduced the observed CD bands, and suggested a correlation between the signs of p or β′ bands and the absolute stereochemistry.     

Diastereoselective synthesis of chiral α-aminoorganotributyltins via ring-opening of 2-tributylstannyloxazolidines

Reactions of 2-tributylstannyloxazolidines 2a-d (cis or trans), derived from (R)-phenylglycinol protected as N-carbamate, with lithium diorganocuprates in presence of boron trifluoride in diethyl ether provide the corresponding functionalized tributylstannyl-α-aminoalcohols 3-10 with diastereoselectivities close to 85:15 in favour of the (S,R)-isomer. The stereochemical trend is preserved using allyltributyltin as nucleophile and TiCl₂(Oi-Pr)₂ as Lewis acid in dichloromethane. The assignments of the (S,R) or (R,R) configurations in 3-10 were achieved on the basis of physicochemical data combined with a radiocrystallographic structure. Stereochemical preferences were rationalized by consideration of the interactions occurring in the iminium intermediates.     

Enantio- and diastereoselective synthesis of 4′-α-substituted carbocyclic nucleosides

Enantio- and diastereoselective synthesis of 4-α-alkylcarbovir derivatives 5 were achieved based on Sakai's asymmetric alkylation of β-keto esters. The key carbocyclic intermediate 14 was synthesized from 8 via an eleven-step sequence. Coupling of 14 with 2-amino-6-chloropurine followed by desilylation and subsequent hydrolysis gave the target compounds 5 in moderate yields.     

Saturated heterocycles—113: Synthesis and stereochemical investigation of cis- and trans-1-substituted 7,8-dimethoxy-1,4,5,9b-tetrahydro-2H-azeto[2,1-a]isoquinolines

Stereospecific and stereoselective syntheses starting from 1-[bis(hydroxymethyl)methyl)]- (1) and 1-ethoxycarbonyl-methylene-6, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (13) gave cis- and trans-1-chloromethyl- (10, 4a), 1-methyl- (11, 12) and 1-benzyl-1,4,5,9b-tetrahydro-2A-azeto(2,1-a]iso-quinolines (20, 21). The steric structures of the diastereomers were determined'By NMR spectroscopy.     

Cycloaddition of alkynes RCCR′ with free singlet dimethyl germylene Me2Ge

Alkynes RCCR′ exhibit a high and specific reactivity towards free dimethyl germylene Me₂Ge as a typical singlet heavy carbene analogue. New and novel unsaturated² 4-,5-, and 6-membered germa heterocycles with 1–3 Ge atoms are formed, dependent on R and R′ in the 7 alkynes used. Corresponding reaction mechanisms are proposed.     

TMSI-Promoted Diastereoselective Synthesis of 5-(1′-Hydroxy)-γ-butyrolactones

Trimethylsilyl iodide (TMSI) was found to be an efficient catalyst for the vinylogous Mukaiyama aldol reaction of 2-(trimethylsilyloxy)furan with various aldehydes with good diastereoselection. The reaction proceeds rapidly in CH₂Cl₂ affording the corresponding 5-(hydroxy(aryl)methyl)furan-2(5H)-ones in good yields. This method offers significant advantages such as efficiency, generality, and mild reaction conditions with shorter reaction time.

Orbital phase control of the conformations of α- and β-substituted enamines and vinyl ethers

The conformational stabilities of the α- and β-substituted enamines and vinyl ethers were predicted by orbital phase theory and confirmed by ab initio molecular orbital calculations. Cyclic interaction significantly occurs among the nonbonding orbital n _Y for the lone pair on the hetero atom Y (N in the enamines or O in the ethers), the π and π* orbitals of the CC bond, and the σ_C-H or σ*_C-X orbitals on the substituent CH₂X. The cyclic -n _Y-π-σ_C-H-π*- interaction is favored by the orbital phase continuity in the α-substituted molecules, while the cyclic -n _Y-π-σ*_C-X-π*- interaction is favored in the β-substituted molecules. The most stable conformation was then predicted to be synperiplanar or (pseudo)equatorial in the α-substituted molecules and anticlinical or (pseudo)axial in the β-substituted molecules. Received: 8 May 1998 / Accepted: 30 July 1998 / Published online: 16 November 1998     

Diastereoselective Synthesis of P-Chirogenic and Atropisomeric 2,2′-Bisphosphino-1,1′-binaphthyls Enabled by Internal Phosphine Oxide Directing Groups

Diphosphine ligands that merge both axial and P-centered chirality may exhibit superior or unique properties. Herein we report the diastereoselective introduction of P-centered chirality at the 2-position of the axially chiral 2′-(phosphine oxide)-1,1′-binaphthyl scaffold. A lithium–bromide exchange reaction of a 2-bromo-2′-(phosphine oxide)-1,1′-binaphthyl and treatment with dichlorophosphines followed by a nucleophilic organometallic reagent afforded unsymmetrical 2-phosphino-2′-(phosphine oxide)-1,1′-binaphthyls with binaphthyl axial chirality and one or two phosphorus stereocenters with a variety of P substituents. The final diastereomerically pure 2,2′-bisphosphino-1,1′-binaphthyls were obtained by reduction of the phosphine oxide directing group. Preliminary results demonstrated that a ligand with this hybrid chirality could induce higher stereoselectivity in the metal-complex-catalyzed asymmetric hydrogenation of a dialkyl ketone.