Synthesis of 1-azabicyclo[3.1.0]hexane systems

The synthesis of aziridino[1,2-a]pyrrolidine systems related to the azinomycin family of antitumor agents is reported and was based on an intramolecular addition-elimination reaction sequence. Department of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1632–1635, December, 1998.     

Tactics for the asymmetric preparation of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane scaffolds

In this contribution, two methods are presented for the removal of benzyl-type protecting groups attached to the nitrogen atom of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane systems. The first, based on the Polonovski reaction, is suitable for [3.1.0] systems. The second relies on an elimination process, starting from derivatives of O-methyl phenylglycinol, and is more general in terms of the substrates tolerated. Secondary bicyclic cyclopropylamines, including enantiomerically pure molecules, can thus be accessed. These compounds are then ready for further functionalisation.     

Novel type of rearrangement of the carane system into a 2-methyl-4-isopropylbicyclo[3.1.0]hexane skeleton

Conclusions X-ray structural analysis has established that one of the oxidation products of 3-carene by trivalent thallium acetate is 2-methyl-4-(1-hydroxy-1-methylethyl)bicyclo [3.1.0]-hexan-2-ol. Its formation depends primarily on rearrangement of the carane skeleton into a bicyclohexane skeleton via 1,3-trans-annular participation of the C⁶-C⁷ bond in the cyclopropane fragment.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1777–1779, August, 1988.     

Poly-L-proline type II peptide mimics based on the 3-azabicyclo[3.1.0]hexane system.

This paper describes conformational studies of proline-templated amino acids (PTAAs) based on the 3-azabicyclo[3.1.0]hexane system as well as conformational studies on short peptides composed of these PTAAs. NOE data, coupling constants, and molecular modeling are consistent with a flattened boat conformation for monomeric and oligomeric residues based on this bicyclic system. NMR studies on dimeric and trimeric oligomers are consistent with a populated poly-L-proline type II conformation in CDCl3 and D2O. Solution studies and molecular modeling predicts phi approximately -70 degrees, psi approximately 131 degrees, chi 1 approximately -57 degrees, and chi 2 approximately -158 degrees for oligomeric residues.     

Crystal and molecular structure of 6-(p-bromobenzoyl)-6-azabicyclo[3.1.0]hexane

The molecular structure of 6-(p-bromobenzoyl)-6-azabicyclo[3.1.0]hexane has been determined by a single crystal, three-dimensional x-ray study. The compound crystallizes in the monoclinic space group (P) with four molecules in a unit cell of dimensions a = 8.83, b = 10.15, c = 12.63 ± 0.02Å and β = 94°55′ ± 5′. The aziridine ring is eis fused to the cyclopentane ring with the two rings together in a boat conformation. The fusion angle of the two rings is 110.8°. The aziridine ring has all angles of 60 ±1° and all bond distances of 1.48 ± 0.03Å. The cyclopentane ring has alternately long (1.61 ± 0.04Å) and short (1.52 ± 0.02Å) distances. Non-fusion angles in the cyclopentane ring are 106.0 ± 0.5°. Other molecular parameters are as anticipated. The 844 independent reflections obtained were refined to a final value of R = 0.11₆ using full-matrix least squares techniques.     

Conformational analysis of 2-phenyl-1,3-diazabicyclo[3.1.0]hexane

The 2-phenyl-1,3-diazabicyclo[3.1.0]hexane molecule was subjected to conformational analysis within the framework of the Westheimer method. The optimum conformations of two of its possible stereoisomers (endo and exo) were found, and the equilibrium concentrations of the latter were calculated and found to be 62 and 38%, respectively. The results of the calculations are in good agreement with the PMR spectroscopic data.     

First synthesis of 1,5-diazabicyclo[3.1.0]hexane complexes with cadmium salts

Complexes of bicyclic diaziridines 6,6′-bi(1,5-diazabicyclo[3.1.0]hexane) (L ¹ ) and 6-(4-methoxyphenyl)-1,5-diazabicyclo[3.1.0]hexane (L ² ) with the salts Cd(NO₃)₂ · 4H₂O and Cd(ClO₄)₂ · 6H₂O have been synthesized. The fact of complexation has been established by cyclic voltammetry. The crystal structure of complex L ¹ with Cd(NO₃)₂ (the coordination number of cadmium is 8) has been studied by X-ray diffraction.     

Stereoselective synthesis of cis and trans 2-substituted 1-phenyl-3-azabicyclo[3.1.0]hexanes

The Stereoselective synthesis of cis and trans 2-methyl-1-phenyl-3-azabicyclo[3.1.0]hexanes and 1,2-diphen-yl-3-azabicyclo[3.1.0]hexanes from 2-oxo-1-phenyl-3-azabicyclo[3.1.0]hexane is described. The relative stereochemistry of the products was established by nuclear magnetic resonance and molecular modeling studies.     

An efficient stereoselective synthesis of 1-iodo- or 1-phenyl selenenyl-2-aryl-3-azabicyclo[3.1.0]hexane via electrophilic cyclization of benzyl-2-arylmethylidenecyclopropylmethyl-amines

The reaction of benzyl-2-arylmethylidenecyclopropylmethyl-amine 1 with iodine in the presence of potassium carbonate or PhSeBr stereoselectively gives ring-closure product 1-iodo-2-aryl-3-azabicyclo[3.1.0]hexane or 1-phenylselenenyl-2-aryl-3-azabicyclo[3.1.0]hexane in good yields at room temperature. A plausible reaction mechanism has been proposed.     

Synthesis of unsubstituted 1,3,5-triazabicyclo[3.1.0]hexane

Unsubstituted 1,3,5-triazabicyclo[3.1.0]hexane has been syntesized for the first time by treating a Henry solution with NaOCl.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1665–1666, September, 1993.     

Functionalized chloroenamines in aminocyclopropane synthesis - VI. Chlorotetrahydropyridines as a basis for the synthesis of 3-azabicyclo[3.1.0.]hexane derivatives

Enamines 8a-e could be chlorinated by equimolar amounts of N-chlorosuccinimide (9) generating monochloroenamines 10a-e; 10a and 10d were isolated as pure substances. Two equivalents of 9 afforded the dichloroenamines 12a,c from 8a,c. Interaction of the chlorinated enamines 10a-e and 12a,c with cyanide gave morpholino-azabicyclohexane derivatives. 10a-d, thereby, led to exo-cyano-isomers lla-c; 12a,c generated endo-cyano compounds 13a,c. In the case of the ethoxycarbonylated chloroenamine 10e a mixture of diastereomeric products 11e and 14e resulted from the analogous reaction. Reduction of 11a and 14e with lithium aluminum hydride produced a pair of diastereomeric triamines 15 and 16. A tricyclic diazasystem 19 was formed from the reaction of cyanide with the carbamoylated chloroenamine 18. Monochloroenamine 10a and dichloroenamine 12a showed a significant mutagenic behaviour in the Ames test.     

Synthetic studies of carzinophilin. Part 1: Synthesis of 2-methylidene-1-azabicyclo[3.1.0]hexane systems related to carzinophilin

Synthesis of the model compounds of carzinophilin carrying 2-methylidene-1-aza-bicyclo[3.1.0]hexane systems was achieved. Formation of malonylidenes or N-acyl-glycinylidenepyrrolidines was carried out by utilizing Eschenmoser's sulfide contraction or Herdeis's condensation between the 2-methylthio-Δ¹-pyrrolone derivatives and ethyl nitroacetate, respectively. The 1-azabicyclo-[3.1.0]hexane systems were constructed by base-promoted aziridine formation.     

Crystal and molecular structure of 6-(p-iodobenzenesulfonyl)-3-oxa-6-azabicyclo[3.1.0]hexane

The crystal and molecular structure of 6-(p-iodobenzenesulfonyl)-3-oxa-6-azabicyclo-[3.1.0]hexane has been determined by a three-dimensional single-crystal x-ray diffraction study. The compound crystallizes in the monoclinic space group C₂/c with cell dimensions, a = 19.76, b = 8.17, c = 15.72 ± 0.003 Å and β = 109.3° ± 0.2°. The aziridine ring is fused cis to the oxa-cyclopentane ring with fusion angles of 112°. The bicyclic system is in the boat conformation with the p-iodobenzenesulfonate group at an angle of 98.0° to it. The conformation of the ring system is discussed. A final value of R = 0.099 was obtained for the 1107 independent reflections.     

Asymmetric synthesis of 6-formyl-1-alkoxycarbonylbicyclo[3.1.0]hex-2-ene-2-carboxylic acids by a novel buffer-mediated rearrangement

Asymmetric synthesis of 6-formyl-1-alkoxycarbonylbicyclo[3.1.0]hex-2-ene-2-carboxylic acids has been achieved and the absolute configurations of the products of a novel buffer-mediated rearrangement have been established.     

6,6′-Bis(1,5-diazabicyclo[3.1.0]hexane)

The interaction of 1,3-diaminopropane with glyoxal and NaOCl in water at pH 9.5–10.5 afforded the previously unknown 6,6′-bis(1,5-diazabicyclo[3.1.0]hexane). According to X-ray diffraction data, both bicyclic fragments of the title compound adopt a boat conformation. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 623–625, March, 1999.