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Enantiospecific synthesis of (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid by a modified Corey-Link reaction

Abstract ( 1S,2S,5R,6S )-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) was synthesised enantiospecifically from a sugar derived enantiomerically pure cyclopentenone. The α-amino acid stereogenic centre was formed by reacting the ketone with chloroform anion and then the alcohol so formed was reacted with sodium azide/DBU in methanol to give an azido ester. Critically, this modified Corey-Link reaction gives the opposite stereochemical outcome to the traditional Bucherer-Bergs and Strecker reactions. The azide was reduced and acylated, the 1,2 diol deoxygenated and the protecting groups removed to give LY354740 with an e.e.>98%.

Asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740)

Abstract The asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) 1, a potent and selective group 2 mGluR agonist, has been accomplished starting from the readily available enantiomerically pure cyclopentenone 4. Thus, cyclopropanation with ethyl(dimethylsulfuranylidene)acetate generated in situ with DBU, followed by deketalization gave rise to the dihydroxy bicyclic ketone 9. After protecting the ketone as 1,3-dioxolane and its transformation to the orthoformate 11, this was pyrolytically deoxygenated in a sealed tube to the bicyclic enone 13. The synthesis was completed after hydrogenation, stereoselective Bucherer-Bergs reaction and hydantoin hydrolysis, yielding LY354740 (+)-1 with an e.e. ≥98%.

The problem of the existence of C(Ar)–H ⋯ N intramolecular hydrogen bonds in a family of 9-azaphenyl-9H-carbazoles

In order to demonstrate the possibility of intramolecular hydrogen bonds (IMHB) between an aromatic C–H and a pyridine nitrogen atom, the family of 9-arylcarbazoles [Ar = phenyl (1), 2-pyridyl (2) or 2-pyrimidinyl (3)], their 9-aryl-1-azacarbazole analogues [Ar = phenyl (4). 2-pyridyl (5) or 2-pyrimidinyl (6)] and 9-phenyl-1,8-diazacarbazole (7), have been synthesized and the X-ray structure of all of them, except 4, has been determined. The unit cell parameters are as follows. For 1: a= 14.526(5)A, b= 10.985(1)A, c= 18.094(2)A, β= 113.45(2)°, V= 2649(1)A3, Z= 8, P21/n. For 2: a= 14.625(4)A, b= 11.685(6)A, c= 16.636(1)A, β= 114.07(4)°, V= 2596(3)A3, Z= 8, P21/n. For 3: a= 25.76(2)A, b= 5.200(6)A, c= 19.47(1)A, β= 112.07(5)°, V= 2417(4)A3, Z= 8, C2/c. For 5: a= 12.825(2)A, b= 12.336(4)A, c= 16.468(6)A, β= 111.41(3)°, V= 2426(2)A3, Z= 8, P21/n. For 6: a= 10.682(3)A, b= 29.033(9)A, c= 7.524(3)A, β= 90.46(3)°, V= 2333(1)A3, Z= 8, P21/c. For 7: a= 10.895(2)A, b= 13.407(4)A, c= 17.552(6)A, β= 107.81(2)°, V= 2441(2)A3, Z= 8, P21/c. The data were obtained at 293 K except for compound 7 for which the experimental temperature was 200 K. All compounds except 3 exist in the crystal in two different conformations. The potential curves corresponding to the rotation about the N(9)–C(aryl) bond of nine compounds (1–7 plus the non-synthesized 2-pyridyl- and 2-pyrimidinyl-1,8-diaza analogues) have been calculated. The crystallographic torsion angles are near the zone of minimum energies according to AM1 calculations, save in the case of compound 1(9-phenylcarbazole) where one of the independent molecules has a torsion angle of 78.4°, much larger than calculated. The calculated barrier through the planar state, ΔE°, contains much information and appears to be related to the 1H and 13C chemical shifts of some selected molecules. Compound 3[9-(2-pyrimidinyl)-9H-carbazole], with a torsion angle of 7.4(4)°, is the clearest representative of the existence of C–H ⋯ N IMHBs.

Conformationally constrained ACPD analogues. Synthesis and resolution of 3-aminobicyclo[3,3,0]octane-1,3-dicarboxylic acids

Abstract The synthesis of racemic 3-aminobicyclo[3.3.0]octane-1,3-dicarboxylic acids (2 and 3) which are conformationally constrained ACPD analogues, has been achieved in seven steps starting from the readily available Weiss diketone (4). Partial reduction of of 4 to 5, followed by phenyl ring oxidation with RuCl3/NaIO4, gave the bicyclic ketoacid 6 which, after Bucherer-Bergs reaction and fractional crystallization, afforded spirohydantoins 7 and 8 in a 2/1 ratio. Both isomers were hydrolyzed to amino acids 2 and 3. Optical resolution of racemic 7 was performed by crystallization of the corresponding (−)-(S)-brucine diasteromeric salts and, after decomposition and hydrolysis, (+)-(1S ∗ , 3R ∗ , 5R ∗ ) and (−)-(1R ∗ , 3S ∗ , 5S ∗ )- 3-aminobicyclo[3,3,0]octane-1,3-dicarboxylic acids (2a and 2b) were obtained to be biologically compared with (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD). Due to the solubility profile of hydantoins 7 and amino acids 2, the enantiomeric purity was measured in the dimethyl derivative 9, being determined by chiral-HPLC.

N-Oxides of azaanthraquinones

Abstract A procedure is described for the efficient N-oxidation of heterocyclic quinones, which represents a considerable improvement over previous, multi-step methods.

Regio- and diastereoselective dialkylation of (4S)-2,4-dimethyl-2,4-dihydro-1H-pirazino[2,1-b]quinazoline-3,6-dione

Abstract Dialkylation of the title compound occurs regioselectively at C-1. Addition of N,N′-dimethyl-N,N′-propylene urea (DMPU) permits the one-pot synthesis of 1,1-dialkylation products in good yields. The asymmetric induction of the stereogenic C-4 center directs the first and the second alkylation steps.

(4S)-2,4-Dimethyl-2,4-dihydro-3,6-dioxo-(1H)-pyrazino[2,1-b]quinazolyl tosylate as an electrophilic glycine template

Abstract (4S)-2,4-Dimethyl-2,4-dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-dione was converted into to the cis-tosylate 2, whose reactivity as an electrophilic glycine template is discussed. It was found that this compound does not give direct SN2-type displacement of the tosyloxy group. However, the 1-hydoxy derivative 3, obtained by hydrolysis of 2 with net retention of the stereochemistry, and its 1-methoxy derivative 4a are electrophilic glycine templates.

Reactions of aza- and diazaanthraquinone N-oxides

Abstract 1-Azaanthracene-2,5,8-triones and 1,8-diazaanthracene-2,7,9,10-tetraones, which are structurally related to diazaquinomycin, are prepared by functionalization of azaathraquinone N-oxides. The complete procedure implies a Diels-Alder reaction as a key step, followed by N-oxidation and treatment of the N-oxides with benzoyl or tosyl chlorides in the presence of water.

The structure of N-(azol-N-yl) formamides: a crystallographic and dynamic NMR spectroscopy study

The molecular structures of N-(pyrazol-1-yl) formamide 1[C4H5N3O, orthorhombic, space group P212121, a= 5.269(8). b= 8.039(8). c= 12.79(2), Z= 4] and N-(indazol-1 -yl) formamide, 5[C8H7N3O, monoclinic, space group P21/c, a= 9.065(2). b= 11.089(7), c= 8.463(7), Z= 4] have been solved by X-ray crystallography. Regarding the amide bond, both compounds exist in the Z configuration, a configuration which also prevails in solution for all the N-H azolyl formamides whilst the N-substituted derivatives prefer the E configuration. The rotation barriers about the amide bond are similar although a little lower than those of N-phenylformamide and N-methyl-N-phenylformamide, a fact that may be related to the electronic properties of the N-azolyl substituent.

Rearrangement of 1-amino- and 1-alkylamino-pyrazoles to 5-aminopyrazoles

Rearrangement of 1-aminopyrazole and 1-alkylaminopyrazoles into the corresponding 5-aminopyrazoles has been achieved in 48% aqueous hydrobromic acid. The reaction, occurring through a ring opening–ring closure mechanism, constitutes a new and unambiguous procedure for the preparation of 1-substituted 5-aminopyrazoles. The products have been identified on the basis of 1H and 13C n.m.r. spectroscopic results and comparison with authentic samples.