Asymmetric synthesis of a dopamine D1 agonist,dihydrexidine from d-serine

A scalable asymmetric synthesis of trans-2-amino-6,7-dimethoxy-1-phenyltetralin 2 and its N-nosyl derivative 12 have been achieved from Garner aldehyde derived from easily available d-serine using a stereoselective PhMgBr addition, Wittig reaction and TFA-mediated Friedel–Crafts cyclization as the key steps. The synthesis of dihydrexidine is accomplished from the N-nosyl-2-amino-1-phenyltetralin 12.     

Catalytic enantioselective synthesis of A-86929, a dopamine D1 agonist

A-86929, a dopamine D1 agonist was synthesized with 95% ee in five steps with overall yield of 56% via catalytic enantioselective one-pot aziridination followed by Friedel-Crafts cyclization and a mild Pictet-Spengler cyclization protocol.     

Synthesis of 6,7,8,9-tetrahydro-N,N-di-n-propyl-1H-benz[g] indol-7-amine,a potential dopamine receptor agonist

In this work, the synthesis of 6,7,8,9-tetrahydro-N,N-di -n-propyl-1H-benz[g]indol-7-amine (1) is described. This compound was designed as an indole bioisostere to the known dopamine receptor agonist 5-OH-aminotetraline 2 . The key step of the synthesis was a Mukaiyama type aldol condensation between the dimethyl acetal of 1-(p-toluenesulfonyl)pyrrole-3-acetaldehyde ( 4 ) and 4-di-n-propylamino-1-trimethylsilyloxycyclohexene ( 8 ) followed by cycloaromatization to afford 1-p-toluenesulfonyl-6,7,8,9-tetrahydro-N,N-di-n- propyl-1H-benz[g]indol-7-amine ( 10 ). Scission of the sulfonamide bond in 10 gave the target compound 1 . A byproduct which was isolated was assigned to the structure of 1-(p-toluenesul-fonyl)-6-[3-[1-(p-toluenesulfonyl)]pyrrolyl]indole ( 11 ). This compound was also synthesized in good yield by an acid catalyzed dimerization of the dimethyl acetal of 1-(p-toluenesulfonyl)pyrrole-3-acetaldehyde ( 4 ). Preliminary screening of 1 indicated that it possesses central dopamine receptor agonist properties.     

Asymmetric synthesis of the dopamine D1 agonist, dihydrexidine

A concise asymmetric synthesis of first, high affinity domaine D1 full agonist, dihydrexidine has been accomplished via catalytic enantioselective aziridination and subsequent one-pot Friedel-Crafts cyclization of an in situ generated tethered aziridine with high diastereo- and enantioselectivities.     

Synthesis of fluorodinitromethane and 2-fluoro-2, 2-dinitroethanol

Conclusions The authors have obtained fluorodinitromethane and 2-fluoro-2, 2-dinitroethanol and studied some of their physiocochemical properties.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 912–914, April, 1968.     

Synthesis and structure of o-bis(2-fluoro-2,2-dinitroethyl)-nitromethyl ester of 2′-fluoro-2′, 2′-dinitroethyl-2″-fluoro-2″-nitroethylenecarboxime

Conclusions The product of conversion of O-bis(2-fluoro-2,2-dinitroethyl)nitromethylbis(2-fluoro-2,2-dinitroethyl)carboxime in methanol or ether is O-bis(2-fluoro-2,2-dinitroethyl)nitromethyl-2-fluoro-2,2-dinitroethyl-2'-fluoro-2-nitroethylenecarboxinie, the structure of which has been established by x-ray diffraction analysis.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2019–2021, September, 1987.     

Synthesis and conformation of 2-fluoro-3-ketoestrane derivatives

Treatment of 3-methoxy-17β-acetoxyestra-2,5(10)-diene with perchloryl fluoride in aqueous dioxane or tetrahydrofuran yielded a 2-fluoro-3-ketosteroid with unusual properties. Unlike the known 2-fluoro-19-nortestosterone, this fluoroketone possessing a 5(10) double bond easily lost hydrogen fluoride to form estradiol 17-acetate; aromatization took place on melting, on exposure to pyridine or acid or even during chromatography on silica gel or Florisil. Because of the Δ-5(10) structure and the absence of the C₁₉ Me group, it is difficult to infer the exact orientation of the 2-fluorine substituent from its effect on the NMR spectrum, CD or the CO absorption in the IR. However, the properties of certain derivatives suggested that the fluorine substituent was 2β. Treatment of the unsaturated fluorketone with peracid gave a mixture of epoxides which on basic hydrolysis furnished two 2-fluoro-10-hydroxy-17-acetoxyestr-4-en-3-ones epimeric at C₁₀. The UV and NMR spectra of the 10-hydroxy epimer indicated an equatorial 2β-orientation of fluorine, whereas the 10β-hydroxy epimer showed an axial 2β-fluorine substituent which could be isomerized by acid to the more stable equatorial 2-configuration.     

Synthesis of 3-substituted 2-fluoro- and 2,2-difluoroaziridines

A new route for the synthesis of stable 3-alkyl- and 3-aryl-2(,2)-(di)fluoroaziridines was developed by hydride reduction of novel alpha-bromo- and alpha-chloro-alpha(,alpha)-(di)fluoroketimines and subsequent ring closure of beta-fluorinated beta-chloro- and beta-bromoamines. This is the first report on the synthesis of 2,2-difluoroaziridines sensu stricto.     

Synthesis of bis-(2-fluoro-2, 2-dinitroethyl) nitramine and tris-(2-fluoro-2,2-dinitroethyl) amine

Russian Chemical Bulletin -     

Synthesis of 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine as potential in vivo precursors of fluorinated norepinephrines.

The title compounds were prepared by the aldol condensation of 3,4-dibenzyloxy-2-fluorobenzaldehyde and 4,5-dibenzyloxy-2-fluorobenzaldehyde with the oxazolidinone 2, a chiral glycine equivalent. Removal of the chiral auxiliary and blocking groups produced the target amino acids 2-fluoro- and 6-fluoro-(2S,3R)-(3,4-dihydroxyphenyl)serine (1b and 1c) in >98% ee.     

Vibrational spectra of 2-fluoro-5-nitro-, 2-fluoro-4-nitro-, 4-fluoro-2-nitro- and 5-fluoro-2-nitrotoluene

The mid- and far-IR absorption spectra of four substituted toluenes, namely 2-fluoro-5-nitro-, 2-fluoro-4-nitro-, 4-fluoro-2-nitro- and 5-fluoro-2-nitrotoluene were recorded. Vibrational assignments are proposed assuming C_s, symmetry for the molecules.     

Ropinirole hydro­chloride,a dopamine agonist

Ropinirole hydro­chloride, or diethyl[2‐(2‐oxo‐2,3‐dihydro‐1H‐indol‐4‐yl)ethyl]ammonium chloride, C₁₆H₂₅N₂O⁺·Cl⁻, belongs to a class of new non‐ergoline dopamine agonists which bind specifically to D2‐like receptors with a selectivity similar to that of dopamine (D3 > D2 > D4). The N atom in the ethyl­amine side chain is protonated and there is a hydrogen bond between it and the Cl⁻ ion. In the crystal structure, two cations and two anions form inversion‐related cyclic dimers via N—H⋯Cl hydrogen bonds.     

Computer-aided molecular modeling of a D2-agonist dopamine pharmacophore

Summary Using computer-aided molecular modeling techniques to analyze models recently proposed for the receptor binding sites of dopaminergic agonists, we superimposed the chemical structures of various compounds that mimic the pharmacological behavior of dopamine, as well as inactive enantiomers, on a postulated three-dimensional frame of reference. We analyzed the vector directionalities of the lone pairs of the nitrogen common to these molecules, and the acidic hydrogen of phenols (in aminoindanes, aminotetralins, apomorphines,p-phenol-piperazines, octahydrobenzo(g)quinolines, octahydrobenzo(f)quinolines, and benzazepines) or of nitrogen (in ergoline-type compounds and related structures). This model, when expressed as distances from that of the reference compound pergolide, correlates with the dopaminergic binding affinity observed in compounds previously reported to act on the dopaminergic system in the central nervous system (CNS). The regression analysis of log K_D with respect to the distances of the vectors of the acidic hydrogen support the hypothesis that these compounds bind to the receptor as donors in hydrogen bond formation.     

Construction of arene-fused-piperidine motifs by asymmetric addition of 2-trityloxymethylaryllithiums to nitroalkenes: the asymmetric synthesis of a dopamine D1 full agonist, A-86929

The straightforward methodology for the construction of chiral arene-fused-piperidine motifs using a highly enantioselective addition of 2-trityloxymethylaryllithiums to cyclic and acyclic nitroalkenes has been developed. The versatility of the process was highlighted by the first asymmetric synthesis of a dopamine D1 full agonist, A-86929.     

Synthesis and reactivity of 1-substituted 2-fluoro- and 2,2-difluoroaziridines

A straightforward synthesis toward 2-fluorinated aziridines was developed via ring closure of beta-fluorinated beta-chloroamines, which were obtained via reduction of the corresponding alpha-fluorinated amides by borane. When 1-benzyl-2-fluoroaziridine was treated with methanol, reaction occurred at the 2-position, giving rise to N-benzyl-2,2-dimethoxyethylamine, while in the case of 1-benzyl-2,2-difluoroaziridine the 3-position was attacked, giving rise to N-benzyl-2-methoxyacetamide. These reactions point to the divergent reactive behavior of monofluoro- and difluoroaziridines.     

Synthesis of 3-fluoro-2-(trinitromethyl)-1-propanol

Conclusions 3-Fluoro-2-(trinltromethyl)-1-propanol nitrate, the acid hydrolysis of which resulted in 3-fluoro-2-(trinitromethyl)-1-propanol, was obtained by the direct fluorination of 2,4-bis(trinitromethyl)-4-mercuri-1,7-heptanediol.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1650–1651, July, 1972.     

Synthesis of 9-Bromo-2-fluoro-6,7-dihydro-5H-benzocycloheptene-8-carboxaldehyde

Cinnamaldehye is an antioxidant shown to induce apoptotic cell death in a number of human cancer cells. This article reports a synthesis of 9-bromo, 2-fluoro substituted, and Z-ring locked (by a trimethylene bridge at C-8 and C-11) crystalline fluorine-substituted derivative of cinnamaldehyde. The synthon, 8-fluoro-1-benzosuberone was treated with PBr₃, dimethylformamide (DMF), and CHCl₃ as a solvent to obtain 9-bromo-2-fluoro-6,7-dihydro-5H-benzocycloheptene-8-carboxaldehyde. The one-step trifunctionalization process converts a bicyclic ring–fused ketone into a β-bromo-α,β-unsaturated aldehyde in a chemoselective and regioselective manner. The process also creates a new carbon–carbon bond between C-8 and C-12. The structure of the previously unreported product has been obtained by x-ray crystallographic analysis. It has been characterized spectroscopically by infrared (IR), ¹H NMR, ¹³C NMR, gas chromatography–mass spectrometry (GC-MS), and elemental analysis. It is a structural element found in sterically hindered retinoids and is a useful advanced intermediate in the total synthesis of these naturally occuring bioactive polyenes.     

Conformational and electronic study of dopamine interacting with the D2 dopamine receptor

We report an exhaustive conformational and electronic study on dopamine (DA) interacting with the D₂ dopamine receptor (D₂DR). For the first time, the complete surface of the conformational potential energy of the complex DA/D₂DR is reported. Such a surface was obtained through the use of QM/MM calculations. A detailed study of the molecular interactions that stabilize and destabilize the different molecular complexes was carried out using two techniques: Quantum Theory of Atoms in Molecules computations and nuclear magnetic shielding constants calculations. A comparative study of the behavior of DA in the gas phase, aqueous solution, and in the active site of D₂DR has allowed us to evaluate the degree of deformation suffered by the ligand and, therefore, analyze how rustic are the lock-key model and the induced fit theory in this case. Our results allow us to propose one of the conformations obtained as the “biologically relevant” conformation of DA when it is interacting with the D₂DR.