Jean Bourguignon

Effect of gamma-hydroxybutyrate and its antagonist NCS-382 on spontaneous cell firing in the prefrontal cortex of the rat

Gamma-hydroxybutyrate (GHB) at low doses (5-10 mg/kg i.p.) increased and at high doses (160-320 mg/kg i.p.) decreased the spontaneous firing rate of prefrontal cortex (PFC) neurons recorded in urethane-anesthetized rats. Only excitations were blocked by NCS-382, a specific GHB receptor antagonist; this suggests that the excitatory effect of low doses of GHB is mediated by a GHB receptor whereas the inhibitory effect of high doses of GHB involves a more complex mechanism.

Deracemization of alkyl diarylmethanes using (−)-sparteine or a chiral proton source

Abstract In a first stage, deracemization of 2-(1-phenylethyl)pyridine 1 and chlorpheniramine 2 was investigated in the presence of (−)-sparteine as a chiral ligand. Whereas ( R )-2-(1-phenylethyl)pyridine 1 was obtained in 65% ee with 2,6-di- tert -butyl-4-methylphenol as a proton donor, the opposite stereoselection was observed with EtOH leading to ( S )-2-(1-phenylethyl)pyridine 1 in 53% ee. A second methodology making use of (+)-( R )-1-[5-chloro-2-(methylamino)-phenyl]-1,2,3,4-tetrahydroisoquinoline 4 as a chiral proton source gave higher enantioselectivities, affording ( R )- 1 and ( R )- 2 in up to 84 and 75% ee, respectively.

An efficient synthesis of 3-cyanoquinoline derivatives

Abstract A short and efficient method is reported for the preparation of 3-cyanoquinoline derivatives. Reaction of 3,3-dimethoxy-2-formyl-propanenitrile sodium salt 1 with various anilines 2 afforded (E) enamines 3 which were subsequently isomerized into (Z) enamines 4 and cyclized in a one pot procedure to give 3-cyanoquinolines 5 in good yields.

Chiral biomimetic NADH models in the benzo[b]-1,6-naphthyridine series. A novel class of stable, reactive and highly enantioselective NADH mimics

Abstract The preparation of a new class of tricyclic models 1 based on a Friedlander reaction between chiral piperidine-2,4-diones 2 and azomethine 3 is reported. Alkylation of the lactam allowed to install various pendant arms on the chiral cyclic inducer. The so-obtained mimics 1a,d,f,g,h,k were involved in the reduction of methyl benzoylformate to furnish methyl mandelate in 4–87% ee (R). The presence of a coordinating pendant arm proved to be essential to reach optimum results in terms of enantioinduction. Asymmetric reduction of 2-benzoylpyridine with mimics 1d,f,g produced α-phenyl-2-pyridinemethanol in 30–84% ee (R).

Stable annelated chiral NADH models with a rigidified amide part in the quinoline series: synthesis, reactivity and grafting on a Merrifield resin

Abstract The synthesis of new chiral nicotinamide adenine dinucleotide hydrogenated models derived from quinoline is described. Using a biomimetic approach, the out-of-plane positioning of the amide carbonyl was obtained by involving the chiral auxiliary in a lactam structure. It is shown that electron-donating groups on the benzene ring of the quinoline structure are necessary to obtain high chemical yields during the reduction of methyl benzoylformate. An interesting variation of the enantioselectivity as a function of magnesium ion concentration has been observed. Under the best conditions, methyl mandelate was obtained in up to 95% ee ( R ). To facilitate the recycling of these models, grafting of reagent 4 on a Merrifield resin has been developed. The resulting polymer-supported reagent 4 was tested in the asymmetric reduction of methyl benzoylformate.

Variations of the nature of the chiral auxiliary with a highly enantioselective chiral NADH model

Abstract Various chiral amino alcohols have been used as chiral auxiliaries for a highly enantioselective NADH model. Some of these are new reagents which have been obtained by an enzymic resolution method.

Atropoisomeric quinolinium salt promoting the access to both enantiomeric forms of methyl mandelate: a versatile NADH mimicElectronic supplementary information (ESI) available: experimental. See http://www.rsc.org/suppdata/cc/b2/b207434f/

Asymmetric reduction of methyl benzoylformate by a new NADH mimic is reported; depending on the hydride source used to reduce the NAD+ precursor, NADH mimics so obtained lead to an inversion of enantioselectivity, affording either (R)-methyl mandelate in 88% ee or (S)-methyl mandelate in 78% ee.

New NADH models bearing a phosphonate or a chiral oxazaphospholidine oxide at the dihydropyridine ring

Abstract Novel NADH models bearing a phosphonate at the 3-position of a stable 1,4-dihydroquinoline structure were successfully involved in the reduction of methyl benzoylformate. Asymmetric reduction of the former ketone with a NADH model bearing a chiral oxazaphospholidine oxide is reported affording methyl benzoylformate in 45% e.e.

Influence of the C(4)C(3)CO dihedral angle of chiral NADH mimics on the stereoselectivity of reductions

Abstract Herein we report the stereoselective synthesis of new chiral NADH mimics 2 and 13 of the benzo [ b ]-1,6-naphthryridine series. The synthesis of 2 and 13 relies upon a Friedlander-type condensation between the amino imine 3 and the piperidine-2,4-dione 4 bearing a stereogenic center at C(6). The resulting NADH models were involved in the reduction of methyl benzoylformate. A comparison of their performance with that of previously reported NADH mimics such as model 1 , throws new light on the role played by the C(4)C(3)CO dihedral angle ( α ) on the stereoselectivity of the hydride transfer.

Design of new axially chiral NADH mimics. Mechanistic investigation of the enantioselective hydride transfer

This paper reports the design of a new axially chiral NADH model which relies on the configurational control around the C3-CO chiral axis by means of a chiral relay installed on the cyclic structure. The conformational and configurational control of the lactam moiety was successfully achieved affording two conformational diastereoisomers (aS,S)-1 and (aR,S)-1 in a ratio of 95:5, respectively. Reduction of methyl benzoylformate with model 1 afforded (R)-methyl mandelate in up to 84% e.e. The stereoselective synthesis of 4-deuterated model 1 allowed us to establish that this enantioselective reduction arises from the migration of the syn-oriented hydrogen with regard to the carbonyl dipole.