The synthesis of a tricyclic receptor having a bowl shape and three binding points for carboxylic acids has been achieved starting from readily available 1-tetralone derivatives according to two different methods. This host possesses a six-membered lactam moiety and a carboxamide at the end of a flexible arm. Association constant with benzoic acid and stoichiometry of the complex have been determined using 1H NMR dilution experiments.

Two routes are examined to achieve the synthesis of a glutarimide possessing a quaternary asymmetric centre with good stereocontrol. It appears that the first one. involving enantioselective Michael addition of cyano-4-(3,4-dichlorophenyl)butanoate oil allyl acrylate is the most interesting in terms of cleanness of reactions and stereocontrol. The best system involves a quinidine derived catalyst at - 40degreesC with potassium hydroxide as a base and gave a medium ee (60%).

The preparation of a new class of tricyclic models 1 based on a Friedländer 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).

Chiral pyridinooxazoline, quinolinooxazoline, bis(oxazolino)pyridine (pybox), and bisoxazoline (box) derivatives containing crown ether residues were prepared. Some of the ligands were assessed in substrate binding studies and in palladium catalyzed allylic alkylations.

A significant acceleration of acyl transfer has been achieved on 8-acetoxy-2-oxazolinylquinoline in the presence of benzylamine. Comparison of the aminolysis by the new acylating reagent with that of 8-acetoxyquinoline and 8-acetoxyquinoline-2-carbonitrile has been carried out. The results of these experiments suggest that the proximity of a supplementary basic atom to the ester group increases the participation effect of the basic site mainly by formation of a possible second hydrogen bond. The association constant of benzylamine into the basic cavity of 8-methoxy-2-oxazolinylquinoline (K-d = 80 M-1) has been measured by H-1 NMR titration experiments. (C) 2002 Elsevier Science Ltd. All rights reserved.

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.

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.

An efficient and direct preparation of functionalized δ-carbolines, via a ring closure reaction between the appropriate indole amine and a masked 1,3-dicarbonyl compound is described. This method afforded new 3-substituted δ-carbolines and these products were subjected to ortho-lithiation experiments. Various 3,4-disubstituted δ-carbolines were obtained in acceptable yields.

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.

The preparation of a new class of axially chiral NADH models based on configurational control of atropisomeric lactams is described. The configurational control of this chiral axis is achieved via the presence of a second chirality element installed on the lactam moiety of the reagent 2. Reduction of methyl benzoylformate led to methyl mandelate in 89% yield and 92% e.e. This result suggests that the chiral axis about C3CO bond is the main configurational element responsible for the high enantioselectivity observed with this biomimetic model.

The synthesis of a tricyclic receptor having a bowl shape and three binding points for carboxylic acids has been achieved starting from readily available 1-tetralone derivatives. This host possesses a six-membered lactam moiety and a carboxamide at the end of a flexible arm. The association constant with benzoic acid and the stoichiometry of the complex have been determined using 1H NMR dilution experiments.

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.

Various NADH models with the following characteristics were studied and compared with previously reported models: (1) use of (S)-phenylalaninol as chiral auxiliary; (2) orientation in or out of the plane of the amide carbonyl. Despite the occurrence of apparently similar characteristics, they gave very different results in the asymmetric reduction of methyl benzoylformate. A detailed NMR study was performed in order to explain the behaviour of these models.

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.

The synthesis of N-methyl-4-pyridyl-1,2,3,4-tetrahydroisoquinolines (6a,b,c) was achieved via a Pictet-Spangler cyclization of an activated amino group derivatized in a carbamate form. The obtained compounds have been designed as potential serotonin analogs.

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.

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The synthesis of a molecule able to bind both with an amine and a carboxylic acid is described. This new host consists in a pyrroloisoquinoline structure possessing a side arm with an acetamidopyridine moiety. The pyrroloisoquinoline part was obtained after improvement of the previously published route involving regioselective reduction of appropriate 3-arylalkylaminosuccinimides followed by ring closure using iminium chemistry. The tricyclic structure was then functionalized by cross-coupling reaction under Pd0 catalysis of its triflate derivative with the trimethylsilyl ketene acetal of methyl acetate. The so-obtained ester was then reacted with 2-amino-4,6-dimethylpyridine leading to the targeted host. The association constants of this latter compound with some carboxylic acids and amines were determined by 1H NMR titration. NOESY experiments and molecular modeling calculations were performed in order to precise the actual host–guest interactions.

Highly diastereoselective protonation of chiral lactam enolates of 4-substituted-1,4-dihydroisoquinolin-3-ones is reported. Protonation and alkylation processes of these lactam enolates derived from phenylglycinol occur with opposite diastereofacial selectivity. This diastereoselective protonation has been applied to the asymmetric synthesis of (4S)-N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline 9 obtained in up to 97% ee.

In order to synthesize the pyrrolo[3,2-c]isoquinoline structure, three different routes starting from readily available isoquinolines were tried. The ring closure reaction of a malonic derivative of 4-amino-3-bromoisoquinoline led to an oxazolo[3,2-c]isoquinoline instead of the target molecule. This latter was obtained via Sonagashira coupling reaction followed by ring closure under basic conditions. A study of the lithiation of the N-sulfonated pyrrolo[3,2-c]isoquinoline was undertaken. After optimization of the lithiation conditions, various 2-substituted pyrrolo[3,2-c]isoquinolines were obtained and their oxidation reactions studied.