Stefano Grilli

Stereomutations of Conformational Atropisomers of Hindered 1,2‐Diaryltetrahydropyrimidines

The barriers required to interconvert the conformational enantiomers (atropisomers) of three 2-(o-halophenyl)-1-mesityl-1,4,5,6-tetrahydropyrimidines (the ortho-halogen substituents being I, Br, Cl) have been measured by low-temperature 1H NMR spectroscopy. In addition, the barrier for the inversion of the heterocyclic six-membered ring has been determined by monitoring the 13C NMR spectra at even lower temperatures. When the mesityl substituent is replaced by a 2,3-dimethylphenyl group, two stereogenic axes are created, generating two diastereomeric conformers. These were identified by low-temperature NMR as existing in a 10:1 population ratio, with a 11.5 kcal·mol−1 interconversion barrier. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of N,N′-Disubstituted (1R,2R)-1,2-Diaminocyclohex-4-enes by a Ruthenium-Catalyzed Ring-Closing Metathesis Reaction

Enantiopure (1R,2R)-1,2-diaminocyclohex-4-ene derivatives have been synthesized by the ruthenium-catalyzed ring-closing metathesis reaction of (4R,5R)-N,N′-bis[(S)-1-phenylethyl]-4,5-diamino-1,7-octadiene dihydrochloride.

Organocatalytic Stereoselective α-Formylation of Ketones

Organocatalytic stereoselective a-alkylation of the carbonyl moiety represents a difficult and challenging transformation. An interesting solution for this goal was presented by Jacobsen, Trost, Hartwig, Stoltz, and Braun. These authors have introduced valuable chiral technologies for the enantioselective alkylation of metal enolates. Despite the fact that brilliant solutions have been introduced for the stereoselective alkylation of aldehydes, the enantioselective catalytic a-alkylation of simple ketones still remains a fundamental problem in chemical synthesis. Recently, MacMillan was able to translate the catalytic principle of singly occupied molecular orbital (SOMO) activation into ketonic systems, providing an unprecedented direct and enantioselective a-alkylation of ketones. Very recently another quite interesting approach based on Brønsted acid catalysis was reported. The lacking of methodologies for the stereoselective alkylation of ketones is connected to the different steric and electronic properties with respect to catalyst interactions. Particularly in organocatalysis the activation modes (enamine catalysis, iminium catalysis, SOMO catalysis) between these carbonyl subclasses is often difficult (if not achievable in many cases). Recently, we have presented a general methodology for the a-alkylation of aldehydes. Our system is based on the easy reaction of enamine in SN1-type reactions (Scheme 1). [15] In particular, we have discovered that the commercially available benzodithiolylium tetrafluoborate easily reacts with enamine formed in situ in the presence of the MacMillan catalyst. The procedure is quite versatile and useful for the synthesis of natural products. We wanted to extend our alkylation procedure using ketones as substrates. Therefore we set up a model reaction using cyclohexanone and benzodithiolylium as prototypical substrates (Scheme 1), in the presence of several organocatalysts (Table S1, see the Supporting Information, SI), including primary and secondary amines. Tryptophan was selected for further optimization. Many different tryptophan derivatives were investigated in the reaction (Table S2, see SI), but the enantiomeric excesses were not improved. Unfortunately, after these encouraging preliminary results (Scheme 1) we found that the conditions were not quite reproducible and the reaction was very capricious, particularly when other ketones were used. The enantiomeric excesses measured varied from reaction to reaction. The major problem encountered was the quite fast background reaction. In fact, the reaction between cyclohexanone and benzodithiolylium occurred without an organocatalyst and was probably driven by traces of acids liberated during the process that are able to promote the formation of the corresponding enol of the ketone. The difficulties and the lack of reproducibility hampered the optimization of the process promoted by tryptophan. We reasoned that other heterocyclic substrates, such as benzoimidazolium or benzothiazolium, bearing a stabilized cationic charge, could be used in the stereoselective formylation of ketones with enamines. In fact 3-methylbenzothiazoline hydrolysis has been reported to be accomplished in mild conditions by AgNO3 in aqueous acetonitrile-phosphate buffer (0.05 m, pH 7) and the use of benzothiazole as a formyl equivalent has been previously investigated in literature. To test this hypothesis, we have prepared the substrates indicated in the Figure 1 and subjected them to a model reaction with cyclopentanone in the presence of different organocatalysts.

Rearrangement and Substitution of Pentadienyl Groups in Homopentadienylamines on Treatment with Organolithium Reagents

(4R,5R)-N,N′-Bis[(1S)-1-phenylethyl]-3,6-divinyl-1,7-octadiene-4,5-diamine underwent rearrangement and/or substitution of one/two pentadienyl groups on treatment with 2−4 equiv. of an organolithium reagent (nBuLi, PhLi) in THF. By careful choice of experimental conditions, C1- or C2-symmetric 1,2-disubstituted 1,2-diamines could generally be obtained with good stereocontrol. It is proposed that the reaction proceeds through competitive pathways involving a 1,3-shift of the branched homopentadienyllithium amide moiety with retention of configuration and retro-pentadienyllithiation to form an intermediate imine. In contrast, only rearrangement was observed on treatment of (1R,S)-N-[(1S)-1-phenylethyl]-1-(2-pyridyl)-2-vinyl-3-butenylamine with 2 equiv. of nBuLi at −78 °C.

Asymmetric synthesis of 3,4-diaminocyclohexanol and endo-7-azabicyclo[2.2.1]heptan-2-amine.

Hydroboration of (1R,2R)-bis[(S)-1-phenylethylamino]cyclohex-4-ene and its derivatives with several borane reagents gave diastereomeric mixtures of the 3,4-diaminocyclohexanol derivatives. Cyclization of the prevalent diastereomer with the R configuration of the newly formed stereocenter under Mitsunobu conditions, followed by reductive removal of the N-substituents, gave the optically pure endo-7-azabicyclo[2.2.1]heptane-2-amine.