Search

Herein we describe a new methodology for the asymmetric hydrogenation (AH) of 2-substituted pyridinium salts. An iridium catalyst based on a mixture of a chiral monodentate phosphoramidite and an achiral phosphine was shown to hydrogenate N-benzyl-2-arylpyiridinium bromides to the corresponding N-benzyl-2-arylpiperidines with full conversion and good enantioselectivity. The mechanism of the reaction under optimized conditions was investigated via kinetic measurements and isotopic labeling experiments. Our study suggests that the hydrogenation starts with a 1,4-hydride addition and that the enantiodiscriminating step involves the reduction of an iminium intermediate.

The use of an equivalent amount of an organic base leads to high enantiomeric excess in the asymmetric hydrogenation of N-benzylated 3-substituted pyridinium salts into the corresponding piperidines. Indeed, in the presence of Et3N, a Rh-JosiPhos catalyst reduced a range of pyridinium salts with ee values up to 90%. The role of the base was elucidated with a mechanistic study involving the isolation of the various reaction intermediates and isotopic labeling experiments. Additionally, this study provided some evidence for an enantiodetermining step involving a dihydropyridine intermediate.

Herein, we report the successful transformation of a 1(st) generation Grubbs metathesis catalyst into an asymmetric transfer hydrogenation (ATH) catalyst. Upon addition of a chiral amine ligand, an alcohol and a base, the 1(st) generation Hoveyda-Grubbs catalyst (HG-I) was found to promote the enantioselective reduction of acetophenone to 1-phenylethanol. After optimizing the order of addition and the reaction conditions, the substrate scope was assessed leading to enantiomeric excesses up to 97% ee. NMR experiments were run in order to get information about the in situ-generated ATH catalyst. Furthermore, the possibility to perform olefin metathesis and ketone transfer hydrogenation sequentially in one pot was demonstrated, and the first tandem olefin metathesis-ketone asymmetric transfer hydrogenation was carried out.

Li4(NH2)3Cl is prepared by ball milling of a stoichiometric mixture of LiNH2 and LiCl (400 rpm, 5 h) followed by ball milling with LiH to form a composite.

A detailed investigation is presented concerning the choice of Pd source, PhthalaPhos ligand, solvent, temperature and Pd-ligand ratio.

Chiral (cyclopentadienone)iron complexes, featuring an (R)-BINOL-derived backbone, are prepared and their application in the asymmetric hydrogenation of ketones is described.

Here we report the first example of a tandem metathesis-asymmetric hydrogenation protocol where the prochiral olefin generated by metathesis is hydrogenated with high enantioselectivity by an in situ formed chiral ruthenium catalyst. We show that either the ruthenium metathesis catalysts or the ruthenium species formed during the metathesis reaction can be converted into an efficient asymmetric hydrogenation catalyst upon addition of a chiral ligand and an alcohol. The performance in asymmetric hydrogenation appears to be very dependent on the solvent, the chiral ligand, and the prochiral substrate.

New BINOL-derived chiral (cyclopentadienone)iron complexes are prepared which display high stability to air, moisture, and chromatography.

It is demonstrated that (S)-BINOL based PhthalaPhos ligands can be used as catalyst for the intramolecular asymmetric allylic amidation of achiral aminocarbamates such as (I) and (III).

The new compound Er(BH4)3 is synthesized by milling of LiBH4 and ErCl3 under argon (200 rpm, 5 h interrupted by periods of rest).

A new class of diketopiperazine-based peptidomimetic organocatalysts is prepared consisting of aspartic acid, diaminopropionic acid and proline building blocks.

2,5-Diketopiperazines (DKPs) are heterocyclic scaffolds easily accessible from α-amino acids and characterized by rather flat six-membered-ring cores that can be functionalized at four positions (N1, N4, C3, C6), two of which are stereogenic centers (C3, C6). In this microreview, the syntheses and the solution conformations of several DKP scaffolds are discussed with regard to their application as two-armed receptors for the selective recognition of small peptides and anions and as peptidomimetics mimicking topologically relevant elements of protein secondary structure (e.g., β-turns, β-hairpins, and α-helices). In many cases the properties of these compounds can be interpreted in terms of their conformationally defined three-dimensional structures, which can be assessed by spectroscopic and computational methods.

Different protocols (lithium enolate reactions, fluoride catalyzed and Lewis acid mediated silyl ketene acetal reactions) were studied to achieve stereoselectivity in the aldol reactions of γ-thiobutyrolactone: in all cases benzaldehyde showed a striking peculiarity compared to aliphatic aldehydes.

The ground state conformational equilibrium of trans-n-styrylquinolines (n=2, 3, 4, 6, 7 and 8) and n-styrylisoquinolines (n = 1 and 3) has been studied in polar and apolar solvents. The fluorescence and trans→cis photoisomerization properties show that the presence of the hetero- cyclic nitrogen does not modify the steric requirements for the stability of the possible conformers. The influence of the styryl position with respect to the heteroatom, and of the solvent on the equilibrium composition and on the photophysical behaviour of the individual rotamers has been particularly investigated.

Hemiacetal cleavage catalyst was designed, synthesized, and shown to be effective in promoting glycoaldehyde dimer dissociation and tetramethylglucose mutarotation

A method for assigning atom-centred point charges, within the constraints of the MacroModel implementation of the MM2 force field, is described. The method has been applied to obtain charges with sensible magnitudes for the transition structures of boron enolate aldol reactions. The effect of these new charges on the aldol force field model is discussed, and it is concluded that atom-centred point charges do not help in the analysis of this transition state, and a more flexible system for the treatment of electrostatics is essential.

Radical-mediated cyclization of norephedrine derived o -bromobenzamide 5 was found to be fairly stereoselective (85:15) favouring diastereoisomer trans-6 . Tricyclic δ-lactams 6 were transformed in high yield into enantiomerically enriched ( R )-1,2,3,4-tetrahydro-2,4-dimethylisoquinoline 8 . Transition state modelling with a force field developed ad hoc (see also: Belvisi, L. Tetrahedron 1992, 48, 3945) nicely predicts the stereochemical results.

A molecular mechanics transition state model is used to analyse the stereoselectivity of a series of aldol reactions of E-enol borinates of type 3 with aldehydes. The model reproduces the sense and degree of π-face selectivity for the chiral E-enol borinates 8, 11, 13 and 14 in the Table. Enolates 8 and 10 preferentially attack the re-face of aldehydes, which is explained (Scheme 5) by the aldol addition proceeding through the preferred transition structure TS-A for both electronic and steric reasons. In contrast, enolates 11, 13 and 14 preferentially attack the si-face of aldehydes solely for steric reasons, which is explained by invoking the favoured transition structure TS-B derived from the modelling results. These two transition state models, TS-A and TS-B, which apply to E-enol borinates, differ substantially from the transition state model, TS-C, used for chiral Z-enol borinates with similar substituents. Our force field model of the boron aldol transition state is shown to be useful in understanding the origins of the π-face selectivity over a wide range of substrates.

Transition-state modelling for the aldol reaction of chiral Z and E enol borinates ( 1 and 2 , Scheme 1 ) bearing mixed ligands (L 1 = Ipc, L 2 = 9 ) predicted higher enantioselectivities than those calculated and experimentally tested with C 2 symmetric systems (L 1 = L 2 = Ipc, L 1 = L 2 = 9 ). Reagent 8 was prepared and used to generate E enol borinates 24 , which reacted with aldehydes to give the anti aldol products 25–28 with substantially lower enantiomeric excesses than predicted. This unexpected suggested that ate complex formation may be an important factor in controlling the selectivity of the boron-mediated aldol reaction. In particular, the presence of two different ligands on boron makes it a prostereogenic centre, and two diastereomeric ate complexes ( 29 and 30 ) can be formed on aldehyde complexation. These ate complexes are calculated to display different re : si face selectivities. The experimental results are similar to the ones predicted if the aldol reaction proceeds via the less selective ate complex 29 .

Boron enolates derived from α-heterosubstituted thioacetates and bearing menthone-derived chiral ligands react with aldehydes to give anti aldols with excellent diastero- and enantiocontrol.

Boron enolates bearing menthone-derived chiral ligands are capable of fair to excellent diastereocontrol in their reactions with chiral aldehydes. Thioester-derived (better than ketone derived) enolates are able to control aldol stereochemistry irrespective of the aldehyde preferences.

Boron enolates bearing menthone-derived chiral ligands are capable of fair to excellent diastereocontrol in their reactions with chiral aldehydes. Thioester-derived (better than ketone derived) enolates are able to control aldol stereochemistry irrespective of the aldehyde preferences. With thioacetate-derived chiral enolates and enantiopure N , N -dibenzyl α-amino aldehydes, either the 3,4- anti or the 3,4- syn aldol adduct can be obtained with very high diastereoselectivity just by changing the chiral boron ligand configuration. The above procedure was used for a stereoselective total synthesis of (3 S , 4 S )-statine.

The aldol-type addition of enol borinates to imines was studied with ab initio MO methods (3–21G basis set). Calculations performed on unsubstituted, mono- and di-substituted structures have shown that only two competing cyclic transition states (chair-like and boat-like) are important. Their relative energy depends on the enolate geometry and on the substitution pattern. This approach allows a qualitative rationalization of the observed stereoselectivity trends in the title reaction.

Boron enolates derived from α-heterosubstituted thioacetates and bearing menthone-derived chiral ligands react with aldehydes to give anti aldols with excellent diastero- and enantiocontrol. Boron enolates derived from tert-butyl α-halothioacetate and bearing menthone-derived chiral ligands react with imines with excellent diastero- and enantiocontrol to give syn α-halo-β-aminothioesters, which can be converted to the corresponding aziridines by simple ring closure during LAH reduction. A key precursor of antibiotics (+)-thiamphenicol and (−)-florfenicol was synthesized.

A very simple, new, and straightforward approach to the Paclitaxel (Taxol) and Docetaxel (Taxotere) side chains has been developed using the imine addition reaction of thioester-derived boron enola...