An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.     

Assessment of docking poses: interactions-based accuracy classification (IBAC) versus crystal structure deviations

Six docking programs (FlexX, GOLD, ICM, LigandFit, the Northwestern University version of DOCK, and QXP) were evaluated in terms of their ability to reproduce experimentally observed binding modes (poses) of small-molecule ligands to macromolecular targets. The accuracy of a pose was assessed in two ways: First, the RMS deviation of the predicted pose from the crystal structure was calculated. Second, the predicted pose was compared to the experimentally observed one regarding the presence of key interactions with the protein. The latter assessment is referred to as interactions-based accuracy classification (IBAC). In a number of cases significant discrepancies were found between IBAC and RMSD-based classifications. Despite being more subjective, the IBAC proved to be a more meaningful measure of docking accuracy in all these cases.     

Molecular rearrangements of 4-iminomethyl-1,2,3-triazoles. Replacement of 1-aryl substituents in 1H-1,2,3-triazole-4-carbaldehydes

The two structural isomers, 4 and 5 , of 1-substituted-4-iminomethyl-1,2,3-triazoles are interconvertible when heated in dimethyl sulfoxide at 80°. The equilibrium position depends on the electronic properties of the R-substituent, favoring 5 for R = alkyl, benzyl and anisyl, and 4 for p-chlorophenyl and p-nitrophenyl. An interesting application is the synthesis of 1-alkyl-1,2,3-triazole-4-carbaldehydes from 1-phenyl-1,2,3-triazole-4-carbaldehyde by Scheme I. The hydrazones 4ij and the oxime 4k do not rearrange due to an unfavorable Z-configuration around the C ? N bond, whereas the acyloximino derivative 4m is converted into the nitrile 11 . The structures of the products have been fully characterized by ¹³C nmr spectroscopy and the mechanistic details of the rearrangement are discussed.     

Template-aluminosilicate structures at the early stages of zeolite ZSM-5 formation. A combined preparative, solid-state NMR, and computational study

Species at three stages in the self-assembly of zeolite ZSM-5 have been studied with one- and two-dimensional magic-angle-spinning 13C, 27Al, 29Si, and 1H NMR spectroscopy and compared with the earlier proposed structures: (1) precursor species containing 33-36 T sites around a tetrapropylammonium (TPA) cation, (2) nanoslabs consisting of a flat 4 x 3 array of such precursors, and (3) the final TPA-ZSM-5 zeolite. Synthesis was carried out in D2O to suppress the water and silanol protons. Under such conditions, the effective Si-H and Al-H distances measured with 29Si-{1H} and 27Al-{1H} rotational echo double resonance (REDOR) reflect the interactions between TPA cations and the surrounding aluminosilica. The 29Si-{1H} REDOR curves for Q4-type silicon atoms at the three mentioned stages are closely similar, as well as the observed 27Al-1H REDOR curve for the precursor species compared to that for the TPA-ZSM-5. This indicates that in addition to externally attached TPA, there is also internal TPA already incorporated at an early stage into the aluminosilicate in a similar way as in the final zeolite, in accordance with the earlier proposed MFI self-assembly pathway (Kirschhock et al. Angew. Chem. Int. Ed. 2001, 40, 2637). However, the effective distances extracted from the initial REDOR curvatures are significantly (10-15%) larger than those computed for the model. Since there is no temperature effect, we tentatively assign this difference to a reduction of the 29Si-1H and 27Al-1H interactions by multispin decoherence effects or self-decoupling caused by proton spin diffusion. By assuming the computed model distances and fitting Anderson-Weiss curves to the observed REDOR data, we obtain similar "decoherence times" in the order of 0.1 ms. The observed 29Si-{1H} REDOR dephasing for the Q3 sites in the precursors is significantly faster than that for the Q4 sites. This is tentatively ascribed to a partial deuteron-proton back exchange at the silanol positions.     

New Organorhodium and -Iridium Compounds of Iminophosphoranylmethanes

Abstract

The synthesis and structure of new metallacyclic compounds of Rh(I) and Ir(I) containing bidentate mono- and bis(iminophosphoranyl)methane or -methanide ligands and their reactions with CO, phosphine and HCl are described.     

Hexakis(adamantyltrimethylammonium) cyclooctasilicate tetratetracontahydrate

The title compound, 6C₁₃H₂₄N⁺·H₂Si₈O₂₀⁶⁻·44H₂O, belongs to the class of cyclosilicate hydrates, which structurally can be positioned between the zeosils and the clathrate hydrates. [Si₈O₁₈(OH)₂] cubes carrying six negative charges are located on crystallographic inversion centres and are surrounded by six adamantyltrimethylammonium cations.     

Enantioselective synthesis of chiral porphyrin macrocyclic hosts and kinetic enantiorecognition of viologen guests

The construction of macromolecular hosts that are able to thread chiral guests in a stereoselective fashion is a big challenge. We herein describe the asymmetric synthesis of two enantiomeric C₂-symmetric porphyrin macrocyclic hosts that thread and bind different viologen guests. Time-resolved fluorescence studies show that these hosts display a factor 3 kinetic preference (ΔΔG^‡_on = 3 kJ mol⁻¹) for threading onto the different enantiomers of a viologen guest appended with bulky chiral 1-phenylethoxy termini. A smaller kinetic selectivity (ΔΔG^‡_on = 1 kJ mol⁻¹) is observed for viologens equipped with small chiral sec-butoxy termini. Kinetic selectivity is absent when the C₂-symmetric hosts are threaded onto chiral viologens appended with chiral tails in which the chiral moieties are located in the centers of the chains, rather than at the chain termini. The reason is that the termini of the latter guests, which engage in the initial stages of the threading process (entron effect), cannot discriminate because they are achiral, in contrast to the chiral termini of the former guests. Finally, our experiments show that the threading and de-threading rates are balanced in such a way that the observed binding constants are highly similar for all the investigated host–guest complexes, i.e. there is no thermodynamic selectivity.

Chiral guests display kinetic stereoselective threading through chiral porphyrin cages if their chirality is located at the chain ends and not in the centers, supporting the previously reported entron effect of threading.