Michael North

Synthesis and applications of non-racemic cyanohydrins

Methods for the catalytic asymmetric synthesis of cyanohydrins derived from both aldehydes and ketones are reviewed. Successful catalysts based on enzymes, peptides and transitional metal complexes are included, and mechanistic detail is included where appropriate. Illustrations of the many synthetic applications of non-racemic cyanohydrins are given.

THE ASYMMETRIC ADDITION OF TRIMETHYLSILYL CYANIDE TO ALDEHYDES CATALYZED BY CHIRAL (SALEN)TITANIUM COMPLEXES

The use of chiral (salen)TiCl2 complexes to induce the asymmetric addition of trimethylsilyl cyanide to aldehydes has been investigated. The complexes are catalytically active at substrate-to-catalyst ratios as high as 1000:1, and the optimal catalyst (2e) which is derived from (R,R)-1,2-diaminocyclohexane and 3,5-di-tert-butyl-2-hydroxybenzaldehyde produces trimethylsilyl ethers of cyanohydrins with up to 90% enantiomeric excess at ambient temperature. Water plays a key role in these reactions since under strictly anhydrous conditions much lower enantiomeric excesses are produced. The role of water has been shown to be to generate dimeric complexes of the form [(salen)Ti(μ-O)]2 (4) which are the real catalyst precursors. A structure for one of these complexes (4a derived from (R,R)-1,2-diaminocyclohexane and 2-hydroxybenzaldehyde) has been determined by X-ray crystallography. The dimeric complexes are more active than the dichloride precursors, and at substrate-to-catalyst ratios between 100 and 1000:1 g...

Mechanistic Investigation of the Asymmetric Addition of Trimethylsilyl Cyanide to Aldehydes Catalysed by Dinuclear Chiral (Salen)titanium Complexes

Titanium complexes 1 derived from chiral salen ligands are highly active precatalysts for the asymmetric addition of trimethylsilyl cyanide to aldehydes and ketones. Based on spectroscopic studies and the identification of adducts between complexes 1 and carbonyl compounds or trimethylsilyl cyanide, a catalytic cycle which explains the origin of the asymmetric induction is proposed. Kinetics studies have been carried out, the results of which are consistent with the proposed catalytic cycle.

A Chiral Solvent Effect in Asymmetric Organocatalysis

Proline-catalyzed aldol reactions between enolizable ketones and aromatic aldehydes can be carried out in propylene carbonate. When enantiomerically pure propylene carbonate is used, the combination of (R)-proline and (R)-propylene carbonate constitutes a matched pair, while (S)-proline and (R)-propylene carbonate constitutes a mismatched pair.

Proline-Catalysed Amination Reactions in Cyclic Carbonate Solvents

Propylene carbonate is shown to be an environmentally friendly and sustainable replacement for dichloromethane and acetonitrile in proline-catalysed α-hydrazinations of aldehydes and ketones. Enantioselectivities comparable to those obtained in conventional solvents or ionic liquids can be obtained, even when using a lower catalyst loading.

Enyne metathesis of norbornene derivatives: a facile approach to polycyclic heterocycles

Norbornene derivatives bearing propargyloxy substituents in the 5- and 6-positions undergo a cascade series of enyne metatheses when treated with Grubbs catalyst and a terminal alkene, leading to heterocyclic dienes which undergo a stereoselective DielsAlder reaction, giving access to a range of polycyclic heterocycles. The process is compatible with both terminal and internal alkynes, and depending upon the structure of the alkene can give symmetrical or unsymmetrical products. Mechanistic studies have shown that the initial metathesis reaction is between the strained norbornene and Grubbs catalyst, rather than between the alkyne and Grubbs catalyst.

Ruthenium initiated ring opening metathesis polymerisation of amino-acid and -ester functionalised norbornenes and a highly selective chain-end functionalisation reaction using molecular oxygen

Abstract [Ru( CHPh)(PCy 3 ) 2 Cl 2 ] is shown to initiate the living ring opening metathesis polymerisation of amino-acid and -ester functionalised norbornenes; treatment of the living polymers with molecular oxygen gives rise to a highly selective chain-end functionalisation reaction.

Totally atom economical tandem-metathesis and Diels–Alder approach to polycyclic compounds

Abstract Norbornene derivatives bearing pendant alkynes undergo a series of tandem metathesis reactions when treated with Grubbs’ catalyst. The products of this cascade are dienes which can be trapped in situ by dienophiles in Diels–Alder reactions to yield polycyclic compounds.

Catalytic, asymmetric synthesis of α, α-disubstituted amino acids

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.

Copolymerization of peptide derived monomers and methyl methacrylate

The copolymerization of a series of peptide derived (meth)acrylate derivatives with methyl methacrylate is reported. The resulting polymers are optically active and display a variety of non-linear dependencies of specific rotation against %-chiral monomer incorporation. The polymers contain acid labile protecting groups that can be removed to generate a second series of polymers, which also show non-linear dependencies of specific rotation against %-chiral monomer incorporation. All of the non-linear effects can be explained by a model based on asymmetric induction from the stereocenters within the peptide, to prochiral centers within the peptide unit and the adjacent methyl methacrylate unit.