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A novel class of recoverable and highly stable phosphinamide catalysts for the asymmetric reduction of ketones by borane is described. Enantiomeric excesses of up to 92% have been obtained using 10 mol% of the optimum catalyst.

The effect of the configuration of the phosphorus atom in phosphinamide reduction catalysts has been studied through the preparation and use of a series of catalysts containing stereogenic phosphorus atoms of known configuration. The conclusion of this work is that a stereogenic centre at phosphorus can improve the selectivity of reductions using this catalyst, but is not sufficient in itself to generate the higher levels of selectivity which have been achieved with related catalysts. The X-ray crystallographic structure of a key compound is also featured.

We have designed and prepared a catalyst for the asymmetric reduction of ketones which combines a phosphinamide and a boron-containing heterocyclic ring. The former group acts to direct and activated the borane, whilst the latter provides a well defined position for location of the ketone. The resulting reduction therefore takes place in a well-defined stereochemical environment. Enantiomeric excesses of up to 59%, in a predictable absolute sense, were achieved. Evidence that O- co-ordination of borane is important in the reduction mechanism is also presented

The phosphinamide N-protecting group is demonstrated to be an effective directing group for diastereoselective reductions of proximal ketones. A range of methods for the preparation of the requisite α-amino ketones substrates are described.

The use of (i) enantiomerically pure phosphinamides coupled to borane and (ii) an enantiomerically pure amino alcohol coupled to a transfer hydrogenation process, in the asymmetric catalysis of the reduction of ketones to alcohols, is described. The former process is particularly suited to the reduction of alpha-chlorinated substrates, affording e.e.s of up to 94%, whilst the latter process is optimal for unfunctionalised ketones, affording e.e.s of up to 98%.

A practical, general, and convergent route to epoxides with control of the relative and absolute stereochemistry has been achieved by generating the reactive intermediate (the diazo compound) in situ from tosylhydrazone salts (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl). High yields (58-82 %), high d.r. (88:12-98:2), and high ee values (87-94 %) have been obtained using a new class of stable chiral sulfides at low catalyst loading (5 mol %) and [Rh2 (OAc)4 ] (0.5 mol %).

The development of catalytic methods for the synthesis of non-racemic epoxides has been a long standing goal in asymmetric synthesis. For epoxide synthesis, attention has largely focused on the asymmetric oxidation of alkenes and good enantioselectivities are now beginning to emerge for an increasing range of substrates.1-3 Alkenes are themselves commonly obtained by Wittig reaction from the corresponding aldehyde or ketone and so epoxidation is usually a two step process from carbonyl compounds. However, in terms of efficiency and atom economy this overall process is poor compared to direct epoxidation of carbonyl compounds using sulfur ylides. However, in terms of catalysis and asymmetric induction, oxidation of alkenes is still superior as epoxidation of carbonyl compounds using sulfur ylides usually requires stoichiometric amounts of sulfides/sulfur ylides and only gives moderate enantioselectivities.4 We have described a catalytic process for epoxidation involving sulfur ylides which now overcomes this limitation (Scheme 1).5 Whilst only low levels of enantioselectivity were originally achieved we now report significant improvements and describe chiral sulfides which provide high levels of asymmetric induction.6