Asymmetric isomerisation

BINAP has been extensively used for the asymmetric hydrogenation, transfer hydrogenation and isomerisation of double bonds using both ruthenium and rhodium complexes. 

Asymmetric catalysis involving metal catalysed hydrogenations and isomerisations is becoming increasingly important in the production of pharmaceuticals, agrochemicals and flavours and fragrances. More examples of asymmetric homogeneous catalysts used are found in reference [3], 

Industrial practice. Both the ligand, S-BINAP, and rhodium are rather expensive (both = 50-150 per gram) and the turnover per mole of catalyst 

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There are rather few reactions that can be described as fully atom economical , i.e. when there are no co-products and all the atoms in the starting material(s) appear in the product(s). However, all isomerisation reactions necessarily fall into this category. The use of a transition metal to catalyse such a process with an appropriate substrate brings the possibility of effecting asymmetric isomerisation, a very efficient method to generate enantiomerically enriched products. Indeed, the asymmetric Rh-catalysed isomerisation of an allylamine to an enamine, which proceeds in over 96% ee, was scaled up a number of years ago for industrial production. The enamine product forms a multi-tonne feedstock for menthol and perfumery synthesis. In contrast, the cyclo-isomerisation of dienes, an equally atom-economical process that generates synthetically useful cyclic products, has seen relatively little development despite the reaction having been known for some 30 years. 

On the other hand, a chiral ruthenium catalyst, prepared from a chiral P/N ligand derived from L-proline, was applied in 2005 to the asymmetric isomerisation of racemic allylic alcohols via DKR. This new type of reaction was applicable to the asymmetric synthesis of muscone, as shown in Scheme 2.45. 

The Pd(II)-catalysed asymmetric carbonylation of olefins with a chiral thiourea as the hgand has been reported recently. Since these ligands are stable in the presence of oxidising agents, they prevent Pd precipitation and double-bond isomerisation (Scheme 35) [141]. 

An important application of an isomerisation is found in the Takasago process for the commercial production of (-)menthol from myreene. The catalyst used is a rhodium complex of BINAP, an asymmetric ligand based on the atropisomerism of substituted dinaphthyl (Figure 5.5). It was introduced by Noyori [1],... 

The synthesis of menthol is given in the reaction scheme, Figure 5. 6. The key reaction [2] is the enantioselective isomerisation of the allylamine to the asymmetric enamine. It is proposed that this reaction proceeds via an allylic intermediate, but it is not known whether the allyl formation is accompanied by a base-mediated proton abstraction or hydride formation. 

The use of cyclic alkenes as substrates or the preparation of cyclic structures in the Heck reaction allows an asymmetric variation of the Heck reaction. An example of an intermolecular process is the addition of arenes to 1,2-dihydro furan using BINAP as the ligand, reported by Hayashi [23], Since the addition of palladium-aryl occurs in a syn fashion to a cyclic compound, the 13-hydride elimination cannot take place at the carbon that carries the phenyl group just added (carbon 1), and therefore it takes place at the carbon atom at the other side of palladium (carbon 3). The normal Heck products would not be chiral because an alkene is formed at the position where the aryl group is added. A side-reaction that occurs is the isomerisation of the alkene. Figure 13.20 illustrates this, omitting catalyst details and isomerisation products. 

An elegant example of a highly efficient catalytic asymmetric synthesis is the Takasago process [128] for the manufacture of 1-menthol, an important flavour and fragrance product. The key step is an enantioselective catalytic isomerisation of a prochiral enamine to a chiral imine (Fig. 1.44). The catalyst is a Rh-Binap complex (see Fig. 1.44) and the product is obtained in 99% ee using a sub-strate/catalyst ratio of 8000 recycling of the catalyst affords total turnover numbers of up to 300000. The Takasago process is used to produce several thousand tons of 1-menthol on an annual basis. 

The few catalytic applications reported so far using imino functionalised NHC gave very ordinary results and given the isomerisation behaviour depicted in Figure 3.41, it is not expected that performance in asymmetric applications will be satisfactory. 

Although the hemilabile behaviour of the imino functional group together with an apparent isomerisation process on palladium may make it difficult to achieve high chiral resolution (ee) in asymmetric catalysis. Bonnet and Douthwaite developed an imino functionalised carbene ligand system based on the diamino cyclohexane framework that has achieved ees of up to 92% in palladium catalysed allylic alkylatiou reactions using ( )-l,3-diphenylprop-... 

The structure revealed the basis for the pronounced allosteric nature of the enzyme. Initial rates of UDPGlcNAc isomerisation give a Hill coefficient [eqn. (5.20), Figure 5.5] of 2.29 and epimerisation of UDPManNAc does not take place except in the presence of its epimer. The asymmetric unit of the crystals of UDPGlcNAc 2-epimerase contains four copies of the enzyme arranged as two similar copies of the biological homodimer, with each dimer composed of one... 

With cracking, the active zone is, by definition, asymmetric. Consequently, the possibilities of external symmetries are eliminated. In addition, in this case each activated complex corresponds to one and only one reaction type—in our example, secondary-secondary. The same is not true for PCP isomerisation, whose activated complexes include nc carbon atoms and nb-1 branches, and which requires some additional developments (external symmetries, etc. Valery, 2002). 

There are bicyclic monoterpenes too - a-pinene 89 and p-pinene 91 share a common skeleton with four- and six-membered rings but have the alkene in different places. There is a discussion in chapter 24 on the variable ee of a-pinene and it is better to make the ( )-enantiomer from the more reliable P-pinene 91 (99% ee) that can be isomerised with strong base ( KAPA ) 92 in 93% yield to ( -)-90 without loss of ee. Many asymmetric reagents for reduction (chapter 24) and chiral auxiliaries for asymmetric aldol reactions (chapters 27 and 30) are based on a-pinene.25... 

The acid components required for the synthesis of the ester alkaloids, (+)-trachelanthic and viridifloric acids, were synthesised by stereospecific routes, since the relative stereochemistry of the asymmetric centres in these acids was still uncertain. Eventually they were obtained by appropriate stereospecific icis or trans) hydroxylation of trans-2-isopropylcrotonic acid (34), and its cis-isomer obtained by photochemical isomerisation. After resolution, (+)-trachelanthic acid was identified as the t/irco-2-isopropyl-2,3-dihydroxybutyric acid (35) the corresponding erythro-isomet was identified as viridifloric acid. 

In some cases the formation of carbonyl derivatives of the amines can reduce the useful yield.6 These products arise from the hydrolysis of the isomerised Schiff base 14. Interestingly, it has been shown that the final product is not derived from these carbonyl byproducts. Cope et al. showed that, in the case of methylation of optically active amines in which the asymmetric carbon is alpha to the amine, complete retention of configuration was... 

While the use of achiral ACTCs in catalytic hydrogenation and isomerisation reactions is well-studied [14], planar chiral derivatives for asymmetric catalysis have so far received relatively scant attention. 

The isomerisation of allyhc amines into the corresponding enamines is an excellent example of asymmetric catalysis, which has been exploited on a commercial basis. The isomerisation of the aUylamine (12.01) with a rhodium/BINAP complex occurs with excellent yield and enantioselectivity to give the enamine (12.02) as the initial product. ... 

The ring-chain isomerisation of phosphino-substituted triazolo-pyridines was found to depend on the nature of the phosphine substituent. Conversion of the phosphines to their selenides resulted in a complete shift of the equilibrium towards electron-acceptor structure D (Scheme 10). Acenaphthene and acenaphthylene were converted to polycyclic phosphole derivatives via Ti(II)-mediated cyclization of the corresponding dialkynylated arenas. The related phosphole oxides were stable species (Scheme 11). Asymmetric lithiation of dimethyl-tert-butylphosphine sulfide and trimethylsilylation gave an intermediate that was subjected to a five-step reaction sequence including metallation, P-functionalization (in three steps) and removal of the silyl group to yield the precursor of Mini-PHOS (Scheme 12). ... 

Isomerisation studies indicate that the iminium ion formed initially prior to isomerisation as the amount of ( ) product increased over time. Only the (Z) isomer was observed after 10 min. Notably, nonenolisable aldehydes i.e. acrylaldehyde and cinnamaldehyde) were unreactive, indicative of an enamine-type mechanism as opposed to a typical aza-MBH route. Several procedures for the asymmetric, proline-catalysed MBH reaction between methyl vinyl ketone (MVK) and aromatic aldehydes have been developed to date. ... 

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