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173 Conclusions and Perspectives

Conclusions and Perspectives

This work has dem onstrated the applicability of nickel based catalyst system s in the generation of m etal enolates from allylic alkoxides.

Much of the work has used the Ni(C0D)2 com plex in combination with a ligand. Although good levels of stereocontrol were achieved using trialkyl- or triaryl-phosphine ligands, the use of pyridine as ligand offered the highest stereoselectivity, particularly fo r prim ary allylic alkoxides in which (E) : (Z) enolate ratios greater than 1 5 : 1 were observed.

Mixing, or equilibration, of the enolate regioisomers was observed fo r both the Ni(COD)2/Ligand and NiCl2(DIPH O S)/LiBEt3H catalyst systems. Sim ilar observations were noted with the previous rhodium catalysts but not, surprisingly, with the (Cy3P)NiCl2/n-BuLi catalyst system. The equilibration process is likely to operate via a transition metal mediated process, however the reason fo r the high regioselectivity exclusively with the (Cy3P)NiCl2/n-BuLi nickel catalyst is not clear.

The form ation of tetrasubstituted enolates using this methodology was m oderately successful with the best (E) : (Z) enolate ratio obtained approxim ately 5 : 1 . This com pares well against the highest (E) : (Z) ratios obtained with the other catalyst systems used within the group.

Chiral bidentate phosphine ligands were previously shown to be ineffective as ligands in the N i(C0D)2 catalyst system, in that the aikoxide of the prochiral allylic alcohol, geraniol, failed to isomerise. Nitrogen based ligands were therefore employed, such as the chiral jb/s(oxazoline) or chiral bipyridyl ligands. Although these ligands have been used to great effect in several other asym m etric catalytic systems, no enantiomeric excesses were detected i n . t h e isomerised products either by chiral shift ^H-NMR, or by chiral GC.

The influence of the ligand on the outcome of the isomérisation reaction was noted in two ways. First, the use of excess ligand led to a reduction in the rate of the reaction. Second, the varying yields of isom erised product, from 0% to 83%, indicated a significant influence by the ligand on the outcom e of the isom érisation reaction. Colloidal nickel, which is an aggregate of Ni(0), was shown not to play a significant part in the isomérisation process, thereby confirm ing that the active species is homogeneous, possibly Ni(0)(Ligand).

Although m odification to the reaction mixture, such as using benzene instead of TH F as solvent, led to a dram atic increase in the stereoselectivity of the reaction, even at room tem perature, no asym m etric induction was achieved. The use of polyalkylated sugars, however, to provide an asym m etric environm ent about the 0 -L i aggregate was an intriguing m ethod in which to achieve enantioselectivity, although initial experiments offered no asym m etric induction. Nevertheless,

174 Conclusions and Perspectives

sugars are commonly used as chiral tem plates in a range of asym m etric and catalytic reactions, and therefore further attempts to incorporate this chemistry into our m ethodology could lead to som e encouraging results.

Isotope labelling studies demonstrated that the isomérisation reaction operates via a 1,3-hydride shift, and not via a metal-hydride addition and elimination mechanism, which was originally considered to account fo r the absence in enantioselectivity. Further studies will attem pt to confirm that the 1,3-hydride shift mechanism operates via an intram olecular process. If this is not the case, then dissociation of the interm ediates during the isom érisation process is likely, w hich would lead to a decrease in the enantioselective capability of the catalyst system.

A uthentic chiral enolate, under the standard conditions of the isom érisation reaction, was found to racemise, affording racemic enol acetate following reaction of the enolate with acetic anhydride. Several suggestions have been made which may account fo r the racém isation of the chiral enolate product, depending on whether a jc-allyl or enone m echanism was in operation. The possible involvem ent of the COD ligand itself in the isom érisation process would also need to be investigated, as the form ation of achiral com plexes is possible, which may function as better catalysts than the chiral complexes, thus reducing the level of asym m etric induction. A lternative ligands, such as NBD, may therefore provide a fascinating insight into this nature of th e active catalytic species.

Noyori and co-workers have reported the asym m etric isomérisation of geraniol, in the presence of the chiral [Rh(BINAP)]^ catalyst, to the aldehyde, citronellal, in 70% yield and 37% ee. No other products were reported. When we repeated the same reaction, however we detected only trace amounts of the aldehyde amongst the plethora of products that were also produced. Analysis of the reaction mixture by chiral GC detected iso-pulegol with an optical yield of nearly 50%, and iso-iso-pulegol, detected in 48% ee. Iso-pulegol may be synthesised from citronellal by a Lewis acid catalysed ene cyclisation reaction, and it was apparent that some of the isomerised product, citronellal, had cyclised to iso-pulegol. The same catalyst was able to isom erise N,N-

diethylgeranylam ine in good yield, thereby confirm ing the activity of our prepared rhodium catalyst. It is uncertain why the aldehyde was not isolated in thé sam e proportion as that reported by Noyori and co-workers, but nevertheless, the form ation of iso- and iso-iso-pulegol, albeit in low yield (ca. 13%), was of great interest as its preparation form s one of the key steps in the Tagasako process fo r the industrial synthesis of menthol. Further investigations will be conducted in this area in order to increase the chem ical and optical yields of these compounds. The addition of catalytic quantities of base is com m only employed in order to increase the rate of transfer hydrogenation reactions, therefore, it will be interesting to see what effect the addition of base, for example potassium f-butoxide, will have on the outcom e of the isom érisation reaction of geraniol.

175 Conclusions and Perspectives

It was also unexpected that the same rhodium catalyst was able to isomerise the aikoxide of geraniol, as all previous attempts to isomerise this substrate using other rhodium catalysts had failed, it was realised that the addition of a slight excess of />BuLI had contributed to this activity, with the possible form ation of a hydridorhodium species. Although hydridorhodium species such as (Ph3P)4RhH have been shown to isomerise allylic alcohols, yields are generally low fo r substituted substrates,^® and it should be noted that the aikoxide of geraniol, a hindered and tri-substituted allylic alcohol, was isomerised in 69% yield. It is not clear whether a new catalytic species has been generated, or if it is the same interm ediary species that is form ed follow ing hydride abstraction from the aikoxide, but in greater concentration.

Ligand architecture certainly has an influence on the outcom e of the reaction, and it is likely that ligands specifically tailored to meet the needs of the isom érisation will be required in order to enforce a rigid and an extensive chiral environment about the transition metal centre fo r an enantioselective isomérisation to occur. Ligands such as (271) com bine the use of steric bulk to create such an environment, in addition to coordination sites fo r the aikoxide counter cation to chelate, thus drawing the substrate into closer proxim ity to the catalytic centre, and increasing the prospect for enantioselectivity.

p—N

(271)

In summary, this work demonstrates the applicability of using transition metals to m ediate the isom érisation of allylic alkoxides to prepare enolates in a regio- and stereoselective manner. The reasons fo r the lack of enantioselectivity exhibited by both the nickel and rhodium catalyst system s using an allylic aikoxide as substrate remains unclear, nevertheless, such a transform ation, albeit ambitious, is not impossible and it is likely that in tim e such a goal can be achieved.

Chapter 3