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Solvent plays an im portant role during transition metal catalysis as vacant coordination sites on the metal are invariably occupied by the solvent. M odifying the properties of the solvent would effect the progress and possibly the outcom e of the reaction. TH F solvates the form ed allylic alkoxide follow ing basic deprotonation of the corresponding alcohol, and it is known that lithium aikoxides form aggregates in s o l u t i o n , t h u s rendering the oxygen lone pairs on the alkoxide less available fo r donation.

THF was also considered to be a possible source of hydride or protons, which may be vital, or progressively detrim ental to the isomérisation process. The hydrogen on the a-carbon in THF

112 Results and D iscussion

could be abstracted as a hydride by the catalyst in the same way as the hydride fro m the substrate during isomérisation (Schem e 145)}^° Solvents such as benzene, toluene, and 2,2,5,5-tetram ethyl-tetrahydrofuran were accordingly considered as each did not possess a possibie source of hydride or protons.

Hydride Source Ni-H

o

2,2,5,5-Tetram ethyl-tetrahydrofuran was impractical as a solvent as it faiied to dissoive any of the starting materiais. However, the choice of benzene as solvent offered som e unexpected results (Figure 146). Although the lithium aikoxide did not appear to dissolve in the solvent, the corresponding enol acetates were nevertheless isolated in 46% yield, with an (E):(Z) ratio of >20:1. Conducting the same experiment at room temperature gave the enol acetate in a lower 17% yield, but still with an (E):(Z) ratio of >20:1. Disappointingiy, no asym m etric induction was detected in either case by chiral ^H-NMR.

(61) (i) n-BuLi O H (') N i(C0 D )2/L igan d, Benzene (ii) ACgO, -7 8 °C - - - a 2.5 hours 1 7 % a t 2 0 ° C 4 6 % at 80°C O A c O Ac 20 : 1 0% ee Ligand : (115) (116)

Figure 146 : isomérisations of geraniol in benzene

( IT Ti >

The use of benzene as solvent was clearly a desirable facet in term s of stereocontrolled enolate form ation, and it was of some consternation that the enantiomeric excess did not reflect this resuit, even when the reaction was performed at room tem perature. In addition, significant quantities of oligom eric m aterial was also formed during the reaction, contam inating the enol acetate despite purification by coiumn chromatography. Nevertheless, the stereochem ical outcom e of the reaction, even at room temperature, was considerably greater than the stereoselectivities obtained with previous catalyst systems.

113 Results and Discussion

The poor solubility of the alkoxide in benzene suggested the form ation of extensive aggregates by the alkoxide in solution, and therefore the unlikely form ation of a “ m onom eric” alkoxide species. Previous studies in which an attem pt to break up this aggregation in order to form “ m onom eric” aikoxides by the addition of complexing agents such as TMEDA, DMPU, TDA-1^'*\ LiCI and 12-crown-4 had been carried out within our group.^^^ Decreased reaction rates were noted, but without significant influence to the stereochemical outcom e of the isomerisations.^^^ In an attem pt to enforce an asymmetric environm ent for an enantioselective isom érisation to occur, we considered using chiral lithium chelating agents as an alternative to using chiral ligands. An abundance of such chelating agents are readily available from carbohydrates by simple alkylation of the hydroxyl functionalities. The wealth of knowledge and m ethodology that has accum ulated with respect to the application of carbohydrates as chiral tem plates for asym m etric induction is quite extensive,^'^^ thus it seemed appropriate to exploit these poly­ alkylated carbohydrates for our own purposes.

Two derivatives of D-mannitol (182) were investigated, namely 1,2:5,6-di-0-isopropylidene-3,4- d i-O m ethyl-D -m annitol (IBS) and 1,2,3,4,5,6-hexa-O-methyl-D-mannitol (184). Both were prepared in excellent yield by the Purdie méthylation on 1,2:5,6-di-0-isopropylidene-D -m annitol (185) and D-mannitol (182) respectively, using silver(l)oxide and methyl iodide (Figure

147).243,244 O H O H A g p , M el, M eCN 92% (185) O M e O M e (183) H O O H 80% Figure 147 M eO O M e A g p , Mel, M eCN O M e ,M e O O M e (184)

In a typical experim ent one equivalent of the poly-alkylated carbohydrate was added to a solution of the alkoxide in THF. The resulting mixture was then added via cannula to the catalyst solution. Results using the alkoxide of geraniol (61) and 1,2,3,4,5,6-hexa-O -m ethyl-D-m annitol (184) are given below (Figure 148).

114 Results and Discussion

(i) n-BuU

(ii) 1 equiv. Sugar

(iii) NiCl2(PPh3)2/r>BuLi (iv) ACgO

O H

(i) n-BuU

(ii) 20 mol% Sugar

(iii) N i(C0 D )2&igand

(iv) ACgO

(61)

No Reaction.

Deactivation of

the catalyst Sugar : M e O E :Z 4.7:1 N o ee. M e O ' 11 O M e M eO I' OMe M eO (184) Figure 148

The NiCl2(PPh3)2/n-BuLi catalyst was able to isomerise the aikoxide of geraniol (61) in 65%, but in the presence of the sugar, it was noted that the catalyst had deactivated very shortly after m ixing the alkoxide/sugar and catalyst solutions. This was possibly due to therm odynam ic reasons, whereby the coordinating ability by the hexadentate sugar being superior to that achieved by the two monodentate tricyclohexylphosphine ligands. Ligands with a greater capacity to bind to the metal were attempted, and using the bipyridyl ligand with Ni(CO D)2, 46% yield of the enol acetates were isolated. Although, no enantiom eric excess were detected by chiral shift ^H-NMR, nevertheless the reaction proceeded in good yield in the presence of the chiral lithium chelating agent. Clearly, a system based on this method of asym m etric induction, perhaps in combination with a suitable metal chelating ligand, has potential and therefore warrants further investigation.