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6.1 Asymmetric epoxidations

The asymmetric epoxidation is a widely used technique in asymmetric synthesis. This is because chiral epoxides are an effective source for the stereocontrolled introduction of a nucleophile adjacent to a chiral alcohol (which is itself a useful group for functional group interconversions).

The lability o f the titanium-oxygen bond is the prime reason for the success o f the Sharpless asymmetric epoxidation. The ability for the substrates to attach themselves around this metallic centre and disassociate easily is what makes the reaction catalytic (see section 1.5.1). The chiral source of the epoxidation is the tartrate unit and the absolute configurations of the chiral centres within this dictate the enantioselectivity of the reaction. It is conceivable, therefore, for any chiral diol to exert some chiral control upon this reaction, as long as the resulting structure is geometrically possible. Ci-symmetric diamine- diol 224 was used with this in mind. It was hoped that where the use o f a tartrate normally forms the catalytic structure 139, ligand 224 might for analogous catalytic structure 349. R" _R' OiPr COgR iPrO,, RO :Ti COoP'-Ti’ m o ^ R ,„ / 0 X 0 2 R tBu O iP r / R tBu 139 349

Chapter 6 Other asymmetric processes 138

The epoxidation was performed on geraniol; an allylic alcohol whose epoxidation is well d o c u m e n te d /T h e reaction was carried out under exactly the same conditions as for a normal Sharpless asymmetric epoxidation save for the direct replacement of the tartrate with ligand 224 (Scheme 6.1). This gave a 22% yield of 351.

OH

350 351

Scheme 6.1 : Reagents : i) Ti(OfPr)*, 224, r-BuOOH, 4A molecular sieves, DCM, -20 °C.

Initially, the introduction of a phenyl group into 351 by acylation of the alcohol with diphenylcarbamyl chloride was attempted. This would allow analysis of the enantiomeric excess by HPLC. Unfortunately, this led to a mixture of compounds o f which 352 and 353 were identified in the low resolution mass spectrum (the HCl that was produced presumably added across the double bond in a Markownikov fashion. Scheme 6.2).

351 352 353

Scheme 6.2 : Attempted 0-acylation with diphenyl carbamyl chloride led to a mixture of compounds.

Fortunately, the optical rotation of the 100% optically pure material is known and so the enantiomeric excess of the material produced in this reaction could be discerned, as is common practice. It was found by this method that the enantiomeric excess relative to this value was 5% in favour of the (S)-enantiomer. However, in practice this method has a similar error margin and so all that can be deduced is that the enantioselectivity o f ligand 224 is either very low or none at all.

Chapter 6 Other asymmetric processes 139

The epoxidation using the Julia-Colonna methodology discussed in Section 1.5.3 was applied to ligand 213 in the hope that the intramolecular hydrogen bonded system might act in the same way as poly-L-leucine. This rather naïve position was taken in the epoxidation of chalcone with 213 and did give epoxychalcone in a yield of 12% but with no enantioselectivity (Scheme 6.3).

1 0 2a

Scheme 6.3 : Reagents : i) Ligand 213, toluene, H2O2, NaOH

6.2 Asymmetric deprotonations

157

A key feature o f many of the ligands used to induce chirality on lithium mediated reactions is that they have a tertiary amine with another heteroatom, commonly a secondary amine, in a position beta to it (see section 1.6). With this in mind, ligand 233 was used in the attempted desymmetrisation o f cyclohexene oxide which had already been successfully carried out using ligand 354, available from Aldrich. Unfortunately, the use of ligand 233 did not produce any allylic alcohol product (Scheme 6.4).

0 H OH 164 165 ₃₅₄ 11 OH 164 165 Ph Ph NH Ph 233

Scheme 6.4 : Reagents ; i) 354, diisopropylamine, DBU, THF, n-BuLi, 0 “C, 24 h. ii) 233, diisopropylamine, DBU, THF, n-BuLi, 0 T , 24 h.

Chapter 6 Other asymmetric processes 140

Ligand 233 was also attempted in the deprotonation o f ^-tert-

butylcyclohexanone. This was also successfully executed with ligand 354, but again ligand 233 failed to give any deprotonation product at all (Scheme 6.5). It was thought that this was due to the benzyl groups on the diamine being to large and bulky for any substrate to orientate around. This was the primary reason for the attempted synthesis o f ligand 248, although the enantiopure synthesis of this was eventually abandoned (see section 2.5).

O SiM e, 187 188

9 ^ »

o

Scheme 6.5 ; Reagents : i) 354, /j-BuLi, hexamethylphosphoramide (HMPA), -78 “C, 1 h, trimethylsilyl chloride, -78 °C, 15 min. ii) 233, «-BuLi, hexamethylphosphoramide (HMPA), -78 “C, 1 h, trimethylsilyl chloride, -78 °C, 15 min.

Chapter 6 Other asymmetric processes 141

6.3 Asymmetric hydrocyanations

The enantioselective addition o f a cyanide group to a carbonyl is another important carbon-carbon bond forming reaction as has been discussed in section

1.3.4. Amide ligands 286 and 287 were attempted in the addition o f trimethylsilylcyanide to benzaldehyde (scheme 6.6).^^^ It was hoped that they

would resemble amides such as that used by Inoue^^ in that they were optically pure and had two secondary amides.

N '^ 0 H 65 286 ^ 287 f.NH O 17 54

Scheme 6.6 ; Reagents : i) Ti(OiPr)*, 4Â molecular sieves, TMSCN.

Unfortunately, the results to this reaction were highly inconsistent and the enantioselectivities ranged from 10% o f (S)-54 to 94% in the case of ligand 286. Enantioselectivities for the reaction using amide 287 as a catalyst gave (S)-54 in a range o f 5% e.e to 24% e.e. The inconsistencies in this process are not understood and further investigation is required on this potentially useful catalytic system.

Chapter 7