Descripción textual de los casos de uso del Sistema

Chiral ketones are synthesised by deprotonation of the desired chiral hydrazone, alkylation with a suitable electrophile and cleavage of the hydrazone to the parent ketone using a suitable cleavage method.

The first step in this investigation was to perform a solvent screen to ascertain which solvent gave the best enantioselectivity for the alkylation of the chiral hydrazone. The alkylation of 3-pentanone hydrazone (S)-156 was carried out using benzyl bromide as the electrophile in three different solvents (Table 2.1) to provide alkylated chiral hydrazone (S)-161. Cleavage was implemented using a biphasic HCl/diethyl ether system to provide desired chiral ketone (S)-143. The

72 highest enantioselectivity of (S)-143 was observed when diethyl ether was the solvent used in the reaction (Table 2.1, entry 1) and so deemed to be the solvent of choice for the rest of the investigation. This was as expected, as SAMP-hydrazone methodologies also usually involve diethyl ether as solvent.^15-17 Table 2.1 Solvent Screen for alkylation of hydrazone.

Entry Solvent Yield (S)-143 (%)^a

ee (S)-143 (%)^b

1 Diethyl ether 10 89

2 THF 12 66

3 Toluene 15 61

a Isolated yields quoted over 2 steps; ^b as determined by chiral GC analysis.

Next, it was necessary to establish how many equivalents of LDA would be required and at what temperature the deprotonation step was most successful.

A range of equivalents of LDA and temperatures were chosen (Table 2.2) for the alkylation of 3-pentanone hydrazone (S)-156 with allyl bromide.

73 Table 2.2 Investigation into deprotonation conditions required for alkylation.

Entry Deprotonation Conditions

LDA (equiv.)

Conversion^a (S)-156 → (S)-162

1 33 °C, 5 h 1.1 82%

2 RT, 5 h 2.1 100%

3 0 °C, 16 h 1.1 100%

aAs determined by ¹H NMR.

Two of the conditions investigated achieved 100% conversion (Table 2.2, Entries 2 and 3). However, in the interest of keeping the amount of LDA used at a minimum, it was decided to proceed with deprotonation conditions using 1.1 equivalents of LDA at 0 °C for 16 h for the rest of the investigation.

Various methods for the cleavage of α-substituted hydrazones to the corresponding ketone are available.¹⁸ Oxalic acid has been reported as a convenient, high yielding, racemisation-free method for the hydrolytic cleavage of SAMP hydrazones.¹⁹ Two biphasic cleavage methods, oxalic acid/diethyl ether and the well-established HCl/diethyl ether, were investigated with both the novel chiral auxiliary and SAMP. Hydrazone (S)-157 and the corresponding SAMP variant (S)-163 were prepared and subjected to LDA and benzyl bromide (Table 2.3). Both alkylated hydrazones were hydrolysed using oxalic acid/diethyl ether and HCl/diethyl ether. Using the SAMP hydrazone (S)-163, benzylated propiophenone (S)-152 was obtained in 92% ee and 88% ee using oxalic acid and HCl/diethyl ether cleavage methods, respectively (Table 2.3, entries 3 and 4). A larger variation in enantioselectivity was observed between the two cleavage methods when hydrazone (S)-157 was employed in the reaction, with 51% and 78% ee observed when using oxalic acid and HCl/diethyl ether cleavage methods,

74 respectively (Table 2.3, entries 1 and 2). The low yields of benzylated ketones observed using both the novel chiral auxiliary and SAMP reflect the challenges of this particular transformation.

Table 2.3 Racemisation studies of chiral hydrazones (S)-157 and SAMP variant (S)-163.

Conditions: (a) 1. n-BuLi (1.15 equiv.)/DIPA (1.10 equiv.), diethyl ether; 2.

Benzyl bromide (1.20 equiv.); (b) Oxalic acid, diethyl ether; (c) 4M HCl, diethyl ether.

Entry Hydrazone Cleavage method

Yield (S)-152 (%)^a

ee (S)-152 (%)^b

1 (S)-157 Oxalic acid,

Et2O

15 51

2 (S)-157 4M HCl,

Et2O

31 78

3 (S)-163 Oxalic acid,

Et2O

36 92

4 (S)-163 4M HCl,

Et2O

26 88

a Isolated yields quoted over 2 steps; ^b as determined by chiral GC analysis.

It is possible that the decrease in enantioselectivity was caused by either epimerisation of the chiral benzylated hydrazone or by racemisation of the chiral ketone itself. To investigate which of these was the case, (S)-152 was exposed to the oxalic acid cleavage conditions for 28 h and subsequent enantiopurity determined (78% ee). As no change to the value of the enantiopurity (78% ee) was observed, this indicates that epimerisation of the chiral benzylated hydrazone

75 occurs when oxalic acid is used in combination with our hydrazone. This may be due to protonation of the pyrrolidine in the chiral arm, resulting in increased solubility and exposure to the aqueous acidic layer. This result underlines the need for thorough investigation of cleavage methods in such cases.

With usable hydrolysis conditions in hand, a variety of electrophiles was reacted with the azaenolate derived from (S)-156. Cleavage of the hydrazone moiety resulted in chiral ketones with good to excellent enantioselectivity, albeit in low yield (Figure 2.6). In all cases, the alkylated hydrazone was not isolated.

The use of benzyl bromides as electrophiles in hydrazone chiral auxiliary methodology has been very limited. In fact, no thorough investigation of benzyl based electrophiles has been reported using chiral hydrazone methodology. A plethora of electrophiles were used affording ketones (S)-143-148 and (S)-164-165, all with moderate to high enantioselectivity. Substituted benzyl groups allowed investigation of the effect of electron donating and electron withdrawing groups present on the electrophile. From Figure 2.6, it is apparent that the presence of electron withdrawing groups on the benzyl moiety caused a decrease in enantioselectivity of the resultant ketone when compared to the unsubstituted benzyl bromide [(S)-143, 89% ee], which is most apparent with the use of perfluorobenzyl bromide [(S)-144, 48% ee] and p-nitrobenzyl bromide [(S)-147, 58% ee]. The presence of an electron donating group, for example the use of p-methoxybenzyl bromide [(S)-146, 84% ee] and t-butylbenzyl bromide [(S)-148, 87% ee], had little effect on the enantioselectivity observed. When 2-bromobenzyl bromide was used as the alkylating agent, the final ketone (S)-145 was obtained in 86% ee. This is similar to the enantioselectivity of the ketone obtained when benzyl bromide is used as the electrophile [(S)-143], which suggests that the position of the substituent on the benzyl ring, as well as the nature of the substituent itself, is crucial to affecting the enantioselectivity. The cleavage of p-bromobenzylated and p-trifluoromethylbenzylated hydrazones was carried out using sat. aq. oxalic acid/diethyl ether prior to the discovery that this method resulted in racemisation. Thus the enantioselectivity of chiral ketones (S)-164 and (S)-165 obtained cannot be directly compared with that of (S)-143, however it can be speculated that the enantioselectivity obtained would be lower than that observed for (S)-143 due to the presence of electron withdrawing groups at the para-position.

76 To the best of our knowledge, the enzymatic cleavage of chiral hydrazones has not been reported. Mino and co-workers²⁰ reported the use of porcine pancreatic lipase (PPL) as an effective method of deprotecting ketone dimethylhydrazones. The reaction was carried out on achiral substrates and achieved generally high yields. As a lipase-catalysed deprotection of chiral hydrazones had not been attempted to date, it was decided to investigate how successfully this methodology could be applied to our system. Results obtained from the cleavage of chiral benzylated 3-pentanone hydrazone gave the chiral product (S)-143 in 83% ee, albeit in a low yield of ca. 10 % over 2 steps. Due to the increasing emphasis on green chemistry in both industry and academia, this result is promising and encouraging as a method for hydrolysis of chiral hydrazones as the reaction is carried out in a biphasic acetone/water mixture at ambient temperature.

77 Figure 2.6 Chiral ketones synthesised using novel chiral hydrazone methodology.

Yield is calculated over 2 steps – alkylated hydrazone not isolated. ^a HCl/Et2O hydrolysis; ^b PPL hydrolysis; ^c sat. aq. oxalic acid hydrolysis; ^d t-BuLi used as base.

78 Reaction of (S)-156 with allyl bromide, 3,3-dimethylallyl bromide and geranyl bromide provided (S)-149-151 respectively in similar enantioselectivity (Figure 2.6), suggesting that an increase in alkyl chain length has no detrimental effect on the enantioselectivity of the product. The reaction of 3-pentanone hydrazone (S)-156 with LDA and pentyliodide provided (S)-166 in 92% ee (Figure 2.7), albeit in moderate yield. When t-BuLi was employed as the base instead of LDA, the selectivity dropped slightly to 82% ee, reaffirming that LDA is the optimum base for the reaction.

Figure 2.7 GC trace of product of reaction of (S)-156 with n-pentyl iodide showing (S)-166 obtained in 92% ee.

Further to these studies, it was decided to investigate the effect of electronic substituents present on the hydrazone moiety. Propiophenone, p-methoxypropiophenone and p-fluoropropiophenone hydrazones (S)-157-159 were chosen as substrates and subjected to the standard conditions using allyl bromide as the electrophile. The resultant ketones (Figure 2.8) demonstrate that the presence of an electron donating substituent on the ring ((S)-154, 79% ee) results in a decrease in enantioselectivity when compared to the unsubstituted ketone ((S)-153, 89% ee). The presence of an electron withdrawing substituent ((S)-155, 90%

79 ee) had little effect on the enantioselectivity. It was also noted that an increase in enantioselectivity was observed when allylbromide was used as the electrophile ((S)-153, 89% ee) compared to when benzyl bromide was used as the electrophile ((S)-152, 78% ee), suggesting that the structure of the electrophile may have an influence on the enantioselectivity of the final product, at least when dealing with propiophenone-based hydrazones.

Figure 2.8 Chiral ketones synthesised using novel chiral hydrazone methodology.

Yield is calculated over 2 steps – alkylated hydrazone not isolated. ^a HCl/Et2O hydrolysis; ^b sat. aq. oxalic acid hydrolysis.

The ketone products (S)-143-155 and (S)-164-166 have been assigned as (S) by comparison of the optical rotation value of chiral 153 with that reported in the literature²¹ and others by analogy. All ee values were determined using chiral GC analysis and confirmed by comparison with independently prepared racemic ketones.

80 2.6 Origin of stereoselectivity in alkylation reactions with novel hydrazone

The selectivity of the chiral ketones obtained from the alkylation of novel hydrazones was observed to be the same as those obtained from the alkylation of SAMP hydrazones. This suggests that a similar azaenolate intermediate occurs, with an ECCZCN configuration resulting on deprotonation with LDA. This rigid intermediate allows attack of an electrophile to proceed under high diastereofacial differentiation, yielding highly diastereomerically enriched hydrazones and ultimately enantiomerically enriched α-substituted ketones upon cleavage of the chiral auxiliary. Attack of the electrophile from the top (re) face is sterically disfavoured, so preferential attack occurs from the bottom (si) face.