Desarrollo de la práctica

Having shown that substitution at the C-5” position had little influence over selectivity, and yet with evidence in hand that catalysts 130 and 147 perhaps adopted different

conformations and possessed very different selectivity profiles, it was decided that investigating substitution at 6” would allow us to clarify that this effect was in fact due to difference in conformation and not any other unspecified reason.

Figure 4.4 The difference in demand at C-6” is shown for 130, 147 and148.

Figure 4.4 highlights the differences and similarities of catalysts 130, 147 and 303,

showing that steric bulk at C-6” (highlighted in red) appears to confer significant change in the selectivity and activity profiles of otherwise similar catalysts. To investigate this, a number of potential catalysts were proposed. These are shown in Figure 4.5 .

135

Figure 4.5 Proposed C-6” substituted catalyst candidates

The range of catalysts was chosen such as to give as wide an array of size of substituent as possible while also allowing for practical synthesis. It was also envisaged that the meta- substitution pattern of the oxygen atoms on the C-9 phenyl ring would lower the pKa of the

phenol in a manner that would increase reactivity. Some pKa data for meta substituted

phenols related to 130, 317, 318 and 319 are provided for reference, these data refers to

pKa in water as data for these molecules in DMSO were unavailable.221,229

It was envisaged from the outset that the SNi reaction might prove highly challenging

given the difficulty experienced thus far with other highly hindered substrates in this reaction. As a result it was decided to approach the reaction by attempting the synthesis of the most structurally simple member of this group i.e. 318.

In order to achieve the required 2,6-dihydroxy substitution pattern, the synthetic route began with resorcinol (323) with the ortho-directing meta distributed hydroxyl groups

providing the necessary directing effect to allow facile, regioselective iodination. In this case iodine was used as the halogen in place of bromine as the resulting Grignard reagent was shown to give superior results in the SNi reaction when compared to the equivalent

aryl magnesium bromide.214

HO OH HO OH O O I Ph Ph I I₂, NaHCO₃ H₂O, 0oC 30 min BnBr (2.01 eq.) K₂CO₃(3.0 eq.) Acetone 323 32494% 32591%

136

Reaction of 323 with molecular iodine at reduced temperature gave rapid and selective

formation of 324. The iodoresorcinol 324 was benzylated using the standard procedure

(Scheme 4.17) and the resulting aryl halide was transformed into the corresponding Grignard reagent and allowed to react with Q22a as shown in Scheme 4.18.

Scheme 4.18 Synthesis of 9-epi-deoxy(2,6-dihydroxy)phenylquinine (327)

Pleasingly (with use of sufficient excess of Grignard reagent) it was possible to obtain a reasonable yield of the protected catalyst 326. Deprotection proceeded smoothly under

catalytic hydrogenation conditions to give 327. The resulting product was however

unstable, slowly oxidising over time requiring it to be used promptly after synthesis.

With the other synthetic objectives now seemingly more tractable it was decided to attempt the synthesis of other analogues. Precursors 329, 330 and 331 were synthesised via

acetalisation, as shown in Scheme 4.19 with the MOM protecting group chosen both for synthetic ease (as it was expected to provide higher yields in the desymmetrisation of 324)

and because its (marginally) lower steric bulk when compared to a benzyl group was expected to provide a Grignard reagent which would more readily undergo the required SNi reaction.

137

Scheme 4.19 Synthesis of precursors required for 319, 321 and 322

Unfortunately the subsequent reaction failed in all three cases, despite clear formation of the Grignard reagent in all three cases. Even trace product formation was not observed. It was thus speculated (since the steric demand of the methyl derivative was definitely lower than the already successful benzyl analogue) that the MOM protecting group may be incompatible with the SNi reaction mechanism in these cases (where two oxygen atoms are

situated ortho to the carbon-magnesium bond) as it may result in over coordination of the magnesium atom preventing its participation in the coordination steps required for the SNi

mechanism. O O I O R 329X = I, R = Me 330X = Br, R =iPr 331X = Cl, R = 9-anthracenylmethyl Mg, THF Reflux O O IMg O R 329aR = Me 330aR =iPr 331aR = 9-anthracenylmethyl Q22a, THF reflux no product

Scheme 4.20 Substrates 329-331 were incapable of undergoing the required SNi reaction

With this in mind, precursors 333 and 334 were synthesised with benzyl protecting groups

by the desymmetrisation of 324 by a single deprotonation step followed by addition of

benzyl bromide and subsequent alkylation with the required alkylation reagent to provide

138

Scheme 4.21 Formation of the benzyl protected iodoresorcinol derivatives 333 and 334

The resulting Grignard formation and reaction with chloroquinine (Scheme 4.22) gave only small amounts of product not readily isolated in the case of the methyl derivative 333,

and no product in the case of the isopropyl derivative 334.

Scheme 4.22 Attempts at synthesis of C-6” substituted catalysts 335 and 336

Having shown that synthesis of the methyl derivative 335 was possible, it was decided to

approach the synthesis of this catalyst by a more efficient route that would more easily allow for a large excess of the required 2-iodo-methylbenzylresorcinol to be synthesised. Precursor 337 was cheaply available and obviated the need for the desymmetrisation step

shown in Scheme 4.21, which had given a poor yield. The synthetic route outlined in Scheme 4.23 was thus undertaken.

139

Benzylation of the commercially available m-hydroxyanisole (337) to give 338 was

followed by ortho-lithiation with n-BuLi. The ortho-directing nature of both substituents provides regiospecific deprotonation at the desired position. Reaction of the aryllithium with a solution of iodine yielded the desired product 333 in 50% yield over the two steps.

With this in hand, the Grignard reaction in Scheme 4.22 was re-evaluated this time using a large excess of Grignard.

Scheme 4.24 A more efficient route to 335 and subsequent deprotection to give 339

The reaction resulted in the formation of the desired product 336 in high yield, with the

subsequent deprotection also proceeding smoothly to give 319. With two of the desired

products in hand, and a high yielding route to the remaining targets (i.e. 317 and 320-322)

difficult to identify, it was decided to test our hypothesis regarding the importance of substitution at C-6” by evaluating the performance of these two catalysts 327 and 339 (i.e.

the C-10-C-11 dihydro analogues of 318 and 319).

4.5.1 Testing of 327 and 340 in the DKR of azlactones

Catalysts 327 and 339 were tested in the DKR of azlactone 110 under standard conditions

140

Scheme 4.25 Testing of 327 and 340 in the DKR of azlactone 110

It was clear that substitution at C-6” was highly important to determining the stereochemical outcome of this reaction with both 327 and 339 exhibiting markedly

different behaviour to 130. Catalyst 339, selecting for the opposite enantiomer of 110 to

that preferentially ring opened in the presence of 130, demonstrated that substitution of

this position was key to controlling the sense of enantiodiscrimination in these reactions. Perhaps of equal interest is the excellent selectivity profile exhibited by catalyst 339,

which promoted more efficient and more enantioselective DKR of 110 than any catalyst

previously designed and synthesised in this work.