ENSAYO DE LA CAJA EN “L”.

.2.5.1 Synthesis

The strategy for preparation of the ketone precursors to230and231was by functionalisation of

the α-carbon of isobutyrophenone 82. It was envisaged that substrate237could be prepared by

the conjugate addition of the potassium enolate of isobutyrophenone 82 to acrylonitrile, in a procedure similar to that reported by Campbell et al.35 This was successfully accomplished, albeit in low un-optimised yield, and the desired product was easily recovered, giving the pure ketone in sufficient quantities for investigation in catalysis (Scheme II-23). It should be noted here that this is a quick and facile route into such compounds and it can be imagined that a large number of functionalised derivatives could be prepared by such methods from relatively cheap,

commercially-available starting materials. Thus, there is potential to create a expanded range of functionalised chiral secondary alcohol products.

Scheme II-23Preparation of 4,4-dimethyl-5-oxo-5-phenylpentanenitrile 237. Reaction Conditions:82(1 eq.), acrylonitrile (1 eq.), methanolic KOH solution (30%), dioxane, 50C, 24 h, 21%.

The preparation of substrate 239 proved more troublesome. Isobutyrophenone 82 was first converted to the keto-alcohol238in good yield by aldol condensation with paraformaldehyde in the presence of trifluoroacetic acid, and subsequent base hydrolysis of the trifluoracetate ester (Scheme II-24). Multiple attempts to prepare the benzyl protected form of the alcohol (thought to be required to provide steric bulk for efficient enantioselective catalysis) failed however. This was likely due to retro-Aldol reaction taking place under the forcing basic conditions needed in ether synthesis, yielding isobutyrophenone as the primary product.

Scheme II-24Attempted preparation of substrate239.Reaction Conditions:(i)82(1 eq.), paraformaldehyde (1.3 eq.), trifluoroacetic acid, 60C, 16 h then 2M NaOH, rt, 2 h, 74%; (ii)238(1 eq.), BnBr (1 eq.),tBuNI (0.015 eq.) H2O, Me-THF, reflux, 16 h or 238(1 eq.), BnBr (1 eq.), NaH (2.5 eq.), THF or DMF, reflux, 16 h.

A second route was thus needed, which could prepare substrate239in a good yield in few steps, but which could be customisable in preparing a range of derivatives. It was decided to make use of the catalytic monoalkylation protocol of Onomura and co-workers36 to first prepare the monobenzylated 1,3-diol241 in an easy, high-yielding and customisable step (Scheme II-25). Subsquent oxidation, addition of arylmagnesium bromide reagent (opening the door to potential preparation of substituted derivatives), and final oxidation step, furnished the desired product. Although this is not an elegant process, the product is delivered using easy, high-yielding reactions.

Scheme II-25Successful preparation of substrate239.Reaction Conditions:(i)240(1 eq.), BnBr (1.5 eq.), K2CO3(1.5 eq.),p-fluorobenzene boronic acid (0.1 eq.), DMF, rt, 36 h, 80%; (ii)241(1 eq.), (COCl)2(2 eq.), DMSO (4 eq.), NEt3(4 eq.), CH2Cl2, -78C → rt, 2 h, 81%; (iii) 242(1 eq.), PhMgBr (1.2 eq.), Et2O, -78C → rt, 16 h; (iv) 231 (1 eq.), (COCl)2(2 eq.), DMSO (4 eq.), NEt3(4 eq.), CH2Cl2, -78C → rt, 2 h, 69 % (step (iii) and (iv)).

The imidazole-functionalised ketone substrate244was prepared by modification of a procedure by Bildstein (Scheme II-26),37presumablyviaan SN1 mechanism, with the second equivalent of

imidazole acting to neutralise the HBr which is formed. This procedure provided ketone244in good yield and purity for subsequent use in catalysis.

Scheme II-26 The synthesis of 2-(1H-imidazol-1-yl)-2- methyl-1-phenylpropan-1-one 244. Reaction conditions:

243(1 eq.), imidazole (2 eq.), EtOH, reflux, 3 d, 62%.

2.5.2 Catalysis

Hydrogenation of both the functionalised ketone substrates237and239with catalyst (R,R)-174 at 50 bar hydrogen pressure and 50C resulted in the quantitative conversion in each case to alcohol product (Table II-6). It was gratifying to find that substrate237was hydrogenated with enantioselectivity on par with that of the model ketone ,,-trimethylacetophenone 159. The uses of the chiral alcohol product237will be underlined further in section 2.5.3. It was pleasing to find that catalysis is tolerant of the useful nitrile functionality, given that ruthenium catalysed nitrile hydrogenation is a well known reaction.38,39

(R,R)-174 N H2 NH P Ru Cl Cl S O Ph O Ru Cat KOt_Bu,i_PrOH H2 16h R 237, R= CH2CH2CN 239, R = CH2OBn Ph OH R 230, R= CH2CH2CN 231, R = CH2OBn Entry Ketone R= PH2 [bar] T [C] Conversion (yield) [%] ee [%] 1 237 CH2CH2CN 50 50 >99 74 2 239 CH2OBn 50 50 >99 50

Table II-6 The hydrogenation of ketones with gem-dimethyl substituents using catalyst (R,R)-174. General conditions: ketone (~1 mmol), catalyst (R,R)-174 (0.5 mol%), potassiumtert-butoxide (1 mol%), isopropanol (3 mL), molecular H2, 16 h.

Chiral alcohol231was furnished in only moderate enantioselectivity upon hydrogenation with catalyst (R,R)-174. This may be due to the significant extension of the substrate structure away from the ketone function, resulting in unfavourable interactions with the catalyst structure. However, bearing in mind the limited number of catalysts which can hydrogenate such ketones with bulk around the carbonyl group, this result is still promising and catalyst optimisation has the potential of leading to more selective catalysts.

Hydrogenation of the gem-dimethyl substituted ketone 244 was again accomplished quantitatively in 16 h by catalyst (R,R)-174 at 70 bar hydrogen pressure and 40C. Disappointingly, however, levels of enantioselectivity were slightly diminished for this substrate, relative to that obtained in producing the less sterically demanding derivative235.

Scheme II-27 The hydrogenation of 2-(1H-imidazol-1-yl)-2-methyl-1- phenylpropan-1-one244 using catalyst (R,R)-174. Reaction conditions: ketone

244 (1 eq.), catalyst (R,R)-174 (0.5 mol%), potassiumtert-butoxide (1 mol%), isopropanol (3 mL), molecular H2(70 bar), 40C, 16 h, >99% conversion, 86% yield.

Despite achieving only moderate enantioselectivity, these results are encouraging bearing in mind that this class of substrate is envisaged to be of low reactivity using Noyori-type catalysts, and such useful chiral products cannot be prepared by existing H2-hydrogenation technology.

Hopefully, the moderate level of enantioselectivity can be elevated by catalyst optimisation, and some important preliminary steps towards this have been achieved in chapter IV.

2.5.3 Practical Uses of Chiral Alcohol Products

It has been demonstrated that useful chiral secondary alcohol 237, with gem-dimethyl substituents, and remote functionality, can be prepared with good enantioselectivity using catalyst (R,R)-174. In order to showcase the utility of such chiral products, it was undertaken to employ 237 in the preparation of the chiral cyclic ester (-butyrolactone) 248, and show that enantioselectivity could be preserved throughout the process.

Scheme II-28

The cyclic ester component constitutes a frequently encountered structural motif within a huge variety of natural products and biologically active compounds. Furthermore, the lactone functionality exists in common flavour components and is thus employed in the perfumery and food industry.40,41Derivatives of lactones also play important roles as sex attraction pheromones of different insects, and plant regulators42,43as well as being building blocks in the synthesis of natural products, such as alkaloids and terpenoids,44,45and other biologically active compounds, such as antitumour, antidepressant and antiviral agents (Scheme II-29).46,47

While a variety of methods exist for the preparation of enantiomeric pure γ- (five membered ring) and δ-lactones (six-membered), many of these rely on asymmetric induction from

stoichiometric amounts of chiral auxialliary or chiral reducing agent, or require problematic enzyme based reductions.48,47,49The use of a metal-based catalyst to hydrogenate functionalised ketones enantioselectively and subsequent intermolecular ring closing is an underdeveloped technology, and only limited reports of such exists in the literature to date, making use of first generation Noyori [Ru(P^P)L2] catalysts to enantioselectively hydrogenate β-ketoesters and γ-

ketoacids.50,51 To the best of our knowledge, enantioselective synthesis of δ-lactones from enantio-enriched hydroxy nitriles is unprecedented. Our plan was to employ the chiral

secondary alcohol237, preparedviaenantioselective hydrogenation using catalyst (R,R)-174, in a ring-closing reaction to prepare lactone 248, whilst maintaining the enantioselectivity introduced in the hydrogenation step.

Scheme II-29Examples of the cyclic ester motif in biologically active compounds including perfumery ingredients, insect pheromones and compounds of pharmaceutical interest.40,41,42,43,44,45,46,47