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can be used as intermediates in cascade reactions. The first example was reported by Studer

et al. who treated an external nucleophile with a tethered dielectrophile in the presence of

an NHC catalyst in a Michael-Michael-lactonisation (MML) process (Scheme 98).121 _{An α,β-}

unsaturated acyl azolium intermediate is generated in situ by oxidation of the Breslow

intermediate (see Section 1.2.7 for more details). Diketone addition to the α,β-unsaturated

acyl azolium species then affords enolate 350, which can undergo an intramolecular

Michael addition followed by lactonisation to form tricyclic product 351/352 and

regenerate the catalyst. Alkyl diketones afforded higher diastereoselectivity than aryl diketones, but excellent enantioselectivity was observed for all examples.

Scheme 98: NHC-catalysed Michael-Michael-lactonisation organocascade via addition of an external nucleophile

An alternative to this tethering strategy (Figure 36, A) is to react a simple α,β-unsaturated acyl species with a tethered nucleophile-electrophile (Figure 36, B). This gives access to

different product architectures and enables the use of commercially available α,β- unsaturated acyl ammonium/azolium precursors.

Figure 36: Organocascade strategies using α,β-unsaturated acyl ammonium/azolium intermediates

Romo et al. were the first to use this tethering method in a Michael-Aldol-lactonisation

(MAL) process (Scheme 99).122 _{Commercially available α,β-unsaturated acid chlorides were}

employed in this transformation to generate complex cyclopentanes 355 in good yields and

high diastereo- and enantioselectivity. The dicarbonyl portion of the nucleophile 353 acts

as a Michael donor to generate intermediate 354, which is set up to do an Aldol reaction

followed by lactonisation to give the products. The reaction requires a lithiated base

(LiHMDS or t-butyllithium) and the authors postulate that the lithium is required to chelate

enolate 354 in order to facilitate the cyclisation process. Initial Michael addition anti to the

stereodirecting groups on the isothiourea catalyst gives good stereocontrol, with the

proposed cyclisation transition state (354) alleviating 1,3-allylic strain between R3 _{and the}

enolate. This gives a high level of stereocontrol over the cyclisation step and the reaction affords a single diastereomer in all examples.

Scheme 99: Isothiourea-catalysed Michael-Aldol-lactonisation organocascade via acid chlorides

Studer et al. then showed that this MAL cascade was amenable to NHC catalysis, with

used.123 _{The two reactions proceed via the same mechanism but CO}

2 is eliminated more

readily in aryl-substituted examples thus none of the cyclopentane was observed, only the eliminated cyclopentene product in these cases. LiCl was used as an additive to speed up the reaction and also to enhance enantioselectivity.

Scheme 100: Oxidative NHC-catalysed Michael-Aldol-lactonisation organocascade via α,β-unsaturated aldehydes

This elimination of CO2 was also observed by Biju et al. who investigated an MAL reaction

between α-bromoenal 359 and the same ketoester 356 under NHC-redox catalysis.124 _The

authors only investigated the use of aryl ketones in the MAL process therefore only

cyclopentenes 358 were isolated. Compared with Studer’s work the yield of 358 is slightly

lower however the enantioselectivity is enhanced even in the absence of the LiCl additive,

using the same NHC catalyst (128).

Scheme 101: NHC-catalysed Michael-Aldol-lactonisation organocascade via α-bromoenals

Hui et al. have recently used α-bromoenals in a Michael-Mannich-lactamisation cascade,

affording complex tricyclic products 362 in good yields and excellent diastereo- and

enantioselectivity.125 _{The malonate portion of the nucleophile-electrophile substrate 360}

initiates a Michael addition into an α,β-unsaturated acyl azolium species, affording enolate

361 that undergoes ring closure via an intramolecular Mannich reaction. Lactamisation from

Scheme 102: Michael-Mannich-lactamisation organocascade via α-bromoenals

4.2 Project Aims

The utility of the α,β-unsaturated acyl ammonium intermediate is still relatively underexplored and we hoped to further investigate the chemistry that these intermediates can undergo. Combining the chemistry developed within this thesis and the MAL

chemistry initiated by Romo et al. 122 _{we aimed to access an isothiourea-catalysed MML}

cascade (Scheme 103) utilising tethered Michael donor-acceptor substrates and α,β- unsaturated acyl ammonium intermediates.

Scheme 103: Isothiourea-catalysed Michael-Aldol-Lactonisation process

A tethered nucleophile-electrophile would initiate the cascade by adding into the α,β- unsaturated acyl ammonium intermediate, forming an enolate that can undergo an intramolecular Michael addition to form a 5-membered ring. Finally, lactonisation would form a 5,6-bicyclic product and regenerate the catalyst (Scheme 104).

Scheme 104: Proposed MML reaction between a tethered nucleophile-electrophile and an α,β-unsaturated acyl ammonium intermediate

A related process has been demonstrated by Li et al. who used NHC catalysis to generate

Unfortunately in this process they were unable to achieve any enantioselectivity, with a wide range of chiral NHC catalysts trialled affording 0% ee. This process was therefore thought to be a good challenge for isothiourea catalysis, to investigate whether it is possible to achieve enantioselectivity in a novel MML cascade reaction.

Scheme 105: NHC-catalysed Michael-Michael-Lactonisation process

In Li’s process the second (intramolecular) Michael-addition is thought to be highly diastereoselective, therefore the low diastereoselectivity must arise from poor facial control over the initial nucleophilic addition (Figure 37). The use of a symmetrical nucleophile would remove this complication and therefore dicarbonyl nucleophile-electrophiles were targeted for our isothiourea-catalysed process.

Figure 37: Facial selectivity in the nucleophilic addition of non-symmetrical oxindole nucleophiles and symmetrical dicarbonyl nucleophiles

Symmetrical dicarbonyl nucleophiles containing an enone Michael acceptor such as 366

have been demonstrated in a Lewis base-catalysed Michael-Michael cascade in work by

Wang et al. (Scheme 106). The enone-malonate acts as a Michael donor in the absence of

base, forming enamine 368 that can undergo a second Michael addition followed by

hydrolysis to give cyclopentane products 369 containing 3 contiguous stereocentres. The

process works well for electron poor and electron rich aryl enals 367, giving high yields and

gave us confidence that enone-malonates would be suitable for testing in an isothiourea- catalysed MML cascade.

Scheme 106: Lewis base-catalysed Michael-Michael-Lactonisation process

4.3 Reaction Optimisation