Sobre corriente de tiempo definido (con sello de tensión) (50/51)

The Smith group have previously investigated the generation and uses of ammonium enolates formed from carboxylic acid derivatives and Lewis basic isothiourea (ITU) organocatalysts. For

18 example, ammonium enolates generated from arylacetic acids and achiral isothioureas undergo Michael addition-lactonisation reactions with trifluoromethylenones, affording racemic dihydropyranones (DHPs) in solution with moderate to high diastereoselectivity (Figure 25).[101]

Figure 25: Generation of racemic DHPs with high diastereoselectivity in solution using DHPB.

Furthermore, chiral isothioureas such as HyperBTM-(2S,3R) 61 catalyse the enantioselective Michael addition-lactonisation of trifluoromethylenones in solution, yielding anti-DHPs with high diastereo-and enantiocontrol (Figure 26).[101]

Figure 26: Generation of enantiopure DHPs in solution using HyperBTM.

The proposed mechanism of the Michael addition-lactonisation proceeds via initial formation of a mixed anhydride 62 formed in situ from pivaloyl chloride and the appropriate phenylacetic acid. Subsequent N-acylation with HyperBTM-(2S,3R) 61 generates the corresponding acyl isothiouronium 63, with deprotonation generating the (Z)-ammonium enolate 64. This undergoes a stereoselective Michael addition with the trifluormethylenone 59, followed by intramolecular cyclisation, to generate DHP 66 (Figure 27).

19

Figure 27: Proposed catalytic cycle for the enantioselective Michael-lactonisation process.

Detailed DFT calculations were used to investigate the minimum energy transition state(s) involved in the conjugate addition step of the reaction (Figure 28).[102] _{The structure of 69}

highlights the preference for the intermediate isothiouronium enolate 64 to adopt a half-chair type confirmation with the phenyl component pseudo-axial. The enantioselectivity of the process arises from the stereodirecting groups on the isothiourea that block the Si face of the enolate favouring addition onto the Re face, while the diastereoselectivity comes from enolate geometry ((E) vs (Z)). The 1,5-planar geometry associated with O˙˙˙S interactions allows for the orbital

containing the non-bonding lone pair of electrons on the donor atom to overlap more effectively with the σ* _{orbital of C-S bond (n}

о to σ*C-S).[103] Tantillo and Romo have shown that nо to σ*C-S

interactions can govern the selectivity of Diels-Alder cycloadditions by restricting rotation about the C-N bond of the acylammonium salt intermediate (64 in this case) giving high endo selectivity in the products.[104] _{Birman and Houk have also used computational studies to model the origin}

of enantioselectivity in benzotetramisole-catalysed dynamic kinetic resolution of azalactones.[105]

The authors postulate that the oxygen atom of the acyl carbonyl is nearly coplanar with the thiazolium moiety and points towards the sulfur atom, basing their arguments on non-bonding S- O interactions.

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Figure 28: Possible pre-transition state assembly for conjugate addition step

Such nо to σ*C-S interactions have been reported by others in reaction processes utilising

isothioureas[106-107] _{and is well precedented in the literature.}[108] _{Stahl and co-workers have shown,}

through a comprehensive study of small molecule crystals, that carbonyl groups display a strong preference for 1,5-O˙˙˙S interactions.[109] An example of a non-covalent O˙˙˙S interaction was

elegantly shown by Nagao and co-workers where the authors show, through analysis of X-ray crystal structures and ab initio calculations, that (acylamino)thiadiazoline derivatives exhibit an O˙˙˙S attractive force.[110] This attractive force holds the thiadiazoline in a in rigid cis conformation

(70b) and reduces the bond distance to 2.65 Å, which is significantly shorter than the sum of the Van der Waals radii (3.32 Å) (Figure 29).

Figure 29: nо to σ*

C-S interactions in thiadiazoles.

In the context of isothioureas, Birman and co-workers have proposed that the 1,5-O˙˙˙S interaction

present in acylated isothioureas may provide enhanced activity compared with their amidine derivatives due to a conformational lock being present (Figure 30 (a)).[107] _{This view was}

corroborated by Romo and co-workers who postulated the reason for high selectivity in their nucleophile-catalysed aldol lactonisation (NCAL) process using (S)-HBTM 73 was due to a conformation lock in the pre-transition state assembly between the sulfur atom of the N-acylated catalyst and the oxygen atom on the carbonyl group (Figure 30 (b)).

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Figure 30: Rotation in acylated amidines and isothioureas.

The challenges associated with transferring a well studied homogeneous reaction to the heterogenous state are many. How the enantioselection process will proceed is a large unknown. How will the reaction proceed mechanistically? Indeed chiral molecules on surfaces have been shown to form complex two-dimensional structures with specific enantiomeric chracteristics, different from what might be expected when considering the single molecule itself.[111] _As

surfaces can lower the symmetry of the adsorbates, chiral molecules can display more complex behaviours on surfaces than in the gas/liquid phase and prochiral molecules can become chiral upon adsorption, also displaying specific enantiomeric chracteristics.[111] _{How this intrinsic}

feature of surfaces may play a role in the development of new enantioselective processes on surfaces is unknown. The concept of homo and heterochirality may come into play where particular domains of the monolayer on a surface posseses different chirality, possibly influencing the reaction pathway and potentially increasing or decreasing the resulting enantioselectivity. As homochirality is proposed to have originated from specific enantioselective processes occurring on chiral surfaces [112] _{this may potentially play a major role in the selectivity of the reaction. One}

of the main challenges associated with the analysis of chiral surfaces is the measurement and quantification of the resulting selectivity. These difficulities arise from the limitations of the current state-of-the-art methodologies, not allowing for quantification of the reaction selectivity on the surface. These limitations must be overcome in order to obtain a clearer picture of what is occurring during the reaction process.

The generality and scope of this Michael addition-lactonisation procedure led us to believe that it would be a suitable candidate for optimisation on a surface functionalised with SAMs. Moreover, the potential for the generation of enantioenriched surfaces from an achiral starting material on a

22 surface via enantioselective organocatalysis offers a direct route towards highly functionalised SAMs with what is hoped to be high levels of selectivity.