Enantioselective Lewis-acid catalysis

Chirality (handedness) is older than life on tliis planet. Still it was not until 1848 when Pasteur manually separated enantiomeric crystals that chirality in chemistry was first appreciated . The independent work of Van t Hoff and Le Bel revealed the molecirlar origin behind this phenomenon. 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic 

The first example of enantioselective catalysis of a Diels-Alder reaction was reported in 1979 . Since then, an extensive set of successful chiral Lewis-acid catalysts has been prepared. Some selected examples will be presented here together with their mechanistic interpretation. For a more complete 

Interestingly, G jrey et al. , employing a similar tryptophan-derived catalyst (3.4), observed a 99% enantiomeric excess (ee) in the Diels-Alder reaction of 2-bromoacrolein with cyclopentadiene 

In Chapter 2 it has been demonstrated that Co, Ni, Cu and Zn exhibit pronounced catalytic 

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Towards Enantioselective Lewis-Acid Catalysis in Water ... 

To our knowledge, the results presented in this chapter provide the first example of enantioselective Lewis-acid catalysis of an organic reaction in water. This discovery opens the possibility of employing the knowledge and techniques from aqueous coordination chemistry in enantioselective catalysis. This work represents an interface of two disciplines hitherto not strongly connected. 

In Chapter 2 the Diels-Alder reaction between substituted 3-phenyl-l-(2-pyridyl)-2-propene-l-ones (3.8a-g) and cyclopentadiene (3.9) was described. It was demonstrated that Lewis-acid catalysis of this reaction can lead to impressive accelerations, particularly in aqueous media. In this chapter the effects of ligands attached to the catalyst are described. Ligand effects on the kinetics of the Diels-Alder reaction can be separated into influences on the equilibrium constant for binding of the dienoplule to the catalyst (K ) as well as influences on the rate constant for reaction of the complex with cyclopentadiene (kc-ad (Scheme 3.5). Also the influence of ligands on the endo-exo selectivity are examined. Finally, and perhaps most interestingly, studies aimed at enantioselective catalysis are presented, resulting in the first example of enantioselective Lewis-acid catalysis of an organic transformation in water. 

Giovanni Boocaletti is gratefully acknowledged for the large number of experiments that paved the way to enantioselective Lewis-acid catalysis in water. Furthermore, we kindly thank the Syncom company for the use of the chiral HPLC column. 

The merits of (enantioselective) Lewis-acid catalysis of Diels-Alder reactions in aqueous solution have been highlighted in Chapters 2 and 3. Both chapters focused on the Diels-Alder reaction of substituted 3-phenyl-1-(2-pyr idyl)-2-prop ene-1-one dienophiles. In this chapter the scope of Lewis-acid catalysis of Diels-Alder reactions in water is investigated. Some literature claims in this area are critically examined and requirements for ejfective Lewis-acid catalysis are formulated. Finally an attempt is made to extend the scope of Lewis-acid catalysis in water by making use of a strongly coordinating auxiliary. 

I owe a lot to Federica Bertondn and Giovanni Boccaletti. During their stay as Erasmus students in Groningen they brought a little bit of Italy with them (I remember some very good meals). Also from a chemical point of view their stays were successful. The compounds prepared and purified by Federica are at the basis of the work described in this thesis. The work of Giovanni has paved the way to enantioselective Lewis-acid catalysis in water, which is perhaps the most significant result of this thesis. 

Brimioulle R, Bach T (2013) Enantioselective Lewis acid catalysis of intramolecular enone [2 +2] photocycloaddition reactions. Science 342 840-843... 

As with D-A reactions, it is possible to achieve enantioselective cycloaddition in the presence of chiral catalysts.156 Many of the catalysts are similar to those used in enantioselective D-A reactions. The catalysis usually results from a lowering of the LUMO energy of the dipolarophile, which is analogous to the Lewis acid catalysis of D-A reactions. The more organized TS, incorporating a metal ion and associated... 

Zincate reagents can add to imines with or without Lewis acid catalysis. Alkylimines require BF3 but imines of pyridine-2-carboxaldehyde react directly. If the imines are derived from chiral amines, diastereoselectivity is observed. Both a-phenylethyl amine and ethyl valinate have been tried. Higher enantioselectivity was observed with mixed magnesium reagents.175... 

Uncatalysed Diels-Alder reactions usually have to be carried out at relatively high temperatures (normally around 100 °C)73, often leading to undesired side reactions and retro-Diels-Alder reactions which are entropically favoured. The Diels-Alder reaction became applicable to sensitive substrates only after it was realized that Lewis acids (e.g. A Clg) are catalytically active56. As a consequence, Diels-Alder reactions can now be carried out at temperatures down to — 100°C85. The use of Lewis acid catalysts made the [4 + 2]-cycloaddition applicable to the enantioselective synthesis of many natural compounds51,86. Nowadays, Lewis acid catalysis is the most effective way to accelerate and to stereochemically control Diels-Alder reactions. Rate accelerations of ten-thousand to a million-fold were observed (Table 7, entries A and B). 

Lewis acid catalysis is not limited to cases in which increased yields or enhanced selectivities are desired. Lewis acids offer also the possibility to induce chiral information leading to enantioselective product formation. The enantioselective induction by chiral Lewis acids found widespread application in organic synthesis, especially in the synthesis of natural products with many chiral centres. An enantioselective Diels-Alder reaction is the key step in the synthesis of an iodolactone prostaglandine precursor (Scheme 6).88... 

Lewis-acid catalysis (Table 7.2) was observed for Cu, Ni " , Co, and Zn " ", with Cu being the best catalyst (both strongest binding and most efficient in accelerating the reaction with CPD). Varying the solvent (Table 7.3) in the catalysis by Cu ions with L-abrine as a ligand illustrates a large increase in enantioselectivity in water. So water promotes enantioselectivity. ... 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

Carreira et al. used their experience in the addition of simple silyl ketene acetals to aldehydes under Lewis acid catalysis [15]. In these experiments their 2-amino-2 -hydroxy-l,rbinaphthyl-derived catalyst (19) was used to provide aldol products with very high enantioselectivity (Scheme 8, Table 7). 

Nugent, W. A. (1992) Chiral Lewis acid catalysis Enantioselective addition of azide to meso-epoxides., J. Am. Chem. Soc, 114 2768-2769. 

The Catalysis Concept of Iminium Activation In 2000, the MacMillan laboratory disclosed a new strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalytic concept was founded on the mechanistic postulate that the reversible formation of iminium ions from a,p-unsaturated aldehydes and amines [Eq. (11.10)] might emulate the equilibrium dynamics and 7i-orbital electronics that are inherent to Lewis acid catalysis [i.e., lowest unoccupied molecular orbital (LUMO)-lowering activation] [Eq. (11.9)] ... 

The first examples of chiral Lewis acid catalysis in the opening of diactivated cyclopropane derivatives (224) with nitrones (225) has been demonstrated, giving rise to the tetrahydro-l,2-oxazines (226). High enantioselectivities (71-96% ee) were attained with Ni(C104)2 and Ph-DBFOX ligand (227).262... 

Epoxides too will react with indoles using Lewis acid catalysis with (l/ ,2 S -l,2-dihydronaphthalene oxide, high enantioselectivity (83% ee) shows the effectiveness of InBrj (Scheme 53) <2002JOC5386>. 

A useful synthetic alternative to the Mukaiyama aldol addition is the carbonyl-ene reaction [17], This reaction of an aldehyde 51 with an enol ether 55, bearing at least one hydrogen atom in the allylic position, under Lewis-acid catalysis, yields a ff-hydroxy-enol ether of type 56 (Scheme 10). By use of a chiral Lewis acid (L ) enantioselectivity can be achieved. For the... 

Two groups have recently examined enantioselective A -sulfinyl dienophile Diels-Alder reactions. In one case, Whitesell et al. found that a phenylmenthol derived N-sulfinyl carbamate adds to ( , )-2,4-hexadiene under Lewis acid catalysis to afford a single diastereomer (equation 52). If the Lewis acid was omitted, a complex mixture of cycloaddition products was obtained. Attack of the diene on the N-sulBnyl dienophile as shown in the equation would rationalize the observed results. The site of Lewis acid complexation, however, is unknown. 

Marshall and co-workers have demonstrated that allenylindium [277] and allen-ylzinc [276] reagents can be formed in situ from propargyl mesylate 389 and that these reagents react enantioselectively with aldehydes without additional Lewis acid catalysis (Scheme 11-28). The allenylzinc and allenylindium reagents 392 and 391 are derived from the allenylpalladium intermediate 390 via metathesis with Et2Zn and Ini, respectively. Allenylpalladium intermediate 390 in turn is derived from (7 )-389 via invertive displacement of the mesylate functionality of 389 with Pd(0). 

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