Enantioselective reactions mechanistic studies

Of all the work described in this thesis, this discovery is probably the most significant. Given the fact that the arene - arene interactions underlying the observed enantioselectivity of ftie Diels-Alder reactions described in Chapter 3 are also encountered in other organic reactions, we infer that, in the near future, the beneficial influence of water on enantioselectivity can also be extended to these transformations. Moreover, the fact that water can now be used as a solvent for enantioselective Lewis-add catalysed reactions facilitates mechanistic studies of these processes, because the number of equilibria that need to be considered is reduced Furthermore, knowledge and techniques from aqueous coordination chemistry can now be used directly in enantioselective catalysis. 

The catalytic enantioselective cycloaddition reaction of carbonyl compounds with conjugated dienes has been in intensive development in recent years with the main focus on synthetic aspects the number of mechanistic studies has been limited. This chapter will focus on the development and understanding of cycloaddition reactions of carbonyl compounds with chiral Lewis acid catalysts for the preparation of optically active six-membered ring systems. 

Similar to the CuOTf/PyBox system, the CuBr/QUINAP system also gave high enantioselectivities of the three component reactions to construct propargyl amines from aldehydes, amines, and alkynes (Scheme 5.6). In this system various aldehydes including aromatic aldehydes and aliphatic aldehydes could be used and a wide range of chiral propargyl amines were prepared in good yields and enantioselectivities. Mechanistic studies showed that the dimeric Cu/QUINAP complex is the catalytically active species that differs from the previous reaction. 

The plot eepjod = f(eeaux) in an enantioselective reaction is a simple operation that can sometimes be very informative from both synthetic and mechanistic perspectives. This plot is now widely used in mechanistic discussions concerning enantioselective catalysis. However, some cautions are needed, since this approach has to be combined with additional studies in order to get firm conclusions. If linearity is observed, one cannot reach conclusions on the mechanism, since even with species involving several chiral auxiliaries one may remain linear, as in the ML2 model with g = 1 in Eq. (7.3). If there are deviations from linearity, this could be a piece of information on the mechanism, for example, aggregations at some level of the chemical system, or some competitive mechanisms. References 27, 44, and 68 are only three among many published examples. 

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

The efficiency with which modified Cinchona alkaloids catalyze conjugate additions of a-substituted a-cyanoacetates highlights the nitrile group s stereoselective role with the catalyst. Deng et al. [60] utilized this observation to develop a one-step construction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quatemary stereocenters. Based on their mechanistic studies and proposed transition state model, the bifimctional nature of the quinoline C(6 )-OH Cinchona alkaloids could induce a tandem conjugate addition-protonation reaction to create the tertiary and quaternary stereocenters in an enantioselective and diastereoselective manner (Scheme 18). 

A further catalytic method for asymmetric sulfoxidation of aryl alkyl sulfides was reported by Adam s group, who utilized secondary hydroperoxides 16a, 161 and 191b as oxidants and asymmetric inductors (Scheme 114) . This titanium-catalyzed oxidation reaction by (S)-l-phenylethyl hydroperoxide 16a at —20°C in CCI4 afforded good to high enantiomeric excesses for methyl phenyl and p-tolyl alkyl sulfides ee up to 80%). Detailed mechanistic studies showed that the enantioselectivity of the sulfide oxidation results from a combination of a rather low asymmetric induction in the sulfoxidation ee <20%) followed by a kinetic resolution of the sulfoxide by further oxidation to the sulfone... 

An extensive spectroscopic and mechanistic study on the enantioselective Cu/ferrocenyl bisphosphine-catalyzed conjugate addition has been performed. Several parameters such as solvent, nature of the halide present in the Grignard reagent and Cu(I) source, and additives (i.e. dioxane and crown ethers) were identified. These factors directly affect the formation and nature of the intermediate active species, and therefore the selectivity, rate and overall outcome of the reaction. Importantly, the presence of and Br ions in the reaction are essential in order to achieve high selectivity and efficiency. 

As recently highlighted by Woodward, enantioselective Sf/2 allylic substitution reactions are mechanistically related to conjugate addition reactions . Theoretical studies carried out by Nakamura and coworkers for the conjugate addition and allylic alkylation using Gilman s cuprates revealed profound mechanistic similarities between these two processes . ... 

L-Prolinethioamides (39, R = alkyl including chiral alkyl), prepared from proline and amines, are effective in acetone-benzaldehyde reactions.110 Mechanistic studies focused in particular on suppression of non-enantioselective side-reactions, and also on the role of the side-chain of the catalyst acting as hydrogen bond donor, especially as the thioamides (with their more acidic N—H protons) are more catalytic than their amide analogues. 

Optimization of the alkaloid phase-transfer catalysts included both the development of improved reaction conditions and the design of more efficient organocatalysts. Addressing this latter issue, O Donnell observed the first remarkable improvement of the enantioselectivity on use of modified alkaloid organocatalysts with an O-substituent, in particular an O-allyl or O-benzyl substituent, for example 23 and 24, respectively. This positive effect of O-alkylated structures was discovered during a detailed mechanistic study [22]. In this study it was found that O-alkylation of the previously used alkaloid catalysts, e.g. 21, and N-alkylated derivatives thereof, e.g. 22, by reaction with an alkyl halide (which is used in 1.2-5... 

THF, ethyl acetate, and methanol. In contrast, use of other chlorinated solvents, e.g. CCI4, and cyclohexane resulted in higher enantioselectivity, comparable with that for chloroform. The range of dienophile substrates was also studied. Replacing N-methylmaleimide by N-phenylmaleimide, in the presence of quinidine as a catalyst, also led to a good yield, although enantioselectivity was lower (20% ee compared with 61% ee). Much slower reaction rates were observed when methyl acrylate and methyl fumarate were used and enantioselectivity was low (0% ee for methyl acrylate and 30% ee for methyl fumarate). With methyl maleate as a dienophile no reaction was observed. Mechanistic studies were also conducted by Kagan et al. results were in accordance with a concerted [4+2]-cycloaddition process. 

Transformations shown in Schemes 12-14 constitute the first examples of catalytic AROM reactions ever reported. Meso-triene 50 is converted to chiral heterocyclic triene 51 in 92% ee and 68% yield with 5 mol% 4a (Scheme 12) [21]. Presumably, stereoselective approach of the more reactive cydobutenyl alkene in the manner shown in Scheme 12 (II) leads to the enantioselective formation of Mo-alkylidene III, which in turn reacts with an adjacent terminal olefin to deliver 51. Another example in Scheme 12 involves the net rearrangement of meso-bicycle 52 to bicyclic structure 54 in 92% ee and 54% yield. The reaction is promoted by 5 mol% 4a and requires the presence of diallyl ether 53 [22], Mechanistic studies suggest that initial reaction of 53 with 4a leads to the formation of the substantially more reactive chiral Mo=CH2 complex (vs neophylidene 4a) which can react with the sterically hindered norbornyl alkene to initiate the catalytic cycle. 

Asymmetric amplification in reactions involving partially resolved chiral auxiliaries is now a well-established phenomenon that is very attractive since it gives improved enantioselectivities witb respect to expectations based upon the ee of the auxiliary. It may have practical application in that enantiomerically pure chiral auxiliaries are not always required for highly selective asymmetric synthesis. Asymmetric amplification is also of fundamental importance in order to achieve efficient asymmetric autocatalysis. Finally, evidence of an asymmetric amplification is a very useful piece of information in mechanistic studies. 

To explain this different behaviour, mechanistic studies of the system were performed with the aid of molecular modelling, 13C NMR spectroscopy, induced circular dichroism, a systematic variation of the reaction parameters, and variation of the molecular structure of the sugar moieties and of the linking units. These studies established that under homogeneous reaction conditions (water), the main factor influencing the enantioselectivity is probably the ordering and specific orientation of the ketone at the chiral interface. Under heterogeneous conditions in THF the situation appears to be more complex. 

In 2006, Hoveyda and coworkers developed an asymmetric Mannich reaction of silyloxyfurans and aldimines using a similar catalyst system (Scheme 9.18).28 The diastereo- and enantioselective reaction between silyloxyfurans and aldimines in the presence of catalyst gave y-butenolides, which are useful building blocks for organic synthesis. They also reported a mechanistic study of this reaction.2811... 

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