Origins of Enantioselectivity during Allylic Substitution Reactions Catalyzed by Metallacyclic Iridium Complexes

Abstract

In depth mechanistic studies of iridium catalyzed regioselective and enantioselective allylic substitution reactions are presented. A series of cyclometallated allyliridium complexes that are kinetically and chemically competent to be intermediates in the allylic substitution reactions was prepared and characterized by 1D and 2D NMR spectroscopies and solid state structural analysis. The rates of epimerization of the less thermodynamically stable diastereomeric allyliridium complexes to the thermodynamically more stable allyliridium stereoisomers were measured. The rates of nucleophilic attack by aniline and by N-methylaniline on the isolated allyliridium complexes were also measured. Attack on the thermodynamically less stable allyliridium complex was found to be orders of magnitude faster than attack on the thermodynamically more stable complex, yet the major enantiomer of the catalytic reaction is formed from the more stable diastereomer. Comparison of the rates of nucleophilic attack to the rates of epimerization of the diastereomeric allyliridium complexes containing a weakly-coordinating counterion showed that nucleophilic attack on the less stable allyliridium species is much faster than conversion of the less stable isomer to the more stable isomer. These observations imply that Curtin-Hammett conditions are not met during iridium catalyzed allylic substitution reactions by η3-η1-η3 interconversion. Rather, these data imply that when these conditions exist for this reaction, they are created by reversible oxidative addition and the high selectivity of this oxidative addition step to form the more stable diastereomeric allyl complex leads to the high enantioselectivity. The stereochemical outcome of the individual steps of allylic substitution was assessed by reaction of deuterium-labeled substrates. The reaction was shown to occur by oxidative addition with inversion of configuration, followed by an outer sphere nucleophilic attack that leads to a second inversion of configuration. This result contrasts the changes in configuration that occur during reactions of molybdenum complexes studied with these substrates previously. In short, these studies show that the factors that control enantioselectivity of iridium-catalyzed allylic substitution are distinct from those that control enantioselectivity during allylic substitution catalyzed by palladium or molybdenum complexes and lead to the unique combination of high regioselectivity, enantioselectivity, and scope of reactive nucleophile.

Origins of Regioselectivity in Iridium Catalyzed Allylic Substitution

“…16 Thus, we studied the oxidative addition of allylic trifluoroacetates, which contain a good leaving group and were shown to add to Ir(I) complexes of a cyclometalated phosphoramidite. 18 In particular, the reactions of the linear and branched isomers of the phenalkyl-substituted allylic trifluoroacetates 8 and 9 with the Ir(I) ethylene adduct 5 were studied. These reactions occurred to form an equilibrium mixture of unreacted 5 and two diastereoisomers of allyliridium complexes 3c .…”

“…3,4 Mechanistic studies on reactions catalyzed by these iridium complexes have revealed the resting state of the catalyst, the origins of enantioselection, and the importance of cyclometalation to generate the active catalyst. 15–18 However, mechanistic studies of reactions catalyzed by iridium complexes of triphenylphosphite, the first system shown by Takeuchi to give branched products from linear allylic carbonates 19–21 are limited. A cyclometalated species was proposed to be the active catalyst, but this species was never observed directly and characterized.…”

Enantioselective Functionalization of Allylic C–H Bonds Following a Strategy of Functionalization and Diversification

“…8a The relative configuration of the product and iridium catalyst shows that the allylic substitution step of the functionalization sequence occurs with the same stereoselectivity as previously reported substitutions of allylic carbonates. 7c,15 Previously reported mechanistic studies from our group on iridium catalyzed allylic substitution reactions 7d,16 have shown that the reaction occurs by a highly diastereoselective oxidative addition of an allylic benzoate to an iridium complex 1 , followed by attack of the nucleophile onto the allyl ligand from the side opposite to the metal for all of the nucleophiles in the current study. This nucleophilic attack is a faster than the η 3 -η 1 -η 3 isomerization of the allyl complex.…”

Iridium‐Catalyzed Enantioselective Allylic Substitution of Aliphatic Esters with Silyl Ketene Acetals as the Ester Enolates

“…[8,9] Thelow acidity of the a hydrogen atoms of aliphatic esters and the instability of the ester-derived enolates make the allylation of ester enolates challenging.Stoichiometric strong bases are required to form the enolates in situ without selfcondensation, substrates that bear base-sensitive functionalities (for example,a na cetoxy group) are not tolerated, and Claisen condensation between the ester products and the enolates can lead to side products.F inally,c yclopropanation has been shown to compete with the allylation process when palladium catalysts are used. [11] Thea llylation of silyl ketene acetals containing gemdialkyl groups would be particularly valuable because the resulting enantioenriched a-allyl esters containing aq uaternary a carbon atom and at ertiary b stereocenter are inaccessible by asymmetric Michael addition or asymmetric hydrogenation of the a,b-unsaturated esters.F urthermore, the enantioselective allylation of stabilized malonate-type nucleophiles,followed by fragmentation (desulfonylation and decarboxylation), would not afford these highly substituted products. Iridium complexes [Ir] (Scheme 1) developed in our research group could catalyze this proposed transformation because they enable enantioselective allylic substitution reactions with various nucleophiles under relatively neutral conditions,w ithout competing formation of cyclopropanes.…”

“…Iridium complexes [Ir] (Scheme 1) developed in our research group could catalyze this proposed transformation because they enable enantioselective allylic substitution reactions with various nucleophiles under relatively neutral conditions,w ithout competing formation of cyclopropanes. [11] Thea llylation of silyl ketene acetals containing gemdialkyl groups would be particularly valuable because the resulting enantioenriched a-allyl esters containing aq uaternary a carbon atom and at ertiary b stereocenter are inaccessible by asymmetric Michael addition or asymmetric hydrogenation of the a,b-unsaturated esters.F urthermore, the enantioselective allylation of stabilized malonate-type nucleophiles,followed by fragmentation (desulfonylation and decarboxylation), would not afford these highly substituted products. [12] Herein we report the enantioselective allylation of silyl ketene acetals catalyzed by am etallacyclic iridium complex (Scheme 1) to form the allylated aliphatic esters with high regio-and enantioselectivity under mild conditions.Owing to the versatility of the ester functionality in organic synthesis, these products are readily transformed into primary alcohols, carboxylic acids,amides,isocyanates,carbamates,tetrahydrofuran (THF) derivatives,a nd g-butyrolactone derivatives without erosion of enantiomeric purity.We began our studies on the enantioselective allylic substitution of aliphatic silyl ketene acetals by examining the reaction between cinnamyl methyl carbonate and ketene acetal 2a in the presence of as eries of metallacyclic iridium complexes containing various aryl substituents on the chiral ligand (Table 1, entry 1-4).…”