Iminium ions enantioselective

An enantioselective organocatalytic 1,3-DC reaction, based on the activation of a,fi-unsaturated aldehydes through the reversible formation of iminium ions with chiral imidazolidinones 100, was described. Good levels of asymmetric induction and diastereocontrol were achieved (up to 94% ee and 94 6 dr) <00JA9874>. 

CuBr/QUINAP System The CuBr/QUlNAP system was initially used in the enan-tioselective synthesis of proparyl amines via the reaction of alkynes and enamines (Scheme 5.5). It was rationalized that the enamines reacted with protons in terminal alkynes in the presence of copper catalyst to form zwitterionic intermediates in which both the generated iminiums and alkyne anions coordinate to the copper metal center. After an intermolecular transfer of the alkyne moiety to the iminium ion, the desired products were released and the catalyst was regenerated. The combination of CuBr as catalyst and the chiral ligand QUEMAP is crucial for the good reactivities and enantioselectivities seen in the reaction. Another potential... 

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 report of an enantioselective organocatalytic [3+2] cycloaddition between nitrones and a,P-nnsaturated aldehydes was reported by MacMillan and co-workers who showed that iminium ion activation was effective in this reaction (Scheme 8) [64], After a survey of seven catalysts the imidazolidinonium salt 12 HC10 emerged as the most efficient system. The reactions were conducted in a mixture of nitromethane and water at -20 °C in the presence of 20 mol% catalyst... 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

Cheap and readily available L-proline has been used numerous times for the intermediate and reversible generation of chiral iminium ions from a,/ -unsaturated carbonyl compounds. For example, Yamaguchi et al. reported in 1993 that the rubidium salt of L-proline catalyzes the addition of di-iso-propyl malonate to the acyclic Michael acceptors 40a-c (Scheme 4.13), with enantiomeric excesses as high as 77% [22], With 2-cycloheptenone and 2-cyclohexenone as substrates ca 90% yield and ee of 59% and 49% were obtained. Later the enantioselectivity of this process was increased to a maximum of 88% ee in the addition of di-tert-butyl malonate to the E-pentenone 40a in the presence of 20 mol% Rb-L-prolinate and 20 mol% CsF [23], Taguchi and Kawara employed the L-proline-derived ammonium salts 41a and... 

The binaphthyl-derived iminium-ion catalysts 41a and 41b were introduced by Aggarwal et al. [48a] and Page et al. [48b], respectively (Table 10.7). The highest enantioselectivities reported to date for an iminium-based olefin epoxidation -95% ee using 1-phenyl-3,4-dihydronaphthalene as substrate - were achieved with the catalyst 41b [48b]. 

Diphenylpyrrolidine (77) catalyses the enantioselective cy-chlorination of aldehydes.299 Mechanistic and computational studies suggest that - in contrast to pre- viously proposed mechanisms involving direct formation of the carbon-electrophile bond - iV-chlorination occurs first, followed by a 1,3-sigmatropic shift of chlorine to the enamine carbon. The product iminium ion is then hydrolysed in the ratedetermining step. 

In order to test the iminium-activation strategy, MacMillan first examined the capacity of various amines to enantioselectively catalyze the Diels-Alder reaction between dienes and a,/ -unsaturated aldehyde dienophiles [6]. Preliminary experimental findings and computational studies proved the importance of four objectives in the design of a broadly useful iminium-activation catalyst (1) the chiral amine should undergo efficient and reversible iminium ion formation (2) high... 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Overman et al. exercised the CBS reduction strategy during synthesis of the natural opium alkaloid (—)-morphine (50)21 (Scheme 4.3q). Enantioselective reduction of 2-allylcyclohex-2-en-l-one (51) with catecholborane in the presence of the (R)-oxazaborolidinc catalyst (l )-28a provided the corresponding (S)-cyclohexenol 52 in greater than 96% ee. Condensation of this intermediate with phenyl isocyanate, regioselective catalytic dihydroxylation of the terminal double bond, and protection of the resulting diol afforded 53 in 68% overall yield from 51. The ally lie silane 54 for the upcoming iminium ion-ally lsilane cycliza-tion step was obtained in 81% yield by a stereoselective Sn2 displacement of allylic carbamate. 

Somfai et al. demonstrated that it is also possible to use A-sulphonyl groups (Somfai and Ahman 1992 Ahman and Somfai 1992 Weinreb 1997) using the same concept for the cyclization step developed by Speckamp with the allylsilanes (Esch et al. 1987). In this case, the starting product was the L-pyroglutamic acid, inside the succinimide (Esch et al. 1987), allowing the enantioselective synthesis of the (+)-anatoxin-a. The key step consisted of an intramolecular cyclization of an 7V-tosyl iminium ion, catalysed by a Lewis acid, TiCl, to set up the desired bicyclic ring system (Somfai and Ahman 1992). 

The first enantioselective organocatalytic 1,3-dipolar cycloaddition of acyclic nitrones with acrolein and crotonal-dehyde has been reported <2000JA9874>. In particular, the reversible formation of iminium ions from a,/3-unsatu-rated aldehydes and the enantiopure imidazolidinone 535 provided ( A-4-formylisoxazolidines in high yields and ees (Equation 86). A polymer-supported version of catalyst 535 was also prepared <2004EJ0567>. The catalytic performance of various chiral pyrrolidinium salts in the cycloaddition of 1-cycloalkene-l-carboxaldehydes was also evaluated <2003EJO2782>. 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

In the laboratory of S.F. Martin, the vinylogous Mannich reaction (VMR) of a 2-silyloxyfuran with a regioselectively generated iminium ion was utilized as the key step in the enantioselective construction of (+)-croomine. " The carboxylic acid moiety of the starting material was converted to the acid chloride which spontaneously underwent decarbonylation to give the corresponding iminium ion. Reaction of this iminium ion with the 2-silyloxyfuran afforded the desired threo butenolide isomer as the major product. 

Imine hydrogenation produces an N H bond, so the chiral amines produced by this method will necessarily have mono or disubstituted N atoms. Chiral NR-R R amines can, however, be produced by asymmetric hydrogenation, using N,N disubstituted iminium ions or enamines as substrates. Neither of these substrate classes has been studied to the same extent that imines have, but both can be hydrogenated enantioselectively. 

Scheme 13.26 Model proposed to explain the origin ofthe enantioselectivity. (Source E.L. Myers. J.C. de Vries, V.K. Aggarwal, Reactions of iminium ions with Michael acceptors through a Morita Baylis Hillman...

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