Indoles enantioselective reactions

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

Nitroalkenes react enantioselectively (ee usually 40%) with indoles using chiral hydrogen-bonding bis-sulfonamides as catalysts [e.g. to form (41)].44 An enantioselective reaction (usually ee 83-95%) has been shown to occur between indoles and ethyl ... 

The enantioselective reactions of indoles using alkylidene malonates gave the alkylation products 92 in excellent yield and with moderate ee. 

Gouverneur et al. described the catalytic enantioselective fluorocyclisation of prochiral indoles. The reaction was catalysed by 20 mol% of (DHQ)2PHAL and NFSI was used as fluorine source. Products were obtained in up to 95% yield and with up to 92% ee (Scheme 15.39). 

NitroaUCBnes. Organocatalytic enantioselective reaction of indoles with nitroalkenes appeared recently using chiral sulfonyl vicinal diamine 13 or chiral thiourea 14 as catalysts, which improved the electrophihcity of nitroalkene by double... 

Enantioselective hydrogenation of pyrroles has also been conducted, and is somewhat more complex than that of indoles. These reactions were conducted with N-Boc-substituted pyrroles and a ruthenium-TRAP catalyst. The pyrroles can be mono-, di-, or tri-substituted. For example, the asymmetric reduction of 4,5-dimethylpyrrole-2-carboxylate gave the product from addition of hydrogen to the same face of both olefin units to form products containing three stereocenters in high enantioselectivity. These reactions occur by initial reduction of the less-substituted carbon-carbon double bond. 

More recently, Palomo and co workers reported the application of Cu(OTf)2/(13) for highly enantioselective addition of pyrroles and indoles to a -hydroxy enones [10]. The a -hydroxy enone substrate-Cu(OTf)2/(13) catalyst system provides for excellent enantioselectivities with a variety of P substituents. It is also noteworthy that remarkable increases in enantioselectivity were observed in Friedel-Crafts alkylations of indoles when reactions were conducted under refluxing conditions (Scheme 17.5). 

The Dy(OTf)3-PyBOX ligand-catalyzed Friedel-Crafts alkylation of indoles with a,/3-unsaturated trifluoromethyl ketones represents the only known example of a highly enantioselective reaction that employs Dy(OTf)3 (eq 14). ... 

The enantioselective, copper (II) phosphate (340) catalysed cycloisomerisation-indole addition reaction of 2-(l-alkynyl)-2-alkene-l-ones (337) and... 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

Much like the enol systems discussed in Sect. 6.1, enamines are predictably difficult substrates for most iridium asymmetric hydrogenation catalysts. Both substrate and product contain basic functionahties which may act as inhibitors to the catalyst. Extended aromatic enamines such as indoles may be even more difficult substrates for asymmetric hydrogenation with an additional energetic barrier to overcome. Initial reports by Andersson indicated a very difficult reaction indeed (Table 14) [75]. Higher enantioselectivities were later reported by Baeza and Pfaltz (Table 14) [76]. 

Bandini, M. Cozzi, P. G. Melchiorre, P. Umani-Ronchi, A. (2004) Kinetie resolution of epoxides by a C-C bond-forming reaction Highly enantioselective addition of indoles to cis, trans, and meso aromatic epoxides eatalyzed by [Cr(salen)] eomplexes., Angew. Chem. Int. Ed., 43 84-87. 

Although the initial report included amine nucleophiles, the scope was limited to activated amines such as indole (which actually undergoes C-alkylation at the 3-position), phthalimide, and 7/-methylaniline. Furthermore, enantioselectivities were inferior to those observed with alcohols as nucleophiles. Lautens and Fagnou subsequently discovered a profound halide effect in these reactions. The exchange of the chloride for an iodide on the rhodium catalyst resulted in an increased enantioselectivity that is now comparable to levels achieved with alcoholic nucleophiles ... 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

Additionally, You reported a F-C reaction of indole with electronically diverse aryl aldimines (Scheme 5.8) [16]. In general, products could be obtained in excellent yields and enantioselectivities in short reaction times. 

Ricci and co-workers introduced a new class of amino- alcohol- based thiourea derivatives, which were easily accessible in a one-step coupling reaction in nearly quanitative yield from the commercially available chiral amino alcohols and 3,5-bis(trifluoromethyl)phenyl isothiocyanate or isocyanate, respectively (Figure 6.45) [307]. The screening of (thio)urea derivatives 137-140 in the enantioselective Friedel-Crafts reaction of indole with trans-P-nitrostyrene at 20 °C in toluene demonstrated (lR,2S)-cis-l-amino-2-indanol-derived thiourea 139 to be the most active catalyst regarding conversion (95% conv./60h) as well as stereoinduction (35% ee), while the canditates 137, 138, and the urea derivative 140 displayed a lower accelerating effect and poorer asymmetric induction (Figure 6.45). The uncatalyzed reference reaction performed under otherwise identical conditions showed 17% conversion in 65 h reaction time. 

Figure 6.45 Hydroxy-flinctionalized thiourea derivatives (20mol% loading) screened in the enantioselective Friedel-Crafts reaction of indole with trons-P-nitrostyrene at 20°C in toluene.

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