Indole enantioselective alkylation

Interestingly, enantioselective alkylation reactions [64] were also developed using, for instance, Cu(OTf)2, [65], [Cu(SbF6)2, Zn(OTf)2] [66], Cu(C104)2-6H20 [67] or Sc (OTf)3 [68] in combination with diverse chiral ligands. Remarkably, organocatalytic alkylations of pyrroles, indoles and anilines by 3-phenylpropenal have been also developed [69]. 

The enantioselective alkylation of indoles catalyzed by C2-symmetric chiral bisoxazoline-metal complexes 90 encouraged many groups to develop superior asymmetric catalysts which are cheap, accessible, air-stable and water-tolerant. Other analogs of the bisoxazoline-metal complex 90 as chiral catalysts and new Michael acceptors have also been studied. The enantioselective alkylations of indole derivatives with of-hydroxy enones using Cu(II)-bis(oxazoline) catalysts 93 and 94 provided the adducts in good yields... 

The additions of indoles to ethenetricarboxylates as Michael acceptors in the presence of copper(II) complexes (10%) of chiral bisoxazolines (97-100) under mild conditions gave the alkylated products in high yield and up to 96% ee [101]. The observed enantioselectivity could be explained by secondary orbital interaction on approach of indole to the less hindered side of the 102-Cu(II)-ligand complex. The chiral ligands 97-99 of the catalyst gave similar ee%. The phenyl derivative 100 produced inferior results compared to 97-99, while (S,S)-2,6-bis(4-isopropyl-2-oxazoline-2-yl)pyridine (101) gave no reaction (Scheme 29) [56]. The enantioselective alkylation of indoles with arylidene malonates catalyzed by z-Pr-bisoxazoline-Cu(OTf)2 was also reported [102],... 

Friedel-Crafts Alkylation Reactions. The activation of glyoxylate esters,trifluoromethyl pyruvate esters, and unsaturated a-ketoesters by catalyst 2 converts these materials into effective electrophiles for asymmetric Friedel-Crafts alkylation reactions with activated arenes (eqs 16 and 17). In fact, bis(triflate) (2) is far superior to tbe bis(hexafluoroantimonate) complex at catalyzing the enantioselective alkylation of benzene derivatives. Aniline and anisole derivatives both give the reaction, as do heterocyclic aromatic compounds such as indole and furan. 

Enantioselective alkylation occurs with alkenoylphosphonates [250], The preferred catalyst is a Sc(III)pybox triflate. ZV-Substituted indoles give somewhat higher enantioselectivity than indole itself. The acyl phosphonate adducts are reactive acylating agents and can be readily converted to esters or amides. 

After the success of Macmillan s catalysts, other types of chiral amine were disclosed and applied in the FCA reaction as activators of a,(3-unsaturated aldehydes. Reports from a few groups have revealed that diaryIprolinol silyl ethers [11], camphor sulfonyl hydrazine [12], chiral aziridin-2-yl methanols [13], and A-isopropylated bipyrrolidine [14] were efficient catalysts in the enantioselective alkylations of 4,7-dihydroindoles, 1-naphthols, and indoles. NEt3, benzoic acid, or... 

Gordillo R, Carter J, Houk KN (2004) Theoretical explorations of enantioselective alkylation reactions of pyrroles and indoles organoeatalyzed by chiral imidazolidinones. Adv Synth Catal 346 1175 1185. doi 10.1002/adsc.200404107... 

Indole 7 was enantioselectively alkylated by nitrostyrene 8 applying chiral phosphoric acid catalysis (Scheme 3.4). The highest enantioselectivity of the product 9 was obtained when the bis-TMS substituted phosphoric acid was applied. ... 

One representative example in enantioselective alkylation of benzylic C-H bond was disclosed by Gong and co-workers in 2010. Highly enantioselective alkylation of 3-arylmethylindoles with dibenzyl malonate was achieved in the presence of catalytic amounts of chiral copper complex L4 (Scheme 2.31) [169]. This protocol provides an excellent enantioselective route to natural product skeleton of 2,3,4,4a,9,9a-hexahydro-lH-pyrido[2,3-b]indoles. 

The phosporic acid (261) catalysed three component reaction involving asymmetric 1,3-dipolar cycloaddition of electron-deficient azomethine ylides (327), aromatic aldehydes (328) and 2-aminomalonates (329) to provide to novel 2,5-dihydropyrrole derivatives (330) with potential bioactivities with enantioselectivities of up to >99% ee (Scheme 86). The Bronsted acids (253) catalysed intermolecular enantioselective alkylation of indoles (332) with cx,p-unsaturated y-lactams (331) thus providing a highly enantioselective method for the synthesis of chiral pyrroli-dinones (333) containing indole moieties, with enantioselectivity (up to 95% ee), has been described by Huang et al. (Scheme 87). " ... 

DNA can be used to induce chirality in Friedel-Crafts alkylation in water. Boersma et al. [115] first explored the enantioselective alkylation of indoles, using Cu-dmbpy/st-DNA as catalyst A variety of indoles reacted with 2-acyl imidazole, achieving moderate ee s, and full conversions in 10 h, as shown in Scheme 6.23. The small variation in the ee values indicates that substitution at the indole does not have a significant influence on the enantioselection. Recently, Li s group demonstrated the same reaction with a human telomeric G-quadruplex (G4DNA) metalloenzyme assembled with G4DNA and Cu ions. The enantioselectivity (up to 75% ee) was found to vary with the conformation and the sequence of G4DNA [116]. 

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>. 

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>. 

A closely related dicationic platinum complex has been shown to transform efficiently /3-citronellene into cis-thujane in a highly diastereoselective manner, which mimics terpene biosynthesis.362 Also, using platinum(n) catalysis, Widenhoefer has reported an intramolecular alkylation of indoles with unactivated olefins, which can be carried out in an enantioselective fashion (Scheme 99).363... 

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 ... 

Akiyama and coworkers extended the scope of electrophiles applicable to asymmetric Brpnsted acid catalysis with chiral phosphoric acids to nitroalkenes (Scheme 57). The Friedel-Crafts alkylation of indoles 29 with aromatic and aliphatic nitroalkenes 142 in the presence of BINOL phosphate (7 )-3r (10 mol%, R = SiPhj) and 3-A molecular sieves provided Friedel-Crafts adducts 143 in high yields and enantioselectivities (57 to >99%, 88-94% ee) [81]. The use of molecular sieves turned out to be critical and significantly improved both the yields and enantioselectivities. 

Scheme 6.148 Product range of the enantioselective 139-catalyzed Friedel-Crafts alkylations of various indols. The product configurations were not determined.

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. 

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

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