Chiral 3-amino-2-substituted indoles

A Br0nsted-acid-catalysed enantioselective indole aza-Claisen rearrangement has been applied for the synthesis of chiral 3-amino-2-substituted indoles where an arene CH-O interaction is the source of activation and stereoinduction (Scheme 24) ... 

The usefulness of aminosiloxy diene Diels-Alder chemistry to the preparation of different substituted cyclohexenones is demonstrated in Table 11.3 The functionality at the 4 and 5-positions of the cyclohexenones can be easily controlled by the substitution pattern in the dienophile. The differing endo-exo selectivity found in the initial cycloadducts does not impact the usefulness of this route to cyclohexenones, since the amino group is eliminated in the last step. Chiral versions of aminosiloxy dienes provide the opportunity for asymmetric synthesis. Indeed, the diphenylpyrrolidine-substituted diene allows the synthesis of a variety of cyclohexenones, with good to excellent ee s 2b The usefulness of aminosiloxy diene Diels-Alder reactions to natural product synthesis is exemplified through the stereocontrolled synthesis of the pentacyclic indole alkaloid tabersonine 2c... 

In the previous section, chiral secondary amines are shown to be efficient catalysts for the AFC reaction of 4,7-dihydroindoles with a,p-unsaturated aldehydes by Wang and co-workers. Subsequently, the same group extended the AFC reaction to a,p-unsaturated ketones by using a new chiral primary/ secondary diamine catalyst derived from an amino acid. They found that chalcones, particularly challenging substrates for iminium catalysis, could afford the AFC products 122 in high yields (69-97%) with moderate to excellent enantioselectivity (66-97% ee). Note that the substitution on the 4,7-dihydroindolic nitrogen had a detrimental effect on the reactivity (<10% yield for Al-methyl indole) (Scheme 6.50). 

L-Tryptophan is an essential amino acid that provides the biosynthetic precursor for many naturally occurring indole alkaloids [36]. The ability to synthesize enantiomerically pure tryptophan analogs substituted in the benzenoid ring constitutes a useful approach toward the total synthesis of chiral indole alkaloids of natural and nonnatural origin. Consequently, it provides a general entry into the nonnatural amino acid derivatives of potential pharmacologic value [37]. Hino has demonstrated [38] the powerful utility of cyclic tryptophan tautomers as intermediates for direct functionalization of chiral tryptophans. Cyclic tautomers allow standard electrophilic substitution at 5 position... 

An interesting example of aminocatalysis where a chiral primary amine activates a-substituted a,p-unsaturated aldehydes in a cascade sequence for the addition of indoles and azocarboxylate was reported by Melchiorre and coworkers (Scheme 6.16) [43]. Primary amine 128 directly derived from natural cinchona alkaloid was the catalyst of choice, which promoted this cascade reaction providing final adducts 129, as valuable precursors for a-amino acids having two adjacent stereogenic centers, one of which is quaternary, with very high enantioselectivities (83-99%). The yields are moderate to good (31-80%), and different substituents on the indole core (Cl, OMe, Me) are well tolerated. 

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