Indoline asymmetric synthesis

Chiral butyrolactones of type 27 and 28 have substantial value in asymmetric synthesis because they contain readily differentiable difunctional group relationships e.g. 1,5-di-carboxylic acid, 1,4-hydroxy carboxylic acid, 1,6-hydroxy-carboxylic acid, 1,6-diol etc.) that would be difficult to assemble by existing asymmetric condensation and pericyclic processes. Applications of these chiral derivatives of glutaric acid to syntheses of indole, indoline and quinolinone alkaloids are illustrated in Schemes 16-18. 

The optically active N-aminoindoline (265) has been applied to the asymmetric synthesis of a variety of a-amino acids (70JA2476, 2488). Starting from TV-benzoyl-1,2,3,4-tetrahy-droquinaldine (257), the chloro amide (258) was prepared by von Braun cleavage. Thermolysis converted (258) to the rrans-unsaturated amide (259) which was epoxidized. On base treatment the epoxide (260) underwent intramolecular nucleophilic displacement and amide hydrolysis to afford indoline (261) stereospecifically. Resolution of (261) was accomplished via the brucine salt of the N-o-carboxybenzoyl derivative (262). Alkaline hydrolysis, N-nitrosation and reduction yielded the levorotatory 1-aminoindoline (265). Reaction of... 

Brodbeck, R., Primus, R., Wasley, J. Indoline and piperazine containing derivatives as a novel class of mixed D2/D4 receptor antagonists. Part 2 asymmetric synthesis and biological evaluation. Bioorg. Med. Chem. Lett. 2002,12, 3111-3115. 

ASYMMETRIC SYNTHESIS l-Amino(S)-2-[(R)-l-hydroxyethyl]indoline. (S)-l-Amino-24iydroxymethylindoline. d- and i-a-Methylbenzylamine. 

Table 5.3 Palladium/NHC-catalyzed asymmetric synthesis of fused indolines reported by Kundig. ...

Almost at the same time as the first report of the Kiindig group in 2011, Kagan and co-workers realized an asymmetric synthesis of chiral indoline scaffolds via Pd°/bisphosphine catalyzed C(sp )—H bond functionalization. They briefly investigated a number of chiral ligands (R,R)-L16 gave the cyclization product in best results (Scheme 5.35). They also employed this method to synthesize cyclohexyl fused indolines in promising yields (up to 97%) and enantioselectivity (up to 93% ee). 

Katayev D, Lariraiov E, Nakanishi M, Besnard C, Kiindig EP (2014) Palladium-N-heterocyclic carbene (NHC)-catalyzed asymmetric synthesis of indolines through regiodivergent C (sp3)-H activation scope and DFT study. Chem Eur J 20(46) 15021-15030... 

Hsieh J-C, Ebata S, Nakao Y, Hiyama T (2010) Asymmetric synthesis of indolines bearing a benzylic quaternary stereocenter through intramolecular arylcyanation of alkenes. Synlett 2010(11) 1709-1711. doi 10.1055/s-0029-1219964... 

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

Miscellaneous Iminium Catalyzed Transformations The enantioselective construction of three-membered hetero- or carbocyclic ring systems is an important objective for practitioners of chemical synthesis in academic and industrial settings. To date, important advances have been made in the iminium activation realm, which enable asymmetric entry to a-formyl cyclopropanes and epoxides. In terms of cyclopropane synthesis, a new class of iminium catalyst has been introduced, providing the enantioselective stepwise [2 + 1] union of sulfonium ylides and ot,p-unsaturated aldehydes.As shown in Scheme 11.6a, the zwitterionic hydro-indoline-derived catalyst (19) enables both iminium geometry control and directed electrostatic activation of sulfonium ylides in proximity to the incipient iminium reaction partner. This combination of geometric and stereoelectronic effects has been proposed as being essential for enantio- and diastereocontrol in forming two of the three cyclopropyl bonds. 

Many methods have been developed for the enantioselective synthesis of unnatural a-amino acids. Jeff Johnston of Indiana University reports (J. Am. Chem. Soc. 125 163,2003) coupling the asymmetric alkylation of O Donnell with intramolecular radical cyclization, leading to what appears to be a general method for the enantioselective construction of indolines. 

This method was successfully applied to the total synthesis of chiral indoline alkaloid 2Sh, which is Wierenga s synthetic intermediate for the left hand segment of the antitumor agent ( + ) CC 1065. As shown in Scheme 10.28, the asymmetric hydrogenation of N methanesulfonyl indole (24g) to the corresponding indoline (25g) with 93% ee was the key step. 

Maciver EE, Thompson S, Smith MD (2009) Catalytic Asymmetric 6tt Electrocyclization Enantioselective Synthesis of Functionalized Indolines. Angew Chem Int Ed 48 9979... 

Kuwano, R. Kaneda, K. Ito, T. Sato, K. Kurokawa, T. Ito, Y. Highly enantio-selective synthesis of chiral 3-substituted indolines by catalytic asymmetric hydrogenation of indoles. Org. Lett. 2004, 6,2213-2215. 

SCHEME 19.11. Phase transfer catalytic asymmetric indoline synthesis through 6jt-electrocychzation. 

The asynunetric alkylation of 14 with o-hromobenzyl bromide 110 catalyzed by the (/ ,/ )-enantiomer of ammonium salt 105 was employed by Mar-uoka and coworkers for the efficient asynunetric synthesis of (S)-A -acetyl indoline-2-carboxylate 111. Following the initial asymmetric alkylation, hydrolysis, and (V-acetylation gave the key intermediate 112, which could be further converted into 111 [20f]. (S)-A -acetyl indoline-2-carboxylate 111 is the key intermediate in the synthesis of the ACE inhibitor 113 (Scheme 22). 

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