Tetrahydroquinolines, enantioselective synthesis

Mani, N. S., Wu, M. An efficient synthetic route to chiral 4-alkyl-1,2,3,4-tetrahydroquinolines enantioselective synthesis of (R)-4-ethyl-1,2,3,4-tetrahydroquinoline. Tetrahedron Asymmetry 2000, 11,4687-4691. 

Catalytic asymmetric aza-Diels-Alder reactions using a chiral lanthanide Lewis acid. Enantioselective synthesis of tetrahydroquinoline derivatives using a catalytic amount of a chiral source [98]... 

METAL-FREE BR0NSTED ACID CATALYZED TRANSFER HYDROGENATION ENANTIOSELECTIVE SYNTHESIS OF TETRAHYDROQUINOLINES... 

The enantioselective synthesis of 3-substituted tetrahydroquinolines was achieved with 98% ee starting from o-nitrocinnamyl intermediates and using rhodium-catalyzed asymmetric hydrogenation, with subsequent cyclization yielding the heterocycle (Scheme 10) <20010L2053>. In an analogous fashion, Sharpless epoxidation of similar o-nitrocinnamyl alcohols yields 3-substituted tetrahydroquinolines with 90% ee. 

A procedure for the highly enantioselective synthesis of chiral chromenes and tetrahydroquinolines was achieved in 2012 by Feringa and co-workers. By combining asymmetric copper-catalyzed allylic substitution with Grignard reagents and an efficient palladium-catalyzed intramolecular Heck... 

Rueping and co-workers have recently developed a highly enantioselective synthesis of differently substituted tetrahydroquinolines 40 via a first photocyclization of substituted 2-aminochalcones 38 and subsequent Br0nsted acid catalyzed asymmetric reduction of the in situ generated quinoline 39, to give final products in moderate to high yields and with excellent enantioselectivities (Scheme 15) [106,107]. 

In a same area, an efficient and simple method for the enantioselective synthesis of indolines, isoindolines, tetrahydroquinolines and tetraisoquino-lines was achieved by means of the organocatalytic intramolecular aza-Michael reaction of the corresponding aniline and benzylamine derivatives. " This process was catalysed by a diarylprolinol silyl ether used in the presence of benzoic acid as an additive, which provided the Michael adducts in good yields and excellent enantioselectivities of up to 99% ee (Scheme 1.85). This methodology was applied to the synthesis of the biologically active tetra-hydroquinoline alkaloid (-l-)-angustureine. 

Jia, Z.-X., Luo, Y.-C., Xu, P.-F. (2011). Highly enantioselective synthesis of polysub-stituted tetrahydroquinolines via organocatalytic Michael/Aza-Henry tandem reactions. Organic Letters, 13, 832-835. 

Scheme 11.15 Enantioselective synthesis of 3-substituted tetrahydroquinolines via asymmetric protonation.

Ghorai MK, Nanaji Y, Yadav AK. Ring opening/C-iV cyclization of activated aziridines with carbon nucleophiles highly diastereo- and enantioselective synthesis of tetrahydroquinolines. Org. Lett. 2011 13(16) 4256 4259. 

Chiral formamidines 1.115 have been developed by Meyers and cowoikers [388-392], These reagents are prepared from HC(NMe2XOMe)2 d a-aminoethers 1.60 (R = Me or ferf-Bu) [393], Once again, (5)-valinol and (S)-terf-leudnol derivatives 1.115 (R = /-Pr or tert-Bu) are the most effective chiral auxiliaries. The main applications of these reagents are enantioselective alkylations of tetrahydroquinolines, and the products of these alkylations are very useful in alkaloid synthesis [343, 391, 394], The chiral auxiliaiy is regenerated by treating the products with hydrazine. 

Zhu and co-workers [77] have successfully developed the first organocatalytic enantioselective three-component Povarov reaction for the efficient synthesis of enantiomerically enriched (2,4-cis)-4-amino-2-aryl(alkyl)-tetrahydroquinolines. To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, they applied this methodology to the short and efficient synthesis of torcetrapib (188), a potent cholesteryl ester transfer protein (CETP) inhibitor (Scheme 17.31). Reaction of 4-trifluoromethylaniline 184, propionaldehyde 18, and enecarbamate 185 using phosphoric acid catalyst 186 afforded tetrahydroquino-line 187 in 57% yield with 93% ee. Ethoxycarbonylation, deprotection/acylation, and benzylation provided torcetrapib (188) in four steps with 32% overall yield. 

The Fustero group recently also applied this strategy for the enantioselective total synthesis of (-i-)-angustureine (308) 289). (Scheme 70) Angustureine (308) is a tetrahydroquinoline alkaloid isolated from the bark of the Venezuelan shrubby tree Galipea officinalis 291). Carrying out the iminium-catalyzed intramolecular... 

By introducing chiral information into the substrate, a diastereo- and enantioselective preparation of 1,2,3,4-tetrahydroquinolines is possible. Jprgensen therefore combined an organocatalytic Michael addition (not shown) with a Povarov reaction in a one-pot process to achieve good selectivities in the synthesis of octahydroacridines 527 (Scheme 13.119) [199]. 

The synthesis of tetrahydroquinolines has received a great deal of attention owing to their presence in many natural frameworks and also to their pharmacological importance [59], Enantioselective [4 -1- 2] cycloadditions constitute one of the most widely employed tools for the preparation of six-membered nitrogen heterocycles [60], Among them, the Povarov reaction is one of the main approaches to... 

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