Tetrahydroquinolines, enantioselective

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]... 

Kwong and Lee [39] prepared various chiral 2,2 6, 2"-terpyridines and tested them as copper ligands for the cyclopropanation of alkenes. High enantioselectivities were obtained, the presence of bulky alkyl groups at the 8-position of the tetrahydroquinoline ring being crucial (structure 29 in Scheme 17). Thus when = Bu, up to 90% ee for the trans and 94% for the cis isomer were obtained by performing the reaction at 0 °C (transIds = 69/31). 

The asymmetric addition of different types of nucleophiles at the C-l position of 3,4-dihydroisoquinolines were highlighted in a number of publications. Schreiber et al. described an enantioselective addition of terminal alkynes 136 to 3,4-dihydroisoquinolinium bromide 137 in the presence of triethylamine, catalytic copper bromide, and QUINAP <06OL143>. The resulting 1-substituted tetrahydroquinolines 138 were isolated in high yield and high enantiomeric excess in most cases. 

Asymmetric aza Diels-Alder reactions provide a useful route to optically active heterocyclics such as piperidines and tetrahydroquinolines.45 Although successful examples of diastereoselective approaches had been reported as early as 10 years ago,46 only recently have enantioselective reactions been accomplished.47 For example, the reaction of chiral amine-derived aromatic imine 115 with Brassard s diene 116 gives adduct 117 with up to 95% diaster-eoselectivity (Scheme 5-37).48... 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

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

The enantioselective hydrogenation of olefins, ketones and imines still represents an important topic and various highly enantioselective processes based on chiral Rh, Ru or Ir complexes have been reported. However, most of these catalysts failed to give satisfactory results in the asymmetric hydrogenation of aromatic and heteroaromatic compounds and examples of efficient catalysts are rare. This is especially the case for the partial reduction of quinoline derivatives which provide 1,2,3,4-tetrahydroquinolines, important synthetic intermediates in the preparation of pharmaceutical and agrochemical products. Additionally, many alkaloid natural products consist of this stmctural key element. 

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. 

The Brpnsted acid catalyzed enantioselective hydrogenation of the corresponding readily available 2-substituted quinolines (for an interesting approach to 2-alkyl tetrahydroquinolines by an aza-xylene Diels-Alder reaction, see Steinhagen and Corey 1999 Avemaria et al. 2003), which we prepared by simple alkylation of 2-methylquinoline, generated the tetrahydroquinoline derivatives in excellent enantioselectivities and subsequent A-methylation gave the desired natural products in good overall yields (Fig. 5). 

Cunninghamella elegans has shown a degree of generality in the oxidation of benzylic substrates. For example the tetrahydroquinoline (88) is converted to the derivative (89 equation 30), but the degree of enantioselectivity is not known." Similarly triprolidine (90) is converted to the alcohol (91 equation 31) in respectable yield. 

The enantioselective version of the relay transformation by organic and metallic catalyses was successfully demonstrated by Gong and coworkers (Scheme 3.39) [83]. They accomplished the direct transformation of o propargylaniline derivatives into tetrahydroquinolines in a highly enantioselective manner through the hydroamina tion of alkynes/isomerization/enantioselective transfer hydrogenation (see Sec tion 3.3 for details) sequence under the relay catalysis of an achiral Au complex/ chhal phosphoric acid binary system. 

Thus although 2 substituted quinolines have been reduced to chiral 1,2,3,4 tetrahydroquinolines with good enantioselectivity, there remains considerable prog ress to be made in this area. Some 2 substituted quinolines can be hydrogenated in >95% ee, but others, such as 2 phenylquinoline, give considerably lower values. More important, none of the catalyst systems that hydrogenate quinolines highly... 

In 2008, Fan and Xu developed an air stable and phosphine free Ir catalyst for the asymmetric hydrogenation of quinolines [20]. They used chiral cationic Cp Ir(OTf) (CF3TSDPEN) complex as catalyst ]21]. The reaction proceeded smoothly in unde gassed methanol with no need for inert gas protection and afforded the 1,2,3,4 tetrahydroquinoline derivatives in up to 99% ee (Table 10.3). The counterion of iridium catalyst is very important, OTf gave high reactivity and enantioselectivity, and no reactivity was observed for chloride. It is noted that it is one ofthe best results of asymmetric hydrogenation of quinolines. 

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. 

Transition-metal-stabilized carbocations can be generated from functionalized butadieneiron carbonyl or arenechromium tricarbonyl complexes [92], Reactions of such carbocations formed from chiral complexes have been studied, but low selectivities are usually observed [526, 528, 535]. However, chromium tricarbonyl complexes derived from ephedrine 5.66 suffer cyclization in acidic medium. After decomplexation, c/s-tetrahydroquinolines are formed with a high diastereo-and enantioselectivity [540,542] (Figure 5.44). 

There are few examples of enantioselective reductions of imines bearing chiral substituents. According to Polniaszek and Dillard [139], reduction ofimmin-ium salts 6.23 by NaBHLj, followed by hydrogenolysis, leads to nonracemic-substituted tetrahydroquinolines. To observe a high asymmetric induction, it is necessary to introduce a 2,6-dichlorophenyl group on the chiral substituent (Figure 6.19). 

The reverse eledron-demand aza-Diels-Alder reaction of eledron-rich alkenes with 2-azadienes was catalyzed by 21 j to give tetrahydroquinoline derivatives in favor of the ds-isomer with excellent enantioselectivities (Equation 10.44) [91]. 

In the previous section, lanthanide triflates were shown to be excellent catalysts for achiral aza Diels-Alder reactions. While stoichiometric amounts of Lewis acids are required in many cases, a small amount of the triflate effectively catalyzes the reactions. On the other hand, chiral lanthanide Lewis acids have been developed to realize highly enantioselective Diels-Alder reactions of 2-ox-azolidin-l-one with dienes [89]. The reaction of N-benzylideneaniline with cyclop entadiene was first performed under the influence of 20 mol% of a chiral ytterbium Lewis acid prepared from ytterbium triflate (Yb(OTf)3), fR)-(+)-l,l -bi-naphthol (BINOL), and trimethylpiperidine (TMP). The reaction proceeded smoothly at room temperature to afford the desired tetrahydroquinoline derivative in a 53% yield, although no chiral induction was observed. At this stage, it was indicated that bidentate coordination between a substrate and a chiral Lewis acid would be necessary for reasonable chiral induction. N-Benzylidene-2-hydroxy aniline (31a) was then prepared, and the reaction with cyclopentadiene (32a) was examined. It was found that the reaction proceeded smoothly to afford the corresponding 8-hydroxyquinoline derivative (33a) [90] in a high yield. The enantiomeric excess of the cis adduct in the first trial was only 6% however, the selectivity increased when diazabicyclo-[5,4,0]-undec-7-ene (DBU) was used in-... 

Other substrates were tested, and the results are summarized in table 34 (Ishitani and Kobayashi 1996). Vinyl ethers (34b-d) also worked well to afford the corresponding tetrahydroquinoline derivatives (35b-e) in good to high yields with good to excellent diastereo- and enantioselectivities (entries 1-9). Use of 10mol% of the chiral catalyst also gave the adduct in high yields and selectivities (entries 2 and 6). As for additives,... 

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