Quinidine derivative catalyst

Later, a dramatic jump in the ee values was achieved by the same research group by introducing the thiourea moiety at the 6 -position of 44 [22]. Using 10 mol% of the quinidine-derived catalyst 46, the highly enantioselective Henry reaction between nitromethane and the aromatic aldehydes (electron-rich, electron-deficient, and... 

In 2006, Deng and coworkers reported that quinine/quinidine-derived catalysts (64a,b) bearing a free OH group at the C6 -position and bulky phenanthryl moiety at the 9( Opposition quite efficiently promoted the Michael addition of the a-substituted P-ketoesters 65 to the a,P-unsaturated ketones 66 (Scheme 9.21) [18]. The reaction with as little as 1.0mol% of catalyst 64 afforded excellent stereoselectivity and chemical yields (up to 98% ee with quantitative yield) for a wide range of both donors and acceptors. 

Shibata and Tom used this strategy for a highly enantioselective mono-fluoromethylation by an asymmetric Mannich reaction using 1-fluorobi-s(phenylsulfonyl)methane (FBSM) with quinidine-derived catalyst 49c and subsequent removal of the sulfonyl group by treatment with magnesium powder (99% enantiomeric excess). Palomo and coworkers used sulfonyl acetonitrile as a synthetic equivalent of acetonitrile and obtained the optically active p-aminonitriles 97 (76% enantiomeric excess). Bernard , Ricci, and coworkers also introduced the same strategy to synthesise N-protected p -amino acid esters 98 (R = Ph, 92% enantiomeric excess) and a-alkylidene-p-aminoesters 99 (R = Ph, 91% enantiomeric excess) by an asymmetric Mannich reaction of sulfonylacetate followed by the subsequent reductive removal of the sulfonyl moiety and olefination with formaldehyde, respectively (Scheme 16.32). ... 

The enantioselective cyanoformylation of aldehydes organocatalyzed by chiral quaternary ammonium salts is representative, and has been the center of complementary contributions [38,39,40], In 2007, Feng and coworkers reported the use of the quinidine-derived catalyst 67 to promote the reaction between ethyl cyanoformate and various aldehydes (Scheme 12.29). The targets 68 were obtained in 57-87% yields... 

In nearly aU cases, catalysts bearing the unnatural C9-epi configuration (e.g. SS, 9S for the quinine derivatives or R,9R for the quinidine-derived catalysts) have turned out to be more enantioselective [2]. A thorough review by Schreiner and Kotke discusses the developments in this area until 2009 [2, 13]. In spite of recent developments in the area, only a handful of X-ray crystal structures of the active catalysts have been reported. The X-ray stracture of a cinchonine-derived (8R, 9R configuration) squaramide catalyst is displayed in Fig. 6.3. 

Very recently, Gilmour et al. [52] reported the synthesis and application of a 9-fluorinated quinidine-derived catalyst 20 for the asymmetric electrophilic flu-orination of p-ketoesters. The authors envisioned that installation of a fluorine substituent at the C9 position would restrict internal rotation around the C8-C9 bond through a large charge-dipole interaction between the C-F bond and the ammonium cation. 

Ricci et al. [85] reported the use of a quinidine-derived chiral catalyst in the asymmetric addition of nitromethane to iV-Boc imine 40. At around the same time, S chans and co-workers used a dihydroquinidine-derive chiral thiourea DHQD-134 applicable to nitromethane and nitroethane 149 [86]. The application of nitroethane conveniently generates a tertiary stereogenic center in the P-nitroamine product 151. The methodology presented by Schaus is also applicable to novel... 

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

By a similar but solvent-free method Plaquevent et al. produced the Michael adduct 30 from 2-pentyl-2-cyclopentenone in 91% yield and with 90% ee, by use of the quinine-derived catalyst 31 (Scheme 4.10) [16], When the quinidine-derived ammonium salt 32 was employed, 80% of the enantiomeric product ent-30 was ob-... 

A detailed study of the effect of modified quinidine derivatives was conducted by the same group [103]. In particular the effects on enantioselectivity of several substituents at the C9 position and of catalyst conformation were investigated, with interesting results - the enantioselectivity was almost unaffected by the O-acyl substituent at the C9 carbon atom (Scheme 6.41). For example, use of catalysts 90, 91, and 92, which are based on structurally different acyl substituents, gave the product (1 R,2S)-( I )-89a with enantioselectivity in the narrow range 89-92% ee. The yields, however, differed substantially, and did not exceed 54%. Interestingly, a more rigid quinidine derivative resulted in complete reversal of enantioselectivity... 

An important step in the development of asymmetric MBH reactions was the introduction of the quinidine-derived /Msocupreidine catalyst (/MCD) 44, by the Hatalceyama group [64, 65]. /MCD mediated the addition of acrylate 43 to a variety of aromatic and aliphatic aldehydes even at —55 °C in DMF, and afforded (R)-adducts in good yields (40-58%) and excellent enantioselectivity (ee up to 99%) (Table 5.3). The contribution of the 1,1,1,3,3,3-hexafluoroisopropyl acryl ester (HFIPA) to the reactivity of the system deserves comment. This ester displayed... 

In addition to the immobilization of boron-derived catalysts, other commonly used homogeneous catalysts have been supported on polymers. Sharpless and others [82-87] prepared various quinine-based catalysts to achieve asymmetric dihydroxylations of alkenes. Initial studies were performed with catalyst 109 (Fig. 3), obtained by co-polymerization of 9-(4-chlo-robenzoyl)quinidine with acrylonitrile [82]. 

Enolates, generated by Michael addition reactions of a,p-unsaturated esters or ketones, can add to aldehydes. If the Michael addition is carried out with a tertiary amine (or phosphine) then this is referred to as the Baylis-Hillman reaction. Typically, an amine such as l,4-diazabicyclo[2.2.2]octane (DABCO) is used. After the aldol reaction, the tertiary amine is eliminated and it can therefore be used as a catalyst (1.61). The reaction is somewhat slow (requiring several days), but rates may be enhanced with other amines such as quinuclidine or quinidine derivatives, the latter effecting asymmetric reaction with high levels of selectivity. ... 

In 2013, Kang and Kim expanded the substrate scope of [l,5]-hydride transfer/ eyelization reactions to ortho tertiary amine substituted benzylidene aeetones 17 (Seheme 4.10). Quinidine-derived primary amine C2 was found to be the optimal catalyst to activate the o,p-unsaturated ketone group. An array of poly-eyelie tetrahydroquinolines 18 was delivered in satisfaetory yields with high level of diastereo- and enantioseleetivity (up to 97% yield, 19 1 dr and 92% ee). 

Feng developed a combinatorial catalyst system containing the ehiral sodium binaphtholate 49 and a quinidine-derived chiral quaternaiy ammonium salt 50 for the enantioseleetive trifluoromethylation of aromatic aldehydes in up to 71% ee (Scheme 2.31). A lack of either 49 or 50 completely prevented the reaction from proceeding. 

In 2010 the Palomo group used the related quinidine-derived phase-transfer catalyst 109 to facilitate the addition of sulfonylacetonitrile 110 to either A-Boc-protected a-amidosulfones 107 or imines (not shown) in order to obtain - upon subsequent treatment with Mg in MeOH - the enantioenriched a-unsubstituted P-aminonitriles llla-f (Scheme 5.45) [62]. The latter compounds were obtained in moderate to good yields (65-85%) and moderate ee (55-76%). 

An important contribution elucidating the potential of primary amines derived from Cinchona alkaloids has been the aldol cyclodehydration of achiral 4-substituted-2,6-heptanediones to enantiomerically enriched 5-substituted-3-methyl-2-cyclohexene-l-ones, presented by List and coworkers in 2008 (Scheme 14.26). Both 9-deo>y-9-amino-epr-quinine (QNA) and its pseudoenantiomeric, quinidine-derived amine QDA, in combination with acetic acid as cocatalyst, proved to be efficient and highly enantio-selective catalysts for this transformation, giving both enantiomers of 5-substituted-3-methyl-2-cyclohexene-l-ones with very good results. The authors observed that proline and the catalytic antibody 38C2 delivered poor enantioselectivity in this reaction. Furthermore, the synthetic utility of the reaction was exemplified by the first asymmetric synthesis of both... 

---