Cinchona alkaloid catalysts

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

Modified Cinchona alkaloids catalysts have been developed in the last two decades to enhance further the bifunctional mode of the catalyst. Derivations at the C(9)-OH group, replacement of quinoline C(6 )-OCH3 with a hydroxyl group to enhance hydrogen bonding, syntheses of bis-Cinchona alkaloids, and development of thiourea-derived Cinchona alkaloids are most notable. 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

Scheme 8. Catalytic enantioselective desymmetrizations of anhydrides using cinchona alkaloid catalysts...

Direct Mannich reactions of cyclic 1,3-dicarbonyls with acyl imines, R1-CH=N-CO2R2, gives o -quaternary-carbon-bearing products (9 X = CH2, O Y = Me, OMe, OEt) with yieldIdelee up to 98/90/99%, using cinchona alkaloid catalysts 25 ... 

Ketones have been enantioselectively cyanocarbonated to give tetrasubstituted carbon stereocentres (84), using cinchona alkaloid catalysts and cyano esters, with ees up to 97%.254 A fall-off in ee at high conversions has been explained by a mechanism involving competing asymmetric processes, and significant retro-cyanation. 

Continuous reactors are not always beneficial to achievement of good reactor performance (Woltinger, 2002) in the asymmetric opening of meso-anhydrides, due to product inhibition of the cinchona alkaloid catalyst the conversion and enantiomeric excess decreased rapidly during a continuous reaction. Even optimization of reaction parameters to decrease residence time to a very low value (1 h) did not improve the situation sufficiently. In contrast, performing the reaction in repetitive batch mode allowed a modest 60% e.e. to be sustained over 18 cycles. 

One example is the optically active amino acid derivative (S)-20n which contains a bipyridyl substituent (Scheme 3.14). The alkylation reaction in the presence of the cinchona alkaloid catalyst 33 proceeds with 53% ee (83% yield of (S)-20n) and gave the desired enantiomerically pure a-amino acid ester (S)-20n in >99% ee after re-crystallization [43]. Subsequent hydrolysis of the optically pure (S)-20n furnished the desired unprotected a-amino acid 35. A different purification method, subsequent enzymatic resolution, reported by Bowler et al., furnished the a-amino acid product 35 with enantioselectivity of 95% ee [44],... 

Scheme 13.8 summarized kinetic resolution of the 5-oIfcyI-l,3-dixolane-2,4-diones roc-15 by alcoholysis in the presence of the dimeric cinchona alkaloid catalyst 11, (DHQD)2AQN, as reported by Tang and Deng [19]. These authors observed that the related 5-oryl-l,3-dioxolane-2,4-diones 29 (Scheme 13.12) underwent rapid rac-emization under the reaction conditions used, thus enabling dynamic kinetic resolution. This difference in reactivity was attributed to the higher acidity of the a-CH... 

Scheme 13.9 summarized kinetic resolution of N-urethane protected N-carboxy anhydrides rac-18 by methanolysis in the presence of the dimeric cinchona alkaloid catalyst 11, (DHQD)2AQN, as reported by Deng et al. [20]. These kinetic resolutions were typically conducted at low temperature - from —78 to —60 °C. Deng et al. later observed that if the reaction temperature was increased racemization of the starting aryl N-carboxy anhydrides rac-18 becomes sufficiently rapid to enable a dynamic kinetic resolution [21]. Configurational stability of the product esters... 

Figure 3.39 a The structure and proposed mode of action of the modified Cinchona alkaloid catalyst b an example ofthe catalytic Henry reaction between benzaldehyde and nitromethane. 

Fig. 6.2 Cinchona alkaloid catalysts for 1,4-additions of thiols to cyclic enones.

Catalyst 3 is proposed to function in a manner similar to the cinchona alkaloid catalysts (1 and 2), with the tertiary amine providing activation for the nucleophilic thiol, which is held in close proximity to the thiourea-bound carbonyl substrate. 

Enantioselective variants of these cyclopropanation reactions were achieved by replacing DABCO with cinchona alkaloid catalysts 53a-d [100-102]. 

A series of (1-lactams (64) have been synthesized through the use of an immobilized cinchona alkaloid catalyst. This is postulated to proceed via the cycloaddition of an imine, and a ketene formed in situ through deprotonation of an acid chloride (Scheme 4.81). Different system configurations were described in the paper however, a column filled with a 5 1 mixture of solid K2C03 and immobilized-quinine derivative 65 cooled to —45 °C was found to be the most practical. The solution of the acid chloride and imine was dripped through the column and then directed... 

Corey, E. J., Noe, M. C., Guzman-Perez, A. Kinetic Resolution by Enantioselective Dihydroxylation of Secondary Allylic 4-Methoxybenzoate Esters Using a Mechanistically Designed Cinchona Alkaloid Catalyst. J. Am. Chem. Soc. 1995, 117, 10817-10824. 

Lectka and coworkers first demonstrated that the ammonium enolates 18 generated from acid chlorides in the presence of a cinchona alkaloid catalyst (BQn, 19) and... 

Stereoselective a-fluorination of a-nitro esters 107 was performed using Selectfluor as a fluorinating agent and cinchona alkaloid catalyst 109 by Togni and coworkers (Scheme 6.32) [60]. Under the basic condition (NaH inTHFat —40 °C) were obtained the a-fluorinated products 99 in high yield (up to 91%) with relatively low enantios-electivities (up to 31%). 

This group continuously enlarged the scope of substrate to allylsilane, silyl enol ether 113 and oxindoles 115 for enantioselective catalytic a-fluorination (Scheme 6.34) [62]. They employed N-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with bis-cinchona alkaloid catalysts and excess base to provide the corresponding fluorinated compounds 114,115 in excellent enantioselectivities up to 95% ee. 

However, the catalysts 64 were found to be ineffective for the a-substituted-a-cyanoacetate donors 72 (up to 48% ee). The same authors overcame this problem by introducing the new 6 -OH cinchona alkaloid catalyst 71 that afforded excellent yields (90-100%) and a synthetically useful level of enantioselectivities (80-95% ee) for conjugate addition to acrolein with the a-cyanoacetates 72 bearing a range of a-aryl and a-heteroaryl groups (Scheme 9.24). 

In 2007, Jorgensen and coworkers demonstrated that the bifunctional thiourea-cinchona alkaloid catalysts 81b also promoted the enantioselective addition of oximes 153 as oxygen nucleophiles to nitroolefins 124 giving the adduct 154 in good yield with a high level of enantioselectivity (Scheme 9.52) [45]. The obtained adduct 154 can be converted to the optically active aliphatic nitro- or aminoalcohols. It is believed that the... 

Chiral versions of PEG-bound PTCs have been prepared by the attachment of cinchona alkaloids. Catalysts 101 and 102 (Figure 10.9), related to non-cationic 77, were prepared starting from monomethylated PEG5000 and using spacers similar to that of 98 [216]. Both materials were tested as catalysts for the synthesis of the tert-butyl ester related to 94 and similar compounds, using the standard O Donnell-Corey-Lygo procedure. Under optimized conditions (DCM, solid CsOH, — 78 °C,... 

Hatakeyama and co-workers reported the highly enantioselective Baylis-Hillman reaction of 1,1,1,3,3,3-hexafluoroisopropyl acrylate with an aldehyde, which is catalyzed by the cinchona alkaloid catalyst 4 that was readily available from (+ )-quinidine (Equation 10.11) [25],... 

The condensation reaction of (3-dicarbonyl compounds with a-haloketones to generate hydroxydihydrofuran is known as an interrupted Feist-Benary reaction. Calter et al. reported an enantioselective version of this reaction [26]. The aldol reaction of diketone with a-bromo-a-ketoester followed by cyclization proceeded in the presence of dimeric cinchona alkaloid catalyst to give cyclized product in high yield with high ee... 

Collier P.J., Goulding T., Iggo J.A. and Whyman R. (1995) Studies of the Pt-cinchona alkaloid catalyst for enantioselective alpha-keto esters hydrogenation, in Jannes G. and Dubois V. (eds.). Chiral Reactions in Heterogeneous Catalysis, Plenum Press, N.Y. p. 105-110. 

Bartok, M., Balazsik, K., Notheisz, F. (2002) Heterogeneous asymmetric reactions. Part 33. Novel interpretation of the enantioseleetive hydrogenation of o//i/i -ketoesters on Pt/alumina-cinchona alkaloid catalyst system. React. Kinet Catal. Lett. 77, 363-370. 

Shortly afterwards, asymmetric addition of indoles to isatins catalyzed by bifunctional cinchona alkaloid catalysts was reported by the groups of Wang and Li (Scheme 6.6, eqn (1)) and Chimni (Scheme 6.6, eqn (2)) independently. Comparable yields and enantioselectivity were obtained by employing slightly different catalytic systems. The 6 -OH group of catalyst 18 and 19 was found to play an important role in controlling the stereochemical outcome and tuning activity of catalysts in these reactions. 

Scheme 6.6 AFC reaction of indoles with isatins catal3rzed by bifunctional modified cinchona alkaloid catalysts reported by Wang, and by Li and Chimni.

Wang and co-workers developed an AFC reaction of naphthols with aldi-mines employing a bifunctional modified cinchona alkaloid catalyst 48 (Scheme With 10 mol% 48, the reaction of naphthols with a wide... 

After this study, the employment of ammonium salts derived from Cinchona alkaloid catalysts, such as [4-(trifluoromethyl)benzyl]cinchoninium bromide (60), for the PTC conjugate addition of 2-afkyUndanones to methyl vinyl ketone was carried out in a two phase toluene/50% aqueous NaOH system yielding higher enantioselec-tivities (up to 80% ee) of the corresponding Michael adduct which is a key intermediate in drug synthesis (Scheme 2.33) [102]. 

Preliminary studies led to the employment of the Cinchona alkaloid catalysts 144 [230], 145 [231], and 146 [232] in the enantioselective conjugate addition of malonates to enones in the presence of K COj as base Fig. 2.14. Different fragances... 

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