Bis-cinchona alkaloids

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. 

An important improvement with regard to both substrate tolerance and enantioselectivity of the AD was the introduction of the anthraquinone-bridged ligands (DHQ)2AQN and (DHQD)2AQN [2], These ligands are easily accessible fromphthalic anhydride and 1,4-difluoro benzene, and in many aspects their catalytic behavior reflects that of the standard bis-cinchona alkaloids described in Section 6D.1. 

To improve the position selectivity in the AD of oligoprenyl compounds bis-cinchona alkaloid ligand 8 was introduced by Corey 15,6]. Its design was based on the [3+2]-cycloaddition model for the AD mechanism, which will be discussed in Section 6E. 1.2. The two 4-heptyl ether substituents of the quinolines are supposed to assist fixation of the substrate in the binding cleft. Additionally, the jV-methylquinuclidinium unit and the linking naphthopyridazine were introduced to rigidify the osmium tetroxide complex of 8 [6],... 

The following facts can be deduced from Sharpless study a) the ligands have a substantial accelerating effect on the reaction rate b) the bis-cinchona alkaloids are uniformly more effective than the monodentate quinuclidine and c) the increase in rate is substrate-dependent. 

Most recently, silica gel-supported bis-cinchona alkaloid 20 was successfully employed in the A A of fraws-cinnamate derivatives [62b]. The resulting products had excellent enantiopuri-ties (>99% ee). Recovered samples of 20 contained osmium and could be used in the AA again, though with a slight loss of activity. Therefore, recovered catalyst was regenerated upon addition of osmium salts. 

Canali, L., Song, C. E. and Sherrington, D. C. Polymer-supported bis-cinchona alkaloid ligands for asymmetric dihydroxylation of alkenes - a cautionary tale. Tetrahedron Asymmetry, 1998, 9, 1029-1034. 

The phthalazide bis(cinchona) derivatives [(DHQD)2-PHAL] are the best ligands for the asymmetric dihydroxyla-tion of trans, 1,1-disubstituted, and trisubstituted alkenes, enol ethers, a,p-unsaturated ketones, and a,p- and p,y-unsaturated esters, whereas the DHQD-IND ligand turns out to be superior for c/j -alkenes (Table 1). The bis(cinchona) alkaloid-substituted pyrimidine ligand was found to be the best for monosubstituted terminal alkenes. The addition of Methanesulfonamide to enhance the rate of osmate(VI) ester hydrolysis is recommended for all nonterminal alkenes. 

Corey, E. J., Noe, M. C., Lin, S. A mechanistically designed bis-cinchona alkaloid ligand allows position- and enantioselective dihydroxylation offarnesol and other oligoprenyl derivatives at the terminal isopropylidene unit. Tetrahedron Lett. 1995, 36, 8741-8744. 

Aminohydroxylations. Several carbamates HjNCOOR (R = Et, t-Bu, CljCI ), the corresponding A-chloro-iV-sodio derivatives, and A-bromoacetamide have been employed as nitrogen source in the reaction mediated by bis-cinchona alkaloid ligand complexed osmate. The products are readily manipulated to give two pairs of chiral diamines. In one version the cinchona alkaloid derivatives are linked to silica gel surface through thiopropyl chains. ... 

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. 

Recently, Shibata, Torn and coworkers reported that modified bis-cinchona alkaloids such as (DHQD)2PHAL (32) and (DHQ)2PHAL (33), known as Sharpless... 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

In 2000, Deng and coworkers [8] found that, in the absence of a stoichiometric achiral base such as 10, commercially available bis-cinchona alkaloids such as the... 

Scheme 11.31 Dual catalytic motion of modified bis-cinchona alkaloid.

Catalyst = silica-supported bis-cinchona alkaloid/ K2Os02(OH)4 Figure 4.32 Silica gel-supported bis-cinchona alkaloid used for strong binding of 0s04... 

Two examples of hetero-Michael reactions have been reported using these kinds of bis-cinchona alkaloid-based chiral Bronsted bases as catalysts. One of them refers to a sulfa-Michael reaction and the other is a case of an aza-Michael reaction. 

One-pot annulation of 2-naphthol analogs to heterocycles 12COS613. Organocatalytic asymmetric halocyclization (among catalysts are bis-cinchona alkaloids and chiral trisimidazolines) 13H(87)763. Photoredox functionalization of C—H bonds adjacent to a nitrogen atom 12CSR7687. 

Allyl silanes and silyl enol ethers undergo enantioselective fluor-odesilylation using NFSI in combination with a catalytic amount of a bis-Cinchona alkaloid and in the presence of excess (DHQ)2PYR was... 

Starting with the reaction conditions developed by Shibata, summarized in Scheme 13.1, Gouverneur and co-workers [5] extended this methodology to include the fluorodesilylation of cyclic allyl silanes (Scheme 13.2). A variety of stoichiometric Cinchona alkaloids were assessed in this transformation, and in most cases the bis-Cinchona alkaloid (DHQ)2PYR afforded the highest enantiomeric excesses. 

Shibata et al. [2,6] further extended this Cinchona alkaloid-mediated asymmetric transfer fluorination reaction to substrates with activated methylene groups, including acyclic (3-cyanoesters, cyclic (3-ketoesters, and oxindole substrates. Representative products, along with the optimal Cinchona alkaloids for these reactions, are shown in Scheme 13.3. Reaction conditions for the acyclic (3-cyanoesters and the cyclic (3-ketoesters used both (a) Selectfluor as the achiral electrophilic fluorine source in MeCN/CHaCla (3 4) at — 80 C and (b) dihydroquinidine acetate (DHQDA) in stoichiometric quantities. The oxindole substrates required the use of stoichiometric bis-Cinchona alkaloids, (DHQlaAQN or (DHQDlaPYR, to obtain useful yields and selectivities. Reactions of these substrates were run in MeCN at 0°C and also employed Selectfluor as the achiral electrophilic fluorine source. 

Shibata successfully adapted the asymmetric transfer fluorination to cyclic silyl enol ethers, cyclic allyl silanes and oxindoles, illustrated in Schemes 13.1-13.3, as a catalytic method (Scheme 13.6) [16]. Similar reaction conditions were identified for all three substrates, including the use of stoichiometric NFSI as the electrophilic fluorine source and a stoichiometric inorganic base additive. It was observed that bis-Cinchona alkaloid (DHQ)2PHAL was best for cyclic silyl enol ethers (X = 0), (DHQ)2PYR (Scheme 13.2) was best for cyclic allyl silanes (X = CH2), while (DHQD)2AQN was best for oxindoles. A similar method was applied to cyclic enol ethers, providing products in modest ee s [17]. 

Borhan and co-workers [41, 42] have developed several asymmetric organocatalytic chlorocyclization reactions using the bis-Cinchona alkaloid (DHQDlaPHAL as the organocatalyst and l,3-dichloro-5,5-diphenylhydantoin (Scheme 13.17) as an electrophilic source of chlorine. Chlorolactonization of... 

In 2008, Shibata et al. disclosed the first successful catalytic enantioselective fluorination based on the use of cinchona alkaloids. Therefore, it was demonstrated that allyl silanes and silyl enol ethers underwent efficient enantioselective fluorodesilylation with NFSI and a catalytic amount of a bis-cinchona alkaloid in the presence of an excess of base to provide the corresponding fluorinated compounds with an F-substituted quaternary carbon centre with enantioselectivities of up to 95% ee (Scheme 5.3). Furthermore, the authors showed that this catalytic system could be applied to the catalytic... 

An asymmetric a-alkylation of 2-oxindoles has been developed (Scheme 40). The chemistry utilizes a catalytic system with a Brpnsted acid and bis-cinchona alkaloid template (i.e., 191). Thus, the 2-oxindole (188) is alkylated by Michler s hydrol (189) to give the 2-oxindole product (190) in good yield and modest enantioselectivity. 

The Sn 1 reaction between various N-Boc 2-oxindoles with 3-alkyl substituents and the carbenium ion formed from bis(4-dimethylaminophenyl)methanol (Michler s hydrol) in the presence of a chiral bis-cinchona alkaloid-Brpnsted acid co-catalyst, gives the a-alkylation product in yields of 58-85% with 70-82% eeP A mechanism is suggested 0 for the reactions. 

Oxindoles are fluorinated by NFSi with excellent enantioselec-tivity in the presence of bis-cinchona alkaloid, (DHQD)2AQN, to furnish (5)-fluorinated oxindole in 87% yield with 87% ee. In the presence of (DHQ)2 AQN, (/ )-fluorinated oxindole was obtained in 85% yield with 89% ee (eq 22). This enantioselective... 

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