Cinchona asymmetric organocatalysis

Keywords Asymmetric organocatalysis Bifunctional catalyst Brpnsted base Chiral scaffold Cinchona akaloid Cyclohexane-diamine Guanidine... 

In particular, it is not only the cinchona alkaloids that are suitable chiral sources for asymmetric organocatalysis [6], but also the corresponding ammonium salts. Indeed, the latter are particularly useful for chiral PTCs because (1) both pseudo enantiomers of the starting amines are inexpensive and available commercially (2) various quaternary ammonium salts can be easily prepared by the use of alkyl halides in a single step and (3) the olefin and hydroxyl functions are beneficial for further modification of the catalyst. In this chapter, the details of recent progress on asymmetric phase-transfer catalysis are described, with special focus on cinchona-derived ammonium salts, except for asymmetric alkylation in a-amino acid synthesis. 

An enantioselective fluorination method with catalytic potential has not been realized until recently, when Takeuchi and Shibata and co-workers and the Cahard group independently demonstrated that asymmetric organocatalysis might be a suitable tool for catalytic enantioselective construction of C-F bonds [78-80]. This agent-controlled enantioselective fluorination concept, which requires the use of silyl enol ethers, 63, or active esters, e.g. 65, as starting material, is shown in Scheme 3.25. Cinchona alkaloids were found to be useful, re-usable organocata-lysts, although stoichiometric amounts were required. 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

Asymmetric phase-transfer catalysis usually stands somewhat separate from the rest of asymmetric organocatalysis and has always been dominated by metal-free catalysts. The earliest report in asymmetric phase-transfer catalysis dates back 30 years to 1984 when Dolling and coworkers first reported the use of a quaternised Cinchona alkaloid (6) as a phase-transfer catalyst for the asymmetric alleviation of ketone 7 during an asymmetric synthesis of (- -)-Indacrinone (Scheme 1.5). Quaternised Cinchona alkaloids dominated the area of asymmetric phase-transfer catalysis for the rest of the 20th century, and were especially used as catalysts for asymmetric amino... 

For some years the group of Li Deng has been investigating carefully the use of Cinchona alkaloids in asymmetric organocatalysis resulting in the development of numerous highly useful applications 424). Recently, they developed a catalytic tandem conjugate addition/protonation protocol to access compounds with tertiary... 

Marcelli T, Hiemstra H (2010) Cinchona Alkaloids in Asymmetric Organocatalysis. Synthesis 1229... 

In 1981, Hiemstra and Wynberg reported a thorough investigation of the cinchona alkaloid-catalyzed addition of thiols to a,p-unsaturated enones [24] (Scheme 6.30). Mechanistic studies revealed that the free OH group is ctu-cial in this reaction and thus cinchona alkaloids most likely act as bifunctional catalysts herein. This report may now be considered as one of the major breakthroughs in asymmetric organocatalysis and has inspired a lot of further research toward the development of asymmetric Lewis or Brpnsted base catalysts. 

New cinchona derivatives are continuously being developed for appUcation in asymmetric organocatalysis. Examples of catalysts obtained by further modification of existing derivatives include an N-oxide of dihydrocupreidine [127], a C6 -N-Boc-glycine-P-isocupreine (53) [128], a C9 thiourea substituted at a remote site with a sulfonamide group (54) [129, 130], and catalysts with an amine as well as a thiourea group (55) [131] (Figure 6.16). 

This gives chapter an overview of natural cinchona alkaloids and synthetic derivatives together with examples of their use in asymmetric organocatalysis. In recent years, the emphasis has been on the development of cinchona-based bifunctional catalysts, in particular species with a thiourea moiety. The search for new cinchona-based organocatalysts continues and new derivatives are relentlessly being prepared and applied for specific enantioselective reactions. The design of these new... 

Cinchona alkaloids are readily available natural chiral compounds and have a long history to be utilized as organocatalysts in asymmetric catalysis [3, 4]. They are multifunctional, tunable, and more importantly, they could promote a diversity of reactions through different catalytic mechanisms, which make them privileged catalysts in organocatalysis. In this chapter, the applications of cinchona alkaloids and their derivatives for asymmetric cydoaddition reactions after 2000, especially for the construction of a variety of five- and six-membered cyclic compounds, are discussed. 

Beside the cross aldol reaction, the Mannich reaction, too, has been the object of successful efforts using organocatalysis. The use of small organic molecules such as proline, cyclohexane diamine and Cinchona alkaloid-derived catalysts has proven extraordinarily useful for the development of asymmetric Mannich reactions in traditional polar solvents such as DMSO, DMP, DMF, etc. However, very few studies have been conducted so far in non-conventional solvents. 

Asymmetric cyanohydrin synthesis remains an important reaction for organocatalysis and many of the catalyst classes discussed in subsequent chapters give highly effective catalysts for this reaction. These include Cinchona alkaloid derivatives, thioureas, guanidines, amine-oxides, diols and diamines. 

After the first successful application of Cinchona alkaloid-based quaternary amo-nium salts as chiral phase-transfer catalysts in 1984 [187], the use of chiral quaternary ammonium salts in asymmetric catalysis has experienced a notable growth [177a, 188]. In particular, the asymmetric alkylation of glycine-derived Schiff bases by means of phase-transfer organocatalysis, pioneered by O Donnell et al. [ 189] and further improved by Lygo and Wainwright [190] and by Maruoka and co-workers [191], among others, has become one of the most reliable procedures for... 

Wu EH, Hong R, Khan JH, Liu XF, Deng L (2006) Asymmetric Synthesis of Chiral Aldehydes by Conjugate Additions with Bifunctional Organocatalysis by Cinchona Alkaloids. Angew Chem Int Ed 45 4301... 

The first highly enantio-selective a-fluorination of ketones using organocatalysis has been accomplished. " The optimal catalytic system, a primary amine-functionalized cinchona alkaloid (24), allows the direct and asymmetric a-fluorination of a variety of carbo- and hetero-cyclic substrates. Furthermore, this protocol also provides diastereo-, regio-, and chemo-selective catalyst control in fluorinations involving complex carbonyl systems (up to 98 2 dr, 99% ee, and >99 1 regiocontrol). 

Chiral oxazaborolidine catalysts were applied in various enantioselective transformations including reduction of highly functionalized ketones/ oximes or imines/ Diels-Alder reactions/ cycloadditions/ Michael additions, and other reactions. These catalysts are surprisingly small molecules compared to the practically efficient chiral phosphoric acids, cinchona alkaloids, or (thio)ureas hence, their effectiveness in asymmetric catalysis demonstrates that huge substituents or extensive hydrogen bond networks are not absolutely essential for successful as5unmetric organocatalysis. 

The simple C9 ethers derived from the natural cinchona alkaloids are infrequently applied in organocatalysis. A relatively recent example concerns an asymmetric cyclopropanation reaction with the C9 O-methyl derivatives of 1 and 4, respectively (Scheme 6.13) [35]. The functionalized cyclopropanes were obtained in excellent diastereo- and enantioselectivity as well as in high yields. 

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