Cinchona alkaloids asymmetric transformations

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

In addition to metal catalysts, organocatalysts could also be used in asymmetric cyanation reactions. Chiral Lewis bases, modified cinchona alkaloids, catalyzed asymmetric cyanation of ketones by using ethyl cyanoformate as the cyanide source (Scheme 5.34)." Similar to metal-catalyzed reactions, ethyl cyanoformate was first activated by chiral Lewis bases to form active nucleophiles. Various acyclic and cyclic dialkyl ketones were transformed into the desired products. Because of using... 

Early work from the McIntosh group [1 lh,85] and extensive research from the Dehmlow group [24e-i,48b] concerning chiral catalyst design is noted. Recently, Lygo and co-workers have reported short enantio- and diastereoselective syntheses of the four stereoisomers of 2-(phenylhydroxymethyl)quinuclidine. The authors report that these compounds, which contain the basic core structure of the cinchona alkaloids, will be examined as possible chiral control elements in a variety of asymmetric transformations [86]. 

A wide variety of catalytic asymmetric transformations have been achieved in the above investigations, which clearly indicates that quaternary ammonium salts derived from cinchona alkaloids are still powerful reagents, despite their limited structural diversity. Moreover, as PTC chemistry has been recognized as a highly practical approach, further progress should be expected in this area of research. 

Cinchona alkaloids, of course, have occupied the central position in the design of chiral PTCs. By employing a simple chemical transformation of the tertiary amine ofthe natural cinchona alkaloids to the corresponding quaternary ammonium salts, using active halides (e.g., aryl-methyl halides), a basic series of PTCs can be readily prepared. Cinchona alkaloid-derived PTCs have proved their real value in many types of catalytic asymmetric synthesis, including a-alkylation of modified a-amino acids for the synthesis of higher-ordered a-amino acids [2], a-alkylation of... 

As mentioned above, quaternary ammonium salts derived from cinchona alkaloids have occupied the central position as efficient PTCs in various organic transformations, especially in the asymmetric a-substitution reaction of carbonyl derivatives. A cinchona alkaloidal quaternary ammonium salt, which acts as a PTC in various organic reactions, is prepared by a simple and easy chemical transformation of the bridgehead tertiary nitrogen with a variety of active halides, mainly arylmethyl halides. Other moieties of cinchona alkaloids (the 9-hydroxy, the 6 -methoxy, or the 10,11-vinyl) are occasionally modified for the enhancement of both chemical and optical yields (Figure 6.4). 

During the last two decades, cinchona alkaloids have emerged as powerful chiral auxiliaries leading to well-known landmark developments in asymmetric synthesis already described in preceding chapters but more recently, these alkaloids themselves have been shown to undergo some remarkable transformations and skeletal shifts that are rapidly widening the outlook in the chemistry of cinchona bases. 

Formation of the chiral 1,2-amido-alcohol 12 can be achieved in a single transformation by using the asymmetric amino-hydroxylation reaction (see Section 5.3.3). For the regioisomer 12, the linker anthraquinone (AQN) rather than the normal phthalazine (PHAL) is required. For the enantiomer 12, the cinchona alkaloid dihydroquinidine (DHQD) is required. Hence, the reagents and conditions effective for the formation of 12 are ... 

Amine-catalyzed non-asymmetric transformations 13. 0542. Asymmetric cycHzation reactions of allenoates -with imines or a,P-unsat-urated ketones catalyzed by organocatalysts derived from cinchona alkaloids 12CEJ6712. 

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... 

An enamine-catalyzed asymmetric a-fluorination of ketones, which are notoriously challenging substrates for this reaction, was reported by MacMillan and coworkers in 2011 [27]. After exhaustive automated screening of over 250 organo-catalysts, a Cinchona alkaloid-derived primary amine organocatalyst was identified as the optimal catalyst for this transformation (Scheme 13.11). Only cyclic ketones provided fluorinated products in high yields and enantiomeric excesses. 

By using the Cinchona alkaloid-derived quaternary ammonium bromide 371, a stereoselective methylation of the phenylindanone 372 was achieved under biphasic conditions, thus representing one of the first examples of such a highly stereoselective organocatalytic asymmetric transformation. These types of transformations may be conducted in a stereoselective fashion using more commonly employed methods only with great difficulty. 

Asymmetric phase-transfer catalysis is a method that has for almost three decades proven its high utility. Although its typical application is for (non-natural) amino acid synthesis, over the years other types of applications have been reported. The unique capability of quaternary ammonium salts to form chiral ion pairs with anionic intermediates gives access to stereoselective transformations that are otherwise very difficult to conduct using metal catalysts or other organocatalysts. Thus, this catalytic principle has created its own very powerful niche within the field of asymmetric catalysis. As can be seen in Table 5 below, the privileged catalyst structures are mostly Cinchona alkaloid-based, whereas the highly potent Maruoka-type catalysts have so far not been applied routinely to complex natural product total synthesis. 

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