Cinchona total synthesis

En route to the total synthesis of cinchona alkaloid meroquinene, a Hoffmann-La Roehe group took advantage of the Hofmann-Loffler-Freytag reaetion to funetionalize the ethyl side ehain in piperidine 49 to give ehloroethylpiperidine 51 via the intermediaey of protonated aminyl radieal 50. °... 

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. 

The Cinchona tree remains the only economically practical source of quinine. Although the development of synthetic quinine is considered a milestone in organic chemistry, it has never been produced industrially as a substitute for naturally occurring quinine. Nevertheless, the implications of the total synthesis of quinine in new strategies for the development of safer and more efficient antimalarial drugs, as we will show in the course of the next paragraphs, is priceless. But, let us discuss this total synthesis first. 

The availability of ctetq) advanced synthons that carry the required chirality is an advantage, particularly in projects aimed at industrial total synthesis. Natural products are often used as synthons, ideally fi om a renewable source, such as microbial fermentations. In a few cases, biotechnology has become an ahemative source. The total theses of the antitumor agent esperamicin A and the immunosuppressant FK-506 are exanq>les. In both cases, the synthon was quinic acid (Barco 1997), cheaply obtained by biotechnology (Chapter 14.1.e) rather than fi om the environmentally noxious extraction fi om the bark of Cinchona spp. Used to build up combinatorial libraries, quinic acid has gained further inq)ortance in organic thesis (Phoon 1999). 

In addition to dimethylcuprates, various alternate cuprate reagents can be used. As shown in Scheme 11.12, a divinylcuprate was used in a 1,4-addition employed in the total synthesis of meroquinene 42 (Scheme 11.12), a degradation product of cinchonine and also an intermediate en route to cinchona alkaloids such as quinine [52,53]. As illustrated, enone 36, available via acetoxyglucal 35 (Scheme 11.11), was treated with divinylcuprate to exclusively afford the axially substituted 4-vinyl derivative 38. Trapping of this intermediate with methyl bromoacetate gave a mixture of C3 epimers readily equilibrated to 39 in the presence of triethylamine. Further manipulations of 39 gave the 2-deoxy derivative 40 and, in turn, the dialdehyde 41. Cyclization of the latter to enantiomerically pure meroquinene 42 proceeded uneventfully. 

Hydroxyquinine 97 was prepared recently in the course of a novel total synthesis approach toward cinchona alkaloids (Scheme 12.27). Interestingly, studies on stereocontrolled synthesis of quinine, apart from that of Uskokovic [66], were not published until 2001 and 2004, again underlining the fact that cinchona alkaloid... 

Due to the high number of steps, challenging stereocontrol, and low overall yield, the known total synthesis of cinchona alkaloids cannot compete with the extraction of the natural products from readily available cinchona bark and any subsequent semisynthetic modifications. 

Quinine (2) is the major active principle of cinchona, which was isolated by Pelletier and Caventou in 1820 [16] however, its structure could only be established after 100 years [17]. The total synthesis of quinine was accomplished by Woodward and Doering [18] and others [19] but none of the synthetic methods are economical and, therefore, can not compete with the natural production of quinine the bark of the cinchona tree is still the only source of the drug. In addition to quinine (2), three more antimalarial components, quinidine (3), cinchonidine (4) and cinchonine (5) are present in the bark. 

For almost two centuries, the bark was used in medicine as a powder, extract, or infusion. In 1820 Pelletier and Caventou isolated quinine and cinchonine from cinchona, and the use of the alkaloids as such gained favor rapidly. Extensive and classic studies led to elucidation of the structure of quinine (Figure 2) (4) and to its total synthesis in 1944 (5). Cinchona contains 25 closely related alkaloids, of which the most important are quinine, quinidine, cinchonine, and cinchonidine. The average yield of alkaloid is about 6-7 %, of which one-half to two-thirds is quinine. It has been said that quinine owes its dominant position in the treatment of malaria only to the fact that it was the first alkaloid isolated from cinchona, and that there is little among the four major alkaloids to choose from in treating this disease (6). 

The classic work in the synthesis of Cinchona alkaloids, which was initiated in the 1920s by Rabe and his co-workers and completed in the 1940s by Woodward and Doering, is described fully in a previous chapter (9). After a dormant period of more than 20 years in this field, interest was renewed in these alkaloids because of their antimalarial properties. Shortages of the Cinchona alkaloids from natural sources led to new efforts at total synthesis. 

The synthetic preparation of ethyl 5(R)-vinyl-4(S)-quinuolidine-2 -carboxylate (124) meant also the formal completion of the first total synthesis of cinchonamine—the main representative of the indole cinchona alkaloids. Preobrazhenskii and co-workers had previously synthesized cinchonamine from 124 24) which had been obtained by degradation (25). Renewed interest in these alkaloids has resulted for the time being only in the total synthesis of dihydrocinchonamine (143) (Scheme 15). 

P. falciparum strains are reported also to be resistant to quinine (S3). It is noteworthy that quinine can now be made by total synthesis and that analogs of quinine with improved activity or fewer side effects also can be made available (52). In this connection it is important to know that the antimalarial activity of Cinchona alkaloids is not dependent on their absolute configuration the racemates and the unnatural enantiomers were shown to be as active as the natural alkaloids (51). An excellent summary by R. M. Finder of the mode of action of quinine as an antimalarial drug appeared recently in Progress in Medicinal Chemistry where pertinent details can be found (52). 

Secologanin 17 is a key precursor in alkaloidal biogenesis from which over 1000 alkaloids (indol-, cinchona-, ipecacuanha-, pyrroloquinone-alkaloids) are derived. A stereoselective total synthesis of secologanin has been achieved (Tietze 1983) [20]. 

The outstanding contributions of Rabe to the study of the cinchona alkaloids were crowned by the achievement in 1931 of the total synthesis of dihydroquinine (188). The methods used had been developed over the course of a quarter of a century. During this time, as has been indicated in previous sections, processes had been discovered for the synthesis of quininic acid and dl-homocincholoipon. Reactions had been found which served for the condensation of such components, and for the transformation of the resulting toxines into natural alkaloids. 

The cinchona bark was in scarce supply in World War 11. The plantations had been captured by Germany and Japan, which caused thousands of Allied soldiers fighting in Africa and the Pacific to die after contracting malaria. This prompted the need for a synthetic source. In 1944, Woodward and Doering reported the total synthesis of quinine, which is an alkaloid that was later claimed to be the dmg to have relieved more human suffering than any other in history. ... 

Details of the extensive contributions of Uskokovic and his collaborators on the total synthesis of the Cinchona alkaloids have now been given in a series of four comprehensive papers. 

With respect to the use of Cinchona alkaloid-derived organocatalysts, the first example of asymmetric Michel addition of ketones to enones appeared in 1979 when Trost illustrated, during the total synthesis of the sesquiterpene ( )-hirsutic acid C [101], a stereoselective (30% ee) quinine (59)-catalyzed intramolecular conjugate addition of an intermediate functionalized cyclohexanone (Scheme 2.32). 

Nelson and co-workers reported a cinchona alkaloid-Lewis acid-catalyzed acycl chloride aldehyde reaction, an extension of ketene-aldehyde cycloaddition, providing 3,4-cw-p-lactones 168 with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (>96% de), [69], The methodology was later applied by the group in the enantioselective total synthesis of (-)-pironetin (Scheme 3.53). 

Scheme 111 Cinchona alkaloid-derived bifunctional urea catalyst 507 in the total synthesis of (-)-nakadomarin (506)...

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. 

Chiral base catalysis is one of the most versatile and broadly applicable types of catalysis. In particular, the potential of tertiary amines to act both as a base and as a nucleophilic catalyst makes chiral tertiary amines like Cinchona alkaloids a privileged catalyst structure in modem synthesis chemistry. In addition, the field of achiral phosphine and carbene catalysis has proven its potential in numerous applications in the past and it is probably only a matter of time until chiral phosphines and carbenes will also be used routinely for other presently demanding natural product total synthesis (Table 7). 

Of the synthetic work of this period J. Meisenheimer s research [14] on the preparation of unsubstituted quinuclidine, V. Prelog and coworkers investigation [48-53] of methods of quinuclidine ring closure based on tribromoalkanes and dibromoalkylamines, and G. Clemo and T. Metcalf s work [55] on the conversion of isonicotinic acid to quinuclidon-3 are worth mentioning. Systematic research into the synthesis of Cinchona alkaloids carried out by P. Rabe s school [56-60] and a brilliant total synthesis of quinine performed by R.B. Woodward and W. E. Doering [61] are of particular merit. However, further progress in quinuclidine chemistry was hampered by the absence of suitable synthetic methods. 

Bicyclic products in the Cy6/Cy7 case have been reported by Lessard in his studies of amidyl radicals (Scheme 128). For instance, the carbox-amidyl radical generated from the corresponding 7V-chloroamide (332) gives the (Cy6) compound (75% exro, 15% endo but the corresponding acetamidyl radical, generated from the amide 333, does not give any cyclized product. The compound 334 has been cyclized under conditions in which aminium radicals are formed, to the corresponding quinuclidine derivative (Cy6) (yield 72%), a possible precursor for the total synthesis of Cinchona alkaloids." ... 

Z-Quinic acid (D-l,3-dideoxy-6pz-inositol-2-carboxylic acid) (Fig. 2), m.p. 162°, [a]jy —44°, is found in cinchona bark, meadow hay, the tops of whortle berries (Vaccinum myrtillus L.), the leaves of the mountain cranberry (Vcxcinum vitisidaea L.), and combined with caffeic acid as chloro genic acid in plants (69), The equivalent of a total synthesis has been effected, starting with 4-chlorocyclohexanone (70),... 

Vhh conplings together with chemical shifts have been calcnlated by Chini et al for kedarcidin chromofore and palau amine in the attempt to establish the correct configuration of these two compoimds prior to their total synthesis. Kedarcidin chromofore is a compoimd that belongs to the enediyne family of antitumor antibiotics, whereas palau amine is an oroidin dimer, belonging to the class of pyrrole-imidazole alkaloid family isolated from the sponge Stylotella aurantiwn. Populations of conformers in three cinchona alkaloid O-ethers at ambient and low temperatnres have been estimated by Bnsygin et al ... 

Recently, Wang et al. reported the reaction of isatins with nitromethane using C6 -OH cinchona alkaloid catalyst 15 (Scheme 29.8). 3-Substituted 3-hydroxy-oxindoles are obtained in excellent yields and enantioselectivities albeit long reaction times are required [22]. For the 4,7-dichloroisatin and N-benzyl-isatin, only moderate enantioselectivities were obtained (71% and 76%, respectively). The methodology was applied to the total synthesis of (R)-(+)-dioxibrassinin (20) and the formal synthesis of (S)-(-)-spirobrassinin (21). 

The diastereoselective Michael addition of P-amidoester 47 to nitroalkene 48, catalyzed by the bifunctional urea derived from cinchona alkaloid (49), was one of the key-steps in the total synthesis of nakadomarin A (Scheme 34.15) reported by Dixon et al. [47, 48]. The same catalytic system was employed successfully in the synthesis of two anti-depressant molecules. Rolipram and Paroxetine , by this group [49]. 

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