Indole-cinchona alkaloids

Several new syntheses of quinoline and indole Cinchona alkaloids were reported in the last few years. In these synthetic routes the quinuclidine moiety of the alkaloids was derived from various synthetic meroquinene derivatives 18. These new syntheses all proceed through intermediates of general formula 19 which are characterized by a properly positioned functional group (t.e., X) which facilitates the formation of quinuclidine ring 20. 

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). 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

Extension of the approach described resulted in a short synthesis of (+)-mero-quinene (Fig. 13). Formation of this alkaloid also synthetically connects the indole with the quinoline alkaloids, a link which has been suggested from the biosynthetic point of view for multiple decades quinine alkaloids are expected to be enzymatically formed from the indole framework. Meroquinene is a simple piperidine derivative which can be obtained by degradation of cinchonine and other Cinchona alkaloids under acidic conditions. It also plays a key role in the chemical synthesis... 

The use of bifunctional thiourea-substituted cinchona alkaloid derivatives has continued to gamer interest, with the Deng laboratory reporting the use of a 6 -thiourea-substituted cinchona derivative for both the Mannich reactions of malo-nates with imines [136] and the Friedel-Crafts reactions of imines with indoles [137]. In both reports, a catalyst loading of 10-20 mol% provided the desired products in almost uniformly high yields and high enantioselectivities. Thiourea-substituted cinchona derivatives have also been used for the enantioselective aza-Henry reactions of aldimines [138] and the enantioselective Henry reactions of nitromethane with aromatic aldehydes [139]. 

Early work had shown cinchonamine to give color reactions typical of indole alkaloids (7), and this was also evident from its UV-spectrum (8). The base differs from the major cinchona alkaloids in yielding, upon oxidation with chromic acid (6), 3-vinylquinuclidine-8-carboxylic acid (III), mp 209°, [a]D — 29° (CHCI3), which was first obtained from quinamine (9). The nature of the remainder of the molecule followed from the conversion of cinchonamine into 0,iVb-diacetylallocinchon-amine (I), mp 159°, [a]D — 7° (CHCI3), by refluxing acetic anhydride and its subsequent oxidation to 3-/3-acetoxyethylindole-2-aldehyde (H) (6). 

From corynantheal onwards the pathways diverge completely. The generation of the skeleton of the Cinchona bases requires not only a further reorganization of the terpenoid moiety but also a fundamental rearrangement of the indolic portion of the molecule to generate the quinoline residue. The currently favoured working hypothesis for this transformation is shown in Scheme 2 (13) — (14) — (15)— (16)—>(17) and (18). With the required skeleton in hand, only relatively trivial biochemical reactions are required to produce the known Cinchona alkaloids (21), (22), and (23). 

Thus, the early and late stages of Cinchona alkaloid biosynthesis are well worked out. However, the really unique steps in the pathway lie between (13) and (17) or (18) it is this stage of the biosynthesis that sees the profound skeletal reorganization of the indolic unit to a quinoline. The sequence of intermediates proposed in Scheme 2 is intellectually appealing but, at this stage, remains purely speculative. 

Aza-Henry reaction is rendered asymmetric by quaternary salts of Cinchona alkaloids. Addition reactions. Changing the 9-hydroxy group of Cinchona alkaloids to a 9-epiamino group not only is synthetically expedient, such products often show excellent catalytic activities in many asymmetric reactions. Those derived from dihydrocinchona alkaloids mediate Michael reactions to good results, including addition of indole to enones, and carbonyl compounds to nitroalkenes. Salt 4 has also been successfully employed in the alkenylation of t-butyl a-aryl-a-cyanoacetate. ... 

One of the most fascinating problems in natural product biosynthesis during the last decade was the origin of the C9-10 unit found in Ipecacuanha, indole, and Cinchona alkaloids. In the initial phases of the work it was proved by tracer studies that this unit did not arise from phenylalanine (45), tyrosine (45), shikimic acid (49), malonate (45), acetate (45,50,51), formate (45), or methionine (52). The role of glycine has also been investigated (53). 

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]. 

Kirby showed that quinamine and the substances derived from it gave indole color reactions, and isolated 2,3-dimethylindole from zinc dust distillation of the alkaloid (252). Henry, Kirby, and Shaw oxidized quinamine with chromic acid, and obtained the quinuclidine acid (CCVII) (253). It was thus clear that quinamine contained the vinylquinuclidine system of the major cinchona alkaloids, attached to an easily oxidizable residue, CioHioO (c/. Section V, 1). Decisive clarification of the character of the residue was achieved, and quinamine was shown to have the structure CCXIII, when Goutarel, Janot, Prelog, and Taylor found (248) that quinamine is reduced to cinchonamine (OCX) by lithium... 

A number of terpenoid indole alkaloids have pharmaceutical interest. These alkaloids are isolated from plants belonging to the families Apocy-naceae, Loganiaceae, and Rubiaceae. For the production of alkaloids by means of plant cell cultures, plants of the latter two families have proved to be rather recalcitrant (e.g., see Cinchona alkaloids). On the other hand, it has been reported by Pawelka and Stockigt that all apocynaceous cell suspensions they studied did produce terpenoid indole alkaloids 588). Here we confine ourselves to alkaloids which have direct commercial interest the production of new, potentially interesting, compounds is not reviewed here. For this we refer the reader to reviews by Balsevich (589), van der Heijden et al. (tribe Tabernaemontaneae) (590), and Omar (Rhazya stricta) (591). 

Isoprenoids (isopentenoids). The name for a group of natural products made up of isoprene units (e.g., ses-qui-, di-, and triterpenes, iridoids, carotinoids, steroids, natural rubber, etc.). Many non-isoprenoid compounds, however, do possess isoprenoid side chains, e.g., tocopherols, ubiquinones, chlorophyll, or contain isoprenoid structures incorporated into their skeletons, e.g., monoterpenoid indole alkaloids, penitrems, Cinchona alkaloids. 

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.

The AFC reaction of indoles with less reaetive aryl aldimines catalyzed by organocatalystwas reported by the group of Deng in 2006. Bifunctional cinchona alkaloid-derived thioureas were utilized to promote the AFC reaetion of indoles with N-Ts- or AT-Bs-protected imines. With 10 mol% of eatalyst 29, 3-indolyl methanamine derivatives 30 were obtained in high yields with up to 97% ee for both aryl and alkyl imines (Scheme 6.12). 

Chen et al. developed the first asymmetric and chemoselective A-allylic alkylation of indoles with MBH carbonates. This method was realized by employing modified cinchona alkaloids (DHQD)2PHAL as organocatalysts. Either electron-rich or electron-deficient indoles could be employed and moderate to excellent enantioselectivity was achieved (62-93% ee) (Scheme 3.115). ... 

The additions of indoles to imines were documented in a similar way. In this context, Deng investigated bifunctional cinchona alkaloid 181 for its ability to promote the addition of indoles to a wide range of imines 186 (Figure 8.13 Scheme 8.50) [142], with substituted aryl aldimines being shown to be equally effective acceptors as the traditionally more challenging alkyl imines. 

Shortly afterward, a breakthrough came in 2007 when Chen s and Melchiorre s groups discovered independently that structure-similar 9-NHa-substituted cinchona alkaloids 6a and 6b were efficient catalysts in the reaction of indoles and enones (Scheme 9.6) [20]. Excellent reactivity and enantioselectivities were ascribed to the... 

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