Natural cinchona alkaloids

Stereoisomerism in the Cinchona Bases It was at first common practice to number the four asymmetric carbon atoms indicated in the general formula (I), 1, 2, 3 and 4, but this is now replaced by the more general system introduced by Rabe, who suggested the name ruban for (HI), which can be regarded as the parent substance of the natural cinchona alkaloids, and rubatoxan (IV) for that of the quinicines (quinatoxines). The formifiae, with notation, for ruban (III) and rubatoxan (IV) are shown below, and the general formula (I) for cinchona bases has been numbered in accordance with that scheme. 

Asymmetric dihydroxylation can be achieved using osmium tetroxide in conjunction with a chiral nitrogen ligand. " The very successful Sharpless procedure uses the natural cinchona alkaloids dihydroquinine (DHQ) and its diastereomer dihy-droquinidine (DHQD), as exemplified in the epoxidation of imni-stilbene... 

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

Cinchona Alkaloids - Natural Products as a Source of Organocatalysts Appendix 7.A [91,92,94-96,108-120]... 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

Quinuclidine (l-azabicyclo[2.2.2]octane) is a heterocyclic system which is part of the structure of a number of natural physiologically active compounds and synthetic drugs.1 Among the natural alkaloids, the following quinoline and indole derivatives contain the quinuclidine ring cinchonine, cinchonamine (alkaloids of Cinchona species),8-12... 

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... 

Dehmlow and coworkers [17] compared the efficiency of monodeazadnchona alkaloid derivatives 14a-c in the enantioselective epoxidation of naphthoquinone 50 with that of cinchona alkaloid-derived chiral phase-transfer catalysts 15a-c (Table 7.7) (for comparison of the alkylation reaction, see Table 7.1). Interestingly, the non-natural cinchona alkaloid analogues 14a-c afforded better results than natural cinchona alkaloids 15a-c. The deazacinchonine derivatives 14a,b produced epoxidation product 51 in higher enantioselectivity than the related cinchona alkaloids 15a,b. Of note, catalyst 14c, which possessed a bulky 9-anthracenylmethyl substituent on the quaternary nitrogen, afforded the highest enantioselectivity (84% ee). 

Table 7.7 Asymmetric epoxidation using monodeazacinchona analogues 14a-c and natural cinchona alkaloids 15a-c.

The chiral phase-transfer catalyst 3 afforded product 61 in 49% ee. The same group studied this reaction further by employing monodeazacinchona derivatives 14a-c [17]. The newly prepared non-natural analogues of cinchona alkaloids effectively promoted the hydroxylation reaction, although the enantioselectivity was lower than with natural cinchona alkaloid-derived chiral phase-transfer catalysts (Scheme 7.15). 

All four natural cinchona alkaloids (R=H) are commercially available in large quantities. 

In 2005, Schaus and coworkers found that the natural cinchona alkaloids such as cinchonine (CN) or cinchonidine (CD) themselves can serve as highly enantioselective catalysts (10mol%) for the Mannich reaction of P-keto esters 57 with the various carbamate-protected aryl imines 58 [25]. Using either CN or CD, both enantiomers of the resulting secondary amine products 59 were obtained in excellent yields (up to 99%) and ee values (up to 96% ee) (Scheme 8.19). The extension of this protocol to encompass the use of the 2-substituted-l,3-dicarbonyl nucleophiles 60... 

Quite recently, the use of natural cinchona alkaloids as catalysts for the intramolecular oxo-Michael addition of o-tigloylphenol (3), furnishing chiral ris-2,3-dimethyl-4-chromanone 4, which is a valuable intermediate for the synthesis of the anti-HIV-1 active coumarins, (+ )-calanolide A (5a), and (+ )-inophyllum B (5b), was reexamined by Ishikawa and coworkers (Scheme 9.2) [2], The parent cinchona alkaloids,... 

For the asymmetric synthesis of the 2-substituted chromane 7 via the intramolecular Michael addition reaction of 6, Merschaert et al. also employed natural cinchona alkaloids such as HCD as catalysts (Scheme 9.3) [3]. Here again, the 9-0 functionalization and dehydroxylation of the natural alkaloid showed a large negative effect, indicating that the presence of the 9-OH group is needed to achieve both good kinetics and enantioselectivity. Moreover, C3 modifications of this parent alkaloid did not lead to any significant improvement in the results in terms of the enantioselectivity and catalytic activity. 

Natural cinchona alkaloids were recently examined as catalysts for Michael addition reactions. In the presence of a natural cinchona alkaloid such as cinchonine (CN), 2-hydroxy-l,4-naphthoquinone 168 as the nucleophilic component was added... 

Natural cinchona alkaloids are bifunctional aminoalcohol compounds. They can catalyze some asymmetric reactions through concerted activation modes, which could generally provide better stereocontrol. In 1996, Nakatani and coworkers... 

Recently, more efforts have been devoted to the design of novel bifunctional organocatalysts derived from natural cinchona alkaloids, which have been successfully applied in a number of asymmetric reactions. Deng et al. promoted the extensive... 

In 1985, the first nonenzymatic catalytic process was reported by Oda and coworkers who found that the natural cinchona alkaloids 1-4 catalyzed the methanolytic... 

Figure 2 Structures and configurations of four natural cinchona alkaloids...

As pointed out previously, the various naturally occurring alkaloids of cinchona and particularly quinine have long been recognized as potent weapons for control of all human malarias. Limitations in effectiveness have also been apparent for some time. It is only recently, however, that the use of these compounds has been placed on a truly rational basis. This event, largely an outgrowth of studies on human malarias under controlled laboratory conditions, has rested on acquisition of a reasonably complete picture of the life cycle of the malaria parasite. Inasmuch as an understanding of this cycle is imperative for interpretation of malaria chemo-therapeutics, a few comments thereon are in order. 

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. 

The parent compound of the S. is secologanin, a key compound in the biosyntheses of most indole alkaloids, the Cinchona, ipecac, and pyrroloquinoline alkaloids as well as simple monoterpene alkaloids. Over 1000 indole alkaloids are formed from secologanin in vivo - comprising almost a quarter of this large group of natural products. 

Scheme 4.66 Enantioselective sulfa-Michael reaction of arylthiols with enones catalyzed by natural cinchona alkaloids.

The adducts were isolated in good yield and up to 75% ee. Experimental findings and DFT calculations were both consistent with noncovalent catalysis, highlighting the ability of diatyl prolinols to behave in a similar mode of action as previously attested by die pivotal work of Wynberg and coworkers in natural Cinchona alkaloid-catalysed Michael addition reactions. ... 

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