Cinchona natural products synthesis

Following the reaction, simple extraction provided access to both the hemiester prodnct and the alkaloid withont chromatography and the recovered cinchona alkaloid conld be reused with no deterioration in the ee or yield. This method has found use in the synthesis of P-amino alcohols and in natural product synthesis [198-201] and has recently been reported as an Organic Syntheses method [202],... 

The hetero [2+2] cycloaddition reaction is a synthetically important reaction for the construction of 4-membered heterocyclic compounds. As far as the catalytic asymmetric reaction is concerned, however, only the cycloaddition between ketenes and aldehydes has been reported. The thus synthesized chiral oxetan-2-ones are employed as monomer precursors for the biologically degradable co-polyesters and also as chiral building blocks for natural product synthesis. Two types of catalysts. Cinchona alkaloids and a chiral Lewis acid, are known to promote this reaction. 

Another class of reaction for which chiral tertiary amines are privileged catalysts is the Morita-Baylis-Hillman type (477, 478). One of the first applications of Cinchona alkaloids to mediate an asymmetric Morita-Baylis-Hillman reaction in a natural product synthesis was reported by Hatakeyama et al. in 2001 (479). Using a stoichiometric amount of (3-isocupreidine (568), a stereoselective addition of hexafluoroisopropyl acrylate (569) to aldehyde 570 could be carried out in good yield and with excellent selectivity (99% ee) (Scheme 119). The chiral p-hydroxy ester 571 was converted further into the epoxide 572, a known intermediate in the synthesis of epopromycin B (573). Epopromycin B (573) is a plant cell wall... 

Chiral H-bond donors and acids have proven their potential many times over several decades. Some useful apphcations in natural product synthesis have been reported, using either hydrogen bonding activation as the sole catalytically active principle, or utilizing bifunctional catalysts. With respect to the catalytic moiety of choice, the considerable potential of thioureas can be emphasized, especially those based on Cinchona alkaloids (Table 6). 

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 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). 

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. 

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). 

As shown in the next chapters, some of these reactions were also successfully employed to access the chiral skeletons of complex natural products or biologically active molecules. The following chapters will therefore highlight the successful use of the three most prominent chiral ammonium salt PTC classes Cinchona alkaloids, Maruoka s catalysts, and Shibasaki s catalysts) to facilitate demanding stereoselective key steps in complex natural product syntheses and in the synthesis of biologically active (either natural or synthetic) compounds. 

The applications of cinchona-catalyzed ketene enolates can be extended to a,P-unsaturated aliphatic acyl halides. Peters et al. presented a new concept for the synthesis of a,P-unsaturated 8-lactones, which are subunits of a number of natural and unnatural products that display a wide range of biological activity. They proposed... 

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