Cinchona Alkaloids In Synthesis And Catalysis Ligands Immobilization And Organocatalysis Pdf

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During the last two decades, cinchona alkaloids have emerged as powerful chiralauxiliaries leading to well-known landmark developments in asymmetric syn-thesis already described in preceding chapters; but more recently, these alkaloidsthemselves have been shown to undergo some remarkable transformations andskeletal shifts that are rapidly widening the outlook in the chemistry of cinchonabases.

Nature is full of dimeric alkaloids of various types from many plant families, some of them with interesting biological properties. However, dimeric Cinchona alkaloids were not isolated from any species but were products of designed partial chemical synthesis. Although the Cinchona bark is amongst the sources of oldest efficient medicines, the synthetic dimers found most use in the field of asymmetric synthesis.

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Nature is full of dimeric alkaloids of various types from many plant families, some of them with interesting biological properties. However, dimeric Cinchona alkaloids were not isolated from any species but were products of designed partial chemical synthesis. Although the Cinchona bark is amongst the sources of oldest efficient medicines, the synthetic dimers found most use in the field of asymmetric synthesis. Prominent examples include the Sharpless dihydroxylation and aminohydroxylation ligands, and dimeric phase transfer catalysts.

In this article the syntheses of Cinchona alkaloid dimers and oligomers are reviewed, and their structure and applications are outlined. Various synthetic routes exploit reactivity of the alkaloids at the central 9-hydroxyl group, quinuclidine, and quinoline rings, as well as 3-vinyl group.

This availability of reactive sites, in combination with a plethora of linker molecules, contributes to the diversity of the products obtained.

The term alkaloid is used for many vastly different nitrogen heterocycles of mostly plant origin. Alkaloids are classified according to the heterocycle and the taxonomy of the species they were isolated from.

The natural diversity of the alkaloids is further extended by the presence of numerous dimeric alkaloids Fig. Some dimers appear as byproducts by coupling of a small portion of the monomers e. Alkaloid dimers can exhibit biological activities unrelated to that of the corresponding monomer [ 1 ], such as in vitro anti-HIV and antimalarial properties of Michelleamine A [ 2 ], or fungicidal activity of Bismurrafoline B [ 3 ].

Natural alkaloid dimers of different symmetry and heterodimers were isolated Fig. Additionally, dimers of alkaloids can be synthesized in the laboratory giving rise to a virtually unlimited number of combinations [ 1 ].

These quinoline alkaloids are isolated on an industrial scale in multi-ton amounts. Their structures contain a central hydroxyl group as well as quinoline and quinuclidine rings. The individual alkaloids differ in the configuration at two crucial stereogenic centers C-8 and C-9, Fig. Quinine has been used for nearly four centuries to treat malaria. On the other hand, quinidine is often used to treat certain arrhythmias. Cinchona alkaloids are also employed in enantioselective synthesis catalysts, ligands and separation processes resolving agents, solid phases, assays [ 4 ].

To date, no dimeric alkaloid in this family has been isolated from a natural source. Nevertheless, many synthetic dimers were made exploiting a few reactive sites in the Cinchona alkaloids Fig.

Four major Cinchona alkaloids. Arrows mark the reactive sites used for dimerization. These synthetic dimers were examined for their biological activities and applicability in asymmetric reactions. For the purposes of medicinal chemistry, the multiplication of the pharmacophore in the dimers could improve binding or cause crosslinking of the biological receptors. The transition from a monomeric to dimeric alkaloid molecule results in accumulation of functional groups confined within a limited space.

Modifications of Cinchona alkaloids at the central 9-OH group and at the quinuclidine N-1 atom led to the most effective dimeric catalysts and biologically active compounds. For the purpose of this review, alkaloid derivatives are labeled with the corresponding alkaloid QN , QD It has to be emphasized that some derivatization reactions were reported only for a single alkaloid, while others were exercised on a set of Cinchona alkaloids.

The central 9-OH group offers an attractive site for modification i. Alternatively, the hydroxyl group can be replaced with a few other groups e. Dimers, in which the Cinchona alkaloid units are connected through 9-aryl ethers, represent a class of the most successful ligands for the Sharpless asymmetric dihydroxylation AD and related aminohydroxylation reactions Figs. The same ligands with tungstate catalyzed enantioselective sulfur oxidation with hydrogen peroxide [ 9 ].

Furthermore, numerous applications in metal-free catalysis emerged [ 4 , 10 , 11 ] and made Cinchona alkaloid derivatives included to the privileged chiral structures [ 12 ]. Examples of these asymmetric organocatalytic reactions include Fig. In dimeric Cinchona aryl ethers Fig. All of these compounds were obtained through aromatic nucleophilic substitution.

Thus, the alkaloid units are mostly in the para position with the exception for few meta derivatives, but no ortho -diethers are known.

The lack of such products arises from the reactivity of halo-aryls in the nucleophilic substitution, rather than steric interactions, since heavily substituted pyrimidine derivatives were obtained with relative ease.

Up to there was an incremental progress in osmium-catalyzed asymmetric dihydroxylation reactions, and promising results were obtained with monomeric Cinchona alkaloid derivatives in the role of ligands. Then, the discovery of dimeric phthalazine ether ligands PHAL, 3 marked an enormous leap for asymmetric synthesis [ 27 , 28 ]. The respective dimers 3 were obtained from reactions of alkaloids with 1,4-dichlorophthalazine 2.

The process required basic conditions and azeotropic removal of water with toluene [ 29 ]. In an alternative synthesis, the alkaloids were first deprotonated with NaH in DMF and subsequently treated with dichloride 2 [ 30 ]. This change in protocol often provided better preparative yields. Also, a stepwise protocol for the synthesis of unsymmetrical dimers was devised.

The resulting quinidine-dihydroquinidine and quinine-dihydroquinine heterodimers 3 had a single vinyl group that was used to anchor the molecule to polymer supports using the radical addition of thiols Fig. A single reactivity averts crosslinking, and in the cases presented by the authors, also prevents significant distortion of geometry in the parent structure. The symmetrical phthalazine dimers 3 were also subject to many subsequent derivatization attempts.

These include primarily immobilization, for example, direct copolymerization of quinine-based dimer with methacrylates [ 34 ], or copolymerization of more reactive alkaloid-derived acrylate DHQN Fig. Apart from simple alkaloids, also their elaborate derivatives were dimerized with phthalazine [ 36 ].

Didehydroquinidine QD , vide infra was coupled in a Sonogashira reaction with various aryl halides to yield alkaloids with extended carbon scaffold QDa — b. Also, iodinated didehydro-alkaloid QDc was prepared by addition of iodine to the triple bond of didehydro-alkaloid followed by elimination of HI. The yields of the dimerization step were similar to that of unmodified quinidine [ 37 ]. Under osmium-catalyzed asymmetric dihydroxylation conditions, the two native vinyl groups in Cinchona dimers QN-3 , QD-3 are transformed to the corresponding tetraols.

Nevertheless, the polar character of these compounds was advantageous for reactions carried in special solvents, including ionic liquids, polyethylene glycol PEG , and water.

It was transformed in situ to water soluble ammonium salt DHQD having six hydroxyl groups, which facilitated recycling of the ligand through aqueous extraction Fig. The obtained dimeric quaternary salts were not suitable for AD reactions, but were considered for phase transfer catalysis PTC [ 39 ]. These immobilized soluble ligands DHQNa — c were still successful in aminohydroxylation reactions and could be recycled; however, significant catalyst loading was required [ 40 ].

Modification at the spacer unit required de novo synthesis of the dimers. A similar linker with two more nitrogen atoms incorporated into the planar ring system was also applied: 1,4-Dichloro-6,7-diphenyl-pyrazinopyridazine 25 [ 42 ] was coupled with two dihydroquinidine units providing the respective DPP dimer DHQD Fig.

Also, linkers with extended fused ring systems were applied. DHQD provided a highly regioselective and enantioselective course of AD reaction of terminal isopropylidene groups in selected terpenoids [ 44 ].

The coupling was accomplished by refluxing the respective 3,6- or 2,5-dichloro heterocycles 35 and 40 with dihydroquinidine in toluene in the presence of a base and the azeotropic removal of water. On the other hand 2,5-dichloropyrazine 40 is more challenging to obtain Fig. Double tethered derivatives of 36 are presented in the last section of this article.

Dimer 36 was also partially quaternized with 9-anthracenylmethyl group [ 50 ]. A pyridazine linker substituted with a short alkyl chain flanked with a terminal alkyne group was also obtained. The functionalized reactive dichloroheterocycle 44 was obtained via the sequential Diels-Alder and retro-Diels-Alder reactions of dichlorotetrazine 42 and 1,7-octadiyne 43 in one pot.

Thus 1,2,3-triazoles were obtained with various azides including small molecules [ 52 ] and polymers Fig. Pyrimidine-based dimers 51 PYR constitute another important group of ligands, particularly useful in AD of branched olefins. Their major distinction is that the alkaloid units are positioned meta instead of para to each other. The synthesis again relied on refluxing the dichloroheterocycle 50 with the alkaloid in the presence of a base in toluene and the azeotropic removal of water Fig.

The reactive dichloride 50 was obtained in a two-step procedure starting from the condensation of adequately substituted diethyl malonate 47 and amidine An important feature of the pyrimidine scaffold is that 2- and 5- substituted derivatives are often easily accessible.

Sharpless obtained dimers with pyrimidine linkers substituted at position 2 and 5 with combinations of phenyl and tert- butyl groups [ 53 ]. In later reports, more differently 2- and 5-substituted and unsubstituted pyrimidine dimers were mentioned [ 55 ]. The diversity of the products was further enhanced in a synthesis of several 2-aryl substituted dimers. The commercially available 4,6-dichloromethylthiophenylpyrimidine 52 reacted with a series of arylboronic acids in a Suzuki-type reaction.

The obtained intermediates with quinine provided the dimers QNa — d in very good yields Fig. Also, an analogue of DHQN substituted at the 2-position of the pyridine with 3,4,5-trimethoxyphenyl group was specifically designed for AD step in a synthesis of a natural product [ 57 ]. It was established that for applications in AD the presence of 2- tert -butyl is detrimental, while substitutions at 5-position are more tolerated [ 53 ]. Also, a related spacer with 1,3,4-triazine core was exploited.

The synthesis was based on the reaction of inexpensive cyanuric chloride 53 with aniline to replace one of the reactive chlorides. Then, dichloride 55 was reacted with the prepared in situ quinine sodium salt in THF to provide the respective dimer QN in nearly quantitative yield. Although the authors used only 4-bromoaniline 54 , they proposed that a diverse array of products could be obtained using different aniline or amine derivatives.

However, only dimer 56 showed promise in AD reactions [ 58 ]. Apart from the heterocyclic spacers, also the anthraquinone unit was extensively studied. For the coupling, dihydroalkaloid was converted in situ into a lithium salt with butyllithium, and then a reaction with difluorocompound 60 yielded the anthraquinone dimers AQN, DHQN , DHQD in very good yield Fig. These ligands are superior in AD of alkenes with aliphatic substituents. Similarly to the phthalazine ligands, also a stepwise synthesis was devised.

Consecutive reactions of 60 were carried out with alkaloid sodium salts in DMF. Other immobilization attempts included addition of thiols to quinine and quinidine homodimers QN and QD [ 61 ]. Also, the spacer was modified to accommodate further transformations. The silyl ether was cleaved, and the obtained phenol group was exploited to obtain a series of derivatives 69 — 73 Fig. Among these were linear polystyrene [ 63 ], silica gel supported material, polyethylene glycol derivatives [ 62 ] including a tetramer DHQN formed from tethered dimeric quinine units [ 64 ].

Dimeric alkaloid alkyl ethers constitute a much less studied group of compounds. Their synthesis is, however, straightforward and involves the Williamson etherification of an alkali metal alkaloid salt and the respective alkyl dihalide.

Thieme E-Journals - Synthesis / Abstract

These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric. Find more information on the Altmetric Attention Score and how the score is calculated. To facilitate the asymmetric catalysis process, we designed novel polymeric chiral catalysts.

The C8C9 bond was made using the Claisen condensation with quininic acid ester. Synthesis, , 7, Kwan, B. MacMillan, D. Kolb, H.

Cinchona alkaloids in synthesis and catalysis : ligands, immobilization and organocatalysis

The book is sure to become dogeared as it is read, used, and reread to help evaluators conduct their work in a manner consistent with the complexity of the challenges they are addressing. It represents the first attempt to comprehensively describe the many facets of the chemistry of this privileged compound class, which has been generously provided by nature. Song has succeeded in providing the synthesis community with a high-quality source of teaching materials as well as a useful handbook for scientists working in the exciting and fast developing field of cinchona-based asymmetric catalysis. This book will be a valuable addition to many libraries, whether personal, academic, or industrial.

This organocatalytic reaction proceeded in high yield and gave excellent enantiomeric excess with only 0. In addition, an imidate group, derived from a cyano group, was incorporated in the strategy for site-selective modification of the C4-alkyl chiral piperidine ring of quinine. Furthermore, an efficient coupling between the quinuclidine precursor and dihydroquinoline unit was achieved on a gram scale. The synthetic plan for our approach is shown in Fig.

This comprehensive review of cinchona-based chiralilty inducers and their applications covers every topic, including ligands, immobilization and organocatalysis. Each chapter summarizes the scope and limitations of the new methods and technologies,MoreThis comprehensive review of cinchona-based chiralilty inducers and their applications covers every topic, including ligands, immobilization and organocatalysis.

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Daniel, and Daniel Seidel Angew. Abboud, Rachael W. Karugu, Mathew J. Vetticatt, Jennifer S.

Cinchona alkaloids in synthesis and catalysis ligands immobilization and organocatalysis

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Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis

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