Natural product alkaloids

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

The Bischler-Napieralski reaction is one of the most widely used methods for the construction of dihydro- and tetrahydroisoquinoline units in the synthesis of alkaloid natural products. A few representative examples of the Bischler-Napieralski reaction in complex alkaloid syntheses are shown below. 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Baxendale, I.R., Deeley, J., Griffiths-Jones, C.M., Ley, S.V., Saaby, S., Tranmer, G.K. (2006) A Flow Process for the Multi-Step Synthesis of the Alkaloid Natural Product Oxomaritidine A New Paradigm for Molecular Assembly. Chemical Communications, 2566-2568. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

The genera of Aconitum (commonly known as Monkshood) and Delphinium, and to a lesser extent Rumex, Consolida, and Spiraea, have long been recognized as a rich source of alkaloid natural products [1], The diterpenoid alkaloids are generally classified into two major groups the Ci9-diterpenoid alkaloids (sometimes referred to as the Cig-norditerpenoid alkaloids) and the C2o-diterpenoid alkaloids. Within the C2o-diterpenoid alkaloids, at least 11 separate classes have been isolated, including the hetisine alkaloids (Chart 1.1). 

Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006) A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine a new paradigm for molecular assembly. Chem Commun, p 2566-2568... 

Keywords Alkaloids Natural products Photochemistry Terpenes Total synthesis... 

Two major alkaloidal natural products that are known to be... 

Ihara, M. and Fukumoto, K. 1996. Recent progress in the chemistry of nonmonoterpenoid indole alkaloids. Nature Product Reports, 13 241-261. 

Lewis, J. R. 2001. Amaryllidaceae, muscarine, imidazole, oxazole, thiazole, peptide and miscellaneous alkaloids. Nature Product Reports, 18 95-128. 

Bentley, K. W. 2000. (3-Phenylethylamines and the isoquinoline alkaloids. Nature Product Reports, 17 247-268. 

Michael, J. P. 2000. Quinoline, quinazoline and acridone alkaloids. Nature Product Reports, 17 603-620. 

O Hagan, D. 2000. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids. Nature Product Reports, 17 435 46. 

Michael, J. P. 1993. Indolizidine and quinolizidine alkaloids. Natural Product Reports, 10 51-70. 

The enantioselective hydrogenation of olefins, ketones and imines still represents an important topic and various highly enantioselective processes based on chiral Rh, Ru or Ir complexes have been reported. However, most of these catalysts failed to give satisfactory results in the asymmetric hydrogenation of aromatic and heteroaromatic compounds and examples of efficient catalysts are rare. This is especially the case for the partial reduction of quinoline derivatives which provide 1,2,3,4-tetrahydroquinolines, important synthetic intermediates in the preparation of pharmaceutical and agrochemical products. Additionally, many alkaloid natural products consist of this stmctural key element. 

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

Recent advances in the Stevens rearrangement of ammonium ylides have been reviewed in terms of application to the synthesis of alkaloid natural products.147... 

Since the first publication, amine-catalyzed Diels-Alder reactions of a,/ -unsaturated aldehydes have been investigated in much detail [15, 26-33]. Catalyst immobilization studies on solid support [26, 27], as well as in ionic liquids [29], have shown advantages for amine recycling, while partially maintaining good levels of asymmetric induction [34]. The use of this reaction in total synthesis has allowed the rapid preparation of (+)-hapalindole Q, a tricyclic alkaloid natural product containing four contiguous stereocenters (Scheme 3.2) [28]. 

Synthesis of alkaloid natural products - epimaritidine and epibatadine... 

Scheme 7, Synthesis of the alkaloid natural product ( )-epimaritidine...

The double aldol reaction strategy can also be used in conjunction with palladium-mediated reductive animation to produce tetrahydroxy pyrroli-zidine alkaloids, including 3-epiaustraline, australine, and 7-epialexine (Scheme 5.26(b)).47b These alkaloid natural products are active as glyco-sidase inhibitors. 

Alkaloid Natural Products as Chemical Probes of Protein-Protein Interactions... 

Fig. 17.4 A few examples of alkaloid natural products as modulators of protein-protein interactions.

Isolated in 1977 from the bacterium Streptomyces staurosporeus, staurosporine (3) is a natural product that inhibits most protein kinases at low nanomolar concentrations [23]. Through small-molecule/protein complex cocrystallization, it was shown that staurosporine binds tightly to the adenosine binding pocket ofthe catalytic subunit of the cAMP-dependent protein kinase. Chelerythrine (4) was identified as an inhibitor of Bcl-XL-Bak BH3 peptide binding vdth an IC50 of 1.5 p,M, and also displaced Bax from Bcl-XL [24]. Chelidonine (S) is another example of an alkaloid natural product that inhibits the taxol-mediated polymerization of tubulin in the micromolar range ( 24.0 p,M). 

Indoline Alkaloid Natural Product-inspired Chemical Probes... 

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