Synthese des <i>Lycopodium</i>‐Alkaloids <i>rac</i>‐α‐Obscurin durch 1,3‐Anellierung eines Enimins

Schumann, D.; Naumann, A.

doi:10.1002/jlac.198319830206

Cited by 19 publications

(17 citation statements)

References 20 publications

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“…Enamide 8 was in turn envisioned to arise from an acid-promoted formal cycloaddition of 9 and 10 following the precedent of Schumann for the synthesis of racemic N -desmethyl-α-obscurine ( 17 , Scheme 2). 12…”

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confidence: 99%

Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine C−H Functionalization

2010

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Total synthesis of the Lycopodium alkaloid complanadine A, which is an unsymmetrical dimer of lycodine, was achieved by exploiting a common tetracyclic precursor. Key to the success of the synthesis was the development of a late-stage site-selective C-H functionalization of a pyridine moiety to arrive at a key boronic ester intermediate.The Lycopodium alkaloids are among the most skeletally diverse families of natural products that have been isolated to date. 1 In addition to their complex architecture, many of the alkaloids in this family possess potentially useful biological activity, which includes acetylcholinesterase (AChE) inhibition. 2 The utility of known AChE inhibitors, such as the Lycopodium alkaloid huperzine A (1 , Figure 1), 3 to partially address the treatment of Alzheimer's disease is supported by the observation of increased memory and learning in rats upon administration of 1. 4 Furthermore, several AChE inhibitors, including galanthamine 5 and Aricept®, 6 are commercial pharmaceuticals that are used to treat Alzheimer's disease indications. However, because AChE inhibition appears only to treat the symptoms of neurodegenerative diseases, there continues to be a need to identify other natural products that promote the growth of new neural networks. In this regard, Lycopodium alkaloids, such as the lyconadins (e.g., 3) 7 and complanadine A (4), 8 are especially interesting since they enhance mRNA expression for nerve growth factor (NGF) and the production of NGF in human glial cells. 9 As a first step in a program aimed at the biological evaluation of Lycopodium alkaloids and their analogs as neurotrophic factors, we have undertaken the synthesis of several of these compounds. We recently reported the total synthesis of lyconadin A (3). 10 In this manuscript, we present the details of our total synthesis of complanadine A (4), which is a dimer of the well-known phlegmarine-derived alkaloid lycodine (5). 11 The synthetic challenge posed by 4 stems primarily from the fact that it is an unsymmetrical dimer of lycodine (C2-C3' linkage; see 4 ) and therefore requires the introduction of position-control elements prior to merging the two halves (see 6 and 7 , Scheme 1). A powerful simplification of the synthesis would entail 6 and 7 arising from the same intermediate (e.g., tricyclic enamide 8). Enamide 8 was in turn envisioned to arise from an acid-promoted formal cycloaddition of 9 and 10 following the precedent of Schumann for the synthesis of racemic N-desmethyl-α-obscurine (17 , Scheme 2). 12The synthesis of complanadine A commenced with the preparation of ketal 12 (Eq. 1), which is available from (+)-pulegone using literature procedures. 13 Aminoketal 12 was used as a direct precursor to oxygen-sensitive α,β-unsaturated imine 10. 14 rsarpong@berkeley.edu. Supporting Information Available. Experimental details and characterization data for all new compounds are available free of charge via the Internet at http://pubs.acs.org. Enamide 9 was prepared from commercially available 5-keto...

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confidence: 99%

Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine C−H Functionalization

2010

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“…In the former study, Fischer and Sarpong started the synthesis [140] from tetracyclic compound 123 following the procedure developed by Schumann and Naumann (Scheme 20). [141] The authors converted triflated lycodine derivative 124 into boronic ester 125 under reductive detriflation conditions, followed by an Ir I -catalyzed Miyaura–Hartwig C–H borylation. [142] Pd-based cross-coupling between 125 and triflate 124 , followed by cleavage of the Boc group, produced (+)- 94 .…”

Section: Neurotrophic Natural Productsmentioning

confidence: 99%

Neurotrophic Natural Products: Chemistry and Biology

2013

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Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project.

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“…Among many studies worldwide, a Japanese team isolated pelletierine from pomegranate root bark following Hess' procedure, made a comparison with data provided by Hess and Eichel and concluded that the so-called pelletierine (129) sample of pelletierine sulfate isolated by Tanret himself and showed the presence of a ketone instead of an aldehyde, confirming that the pelletierine of Tanret was 1-(2-piperidyl)-2-propanone [100]. Part of the questioning concerning the exact structure of pelletierine (129) found its roots in the epimerization that is now a well-known phenomenon with 129 and is believed to be a base-catalyzed reaction operating via retro-Michael intermediate 180. The curious history of this small molecule has been brilliantly analyzed with an historical perspective in the 1960s [101].…”

Section: Pelletierine: a Small Alkaloid With A Long Historymentioning

confidence: 99%

“…Simple biosynthetic hypotheses may be put forward to explain the formation of senepodine G, a possible direct precursor of cermizine C through iminium reduction. Despite no mention of biosynthesis, their first approach started from pelletierine (129) and is worth noting as an interesting example of the conversion of one simple natural product into another (Scheme 1.60). Despite no mention of biosynthesis, their first approach started from pelletierine (129) and is worth noting as an interesting example of the conversion of one simple natural product into another (Scheme 1.60).…”

Section: When Chemical Predisposition Does Not Follow Biosynthetic Hymentioning

confidence: 99%

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Biomimetic Synthesis of Ornithine/Arginine and Lysine‐Derived Alkaloids: Selected Examples

Poupon¹,

Salame²,

Yan³

2011

Biomimetic Organic Synthesis

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Synthese des Lycopodium‐Alkaloids rac‐α‐Obscurin durch 1,3‐Anellierung eines Enimins

Cited by 19 publications

References 20 publications

Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine C−H Functionalization

Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine C−H Functionalization

Neurotrophic Natural Products: Chemistry and Biology

Biomimetic Synthesis of Ornithine/Arginine and Lysine‐Derived Alkaloids: Selected Examples

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