Heterocyclic Scaffolds II: Reactions and Applications of Indoles
Yong-Jin Wu New Indole-Containing Medicinal Compounds Timothy C. Barden Indoles: Industrial, Agricultural and Over-the-Counter Uses Richard J. Sundberg Electrophilic Substitution Reactions of Indoles Tara L.S. Kishbaugh Reactions of Indole with Nucleophil
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Advances in the Total Syntheses of Complex Indole Natural Products Liangfeng Fu
Abstract Total syntheses of several complex indole alkaloids having potent biological activities are discussed in detail. Keywords Biological activity Indole Natural products Total synthesis Contents 1 2
Introduction Indole Alkaloids with Potent Biological Activity 2.1 Actinophyllic Acid 2.2 Communesin F and Perophoramidine 2.3 Diazonamide A 2.4 Minfiensine 2.5 Stephacidin B 2.6 Yatakemycin 3 Other Complex Indole Alkaloids 3.1 Chartelline C 3.2 Haplophytine 3.3 Kapakahine B 3.4 (-)-Penitrem D 3.5 Phalarine 3.6 Quadrigemine C and 11,11’-Dideoxyvertillin A 3.7 Welwitindolinone A References
L. Fu Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN, 47405, USA e-mail: [email protected]
L. Fu
1 Introduction Since its first isolation in 1866, indole is one of the most important building blocks in natural occurring compounds. Moreover, indole has shown wide application in medicinal chemistry and in many other areas of chemistry. At least one thousand publications have described the isolation or synthesis of the natural products of indole in the last decade, including many complex indole alkaloids, especially those with novel skeletons, potent biological activities, or posing synthetic challenges. Manzamine A (1) (for recent isolations see [1–8]; for recent syntheses see [9–11]) and vinblastine (2) (for recent isolations see [12–17]; for recent syntheses see [18–22]) (Fig. 1) are two recent typical examples of great interest for both their syntheses and biological applications. In this chapter, only indole alkaloids initially described since 2000 will be covered.
2 Indole Alkaloids with Potent Biological Activity 2.1
Actinophyllic Acid
Actinophyllic acid (3), an indole alkaloid with novel 1-azabicyclo-[4.4.2]dodecane and 1-azabicyclo[4.2.1]nonane fragments, was isolated from the tree Alstonia actinophylla, collected on the Cape York Peninsula, Queensland, Australia, in 2005 by Quinn, Carroll and coworkers [23]. As a carboxypeptidase U inhibitor (IC50 = 0.84 mM), actinophyllic acid shows potential application for the treatment of cardiovascular disorders [23]. Much effort has been devoted to this unique molecule, including recent synthetic studies by Wood and coworkers [24], but only Overman et al. has accomplished its synthesis [25]. Overman’s retrosynthetic analysis is depicted in Scheme 1. Pentacyclic ketone 4, derived from allylic alcohol 7 by an aza-Cope-Mannich rearrangement of formaldiminium ion derivative 6 furnished 3 through the C5 hemiketal disconnection. An intramolecular oxidative coupling of a dienolate generated from indole-
OH
N H
N H
N
OH
H
N H H
N
Fig. 1 Manzamine A (1) and Vinblastine (2)
N H MeO2C MeO
N
H
OH N OAc H Me CO2Me
Advances in the Total Syntheses of Complex Indole Natural Products
N 5 N H
aza-Cope-Mannich
Hemiketal formation OH
N H
O
HO2C
RO2C
HO NP
N H 8
N H
O CO2R
RO2C
4
3
O
+ N
N
CO2R CO2R
5
HO
HO +
NH N H RO2C 7
CO2R
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