This chapter, covering the chemistry literature up until June 2013 and comprising 142 references, records the chemical structures of 130 bi-, bis-, and trisindole alkaloids isolated from a plethora of marine phyla including bacteria, algae, bryozoans, sponges, mollusks, hard corals, and ascidians. While the vast majority of bisindoles have been isolated from marine sponges, biindoles are more commonly found in red algae species than sponges. Trisindoles are far less common than bisindoles in the marine environment and have been limited to two species of sponge and a single species of marine microbe. Antimicrobial activity and cytotoxicity dominate the bioactivities explored for selected members of this family of alkaloids. Synthetic approaches to 28 natural products are presented in 33 schemes, and in the absence of any in vivo biosynthetic studies, the putative biosyntheses of eight bisindole metabolites are presented.

Isolated from diverse cyanobacteria, the hapalindole family of indole alkaloids comprises over 80 interrelated natural products. The family is further divided into several subclasses including the hapalindoles, fischerindoles, ambiguines, and welwitindolinones, each sharing one or more of the many common structural motifs, including an indole or oxindole core, a highly functionalized cyclohexane unit fused to the indole at C-3, and the uncommon isonitrile or isothiocyanate functionalities. Reported here is a comprehensive review covering the isolation of all currently known hapalindole-type alkaloids, the biological activity for several members of the family, and the proposed biosyntheses that give rise to the intricate structural diversity within the family. Finally, the major thrust of this chapter is a comprehensive outline of decades of cutting edge synthetic chemistry toward these complex alkaloids. To date, only a small fraction of the hapalindole-type alkaloids have yielded to chemical synthesis, yet the strategies and methodologies developed showcase the state of the art in synthetic chemistry and provide access to new compounds that can be evaluated for their biological activities.

Saraines have been isolated by the group of Cimino from the marine sponge Reniera sarai collected in the Bay of Naples. These alkaloids can be classified into two categories, depending on the type of their structure. Saraines 1-3 and isosaraines 1-3 are characterized by a trans-2-oxoquinolizidine moiety bound directly to a tetrahydropyridine ring, both nuclei being also linked by two alkyl chains of different lengths. On the other hand, saraines A-C and misenine present a diazatricyclic central core, showing an unusual interaction between an aldehyde and a tertiary amine and giving them a zwitterionic character, and flanked with two chains forming macrocycles. In a first part of the chapter, the isolation, spectral data, and structure elucidation of saraines are presented. Biological properties and biogenetic proposals concerning these compounds are then described. The most important part is devoted to synthetic approaches and total synthesis of saraine A.

Research in the hasubanan and acutumine alkaloid fields up to 1970 was discussed under "morphine alkaloids" in Volume 13 of this chapter. Advances in the field of hasubanan alkaloids from 1971 to 1975 were reviewed in Volume 16 and from 1976 to 1986 in Volume 33. This chapter extends the information in the three preceding reviews to hasubanan alkaloid literature published from 1987 to June 2013. This chapter covers acutumine alkaloid literature since (-)-acutumine (3) was isolated in 1929. This chapter includes occurrence and physical constants, new alkaloids, synthesis, biosynthesis, and pharmacology. Section 1 introduces the foremost alkaloids, (-)-hasubanonine (1) and (-)-acutumine (3), and the numbering systems of the hasubanan (2) and acutumine (4) skeletons. Section 2 details the occurrence and physical constants of 29 new hasubanan and 15 acutumine alkaloids. The isolation and structural determination of these new alkaloids are described in Section 3. Section 4 summarizes total syntheses and synthetic studies toward hasubanan and acutumine alkaloids. Completed syntheses of the hasubanan alkaloids (+)-cepharamine (ent-71), (-)-hasubanonine (1), (-)-runanine (8), (-)-delavayine (6), (+)-periglaucine B (19), and (-)-8-demethoxyrunanine (12) are reviewed. Completed syntheses of (-)-acutumine (3) and (-)-dechloroacutumine (52) are also described. Section 5 details biosyntheses of (-)-acutumine (3) advanced by Barton, Wipf, and Sugimoto. Section 6 summarizes pharmacological studies of hasubanan and acutumine alkaloids. Opioid receptor affinity, anti-HBV activity, and antimicrobial activity of hasubanan alkaloids are reported. Antiamnesic properties, cytotoxicity, and anti-HBV activity of acutumine alkaloids are described.