## 4 Indole Alkaloids from the Stigonematales: Chemical Diversity
### Hapalindoles  
Of the indole alkaloids produced by the Stigonematales, the haplindoles are the largest and most widespread group, and ostensibly represent the archetypal sub-class of the indole alkaloids from the order [29; 30]. In fact, biosynthesis studies suggest that haplindoles are the precursors to other sub-classes of the so-called _napalindole-type alkaloids_ from the Stigonematales. First identified more than 30 years ago by [PERSON] _et al._[29] from _H. intricatus_, specifically based on a suggested allebotathic role (see Section 7, Possible Ecological Function), a diversity of haplindoles have been since isolated from numerous species of _Hapalosiphon_, as well as _Fischerella_ and _Westelliopsis_. Structurally, the haplindoles are further sub-classified into tetracyclic (Group 1) and tricyclic (Group 2) variants--with the latter being more common--and, within both of these sub-classes, there is considerable variation including both chlorinated and non-chlorinated (at C-13; see Figures 4 and 5), and occasionally hydroxylated (e.g., haplindole O), representatives. In some rare cases (e.g., haplindole N and P), the vinylic group is replaced by an epoxide. Moreover, all members of the sub-class and, more generally, nearly all members of the larger class identified so far, contain reactive functional  
Figure 3: Classification scheme of indole alkaloids from Order Stigonematales. The previously described indole alkaloids are classified here as nine proposed groups; given are group number (as defined here), and corresponding chemical name of each group (based on previously named carbon skeletons). Note that stereochemistry is illustrated only for those sub-classes for which either a very limited number of variants have been identified (_i.e._, Groups 3, 6 and 8), and/or no variability in stereodisposition (e.g., 12-epimers, C-10/11/15) has been yet reported (_i.e._, Group 5 and 9). For more detailed explanation of variation within the subclasses, see Figures 4–11. groups at the C-11 (Figures 4 and 5) position; in this regard, isonitrile- and isothicyanate-bearing hapalindoles are, by far, the most common, but thiocarbamates (e.g., hapalindole T) [31] have also been identified. Finally, within the group, there is variability with respect to stereochemistry most notably including epimers at the C-12 position, and the diastereomers at the C-10 and C-15 positions (Figure 4). Chemical variants of the hapalindoles (and, indeed, other sub-classes) are generally named alphabetically (_i.e._, hapalindole A, B, C, _etc._) in order of their identification with most of the core structures (hapalindoles A, B, C-Q and T-V) notably identified by [PERSON] _et al._[29; 30]; however, additional nomenclature (e.g., 12-_epi_-hapalindoles, deschloro haplindoles) are also frequently found in the literature to further elaborate structural variants. As an example, hapalindole A is a tetracyclic, chlorinated isonitrile-containing congener, whereas hapalindole B is the corresponding isothicyanate. Hapalindole J and M, in turn, are the non-chlorinated isonitrile and isothicyanate congeners, respectively (Figure 4), whereas 12-_epi_-hapalindole J has been identified [32] as an epimer of the former. Notably alongside hapalindoles from _H. fontinalis_, [PERSON] _et al._[30; 33] isolated several more polar, minor constituents, namely fontonamides, haplonamides and haploxindoles (Figure 6). It was experimentally shown [30] that these congeners were likely oxidation products of hapalindoles, and specifically hapalindole A, formed by singlet oxygen with haploxindole serving as a precursor for fontonamide and haplonamide, whereby subsequent oxidation leads to opening of the indole-ring in the latter (Figure 6). These oxidation products are seemingly widespread as they have also recently been found [34], alongside hapalindoles, from _Fischerella_.