*3.3. Sceptrins*

The members of the exceptional family of the sceptrin alkaloids are characterized by their cyclobutane ring which is constructed by the dimerization of oroidin and its derivatives [301]. They are known to exhibit a broad range of biological activities, such as anticancer, antifungal, antibacterial, and anti-inflammatory [226,302–304]. Sceptrin was isolated and fully elucidated in 1981 by Faulkner and co-workers who also established its absolute configuration [224]. Many sceptrin derivatives have been isolated since.

In 2017, agelestes A (**397**) and B (**398**) were isolated from a South China sponge of the genus *Agelas* (Figure 56) [305]. Although nakamuric acid (**400**) was already isolated in 1999 [306], the authors revealed its absolute configuration for the first time (Figure 56) [306]. The same sponge *Agelas* sp. also led to the isolation of hexazosceptrin (**401**), bearing a

rare cyclohexane-fused-cyclobutane skeleton. All relative and absolute configurations were determined by extensive spectroscopic analyses and ECD. All four compounds **397**, **398**, **400**, and **401** displayed moderate antimicrobial activity (MIC values ranging between 16 μg/mL and 32 μg/mL) [305].

**Figure 56.** Several different substituted bromopyrroles **397**–**402** belonging to the sceptrin-family.

One year later, two sceptrin derivatives, ageleste C (**399**) and dioxysceptrin (**402**) were isolated from the marine sponge *Agelas Kosrae* (Figure 56) [307]. The relative and absolute configurations of compounds **399** and **402** were determined by ROESY correlations and by ECD spectroscopy. However, due to the absence of reliable ROESY correlations, the configuration at C-11 and C-11- could not be determined. Ageleste C (**399**) and the bisepimeric dioxysceptrin (**402**) showed good to moderate anti-proliferative activity against six cancer cell lines (IC50 values ranging between 7.92 μM and > 50 μM), however, only compound **399** displayed moderate inhibition of *Candida albicans*-derived isocitrate lyase (IC50 value 22.09 μM), a key enzyme in microbial metabolism [307].

In 2010, the New Caledonian sponge *Agelas dendromorpha* led to the isolation of benzosceptrin C (**403**) featuring a rare benzocyclobutane moiety (Figure 57). Unfortunately, no cytotoxicity against the KB cell line was observed [295].

**Figure 57.** Further sceptrins **403** and **404** together with the congener agelanemoechine (**405**).

In 2016, the Köck group investigated the tropical sponge *Agelas sceptrum* which led to the isolation of 15--oxoadenosceptrin (**404**), a hybrid PIA incorporating an adenine moiety. Unfortunately, no cytotoxic or antimicrobial activity was observed for compound **404** (Figure 57) [274].

In 2019, a unique alkaloid **405** bearing an imidazo [1,5-*a*] azepine nucleus was isolated from the marine sponge *Agelas nemoechinata*, with its relative and absolute configuration being determined by NOESY correlations and ECD spectroscopy, respectively. Agelanemoechine (**405**) showed potent pro-angiogenic activity in zebrafish (effect equivalent to the established Danhong injection as a positive control, Figure 57) [308].

At this point, the very recently published total synthesis of the dimeric PIA sceptrin (**411**) should be mentioned, which enables direct entry to this class of biologically active metabolites (Scheme 24) [309]. Astonishingly, sceptrin (**411**) was synthesized in only four steps by applying a photochemical intermolecular [2+2] dimerization of compound **408**. The authors synthesized building block **408** by initial hydroboration of protected propargylamine **406** to give pinacol ester **407** which then underwent a Suzuki–Miyaura cross-coupling with 3-bromoimidazopyrimidine. The key dimerization was carried out with blue LEDs in the presence of an iridium catalyst and provided the *all-trans* dimer **409** in 41% yield. Completion of the synthesis included acid-promoted deprotection, installation of the bromopyrrole unit **410**, and hydrazine-based conversion of the guanidine unit to an imidazole moiety in one pot [309].

**Scheme 24.** A four-step synthesis of sceptrin (**411**), including a photochemical intermolecular [2 + 2] dimerization as the key step.

Although there have been successful approaches towards sceptrin (**411**) since 2004, this new approach gives synthetic access to the sceptrin family in a minimum number of steps compared to the 11–25 steps required before [310–312]. It should also be mentioned that the synthetic work of the Chen laboratory in 2014 led to the revision of the absolute stereochemistry of many sceptrin-based natural products and of sceptrin (**411**) itself [312]. For more than 30 years, many groups have based their stereochemical results on the comparison with the incorrectly determined absolute configuration of sceptrin (**411**) from a publication of 1981 [224]. Hence, careful reading and checking are strongly recommended to avoid confusion.
