Marine Pyrrole Alkaloids

Abstract

Nitrogen heterocycles are essential parts of the chemical machinery of life and often reveal intriguing structures. They are not only widespread in terrestrial habitats but can also frequently be found as natural products in the marine environment. This review highlights the important class of marine pyrrole alkaloids, well-known for their diverse biological activities. A broad overview of the marine pyrrole alkaloids with a focus on their isolation, biological activities, chemical synthesis, and derivatization covering the decade from 2010 to 2020 is provided. With relevant structural subclasses categorized, this review shall provide a clear and timely synopsis of this area.

Keywords: alkaloids; bromopyrroles; marine natural products; nitrogen heterocycles; pyrrole-aminoimidazole alkaloids; pyrrole-imidazole alkaloids; pyrroles.

Figure 1

Simple pyrrole alkaloids 1–3 isolated from different marine organisms.

Scheme 1

Enantioselective approach towards the total synthesis of pyrrolosesquiterpenoid 10b by a Sharpless epoxidation/dihydroxylation sequence, leading to the unnatural ent-(−)-glaciapyrrol A (10a).

Figure 2

Pseudocerolide A (11) and quinolinone alkaloids 12–17 isolated from marine origin.

Scheme 2

A high-yield sequence towards pyrrolyl 4-quinolinones 14, 15, and 16 starting from 2-chloroquinoline precursors 18 and 19 by Nagarajan et al.

Figure 3

Three new members 23–25 of the indanomycin-group, discovered in 2013.

Figure 4

Isolation of five pyrrole-2-carboxamides (26–30) from the sea sponge Agelas nakamurai.

Figure 5

Isolation of nemoechine A (31) and C (32), debromokeramadine (33), and clathrirole B (34).

Scheme 3

Synthesis of keramadines 33 and 41, including a regioselective oxidative addition followed by acid mediated bond cleavage of the aminal.

Figure 6

Synthetically known pyrrole-2-carboxamides 42–47, isolated for the first time from marine origin.

Figure 7

Molecular structures of breitfussins 48–51 isolated from the marine hydrozoan Thuiaria breitfussi.

Scheme 4

Total synthesis of the three breitfussins A (48), C (49), and D (50) by introducing the oxazole and pyrrole functionalities via two consecutive Suzuki coupling reactions.

Figure 8

Structures of lynamicins F (59) and G (60), indimicins A–E (61–65), dichlorochromopyrrolic acid derivative 66, and isohalitulin (67).

Scheme 5

Key step of the synthesis of lynamicin D (72) by a Suzuki coupling.

Figure 9

Highly substituted 3,4-diarrylpyrroles suberitamide B (73) and denigrin E (74).

Figure 10

Representation of an APK (75) and three pyrroles 76–78 including the important class of tambjamines.

Scheme 6

A linear 3-step sequence to tambjamine K (77).

Figure 11

Different prodiginine-based pyrrole alkaloids 81 and 82 together with marineosin-type spiroaminals 83–86.

Scheme 7

Divergent synthesis of premarineosin A (84) including a bioinspired MarG catalyzed spirocyclization as the final step.

Scheme 8

The first total synthesis of 7-epi-marineosin A (85a) by Shi and co-workers in a linear 19 step sequence and the structural reassignment of C7-OMe from (R) to (S) by the Harran laboratory using a chromophore disruption approach.

Figure 12

Mycalenitrile 96 and 97 as well as the pyrrole-terpenoid 98.

Figure 13

Representation of five tetrahydroindoles 99–103 isolated from Moorea producens.

Figure 14

Nitropyrrolins A–E (104–108) represent the family of 4-farnesylated 2-nitropyrroles.

Scheme 9

Total synthesis of nitropyrrolins 104 and 105 via the key intermediate nitropyrrolin B (105) that is also suggested to be a biosynthetic precursor of nitropyrrolins A (104) and D (107).

Figure 15

The heronapyrroles A–D (111–114) only differ in their oxidation state in the farnesyl side chain.

Scheme 10

First total synthesis of (+)-heronapyrrole C (113a) by Brimble in 2014 and its enantiomer (−)-heronapyrrole C (ent-113b) by Stark.

Scheme 11

Total synthesis of (+)-heronapyrrole A (111) and (+)-heronapyrrole B (112) by a convergent approach leading to stereochemical reassignments.

Figure 16

Structures of 1,2-annellated marine pyrrole alkaloids 124–127.

Figure 17

Various 2,3-fused pyrrole alkaloids 128–134 isolated between 2010 and 2020.

Scheme 12

The so-far shortest synthetic approach towards rigidin A (146), including the first syntheses of rigidins B–D (147–149) in a one-pot multicomponent reaction.

Figure 18

Series of isolated isopyrrolo-p-benzoquinone 150 and isopyrrolo-1,4-naphthoquinones 151–154.

Figure 19

Structures of spiroindimicins A–H (155–162) isolated from marine actinobacteria.

Scheme 13

Total synthesis of spiroindimicins 156, 157 using the Fischer indolization and Montforts pyrrole synthesis.

Figure 20

Subtipyrrolines A–C (168–170) as novel alkaloids from Bacillus subtilis SY2101.

Figure 21

Members of the lamellarins 171–182 (type I) isolated from Didemnum sp. in 2012 and 2019.

Figure 22

Related congeners 183–185 of the lamellarins sharing the central fused pyrrole core.

Figure 23

Simple bromopyrrole alkaloids 186–191 isolated from different marine sponges.

Figure 24

Simple bromopyrrole alkaloids 192–195 and structural similar agelanesins A–D (196–199).

Figure 25

Structure of compound 200 and the bromotyrosine-based keronopsamides A–C (201–203).

Figure 26

Molecular structures of bromopyrroles 204–211 isolated from sponges and bryozoans.

Scheme 14

First total syntheses of aspidostomides B (208) and C (209) starting from compound 212.

Figure 27

Nine new pseudoceratidines 218–226 from the marine sponge Tedania brasiliensis.

Figure 28

New bromopyrrole alkaloid 227. N-Methylmanzacidin C (228) is shown for comparison.

Scheme 15

An alternative synthetic route towards manzacidin B (232a) in 2010 revealed that it was incorrectly assigned as compound 232b in 2007.

Figure 29

Simple bromopyrrole alkaloids 233–236 isolated from the Agelas sp.

Figure 30

Mindapyrroles A–C (237–239) featuring several central resorcinol-cores.

Figure 31

Agelasines O–R (240–243) with a 9-N-methyladenine unit from a marine sponge Agelas sp.

Figure 32

The unusual structure of marinopyrroles C–E (244–246) contain a rare 1,3′-bispyrrole functionality.

Scheme 16

First total synthesis of (±)-marinopyrrole A (250) by Li in 2010 and its congener marinopyrrole B (253) by Chen in 2013.

Figure 33

Phorbazol-based marine bromopyrrole alkaloids 254–259.

Scheme 17

Total synthesis of breitfussin B (256) starting from phenol 260.

Figure 34

C-9 functionalized ene-hydantion marine pyrrole alkaloids 263 and 264.

Scheme 18

Total synthesis of (S)-mukanadin F (264b).

Figure 35

Related bromopyrrole alkaloids 271–274 bearing hydantoin.

Figure 36

Three new PIAs 275–277 isolated from the sponge Agelas spp. in 2020.

Figure 37

Oroidin-derived bromopyrrole alkaloids 278–283 bearing imidazole moieties.

Figure 38

Stylissazoles A–C (284–286) isolated from the marine sponge Stylissa carteri.

Figure 39

Unusual aminoimidazole pyrrole alkaloids 287–291 with compounds 289–291 incorporating a complex contiguous imidazole ring system.

Figure 40

Biologically active bromopyrrole imidazole alkaloids 292–295 possessing unique structural motifs.

Figure 41

Related bromopyrrole alkaloids 296–300 and the antifungal mukanadin G (300) isolated from Agelas sp.

Figure 42

Oroidin-based bromopyrrole alkaloids 301–303 with nagelamide D (304) underwent a reevaluation in 2020.

Scheme 19

A total synthesis of nagelamide D published by the Lovely group led to the correct assignment of nagelamide D (304).

Figure 43

The dimeric bromopyrrole alkaloids citrinamines A–D (312–315).

Figure 44

Five new family members (316–320) of the nagelamides from Agelas sp.

Figure 45

Donnazoles A (321) and B (322) from a marine sponge Axinella donnani and further agelamadins C–E (323–325).

Figure 46

Annellated halopyrroles 326–328 derived from marine bacteria.

Figure 47

Structures of 2,3-annellated marine pyrrole alkaloids 329–332.

Figure 48

Stylisines A (333), D (334), and E (335) from the marine sponge Stylissa massa.

Scheme 20

Synthesis of stylisine D (334) and intermediate longamide B (341) via a metal-catalyzed cyclisation of allene 339 in a stereoselective manner.

Figure 49

Longamides D–F (342–344) from the South China Sea sponge Agelas sp.

Figure 50

New aspidostomides D–F (345–347) and aspidazide A (348) from the patagonian bryozoan Aspidostoma giganteum.

Figure 51

Callyspongisines A–D (349–352) and pyrrololactam 353 of which only compound 349 is speculated to be of natural origin.

Figure 52

Brominated pyrrole-imidazole alkaloids 354–356 bearing guanidine units.

Scheme 21

First total synthesis of (+)-cylindradine B (356) via key Pictet–Spengler reaction.

Figure 53

Structurally complex annellated bromopyrroles 364–369 isolated from Dyctionella sp. or Agelas sp.

Scheme 22

Enantioselective synthesis of all known (−)-agelastatins, including the first total synthesis of agelastatins C–F (377, 378, 368, 369).

Figure 54

Structurally diverse bromopyrrole alkaloids 379–383 isolated from Agelas oroides.

Figure 55

Annellated bromopyrroles 384–390 from different marine sponges.

Scheme 23

Total synthesis of 2-debromohymenin (396) via a key gold-catalyzed alkyne hydroarylation.

Figure 56

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

Figure 57

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

Scheme 24

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

Figure 58

Polycyclic, complex molecular frameworks of condensed pyrrole MNPs 412–416.

Scheme 25

A linear ten-step sequence yielding the natural bispyrrole (−)-curvulamine 413a.

Figure 59

Members of the macrophilones group 423–429.

Scheme 26

Synthesis of macrophilone A (423) in a linear sequence of 5 total steps.

Figure 60

Pyrroloiminoquinones and related derivatives 432–436 isolated from natural sources, which share a similar biosynthetic pathway.

Scheme 27

Two different routes which target pyrroloquinolines 442, 443, and 444. The first route favors the formation of the quinoline followed by pyrrole aromatization, while the second one uses a biomimetic approach with a late-stage quinoline ring closure.

Figure 61

Pyrroloiminoquinones 445 and 446 as well as pyrroloquinones 447–450.

Scheme 28

Facile total synthesis of thiaplakortone A (447) in a nine-step approach.

Scheme 29

A divergent modular approach providing access to known zyzzyanones A–D (457–460).

Figure 62

Discorhabdins 461–465 resulted from the sponge Latrunculia sp. collected in Alaskan and New Zealandian oceans.

Figure 63

Further discorhabdins 466–471, including a new complex pyrroloiminoquinone 472.

Figure 64

Sugar-substituted marine pyrrole alkaloids 473–474.

Figure 65

Oligosaccharide-substituted pyrroles 475 and 476 from a marine starfish Acanthaster planci.

Figure 66

A new group of phallusialides A–D (477–481) discovered from a marine bacterium.

Figure 67

Bromopyrrole peptides 482–483 isolated from marine sponges.

Figure 68

Macrocyclic peptides 484–486 containing a pyrrole motif on their N-termini.