Spirocyclic Motifs in Natural Products

Abstract

Spirocyclic motifs are emerging privileged structures for drug discovery. They are also omnipresent in the natural products domain. However, until today, no attempt to analyze the structural diversity of various spirocyclic motifs occurring in natural products and their relative populations with unique compounds reported in the literature has been undertaken. This review aims to fill that void and analyze the diversity of structurally unique natural products containing spirocyclic moieties of various sizes.

Keywords: biological activity; chemical diversity; natural products; privileged structures; spirocycles.

Figure 1

Examples of pharmaceutically important compounds bearing a spirocyclic motif.

Figure 2

Sesquiterpenes from Schinus terebinthifolius fruit containing a [2.4.0] spirocyclic moiety.

Figure 3

Cyclohelminthol X (8) from Helminthosporium velutinum plant.

Figure 4

Valtrate (9) isolated from Valerianae Radix plant extract inhibiting HIV-1 transport.

Figure 5

Structures of fungi-derived illudins M and S.

Figure 6

Structures of sesquiterpenes 12–14 isolated from fungus Agrocybe aegerita.

Figure 7

Structures of antiparasitic, fungus-derived (−)-ovalicin (15) and fumagillin (16).

Figure 8

Structures of duocarmycin antitumor antibiotics.

Figure 9

The only known natural product containing a [3.4.0] spirocyclic motif.

Figure 10

Cleroindicin A isolated from fungus Clerodendrum japonicum.

Figure 11

Sesquiterpene bis-lactones isolated from Illicium plants containing a [3.7.0] spirocyclic motif.

Figure 12

Various naturally occurring [4.4.0] spirocyclic lactones.

Figure 13

Limonoids 31–32 containing both a [4.4.0] and a [2.4.0] spirocyclic system.

Figure 14

Tricyclic spirolactones (incorporating two [4.4.0] spirocyclic systems) isolated from Penicillium purpurogenum.

Figure 15

New spirocyclic curcumanolides possessing a [4.4.0] spirocyclic system each, isolated from Curcuma heyneana.

Figure 16

New iridoid glycosides isolated from Morinda citrifolia plant.

Figure 17

Diastereomeric spirophthalides recently isolated from marine-sponge-derived fungus Setosphaeria sp.

Figure 18

Spirocyclic mycotoxins produced by P. aethiopicum.

Figure 19

Spirocyclic lcatones isolated from Penicillium dangeardii.

Figure 20

Structure of herbicidal hydantocidine isolated from Streptomyces hygroscopicus.

Figure 21

Spirocyclic benzofuranones isolated from Ganoderma Applanatum.

Figure 22

Examples of naturally occurring spirooxyindoles.

Figure 23

Structures of mitragynine pseudoindoxyl (59) and hydroxy mitragynine pseudoindoxyl (60).

Figure 24

Structures of [4.4.0] spirocyclic pseudoindoxyl alkaloids fluorocurine (61), fungus-derived diketopiperazines (62a–d), brevianamide B (63), and rauniticine pseudoindoxyl (64).

Figure 25

Members of a family of spirocyclic lactone lactams isolated from marine sediment-derived fungus Aspergillus sydowi D2–6.

Figure 26

Natural products illustrating the range of heterospirocyclic [4.4.0]-sized motifs.

Figure 27

1,6-Dioxaspiro[4.4]nonane secondary metabolite isolated from entomogenous fungus Isaria cateniannulata.

Figure 28

Bipolaricins from phytopathogenic Bipolaris sp. fungus.

Figure 29

Structure of fredericamycin A possessing a [4.4.0] spirocyclic motif.

Figure 30

Overall diversity of [4.4.0] spirocyclic scaffolds represented in the natural products domain.

Figure 31

Spiro pentacyclic secondary metabolite isolated from Teucrium viscidum.

Figure 32

New spirocyclic triterpenoids isolated from Leonurus japonicas.

Figure 33

Spirocarolitone isolated from Ruptiliocarpon caracolito.

Figure 34

Structurally novel triterpenoids isolated from Belamcanda chinensis.

Figure 35

The [4.5.0] spirocyclic sesquiterpenoids from rhizomes of Acorus calamus.

Figure 36

Canusesnols from Capsicum annum.

Figure 37

Anti-ring worm drug griseofulvin (Grisovin^TM).

Figure 38

Examples of natural [4.5.0] spirocyclic lactones.

Figure 39

Abyssomycins from Actinobacteria.

Figure 40

Antibacterial and antitumor compound lactonamycin Z isolated from Streptomyces sanglieri.

Figure 41

Spirocyclic lactones isolated from endophyte fungal parasites.

Figure 42

Lambertollols A and B.

Figure 43

Spirocyclic lactones from traditional Chinese medicinal plant Rehmannia glutinosa.

Figure 44

Perenniporide A, the only spirocyclic lactone of the perenniporide family.

Figure 45

Secochiliolide acid.

Figure 46

Abiespiroside A isolated from Chinese tree Abies dalavayi.

Figure 47

Pathylactone A isolated from marine sources.

Figure 48

Spirocyclic carane lactones with insect-feeding deterrent activity.

Figure 49

Natural spirocyclic tetrahydrofurans.

Figure 50

Enantiomers of [4.5.0] spirocyclic dihydrofuran 8,9-dehydrotheaspirone reported in the literature.

Figure 51

Spirocyclic labdane–type diterpenoids isolated from the fruit of Vitex agnus-castus.

Figure 52

Spirocyclic natural product heliespirone featuring a tetrahydrofurane and a quinone-like moiety.

Figure 53

Erectile function-potentiating toxin featuring a [4.5.0] spirocyclic motif.

Figure 54

[4.5.0] spirocyclic quinochalcone saffloquinoside A isolated from Carthamus tinctorius.

Figure 55

Alkaloid (±)-pandamarine isolated from Pandanus amaryllif olius.

Figure 56

Surugatoxin isolated from the toxic Japanese ivory shell (Babylonica japonica).

Figure 57

Structures of representative spirostaphylotrichins possessing a [4.5.0] spirocyclic motif.

Figure 58

Current diversity of [4.5.0] spirocyclic scaffolds.

Figure 59

Spiro meroterpenoids spiroapplanatumines (122–124) isolated from fungus Ganoderma applanatum.

Figure 60

Fomlactones A–C possessing a [4.6.0] spirocyclic moiety.

Figure 61

Enantiopure juglanaloid A (128a–b) and juglanaloid B (129a–b) isolated from Juglans mandshurica and further obtained by chiral separation.

Figure 62

Lanostane-type triterpenoid spirolactones from Ganoderma applanatum.

Figure 63

Structure of auriculatol A possessing a [4.6.0] spirocyclic motif.

Figure 64

Structure of [4.6.0] spirocyclic seconoriridone A.

Figure 65

Structures of gelsenium alkaloids possessing a [4.6.0] spirocyclic system.

Figure 66

Natural product phyllanthunin possessing a [4.7.0] spirocyclic moiety isolated from Phyllanthus emblica.

Figure 67

Portimines A and B isolated from Vulcanodinium rugosum containing both one [4.7.0] and one [4.5.0] spirocyclic motif.

Figure 68

Spirocyclic chamigrane sesquiterpenes, merulinols B (143), C (144), E (145), and F (146).

Figure 69

Hyperbeanol C isolated from Hypericum beanie.

Figure 70

Thielavialides A−E (148–152) and pestafolide A (153).

Figure 71

Pteridic acids C and F isolated from Streptomyces sp. SCSGAA 0027 possessing a 1,7-dioxaspiro[5.5.0]undecane motif.

Figure 72

Pollenopyrroside A isolated from bee-collected Brassica campestris pollen.

Figure 73

New spirocyclic piperazin-2,5-dione alkaloids isolated from Aspergillus variecolor.

Figure 74

Spirocyclic piperazin-2,5-dione variecolortin B isolated from the marine-derived fungus Eurotium sp. SCSIO F452.

Figure 75

Bioactive [5.5.0] spirocyclic meroterpenoids isolated from mangrove-derived fungus Penicillium sp.

Figure 76

Alkaloids 163–i of the histrionicotoxin class isolated from ant Carebarella bicolor.

Figure 77

General structure of [5.6.0] spirocyclic orthoester periplosides.

Figure 78

Spirolide G isolated from toxigenic dinoflagellate Alexandrium ostenfeldii.

Figure 79

A [5.6.0] spirocyclic compound isolated from marine-derived fungus Eurotium sp. SCSIO F452.

Figure 80

Vieloplain G isolated from Xylopia vielana containing a [5.6.0] spirocyclic scaffold.

Figure 81

Spiroschincarin A isolated from the fruit of Schisandra incarnate.

Figure 82

Structurally diverse spirocyclic frameworks isolated from a single plant species (Gelsemium elegans).