Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

Abstract

Terpene compounds probably represent the most diversified class of secondary metabolites. Some classes of terpenes, mainly diterpenes (C20) and sesterterpenes (C25) and to a lesser extent sesquiterpenes (C15), share a common bicyclo[3.6.0]undecane core which is characterized by the presence of a cyclooctane ring fused to a cyclopentane ring, i.e., a [5-8] bicyclic ring system. This review focuses on the different strategies elaborated to construct this [5-8] bicyclic ring system and their application in the total synthesis of terpenes over the last two decades. The overall approaches involve the construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki-Hiyama-Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson-Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition and biocatalysis.

Keywords: 5-8 bicycle; cyclization strategies; terpenes.

Figure 1

Examples of terpenes containing a bicyclo[3.6.0]undecane motif.

Figure 2

Commercially available first and second generation Grubbs and Hoveyda–Grubbs catalysts.

Figure 3

Examples of strategies to access the fusicoccan and ophiobolin tricyclic core structure by RCM.

Scheme 1

Synthesis of bicyclic core structure 12 of ophiobolin M (13) and cycloaraneosene (14).

Scheme 2

Synthesis of the core structure 21 of ophiobolins and fusicoccanes.

Scheme 3

Ring-closing metathesis attempts starting from thioester 22.

Scheme 4

Total synthesis of ent-fusicoauritone (28).

Figure 4

General structure of ophiobolins and congeners.

Scheme 5

Total synthesis of (+)-ophiobolin A (8).

Scheme 6

Investigation of RCM for the synthesis of ophiobolin A (8). Path A) RCM with TBDPS-protected alcohol. Path B) RCM with benzyl-protected alcohol.

Scheme 7

Synthesis of the core structure of cotylenin A aglycon, cotylenol (50).

Scheme 8

Synthesis of tricyclic core structure of fusicoccans.

Scheme 9

Total synthesis of (−)-teubrevin G (59).

Scheme 10

Synthesis of the core skeleton 63 of the basmane family.

Scheme 11

Total synthesis of (±)-schindilactone A (68).

Scheme 12

Total synthesis of dactylol (72).

Scheme 13

Ring-closing metathesis for the total synthesis of (±)-asteriscanolide (2).

Scheme 14

Synthesis of the simplified skeleton of pleuromutilin (1).

Scheme 15

Total synthesis of (−)-nitidasin (93) using a ring-closing metathesis to construct the eight-membered ring.

Scheme 16

Total synthesis of (±)-naupliolide (97).

Scheme 17

Synthesis of the A-B ring structure of fusicoccane (101).

Scheme 18

First attempts of TRCM of dienyne substrates.

Scheme 19

TRCM on optimized substrates towards the synthesis of ophiobolin A (8).

Scheme 20

Tandem ring-closing metathesis for the synthesis of variecolin intermediates 114 and 115.

Scheme 21

Synthesis of poitediol (118) using the allylsilane ring-closing metathesis.

Scheme 22

Access to scaffold 122 by a NHK coupling reaction.

Scheme 23

Key step to construct the [5-8] bicyclooctanone core of aquatolide (4).

Scheme 24

Initial strategy to access aquatolide (4).

Scheme 25

Synthetic plan to cotylenin A (130).

Scheme 26

[5-8] Bicyclic structure of brachialactone (7) constructed by a Mizoroki–Heck reaction.

Scheme 27

Influence of the replacement of the allylic alcohol moiety.

Scheme 28

Formation of variecolin intermediate 140 through a SmI₂-mediated Barbier-type reaction.

Scheme 29

SmI₂-mediated ketyl addition. Pleuromutilin (1) eight-membered ring closure via C⁵–C¹⁴ bond formation.

Scheme 30

SmI₂-mediated dialdehyde cyclization cascade of [5-8-6] pleuromutilin scaffold 149.

Scheme 31

A) Modular synthetic route to mutilin and pleuromutilin family members by Herzon’s group. B) Scaffolds of pleuromutilin derivatives reported by Herzon’s group.

Scheme 32

Photocatalyzed oxidative ring expansion in pleuromutilin (1) total synthesis.

Scheme 33

Reductive radical cascade cyclization route towards (−)-6-epi-ophiobolin N (168).

Scheme 34

Reductive radical cascade cyclization route towards (+)-6-epi-ophiobolin A (173).

Scheme 35

Radical 8-endo-trig-cyclization of a xanthate precursor.

Figure 5

Structural representations of hypoestin A (177), albolic acid (178), and ceroplastol II (179) bearing the same [5-8-5] core structure.

Scheme 36

Synthesis of the common [5-8-5] tricyclic intermediate of hypoestin A (177), albolic acid (178), and ceroplastol II (179).

Scheme 37

Asymmetric synthesis of hypoestin A (177), albolic acid (178), and ceroplastol II (179).

Figure 6

Scope of the Pauson–Khand reaction.

Scheme 38

Nazarov cyclization revealing the fusicoauritone core structure 192.

Scheme 39

Synthesis of fusicoauritone (28) through Nazarov cyclization.

Scheme 40

(+)-Epoxydictymene (5) synthesis through a Nicholas cyclization followed by a Pauson–Khand reaction to build the overall tetracyclic backbone.

Scheme 41

Synthesis of aquatolide (4) by a Mukaiyama-type aldolisation.

Scheme 42

Tandem Wolff/Cope rearrangement furnishing the A-B bicyclic moiety 204 of variecolin.

Scheme 43

Asymmetric synthesis of the A-B bicyclic core 205 and 206 of variecolin.

Scheme 44

Formation of [5-8]-fused rings by cyclization under thermal activation.

Scheme 45

Construction of the [5-8-6] tricyclic core structure of variecolin (3) by Diels–Alder reaction.

Scheme 46

Synthesis of the [6-4-8-5]-tetracyclic skeleton by palladium-mediated cyclization.

Scheme 47

Access to the [5-8] bicyclic core structure of asteriscanolide (227) through rhodium-catalyzed cyclization.

Scheme 48

Total syntheses of asterisca-3(15),6-diene (230) and asteriscanolide (2) with a Rh-catalyzed cyclization as the key step.

Scheme 49

Photocyclization of 2-pyridones to access the [5-8-5] backbone of fusicoccanes.

Scheme 50

Total synthesis of (+)-asteriscunolide D (245) and (+)-aquatolide (4) through photocyclization.

Scheme 51

Biocatalysis pathway to construct the [5-8-5] tricyclic scaffold of brassicicenes.

Scheme 52

Influence of the CotB2 mutant over the cyclization’s outcome of GGDP.