Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

Abstract

This account surveys the current progress on the application of intra- and intermolecular enyne metathesis as main key steps in the synthesis of challenging structural motifs and stereochemistries found in bioactive compounds. Special emphasis is placed on ruthenium catalysts as promoters of enyne metathesis to build the desired 1,3-dienic units. The advantageous association of this approach with name reactions like Grignard, Wittig, Diels-Alder, Suzuki-Miyaura, Heck cross-coupling, etc. is illustrated. Examples unveil the generality of such tandem reactions in providing not only the intricate structures of known, in vivo effective substances but also for designing chemically modified analogs as valid alternatives for further therapeutic agents.

Keywords: bioactive compounds; enyne metathesis; ring-closing metathesis; ruthenium catalysts; tandem reactions.

Scheme 1

Intramolecular (A) and intermolecular (B) enyne metathesis reactions.

Scheme 2

Ene–yne and yne–ene mechanisms for intramolecular enyne metathesis reactions.

Scheme 3

Metallacarbene mechanism in intermolecular enyne metathesis.

Scheme 4

The Oguri strategy for accessing artemisinin analogs 1a–c through enyne metathesis.

Scheme 5

Access to the tetracyclic core of nanolobatolide (2) via tandem enyne metathesis followed by an Eu(fod)₃-catalyzed intermolecular Diels–Alder cycloaddition, an epoxidation, and a biomimetic epoxide opening.

Scheme 6

Synthesis of (−)-amphidinolide E (3) using an intermolecular enyne metathesis as the key step.

Scheme 7

Synthesis of amphidinolide K (4) by an enyne metathesis route.

Scheme 8

Trost synthesis of des-epoxy-amphidinolide N (5) [72].

Scheme 9

Enyne metathesis between the propargylic derivative and the allylic alcohol in the synthesis of the southern fragment of des-epoxy-amphidinolide N.

Scheme 10

Synthetic route to amphidinolide N (6a).

Scheme 11

Synthesis of the stereoisomeric precursors of amphidinolide V (7a and 7b) through alkyne ring-closing metathesis and enyne metathesis as the key steps.

Scheme 12

Synthesis of the anthramycin precursor 8 from ʟ-methionine by a tandem enyne metathesis–cross metathesis reaction.

Scheme 13

Synthesis of (−)‐clavukerin A (9) and (−)‐isoclavukerin A (10) by an enyne metathesis route starting from (S)- and (R)-citronellal.

Scheme 14

Synthesis of (−)-isoguaiene (11) through an enyne metathesis as the key step.

Scheme 15

Synthesis of erogorgiaene (12) by a tandem enyne metathesis/cross metathesis sequence using the second-generation Hoveyda–Grubbs catalyst.

Scheme 16

Synthesis of (−)-galanthamine (13) from isovanilin by an enyne metathesis.

Scheme 17

Application of enyne metathesis for the synthesis of kempene diterpenes 14a–c.

Scheme 18

Synthesis of the alkaloid (+)-lycoflexine (15) through enyne metathesis.

Scheme 19

Synthesis of the AB subunits of manzamine A (16a) and E (16b) by enyne metathesis.

Scheme 20

Jung's synthesis of rhodexin A (17) by enyne metathesis/cross metathesis reactions.

Scheme 21

Total synthesis of (−)-flueggine A (18) and (+)-virosaine B (19) from Weinreb amide by enyne metathesis as the key step.

Scheme 22

Access to virgidivarine (20) and virgiboidine (21) by an enyne metathesis route.

Scheme 23

Enyne metathesis approach to (−)-zenkequinone B (22).

Scheme 24

Access to C-aryl glycoside 23 by an intermolecular enyne metathesis/Diels–Alder cycloaddition.

Scheme 25

Synthesis of spiro-C-aryl glycoside 24 by a tandem intramolecular enyne metathesis/Diels–Alder reaction/aromatization.

Scheme 26

Pathways to (−)-exiguolide (25) by Trost’s Ru-catalyzed enyne cross-coupling and cross-metathesis [94].