Synthesis of Natural (-)-Antrocin and its Enantiomer via Stereoselective Aldol Reaction.

Venkatachalam Angamuthu,Dar-Fu Tai

doi:10.3390/molecules25040831

Abstract

The total synthesis of (−)-antrocin and its enantiomer are presented. Antrocin (−)-1 is an important natural product which acts as an antiproliferative agent in a metastatic breast cancer cell line (IC50: 0.6 μM). The key features of this synthesis are: (a) selective anti-addition of trimethylsilyl cyanide (TMSCN) to α,β-unsaturated ketone; (b) resolution of (±)-7 using chiral auxiliary L-dimethyl tartrate through formation of cyclic ketal diastereomers followed by simple column chromatography separation and acid hydrolysis; (c) substrate-controlled stereoselective aldol condensation of (+)-12 with monomeric formaldehyde and pyridinium chlorochromate (PCC) oxidation for synthesis of essential lactone core in (−)-14; and (d) non-basic Lombardo olefination of the carbonyl at the final step to yield (−)-antrocin. In addition, (+)-9 cyclic ketal diastereomer was converted to (+)-antrocin with similar reaction sequences.

Highlights

Sesquiterpene lactones belong to an important class of naturally occurring terpenoids that represent a diverse and unique class of natural products
Antrocin (−)-1 is a cyclic sesquiterpene containing a five-membered γ-lactone ring with an exocyclic double bond. It was isolated from Antrodia camphorata, a valuable medicinal fungus grown in the inner wall of a heartwood of Cinnamomum kanehirai—an indigenous tree in Taiwan
The significant medicinal application of this fungus is well-known to the native Taiwanese for several decades, even long before it was biologically categorized under the class of Antrodia camphorata in 1990 [4,5,6,7]

Summary

Introduction

Sesquiterpene lactones belong to an important class of naturally occurring terpenoids that represent a diverse and unique class of natural products. Antrocin (−)-1 is a cyclic sesquiterpene containing a five-membered γ-lactone ring with an exocyclic double bond. It was isolated from Antrodia camphorata, a valuable medicinal fungus grown in the inner wall of a heartwood of Cinnamomum kanehirai—an indigenous tree in Taiwan. The difficulties for purification of (–)-1 from natural fungal resources triggers us to find an alternative in vitro synthetic route for it. Isolating the intermediatesreactions from ozonolyses and low isolating the key intermediates from ozonolyses andkey low temperature require sophisticated temperature reactions require sophisticated instrumental facilities, along with skilled synthetic instrumental facilities, along with skilled synthetic knowledge Another synthetic method for (+)-antrocin was reported [22] by Sheng-Han Huang et al. TheirAnother tricyclicsynthetic lactone core ring was constructedwas by an intramolecular.

Results and Discussion

Alkylation

Conclusions

General