A modular synthesis of tetracyclic meroterpenoid antibiotics

Abstract

Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary-controlled Diels–Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2–sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus.

Marine natural products

“…502 A large number of indole-containing alkaloids have been synthesised including makaluvamine O and batzelline D, 503 dictyodendrin G, 504 leucettamine C, 505 isonaamidine E, 506 and cylindradine B, 507 while both enantiomers of the bromotyrosine itampolin A have been produced. 508 Smenospongine A, 509 smenoqualone, 509,510 dehydrocyclospongiaquinone-1, 511 haterumadienone (done in a protecting group-free manner), 512 cheloviolenes A, B and dendrillolide C, 513 astakolactin (revised to 1217), 514 phorbaketal A, 515,516 alotaketals B, C and D, 516 and ansellones A, B and phorbadione 517 are all terpenoids that had syntheses published in 2017. One notable synthetic campaign was published by Kishi's group.…”

A Concise Route for the Synthesis of Tetracyclic Meroterpenoids: (±)-Aureol Preparation and Mechanistic Interpretation

“…In this way, the methodology here described can be considered a general method for the synthesis of tetracyclic meroterponoids. already been reported [10]. From these two compounds, aureol (1) and 5-epi-aureol (11), adequate functionalization sequences can lead to (-)-cyclomenospongine (3), (+)-strongylin A (2) and (+)-smenoquealone (4), sequences that can be considered alternative formal syntheses of these tetracyclic compounds [9,28].…”

“…Thus, the synthesis of (±)-aureol ((±)- 1 ) from (±)-albicanol ( 5 ) was completed in only seven steps and a global 28% yield, substantially improving the synthetic procedures previously published [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Moreover, a simple epimerization of aureol ( 1 ) to 5- epi -aureol ( 11 ) has already been reported [ 10 ]. From these two compounds, aureol ( 1 ) and 5- epi -aureol ( 11 ), adequate functionalization sequences can lead to (-)-cyclomenospongine ( 3 ), (+)-strongylin A ( 2 ) and (+)-smenoquealone ( 4 ), sequences that can be considered alternative formal syntheses of these tetracyclic compounds [ 9 , 28 ].…”

“…It shows anti-influenza-A virus activity [8] and selective cytotoxicity against human tumor cells, including colon adenocarcinoma HT-29 cells [9] and nonsmall cell lung cancer A549 [9]. Although the tetracyclic meroterpenoids have exclusive structural features and a wide assortment of biological activities, only one highly modular and robust platform for the synthesis of this class of natural products has been reported to date [10]. The rest of the reported routes are synthetic operations (10-27 linear steps) that have not enabled straightforward access to the whole family of these interesting natural products [11][12][13][14][15][16][17][18][19][20].…”

“…Although the tetracyclic meroterpenoids have exclusive structural features and a wide assortment of biological activities, only one highly modular and robust platform for the synthesis of this class of natural products has been reported to date [ 10 ]. The rest of the reported routes are synthetic operations (10–27 linear steps) that have not enabled straightforward access to the whole family of these interesting natural products [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”