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

Abstract

A new concise general methodology for the synthesis of different tetracyclic meroterpenoids is reported: (±)‑aureol (1), the key intermediate of this general route. The synthesis of (±)‑aureol (1) was achieved in seven steps (28% overall yield) from (±)‑albicanol. The key steps of this route include a C–C bond-forming reaction between (±)‑albicanal and a lithiated arene unit and a rearrangement involving 1,2‑hydride and 1,2-methyl shifts promoted by BF3•Et2O as activator and water as initiator.

Divergent Strategy in Marine Tetracyclic Meroterpenoids Synthesis

“…With alkyl iodide 52 in their hands, the cross-coupling reaction between Grignard reagent 53 and alkyl iodide 52 generated the key intermediate 51 in a 56% yield. As olefin 51 was an advanced intermediate in the Rosales’s synthesis [ 38 , 39 ] of (±)-aureol ( 1 ), their strategy constituted a formal synthesis of (+)-aureol ( 1 ). This formal synthesis was completed in four steps (27% overall yield) from starting material (+)-sclareolide ( 47 ).…”

“…As a part of our efforts directed towards the synthesis of marine terpenoids [ 40 ], we embarked on a project aimed at the divergent synthesis of tetracyclic meroterpenoids. Our endeavors started with the racemic preparation of (±)-aureol ( 1 ) in 2015 [ 38 ], a process we latter improved in 2020 [ 39 ]. This effort continues with the divergent synthesis of other tetracyclic meroterpenoids using aureol ( 1 ) as a common synthetic intermediate.…”

“…The subsequent deoxygenation of alcohol 62 was carried out using the Barton–McCombie procedure, which afforded 57 in an 86% overall yield (two steps). Later [ 39 ], the key intermediate 57 was also prepared through a C-C bond-forming reaction between 2-lithiohydroquinone dimethyl ether and (±)-albicanal ( 59 ) as starting material, which was previously obtained by oxidation of (±)-albicanol ( 63 ) with the Dess–Martin reagent (99.7% yield). In this way, the coupling of 59 with 2-lithiohydroquinone dimethyl ether gave a mixture of diastereomeric benzylic alcohols which, without separation, was treated with lithium in liquid NH 3 /THF followed by aqueous NH 4 Cl to give the deoxygenated product 57 in a 90% yield (two steps).…”

“…Under these conditions, 51 was obtained in a 63% yield, together with the by-product 64 in a 30% yield. In this reaction, the intermediate carbocations IX - XI could be involved [ 39 ]. The cationic rearrangement might be initiated by a proton from HF, which could be formed through hydrolysis of BF 3 , since is known that BF 3 .…”

Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances

“…Martinez et al showed a concise strategy for the preparation of sponge derived tetracyclic meroterpenoids characterized by a sesquiterpene skeleton linked to a phenolic or quinone part [8]. Aureol, strongylin A, cyclosmenospongine and smenoqualone are representative examples of this class of bioactive compounds.…”