Synthesis of the Bicyclic Lactone Core of Leonuketal, Enabled by a Telescoped Diels–Alder Reaction Sequence

Abstract

The Diels-Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels-Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]-bicyclic lactone ring system and its [3.2.1] isomer. Our four-step, protecting-group-free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels-Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.

Asymmetric Synthesis of [2.2.2]-Bicyclic Lactones via All-Carbon Inverse-Electron-Demand Diels–Alder Reaction

“…Among them, bicyclic systems containing a heterocyclic δ-lactone ring occupy a prominent position (Figure , top) . Such a structural motif can be found in scholarisine A (compound isolated from Alstonia scholaris ) and crispatanolide , (natural product isolated in 1980 from Makinoa crispata (liverwort)) as well as in the products from the harringtonolide family. − Furthermore, the ability of bicyclic systems possessing a δ-lactone ring incorporated to undergo decarboxylative transformations to provide access to important building blocks capable of further derivatizations has found important applications in target oriented synthesis. , Selected important building blocks of such a type are shown in the bottom of Figure .…”

seco‐Labdanes: A Study of Terpenoid Structural Diversity Resulting from Biosynthetic C−C Bond Cleavage

“…In 2018, Brimble and Furkert et al., published a preliminary study towards the bicyclic core of leonuketal ( 105 ; Scheme 15 A). [135] This strategy involved the [4+2]‐cycloaddition of 269 and 270 to give ketone 271 (upon desilylation), followed by treatment of 271 with sodium cyanoborohydride to effect a reductive cyclisation reaction. This process efficiently furnished the bicyclic core of leonuketal ( 105 ) as 272 , however, the undesired lactone 274 was observed owing to competing cyclisation at the proximal side of the anhydride.…”

Supramolecular Diversity of Oxabicyclo[2.2.2]octenes Formed between Substituted 2H-Pyran-2-ones and Vinyl-Moiety-Containing Dienophiles

“…For example, in the case of cycloaddition between a substituted 3-acylamino-2H-pyran-2-one and ethyl vinyl ether [17] (or any other suitable alkene dienophile), in the first step a carbon-dioxide bridge system (i.e., 7-oxabicyclo[2.2.2]octene) is formed, such systems (including those formed via other reaction pathways) are known from the literature, but their solid-state structures were described just in a few cases, for some recent examples see ref. [18][19][20][21][22][23][24][25][26][27][28]. However, 7-oxabicyclo[2.2.2]octenes produced as described above can be formed as two possible regioisomers and each of these can exist as a mixture of two diastereoisomers (endo or exo), in turn each of the four distinctive possibilities is actually composed of a pair of enantiomers.…”