Sesquiterpene cyclizations catalysed inside the resorcinarene capsule and application in the short synthesis of isolongifolene and isolongifolenone

Abstract

Terpenes constitute the largest class of natural products and serve as an important source for medicinal treatments. Despite constant progress in chemical synthesis, the construction of complex polycyclic sesqui- and diterpene scaffolds remains challenging. Natural cyclase enzymes, however, are able to form the whole variety of terpene structures from just a handful of linear precursors. Man-made catalysts able to mimic such natural enzymes are lacking. Here, we describe the examples of sesquiterpene cyclisations inside an enzyme-mimicking supramolecular catalyst. This strategy allowed the formation of the tricyclic sesquiterpene isolongifolene in only four steps. The mechanism of the catalysed cyclisation reaction was elucidated using C-labelling studies and DFT calculations.

En route to terpene natural products utilizing supramolecular cyclase mimetics

“…Recently, the Tiefenbacher group also reported the rst examples of sesquiterpene cyclizations inside the capsule II. 44,45 Utilizing the optimized conditions for monoterpene cyclizations, all alkene isomers of farnesol and farnesol acetate were investigated (Scheme 6a). Compared to monoterpenes, formation of more complex product mixtures was observed.…”

Sesquiterpene Cyclizations inside the Hexameric Resorcinarene Capsule: Total Synthesis of δ‐Selinene and Mechanistic Studies

“…Complete conversion of the substrate was reached after 4 d as indicated by GC analysis (see the Supporting Information, Figure S1). Based on 1 H and 13 C NMR comparison, supported by GC‐MS database analysis, the major cyclization products were identified to be α‐cedrene ( A ), δ‐selinene ( B ), 2‐ epi ‐α‐cedrene ( C ), ϵ‐patchoulene ( D ), and 10‐ epi ‐zonarene ( E ; Table ) . The cyclization products were obtained in racemic form as capsule I is assembled from achiral building blocks.…”

“…In the initial report, a selective cyclization reaction was achieved using the monoterpene geranyl acetate as the substrate. We later expanded our investigations to sesquiterpenes . Due to the higher flexibility of the farnesyl substrates, control over the product selectivity is more challenging.…”

The Hexameric Resorcinarene Capsule at Work: Supramolecular Catalysis in Confined Spaces

“…Recently,t he same group reporteda ne xample of terpenec yclase mimicking, in which the linear sesquiterpene( 2 E,6Z)-farnesyl acetate was cyclized into d-selinene and 10-epi-zonarene in 18 and 10 % yield, respectively,i nt he presence of CR 6 H + + (10 %o fCR 6 and 3% of HCl). [32] The formation of d-selinene occurs inside the CR 6 cavity through 1,10-cyclization followed by ar eaction cascade in which the stabilization of cationic transition states and intermediates plays ac rucial role. If (2E,6E)-farnesyl acetate was used, the selectivity for d-selinene was significantly lower, whereas no traces of d-selinene were observed in the cyclization reactions of (2Z,6E)-and (2Z,6Z)-farnesyl acetate.…”

“…In addition, the cyclization of monocyclics esquiterpenes was reported. [32] Thus, the cyclofarnesyl acetate was cyclized into the tricyclic sesquiterpene isolongifolene in the presence of CR 6 H + + .…”