Leonuketal, a Spiroketal Diterpenoid from Leonurus japonicus

Abstract

An architecturally complex spiroketal diterpenoid, leonuketal (1), was isolated from the aerial parts of the plant Leonurus japonicus. This compound possessed an unprecedented tetracyclic skeleton that comprised a bridged spiroketal moiety fused with a ketal-γ-lactone unit. The structure and absolute configuration were determined by spectroscopic analyses, a modified Mosher's method, and ECD (electronic circular dichroism) calculations. Leonuketal (1) showed significant vasorelaxant activity against KCl-induced contraction of rat aorta, with the EC50 value of 2.32 μM.

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

“…Pleasingly, in contrastt ot he trans-dienophiles, the thermal reaction of compound 8a with the model cis-dienophilem aleic anhydride (14)p roceeded cleanly to afford the corresponding cycloadduct (22)i n3 6% yield (Table 1, entry 6). More pleasingly,o nh eating with diene 8a at 150 8Ci nt oluene, citraconic anhydride( 11)a lso underwent complete conversioni nto the desired cycloaddition product (23), as established by using 1 HNMR analysis( Ta ble 1, entry 7). Importantly,t his result also revealed completer egioselectivity for the desired cycloadduct regioisomer,l ikely driven by unfavorable steric interactions between the 1,1-dimethylg roups of the diene and the methyl group of dienophile 11 in the transition state for the undesired regioisomer.N otwithstanding this encouragingr esult, our optimizationo ft he reactionw as hampered by the concomitant desilylation of diene 8a to give compound 13,a sw ell as by the instability of compound 23 during its isolation and purification on silica gel, whichresulted in very low yields of the isolated product (< 5%).…”

“…Having established access to crude ketone 7,w et urned our attention to the formation of the [2.2.2]-oxabicyclic core of leonuketal (1). Reduction of the a,b-unsaturated ketone with sodium cyanoborohydride in acetic acid afforded an inseparable mixture of the desired product [2.2.2]-5 with as econd product, [3.2.1]-24.T his reaction favored the formation of compound 5 in an approximately 2:1r atio in most cases;h owever, this selectivity was somewhat variable and was occasionallyr eversed, for reasonst hat remain to be identified.…”

“…We anticipated that bicyclic anhydride 7,o rasuitable synthon, would be accessible through aD iels-Alder cycloaddition reaction( Scheme 2). The cycloaddition of 1,1-dimethyl Danishefsky-type diene 8 with methyl-substituted fumarate 9 should lead to 3,4-trans-10,asynthetic equivalent of 7 with the appropriate relative stereochemistry for leonuketal ( 1). However, there have been very few reportso fs uccessful cycloaddition reactions that involves uch highly substitutedd iene/ trans-dienophile combinations.…”

“…However, there have been very few reportso fs uccessful cycloaddition reactions that involves uch highly substitutedd iene/ trans-dienophile combinations. As an alternative, we also envisaged that ac ycloaddition reaction of compound 8 with the more-reactive commercially availablec yclic cis-dienophile citraconic anhydride (11;c a. US$0.70 g À1 )s hould give access to the fused cyclic anhydride 3,4-cis-7,w ith the additional benefit of (1), as proposed by Peng and co-workers. [1] shortening the number of synthetic steps.…”

“…As an alternative, we also envisaged that ac ycloaddition reaction of compound 8 with the more-reactive commercially availablec yclic cis-dienophile citraconic anhydride (11;c a. US$0.70 g À1 )s hould give access to the fused cyclic anhydride 3,4-cis-7,w ith the additional benefit of (1), as proposed by Peng and co-workers. [1] shortening the number of synthetic steps. The stereochemistry of 3,4-cis-7 by following this latter sequence would be C3-epimeric with respect to compound 1.T herefore, an additional epimerization step would be required later in the synthesis.…”