The secondary ent-beyeran-16-yl carbocation (7) is a key branch point intermediate in mechanistic schemes to rationalize the cyclic structures of many tetra-and pentacyclic diterpenes including ent-beyerene, ent-kaurene, ent-trachylobane, and ent-atiserene, presumed precursors to > 1,000 known diterpenes. (Scheme 1) To evaluate these mechanistic hypotheses, we synthesized the heterocyclic analogues, 16-aza-ent-beyerane (12) and 16-aza-ent-trachylobane (13), by means of Hg(II)-and Pb(IV)-induced cyclizations onto the Δ 12 double bonds of tricyclic intermediates bearing carbamoylmethyl and aminomethyl groups at C-8. The 13,16-seco 16-nor carbamate (20a) was obtained from ent-beyeran-16-one oxime (17) by Beckmann fragmentation, hydrolysis, and Curtius rearrangement. The aza analogues inhibited recombinant ent-kaurene synthase from Arabidopsis thaliana (GST-rAtKS) with inhibition constants (IC = 1 × 10 −7 and 1 × 10 −6 50 M) similar in magnitude to the pseudo-binding constant of the bicyclic ent-copalyl diphosphate substrate (K m = 3 × 10 −7 M). Large enhancements of binding affinities (IC 50 = 4 × 10 −9 and 2 × 10 −8 M) were observed in the presence of 1 mM pyrophosphate which is consistent with a tightly bound ent-beyeranyl + /pyrophosphate − ion pair intermediate in the cyclization-rearrangement catalyzed by this diterpene synthase. The weak inhibition (IC 50 = 1 × 10 −5 M) exhibited by entbeyeran-16 exo-yl diphosphate (11), and its failure to undergo bridge rearrangement to kaurene, appear to rule out the covalent diphosphate as a free intermediate. 16-Aza-ent-beyerane is proposed as an effective mimic for the ent-beyeran-16-yl carbocation with potential applications as an active site probe for the various ent-diterpene cyclases, and as a novel, selective inhibitor of gibberellin biosynthesis in plants.
Efforts toward the synthesis and process optimization of amtolmetin guacil 1 are described. High-yielding electrophilic substitution followed by Wolf-Kishner reduction are the key features in the novel synthesis of tolmetin 2 which is an advanced intermediate of 1.
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