Synthesis of Natural Atisane‐Type Diterpenoids by retro‐Biomimetic Transformations

Abstract

An efficient one step, retro-biomimetic procedure for the synthesis of natural products having the atisane structure is described (Scheme 2), natural products which are components of medicinal plants and possess relevant biological activity. Their structures were confirmed by chemical transformations and spectral data. The starting materials were the known ent-kaur-16-en-19-oic acid (1) and ent-trachyloban-19-oic acid (2), diterpenoids readily available from the waste of sunflower.Introduction. -Tetracyclic atisanes, beyeranes, kauranes, and pentacyclic trachylobanes represent an important group of biosynthetically closely related polycyclic diterpenes, many of which display a wide range of biological activities [1 -7]. According to the hypothesis of diterpene biogenesis [8], diterpenes belonging to the families of ent-beyerene (A), ent-kaurene (B), ent-trachylobane (C), and ent-atisene (D) might all arise from (À)-copalyl pyrophosphate E via nonclassical carbocations such as F as common intermediates (Scheme 1). This hypothesis [8] has been formulated on the basis of the known isoprene rule and, to the best of our knowledge, has not been turned down yet. Scheme 1 provides a general overview of this biogenetic scheme, and our primary intention was to perform the retro-biomimetic transformation of ent-kaurene (B) to ent-beyerene (A) or ent-atisene (D) (path B ! F ! A or D).The rearrangements of ent-kaurane-and ent-trachylobane-type diterpenes have been reported under the action of different reagents [9]. Most of the examples relate on the reactions involving the formation of the nonclassical carbocation of type F (Scheme 1). It is well-known from the work of Olah and co-workers [10] that superacids are very convenient generators of these species, and our own experience on the use of fluorosulfuric acid (¼ fluorosulfonic acid; FSO 3 H) as an efficient promoter of terpenoid cyclizations [11 -15] and rearrangements [16 -18] provided a motivation to investigate the behavior of ent-kaur-16-en-19-oic acid (1) [19] and ent-trachyloban-19-oic acid (2) under superacid treatment (Scheme 2).

Skeletal Rearrangements of Rings C and D of the Kaurene and Beyerene Tetracyclic Diterpenoids

“…Since both ent-kaur-16-en-19-oic acid and ent-trachyloban-19-oic acid co-occur in the sunflower, Helianthus annuus, treatment of the waste from the production of sunflower oil with the super-acid, fluorosulfonic acid at −60 °C followed by triethylamine, gave a high yield of the corresponding ent-atisir-15-and -16-enes. 14 Diazotisation of ent-beyerene-16-amine with the exo-configuration gave ent-kauran-16ol and ent-kaurenes together with smaller amounts of the corresponding ent-beyeran-16-ols and beyerenes. 15 Thus it is possible to interconvert these skeleta and favour the formation of the ent-atisirenes.…”

Viability of Nonclassical Carbocations Proposed as Intermediates in the Biosynthesis of Atiserene, Beyerene, Kaurene, and Trachylobane Diterpenes

“…Structural drawings were produced using Ball & Stick [8]. The results of calculations on cations C -E with the attached COOH group present in the natural products from [3] indicated that the COOH group has little effect on the rearrangement chemistry and carbocation structures. …”

“…Despite extensive theoretical studies revealing energetically viable pathways to these diterpenes (Scheme) [2], the intermediacy of several unusual carbocations F -H (Fig. 1) has still been advocated for in the recent literature [3]. Herein, we expand on our previous work to specifically address the energetic viability of carbocations F -H 1 ).…”

Synthetic Transformations of Ent-Kaurenoic Acid

“…Recently [49] an effi cient one-step, retro-biomimetic procedure for the synthesis of natural products having the atisane structure has been reported (Scheme 10), which are natural components of medicinal plants and possess a relevant biological activity. As a part of the program of transformation the diterpenoids by microorganisms, Silva et al [51] carried out the transformation of ent-kaur-16-en-19-oic acid 1, by using Rhizopus stolonifer.…”