Conformational Studies on (+)-epi-goniofufrone and Hirsutic Acid Reveals Patterns of Conformer Populations in Triquinane Sesquiterpenes

Hoffmann et al. [1] asked the pivotal question of whether natures is deliberately dictating conformational patterns for natural products or not. He suggested that cyclic compounds containing oxygen can attain conformational preferences that are of prime importance to bio activity Still et al. [2]. were among the pioneers to show theses conformational preferences in oxygen containing sixmembered rings can collectively determine the final shape of some natural products. Our new results seems to back up the idea of nature’s deliberation in choosing fused cyclic carbonic skeletons to exploit their conformational space in sculpting bio active molecular shapes Lipnick et al. introduced a wheel model of a of up to 20 conformers [1,3,4] to show cyclopentane conformational mobility. Further attempts [5-12] to classify these conformers mostly proved unsuccessful [13-15]. The concept of a spherical conformational landscape (see SI) decisively classified the conformers into so called bent and twist conformers arranged along two ring coordinates [16]. The model has then developed over the recent years to study the fused cyclic compounds [17]. Figure one shows such a conformational wheel model for cis-octahydropentalene (see SI for conformer legend), recently being studied along with other fused cyclic systems in our studies on conformational analysis Table 1. provides the relative energies of these conformers. Clearly the pseudorotational ring coordinates are not fully accessible in fused cyclic systems [16,17] (Figure 1 & Table 1).

Table 1: Relative energies and symmetry point groups for double envelope conformers in cis-octahydropentalene.

To study conformational forms in cis-octahydropentalenes as well as hirsutic acid and goniofufrone, density functional methods like xb97xd, in particular yield results similar, if not close, to those obtained via correlational methods like MP2. most local density functional methods, slightly overestimate barriers due to their inability to account for van der Waals attractions in some strained conformers [18,19]. The ωb97xd basis set can reliably result in accurate van der Waals modifications. The geometries computations were done at ωb97xd/6-311+G(d) level [20-22], using Gaussian g09 package [23]. Larger basis sets like 6-311+G(d,p) proved no better accuracy.

(+)-epi-goniofufrone [24] is one of herbal pharmaceutical polyketide components found in plant family Annonaceae with about 2000 species and have been historically important. This marine natural product is a triquinane sesquiterpene with a main cis-octahydropentalene framework. The molecule switches between conformational forms cEE2 and cEE10, with latter being more fluxional and dynamic in ring coordinate, while cEE2 is rather a trapped conformer with minimal fluxional nature. The two conformers are believed to cooperatively populate the cEE10 in the conformational landscape (Figure 1). It is also noteworthy that more axial/equatorial character is given to hydroxy substituent in cEE10 compared to cEE2, as the substituents are closer the puckered tip of the envelope rather its terminal planar carbons. This more axial/equatorial character may well suggest how nature uses fused cyclic rings to its benefit (Figure 2).

Hirsutic acid is an antibiotic isolated from a fungus, Stereum Hisrsutumm, with the main skeleton of three successive fused cyclopentane rings. Hirsutic acid is also a triquinane sesquiterpene that has three five membered rings fused together in two cis configurations, here a mobile cEE3 part of the molecule seems to balance the other end of the molecule to attain a trapped cEE5 conformation (Figure 3) (Figure S1, S2 & S3).

In Conclusion, two triquinane sesquiterpenes have been shown two adopt pseudorotationally localized conformers, in which their functional substituents can attain maximum axial/equatorial characters. Both compounds possess a cis-octahydropentalene carbonic backbone. Our results show cis-octahydropentalene frameworks can populate desired conformers mainly because of if the intersected ring coordinates in their conformational landscape model. The conformational landscape shown here, successfully explains the bioactive conformers in these two triquinane sesquiterpenes. Further ongoing research is underway to explore a more in depth understanding of such conformational landscapes in cyclic and cyclic fused compounds.

None

No conflict of interest.

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