The absolute axial configurations of knipholone and knipholone anthrone by TDDFT and DFT/MRCI CD calculations: a revision
Graphical abstract
Introduction
Knipholone (1)1 and knipholone anthrone (2)2 are the most prominent representatives of the phenylanthraquinones (Fig. 1). These naturally occurring biaryls, which have initially been discovered by Steglich, Dagne, and Yenesew in 1984 and 1993, are fascinating in many respects: structurally, because of their rotationally hindered and thus configurationally stable biaryl axis, which gives rise to atropo-enantiomers (or, in the case of glycosides, atropo-diastereomers), biosynthetically, because their two molecular portions, the anthraquinone part and the trioxyacetophenone moiety, are built up from eight and four acetate units, respectively,3 and pharmacologically, because they display significant antimalarial4 and antitumor5 activities as well as antioxidant6 properties, along with an inhibition of leukotriene formation.7 Remarkably, the antitumoral activities of natural phenylanthraquinones significantly depend on the absolute configuration at the biaryl axis,5 showing the importance of axial chirality in these and other8 biaryls. This stereochemical aspect seems to be substantial for the phenylanthraquinone-producing plants, too: as an example, knipholone (1) and its 6′-O-sulfate, although co-occurring in the same plant, have the opposite axial configurations.9
Given the importance of axial chirality for these compounds, we investigated the absolute axial configuration of 1 and 2 by quantum chemical CD calculations at a semiempirical level in 1999 and deduced the main (dextrorotatory) atropo-enantiomers of both, 1 and 2, to be M-configured.10
In view of this stereochemical assignment, the result of our first, atropo-enantioselective total synthesis of both 1 and 2,11, 12 following our ‘lactone concept’,13, 14 was unexpected. The ring cleavage reaction of the respective configurationally unstable biaryl lactone intermediate, when using the R-enantiomer of the CBS reagent, which would have been expected to lead to the assumed axial M-configuration of (+)-knipholone, actually gave the ‘wrong’, laevorotatory enantiomer of the natural product. This seemed to hint at a non-predictability of the ring cleavage direction within the ‘lactone method’. Still, this has, ever since, remained the only exception to the—otherwise fully consistent—stereochemical course of all such lactone cleavage reactions. A second inconsistency originated from the renewed isolation of 1 and 2 with varying enantiomeric ratios (according to LC–CD) from diverse sources and, in particular, with a higher chemical purity; these samples provided CD spectra different from those initially measured, i.e., from the curves that had been the basis for the configurational assignment in 1999. The pretendedly inconsistent lactone cleavage direction and the new CD measurements, together with the more accurate computational methods available meanwhile, warranted a systematic re-investigation of the absolute configurations of knipholone (1) and knipholone anthrone (2).
In this paper, we report on the renewed investigation of the absolute configuration of 1 and 2 by using advanced quantum chemical CD calculations based on time-dependent DFT (TDDFT) and multireference configurational interaction (DFT/MRCI) approaches, reassigning the naturally predominant, dextrorotatory enantiomers of knipholone, (+)-1, and knipholone anthrone, (+)-2, as both being P-configured. This stereochemical attribution was further corroborated by converting 1 into the related likewise axially chiral phenylanthracene derivative 3 (Fig. 2), i.e., a compound with a substantially different chromophore, and its independent configurational assignment, again as P.
Section snippets
The stereochemical course of the ring cleavage of configurationally unstable biaryl lactones within the ‘lactone concept’
A first hint at a possibly wrong configurational assignment of 1 and 2 by the early quantum chemical CD calculations resulted from the above-mentioned unexpected stereochemical course of the first (and as yet only) total synthesis of 1 and 2. The key step of this synthesis was the atropo-enantioselective ring cleavage reaction of the configurationally unstable biaryl lactone precursor 4 by using the CBS system (Scheme 1a). From previous experience with quite a broad spectrum of different
Conclusion
The absolute axial configuration of the naturally occurring phenylanthraquinones, knipholone (1) and knipholone anthrone (2), was re-investigated by quantum chemical CD calculations showing that the previous assignment, based on merely semiempirical calculations (in combination with not entirely pure samples, due to instability reasons) had been erroneous. The renewed CD calculations using highly advanced methods, viz. TDDFT and DFT/MRCI, unequivocally prove that the naturally predominant,
Conformational analysis
The detailed conformational analyses of the M-enantiomers of knipholone (1), knipholone anthrone (2), and the phenylanthracene 3 were carried out at the semiempirical PM337 level within the GAUSSIAN 0360 program package, starting with geometries pre-optimized by the TRIPOS61, 62 force field. The obtained conformers were further optimized by DFT-based methods, viz. RI-BLYP/SVP38, 39, 41 and B3LYP/TZVP,40, 43, 44 within the TURBOMOLE 5.863 suite of programs.
CD calculations
The excited-state energy calculations
General
All reagents used were reagent grade and solvents were distilled prior to usage. Analytical TLC was performed on Merck pre-coated silica gel 60 F254 plates. Compounds on TLC were visualized under long (365 nm) and short (254 nm) UV light. Column chromatography was performed using Merck silica gel (0.063–0.2 mm). Preparative HPLC was achieved on a Chromolith RP18 column (100×10 mm). Stereoanalytical separations were carried out on a chiral stationary phase employing a Chiralcel OD-H HPLC column
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie and by the DFG project Br 699/13-5 (‘Natural Products from African Medicinal Plants’). J.M.-C. acknowledges the Alexander-von-Humboldt Foundation for her Georg-Forster research fellowship. We are also grateful to Prof. S. Grimme, Univ. of Münster, Germany for providing us with the software required for the DFT/MRCI calculations and to Dr. A. Yenesew, Univ. of Nairobi, Kenya for authentic samples of phenylanthraquinones.
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