Evidence and knowledge of the medical value of Hypericum perforatum L.1 in ancient times are contained in the writings of Galen, Dioscorides, Pliny, and Hippocrates. In the middle of the 20th century, Osborn published a review  in which he described the occurrence of an antibiotic substance in H. perforatum. In the former USSR, many publications addressed the biological activity of extracts from H. perforatum     .
In 1975, Bystrov et al.  described the structure of hyperforin, which is the principal pharmacological active substance (PAS) in H. perforatum. Further publications on the same topic followed until the end of 1978      . There were some conflicting findings and inconsistencies  -  . Thus, Brondz et al., and Brondz  -  , at the University of Oslo, Oslo, Norway, decided to challenge the relative and absolute stereochemistry of hyperforin as described in  ,  ,  , and which describe the content and biological activity of H. perforatum and the stereochemistry of the main PAS, hyperforin. This paper is the third in a series of papers, “Super Antibiotics”  ,  . It should offer some clarity on the longstanding differences in the presentation of the relative and absolute stereochemistry of hyperforin.
1.1. Known Facts Prior to the Publication of Bystrov et al. Structures Reported 1975-1978
As mentioned in the Introduction, the pharmacological usefulness of H. perforatum has been described by Galen, Dioscorides, Pliny, and Hippocrates. The usefulness of H. perforatum in the Middle Ages has also been reported. More recently, in the middle of the 20th century, antibacterial properties of the drug were considered      . In 1975, Bystrov et al. reported that the PAS in H. perforatum is hyperforin, and they further described hyperforin’s structure and the stereochemistry (Figure 1)  .
Figure 1. The structure of hyperforin reproduced from  (The author of this paper has added numbers in red and the IUPAC name of the substance for better understanding).
1.2. Challenging the Relative and Absolute Stereochemistry as Published by Bystrov et al.
In the very early days of scientific chemistry, several important criteria were established for elucidation of the chemistry of unknown molecules: atom composition (qualitative and quantitative), molecular weight (MW), structure, and stereochemistry. As ultimate evidence for the correct elucidation of the chemistry and stereochemistry of an unknown molecule was the synthesis of a substance that complied with the nature of the molecule under investigation. A correct hypothesis about the structure was accepted also based on X-ray crystallography. However, the last word in confirming correctness was left to the de novo synthesis of the unknown molecule and comparison of its nature with the molecule under investigation. Only if all parameters of the unknown molecule and the synthetically prepared analog are in compliance, and the identity of the two molecules is established, can the structure of the unknown molecule, be claimed as known. This is especially important in the case of isomeric molecules and molecules with chirality. Partial degradation of a molecule that is under investigation and spectral comparison with known molecules can lead to errors because the degradation can affect the chirality of the resulting substance in relation to the chirality of the molecule under investigation. Here, it is important to note that R and S chirality has no direct reflection on or relation with the + or − signs: “… the (+)/(−) system has no fixed relationship with the (R)/(S) system”  . Hence, claiming as evidence that a molecule is + or − does not tell us enough about the “(R)/(S) system” state of chiral centers.
According to Bystrov et al.  : “… the antibiotic, Hyperforin, is therefore the 6S, 7R configuration” and, furthermore, “Therefore the trans configuration has been assigned to the hydroxyl (and consequently to the angular C-1 and C-5 side chain) with respect to the 6-methyl group, as shown in formula I”  . In the present paper, formula I is reproduced as Figure 1. It is later stated in  that “Independent proof of the absolute configuration I was furnished by the CD spectrum of III which, like that of 5S-spiro-[4,4]-nonane-1,6-dione”. Considering the statements in  , the chirality of centers 5, 6, and 7 should be S, S, and R, respectively. However, following the formula I, reproduced as Figure 1, the chirality is 5R, 6R, and 7S as it should be when following IUPAC nomenclature. In their following publications about the stereochemistry of antibiotic hyperforin  and  , the authors of  changed the numbering of the C atoms in the bicyclic system, and consequently the stereochemistry and the chirality (see Figure 2).
In  , the authors have not presented the chirality of the molecule; however, in  , the absolute stereochemistry was already presented based on a new numbering of the C atoms earlier published in  (see Figure 3).
Following the logic of the numbering presented by Bystrov et al. in  , the name and chirality should beas follows: (1R,5S,7S,8R)-2-hydroxy-1-isobuty- ryl-8-methyl-1,3,7-tris(3-methylbut-2-en-1-yl)-8-(4-methylpent-3-en-1-yl)bicyclo[3.3.1]non-3-ene-4,9-dione. However, in text of  , the chirality is given for
Figure 2. The structure of hyperforin reproduced from  (The author of this paper has added numbers in red and the IUPAC name of the substance for better understanding).
Figure 3. The structure and stereochemistry of hyperforin reproduced from  (The author of this paper has added numbers in red for better understanding).
C-7 and C-8 as R and S, respectively. Concerning the chirality of C-5, there exists many conflicting explanations. It is nonetheless possible to extract the conclusion that the authors designated it as 5S-spiro[4,4]-nonane-1,6-dione, which means that C-5 has chirality S. However, following the IUPAC rules for this structure presented in  , the numbering and chirality of this structure should be as follows: (1S,5R,6R,7S)-4-hydroxy-5-isobutyryl-6-methyl-1,3,7-tris(3-me-thylbut- 2-en-1-yl)-6-(4-methylpent-3-en-1-yl)bicyclo[3.3.1]non-3-ene-2,9-dione.
Figure 4. Explanation for construction of names and numbering of C atoms for bicyclic compounds following IUPAC rules. Compounds 8 and 9 are the same molecules; however, compounds 11 and 12 differ because they are isomers. Compounds 13 and 14 are also isomers.
Upon inspection of  with  , and  , it is evident that the figures that should support the stereochemistry of hyperforin differ (see Figure 6). Numbering of the chiral carbons also differs. It is noted that in  and  , the same stereochemical expression for hyperforin is presented. However, the authors state in  that it has a configuration of 6S and 7R, whereas they state in  that it has a configuration of 7R and 8S. In both papers, the description of the configuration of C-1 and C-5 is rather unclear; the conclusions are only made based on figures presented in  and  . However, numbering of the carbons
Figure 5. Explanation for construction of names and numbering of C atoms for bicyclic compounds following IUPAC rules. Compound pairs 15 and 16, 17 and 18, and 19 and 20 are differing isomer pairs; they are isomers in each of the pairs.
in the bicyclic system is confusing, and the C-1 and C-5 positions were exchanged. For this reason, it could be expected that the chirality was also ch- anged. However, it was overall not possible to comment confidently on the chirality of these carbons because the numbering of the carbon atoms compromised the relative chemistry of this substance  .
Figure 6. The structures of hyperforin are reproduced from  ,  , and  (The author of this paper added numbers in red and the names of the substances in black for better understanding). The numbering of the C atoms, published in  , contradicts the IUPAC rules of numbering C atoms. The IUPAC name in red is constructed from the figure presented in  .
In 1978, the same team published further information  , in which an even stranger numbering of carbon atoms in a bicyclic system was used (see Figure 7). In addition, a team of Chinese authors presented a new numbering of carbon atoms in a bicyclic system in another publication on hyperforin (Figure 7)  . It appears that weakness in the knowledge of chemical nomenclature is common in some scientific communities.
The same team of authors was responsible for    and  . In  , the relative and absolute stereochemistry of hyperforin contradicts the relative and absolute stereochemistry of hyperforin in  and  . In    and  , the IUPAC rules for the numbering of C atoms and the description of chirality were not followed. As long as   and  continue to be cited and    or  are not withdrawn or corrected, it is absurd to state that Bystrov et al. defined the relative and absolute stereochemistry of hyperforin. The citing of these publications as the basis for the relative and absolute stereochemistry of
Figure 7. Numbering of C-atoms in the bicyclic system of hyperforin: (top) reproduced from  and (bottom) reproduced from  .
hyperforin is incorrect. The value of the other publications by Bystrov et al. describing the determination of the relative and absolute stereochemistry of hyperforin is very limited, and this literature cannot be recommended as a basis for scientific work. Attempts to present Bystrov et al. as the discoverer of the relative and absolute stereochemistry of hyperforin in Wikipedia and in other publications at the expense of other authors are not ethical, and do not give prestige to the former USSR Academy of Sciences or to Wikipedia. This issue reflects the fact that Wikipedia is missing an Editor-in-Chief and qualified editorial staff.
1Hyperforin, Revision of the Relative and Absolute Stereochemistry.