Stefan Berger, Dieter Sicker

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/331462070 Chemical Substances Index Chapter · March 2019 DOI: 10.1002/9783527806508.oth1 CITATIONS READS 0 1,488 4 authors, including: Dieter Sicker Hans Siehl University of Leipzig Ulm University 241 PUBLICATIONS 1,997 CITATIONS 187 PUBLICATIONS 1,836 CITATIONS SEE PROFILE SEE PROFILE Stefan Berger University of Leipzig 357 PUBLICATIONS 7,860 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Syntheses with Microbiologically Produced Oxocarboxylic Acids View project Relaxation View project All content following this page was uploaded by Stefan Berger on 06 June 2019. The user has requested enhancement of the downloaded file. Dieter Sicker, Klaus-Peter Zeller, Hans-Ullrich Siehl, Stefan Berger Natural Products Isolation, Structure Elucidation, History Supporting Information This file contains all supporting information including answers on the questions of all 20 sections. Chapter 1. Alkaloids 3 1.1 Pseudopelletierine from the root-bark of the pomegranate tree 3 1.2 Colchicine from the seeds of the autumn crocus 17 1.3 Capsaicin from Kenyan "African Bird’s Eye Chilies" 21 Chapter 2. Coloured Compounds 33 2.1 Thymoquinone from the oil of the seeds of black caraway 33 2.2 Berberine chloride from the bark of the common barberry 39 2.3 Carminic acid from dried cochineal 45 2.4 Safflomin A from flowers of the safflower 47 2.5 Chlorophyll a from deep frozen spinach leaves 57 Chapter 3. Carbohydrates and glycosides 74 3.1 Raffinose from the seeds of blue lupins 74 3.2 Fraxin from the shredded bark of the ash tree 83 3.3 Stevioside from the dried leaves of Stevia rebaudiana 93 Chapter 4. Terpenoids 109 4.1 Linalool from Brazilian rosewood oil 109 4.2 Camphor from camphor tree oil 120 4.3 Cantharidin from Spanish fly Lytta vesicatoria 124 4.4 Artemisinin from the dried leaves of the annual mugwort 126 4.5 Diosgenin from an extract of the roots of Mexican yams 136 4.6 Friedelin from cork from the bark of the cork-oak 143 4.7 Boswellic acid from frankincense, the resin of the Arabian olibanum tree 152 Chapter 5. Aromatic Compounds 158 5.1 Sinensetin from cold-pressed orange oil 158 5.2 Rosmarinic acid from the dried leaves of lemon balm 160 Supporting information Pseudopelletierine Chapter 1 1.1 Pseudopelletierine Fig. S1.1-1 Structure of pseudopelletierine Fig. 1.1-2 Excerpt from the title page of the "Universal-Lexicon der practischen Medizin und Chirurgie" (Universal Lexicon of Medicine and Surgery), 5th Volume, H. Frank'sche Verlagsexpedi- tion, Leipzig 1838; for the quotation in text see page 13 of the main book 3 3 Supporting information Pseudopelletierine Piccinini's Degradation of Pseudopelletierine to Suberic Acid Fig. S1.1-3 Piccinini's degradation of pseudopelletierine to suberic acid [10] Synthesis of Pseudopelletierine Fig. S1.1-4 Robinson-Schöpf synthesis of pseudopelletierine by a double Man- nich reaction 4 5 Supporting information Pseudopelletierine Biosynthesis of Pelletierine, N-Methylpelletierine and Pseudopelletierine Fig. S1.1-5 Biosynthesis of pelletierine, N-methylpelletierine and pseudopelletierine. The biosynthesis of the Punica granatum alkaloids [21] shows several sim- ilarities to the laboratory synthesis. It begins with the amino acid lysine, which is initially cyclized to Δ1-piperideine. The iminium ion derived from this adds subsequently to the enolate of the activated acetonedicarboxyl- ic acid (Fig. S1.1-5). Parallel to the decarboxylation, the precursor of the N-methylpelletierine can be oxidized to a further iminium ion, which via intramolecular enolate addition and decarboxylation forms pseudopelletierine. Willstätter's Synthesis of Cyclooctatetraene Willstätter's degradation of pseudopelletierine to COT begins with the re- duction of the carbonyl group by the Bouveault-Blanc method and subse- quent acid catalysed dehydration. The second double bond is introduced by Hofmann elimination with opening of the N-bridge. With this step the first difficulty occurs. On heating the quaternary ammonium hydroxide under normal pressure, instead of the desired 5-dimethylamino-1,3-cyclooctadiene the isomeric 1-dimethylamino compound is formed. The reaction only proceeds as desired, when the reaction is carried out under vacuum. A further Hofmann elimination leads to 1,3,5-cyclooctatriene. Its reaction with Br2 gives the dibromo-adduct. Without having a proof, Willstätter assumed, that a 1,6-addition occurs. The debromination of the dibromo-compound gives a product C8H8 that, however, on catalytic hydrogenation takes up less than 8 H-atoms. The detour over an exchange of both bromine atoms by dimethylamino substituents and further Hofmann eliminations proved to be successful (Fig. 1.1-16). 4 5 Supporting information Pseudopelletierine 1. How is 1-dimethylamino-1,3-cyclooctadiene formed under "normal" conditions by the first Hofmann exhaustive methylation? The formation of this product during the distillation under atmospheric pressure can be considered to be a further reaction, i.e. a thermally allowed superfacial 1,5-H-shift, of the formed primary product. Under mild conditions the desired primary product can be obtained. 2. Willstätter's assumption, the 1,6-addition of Br2, was later confirmed by Cope [1]. The adduct is identical to an independently synthesised 1,6-dibromo-2,4-cyclooctadiene. After the elucidation of the structure, the question of the stereochemistry remains. We can only speculate. If the addition of bromine takes place via a bromonium intermediate by transfer of Br+ to the ends of the conjugated triene, then the two bromine atoms must be in a trans-arrangement. 3. Why does the double dehydrobromination of 1,6-dibromo-2,4-cyclooctadiene with quinolone as a base give a C8H8-product that has less than four easily hydrogenated double bonds instead of COT? Will- stätter assumed that the high temperature required for the dehydrobromination produced a mixture of bicyclo[4.2.0]octa-2,4,7-triene and tricyclo[4.2.0.02.5]octa-3,7-diene. Today we know, that the bicyclic compound is contained to 0.01% in COT in a valence tautomeric equilibrium. Independently synthesised bicyclo[4.2.0]octa-2,4,7-triene isomerizes at 0°C with a half-life of 14 minutes to COT [S2]. A further ring closure to the tricyclic diene is improbable, because of ring strain. Therefore, both C8H8-isomers can be eliminated as products of the base catalysed dehydrobromination. Willstätter mentioned, that the smell of the hydrocarbon was reminiscent of benzene and reported the boiling point at 737 torr to be 142.8 – 143.8°C and the specific gravity to be 0.912 g/mL. These properties agree with those of styrene (bp = 146°C, d = 0.909 g/mL), its smell is strongly reminiscent of benzene. The formation of styrene from 1,6-dibromocycloocta-2,4-diene and COT from 1,6-diaminocycloocta-2,4-diene must depend upon different mecha- nisms of the β-elimination. 6 7 Supporting information Pseudopelletierine The properties of the Br-substituents in the allylic positions as good leaving groups point to an E1-type mechanism for the two dehydrobromination steps. In the second elimination step, a cation is formed that corresponds to the protonated COT and therefore exists in the form of the homotropylium ion. To explain the formation of styrene, we suggest, that the homotropylium ion is in equilibrium with a low concentration of the bicyclo[4.2.0]-octa-2,4-di- en-7-yl cation, which can be deprotonated to styrene, as shown. Hofmann eliminations are typical E2-eliminations with a certain E1cB-char- acter, i.e. carbenium ions are avoided. Therefore, the stepwise cleavage of two trimethylamine molecules occurs as follows: For the sake of simplification we have up to now usually shown cyclooctatetraene as a planar eight-membered ring. In reality, the spacial arrangement of COT is tub-shaped [S3], with the conse- quence, that neighbouring double bonds build a dihedral angle of 56°. Because of the poor overlapping of neighbouring p-orbitals, we are dealing with fixed alternating double and single bonds. If cyclooctatetraene were planar and the π-system could therefore be delocalized, then according to the Hückel Rule COT would be antiaromatic and not aromatic (the number of electrons is 4n and not 4n+2). However, it is neither, because the antiaromaticity is avoided by the non-planar structure and it exists as a polyolefine (annulene). 6 7 Supporting information Pseudopelletierine Apart from the already mentioned valence isomerism to bicyclo[4.2.0]-octa-2,4,7-triene COT demonstrates two further dynamic processes that can be most easily explained by planar D8h or respectively D4h structures as transition states. This refers to the shift of the double bond and the ring inversion [S4]. Because of the only slight overlapping of for example the p-orbitals of C-1 and C-8, the shifts of the double bonds cannot be obtained by a simple relocation of the π-bonds. However, it could succeed via a flattening to a delocalized π-system (TS(bs)). With this approach, the ring inversion re- quires the formation of a transition state TS(ri) with localized π-bonds. Both processes can be observed independently of each other, e.g. with dynamic NMR spectroscopy of cyclooctatetraene with a suitable substitution. Be- cause of the antiaromatic transition state, the activation energy of the shift of the double bond is higher. Pelletierine, "Isopelletierine", N-Methylpelletierine Our article focuses on pseudopelletierine, the main alkaloid of the pomegranate tree. However, pelletierine and N-methylpelletierine were respon- sible for the pharmaceutical and medical interest. The history of these two alkaloids with their apparently simple structures is a textbook example of how difficult and time-consuming structure elucidation could be a century ago.

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