2.1. Bioinspired approach to natural arylindanes and aryltetralins
The carbon atoms that make up the skeleton of stilbenoids, lignans and other polyphenols come from different biosynthetic pathways (chapter 1.1). However, starting with the key desymmetrizing oxidative coupling and further downstream, their chemistry follows common reactivity patterns that originate from the highly electron rich nature of the aromatic rings. We hypothesize, that some of these reactivity patterns can be reproduced in vitro by linking them to known synthetic transformations and thereby exploiting them in total synthesis of cyclolignans, FISs and other natural phenols.
Pattern 1) SET oxidation of phenols to form highly delocalized phenoxyl radicals, followed by radical coupling to form 8-8’ lignol dimers and other similar β-linked (hetero)dimers. Coupling of free radicals, although possible to arrange in principle (see chapter 1.4.3), is an uncommon reaction type in vitro due to the high reactivity of free radicals. They can only form in low concentration which makes their collision in free solution a statistically unlikely event. However, radical addition to double bonds, especially intramolecular, doesn’t suffer from this entropic limitation. Therefore, we propose radical cyclisation in 5-exo-trig, 6-endo-trig and 6-exo-trig modes as a suitable substitute for the free radical coupling in vitro.
Pattern 2) Nucleophilic capture of formal benzylic carbenium ions or quinone methides by intramolecular Friedel-Crafts (FCA) reaction and oxa-Michael addition, leading to indanes, tetrahydro- and dihydrofurans. Friedel Crafts alkylation, despite being an important industrial process, is often unsuited for stereoselective synthesis, because of the high reactivity of carbenium ions and their tendency to rearrange. We propose to replace it with a reaction type more suited for exerting control - the conjugate addition to electron poor double bonds, which is often used for fragment union in the synthesis of complex molecules.129,149 Conjugate addition occurs in a different kinetic regime than FCA (figure11),150a-c which combines weakly nucleophilic aromates with extremely electrophilic and short-lived carbenium ions. Instead, conjugate addition combines formally anionic stable reagents like organomagnesium and organolithium compounds with weakly or moderately electrophilic unsaturated esters. Figure 11 correlates nucleophile and electrophile strength in common reactions, FCA and the Michael addition are located in the opposing corners on the main diagonal, which represents the zone of controllable reaction rate.150a-c
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Figure 11. Nucleophilicity/electrophilicity correlation in common rection types.151d
Pattern 3) Oxidation of aromatic rings and of the neighbouring benzylic positions. Benzylic positions next to electron rich aromatic rings undergo easy oxidation, due to the increased stabilisation of benzylic carbocations. This should facilitate the formation of such cations by SET oxidation of stabilised benzylic radicals, formed by previous radical cyclisation (pattern 1). If such radicals are long-lived enough they could undergo a second SET oxidation leading to cationic lactonisation.
Pattern 4) Heterolytic lability of benzylic C-O bonds. The increased stability of benzylic carbocations next to electron-rich aromatic rings makes ether links at these positions sensitive to acid-catalysed opening.152,153 While this may decrease the stability of the natural products or synthetic intermediates, it may also open an opportunity to correct the configuration on such benzylic centres, if the thermodynamic isomer is desired.
Based on these principles, we propose a general retrosynthesis, applicable to FISs (chapter 1.5) and 2,7′-cyclolignans like podophyllotoxin (11) (chapter 1.3). Although not included in this thesis, the strategy should also be applicable to the synthesis of arylindane stilbene dimers (chapter 1.4.3) and furofuran lignans like pinoresinol (13) (chapter 1.3.1).
35 Scheme 30. General retrosynthetic analysis for FISs (top) and (–)-podophyllotoxin (11) (bottom), based on inherent reactivity of natural lignols and stilbenes. Nucleophilic atoms marked by (–), electrophilic atoms marked by (+).
Using the so-called alternation rule, also known as the concept of consonant and dissonant rings,154 each atom of the targets can be assigned natural polarity, annotated in scheme 30 by (+) and (–) signs. The inherent dissonance of five-membered rings in FISs (92) can be solved by two consecutive SET oxidation steps, that adjust the oxidation state of atoms C-7 and C-8’ from formal anion in 93 to a radical in 94. The bond between atoms C-2 and C-7’ in 92 can be formed by conjugate addition, the second bond by addition of radical at C-8’ to C-7 followed by SET oxidation and the third bond between C-8 and the oxygen atom on C-9’ can be formed via lactonization of benzylic carbocation at C-8.
Similarly, in 11, the dissonant relationship between nucleophilic atoms C-8 and C-8’ can be solved by to consecutive SET oxidations with an “in-between” radical cyclisation. Therefore, the C- 2/C-7’ bond is formed by conjugate addition of 95 to tert-butyl cinnamate, followed by radical addition of C-8’ to C-8. The C-O bonds at C-7 and C-9 can be either carried from the building blocks or formed by a formal oxidation of radical by TEMPO trapping (at C-9 of 95b) or SET (at C-7 of 95a). Such bioinspired disconnection respects the natural polarity and reactivity of each atom, and therefore leads to the most rapid decrease in molecular complexity. All starting synthons are derivatives of the natural polyphenol building blocks - stilbenes, cinnamic acids, and monolignols.
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2.2. Dirigent protein hypothesis and optical purity of natural FIS
As discussed in chapter 1.5, at least two isolated natural FISs were optically active, namely lehmbachol D (II) 102 and 11-deoxykompasinol A (IV).110 In all other cases, in which authors repot specific rotation, the natural products were either racemic, these were: gnetifolin F (I),98,99 kompasinol A (III, maackoline) 103,106,113 and 13-hydroxykompasinol A (IV) 106 or the value of specific rotation was very low [α]D< 5, these were: kompasinol A,109 kompasinol P 109 and Cararosin A.111
This naturally raises the question regarding the role of enzymes in their biosynthesis. The racemic compounds most likely result from oxidative radical coupling in free solution, either inside or outside of cells. Abiotic formation during drying of plant material or extraction cannot be ruled out,114 as was demonstrated by the formation of racemic gnetifolin F (I) and lehmbachol D (II) by simple oxidation of precursor phenols using Ag2O in acetone 97 (chapter 1.4.3). However, the optically active FISs must be formed by a separate pathway enzymatically, or other source of chirality must exist, for example they may be enantiomerically enriched post-synthetically through preferential degradation of one enantiomer.
Proving the enzymatic origin of some FISs would be of high interest in biology, because to our knowledge, there are no known enzymes capable of catalysing stereoselective cross-coupling of stilbenes with monolignols. The closest analogue of such process is the unique stereoselective dimerization of coniferyl alcohol assisted by dirigent proteins (DIR). Dirigent domains were found also in other extracellular proteins involved in lignification and plant stress response, therefore these proteins would be potential candidates in the search for the chiral factors behind the biosynthesis of optically active FISs.
However, in order to verify that there reported minute quantities of natural optically active FISs were indeed chemically and optically pure, their specific rotation values and ECD spectra should be compared with independently prepared samples of known composition. Total syntheses of selected members of FID family should give access to pure samples of either enantiomer, so that their physicochemical properties can be determined. This would provide additional evidence in favour or against their possible enzymatic origin.
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