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To prenylcoumarins in one or two steps by microwave promoted tandem Claisen rearrangement / Wittig olefination / cyclization sequence Christiane Schultze, and Bernd Schmidt J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00667 • Publication Date (Web): 11 Apr 2018 Downloaded from http://pubs.acs.org on April 11, 2018
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The Journal of Organic Chemistry
To prenylcoumarins in one or two steps by microwave promoted tandem Claisen rearrangement / Wittig olefination / cyclization sequence
Christiane Schultze and Bernd Schmidt* Universitaet Potsdam, Institut fuer Chemie, Karl-Liebknecht-Straße 24-25, D-14476 PotsdamGolm, Germany e-mail:
[email protected] Table of contents graphic:
Abstract: The one-pot synthesis of 8-prenylcoumarins from 1,1-dimethylallylated salicylaldehydes and the stabilized ylide [(ethoxycarbonyl)methylene]triphenylphosphorane under microwave conditions was found to have a limited scope. The sequence suffers from a difficult and sometimes low-yielding synthesis of the precursors and from a competing deprenylation upon microwave irradiation. This side reaction occurs in particular with electron rich arenes with two or more alkoxy groups at adjacent positions, a prominent substitution pattern in naturally occurring 8-prenylcoumarins. Both limitations of this one-step sequence were overcome by a two step synthesis consisting of a microwave promoted tandem allyl ether Claisen-rearrangement / Wittig-olefination and a subsequent olefin cross metathesis with 2-methyl-2-butene. The cross metathesis step proceeds with high selectivity and yields exclusively the desired prenyl- rather than the alternative crotyl substituent. Several naturally occurring 8-prenylcoumarins that were previously inaccessible have been synthesized in good overall yields along this route.
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Introduction Substituted coumarins are ubiquitious secondary metabolites that have been isolated from more than 800 different species, mostly plants but also some microorganisms.1,2 From 2012 to 2015 the isolation of more than 400 coumarins, including new compounds and re-isolations of known compounds from new sources, have been reported.2 With these figures coumarins remain among the most intensely investigated classes of secondary metabolites in phytochemistry. Their pharmacological and physiological activities are too diverse to be comprehensively reviewed: they range from growth regulation3 and protection against UVlight4 in the metabolite producing plants to anti-inflammatory,5 estrogenic,6 diuretic7 or acetylcholinesterase
inhibiting8
activities
in
mammals.
Coumarins
and
other
phenylpropanoids often undergo a biosynthetic prenylation with dimethylallyldiphosphate in the presence of prenyltransferases.9-11 In many cases the presence of one or more prenyl side chains at the aromatic core enhances the bioactivity of secondary metabolites dramatically.12 This was for example observed for the cytotoxicities against glioma cells of the flavonoids apigenin (not prenylated and inactive) and licoflavone C (structurally identical to apigenin, but prenylated at position 8 and active at micromolar concentrations).13 One reason for the beneficial effect of lipophilic prenyl groups on the bioactivity might be a faster permeation through cell membranes.14 Prenylation is, however, not always the terminal step in the biosynthesis of secondary plant metabolites: many naturally occurring coumarins bear alkyl substituents at the aromatic core which are derived from the prenyl group by hydrogenation, epoxidation (e. g. meranzin)15 and subsequent epoxide opening (e. g. muralatin E),16 dihydroxylation followed by conjugation with other compounds (e. g. integerrimelin),17 dimerization to bicoumarins18 or allylic oxidation (which is occasionally followed by cyclization to γ-butyrolactones, e. g. micromunitin C,19 or furan substituents).20 Thus prenylated coumarins are not only bioactive secondary metabolites themselves, they are also important intermediates in the biosynthesis and synthesis of other natural products. Although ACS Paragon Plus Environment
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the original prenyl group has been modified (mostly by oxidative transformations) in these compounds, they are still considered as “simple prenylated coumarins” in the coumarin taxonomy (Figure 1).2
Figure 1. Representative simple prenylated coumarins.
The chemical synthesis of C-prenylated coumarins and other phenylpropanoids is often accomplished via thermally induced Claisen rearrangements of either prenyl- or 1,1dimethylallyl ethers of phenols.21 While 1,1-dimethylallyl ethers undergo a rearrangement to ortho-prenylated phenols, prenyl ethers react to afford para-prenylated phenols through successive Claisen and Cope-rearrangements.22 Many syntheses of C6- or C8-prenylated coumarins start from precursors with a preformed coumarin skeleton and an unprotected hydroxy group, such as umbelliferone, which is first 1,1-dimethylpropargylated, then partially hydrogenated to the 1,1-dimethylallylether and finally heated to induce a Claisen rearrangement to the prenylated coumarin.21 To access a wider scope of substitution patterns it is often advantageous to start from other aromatic compounds and construct the coumarin scaffold during the synthesis. One strategy, pioneered by the groups of Harwood and Mali, ACS Paragon Plus Environment
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uses O-prenylated cinnamates or salicylic aldehydes, respectively. The cinnamates undergo, upon heating, a Claisen rearrangement, E/Z-isomerization and cyclization reaction to coumarins.23 With salicylic aldehydes as starting materials this tandem sequence is extended by a Wittig-olefination step, which is achieved by addition of a stable ethoxycarbonyl-ylide to the reaction mixture.24-27 In the course of a research program on microwave promoted tandem reactions we also investigated this Wittig-olefination / Claisen-rearrangement / cyclization sequence. We found, for example, that osthole (see figure 1) can be conveniently synthesized from 4-methoxy salicyl aldehyde in just two steps by a Pd-catalyzed 1,1-dimethylallylation and the above mentioned microwave promoted tandem sequence.28 In continuation of this project we planned to extend the synthesis to other prenylated coumarins, but met some unforeseen difficulties. These problems and our solutions are discussed in this contribution.
Results and discussion Scope and limitations of the one-step route. When we applied the conditions for the successful Pd-catalyzed 1,1-dimethylallylation29 of the osthole precursor28 4-methoxy salicyl aldehyde with allylcarbonate 2 to the double MOM-protected salicyl aldehyde 1a, the desired product 3a was obtained in only 26% yield (Table 1, entry 1). Raising the reaction temperature from 0 °C to ambient temperature improved the yield only marginally to 30% (entry 2), whereas heating to 40 °C (entry 3) or increasing the amount of catalyst to 5 mol % led to a complete failure of the dimethylallylation (entry 4). A comparable yield of 28% was obtained for the 2,4-dimethoxysalicyl aldehyde 1n (entry 16). Interestingly, for the similarly substituted benzophenone 1b the desired product could not even be detected in trace amounts with this method (entry 5). Complete failure was also observed when we applied the Pdcatalyzed 1,1-dimethylallylation to aldehyde 1c and benzophenone 1d, without any electron donating substituents at the aromatic core (entries 6 and 7). Several other alkoxy salicyl aldehydes, acetophenones and benzophenones 1e to 1l were converted to the expected 1,1ACS Paragon Plus Environment
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dimethylallyl ethers 3e to 3l in yields varying from 40% to 93% (entries 8 to 15), with the exception of acetophenone 1h (entry 11) which reproducibly and unexplainably reacted only in trace amounts to 3h (Table 1). Table 1. Pd-catalyzed 1,1-dimethylallylation of phenols 1.
entry
1
R1
R2
R3
R4
3
Yield (%)
1a
1a
OMOM
H
OMOM
H
3a
26
2
1a
OMOM
H
OMOM
H
3a
30
3b
1a
OMOM
H
OMOM
H
3a
