Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 5210−5224
Prenylcoumarins in One or Two Steps by a 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 Potsdam-Golm, Germany S Supporting Information *
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 a 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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epoxide opening (e.g., muralatin E),16 dihydroxylation followed by conjugation with other compounds (e.g., integerrimelin),17 dimerization to bicoumarins,18 or allylic oxidation (which is occasionally followed by cyclization to γ-butyrolactones, e.g., microminutin C,19 or furan substituents).20 Thus, prenylated coumarins are not only bioactive secondary metabolites themselves but are also important intermediates in the biosynthesis and synthesis of other natural products. Although the original prenyl group has been modified (mostly by oxidative transformations) in these compounds, they are still considered “simple prenylated coumarins” in the coumarin taxonomy (Figure 1).2 The chemical synthesis of C-prenylated coumarins and other phenylpropanoids is often accomplished via thermally induced Claisen rearrangements of either prenyl- or 1,1-dimethylallyl 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 C8prenylated 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
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, has 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 UV light4 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 © 2018 American Chemical Society
Received: March 15, 2018 Published: April 11, 2018 5210
DOI: 10.1021/acs.joc.8b00667 J. Org. Chem. 2018, 83, 5210−5224
Article
The Journal of Organic Chemistry
Table 1. Pd-Catalyzed 1,1-Dimethylallylation of Phenols 1
entry a
1 2 3b 4c 5 6 7 8 9 10 11 12 13 14 15 16
Figure 1. Representative simple prenylated coumarins.
1
R1
R2
R3
R4
3
yield (%)
1a 1a 1a 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1n
OMOM OMOM OMOM OMOM OMOM H H H OMe H OMe H OMe OMOM OMe OMe
H H H H H H H OMe H OMe H OMe OMe OMe OMe H
OMOM OMOM OMOM OMOM OMOM H H H H H H H H H OMe OMe
H H H H C6H5 H C6H5 H C6H5 C6H5 CH3 CH3 H H H H
3a 3a 3a 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3n
26 30
