Naturally occurring dibenzofurans. Part 1. A synthesis of cannabifuran

Abstract

The synthesis of dibenzofurans from diphenyl ethers by non-phenolic oxidative coupling, U.V. irradiation, and by reaction with palladium(ll) acetate has been investigated. 9-lsopropyl-6-methyl-3-pentyldibenzofuran-l-ol (cannabifuran) (35), a minor cannabis constituent, has been synthesized by annulation of 4-isopropyl-7-methylbenzofuran-2-carbaldehyde (28) by Wittig reaction with 2-carboxy-1 -methoxycarbonylethyltriphenylphosphorane and ring closure and functional-group modification of the resultant (€)-4-(4-isopropyl-7-methyIbenzofuran-2-yl)-3-methoxycarbonylbut-3-enoic acid (29).DIBENZOFURANS are comparatively rare natural products: nine are known to occur in lichens,132 and five have been isolated from higher plant^.^-^ We are interested in developing syntheses of some of these compounds since there is a dearth of good general synthetic methods available for dibenzofurans. The classical met hods of synthesis involve Pschorr cyclization of 2-phenoxyanilines,6 or cyclization of 2,2'-dihydroxybiphenyls or their methyl ethers under acidic condition^.^,^ Owing to the difficulty of preparation of many of these intermediates these methods are not easily adapted to the synthesis of the natural products. Some success has been achieved by Diels-Alder annulation of 2-vinylbenzofurans and by rearrangement of 3-(2-methylbenzofuran-3-yl)prop-l ,%dienones but these methods are of limited use.l0Non-phenolic oxidative coupling of suitably substituted diphenyl ethers appeared to be an attractive method for the synthesis of dibenzofurans. Consequently we prepared the diphenyl ethers (1) and (3) by conventional methods and attempted to convert them into dibenzofurans by treating them with vanadium trifluoride oxide l1 or thallium( 111) trifluoroacet ate l2 under a variety of conditions. In no case was any dibenzofuran detected. The diphenyl ether (4) was recovered unchanged from an attempted reaction with vanadium trifluoride oxide under conditions whereby the methyl phosphinate analogue undergoes smooth cyclization to the dibenzophosphole.13~tThe preparation of a number of alkyldibenzofurans by U.V. irradiation of diphenyl ethers in the presence of iodine has been reported.l* We investigated this method using the diphenyl ethers (1) and (3). In the first example poor yields of the isomeric dibenzofurans (5) and (7) were isolated. Their structures were deduced from their lH n.m.r. spectra. Similarly the diphenyl ether (3) gave the three possible products (9), (ll), and (12) in poor yield. Again their structures were deduced from their lH n.m.r. spectra. An attempt was made to convert the diphenyl ether (2), which contains an ester function as a blocking group, into the dibenzofuran (8). The only product which was isolated from this irradiation was the xanthone (13).It has been reported that diphenyl ether is converted t We thank Dr. A. Sierakowski for these experimental details.into dibenzofuran on treatment with palladium(I1) acetate in boiling acetic acid.15 We investigated this reaction for a number of diphenyl ethers but the ...

Diverse Secondary Metabolites from the Marine-Derived Fungus Dichotomomyces cejpii F31-1

“…According to a comparison of the spectroscopic data of compounds 6 – 14 and 17 – 28 ( Supplementary Figures S41–S58 and S75–S98 ) with literature reports, their chemical structures were identified as dichotone A ( 6 ) [ 13 ], diorcinol ( 7 ) [ 14 ], 3- O -methyldiorcinol ( 8 ) [ 14 ], 5,5′-oxybis(1-methoxy-3-methylbenzene) ( 9 ) [ 15 ], dibutyl phthalate ( 10 ) [ 16 ], butyl (2-ethylhexyl) phthalate ( 11 ) [ 17 ], (2a R , 5 R , 5a R , 8 S , 8a S )-2,2,5,8-tetramethyldecahydro-2H-naphtho[1,8-bc]furan-5-ol ( 12 ) [ 18 ], aspewentin A ( 13 ) [ 19 ], JBIR-03 ( 14 ) [ 20 ], dichotocejpin A ( 17 ) [ 21 ], didehydrobisdethiobis (methylthio) gliotoxin ( 18 ) [ 12 ], bisdethiobis (methylthio) gliotoxin ( 19 ) [ 10 ], 6-acetylbis (methylthio) gliotoxin ( 20 ) [ 12 ], haematocin ( 21 ) [ 10 ], pityriacitrin ( 22 ) [ 22 ], stellarine A ( 23 ) [ 23 ], perlolyrine ( 24 ) [ 24 ], fiscalin C ( 25 ) [ 25 ], epi-fiscalin C ( 26 ) [ 25 ], indolyl-3-acetic acid methyl ester ( 27 ) [ 26 ], and anthranilic acid ( 28 ) [ 27 ].…”

Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation‐Inhibitory Activity

“…Ac omparison of the 1 Ha nd 13 CNMR spectra and optical rotations of synthetic 3 with those of natural 3 ([a] D = À2258)i ndicatedt hat the natural product was (3S,4R)-3.B ecause 3 is the biosynthetic precursor of 1, [24] the absolute stereochemistry of 1 was determined to be (3S,4R,3"R,4"S)-1.A lthough [a] D of natural 2 is unknown, (3S,4R)-2 is probably the natural form of 2.Acomparison of the calculated and observedc irculard ichroism spectra of (+ +)-(3R,4S)-2 (ent-SMA1) indicated that the M atropisomer of (À)-(3S,4R)-2 (natural SMA1) was predominant in solution,a sd iscussed previously ( Figure 1C and Figure S6 in the Supporting Information). [10] The protein SUMOylation-inhibitory activities of all stereoisomers of 2 and 3 were evaluated in vitro by using RanGAP1a s as ubstrate ( Figure S7 in the Supporting Information).…”

“…[11] LiAlH 4 reductiono ft he ester gave naphthylalcohol 8,a nd then treatment with iodine in the presence of NMM selectively afforded o-iodophenol 5a. [12] For 3,M OM-protected 5b was prepared from 6b in as imilar manner to that of 5a.W ittig reaction of 6b with half ester ylide 9 [13] afforded 10,w hich was convertedi nto naphthalene 11 by treatment with Ac 2 Oa nd NaOAc. Transformation of 11 into 5b wass imilarly carried out in three steps.…”

“…For 3 , MOM‐protected 5 b was prepared from 6 b in a similar manner to that of 5 a . Wittig reaction of 6 b with half ester ylide 9 afforded 10 , which was converted into naphthalene 11 by treatment with Ac 2 O and NaOAc. Transformation of 11 into 5 b was similarly carried out in three steps.…”

Antibiotics from Extremophilic Micromycetes

“…Instead of terpenoids, eighteen aromatic compounds were isolated in this case, including six new compounds, trichoderolides A-F (462-467), of which only compound (463) showed weak cytotoxicity. The known cytotoxic aromatic compounds, i.e., 3,3'-dimethoxy-5,5'-dimethyldiphenyl ether (468) [304], 3-O-methyldiorcinol (469) [305], and isolated from a natural source for the first time 4'-[(2-hydroxy-1,3-propanyl)bis[oxy-4,1-phenylene(1-methylethylidene)]]bisphenol (470) [306] were also obtained.…”