Total Synthesis of Marchantinquinone

Introduction Bisbibenzylic systems such as Marchantins, Perrottetins, Riccardins are found only in Hepatica and have been shown to display a wide range of biological activities [1,2]. Marchantinquinone (1), from extracts of Reboulia hemisphaerica, formerly described as Mannia subpilosa, [3,4] was the first bisbibenzylic diether possessing a quinone structure isolated from Bryophytes. Herein its first synthesis is reported. Experimental Relevant steps of the synthesis are shown in the following retrosynthetic scheme:

In 1991, Wei and Wu 4,5 reported the isolation and structural determination of Marchantinquinone (1), from extracts of Reboulia hemisphaerica, formerly described as Mannia subpilosa. This compound, possessing a p-quinone structure embedded in an 18-membered macrocycle, was the first quinonic bisbibenzylic diether isolated from Bryophytes. In addition to its novel structure, Marchantinquinone is endowed with interesting biological activity, 5-7 namely antioxidant 7 and antiplatelet 5 activity. As part of our work on the synthesis and biological evaluation of Bryophyte constituents, [8][9][10][11] we became interested in the preparation of 1, whose first total synthesis is reported herein.
The starting point of the synthesis was diphenyl ether 2, whose structure is common to a number of Perrottetin pre-cursors. 9 Selective reduction of the aldehyde functionality in 2 and further treatment with SOCl 2 afforded the benzylic chloride 4, which was then converted into the phosphonium salt 5. This salt can be coupled to the ring B precursor through an olefination reaction, Scheme 1.
Considering the reactivity of the quinone system present in ring B, our strategy called for the introduction of this functionality at the last steps of the synthetic sequence. Consequently, a protected p-hydroquinone 7 obtained in 55% yield from 3,6-dimethoxy-2-hydroxybenzaldehyde (6) 12 was used as the precursor of ring B.
Wittig olefination between aldehyde 7 and the corresponding ylide from 5, performed under Boden conditions, 13 gave stilbene 8 as a single stereoisomer. In this sense, NMR data showed the presence of only one alkene and the measured coupling constants around the double bond (16.7 Hz) are in agreement with an E geometry. This stereochemical outcome is unexpected, since there is no precedent for the predominance of the E-isomer neither in the work of Boden nor in our previous work. [8][9][10][11] In particular, for this reaction the ratio of E/Z isomers is heavily dependent on the solvent, ranging from 70/30 (E/Z) in CH 2 Cl 2 to exclusively the E-isomer in toluene.
The stilbene was hydrogenated using 5% Pd/C as catalyst to afford the corresponding bibenzylphenyl ether 9, with concomitant deprotection of the benzyl ether of ring B. The resulting free phenolic group of 9 acted as the nucleophile in a S N Ar reaction 14 on an activated benzoate derivative to give a diether possessing the four required phenyl groups of Marchantinquinone. Several electrophiles were tried for this reaction, including 5-fluoro-2,4-dinitrotoluene, 5-fluoro-2-nitrotoluene, methyl 5-fluoro-2,4-dinotrobenzoate and methyl 5-fluoro-2-nitrobenzoate. After extensive experimentation, the best electrophilic partner found was methyl 5-fluoro-2-nitrobenzoate (10), 15 which, when reacted with 9 in presence of 1.7 equivalents of K 2 CO 3 , afforded diether 11 through a clean reaction in high yield (Scheme 2). The nitro group was then removed to give 13 via a high yielding reduction-deamination sequence.
Final macrocyclization was accomplished as shown in Scheme 3. Reduction of the diester of 13 and further halogenation led to dichloride 15, which was subjected to intramolecular coupling using an active [Ni]º complex 16a-e under high dilution conditions. This methodology had been previously applied by Iyoda et al. to the synthesis of bibenzyls. 16b,c The macrocyclization reaction was tried according to protocols by Kende et al., 16e which were modi-fied to improve the final yield. Interestingly, the dichloride always gave the macrocycle 16, although with different yields, whereas the dibromide afforded only trace amounts of the cyclized product under the reported conditions. Details of the optimization are shown in the Table. Using the optimized conditions (entry 3), namely equimolar amounts of [Ni] 2+ complex and Zn in presence of two equivalents of triphenylphosphine and one equivalent of potassium iodide, in DMF at room temperature, the reac-tion proceeded uneventfully giving 16 in 60% yield as the sole isolated product. Deprotection of the methyl ethers using BBr 3 afforded an unstable p-hydroquinone that was partially oxidized in air to quinone 1. Alternatively, the crude p-hydroquinone 17 was oxidized using silver oxide to give 1 in 64% overall yield. Melting point and spectral data for 1 were identical to those reported for natural Marchantinquinone. 4,5 In summary, we have described the preparation of Marchantinquinone 1 with an overall yield of 5.1% in 13 steps