A Unified Strategy for the Synthesis of Highly Oxygenated Diaryl Ethers
Total Page：16
File Type：pdf, Size：1020Kb
ARTICLE Received 20 Sep 2013 | Accepted 20 Feb 2014 | Published 24 Mar 2014 DOI: 10.1038/ncomms4478 A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins Tsukasa Hirokane1, Yasuaki Hirata1, Takayuki Ishimoto1, Kentaro Nishii1 & Hidetoshi Yamada1 Ellagitannins are a family of polyphenols containing more than 1,000 natural products. Nearly 40% of these compounds contain a highly oxygenated diaryl ether that is one of the most critical elements to their structural diversity. Here, we report a unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins. The strategy involves oxa-Michael addition of phenols to an orthoquinone building block, with subsequent elimination and reductive aromatization. The design of the building block—a halogenated orthoquinone monoketal of gallal—reduces the usual instability of orthoquinone and controls addition/elimination. Reductive aromatization is achieved with perfect chemo- selectivity in the presence of other reducible functional groups. This strategy enables the synthesis of different diaryl ethers. The first total synthesis of a natural ellagitannin bearing a diaryl ethers is performed to demonstrate that the strategy increases the number of synthetically available ellagitannins. 1 School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan. Correspondence and requests for materials should be addressed to H.Y. (email: [email protected]). NATURE COMMUNICATIONS | 5:3478 | DOI: 10.1038/ncomms4478 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4478 he structural diversity of natural products often derives hexahydroxydiphenoyl (HHDP) groups (Fig. 1); however, the from the oligomerization of monomers that are specific to simple combination of these basic constituents is insufficient to Teach family of compounds. Snyder and co-workers have generate structural diversity. Despite Snyder’s classification of divided a large number of oligomeric natural products into two ellagitannins as serially produced oligomers1, the reality is not categories1: serially and non-serially produced oligomers. In that simple. The HHDP groups on the glucose cores do not serially produced oligomers, monomers unite regiospecifically appear at fixed positions. Furthermore, disorders of the routine with definite bonding patterns; examples include DNA patterns in uniting the component parts frequently appear in (Supplementary Note) and proteins. In contrast, in non-serially higher ellagitannins. In addition, the family includes numerous produced cases, oligomerization apparently unites monomers in a component parts, including overoxidation8,9, modifications of the random manner, with no fixed position. This division can also be HHDP group10, conjugation with other natural constituents11–13 applied to polyphenols, although their structural diversity is and production of the highly oxygenated diaryl ethers. Among sufficiently large to classify them into several structural families2. these factors conferring structural diversity, the production of Polyphenols have potential applications in medicine and health highly oxygenated diaryl ethers, C–O digallates, is the most enhancement. However, their structure-activity/affinity relation- significant. C–O digallates are structures that contain dimerized ships are not well understood due to the difficulty in obtaining a galloyl group(s) connected by a C–O bond, such as the complete collection of systematically related analogues from dehydrodigalloyl (DHDG), tergalloyl and valoneoyl groups. nature. This difficulty might be resolved through chemical These motifs allow oligomerization of basic ellagitannins, which synthesis if all compounds of a polyphenol family could be expands diversity14. Nearly 40% of characterized natural synthesized. The methodologies required to achieve this exhaus- ellagitannins contain C–O digallates. tive synthesis would differ from those used for a one-off total For the exhaustive synthesis of ellagitannins, one of the most synthesis of a single compound. For the exhaustive synthesis of fundamental tasks is the formation of the chiral HHDP group, serially produced oligomers, the procurement of all component a C–C digallate, which has been achieved through several parts and the development of effective methods for assembling procedures15–18. The second and most impactful task would be the parts are the most important tasks. For exhaustive synthesis of the establishment of a methodology for synthesizing C–O non-serially produced oligomers, the discovery of latent systems digallates because their structure is the primary cause of that exhibit structural diversity and the development of structural diversity in this family. Therefore, establishment of methodologies to address multipoint random oligomerizations this methodology should increase the number of synthetically are required. Attempts to satisfy these requirements for both available ellagitannins in an innovative manner. However, few serially and non-serially produced polyphenols have already reports of the synthesis of C–O digallates have appeared in the begun, as evidenced by the work of Ohmori et al.3 and Snyder literature. One of the rare examples is Feldman’s synthesis of et al.4, who have developed methods for synthesizing higher DHDG derivative 3 (Fig. 2a)19–21. This synthesis is a four-step catechin oligomers and programmable resveratrol oligomers, sequence that starts from orthoquinone 4 through (1) the respectively. self-hetero Diels-Alder cycloaddition of 4 to produce a mixture The family of ellagitannins, which consists of bioactivity- and of regioisomers 5a and 5b, (2) b-elimination, as indicated by structure-rich polyphenols5,6, has been found to contain more the curved arrows, (3) reduction of the orthoquinone, and than 1,000 natural products to date7. The most basic ellagitannins (4) benzylation accompanying the Smiles rearrangement22, which consist of a glucose core with esterified galloyl and converges the mixture into 3. Utilizing the DHDG derivative of 3, HO HO OH Hexahydroxydiphenoyl (HHDP) group HO S HO HO OH HO OH = GG Dehydrodigalloyl (DHDG) group O O O OH HO O O O G HO O O O O S OG O O O Galloyl group GO O G O HO OG Coriariin A (1) OH = G HO HO OH OH OH OH Valoneoyl group HO OH HO OH O OH HO HO O HO O O OH HO HO O OH S S O S HO HO O HO O O O O O O OH O O O G G O O O O S HO HO OH Tergalloyl group O O O O HO GO OG O Platycaryanin C OG O OH Rugosin A (2) G S G Figure 1 | Natural ellagitannins possessing highly oxygenated diaryl ethers. The parts indicated with bold lines are the highly oxygenated diaryl ethers, C–O digallates. Each common name is also indicated. The C–O digallates allow oligomerization of basic ellagitannins, which is a major factor in conferring structural diversity. However, the methods for synthesizing C–O digallates have been quite limited to date. 2 NATURE COMMUNICATIONS | 5:3478 | DOI: 10.1038/ncomms4478 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4478 ARTICLE Previous work BnO OBn BnO O BnO O OBn O O BnO2C H BnO2C H BnO C 2 O O O OO OO BnO (2) NaOAc (3) Na S O (1) B(OAc)3 2 2 4 OBn OBn + BnO BnO (4) K2CO3, BnBr CO Bn CO Bn BnO C 2 2 2 BnO2C 45a5b 3 This work BnO OH OBn O OBn O R1O R1O OR1 OR1 BnO BnO Oxa-Michael addition/ Oxidation elimination BnO X BnO X + HO Aryl BnO O OR1 2 2 6 O 7 O 12 O R O2C CO2R H H H R3OOR3 R1O R1O OR1 OR1 HO R1O OR1 OR1 Protecting groups HO HO OR1 R1O OR1 H, alkyl, or sugar derivative(s) 2 2 2 2 2 R O2C R O2CCO2R R O2CCO2R 8: R3 = PhCH 10 11 9: R3 = Bn (for valoneoyl group) (for tergalloyl group) (for DHDG group) The C–O digallate-containing motifs BnO BnO R1O R1O OR1 OR1 HO HO HO HO OH OH Reductive aromatization BnO O OR1 HO O OH 2 2 4 4 4 13 O R O2CCO2R 14 R O2CRO2CCO2R H H or cabohydrate(s) Figure 2 | Outlines of previous and present methods for the synthesis of C–O digallates. (a) Feldman’s synthesis of the DHDG group, which was formerly the sole method for synthesizing a C–O digallate, the DHDG group, as applied to the total synthesis of ellagitannins. (b) The unified strategy of C–O digallates (this work). Oxa-Michael addition of phenols 8–11 to key building block 7 and subsequent elimination formed the C–O bond of the digallates. The design of building block 7 was critical. The monoketal and halogen X stabilized the structure. Halogen X made the oxa-Michael addition irreversible because leaving group X caused smooth elimination after the oxa-Michael addition. In addition, X limited the electrophilic position in oxa- Michael addition to the b-carbon of the aldehyde but not to that of the ketone. The reductive aromatization of 12 required selective reduction of the orthoquinone monoketal in the presence of an aldehyde, an ester in the ‘Aryl’ part, and a benzylidene acetal when 8 was employed. The (S)-axial chiralities of 10 and 11 are drawn tentatively; thus, usage of the corresponding (R)-isomers and the racemates is also possible. Ac, acetyl; Bn, benzyl; Ph, phenyl. they achieved the total synthesis of coriariin A (1)20, which is the tergalloyl and valoneoyl groups, which is a significant step toward sole ellagitannin containing the C–O digallate synthesized to date. the exhaustive synthesis of ellagitannins. To demonstrate the However, the application of this method to HHDP-containing effectiveness of this strategy, we performed the first total synthesis C–O digallates is quite difficult because the first step, the C–O of the valoneoyl-group-containing ellagitannin rugosin A (2). bond-forming reaction, relies on the self-dimerization of 4. Alternatively, Ullmann coupling can be used to prepare C–O digallates.