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Carbohydrate chemistry　––––––––––
A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins

■Carbohydr. Res. 2014, in press. doi: 1016/j.carres.2014.10.004.■The 3,6-O-(o-xylylene) bridge locks the conformation of glucopyranose to an axial-rich form. Although the conformational lock induces complete β-selectivity in a glycosylation reaction, the leaving group of the glycosyl donor is limited to fluorine. On the other hand, the bridge confers the furanose-preferred property to glucose, which makes synthesis of corresponding pyranosyl derivatives that equip various leaving groups difficult. This problem was solved through direct phenylthio glucosidation of 3,6-O-(o-xylylene)-1,2,4-O-orthoacetylglucose accompanying cleavage of the orthoester moiety. This paper describes the process of establishing direct thiophenylation. This process reduced the synthetic steps for the known glucopyranosyl fluoride and will expand application of conformationally locked glycosyl donors.

Ellagitannin synthesis　––––––––––
A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins

■Nat. Commun. 2014, 5:3478 doi: 10.1038/ncomms4478.■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 chemoselectivity 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.

Carbohydrate chemistry　––––––––––
Synthesis of 3,6-O-(o-Xylylene)glucopyranosyl Fluoride, an Axial-Rich Glycosyl Donor of β-Glycosylations

■J. Org. Chem. 2013, 78, 9482-9487.■Despite the reported complete β-selectivity in glycosylation with 2,4-di-O-benzyl-3,6-O-(o-xylylene)glucopyranosyl fluoride, its preparation has been inefficient. This paper describes an improved route for the donor, including the formation of the 3,6-bridge on 1,2,4-orthoacetylglucose, the preparation of which was also refined, along with a discovered feature that the 3,6-bridged glucose prefers the furanose form. Although this feature made the synthesis of the desired glucopyranosyl donor difficult, application of thermal glycosylation solved the problem. With a modifiable intermediate, the improved availability of the donor would expand the applications.

Ellagitannin synthesis　––––––––––
Total Synthesis of Cercidinin A

■Eur. J. Org. Chem. 2013, 7872-7875.■An ellagitannin, cercidinin A, was synthesized through both intramolecular coupling of gallates on a glucose moiety and double esterification of protected hexahydroxydiphenic acid to a diol. The total synthesis confirmed the revised structure of cercidinin A as 1,2,6-tri-O-galloyl-3,4-(R)-hexahydroxydiphenoyl (HHDP) β-D-glucose. This is the first synthesis of 3,4-HHDP-bridged ellagitannins and was achieved after overcoming two challenges: (1) full galloylation of β-glucose hindered the formation of the 3,4-HHDP group, and (2) the fully benzylated galloyl group, which is a routine component in ellagitannin synthesis, was not always appropriate. The solutions to these problems can be used to form a strategy for the synthesis of complex ellagitannins.

Ellagitannin synthesis　––––––––––
Roxbin B is Cuspinin: Structural Revision and Total Synthesis

■J. Org. Chem. 2013, 78, 5410-5417.■Prompted by the outcome that the synthesized roxbin B was not identical to the natural roxbin B, the structural determination process and spectral data were re-examined, with the finding that roxbin B was very likely to be 1-O-galloyl-2,3-(R);4,6-(S)-bis-O-hexahydroxydiphenoyl-β-D-glucose (cuspinin). Because the (R)-axial chirality is rare in natural products when the hexahydroxydiphenoyl group bridges the 2- and 3-oxygens, the proposed structure of cuspinin was confirmed by the total synthesis, leading to the conclusion that roxbin B is the same as cuspinin.

Ellagitannin synthesis　––––––––––
High-Yield Total Synthesis of (−)-Strictinin through Intramolecular Coupling of Gallates

■J. Org. Chem. 2013, 78, 4319-4328.■This paper describes a total synthesis of (−)-strictinin, an ellagitannin that is 1-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl (HHDP)-β-D-glucose. In the study, total efficiency of the synthesis was improved to produce a 78% overall yield in 13 steps from D-glucose. In the synthesis, formation of the 4,6-(S)-HHDP bridge including the 11-membered bislactone ring was a key step, in which intramolecular aryl–aryl coupling was adopted. The coupling was oxidatively induced by CuCl₂–n-BuNH₂ with perfect control of the axial chirality, and the reaction conditions of this coupling were optimized thoroughly to achieve the quantitative formation of the bridge.

Ellagitannin synthesis　––––––––––
Total Synthesis of the Proposed Structure of Roxbin B; the Nonidentical Outcome

■Org. Lett. 2012, 14, 5928-5931.■A proposed structure of roxbin B was synthesized. For the synthesis, a new synthetic method for the preparation of the hexahydroxydiphenoyl (HHDP) bridge was developed that involved the stepwise esterification of axially chiral HHDP acid anhydride. The synthesized compound was not identical to the natural roxbin B.

Ellagitannin synthesis　––––––––––
Total Synthesis of (+)-Davidiin

■Angew. chem. Int. Ed. 2012, 51, 8026-8029.■Quite strained: The total synthesis of (+)-davidiin, an ellagitannin with more substituents in axial than in equatorial positions, requires a conformational lock of the glucose, induced by steric repulsion between adjacent bulky silyloxy groups. This conformational lock played a pivotal role in 1) the β-selective formation of the glycosyl ester at the anomeric position, 2) the formation of the 1,6-HHDP bridge, and 3) the complete control of axial chirality in the aryl–aryl coupling.

Carbohydrate chemistry　––––––––––
Completely β-Selective Glycosylation Using 3,6-O-(o-Xylylene)-Bridged Axial-Rich Glucosyl Fluoride

■J. Am. Chem. Soc. 2012, 134, 6940-6943.■A completely β-selective glycosylation that does not rely on neighboring group participation is described. The novelty of this work is the design of the glycosyl donor locked into the axial-rich form by the o-xylylene bridge between the 3-O and 6-O of D-glucopyranose. The synthesized 2,4-di-O-benzyl-3,6-O-(o-xylyene)glucopyranosyl fluoride could efficiently react with various alcohols in a SnCl₂–AgB(C₆F₅)₄ catalytic system. The mechanism composed of the glycosylation and isomerization cycles was revealed through comparative experiments using acidic and basic molecular sieves. The achieved perfect stereocontrol is attributed to the synergy of the axial-rich conformation and convergent isomerization caused by HB(C₆F₅)₄ generated in situ.
Addition Correction: J. Am. Chem. Soc. 2013, 135, 9558.

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