Cyclodextrins (CDs) are cyclic oligomers of α-1,4-d-glucopyranoside and are known mainly as hexamers to octamers. The central cavities of CDs can retain small molecules, enabling diverse applications. The smallest members, CD3 and CD4, have ring sizes too small to permit the most stable conformations of glucopyranose and have not been accessible synthetically. In this study, we present methods to chemically synthesize both CD3 and CD4. The main factor in the successful synthesis is the creation of a glucopyranose ring conformationally counterbalanced between equatorial- and axial-rich forms. This suppleness is imparted by a bridge between O-3 and O-6 of glucose, which enables the generation of desirable, albeit deformed, conformers when synthesizing the cyclic trimer and tetramer.

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.