Seven-Step Stereodivergent Total Syntheses of Punicafolin and Macaranganin.

The first total syntheses of punicafolin (1) and macaranganin (2) were achieved in seven steps, respectively, from commercial α-d-glucose. The characteristic features of the synthesis are (1) sequential site-selective introduction of the adequate galloyl groups into unprotected d-glucose by a catalyst-controlled manner and (2) stereodivergent construction of the 3,6-HHDP bridge by oxidative phenol coupling of a common intermediate via a ring-flipping process of the glucose core. Because no protective groups were used for glucose throughout the process, extremely short-step total syntheses of natural glycosides 1 and 2 (MW 938) were performed.

Solvent-Dependent Mechanism and Stereochemistry of Mitsunobu Glycosylation with Unprotected Pyranoses.

An SN2 mechanism was proposed for highly stereoselective glycosylation of benzoic acid with unprotected α-d-glucose under Mitsunobu conditions in dioxane, while an SN1 mechanism was indicated for nonstereoselective glycosylation in DMF. The SN2-type stereoselective Mitsunobu glycosylation is generally applicable to various unprotected pyranoses as glycosyl donors in combination with a wide range of acidic glycosyl acceptors such as carboxylic acids, phenols, and imides, retaining its high stereoselectivity (33 examples). Glycosylation of a carboxylic acid with unprotected α-d-mannose proceeded also in an SN2 manner to directly afford a usually less accessible 1,2-cis-mannoside. One- or two-step total syntheses of five simple natural glycosides were performed using the glycosylation strategy presented here using unprotected α-d-glucose.

Site-selective redox isomerizations of furanosides using a combined arylboronic acid/photoredox catalyst system.

In the presence of an arylboronic acid and a hydrogen atom transfer mediator under photoredox conditions, furanoside derivatives undergo site-selective redox isomerizations to 2-keto-3-deoxyfuranosides. Experimental evidence and computational modeling suggest that the transformation takes place by abstraction of the hydrogen atom from the 2-position of the furanoside-derived arylboronic ester, followed by C3-O bond cleavage via spin-center shift. This mechanism is reminiscent of the currently accepted pathway for the formation of 3'-ketodeoxynucleotides by ribonucleotide reductase enzymes.

Optimization of the alkyl side chain length of fluorine-18-labeled 7α-alkyl-fluoroestradiol.

INTRODUCTION: Several lines of evidence suggest that 7α-substituted estradiol derivatives bind to the estrogen receptor (ER). In line with this hypothesis, we designed and synthesized (18)F-labeled 7α-fluoroalkylestradiol (Cn-7α-[(18)F]FES) derivatives as molecular probes for visualizing ERs. Previously, we successfully synthesized 7α-(3-[(18)F]fluoropropyl)estradiol (C3-7α-[(18)F]FES) and showed promising results for quantification of ER density in vivo, although extensive metabolism was observed in rodents. Therefore, optimization of the alkyl side chain length is needed to obtain suitable radioligands based on Cn-7α-substituted estradiol pharmacophores. METHODS: We synthesized fluoromethyl (23; C1-7α-[(18)F]FES) to fluorohexyl (26; C6-7α-[(18)F]FES) derivatives, except fluoropropyl (C3-7α-[(18)F]FES) and fluoropentyl derivatives (C5-7α-[(18)F]FES), which have been previously synthesized. In vitro binding to the α-subtype (ERα) isoform of ERs and in vivo biodistribution studies in mature female mice were carried out. RESULTS: The in vitro IC50 value of Cn-7α-FES tended to gradually decrease depending on the alkyl side chain length. C1-7α-[(18)F]FES (23) showed the highest uptake in ER-rich tissues such as the uterus. Uterus uptake also gradually decreased depending on the alkyl side chain length. As a result, in vivo uterus uptake reflected the in vitro ERα affinity of each compound. Bone uptake, which indicates de-fluorination, was marked in 7α-(2-[(18)F]fluoroethyl)estradiol (C2-7α-[(18)F]FES) (24) and 7α-(4-[(18)F]fluorobutyl)estradiol (C4-7α-[(18)F]FES) (25) derivatives. However, C1-7α-[(18)F]FES (23) and C6-7α-[(18)F]FES (26) showed limited uptake in bone. As a result, in vivo bone uptake (de-fluorination) showed a bell-shaped pattern, depending on the alkyl side chain length. C1-7α-[(18)F]FES (23) showed the same levels of uptake in uterus and bone compared with those of 16α-[(18)F]fluoro-17ß-estradiol. CONCLUSIONS: The optimal alkyl side chain length of (18)F-labeled 7α-fluoroalkylestradiol was the shortest: C1-7α-[(18)F]FES. Our results indicate that shorter chain lengths within the 4-Å ligand binding cavities of ERα are suitable for 7α-fluoroalkylestradiol derivatives.