A Short Synthesis of (+)-Cyclophellitol

Abstract

[reaction: see text] A new synthesis of (+)-cyclophellitol, a potent beta-glucosidase inhibitor, has been completed in nine steps from D-xylose. The key transformations involve a zinc-mediated fragmentation of benzyl-protected methyl 5-deoxy-5-iodo-xylofuranoside followed by a highly diastereoselective indium-mediated coupling with ethyl 4-bromocrotonate. Subsequent ring-closing olefin metathesis, ester reduction, olefin epoxidation, and deprotection then afford the natural product. This constitutes the shortest synthesis of (+)-cyclophellitol reported to date.

Synthesis and Evaluation of Hydroxymethylaminocyclitols as Glycosidase Inhibitors

“…The spectroscopic data obtained for cyclohexene (+)-7 were in agreement with those described, 26,27 but the magnitude and sign of the optical rotation found for this compound ([α] D 25 +120.9 (c 1.1, MeOH)) were different from those reported in the literature ([α] D −13.4 (c 1.1, MeOH)). 26 The stereochemistry of (+)-7 was unambiguously confirmed by the synthesis of compounds (+)-16, 21 (−)-16, 21 (+)-17, 28 (+)-18, 28 and (+)-19 26,28 (see Scheme 2), and comparison of their spectroscopic and analytical data that matched those reported in the literature for the same compounds obtained by different synthetic sequences.…”

“…NMR data are in accordance with literature values 26,28. (1R,2R,3S,4R,5R,6S)-5-Hydroxymethyl-7-oxa-bicyclo[4 1…”

“…26 The stereochemistry of (+)-7 was unambiguously confirmed by the synthesis of compounds (+)-16, 21 (−)-16, 21 (+)-17, 28 (+)-18, 28 and (+)-19 26,28 (see Scheme 2), and comparison of their spectroscopic and analytical data that matched those reported in the literature for the same compounds obtained by different synthetic sequences. These results confirmed the structure and enantiomeric purity of intermediate (+)- 7. With the key intermediate (+)-7 in hand, cyclophellitol and epi-cyclophellitol benzylated derivatives (+)-5 and (+)-6 were obtained as shown in Scheme 3.…”

An overview of key routes for the transformation of sugars into carbasugars and related compounds

“…80 Madsen et al used this protocol in 2005 for the synthesis of (þ)-cyclophelitol (Scheme 35). 81 Thus, a Zn-promoted reductive elimination of iododerivative 161 provided compound 162, with the terminal carbon-carbon double bond. Consequently, an indium-mediated allylation at the reducing end of the carbohydrate, produced diene 164, which after reaction with a 2 nd generation Grubbs' catalyst, allowed the construction of the cyclohexene ring of compound 165.…”

Synthesis of Calystegine A3 from Glucose by the Use of Ring‐Closing Metathesis

“…The resulting diene C is subsequently cyclized by olefin metathesis to generate the seven-membered carbon skeleton in the calystegines. Recently, we have also used this sequence for preparation of other carbocyclic natural products from carbohydrates including cyclophellitol, [12] 7-deoxypancratistatin [13] and gabosine A and N. [14] Scheme 2. Calystegine retrosynthesis.…”