Partially Hydroxylated 2, 5‐Disubstituted Bis‐Tetrahydrofurans from Carbohydrates

The diverse bioactivities of annonaceous acetogenins have recently attracted increasing interest. Many of these natural products contain one or more 2,5‐disubstituted tetrahydrofuran rings as a core unit; these are important for the bioactivity, since it is believed that these anchor the compounds to the surface of the membrane. Therefore, the synthesis of functionalized bis‐tetrahydrofurans is an important task and we have developed a synthetic pathway to all four diastereomeric, partially hydroxylated bis‐tetrahydrofurans, that is, 3,6:7,10‐dianhydro‐2,8,9‐trideoxy‐ L ‐ erythro ‐ D ‐ ido ‐undecitol ( 1 ), 3,6:7,10‐dianhydro‐2,8,9‐trideoxy‐ D ‐ threo ‐ D ‐ ido ‐undecitol ( 2 ), 3,6:7,10‐dianhydro‐2,8,9‐trideoxy‐ L ‐ threo ‐ D ‐ ido ‐undecitol ( 3 ), and 3,6:7,10‐dianhydro‐2,8,9‐trideoxy‐ D ‐ erythro ‐ D ‐ ido ‐undecitol ( 4 ) starting from D ‐glucose. The reaction of the aldose with Meldrum's acid led to the C‐glycosidic 3,6‐anhydro‐1,4‐lactone 6 , which was converted to the aldehyde building block 2,5‐anhydro‐3,4,7‐tri‐ O ‐benzyl‐6‐deoxy‐ aldehydo ‐ D ‐ ido ‐heptose ( 11 ). Chain elongation of 11 with the Grignard reagent derived from 1‐bromo‐3‐butene gave the diastereomers 3,6‐anhydro‐1,4,5‐tri‐ O ‐benzyl‐2,8,9,10,11‐pentadeoxy‐ L ‐ glycero ‐ D ‐ ido ‐undec‐10‐enitol ( 12 ) and 3,6‐anhydro‐1,4,5‐tri‐ O ‐benzyl‐2,8,9,10,11‐pentadeoxy‐ D ‐ glycero ‐ D ‐ ido ‐undec‐10‐enitol ( 13 ). The relative threo configuration of the major product 12 was confirmed by X‐ray structure analysis. Epoxidation and subsequent cyclization afforded the cis and trans diastereomers 19 and 20 , respectively, in a 1:1 ratio. Subsequent cleavage of the protecting groups and separation of the isomers furnished the target compounds in good overall yields.