No abstract

The preparation of challenging 2-deoxy-2-iodo-β-D-allo precursors of 2-deoxy-β-D-ribo-hexopyranosyl units and other analogues is reported using a robust olefination-cyclization-glycosylation sequence. Here, we particularly focus on tuning the stereoelectronic properties of the alkenyl sulfides intermediates in order to improve the diastereoselectivity of the cyclization step and, hence, the efficiency of the overall transformation. Phosphine oxides with the general formula Ph2P(O)CH2SR (R = t-Bu, Cy, p-MeOPh, 2,6-di-ClPh, and 2,6-di-MePh) were easily synthesized and subsequently used in the olefination reaction with 2,3,5-tri-O-benzyl-D-ribose and -D-arabinose. The corresponding sugar-derived alkenyl sulfides were submitted to a 6-endo [I(+)]-induced cyclization, and the resulting 2-deoxy-2-iodohexopyranosyl-1-thioglycosides were used as glycosyl donors for the stereoselective synthesis of 2-deoxy-2-iodohexopyranosyl glycosides. Among the different S-groups studied, t-Bu derivative was the best performer for the synthesis of cholesteryl 2-deoxy-2-iodomannopyranosides, whereas for the synthesis of 2-deoxy-2-iodoallopyranosides none of the derivatives here studied proved superior to the phenyl analogue previously described. Glycosylation of cholesterol with different d-allo and d-manno derivatives produced 2-deoxy-2-iodoglycosides with stereoselectivities in the same order in each case, reinforcing the involvement of an oxocarbenium ion as the common intermediate of this crucial glycosylation step.

A procedure for the stereoselective synthesis of 2-deoxy-2-iodo-septanosides from pyranoses is reported. The procedure involves two reactions: Wittig-Horner olefination to give alkenyl sulfanyl derivatives, and electrophilic iodine-induced cyclization to give phenyl 2-deoxy-2-iodo-1-thio-septanosides (20) or 2-deoxy-2-iodo-septanosides (26a,b), in this case by subsequent hydrolysis of a phenylsulfanyl group under the reaction conditions. The seven membered ring of septanosides was only formed in moderate to low yields, preferably through a 7-endo cyclization, when an isopropylidene group was present as protecting group. The use of benzyl groups as protecting moieties in the pyranose does not afford the septanoside ring. However, when the reactions conditions were forced using more basic media, the furanoside derivatives 3 were obtained.

A straightforward synthesis of the Met antagonist JLK1360 involving an alkylationcyclocondensation process using aminothiazole 1 and nitrophenacyl bromide 2, reduction of the nitro group, and coupling of the resulting tetracyclic aniline 5 with an appropriate N-acyl alanine derivative, is reported.