Functionalised Monocyclic Five‐ to Seven‐Membered exo‐Glycals by Alkynol Cycloisomerisation of Hydroxy Buta‐1,3‐diynes and 1‐Haloalkynols

Abstract

AbstractBase‐promoted (KOH or MeONa in MeOH, or NaH in THF) cycloisomerisation of partially benzylated, 1‐substituted (R = PhCC, pyridin‐2‐yl, or Br) ald‐1‐ynitols leads to (Z)‐configured five‐, six‐, and seven‐membered exo‐glycals. The reactivity of the ald‐1‐ynitols depends upon their configuration. The ald‐1‐ynitols were derived from 2,3,5‐tri‐O‐benzyl‐D‐ribofuranose 1, and the corresponding, partially O‐benzylated galactose, glucose, and mannose hemiacetals by ethynylation. The hex‐1‐ynitol 2 derived from 1 (61%) was transformed via the 1‐phenylbuta‐1,3‐diyne 3 and the 1‐(pyridin‐2‐yl)acetylene 5 into the five‐membered exo‐glycals 4 and 6 (in 66 and 72% yields, resp., from 2). The analoguous ethynylation of 2,3,4,6‐tetra‐O‐benzyl‐D‐galactose 8 was accompanied by elimination of one benzyloxy (BnO) group to the hept‐3‐en‐1‐ynitol 9 (71%), which was transformed into the non‐5‐ene‐1,3‐diynitol 10 and further into the six‐membered exo‐glycal 11 (50% from 9). Addition of Me3SiCCH to the galactose 8 and to the gluco‐ and manno‐analogues 16 and 24 gave epimeric mixtures of the silylated oct‐1‐ynitols (86% of 12L/12D 45 : 55, 94% of 17L/17D 7 : 3, and 86% of 25L/25D 55 : 45), which were separated by flash chromatography, and individually transformed into the corresponding 1‐bromooct‐1‐ynitols. Upon treatment with NaH in THF, only the minor epimers 13L, 18D, and 26D cyclised readily to form the seven‐membered hydroxy exo‐glycals. They were acetylated to the more stable monoacetates 14L, 23D, and 28D (82–89% overall yield). Under the same conditions, the epimers 13D, 18L, and 26L decomposed within 12 h mostly to polar products. The difference of reactivity was rationalised by analysing the consequences of an intramolecular C(3)OH ⋅⋅⋅ −OC(7) H‐bond of the intermediate alkoxides on the orientation of −OC(7) of 13L, 18D, and 26D and its proximity to the ethynyl group.