Synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose

Abstract

In this work, we describe the synthesis of halogenated pyran analogues of ᴅ-talose using a halo-divergent strategy from known 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-ᴅ-mannopyranose. In solution and in the solid-state, all analogues adopt standard ⁴ C ₁-like conformations despite 1,3-diaxial repulsion between the F2 and the C4 halogen. Moreover, the solid-state conformational analysis of halogenated pyrans reveals deviation in the intra-annular torsion angles arising from repulsion between the axial fluorine at C2 and the axial halogen at C4, which increases with the size of the halogen at C4 (F < Cl < Br < I). Crystal packing arrangements of pyran inter-halides show hydrogen bond acceptor and nonbonding interactions for the halogen at C4. Finally, density functional theory (DFT) calculations corroborate the preference of talose analogues to adopt a ⁴ C ₁-like conformation and a natural bonding orbital (NBO) analysis demonstrates the effects of hyperconjugation from C-F antibonding orbitals.

Keywords: organofluorine; pyran inter-halide; solid-state conformation; solution-state conformation.

Figure 1

Synthesis of trihalogenated pyrans: a) Chiron approach to multivicinal inter-halide derived from allopyranoses; b) synthesis and conformational analysis of pyran inter-halide analogues of ᴅ-talose integrating the 2,3-cis, 3,4-cis relationship for the halogens (this work).

Scheme 1

Synthesis of halogenated talopyranose analogues 13–15, and 17 that include a 2,3-cis, 3,4-cis relationship for the halogens.

Figure 2

Direct comparison of ¹⁹F resonances of halogenated talose analogues 12–15 (¹⁹F NMR; 470 MHz, CDCl₃).

Figure 3

X-ray analysis of compound 13–15, 17, and α-ᴅ-talose 18. ORTEP diagram showing 50% thermal ellipsoid probability (except for 18): carbon (gray), oxygen (red), fluorine (green), chlorine (orange), bromine (dark red), iodine (purple), and hydrogen (white).

Figure 4

Packing arrangement of compound compound 15; a) View down the b axis; b) proposed intermolecular interactions involving halogens. ORTEP diagram showing 50% thermal ellipsoid probability: carbon (gray), oxygen (red), fluorine (green), iodine (purple), and hydrogen (white).