Structure of 9-deoxo-9a-<i>N</i>-[<i>N</i>'-(4-pyridyl)-carbamoyl]-9a-aza-9a-homoerythromycin A and conformational analysis of analogous 9a-aza 15-membered azalides in the solid state

C 43 H 74 N 4 O 13 .C 3 H 6 O, M r = 913, triclinic, P1, a = 10.3796(5), b = 14.5809(5), c = 17.1521(9)A, α = 105.225(3), β = 96.140(5), γ = 90.248(3)°, V = 2489.0 (2)A 3 , Z = 2 (two independent molecules in the asymmetric unit), D x = 1.218g cm -3 , λ(CuKα) = 1.54184A, T = 106(3)K, F(000) = 992, μ(CuKα) = 7.0 cm -1 , R = 0.057 for 8724 observed unique reflections with I>2σ(I). Conformational analysis is based on X-ray structure determinations of 9-deoxo-9a-N-[N'-(4-pyridyl)-carbamoyl]-9a-aza-9a-homoerythromycin A (1) and its N-isopropyl-carbamoyl congener (2) and data for 9a-aza 15-membered azalides retrieved from the Cambridge Structural Database (Version 5.07). The analysis reveals that the aglycone ring conformation has been influenced by the presence or absence of glyco conjugation at C3 and C5 sites in azalide derivatives. However, more drastic influence is related to the appearance of intramolecular hydrogen bonds. Compounds with 9a N atoms in sp 3 hybridization exhibit N-H...O contacts which are absent in compounds with 9a N atoms in sp 2 hybridization ; they reveal O-H...O intramolecular hydrogen bonds. The 15-membered azalides studied are in 'folded-out' conformation in the solid state. The α-L-cladinose sugar moiety is in 1 C 4 conformation, while the β-D-desosamine adopts a 4 C 1 conformation. The absolute configurations at the aglycone chiral centres are as follows : C2R, C3S, C4S, C5R, C6R, C8R, C1OR, C11R, C12S and C13R.