Structural Studies of Norditerpenoid Alkaloids: Conformation Analysis in Crystal and in Solution States

Abstract

Conformational analyses are presented of several pharmacologically important norditerpenoid alkaloids (NDAs), in crystal and in solution states. Crystal data of 8 NDAs (4 free bases and 4 salts) were obtained, in which crassicauline A, aconitine HCl, and methyllycaconitine HClO 4 are reported for the first time. 1D/2D NMR spectroscopies of 7 NDAs (5 free bases and 2 salts) were recorded comprehensively. Crystal conformations of NDAs are described with a revised cyclohexane ring nomenclature. The A/E-rings of NDA-free bases exist in twisted-chair/twisted-chair conformations, leading to examples of the 1 H NMR effect of steric compression shown in the A-ring. The A/E-rings of NDA salts adopt boat/chair crystal conformations, as does the protonated synthetic [3.3.1]azabicycle in its crystal lattice. However, in aqueous solutions at physiological pH, this protonated analogue adopts a true chair/true chair conformation where the NDA salts retain their twisted boat/twisted chair conformations.

Norditerpenoid alkaloids from Aconitum and Delphinium: structural relevance in medicine, toxicology, and metabolism

“…100 Indeed, crystal data of 8 NDA (4 free bases and 4 salts) were obtained, in which crassicauline A (7), aconitine (2) HCl, and methyllycaconitine (11) HClO 4 have been reported for the rst time together with the comprehensive 1D/2D NMR spectroscopies of 7 NDA. 100 The A/E-rings of NDA-free bases exist in twisted-chair/ twisted-chair conformations, with examples of the 1 H NMR effect of steric compression shown in the A-ring. The A/E-rings of NDA salts adopt boat/chair crystal conformations, as do the protonated synthetic [3.3.1]azabicycle.…”

“…99 Moving from bicycles to hexacycles, conformational analyses have very recently been reported of several pharmacologically important NDA in crystal and in solution states. 100 Indeed, crystal data of 8 NDA (4 free bases and 4 salts) were obtained, in which crassicauline A (7), aconitine (2) HCl, and methyllycaconitine (11) HClO 4 have been reported for the rst time together with the comprehensive 1D/2D NMR spectroscopies of 7 NDA. 100 The A/E-rings of NDA-free bases exist in twisted-chair/ twisted-chair conformations, with examples of the 1 H NMR effect of steric compression shown in the A-ring.…”

“…However, in aqueous solutions at physiological pH, this protonated analogue adopts a true chair/true chair conformation where the NDA salts retain their twisted boat/twisted chair. 100 15 N NMR analysis showed that the 15 N chemical shi of 1-OMe NDA increases (electron density decreases) upon protonation 6 due to H-bonding between 1-OMe and N-H + which stabilize the twisted boat-twisted chair conformation of the AE bicycle. 100 Such an increase in the 15 N chemical shi has been observed in the 1-aOH NDA free bases where ring A adopts a twisted boat conformation due to intramolecular Hbonding.…”

“…100 15 N NMR analysis showed that the 15 N chemical shi of 1-OMe NDA increases (electron density decreases) upon protonation 6 due to H-bonding between 1-OMe and N-H + which stabilize the twisted boat-twisted chair conformation of the AE bicycle. 100 Such an increase in the 15 N chemical shi has been observed in the 1-aOH NDA free bases where ring A adopts a twisted boat conformation due to intramolecular Hbonding. 5,6 These results prove that the analysis of the Nelectron density of piperidine containing alkaloids is useful for solution conformational analysis.…”

C18-diterpenoid alkaloids in tribe Delphineae (Ranunculaceae): phytochemistry, chemotaxonomy, and bioactivities

“…1B), sepaconitine (46), 30 N-deacetyllappaconitine (41), 31 and ranaconitine (102), 32 the C 18 -DAs possess stable conformations for most of the rings except for rings A and D, as they only have one or two exible atoms in the skeleta, which is identical to that of C 19 -DAs. 33,34 Generally, rings C and F in C 18 -DAs exist in envelope form, rings E and G adopt chair form, and ring B is xed in a boat conformation. The conformation of ring A in C 18 -DAs (as well as in C 19 -DAs) is mainly affected by the substituents at C-1 and the protonated N. These C 18 -DAs with OMe-1 or OAc-1 possess a chair conformation of ring A, while C 18 -DAs with OH-1 substituent have a ring A in boat conformation, which is stabilized by an intramolecular hydrogen bond between OH-1 and the lone electron pair at N (Fig.…”