A comparative study on the dynamics of epimeric 1-hydroxymethylquinolizidines: I. Conformational analysis of monomers and spectroscopic data for solid state, liquid state, and dilute solutions

Abstract

This paper is dedicated to Dr. 0. E. (Ted) Edwards K. KULIIGSKA and M. WIEWI~ROWSKI. Can. J. Chem. 65, 205 (1987).A systematic comparative study of the conformational dynamics of lupinine and epilupinine, two 1-hydroxymethyl quinolizidine epimers, as a function of phase transition and of their protonation is presented. Lupinine and epilupinine have a trans-quinolizidine configuration and they differ only in the position of the CH20H group. The axial position of this group allows the formation of an intramolecular hydrogen bond OH.. . N in lupinine, in contrast to epilupinine in which this group is in the equatorial position. lntrinsic conformational equilibria for both epimers have been defined. Despite the significant difference in the population of the preferred rotamers of lupinine and epilupinine, both epimers adopt very similar crystal structures, but in all other states and forms, e.g., pure liquids, solutions in inert and polar solvents, and protonated salts, they behave in drastically different ways. On prCsente une Ctude comparative systkmatique des dynamiques conformationnelles de la lupinine et de 1'Cpilupinine (deux Cpimtres de I'hydroxymCthyl-1 quinolizidine) en fonction de la transition de phase ainsi que de leur protonation. La lupinine et 1'Cpilupinine possiident une configuration trans au niveau de la quinolizidine et leur seule diffkrence rCside dans la position du groupement CH20H. Le fait que ce groupement soit en position axiale dans la lupinine lui fournit I'occasion de former des liaisons hydrogtnes intramolCculaires OH.. . N qui ne se foment pas dans le cas de 1'Cpilupinine dans laquelle le groupement se trouve en position Cquatoriale. On a dCfini les Cquilibres conformationnels intrinstques des deux Cpimtres. MalgrC l'existence de differences importantes dans les populations des rotameres prkfCrks dans la lupinine et dans llCpilupinine, chacun des Cpimtres existe dans des structures cristallines assez semblables; toutefois, dans tous les autres Ctats et formes (liquides purs, solutions dans des solvants inertes etpolaires et sous formes de sels protonCs), il se comportent triis diffkremment.[Traduit par la revue] Introduction Two 1-hydroxymethyl quinolizidine epimers, lupinine and epilupinine (Fig. l), have a trans-quinolizidine configuration (trans Q) (1). Rotation of the exocyclic hydroxymethylene group makes three staggered conformers of lupinine and epilupinine (Fig. 2) possible. The axial position of the CH20H group creates good stereochemical conditions for the formation

N-Inversion-Associated Conformational Dynamics Is Unusually Rapid in Morphine Alkaloids

“…H-bonding with participation of the nitrogen lone pair increases NIR barriers in amines 9h. Our calculations (this work) show that in the lowest energy conformer of naloxone 5 the 14-positioned OH group is H-bonded with the N -Me amino group (see Figures and ) . The role of this hydroxy group in diminishing the agonist activity is well-known 2b,25c,d for many morphinans (e.g., 5 is a potent antagonist; compound 6 , with a methylated 14-OH group, possesses much higher agonist activity than the parent oxymorphone 7 25e ).…”

Crowded Piperidines with Intramolecularly Hydrogen-Bonded Nitrogen: Synthesis and Conformation Study

“…Thus, the presence of this bond causes an increase in the barrier approximately by an additional 2 kcal mol −1 . This energy estimate is in excellent agreement with experimental values for piperidines 5 and 24 ; while the Δ ν OH value for 5 is about 340 nm, the intramolecular OH⋅⋅⋅N bond with Δ G 0 of 1.8 kcal mol −1 for 24 is characterized by a Δ ν OH value of 347 nm 14…”