Impacts of Steric Compression, Protonation, and Intramolecular Hydrogen Bonding on the ¹⁵N NMR Spectroscopy of Norditerpenoid Alkaloids and Their Piperidine-Ring Analogues

Abstract

1 H− 15 N HMBC spectra of norditerpenoid alkaloids and their synthetic azabicyclic analogues were obtained to investigate the impacts of the through-space effect of steric compression, protonation, and formation of intramolecular hydrogen bonding on the 15 N NMR spectroscopy of these natural products and their piperidine-containing analogues. A rare 15 N NMR effect of steric compression is demonstrated in half-cage A/E-rings of norditerpenoid alkaloid free bases and their synthetic azabicyclic analogues, in which the distribution of the lone pair of electrons of the tertiary amine N-atom is sterically restricted by bridged cycloalkanes, e.g., cyclopentane, cyclohexane, and cycloheptane rings. This results in significant changes in the 15 N chemical shift, typically by at least ∼10 ppm. The lone pair of electrons of the N-atom in the piperidine ring are sterically compressed whether the bridged cyclohexane ring adopts a chair or boat conformation. The 15 N chemical shifts of 1α-OMe norditerpenoid alkaloid free bases significantly increase (Δδ N ≥ 15.6 ppm) on alkaloid protonation and thence the formation of an intramolecular hydrogen bond between N + -H and 1α-OMe. The intramolecular hydrogen bonds between the N-atom and 1α-OH of 1α-OH norditerpenoid alkaloid free bases, karacoline, condelphine, and neoline stabilize their A-rings, adopting an unusual twisted-boat conformation, and they also significantly increase δ N of the tertiary amine N-atom.

Individual pKa Values of Tobramycin, Kanamycin B, Amikacin, Sisomicin, and Netilmicin Determined by Multinuclear NMR Spectroscopy

“…The aim is to measure p K a values of individual amines on aminoglycosides by using new combinations of 1 H, 13 C, and 15 N HMBC NMR spectroscopic data. 11 − 13 …”

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

“…The equatorial proton of a 6‐membered aliphatic ring is known to resonate at a lower field than its geminal (therefore axial) proton due to the magnetic anisotropic effect [41,42] . However, a significant steric compression acting on an axial proton of a methylene group leads to that axial proton resonating at a lower field than its geminal equatorial proton [49–51] . In simple synthetic [3.3.1]azabicycles, the difference of chemical shift between that of the axial and the equatorial proton is typically larger than 1.0 ppm, e. g., Δδ 7−H =1.33 ppm found in [3.3.1]azabicycle 12 [18,51–53] .…”

“…The 1α‐OMe of NDAs was considered to be a factor for decreasing the Δδ 2−H , and altering the coupling pattern of δ 2−H . However, the reported 1 H NMR data of synthetic [3.3.1]azabicycles bearing 6α‐oxygenated function groups, e. g., 6α‐OH and 6α‐OMe, (C6 of these synthetic [3.3.1]azabicycles corresponds to C2 of NDAs) their 7‐H a typically resonates at ∼2.9 ppm, and the coupling patterns of their 7‐H a are highly similar to that of 7‐H a of [3.3.1]azabicyclic analogue ( 12 ) [51–53] . Therefore, the 1α‐OMe of an NDA‐free base does not influence the steric compression acting at 2‐H a , neither chemical shift nor coupling constants.…”

“…[41,42] However, a significant steric compression acting on an axial proton of a methylene group leads to that axial proton resonating at a lower field than its geminal equatorial proton. [49][50][51] In simple synthetic [3.3.1] azabicycles, the difference of chemical shift between that of the axial and the equatorial proton is typically larger than 1.0 ppm, e. g., Δδ 7À H = 1.33 ppm found in [3.3.1]azabicycle 12. [18,[51][52][53] Here this steric compression effect on 2-H a of the selected NDA freebases is decreased in magnitude, but the 2-H a of the selected free bases do still experience steric compression, as δ (2-H a ) > δ (2-H e ).…”

“…[49][50][51] In simple synthetic [3.3.1] azabicycles, the difference of chemical shift between that of the axial and the equatorial proton is typically larger than 1.0 ppm, e. g., Δδ 7À H = 1.33 ppm found in [3.3.1]azabicycle 12. [18,[51][52][53] Here this steric compression effect on 2-H a of the selected NDA freebases is decreased in magnitude, but the 2-H a of the selected free bases do still experience steric compression, as δ (2-H a ) > δ (2-H e ). The smaller Δδ 2-H compared with that observed in the synthetic analogues, e. g., 12, 15, is consistent with the amine lone-pair electrons not pointing directly at 2-H a , therefore not adopting true-chair/true-chair conformations.…”