The 1α-hydroxy-A-rings of norditerpenoid alkaloids are twisted-boat conformers

Abstract

The skeletal conformations of naturally occurring norditerpenoid alkaloids fix their substituent functional groups in space, thereby directing their bioactivities.

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

“…The coupling patterns of each of 1‐H e and 2‐H b of both the salts ( 5 ) and ( 10 ) are almost the same. Therefore, the A‐ring in lappaconitine HBr ( 5 ) adopts a boat conformation like that of the A‐ring of aconitine HCl ( 10 ), and these boat conformations are twisted [48] …”

“…Secondly, H‐bonding between the N ‐ethylpiperidinium N + ‐H and the O ‐atom of 1‐OMe stabilizes the boat conformations [37,43,44] . The interaction between atoms attached to C1 and C12 is the reason that the A‐rings of both NDA free bases and salts adopt twisted‐chair conformations, both in the crystal lattice and in solution [48] . These twisted conformations may also be due to the 5‐membered F‐ring, which is partly fused to both A‐ and E‐rings and might thereby distort the normal sp 3 bond angles in some C‐atoms.…”

“…Therefore, the A-ring in lappaconitine HBr (5) adopts a boat conformation like that of the A-ring of aconitine HCl (10), and these boat conformations are twisted. [48] Two reasons are known to maintain the A-rings of NDA salts in boat conformations: Firstly, the through-space interaction between 1-OMe and C12 (or protons attached to this C-atom) pushes 1-OMe and C1. Secondly, H-bonding between the Nethylpiperidinium N + -H and the O-atom of 1-OMe stabilizes the boat conformations.…”

“…[37,43,44] The interaction between atoms attached to C1 and C12 is the reason that the A-rings of both NDA free bases and salts adopt twisted-chair conformations, both in the crystal lattice and in solution. [48] These twisted conformations may also be due to the 5-membered F-ring, which is partly fused to both A-and E-rings and might thereby distort the normal sp 3 bond angles in some C-atoms. NOE correlations 1-H/12-H a' of aconitine (1), 1-OMe/12-H e' of crassicauline A (3), 1-H/12-H a' of MLA (7) support the conclusion that the atoms or functional groups attached to C1 are close in space to protons attached to C12.…”

“…The A-rings of the two natural product salts ( 5) and ( 10) adopt twisted boat conformations, as the equatorial 1-OMe experiences repulsion from 12-H e' . [37,44,48] The interaction between 6(α)-H a' (or 6α-OMe) with 19-H a does not change when the NDAs are protonated. Therefore, the piperidine E-rings of NDA salts are considered to adopt a twisted-chair conformation, both in the crystal lattice and in solution.…”