MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2005; 43: 599–601
Spectral Assignments and Reference Data
1H and 13C NMR spectral assignments
of isoquinuclidine-3,5-dione derivatives
Josefina Quirante, Fa¨ıza Diaba, Xavier Vila and
Josep Bonjoch∗
´
`
`
Laboratori de Quımica Organica, Facultat de Farmacia, Universitat de
Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Received 10 March 2005; accepted 6 April 2005
The 1H and 13C NMR spectra of six 5-substituted 2-
azabicyclo[2.2.2]octane derivatives were fully assigned
by COSY and HSQC experiments. Copyright 2005
John Wiley & Sons, Ltd.
KEYWORDS: NMR; 1H NMR; 13C NMR; isoquinuclidines;
chemical shift assignments; stereochemical elucidation
INTRODUCTION
2-Azabicyclo[2.2.2]octan-5-ones (isoquinuclidin-5-ones) and their
corresponding hydroxyl derivatives have been used as starting
materials for the preparation of conformationally constrained
analogs of several interesting pharmaceutical compounds such as
the antiarrhythmic agent BRL-32 872,1 the 5-HT3 antagonist SDZ
205-572 and potent CCR3 antagonists.3 Interestingly, mearsine4 and
grandisine B5 are the only isoquinuclidin-5-one alkaloids reported,
while N-methylisoquinuclidin-5-one (dioscorone) is an intermediate
in the synthesis of the alkaloid dioscorine.6
Isoquinuclidin-5-one derivatives have been synthesized either
by cycloaddition processes of cyclohexadiene compounds7,8 or
by lactamization of 4-aminocyclohexanecarboxylate derivatives,
prepared from benzene derivatives.3 Here, we report detailed NMR
data for some isoquinuclidine-3,5-dione derivatives (Scheme 1),
whose synthesis involves the formation of the azabicyclic ring
through a lactamization of amino esters obtained, in our case, starting
from a Diels–Alder process between Danishefsky’s diene and methyl
acrylate (Scheme 2).
Scheme 2. Synthesis of isoquinuclidinones.
RESULTS AND DISCUSSION
1H and 13C NMR data and assignments for isoquinuclidines 3–6 are
given in Tables 1 and 2, respectively. As can be seen in Table 2,
the signals corresponding to C-5 and C-8 are sensitive to the
configuration of the substituent on C-5, whereas vicinal carbons
C-4 and C-7 are relatively insensitive. The chemical shift of C-8 is
of diagnostic value for the relative configuration at C-5, the signal
in the endo epimers being ¾3.5 ppm upfield with respect to that of
the exo epimers (e.g. υ 16.2 for 5b and υ 20.0 for 5a). Moreover, the
deshielding exerted by the oxygen atom in the anti isomers upon
H-8endo implies a large difference (¾0.65 ppm) between the chemical
shift of H-8endo in the endo series and that of the exo series (e.g. υ 2.30
for 5b and υ 1.61 for 5a, see Table 1).
Another interesting trend in the chemical shifts in this series
of compounds is that the protons eclipsed with the electron-rich
functional group (OH or OMe) resonate at lower frequency than
the geminal partners trans to the substituent. This is the case with
the H-6exo in the exo epimer and H-6endo in the endo epimer, which
show upfield shifts of 0.5 and 0.6 ppm, respectively, compared with
the same protons in the opposite epimers. These data are in fairly
good agreement with those found for some related compounds.9
A noteworthy 1H NMR feature is a large coupling between vicinal
protons at the same face of the carbocyclic ring, indicating that
these protons are nearly eclipsed. As expected, the coupling constant
Jꢀ1, 6endoꢁ is smaller than Jꢀ1, 6exoꢁ, as is Jꢀ1, 7endoꢁ with respect to
Jꢀ1, 7exoꢁ.
Scheme 1. Structures of compounds 3–6.
Ł
´
Correspondence to: Josep Bonjoch, Laboratori de Quımica Orga`nica,
Facultat de Farma`cia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028
Barcelona, Spain. E-mail: josep.bonjoch@ub.edu
Contract/grant sponsor: MEC; Contract/grant number: CTQ2004-04701.
Contract/grant sponsor: DURSI; Contract/grant number: 2001SGR-00083.
Copyright 2005 John Wiley & Sons, Ltd.
Quirante, Josefina
