13C NMR discrimination of regioisomeric bispyrroloquinone/ bispyrroloiminoquinone ring systems

Article abstract of DOI:10.1002/mrc.2529

The structural assignment of bispyrroloquinone and bispyrroloiminoquinone regioisomers was achieved using ¹³C NMR spectral data. In the case of bispyrroloiminoquinones, the carbonyl group in the regioisomer possessing a nitrogen atom in both α-positions was systematically less deshielded than the carbonyl group in the other regioisomer. In the case of bispyrroloquinones, the most deshielded carbonyl group in the regioisomerwith a nitrogen atom in both α-positions wasmore deshielded than the same carbonyl group in the other regioisomer. Copyright

Full text of DOI:10.1002/mrc.2529

Research Article
Received: 23 July 2009
Revised: 3 September 2009
Accepted: 10 September 2009
Published online in Wiley Interscience: 12 October 2009
(www.interscience.com) DOI 10.1002/mrc.2529
13C NMR discrimination of regioisomeric
bispyrroloquinone/bispyrroloiminoquinone
ring systems
Stefan Chassaing and Evelyne Delfourne∗
The structural assignment of bispyrroloquinone and bispyrroloiminoquinone regioisomers was achieved using 13C NMR
spectral data. In the case of bispyrroloiminoquinones, the carbonyl group in the regioisomer possessing a nitrogen atom
in both α-positions was systematically less deshielded than the carbonyl group in the other regioisomer. In the case of
bispyrroloquinones, the most deshielded carbonyl group in the regioisomer with a nitrogen atom in both α-positions was more
c
deshielded than the same carbonyl group in the other regioisomer. Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Keywords: NMR; 13C; marine alkaloid; tsitsikammamine; bispyrroloquinone; bispyrroloiminoquinone
Introduction
could be achieved through simple analysis of 13C NMR chem-
ical shifts of both the carbonyl and the carboimine groups.
We thus considered the three couples of bispyrroloimino-
quinone regioisomers 6–8 and first compared 13C NMR chem-
ical shifts of the carbonyl groups in each regioisomeric couple
(Table 1).[7,8]
Bispyrroloquinoneandbispyrroloiminoquinonearetwoimportant
polycyclic ring systems present in biologically active marine
alkaloids including zyzzyanones 1a–d,[1] tsitsikammamines 2a-
b[2] and wakayin 2c[3] (Fig. 1).
As part of our ongoing research program on the synthesis of
natural compounds of this group[4] and analogues with potential
antitumor properties,[5] we were interested in regioisomeric
derivatives containing the quinone or iminoquinone systems a
and b (Fig. 2).
As these moieties are more and more frequently incorporated
in molecules of biological value,[6] special attention has been
paid to these relevant regiochemical aspects. In the present
work, we describe how 13C NMR appears to be a powerful
tool in the structural assignment of regioisomeric bispyrrolo-
quinone/bispyrroloiminoquinone ring systems.
The appearing trend is that a-type regioisomers exhibit more
deshielded carbonyl groups than b-type ones, ꢀδCO values being
highly discriminative in the case of compounds 6–8, indeed. It is
worth noting that the presence of an additional double-bond on
the functional ethylenic chain exo to the bispyrroloiminoquinone
system (i.e. couple 8 vs couple 6) does not play any role on
the discriminative deshielding effect. Following these promising
observations, the proposed discriminative tool was also checked
forotherstructurallyrelatediminoquinonederivatives(i.e. couples
13–16). In the case of pyrazolic analogues 13a/13b and 14a/14b,
previously synthesized by our group,[5] the deshielding effect
was also observed but to a very less extent, ꢀδCO values being
smaller than 1 ppm here. In the case of sebastianine 15a, another
marine metabolite, and its regioisomer 15b, in which the second
pyrrole ring has been replaced by a pyridinic group,[7] or in
the case of derivatives 16a and 16b comprising two pyridinic
rings instead of pyrrole rings,[8] this deshielding effect was also
observed in 13C NMR, especially in the case of the couple 15. In
parallel, the same NMR analysis was done on the 13C chemical
shifts of carboimine groups. However, it clearly appeared that
there was no clear-cut relationship for the C N group in one
isomer compared to the other, revealing that NMR data of this
Results and Discussion
Our route to tsitsikammamine A was based on Michael
reaction between the indoledione
4
and 2ꢁ-amino-1-(4-
methoxyphenyl)ethanol 3 (Scheme 1). This pivotal reaction gave
two regioisomers 5a and 5b which were submitted to a same
sequence of reactions, thereby, generating a first series of
bispyrroloiminoquinone derivatives including 6–8 (a,b).[4] Sim-
ilarly, a second series of bispyrroloquinones 11–12 (a,b) lacking
the functional ethylenic chain was produced by the conden-
sation of the indoledione 9 with aminoalcohol 3 (A. Rives,
B. Le Calve´, T. Delaine, L. Legentil, R. Kiss, E. Delfourne, in
press).
The structural assignment of each isomer in the first se-
ries was effected by comparison of the spectroscopic data of
the trifluoroacetic salt of 7b which was proved to be identi-
cal to those reported for the natural product tsitsikammamine
A (2). In the case of bispyrroloiminoquinone-containing com-
pounds, we wondered whether an assignment of regioisomers
∗
´
Correspondence to: Evelyne Delfourne, Universite Paul Sabatier, UMR CNRS
`
´
´ ˆ
5068, Laboratoire de Synthese et Physicochimie de Molecules d’Interet
´
Biologique, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France.
E-mail: delfourn@chimie.ups-tlse.fr
´
`
Universite Paul Sabatier, UMR CNRS 5068, Laboratoire de Synthese et
´
´ ˆ
Physicochimie de Molecules d’Interet Biologique, 118 Route de Narbonne,
´
31062 Toulouse Cedex 9, France
c
Magn. Reson. Chem. 2010, 48, 9–12
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

S. Chassaing and E. Delfourne
MeO
NHBoc
NHBoc
NHBoc
O
O
O
O
O
O
H
N
OH
6-8 (a,b)
+
MeO
N
N
Ts
N
Ts
N
Ts
OH
H
+
4
5b
5a
MeO
MeO
OH
NH2
O
O
O
3
H
+
OH
N
+
11-12 (a,b)
N
Ts
N
H
N
Ts
N
Ts
OH
9
O
O
O
10b
10a
MeO
Scheme 1. Synthetic route to tsitsikammamine A and analogues.
HO
(a)
N
(b)
R
1
N
Me
X
X
O
O
1a, zyzzyanone A, R1 = H, R2 = Me
1b ,zyzzyanone B, R1 = H, R2 = H
1c, zyzzyanone C, R1 = CHO, R2 = Me
1d, zyzzyanone D, R1 = CHO, R2 =H
N
N
N
N
H
N
O
O
X = O,N
R2
Figure 2. Quinone and iminoquinone regioisomers.
HO
H
N
chemical shifts of the most deshielded carbonyl group in a-type
regioisomers are smaller than those in b-type regioisomers,
whereas the opposite effect was observed for the other carbonyl
group. This general trend has also been proved, although to a
less extent, in the case of structurally related derivatives 20a and
20b in which both pyrrole rings have been replaced by pyridinic
rings.[8] Moreover, the calculation of ꢀδCO values appears to be
a quantitative tool for discriminating regioisomeric bispyrrolo-
quinone ring systems: (i) in the case of a-type regioisomers, ꢀδCO
values are low and generally close to zero; (ii) in the case of b-type
regioisomers, ꢀδCO values are around 12 ppm. Surprisingly, it has
also to be noted that the average value µ is almost always the
same (i.e. around 174 ppm) in both a- and b-type regioisomers
revealing the rigorous electronic redistribution when passing
from symmetric a-type nucleus to dissymmetric b-type ones.
+
+
HN
HN
N
H
N
H
N
R1
N
H
O
O
2a, tsitsikammamine A, R1 = H
2b, tsitsikammamine B, R1 =
Me
2c,wakayin
Figure 1. Marine bispyrroloquinone and bispyrroloiminoquinone alka-
loids.
functional group are not characteristic for the differentiation of
regioisomers.
In the bispyrroloquinone series, previous work of Qiao et al.[9]
has shown that significant chemical shifts occurred in the 1,4-
benzoquinone units. For instance, in the bispyrroloquinones 17a
and 17b, the 13C NMR chemical shifts of the most deshielded
carbonyl groups are 174.0 and 179.3 ppm, respectively (Table 2).
Furthermore, data reported both by Lee et al.[10] and Li et al.[11]
indicate that the presence of substituents on pyrrole rings has
a very low influence on the 13C NMR chemical shifts of the two
carbonyl groups of bispyrroloquinone ring systems. To illustrate
this low substitution-dependence, one can just compare: (i) NMR
data of unsubstituted 17a with those of natural terreusinone 18a;
(ii) NMR data of 17b with those of natural zyzzyanone B 19b.
As a result, the structure assignments for compounds 11a/11b
and 12a/12b are those reported in Table 2. In a general way, the
Conclusion
13C NMR analysis of different couples of bispyrroloiminoquinone
and bispyrroloquinone regioisomers led to the establishment of
the following discriminative tools:
1. In the case of bispyrroloiminoquinones, regioisomers can be
discriminated by the comparison of carbonyl group chemical
shifts of the two isomers, the one exhibiting the most
deshielded carbonyl group being an a-type regioisomer.
2. In the case of bispyrroloquinones, regioisomers can be
discriminated by a simple calculation of ꢀδCO values (i.e.
chemical shifts’ difference between the most and the less
deshielded carbonyl groups), b-type regioisomers possessing
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2010, 48, 9–12

13C NMR discrimination of bispyrroloquinone/bispyrroloiminoquinone ring systems
Table 1. Diagnostic 13C NMR chemical shifts of bispyrroloiminoquinonesa
Structure
Compound
δCO (ppm)
δCN (ppm)
ꢀδCO (ppm)b
Ref.
[4]
MeO
6a
6b
174.38
167.00
167.48
164.60
7.38
N
O
N
H
N
H
HO
7a
7b
174.71
172.45
156.71
167.99
2.26
[4]
N
N
H
N
H
O
8a
8b
171.49
164.81
158.36
158.45
6.68
[4]
MeO
N
O
N
H
N
H
13a
13b
166.68
166.57
156.14
155.98
0.11
0.95
5.80
[5b]
[5a]
[7]
N
N
N
N
H
H
O
14a
14b
167.60
166.65
154.52
154.82
N
O
N
N
N
H
H
15a
15b
178.38
172.58
149.88
149.76
N
O
N
H
N
16a
16b
181.96
180.73
155.73
152.97
1.23
[8]
N
N
N
O
a All spectra were recorded in DMSO-d6 except for compounds 16a and 16b which were recorded in CDCl3.
b ꢀδCO = δCOa − δCOb
.
characteristic ꢀδCO values around 12 ppm, whereas a-type
regioisomers possess ꢀδCO values generally close to zero. It
is worth noting that this discriminative empirical rule is a
direct tool of characterization, NMR data of both regioisomers
are not required to ascertain the corresponding structure
unambiguously.
compounds 13a/13b, see Ref. [5b]; (iii) for synthetic compounds
14a/14b, see Ref. [5a]; (iv) for synthetic compounds 15a/15b, see
Ref. [7]; (v) for synthetic compounds 16a/16b and 20a/20b, see
Ref. [8]; (vi) for synthetic compounds 17a/17b, see Ref. [9]; for
the natural product 18a, see Ref. [10,11] and for its non-natural
isomer 18b, see Ref. [10].
NMR spectra
Experimental
Materials
In the case of the compounds prepared in our laboratory (i.e.
compounds 6a/6b, 7a/7b, 8a/8b, 13a/13b, 14a/14b, 15a/15b,
16a/16b and 20a/20b), 13C NMR spectra were recorded on a
Bruker Avance 500 spectrometer in DMSO-d6 as the solvent, with
the solvent peak as internal reference. Chemical shifts (δ scale) are
reported in parts per million (ppm) relative to the central peak of
the solvent, i.e. 39.52 ppm for DMSO-d6.
Solvent DMSO, >99.80% pure, was from Euriso-Top. Analytical
data and/or synthetic procedures of all compounds used in this
study were previously described in the literature: (i) for synthetic
compounds 6a/6b, 7a/7b and 8a/8b, see Ref. [4]; (ii) for synthetic
c
Magn. Reson. Chem. 2010, 48, 9–12
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

S. Chassaing and E. Delfourne
Table 2. Diagnostic 13C NMR chemical shifts of bispyrroloquinonesa
Structure
Compound
δCO−4 (ppm)
δCO−8 (ppm)
ꢀδCO (ppm)b
µ (ppm)c
Ref.
[4]
MeO
11a
11b
174.56
168.65
174.83
180.65
0.27
174.70
174.65
12.00
O
4
8
N
N
H
H
O
HO
12a
12b
170.45
168.45
174.18
180.39
3.73
172.32
174.42
[4]
11.94
O
N
H
N
H
O
O
17a
17b
174.00
168.3
174.00
179.3
0.00
174.00
173.8
[9]
11.00
N
H
N
H
O
O
18a
18b
174.00
180.1d
173.3d
174.00
180.1d
186.10d
0.00
0.00
12.8
173.95
[10,11]
e
HO
–
e
–
N
H
N
OH
H
O
19b
168.7
180.4
11.7
174.55
[1b]
[8]
HO
NHMe
O
O
N
Me
N
H
O
20af
20bf
181.46
180.42
182.46
184.02
1.00
3.6
181.96
182.22
N
N
O
a All spectra were recorded in DMSO-d6 except for compounds 18a and 18b which were recorded in CDCl3.
b ꢀδCO = δCO−8 − δCO−4
.
c µ = 1/2 (δCO−8 + δCO−4).
d Relative values issued from quantum chemistry calculations (for details see Ref. [10]).
e Not determined.
f For these compounds the numbering of carbonyl groups is CO-5 and CO-9.
13C NMR parameters were as follows: spectrometer frequency
(SF), 125.77 MHz; acquisition time (AQ), 0.872 s; number of
transients (NS), 20480; receiver gain (RG), 16384; temperature
(TE), 298.0 K; dwell time (DW), 13.3 µs; per scan delay (DE), 6.0 µs;
dummy scans (DS), 0.
[4] A. Rives, T. Delaine, L. Legentil, E. Delfourne, TetrahedronLett. 2009,
50, 1128.
[5] (a) L. Legentil, B. Lesur, E. Delfourne, Bioorg. Med. Chem. Lett. 2006,
16, 427; (b) L. Legentil, L. Benel, V. Bertrand, B. Lesur, E. Delfourne,
J. Med. Chem. 2006, 49, 2979.
[6] S. Murugesan, D. H. Nadkarni, S. E. Velu, Tetrahedron Lett. 2009, 50,
3074.
[7] L. Legentil, J. Bastide, E. Delfourne, Tetrahedron Lett. 2003, 44, 2473.
[8] E. Delfourne, R. Kiss, L. Le Corre, F. Dujols, J. Bastide, F. Collignon,
B. Lesur, A. Frydman, F. Darro, J. Med. Chem. 2003, 46, 3536.
[9] G. G. Qiao, W. Meutermans, M. W. Wong, M. Traubel, C. Wentrup,
J. Am. Chem. Soc. 1996, 118, 3852.
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c
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