Conformational insights into furo- and thieno[2,3-b]indolines derived from coupling constants and molecular modeling

Article abstract of DOI:10.1002/mrc.1479

The extent to which conformational preferences of fused heterocyclic five-membered rings change with the nature of the heteroatom (O and S) was investigated in furo- (1, 2) and thieno[2,3-b]indolines (3, 4) by the combined use of ¹H NMR spectro

Full text of DOI:10.1002/mrc.1479

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2004; 42: 973–976
Published online 6 September 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1479
Note
Conformational insights into furo- and
thieno[2,3-b]indolines derived from coupling
constants and molecular modeling
∗
´
´
´
Martha S. Morales-Rıos, Norma F. Santos-Sanchez, Nadia A. Perez-Rojas
and Pedro Joseph-Nathan
´
´
´
´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado 14-740, Mexico D.F.,
07000 Mexico
Received 15 May 2004; Revised 9 July 2004; Accepted 12 July 2004
The extent to which conformational preferences of fused heterocyclic five-membered rings change with
the nature of the heteroatom (O and S) was investigated in furo- (1, 2) and thieno[2,3-b]indolines (3, 4) by
the combined use of 1H NMR spectroscopy and density functional theory (DFT) calculations. In contrast
to the behavior observed for pyrroloindolines, the furo- and thienoindolines exist in solution in only one
2
conformer, with structures in the 2E–2T3 (1,2) and T3 –E (3,4) North/West region of the pseudorotational
wheel, and with pseudorotation phase angles (P) of 315.8, 311.6, 337.2 and 331.6◦, respectively. Copyright
 2004 John Wiley & Sons, Ltd.
KEYWORDS: NMR; 1H NMR; pyrrolo[2,3-b]indolines; furo[2,3-b]indolines; thieno[2,3-b]indolines; conformation; molecular
modeling
the heteroatom (O and S) in ring C. For this purpose,
the furoindolines 1 and 2 and the thienoindolines 3 and
4 were prepared from the methiodide derivative of the
corresponding pyrroloindoline. The solution conformation
of indolines 1–4 in CDCl3 was assessed with the aid of
1D and 2D NMR (COSY, HETCOR, gHMBC, NOESY)
techniques, DFT calculations and subsequent determination
of pseudorotational parameters. The results reveal that
replacement of the N-1 nitrogen atom by oxygen or sulfur
results in drastic changes in the conformational preferences
of these tricyclic compounds. These studies are in line
with our interest in defining the molecular conformation
in solution of natural products.5
INTRODUCTION
Furobenzofurans and pyrroloindolines are an important
class of natural products with both toxic and therapeutic
properties (for reviews, see Ref. 1). With the advances being
made in their binding to protein receptors, there is significant
interest, from the drug-design perspective, in establishing the
conformational preferences of these compounds. Recent the-
oretical studies lead to only one minimum energy conforma-
tion for furobenzofurans,2 whereas pyrroloindolines, namely
the alkaloids physostigmine and debromoflustramine B, are
characterized by two minimum energy conformations for the
considerably constrained pyrrolidine C-ring.3 Hence, these
two alkaloids exist in solution in a dynamic conformational
equilibrium between two extreme low-energy structures
labeled North/West and South/East conformations, while a
fixed South/East conformation is found for physostigmine
hydrochloride. It was shown that the umbrella inversion
through N-1 in the free base appears to be a major factor in
determining the pseudorotation4 in the pyrrolidine ring.
In this work, we extended these studies to examine the
extent to which conformational preferences in solution of
fused five-membered indolines change with the nature of
RESULTS AND DISCUSSION
Furo- and thienoindolines 1–4 were obtained by reaction
of the methiodide of the corresponding pyrroloindolines 5
and 6 with NaOH or NaSH, respectively (Scheme 1), by
using published procedures.6 Although the tricyclic sys-
tems possessed a certain amount of flexibility, the presence
of a heteroatom in rings B and C could predispose these
molecules to a preferred conformation, which may be ascer-
tained by NMR studies. In all cases, the expected cis B/C
ring junction stereochemistry was deduced by the NOESY
correlation between H-8a and the alkyl protons at C-3a. Con-
formation A (Fig. 1) was established by a detailed analysis
of the 1H NMR spectra. For example, the methylene protons
Ł
´
Correspondence to: Martha S. Morales-Rıos, Departamento de
´
Quımica, Centro de Investigacio´n y de Estudios Avanzados del
Instituto Polite´cnico Nacional, Apartado 14-740, Me´xico D.F., 07000
Mexico. E-mail: smorales@mail.cinvestav.mx
Contract/grant sponsor: CONACYT; Contract/grant number:
34405-N; G-32631-N.
Copyright  2004 John Wiley & Sons, Ltd.

´
974
M. S. Morales-Rıos et al.
°
°
reflecting dihedral angles approaching 40 and 60 , respec-
tively (Table 2), with accordingly the H-2-exo proton being
in a quasi-equatorial orientation. In principle, these coupling
constants are consistent with conformational rigidity of the
molecule in solution and only conformation A can accom-
modate these coupling constant derived constraints. It is
worth mentioning that substitution of the methyl groups in
1 for the prenyl groups in 2 reverses the chemical shift of
the C-3 pair of protons (endo and exo) (Table 1), as was sup-
ported on the basis of the magnitude of the vicinal coupling
constants [3JꢀH,Hꢁ, Table 2] and selective decoupling exper-
iments. Irradiation of the H-8a signal enhanced the H-3-endo
signal. Likewise, for compounds in which the C-ring oxy-
gen is replaced by sulfur, 3 and 4, the NOE spectra clearly
show the spatial proximities between the C-3 pair of protons
(endo and exo) and the alkyl protons at C-3a. Additionally,
a four-bond coupling constant [4JꢀH,Hꢁ] between H-8a-exo
and H-3-endo protons was found (Table 1). Close inspection
of the data in Table 2 reveals that sulfur introduces small
distortions in conformation A, as shown by small changes in
J values, but overall conformer identification is still possible.
According to theoretical calculations using the molecular
mechanics (MMX force field7) method, compounds 1–4 have
two low-energy conformations resulting from the C-ring
inversion A and B, with the former preferred between 1.5 and
3.0 kcal molꢀ1 ꢀ1 kcal D 4.184 kJꢁ. Geometry optimizations
by use of a density functional theory (DFT) method lead
to only one minimum energy conformation (A) for 1 and
two low-energy conformations (A, B) for 2–4. The prenyl
side-chains were rotated in order to establish all minimum
conformations. The computed structures are shown in Fig. 2,
and the corresponding relative energies are listed in Table 2.
The theoretical coupling constants were obtained by means
of a generalized Karplus-type relationship.8 The observed
and calculated couplings are given in Table 2. The calculated
couplings give excellent agreement for thienoindolines,
suggesting that the conformation in CDCl3 solvent is
predominantly A. However, we noted that, for furoindolines,
Scheme 1. Preparation of furo-(1, 2) and thienoindolines (3, 4).
(a) Mel; (b) NaOH; (c) NaSH.
Figure 1. Conformations A and B for the C-ring.
Table 1. 1H NMR chemical shifts of the C-ring for 1–4a
Atom
Compound
2-exo
2-endo
3-exo
3-endo
8a-exo
1
2
3
4
3.95 ddd 3.45 ddd 2.05 ddd 2.14 dddb 5.07 s
3.92 ddd 3.45 ddd 2.13 ddd 2.04 dddb 5.18 s
2.80 ddd 2.65 ddd 2.21 ddd 2.60 dddb 5.07 s
2.75 ddd 2.63 ddd 2.25 ddd 2.55 dddb 5.19 s
3
the calculated coupling J2,3-endo–exo is larger than expected
by as much as 1.2 Hz, and this is presumably due to the
electronegativity effect of the oxygen atom.9 The remaining
3J couplings are in agreement with predictions. Hence the
assignment of the spectra given above was confirmed.
The low-energy conformation A in 1–4 can be conve-
niently described using the Altona–Sundaralingam pseu-
dorotational parameters.10 With the knowledge of the five
endocyclic torsion angles of a given conformer (ꢂ0 –ꢂ4,
Table 3), defined in Fig. 3, the phase angle (P) was calculated
by solving the equation
a 2JꢀH,Hꢁ and 3JꢀH,Hꢁ values are given in Table 2.
b 4
J
³ 0.4 Hz.
ꢀ3-endo,8a-exoꢁ
of 1 exhibited four sets of well-resolved signals at υ 3.95,
3.45, 2.14 and 2.05 (Table 1) with an integral ratio of 1 : 1 : 1 : 1.
Signal connectivities were confirmed by a COSY experiment.
The existence of NOESY correlations between the methyl
protons at C-3a and both methylene protons at C-3 indicates
a quasi-axial conformation of H-3-exo and a quasi-equatorial
disposition of H-3-endo, as shown in Fig. 1, A. The stereospe-
cific assignment of these methylene protons was allowed by
the observation of a weak zig-zag coupling interaction (ca
0.4 Hz) between the ring junction hydrogen H-8a and the less
shielded H-3 proton (υ 2.14). Hence this signal corresponds
to the endo and quasi-equatorial H-3 proton. The vicinal cou-
pling constant values allowed the assignment of H-2-exo (υ
3.95) at higher frequency than H-2-endo (υ 3.45) (Table 1).
On the other hand, H-2-exo shows vicinal coupling con-
stants with the methylene protons at C-3 of 7.0 and 1.5 Hz,
ꢀꢂ2 C ꢂ4ꢁ ꢀ ꢀꢂ1 C ꢂ3ꢁ
tan P D
ꢀ1ꢁ
3.077 ꢂ0
The ꢂ0 –ꢂ4 values were derived from structures calculated by
a DFT method. The puckering amplitude ꢂm is related to P
and ꢂ0 through the equation
ꢂ0
ꢂm
D
ꢀ2ꢁ
cos P
For furoindolines 1 and 2, the tetrahydrofuran C-ring was
biased toward a North/West structure that is intermediate
Copyright  2004 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2004; 42: 973–976

Conformation of furo- and thieno[2,3-b]indolines 975
Table 2. Density functional theory (B3LYP/6–31GŁ) relative energy (kcal molꢀ1), calculated dihedral angles (ϕ, degrees, in
parentheses) and calculated and observed vicinal coupling constants (3J2,3, Hz) of the C-ring for 1–4
3J2,3 ꢀϕꢁ
exo–exo
Calcd Obs.
exo–endo
Calcd
endo–endo
Calcd Obs.
endo–exo
Calcd Obs.
Compound Conformation Erel
Obs.
1a
2b
A
A
B
A
B
A
B
0.0 7.6 (ꢀ38) 7.0 (ꢀ41)
0.0 7.7 (ꢀ37) 8.3 (ꢀ33)
0.3 (84)
0.3 (84)
10.6 (153)
0.8 (77)
11.8 (159)
0.8 (76)
12.0 (161)
1.5 (62)
1.5 (62)
—
1.5 (69)
—
5.7 (ꢀ39) 5.3 (ꢀ40) 11.5 (ꢀ161) 11.4 (ꢀ160)
5.4 (ꢀ39) 5.4 (ꢀ39) 11.5 (ꢀ161) 11.0 (ꢀ157)
2.6 6.6 (33)
—
8.7 (31)
—
0.4 (ꢀ90)
—
3c
0.0 6.6 (ꢀ42) 6.2 (ꢀ44)
2.3 6.9 (40)
0.0 6.4 (ꢀ43) 6.4 (ꢀ43)
2.5 6.5 (42)
5.7 (ꢀ46) 4.9 (ꢀ50) 12.5 (ꢀ165) 12.7 (ꢀ166)
7.7 (37)
0.4 (ꢀ82)
—
—
—
4d
1.4 (71)
—
5.6 (ꢀ47) 4.9 (ꢀ50) 12.6 (ꢀ165) 12.2 (ꢀ162)
—
7.3 (38)
—
0.5 (ꢀ80)
—
a 2
b 2
c 2
d 2
J
D 8.8 Hz; 2J3,3 D 11.7 Hz.
D 8.3 Hz; 2J3,3 D 11.7 Hz.
2,2
J
J
2,2
D 11.4 Hz; 2J3,3 D 12.2 Hz.
D 10.7 Hz; 2J3,3 D 11.7 Hz.
2,2
J
2,2
1A
2A
2B
EDFT = -596.28337
EDFT = -919.26033
EDFT = -919.25667
3A
4B
3B
EDFT = -947.64652
4A
EDFT = -947.65065
EDFT = -1270.62294
EDFT = -1270.62688
Figure 2. Density functional theory molecular models (B3LYP/6–31GŁ, E in hartrees) for 1–4.
Table 3. Endocyclic torsion angles (ꢂ) and pseudorotational parameters (PA, ꢂm) for 1–4
°
Endocyclic torsion angle ( )
°
°
Compound
ꢂ0
ꢂ1
ꢂ2
ꢂ3
ꢂ4
Conformation A
PA ( )
ꢂm ( )
1
2
3
4
34.2
35.8
26.5
29.5
ꢀ37.7
ꢀ37.7
ꢀ43.2
ꢀ44.3
26.9
25.2
41.3
39.3
ꢀ7.7
ꢀ5.1
ꢀ16.3
ꢀ19.1
ꢀ3.8
2E–2T3
2E–2T3
2T3 –E3
2T3 –E3
315.8
311.6
337.2
331.6
37.5
38.0
44.8
44.7
ꢀ20.0
ꢀ16.1
ꢀ7.8
between the idealized envelope 2E and half chair 2T3
°
P values vary by ca 20 . Table 3 describes the A conformers
°
°
which best fit the NMR data.
conformers (P D 315.8 for 1 and 311.6 for 2), whereas
in thienoindolines 3 and 4, the tetrahydrothiophene C-ring
adopts a 2T3-type form deformed towards the envelope
EXPERIMENTAL
°
°
E3 conformation (P D 337.2 for 3 and 331.6 for 4). In
thienoindolines 3 and 4, the conformers populated by the
C-ring differ only slightly from those present in 1 and 2. The
NMR measurements were performed on Varian Mercury
spectrometers operating at 300 MHz (proton) or 75 MHz
Copyright  2004 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2004; 42: 973–976

´
976
M. S. Morales-Rıos et al.
144 (60); 1H NMR (CDCl3), υ 7.11 (1H, td, J D 7.8, 1.5 Hz, H-6), 6.99
(1H, dd, J D 7.3, 1.0 Hz, H-4), 6.70 (1H, td, J D 7.3, 1.0 Hz, H-5),
6.44 (1H, d J D 7.8 Hz, H-7), 5.07 (1H, s, H-8a), 2.81 (3H, s, NMe),
1.43 (3H, s, CMe), for the methylene proton data (H-2 and H-3) see
Table 1; 13C ꢀCDCl3ꢁ, υ 149.7 (C-7a), 135.0 (C-3b), 128.1 (C-6), 121.4
(C-4), 117.8 (C-5), 107.3 (C-7), 86.6 (C-8a), 56.7 (C-3a), 44.5 (C-3), 33.1
(NMe), 32.2 (C-2), 24.8 (CMe).
3a,8-Bis(3-methylbut-2-enyl)-2,3,3a,8a-tetrahydro-
8H-thieno[2,3-b]indole (4)
Figure 3. Definition of endocyclic torsion angles ꢂ0 –ꢂm.
Slightly yellow oil; Rf 0.93 [AcOEt–hexane (2 : 3)]; IR, CHCl3 ꢀcmꢀ1ꢁ,
3050, 2930, 1460, 1380; MS (EI, 70 eV), m/z 313 MC (100), 244 (70),
176 (97); 1H NMR (CDCl3), υ 7.09 (1H, ddd, J D 7.8, 7.3, 1.2 Hz, H-6),
6.96 (1H, dd, J D 7.3, 1.2 Hz, H-4), 6.67 (1H, td, J D 7.3, 1.0 Hz, H-5),
6.48 (1H, d, J D 7.8 Hz, H-7), 5.26 (1H, tsept, J D 6.9, 1.3 Hz, H-15),
5.19 (1H, tsept, J D 6.9, 1.3 Hz, H-10), 5.19 (1H, s, H-8a), 3.87 (1H,
dd, J D 14.2, 5.4 Hz, H-14), 3.63 (1H, dd, J D 14.2, 8.3 Hz, H-140), 2.39
and 2.34 (2H, dd, J D 15.1, 7.0 Hz, H-9,90), 1.76 (3H, s, Me-17), 1.75
(3H, d, J D 1.1 Hz, Me-18), 1.69 (3H, d, J D 1.0 Hz, Me-12), 1.51 (3H,
s, Me-13), for the methylene proton data (H-2 and H-3) see Table 1;
13C NMR (CDCl3), υ 150.0 (C-7a), 136.3 (C-16), 134.8 (C-3b), 134.2
(C-11), 128.3 (C-6), 122.5 (C-4), 120.2 (C-15), 120.1 (C-10), 117.8 (C-5),
107.7 (C-7), 82.1 (C-8a), 60.8 (C-3a), 44.3 (C-14), 42.1 (C-3), 36.3 (C-9),
32.2 (C-2), 26.4 (Me-12), 26.3 (Me-17), 18.5 (Me-18), 18.2 (Me-13).
(carbon). Data were obtained from CDCl3 solutions. Spectra
were of ca 28 mg cmꢀ3 solutions with a probe temperature
of ca 22 C. Typical operating parameters for 1H-detected
°
experiments were an f2 ꢀ1Hꢁ spectral window of 2278 Hz with
1024 data points. For phase-sensitive gHSQC spectra, f1 ꢀ13Cꢁ
was 12 500 Hz, 256 time increments were collected and
linearly predicted to 1024, with 64 transients per increment;
for gHMBC spectra, f1 ꢀ13Cꢁ was 18 188 Hz with 128 transients
per increment and 256 time increments. Phase-sensitive
NOESY spectra used the same 1H spectral windows and
f2 data points with 256 increments linearly predicted to 1024
using a mixing time of 0.8 s and a relaxation delay of 1.0 s.
Calculations were carried out using a Pentium IV-based
PC. For molecular mechanics calculations, the PCMODEL
program (Serena Software, Bloomington, IN, USA) was used.
A systematic conformational search for the five-membered
C-ring was carried out with the aid of Dreiding models and
Acknowledgement
This research was supported by CONACYT, Me´xico (34405-N, G-
32631-N).
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´
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3a,8-Dimethyl-2,3,3a,8a-tetrahydro-8H-thieno[2,3-
b]indole (3)
Colorless oil; Rf 0.82 [AcOEt–hexane (2 : 3)]; IR, CHCl3ꢀcmꢀ1ꢁ, 3060,
2926, 1606, 1376; MS (EI, 70 eV), m/z 205 MC (100), 177 (38), 158 (36),
Copyright  2004 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2004; 42: 973–976