Questioning the γ-gauche effect: Stereoassignment of 1,3-disubstituted-tetrahydro-β-carbolines using 1H-1H coupling constants

Article abstract of DOI:10.1039/c9ob01139k

The Pictet-Spengler reaction of tryptophan esters and aldehydes has been widely applied in natural product synthesis and medicinal chemistry. To date, the trans- or cis-configuration of 1,3-disubstituted tetrahydro-β-carbolines (THβCs) formed in this reac

Full text of DOI:10.1039/c9ob01139k

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OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/C9OB01139K
ARTICLE
Questioning the 훾-gauche effect: stereoassignment of 1,3-
disubstituted-tetrahydro-β-carbolines using 1H-1H coupling
constants
Received 00th January 20xx,
Accepted 00th January 20xx
Kristýna Cagašová, Maryam Ghavami, Zhong-Ke Yao, and Paul R. Carlier*
DOI: 10.1039/x0xx00000x
The Pictet-Spengler reaction of tryptophan esters and aldehydes has been widely applied in natural products synthesis and
medicinal chemistry. To date, the trans- or cis-configuration of 1,3-disubstituted tetrahydro-β-carbolines (THβCs) formed in
this reaction has most often been assigned based on the relative 13C chemical shifts of C1 and C3 in the diastereomers.
Although the upfield shifts of C1 and C3 in trans-THβCs relative to cis-THβCs has been attributed to steric compression
associated with the “γ-gauche” effect, we show that this effect is not borne out experimentally for other carbons that should
suffer this same compression. Thus we developed a robust alternative method for stereochemical assignment based on 1H
NMR coupling constants (31 examples) and supported by extensive DFT-based conformational analysis and calculation of
1H-1H coupling constants. DFT calculations of 13C NMR chemical shifts also cast doubt upon the role of the “γ-gauche” effect
on C1 and C3 chemical shifts in trans-THβCs.
point we have used the 13C NMR empirical rule of Ungemach et
al.12 In brief, C1 and C3 chemical shifts of trans-1,3-
disubstituted THβCs (e.g., 5a, 7a) have been shown to be
Introduction
1,3-Disubsubstituted tetrahydro-β-carbolines (THβCs)
1
show a wide spectrum of biological activities,1, 2 and serve as
synthetic intermediates to the sarpagine/macroline/ajmaline
O
H
R2
3
H
class of natural products,3 such as talcarpine (Figure 1).4 They
2
3
NH
1
NMe
1
O
are also prominent in medicinal chemistry as precursors to
approved drugs and preclinical drug candidates: representative
examples include the erectile dysfunction drug tadalafil (
the anticancer candidate AZD9496 ( , currently in Phase I trials,
Figure 1).6 A compound of special interest for our group is 5a
also known as MMV008138, which was originally identified7
from a screen of a publicly available chemical library (the
Malaria Box8). Although the configuration of 5a was initially
unknown, later studies9-11 confirmed that 5a is (1R,3S)-
configured, and that it is a much more potent antimalarial agent
than its cis-diastereomer 6a (and enantiomers ent-5a and ent-
6a). Compounds 5a and 6a were prepared by Pictet-Spengler
reaction of (S)-Trp-OMe with 2,4-dichlorobenzaldehyde,
H
H
F
R1
N
N
3
)5 and
H
H
4
2
1
,
O
N
3
3
N
N
O
F
1
1
N
H
N
H
F
O
O
4
3
followed by a separation of the diastereomeric esters 7a and 8a
,
COOH
and hydrolysis.9 Ongoing optimization of this scaffold for
antimalarial activity requires an accurate assignment of the
relative stereochemistry of the ester precursors, and to this
O
O
3
OR
3
OR
NH
Cl
NH
Cl
1
1
Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia
Tech, Hahn Hall South, 800 West Campus Drive, Blacksburg, Virginia 24061,
United States.
N
H
N
H
E-mail: pcarlier@vt.edu
Cl
Cl
†.Electronic Supplementary Information (ESI) available: Observed 13C and 1H NMR
5a (R = H)
7a (R = CH3)
6a (R = H)
8a (R = CH3)
chemical shifts and 1H-1H coupling constants of 7a
-
ae and 8a
energies and Boltzmann populations of all conformers of 7a 7b
weighted calculated 1H-1H coupling constants and 13C NMR chemical shifts of 7a
8a
8b; NMR spectra of new compounds; cartesian coordinates and 13C NMR
shielding tensors of all conformers of 7a 7b 8a 8b. See DOI: 10.1039/x0xx00000x
-
,
ae; calculated free
8a 8b; Boltzmann-
7b
,
,
Figure 1 1,3-disubsubstituted THβC 1 and related medicinally important compounds.
Talcarpine’s (2) atom numbering modified to highlight similarity to other THβCs in the
Figure.
,
,
,
,
,
,
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Organic & Biomolecular Chemistry
Page 2 of 13
ARTICLE
Journal Name
reliably upfield of those of the corresponding cis-diastereomers
(e.g., 6a 8a). The accuracy of this assignment method has been
View Article Online
DOI: 10.1039/C9OB01139K
,
confirmed in several cases by X-ray crystallography12-15 and
NOESY/ROESY correlations (between H1 and H3 in cis-
diastereomers),13, 16-18 and appears to be secure. The 13C NMR
method is based on the so-called “γ-gauche effect,” which
attributes upfield shifts of carbons to steric compression
resulting from gauche interaction with a γ-substituent.19, 20 The
γ-gauche effect of sp3-hybridized carbon has been well-
documented in decalins,21 norbornanes,22 acetonides,23 and
conformationally-locked cyclohexanes.24-26 It has also been
invoked to deduce conformational preferences of
conformationally-mobile substituted cyclohexanes,27 and to
deduce relative configuration of natural products28 and various
acyclic compounds.29-32 However, in some cases the magnitude
of this effect is very small.22 In addition, for sp2-hybridized
carbons, γ-gauche substituents can cause both small upfield26
and small downfield26, 27 shifts, and the effect on sp-hybridized
carbons can also be very small.24 As yet there is no firm
consensus that the upfield shift of sp3-carbons possessing a γ-
gauche interaction is actually steric in origin,19, 33 and a number
of observations in our laboratory (detailed below) did not
comport with the steric hypothesis. Given these uncertainties,
1
we validated a H NMR coupling constant method, based on
firm theoretical grounds, to reliably assign relative
configuration in 1,3-disubstituted THβCs (31 examples).
Figure 2 Pictet-Spengler adduct methyl esters studied in this work.9, 37
1
Reliance on H NMR coupling constants rather than 13C NMR
chemical shifts confers several benefits, including reduced
sample mass and experiment time requirements. Most
significantly, unlike the 13C NMR chemical shift method, this
method can be applied reliably when only one diastereomer is
in hand, as is the case for highly diastereoselective Pictet-
Spengler reactions.17, 34-36 Use of the 13C NMR method in these
cases requires further chemical transformation or subsequent
synthesis of the other diastereomer. The assignment method
presented herein is supported by an extensive density
empirical rule12 (See Table S1). Throughout our previous work,
we noted that the cis-isomer was first-eluting in each case, as
long as the eluent comprised a mixture of methylene chloride,
hexane, and ethyl acetate. In the case of 7a and 8a, the
assignment of trans-configuration to diastereomer 7a was
confirmed by X-ray crystallography of its methyl amide
derivative.9 It should be noted that the assignment of the C1
and C3 13C NMR peaks is not always straightforward: the C1
peak may be upfield or downfield of C3, depending on the
substitution of the C1-aryl group. Furthermore, in the trans-
1
functional theory (DFT)-based conformational analysis and H-
1H coupling constant prediction for two pairs of trans- and cis-
isomers 7a
methoxy carbon are often very close. Thus, the chemical shifts
(1H and 13C) of 7a
8a, and 15 other pairs of diastereomers were
-z
, the 13C NMR chemical shifts of C3 and the
diastereomers (7a/8a, 7b/
8b). Lastly, DFT calculations of 13C
chemical shifts of C1 and C3 in these four compounds
demonstrate that steric compression associated with the “γ-
gauche” effect is not responsible for the upfield shift of C1 in
trans-configured Pictet-Spengler adducts.
,
confirmed using HSQC, HMBC, and C-DEPT (See Tables S1-S4,
Figures S1-S5). Taken together, over 31 pairs of diastereomers,
the average C3 chemical shift is 52.5 ± 0.6 ppm for trans- and
56.8 ± 0.2 ppm for cis-, giving an average relative shift of -4.1
± 0.6 ppm for C3 in 7a-ae relative to 8a-ae (C3 Δδ7-8, Table 1).
Note that the C1 chemical shifts of the trans- and cis-esters 7a-
ae and 8a-ae are significantly influenced by the 1-aryl and 1-
alkyl substituents, as evidenced by the large standard deviations
Results and Discussion
13C and 1H NMR Analysis of 1,3-disubstituted THβCs
1
For this study we analyzed the H and 13C NMR data of 30
additional pairs of diastereomeric THβC methyl esters related
seen (51.7 ± 3.2 and 54.6 ± 3.4 ppm, for 7a-ae and 8a-ae
,
to 7a and 8a
. Most of these compounds (7b-z, 8b-z) were
respectively). Nevertheless, within a pair of diastereomers, the
relative shift of C1 in 7a-ae relative to 8a-ae is quite constant
(Δδ7-8 = -2.9 ± 0.5 ppm). With this data in hand, the possible γ-
gauche rationale for the upfield C1 and C3 chemical shifts in 7a-
ae relative to 8a-ae (Δδ7-8, Table 1) can be evaluated. The
tetrahydropyridine ring of cis-esters 8a-ae should adopt an all
previously prepared by Pictet-Spengler reaction of (S)-Trp-OMe
with the requisite benzaldehyde;9, 37 five additional pairs of
diastereomers derived from aliphatic aldehydes were also
prepared for this work (7aa-ae, 8aa-ae, Figure 2). Each pair of
diastereomers was separated by column chromatography, and
their configurations assigned as cis- or trans- using the 13C NMR
pseudoequatorial conformation A, since the alternative half-
2 | J. Name., 2012, 00, 1-3
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ae, C1ʹ of the 1-substituent is gauche to C3, while CO2Me
Table 1 Average 13C NMR chemical shifts (δ, ppm) of C3, C1, C=O, and C1' (CDCl3) in the
trans- and cis-Pictet-Spengler adducts (7a-7ae and 8a-8ae, respectively), and average
relative shifts of the trans-adducts (Δδ7-8, ppm).
View Article Online
remains anti to C1. Similarly, in conformeDrOI: 10.1039/C9OB01139K
ae, the CO2Me group is gauche to C1, while C1ʹ remains anti to
C3. Thus, if (and only if) both conformations and of 7a-ae
C (ψax-CO2Me) of 7a-
B
C
a
δ(7a-ae)
52.5 ± 0.6
51.7 ± 3.2
174.0 ± 0.4
134.2 ± 7.8
41.4 ± 4.7
δ(8a-ae)
56.8 ± 0.2
54.6 ± 3.4
173.3 ± 0.2
133.4 ± 8.2
40.7 ± 5.2
Δδ7-8
are populated, will both C1 and C3 of 7a-ae experience steric
compression relative to those carbons in 8a-ae, and thus be
shifted upfield in the 13C NMR spectrum. Logically, such steric
compression would also be expected to result in similar upfield
C3
C1
C=O
Aryl C1ʹ b
Alkyl C1ʹ c
-4.1 ± 0.6
-2.9 ± 0.5
+0.8 ± 0.2
+0.9 ± 0.5
+0.7 ± 0.4
13C NMR shifts for those carbons in 7a
-ae that interact with C1
and C3 in this γ-gauche relationship, namely the CO2Me C=O,
and C1ʹ. Interestingly however, this reciprocity is not seen. Over
31 pairs of compounds, the C=O 13C NMR resonances of 7a-ae
are not upfield of those in 8a-ae, but are in fact slightly
aDefined at each of the carbons as δ for 7 – δ for 8. bData from 16 1-aryl Pictet-
Spengler analogs for which C1ʹ was unambiguously assigned. cData from 7aa-ae
and 8aa-ae.
downfield (∆δ7 8 = +0.8 ± 0.2 ppm, Table 1). Similarly, in the 16
-
cases of 1-aryl Pictet-Spengler adducts where we have
unequivocally assigned C1ʹ, this resonance is not upfield in the
trans- relative to the cis-isomer (Table 1, ∆δ7 = +0.9 ± 0.5).
-8
These small downfield shifts of the CO2Me C=O and aryl C1ʹ
carbons in 7aa ae might be ascribed to some not yet
understood insensitivity of sp2-hybridized carbons to the
-
훾
-
gauche effect. But in the five pairs of 1-alkyl Pictet-Spengler
adducts, the sp3-hybridized C1ʹ carbons are also not shifted
upfield in 7aa-ae relative to 8a
The failure of the gauche-oriented C1ʹ and C3 sp3-carbons in
7aa ae (Figure 3B) to reciprocally exert upfield shifts on each
other (relative to 8a ae) thus clearly undermines the proposal
-ae (Table 1, ∆δ7 = +0.7 ± 0.4).
-8
-
-
that “steric compression” determines C1 and C3 chemical shifts
in THβCs.
With the rationale of the 13C NMR chemical shift assignment
method now uncertain, we looked for another method by which
to reliably assign relative configuration. As mentioned earlier,
NOESY/ROESY has been used periodically to confirm cis-
configuration (correlation of H1 and H3), 13, 16-18 but we favored
a method of greater operational simplicity. Two previous
studies used the magnitude of vicinal coupling constants as a
means of assigning cis- or trans-configuration, albeit for a single
pair of diastereomers each.13, 16 We sought to validate this
method with the 31 additional pairs of diastereomers depicted
in Figure 2. Inspection of conformer
A for cis-esters 8a-ae
suggests that the three-bond coupling constants 3J4α-3 and 3J4β-3
should be well differentiated: H4α is approximately gauche to
H3, and H4β is approximately anti to H3 (Figure 3). In contrast,
if
the
trans-diastereomers
7a
-
ae
populate
C as predicted, then
both
Figure 3 Proposed half-chair conformations of the tetrahydropyridine rings in 8a-ae (A)
and 7a-ae (B, C), and Newman projections down the C3-N2 and N2-C1 axes. Gauche
interactions of ring substituents are highlighted in red.
tetrahydropyridine conformations
3J4β-3 values will not be as well differentiated from the
corresponding J4α-3 values, since H4β is approximately anti to
B
and
3
H3 in conformer
B, but is approximately gauche to H3 in
conformer . For 8a, HSQC identified H4 resonances at 3.25 and
C
chair conformation (not shown) would feature severe 1,3-
diaxial interactions between C1ʹ and CO2Me (Figure 3). In
contrast trans-esters 7a-ae would likely populate two
3.02 ppm. Individual irradiation of these two resonances
resulted in 6.0% and ~0% NOE enhancement of H3 (3.99 ppm,
Figure S5, Table S5), allowing assignment of H4α to the peak at
3.25 ppm, and H4β to the peak at 3.02 ppm. Based on these
alternative half-chair conformations B and C, each featuring one
pseudoequatorial (ψeq) and one pseudoaxial (ψax) group.38 As
can be seen in the Newman projections in Figure 3 for the cis-
isomers 8a-ae, the CO2Me group on C3 is anti to C1 (view down
C3-N2 axis), and C1ʹ of the C1-substituent is anti to C3 (view
3
3
assignments we measured J4α-3 and J4β-3 as 4.1 and 11.0 Hz,
respectively. Thus, a large difference is seen in these coupling
constants for 8a, as expected. Similarly, we used 1D NOE
experiments to assign H4β and H4α in trans-ester 7a (Figure S4,
down N2-C1 axis). However, in conformer B (ψeq-CO2Me) of 7a-
This journal is © The Royal Society of Chemistry 20xx
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3.26 ppm
ddd
3.25 ppm
ddd
View Article Online
DOI: 10.1039/C9OB01139K
O
O
6.0%
5.5%
4
aH
4
OMe
aH
OMe
3.10 ppm
3.02 ppm
ddd
ddd
4
4
bH
bH
3.99 ppm
dd
3.84 ppm
dd
H3
H3
NH
NH
1.2%
Cl
Cl
Cl
N
N
H
H
8a
2J4 b = 15.1 Hz
7a
2J4 b = 15.4 Hz
4
a
4
a
3J4
Cl
3J4
3J4
=
=
5.0 Hz
7.8 Hz
=
4.1 Hz
3
3
a
a
3J4 3 = 11.0 Hz
3
b
b
Figure 4 Assignment of diastereotopic protons H4α and H4β in 8a and 7a. Abbreviations
used: dd = doublet of doublet, ddd = doublet of doublet of doublet. Note that H4α and
H4β are coupled through 5 bonds to H1 (not shown), see Figure 5.
Table 2 Selected average 1H chemical shifts and coupling constants in 7a-ae and 8a-ae
(CDCl3).
Entry
Avg
7a-ae
8a-ae
1
2
3
4
5
6
7
8
δ H3 (ppm)
δ H4α (ppm)
δ H4β (ppm)
3J4β-3 (Hz)
3.91 ± 0.09
3.23 ± 0.06
3.10 ± 0.05
7.3 ± 0.9
5.2 ± 0.2
15.3 ± 0.1
1.5 ± 0.1
3.94 ± 0.09
3.22 ± 0.04
2.98 ± 0.08
11.1 ± 0.1
4.1 ± 0.1
15.1 ± 0.1
2.5 ± 0.1
1.8 ± 0.1
3J4α-3 (Hz)
2J4α-4β (Hz)
5J4β-1 (Hz)
5J4α-1 (Hz)
Figure 5 Five-bond coupling of H1 to H4α and H4β in 7b and 8b A) H1, H3, H4α, and H4β
resonances in the 1H NMR spectrum of 7b; B) Single frequency decoupling of H1 in 7b;
C) H1, H3, H4α, and H4β resonances in the 1H NMR spectrum of 8b; D) Single frequency
decoupling of H1 in 8b.
1.3 ± 0.2
3
3
Table S5). In this case the values of J4α-3 and J4β-3 were much
more similar (5.0 and 7.8 Hz, respectively). These findings are
occasionally seen at H1, as shown for 8b in Figure 5C. Although
5-bond 1H-1H coupling is rare, it is particularly common in
cyclohexenes,40, 41 (which resemble the tetrahydropyridine ring
of 7a-ae and 8a-ae) and has been noted at least once previously
in Pictet-Spengler adducts.13
1
3
summarized in Figure 4. Based on the H chemical shifts and J
values of 7a and 8a, H4α and H4β were assigned in the other 30
pairs of diastereomers, and the individual coupling constants
1
were determined (Tables S3 & S4). Average H chemical shifts
and J values are shown in Table 2. As expected from their
1
distance from the C1-substituent, the H chemical shifts of H3,
Density Functional Theory (DFT) Conformational Analysis of 7a/8a
and 7b/8b
H4α, and H4β in 7a
(Table 2, entries 1-3). As can be seen, the average value of 3J4β-3
in cis-esters 8a ae is 11.1 ± 0.1 Hz (Table 2, entry 4), suggesting
-ae and 8a-ae fall within very narrow ranges
3
As described above, values of J4β-3 effectively distinguish
-
trans-esters 7a-ae from cis-esters 8a-ae. Furthermore, the
an approximately antiperiplanar arrangement of H4β and H3. In
observed values of 3J4β-3 in these compounds appear reasonable
based on a first-principles conformational analysis (Figure 3). To
further substantiate our method for stereochemical assignment
we undertook computational studies of the possible
3
contrast, the average value of J4β-3 in trans-esters 7a
-
ae is
consistently lower (7.3 ± 0.9 Hz), as expected if both conformers
B
and C
were populated.39 These well-differentiated average
values of 3J4β-3 for cis- and trans-diastereomers are very similar
conformers of 7a
/
8a and 7b
/
8b
.
Multiple automated
to those reported for the two aforementioned pairs of
conformer searches were performed at the MMFF94 level,
starting from at least two initial geometries of each compound.
These structures were then optimized at B3LYP/6-31G(d)42, 43 to
give 16 conformers of 7a, 14 conformers of 8a, and 8
conformers each for 7b and 8b. As shown in Table 3, these
conformers can be classified with respect to four structural
features, and thus grouped into eight ensembles of conformers.
First, the approximate half-chair conformation of the
tetrahydropyridine ring can be classified as having a ψax- or ψeq-
CO2Me group; representative calculated structures of 7a
16
diastereomers noted previously.13,
Note that the average
ae and 8a ae,
3
values of J4α-3 (entry 5) are similar for both 7a
-
-
consistent with a near gauche orientation of H4α and H3 in all
three conformers
One noteworthy feature of the 1H NMR spectra of 7a
ae is the visible 5-bond coupling between H1 and H4α, and
A-C.
-
ae and
8a
-
between H1 and H4β, as shown for 7b and 8b in Figure 5 (Table
2, entries 7-8). Note that for trans-1-aryl derivatives 7a-z, H1
appears as a broad singlet, as shown for 7b in Figure 5A. That
the fine splitting in H4α and H4β is in fact due to 5-bond
coupling to H1 was confirmed by single-frequency decoupling
exhibiting these features are shown in Figure 6 (I and II,
respectively). Interestingly, the orientation of the 1-aryl groups
(Figure 5B). For cis-1-aryl derivatives 8a-z, 5-bond coupling is
4 | J. Name., 2012, 00, 1-3
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Table 3 The number of B3LYP/6-31G(d) potential energy minima found for 7a/8a, 7b/8b
View Article Online
within each conformational ensemble.
DOI: 10.1039/C9OB01139K
Conformer
Total
7a
16
8
8
8
8
8
8
12
4
8a
14
6
8
8
6a
6
8
12
4
7b
8
4
4
-
8b
8
4
4
-
ψax-CO2Me
ψeq-CO2Me
exo-2ʹ-Cl
endo-2ʹ-Cl
ax-H2
eq-H2
H-bondb
No H-bondc
-
-
4
4
6
2
4
4
6
2
aTwo conformers, namely ψax-CO2Me, endo-2ʹ-Cl, ax-H2, were not found in the
initial conformational search, likely due to their expected high energy.
bIntramolecular H-bonding of H2 to C=O or OMe deduced from H2⋯O distances
ranging from 2.3 - 2.7 Å. cLack of H-bond deduced from H2⋯O > 3.7 Å.
in 7a and 7b does not differ significantly among these different
tetrahydropyridine conformers. For 7a, the C1ʹ-C1-C9a-N9
dihedral angle φ for II (66.8°) is only slightly larger than that
seen in
expectation that the 1-aryl group would be pseudoaxial in II and
pseudoequatorial in and III. The larger than expected φ value
in and III is likely a consequence of allylic strain of the 1-aryl
I and III (52.7 and 46.1°, respectively), despite the
I
I
group and N9. Second, the 2ʹ-Cl of 7a and 8a can be oriented
exo- or endo- to the tetrahydropyridine ring: see Figure 6 for
calculated structures
isomerism is absent in 7b and 8b
I
/
II (exo-) vs III (endo-). Note that this
which feature an
,
unsubstituted phenyl ring. Third, the N-H can be axial or
equatorial, and fourth, the CO2Me group can be hydrogen-
bound to the NH, or not hydrogen-bound.44 These last two
features are illustrated in the representative computed
structures of 7a in Figure 6. In trans-ester 7a, eight ψax-CO2Me
and eight ψeq-CO2Me conformations were located (cf.
B and C,
Figure 3). In the cis-isomer 8a, only six ψax-CO2Me conformers
and eight ψeq-CO2Me conformations were found. As expected,
the six ψax-CO2Me conformers of 8a are all much higher in
energy than the ψeq-CO2Me conformations, due to 1,3-di-
pseudoaxial interaction of the C3-CO2Me and C1-aryl groups.45
As depicted in Figure 6, for 7a and 8a, the 2ʹ-Cl group can adopt
an exo- or endo-orientation with respect to the
tetrahydropyridine ring. This type of conformational isomerism
Figure 6 Representative calculated (B3LYP/6-31G(d)) structures of 7a illustrating the
orientation of the CO2Me, NH, and 2ʹ-Cl groups. The C1-C1-C9a-N9 dihedral angle is
represented by φ. In conformers I and II, internal hydrogen bonding between H2 and the
is not observed in 7b
phenyl ring; thus, the number of possible conformations
available to 7a 8a is generally double that of 7b 8b. The axial
/8b, since they bear an unsubstituted
carbonyl or methoxy
O atoms is depicted with orange dashed line. Note that
intramolecular hydrogen bonding is geometrically impossible in conformer III.
Conformers I, II, and III are described as 7a-01, 7a-09, and 7a-10 respectively in the
Supporting Information. Graphics rendered using Chimera.46
/
/
and equatorial orientations of the hydrogen (H2) are roughly
equally represented among the conformers. In conformations
featuring a ψeq-CO2Me group, both ax-H2 and eq-H2 can
hydrogen-bond to the CO2Me group, via the C=O or OMe
oxygen atoms. In contrast, for conformations featuring a ψax-
CO2Me group, only eq-H2 can form an intramolecular H-bond
via the C=O or OMe oxygen atoms. In ψax-CO2Me/ax-H2
conformations, an intramolecular H-bond is geometrically
impossible (e.g. structure III, Figure 6). Structures of the lowest
energies of these conformers at 298 K, single point energies
were calculated using the mPW1PW9147and B3LYP functionals,
at a larger basis set (6-311+G(2d,p)), and with PCM48 implicit
solvation (CHCl3). As described below, the 6-311+G(2d,p) basis
set, mPW1PW91 functional, and PCM solvation model were
chosen based on their suitability for 13C NMR shift
calculations.49 In addition, we also calculated single point
energies at M06-2X/def2-TZVP (with PCM solvation), since the
M06-2X functional50, 51 has been recommended for accurate
energy conformers of 7a, 8a, 7b, and 8b are presented in the
Supporting Information (Figures S6 & S7). To calculate free
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Table 4 Boltzmann distribution of conformational ensembles, based on mPW1PW91/
Table 5 Calculated (B3LYP/6-31(d,p)u+1s//B3LYP/6-31G(d))a vs observed (italics) 1H-1H
View Article Online
6-311+G(2d,p) (PCM, CHCl3)//B3LYP/6-31G(d) free energies at 298 K.
coupling constants for 7a/8a and 7b/8b.
DOI: 10.1039/C9OB01139K
7a
[%]
8a
[%]
2.6
97.4
81.7
18.3
47.8
52.2
99.5
0.5
7b
[%]
39.8
60.2
–
8b
[%]
0.8
99.2
–
7a
(Hz)
8a
(Hz)
10.5/11.0
3.9/4.1
15.1/15.1
3.0/2.5
7b
(Hz)
8b
(Hz)
ψax-CO2Me
ψeq-CO2Me
exo-2ʹ-Cl
endo-2ʹ-Cl
ax-H2
eq-H2
H-bond
No H-bond
26.9
73.1
93.0
7.0
38.6
61.4
95.0
5.0
3J4β-3
3J4α-3
2J4α-4β
5J4β-1
5J4α-1
8.3/7.8
4.5/5.0
15.3/15.4
1.9/1.5
1.2/1.2
6.2/6.8
5.1/5.4
15.3/15.4
1.9/1.6
1.8/1.4
10.7/11.2
3.9/4.3
15.0/15.2
3.0/2.6
2.1/1.9
b
–
–
2.0/1.9
35.9
64.1
94.2
5.8
42.5
57.5
99.9
0.1
aWeighted average over all conformations, based on mPW1PW91/6-
311+G(2d,p)//B3LYP/6-31G(d) Boltzmann distribution (298 K). b 2JHH values for sp3
C-H are calculated to be negative, as expected;55 the absolute values are shown
here.
energies of conformers, especially in conjunction with the def2-
TZVP basis set.52, 53 Free energy corrections (based on B3LYP/6-
31G(d) frequencies) were then applied to these single point
energies (Tables S6-S13).
conformations are similar in energy for all four compounds;
3) intramolecularly H-bonded structures are much more
favorable than non-H-bonded structures for all four
compounds.
Boltzmann distributions of the conformers of 7a/8a, 7b/8b
calculated using mPW1PW91/6-311+G(2d,p) (PCM, CHCl3) free
energies were very similar to those based on B3LYP/6-
311+G(2d,p) (PCM, CHCl3) free energies (Table S14). M06-
2X/def2-TZVP (PCM, CHCl3) free energy-based Boltzmann
distributions largely follow these trends, but for 8a and 8b show
a diminished preference for conformers in the ψeq-CO2Me
DFT calculations of select 1H-1H coupling constants in 7a/8a and
7b/8b
Using mPW1PW91/6-311+G(2d,p) (PCM, CHCl3) Boltzmann
1
weights we then calculated select H-1H coupling constants at
B3LYP/6-31G(d,p)u+1s//B3LYP/6-31G(d), which has been found
to be economical and accurate (RMSD < 0.5 Hz) for a wide range
of organic molecules.56 As can be seen in Table 5, this method
ensemble (e.g. A, Figure 3) vs those in the ψax-CO2Me ensemble
(see Table S14). As a consequence (see below), mPW1PW91
and B3LYP/6-311+G(2d,p)-based Boltzmann distributions give
worked very well for 7a/8a and 7b/8b. For the 5 coupling
3
superior prediction of J4β-3, relative to those based on M06-
constants previously presented in Table 2, over 4 compounds,
excellent accuracy (RMSD < 0.4 Hz, Tables S15,16) was
obtained. Most importantly, the close correspondence of
2X/def2-TZVP.
Furthermore
since
calculations
at
mPW1PW91/6-311+G(2d,p) give improved prediction of 13C
NMR chemical shifts relative to those based on B3LYP/6-
311+G(2d,p), (see below), for simplicity we will base all
calculations below on mPW1PW91/6-311+G(2d,p) (PCM, CHCl3)
Boltzmann weights of the conformers. These values were
summed to calculate the percentage occupying each of the four
pairs of conformational ensembles noted previously (Table 4).
As anticipated, trans-esters 7a and 7b significantly populate
both the ψax-CO2Me and ψeq-CO2Me conformational ensembles
3
calculated and observed values of J4β-3 and 3J4α-3 suggests that
the mPW1PW91/6-311+G(2d,p) (PCM, CHCl3) Boltzmann
weights accurately capture the distribution of ψax-CO2Me and
ψax-CO2Me conformers of the tetrahydropyridine ring in 7a
/8a
and 7b 8b. For reference, use of the M06-2X/def2-TZVP
/
Boltzmann distributions in these calculations gave less accurate
values of 3J4β-3 for 8a and 8b (8.8 and 10.2 Hz, respectively, Table
S16) as a consequence of the diminished energetic difference
between the ψax-CO2Me and ψax-CO2Me conformers.
(cf.
B and C, Figure 3). For 7a, the lowest energy ψax-CO2Me
conformation (7a-01) is only 0.9 kcal/mol higher in energy than
global minimum ψeq-CO2Me structure (7a-08, Table S7, Figure
S6). For 7b, the lowest energy ψax-CO2Me conformation (7b-01)
and lowest energy ψeq-CO2Me conformation (7b-05) are within
0.02 kcal/mol of each other (Table S9, Figure S7). In contrast,
cis-esters 8a and 8b adopt >97% and >99% ψeq-CO2Me
conformations respectively.54 For 8a and 8b, the lowest energy
DFT calculations of 13C chemical shifts of 7a/8a and 7b/8b
With the B3LYP/6-31G(d) geometries and mPW1PW91/6-
311+G(2d,p) (PCM, CHCl3) Boltzmann distribution of the
conformers of 7a/8a and 7b/
8b validated by the calculated 1H-
1H coupling constants in Table 5, we were positioned to
determine whether the distinctive C1 and C3 chemical shifts of
the cis- and trans-diastereomers could be reproduced by
computation. We thus calculated 13C NMR chemical shifts (δ) for
ψax-CO2Me conformations are 3.1 (8a-04) and 4.6 kcal/mol (8b
-
05) higher in energy than global minimum ψeq-CO2Me
structures (8a-01 and 8b-03, Figures S6 & S7, Tables S11 & S13).
As discussed at the outset, ψax-CO2Me conformations of 8a and
8b would be unstable by virtue of 1,3-dipseudoaxial interactions
with the ψax-aryl group at C1. Thus, these DFT calculations
support the first-principles conformational analysis presented
each conformer of 7a, 7b, 8a, and 8b from the B3LYP/6-31G(d)
geometries at the B3LYP/6-311+G(2d,p) (PCM, CHCl3) and
mPW1PW91/6-311+G(2d,p) (PCM, CHCl3) levels of theory
(Table S17-S20). These functionals, basis set, and solvation
model were selected based on their excellent performance in a
recent study of colchicine.49 The weighted average 13C NMR
chemical shifts of each carbon in 7a, 7b, 8a, and 8b were then
calculated using the calculated Boltzmann populations; mean
average deviations (MAD) of the calculated chemical shifts from
3
in Figure 3, and the values of J4β-3 reported in Table 2. Other
noteworthy features of our calculations are: 1) in 7a and 8a
there is a significant preference for the exo-2ʹ-Cl orientation,
which appears to be steric in origin; 2) ax-H2 and eq-H2
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Table 6 All-carbon mean absolute deviation (MAD) in calculated 13C NMR chemical shifts
for 7a, 7b, 8a, and 8b at the indicated levels of theory.
View Article Online
DOI: 10.1039/C9OB01139K
Compound
B3LYP/6-311+G(2d,p)
mPW1PW91/6-311+G(2d,p)
(PCM, CHCl3)//
B3LYP/6-31G(d) (ppm)a
(PCM, CHCl3)//
B3LYP/6-31G(d) (ppm)a
7a
7b
8a
8b
Averageb
2.1
1.5
2.0
1.4
1.8
1.7
1.1
1.6
1.0
1.4
aMean absolute deviation in 13C NMR chemical shift for all 19 carbons in each
Figure 7 Weighted (mPW1PW91/6-311+G(2d,p) (PCM,CHCl3)//B3LYP/6-31G(d))
13C NMR chemical shifts for C1 & C3 of 7a and 7b in the ψeq- and ψax-CO2Me
compound. bAverage of MAD for compounds 7a, 7b, 8a, and 8b.
tetrahydropyridine conformational ensembles
B and C. Gauche interactions of
ring substituents with C1 and C3 are highlighted in red.
Table 7 Calculateda vs observed (italics) 13C NMR chemical shifts (δ) for select carbons in
7a, 7b, 8a, 8b, and corresponding differences in δ between diastereomers (∆δ7-8).
Computational evaluation of the role of steric compression in the
13C chemical shifts of C1 and C3 in 7a and 7b
b
Carbon Compounds
δ(7)
δ(8)
∆δ7-8
C3
7a, 8a
7b, 8b
7a, 8a
7b, 8b
7a, 8a
7b, 8b
7a, 8a
7b, 8b
53.4 / 52.3
54.0 / 52.7
52.9 / 51.3
56.6 / 55.1
175.3 / 173.8 174.9 / 173.1
175.8 / 174.3 175.1 / 173.3
139.2 / 137.9 138.6 / 137.4
143.8 / 142.1 142.2 / 140.8
57.5 / 56.7
57.8 / 57.0
55.8 / 53.9
59.8 / 58.8
-4.1 / -4.4
-3.8 / -4.3
-2.9 / -2.6
-3.2 / -3.7
+0.4 / +0.7
+0.7 / +1.0
+0.6 / +0.5
+1.6 / +1.3
With the accuracy of DFT-derived 13C NMR chemical shifts
for 7a/8a and 7b/8b now established, we are in a position to ask
C1
whether these upfield shifts of C1 and C3 in 7a and 7b relative
to 8a and 8b can be attributed to “steric compression.” If so, the
chemical shifts of C1 and C3 in 7a and 7b should be dependent
on the conformation of the tetrahydropyridine ring. By grouping
the individual conformers of 7a and 7b into two overall ψeq- and
ψax-CO2Me tetrahydropyridine conformational ensembles (i.e.
C=O
C1ʹ
aBoltzmann Weighted mPW1PW91/6-311+G(2d,p) (PCM, CHCl3)//B3LYP/6-31G(d)
13C NMR chemical shifts. b∆δ7-8 = δ(7) – δ(8); values in normal font are derived from
calculated chemical shifts, values in italics are from observed chemical shifts.
B
and C
, Figure 3), and recalculating the weighted average 13C
NMR chemical shifts at C1 and C3, we can assess the effect of γ-
gauche-associated steric compression (Figure 7, Tables S19-
S20). As can be seen, the calculated 13C chemical shifts of C3 in
the observed values were calculated to assess the performance
of each functional. As seen in Table 6, both functionals predict
13C NMR chemical shifts well, giving MAD of ~2 ppm or less. The
7a and 7b in ensemble
in ensemble (C3 ∆δB C = -5.2 and -5.0 ppm respectively). These
calculated upfield shifts could be consistent with steric
compression of C3 resulting from -gauche interaction with the
C1-aryl group in ensemble (cf. Figure 3). However, no
significant differences are seen in the chemical shifts of C1 in 7a
and 7b between ensembles and (C1 ∆δB = -0.3 and +0.6
ppm, respectively), despite its -gauche orientation to the ψax-
C3-CO2Me group in ensemble . These observations are
B are considerably upfield of the values
C
-
slightly smaller MAD values seen for 7b/8b relative to 7a/8a is
a consequence of inaccurate calculation of the 13C chemical
shifts for Cl-bearing carbons C2ʹ and C4ʹ in 7a and 8a (see Tables
S17, S19). However, over the four compounds examined, the
mPW1PW91 functional performs better than the B3LYP
functional (average MAD = 1.4 ppm vs 1.8 ppm). A recent study
of the calculated 13C NMR spectrum of colchicine in CDCl3 also
noted improved accuracy of the mPW1PW91 functional relative
to B3LYP, and our calculated MAD (1.4 ppm) is even lower than
they reported (1.9 ppm).49 As can be seen in Table 7, 13C NMR
chemical shifts for C3, C1, C=O, and C1ʹ calculated by this
method very closely match the observed values (italics) for all
four compounds, with deviations generally less than 2 ppm.
Looking at the difference in chemical shift for a particular
훾
B
B
C
-C
훾
C
replicated at the B3LYP/6-311+G(2d,p) (PCM, CHCl3)//B3LYP/6-
31G(d) level (Tabled S22-S22). Thus, the uniform upfield shift of
C1 in 7a
the -gauche effect, since the C1 chemical shifts remain
unchanged whether the C1-CO2Me group is gauche (ensemble
) or anti- (ensemble ).
-ae relative to 8a-ae (Table 1) cannot be attributed to
훾
C
B
carbon between diastereomers (∆δ7 8), the congruity is even
-
Conclusions
better. For example, the C1 and C3 ∆δ7 8 values for 7a/8a are
-
predicted to be -4.1 and -2.9 ppm; the observed ∆δ7 8 values are
-4.4 and -2.6 ppm, respectively; the correspondences for 7b/8b
are also very close. Note that this DFT method also recapitulates
the observed slight (+0.5 to +1.3 ppm) downfield shifts of C=O
and C1ʹ in the trans-isomers. These close correspondences are
also seen using the B3LYP functional (Table S17-S20). Thus, DFT
-
In this report we have demonstrated that the trans- or cis-
configuration of 1,3-disubstituted THβCs can be reliably
assigned by 1H NMR spectroscopy, based on a particular
coupling constant (3J4β-3). Over 31 cis-esters compounds 8a
-
ae
,
3
the value of J4β-3 is 11.1 ± 0.1 Hz, indicating they exclusively
populate a tetrahydropyridine conformational ensemble that
predicts the observed upfield shifts of C1 and C3 in 7a
-b relative
features a ψeq-CO2Me group at C3 (
the 31 trans-esters compounds 7a
A
, Figure 3). In contrast for
3
to 8a , as well as the slight downfield shifts of C=O and C1ʹ.
-
b
-
ae, the value of J4β-3 is 7.3
± 1.2 Hz, indicating these compounds populate two nearly
equienergetic tetrahydropyridine conformational ensembles:
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one featuring a ψeq-CO2Me group at C3 (
featuring a ψax-CO2Me group at C3 (C, Figure 3). In every case obtained using the B3LYP functional with core-augmented 6-
B
, Figure 3), and one
Calculated JHH coupling constants shown in Table 5 were
View Article Online
DOI: 10.1039/C9OB01139K
these assignments match those made by the 13C NMR chemical 31G(d,p) basis set (“6-31G(d,p)u+1s”). Note that only Fermi
shift method of Ungemach et al,12 but this 1H NMR assignment contact terms were evaluated, and only couplings between the
method has several benefits. In addition to reduced sample hydrogen atoms of interest (H4β, H4α, H3, H1) were specified
quantity and experiment time requirements, it can be applied for calculation. This approach was selected based on its high
when only one stereoisomer is in hand. Extensive DFT accuracy (RMSD <0.5 Hz over a large test set) and low
1
calculations support the conformational analysis undergirding computational cost.56 Interestingly, although H chemical shift
1
the H NMR assignment method, including accurate (RMSD = modeling benefits from inclusion of implicit solvation, this study
3
1
0.4 Hz) calculation of J4β-3 and other H-1H coupling constants. demonstrated that implicit solvation does not improve the
Furthermore, these calculations show that the presence or accuracy of calculated JHH values;56 thus we calculated values in
훾
-gauche substituent has no effect on the 13C NMR the gas phase. The coupling constants (3J4β-3, J4α-3, J4β-4α, J4β-1,
3
2
5
absence of a
chemical shift of C1 in 7a and 7b (Figure 7). This calculated 5J4α-1) in each conformer of 7a
result, combined with the observed failure of C1 and C3 to exert recommend factor of 0.9117) are given in Table S15, which
reciprocal upfield shifts of the C=O and C1ʹ carbons in 7a ae includes a sample Gaussian route section to perform these
,
8a, 7b, and 8b, (scaled by the
-
(Table 1), thus challenge the conceptual foundation of the calculations.
To obtain weighted average JHH coupling
traditional 13C NMR chemical shift assignment method for 1,3- constants, the various Boltzmann distributions were applied
disubstituted THβCs. With this foundation in doubt, one cannot (Table 5 and S16).
predict scenarios under which the method would fail to
Shielding tensors σ for each carbon in each conformer were
properly assign trans- and cis-THBCs. Since biological activity calculated from the B3LYP/6-31G(d) geometries at the B3LYP/6-
within the medicinally important 1,3-disubstituted-THβC 311+G(2d,p) (PCM, CHCl3) and mPW1PW91/6-311+G(2d,p)
scaffold is typically very sensitive to configuration,2, 5, 9, 37
a
(PCM, CHCl3) levels of theory. These functionals, basis set, and
missed assignment could muddy emerging structure-activity solvation model were selected based on their excellent
1
relationships and mislead investigators. In contrast, the sound performance in a recent study of the H and 13C NMR solution
3
theoretical foundation of the J4β-3 assignment method spectra of colchicine.49 The corresponding 13C NMR chemical
described herein allows one to use standard tools of shifts were calculated according to the formula δ = (σ – b)/a,
conformational analysis to anticipate conditions under which it where a = slope and b = intercept.59 The values of a and b were
might fail. This important feature and the other advantages taken from the aforementioned study of colchicine,49 and were
listed above commend its use to synthetic and medicinal a = -1.043 , b = 181.717 for B3LYP/6-311+G(2d,p) (PCM=CHCl3),
chemists.
and a = -1.042, b = 186.357 for mPW1PW91/6-311+G(2d,p)
(PCM=CHCl3). The weighted average 13C chemical shifts of each
carbon were then determined using the calculated Boltzmann
distributions, and compared to experimental chemical shifts to
obtain the MAD for each compound studied.
Methods
Computational
To extensively probe the conformational space available to
compounds 7a 7b 8a, and 8b, automated conformer searches
Chemistry
,
,
All NMR spectra were acquired in CDCl3. As described above, 1-
(MMFF94) were performed using Spartan ’16,57 starting from at
least two different geometries. These MMFF94 minima were
then optimized at B3LYP/6-31G(d) using Gaussian 09,58 giving
the numbers of conformers listed above in Table 4. In each case
vibrational frequency analysis (NIMAG=0) confirmed that each
aryl-substituted Pictet-Spengler adducts 7a-z and 8a-z were
prepared previously;9, 37 1H and 13C NMR analyses described in
this paper were performed on archived samples.
stationary point was a minimum. Individual conformers of 7a
,
Experimental
7b 8a, and 8b are identified in the Supporting Information as
,
7a-01 to 7a-16, 7b-01 to 7b-08, 8a-01 to 8a-14, 8b-01 to 8b-08, Synthesis of 7aa and 8aa
respectively. Single point energies of each conformer were
To a mixture of L-tryptophan methyl ester hydrochloride (514
calculated with three different functionals and larger basis sets,
as described above: B3LYP/6-311+G(2d,p), mPW1PW91/6-
311+G(2d,p) and M06-2X/def2-TZVP each with implicit
solvation SCRF=(PCM,Solvent=Chloroform). Free energies were
calculated by adding the free energy (298 K) corrections derived
from unscaled B3LYP/6-31G(d) frequencies to these single point
energies, to derive the corresponding Boltzmann distributions.
The overall population of each of the eight conformational
ensembles described in Table 4 (and Table S14) were calculated
by summing the Boltzmann populations of the appropriate
individual conformers.
mg, 2.02 mmol), 4Å molecular sieves (1 g, powdered), and
pentanal (0.24 mL, 2.26 mmol), CH2Cl2 (6 mL) was added under
nitrogen. The resulting mixture was stirred at room
temperature for 48 hours. TFA (0.3 mL, 3.92 mmol) was added
dropwise. Reaction mixture was further stirred at room
temperature for additional 24 hours. Reaction was cooled to
0 °C and saturated aqueous solution of NaHCO3 (6 mL) was
added, followed by addition of EtOAc (6 mL). After stirring for
30 min at 0 °C, the molecular sieves were filtered and phases of
the filtrate were partitioned and the aqueous layer was
extracted with EtOAc (3 x 10 mL). The combined organic layers
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were washed with saturated aqueous NaCl solution (25 mL), Methyl (1S,3S)-1-cyclohexyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
View Article Online
DOI: 10.1039/C9OB01139K
dried over Na2SO4 and concentrated in vacuo. Compounds 7aa b]indole-3-carboxylate (8ab):
and 8aa were separated from the crude material by flash 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.48 (ddd, J = 7.6, 1.4,
chromatography (gradient, from 1:1 CH2Cl2 : hexane to 2:2:1 0.7 Hz, 1H), 7.34 (dt, J = 8.0, 1.0 Hz, 1H), 7.19 – 7.08 (m, 2H),
CH2Cl2 : hexane : EtOAc) to give 8aa (190 mg, 33%, first-eluting, 4.16 (q, J = 2.3 Hz, 1H), 3.82 (s, 3H), 3.74 (dd, J = 11.2, 4.1 Hz,
off-white solid) and 7aa (45 mg, 8%, second-eluting, yellow oil). 1H), 3.11 (ddd, J = 14.9, 4.1, 1.8 Hz, 1H), 2.78 (ddd, J = 14.9, 11.2,
A mixed fraction of 7aa and 8aa (162 mg, 28% yield) was also 2.6 Hz, 1H), 1.89 – 1.68 (m, 6H), 1.51 – 1.17 (m, 6H). 13C NMR
obtained.
(101 MHz, CDCl3) δ 174.0, 136.1, 134.9, 127.4, 121.7, 119.6,
Methyl
(1R,3S)-1-butyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- 118.0, 110.9, 109.3, 57.8, 56.6, 52.3, 42.5, 29.8, 27.0, 27.0, 26.7,
b]indole-3-carboxylate (7aa):
26.5, 26.1. mp 132.3-135.3 °C. This compound has been
1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.49 (ddd, J = 7.6, 1.4, previously reported and both NMR and mp data are consistent
0.7 Hz, 1H), 7.31 (ddd, J = 8.0, 1.2, 0.7 Hz, 1H), 7.15 (ddd, J = 8.0, with literature.61, 62
7.1, 1.4 Hz, 1H), 7.10 (ddd, J = 7.6, 7.1, 1.1 Hz, 1H), 4.24 (dd, J = Synthesis of 7ac and 8ac
8.3, 4.9 Hz, 1H), 3.99 (dd, J = 7.3, 5.3 Hz, 1H), 3.75 (s, 3H), 3.12
The procedure for 7aa/8aa above was followed using L-
(ddd, J = 15.3, 5.3, 1.2 Hz, 1H), 2.99 (ddd, J = 15.3, 7.3, 1.5 Hz,
1H), 1.93 (s, 1H), 1.84 – 1.68 (m, 2H), 1.58 – 1.44 (m, 2H), 1.43 –
1.35 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 174.4, 136.0, 135.8, 127.2, 121.7, 119.5, 118.1, 110.8, 107.0,
52.7, 52.2, 50.4, 35.5, 28.5, 25.1, 22.9, 14.2. This compound has
been reported previously without full NMR characterization.60
tryptophan methyl ester hydrochloride (501 mg, 1.97 mmol)
and 2-ethylbutanal (0.27 mL, 2.19 mmol). Purification on
column chromatography (5:5:2 CH2Cl2: hexane: EtOAc) yielded
8ac (166.4 mg, 28%, first-eluting, yellow glass) and 7ac (34.3 mg,
6%, second-eluting, yellow oil). A mixed fraction of 7ac and 8ac
(312.3 mg, 52.8% yield) was also obtained.
Methyl
(1S,3S)-1-butyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
Methyl
(1R,3S)-1-(pentan-3-yl)-2,3,4,9-tetrahydro-1H-
b]indole-3-carboxylate (8aa):
pyrido[3,4-b]indole-3-carboxylate (7ac):
1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H),
7.36 – 7.30 (m, 1H), 7.16 (td, J = 8.1, 7.6, 1.3 Hz, 1H), 7.11 (ddd,
J = 7.6, 7.2, 1.2 Hz, 1H), 4.20 (ddt, J = 8.3, 4.1, 2.2 Hz, 1H), 3.83
(s, 3H), 3.80 (dd, J = 11.2, 4.2 Hz, 1H), 3.13 (ddd, J = 15.1, 4.2,
1.9 Hz, 1H), 2.82 (ddd, J = 15.1, 11.2, 2.6 Hz, 1H), 2.00 – 1.91 (m,
1H), 1.72 (dddd, J = 13.8, 10.5, 8.1, 5.2 Hz, 1H), 1.52 – 1.44 (m,
2H), 1.39 (dddd, J = 14.2, 8.7, 6.9, 5.4 Hz, 2H), 0.94 (t, J = 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 173.9, 136.0, 135.8, 127.3,
121.8, 119.7, 118.1, 110.9, 108.2, 56.6, 52.9, 52.3, 34.7, 27.6,
26.1, 23.1, 14.1. This compound has been reported previously
without full NMR characterization.60
1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.49 (ddt, J = 7.5, 1.5,
0.8 Hz, 1H), 7.31 (dt, J = 7.8, 1.1 Hz, 1H), 7.17 – 7.12 (m, 1H),
7.10 (td, J = 7.4, 1.2 Hz, 1H), 4.48 (dt, J = 3.3, 1.8 Hz, 1H), 4.05 (t,
J = 5.2 Hz, 1H), 3.68 (s, 3H), 3.12 (dt, J = 5.4, 1.7 Hz, 2H), 1.91 (s,
2H), 1.63 – 1.48 (m, 3H), 1.38 – 1.23 (m, 3H), 1.05 (t, J = 7.2 Hz,
3H), 0.84 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.7,
136.0, 134.7, 127.4, 121.6, 119.4, 118.0, 110.8, 108.2, 54.1,
52.2, 51.0, 46.7, 24.4, 23.1, 22.7, 12.6, 12.3. HRMS (ESI) [M+H]+
calculated for C18H24N2O2: 301.1911. Found: 301.1910.
Methyl
(1S,3S)-1-(pentan-3-yl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-3-carboxylate (8ac):
1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.48 (ddt, J = 7.7, 1.5,
Synthesis of 7ab and 8ab
The procedure for 7aa
tryptophan methyl ester hydrochloride (1.281 mg, 5.03 mmol), 1H), 7.11 (ddd, J = 7.6, 7.1, 1.2 Hz, 1H), 4.35 (q, J = 2.3 Hz, 1H),
4Å molecular sieves (3.5 g, powdered), and 3.82 (s, 3H), 3.74 (dd, J = 11.2, 4.1 Hz, 1H), 3.12 (ddd, J = 15.0,
/7ab above was followed using L- 0.7 Hz, 1H), 7.33 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H), 7.18 – 7.13 (m,
cyclohexanecarboxaldehyde (0.58 mL, 5.09 mmol). Following 4.1, 1.9 Hz, 1H), 2.78 (ddd, J = 15.0, 11.2, 2.6 Hz, 1H), 1.69 (s,
workup, 7ab and 8ab were isolated by column chromatography 1H), 1.63 – 1.53 (m, 3H), 1.37 – 1.24 (m, 2H), 1.04 (t, J = 7.3 Hz,
(5:5:3.5 CH2Cl2: hexane: EtOAc) to give 8ab (1.02 g, 65%, first- 3H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.1,
eluting, pale yellow solid) and 7ab (149 mg, 10% yield, second- 136.0, 135.5, 127.5, 121.7, 119.6, 117.9, 110.9, 109.5, 56.6,
eluting, off-white solid). A mixed fraction of 7ab and 8ab (190 54.6, 52.3, 46.1, 26.2, 23.3, 22.8, 13.2, 12.8. HRMS (ESI) [M+H]+
mg, 12% yield) was also obtained.
calculated for C18H24N2O2: 301.1911. Found: 301.1908
Methyl
(1R,3S)-1-cyclohexyl-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-3-carboxylate (7ab):
Synthesis of 7ad and 8ad
1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.49 (ddt, J = 7.6, 1.5,
0.8 Hz, 1H), 7.31 (dt, J = 8.0, 1.0 Hz, 1H), 7.18 – 7.07 (m, 2H),
4.08 (d, J = 5.2 Hz, 1H), 4.02 (dd, J = 6.9, 5.3 Hz, 1H), 3.72 (s, 3H),
3.10 (ddd, J = 15.3, 5.3, 1.3 Hz, 1H), 3.00 (ddd, J = 15.3, 6.9, 1.5
Hz, 1H), 1.87 – 1.78 (m, 4H), 1.76 – 1.65 (m, 4H), 1.37 – 1.10 (m,
6H). 13C NMR (101 MHz, CDCl3) δ 174.7, 135.9, 134.6, 127.2,
121.7, 119.5, 118.1, 110.8, 107.9, 55.4, 53.5, 52.2, 43.3, 30.4,
28.6, 26.7, 26.5, 26.5, 25.0. mp 150.2-154.8 °C. This compound
has been previously reported and both NMR and mp data are
consistent with the literature.61, 62
The procedure for 7aa/8aa above was followed using L-
tryptophan methyl ester hydrochloride (514 mg, 2.02 mmol)
and trimethylacetaldehyde (0.65 mL, 5.98 mmol). Purification
on column chromatography (5:5:2 CH2Cl2: hexane: EtOAc)
yielded 8ad (1.9 mg, 0.3%, first-eluting, yellow oil) a mixed
fraction of 7ad and 8ad (289.7 mg, 50%, yellow oil).
Recrystallization of the mixture from EtOAc gave a small
quantity of pure 7ad (17.1 mg, 3%, colorless crystals).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 13
ARTICLE
Methyl
Journal Name
(1R,3S)-1-(tert-butyl)-2,3,4,9-tetrahydro-1H-
View Article Online
DOI: 10.1039/C9OB01139K
pyrido[3,4-b]indole-3-carboxylate (7ad):
1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.50 (ddt, J = 7.7, 1.5,
0.8 Hz, 1H), 7.35 – 7.28 (m, 1H), 7.18 – 7.13 (m, 1H), 7.10 (ddd,
J = 7.7, 7.1, 1.2 Hz, 1H), 4.09 (app. t, J = 5.2 Hz, 1H), 4.07 (t, J =
1.4 Hz, 1H), 3.63 (s, 3H), 3.11 (ddd, J = 15.0, 5.1, 1.5 Hz, 1H), 3.08
(ddd, J = 15.0, 5.3, 1.6 Hz, 1H), 1.08 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 175.1, 135.9, 133.7, 127.0, 121.8, 119.4, 118.1, 110.7,
109.2, 59.4, 54.4, 52.1, 36.8, 27.3, 24.7. HRMS (ESI) [M+H]+
calculated for C17H22N2O2: 287.1754. Found: 287.1753. mp =
141.3-142.4 °C
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the National Institutes of Health (AI128362) for
financial support, and Mr. Jopaul Mathew for preparing 7ab and
8ab. Molecular graphics and analyses performed with UCSF
Chimera, developed by the Resource for Biocomputing,
Visualization, and Informatics at the University of California, San
Francisco, with support from NIH P41-GM103311.
Methyl
(1S,3S)-1-(tert-butyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole-3-carboxylate (8ad):
1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H),
7.33 (dt, J = 8.1, 0.9 Hz, 1H), 7.17 (ddd, J = 8.1, 7.1, 1.3 Hz, 1H),
7.11 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 4.03 (s, 1H), 3.83 (s, 3H), 3.68
(dd, J = 11.2, 3.6 Hz, 1H), 3.14 (ddd, J = 14.6, 3.6, 1.5 Hz, 1H),
2.77 (ddd, J = 14.6, 11.2, 2.4 Hz, 1H), 1.13 (s, 9H). 13C NMR (101
MHz, CDCl3) δ 174.0, 136.0, 134.6, 126.9, 121.9, 119.6, 118.0,
110.8, 62.6, 56.5, 52.3, 35.7, 27.1, 26.4. This compound has
been previously reported and NMR data are consistent with
literature.63
Notes and references
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0.8 Hz, 1H), 7.15 (ddd, J = 8.0, 7.1, 1.4 Hz, 1H), 7.10 (ddd, J = 7.6,
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Methyl (1R,3S)-1-isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indole-3-carboxylate (8ae): 1H NMR (400 MHz, CDCl3) δ 7.84
(s, 1H), 7.48 (ddt, J = 7.6, 1.5, 0.7 Hz, 1H), 7.33 – 7.30 (m, 1H),
7.19 – 7.14 (m, 1H), 7.11 (ddd, J = 7.1, 1.3 Hz, 1H), 4.23 (ddt, J =
9.0, 4.4, 2.2 Hz, 1H), 3.83 (s, 3H), 3.80 (dd, J = 11.2, 4.2 Hz, 1H),
3.14 (ddd, J = 15.0, 4.2, 1.9 Hz, 1H), 2.83 (ddd, J = 15.0, 11.2, 2.6
Hz, 1H), 2.10 – 1.97 (m, 2H), 1.75 – 1.60 (m, 2H), 1.04 (d, J = 6.6
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Kussmann, C. Ochsenfeld, S.T. Brown, A.T.B. Gilbert, L.V.
Slipchenko, S.V. Levchenko, D.P. O’Neill, R.A. DiStasio Jr.,
R.C. Lochan, T. Wang, G.J.O. Beran, N.A. Besley, J.M.
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