Atropisomerism of aromatic carbamates

Article abstract of DOI:10.1002/chem.201001047

ortho-Haloarylcarbamates like 1-4 show a high rotational barrier about the N-aryl bond of up to 91.6 kJmol^-1 as found for 1, which was determined by 2D exchange NMR spectroscopy (EXSY). It was further demonstrated that the height of the barrier

Full text of DOI:10.1002/chem.201001047

DOI: 10.1002/chem.201001047
Atropisomerism of Aromatic Carbamates
Lutz F. Tietze,*[a] Heiko J. Schuster,[a] J. Marian von Hof,[a] Sonja M. Hampel,[a]
Juan F. Colunga,[a] and Michael John*[b]
Dedicated to Professor Horst Kessler on the occasion of his 70th birthday
Abstract: ortho-Haloarylcarbamates like 1–4 show a high rotational barrier about
À1
À
the N aryl bond of up to 91.6 kJmol as found for 1, which was determined by
2D exchange NMR spectroscopy (EXSY). It was further demonstrated that the
height of the barrier not only depends on the substituents at the axis of chirality,
but is also influenced by electronic effects.
Keywords: atropisomerism · carba-
mates · EXSY spectroscopy · NMR
spectroscopy · rotational barriers
Introduction
logically active atropo-(dia-)stereoisomers, such as that re-
cently completed by Bringmann et al. for N,C-coupled naph-
thylisoquinolines, will become much more important in the
discovery of lead structures.[8]
Atropisomerism is a well-known phenomenon of biaryls, sul-
fonamides, maleimides, succinimides, and simple carboxy-
amides.[1] The latter have been intensively studied not only
A clear requirement for high selectivities in atrop-selec-
tive reactions are high rotational barriers of >96 kJmolÀ1
between the different atropisomers, which allow their sepa-
ration and storage for many weeks at <258C without race-
mization.[9] However, the different contributions to the rota-
tional barriers have still not been sufficiently studied, al-
though the bulkiness of the substituents at the axis of chiral-
ity is known to play a dominant role.[10] But there are also
results indicating that electronic effects within the molecule
are more important than has been anticipated so far.[11]
Herein, we report on the atropisomerism of N-(ortho-hal-
onaphthyl)carbamates 1–3 and the related compound 4
using NMR spectroscopy, showing that the bulkiness of the
halo atom as well as the steric demand of the aryl moiety,
but also electronic effects of the aryl moiety have an impor-
in connection with their existence in peptides, but also as
prochiral auxiliaries in so-called atropselective reactions.[2]
Pioneering work in this field was done by Curran and De-
Mello, as well as Simpkins et al., who found that high enan-
tioselectivities could be achieved with ortho-tert-butylani-
lides.[3] In addition, not only stable carbamate atropisomers
have been reported,[4] but also asymmetric reactions of ax-
ially chiral carbamates.[5] Clayden et al. have shown that
naphthalene-based amides have unusually high rotational
barriers,[6] and the challenge of atropisomerism in drug dis-
covery has recently been reviewed by this group.[7] With re-
spect to the potential impact on medicinal chemistry, the
stereoselective total synthesis of naturally occurring and bio-
À
tant influence on the rotational barriers about the N aryl
bond in 1–4. Details of synthetic procedures are given in the
Supporting Information.
[a] Prof. Dr. L. F. Tietze, Dr. H. J. Schuster, Dr. J. M. von Hof,
Dipl.-Chem. S. M. Hampel, Dr. J. F. Colunga
Institut fꢀr Organische und Biomolekulare Chemie der
Georg-August-Universitꢁt Gçttingen, Tammannstraße 2
37077 Gçttingen (Germany)
Fax : (+49)551-399476
E-mail: ltietze@gwdg.de
[b] Dr. M. John
Institut fꢀr Anorganische Chemie der
Georg-August-Universitꢁt Gçttingen, Tammannstraße 4
37077 Gçttingen (Germany)
Fax : (+49)551-393373
E-mail: mjohn@gwdg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001047.
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Chem. Eur. J. 2010, 16, 12678 – 12682

FULL PAPER
Results and Discussion
Within our work on the development of new selective anti-
cancer agents, we prepared glycosidic prodrugs such as 5,[12]
which are based on the natural antibiotic duocarmycin SA
((+)-6).[13] In the asymmetric synthesis of these prodrugs,[14]
the intermediate 1 was obtained through alkylation of ani-
line 7 with the enantiomerically pure nosylate 8, containing
an epoxy functionality, to give a mixture of two compounds
in a ratio of about 1:1 (Scheme 1), which showed distinct
NMR signals even at elevated temperatures up to 1008C
(Figure 1).
Figure 1. 1H NMR spectra (300 MHz, C2D2Cl4) of (2’R,3’R)-1 at variable
temperatures showing the 1’-, 2’- and 3’-protons of the epoxide side
chain. The spectra indicate the existence of two distinct isomers (denoted
(a) and (b)) of 1.
mediated transformation of 1 led to a single enantiomeri-
cally pure product 11.[14]
We therefore assume that at 1008C 1 exists as a mixture
À
of two diastereomers due to hindered rotation about the N
aryl bond, which can be attributed to the large iodine sub-
stituent in the ortho position. In accordance with earlier re-
ports on related compounds, the naphthyl ring thus adopts
an orientation perpendicular to the carbamate plane, and
[16]
À
the N aryl bond becomes an axis of chirality. As a result
À
À
of the hindered rotation about the N aryl bond and the N
C(O) bond, 1 exists as four different isomers (depicted in
Scheme 3) at room temperature.
À
The N aryl rotation in 1 is so slow that no coalescence of
NMR signals was observed up to 1308C, at which tempera-
ture 1 started to decompose. However, 2D exchange spec-
troscopy (EXSY) revealed that the two rotamers do inter-
convert at much lower temperatures (Figure 2): The spec-
trum contains positive cross peaks (exchange peaks) con-
necting corresponding resonances of the two rotamers as
well as negative cross peaks (NOE peaks) due to spatial
proximity of protons within the individual rotamers.
Scheme 1. Prodrug 5 and the natural antibiotic duocarmycin SA ((+)-6
and the synthesis of 1 from naphthalene 7 using the enantiomerically
pure epoxy nosylate (2R,3R)-8. Boc=tert-butyloxycarbonyl, Ns=nosyl.
Figure 2 shows that the NOE peaks within the C-1’ meth-
ylene group are particularly strong and very close to the cor-
The presence of multiple broad NMR signals of 1 at 258C
À
could be explained by slow rotation around the carbamate
responding exchange peaks, indicating that N aryl bond ro-
À
N C(O) bond resulting in carbamate E and Z isomers. For
tation nearly swaps the chemical shifts of the two protons as
a result of their position relative to the naphthyl ring. As
evidenced by NOE correlations with 3-H (Figure S1 in the
Supporting Information), the downfield 1’-H protons face C-
3, which is in agreement with a shielding effect of the large
iodine atom on the other 1’-H protons. Further NOE corre-
lations between 3-H and 2’-H/3’-H suggest that the bond be-
tween C-1’ and C-2’ is preferentially oriented syn with re-
rotation around such bonds, energy barriers of 50–
67 kJmolÀ1 with little solvent dependence have been repor-
ted.[1b,15] At 1008C, however, this rotation is sufficiently fast
(about 104 sÀ1) to completely average the NMR signals of
the individual carbamate isomers.
The presence of different constitutional isomers of 1
could be excluded by synthetic experiments (Scheme 2; for
details on the synthesis, see the Supporting Information),
since single products without split NMR signals were ob-
tained upon removal of the iodine atom of 1 to give 9
(along with a complex mixture of byproducts), or quantita-
tive cyclization of 1 to oxazolidinone 10. Moreover, the Zn-
À
spect to the N aryl bond (as already indicated in the struc-
tures in Scheme 3), thereby tilting the epoxide side chain
away from the bulky Boc group. If this is true, the absolute
configuration of the two rotamers can be determined from
the stronger NOE correlation between 3’-H and 3-H, which
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12679

L. F. Tietze, M. John et al.
EXSY spectra can be em-
ployed to measure rate con-
stants of isomerization process-
es in the range from about 0.05
to 20 sÀ1. We were thus able to
obtain the rate constants of the
À
N aryl bond rotation in 1 be-
tween 60 and 1108C (Table 1).
As expected, the values in-
crease exponentially with the
temperature and fit well to the
linear
Eyring
equation
(Figure 3, see also the Support-
ing Information). The free
°
À
energy barrier (DG ) of N aryl
bond rotation is dominated by
an enthalpy (DH°) contribution
and amounts to 91.6 kJmolÀ1 at
258C, which corresponds to a
rotamer lifetime of about
30 min.
To investigate the influence
of the size of the ortho substitu-
À
ent on the N aryl rotational
Scheme 2. Experimental exclusion of constitutional isomers of 1. TFA=Trifluoroacetic acid.
barrier, we repeated the analy-
sis on the corresponding ortho-
bromonaphthyl carbamate 2.
À
Scheme 3. Ra and Sa rotamers of the N aryl bond of 1 and their E and Z
À
isomers resulting from rotation around the carbamate N C(O) bond as
well as the projections for the determination of the axial configuration
(showing also the prochiral 1’-HR and 1’-HS protons).
Figure 2. 2D-EXSY spectrum (808C, mixing time 0.5 s) of 1 showing the
1’-, 2’- and 3’-protons of the epoxide side chain. Positive (exchange) and
negative (NOE) peaks are shown in black and grey, respectively. Distinct
isomers are denoted (a) and (b).
identifies the isomer denoted (b) in Figures 1 and 2 as the
one with Sa configuration.
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Chem. Eur. J. 2010, 16, 12678 – 12682

Atropisomerism of Aromatic Carbamates
FULL PAPER
[a]
Table 1. Rate constants k [sÀ1
]
of the N aryl bond rotation in com-
À
pounds 1, 2, 3, and 4 at variable temperature; free energy of activation at
258C; and corresponding rotamer lifetime at 258C.
[b]
T [8C]
60 70
DG°
A
t25
25
25
–
40
–
50
–
80
100 110
[kJmolÀ1
]
[s]
1
2
3
4
0.05 0.13 0.45 2.75
7
–
–
–
91.6
80.9
77.2
78.6
1830
25
5.5
0.04 0.23 0.65 1.65 4.3
0.18 0.93 2.5
0.10 0.55 1.24 3.3
11
–
–
–
–
6.3
15
8.2
19
9.8
[a] Assuming k1 =kÀ1. Experimental errors are ꢀ5%. [b] Derived from
fitting the data to the Eyring model.
Figure 4. 2D-EXSY spectrum (258C, mixing time 0.5 s) of 3 showing the
1’-H, 2’-H, and 3’-H protons of the epoxide side chain. Positive (ex-
change) and negative (NOE) peaks are shown in black and grey, respec-
À
À
tively. Exchange peaks due to N aryl and N C(O) bond rotations are
highlighted with dashed and solid black squares, respectively.
À
Figure 3. Eyring plot of the experimental rate constants of N aryl bond
the epoxide side chain are dominant (Figures S6 and S7 in
the Supporting Information).
~
*
rotation in the compounds studied (&: 1, : 2, <: 3, and : 4). The solid
lines represent best linear fits.
When going from iodonaphthalene 1 to bromonaphtha-
lene 2, the decrease of the steric demand of the halogen sub-
stituent is expected to play the most important role in lower-
ing of the rotational barrier (about 10–11 kJmolÀ1) about
Here, the rate constants obtained in the range of 25 to 808C
were much larger than in 1 by a factor of approximately 30,
corresponding to a barrier that is about 10 kJmolÀ1 lower in
energy (Table 1). Similarly, we studied compound 3, where
the ortho-bromonaphthyl ring of 2 has a CN substituent in
7-position, as well as aniline 4, where the ortho-iodonaphth-
yl ring of 1 is replaced by the corresponding o-iodophenyl
À
the N aryl bond. However, when comparing the barriers
found for 2 and the CN-substituted naphthalene 3, both
compounds have a bromo substituent in the ortho position,
but 2 shows a rotational barrier that is almost 4 kJmolÀ1
higher. As the lone pair of the nitrogen becomes available
for resonance with the aryl–p systems in the transition states
À
moiety. In both cases, the N aryl bond rotation was found
À
to be greatly accelerated by a factor of about 4 and 40 com-
pared with that in 2 and 1, respectively. In 3, the rotational
barrier of 77.2 kJmolÀ1 approaches that of the carbamate
of the rotation about the N aryl bond, we expect additional
stabilization through resonance with the electron-withdraw-
ing CN group in 3 (Scheme 4) to be the most likely explana-
tion for the different barriers of 2 and 3.
À
N C(O) bond so that in EXSY spectra both processes can
be observed simultaneously (Figure 4).
It can also be assumed that a significant change in the
angle (halogen-C1-C2) for the naphthalenes 1, 2, and 3 and
In all compounds investigated the ratio of the Ra and Sa
rotamers deviates less than 5% from unity, whereas the
carbACHTUNGTRENNUNGamate rotamers are populated with a ratio of about 2:1
and, as expected, are separated by a free energy barrier of
(68Æ2) kJmolÀ1. For compound 1 the carbamate E and Z
rotamers were assigned from a NOESY spectrum recorded
at 08C where exchange between the carbamate rotamers is
slower than 0.3 sÀ1 (Figure S5 in the Supporting Informa-
tion). The major Z isomers (the Z/E ratio for 1 was 3:1
rather than 2:1) show dominant NOE correlations between
the tert-butyl group and the 3-H, while in the minor E iso-
mers the NOE correlations between the tert-butyl group and
Scheme 4. Additional generic resonance structure 3-TS in the transition
1
2
À
states of the rotation about the N aryl bond in 3. R =C(O)tBu and R =
epoxide side chain or R1 =epoxide side chain and R2 =C(O)tBu.
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2D-EXSY revealed that ortho-haloarylcarbamates with an
alkyl side chain containing an epoxy moiety exist as two
atrop-diastereomers with a rotational barrier of up to
91.6 kJmolÀ1. As expected, the height of the rotational bar-
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft and
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Received: April 21, 2010
Published online: September 30, 2010
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