Synthesis and axial chirality of an enantiopure aminodibenzazepinone

Article abstract of DOI:10.1016/j.tetasy.2009.04.016

A route for the synthesis of (S,S)-7-amino-5-methyl-5H-dibenzo[b,d]azepin-6(7H)-one hydrochloride is disclosed. The synthesis includes a Friedel-Crafts alkylation to form the seven-membered ring and a highly efficient classical resolution. Additional stud

Full text of DOI:10.1016/j.tetasy.2009.04.016

Tetrahedron: Asymmetry 20 (2009) 1262–1266
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Tetrahedron: Asymmetry
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Synthesis and axial chirality of an enantiopure aminodibenzazepinone
*
Kevin P. Cole , David Mitchell, M. Austin Carr, James R. Stout, Matthew D. Belvo
Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A route for the synthesis of (S,S)-7-amino-5-methyl-5H-dibenzo[b,d]azepin-6(7H)-one hydrochloride is
disclosed. The synthesis includes a Friedel–Crafts alkylation to form the seven-membered ring and a
highly efficient classical resolution. Additional studies on the enantiopure material showed the amine
to be highly resistant to racemization, which led us to investigate the unexpected stability. We propose
that the inherent axial chirality contained in the dibenzazepinone works to produce an interesting chi-
rality transfer mechanism, which accounts for the observed robustness of the stereocenter. This previ-
ously unrecognized stereochemical element exists within this specific class of molecules, and they
should be drawn in a manner which displays the axial chirality.
Received 23 March 2009
Accepted 28 April 2009
Available online 8 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
reduction to afford racemate 5 was then performed using Zn/AcOH
in MeOH. Catalytic hydrogenation could be used, but we preferred
Over the course of our work on a project related to the
c
-secre-
the Zn procedure as high loadings of Pd/C were required, which
tended to have a negative effect on product yield. It is noteworthy
that the major geometrical isomer of the oxime was observed to un-
dergo reduction much more rapidly than the minor isomer.5
tase inhibitor LY4115751 1 (Fig. 1, newly assigned biaryl stereo-
chemistry indicated), the need for large quantities of chiral
amine 2 was recognized. Amine 2 can be formed from lactam 3.
Although a number of methods have been reported for the synthe-
sis of lactam 3,2 an aggressive timeline forced us to rely on proven
and scalable chemistry. Upon isolation of 2 and its congeners, we
noticed the unusual chiral stability of the stereocenter, as we found
it difficult to racemize: a property we had planned to use to our
advantage (vide infra). This led us to investigate the origin of the
unusual stability, and recent publications by Natsugari3 and Wal-
lace4 prompted us to disclose our own findings in this area.
We were then left to develop a robust classical resolution to af-
ford single-enantiomer material. Earlier work had shown us that
the use of (+)-DTTA6 could accomplish this goal, but in our hands
the original procedure7 failed to produce the expected product. We
eventually found that the use of seed (generated by successive
recrystallization of the racemic 1:1 complex from MeOH/water)
and crystallization from MeOH/water was capable of affording 6 in
both high yield and high enantiomeric purity in a single operation.
Karl Fisher titration, TGA, and a single-crystal X-ray structure8 con-
firmed the absolute stereochemistry of 6, and showed the salt to ex-
ist as a mono-hydrate. The presence of water appeared to be crucial
to the success of this resolution, as it was found to improve yield and
reproducibility. Finally, we were able to freebase the amine through
a typical base wash and extraction, but the low melting nature of the
freebase 7 and the desire to avoid an extraction prompted us to at-
tempt a direct conversion to the highly crystalline HCl salt 2. We
found that treatment of a warm slurry of 6 in EtOH with concen-
trated HCl, followed by addition of MTBE afforded an excellent yield
of 2 containing <0.06% residual DTTA. As the next synthetic opera-
tion was an amide bond formation, removal of the DTTA was abso-
lutely critical. It is also noteworthy that a slight enhancement of ee
to >99.9% was typically observed after this procedure.
2. Results and discussion
2.1. Synthesis and classical resolution
The formation of lactam 3 was accomplished by treatment of
chloride 4 (prepared in four steps from commercially available
2-aminobiphenyl) with AlCl3 as a neat mixture at 180–200 °C
(Scheme 1; axial chirality shown). The product was isolated by
way of an aqueous extraction, followed by crystallizationfrom EtOH.
This procedure reliably provided isolated yields of 39–50% (>99%
purity by HPLC) on scales of up to 3 kg, without chromatography.
Next, oxime installation was achieved using t-BuOK and i-Am-
ONO. Purificationandisolationconsistedofextractionof theproduct
(4:1 ratio of oxime isomers, unassigned) into an aqueous base, fol-
lowed by acidification and filtration of the solid product. Oxime
2.2. Atropisomerism and axial chirality
With the successful development of a classical resolution, we
had hoped to be able to employ a dynamic kinetic resolution
* Corresponding author. Tel.: +1 317 276 6923; fax: +1 317 276 4507.
E-mail address: k_cole@lilly.com (K.P. Cole).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.016

K. P. Cole et al. / Tetrahedron: Asymmetry 20 (2009) 1262–1266
1263
NH
O
OH
NH2•HCl
HN
O
F
O
O
O
N
N
N
F
( )-3
1: LY411575
2
Figure 1. LY411575 and congeners.
NH2
O
2 equiv AlCl3
190 °C, neat
(1) t-BuOK, i-AmONO
(2) Zn, AcOH, MeOH
Cl
3
N
77% (2 steps)
39-50%
N
O
5
4
(+)-DTTA
MeOH/H2O
45 °C
NH2
O
NH2
O
• DTTA
• H2O
Na2CO3
99%
N
N
38-40%
>99.8% ee
7
6
conc. HCl
EtOH, 50 °C
90-95%
2
Scheme 1. Synthesis and resolution of 5.
(DKR) in order to increase the yield. A similar DKR was previously
utilized with great success, as shown in Scheme 2.9 This DKR relies
on the facile racemization of the stereocenter (catalyzed by an
electron-deficient, non-enolizable aldehyde), and a slight differ-
ence in solubility of the diastereomeric salts. Our efforts toward
this goal were immediately blocked by the inability to demonstrate
the racemization of 7 either by aldehyde catalysis, or by heating
with amine bases. In stark contrast, amine 8 is racemized simply
upon freebasing.9 This anomalous observation encouraged us to
investigate the dibenzo system in more detail.
D
N
NH2
ND2
O
Et3N, CD3OD
85-90 °C
O
N
(ent)-7-d3
60% D incorporation
at C-7
(ent)-
7
70% ee
70% ee
Scheme 3. Deuterium incorporation.
NH2
O
NH2
O
(R)-mandelic acid
5-NO2-salicylaldehyde
• mandelic
acid
of ꢀ30° between the two benzene rings. The biaryl stereochemistry
in 6 matched that of the downstream compound, and was assigned
to be (S). This led us to the conclusion that the barrier to the rota-
tion about the axis is significant, suggesting that perhaps this axial
chirality could play a role in the stability of the stereogenic center
at C-7. Examination of lactam 3 supported this hypothesis. One
clue came from the 1H NMR of 3, as the C-7 methylene protons ap-
pear as a diastereomeric pair of doublets. Next, we were surprised
when we discovered that 3 could be resolved by chiral HPLC into
separate enantiomers. Upon preparative separation of 3 (enantio-
mers not assigned) we discovered that single enantiomer material
racemized upon standing at ambient temperature in heptane/i-
PrOH. This inspired us to carefully monitor the racemization, as ki-
netic and thermodynamic data could be derived from the decay.
The ee of a freshly separated sample of the first eluting isomer
was monitored at 15 min intervals. The findings are illustrated in
Figure 2 and indicate that the barrier for rotation about the biaryl
bond10 to be 22.34 kcal/mol, which is in good agreement11 with the
recently found value of 23.4 kcal/mol.3 The discrepancy may point
toward some solvent effect, as Natsugari’s results were obtained in
toluene, and ours in i-PrOH/heptane. While we were not surprised
83%, >98% ee
N
N
9
8
Scheme 2. Dynamic kinetic resolution.
We felt that enolization should be possible because the crystal
structure of 6 clearly showed that the enolizable proton, at least
in the solid state, was in the proper geometrical configuration with
respect to the carbonyl for deprotonation. There was some ques-
tion as to whether enolization would be prevented by the poten-
tially large amount of ring strain introduced by the formation of
a sixth sp2 center in the seven-membered ring. This question was
addressed by the experiment shown in Scheme 3. Scalemic amine
(ent)-7 was heated in CD3OD in the presence of Et3N. NMR and MS
analysis clearly showed the incorporation of deuterium
a to the
carbonyl, without racemization by HPLC. With the destruction of
the stereogenic center, one would expect the deuteration to occur
equally from either face, resulting in a racemic product.
It was obvious from the crystal structures of 6 and an additional
downstream compound that there was a significant dihedral angle

1264
K. P. Cole et al. / Tetrahedron: Asymmetry 20 (2009) 1262–1266
NH2
chiral
chromatography
(R)
H
O
O
O
O
and
3
N
N
N
N
Me
NH2
(R,S)
(S)-
Not acidified
Not deprotonated
3
(R)-
3
100
NH2
O
Acidic
H
(S)
90
80
70
60
50
NH2
O
N
N
Me
(S,S)
Et3N
NH2
O-
H+
NH2
O-
N
N
H
Me
Me
H
H+
0
5000
10000
time (sec)
15000
20000
H+
7
Figure 2. Separation and decay of 3 enantiomers.
Figure 3. Proposed explanation for stereochemical stability of 7.
that the rotational barrier for the system was low, an explanation
for the chiral stability of amine 7 was still lacking. Had the atrop-
isomers of 3 been stable, we had hypothesized that the seven-
membered ring was acting as a chiral auxiliary (similar to BINOL),
enforcing a diastereoselective deuteration. The thermodynamic
findings led us to believe that the biaryl bond in 7 is most likely rel-
atively free to rotate, and therefore 7 should racemize.
An additional piece of information was gathered by an observa-
tion made during the reduction of the intermediate oxime to afford
5. If the biaryl portion was stereogenic, one might expect us to ob-
tain two diastereomers from a non-selective reduction. In fact, the
reduction of the oxime (H2, Pd/C or Zn/AcOH) affords a single, race-
mic diastereomer of 5. We surmise that (1) the reduction was com-
pletely diastereoselective, that is, only one face of the oxime
enantiomers was reduced, or (2) the unobserved diastereomer is
thermodynamically unstable and rapidly converts to the observed
compound. If the axial-like amine isomer was initially formed,
then the reaction conditions can promote thermodynamic equili-
bration and the formation of a single racemic diastereomer. Since
no diastereomer of 5 or any related compound has ever been ob-
served, we feel that the energy gained by this potential isomeriza-
tion must be significant.
The lingering question of racemization still remained. A model
that may offer some explanation was examined. We believe that
a synergistic relationship exists between the relative configura-
tions of the biaryl and those of C-7 (Fig. 3). After careful examina-
tion of a structural model, it was realized that even if the biaryl
portion is free to rotate, its motion has a profound effect on the
overall conformation of the azepinone, and that only one of the dias-
teromers can be deprotonated by the base, in this case (S,S). A simple
explanation would be that once the acidic (S,S)-diastereomer is
deprotonated, reprotonation is much faster than a rotation about
the biaryl bond, and racemization is kinetically disfavored. Fur-
thermore, once C-7 is deprotonated, the heterocyclic nitrogen
may partially lose its amide character and become more tetrahe-
dral. This would force the attached methyl group to slide beneath
the plane of the molecule. Nitrogen inversion should not be a fac-
tor, as the A strain1,3 between the methyl group and the o-proton
should impose a severe barrier. The methyl group is now posi-
tioned in a pseudo-axial configuration, but the lack of other ax-
ial-like substituents prevents this from being a destabilizing
interaction. The axial methyl group effectively transfers the stereo-
chemistry of the nitrogen by completely shielding the bottom face
of the enolate, forcing deuterium (or other electrophiles as ob-
served by Natsugari) to approach from the top face, therefore
retaining the overall stereochemistry of the system. This is very
similar to the ‘memory of chirality’ concept popularized by Kawa-
bata and Fuji,12 but is complicated by the presence of the chiral
biaryl and its probable role in determining the reaction outcome.
The system may also very well fit into Seebach’s definition of a
‘self-regenerating stereocenter’.13,14
3. Conclusion
A kilo-scale synthesis of enantiopure 2 has been demonstrated.
We discovered the extraordinary stability of the C-7 stereocenter
and sought out an explanation. We believe that the biaryl portion
of this azepinone system contains a previously unrecognized axis
of chirality, and this most likely plays an important role in the
robustness of the C-7 stereocenter either by way of enforcing a
kinetically controlled protonation, or through an interesting chiral-
ity-transfer mechanism. We have assigned an additional stereo-
chemical element to all molecules of this class, including 1.
Further investigations into the system, as well as the potential
use of 7 and related derivatives as stable asymmetric catalysts
are currently underway and will be reported in due course.
4. Experimental
4.1. General
Unless otherwise stated, all reactions were carried out under a
nitrogen atmosphere with solvents and reagents used without

K. P. Cole et al. / Tetrahedron: Asymmetry 20 (2009) 1262–1266
1265
purification or drying. Reverse-phase HPLC conditions: Analysis
was run on ACE-3 phenyl column (75 ꢁ 3 mm) with solvent system
consisting of (A) water (with 0.1 mL TFA/L) and (B) HPLC grade ace-
tonitrile. Detection was run at 217 and 260 nm with column tem-
perature = 45 °C and a flow rate of 1.5 mL/min. The gradient was as
follows: t(0) 90% A 10% B gradient to t(11 min) 20% A 80% B;
t(11.01 min) 90% A 10% B. Chiral HPLC conditions: analysis was
run on Chiralpak AD-H column (150 ꢁ 4.6 mm) packed with Amy-
and data reduction were performed using the SAINT program
V7.56a.16 The unit cell was indexed, having monoclinic parameters
of a = 12.8949(2) Å, b = 7.56270(10) Å, c = 15.7273(3) Å, and
b = 95.4530(10)°. The cell volume of crystal structure was
1526.79(4) Å.3 The calculated density of the structure is 1.398 g/
cm3 at 100 K. The structure was solved by direct methods.16 All
atomic parameters were independently refined. The space group
choice, that is P21, was confirmed by successful convergence of the
full-matrix least-squares refinement on (F2)17 with a final good-
lose tris-(3,5-dimethylphenylcarbamate) coated on 5 lm silica gel,
solvent was isocratic: methanol containing 0.2% Et2NH. Detection
was run at 260 nm, with column temperature at 30 °C and a flow
rate of 0.6 mL/min. NMR spectra were acquired using Varian
instruments and software. Chemical shifts (d) are reported in
ppm, and spectra were referenced to the residual solvent signal.
Melting points were collected on Büchi melting point apparatus
and are uncorrected. Optical rotations were obtained on a Jasco
DIP-370 polarimeter.
ness-of-fit of 1.021. The final R indices [I > 2r(I)], R1 = 0.0363,
wR2 = 0.0896 and the largest difference peak and hole after the final
refinement cycle were 0.189 and ꢃ0.211 (e Aꢃ3), respectively.
4.2.1. (S,S)-7-Amino-5-methyl-5H-dibenzo[b,d]azepin-6(7H)-
one hydrochloride 2
A 1 L flask equipped with overhead stirrer, nitrogen inlet, and
thermocouple was charged with 6 (40.0 g, 62.2 mmol) and ethanol
(120 mL, 3 vols) was used to rinse all the solid into the flask. The
mixture was stirred as 37% HCl (7.9 mL, 96.5 mmol) was added
to a single portion. A solution was formed within 5 min. The solu-
tion was stirred and warmed to 50 °C. After 2 h at 50 °C, the reac-
tion was cooled to 40 °C. MTBE (400 mL) was added over 1 h at
40 °C. A light tan solid began to form after ꢀ370 mL had been
added (mixture became cloudy after ꢀ320 mL). Heating was dis-
continued, and the slurry was allowed to cool slowly. Once the
temperature reached 23 °C, the solid was filtered through a poly-
propylene pad and washed with MTBE (2 ꢁ 40 mL). The solid was
dried at 50 °C in vacuo overnight to afford 2 (16.55 g, 97%) as a
tan powder. The isolated compound 2 was 99.95 area % by HPLC
with 0.05% DTTA impurity. 1H NMR analysis revealed that the
product was contaminated with EtOH and water (potency not
determined).
4.1.1. (S,S)-7-Amino-5-methyl-5H-dibenzo[b,d]azepin-6(7H)-
one (2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate hydrate 6
Seed material of 6 was developed by precipitation of a 1:1 mix-
ture of 5 and (+)-DTTA in MeOH by the addition of water. The solid
was then successively recrystallized from MeOH/water until the ee
of the freebased amine was >99%.
In a 22 L RBF fitted with internal temperature probe, glycol-
cooled condenser, addition funnel, and heating mantle, amine 5
(600 g, 2.52 mol) was dissolved in MeOH (8 volumes, 4.8 L). Water
(6 volumes, 3.6 L) was then added. The solution was heated to
50 °C. While the amine solution was heating, (+)-DTTA (0.9 equiv,
876 g) was placed in a 5 L flask and dissolved (with gentle heating)
in MeOH (6 vols relative to amine, 3.6 L). This solution was then
transferred to the addition funnel. When the amine solution had
reached 50 °C, the (+)-DTTA solution was slowly added, so as to
maintain the salt solution temperature close to 50 °C (approximate
addition time: 45 min). When the addition was completed, the
Mp decomposed over 215 °C; ½a D23
ꢂ
¼ ꢃ90:6 (c 0.97, water); 1H
NMR (400 MHz, DMSO-d6) d 9.29 (br s, 3H), 7.73–7.69 (m, 2H),
7.67–7.57 (m, 4H), 7.53 (d, 1H, J = 8.0 Hz), 7.47 (dt, 1H, J = 2.0,
8.0 Hz), 4.74 (br s, 1H), 3.30 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) d 166.6, 139.6, 134.2, 132.1, 131.9, 129.9, 129.5, 128.8, 128.8,
128.6, 126.3, 123.1, 122.2, 52.6, 35.7; HPLC tR = 2.42 min.
addition funnel was rinsed with
a small amount of MeOH
(<100 mL). The solution was stirred 1 h at 50 °C, then the internal
temperature was lowered to 40 °C, and seed was introduced
(2 g). It was evident that the seed held, and a large amount of pre-
cipitate was observed to form within 15 min. The temperature was
increased to 45 °C, and the slurry was stirred overnight. The fol-
lowing morning, the temperature was lowered to 40 °C and stirring
was continued; at the end of the second day, the temperature was
lowered to 35 °C, and the slurry was stirred over a second night.
The following morning, heating was discontinued, and the internal
temperature lowered to about 30 °C, at which point the slurry was
filtered and rinsed with 1:1 MeOH/water (2 L) to afford 6 as snow-
white crystals. The solid was dried in vacuo at 35 °C overnight to
afford 6 (631 g, 0.982 mol, 39%). Karl Fischer analysis indicated
the presence of one molecule of water (2.7% by weight).
4.3. Procedure for chiral separation of 3
Compound 3 (500 mg) was dissolved in CHCl3 (2 mL) and 2-pro-
panol (3 mL), then heptane (15 mL) was added for a single 20 mL
injection over a 8 ꢁ 33 cm (20
lm) Chiralpak AS column. The sys-
tem was eluted isocratically using 3:1 heptane/2-propanol with a
flow rate of 375 mL/min, with detection at 260 nm. Both isomers
were collected, and the first eluting (isomer 1) was sampled with-
out further dilution. Isomer 1 was held at ambient temperature
(296 K) and sampled analytically every 15 min over 6 h. Analytical
HPLC conditions: Chiralpak AS-H 4.6 ꢁ 150 mm (5
lm) column
Mp 156.1–163.7 °C; ½a D23
ꢂ
¼ ꢃ22:5 (c 1.07, DMSO); 1H NMR
eluting isocratically with 3:1 heptane/2-propanol containing 0.2%
dimethylethylamine. Flow rate = 0.6 ml/min, detect at 260 nm.
tR = 6.6 min (isomer 1) and 11.4 min (isomer 2).
(400 MHz, DMSO-d6) d 7.81 (d, 4H, J = 8.4 Hz), 7.67 (d, 2H,
J = 7.2 Hz), 7.61-7.50 (m, 5H), 7.44 (ddd, 1H, J = 2.4, 6.0, 8.8 Hz),
7.30 (d, 4H, J = 8.0 Hz), 5.64 (s, 2H), 4.64 (s, 1H), 3.28 (s, 3H), 2.36
(s, 6H); 13C NMR (125 MHz, DMSO-d6) d 168.3, 167.7 (2C), 164.7
(2C), 143.8 (2C), 139.8, 134.4, 134.2, 132.1, 129.8, 129.3, 129.2
(4C), 129.2 (4C), 128.5, 128.4, 128.3, 126.6 (2C), 126.0, 122.9,
122.2, 71.3 (2C), 52.8, 35.7, 21.1 (2C); chiral HPLC of freebase:
tR = 5.68 min (desired isomer) ee > 99.9%.
Acknowledgments
We thank Dr. Greg Stephenson and Mr. Benjamin Diseroad for X-
ray analysis; Mr. Matthew Voss, and Mr. Joseph Phillips for experi-
mental assistance; and Mr. Greg Rener and Mr. Thomas Gunter for
HPLC support. Additionally, we thank PharmaCore Inc. and Asym-
chem Laboratories Inc. for assistance during scale-up activities.
4.2. X-ray acquisition for 6
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a
-
e