Dynamic thermodynamic resolution: Solvent effects, mechanism, and an asymmetric 3,4,5-substituted benzazepine synthesis

Article abstract of DOI:10.1021/ol0604015

The resolution in the lithiation-substitution sequence from 1 to 4-11 in MTBE is shown to be under thermodynamic control in contrast to the previous report of kinetic control in diethyl ether. Diastereomeric equilibration of a soluble complex is shown to

Full text of DOI:10.1021/ol0604015

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2667-2670
Dynamic Thermodynamic Resolution:
Solvent Effects, Mechanism, and an
Asymmetric 3,4,5-Substituted
Benzazepine Synthesis
Yong Sun Park,†,‡ Eul Kgun Yum,†,§ Amit Basu,† and Peter Beak*,†
Department of Chemistry, Roger Adams Laboratory, UniVersity of Illinois at
Urbana-Champaign, Urbana, Illinois 61801, Department of Chemistry, Konkuk
UniVersity, Seoul 143-701, Korea, and Department of Chemistry, Chungnam National
UniVersity, Daejon 305-764, Korea
beak@scs.uiuc.edu
Received February 15, 2006
ABSTRACT
The resolution in the lithiation-substitution sequence from 1 to 4−11 in MTBE is shown to be under thermodynamic control in contrast to the
previous report of kinetic control in diethyl ether. Diastereomeric equilibration of a soluble complex is shown to be controlling and an asymmetric
synthesis of a 3,4,5-substituted benzazepine is reported.
Dynamic resolution under thermodynamic control can be
used to transform a moderately asymmetric reaction into a
highly asymmetric reaction by straightforward procedures.1
Previous work has demonstrated that management of ex-
perimental conditions may offer control of the diastereomeric
equilibrations which can drive dynamic thermodynamic
resolutions (DTR) to provide significantly improved enan-
tioselectivities. Protocols which use DTR have been shown
to provide syntheses of either enantiomer and with thermal
reequilibration to give enantioenrichments which are beyond
that afforded by a single equilibration.1,2 In this Letter, we
demonstrate that a resolution which has been reported to be
kinetically driven to give modest enantioenrichment can be
transformed into a resolution that is thermodynamically
driven and gives high enantioenrichment by solvent selection.
The present work also shows that the resolution step is not
necessarily driven by a selective crystallization and provides
an asymmetric synthesis of a 3,4,5-substituted benzazepine.
† Roger Adams Laboratory.
‡ Konkuk University.
§ Chungnam National University.
(2) For examples see: (a) Coldham, I.; Dufour, S.; Haxell, T. F. N.;
Howard, S.; Vennall, G. P. Angew. Chem., Int. Ed. 2002, 41, 3887. (b)
Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. J. Am. Chem. Soc.
2000, 122, 11340. (c) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am. Chem.
Soc. 2002, 124, 5266.
(1) (a) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757. (b) Basu,
A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718. (c) Beak, P.;
Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger,
G. A. Acc. Chem. Res. 2000, 33, 715.
10.1021/ol0604015 CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/26/2006

Treatment of o-benzyl pivanalide (1) with 2.2 equiv of
n-BuLi at -15 °C in methyl tert-butyl ether (MTBE, 0.13
M) followed by 3.0 equiv of (-)-sparteine (2) at -15 °C,
cooling to -78 °C, and addition of an electrophile provides
the products (R)-4-11 with the enantiomeric ratios shown
in Table 1. The absolute configurations are assigned on the
the corresponding ketone with an er of 82:18. The authors
tested the reaction for DTR and reasonably concluded it was
not operable in diethyl ether under their conditions. They
suggested the diastereomeric complexes of 2‚3 to be rapidly
equilibrating in diethyl ether, i.e., under kinetic control.
In MTBE, however, our investigation of the diastereose-
lectivity and enantioselectivities for the reaction sequence
of 1 with benzaldehyde shows the reaction to give 9 in
MTBE (Table 1) to be under thermodynamic control when
a warm cool sequence is employed.5 When the reaction is
carried out totally at -78 °C, the alcohol 9 is obtained in
71% yield as a 50:50 mixture of diastereomers with er values
of 75:25 and 77:23 as shown for the first two entries in Table
2.6 With use of sequences with warming of the first and
Table 1. Products from the Asymmetric Lithiation Substitution
of 1
Table 2. Temperature Variation for the Synthesis of 9 from 1
E
product
yield (%)
er
C6H5CH2
4
5
6
7
80
85
80
85
93:7
98:2
94:6
p-BrC6H4CH2
CH2dCHCH2
(CH3)3Sn
88:12
temprature (°C)
step 1 step 2 step 3
-78
er
C6H5(CH3)2Si
C6H5CHOH
p-BrC6H4CHOH
(CH3O2C)2CHCHCH3
8
9
10
11
77a
95b
85c
66d
90:10
yield
(%)
99:1; 90:10
98:2; 73:27
99:1; 89:11
dr
major
minor
-78
-78
-78
-78
-78
-78
-78
71
65
87
95
5
49:51
49:51
83:17
81:19
80:20a
77:33
75:25
75:25
75:25
98:2
99:1
99:1
98:2
97:3
77:23
79:21
24:76
10:90
16:84
21:79
26:74
-78
-78
-15
-15
0
-78
-15
-15
-15
0
a Base was s-BuLi. b dr is 81:19. c dr is 97:3. d dr is 92:8.
91
83
basis of the absolute configurations of 5 and a N-p-
bromobenzoyl derivative of 11 as determined by X-ray
crystallography and the assumption the other products
conform to these absolute and relative configurations.3 The
configuration of 9 at the benzylic position was established
by a deoxygenation sequence that provided 4.
The lithiation substitution of 1 with s-BuLi and (-)-
sparteine (2) in diethyl ether has been reported previously
by Wilkinson et al.4 Under a number of reaction conditions
similar to those used for this work, that reaction was found
to provide products with lower enantioenrichments than
shown in Table 1. The conversion of 1 to 6 proceeded in
90-95% yields with er values of 85:15 to 88:12. The
formation of 4 from 1 proceeded in 80% yield with an er of
73:27. The lithiation of 1 followed by the addition of 2 and
reaction with 2-furaldehyde gave the expected alcohols with
a dr of 50:50. Oxidative conversion of those alcohols gave
25
25
a 0.1 equiv of benzaldehyde.
second steps or only the second step, major improvements
in the product selectivities are observed as shown for the
third and fourth entries in Table 2. With the reactants initially
at -15 °C for the steps of lithiation and addition of 2
followed by cooling to -78 °C prior to the addition of
benzaldehyde, the product 9 is obtained in 95% yield as an
81:19 mixture of diastereomers with er values of 99:1 and
10:90. With the warm-cool sequence the diastereoselectivity
has been improved, as has the enantioselectivity of the major
diastereomer. The enantioselectivity for the minor isomer is
both improved and inverted. The fifth entry in the table shows
the stereoselectivities to be relatively independent of the
equivalents of benzaldehyde. Apparently the diastereomeric
(3) The absolute configuration is assigned to 2‚3 based on analogy to
the invertive course established for an analogous reaction. (a) Faibish, N.
C.; Park, Y. S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1997, 119, 11561. (b)
Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1997, 119,
10537. (c) Weisenberger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J.
Am. Chem. Soc. 1999, 121, 9522.
(5) When s-BuLi was used for the sequence in MTBE, 4 was obtained
in 54% yield with an er of 93:7 as opposed to the 80% yield and er of
73:27 in diethyl ether.4
(6) Since subsequent work shows the diastereomeric complexes to have
similar reactivities toward benzaldehyde, the formation of nonracemic major
and minor products in the first two entries is provisionally attributed to an
asymmetric deprotonation.
(4) Wilkinson, J. A.; Rossington, S. B.; Ducki, S.; Leonard, J.; Hussain,
N. Tetrahedron: Asymmetry 2004, 15, 3011.
2668
Org. Lett., Vol. 8, No. 13, 2006

complexes do not have greatly different rates of reaction with
this electrophile. The sixth and seventh entries in Table 2
show the range of improvements for different temperatures
for the first two steps.
Table 3. Temperature Variation for the Synthesis of 11 from 1
Thus an asymmetric lithiation substitution, which was
reported to be under kinetic control in diethyl ether, can be
transformed into a reaction that is under thermodynamic
control when the reaction is carried out in MTBE. Significant
improvement in both diastereoselectivity and enantioselec-
tivities has easily been accomplished.
It is also significant that reactions of 1 in MTBE (0.03
M) at -15 °C remain homogeneous and give comparable
results. This establishes that selective diastereomeric com-
plexation in solution can be the driving force for a DTR.7
An advantage of thermodynamic over kinetic control of a
resolution is that the formation of either enantiomer may be
possible from one ligand. Tin lithium exchange of 7 (88:12
er) in MTBE at -78 °C provides 2‚(R)-3, which is
configurationally stable under these conditions (Scheme 1).
Addition of p-bromobenzyl bromide at -78 °C provides
(S)-5 (85:15 er), consistent with an invertive substitution.
temperature (°C)
solvent step 1 step 2 step 3 (%)
er
yield
dr
major minor
toluene -78
toluene -15
-78
-15
-78
-15
-15
-15
-78
-78
-78
-78
-78
-78
51
90
31
64
66
70
62:38
76:24
66:34
88:12 >99:1
92:8
79:21 50:50
96:4
75:25
ether
ether
MTBE
THF
-78
-15
-15
-15
90:10 75:25
90:10
89:11
>99:1
54:46
57:43 55:45
with an er of 99:1. Further conversions by stereospecific
lithiation-alkylation to 17 or 18, respectively, and reduction
of 17 to 19 complete the synthetic sequence.
Scheme 1
In summary, the present work demonstrates that kinetic
or thermodynamic control of a resolution can be determined
Scheme 2
We have carried out reactions of 2‚(S)-3 with 12 to probe
the effect of solvent and temperature control in a conjugate
addition. As shown in Table 3, the warm to cool sequence
with MTBE is the protocol of choice although diethyl ether
is also satisfactory in this case. The diastereoselectivity of
92:8 and enantioselectivities of >99:1 and 89:11 for entry 5
suggest this approach should be useful for synthesis. Toluene
gives intermediate results while THF is ineffective.
The improvement in diastereomeric and enantiomeric
ratios under DTR can offer an advantage for synthetic
applications. This is demonstrated by the first asymmetric
synthesis of a 3,4,5-substituted 1-benzazepine 19 (Scheme
2).8,9 Lithiation of 1, addition of 2, and conjugate addition
to 13 provides 14 in 67% yield with a dr of 98:2 and an er
of 99:1. The absolute and relative configurations of 14 were
assigned based on the formation of 11. Hydrolysis of 14 to
15, followed by cyclization provides 16 in a yield of 70%
(7) Since many DTRs are carried out at low temperatures with solid
observable, it is possible that some cases do involve resolution by
crystallization. In such cases, the favored crystallized diastereoisomer may
redissolve but maintain its structure before reaction with an electrophile.
by selection of the solvent. It is also established that
crystallization is not a necessary condition for the operation
Org. Lett., Vol. 8, No. 13, 2006
2669

of dynamic thermodynamic resolution. In addition, the first
asymmetric synthesis of a 3,4,5-substituted benzazepine has
been reported. We recommend determination of the effect
of temperature and solvent on any promising reaction, as
this approach often may be more efficient for improving an
asymmetric synthesis than the alternative of testing a number
of different ligands or catalysts in a number of different
experiments.
Acknowledgment. We are grateful to the National
Institute of General Medical Sciences GM-18874 and to
funds provided by the James R. Eiszner chair for support of
this work. Y.S.P. thanks Konkuk University for the support
of this work in 2005.
Note Added in Proof: Wilkinson and co-workers have
reported, based on further work, that equilibration of the
diastereomeric complexes is not occuring at -78 in diethyl
ether. Wilkinson, J. A.; Rossington, S. B.; Ducki, S.;
Leonard, J.; Hussain, N. Tetrahedron 2006, 62, 1833.
(8) Asymmetric syntheses of 5- and 4,5-substituted 1-benzazepines and
3,4-substituted 1-benzazepin-2-ones have been reported as drug candidates.
(a) Matsubara, J.; Kitano, K.; Otsubo, K.; Kawano, Y.; Ohtani, T.; Bando,
M.; Kido, M.; Uchida, M.; Tabusa, F. Tetrahedron 2000, 56, 4667. (b)
Das, J.; Floyd, D. M.; Kimball, S. D.; Duff, K. J.; Vu, T. C.; Lago, M. W.;
Moquim, R. V.; Lee, V. G.; Gougoutas, J. Z.; Malley, M. F.; Moreland, S.;
Brittain, R. J.; Hedberg, S. A.; Cucinotta, G. G. J. Med. Chem. 1992, 35,
773.
(9) An asymmetric synthesis of 4,5,6- and 3,4,5,6-substituted azepanes
by a conjugated addition of an N-Boc allyllithium (-)-sparteine complex
and subsequent conversions has been reported recently. Lee, S. J.; Beak,
P. J. Am. Chem. Soc. 2006, 128, 2178.
Supporting Information Available: All experimental
procedure and spectroscopic data for new compounds, and
crystallographic data for 5 and the N-p-bromobenzoyl
derivative of 11. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0604015
2670
Org. Lett., Vol. 8, No. 13, 2006