Enantioselective route to 5-methyl-And 5,7-dimethyl-6,7-dihydro-sh- dibenz[c,e]azepine: Secondary amines with switchable axial chirality

Article abstract of DOI:10.1021/ol900333c

(-) -5-Methyl-6, 7-dihydro-5H-dibenz[c, e]azepine 4, a new secondary amine featuring an axis-center stereochemical relay, was prepared enantioselectively from 2'-acetylbiphenyl-2-carboxylic acid, using (R) -2-phenylglycinol as an auxiliary for the control

Full text of DOI:10.1021/ol900333c

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1663-1666
Enantioselective Route to 5-Methyl- and
5,7-Dimethyl-6,7-dihydro-5H-dibenz[c,e]azepine:
Secondary Amines with Switchable Axial
Chirality
Silvain L. Pira,† Timothy W. Wallace,*,† and Jonathan P. Graham‡
School of Chemistry, The UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K., and GlaxoSmithKline, Medicines Research Centre,
Gunnels Wood Road, SteVenage, Herts SG1 2NY, U.K.
tim.wallace@manchester.ac.uk
Received February 15, 2009
ABSTRACT
(-)-5-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine 4, a new secondary amine featuring an axis-center stereochemical relay, was prepared
enantioselectively from 2′-acetylbiphenyl-2-carboxylic acid, using (R)-2-phenylglycinol as an auxiliary for the control of both elements of chirality.
The biaryl axis in 4 preferentially adopts the aS-configuration, with the methyl substituent pseudoequatorial, but conversion into the corresponding
N-Boc derivative locks the axis into the aR-configuration, as predicted on the basis of molecular mechanics calculations.
The conformational properties of a three-atom bridged biaryl
of the form 1 equip such a unit with the axis-center
stereochemical relay that is the key structural component in
many catalytic enantioselective processes. This relay is
exemplified by the metal-coordinated BINAP 2, in which
the spatial arrangement of the diphenylphosphine groups in
the region of the metal atom depends on the configuration
of the biaryl axis.1 The same type of axis-center relay is
present in colchicine 3, and its operation has an important
bearing on the ability of this alkaloid and its analogues to
bind to tubulin and thereby act as cytotoxic agents.2
Our interest in the mechanics and reversibility of this type
of stereochemical relay led us to select 5-methyl-6,7-dihydro-
5H-dibenz[c,e]azepine 4, the simplest axis-center combina-
tion, for a detailed study. Simple models of 4 demonstrate
the mechanics of the coupling between the configurations
of C(5) and the biaryl axis and show that the pseudoequa-
torial orientation of a 5R-substituent in the azepine ring
demands an S-configured biaryl axis and vice versa (Scheme
1). By analogy with colchicine 3, it might be anticipated
that the amine (5R)-4 would exist predominantly in the aS-
configuration, although this type of equilibrium can be finely
balanced.2a,3
† The University of Manchester.
‡ GlaxoSmithKline.
(1) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(2) (a) Brossi, A. J. Med. Chem. 1990, 33, 2311. (b) For a correction,
see: Berg, U.; Bladh, H. HelV. Chim. Acta 1999, 82, 323.
Derivatives 5 of 6,7-dihydro-5H-dibenz[c,e]azepine have
become prominent in applications of conformationally flex-
10.1021/ol900333c CCC: $40.75
Published on Web 03/10/2009
2009 American Chemical Society

series that starts with 4 is unknown.9 However, the dimethyl
homologues 8 and 9 have been prepared by Ku¨ndig and co-
workers,10 who identified the lithium amide derived from 8
as an enantioselective base with some promise,11 while more
recently the preparation of the highly oxygenated derivative
10 was described by Baudoin and co-workers.12 The
published routes to 8 and 10 both involve the late formation
of the Ar-Ar bond using Pd-catalyzed triflate-stannane
(Stille)10 or halide-boronate (Suzuki-Miyaura)12 coupling
protocols, respectively. We herein provide the details of an
alternative approach to such compounds in which the axis-
center stereochemical relay in the three-atom bridged biaryl
is exploited at the outset, using a chiral auxiliary strategy,
and in subsequent steps so as to provide (5R)-4 and (5R,7R)-8
in a concise and stereocontrolled sequence.
Scheme 1. Conformational Equilibrium in
5-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine 4
ible (tropos) biaryl units in various structural roles.4 There
is a relatively low barrier to axis inversion in such units (a
value for ∆Gq of 56 kJ/mol for the inversion barrier in the
N,N-dimethylammonium bromide was estimated from NMR
data5), and the axial configuration is sensitive to central
chirality in the R-group.6 Studies into the use of homochiral
amines as reagents, catalysts, and ligands have also featured
fixed-axis dinaphthazepines such as 67 and 7.8 In contrast,
6,7-dihydro-5H-dibenz[c,e]azepines bearing substituents at
C(5) and/or C(7) are surprisingly rare, and the monoalkylated
(3) (a) Brossi, A.; Boye´, O.; Muzaffar, A.; Yeh, H. J. C.; Toome, V.;
Wegrzynski, B.; George, C. FEBS Lett. 1990, 262, 5. (b) For a pertinent
discussion, see: Cavazza, M.; Zandomeneghi, M.; Pietra, F. Tetrahedron
Lett. 2000, 41, 9129.
Our route to (5R)-4 begins with the condensation of the
biphenylcarboxylic acid 11, prepared from diphenic anhy-
dride in two steps by slight modifications of the published
procedures,13 with (R)-2-phenylglycinol 12 under the condi-
tions developed by ourselves14 and, independently, Levach-
er’s group,15 which provides the oxazolidine lactam 1315
diastereoselectively and in good yield (Scheme 2). Lactams
such as these are remarkably resistant to the formation of
acyliminiums,14b and 13 proved stable to various reduction
protocols that would normally involve such intermediates
(Et3SiH/TFA, etc.). However, lactams are susceptible to
hydroborating agents,16 and treating 13 with borane-methyl
sulfide gave a mixture of two reduction products that were
identified from spectroscopic data as the isomeric amines
15 and 16. It seemed likely that carbonyl and oxazolidine
reduction had proceeded sequentially but that the stereose-
lectivity of the second reduction step was poor. This was
remedied by reference to the pioneering work of the Meyers
group, who observed that alane often provided high diaste-
reoselectivity in this type of reduction.17 Accordingly, the
treatment of 13 with 4.7 equiv of alane gave a high yield of
one of the two amines observed previously, and this was
(4) For discussions and examples, see: (a) Mikami, K.; Aikawa, K.; Yusa,
Y.; Jodry, J. J.; Yamanaka, M. Synlett 2002, 1561. (b) Costa, A. M.; Jimeno,
C.; Gavenonis, J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
6929. (c) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K. Angew. Chem.,
Int. Ed. 2002, 41, 1551. (d) Vial, L.; Lacour, J. Org. Lett. 2002, 4, 3939.
(e) Vasse, J.-L.; Stranne, R.; Zalubovskis, R.; Gayet, C.; Moberg, C. J.
Org. Chem. 2003, 68, 3258. (f) Mikami, K.; Yamanaka, M. Chem. ReV.
2003, 103, 3369. (g) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37,
518. (h) Scafato, P.; Cunsolo, G.; Labano, S.; Rosini, C. Tetrahedron 2004,
60, 8801. (i) Vachon, J.; Lauper, C.; Ditrich, K.; Lacour, J. Tetrahedron:
Asymmetry 2006, 17, 2334. (j) Aillaud, I.; Wright, K.; Collin, J.; Schulz,
E.; Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2008, 19, 82.
(5) Sutherland, I. O.; Ramsay, M. V. J. Tetrahedron 1965, 21, 3401.
(6) (a) Superchi, S.; Bisaccia, R.; Casarini, D.; Laurita, A.; Rosini, C.
J. Am. Chem. Soc. 2006, 128, 6893. (b) Dutot, L.; Wright, K.; Wakselman,
M.; Mazaleyrat, J.-P.; Peggion, C.; De Zotti, M.; Formaggio, F.; Toniolo,
C. Tetrahedron Lett. 2008, 49, 3475. (c) See also: Tichy, M.; Gunterova,
J.; Zavada, J. Collect. Czech. Chem. Commun. 1997, 62, 1080.
(7) For examples and leading references, see: (a) Maigrot, N.; Maza-
leyrat, J.-P.; Welvart, Z. J. Org. Chem. 1985, 50, 3916. (b) Hawkins, J. M.;
Lewis, T. A. J. Org. Chem. 1992, 57, 2114. (c) Rosini, C.; Tanturli, R.;
Pertici, P.; Salvadori, P. Tetrahedron: Asymmetry 1996, 7, 2971. (d)
Mazaleyrat, J.-P. Tetrahedron: Asymmetry 1997, 8, 2709. (e) Widhalm, M.;
Nettekoven, U.; Mereiter, K. Tetrahedron: Asymmetry 1999, 10, 4369. (f)
Stranne, R.; Vasse, J.-L.; Moberg, C. Org. Lett. 2001, 3, 2525. (g) Ooi, T.;
Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. (h) Ooi, T.;
Uematsu, Y.; Kameda, M.; Maruoka, K. Tetrahedron 2006, 62, 11425. (i)
Eberhardt, L.; Armspach, D.; Matt, D.; Toupet, L.; Oswald, B. Eur. J. Org.
Chem. 2007, 5395. (j) Shibatomi, K.; Tsuzuki, Y.; Nakata, S.; Sumikawa,
Y.; Iwasa, S. Synlett 2007, 551. (k) Vishnumaya; Singh, V. K. Org. Lett.
2007, 9, 1117. (l) Zalubovskis, R.; Bouet, A.; Fjellander, E.; Constant, S.;
Linder, D.; Fischer, A.; Lacour, J.; Privalov, T.; Moberg, C. J. Am. Chem.
Soc. 2008, 130, 1845. (m) Li, X.-J.; Zhang, G.-W.; Wang, L.; Hua, M.-Q.;
Ma, J.-A. Synlett 2008, 1255. (n) Mazaleyrat, J.-P.; Wright, K. Tetrahedron
Lett. 2008, 49, 4537.
(10) Saudan, L. A.; Bernardinelli, G.; Ku¨ndig, E. P. Synlett 2000, 483.
(11) Pache, S.; Botuha, C.; Franz, R.; Ku¨ndig, E. P.; Einhorn, J. HelV.
Chim. Acta 2000, 83, 2436.
(12) (a) Joncour, A.; De´cor, A.; Thoret, S.; Chiaroni, A.; Baudoin, O.
Angew. Chem., Int. Ed. 2006, 45, 4149. (b) Joncour, A.; De´cor, A.; Liu,
J.-M.; Tran Huu Dau, M.-E.; Baudoin, O. Chem. Eur. J. 2007, 13, 5450.
(13) Ried, W.; Conte, R. Chem. Ber. 1971, 104, 1573.
(8) (a) Meyers, A. I.; Nguyen, T. H. Tetrahedron Lett. 1995, 36, 5873.
(b) Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, H. J. Org. Chem. 1996,
61, 1194. (c) Bourghida, M.; Widhalm, M. Tetrahedron: Asymmetry 1998,
9, 1073. (d) Pisani, L.; Superchi, S. Tetrahedron: Asymmetry 2008, 19,
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(14) (a) Edwards, D. J.; Pritchard, R. G.; Wallace, T. W. Tetrahedron
Lett. 2003, 44, 4665. (b) Edwards, D. J.; House, D.; Sheldrake, H. M.;
Stone, S. J.; Wallace, T. W. Org. Biomol. Chem. 2007, 5, 2658.
(15) Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003, 68,
9517.
(9) It is reported (Chem. Abstr. 1988, 108, 625) that the amine (()-4
was prepared, together with several homologues, in the course of a study
into the control of hyperlipidemia: Hall, I. H.; Wyrick, S. D.; Chapman,
J. M. U.S. 4689326, 1987. However, the preparative procedure and the
NMR data provided in this publication indicate that the compounds prepared
were the symmetrical N-alkyl isomers.
(16) (a) Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912. (b) Brown,
H. C.; Nazer, B.; Cha, J. S.; Sikorski, J. A. J. Org. Chem. 1986, 51, 5264.
(c) Collins, C. J.; Lanz, M.; Singaram, B. Tetrahedron Lett. 1999, 40, 3673.
1664
Org. Lett., Vol. 11, No. 7, 2009

19 [δH (500 MHz, CDCl3) 1.54 (9 H, s, OCMe3), 0.89 (6 H,
d, J ) 7.0 Hz, 5-Me)] (Scheme 3). The product mixture also
Scheme 2.
Enantioselective Route to 4 from the Lactam 13a
Scheme 3. Diastereoselective Methylation of 4 To Obtain 8
contained a significant quantity of the gem-dimethyl isomer
20 [δH (500 MHz, CDCl3) 1.65 (6 H, br s, 2 × 5-Me), 1.51
(9 H, s, CMe3)], and on the basis of limited data it is
speculated that only a small amount of the meso-diastere-
oisomer 21 [δH (300 MHz, CDCl3) 4.90 (1 H, q, J ) 7.0
Hz, 5-H or 7-H), 1.38 (3 H, d, J ) 7.0 Hz, 5-Meeq or 7-Meeq)]
was among the reaction products. Several attempts to
optimize the yield of 19 were thwarted by poor conversion
which we attributed to aggregation phenomena, but the use
of Schlosser’s “LIDAKOR” base19 provided 19 in 87% yield
after chromatography. The removal of the Boc group from
19 using aqueous phosphoric acid20 gave the amine (-)-8,
[R]25D -81 ( 4 (c 0.61, CH2Cl2) {lit.10 [R]20D -83.1 (c 0.61,
CH2Cl2)}.
The properties of the intermediates prepared en route to 4
and 8, when compared to those of the amines themselves,
offer further insight into the mechanics and potential of the
axis-center stereochemical relay in 6,7-dihydro-5H-diben-
z[c,e]azepines. The conformation of the seven-membered
ring can generally be deduced via 1H NMR spectroscopy, a
pseudoaxial methyl group at C(5) or C(7) experiencing a
marked upfield shift due to the effects of the distal aromatic
ring.8,10,21 On this basis it can be seen that the conversion
of the amine (-)-4 (δMe 1.50 ppm) into the Boc derivative
(+)-18 (δMe 0.86 ppm) is accompanied by a change in the
orientation of the methyl group from pseudoequatorial to
a For clarity, the hydrogen atoms are omitted from the X-ray crystal
structure of the quaternary salt 17.
characterized as the expected retention product 15 by X-ray
crystallographic analysis of the derived quaternary am-
monium salt 17, mp 156-157 °C (MeOH). Reductive
cleavage of the chiral auxiliary from 15 via catalytic
hydrogenation cleanly provided the target amine (-)-4 (94%)
as a pale yellow oil, [R]25 -23.5 ( 1 (c 0.65, CHCl3), δH
D
(500 MHz, CDCl3) 1.50 (3 H, d, J ) 6.6 Hz, 5-Me).
With the amine 4 in hand, we sought to introduce a second
methyl group at C(7) and thereby gain access to the 5,7-
dimethyl series that includes Ku¨ndig’s amine 8. The lithia-
tion-based methodology developed for the R-alkylation of
nitrogen heterocycles18 holds out the prospect of diastereo-
selectivity, and conversion of the fixed-axis dinaphthazepine
6 into the trans-5,7-dimethyl analogue 7 can be achieved
through the use of amidine or nitroso activation.8 However,
it was not known how a flexible biaryl such as 4 might
respond to these protocols, and neither of them is particularly
convenient. In the event, treating the Boc derivative 18,
prepared from 4 in the usual way, with 6 equiv of sec-
butyllithium at -78 °C, followed by iodomethane, gave a
mixture of products dominated by the trans-dimethyl system
(19) Mordini, A.; Ben Rayana, E.; Margot, C.; Schlosser, M. Tetrahedron
1990, 22, 2401. (b) Takagishi, S.; Schlosser, M. Synlett 1991, 119.
(20) Li, B.; Berliner, M.; Buzon, R.; Chiu, C. K.-F.; Colgan, S. T.;
Kaneko, T.; Keene, N.; Kissel, W.; Le, T.; Leeman, K. R.; Marquez, B.;
Morris, R.; Newell, L.; Wunderwald, S.; Witt, M.; Weaver, J.; Zhang, Z.;
Zhang, Z. J. Org. Chem. 2006, 71, 9045.
(17) (a) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656.
(b) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 66,
1413.
(18) (a) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. (b) Meyers,
A. I.; Milot, G. J. Am. Chem. Soc. 1993, 115, 6652. (c) Beak, P.; Basu, A.;
Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29,
552, and references cited therein.
(21) For examples in the analogous phosphepine series, see Kasa´k, P.;
Mereiter, K.; Widhalm, M. Tetrahedron: Asymmetry 2005, 16, 3416
.
Org. Lett., Vol. 11, No. 7, 2009
1665

pseudoaxial. The mechanics of the axis-center relay (Scheme
1) require that this change be accompanied by the inversion
of the biaryl axis, as can be inferred from the change in sign
of the specific rotation,22 so it is demonstrated that the axial
configuration of a 5-substituted amine such as 4 can be
“switched” by modification of the nitrogen substituent. The
preference of 18 for the (aR)-configuration is a natural
consequence of the steric interaction between the 5-methyl
and Boc groups, which is accentuated by the trigonalisation
of the nitrogen atom and mirrors the behavior of other Boc-
substituted nitrogen heterocycles.18 To gain a more quantita-
tive view of this phenomenon, various alkyl-substituted 6,7-
dihydro-5H-dibenz[c,e]azepine derivatives were modeled
using molecular mechanics techniques (Table 1).
decreases as its steric bulk increases and its interaction with
H(4) becomes more significant, with the isopropyl system
23 being close to the crossover point. The proposal, made
by Ku¨ndig et al.,10 that substitution at H(4) and H(8) of 8
should increase the preference of the 5- and 7-methyl groups
for pseudoaxial orientations and thereby exaggerate the C2-
symmetric environment around the nitrogen atom is sup-
ported by the results for 25 and 26, suggesting that the
lithium amides derived from these amines may be more
effective than 8 as mediators of enantioselective deprotona-
tion. Finally, the detailed mechanism of the trans-selective
methylation of 18 to give 19 is unclear, but from the
overwhelming preference of the model carbamate 31 for
the aR-configuration, it can be inferred that, for the substrate
18, the pro-R location of C(7) will be pseudoaxial and
therefore the more exposed, kinetically reactive site through-
out the reaction sequence.
In conclusion, we have prepared (R)-5-methyl-6,7-dihydro-
5H-dibenz[c,e]azepine (-)-4, the first of a new series of
secondary amines incorporating an axis-center stereochemical
relay, from 2′-acetylbiphenyl-2-carboxylic acid using an
auxiliary strategy for the simultaneous control of both
elements of chirality. The amine (-)-4 can be stereoselec-
tively methylated to obtain the known (R,R)-5,7-dimethyl
homologue (-)-8 in three steps. The stereochemical relay
in the amine 4 effectively extends to the nitrogen atom, where
acylation has the effect of forcing the 5-methyl substituent
into a pseudoaxial orientation, thereby inverting and locking
the configuration of the biaryl axis. The mechanics of this
type of relay may be useful for controlling the stereochem-
istry of functionalized biaryls, notably those with 2-arylpy-
ridine or 2,2′-bipyridyl cores, or as a component of molecular
devices. We also anticipate that other types of bonding or
coordination at nitrogen will elicit a quantifiable response
in amines with this relay, which may therefore have
analytical applications. These various possibilities are cur-
rently under investigation.
Table 1. Calculated Differences in Steric Energy (kJ mol-1) of
the aS and aR Conformational Minima of Various
6,7-Dihydro-5H-dibenz[c,e]azepine Derivatives (Macromodel
8.0, MM3)
R1
R2
R3
R4
∆Ea
4.4
11.2
3.7
0.5
-2.0
ratiob
4
8
Me
Me
Et
H
Me
H
H
H
H
Me
H
Me
H
Me
H
H
H
H
H
H
H
H
H
H
86:14
99:1
82:18
55:45
31:69
4:96
22
23
24
25
26
27
28
29
30
31
32
Pri
But
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
H
H
H
H
H
H
-8.2
-14.9
-11.4
-26.9
-18.9
-38.6
-19.2
-37.9
0.2:99.8
1:99
CHO
CHO
COMe
COMe
CO2Me
CO2Me
0:100
0:100
0:100
0:100
0:100
Acknowledgment. We are grateful to the EPSRC and
GlaxoSmithKline for their financial support of this work, and
we warmly thank Dr. Robin Pritchard (University of
Manchester) for the X-ray analysis and Mrs. Val Boote
(University of Manchester) for MS measurements. We also
wish to acknowledge the use of the EPSRC’s Chemical
Database Service at Daresbury.24
Me
a Calculated difference in steric energy EaR - EaS (kJ mol-1) of the
respective global conformational minima in the aR and aS manifolds. b The
ratio aS:aR at 298 K assuming dynamic equilibrium.
The modeling results are consistent with the observed
preference of (5R)-4 and (5R,7R)-8 for the aS-configuration
but suggest that N-acylation23 will invert and effectively
“lock” the biaryl axis of this type of amine. The preference
of the 5-alkyl substituent for a pseudoequatorial orientation
Supporting Information Available: Experimental pro-
1
cedures and characterization of compounds, X-ray data, H
and 13C NMR spectra, and structures generated via molecular
mechanics calculations. This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) Fitts, D. D.; Siegel, M.; Mislow, K. J. Am. Chem. Soc. 1958, 80,
480.
OL900333C
(23) The 1H NMR chemical shift of the 5-methyl substituent in the
tertiary amine 15 (δH 0.92) is consistent with a pseudoaxial orientation,
and therefore an aR-configuration for this compound, indicating that the
conformation of the amine 4 can also be modified by N-alkylation.
(24) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput.
Sci. 1996, 36, 746.
1666
Org. Lett., Vol. 11, No. 7, 2009