Novel Extension of Meyers' Methodology: Stereoselective Construction of Axially Chiral 7,5-Fused Bicyclic Lactams

Article abstract of DOI:10.1021/jo035195i

A novel extension of Meyer's lactamization is reported for the preparation of seven-membered ring lactams 1a-d incorporating a biaryl unit. The required keto-esters 2a-c were readily accessible via the Suzuki coupling reaction. A borylation-Suzuki couplin

Full text of DOI:10.1021/jo035195i

Novel Exten sion of Meyer s’ Meth od ology:
Ster eoselective Con str u ction of Axia lly
Ch ir a l 7,5-F u sed Bicyclic La cta m s†
Mae¨l Penhoat, Vincent Levacher,* and Georges Dupas
Laboratoire de Chimie Organique Fine et He´te´rocyclique
Associe´ au CNRS, IRCOF-INSA, Rue Tesnie`res B.P 08,
F-76131 Mont Saint Aignan Ce´dex, France
F IGURE 1. Scope and limitations of Meyers’ methodology.
Vincent.levacher@insa-rouen.fr
Received August 15, 2003
Abstr a ct: A novel extension of Meyer’s lactamization is
reported for the preparation of seven-membered ring lactams
1a -d incorporating a biaryl unit. The required keto-esters
2a -c were readily accessible via the Suzuki coupling reac-
tion. A borylation-Suzuki coupling (BSC) sequence was
successfully developed for the high-yielding preparation of
keto-ester 2d . Cyclization of the resulting keto-esters 2a -d
or keto-acids 5a ,c,d in the presence of (R)-phenylglycinol
afforded the desired lactams 1a -d in high yields (72-93%)
and excellent diastereoselectivities (>95%). This methodol-
ogy provides a facile stereoselective access to new axially
chiral bridged biaryls.
F IGURE 2. Design of new axially chiral bridged ligands by
means of Meyers’ methodology.
the diaryl groups. The first purpose of this chiral bridge
is to dispose of rigid chiral biaryl ligands with tunable
dihedral angles between the two aryl units.3 The second
role is to ensure the configurational control of the
resulting chiral axis of the biaryl motif.4,5 In this context,
we felt that Meyers’ lactamization could provide a
straightforward stereoselective access to seven-membered
bridged biaryls 1.6 We reasoned that the presence of this
biaryl unit in keto-esters 2 might exhibit important
conformational restrictions which may possibly restore
a high level of stereoselectivity and a reactivity compa-
rable to that obtained in the case of five- and six-
membered lactams (Figure 2).1
Meyers’ bicyclic lactam methodology has been widely
used in the stereoselective construction of five- and six-
membered ring nitrogen heterocycles. These lactams
provide a number of highly functionalized chiral building
blocks which may be used further, in a wide range of
stereoselective transformations, making these intermedi-
ates powerful tools in asymmetric synthesis.1 Although
this methodology demonstrated to be highly versatile for
the preparation of five- and six-membered rings, the
stereoselective preparation of higher-membered ring
systems still remains almost unexplored. Only one paper
has recently attempted to extend this methodology to the
preparation of seven-membered lactams such as 2-alkyl-
perhydroazepines. However, lactams were obtained in
low yields and poor diastereoselectivities (Figure 1).2
These rather disappointing results may be ascribed to
the increased flexibility of the larger seven-membered
ring size.
To investigate this approach, the required keto-esters
2a -c were prepared from commercially available boronic
acid 4a and aryl halides 3a -c, 3′a via a Suzuki cross-
coupling reaction. As can be appreciated from Table 1,
yields are excellent ranging from 71 to 91%. Given that
(3) For examples of chiral biaryl bridged ligands with tunable
dihedral angles see: (a) Zhang, Z.; Qian, H.; Longmire, J .; Zhang, X.
J . Org. Chem. 2000, 65, 6223-6226. (b) Wu, S.; Wang, W.; Tang, W.;
Lin. M.; Zhang, X. Org. Lett. 2002, 4, 4495-4497.
As part of a research program dealing with the
development of new axially chiral ligands, we became
interested in the stereoselective preparation of biaryl
lactams 1 (Figure 2). The key structural element of such
chiral ligands is the presence of the chiral bridge, linking
(4) For examples on the configurational control of chiral axis in
biaryl moieties by means of a chiral bridge see: (a) Spring, D. R.;
Krishnan, S.; Schreiber, S. L. J . Am. Chem. Soc. 2000, 122, 5656-
5657. (b) Brecht, R.; Bu¨ttner, F.; Bo¨hm, M.; Seitz, G.; Frenzen, G.; Pilz,
A.; Massa, W. J . Org. Chem. 2001, 6, 2911-2917.
(5) Conformational analysis of bicyclic lactams
1 by molecular
modelling shows a dihedral angle between the two aryl units of 40-
50° (MM2, PCMODEL).
† Presented in part at the third SAJ EC symposium, Strasbourg,
October 21, 2002.
(6) During the preparation of the manuscript, Wallace et al. reported
the condensation of 2′-formylbiphenyl-2-carboxylic acid with (S)-valinol
providing the corresponding bicyclic lactam as a mixture of two epimers
(aS,R,S) and (aR,S,S) with medium diastereoselectivity (de ) 75%).
Edwards, D. J .; Pritchard, R. G.; Wallace, T. W. Tetrahedron Lett. 2003,
44, 4665-4668.
(1) For leading references on chiral bicyclic lactams see: (a) Meyers,
A. I.; Brengel, G. P. Chem. Commun. 1997, 1-8. (b) Amat, M.; Canto,
M.; Llor, N.; Ponzo, V.; Pe´rez, M.; Bosch, J . Angew. Chem., Int. Ed.
2002, 41, 335-337. (c) Amat, M.; Canto, M.; Llor, N.; Escolano, C.;
Molins, E.; Espinosa, E.; Bosch, J . J . Org. Chem. 2002, 67, 5343-5351.
(d) Amat, M.; Llor, N.; Hidalgo, J .; Escolano, C.; Bosch, J . J . Org. Chem.
2003, 68, 1919-1928. (e) Ennis, M. D.; Hoffman R. L.; Ghazal, N. B.;
Old, D. W.; Mooney, P. A. J . Org. Chem. 1996, 61, 5813-5817. (f) Allin,
S. M.; J ames, S. L.; Elsegood, M. R. J .; Martin, W. P. J . Org. Chem.
2002, 67, 9464-9467.
(2) Meyers, A. I.; Downing, S. V.; Weiser, M. J . J . Org. Chem. 2001,
66, 1413-1419.
10.1021/jo035195i CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003
J . Org. Chem. 2003, 68, 9517-9520
9517

TABLE 1. P r ep a r a tion of Bia r yls 2a -c via th e Su zu k i
Cr oss-Cou p lin g Rea ction
TABLE 2. Bor yla tion -Su zu k i Cou p lin g (BSC)
pinacolborane
(equiv)
yield of 4ca
entry
catalyst
(%)
1
2
3
4
5
6
PdCl2(dppf)
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
1.5
1.5
1.1
1.3
1.5
2
66
30
58
76
85
95
a
Determined by 1H NMR analysis of the crude reaction product.
cotinate 3c and Ba(OH)2 were added, and the reaction
mixture was heated at 100 °C for a further 24 h to provide
the desired biaryl 2d in 84% overall yield. This boryla-
tion-Suzuki coupling sequence was found to be highly
sensitive to the reagent concentrations and gives repro-
ducible yields only when the whole process is conducted
at a concentration lower than 0.3-0.4 mol L-1
.
the Meyers’ lactamization is usually reported from keto
acid derivatives, esters 2a ,c were converted into the
corresponding carboxylic acids 5a ,c in 96 and 76% yields,
respectively.
With keto-esters 2a -d and keto-acids 5a ,c,d in hand,
we turned to the proposed 5,7-fused bicyclic lactams
construction. In the presence of (R)-phenylglycinol and
under the classical dehydrating conditions used by Mey-
ers,1 the keto-acid 5a afforded the desired lactam 1a in
88% yield and 86% de. Both diastereoisomers (aR,3R,-
13bS)-1a and (aS,3R,13bR)-1a were isolated by column
chromatography. The relative stereochemistry of the
minor diastereoisomer (aS,3R,13bR)-1a was determined
by a nuclear Overhauser enhancement spectroscopy
(NOESY) experiment. On treating the keto-ester 2a
under the same conditions, we were pleased to isolate
the desired lactam 1a in greater than 90% yield as a
single isomer (de > 95%). This constitutes the first highly
stereoselective formation of a 5,7-fused bicyclic lactam
employing Meyers’ methodology (Scheme 1).
The desired 2-naphthylpyridine 2d was readily pre-
pared from aryl triflate 4b by a one-pot procedure using
a borylation-Suzuki coupling (BSC) sequence, recently
developed by Baudoin et al.7 We first optimized the
borylation step. Under Masuda et al.’s conditions,8 the
use of PdCl2(dppf) or PdCl2(PPh3)2 as catalysts led, in our
case, to naphthylboronate 4c in modest yields (Table 2,
entries 1, 2).9 After screening various conditions, we
found that using Pd(PPh3)4 provided notably higher yields
(Table 2, entries 3-6). The presence of two equivalents
of pinacolborane was found to be critical to reach nearly
quantitative yields of naphthylboronate 4c (Table 2, entry
6). The Suzuki cross-coupling step was carried out in the
presence of Pd(PPh3)4 and Ba(OH)2 in dioxane to afford
2d in 84% yield after flash chromatography. As both the
borylation and Suzuki cross-coupling steps may be
conducted under the same conditions with excellent
yields, we next investigated a one-pot procedure (BSC).
Thus, at the end of the borylation step, ethyl 2-chloroni-
At this stage, some comments related to the presence
of conformational constraints, occurring during the lac-
tamization of the oxazolidine intermediate, are appropri-
ate to account for the stereochemical course of the
process. The stereochemical outcome in lactam 1a is
coherent with Meyer’s observations,1 that is, the major
stereoisomer (aR,3R,13bS)-1a displays both phenyl groups
of the oxazoline moiety in a trans relationship. The trans-
oxazolidine intermediate A lactamizes via a “pro-(aR)
rotation” about the biaryl axis, giving rise to the exclusive
formation of bicyclic lactam (aR,3R,13bS)-1a (Figure 3).
Conformational restrictions in the 5,7-fused bicyclic
lactam 1a prevents the lactamization of the trans-
oxazolidine intermediate A from taking place through a
“pro-(aS) rotation” about the biaryl axis (Figure 3). In
contrast, the only way for the cis-oxazolidine intermedi-
(7) (a) Baudoin, O.; Gue´nard, D.; Gue´ritte, F. J . Org. Chem. 2000,
65, 9268-9271. (b) Baudoin, O.; Cesario, M.; Gue´nard, D.; Gue´ritte,
F. J . Org. Chem. 2002, 67, 1199-1207.
(8) (a) Murata, M.; Watanabe, S.; Masuda, Y. J . Org. Chem. 1997,
62, 6458-6459. (b) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y.
J . Org. Chem. 2000, 65, 164-168.
(9) Substantial amounts of undesirable 2-acetylnaphthalene was
identified by 1H NMR analysis of the crude reaction product and
account for the modest yield of 4c. Reductive dehalogenation has
already been reported during palladium-catalyzed borylation (see ref
7b).
9518 J . Org. Chem., Vol. 68, No. 24, 2003

TABLE 3. Seven -Mem ber ed La cta m s 1b-d F or m a tion
SCHEME 1 . Seven -Mem ber ed La cta m 1a
F or m a tion a
a
Key: (a) (R)-phenylglycinol, toluene; reflux 18 h for 5a and
138 h for 2a .
ester 2d resulted in the formation 1c and 1d in rather
low yields. In summary, a highly stereoselective prepara-
tion of 5,7-fused bicyclic lactams using Meyer’s methodol-
ogy has been developed with success. The excellent
stereoselectivity observed appears to be tightly connected
with the presence of the biaryl motif. Further investiga-
tions of this stereoselective lactamization with other
biaryl systems are underway for the preparation of new
axially chiral bridged ligands with a view to explore their
potential in asymmetric catalysis.
F IGURE 3. Stereochemical course of the lactamization step.
ate B to further react with the carboxylic acid or ester is
to initiate a “pro-(aS) rotation” about the biaryl axis to
produce (aS,3R,13bR)-1a . The absolute configuration of
the chiral axis present in the biaryl unit is therefore
subordinated to that of the N,O-acetal center in the
oxazolidine intermediate (Figure 3).10
Exp er im en ta l Section
The above methodology could be extended to the
preparation of 5,7-fused bicyclic lactams 1b-d incorpo-
rating a heterocyclic ring in the biaryl motif. Thus,
treating 2-phenylquinoline 2b with (R)-phenylglycinol in
toluene under Dean-Stark conditions for 138 h gave 81%
of lactam 1b as a single diastereoisomer (de > 95%). The
keto-ester 2c and keto-acid 5d were subjected to the same
conditions to furnish lactams 1c and 1d in 72 and 78%
yield, respectively, as a single diastereoisomer in both
cases. Surprisingly, despite the high level of stereoselec-
tivity, the lactamization reaction of keto-acid 5c and keto-
(a R,3R,13b S)-13b -Met h yl-3-p h en yl-2,3-d ih yd r o-13bH -
d iben z[c,e]oxa zolo[3,2-a ]a zep in -5-on e (1a ) (Gen er a l P r o-
ced u r e). Keto-ester 2a (1.21 g, 4.5 mmol) and (R)-phenylglycinol
(618 mg, 4.5 mmol) were dissolved in toluene (50 mL) in a Dean-
Stark apparatus. The mixture was stirred at reflux for 138 h,
and toluene was evaporated under reduced pressure. 1H NMR
analysis of the crude product indicated the formation of only
one diastereoisomer (de > 95%). Flash chromatography of the
residue on silica gel (EtOAc/CH2Cl2/cylohexane: 1/8/1) provided
lactam (aR,3R,13bS)-1a (1.46 g, 95%) as a colorless solid (mp
90 °C). [R]20 ) +56.4° (c 0.62, CH2Cl2). 1H NMR (CDCl3): δ
D
7.78 (dd, J ) 1.0 and 7.0 Hz, 1H), 7.57 (m, 1H), 7.50-7.14 (m,
11H), 7.35 (d, J ) 6.0 Hz, 1H), 4.31 (dd, J ) 7.0 and 9.0 Hz,
1H), 4.16 (dd, J ) 1.0 and 9.0 Hz, 1H), 1.44 (s, 3H). 13C NMR
(CDCl3): δ 165.0, 142.3, 141.3, 137.5, 136.3, 133.8, 131.7, 131.2,
130.8, 129.3, 129.2, 129.0 (2 C), 128.7, 128.5, 128.0, 127.3 (2 C),
122.7, 94.3, 71.4, 62.1, 26.1. IR (KBr) νmax: 3061, 2986, 2936,
2877, 1632, 1450, 1395, 1238, 1037, 742, 697 cm-1. Anal. Calcd
for C23H19NO2: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.84; H,
5.68, N, 4.11.
(10) For conformational and configurational analysis of related
axially chiral lactams see: (a) Vasse, J .-L.; Dupas, G.; Duflos, J .;
Que´guiner, G.; Bourguignon, J .; Levacher, V. Tetrahedron Lett. 2001,
42, 4613-4616. (b) Vasse, J .-L.; Dupas, G.; Duflos, J .; Que´guiner, G.;
Bourguignon, J .; Levacher, V. Tetrahedron Lett. 2001, 42, 3713-3716.
(c) Vasse, J .-L.; Levacher, V.; Bourguignon, J .; Dupas. G. Chem.
Commun. 2002, 2256-2257.
J . Org. Chem, Vol. 68, No. 24, 2003 9519

(a S,3R,13b R)-13b -Met h yl-3-p h en yl-2,3-d ih yd r o-13b H -
d iben z[c,e]oxa zolo[3,2-a ]a zep in -5-on e (1a ). Prepared ac-
cording to the general procedure from keto-acid 5a (500 mg, 2.08
one diastereoisomer (de > 95%). Flash chromatography of the
residue on silica gel (EtOAc) afforded lactam (aS,3R,13bS)-1c
as a white solid (118 mg, 72%, mp 149 °C). [R]20 ) +24.9° (c
D
1
1
mmol) and (R)-phenylglycinol (286 mg, 2.08 mmol) for 18 h. H
0.3, CH2Cl2). H NMR (CDCl3): δ 8.82 (dd, J ) 1.0 and 8.0 Hz,
NMR analysis of the crude product indicated the formation of
two diastereoisomers (de ) 86%). Flash chromatography of the
residue on silica gel (EtOAc/CH2Cl2/cyclohexane, 1/8/1) afforded
lactam (aR,3R,13bS)-1a (624 mg, 88%) and its diastereoisomer
(aS,3R,13bR)-1a as a colorless oil (14 mg, 2%). Data for the
1H), 8.18 (dd, J ) 1.0 and 9.0 Hz, 1H), 8.06 (m, 1H), 7.65 (m,
1H), 7.50 (m, 4H), 7.39-7.23 (m, 4H), 5.40 (d, J ) 6.0 Hz, 1H),
4.41 (dd, J ) 2.0 and 8.0 Hz, 1H), 4.28 (dd, J ) 1.0 and 8.0 Hz,
1H), 1.50 (s, 3H). 13C NMR (CDCl3): δ 163.7, 153.7, 152.3, 142.3,
140.9, 139.2, 135.8, 132.0, 130.2, 129.9, 129.3, 129.1 (2 C), 128.2,
minor diastereoisomer (aS,3R,13bR)-1a : [R]20 ) -18.0° (c 0.1,
127.4 (2 C), 123.1, 122.5, 94.2, 71.4, 62.4, 27.2. IR (KBr) ν
:
D
max
1
CH2Cl2). H NMR (CDCl3): δ 7.97 (d, J ) 7.0 Hz, 1H), 7.72 (dd,
1633, 1402, 763, 748, 701 cm-1. Anal. Calcd for C22H18N2O2: C,
77.17; H, 5.30; N, 8.18. Found: C, 77.12; H, 5.46, N, 8.08.
(a S,3R,15b S)-15b -Me t h yl-3-p h e n yl-2,3-d ih yd r o-15b H -
n a p h th [2,1-c]oxa zolo[3,2-a ]p yr id o[2,3-e]a zep in -5-on e (1d ).
Prepared according to the general procedure from keto-acid 5d
(220 mg, 0.75 mmol) and (R)-phenylglycinol (102 mg, 0.75 mmol)
for 72 h. 1H NMR analysis of the crude product indicated the
formation of only one diastereoisomer (de > 95%). Flash chro-
matography of the residue on silica gel (EtOAc/CH2Cl2/cyclo-
hexane, 1/8/1) afforded (aS,3R,15bS)-1d as a colorless oil (229
J ) 2.0 and 7.0 Hz, 1H), 7.57 (dd, J ) 2.0 and 7.0 Hz, 1H), 7.52
(dd, J ) 1.0 and 3.0 Hz, 2H), 7.44-7.36 (m, 3H), 7.05 (m, 3H),
6.84 (m, 2H), 5.34 (dd, J ) 5.0 and 6.0 Hz, 1H), 4.50 (dd, J )
6.0 and 9.0 Hz, 1H), 4.05 (dd, J ) 5.0 and 9.0 Hz, 1H), 1.41 (s,
3H). Anal. Calcd for C23H19NO2: C, 80.92; H, 5.61; N, 4.10.
Found: C, 80.84; H, 5.68, N, 4.11.
(3R,15bS,aS)-15b-Meth yl-3-ph en yl-2,3-dih ydr o-15bH-ben z-
[c]oxa zolo[3,2-a ]q u in olin o[2,3-e]a zep in -5-on e (1b ). Pre-
pared according to the general procedure from keto-ester 2b
(1.83 g, 5.72 mmol) and (R)-phenylglycinol (785 mg, 5.72 mmol).
1H NMR analysis of the crude product indicated the formation
of only one diastereoisomer (de > 95%). Flash chromatography
of the residue on silica gel (EtOAc/CH2Cl2/cyclohexane: 1/8/1)
mg, 78%). [R]20 ) -67.5° (c 0.4, CH2Cl2) 1H NMR (CDCl3): δ
D
8.82 (dd, J ) 1.0 and 1.5 Hz, 1H), 8.14 (dd, J ) 2.0 and 5.0 Hz,
1H), 7.97 (d, J ) 8.0 Hz, 1H), 7.89 (d, J ) 9.0 Hz, 1H), 7.80-
7.73 (m, 2H), 7.43-7.20 (m, 8H), 5.30 (d, J ) 6.0 Hz, 1H), 4.28
(dd, J ) 6.0 and 10.0 Hz, 1H), 4.19 (d, J ) 10.0 Hz, 1H), 1.46 (s,
3H). 13C NMR (CDCl3): δ 163.8, 153.8, 151.1, 142.2, 140.9, 138.4,
134.6, 132.8, 132.0, 131.8, 130.6, 129.1 (2 C), 128.4, 128.2, 127.4,
127.4, 127.3 (2 C), 126.8, 122.9, 120.1, 95.0, 71.6, 61.7, 26.6.
HRMS (EI): calcd for C26H20N2O2 392.1516, found 392.1517.
afforded lactam (aS,3R,15bS)-1b as a white solid (1.825 g, 81%,
1
mp 79 °C). [R]20 ) -54.6° (c 0.4, CH2Cl2). H NMR (CDCl3): δ
D
8.70 (s, 1H), 8.15 (m, 2H), 7.84 (d, J ) 8.0 Hz, 1H), 7.75 (t, J )
8.0 Hz, 1H), 7.64 (m, 1H), 7.55-7.44 (m, 5H), 7.34 (t, J ) 7.0
Hz, 2H), 7.27 (d, J ) 7.0 Hz, 1H), 5.42 (d, J ) 6.0 Hz, 1H), 4.43
(dd, J ) 6.0 and 9.0 Hz, 1H), 4.27 (d, J ) 9.0 Hz, 1H), 1.51 (s,
3H). 13C NMR (CDCl3): δ 163.9, 153.5, 149.3, 142.7, 141.0, 140.5,
136.3, 132.7, 132.1, 130.2, 130.0, 129.5, 129.1 (2 C), 128.8, 128.2,
128.1, 127.8, 127.4, 127.0, 122.4, 94.2, 71.5, 62.5, 27.9. IR (KBr)
Ack n ow led gm en t. We thank the CNRS, the re´gion
Haute-Normandie, and the CRIHAN for financial and
technical support.
ν
max: 2924, 1636, 1618, 1455, 1402, 1307, 760, 701 cm-1. Anal.
Calcd for C26H20N2O2: C, 79.57; H, 5.14; N, 7.14. Found: C,
79.52; H, 5.16, N, 7.11.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 3′a , 3b,c, 4b,c, 2a -d , and 5a ,c,d ;
spectroscopic data for all compounds (including 1H and 13C
NMR spectra). This material is available free of charge via
the Internet at http://pubs.acs.org.
(aS,3R,13bS)-13b-Meth yl-3-ph en yl-2,3-dih ydr o-13bH-ben z-
[c]oxa zolo[3,2-a ]p yr id o[2,3-e]a zep in -5-on e (1c). Prepared
according to the general procedure from keto-ester 2c (129 mg,
0.48 mmol) and (R)-phenylglycinol (66 mg, 0.48 mmol). 1H NMR
analysis of the crude product indicated the formation of only
J O035195I
9520 J . Org. Chem., Vol. 68, No. 24, 2003