Enantioselective synthesis of aminobenzazepinones

Article abstract of DOI:10.1016/j.tetlet.2007.02.078

Enantioselective synthesis of constrained trans-aminobenzazepinone utilizing palladium-mediated Jeffery-Heck reaction and rhodium(II) catalyzed asymmetric hydrogenation as key steps are described. Diverse functional groups such as alkyl, aryl, basic or am

Full text of DOI:10.1016/j.tetlet.2007.02.078

Tetrahedron Letters 48 (2007) 2661–2665
Enantioselective synthesis of aminobenzazepinones
C. V. C. Prasad,* Stephen E. Mercer, Gene M. Dubowchik and John E. Macor
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut, USA
Received 22 January 2007; revised 7 February 2007; accepted 15 February 2007
Available online 20 February 2007
Abstract—Enantioselective synthesis of constrained trans-aminobenzazepinone utilizing palladium-mediated Jeffery–Heck reaction
and rhodium(II) catalyzed asymmetric hydrogenation as key steps are described. Diverse functional groups such as alkyl, aryl, basic
or amino acid moieties were introduced with minimal racemization.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Design approaches involving structural and conforma-
tional changes in the ligand of ligand-receptor/acceptor
interaction can provide important insights that can lead
to critical tests of pharmacophore hypotheses.1 Con-
straining the ligand to prefer a particular backbone con-
formation is an established strategy in the design of
more selective and/or more potent peptides with im-
proved pharmacokinetic profile as GPCR modulators
or enzyme inhibitors. Compounds containing side chain
constrained amino acids such as Freidinger’s c-lactam,2
tetrahydroisoquinoline-3-carboxylic acid (Tic)3 or an
aminobenzazepinone4 are particularly valuable in prob-
ing the active site of a biological target where crystal
structure data are not available. As illustrated in Figure
1, each side chain v1 torsional angle can assume three
low energy, staggered conformations: gauche (ꢀ)
(v1 = ꢀ 60ꢁ); gauche (+) (v1 = +60ꢁ); and trans
(v1 = 180ꢁ). Synthesis of conformationally constrained
tyrosine- glycine-, phenylalanine–glycine dipeptide
mimetics had been described in the literature.5 In these
approaches the presence of neighboring oxazolidinone
moiety is critical, as it serves as a source of N-acylimin-
ium ion (Fig. 2) which then undergoes intermolecular
Pictet–Spengler cyclization in the presence of tin tetra-
chloride6 or trifluoromethanesulfonic acid (TFMSA).7
X
X
O
Pth
+
N
Pth
N
CO2H
N
H
N
H
O
X
O
O
Figure 2. Cyclization through N-acyliminium ion.
X
180o
H
H
H
H
H
H
H
R
R
H
-60o
NH2
L
OC
NH2
OC
OC
NH2
Cbz
OMe
Cbz
N
X
R
N
H
R
H
N
H
+60o
O
O
1
2
X
gauche (+)
trans
gauche (-)
χ1= +60o
χ1= +/-180o
χ1= -60o
Figure 1. Newman projections of three staggered v1 rotamers in
L
Cbz
L-amino acids.
OMe
L
I
N
3
H
O
*
Corresponding author. Tel.: +1 203 677 6699; fax: +1 203 677
7702; e-mail: Prasad.chaturvedula@bms.com
Figure 3. Retrosynthesis of benzazepinone.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.078

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C. V. C. Prasad et al. / Tetrahedron Letters 48 (2007) 2661–2665
In connection with a medicinal chemistry program, we
were interested in the synthesis of trans-benzazepinone
represented by 1 with a diverse array of substituents
(R = alkyl, aryl, amino acids or basic moieties) in enan-
tiomerically pure form. Our retro synthetic bond discon-
nection is shown in Figure 3. A leaving group at the
benzylic position could easily be displaced with a num-
ber of amines. The synthesis of key intermediate 2 with
a leaving group would follow through a tandem palla-
dium mediated Jeffery–Heck coupling8,9 of aryl iodide
3 with dehydroamino acid 4 followed by asymmetric
hydrogenation mediated by rhodium(II)-based chiral
catalysts.10 Iodide functionality needed for Jeffery–Heck
coupling could be introduced regioselectively under the
directing influence of functional group X. Successful
implementation of this strategy is described below.
Aryl iodides 3a–c were synthesized regioselectively with
iodine monochloride in 62–85% yield.11 The aryl iodide
was coupled to dehydroamino acid 4a–b in the presence
of tetrabutylammonium chloride and a base (NaHCO3,
K2CO3 or Et3N) mediated by 5–10 mol % of palla-
dium(II) acetate in refluxing THF or DMF (Table 1).
The coupled products 5a–f were obtained as a single iso-
Table 1. Jeffery–Heck coupling of aryl iodide with dehydroamino acids
Entry
Aryl iodide
Dehydroamino acid
Enamide
Yieldb (%)
OBn
OBn
OAc
nOe
1
74a,c
CbzHN
BocHN
CO2Me
4a
CbzHN
H
3a
3a
3a
I
OAc
OAc
OH
O
OMe
5a
OBn
OBn
2
79a,c
CO2Me
4b
OAc
BocHN
OBn
I
CO2Me
5b
OBn
OBn
3
4a
57 (5c)a
16 (5d)a
O
OH
5d
CbzHN
CbzHN
I
CO2Me
5c
CO2Me
Me
Me
4
5
6
4a
67a
42a
59d
OAc
CbzHN
I
OAc
OAc
3c
3d
CO2Me
Cl
5e
5f
Cl
4a
OAc
CbzHN
I
CO2Me
OBn
OBn
O
O
I
O
O
3e
5g
AcHN
NHAc
a
Reaction conditions: 70 ꢁC for 2.5 h, 1.1 equiv Bu4NCl, 0.05 mol % Pd(OAc)2, 1.3 equiv dehydroamino acid, 3.0 equiv Et3N, in THF.
b
Yields refer to weight of product obtained after flash chromatography. All of the examples in the Table were >95% pure as determined by 1H NMR.
c 3J (Hvinyl, Ccarbonyl) = 6.7 Hz.
d
Purified by Prep HPLC.

C. V. C. Prasad et al. / Tetrahedron Letters 48 (2007) 2661–2665
2663
(3J Hvinyl,Cmethyl
carbonyl = 6.9 Hz) is consistent
OBn
OBn
acetate
with the cis-3JCOOR, H coupling.12 The (Z)-configuration
was further supported by the observed NOE between
the vinyl proton and the methyl protons on the acetate
group. As shown in Table 1, alkoxy, alkyl groups and
chloride functionality on the aryl iodide are compatible
with the reaction conditions. Both Cbz- and Boc-pro-
tected dehydroamino acids provided enamides in 60–
79% yield. Not surprisingly, in the absence of an O-ace-
tate protecting group (entry 3), dihydroisobenzofuran 5c
was obtained as a major product. The stereochemistry
of (Z)-alcohol was confirmed by treating the minor alco-
hol 5d with acetic anhydride and comparing with the
spectral properties of 5a. Aryl iodide 3f also coupled effi-
ciently when an acrylate moiety was delivered in an
intramolecular fashion (entry 6).13 Asymmetric hydro-
genation of (Z)-alkyl substituted enamides were carried
out either with (+)-1,2-bis((2S,5S)-2,5-diethylphospho-
lano)benzene(cyclooctadiene)rhodium(II) tetrafluorobo-
rate10 or its (R,R)-enantiomer in dichloromethane or in
X
X
CbzHN
CbzHN
CO2Me
CO2Me
7a: X = OAc
7b: X = OH
7c: X = Cl
6a: X = OAc
6b: X = OH
6c: X = Cl
Scheme 1. Reagents and conditions: (a) Mg(OMe)2, CHCl3–MeOH
(2:1), 99% and (b) SOCl2, CH2Cl2, 86%.
mer with (Z)-stereochemistry in 42–79% yield. The
geometry of the double bond for Heck coupled prod-
ucts was determined by the proton coupled 13C NMR
experiments using a gated decoupled pulse sequence.
The observed H–C three-bond coupling constant
Table 2. Alkylation and cyclization of benzylic chlorides
Entry
Benzylic chloride
Amine
Azepinone
Yieldc (%)
OBn
OBn
1
91a
Cl
N
O
CbzHN
NH2
NH2
NH2
8a
CO2Me
OBn
6c
CbzHN
OBn
2
3
4
5
93a
91a
97b
42b
N
O
Cl
7c
CbzHN
8b
CO2Me
OBn
CbzHN
OBn
N
O
Cl
CbzHN
CbzHN
CbzHN
8c
CbzHN
OBn
CO2Me
OBn
N
N
N
O
Cl
H2N
8d
8e
CO2Me
OBn
CbzHN
OBn
CO2Me
H2N
CO2Me
N
O
Cl
CO2Me
CbzHN
a Reaction conditions: alkylation with 3.0 equiv of amine in CH2Cl2 at rt for 24 h and then reflux in 10% acetic acid in toluene.
b Reaction conditions: alkylation with 1.5 equiv of amine, 1.0 equiv K2CO3 in CH3CN at rt for 24 h and then reflux in 10% acetic acid in toluene.
c Refers to combined yield of alkylation and cyclization. All of the examples in the Table were >95% pure as determined by 1H NMR.

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C. V. C. Prasad et al. / Tetrahedron Letters 48 (2007) 2661–2665
OBn
OH
a
CbzHN
H2N
N
N
O
O
9
OH
c
b
O
OH
N
O
N
N
H
O
O
HN
N
10
BocHN
N
N
H
O
11
Scheme 2. Reagents and conditions: (a) 10% Pd on carbon, MeOH, 97%; (b) Boc alanine–OH, CH2Cl2, 2-(1H-benzotriazole-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate, triethylamine, 76%; (c) N,N0-disuccinimidylcarbonate, 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2-(1H)-one,
CH2Cl2, 87%.
1:1 dichloromethane–methanol to give the reduced
chiral product in >95% yield. Chiral HPLC analysis of
amino acid esters 6a and 7a suggested that reduction
proceeded in >99% ee.14 The absolute configuration of
hydrogenation products 6–7 were tentatively assigned
based on reported chiral preference of cationic rhodium
catalysts.10 Recently, Danishefsky and co-workers have
also described a Jeffery–Heck reaction of aryl iodides
with in situ generated dehydroalanine derivatives fol-
lowed by asymmetric hydrogenation.15
lowed by cyclization in the presence of acetic acid
in refluxing toluene led to trans(anti)-TyrAla dipeptide
mimetic 8e in 42% yield.20 No detectable racemization
had occurred at either of chiral centers during these trans-
formations as measured by 1H NMR. Functionalization
of the amino terminus of the benzazepinone was accom-
plished by hydrogenolysis of 8a with 10% Pd on carbon
(Scheme 2). The resultant amine 9 was converted either
to urea 10 mediated by N,N0-succinimidylcarbonate or
coupled with Boc-Ala–OH under standard peptide cou-
pling agents (TBTU) to give 11 in good yield.21
The cleavage of acetate proceeded with cat K2CO3 in
MeOH or NaOMe in CHCl3–MeOH in good yield,
but the obtained alcohol had only moderate chiral pur-
ity (60–95% ee). Magnesium methoxide16 in a mixture
(2:1) of chloroform and methanol provided alcohols 6b
and 7b with 98.5% ee and in quantitative yield (Scheme
1). Treatment of alcohol with excess thionyl chloride in
dichloromethane provided chlorides 6c and 7c in 86%
yield.
In summary, a flexible and enantioselective approach to
diverse anti-phenylalanine substituted dipeptide mimet-
ics (8a–e) has been developed using a palladium-medi-
ated Jeffery–Heck reaction, followed by asymmetric
reduction with cationic rhodium catalysts. Alkylation
conditions are mild and cyclization proceeds with a
minimal amount of racemization. Functionalization of
aminoazepinone is efficient and the deprotection and
amide bond formation conditions are compatible with
standard peptide coupling methods. Application of this
methodology in our drug discovery program and rele-
vant biological data will be reported in due course.
Nucleophilic displacement of benzylic chloride 6c by
neopentyl amine proceeded smoothly either in the
presence of excess amine in dichloromethane or potas-
sium carbonate in acetonitrile (Table 2). The crude
benzylic amines in turn were treated with acetic acid in
refluxing toluene to give the desired benzazepinones
8a–b in excellent yield. Both benzazepinones 8a and 8b
retained their chiral integrity as evidenced by chiral
HPLC analysis.17–19
Acknowledgments
We would like to thank Dr. Stella Huang and Daniel
Schroeder of the Discovery Analytical Services (DAS)
for their skillful NMR assistance and to Edward Koz-
lowski of DAS for determining the enantiomeric excess.
Alkylation of chloride 6c with benzyl amine or 2-(piper-
idin-1-yl)ethanamine followed by treatment with acetic
acid in toluene gave the cyclized benzazepinones 8c–d
in good yield (Table 2). Amino acid esters also could
be used to displace benzylic chloride cleanly. Thus,
treatment of chloride 6c with (S)-methyl-2-aminopro-
panoate in the presence of K2CO3 in acetonitrile fol-
References and notes
1. Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich,
M. Biopolymers 1997, 43, 219.

C. V. C. Prasad et al. / Tetrahedron Letters 48 (2007) 2661–2665
2665
2. Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks,
J. R.; Saperstein, R. Science 1980, 210, 656.
B. J. D.; Zhou, B.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2006, 45, 1754.
3. Valle, G.; Kazmierski, W. M.; Crisma, M.; Bonora, G.
M.; Toniolo, C.; Hruby, V. J. Int. J. Peptide Protein Res.
1992, 40, 222.
4. (a) Flynn, G. A.; Giroux, E. L.; Dage, R. J. Am. Chem.
Soc. 1987, 109, 7914; (b) Tourwe, D.; Verschueren, K.;
Frycia, A.; Davis, P.; Porreca, F.; Hruby, V. J.; Toth, G.;
Jasper, H.; Verheyden, P.; Van Binst, G. Biopolymers
1996, 38, 1.
5. (a) Flynn, G. A.; Burkholder, T. P.; Huber, E. W.; Bey, P.
Bioorg. Med. Chem. Lett. 1991, 6, 309; (b) Warshawsky,
A. M.; Flynn, G. A.; Koehl, J. R.; Mehdi, S. Bioorg. Med.
Chem. Lett. 1996, 6, 957; (c) de Laszlo, S. E.; Bush, B. L.;
Doyle, J. J.; Greenlee, W. J.; Hangauer, D. G.; Halgren, T.
A.; Lynch, R. J.; Schorn, T. W.; Siegl, P. K. S. J. Med.
Chem. 1992, 35, 833.
6. Casimir, J. R.; Tourwe, D.; Iterbeke, K.; Giuchard, G.;
Briand, J. P. J. Org. Chem. 2000, 65, 6487–6492.
7. Ruzza, P.; Caldern, A.; Osler, A.; Elardo, S.; Borin, G.
Tetrahedron Lett. 2002, 43, 3769–3771.
8. (a) Heck, R. F. Org. React. 1982, 27, 345; (b) Crisp, G. T.
Chem. Soc. Rev. 1998, 27, 427; (c) Jeffrey, T. J. Chem.
Soc., Chem. Commun. 1984, 19, 1287.
9. For exceptionally mild catalysts for Heck reactions, see:
Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
6989.
10. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L.
J. Am. Chem. Soc. 1993, 115, 10125.
11. Hubig, S. M.; Jung, W.; Kochi, J. K. J. Org. Chem. 1994,
59, 6233.
12. (a) Marshall, J. L. Carbon–Carbon and Carbon–Proton
NMR Couplings: Application to Organic Stereochemistry
and Conformational Analysis; Veriag Chemie Interna-
tional, 1983; (b) NMR experiments were performed on a
Bruker 500 MHz spectrometer equipped with a TXI cryo
probe.
13. Compound 3f was prepared from (5-(benzyloxy)-2-iodo-
phenyl)methanol and 2-acetamidoacrylic acid under Mits-
unobu reaction conditions (1.3 equiv PPh3, 1.3 equiv
diethylazodicarboxylate in CH2Cl2) in 56% yield.
14. Chiral HPLC analysis was performed to determine the
enantiomeric excess of 6a and 7a. The analysis was
performed on a Chiralcel OD–H analytical column
16. Xu, Y.-C.; Bizuneh, A.; Walker, C. J. Org. Chem. 1996,
61, 9086.
17. Chiral HPLC analysis was performed to determine the
enantiomeric excess of 6b and 7b. The analysis was
performed on a Chiralcel OD–H analytical column
(4.6 · 250 mm, 5 mm) using 15% isopropanol in CO2
@
150 Bar and @ 35 ꢁC as mobile phase at a flow rate of
2.0 mL/min. Absorbance was measured @ 220 nm and
5 lL of 1 mg/mL of 6b or 7b in ethanol was injected.
Compound 6b had a retention time of 14.2 min and an
enantiomeric excess of 6b was determined to be 97.7%.
Compound 7b had a retention time of 15.8 min and an
enantiomeric excess of 7b was determined to be 99.5%.
18. Chiral HPLC analysis was performed to determine the
enantiomeric excess of 8a. The analysis was performed on
a Chiralcel OD–H analytical column (4.6 · 250 mm,
5 mm) using 20% isopropanol in CO2 @ 150 Bar and @
35 ꢁC as mobile phase at a flow rate of 2.0 mL/min.
Absorbance was measured @ 220 nm and 5 lL of 1 mg/
mL of 8a in ethanol was injected. Compound 8a had a
retention time of 10.0 min and an enantiomeric excess of
8a was determined to be 96.2%. Compound 8b had a
retention time of 12.6 min and an enantiomeric excess of
8b was determined to be 99.0%.
19. Yields were not optimized. All compounds gave satisfac-
tory spectroscopic data consistent with the proposed
structures. Data for 3a: IR (KBr): 3432, 3272, 2949,
1733, 1691, 1604, 1510, 1255, 1238, 1062, 753, 699 cmꢀ1
;
1H NMR (CDCl3) d 7.48–7.26 (m, 11H), 7.14 (d,
J = 2.5 Hz, 1H), 6.92 (m, 1H), 6.85 (dd, J = 2.5 Hz and
J = 8.5 Hz, 1H), 6.37 (s, 1H), 5.06–5.04 (m, 6H), 3.81 (s,
3H), 2.07 (s, 3H); 13C NMR (CDCl3) d 170.8, 165.7, 159.3,
156,5, 153.7, 138.6, 136.6, 136.3, 136.0, 130.12, 130.02,
127.64, 127.45, 127.28, 125.6, 125.3, 123.4, 120.8, 115.8,
114.6, 112.8, 71.1, 70.2, 67.5, 65.0, 64.0, 52.8, 41.0, 21.1,
21.0; Compound 8a: IR (KBr): 3403, 3063, 2954, 2867,
1
1720, 1659, 1503, 1476, 1363, 1254, 696 cmꢀ1; H NMR
(CDCl3) d 7.43–7.33 (m, 10H), 7.03 (d, J = 8.5 Hz, 1H),
6.86 (dd, J = 2.5 Hz, 8.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H),
6.32 (d, J = 6.5 Hz, 1H), 5.23–5.17 (m, 2H), 5.15 (s, 2H),
5.04 (s, 2H), 3.82 (d, J = 16.5 Hz, 1H), 3.43–3.40 (m, 1H),
3.37 (d, J = 14 Hz, 1H), 3.21 (d, J = 1H), 2.92–2.87 (m,
1H), 0.90 (s, 9H); MS (ES), 487 (M+H)+; HRMS Calcd
for C30H34N2O4: 487.2597. Obtained: 487.2577.
(4.6 · 250 mm, 5 mm) using 15% isopropanol in CO2
@
150 Bar and @ 35 ꢁC as mobile phase at a flow rate of
2.0 mL/min. Absorbance was measured @ 220 nm and
5 lL of 1 mg/mL of 6a or 7a in ethanol was injected.
20. Data for 8e: 1H NMR (300 MHz, CDCl3) d 7.24–7.44 (m,
10H) 6.99 (d, J = 8.42 Hz, 1H) 6.79 (dd, J = 8.42, 2.93 Hz,
1H) 6.56 (d, J = 2.56 Hz, 1H) 6.11 (d, J = 6.59 Hz, 1H)
5.12–5.22 (m, 2H) 5.10 (d, J = 1.83 Hz, 2H) 5.00 (s, 2H)
4.90–5.06 (m, 1H) 3.87 (d, J = 17.20 Hz, 1H) 3.37 (dd,
J = 16.47, 4.03 Hz, 1H) 3.16 (s, 3H) 2.91 (dd, J = 16.47,
13.17 Hz, 1H) 1.38 (d, J = 7.32 Hz, 3H); MS (ES), 503
(M+H)+.
Compound 6a had
a retention time of 11.91 min
and an enantiomeric excess of 6a was determined to be
99.4%. Compound 7a had a retention time of 14.2 min
and an enantiomeric excess of 7b was determined to be
99.9%.
15. (a) Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.;
Furuuchi, T.; Danishefsky, S. J. J. Am. Chem. Soc. 2005,
127, 4596; (b) Zheng, S.; Chan, C.; Furuuchi, T.; Wright,
21. Bodanszky, M.; Bodanszky, A. In The Practice of Peptide
Synthesis; Hafner, K., Ed.; Springer: Berlin, 1984; p 62.