Enantioselective construction of the biologically significant dibenzo[1,4]diazepine scaffold via organocatalytic asymmetric three-component reactions

Article abstract of DOI:10.1002/adsc.201400095

The first catalytic asymmetric construction of the biologically important dibenzo[1,4]diazepine scaffold has been established via SPINOL-derived chiral phosphoric acid-catalyzed three-component reactions of aldehydes, 1,2-phenylenediamines and cyclohexane

Full text of DOI:10.1002/adsc.201400095

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DOI: 10.1002/adsc.201400095
Enantioselective Construction of the Biologically Significant
Dibenzo[1,4]diazepine Scaffold via Organocatalytic Asymmetric
G
Three-Component Reactions
Yang Wang,+a Man-Su Tu,+a Feng Shi,a,* and Shu-Jiang Tua
a
School of Chemistry and Chemical Engineering, and the Key Laboratory of Biotechnology for Medicinal Plant of Jiangsu
Province, Jiangsu Normal University, Xuzhou 221116, Peopleꢀs Republic of China
E-mail: fshi@jsnu.edu.cn
+
These two authors contributed equally to the work.
Received: January 25, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400095.
Abstract: The first catalytic asymmetric construction the first catalytic asymmetric version of this three-
of the biologically important dibenzoACTHNUGRTNEUNG[1,4]diazepine component reaction and provides an easy access to
scaffold has been established via SPINOL-derived structurally rigid seven-membered chiral heterocy-
chiral phosphoric acid-catalyzed three-component re- cles.
actions of aldehydes, 1,2-phenylenediamines and cy-
clohexane-1,3-diones, which afforded structurally
complex and diverse dibenzoACHTUNTRGNEUNG[1,4]diazepines in high Keywords: asymmetric catalysis; chiral heterocycles;
yields and good enantioselectivities (up to 98% enantioselectivity; multicomponent reactions; organ-
yield, 92:8 er). This transformation also represents ic catalysis
Introduction
asymmetric reductive amination to construct a highly
enantioselective diazepine framework [Eq. (1)].[5] In
The dibenzoACHTUNGTRENNUNG[1,4]diazepine scaffold is a privileged spite of this elegant work, the catalytic enantioselec-
structure which is present in a variety of pharmaceuti- tive approaches to construct a chiral diazepine moiety
cally important compounds.[1] As exemplified in are still underdeveloped and full of challenges.
Figure 1, compounds I and II represent a new class of
HIV protease inhibitors.[1a] Compounds III and IV act
as cystathionine b-synthase inhibitor[1b] and neurome-
din B receptor antagonist,[1c] respectively. Besides,
compounds V and VI have proven to be hepatitis C
virus (HCV) NS5B polymerase inhibitors.[1d,e]
The prominent medicinal relevance of this type of
heterocyclic architecture has led to a great demand
for efficient synthetic strategies, especially those con-
structing enantioselective scaffolds, because one of
the two enantiomers may have higher bioactivity than
the other one or the mixed racemates.[2] However,
a survey of the literature only revealed some reports
on the synthesis of racemic products,[3] and no catalyt-
In recent years, organocatalytic enantioselective
ic asymmetric approaches affording enantioselective multi-component reactions (OEMCRs) have become
dibenzo[1,4]diazepines have been described as yet. In a powerful tool to obtain structurally diverse and
ACHTUNGTRENNUNG
fact, the catalytic asymmetric construction of the complex chiral compounds in a single step, which is
structurally rigid seven-membered diazepine motif especially important for the synthesis of pharmaceuti-
had met with little success[4] until Strotman and co- cals without transition metal contamination of the
workers developed a Ru-catalyzed intramolecular products.[6] Therefore, it is highly desirable to develop
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Yang Wang et al.
Figure 1. Pharmaceutically important compounds containing the dibenzoACTHNUGRTENUNG[1,4]diazepine scaffold.
OEMCRs to access optically pure diazepines from CPA-catalyzed three-component reactions of alde-
simple starting materials. hydes, 1,2-phenylenediamines and cyclohexane-1,3-
Chiral phosphoric acids (CPAs) have emerged as diones, which afforded structurally complex and di-
a class of privileged organocatalysts, which have ena- verse dibenzo[1,4]diazepines in high yields and good
AHCTUNGTRENNUNG
bled a wide range of enantioselective transforma- enantioselectivities (up to 98% yield, 92:8 er).
tions.[7] We have established a series of CPA-catalyzed
multi-component reactions for the synthesis of enan-
tiopure heterocycles of biological importance.[8] In- Results and Discussion
spired by these success and considering that there are
so far no catalytic asymmetric approaches affording The initial experiments to test our hypothesis com-
enantioselective dibenzo
to employ a CPA-catalyzed three-component reaction benzaldehyde 1a, 1,2-phenylenediamine 2a and 5,5-di-
to construct a chiral dibenzo[1,4]diazepine scaffold, methylcyclohexane-1,3-dione 3a catalyzed by a wide
ACHTUNGTNER[NUNG 1,4]diazepines, we decided menced with a three-component reaction of 4-nitro-
AHCTUNGTRENNUNG
wherein the nitrogen-containing intermediate should range of BINOL-derived CPAs 5 (in Scheme 2) at
be activated by CPA via hydrogen-bonding interac- 508C in toluene (Table 1). Although the yields of the
tions (Scheme 1).
Herein, we report the first catalytic asymmetric
construction of the dibenzoACTHNUTRGENUGN[1,4]diazepine scaffold via
Scheme 1. Design of the CPA-catalyzed three-component
reaction to construct a chiral dibenzo[1,4]diazepine scaffold.
N
Scheme 2. CPAs employed for the model reaction.
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Enantioselective Construction of the Biologically Significant DibenzoACTHNUGRTNEUNG[1,4]diazepine
Table 1. Screening of catalysts and solvents.[a]
parts 5i and 5j. The employment of CPAs 6a and 6b
as catalysts to the reaction (entries 11 and 12) im-
proved the enantioselectivity to 66:34 er with a quanti-
tative yield (entry 11).
Then, in the presence of catalyst 6a, the preliminary
evaluation of other solvents such as 1,2-dichloro-
ethane (DCE) and 1,4-dioxane disclosed that 1,4-di-
oxane was much superior to toluene and DCE with
regard to enantioselectivity, delivering the chiral
dibenzoACTHNUTRGENUG[N 1,4]diazepine 4a in 78:22 er (Table 1, entry 14
vs. 11 and 13). However, further screening of other
ethers including tetrahydropyran (THP), anisole, tet-
rahydrofuran (THF) and 1,2-dimethoxyethane
(DME) could not realise better results than 1,4-diox-
ane did (entries 15–18 vs. 14). Hence, 1,4-dioxane was
chosen as the most suitable solvent for further optimi-
zation of the reaction conditions.
Entry
CPA
Solvent
Yield [%][b]
er[c]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
66
99
87
92
98
64
90
69
84
94
99
90
61
90
90
84
57
26
50:50
51:49
52:48
51:49
50:50
58:42
58:42
58:42
57:43
62:38
66:34
65:35
67:33
78:22
57:43
68:32
52:48
54:46
Next, other reaction parameters such as tempera-
ture, molecular sieves (MS) and reagent ratios were
optimized for the same model reaction (Table 2). The
tentative elevation of the reaction temperature in 1,4-
dioxane (entries 1 and 2) revealed that 608C could
deliver the same reaction in a higher yield of 97%
with a maintained enantioselectivity of 78:22 er
(Table 2, entry 1 vs. Table 1, entry 14). So, the subse-
quent evaluation of MS was performed at 608C,
which indicated that 3ꢂ MS was better than 4ꢂ and
5ꢂ MS both in regard to enantioselectivity and reac-
tivity (entry 1 vs. 3 and 4). Then, the reagent ratio
was carefully tuned with the aim to enhance the enan-
tioselectivity (entries 5–10). The presence of excess 3a
was detrimental to the enantioselectivity of the reac-
tion (entries 5 and 6 vs. 1). Neither increasing nor de-
creasing the stoichiometry of 1a could benefit the
enantioselectivity (entries 7–9 vs. 1). However, reduc-
ing the stoichiometry of 1a and 3a at the same time
resulted in a slightly improved enantioselectivity of
79:21 er (entry 10 vs. 1). Hence, the most suitable
ratio of 1a:2a:3a was set as 1:1:1.
9
10
11
12
13
14
15
16
17
18
5j
6a
6b
6a
6a
6a
6a
6a
6a
1,4-dioxane
THP
anisole
THF
DME
[a]
Unless indicated otherwise, the reaction was carried out
in 0.1 mmol scale in solvent (1 mL) with 3ꢂ MS
(100 mg) for 17 h, and the ratio of 1a:2a:3a was 1.2:1:1.2.
Isolated yield.
The enantiomeric ratio (er) value was determined by
HPLC.
[b]
[c]
reactions in the presence of catalysts 5 were good to
At this stage, it seemed that the enantioselectivity
excellent, the enantioselectivities of these reactions of the reaction was too difficult to enhance merely by
were frustrating (entries 1–10). In detail, CPAs 5a–5e changing these reaction parameters. Modification on
with relatively small groups at the 3,3’-positions of the the structure of the catalyst has proven to be an effi-
BINOL backbone almost had no inducing effect on cient way to improve the enantioselectivity, and
the enantioselectivity (entries 1–5), while CPAs 5f–5j SPINOL-derived CPAs have recently been recognized
with bulky groups at the same positions exhibited as a type of chiral Brønsted acid possessing higher ca-
a slightly higher catalytic activity on the enantioselec- pability in enantioselective control than their BINOL-
tive control (entries 6–10). Among them, 9-anthracen- based analogues.[9] Therefore, we changed the H8-
yl-substituted CPA 5j delivered the desired product BINOL backbone of catalyst 6a to the SPINOL scaf-
4a in the highest enantioselectivity of 62:38 er fold and employed this type of spiro-CPA 7a (in
(entry 10). From these results, we assumed that the Scheme 2) to the model reaction. Indeed, this struc-
steric effect of the 3,3’-substituents and the rigidity of turally more rigid catalyst 7a enabled the same reac-
the BINOL backbone might play an important role in tion to proceed in a much more efficient and enantio-
the enantioselective control of the reaction. So, we selective way, delivering the targeted product 4a in
synthesized two H8-BINOL-derived CPAs 6a and 6b 93% yield and 89:11 er (Table 2, entry 11). At last, in
with bulky groups (in Scheme 2), which are more the presence of CPA 7a, fine-tuning the reaction tem-
structurally rigid than their BINOL-derived counter- perature (entries 11–15) disclosed that 408C was the
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Table 2. Further optimization of the reaction conditions.[a]
Table 3. The substrate scope of aldehydes.[a]
Entry 4
R
Yield [%][b] er[c]
1
2
3
4
5
6
7
8
4a 4-NO2C6H4 (1a)
4b 4-CF3C6H4 (1b)
4c 4-MeO2CC6H4 (1c) 86
4d 4-CNC6H4 (1d)
4e 4-FC6H4 (1e)
4f 3,4-F2C6H3 (1f)
4g 3-Cl-4-FC6H3 (g)
4h 3-F-4-ClC6H3 (1h) 90
4i 4-PhC6H4 (1i)
4j C6H5 (1j)
4k 2-naphthyl (1k)
4l 4-MeOC6H4 (1l)
4m 4-MeC6H4 (1m)
4n 3-MeC6H4 (1n)
85
78
92:8 (>99:1)[d]
91:9
Entry
CPA
1a:2a:3a
T [oC]
Yield [%][b]
er[c]
1
2
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
7a
7a
7a
7a
7a
7a
7a
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.6
1.2:1:2
1.6:1:1.2
2:1:1.2
1:1:1.2
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
60
70
60
60
60
60
60
60
60
60
60
80
50
40
30
40
40
97
85
96
79
97
93
95
94
92
85
93
79
94
85
77
90
90
78:22
77:23
75:25
72:28
71:29
65:35
74:26
72:28
74:26
79:21
89:11
83:17
90:10
92:8
89:11
87:13
89:11
83:17
84:16
84:16
91:9
88:12
86:14
91:9
84
76
80
98
3[d]
4[e]
5
6
7
8
9
10
11
12
13
14
15
16[f]
17[g]
9
55
90
58
61
81
60
10
11
12
13
14
15
88:12
83:17
78:22
4o 2-thiophenyl (1o) 54
[a]
Unless indicated otherwise, the reaction was carried out
in 0.1 mmol scale in 1,4-dioxane (1 mL) with 3ꢂ MS
(100 mg) at 408C for 17 h, and the ratio of 1:2a:3a was
1:1:1.
84:16
89:11
89:11
[a]
[b]
[c]
Unless indicated otherwise, the reaction was carried out
in 0.1 mmol scale in 1,4-dioxane (1 mL) with 3ꢂ MS
(100 mg) for 17 h.
Isolated yield.
The enantiomeric ratio (er) value was determined by
HPLC.
After recrystallization.
[b]
[c]
[d]
Isolated yield.
The enantiomeric ratio (er) value was determined by
HPLC.
4ꢂ MS was used.
5ꢂ MS was used.
Catalyzed by 5 mol% 7a.
[d]
[e]
[f]
good enantioselectivities (55% to 98% yield, 83:17 to
92:8 er). Basically, there was no remarkable difference
in enantioselectivity among electronically poor, neu-
tral and rich aldehydes, since a good enantioselectivi-
ty of 91:9 er could be offered by all three types of al-
[g]
Catalyzed by 15 mol% 7a.
most suitable temperature to obtain the highest enan- dehydes including 1b, 1i and 1l (entries 2, 9 and 12).
tioselectivity of 92:8 er (entry 14). However, either In detail, among benzaldehydes substituted with elec-
lowering or raising the catalyst loading led to slightly tron-withdrawing groups, p-nitrobenzaldehyde 1a had
decreased enantioselectivity (entries 15 and 16).
the highest capability in enantioselective control, and
With the optimal reaction conditions in hand, we an excellent enantioselectivity of >99:1 er could be
then investigated the substrate scope of this catalytic obtained after simple recrystallization (entry 1, in pa-
asymmetric three-component reaction. Since aryl-sub- rentheses). Disubstituted benzaldehydes 1f–1h deliv-
stituted dibenzoACHTUNGTRENNUNG[1,4]diazepines have exhibited signifi- ered the corresponding products with high yields of
cant bioactivities (Figure 1), a variety of aromatic al- 80–98% albeit with slightly decreased enantioselectiv-
dehydes was employed to the reaction in order to ities (entries 6–8). More important, benzaldehyde 1j
provide structurally diverse dibenzo
ACHTUNGTRENNUNG
substituted with aryl groups. As shown in Table 3, this dibenzoAHCTUNTGRENNUNG
approach is applicable to a wide range of benzalde- good enantioselectivity of 88:12 er (entry 10), which
hydes 1 bearing either electronically poor, neutral, or provided a good opportunity for the synthesis of HIV
rich substituents in generally high yields and fair to protease inhibitor II (in Figure 1) in an enantioselec-
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Enantioselective Construction of the Biologically Significant DibenzoACTHNUGRTNEUNG[1,4]diazepine
Table 4. The generality for 1,2-arylenediamines.[a]
donating substituents appeared to exert some impact
on the enantioselectivity and the yield (entry 13 vs.
14). Besides, this protocol could also be applied to
heteroaromatic aldehydes as exemplified by thio-
phene-2-carbaldehyde 1o in an acceptable yield and
enantioselectivity (entry 15).
Next, the generality for 1,2-arylenediamines 2 was
examined by the reaction with 4-nitrobenzaldehyde
1a and 5,5-dimethylcyclohexane-1,3-dione 3a. As illus-
trated in Table 4, this protocol is amenable to differ-
ent symmetrical 1,2-arylenediamines 2 with electron-
neutral, electron-rich, or electron-withdrawing sub-
stituents on their benzene rings, giving chiral dibenzo-
AHCTUNGTREG[NNUN 1,4]diazepines 4a and 4p–4r in high yields (85–88%)
and good enantioselectivities (85:15 to 92:8 er). In
general, 1,2-arylenediamines 2a–2c substituted with
electron-neutral or electron-rich groups delivered
higher enantioselectivity than those substituted with
electron-withdrawing groups as exemplified by 2d.
More interestingly, 5-phenyl-substituted cyclohex-
ane-1,3-dione 3b proved to be a reactive component
and afforded the targeted product 4s in an excellent
yield of 98% and a high enantioselectivity of 90:10 er
albeit with a moderate diastereoselectivity of 55:45 dr
(Scheme 3). The two diastereomers could be easily
separated by flash column chromatography, thereby
providing a practical method for the synthesis of this
type of bioactive chiral molecules such as compounds
I and III (see Figure 1).
The absolute configuration of compound 4a (>99:1
er after recrystallization) was unambiguously deter-
mined to be (S) by single-crystal X-ray diffraction
analysis (Figure 2).[10] The absolute configurations of
[a]
other dibenzo
ogy.
ACHTUNGTRENN[UNG 1,4]diazepines 4 were assigned by anal-
Unless indicated otherwise, the reaction was carried out
in 0.1 mmol scale in 1,4-dioxane (1 mL) with 3ꢂ MS
(100 mg) at 408C for 17 h, and the ratio of 1a:2:3a was
1:1:1. Yields referred to isolated yield and the enantio-
meric ratio (er) value was determined by HPLC.
On the basis of our experimental results, we suggest
a possible reaction pathway and transition state to ex-
plain the chemistry and the stereochemistry of this
catalytic asymmetric three-component reaction
(Scheme 4). Initially, in the presence of CPA 7a, 1,2-
tive manner by simple treatment of 4j with oxalyl arylenediamine 2 reacted with cyclohexane-1,3-dione
chloride.[1a] Moreover, benzaldehyde 1l with a strong 3 to generate an imine intermediate, which could
electron-donating group was superior to other elec- easily isomerize to the more stable enamine inter-
tronically rich ones in terms of enantioselectivity mediate 8 because of the conjugative effect of the C=
(entry 12 vs. 13 and 14), and the position of electron- C bond with the carbonyl group. Then, enamine 8
Scheme 3. Reaction using 5-phenylcyclohexane-1,3-dione 3b as substrate.
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NH2 groups in 1,2-arylenediamine 2, a control experi-
ment was carried out with N-methyl-1,2-phenylenedi-
amine 2e under the optimal reaction conditions
(Scheme 5). Although this three-component reaction
afforded the desired dibenzoACTHNUGTRNEUNG[1,4]diazepine 4t, the
yield was only 43% and the enantioselectivity was
just 61:39 er. This result indicated that the NH2
groups in 1,2-arylenediamine 2 were very important
for both the reactivity and the enantioselectivity, be-
cause the existence of an N-methyl group allowed
CPA 7a to form just one hydrogen bond with the key
intermediate, which was inferior to the dual hydro-
gen-bonding activation mode in reactivity and enan-
tioselective control.
Figure 2. The absolute configuration of compound 4a.
condensed with aldehyde 1 to produce the corre-
sponding imine 9. This key intermediate 9 possessed Conclusions
both the enamine and the imine functional groups,
thus facilitating the subsequent intramolecular Man- In summary, we have established the first catalytic
nich reaction, again under the catalysis of 7a, to enantioselective construction of the biologically im-
afford the desired dibenzoACTHNUTRGNENGU[1,4]diazepine 4. In the pro- portant dibenzoHCATUNGTREN[NUGN 1,4]diazepine scaffold in high yields
posed transition state of the intramolecular Mannich and good enantioselectivities (up to 98% yield, 92:8
reaction, the 6,6’-bi(phenanthrenyl)phosphoric acid 7a er) catalyzed by a SPNOL-derived chiral phosphoric
acted as a bifunctional catalyst to activate both the acid. Furthermore, this transformation represents the
enamine and the imine groups by dual hydrogen- first catalytic asymmetric version of the three-compo-
bonding interactions. Then, an enantioselective intra- nent reactions of aldehydes, 1,2-phenylenediamines
molecular Mannich reaction occurred because of the and cyclohexane-1,3-diones, providing an easy access
chiral environment created by (R)-SPINOL backbone to structurally rigid seven-membered chiral heterocy-
and the bulky 6,6’-substitutents of CPA 7a, thus pro- cles. This approach also combines the merits of orga-
viding the experimentally observed (S)-configured nocatalysis and asymmetric multi-component reac-
product 4.
tions to afford a variety of enantioselective dibenzo-
ACHTUNGTREN[NUGN 1,4]diazepines with structural complexitzy and diver-
In order to test our hypothesis on the activation
mode of dual hydrogen-bonding interactions as shown sity, which should be promising candidates for chemi-
in Scheme 4 and to demonstrate the crucial role of cal biology and drug discovery.
Scheme 4. Proposed reaction pathway and transition state.
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Enantioselective Construction of the Biologically Significant DibenzoACTHNUGRTNEUNG[1,4]diazepine
Scheme 5. Control experiment involving N-methyl-1,2-phenylenediamine 2e.
1
(c 0.25, acetone); H NMR (CDCl3, 400 MHz): d=7.97 (d,
J=8.4 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.82–6.70 (m, 3H),
6.58 (s, 1H), 6.48–6.31 (m, 1H), 5.98 (s, 1H), 4.48 (s, 1H),
2.63 (d, J=15.9 Hz, 1H), 2.48 (d, J=15.9 Hz, 1H), 2.34 (d,
J=16.3 Hz, 1H), 2.24 (d, J=16.3 Hz, 1H), 1.17 (s, 3H), 1.08
(s, 3H); 13C NMR (CDCl3, 100 MHz): d=194.0, 153.4, 151.5,
146.5, 136.3, 130.7, 127.9, 124.4, 123.5, 121.9, 121.6, 120.2,
110.4, 57.8, 49.7, 46.5, 32.4, 28.7, 27.9; IR (KBr): n=3358,
3566, 3393, 1698, 1683, 1647, 1636, 1541, 1522, 1508, 1385,
842, 737, 669 cmÀ1; ESI-FT-MS: m/z 362.1512, exact mass
calcd. for (C21H21N3O3ÀH)À: 362.1499; enantiomeric ratio:
92:8, determined by HPLC (Kromasil CHI-TBB, hexane/2-
propanol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =5.57 min (major), tR =6.36 min (minor).
Experimental Section
General
NMR spectra were measured at 400 and 100 MHz, respec-
tively. The solvents used for NMR spectroscopy were CDCl3
and CD3OD, using tetramethylsilane as the internal refer-
ence. HR-MS were recorded on an LTQ-Orbitrap mass
spectrometer. Enantiomeric ratios (er) were determined by
chiral high-performance liquid chromatography (chiral
HPLC). The chiral columns used for the determination of
enantiomeric ratios by chiral HPLC were Kromasil CHI-
TBB and Daicel Chirapak OD-H columns. Optical rotation
values were measured with instruments operating at l=
589 nm, corresponding to the sodium D line at the tempera-
tures indicated. Analytical grade solvents for the column
chromatography and commercially available reagents were
used as received.
(S)-3,3-Dimethyl-11-[4-(trifluoromethyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]ACHUTNGTRENN[GUN 1,4]diazepin-1-one
(4b): Flash column chromatography eluent: petroleum
ether/ethyl acetate=1/1; reaction time: 17 h; yield: 78%;
yellow solid; [a]2D0: +85.1 (c 0.28, acetone); 1H NMR
(CDCl3/CD3OD, 400 MHz): d=7.36 (d, J=7.5 Hz, 2H), 7.17
(d, J=7.9 Hz, 2H), 7.0–6.70 (m, 4H), 6.45 (d, J=7.9 Hz,
1H), 6.02 (s, 1H), 4.58 (s, 1H), 2.65–2.50 (m, 1H), 2.44 (d,
J=15.7 Hz, 1H), 2.30 (d, J=16.2 Hz, 1H), 2.22 (d, J=
16.2 Hz, 1H), 1.13 (s, 3H), 1.05 (s, 3H); 13C NMR (CDCl3/
CD3OD, 100 MHz): d=194.1, 128.7, 127.6, 125.2, 125.2,
124.3, 122.7, 122.0, 120.4, 58.1, 55.1, 46.2, 32.4, 28.9, 27.7; IR
(KBr): g 3404, 3217, 1637, 1618, 1541, 1522, 1384, 832,
724 cmÀ1; ESI-FT-MS: m/z=385.1543, exact mass calcd. for
(C22H21F3N2OÀH)À: 385.1528; enantiomeric ratio: 91:9, de-
termined by HPLC (Kromasil CHI-TBB, hexane/2-propa-
nol=80/20, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
5.97 min (major), tR =6.72 min (minor).
Typical Procedure for the Asymmetric Synthesis of
DibenzoACHTUNGTRENNUNG[1,4]diazepines 4
After a solution of 1,2-phenylenediamines 2 (0.1 mmol), cy-
clohexane-1,3-diones (0.1 mmol), the catalyst 7a
3
(0.01 mmol), and 3 ꢂ molecular sieves (100 mg) in 1,4-diox-
ane (0.5 mL) had been stirred at 408C for 2 h, the solution
of aldehydes 1 (0.1 mmol) in 1,4-dioxane (0.5 mL) was
added. After being stirred at 408C for 15 h, the reaction
mixture was filtered to remove molecular sieves and the
solid powder was washed with methanol. The resultant solu-
tion was concentrated under the reduced pressure to give
the residue, which was purified through flash column chro-
matography on silica gel to afford pure product 4.
(S)-Methyl 4-(3,3-dimethyl-1-oxo-2,3,4,5,10,11-hexahydro-
1H-dibenzoACTHNUTRGENN[GU b,e]ACHUTNGTRENN[UGN 1,4]diazepin-11-yl)benzoate (4c): Flash
(S)-3,3-Dimethyl-11-(4-nitrophenyl)-2,3,4,5,10,11-hexahy-
column chromatography eluent: petroleum ether/ethyl ace-
dro-1H-dibenzoACHTUNGTRENNUNG[b,e]ACHTUNTGREN[NUGN 1,4]diazepin-1-one (4a): Flash column
tate=1/1; reaction time: 17 h; yield: 86%; pale yellow solid;
chromatography eluent: petroleum ether/ethyl acetate=1/1;
1
reaction time: 17 h; yield: 85%; yellow solid; [a]2D0: +199.2
[a]2D0: +235.8 (c 0.29, acetone); H NMR (CDCl3, 400 MHz):
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

FULL PAPERS
Yang Wang et al.
d=7.79 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 6.74–
6.70 (m, 4H), 6.45–6.31 (m, 1H), 5.97 (s, 1H), 4.46 (s, 1H),
3.82 (s, 3H), 2.62 (d, J=15.8 Hz, 1H), 2.43 (d, J=15.9 Hz,
1H), 2.32 (d, J=16 Hz, 1H), 2.23 (d, J=16 Hz, 1H), 1.13 (s,
3H), 1.05 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=194.0,
167.0, 153.4, 149.2, 136.7, 130.9, 129.6, 128.3, 127.2, 124.1,
121.6, 121.5, 120.0, 110.8, 58.0, 52.0, 49.7, 46.4, 32.4, 28.8,
27.7; IR (KBr): n=3413, 3125, 2975, 1699, 1637, 1508, 1385,
1090, 1049, 880, 741, 639 cmÀ1; ESI-FT-MS: m/z=375.1684,
exact mass calcd. for (C23H24N2O3ÀH)À: 375.1709; enantio-
meric ratio: 89:11, determined by HPLC (Kromasil CHI-
TBB, hexane/2-propanol=80/20, flow rate 1.0 mLminÀ1, T=
308C, 254 nm): tR =6.74 min (major), tR =7.50 min (minor).
(S)-3,3-Dimethyl-11-[4-(trifluoromethyl)phenyl]-
(Kromasil CHI-TBB, hexane/2-propanol=80/20, flow rate
1.0 mLminÀ1, T=308C, 254 nm): tR =6.31 min (major), tR =
7.20 min (minor).
(S)-11-(3-Chloro-4-fluorophenyl)-3,3-dimethyl-
2,3,4,5,10,11-hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]ACHUTNGTRENN[GUN 1,4]diazepin-1-one
(4g): Flash column chromatography eluent: petroleum
ether/ethyl acetate=1/1; reaction time: 17 h; yield: 98%;
1
pale yellow solid; [a]2D0: +208.3 (c 0.22, acetone); H NMR
(CDCl3, 400 MHz): d=7.15–7.05 (m, 1H), 6.95–6.83 (m,
2H), 6.80–6.72 (m, 3H), 6.64 (s, 1H), 6.47–6.36 (m, 1H),
5.87 (s, 1H), 4.42 (s, 1H), 2.65–2.53 (m, 1H), 2.45 (d, J=
15.8 Hz, 1H), 2.32 (d, J=16.3 Hz, 1H), 2.24 (d, J=16.4 Hz,
1H), 1.15 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3,
100 MHz): d=194.0, 153.5, 136.7, 130.9, 129.4, 126.8, 126.7,
124.3, 121.8, 121.7, 120.1, 116.3, 116.0, 110.8, 57.3, 49.7, 46.4,
32.4, 28.7, 27.9; IR (KBr): n=3311, 3013, 2902, 1684, 1637,
1622, 1385, 732, 669, 617 cmÀ1; ESI-FT-MS: m/z=369.1164,
exact mass calcd. for (C21H20ClFN2O-H)À: 369.1187; enantio-
meric ratio: 84:16, determined by HPLC (Kromasil CHI-
TBB, hexane/2-propanol=80/20, flow rate 1.0 mLminÀ1, T=
308C, 254 nm): tR =6.30 min (major), tR =7.24 min (minor).
(S)-11-(4-Chloro-3-fluorophenyl)-3,3-dimethyl-
2,3,4,5,10,11-hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]ACHUTNGTRENN[GUN 1,4]diazepin-1-one
(4d): Flash column chromatography eluent: petroleum
ether/ethyl acetate=1/1; reaction time: 17 h; yield: 84%;
yellow solid; [a]2D0: +115.7 (c 0.24, acetone); 1H NMR
(CDCl3, 400 MHz): d=7.38 (d, J=7.7 Hz, 2H), 7.15 (d, J=
7.9 Hz, 2H), 6.90–6.72 (m, 4H), 6.44–6.37 (m, 1H), 5.96 (s,
1H), 4.61 (s, 1H), 2.59 (d, J=15.5 Hz, 1H), 2.47 (d, J=
15.8 Hz, 1H), 2.31 (d, J=16.3 Hz, 1H), 2.23 (d, J=16.3 Hz,
1H), 1.14 (s, 3H), 1.06 (s, 3H); 13C NMR (CDCl3,
100 MHz): d=194.1, 153.9, 132.1, 130.9, 127.9, 124.3, 122.0,
121.7, 120.3, 120.3, 118.9, 110.3, 58.1, 49.7, 46.2, 32.4, 28.7,
27.8; IR (KBr): n=3406, 3321, 2173, 1635, 1622, 1540, 1507,
1384, 857, 716 cmÀ1; ESI-FT-MS: m/z 342.1631, exact mass
calcd. for (C22H21N3OÀH)À: 342.1607; enantiomeric ratio:
87:13, determined by HPLC (Kromasil CHI-TBB, hexane/2-
propanol=80/20, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =8.32 min (major), tR =9.74 min (minor).
2,3,4,5,10,11-hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]ACHUTNGTRENN[GUN 1,4]diazepin-1-one
(4h): Flash column chromatography eluent: petroleum
ether/ethyl acetate=1/1; reaction time: 17 h; yield: 90%;
1
pale yellow solid; [a]2D0: +214.3 (c 0.23, acetone); H NMR
(CDCl3, 400 MHz): d=7.19–7.07 (m, 1H), 6.88–6.64 (m,
6H), 6.49–6.34 (m, 1H), 5.88 (s, 1H), 4.44 (s, 1H), 2.65–2.52
(m, 1H), 2.44 (d, J=15.9 Hz, 1H), 2.32 (d, J=16.3 Hz, 1H),
2.23 (d, J=16.3 Hz, 1H), 1.14 (s, 3H), 1.07 (s, 3H);
13C NMR (CDCl3, 100 MHz): d=194.0, 153.6, 136.6, 130.8,
130.2, 124.3, 123.8, 123.7, 121.8, 121.6, 120.2, 115.4, 115.1,
110.7, 57.4, 49.7, 46.3, 32.4, 28.7, 27.9; IR (KBr): n=3375,
(S)-11-(4-Fluorophenyl)-3,3-dimethyl-2,3,4,5,10,11-hexahy-
dro-1H-dibenzoACHTUNGTRENNUNG[b,e]ACHTUNTGREN[NUGN 1,4]diazepin-1-one (4e): Flash column
chromatography eluent: petroleum ether/ethyl acetate=1/1;
3112, 2992, 1647, 1636, 1622, 1541, 1385, 832, 669, 548 cmÀ1
;
reaction time: 17 h; yield: 76%; pale yellow solid; [a]2D0:
ESI-FT-MS: m/z=369.1142, exact mass calcd. for
(C21H20ClFN2OÀH)À: 369.1164; enantiomeric ratio: 84:16,
determined by HPLC (Kromasil CHI-TBB, hexane/2-propa-
nol=90/10, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
16.16 min (major), tR =20.38 min (minor).
(S)-11-[(1,1’-Biphenyl)-4-yl]-3,3-dimethyl-2,3,4,5,10,11-
hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]AHCTUNGTRENN[UGN 1,4]diazepin-1-one (4i): Flash
1
À9.6 (c 0.24, acetone); H NMR (CDCl3/CD3OD, 400 MHz):
d=7.08–6.97 (m, 2H), 6.95–6.65 (m, 6H), 6.52–6.37 (m,
1H), 6.05–5.90 (m, 1H), 4.58 (s, 1H), 2.65–2.47 (m, 1H),
2.46–2.37 (m, 1H), 2.28–2.19 (m, 2H), 1.12 (s, 3H), 1.06 (s,
3H); 13C NMR (CDCl3/CD3OD, 100 MHz): d=194.0, 162.7,
160.3, 128.8, 128.7, 124.1, 121.9, 120.3, 115.1, 114.9, 97.5,
57.7, 55.1, 46.2, 32.3, 28.9, 27.6; IR (KBr): n=3526, 3402,
column chromatography eluent: petroleum ether/ethyl ace-
tate=1/1, then preparative thin layer chromatography, pe-
troleum ether/ethyl acetate=1/2; reaction time: 17 h; yield:
3309, 2935, 1542, 1523, 1508, 1384, 893, 761, 703, 667 cmÀ1
;
ESI-FT-MS: m/z=335.1573, exact mass calcd. for
(C21H21FN2OÀH)À: 335.1560; enantiomeric ratio: 89:11, de-
termined by HPLC (Kromasil CHI-TBB, hexane/2-propa-
nol=80/20, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
5.77 min (major), tR =6.39 min (minor).
(S)-11-(3,4-Difluorophenyl)-3,3-dimethyl-2,3,4,5,10,11-
hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]AHCTUNGTRENN[UGN 1,4]diazepin-1-one (4f): Flash
column chromatography eluent: petroleum ether/ethyl ace-
tate=1/1; reaction time: 17 h; yield: 80%; yellow solid;
[a]2D0: +18.6 (c 0.16, acetone); 1H NMR (CDCl3/CD3OD,
400 MHz): d=6.98–6.69 (m, 7H), 6.51–6.40 (m, 1H), 5.95–
5.84 (m, 1H), 4.58 (s, 1H), 2.61–2.38 (m, 2H), 2.33–2.18 (m,
2H), 1.13 (s, 3H), 1.07 (s, 3H); 13C NMR (CDCl3/CD3OD,
100 MHz): d=194.0, 153.9, 151.2, 148.8, 124.3, 123.3, 121.9,
117.0, 116.8, 116.2, 116.0, 97.5, 57.5, 55.1, 46.2, 32.3, 28.8,
27.8; IR (KBr): n=3446, 3364, 3217, 2935, 2987, 1698, 1683,
1647, 1635, 1507, 1385, 933, 821, 711 cmÀ1; ESI-FT-MS: m/
z=353.1452, exact mass calcd. for (C21H21FN2OÀH)À:
353.1466; enantiomeric ratio: 83:17, determined by HPLC
1
55%; yellow solid; [a]2D0: +32.9 (c 0.23, acetone); H NMR
(CDCl3/CD3OD, 400 MHz): d=7.63–7.41 (m, 3H), 7.40–7.30
(m, 5H), 7.18–7.01 (m, 2H), 6.85–6.70 (m, 3H), 6.50 (s, 1H),
6.15–5.93 (m, 1H), 4.58 (s, 1H), 2.69–2.48 (m, 1H), 2.47–
2.42 (m, 1H), 2.37–2.28 (m, 1H), 2.26–2.23 (m, 1H), 1.12 (s,
3H), 1.10–1.07 (m, 3H); 13C NMR (CDCl3/CD3OD,
100 MHz): d=194.1, 140.7, 139.4, 128.7, 127.8, 127.1, 126.9,
124.1, 97.5, 58.1, 55.1, 50.9, 32.4, 29.1, 27.6; IR (KBr): n=
3305, 3122, 1652, 1557, 1541, 1521, 1507, 1384, 921, 852, 773,
698 cmÀ1; ESI-FT-MS: m/z=393.1976, exact mass calcd. for
(C27H26N2OÀH)À: 393.1967; enantiomeric ratio: 91:9, deter-
mined by HPLC (Kromasil CHI-TBB, hexane/2-propanol=
80/20, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
6.19 min (major), tR =6.79 min (minor).
(S)-3,3-Dimethyl-11-phenyl-2,3,4,5,10,11-hexahydro-1H-
dibenzoACTHNUGRTNENUG[b,e]CAHTUNGTREN[NUNG 1,4]diazepin-1-one (4j): Flash column chroma-
tography eluent: petroleum ether/ethyl acetate=1/1; reac-
tion time: 17 h; yield: 90%; yellow solid; [a]2D0: À32.9 (c 0.14,
8
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Enantioselective Construction of the Biologically Significant DibenzoACTHNUGRTNEUNG[1,4]diazepine
acetone); 1H NMR (CDCl3/CD3OD, 400 MHz): d=7.16–
6.99 (m, 6H), 6.82–6.68 (m, 3H), 6.51–6.39 (m, 1H), 6.12–
5.93 (m, 1H), 4.58 (s, 1H), 2.54–2.31 (m, 2H), 2.29–2.12 (m,
2H), 1.11 (s, 3H), 1.06 (s, 3H); 13C NMR (CDCl3/CD3OD,
100 MHz): d=194.0, 128.2, 127.3, 126.8, 123.9, 122.0, 97.45,
58.3, 55.1, 46.2, 32.3, 29.1, 27.5; IR (KBr): n=3564, 3107,
2962, 1716, 1620, 1539, 1384, 1263, 817, 776, 703 cmÀ1; ESI-
1457, 1385, 821, 730, 669 cmÀ1; ESI-FT-MS: m/z=331.1811,
exact mass calcd. for (C22H24N2OÀH)À: 331.1805; enantio-
meric ratio: 88:12, determined by HPLC (Kromasil CHI-
TBB, hexane/2-propanol=90/10, flow rate 1.0 mLminÀ1, T=
308C, 254 nm): tR =10.58 min (major), tR =11.82 min
(minor).
(S)-3,3-Dimethyl-11-(meta-tolyl)-2,3,4,5,10,11-hexahydro-
1H-dibenzoACTHNUTRGENNU[G b,e]CAHTUNGTRNE[NUGN 1,4]diazepin-1-one (4n): Flash column
FT-MS:
m/z=317.1649,
exact
mass
calcd.
for
(C21H22N2OÀH)À: 317.1654; enantiomeric ratio: 88:12, de-
termined by HPLC (Daicel Chirapak OD-H, hexane/2-prop-
anol=70/30, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
6.98 min (major), tR =17.67 min (minor).
chromatography eluent: petroleum ether/ethyl acetate=1/1,
then preparative thin layer chromatography, petroleum
ether/ethyl acetate=1/2; reaction time: 17 h; yield: 60%;
pale yellow solid; [a]D20: +76.0 (c 0.24, acetone); 1H NMR
(CDCl3, 400 MHz): d=6.99–6.92 (m, 2H), 6.85 (d, J=
7.5 Hz, 1H), 6.81–6.69 (m, 4H), 6.68–6.57 (m, 1H), 6.46–
6.36 (m, 1H), 5.90 (s, 1H), 4.41 (s, 1H), 2.64–2.51 (m, 1H),
2.40 (d, J=15.8 Hz, 1H), 2.35–2.26 (m, 1H), 2.25–2.20 (m,
1H), 2.19 (s, 3H), 1.13 (s, 3H), 1.07 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d=194.0, 153.1, 143.8, 137.6, 131.0,
128.3, 127.9, 127.4, 123.8, 123.8, 121.6, 121.2, 119.9, 111.6,
58.1, 49.8, 46.4, 32.4, 28.9, 27.7, 21.5; IR (KBr): n=3415,
3227, 2998, 1732, 1715, 1698, 1636, 1541, 1385, 902, 862,
701 cmÀ1; ESI-FT-MS: m/z=331.1806, exact mass calcd. for
(C22H24N2OÀH)À: 331.1805; enantiomeric ratio: 83:17, de-
termined by HPLC (Kromasil CHI-TBB, hexane/2-propa-
nol=90/10, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
10.20 min (major), tR =11.65 min (minor).
(S)-3,3-Dimethyl-11-(naphthalen-2-yl)-2,3,4,5,10,11-hexa-
hydro-1H-dibenzo
[b,e]
E
(4k):
Flash
column chromatography eluent: petroleum ether/ethyl ace-
tate=1/1, then preparative thin layer chromatography, pe-
troleum ether/ethyl acetate=1/2; reaction time: 17 h; yield:
1
58%; yellow solid; [a]2D0: À37.7 (c 0.21, acetone); H NMR
(CDCl3/CD3OD, 400 MHz): d=7.70–7.56 (m, 3H), 7.47 (s,
1H), 7.37–7.32 (m, 2H), 7.24–7.12 (m, 1H), 7.01–6.57 (m,
4H), 6.46 (s, 1H), 6.31–6.05 (m, 1H), 4.58 (s, 1H), 2.70–2.47
(m, 1H), 2.46–2.43 (m, 1H), 2.37–2.27 (m, 1H), 2.26–2.22
(m, 1H), 1.10 (s, 6H); 13C NMR (CDCl3/CD3OD, 100 MHz):
d=194.1, 133.2, 132.4, 128.0, 127.4, 125.8, 125.7, 124.1, 97.5,
55.1, 49.8, 32.4, 29.7, 27.6; IR (KBr): g=3444, 3309, 2997,
1541, 1521, 1507, 1385, 831, 793, 727, 615 cmÀ1; ESI-FT-MS:
m/z=367.1839, exact mass calcd. for (C25H24N2OÀH)À:
367.1811; enantiomeric ratio: 86:14, determined by HPLC
(Kromasil CHI-TBB, hexane/2-propanol=80/20, flow rate
1.0 mLminÀ1, T=308C, 254 nm): tR =6.16 min (major), tR =
6.93 min (minor).
(R)-3,3-Dimethyl-11-(thiophen-2-yl)-2,3,4,5,10,11-hexahy-
dro-1H-dibenzoACTHNUTRGENNGU[b,e]ACHTUNGTERN[NUGN 1,4]diazepin-1-one (4o): Flash column
chromatography eluent: petroleum ether/ethyl acetate=1/1,
then preparative thin layer chromatography, petroleum
ether/ethyl acetate=1/2; reaction time: 17 h; yield: 54%;
pale yellow solid; [a]D20: +75.5 (c 0.20, acetone); 1H NMR
(CDCl3, 400 MHz): d=7.02–6.94 (m, 1H), 6.85–6.65 (m,
6H), 6.61–6.52 (m, 1H), 6.21 (s, 1H), 4.46 (s, 1H), 2.64–2.53
(m, 1H), 2.36 (d, J=16 Hz, 1H), 2.32 (d, J=16 Hz, 1H),
2.25 (d, J=16 Hz, 1H), 1.12 (s, 3H), 1.08 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d=193.5, 153.4, 148.0, 137.0, 130.6,
126.3, 124.5, 124.0, 123.9, 121.8, 121.5, 120.2, 112.6, 53.0,
50.0, 46.2, 32.3, 29.2, 27.5; IR (KBr): n=3414, 3217, 2925,
1872, 1618, 1501, 1384, 912, 746, 624 cmÀ1; ESI-FT-MS: m/
z=323.1185, exact mass calcd. for (C19H20N2OSM->H)À:
323.1213; enantiomeric ratio: 78:22, determined by HPLC
(Kromasil CHI-TBB, hexane/2-propanol=90/10, flow rate
1.0 mLminÀ1, T=308C, 254 nm): tR =12.42 min (major), tR =
13.63 min (minor).
(S)-11-(4-Methoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-hexa-
hydro-1H-dibenzo
[b,e]
E
(4l):
Flash
column chromatography eluent: petroleum ether/ethyl ace-
tate=1/1, then preparative thin layer chromatography, pe-
troleum ether/ethyl acetate=1/2; reaction time: 17 h; yield:
1
61%; yellow solid; [a]2D0: À11.4 (c 0.18, acetone); H NMR
(CDCl3, 400 MHz): d=7.08–6.86 (m, 3H), 6.81–6.68 (m,
3H), 6.65–6.60 (m, 2H), 6.50–6.40 (m, 1H), 6.02–5.85 (m,
1H), 4.58 (s, 1H), 3.66 (s, 3H), 2.66–2.42 (m, 1H), 2.41–2.34
(m, 1H), 2.32–2.24 (m, 1H), 2.23–2.17 (m, 1H), 1.13–1.08
(m, 3H), 1.05 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=
194.0, 158.1, 128.3, 123.9, 121.9, 113.5, 57.7, 55.1, 49.8, 46.2,
32.3, 29.1, 27.6; IR (KBr): n=3392, 3113, 2992, 1647, 1636,
1541, 1508, 1385, 863, 733, 662 cmÀ1; ESI-FT-MS: m/z=
347.1786, exact mass calcd. for (C22H24N2O2ÀH)À: 347.1760;
enantiomeric ratio: 91:9, determined by HPLC (Kromasil
(S)-3,3-Dimethyl-13-(4-nitrophenyl)-2,3,4,5,12,13-hexahy-
dro-1H-benzo[e]naphtho
G
G
(4p):
CHI-TBB,
hexane/2-propanol=80/20,
flow
rate
1.0 mLminÀ1, T=308C, 254 nm): tR =5.73 min (major), tR =
6.20 min (minor).
Flash column chromatography eluent: petroleum ether/ethyl
acetate=1/1; reaction time: 17 h; yield: 87%; yellow solid;
[a]2D0: +134.9 (c 0.21, acetone); 1H NMR (CDCl3/CD3OD,
400 MHz): d=8.10–7.71 (m, 3H), 7.60–7.46 (m, 1H), 7.42–
7.36 (m, 2H), 7.23–7.17 (m, 4H), 6.87–6.82 (m, 1H), 6.13–
6.00 (m, 1H), 4.98 (s, 1H), 2.82–2.59 (m, 1H), 2.54 (d, J=
15.3 Hz, 1H), 2.41–2.32 (m, 1H), 2.30–2.22 (m, 1H), 1.17 (s,
3H), 1.12 (s, 3H); 13C NMR (CDCl3/CD3OD, 100 MHz): d=
194.4, 146.6, 132.4, 130.8, 128.1, 126.3, 125.9, 125.5, 124.9,
123.6, 97.5, 57.7, 55.1, 46.3, 32.4, 28.7, 28.0; IR (KBr): n=
(S)-3,3-Dimethyl-11-(para-tolyl)-2,3,4,5,10,11-hexahydro-
1H-dibenzoACHTUNGTRENNUNG[b,e]ACHTUNGTRENNUNG[1,4]diazepin-1-one (4m): Flash column
chromatography eluent: petroleum ether/ethyl acetate=1/1;
reaction time: 17 h; yield: 81%; pale yellow solid; [a]2D0:
1
+193.2 (c 0.23, acetone); H NMR (CDCl3, 400 MHz): d=
7.00–6.88 (m, 4H), 6.82–6.64 (m, 4H), 6.46–6.35 (m, 1H),
5.91 (s, 1H), 4.42 (s, 1H), 2.65–2.48 (m, 1H), 2.42–2.34 (m,
1H), 2.33–2.26 (m, 1H), 2.25–2.20 (m, 1H), 2.18 (s, 3H),
1.12 (s, 3H), 1.05 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=
193.9, 153.2, 140.9, 137.2, 136.0, 131.0, 128.9, 127.0, 123.7,
121.59, 121.2, 119.9, 111.7, 57.8, 49.8, 46.3, 32.3, 28.9, 27.7,
21.0; IR (KBr): n=3327, 3001, 1733, 1698, 1647, 1558, 1508,
3411, 3097, 1805, 1636, 1617, 1519, 1385, 932, 807, 618 cmÀ1
;
ESI-FT-MS: m/z=412.1670, exact mass calcd. for
(C25H23N3O3ÀH)À: 412.1661; enantiomeric ratio: 92:8, deter-
mined by HPLC (Kromasil CHI-TBB, hexane/2-propanol=
Adv. Synth. Catal. 0000, 000, 0 – 0
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Yang Wang et al.
80/20, flow rate 1.0 mLminÀ1, T=308C, 254 nm): tR =
13.90 min (major), tR =15.65 min (minor).
(S)-3,3,7,8-Tetramethyl-11-(4-nitrophenyl)-2,3,4,5,10,11-
3.00 (s, 3H), 2.64 (d, J=15.8 Hz, 1H), 2.49 (d, J=15.9 Hz,
1H), 2.31 (d, J=16.3 Hz, 1H), 2.20 (d, J=16.3 Hz, 1H),
1.18 (s, 3H), 1.08 (s, 3H); 13C NMR (CDCl3, 100 MHz): d=
194.1, 152.7, 148.3, 139.0, 133.1, 128.6, 124.6, 123.0, 122.6,
120.8, 120.0, 110.0, 65.6, 49.7, 46.4, 42.1, 32.5, 28.5, 28.1; IR
(KBr): n=3413, 2992, 1775, 1638, 1618, 1510, 1265, 1050,
925, 739, 619 cmÀ1; ESI-FT-MS: m/z=376.1658, exact mass
calcd. for (C22H23N3O3-H)À: 376.1656; enantiomeric ratio:
61:39, determined by HPLC (Daicel Chirapak OD-H,
hexane/2-propanol=80/20, flow rate 1.0 mLminÀ1, T=308C,
254 nm): tR =10.27 min (major), tR =8.22 min (minor).
hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]AHCTUNGTRENN[UGN 1,4]diazepin-1-one (4q): Flash
column chromatography eluent: petroleum ether/ethyl ace-
tate=1/1; reaction time: 17 h; yield: 87%; orange solid;
[a]2D0: +163.8 (c 0.18, acetone); 1H NMR (CDCl3/CD3OD,
400 MHz): d=7.97–7.85 (m, 2H), 7.21 (d, J=8.3 Hz, 2H),
6.85–6.45 (m, 2H), 6.19 (s, 1H), 6.08–5.92 (m, 1H), 4.58 (s,
1H), 2.65–2.50 (m, 1H), 2.46–2.40 (m, 1H), 2.35–2.27 (m,
1H), 2.22 (d, J=15.7 Hz, 1H), 2.07–2.03 (m, 3H), 2.00–1.95
(m, 3H), 1.14 (s, 3H), 1.05 (s, 3H); 13C NMR (CDCl3/
CD3OD, 100 MHz): d=193.9, 146.5, 133.0, 128.1, 123.5,
122.8, 121.4, 97.5, 57.9, 55.1, 50.8, 46.4, 32.3, 28.8, 18.9, 18.8;
IR (KBr): n=3235, 2962, 2029, 1638, 1617, 1517, 1384, 1342,
1261, 932, 619 cmÀ1; ESI-FT-MS: m/z=390.1845, exact mass
calcd for (C23H25N3O3ÀH)À: 390.1818; enantiomeric ratio:
91:9, determined by HPLC (Kromasil CHI-TBB, hexane/2-
propanol=90/10, flow rate 1.0 mLminÀ1, T=308C, 254 nm):
tR =22.26 min (major), tR =26.77 min (minor).
Acknowledgements
We are grateful for financial support from National Natural
Science Foundation of China (21372002 and 21232007),
PAPD of Jiangsu Higher Education Institutions, and Open
Foundation of Jiangsu Key Laboratory (KLBMP1302 and
K201314).
(S)-7,8-Dichloro-3,3-dimethyl-11-(4-nitrophenyl)-
2,3,4,5,10,11-hexahydro-1H-dibenzoACTHNUTRGENN[UG b,e]ACHUTNGTRENN[GUN 1,4]diazepin-1-one
(4r): Flash column chromatography eluent: petroleum ether/
ethyl acetate=1/1; reaction time: 17 h; yield: 88%; orange
solid; [a]2D0: +225.3 (c 0.39, acetone); 1H NMR (CDCl3,
400 MHz): d=8.09–8.00 (m, 2H), 7.22–7.10 (m, 2H), 6.86 (s,
1H), 6.53 (s, 1H), 6.33 (s, 1H), 5.94 (s, 1H), 4.53 (s, 1H),
2.65–2.57 (m, 1H), 2.43 (d, J=15.9 Hz, 1H), 2.35–2.30 (m,
1H), 2.24 (d, J=16.6 Hz, 1H), 1.17 (s, 3H), 1.08–1.03 (m,
3H); 13C NMR (CDCl3, 100 MHz): d=191.5, 150.5, 146.7,
135.9, 127.8, 123.8, 122.0, 120.9, 57.3, 46.2, 32.4, 28.6, 27.7,
14.1; IR (KBr): n=3376, 2975, 1651, 1507, 1456, 1385, 1090,
1049, 880, 801, 537 cmÀ1; ESI-FT-MS: m/z=430.0751, exact
mass calcd. for (C21H19Cl2N3O3ÀH)À: 430.0725; enantiomeric
ratio: 85:15, determined by HPLC (Kromasil CHI-TBB,
hexane/2-propanol=80/20, flow rate 1.0 mLminÀ1, T=308C,
254 nm): tR =14.54 min (major), tR =16.28 min (minor).
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ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
chromatography eluent: petroleum ether/ethyl acetate=1/1;
reaction time: 17 h; yield: 98%; 55:45 dr; yellow solid; mp
125–1268C; [a]2D0: +159.3 (c 0.14, acetone); 1H NMR
(CDCl3, 400 MHz): d=8.00 (d, J=8.5 Hz, 2H), 7.41–7.34
(m, 2H), 7.32–7.27 (m, 4H), 7.25–7.22 (m, 1H), 6.85–6.70
(m, 3H), 6.68–6.55 (m, 1H), 6.50–6.41 (m, 1H), 6.06 (s, 1H),
4.53 (s, 1H), 3.43–3.35 (m, 1H), 3.18–3.05 (m, 1H), 2.83–
2.56 (m, 3H); 13C NMR (CDCl3, 100 MHz): d=193.4, 154.7,
151.1, 146.5, 142.5, 136.4, 130.2, 129.0, 128.1, 127.3, 126.7,
124.5, 123.6, 121.9, 121.6, 120.2, 111.9, 57.3, 43.1, 40.5, 39.5;
IR (KBr): n=3399, 2975, 1716, 1698, 1617, 1521, 1508, 1385,
1090, 1049, 857, 744 cmÀ1; ESI-FT-MS: m/z=410.1520, exact
mass calcd. for (C25H21N3O3ÀH)À: 410.1505; enantiomeric
ratio: 90:10, determined by HPLC (Kromasil CHI-TBB,
hexane/2-propanol=80/20, flow rate 1.0 mLminÀ1, T=308C,
254 nm): tR =13.24 min (major), tR =17.56 min (minor).
(S)-3,3,5-Trimethyl-11-(4-nitrophenyl)-2,3,4,5,10,11-hexa-
hydro-1H-dibenzo
[b,e]
E
(4t):
Flash
column chromatography eluent: petroleum ether/ethyl ace-
tate=1/1; reaction time: 17 h; yield: 43%; yellow solid;
1
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6.77 (m, 3H), 6.53–6.47 (m, 1H), 6.31 (s, 1H), 5.73 (s, 1H),
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12 Enantioselective Construction of the Biologically Significant
DibenzoACHTUNGTRENNUNG[1,4]diazepine Scaffold via Organocatalytic
Asymmetric Three-Component Reactions
Adv. Synth. Catal. 2014, 356, 1 – 12
Yang Wang, Man-Su Tu, Feng Shi,* Shu-Jiang Tu
12
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