Synthesis of the tetracyclic core (ABCE rings) of daphenylline

Article abstract of DOI:10.1021/jo301533f

A concise synthesis of the tetracyclic core (ABCE rings) of daphenylline has been accomplished involving a benzobicyclo[3.3.1] lactam as the key intermediate. This bridged bicyclic intermediate was efficiently constructed via a Bronsted acid promoted intramolecular Friedel-Crafts type Michael addition of a δ-benzyl α,β-unsaturated δ-lactam.

Full text of DOI:10.1021/jo301533f

Note
pubs.acs.org/joc
Synthesis of the Tetracyclic Core (ABCE Rings) of Daphenylline
Bowen Fang,† Huaiji Zheng,† Changgui Zhao,† Peng Jing,† Huilin Li,† Xingang Xie,†
and Xuegong She*,†,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
Gansu, 730000, PR China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou, Gansu, 730000, PR China
S
* Supporting Information
ABSTRACT: A concise synthesis of the tetracyclic core (ABCE rings) of daphenylline has been accomplished involving a
benzobicyclo[3.3.1] lactam as the key intermediate. This bridged bicyclic intermediate was efficiently constructed via a Brønsted
acid promoted intramolecular Friedel−Crafts type Michael addition of a δ-benzyl α,β-unsaturated δ-lactam.
he daphniphyllum alkaloids, originated from plants of the
genus Daphniphyllum (daphniphyllaceae), is a large and
analgesics10 (Figure 1). Deriving from our previous study on
Friedel−Crafts type Michael addition to α,β-unsaturated
carbonyl compounds,11 we intended to apply our methodology
to synthesize natural products bearing such a benzomorphan
backbone. Herein, we describe a concise synthesis of the
tetracyclic core (2) (ABCE rings) of daphenylline by
employing a benzobicyclo[3.3.1] lactam (3) as the key
intermediate, which was efficiently constructed by a Brønsted
acid (CF3SO3H) promoted intramolecular Friedel−Crafts type
Michael addition of a δ-benzyl α,β-unsaturated δ-lactam (4).
The retrosynthetic pathway of the tetracyclic (ABCE rings)
core 2 was depicted in Scheme 1. The C ring of the polycyclic
core 2 could be readily constructed from the benzomorphan
analogue 3 by an intramolecular N-alkylation. On the basis of
our previous study regarding the formation of the benzobicy-
clo[3.3.1] lactone via an intramolecular Friedel−Crafts type
Michael addition of the corresponding α,β-unsaturated
lactone,11 we envisioned that the key benzomorphan analogue
3 (benzobicyclo[3.3.1] lactam) could be obtained from δ-
benzyl α,β-unsaturated δ-lactam 4 via a similar pathway. The δ-
lactam 4 could be synthesized from anti-sulfonamide 5, which
in turn could be converted from syn-homoallylic alcohol 6 by
the SN2 reaction. The Barbier-type allylation reaction readily
established the relative configuration (syn) of 6, which could be
easily accessed from commercially available (3-methoxyphenyl)
acetonitrile 7.
T
fast growing family of natural products with diverse
structures.1,2 These fused-heteropolycyclic structures have
received broad interest for both total synthesis and biosynthesis
due to their unique complexity.3 Daphenylline (1), a novel
member of the daphniphyllum alkaloids, was isolated from the
fruits of the Daphniphyllum longeracemosum Rosenth by Hao and
co-workers in 2009 (Figure 1).4 The structural features of
Figure 1. Daphenylline (1) and selected natural products bearing the
benzomorphan core.
daphenylline (1) include a polycyclic skeleton with four
carbocycles and two N-heterocycles, on which are embedded
with one full-carbon quaternary and five tertiary stereogenic
centers. More importantly, the daphenylline (1) skeleton
incorporates benzomorphan (benzobicyclo[3.3.1] core) as the
subunit.5 Such a scaffold has been widely recognized in many
biologically active natural products such as sinomenine,6
morphine,7 codeine,8 pentazocine9 along with various artificial
The synthesis of the tetracyclic core (ABCE rings) of
daphenylline (2) was initiated from (3-methoxyphenyl)
acetonitrile 7 (Scheme 2). Monoalkylation of 7 with the
known iodide 812 afforded nitrile 9 in 85% yield followed by
Received: July 26, 2012
Published: August 30, 2012
© 2012 American Chemical Society
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Note
catalyst (GII)14 under high dilution gave the key intermediate,
δ-benzyl α,β-unsaturated δ-lactam 4, in 74% yield.
Scheme 1. Retrosynthetic Plan for Symthesis of the ABCE
Rings of Dapherylline
With the key lactam 4 in hand, we set out to investigate the
one-step construction of the benzomorphan analogue 3.
Different lactam substrates were tested in parallel regarding
the postulated intramolecular Friedel−Crafts type Michael
addition. Optimization of the reaction conditions started with
using m-methoxy-substituted lactam 13a as the model
substrate, which closely resembled the key lactam 4. A series
of both Lewis and Brønsted acids were examined (Table 1). It
a
Table 1. Optimization of Reaction Conditions
temp
time
(h)
yield
b
entry
acid
solvent
CH2Cl2
(°C)
(%)
c
1
SnBr4
TiCl4
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
50
24
24
24
24
24
24
24
24
24
24
24
24
12
0
d
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
trace
0
c
c
3
BF3·Et2O
FeCl3
4
0
5
TMSOTf
AlCl3
43
trace
35
0
d
DIBAL-H reduction of the cyano functionality into the
corresponding aldehyde 10. It was found that aldehyde 10
reacted smoothly with allyl bromide in the presence of activated
zinc powder in a mixed solvent of saturated aqueous
ammonium chloride and THF,13 giving the homoallylic
alcohols in high yield. Although the diastereoselectivity
remained moderate (d.r. = 6/1), the desired alcohol 6 could
be easily isolated by silica-based column chromatography.
Activation of syn-secondary alcohol 6 as its mesylate and
subsequent SN2 reaction generated anti-homoallylic azide 11 in
86% yield. Subsequent treatment of azide 11 with LiAlH4,
followed by N-nosylation to smoothly furnish the anti-
sulfonamide 5 in 85% yield for two consecutive steps.
Amidation between 5 and acryloyl chloride afforded olefinic-
amide 12 as the ring closing metathesis precursor in 76% yield.
Ring closure of 12 employing the second generation Grubbs’
6
7
AlBr3
c
e
f
8
BCl3
9
BBr3
trace
81
0
10
11
12
13
TfOH
c
c
g
p-TsOH
CF3COOH
0
TfOH
18
(1.0 equiv)
14
TfOH
ClCH2CH2Cl
50
8
90
(2.0 equiv)
a
13a (0.1 mmol), acid (0.25 mmol, 2.5 equiv otherwise indicated in
parentheses), and 1 mL of solvent were mixed. Isolated yield.
Quantitative recovery of the starting material. Recovery of most of
the starting material. Starting material decomposition. Recovery of
b
c
d
e
f
g
10% of the starting material. Recovery of 75% of the starting matetial.
Scheme 2. Synthesis of Lactam 4
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Note
was found that triflic acid promoted the desired intramolecular
Friedel−Crafts type Michael addition with great efficiency in
dichloromethane (DCM), giving the corresponding benzomor-
phan derivative 14a in 81% yield (Table 1, entry 10). Among all
the other tested acids, only AlBr3 and TMSOTf could
successfully render the desired cyclization, however in much
lower yields (Table 1, entries 5 and 7). Treatment of lactam
13a with BBr3 led to a complex mixture with decomposition of
the starting material (Table 1, entry 9). The rest of the Lewis
acids (SnBr4, TiCl4, BF3·OEt2, FeCl3, AlCl3 and BCl3) or protic
acids (p-TsOH and CF3COOH) resulted in no observable
reaction or trace amount in conversion (Table 1, entries 1−4, 6,
8, 11 and 12). When dichloromethane was replaced with 1,2-
dichloroethane (DCE), the desired benzobicyclo[3.3.1] lactam
14a was obtained in excellent yield (90%) using 2 equiv of
triflic acid at 50 °C in 8 h, which was set as the optimized
conditions (Table 1, entry 14).15
substituted lactams (Table 2 entries 5 and 8) proceeded
smoothly under the optimized reaction conditions, while 4-
methoxy and 2,5-dimethoxy substitution failed to give any
desired cyclization products (Table 2 entries 2 and 6). This
indicated that the methoxy group locating at the meta-position
to the reaction site significantly lowered the overall activity,
giving no desired products. To our delight, substrates 13c and
13g could also react well to give the corresponding
benzobicyclo[3.3.1] products 14c and 14g, which contained a
bridged methyl group and a quaternary bridgehead carbon,
respectively (Table 2 entries 3 and 7). The structure of 14g was
characterized by X-ray diffraction analysis confirming the
relative stereochemistry of formed bridged lactams.16
Encouraged by the optimized conditions of the intra-
molecular Friedel−Crafts type Michael addition, we continued
to complete the synthesis of the tetracyclic core (ABCE rings)
of daphenylline (2) (Scheme 3). Gratifyingly, subjection of the
key lactam 4 to the optimized conditions successfully afforded
the bridged lactam 3 in 71% yield, while O-THP protection was
removed in the same pot as well because of the overall acidic
condition. Removal of the nosyl group was readily accom-
plished using thiophenol and potassium carbonate in DMF to
give alcohol lactam 15.17 The primary hydroxyl group was
converted to its mesylate 16 in excellent yield, followed by N-
cyclization in DMF at 0 °C to furnish the targeted tetracyclic
lactam 2 in 77% yield (ABCE rings of daphenylline). The
structure of lactam 2 was unambiguously illustrated by X-ray
crystallography analysis.18
Further investigation was focused on the substrate scope of
the intramolecular Michael addition of lactams possessing
electron-rich aryl groups along with the limitation of this
reaction (Table 2). 3,5-Dimethoxy and 3,4,5-trimethoxy
a
Table 2. Synthesis of Benzobicyclo[3.3.1] Lactam 14
In summary, we have achieved a concise synthesis of the
tetracyclic core (ABCE rings) of daphenylline with overall yield
of 7.5% over 13 steps. The key feature of the synthesis involves
a Brønsted acid promoted intramolecular Friedel−Crafts type
Michael addition reaction of a δ-benzyl α,β-unsaturated lactam,
which efficiently constructed the benzomorphan (benzobicy-
clo[3.3.1] lactam) backbone.
EXPERIMENTAL SECTION
■
Synthesis of Nitrile 9. To a solution of acetonitrile 7 (2.74 g, 18.6
mmol) in dry THF (60 mL) was added LDA (10 mL, 20 mmol, 2.0 M
in THF) at −78 °C under Ar. The reaction mixture was stirred for 0.5
h, and iodide 812 (5.24 g, 20.5 mmol) in dry THF (10 mL) was added
dropwise. After 2 h, saturated aqueous NH4Cl (15 mL) was added at
−78 °C, and the mixture was warmed to room temperature, followed
by extraction with ethyl acetate (3 × 10 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. Purification by column chromatography
(petroleum ether/EtOAc 20:1) gave nitrile 9 (4.35 g, 85% yield) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 7.9 Hz, 1H),
6.97−6.85 (m, 3H), 4.62−4.57 (m, 1H), 4.05 (t, J = 7.9 Hz, 1H),
3.93−3.84 (m, 2H), 3.82 (s, 3H), 3.60−3.38 (m, 2H), 2.20−2.12 (m,
2H), 1.87−1.70 (m, 2H), 1.64−1.54 (m, 4H); 13C NMR (100 MHz,
CDCl3 most of peaks double due to the presence of OTHP group) δ
160.0, 137.0, 136.9, 130.0, 120.7, 120.6, 119.6, 119.5, 113.5, 113.4,
113.2, 113.1, 99.4, 98.7, 63.9, 63.3, 62.6, 62.1, 55.2, 35.9, 35.7, 33.9,
33.8, 30.5, 30.4, 25.3, 19.6, 19.3; HRMS (ESI) Calcd. for C16H22NO3
[M + H]+ 276.1594, found 276.1587.
Synthesis of Aldehyde 10. To a solution of nitrile 9 (4.32 g, 15.7
mmol) in dry CH2Cl2 (50 mL) was added DIBAL-H (13.5 mL, 16
mmol, 1.2 M in toluene) at −78 °C under Ar. The mixture was stirred
for 4 h until 9 was completely consumed. Saturated aqueous NaHCO3
was added slowly at −78 °C to quench the excessive DIBAL-H. After
warming to room temperature, the mixture was filtered, and the
filtration residue was washed with CH2Cl2 (3 × 15 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification by column chromatography
(petroleum ether/EtOAc 15:1) gave aldehyde 10 (3.19 g, 87%
a
All reactions were performed on a 0.1 mmol scale at 0.1 M in
b
c
ClCH2CH2Cl for 8 h at 50 °C. Isolated yield. Quantitative recovery
of the starting material. A 1:1 diastereomeric mixture of 13c was
illustrated. A 2:1 diastereomeric mixture of 14c was illustrated.
d
e
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Note
Scheme 3. Synthesis of the Tetracyclic Core of Daphenylline (2)
yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 9.69 (t, J = 1.7
Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 6.85−6.73 (m, 3H), 4.52 (dt, J =
30.8, 3.6 Hz, 1H), 3.84−3.82 (m, 1H), 3.81 (s, 3H), 3.79−3.66 (m,
2H), 3.49−3.28 (m, 2H), 2.46−2.40 (m, 1H), 2.00−1.95 (m, 1H),
1.82−1.80 (m, 1H), 1.72−1.66 (m, 1H), 1.59−1.50 (m, 4H); 13C
NMR (100 MHz, CDCl3 most of peaks double due to the presence of
OTHP group) δ 200.2, 200.1, 160.0, 137.4, 137.3, 130.0, 129.9, 121.1,
114.6, 114.5, 112.8, 99.0, 98.5, 64.6, 64.5, 62.3, 61.9, 56.0, 55.9, 55.1,
30.5, 29.8, 25.4, 25.3, 19.5, 19.2; HRMS (ESI) Calcd. for C16H26NO4
[M + NH4]+ 296.1856, found 296.1850.
product was dissolved in anhydrous DMF (10 mL) and sodium azide
(453 mg, 6.6 mmol) was added. The mixture was stirred at 80 °C for
12 h before quenching with H2O (10 mL). The aqueous phase was
extracted with Et2O (3 × 15 mL), and the combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification by column chromatography
(petroleum ether/EtOAc 40:1) gave azide 11 (875 mg, 86% yield
for two steps) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.26−
7.20 (m, 1H), 6.88−6.77 (m, 3H), 5.93−5.73 (m, 1H), 5.17−5.13 (m,
2H), 4.45 (dt, J = 45.6, 3.6 Hz, 1H), 3.81 (s, 3H), 3.76−3.51 (m, 3H),
3.48−3.37 (m, 1H), δ 3.31−3.11 (m, 1H)., 2.99−2.87 (m, 1H), 2.37−
2.25 (m, 1H), 2.24−2.14 (m, 1H), 2.12−1.96 (m, 2H), 1.85−1.77 (m,
1H), 1.72−1.62 (m, 1H), 1.60−1.45 (m, 4H); 13C NMR (100 MHz,
CDCl3 most of peaks double due to the presence of OTHP group) δ
159.4, 141.4, 134.0, 129.2, 129.1, 121.4, 118.2, 114.9, 114.9, 112.0,
112.0, 99.2, 98.5, 66.3, 66.2, 65.2, 65.2, 62.4, 61.9, 55.1, 46.3, 46.0,
37.0, 36.9, 32.8, 32.7, 30.6, 30.6, 25.3, 19.6, 19.4; HRMS (ESI) Calcd.
for C19H28N3O3 [M + H]+ 346.2125, found 346.2122.
Synthesis of syn-Alcohol 6. To a solution of aldehyde 10 (2.28 g,
8.2 mmol) in saturated aqueous NH4Cl (25 mL) and THF (5 mL)
were added allyl bromide (3 g, 2.1 mL, 24.6 mmol) and activated zinc
dust (1.6 g, 24.6 mmol). The mixture was stirred at room temperature
for 3 h, followed by extraction with ethyl acetate (3 × 20 mL). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification by column
chromatography (petroleum ether/EtOAc, 7:1) yielded 2.00 g
(76%) of syn-alcohol 6 and 313 mg (12%) anti-alcohol 17 as colorless
oils. syn-product 6: 1H NMR (400 MHz, CDCl3) δ 7.20 (t, J = 7.8 Hz,
1H), 6.78−6.72 (m, 3H), 5.88−5.71 (m, 1H), 5.12−4.97 (m, 2H),
4.48 (dt, J = 29.2, 3.6 Hz, 1H), 3.78 (s, 3H), 3.77−3.57 (m, 3H),
3.43−3.38 (m, 1H), 3.23 (dddd, J = 14.6, 9.6, 7.9, 5.5 Hz, 1H), 2.72
(ddt, J = 9.9, 8.1, 4.0 Hz, 1H), 2.41 (dd, J = 4.4, 2.7 Hz, 1H), 2.36−
2.23 (m, 1H), 2.19−2.08 (m, 1H), 2.03−1.85 (m, 2H), 1.84−1.73 (m,
1H), 1.72−1.61 (m, 1H), 1.59−1.44 (m, 4H); 13C NMR (100 MHz,
CDCl3 most of peaks double due to the presence of OTHP group) δ
159.5, 143.9, 143.8, 135.0, 129.4, 129.3, 120.6, 120.5, 117.7, 114.3,
114.2, 111.3, 99.0, 98.3, 74.1, 74.0, 65.8, 65.6, 62.1, 61.8, 55.0, 49.2,
49.1, 39.6, 39.5, 32.0, 31.7, 30.6, 30.5, 25.3, 25.3, 19.4, 19.2; HRMS
(ESI) Calcd. for C19H32NO4 [M + NH4]+ 338.2326, found 338.2321.
anti-alcohol 17: 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.8 Hz,
1H), 6.92−6.71 (m, 3H), 5.91−5.78 (m, 1H), 5.13−5.02 (m, 2H),
4.53−4.41 (m, 1H), 3.85 (dt, J = 12.9, 4.2 Hz, 1H), 3.79 (s, 3H),
3.77−3.55 (m, 2H), 3.47−3.37 (m, 1H), 3.24 (dddd, J = 14.4, 9.7, 7.8,
5.5 Hz, 1H), 2.85−2.76 (m, 1H), 2.29 (ddd, J = 8.3, 6.5, 4.9 Hz, 1H),
2.16−1.92 (m, 3H), 1.90−1.75 (m, 2H), 1.72−1.63 (m, 1H), 1.60−
1.44 (m, 4H); 13C NMR (100 MHz, CDCl3 most of peaks double due
to the presence of OTHP group) δ 159.5, 142.4, 142.3, 135.1, 135.1,
129.2, 121.3, 117.4, 117.4, 114.9, 114.8, 111.8, 111.7, 99.1, 98.4, 73.6,
73.5, 65.8, 65.5, 62.3, 61.9, 55.0, 48.2, 48.1, 39.4, 39.3, 32.2, 32.1, 30.6,
30.5, 25.3, 25.3, 19.6, 19.3; HRMS (ESI) Calcd. for C19H32NO4 [M +
NH4]+ 338.2326, found 338.2317.
Synthesis of anti-Sulfonamide 5. To a solution of azide 11 (875
mg, 2.5 mmol) in dry THF (25 mL) was added LiAlH4 (200 mg, 5
mmol) at 0 °C. After being stirred for 1 h at room temperature, the
mixture was quenched with 15% NaOH solution at 0 °C and filtered
through Celite. The filtration residue was washed with ethyl acetate (3
× 10 mL). Concentration in vacuo gave the crude product as oil,
which was used immediately without further purification. The crude
product was dissolved in dry CH2Cl2 (20 mL) at 0 °C, and then
diisopropylethylamine (647 mg, 0.83 mL, 5 mmol) and 2-nitro-
benzenesulfonyl chloride (1 g, 4.5 mmol) were added. The mixture
was stirred at room temperature for 2 h and quenched with H2O (15
mL). The mixture was extracted with ethyl acetate (3 × 10 mL), and
the combined organic layers were washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification by column
chromatography (petroleum ether/EtOAc 2:1) gave anti-sulfonamide
1
5 (1.08 g, 76% yield for two steps) as a yellow oil: H NMR (400
MHz, CDCl3) δ 8.04 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H),
7.72−7.63 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H), 6.71 (t, J = 7.4 Hz, 1H),
6.68−6.63 (m, 2H), 5.64−5.51 (m, 1H), 5.26 (dd, J = 11.9, 8.6 Hz,
1H), 4.96 (d, J = 17.1 Hz, 1H), 4.88 (dd, J = 9.8, 4.9 Hz, 1H), 4.41
(dd, J = 48.8, 3.6 Hz, 1H), 3.82−3.77 (m, 2H), 3.75 (s, 3H), 3.69−
3.33 (m, 2H), 3.26−3.05 (m, 1H), 3.02−2.95 (m, 1H), 2.40−2.28 (m,
1H), 2.14−2.01 (m, 2H), 2.00−1.86 (m, 1H), 1.83−1.75 (m, 1H),
1.70−1.60 (m, 1H), 1.56−1.42 (m, 4H); 13C NMR (100 MHz, CDCl3
most of peaks double due to the presence of OTHP group) δ 159.6,
159.5, 147.2, 141.0, 140.8, 135.2, 133.4, 133.4, 132.9, 132.8, 130.2,
130.1, 129.5, 129.4, 125.3, 120.9, 120.9, 118.5, 118.4, 114.4, 114.3,
112.4, 112.3, 99.0, 98.3, 65.1, 64.9, 62.3, 61.7, 59.1, 59.0, 55.0, 45.6,
45.6, 38.3, 31.9, 31.8, 30.6, 30.5, 25.3, 19.5, 19.2; HRMS (ESI) Calcd.
for C25H33N2O7S [M + H]+ 505.2003, found 505.1995.
Synthesis of Azide 11. To a solution of syn-alcohol 6 (950 mg, 3
mmol) in dry CH2Cl2 (20 mL) at 0 °C were added Et3N (0.75 mL, 5.4
mmol) and mesyl chloride (0.35 mL, 4.5 mmol). The mixture was
stirred for 1 h at room temperature and quenched with H2O (10 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4. Concentration in vacuo gave crude product as oil,
which was used immediately without further purification. The crude
Synthesis of Olefinic Amide 12. To a solution of anti-
sulfonamide 5 (1.08 g, 2.15 mmol) in dry CH2Cl2 (20 mL) at 0 °C
were added diisopropylethylamine (556 mg, 0.71 mL, 4.3 mmol),
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Note
acryloyl chloride (350 mg, 0.31 mL, 3.9 mmol) and DMAP (5 mg,
0.02 mmol); the mixture was stirred at room temperature for 6 h and
quenched with H2O (15 mL). The mixture was extracted with ethyl
acetate (3 × 10 mL), and the combined organic layers were washed
with brine, dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification by column chromatography (petroleum ether/EtOAc 4:1)
147.8, 138.5, 138.3, 135.3, 135.1, 134.7, 134.4, 132.7, 132.5, 131.7,
129.7, 129.3, 124.2, 124.1, 122.3, 122.2, 122.0, 121.5, 115.3, 114.9,
112.6, 112.2, 62.4, 61.8, 55.1, 41.0, 36.1, 33.6, 32.1, 19.1, 16.2; HRMS
(ESI) Calcd. for C20H24N3O6S [M + NH4]+ 434.1380, found
434.1371.
13d: a pale yellow solid (251 mg, 29% yield); mp 146−147 °C; 1H
NMR (400 MHz, CDCl3) δ 8.57−8.52 (m, 1H), 7.80−7.74 (m, 3H),
6.80 (t, J = 7.9 Hz, 1H), 6.72 (dd, J = 8.1, 1.8 Hz, 1H), 6.63 (t, J = 7.9
Hz, 1H), 5.81 (dd, J = 9.9, 2.8 Hz, 1H), 4.87−4.78 (m, 1H), 3.89 (s,
3H), 3.86 (s, 3H), 3.07 (qd, J = 13.5, 7.1 Hz, 2H), 2.94−2.83 (m, 1H),
2.42 (dd, J = 18.9, 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.7,
149.0, 148.0, 147.9, 142.7, 135.1, 134.5, 132.5, 131.8, 129.2, 124.3,
123.5, 121.3, 112.2, 111.1, 56.6, 55.8, 55.7, 40.4, 26.3; HRMS (ESI)
Calcd. for C20H24N3O7S [M + NH4]+ 450.1329, found 450.1329.
13e: a pale yellow solid (285 mg, 33% yield); mp 177−178 °C; 1H
NMR (400 MHz, CDCl3) δ 8.61−8.55 (m, 1H), 7.81−7.75 (m, 3H),
6.66 (t, J = 7.9 Hz, 1H), 6.42−6.35 (m, 3H), 5.85 (dd, J = 9.9, 2.8 Hz,
1H), 4.88 (ddd, J = 6.9, 6.2, 4.9 Hz, 1H), 3.81 (s, 6H), 3.09 (ddd, J =
23.5, 13.3, 7.3 Hz, 2H), 2.95−2.85 (m, 1H), 2.44 (dd, J = 18.8, 6.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 161.8, 161.0, 148.0, 142.7,
139.0, 135.2, 134.6, 132.6, 131.9, 124.4, 123.6, 107.3, 98.8, 56.5, 55.3,
40.9, 26.3; HRMS (ESI) Calcd. for C20H24N3O7S [M + NH4]+
450.1329, found 450.1320.
1
gave olefinic amide 12 (906 mg, 76% yield) as a thick brown oil: H
NMR (400 MHz, CDCl3) δ 7.70−7.54 (m, 2H), 7.31 (s, 1H), 7.10 (t,
J = 7.9 Hz, 1H), 6.83−6.64 (m, 4H), 6.31 (ddd, J = 16.4, 10.2, 2.8 Hz,
1H), 6.23−6.12 (m, 1H), 5.81 (tt, J = 24.5, 12.4 Hz, 1H), 5.58−5.46
(m, 1H), 5.07−5.00 (m, 1H), 4.38 (dd, J = 50.0, 3.8 Hz, 1H), 3.81−
3.61 (m, 5H), 3.70 (s, 3H), 3.55−3.36 (m, 2H), 3.12−2.97 (m, 1H),
2.86 (t, J = 6.5 Hz, 2H), 2.30−2.18 (m, 1H), 1.92−1.75 (m, 2H),
1.70−1.59 (m, 1H), 1.56−1.44 (m, 4H); 13C NMR (100 MHz, CDCl3
most of peaks double due to the presence of OTHP group) δ 166.6,
159.7, 159.7, 148.1, 142.7, 135.3, 133.8, 133.1, 131.9, 130.1, 129.5,
124.5, 121.2, 117.8, 113.9, 113.8, 113.2, 113.2, 99.2, 98.4, 65.4, 65.2,
65.2, 62.3, 61.8, 55.0, 46.0, 45.9, 37.8, 34.1, 33.9, 30.6, 30.5, 25.3, 25.3,
19.5, 19.3; HRMS (ESI) Calcd. for C28H35N2O8S [M + H]+ 559.2109,
found 559.2113.
Synthesis of Lactam 4. To a solution of the second generation
Grubbs catalyst (40 mg, 0.05 mmol) in dry CH2Cl2 (90 mL) was
added a solution of olefinic amide 12 (491 mg, 0.88 mmol) in dry
CH2Cl2 (2 mL) under argon atmosphere. The mixture was refluxed for
12 h and concentrated in vacuo. Purification by column chromatog-
raphy (petroleum ether/EtOAc 2:1) gave lactam 4 (345 mg, 74%
1
13f: a pale yellow solid (257 mg, 30% yield); mp 182−183 °C; H
NMR (400 MHz, CDCl3) δ 8.58−8.51 (m, 1H), 7.80−7.71 (m, 3H),
6.81−6.79 (m, 3H), 6.67 (t, J = 7.9 Hz, 1H), 5.84 (dd, J = 9.9, 2.8 Hz,
1H), 4.98−4.87 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.16 (ddd, J =
18.0, 13.1, 7.3 Hz, 2H), 2.95−2.82 (m, 1H), 2.40 (dd, J = 18.6, 6.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 162.0, 153.5, 152.0, 148.0,
143.4, 135.2, 134.4, 132.7, 131.8, 126.2, 124.3, 123.1, 117.1, 112.8,
111.4, 56.0, 55.7, 55.7, 34.9, 27.0; HRMS (ESI) Calcd. for
C20H24N3O7S [M + NH4]+ 450.1329, found 450.1316.
1
yield) as a pale yellow solid: H NMR (400 MHz, CDCl3) δ 8.52−
8.48 (m, 1H), 7.74−7.73 (m, 3H), 7.21 (t, J = 7.8 Hz, 1H), 6.86−6.77
(m, 3H), 6.49−6.43 (m, 1H), 5.50−5.44 (m, 1H), 4.85 (dd, J = 7.4,
4.4 Hz, 1H), 4.52−4.35 (m, 1H), 3.80 (s, 3H), 3.79−3.69 (m, 1H),
3.68−3.47 (m, 1H), 3.45−3.30 (m, 2H), 3.27−3.09 (m, 2H), 2.62 (dd,
J = 19.3, 6.2 Hz, 1H), 2.20 (dd, J = 13.2, 6.3 Hz, 2H), 1.85−1.75 (m,
1H), 1.70−1.62 (m, 1H), 1.57−1.46 (m, 4H); 13C NMR (100 MHz,
CDCl3 most of peaks double due to the presence of OTHP group) δ
162.3, 162.3, 159.9, 159.9, 147.9, 142.5, 140.8, 140.8, 135.8, 134.3,
132.7, 131.7, 129.6, 129.6, 124.3, 122.5, 122.5, 121.4, 121.3, 114.2,
114.1, 113.0, 112.9, 99.2, 98.2, 65.4, 64.9, 62.3, 61.7, 59.9, 59.9, 55.1,
48.7, 48.6, 31.5, 31.1, 30.6, 30.5, 27.3, 27.2, 25.3, 19.6, 19.2; HRMS
(ESI) Calcd. for C26H31N2O8S [M + H]+ 531.1796, found 531.1790.
Following the typical procedure described for the preparation of 4,
lactams 13a−13h were obtained from corresponding acetaldehyde in 7
steps.
13g: a pale yellow solid (143 mg, 16% yield); mp 190−191 °C; 1H
NMR (400 MHz, CDCl3) δ 8.58−8.52 (m, 1H), 7.79−7.73 (m, 3H),
6.36 (s, 3H), 5.62 (d, J = 0.8 Hz, 1H), 4.82 (ddd, J = 10.3, 6.2, 4.3 Hz,
1H), 3.80 (s, 6H), 3.05 (ddd, J = 23.5, 13.2, 7.2 Hz, 2H), 2.90 (dd, J =
18.2, 6.8 Hz, 1H), 2.24 (d, J = 18.2 Hz, 1H), 1.90 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 162.2, 161.0, 155.0, 147.9, 139.1, 135.1, 134.4,
132.7, 131.8, 124.3, 118.9, 107.3, 98.9, 56.2, 55.3, 41.1, 31.4, 23.3;
HRMS (ESI) Calcd. for C21H26N3O7S [M + NH4]+ 464.1486, found
464.1480.
13h: a pale yellow solid (314 mg, 34% yield); mp 156−157 °C; 1H
NMR (400 MHz, CDCl3) δ 8.58−8.50 (m, 1H), 7.81−7.74 (m, 3H),
6.63 (t, J = 7.9 Hz, 1H), 6.43 (s, 2H), 5.79 (dd, J = 9.9, 2.7 Hz, 1H),
4.85 (t, J = 10.3 Hz, 1H), 3.86 (s, 6H), 3.82 (s, 3H), 3.12−2.99 (m,
2H), 2.97−2.87 (m, 1H), 2.43 (dd, J = 18.9, 6.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 161.7, 153.3, 147.9, 142.5, 136.9, 135.1, 134.6,
132.4, 132.4, 131.9, 124.3, 123.4, 106.1, 60.7, 56.5, 56.1, 41.2, 26.6;
HRMS (ESI) Calcd. for C21H26N3O8S [M + NH4]+ 480.1435, found
480.1425.
13a: a pale yellow solid (233 mg, 29% yield); mp 191−193 °C; 1H
NMR (400 MHz, CDCl3) δ 8.59−8.55 (m, 1H), 7.80−7.75 (m, 3H),
7.24 (t, J = 7.9 Hz, 1H), 6.84−6.77 (m, 3H), 6.69−6.64 (m, 1H), 5.86
(dd, J = 9.9, 2.8 Hz, 1H), 4.91−4.82 (m, 1H), 3.82 (s, 3H), 3.13 (ddd,
J = 23.7, 13.3, 7.3 Hz, 2H), 2.88 (ddd, J = 9.3, 6.7, 3.2 Hz, 1H), 2.42
(dd, J = 18.8, 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.7,
159.8, 148.0, 142.7, 138.3, 135.1, 134.5, 132.6, 131.9, 129.7, 124.3,
123.6, 121.6, 115.0, 112.4, 56.6, 55.2, 40.6, 26.2; HRMS (ESI) Calcd.
for C19H22N3O6S [M + NH4]+ 420.1224, found 420.1217.
13b: a pale yellow solid (250 mg, 31% yield); mp 134−135 °C; 1H
NMR (400 MHz, CDCl3) δ 8.58−8.53 (m, 1H), 7.80−7.74 (m, 3H),
7.15 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.67 (t, J = 8 Hz,
1H), 5.87 (dd, J = 9.9, 2.9 Hz, 1H), 4.85−4.77 (m, 1H), 3.80 (s, 3H),
3.09 (ddd, J = 23.9, 13.5, 7.3 Hz, 2H), 2.92−2.83 (m, 1H), 2.41 (dd, J
= 18.9, 6.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.7, 158.6,
148.0, 142.8, 135.1, 134.5, 132.6, 131.8, 130.3, 128.7, 124.3, 123.7,
114.1, 56.9, 55.2, 39.7, 26.1; HRMS (ESI) Calcd. for C19H22N3O6S [M
+ NH4]+ 420.1224, found 420.1213.
Synthesis of Bridged Lactam 14a. To a solution of lactam 13a
(40 mg, 0.1 mmol) in dry ClCH2CH2Cl (1 mL) was added triflic acid
(18 μL, 0.2 mmol, 2.0 equiv) at room temperature under Ar. The
mixture was stirred at 50 °C for 8 h and quenched with saturated
aqueous NaHCO3 (1 mL). The mixture was extracted with ethyl
acetate (10 mL), and the organic layer was washed with brine, dried
over anhydrous Na2SO4 and concentrated in vacuo. Purification by
column chromatography (petroleum ether/EtOAc 1:1) gave bridged
1
lactam 14a (36 mg, 90% yield) as a white solid: mp 210−211 °C; H
NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 5.8, 3.0 Hz, 1H), 7.78−7.72
(m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.3 Hz, 1H), 6.68
(d, J = 1.9 Hz, 1H), 4.96 (s, 1H), 3.79 (s, 3H), 3.24 (s, 3H), 2.74 (dd, J
= 17.9, 5.4 Hz, 1H), 2.56 (d, J = 17.9 Hz, 1H), 2.42 (d, J = 13.3 Hz,
1H), 2.27 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.7,
158.7, 147.9, 135.0, 134.4, 133.1, 132.3, 131.8, 130.0, 129.6, 124.2,
113.9, 55.2, 52.5, 43.4, 37.4, 30.5, 28.7; HRMS (ESI) Calcd. for
C19H19N2O6S [M + H]+ 403.0958, found 403.0950.
13c: a pale yellow solid (216 mg, 26% yield as a 1:1 diastereomeric
mixture); H NMR (400 MHz, CDCl3) δ 8.66−8.60 (m, 1H), 8.53−
1
8.48 (m, 1H), 7.81−7.72 (m, 6H), 7.22 (dd, J = 15.3, 7.6 Hz, 2H),
6.93−6.76 (m, 6H), 6.69 (ddd, J = 9.7, 6.2, 1.2 Hz, 1H), 6.36 (dd, J =
9.9, 1.6 Hz, 1H), 5.82 (d, J = 9.8 Hz, 1H), 5.62 (dd, J = 9.8, 3.1 Hz,
1H), 4.93−4.84 (m, 1H), 4.65 (dd, J = 10.7, 3.2 Hz, 1H), 3.82 (s, 3H),
3.81 (s, 3H), 3.59−3.49 (m, 1H), 3.30 (dd, J = 13.4, 3.4 Hz, 1H),
3.28−3.02 (m, 2H), 2.99 (dd, J = 13.4, 10.8 Hz, 1H), 2.61 (p, J = 6.9
Hz, 1H), 1.29 (d, J = 7.7 Hz, 3H), 1.22 (d, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 162.0, 162.0, 159.8, 159.6, 148.9, 148.4, 148.0,
Following the typical procedure described for the preparation of
14a, lactams 14c−14e, 14g, 14h and 3 were obtained in one step.
8371
dx.doi.org/10.1021/jo301533f | J. Org. Chem. 2012, 77, 8367−8373

The Journal of Organic Chemistry
Note
14c: a white solid (34 mg, 84% yield as a 2:1 diastereomeric
mixture); H NMR (400 MHz, CDCl3) δ 8.48−8.39 (m, 1H), 7.79−
2.38 (d, J = 17.6 Hz, 1H), 2.28−2.23 (m, 1H), 2.16 (ddd, J = 12.7, 4.5,
2.0 Hz, 1H), 2.05 (d, J = 12.8 Hz, 1H), 1.82−1.72 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 172.1, 158.6, 137.4, 131.6, 129.9, 112.8, 112.3,
61.1, 55.2, 47.7, 43.7, 40.7, 33.3, 31.2, 28.6; HRMS (ESI) Calcd. for
C15H20NO3 [M + H]+ 262.1438, found 262.1435.
1
7.71 (m, 3H), 7.00 (dd, J = 8.4, 3.2 Hz, 1H), 6.81−6.75 (m, 1H), 6.69
(d, J = 2.8 Hz, 1H), 4.74 (d, J = 1.8 Hz, 0.65H), 4.65 (s, 0.35H), 3.79
(s, 3H), 3.39−3.12 (m, 2H), 2.99−2.91 (m, 1H), 2.89−2.71 (m, 1H),
2.60−2.43 (m, 2H), 1.36 (d, J = 7.0 Hz, 2H), 1.16 (d, J = 7.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 169.7, 158.7, 158.6, 148.2, 147.8,
135.5, 135.1, 134.5, 134.4, 133.2, 132.0, 131.8, 131.7, 131.6, 131.4,
130.6, 129.4, 128.4, 124.2, 114.2, 113.8, 113.7, 57.7, 56.5, 55.1, 43.8,
38.5, 38.3, 36.5, 36.2, 32.6, 32.4, 32.2, 29.6, 16.4, 16.3; HRMS (ESI)
Calcd. for C20H21N2O6S [M + H]+ 417.1115, found 417.1109.
Synthesis of Mesylate 16. To a solution of alcohol lactam 15 (33
mg, 0.13 mmol) in dry CH2Cl2 (2 mL) at 0 °C were added Et3N (36
μL, 0.26 mmol), mesyl chloride (18 μL, 0.23 mmol) and DMAP (1
mg). The mixture was stirred at room temperature for 1 h and
quenched with H2O (2 mL). The mixture was extracted with CH2Cl2
(3 × 2 mL), and the combined organic layers were washed with brine,
dried over anhydrous Na2SO4 and concentrated in vacuo. Purification
by column chromatography (CH2Cl2/CH3OH, 20:1) gave mesylate
1
14d: a white solid (38 mg, 89% yield); mp 199−201 °C; H NMR
(400 MHz, CDCl3) δ 8.44−8.41 (m, 1H), 7.78−7.73 (m, 3H), 6.63 (s,
1H), 6.58 (s, 1H), 4.97 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.19 (d, J =
2.7 Hz, 3H), 2.74 (dd, J = 17.8, 5.4 Hz, 1H), 2.60 (d, J = 17.9 Hz, 1H),
2.41 (dd, J = 13.4, 2.1 Hz, 1H), 2.33−2.24 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 169.7, 148.5, 148.1, 147.9, 135.1, 134.4, 133.2, 131.8,
129.7, 124.2, 123.0, 112.1, 110.9, 55.9, 55.8, 52.6, 43.1, 36.8, 30.9, 28.6;
HRMS (ESI) Calcd. for C20H21N2O7S [M + H]+ 433.1064, found
433.1058.
1
16 (42 mg, 98% yield) as a white solid: mp 171−172 °C; H NMR
(400 MHz, CDCl3) δ 7.07 (d, J = 8.3 Hz, 1H), 6.81−6.74 (m, 3H),
4.44 (d, J = 4.5 Hz, 2H), 3.97 (s, 1H), 3.80 (s, 2H), 3.23 (s, 1H), 3.08
(s, 3H), 3.08 −3.05 (m, 4H), 2.72 (dd, J = 17.5, 5.4 Hz, 1H), 2.50−
2.47 (m, 1H), 2.41 (d, J = 17.6 Hz, 1H), 2.23 (d, J = 10.5 Hz, 1H),
2.10 (d, J = 12.5 Hz, 1H), 2.04−1.94 (m, 1H), 1.64 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 158.8, 135.8, 131.6, 130.2, 112.7, 112.5, 68.0,
55.3, 47.5, 41.6, 37.5, 31.2, 30.0, 28.8; HRMS (ESI) Calcd. for
C16H22NO5S [M + H]+ 340.1213, found 340.1209.
1
14e: a white solid (37 mg, 88% yield); mp 202−203 °C; H NMR
(400 MHz, CDCl3) δ 8.46−8.35 (m, 1H), 7.78−7.72 (m, 3H), 6.33 (s,
1H), 6.28 (s, 1H), 4.93 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.49 (s,
1H), 3.21 (s, 2H), 2.62 (d, J = 3.7 Hz, 2H), 2.38 (d, J = 11.9 Hz, 1H),
2.19 (d, J = 13.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.6,
159.6, 157.5, 148.0, 135.1, 134.3, 133.4, 133.0, 131.8, 124.2, 119.0,
104.5, 97.1, 55.3, 52.7, 40.9, 37.5, 28.8, 24.4; HRMS (ESI) Calcd. for
C20H21N2O7S [M + H]+ 433.1064, found 433.1060.
Synthesis of Tetracyclic Lactam 2. To a solution of mesylate 16
(42 mg, 0.13 mmol) in anhydrous DMF (2 mL) at 0 °C was added
NaH (8 mg of 60% oil dispersion, 0.2 mmol). After stirring for 12 h at
room temperature, the reaction was quenched with saturated aqueous
NH4Cl (1 mL), and the mixture was extracted with ethyl acetate (10
mL). The organic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuo. Purification by column
chromatography (petroleum ether/EtOAc 1:1) gave lactam 2 (23
1
14g: a white solid (35 mg, 78% yield); mp 242−243 °C; H NMR
(400 MHz, CDCl3) δ 8.39−8.34 (m, 1H), 7.77−7.71 (m, 3H), 6.33
(d, J = 2.3 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 4.84 (t, J = 3.0 Hz, 1H),
3.78 (s, 3H), 3.78 (s, 3H), 3.25 (dd, J = 17.7, 3.5 Hz, 1H), 3.17 (d, J =
17.6 Hz, 1H), 3.00 (d, J = 17.7 Hz, 1H), 2.27 (d, J = 17.7 Hz, 1H),
2.15 (s, 2H), 1.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8,
159.4, 159.4, 148.0, 135.0, 134.2, 133.9, 133.5, 131.8, 124.1, 121.3,
105.0, 98.2, 55.2, 55.0, 53.0, 46.5, 39.8, 38.7, 32.1, 27.1; HRMS (ESI)
Calcd. for C21H23N2O7S [M + H]+ 447.1220, found 447.1214.
1
mg, 77% yield) as a white solid: mp 144−145 °C; H NMR (400
MHz, CDCl3) δ 6.99 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.3 Hz,
1H), 6.66 (s, 1H), 4.23−4.16 (m, 1H), 3.77 (s, 4H), 3.30 (dd, J = 7.5,
4.5 Hz, 1H), 3.16 (s, 1H), 2.98 (td, J = 11.1, 5.5 Hz, 1H), 2.66 (dd, J =
16.6, 4.1 Hz, 1H), 2.48−2.37 (m, 2H), 2.35−2.29 (m, 1H), 2.24 (d, J
= 13.2 Hz, 1H), 2.16−2.05 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
171.6, 158.9, 139.1, 130.3, 130.1, 114.5, 112.4, 57.1, 55.2, 43.1, 41.7,
40.3, 32.4, 31.8, 26.5; HRMS (ESI) Calcd. for C15H18NO2 [M + H]+
244.1332, found 244.1325.
1
14h: a white solid (37 mg, 81% yield); mp 217−218 °C; H NMR
(400 MHz, CDCl3) δ 8.43−8.37 (m, 1H), 7.79−7.73 (m, 3H), 6.43 (s,
1H), 4.92 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.47 (s,
1H), 3.18 (s, 2H), 2.68 (dd, J = 18.1, 5.3 Hz, 1H), 2.58 (d, J = 18.1 Hz,
1H), 2.38 (d, J = 13.0 Hz, 1H), 2.19 (dd, J = 11.5, 1.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 170.3, 152.9, 150.6, 147.9, 140.4, 135.0,
134.4, 133.2, 131.8, 126.6, 124.2, 123.5, 107.6, 60.8, 60.6, 55.8, 52.6,
41.7, 37.1, 28.6, 25.0; HRMS (ESI) Calcd. for C21H23N2O8S [M + H]+
463.1170, found 463.1170.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of all new compounds, and
crystallographic information in CIF format for compounds 2
and 14g. This material is available free of charge via the Internet
at http://pubs.acs.org.
Bridged Lactam 3. 182 mg of 3 was obtained from lactam 4 (305
1
mg, 0.57 mmol) in 71% yield as a white solid: mp 198−199 °C; H
AUTHOR INFORMATION
Corresponding Author
*E-mail: shexg@lzu.edu.cn.
NMR (400 MHz, CDCl3) δ 8.45−8.39 (m, 1H), 7.81−7.73 (m, 3H),
7.00 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 1.7 Hz, 1H), 6.76 (dd, J = 8.3, 2.2
Hz, 1H), 4.98 (s, 1H), 3.99 (t, J = 6.3 Hz, 2H), 3.80 (s, 3H), 3.32−
3.29 (m, 1H), 3.25 (s, 1H), 2.73 (dd, J = 17.8, 5.5 Hz, 1H), 2.67 (ddd,
J = 13.4, 4.5, 2.3 Hz, 1H), 2.53 (d, J = 17.8 Hz, 1H), 2.41−2.36 (m,
3H), 1.80 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.4, 159.0,
147.8, 136.6, 136.3, 134.5, 132.8, 131.8, 130.9, 129.5, 124.4, 113.0,
112.5, 61.3, 55.9, 55.3, 44.1, 41.4, 32.9, 31.6, 29.6; HRMS (ESI) Calcd.
for C21H23N2O7S [M + H]+ 447.1220, found 447.1215.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this research was provided by the NSFC
(21125207, 21072086, 21102062), the MOST
(2010CB833200), and Program 111. We are grateful to Tuo
Jiang for his valuable suggestions in manuscript preparation.
Synthesis of Alcohol Lactam 15. To a solution of bridged lactam
3 (152 mg, 0.34 mmol) in DMF (2 mL) were added anhydrous
K2CO3 (150 mg, 1.09 mmol) and PhSH (80 μL, 0.78 mmol) at room
temperature. After stirring for 1 h at 40 °C, the reaction was quenched
with H2O (1 mL), and the mixture was extracted with ethyl acetate (3
× 2 mL). The combined organic layers were washed with saturated
aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification by column chromatography
(CH2Cl2/CH3OH, 20:1) gave amide 15 (58 mg, 66% yield) as a
white solid: mp 192−193 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (s,
1H), 7.04 (d, J = 8.3 Hz, 1H), 6.79−6.73 (m, 2H), 4.16 (d, J = 3.5 Hz,
1H), 3.98−3.93 (m, 1H), 3.78 (s, 3H), 3.80−3.74 (m, 4H), 3.18 (s,
1H), 2.91 (dt, J = 11.3, 3.8 Hz, 1H), 2.69 (dd, J = 17.6, 5.5 Hz, 1H),
REFERENCES
■
(1) For a comprehensive review, see: Kobayashi, J.; Kubota, T. Nat.
Prod. Rep. 2009, 26, 936−962.
(2) For recent isolations see: (a) Li, C.-S; Di, Y.-T.; Zhang, Q.;
Zhang, Y.; Tan, C.-J.; Hao, X.-J. Helv. Chim. Acta 2009, 92, 653−659.
(b) Zhang, Y.; Di, Y.; He, H.; Li, S.; Lu, Y.; Gong, N.; Hao, X. Eur. J.
Org. Chem. 2011, 74, 4103−4107. (c) Zhang, C.-R.; Fan, C.-Q.; Dong,
S.-H.; Liu, H.-B.; Zhou, W.-B.; Wu, Y.; Yue, J.-M. Org. Lett. 2011, 13,
8372
dx.doi.org/10.1021/jo301533f | J. Org. Chem. 2012, 77, 8367−8373

The Journal of Organic Chemistry
Note
2440−2443. (d) Yang, T.-Q.; Di, Y.-T.; He, H.-P.; Zhang, Q.; Zhang,
Y.; Hao, X.-J. Helv. Chim. Acta 2011, 94, 397−403. (e) Cao, M.;
Zhang, Y.; He, H.; Li, S.; Huang, S.; Chen, D.; Tang, G.; Li, S.; Di, Y.;
Hao, X. J. Nat. Prod. 2012, 75, 1076−1082.
(3) For recent synthetic approaches to daphniphyllum alkaloids, see:
(a) Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem. 1992,
57, 2575−2585. (b) Heathcock, C. H.; Kath, J. C.; Ruggeri, R. B. J.
́
Org. Chem. 1995, 60, 1120−1130. (c) Sole, D.; Urbaneja, X.; Bonjoch,
J. Org. Lett. 2005, 7, 5461−5464. (d) Denmark, S. E.; Baiazitov, R. Y. J.
Org. Chem. 2006, 71, 593−605. (e) Ikeda, S.; Shibuya, M.; Kanoh, N.;
Iwabuchi, Y. Org. Lett. 2009, 11, 1833−1836. (f) Dunn, T. B.; Ellis, J.
M.; Kofink, C. C.; Manning, J. R.; Overman, L. E. Org. Lett. 2009, 11,
5658−5661. (g) Coldham, I.; Burrell, A. J. M.; Guerrand, H. D. S.;
Oram, N. Org. Lett. 2011, 13, 1267−1269. (h) Xu, C.; Liu, Z.; Wang,
H.; Zhang, B.; Xiang, Z.; Hao, X.; Wang, D. Z. Org. Lett. 2011, 13,
́ ́
1812−1815. (i) Belanger, G.; Boudreault, J.; Levesque, F. Org. Lett.
2011, 13, 6204−6207. (j) Coldham, I.; Watson, L.; Adams, H.; Martin,
N. G. J. Org. Chem. 2011, 76, 2360−2366. (k) Weiss, M. E.; Carreira,
E. M. Angew. Chem., Int. Ed. 2011, 50, 11501−11505. (l) Darses, B.;
Michaelides, I. N.; Sladojevich, F.; Ward, J. W.; Rzepa, P. R.; Dixon, D.
J. Org. Lett. 2012, 14, 1684−1687. (m) Xu, C.; Wang, L.; Hao, X.;
Wang, D. Z. J. Org. Chem. 2012, 77, 6307−6313.
(4) Zhang, Q.; Di, Y.-T.; Li, C.-S.; Fang, X.; Tan, C.-J.; Zhang, Z.;
Zhang, Y.; He, H.-P.; Li, S.-L.; Hao, X.-J. Org. Lett. 2009, 11, 2357−
2359.
(5) Palmer, D. C.; Strauss, M. J. Chem. Rev. 1977, 77, 1−36.
(6) Knorr, L.; Horlein, H. Chem. Ber. 1907, 40, 4883−4889.
(7) Hudlicky, T.; Rinner, U. Synthesis of Morphine Alkaloids and
Derivatives. In Alkaloid Synthesis; Knolker, H. J., Ed.; Springer-Verlag:
̈
Berlin, 2012; Topics in Current Chemistry Series 309, pp 33−66.
(8) (a) Rice, K. C.; In The Chemistry and Biology of Isoquinoline
Alkaloids; Phillipson, J. D., Roberts, M. F., Zenk, M. H.; Eds.; Springer-
Verlag: Berlin, 1985; pp 191−203. (b) Hudlicky, T.; Butora, G.;
Fearnley, S. P.; Gum, A. G.; Stabile, M. R. Stud. Nat. Prod. Chem. 1995,
18, 43−154. (c) Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.;
Trauner, D. Curr. Org. Chem. 2000, 4, 343−362. (d) Blakemore, P. R.;
White, J. D. Chem. Commun. 2002, 1159−1168.
(9) (a) Archer, S.; Albertson, N. F.; Harris, L. S.; Pierson, A. K.; Bird,
J. G. J. Med. Chem. 1964, 7, 123−127. (b) Tullar, B. F.; Harris, L. S.;
Perry, R. L.; Pierson, A. K.; Soria, A. E.; Wetterau, W. F.; Albertson, N.
F. J. Med. Chem. 1967, 10, 383−386. (c) Rice, K. C.; Jacobson, A. E. J.
Med. Chem. 1976, 19, 430−432.
(10) For selected examples, see: (a) Grauert, M.; Bechtel, W. D.;
Weiser, T.; Stransky, W.; Nar, H.; Carter, A. J. J. Med. Chem. 2002, 45,
3755−3764. (b) Wentland, M. P.; Ye, Y.; Cioffi, C. L.; L, R.; Zhou, Q.;
Xu, G.; Duan, W.; Dehnhardt, C. M.; Sun, X.; Cohen, D. L.; Bidlack, J.
M. J. Med. Chem. 2003, 46, 838−849. (c) Zhang, A.; Xiong, W.;
Bidlack, J. M.; Hilbert, J. E; Knapp, B. I.; Wentland, M. P.; Neumeyer,
J. L. J. Med. Chem. 2004, 47, 165−174. (d) Wentland, M. P.;
VanAlstine, M.; Kucejko, R.; Luo, R.; Cohen, D. L.; Parkhill, A. L.;
Bidlack, J. M. J. Med. Chem. 2006, 49, 5635−5639.
(11) Sun, Y.; Yu, B.; Wang, X.; Tang, S.; She, X; Pan, X. J. Org. Chem.
2010, 75, 4224−4229.
(12) (a) Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J. J.
Org. Chem. 1979, 44, 1438−1447. (b) Bowman, R. K.; Johnson, J. S.
Org. Lett. 2006, 8, 573−576.
(13) (a) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910−912.
(b) Wilson, S. R.; Guazzaroni, M. E. J. Org. Chem. 1989, 54, 3087−
3091.
(14) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953−956.
(15) For Friedel-Crafts alkylation with α,β-unsaturated amides using
Lewis acid, see: Koltunov, K. Y.; Walspurger, S.; Sommer, J.
Tetrahedron Lett. 2004, 45, 3547−3549.
(16) CCDC number: 891316; see the Supporting Information.
(17) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373−6374.
(18) CCDC number: 891317; see the Supporting Information.
8373
dx.doi.org/10.1021/jo301533f | J. Org. Chem. 2012, 77, 8367−8373