Formal synthesis of (±)-cycloclavine

Article abstract of DOI:10.1021/jo4023588

An efficient formal synthesis of (±)-cycloclavine is achieved in seven steps and 27% overall yield from the known 2-(4-bromo-1-tosyl-1H-indol-3- yl)acetaldehyde. Key features include an iron(III)-catalyzed aza-Cope-Mannich cyclization and an intramolecular Heck reaction or a self-terminating 6-exo-trig aryl radical-alkene cyclization.

Full text of DOI:10.1021/jo4023588

Article
pubs.acs.org/joc
Formal Synthesis of ( )-Cycloclavine
Wei Wang, Jia-Tian Lu, Hao-Li Zhang, Zi-Fa Shi, Jing Wen, and Xiao-Ping Cao*
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou, 730000, P. R. China
S
* Supporting Information
ABSTRACT: An efficient formal synthesis of ( )-cycloclavine is achieved in seven steps and 27% overall yield from the known
2-(4-bromo-1-tosyl-1H-indol-3-yl)acetaldehyde. Key features include an iron(III)-catalyzed aza-Cope−Mannich cyclization and
an intramolecular Heck reaction or a self-terminating 6-exo-trig aryl radical−alkene cyclization.
amine and aldehydes to obtain 3-formyl-α,β-unsaturated
pyrrolidines,30 which inspired us to use the aza-Cope−Mannich
reaction as a potential tool for construction of the function-
alized pyrrolidine of cycloclavine.
INTRODUCTION
■
The Ergot family represents a significant class of indole alkaloids
of broad pharmacological activity,1 whose 3,4-fused polycyclic
molecular architectures have been considered as attractive
synthetic targets for decades.2−10 As one of the clavine-type
alkaloids, cycloclavine (1, Scheme 1) was first isolated in 1969
from the seeds of the African morning glory (Ipomea
hildebrandtii) by Hoffman and co-workers.11 Cycloclavine
demonstrates appealing structure containing the same 3,4-
fused indole skeleton as lysergic acid and a pithy cyclopropane
ring on three contiguous stereocenters. Its striking compact but
highly congested structure poses considerable challenges for
synthesis.
RESULTS AND DISCUSSION
■
With the above considerations, the retrosynthetic analysis of
( )-cycloclavine (1) is outlined in Scheme 1. We envisioned
that ( )-cycloclavine could be accessed via a late-stage
cyclopropanation of the Szan
́
tay’s intermediate 2.12 The crucial
compound 2 could be reached by intramolecular Heck reaction
Scheme 1. Retrosynthetic Analysis of ( )-Cycloclavine (1)
Although over 40 years has passed after the isolation of
cycloclavine, only two racemic syntheses have been reported
recently: (1) Szantay’s first synthesis in 2008 involving
́
intramolecular aldol condensation of Uhle’s ketone derivative
in 14 steps and 0.2% overall yield12 and (2) Wipf’s synthesis in
2011 employing intramolecular Diels−Alder cycloaddition of
furan (IMDAF) reaction in 14 steps and 1.2% overall yield for
( )-cycloclavine and in 17 steps and 2.3% overall yield for
( )-5-epi-cycloclavine.13 Clearly, an efficient and novel strategy
for the synthesis of this alkaloid is needed.
Inspired by robust tandem and step-economical synthetic
strategies,14−16 herein we reported a more efficient route for
the synthesis of ( )-cycloclavine (1) based on aza-Cope−
Mannich cyclization for the construction of the D ring within it
and rapid assembly of its 3,4-fused indole structure by Heck
reaction or radical cycloaddition. The aza-Cope−Mannich
tandem reaction, which is initiated by a cationic 2-aza-Cope
rearrangement (2-azonia-[3,3]-sigmatropic rearrangement) fol-
lowed by Mannich reaction,17,18 has been applied successfully
into numerous alkaloid syntheses19−24 since it was discovered
by Overman and co-workers in 1979.25−29 In 2010, Padron
́
’s
group first reported an iron(III)-catalyzed alkyne aza-Cope−
Received: October 23, 2013
Mannich reaction between 2-hydroxy homopropargyl tosyl-
© XXXX American Chemical Society
A
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Article
of aldehyde 5 followed by deoxygenation (path a) or 6-exo-trig
aryl radical−alkene cyclization of sulfide 4 resulting in
tetracyclic compound 3 and then followed by isomerization
(path b). The sulfide 4 could be obtained from aldehyde 5
through Luche reduction and thioetherfication. The aldehyde 5
could be constructed by the aza-Cope−Mannich reaction from
the known aldehyde 631 and alkyne 7.30
The synthesis commenced with the known 2-(4-bromo-1-
tosyl-1H-indol-3-yl)acetaldehyde (6), which was prepared from
the commercially available 4-bromoindole (8) in 4 steps and
72% overall yield (Scheme 2).31 Aldehyde 6 was then subjected
to different aza-Cope−Mannich conditions with 2-hydroxy
homopropargyl tosylamine (7) to afford the tricyclic aldehyde 5
(Table 1). Unexpectedly, a serious setback was encountered
when the reaction was carried out under the standard
conditions, i.e., FeCl3 (1.2 equiv) and TMSCl (1.3 equiv) in
Table 1. Optimization of Iron-Catalyzed Aza-Cope−
Mannich Cyclization of Aldehyde 6 with 2-Hydroxy
a
Homopropargyl Tosylamine (7) Resulting in Aldehyde 5
c
entry FeCl3 (equiv) TMSCl (equiv) temp (°C) time (h) yield (%)
1
2
3
4
1.2
1.2
1.2
1.3
1.3
1.3
0.2
0
rt
3
complex
53
reflux
reflux
reflux
4
2
69
b
0.2
83
a
Reaction conditions: 6 (102 mg, 0.26 mmol), 7 (62 mg, 0.26 mmol),
b
FeCl3, and TMSCl in CH2Cl2 (2.6 mL). The oil bath was preheated
to 45 °C. Isolated yield.
c
K2CO3) with or without additive (TBAB) in various solvents
(CH3CN, DMF, CH3CN/H2O) was used, only Heck product
10 could be obtained (Table 2, entries 2−4).33−35 In contrast,
we found that the outcome of the cyclization changed
completely on exposure of aryl bromide 5 to Pd(OAc)2/PPh3
and Ag2CO3 in toluene/Et3N (1:1, v/v) at 80 °C to afford
tetracyclic aldehyde 9 in 28% yield (Table 2, entry 5),36 which
would be directly transformed to target molecule 2 by
deoxygenation. Unfortunately, only compound 10 was still
obtained when investigating other ligands such as xantphos and
dppp (Table 2, entries 6 and 7). In addition, attempts to
isomerize aldehyde 10 to 9 under various conditions (p-TsOH,
hν, K2CO3, DBU) failed.
́
CH2Cl2 at room temperature, established by Padron (Table 1,
entry 1), which gave only complex mixture instead of the
desired pyrrolidine compound.30 However, aldehyde 5 could be
achieved in moderate yields when the reactants were treated
with an excessive or catalytic amounts of TMSCl at reflux
temperature (Table 1, entries 2 and 3). Eventually, desired
aldehyde 5 could be obtained in excellent yield (83%) in the
presence of FeCl3 (1.3 equiv) without TMSCl in the preheated
oil bath (45 °C) for 0.2 h (Table 1, entry 4). The plausible
mechanism is based on a consecutive generation of γ-
unsaturated iminium ion A, 2-azonia[3,3]-sigmatropic rear-
rangement intermediate B and further intramolecular Mannich
reaction (Scheme 2).30
Since the yield and scale (less than 0.2 mmol scale) of the
desired tetracyclic aldehyde 9 could not be improved, we hoped
that compound 10 could be deoxygenized and then isomerized
to compound 2 (Scheme 3). Under the typical experimental
conditions developed by Meleties, i.e., NaBH3CN (6.0 equiv)
and TMSCl (6.0 equiv) in CH3CN at rt for 24 h,37 the desired
product 3 was obtained in only 12% yield. Furthermore, after
several optimizations, the compound 3 could be achieved in
22% yield under the modified procedure: NaBH3CN (10.0
equiv) and TMSCl (15.0 equiv) and powdered molecular sieves
(3 Å) in CH3CN at rt for 24 h. Subsequently, isomerization of
3 by the treatment with p-TsOH·H2O in refluxing benzene for
24 h furnished the intermediate 11 in 63% yield.38 Removal of
the tosyl group with sodium naphthalenide and subsequent N-
Scheme 2. Synthesis of Aldehydes 9 and 10
methylation led to the Szan
which had been converted to ( )-cycloclavine (1) by
cyclopropanation by Szan
tay and co-workers.12 All of the
́
tay’s intermediate 2 in 71% yield,31
́
spectroscopic data of compound 2 were in agreement with
those reported previously. This result showed that path a is a
concise route (six steps from the known aldehyde 6, 6% yield)
for the synthesis of ( )-cycloclavine (1).
To the best of our knowledge, the radical cyclization, an
efficient method for synthesis of natural products,39−43 had not
yet been applied to the construction of the C/D ring system of
the ergot alkaloids. Herein, the stage was now set for our path
b, which was an efficient method for the transformation of
compound 5 to 3 (Scheme 4). Thus, the Luche reduction of
aldehyde 5 (NaBH4, CeCl3·7H2O in MeOH) followed by the
treatment of the corresponding alcohol under the modified
condition developed by Hata (phenyl disulfide, tri-n-butylphos-
phine in benzene) provided the desired sulfide 4 in 81% yield.44
Then the self-terminating 6-exo-trig aryl radical−alkene
cyclization of sulfide 4 was effected by treatment with tri-n-
butyltin hydride (n-Bu3SnH, 2.2 equiv) and a catalytic amount
of 2,2′-azobis(2-methylpropionitrile) (AIBN, 0.3 equiv) in
refluxing benzene for 18 h to result in the common
intermediate 3 in 91% yield.42 Thus, the tetracyclic compound
We then paid attention to the assembly of the C ring of
( )-cycloclavine by intramolecular Heck reaction between the
aryl bromide and the double bond in the dihydropyrrole ring
(Scheme 2 and Table 2). The first assay was discouraging with
only recovery of the starting material in the presence of
Pd2(dba)3 and t-Bu3P·HBF4 with DABCO as base in dioxane
(Table 2, entry 1).32 When Pd(OAc)2 combined with different
ligands (PPh3 or dppp) and base (Ag2CO3, Ag2CO3/CaCO3, or
B
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Table 2. Optimization of the Intramolecular Heck Reaction of Aldehyde 5 Resulting in Tetracyclic Aldehyde 9 or 10
f
entry
catalyst (equiv)
ligand (equiv)
base (equiv)
additive (equiv)
solvent
dioxane
temp (°C) time (h) product yield (%)
a
d
1
2
3
Pd2(dba)3 (0.05)
t-Bu3P·HBF4 (0.2)
DBACO (3.0)
none
none
none
60
80
60
12
5
NR
10
Pd(OAc)2 (0.3)
Pd(OAc)2 (0.3)
PPh3 (0.6)
Ag2CO3 (1.1)
CH3CN
DMF
54
28
b
dppp (0.6)
Ag2CO3/CaCO3
(1.1/1.1)
100
10
e
4
5
6
7
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.2)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.2)
PPh3 (0.1)
PPh3 (0.6)
K2CO3 (2.5)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
TBAB (1.0)
CH3CN/H2O
(10:1, v/v)
85
80
80
80
8
18
18
18
10
9
69
28
63
12
none
none
toluene/Et3N
(1:1, v/v)
c
xantphos (0.6)
toluene/Et3N
(1:1, v/v)
10
10
dppp (0.4)
none
toluene/Et3N
(1:1, v/v)
a
b
c
dba = dibenzylideneacetone. dppp = 1,3-bis(diphenylphosphino)propane. xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
d
e
f
DABCO = 1,4-diazabicyclo[2.2.2]octane. TBAB = tetra-n-butylammonium bromide. Isolated yield.
Scheme 3. Synthesis of Compound 2
Heck reaction or a self-terminating 6-exo-trig aryl radical−
alkene cyclization. Further use of this strategy in the total
synthesis of alkaloids is in progress, and the results will be
reported in due course.
EXPERIMENTAL SECTION
■
General Information. All reactions that required anhydrous
conditions were carried by standard procedures under argon.
Commercially available reagents were used as received. The solvents
were dried by distillation over the appropriate drying reagents.
Petroleum ether (PE) used had a boiling range of 60−90 °C.
Reactions were monitored by TLC on silica gel GF 254 plates.
Column chromatography was generally performed through silica gel
(200−300 mesh). IR spectra were recorded on a FT-IR spectropho-
tometer and reported in wavenumbers (cm−1). 1H and 13C NMR
spectra were recorded on a 400 MHz spectrometer, as were the DEPT
135 experiments. Chemical shift values are given in ppm and coupling
constants (J) in hertz. Residual solvent signals in the 1H and 13C NMR
spectra were used as an internal reference (CDCl3: δH = 7.26, δC
=
77.0 ppm). Multiplicity was indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of
doublet), ddd (doublet of doublet of doublets). High resolution mass
spectra (HRMS) were obtained on a 4G mass spectrometer by using
electrospray ionization (ESI) analyzed by quadrupole time-of-flight
(QTof).
Scheme 4. Transformation of Compound 5 to 3
4-Bromo-3-(2,5-dihydro-4-formyl-1-tosylpyrrol-2-yl)methyl-
1-tosylindole (5).
To a solution of 2-hydroxy homopropargyl tosylamine (7, 62 mg, 0.26
mmol) in dry CH2Cl2 (2.6 mL) was added a mixture of aldehyde 6
(102 mg, 0.26 mmol) and anhydrous FeCl3 (55 mg, 0.34 mmol) in
one portion at room temprature. The resultant mixture was stirred in a
preheated oil bath (45 °C) for 12 min and then quenched by addition
of H2O (5 mL) with stirring and extracted with CH2Cl2 (10 mL × 3).
The combined organic layers were dried over anhydrous MgSO4 and
concentrated under reduced pressure. Flash chromatography of the
residue on silica gel column (PE/EtOAc = 2/1) afforded the aldehyde
5 (132 mg, 83%) as a yellow foam. Rf = 0.40 (silica gel, PE/EtOAc =
3 was achieved in 3 steps with 74% overall yield from aldehyde
5, which showed that path b is more efficient than path a (15%
yield from 5).
CONCLUSIONS
■
In summary, we have developed an efficient and concise formal
synthesis of ( )-cycloclavine (1) in seven steps and 27%
overall yield from the known 2-(4-bromo-1-tosyl-1H-indol-3-
yl)acetaldehyde (6) (path b). Namely, ( )-cycloclavine could
be achieved in 12 steps and 6% overall yield from commercially
available 4-bromoindole (8). Key features of the synthesis
include rapid construction of the C/D ring system of
( )-cycloclavine (1) by using an iron(III)-catalyzed consec-
utive aza-Cope−Mannich cyclization and an intramolecular
1
2/1). H NMR (400 MHz, CDCl3, δ): 9.41 (1H, s), 8.00 (d, J = 8.0
Hz, 1H), 7.74 (d, J = 8.4 Hz, 4H), 7.55 (s, 1H), 7.39 (d, J = 8.0 Hz,
1H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 8.4
Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 5.07 (dd, J = 5.2, 2.4 Hz, 1H), 4.21
(d, J = 14.8 Hz, 1H), 4.03 (ddd, J = 15.2, 5.2, 1.6, 1H), 3.88 (dd, J =
14.8, 5.2 Hz, 1H), 3.33 (dd, J = 14.8, 7.6 Hz, 1H), 2.40 (s, 3H), 2.34
C
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(s, 3H). 13C NMR (100 MHz, CDCl3, δ): 186.5 (CH), 145.9 (CH),
145.5 (C), 144.0 (C), 140.6 (C), 136.1 (C), 134.6 (C), 134.0 (C),
130.0 (CH), 129.9 (CH), 128.2 (C), 128.0 (CH), 127.4 (CH), 127.1
(CH), 126.7 (CH), 125.5 (CH), 117.0 (C), 114.0 (C), 113.0 (CH),
68.2 (CH), 52.5 (CH2), 31.8 (CH2), 21.5 (CH3), 21.4 (CH3). IR
1,6-Ditosyl-8-methylene-4,5,6,7,9-pentahydroindolo[4,3-
ef ]indole (3).
(KBr) vmax: 3291, 2925, 1684, 1349, 1172, 705, 668 cm−1. HRMS
̅
(ESI) m/z: [M + H]+ calcd for C28H26BrN2O5S2 613.0461, found
613.0461.
1,6-Ditosyl-8-formyl-4,5,6,7-tetrahydroindolo[4,3-ef ]indole
(9).
Method 1. According to the procedure in Scheme 3 (path a), to a
cold (ice bath) solution of aldehyde 10 (106 mg, 0.20 mmol) and
TMSCl (0.38 mL, 3.0 mmol) in dry CH3CN (4 mL), containing
́
powdered molecular sieves (3 Å), was added NaBH3CN (126 mg, 2.0
mmol) under argon. After the suspension was stirred at room
temperature for 24 h, it was diluted with CH2Cl2 (10 mL) and filtered
through Celite. The filtrate was washed with brine (10 mL), dried over
anhydrous MgSO4, and concentrated under reduced pressure. Flash
chromatography of the residue on silica gel (PE/EtOAc = 5/1)
afforded the tetracyclic compound 3 (23 mg, 22%) as a white foam. Rf
= 0.41 (silica gel, PE/EtOAc = 5/1). 1H NMR (400 MHz, CDCl3, δ):
7.80−7.72 (m, 5H), 7.32−7.19 (m, 6H), 6.94 (d, J = 7.6 Hz, 1H), 5.04
(d, J = 1.2 Hz, 1H), 4.64 (d, J = 2.0 Hz, 1H), 4.30−4.24 (m, 1H),
4.17−4.08 (m, 2H), 3.43 (d, J = 6.8 Hz, 1H), 3.22 (dd, J = 15.6, 6.0
Hz, 1H), 2.59 (ddd, J = 15.6, 10.8, 2.0 Hz, 1H), 2.43 (s, 3H), 2.35 (s,
3H). 13C NMR (100 MHz, CDCl3, δ): 145.1 (C), 144.8 (C), 143.7
(C), 135.53 (C), 135.46 (C), 133.4 (C), 129.92 (CH), 129.86 (CH),
128.3 (C), 127.2 (CH), 126.8 (CH), 125.4 (CH), 122.0 (CH), 120.2
(CH), 116.7 (C), 112.3 (CH), 109.5 (CH2), 59.1 (CH), 51.2 (CH2),
45.8 (CH), 25.8 (CH2), 21.54 (CH3), 21.52 (CH3), one quaternary
To a solution of aldehyde 5 (122 mg, 0.20 mmol) in toluene/Et3N
(1:1, 20 mL) were added Pd(OAc)2 (9 mg, 0.040 mmol),
triphenylphosphine (31 mg, 0.12 mmol), and Ag2CO3 (111 mg,
0.40 mmol) under argon. The resultant mixture was heated at 80 °C
for 18 h. The solvent was removed under reduced pressure, and the
residue was partitioned between CH2Cl2 (10 mL) and a saturated
aqueous NaHCO3 (10 mL) solution. The organic layer was separated,
dried over anhydrous MgSO4, and concentrated under reduced
pressure. Flash chromatography of the residue on silica gel column
(PE/EtOAc = 2/1) afforded the tetracyclic aldehyde 9 (30 mg, 28%)
as a white foam. Rf = 0.37 (silica gel, PE/EtOAc = 2/1). 1H NMR (400
MHz, CDCl3, δ): 10.21 (s, 1H), 8.00 (dd, J = 6.0, 2.8 Hz, 1H), 7.80
(d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.37−7.29 (m, 7H),
4.78−4.72 (m, 1H), 4.56 (dd, J = 14.4, 4.8 Hz, 1H), 4.38 (dd, J = 14.4,
2.8 Hz, 1H), 3.88 (dd, J = 15.6, 6.4 Hz, 1H), 3.06 (ddd, J = 15.2, 11.2,
1.6 Hz, 1H), 2.40 (s, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3,
δ): 186.3 (CH), 148.9 (C), 145.3 (C), 144.2 (C), 135.1 (C), 133.3
(C), 132.8 (C), 131.1 (C), 130.7 (C), 130.1 (CH), 130.0 (CH), 127.8
(CH), 126.8 (CH), 125.9 (CH), 122.2 (C), 121.9 (CH), 121.8 (CH),
116.4 (C), 116.3 (CH), 67.0 (CH), 54.8 (CH2), 31.4 (CH2), 21.6
carbon overlapped. IR (KBr) vmax: 3027, 2925, 1598, 1376, 1176, 764,
̅
670 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C28H27N2O4S2
519.1407, found 519.1419.
Method 2. According to the procedure in Scheme 4 (path b), to a
solution of sulfide 4 (268 mg, 0.38 mmol) in dry benzene (10 mL)
were added tri-n-butyltin hydride (244 mg, 0.84 mmol) and a catalytic
amount of 2,2′-azobis(2-methylpropionitrile) (AIBN, 18 mg, 0.11
mmol). The resultant mixture was refluxed for 18 h under under argon
and then concentrated under reduced pressure. Flash chromatography
of the residue on silica gel (PE/EtOAc = 5/1) afforded the tetracyclic
compund 3 (179 mg, 91%). All of the spectrospic data of it were in
(CH3), 21.5 (CH3). IR (KBr) vmax: 2925, 2856, 1663, 1352, 1166, 756,
̅
669 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C28H25N2O5S2
533.1199, found 533.1207.
1,6-Ditosyl-8-formyl-4,5,6,9-tetrahydroindolo[4,3-ef ]indole
(10).
1
agreement with those obtained via method 1. H NMR (400 MHz,
CDCl3, δ): 7.80−7.73 (m, 5H), 7.32−7.19 (m, 6H), 6.94 (d, J = 7.6
Hz, 1H), 5.04 (s, 1H), 4.65 (d, J = 2.0 Hz, 1H), 4.30−4.24 (m, 1H),
4.16−4.08 (m, 2H), 3.43 (d, J = 6.8 Hz, 1H), 3.22 (dd, J = 15.6, 6.0
Hz, 1H), 2.59 (ddd, J = 15.6, 10.8, 2.0 Hz, 1H), 2.43 (s, 3H), 2.35 (s,
3H).
1,6-Ditosyl-8-methyl-4,5,6,7-tetrahydroindolo[4,3-ef ]indole
(11).
To a solution of aldehyde 5 (98 mg, 0.16 mmol) in CH3CN (2.0 mL)
was added triphenylphosphine (4 mg, 0.015 mmol), and the resulting
solution well stirred for 10 min under argon. Pd(OAc)2 (1.8 mg, 0.008
mmol) was then added and the suspension stirred for another 15 min
before addition of K2CO3 (55 mg, 0.40 mmol), tetra-n-butylammo-
nium bromide (52 mg, 0.16 mmol), and H2O (0.2 mL). The resultant
mixture was heated at 85 °C for 8 h and then worked up according to
the procedure given above for compound 9 to afford the tetracyclic
aldehyde 10 (59 mg, 69%) as a white foam. Rf = 0.18 (silica gel, PE/
EtOAc = 2/1). 1H NMR (400 MHz, CDCl3, δ): 9.62 (s, 1H), 7.73 (d,
J = 8.4 Hz, 2H), 7.71−7.69 (m, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.45 (s,
1H), 7.32 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 8.4 Hz, 4H), 6.90 (s, 1H),
4.49 (d, J = 7.2 Hz, 1H), 4.45−4.42 (m, 1H), 3.66 (dd, J = 17.6, 2.8
Hz, 1H), 2.97 (dd, J = 17.6, 2.8 Hz, 1H), 2.50 (s, 3H), 2.34 (s, 3H).
13C NMR (100 MHz, CDCl3, δ): 185.9 (CH), 149.4 (CH), 145.6 (C),
144.8 (C), 135.4 (C), 134.0 (C), 133.0 (C), 130.1 (CH), 129.9 (CH),
128.6 (C), 128.4 (C), 128.1 (C), 127.2 (CH), 126.7 (CH), 126.2
(CH), 121.7 (CH), 120.1 (CH), 113.7 (C), 111.9 (CH), 65.2 (CH),
To a solution of tetracyclic compound 3 (119 mg, 0.23 mmol) in
benzene (4 mL) was added p-TsOH·H2O (65 mg, 0.34 mmol). The
resultant mixture was refluxed for 24 h and then diluted with CH2Cl2
(10 mL), quenched with saturated NaHCO3 (10 mL), and extracted
with CH2Cl2 (10 mL × 3). The combined organic layers were washed
with brine (10 mL), dried over anhydrous MgSO4, and concentrated
under reduced pressure. Flash chromatography of the residue on silica
gel (PE/EtOAc = 5/1) afforded tetracyclic compound 11 as a white
foam (75 mg, 63%). Rf = 0.36 (silica gel, PE/EtOAc = 5/1). 1H NMR
(400 MHz, CDCl3, δ): 7.79 (dd, J = 8.0, 5.6 Hz, 3H), 7.72 (d, J = 8.4
Hz, 2H), 7.30−7.17 (m, 7H), 4.50 (dd, J = 3.6, 2.0 Hz, 1H), 4.28−
4.16 (m, 2H), 3.73 (dd, J = 15.2, 5.6 Hz, 1H), 2.87 (ddd, J = 15.2,
11.2, 2.0 Hz, 1H), 2.39 (s, 3H), 2.35 (s, 3H), 1.95 (d, 0.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3, δ): 144.9 (C), 143.7 (C), 135.4 (C), 133.6
(C), 133.3 (C), 129.9 (CH), 129.8 (CH), 129.5 (C), 128.8 (C),
41.3 (CH), 21.9 (CH2), 21.7 (CH3), 21.6 (CH3). IR (KBr) vmax: 3296,
̅
2927, 1658, 1372, 1172, 774, 671 cm−1. HRMS (ESI) m/z: [M + Na]+
calcd for C28H24N2O5S2Na 555.1019, found 555.1021.
D
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127.72 (CH), 127.67 (C), 126.8 (CH), 125.47 (CH), 125.45 (C),
120.5 (CH), 118.8 (CH), 117.8 (C), 112.7 (CH), 66.2 (CH), 60.8
(CH2), 31.5 (CH2), 21.52 (CH3), 21.48 (CH3), 12.6 (CH3). IR (KBr)
4.73 (d, J = 1.6 Hz, 1H), 4.19−4.07 (m, 2H), 3.74 (dd, J = 14.0, 4.8
Hz, 1H), 3.33 (d, J = 14.4 Hz, 1H), 3.26 (d, J = 14.4 Hz, 1H), 2.93
(dd, J = 14.4, 8.4 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H). 13C NMR (100
MHz, CDCl3, δ): 145.2 (C), 143.4 (C), 136.2 (C), 135.3 (C), 134.8
(C), 134.7 (C), 134.5 (C), 130.8 (CH), 129.9 (CH), 129.7 (CH),
128.9 (CH), 128.8 (C), 127.9 (CH), 127.4 (CH), 127.0 (CH), 126.8
(CH), 126.6 (CH), 126.0 (CH), 125.3 (CH), 118.4 (C), 114.4 (C),
112.8 (CH), 67.4 (CH), 56.2 (CH2), 33.1 (CH2), 32.9 (CH2), 21.49
vmax: 3028, 2924, 1596, 1349, 1164, 757, 670 cm−1. HRMS (ESI) m/z:
̅
[M + H]+ calcd for C28H27N2O4S2 519.1407, found 519.1413.
6,8-Dimethyl-4,5,6,7-tetrahydro-1H-indolo[4,3-ef]indole (2).
(CH3), 21.46 (CH3). IR (KBr) vmax: 3025, 2925, 1597, 1375, 1172,
̅
756, 670 cm−1. HRMS (ESI) m/z: [M + Na]+ calcd for
C34H31BrN2O4S3Na 729.0522, found 729.0545.
ASSOCIATED CONTENT
■
To a stirred solution of compound 11 (78 mg, 0.15 mmol) in THF (4
mL) was added sodium naphthalenide (0.67 M solution in THF; 2.2
mL, 1.47 mmol) at −78 °C under argon. The resultant mixture was
stirred for 6 min at this temperature and quenched with saturated
NH4Cl (5 mL). The mixture was made basic with saturated NaHCO3
(10 mL) and then extracted with EtOAc (10 mL × 3). The combined
organic layers were washed with brine (10 mL), dried over anhydrous
MgSO4, and concentrated under reduced pressure to give a crude
amine, which was used without further purification. To a stirred
solution of this amine in MeOH (7 mL) were added AcOH (0.16
mL), NaBH3CN (68 mg, 1.08 mmol), and formalin (0.091 mL, 1.21
mmol) at room temperature. After being stirred for 2 h, the reaction
mixture was quenched with saturated NaHCO3 (5 mL), concentrated
under reduced pressure, and extracted with EtOAc (10 mL × 3). The
combined organic layers were washed with saturated NaHCO3 (10
mL) and brine (10 mL), dried over anhydrous MgSO4, and
concentrated under reduced pressure. Flash chromatography of the
residue on silica gel (MeOH/CHCl3 = 1/5) afforded target compound
2 as a brown foam (24 mg, 71% yield). Rf = 0.34 (silica gel, MeOH/
CHCl3 = 1/4). All spectral data were in agreement with those of
S
* Supporting Information
1H, 13C NMR (DEPT 135) spectra of compounds 5, 9, 10, 3,
11, 2, and 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: caoxplzu@163.com.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Basic Research Program (973
program) of China (Grant No. 2010CB833203), the National
Natural Science Foundation of China (Grant Nos. 21272098,
21190034, 21061160494, and J1103307), the Program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT: IRT1138), the Fundamental Research
Funds for the Central University (FRFCU: lzujbky-2013-ct02),
and the 111 Project for financial support.
1
previous report. H NMR (400 MHz, CDCl3, δ): 8.14 (s, 1H), 7.27−
7.19 (m, 3H), 6.88 (s, 1H), 3.91 (dd, J = 14.0, 3.6 Hz, 1H), 3.72−3.66
(m, 1H), 3.51 (ddd, J = 13.6, 4.8, 1.6 Hz, 1H), 3.34 (dd, J = 14.4, 6.0
Hz, 1H), 2.69 (ddd, J = 14.0, 10.8, 1.6 Hz, 1H), 2.59 (s, 3H), 2.14 (s,
3H). 13C NMR (100 MHz, CDCl3, δ): 134.1 (C), 130.6 (C), 130.2
(C), 127.3 (C), 125.9 (C), 123.0 (CH), 118.3 (CH), 114.7 (CH).
112.2 (C), 109.2 (CH), 72.3 (CH), 68.3 (CH2), 40.5 (CH3), 29.4
REFERENCES
■
(1) Somei, M.; Yokoyama, Y.; Murakami, Y.; Ninomiya, I.; Kiguchi,
T.; Naito, T. Recent Synthetic Studies on the Ergot Alkaloids and
Related Compounds. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 2000; Vol. 54, pp 191−257.
(2) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404.
(3) Greshock, T. J.; Funk, R. L. J. Am. Chem. Soc. 2006, 128, 4946.
(4) Park, I.-K.; Park, J.; Cho, C.-G. Angew. Chem. 2012, 124, 2546.
(5) Rafferty, R. J.; Williams, R. M. J. Org. Chem. 2012, 77, 519.
(CH2), 13.6 (CH3). IR (KBr) vmax: 3209, 2927, 1607, 1445, 1116, 912,
̅
740 cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C15H17N2 225.1386,
found 225.1392.
4-Bromo-3-[2,5-dihydro-4-(phenylthio)methyl-1-tosylpyr-
rol-2-yl]methyl-1-tosylindole (4).
(6) Schonherr, H.; Leighton, J. L. Org. Lett. 2012, 14, 2610.
̈
(7) Shan, D.; Gao, Y.; Jia, Y. X. Angew. Chem., Int. Ed. 2013, 52, 4902.
(8) Trost, B. M.; McDougall, P. J. Org. Lett. 2009, 11, 3782.
(9) Xu, Q. L.; Dai, L. X.; You, S. L. Chem. Sci. 2013, 4, 97.
(10) Yonemitsu, O.; Cerutti, P.; Witkop, B. J. Am. Chem. Soc. 1966,
88, 3941.
To a solution of aldehyde 5 (245 mg, 0.40 mmol) in MeOH (6 mL)
and THF (1 mL) were added CeCl3·7H2O (164 mg, 0.44 mmol) and
NaBH4 (19 mg, 0.50 mmol) at 0 °C. The resultant mixture was stirred
at 0 °C for 30 min. The reaction mixture was diluted with ether (10
mL), quenched with saturated NaHCO3 (10 mL), and extracted with
EtOAc (15 mL × 3). The combined organic layers were dried over
anhydrous MgSO4 and concentrated under reduced pressure. Flash
chromatography of the residue on silica gel (PE/EtOAc = 1/2) gave
the crude alcohol as a white solid, which was then dissolved in benzene
(14 mL). To this solution were added diphenyl disulfide (873 mg, 4.00
mmol) and tri-n-butylphosphine (809 mg, 4.00 mmol) at room
temperature. The resultant mixture was stirred for 30 min and then
concentrated under reduced pressure. Flash chromatography of the
residue on silica gel (PE/EtOAc = 4/1) afforded the sulfide 4 as a
white foam (229 mg, 81% for two steps). Rf = 0.45 (silica gel, PE/
(11) Stauffacher, D.; Niklaus, P.; Tscherter, H.; Weber, H. P.;
Hofmann, A. Tetrahedron 1969, 25, 5879.
(12) Incze, M.; Dornyei, G.; Moldvai, I.; Temesvar
́
i-Major, E.; Egyed,
̈
O.; Szan
́
tay, C. Tetrahedron 2008, 64, 2924.
(13) Petronijevic, F. R.; Wipf, P. J. Am. Chem. Soc. 2011, 133, 7704.
(14) Lu, L. Q.; Chen, J. R.; Xiao, W. J. Acc. Chem. Res. 2012, 45,
1278.
(15) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96,
195.
(16) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40.
(17) Overman, L. E. Acc. Chem. Res. 1992, 25, 352.
(18) Overman, L. E. Aldrichimica Acta 1995, 28, 107.
(19) Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M.
̈
1
D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284.
(20) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.; Manning, J. R.;
Overman, L. E. Org. Lett. 2009, 11, 5658.
EtOAc = 5/1). H NMR (400 MHz, CDCl3, δ): 7.96 (d, J = 8.4 Hz,
1H), 7.71 (dd, J = 8.4, 4.0 Hz, 4H), 7.36 (d, J = 7.6 Hz, 1H), 7.28 (d, J
= 8.4 Hz, 3H), 7.20−7.19 (m, 5H), 7.12−7.06 (m, 3H), 5.15 (s, 1H),
E
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Article
(21) Earley, W. G.; Jacobsen, J. E.; Madin, A.; Meier, G. P.;
O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J.
Am. Chem. Soc. 2005, 127, 18046.
(22) Martin, C. L.; Nakamura, S.; Otte, R.; Overman, L. E. Org. Lett.
2011, 13, 138.
(23) Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc.
2008, 130, 7568.
(24) Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc.
2010, 132, 4894.
(25) Overman, L. E.; Kakimoto, M.; Okazaki, M. E.; Meier, G. P. J.
Am. Chem. Soc. 1983, 105, 6622.
(26) Overman, L. E.; Kakimoto, M.-A. J. Am. Chem. Soc. 1979, 101,
1310.
(27) Overman, L. E.; Mendelson, L. T. J. Am. Chem. Soc. 1981, 103,
5579.
(28) Overman, L. E.; Mendelson, L. T.; Flippin, L. A. Tetrahedron
Lett. 1982, 23, 2733.
(29) Overman, L. E.; Sworin, M.; Bass, L. S.; Clardy, J. Tetrahedron
1981, 37, 4041.
(30) Carballo, R. M.; Purino, M.; Ramírez, M. A.; Martín, V. S.;
́
Padron, J. I. Org. Lett. 2010, 12, 5334.
(31) Inuki, S.; Iwata, A.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem.
2011, 76, 2072.
(32) Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679.
(33) Jeffery, T. Tetrahedron 1996, 52, 10113.
(34) Liu, Q.; Jia, Y. Org. Lett. 2011, 13, 4810.
(35) Yokoyama, Y.; Kondo, K.; Mitsuhashi, M.; Murakami, Y.
Tetrahedron Lett. 1996, 37, 9309.
(36) Bennasar, M. L.; Zulaica, E.; Sole,
Alonso, S. J. Org. Chem. 2009, 74, 8359.
́
D.; Roca, T.; García-Díaz, D.;
(37) Box, V. G. S.; Meleties, P. C. Tetrahedron Lett. 1998, 39, 7059.
(38) He, W.; Huang, J.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc.
2007, 130, 300.
(39) Boger, D. L.; Coleman, R. S. J. Org. Chem. 1988, 53, 695.
(40) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 4796.
(41) Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1988, 110, 1321.
(42) Boger, D. L.; Wysocki, R. J., Jr. J. Org. Chem. 1989, 54, 1238.
(43) Boger, D. L.; Wysocki, R. J., Jr.; Ishizaki, T. J. Am. Chem. Soc.
1990, 112, 5230.
(44) Hata, T.; Sekine, M. Chem. Lett. 1974, 837.
F
dx.doi.org/10.1021/jo4023588 | J. Org. Chem. XXXX, XXX, XXX−XXX