Total Synthesis of (-)-Chanoclavine i and an Oxygen-Substituted Ergoline Derivative

Article abstract of DOI:10.1021/acs.joc.7b00573

An efficient and direct route to ergot alkaloid (-)-chanoclavine I (3) is described using the inexpensive compound (2R)-(+)-phenyloxirane (15) as a chiral pool in 13 steps with 17% overall yield. Key features of the synthesis include a palladium-catalyzed intramolecular aminoalkynylation of terminal olefin and a rhodium-catalyzed intramolecular [3 + 2] annulation. An oxygen-substituted ergoline derivative (-)-25 was also achieved by using the same strategy.

Full text of DOI:10.1021/acs.joc.7b00573

Article
pubs.acs.org/joc
Total Synthesis of (−)-Chanoclavine I and an Oxygen-Substituted
Ergoline Derivative
Jia-Tian Lu, Zi-Fa Shi, 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 and direct route to ergot alkaloid
(−)-chanoclavine I (3) is described using the inexpensive
compound (2R)-(+)-phenyloxirane (15) as a chiral pool in 13
steps with 17% overall yield. Key features of the synthesis
include a palladium-catalyzed intramolecular aminoalkynyla-
tion of terminal olefin and a rhodium-catalyzed intramolecular
[3 + 2] annulation. An oxygen-substituted ergoline derivative
(−)-25 was also achieved by using the same strategy.
tion of this intermediate.6 Developing a more efficient total
synthesis strategy in obtaining chanoclavine I (3) has potential
in simplifying the process of ergot alkaloid biosynthesis and
chemical synthesis study.
INTRODUCTION
■
Ergot alkaloids are a class of indole compounds biosynthetically
derived from L-tryptophan. Most of the ergot alkaloids are
isolated from various Claviceps species, although they can also
be isolated from other fungi and higher plants.1 Ergot alkaloids
The common strategy in synthesizing ergot alkaloids
typically begins with a preformed indole; our search team7
are popular among researchers because of their multimodal
biological activities2−4 and interesting molecular architectures,
which present practical challenges in synthesis. The character-
has successfully formal synthesized ( )-cycloclavine (4) using
this indole-derived method. Several transformations were
needed because of the low reactivity at the 4-position of indole
istic structural feature of all ergot alkaloids is the tetracyclic
ergoline skeleton (see 1, Figure 1).5 The 3,4-fused tricyclic
core. Therefore, a later stage indole synthesis provided an
alternative to accomplish natural products possessing 3,4-fused
indole skeleton in a more concise manner. Over the past
decade, improvements toward a more efficient and direct
formation of iodole and its derivatives have been made, and
new methodologies have been successfully applied into total
synthesis.8 In 2006, Funk9 reported a 6π electrocyclic reactions
strategy to construct the skeleton of dragmacidin E. In 2009
and 2017, Wipf10,11 reported an intramolecular Diels−Alder
reaction of furan to furnish total synthesis of ( )-cycloclavine
and (−)-cycloclavine. In 2011, Jia12 reported the total synthesis
of (+)-lysergic acid by using the intramolecular Larock
indolization process. In 2016, Cho13 reported intramolecular
Fisher indole synthesis and subsequent Claisen rearrangement
that resulted in total synthesis of (−)-aurantioclavine. Based on
the previous research, we were interested in developing a more
efficient strategy to construct the ergot alkaloids.
indole skeleton is a key feature of all ergot alkaloids, including
lysergic acid (2), chanoclavine I (3), cycloclavine (4),
agroclavine (5), pergolide (6), etc. Nearly all ergot alkaloids
are derived from a common biosynthetic intermediate
chanoclavine I (3), and the structural diversity within the
ergot alkaloids results from the elaborate chemical derivatiza-
The current study focuses on the synthesis of (−)-chano-
clavine I (3),14,15 the biosynthetic processor of ergot alkaloids.
Previous research has reported two strategies (Scheme 1) for
optical total syntheses of (−)-chanoclavine I (3), both of which
start from the 4-substituted indole derivatives. In 1994, Genet16
first reported the total synthesis of (−)-chanoclavine I (3) in a
12-step process, with 1.6% overall yield, stemming from indole-
Received: March 10, 2017
Figure 1. Structures of several typical ergot alkaloids.
© XXXX American Chemical Society
A
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exhibited an intramolecular [3 + 2] cycloaddition of the α-
imino rhodium carbene complexes with aryl groups and
subsequent oxidative aromatization to produce the indole
core. This methodology was successfully applied in the total
synthesis of (+)-lysergol by Luo.20 These work provided the
groundwork for a concise and efficient route for the total
synthesis of (−)-chanoclavine I (3) based on palladium-
catalyzed intramolecular aminoalkynylation, followed by intra-
molecular [3 + 2] annulation reaction. The synthesis of an
oxygen-substituted ergoline derivative was also demonstrated in
the same manner.
Scheme 1. Previous Optical Synthetic Approaches to
(−)-Chanoclavine I
RESULTS AND DISCUSSION
■
It was suggested that (−)-chanoclavine I (3) would be formed
in the late stage by rhodium-catalyzed intramolecular [3 + 2]
annulation of compound 11 retrosynthetically (Scheme 2). In
turn, intermediate 11 would be derived from compound 12
using a Wittig reaction and a subsequent Cu(I)-catalyzed click
reaction with tosyl azide (TsN3). Cyclic carbamate 12 could be
prepared from 14 using a lithium palladate catalyzed intra-
molecular aminoalkynylation. The hypervalent iodine reagent
triisopropylsilyl ethynylbenziodoxolone (TIPS-EBX, 13) is
considered an effective reagent for this transformation due to
its mild reaction conditions and high stereoselectivity. The N-
tosylcarbamate 14 should be accessible from commercially
available (2R)-(+)-phenyloxirane 15.
The total synthesis of (−)-chanoclavine I (3) began by
preparing (2S)-(+)-phenylbut-3-en-1-ol (16, Scheme 3)
according to the literature procedure21 using an inexpensive
(2R)-(+)-phenyloxirane (15) as the chiral pool. The chloro-
(1,5-cyclooctadiene)copper(I) dimer [CuCl(COD)]2 catalyzed
vinylation of (2R)-(+)-phenyloxirane (15), resulting in alcohol
(+)-16 with a 71% yield. Subsequently, the carbamation from
the obtained alcohol (+)-16 was prepared by exposing (+)-16
to p-tosyl isocyanate (p-Ts-NCO) in DCM to provide (2S)-
(+)-phenylbut-3-en-1-yl tosylcarbamate (14) with a 97% yield.
The substrate (+)-14 was now present, allowing the key
aminoalkynylation to be investigated by utilizing the procedure
that was described by Waser.18 The phenyl-substituted
homoallyl carbamate (+)-14 was then treated with TIPS−
EBX (13), palladium(II) chloride (PdCl2), and lithium chloride
(LiCl) in EtOH for 5 h at room temperature where the desired
4,5-trans-substituted 1,3-oxazinan-2-one product (−)-12 was
4-carboxaldehyde. The key step of the synthesis was a chiral
BINAP−palladium complex catalyzed cyclization reaction with
nitroacetate 7 to construct trans-substituted tricyclic compound
8, resulting in a 60% yield and 95% ee. After the six-step
manipulation from intermediate 8, the target molecule was
produced. Two years later, Yokoyama and Murakami17
reported an additional approach, using 16 linear steps with
9% overall yield stemming from a tryptophan derivative. The
synthesis was based on a PdCl2−BPPP (1,3-bisdiphenylphos-
phinopropane)-catalyzed intramolecular cyclization (Heck−
Mizoroki reaction) on 9, used to establish the key Z-selective
olefin intermediate 10 with 77% yield. The target molecular was
produced after the 11-step manipulation from intermediate 10.
These routes were not efficient, and more research was needed
to increase efficiency. The current synthetic design was
primarily based on two papers. In 2011, Waser18 reported the
exceptional efficiency of lithium palladate catalysts for the
intramolecular aminoalkynylation of terminal olefins using
hypervalent iodine reagents. This novel strategy allowed both
C−N formation and introduced a terminal alkyne in a single
transformation. In 2014, Murakami19 reported a novel
construction strategy for a 3,4-fused indole skeleton that
Scheme 2. Retrosynthetic Analysis
B
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Scheme 3. Synthesis of (−)-Chanoclavine I
produced as the sole rearrangement product with a 87% yield
(>99% ee was determined by chiral HPLC, see the Supporting
Information, S21). The relative stereochemistry of (−)-12 was
confirmed by an X-ray crystallographic analysis of the final
natural product obtained, although the exact mechanism for
this transformation was unclear. The LiAlH4 reduction of the
cyclic carbamate (−)-12 in THF at 0 °C for 30 min resulted in
the cleavage of the carbamate ring that yielded an amino
alcohol that subsequently oxidized with Dess−Martin period-
inane (DMP) to result in the aldehyde (+)-17 with 84% yield.
Note that the ee (%) was not determined by chiral HPLC as
the sample was unstable and had a weak absorption signal; see
the Supporting Information, S22. The nitrogen atom of the
original methyl group from the natural product was originally
going to be produced via reduction of the cyclic carbamate ring
of (−)-12. Unfortunately, only the decarboxylation product was
obtained under different reaction conditions such as NaBH4,
LiBH4, DIBAL-H, BH3·SMe2, and L-Selectride, and the methyl
group was rebuilt afterward. This produced the (+)-17, where
the Wittig olefination of aldehyde reacted with Ph3P
C(CH3)CO2Me in THF after 50 °C for 5 h, which produced
the E-selective α,β-unsaturated ester (+)-18 with a 82% yield
(80% ee was determined by chiral HPLC; see the Supporting
Information, S23). From the obtained (+)-18 we were able to
rebuild the methyl group at the nitrogen atom, resulting in a
reaction of (+)-18 with MeI and K2CO3 in DMF at room
temperature. This produced a methylation product (+)-19 with
a 98% yield. Subsequently, desilylation of the triple bond of
compound (+)-19 using tetrabutylammonium fluoride (TBAF)
was carried out successfully, resulting in terminal alkyne (−)-20
with a 80% yield. Utilizing the well-established method,22
copper(I) thiophene-2-carboxylate (CuTC) catalyzed the click
reaction of (−)-20 with TsN3 in toluene at room temperature,
which formed 1,2,3-triazoles (+)-11 with 90% yield. With
(+)-11, we were able to produce the 3,4-fused indole skeleton
through the crucial [3 + 2] annulation based on the
Murakami19 protocol. By heating the (+)-11 to rhodium(II)
pivalate dimer Rh2(OCOtBu)4 and 4 Å molecular sieves (MS)
in 1,2-dichloroethane (DCE) at 85 °C for 3 h, the desired [3 +
2] annulation product (dihydroindole) was obtained. After the
compounds were confirmed by TLC spectra, the solvent was
evaporated and the pale residue was obtained. The residue was
treated with manganese dioxide (MnO2) in DCM at room
temperature for 24 h, which yielded the tricyclic indole
compound (−)-21 with 77% yield within this two-step process
without intermediate separation or identification. The single
crystal of the ( )-21 was obtained from the synthesis scheme
starting from the ( )-2-phenyloxirane (see Figure 2 and ref
23). Compound (−)-21 possessed the framework of the nature
product. The last stage was simply a reduction of the ester to
Figure 2. Single crystal of ( )-21 from ( )-15.
C
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alcohol and deprotection of tosyl group. Hence, DIBAL-H
reduction of the α,β-unsaturated ester (−)-21 in THF at −78
°C resulted in a primary allylic alcohol, where the direct
removal of the tosyl group with freshly prepared lithium
naphthalenide at −78 °C produced (−)-chanoclavine I (3) with
a 77% yield (>99% ee, see Supporting Information, S20). The
absolute configuration of (−)-3 was confirmed through a
single-crystal X-ray crystallographic analysis (see ref 24). The
(−)-chanoclavine I (3) was synthesized in this 13-step process,
with a 17% overall yield from (R)-(+)-phenyloxirane (15). The
spectroscopic data, i.e., 1H NMR (see Table S1) and IR spectra
of the synthetic sample, were in agreement with the reported
data.16,25 The optical rotation of the synthetic sample was [α]1D6
−196.0 (c 1.5, pyridine), which is analogous with the isolation
literature14,15 reported [α]2D0 −240 (c 1, pyridine) and the
synthetic literature16 reported [α]2D0 −213 (c 0.4, pyridine).
To investigate the further applicability of the strategy, total
synthesis of an oxygen-substituted ergoline derivative was
performed. Various cases19 have shown that intramolecular [3 +
2] annulation is a versatile synthetic strategy within the
construction of the 3,4-fused indole skeleton on various linear
substrates. Considering that most of the ergot alkaloids
contained a trans-substituted D ring, we postulated that a
substrate containing a trans-six-membered ring between the
phenyl and alkynyl groups would be tolerated. To answer this,
we designed a module experiment on substrate (−)-12
(Scheme 4) that contained a trans-substituted D ring (in
contrast with the ergoline skeleton). Thus, exposure of (−)-12
to TBAF in THF at 0 °C for 2 h resulted in cleavage of the
silicon protecting group quantitatively. Following the same
protocol as above, the obtained terminal alkyne (−)-22 was
converted to the 1,2,3-triazole (−)-23 with a 95% yield via
copper(I) thiophene-2-carboxylate (CuTC) catalyzed click
reaction with TsN3. The treatment of (−)-23 with rhodium(II)
pivalate dimer Rh2(OCOtBu)4 and 4 Å MS in DCE at 85 °C for
3 h resulted in the formation of the [3 + 2] product. The
dihydroindole compound was directly oxidized with MnO2 in
DCM without intermediate separation or purification. After
being stirred at room temperature for 24 h, the tetracyclic 3,4-
fused indole skeleton (−)-24 was achieved with a 74% yield
over the two steps. Eventually, the tosyl group of (−)-24 was
removed with a 59% yield with freshly prepared lithium
naphthalenide in THF at −78 °C. An oxygen-substituted
ergoline derivative (−)-25 was obtained in the eight-step
process with a 24% overall yield from the (R)-(+)-phenyl-
oxirane (15). This synthesis lays the foundation for total
synthesis of other ergot alkaloids in a novel and efficient
manner. Compounds (−)-24 and (−)-25 were believed to be
useful intermediates for the total synthesis of many other ergot
alkaloids. For example, in 2013, Jia12 reported an unfinished
scheme for the total synthesis of (+)-lysergic acid. Baylis−
Hillman reaction was designed to construct the D ring of
lysergic acid in later stage, although this design fell short, as the
key substrate of the Baylis−Hillman reaction could not be
prepared. However, compound (−)-24 could be transferred to
a cyclic amino aldehyde (+)-26, the necessary substrate of the
Baylis−Hillman reaction, by cleavage of the cyclic carbamate
ring by LiAlH4 reduction followed by a Dess−Martin oxidation
of the resulting hydroxyl group with a 64% yield over a two-
step process. Thus, the synthesis of the (+)-lysergic acid should
be achieved.
CONCLUSION
■
A straightforward asymmetric total synthesis of (−)-chanocla-
vine I (3) in a 13-step process with a 17% overall yield was
developed. Our synthesis featured an efficient construction of
the trans-substituted cyclic carbamate ring via a palladium-
catalyzed intramolecular aminoalkynylation of terminal alkene
and a rhodium-catalyzed intramolecular [3 + 2] annulation to
construct the 3,4-fused indole skeleton. The highly efficient
total synthesis of (−)-chanoclavine I (3) provided the basis for
an extended study both the biosynthesis and chemical synthesis
pathway for ergot alkaloids. An additional oxygen-substituted
ergoline derivative (−)-25 was synthesized that has potential
application in the synthesis of various ergot alkaloids including
lysergic acid (2). At this time, further studies are underway.
Scheme 4. Synthesis of (−)-25 and (+)-26
EXPERIMENTAL SECTION
■
General Information. All reactions that required anhydrous
conditions were carried out 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 an FT-IR
spectrophotometer and reported in wavenumbers (cm−1). Melting
points were determined by use of a microscope apparatus and are
1
uncorrected. H and 13C NMR spectra were recorded on a 400 MHz
spectrometer, as were the DEPT 135 experiments, except for the
NMR experiment on compound (+)-26 which was recorded on a 300
MHz spectrometer. Chemical shift values were given in ppm and
coupling constants (J) in Hz. Except for the 1H NMR spectra
experiments made in CDCl3 which used TMS as an internal standard,
1
in the other H and 13C NMR spectra experiments, solvent residue
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signals were used as an internal references (CDCl3: δC = 77.00 ppm;
C5D5N: δH = 8.74 ppm, δC = 150.35 ppm). Accurate mass
measurements were obtained on a 7.0 T FT-ICR or 4G mass
spectrometer or on a double-focusing sector-field instrument. Single-
crystal X-ray diffraction measurements were performed with a
diffractometer working with graphite-monochromated Mo Kα
(CH), 21.6 (CH3). IR (KBr, neat): 3241, 1751, 1452, 1350, 1162, 702,
663 cm−1. HRMS (ESI-ToF) m/z: [M + NH4]+ calcd for
C18H23N2O4S 363.1373, found 363.1375.
26
radiation. TIPS-EBX (13)18 and Rh2(OCOtBu)4 were synthesized
according to the reported procedure.
(−)-(4R,5R)-5-Phenyl-3-tosyl-4-(3-(triisopropylsilyl)prop-2-ynyl)-
1,3-oxazinan-2-one (12). To a solution of tosyl amide (+)-14 (2.21 g,
6.37 mmol, 1.0 equiv) in EtOH (160 mL) was added LiCl (972 mg,
22.93 mmol, 3.6 equiv) followed by PdCl2 (113 mg, 0.64 mmol, 0.1
equiv) and benziodoxolone reagent triisopropylsilyl ethynylbenziodox-
olone (TIPS-EBX, 13, 3.27 g, 7.64 mmol, 1.2 equiv). The reaction
mixture was stirred for 5 h at room temperature. The solvent was then
removed under reduced pressure to give a dark residue, which was
subsequently suspended in Et2O (50 mL). The organic layer was
washed with a saturated solution of Na2CO3 (50 mL). The aqueous
layer was extracted with Et2O (3 × 50 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The resulting crude residue was purified by flash
chromatography (PE/EtOAc 4/1) to give the product (−)-12 as a
colorless needle crystal (2.92 g, 87%). Rf = 0.5 (PE/EtOAc 4/1). Mp:
121−127 °C. [α]1D6 −4.0 (c 2.0, DCM). 1H NMR (400 MHz, CDCl3):
δ 7.49 (d, 2H, J = 8.0 Hz), 7.34−7.31 (m, 3H), 7.26−7.23 (m, 2H),
7.11 (d, 2H, J = 8.0 Hz), 4.78−4.74 (m, 1H), 4.65−4.55 (m, 2H), 3.78
(q, 1H, J = 4.7 Hz), 2.92−2.90 (m, 2H), 2.37 (s, 3H), 1.05 (m, 21H).
13C NMR (100 MHz, CDCl3): δ 148.3 (C), 144.6 (C), 137.8 (C),
1-[(Triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-
EBX, 13). 1H NMR (400 MHz, CDCl3) δ 8.43−8.41 (m, 1H),
8.32−8.29 (m, 1H), 7.78−7.76 (m, 2H), 1.16−1.15 (m, 21H). 13C
NMR (100 MHz, CDCl3): δ 166.4 (C), 134.7 (CH), 132.4 (CH),
131.5 (CH), 131.4 (C), 126.0 (CH), 115.6 (C), 114.2 (C), 64.6 (C),
18.5 (CH3), 11.1 (CH). The NMR data are in accordance with the
literature values.18
(+)-(S)-2-Phenyl-but-3-en-1-ol (16). Following the literature
procedure,21 to a suspension of (+)-(R)-phenyloxirane (15) (1.99 g,
16.56 mmol, 1.0 equiv) and chloro(1,5-cyclooctadiene)copper(I)
dimer [CuCl(COD)]2 (344 mg, 0.83 mmol, 0.05 equiv) in THF
(24 mL) was added vinylmagnesium bromide (20.0 mL, 20.0 mmol,
1.0 M solution in THF, 1.2 equiv) at −78 °C. The reaction mixture
was then allowed to warm to room temperature overnight and
quenched by the addition of a saturated solution of NH4Cl (60 mL).
The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography (PE/EtOAc 10/1) to afford the title
compound as a colorless oil (1.75 g, 71%). Rf = 0.6 (PE/EtOAc 4/
135.1 (C), 129.3 (CH), 129.1 (CH), 128.7 (CH), 127.9 (CH), 127.3
(CH), 101.5 (C), 86.3 (C), 67.7 (CH2), 61.0 (CH), 40.3 (CH), 26.2
(CH2), 21.5 (CH3), 18.3 (CH3), 11.1 (CH). IR (KBr, neat): 3412,
2943, 2864, 2175, 1711, 1355, 1172, 1153 cm−1. HRMS (ESI-ToF) m/
z: [M + H]+ calcd for C29H40NO4SSi 526.2442, found 526.2447.
1
1). H NMR (400 MHz, CDCl3): δ 7.34−7.31 (m, 2H), 7.25−7.21
(m, 3H), 6.03−5.95 (m, 1H), 5.19 (d, 1H, 8.0 Hz), 5.16 (d, 1H, 15.6
Hz), 3.80−3.78 (m, 2H), 3.54 (q, 1H, J = 7.3 Hz), 1.53 (br s, 1H). 13C
NMR (100 MHz, CDCl3): δ 140.6 (C), 138.2 (CH), 128.7 (CH),
127.9 (CH), 126.8 (CH), 117.0 (CH2), 66.0 (CH2), 52.4 (CH). The
spectroscopic properties of this compound are consistent with the
literature reported value.
(+)-(2S,3R)-3-(4-Methylphenylsulfonamido)-2-phenyl-6-(triiso-
propylsilyl)hex-5-ynal (17). To a solution of compond (−)-12 (1.81
g, 3.44 mmol, 1 equiv) in THF (20 mL) was added LiAlH4 (95%, 0.68
g, 17.2 mmol, 5 equiv) at 0 °C. After the solution was stirred for 1 h,
water (0.7 mL) and a solution of NaOH (10%, 1.4 mL) were added
dropwise carefully at the same temperature, and the mixture was
filtered over Celite. The filter was extracted with methyl tert-butyl
ether (3 × 50 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated under reduced pressure to
give a white solid, which was used in the next step directly without
further purification.
To a solution of the above product in DCM (20 mL) was added
Dess−Martin periodinane (1.75 g, 4.13 mmol, 1.2 equiv) at 0 °C. The
reaction mixture was stirred at 0 °C for 3 h shielded from light. The
reaction mixture was quenched with a solution of saturated NaHCO3
solution (20 mL). The organic layer was separated, and the aqueous
layer was extracted with the DCM (3 × 50 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude residue was purified by flash
chromatography (PE/EtOAc 4/1) to give aldehyde (+)-17 as a white
solid (1.44 g, 84%). Rf 1= 0.3 (PE/EtOAc 2/1). Mp: 86−89 °C. [α]D16
+10.0 (c 0.6, MeOH). H NMR (400 MHz, CDCl3): δ 9.65 (s, 1H),
7.68 (d, 2H, J = 8.4 Hz), 7.32−7.30 (m, 3H), 7.24 (s, 1H), 7.15−7.12
(m, 2H), 5.10 (d, 1H, J = 9.6 Hz), 4.00 (br s, 2H), 2.42 (s, 3H), 2.39−
2.35 (m, 1H), 2.20−2.15 (m, 1H), 1.09 (m, 21H). 13C NMR (100
MHz, CDCl3): δ 198.8 (CH), 143.6 (C), 137.6 (C), 132.9 (C), 129.7
(CH), 129.3 (CH), 129.2 (CH), 128.3 (CH), 126.9 (CH), 102.3 (C),
85.9 (C), 60.6 (CH), 53.1 (CH), 24.3 (CH2), 21.5 (CH3), 18.6
(CH3), 11.2 (CH). IR (KBr, neat): 3241, 2941, 2173, 1731, 1461,
(+)-(S)-2-Phenylbut-3-en-1-yl Tosylcarbamate (14). To a solution
of alcohol (+)-16 (1.86 g, 12.55 mmol, 1.0 equiv) in CH2Cl2 (32 mL)
was added p-tosyl isocyanate (p-Ts-NCO) (3.71 g, 18.83 mmol, 1.5
equiv) dropwise at 0 °C. The reaction mixture was allowed to warm to
room temperature, stirred for 30 min, and then diluted with H2O (15
mL). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography (PE/EtOAc 4:1) to
provide compound (+)-14 as a white solid (4.20 g, 97%). Rf = 0.4
(PE/EtOAc 4/1). Mp: 79−81 °C. [α]1D6 +22.3 (c 1.1, MeOH). H
1
NMR (400 MHz, CDCl3): δ 8.19−8.11 (br, 1H), 7.86−7.83 (m, 2H),
7.29−7.20 (m, 5H), 7.13−7.11 (d, 2H, J = 7.4 Hz), 5.92−5.83 (m,
1H), 5.09−5.00 (m, 2H), 4.36−4.23 (m, 2H), 3.61 (q, 1H, J = 7.2
Hz), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 150.5 (C), 144.9
(C), 139.3 (C), 136.8 (CH), 135.3 (C), 129.5 (CH), 128.6 (CH),
128.2 (CH), 127.7 (CH), 127.0 (CH), 117.0 (CH2), 68.9 (CH2), 48.2
E
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1432, 1332, 1167, 698, 661 cm−1. HRMS (ESI-ToF) m/z: [M + H]+
calcd for C28H40NO3SSi 498.2493, found 498.2495.
(−)-(4R,5R,E)-Methyl 5-(N,4-Dimethylphenylsulfonamido)-2-
methyl-4-phenyloct-2-en-7-ynoate (20). To a solution of compound
(+)-19 (930 mg, 1.60 mmol, 1.0 equiv) in THF (10 mL) was added a
solution of TBAF (1.0 M in THF, 4.8 mL, 4.80 mmol, 3.0 equiv)
dropwise at 0 °C. The mixture was allowed to warm to room
temperature over 2 h. The reaction was quenched with a solution of
NaHCO3 (1 M, 10 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography (PE/EtOAc 4/1) to afford compound
(−)-20 as a white solid (544 mg, 80%). Rf = 0.3 (PE/EtOAc 4/1). Mp:
(+)-(4R,5R,E)-Methyl 2-Methyl-5-(4-methylphenylsulfonamido)-
4-phenyl-8-(triisopropylsilyl)oct-2-en-7-ynoate (18). To a solution
of aldehyde (+)-17 (1.40 g, 2.81 mmol, 1 equiv) in dry THF (35 mL)
was added crystalline (α-carbomethoxyethylidene)triphenylphos-
phorane (1.96 g, 5.62 mmol, 2 equiv). The reaction mixture was
stirred and heated from room temperature to 50 °C for 2 h under
argon. The solvent was then removed under reduced pressure. The
residue was purified by flash chromatography (PE/EtOAc 4/1) to give
the ester (+)-18 as a white solid (1.31 g, 82%). Rf = 0.6 (PE/EtOAc 2/
1). Mp: 34−38 °C. [α]1D6 +17.6 (c 0.9, MeOH). 1H NMR (400 MHz,
CDCl3): δ 7.72 (d, 2H, J = 8.4 Hz), 7.29−7.21 (m, 5H), 7.17−7.15
(m, 2H), 6.87−6.84 (dd, 1H, J = 10.0, 1.6 Hz), 4.75 (d, 1H, J = 9.6
Hz), 3.95 (t, 1H, J = 10.0 Hz), 3.70 (s, 3H), 2.43 (s, 3H), 2.28−2.23
(m, 1H), 2.28−2.03 (m, 1H), 1.79 (d, 3H, J = 1.3 Hz), 1.11 (m, 21H).
13C NMR (100 MHz, CDCl3): δ 167.9 (C), 143.5 (C), 140.7 (CH),
101−103 °C. [α]1D6 −137.3 (c 0.5, MeOH). H NMR (400 MHz,
1
CDCl3): δ 7.75 (d, 2H, J = 8.4 Hz) 7.35−7.25 (m, 7H), 7.04−7.01 (m,
1H), 4.52−4.47 (m, 1H), 4.00 (t, 1H, J = 10.4 Hz), 3.71 (s, 3H), 2.80
(s, 3H), 2.42 (s, 3H), 2.25−2.19 (m, 1H), 2.14−2.08 (m, 1H), 1.89 (t,
1H, J = 2.7 Hz), 1.85 (d, 3H, J = 1.4 Hz). 13C NMR (100 MHz,
CDCl3): δ 168.0 (C), 143.2 (C), 141.3 (CH), 139.4 (C), 136.8 (C),
129.5 (CH), 129.1 (CH), 128.5 (C), 128.2 (CH), 127.48 (CH),
127.46 (CH), 80.1 (C), 72.1 (CH), 59.1 (CH), 51.9 (CH3), 47.0
(CH), 29.4 (CH3), 21.5 (CH3), 20.9 (CH2), 12.6 (CH3). IR (KBr,
neat): 3265, 2953, 2109, 1703, 1435, 1334, 1166, 1073, 667 cm−1.
HRMS (ESI-ToF) m/z: [M + NH4]+ calcd for C24H31N2O4S
443.1999, found 443.1998.
139.4 (C), 137.6 (C), 129.74 (C), 129.71 (CH), 129.0 (CH), 127.9
(CH), 127.4 (CH), 127.0 (CH), 102.5 (C), 85.5 (C), 56.1 (CH), 51.8
(CH3), 47.7 (CH), 24.1 (CH2), 21.6 (CH3), 18.7 (CH3), 12.8 (CH3),
11.2 (CH); IR (KBr, neat): 3259, 2945, 2170, 1714, 1435, 1334, 1162,
735, 622 cm−1. HRMS (ESI-ToF) m/z: [M + NH4]+ calcd for
C32H49N2O4SSi 585.3177, found 585.3178.
(+)-(4R,5R,E)-Methyl 5-(N,4-Dimethylphenylsulfonamido)-2-
methyl-4-phenyl-6-(1-tosyl-1H-1,2,3-triazol-4-yl)hex-2-enoate (11).
To a solution of compound (−)-20 (787 mg, 1.85 mmol, 1.0 equiv) in
toluene (10 mL) were added copper(I) thiophene-2-carboxylate
(CuTC) (36 mg, 0.19 mmol, 0.1 equiv) and a solution of TsN3 (365
mg, 1.85 mmol, 1.0 equiv) in toluene (10 mL) in room temperature.
The reaction mixture was stirred for 12 h at the same temperature.
The mixture was then quenched with a saturated solution of NH4Cl
(30 mL) and extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography (PE/EtOAc 4/1) to give 1,2,3-triazole
(+)-11 as a white powder (1.02 g, 90%). Rf = 0.5 (PE/EtOAc 1/1).
(+)-(4R,5R,E)-Methyl 5-(N,4-Dimethylphenylsulfonamido)-2-
methyl-4-phenyl-8-(triisopropylsilyl)oct-2-en-7-ynoate (19). To a
solution of compound (+)-18 (1.30 g, 2.29 mmol, 1 equiv) in freshly
distilled N,N-dimethylformamide (10 mL) were added methyl iodide
(2.60 g, 18.32 mmol, 8 equiv) and potassium carbonate (633 mg, 4.58
mmol, 2 equiv). The reaction mixture was stirred vigorously at room
temperature for 20 h, quenched with water (5 mL), and then diluted
with EtOAc (150 mL). The organic phase was washed with water (5 ×
30 mL) and then a solution saturated Na2S2O3 (30 mL), dried over
anhydrous MgSO4, and concentrated under reduced pressure. The
crude residue was purified by flash chromatography (PE/EtOAc 4/1)
to afford compound (+)-19 as a white solid (1.31 g, 98%). Rf = 0.6
Mp: 101−104 °C.[α]1D6 +28.7 (c 1.2, DCM). H NMR (400 MHz,
1
CDCl3): δ 7.9 (d, 2H, J = 8.4 Hz), 7.62 (s, 1H), 7.49 (d, 2H, J = 8.2
Hz), 7.32 (d, 2H, J = 8.2 Hz), 7.28−7.26 (m, 4H), 7.20−7.18 (m, 3H),
7.02 (d, 1H, J = 8.4 Hz), 4.80−4.74 (m, 1H), 3.86−3.81 (t, 1H, J =
10.4 Hz), 3.70 (s, 3H), 2.80−2.69 (m, 2H), 2.58 (s, 3H), 2.40 (d, 6H),
1.82 (d, 3H, J = 1.2 Hz). 13C NMR (100 MHz, CDCl3): δ 167.9 (C),
147.0 (C), 143.7 (C), 143.3 (C), 141.4 (CH), 139.5 (C), 136.6 (C),
133.1 (C), 130.2 (CH), 129.5 (CH), 129.2 (CH), 128.6 (CH), 128.4
(C), 128.2 (CH), 127.5 (CH), 126.9 (CH), 122.0 (CH), 61.5 (CH),
51.9 (CH3), 49.1 (CH), 26.8 (CH2), 21.7 (CH3), 21.5 (CH3), 12.5
(CH3). IR (KBr, neat): 2951, 1712, 1597, 1494, 1437, 1392, 1268,
736, 672 cm−1. HRMS (ESI-ToF) m/z: [M + H]+ calcd for
C31H35N4O6S2 623.1993, found 623.1994.
(PE/EtOAc 2/1). Mp: 70−73 °C. [α]1D6 +11.4 (c 0.4, MeOH). H
1
NMR (400 MHz, CDCl3): δ 7.74 (d, 2H, J = 8.0 Hz), 7.35−7.27 (m,
6H), 7.25−7.23 (m, 1H), 6.97−6.95 (m, 1H), 4.47−4.42 (m, 1H),
4.23 (t, 1H, J = 10.6 Hz), 3.70 (s, 3H), 2.94 (s, 3H), 2.42 (s, 3H),
2.38−2.33 (m, 1H), 2.20−2.15 (m, 1H), 1.84 (d, 3H, J = 0.8 Hz), 1.09
(s, 21H). 13C NMR (100 MHz, CDCl3): δ 167.8 (C), 143.2 (C),
141.5 (CH), 139.5 (C), 136.6 (C), 129.6 (CH), 128.9 (CH), 128.3
(C), 128.2 (CH), 127.3 (CH), 127.2 (CH), 104.2 (C), 85.5 (C), 58.2
(CH), 51.7 (CH3), 45.6 (CH), 30.1 (CH3), 22.7 (CH2), 21.4 (CH3),
18.5 (CH3), 12.3 (CH3), 11.2 (CH). IR (KBr, neat): 3360, 2928,
2864, 2170, 1718, 1598, 1460, 1343, 1162, 739, 677 cm−1. HRMS
(ESI-ToF) m/z: [M + NH4]+ calcd for C33H51N2O4SSi 599.3333,
found 599.3331.
(−)-(E)-Methyl 3-((4R,5R)-4-(N,4-Dimethylphenylsulfonamido)-1-
tosyl-1,3,4,5- tetrahydrobenzo[cd]indol-5-yl)-2-methylacrylate (21).
To solution of 1,2,3-triazole (+)-11 (765 mg, 1.25 mmol, 1.0 equiv) in
1,2-dichloroethane (20 mL) were added rhodium(II) pivalate dimer
Rh2(OCOtBu)4 (7.6 mg, 12.5 μmol, 0.01 equiv) and 4 Å MS (200 mg)
under argon. It was note that the reaction vessel was evacuated and
F
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
refilled with argon five times before the reaction. The reaction mixture
was heated to 85 °C under argon for 3 h. After being cooled to room
temperature, the molecular sieves were filtered off, and the remaining
solution was concentrated to a viscous residue. To a suspension of the
crude residue in anhydrous DCM (20 mL) was added activated MnO2
(1.09 g, 12.50 mmol, 10 equiv) at room temperature. After being
stirred at room temperature for 20 h, the reaction mixture was passed
through a pad of Celite. The filtrate was concentrated under reduced
pressure, and the residue was purified by flash chromatography (PE/
EtOAc 4/1) to give the product (−)-21 as colorless needle crystals
(570 mg, 77%). Rf = 0.6 (PE/EtOAc 1/1). Mp: 168−174 °C. [α]D16
123.4 (CH), 119.9 (CH), 116.6 (CH), 111.8 (C), 109.9 (CH), 68.3
(CH2), 62.8 (CH), 44.1 (CH), 34.7 (CH3), 27.5 (CH2), 15.1 (CH3).
IR (KBr, neat): 3418, 2923, 1616, 1444, 1072, 744 cm−1. HRMS (ESI-
ToF) m/z: [M + H]+ calcd for C16H21N2O 257.1648, found 257.1647.
1
(The H NMR data of the synthetic sample are agreement with the
literature reported value,16,25 and the detailed comparison is listed in
the Supporting Information. To the best of our knowledge, there was
no 13C NMR data reported before.)
1
−43.9 (c 2.2, DCM). H NMR (400 MHz, CDCl3): δ 7.78−7.74 (m,
3H), 7.67 (d, 2H, J = 8.4 Hz), 7.27−7.20 (m, 5H), 7.16 (d, 1H, J = 1.2
Hz), 6.75 (d, 1H, J = 7.6 Hz), 6.60−6. 57 (m, 1H), 4.41−4.35 (m,
1H), 4.09−4.04 (t, 1H, J = 10.2 Hz), 3.76 (s, 3H), 2.99−2.82 (m, 2H),
2.74 (s, 3H), 2.43 (s, 3H), 2.35 (s, 3H), 1.93 (d, 3H, J = 1.2 Hz). 13C
NMR (100 MHz, CDCl3): δ 167.7 (C), 144.9 (C), 143.4 (C), 139.6
(CH), 136.6 (C), 135.2 (C), 133.3 (C), 131.1 (C), 130.0 (C), 129.9
(CH), 129.6 (CH), 128.0 (C), 127.3 (CH), 126.7 (CH), 125.7 (CH),
120.1 (CH), 120.0 (CH), 117.4 (C), 112.3 (CH), 57.9 (CH), 52.0
(CH3), 40.9 (CH), 28.7 (CH3), 25.3 (CH2), 21.6 (CH3), 12.8 (CH3).
IR (KBr, neat): 2943, 1709, 1598, 1165, 674 cm−1. HRMS (ESI-ToF)
m/z: [M + Na]+ calcd for C31H32N2O6S2Na 615.1594, found
615.1592.
(−)-(4R,5R)-5-Phenyl-4-(prop-2-yn-1-yl)-3-tosyl-1,3-oxazinan-2-
one (22). In analogy to the synthesis of compound (−)-20, the
desilylation was carried out by starting from cyclic carbamate (−)-12
(646 mg, 1.23 mmol, 1.0 equiv) to give compound (−)-22 (445 mg,
98%) as a white solid. Rf = 0.2 (PE/EtOAc 4/1). Mp: 187−194 °C.
[α]1D6 −63.2 (c 0.02, MeOH). 1H NMR (400 MHz, CDCl3): δ 7.44 (d,
2H, J = 8.4 Hz), 7.35−7.33 (m, 3H), 7.27−7.24 (m, 2H), 7.11 (d, 2H,
J = 8.4 Hz), 4.81−4.77 (m, 1H), 4.67−4.55 (m, 2H), 3.7 (q, 1H, J =
4.4 Hz), 2.91−2.79 (m, 2H), 2.38 (s, 3H), 2.19 (t, 1H, J = 2.8 Hz). 13C
NMR (100 MHz, CDCl3): δ 148.3 (C), 144.8 (C), 137.7 (C), 134.8
(C), 129.3 (CH), 129.1 (CH), 128.6 (CH), 127.9 (CH), 127.3 (CH),
78.0 (C), 73.3 (CH), 67.7 (CH2), 60.8 (CH), 40.0 (CH), 25.1 (CH2),
21.6 (CH3). IR (KBr, neat): 3431, 2957, 2864, 2176, 1762, 1369,
1135, 676 cm−1. HRMS (ESI-ToF) m/z: [M + H]+ calcd for
C20H20NO4S 370.1108, found 370.1110.
(−)-(E)-2-Methyl-3-((4R,5R)-4-(methylamino)-1,3,4,5-tetrahydro-
benzo[cd]indol-5-yl)prop-2-en-1-ol (3). To a solution of compound
(−)-21 (231 mg, 0.39 mmol, 1.0 equiv) in dry DCM (50 mL) was
added DIBAL-H (1 M in THF, 0.78 mL, 0.78 mmol, 2.0 equiv) at −78
°C, and the resulting mixture was stirred for 1.5 h at the same
temperature. Then methanol (2 mL) and a solution of saturated
potassium tartrate (10 mL) were added dropwise sequentially. The
mixture was allowed to warm to room temperature and stirred for a
further 10−15 min. The obtained white precipitate was filtered
through a pad of Celite, and the aqueous phase was extracted with
DCM. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude residue was used
directly in the next step without further purification.
(−)-(4R,5R)-5-Phenyl-3-tosyl-4-((1-tosyl-1H-1,2,3-triazol-4-yl)-
methyl)-1,3-oxazinan-2-one (23). In analogy to the synthesis of
compound (+)-11, this click reaction was carried out by starting from
terminal alkyne (−)-22 (919 mg, 2.49 mmol, 1.0 equiv) to give 1,2,3,-
triazole (−)-23 (1.34 g, 95%) as a white powder. Rf = 0.4 (PE/EtOAc
1/1). Mp: 206 °C dec. [α]D16 −57.4 (c 0.5, DCM). H NMR (400
1
MHz, CDCl3): δ 7.99−7.97 (m, 3H), 7.43−7.38 (m, 4H), 7.32−7.26
(m, 3H), 7.19−7.17 (m, 2H), 7.13 (d, 2H, J = 8 Hz), 4.93 (dd, 1H, J =
10.8, 6.0 Hz), 4.62−4.58 (m, 1H), 4.50−4.46 (m, 1H), 3.50 (q, 1H, J
= 4.4 Hz), 3.36 (d, 2H, J = 6.0 Hz), 2.44 (s, 3H), 2.40 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 148.4 (C), 147.4 (C), 145.1 (C), 141.8
(C), 137.7 (C), 134.6 (C), 132.8 (C), 130.5 (CH), 129.3 (CH), 128.8
(CH), 128.7 (CH), 127.9 (CH), 127.4 (CH), 123.1 (CH), 67.9
(CH2), 62.1 (CH), 39.8 (CH), 30.8 (CH2), 21.8 (CH3), 21.6 (CH3);
IR (KBr, neat): 3122, 1713, 1396, 1197, 670 cm−1. HRMS (ESI-ToF)
m/z: [M + H]+ calcd for C27H27N4O6S2 567.1367, found 567.1368.
To a solution of naphthalene (1.12 g, 8.75 mmol) in previously
degassed THF (17 mL) was added lithium (61 mg, 8.75 mmol). The
mixture was sonicated for 30 min and then stirred at room
temperature for another 2 h in order to obtain a dark green (lithium
naphthalenide) solution of 0.5 M.18 To a solution of the previously
obtained alcohol in THF (5 mL) was added the freshly prepared
solution of lithium naphthalenide dropwise at −78 °C until the
reaction mixture stayed permanently dark green (3 mL, 4.0 equiv).
The reaction mixture was stirred at −78 °C for 30 min and warmed to
room temperature for another 30 min. The reaction mixture was
quenched with a solution of NaHCO3 (1 M, 3 mL) and extracted with
DCM (3 × 10 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated under reduced pressure to
give a pale residue. The crude residue was purified by flash
chromatography (CHCl3/MeOH/NH4OH 46/5/0.5) and recrystal-
lized in acetone to give (−)-chanoclavine I (3) as a pale crystal (77
mg, 77%). Rf = 0.2 (CHCl3/MeOH/NH4OH 46/5/0.5). Mp: 216−
220 °C (lit.14 mp 220−222 °C, lit.15 mp 222 °C, lit.16 mp 192 °C).
[α]1D6 −196.0 (c 1.5, pyridine) [lit.14,15 [α]D20 −240 (c 1, pyridine), lit.16
(−)-(6aR,10aR)-4,7-Ditosyl-4,6,6a,7,10,10a-hexahydro-8H-[1,3]-
oxazino[5′,4′:4,5]benzo[1,2,3-cd]indol-8-one (24). In analogy to the
synthesis of compound (−)-21, [3 + 2] annulation reaction was
carried out by starting from 1,2,3,-triazole (−)-23 (1.29 g, 2.27 mmol,
1.0 equiv) to give tetracyclic indole compound (−)-24 (901 mg, 74%)
as a white powder. Rf = 0.6 (PE/EtOAc 1/1). Mp: >300 °C.[α]D16
−103.1 (c 1.0, DCM). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 2H, J
= 8.0 Hz), 7.85 (d, 1H, J = 8.4 Hz), 7.80 (d, 2H, J = 8.4 Hz), 7.37−
1
[α]2D0 −213 (c 0.4, pyridine)]. H NMR (400 MHz, C5D5N): δ 11.63
(br, s, 1H), 7.43 (d, 1H, J = 8.0 Hz), 7.29−7.25 (m, 2H), 7.04 (d, 1H,
J = 7.2 Hz), 6.56 (t, 1H, J = 6.0 Hz, disappeared on addition of D2O)
5.91 (dd, 1H, J = 10.0, 1.4 Hz), 4.46 (m, 2H), 4.21 (t, 1H, 8.8 Hz),
3.43 (dd, 1H, J = 14.8, 4.0 Hz), 3.05−3.02 (m, 1H), 2.94−2.88 (m,
1H), 2.41 (s, 3H), 2.04 (d, 3H, J = 1.2 Hz). 13C NMR (100 MHz,
C5D5N): δ 140.7 (C), 135.6 (C), 133.5 (C), 127.9 (C), 125.8 (CH),
G
DOI: 10.1021/acs.joc.7b00573
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The Journal of Organic Chemistry
Article
7.30 (m, 4H), 7.27−7.24 (m, 2H), 6.90 (d, 1H, J = 7.2 Hz), 4.87 (dd,
1H, J = 10.8, 3.6 Hz), 4.38−4.27 (m, 2H), 4.09 (dd, 1H, J = 14.4, 3.2
Hz), 3.50−3.44 (m, 1H), 2.82−2.75 (m, 1H), 2.46 (s, 3H), 2.37 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 149.5 (C), 145.3 (C), 145.2
(C), 136.0 (C), 135.3 (C), 133.1 (C), 130.0 (CH), 129.6 (CH), 128.9
(CH), 128.5 (C), 126.8 (CH), 126.5 (C), 125.7 (CH), 121.1 (CH),
116.42 (CH), 116.39 (C), 113.3 (CH), 66.3 (CH2), 61.4 (CH), 40.6
(CH), 30.2 (CH2), 21.7 (CH3), 21.6 (CH3). IR (KBr, neat): 3430,
1735, 1350, 1166, 607 cm−1. HRMS (ESI-ToF) m/z: [M + Na]+ calcd
for C27H24N2O6S2Na 559.0968, found 559.0952.
MHz, CDCl3): δ 9.46 (s, 1H), 7.87 (d, 1H, J = 8.1 Hz), 7.79 (d, 2H, J
= 8.4 Hz), 7.68 (d, 2H, J = 8.1 Hz), 7.21−7.39 (m, 6H), 7.10 (d, 1H, J
= 7.2 Hz), 4.54−4.57 (m, 1H), 4.40−4.46 (m, 1H), 3.89 (d, 1H, J =
2.7 Hz), 2.92−2.98 (m, 1H), 2.62−2.68 (m, 1H), 2.45 (d, 3H), 2.36
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 197.9, 145.2, 143.9, 137.5,
135.2, 133.4, 130.1, 129.9, 128.3, 127.0, 126.8, 126.3, 122.5, 122.13,
122.10, 113.7, 113.4, 56.9, 48.2, 26.2, 21.60, 21.57. IR (neat): 3286,
2924, 1728, 1460, 1262, 1119, 795, 684, 582 cm−1. HRMS (ESI-ToF)
m/z: [M + H]+ calcd for C26H25N2O5S2 509.1199, found 509.1196.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00573.
■
S
1H, 13C NMR (DEPT 135) spectra for known
compounds (13,18 (+)-16,21 (−)-314−17,25) and un-
known compounds [(+)-14, (−)-12, (+)-17, (+)-18,
(−)-19, (−)-20, (+)-11, (−)-21, (−)-22, (−)-23,
(−)-24, (−)-25, and (+)-26]; HPLC spectra of 12, 17,
18, and 3 (PDF)
(−)-(6aR,10aR)-4,6,6a,7,10,10a-Hexahydro-8H-[1,3]oxazino-
[5′,4′:4,5]benzo[1,2,3-cd]indol-8-one (25). To a solution of naph-
thalene (4.49 g, 35.0 mmol) in previously degassed THF (70 mL) was
added lithium (243 mg, 35.0 mmol), and the mixture was sonicated for
30 min and then stirred at room temperature for 2 h in order to obtain
a 0.5 M dark green (lithium naphthalenide) solution.18 To a solution
of (−)-24 (826 mg, 1.54 mmol, 1.0 equiv) in THF (20 mL) at −78 °C
was added the freshly prepared lithium naphthalenide dropwise until
the reaction mixture stayed permanently dark green (11 mL, 4.0
equiv). The mixture was stirred at −78 °C for 30 min and at room
temperature for another 30 min. The mixture was quenched with 1 M
NaHCO3 (11 mL) and extracted with AcOEt (3 × 20 mL). The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The provided
residue was purified by flash chromatography (PE/AcOEt 4/1) to give
(−)-25 as a white powder (207 mg, 59%). Rf = 0.3 (EtOAc). Mp:
>300 °C. [α]1D6 −50.0 (c 0.06, pyridine). 1H NMR (400 MHz, C5D5N)
δ 11.87 (br s, 1H), 8.97 (br s, 1H), 7.45 (d, 1H, J = 8 Hz), 7.28−7.26
(m, 2H), 6.91 (d, 1H, J = 6.8 Hz), 5.20 (dd, 1H, J = 10.8, 4.4 Hz), 4.46
(t, 1H, J = 10.8 Hz), 3.89−3.82 (m, 1H), 3.47 (dd, 2H, J = 14.2, 4.6
Hz), 3.00 (t, 1H, J = 12.8 Hz). 13C NMR (100 MHz, C5D5N) δ 154.2
(C), 135.4 (C), 128.0 (C), 127.5 (C), 123.4 (CH), 120.6 (CH), 113.6
(CH), 111.2 (CH), 110.5 (C), 69.6 (CH2), 55.8 (CH), 39.1 (CH),
29.8 (CH2). IR (KBr, neat): 3397, 1718, 1367, 1044, 746 cm−1. HRMS
(ESI-ToF) m/z: [M + Na]+ calcd for C13H12N2O2Na 251.0791, found
251.0790.
X-ray crystallographic data for ( )-21 (CIF)
X-ray crystallographic data for (−)-3 (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: caoxplzu@163.com.
ORCID
Jia-Tian Lu: 0000-0002-0824-2552
Zi-Fa Shi: 0000-0001-9231-5963
Xiao-Ping Cao: 0000-0001-8340-1122
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21272098, 21572085, and 21572086), the
Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT: IRT_15R28), the Fundamental
Research Funds for the Central University (FRFCU: lzujbky-
2016-ct02), and the 111 Project for financial supports. We
gratefully acknowledge Dr. Yong-Liang Shao at Lanzhou
University for conducting X-ray crystallographic analyses. We
also thank Dr. Peng An and Dr. Wei Wang for their helpful
guidance in the preparation of the manuscript.
(+)-N-((4R,5R)-5-Formyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]-
indol-4-yl)-4-methylbenzenesulfonamide (26). In analogy to the
synthesis of compound (+)-17, to a solution of (−)-24 (28 mg, 5.1 ×
10−2 mmol, 1.0 equiv) in THF (2 mL) at 0 °C was added LiAlH4
(95%, 22.7 mg, 0.26 mmol, 5 equiv) at 0 °C. After the mixture was
stirred for 20 min, water (0.03 mL) and a solution of NaOH (10%,
0.06 mL) were carefully added dropwise careful at the same
temperature, and the mixture was filtered over Celite. The filter cake
was washed with DCM (50 mL). The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure to give a
white solid, which was used in the next step directly without further
purification.
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I
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J. Org. Chem. XXXX, XXX, XXX−XXX