Ni-catalyzed reductive homocoupling of unactivated alkyl bromides at room temperature and its synthetic application

Article abstract of DOI:10.1021/jo401936v

A room-temperature Ni-catalyzed reductive approach to homocoupling of unactivated primary, secondary, and tertiary alkyl bromides is described. The catalytic system can be easily generated from air-stable and cheap materials and demonstrates broad functional group tolerance, thus allowing facile access to useful dimeric triterpene and lignan-like molecules. Moreover, the dimerization of tertiary bromide 6 efficiently establishes sterically hindered vicinal quaternary carbons (C3a and C3a′), which is a key linkage of intriguing bispyrrolo[2,3-b]indoline alkaloids, thereby enabling us to complete the total syntheses of racemic chimonanthine (9) and folicanthine (10). In addition, this dimerization method can be expanded to the highly stereoselective synthesis of bisperhydrofuro[2,3-b]furan (5a) and the dimeric spiroketal 5b, signifying the involvement of possible radical species.

Full text of DOI:10.1021/jo401936v

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Article
Ni-Catalyzed Reductive Homocoupling of Unactivated Alkyl
Bromides at Room Temperature and Its Synthetic Application
Yu Peng, Long Luo, Chang-Song Yan, Jian-Jian Zhang, and Ya-Wen Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401936v • Publication Date (Web): 02 Oct 2013
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Ni-Catalyzed Reductive Homocoupling of Unactivated Alkyl Bromides
at Room Temperature and Its Synthetic Application
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Yu Peng*, Long Luo, Chang-Song Yan, Jian-Jian Zhang and Ya-Wen Wang
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metals Chemistry
and Resources Utilization of Gansu Province and College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, People’s Republic of China
pengyu@lzu.edu.cn
Abstract: A room temperature Ni-catalyzed reductive approach to homocoupling of unactivated
primary, secondary and tertiary alkyl bromides is described. The catalytic system can be easily
generated from air-stable and cheap materials and demonstrates broad functional group tolerance, thus
allowing facile access to useful dimeric triterpene and lignan-like molecules. Moreover, dimerization of
tertiary bromide 6 efficiently establishes sterically hindered vicinal quaternary carbons (C3a and C3a′),
that is a key linkage of intriguing bispyrrolo[2,3-b]indoline alkaloids, thereby enabling us to complete
the total syntheses of racemic Chimonanthine (9) and Folicanthine (10). In addition, this dimerization
method can be expanded to highly stereoselective synthesis of bisperhydrofuro[2,3-b]furan (5a) and
dimeric spiroketal (5b), signifying the involvement of possible radical species.
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Introduction
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Scheme 1. Cross-Coupling versus Homocoupling
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Dimeric molecules could be found in a wide array of natural occurring products and
pharmaceuticals.1 They have attracted increasing attentions due to unique biological functions
compared to the respective monomers. Thus, a number of efficient methodologies for stereoseletive
dimerization of two monomers have appeared, among which biomimetic Diels−Alder cycloaddition
reaction2 has demonstrated its powerful capacity. Alternatively, transition-metal-catalyzed reductive
homocoupling of organohalides is a valuable transformation, but the current advances are mainly
directed toward the Csp2−Csp2 bond construction,3 as evident for the synthesis of biaryl or 1,3-diene
motifs in the target molecules. Moreover, the harsh conditions (large excess of Na) associated with the
classic Wurtz dimeriation4 of alkyl halides largely limited its synthetic value. Hence, development of
mild catalytic Csp3−Csp3 reductive homocoupling of unactivated alkyl halides is of high importance,5
especially considering its potential application in the total synthesis of complex dimeric molecules.
Indeed such protocols have been nicely documented in Leigh’s Ni/Pybox5e and Weix’s5f
Ni/terpy-catalyzed homocoupling, and Gong’s related cross-coupling6 conditions. However, none of
these studies demonstrated its use in the synthesis of complex molecules. In line with our recent work
on the inter- and intramolecular C−C/C−S bond forming reactions (Scheme 1),7 herein, we report
analogous Ni/Ec and Ni/Bipy-catalyzed reductive homocoupling of (1º, 2º, 3º) alkyl bromides, with
emphasis on their applications in the expeditious synthesis of dimeric sesquiterpene, lignan and
pyrrolo[2,3-b]indoline alkaloids, respectively.
Results and Discussion
We first carried out the model study with 2-phenylethyl bromide as a substrate (Table 1). The
Ni(0)•2EC•Py catalyst can be easily prepared in situ from a mixture of Zn/NiCl2/ethyl crotonate
(EC)/pyridine,7 where EC acts as a π-ligand to Ni. With substoichiometric amount of this catalyst, the
desired reductive homocoupling indeed proceeded in DMF at room temperature, and the dimeric
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product 1a formed in 35% yield (entry 1) along with 40% recovery of starting material (SM). A good
result was obtained with 30 mol% Ni complex albeit at a slower reaction rate (entry 2). Considering
both the yield and reaction time (entries 3–6), CH3CN was identified as the best solvent. This Ni
catalyst can be lowered down to 15 mol%, and the triggered homocoupling reaction was completed
within 4 h with 95% isolated yield of 1a due to further suppression of competitive reduction of the
bromide (entry 7).
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Table 1. Optimization of Conditions for Reductive Homocouplinga
NiCl2
(equiv)
0.5
yieldb (%)
(2a : SM)
35 : 40
46 : 33
44 : 40
56 : 38
78 : 0
entry
Zn (equiv)
solvent
time (h)
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3
DMF
DMF
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8
0.3
0.3
3
dioxane
dioxane
MeOH
CH3CN
CH3CN
0.3
3
24
5
0.3
3
0.3
3
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78 : 0
96c : 0
0.15
1.5
4
a
(1 mmol scale) A mixture of Zn (indicated by table), NiCl2 (indicated by table), EC (3 equiv to Ni), and Pyridine (0.5 mL) were
o
employed for the generation of Ni(0)•2EC•Py at 55 C; then a solution of 2-phenylethyl bromide in CH3CN (2 mL) was added to the
above Ni(0) complex dropwise over a 10 second period at RT. b The yield was estimated by 1H NMR spectroscopic analysis with diethyl
phthalate as internal standard. c The isolated yield was 95%.
With the above optimized conditions in hand, reductive homocouplings of various functionalized
bromides were then investigated (Scheme 2). To our delight, the primary bromides bearing electrophilic
cyano group and hydroxyl protecting-groups (OTBS and OTHP) reacted smoothly, affording the
corresponding dimeric products (1b–1d) in good yields. In particular, the substrate with a free hydroxyl
group also proceeded smoothly in the present conditions, and 1,10-decanediol (1e) was isolated in 71%
yield, demonstrating the mild nature of this homocoupling reactions because its acidic proton of
hydroxyl group cannot be compatible with sodium metal imparted from Wurtz coupling conditions.
The desired dimers with differently protected amino groups such as NTs (1f) and NPhth (1g) were
obtained in high yields. Other bromide containing benzene ring was also suitable, providing
meta-methoxyphenol-derived dimer (1h) in 82% yield. Activated alkyl halides such as
para-methoxybenzyl bromide8 and α-bromo acetophenone were next tried, and the corresponding
dibenzyl 1i and 1,4-diketone 1j were produced in 75% and 78% yields, respectively. Unprecedented
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homocoupling of the neopentyl bromide such as ethylene ketal-protected (+)-9-bromo camphor could
be realized albeit its notorious steric hindrance, leading to the chiral dimer 1k in 88% yield. The
sophisticated primary bromide with a labile acetonide, which is degraded from natural diterpene
andrographolide,7a was exposed to this homocoupling condition as well, and the expected hexacycle
(–)-1l was isolated in 65% yield. All of chiral centers in the starting bromide were reserved, which
could be confirmed through X-ray crystal structure of 1l (inset, Scheme 2a: selected H atoms have been
omitted for clarity).9 This case provided an alternative access to analogs of onocerane-type triterpenes,
which were previously synthesized by Cp2TiCl-catalyzed regioselective homocoupling of activated
allylic bromides instead.10 In addition, the secondary bromides can also participate the above
homocoupling (Scheme 2b). The cyclopentyl and cyclohexyl bromide gave moderate yields of
homodimers 1m and 1n due to their volatile nature. Moreover, reductive homocoupling of
Boc-protected 4-bromopiperidine afforded the desired 4,4′-bipiperidine 1o in 62% yield, suggesting
that this common amino protecting-group (Boc) was also tolerated. The most stable conformation of 1o
was unambiguously established by its single-crystal analysis:9 the newly formed Csp3−Csp3 bond
occupies equatorial position in the respective chair conformation of two piperidine rings whereas two
tertiary hydrogen atoms adopt 1,2-anti axial orientation (inset, Scheme 2b: selected H atoms have been
omitted for clarity).
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Scheme 2. Homocouplings of Primary and Secondary Bromides
Due to our ongoing interest in the total synthesis of bioactive lignans,11 we next utilized the
above-developed methodology for the synthesis of their dimers (Scheme 3). We chose natural
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(−)-podophyllotoxin as a monomer precursor because extensive studies of pharmaceutical chemistry
towards this natural product12 and its monomer derivatives have led to the invention of several
anticancer drugs such as etoposide and etopophos. However, the development of its dimeric derivatives
is relatively rare,13 therefore hampering further investigation of their structure-activity relationship.
Aiming at providing a potential drug lead, we synthesized a new C7−C7 dimeric deoxypodophyllotoxin
3 from the easily available bromide 2 in 40% isolated yield along with 30% of (epi)podophyllotoxin
being recovered. In this Ni catalytic dimerization, the ligand EC was replaced by 2,2′-bipyridine14 that
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proved to be best. It is noteworthy that only dimer 3 ([α] 2D7 = –175) as the sole diastereomer could be
detected from the reaction mixture, indicating that excellent stereoselectivity has been achieved during
this Ni-catalyzed assembly.
Scheme 3. Stereoselective Dimerization of Podophyllotoxin-derived Bromide
On the basis of our previous mechanistic hypotheses about the reductive cross-coupling of alkyl
halides,7a a similar catalytic cycle with NiI~NiIII species15 probably occurs for the present
homocoupling. However, the involvement of radical species16 is also possible since the tandem
reactions demonstrated in Schemes 4 could be rationalized accordingly. Upon the subjection of
β-bromo acetal 4a into the Ni catalytic system generated in situ from 2,2′-bipyridine, the unprecedented
cyclization−homocoupling
cascade
indeed
works,
affording
ethylene-bridged
bisperhydrofuro[2,3-b]furan 5a as the only diastereomeric isomer in 65% yield. Its cis/syn-fused
relationship was unambiguously established by the single-crystal analysis (inset, Scheme 4: selected H
atoms have been omitted for clarity).9 Notably, three C−C bonds and four stereogenic centers were
simultaneously formed in such a single operation. A similar stereoselective tandem reaction also
occurred with β-bromo ketal 4b, and the unique bisspiroketal 5b was obtained in 70% yield under the
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same condition.
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Scheme 4. Stereoselective Cyclization−Homocoupling Cascade
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Recently, Fu and co-worker reported the first Nickel-catalyzed Suzuki arylations of tertiary alkyl
halides;17 however, the reductive homocouplings of this kind of challenging substrates with the aid of
Ni catalyst have not been found yet, to the best of our knowledge. Thus, we expanded the substrate
scope of the above homocoupling reactions to tertiary bromide 6 (Scheme 5) in order to realize the total
synthesis of Chimonanthine (9) and Folicanthine (10).18,19 These two natural products were isolated
from dendrobatid frog and various plants,20 and they are the simplest and typical members in
C3a−C3a′-bispyrrolo[2,3-b]indoline alkaloids family.21 Their challenging structure and biological
activities have attracted significant attention from the synthetic community, and especially they can be
served as a versatile platform for the development of novel synthetic methods such as the relevant
CoI-mediated dimerization by Movassaghi.19d As shown in Scheme 5, our strategy is Ni-catalyzed
reductive homocoupling of tertiary bromide (±)-6 for the establishment of two vicinal quaternary
carbons (C3a and C3a′) with steric congestion. To this end, treatment of tryptamine with ethyl
chloroformate
followed
by
Na-protection
with
di-tert-butyl
dicarbonate
provided
Na-Boc-Nb-ethoxycarbonyltryptamine in 80% yield over two steps. Following the protocol by de Lera
and co-workers,22 the desired racemic precursor 6 can be prepared in 92% yield and sufficient amount,
which set the stage for key reductive homocoupling. Subjection of this tricyclic bromide into the
optimized Ni catalytic system, the C2 symmetric bispyrrolo[2,3-b]indoline 7 with the connection of
vicinal quaternary stereocenters was obtained in 21% yield. Meso-isomer 7′ resulting from the
dimerization of 6 and ent-6, was also isolated in 22% yield. Its structure was unambiguously assigned
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by the single-crystal analysis (inset, Scheme 5: selected H atoms have been omitted for clarity).9
Starting from 7, successive steps to the ultimate targets (9 and 10) were straightforward. Cleavage of
two Boc protecting-groups in 7 by iodotrimethylsilane gave rise to bisester 8 in 87% yield. Reduction
of Nb-ethoxycarbonyl groups in 8 with bis(2-methoxyethoxy)aluminum hydride (Red-Al) afforded
( )-Chimonanthine (9) in 82% yield. Eventually, Na-methylation of 9 completed the synthesis of
(±)-Folicanthine (10) in 87% yield. Spectroscopic data of synthetic samples are consistent with those
published in the previous syntheses.18a,18c,19a−d
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Scheme 5. Total Synthesis of (±)-Chimonanthine and (±)-Folicanthine
Reagents and conditions: (a) ClCO2Et (1.0 equiv), CHCl3/aq. NaOH, 0 ºC, 10 min then rt, 1.5 h, 91%; (b) nBu4NHSO4 (0.1 equiv), NaOH
(5.0 equiv), CH2Cl2, rt, 30 min; then (Boc)2O (1.1 equiv), 0 ºC to rt, 2 h, 88%; (c) NBS (1.0 equiv), PPTs (1.0 equiv), CH2Cl2, rt, 10 min,
92%; (d) Zn (1.5 equiv), NiCl2 (15 mol%), 2,2′-bipyridine (45 mol%), and pyridine/CH3CN, 25 ºC, 30 min, 43%; (e) TMSI (3.0 equiv),
CH3CN, 0 ºC to rt, 4 h, 87%; (f) Red-Al (10.0 equiv), toluene, rt to 90 ºC, 1.5 h, 82%; (g) aq. HCHO (10.0 equiv), NaBH(OAc)3 (10.0
equiv), rt, CH3CN, 1.5 h, 87%.
Conclusion
In summary, we have developed a versatile method for Csp3−Csp3 bond construction based on
reductive homocoupling reactions of various alkyl halides catalyzed by the Ni complex generated in
situ from air-stable and cheap materials. Exceptionally mild conditions and broad functional groups
tolerance make this method especially valuable to access structurally complex dimeric natural
product-like molecules such as 1l and 3. Moreover, the successful synthesis of racemic Chimonanthine
(9) and Folicanthine (10) using this protocol as a key step, further demonstrates its remarkable power
for the establishment of sterically hindered vicinal all-carbon quaternary stereocenters. We believe that
this method holds great promise in the expeditious synthesis of many other dimeric natural products
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and pharmaceutical molecules.
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Experimental Section
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General. For product purification by flash column chromatography, silica gel (200~300 mesh) and
petroleum ether (bp. 60~90 °C) are used. All solvents were purified and dried by standard techniques,
and distilled prior to use. All organic extracts were dried over Na2SO4 or MgSO4, unless otherwise
noted. All experiments were conducted under an argon or nitrogen atmosphere in oven-dried or
flame-dried glassware with magnetic stirring, unless otherwise specified. NMR spectra were measured
on 300, 400 and 600 MHz instruments at room temperature. High-resolution mass spectra data were
measured with electrospray ionization mode (ESI). Infrared spectra were recorded on FT-IR
spectrophotometer. The following chemicals were purchased and used as received: Zn (99.9%, powder),
NiCl2 (99%), Pyridine (99.5%, SuperDry, with molecular sieves), DMF (99.8%, SuperDry, with
molecular sieves), CH3CN (99.9%, SuperDry, with molecular sieves).
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Typical procedure for homocoupling reaction catalyzed by Ni(0)•2EC•Py complex.
(General Procedure)
To a stirred slurry of Zn (195 mg, 1.5 mmol) in pyridine (0.5 mL) was added ethyl crotonate (0.06
mL, 0.45 mmol) at room temperature. Under stirring vigorously, NiCl2 (19 mg, 0.15 mmol) was added
to the above mixture. Then the temperature rose to 55 °C and stirring was continued for 15 min. The
resulting red–brown Ni(0)•2EC•Py complex was cooled to room temperature, to which the solution of
alkyl bromide (1.0 mmol) in CH3CN (2 mL) was added dropwise over a 10 second period. After 4 h,
the mixture was filtered with a short plug (elution with 30 mL Et2O) and washed with water and brine,
dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography
on silica gel to afford desired dimeric products.
1a5f was prepared as a colorless solid (95% yield) according to General Procedure. Rf = 0.20
(petroleum ether); Mp. 54–55 °C; IR (film): νmax = 3057, 2931, 2854, 1600, 1493, 1459, 1341, 1063,
1028, 907, 750, 700 cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.27 (t, J = 8.0 Hz, 4H), 7.20−7.16 (m, 2H),
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7.17 (d, J = 8.0 Hz, 4H), 2.63 (t, J = 6.8 Hz, 4H), 1.67 (quint, J = 4.0 Hz, 4H) ppm; 13C NMR (100
MHz, CDCl3): δ = 142.5 (2C), 128.4 (4C), 128.2 (4C), 125.6 (2C), 35.8 (2C), 31.1 (2C) ppm; EI−MS
(70 eV): m/z 210 [M]+.
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1b23 was prepared as a colorless oil (92% yield) according to General Procedure. Rf = 0.40
(petroleum ether/EtOAc = 4 : 1); IR (film): νmax = 2930, 2857, 2245, 1607, 1464, 1426, 1354, 1328,
1242, 1217, 1135, 1071, 845, 724 cm–1; 1H NMR (400 MHz, CDCl3): δ = 2.34 (t, J = 7.2 Hz, 4H), 1.66
(quint, J = 7.2 Hz, 4H), 1.45 (quint, J = 7.2 Hz, 4H), 1.31 (brs, 8H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 119.8 (2C), 29.1 (2C), 28.63 (2C), 28.56 (2C), 25.3 (2C), 17.1 (2C) ppm; ESI−MS: m/z 193.3
[M+H]+.
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1c24 was prepared as a colorless oil (73% yield) according to General Procedure. Rf = 0.20
(petroleum ether/EtOAc = 4 : 1); IR (film): νmax = 2930, 2899, 2857, 1467, 1387, 1361, 1253, 1101,
1
1006, 837, 775, 661 cm–1; H NMR (400 MHz, CDCl3): δ = 3.60 (t, J = 6.8 Hz, 4H), 1.51 (quint, J =
6.8 Hz, 4H), 1.28 (brs, 12H), 0.90 (s, 18H), 0.05 (s, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ = 63.3
(2C), 32.9 (2C), 29.6 (2C), 29.4 (2C), 26.0 (6C), 25.8 (2C), 18.4 (2C), −5.3 (4C) ppm; ESI−MS: m/z:
403.4 [M+H]+.
1d25 was prepared as a colorless oil (70% yield) according to General Procedure. Rf = 0.22
(petroleum ether/EtOAc = 4 : 1); IR (film): νmax = 2931, 2856, 1457, 1351, 1261, 1200, 1124, 1075,
1031, 986, 906, 870, 814 cm–1; 1H NMR (400 MHz, CDCl3): δ = 4.57 (t, J = 4.4 Hz, 2H), 3.91−3.85 (m,
2H), 3.73 (dt, J = 6.8, 9.2 Hz, 2H), 3.49 (dd, J = 4.8, 10.4 Hz, 2H), 3.38 (dt, J = 6.8, 9.6 Hz, 2H),
1.87−1.79 (m, 2H), 1.76−1.68 (m, 2H), 1.62−1.51 (m, 12H), 1.40−1.25 (m, 12H) ppm; 13C NMR (100
MHz, CDCl3): δ = 98.8 (2C), 67.7 (2C), 62.3 (2C), 30.7 (2C), 29.7 (2C), 29.5 (2C), 29.4 (2C), 26.2
(2C), 25.5 (2C), 19.7 (2C) ppm; ESI−MS: m/z 360.4 [M+NH4]+.
1e26 was prepared as a colorless solid (71% yield) according to General Procedure. Rf = 0.23
(petroleum ether/EtOAc = 4 : 1); Mp. 63–65 °C; IR (film): νmax = 3405, 3338, 2924, 2849, 1460, 1361,
1057, 1018, 969, 727, 616 cm–1; 1H NMR (400 MHz, CDCl3): δ = 3.64 (t, J = 6.8 Hz, 4H), 1.56 (quint,
J = 6.8 Hz, 4H), 1.47 (s, 2H, −OH), 1.37−1.27 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ = 63.0
(2C), 32.7 (2C), 29.5 (2C), 29.4 (2C), 25.7 (2C) ppm; ESI−MS: m/z 175.3 [M+H]+.
1f27 was prepared as a colorless solid (83% yield) according to General Procedure. Rf = 0.20
(petroleum ether/EtOAc = 4 : 1); Mp. 156–157 °C; IR (film): νmax = 3059, 2930, 2859, 1596, 1491,
1454, 1347, 1214, 1158, 1075, 908, 816, 771, 698, 657, 576, 549 cm–1; 1H NMR (400 MHz, CDCl3): δ
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= 7.44 (d, J = 8.4 Hz, 4H), 7.30−7.26 (m, 6H), 7.22 (d, J = 8.0 Hz, 4H), 7.02−6.98 (m, 4H), 3.47 (t, J =
6.8 Hz, 4H), 2.40 (s, 6H), 1.33 (t, J = 5.6 Hz, 4H), 1.26 (d, J = 6.0 Hz, 4H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 143.2 (2C), 138.9 (2C), 135.0 (2C), 129.2 (4C), 128.8 (4C), 128.6 (4C), 127.7 (2C), 127.5
(4C), 50.1 (2C), 27.8 (2C), 25.7 (2C), 21.4 (2C) ppm; ESI−MS: m/z 577.3 [M+H]+.
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1g28 was prepared as a colorless solid (83% yield) according to General Procedure. Rf = 0.20
(petroleum ether/EtOAc = 4 : 1); Mp. 180–181 °C; IR (film): νmax = 2929, 2858, 1765, 1610, 1466,
1436, 1398, 1371, 1063, 970, 717, 625, 529 cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.83 (dd, J = 3.2,
5.6 Hz, 4H), 7.70 (dd, J = 3.2, 5.6 Hz, 4H), 3.67 (t, J = 7.2 Hz, 4H), 1.67 (quint, J = 6.8 Hz, 4H), 1.39
(quint, J = 3.6 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 168.3 (4C), 133.7 (4C), 132.0 (4C),
123.0 (4C), 37.8 (2C), 28.3 (2C), 26.3 (2C) ppm; ESI−MS: m/z 377.3 [M+H]+.
1h was prepared as a colorless solid (82% yield) according to General Procedure. Rf = 0.25
(petroleum ether/EtOAc = 2 : 1); Mp. 142–143 °C; IR (film): νmax = 2939, 2866, 2837, 1598, 1494,
1454, 1394, 1337, 1288, 1262, 1201, 1154, 1089, 1047, 1025, 922, 839, 813, 762, 687 cm–1; 1H NMR
(400 MHz, CDCl3): δ = 7.17 (t, J = 8.0 Hz, 2H), 6.50 (d, J = 8.0 Hz, 2H), 6.49 (d, J = 8.4 Hz, 2H), 6.47
(d, J = 2.0 Hz, 2H), 3.95 (t, J = 6.4 Hz, 4H), 3.79 (s, 6H), 1.81 (quint, J = 6.4 Hz, 4H), 1.53 (quint, J =
3.6 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 160.8 (2C), 160.4 (2C), 129.8 (2C), 106.7 (2C),
106.2 (2C), 101.0 (2C), 67.8 (2C), 55.2 (2C), 29.2 (2C), 25.9 (2C) ppm; ESI−MS: m/z 331.3 [M+H]+;
+
HRMS (ESI): calcd. for C20H27O4 [M+H]+: 331.1904, found: 331.1905.
1i29 was prepared as a colorless solid (75% yield) according to General Procedure. Rf = 0.30
(petroleum ether/EtOAc = 2 : 1); Mp. 126–127 °C; IR (film): νmax = 2916, 2850, 1606, 1580, 1508,
1
1457, 1298, 1243, 1175, 1028, 828, 540 cm–1; H NMR (400 MHz, CDCl3): δ = 7.13 (d, J = 8.8 Hz,
4H), 6.87 (d, J = 8.8 Hz, 4H), 3.83 (s, 6H), 2.88 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 157.7
(2C), 133.9 (2C), 129.3 (4C), 113.6 (4C), 55.2 (2C), 37.2 (2C) ppm; EI−MS (70 eV): m/z 242 [M]+.
1j30 was prepared as a colorless solid (78% yield) according to General Procedure. Rf = 0.30
(petroleum ether/EtOAc = 2 : 1); Mp. 142–143 °C; IR (film): νmax = 2906, 1679, 1592, 1444, 1397,
1373, 1354, 1257, 1223, 1179, 1066, 991, 774, 737, 693 cm–1; 1H NMR (400 MHz, CDCl3): δ = 8.05 (d,
J = 7.2 Hz, 4H), 7.61−7.56 (m, 2H), 7.49 (t, J = 7.2 Hz, 4H), 3.48 (s, 4H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 198.7 (2C), 136.7 (2C), 133.2 (2C), 128.6 (4C), 128.1 (4C), 32.6 (2C) ppm; ESI−MS: m/z
239.2 [M+H]+.
1k was prepared as a colorless solid (88% yield) according to General Procedure. Rf = 0.55
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(petroleum ether/EtOAc = 10 : 1); [α] 2D4 = +42 (c = 0.5, CHCl3); Mp. 215–216 °C; IR (film): νmax
=
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2965, 2875, 1607, 1509, 1476, 1452, 1381, 1304, 1262, 1245, 1182, 1114, 1044, 966, 895, 841, 740,
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cm–1; H NMR (400 MHz, CDCl3): δ = 3.97−3.91 (m, 2H), 3.89−3.79 (m, 4H), 3.77−3.71 (m, 2H),
2.00−1.91 (m, 4H), 1.84 (t, J = 4.4 Hz, 2H), 1.65−1.56 (m, 2H), 1.46 (dd, J = 4.0, 12.0 Hz, 2H), 1.40 (d,
J = 13.2 Hz, 2H), 1.31−1.18 (m, 2H), 1.25 (d, J = 12.0 Hz, 2H), 1.07 (d, J = 12.0 Hz, 2H), 1.01 (s, 6H),
0.81 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ = 117.5 (2C), 65.0 (2C), 63.6 (2C), 53.3 (2C), 50.9
(2C), 44.5 (2C), 41.9 (2C), 29.6 (2C), 27.0 (2C), 26.8 (2C), 16.7 (2C), 9.9 (2C) ppm; ESI−MS: m/z
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391.3 [M+H]+; HRMS (ESI): calcd. for C24H39O4 [M+H]+: 391.2842, found: 391.2842.
+
1l was prepared as a colorless solid (65% yield) according to General Procedure. Rf = 0.30
(petroleum ether/EtOAc = 3 : 1); [α] 2D4 = –38 (c = 0.5, CHCl3); Mp. 126–127 °C; IR (film): νmax
=
3088, 29876, 2937, 2870, 2852, 1642, 1513, 1464, 1377, 1225, 1149, 1094, 1070, 1028, 998, 886, 864,
cm–1; 1H NMR (400 MHz, CDCl3): δ = 4.84 (s, 2H), 4.53 (s, 2H), 3.98 (d, J = 11.6 Hz, 2H), 3.48 (dd, J
= 3.6, 8.8 Hz, 2H), 3.16 (d, J = 11.6 Hz, 2H), 2.39 (dd, J = 3.6, 10.8 Hz, 2H), 2.03−1.91 (m, 4H) ,
1.80−1.68 (m, 6H), 1.59−1.51 (m, 2H), 1.42 (s, 6H), 1.38 (brs, 6H), 1.36 (s, 6H), 1.29−1.23 (m, 6H),
1.20 (s, 6H), 1.10 (brs, 2H), 0.87 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ = 148.2 (2C), 107.1
(2C), 99.0 (2C), 63.9 (2C), 56.6 (2C), 52.5 (2C), 38.5 (2C), 38.2 (2C), 37.9 (2C), 34.5 (2C), 29.4 (2C),
27.4 (2C), 26.1 (2C), 25.3 (4C), 25.2 (2C), 24.2 (2C), 23.5 (2C), 16.2 (2C) ppm; HRMS (ESI): calcd.
for C38H62O4Na+ [M+Na]+: 605.4540, found: 605.4542. This dimeric product was dissolved in
Hexane/EtOAc (5 : 1). After two days, colorless single crystals were obtained by slow evaporation of
solvent at room temperature.
1m5f was prepared as a colorless oil (48% yield) according to General Procedure. Rf = 0.80
(petroleum ether); IR (film): νmax = 2949, 2865, 1450, 1362, 1327, 1247, 927, 894 cm–1; 1H NMR (400
MHz, CDCl3): δ = 1.76−1.69 (m, 4H), 1.63−1.55 (m, 6H), 1.54−1.46 (m, 4H), 1.18−1.07 (m, 4H) ppm;
13C NMR (100 MHz, CDCl3): δ = 46.4 (2C), 31.8 (4C), 25.4 (4C) ppm; EI−MS (70 eV): m/z 138 [M]+
1n5e,31 was prepared as a colorless oil (45% yield) according to General Procedure. Rf = 0.80
(petroleum ether); IR (film): νmax = 2923, 2851, 2667, 1448, 1350, 1263, 996, 889, 847 cm–1; 1H NMR
(400 MHz, CDCl3): δ = 1.75−1.61 (m, 10H), 1.26−1.13 (m, 6H), 1.12−0.90 (m, 6H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 43.5 (2C), 30.2 (4C), 26.9 (6C) ppm; EI−MS (70 eV): m/z 166 [M]+.
1o was prepared as a colorless solid (62% yield) according to General Procedure. Rf = 0.40
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(petroleum ether/EtOAc = 4 : 1); Mp. 151–152 °C; IR (film): νmax = 2975, 2931, 2855, 1694, 1513,
1421, 1365, 1274, 1239, 1168, 1023, 867, 769 cm–1; 1H NMR (400 MHz, CDCl3): δ = 4.12 (d, J = 12.8
Hz, 4H), 2.63 (t, J = 12.0 Hz, 4H), 1.65 (d, J = 12.0 Hz, 4H), 1.45 (s, 18H), 1.30−1.10 (m, 6H) ppm;
13C NMR (100 MHz, CDCl3): δ = 154.8 (2C), 79.2 (2C), 44.2 (br, 2C), 41.0 (4C), 29.2 (4C), 28.5 (6C)
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ppm; HRMS (ESI): calcd. for C20H37N2O4 [M+H]+: 369.2748, found: 369.2744. This dimeric product
+
was dissolved in Hexane/EtOAc (1 : 1). After one day, colorless single crystals were obtained by slow
evaporation of solvent at room temperature.
Stereoselective dimerization of Podophyllotoxin-derived bromide 2
To a stirred slurry of Zn (100 mg, 1.5 mmol) and NiCl2 (20 mg, 0.15 mmol) in pyridine (0.5 mL) was
added 2,2′-bipyridine (70 mg, 0.45 mmol) at room temperature. Then the temperature rose to 55 °C and
vigorous stirring was continued for 10 min. The resulting black Ni(0) complex was cooled to room
temperature, to which the solution of bromide 232 (477 mg, 1 mmol) in CH3CN (2 mL) was added
dropwise. After stirring for 2 h, the mixture was filtered with a short plug of silica (elution with 80 mL
Et2O), and the combined organic phase was washed with water (2 × 10 mL) and brine (10 mL), dried
over Na2SO4, filtered and concentrated. The crude product was carefully purified by flash column
chromatography (petroleum ether/EtOAc
=
4
:
1) on silica gel to afford desired
bis-deoxypodophyllotoxin 3 (160 mg, 40%) as a colorless solid. Rf = 0.20 (petroleum ether/EtOAc = 4 :
1
1); [α] 2D7 = –175 (c = 0.04, CHCl3); Mp. 256−258 °C; H NMR (400 MHz, CDCl3): δ = 6.43 (s, 2H),
6.29 (s, 4H), 5.83 (s, 2H), 5.71 (s, 2H), 5.69 (s, 2H), 4.75 (d, J = 4.0 Hz, 2H), 4.39 (t, J = 7.2 Hz, 2H),
4.07 (t, J = 9.6 Hz, 2H), 3.81 (s, 6H), 3.75 (s, 12H), 3.51 (s, 2H), 3.26 (d, J = 3.2 Hz, 4H) ppm; 13C
NMR (100 MHz, CDCl3): δ = 174.0 (2C), 152.5 (4C), 146.8 (2C), 146.3 (2C), 137.2 (2C), 135.7 (2C),
131.1 (2C), 129.7 (2C), 109.8 (2C), 108.9 (2C), 108.4 (4C), 101.0 (2C), 68.0 (2C), 60.7 (2C), 56.2 (4C),
43.8 (2C), 42.4 (2C), 40.3 (2C), 36.4 (2C) ppm; ESI−MS: m/z 795.2 [M+H]+; HRMS (ESI): calcd. for
C44H43O14+ [M+H]+: 795.2647, found: 795.2653.
Stereoselective cyclization−homocoupling cascade
To a stirred slurry of Zn (100 mg, 1.5 mmol) and NiCl2 (20 mg, 0.15 mmol) in pyridine (0.5 mL) was
added 2,2′-bipyridine (70 mg, 0.45 mmol) at room temperature. Then the temperature rose to 55 °C and
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vigorous stirring was continued for 15 min. The resulting black Ni(0) complex was cooled to room
temperature, to which the solution of bromide 4a7a (208 mg, 1.0 mmol) in CH3CN (2 mL) was added
dropwise (ca. 10s). After stirring for 25 min, the mixture was filtered with a short plug of silica (elution
with 60 mL Et2O), and the combined organic phase was washed with water (10 mL) and brine (10 mL),
dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column
chromatography (petroleum ether/EtOAc = 4 : 1) on silica gel to afford desired 5a (83 mg, 65%) as a
colorless solid. Rf = 0.20 (petroleum ether/EtOAc = 1 : 1); Mp. 94−96 °C; IR (film): νmax = 2942, 2867,
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1489, 1453, 1371, 1257, 1206, 1109, 1082, 1018, 954, 923, 829, 733 cm–1; H NMR (400 MHz,
CDCl3): δ = 5.73 (d, J = 5.2 Hz, 2H), 3.95 (q, J = 7.2 Hz, 2H), 3.88 (t, J = 7.2 Hz, 4H), 3.43 (t, J = 10.0
Hz, 2H), 2.81 (quint, J = 6.8 Hz, 2H), 2.36−2.26 (m, 2H), 1.85 (ddd, J = 2.4, 6.8, 9.2 Hz, 4H),
1.52−1.34 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 109.60, 109.58, 72.24, 72.21, 68.93, 68.89,
45.20, 45.13, 42.30, 42.19, 26.48, 26.37, 24.75, 24.67 ppm; ESI−MS: m/z 255.2 [M+H]+; HRMS (ESI):
+
calcd. for C14H23O4 [M+H]+: 255.1591, found: 255.1594. This dimeric product was dissolved in
Hexane/EtOAc (5 : 1). After two days, colorless single crystals were obtained by slow evaporation of
solvent at room temperature.
5b was prepared as a colorless oil (70% yield) starting from 4b according to the above procedure for
5a. Rf = 0.50 (petroleum ether/EtOAc = 1 : 1); IR (film): νmax = 2971, 2935, 2878, 1456, 1440, 1343,
1283, 1174, 1153, 1114, 1019, 949, 921, 830 cm–1; 1H NMR (400 MHz, C6D6): δ = 3.94−3.85 (m, 4H),
3.74 (q, J = 7.6 Hz, 2H), 3.55 (dt, J = 6.0, 8.0 Hz, 2H), 2.01 (dd, J = 3.6, 8.4 Hz, 2H), 1.98 (dd, J = 3.2,
8.4 Hz, 2H), 1.95−1.84 (m, 4H), 1.77 (quint, J = 5.6 Hz, 2H), 1.67−1.61 (m, 1H), 1.62 (dd, J = 7.6, 11.6
Hz, 1H), 1.59−1.50 (m, 2H), 1.35−1.15 (m, 4H) ppm; 13C NMR (100 MHz, C6D6): δ = 114.8 (2C), 72.4
(2C), 66.9 (2C), 41.4, 41.3, 39.3 (2C), 35.8 (2C), 32.8 (2C), 24.7 (2C) ppm; ESI−MS: m/z: 283.3
+
[M+H]+; HRMS (ESI): calcd. for C16H27O4 [M+H]+: 283.1904, found: 283.1902.
Total synthesis of (±)-chimonanthine and (±)-folicanthine
To a stirred solution of tryptamine (3.2 g, 20 mmol) in CHCl3 (60 mL) was added the solution of
NaOH (0.8 g, 20 mmol, 1.0 equiv) in H2O (5 mL) dropwise at 0 °C. The resulting mixture was treated
ClCO2Et (1.9 mL, 20 mmol, 1.0 equiv) dropwise at 0 °C then allowed to warm to room temperature
after 10 min. The stirring was continued for 1.5 h, and the mixture was diluted with CH2Cl2 (100 mL)
and poured into a separatory funnel that contained H2O (10 mL). The combined organic layers were
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washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash column chromatography (petroleum
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=
2
:
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Nb-ethoxycarbonyltryptamine33 (4.23 g, 91%) as a brown oil. Rf = 0.32 (petroleum ether/EtOAc = 1 : 1);
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IR (film): νmax = 3409, 3327, 3057, 2980, 2932, 1697, 1620, 1523, 1457, 1338, 1259, 1141, 1094, 1037,
1
955, 778, 743 cm–1; H NMR (400 MHz, CDCl3): δ = 8.28 (brs, 1H, −NH), 7.59 (d, J = 8.0 Hz, 1H),
7.34 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.97 (s, 1H), 4.79 (brs, 1H,
−NH), 4.12 (q, J = 6.8 Hz, 2H), 3.50 (q, J = 6.4 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H), 1.21 (t, J = 6.8 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 156.8, 136.4, 127.2, 122.1, 122.0, 119.3, 118.6, 112.7,
111.2, 60.7, 41.1, 25.7, 14.6 ppm; ESI−MS: m/z 233.2 [M+H]+. To a stirred solution of the above
Nb-ethoxycarbonyltryptamine (3.7 g, 16 mmol) in CH2Cl2 (50 mL) was added NaOH (3.2 g, 80 mmol,
5.0 equiv) and (n-Bu)4NHSO4 (544 mg, 1.6 mmol, 0.1 equiv) portionwise at room temperarure. The
reaction system was cooled down to 0 °C followed by the addition of (Boc)2O (3.84 g, 17.6 mmol, 1.1
equiv) portionwise. Then the resulting mixture was allowed to warm to room temperature and stirred
for 2 h. Eventually the reaction mixture was diluted with CH2Cl2 (90 mL) and poured into a separatory
funnel that contained H2O (10 mL). The combined organic layers were washed with water (3 × 20 mL)
and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (petroleum ether/EtOAc = 2 : 1) on silica gel
(basified with Et3N) to afford the desired Na-Boc-Nb-ethoxycarbonyltryptamine (4.67 g, 88%) as a
brown oil. Rf = 0.41 (petroleum ether/EtOAc = 1 : 1); IR (film): νmax = 3341, 2980, 2934, 1730, 1610,
1527, 1477, 1454, 1382, 1331, 1309, 1255, 1226, 1160, 1092, 1060, 1035, 912, 857, 768, 747 cm–1; 1H
NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.32 (t, J
= 8.0 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 4.89 (brs, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.50 (q, J = 6.8 Hz, 2H),
2.90 (t, J = 6.8 Hz, 2H), 1.66 (s, 9H), 1.23 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ =
156.6, 149.6, 135.5, 130.3, 124.4, 123.1, 122.4, 118.8, 117.5, 115.2, 83.5, 60.6, 40.4, 28.1 (3C), 25.5,
14.6 ppm; ESI−MS: m/z 665.2 [2M+H]+; HRMS (ESI): calcd. for C36H48N4O8Na+ [2M+Na]+:
687.3364, found: 687.3353.
To a stirred solution of the above Na-Boc-Nb-ethoxycarbonyltryptamine (3.19 g, 9.6 mmol) in
CH2Cl2 (25 mL) was added NBS (1.71 g, 9.6 mmol, 1.0 equiv) and PPTs (2.41 g, 9.6 mmol, 1.0 equiv)
portionwise at room temperarure. After 10 min, the resulting mixture was diluted with CH2Cl2 (80 mL)
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and poured into a separatory funnel that contained H2O (10 mL). The combined organic layers were
washed with saturated aqueous NaHCO3 (3 × 20 mL) and brine (3 × 15 mL), dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash column
chromatography (petroleum ether/EtOAc = 2 : 1) on silica gel (basified with Et3N) to afford the desired
tertiary benzylic bromide (±)-6 (3.63 g, 92%) as a brown oil. Rf = 0.65 (petroleum ether/EtOAc = 2 : 1);
IR (film): νmax = 2980, 2933, 2894, 1713, 1604, 1538, 1479, 1414, 1383, 1369, 1331, 1289, 1273, 1256,
1231, 1200, 1154, 1113, 1098, 1077, 1017, 904, 754, 732 cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.61
(d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.41 (s,
1H), 4.19 (q, J = 7.2 Hz, 2H), 3.77 (dd, J = 7.6, 10.4 Hz, 1H), 2.91−2.81 (m, 2H), 2.77 (dd, J = 7.6,
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12.0 Hz, 1H), 1.59 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl3): δ = 154.1,
151.9, 141.9, 132.4, 130.3, 124.0, 123.6, 117.3, 83.8, 81.9, 61.9, 61.5, 46.0, 40.8 (br), 28.1 (3C), 14.5
ppm; ESI−MS: m/z 411.1 [M+H]+; HRMS (ESI): calcd. for C18H2379BrN2O4Na+ [M+Na]+: 433.0733,
found: 433.0734.
To a stirred slurry of Zn (197 mg, 3 mmol, 1.5 equiv) and NiCl2 (40 mg, 0.3 mmol, 0.15 equiv) in
pyridine (1.5 mL) was added 2,2′-bipyridine (141 mg, 0.9 mmol, 0.45 equiv) at room temperature.
Then the temperature rose to 55 °C and vigorous stirring was continued for 10 min. The resulting black
Ni(0) complex was cooled to room temperature, to which the solution of bromide 6 (822 mg, 2 mmol)
in CH3CN (10 mL) was added dropwise. After stirring for 30 min, the mixture was filtered with a short
plug of silica (elution with 25 mL EtOAc), and the combined organic phase was washed with water (3
× 10 mL) and brine (3 × 10 mL), dried over Na2SO4, filtered and concentrated. The crude product was
carefully purified by flash column chromatography (petroleum ether/EtOAc = 6 : 1→petroleum
ether/acetone = 8 : 1) on silica gel (basified with Et3N) to afford 148 mg (22%) of meso-dimer 7′ as a
pale yellow solid and 141 mg (21%) of dl-dimer 7 as a pale yellow oil. (7): Rf = 0.36 (petroleum
ether/acetone = 4 : 1); IR (film): νmax = 3049, 2979, 2933, 2889, 1711, 1600, 1539, 1481, 1463, 1411,
1384, 1318, 1278, 1254, 1236, 1203, 1161, 1103, 1019, 902, 857, 753, 737 cm–1; 1H NMR (400 MHz,
CDCl3): δ = 7.37 (brs, 2H), 7.09 (d, J = 7.6 Hz, 2H), 7.06 (t, J = 7.6 Hz, 2H), 6.84 (t, J = 7.6 Hz, 2H),
6.42 (brs, 2H), 4.19 (q, J = 6.8 Hz, 4H), 3.81 (dd, J = 8.0, 11.2 Hz, 2H), 2.80 (td, J = 5.6, 11.2 Hz, 2H),
2.24 (td, J = 8.0, 11.6 Hz, 2H), 2.14 (dd, J = 5.2, 12.0 Hz, 2H), 1.60 (s, 18H), 1.30 (t, J = 7.2 Hz, 6H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 154.4 (2C), 152.0 (2C), 142.8 (2C), 131.4 (2C), 128.9 (2C),
123.4 (br, 2C), 122.9 (2C), 116.5 (br, 2C), 81.7 (2C), 78.7 (2C), 61.5 (2C), 60.5 (2C), 45.1 (2C), 33.0
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(br, 2C), 28.4 (6C), 14.7 (2C) ppm; ESI−MS: m/z 685.5 [M+Na]+; HRMS (ESI): calcd. for
C36H46N4O8Na+ [M+Na]+: 685.3208, found: 685.3191. meso-Dimer 7′ was dissolved in Hexane/EtOAc
(1 : 1). After a day, colorless single crystals were obtained by slow evaporation of solvent at room
1
temperature. (7′): Rf = 0.38 (petroleum ether/acetone = 4 : 1); Mp. 198−199 °C; H NMR (600 MHz,
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CDCl3, 50 °C): δ = 7.58 (brs, 2H), 7.23 (t, J = 7.8 Hz, 2H), 6.96 (brs, 2H), 6.84 (brs, 2H), 6.21 (brs,
2H), 4.14 (d, J = 7.2 Hz, 4H), 3.71 (brs, 2H), 2.82 (td, J = 5.4, 11.4 Hz, 2H), 2.11 (dd, J = 5.4, 12.0 Hz,
2H), 1.93 (brs, 2H), 1.52 (s, 18H), 1.25 (t, J = 7.2 Hz, 6H) ppm; 13C NMR (150 MHz, CDCl3, 50 °C): δ
= 154.4 (2C), 151.8 (2C), 143.8 (2C), 131.7 (2C), 129.34 (2C), 129.25 (2C), 123.5 (2C), 117.5 (br, 2C),
81.6 (2C), 78.0 (2C), 61.3 (2C), 60.1 (2C), 45.6 (2C), 33.0 (br, 2C), 28.3 (6C), 14.7 (2C) ppm; HRMS
(ESI): calcd. for C36H46N4O8Na+ [M+Na]+: 685.3208, found: 685.3196.
To a stirred solution of 7 (20 mg, 0.03 mmol) in CH3CN (3 mL) was added TMSI (10 ꢀL, 0.09 mmol,
3.0 equiv) at 0 °C over a 10 second period. The resulting mixture was allowed to warm to room
temperature, and stirred for 4 h then diluted with CH2Cl2 (50 mL) and poured into a separatory funnel
that contained H2O (5 mL). The combined organic layers were washed with saturated aqueous Na2S2O3
(20 mL), water (3 × 10 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash column chromatography
(CH2Cl2/MeOH/Et3N = 49 : 1 : 1) on silica gel to afford the desired 8 (12 mg, 87%) as a colorless oil.
Rf = 0.15 (petroleum ether/EtOAc/MeOH = 8 : 1 : 1); IR (film): νmax = 3354, 2977, 2928, 2880, 1691,
1
1606, 1482, 1467, 1420, 1381, 1348, 1320, 1239, 1202, 1173, 1112, 1065, 896, 745 cm–1; H NMR
(300 MHz, CDCl3): δ = (rotamers) 7.18 (d, J = 7.5 Hz, 2H), 7.11 (d, J = 7.5 Hz, 2H), 6.78 (t, J = 6.9 Hz,
2H), 6.64 (t, J = 7.5 Hz, 2H), 5.23 (s, 0.5H), 5.18 (s, 0.5H), 5.14 (s, 1H), 5.01 (s, 0.5H), 4.97 (s, 0.5H),
4.88 (s, 0.5H), 4.73 (s, 0.5H), 4.23−4.00 (m, 4H), 3.71−3.62 (m, 1H), 3.56 (dd, J = 8.1, 10.2 Hz, 1H),
2.95−2.83 (m, 2H), 2.66−2.52 (m, 2H), 2.15−1.97 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ = (rotamers) 154.8, 150.64, 150.57, 129.2, 129.1, 125.4,
125.2, 118.9, 118.7, 118.5, 118.4, 109.9, 109.8, 79.2, 78.4, 61.3, 61.1, 60.9, 60.8, 45.4, 45.2, 31.6, 31.5,
+
14.8, 14.6 ppm; ESI−MS: m/z 463.2 [M+H]+; HRMS (ESI): calcd. for C26H31N4O4 [M+H]+: 463.2340,
found: 463.2340.
To a stirred solution of 8 (45 mg, 0.097 mmol) in toluene (8 mL) was added Red-Al (0.3 mL, 70% in
toluene, 1.0 mmol, 10.0 equiv) dropwise at room temperature. The resulting mixture was heated up to
90 °C and stirred for 1.5 h. Then the reaction system was cooled down to room temperature, and
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concentrated directly under reduced pressure. The resulting residue was purified by flash column
chromatography (CH2Cl2/MeOH/Et3N = 60 : 1 : 1) on silica gel to afford the desired
( )-Chimonanthine (9) (28 mg, 82%) as a colorless crystal. Rf = 0.15 (CH2Cl2/MeOH = 8 : 1); Mp.
165−167 °C; IR (film): νmax = 3365, 3047, 2955, 2927, 2855, 2673, 2477, 1607, 1485, 1470, 1373,
1352, 1318, 1248, 1215, 1156, 1076, 1044, 749 cm–1; 1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 7.5
Hz, 2H), 7.01 (t, J = 7.5 Hz, 2H), 6.68 (t, J = 7.5 Hz, 2H), 6.56 (d, J = 7.5 Hz, 2H), 4.46 (br, 4H),
2.64−2.46 (m, 6H), 2.34 (s, 6H), 2.11−2.04 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 150.6,
133.1, 128.2, 124.4, 118.7, 109.3, 85.3, 63.3, 52.7, 37.2, 35.5 ppm; ESI−MS: m/z 347.3 [M+H]+;
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HRMS (ESI): calcd. for C22H27N4 [M+H]+: 347.2230, found: 347.2231.
To a stirred solution of ( )-Chimonanthine (16 mg, 0.046 mmol) in CH3CN (10 mL) was added
HCHO (35 ꢀL, 37% in water, 10.0 equiv) and NaBH(OAc)3 (99 mg, 0.46 mmol, 10.0 equiv)
successively at room temperature. The reaction mixture was stirred for 1.5 h, then concentrated directly
under reduced pressure. The resulting residue was purified by flash column chromatography
(CH2Cl2/MeOH = 49 : 1) on silica gel to afford the desired ( )-Folicanthine (10) (15 mg, 87%) as a
colorless crystal. Rf = 0.20 (CH2Cl2/MeOH = 8 : 1); Mp. 175−177 °C; IR (film): νmax = 3046, 2959,
2928, 2858, 2792, 1602, 1492, 1463, 1427, 1380, 1347, 1325, 1299, 1254, 1211, 1159, 1124, 1040,
1022, 1021, 965, 927, 743, 725 cm–1; 1H NMR (400 MHz, CDCl3): δ = 6.97 (t, J = 7.2 Hz, 2H), 6.91
(brs, 2H), 6.49 (t, J = 6.8 Hz, 2H), 6.26 (d, J = 7.6 Hz, 2H), 4.39 (brs, 2H), 2.99 (s, 6H), 2.64 (brs, 2H),
2.48−2.39 (m, 4H), 2.40 (s, 6H), 1.98−1.92 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 152.8 (2C),
132.7 (2C), 128.0 (2C), 123.6 (2C), 116.6 (2C), 105.8 (2C), 91.9 (2C), 62.6 (2C), 52.6 (2C), 37.8 (2C),
+
35.4 (2C), 35.2 (2C); ESI−MS: m/z 375.1 [M+H]+; HRMS (ESI): calcd. for C24H31N4 [M+H]+:
375.2543, found: 375.2540.
Acknowledgment. This work was supported by NSFC (No. 21172096), the Fundamental Research
Funds for the Central Universities (lzujbky-2012-57 and lzujbky-2013-ct02), Program for Changjiang
Scholars and Innovative Research Team in University (IRT1138) and the “111” Project of MoE. We
also appreciate Prof. Chun-An Fan (Lanzhou University) for his helpful discussion.
Supporting Information: Copies of 1H, 13C NMR, and crystallographic information files (CIFs) for 1l,
1o, 5a and 7′. This material is available free of charge via the Internet at http://pubs.acs.org.
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ACS Paragon Plus Environment