Total synthesis of (±)-8-Oxo-erythrinine, (±)-8-oxo-erythraline, and (±)-clivonine

Article abstract of DOI:10.1002/ejoc.201500265

Total syntheses of the erythrina alkaloids (±)-8-oxo-erythrinine and (±)-8-oxo-erythraline have been developed, based on a substrate-controlled intramolecular 6-exo-trig selective radical spirocyclization that establishes the quaternary center of the B-ri

Full text of DOI:10.1002/ejoc.201500265

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FULL PAPER
DOI: 10.1002/ejoc.201500265
Total Synthesis of (؎)-8-Oxo-erythrinine, (؎)-8-Oxo-erythraline, and (؎)-
Clivonine
Maomao He,[a][‡] Chunrong Qu,[a][‡] Bingbing Ding,[a] Hao Chen,[a] Yangyan Li,[a]
Guofu Qiu,[a] Xianming Hu,[a] and Xuechuan Hong*[a]
Keywords: Total synthesis / Alkaloids / Polycycles / Radical reactions / Cyclization
Total syntheses of the erythrina alkaloids (Ϯ)-8-oxo-erythrin-
ine and (Ϯ)-8-oxo-erythraline have been developed, based
on a substrate-controlled intramolecular 6-exo-trig selective
radical spirocyclization that establishes the quaternary cen-
ter of the B-rings. An improved total synthesis of (Ϯ)-clivon-
ine has also been reported, based on an intramolecular 6-
endo-trig free-radical cyclization of a highly functionalized
enamide, and a biomimetic ring-switch of a lycorine-type in-
termediate. These endo/exo-selective sequences enabled us
to rapidly assemble two different complex alkaloids from a
common building block in an economical fashion.
Introduction
Alkaloids featuring the hydroindole skeleton,[1] form a
large class of structurally diverse compounds that are
widely found in nature. This class of compounds is exem-
plified by the structures shown in Figure 1, members of the
aspidosperma (1),[2] strychnos (2),[3] erythrina (3a),[4] and
amaryllidaceae (4)[5] families. Such compounds show di-
verse biological activities, including antitumor, antiviral,
sedative, and hypotensive activities, and activities as acetyl-
cholinesterase (AChE) inhibitors and neuromuscular block-
ers.[6–9] Efficient approaches to the synthesis of cis-fused
hydroindoles or related frameworks would allow the syn-
thesis not only of other related natural products, but also
of related nonnatural products with a variety of biological
activities.[7]
Two erythrina alkaloids, 8-oxo-erythrinine (3a)[10] and 8-
oxo-erythraline (3b)[11] were isolated by two different
groups in 1984. To date, there is only one report dealing
with the total synthesis of these compounds.[12] Clivonine
(4), a lycorenine-type amaryllidaceae alkaloid, was first iso-
lated from Clivia miniata Regel,[13] and was studied for its
biological properties long before a biosynthetic route to the
compound was proposed.[14] Spivey’s group reported the
synthesis of clivonine (4) through a biomimetic ring-switch
from a lycorine-type precursor.[15] Several syntheses of lyco-
rane and erythrina skeletons have also been reported,
Figure 1. Representative alkaloids containing the hydroindole skel-
eton.
through synthetic routes involving Heck coupling,[16] or an
[17]
NBS (N-bromosuccinimide) induced
or Lewis-acid-in-
[a] State Key Laboratory of Virology, Key Laboratory of Combi-
natorial Biosynthesis and Drug Discovery (Wuhan University),
Ministry of Education, and Wuhan University School of Phar-
maceutical Sciences,
duced[18] Pictet–Spengler reaction of tetrahydroindolinones
bearing tethered heteroaromatic rings to construct the key
rings. Inspired by Padwa’s work using an intramolecular 6-
endo-trig radical cyclization to access epi-zephyranthine,[17]
we set out to develop a highly efficient route for the synthe-
sis of 8-oxo-erythrinine (3a), 8-oxo-erythraline (3b), and cli-
vonine (4) from a common intermediate. We report the re-
Wuhan 430071, P. R. China
E-mail: xhy78@whu.edu.cn
http://www.hxcgroup.icoc.cc/
[‡] These two authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500265.
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FULL PAPER
sults of our investigations in this paper. To the best of our deprotection/esterification of acid 8, which is expected to
knowledge, no radical cyclization protocols have previously be formed from amine 6 through the biomimetic cleavage
been used in the total synthesis of 8-oxo-erythrinine (3a), of a C–N bond. Intermediates 7a and 7b could be as-
8-oxo-erythraline (3b), and clivonine (4).
sembled from substituted amidofuran 9.
Spirocyclic Ring Construction of Oxo-erythrinine through
Intramolecular Radical Cyclization
Results and Discussion
Synthetic Plan
As shown in Scheme 2, we began a program of research
Our initial retrosynthetic analysis of (Ϯ)-8-oxo-erythrin- based on the intramolecular [4+2]-cycloaddition/rearrange-
ine (3a), (Ϯ)-8-oxo-erythraline (3b), and (Ϯ)-clivonine (4) is ment cascade of 2-amidofurans (IMDAF), which was devel-
shown in Scheme 1. We envision that compounds 5, which oped by Padwa’s group and used intensively for the prepa-
is the core skeleton of (Ϯ)-8-oxo-erythrinine (3a) and (Ϯ)- ration of complex oxygenated polycyclic compounds.[17,19]
8-oxo-erythraline (3b), and 6, the core skeleton of (Ϯ)-cli- This concise process provided tetrahydro-1H-indol-2(3H)-
vonine (4), could be assembled from intermediates 7a and one derivative 10 as a readily accessible starting material
7b, respectively, by controlling the endo/exo selectivity of an (38% overall yield prepared from 2-furoic acid in a four-
intramolecular free-radical cyclization process (pathways I step procedure).[19b] The coupling reaction of bromide 11[20]
and II). (Ϯ)-8-Oxo-erythrinine (3a) and (Ϯ)-8-oxo-erythra- and enamide 10 gave tetrahydroindolinone 12 in 82% yield.
line (3b), could be reached from spiro-compound 5 in a few We expected that compound 5 would be formed under radi-
steps. (Ϯ)-Clivonine could be accessed through a one-pot cal cyclization conditions. However, only 7-endo-trig adduct
Scheme 1. Retrosynthetic analysis of 8-oxo-erythirinine, 8-oxo-erythraline, and clivonine; Boc = tert-butoxycarbonyl.
Scheme 2. Attempted synthesis of spiro adduct 5. a) NaH, 10, DMF, 0 °C to r.t., 82%; b) Bu3SnH, AIBN, benzene, reflux, 3 h, 68%.
2
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(Ϯ)-8-Oxo-erythrinine, (Ϯ)-8-Oxo-erythraline, and (Ϯ)-Clivonine
13, which contains the core of hexahydroapoerysopine, was
Calculations have indicated[22] that the 2-oxo group has
obtained in 68% yield. None of spiro adduct 5 was observed a great influence on the endo/exo selectivity of radical cycli-
under
a
variety of reaction conditions,[21] including zation reactions. To overcome this unfavorable substrate
Ph3SnH/AIBN (azobisisobutyronitrile)/benzene, nBu3SiH/ control, a more torsionally strained sp2 carbonyl group was
MeCN/nBu3SnF/toluene, and Ph3SnH/nBu3SnOAc/AIBN/ introduced into compound 12, which we expected would
xylene. We hypothesized that this outcome may be attrib- favor a 6-exo-trig free-radical cyclization. As shown in
uted to the smaller torsional stress of the benzyl methylene Scheme 3, α-bromination[23] of aryl ketone 14 followed by
group.
coupling with enamide 10 gave highly functionalized en-
Scheme 3. Synthesis of key intermediate 16. a) NBS, TsOH, CH3CN, reflux, 81%; b) NaH, 10, DMF, 0 °C, 92.6%; c) Bu3SnH, AIBN,
benzene, reflux, 3 h, 72%.
Scheme 4. Complete total syntheses of (Ϯ)-8-oxo-erythraline and (Ϯ)-8-oxo-erythrinine. a) NaBH4, MeOH, 0 °C, 30 min; b) TBSOTf,
Et3N, r.t., 30 min, 80% over two steps; c) BuLi, PhSeCl, THF, –78 °C; d) NaIO4, MeOH/H2O (3:1), r.t., 30 min, 85% over two steps;
e) LiOH (0.5 m), THF, r.t., 48 h, 93%; f) TBAB (tetrabutylammonium bromide), MeI, KOH, THF, r.t., 36 h, 91%; g) TBAF (tetrabutylam-
monium fluoride), THF, r.t., 95%; h) p-NO2PhCO2H, PPh3, DIAD (diisopropyl azodicarboxylate), THF, r.t., 5 h; i) LiOH (1 m), THF,
r.t., 1 h, 90% over two steps; j) TFA, Et3SiH, CH2Cl2, 0 °C, 85%.
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M. He, C. Qu, B. Ding, H. Chen, Y. Li, G. Qiu, X. Hu, X. Hong
FULL PAPER
amide 15 in 75% yield over two steps. Fortunately, radical quence starting from ketone 14. Additionally, the total syn-
cyclization of compound 15 under the conditions used thesis of (Ϯ)-8-oxo-erythraline (3b) was accomplished by
above gave 6-exo-trig product 16 in 72% yield; this com- reduction of benzyl alcohol 21 using Et3SiH in TFA (tri-
pound contains the core structure of the erythrina alka- fluoroacetic acid)[27] in 85% yield. The overall yield for (Ϯ)-
loids. The difference between compounds 13 and 16 was 8-oxo-erythraline (3b) was 25% from ketone 14 (11 steps).
further confirmed by DEPT-135 analysis (see Supporting
Significantly, exposure of α,β-unsaturated ketone 18 to
Information page 40). This efficient substrate control in the TBSCl in the presence of DBU (1,8-diazabicyclo[5.4.0]un-
radical cyclization gives us the possibility to prepare related dec-7-ene) at reflux directly gave silyl protected diene 22 in
amaryllidaceae and erythrina natural products from the 73% yield. One-pot deprotection/methylation of 22 pro-
same starting point.
vided dimethyl product 23 in 89% yield. In this process,
TBAF acted as both the desilylation agent and the phase-
transfer reagent. Finally, compound 23 was converted into
(Ϯ)-11-epi-methoxyerythraline (24) by treatment with AlH3
(Scheme 5).
Total Syntheses of (؎)-8-Oxo-erythraline, (؎)-8-Oxo-
erythrinine and (؎)-11-epi-Methoxyerythraline
With the crucial carbocyclic framework 16 established,
we turned our focus onto the final stage of the synthesis of
(Ϯ)-8-oxo-erythrinine (3a) and (Ϯ)-8-oxo-erythraline (3b),
as shown in Scheme 4. Reduction of the ketone in 16 using
Total Synthesis of (؎)-Clivonine
Having successfully completed the synthesis of (Ϯ)-8-
NaBH4 followed by protection of the secondary alcohol oxo-erythrinine (3a) and (Ϯ)-8-oxo-erythraline (3b), next
gave silyl ether 17 as a single diastereomer in 80% overall we moved onto the synthesis of the structurally related am-
yield. The configuration of 17 was determined by X-ray aryllidaceae alkaloid (Ϯ)-clivonine (Scheme 6). Imide
crystallographic analysis. The double bond of the d-ring was 25[19b] was converted into its 6-endo-trig tetracyclic product
introduced by phenylselenylation/oxidative elimination,[24] 26 through an intramolecular free-radical cyclization. Com-
which resulted in the formation of α,β-unsaturated ketone pound 26 was then reduced by BH3 to give amine 6 in high
18 in 85% yield. Then, a unique base-promoted one-pot yield. At this stage, the proposed bioinspired strategy was
elimination/ring-opening sequence produced α,β,γ-unsatu- applied to construct the ring-opened skeleton. Unfortu-
rated in ketone 20 in 93% yield (Scheme 4).[25] The reaction nately, efforts to effect the chemoselective benzyl C–N
possibly proceeded through a base-induced elimination to bond cleavage were unfruitful. Various reaction conditions
generate intermediate 19, followed by loss of acetone. Sub- were tested (including using CAN [cerium(IV) ammonium
sequent methylation and TBS (tert-butyldimethylsilyl) de- nitrate],[28] BrCN,[29] and Ac2O/NaOAc[30]), but these led
protection gave rise to secondary alcohol 21 in 86% yield either to the recovery of the starting material or to the for-
over two steps. Finally, inversion of configuration of the mation of a mixture of unidentified products. However,
secondary alcohol center in 21 using the Mitsunobu pro- amine 6 was converted into the ring-opened product in a
cedure[26] led to the desired (Ϯ)-8-oxo-erythrinine (3a) in relatively low yield (30%; 70% based on recovered starting
90% yield. The overall yield was 26.5% for the 12-step se- material) when it was exposed to PhOCOCl/CH2Cl2[31,32] at
Scheme 5. Synthesis of (Ϯ)-11-epi-methoxyerythraline. a) DBU, TBSCl, benzene, reflux, 73%; b) MeI, TBAF, KOH, THF, r.t., 89%;
c) AlCl3, LiAlH4, THF, –10 °C, 68%.
Scheme 6. Construction of key intermediate 27. a) nBu3SnH, AIBN, benzene, 90 °C, 78%; b) BH3, THF, reflux, 88%; c) CbzCl, CHCl3/
THF (1:1), microwave, 55 °C, 82%.
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(Ϯ)-8-Oxo-erythrinine, (Ϯ)-8-Oxo-erythraline, and (Ϯ)-Clivonine
room temperature. The resulting NMR spectroscopic data (4) in 26% overall yield from intermediate 6 (five steps),
were consistent with those reported in the literature. En- and so is more efficient than Spivey’s synthesis (5%, six
couraged by this promising result, other reagents of general steps). A two-step protocol, involving removal of N-Cbz
structure RCOCl were screened, and we were pleased to group of compound 29 by Pd/C (10%) reduction under a
find out that the reagents ClCO2Me, EtCOCl, AcCl, hydrogen atmosphere, and subsequent chemoselective in-
PhCOCl, and CbzCl (benzyloxycarbonyl chloride) all stallation of the N-Me group through reductive amin-
worked under the general reaction conditions. We elected ation[36] also gave the final product (i.e., 4) in 67% yield
to use CbzCl as the ring-opening reagent based on the fact over two steps. The synthetic (Ϯ)-clivonine was identical in
that the Cbz group could be transformed into a methyl all respects to the reported compound (i.e., 1H and 13C
group in a one-pot linear protocol under Pd/C/H2/HCHO NMR spectroscopic data, HRMS parent ion).[15,37]
conditions at a later stage. The optimum reaction condi-
tions for the chemoselective benzyl C–N bond cleavage were
thus to use CbzCl (2 equiv.) in THF/CHCl3 (1:1 v/v) in a
microwave synthesis reactor (Anton Paar W300) for 2 h.
This gave Cbz-protected product 27 in 82% yield.
Conclusions
An efficient strategy for the synthesis of both aromatic-
type erythrina alkaloids and a clivonine-type amaryllida-
ceae alkaloid has been developed. The total syntheses of
(Ϯ)-8-oxo-erythrinine and (Ϯ)-8-oxo-erythraline were ac-
complished in 26.5% overall yield (12 steps) and 25% over-
all yield (11 steps), respectively, from ketone 14. The critical
steps in the synthetic strategy include: 1) the substrate-con-
trolled intramolecular 6-exo-trig selective radical spirocycli-
zation that serves to establish the quaternary center of the
B-rings; 2) a regioselective base-promoted elimination/ring-
opening sequence to generate the desired α,β,γ-unsaturated
ketone. Additionally, an improved total synthesis of (Ϯ)-
clivonine has also been described (26% overall yield, five
steps from intermediate 6) based on an intramolecular 6-
endo-trig free-radical cyclization of a highly functionalized
enamide and a biomimetic ring-switch of a lycorine-type
intermediate. The application of this approach to other nat-
ural product targets is currently under investigation, and
the results of this research will be reported in due course.
To complete the total synthesis of (Ϯ)-clivonine
(Scheme 7), intermediate 27 was treated with anhydrous
NaHCO3/DMSO in a Kornblum-type oxidation,[33] fol-
lowed by standard Pinnick oxidation[34] to produce benzoic
acid 28 in 65% yield over two steps. One-pot deprotection/
esterification of acid 28 in THF/HCl (1 n) (3:1, v/v) resulted
in the formation of ester 29 in 92% yield. At this point,
crystals of 29 suitable for X-ray crystallographic analysis
were obtained (see ORTEP structure, Scheme 7), which
confirmed our stereochemical assignment of the tricyclic
core. Finally, direct subjection of ester 29 to Pd/C (10%)
and formaldehyde (37% aq.) under a hydrogen atmo-
sphere[35] successfully accomplished the total synthesis of
(Ϯ)-clivonine (4) in 50% yield (75% based on recovered
starting material). This linear sequence gave (Ϯ)-clivonine
Experimental Section
General Procedures: All reactions were carried out under an argon
atmosphere with dry solvents under anhydrous conditions unless
otherwise noted. Toluene and tetrahydrofuran (THF) were distilled
immediately before use from sodium benzophenone ketyl. Methyl-
ene chloride (CH2Cl2), dimethyl sulfoxide (DMSO), and triethyl-
amine (Et3N) were distilled from calcium hydride, and stored under
an argon atmosphere. Methanol (MeOH) was distilled from mag-
nesium, and stored under an argon atmosphere. Reagents were pur-
chased at the highest commercial quality, and were used without
further purification unless otherwise stated. “Brine” refers to a sat-
urated aqueous solution of NaCl. IR spectra were recorded with a
Themo Nicolet Nexux 470 FTIR instrument. Melting points (m.p.)
were recorded with a YH X-4 apparatus. NMR spectra were re-
corded with a Bruker AV-400 instrument, and were calibrated using
residual CHCl3 (δH = 7.26 ppm) and CDCl3 (δC = 77.0 ppm) as
internal references. Data are reported in the following order: chemi-
cal shifts (δ); multiplicities: br. (broadened), s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), app (apparent); coupling con-
stants (J) [Hz]; integration. High-resolution MS was carried out
with a Thermo LTQ XL Orbitrap instrument. Analytical thin-layer
chromatography (TLC) was carried out on silica gel aluminum
sheets with F-254 indicator. Visualization was accomplished with
UV light or with solutions of K2CO3/KMnO4 in water. Microwave
irradiation was carried out with an Anton Paar monowave 300 mi-
Scheme 7. Total synthesis of (Ϯ)-clivonine. a) NaHCO3, DMSO,
microwave, 85 °C, 20 min; b) NaClO2/NaH2PO4, 2-methyl-2-but-
ene, tBuOH/THF, r.t., 5 h, 69% over two steps; c) THF/HCl (1 n)
(3:1), 50 °C, 6 h, 92%; d) HCHO (37% aq.), Pd/C, H2 (20 atm),
MeOH, r.t., 48 h, 75% based on recovered starting material.
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crowave synthesis reactor. Purification by chromatography was car-
ried out using 200–400 mesh SiO2 with compressed air as a source
of positive pressure.
Compound 15: Compound 14[40] (4.50 g, 18.50 mmol) and TsOH
(4.78 g, 27.75 mmol) were dissolved in freshly distilled CH3CN
(50 mL), and
a solution (1 m in CH3CN) of NBS (3.30 g,
18.50 mmol) was added slowly by syringe over 1 h at room tem-
perature. The mixture was then heated to reflux, and it was stirred
at reflux for 3 h. The mixture was then poured into ice-water, and
the resulting mixture was extracted with CH2Cl2 (3ϫ 20 mL). The
combined organic layers were dried with anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (petroleum ether/
CH2Cl2, 10:1 to CH2Cl2) to give 2-bromo-1-(6-bromobenzo[d][1,3]-
dioxol-5-yl)ethan-1-one (4.80 g, 81%) as a white solid, m.p. 88–
90 °C. Rf = 0.2 (petroleum ether/CH2Cl2, 3:1). The spectroscopic
data matched those reported in the literature.[41] 1H NMR
(400 MHz, CDCl3): δ = 7.06 (d, J = 2.4 Hz, 1 H), 7.02 (d, J =
1.5 Hz, 1 H), 6.07 (d, J = 0.9 Hz, 2 H), 4.49 (d, J = 1.0 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 193.3, 151.0, 147.6, 131.3,
113.8, 112.2, 109.9, 102.6, 33.9 ppm.
Compound 11: 2-(6-Bromobenzo[d][1,3]dioxol-5-yl)ethan-1-ol[38]
(300 mg, 1.22 mmol), triphenylphosphine (480 mg, 1.5 mmol), and
imidazole (208 mg, 2.5 mmol) were dissolved in CH2Cl2 (5 mL),
and the mixture was cooled to 0 °C. Br2 (94 μL, 1.5 mmol) was
added dropwise to the stirred solution. The reaction mixture was
stirred at room temperature for 3 h, then it was cooled to 0 °C, and
satd. aqueous NaHCO3 was added. The mixture was extracted with
CH2Cl2 (3ϫ 5 mL), and the combined organic extracts were
washed with brine, dried with Na2SO4, and concentrated in vacuo.
The residue was purified by chromatography (petroleum ether/
EtOAc, 5:1) to give 11 (370 mg, 98%) as a white solid, m.p. 48–
50 °C. The spectroscopic data matched those reported in the litera-
ture.[39] 1H NMR (400 MHz, CDCl3): δ = 7.00 (s, 1 H), 6.75 (s, 1
H), 5.97 (s, 2 H), 3.53 (t, J = 7.5 Hz, 2 H), 3.18 (t, J = 7.5 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.5, 147.4, 131.1,
114.5, 112.9, 110.6, 101.8, 39.4, 31.2 ppm.
Amide 10 (400 mg, 1.91 mmol) was dissolved in freshly distilled
DMF (5 mL), and the solution was cooled to 0 °C. NaH (60% in
mineral oil; 153 mg, 3.82 mmol) was added. The mixture was
stirred at 0 °C for 0.5 h, then a solution of the bromide prepared
as described above (740 mg, 2.3 mmol) in THF (1 mL) was added.
The mixture was stirred for a further 30 min, then it was quenched
with water. The aqueous layer was extracted with EtOAc (3ϫ
5 mL). The combined organic layers were washed with water and
brine, and dried with Na2SO4, and the solvent was removed under
vacuum. The residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc, 1:1) to give 15 (795 mg, 92.6%)
as a white solid, m.p. 122–123 °C. Rf = 0.3 (petroleum ether/EtOAc,
1:1). 1H NMR (400 MHz, CDCl3): δ = 7.14–7.00 (m, 2 H), 6.07
(d, J = 2.1 Hz, 2 H), 5.02 (dd, J = 17.9, 2.9 Hz, 1 H), 4.96 (d, J =
2.9 Hz, 1 H), 4.66 (dd, J = 3.4, 2.3 Hz, 1 H), 4.61 (d, J = 17.9 Hz,
1 H), 4.29 (ddd, J = 11.2, 7.4, 3.7 Hz, 1 H), 2.91–2.78 (m, 1 H),
2.70 (ddd, J = 16.6, 9.1, 2.0 Hz, 1 H), 2.39–2.27 (m, 1 H), 2.27–
2.15 (m, 1 H), 1.59–1.51 (m, 1 H), 1.48 (s, 3 H), 1.38 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 193.6, 174.9, 151.0, 147.5, 147.4,
131.3, 114.0, 112.2, 109.2, 108.9, 102.6, 93.6, 73.8, 71.1, 48.6, 35.0,
Compound 12: Amide 10[19b] (200 mg, 0.96 mmol) was dissolved in
freshly distilled DMF (3 mL), and the solution was cooled to 0 °C.
NaH (60% in mineral oil; 46 mg, 1.15 mmol) was added. The mix-
ture was stirred at 0 °C for 0.5 h, then a solution of 11 (354 mg,
1.15 mmol) in THF (0.5 mL) was added by syringe. The reaction
mixture was allowed to warm to room temperature, and was stirred
for a further 12 h. After this time, it was quenched with water,
and the aqueous layer was extracted with EtOAc (4ϫ 5 mL). The
combined organic layers were washed with water and brine, and
dried with Na2SO4, and the solvent was removed under vacuum.
The residue was purified by column chromatography on silica gel
(petroleum ether/EtOAc, 2:1) to give 12 (342 mg, 82%) as a white
1
solid, m.p. 115–118 °C. Rf = 0.5 (petroleum ether/EtOAc, 1:1). H
NMR (400 MHz, CDCl3): δ = 6.98 (s, 1 H), 6.73 (s, 1 H), 5.96 (s,
2 H), 5.16 (s, 1 H), 4.67 (s, 1 H), 4.37–4.16 (m, 1 H), 3.85–3.73 (m,
1 H), 3.55–3.45 (m, 1 H), 3.01–2.82 (m, 2 H), 2.77–2.56 (m, 2 H),
2.35–2.11 (m, 2 H), 1.49 (s, 3 H), 1.44 (d, J = 8.2 Hz, 1 H), 1.40
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.7, 147.6,
147.5, 147.3, 130.7, 114.6, 112.8, 110.4, 108.9, 101.7, 93.3, 73.9,
32.2, 32.1, 28.3, 25.7 ppm. IR (KBr): ν = 2984, 2927, 1724, 1681,
˜
71.4, 39.8, 35.3, 33.4, 32.33, 32.30, 28.4, 25.8 ppm. IR (KBr): ν =
˜
1479, 1411, 1244, 1204, 1031, 872 cm–1. HRMS (ESI): calcd. for
[(C20H20BrNO6) + H]+ 450.0552; found 450.0541.
2939, 2876, 1723, 1674, 1477, 1235, 1174, 1030, 875 cm–1. HRMS
(ESI): calcd. for [(C20H22BrNO5) + H]+ 436.0760; found 436.0761.
Compound 13: A solution of AIBN (30 mg, 0.17 mmol) and
Bu3SnH (183 μL, 0.68 mmol) in benzene (20 mL) was heated to
reflux. A solution (0.05 m in benzene) of bromide 12 (150 mg,
0.34 mmol) was added slowly over 30 min. The mixture was heated
at reflux for a further 16 h, then KF (1 m aq.; 2 mL) was added.
The aqueous layer was extracted with EtOAc (3ϫ 5 mL). The com-
bined organic layers were washed with brine, and dried with
Na2SO4, and the solvent was removed under vacuum. The residue
was purified by column chromatography on silica gel (petroleum
ether/EtOAc, 1:1 to 1:2) to give 13 (82 mg, 68%) as a white solid,
Compound 16: AIBN (182.3 mg, 1.11 mmol) and Bu3SnH
(646.15 mg, 2.22 mmol) were dissolved in benzene (150 mL), and
the solution was heated to reflux. A solution (0.1 m in benzene) of
aryl bromide 15 (1.0 g, 2.22 mmol) was added slowly over 30 min.
The solution was heated at reflux for a further 3 h, then KF (1 m
aq.; 10 mL) was added. The aqueous layer was extracted with
EtOAc (3ϫ 10 mL). The combined organic layers were washed
with brine, and dried with Na2SO4, and the solvent was removed
under vacuum. The residue was purified by column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 1:1 to 1:2) to give 16
(600 mg, 72%) as a white solid, m.p. 232–235 °C. Rf = 0.2 (petro-
1
m.p. 220–221 °C. Rf = 0.3 (petroleum ether/EtOAc, 1:2). H NMR
(400 MHz, CDCl3): δ = 6.99 (s, 1 H), 6.67 (s, 1 H), 5.94 (d, J =
1
leum ether/EtOAc, 1:2). H NMR (400 MHz, CDCl3): δ = 7.41 (s,
1.9 Hz, 2 H), 4.57–4.40 (m, 3 H), 3.29–3.17 (m, 1 H), 3.04–2.86 (m, 1 H), 6.64 (s, 1 H), 6.04 (d, J = 1.2 Hz, 2 H), 4.85 (d, J = 19.1 Hz,
2 H), 2.70 (dd, J = 14.7, 5.3 Hz, 1 H), 2.61 (dd, J = 17.3, 9.7 Hz,
1 H), 2.49 (t, J = 12.9 Hz, 1 H), 2.30–2.21 (m, 1 H), 2.14 (d, J =
1 H), 4.54 (dt, J = 8.2, 4.1 Hz, 1 H), 4.33 (dt, J = 8.3, 4.2 Hz, 1
H), 3.85 (d, J = 19.1 Hz, 1 H), 2.91 (dd, J = 10.4, 5.6 Hz, 1 H),
17.3 Hz, 1 H), 2.09–2.05 (m, 1 H), 1.92–1.81 (m, 1 H), 1.39 (s, 3 2.63 (dd, J = 10.2, 7.6 Hz, 2 H), 2.27 (dd, J = 15.2, 4.3 Hz, 1 H),
H), 1.36 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.9, 2.15 (dd, J = 12.1, 7.5 Hz, 1 H), 2.09–1.99 (m, 1 H), 1.73 (dd, J =
146.4, 145.8, 134.9, 132.7, 109.7, 108.8, 107.2, 101.0, 73.7, 72.8,
15.2, 4.2 Hz, 1 H), 1.38 (s, 3 H), 1.28 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 190.3, 172.4, 152.8, 147.6, 146.3, 125.2,
108.0, 107.0, 103.5, 102.2, 71.2, 70.6, 61.6, 45.8, 37.7, 35.7, 32.9,
61.5, 44.8, 42.4, 36.4, 34.2, 31.5, 27.4, 24.6 ppm. IR (KBr): ν =
˜
2921, 2864, 1685, 1498, 1372, 1170, 1037, 931, 854 cm–1. HRMS
(ESI): calcd. for [(C20H23NO5) + H]+ 358.1649; found 358.1641.
30.5, 25.3, 23.1 ppm. IR (KBr): ν = 2921, 2855, 1680, 1477, 1376,
˜
6
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© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 000, 0–0

Job/Unit: O50265
/KAP1
Date: 02-04-15 15:29:06
Pages: 12
(Ϯ)-8-Oxo-erythrinine, (Ϯ)-8-Oxo-erythraline, and (Ϯ)-Clivonine
1262, 1033 cm–1. HRMS (ESI): calcd. for [(C20H21NO6) + H]+ 146.8, 133.1, 128.7, 123.4, 108.7, 107.6, 104.4, 101.4, 74.4, 72.0,
372.1442; found 372.1434.
66.0, 65.9, 42.5, 41.8, 29.6, 27.8, 25.8, 18.1, –4.3, –4.9 ppm. IR
(KBr): ν = 2936, 2890, 1680, 1483, 1376, 1248, 1098, 1043, 864,
˜
Compound 17: NaBH4 (61 mg, 1.61 mmol) was added portionwise
to a solution of 16 (500 mg, 1.34 mmol) in MeOH (5.0 mL) at 0 °C.
The reaction mixture was stirred at 0 °C for 0.5 h, then it was con-
centrated in vacuo. The residue was dissolved in CH2Cl2 (5 mL),
and poured into a separating funnel containing H2O (5 mL). The
resulting mixture was extracted with CH2Cl2 (4ϫ 5 mL), and the
combined organic extracts were dried with Na2SO4, filtered, and
concentrated in vacuo to give a white solid, which was used without
further purification.
780 cm–1. HRMS (ESI): calcd. for [(C26H35NO6Si) + H]+ 486.2306;
found 486.2295.
Compound 20: Lithium hydroxide solution (0.5 m aq.; 3 mL) was
added slowly by syringe to a stirred solution of ketone 18 (240 mg,
0.5 mmol) in THF (3 mL) at 0 °C. The resulting mixture was stirred
for 48 h at room temperature. The mixture was then diluted with
CH2Cl2 (5 mL), and satd. aqueous NH4Cl (5 mL) was added. The
solution was transferred to a separatory funnel, and the layers were
separated. The aqueous layer was extracted with EtOAc (3ϫ
5 mL). The combined organic layers were dried with Na2SO4, fil-
tered, and concentrated. The residue was purified by flash column
chromatography (petroleum ether/EtOAc, 3:2) to give 20 (198 mg,
93%) as a white crystalline solid, m.p. 192–195 °C. Rf = 0.2 (petro-
Freshly distilled CH2Cl2 (10 mL) and triethylamine (0.93 mL,
6.7 mmol) were added to the above residue (500 mg), and the mix-
ture was cooled to 0 °C. TBSOTf (1.06 g, 4.02 mmol) was added
slowly, and after the addition was complete, the white suspension
turned into a clear solution. The reaction mixture was stirred at
0 °C for a further 0.5 h, then it was quenched with brine. The re-
sulting mixture was extracted with CH2Cl2 (3ϫ 5 mL). The com-
bined organic extracts were dried with Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by flash column
chromatography (petroleum ether/EtOAc, 1:1) to give 17 (523 mg,
80% over two steps) as a white crystalline solid, m.p. 205–208 °C.
Rf = 0.2 (petroleum ether/EtOAc, 1:1). 1H NMR (400 MHz,
CDCl3): δ = 6.85 (s, 1 H), 6.45 (s, 1 H), 5.93 (s, 2 H), 4.72 (dd, J
= 9.8, 7.0 Hz, 1 H), 4.52 (dd, J = 8.1, 4.0 Hz, 1 H), 4.41 (dd, J =
8.2, 4.1 Hz, 1 H), 4.33 (dd, J = 12.9, 6.9 Hz, 1 H), 3.01 (dd, J =
12.6, 10.3 Hz, 1 H), 2.73–2.52 (m, 3 H), 2.37 (dd, J = 15.3, 4.3 Hz,
1 H), 2.19–2.08 (m, 1 H), 2.05–1.94 (m, 1 H), 1.82 (dd, J = 15.4,
4.2 Hz, 1 H), 1.42 (s, 3 H), 1.30 (s, 3 H), 0.95 (s, 9 H), 0.21 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2, 146.94, 146.89,
137.1, 132.0, 107.6, 107.0, 103.9, 101.1, 71.3, 71.2, 65.3, 61.8, 41.8,
37.9, 36.2, 34.8, 30.4, 25.9, 25.6, 23.1, 18.0, –4.1, –4.9 ppm. IR
1
leum ether/EtOAc, 3:2). H NMR (400 MHz, CDCl3): δ = 6.84 (d,
J = 1.9 Hz, 2 H), 6.81 (dd, J = 10.2, 2.3 Hz, 1 H), 6.31 (d, J =
10.1 Hz, 1 H), 5.98 (s, 1 H), 5.93 (dd, J = 11.3, 1.2 Hz, 2 H), 4.83
(t, J = 6.3 Hz, 1 H), 4.43 (s, 1 H), 4.32 (dd, J = 13.4, 6.6 Hz, 1 H),
3.37 (dd, J = 13.4, 6.1 Hz, 1 H), 3.23 (dd, J = 11.6, 5.2 Hz, 1 H),
1.66 (m, 1 H), 0.93 (s, 9 H), 0.22 (s, 3 H), 0.14 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.4, 158.2, 147.2, 146.9, 139.7,
130.9, 129.8, 123.8, 119.8, 108.9, 104.7, 101.3, 66.7, 66.3, 66.2, 45.9,
44.4, 25.8, 18.0, –4.4, –4.6 ppm. IR (KBr): ν = 3400, 2952, 2855,
˜
1664, 1478, 1377, 1249, 1102, 1040, 872, 838, 776 cm–1. HRMS
(ESI): calcd. for [(C23H29NO5Si) + H]+ 428.1888; found 428.1878.
Compound 21: KOH (202 mg, 3.6 mmol) and TBAB (290 mg,
0.9 mmol) were added to a mixture of alcohol 20 (130 mg,
0.3 mmol), THF (2 mL), and methyl iodide (1 mL). The reaction
mixture was stirred for 12 h at 25 °C. The solution was poured into
ice-water, and the resulting mixture was extracted with CH2Cl2 (3ϫ
5 mL). The combined organic layers were dried with Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (petroleum ether/EtOAc,
1:1) to give the O-methylation product 9-[(tert-butyldimethylsilyl)-
oxy]-2-methoxy-1,2,8,9-tetrahydro-6H-[1,3]dioxolo[4,5-g]indolo-
[7a,1-a]isoquinolin-6-one (120 mg, 91%) as a white solid, m.p. 175–
(KBr): ν = 2932, 2858, 1686, 1481, 1415, 1248, 1204, 1088, 1037,
˜
845, 782 cm–1. HRMS (ESI): calcd. for [(C26H37NO6Si) + H]+
488.2463; found 488.2452.
Compound 18: nBuLi (1.6 m in hexane; 0.55 mL, 0.88 mmol) was
added to a stirred solution of 17 (360 mg, 0.74 mmol) in freshly
distilled THF (5 mL) at –78 °C under an argon atmosphere, and
the mixture was stirred at –78 °C for 30 min. A solution of PhSeCl
(170 mg, 0.88 mmol) in THF (2 mL) was added dropwise over
1 min. The reaction mixture was stirred for 1 h at –78 °C, then the
reaction was quenched by the addition of satd. aqueous NaHCO3
(5 mL). The aqueous layer was extracted with CH2Cl2 (3ϫ 5 mL).
The combined organic extracts were dried with Na2SO4, and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (petroleum ether/EtOAc, 2:1) to give a white
solid, which was used directly in the next step.
1
178 °C. Rf = 0.2 (petroleum ether/EtOAc, 1:1). 400 MHz, CDCl3 H
NMR (400 MHz, CDCl3): δ = 6.85 (d, J = 4.6 Hz, 2 H), 6.82 (d,
J = 2.2 Hz, 1 H), 6.32 (d, J = 10.2 Hz, 1 H), 5.98 (s, 1 H), 5.94
(dd, J = 14.9, 1.3 Hz, 2 H), 4.85 (t, J = 6.2 Hz, 1 H), 4.34 (dd, J
= 13.4, 6.6 Hz, 1 H), 4.01–3.89 (m, 1 H), 3.45–3.37 (m, 1 H), 3.36
(s, 3 H), 3.26 (dd, J = 11.5, 5.1 Hz, 1 H), 1.66 (dd, J = 11.5,
10.3 Hz, 1 H), 0.93 (s, 9 H), 0.23 (s, 3 H), 0.15 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.3, 158.2, 147.2, 146.8, 137.2,
130.9, 130.1, 124.2, 119.7, 109.0, 104.6, 101.3, 74.7, 66.7, 66.0, 56.7,
44.5, 42.2, 25.8, 18.0, –4.4, –4.6 ppm. IR (KBr): ν = 2945, 2857,
˜
The residue was dissolved in MeOH/H2O (5:1 v/v; 6 mL), and
NaIO4 (1.0 g, 4.5 mmol) was added. The reaction mixture was
stirred for 20 min at room temperature, then the solvent was re-
moved in vacuo, and CH2Cl2 (10 mL) was added. The organic layer
was washed with brine (5 mL), dried with anhydrous Na2SO4, and
concentrated. The residue was purified by column chromatography
on silica gel (petroleum ether/EtOAc, 3:1) to give 18 (305 mg, 85%
over two steps) as a white solid, m.p. 180–182 °C. Rf = 0.4 (petro-
1680, 1477, 1380, 1248, 1246, 1092, 1038, 841, 779 cm–1. HRMS
(ESI): calcd. for [(C24H31NO5Si) + H]+ 442.2044; found 442.2028.
The O-methylation product obtained above (100 mg, 0.23 mmol)
was dissolved in THF (2 mL), and TBAF·3H2O (89 mg,
0.34 mmol) was added. The reaction mixture was stirred at 25 °C
for 1 h, and then the reaction was quenched with water. The aque-
ous layer was extracted with EtOAc (3ϫ 2 mL). The combined
organic layers were dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (EtOAc) to give 21 (70 mg, 95%) as a white crys-
1
leum ether/EtOAc, 2:1). H NMR (400 MHz, CDCl3): δ = 6.98 (s,
1 H), 6.62 (s, 1 H), 6.01 (s, 1 H), 5.95 (d, J = 9.8 Hz, 2 H), 4.69 (t,
J = 4.6 Hz, 1 H), 4.65–4.56 (m, 2 H), 4.43 (dd, J = 12.7, 6.2 Hz, 1
H), 3.16 (dt, J = 16.2, 9.7 Hz, 2 H), 2.95 (dd, J = 12.5, 10.1 Hz, 1 talline solid, m.p. 215–220 °C; Rf = 0.1 (petroleum ether/EtOAc,
1
H), 2.56 (dd, J = 13.6, 5.8 Hz, 1 H), 1.86 (dd, J = 13.6, 8.9 Hz, 1
H), 1.40 (s, 3 H), 1.34 (s, 3 H), 0.97 (s, 9 H), 0.24 (s, 3 H), 0.21 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1, 159.9, 147.2,
1:1). H NMR (400 MHz, CDCl3): δ = 7.01 (s, 1 H), 6.86 (s, 1 H),
6.86–6.81 (s, 1 H), 6.36 (d, J = 10.2 Hz, 1 H), 5.97 (s, 1 H), 5.93
(dd, J = 12.3, 1.3 Hz, 2 H), 4.90 (t, J = 6.8 Hz, 1 H), 4.47 (dd, J
Eur. J. Org. Chem. 000, 0–0
© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50265
/KAP1
Date: 02-04-15 15:29:06
Pages: 12
M. He, C. Qu, B. Ding, H. Chen, Y. Li, G. Qiu, X. Hu, X. Hong
FULL PAPER
= 13.7, 7.0 Hz, 1 H), 4.07–3.96 (m, 1 H), 3.40 (dd, J = 12.0, 5.0 Hz, 10 min, and then heated to reflux for 36 h. The reaction mixture
1 H), 3.37 (s, 3 H), 3.16 (dd, J = 11.7, 5.2 Hz, 1 H), 1.70 (dd, J = was cooled to room temperature, and diluted with diethyl ether.
11.5, 10.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1,
158.4, 147.5, 147.0, 137.2, 130.5, 129.9, 124.3, 119.6, 109.1, 104.6,
The organic layer was washed with water (5 mL), HCl (0.1 n aq.;
2ϫ 5 mL), satd. aqueous NaHCO3, and brine. The solution was
101.3, 74.5, 66.0, 65.5, 56.5, 43.3, 42.1 ppm. IR (KBr): ν = 3312, dried with Na2SO4, and concentrated in vacuo. The residue was
˜
2952, 2844, 1660, 1489, 1408, 1243, 1098, 1038, 864 cm–1. HRMS
(ESI): calcd. for [(C18H17NO5) + H]+ 328.1185; found 328.1180.
passed through a short column of silica gel (petroleum ether/
EtOAc, 2:1) to give 22 (150 mg, 73%) as a colorless oil. Rf = 0.4
(petroleum ether/EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ =
6.86 (d, J = 7.4 Hz, 2 H), 6.77 (dd, J = 10.1, 2.1 Hz, 1 H), 6.18 (d,
J = 10.1 Hz, 1 H), 5.97 (d, J = 1.3 Hz, 1 H), 5.96 (s, 1 H), 5.92 (d,
J = 1.2 Hz, 1 H), 4.83 (t, J = 6.4 Hz, 1 H), 4.41 (d, J = 7.3 Hz, 1
H), 4.36 (dd, J = 13.4, 6.7 Hz, 1 H), 3.34 (dd, J = 13.4, 6.2 Hz, 1
H), 3.01 (dd, J = 11.8, 5.4 Hz, 1 H), 1.75 (dd, J = 11.8, 9.8 Hz, 1
H), 0.95 (s, 9 H), 0.86 (s, 9 H), 0.23 (s, 3 H), 0.17 (s, 3 H), 0.06 (s,
3 H), 0.01 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4,
158.3, 147.2, 146.8, 140.3, 131.0, 130.3, 123.2, 119.5, 108.9, 104.5,
101.3, 66.6, 66.2, 46.0, 44.3, 25.9, 25.7, 18.1, 17.9, –4.3, –4.5,
(؎)-8-Oxo-erythrinine (3a): Diethyl azodicarboxylate (210 mg,
1.0 mmol) was added dropwise to a stirred mixture of 21 (60 mg,
0.18 mmol), triphenylphosphine (240 mg, 0.9 mmol), and 4-nitro-
benzoic acid (100 mg, 0.55 mmol) in THF (2 mL), and the mixture
was stirred at room temperature for 1 h. The reaction mixture was
then cooled to 0 °C, and satd. aqueous NaHCO3 was added. The
mixture was extracted with CH2Cl2 (3ϫ 3 mL). The combined or-
ganic extracts were washed with brine, dried with Na2SO4, and
concentrated in vacuo. The residue was passed through a short col-
umn of silica gel (petroleum ether/EtOAc, 1:1) to give the crude p-
nitrobenzoate of 21 (80 mg) as a colorless oil.
–4.6 ppm. IR (film): ν = 2954, 2927, 2856, 1692, 1484, 1377, 1254,
˜
1095, 1041, 1037, 837, 777 cm–1. HRMS (ESI): calcd. for
[(C29H43NO5Si2) + H]+ 542.2758; found 542.2758.
The p-nitrobenzoate was dissolved in THF (1 mL), and the solution
was cooled to 0 °C. LiOH (1 m aq.; 1 mL) was added, and the re-
sulting mixture was stirred at room temperature for 30 min. The
reaction mixture was diluted with CH2Cl2, and extracted with
CH2Cl2 (3ϫ 3 mL). The combined organic extracts were washed
with brine, and dried over Na2SO4, and the solvent was evaporated
in vacuo. The residue was purified by preparative TLC (petroleum
ether/EtOAc, 1:2) to give (Ϯ)-8-oxo-erythrinine (3a) (58 mg, 90%
over two steps) as a colorless oil. Rf = 0.1 (petroleum ether/EtOAc,
Compound 23: KOH (24 mg, 0.4 mmol) and TBAF·3H2O (24 mg,
0.09 mmol) were added to a mixture of 22 (20 mg, 0.036 mmol),
THF (1 mL), and methyl iodide (0.1 mL). The reaction mixture
was stirred for 6 h at 25 °C. The solution was poured into ice-water,
and the resulting mixture was extracted with CH2Cl2 (3ϫ 1 mL).
The combined organic layers were dried with anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by chromatography (petroleum ether/EtOAc, 2:1) to give
23 (11 mg, 89%) as a colorless oil . Rf = 0.6 (petroleum ether/
EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 6.86 (d, J = 4.5 Hz,
2 H), 6.84 (d, J = 2.4 Hz, 1 H), 6.34 (d, J = 10.2 Hz, 1 H), 6.00 (s,
1 H), 5.96 (dd, J = 11.5, 1.3 Hz, 2 H), 4.45 (dd, J = 6.6, 3.1 Hz, 1
H), 4.35 (dd, J = 13.9, 6.6 Hz, 1 H), 3.91–3.81 (m, 1 H), 3.63 (dd,
J = 13.9, 3.1 Hz, 1 H), 3.41 (s, 3 H), 3.34 (s, 3 H), 3.31 (dd, J =
11.9, 5.1 Hz, 1 H), 1.72–1.62 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.6, 157.9, 147.4, 147.0, 137.5, 131.5, 127.1, 123.9,
119.8, 110.6, 105.3, 101.4, 75.4, 74.8, 66.3, 56.3, 56.2, 42.5,
1
2:3). H NMR (400 MHz, CDCl3): δ = 7.02 (s, 1 H), 6.86 (dd, J =
10.2, 2.2 Hz, 1 H), 6.80 (s, 1 H), 6.34 (d, J = 10.2 Hz, 1 H), 6.01
(s, 1 H), 5.95 (d, J = 1.1 Hz, 1 H), 5.91 (d, J = 1.1 Hz, 1 H), 4.88
(s, 1 H), 4.15 (dd, J = 13.7, 4.3 Hz, 1 H), 4.00–3.88 (m, 1 H), 3.67
(dd, J = 13.7, 4.8 Hz, 1 H), 3.36 (s, 3 H), 2.68 (dd, J = 11.6, 5.1 Hz,
1 H), 1.72–1.57 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
171.0, 157.1, 147.4, 147.1, 136.7, 130.3, 128.5, 124.3, 120.0, 109.0,
104.3, 101.3, 74.5, 66.3, 66.0, 56.6, 44.0, 41.4 ppm. IR (KBr): ν =
˜
3352, 2926, 2825, 1667, 1483, 1369, 1259, 1101, 1038, 930, 864,
733 cm–1. HRMS (ESI): calcd. for [(C18H17NO5) + H]+ 328.1185;
found 328.1186.
42.1 ppm. IR (KBr): ν = 2925, 2852, 1684, 1485, 1378, 1255, 1103,
˜
1038, 870 cm–1. HRMS (ESI): calcd. for [(C19H19NO5) + H]+
342.1336; found 342.1330.
(؎)-8-Oxo-erythraline (3b): Triethylsilane (17.4 mg, 0.15 mmol) was
added dropwise to a solution of 21 (30 mg, 0.1 mmol) in CH2Cl2/
TFA (1:2; 0.6 mL) at 0 °C, and the mixture was stirred at that tem-
perature for 30 min. The reaction was then quenched by the careful
addition of satd. aqueous NaHCO3. The mixture was extracted
with CH2Cl2 (3ϫ 2 mL). The combined organic extracts were
washed with brine, dried with Na2SO4, and concentrated in vacuo.
The residue was passed through a short column of silica gel (petro-
leum ether/EtOAc, 1:2) to give (Ϯ)-8-oxo-erythraline (3b) (26 mg,
85%) as a white solid, m.p. 170–172 °C. Rf = 0.2 (petroleum ether/
EtOAc, 1:2). 1H NMR (400 MHz, CDCl3): δ = 6.86 (d, J =
10.2 Hz, 1 H), 6.72 (d, J = 7.7 Hz, 2 H), 6.30 (d, J = 10.3 Hz, 1
H), 6.02 (s, 1 H), 5.91 (d, J = 13.7 Hz, 2 H), 3.95–3.83 (m, 1 H),
3.76 (d, J = 2.1 Hz, 1 H), 3.68–3.58 (m, 1 H), 3.34 (s, 3 H), 3.20–
3.06 (m, 1 H), 2.96 (ddd, J = 15.8, 6.5, 4.0 Hz, 1 H), 2.79 (dd, J =
11.5, 5.0 Hz, 1 H), 1.69 (t, J = 10.9 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.1, 157.0, 147.0, 146.0, 136.3, 129.9,
127.8, 123.8, 120.3, 109.4, 104.9, 101.1, 74.8, 66.8, 56.4, 41.2, 37.8,
Compound 24: LiAlH4 (1 m solution in ether; 0.18 mL, 0.18 mmol)
was added to a solution of AlCl3 (8 mg, 0.06 mmol) in freshly dis-
tilled THF (2 mL) at –10 °C, and the mixture was stirred at the
same temperature for 30 min. Then a solution of 23 (10 mg,
0.03 mmol) in THF (0.5 mL) was added. The mixture was stirred
for 0.5 h at –10 °C, then the reaction was quenched by the addition
of NH4OH (5% aq.). The aqueous layer was extracted with CH2Cl2
(3ϫ 2 mL). The combined organic extracts were washed with brine,
dried with Na2SO4, and concentrated in vacuo. The residue was
purified by preparative TLC (petroleum ether/EtOAc, 1:1) to give
(Ϯ)-11-epi-methoxyerythraline (24) (6 mg, 68%) as a colorless oil.
Rf = 0.2 (petroleum ether/EtOAc, 1:1). 1H NMR (400 MHz,
CDCl3): δ = 6.91 (s, 1 H), 6.81 (s, 1 H), 6.52 (d, J = 9.9 Hz, 1 H),
6.00 (d, J = 10.2 Hz, 1 H), 5.91 (d, J = 6.8 Hz, 2 H), 5.70 (s, 1 H),
4.51 (t, J = 7.3 Hz, 1 H), 4.07 (s, 1 H), 3.74 (d, J = 12.5 Hz, 1 H),
3.55 (d, J = 14.4 Hz, 1 H), 3.45 (s, 3 H), 3.40–3.35 (m, 2 H), 3.33
(s, 3 H), 2.74 (dd, J = 11.6, 5.5 Hz, 1 H), 1.80 (t, J = 11.0 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.1, 146.6, 143.3,
133.3, 132.1, 127.8, 125.2, 122.9, 108.3, 105.9, 100.9, 75.8, 71.4,
27.3 ppm. IR (KBr): ν = 2921, 2883, 2818, 1679, 1487, 1374, 1245,
˜
1105, 1032, 925, 849 cm–1. HRMS (ESI): calcd. for [(C18H17NO4)
+ H]+ 312.1230; found 312.1225.
66.4, 57.1, 56.2, 56.1, 46.6, 40.6 ppm. IR (KBr): ν = 2924, 2821,
˜
Compound 22: TBSCl (66 mg, 0.44 mmol) and DBU (91 mg, 1686, 1503, 1482, 1380, 1239, 1102, 1038, 930, 872, 811 cm–1.
0.6 mmol) were added to a solution of 18 (200 mg, 0.4 mmol) in
benzene (5 mL). The mixture was stirred at room temperature for
HRMS (ESI): calcd. for [(C19H21NO4) + H]+ 328.1549; found
328.1549.
8
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(Ϯ)-8-Oxo-erythrinine, (Ϯ)-8-Oxo-erythraline, and (Ϯ)-Clivonine
Compound 6: AIBN (25 mg, 0.15 mmol) and Bu3SnH (162 μL,
0.6 mmol) were dissolved in benzene (100 mL), and the mixture
was heated to reflux. A solution (0.05 m in benzene) of iodide 25[17]
(dd, J = 14.7, 7.2 Hz, 1 H), 2.25–2.15 (m, 1 H), 2.11 (dd, J = 12.8,
5.4 Hz, 1 H), 2.02 (dd, J = 19.2, 8.7 Hz, 1 H), 1.89–1.80 (m, 1 H),
1.42 (s, 3 H), 1.30 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
(150 mg, 0.3 mmol) was added slowly over 30 min. The mixture was = 189.6, 154.8, 152.3, 146.8, 139.7, 136.6, 130.3, 128.3, 127.7, 127.5,
heated at reflux for a further 2 h, then KF (1 m aq.; 2 mL) was
added. The aqueous layer was extracted with EtOAc (3ϫ 5 mL).
The combined organic layers were washed with brine, and dried
with Na2SO4, and the solvent was removed under vacuum. The
residue was purified by column chromatography on silica gel (pe-
troleum ether/EtOAc, 1:1 to 1:2) to give cyclization product 26
(83 mg, 78%) as a white solid. The spectroscopic data matched
those reported in the literature.[17]
110.0, 108.9, 108.1, 101.8, 77.6, 73.1, 67.9, 66.6, 60.4, 45.5, 39.7,
27.6, 25.6, 24.9 ppm. IR (KBr): ν = 2981, 2936, 2895, 2731, 1697,
˜
1614, 1485, 1412, 1358, 1250, 1040, 933, 872, 699 cm–1. HRMS
(ESI): calcd. for [(C27H29NO7) + H]+ 480.2017; found 480.2014.
The aryl aldehyde obtained above (30 mg, 0.063 mmol) was dis-
solved in a mixture of THF and tBuOH (1:1; 1 mL), and then 2-
methyl-2-butene (157 mg, 3.15 mmol) was added. In a separate
flask, NaClO2 (57 mg, 0.63 mmol) and NaH2PO4 (53 mg,
0.38 mmol) were dissolved in water (0.5 mL). Once fully dissolved,
the aqueous solution was poured into the stirred organic solution,
and the mixture was stirred vigorously. When TLC indicated that
the reaction was complete (2 h), the solvent was evaporated, and
water (2 mL) was added. The aqueous layer was extracted with
EtOAc (4ϫ 2 mL). The combined organic layers were washed with
brine, and dried with Na2SO4, and the solvent was removed under
vacuum. The residue was purified by column chromatography on
silica gel (EtOAc/MeOH, 10:1) to give 28 (29 mg, 92%) as a white
The cyclization product (80 mg, 0.22 mmol) was dissolved in
freshly distilled THF (1 mL), and the solution was cooled to 0 °C.
BH3 (1.0 m in THF; 1.1 mL, 1.1 mmol) was added. The reaction
mixture was stirred at 0 °C for 0.5 h, then it was heated to reflux
for 12 h, and then quenched with MeOH (3 mL). The solution was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (basified with 5% Et3N; petroleum ether/
EtOAc/Et3N, 4:1:0.2) to give aminodioxolane 6 (65 mg, 89%) as a
white solid. The spectroscopic data matched those reported in the
literature.[17]
1
solid, m.p. 172–175 °C. Rf = 0.2 (petroleum ether/EtOAc, 1:2). H
NMR (400 MHz, CDCl3): δ = 7.38 (s, 1 H), 7.28 (t, J = 7.1 Hz, 3
H), 7.12 (d, J = 5.8 Hz, 3 H), 5.90 (br. s, 2 H), 4.94 (d, J = 12.5 Hz,
1 H), 4.46 (d, J = 23.4 Hz, 2 H), 4.41–4.24 (m, 2 H), 3.97 (br. s, 1
H), 3.52 (br. s, 1 H), 3.43 (d, J = 5.3 Hz, 1 H), 2.35 (dd, J = 14.9,
7.5 Hz, 1 H), 2.24–2.12 (m, 1 H), 2.05 (t, J = 5.9 Hz, 3 H), 1.46 (s,
3 H), 1.31 (s, 3 H) ppm. 1H NMR (400 MHz, [D6]DMSO): δ =
12.53 (br. s, 1 H), 7.54–7.16 (m, 5 H), 7.04 (s, 2 H), 5.92 (br. t, J =
71.7 Hz, 2 H), 4.83 (br. s, 1 H), 4.47 (br. s, 1 H), 4.30 (dd, J = 24.6,
14.0 Hz, 2 H), 4.00 (dd, J = 11.0, 7.4 Hz, 1 H), 3.45–3.38 (m, 1 H),
2.29 (br. s, 1 H), 2.09 (dt, J = 9.0, 5.6 Hz, 1 H), 2.06–1.87 (m, 2
H), 1.76 (br. s, 1 H), 1.32 (s, 3 H), 1.19 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.2, 155.0, 151.2, 145.9, 138.6, 136.7,
128.2, 127.6, 127.4, 124.0, 110.7, 108.9, 108.4, 101.7, 78.2, 73.2,
Compound 27: Aminodioxolane 6 (300 mg, 0.91 mmol) was dis-
solved in THF/CHCl3 (1:1; 10 mL), and CbzCl (250 μL,
1.82 mmol) was added. The reaction mixture was heated to 55 °C
in a sealed tube in a microwave reactor (Anton Paar W300). After
2 h, the mixture was cooled to room temperature, and the reaction
was quenched by the addition of satd. aqueous NaHCO3 (1 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ 5 mL). The
combined organic layers were washed with brine, and dried with
Na2SO4, and the solvent was removed under vacuum. The residue
was purified by column chromatography on silica gel (petroleum
ether/EtOAc, 3:1) to give 27 (375 mg, 82%) as a colorless oil. Rf =
1
0.3 (petroleum ether/EtOAc, 2:1). H NMR (400 MHz, CDCl3): δ
= 7.29 (d, J = 7.2 Hz, 3 H), 7.18–7.08 (m, 3 H), 6.71 (s, 1 H), 5.87
(br. s, 2 H), 5.01 (d, J = 12.5 Hz, 2 H), 4.66 (d, J = 11.5 Hz, 1 H),
4.41 (d, J = 11.4 Hz, 1 H), 4.31 (ddd, J = 24.3, 12.3, 8.2 Hz, 3 H),
3.75 (t, J = 6.4 Hz, 1 H), 3.44–3.37 (m, 1 H), 3.21 (m, 1 H), 2.43
(dd, J = 16.9, 7.2 Hz, 1 H), 2.16 (ddd, J = 26.5, 12.4, 6.5 Hz, 2 H),
1.85 (dd, J = 6.4, 3.9 Hz, 2 H), 1.45 (s, 3 H), 1.27 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.1, 148.0, 145.9, 141.0, 129.9,
128.4, 128.3, 128.2, 127.7, 127.6, 127.4, 126.9, 109.8, 108.6, 101.1,
81.1, 73.0, 66.5, 65.1, 53.5, 45.2, 42.2, 31.0, 27.4, 24.4 ppm. IR
66.6, 60.6, 45.6, 40.7, 29.3, 27.4, 25.1 ppm. IR (KBr): ν = 2958,
˜
2923, 1662, 1439, 1260, 1111, 1041, 919, 879, 805, 699 cm–1. HRMS
(ESI): calcd. for [(C27H29NO8) + H]+ 496.1966; found 496.1951.
Compound 29: A magnetically stirred solution of acid 28 (37.1 mg,
0.075 mmol) in a mixture of THF and HCl (1 n aq.) (3:1 v/v; 2 mL)
was heated at 50 °C for 5 h. Then the mixture was cooled to room
temperature, and quenched with satd. aqueous NaHCO3 (1 mL).
The mixture was extracted with CH2Cl2 (3ϫ 2 mL). The combined
organic phases were dried (Na2SO4), filtered, and concentrated un-
der vacuum. The residue was purified by column chromatography
on silica gel (petroleum ether/EtOAc, 1:1) to give 29 (30 mg, 92%)
as a white solid, m.p. 147–149 °C. Rf = 0.5 (petroleum ether/EtOAc,
(KBr): ν = 2926, 1697, 1487, 1359, 1267, 1211, 1040, 937, 869 cm–1.
˜
HRMS (ESI): calcd. for [(C27H30ClNO6) – Cl]+ 464.2068; found
464.2061.
1
Compound 28: Flame-dried NaHCO3 (97 mg, 1.16 mmol)was
added to a solution of 27 (115 mg, 0.23 mmol) in dry DMSO
(2 mL). The reaction mixture was heated to 85 °C in a sealed tube.
After 30 min, the mixture was cooled down, and water (5 mL) was
added. The aqueous layer was extracted with EtOAc (4ϫ 5 mL).
The combined organic extracts were washed with water and brine,
and dried with Na2SO4, and the solvent was removed under vac-
uum. The residue was purified by column chromatography on silica
gel (petroleum ether/EtOAc, 1:1) to give the aldehyde benzyl 4-(6-
formylbenzo[d][1,3]dioxol-5-yl)-2,2-dimethyloctahydro-5H-[1,3]-
dioxolo[4,5-f]indole-5-carboxylate (82 mg, 75%) as a colorless oil.
Rf = 0.2 (petroleum ether/EtOAc, 2:1). 1H NMR (400 MHz,
CDCl3): δ = 9.96 (s, 1 H), 7.30 (q, J = 5.4 Hz, 3 H), 7.11 (s, 4 H),
5.94 (br. s, 2 H), 4.89 (d, J = 12.5 Hz, 1 H), 4.44 (br. s, 1 H), 4.36
(dd, J = 13.7, 6.2 Hz, 1 H), 4.14 (br. s, 1 H), 4.06–3.96 (m, 1 H),
1:1). H NMR (400 MHz, CDCl3): δ = 7.56–7.28 (m, 7 H), 6.04 (s,
2 H), 5.22 (d, J = 10.8 Hz, 2 H), 4.46 (br. s, 1 H), 4.31–4.20 (m, 2
H), 3.89 (br. s, 1 H), 3.49–3.38 (m, 2 H), 2.66 (br. s, 1 H), 2.50 (s,
1 H), 2.28–2.19 (m, 2 H), 2.12–2.02 (m, 1 H), 1.92–1.80 (m, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 164.2, 156.7, 152.8, 146.8,
137.9, 128.5, 128.1, 127.9, 118.5, 109.4, 106.7, 101.9, 81.0, 67.5,
66.9, 65.8, 60.3, 44.5, 42.6, 37.3, 33.5, 27.6 ppm. IR (KBr): ν =
˜
3420, 2925, 2853, 1696, 1483, 1405, 1280, 1120, 1033, 930, 870,
772 cm–1. HRMS (ESI): calcd. for [(C24H23NO7) + H]+ 438.1547;
found 438.1534.
(؎)-Clivonine (4)
Method A: Pd/C (5 mg) was added to a solution of ester 29 (18 mg,
0.04 mmol) in methanol (1 mL) at room temperature. The mixture
was stirred under a hydrogen atmosphere (20 atm) at room tem-
3.74 (t, J = 6.4 Hz, 1 H), 3.59 (br. s, 1 H), 3.44–3.31 (m, 1 H), 2.40 perature for 6 h, and then it was filtered through a pad of Celite.
Eur. J. Org. Chem. 000, 0–0
© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. He, C. Qu, B. Ding, H. Chen, Y. Li, G. Qiu, X. Hu, X. Hong
FULL PAPER
[7]
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The solid was washed carefully with methanol (10 mL), and the
combined filtrates were concentrated to give the crude amine.
Methanol (1 mL) was then added to the free amine, and then form-
aldehyde solution (37% HCHO aq.; 10 μL) and NaBH3CN (5 mg,
0.08 mmol) were added sequentially at room temperature. Then
ZnCl2 (2.2 mg, 0.016 mmol) was added. The mixture was stirred at
room temperature for 0.5 h. Then it was cooled to 0 °C, and NaOH
(0.1 m aq.; 0.5 mL) was added. The aqueous layer was extracted
with CH2Cl2 (3ϫ 2 mL). The combined organic layers were washed
with brine, and dried with Na2SO4, and the solvent was removed
under vacuum. The residue was purified by preparative TLC (pe-
troleum ether/EtOAc, 1:4) to give (Ϯ)-clivonine (4) (8 mg, 67%
over two steps) as a white solid.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Method B: Formaldehyde solution (37% HCHO aq.; 10 μL) and
Pd/C (5 mg) were added to a solution of ester 29 (15 mg,
0.034 mmol) in methanol (1 mL) at room temperature. The mixture
was stirred under a hydrogen atmosphere (20 atm) at room tem-
perature for 48 h, and then it was filtered through a pad of Celite.
The solid was washed carefully with methanol (10 mL), and the
combined filtrates were concentrated. The residue was purified by
preparative TLC (petroleum ether/EtOAc, 1:4) to give (Ϯ)-clivon-
ine (4) (5 mg, 50%; 75% based on recovered starting material) as a
white solid, m.p. 197–200 °C (ref.[15] 199–200 °C). Rf = 0.2 (EtOAc/
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1
MeOH, 4:1). H NMR (400 MHz, CDCl3): δ = 7.76 (s, 1 H), 7.48
[19]
(s, 1 H), 6.04 (d, J = 5.0 Hz, 2 H), 4.26 (d, J = 3.1 Hz, 1 H), 4.11
(dd, J = 12.4, 2.5 Hz, 1 H), 3.38–3.17 (m, 2 H), 2.91 (dd, J = 9.7,
6.5 Hz, 1 H), 2.63–2.48 (m, 5 H), 2.35–2.25 (m, 2 H), 2.18–2.10 (m,
1 H), 1.82 (ddd, J = 15.3, 6.5, 3.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 164.7, 152.7, 146.7, 140.8, 118.7, 109.3,
107.2, 101.8, 81.8, 69.5, 67.4, 53.0, 45.2, 33.5, 33.2, 30.8, 28.8 ppm.
[20]
[21]
IR (KBr): ν = 3456, 2921, 1701, 1470, 1262, 1032 cm–1. HRMS
˜
(ESI): calcd. for [(C17H19NO5) + H]+ 318.1341; found 318.1338.
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Acknowledgments
The authors appreciate the financial support provided by the
National Natural Science Foundation of China (NSFC) (grant
numbers 81373254 and 21390402), the Natural Science Foundation
of Hubei Province (grant number 2014CFB704), the Applied Basic
Research Program of Wuhan Municipal Bureau of Science and
Technology, the Fundamental Research Funds for the Central Uni-
versities, and the China Scholarship Council Fellowship. We also
want to thank Professor Alan C. Spivey from the Department of
Chemistry, Imperial College London for his fruitful discussions
and encouragement.
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Intermediate 6 has been reported previously by both Spivey
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10
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© 000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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(Ϯ)-8-Oxo-erythrinine, (Ϯ)-8-Oxo-erythraline, and (Ϯ)-Clivonine
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Received: February 24, 2015
Published Online: ᭿
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Job/Unit: O50265
/KAP1
Date: 02-04-15 15:29:06
Pages: 12
M. He, C. Qu, B. Ding, H. Chen, Y. Li, G. Qiu, X. Hu, X. Hong
FULL PAPER
Total Synthesis
M. He, C. Qu, B. Ding, H. Chen, Y. Li,
G. Qiu, X. Hu, X. Hong* ............... 1–12
Total Synthesis of (Ϯ)-8-Oxo-erythrinine,
(Ϯ)-8-Oxo-erythraline, and (Ϯ)-Clivonine
Keywords: Total synthesis / Alkaloids /
Polycycles / Radical reactions / Cyclization
Total syntheses of the erythrina alkaloids
(Ϯ)-8-oxo-erythrinine and (Ϯ)-8-oxo-
erythraline have been developed, based on
an intramolecular 6-exo-trig radical cycli-
zation of a highly functionalized enamide (X
= O, n = 1). An improved linear total syn-
thesis of the amaryllidaceae alkaloid (Ϯ)-
clivonine through a 6-endo-trig cyclization
of a similar intermediate (X = O, n = 0) is
also reported.
12
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