Total Synthesis of Two 8-Oxoprotoberberine Alkaloids: Alangiumkaloids A and B

Article abstract of DOI:10.1002/ejoc.201701557

A new and versatile synthetic route for 8-oxoprotoberberine 17 through synthesis of isoquinolinone 16 and construction of a B-ring is described. The key step is the synthesis of isoquinolinone 14 through thermal cyclization of 2-alkynylbenzaldehyde oxime 12 to afford isoquinoline N-oxide 13, followed by a Reissert–Henze-type reaction. The first total synthesis of 8-oxoprotoberberine alkaloid alangiumkaloids A and B was achieved by using this strategy.

Full text of DOI:10.1002/ejoc.201701557

DOI: 10.1002/ejoc.201701557
Full Paper
Total Synthesis
Total Synthesis of Two 8-Oxoprotoberberine Alkaloids:
Alangiumkaloids A and B
Takashi Nishiyama,[a] Miharu Hironaka,[a] Mizuki Taketomi,[a] Eri Taguchi,[a] Rika Kotouge,[a]
Yoshiyuki Shigemori,[a] Noriyuki Hatae,[b] Minoru Ishikura,[b] and Tominari Choshi*[a]
Abstract: A new and versatile synthetic route for 8-oxoproto- benzaldehyde oxime 12 to afford isoquinoline N-oxide 13, fol-
berberine 17 through synthesis of isoquinolinone 16 and con- lowed by a Reissert–Henze-type reaction. The first total synthe-
struction of a B-ring is described. The key step is the synthesis sis of 8-oxoprotoberberine alkaloid alangiumkaloids A and B
of isoquinolinone 14 through thermal cyclization of 2-alkynyl- was achieved by using this strategy.
Introduction
which includes those that are natural products, and have
achieved the total synthesis of several heteroaromatic com-
pounds (e.g., scorpinone,[3] calothrixins,[4] benzo[c]phenanthrid-
ines,[5] cassiarin C,[6] dichotomines,[7] marinacarbolines,[8] and
isocryptolepine[9]) by using an electrocyclic reaction of the 6π-
electron system as our original method.[10] Moreover, we have
been searching for highly active compounds based on these
naturally occurring compounds and their derivatives.[11] We
have also published the total syntheses of (R)-(–)-pyridindol-
ols,[12] which are ꢀ-carboline alkaloids, my means of a route
that includes the construction of key intermediate ꢀ-carboline
N-oxides by thermal cyclization of 3-alkynylindole-2-aldoxime
in accordance with a modified Sakamoto's method.[13]
Two 8-oxoprotoberberine alkaloids, alangiumkaloids A (1) and
B (2), were isolated from Alangium salviiforlium by Kittakoop
and co-workers in 2011 (Figure 1).[1] The cytotoxic activity of 1
and 2 along with that of other alangiumkaloids was evaluated
against four cancer cell lines: MOLT-3, HepG2, A549, and
HuCCA-1. Alangiumkaloid A (1) was reported to exhibit weak
cytotoxic activity toward the MOLT-3 cancer cell line (IC50
13.0 μM). The structures of protoberberines and 8-oxoprotober-
berines, which include isoquinoline moieties, are interesting,
and these compounds exhibit a wide range of pharmacological
properties, which include antitumor activity. Many approaches
for synthesis of the biologically active protoberberine alkaloids
have been reported; these routes involve the construction of
either B- or C-rings in the final or semifinal stage.[2]
Herein, we describe the details of the first total synthesis
of alangiumkaloids A (1) and B (2) through construction of an
isoquinolinone framework formed by thermal cyclization of 2-
alkynylbenzaldehyde oxime to produce isoquinoline N-oxide,
followed by a Reissert–Henze-type reaction.
Results and Discussion
Scheme 1 illustrates the strategy used in this paper to synthe-
size alangiumkaloids. Alangiumkaloids are prepared from iso-
quinolinones 3, which are derived by the disconnection of the
C6–N7 bond of an 8-oxoprotoberberine framework, by the con-
struction of the B-ring. We hypothesized that isoquinolinones
3 could be obtained from isoquinoline N-oxides 4 by thermal
cyclization of 2-alkynylbenzaldehyde oximes 5 followed by
heating with acetic anhydride. We further hypothesized that 2-
alkynylbenzaldehyde oximes 5 could be prepared from 2-iodo-
phenylacetate (6) and 2-ethynylbenzaldehyde 7 by a Sonoga-
shira reaction.
Figure 1. Alangiumkaloid A (1) and B (2).
We have been interested in the unique structure and phar-
macological action of condensed heteroaromatic compounds,
[a] Graduate School of Pharmacy Pharmaceutical Sciences,
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
E-mail: choshi@fupharm.fukuyama-u.ac.jp
http://web.fukuyama-u.ac.jp/pharm/htmls/Labo/labs/IYAKUHIN/index.html
[b] Faculty of Pharmaceutical Sciences,
To synthesize alangiumkaloids A and B, we prepared 2-
ethynylbenzaldehydes 7 as starting materials. On the basis of
the sequence in Scheme 2, treatment of 2-bromo-3-hydroxy-
methylbenzaldehyde (8) with chloromethyl methyl ether
Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201701557.
(MOMCl) afforded desired O-MOM ether
9 by Ojima's
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Scheme 3. Reagents and conditions: a) CuI, PdCl2(PPh3)2, iPr2NH, THF, reflux,
2.5 h, 11a (81 %); b) CuI, PdCl2(PPh3)2, iPr2NH, 100 °C, 2 h, 11b (77 %);
c) NH2OH·HCl, AcONa, EtOH, 80 °C, 2 h, 12a (98 %), 12b (92 %).
Scheme 1. Retrosynthetic analysis of alangiumkaloid A and B.
method.[14] Subsequently, the Sonogashira reaction of 9 with
trimethylsilyl (TMS)-acetylene afforded 2-ethynylbenzaldehyde
7 in 68 % yield.
Scheme 4. Reagents and conditions: a) 1,2-dichlorobenzene, 180 °C, 1 h, 13a;
2 h, 13b; b) Ac2O, 110 °C, 5 h, 14a (44 %) and 15a (31 %); 3 h, 14b (33 %)
and 15b (25 %).
Scheme 2. Reagents and conditions: a) MOMCl, iPr2NH, CH2Cl2, room temp.,
30 min, 96 %; b) (i) TMS-C≡ CH, PdCl2(PPh3)2, CuI, iPr2NH, 100 °C, 3 h; (ii) H2O,
68 %.
We then prepared important substrates 12 to synthesize iso-
Next, selective reduction of the ester part of 14, 15 was car-
quinolinones 14 (Scheme 3). The Sonogashira reaction of 2- ried out in accordance with Bois-Choussy's procedure.[16] Treat-
iodophenylacetate 6 with 2-ethynylbenzaldehydes 10 and 7 in ment of 14a and/or 15a with LiAlH4 at 70 °C provided alcohol
the presence of PdCl2(PPh3)2 and CuI provided 3-alkynylbenz- 16a in 57 and 49 % yields, respectively (Table 1). Subsequent
aldehydes 11a and 11b in 81 and 77 % yields, respectively.[15] treatment of a mixture of 14a and 15a under the same condi-
Treatment of 11a and 11b with hydroxylamine gave oximes tions led to 16a in 62 % yield (three steps from 12a). Similarly,
12a and 12b in 98 and 92 % yields, respectively.
As shown in Scheme 4, we next examined the construction
of isoquinoline N-oxide 13a from oxime 12a by heating at
a mixture of 14b and 15b afforded desired alcohol 16b in 68 %
yield (three steps from 12b).
Next, to construct the B-ring of 8-oxoprotoberberines 17,[16]
180 °C in 1,2-dichlorobenzene. However, desired isoquinoline treatment of 16a and 16b with 4-toluenesulfonyl chloride (TsCl)
N-oxide 13a could not be isolated because of its high polarity. in the presence of K2CO3 afforded 8-oxoprotoberberines 17a
Therefore, after 1,2-dichlorobenzene was removed, crude N-ox- and 17b in 60 and 56 % yields, respectively (Scheme 5). Depro-
ide 13a (without purification) was heated at 110 °C in acetic tection of the Me group and/or MOM group of 17a and 17b
anhydride to give isoquinolinone 14a. As a result, desired iso- with BBr3 afforded 8-oxoprotoberberine 18 and alangiumkaloid
quinolinone 14a and 2-acetoxyisoquinoline 15a were obtained B (2) in 52 and 62 % yields, respectively. Finally, oxidation of 2
in 44 and 31 % yields, respectively.
with MnO2 afforded alangiumkaloid A (1) in 42 % yield.
Similarly, thermal cyclization of oxime 12b by using the same
In addition, we investigated another route to synthesize
procedure afforded isoquinolinone 14b and 2-acetoxyisoquin- alangiumkaloid A (1) from 17b. Deprotection of the MOM
oline 15b in 33 and 25 % yields, respectively. group of 17b with HCl (6 ) in MeOH, followed by oxidation of
M
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Table 1. Synthesis of isoquinolinone 16 by reduction.
B (2) are consistent with those for natural alangiumkaloids A
(1) and B (2) in all respects.[1]
Conclusions
In conclusion, a versatile synthesis of 8-oxoprotoberberines
from appropriate 2-iodophenylacetate and 2-ethynylbenzalde-
hydes was achieved through a six-step sequence. The key step
is the synthesis of an isoquinolinone through thermal cycliza-
tion of a 2-alkynylbenzaldehyde oxime, followed by a Reissert–
Henze-type reaction to an isoquinoline N-oxide. The first total
synthesis of 8-oxoprotoberberine alkaloid alangiumkaloids A
and B was achieved by using this strategy. This will be a useful
procedure for the synthesis of other 8-oxoprotoberberine
alkaloids. In addition, the biologic activity of alangiumkaloids A
(1) and B (2) and their derivatives is under evaluation.
SM
R
Compd. No.
Yield [%]
14a
15a
14a + 15a
14b
14b + 15b
H
H
H
16a
16a
16a
16b
16b
57
49
62[a]
71
CH2OMOM
CH2OMOM
68[b]
[a] Three-step yield from 12a. [b] Three-step yield from 12b.
Experimental Section
General: All non-aqueous reactions were carried out under an at-
mosphere of nitrogen in dried glassware. Solvents were dried and
distilled in accordance with standard protocols. Analytical thin-layer
chromatography was performed with Silica gel 60PF254 (Merck).
Silica-gel column chromatography was performed with Silica gel 60
(70–230 mesh, Kanto Chemical Co. Lit.). All melting points were
determined with a Yanagimoto micro melting point apparatus. 1H
NMR spectra were recorded with a JEOL AL-300 at 300 MHz. Chemi-
cal shifts are reported relative to Me4Si (δ = 0.00 ppm). Signal multi-
plicity is indicated by one or more of the following: s (singlet); d
(doublet); t (triplet); q (quartet); m (multiplet); br. (broad). 13C NMR
spectra were recorded with a JEOL AL-300 at 75 MHz. Chemical
shifts are reported relative to CDCl3 (δ = 77.0 ppm) and [D6]di-
methyl sulfoxide ([D6]DMSO; δ = 39.7 ppm). Infrared spectra were
recorded by using the ATR method with a Shimadzu FTIR-8000
spectrophotometer and Technologies DuraScop. Low- and High-res-
olution mass spectra were recorded with a JEOL JMS-700 spectrom-
eter equipped with a direct inlet system.
2-Bromo-3-[(methoxymethoxy)methyl]benzaldehyde (9): To a
solution of 2-bromo-3-hydroxymethylbenzaldehyde (8; 1.5 g,
6.98 mmol) and diisopropylamine (iPr2NH; 6.1 mL, 34.9 mmol) in
CH2Cl2 (30 mL) was added MOMCl (1.59 mL, 20.9 mmol). The reac-
tion mixture was stirred at room temp. for 30 min. The reaction
mixture was quenched with water and extracted with EtOAc. The
organic layer was washed with water and brine, dried with Na2SO4,
and evaporated in vacuo. The residue was purified by column chro-
matography (EtOAc/hexane 3:7 v/v) to give O-MOM ether 9 (1.74 g,
Scheme 5. Reagents and conditions: a) TsCl, K2CO3, DMF, 100 °C, 24 h, 17a
(60 %), 17b (56 %); b) BBr3, CH2Cl2, room temp., 2 h, 18 (52 %), 2 (62 %);
96 %) as a yellow oil. IR (ATR): ν = 1732 cm–1 1H NMR (300 MHz,
.
˜
c) MnO2, CH2Cl2, room temp., 48 h, 42 %; d) 6
M HCl, MeOH, room temp.,
CDCl3): δ = 3.45 (s, 3 H), 4.75 (s, 2 H), 4.81 (s, 2 H), 7.45 (t, J = 7.7 Hz,
1 H), 7.76 (tdd, J = 0.8, 1.8, 7.5 Hz, 1 H), 7.85 (dd, J = 1.8, 7.7 Hz, 1
H), 10.46 (d, J = 0.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
55.6, 68.3, 96.3, 127.2, 127.6, 128.9, 133.8, 134.4, 139.1, 192.0 ppm.
MS (EI): m/z = 257 [M+], 259 [M+ + 2]. HRMS (EI): calcd. for
C10H11BrO3 257.9892; found 257.9888.
20 h, 81 %; e) MnO2, CH2Cl2, room temp., 70 h, 56 %; f) BBr3, CH2Cl2, room
temp., 2 h, 65 %.
alcohol 19 with MnO2, afforded aldehyde 20. Finally, treatment
of 20 with BBr3 afforded alangiumkaloid A (1) in 65 % yield.
The synthetic yield of 1 from 17b was better in the latter route
(26.0 versus 29.5 %). We synthesized the 8-oxoprotoberberine
framework in six steps from phenylacetate 6 and achieved the
first total syntheses of alangiumkaloids A (1) and B (2). The
structures of all synthetic compounds were supported by 1H
and 13C NMR spectra, and by mass spectra. The physical and
2-Ethynyl-3-[(methoxymethoxy)methyl]benzaldehyde (7): To a
solution of O-MOM ether 9 (300 mg, 1.12 mmol), CuI (22 mg,
0.11 mmol) and PdCl2(PPh3)2 (77 mg, 0.11 mmol) in iPr2NH (5 mL)
was added TMS-acetylene (0.19 mL, 1.34 mmol). The reaction mix-
ture was stirred for 3 h at 100 °C. The reaction mixture was
quenched with water and extracted with EtOAc. The organic layer
spectroscopic data for our synthetic alangiumkaloid A (1) and was washed with water and brine, dried with Na2SO4, and evapo-
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rated in vacuo. The residue was purified by column chromatography
0.73 mmol) to give oxime ether 12b (286 mg, 92 %) as white solid.
1
(EtOAc/hexane 1:9 v/v) to give 2-ethynylbenzaldehyde 7 (155 mg,
M.p. 111–112 °C (EtOAc/hexane). IR (ATR): ν = 1731, 3460 cm–1. H
˜
68 %) as a yellow oil. IR (ATR): ν = 1693 cm–1
CDCl3): δ = 3.44 (s, 3 H), 3.73 (s, 1 H), 4.79 (s, 2 H), 4.84 (s, 2 H), 7.50
(t, J = 7.5 Hz, 1 H), 7.78 (d, J = 7.5 Hz, 1 H), 7.88 (d, J = 7.5 Hz, 1 H),
10.58 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.5, 66.8, 76.4,
.
1H NMR (300 MHz,
NMR (300 MHz, CDCl3): δ = 3.42 (s, 3 H), 3.72 (s, 3 H), 3.91 (s, 2 H),
3.92 (s, 3 H), 4.79 (s, 2 H), 4.87 (s, 2 H), 6.86 (s, 1 H), 7.06 (s, 1 H),
7.35 (t, J = 7.7 Hz, 1 H), 7.55 (d, J = 7.7 Hz, 1 H), 7.68 (s, 1 H), 7.77
(d, J = 7.7 Hz, 1 H), 7.83 (br. s, 1 H), 8.71 (s, 1 H) ppm. 13C NMR
˜
89.3, 96.3, 123.7, 126.2, 128.9, 132.8, 136.7, 142.0, 191.5 ppm. MS (75 MHz, CDCl3): δ = 39.4, 52.3, 55.5, 56.0, 56.1, 67.5, 86.6, 96.2, 98.3,
(EI): m/z = 204 [M+]. HRMS (EI): calcd. for C12H12O3 204.0786; found 112.8, 114.6, 115.1, 121.4, 125.0, 128.3, 128.9, 129.3, 133.3, 140.5,
204.0793.
148.0, 129.3, 149.9, 171.9 ppm. MS (EI): m/z = 427 [M+]. HRMS (EI):
calcd. for C23H25NO7 427.1631; found 427.1618.
Methyl
2-[2-(2-Formylphenyl)ethynyl]-4,5-dimethoxyphenyl-
acetate (11a): To a solution of 2-iodophenylacetate 6 (749 mg,
2.23 mmol), CuI (35 mg, 0.186 mmol), PdCl2(PPh3)2 (130 mg,
0.186 mmol) and iPr2NH (3 mL, 16.7 mmol) in tetrahydrofuran (THF;
6 mL) was added the solution of 2-ethynylbenzaldehyde (10;
242 mg, 1.86 mmol) in THF (4 mL). The reaction mixture was stirred
for 2.5 h at 100 °C. After removal of solvent, the residue was purified
by column chromatography (EtOAc/hexane 3:7 v/v) to give 3-alkyn-
3-[2-(Methoxycarbonylmethyl)-4,5-dimethoxyphenyl]isoquinol-
in-1-one (14a) and 1-Acetoxy-3-[2-(methoxycarbonylmethyl)-
4,5-dimethoxyphenyl]isoquinoline (15a): A solution of oxime
ether 12a (100 mg, 0.28 mmol) in 1,2-dichlorobenzene (6 mL) was
stirred at 180 °C for 1 h. After removal of solvent, acetic anhydride
(6 mL) was added to the residue, and the mixture was stirred at
110 °C for 5 h. After removal of the solvent, the residue was purified
by column chromatography (EtOAc/hexane 1:1 v/v) to give corre-
sponding isoquinolone 14a (42 mg, 44 %) as an orange oil and 1-
ylbenzaldehyde 11a (509 mg, 81 %). M.p. 90–91 °C (EtOAc/hexane).
1
IR (ATR): ν = 1731, 1693 cm–1. H NMR (300 MHz, CDCl3): δ = 3.71
˜
(s, 3 H), 3.87 (s, 2 H), 3.92 (s, 3 H), 3.93 (s, 3 H), 6.85 (s, 1 H), 7.05 (s,
1 H), 7.45 (t, J = 7.7 Hz, 1 H), 7.59 (t, J = 7.7 Hz, 1 H), 7.64 (d, J =
7.7 Hz, 1 H), 7.92 (d, J = 7.7 Hz, 1 H), 10.63 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 39.6, 52.2, 56.0 (×2), 56.1, 88.0, 94.7 (×2), 112.9,
114.5, 126.9, 128.5, 129.9, 133.2, 133.8, 135.6, 148.0, 150.1, 171.6,
191.7 ppm. MS (EI): m/z = 338 [M+]. HRMS (EI): calcd. for C20H18O5
338.1154; found 338.1162.
acetoxyisoquinoline 15a (34 mg, 31 %). 14a. IR (ATR): ν = 1732,
˜
1631 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.64 (s, 2 H), 3.77 (s, 3 H),
3.92 (s, 3 H), 3.94 (s, 3 H), 6.49 (s, 1 H), 6.82 (s, 1 H), 6.95 (s, 1 H),
7.49 (t, J = 7.7 Hz, 1 H), 7.55 (d, J = 7.7 Hz, 1 H), 7.68 (t, J = 7.7 Hz,
1 H), 8.42 (d, J = 7.7 Hz, 1 H), 9.59 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 38.5, 52.7, 56.1, 56.1, 106.5, 112.6, 113.2, 124.8, 125.1,
126.3, 126.7, 127.6, 127.9, 132.8, 138.0, 139.1, 148.4, 149.9, 162.9,
173.0 ppm. MS (EI): m/z = 353 [M+]. HRMS (EI): calcd. for C20H19NO5
Methyl
2-{2-[2-Formyl-6-(methoxymethoxymethyl)phenyl]-
353.1263; found 353.1247. 15a. IR (ATR): ν = 1636 cm–1 1H NMR
.
˜
ethynyl}-4,5-dimethoxyphenylacetate (11b): To a solution of 2-
iodophenylacetate 6 (670 mg, 1.63 mmol), CuI (26 mg, 0.136 mmol)
and PdCl2(PPh3)2 (95 mg, 0.136 mmol) in iPr2NH (6 mL) was added a
solution of 2-ethynylbenzaldehyde 7 (340 mg, 1.36 mmol) in iPr2NH
(4 mL). The reaction mixture was stirred for 2 h at 100 °C. After
removal of solvent, the residue was purified by column chromatog-
raphy (EtOAc/hexane 3:7 v/v) to give 3-alkynylbenzaldehyde 11b
(300 MHz, CDCl3): δ = 2.17 (s, 3 H), 3.53 (s, 2 H), 3.61 (s, 3 H), 3.86
(s, 3 H), 3.96 (s, 3 H), 6.92 (s, 1 H), 6.94 (s, 1 H), 7.67 (dt, J = 1.2,
7.7 Hz, 1 H), 7.55 (dt, J = 1.2, 7.7 Hz, 1 H), 7.82 (d, J = 7.7 Hz, 1 H),
8.07 (d, J = 7.7 Hz, 1 H), 9.23 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 20.5, 38.1, 51.8, 55.9, 112.7, 113.6, 120.7, 125.6, 127.7, 127.7,
128.4, 129.1, 129.1, 130.6, 131.1, 140.1, 144.7, 147.6, 148.9, 149.8,
168.8, 172.2 ppm. MS (EI): m/z = 395 [M+]. HRMS (EI): calcd. for
C22H21NO6 395.1369; found 395.1372.
(431 mg, 77 %). M.p. 93–94 °C (EtOAc/hexane). IR (ATR): ν = 1731,
˜
1693 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.42 (s, 3 H), 3.71 (s, 3 H),
3.89 (s, 2 H), 3.92 (s, 3 H), 3.93 (s, 3 H), 4.80 (s, 2 H), 4.91 (s, 2 H),
6.87 (s, 1 H), 7.06 (s, 1 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.79 (d, J = 7.7 Hz,
1 H), 7.90 (d, J = 7.7 Hz, 1 H), 10.67 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 39.4, 52.2, 55.5, 56.0, 56.1, 67.0, 85.1, 96.2, 99.8, 112.8,
114.5, 114.6, 125.3, 126.5, 128.3, 129.7, 133.0, 136.0, 141.1, 148.1,
150.3, 171.5, 191.9 ppm. MS (EI): m/z = 412 [M+]. HRMS (EI): calcd.
for C23H24O7 412.1522; found 412.1534.
3-[2-(Methoxycarbonylmethyl)-4,5-dimethoxyphenyl]-5-
(methoxymethoxymethyl)isoquinolin-1-one (14b) and 1-
Acetoxy-3-[2-(methoxycarbonylmethyl)-4,5-dimethoxyphenyl]-
5-(methoxymethoxymethyl)isoquinoline (15b): The same proce-
dure as above was carried out with aldehyde 12b (70 mg,
0.16 mmol) to give isoquinolone 14b (23 mg, 33 %) as a yellow
solid and 1-acetoxyisoquinoline 15b (19 mg, 25 %). M.p. 144–145 °C
(EtOAc/hexane). 14b. IR (ATR): ν = 1731, 1650 cm–1 1H NMR
.
Methyl
phenylacetate (12a):
2-[2-(2-Hydroxyiminophenyl)ethynyl]-4,5-dimethoxy-
mixture of aldehyde 11a (146 mg,
˜
(300 MHz, CDCl3): δ = 3.40 (s, 3 H), 3.65 (s, 2 H), 3.78 (s, 3 H), 3.91
(s, 3 H), 3.94 (s, 3 H), 4.73 (s, 2 H), 4.86 (s, 2 H), 6.71 (s, 1 H), 6.83 (s,
1 H), 6.96 (s, 1 H), 7.47 (t, J = 7.4 Hz, 1 H), 7.72 (d, J = 7.4 Hz, 1 H),
8.41 (d, J = 7.4 Hz, 1 H), 9.59 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 38.5, 52.7, 55.6, 56.1, 56.1, 66.8, 95.7, 102.8, 112.6, 113.2, 124.8,
125.6, 126.2, 127.7, 128.0, 132.7, 133.2, 136.6, 139.3, 148.4, 150.0,
162.9, 172.9 ppm. MS (EI): m/z = 427 [M+]. HRMS (EI): calcd. for
A
0.43 mmol), NH2OHHCl (60 mg, 0.86 mmol), and AcONa (71 mg,
0.86 mmol) in EtOH (5 mL) was stirred at 80 °C for 2 h. After removal
of solvent, the mixture was extracted with EtOAc. The organic layer
was washed with water and brine, dried with Na2SO4, and evapo-
rated in vacuo. The residue was purified by column chromatography
(EtOAc/hexane 3:7 v/v) to give oxime ether 12a (149 mg, 98 %) as
C23H25NO7 427.1631; found 427.1620. 15b. IR (ATR): ν = 1650 cm–1
.
white solid. M.p. 136–138 °C (EtOAc/hexane). IR (ATR): ν = 1728,
˜
˜
1H NMR (300 MHz, CDCl3): δ = 2.00 (s, 3 H), 3.36 (s, 3 H), 3.47 (s, 2
H), 3.65 (s, 3 H), 3.88 (s, 3 H), 3.95 (s, 3 H), 4.62 (s, 2 H), 5.09 (br. s,
2 H), 6.94 (s, 1 H), 6.95 (s, 1 H), 7.62 (t, J = 7.7 Hz, 1 H), 7.84 (d, J =
7.7 Hz, 1 H), 8.01 (d, J = 7.7 Hz, 1 H), 9.22 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.1, 38.0, 51.8, 55.4, 56.0, 56.0, 56.1, 67.7, 94.7,
113.1, 113.5, 125.5, 127.2, 128.3, 129.5, 130.4, 131.7, 132.7, 140.3,
146.8, 147.6, 148.9, 150.5, 168.7, 172.3 ppm. MS (EI): m/z = 469 [M+].
HRMS (EI): calcd. for C25H27NO8 469.1737; found 469.1758.
1604 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.72 (s, 3 H), 3.90 (s, 2 H),
3.92 (s, 3 H), 3.92 (s, 3 H), 6.85 (s, 1 H), 7.04 (s, 1 H), 7.31–7.38 (m, 1
H), 7.55–7.58 (m, 1 H), 7.77–7.82 (m, 2 H), 8.38 (br. s, 1 H), 8.68 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 39.5, 52.2, 55.9 (×2), 56.1,
89.5, 93.1 (×2), 112.8, 114.5, 115.0, 122.9, 125.7, 128.4, 129.5, 132.8,
147.9, 149.0, 149.7, 172.0 ppm. MS (EI): m/z = 353 [M+]. HRMS (EI):
calcd. for C20H19NO5 353.1263; found 353.1245.
Methyl
2-{2-[2-Hydroxyimino-6-(methoxymethoxymethyl)-
phenyl]ethynyl}-4,5-dimethoxyphenylacetate (12b): The same
procedure as above was carried out with aldehyde 11b (300 mg,
3-(2-Hydroxyethyl-4,5-dimethoxyphenyl)isoquinolin-1-one
(16a): A solution of 1-acetoxyisoquinoline 14a (80 mg, 0.23 mmol)
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in THF (5 mL) was added dropwise to an ice/water-cooled suspen-
sion of LiAlH4 (43 mg, 1.15 mmol) in THF (5 mL). After stirring at
70 °C for 10 min, the reaction mixture was quenched with water,
and filtered through a Celite pad. The filtrate was extracted with
EtOAc. The organic layer was washed with brine, dried with Na2SO4,
and evaporated in vacuo. The residue was purified by column chro-
matography (EtOAc/hexane 1:1, v/v) to give alcohol 16a (43 mg,
m/z = 307 [M+]. HRMS (EI): calcd. for C19H17NO3 307.1208; found
307.1222.
2,3-Dimethoxy-12-(methoxymethoxymethyl)-8-oxoprotober-
berine (17b): The same procedure as above was carried out with
alcohol 16b (60 mg, 0.14 mmol) to give 8-oxoprotoberberine 17b
(26 mg, 56 %) as a yellow solid. M.p. 147–148 °C (EtOAc/hexane). IR
(ATR): ν = 1735 cm–1 1H NMR (300 MHz, CDCl3): δ = 2.95 (t, J =
.
˜
57 %) as a yellow oil. IR (ATR): ν = 1635 cm–1 1H NMR (300 MHz,
.
˜
6.2 Hz, 2 H), 3.45 (s, 3 H), 3.95 (s, 3 H), 4.00 (s, 3 H), 4.37 (t, J =
6.2 Hz, 2 H), 4.77 (s, 2 H), 4.94 (s, 2 H), 6.76 (s, 1 H), 7.15 (s, 1 H),
7.33 (s, 1 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 8.44
(d, J = 7.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.1, 39.8,
55.7, 56.1, 56.3, 67.0, 95.7, 97.8, 108.4, 110.5, 122.6, 125.1, 125.7,
128.4, 129.0, 132.1, 133.1, 135.5, 137.7, 148.5, 150.5, 162.3 ppm. MS
(EI): m/z = 381 [M+]. HRMS (EI): calcd. for C22H23NO5 381.1576; found
381.1585.
CDCl3): δ = 2.83 (t, J = 5.3 Hz, 2 H), 3.88 (s, 3 H), 3.93 (s, 3 H), 4.10
(t, J = 5.3 Hz, 2 H), 4.92 (br. s, 1 H), 6.54 (s, 1 H), 6.81 (s, 1 H), 6.89
(s, 1 H), 7.46 (t, J = 7.9 Hz, 1 H), 7.56 (d, J = 7.9 Hz, 1 H), 7.66 (t, J =
7.9 Hz, 1 H), 8.35 (d, J = 7.9 Hz, 1 H), 11.61 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 34.7, 56.0, 56.1, 63.1, 106.4, 112.4, 112.8, 124.5,
126.1, 126.3, 127.4, 128.0, 130.3, 132.5, 138.4, 140.6, 147.4, 150.1,
163.4 ppm. MS (EI): m/z = 325 [M+]. HRMS (EI): calcd. for C19H19NO4
325.1314; found 325.1304.
2,3-Dihydroxy-8-oxoprotoberberine (18): BBr3 (0.01 mL,
0.121 mmol) was added dropwise to a solution of 8-oxoprotober-
berine 17a (33 mg, 0.11 mmol) in CH2Cl2 (10 mL) at –78 °C. After
stirring at room temp. for 1 h, the reaction mixture was quenched
with ice-water, and extracted with CH2Cl2. The organic layer was
washed with brine, dried with Na2SO4, and evaporated in vacuo.
The residue was purified by column chromatography (EtOAc/hex-
ane 1:1, v/v) to give 8-oxoprotoberberine 18 (16 mg, 52 %). M.p.
3-(2-Hydroxyethyl-4,5-dimethoxyphenyl)-5-(methoxymethoxy-
methyl)isoquinolin-1-one (16b): The same procedure as above
was carried out with isoquinolone 14b (70 mg, 0.16 mmol) to give
alcohol 16b (46 mg, 71 %) as a yellow solid. M.p. 177–178 °C
(EtOAc/hexane). IR (ATR): ν = 3733, 1735 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 2.85 (t, J = 5.1 Hz, 2 H), 3.41 (s, 3 H), 3.88 (s, 3 H), 3.94
(s, 3 H), 4.09 (t, J = 5.1 Hz, 2 H), 4.74 (s, 2 H), 4.89 (s, 2 H), 6.75 (s, 1
H), 6.82 (s, 1 H), 6.92 (s, 1 H), 7.44 (t, J = 7.7 Hz, 1 H), 7.71 (d, J =
7.7 Hz, 1 H), 8.40 (d, J = 7.7 Hz, 1 H), 11.34 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 34.7, 55.6, 56.0, 56.1, 63.2, 67.0, 95.8, 102.7,
112.5, 112.9, 125.0, 125.8, 127.6, 128.2, 130.5, 132.4, 133.1, 137.1,
140.9, 147.5, 150.2, 163.4 ppm. MS (EI): m/z = 399 [M+]. HRMS (EI):
calcd. for C22H25NO6 399.1682; found 399.1666.
152–153 °C (EtOAc/hexane). IR (ATR): ν = 1639 cm–1 1H NMR
.
˜
(300 MHz, [D6]DMSO): δ = 2.81 (t, J = 6.5 Hz, 2 H), 4.17 (t, J = 6.5 Hz,
2 H), 6.70 (s, 1 H), 7.00 (s, 1 H), 7.30 (s, 1 H), 7.43 (t, J = 7.3 Hz, 1 H),
7.64–7.71 (m, 2 H), 8.19 (d, J = 7.3 Hz, 1 H), 9.07 (br. s, 1 H), 9.57 (br.
s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 26.9, 40.7, 99.8,
112.1, 114.5, 120.4, 123.5, 125.7, 126.3, 127.0, 127.2, 132.3, 136.7,
137.8, 144.8, 147.4, 161.0 ppm. MS (EI): m/z = 279 [M+]. HRMS (EI):
calcd. for C17H13NO3 279.0895; found 279.0884.
16a from 12a: A solution of oxime ether 12a (100 mg, 0.28 mmol)
in 1,2-dichlorobenzene (5 mL) was stirred at 180 °C for 1 h. After
removal of solvent, acetic anhydride (5 mL) was added to the resi-
due, and then stirred at 110 °C for 5 h. After removal of solvent, the
residue was purified by column chromatography (EtOAc/hexane 1:1
v/v) to give a mixture of isoquinolone 14a and 1-acetoxyisoquino-
line 15a. The mixture in THF (5 mL) was added dropwise to an ice/
water-cooled solution of LiAlH4 (16 mg, 0.42 mmol) in THF (5 mL).
After stirring at 70 °C for 10 min, the reaction mixture was
quenched with water, and filtered through a Celite pad. The filtrate
was extracted with EtOAc. The organic layer was washed with brine,
dried with Na2SO4, and evaporated in vacuo. The residue was puri-
fied by column chromatography (EtOAc/hexane 1:1, v/v) to give
alcohol 16a (56 mg, 62 %).
Alangiumkaloid B (2): The same procedure as above was carried
out with 8-oxoprotoberberine 17b (27 mg, 0.071 mmol) to give
alangiumkaloid B (2; 13 mg, 62 %) as a yellow solid. M.p. 123–126 °C
(EtOAc/hexane). IR (ATR): ν = 1636 cm–1 1H NMR (300 MHz,
.
˜
[D6]DMSO): δ = 2.88 (t, J = 6.5 Hz, 2 H), 4.23 (t, J = 6.5 Hz, 2 H), 5.21
(s, 2 H), 6.77 (s, 1 H), 7.16 (s, 1 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.51 (s, 1
H), 7.85 (d, J = 7.6 Hz, 1 H), 8.26 (d, J = 7.6 Hz, 1 H), 9.20 (br. s, 1
H), 9.74 (br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 27.0,
60.9, 96.4, 112.3, 114.6, 120.5, 123.8, 125.2, 126.3, 127.4, 130.7, 134.6,
137.0, 137.7, 144.9, 147.7, 161.2 ppm. 13C NMR (75 MHz, CD3OD):
δ = 28.5, 41.5, 63.0, 99.2, 113.1, 115.3, 122.5, 125.3, 126.7, 128.1,
129.2, 132.9, 136.8, 137.4, 139.2, 146.2, 148.9, 164.1 ppm. MS (EI):
m/z = 309 [M+]. HRMS (EI): calcd. for C18H15NO4 309.1001; found
309.1017.
16b from 12b: The same procedure as above was carried out with
oxime ether 12b (200 mg, 0.47 mmol) to give alcohol 16b (127 mg,
68 %).
12-Hydroxymethyl-2,3-dimethoxy-8-oxopotoberberine (19): HCl
( aq. 6 M, 2 mL) was added dropwise to a solution of 8-oxoprotober-
berine 17b (28 mg, 0.073 mmol) in MeOH (2 mL). After stirring at
room temp. for 48 h, the reaction mixture was quenched with water,
2,3-Dimethoxy-8-oxoprotoberberine (17a): A mixture of alcohol
16a (68 mg, 0.21 mmol), K2CO3 (116 mg, 0.84 mmol), and p-tolu-
enesulfonyl chloride (104 mg, 0.55 mmol) in dimethylformamide
(DMF; 5 mL) was stirred at 100 °C for 18 h. The reaction mixture and extracted with EtOAc. The organic layer was washed with brine,
was quenched with water, and extracted with EtOAc. The organic
layer was washed with water, HCl (1 ), NaHCO3 (aq. 20 %) and
brine, dried with Na2SO4, and evaporated in vacuo. The residue was
purified by column chromatography (EtOAc/hexane 1:1, v/v) to give
dried with Na2SO4, and evaporated in vacuo. The residue was puri-
fied by column chromatography (EtOAc/hexane 1:1, v/v) to give
alcohol 19 (20 mg, 81 %) as white solid. M.p. 211–212 °C (EtOAc/
M
hexane). IR (ATR): ν = 1735 cm–1 1H NMR (300 MHz, CDCl3): δ =
.
˜
8-oxoprotoberberine 17a (39 mg, 60 %) as a yellow solid. M.p. 132–
2.09 (br. s, 1 H), 2.93 (t, J = 6.0 Hz, 2 H), 3.96 (s, 3 H), 4.00 (s, 3 H),
4.35 (t, J = 6.0 Hz, 2 H), 5.03 (d, J = 6.0 Hz, 2 H), 6.74 (s, 1 H), 7.15
(s, 1 H), 7.30 (s, 1 H), 7.34 (t, J = 7.7 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1
H), 8.34 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.1,
39.8, 56.1, 56.4, 63.4, 97.9, 108.4, 110.5, 122.4, 125.0, 125.7, 128.2,
129.0, 131.8, 135.1, 135.1, 137.7, 148.5, 150.6, 162.3 ppm. MS (EI):
m/z = 337 [M+]. HRMS (EI): calcd. for C20H19NO4 337.1314; found
1
134 °C (EtOAc/hexane). IR (ATR): ν = 1643 cm–1. H NMR (300 MHz,
˜
CDCl3): δ = 2.96 (t, J = 5.9 Hz, 2 H), 3.95 (s, 3 H), 4.01 (s, 3 H), 4.38
(t, J = 5.9 Hz, 2 H), 6.75 (s, 1 H), 6.90 (s, 1 H), 7.28 (s, 1 H), 7.44 (dt,
J = 1.3, 7.6 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.63 (dt, J = 1.3, 7.6 Hz,
1 H), 8.44 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
28.1, 39.7, 56.1, 56.3, 101.5, 107.9, 110.5, 122.3, 124.6, 125.9, 126.2,
128.0, 128.8, 132.3, 136.7, 137.4, 148.5, 150.4, 162.3 ppm. MS (EI): 337.1314.
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2,3-Dimethoxy-8-oxoprotoberberine-12-carbaldehyde (20):
A
suspension of alcohol 19 (18 mg, 0.053 mmol) and active MnO2
(22 mg, 0.25 mmol) in CH2Cl2 (3 mL) was stirred at room temp. for
70 h. The reaction mixture was filtered through a Celite pad. The
filtrate was evaporated in vacuo. The residue was purified by col-
umn chromatography (EtOAc/hexane 1:1, v/v) to give aldehyde 20
(10 mg, 56 %) as white solid. M.p. 233–235 °C (EtOAc/hexane). IR
1
(ATR): ν = 1646, 1735 cm–1. H NMR (300 MHz, CDCl3): δ = 2.97 (t,
˜
J = 6.2 Hz, 2 H), 3.96 (s, 3 H), 4.04 (s, 3 H), 4.38 (t, J = 6.2 Hz, 2 H),
6.75 (s, 1 H), 7.41 (s, 1 H), 7.57 (t, J = 7.7 Hz, 1 H), 8.08 (d, J = 7.7 Hz,
1 H), 8.41 (s, 1 H), 8.71 (d, J = 7.7 Hz, 1 H), 10.30 (s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 27.9, 39.8, 56.1, 56.3, 98.1, 108.6, 110.4,
122.0, 125.1, 125.6, 129.1, 129.8, 134.4, 136.0, 140.8, 140.9, 148.7,
151.0, 161.6, 193.0 ppm. MS (EI): m/z = 335 [M+]. HRMS (EI): calcd.
for C20H17NO4 335.1158; found 335.1144.
Alangiumkaloid A (1) from 2: A suspension of alangiumkaloid B
(2; 10 mg, 0.032 mmol) and active MnO2 (28 mg, 0.32 mmol) in
CH2Cl2 (5 mL) was stirred at room temp. for 48 h. The reaction
mixture was filtered through a Celite pad. The filtrate was evapo-
rated in vacuo. The residue was purified by column chromatography
(EtOAc/hexane 1:1, v/v) to give aldehyde 20 (4 mg, 42 %) as a yel-
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low solid. M.p. 152–154 °C (EtOAc/hexane). IR (ATR): ν = 1636,
˜
1
1756 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 2.83 (t, J = 6.7 Hz, 2
H), 4.18 (t, J = 6.7 Hz, 2 H), 6.71 (s, 1 H), 7.34 (s, 1 H), 7.62 (t, J =
7.6 Hz, 1 H), 8.15 (s, 1 H), 8.27 (d, J = 7.6 Hz, 1 H), 8.50 (d, J = 7.6 Hz,
1 H), 9.34 (br. s, 1 H), 9.64 (br. s, 1 H), 10.32 (s, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 26.6, 95.8, 112.2, 114.7, 120.0, 124.5, 125.1,
128.0, 129.4, 133.6, 135.5, 140.7, 141.0, 145.0, 148.2, 160.6,
194.0 ppm. 13C NMR (75 MHz, CD3OD): δ = 28.2, 41.4, 98.9, 113.3,
115.4, 122.0, 125.9, 126.3, 128.8, 129.7, 131.4, 134.8, 137.3, 142.5,
146.3, 149.5, 163.3, 164.8 ppm. MS (EI): m/z = 307 [M+]. HRMS (EI):
calcd. for C18H13NO4 307.0845; found 307.0855.
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Alangiumkaloid A (1) from 20: BBr3 (0.01 mL, 0.1 mmol) was
added dropwise to a solution of aldehyde 20 (30 mg, 0.1 mmol) in
CH2Cl2 (5 mL) at –78 °C. After stirring at room temp. for 1 h, the
reaction mixture was quenched with water, and extracted with
CH2Cl2. The organic layer was washed with brine, dried with
Na2SO4, and evaporated in vacuo. The residue was purified by
column chromatography (EtOAc/hexane 1:1, v/v) to give alangium-
kaloid A (1; 20 mg, 65 %).
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Acknowledgments
This work was supported in part by a Grant-in Aid for Scientific
Research (C) of the Japan Society for the Promotion of Science
(grant number 15K07880 for T. C.).
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Keywords: Natural products · 8-Oxoprotoberberine
alkaloid · Alangiumkaloid A · Alangiumkaloid B ·
Cyclization · Total synthesis
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Received: November 8, 2017
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