Novel Total Synthesis of Mansouramycin B

Article abstract of DOI:10.1002/cjoc.201600020

A novel total synthesis of Mansouramycin B (1) was performed via 10 steps in 28% overall yield starting from the readily available and cheap salicylaldehyde. Two key steps of this total synthesis are noteworthy. The first one is base-promoted one-pot aerobic aromatization of N-tosyltetrahydroisoquinoline 6, the second one is oxidation of 5-hydroxy-3-methyl-isoquinoline 8 with iodobenzene diacetate [PhI(OAc)₂].

Full text of DOI:10.1002/cjoc.201600020

FULL PAPER
DOI: 10.1002/cjoc.201600020
Novel Total Synthesis of Mansouramycin B
Yi Zhang, Xiaoxin Shi,* Tianzhuo Meng, Qiqi Fan, and Xia Lu
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology,
Shanghai 200237, China
A novel total synthesis of Mansouramycin B (1) was performed via 10 steps in 28% overall yield starting from
the readily available and cheap salicylaldehyde. Two key steps of this total synthesis are noteworthy. The first one is
base-promoted one-pot aerobic aromatization of N-tosyltetrahydroisoquinoline 6, the second one is oxidation of
5-hydroxy-3-methyl-isoquinoline 8 with iodobenzene diacetate [PhI(OAc)2].
Keywords Mansouramycin B, total synthesis, isoquinoline, quinone, alkaloid, salicylaldehyde
Introduction
ities, synthesis of the marine isoquinoline-quinone al-
kaloids and their derivatives is very important, and has
received much attention from the synthetic communi-
ty.[6] In this paper, we focus on the total synthesis of
Mansouramycin B (1). To the best of our knowledge,
only one total synthesis of Mansouramycin B (1) was
reported by Vaquero et al. in 2015[7] since its isolation,
but an unpublished total synthesis of Mansouramycin B
(1) starting from 2,5-dimethoxybenzaldehyde has also
been developed.[8] Herein, we describe a new total syn-
thesis of this marine isoquinoline-quinone alkaloid
starting from commercially available and cheap salic-
ylaldehyde (see Scheme 1).
The structurally unique isoquinoline-quinone alka-
loids have been isolated from various marine sources.[1]
This type of sponge-derived alkaloids and analogues
have shown a wide array of biological activities includ-
ing antimicrobial, insecticidal, antifungal, antitumor and
cytototoxic properties,[1,2] inhibition of HIV and AMV
reverse transcriptases,[3] as well as inhibition of Cdc25
phosphatases.[4] Mansouramycins A－D, as four new
isoquinoline-quinone alkaloids (see Figure 1), were first
isolated from marine Sterptomycete sp. Mei37 by
Hawas and co-workers in 2009.[5] Mansouramycins A－
D have shown cytotoxicity against 36 cancer cell lines
and were found to have significant activity against
non-small cell lung cancer, breast cancer, melanoma,
and prostate cancer cells. Specifically, high cytotoxicity
was shown against human lung cancer cells with an IC50
value up to 0.089 μmol/L.
Results and Discussion
As illustrated in Scheme 1, our synthetic efforts be-
gan with the protection of the hydroxyl group of salic-
ylaldehyde. When salicylaldehyde was treated with 1.1
equiv. of benzyl bromide and 3.0 equiv. of K2CO3 in
acetonitrile at reflux for 5 h, O-benzyl salicylaldehyde 2
was obtained in 96% yield. According to our previous
report,[9] condensation of the protected aldehyde 2 with
nitroethane with ethylenediamine (2 mol%) as catalyst
was easily achieved after refluxing for approximately 8
h, trans aryl nitroalkene 3 was thus obtained in the 94%
yield as yellow crystals. Next, phenylethylamine 4
could be prepared by the reduction of aryl nitroalkene 3.
We first carried out the reduction of compound 3 by two
steps: reduction of double bond with sodium borohy-
dride and the reduction of nitro group with zinc pow-
der,[10] but the desired amine 4 was obtained in moderate
yield. We then tried the reduction of nitroalkene 3 with
excessive (6.0 equiv.) lithium aluminum hydride
(LiAlH4) in tetrahydrofuran at reflux,[11] both of double
O
O
COOMe
N
N
N
N
H
H
O
O
Mansouramycin C
Mansouramycin A
NH
O
O
Cl
N
N
N
N
H
H
O
O
Mansouramycin D
Mansouramycin B
Figure 1 Structures of the four isoquinoline-quinone alkaloids
Mansouramycins A－D
Owing to the above-mentioned rich biological activ-
*
E-mail: xxshi@ecust.edu.cn; Tel.: 0086-021-64252052; Fax: 0086-021-64252052
Received January 7, 2016; accepted February 23, 2016; published online XXXX, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600020 or from the author.
Chin. J. Chem. 2016, XX, 1—6
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Zhang et al.
FULL PAPER
Scheme 1 A new total synthesis of Mansouramycin B (1) starting from salicylaldehyde
OH
OBn
OBn
OBn
H2NCH2CH2NH2 (2 mol%)
EtNO2, reflux for 8 h
BnBr, K2CO3, CH3CN
reflux for 5 h
LiAlH4, THF
NO2
reflux for 10 h
CHO
CHO
NH2
82%
96%
94%
4
3
2
Salicylaldehyde
OBn
OBn
OBn
.
CH2(OMe)2, BF3 OEt2
EtOAc, 0 oC for 1.5 h
NaOH, DMSO, air
125 oC for 5 h
p-TsCl, Et3N, CH2Cl2
Pd/C (10%), EtOH
reflux for 10 h
r.t. for 1 h
NTs
N
NHTs
73%
85%
95%
95%
6
7
5
O
O
OH
.
PhI(OAc)2, CH3CN/H2O (2:1)
0 oC for 2 h
CH3NH2, CeCl3 7H2O, CH3CN/H2O (2:1)
0 oC to r.t. for 20 h
N
N
N
72% over 2 steps
N
H
O
O
8
10
9
O
NCS, CH3OH
r.t. for 1 h
Cl
N
94%
N
H
O
Mansouramycin B (1)
bond and nitro group were successively reduced in the
one-pot reaction, and the desired amine 4 was accord-
ingly prepared in 82% yield.
moval of the benzyl protecting group.[16] When com-
pound 7 was treated with catalytic amount of palladium
on charcoal in ethanol at reflux, the benzyl (Bn) group
was smoothly removed, and 5-hydroxy-3-methyl-iso-
quinoline 8 was thus obtained in 95% yield.
Pictet-Spengler reaction has been widely used to
construct tetrahydroisoquinoline skeleton.[12] Therefore,
we initially attempted the direct Pictet-Spengler reaction
of phenylethylamine 4 with dimethoxymethane in di-
chloromethane or chloroform in the presence of an acid
such as borontrifluoride diethyl etherate (BF3•OEt2),
hydrochloric acid, phosphoric acid, p-toluenesulfonic
acid, zinc chloride or trifluoroacetic acid (CF3COOH).
To our disappointment, the above direct Pictet-Spengler
reaction only gave low yields of tetrahydroisoquinoline
under all tested conditions. Compound 4 was then
treated with 1.1 equiv. of p-toluenesulfonyl chloride and
2.0 equiv. of trimethylamine in dichloromethane at
room temperature, N-tosyl-phenylethylamine 5 was thus
obtained in 95% yield.[13] The Pictet-Spengler reaction
of sulfonamide 5 with 5.0 equiv. of dimethoxyme-
thane[14] and 2.2 equiv. of borontrifluoride diethyl
etherate in ethyl acetate took place rapidly at 0 ℃ to
afford N-tosyl-tetrahydroisoquinoline 6 in 73% yield.
With the compound 8 in hand, we then attempted to
construct quinone moiety via oxidation of phenol with
an appropriate oxidant. Barret and co-worker reported a
method[17] for oxidizing phenols to quinones with
bis(trifluoroacetoxy) iodobenzene [PhI(O2CCF3)2],
which was successfully applied in syntheses of isoquin-
oline-quinone alkaloids caulibugulones A－E.[6c] Herein,
we were able to convert compound 8 to isoquinolin-
equinone 9 in good yield with much cheaper iodoben-
zene diacetate [PhI(OAc)2] as oxidant instead of
bis(trifluoroacetoxy) iodobenzene. Compound 9 was too
unstable to be isolated in high yield and purity. There-
fore, crude compound 9 was immediately treated with
1.5 equiv. of CeCl3•7H2O and 10.0 equiv. of CH3NH2 in
a mixed solvent of acetonitrile and water (CH3CN/H2O
＝2∶1) at 0 ℃ to room temperature for 20 h to fur-
nish compound 10 in 72% yield over 2 steps (from 8).
Finally, N-chlorosuccinimide (NCS)-mediated chlo-
rination of compound 10 would produce the target alka-
loid Mansouramycin B (1). After screening of solvent
for the chlorination, we found that methanol was obvi-
ously better than ethanol, acetonitrile, acetone and tet-
rahydrofuran. Consequently, compound 10 was treated
with 1.5 equiv. of N-chlorosuccinimide in methanol at
room temperature for 1 h, Mansouramycin B (1) was
Subsequently, N-tosyl-tetrahydroisoquinoline
6
could be successfully converted to isoquinoline 7 by
applying our previously reported method.[15] When
compound 6 was treated with 3.0 equiv. of sodium hy-
droxide in dimethyl sulfoxide (DMSO) at 125 ℃ for 5
h, cascade β-elimination and aerobic oxidation of dihy-
droisoquinoline intermediate took place smoothly to
furnish isoquinoline 7 in 85% yield. Compound 7 was
then subjected to Pd/C-catalyzed hydrogenation for re-
1
thus obtained in 94% yield. As shown in Table 1, H
2
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Novel Total Synthesis of Mansouramycin B
NMR spectra data of the sample of Mansouramycin B
(1) from this total synthesis is almost fully identical
with the data of the isolated sample from the nature.[5]
with acetonitrile. Filtrate was concentrated under vac-
uum to give a viscous oily residue, which was then par-
titioned between ethyl acetate (100 mL) and water (50
mL). Two phases were then separated, and the aqueous
phase was extracted twice with ethyl acetate (50 mL×
2). Extracts were combined, washed with brine (20 mL),
and dried over anhydrous magnesium sulfate. Removal
of solvent by vacuum distillation gave oily crude prod-
uct, which solidified on standing. The solid crude prod-
uct was then triturated in a mixed solvent of ethyl ace-
tate (20 mL) and hexane (180 mL), suction through a
Buchner funnel finally afforded pure compound 2
(16.68 g, 78.59 mmol) as off-white crystals in 96%
Table 1 Comparison between 1H NMR data (δ) of the synthetic
and isolated samples
Entry Protons
Synthetic sample δa
Isolated sample δb
9.14 (s)
1
2
3
4
5
H-1
H-4
9.12 (s)
7.81 (s)
7.82 (s)
NH
6.08 (brs)
6.08 (brs)
NCH3
3.48 (d, J＝5.8 Hz)
2.72 (s)
3.48 (d, J＝5.5 Hz)
2.73 (s)
1
CH3
yield, m.p. 48－49 ℃. H NMR (400 MHz, CDCl3) δ:
a 1H NMR was recorded at 400 MHz in CDCl3 (see experimental
10.56 (s, 1H, CHO), 7.86 (dd, J＝8.0, 1.8 Hz, 1H, ArH),
7.54 (dt, J1＝7.8 Hz, J2＝1.8 Hz, 1H, ArH), 7.48－7.32
(m, 5H, ArH), 7.06 (d, J＝7.6 Hz, 1H, ArH), 7.04 (t, J＝
7.6 Hz, 1H, ArH), 5.20 (s, 2H, OCH2); 13C NMR (100
MHz, CDCl3) δ: 189.79 (CHO), 161.08, 136.10, 135.94,
128.76 (2C), 128.48, 128.31, 127.32 (2C), 125.20,
121.04, 113.05, 70.48. IR (KBr film) ν: 3061, 2873,
1682 (C＝O), 1637, 1597, 1482, 1455, 1381, 1287,
1238, 1117, 994, 927, 762, 699, 657 cm1.
b
section of this paper). 1H NMR was recorded at 600 MHz in
CDCl3 (see ref.[5]).
Conclusions
In summary, a novel total synthesis of Mansouramy-
cin B (1) was performed via 10 steps in 28% overall
yield starting from salicylaldehyde. The key point for
the total synthesis of Mansouramycin B (1) is the con-
struction of isoquinoline and quinone moieties, the
base-promoted one-pot aerobic aromatization of
N-tosyltetrahydroisoquinoline 6 and PhI(OAc)2-medi-
ated oxidation of 5-hydroxy-3-methyl-isoquinoline 8 are
two key steps for the present total synthesis. Compared
with two known total syntheses[7.8] of Manosuramycin B
(1), the present total synthesis used much cheaper salic-
ylaldehyde as the starting material, and was obviously
more practical. In addition, the overall yield of the total
synthesis was increased from 23%[7] or 20%[8] to 28%.
(E)-1-(Benzyloxy)-2-(2-nitroprop-1-en-1-yl)benzene
3
O-Benzyl salicylaldehyde 2 (10.00 g, 47.12 mmol)
was dissolved in nitroethane (50 mL). A freshly pre-
pared solution of ethylenediamine (1.0 mL, 1 mol/L) in
nitromethane was injected by a syringe. The resulting
solution was then stirred and heated to reflux, and stir-
ring was continued at reflux for approximately 8 h. The
reaction was monitored by TLC (eluent: CH2Cl2/hexane
＝1∶1). After the reaction was complete, the solution
was concentrated under vacuum to give crude product
as yellowish crystals, the crude product was then tritu-
rated in aqueous ethanol (20 mL, EtOH/H2O＝1∶1).
Pale yellow crystals were collected on a Buchner funnel
by suction, and rinsed again with aqueous ethanol (10
mL, EtOH/H2O＝1∶1). After being dried overnight in
warm air, pure compound 3 (11.92 g, 44.26 mmol) was
Experimental
General methods
1H NMR and 13C NMR spectra were acquired on
Bruker AM-400, chemical shifts were given on the delta
scale as parts per million with tetramethylsilane (TMS)
as the internal standard. IR spectra were recorded on
Nicolet Magna IR-550. Mass spectra were recorded on
HP5989A. Melting points were determined on a
Mel-TEMP II apparatus. Column chromatography was
performed on silica gel. All chemicals were analytically
pure, and were used as such from commercial suppliers.
O-Benzyl salicylaldehyde 2 Powdered K2CO3
(33.95 g, 245.6 mmol) was added into a stirred solution
of salicylaldehyde (10.00 g, 81.88 mmol) in acetonitrile
(100 mL), and then benzyl bromide (15.43 g, 90.22
mmol) was added. While the mixture was vigorously
stirred, it was heated to reflux (81 ℃). The stirring was
continued at reflux for approximately 5 h, and the reac-
tion was traced by TLC (eluent: EtOAc/hexane＝1∶5).
After the reaction was complete, the mixture was cooled
down to room temperature, and filtered by suction on a
Buchner funnel. The filter cake was rinsed several times
1
obtained in 94% yield, m.p. 57－58 ℃. H NMR (400
MHz, CDCl3) δ: 8.35 (s, 1H, olefinic proton), 7.44－
7.30 (m, 7H, ArH), 7.04 (d, J＝7.6 Hz, 1H), 7.00 (d, J＝
7.8 Hz, 1H), 5.15 (s, 2H, OCH2), 2.38 (s, 3H, CH3); 13C
NMR (100 MHz, CDCl3) δ: 157.27, 147.65, 136.35,
131.49, 130.17, 129.90, 128.73 (2C), 128.15, 127.11
(2C), 122.08, 120.89, 112.61, 70.49, 14.23; IR (KBr
film) ν: 2949, 1651, 1599, 1511, 1483, 1319, 1146, 1121,
1020, 905, 755, 731, 692, 565 cm1. HRMS (ESI) cacld
＋
for C16H15NO3Na [M ＋ Na] : 292.0950; found
292.0949.
1-(2-(Benzyloxy)phenyl)propan-2-amine
4
A
solution of compound 3 (10.00 g, 37.13 mmol) in anhy-
drous tetrahydrofuran (80 mL) was added dropwise to a
stirred slurry of lithium aluminum hydride (8.470 g,
222.9 mmol) in anhydrous tetrahydrofuran (50 mL) at
0 ℃. After addition was finished, the mixture was then
heated to reflux, and stirring was continued at reflux for
approximately 10 h. After the reaction was complete,
Chin. J. Chem. 2016, XX, 1—6
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Zhang et al.
FULL PAPER
more tetrahydrofuran (120 mL) was added, and the
mixture was cooled to 0 ℃ by an ice-bath. Water (8
mL) was dropwise added over 15 min, an aqueous solu-
tion of sodium hydroxide (5%, w/w, 35 mL) was then
slowly added over 20 min. After the addition was fin-
ished, vigorous stirring was continued for 1 h at room
temperature. Anhydrous MgSO4 (8.0 g) was added, and
the suspension was further stirred for another 1 h. The
mixture was diluted with ethanol (150 mL) and filtered
through Buchner funnel. The filter cake was rinsed three
times with ethanol (80 mL×3). The combined filtrate
was concentrated under vacuum to give a viscous oily
residue. Concentrated HCl (36% w/w, 10 mL) and ethyl
acetate (90 mL) were added, the mixture was vigorously
stirred for 2 h. Suction on Buchner funnel gave the first
batch of hydrochloride salt, which was rinsed twice with
ethyl acetate (15 mL×2). The filtrate was concentrated
to dryness under vacuum. The residue was triturated
with a mixed solvent of toluene (35 mL) and ethyl ace-
tate (35 mL), suction on Buchner funnel gave the se-
cond batch of hydrochloride salt, which was rinsed
twice with a mixed solvent of toluene and ethyl acetate
(1∶1, 15 mL×2). Two batches of the above hydro-
chloride salts were combined and then partitioned be-
tween aqueous K2CO3 solution (15% w/w, 50 mL) and
dichloromethane (100 mL). Two phases were separated,
and the aqueous phase was extracted twice with di-
chloromethane (50 mL × 2). Organic extracts were
combined, and dried over anhydrous MgSO4. Removal
of solvent by vacuum distillation gave compound 4
(7.348 g, 30.45 mmol) as a colorless oil in 82% yield.
1H NMR (400 MHz, CDCl3) δ: 7.44－7.30 (m, 5H,
ArH), 7.22－7.13 (m, 2H, ArH), 6.92 (d, J＝7.8 Hz, 1H,
ArH), 6.90 (d, J＝7.7 Hz, 1H, ArH), 5.07 (s, 2H, OCH2),
3.28－3.18 (m, 1H, CHN), 2.82 (dd, J＝13.0, 5.4 Hz,
1H, CHHCHN), 2.58 (dd, J ＝ 13.0, 7.8 Hz, 1H,
CHHCHN), 1.10 (d, J＝6.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ: 156.81, 137.37, 131.25, 128.59
(2C), 128.46, 127.81, 127.53, 127.07 (2C), 120.68,
111.75, 69.85, 47.21, 41.32, 23.59. IR (neat) ν: 3360,
3032, 2958, 2922, 1599, 1585, 1493, 1451, 1380, 1241,
1122, 1022, 857, 752, 697 cm1. HRMS (ESI) cacld for
C16H20NO [M＋H]＋: 242.1545; found 242.1538.
as a pale yellow solid, which was triturated in a mixed
solvent of ethanol (15 mL) and water (10 mL), and then
was filtered by suction to afford pure compound 5
(9.338 g, 23.61 mmol) as white crystals in 95% yield,
1
m.p. 111－112 ℃. H NMR (400 MHz, CDCl3) δ:
7.44－7.32 (m, 6H, ArH), 7.15 (t, J＝7.6 Hz, 1H, ArH),
7.03 (d, J＝8.2 Hz, 2H, ArH in Ts), 6.94 (d, J＝7.6 Hz,
1H, ArH), 6.81 (d, J＝7.6 Hz, 1H, ArH), 6.80 (d, J＝7.7
Hz, 1H, ArH), 5.00 (ab peak, J＝11.5 Hz, 1H, OCHH),
4.93 (ab peak, J＝11.5 Hz, 1H, OCHH), 3.52－3.45 (m,
1H, CHN), 2.71 (dd, J＝13.6, 8.4 Hz, 1H, CHHCHN),
2.64 (dd, J＝13.6, 5.2 Hz, 1H, CHHCHN), 2.34 (s, 3H,
CH3 in Ts), 1.18 (d, J＝6.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ: 156.42, 142.53, 137.31, 136.62,
131.38, 129.34 (2C), 128.77 (2C), 128.19, 128.04,
127.60 (2C), 126.82 (2C), 126.23, 121.07, 111.79, 70.22,
50.84, 37.71, 22.48, 21.47; IR (KBr film) ν: 3451, 3310,
2983, 2961, 1621, 1598, 1494, 1453, 1326, 1230, 1156,
1121, 1012, 920, 752, 661 cm1. HRMS (ESI) cacld for
C23H25NO3SNa [M＋Na]＋: 418.1453; found 418.1456.
5-(Benzyloxy)-3-methyl-2-tosyl-1,2,3,4-tetrahy-
droisoquinoline 6 A solution of compound 5 (4.000 g,
10.11 mmol) and dimethoxy methane (3.846 g, 50.54
mmol) in ethyl acetate (60 mL) was stirred and cooled
to 0 ℃ by an ice-bath. BF3•Et2O (3.158 g, 22.25 mmol)
was then dropwise added over 5 min, the mixture was
further stirred at 0 ℃ for 1.5 h. The reaction was mon-
itored by TLC (eluent: EtOAc/hexane＝1∶6). After the
reaction was complete, an aqueous solution of K2CO3
(10% w/w, 30 mL) was added to quench the reaction.
After stirring was continued for 1 h, two phases were
separated. The aqueous solution was extracted twice
with ethyl acetate (30 mL×2). The combined organic
extracts were washed with brine (20 mL), and dried
over anhydrous MgSO4. Removal of solvent under
vacuum gave the crude product, which was purified by
column chromatography (eluent: EtOAc/hexane＝1∶6)
to furnish compound 6 (3.008 g, 7.381 mmol) as a col-
1
orless oil in 73% yield. H NMR (400 MHz, CDCl3) δ:
7.70 (d, J＝8.2 Hz, 2H, both orth-H in Ts), 7.40－7.29
(m, 5H, ArH), 7.24 (d, J＝8.2 Hz, 2H, both para-H in
Ts), 7.11 (t, J＝7.9 Hz, 1H, Ar-H), 6.75 (d, J＝7.9 Hz,
1H, ArH), 6.70 (d, J＝7.9 Hz, 1H, ArH), 5.02 (s, 2H,
OCH2), 4.69 (ab peak, J＝16.2 Hz, 1H, H-1), 4.51－
4.43 (m, 1H, H-3), 4.24 (ab peak, J＝16.2 Hz, 1H, an-
other H-1), 2.80－2.65 (m, 2H, H-4), 2.38 (s, 3H, CH3
in Ts), 0.99 (d, J＝6.8 Hz, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ: 156.79, 143.17, 137.07, 137.02, 132.74,
129.62 (2C), 128.57 (2C), 127.92, 127.22 (2C), 127.13
(2C), 126.61, 121.52, 118.42, 109.46, 69.90, 47.02,
42.28, 28.83, 21.51, 17.13; IR (neat) ν: 2978, 2931,
1734 (weak), 1597, 1494, 1453, 1336, 1241, 1159, 1072,
1024, 753, 661, 584, 551 cm1. HRMS (ESI) cacld for
C24H26NO3S [M＋H]＋: 408.1633; found 408.1633.
5-(Benzyloxy)-3-methylisoquinoline 7 To a solu-
tion of compound 6 (3.000 g, 7.362 mmol) in dimethyl
sulfoxide (18 mL) was added an aqueous solution of
NaOH (3.000 g, 30% w/w, 22.50 mmol). The resulting
N-(1-(2-(Benzyloxy)phenyl)propan-2-yl)-4-methyl-
benzenesulfonamide 5
A solution of compound 4
(6.000 g, 24.86 mmol) and Et3N (5.035 g, 49.76 mmol)
in dichloromethane (35 mL) was stirred and cooled by
an ice-bath. The powdered solid p-TsCl (5.215 g, 27.35
mmol) was then added in portions. After the addition
was finished, the mixture was further stirred at 0 ℃ for
1 h. The reaction was monitored by TLC (eluent:
EtOAc/hexane＝1∶4). After the reaction was complete,
water (30 mL) was added, and the biphasic mixture was
stirred overnight. Two phases were separated, and the
aqueous solution was extracted twice with dichloro-
methane (30 mL×2). The combined organic extracts
were dried over anhydrous MgSO4, and then concen-
trated under reduced pressure to give the crude product
4
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Chin. J. Chem. 2016, XX, 1—6

Novel Total Synthesis of Mansouramycin B
mixture was heated to around 125 ℃ and then stirred
at this temperature for 5 h. The reaction was monitored
by TLC (eluent: EtOAc/hexane＝2∶1). After the reac-
tion was complete, the mixture was allowed to cool to
room temperature and dilute with water (100 mL). The
aqueous solution was then extracted twice with ethyl
acetate (80 mL×2). The combined organic extracts
were washed with brine (30 mL), dried over anhydrous
MgSO4, and concentrated under vacuum to give the
crude product, which was purified by flash column
chromatography (CH2Cl2/EtOAc ＝ 8 ∶ 1) to afford
compound 7 (1.560 g, 6.257 mmol) as a yellow oil in
lution of methylamine (0.685 g, 40% w/w, 8.822 mmol)
were added. The ice-bath was removed, and the reaction
mixture was further stirred at 0 ℃ to room temperature
for 20 h. After completion of the reaction as indicated
by TLC (eluent: EtOAc/hexane＝1∶2), ethyl acetate
(25 mL) and water (10 mL) were added and stirred for 5
min. Two phases were separated, and the aqueous phase
was extracted again with ethyl acetate (25 mL). The
combined organic extracts were washed with brine (10
mL), and dried over anhydrous MgSO4. Removal of
solvent under vacuum gave the crude product, which
was purified by column chromatography (eluent:
CH2Cl2/EtOAc＝3∶1) to afford compound 10 (150 mg)
with contamination of 10% of its regioisomer. Further
purification by preparative TLC on silica gel plates
(HSHF, 20×20) (eluent: CH2Cl2/EtOAc＝2∶1) was
performed to furnish the pure compound 10 (128 mg,
0.633 mmol) as a dark red solid in 72% yield, m.p.
1
85% yield. H NMR (400 MHz, CDCl3) δ: 9.13 (s, 1H,
H-1), 7.90 (s, 1H, H-4), 7.53－7.47 (m, 3H, ArH), 7.46
－7.35 (m, 4H, ArH), 7.01 (d, J＝7.6 Hz, 1H, ArH),
5.22 (s, 2H, OCH2), 2.71 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 153.11, 151.35, 151.22, 136.58, 129.40,
128.72 (2C), 128.20, 127.65, 127.50 (2C), 126.29,
119.61, 113.22, 108.91, 70.27, 24.34; IR (neat) ν: 2979,
2924, 1629, 1587, 1495, 1452, 1393, 1331, 1283, 1259,
1168, 1073, 1005, 865, 749, 697, 660, 584 cm1. HRMS
(ESI) cacld for C17H16NO [M＋H]＋: 250.1232; found
250.1233.
1
290 ℃ (decom.). H NMR (400 MHz, CDCl3 and one
drop of D2O) δ: 9.14 (s, 1H, H-1), 7.77 (s, 1H, H-4),
5.79 (s, 1H, H-6), 2.96 (s, 3H, NCH3), 2.72 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3) δ: 181.27, 180.93, 166.82,
148.97, 147.73, 139.49, 122.15, 118.58, 100.97, 29.08,
25.45; IR (KBr film) ν: 3343, 2922, 1724, 1684, 1603,
1585, 1503, 1340, 1271, 1067 cm1. HRMS (ESI) cacld
for C11H11N2O2 [M＋H]＋: 203.0821; found 203.0826.
6-Chloro-3-methyl-7-(methylamino)isoquinoline-
5,8-dione 1 (Mansouramycin B) To a stirred solution
of compound 10 (100 mg, 0.495 mmol) in methanol (1
mL) was added powdered NCS (100 mg, 0.749 mmol)
at room temperature. The mixture was stirred at room
temperature for 1 h. The reaction was monitored by
TLC (eluent: EtOAc/hexane＝2∶1). After the reaction
was complete, the solvent was removed by vacuum dis-
tillation. The residue was then directly purified by flash
column chromatography (eluent: EtOAc/CH2Cl2/hexane
＝1∶3∶5) to afford Mansouramycin B 1 (110 mg,
0.465 mmol) as a dark red solid in 94% yield, m.p.
3-Methylisoquinolin-5-ol 8 A solution of com-
pound 7 (1.000 g, 4.011 mmol) in ethanol (10 mL) was
placed in a three-necked round-bottomed flask, which
was equipped with a magnetic stir bar, a gas inlet and a
gas outlet. The Pd/C catalyst (10% w/w, 150 mg) was
added, and the flask was then purged several times with
hydrogen gas. The reaction mixture was vigorously
stirred under an atmosphere of hydrogen gas (1.1 atm.).
After the mixture was heated to reflux, stirring was then
continued at reflux for 10 h. The reaction was monitored
by TLC (eluent: THF/hexane＝1∶2). After the reaction
was complete, the mixture was cooled down to room
temperature, and then passed through a short column (5
cm) of Celite to remove the catalyst. The solvent was
removed by rotary evaporation to give pure compound 8
(0.607 g, 3.813 mmol) as off-white crystals in 95%
yield, m.p. 282 － 283 ℃ . 1H NMR (400 MHz,
DMSO-d6) δ: 10.37 (br. s, 1H, OH), 9.12 (s, 1H, H-1),
7.77 (s, 1H, H-4), 7.48 (d, J＝7.7 Hz, 1H, H-6), 7.38 (t,
J＝7.7 Hz, 1H, H-7), 7.07 (d, J＝7.7 Hz, 1H, H-8), 2.61
(s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ: 152.04,
151.18, 150.01, 127.68, 127.59, 126.79, 117.35, 112.55,
111.85, 23.95; IR (KBr film) ν: 3420, 3106, 2948, 2626,
1626, 1591, 1574, 1401, 1290, 1281, 1147, 1128, 911,
892, 750, 563 cm1. HRMS (ESI) cacld for C10H10NO
[M＋H]＋: 160.0762; found 160.0761.
1
295 ℃ (decom.). H NMR (400 MHz, CDCl3) δ: 9.12
(s, 1H, H-1), 7.81 (s, 1H, H-4), 6.08 (brs. 1H, NH), 3.48
(d, J＝5.8 Hz, 3H, NCH3), 2.72 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) δ: 169.32, 166.93, 163.55,
147.21, 131.63, 131.50, 128.66, 128.62, 117.55, 29.96,
24.75. IR (KBr film) ν: 3446, 3422, 2959, 2926, 1718,
1685, 1584, 1552, 1513, 1403, 1146, 1127, 915, 564
cm1. HRMS (ESI) cacld for C11H10N2O2Cl [M＋H]＋:
237.0431; found 237.0425.
Supporting Information
3-Methyl-7-(methylamino)isoquinoline-5,8-dione
10 A solution of compound 8 (140 mg, 0.879 mmol)
1
Copies of H and 13C NMR spectra of compounds
in
a
mixed solvent of acetonitrile and water
1－8 and 10.
(CH3CN/H2O＝2∶1, 2 mL) was cooled to 0 ℃ by an
ice-bath, and iodobenzene diacetate (0.625 g, 1.940
mmol) was added. The resulting mixture was then
stirred at 0 ℃ for 2 h, until compound 8 could not be
detected by TLC (eluent: EtOAc/hexane ＝ 1 ∶ 2).
CeCl3•7H2O (0.495 g, 1.328 mmol) and an aqueous so-
Acknowledgement
We thank the National Natural Science Foundation
of China (No. 20972048) for the financial support of
this work.
Chin. J. Chem. 2016, XX, 1—6
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Zhang et al.
FULL PAPER
Nat. Prod. 2009, 72, 2120.
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6
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