Convergent Total Synthesis of Lamellarins and Their Congeners

Article abstract of DOI:10.1021/acs.joc.0c00998

A convergent total synthesis of lamellarins S and Z is described. The synthesis features a halogen dance of an easily accessible α,β-dibromopyrrole promoted by an ester moiety. The resultant β,β′-dibromopyrrole undergoes a ligand-controlled Suzuki-Miyaura coupling to provide a range of diarylated pyrrole derivatives. The established synthetic method was also applicable to the synthesis of ningalin B and lukianols A and B.

Full text of DOI:10.1021/acs.joc.0c00998

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Article
Convergent Total Synthesis of Lamellarins and Their Congeners
Daiki Morikawa, Kazuki Morii, Yuto Yasuda, Atsunori Mori, and Kentaro Okano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00998 • Publication Date (Web): 28 May 2020
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Page 1 of 18
The Journal of Organic Chemistry
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Convergent Total Synthesis of Lamellarins and Their Congeners
,
Daiki Morikawa,† Kazuki Morii,† Yuto Yasuda,† Atsunori Mori,† ‡ and Kentaro Okano*,†
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†Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
‡Research Center for Membrane and Film Technology, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
Supporting Information Placeholder
ABSTRACT: A convergent total synthesis of lamellarins S and Z is described. The synthesis features a halogen dance of an
easily accessible α,β-dibromopyrrole promoted by an ester moiety. The resultant β,β’-dibromopyrrole undergoes a ligand-
controlled Suzuki–Miyaura coupling to provide a range of diarylated pyrrole derivatives. The established synthetic meth-
od was also applicable to the synthesis of ningalin B, and lukianols A and B.
Figure 1. Lamellarins and the related pyrrole alkaloids.
INTRODUCTION
The number of pyrrole alkaloids have continued to
tions of the pyrrole ring (Figure 1).2,4 In addition to their
grow over recent years.1 Among them, more than 50 la-
structural diversity, their wide range of biological activi-
ties attract considerable interest as synthetic targets.5 The
common key feature of the synthesis of these pyrrole al-
kaloids is construction of the polysubstituted pyrrole core.
Most of the reported synthetic methods use a symmet-
rical pyrrole diester or diarylacetylene as the synthetic
intermediates, and most of the syntheses focus on sym-
metrical natural products.2,6 To the best of our knowledge,
there are only a limited number of synthetic methods that
can be applied to a series of these unsymmetrical lamel-
larins.7 Herein, we describe an approach toward a diver-
gent synthesis of symmetrical/unsymmetrical lamellarins
and their congeners, featuring a halogen dance8,9 of a di-
bromopyrrole derivative.
mellarins have been reported2 since lamellarins A–D were
isolated in 1985 by Faulkner and Clardy from the marine
prosobranch
mollusks.3
Ningalins,
lukianols,
didemnimides, dictyodendrins, polycitrins, and stor-
niamides are also part of this class, as related pyrrole alka-
loids, which possess various aryl groups at the two β posi
HO
HO
HO
HO
HO
MeO
HO
HO
HO
MeO
HO
HO
OH
OMe
OH
HO
O
O
O
HO
N
N
N
O
O
O
HO
HO
Lamellarin S
Lamellarin Z
Ningalin B
OSO3Na
HO
OH
HO
OH
The major challenge toward accomplishing a conver-
gent total synthesis of lamellarins and their congeners is
the construction of a multiply arylated pyrrole. We de-
scribe an inventive method for introducing the desired
functional groups onto the pyrrole in a straightforward
and divergent synthesis, superior to the classical Parr–
Knorr synthesis and Hantzsch syntheses for this pur-
pose.10 Recently we have been investigating the synthetic
potential of a halogen dance for the regiocontrolled and
I
NH
OH
O
O
O
N
N
N
O
O
OH
HO
OH
OH
HO
Dictyodendrin B
Lukianol A
Lukianol B
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step-economical synthesis of tri- and tetra-substituted smooth migration of the α-bromo group within 10 min,
thiophenes and furans (Scheme 1A).11 Differential reactivi-
ty of the bromo groups enabled a one-pot double Suzuki–
Miyaura coupling, and afforded a triarylated thiophene in
a regioselective manner. In contrast, attempted regiose-
lective cross-coupling reaction of 2,3,5-tribromothiophene
was difficult, and the same compound was afforded in low
yield.12 In addition to the superior regioselectivity, this
reaction allows migration of the bromo group which can
be used as a handle for further transformation. This ena-
bles a highly efficient atom-economical process, and im-
portantly, also avoids late-stage bromination, which often
causes side reactions in the presence of highly reactive
electron-rich aromatic rings such as pyrrole. A halogen
dance with a bromopyrrole derivative has not yet been
reported, possibly due to the lower acidity of the pyrrole
compared with thiophene and furan. We started the syn-
thetic studies toward the pyrrole alkaloids based on our
recent observation that an ester group significantly pro-
moted the halogen dance (Scheme 1B).13 In preliminary
experiments, we investigated the regioselective meta-
lation of tribromopyrrole 1 to obtain dibromopyrrole 2 as
a common intermediate for the synthesis of these pyrrole
alkaloids through regioselective arylation; however, the
use of several organolithiums or Grignard reagents pro-
vided 2 as a major product, but with several inseparable
byproducts. We anticipated that the readily available di-
bromopyrrole 3 could be converted into the desired 2 by
protonation of organolithium 5, derived from the first-
generated organolithium 4 through a halogen dance.
and aqueous workup provided β,β’-dibromopyrrole 8 in
82% yield on a multi-gram scale. Based on our prelimi-
nary experiments, two bromo groups and an ester moiety
are essential for this halogen dance of a bromopyrrole
derivative.14 Both the reaction temperature and the reac-
tion time proved critical for a high-yielding process, due
to the instability of either β-lithio-α,β-dibromopyrrole 9
or α-lithio-β,β’-dibromopyrrole 10.15
1
2
3
4
5
6
7
8
9
Br
Br
Li
1) Br2, CHCl3
0 °C to rt, 80%
LDA
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CO2Et
Br
CO2Et
Br
CO2Et
N
H
2) NaH, SEMCl
THF, 0 °C to rt
71%
N
N
THF
–78 °C
10 min
SEM
SEM
6
7
9
Br
Br
Br
Br
H2O
CO2Et
Li
CO2Et
N
N
–78 °C
82%
SEM
SEM
8
10
Scheme 2. Halogen dance of α,β-dibromopyrrole 7.
With β,β’-dibromopyrrole 8 in hand, we then explored
suitable palladium catalysts for the regioselective Suzuki–
Miyaura coupling with two equivalents of arylboronate
ester 11 (Table 1). First, the reaction with Pd(PPh3)4 fur-
nished monoarylated pyrrole 1216 and diarylated pyrrole 13
in 13% and 52% yields, respectively (entry 1). This mono-
arylation proceeded in a completely regiospecific manner,
despite the expected difficulty in controlling the reactivi-
ties of two bromo groups at the β positions.17 A combina-
tion of Pd2(dba)3 (5 mol%) and PPh3 (20 mol%) led to the
formation of a 1:1 mixture of 12 and 13 with 36% recovery
of the starting dibromopyrrole 8 (entry 2). Prolonged re-
action time resulted in significant reduction of the yields
of the products, due to hydrolysis of the ester moiety. The
use of Pd(PCy3)2 and Pd(t-Bu3P)2 provi-
A. Two-pot synthesis of triarylated thiophene using halogen dance (Ref. 11a)
halogen
dance
ZnCl2·TMEDA;
cat. Pd(PPh3)4
H
Li
Br
LDA
I
THF
–78 °C
Br
Br
Ar3
Br
Br
Li
Br
S
S
S
Ar1
Table 1. Effects of phosphine ligandsa
one-pot regioselective
Br
cat. Pd(PPh3)4
OBn
Br
sole isomer
Ar1
S
(HO)2B
OBn BnO
OBn
Ar1
S
Ar2
Ar3
pinB
Pd catalyst
Ar2
11
B(OH)2
Br
Br
CO2Et
Br
Ba(OH)2·8H2O
B. Halogen dance of dibromopyrrole promoted by ester (This work)
+
unsuccessful
regioselective
metalation
1,4-dioxane/H2O (4:1)
reflux, 15 min
Br
Br
Br
Br
Br
Br
CO2Et
CO2Et
N
N
SEM
N
SEM
SEM
H2O
Li
CO2Et
H
CO2Et
Br
CO2Et
8
12
13
N
P
N
P
N
P
2
1
5
entry
catalyst
8b (%)
12b (%)
13b (%)
52
halogen
dance
stepwise
arylation
Br
H
Br
Li
1
Pd(PPh3)4
3
36
10
2
13
22
3
LDA
2
Pd2(dba)3, PPh3
Pd(PCy3)2
19
THF
–78 °C;
Lamellarins S and Z
Br
CO2Et
Br
CO2Et
N
P
N
P
Lukianols A and B
Ningalin B
3
63
3
4
4
Pd(t-Bu3P)2
Pd(t-Bu3P)2
3
75
Scheme 1. Strategy for the convergent synthesis of lamel-
larins and their congeners.
c
5d
6d
7d
8
21
26
–
36
Pd(t-Bu3P)2 + Ph2S (1.0 equiv)
<1
7
36
RESULTS AND DISCUSSION
Pd(t-Bu3P)2 + THT (1.0 equiv) 41
8
The synthesis began with the regioselective dibromina-
tion of the commercially available pyrrole carboxylic acid
ethyl ester (6) (Scheme 2). Protection of the pyrrole ni-
trogen with a 2-(trimethylsilyl)ethoxymethyl (SEM) group
provided α,β-dibromopyrrole 7 for the key halogen dance
step. Treatment with LDA at –78 °C resulted in the
Pd2(dba)3, P(4-CF3C6H4)3
14
36
24
c
c
9
Pd2(dba)3, P[3,5-(CF3)2C6H3]3
85
–
–
a Reaction conditions: dibromopyrrole 8 (1.0 equiv, 0.30 mmol), 11
(2.0 equiv, 0.60 mmol), Pd source (0.030 mmol for palladium, 10
mol%), phosphine ligand (0.060 mmol, 20 mol%) Ba(OH)2·8H2O (6.0
b
equiv, 1.8 mmol), 1,4-dioxane/H2O (4:1), reflux, 15 min. The yield
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The Journal of Organic Chemistry
was determined from the 1H NMR spectrum of the crude product
In this Suzuki–Miyaura cross coupling the use of
c
using 1,1,2,2-tetrachloroethane as an internal standard. Not detected
1
2
3
4
5
6
7
8
Ba(OH)2 proved effective for the smooth arylation; how-
ever, the strongly basic conditions led to a significant re-
duction of the yield of the products after prolonged reac-
tion time, probably due to hydrolysis of the ethyl ester.
This limitation prohibited our further optimization to
improve the yield of monoarylated pyrrole 12. In addition,
laborious purification process was required to obtain the
monoarylated pyrrole 12 in a pure form on a preparative
scale. The monoarylated pyrrole 12 was separated from
the diarylated pyrrole 13 by column chromatography.
Subsequent preparative SEC-HPLC was necessary for sep-
arating the monoarylated pyrrole 12 from a minute
amount of an unidentified byproduct. During the process,
substantial amount of the monoarylated pyrrole was not
recovered, which resulted in the low isolated yield (22%
in Scheme 4) compared to the NMR yield (36% in Table 1).
1
d
in the crude H NMR spectrum. Arylboronate ester 11 (1.0 equiv,
0.30 mmol).
ded diarylated pyrrole 13 in 63% and 75% yields, respec-
tively (entries 3 and 4). Encouraged by this superior cata-
lytic activity, we performed the same reaction with one
equivalent of arylboronate ester 11 in order to obtain
monoarylated pyrrole 12; however, Pd(t-Bu3P)2 favored
the exclusive formation of 13 with 21% recovery of the
starting dibromopyrrole 8 (entry 5). These results can be
rationalized by “intramolecular catalyst transfer”,18 which
has been observed in a Ni-/Pd-catalyzed living chain-
growth polymerization (Scheme 3). The complex 14
formed after transmetalation is converted to palladium
(0)-π complex 15. Dissociation of the π complex 15 gives
the monoarylated pyrrole 12. In contrast, the palladium
(0) in 15 is transferred to the distal C–Br bond through
oxidative addition to form palladium (II) species 16. Sub-
sequent Suzuki – Miyaura coupling furnishes the dia-
rylated pyrrole 13. We next examined the effects of an
additive to suppress the catalyst transfer. Apart from the
recent report by Yokozawa’s group,18e stoichiometric
amount of Ph2S did not suppress the formation of the
diarylated pyrrole,19 whereas tetrahydrothiophene (THT)
reduced the catalytic activity (entries 6 and 7). Additional
BnO
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This catalyst screening enabled a stepwise and regio-
controlled introduction of two aryl groups, which led to
the synthesis of lukianols A6c,21 and B21a,21g (Scheme 4).
Similar to the report by Banwell,7a dibromopyrrole 8 un-
derwent a one-pot double Suzuki–Miyaura coupling with
catalytic Pd(PPh3)4, providing the desired product 13 in
78% yield. Deprotection of the SEM group was performed
in a stepwise manner,22 namely, TFA-promoted removal
of the (trimethylsilyl)ethyl group and subsequent treat-
ment of the resulting hemiaminal with aqueous sodium
carbonate in the presence of hydroxylamine as a formal-
dehyde scavenger. The unprotected pyrrole underwent N-
alkylation with 17 to provide the desired product 18,
which was then transformed to the fused pyrrole 19
through hydrolysis of the ester by KOSiMe323 followed by
cyclization.21b Removal of the benzyl groups with a com-
bination of BCl3 and C6HMe524 provided lukianol A. The
established stepwise arylation was effective for the syn-
thesis of lukianol B bearing different aromatic rings. The
trimethylsilyl group of the obtained diarylated pyrrole 21
was converted to an iodo group by ICl at –78 °C, without
affecting the reactive pyrrole ring. Deprotection of the
SEM group, lactone formation, and removal of the benzyl
groups completed the synthesis of lukianol B. This cata-
lyst-controlled arylation strategy allows introduction of
two different aryl groups in a completely regioselective
manner. This proved effective for the synthesis of these
pyrrole alkaloids, as a late-stage iodination of lukianol A
was not regioselective due to the multiple phenol moie-
ties and reactive pyrrole α-position.21g
OBn
OBn
Pd0
Br
Br Pd
Br
Pd
CO2Et
8
CO2Et
CO2Et
N
SEM
N
SEM
N
SEM
14
15
16
OBn
BnO
OBn
Br
CO2Et
CO2Et
N
SEM
N
SEM
12
13
Scheme 3. Potential catalyst transfer mechanism of the
exclusive formation of the diarylated pyrrole.
PhSMe and 1,5-cyclooctadiene20 did not provide satisfac-
tory results. Among a series of phosphine ligands tested,
P(4-CF3-C6H4)3 led to the formation of monoarylated pyr-
role 12 in 36% yield (entry 8); however, more electron-
deficient P[3,5-(CF3)2C6H3]3 provided neither 12 nor 13
with 85% recovery of the starting dibromopyrrole 8 (entry
9).
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BnO
OBn
BnO
OBn
HO
OH
OBn
BnO
OBn
1
2
3
4
5
6
pinB
1) TFA, CH2Cl2, 0 °C
11
2) NH2OH·HCl
1) KOSiMe3
Br
Br
CO2Et
Pd(PPh3)4 (10 mol%)
Ba(OH)2·8H2O
BCl3
C6HMe5
Na2CO3, THF/H2O
rt, 82% (2 steps)
1,2-DCE
80 °C, 72%
O
O
CO2Et
O
N
N
N
O
O
CO2Et
N
1,4-dioxane/H2O (4:1)
reflux
CH2Cl2
3) K2CO3, DMF
rt, 75%
2) KOAc
Ac2O
100 °C, 76%
N
SEM
SEM
–78 °C to 0 °C
63%
13
8
O
78%
Br
7
8
Pd2(dba)3 (5 mol%), P(4-CF3C6H4)3 (20 mol%)
Ba(OH)2·8H2O, 1,4-dioxane/H2O (4:1)
reflux, 22%
OBn
OH
OBn
OBn
18
17
OBn
19
Lukianol A
11
pinB
9
BnO
BnO
I
OBn
HO
I
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OBn
BnO
Me3Si
OBn
Me3Si
Bpin
1) ICl, CH2Cl2
–78 °C to –40 °C
96%
20
5) KOSiMe3
1,2-DCE
80 °C, 64%
Pd(PPh3)4 (10 mol%)
Ba(OH)2·8H2O
BCl3
C6HMe5
Br
O
O
2) TFA, CH2Cl2, 0 °C
N
N
O
O
CO2Et
CO2Et
3) NH2OH·HCl
Na2CO3, THF/H2O
rt, 68% (2 steps)
4) 17, K2CO3, DMF
rt, 89%
6) KOAc
Ac2O
100 °C
1,4-dioxane/H2O (4:1)
reflux
CH2Cl2
–78 °C to 0 °C
N
N
SEM
SEM
21
12
44%
45%
(2 steps)
OBn
OH
22
Lukianol B
Scheme 4. Regiocontrolled synthesis of lukianol A and B.
The β,β’-dibromopyrrole 8 was also the common in-
termediate for the synthesis of ningalin B6f,6h,25, and lamel-
larins S26 and Z27 (Scheme 5). A one-pot double Suzuki–
Miyaura coupling with arylboronate ester 23 took place to
give the corresponding pyrrole 24 in 59% yield. Hydroly-
sis of the ester and Pb(OAc)4-mediated lactone formation
proceeded smoothly. Removal of the SEM group was car-
ried out to provide the compound 25 in 24% yield over
three steps from compound 24. N-Alkylation was per-
formed with phenylethyl alcohol 26 under Mitsunobu
conditions, and subsequent hydrogenolysis of the six ben-
zyl ethers was carried out to provide ningalin B in 97%
yield. The lactone-fused pyrrole 25 was also a synthetic
intermediate for the total synthesis of lamellarin S. Thus,
N-alkylation was carried out with phenylethyl alcohol 27
under the standard Mitsunobu conditions to provide
compound 28 in 71% yield. Subsequent treatment with
PIFA28 achieved the oxidative C–C bond formation to con-
struct the lamellarin skeleton. Hydrogenolysis of the ben-
zyl ethers gave lamellarin S in 98% yield. In addition to
these natural products, lamellarin Z, which has different
aryl groups at the two β positions, was synthesized using
the established stepwise arylation from the synthesis of
lukianol B. The optimal monoarylation conditions were
effective for arylboronate ester 29, and the corresponding
monoarylated pyrrole 30 was isolated in 30% yield, with
the excellent regioselectivity. The second arylation was
performed with arylboronate ester 23 in the presence of
catalytic Pd(PPh3)4 to provide the desired compound 31 in
moderate yield. Similar to the synthetic route of lamellar-
in S, the ethyl ester was then converted to the lactone.
Removal of the SEM group and subsequent N-alkylation
took place smoothly with phenylethyl alcohol 27 to pro-
vide the desired compound 32. The PIFA-promoted oxida-
tive formation of the lamellarin skeleton and subsequent
palladium-catalyzed hydrogenolysis of the benzyl ethers
provided lamellarin Z in 80% yield over two steps from
compound 32.
CONCLUSIONS
In summary, we have achieved the convergent total
synthesis of ningalin B, lukianols A and B, and lamellarins
S and Z, by developing an unprecedented ester-promoted
halogen dance of the α,β-dibromopyrrole derivative. The
two bromo groups at the β positions were converted to
the corresponding aryl groups by a regioselective Suzuki–
Miyaura coupling. Significant ligand effects were observed
for the ratio of monoarylated and diarylated products,
which paved the way for the straightforward syntheses of
the related pyrrole alkaloids.
EXPERIMENTAL SECTION
GENERAL
Analytical thin layer chromatography (TLC) was performed
on Merck 60 F254 aluminum sheets precoated with a 0.25 mm
thickness of silica gel. Melting points (m.p.) were measured
on a Yanaco MP-J3 and are uncorrected. Infrared (IR) spectra
were recorded on a Bruker Alpha with an ATR attachment
(Ge) and are reported in wave numbers (cm– ). 1H NMR (400
MHz) and 13C{1H} NMR (100 MHz) spectra were measured on
1
1
a JEOL ECZ400 spectrometer. Chemical shifts for H NMR
are reported in parts per million (ppm) downfield from tet-
ramethylsilane with the solvent resonance as the internal
standard (CHCl3: δ 7.26 ppm, THF-d7: δ 1.72 ppm, DMSO-d5:
δ 2.50 ppm, CHD2OD: δ 3.31 ppm, acetone-d5: δ 2.05 ppm,
tetramethylsilane: δ 0 ppm) and coupling constants are in
Hertz
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BnO
BnO
BnO
BnO
1)
BnO
BnO
HO
BnO
BnO
OBn
BnO
BnO
HO
1) KOH
18-crown-6
EtOH, reflux
2) Pb(OAc)4
EtOAc, reflux
OBn
OH
1
2
3
4
5
6
7
8
9
Bpin
OH
23
26
HO
Br
Br
Pd(PPh3)4 (10 mol%)
Ba(OH)2·8H2O
PPh3, DIAD
THF, rt, 70%
O
O
HO
HO
CO2Et
CO2Et
N
N
SEM
N
H
N
1,4-dioxane/H2O (4:1)
reflux
3) TFA, CH2Cl2, rt
then evaporation
2) cat. Pd/C, H2 (1 atm)
EtOH/EtOAc, rt, 97%
SEM
O
O
NH2OH·HCl, Na2CO3
THF/H2O, rt
24
25
8
OBn
59%
OMe
MeO
BnO
Ningalin B
24% (3 steps)
Pd2(dba)3 (5 mol%)
P(4-CF3C6H4)3 (20 mol%)
Ba(OH)2·8H2O, 1,4-dioxane/H2O (4:1)
reflux, 30%
OH
pinB
27
PPh3, DIAD
THF, rt, 71%
29
HO
BnO
HO
HO
BnO
BnO
BnO
OMe
OH
OBn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1) PIFA, BF3·OEt2
CH2Cl2, –40 °C, 61%
Br
O
O
MeO
HO
MeO
BnO
CO2Et
N
N
2) cat. Pd/C, H2 (1 atm)
EtOH/EtOAc, rt, 98%
N
O
O
SEM
1) KOH, 18-crown-6
EtOH, reflux
2) Pb(OAc)4
30
28
Lamellarin S
HO
BnO
BnO
EtOAc, reflux
BnO
3) TFA, CH2Cl2, rt
then evaporation
NH2OH·HCl, Na2CO3
THF/H2O, rt
BnO
BnO
BnO
OMe
BnO
BnO
HO
HO
Bpin
OMe
OMe
23
Pd(PPh3)4 (10 mol%)
Ba(OH)2·8H2O
1) PIFA, BF3·OEt2
CH2Cl2, –40 °C
42% (3 steps)
O
O
MeO
HO
MeO
BnO
1,4-dioxane/H2O (4:1)
reflux
CO2Et
4) 27, PPh3, DIAD
THF, rt, 86%
2) cat. Pd/C, H2 (1 atm)
EtOH/EtOAc, rt
80% (2 steps)
N
SEM
N
N
O
O
72%
31
32
Lamellarin Z
Scheme 5. Convergent synthesis of lamellarins and their congeners.
(Hz). The following abbreviations are used for spin multiplic-
ity: s = singlet, d = doublet, t = triplet, q = quartet, sept =
septet, m = multiplet, and br = broad. Chemical shifts for
13C{1H} NMR are reported in ppm from tetramethylsilane
with the solvent resonance as the internal standard (CDCl3: δ
77.16 ppm, THF-d8: δ 67.21 ppm, DMSO-d6: δ 39.52 ppm,
CD3OD: δ 49.00 ppm, acetone-d6: δ 29.84 ppm). High-
resolution mass spectra (HRMS) were performed on a JEOL
JMS-T100LP AccuTOF LC-Plus (ESI) with a JEOL MS-
5414DART attachment.
to room temperature with stirring over 5 h, at which time the
mixture was treated with saturated aqueous sodium thiosul-
fate (200 mL). After partitioned, the aqueous layer was ex-
tracted with CHCl3 (200 mL). The organic extracts were
washed with water (200 mL) and brine (200 mL), dried over
sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was
recrystallized from hexane to provide the title compound S1
as a colorless solid (19.00 g, 64.0 mmol, 80%), whose 1H NMR
spectra was identical to that reported in the literature.29 Rf =
0.21 (hexane/diethyl ether = 6:1); M.p. 111–112 °C; IR (ATR,
cm– ): 3230, 2925, 1694, 1412, 1385, 1319, 1235, 1205, 1022, 973,
830, 759, 637, 622; H NMR (400 MHz, CDCl3): δ 9.45 (br s,
1H), 6.88 (d, 1H, J = 3.2 Hz), 4.33 (q, 2H, J = 7.2 Hz), 1.36 (t, 3H,
J = 7.2 Hz); 13C{1H} NMR (100 MHz, CDCl3): δ 160.5, 124.0,
118.0, 107.6, 100.5, 61.5, 14.5; HRMS (DART/TOF) m/z: [M +
H]+ Calcd for C7H879Br81BrNO2 297.8901; Found 297.8905.
1
MATERIALS
1
Unless otherwise stated, all reactions were conducted in
flame-dried glassware under an inert atmosphere of nitrogen.
All work-up and purification procedures were carried out
with reagent solvents in air. Unless otherwise noted, materi-
als were obtained from commercial suppliers and used with-
out further purification. Flash column chromatography was
performed on Wakogel® 60N (45–75 µm, Wako Pure Chemi-
cal Industries, Ltd.). Recycling preparative SEC-HPLC was
performed with LC-9201 (Japan Analytical Industry Co., Ltd.)
equipped with preparative SEC columns (JAI-GEL-1H and
JAI-GEL-2H). Anhydrous THF (>99.5%, water content: < 10
ppm) was purchased from Kanto Chemical Co., Inc. and fur-
ther dried by passing through a solvent purification system
(Glass Contour) prior to use. LDA (2.0 M in THF/heptane
/ethylbenzene) was purchased from Sigma-Aldrich Co.
(Product number: 361798).
Ethyl 4,5-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-
1H-pyrrole-2-carboxylate (7).
A flame-dried 500-mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was
charged with S1 (3.715 g, 15.0 mmol, 1.0 equiv) and anhydrous
THF (50 mL). After the solution was cooled to 0 °C, SEMCl
(3.367 g, 20.2 mmol, 1.3 equiv) and NaH (771.9 mg, 19.3 mmol,
1.3 equiv) were added to the Schlenk tube at 0 °C. The reac-
tion mixture was allowed to warm to room temperature with
stirring over 80 min, at which time the mixture was treated
with water (50 mL). The resulting mixture was extracted
twice with diethyl ether (70 mL). The combined organic ex-
tracts were washed with water (100 mL) and brine (100 mL),
dried over sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product,
which was purified by silica gel column chromatography
(hexane/CH2Cl2 = 1:1) to provide the corresponding product 7
as a brown oil (4.517 g, 10.6 mmol, 71%). Rf = 0.78 (hex-
SYNTHESIS OF DIPROMOPYRROLE 8
Ethyl 4,5-dibromo-1H-pyrrole-2-carboxylate (S1).
A 1-L round-bottomed flask equipped with a Teflon-coated
magnetic stirring bar was charged with ethyl 1H-pyrrole-2-
carboxylate (6) (11.20 g, 80.5 mmol, 1.0 equiv) and CHCl3 (400
mL). After the solution was cooled to 0 °C, Br2 (25.56 g, 160
mmol, 2.0 equiv) in CHCl3 (8 mL) was added dropwise to the
flask over 5 min. The reaction mixture was allowed to warm
1
ane/diethyl ether = 6:1); IR (ATR, cm– ): 1712, 1415, 1315, 1220,
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The Journal of Organic Chemistry
Page 6 of 18
1094, 859, 836, 757, 635; 1H NMR (400 MHz, CDCl3): δ 7.06 (s,
A 100-mL round-bottomed flask equipped with a Teflon-
1
2
3
4
5
6
7
8
1H), 5.83 (s, 2H), 4.29 (q, 2H, J = 7.2 Hz), 3.57 (t, 2H, J = 8.2
Hz), 1.34 (t, 3H, J = 7.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), –0.03 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.5, 124.5, 120.5, 113.4,
100.5, 75.3, 66.1, 60.6, 17.8, 14.4, –1.4; HRMS (ESI/TOF) m/z:
[M + Na]+ Calcd for C13H2179Br81BrNO3SiNa 449.9535; Found
449.9520.
coated magnetic stirring bar was charged with 8 (438.5 mg,
1.03 mmol, 1.0 equiv), 11 (1.270 g, 4.09 mmol, 4.0 equiv),
Ba(OH)2·8H2O (1.946 g, 6.17 mmol, 6.0 equiv), Pd(PPh3)4
(115.7 mg, 0.100 mmol, 10 mol%), water (2 mL), and 1,4-
dioxane (8 mL). The flask was placed in a preheated oil bath
and heated at 100 °C for 15 min, at which time the solution
was treated with saturated aqueous ammonium chloride (30
mL). The resulting mixture was extracted twice with ethyl
acetate (30 mL). The combined organic extracts were washed
with water (50 mL) and brine (50 mL), dried over sodium
sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude product, which was purified
by silica gel column chromatography (hexane/diethyl ether =
8:1 to 3:1, gradient) to provide the corresponding product 13
as a brown oil (511.0 mg, 0.806 mmol, 78%). Rf = 0.27 (hex-
Ethyl 3,4-dibromo-1-[(2-(trimethylsilyl)ethoxy)methyl]-
1H-pyrrole-2-carboxylate (8).
9
A flame-dried 500-mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was
charged with 7 (3.66 g, 8.56 mmol, 1.0 equiv) and anhydrous
THF (86 mL). After the solution was cooled to –78 °C, LDA
(2.0 M in THF/heptane/ethylbenzene, 4.7 mL, 9.4 mmol, 1.1
equiv) was added to the Schlenk tube and stirred at –78 °C
for 10 min. The reaction mixture was treated with water (2
mL) at –78 °C and allowed to warm to room temperature
with stirring over 1 h, at which time the resulting mixture
was treated with saturated aqueous ammonium chloride (90
mL) and extracted twice with diethyl ether (100 mL). The
combined organic extracts were washed with water and brine,
dried over sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product,
which was purified by silica gel column chromatography
(hexane/CH2Cl2 = 1:1) to provide the title product 8 as a yel-
low oil (2.99 g, 7.01 mmol, 82%). Rf = 0.32 (hexane/CH2Cl2 =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
ane/diethyl ether = 3:1); IR (ATR, cm– ): 2953, 1694, 1240, 1176,
1
1104, 1082, 834, 697; H NMR (400 MHz, CDCl3): δ 7.46–7.31
(m, 10H), 7.12 (d, 2H, J = 8.8 Hz), 7.10 (s, 1H), 7.00 (d, 2H, J =
8.8 Hz), 6.90 (d, 2H, J = 8.8 Hz), 6.81 (d, 2H, J = 8.8 Hz), 5.71
(s, 2H), 5.08 (s, 2H), 5.00 (s, 2H), 4.06 (q, 2H, J = 7.2 Hz), 3.62
(t, 2H, J = 8.0 Hz), 0.99–0.93 (m, 5H), 0.00 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 161.7, 157.6, 157.2, 137.2, 137.1, 131.8,
131.6, 129.3, 128.5, 128.3, 127.9, 127.5, 127.2, 125.4, 124.6, 120.2,
114.5, 114.0, 77.7, 69.9, 66.2, 59.8, 17.9, 13.8, –1.3; HRMS
(ESI/TOF) m/z: [M + Na]+ Calcd for C39H43NO5SiNa
656.2808; Found 656.2831.
1
1:1); IR (ATR, cm– ): 3118, 1692, 1394, 1375, 1312, 1281, 1248, 1168,
1096, 1081, 834; 1H NMR (400 MHz, CDCl3): δ 7.06 (s, 1H), 5.63
(s, 2H), 4.36 (q, 2H, J = 7.6 Hz), 3.51 (t, 2H, J = 8.0 Hz), 1.40 (t,
2H, J = 7.6 Hz), 0.90 (t, 3H, J = 8.0 Hz), –0.02 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 159.7, 126.6, 121.0, 108.6, 101.6, 78.6,
66.8, 61.1, 17.9, 14.3, –1.3; HRMS (ESI/TOF) m/z: [M + Na]+
Calcd for C13H2179Br81BrNO3SiNa 449.9535; Found 449.9534.
Ethyl 3,4-bis(4-(benzyloxy)phenyl)-1H-pyrrole-2-
carboxylate (S2).
A 100-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 13 (115.8 mg,
0.183 mmol, 1.0 equiv) and CH2Cl2 (4 mL). The solution was
cooled to 0 °C. TFA (100 µL, 1.31 mmol, 7.3 equiv) was added
to the flask and the resulting mixture was stirred at 0 °C for
4 h, at which time the reaction mixture was treated with wa-
ter (8 mL) and extracted with CH2Cl2 (10 mL) three times.
The combined organic extracts were washed with saturated
aqueous sodium hydrogen carbonate (30 mL), water (30 mL),
and brine (30 mL), dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give
a crude hemiaminal (118.8 mg), which was used for the next
step without further purification.
–
CATALYST SCREENING IN SUZUKI MIYAURA
COUPLING
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 8 (0.30 mmol,
1.0 equiv), 11 (0.60 mmol, 2.0 equiv), Ba(OH)2‧8H2O (1.8
mmol, 6.0 equiv), palladium catalyst (30 µmol for palladium,
10 mol%), phosphorus ligand (60 µmol, 20 mol%), water (0.6
mL), and 1,4-dioxane (2.4 mL). The flask was placed in a pre-
heated oil bath and heated at 100 °C for 15 min, at which
time the reaction mixture was treated with water (3 mL). The
resulting mixture was extracted with diethyl ether (5 mL)
three times. The combined organic extracts were washed
with water and brine, dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give
a crude product. The yields of the monoarylated pyrrole 12
and diarylated pyrrole 13 were determined by 1H NMR analy-
sis using 1,1,2,2-tetrachloroethane as an internal standard by
comparing relative values of integration for the peaks ob-
served at 5.71 ppm (2 protons for 13), 5.66 ppm (2 proton for
12), and 5.63 ppm (2 proton for 8) with that of 1,1,2,2-
tetrachloroethane observed at 5.96 ppm.
A 20-mL test tube equipped with a Teflon-coated magnetic
stirring bar was charged with the crude hemiaminal, sodium
carbonate (152.4 mg, 1.44 mmol, 7.9 equiv), NH2OH·HCl
(13.7 mg, 0.21 mmol, 1.1 equiv), water (0.3 mL), and THF (1.2
mL). The resulting mixture was stirred at room temperature
for 4.5 h, at which time the reaction mixture was treated with
1 M aqueous hydrochloric acid (2 mL) and extracted with
ethyl acetate (4 mL) three times. The combined organic ex-
tracts were washed with water (20 mL) and brine (20 mL),
dried over sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product,
which was purified by silica gel column chromatography
(hexane/methyl acetate = 5:1) to provide the title product S2
as a colorless solid (75.0 mg, 0.15 mmol, 82%). Rf = 0.50 (hex-
1
ane/CH2Cl2 = 1:2); M.p. 82–85 °C; IR (ATR, cm– ): 3301, 1681,
TOTAL SYNTHESIS OF LUKIANOLA
1
1535, 1455, 1379, 1289, 1239, 1176, 1025, 833, 737, 698; H NMR
Ethyl
3,4-bis(4-(benzyloxy)phenyl)-1-((2-
(400 MHz, CDCl3): δ 9.12 (br s, 1H), 7.47–7.30 (m, 10H), 7.20
(d, 2H, J = 8.8 Hz), 7.05–7.03 (m, 3H), 6.92 (d, 2H, J = 8.8 Hz),
6.83 (d, 2H, J = 8.8 Hz), 5.07 (s, 2H), 5.01 (s, 2H), 4.19 (q, 2H, J
(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate
(13).
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Page 7 of 18
The Journal of Organic Chemistry
3,7,8-Tris(4-(benzyloxy)phenyl)-1H-pyrrolo[2,1-
= 7.2 Hz), 1.17 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (100 MHz,
1
2
3
4
5
6
7
8
CDCl3): δ 161.3, 157.9, 157.4, 137.3, 137.2, 132.1, 129.6, 129.0, 128.7,
128.07, 128.05, 127.74, 127.65, 127.5, 126.9, 126.5, 120.0, 119.9,
114.7, 114.1, 70.1, 60.3, 14.3; HRMS (ESI/TOF) m/z: [M + Na]+
Calcd for C33H29NO4Na 526.1994; Found 526.2018.
c][1,4]oxazin-1-one (19).
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with S3 (65.4 mg,
93.5 µmol, 1.0 equiv), potassium acetate (162.5 mg, 1.66 mmol,
18 equiv), and acetic anhydride (9.4 mL). The flask was
placed in a preheated oil bath and heated at 100 °C for 30
min. After cooling to room temperature, the acetic anhydride
was removed azeotropically with toluene (60 mL) under re-
duced pressure. The oily residue was dissolved in ethyl ace-
tate (10 mL) and the resulting mixture was washed with satu-
rated aqueous ammonium chloride (5 mL). After partitioned,
the aqueous layer was extracted twice with ethyl acetate (5
mL). The combined organic extracts were washed with water
(10 mL) and brine (10 mL), dried over sodium sulfate, and
filtered. The filtrate was concentrated under reduced pres-
sure to give a crude product, which was purified by silica gel
column chromatography (hexane/methyl acetate = 3:1) to
provide the corresponding product 19 as a yellow amorphous
(48.6 mg, 71.3 µmol, 76%). Rf = 0.59 (hexane/methyl acetate =
Ethyl
3,4-bis(4-(benzyloxy)phenyl)-1-(2-(4-
(benzyloxy)phenyl)-2-oxoethyl)-1H-pyrrole-2-
carboxylate (18).
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with S2 (109.0 mg,
0.216 mmol, 1.0 equiv), 17 (93.0 mg, 0.305 mmol, 1.4 equiv),
K2CO3 (59.9 mg, 0.433 mmol, 2.0 equiv), and DMF (720 µL).
After stirring at room temperature for 3 h, the reaction was
quenched with water (4 mL). The resulting mixture was
washed twice with diethyl ether (4 mL). The aqueous layer
was extracted twice with ethyl acetate (4 mL). The combined
organic extracts were washed with brine (8 mL), dried over
sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to provide the title product 18 as a
colorless solid (118.0 mg, 0.162 mmol, 75%), which was used
for the next step without further purification. Rf = 0.53 (hex-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3:2); IR (ATR, cm– ): 1732, 1608, 1514, 1429, 1415, 1242, 1176, 1026,
1
834, 751, 697; H NMR (400 MHz, CDCl3): δ 7.66 (d, 2H, J =
1
ane/methyl acetate = 3:2); M.p. 152–153 °C; IR (ATR, cm– ):
9.2 Hz), 7.46–7.29 (m, 18H), 7.22 (s, 1H), 7.09 (d, 2H, J = 8.8
Hz), 7.04 (d, 2H, J = 8.8 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.88 (d,
2H, J = 8.8 Hz), 5.12 (s, 2H), 5.08 (s, 2H), 5.04 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 159.8, 158.4, 158.0, 154.5, 142.1, 137.2,
137.0, 136.7, 132.2, 130.0, 129.8, 128.8, 128.73, 128.71, 128.3, 128.2,
128.1, 127.8, 127.6, 126.2, 126.0, 125.1, 123.5, 119.1, 115.3, 114.9, 114.3,
113.1, 102.9, 70.2, 70.1; HRMS (DART/TOF) m/z: [M + H]+
Calcd for C46H36NO5 682.2594; Found 682.2608.
1
2932, 1688, 1600, 1373, 1233, 1171, 1102, 1015, 834, 739, 697; H
NMR (400 MHz, CDCl3): δ 8.02 (d, 2H, J = 8.8 Hz), 7.46–7.30
(m, 15H), 7.17 (d, 2H, J = 8.8 Hz), 7.06 (d, 2H, J = 8.8 Hz), 7.03
(d, 2H, J = 8.8 Hz), 6.92 (s, 1H), 6.90 (d, 2H, J = 8.8 Hz), 6.80
(d, 2H, J = 8.8 Hz), 5.74 (s, 2H), 5.16 (s, 2H), 5.08 (s, 2H), 5.00
(s, 2H), 3.93 (q, 2H, J = 7.3 Hz), 0.85 (t, 3H, J = 7.3 Hz); 13C{1H}
NMR (100 MHz, CDCl3): δ 191.9, 163.3, 162.0, 157.6, 157.2,
137.34, 137.25, 136.2, 132.1, 131.1, 130.5, 129.5, 128.9, 128.7, 128.4,
128.2, 128.04, 128.00, 127.7, 127.6, 127.5, 127.0, 124.6, 120.3, 115.1,
114.6, 114.0, 70.3, 70.1, 59.8, 55.6, 13.8; HRMS (ESI/TOF) m/z:
[M + Na]+ Calcd for C48H41NO6Na 750.2832; Found 750.2850.
Lukianol A.
A flame-dried 20-mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was
charged with 19 (23.7 mg, 34.8 µmol, 1.0 equiv), pentame-
thylbenzene (31.0 mg, 209 µmol, 6.0 equiv), and CH2Cl2 (3.5
mL). The solution was cooled to –78 °C. BCl3 (1 M in CH2Cl2,
209 µL, 0.21 mmol, 6.0 equiv) was added dropwise to the
Schlenk tube. After stirring at –78 °C for 30 min, the reac-
tion mixture was allowed to warm to 0 °C and stirred for 20
min, at which time the mixture was treated with methanol (4
mL) and concentrated under reduced pressure. The residue
was dissolved in methanol (3 mL), washed twice with hexane
(2 mL), and concentrated under reduced pressure to give a
crude product, which was purified by silica gel column
chromatography (hexane/acetone = 1:1). The obtained prod-
uct was washed with a mixture of acetone (2.3 mL) and hex-
ane (0.75 mL) to provide lukianol A as a colorless solid (9.0
3,4-Bis(4-(benzyloxy)phenyl)-1-(2-(4-(benzyloxy)phenyl)-
2-oxoethyl)-1H-pyrrole-2-carboxylic acid (S3).
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with 18 (61.0 mg, 83.8
µmol, 1.0 equiv), potassium trimethylsilanolate (66.3 mg,
0.465 mmol, 5.6 equiv), and 1,2-dichloroethane (840 µL). The
test tube was placed in a preheated aluminum block and
heated at 80 °C for 15 min. The reaction was quenched with
1 M aqueous hydrochloric acid (5 mL). The resulting mixture
was extracted with CHCl3 (4 mL) three times. The combined
organic extracts were washed with brine (10 mL), dried over
sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was
washed with the mixture of diethyl ether (4 mL) and hexane
(2 mL) to provide the title compound S3 as a colorless solid
(42.2 mg, 60.3 µmol, 72%). Rf = 0.37 (hexane/methyl acetate =
1
13
mg, 22 µmol, 63%), whose H and C NMR spectra (DMSO-
d6) were identical to those reported in the literature.21a Rf =
1
0.28 (hexane/acetone = 1:1); M.p. 210–214 °C; IR (ATR, cm– ):
1
3:2); M.p. 177–180 °C; IR (ATR, cm– ): 2922, 1650, 1600, 1454,
3321, 1703, 1612, 1544, 1537, 1519, 1504, 1421, 1259, 1236, 1203, 1174,
1042, 1023, 836, 759, 635, 608; 1H NMR (400 MHz, CD3OD): δ
7.84 (s, 1H), 7.61 (d, 2H, J = 8.4 Hz), 7.49 (s, 1H), 7.13 (d, 2H, J
= 8.4 Hz), 7.01 (d, 2H, J = 8.4 Hz), 6.87 (d, 2H, J = 8.4 Hz),
6.74 (d, 2H, J = 8.4 Hz), 6.67 (d, 2H, J = 8.4 Hz); 1H NMR (400
MHz, DMSO-d6): δ 9.88 (s, 1H), 9.45 (s, 1H), 9.41 (s, 1H), 8.08
(s, 1H), 7.59 (s, 1H), 7.56 (d, 2H, J = 8.4 Hz), 7.05 (d, 2H, J =
8.4 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.87 (d, 2H, J = 8.4 Hz), 6.70
(d, 2H, J = 8.4 Hz), 6.66 (d, 2H, J = 8.4 Hz); 13C{1H} NMR (100
MHz, DMSO-d6): δ 158.4, 156.6, 156.3, 153.6, 140.8, 131.8, 129.5,
128.8, 127.4, 125.5, 123.9, 123.2, 121.3, 120.0, 115.8, 115.3, 114.6,
1
1240, 1171, 1026, 835, 735, 697, 639; H NMR (400 MHz,
CDCl3): δ 8.01 (d, 2H, J = 8.8 Hz), 7.46–7.30 (m, 16H), 7.06 (d,
2H, J = 8.8 Hz), 7.00–6.96 (m, 6H), 6.80 (d, 2H, J = 8.8 Hz),
5.76 (s, 2H), 5.15 (s, 2H), 5.07 (s, 2H), 5.00 (s, 2H); 13C{1H}
NMR (100 MHz, THF-d8): δ 191.8, 163.6, 163.1, 158.4, 157.9,
138.6, 138.5, 137.7, 132.8, 130.9, 130.7, 129.8, 129.6, 129.0, 128.9,
128.7, 128.5, 128.11, 128.07, 128.0, 127.7, 124.7, 121.0, 115.2, 114.8,
114.0, 70.5, 70.2, 56.0; HRMS (ESI/TOF) m/z: [M + Na]+ Calcd
for C46H37NO6Na 722.2519; Found 722.2545.
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111.9, 103.1; HRMS (DART/TOF) m/z: [M + H]+ Calcd for
A 100-mL round-bottomed flask equipped with a Teflon-
1
2
3
4
5
6
7
8
C25H18NO5 412.1185; Found 412.1170.
coated magnetic stirring bar was charged with 8 (427.0 mg,
1.00 mmol, 1.0 equiv), 11 (465.8 mg, 1.50 mmol, 1.5 equiv),
Ba(OH)2·8H2O (1.893 g, 6.00 mmol, 6.0 equiv), Pd2(dba)3
1-Bromo-4-(phenylmethoxy)-benzene (S4).
A 500-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 4-
bromophenol (6.961 g, 40.2 mmol, 1.0 equiv), potassium car-
bonate (11.15 g, 81.0 mmol, 2.0 equiv), benzyl bromide (5.0 mL,
42.2 mmol, 1.05 equiv), and acetonitrile (40 mL). The flask
was placed in a preheated oil bath and heated at reflux for 1 h.
After cooling to room temperature, the resulting mixture was
filtered through a pad of Celite. The filtrate was concentrated
under reduced pressure to provide the corresponding prod-
uct S4 as a colorless solid (9.79 g, 37.2 mmol, 93%), whose 1H
(45.9
mg,
50.1
µmol,
5
mol%),
tris[4-
(trifluoromethyl)phenyl]phosphine (92.0 mg, 0.197 mmol, 20
mol%), water (2 mL), and 1,4-dioxane (8 mL). The flask was
placed in a preheated oil bath and heated at 100 °C for 15
min, at which time the reaction was quenched with water (10
mL) and saturated aqueous ammonium chloride (10 mL).
The resulting mixture was extracted with ethyl acetate (15
mL) three times. The combined organic extracts were
washed with water (40 mL) and brine (40 mL), dried over
sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was
purified by silica gel column chromatography (hex-
ane/diethyl ether = 10:1 to 5:1, gradient) followed by prepara-
tive SEC-HPLC to provide the title compound 12 as a color-
less oil (118 mg, 0.222 mmol, 22%). Rf = 0.31 (hexane/diethyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
and C NMR spectra were identical to those reported in the
literature.30
4,4,5,5-Tetramethyl-2-[4-(phenylmethoxy)phenyl]-1,3,2-
dioxaborolane (11).
1
ether = 3:1); IR (ATR, cm– ): 1699, 1288, 1246, 1179, 1100, 1084,
A flame-dried 50-mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was
charged with S4 (1.00 g, 3.80 mmol, 1.0 equiv) and anhydrous
THF (19 mL). After the solution was cooled to –78 °C, n-
BuLi (1.59 M in n-hexane, 2.62 mL, 4.18 mmol, 1.1 equiv) was
added to the Schlenk tube. The reaction mixture was stirred
at –78 °C for 10 min. To the white suspension was added i-
PrOBpin (850.0 mg, 4.57 mmol, 1.2 equiv) at –78 °C. After
stirring at –78 °C for 10 min, the resulting mixture was al-
lowed to warm to room temperature with stirring over 30
min, at which time the reaction mixture was treated with
water (20 mL). The mixture was extracted twice with diethyl
ether (20 mL). The combined organic extracts were washed
with brine (40 mL), dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give
a crude product, which was purified by silica gel column
chromatography (hexane/CH2Cl2 = 10:1 to hexane/methyl
acetate = 3:1, gradient) to provide the corresponding product
1018, 858, 833, 736, 697; 1H NMR (400 MHz, CDCl3): δ 7.46 (d,
2H, J = 7.6 Hz), 7.40 (dd, 2H, J = 8.0, 7.6 Hz), 7.33 (t, 1H, J =
8.0 Hz), 7.22 (d, 2H, J = 8.2 Hz), 7.08 (s, 1H), 7.00 (d, 2H, J =
8.2 Hz), 5.66 (s, 2H), 5.11 (s, 2H), 4.06 (q, 2H, J = 7.2 Hz), 3.58
(t, 2H, J = 8.2 Hz), 0.99–0.91 (m, 5H), 0.00 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 160.8, 158.2, 137.1, 132.9, 131.6, 128.6,
128.0, 127.6, 126.7, 119.8, 113.9, 99.4, 77.8, 70.0, 66.5, 60.2, 17.9,
13.8, –1.3; HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for
C26H3281BrNO4SiNa 554.1161; Found 554.1165.
Ethyl
4-(4-(benzyloxy)-3-(trimethylsilyl)phenyl)-3-(4-
(benzyloxy)phenyl)-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate
(21).
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 12 (288.1 mg,
0.543 mmol, 1.0 equiv), 20 (621.5 mg, 1.63 mmol, 3.0 equiv),
Ba(OH)2·8H2O (1.026 g, 3.25 mmol, 6.0 equiv), Pd(PPh3)4
(62.2 mg, 53.8 µmol, 10 mol%), water (1.1 mL), and 1,4-
dioxane (4.3 mL). The flask was placed in a preheated oil
bath and heated at 100 °C for 15 min, at which time the re-
action was quenched with saturated aqueous ammonium
chloride (10 mL). The resulting mixture was extracted twice
with ethyl acetate (10 mL). The combined organic extracts
were washed with brine (20 mL), dried over sodium sulfate,
and filtered. The filtrate was concentrated under reduced
pressure to give a crude product, which was purified by silica
gel column chromatography (hexane/diethyl ether = 10:1)
followed by preparative SEC-HPLC to provide the title com-
pound 21 as a colorless oil (167.8 mg, 0.238 mmol, 44%). Rf =
1
11 as a colorless solid (922.5 mg, 2.97 mmol, 78%), whose H
13
and C NMR spectra were identical to those reported in the
literature.31
2-Bromo-1-[4-(phenylmethoxy)phenyl]-ethanone (17).
A 100-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 1-[4-
(benzyloxy)phenyl]-ethanone (452.6 mg, 2.00 mmol, 1.0
equiv), CuBr2 (893.8 mg, 4.00 mmol, 2.0 equiv), CHCl3 (4
mL), and ethyl acetate (4 mL). The flask was placed in a pre-
heated oil bath and heated at 80 °C for 3 h. After cooling to
room temperature, the resulting mixture was filtered
through a pad of Celite. The filtrate was concentrated under
reduced pressure to give a crude product, which was purified
by silica gel column chromatography (hexane/CH2Cl2 = 3:1 to
hexane/diethyl ether = 10:1, gradient) to provide the corre-
sponding product 17 as a colorless solid (350.6 mg, 1.15 mmol,
1
0.43 (hexane/diethyl ether = 3:1); IR (ATR, cm– ): 1693, 1236,
1
1175, 1104, 1080, 836, 736, 696; H NMR (400 MHz, CDCl3): δ
7.46–7.31 (m, 10H), 7.14–7.05 (m, 5H), 6.91 (d, 2H, J = 8.0 Hz),
6.73 (d, 1H, J = 8.0 Hz), 5.72 (s, 2H), 5.07 (s, 2H), 5.01 (s, 2H),
4.06 (q, 2H, J = 7.2 Hz), 3.62 (t, 2H, J = 8.2 Hz), 0.99–0.93 (m,
5H), 0.09 (s, 9H), 0.00 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 161.8, 161.7, 157.7, 137.3, 137.2, 135.2, 131.8, 131.7, 130.1,
128.5, 128.4, 127.9, 127.7, 127.4, 126.6, 125.2, 124.8, 120.2, 114.0,
110.2, 77.6, 70.0, 69.8, 66.2, 59.8, 17.9, 13.8, –0.9, –1.3; HRMS
(ESI/TOF) m/z: [M + Na]+ Calcd for C42H51NO5Si2Na
728.3203; Found 728.3184.
1
13
57%), whose H and C NMR spectra were identical to those
reported in the literature.32
TOTAL SYNTHESIS OF LUKIANOL B
Ethyl
3-(4-(benzyloxy)phenyl)-4-bromo-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate
(12).
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The Journal of Organic Chemistry
1
mmol, 68%). Rf = 0.43 (hexane/CH2Cl2 = 1:2); IR (ATR, cm– ):
1669, 1530, 1454, 1378, 1282, 1240, 1175, 1040, 1024, 834, 736,
697; 1H NMR (400 MHz, CDCl3): δ 9.20 (br s, 1H), 7.66 (d, 1H,
J = 2.3 Hz), 7.49–7.31 (m, 10H), 7.18 (d, 2H, J = 8.7 Hz), 7.03 (d,
1H, J = 3.2 Hz), 6.94–6.89 (m, 3H), 6.65 (d, 1H, J = 8.7 Hz),
5.09 (s, 2H×2), 4.20 (q, 2H, J = 7.2 Hz), 1.17 (t, 3H, J = 7.2 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 161.4, 157.9, 155.6, 138.9,
137.1, 136.6, 132.0, 129.6, 129.4, 128.8, 128.6, 128.5, 127.93, 127.86,
127.6, 127.0, 126.7, 124.7, 120.3, 119.9, 114.1, 112.3, 86.5, 70.8, 70.0,
60.3, 14.2; HRMS (DART/TOF) m/z: [M + H]+ Calcd for
C33H29INO4 630.1141; Found 630.1136.
Ethyl
4-(4-(benzyloxy)-3-iodophenyl)-3-(4-
1
2
3
4
5
6
7
8
(benzyloxy)phenyl)-1-((2-
(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate
(S5).
A 20-mL test tube equipped with a Teflon-coated magnetic
stirring bar was charged with 21 (46.7 mg, 66.1 µmol, 1.0
equiv) and CH2Cl2 (1.7 mL). After the solution was cooled to
–78 °C, ICl (0.1 M in CH2Cl2, 730 µL, 73 µmol, 1.1 equiv) was
added dropwise to the test tube. After stirring at –78 °C for
20 min, the mixture was allowed to warm to –40 °C for 20
min, at which time the mixture was treated with saturated
aqueous sodium thiosulfate (3 mL). After partitioned, the
aqueous layer was extracted with CH2Cl2 (2 mL) three time.
The combined organic extracts were washed with brine (6
mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to provide the title
compound S5 as a brown oil (48.4 mg, 63.7 µmol, 96%). Rf =
0.47 (hexane/diethyl ether = 2:1); M.p. 187–188 °C; IR (ATR,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl
4-(4-(benzyloxy)-3-iodophenyl)-3-(4-
(benzyloxy)phenyl)-1-(2-(4-(benzyloxy)phenyl)-2-
oxoethyl)-1H-pyrrole-2-carboxylate (S7).
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with S6 (116 mg, 0.185
mmol, 1.0 equiv), 17 (84.5 mg, 0.277 mmol, 1.5 equiv), K2CO3
(50.9 mg, 0.368 mmol, 2.0 equiv), and DMF (620 µL). After
stirring at room temperature for 4 h, the reaction was
quenched with water (4 mL). The resulting mixture was ex-
tracted twice with diethyl ether (4 mL). The combined or-
ganic extracts were washed with water (5 mL) and brine (5
mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude product,
which was purified by silica gel column chromatography
(hexane/CH2Cl2 = 1:1 to hexane/methyl acetate = 3:1, gradi-
ent) to provide the title compound S7 as a yellow amorphous
(141 mg, 0.165 mmol, 89%). Rf = 0.43 (hexane/diethyl ether =
1
cm– ): 1695, 1281, 1240, 1176, 1104, 1082, 1043, 1020, 858, 834,
1
805, 735, 697; H NMR (400 MHz, CDCl3): δ 7.62 (d, 1H, J =
2.2 Hz), 7.48–7.31 (m, 10H), 7.12–7.09 (m, 3H), 6.92 (d, 2H, J =
8.7 Hz), 6.87 (dd, 1H, J = 8.6, 2.2 Hz), 6.63 (d, 1H, J = 8.6 Hz),
5.71 (s, 2H), 5.09 (s, 2H), 5.08 (s, 2H), 4.06 (q, 2H, J = 7.2 Hz),
3.61 (t, 2H, J = 8.2 Hz), 0.99–0.94 (m, 5H), 0.01 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 161.7, 157.8, 155.6, 139.0, 137.2, 136.7,
131.8, 131.7, 129.4, 129.3, 128.7, 128.6, 128.0, 127.9, 127.6, 127.1,
125.4, 123.2, 120.4, 114.2, 112.3, 86.5, 77.8, 70.9, 70.1, 66.4, 60.0,
17.9, 13.9, –1.3; HRMS (DART/TOF) m/z: [M + H]+ Calcd for
C39H43INO5Si 760.1955; Found 760.1927.
1
2:1); IR (ATR, cm– ): 1688, 1681, 1600, 1280, 1233, 1171, 1100, 833,
736, 697, 632; H NMR (400 MHz, CDCl3): δ 8.02 (d, 2H, J =
1
Ethyl
4-(4-(benzyloxy)-3-iodophenyl)-3-(4-
8.8 Hz), 7.66 (d, 1H, J = 2.3 Hz), 7.48–7.31 (m, 15H), 7.16 (d, 2H,
J = 8.8 Hz), 7.07 (d, 2H, J = 8.8 Hz), 6.93–6.89 (m, 4H), 6.63
(d, 1H, J = 8.8 Hz), 5.74 (s, 2H), 5.16 (s, 2H), 5.10 (s, 2H), 5.07
(s, 2H), 3.94 (q, 2H, J = 7.2 Hz), 0.85 (t, 3H, J = 7.2 Hz); 13C{1H}
NMR (100 MHz, CDCl3): δ 191.7, 163.1, 161.7, 157.6, 155.4, 138.9,
137.2, 136.6, 136.0, 131.9, 130.9, 130.3, 130.0, 129.5, 129.2, 128.7,
128.52, 128.50, 128.3, 128.2, 128.0, 127.84, 127.80, 127.5, 127.0,
122.8, 120.3, 114.9, 114.0, 112.2, 86.4, 70.7, 70.1, 69.9, 59.7, 55.5,
(benzyloxy)phenyl)-1H-pyrrole-2-carboxylate (S6).
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with S5 (220 mg,
0.290 mmol, 1.0 equiv) and CH2Cl2 (18 mL). After the solution
was cooled to 0 °C, TFA (222 µL, 2.90 mmol, 10 equiv) was
added dropwise to the flask. After stirring at 0 °C for 4 h, to
the flask was added TFA (111 µL, 1.45 mmol, 5.0 equiv). The
reaction mixture was stirred at 0 °C for 4 h, at which time
the reaction was quenched with water. After partitioned, the
aqueous layer was extracted twice with CH2Cl2 (6 mL). The
combined organic extracts were washed with saturated
aqueous sodium hydrogen carbonate (20 mL) and brine (20
mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude hemi-
aminal (186 mg) as a yellow amorphous, which was used for
the next step without further purification.
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with the crude
hemiaminal, Na2CO3 (246 mg, 2.32 mmol, 8.0 equiv), NH2OH
·HCl (20.4 mg, 0.316 mmol, 1.1 equiv), THF (1.9 mL), and
water (0.44 mL). After stirring at room temperature for 15 h,
the reaction was quenched with water (5 mL) and 1 M aque-
ous hydrochloric acid (2 mL). The resulting mixture was ex-
tracted with ethyl acetate (5 mL) three times. The combined
organic extracts were washed with brine (20 mL), dried over
sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was
purified by silica gel column chromatography (hex-
ane/CH2Cl2 = 1:2 to hexane/methyl acetate = 3:1, gradient).
The obtained product was washed with hexane to provide
the title compound S6 as a yellow amorphous (123 mg, 0.196
13.7; HRMS (ESI/TOF) m/z: [M
C48H40INO6Na 876.1798; Found 876.1786.
+
Na]+ Calcd for
4-(4-(Benzyloxy)-3-iodophenyl)-3-(4-
(benzyloxy)phenyl)-1-(2-(4-(benzyloxy)phenyl)-2-
oxoethyl)-1H-pyrrole-2-carboxylic acid (S8).
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with S7 (38.3 mg, 44.9
µmol, 1.0 equiv), potassium trimethylsilanolate (38.7 mg,
0.271 mmol, 6.0 equiv), and 1,2-dichloroethane (0.45 mL).
The test tube was placed in a preheated aluminum block and
heated at 80 °C for 15 min, at which time the reaction mix-
ture was treated with 1 M aqueous hydrochloric acid (3 mL).
After partitioned, the aqueous layer was extracted with
CHCl3 (3 mL) three times. The combined organic extracts
were washed with brine (3 mL), dried over sodium sulfate,
and filtered. The filtrate was concentrated under reduced
pressure to give a crude product, which was washed with the
mixture of diethyl ether (2 mL) and hexane (1 mL) to provide
the title compound S8 as a colorless solid (23.8 mg, 28.8
µmol, 64%). Rf = 0.18 (hexane/methyl acetate = 2:1); M.p. 187–
1
188 °C; IR (ATR, cm– ): 1686, 1650, 1600, 1451, 1287, 1239, 1172,
1011, 736, 696; 1H NMR (400 MHz, THF-d8): δ 8.02 (d, 2H, J =
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(3.820 g, 17.4 mmol, 1.0 equiv), NaOH (1.114 g, 28.9 mmol 1.7
8.8 Hz), 7.64 (d, 1H, J = 2.0 Hz), 7.48–7.24 (m, 15H), 7.14 (d,
2H, J = 8.8 Hz), 7.11–7.09 (m, 3H), 6.91–6.87 (m, 3H), 6.74 (d,
1H, J = 8.8 Hz), 5.84 (s, 2H), 5.18 (s, 2H), 5.064 (s, 2H), 5.059
(s, 2H); 13C{1H} NMR (100 MHz, THF-d8): δ 191.6, 163.6, 162.9,
158.6, 156.2, 139.4, 138.6, 138.0, 137.7, 132.7, 130.94, 130.87, 130.7,
129.8, 129.5, 129.3, 129.0, 128.9, 128.5, 128.1, 128.0, 127.9, 127.6,
123.1, 121.2, 115.2, 114.2, 112.6, 86.4, 71.1, 70.6, 70.2, 56.0; HRMS
(ESI/TOF) m/z: [M – H]– Calcd C46H35INO6 824.1509; Found
824.1533.
1
2
3
4
5
6
7
8
equiv), and methanol (43 mL). After the solution was cooled
to 0 °C, I2 (6.166 g, 24.3 mmol, 1.4 equiv) in methanol (43
mL) was added dropwise to the flask at 0 °C. After stirring
for 85 min at 0 °C, I2 (668.0 mg, 2.63 mmol, 0.15 equiv) in
methanol (5 mL) was added dropwise to the flask at 0 °C
and the resulting mixture was stirred for 40 min, at which
time the reaction mixture was treated with saturated aque-
ous sodium thiosulfate (100 mL) and concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 (50
mL) and the resulting mixture was washed with saturated
aqueous ammonium chloride (50 mL). After partitioned, the
aqueous layer was extracted with CH2Cl2 (50 mL). The com-
bined organic extracts were washed with brine (100 mL),
dried over sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product,
which was purified by silica gel column chromatography
(hexane/CH2Cl2 = 2:1) to provide the corresponding product
9
Lukianol B.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with S8 (44.4 mg,
53.8 µmol, 1.0 equiv), potassium acetate (95.7 mg, 0.975
mmol, 18 equiv), and acetic anhydride (5.4 mL). The flask
was placed in a preheated oil bath and heated at 100 °C for
30 min. After cooling to room temperature, the acetic anhy-
dride was removed azeotropically with toluene (50 mL) un-
der reduced pressure. The residue was dissolved in ethyl ace-
tate (6 mL) and the resulting mixture was washed with satu-
rated aqueous ammonium chloride (6 mL). After partitioned,
the aqueous layer was extracted twice with ethyl acetate (6
mL). The combined organic extracts were washed with brine
(10 mL), dried over sodium sulfate, and filtered. The filtrate
was concentrated under reduced pressure to give a crude
product, which was purified by silica gel column chromatog-
raphy (hexane/methyl acetate = 3:1) to provide the corre-
sponding product 22 (27.3 mg) as a yellow amorphous, which
was used for the next reaction without further purification.
Rf = 0.29 (hexane/methyl acetate = 3:1).
1
S9 as a colorless solid (3.966 g, 11.5 mmol, 66%), whose H
13
and C NMR spectra were identical to those reported in the
literature.33
2,4-Diiodo-1-(phenylmethoxy)-benzene (S10).
A 200-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with S9 (3.732 g,
10.8 mmol, 1.0 equiv), potassium carbonate (2.986 g, 21.6
mmol, 2.0 equiv), benzyl bromide (1.849 g, 10.8 mmol, 1.0
equiv), and acetonitrile (22 mL). The flask was placed in a
preheated oil bath and heated at 80 °C for 30 min. After
cooling to room temperature, the resulting mixture was fil-
tered through a pad of Celite. The filtrate was concentrated
under reduced pressure to give a crude product, which was
purified by silica gel column chromatography (hexane) to
provide the corresponding product S10 as a colorless solid
A flame-dried 20-mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was
charged with 22 (27.3 mg, 33.8 µmol, 1.0 equiv), pentame-
thylbenzene (29.3 mg, 198 µmol, 6.0 equiv), and CH2Cl2 (3.4
mL). The solution was cooled to –78 °C. BCl3 (1 M in CH2Cl2,
200 µL, 0.20 mmol, 6.0 equiv) was added dropwise to the
Schlenk tube. After stirring at –78 °C for 30 min, the reac-
tion mixture was allowed to warm to 0 °C and stirred for 20
min, at which time the mixture was treated with methanol (4
mL) and concentrated under reduced pressure. The residue
was dissolved in methanol (3 mL) and the resulting mixture
was washed with hexane (3 mL) three times. The methanol
layer was concentrated under reduced pressure to give a
crude product, which was washed with acetone (2 mL) to
provide lukianol B as a colorless solid (13.1 mg, 24.4 µmol,
1
(4.389 g, 10.1 mmol, 93%), whose H and 13C NMR spectra
were identical to those reported in the literature.34
(2-(Benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)trimethylsilane (20).
A flame-dried 100-mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was
charged with S10 (1.005 g, 2.30 mmol, 1.0 equiv), TMSCl (1.5
mL, 12 mmol, 5 equiv), and anhydrous THF (11.5 mL). After
the solution was cooled to –78 °C, n-BuLi (1.55 M in n-
hexane, 1.48 mL, 2.3 mmol, 1.0 equiv) was added to the
Schlenk tube. The reaction mixture was stirred at –78 °C for
30 min, the resulting mixture was allowed to warm to room
temperature with stirring over 1 h, at which time the reaction
mixture was treated with water (20 mL) and saturated aque-
ous ammonium chloride (5 mL). The resulting mixture was
extracted twice with diethyl ether (15 mL). The combined
organic extracts were washed with brine (30 mL), dried over
sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was
purified by silica gel column chromatography (hexane) to
provide a mixture of the corresponding product S11 and the
disilylated byproduct (673.3 mg).
1
45% over 2 steps), whose H and 13C NMR spectra (acetone-
d6) were identical to those reported in the literature.21a Rf =
0.26 (CH2Cl2/methanol = 20:1); M.p. >275 °C; IR (ATR, cm–
1): 2924, 1697, 1680, 1658, 1612, 1536, 1518, 1503, 1433, 1422, 1415,
1
1408, 1274, 1239, 1208, 1181, 836; H NMR (400 MHz, acetone-
d6): δ 9.15 (s, 1H), 8.81 (s, 1H), 8.44 (s, 1H), 7.93 (s, 1H), 7.65 (d,
2H, J = 8.8 Hz), 7.63 (d, 1H, J = 2.0 Hz), 7.61 (s, 1H), 7.18 (d, 2H,
J = 8.8 Hz), 7.00 (dd, 1H, J = 8.8, 2.0 Hz), 6.96 (d, 2H, J = 8.8
Hz), 6.84–6.81 (m, 3H); 13C{1H} NMR (100 MHz, acetone-d6): δ
159.5, 157.9, 156.5, 154.4, 142.9, 140.1, 133.0, 130.9, 130.5, 128.5,
127.3, 126.8, 124.9, 123.4, 120.8, 116.8, 115.7, 115.6, 113.8, 103.8,
84.4; HRMS (DART/TOF) m/z: [M
+
H]+ Calcd for
A flame-dried 50-mL Schlenk tube equipped with a Teflon-
coated magnetic stirring bar and a rubber septum was
charged with S11 (673.3 mg, 1.51 mmol, 1.0 equiv) and anhy-
drous THF (7.6 mL). After the solution was cooled to –78 °C,
n-BuLi (1.55 M in n-hexane, 1.1 mL, 1.7 mmol, 1.1 equiv) was
C25H17INO5 538.0151; Found 538.0177.
2,4-Diiodophenol (S9).
A 500-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 2-iodo-phenol
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The Journal of Organic Chemistry
A 10-mL screw-top test tube equipped with a Teflon-coated
added to the Schlenk tube. The reaction mixture was stirred
1
2
3
4
5
6
7
8
at –78 °C for 5 min, to the solution was added i-PrOBpin
(337.4 mg, 1.81 mmol, 1.2 equiv) at –78 °C. After stirring at –
78 °C for 10 min, the resulting mixture was allowed to warm
to room temperature with stirring over 1 h, at which time the
reaction mixture was treated with water (10 mL). The result-
ing mixture was extracted twice with diethyl ether (10 mL).
The combined organic extracts were washed with brine (20
mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude product,
which was purified by silica gel column chromatography
(hexane to hexane/CH2Cl2 = 2:1, gradient) to provide the cor-
responding product 20 as a colorless solid (388.7 mg, 1.02
mmol, 44% over 2 steps). Rf = 0.26 (hexane/CH2Cl2 = 2:1);
magnetic stirring bar was charged with compound 24 (245.1
mg, 0.290 mmol, 1.0 equiv), 18-crown-6 (153.3 mg, 0.580
mmol, 2.0 equiv), KOH (162.7 mg, 10.0 mmol, 10.0 equiv),
and EtOH (1.5 mL). The test tube was placed in a preheated
aluminum block and heated at reflux for 14.5 h, at which time
the resulting mixture was added 18-crown-6 (76.2 mg, 0.288
mmol, 1.0 equiv) and KOH (80.3 mg, 1.43 mmol, 4.9 equiv).
After stirring at reflux for 20.5 h, the reaction mixture was
treated with 1 M aqueous hydrochloric acid, at which time
yellow solid was precipitated and filtered to give a crude S12
as a yellow solid (281.0 mg), which was used for the next step
without further purification.
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with the crude S12
(281.0 mg) and anhydrous ethyl acetate (29 mL). To the solu-
tion was added Pb(OAc)4 (258.4 mg, 0.58 mmol), and the
flask was placed in a preheated oil bath and heated at reflux
for 30 min. Pb(OAc)4 (130.2 mg, 0.29 mmol) was added to the
solution, and the reaction mixture was heated at reflux for 20
min. Pinacol (113.2 mg, 0.956 mmol) was added to the flask,
and the reaction mixture was treated with water (30 mL).
The resulting mixture was extracted with ethyl acetate (30
mL) three times. The combined organic extracts were
washed with water and brine, dried over sodium sulfate, and
filtered. The filtrate was concentrated under reduced pres-
sure to give a crude product, which was purified by silica gel
column chromatography (hexane/CH2Cl2 = 1:1 to CH2Cl2,
gradient) to provide the corresponding product S13 as a yel-
low solid (89.6 mg, 0.110 mmol).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
M.p. 99–100 °C; IR (ATR, cm– ): 1588, 1371, 1352, 1279, 1231,
1
1145, 1102, 854, 838, 695, 669; H NMR (400 MHz, CDCl3): δ
7.83 (s, 1H), 7.78 (d, 1H, J = 8.2 Hz), 7.41–7.30 (m, 5H), 6.85 (d,
1H, J = 8.2 Hz), 5.09 (s, 2H), 1.31 (s, 12H), 0.24 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 166.0, 142.1, 138.3, 137.0, 128.6, 127.9,
127.6, 127.4, 120.7, 109.9, 83.6, 69.8, 25.0, – 0.7; HRMS
(ESI/TOF) m/z: [M + Na]+ Calcd for C22H32BO3SiNa 405.2148;
Found 405.2145.
TOTAL SYNTHESIS OF NINGALIN B
Ethyl
3,4-bis[3,4-bis(benzyloxy)phenyl]-1-[(2-
(trimethylsilyl)ethoxy)methyl]-1H-pyrrole-2-carboxylate
(24).
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 8 (424.6 mg,
0.994 mmol, 1.0 equiv), Ba(OH)2‧8H2O (1.88 g, 5.97 mmol,
6.0 equiv), 23 (1.66 g, 3.99 mmol, 4.0 equiv), Pd(PPh3)4 (113.9
mg, 98.6 µmol, 10 mol%), water (2 mL), and 1,4-dioxane (8
mL). The flask was placed in a preheated oil bath and heated
at 100 °C for 15 min, at which time the solution was treated
with water (5 mL). The reaction mixture was extracted twice
with diethyl ether (10 mL). The combined organic extracts
were washed with water and brine, dried over sodium sulfate,
and filtered. The filtrate was concentrated under reduced
pressure to give a crude product, which was purified by silica
gel column chromatography (hexane/diethyl ether = 5:1 to
hexane/diethyl ether = 3:1, gradient) and followed by prepar-
ative SEC-HPLC to provide the title product 24 as a pale yel-
low oil (499 mg, 0.590 mmol, 59%). Rf = 0.21 (hexane/diethyl
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with compound S13
(89.6 mg, 0.110 mmol, 1.0 equiv) and CH2Cl2 (2.8 mL). TFA
(0.60 mL, 18 mmol, xs) was added to the flask. The resulting
mixture was stirred at room temperature for 10 min. After the
reaction mixture was concentrated under reduced pressure,
the flask was charged with anhydrous THF (0.8 mL), water
(0.2 mL), NH2OH‧HCl (6.9 mg, 99 µmol, 0.90 equiv), and
Na2CO3 (35.1 mg, 0.331 mmol, 3.0 equiv). After stirring at
room temperature for 25 min, the reaction mixture was
treated with water (1 mL). The resulting mixture was extract-
ed with ethyl acetate (2 mL) three times. The combined or-
ganic extracts were washed with water and brine, dried over
sodium sulfate, and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was
washed with diethyl ether (10 mL) to provide the title com-
pound 25 as a pale yellow solid (48.3 mg, 70.4 µmol, 24% over
3 steps). Rf = 0.30 (CH2Cl2/methanol = 100:1); M.p. 178–179 °
1
ether = 3:1); IR (ATR, cm– ): 2949, 1695, 1530, 1498, 1455, 1426,
1373, 1355, 1247, 1212, 1136, 1081, 1023, 836; 1H NMR (400 MHz,
CDCl3): δ 7.44–7.21 (m, 20H), 7.07 (s, 1H), 6.89 (d, 1H, J = 8.2
Hz), 6.84 (d, 1H, J = 1.6 Hz), 6.76 (d, 1H, J = 8.2 Hz), 6.73 (dd,
1H, J = 8.0 Hz, 2.3 Hz), 6.65 (dd, 1H, J = 8.2, 2.3 Hz), 6.61 (d,
1H, J = 2.3 Hz), 5.69 (s, 2H), 5.15 (s, 2H), 5.10 (s, 2H), 5.02 (s,
2H), 4.75 (s, 2H), 3.98 (q, 2H, J = 7.2 Hz), 3.60 (t, 2H, J = 8.1
Hz), 0.95 (t, 2H, J = 8.1 Hz), 0.89 (t, 3H, J = 7.2 Hz), –0.01 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3): δ 161.7, 148.6, 148.3,
147.8, 147.2, 137.6, 137.5, 137.4, 131.5, 129.5, 128.6, 128.5, 127.9,
127.8, 127.7, 127.4, 127.3, 127.2, 125.2, 124.5, 123.9, 120.6, 120.3,
117.7, 115.0, 114.8, 114.4, 77.7, 71.4, 71.3, 70.9, 66.4, 59.9, 17.9,
13.9, –1.3; HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for
C53H55NO7SiNa 868.3646; Found 868.3667.
1
C; IR (ATR, cm– ): 3242, 3063, 3033, 1696, 1549, 1516, 1499, 1272,
1207, 1023, 735, 695; 1H NMR (400 MHz, CDCl3): δ 9.60 (br s,
1H), 7.51–7.29 (m, 15H), 7.22–7.19 (m, 3H), 7.17 (s, 1H), 7.14 (d,
1H, J = 3.2 Hz), 7.12–7.08 (m, 2H), 7.07 (d, 1H, J = 1.8 Hz), 7.03
(d, 1H, J = 8.2 Hz), 6.965 (dd, 1H, J = 7.8, 1.8 Hz), 6.959 (s, 1H),
5.26 (s, 2H), 5.21 (s, 2H), 5.18 (s, 2H), 4.84 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 156.7, 149.1, 148.8, 148.7, 146.1, 145.2,
137.3, 137.1, 136.6, 136.5, 128.73, 128.70, 128.66, 128.5, 128.3, 128.2,
128.1, 128.0, 127.8, 127.6, 127.5, 127.4, 126.6, 123.0, 121.3, 116.7,
116.4, 115.0, 111.1, 108.1, 103.6, 71.5, 71.1, 70.9; HRMS (ESI/TOF)
m/z: [M + Na]+ Calcd for C45H35NO6Na 708.2362; Found
708.2367.
7,8-Bis(benzyloxy)-1-[3,4-
bis(benzyloxy)phenyl]chromeno[3,4-b]pyrrol-4(3H)-one
(25).
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Page 12 of 18
13
7,8-Bis(benzyloxy)-3-[3,4-bis(benzyloxy)phenethyl]-1-
[3,4-bis(benzyloxy)phenyl]chromeno[3,4-b]pyrrol-4(3H)-
one (S14).
4.49 (t, 2H, J = 7.4 Hz), 2.87 (t, 2H, J = 7.4 Hz); C{1H} NMR
(100 MHz, DMSO-d6/CD3OD (4:1)): δ 155.2, 146.3, 145.5, 145.4,
145.3, 145.0, 144.1, 142.4, 133.0, 129.5, 126.8, 125.7, 121.1, 120.0,
119.5, 117.3, 116.5, 116.1, 115.8, 114.3, 110.0, 108.9, 103.7, 50.3, 37.5;
HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for C25H19NO8Na
484.1008; Found 484.1031.
1
2
3
4
5
6
7
8
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with compound 25 (42.9
mg, 62.4 µmol, 1.0 equiv), 2-[3,4-bis(benzyloxy)-
phenyl]ethanol (26) (31.3 mg, 93.6 µmol, 1.5 equiv), and PPh3
(48.9 mg, 0.187 mmol, 3.0 equiv). After the flask was evacuat-
ed and backfilled with N2, anhydrous THF (0.3 mL) and
DIAD (1.9 M, 99 µL, 0.19 mmol, 3.0 equiv) were added to the
flask. The solution was stirred at room temperature for 15
min, at which time the reaction mixture was treated with
water (1 mL). The resulting mixture was extracted with di-
ethyl ether (1 mL) three times. The combined organic ex-
tracts were washed with water and brine, dried over sodium
sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude product, which was purified
by silica gel column chromatography (hexane/CH2Cl2 = 4:1 to
CH2Cl2, gradient). The amorphous was washed with hexane
(2 mL) to provide the titled product S14 as a white amor-
phous (43.9 mg, 43.7 µmol, 70%). Rf = 0.21 (hexane/CH2Cl2 =
2-[3,4-Di(benzyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (23).
A flame-dried 100-mL two-necked test tube equipped with a
Teflon-coated magnetic stirring bar and a rubber septum was
charged with 3,4-dibenzyloxy-1-iodobenzene35 (1.04 g, 2.53
mmol, 1.0 equiv) and anhydrous THF (13 mL). After the solu-
tion was cooled to –78 °C, the resulting mixture was treated
with n-BuLi (1.59 M in n-hexane, 1.65 mL, 2.63 mmol, 1.0
equiv) and stirred at –78 °C for 5 min. To the solution was
added i-PrOBpin (522.2 mg, 2.81 mmol, 1.1 equiv) at –78 °C.
After stirring at –78 °C for 10 min, the resulting mixture was
allowed to warm to room temperature with stirring over 40
min, at which time the reaction mixture was treated with
saturated aqueous ammonium chloride (10 mL). After parti-
tioned, the aqueous layer was extracted with diethyl ether (10
mL) three times. The combined organic extracts were
washed with water and brine, dried over sodium sulfate, and
filtered. The filtrate was concentrated under reduced pres-
sure to give a crude product, which was purified by silica gel
column chromatography (hexane/diethyl ether = 10:1) to pro-
vide the title product 23 as a colorless solid (795.6 mg, 1.91
mmol, 76%), whose 1H and 13C NMR spectra were identical to
those reported in the literature.36
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
4:1); IR (ATR, cm– ): 1714, 1510, 1499, 1454, 1376, 1262, 1229, 1159,
1
1024, 745, 695; H NMR (400 MHz, CDCl3): δ 7.48–7.28 (m,
21H), 7.24–7.17 (m, 6H), 7.11 (s, 1H), 7.10–7.08 (m, 2H), 6.96 (d,
2H, J = 7.8 Hz), 6.93 (d, 1H, J = 1.8 Hz), 6.83–6.80 (m, 2H),
6.61 (dd, 1H, J = 8.2, 2.3 Hz), 6.56 (d, 1H, J = 1.8 Hz), 6.51 (s,
1H), 5.21 (s, 2H×2), 5.10 (s, 2H), 5.08 (s, 2H), 4.97 (s, 2H),
4.79 (s, 2H), 4.53 (t, 2H, J = 6.6 Hz), 3.00 (t, 2H, J = 6.6 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 155.5, 149.1, 149.0, 148.7,
148.6, 147.8, 146.3, 144.9, 137.4, 137.3, 137.2, 137.0, 136.7, 136.6,
132.2, 131.5, 128.8, 128.7, 128.58, 128.55, 128.51, 128.4, 128.1, 128.0,
127.9, 127.8, 127.59, 127.56, 127.4, 127.35, 127.32, 127.1, 122.9,
121.8, 119.0, 116.5, 115.7, 115.5, 115.0, 114.9, 111.0, 108.1, 103.5, 71.6,
71.5, 71.3, 71.2, 71.1, 70.9, 51.0, 37.6; HRMS (ESI/TOF) m/z: [M
+ Na]+ Calcd for C67H55NO8Na 1024.3825; Found 1024.3788.
2-[3,4-Di(benzyloxy)phenyl]ethanol (26).
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 2-(3,4-
dihydroxyphenyl)ethyl alcohol (347.4 mg, 2.25 mmol, 1.0
equiv), K2CO3 (937.3 mg, 6.75 mmol, 3.0 equiv), benzyl bro-
mide (643 µL, 5.41 mmol, 2.4 equiv), and acetonitrile (2.25
mL). The flask was placed in a preheated oil bath and heated
at reflux for 15 h. After cooling to room temperature, the re-
sulting mixture was filtered through a pad of Celite. The fil-
trate was concentrated under reduced pressure to give a
crude product, which was purified by silica gel column
chromatography (hexane/diethyl ether = 3:1) to provide the
title product 26 as a colorless solid (631 mg, 1.88 mmol, 84%),
Ningalin B.
A 25-mL pear-shaped flask equipped with a Teflon-coated
magnetic stirring bar was charged with compound S14 (31.9
mg, 31.8 µmol, 1.0 equiv), Pd/C (31.9 mg, 100 wt%), EtOH (0.5
mL), and ethyl acetate (0.5 mL). After the flask was evacuat-
ed and backfilled with H2 three times, the resulting mixture
was stirred at room temperature for 30 min. The resulting
mixture was filtered through a pad of Celite, and the filter
cake was washed with hot methanol (10 mL). The filtrate was
concentrated under reduced pressure to provide ningalin B
1
whose H NMR spectrum was identical to that reported in
the literature.37
1
as a pale gray solid (14.3 mg, 30.8 µmol, 97%), whose H and
13C NMR spectra (DMSO-d6/CD3OD (4:1)) were not in good
TOTAL SYNTHESIS OF LAMELLARIN S
1
agreement with those reported in the literature.25a The H
7,8-Bis(benzyloxy)-3-[3-(benzyloxy)-4-
methoxyphenethyl]-1-[3,4-
NMR spectrum (CD3OD) was identical to that reported in
Fenical’s supporting information (page 10). 1H and 13C NMR
spectra (DMSO-d6/CD3OD (4:1)) were in good agreement
with those reported.6h,25b Rf = 0.52 (CH2Cl2/methanol = 3:1);
bis(benzyloxy)phenyl]chromeno[3,4-b]pyrrol-4(3H)-one
(28).
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with compound 25 (55.0
1
M.p. >250 °C; IR (ATR, cm– ): 3269, 2927, 1682, 1416, 1366,
1255, 1230, 1168, 816; 1H NMR (400 MHz, CD3OD) δ 7.14 (s, 1H),
6.89 (s, 1H), 6.84 (d, 1H, J = 7.8 Hz), 6.82 (d, 1H, J = 1.8 Hz),
6.79 (s, 1H), 6.71–6.65 (m, 2H), 6.54 (d, 1H, J = 1.8 Hz), 6.46
(dd, 1H, J =8.2, 1.8 Hz), 4.56 (t, 2H, J = 7.0 Hz), 2.96 (t, 2H, J =
7.0 Hz); 1H NMR (400 MHz, DMSO-d6/CD3OD (4:1)) δ 7.19 (s,
1H), 7.06 (s, 1H), 6.81 (d, 1H, J = 8.4 Hz), 6.77 (d, 1H, J = 2.0
Hz), 6.75 (s, 1H), 6.63 (dd, 1H, J = 7.6, 2.4 Hz), 6.62 (d, 1H, J =
7.8 Hz), 6.59 (d, 1H, J = 2.0 Hz), 6.43 (dd, 1H, J = 8.0, 2.0 Hz),
mg,
80.0
µmol,
1.0
equiv),
3-benzyloxy-4-
methoxybenzeneethanol (27) (31.9 mg, 0.123 mmol, 1.5 equiv),
PPh3 (61.8 mg, 0.236 mmol, 3.0 equiv). After the flask was
evacuated and backfilled with N2, anhydrous THF (0.4 mL),
and DIAD (1.9 M, 126 µL, 0.240 mmol, 3.0 equiv) were added
to the flask. The solution was stirred at room temperature for
20 min, at which time the reaction mixture was treated with
water (1 mL). The resulting mixture was extracted with di-
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The Journal of Organic Chemistry
ethyl ether (1 mL) three times. The combined organic ex-
tracts were washed with water and brine, dried over sodium
1
Lamellarin S.
2
3
4
5
6
7
8
9
sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude product, which was purified
by silica gel column chromatography (hexane/CH2Cl2 = 1:3 to
hexane/CH2Cl2 = 1:4, gradient) to provide the title product 28
as a yellow amorphous (52.4 mg, 56.6 µmol, 71%). Rf = 0.34
A 10 mL pear-shaped flask equipped with a Teflon-coated
magnetic stirring bar was charged with compound S17 (17.1
mg, 18.5 µmol, 1.0 equiv), Pd/C (17.1 mg, 100 wt%), EtOH (0.3
mL), and EtOAc (0.3 mL). After the flask was evacuated and
backfilled with H2 three times, the resulting mixture was
stirred at room temperature for 14 h. The resulting mixture
was filtered through a pad of Celite, and the filter cake was
washed with hot methanol (8 mL). The filtrate was concen-
trated under reduced pressure to provide lamellarin S as a
1
(hexane/CH2Cl2 = 1:4); IR (ATR, cm– ): 1709, 1588, 1513, 1419,
1260, 1137, 1025, 736, 696; 1H NMR (400 MHz, CDCl3): δ 7.49–
7.28 (m, 15H), 7.25–7.16 (m, 7H), 7.13 (s, 1H), 7.11–7.07 (m, 2H),
6.98 (d, 1H, J = 8.2 Hz), 6.95 (s, 1H), 6.91 (d, 1H, J = 1.8 Hz),
6.83 (dd, 1H, J = 8.2, 2.1 Hz), 6.78 (d, 1H, J = 8.2 Hz), 6.65 (dd,
1H, J = 8.0, 2.1 Hz), 6.48 (d, 1H, J = 2.3 Hz), 6.47 (s, 1H), 5.222
(s, 1H), 5.219 (s, 2H), 5.11 (s, 2H), 4.94 (s, 2H), 4.80 (s, 2H),
4.52 (t, 2H, J = 6.9 Hz), 3.81 (s, 3H), 3.00 (t, 2H, J = 6.9 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 155.4, 149.1, 148.7, 148.5,
148.1, 146.3, 144.9, 137.3, 137.1, 137.0, 136.64, 136.58, 132.2, 130.5,
128.73, 128.66, 128.6, 128.5, 128.4, 128.1, 128.01, 127.99, 127.83,
127.76, 127.60, 127.56, 127.3, 127.1, 122.9, 121.6, 119.0, 116.5, 115.0,
114.8, 112.0, 111.0, 108.1, 103.5, 71.5, 71.3, 71.1, 70.87, 70.86, 56.1,
51.1, 37.5 (five aromatic carbon signals are missing due to
overlapping); HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for
C61H51NO8Na 948.3512; Found 948.3548.
1
pale gray solid (8.6 mg, 18 µmol, 98%), whose H and 13C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR spectra (CD3OD) were identical to those reported in
the literature.26a,26b Rf = 0.69 (chloroform/ethanol = 3:1); M.p.
1
>250 °C; IR (ATR, cm– ): 3251, 2929, 2854, 1680, 1597, 1420,
1279, 1252, 1201, 1159, 1040; 1H NMR (400 MHz, CD3OD) δ 6.99
(d, 1H, J = 8.0 Hz), 6.88 (d, 1H, J = 1.4 Hz), 6.83 (s, 1H), 6.77
(dd, 1H, J = 8.0, 1.4 Hz), 6.76 (s, 1H), 6.71 (s, 1H), 6.62 (s, 1H),
4.73–4.53 (m, 2H), 3.38 (s, 3H), 3.01 (t, 2H, J = 6.2 Hz); 13C{1H}
NMR (100 MHz, CD3OD): δ 157.6, 148.1, 147.4, 147.3, 146.7,
146.6, 143.4, 138.6, 129.9, 128.7, 128.1, 123.7, 120.2, 119.1, 117.5,
116.4, 115.8, 113.8, 111.3, 110.4, 109.8, 104.2, 55.6, 43.5, 29.3;
HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for C26H19NO8Na
496.1008; Found 496.1028.
2,3,11-Tris(benzyloxy)-14-(3,4-bis(benzyloxy)phenyl)-12-
methoxy-8,9-dihydro-6H-chromeno[4',3':4,5]pyrrolo[2,1-
a]isoquinolin-6-one (S15).
4-Methoxy-3-(phenylmethoxy)-benzeneethanol (27).
A 500-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring was charged with (methoxyme-
thyl)triphenylphosphonium chloride (14.18 g, 41.4 mmol, 1.5
equiv) and THF (140 mL). After the solution was cooled to
0 °C, potassium tert-butoxide (6.184 g, 55.1 mmol, 2.0 equiv)
was added potionwise over 3 min to the flask and the result-
ing mixture was stirred at 0 °C for 30 min. To the solution
was added 4-methoxy-3-(phenylmethoxy)-benzaldehyde
(6.701 g, 27.7 mmol, 1.0 equiv) at 0 °C. The resulting mixture
was allowed to warm to room temperature with stirring over
2 h, at which time the reaction mixture was treated with sat-
urated aqueous ammonium chloride (70 mL). The resulting
mixture was extracted twice with diethyl ether (50 mL). The
combined organic extracts were washed with water (70 mL)
and brine (70 mL), dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give
a crude product, which was dissolved in diethyl ether (40
mL) and CH2Cl2 (40 mL). To the resulting solution was add-
ed hexane (300 mL), the resulting precipitate (tri-
phenylphosphine oxide) was removed by filtration. The fil-
trate was concentrated under reduced pressure to give a col-
orless solid (13.96 g). This procedure was repeated once again
to provide a crude enol ether S16 as a colorless solid (8.94 g),
which was used for the next step without further purification.
A 1-L round-bottomed flask equipped with a Teflon-coated
magnetic stirring bar was charged with the enol ether S16,
THF (50 mL), and 6 M aqueous hydrochloric acid (50 mL).
The resulting mixture was stirred at room temperature for 45
min, at which time the mixture was extracted with diethyl
ether (100 mL) three times. The combined organic extracts
were washed with water (100 mL) three times and brine (20
mL), dried over sodium sulfate, and filtered. The filtrate was
concentrated under reduced pressure to give a crude alde-
hyde S17, which was used for the next step without further
purification.
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with compound 28
(33.1 mg, 35.7 µmol, 1.0 equiv) and anhydrous CH2Cl2 (1 mL).
After the resulting solution was cooled to –40 °C, a solution
of PIFA (18.1 mg, 42.1 µmol, 1.2 equiv) and BF3‧OEt2 (11 µL, 87
µmol, 2.4 equiv) in anhydrous CH2Cl2 (2.6 mL) was added
dropwise to the flask. The reaction mixture was stirred at –
40 °C for 1 h, at which time the reaction was quenched with
2 M aqueous NH3 (3 mL). The reaction mixture was extracted
twice with CH2Cl2 (3 mL). The combined organic extracts
were washed with water and brine, dried over sodium sulfate,
and filtered. The filtrate was concentrated under reduced
pressure to give a crude product, which was purified by silica
gel column chromatography (hexane/diethyl ether = 1:1 to
CH2Cl2, gradient). The solid was washed twice with diethyl
ether (2 mL) to provide the titled product S15 as a colorless
solid (20.1 mg, 21.8 µmol, 61%). Rf = 0.14 (hexane/diethyl
1
ether = 1:1); M.p. 167–168 °C; IR (ATR, cm– ): 1704, 1543, 1512,
1484, 1454, 1420, 1270, 1210, 1165, 1037, 1026, 735, 696; 1H NMR
(400 MHz, CDCl3): δ 7.48–7.28 (m, 19H), 7.24–7.21 (m, 4H),
7.17–7.15 (m, 2H), 7.10 (d, 1H, J = 8.2 Hz), 7.05 (d, 1H, J = 1.8
Hz), 6.98 (dd, 1H, J = 8.2, 1.8 Hz), 6.92 (s, 1H), 6.73 (s, 1H),
6.72 (s, 1H), 6.53 (s, 1H), 5.29 (d, 1H, J = 12.4 Hz), 5.24 (d, 1H, J
= 12.4 Hz), 5.19 (s, 2H), 5.148 (s, 2H), 5.145 (d, 1H, J = 12.4 Hz),
5.10 (d, 1H, J = 12.4 Hz), 4.85–4.78 (m, 1H), 4.73 (d, 1H, J = 12.8
Hz), 4.68 (d, 1H, J = 12.4 Hz), 4.64–4.57 (m, 1H), 3.18 (s 3H),
3.06–2.92 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.6,
149.6, 148.7, 148.5, 148.2, 148.1, 146.2, 144.9, 137.2, 136.83, 136.77,
136.7, 136.0, 128.8, 128.7, 128.60, 128.56, 128.5, 128.14, 128.08,
128.0, 127.8, 127.4, 127.32, 127.27, 127.20, 127.18, 126.4, 124.0,
120.5, 117.3, 115.4, 114.9, 113.8, 113.3, 110.9, 109.1, 107.8, 103.3, 71.3,
71.02, 70.97, 70.5, 55.2, 42.5, 28.7 (four aromatic carbon sig-
nals and a benzylic position carbon are missing due to over-
lapping); HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for
C61H49NO8Na 946.3356; Found 946.3365.
A 500-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with the crude
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The Journal of Organic Chemistry
Page 14 of 18
dioxane (1.6 mL). The flask was placed in a preheated oil bath
aldehyde S17 and methanol (50 mL). After cooling to 0 °C,
NaBH4 (3.021 g, 79.9 mmol) was added potionwise to the
flask at 0 °C. The resulting mixture was allowed to warm to
room temperature with stirring over 2 h. Additional NaBH4
(1.496 g, 39.5 mmol) was added potionwise to the reaction
mixture at 0 °C. The resulting mixture was stirred for 17 h,
at which time the reaction mixture was treated with water
(80 mL) and concentrated under reduced pressure. The re-
sulting mixture was extracted with ethyl acetate (80 mL)
three times. The combined organic extracts were washed
with brine (80 mL), dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give
a crude product, which was purified by silica gel column
chromatography (hexane/methyl acetate = 4:1 to 2:1, gradi-
ent) followed by SEC-HPLC to provide the title compound 27
as a colorless solid (2.346 g, 9.08 mmol, 33% over 3 steps),
1
2
3
4
5
6
7
8
and heated at 100 °C for 15 min, at which time the solution
was treated with water (2 mL). The reaction mixture was
extracted with diethyl ether (3 mL) three times. The com-
bined organic extracts were washed with water and brine,
dried over sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product,
which was purified by silica gel column chromatography
(hexane/diethyl ether = 5:1 to hexane/diethyl ether = 3:1) fol-
lowed by preparative SEC-HPLC to provide the title product
31 as a pale yellow oil (109.5 mg, 0.142 mmol, 72%). Rf = 0.20
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(hexane/diethyl ether = 3:1); IR (ATR, cm– ): 2954, 1695, 1530,
1
1506, 1455, 1355, 1249, 1217, 1102, 1024, 859, 737, 697; H NMR
(400 MHz, CDCl3): δ 7.43–7.23 (m, 15H), 7.06 (s, 1H), 6.84 (d,
1H, J = 8.2 Hz), 6.81 (d, 1H, J = 1.8 Hz), 6.78–7.75 (m, 2H), 6.64
(dd, 1H, J = 8.2, 2.3 Hz), 6.61 (d, 1H, J = 1.8 Hz), 5.69 (s, 2H),
5.10 (s, 2H), 5.01 (s, 2H), 4.77 (s, 2H), 4.01 (q, 2H, J = 7.2 Hz),
3.88 (s, 3H), 3.61 (t, 2H, J = 8.2 Hz), 0.96 (t, 3H, J = 7.2 Hz),
1
whose H NMR spectrum was identical to that reported in
the literature.38
13
0.95 (t, 2H, J = 8.2 Hz), 0.00 (s, 9H); C{1H} NMR (100 MHz,
TOTAL SYNTHESIS OF LAMELLARIN Z
CDCl3): δ 161.6, 148.6, 148.5, 147.4, 147.2, 137.5, 137.3, 137.1, 131.5,
128.5, 128.44, 128.39, 127.9, 127.8, 127.72, 127.65, 127.30, 127.25,
127.1, 125.1, 124.5, 123.6, 120.6, 120.3, 116.8, 114.91, 114.88, 111.1,
77.7, 71.3, 70.92, 70.86, 66.3, 59.8, 56.0, 17.9, 13.9, –1.4; HRMS
(ESI/TOF) m/z: [M + Na]+ Calcd for C47H51NO7SiNa 792.3333;
Found 792.3345.
Ethyl 3-[3-(benzyloxy)-4-methoxyphenyl]-4-bromo-1-[(2-
(trimethylsilyl)ethoxy)methyl]-1H-pyrrole-2-carboxylate
(30).
A 100-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 8 (512.5 mg,
1.20 mmol, 1.0 equiv), Ba(OH)2‧8H2O (2.27 g, 7.18 mmol, 6.0
equiv), 29 (557.0 mg, 1.64 mmol, 1.4 equiv), Pd2(dba)3‧CHCl3
8-(Benzyloxy)-1-(3,4-bis(benzyloxy)phenyl)-7-
methoxychromeno[3,4-b]pyrrol-4(3H)-one (S20).
(55.2
mg,
60.3
µmol,
5
mol%),
tris[4-
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with compound 31 (108.5
mg, 0.141 mmol, 1.0 equiv), 18-crown-6 (74.3 mg, 0.281 mmol,
2.0 equiv), KOH (79.0 mg, 1.41 mmol, 10 equiv), and EtOH
(705 µL). The test tube was placed in a preheated aluminum
block and heated at reflux for 19 h, at which time the solution
was treated with 1 M aqueous hydrochloric acid. The desired
carboxylic acid S18 was collected by filtration as a yellow
solid (108.4 mg), which was used for the next step without
further purification.
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with the crude S18
(108.4 mg) in anhydrous ethyl acetate (14 mL). To the solu-
tion was added Pb(OAc)4 (93.8 mg, 0.212 mmol). The flask
was placed in a preheated oil bath and heated at reflux for 20
min. After Pb(OAc)4 (31.5 mg, 0.0710 mmol) was added to the
solution, and the reaction mixture was heated at reflux for 15
min. Pinacol (43.2 mg, 0.366 mmol) was added to the flask,
and resulting mixture was treated with water (14 mL). The
reaction mixture was extracted with diethyl ether (10 mL)
three times. The combined organic extracts were washed
with water and brine, dried over sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure to give
a crude product, which was purified by silica gel column
chromatography (hexane/diethyl ether = 3:1) to provide the
corresponding product S19 as a yellow solid (54.1 mg, 73.1
µmol).
(trifluoromethyl)phenyl]-phosphine (111.7 mg, 0.24 mmol, 20
mol%), water (2.4 mL), and 1,4-dioxane (9.6 mL). The flask
was placed in a preheated oil bath and heated at 100 °C for
15 min, at which time the solution was treated with water (10
mL). The reaction mixture was extracted with diethyl ether
(10 mL) three times. The combined organic extracts were
washed with water and brine, dried over sodium sulfate, and
filtered. The filtrate was concentrated under reduced pres-
sure to give a crude product, which was purified by silica gel
column chromatography (hexane/diethyl ether = 10:1 to hex-
ane/diethyl ether = 5:1, gradient) and followed by preparative
SEC-HPLC to provide the title product 30 as a pale yellow oil
(202.0 mg, 0.36 mmol, 30%). Rf = 0.23 (hexane/diethyl ether
1
= 5:1); IR (ATR, cm– ): 1700, 1541, 1508, 1428, 1377, 1253, 1223,
1
1106, 1181, 1024, 856, 745, 702; H NMR (400 MHz, CDCl3): δ
7.45 (d, 2H, J = 7.3 Hz), 7.39–7.27 (m, 3H), 7.04 (s, 1H), 6.91 (d,
1H, J = 8.2 Hz), 6.88 (d, 1H, J = 1.8 Hz), 6.86 (dd, 1H, J = 8.2,
1.8 Hz), 5.64 (s, 2H), 5.15 (s, 2H), 4.00 (q, 2H, J = 7.1 Hz), 3.92
(s, 3H), 3.57 (t, 2H, J = 8.2 Hz), 0.96 (t, 3H, J = 7.1 Hz), 0.93 (q,
2H, J = 8.2 Hz), 0.00 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3):
δ 160.7, 149.1, 147.3, 137.3, 132.8, 128.5, 127.8, 127.4, 126.7, 126.5,
123.5, 119.9, 116.6, 110.9, 99.4, 77.8, 71.1, 66.5, 60.1, 56.0, 17.8,
13.8, –1.4; HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for
C27H34NO5SiNa 584.1267; Found 584.1291.
Ethyl
[3-(benzyloxy)-4-methoxyphenyl]-4-[3,4-
bis(benzyloxy)phenyl]-1-[(2-
(trimethylsilyl)ethoxy)methyl]-1H-pyrrole-2-carboxylate
(31).
A 50-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 30 (110.0 mg,
0.196 mmol, 1.0 equiv), Ba(OH)2‧8H2O (370.1 mg, 1.17 mmol,
6.0 equiv), 23 (163.7 mg, 0.393 mmol, 2.0 equiv), Pd(PPh3)4
(22.6 mg, 19.6 µmol, 10 mol%), water (0.4 mL), and 1,4-
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with compound S19 (54.1
mg, 73.1 µmol, 1.0 equiv) and CH2Cl2 (1.8 mL). TFA (400 µL,
5.22 mmol) was added to the flask. The resulting mixture was
stirred at room temperature for 15 min. After the reaction
mixture was concentrated under reduced pressure, the flask
was charged with anhydrous THF (585 µL), water (146 µL),
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Page 15 of 18
The Journal of Organic Chemistry
A 25-mL two-necked pear-shaped flask equipped with a Tef-
NH2OH‧HCl (4.7 mg, 68 µmol, 0.92 equiv), and Na2CO3
1
2
3
4
5
6
7
8
lon-coated magnetic stirring bar was charged with com-
pound 32 (45.0 mg, 52.9 µmol, 1.0 equiv) and anhydrous
CH2Cl2 (4.4 mL). After the resulting solution was cooled to –
40 °C, a solution of PIFA (26.5 mg, 61.6 µmol, 1.2 equiv) and
BF3‧OEt2 (17 µL, 0.14 mmol, 2.6 equiv) in anhydrous CH2Cl2
(0.9 mL) was added dropwise to the flask. The reaction mix-
ture was stirred at –40 °C for 1.5 h, at which time the result-
ing mixture was treated with 2 M aqueous NH3 (5 mL). The
mixture was extracted with CH2Cl2 (5 mL) three times. The
combined organic extracts were washed with water and brine,
dried over sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product,
which was washed with diethyl ether (6 mL) to provide the
corresponding product S21 as a colorless solid (36.9 mg).
A 25-mL two-necked pear-shaped flask equipped with a Tef-
lon-coated magnetic stirring bar was charged with com-
pound S21 (36.1 mg, 42.6 µmol, 1.0 equiv), Pd/C (35.8 mg, 100
wt%), EtOH (0.7 mL), and ethyl acetate (0.7 mL). After the
flask was evacuated and backfilled with H2 three times, the
resulting mixture was stirred at room temperature for 17 h, at
which time the resulting mixture was filtered through a pad
of Celite with hot methanol (15 mL) followed by DMSO (3
mL). The filtrate was concentrated under reduced pressure to
provide lamellarin Z as a gray solid (20.7 mg, 42.5 µmol, 80%
(23.8 mg, 0.225 mmol, 3.1 equiv). The reaction mixture was
stirred at room temperature for 3 h, at which time
NH2OH‧HCl (4.9 mg, 71 µmol, 1.0 equiv) and Na2CO3 (22.3
mg, 0.210 mmol, 3.0 equiv) were added to the flask. After
stirring at room temperature for 4 h, the reaction mixture
was treated with water (0.6 mL). The resulting mixture was
extracted with ethyl acetate (1 mL) three times. The com-
bined organic extracts were washed with water and brine,
dried over sodium sulfate, and filtered. The filtrate was con-
centrated under reduced pressure to give a crude product,
which was washed with diethyl ether (5 mL) to provide the
title compound S20 as a pale yellow solid (36.1 mg, 59.2 µmol,
42% over 3 steps). Rf = 0.31 (hexane/CH2Cl2 = 100:1); IR (ATR,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
cm– ): 3237, 1696, 1549, 1494, 1402, 1272, 1192, 1026, 736, 696;
1H NMR (400 MHz, CDCl3): δ 9.56 (br s, 1H), 7.51–7.45 (m,
4H), 7.38–7.28 (m, 6H), 7.23–7.17 (m, 3H), 7.15 (d, 1H, J = 2.3
Hz), 7.14 (s, 1H), 7.09–7.05 (m, 3H), 7.02 (d, 1H, J = 8.2 Hz),
6.97 (dd, 1H, J = 8.2, 1.8 Hz), 6.95 (s, 1H), 5.25 (s, 2H), 5.18 (s,
2H), 4.82 (s, 2H), 3.92 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.5, 149.8, 149.2, 148.7, 146.3, 144.6, 137.3, 137.1,
136.4, 128.71, 128.68, 128.5, 128.1, 128.0, 127.9, 127.6, 127.5, 127.40,
127.35, 126.7, 123.0, 121.4, 116.7, 116.5, 115.0, 110.5, 107.4, 101.2,
71.50, 71.46, 70.7, 56.3 (one aromatic carbon signal is missing
due to overlapping); HRMS (ESI/TOF) m/z: [M + Na]+ Calcd
for C39H31NO6Na 632.2049; Found 632.2035.
1
over 2 steps), whose H and 13C NMR spectra (DMSO-d6)
were identical to those reported in the literature.27 Rf = 0.43
1
(CH2Cl2/methanol = 10:1); M.p. >250 °C; IR (ATR, cm– ): 3410,
8-(Benzyloxy)-3-[3-(benzyloxy)-4-methoxyphenethyl]-1-
[3,4-bis(benzyloxy)phenyl]-7-methoxychromeno[3,4-
b]pyrrol-4(3H)-one (32).
A 10-mL screw-top test tube equipped with a Teflon-coated
magnetic stirring bar was charged with compound S20 (38.3
1684, 1587, 1488, 1425, 1276, 1245, 1206, 1158, 1041, 1024, 870,
761; 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.19 (s, 1H),
9.14 (s, 1H), 8.98 (s, 1H), 7.00 (s, 1H), 6.94 (d, 1H, J = 7.8 Hz),
6.76 (s, 1H), 6.73 (s, 1H), 6.71–6.67 (m, 2H), 6.54 (s, 1H), 4.72–
4.63 (m, 1H), 4.55–4.46 (m, 1H), 3.81 (s, 3H), 3.28 (s, 3H),
3.04–2.93 (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 154.5,
147.9, 147.0, 146.2, 146.0, 145.4, 144.7, 142.8, 136.1, 127.2, 127.0,
125.5, 121.6, 118.2, 117.8, 116.7, 115.3, 114.8, 112.5, 110.3, 109.3, 108.4,
100.7, 55.9, 54.7, 42.0, 27.6; HRMS (ESI/TOF) m/z: [M + Na]+
Calcd for C27H21NO8Na 510.1165; Found 510.1165.
mg,
62.8
µmol,
1.0
equiv),
3-benzyloxy-4-
methoxybenzeneethanol (27) (24.3 mg, 94.2 µmol, 1.5 equiv),
and PPh3 (49.3 mg, 0.188 mmol, 3.0 equiv). After the flask was
evacuated and backfilled with N2, anhydrous THF (320 µL)
and DIAD (1.9 M, 100 µL, 0.19 mmol, 3.0 equiv) were added to
the flask. The solution was stirred at room temperature for 15
min, the resulting mixture was concentrated under reduced
pressure to give a crude product, which was purified by silica
gel column chromatography (hexane/CH2Cl2 = 1:3 to CH2Cl2,
gradient). The amorphous was washed twice with methanol
(1 mL) to provide the title compound 32 as a white amor-
phous (46.0 mg, 54.1 µmol, 86%). Rf = 0.21 (hexane/CH2Cl2 =
2-Benzyloxy-4-bromo-1-methoxybenzene (S22).
A 100-mL round-bottomed flask equipped with a Teflon-
coated magnetic stirring bar was charged with 5-bromo-2-
methoxy-phenol (3.05 g, 15.0 mmol, 1.0 equiv), K2CO3 (4.15 g,
30.0 mmol, 2.0 equiv), benzyl bromide (2.57 g, 15.0 mmol, 1.0
equiv), and acetonitrile (15 mL). The flask was placed in a
preheated oil bath and heated at reflux for 4 h. After cooling
to room temperature, the resulting mixture was filtered
through a pad of Celite. The filtrate was concentrated under
reduced pressure to give the title product S22 as a colorless
solid (4.35 g, 14.8 mmol, 99%), whose 1H and 13C NMR spectra
were identical to those reported in the literature.39
1
1:3); IR (ATR, cm– ): 1707, 1513, 1455, 1419, 1260, 1235, 1137, 1025,
1
739, 697; H NMR (400 MHz, CDCl3): δ 7.47–7.43 (m, 4H),
7.37–7.28 (m 6H), 7.25–7.16 (m, 7H), 7.10 (s, 1H), 7.08–7.04 (m,
2H), 6.97 (d, 1H, J = 8.2 Hz), 6.94 (s, 1H), 6.91 (d, 1H, J = 2.3
Hz), 6.83 (dd, 1H, J = 8.2, 1.8 Hz), 6.79 (d, 1H, J = 8.2 Hz), 6.67
(dd, 1H, J = 8.2, 1.8 Hz), 6.51 (d, 1H, J = 1.8 Hz), 6.49 (s, 1H),
5.22 (s, 2H), 5.10 (s, 2H), 4.95 (s, 2H), 4.78 (s, 2H), 4.54 (t, 2H,
J = 6.8 Hz), 3.92 (s, 3H), 3.81 (s, 3H), 3.02 (t, 2H, J = 6.8 Hz);
13C{1H} NMR (100 MHz, CDCl3): δ 155.5, 149.7, 149.1, 148.54,
148.51, 148.1, 146.5, 144.3, 137.3, 137.1, 137.0, 136.4, 132.2, 130.5,
128.7, 128.6, 128.54, 128.46, 128.02, 127.99, 127.9, 127.8, 127.6,
127.35, 127.31, 127.1, 122.9, 121.6, 118.9, 116.5, 115.0, 114.8, 112.0,
110.4, 107.3, 101.0, 71.5, 71.3, 70.9, 70.6, 56.3, 56.1, 51.1, 37.6 (four
aromatic carbon signals are missing due to overlapping);
HRMS (ESI/TOF) m/z: [M + Na]+ Calcd for C55H47NO8Na
872.3229; Found 872.3199.
2-[3-(Benzyloxy)-4-methoxyphenyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (29).
A flame-dried 100-mL two-necked round-bottomed flask
equipped with a Teflon-coated magnetic stirring bar and a
rubber septum was charged with 2-benzyloxy-4-bromo-1-
methoxybenzene (S22) (880.2 mg, 3.00 mmol, 1.0 equiv) and
anhydrous THF (15 mL). After the solution was cooled to –
78 °C, the reaction mixture was treated with n-BuLi (1.59 M
in n-hexane, 1.9 mL, 3.0 mmol, 1.0 equiv) and stirred at –
78 °C for 5 min. To the solution was added i-PrOBpin (658.3
Lamellarin Z.
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(4) Warabi, K.; Matsunaga, S.; van Soest, R. W. M.; Fusetani, N.
mg, 3.54 mmol, 1.2 equiv) at –78 °C. After stirring at –78 °C
for 10 min, the reaction mixture was allowed to warm to
room temperature with stirring over 1 h, at which time the
reaction mixture was treated with saturated aqueous ammo-
nium chloride (15 mL). The reaction mixture was extracted
with diethyl ether (15 mL) three times. The combined organic
extracts were washed with water and brine, dried over sodi-
um sulfate, and filtered. The filtrate was concentrated under
reduced pressure to give a crude product, which was purified
by silica gel column chromatography (hexane/CH2Cl2 = 1:1 to
hexane/diethyl ether = 10:1, gradient) to provide the title
product 29 as a colorless solid (795.6 mg, 2.34 mmol, 78%). Rf
1
2
3
4
5
6
7
8
Dictyodendrins A-E, the frst telomerase-inhibitory marine natu-
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9
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ing topoisomerase I. J. Org. Chem. 2009, 74, 8143–8153. (h) Li, Q.;
Jiang, J.; Fan, A.; Cui, Y.; Jia, Y. Total synthesis of lamellarins D,
H, and R and ningalin B. Org. Lett. 2011, 13, 312–315. (i) Lade, D.
M.; Pawar, A. B.; Mainkar, P. S.; Chandrasekhar, S. Total synthe-
sis of lamellarin D trimethyl ether, lamellarin D, and lamellarin
H. J. Org. Chem. 2017, 82, 4998–5004.
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1
= 0.21 (hexane/CH2Cl2 = 1:1); M.p. 112–113 °C; IR (ATR, cm– ):
2978, 1600, 1416, 1372, 1352, 1295, 1257, 1219, 1137, 1026, 966, 855,
737, 698, 685; 1H NMR (400 MHz, CDCl3): δ 7.51–7.28 (m, 7H),
6.91 (d, 1H, J = 8.2 Hz), 5.15 (s, 2H), 3.89 (s, 3H), 1.33 (s, 12H);
13C{1H} NMR (100 MHz, CDCl3): δ 152.4, 147.8, 137.2, 129.1,
128.5, 127.8, 127.6, 120.8, 119.3, 111.1, 83.6, 70.9, 55.8, 24.9;
HRMS (DART/TOF) m/z: [M + H]+ Calcd for C20H26BO4
341.1924; Found 341.1909.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxx.
Tabular comparisons of NMR data with the natural products
and copies of 1H and 13C NMR spectra for all new compounds
(PDF).
AUTHOR INFORMATION
Corresponding Author
Kentaro Okano*
*E-mail: okano@harbor.kobe-u.ac.jp
Notes
(7) (a) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C.
R. Convergent syntheses of the pyrrolic marine natural products
lamellarin-O, lamellarin-Q, lukianol-A and some more highly
oxygenated congeners. Chem. Commun. 1997, 207–208. (b) Ishi-
bashi, F.; Miyazaki, Y.; Iwao, M. Total syntheses of lamellarin D
and H. The first synthesis of lamellarin-class marine alkaloids.
Tetrahedron 1997, 53, 5951–5962. (c) Ridley, C. P.; Reddy, M. V.
R.; Rocha, G.; Bushman, F. D.; Faulkner, D. J. Total synthesis and
evaluation of lamellarin α 20-sulfate analogues. Biorg. Med.
Chem. 2002, 10, 3285–3290. (d) Pla, D.; Marchal, A.; Olsen, C. A.;
Albericio, F.; Álvarez, M. Modular total synthesis of lamellarin D.
J. Org. Chem. 2005, 70, 8231–8234. (e) Imbri, D.; Tauber, J.; Opatz,
T. A high-yielding modular access to the lamellarins: synthesis of
lamellarin G trimethyl ether, lamellarin η and dihydrolamellarin
η. Chem. Eur. J. 2013, 19, 15080–15083. (f) Ueda, K.; Amaike, K.;
Maceiczyk, R. M.; Itami, K.; Yamaguchi, J. β-Selective C–H aryla-
tion of pyrroles leading to concise syntheses of lamellarins C and
I. J. Am. Chem. Soc. 2014, 136, 13226–13232. (g) Zheng, K.-L.; You,
M.-Q.; Shu, W.-M.; Wu, Y.-D.; Wu, A.-X. Acid-mediated inter-
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Numbers
(JP16K05774, JP16H01153, JP18H04413, JP19H02717) and the
Sasakawa Scientific Research Grant. We thank Mr. Yoshiki
Yamane for performing some preliminary experiments. We
also thank Dr. Alison McGonagle from Edanz Group
(https://en-author-services.edanzgroup.com/) for editing a
draft of this manuscript.
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