Construction of Pentacyclic Lamellarin Skeleton via Grob Reaction: Application to Total Synthesis of Lamellarins H and D

Article abstract of DOI:10.1021/acs.joc.7b01061

An efficient construction of phenyl-substituted coumarin-pyrrole-isoquinoline-fused pentacycle via base-promoted Grob-type coupling of 3-nitrocoumarin and papaverine in a sealed tube is reported. This reaction is further applied to the total synthesis of lamellarin H in three linear steps and lamellarin D in eight linear steps with overall yields of 31% and 14%, respectively.

Full text of DOI:10.1021/acs.joc.7b01061

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Note
Construction of Pentacyclic Lamellarin Skeleton via Grob
Reaction: Application to Total Synthesis of Lamellarins H and D
Kiran B Manjappa, Jhih-Min Lin, and Ding-Yah Yang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 Jun 2017
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The Journal of Organic Chemistry
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Construction of Pentacyclic Lamellarin Skeleton via Grob Reaction: Application to
Total Synthesis of Lamellarins H and D
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Kiran B. Manjappa, Jhih-Min Lin, and Ding-Yah Yang*
Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung City 40704,
Taiwan, Republic of China
Keywords: Grob reaction, 3-nitrocoumarin, papaverine, lamellarin H, lamellarin D.
Scheme 1. Previous Synthesis of Lamellarin Alkaloids and
Analogues via Coupling of 3-Nitrocoumarins and Papaver-
ine Derivatives
ABSTRACT: An efficient construction of phenyl-substituted
coumarin-pyrrole-isoquinoline-fused pentacycle via base-
promoted Grob-type coupling of 3-nitrocoumarin and papaver-
ine in sealed tube is reported. This reaction is further applied
to the total synthesis of lamellarin H in three linear steps and
lamellarin D in eight linear steps with overall yields of 31 and
14%, respectively.
Having a unique pyrrolocoumarin structure, lamellarin D is a
natural product isolated from marine mollusks and ascidians.1
It exhibits potent cytotoxic activities against multidrug-
resistant tumor cell lines2 and is a potent DNA topoisomerase I
inhibitor.3 Owing to its intriguing biological properties along
with the difficulty in obtaining bulk quantities from natural
sources, the synthesis of lamellarin D and related alkaloids has
lactone ring opening of the coumarin moiety during the reac-
attracted considerable attention to organic and medicinal
tion. Nevertheless, this strategy has been employed later by
chemists in the past three decades.4 Previous lamellarin D
Sosnovskikh7 to prepare trifluromethyl-substituted lamellarin
synthetic approaches can be generally classified into two cate-
analogues by replacing 3-nitrocoumarin with 3-nitro-2-
gories. One involves the construction of the pyrrole core as the
(trifluoromethyl)-2H-chromenes. Also, we have reported the
key step; the other refers to the functionalization of the pre-
construction of the lamellarin pentacycle by Yb(OTf)3-
existed pyrrole to the target.5 Recently, a third approach has
catalyzed coupling of papaverine with 4-chloro-3-
emerged, which involves the direct annulation of pyrrole ring
nitrocoumarin8 (Scheme 1). Among the aforementioned reac-
onto functionalized coumarin derivatives to afford the lamel-
tions, none has engaged in a direct coupling of papaverine
larin pentacyclic core via the coupling of 3,4-
with 3-nitrocoumarin, in which the target lamellarin alkaloid
dihydropapavarine with 3-nitrocoumarin. This approach is
can be generated in a single step. Therefore, the method
highly attractive since the coumarin/pyrrole-fused lamellarin
installing the pyrrole ring onto appropriately substituted cou-
skeleton can be constructed in a high atom-economical fashion
marins to afford lamellarin skeleton remains highly sought till
without any protection/deprotection. Unfortunately, Ruchi-
today. Herein, we described, for the very first time, the suc-
rawat6 has reported that this coupling reaction suffered from
cessful construction of phenyl-substituted coumarin-pyrrole-
poor yield (only 5−6%), which may be attributed to the
isoquinoline-fused pentacycle (lamellarin skeleton) via Grob
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coupling9 of commercial and inexpensive papaverine with 3-
nitrocoumarins in sealed tube. This methodology was further
applied to the total synthesis of biologically active lamellarins
H, D, and 501 (Figure 1).
aminations, xylene was found to be the most effective solvent.
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Also, the effect of pressure was studied by performing the
coupling reaction in a sealed tube. The reactions carried out in
a closed sealed tube system usually gave better yields and
higher conversions than those of the open system reactions
(see Table S1 in the SI for optimization results). Among the
various conditions explored, sodium bicarbonate, xylene, and
o
sealed tube with the temperature between 150–160 C were
found to be effective combinations. Hence these conditions
were employed to all subsequent coupling reactions.
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Figure 1. Structures of lamellarins D trimethyl ether, H, D,
and 501.
Scheme 3. Synthesis of 8b
In the present investigation, we chose 1-benzylisoquinoline
rather than 1-benzyl-3,4-dihydroisoquinoline as one of the
model substrates due to the fact that the latter is susceptible to
oxidation at the benzylic carbon. Additionally, the use of 1-
benzylisoquinoline also gives an added advantage of pos-
sessing the pre-existed C5-C6 double bond (see Figure 1 for
atom-numbering) which plays a pivotal role in imparting bio-
logical activity.3a Keeping these in mind, we initiated our stud-
ies by investigating the direct coupling of 3-nitrocoumarin
(1)10 with 1-benzylisoquinoline (2) as shown in Scheme 2. To
our delight, simple refluxing of a mixture of 1 and 2 in the
presence of one equivalent of AlCl3 in toluene overnight led to
the formation of the desired lamellarin core 3 in 32% yield.
We envisioned that the mechanism for this reaction presuma-
bly involves AlCl3-mediated formation of Michael adduct 4
which further undergoes isomerization to generate the
enamine 5. The intramolecular cyclization of 5 via nucleo-
philic addition of the amine nitrogen to the iminium carbon
generates the cyclized dihydroxyamine 6. Final elimination of
water and hyponitrous acid from 6 gives the aromatized phe-
nyl-substituted pentacyclic lamellarin core 3 (Scheme 2).7a
Figure 2 lists the structures and yields of various prepared
lamellarin derivatives 8a−h and 9a−h. Lamellarins 8b−h were
synthesized by NaHCO3-mediated coupling of substituted 3-
nitrocoumarins and papaverine (7) in sealed tube in moderate
yields 19−41% (An average of 20% of 7 was recovered). The
methoxy groups on coumarin moiety of these lamellarins can
be readily introduced by employing the appropriately substi-
tuted 3-nitrocoumarins (8c−f)12 as the starting material. Other
substituents such as chloro (8g) and naphthyl moiety (8h)13
were also incorporated into the lamellarin structure to demon-
strate the scope of the coupling reaction. Further exhaustive
demethylation of 8a−h with an excess of boron tribromide (18
equiv.) gave the corresponding hydroxyl substituted lamellarin
derivatives 9a−h in good yields. The methoxy group substitut-
ed at the C-5 position of the coumarin ring of 8c survived the
deprotection, presumably due to the presence of the nearby
benzene moiety which sterically hindered the approach of
BBr3 to the C-5 methoxy group (see 8c in Figure 2 for atom-
numbering). Generally, this methodology provides a quick
access to lamellarin derivatives with different substituents on
the coumarin moiety.
Scheme 2. Synthesis of lamellarin core 3
Since the hydroxyl and methoxy substituents on the lamellarin
alkaloids are indispensable for their biological activities,11 our
next aim was to introduce the methoxy groups onto the lamel-
larin core (3) by replacing 1-benzylisoquinoline (2) with
commercially available natural product papaverine (7). To our
disappointment, reaction of 1 and papaverine under the condi-
tions shown in Scheme 2 gave the desired coupled product 8b
in extremely low yield. In an effort to search for the reaction
conditions that could enhance the reaction conversion and
maximize the formation of lamellarin derivative 8b, the cou-
pling reaction between 3-nitrocoumarin (1) and papaverine (7)
under various bases, solvents, temperatures, and different reac-
tion conditions were examined (Scheme 3). Among these ex-
Figure 2. Structures of the Prepared 8a−h and 9a−h.
In addition to the preparation of lamellarin derivatives, this
Grob coupling reaction strategy was also employed to the syn-
thesis of naturally occurring alkaloids such as lamellarin H. As
outlined in Scheme 4, the synthesis of lamellarin H began with
the piperidine-catalyzed condensation of commercially availa-
ble o-hydroxy-2,4-dimethoxybenzaldedyde (10) with ethyl
nitroacetate in Dean-Stark trap to yield the 6,7-dimethoxy-3-
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nitrocoumarin (11). The subsequent coupling of 11 with papa-
With compounds 16 and 21 in hand, we then pursued the la-
verine (7) in sealed tube afforded lamellarin D trimethyl ether
(12) in 40% yield (~20% of 7 was recovered). Final exhaustive
demethylation of 12 with excess of boron tribromide at low
temperature furnished lamellarin H (13). With this methodolo-
gy, lamellarin H was prepared in three steps with an overall
yield of 31% from the benzaldedyde 10. To the best of our
knowledge, this synthetic scheme represents the shortest route
for both lamellarin D trimethyl ether and lamellarin H prepara-
tions ever reported in the literature.8,14
mellarin D synthesis by coupling of the two building blocks as
shown in Scheme 6. The NaHCO3-mediated coupling of 3-
nitrocoumarin 16 and 1-methylisoquinoline 21 in sealed tube
gave the lamellarin pentacycle core 22 in 43% yield (22% of
21 was recovered), presumably proceeding with a similar reac-
tion mechanism as described in Scheme 2. Bromination of 22
by NBS in THF at room temperature overnight afforded the
brominated pentacycle 23.15 The Suzuki coupling16 of 23 with
phenylboronic acid 24 in DME yielded the protected lamellar-
in 25.
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Scheme 4. Synthesis of Lamellarin D Trimethyl Ether and
Lamellarin H
Scheme 6. Synthesis of OBn-protected Lamellarin D (25)
After successfully realizing the preparation of lamellarin H via
Grob pyrrolocoumarin synthesis, we believe that the same
approach could lead us to prepare biologically important la-
mellarin D using appropriately substituted coumarins and iso-
quinolines. Scheme 5 depicts the preparation of the two key
building blocks 3-nitrocoumarin 16 and 1-methylisoquinoline
21 for the crucial Grob coupling reaction. The 3-nitrocoumarin
16 was synthesized in two steps by selective benzylation at C-
4 hydroxyl group of aldehyde 14 and then followed by con-
densation of the benzylated aldehyde 15 with ethyl nitroace-
tate to give the 3-nitrocoumarin 16 in 56% overall yield. On
the other hand, compound 21 was prepared by methoxylation
at the -position of the commercial nitrostyrene 17 with sodi-
um methoxide to give compound 18 which was subsequently
reduced by zinc in HCl to yield the amine 19. The amine 19
was then treated with acetic anhydride to generate the corre-
sponding amide 20. Final POCl3-promoted Bischler-
Napieralski cyclization of 20 furnished the protected 1-
methylisoquinoline 21.
Alternatively, the OBn-protected lamellarin D (25) can also be
synthesized by coupling of 3-nitrocoumarin 16 with appropri-
ately substituted benzylisoquinoline 26 (prepared according to
the literature procedure14a in four steps from 17) in sealed tube
to give the compound 25 in 27% yield (23% of 26 was recov-
ered). The subsequent Pd(OH)2-catalyzed debenzylation of 25
in EtOAc under hydrogen atmosphere furnished the target
lamellarin D (27)13. In the case of Pd/C catalysis, the double
bond at C-5 and C-6 of 25 was also hydrogenated, resulting to
the lamellarin 501 (28) (see 25 in Scheme 7 for atom-
numbering). Essentially, lamellarin D was prepared in 12 and
14% overall yields over six and eight linear steps starting from
the commercial -nitrostyrene 17 by virtue of the successful
Grob coupling reaction. This synthetic scheme represents the
shortest route for lamellarin D preparation ever reported so
far.14a,14c,17 Even though the conversion of this coupling reac-
tion requires improvement, the successful preparation of pen-
tacycles 22 and 25 via coupling of 3-nitrocoumarin 16 with
respective 1-methylisoquinoline 21 and benzylisoquinoline 26
clearly demonstrates the wide scope of the Grob reaction in
construction of pentacyclic lamellarin skeleton. We envision
the rapid synthesis of lamellarins H, D, and their analogues via
Grob-type reaction may greatly facilitate the process for the
development of lamellarin-based anticancer drugs.1c
Scheme 5. Preparation of 3-Nitrocoumarin 16 and
1-Methylisoquinoline 21
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Scheme 7. Synthesis of Lamellarin D (27) and Lamellarin
501 (28)
cipitated. The solid was filtered, washed with plenty of 2–5%
EA/hexanes, and dried under vacuum to remove the excess
ethyl nitroacetate.
3-Nitrocoumarin12a: Pale-yellow solid; 640 mg; yield 82%;
o
1
mp 138–140 C; H NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H),
7.79 (td, J = 8.8, 1.6 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H),
7.48–7.44 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 154.9,
152.0, 142.4, 136.2, 134.9, 130.7, 126.0, 117.1, 116.2; IR νmax
(KBr) 3483, 2970, 1732, 1717, 1606, 1520, 1365, 1253, 1118,
977 cm-1; HRMS (EI) m/z calcd for C9H5NO4 [M+] 191.0219,
found 191.0215.
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6,7-Dimethoxy-3-nitrocoumarin (11)12b: Saffron yellow
solid; 580 mg; yield 93%; mp 268–270 oC; 1H NMR (CD3OD,
400 MHz) δ 9.05 (s, 1H), 7.36 (s, 1H), 7.13 (s, 1H), 4.02 (s,
3H), 3.94 (s, 3H); 13C NMR (Acetone-d6, 150 MHz) δ 158.2,
153.5, 153.1, 148.5, 144.1, 133.1, 111.0, 110.1, 100.5, 57.2,
56.6; IR νmax (KBr) 3461, 2947, 1717. 1616, 1520, 1367, 1227,
1002, 849, 770 cm-1; HRMS (EI) m/z calcd for C11H9NO6
[M+] 251.0430, found 251.0426.
CONCLUSION: We have demonstrated that the phenyl-
substituted pentacyclic lamellarin skeleton can be efficiently
constructed via NaHCO3-mediated Grob coupling of 3-
nitrocoumarin and 1-benzylisoquinoline or papaverine in
sealed tube. The scope of the reaction was illustrated by the
preparation of eight lamellarin derivatives 8a−h in two steps,
along with concise synthesis of the natural product lamellarin
H in three steps with an overall yield of 31%. Moreover, the
Grob coupling was successfully employed as a key step to two
total syntheses of lamellarin D in six and eight linear steps
with overall yields of 12 and 14%, respectively. Finally, the
molecular structure of lamellarin D (27) was unambiguously
confirmed by the X-ray crystallography.
5-Methoxy-3-nitrocoumarin12a: Brown solid; 612 mg; yield
o
1
84%; mp 116–118 C; H NMR (CDCl3, 400 MHz) δ 9.16 (s,
1H), 7.71 (t, J = 8.6 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.84 (d,
J = 8.4 Hz, 1H), 4.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
158.4, 155.9, 152.1, 138.5, 137.5, 133.1, 109.0, 107.5, 106.2,
56.6; IR νmax (KBr) 2944, 1746, 1602, 1470, 1336, 1230, 1090,
971, 772 cm-1; HRMS (EI) m/z calcd for C10H7NO5 [M+]
221.0324, found 221.0331.
6-Methoxy-3-nitrocoumarin12a: Pale brown solid; 592 mg;
o
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yield 81%; mp 159–161 C; H NMR (CDCl3, 400 MHz) δ
8.71 (s, 1H), 7.39 (s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.11 (d, J =
2.4 Hz, 1H), 3.92 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
157.2, 152.1, 149.6, 142.1, 135.2, 124.8, 118.3, 116.6, 111.2,
56.1; IR νmax (KBr) b3473, 2949, 1738, 1607, 1525, 1364,
1227, 1030, 815, 773 cm-1; HRMS (EI) m/z calcd for
C10H7NO5 [M+] 221.0324, found 221.0321.
EXPERIMENTAL SECTION:
Instrumentation. Melting points were determined on a
Mel-Temp melting point apparatus in open capillaries and are
uncorrected. Infrared (IR) spectra were recorded using
1725XFT-IR spectrophotometer. High resolution mass spectra
(HRMS) were obtained on a Thermo Fisher Scientific Finni-
gan MAT95XL spectrometer using magnetic sector analyzer
1H NMR (400 MHz) and 13C NMR (100, or 150 MHz) spectra
were recorded on a Varian VXR300 or Bruker 400/600 spec-
trometer. Chemical shifts were reported in parts per million on
the  scale relative to an internal standard (tetramethylsilane,
or appropriate solvent peaks) with coupling constants given in
7-Methoxy-3-nitrocoumarin12a: Yellow solid; 618 mg;
o
1
yield 85%; mp 148–150 C; H NMR (CDCl3, 400 MHz) δ
8.80 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 8.8, 2.4 Hz,
1H), 6.90 (d, J = 2.4 Hz, 1H), 4.98 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 167.0, 157.8, 152.4, 143.2, 132.1, 131.7, 115.1,
109.8, 100.7, 56.4; IR νmax (KBr) 3461, 2970, 1739, 1716,
1621, 1598, 1383, 1132, 1000, 846 cm-1; HRMS (EI) m/z
calcd for C10H7NO5 [M+] 221.0324, found 221.0322.
8-Methoxy-3-nitrocoumarin12a: Dark brown solid; 575 mg;
1
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hertz. H NMR multiplicity data are denoted by s (singlet), d
yield 79%; mp 170–172 C; H NMR (CDCl3, 400 MHz) δ
8.73 (s, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.33–7.29 (m, 2H), 4.02
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 151.5, 147.3, 144.6,
142.6, 135.1, 126.0, 121.5, 117.5, 116.9, 56.5; IR νmax (KBr)
3442, 3011, 1728, 1717, 1603, 1572, 1463, 1371, 1332, 1091
cm-1; HRMS (EI) m/z calcd for C10H7NO5 [M+] 221.0324,
found 221.0317.
(doublet), t (triplet), q (quartet), m (multiplet), ABdq (AB
doublet quartet) and ABddq (AB doublet doublet quartet).
Analytical thin-layer chromatography (TLC) was carried out
on Merck silica gel 60G-254 plates (25 mm) and developed
with the solvents mentioned. Visualization was accomplished
by using portable UV light, ninhydrin spray and iodine cham-
ber. Flash chromatography was performed in columns of vari-
ous diameters with Merck silica gel (230-400 mesh ASTM
9385 kieselgel 60H) by elution with the solvent systems. Sol-
vents, unless otherwise specified, were reagent grade and dis-
tilled once prior to use. All new compounds exhibited satisfac-
tory spectroscopic and analytical data.
7-Chloro-3-nitrocoumarin12c: Off-white solid; 640 mg;
o
1
yield 89%; mp 128–130 C; H NMR (CDCl3, 400 MHz) δ
8.73 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H),
7.46 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
155.1, 151.2, 142.9, 141.8, 134.5, 131.5, 126.8, 117.5, 114.8;
IR νmax (KBr) 3441, 2857, 1723, 1615, 1522, 1337, 1206, 1074,
976, 869 cm-1; HRMS (EI) m/z calcd for C9H4ClNO4 [M+]
224.9829, found 224.9830.
Synthesis of 3-nitrocoumarin derivatives: To a mixture of
appropriately substituted o-hydroxybenzaldehyde (1 equiv.),
ethyl nitroacetate (1.2 equiv.), and piperidine (1.2 equiv.) in
benzene was placed in a round-bottom flask and fitted with
2-Nitro-3H-benzo[f]coumarin12d: Brown solid; 560 mg;
o
1
yield 80%; mp 194–196 C; H NMR (CDCl3, 400 MHz) δ
9.60 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H),
o
Dean-Stark trap. The mixture was heated at 110 C for 6 h.
After cooled down to room temperature, the product was pre-
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8.02 (d, J = 8.0 Hz, 1H), 7.87 (td, J = 7.2, 1.2 Hz, 1H), 7.72 (t,
108.3, 107.3, 105.2, 56.1, 56.0, 55.9, 55.2; IR νmax (KBr) 3447,
J = 8.0 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 156.5, 152.0, 138.8, 138.5, 133.4, 130.4, 130.1,
129.7, 129.6, 127.4, 121.5, 116.5, 111.1; IR νmax (KBr) 3441,
2970, 1737, 1714, 1552, 1439, 1365, 1228, 1022, 820 cm-1;
HRMS (EI) m/z calcd for C13H7NO4 [M+] 241.0475, found
241.0380.
3005, 1737, 1710, 1610, 1505, 1366, 1219, 1024, 753 cm-1;
HRMS (EI) m/z calcd for C29H23NO6 [M+] 481.1525, found
481.1534.
8c. Rf = 0.35 (50% EtOAc/hexanes); brown solid; 152 mg;
o
1
yield 22%; mp 234–236 C; H NMR (CDCl3, 400 MHz) δ
9.50 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.11–7.07
(m, 4H), 7.03 (s, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.74 (s, 1H),
6.62 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.88 (s,
3H), 3.45 (s, 3H), 3.16 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ
156.4, 155.3, 152.8, 149.8, 148.9, 148.8, 147.8, 135.2, 133.1,
128.6, 127.4, 124.9, 123.8, 123.1, 119.4, 114.9, 114.0, 113.1,
110.9, 109.9, 108.7, 108.6, 107.3, 105.9, 105.2, 56.2, 56.1,
55.9, 55.2, 54.7; IR νmax (KBr) 3602, 2969, 1714, 1608, 1435,
1365, 1226, 1027, 855, 787 cm-1; HRMS (EI) m/z calcd for
C30H25NO7 [M+] 511.1631, found 511.1634.
Synthesis of lamellarin core (3): To a mixture of 3-
nitrocoumarin 1 (209 mg, 1.09 mmol, 1.2 equiv.), 1-
benzylisoquinoline 2 (200 mg, 0.912 mmol, 1 equiv.) and
AlCl3 (243 mg, 1.82 mmol, 2 equiv.) in a flame-dried 50 mL
round-bottom flask was added toluene (20 mL) under nitrogen
atmosphere. The mixture was degassed and refluxed overnight.
After reaction mixture was cooled down to room temperature,
the solvent was evaporated in vacuo. The crude mixture was
purified by column chromatography to give lamellarin core as
a pale yellow compound 3. Rf = 0.40 (40% EtOAc/hexanes);
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8d. Rf = 0.35 (50% EtOAc/hexanes); pale brown solid; 187
o
o
1
o
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105 mg; yield 32%; mp 222–224 C (Lit.8 222–224 C); H
NMR (CDCl3, 400 MHz) δ 9.36 (d, J = 7.2 Hz, 1H), 7.71 (d, J
= 8.0 Hz, 1H), 7.67–7.63 (m, 3H), 7.58–7.53 (m, 2H), 7.52–
7.49 (m, 2H), 7.47–7.43 (m, 1H), 7.35 (td, J = 7.6, 1.6 Hz,
1H), 7.25 (td, J = 8.0, 1.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H),
7.11 (dd, J = 8.0, 1.6 Hz, 1H), 7.00 (td, J = 8.4, 1.2 Hz, 1H);
13C NMR (CDCl3, 150 MHz) δ 155.3, 151.7, 135.6, 134.1,
130.9, 129.9, 129.7, 128.7, 128.7, 128.4, 128.2, 127.5, 127.3,
125.0, 124.4, 124.4, 124.2, 123.9, 117.9, 117.4, 114.3, 113.5,
109.4; IR νmax (KBr) 3463, 2970, 1738, 1538, 1411, 1367,
1229, 1048, 968, 898 cm-1; HRMS (EI) m/z calcd for
C25H15NO2 [M+] 361.1103, found 361.1106.
mg; yield 27%; mp 252–254 C; H NMR (CDCl3, 400 MHz)
δ 9.30 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.23 (dd, J
= 8.4, 2.0 Hz, 1H), 7.19 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.16
(d, J = 2.0 Hz, 1H), 7.15 (s, 1H), 7.11 (s, 1H), 7.09 (d, J = 7.6
Hz, 1H), 6.94 (dd, J = 8.8, 2.8 Hz, 1H), 6.83 (d, J = 2.8 Hz,
1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.91 (s, 3H), 3.52 (s, 3H), 3.49
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.4, 155.3, 150.1,
149.9, 149.2, 149.1, 146.0, 134.2, 128.6, 128.0, 124.6, 123.9,
123.2, 119.1, 118.3, 118.1, 115.9, 114.2, 112.7, 112.0, 111.8,
108.6, 107.3, 106.7, 105.2, 56.2, 56.1, 55.9, 55.2, 55.1; IR νmax
(KBr) 3461, 2933, 1713, 1690, 1479, 1411, 1225, 1045, 1005,
866, 799 cm-1; HRMS (EI) m/z calcd for C30H25NO7 [M+]
511.1631, found 511.1635.
Synthesis of lamellarin derivatives: Mixtures of 3-
nitrocoumarin
derivative
(1.2
equiv.),
1-
8e. Rf = 0.30 (60% EtOAc/hexanes); yellow solid; 255 mg;
o
1
benzylisoquinoline/papaverine
(1 equiv.), and NaHCO3
yield 37%; mp 256–258 C; H NMR (CDCl3, 400 MHz) δ
9.26 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.19 (d, J =
1.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.11–7.10 (m, 3H), 7.07
(d, J = 7.6 Hz, 1H), 6.98–6.96 (m, 1H), 6.67 (d, J = 8.8, 2.4 Hz,
1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.48
(s, 3H); 13C NMR (CDCl3, 150 MHz) δ 160.0, 155.3, 155.2,
150.1, 149.9, 149.2, 149.1, 134.6, 129.3, 128.1, 124.9, 124.8,
123.8, 123.3, 119.1, 114.1, 112.4, 112.0, 111.6, 111.3, 111.2,
107.5, 107.3, 105.3, 101.6, 56.1, 56.0, 55.9, 55.5, 55.2; IR νmax
(KBr) 2936, 1707, 1617, 1431, 1314, 1225, 1139, 1046, 841,
756 cm-1; HRMS (EI) m/z calcd for C30H25NO7 [M+] 511.1631,
found 511.1625.
(2.2 equiv.) in xylene (25 mL) were placed in a 50 mL flame-
dried sealed tube under argon atmosphere. The sealed tube
was closed tightly with Teflon ring screw cap and was heated
to 160 oC for 16 h. After the mixture was cooled down to room
temperature, the solvent was evaporated in vacuo and the
crude mixture was purified by column chromatography to
afford lamellarin derivatives 8a–h. During the purification, the
starting material papaverine (about 20%) was recovered.
8a. Rf = 0.30 (50% EtOAc/hexanes); off-white solid; 155
o
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mg; yield 30%; mp 248–250 C; H NMR (CDCl3, 400 MHz)
δ 9.34 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.75–7.49
(m, 4H), 7.68 (s, 1H), 7.64 (s, 1H), 7.51 (td, J = 8.0, 1.2 Hz,
1H), 7.28 (td, J = 8.0, 1.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H),
6.97 (s, 1H), 6.53 (s, 1H), 3.92 (s, 3H), 3.42 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ 155.6, 149.5, 146.6, 145.5, 135.8, 134.0,
131.4, 129.7, 129.4, 128.5, 128.1, 127.4, 127.3, 124.9, 124.5,
124.4, 113.1, 113.0, 109.7, 108.7, 104.8, 100.5, 56.1, 55.3; IR
νmax (KBr) 3461, 2970, 1708, 1428, 1360, 1216, 1008, 788,
728 cm-1; HRMS (EI) m/z calcd for C27H19NO4 [M+]
421.1314, found 421.1311.
8f. Rf = 0.40 (50% EtOAc/hexanes); dark brown solid; 135
o
1
mg; yield 19%; mp 254–256 C; H NMR (CDCl3, 400 MHz)
δ 9.32 (d, J = 7.6 Hz, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 7.16
(d, J = 8.0 Hz, 1H), 7.13–7.10 (m, 1H), 7.11 (s, 1H), 7.10 (s,
1H), 7.09 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.69–
6.91 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.99 (s, 3H), 3.90 (s,
3H), 3.48 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 154.6, 150.0,
149.9, 149.1, 149.0, 147.8, 141.2, 134.4, 128.7, 128.1, 124.7,
123.8, 123.6, 123.3, 119.2, 118.8, 115.9, 114.2, 112.7, 112.2,
112.0, 110.4, 108.5, 107.4, 105.3, 56.2, 56.1, 56.0, 55.9, 55.2;
IR νmax (KBr) 3631, 2837, 1702, 1611, 1503, 1462, 1399, 1264,
1171, 1094 cm-1; HRMS (EI) m/z calcd for C30H25NO7 [M+]
511.1631, found 511.1635.
8b. Rf = 0.25 (50% EtOAc/hexanes); pale white solid; 261
mg; yield 35%; mp 250–252 oC (Lit.18a 254–256 oC); 1H NMR
(CDCl3, 400 MHz) δ 9.28 (d, J = 7.2 Hz, 1H), 7.44 (dd, J =
8.0, 0.4 Hz, 1H), 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 (td, J =
8.0, 2.8 Hz, 1H), 7.18 (dd, J = 6.4, 1.6 Hz, 1H), 7.14 (d, J =
8.4 Hz, 1H), 7.10–7.09 (m, 3H), 7.68 (s, 1H), 7.04 (d, J = 8.0
Hz, 1H), 4.02 (s, 3H), 3.98 (s, 3H), 3.87 (s, 3H), 3.46 (s, 3H);
13C NMR (CDCl3, 150 MHz) δ 155.1, 151.7, 150.0, 149.9,
149.2, 149.1, 134.4, 128.6, 128.3, 128.0, 124.7, 124.1, 123.8,
123.7, 123.1, 119.1, 118.0, 117.2, 114.0, 112.7, 112.1, 112.0,
8g. Rf = 0.30 (50% EtOAc/hexanes); off white solid; 298
o
1
mg; yield 41%; mp 296–298 C; H NMR (CDCl3, 400 MHz)
δ 9.24 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.22 (d, J
= 8.4 Hz, 1H), 7.16 (s, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.11–
7.10 (m, 4H), 7.03 (dd, J = 8.8, 2.4 Hz, 1H), 4.02 (s, 3H), 3.97
(s, 3H), 3.87 (s, 3H), 3.46 (s, 3H); 13C NMR (CDCl3, 150
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MHz) δ 154.6, 152.0, 150.3, 150.0, 149.3, 149.2, 134.7, 133.8,
150 MHz) δ 156.2, 154.1, 152.2, 147.4, 146.4, 145.0, 144.2,
128.0, 127.6, 125.0, 124.8, 124.3, 123.7, 123.1, 119.1, 117.6,
116.7, 114.1, 113.1, 112.1, 112.0, 108.0, 107.4, 105.2, 56.13,
56.10, 56.0, 55.3; IR νmax (KBr) 3452, 2970, 1711, 1504, 1428,
1385, 1210, 1030, 858, 755 cm-1; HRMS (EI) m/z calcd for
C29H22ClNO6 [M+] 515.1136, found 515.1131.
134.8, 130.6, 129.0, 126.7, 124.0, 121.5, 121.0, 118.4, 118.6,
115.5, 114.6, 113.6, 111.3, 110.7, 109.1, 107.9, 107.5, 106.0,
54.9; IR νmax (KBr) 3017, 1736, 1604, 1418, 1365, 1278, 1217,
1095, 867, 763 cm-1; HRMS (EI) m/z calcd for C26H17NO7
[M+] 455.1005, found 455.1002.
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8
9
8h. The compound was recrystallized from 70%
DCM/hexanes biphasic system. Rf = 0.40 (1% MeOH/DCM);
9d. Dark brown solid; 77 mg; yield 89%; mp charred at
o
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300 C; H NMR (CD3OD, 400 MHz) δ 9.01 (d, J = 7.2 Hz,
1H), 7.14 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 7.02 (s, 1H), 7.01
(d, J = 8.0 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 2.0
Hz, 1H), 6.78 (dd, J = 8.4, 2.0 Hz, 1H), 6.75 (dd, J = 8.0, 2.0
Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H); 13C NMR (DMSO-d6, 150
MHz) δ 154.2, 153.2, 147.8, 146.7, 146.3, 145.6, 144.5, 133.8,
127.8, 125.2, 123.7, 121.3. 121.1, 118.2, 118.2, 117.6, 117.4,
117.1, 116.2, 113.3, 112.5, 111.5, 109.6, 109.2, 107.3; IR νmax
(KBr) 3443, 1738, 1621, 1473, 1366, 1227, 1110, 1036, 958,
755 cm-1; HRMS (EI) m/z calcd for C25H15NO7 [M+] 441.0849,
found 441.0845.
o
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brown solid; 149 mg; yield 23%; mp 218–220 C; H NMR
(CDCl3, 400 MHz) δ 9.54 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.8
Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),
7.61 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.31 (t, J = 7.2 Hz, 1H),
7.43 (d, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.13 (d, J = 6.4 Hz, 1H),
7.05 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 6.90 (td, J =
8.0, 1.6 Hz, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.70 (s, 3H), 3.53
(s, 3H); 13C NMR (CDCl3, 150 MHz) δ 155.3, 150.6, 150.0,
149.7, 149.0, 134.6, 130.9, 130.5, 130.0, 129.3, 128.4, 127.7,
127.9, 125.1, 125.0, 124.7, 124.6, 124.5, 123.1, 119.2, 117.8,
115.7, 113.4, 113.2, 113.0, 111.8, 110.3, 107.5, 105.9, 56.3,
56.1, 55.9, 55.4; IR νmax (KBr) 3439, 3004, 1715, 1617, 1416,
1365, 1226, 1049, 989, 810, 752 cm-1; HRMS (EI) m/z calcd
for C33H25NO6 [M+] 531.1682, found 531.1683.
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9e. Dark brown solid; 80 mg; yield 90%; mp charred at
o
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300 C; H NMR (CD3OD, 400 MHz) δ 8.95 (d, J = 7.2 Hz,
1H), 7.14 (s, 1H), 7.03 (s, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.99
(d, J = 2.8 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 2.0
Hz, 1H), 6.76 (dd, J = 8.0, 2.0 Hz, 1H), 6.71 (d, J = 2.4 Hz,
1H), 6.47 (dd, J = 8.8, 2.4 Hz, 1H); 13C NMR (DMSO-d6, 150
MHz) δ 158.2, 154.2, 152.7, 147.9, 146.7, 146.3, 145.6, 134.1,
128.8, 125.6, 124.6, 123.9, 121.5, 121.2, 118.9, 117.6, 117.1,
112.8, 112.4, 111.5, 111.4, 109.6, 109.4, 106.0, 103.1; IR νmax
(KBr) 3393, 2970, 1737, 1616, 1472, 1366, 1217, 1081, 981,
753 cm-1; HRMS (EI) m/z calcd for C25H15NO7 [M+] 441.0849,
found 441.0843.
Exhaustive demethylation of lamellarin derivatives (9a–h):
To an ice cooled solution of lamellarin derivatives 8a–h (1
equiv.) in dry CH2Cl2, was added dropwise BBr3 (1 M solution
o
in DCM, 18.0 equiv.) at -78 C under nitrogen atmosphere.
The resultant deep green reaction mixture was further allowed
to stir at room temperature for 16 h. After this, the reaction
was carefully quenched by the addition of MeOH (10 mL).
The dark colored solution was then concentrated in vacuo and
the residue was suspended in water. The resultant precipitate
was filtered off and dried in vacuo to yield the demethylated
lamellarin derivatives 9a–h.
o
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9f. Dark brown solid; 72 mg; yield 83%; mp >300 C; H
NMR (CD3OD, 400 MHz) δ 9.01 (d, J = 7.6 Hz, 1H), 7.13 (s,
1H), 7.03 (s, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz,
1H), 6.86 (d, J = 2.0 Hz, 1H), 6.82 (s, 1H), 6.80 (d, J = 2.8 Hz,
1H), 6.75 (dd, J = 8.0, 2.0 Hz, 1H), 6.67 (dd, J = 6.4, 3.6 Hz,
1H); 13C NMR (DMSO-d6, 150 MHz) δ 153.9, 147.8, 146.8,
146.3, 145.6, 145.3, 140.0, 133.9, 128.3, 125.5, 123.8, 123.7,
121.5, 121.2, 118.6, 118.2, 117.6, 117.1, 115.1, 114.0, 113.3,
112.5, 111.5, 109.6, 107.2; IR νmax (KBr) 3429, 3016, 1737,
1622, 1584, 1449, 1366, 1285, 1022, 854 cm-1; HRMS (EI)
m/z calcd for C25H15NO7 [M+] 441.0849, found 441.0852.
9a. Brown solid; 85 mg; yield 91%; mp charred at 330 oC;
1H NMR (DMSO-d6, 400 MHz) δ 9.85 (br s, 1H), 9.21 (d, J =
7.2 Hz, 1H), 8.91 (br s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.72–
7.69 (m, 3H), 7.57–7.53 (m, 3H), 7.37 (d, J = 7.6 Hz, 1H),
7.35–7.33 (m, 1H), 7.30 (dd, J = 8.0, 0.8 Hz, 1H), 6.86 (s,
1H), 6.44 (s, 1H); 13C NMR (DMSO-d6, 150 MHz) δ 154.6,
147.2, 145.3, 142.4, 135.0, 133.2, 130.7, 130.0, 129.3, 128.9,
128.8, 128.4, 127.7, 127.6, 124.2, 123.8, 123.4, 113.1, 113.0,
109.1, 108.3, 107.7, 103.5; IR νmax (KBr) 3292, 1738, 1716,
1668, 1441, 1365, 1227, 1144, 1050, 862 cm-1; HRMS (EI)
m/z calcd for C25H15NO4 [M+] 393.1001, found 393.1006.
o
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9g. Dark green solid; 80 mg; yield 90%; mp >300 C; H
NMR (CD3OD, 400 MHz) δ 8.92 (d, J = 7.2 Hz, 1H), 7.31 (d,
J = 1.2 Hz, 1H), 7.134 (d, J = 8.4 Hz, 1H), 7.130 (s, 1H), 7.02
(s, 1H), 7.00 (s, 1H), 6.99 (dd, J = 6.8, 2.0 Hz, 1H), 6.98 (d, J
= 4.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.0, 2.0
Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) δ 153.0, 151.6,
148.0, 146.9, 146.4, 145.7, 134.2, 132.5, 126.9, 125.0, 124.7,
124.1, 123.8, 121.3, 120.9, 118.1, 117.4, 117.2, 117.0, 116.7,
113.6, 112.5, 111.5, 109.5, 106.8; IR νmax (KBr) 3460, 1737,
1607, 1475, 1421, 1366, 1280, 1164, 1031, 782 cm-1; HRMS
(EI) m/z calcd for C25H14ClNO6 [M+] 459.0510, found
459.0509.
o
9b. Grey solid; 77 mg; yield 87%; mp charred at 300 C
(Lit.8 ≥300 oC); 1H NMR (DMSO-d6, 400 MHz) δ 10.01 (br s,
1H), 9.53 (br s, 1H), 9.25 (br s, 2H), 9.02 (d, J = 7.6 Hz, 1H),
7.47–7.45 (m, 1H), 7.44–7.41 (m, 1H), 7.24 (d, J = 7.2 Hz,
1H), 7.18 (s, 1H), 7.16–7.13 (m, 2H), 7.08 (s, 1H), 7.01 (d, J =
7.6 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 7.6, 2.0 Hz,
1H); 13C NMR (DMSO-d6, 150 MHz) δ 153.9, 151.2, 147.9,
146.8, 146.3, 145.6, 133.9, 128.5, 127.7, 125.4, 123.8, 123.7,
123.6, 121.3, 121.0, 118.1, 117.6, 117.4, 117.1, 117.0, 113.3,
112.4, 111.5, 109.5, 107.1; IR νmax (KBr) 3424, 2970, 1737,
1681, 1504, 1473, 1203, 1108, 1026, 744 cm-1; HRMS (EI)
m/z calcd for C25H15NO6 [M+] 425.0899, found 425.0896.
9c. Dark brown solid; 82 mg; yield 92%; mp charred at
o
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9h. Dark brown solid; 75 mg; yield 84%; mp >330 C; H
NMR (CD3OD, 400 MHz) δ 9.21 (d, J = 7.2 Hz, 1H), 7.85 (d,
J = 8.8 Hz, 1H), 7.78 (t, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.446 (t,
J = 8.4 Hz, 1H), 7.454 (s, 1H), 7.28 (t, J = 8.4 Hz, 1H), 7.11
(s, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.90
(t, J = 8.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.0,
2.0 Hz, 1H); 13C NMR (DMSO- d6, 150 MHz) δ 154.0, 149.9,
147.7, 146.6, 146.0, 145.5, 134.2, 130.6, 130.0, 128.4, 128.0,
127.7, 127.5, 127.4, 124.7, 124.5, 124.1, 122.7, 120.9, 118.7,
o
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300 C; H NMR (CD3OD, 400 MHz) δ 9.13 (d, J = 7.2 Hz,
1H), 7.24 (t, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.95 (d, J = 7.2 Hz,
1H), 6.89 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.76 (s,
1H), 6.75 (d, J = 1.6 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.60
(dd, J = 8.0, 2.0 Hz, 1H), 3.13 (s, 3H); 13C NMR (DMSO-d6,
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118.2, 117.5, 116.6, 113.9, 113.8, 112.6, 111.5, 110.3, 109.1;
was extracted with EtOAc (50 mL x 3). The combined organic
IR νmax (KBr) 3438, 1737, 1715, 1515, 1366, 1228, 1160, 1033,
869, 753 cm-1; HRMS (EI) m/z calcd for C29H17NO6 [M+]
475.1056, found 475.1050.
layer was washed with brine (2 times), dried over MgSO4, and
evaporated in vacuo. The residue was further purified by flash
column chromatography to afford the product 15 as a white
solid; Rf = 0.45 (30% EtOAc/hexanes); 1.40 g; yield 61%; mp
Synthesis of lamellarin D trimethyl ether (12): A 100 mL
flame-dried sealed tube was charged with 6,7-dimethoxy-3-
nitrocoumarin (11, 0.444 g, 1.77 mmol, 1.2 equiv.), papaver-
ine 7 (0.500 g, 1.47 mmol, 1 equiv.), and NaHCO3 (0.273 g,
3.24 mmol, 2.2 equiv.) in anhydrous xylene (35 mL) under
argon atmosphere. The sealed tube was closed tightly with
o
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92–94 C; H NMR (CDCl3, 400 MHz) δ 11.34 (s, 1H), 9.70
(s, 1H), 7.45–7.34 (m, 5H), 6.94 (s, 1H), 6.51 (s, 1H), 5.20 (s,
2H), 3.90 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 197.0,
159.1, 156.3, 143.2, 135.4, 128.7, 128.3, 127.3, 113.7, 113.0,
101.5, 70.8, 56.6; IR νmax (KBr) 3440, 2970, 1737, 1651, 1503,
1369, 1269, 1235, 1142, 1023, 984 cm-1; HRMS (EI) m/z
calcd for C15H14O4 [M+] 258.0892, found 258.0893.
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
o
Teflon ring screw cap and was subjected to heat at 160 C for
16 h. After the dark colored reaction mixture was cooled down
to room temperature, the solvent was evaporated in vacuo. The
residue was dissolved in DCM (50 mL), filtered, and washed
with copious amounts of DCM. The resulting solvent was
concentrated in vacuo and the product was purified over col-
umn chromatography to afford lamellarin D trimethyl ether 12
as a pale yellow solid. Rf = 0.45 (2% MeOH/DCM); 317 mg;
7-(Benzyloxy)-6-methoxy-3-nitrocoumarin (16): To a solu-
tion of 4-(benzyloxy)-2-hydroxy-5-methoxybenzaldehyde (15,
2.0 g, 10.3 mmol, 1 equiv.) in benzene (100 mL) was added
ethyl nitroacetate (1.51 g, 11.33 mmol, 1.1 equiv.) and a cata-
lytic amount of piperidine at room temperature. The resulting
mixture was then refluxed with Dean-Stark trap for overnight.
After cooled down to room temperature, the dark yellow solu-
tion was concentrated under reduced pressure and residue was
thoroughly washed with 5% EtOAc/hexanes to remove excess
ethyl nitroacetate and trace of piperidine. The vacuum-dried
residue resulted the product 16 as a brown-yellow solid; Rf =
o
o
yield 40%; mp 278–280 C (Lit.8 278–280 C); During the
purification, unreacted papaverine 7 was recovered (97 mg,
1
~20%). H NMR (CDCl3, 400 MHz) δ 9.24 (d, J = 7.2 Hz,
1H), 7.28 (s, 1H), 7.26 (dd, J = 6.4, 1.6 Hz, 1H), 7.19–7.17
(m, 3H), 7.11 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H),
6.76 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.91 (s, 3H), 3.90 (s,
3H), 3.50 (s, 3H), 3.49 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ
155.5, 150.1, 149.9, 149.5, 149.2, 149.0, 146.7, 145.5, 134.4,
129.4, 128.2, 124.8, 124.1, 123.3, 119.1, 114.4, 112.3, 111.9,
110.9, 109.9, 107.8, 107.4, 105.3, 105.0, 100.5, 56.3, 56.2,
56.01, 56.00, 55.5, 55.2; IR νmax (KBr) 2944, 1746, 1602, 1520,
1470, 1365, 1230, 1128, 971, 772 cm-1; HRMS (EI) m/z calcd
for C31H27NO8 [M+] 541.1737, found 541.1740.
o
1
0.45 (100% DCM); 2.65 g; yield 92%; mp 208–210 C; H
NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 7.45–7.36 (m, 5H),
7.00 (s, 1H), 6.91 (s, 1H), 5.28 (s, 2H), 3.96 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ 156.4, 152.5, 148.1, 143.1, 134.5, 131.5,
129.0, 128.9, 128.8, 127.4, 109.2, 109.1, 101.2, 71.7, 56.5; IR
νmax (KBr) 3472, 1736, 1728, 1519, 1363, 1280, 1188, 1004,
866, 769 cm-1; HRMS (EI) m/z calcd for C17H13NO6 [M+]
327.0743, found 327.0740.
Synthesis of lamellarin H (13): To a solution of lamellarin
D trimethyl ether 12 (0.200 g, 0.37 mmol, 1 equiv.) in dry
CH2Cl2 (39 mL) was carefully added dropwise BBr3 (1 M so-
2-(Benzyloxy)-1-methoxy-4-(1-methoxy-2-nitroethyl) ben-
zene (18)14a: To a solution of compound 17 (2.0 g, 7.0 mmol, 1
equiv.) in dry DCM (50 mL) was added freshly prepared satu-
rated methanolic solution of NaOMe (4 mL) at room tempera-
ture under nitrogen atmosphere. After the resultant dark brown
solution was stirred for 8 min, the reaction was quenched by
adding AcOH (3 mL). The organic layer was washed with
copious amounts of water (100 mL x 3), dried over MgSO4,
and concentrated in vacuo. The residue was further purified by
flash column chromatography to afford the product 18 as a
yellow solid; Rf = 0.35 (30% EtOAc/hexanes); 1.90 g; yield
85%; mp 97–99 oC; 1H NMR (CDCl3, 400 MHz) δ 7.46 (d, J =
7.2 Hz, 1H), 7.45 (s, 1H), 7.392 (td, J = 8.0, 0.8 Hz, 1H),
7.388 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 6.924 (d, J = 1.2 Hz,
1H), 6.923 (s, 1H), 6.90 (d, J = 0.8 Hz, 1H), 5.19 (s, 2H), 4.85
(dd, J = 10.0, 3.2 Hz, 1H), 4.55 (ABdq, J = 12.8, 10.0 Hz,
1H), 4.33 (ABdq, J = 12.8, 3.2 Hz, 1H), 3.92 (s, 3H), 3.20 (s,
3H); 13C NMR (CDCl3, 150 MHz) δ 150.3, 148.5, 136.6,
128.6, 128.0, 128.0, 127.4, 120.0, 112.1, 111.8, 80.5, 79.6,
71.0, 56.8, 56.0; IR νmax (KBr) 3444, 3004, 1737, 1714, 1552,
1363, 1222, 1026, 810, 730 cm-1; HRMS (EI) m/z calcd for
C17H19NO5 [M+] 317.1263, found 317.1270.
o
lution in DCM, 6.65 mL, 6.65 mmol, 18.0 equiv.) at -78 C
under nitrogen atmosphere. The resultant dark green reaction
mixture was further allowed to stir at room temperature for 16
h. After this, the reaction was carefully quenched by the addi-
tion of MeOH (15 mL). The dark colored solution was then
concentrated in vacuo and the residue was suspended in water.
The resultant precipitate was filtered off and dried in vacuo to
yield lamellarin H (13) as a grey solid; 140 mg; yield 83%; mp
o
o
1
>300 C (Lit.8 >300 C); H NMR (DMSO-d6, 400 MHz) δ
9.98 (br s, 1H), 9.76 (br s, 1H), 9.40 (br s, 1H), 9.19 (br s, 2H),
9.50 (d, J = 7.6 Hz, 1H), 8.90 (br s, 1H), 7.15 (d, J = 7.2, Hz,
1H), 7.14 (s, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.81
(s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 7.6, 2.0 Hz,
1H), 6.58 (s, 1H); 13C NMR (DMSO-d6, 150 MHz) δ 154.3,
147.7, 146.8, 146.6, 146.2, 145.5, 145.3, 142.1, 134.0, 128.9,
125.4, 123.8, 121.5, 121.2, 118.1, 117.6, 117.0, 112.6, 111.44,
111.42, 109.64, 109.57, 108.8, 106.3, 103.4; IR νmax (KBr)
3430, 2970, 1737, 1556, 1417, 1366, 1210, 1082, 957, 753 cm-
1; HRMS (EI) m/z calcd for C25H15NO8 [M+] 457.0798, found
457.0793.
2-(3-(Benzyloxy)-4-methoxyphenyl)-2-methoxyethan-1-
4-(Benzyloxy)-2-hydroxy-5-methoxybenzaldehyde (15)18b
:
amine (19)14a: To a suspension of 2-(benzyloxy)-1-methoxy-4-
(1-methoxy-2-nitroethyl)benzene (18, 1.5 g, 4.73 mmol, 1
equiv.) in MeOH:THF (2:1) (150 mL) was added zinc powder
(3.0 g) at room temperature and the mixture was stirred for 10
min at that temperature. Upon the careful addition of concen-
trated HCl (12 M, 4 mL), the slurry was subjected to reflux for
10 h. After the reaction was cooled down to room temperature,
the solution was concentrated in vacuo and the residue was re-
To a mixture of 2,4-dihydroxy-5-methoxybenzaldehyde (1.5 g,
8.9 mmol, 1 equiv.) and NaHCO3 (0.9 g, 10.7 mmol, 1.2
equiv.) in dry DMF (50 mL) was added BnBr (1.27 mL, 10.7
mmol, 1.2 equiv.) at room temperature under nitrogen atmos-
o
phere. The resultant solution was then heated at 85 C for 2
days (typically 48–56 h). After cooled down to room tempera-
ture, the reaction was quenched with water and the product
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dissolved in DCM. The organic layer was washed with water
benzyloxy-3-methoxy phenylacetic acid (1.04 g, 3.83 mmol,
and brine solution twice, dried, and concentrated under re-
duced pressure to afford 19 as an off-white spongy hygroscop-
ic solid. The crude product 19 was taken to the next step with-
out further purification; Rf = 0.15 (5% MeOH/DCM); 1.23 g;
yield 91%; mp 76–78 oC; 1H NMR (CD3OD, 400 MHz) δ 7.44
(d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.36 (td, J = 8.4, 1.6 Hz, 1H),
7.35 (s, 1H), 7.30 (d, J = 6.8 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H),
6.99 (s, 1H), 6.95 (dd, J = 8.4, 2.0 Hz, 1H), 5.12 (s, 2H), 4.41
(dd, J = 9.2, 4.0 Hz, 1H), 3.85 (s, 3H), 3.21 (s, 3H), 3.05
(ABdq, J = 12.8, 9.2 Hz, 1H), 3.00 (ABdq, J = 12.8, 4.0 Hz,
1H); 13C NMR (CDCl3, 150 MHz) δ 151.5, 149.6, 138.4,
131.0, 129.4, 128.9, 128.8, 121.4, 114.1, 113.5, 80.6, 72.1,
56.8, 56.6, 46.6; IR νmax (KBr) 3452, 2970, 1715, 1606, 1515,
1429, 1365, 1257, 1086, 815 cm-1; HRMS (EI) m/z calcd for
C17H21NO3 [M+] 287.1521, found 287.1519.
1.1 equiv.) in dry DCM (100 mL) was added N,N'-
dicyclohexylcarbodiimide (DCC) (1.08 g, 5.22 mmol, 1.5
equiv.) in one portion under nitrogen atmosphere. The mixture
was stirred at room temperature for 2 days. The progress of the
reaction was monitored constantly by TLC and more DCC
(0.4 equiv. x 2) was added. The precipitate was then filtered
off and the solvent was washed with water, brine (x 2), dried
over MgSO4, and evaporated to dryness. The residue was fur-
ther purified by column chromatography to afford a pale yel-
low solid. Rf = 0.45 (5% MeOH/DCM); 1.43 g; yield 76%; mp
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
o
1
93–95 C; H NMR (CDCl3, 400 MHz) δ 7.47–7.44 (m, 4H),
7.39 (s, 1H), 7.34 (s, 1H), 7.41–7.30 (m, 4H), 6.87 (d, J = 8.0
Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H),
6.78 (d, J = 1.6 Hz, 1H), 6.74 (dd, J = 8.0, 2.0 Hz, 1H), 6.69
(dd, J = 8.0, 2.0 Hz, 1H), 5.75 (t, J = 6.8 Hz, 1H), 5.17 (s, 2H),
5.14 (s, 2H), 4.10–4.06 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H),
3.59–3.49 (m, 3H), 3.18–3.09 (m, 4H); 13C NMR (CDCl3, 150
MHz) δ 171.1, 149.9, 149.6, 148.2, 147.4, 137.0, 136.9, 131.2,
128.51, 128.46, 127.8, 127.7, 127.4, 127.2, 127.1, 121.5,
119.8, 114.3, 112.9, 112.1, 111.6, 81.6, 71.0, 70.9, 56.5, 56.0,
55.9, 45.5, 43.4; IR νmax (KBr) 3005, 2938, 1738, 1716, 1512,
1365, 1217, 1026, 781, 695 cm-1; HRMS (EI) m/z calcd for
C33H35NO6 [M+] 541.2464, found 541.2456.
N-(2-(3-(Benzyloxy)-4-methoxyphenyl)-2-methoxyethyl)
acetamide (20): To an ice cooled solution of amine 19 (1.0 g,
3.5 mmol, 1 equiv.), TEA (1.1 equiv) in DCM was added
dropwise Ac2O (1.32 mL, 4 equiv, 13.4 mmol) under nitrogen
o
atmosphere at 0 C. The solution was allowed to stir for addi-
tional 14 h at room temperature before it was quenched by
water. The crude reaction mixture was then extracted with
DCM. The organic layer was washed with water, brine solu-
tion (3 times each) and dried over MgSO4, and evaporated
under reduced pressure. The pure product 20 was obtained
after filter-column separation as an off-white solid; Rf o= 0.45
6-(Benzyloxy)-1-(4-(benzyloxy)-3-methoxybenzyl)-7-
methoxy isoquinoline (26)14a
:
To a solution of 2-(4-
(benzyloxy)-3-methoxyphenyl)-N-(2-(3-(benzyloxy)-4-
1
(5% MeOH/DCM); 890 mg; yield 78%; mp 85–87 C; H
methoxyphenyl)-2-methoxyethyl)acetamide (1.0 g, 1.85 mmol,
1 equiv.) in DCE (70 mL) was added POCl3 (0.8 mL, 4 equiv.)
at room temperature. The resulting mixture was refluxed for
18 h under nitrogen atmosphere and the progress of the reac-
tion was monitored by TLC. After cooled down to room tem-
perature, the reaction mixture was neutralized by the addition
of aqueous NaOH (20%) solution. The crude compound was
extracted with DCM and washed thoroughly with water and
brine solution (50 mL x 3). The collected organic layer was
dried over MgSO4 and concentrated in vacuo. The crude prod-
uct was purified by column chromatography to yield a pale
yellow solid. Rf = 0.35 (5% MeOH/DCM); 730 mg; yield
80%; mp 147–149 oC; 1H NMR (CD3OD, 400 MHz) δ 8.24 (d,
J = 6.0 Hz, 1H), 7.60 (d, J = 6.0 Hz, 1H), 7.53 (d, J = 6.8 Hz,
1H), 7.52 (s, 1H), 7.49 (s, 1H), 7.44–7.42 (m, 4H), 7.412–7.31
(m, 5H), 6.97 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H),
6.79 (dd, J = 8.4, 2.0 Hz, 1H), 5.28 (s, 2H), 5.06 (s, 2H), 4.57
(s, 2H), 3.88 (s, 3H), 3.79 (s, 3H); 13C NMR (CD3OD, 150
MHz) δ 159.1, 153.6, 152.0, 151.4, 148.1, 140.4, 138.7, 137.8,
135.3, 134.4, 129.6, 129.4, 129.2, 128.9, 128.8, 128.7, 124.4,
121.9, 120.6, 116.2, 114.0, 108.2, 105.8, 72.4, 71.7, 56.5,
56.4, 42.1; IR νmax (KBr) 3449, 3328, 2929, 1737, 1713, 1623,
1365, 1227, 1144, 1025 cm-1; HRMS (EI) m/z calcd for
C32H29NO4 [M+] 491.2097, found 491.2097.
NMR (CDCl3, 400 MHz) δ 7.44 (d, J = 7.2 Hz, 1H), 7.43 (s,
1H), 7.36 (s, 1H), 7.36 (t, J = 8.8 Hz, 1H), 7.30 (d, J = 4.8 Hz,
1H), 6.89–6.82 (m, 2H), 6.88 (s, 1H), 5.79 (br s, 1H), 5.15 (s,
2H), 4.14 (dd, J = 8.8, 4.0 Hz, 1H), 3.89 (s, 3H), 3.61 (ABddq,
J = 11.6, 8.8, 4.0 Hz, 1H), 3.14 (s, 3H), 3.13–3.10 (m, 1H),
1.96 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.0, 149.5,
148.1, 136.9, 131.2, 128.5, 127.9, 127.4, 119.4, 112.1, 111.6,
81.7, 70.9, 56.5, 56.0, 45.6, 23.3; IR νmax (KBr) 3442, 2942,
1714, 1630, 1511, 1365, 1246, 1097, 1011, 824 cm-1; HRMS
(EI) m/z calcd for C19H23NO4 [M+] 329.1627, found 329.1626.
6-(Benzyloxy)-7-methoxy-1-methylisoquinoline (21) 18c: To
a vigorously stirred solution of amide 20 (2.0 g, 6.0 mmol, 1
equiv.) in dry DCM (50 mL) was cautiously added POCl3 (2.3
mL, 24.2 mmol, 4 equiv.) and mixture was refluxed overnight.
The solution was neutralized by adding the aq. NaOH (20%)
solution and the crude compound was extracted by DCM (30
mL x 5). The collected organic layer again washed with water
and brine solution (3 times), dried over MgSO4, and concen-
trated in vacuo. The flash column chromatography of the resi-
due
afforded
the
6-(benzyloxy)-7-methoxy-1-
methylisoquinoline (21) as a pale yellow solid. Rf = 0.40 (5%
o
1
MeOH/DCM); 1.40 g; yield 83%; mp 138–140 C; H NMR
(CDCl3, 400 MHz) δ 8.27 (d, J = 5.6 Hz, 1H), 7.516 (d, J =
7.2 Hz, 1H), 7.507 (s, 1H), 7.43 (s, 1H), 7.42 (t, J = 7.6 Hz,
1H), 7.37 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 5.6 Hz, 1H), 7.32 (s,
1H), 7.12 (s, 1H), 5.32 (s, 2H), 4.07 (s, 3H), 2.91 (s, 3H); 13C
NMR (CDCl3, 150 MHz) δ 15 5.8, 151.6, 150.2, 140.7, 136.0,
132.5, 128.7, 128.2, 127.3, 123.3, 118.2, 107.0, 104.0, 70.7,
56.0, 22.3; IR νmax (KBr) 3460, 2949, 1737, 1619, 1504, 1365,
1217, 1054, 855, 699 cm-1; HRMS (EI) m/z calcd for
C18H17NO2 [M+] 279.1259, found 279.1257.
Synthesis of lamellarin D pentacycle (22): To a flame-
dried 50 mL glass sealed tube fitted with Teflon ring screw
cap was charged with 6-(benzyloxy)-7-methoxy-1-
methylisoquinoline (21, 150 mg, 0.536 mmol, 1 equiv.), 7-
(benzyloxy)-6-methoxy-3-nitrocoumarin (16, 211 mg, 0.644
mmol, 1.2 equiv.), NaHCO3 (90 mg, 1.07 mmol, 2 equiv.), and
anhydrous xylene (15 mL) under argon atmosphere. The
sealed tube was tightly closed by Teflon screw and heated to
o
2-(4-(Benzyloxy)-3-methoxyphenyl)-N-(2-(3-(benzyloxy)-4-
120 C for 18 h. After cooled down to room temperature, the
methoxyphenyl)-2-methoxyethyl)acetamide14a
:
To an ice
reaction mixture was filtered-off, washed with DCM (20 mL x
2) and the collective organic solvent was concentrated in vac-
cooled mixture of amine 19 (1.0 g, 3.48 mmol, 1 equiv.), 4-
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uo. The crude product was purified by column chromatog-
product was subjected to column chromatography to give the
desired compound 25 as a pale yellow solid; 63 mg; yield
raphy to yield lamellarin D pentacycle 22 as a pale-white sol-
id; 128 mg; yield 43%; the starting material isoquinoline 21
(34 mg, 22%) was recovered during the purification process;
Rf = 0.40 (1% MeOH/DCM); mp 254–256 oC; 1H NMR
(CDCl3, 400 MHz) δ 9.02 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H),
7.51–7.32 (m, 10H), 7.31 (s, 1H), 7.12 (s, 1H), 7.11 (s, 1H),
6.95 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 5.27 (s, 2H), 5.19 (s,
2H), 4.10 (s, 3H), 4.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
155.3, 150.6, 150.0, 149.2, 146.8, 146.4, 138.4, 136.3, 136.2,
132.1, 128.8, 128.7, 128.21, 128.16, 127.6, 127.3, 124.0,
123.3, 118.6, 112.2, 109.95, 109.56, 109.2, 105.1, 104.5,
102.9, 91.4, 71.0, 70.9, 56.5, 56.2; IR νmax (KBr) 3444, 1737,
1711, 1453, 1366, 1218, 1147, 1018, 844, 737, 694 cm-1;
HRMS (EI) m/z calcd for C35H27NO6 [M+] 557.1838, found
557.1835.
27%; During the purification process, some of the starting
1
material 26 was recovered (34 mg, 23%); H NMR (CDCl3,
400 MHz) δ 9.20 (d, J = 8.0 Hz, 1H), 7.53–7.33 (m, 16H),
7.29–7.12 (m, 1H), 7.16 (s, 1H), 7.15 (s, 1H), 7.11 (s, 1H),
6.99 (dd, J = 7.2, Hz, 1H), 6.96 (s, 1H), 6.74 (s, 1H), 5.34 (s,
2H), 5.27 (s, 2H), 5.21 (s, 2H), 3.92 (s, 3H), 3.41 (s, 3H), 3.38
(s, 3H); 13C NMR (CDCl3, 150 MHz) δ 155.5, 150.5, 149.6,
149.2, 148.5, 147.8, 146.4, 146.0, 136.9, 136.3, 136.2, 134.3,
129.3, 128.8, 128.72, 128.70, 128.13, 128.10, 128.0, 127.3,
127.2, 127.0, 126.9, 124.6, 123.9, 123.2, 119.3, 114.9, 114.6,
112.3, 111.0, 110.3, 109.5, 107.9, 105.5, 105.4, 102.7, 71.0,
70.9, 70.8, 56.3, 55.5, 55.2; IR νmax (KBr) 3462, 2947, 1738,
1716, 1423, 1365, 1217, 1017, 857, 753 cm-1; HRMS (EI) m/z
calcd for C49H39NO8 [M+] 769.2676, found 769.2672.
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
Bromination of lamellarin D pentacycle (23): To a vigor-
ously stirred solution of lamellarin D pentacycle 22 (100 mg,
179.3 mmol, 1 equiv.) in THF (25 mL) was added N-
bromosuccinimide (NBS, 35.1 mg, 197.3 mmol, 1.1 equiv.) at
Debenzylation of benzyloxy protected of lamellarin D (25):
lamellarin D (27): The mixture of benzyloxy protected lamel-
larin D (25, 100 mg) in 50 mL of EtOAc and Pd(OH)2/C (20%,
50 mg) was hydrogenated at atmospheric pressure for over-
night at room temperature. The Pd(OH)2/C was removed by
filtering over celite pad and washed with copious amounts of
EtOAc (40 mL x 3). The combined solvent was concentrated
in vacuo to the dryness. The residue was further sonicated
with DCM:hexanes (1:2), and the precipitate was filtered and
dried to afford lamellarin D (27) as a yellow solid. 59 mg;
o
0 C and the mixture was stirred for 1 h at that temperature.
The reaction mixture was further stirred for overnight at room
temperature. The precipitate was then filtered-off, washed
with hexanes (10 mL x 5), and dried in vacuo to yield the
1
compound 23 as a white solid; 103 mg; yield 90%; H NMR
(CDCl3, 400 MHz) δ 9.18 (d, J = 7.2 Hz, 1H), 8.83 (s, 1H),
8.32 (s, 1H), 7.52–7.37 (m, 9H), 7.05 (s, 1H), 6.92 (d, J = 7.2
Hz, 1H), 6.918 (s, 1H), 5.26 (s, 2H), 5.20 (s, 2H), 4.10 (s, 3H),
4.03 (s, 3H).
o
o
yield 91%; mp > 300 C (Lit.14a ≥300 C); some of the com-
pound was further recrystallized in DMSO. 1H NMR (DMSO-
d6, 400 MHz) δ 9.97 (br s, 1H), 9.83 (br s, 1H), 9.33 (br s,
1H), 8.99 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.18 (s,
1H), 7.14 (d, J = 1.6 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 8.0
1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H), 6.86 (s, 1H), 6.70 (s, 1H),
3.76 (s, 3H), 3.37 (s, 3H), 3.33 (s, 3H); 13C NMR (DMSO-d6,
150 MHz) δ 154.3, 148.7, 148.5, 148.3, 147.8, 146.8, 146.3,
144.6, 134.1, 129.0, 125.4, 124.6, 123.8, 122.0, 117.5, 116.4,
115.0, 112.4, 111.5, 110.8, 108.3, 106.4, 105.7, 105.3, 103.7,
56.0, 55.0, 54.5; IR νmax (KBr) 3386, 2928, 2835, 1671, 1589,
1444, 1377, 1270, 1080, 985 cm-1; HRMS (EI) m/z calcd for
C28H21NO8 [M+] 499.1267, found 499.1277.
Synthesis of benzyloxy protected lamellarin D (25) : In a
100 mL round bottom flask (flame dried and cooled under Ar
atmosphere), 23 (100 mg, 0.157 mmol, 1 equiv.), 24 (44 mg,
0.173 mmol, 1.1 equiv.), CsF (48 mg, 0.314 mmol, 2 equiv.),
Ag2O (55 mg, 0.235 mmol, 1.5 equiv.), and Pd(Ph3)4 (16 mg,
0.016 mmol, 0.1 equiv. ) were placed under Ar atmosphere
followed by the addition of dried DME (35 mL). The reaction
mixture was refluxed for 24 h. After the reaction was complet-
ed and the solution was cooled down to room temperature, the
solvent was evaporated to dryness, and the residue was re-
dissolved in DCM. The organic layer was washed with water,
dried over MgSO4, and concentrated in vacuo. The silica gel
slurry was made and the crude product was purified by column
chromatography to afford benzyloxy protected lamellarin D 25
as a pale yellow solid; 94 mg; Rf = 0.55 (5% MeOH/DCM);
Hydrogenation of benzyloxy protected of Lamellarin D
(25): Lamellarin 501 (28): To a solution of benzyloxy protect-
ed lamellarin D (25, 100 mg) in MeOH-EtOAc (2:1, 50 mL)
was added Pd/C (10%, ca. 20–25 mg). The resulting solution
was stirred under hydrogen atmosphere for 18 h at room tem-
perature. Once the reaction was complete, the mixture was
passed through celite pad and washed thoroughly with MeOH
(25 mL x 6). The collective organic solvent was dried and
concentrated in vacuo. The grey residue was further sonicated
in hexanes to afford fine powder of lamellarin 501 (28) as pale
o
o
1
yield 80%; mp 206–208 C (Lit.14a 217–218 C); H NMR
(CDCl3, 400 MHz) δ 9.20 (d, J = 7.2 Hz, 1H), 7.53–7.30 (m,
16H), 7.18–7.12 (m, 1H), 7.16 (s, 1H), 7.14 (s, 1H), 7.12 (s,
1H), 6.98 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.73 (s, 1H), 5.32
(s, 2H), 5.26 (s, 2H), 5.20 (s, 2H), 3.91 (s, 3H), 3.41 (s, 3H),
3.37 (s, 3H).
o
o
grey solid; 58 mg; yield 89%; mp > 300 C (Lit.17b ≥250 C);
1H NMR (DMSO-d6, 400 MHz) δ 9.32 (br s, 1H), 7.04 (d, J =
7.6 Hz, 1H), 7.03 (s, 1H), 6.90 (dd, J = 7.6, 1.2 Hz, 1H), 6.83
(s, 1H), 6.78 (s, 1H), 6.69 (s, 1H), 6.61 (s, 1H), 4.60 (t, J = 6.4
Hz, 2H), 3.75 (s, 3H), 3.37 (s, 3H), 3.28 (s, 3H), 3.01 (t, J =
6.4 Hz, 2H); 13C NMR (DMSO-d6, 150 MHz) δ 154.3, 148.5,
147.1, 146.9, 146.5, 146.0, 145.7, 144.4, 135.9, 127.7, 127.1,
125.4, 123.4, 118.0, 116.3, 115.3, 114.6, 114.2, 112.2, 109.3,
108.7, 105.1, 103.6, 55.9, 55.0, 54.7, 42.0, 27.5; IR νmax (KBr)
3385, 2832, 1666, 1580, 1473, 1294, 1145, 1029, 953, 856 cm-
1; HRMS (EI) m/z calcd for C28H23NO8 [M+] 501.1424, found
501.1428
Alternate route to benzyloxy protected lamellarin D (25):
To a sealed tube with Teflon screw-stopper (flame dried and
cooled under
a
stream of nitrogen) was charged
with 6-(benzyloxy)-1-(4-(benzyloxy)-3-methoxybenzyl)-7-
methoxyisoquinoline (26, 150 mg, 0.305 mmol, 1 equiv.), 7-
(benzyloxy)-6-methoxy-3-nitrocoumarin (16, 120 mg, 0.366
mmol, 1.2 equiv.), NaHCO3 (52 mg, 0.60 mmol, 2 equiv.), and
anhydrous xylene (20 mL). The sealed tube was then heated at
o
130 C for 24 h. After cooled down to room temperature, the
solvent was evaporated to dryness and the residue was re-
dissolved in DCM. The slurry was filtered, and the solid was
washed with DCM and concentrated in vacuo. The crude
ASSOCIATED CONTENT
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Supporting Information
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Optimization of the reaction conditions and copies of NMR of
the synthesized compounds and X-ray crystal structure details
for 8h and 27 (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
9
*yang@thu.edu.tw
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13. Crystallographic data (excluding structure factors) for
8h and 27 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC–1534808 and –1537503, respective-
ly. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing da-
ta_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Note: The authors declare the following competing finan-
cial interest(s): A patent application of this work has been
filed.
ACKNOWLEDGMENTS
We thank the Ministry of Science and Technology of the Republic
of China, Taiwan, for financially supporting this research under
Contract No. MOST 105-2113-M-029-001.
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