An inverse electron demand Diels-Alder-based total synthesis of defucogilvocarcin V and some C-8 analogues

Article abstract of DOI:10.1021/jo3012682

A concise total synthesis of defucogilvocarcin V is reported. The key features of the approach are the formation of the C-ring using a vinylogous Knoevenagel/transesterification reaction and construction of the D-ring by way of an inverse electron demand Diels-Alder-driven domino reaction. The resulting C-8 ester functionality provides a handle for the synthesis of defucogilvocarcin V as well as some C-8 analogues from a common late-stage intermediate.

Full text of DOI:10.1021/jo3012682

Article
pubs.acs.org/joc
An Inverse Electron Demand Diels−Alder-Based Total Synthesis of
Defucogilvocarcin V and Some C‑8 Analogues
Penchal Reddy Nandaluru and Graham J. Bodwell*
Department of Chemistry, Memorial University, St. John’s, Newfoundland and Labrador, A1B 3X7, Canada
S
* Supporting Information
ABSTRACT: A concise total synthesis of defucogilvocarcin V
is reported. The key features of the approach are the formation
of the C-ring using a vinylogous Knoevenagel/transesterifica-
tion reaction and construction of the D-ring by way of an
inverse electron demand Diels−Alder-driven domino reaction.
The resulting C-8 ester functionality provides a handle for the
synthesis of defucogilvocarcin V as well as some C-8 analogues
from a common late-stage intermediate.
fermentation broth of Streptomyces arenae 2064 by Mishra
and co-workers.15 Studies suggested that the antitumor activity
of defucogilvocarcin V (5c), on activation by light, is similar to
that of the parent gilvocarcin V (1c).15,16 This implies that the
role of sugar moiety in the anticancer activity may be of minor
importance.
INTRODUCTION
■
A class of aryl C-glycoside-containing natural products,
composed of the gilvocarcins,1−4 ravidomycin (2),5,6 the
chrysomycins (3),7,8 and polycarcin (4),9 has been isolated
from different species of Streptomyces. These compounds
exhibit impressive biological properties, including antibacte-
rial2,10 and strong antitumor activity.11−14 Structurally, they
share a common tetracyclic aromatic core (6H-benzo[d]-
naphtho[1,2-b]pyran-6-one) to which a sugar is attached at C-
4. Individual gilvocarcins (Figure 1) are distinguished by
variation of the R group at C-8 by which they were named as
gilvocarcin M (R = methyl), gilvocarcin E (R = ethyl), and
gilvocarcin V (R = vinyl). Furthermore, the aglycon of one of
them, defucogilvocarcin V (5c), was isolated from the
The gilvocarcins (1) and their aglycons (defucogilvocarcins,
5) have been targets of the synthetic community because of
their impressive biological profiles. Whereas only a handful of
total syntheses of gilvocarcins have been accomplished,17−20
a
relatively large number of defucogilvocarcin syntheses has been
reported. The strategies used to approach the defucogilvocar-
cins can be sorted into three categories according to the ring(s)
generated during the key step(s): (1) formation of the C ring
using (a) Suzuki coupling followed by lactonization,21−23 (b)
esterification/intramolecular biaryl bond formation,24 (c)
nucleophilic aromatic substitution/lactonization,25,26 (d) Pech-
mann condensation,27 and (e) conjugate addition/lactoniza-
tion;28 (2) formation of the A and C rings using (f) Diels−
Alder reaction (A ring)/Meerwein coupling/lactonization (C
ring);29−31 and (3) formation of the B and C rings using (g) a
Dotz chromium carbene benzannulation/lactonization,32 (h) a
̈
[2 + 2] cycloaddition/pericyclic ring-opening−ring closing/
lactonization,33 and (i) a condensation reaction between a
styryl sulfone and a phthalide.34 More recently, a one-pot
enzymatic synthesis of defucogilvacarcin M starting from acetyl-
CoA and malonyl-CoA using 15 enzymes has been reported.35
Notably, none of the nonenzymatic synthetic approaches to the
defucogilvocarcins involves the formation of the D-ring, which
is where variations at C-8 of natural products are present.
Received: June 18, 2012
Published: August 27, 2012
Figure 1. Gilvocarcin family of natural products.
© 2012 American Chemical Society
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RESULTS AND DISCUSSION
Scheme 2. Model Study
■
In connection with ongoing work aimed at the development
and application of the inverse electron demand Diels−Alder
(IEDDA) reaction,36 our group has reported the synthesis of a
variety of electron deficient dienes.37−44 The common
structural feature of these systems is the presence of two
electron withdrawing groups on the diene unit with a 1,3-
relationship. This motif allows the two electron-withdrawing
groups to electronically bias the diene in a co-operative fashion,
which results in completely regioselective cycloaddition upon
reaction with electron rich dienophiles. This chemistry has
provided access to several different classes of compounds,
including 2-hydroxybenzophenones,38 isophthalates,39 xan-
thones,40 pyrido[2,3-c]coumarins,41 and 6H-dibenzo[b,d]-
pyran-6-ones (DBPs).42−44 Additionally, the methodology
developed for the synthesis of DBPs has been exploited in
total syntheses of cannabinol44 and urolithin M7,45 as well as in
the synthesis of an elaborate chiral cyclophane.46 To further
demonstrate the value of this methodology, defucogilvocarcins
were identified as attractive synthetic targets. Reported herein
are details of the total synthesis of defucogilvocarcin V (5c) and
some of its C-8 analogues.
The retrosynthetic analysis of 5c based on our DBP-forming
methodology commences with functional group interconver-
sion to provide 6H-benzo[d]naphtho[1,2-b]benzopyran-6-one
(6) (Scheme 1). The D-ring and C-ring are then opened
dimethyl glutaconate (10) afforded diene 13 in high yield
(87%). Diene 13 was then subjected to the key IEDDA
reaction with a series of enamines derived from dimethox-
yacetaldehyde, i.e., 8a−c, whereby it was found that the nature
of the secondary amine used to generate the enamine played a
critical role in the reaction. While the use of the pyrrolidine-
derived enamine 8a resulted in the consumption of the starting
diene, no identifiable product was obtained from the reaction.
However, the morpholine-derived enamine 8b did not undergo
reaction with 13 under the same conditions. After some
experimentation, it was found that diene 13 reacted smoothly
with the piperidine-derived enamine 8c to afford 14 (86%). In
this case, more concentrated solutions were required to drive
the reaction to completion. The reasons for differences in
reactivity between the various enamines 8a−c are not
immediately obvious. In any event, the IEDDA reaction
involving 8c proceeded with complete regioselectivity, in line
with previous observations.37−45 Consequently, the newly
generated D-ring was endowed with correctly placed methoxy
and methoxycarbonyl groups, the latter of which was poised for
conversion to the required vinyl functionality. Both the ester
and lactone functionalities present in 14 were reduced with
LiAlH4 to give triol 15 (96%). It was envisaged that oxidation
of 15 would afford lactone-aldehyde 16 (via a hemiacetal), but
all attempts to accomplish this transformation using various
Scheme 1. Retrosynthetic Analysis of Defucogilvocarcin V
(5c)
́
oxidizing agents (PCC, MnO2, IBX, and Fetizon’s reagent)
failed. In all cases, the starting material was consumed to give a
deeply colored reaction mixture, from which no identifiable
product was isolated. Quinone formation may compete with
the desired transformation.
Although the viability of the two key steps had been
established, an alternative approach to functional group
management was required. Accordingly, methods for achieving
the chemoselective reduction of the ester over the lactone were
investigated. To this end, hydrolysis of 14 afforded carboxylic
acid 17 (93%) (Scheme 3). In this reaction, both the ester and
lactone were presumably hydrolyzed, and the lactone reformed
during the acidic workup. Weinreb amide 18 was then prepared
in moderate yield (55%) in preparation for a chemoselective
successively using an IEDDA-driven domino transform,42,43,45
(giving naphthalene-derived diene 7 and electron rich
dienophile 8) and a vinylogous Knoevenagel condensation/
transesterification transform to afford 1-hydroxy-2-naphthalde-
hyde 9 and dimethyl glutaconate (10). The differentially O-
protected 1-hydroxy-2-naphthaldehyde 9 leads back to
commercially available juglone (11).
Before initiating work on the synthesis of 9, a model study
starting from more abundantly and inexpensively available 1-
hydroxy-2-naphthaldehyde (12) was conducted to test the
viability of the key steps (Scheme 2). The reaction of 12 with
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Scheme 3. Completion of the Model Study
Scheme 4. Synthesis of Hydroxynaphthaldehyde 9
Skattebøl ortho-formylation52 to provide the required hydrox-
ynaphthaldehyde 9 (63%).
With 9 in hand, a vinylogous Knoevenagel reaction was
carried out with dimethyl glutaconate (10) to generate the
corresponding electron deficient diene 7 (87%) (Scheme 5).
Scheme 5. Synthesis of MOM-Protected Defucogilvocarcin
V (29)
reduction with DIBAL-H, which was intended to result in the
formation of aldehyde 16. Unfortunately, this reaction showed
no evidence of progress at −78 °C, the temperature typically
used for this transformation.47 Upon warming the reaction
mixture to room temperature and stirring at this temperature
for 12 h, the starting material was consumed, but a complex
1
mixture of products was produced (tlc and H NMR analysis).
However, a chemoselective reduction of acid 17 was achieved
using Me2S·BH3. This afforded benzylic alcohol 20 (79%)
along with a minor, but still significant, amount of the
overreduced benzylic alcohol 19 (17%). Oxidation of 20 was
achieved using PCC/celite to give aldehyde 16 (74%). Finally,
a Wittig reaction under mild conditions48 using DBU as the
base was employed to obtain the olefin 21 (70%), thereby
completing the model study. Model compound 21 was
synthesized in six steps from commercially available 1-
hydroxy-2-naphthaldehyde (12) in 28% overall yield.
Upon successful completion of the model study, attention
was turned to applying the approach to the synthesis of
defucogilvocarin V (5c). The synthesis began from juglone
(11), which is commercially available or readily accessible from
1,5-dihydroxynaphthalene.49 The hydroxy group of juglone
(11) was MOM-protected,50 and the resulting 1,4-naphthoqui-
none 22 (92%) was subjected to a reductive acylation/
methylation protocol, which was based upon procedures
described for the O-methyl analogue of 22 (Scheme 4).51
This involved reduction of the naphthoquinone 22 with Zn and
selective O-acetylation at the less sterically hindered site. The
monoacylated product 23 (75%) was then O-methylated upon
treatment with dimethyl sulfate to give 24 (97%). The acetyl
group was removed using K2CO3 in MeOH to afford naphthol
25 (80%), which was regioselectively formylated using the
Reaction of 7 with enamine 8c resulted in the formation of
ester 6 (89%), which differs from the natural product only in
the nature of the C-8 substituent and the presence of the
protected OH group at C-1. Hydrolysis of the ester provided
carboxylic acid 26 (86%), which was then reduced to afford
benzylic alcohol 27 (51%). Oxidation of 27 gave aldehyde 28
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(73%), which was subjected to a Wittig reaction to furnish
olefin 29 (76%). To mirror the model study, carboxylic acid 26
was converted into the corresponding Weinreb amide 30
(40%).
Finally, compounds 6, 28, 29, and 30 were deprotected using
BCl3 (Scheme 6). This reaction smoothly afforded defuco-
temperature for 1 h and then at 70 °C for 3 h. The reaction
mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was dissolved in
CHCl3 (600 mL), and the resulting solution was washed with
aqueous 1.0 M HCl solution (1×). The layers were separated,
and the organic layer was dried over Na2SO4 and gravity
filtered. The solvent was removed under reduced pressure, and
diethyl ether (15 mL) was added to the residue. The resulting
mixture was stirred for 10 min and vacuum filtered. On
repetition of this process (ether addition to the solids, stirring,
and filtration), 13 (2.83 g, 87%) was obtained as a yellow solid.
Rf = 0.30 (30% ethyl acetate/hexanes); mp 191−193 °C; IR
Scheme 6. Synthesis of Defucogilvocarcin V (5c) and C-8
Analogues 31−33
1
(neat) ν = 1708 (s) cm−1; H NMR (CDCl3, 500 MHz) δ
8.57−8.55 (m, 1H), 7.98 (s, 1H), 7.89−7.87 (m, 1H), 7.70 (d, J
= 8.5 Hz, 1H), 7.69−7.66 (m, 2H), 7.63 (d, J = 15.9 Hz, 1H),
7.49 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 15.8 Hz, 1H), 3.83 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 167.7, 159.3, 151.4, 144.7,
138.5, 135.6, 129.6, 128.2, 127.7, 125.1, 123.9, 123.1, 122.94,
122.86, 121.7, 114.7, 52.1; ESI-(+)-MS m/z (%) 303 (100, [M
+ Na]+); HRMS [EI-(+)] calcd for C17H12O4 280.0736, found
280.0732.
10-Methoxy-6H-benzo[d]naphtho[1,2-b]pyran-6-one-8-
carboxylic Acid Methyl Ester (14). A mixture of dimethox-
yacetaldehyde (1.86 g, 10.7 mmol, 60% solution in water) and
piperidine (0.73 g, 8.6 mmol) in benzene (35 mL) was heated
at reflux for 1 h using a Dean−Stark apparatus. Solvent (∼30
mL) was removed from the reaction flask through the Dean−
Stark condenser. The reaction mixture was cooled to room
temperature, and 13 (0.30 g, 1.1 mmol) was added in one
portion. The resulting mixture was then heated at reflux for 48
h (note: the low dilution is critical for the complete
consumption of the starting material). The reaction was
gilvocarcin V (5c) (83%) along with three C-8 analogues, 31
(87%), 32 (82%), and 33 (63%). The total synthesis of
defucogilvocarcin V (5c) was accomplished in 12 steps from
juglone in 5.3% overall yield.
CONCLUSIONS
■
The approach to defucogilvocarcin V (5c) described here
differs from all previously reported approaches in that it
involves construction of the D-ring. Not only is the D-ring
formed with the required C-10 methoxy group, but it also bears
an ester at C-8, which is where differences in the natural
defucogilvocarcins and gilvocarcins occur. Synthetic manipu-
lation of the ester group led to the natural product
defucogilvocarcin V (5c) as well as three C-8 analogues,
which all offer opportunities for further elaboration.
1
monitored by H NMR analysis (an aliquot was taken from
the reaction using a pipet, ether (0.5 mL) was added, the
supernatant was decanted, and the residue was dried under
1
vacuum; H NMR was performed after every 12 h, starting
from 24 h). The reaction mixture was cooled to room
temperature, and the solvent was removed under reduced
pressure. The residue was dissolved in CHCl3 (70 mL) and
washed with aqueous 1.0 M HCl solution (2×). The layers
were separated, and the organic layer dried over Na2SO4 and
gravity filtered. The solvent was removed under reduced
pressure, and the residue was subjected column chromatog-
raphy (CHCl3). The product obtained from chromatography
was triturated with ether (2 × 7 mL) to give 14 (0.30 g, 86%)
as a pale yellow solid. Rf = 0.30 (30% ethyl acetate/hexanes);
EXPERIMENTAL SECTION
■
General. Reactions were performed using anhydrous
solvents under a balloon containing N2 unless otherwise
indicated. All reactions were performed with oven-dried (120
°C) glassware. THF was distilled immediately prior to use from
sodium/benzophenone, and acetone was distilled from K2CO3.
Acetonitrile and triethylamine were distilled over CaH2.
Solvents were removed from reaction mixtures under reduced
pressure using a rotary evaporator. Chromatographic separa-
tions were achieved using silica gel with a particle size of 40−63
mm. Thin-layer chromatography (TLC) was performed using
precoated plastic-backed silica gel plates with a layer thickness
of 200 mm. Compounds on TLC plates were visualized using a
UV lamp (254 and 365 nm). Melting points are uncorrected.
1
mp 247−250 °C; IR (neat) ν = 1715 (s) cm−1; H NMR
(CDCl3, 500 MHz) δ 8.96 (d, J = 9.2 Hz, 1H), 8.75 (d, J = 1.7
Hz, 1H), 8.61−8.57 (m, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.85−
7.82 (m, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.63−7.59 (m, 2H),
4.14 (s, 3H), 3.99 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
165.9, 160.7, 157.6, 147.7, 134.3, 130.6, 128.7, 128.5, 127.4,
127.0, 124.7, 124.3, 124.0, 123.5, 123.1, 122.8, 116.8, 112.8,
56.6, 52.8; APCI-(+)-MS m/z (%) 335 ([M + H]+, 100);
HRMS [CI-(+)] calcd for C20H15O5 335.0919, found 335.0930.
2-(2,4-Bis(hydroxymethyl)-6-methoxy)-1-naphthol (15).
To a 0 °C slurry of LiAlH4 (0.18 g, 4.7 mmol) in THF (20
mL) was added 14 (0.40 g, 1.2 mmol) in several portions, and
the reaction mixture was heated at reflux for 4 h. After cooling
to 0 °C, the reaction was quenched by the careful addition of
aqueous 1.0 M HCl solution (20 mL). The resulting mixture
was vacuum filtered, and the filtrate was washed thoroughly
with CHCl3 (4×). The layers were separated, and the aqueous
1
Infrared (IR) spectra were recorded using solid samples. H
and 13C spectra were obtained from CDCl3 or DMSO-d6
solutions. Chemical shifts are relative to internal standards:
TMS (δH = 0.00 ppm) and CDCl3 (δC = 77.23 ppm),
respectively. For high-resolution mass spectroscopic measure-
ments, a TOF mass analyzer was employed.
Methyl (E)-3-(6H-Naphtho[1,2-b]pyran-6-on-5-yl)acrylate
(13). To a solution of 1-hydroxy-2-naphthaldehyde (12) (2.00
g, 11.6 mmol) and dimethyl glutaconate (10) (2.76 g, 17.5
mmol) in THF (40 mL) was added piperidine (0.99 g, 12
mmol), and the resulting mixture was stirred at room
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layer was washed with CHCl3 (1×). The combined organic
layers were dried over Na2SO4 and gravity filtered. The solvent
was removed under reduced pressure, and the residue was
triturated with ether (2 × 3 mL) to afford 15 (0.39 g, 96%) as a
colorless solid. Rf = 0.20 (50% ethyl acetate/hexanes); mp
197−200 °C; IR (neat) ν = 3389 (w) cm−1; 1H NMR (DMSO-
d6, 500 MHz) δ 8.18−8.17 (m, 1H), 7.82−7.80 (m, 1H), 7.48−
7.42 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 1.6 Hz,
1H), 7.01 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 1.6 Hz, 1H), 5.20 (t,
J = 5.8 Hz, 1H), 4.56 (d, J = 4.7 Hz, 2H), 4.18 (d, J = 13.9 Hz,
1H), 4.10 (d, J = 13.8 Hz, 1H), 3.29 (s, 3H); 13C NMR
(DMSO-d6, 75 MHz) δ 156.8, 149.4, 142.8, 141.9, 133.7, 129.6,
127.4, 125.7, 125.3, 124.7, 122.8, 122.2, 118.7, 117.7, 116.7,
107.6, 63.3, 60.9, 55.3; APCI-(−)-MS m/z (%) 309 (100, [M −
1]−); HRMS [EI-(+)] calcd for C19H18O4 310.1205, found
310.1208.
[d]naphtho[1,2-b]pyran-6-one (20). To a 0 °C suspension of
17 (0.20 g, 0.63 mmol) in THF (20 mL) was added H3B·SMe2
(1.8 mL, 3.7 mmol) dropwise over a period of 5 min, and the
resulting mixture was stirred at room temperature for 20 h. The
reaction mixture was cooled to 0 °C, and methanol (3.0 mL)
was added dropwise. The solvent was removed under reduced
pressure, and the residue was dissolved in CHCl3 (200 mL).
The resulting solution was washed with aqueous 1.0 M HCl
solution (1×) and then with saturated aqueous NaHCO3
solution (1×). The layers were separated, and the organic
layer was dried over Na2SO4 and gravity filtered, and the
solvent was removed under reduced pressure. The residue was
triturated with ether (3 × 3 mL) to afford 20 (153 mg, 79%) as
a colorless solid. The ether layer was concentrated under
reduced pressure, and the residue was subjected to column
chromatography (40% ethyl acetate/hexanes) to afford 19 (30
mg, 17%) as a colorless solid. 20: Rf = 0.70 (ethyl acetate); mp
231−234 °C; IR (neat) ν = 3433 (m), 1692 (s) cm−1; 1H NMR
(DMSO-d6, 500 MHz) δ 9.02 (d, J = 9.1 Hz, 1H), 8.43−8.41
(m, 1H), 8.02−8.00 (m, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.86 (d,
J = 9.1 Hz, 1H), 7.72−7.66 (m, 2H), 7.60 (d, J = 1.6 Hz, 1H),
5.54 (t, J = 5.6 Hz, 1H), 4.70 (d, J = 3.5 Hz, H), 4.11 (s, 3H);
13C NMR (DMSO-d6, 75 MHz) δ 160.2, 157.1, 145.5, 145.1,
132.9, 127.7, 127.5, 127.0, 124.4, 123.5, 122.7, 122.1, 121.8,
121.4, 118.9, 115.8, 113.0, 62.2, 56.4; ESI-(+)-MS m/z (%) 307
(100, [M + H]+); HRMS [EI-(+)] calcd for C19H14O4
306.0892, found 306.0901. 19: Rf = 0.80 (ethyl acetate); mp
122−125 °C; IR (neat) ν = 3400−3100 (br, w) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 8.49 (d, J = 8.8 Hz, 1H), 8.28−8.26 (m,
1H), 7.81−7.78 (m, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.48−7.44
(m, 2H), 7.00 (d, J = 1.5 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H),
5.16 (s, 2H), 4.73 (s, 2H), 3.97 (s, 3H), 1.73 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 156.5, 150.8, 141.4, 134.2, 133.8, 127.3,
126.4, 125.9, 125.3, 125.0, 122.2, 120.4, 118.8, 117.0, 115.6,
110.1, 69.3, 65.1, 55.7; APCI-(+)-MS m/z (%) [M + H]+ not
observed, 291 (11), 275 (100); HRMS [EI-(+)] calcd for
C19H16O3 292.1099, found 292.1116.
10-Methoxy-6H-benzo[d]naphtho[1,2-b]pyran-6-one-8-
carbaldehyde (16). To a mixture of 20 (0.19 g, 0.62 mmol)
and celite (0.20 g) in CH2Cl2 (10 mL) was added PCC (0.33 g,
1.5 mmol) in several portions, and the resulting mixture was
stirred at room temperature for 20 h. The reaction mixture was
gravity filtered, and the filter cake was washed repeatedly with
CHCl3 (3×). The solvent was removed under reduced
pressure, and the residue was subjected to column chromatog-
raphy (4% methanol/CHCl3). The product was triturated with
ether (3 × 1 mL) to afford 16 (0.14 g, 74%) as a pale yellow
solid. Rf = 0.30 (30% ethyl acetate/hexanes); mp 238−241 °C;
IR (neat) ν = 1722 (m), 1688 (s) cm−1; 1H NMR (CDCl3, 500
MHz) δ 10.11 (s, 1H), 9.03 (d, J = 9.1 Hz, 1H), 8.64−8.62 (m,
1H), 8.59 (s, 1H), 7.89−7.88 (m, 1H), 7.83 (s, 1H), 7.74 (d, J
= 9.1 Hz, 1H), 7.66−7.64 (m, 2H), 4.18 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 190.4, 160.3, 158.1, 148.0, 136.2, 134.4,
130.3, 128.6, 127.3, 127.1, 126.9, 124.5, 124.0, 123.33, 123.31,
122.7, 112.8, 112.6, 56.5; ESI-(+)-MS m/z (%) 305 (7, [M +
H]+), 102 (100); HRMS [EI-(+)] calcd for C19H12O4
304.0736, found 304.0725.
10-Methoxy-6H-benzo[d]naphtho[1,2-b]pyran-6-one-8-
carboxylic Acid (17). A suspension of 14 (0.60 g, 1.8 mmol) in
10% KOH/methanol (30 mL) was heated at reflux for 5 h. The
reaction mixture was cooled to room temperature, and the
solvent was removed under reduced pressure. To the residue
was added water (10 mL), and the pH was adjusted to ∼2.0
using aqueous 5.0 M HCl solution. The resulting mixture was
suction filtered. The solids were vacuum-dried for 1 h, and then
air-dried in an oven at 90−100 °C for 12 h to afford 17 (0.53 g,
93%) as a pale yellow solid. Rf = 0.60 (ethyl acetate); mp 266−
1
269 °C; IR (neat) ν = 3200−2700 (br, w), 1734 (s) cm−1; H
NMR (DMSO-d6, 500 MHz) δ 8.99 (d, J = 9.1 Hz, 1H), 8.46
(d, J = 1.6 Hz, 1H), 8.42−8.38 (m, 1H), 8.03−7.99 (m, 1H),
7.95 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.72−7.68
(m, 2H), 4.15 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ
165.8, 159.5, 157.1, 146.5, 133.4, 131.3, 128.2, 127.3, 127.0,
126.8, 124.2, 123.6, 122.5, 122.4, 122.3, 121.5, 116.7, 112.2,
56.4; APCI-(−)-MS m/z (%) 319 (100, [M−1]−); HRMS [EI-
(+)] calcd for C19H12O5 320.0685, found 320.0687.
N-10-Dimethoxy-N-methyl-6H-benzo[d]naphtho[1,2-b]-
pyran-6-one-8-carboxamide (18). To a mixture of 17 (0.18
mg, 0.55 mmol) and EDCI·HCl (0.20 g, 1.0 mmol) in CH2Cl2
(3.0 mL) was added iPr2NEt (0.28 g, 2.2 mmol), and the
resulting mixture was stirred at room temperature for 1 h. To
the resulting mixture was added N,O-dimethylhydroxylamine
hydrochloride (0.13 g, 1.3 mmol) in one portion, and the
mixture was stirred at room temperature for a further 24 h.
Water (20 mL) was then added followed by the aqueous 1.0 M
HCl solution (15 mL). The layers were separated, and the
aqueous layer was washed with CHCl3 (2×). The combined
organic layers were dried over Na2SO4 and gravity filtered. The
solvent was removed under reduced pressure, and the residue
was subjected to column chromatography (3% methanol/
CHCl3); the product was triturated with ether (2 × 1 mL) to
afford 18 (0.11 g, 55%) as a colorless solid. Rf = 0.50 (50%
ethyl acetate/hexanes); mp 164−167 °C; IR (neat) ν = 1718
(s), 1633 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ 9.03 (d, J
= 9.1 Hz, 1H), 8.64−8.62 (m, 1H), 8.53 (d, J = 1.6 Hz, 1H),
7.89−7.87 (m, 1H), 7.75−7.73 (m, 2H), 7.65−7.61 (m, 2H),
4.15 (s, 3H), 3.67 (s, 3H), 3.44 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 168.1, 161.0, 157.5, 147.5, 134.5, 134.2, 128.3, 127.5,
127.0, 124.8, 124.0, 123.7, 122.81, 122.79, 122.7, 117.1, 113.0,
61.7, 56.6, 34.0; APCI-(+)-MS m/z (%) 364 (100, [M + H]+);
HRMS [EI-(+)] calcd for C21H17NO5 363.1107, found
363.1111.
10-Methoxy-8-vinyl-6H-benzo[d]naphtho[1,2-b]pyran-6-
one (21). A mixture of PPh3MeBr (0.59 g, 1.7 mmol) and DBU
(0.30 g, 2.0 mmol) in CH2Cl2 (8.0 mL) was heated at reflux for
1 h. The reaction mixture was cooled to room temperature, and
16 (0.10 g, 0.32 mmol) was added in one portion. The resulting
mixture was stirred at room temperature for 16 h. The reaction
8-(Hydroxymethyl)-10-methoxy-6H-benzo[d]naphtho[1,2-
b]pyran (19) and 8-(Hydroxymethyl)-10-methoxy-6H-benzo-
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mixture was diluted with CHCl3 (50 mL) and washed with
aqueous 1.0 M HCl solution (1×). The organic layer was dried
over Na2SO4 and gravity filtered. The solvent was removed
under reduced pressure, and the residue was subjected to
column chromatography (CH2Cl2) to afford 21 (70 mg, 70%)
as a colorless solid. Rf = 0.50 (30% ethyl acetate/hexanes); mp
202−205 °C; IR (neat) ν = 1718 (s), 1599 (w) cm−1; 1H NMR
(CDCl3, 500 MHz) δ 8.96 (d, J = 9.1 Hz, 1H), 8.60 (dd, J =
7.1, 2.2 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.85 (dd, J = 6.8, 2.3
Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.62−7.57 (m, 2H), 7.36 (d,
J = 1.7 Hz, 1H), 6.81 (dd, J = 17.5, 10.8 Hz, 1H), 5.95 (d, J =
17.5 Hz, 1H), 5.44 (d, J = 10.8 Hz, 1H), 4.11 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 161.5, 157.8, 146.7, 138.7, 135.6,
133.8, 127.8, 127.4, 126.8, 124.7, 124.4, 123.8, 123.7, 123.4,
122.6, 120.7, 116.5, 114.2, 113.5, 56.3; APCI-(+)-MS m/z (%)
303 (100, [M + H]+); HRMS [EI-(+)] calcd for C20H14O3
302.0943, found 302.0934.
(1×). The layers were separated, and the organic layer was
dried over Na2SO4 and gravity filtered. The solvent was
removed under reduced pressure, and the residue was subjected
to column chromatography (20% ethyl acetate/hexanes) to
afford 23 (0.90 g, 75%) as an off-white solid. Rf = 0.40 (30%
ethyl acetate/hexanes); mp 92−93 °C; IR (neat) ν = 1753 (m)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 9.26 (s, 1H), 7.44 (d, J =
8.5 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H),
7.10 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.45 (s, 2H),
3.58 (s, 3H), 2.42 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
169.9, 153.8, 152.3, 138.7, 129.3, 126.6, 120.0, 115.9, 115.7,
109.5, 108.4, 95.8, 56.9, 20.9; APCI-(−)-MS m/z (%) 261
(100, [M − 1]−); HRMS [EI-(+)] calcd for C14H14O5
262.0841, found 262.0844.
1-Acetoxy-4-methoxy-5-(methoxymethoxy)naphthalene
(24). To a solution of 23 (1.00 g, 3.82 mmol) in acetone (20
mL) was added K2CO3 (2.63 g, 19.0 mmol) and Me2SO4 (3.85
g, 30.5 mmol), and the mixture was heated at reflux for 16 h.
The reaction mixture was cooled to room temperature and
gravity filtered. The solvent was removed under reduced
pressure, and the residue was subjected to column chromatog-
raphy (10% ethyl acetate/hexanes to remove excess dimethyl
sulfate, then 25% ethyl acetate/hexanes to elute the product),
and the product was triturated with hexanes (2 × 5 mL) to
afford 24 (1.02 g, 97%) as a colorless solid. Rf = 0.35 (30%
ethyl acetate/hexanes); mp 55−57 °C; IR (neat) ν = 1748 (m)
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.49 (d, J = 8.4 Hz, 1H),
7.40 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.12 (d, J =
8.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.26 (s, 2H), 3.96 (s,
3H), 3.60 (s, 3H), 2.43 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
169.9, 154.8, 154.2, 140.0, 130.1, 127.1, 119.4, 118.4, 115.6,
114.1, 105.3, 96.8, 56.6, 56.4, 21.0; ESI-(+)-MS m/z (%) 299
(100, [M + Na]+); HRMS [EI-(+)] calcd for C15H16O5
276.1008, found 276.0995.
4-Methoxy-5-(methoxymethoxy)-1-naphthol (25). A 0 °C
solution of 24 (2.20 g, 7.97 mmol) in methanol (25 mL) was
purged with nitrogen for 15 min, and then, K2CO3 (1.21 g, 8.75
mmol) was added in one portion. The resulting mixture was
stirred at room temperature for 20 min, and the solvent was
removed under reduced pressure. Cold deionized water (50
mL) was added slowly to the residue, and the resulting mixture
was extracted with ethyl acetate (3×). The combined organic
layers were dried over Na2SO4 and gravity filtered. The solvent
was removed under reduced pressure, and the residue was
subjected to column chromatography (25% ethyl acetate/
hexanes) to afford 25 (1.50 g, 80%) as an off-white solid. Rf =
0.30 (30% ethyl acetate/hexanes); mp 108−111 °C; IR (neat)
ν = 3413 (br, s) cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.86 (d,
J = 8.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz,
1H), 6.75 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 5.26 (s,
2H), 4.94 (s, 1H), 3.91 (s, 3H), 3.61 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 153.7, 150.8, 145.4, 127.8, 125.9, 119.6,
116.5, 114.5, 108.6, 107.2, 97.0, 57.4, 56.4; APCI-(−)-MS m/z
(%) 233 (100, [M − 1]−); HRMS [EI-(+)] calcd for C13H14O4
234.0892, found 234.0887.
5-Hydroxy-1,4-naphthoquinone (Juglone) (11). This com-
pound was both purchased and synthesized using the following
procedure, which is a modified version of a literature
procedure.49 To a mechanically stirred suspension of 1,5-
dihydroxynaphthalene (17.5 g, 109 mmol) in acetonitrile (260
mL) was added freshly prepared CuCl53 (6.50 g, 65.7 mmol)
and a strong current of O2 gas was bubbled through the
reaction mixture for 2 h. The reaction mixture was vacuum
filtered through a plug of celite, and the filter cake was washed
thoroughly with CHCl3 (500 mL). The filtrate was
concentrated under reduced pressure, and the residue was
subjected to column chromatography (CHCl3) to afford 11
(8.51 g, 45%) as an orange solid. Rf = 0.60 (30% ethyl acetate/
hexanes); mp 147−152 °C (lit. mp49 154−161 °C); H NMR
1
(CDCl3, 500 MHz) δ 11.90 (s, 1H), 7.66−7.61 (m, 2H), 7.29
(dd, J = 7.8, 1.9 Hz, 1H), 6.96 (s, 2H); 13C NMR (CDCl3, 75
MHz) δ 190.3, 184.3, 161.5, 139.6, 138.7, 136.6, 131.8, 124.5,
119.2, 115.0; HRMS [EI-(+)] calcd for C10H6O3 174.0317,
found 174.0320.
5-(Methoxymethoxy)-1,4-naphthoquinone (22). To a 0 °C
solution of 11 (5.00 g, 28.7 mmol) and MOMCl (5.78 g, 71.8
mmol) in CH2Cl2 (80 mL) was added iPr2NEt (7.43 g, 57.5
mmol) dropwise over 15 min, and the reaction mixture was
stirred at room temperature for 14 h. To this mixture was
added saturated aqueous NH4Cl solution (50 mL), and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (1×), and the combined organic layers were dried over
Na2SO4 and gravity filtered. The solvent was removed under
reduced pressure and the residue was subjected to column
chromatography (25% ethyl acetate/hexanes). The product was
triturated with hexanes (2 × 15 mL) to afford 22 (5.80 g, 92%).
Rf = 0.30 (30% ethyl acetate/hexanes); mp 98−101 °C (lit.
mp50 102.5−103 °C); 1H NMR (CDCl3, 500 MHz) δ 7.80 (dd,
J = 7.6, 1.2 Hz, 1H), 7.67 (dd, J = 8.5, 7.5 Hz, 1H), 7.54 (d, J =
8.4, 1.2 Hz, 1H), 6.89 (d, J = 10.3 Hz, 1H), 6.86 (d, J = 10.3
Hz, 1H), 5.36 (s, 2H), 3.55 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 185.0, 184.2, 157.1, 140.8, 136.4, 134.7, 134.0, 122.3,
120.7, 120.5, 95.1, 56.6; HRMS [EI-(+)] calcd for C12H10O4
218.0579, found 218.0582.
1-Hydroxy-4-methoxy-5-(methoxymethoxy)-2-naphthal-
dehyde (9). Acetonitrile (21 mL) was purged with nitrogen for
a period of 15 min, and then, 25 (0.70 g, 3.0 mmol) was added,
followed by para-formaldehyde (0.62 g, 21 mmol) and
triethylamine (1.50 g, 14.9 mmol). The resulting mixture was
heated at 60 °C for 2 h with vigorous stirring. The reaction
mixture was cooled to 0 °C and diluted with cold ethyl acetate
(30 mL). To the resulting mixture was added slowly cold
4-Acetoxy-8-(methoxymethoxy)-1-naphthol (23). To a
mixture of 22 (1.00 g, 4.59 mmol) and zinc (3.00 g, 45.9
mmol) in CHCl3 (30 mL) was added acetic anhydride (0.93 g,
9.1 mmol) and pyridine (0.89 g, 11 mmol). The resulting
mixture was heated at gentle reflux for 20 min. The reaction
mixture was cooled to room temperature, diluted with CHCl3
(60 mL), and washed with cold aqueous 1.0 M HCl solution
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saturated aqueous NH4Cl solution (20 mL), followed by cold
aqueous 1.0 M HCl solution (10 mL). The layers were
separated, and the aqueous layer was washed with ethyl acetate
(2×). The combined organic layers were dried over Na2SO4
and gravity filtered. The solvent was removed under reduced
pressure, and the residue was subjected to column chromatog-
raphy (30% ethyl acetate/hexanes). The product was triturated
with hexanes (2 × 3 mL) to afford 9 (0.49 g, 63%) as a yellow
solid. Rf = 0.40 (30% ethyl acetate/hexanes); mp 91−94 °C, IR
cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.76 (d, J = 1.7 Hz, 1H),
8.41 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H),
7.52 (t, J = 8.1 Hz, 1H), 7.26−7.24 (m, 1H), 5.30 (s, 2H), 4.15
(s, 3H), 4.03 (s, 3H), 3.99 (s, 3H), 3.63 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 165.9, 160.8, 157.6, 153.9, 152.9, 142.2,
130.7, 128.4, 127.6, 126.8, 124.5, 123.5, 119.6, 117.3, 116.9,
116.1, 113.0, 104.3, 97.1, 56.80, 56.76, 56.7, 52.8; APCI-
(+)-MS m/z (%) 425 (58, [M + H]+), 393 (100); HRMS [CI-
(+)] calcd for C23H21O8 425.1236, found 425.1248.
1
(neat) ν = 1646 (m) cm−1; H NMR (CDCl3, 500 MHz) δ
10,12-Dimethoxy-1-(methoxymethoxy)-6H-benzo[d]-
naphtho[1,2-b]pyran-6-one-8-carboxylic Acid (26). A sus-
pension of 6 (0.11 g, 0.26 mmol) in 10% KOH/methanol (3.0
mL) was heated at reflux for 2 h. The reaction mixture was
cooled to room temperature, and a majority of the solvent was
removed under reduced pressure. The residue was cooled to 0
°C, and cold water (1 mL) was added dropwise to dissolve the
residue. The pH was adjusted to ∼4.0 using cold aqueous 1.0
M HCl solution. The yellow precipitate that formed was
isolated by suction filtration. The solids were vacuum-dried for
2 h and then dried under air in an oven at 90−100 °C for 12 h
to afford 26 (91 mg, 86%) as a pale yellow solid. Rf = 0.20
(ethyl acetate); mp 197−200 °C; IR (neat) ν = 3300−2400
12.24 (s, 1H), 9.93 (s, 1H), 8.19 (dd, J = 8.4, 1.2 Hz, 1H), 7.49
(t, J = 8.0 Hz, 1H), 7.35 (dd, J = 7.7, 1.2 Hz, 1H), 6.83 (s, 1H),
5.26 (s, 2H), 3.96 (s, 3H), 3.61 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 195.9, 156.2, 153.8, 149.8, 128.1, 127.0, 123.1, 119.09,
119.05, 113.2, 105.1, 97.1, 57.1, 56.5; APCI-(−)-MS m/z (%)
261 (100, [M − 1]−); HRMS [EI-(+)] calcd for C14H14O5
262.0841, found 262.0844.
Methyl (E)-4-Methoxy-5-(methoxymethoxy)-3-(6H-
naphtho[1,2-b]pyran-6-on-5-yl)acrylate (7). To a solution of
9 (0.78 g, 3.0 mmol) and dimethyl glutaconate (10) (0.94 g,
5.9 mmol) in THF (15 mL) was added piperidine (0.26 g, 3.0
mmol), and the resulting mixture was stirred at room
temperature for 1 h and then heated at 70 °C for 3 h. The
reaction mixture was cooled to room temperature, diluted with
CHCl3 (350 mL), and washed with cold aqueous 1.0 M HCl
solution (1×). The layers were separated, and the organic layer
was dried over Na2SO4 and gravity filtered. The solvent was
removed under reduced pressure, and the residue was slurried
with diethyl ether (20 mL), stirred for 10 min, and vacuum
filtered. This process (ether addition, stirring, and filtration)
was repeated to afford 7 (0.96 g, 87%) as a yellow solid. Rf =
0.30 (50% ethyl acetate/hexanes); mp 184−187 °C; IR (neat)
1
(br, w), 1733 (m), 1689 (s) cm−1; H NMR (DMSO-d6, 500
MHz) δ 8.41 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 8.01 (d, J = 8.4
Hz, 1H), 7.90 (d, J = 1.7 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.24
(d, J = 7.7 Hz, 1H), 5.29 (s, 2H), 4.14 (s, 3H), 3.95 (s, 3H),
3.52 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 165.9, 159.6,
157.1, 153.5, 152.2, 140.7, 131.7, 127.7, 126.5, 125.7, 122.7,
118.2, 116.8, 115.4, 114.7, 112.5, 103.2, 95.9, 56.6, 56.1, 56.0;
ESI-(−)-MS m/z (%) 409 (100, [M − 1]−); MALDI-TOF
HRMS calcd for C22H18O8 410.1002, found 410.0991.
8-(Hydroxymethyl)-10,12-dimethoxy-1-(methoxyme-
thoxy)-6H-benzo[d]naphtho[1,2-b]pyran-6-one-8-carboxylic
Acid (27). To a 0 °C suspension of 26 (80 mg, 0.20 mmol) in
THF (8.0 mL) was added H3B·SMe2 (0.60 mL, 1.2 mmol)
dropwise over a period of 5 min, and the resulting mixture was
stirred at room temperature for 5 h. The reaction mixture was
cooled to 0 °C, methanol (1 mL) was added dropwise, and the
solvent was removed under reduced pressure. The residue was
dissolved in CHCl3 (20 mL), and the resulting solution was
washed with aqueous NaHCO3 solution (1×), dried over
Na2SO4, and gravity filtered. The solvent was removed under
reduced pressure and the residue was subjected to column
chromatography (2% methanol/CHCl3). The product was
triturated with ether (2 × 1 mL) to afford 27 (40 mg, 51%) as a
pale yellow solid. Rf = 0.50 (ethyl acetate); mp 165−168 °C;
1H NMR (CDCl3, 500 MHz) δ 8.24 (d, J = 8.7 Hz, 1H), 8.10
(s, 1H), 7.88 (s, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 7.8
Hz, 1H), 7.06 (s, 1H), 5.30 (s, 2H), 4.69 (s, 2H), 3.94 (s, 3H),
3.89 (s, 3H), 3.67 (s, 3H), 2.55 (br s, 1H); 13C NMR (CDCl3,
75 MHz) δ 161.1, 157.1, 153.4, 151.8, 142.8, 140.5, 126.9,
126.5, 122.9, 122.8, 119.5, 118.6, 117.1, 116.0, 114.5, 113.3,
103.8, 97.2, 64.4, 56.6, 56.1, 55.9; APCI-(+)-MS m/z (%) 397
(95, [M + H]+), 214 (100); HRMS [EI-(+)] calcd for
C22H20O7 396.1209, found 396.1222.
1
ν = 1714 (m), 1697 (s), 998 (s) cm−1; H NMR (CDCl3, 500
MHz) δ 8.26 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H), 7.62 (d, J = 15.9
Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.17
(d, J = 15.8 Hz, 1H), 6.74 (s, 1H), 5.29 (s, 2H), 4.01 (s, 3H),
3.83 (s, 3H), 3.61 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
167.6, 159.2, 154.3, 153.9, 145.8, 144.0, 138.3, 128.3, 126.2,
122.9, 122.2, 120.5, 117.2, 117.1, 114.5, 101.4, 96.8, 56.6, 56.6,
51.9; APCI-(+)-MS m/z (%) 371 (50, [M + H]+, 50), 339
(100); HRMS [CI-(+)] calcd for C20H19O7 371.1131, found
371.1136.
10,12-Dimethoxy-1-(methoxymethoxy)-6H-benzo[d]-
naphtho[1,2-b]pyran-6-one-8-carboxylic Acid Methyl Ester
(6). A mixture of dimethoxyacetaldehyde (2.35 g, 13.5 mmol,
60% solution in water) and piperidine (0.92 g, 11 mmol) in
benzene (40 mL) was heated at reflux for 1 h using a Dean−
Stark apparatus. Approximately 30 mL of solvent was removed
from the reaction flask through the Dean−Stark apparatus. The
reaction mixture was cooled to room temperature, and 7 (0.50
g, 1.4 mmol) was added in one portion. The resulting mixture
was then heated at reflux for 48 h. The reaction mixture was
cooled to room temperature, and the solvent was removed
under reduced pressure. The residue was dissolved in CHCl3
(400 mL) and washed with water (1×). The organic layer was
dried over Na2SO4 and gravity filtered. The solvent was
removed under reduced pressure, and the residue was subjected
to column chromatography (5% methanol/CHCl3). Diethyl
ether (20 mL) was added to the residue, and the mixture was
stirred well for 10 min and vacuum filtered. This process (ether
addition to the solids, stirring, and filtration) was repeated to
afford 6 (0.51 g, 89%) as an orange solid. Rf = 0.30 (50% ethyl
acetate/hexanes); mp 222−225 °C; IR (neat) ν = 1735 (s)
10,12-Dimethoxy-1-(methoxymethoxy)-6H-benzo[d]-
naphtho[1,2-b]pyran-6-one-8-carbaldehyde (28). To a mix-
ture of 27 (60 mg, 0.15 mmol) and celite (100 mg) in CH2Cl2
(8.0 mL) was added PCC (65 mg, 0.30 mmol) in three
portions, and the resulting mixture was stirred at room
temperature for 3 h. The reaction mixture was gravity filtered,
and the filter cake was washed thoroughly with CHCl3. The
solvent was removed under reduced pressure, and the residue
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was subjected to column chromatography (2% methanol/
CHCl3). The residue was triturated with diethyl ether (2 × 1
mL) to afford 28 (44 mg, 73%) as a yellow solid. Rf = 0.40
(50% ethyl acetate/hexanes); mp 200−203 °C; 1H NMR
(CDCl3, 500 MHz) δ 10.10 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H),
8.44 (s, 1H), 8.33 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H),
7.55 (t, J = 8.5 Hz, 1H), 7.29−7.28 (m, 1H), 5.31 (s, 2H), 4.18
(s, 3H), 4.05 (s, 3H), 3.63 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 190.3, 160.2, 157.9, 153.6, 152.7, 142.3, 136.1, 129.8,
127.5, 127.1, 126.5, 123.6, 119.5, 117.0, 116.0, 112.6, 103.8,
96.7, 56.51, 56.45, 56.4; APCI-(+)-MS m/z (%) 395 (52, [M +
H]+), 394 (100), 363 (99); HRMS [EI-(+)] calcd for C22H18O7
394.1053, found 394.1067.
(CDCl3, 300 MHz) δ 8.52 (d, J = 1.7 Hz, 1H), 8.47 (s, 1H),
8.34 (dd, J = 8.5, 1.1 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.53 (t,
J = 8.1 Hz, 1H), 7.27−7.24 (m, 1H), 5.31 (s, 2H), 4.15 (s, 3H),
4.05 (s, 3H), 3.66 (s, 3H), 3.63 (s, 3H), 3.44 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 167.9, 160.8, 157.2, 153.6, 152.6, 141.7,
134.4, 127.4, 126.7, 126.5, 123.0, 122.6, 119.2, 117.0, 116.9,
115.7, 112.9, 104.3, 96.9, 61.5, 56.63, 56.55, 56.5, 33.8; APCI-
(+)-MS m/z (%) 454 (96, [M + H]+), 422 (100); HRMS [EI-
(+)] calcd for C24H23NO8 453.1424, found 453.1421.
1-Hydroxy-10,12-dimethoxy-6H-benzo[d]naphtho[1,2-b]-
pyran-6-one-8-carboxylic Acid Methyl Ester (31). To a −78
°C solution of 6 (100 mg, 0.24 mmol) in CH2Cl2 (20 mL) was
added BCl3 (1.0 M solution in CH2Cl2, 1.2 mL, 1.2 mmol)
dropwise, and the resulting mixture was stirred at this
temperature for 1 h. The reaction mixture was warmed to
room temperature and stirred for an additional 30 min. To this
mixture was added cold water (15 mL) and then CHCl3 (25
mL). The layers were separated, and the aqueous layer was
extracted with CHCl3 (2×). The combined organic layers were
dried over Na2SO4 and gravity filtered. The solvent was
removed under reduced pressure, and the residue was subjected
to column chromatography (2% methanol/CHCl3). The
product was triturated with ether (2 × 2 mL) to afford 31
(81 mg, 87%) as a yellow solid. Rf = 0.30 (50% ethyl acetate/
10,12-Dimethoxy-1-(methoxymethoxy)-8-vinyl-6H-benzo-
[d]naphtho[1,2-b]pyran-6-one (29). A mixture of PPh3MeBr
(135 mg, 0.38 mmol) and DBU (68 mg, 0.45 mmol) in CH2Cl2
(2.5 mL) was heated at reflux for 1 h. The reaction mixture was
cooled to room temperature, and 28 (25 mg, 0.06 mmol) was
added in one portion. The resulting mixture was stirred at room
temperature for 16 h and then heated at reflux for 2 h. The
reaction mixture was cooled to room temperature and diluted
with CHCl3 (20 mL). The resulting mixture was washed with
aqueous 1.0 M HCl solution (1×), and the layers were
separated. The organic layer was dried over Na2SO4 and gravity
filtered. The solvent was removed under reduced pressure, and
1
hexanes); mp 258−261 °C; H NMR (CDCl3, 500 MHz) δ
1
the residue was triturated with ether (2 × 0.5 mL). H NMR
9.28 (s, 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.26 (s, 1H), 8.03 (d, J =
8.5 Hz, 1H), 7.84 (s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.02 (d, J =
7.7 Hz, 1H), 4.12 (s, 3H), 4.11 (s, 3H), 4.00 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 165.5, 160.4, 157.1, 154.2, 152.0, 142.7,
130.5, 128.8, 127.9, 126.0, 124.2, 123.1, 116.6, 115.3, 113.7,
113.4, 112.1, 101.4, 56.6, 56.1, 52.6; APCI-(+)-MS m/z (%)
381 (70, [M + H]+), 214 (100); HRMS [EI-(+)] calcd for
C21H16O7 380.0896, found 380.0905.
analysis of the residue showed the presence of starting material
(ca. 10%), so the material was resubjected to the original
reaction conditions using freshly prepared ylide. This time, the
reaction mixture was refluxed first for 3 h and then stirred at
room temperature for 12 h. The workup was performed as
before. The residue was subjected to column chromatography
(2% methanol/CHCl3), and the product was triturated with
ether (2 × 1 mL) to afford 29 (19 mg, 76%) as a yellow solid.
1-Hydroxy-10,12-dimethoxy-6H-benzo[d]naphtho[1,2-b]-
pyran-6-one-8-carboxaldehyde (32). To a −78 °C solution of
28 (11 mg, 0.028 mmol) in CH2Cl2 (3.0 mL) was added BCl3
(1.0 M solution in CH2Cl2, 0.25 mL, 0.25 mmol) dropwise, and
the resulting mixture was stirred at this temperature for 1 h.
The reaction mixture was warmed to room temperature and
stirred for an additional period of 30 min. To this mixture was
added cold water (10 mL) and then CHCl3 (15 mL). The
layers were separated, and the aqueous layer was extracted with
CHCl3 (2×). The combined organic layers were dried over
Na2SO4 and gravity filtered. The solvent was removed under
reduced pressure, and the residue was subjected to column
chromatography (2% methanol/CHCl3); the product was
triturated with ether (2 × 1 mL) to afford 32 (8 mg, 82%)
as a yellow solid. Rf = 0.45 (50% ethyl acetate/hexanes); mp
1
Rf = 0.60 (50% ethyl acetate/hexanes); mp 184−187 °C; H
NMR (CDCl3, 500 MHz) δ 8.44 (s, 1H), 8.33 (d, J = 8.4 Hz,
1H), 8.18 (s, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.25−
7.22 (m, 1H), 6.82 (dd, J = 17.6, 11.1 Hz, 1H), 5.96 (d, J = 18.4
Hz, 1H), 5.45 (d, J = 11.0 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 3H),
4.04 (s, 3H), 3.63 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
161.3, 157.5, 153.6, 152.5, 141.0, 138.6, 135.4, 127.2, 126.7,
123.9, 123.5, 120.7, 118.8, 117.0, 116.4, 115.5, 114.1, 113.4,
104.3, 96.9, 56.6, 56.5, 56.3; APCI-(+)-MS m/z (%) 393 (100,
[M + H]+); HRMS [EI-(+)] calcd for C23H20O6 392.1260,
found 392.1272.
N-10,12-Trimethoxy-1-(methoxymethoxy)-N-methyl-6H-
benzo[d]naphtho[1,2-b]pyran-6-one-8-carboxamide (30).
To a solution of EDCI·HCl (23 mg, 0.12 mmol) in CH2Cl2
(1.5 mL) was added DIPEA (47 mg, 0.36 mmol), and the
resulting mixture was stirred at room temperature for 15 min.
Carboxylic acid 26 (25 mg, 0.061 mmol) was added, and the
resulting mixture was stirred for 30 min. N,O-Dimethylhydrox-
ylamine hydrochloride (18 mg, 0.18 mmol) was then added in
three portions, and the reaction mixture was stirred for a further
16 h. The reaction mixture was diluted with CHCl3 (15 mL)
and washed with aqueous 1.0 M HCl solution (1×). The layers
were separated, and the aqueous layer was washed with CHCl3
(2×). The combined organic layers were dried over Na2SO4
and gravity filtered. The solvent was removed under reduced
pressure, and the residue was subjected to column chromatog-
raphy (1% methanol/CHCl3). The product was triturated with
ether (2 × 0.5 mL) to afford 30 (11 mg, 40%) as a pale yellow
1
269−271 °C; H NMR (CDCl3, 300 MHz) δ 10.11 (s, 1H),
9.35 (s, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.12 (d, J = 8.4 Hz,
1H), 7.83 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 7.6 Hz,
1H), 4.19 (s, 3H), 4.17 (s, 3H); APCI-(+)-MS m/z (%) 351
(16, [M + H]+), 214 (100); HRMS [EI-(+)] calcd for
C20H14O6 350.0790, found 350.0799.
1-Hydroxy-10,12-dimethoxy-8-vinyl-6H-benzo[d]naphtho-
[1,2-b]pyran-6-one (Defucogilvocarcin V) (5c). To a −78 °C
solution of 29 (14 mg, 0.035 mmol) in CH2Cl2 (4.0 mL) was
added BCl3 (1.0 M solution in CH2Cl2, 0.30 mL, 0.30 mmol)
dropwise, and the resulting mixture was stirred at this
temperature for 1 h. The reaction mixture was warmed to
room temperature and stirred for an additional min. To this
mixture was added cold water (10 mL) and then CHCl3 (15
mL). The layers were separated, and the aqueous layer was
1
solid. Rf = 0.40 (ethyl acetate); mp 134−137 °C; H NMR
8035
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Article
(2) For the isolation of gilvocarcin V, M, and E, see Balitz, D. M.;
O’Herron, F. A.; Bush, J.; Vyas, D. M.; Nettleton, D. E.; Grulich, R. E.;
Bradner, W. T.; Doyle, T. W.; Arnold, E.; Clardy, J. J. Antibiot. 1981,
34, 1544.
(3) For the structure determination of the gilvocarcins, see
Takahashi, K.; Yoshida, M.; Tomita, F.; Shirahata, K. J. Antibiot.
1981, 34, 271.
(4) For the crystal structure of gilvocarcin M, see Hirayama, N.;
Takahashi, K.; Shirahata, K.; Ohashi, Y.; Sasada, Y. Bull. Chem. Soc. Jpn.
1981, 54, 1338.
(5) For the proposed structure of the ravidomycin, see Findlay, J. A.;
Liu, J.-S.; Radics, L.; Rakhit, S. Can. J. Chem. 1981, 59, 3018.
(6) For the spectroscopic data of ravidomycin, see Findlay, J. A.; Liu,
J.-S.; Radics, L. Can. J. Chem. 1983, 61, 323.
extracted with CHCl3 (2×). The combined organic layers were
dried over Na2SO4 and gravity filtered. The solvent was
removed under reduced pressure, and the residue was subjected
to column chromatography (2% methanol/CHCl3). The
product was triturated with ether (2 × 1 mL) to afford 5c
(10 mg, 83%) as a yellow solid. Rf = 0.65 (50% ethyl acetate/
hexanes); mp 240−245 °C (lit. mp15 253−257 °C); H NMR
1
(CDCl3, 500 MHz) δ 9.30 (s, 1H), 8.22 (s, 1H), 8.08 (s, 1H),
8.03 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.27 (s, 1H),
6.78 (d, J = 7.9 Hz, 1H), 6.76 (dd, J = 17.7, 10.7 Hz, 1H), 5.92
(d, J = 17.5 Hz, 1H), 5.43 (d, J = 10.9 Hz, 1H), 4.07 (s, 6H);
13C NMR (CDCl3, 75 MHz) δ 161.1, 157.2, 154.2, 151.8,
141.5, 138.6, 135.3, 128.5, 126.0, 123.5, 123.2, 120.5, 116.4,
114.7, 113.9, 113.4, 112.7, 101.4, 56.1, 55.9; APCI-(+)-MS m/z
(%) 349 (100, [M + H]+); HRMS [EI-(+)] calcd for C21H16O5
348.0998, found 348.1013.
(7) For the isolation of chrysomycin, see Strelitz, F.; Flon, H.;
Asheshov, I. N. J. Bacteriol. 1955, 69, 280.
(8) For the structure elucidation of the chrysomycins, see Weiss, U.;
Yoshihira, K.; Highet, R. J.; White, R. J.; Wei, T. T. J. Antibiot. 1982,
35, 1194.
(9) For the identification and structure elucidation of polycarcin, see
Li, Y. X.; Huang, X. S.; Ishida, K.; Maier, A.; Kelter, G.; Jiang, Y.;
Peschel, G.; Menzel, K. D.; Li, M. G.; Wen, M. L.; Xu, L. H.; Grabley,
S.; Fiebig, H. H.; Jiang, C. L.; Hertweck, C.; Sattler, I. Org. Biomol.
Chem. 2008, 6, 3601.
(10) Tomito, F.; Takahashi, K.-I.; Tamaoki, T. J. Antibiot. 1982, 35,
1038.
(11) Elespuru, R. K.; Gonda, S. K. Science 1984, 223, 69.
(12) McGee, L. R.; Mishra, R. J. Am. Chem. Soc. 1990, 112, 2386.
(13) Morimoto, M.; Okubo, S.; Tomito, F.; Marumo, H. J. Antibiot.
1981, 34, 701.
1-Hydroxy-N-10,12-trimethoxy-N-methyl-6H-benzo[d]-
naphtho[1,2-b]pyran-6-one-8-carboxamide (33). To a −78
°C solution of 30 (9 mg, 0.02 mmol) in CH2Cl2 (2.0 mL) was
added BCl3 (1.0 M solution in CH2Cl2, 0.20 mL, 0.20 mmol)
dropwise, and the resulting mixture was stirred at this
temperature for 1 h. The reaction mixture was cooled to
room temperature and stirred for an additional 30 min. To this
mixture was added cold water (10 mL) and then CHCl3 (15
mL). The layers were separated, and the aqueous layer was
extracted with CHCl3 (2×). The combined organic layers were
dried over Na2SO4 and gravity filtered. The solvent was
removed under reduced pressure, and the residue was subjected
to column chromatography (1% methanol/CHCl3). The
product was triturated with hexanes (2 × 1 mL) to afford 33
(5 mg, 63%) as a pale yellow solid. Rf = 0.40 (ethyl acetate);
mp 178−181 °C; 1H NMR (CDCl3, 300 MHz) δ 9.35 (s, 1H),
8.51 (d, J = 1.7 Hz, 1H), 8.38 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H),
7.73 (d, J = 1.7 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.04 (d, J =
7.8 Hz, 1H), 4.15 (s, 3H), 3.67 (s, 3H), 3.44 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 167.8, 160.6, 157.0, 154.2, 152.0, 142.4,
134.4, 128.7, 126.3, 126.1, 122.9, 122.7, 116.9, 115.2, 113.7,
113.2, 112.3, 101.6, 100.0, 61.5, 56.6, 56.1, 33.8; APCI-(+)-MS
m/z (%) 410 (100, [M + H]+); HRMS [EI-(+)] calcd for
C22H19NO7 409.1162, found 409.1153.
(14) Matsumoto, A.; Fujiwara, Y.; Elespuru, R. K.; Hanawalt, P. C.
Photochem. Photobiol. 1994, 60, 225.
(15) Mishra, R.; Tritch, H. R.; Pandey, R. C. J. Antibiot. 1985, 38,
1280.
(16) Tse-Dinh, T. C.; McGee, L. R. Biochem. Biophys. Res. Commun.
1987, 143, 808.
(17) For a total synthesis and absolute stereochemical assignment of
gilvocarcin M, see Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem.
Soc. 1992, 114, 3568.
(18) For total syntheses of gilvocarcin V and M, see Hosoya, T.;
Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116,
1104.
(19) For model studies towards the synthesis of gilvocarcin M, see
Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z. Org. Biomol. Chem.
2005, 3, 4432.
(20) For a total synthesis and revision of absolute and relative
stereochemistry of ravidomycin, see Futagami, S.; Ohashi, Y.; Imura,
K.; Ohmori, K.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41,
1063.
(21) James, C. A.; Snieckus, V. Tetrahedron Lett. 1997, 38, 8149.
(22) James, C. A.; Snieckus, V. J. Org. Chem. 2009, 74, 4080.
(23) Jung, M. E.; Jung, Y. H. Tetrahedron. Lett. 1988, 29, 2517.
(24) Deshpande, P. P.; Martin, O. R. Tetrahedron Lett. 1990, 31,
6313.
(25) Findlay, J. A.; Daljeet, A.; Murray, P. J.; Rej, R. N. Can. J. Chem.
1987, 65, 427.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 5c, 6, 7, 9, 11,
and 13−33. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gbodwell@mun.ca.
■
Notes
The authors declare no competing financial interest.
(26) Petten, A. D.; Nguyen, N. H.; Danishefsky, S. J. J. Org. Chem.
1988, 53, 1003.
ACKNOWLEDGMENTS
(27) McGee, L. R.; Confalone, P. N. J. Org. Chem. 1988, 53, 3695.
(28) Hart, D. J.; Merriman, G. H. Tetrahedron. Lett. 1989, 30, 5093.
(29) McKenzie, T. C.; Hassen, W. Tetrahedron Lett. 1987, 28, 2563.
(30) McKenzie, T. C.; Hassen, W. D.; MacDonald, S. J. F.
Tetrahedron Lett. 1987, 28, 5435.
■
Financial support of this work from the Natural Sciences and
Engineering Research Council (N.S.E.R.C.) of Canada is
gratefully acknowledged.
(31) MacDonald, S. J. F.; McKenzie, T. C.; Hassen, W. D. J. Chem.
Soc., Chem. Commun. 1987, 1528.
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