Enantioselective Total Synthesis of (+)-Monocerin, a Dihydroisocoumarin Derivative with Potent Antimalarial Properties

Article abstract of DOI:10.1021/acs.joc.9b00414

We describe here the enantioselective synthesis of (+)-monocerin and its acetate derivative. The present synthesis features an efficient optically active synthesis of the β-hydroxy-?-lactone derivative with high enantiomeric purity using Sharpless dihydroxylation as the key step. The synthesis also highlights a tandem Lewis acid-catalyzed, oxocarbenium ion-mediated diastereoselective syn-allylation reaction, and a methoxymethyl group promoted methylenation reaction. We investigated this reaction with a variety of Lewis acids. A selective CrO₃-mediated oxidation of isochroman provided the corresponding lactone derivative. The synthesis is quite efficient and may be useful for the preparation of derivatives.

Full text of DOI:10.1021/acs.joc.9b00414

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Enantioselective Total Synthesis of (+)-Monocerin, a
Dihydroisocoumarin Derivative with Potent Antimalarial Properties
Arun K. Ghosh* and Daniel S. Lee
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana
47907, United States
S
* Supporting Information
ABSTRACT: We describe here the enantioselective synthesis of (+)-monocerin and its acetate derivative. The present
synthesis features an efficient optically active synthesis of the β-hydroxy-γ-lactone derivative with high enantiomeric purity using
Sharpless dihydroxylation as the key step. The synthesis also highlights a tandem Lewis acid-catalyzed, oxocarbenium ion-
mediated diastereoselective syn-allylation reaction, and a methoxymethyl group promoted methylenation reaction. We
investigated this reaction with a variety of Lewis acids. A selective CrO3-mediated oxidation of isochroman provided the
corresponding lactone derivative. The synthesis is quite efficient and may be useful for the preparation of derivatives.
constituent of the entomogenous fungus Fusarium larvarum
Fuckel and showed its insecticidal properties.7 The assignment
of absolute configuration of monocerin was addressed by
Grove and Pople as well as by Scott and co-workers.7,8
Subsequently, the synthesis and biosynthesis of the first
polyketide synthase-free intermediate in monocerin was
reported by Axford and co-workers.9 Since then, there have
been many reports concerning the phytotoxic properties of
monocerin and its derivatives 2−4.8,10−13 In 2008, Sappapan
and co-workers reported potent antimalarial properties of
monocerin against the multidrug-resistant strain of Plasmodium
falcifarum with an IC50 value of 680 nM.14 Its acetate derivative
2 also showed good antimalarial activity (IC50 = 820 nM).14
Lasionectrin (5), a dihydronaphthopyrone natural product,
was isolated from fermentations of the fungus Lasionectria (F-
176,994).15 Like monocerin, lasionectrin also exhibited
antimalarial activity, although subsequently weaker than that
of monocerin.15 Monocerin features a 4-oxyisochroman-1-one
structural unit and 2,3,5-trisubstituted tetrahydrofuran ring
containing all-cis stereochemistry.
INTRODUCTION
■
Dihydrocoumarin and dihydroisocoumarin derivatives fre-
quently occur in nature.1,2 These natural products exhibit a
wide range of biological properties including antifungal,
insecticidal, antiparasitic, and plant pathogenic activity.3−5
Monocerin (1, Figure 1), which was first isolated by Aldridge
and Turner from Exserohilum monoceras (Drechsler), is a
dihydroisocoumarin natural product that protects wheat
against the powdery mildew Erysiphe graminis.6 Aldridge and
Turner also demonstrated monocerin’s antifungal properties.
Subsequently, Grove and Pople identified monocerin as a
Structural features and broad-spectrum biological properties
of monocerin led to considerable synthetic attention over the
years. Mori and Takaishi reported the first synthesis of
monocerin in racemic form.16 Simpson and co-workers then
reported a biomimetic synthesis of monocerin.17 Since then,
monocerin and its derivatives have attracted much synthetic
interest due to their broad medicinal potential. A number of
Received: February 11, 2019
Figure 1. Structures of dihydroisocoumarin natural products 1−5.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00414
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The Journal of Organic Chemistry
Article
total syntheses of monocerin have been reported.18−23
Recently, an enantioselective total synthesis of lasionectrin
has also been reported.24 Herein, we report a short and
practical synthesis of monocerin and its acetate derivative in
optically active form. The synthesis features Sharpless
asymmetric dihydroxylation, Lewis acid-catalyzed, oxocarbe-
nium ion-mediated stereoselective allylation, formulation
reaction, and CrO3-mediated oxidation of the benzopyran to
a dihydroisocoumarin derivative. The synthesis is potentially
amenable toward the synthesis of structural variants of
monocerin for biological studies.
a
Scheme 2. Synthesis of Allyl Derivatives 13a and 14a
RESULTS AND DISCUSSION
Our synthetic strategy for (+)-monocerin is shown in Scheme
1. We planned an oxocarbenium ion-mediated allylation of
■
Scheme 1. Retrosynthetic Analysis of (+)-Monocerin
a
Reagents and conditions: (a) Ph3P+CH2CO2HBr−, t-BuOK, THF,
−78 to 23 °C, 18 h, (65%); (b) TMSCI, dry MeOH, 0 to 23 °C, 18 h
(76%); (c) AD-mix-β, NaHCO3, MeSO2NH2, t-BuOH/H2O = 1.1, 0
°C, 24 h (90%); (d) DIPEA, MOMCI, TBAI (cat.), THF, 50 °C, 24
h (95%); (e) DIBAL-H, toluene, −78 °C; (f) Et3N, DMAP, Ac2O,
DCM, 0 to 23 °C, 1.5 h (88%); (g) TBSOTf, 2,6-lutidine, DCM, 0 to
23 °C, 3 h (51%); (h) MEMCl, DIPEA, TBAI, THF, 0 to 55 °C, 72 h
(79%); (i) allyltrimethylsilane, SnBr4, DCM, −78 °C, 3 h, (84%).
acetate derivative 6 for stereoselective installation of the propyl
chain of monocerin. We also envisioned an intramolecular
oxocarbenium ion-mediated formulation of the aromatic ring
through the MOM group to install the isochroman structure.
We planned to investigate these transformations in a “one-pot”
operation. A related C3-benzyloxy-substituted five-membered
ring oxocarbenium ion has been shown to promote allylation
selectivity to provide the 1,3-cis product.25,26 The stereo-
chemical outcome and selectivity with a methoxymethyl group
are expected to be similar. The key allylation substrate can be
synthesized from 3-hydroxy-γ-lactone 7, which can be
synthesized in an optically active manner by asymmetric
dihydroxylation of E-olefin 8.27,28 The requisite E-olefin can be
synthesized by a stereoselective Wittig olefination using a γ-
oxido-ylid and commercially available 3,4,5-trimethoxy benzal-
dehyde.29,30
Our synthesis of multigram quantities of γ-lactone 7 and its
derivatives is shown in Scheme 2; Wittig olefination of 3,4,5-
trimethoxybenzaldehyde 9 was carried out with ylid generated
from (2-carboxyethyl)triphenyl phosphonium bromide and
potassium t-butoxide in THF at −78 to 23 °C for 18 h.29,31
The resulting β,γ-unsaturated acid was esterified by exposure
to TMSCl in MeOH at 0 to 23 °C for 12 h to provide methyl
ester 8 in 49% yield over two steps. Asymmetric dihydrox-
ylation of methyl ester 8 with AD-mix-β in the presence of
methanesulfonamide and sodium bicarbonate in aqueous t-
BuOH at 0 °C for 22 h afforded β-hydroxy-γ-lactone 7 in 90%
yield.27 Optical purity of lactone 7 was over 95% ee, as
determined by chiral HPLC analysis using a chiralpak IC
column. Protection of the hydroxyl group as a MOM ether was
achieved by reaction of lactone 7 with MOMCl in THF in the
presence of diisopropylethylamine (DIPEA) and a catalytic
amount of tetrabutylammonium iodide (TBAI) at 50 °C for 24
h to provide MOM ether 10 in 95% yield. It was then
converted to acetate derivative 6 in a two-step sequence: first,
by DIBAL-H reduction in CH2Cl2 at −78 °C for 2 h, followed
by acetylation of the resulting crude lactol with acetic
anhydride and triethylamine in the presence of a catalytic
amount of DMAP in CH2Cl2 at 0 °C for 2 h to provide 6 as
the major anomer along with a small amount of the other
anomer (ratio 14:1) in 88% combined yield over two steps.
Lactone 7 was converted to TBS-protected acetate derivative
11 by protection of the hydroxyl group as TBS ether followed
by DIBAL-H reduction and acetylation, as described above.
Similarly, lactone 7 was also converted to MEM-derivative 12,
as described above. The stereochemistry of the chiral center
bearing an acetate group for 6, 11, and 12 was assigned by
using 1H NMR nuclear Overhauser enhancement spectroscopy
(NOESY) experiments (see the Supporting Information).
With the synthesis of these acetates, we have investigated
allylation promoted by various Lewis acids. We first carried out
allylation of 6 with 1.1 equiv of SnBr4 and 4 equiv of
allyltrimethylsilane in CH2Cl2 at −78 °C for 3 h. This resulted
in a mixture (62:38) of allyl derivatives 13a and 14a in 84%
combined yield. The ratio was determined by 1H NMR
analysis of diastereomeric protons. We then investigated other
Lewis acids under various conditions, and the results are
B
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Article
1H NMR NOESY experiments (see the Supporting Informa-
tion for details).
shown in Table 1. The use of 2 equiv of SnBr4 did not improve
diastereoselectivity, and the reaction yield was reduced (entry
The observed cis-diastereoselectivity is consistent with C3-
alkoxy-substituted tetrahydrofuranyl substrates examined by
Woerpel and co-workers.25,26 However, the extent of
diastereoselectivity of allylation is significantly lower presum-
ably due to competing stereoelectronic effects. As shown in
Figure 2, allylation of acetates can proceed through
Table 1. Allylation of Acetate Derivatives with Various
Lewis Acids
a
entry compd. Lewis acid (equiv) time yield (%) dr (13/14 ratio)
1
2
3
4
5
6
7
8
9
10
6
6
6
6
6
6
11
11
12
12
SnBr4 (1.1)
SnBr4 (2.0)
TiCl4 (1.1)
3 h
3 h
3 h
4 h
3 h
3 h
3 h
3 h
3 h
3 h
83.9
75.1
69.4
38.2
52.1
57.1
80.7
76
62:38
63:37
60:40
58:42
63:37
58:42
70:30
72:28
51:49
63:37
TiCl4 (2.0)
BF3·OEt2 (1.1)
TMSOTf (1.0)
SnBr4 (1.1)
TiCl4 (1.1)
SnBr4 (1.1)
BF3·OEt2 (1.1)
Figure 2. Stereochemical analysis of cis-allylation reaction.
32.7
36.4
oxocarbenium ion intermediates 15 and 16. Intermediate 15
is preferred over 16 due to the pseudoequatorial orientation of
the bulky trimethoxyphenyl group at the C4 position.26,32,33
The axial alkoxy group forms a gauche interaction with the
aromatic group. Inside attack on the oxocarbenium ion
intermediate 15 leads to the major diastereomer 13.
Intermediate 16 also shows a gauche interaction as well as
1,3-interactions between the bulky aromatic group and the C2-
axial hydrogen. Changing of Lewis acids did not make much
difference in selectivity. The size and nature of protecting
groups also did not show much influence in diastereoselectiv-
ity. Moreover, the protecting groups remained unaffected
under the reaction conditions.
We then investigated a Lewis acid-catalyzed allylation
reaction at −78 to 23 °C in an effort to promote selective
allylation, as well as to carry out Friedel−Crafts alkylation
through the MOM or MEM groups onto the aromatic ring in a
one-pot operation.34,35 The results of these tandem allylation
and Oxa-Pictet−Spengler cyclization are shown in Table 2.
Initial reaction of MOM derivative 6 with 1.6 equiv of SnBr4 in
the presence of allyltrimethylsilane at −78 to 23 °C for 4 h
provided a diastereomic mixture of allylated products 13a and
14a in 54% yield as well as isochroman derivatives 17 and 18
in 22% yield (entry 1, Table 2). To promote complete
formation of isochroman derivatives, we examined the reaction
with additional equivalents of Lewis acid, and the reaction was
carried out for a longer period of time. Thus, the reaction of
MOM derivative 6 was carried out with 1.6 equiv of SnBr4 in
the presence of allyltrimethylsilane at −78 to 23 °C for 4 h.
Reaction was monitored by TLC and showed complete
consumption of the starting acetate derivatives. After this
b
a
All reactions were carried out in CH2Cl2 at −78 °C and
allyltrimethylsilane (4.0 equiv). Ratios were determined by 1H
b
NMR analysis. 1.5 equiv of allyl trimethylsilane was added instead
of 4 equiv.
2). The use of 1.1 equiv of TiCl4 resulted in 69% yield of a
mixture of diastereomers (60:40) similar to SnBr4 reaction
(entry 3). An increase of Lewis acid to 2 equiv resulted in a
decrease of reaction yields as well as a slight reduction of
diastereomeric ratio (entry 4). We also investigated the
allylation reaction with BF3·OEt2 and TMSOTf as the Lewis
acids. In both cases, the reaction provided similar diastereo-
meric ratios, and the reaction yields were 52 and 57%,
respectively (entries 5 and 6). We then examined allylation of
TBS-protected acetate derivative 11 with 1.1 equiv of SnBr4
and 4 equiv of allyltrimethylsilane in CH2Cl2 at −78 °C for 3
h. This has resulted in a slight improvement in the
diastereomeric ratio (70:30) of allyl derivatives 13b and 14b
in 81% yield (entry 7). The use of 1.1 equiv of TiCl4 also
provided comparable diastereoselectivity and yield (entry 8).
Interestingly, allylation of MEM-protected acetate derivative
12 with 1.1 equiv of SnBr4 and 4 equiv of allyltrimethylsilane in
CH2Cl2 at −78 °C for 3 h resulted in allyl derivatives 13c and
14c in a 1:1 ratio and 33% yield (entry 9). The reaction of 12
with 1.1 equiv of BF3·OEt2 and 1.5 equiv of allyltrimethylsilane
provided allyl derivatives 13c and 14c in a 63:37 ratio, and the
reaction yield was 36% (entry 10). While the observed
diastereoselectivity of allylation was moderate, we assigned
stereochemical identity of diastereomers 13b and 14b by using
C
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Article
a
Table 2. Lewis Acid-Catalyzed Tandem Allylation and Oxa-
Pictet−Spengler Cyclization of Acetate Derivative 6 and 12
Scheme 3. Synthesis of (+)-Monocerin
a
yield %
yield %
entry compd. Lewis acid (equiv, time) (13/14) (17/18 and ratio)
1
2
6
6
SnBr4 (1.6, 4 h)
SnBr4 (1.6, 4 h), then
(2, 12 h)
SnBr4 (1.1, 3 h), then
(2, 12 h)
SnBr4 (1.1, 3 h), then
(2, 12 h)
TiCl4 (1, 4 h), then
(1.5, 12 h)
SnBr4 (1.6, 3 h), then
(2, 12 h)
54
-
22 (3:1)
52 (4:1)
b
c
3
4
5
6
6
35 (3.2:1)
42 (3:1)
trace
a
b d
,
6
Reagents and conditions: (a) SnBr4, allyltrimethylsilane, CH2Cl2,
−78 to 23°C, 18 h (52%); (b) H2, 10% Pd-C, EtOAc, 23 °C, 12 h
(88%); (c) CrO3, pyridine, CH2Cl2, 0 to 23 °C, 36 h (40%, 60%
brsm); (d) BCl3, CH2Cl2, −10 °C, 2 h (41%, 88% brsm); (e) Ac2O,
pyridine, CH2Cl2, 23 °C, 5 h (96%).
c
6
trace
b
12
21 (1.7:1)
a
All reactions were carried out in CH2Cl2 with 4 equiv of
b
hydrogenated under a hydrogen-filled balloon in the presence
of a catalytic amount of 10% Pd-C in ethyl acetate at 23 °C for
12 h to provide saturated bicyclic ether 19 in 88% yield. The
1H NMR and 13C NMR spectra of our synthetic bicyclic ether
19 showed excellent agreement with the reported derivative.18
Furthermore, NOESY correlation of cis-hydrogens in com-
pound 17 supported stereochemistry of 17 and 19 (see the
Supporting Information for details). Oxidation of the isochro-
man ring was carried out with CrO3 and pyridine in CH2Cl2 at
0 to 23 °C for 36 h to provide lactone derivative 20 in 40%
yield (60% brsm). To complete the synthesis of monocerin,
selective deprotection of methyl ether was carried out by
exposure to BCl3 in CH2Cl2 at −10 °C for 2 h to provide
allyltrimethylsilane at −78 to 23 °C. Additional Lewis acid was
added at 0 °C, and the reaction mixture was slowly warmed to 23 °C.
c
Additional Lewis acid was added at −78 °C, and the reaction mixture
d
was warmed to 23 °C. After adding 1.1 equiv of Lewis acid, the
reaction mixture was stirred at −78 °C for 3 h.
period, the reaction was cooled to 0 °C, 2 equiv of SnBr4 was
added, and the resulting mixture was warmed to 23 °C for 12
h. This resulted in the formation of isochroman derivatives 17
and 18 in 52% yield. The diastereomeric ratio was determined
to be 4:1 by 1H NMR analysis (entry 2). Addition of additional
equivalents of Lewis acid was then investigated at lower
temperature. Acetate 6 was treated with 1.1 equiv of SnBr4 at
−78 to 23 °C for 3 h, and 2 equiv of SnBr4 was added at −78
°C. The resulting mixture was allowed to warm from −78 to
23 °C for 12 h. This reaction protocol furnished products 17
and 18 as a mixture (3.2:1) of diastereomers in 35% yield
(entry 3). In a further optimization effort, acetate 6 was treated
with 1.1 equiv of SnBr4 at −78 °C for 3 h, then 2 equiv of
SnBr4 was added at −78 °C, and the reaction was warmed to
23 °C for 12 h. This has resulted to products 17 and 18 as a
3:1 mixture in 42% combined yield (entry 4). Oxa-Pictet−
Spengler cyclization of acetate derivative 6 with TiCl4 in place
of SnBr4 under similar reaction conditions, however, provided
only a trace amount of the products (entry 5). Interestingly,
the reaction of MEM derivative 12 with SnBr4 and
allyltrimethylsilane using conditions described in entry 2
provided a mixture (1.7:1) of isochroman derivatives 17 and
18 in 21% combined yield (entry 6).
1
synthetic (+)-monocerin 1 in 41% yield (88% brsm). The H
NMR and 13C NMR spectra of synthetic (+)-monocerin
23
{[α]D + 57.8 (c 0.29, CHCl3)} are in complete agreement
24
with spectra reported for the natural (+)-monocerin {[α]D
+
53 (c 0.85, CHCl3)}.6 We have also synthesized (+)-acetox-
ymonocerin 2 by treatment of 1 with acetic anhydride and
pyridine in the presence of a catalytic amount of DMAP at 0 to
23 °C for 5 h to furnish acetate derivative 2 in 96% yield.
23
{[α]D + 3.6 (c 0.29, CHCl3)}. Thus, (+)-monocerin 1 was
synthesized in 10 steps in an overall 9% yield. The acetate
derivative 2 was obtained in 11 steps in an overall 8.6% yield.
CONCLUSIONS
■
In summary, we have accomplished an enantioselective total
synthesis of (+)-monocerin and its acetate derivative. The
synthesis highlights a Lewis acid-catalyzed, tandem oxocarbe-
nium ion-mediated stereoselective allylation and Friedel−
Crafts-type alkylation to provide the isochroman framework in
a one-pot operation. The allylation reaction was investigated
with various Lewis acids and by varying protecting groups at
The synthesis of (+)-monocerin is shown in Scheme 3.
MOM ether 6 was converted to allylated Oxa-Pictet−Spengler
products 17 and 18. The diastereomers were separated by
silica gel chromatography, and the major isomer 17 was
D
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Article
mL) was added. The mixture was stirred at 0 °C for 22 h. After this
period, sodium sulfite (5.0 g) was added. The mixture was stirred for
1 h at 23 °C and extracted with EtOAc (3×). The combined organic
layer was dried with Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was then purified by column
chromatography on silica gel (50−80% EtOAc in hexanes) to afford
lactone 7 (700 mg, 90%) as a white amorphous solid. [α]D20 − 23.9 (c
0.41, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.54 (s, 2H), 5.38 (d, J
= 3.3 Hz, 1H), 4.62−4.56 (m, 1H), 3.82 (s, 6H), 3.78 (s, 3H), 2.85
(ddd, J = 17.5, 5.0, 1.5 Hz, 1H), 2.71 (d, J = 17.5 Hz, 1H), 2.06 (m,
1H, OH); 13C{1H} NMR (100 MHz, CDCl3): δ 175.4, 153.6, 137.9,
128.5, 103.0, 85.1, 70.1, 60.7, 56.1, 38.4. LRMS (ESI) 269.0 [M +
H]+. HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C13H16O6 + H,
269.1020; found, 269.1024.
the C3 position. While the stereochemical outcome for the
major product has all cis-stereochemistry, the extent of
diastereoselectivity was moderate due to competing stereo-
electronic effects. The allylation substrate β-hydroxy-γ-lactone
was synthesized conveniently in optically active form using
Sharpless asymmetric dihydroxylation as the key step. The
corresponding E-olefin was prepared selectivity by olefination
with γ-oxido-ylid. Since monocerin and derivatives show a
broad range of biological activity, the current synthesis will
provide access to structural variants in optically active form.
EXPERIMENTAL SECTION
■
All chemical and reagents were purchased from commercial suppliers
and used without further purification, unless otherwise noted. The
following reaction solvents were distilled prior to use: CH2Cl2 from
calcium hydride, diethyl ether and tetrahydrofuran from Na/
benzophenone, and methanol from activated magnesium under
argon. All reactions were carried out under an argon atmosphere in
either flame- or oven-dried (120 °C) glassware. TLC analysis was
conducted using glass-backed thin-layer silica gel chromatography
plates (60 Å, 250 μm in thickness, F-254 indicator). Column
chromatography was performed using 230−400 mesh silica gel (pore
diameter, 60 Å). 1H NMR spectra were recorded at room temperature
on a 400 MHz spectrometer. 13C NMR spectra were recorded on 100
and 200 MHz spectrometers. Chemical shifts (δ values) were
reported in parts per million and are referenced to the deuterated
residual solvent peak. NMR data are reported as follows: δ value
(chemical shift, J-value (Hz), integration, where s = singlet, d =
doublet, t = triplet, q = quartet, quint = quintet, sep = septet, m =
multiplet, dd = doublet of doublets, ddd = doublet of doublet of
doublets, td = triplet of doublets, dq = doublet of quartets, brs =
broad singlet, app = apparent). Optical rotations were recorded on a
digital polarimeter. Low-resolution mass spectrometry (LRMS) and
high-resolution mass spectrometry (HRMS) spectra were recorded at
the Purdue University Department of Chemistry Mass Spectrometry
Center. These experiments were performed under ESI+ and positive
atmosphere pressure chemical ionization (APCI+) conditions using
an Orbitrap XL Instrument.
(4R,5R)-4-(Methoxymethoxy)-5-(3,4,5-trimethoxyphenyl)-
dihydrofuran-2(3H)-one (10). To a stirred solution of lactone 7
(272 mg, 1.02 mmol) in distilled THF (4 mL) at 0 °C under argon
atmosphere were consecutively added DIPEA (1.77 mL, 10.2 mmol),
TBAI (75 mg, 0.20 mmol), and MOM-Cl (0.44 mL, 5.80 mmol). The
reaction mixture was then stirred at 50 °C for 24 h. After dilution with
CH2Cl2, the mixture was washed with water, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude residue
was purified by column chromatography on silica gel (60% EtOAc in
hexane) to give MOM-protected lactone 10 (300 mg, 95%) as a
20
1
yellow amorphous solid. [α]D − 46.1 (c 0.79, CHCl3). H NMR
(400 MHz, CDCl3): δ 6.58 (d, J = 0.6 Hz, 2H), 5.43 (d, J = 3.8 Hz,
1H), 4.56 (ddd, J = 5.1, 3.8, 0.9 Hz, 1H), 4.32 (d, J = 7.1 Hz, 1H),
4.14 (d, J = 7.1 Hz, 1H), 3.85 (s, 6H), 3.83 (s, 3H), 3.06 (s, 3H), 2.88
(dd, J = 17.5, 5.3 Hz, 1H), 2.73 (dd, J = 17.5, 0.9 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 174.9, 153.2, 137.9, 129.3, 103.6, 95.1,
84.6, 74.1, 60.8, 56.1, 55.4, 37.5. LRMS (ESI) 647.2 [2M + Na]+.
HRMS (ESI-Orbitrap) m/z: [M + Na]+ calcd for C15H20O7Na,
335.1101; found, 335.1103.
(4R,5R)-4-(Methoxymethoxy)-5-(3,4,5-trimethoxyphenyl)-
tetrahydrofuran-2-ol (6). To a stirred solution of lactone 10a (240
mg, 0.77 mmol) in CH2Cl2 (6 mL) at −78 °C under argon
atmosphere was added DIBAL-H (0.92 mL, 0.92 mmol), and the
resulting mixture was stirred at the same temperature for 2 h. After
this period, the reaction mixture was quenched by the addition of
MeOH (3 mL) and warmed to 23 °C. Then, saturated aqueous
solution of sodium potassium tartarate was added and stirred
vigorously at 23 °C for 2 h until it forms into a white suspension.
The suspension was filtered through a plug of Celite, and solvents
were removed under reduced pressure.
To a crude lactol, DMAP (17 mg, 0.14 mmol), Et3N (0.50 mL,
3.59 mmol), and Ac2O (0.17 mL, 1.80 mmol) were added at 0 °C
under argon atmosphere, and the resulting mixture was stirred for 2 h.
Upon completion, solvents were removed under reduced pressure,
and the crude product was purified by column chromatography over
silica gel (50% EtOAc in hexanes) to give acetate 6 (240 mg) as the
major isomer and the corresponding minor anomer (16 mg) as
colorless oils in 88% over two steps. Acetate 6: 1H NMR (400 MHz,
CDCl3): δ 6.61 (s, 1H), 6.59 (dd, J = 6.1, 3.3 Hz, 1H), 5.09 (d, J = 3.8
Hz, 1H), 4.45 (ddd, J = 5.8, 3.8, 1.9 Hz, 1H), 4.30 (d, J = 7.0 Hz,
1H), 4.12 (d, J = 6.9 Hz, 1H), 3.84 (s, 6H), 3.81 (s, 3H), 3.06 (s,
3H), 2.53 (ddd, J = 14.7, 6.1, 1.9 Hz, 1H), 2.37 (ddd, J = 14.7, 6.1, 3.3
Hz, 1H), 2.06 (s, 3H). 13C{1H} NMR (major anomer, 101 MHz,
CDCl3): δ 170.2, 152.9, 137.5, 131.1, 104.2, 97.4, 95.1, 83.7, 76.6,
60.8, 56.1, 55.2, 40.4, 21.2. LRMS (ESI), 735.2 ([2M + Na]+). HRMS
(ESI-Orbitrap) m/z: [M + Na]+ calcd for C17H24O8Na, 379.1363;
found, 379.1360. Minor isomer: 1H NMR (400 MHz, CDCl3): δ 6.63
(s, 2H), 6.42 (d, J = 5.8 Hz, 1H), 5.08 (d, J = 4.5 Hz, 1H), 4.42−4.35
(m, 2H), 4.23−4.17 (m, 1H), 3.88−3.85 (s, 6H), 3.83 (s, J = 0.9 Hz,
3H), 3.11 (s, 3H), 2.50−2.42 (m, 1H), 2.40−2.34 (m, 1H), 2.13 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.4, 152.8, 132.14,
129.8, 104.4, 98.0, 95.2, 86.4, 75.4, 60.8, 56.0, 55.2, 39.3, 21.4. LRMS
(ESI), 357.1 ([M + H]+).
Methyl (E)-4-(3,4,5-Trimethoxyphenyl)but-3-enoate (8). To
a cooled suspension of (2-carboxyethyl) triphenylphosphonium
bromide (2.99 g, 7.2 mmol, 1.2 equiv) and 3,4,5-trimethoxybenzalde-
hyde (1.18 g, 6 mmol, 1.0 equiv) in THF (45 mL) at −78 °C was
slowly added a solution of t-BuOK (15 mL, 15 mmol, 1.0 M THF
solution, 2.5 equiv). After addition, the mixture was stirred at −78 °C
for 1 h and was then warmed to 23 °C overnight. The resulting
suspension was concentrated under reduced pressure, H2O (100 mL)
was added, and the mixture was washed with CH2Cl2. The aqueous
phase was acidified to pH = 1 with a 1 M solution of HCl and
extracted with Et2O (3×). The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude β,γ-unsaturated carboxylic acid above was then dissolved
in distilled MeOH (20 mL), and TMSCl (0.97 mL, 1.26 equiv) was
dropwise added at 0 °C under argon atmosphere. The mixture was
stirred at 23 °C overnight and then concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (10% EtOAc in hexanes) to yield 8 (746 mg, 49%
over two steps) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.58
(s, 2H), 6.41 (d, J = 15.8, 1H), 6.20 (dt, J = 15.8, 7.1 Hz, 1H), 3.86 (s,
6H), 3.83 (s, 3H), 3.71 (s, 3H), 3.24 (dd, J = 7.1, 1.5 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 171.9, 153.2, 137.7, 133.3,
132.5, 121.0, 103.3, 60.8, 56.0, 51.9, 38.0. LRMS (ESI) 267.0 ([M +
H]+). HRMS (ESI-Orbitrap) m/z: [M + Na]+ calcd for C14H18O5Na,
289.1046; found, 289.1049.
(4R,5R)-4-Hydroxy-5-(3,4,5-trimethoxyphenyl)-
dihydrofuran-2(3H)-one (7). AD-mix-β (3.926 g), NaHCO3 (706
mg, 8.4 mmol), and methanesulfonamide (267 mg, 2.8 mmol) were
dissolved in t-BuOH (7 mL) and water (14 mL). After the mixture
was cooled to 0 °C, methyl ester 8 (746 mg, 2.8 mmol) in t-BuOH (7
(4R,5R)-4-(Methoxymethoxy)-5-(3,4,5-trimethoxyphenyl)-
tetrahydrofuran-2-yl Acetate (11). To a stirred solution of lactone
7 (95 mg, 0.354 mmol) in CH2Cl2 (3 mL) at 0 °C under argon
E
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The Journal of Organic Chemistry
Article
atmosphere were added 2,6-lutidine (0.12 mL, 1.06 mmol) and
TBSOTf (0.12 mL, 0.53 mmol). The reaction mixture was warmed to
23 °C and stirred for 3h. When the reaction was finished, the mixture
was quenched by the addition of saturated aqueous NaHCO3 and
extracted with dichloromethane. The extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography (40%
EtOAc in hexanes) to give silyl ether derivative (69 mg, 51%) as an
orange amorphous solid. [α]D − 34.7 (c 0.29, CHCl3). H NMR
(400 MHz, CDCl3): δ 6.54 (s, 2H), 5.37 (d, J = 3.5 Hz, 1H), 4.55
(ddd, J = 4.8, 3.5, 0.7 Hz, 1H), 3.85 (s, 6H), 3.82 (s, 3H), 2.87 (dd, J
= 17.1, 4.8 Hz, 1H), 2.59 (dd, J = 17.1, 0.7 Hz, 1H), 0.67 (s, 9H),
−0.13 (s, 3H), −0.34 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
175.5, 153.1, 138.0, 129.9, 103.8, 86.0, 71.5, 60.8, 56.1, 40.2, 25.3,
17.7, −5.4, −5.6. LRMS (ESI), 405.2 [M + Na]+.
The title compound was prepared from above lactone (55 mg),
reduced, and protected as acetate derivatives following the procedure
described for the preparation of acetate 6. The compound was
purified by flash column chromatography over silica gel (20% EtOAc
in hexanes) to give acetate 11 (50 mg, 81% over two steps) as a white
amorphous solid. [α]D20 − 13.6 (c 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 6.60 (dd, J = 5.9, 3.8 Hz, 1H), 6.56 (d, J = 0.5 Hz, 2H),
5.03 (d, J = 3.6 Hz, 1H), 4.43 (ddd, J = 5.4, 3.6, 1.9 Hz, 1H), 3.83 (s,
6H), 3.78 (s, 3H), 2.44−2.27 (m, 2H), 2.05 (s, 3H), 0.67 (s, 9H),
−0.17 (s, 3H), −0.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
170.3, 152.7, 137.5, 131.7, 104.6, 97.9, 85.2, 73.7, 60.7, 56.0, 43.1,
25.4, 21.2, 17.8, −5.4, −5.5. LRMS (ESI), 449.2 [M + Na]+. HRMS
(ESI-Orbitrap) m/z: [M + Na]+ calcd for C21H34O7SiNa, 449.1966;
found, 449.1969.
acetate). The aqueous layer was then extracted three times with
CH2Cl2, and the collected organic phases were dried (Na2SO4),
filtered, and concentrated under reduced pressure.
Preparation of (2R,3R,5S)-5-Allyl-3-(methoxymethoxy)-2-(3,4,5-
trimethoxyphenyl)tetrahydrofuran (13a) and (2R,3R,5R)-5-Allyl-3-
(methoxymethoxy)-2-(3,4,5-trimethoxyphenyl)tetrahydrofuran
(14a) Mixture. Following the general procedure described above and
starting from acetate 6 (18 mg, 0.05 mmol) in CH2Cl2 (1 mL),
compounds 13a and 14a (14.4 mg, 84% yield) were obtained as a
colorless oil after the crude residue was purified by column
chromatography over silica gel (5−20% EtOAc in hexanes). The
20
1
1
results are summarized in Table S1. H NMR (mixture, 400 MHz,
CDCl3): δ 6.64 (s, 3.2H), 6.61 (s, 2H), 6.00−5.74 (m, 2.6H), 5.18−
5.04 (m, 5.2H), 4.93 (d, J = 3.3 Hz, 1H), 4.73 (d, J = 4.1 Hz, 1.6H),
4.58−4.44 (m, 1H), 4.41−4.25 (m, 5.3H), 4.18−4.01 (m, 4.8H), 3.85
(s, 15.2H), 3.81 (s, 4.6H), 3.81 (s, 3H), 3.07 (s, 4.8H), 3.04 (s, 3H),
2.70−2.57 (m, 1.7H), 2.52−2.29 (m, 5.8H), 2.19 (ddd, 1H), 1.91
(ddd, J = 13.2 Hz, 1H), 1.85 (ddd, J = 11.4, 6.0 Hz, 1.7H). 13C{1H}
NMR (mixture, 100 MHz, CDCl3): δ 152.8, 134.8, 134.1, 133.6,
133.1, 117.4, 116.9, 104.2, 104.0, 95.0, 84.30, 83.7, 78.7, 77.8, 77.6,
77.1, 60.8, 56.0, 55.1, 40.4, 40.2, 38.8, 38.3. LRMS (ESI) m/z: 361.2
[M + Na]+. HRMS (ESI-Orbitrap) m/z: [M + Na]+ calcd for
C18H26O6Na, 361.1622; found, 361.1624.
Preparation of (((2R,3R,5S)-5-Allyl-2-(3,4,5-trimethoxyphenyl)-
tetrahydrofuran-3-yl)oxy)(tert-butyl)dimethylsilane (13b). Follow-
ing the general procedure described above and starting from acetate
11 (21.7 mg, 0.05 mmol) in CH2Cl2 (1 mL), the title compound 13b
(16.8 mg, 81% yield) was prepared as a colorless oil after the crude
residue was purified by column chromatography over silica gel (5−
20% EtOAc in hexanes). The results are summarized in Table S1.
[α]D20 − 62.0 (c 0.79, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.59
(s, 2H), 5.99−5.85 (m, 1H), 5.18−5.04 (m, 2H), 4.73 (d, J = 3.7 Hz,
1H), 4.30 (td, J = 3.7, 1.8 Hz, 1H), 4.22−4.13 (m, 1H), 3.84 (s, 6H),
3.79 (s, 3H), 2.67 (dt, J = 13.6, 6.7 Hz, 1H), 2.48 (dt, J = 13.8, 6.9 Hz,
1H), 2.35 (ddd, J = 13.6, 8.5, 5.4 Hz, 1H), 1.80 (ddd, J = 13.2, 4.4, 1.7
Hz, 1H), 0.68 (s, 9H), −0.13 (s, 3H), −0.37 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 152.6, 135.3, 133.9, 116.6, 104.6, 85.9, 77.4,
74.6, 60.7, 55.9, 41.0, 40.6, 25.5, 17.7, −5.3, −5.6. LRMS (ESI), 431.2
[M + Na]+. HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C22H37O5Si, 409.2405; found, 409.2401.
(4R,5R)-4-((2-Methoxyethoxy)methoxy)-5-(3,4,5-
trimethoxyphenyl)tetrahydrofuran-2-yl Acetate (12). To a
stirred solution of lactone 7 (125 mg, 0.47 mmol) in distilled THF
(2 mL) at 0 °C under argon atmosphere were consecutively added
DIPEA (0.81 mL, 4.7 mmol), TBAI (43 mg, 0.12 mmol), and MEM-
Cl (0.27 mL, 2.33 mmol). The resulting reaction mixture was stirred
at 55 °C for 72 h. Upon completion, the mixture was diluted with
EtOAc and washed with water. The organic phase was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel (80%
EtOAc in hexanes) to give MEM-protected lactone (131 mg, 79%) as
20
1
Preparation of (((2R,3R,5S)-5-Allyl-2-(3,4,5-trimethoxyphenyl)-
tetrahydrofuran-3-yl)oxy)(tert-butyl)dimethylsilane (13c). Follow-
ing the general procedure described above and starting from acetate
12 (20 mg, 0.05 mmol) in CH2Cl2 (1 mL), the title compound 13c
(6.3 mg, 33% yield) was prepared as a colorless oil after the crude
a yellow amorphous solid. [α]D − 25.5 (c 0.29, CHCl3). H NMR
(400 MHz, CDCl3): δ 6.57 (s, 2H), 5.43 (d, J = 3.8 Hz, 1H), 4.62
(ddd, J = 5.0, 3.8, 1.0 Hz, 1H), 4.42 (d, J = 7.3 Hz, 1H), 4.23 (d, J =
7.3 Hz, 1H), 3.85 (s, 6H), 3.83 (s, 3H), 3.45 (ddd, J = 10.6, 5.6, 3.3
Hz, 1H), 3.41−3.36 (m, 2H), 3.32 (s, 3H), 3.22 (ddd, J = 10.6, 5.3,
3.4 Hz, 1H), 2.87 (dd, J = 17.6, 5.2 Hz, 1H), 2.74 (dd, J = 17.5, 1.0
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 175.0, 153.2, 137.9,
129.3, 103.5, 93.9, 84.6, 74.0, 71.4, 67.0, 60.8, 58.9, 56.1, 37.4. LRMS
(ESI), 379.4 [M + Na]+.
residue was purified by column chromatography over silica gel (40%
20
EtOAc in hexanes). The results are summarized in Table S1. [α]D
−
1
85.0 (c 0.12, CHCl3). H NMR (800 MHz, CDCl3): δ 6.63 (s, 2H),
5.91−5.86 (m, 1H), 5.15 (dd, J = 35.1, 13.7 Hz, 2H), 4.96 (d, J = 3.2
Hz, 1H), 4.53 (dq, J = 12.2, 6.1 Hz, 1H), 4.49 (d, J = 7.2 Hz, 1H),
4.43 (t, J = 3.7 Hz, 1H), 4.28 (d, J = 7.2 Hz, 1H), 3.88 (s, 6H), 3.84
(s, 3H), 3.44 (ddd, J = 10.7, 6.2, 3.2 Hz, 1H), 3.41−3.36 (m, 2H),
3.35 (s, 3H), 3.19 (ddd, J = 10.7, 5.5, 3.2 Hz, 1H), 2.51 (dt, J = 13.2,
6.3 Hz, 1H), 2.41 (dt, J = 14.0, 6.9 Hz, 1H), 2.25 (dd, J = 13.3, 5.9
Hz, 1H), 1.93 (ddd, J = 13.6, 9.6, 4.5 Hz, 1H). 13C{1H} NMR (200
MHz, CDCl3): δ 152.9, 137.2, 134.2, 133.8, 117.5, 104.1, 94.0, 83.8,
78.7, 77.8, 71.6, 66.6, 60.9, 59.0, 56.1, 40.3, 38.8. LRMS (ESI), 405.1
[M + Na]+. HRMS (ESI-Orbitrap) m/z: [M + Na]+ calcd for
C20H30O7Na, 405.1884; found, 405.1882.
The title compound was prepared from above lactone (111 mg)
following the procedure described for the preparation of acetate 6.
The compound was purified by flash column chromatography (20%
EtOAc in hexane) to give acetate 12 (50 mg, 72% over two steps) as a
white amorphous solid. [α]D20 + 4.1 (c 0.69, CHCl3). 1H NMR (400
MHz, CDCl3): δ 6.58 (s, 2H), 6.55 (dd, J = 6.1, 3.3 Hz, 1H), 5.07 (d,
J = 3.8 Hz, 1H), 4.48 (ddd, J = 5.8, 3.8, 1.7 Hz, 1H), 4.37 (d, J = 7.2
Hz, 1H), 4.19 (d, J = 7.1 Hz, 1H), 3.81 (s, 6H), 3.78 (s, 3H), 3.41
(ddd, J = 10.4, 5.8, 3.3 Hz, 1H), 3.37−3.32 (m, 2H), 3.29 (s, 3H),
3.17 (ddd, J = 10.4, 5.2, 3.3 Hz, 1H), 2.50 (ddd, J = 14.7, 6.1, 1.8 Hz,
1H), 2.34 (ddd, J = 14.7, 6.0, 3.3 Hz, 1H), 2.03 (s, 3H).13C{1H}
NMR (100 MHz, CDCl3): δ 170.2, 152.8, 137.3, 131.1, 104.1, 97.4,
93.9, 83.7, 76.5, 71.4, 66.7, 60.8, 58.8, 56.0, 40.3, 21.2. LRMS (ESI),
423.2 [M + Na]+. HRMS (ESI-Orbitrap) m/z: [M + Na]+ calcd for
C19H28O9Na, 423.1626; found, 423.1623.
(2S,3aR,9bR)-2-Allyl-6,7,8-trimethoxy-3,3a,5,9b-tetrahydro-2H-
furo[3,2-c]isochromene (17). To a stirred solution of acetate 6 (13.2
mg, 0.037 mmol) in CH2Cl2 (2.4 mL) at −78 °C under argon
atmosphere were added allyltrimethylsilane (24 μL, 0.148 mmol) and
SnBr4 (26 mg, 0.059 mmol, 1.6 equiv). The reaction mixture was
stirred for 3 h at the same temperature, and the reaction progress was
monitored by TLC. When the starting material was completely
consumed, additional portion of SnBr4 (33 mg, 0.075 mmol, 2.0
equiv) was added at 0 °C, and the resulting mixture was warmed to 23
°C overnight. After this period, the reaction mixture was quenched by
the addition of saturated aqueous Na2HPO4 (0.4 mL) and extracted
General Procedure for the Allylation of Tetrahydrofuranyl
Acetate. A solution of tetrahydrofuranyl acetate in distilled CH2Cl2
at −78 °C under argon atmosphere was treated with allyltrimethylsi-
lane (4.0 equiv) and Lewis acid. The resulting reaction mixture was
stirred at −78 °C for 3 h. After this period, the reaction mixture was
treated with saturated aqueous Na2HPO4 (1 mL per mmol of
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The Journal of Organic Chemistry
Article
with dichloromethane (2×). The extracts were dried over Na2SO4,
filtered, and concentrated under reduced pressure. NMR analysis of
the unpurified crude product showed a pair of diastereomers in a 4:1
ratio (cis/trans diastereomers). The crude product was purified by
column chromatography over silica gel (10% EtOAc in hexanes) to
give 17 and 18 (5.9 mg, 52%) as a colorless oil. [α]D20 + 25.6 (c 0.67,
CHCl3). cis-Isomer 17 (major): 1H NMR (400 MHz, CDCl3): δ 6.79
(s, 1H), 5.96−5.64 (m, 1H), 5.21−4.97 (m, 2H), 4.90 (d, J = 15.1
Hz, 1H), 4.42 (d, J = 15.1 Hz, 1H), 4.30 (d, J = 3.3 Hz, 1H), 4.16
(ddd, J = 6.8, 3.3, 1.7 Hz, 1H), 4.02 (qd, J = 7.4, 5.8 Hz, 1H), 3.87 (s,
3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.65−2.44 (m, 2H), 2.43−2.29 (m,
1H), 1.81 (ddd, J = 14.0, 7.2, 1.7 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 152.9, 149.0, 141.7, 134.7, 126.5, 121.8, 117.1, 108.7, 78.1,
75.4, 63.3, 60.9, 60.7, 56.1, 40.3, 39.0. LRMS (ESI), 307.1 [M + H]+.
HRMS (ESI-Orbitrap) m/z: [M + Na]+ calcd for C17H22O5,
329.1359; found, 329.1357. trans-Isomer 18 (minor): 1H NMR
(400 MHz, CDCl3): δ 6.79 (s, 1H), 5.92−5.76 (m, 1H), 5.18−5.04
(m, 2H), 4.91 (d, J = 15.0 Hz, 1H), 4.61 (d, J = 3.0 Hz, 1H), 4.45−
4.32 (m, 2H), 4.26−4.18 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84 (s,
3H), 2.48 (dt, J = 12.6, 6.2 Hz, 1H), 2.34 (dt, J = 14.0, 7.0 Hz, 1H),
2.26 (dd, J = 13.5, 5.7 Hz, 1H), 1.94 (ddd, J = 13.6, 9.8, 4.8 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 152.8, 148.8, 141.4, 134.2,
reduced pressure. Purification by column chromatography over silica
gel (20% EtOAc in hexanes) gave (+)-monocerin (1) (4.9 mg, 41%
yield; 88% yield brsm) as a colorless oil with the recovered starting
24
material 20 (7.6 mg). [α]D20 + 57.8 (c 0.29, CHCl3); reported [α]D
+ 53.0 (c 0.85, MeOH).6 1H NMR (400 MHz, CDCl3): δ 11.28 (s,
1H), 6.59 (s, 1H), 5.05 (ddd, J = 6.3, 3.2, 1.2 Hz, 1H), 4.54 (d, J = 3.1
Hz, 1H), 4.12 (dq, J = 8.6, 6.3 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H),
2.59 (ddd, J = 14.6, 8.6, 6.2 Hz, 1H), 2.16 (ddd, J = 14.5, 5.9, 1.2 Hz,
1H), 1.74−1.65 (m, 1H), 1.62−1.52 (m, 1H), 1.49−1.29 (m, 2H),
0.91 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 167.9,
158.8, 156.4, 137.5, 131.3, 104.5, 102.2, 81.4, 78.9, 74.6, 60.9, 56.4,
39.2, 38.2, 19.3, 14.1. LRMS (ESI), 309.1 [M + H]+. HRMS (ESI-
Orbitrap) m/z: [M + H]+ calcd for C16H21O6, 309.1333; found,
309.1335.
(+)-Acetylmonocerin (2). Acetic anhydride (75 μL, 0.8 mmol) and
DMAP (catalytic amount) were added to a solution of (+)-monocerin
(1) (2.2 mg, 0.007 mmol) in 0.2 mL of distilled pyridine at 0 °C
under argon atmosphere, and the mixture was stirred at 23 °C for 5 h.
After removing the solvent under reduced pressure, the crude product
was purified by flash column chromatography on silica gel (33%
EtOAc in hexanes) to give (+)-acetylmonocerin (2) (2.4 mg, 96%
25
yield) as a white amorphous solid. [α]D + 3.6 (c 0.29, CHCl3);
24
reported [α]D − 3.0 (c 0.1, EtOH) for enantiomer of compound
127.2, 121.0, 117.3, 108.4, 77.6, 77.4, 74.5, 62.8, 60.7, 60.6, 56.0, 39.9,
2.19 1H NMR (800 MHz, CDCl3): δ 6.90 (s, 1H), 4.99 (m, 1H), 4.55
(d, J = 3.1 Hz, 1H), 4.14 (m, 1H), 3.97 (s, 3H), 3.85 (s, 3H), 2.53
(ddd, J = 14.5, 8.7, 5.9 Hz, 1H), 2.42 (s, 3H), 2.13 (dd, J = 14.3, 5.5
Hz, 1H), 1.71−1.64 (m, 1H), 1.58−1.54 (m, 1H), 1.44−1.39 (m,
1H), 1.35−1.32 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H). 13C{1H} NMR
(200 MHz, CDCl3): δ 169.3, 159.9, 158.0, 146.1, 143.3, 132.7, 110.4,
109.9, 79.9, 79.0, 74.6, 61.2, 56.3, 39.0, 38.2, 21.0, 19.1, 14.0. LRMS
(ESI), 373.1 [M + Na]+.
39.4. LRMS (ESI), 307.1 [M + H]+.
(2S,3aR,9bR)-6,7,8-Trimethoxy-2-propyl-3,3a,5,9b-tetrahydro-
2H-furo[3,2-c]isochromene (19). To a stirred of isochromene 17
(47.4 mg, 0.156 mmol) in EtOAc (2 mL) at 23 °C was added 10%
Pd/C (10 mg). The resulting solution was stirred at 23 °C under a
hydrogen-filled balloon over 12 h. Upon completion, the mixture was
filtered through a plug of Celite, and solvents were removed under
reduced pressure. The crude product was purified by silica gel column
chromatography (20% EtOAc in hexane) to give propyl derivative 19
20
26
(42.2 mg, 88%). [α]D + 15.3 (c 0.40, CHCl3); reported [α]D
+
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00414.
■
16.5 (c 1.02, CHCl3).17 1H NMR (400 MHz, CDCl3): δ 6.80 (s, 1H),
4.89 (d, J = 15.0 Hz, 1H), 4.41 (d, J = 15.1 Hz, 1H), 4.26 (d, J = 3.3
Hz, 1H), 4.20−4.09 (m, 1H), 3.93 (q, J = 7.1 Hz, 1H), 3.87 (s, 3H),
3.86 (s, 3H), 3.84 (s, 3H), 2.52 (dt, J = 14.3, 7.3 Hz, 1H), 1.80−1.69
(m, 2H), 1.61−1.52 (m, 1H),1.47−1.36 (m, 2H), 0.92 (t, J = 7.3 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 152.8, 148.9, 141.6, 126.6,
121.8, 108.7, 78.6, 77.4, 75.2, 63.3, 60.9, 60.7, 56.1, 39.6, 38.1, 19.6,
14.1. LRMS (ESI), 309.1 [M + H]+.
S
Full spectroscopic data for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: akghosh@purdue.edu.
■
(2S,3aR,9bR)-6,7,8-Trimethoxy-2-propyl-2,3,3a,9b-tetrahydro-
5H-furo[3,2-c]isochromen-5-one (20). To a solution of propyl
derivative 19 (41.2 mg, 0.135 mmol) in CH2Cl2 (4 mL), pyridine
(54 μL, 0.67 mmol), and CrO3 (40 mg, 0.40 mmol) were added and
stirred for 36 h at 23 °C. After this period, the reaction mixture was
concentrated under reduced pressure, and ethyl acetate (10 ml) was
added and filtered. The filtrate was washed with aqueous CuSO4
solution followed by water. The organic phase was dried over Na2SO4,
filtered, and concentrated under reduced pressure. Flash chromatog-
raphy over silica gel (30% EtOAc in hexanes) provided δ-
valerolactone 20 (17.2 mg, 40%; 60% brsm) as a pale yellow oil
ORCID
Arun K. Ghosh: 0000-0003-2472-1841
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support of this work was provided by the National
Institutes of Health (GM122279) and Purdue University.
■
20
with the recovered starting material 19 (13.7 mg). [α]D + 20.4 (c
0.31, CHCl3); reported [α]D + 21.5 (c 0.50, CHCl3).18 1H NMR
26
(400 MHz, CDCl3): δ 6.78 (s, 1H), 4.94 (ddd, J = 5.8, 2.9, 1.0 Hz,
1H), 4.51 (d, J = 2.9 Hz, 1H), 4.25−4.06 (m, 1H), 3.97 (s, 3H), 3.94
(s, 3H), 3.88 (s, 3H), 2.51 (ddd, J = 14.4, 8.8, 5.8 Hz, 1H), 2.16 (ddd,
J = 14.3, 5.5, 1.1 Hz, 1H), 1.76−1.69 (m, 1H), 1.66−1.58 (m, 1H),
1.45−1.31 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 159.8, 157.9, 156.4, 144.2, 132.5, 111.2, 108.0, 79.4,
78.9, 75.0, 61.7, 61.0, 56.1, 39.0, 38.0, 19.1, 13.9. LRMS (ESI), 323.0
[M + H]+. HRMS (ESI-Orbitrap) m/z: [M + Na]+ calcd for
C17H22O6Na, 345.1309; found, 345.1306.
(+)-Monocerin (1). To a solution of δ-valerolactone 20 (13.4 mg,
0.042 mmol) in dry CH2Cl2 (1 mL) at −10 °C under argon
atmosphere was added BCl3 (1.0 M in DCM, 50 μL, 0.11 mmol). The
mixture was stirred at −10 °C for 2 h, and the reaction was quenched
by the addition of saturated aqueous NaHCO3 (1 mL). The mixture
was extracted with ethyl acetate, and the organic layer was washed
with brine, dried over Na2SO4, filtered, and concentrated under
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