Formation of an endoperoxide upon chromium-catalyzed allylic oxidation of a triterpene by oxygen

Article abstract of DOI:10.1021/jo502344x

The chromium-catalyzed allylic oxidation of triterpene 1 with O₂ and N-hydroxyphthalimide (NHPI, 5 equiv) formed endoperoxide 2 in 76% yield at ambient temperature. Unlike standard allylic oxidations, this oxidation is catalytic in chromium bec

Full text of DOI:10.1021/jo502344x

Article
pubs.acs.org/joc
Formation of an Endoperoxide upon Chromium-Catalyzed Allylic
Oxidation of a Triterpene by Oxygen
Abbie Chung, Matthew R. Miner, Kathleen J. Richert, Curtis J. Rieder, and K. A. Woerpel*
Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003 United States
S
* Supporting Information
ABSTRACT: The chromium-catalyzed allylic oxidation of
triterpene 1 with O2 and N-hydroxyphthalimide (NHPI, 5
equiv) formed endoperoxide 2 in 76% yield at ambient
temperature. Unlike standard allylic oxidations, this oxidation
is catalytic in chromium because oxygen, not the chromium
reagent, is the oxidant. This oxidation is sensitive to the precise
structure of the substrate. The endoperoxide is only formed if
ring A is unsaturated and ring C contains an enone. A
mechanism is proposed that involves the coupling of two
stabilized radicals on rings A and C to form endoperoxide 2.
performed under an inert atmosphere in a glovebox using
degassed solvents to exclude oxygen. These conditions formed
isomeric allylic oxidation products, enones 3 and 4,
accompanied by small amounts of the endoperoxide 2 (Scheme
2). The identities of the enone 4 and peroxide 2 were
INTRODUCTION
■
Allylic oxidation is an important method for the functionaliza-
tion of alkenes. Although generally used to convert alkenes to
allylic alcohols and enones,1,2 allylic oxidation reactions have
been developed to prepare allylic hydroperoxides,3,4 including
enantioenriched substrates.5,6 Recently, an allylic oxidation that
formed two new C−O bonds was reported for the triterpene 1
and structural relatives (Scheme 1).7,8 The formation of
Scheme 2. Formation of Dienediones without Oxygen
Scheme 1. Allylic Oxidation To Form Endoperoxide
established by X-ray crystallography, and the structure of enone
3 was assigned by spectroscopic methods.10 The regioisomeric
enones 3 and 4 are the products expected from allylic oxidation
reactions1,2 and are similar to those observed upon oxidation of
triterpenes related to 1.11−13 Because O2 appeared to be
required to form endoperoxide 2, the oxidation was repeated
under an atmosphere of O2 supplied by a balloon. Under these
conditions, endoperoxide 2 was formed from triterpene 1 in
55% yield after only 6 h at 40 °C (compared to 72 h, Scheme
1). These results indicate that O2 from the atmosphere, not the
chromium oxide source, must be the terminal oxidant for the
formation of peroxide 2.14,15
endoperoxides such as 2, which are of interest because of
their potent antitumor activity,7,8 requires stereoselective
oxidation of both C-1 and C-9. Although few examples have
been reported, the value of this biologically active compound
justifies an improved synthetic method. We report experiments
that suggest the reaction involves generation and coupling of
two stabilized radicals, an alkylperoxyl radical and an α-acyl
radical. We also demonstrate that the formation of endoper-
oxide 2 requires O2 as the terminal oxidant, and because
chromium reagents serve only to generate radicals from an N-
hydroxylamine,9 chromium reagents can be used catalytically.
Because the oxidant was found to be O2, an attractive oxidant
for the functionalization of organic compounds,9 conditions
were developed to improve the efficiency of the peroxidation
reaction (Table 1). The radical precursor NHS was replaced
RESULTS AND DISCUSSION
■
Initial experiments revealed that O2 was the source of the two
new oxygen atoms of the endoperoxide 2. The oxidation with
sodium dichromate and N-hydroxysuccinimide (NHS) was
Received: October 13, 2014
© XXXX American Chemical Society
A
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triterpene; those functional groups must be properly
positioned. The δ,ε-unsaturated ketone 6 (Figure 1), which
possesses the key functional groups at the appropriate distance
but different orientation in space, did not undergo oxidation
under either stoichiometric or catalytic conditions.
Table 1. Optimization of Oxidation Conditions
The enone functional group in ring C is also necessary for
the formation of the endoperoxide. Oxidation of the acetylated
triterpenes 7α and 7β, formed by reduction and acetylation of
triterpene 1,10 resulted in the endoperoxide 8 in 1% yield along
with unidentified NHPI-containing compounds (Scheme 3).23
entry
catalyst
NHPI (equiv)
time (h)
yield (%)
a
1
2
3
4
5
6
7
8
Na2Cr2O7·2H2O
10
5
15
76
73
73
0
Scheme 3. Oxidation of Protected Triterpene
a
Na2Cr2O7·2H2O
Na2Cr2O7·2H2O
Na2Cr2O7·2H2O
15
a
c
10
3
8
a
15
15
35
42
b
CrO3
5
73
68
51
15
a
CrO3
10
10
10
a
PCC
b
c
MnO2
48
a
b
c
Catalyst loading: 20 mol %. Catalyst loading: 40 mol %. Reaction
temp: 40 °C.
with the more reactive reagent N-hydroxyphthalimide
(NHPI),16 which afforded endoperoxide 2 in only 15 h at
room temperature (compared to 24 h for NHS) and in higher
yields (76% compared to 42%). More than 3 equiv of NHPI
was necessary to conduct the reaction (entries 2 and 4, Table
1),17 likely due to the decomposition of NHPI to inert
phthalimide and phthalic anhydride under the reaction
conditions.18 Oxidation could be performed using only catalytic
amounts (20−40 mol %) of CrO3 and Na2Cr2O7, decreasing
the loading of toxic chromium1 (entries 1−6, Table 1). Some
metal complexes, such as pyridinium chlorochromate (PCC,
entry 7) and MnO2 (entry 8), provided the product, but the
reactions were less efficient. The use of other allylic oxidation
catalysts, such as Co(OAc)2·4H2O, Co(acac)2, Mn(OAc)2·
2H2O, and [Cu(MeCN)4]ClO4, led to little or no product.
Contrary to observations with other allylic oxidation con-
ditions,1 acetic acid was not needed for the peroxidation
reaction. A variety of solvents can be used, including acetone,
acetonitrile, nitromethane, ethyl acetate, and chloroform, but
the oxidation does not work in trifluorotoluene, trifluoroetha-
nol, dichloroethane, dimethyl sulfoxide, and benzene.
This reaction may involve activation of the carbon−hydrogen
bond at C-11, trapping with O2, and hydrolysis of the mixed
peroxyketal 9 to form a small amount of enone 10 (Scheme 4).
Subsequent peroxidation would occur as for triterpene 1.
Scheme 4. Oxidative Deacetylation
Reactions of a tertiary alcohol derived from triterpene 1
reinforce the conclusion that the enone moiety in the C ring is
necessary for oxidation (Scheme 5). The alkylated triterpene
Scheme 5. Oxidation of Alkylated Triterpene
The allylic oxidation appears to be specific to the triterpene 1
and its close structural relatives.7,8 The triterpene 5 (Figure 1),
Figure 1. Substrates of unsuccessful attempted oxidations.
11, formed by addition of MeMgBr to enone 1, gave several
products upon exposure to the optimized conditions using
catalytic chromium reagents, none of which were peroxides
(Scheme 5). Triene 12 was formed by elimination of the
tertiary hydroxyl group of triterpene 11 by the acidic chromium
which lacks the carbon−carbon double bond in the A ring, was
recovered unchanged upon attempted oxidation. This result
indicates that activation of a carbon−hydrogen bond at C-1, the
less sterically hindered carbon, must occur to give a stabilized
radical,19 which is presumably trapped by O2 at a diffusion-
limited rate.20−22 It is also not sufficient for a compound to
contain both the ketone and alkene functional groups of the
reagent.24,25 The structure of triene 12 was assigned by H
1
NMR spectroscopy and mass spectrometry, but the isolated
sample was unstable to air, forming dienone 1 upon handling.
The dienone 1 was also formed (9% yield) in the course of
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oxidation of allylic alcohol 11, presumably by conversion of the
triene 12 to a dioxetane and subsequent cleavage.26 When the
oxidation was repeated with stoichiometric quantities of the
chromium complex (3 equiv), the dienone 1 formed in situ was
further oxidized to form endoperoxide 2 (17% yield). Two
other products, aldehydes 13 and 14, were formed in small
quantities during the attempt to oxidize allylic alcohol 11 under
catalytic conditions (Scheme 5). The identity of the aldehyde
13 was established by X-ray crystallography, and the structure
of its oxidized analogue, 14, was determined by spectroscopic
methods.10 The aldehyde 13 could be formed by chromium-
mediated oxidation of triene 12 (Scheme 6),27−30 a reaction
that would proceed via epoxide 15.27 The more oxidized
aldehyde, 14, may result from allylic oxidation of aldehyde 13
or hydroxylation of its enol form.31
to the cyclic peroxide, it was converted to the enone by metal-
promoted decomposition of the allylic hydroperoxide.33,34
The experiments described here give insight into the
mechanism of the formation of the cyclic peroxide 2 illustrated
in Scheme 1 and Table 1. It is expected that a chromium-
coordinated peroxide abstracts the hydrogen atom of NHPI to
generate PINO.35,36 PINO then removes the allylic hydrogen
atom at C-1 of 1 (Scheme 9). Following activation of the
Scheme 9. Allylic Oxidation Mechanism
Scheme 6. Mechanism of Formation of Aldehydes 13 and 14
carbon−hydrogen bond, an allylic peroxyl group is formed at
C-1 of 20 by trapping with O2.20−22,37 The axial orientation of
the peroxyl group likely results from attack of O2 to the allylic
radical from an orientation that maximizes orbital overlap in the
transition state.38 This peroxyl radical is persistent39−41 and
could perform radical translocation by a 1,5-hydrogen atom
abstraction42,43 at C-9 to form the stabilized radical 22 (Scheme
9). PINO could regenerate the persistent peroxyl radical group
of 23, which could then couple to the radical on C-9.44−48 The
coupling of persistent radicals has been suggested39,49 as the
key step in related intermolecular coupling reactions of ketones
with hydroperoxides, a preparatively useful transformation44,50
first reported by Kharasch.2 Mechanistically related couplings of
persistent peroxyl radicals and benzylic radicals have been
reported.40 An alternative mechanism has been suggested
involving the addition of peroxyl radical 21 to the enol
tautomer of the ring C carbonyl group.51 The enol form,
however, is strongly disfavored in both aromatic and non-
aromatic ketones,52 and the cyclization is likely to be
considerably slower than related reactions with carbon
radicals.53
Not only must the carbonyl group be present on the C ring
to form endoperoxide 2 but it must also be an unsaturated
carbonyl group. To saturate the C ring, Birch reduction was
performed on a silyl-protected glycyrrhetinic acid10,32 to give
ketone 16, followed by esterification, and deprotection of the
alcohol to afford ketone 17 (Scheme 7). Oxidation of the
Scheme 7. Saturation of Ring C
saturated ketone 18, formed by elimination of 17 under
Mitsunobu conditions, gave enone 19 as a single regioisomer
(Scheme 8). The regioselective introduction of the oxygen
The preference for oxidation of the unsaturated ketone 1
(Scheme 1) over the saturated ketone 18 (Scheme 8) may
reflect the orientation of the α-hydrogen atom at C-9 (Figure
2). Computational studies (HF/6-31G*) indicate that the two
Scheme 8. Oxidation of Saturated Ring C
Figure 2. Dihedral angle of interest.
types of ketones have subtly different structures in the region
undergoing oxidation. In both the saturated and unsaturated
ketones, the pentacyclic ring systems have few possible
conformations available to them.10 Saturation of the C ring
of 18 alters the orientation of this ring compared to the
unsaturated system (1). The calculated dihedral angle ∠H9−
C9−C11−O11 (Figure 2) of the saturated ketone 18 is much
larger (116°) than that for the unsaturated ketone 1 (100°).
atom at C-1 is consistent with the allylic oxidation reaction in
the presence of O2 but not the reaction in the absence of O2
(Scheme 2). This result suggests that the allylic radical formed
by activation of the carbon−hydrogen bond at C-1 occurred
first, and that this allylic radical was trapped by O2 to form an
allylic hydroperoxide. Because this intermediate cannot proceed
C
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in hexanes. Crystallographic data are included in Supporting
Information.
The smaller dihedral angle for the unsaturated ketone is closer
to the angle calculated (105°) for the transition state for
removal of an allylic hydrogen atom by the hydroxyl radical.54
Consequently, it may be easier to remove the hydrogen atom
from the unsaturated ketone 1, thus increasing the likelihood
that the radical 22 (Scheme 9) would be formed.
Methyl 2,3-Dihydro-1α,9α-peroxo-11-oxoolean-12-en-30-oate 2
(Table 1, entry 5). Following the representative procedure for the
preparation of oxidized triterpenes, to 1 (0.047 g, 0.10 mmol) in
acetone (5 mL) were added N-hydroxyphthalimide (0.082 g, 0.50
mmol) and chromium(VI) oxide (0.002 g, 0.02 mmol) to afford 2 as a
white solid (0.036 g, 73%). The spectral data match the data reported
(vide supra).7
CONCLUSION
■
Methyl 1,11-Dioxoolean-2,12-dien-30-oate 3 and Methyl 3,11-
Dioxoolean-1,12-dien-30-oate 4. Modifying a reported procedure,7
each of the components of the reaction were carefully dried and
degassed to remove H2O and oxygen before performing the oxidation
reaction in a glovebox. For drying acetic acid, AcOH (10 mL) was
treated with Ac2O (20 μL), followed by the addition of chromium(VI)
oxide (0.200 g, 2.00 mmol). After being heated (100 °C) for 1 h, the
AcOH was fractionally distilled, freeze−pump−thawed (3× at 50
mTorr) in a Schlenk bomb, and transferred into a glovebox under
vacuum. For drying acetone, acetone (40 mL) was dried overnight
over 4 Å molecular sieves, filtered, distilled (short path), freeze−
pump−thawed (3× at 50 mTorr) in a Schlenk bomb, and transferred
into a glovebox under vacuum. Enone 1, sodium dichromate dihydrate,
and N-hydroxysuccinimide were dried in Schlenk flasks under vacuum
(50 mTorr) for 24 h, flushed with argon (3×), and transferred into a
glovebox under vacuum. Enone 1 (0.192 g, 0.411 mmol), sodium
dichromate dihydrate (0.424 g, 1.42 mmol), and N-hydroxysuccini-
mide (0.521 g, 4.53 mmol) in acetone (20 mL) and AcOH (4.0 mL)
were stirred in the glovebox at ambient temperature for 4 days. After
the the reaction mixture was removed from the glovebox under argon,
saturated aqueous NaHSO3 (10 mL) was added. The reaction mixture
was opened to air and diluted with CH2Cl2 (40 mL) and saturated
aqueous NaHCO3 (10 mL). The phases were separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The combined
organic layers were washed with NaHCO3 (10 mL), dried over
MgSO4, and concentrated in vacuo. Purification by flash chromatog-
raphy (10:90 EtOAc/hexanes) afforded dienedione 3 as a white solid
(0.072 g, 36%), dienedione 4 as a white solid (0.029 g, 15%), and
endoperoxide 2 as a white solid (0.019 g, 9%). The spectral data of
endoperoxide 2 match the data reported (vide supra). 3: mp 205−207
°C; 1H NMR (400 MHz, CDCl3) δ 6.22 (d, J = 10.2, 1H), 5.78 (d, J =
10.2, 1H), 5.75 (s, 1H), 3.68 (s, 3H), 3.07 (s, 1H), 2.10−2.06 (m,
1H), 2.03−1.97 (m, 3H), 1.83 (td, J = 13.6, 4.5, 1H), 1.66−1.59 (m,
4H), 1.55 (s, 3H), 1.46−1.40 (m, 1H), 1.39 (s, 3H), 1.37−1.29 (m,
2H), 1.24−1.17 (m, 2H), 1.14 (s, 6H), 1.12 (s, 3H), 1.04 (s, 3H),
1.02−0.98 (m, 1H), 0.87−0.81 (m, 1H), 0.79 (s, 3H); 13C NMR (100
MHz, CDCl3, diagnostic peaks) δ 205.2 (C), 197.7 (C), 176.9 (C),
167.8 (C), 152.9 (CH), 128.5 (CH), 124.0 (CH), 51.8 (CH3), 51.6
(CH), 51.4 (CH), 48.7 (CH), 47.0 (C), 45.0 (C), 44.0 (C), 43.5 (C),
40.9 (CH2), 37.7 (CH2), 36.2 (C), 31.9 (CH2), 31.6 (CH2), 31.2
(CH3), 28.5 (CH3), 28.3 (CH3), 26.5 (CH2), 23.0 (CH3), 22.4 (CH3),
18.6 (CH3), 18.5 (CH2), 16.0 (CH3); IR 2926, 1724, 1683, 1458
cm−1; HRMS (TOF MS ES+) m/z calcd for C31H45O4 (M + H)+
In conclusion, we have demonstrated that the peroxidations of
triterpenes related to 1 require O2 to install the peroxide
functional group. These reactions can be conducted with only
catalytic quantities of chromium complexes, which significantly
simplifies the isolation and purification of the biologically active
products. The reaction is sensitive to the precise nature and
orientation of the functional groups present in this triterpene
because the mechanism appears to involve two stabilized
radicals that combine in the key ring-forming step.
EXPERIMENTAL SECTION
■
General Methods. 1H NMR spectra were recorded at 400, 500, or
600 MHz at ambient temperature, and 13C NMR spectra were
recorded at 100, 125, or 150 MHz at ambient temperature, as
indicated. 1H and 13C NMR spectroscopic data are reported as follows:
chemical shifts are reported in parts per million on the δ scale,
referenced to internal tetramethylsilane (δ 0.00) or residual solvent
(1H NMR: δ 7.26 for CDCl3; 13C NMR: δ 77.2 for CDCl3),55
multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, qu = quintet, m = multiplet), coupling constants (Hz), and
integration. For products that are difficult to purify, distinguishable
peaks are listed in 1H NMR and 13C NMR spectral data, as indicated.
Multiplicity of carbon peaks was determined using HSQC. Infrared
(IR) spectra were obtained by a FT-IR using attenuated total
reflectance. High-resolution mass spectra (HRMS) were acquired on
an accurate-mass time-of-flight spectrometer using peak matching.
Melting points were reported uncorrected. Analytical thin layer
chromatography was performed on silica gel 60 Å F254 plates. Liquid
chromatography was performed using forced flow (flash chromatog-
raphy) of the indicated solvent system on silica gel (SiO2) 60 (230−
400 mesh). Tetrahydrofuran, methylene chloride, diethyl ether, and
triethylamine were dried by filtration through alumina following the
method of Grubbs.56
Preparation of Substrates. Triterpene 17 was prepared according
to the previously reported procedures.
Representative Procedure for the Preparation of Oxidized
Triterpenes. Methyl 2,3-Dihydro-1α,9α-peroxo-11-oxoolean-12-
en-30-oate 2 (Table 1, entry 1). Modifying a reported procedure,7
to an oxygen-flushed solution of 1 (0.085 g, 0.18 mmol) in acetone (5
mL) were added N-hydroxyphthalimide (0.148 g, 0.905 mmol) and
sodium dichromate dihydrate (0.011 g, 0.036 mmol). The reaction
mixture was stirred under O2 (balloon) at ambient temperature for 15
h, filtered through silica gel with CHCl3 (20 mL), and concentrated in
vacuo. Purification by flash chromatography (10:90 EtOAc/hexanes)
afforded 2 as a white solid (0.070 g, 76%). The spectral data are
consistent with the data reported:7 1H NMR (500 MHz, CDCl3) δ
5.82 (d, J = 9.9, 1H), 5.80 (s, 1H), 5.51 (dd, J = 9.9, 5.2, 1H), 4.92 (dd,
J = 5.2, 1H), 3.69 (s, 3H), 2.13−1.97 (m, 6H), 1.79 (td, J = 13.4, 4.2,
1H), 1.69−1.63 (m, 2H), 1.52 (dd, J = 13.1, 2.9, 1H), 1.47 (dd, J =
12.7, 2.8, 1H), 1.43−1.40 (m, 1H), 1.38 (s, 3H), 1.35 (s, 3H), 1.32−
1.30 (m, 2H), 1.26 (s, 3H), 1.25−1.23 (m, 1H), 1.15 (s, 3H), 1.06 (s,
3H), 1.02−0.98 (m, 1H), 0.96 (s, 3H), 0.80 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 194.0 (C), 177.1 (C), 169.3 (C), 144.8 (CH), 126.5
(CH), 117.8 (CH), 90.7 (C), 80.5 (CH), 51.9 (CH3), 49.9 (CH), 46.8
(C), 44.5 (C), 44.2 (C), 43.1 (CH), 40.7 (CH2), 37.8 (CH2), 35.4
(C), 32.7 (C), 31.36 (CH3), 31.35 (CH2), 31.34 (C), 30.0 (CH2),
28.8 (CH3), 28.4 (CH3), 28.0 (CH2), 26.6 (CH2), 26.3 (CH3), 21.9
(CH3), 20.4 (CH3), 17.7 (CH2), 15.8 (CH3). Suitable crystals for X-
ray crystallography were obtained by slow evaporation of 10% EtOAc
1
481.3312, found 481.3324. 4: mp 175−177 °C; H NMR (400 MHz,
CDCl3) δ 7.73 (d, J = 10.1, 1H), 5.79 (d, J = 10.2, 1H), 5.76 (s, 1H),
3.69 (s, 3H), 2.67 (s, 1H), 2.14 (dd, J = 13.8, 3.7, 1H), 2.08−1.81 (m,
5H), 1.72−1.45 (m, 6H), 1.41 (s, 3H), 1.38 (s, 3H), 1.33−1.30 (m,
2H), 1.17 (s, 3H), 1.152 (s, 3H), 1.148 (s, 3H), 1.11 (s, 3H), 1.06−
0.99 (m, 1H), 0.87−0.85 (m, 1H), 0.83 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 204.5 (C), 199.0 (C), 176.9 (C), 170.7 (C), 161.5 (CH),
128.2 (CH), 124.6 (CH), 55.6 (CH), 52.8 (CH), 51.8 (CH3), 48.5
(CH), 45.6 (C), 44.8 (C), 44.0 (C), 43.5 (C), 41.1 (CH2), 38.8 (C),
37.7 (CH2), 32.1 (CH2), 31.9 (C), 31.1 (CH2), 28.6 (CH3), 28.3
(CH3), 27.6 (CH3), 26.5 (CH2), 26.3 (CH2), 23.4 (CH3), 21.6 (CH3),
20.1 (CH3), 18.9 (CH3), 18.2 (CH2); IR 2948, 1730, 1659, 1453
cm−1; HRMS (TOF MS ES+) m/z calcd for C31H45O4 (M + H)+
481.3312, found 481.3327. Suitable crystals for X-ray crystallography
were obtained by slow evaporation of EtOAc in hexanes. Crystallo-
graphic data are included in Supporting Information.
3β-(Acetyloxy)-11-oxo-18β-olean-12-en-30-oic Acid Methyl Ester
5. The precursor of 5, the methyl ester of glycyrrhetinic acid, was
D
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prepared according to a reported procedure,7 and the spectral data are
consistent with the data reported. To a solution of acetic anhydride
(0.05 mL, 0.5 mmol) and DMAP (0.0003 g, 0.002 mmol) in NEt3
(0.05 mL) was added a solution of methylated glycyrrhetinic acid
(0.051 g, 0.10 mmol) in CH2Cl2 (0.7 mL). After 20 h, C6H6 (5 mL)
and HCl (4 mL, 2 M in H2O) were added. The organic layer was
washed with saturated aqueous NaHCO3 (4 mL). The combined
aqueous layers were extracted with CH2Cl2 (2 × 5 mL). The
combined organic layers were dried over Na2SO4 and concentrated in
vacuo. Purification by flash chromatography (10:90 EtOAc/hexanes)
afforded 5 as a white solid (0.043 g, 80%). The spectral data are
consistent with the data reported:57 1H NMR (600 MHz, CDCl3) δ
5.56 (s, 1H), 4.50 (dd, J = 11.8, 4.7, 1H), 3.67 (s, 3H), 2.78 (dt, J =
13.7, 3.6, 1H), 2.34 (s, 1H), 2.08−1.89 (m, 4H), 2.03 (s, 3H), 1.80
(td, J = 13.8, 4.5, 1H), 1.72−1.56 (m, 6H), 1.47−1.37 (m, 4H), 1.34
(s, 3H), 1.30−1.29 (m, 2H), 1.14 (s, 3H), 1.13 (s, 3H), 1.11 (s, 3H),
1.06−0.98 (m, 2H), 0.863 (s, 3H), 0.860 (s, 3H), 0.79 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 200.2 (C), 177.0 (C), 171.1 (C), 169.3
(C), 128.6 (CH), 80.7 (CH), 61.8 (CH), 55.1 (C), 51.9 (CH3), 48.5
(CH3), 45.5 (C), 44.1 (C), 43.3 (CH2), 41.2 (CH2), 38.9 (CH), 38.1
(CH2), 37.8 (C), 37.0 (C), 32.8 (CH2), 31.9 (CH2), 31.2 (CH2), 28.6
(CH3), 28.4 (CH3), 28.2 (CH3), 26.6 (C), 26.5 (CH), 23.7 (CH2),
23.4 (CH2), 21.4 (CH2), 18.8 (CH3), 17.5 (CH3), 16.8 (CH3), 16.5
(CH3).
1-(4-Methoxyphenyl)hex-5-en-1-one 6. The alcohol precursor to
ketone 6 was synthesized according to a reported procedure,58 and the
spectral data are consistent with the data reported. To a solution of
this alcohol (0.19 g, 0.93 mmol) in CH2Cl2 (5 mL) was added Celite
(0.5 g) followed by PCC (0.30 g, 1.4 mmol). After 18 h, the reaction
mixture was filtered through Celite and concentrated in vacuo.
Purification by flash chromatography (10:90 EtOAc/hexanes) afforded
6 as a colorless oil (0.17 g, 90% yield). The spectral data are consistent
with the data reported:59 1H NMR (600 MHz, CDCl3) δ 7.93 (d, J =
8.9, 2H), 6.92 (d, J = 8.9, 2H), 5.82 (ddt, J = 16.9, 10.3, 6.7, 1H), 5.03
(dq, J = 17.1, 1.6, 1H), 4.99 (m, 1H), 3.86 (s, 3H), 2.92 (t, J = 7.3,
2H), 2.14 (m, 2H), 1.83 (qu, J = 7.3, 2H); 13C NMR (150 MHz,
CDCl3) δ 199.0 (C), 163.5 (C), 138.3 (CH), 130.4 (CH), 130.3 (C),
115.3 (CH2), 113.8 (CH), 55.6 (CH3), 37.5 (CH2), 33.4 (CH2), 23.7
(CH2).
11α,30-(Acetyloxy)-18β,20β-olean-2,12-dienol 7α and 11β,30-
(Acetyloxy)-18β,20β-olean-2,12-dienol 7β. To a cooled (0 °C)
solution of dienone 1 (0.501 g, 1.07 mmol) in THF (10 mL) was
added lithium aluminum hydride (0.124 g, 3.27 mmol). The reaction
mixture was warmed to ambient temperature for 15 h, and then H2O
(10 mL) was added. The reaction mixture was extracted with EtOAc
(3 × 15 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo. Purification by flash chromatography
(30:70 EtOAc/hexanes) afforded a mixture of alcohol diastereomers as
a white solid (0.473 g, quantitative, α/β = 88:12 ≈ 7:1). The
stereochemistry was determined by correlation of the alkene 1H NMR
shifts and J values to a similar allylic alcohol triterpene:60 mp 120−125
°C; 1H NMR (600 MHz, CDCl3) δ 5.48 (ddd, J = 10.1, 6.0, 1.9, 7H),
5.43 (ddd, J = 10.0, 6.1, 1.8, 1H), 5.39 (dd, J = 10.1, 2.2, 7H), 5.36 (d,
J = 2.4, 1H), 5.35 (d, J = 4.1, 7H), 5.25 (d, J = 3.4, 1H), 4.29−4.27 (m,
8H), 3.56 (d, J = 10.7, 8H), 3.49 (d, J = 10.7, 8H), 2.39 (dd, J = 17.3,
6.2, 1H), 2.31 (dd, J = 17.1, 6.0, 7H), 2.04−1.97 (m, 14H), 1.92−1.88
(m, 2H), 1.85−1.77 (m, 14H), 1.73−1.71 (m, 2H), 1.67−1.61 (m,
21H), 1.55−1.50 (m, 14H), 1.44 (s, 21H), 1.42−1.40 (m, 7H), 1.39
(s, 3H), 1.38−1.34 (m, 18H), 1.32−1.26 (m, 24H), 1.25 (s, 24H),
1.23−1.21 (m, 2H), 1.19−1.16 (m, 2H), 1.11 (s, 24H), 1.10−1.08 (m,
14H), 1.05 (s, 6H), 1.02−0.99 (m, 4H), 0.97 (s, 3H), 0.95 (s, 21H),
0.93 (s, 24H), 0.91 (s, 3H), 0.90 (s, 21H), 0.87 (s, 21H), 0.84 (s, 3H);
13C NMR (150 MHz, CDCl3, major diastereomer α) δ 147.8 (C),
To a solution of acetic anhydride (0.1 mL, 1.0 mmol) and DMAP
(0.0006 g, 0.005 mmol) in NEt3 (0.3 mL) was added a diastereomeric
mixture of this dienol (0.051 g, 0.10 mmol, α/β = 88:12). After 19 h,
C6H6 (5 mL) and HCl (4 mL, 2 M in H2O) were added. The aqueous
layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 (4 mL), dried
over Na2SO4, and concentrated in vacuo. Purification by flash
chromatography (10:90 EtOAc/hexanes) afforded a diastereomeric
mixture of 7 as a colorless oil (0.051 g, 80%, α/β = 75:25 ≈ 3:1).
Characterization was performed using the mixture of diastereomers,
but only the major diastereomer showed distinguishable peaks by 13C
NMR spectroscopy: 1H NMR (600 MHz, CDCl3) δ 5.51 (dd, J = 9.0,
2.5, 1H), 5.48−5.46 (m, 3H), 5.44−5.42 (m, 3H), 5.39−5.37 (m, 3H),
5.36−5.35 (m, 2H), 5.19−5.17 (m, 4H), 4.05 (d, J = 10.9, 1H), 4.00
(d, J = 10.9, 3H), 3.93 (d, J = 10.9, 3H), 3.89 (d, J = 10.7, 1H), 2.07 (s,
3H), 2.06 (s, 3H), 2.047 (s, 9H), 2.045 (s, 9H), 2.022−2.021 (m, 5H),
2.00−1.99 (m, 6H), 1.96−1.92 (m, 7H), 1.88−1.80 (m, 4H), 1.77−
1.75 (m, 6H), 1.70 (d, J = 5.5, 3H), 1.66−1.60 (m, 10H), 1.56−1.54
(m, 8H), 1.39−1.37 (m, 14H), 1.34−1.28 (m, 8H), 1.27−1.26 (m,
3H), 1.25 (s, 3H), 1.23 (s, 9H), 1.22 (s, 9H), 1.18−1.16 (m, 2H), 1.12
(s, 9H), 1.08 (s, 3H), 1.07 (s, 6H), 0.97 (s, 3H), 0.95 (s, 9H), 0.92 (s,
9H), 0.90 (s, 12H), 0.87 (s, 9H), 0.83 (s, 3H); 13C NMR (150 MHz,
CDCl3, major diastereomer α) δ 171.6 (C), 170.7 (C), 149.5 (C),
137.8 (CH), 122.1 (CH), 121.0 (CH), 68.7 (CH), 68.0 (CH2), 52.9
(CH2), 50.3 (CH), 46.4 (CH), 42.4 (C), 42.0 (CH2), 40.2 (CH2),
39.7 (C), 37.1 (CH3), 36.5 (CH2), 34.4 (C), 34.3 (C), 32.3 (CH3),
32.2 (CH2), 30.3 (CH3), 28.4 (CH3), 28.0 (C), 27.1 (CH2), 27.0
(CH), 26.4 (CH2), 25.4 (CH3), 23.2 (C), 22.1 (CH3), 21.1 (CH3),
19.9 (CH2), 18.5 (CH3), 17.8 (CH3); IR 2953, 2867, 1731, 1465, 1386
cm−1; HRMS (TOF MS ES+) m/z calcd for C32H49O2 (M − OAc)+
465.3727, found 465.3741.
2,3-Dihydro-1α,9α-peroxo-11-oxoolean-12-en-30-(acetyloxy)ol
8. Following the representative procedure for the preparation of
oxidized triterpenes, to 7 (0.029 g, 0.056 mmol, α/β = 75:25 ≈ 3:1) in
acetone (0.6 mL) were added N-hydroxyphthalimide (0.062 g, 0.38
mmol) and chromium(VI) oxide (0.021 g, 0.21 mmol) at 40 °C under
1
O2 to afford 8 as a white solid (0.0004 g, 1%): mp 137−140 °C; H
NMR (600 MHz, CDCl3) δ 5.83 (d, J = 9.8, 1H), 5.72 (s, 1H), 5.52
(dd, J = 9.8, 5.2, 1H), 4.92 (d, J = 5.3, 1H), 4.07 (d, J = 11.0, 1H), 3.90
(d, J = 10.9, 1H), 2.15−2.09 (m, 2H), 2.08 (s, 3H), 2.02−1.98 (m,
2H), 1.82−1.78 (m, 1H), 1.71−1.66 (m, 2H), 1.50−1.49 (m, 1H),
1.48−1.45 (m, 1H), 1.44−1.41 (m, 1H), 1.40 (s, 3H), 1.36 (s, 3H),
1.34−1.30 (m, 2H), 1.27 (s, 3H), 1.26−1.24 (m, 2H), 1.23−1.21 (m,
1H), 1.15−1.13 (m, 1H), 1.07 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.86
(s, 3H); 13C NMR (100 MHz, CDCl3, diagnostic peaks) δ 193.7 (C),
171.4 (C), 169.4 (C), 144.7 (CH), 126.3 (CH), 117.6 (CH), 90.6
(C), 80.4 (CH), 67.5 (CH2), 55.3 (CH), 48.3 (CH2), 46.7 (C), 44.5
(C), 43.0 (CH), 39.5 (CH2), 35.9 (CH2), 35.3 (C), 34.1 (CH2), 33.0
(C), 31.2 (CH3), 30.3 (C), 29.8 (CH2), 28.6 (CH3), 27.8 (CH3), 26.5
(CH2), 26.4 (CH3), 21.8 (CH3), 20.9 (CH3), 20.3 (CH3), 17.6 (CH2),
15.6 (CH3); IR 2928, 1738, 1669, 1462 cm−1; HRMS (TOF MS ES+)
m/z calcd for C32H47O5 (M + H)+ 511.3418, found 511.3421.
11β-Hydroxy-11α-methyl-18β-olean-2,12-dien-30-oic Acid Meth-
yl Ester 11. To a cooled (0 °C) solution of dienone 1 (0.080 g, 0.17
mmol) in THF (0.7 mL) was added MeMgBr (0.3 mL, 3 M in THF,
0.9 mmol). The reaction mixture was warmed to ambient temperature
for 12 h, and then H2O (5 mL) was added. The reaction mixture was
extracted with Et2O (3 × 10 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. Purification by flash
chromatography (10:90 EtOAc/hexanes) afforded 11 as a white solid
(0.044 g, 57%). The stereochemistry was determined by correlation to
a similar alkylated triterpene61 and correlation to the X-ray structure of
13 in Supporting Information: mp 120−124 °C; 1H NMR (600 MHz,
CDCl3) δ 5.47−5.45 (m, 1H), 5.37 (d, J = 10.1, 1H), 5.08 (s, 1H),
3.69 (s, 3H), 2.45 (dd, J = 16.1, 6.2, 1H), 2.06 (d, J = 16.1, 1H), 1.96−
1.92 (m, 3H), 1.84−1.81 (m, 1H), 1.70 (td, J = 13.9, 4.5, 1H), 1.63 (s,
1H), 1.55−1.47 (m, 4H), 1.44 (s, 3H), 1.41 (s, 3H), 1.37−1.26 (m,
4H), 1.22−1.21 (m, 1H), 1.19 (s, 3H), 1.16−1.14 (m, 1H), 1.12 (s,
3H), 1.06 (s, 3H), 1.04−1.02 (m, 1H), 0.95 (s, 3H), 0.92 (s, 3H),
0.90−0.85 (m, 1H), 0.82 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
137.8 (CH), 126.4 (CH), 121.3 (CH), 67.0 (CH), 66.8 (CH2), 52.8
(CH2), 51.4 (CH2), 46.7 (CH2), 42.8 (C), 42.1 (CH2), 40.4 (CH),
39.8 (C), 37.7 (C), 36.5 (CH2), 35.7 (C), 34.4 (C), 33.1 (CH2), 32.5
(CH3), 32.2 (C), 29.7 (CH), 28.5 (CH3), 27.5 (CH3), 27.4 (CH3),
26.5 (CH), 25.2 (CH3), 23.2 (CH2), 19.9 (CH2), 19.5 (CH3), 18.3
(CH3); IR 3369, 2950, 2865, 1455, 1382 cm−1; HRMS (TOF MS ES
+) m/z calcd for C30H47O (M − OH)+ 423.3621, found 423.3634.
E
dx.doi.org/10.1021/jo502344x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
177.7 (C), 143.5 (C), 137.3 (CH), 134.7 (CH), 121.6 (CH), 73.3
(C), 55.9 (CH), 53.3 (CH3), 51.8 (CH3), 47.0 (CH), 44.4 (C), 43.13
(CH), 43.10 (CH2), 41.8 (C), 41.7 (C), 40.3 (C), 38.5 (CH2), 34.6
(CH2), 34.3 (C), 32.4 (CH3), 32.3 (CH2), 31.6 (CH2), 31.4 (CH2),
28.61 (CH3), 28.58 (CH3), 27.2 (CH2), 27.0 (C), 24.1 (CH3), 23.5
(CH3), 20.3 (CH2), 18.8 (CH3), 18.3 (CH3); IR 3531, 2949, 1720,
1457, 1383 cm−1; HRMS (TOF MS ES+) m/z calcd for C32H50NaO3
(M + Na)+ 505.3652, found 505.3642.
(800 mL), which was dried over lithium (6 g) at −78 °C, was added a
solution of the silyl-protected glycyrrhetinic acid (5.30 g, 9.76 mmol)
in THF (150 mL) dropwise by addition funnel over 1 h under argon.
After 1 h, to the cold (−78 °C) reaction mixture was added acetone
(100 mL) dropwise by addition funnel over 45 min. The cooling bath
was removed from the reaction mixture, and when the blue color
vanished, ammonium chloride (33 g) was added portionwise over 15
min. After the ammonia was allowed to evaporate overnight, the
reaction mixture was dissolved in THF (500 mL) and concentrated in
vacuo. Purification by flash chromatography (20:80−50:50 EtOAc/
hexanes) afforded 16 as a white solid (0.296 g, 6%): mp 230 °C dec;
1H NMR (500 MHz, CDCl3) δ 3.15 (dd, J = 11.6, 4.2, 1H), 2.46−2.44
(m, 1H), 2.25−2.22 (m, 1H), 2.11 (s, 1H), 1.95−1.85 (m, 4H), 1.73−
1.64 (m, 2H), 1.59−1.51 (m, 2H), 1.48−1.39 (m, 4H), 1.36−1.24 (m,
6H), 1.22 (s, 3H), 1.18 (s, 3H), 1.17 (s, 3H), 1.11−1.06 (m, 1H), 0.98
(s, 3H), 0.93 (s, 3H), 0.87 (s, 3H), 0.83−0.79 (m, 1H), 0.75 (s, 3H),
0.54−0.52 (m, 1H), 0.09 (s, 9H); 13C NMR (150 MHz, CDCl3) δ
212.2 (C), 182.3 (C), 79.7 (CH), 64.6 (CH), 54.7 (CH), 46.3 (C),
45.4 (CH2), 44.0 (C), 43.0 (CH), 40.9 (C), 39.4 (C), 38.6 (CH2),
38.5 (CH2), 36.5 (C), 35.8 (CH), 33.5 (CH2), 32.9 (CH2), 32.0
(CH2), 31.2 (CH2), 29.1 (CH3), 28.6 (CH3), 27.9 (CH3), 27.6 (CH2),
27.1 (CH2), 26.5 (C), 18.8 (CH3), 18.4 (CH2), 17.4 (CH3), 16.3
(CH3), 16.1 (CH3), 0.63 (CH3); IR 2954, 2869, 1720, 1700, 1466,
1387 cm−1; HRMS (TOF MS ES+) m/z calcd for C33H57O4Si (M +
H)+ 545.4021, found 545.4023.
11-Methylene-18β-olean-2,12-dien-30-oic Acid Methyl Ester 12,
11α-Formyl-18β-olean-2,12-dien-30-oic Acid Methyl Ester 13, and
11α-Formyl-11β-hydroxy-18β-olean-2,12-dien-30-oic Acid Methyl
Ester 14. Following the representative procedure for the preparation of
oxidized triterpenes, to 11 (0.061 g, 0.13 mmol) in acetone (1 mL)
were added N-hydroxyphthalimide (0.160 g, 0.978 mmol) and
chromium(VI) oxide (0.005 g, 0.05 mmol) at 40 °C under O2.
Purification by flash chromatography (5:95−10:90 EtOAc/hexanes)
afforded triene 12 as a white solid (0.0106 g, 18%), dienone 1 as a
white solid (0.006 g, 9%), 13 as a white solid (0.004 g, 6%), and 14 as
a white solid (0.002 g, 3%). The spectral data of dienone 1 match the
data reported.7 12: H NMR (600 MHz, CDCl3) δ 5.72 (s, 1H),
1
5.42−5.41 (m, 2H), 5.08−5.06 (m, 2H), 3.70 (s, 3H), 2.72 (dd, J =
17.2, 4.7, 1H), 2.37 (s, 1H), 1.99−1.91 (m, 4H), 1.81−1.78 (m, 1H),
1.74 (td, J = 13.6, 4.2, 1H), 1.63−1.58 (m, 2H), 1.51−1.49 (m, 1H),
1.43−1.40 (m, 1H), 1.37−1.25 (m, 4H), 1.22 (s, 3H), 1.21 (s, 3H),
1.151−1.146 (m, 1H), 1.13 (s, 3H), 1.09−1.08 (m, 1H), 0.99 (s, 3H),
0.98 (s, 3H), 0.94 (s, 3H), 0.91−0.88 (m, 1H), 0.79 (s, 3H); IR 2952,
2925, 2854, 1733, 1593, 1463 cm−1; HRMS (TOF MS ES+) m/z calcd
for C32H49O2 (M + H)+ 465.3727, found 465.3719. This compound
was found to be air-sensitive, undergoing extensive decomposition
before a 13C NMR spectrum and melting point were acquired. 13: 1H
NMR (600 MHz, CDCl3) δ 9.26 (d, J = 4.9, 1H), 5.38 (dd, J = 10.2,
2.3, 1H), 5.34 (ddd, J = 10.0, 5.6, 1.5, 1H), 4.95 (d, J = 4.0, 1H), 3.67
(s, 3H), 3.15 (qu, J = 3.5, 1H), 2.07−2.05 (m, 1H), 2.02−1.99 (m,
1H), 1.98−1.93 (m, 1H), 1.80−1.76 (m, 2H), 1.68 (dd, J = 16.0, 5.9,
1H), 1.61−1.57 (m, 2H), 1.51−1.46 (m, 1H), 1.44−1.39 (m, 1H),
1.37−1.32 (m, 2H), 1.30−1.27 (m, 3H), 1.26−1.25 (m, 1H), 1.23 (s,
3H), 1.11 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.96−0.92
(m, 2H), 0.90 (s, 3H), 0.89−0.87 (m, 1H), 0.80 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 201.8 (CH), 177.6 (C), 153.7 (C), 138.2 (CH),
120.6 (CH), 116.9 (CH), 52.2 (CH), 52.1 (CH), 51.8 (CH3), 48.4
(CH), 47.4 (CH), 44.4 (C), 43.7 (CH2), 42.0 (CH2), 41.9 (C), 40.3
(C), 38.4 (CH2), 37.8 (C), 34.7 (C), 31.9 (CH3), 31.6 (CH2), 31.4
(CH2), 29.8 (CH2), 28.6 (CH3), 28.5 (CH3), 26.9 (C), 26.8 (CH3),
26.7 (CH2), 22.8 (CH3), 19.7 (CH2), 17.9 (CH3), 17.2 (CH3); IR
2951, 2866, 1720, 1458 cm−1; HRMS (TOF MS ES+) m/z calcd for
C32H49O3 (M + H)+ 481.3676, found 481.3677. Suitable crystals for X-
ray crystallography were obtained by slow evaporation of CHCl3.
Crystallographic data are included in Supporting Information. Not
3β-Hydroxy-11-oxo-18β-olean-30-oic Acid Methyl Ester 17.
Following a reported procedure for a related triterpene,62 to a cooled
(0 °C) solution of saturated ketone 16 (0.071 g, 0.13 mmol) in
toluene (0.93 mL) and MeOH (0.33 mL) was added trimethylsilyl
diazomethane (0.17 mL, 2.0 M in hexanes, 0.26 mmol). After 1.5 h,
aqueous AcOH (3 drops) was added, followed by EtOAc (35 mL).
The phases were separated, and the organic layer was washed with
saturated aqueous NaHCO3 (5 mL) and H2O (5 mL), dried over
Na2SO4, and concentrated in vacuo. Purification by flash chromatog-
raphy (5:95 EtOAc/hexanes) afforded the corresponding methyl ester
1
as a white solid (0.048 g, 66%): mp 235−237 °C; H NMR (600
MHz, CDCl3) δ 3.62 (s, 3H), 3.14 (dd, J = 11.6, 4.4, 1H), 2.48−2.39
(m, 2H), 2.23 (dt, J = 13.3, 3.5, 1H), 2.10 (s, 1H), 1.95−1.83 (m, 4H),
1.72−1.63 (m, 3H), 1.58−1.53 (m, 2H), 1.45−1.38 (m, 2H), 1.34−
1.25 (m, 5H), 1.17 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 1.08−1.05 (m,
1H), 0.97 (s, 3H), 0.92−0.91 (m, 1H), 0.89 (s, 3H), 0.86 (s, 3H),
0.80−0.77 (m, 1H), 0.74 (s, 3H), 0.52 (dd, J = 11.9, 1.7, 1H), 0.08 (s,
9H); 13C NMR (150 MHz, CDCl3) δ 212.2 (C), 177.4 (C), 79.7
(CH), 64.5 (CH), 54.7 (CH), 51.7 (CH3), 46.2 (C), 45.5 (CH2), 44.2
(C), 43.1 (CH), 40.9 (C), 39.4 (C), 38.6 (CH2), 38.4 (CH2), 36.5
(C), 35.8 (CH), 33.7 (CH2), 32.8 (CH2), 32.0 (CH2), 31.4 (CH2),
29.0 (CH3), 28.6 (CH3), 27.9 (CH3), 27.6 (CH2), 27.1 (CH2), 26.5
(C), 18.8 (CH3), 18.4 (CH2), 17.4 (CH3), 16.3 (CH3), 16.1 (CH3),
0.61 (CH3); IR 2961, 2868, 1729, 1697, 1465, 1366 cm−1; HRMS
(TOF MS ES+) m/z calcd for C34H59O4Si (M + H)+ 559.4177, found
559.4189.
1
enough material was available to determine a melting point. 14: H
NMR (600 MHz, CDCl3) δ 9.85 (d, J = 1.0, 1H), 5.38 (ddd, J = 10.1,
6.2, 1.9, 1H), 5.31 (dd, J = 10.2, 2.4, 1H), 4.65 (s, 1H), 3.79 (d, J = 1.0,
1H), 3.67 (s, 3H), 2.37 (s, 1H), 2.13−2.10 (m, 1H), 2.01−1.94 (m,
5H), 1.84−1.79 (m, 1H), 1.71−1.66 (m, 1H), 1.62−1.57 (m, 1H),
1.49−1.45 (m, 1H), 1.38 (s, 3H), 1.33 (s, 3H), 1.32−1.27 (m, 3H),
1.25 (s, 2H), 1.24−1.19 (m, 1H), 1.17−1.15 (m, 1H), 1.12 (s, 3H),
1.06 (s, 3H), 0.96 (s, 3H), 0.92−0.90 (m, 1H), 0.88 (s, 3H), 0.82 (s,
3H); 13C NMR (100 MHz, CDCl3, diagnostic peaks) δ 177.5 (C),
136.7 (CH), 122.1 (CH), 121.9 (CH), 81.4 (C), 58.2 (CH), 52.7
(CH), 51.8 (CH3), 47.7 (CH), 44.3 (C), 43.7 (C), 42.5 (CH2), 42.4
(CH2), 41.8 (CH2), 38.7 (C), 38.3 (CH2), 34.4 (C), 33.6 (CH2), 32.2
(CH3), 31.8 (CH2), 31.4 (CH2), 28.5 (CH3), 28.4 (CH3), 26.8 (C),
25.8 (CH3), 23.0 (CH3), 20.4 (CH3), 19.7 (CH2), 19.6 (CH3); IR
3484, 2929, 2869, 1730, 1462 cm−1; HRMS (TOF MS ES+) m/z calcd
for C32H48NaO4 (M + Na)+ 519.3445, found 519.3434. Not enough
material was available to determine a melting point.
To a solution of this methyl ester (0.044 g, 0.079 mmol) in THF
(1.5 mL) was added tetrabutylammonium fluoride (0.17 mL, 1.0 M in
THF, 0.12 mmol). After 23 h, brine (10 mL) was added. The reaction
mixture was extracted with EtOAc (3 × 25 mL). The combined
organic layers were dried over Na2SO4 and concentrated in vacuo.
Purification by flash chromatography (30:70 EtOAc/hexanes) afforded
1
17 as a white solid (0.035 g, 92%): mp 225−227 °C; H NMR (600
MHz, CDCl3) δ 4.30 (q, J = 7.1, 1H), 3.62 (s, 3H), 3.16 (dd, J = 11.6,
4.7, 1H), 2.46−2.39 (m, 2H), 2.27 (dt, J = 13.3, 3.5, 1H), 2.10 (s, 1H),
1.94−1.85 (m, 4H), 1.70−1.65 (m, 1H), 1.63−1.59 (m, 1H), 1.57−
1.54 (m, 2H), 1.46−1.38 (m, 2H), 1.33−1.24 (m, 6H), 1.17 (s, 3H),
1.16 (s, 3H), 1.13 (s, 3H), 1.08−1.05 (m, 1H), 0.97 (s, 3H), 0.96 (s,
3H), 0.92−0.91 (m, 1H), 0.89 (s, 3H), 0.84−0.80 (m, 1H), 0.77 (s,
3H), 0.54 (dd, J = 12.1, 1.8, 1H); 13C NMR (150 MHz, CDCl3) δ
212.1 (C), 177.4 (C), 79.0 (CH), 64.4 (CH), 54.6 (CH), 51.7 (CH3),
46.2 (C), 45.5 (CH2), 44.2 (C), 43.1 (CH), 40.9 (C), 39.0 (C), 38.6
(CH2), 38.4 (CH2), 36.5 (C), 35.8 (CH), 33.7 (CH2), 32.8 (CH2),
31.9 (CH2), 31.4 (CH2), 28.9 (CH3), 28.2 (CH3), 27.9 (CH3), 27.2
(CH2), 26.5 (C), 18.8 (CH3), 18.1 (CH2), 17.4 (CH3), 16.2 (CH3),
3β-Trimethylsiloxy-11-oxo-18β-olean-30-oic Acid 16. The silyl-
protected glycyrrhetinic acid precursor to ketone 16 was synthesized
according to a reported procedure,57 and the spectral data are
consistent with the data reported. Following a reported procedure,32
to a cooled (−78 °C) solution of lithium (3.5 g, 0.50 mol) in ammonia
F
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Article
15.6 (CH3), 14.2 (CH2); IR 3348, 2937, 2870, 1723, 1699, 1465 cm−1;
HRMS (TOF MS ES+) m/z calcd for C31H51O4 (M + H)+ 487.3782,
found 487.3788.
thank Dr. Chin Lin (NYU) for assistance with NMR
spectroscopy and mass spectrometry. We also thank the
Molecular Design Institute of NYU for purchasing a single-
crystal diffractometer, and Dr. Chunhua Hu (NYU) for his
assistance with data collection and structure determination.
11-Oxo-18β-olean-2-en-30-oic Acid Methyl Ester 18. Following a
reported procedure for the related unsaturated ketone 1 (vide supra),7
to a cooled (0 °C) solution of alcohol 17 (0.035 g, 0.072 mmol), PPh3
(0.104 g, 0.397 mmol), and 3,3-dimethylglutarimide (0.055 g, 0.39
mmol) in THF (1.2 mL) was added diethyl azodicarboxylate (0.06
mL, 0.4 mmol). The reaction mixture was warmed to ambient
temperature for 10 h and then was concentrated in vacuo. Purification
by flash chromatography (2:98 EtOAc/hexanes) afforded 18 as a white
solid (0.004 g, 10%): mp 195−197 °C; 1H NMR (600 MHz, CDCl3)
δ 5.41−5.35 (m, 2H), 4.63 (dd, J = 13.4, 6.4, 1H), 3.64 (s, 3H), 2.59
(dd, J = 16.9, 5.0, 1H), 2.51−2.44 (m, 2H), 2.10 (s, 1H), 1.96−1.86
(m, 4H), 1.72 (t, J = 12.9, 1H), 1.65−1.61 (m, 1H), 1.53−1.43 (m,
3H), 1.34−1.27 (m, 6H), 1.24 (s, 3H), 1.18 (s, 3H), 1.15 (s, 3H),
1.12−1.10 (m, 1H), 1.02 (s, 3H), 0.98−0.96 (m, 1H), 0.94 (s, 3H),
0.91 (s, 3H), 0.90 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 212.6 (C),
177.6 (C), 137.5 (CH), 121.6 (CH), 76.2 (CH), 63.5 (CH), 51.7
(CH), 51.4 (CH3), 46.2 (C), 45.4 (CH2), 44.3 (C), 43.1 (CH), 40.9
(C), 40.4 (C), 38.7 (CH2), 35.8 (CH2), 35.7 (C), 33.8 (CH2), 32.9
(CH2), 32.0 (CH2), 31.4 (CH2), 31.1 (CH3), 29.0 (CH3), 28.0 (CH3),
27.1 (CH2), 26.6 (C), 23.4 (CH3), 19.3 (CH3), 18.3 (CH2), 17.3
(CH3), 16.1 (CH3); IR 2950, 2867, 1729, 1701, 1463 cm−1; HRMS
(TOF MS ES+) m/z calcd for C31H49O3 (M + H)+ 469.3676, found
469.3680.
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ASSOCIATED CONTENT
* Supporting Information
Computational data, X-ray crystallographic data (CIF), and
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
*E-mail: kwoerpel@nyu.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Science
Foundation (CHE-0848121) and is based on work supported
for K.J.R. by the National Science Foundation Graduate
Research Fellowship under Grant No. DGE-1342536 and a
Sokol Fellowship from the NYU Department of Chemistry.
M.R.M. was supported by a Margaret Strauss Kramer
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