Total synthesis of optically active lycopladine a by utilizing diastereoselective protection of carbonyl group in a 1,3-cyclohexanedione derivative

Article abstract of DOI:10.1021/jo200418y

We successfully synthesized two enantiomers of bicyclic enones, (7R,7aR)- and (7S,7aS)-9, from the hemiacetal 2a, which we first synthesized from the symmetrical diketone 1a via diastereoselective carbon-oxygen bond formation between one of the carbonyl g

Full text of DOI:10.1021/jo200418y

ARTICLE
pubs.acs.org/joc
Total Synthesis of Optically Active Lycopladine A by Utilizing
Diastereoselective Protection of Carbonyl Group
in a 1,3-Cyclohexanedione Derivative
Kou Hiroya,* Yoshihiro Suwa, Yusuke Ichihashi, Kiyofumi Inamoto, and Takayuki Doi
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki, Aza Aoba, Aoba-ku, Sendai 980-8578, Japan
S Supporting Information
b
ABSTRACT: We successfully synthesized two enantiomers of
bicyclic enones, (7R,7aR)- and (7S,7aS)-9, from the hemiacetal
2a, which we first synthesized from the symmetrical diketone 1a via
diastereoselective carbonꢀoxygen bond formation between one of
the carbonyl groups and the chiral alcohol on the C2 side chain in a
2,2-disubstituted 1,3-cycloalkanedione derivative. We also report
the total synthesis of natural (þ)-lycopladine A [(þ)-6] from
(7R,7aR)-9 and the formal synthesis of unnatural (ꢀ)-lycopladine A [(ꢀ)-6] from (7S,7aS)-9.
’ INTRODUCTION
intramolecular addition of the lithium amide,5j and Elliot et al.
reported the addition of alkyllithium to 3,3-disubstituted 1,4-
cyclohexadiene derivatives5b (Scheme 2c,d). However, the major
difference between our method and the examples shown in
Scheme 2 is reversibility. Our method is based on an addition
of the oxygen atom to the carbonyl group and can be regarded as
the diastereoselective protection of the carbonyl group at the
symmetrical position. After being modified from the unprotected
carbonyl group to the suitable functional group, the diastereo-
selectively protected carbonyl group can revert to a carbonyl
group when necessary, and it can be utilized for the transforma-
tion to the other functional group. Moreover, the diastereoselec-
tivities by internal asymmetric induction in most examples were
achieved by kinetic control. It is noteworthy that the diastereos-
electivities of the hemiacetal syntheses in our method (Scheme 1;
1aꢀe f 2aꢀe) were controlled by the thermodynamic stabi-
lities among the possible compounds. Therefore, the diastereos-
electivities were almost independent of the substituents on C2
(R for 1aꢀe in Scheme 1). On the other hand, the preferential
formation of 5aꢀe over 4aꢀe can be rationalized by kinetic
controls.
Kobayashi et al. in 2006 isolated (þ)-lycopladine A [(þ)-(6)]
from the club moss Lycopodium complanatum and clarified its
structure and relative stereochemistry by careful analysis of the
NMR spectra.6 In 2006, Toste et al. reported the first total
synthesis of (þ)-lycopladine A [(þ)-(6)] by utilizing a Au(I)-
catalyzed cyclization reaction as a key step and also determined
the absolute configuration of (þ)-6 (Scheme 3).7a Recently,
Martin et al. reported the second efficient total synthesis of (()-6
via sequential conjugate addition and enolate arylation to con-
struct the tricyclic framework (Scheme 3).7b
Chiral quaternary centers at the angular positions are com-
monly found in biologically active compounds such as steroidal
compounds, terpenes, and alkaloids. Thus, the discovery of
general and efficient methods to prepare such structures, parti-
cularly in optically pure forms, may be the long-awaited solution
for synthesizing complex natural products.
Chiral discrimination of the symmetrical substrates utilizing
remote chiral sources is an efficient strategy to construct qua-
ternary carbon centers.1 We have established an efficient method
to construct asymmetric quaternary carbon centers based on
discrimination of the carbonyl groups at C1 and C3, which have
reflected the chirality on the C2 side chain of 2,2-disubstituted
1,3-cycloalkanedione derivatives (Scheme 1).2 Hydrolysis of the
acetal group of 1aꢀe, followed by intramolecular hemiacetal
formation, and conversion of the primary alcohol to tert-butyldi-
phenylsilyl (TBDPS) ether briefly gave the hemiacetals 2aꢀe
and 3aꢀe in more than 95:5 diastereomeric ratios. The hydrogen
bonds between the hydrogen atom in the hydroxyl group and the
oxygen atom in the TBDPS ether in 2aꢀe play an important role
in maintaining their configurations. Alternatively, acetal forma-
tion could be directed to the other carbonyl group when using
isopropyl alcohol to produce 5aꢀe with high selectivity
(Scheme 1; 2aꢀe f 5aꢀe). Although the relationship between
compounds 2 and 5 is diastereomeric, their absolute configura-
tion at C3a is opposite to each other.
Researchers have widely investigated desymmetrization reac-
tions of 2,2-disubstituted 1,3-cyclohexanedione or 3,3-disubsti-
tuted 1,4-cyclohexadiene derivatives3 by either catalytic reaction4
or intramolecular chiral induction.5 As recent examples, Scheidt
et al. reported NHC-catalyzed reactions,4a and Riant proposed
the Cu(I)-catalyzed, highly stereoselective desymmetrization
reactions of 2,2-disubstituted 1,3-cyclohexanedione derivatives4b
(Scheme 2a,b). On the other hand, Landais et al. developed the
Received: February 24, 2011
Published: May 04, 2011
r
2011 American Chemical Society
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Scheme 1. Desymmetrization Reactions of 2,2-Disubstituted 1,3-Cyclohexanedione Derivatives
Scheme 2. Previous Examples of Desymmetrization Reactions of 2,2-Disubstituted 1,3-Cyclohexanedione or 3,3-Disubstituted
1,4-Cyclohexadiene Derivatives
The key features of the synthesis of lycopladine A [(þ)-(6)]
are the installation of all carbon quaternary centers at the benzylic
position (C12), the construction of the cis-fused bicyclo[4.3.0]
ring system, and the stereoselective introduction of the methyl
group at C15. With these difficulties in mind, we planned the
synthetic strategy for (þ)-lycopladine A [(þ)-(6)], as shown in
Figure 1.
The introduction of the methyl group at C15 was planned on
the conjugate addition from the convex face into 7. Both the
primary alcohol and the R,β-unsaturated ketone in 7 were
considered being converted from the allyl group and the
protected secondary alcohol in 8, respectively. We considered
both the construction of the cis-fused ring system by the
stereoselective reduction of the enone and generating the
pyridine ring from the resulting ketone of (7R,7aR)-9. The
bicyclic R,β-unsaturated ketone (7R,7aR)-9 was expected to be
synthesized from 2a, whose synthesis from 1a has been already
established.2
In this study, we report the synthesis of both enantiomers of 9
using 2a as a common intermediate and the total synthesis of
natural (þ)-lycopladine A [(þ)-(6)] from (7R,7aR)-9.
’ RESULTS AND DISCUSSION
Synthesis of Bicyclic Intermediates (7R,7aR)- and (7S,7aS)-9.
According to the synthetic plan shown in Figure 1, we proceeded
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Scheme 3. Previous Synthesis of Lycopladine A
observed were recovered portions or the decomposition of the
starting material. Finally, we solved this problem by utilizing the
triflate as a transient intermediate. First, the primary alcohol,
which was obtained from 10, was converted to the triflate group
by triflic anhydride and 2,6-lutidine. Next, it was immediately
treated with sodium iodide and tetrabutylammonium iodide to
derive the corresponding iodide, followed by adding DBU to the
reaction mixture to promote an E2 reaction of hydrogen iodide
yielding the enol ether.12 Finally, the enol ether was hydrolyzed
under weak acidic conditions to give the diketone (2S,3R)-11,
which could be converted to the desired bicyclic compound
(7R,7aR)-9 via an intramolecular aldol reaction in the presence
of potassium tert-butoxide in 41% overall yield from 10
(Scheme 4).13
Figure 1. Retrosynthetic analysis of (þ)-lycopladine A [(þ)-(6)].
We also synthesized (7S,7aS)-9, which is the enantiomer of
(7R,7aR)-9, from 5a, as shown in Scheme 5. The stereoselective
reduction of the carbonyl group in 5a was accomplished with
DIBALH at ꢀ78 °C to afford 12 in an 80% yield. The protection
of the resulting hydroxyl group with the MOM group and the
removal of the TBDPS group were performed under standard
reaction conditions to give 13 in a good overall yield. 13 was
successfully converted to (7S,7aS)-9 by reactions identical to
those required for converting 10 to (7R,7aR)-9, as shown in
Scheme 4. All of the spectral data of (7S,7aS)-9 were correlated to
those of (7R,7aR)-9 except for the sign of the specific rotation
to establish the synthetic method of the chiral intermediate
(7R,7aR)-9 for the synthesis of natural (þ)-lycopladine A
[(þ)-(6)]. First, the carbonyl group of hemiacetal 2a was
stereo- and chemoselectively reduced by sodium boro-
hydride in the presence of cerium trichloride heptahydrate at
ꢀ78 °C (Scheme 4). After converting the hemiacetal group to
the corresponding ethyl acetal, the secondary hydroxyl group was
protected by a MOM ether under standard reaction conditions.8
We encountered some problems in the conversion of 10
to (2S,3R)-11, for example, the application of Mitsunobu
conditions9 or Burgess reagent10 to the primary alcohol, which
was obtained from 10 via its treatment with TBAF, for the
dehydration reaction or the conversion of 10 to 2-nitrophenyl-
selenyl derivatives11 all failed, and the compounds that we
[(7R,7aR)-9: [R]24D ꢀ76.8 (c 1.00, CHCl3). (7S,7aS)-9: [R]24
D
þ79.9 (c 1.20, CHCl3)].
Enantioselective Synthesis of Natural (þ)-Lycopladine A
(6) from (7R,7aR)-9. The introduction of the three-carbon unit
Scheme 4. Synthesis of (7R,7aR)-9 from 2a
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Scheme 5. Synthesis of (7S,7aS)-9 from 5a
Scheme 6. Deuterium Experiment of (7R,7aR)-9
Table 1. Introduction of the Three-Carbon Unit at C1 of 15
entry
base
electrophile
solvent
DMF
temperature
product (yield %)
1
2
3
4
5
NaH
2-(2-bromoethyl)-1,3-dioxolane
epichlorohydrin
chloroacetonitrile
propiolamide
0 to 60 °C
rt
no reaction
16b (25)
DBU
DBU
CsCO3
DBU
MeCN
DMSO
MeCN
rt
no reaction
no reaction
16e (50)
0 to 100 °C
rt
acrolein
into the C1 position was the main objective of our strategy.
Because the C1 position is the neopentyl position (neighboring
the quaternary center), we wondered about the possibility of the
regioselective deprotonation followed by the substitution reac-
tion at C1 over the C4 position. Therefore, we attempted to
identify the reactivity of (7R,7aR)-9 with a base by utilizing the
deuterium experiment. When (7R,7aR)-9 was treated with
LHMDS at ꢀ78 °C for 1 h followed by treating with metha-
nol-d4, 14a was afforded in a quantitative yield, and the 1H NMR
spectrum confirmed more than 90% deuterium induction at C1.
attempts failed. Therefore, we converted (7R,7aR)-9 into 15,
which has an alkoxycarbonyl group as an activator, and attempted
to introduce the three-carbon unit at C1. Table 1 summarizes the
results.
The desired compounds could not be obtained in good yields
by the alkylation reaction of 15 with the alkyl bromide or
epichlorohydrin (Table 1, entries 1 and 2). The Michael addition
reactions between 15 and 2-chloroacrylonitrile and propiol-
amide14 did not proceed at all (Table 1, entries 3 and 4).
However, we successfully obtained 16e via the reaction of 15
with acrolein in the presence of DBU, although the yield was
moderate [50% from (7R,7aR)-9] (Table 1, entry 5).
1
In this case, both 14b and 14c were not detected by H NMR
spectrum (Scheme 6).
On the basis of the results shown in Scheme 6, we then
attempted the direct introduction of the three-carbon unit at C1.
However, in spite of our efforts to introduce the side chain
directly by alkylation or by an aldol-type reaction at C1, all
To construct the pyridine ring of lycopladine A, we then
attempted to remove the alkoxycarbonyl group of 16e. Unfortu-
nately, 16e was unstable in the presence of the nucleophile
(lithium iodide in DMF) or under basic (lithium hydroxide in
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Scheme 7. Removal of the Methoxycarbonyl Group of 16e
Scheme 8. Synthesis of 23 from (7R,7aR)-9
acetate in ethanol, and pyridine 20 was afforded in a 51% yield
(Scheme 8).
Because we performed the synthesis of lycopladine A skeleton
20, the resulting task was assigned as follows: (A) stereoselective
introduction of a methyl group, (B) conversion of the vinyl group
to its primary alcohol, and (C) stereoselective reduction of the
double bond. Although several possible orders of the above
conversions (AꢀC) can be considered, we chose A as the first
reaction. However, the alcohol 21, which was obtained by removing
the MOM group under acidic conditions, resisted oxidation (sulfur
trioxide pyridine complex and triethylamine in DMSO).18,19 Accord-
ingly, we altered our approach and selected B as the first reaction.
The hydroborationꢀoxidation reaction of 20 with 9-BBN-H
and an aqueous hydrogen peroxideꢀsodium hydroxide solution,
hydrogenation of the double bond with hydrogen gas and
palladium on carbon, removal of the MOM group under acidic
conditions, and selective protection of the primary alcohol as the
TBS-ether gave 22 in a 75% overall yield from 20. The oxidation
of the secondary hydroxyl group smoothly proceeded by treatment
with a sulfur trioxide pyridine complex and triethylamine in DMSO18
to obtain the tricyclic ketone 23 in a 91% yield. The stereochemistry
between the cyclohexanone and cyclopentene moiety in 23 was
confirmed as cis via NOESY spectroscopy, as shown in Figure 3.
Oxidation from cyclohexanone 23 to cyclohexenone 26
proved to be another difficult reaction (Table 2). The reaction
via R-phenylselenyl ketone 24 did not give 26 in satisfactory
yields (Table 2, entries 1ꢀ3). Direct oxidation of 23 by
2-iodoxybenzoic acid (IBX)20 or the Saegusa reactions21 via silyl
enol ether 25 by palladium acetate afforded trace amount of 26
(Table 2, entries 4ꢀ6). Fortunately, we obtained 26 from 25 in
Figure 2. Observed NOE in 18 (a) and 19 (b).
aqueous THF) or nearly neutral conditions (ammonium acetate
in toluene). We only observed the decomposition of 16e or the
recovery of (7R,7aR)-9 via sequential retro reactions (Scheme 7).
Owing to these disappointing results, we focused on the
utilization of another activator. It is well-known that the deal-
koxycarbonylation reaction of R-allyloxycarbonyl ketone deriva-
tives can be carried out under neutral conditions utilizing a Pd
catalyst.15 We treated the lithium enolate of (7R,7aR)-9 with allyl
cyanoformate, which was prepared according to the literature,16
to afford 17 (Scheme 8). The reaction of 17 with acrolein in the
presence of DBU gave 18 as a single isomer in a 50% yield from
(7R,7aR)-9. The stereoselectivity may arise from the blocking of
the enolate’s β-face by the angular substituent and acrolein’s
selective approach from the R-face. The deallyloxycarbonylation
reaction was carried out according to the method reported by
Kim et al.17 to afford the desired 19 as a single diastereomer in a
90% yield. We determined the configuration of 18 and 19 at C1
via NOESY spectroscopy as shown in Figure 2a,b, respectively.
Fortunately, the oxidation of the dihydropyridine moiety
proceeded during the reaction between 19 and ammonium
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good yields by using IBX and 4-methoxypyridine N-oxide
(MPO) in DMSO, which was developed by Nicolaou et al.
(Table 2, entry 7).22
In conclusion, we successfully synthesized both the enantio-
mers of bicyclic enones (7R,7aR)- and (7S,7aS)-9 from the
hemiacetal 2a, which could be synthesized from the symmetrical
diketone 1a via the diastereoselective protection of one carbonyl
group. Furthermore, we provided the total synthesis of natural
lycopladine A [(þ)-(6)] from (7R,7aR)-9.
The installation of the methyl group at the β-position of the
carbonyl group by treating with Me2CuLi in THF at ꢀ40 °C did
not give satisfactory results in terms of both yield (38%) and
stereoselectivity (27a/27b = 10:1, inseparable mixture). This
problem was solved by utilizing a higher order cuprate
[Me2Cu(CN)Li2, THF, ꢀ40 °C].23 The yield of the product
27a24 was improved up to 78% and realized perfect stereoselec-
tivity (Scheme 9). Finally, the TBS group was removed by TBAF
to accomplish the total synthesis of (þ)-lycopladine A [(þ)-(6)]
(Scheme 9). All of the spectral data of the synthesized (þ)-6
were correlated to those reported.6,7 Because we have established
the synthesis of (7S,7aS)-9, which is the enantiomer of the staring
material of the proposed (þ)-lycopladine A synthesis, the formal
synthesis of unnatural (ꢀ)-lycopladine A [(ꢀ)-(6)] has also
been provided.
’ EXPERIMENTAL SECTION
General Experimental Methods. For 1H NMR spectra, chemi-
cal shifts (δ) are given from TMS (0.00 ppm) in CDCl3 and from
residual nondeuterated solvent peak in the other solvents (benzene-d6,
7.15 ppm; pyridine-d5, 7.55 ppm; and MeOH-d4, 3.30) as internal
standards. For 13C NMR spectra, chemical shifts (δ) are given from
CDCl3 (77.0 ppm), pyridine-d5 (149.0 ppm), benzene-d6 (128.0 ppm),
and MeOH-d4 (49.0 ppm) as internal standards. The synthesis of the
starting material 2a was reported in our previous communication,2 and
the Supporting Information is available. The commercially available
anhydrous solvents were used without further distillation.
((2S,3aS,4R,7aR)-3a-Allyl-7a-ethoxy-4-methoxymethox-
yoctahydrobenzofuran-2-ylmethoxy)-tert-butyldiphenyl-
silane (10). A suspension of cerium trichloride heptahydrate (0.847 g,
2.27 mmol) in methanol (20 mL) was added to a solution of 2a (2.113 g,
4.55 mmol) in methanol (25 mL) at ꢀ78 °C and stirred for 30 min at the
same temperature. Sodium borohydride (0.138 g, 3.64 mmol) was
added in a portion, and the mixture was stirred for 1.75 h at the same
temperature. Acetone was added to quench the excess sodium borohy-
dride, and water was added to the mixture. The aqueous phase was
extracted with ethyl acetate, and the combined organic solution was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and concentrated. The residue was
Figure 3. Selected data of the 1H NMR spectrum and observed NOE
in 23.
Table 2. Conversion of 23 to 26
entry
compounds
conditions
(1) LHMDS, PhSeCl, THF ꢀ78 to ꢀ40 °C
yield (%)a
1
2
3
4
5
6
7
23 f 24 f 26
(2) aq H2O2, pyridine, CH2Cl2, 0 °C
(2) aq H2O2, pyridine, CH2Cl2, ꢀ30 °C
(2) NaIO4, aq MeOH, rt
30ꢀ50
42
44
23 f 26
IBX, MPO, DMSO, rt
trace
trace
trace
80
IBX, DMSO, 70 °C
(1) LHMDS, TMSCl HMPA, THF, ꢀ40 °C
23 f 25 f 26
(2) Pd(OAc)2, MeCN
(2) IBX, MPO, DMSO, rt
a Overall yield from 23.
Scheme 9. Synthesis of (þ)-Lycopladine A [(þ)-(6)]
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passed through a silica gel pad to afford the alcohol (1.81 g) as a colorless
oil, which was used in the next reaction without further purification.
Acetyl chloride (0.011 g, 0.14 mmol) was added to a solution of the
alcohol (1.81 g) in anhydrous ethanol (45 mL) at room temperature.
After stirring for 25 min, one drop of N,N-diisopropylethylamine was
added to the mixture to neutralize the reaction mixture. The solvent and
the excess reagent were evaporated to give the residue that was passed
through a silica gel pad to afford the crude acetal (1.64 g) as a colorless
oil, which was used in the next reaction without further purification.
N,N-Diisopropylethylamine (2.538 g, 19.64 mmol), chloromethyl
methyl ether (1.318 g, 16.37 mmol), and DMAP (0.040 g, 0.33 mmol)
were successively added to a solution of the crude acetal (1.64 g) in
anhydrous dichloromethane (13 mL) at 0 °C, and the mixture was
refluxed for 11 h. Saturated aqueous ammonium chloride solution was
added to the mixture, and the aqueous phase was extracted with
chloroform. The combined organic solution was washed with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated. The residue was purified by silica gel column
chromatography [ethyl acetateꢀhexane (1:15)] to afford 10 (1.68 g,
(neat, cmꢀ1) 1146, 1113, 1078, 1042, 702; 1H NMR (600 MHz,
C5D5N) δ 0.94 (3H, t, J = 7.2 Hz), 1.14 (9H, s), 1.27ꢀ1.41 (2H, m),
1.44ꢀ1.56 (2H, m), 1.82 (1H, m), 1.88 (1H, dd, J = 12.0, 8.4 Hz), 2.08
(1H, br d, J = 12.0 Hz), 2.30 (1H, dd, J = 12.0, 7.2 Hz), 2.61 (2H, d, J =
7.8 Hz), 3.33 (1H, dq, J = 9.0, 7.2 Hz), 3.38 (3H, s), 3.51 (1H, dq, J = 9.0,
7.2 Hz), 3.57 (1H, dd, J = 12.0, 4.2 Hz), 3.81 (1H, dd, J = 10.2, 5.4 Hz),
3.96 (1H, dd, J = 10.2, 7.2 Hz), 4.55ꢀ4.62 (1H, m), 4.70 (1H, d, J = 7.2
Hz), 4.81 (1H, d, J = 7.2 Hz), 5.02ꢀ5.06 (1H, m), 5.10ꢀ5.16 (1H, m),
6.29 (1H, ddt, J = 18.0, 10.2, 7.8 Hz), 7.14ꢀ7.50 (6H, m), 7.82ꢀ7.91
(4H, m); 13C NMR (150 MHz, C5D5N) δ 15.7, 19.5, 20.2, 27.1, 27.4,
28.3, 33.3, 36.1, 53.9, 55.2, 55.5, 69.5, 78.1, 80.4, 96.3, 108.8, 115.5,
123.1, 128.2, 128.3, 130.2, 135.1, 136.1, 139.4; MS m/z 538 (Mþ, 9.4%),
481 (Mþ ꢀ t-Bu, 100.0%), 435 (60.6%), 373 (47.4%); HRMS calcd for
C32H46O5Siþ (Mþ) 538.3114, found 538.3091.
(7R,7aR)-7a-Allyl-7-methoxymethoxy-1,4,5,6,7,7a-hexa-
hydroinden-2-one [(7R,7aR)-9]. TBAF (1.0 M solution in THF,
2.54 mL, 2.54 mmol) was added to a solution of 10 (0.94 g, 1.56 mmol)
in THF (8.5 mL) at room temperature. After stirring for 3 h, phosphate
buffer solution (pH 6.86) was added to the mixture. The aqueous phase
was extracted with ethyl acetate, and the combined extract was washed
with saturated aqueous NaCl solution, dried over anhydrous magnesium
sulfate, and concentrated. The residue was passed through a silica gel pad
to afford the crude alcohol (0.423 g) as a colorless oil, which was used in
the next reaction without further purification.
2,6-Lutidine (0.362 g, 3.38 mmol) and trifluoromethanesulfonic
anhydride (0.477 g, 1.69 mmol) were successively added to a solution
of the crude alcohol (0.423 g) in anhydrous dichloromethane (14 mL) at
ꢀ40 °C, and the mixture was stirred for 20 min at the same temperature.
Diethyl ether was added to the mixture, and the precipitate was filtered
through a pad of Celite eluting with diethyl ether. The filtrate was
concentrated to afford the crude triflate as a yellow oil, which was
immediately subjected to the next reaction.
A solution of the crude enol ether and PPTS (0.171 g, 0.282 mmol) in
a mixture of THF and water (1:1, 14 mL) was stirred for 12 h at room
temperature. Saturated aqueous sodium hydrogen carbonate solution
was added to the mixture, and the aqueous phase was extracted with
ethyl acetate. The combined organic solution was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated. The residue was purified by silica gel column chromatog-
raphy [ethyl acetateꢀhexane (1:6)] to afford (2S,3R)-11 (0.220 g) as a
yellow oil with inseparable impurities. It was used in the next reaction
without further purification.
Potassium tert-butoxide (0.097 g, 0.865 mmol) was added to a
solution of (2S,3R)-11 (0.220 g) in anhydrous tert-butyl alcohol
(8.6 mL) at room temperature. After stirring for 5 h at the same
temperature, saturated aqueous ammonium chloride solution was added
to the mixture and the aqueous phase was extracted with ethyl acetate.
The combined organic phase was washed with saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate,
and concentrated to afford the solid, which was recrystallized from
hexane to provide (7R,7aR)-9 (0.150 g, 41% from 10) as colorless
needles: mp 104ꢀ105 °C; [R]24 ꢀ76.8 (c 1.00, CHCl3); IR ν
69% from 2a) as a colorless oil: [R]25 ꢀ33.2 (c 1.00, CHCl3); IR ν
D
D
(neat, cmꢀ1) 1703, 1624, 1097, 1028, 910; 1H NMR (400 MHz,
CDCl3) δ 1.38 (1H, qt, J = 13.6, 4.0 Hz), 1.65ꢀ1.83 (1H, m),
1.92ꢀ2.11 (2H, m), 2.23 (1H, td, J = 13.6, 6.8 Hz), 2.35 (1H, d, J =
19.2 Hz), 2.44 (1H, d, J = 19.2 Hz), 2.50 (2H, d, J = 7.6 Hz), 2.61 (1H,
m), 3.37 (3H, s), 3.38ꢀ3.45 (1H, m), 4.58 (1H, d, J = 7.2 Hz), 4.73 (1H,
d, J = 7.2 Hz), 5.04 (1H, dd, J = 9.6, 1.6 Hz), 5.08 (1H, dd, J = 17.2, 1.6
Hz), 5.47 (1H, ddt, J = 17.2, 9.6, 7.2 Hz), 5.88 (1H, d, J = 1.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 24.0, 26.9, 27.1, 34.1, 46.6, 51.7, 55.6, 83.7,
95.3, 118.8, 129.4, 132.1, 182.6, 207.5; MS m/z 236 (Mþ, 66.1%), 20þ4
(Mþ ꢀ MeOH, 19.3%), 174 (42.3%); HRMS calcd for C14H20O3
(Mþ) 236.1412, found 236.1400.
(2S,3aR,4S,7aS)-3a-Allyl-2-(tert-butyldiphenylsilanyloxy-
methyl)-7a-isopropoxyoctahydrobenzofuran-4-ol (12). DI-
BALH (0.99 M solution in toluene, 1.6 mL, 1.584 mmol) was added
to a solution of 5a (0.540 g, 1.067 mmol) in anhydrous dichloromethane
(20 mL) at ꢀ78 °C. After stirring for 1.5 h at the same temperature,
diethyl ether and phosphate buffer solution (pH 6.86) were successively
added to the mixture. The precipitate was filtered through a pad of Celite
eluting with ethyl acetate, and the filtrate was extracted with ethyl
acetate. The combined organic solution was washed with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated. The residue was purified by silica gel column
chromatography [ethyl acetateꢀhexane (1:12)] to afford 12 (0.435 g,
80%) as a colorless oil: [R]25D þ9.3 (c 1.40, CHCl3); IR ν (neat, cmꢀ1
)
3425, 1113, 702; 1H NMR (400 MHz, CDCl3) δ 1.06 (9H, s), 1.09 (3H,
d, J = 6.4 Hz), 1.10 (3H, d, J = 6.4 Hz), 1.32ꢀ1.70 (5H, m), 1.95ꢀ2.08
(2H, m), 2.12 (1H, d, J = 12.0 Hz), 2.41 (1H, dd, J = 14.8, 8.8 Hz), 2.53
(1H, m), 3.61 (1H, m), 3.76 (2H, d, J = 4.8 Hz), 4.06 (1H, quint, J = 2.4
Hz), 4.20 (1H, m), 4.97 (1H, br d, J = 10.0 Hz), 5.09 (1H, dd, J =
17.2, 1.2 Hz), 6.00ꢀ6.14 (1H, m), 7.31ꢀ7.47 (6H, m), 7.62ꢀ7.79
(4H, m); 13C NMR (100 MHz, CDCl3) δ 19.2, 19.8, 24.4, 24.7, 26.8,
29.2, 30.6, 33.4, 34.7, 53.6, 62.7, 66.6, 75.4, 76.9, 108.8, 115.6, 127.60,
127.63, 129.6, 133.66, 133.71, 135.68, 135.70, 139.4; MS m/z 451
(Mþ ꢀ t-Bu, 21.0%), 391 (Mþ ꢀ t-Bu ꢀ i-PrOH, 100.0%), 373 (32.4%),
335 (29.9%); HRMS calcd for C27H35O4Siþ (Mþ ꢀ t-Bu) 451.2305,
found 451.2289.
Tetrabutylammonium iodide (0.111 g, 0.282 mmol) and sodium
iodide (0.634 g, 4.224 mmol) were successively added to a solution of
the crude triflate in anhydrous DMSO (14 mL) at room temperature.
After stirring for 10 min, DBU (2.144 g, 14.08 mmol) was added and the
mixture was stirred at 60 °C for 8 h. Saturated aqueous ammonium
chloride solution was added to the mixture, and the aqueous phase was
extracted with ethyl acetate. The combined organic solution was
successively washed with saturated aqueous ammonium chloride solu-
tion (3 times) and saturated aqueous sodium chloride solution. The
organic solution was dried over anhydrous magnesium sulfate and
concentrated to give the crude enol ether as a yellow oil, which was
immediately used in the next reaction.
((2S,3aR,4S,7aS)-3a-Allyl-7a-isopropoxy-4-methoxymeth-
oxyoctahydrobenzofuran-2-yl)methanol (13). N,N-Diisopro-
pylethylamine (0.126 g, 0.971 mmol), chloromethyl methyl ether (1.318
g, 16.37 mmol), and DMAP (0.004 g, 0.028 mmol) were successively
added to a solution of 12 (0.141 g, 0.278 mmol) in anhydrous dichlor-
omethane (2.8 mL) at 0 °C, and the mixture was refluxed for 15 h.
Saturated aqueous ammonium chloride solution was added to the mixture,
and the aqueous phase was extracted with diethyl ether. The combined
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ARTICLE
organic solution was successively washed with saturated aqueous ammo-
nium chloride solution (2 times), saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and concentrated. The
residue (0.160 g) was used in the next reaction without further purification.
TBAF (1.0 M solution in THF, 0.416 mL, 0.416 mmol) was added to
a solution of the crude product (0.160 g) in THF (2.8 mL) at room
temperature. After stirring for 2 h, water was added to the mixture and
the aqueous phase was extracted with diethyl ether. The combined
extract was washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and concentrated. The residue
was purified by silica gel column chromatography [ethyl acetateꢀhexane
þ80.6 (c 1.05, CHCl3); IR ν (neat, cmꢀ1) 3450, 1070, 1036; 1H NMR
(400 MHz, CDCl3) δ 1.11 (3H, d, J = 6.8 Hz), 1.13 (3H, d, J = 6.8 Hz),
1.32ꢀ1.55 (3H, m), 1.61 (1H, m), 1.66 (1H, dd, J = 8.4, 4.4 Hz), 1.75
(1H, m), 2.05 (1H, dd, J = 8.8, 6.0 Hz), 2.10ꢀ2.26 (2H, m), 2.35ꢀ2.44
(2H, m), 3.38 (3H, s), 3.49 (1H, dd, J = 12.0, 4.0 Hz), 3.65ꢀ3.72 (2H,
m), 4.08 (1H, septet, J = 6.8 Hz), 4.15ꢀ4.24 (1H, m), 4.56 (1H, d, J = 6.8
Hz), 4.70 (1H, d, J = 6.8 Hz), 4.92 (1H, m), 5.00 (1H, m), 6.08 (1H, ddt,
J = 13.2, 10.0, 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 19.9, 24.5, 24.7,
27.1, 29.1, 33.1, 34.6, 53.1, 55.6, 62.7, 65.8, 81.4, 95.7, 109.2, 115.2,
138.9; MS m/z 314 (Mþ, 3.5%), 283 (Mþ ꢀ MeO, 84.1%), 25þ5
(76.9%), 197 (100.0%), 179 (86.6%); HRMS calcd for C17H30O5
(Mþ) 314.2094, found 314.2086.
(2R,3S)-2-Allyl-3-methoxymethoxy-2-(2-oxopropyl)cyclo-
hexanone [(2R,3S)-11]. 2,6-Lutidine (0.030 g, 0.278 mmol) and
trifluoromethanesulfonic anhydride (0.041 g, 0.145 mmol) were succes-
sively added to a solution of 13 (0.035 g, 0.111 mmol) in anhydrous
dichloromethane (1.1 mL) at ꢀ40 °C, and the mixture was stirred for
30 min at the same temperature. Diethyl ether was added to the mixture,
and the precipitate was filtered through a pad of Celite eluting with
diethyl ether. The filtrate was concentrated to afford the crude triflate as
a yellow oil, which was immediately subjected to the next reaction.
Tetrabutylammonium iodide (0.009 g, 0.022 mmol) and sodium
iodide (0.050 g, 0.334 mmol) were successively added to a solution of
the crude triflate in anhydrous DMSO (1.1 mL) at room temperature.
After stirring for 5 min, DBU (0.169 g, 1.113 mmol) was added and the
mixture was stirred at 60 °C for 7.5 h. Saturated aqueous ammonium
chloride solution was added to the mixture, and the aqueous phase was
extracted with ethyl acetate. The combined organic solution was
successively washed with saturated aqueous ammonium chloride solu-
tion (3 times) and saturated aqueous sodium chloride solution. The
organic solution was dried over anhydrous magnesium sulfate and
concentrated to give the crude enol ether as a yellow oil, which was
immediately used in the next reaction.
(7S,7aS)-7a-Allyl-7-methoxymethoxy-1,4,5,6,7,7a-hexa-
hydroinden-2-one [(7S,7aS)-9]. Potassium tert-butoxide (0.026 g,
0.232 mmol) was added to a solution of (2R,3S)-11 (0.059 g, 0.232
mmol) in anhydrous tert-butyl alcohol (1.5 mL) at room temperature.
After stirring for 4 h at the same temperature, saturated aqueous
ammonium chloride solution was added to the mixture and the aqueous
phase was extracted with ethyl acetate. The combined organic phase was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and concentrated. The residue was
purified by silica gel column chromatography [ethyl acetateꢀhexane
(1:4)] to afford (7S,7aS)-9 (0.047 g, 85%) as a colorless solid: mp
103ꢀ105 °C (hexane); [R]24D þ79.9 (c 1.20, CHCl3); IR, 1H NMR,
13C NMR, and MS spectra were identical to those of (7R,7aR)-9.
(7R,7aR)-7a-Allyl-1-deuterio-7-methoxymethoxy-1,4,5,6,
7,7a-hexahydroinden-2-one (14a). LHMDS (1.0 M solution in
THF, 0.279 mL, 0.279 mmol) was added to a solution of (7R,7aR)-9
(0.044 g, 0.186 mmol) in THF (1.9 mL) at ꢀ78 °C. After stirring for 1 h
at the same temperature, methanol-d4 (0.5 mL) was added and the
mixture was stirred for 5 min. Phosphate buffer solution (pH 6.86) was
added to the mixture, and the aqueous phase was extracted with diethyl
ether. The combined organic solution was dried over anhydrous
magnesium sulfate and concentrated. The residue was purified by silica
gel column chromatography [ethyl acetateꢀhexane (1:4)] to afford 14a
(0.043 g, 99%) as a colorless solid: IR ν (neat, cmꢀ1) 1701, 1624, 1097,
1028, 911; 1H NMR (400 MHz, CDCl3) δ 1.38 (1H, qt, J = 13.2, 4.4
Hz), 1.65ꢀ1.82 (1H, m), 1.94ꢀ2.08 (2H, m), 2.23 (1H, tdd, J = 13.6,
6.0, 2.0 Hz), 2.30ꢀ2.46 (1H, m), 2.50 (2H, d, J = 7.6 Hz), 2.57ꢀ2.65
(1H, m), 3.38 (3H, s), 3.42 (1H, dd, J = 11.6, 4.4 Hz), 4.59 (1H, d, J = 6.8
Hz), 4.73 (1H, d, J = 6.8 Hz), 5.04 (1H, br d, J = 9.6 Hz), 5.09 (1H, dd,
J = 17.2, 1.6 Hz), 5.47 (1H, ddt, J = 17.2, 9.6, 7.2 Hz), 5.88 (1H, d, J = 1.6
Hz); 13C NMR (100 MHz, CDCl3) δ 24.0, 26.9, 27.0, 34.1, 46.2 (t),
51.7, 55.6, 83.8, 95.4, 118.9, 129.5, 132.3, 182.8, 207.8; MS m/z 237
(Mþ, 72.6%), 181 (41.4%), 175 (48.1%), 45 (100.0%); HRMS calcd for
C14H19DO3þ (Mþ) 237.1475, found 237.1473.
(1:4ꢀ1:2)] to afford 13 (0.071 g, 81% from 12) as a colorless oil: [R]23
D
(1R,7R,7aS)-7a-Allyl-7-methoxymethoxy-2-oxo-1-(3-oxo-
propyl)-2,4,5,6,7,7a-hexahydro-1H-indene-1-carboxylic Acid
Methyl Ester (16e) (Table 1, Entry 5). LHMDS (1.0 M solution in
THF, 3.8 mL, 3.81 mmol) was added to a solution of (7R,7aR)-9 (0.60 g,
2.54 mmol) in THF (26 mL) at ꢀ78 °C. After stirring for 1 h at the same
temperature, methyl cyanoformate (0.864 g, 10.2 mmol) was added and
the mixture was stirred for 30 min. Saturated aqueous ammonium
chloride solution was added to the mixture, and the aqueous phase was
extracted with ethyl acetate. The combined organic solution was washed
with saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and concentrated. The residue was passed through a
silica gel pad to afford the crude 15 (1.01 g) as a yellow oil, which was
used in the next reaction without further purification.
A solution of the crude enol ether and PPTS (0.006 g, 0.022 mmol) in
a mixture of THF and water (1:1, 2.2 mL) was stirred for 20 h at room
temperature. Saturated aqueous sodium hydrogen carbonate solution
was added to the mixture, and the aqueous phase was extracted with
ethyl acetate. The combined organic solution was washed with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated. The residue was purified by silica gel column
chromatography [ethyl acetateꢀhexane (1:4)] to afford (2R,3S)-11
(0.016 g, 57% from 13) as a yellow oil: [R]21D þ115.7 (c 1.02, CHCl3);
IR ν (neat, cmꢀ1) 1715, 1705, 1030; 1H NMR (400 MHz, CDCl3) δ
1.64ꢀ1.77 (1H, m), 1.80ꢀ1.96 (2H, m), 2.09 (1H, m), 2.14 (3H, s),
2.27 (1H, ddd, J = 16.0, 12.8, 6.0 Hz), 2.32ꢀ2.43 (2H, m), 2.46 (1H, dd,
J = 14.4, 6.8 Hz), 2.57 (1H, d, J = 17.6 Hz), 3.06 (1H, d, J = 17.6 Hz), 3.35
(3H, s), 4.24 (1H, dd, J = 11.2, 5.2 Hz), 4.58 (1H, d, J = 6.4 Hz), 4.65
(1H, d, J = 6.4 Hz), 5.01ꢀ5.08 (2H, m), 5.50ꢀ5.62 (1H, m); 13C NMR
(100 MHz, CDCl3) δ 19.5, 26.9, 30.7, 35.7, 38.3, 44.3, 55.6, 56.5, 79.3,
96.4, 118.4, 133.0, 207.0, 210.0; MS m/z 254 (Mþ, 30.2%), 211 (60.5%),
DBU (0.464 g, 3.05 mmol) was added to a solution of the crude 15
(1.01 g) in anhydrous acetonitrile (20 mL) at room temperature. After
stirring for 5 min, a solution of acrolein monomer (90%, 0.158 g, 2.54
mmol) in anhydrous acetonitrile (5 mL) was dropped over 30 min and
the mixture was stirred at the same temperature for 30 min. Saturated
aqueous ammonium chloride solution was added to the mixture, and the
aqueous phase was extracted with ethyl acetate. The combined organic
solution was washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and concentrated. The residue
was purified by silica gel column chromatography [ethyl acetateꢀhexane
(1:4ꢀ1:1)] to afford 16e [0.445 g, 50% from (7R,7aR)-9] as a pale
yellow oil: [R]26 ꢀ144.4 (c 1.05, CHCl3); IR ν (neat, cmꢀ1) 1741,
D
1726, 1701, 1633, 1039; 1H NMR (400 MHz, CDCl3) δ 1.35 (1H, qt, J =
13.7, 3.9 Hz), 1.70ꢀ1.90 (2H, m), 1.96 (1H, m), 2.08 (1H, tdd, J = 14.2,
5.6, 1.6 Hz), 2.25 (1H, m), 2.45ꢀ2.72 (5H, m), 2.92 (1H, ddd, J = 18.6,
10.0, 4.6 Hz), 3.44 (3H, s), 3.71 (3H, s), 3.98 (1H, dd, J = 11.2, 5.2 Hz),
4.72 (1H, d, J=6.8Hz), 4.79(1H, d, J=6.8Hz), 4.93(1H, brd,J=10.8Hz),
209 (Mþ ꢀ MeOCH2, 100.0%); HRMS calcd for C14H22O4 (Mþ)
þ
254.1518, found 254.1517.
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ARTICLE
4.99 (1H, dd, J = 16.8, 1.2 Hz), 5.60 (1H, m), 5.80 (1H, d, J = 1.6 Hz),
9.74 (1H, s); 13C NMR (100 MHz, CDCl3) δ 22.2, 25.7, 27.3, 28.4, 34.3,
39.5, 51.7, 56.1, 58.2, 64.3, 77.4, 95.5, 117.1, 126.3, 133.2, 170.8, 179.1,
200.8, 203.7; MS m/z 350 (Mþ, 5.6%), 294 (34.1%), 262 (69.7%), 232
(84.9%), 200 (100.0%); HRMS calcd for C19H26O6þ (Mþ) 350.1729,
found 350.1719.
(1R,7R,7aS)-7a-Allyl-7-methoxymethoxy-2-oxo-1-(3-oxo-
propyl)-2,4,5,6,7,7a-hexahydro-1H-indene-1-carboxylic Acid
Allyl Ester (18). LHMDS (1.0 M solution in THF, 19.8 mL, 19.8
mmol) was added to a solution of (7R,7aR)-9 (3.12 g, 13.2 mmol) in
THF (132 mL) at ꢀ78 °C. After stirring for 1 h at the same temperature,
allyl cyanoformate (7.33 g, 66.0 mmol) was added and the mixture was
stirred for 30 min. Saturated aqueous ammonium chloride solution was
added to the mixture, and the aqueous phase was extracted with ethyl
acetate. The combined organic solution was washed with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and concentrated. The residue was passed through a silica gel pad
to afford the crude 17 (4.20 g) as a yellow oil, which was used in the next
reaction without further purification.
DBU (2.54 mL, 17.0 mmol) was added to a solution of the crude 17
(4.20 g) in anhydrous acetonitrile (130 mL) at room temperature. After
stirring for 5 min, a solution of acrolein monomer (90%, 0.953 g, 17.0
mmol) in anhydrous acetonitrile (40 mL) was dropped over 30 min and
the mixture was stirred at the same temperature for 30 min. Saturated
aqueous ammonium chloride solution was added to the mixture, and the
aqueous phase was extracted with ethyl acetate. The combined organic
solution was washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and concentrated. The residue
was purified by silica gel column chromatography [ethyl acetateꢀhexane
(1:4ꢀ1:1)] to afford 18 [2.48 g, 50% from (7R,7aR)-9] as a yellow oil:
[R]25D ꢀ123.5 (c 0.98, CHCl3); IR ν (neat, cmꢀ1) 1739, 1724, 1703,
1040; 1H NMR (600 MHz, CDCl3) δ 1.35 (1H, qt, J = 13.8, 3.6 Hz),
1.75ꢀ1.88 (2H, m), 1.95 (1H, m), 2.07 (1H, tdd, J = 14.1, 5.6, 1.8 Hz),
2.25 (1H, m), 2.54 (1H, ddd, J = 19.0, 10.5, 4.8 Hz), 2.59 (2H, d, J = 7.2
Hz), 2.60 (1H, m), 2.65 (1H, ddd, J = 13.7, 10.1, 5.0 Hz), 2.93 (1H, ddd,
J = 19.0, 10.1, 4.7 Hz), 3.43 (3H, s), 3.99 (1H, dd, J = 11.4, 4.8 Hz), 4.53
(1H, ddt, J = 13.2, 5.4, 1.2 Hz), 4.67ꢀ4.76 (2H, m), 4.77 (1H, d, J = 6.6
Hz), 4.91 (1H, dd, J = 10.2, 1.8 Hz), 4.97 (1H, dd, J = 16.8, 1.8 Hz), 5.25
(1H, dd, J = 10.2, 1.2 Hz), 5.39 (1H, dd, J = 16.8, 1.2 Hz), 5.62 (1H, ddt,
J = 16.8, 10.2, 7.2 Hz), 5.79 (1H, d, J = 1.8 Hz), 5.91 (1H, ddt, J = 16.8,
10.8, 6.0 Hz), 9.74 (1H, s); 13C NMR (150 MHz, CDCl3) δ 22.2, 25.7,
27.4, 28.4, 34.4, 39.6, 56.1, 58.3, 64.3, 65.5, 77.4, 95.6, 117.0, 118.8,
126.3, 131.5, 133.5, 169.9, 179.0, 200.9, 203.5; MS m/z 376 (Mþ, 3.5%),
320 (33.3%), 288 (36.7%), 262 (41.5%), 258 (73.4%), 230 (51.6%), 217
(39.8%), 200 (100.0%); HRMS calcd for C21H28O6þ (Mþ) 376.1886,
found 376.1869.
3-((1R,7R,7aR)-7a-Allyl-7-methoxymethoxy-2-oxo-2,4,5,
6,7,7a-hexahydro-1H-inden-1-yl)propionaldehyde (19). Pal-
ladium acetate (0.0224 g, 0.0999 mmol), triphenylphosphine (0.052 g,
0.199 mmol), and triethylamine (0.121 g, 1.20 mmol) were successively
added to a solution of 18 (0.376 g, 0.999 mmol) in a mixture of
acetonitrile and water (9:1, 22 mL) at room temperature. After stirring
for 1 h at the same temperature, saturated aqueous ammonium chloride
solution was added to the mixture and the aqueous phase was extracted
with ethyl acetate. The combined organic solution was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and concentrated. The residue was purified by silica
gel column chromatography [ethyl acetateꢀhexane (1:2ꢀ1:1)] to
afford 19 (0.263 g, 90%) as a yellow oil: [R]25D þ8.5 (c 1.28, CHCl3);
IR ν (neat, cmꢀ1) 1720, 1701, 1626, 1036; 1H NMR (600 MHz, CDCl3)
δ 1.40 (1H, qt, J = 13.8, 4.2 Hz), 1.75 (1H, tdd, J = 13.5, 11.8, 4.2 Hz),
1.94ꢀ2.15 (5H, m), 2.17 (1H, t, J = 7.5 Hz), 2.48 (1H, dd, J = 15.6, 7.8
Hz), 2.60 (1H, m), 2.64 (1H, dd, J = 15.6, 6.6 Hz), 2.75 (1H, dtd, J =
18.0, 7.2, 1.2 Hz), 3.06 (1H, dtd, J = 18.0, 7.2, 1.2 Hz), 3.37 (3H, s), 3.43
(1H, dd, J = 11.8, 4.2 Hz), 4.67 (1H, d, J = 6.0 Hz), 4.75 (1H, d, J = 6.0
Hz), 4.97 (1H, dd, J = 9.6, 1.8 Hz), 5.07 (1H, dd, J = 16.8, 1.8 Hz), 5.29
(1H, ddt, J = 16.8, 9.6, 7.2 Hz), 5.89 (1H, d, J = 1.2 Hz), 9.81 (1H, s); 13
C
NMR (150 MHz, CDCl3) δ 19.0, 23.3, 27.3, 27.4, 31.1, 43.0, 54.5, 55.6,
57.5, 86.2, 95.9, 118.0, 128.1, 133.2, 179.7, 202.4, 209.0; MS m/z 292
(Mþ, 5.8%), 260 (13.0%), 230 (15.2%), 149 (21.4%), 45 (100.0%);
HRMS calcd for C17H24O4þ (Mþ) 292.1674, found 292.1670.
(4bS,5R)-4b-Allyl-5-methoxymethoxy-5,6,7,8-tetrahydro-
4bH-indeno[2,1-b]pyridine (20). Ammonium acetate (4.40 g, 57.5
mmol) was added to a solution of 19 (2.80 g, 9.58 mmol) in anhydrous
ethanol (479 mL) at room temperature, and the mixture was stirred for
12 h at 60 °C. Saturated aqueous sodium hydrogen carbonate solution
was added to the mixture, and the aqueous phase was extracted with
ethyl acetate. The combined organic solution was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate, and
concentrated. The residue was purified by silica gel column chromatog-
raphy [ethyl acetateꢀhexane (1:4ꢀ1:1)] to afford 20 (1.33 g, 51%) as a
yellow oil: [R]24D þ51.9 (c 1.20, CHCl3); IR ν (neat, cmꢀ1) 1408, 1146,
1137, 1103, 1037, 916; 1H NMR (400 MHz, CDCl3) δ 1.26 (1H, qt, J =
13.5, 4.4 Hz), 1.79 (1H, tdd, J = 13.5, 11.6, 4.4 Hz), 1.94ꢀ2.08 (2H, m),
2.19 (1H, tdd, J = 13.5, 5.4, 1.8 Hz), 2.60ꢀ2.73 (2H, m), 2.90ꢀ3.00
(2H, m), 3.33 (3H, s), 4.55 (1H, d, J = 6.8 Hz), 4.69 (1H, dd, J = 9.6, 2.8
Hz), 4.75 (1H, d, J = 6.8 Hz), 4.80ꢀ5.00 (2H, m), 6.62 (1H, d, J = 1.6
Hz), 7.01 (1H, dd, J = 7.5, 5.2 Hz), 7.77 (1H, ddd, J = 7.5, 1.4, 0.6 Hz),
8.39 (1H, dd, J = 5.2, 1.4 Hz); 13C NMR (100 MHz, CDCl3) δ 25.6,
26.1, 27.6, 32.2, 55.6, 57.2, 83.1, 96.3, 117.0, 118.5, 125.3, 130.6, 132.2,
143.4, 147.1, 158.5, 163.2; MS m/z 271 (Mþ, 81.3%), 243 (100.0%),
215 (73.8%), 210 (62.7%), 209 (79.7%), 200 (51.3%), 170 (69.6%);
HRMS calcd for C17H21O2Nþ (Mþ) 271.1572, found 271.1577.
(4bS,5R,8aS)-4b-[3-(tert-Butyldimethylsilanyloxy)propyl]-
5,6,7,8,8a,9-hexahydro-4bH-indeno[2,1-b]pyridin-5-ol (22).
9-BBN-H (0.5 M solution in THF, 1.65 mL, 0.825 mmol) was added to a
solution of 20 (0.0320 g, 0.118 mmol) in anhydrous THF (3.0 mL) at
0 °C. After stirring for 1 h at the same temperature, a mixture of 6.0 M
sodium hydroxide solution (1.0 mL) and 30% hydrogen peroxide
solution (1.0 mL) was added and the solution was stirred for 10 min.
Water was added to the mixture, and the aqueous phase was extracted
with dichloromethane. The combined organic solution was washed with
saturated aqueous sodium chloride solution, dried over sodium sulfate,
and concentrated. The residue was passed through a silica gel pad to
afford the crude alcohol as a yellow oil, which was used in the next
reaction without further purification.
A solution of the crude alcohol in methanol (5.0 mL) was hydro-
genated in the presence of 10% palladium on carbon (0.0630 g, 0.0590
mmol) under atmospheric pressure of hydrogen gas. After stirring for
12 h, the mixture was filtered through a pad of Celite eluting with ethyl
acetate and the filtrate was concentrated to give the crude alcohol
as a yellow oil, which was used in the next reaction without further
purification.
A solution of the crude alcohol in a mixture of methanol (2.6 mL) and
3.0 M hydrogen chloride solution (1.3 mL) was stirred at 60 °C for 1 h.
Saturated aqueous sodium hydrogen carbonate solution was added to
the mixture, and the aqueous phase was extracted with dichloromethane.
The combined organic solution was dried over anhydrous sodium sulfate
and concentrated to afford the crude diol as a yellow oil, which was used
in the next reaction without further purification.
To a solution of the crude diol in anhydrous dichloromethane
(4.0 mL) were successively added imidazole (0.024 g, 0.354 mmol)
and tert-butyldimethylsilyl chloride (0.027 g, 0.177 mmol) at room
temperature. After stirring for 5 h at the same temperature, phosphate
buffer solution (pH 6.86) was added to the mixture and the aqueous
phase was extracted with dichloromethane. The combined organic
solution was dried over anhydrous sodium sulfate and concen-
trated. The residue was purified by silica gel column chromatography
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The Journal of Organic Chemistry
ARTICLE
[ethyl acetateꢀhexane (1:1)] to afford 22 (0.032 g, 75% from 20) as a
6.17 (1H, dt, J = 10.4, 1.9 Hz), 6.95 (1H, m), 7.14 (1H, dd, J = 7.6, 5.0
colorless solid: mp 93ꢀ95 °C; [R]22 þ1.7 (c 0.80, CHCl3); IR ν
Hz), 7.69 (1H, dd, J = 7.6, 1.6 Hz), 8.38 (1H, dd, J = 5.0, 1.6 Hz); 13
C
D
(neat, cmꢀ1) 3375, 1256, 1099, 835, 775; 1H NMR (400 MHz, CDCl3)
δ 0.03 (6H, s), 0.89 (9H, s), 1.18ꢀ1.41 (2H, m), 1.47ꢀ1.78 (7H, m),
1.80 (1H, br s), 2.08 (1H, ddd, J = 14.2, 11.8, 4.4 Hz), 2.49ꢀ2.62 (1H,
m), 2.86 (1H, dd, J = 16.8, 10.2 Hz), 2.93 (1H, dd, J = 16.8, 8.6 Hz),
3.54ꢀ3.67 (3H, m), 7.05 (1H, dd, J = 7.6, 4.8 Hz), 7.43 (1H, dd, J = 7.6,
1.6 Hz), 8.33 (1H, dd, J = 4.8, 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ
ꢀ5.3, 18.3, 20.1, 22.8, 24.5, 25.9, 27.4, 29.6, 36.6, 40.8, 52.2, 63.5, 72.5,
120.9, 131.5, 142.4, 147.5, 164.3; MS m/z 361 (Mþ, 2.8%), 346 (4.2%),
304 (Mþ ꢀ t-Bu, 100.0%), 212 (39.9%), 170 (25.5%); HRMS calcd for
C21H35O2NSiþ (Mþ) 361.2437, found 361.2432.
NMR (100 MHz, CDCl3) δ ꢀ5.4, 18.3, 25.9, 27.2, 28.1, 33.4, 38.9, 39.7,
58.5, 63.0, 122.0, 130.8, 133.4, 138.3, 148.2, 148.4, 162.7, 198.6; MS m/z
342 (Mþ ꢀ Me, 3.7%), 300 (Mþ ꢀ t-Bu, 100.0%), 232 (14.1%), 20þ8
(28.0%) 182 (14.0%), 180 (8.8%); HRMS calcd for C17H22O2NSi
(Mþ ꢀ t-Bu) 300.1420, found 300.1403.
(4bS,7R,8aS)-4b-[3-(tert-Butyldimethylsilanyloxy)propyl]-
7-methyl-4b,6,7,8,8a,9-hexahydroindeno[2,1-b]pyridin-5-
one (27a)7b. A solution of methyllithium (1.0 M in diethyl ether,
0.738 mL, 0.738 mmol) was added to a suspension of cuprous cyanide
(0.033 g, 0.369 mmol) in anhydrous THF (2.0 mL) at 0 °C, and the
mixture was stirred for 30 min. A solution of 26 (0.033 g, 0.0923 mmol)
in anhydrous THF (1.0 mL) was added at ꢀ40 °C, and the resulting
mixture was stirred for 1 h at the same temperature. Phosphate buffer
solution (pH 6.86) was added to the mixture, and the aqueous phase was
extracted with ethyl acetate. The combined organic solution was dried
over anhydrous sodium sulfate and concentrated. The residue was
purified by silica gel column chromatography [ethyl acetateꢀhexane
(4bS,8aS)-4b-[3-(tert-Butyldimethylsilanyloxy)propyl]-
4b,6,7,8,8a,9-hexahydroindeno[2,1-b]-pyridin-5-one (23).
Sulfur trioxide pyridine complex (0.180 g, 1.13 mmol) and triethyla-
mine (0.229 g, 2.27 mmol) were successively added to a solution of 22
(0.164 g, 0.454 mmol) in anhydrous DMSO (10 mL) at room
temperature, and the mixture was stirred at the same temperature
for 12 h. Water was added to the mixture, and the aqueous phase was
extracted with ethyl acetate. The combined organic solution was dried
over anhydrous sodium sulfate and concentrated. The residue was
purified by silica gel column chromatography [ethyl acetateꢀhexane
(1:3)] to afford 23 (0.148 g, 91%) as a colorless oil: [R]25D þ28.8 (c
(1:4)] to afford 27a (0.027 g, 78%) as a yellow oil: [R]28 þ111.8
D
(c 0.70, MeOH); IR ν (neat, cmꢀ1) 1704, 1424, 1255, 1098, 836, 776;
1H NMR (400 MHz, CDCl3) δ 0.02 (6H, s), 0.88 (9H, s), 1.06 (3H, d,
J = 6.0 Hz), 1.30ꢀ1.41 (1H, m), 1.47ꢀ1.58 (1H, m), 1.72 (1H, ddd, J =
14.4, 10.0, 5.0 Hz), 1.78ꢀ1.90 (2H, m), 1.98 (1H, ddd, J = 14.4, 12.2, 5.0
Hz), 2.05ꢀ2.20 (2H, m), 2.30ꢀ2.41 (1H, m), 2.83 (1H, dd, J = 15.6, 8.8
Hz), 2.85ꢀ2.94 (1H, m), 3.12 (1H, dd, J = 15.6, 7.2 Hz), 3.53ꢀ3.62
(2H, m), 7.11 (1H, dd, J = 7.6, 4.8 Hz), 7.53 (1H, dd, J = 7.6, 1.6 Hz),
8.38 (1H, dd, J = 4.8, 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ ꢀ5.4,
18.3, 21.7, 25.9, 28.0, 28.3, 32.7, 34.4, 38.4, 41.8, 46.9, 61.3, 62.8, 121.5,
133.6, 137.8, 148.6, 163.3, 212.8; 1H NMR (400 MHz, C6D6) δ 0.026
(3H, s), 0.029 (3H, s), 0.60 (3H, d, J = 6.4 Hz), 0.95 (9H, s), 1.19 (1H,
ddd, J = 14.1, 10.1, 5.5 Hz), 1.24ꢀ1.38 (2H, m), 1.38ꢀ1.56 (2H, m),
1.71 (1H, ddd, J = 13.5, 12.5, 4.1 Hz), 1.81 (1H, dd, J = 15.4, 10.2 Hz),
1.91 (1H, ddd, J = 13.4, 12.4, 4.8 Hz), 2.09 (1H, ddd, J = 15.4, 4.5, 0.9
Hz), 2.42ꢀ2.51 (1H, m), 2.66 (1H, dd, J = 16.8, 7.8 Hz), 3.04 (1H, dd,
J = 16.8, 8.4 Hz), 3.36ꢀ3.48 (2H, m), 6.70 (1H, dd, J = 7.8, 4.8 Hz), 7.44
(1H, dd, J = 7.8, 1.4 Hz), 8.43 (1H, dd, J = 4.8, 1.4 Hz); 13C NMR (100
MHz, C6D6) δ ꢀ5.2, 18.4, 21.3, 26.1, 27.5, 28.8, 33.6, 34.7, 39.1, 41.3,
46.8, 61.2, 63.2, 121.5, 133.2, 138.1, 149.3, 164.1, 210.8; MS m/z 358
(Mþ ꢀ Me, 4.2%), 316 (Mþ ꢀ t-Bu, 100.0%), 224 (16.8%), 185 (12.5%);
HRMS calcd forC18H26O2NSi þ (Mþ ꢀ t-Bu) 316.1732, found 316.1715.
(þ)-Lycopladine A [(þ)-(6)]6,7. TBAF (1.0 M solution in THF,
0.217 mL, 0.217 mmol) was added to a solution 27a (0.054 g, 0.145
mmol) in THF (2.0 mL) at room temperature. After stirring for 5.5 h at
the same temperature, phosphate buffer solution (pH 6.86) was added
to the mixture. The aqueous phase was extracted with ethyl acetate and
the combined extract was washed with saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate, and concen-
trated. The residue was purified by silica gel column chromatography
[ethyl acetateꢀhexane (1:1) f chloroformꢀmethanol (95:5)] to afford
(þ)-lycopladine A [(þ)-(6)] (0.034 g, 92%) as a colorless solid: mp
153ꢀ155 °C [lit.7b 119ꢀ121 °C for (()-(6)]; [R]27D þ155.5 (c 1.10,
MeOH) [lit. [R]23 þ102 (c 1.0, MeOH),6 [R]23 þ144 (c 0.7,
1
1.24, MeOH); IR ν (neat, cmꢀ1) 1703, 1421, 1256, 1097, 835; H
NMR (600 MHz, C6D6) δ 0.02 (3H, s), 0.03 (3H, s), 0.95 (9H, s),
0.97ꢀ1.07 (1H, m), 1.15ꢀ1.31 (2H, m), 1.32ꢀ1.51 (3H, m), 1.57
(1H, td, J = 12.6, 4.2 Hz), 1.87 (1H, ddd, J = 16.2, 9.3, 6.3 Hz), 1.95
(1H, td, J = 12.6, 4.6 Hz), 2.11 (1H, dt, J = 16.2, 6.0 Hz), 2.33 (1H,
ddd, J = 13.1, 8.2, 4.9 Hz), 2.64 (1H, dd, J = 16.8, 4.2 Hz), 3.11 (1H,
dd, J = 16.8, 7.8 Hz), 3.40 (1H, dt, J = 10.2, 6.6 Hz), 3.46 (1H, dt, J =
10.2, 6.1 Hz), 6.65 (1H, ddd, J = 7.6, 4.8, 0.9 Hz), 7.41 (1H, d, J = 7.6
Hz), 8.40 (1H, d, J = 4.8 Hz); 13C NMR (150 MHz, C6D6) δ ꢀ5.24,
ꢀ5.22, 18.4, 21.5, 26.1, 28.4, 29.3, 34.5, 39.1, 39.5, 42.6, 62.3, 63.3,
121.6, 132.5, 138.2, 149.3, 164.1, 210.4; MS m/z 344 (Mþ ꢀ Me,
8.6%), 302 (Mþ ꢀ t-Bu, 100.0%), 210 (46.6%), 171 (30.0%); HRMS
calcd for C17H24NO2Siþ (Mþ ꢀ t-Bu) 302.1576, found 302.1565.
(4bS,8aS)-4b-[3-(tert-Butyldimethylsilanyloxy)propyl]-
4b,8,8a,9-tetrahydroindeno[2,1-b]-pyridin-5-one (26) (Table 2,
Entry 7). LHMDS (1.0 M solution in THF, 1.0 mL, 1.0 mmol) was
added to a solution of 23 (0.073 g, 0.2030 mmol) in THF (2.8 mL) at
ꢀ78 °C. After stirring for 1 h at ꢀ40 °C, HMPA (0.3 mL) was added
and the mixture was stirred for 30 min. Chlorotrimethylsilane (0.22 g,
2.03 mmol) was added at ꢀ40 °C, and the stirring was continued for a
further 1 h at the same temperature. Triethylamine (0.5 mL) and
phosphate buffer solution (pH 6.86) were added to the mixture, and
the aqueous phase was extracted with hexane. The combined mixture
was dried over potassium carbonate and concentrated to afford the crude
silyl enol ether 25 as a yellow oil, which was used in the next reaction
without further purification.
To a solution of 2-iodoxybenzoic acid (0.227 g, 0.812 mmol) and
4-methoxypyridine N-oxide hydrate (MPO) (0.102 g, 0.812 mmol) in
anhydrous DMSO (0.7 mL) was successively added a solution of the
crude 25 in anhydrous DMSO (0.30 mL) at room temperature, and the
mixture was stirred for 2 days at the same temperature. Water was added
to the mixture, and the aqueous phase was extracted with diethyl ether.
The combined organic solution was washed with saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate, and
concentrated. The residue was chromatographed on silica gel [ethyl
acetateꢀhexane (1:3)] to provide 26 (0.058 g, 80% from 23) as a yellow
oil: [R]28D þ149.7 (c 1.46, MeOH); IR ν (neat, cmꢀ1) 1666, 1097; 1H
NMR (400 MHz, CDCl3) δ 0.03 (6H, s), 0.88 (9H, s), 1.43ꢀ1.59 (2H,
m), 1.86 (1H, ddd, J = 13.8, 11.2, 5.1 Hz), 2.11 (1H, ddd, J = 13.8, 11.2,
5.7 Hz), 2.41ꢀ2.54 (1H, m), 2.74 (1H, dquint, J = 18.0, 2.8 Hz),
2.87ꢀ3.07 (2H, m), 3.19 (1H, dd, J = 14.6, 6.6 Hz), 3.51ꢀ3.67 (2H, m),
D
D
MeOH)7a]; IR ν (neat, cmꢀ1) 3363, 1700, 1424; 1H NMR (400
MHz, CD3OD) δ 1.07 (3H, d, J = 6.4 Hz), 1.27ꢀ1.39 (1H, m),
1.49ꢀ1.61 (1H, m), 1.76ꢀ1.91 (3H, m), 2.05 (1H, ddd, J = 13.7, 12.5,
4.7 Hz), 2.09ꢀ2.15 (1H, m), 2.25ꢀ2.30 (2H, m), 2.82 (1H, dd, J = 16.3,
9.0 Hz), 2.88ꢀ2.99 (1H, m), 3.08 (1H, dd, J = 16.3, 8.0 Hz), 3.47ꢀ3.56
(2H, m), 7.23 (1H, dd, J = 8.0, 4.8 Hz), 7.66 (1H, dd, J = 8.0, 1.6 Hz),
8.29 (1H, dd, J = 4.8, 1.6 Hz); 13C NMR (100 MHz, CD3OD) δ 22.0,
29.1, 29.5, 33.4, 34.8, 38.6, 43.4, 47.7, 62.6, 62.8, 123.0, 136.1, 140.0,
148.7, 164.3, 214.5; MS m/z 259 (Mþ, 45.4%), 241 (40.1%), 215
(100.0%), 172 (53.9%), 144 (43.3%), 131 (36.6%), 130 (29.7%);
HRMS calcd for C16H21O2Nþ (Mþ) 259.1572, found 259.1584.
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The Journal of Organic Chemistry
ARTICLE
’ ASSOCIATED CONTENT
Gonzꢀalez-Lꢀopez, M.; Latorre, A.; Urbano, A. Org. Lett. 2007, 9, 5019–
5022. (h) Butters, M.; Elliott, M. C.; Hill-Cousins, J.; Paine, J. S.; Walker,
J. K. E. Org. Lett. 2007, 9, 3635–3638. (i) Lertpibulpanya, D; Marsden,
S. P.; Rodriguez Garcia, I.; Kilner, C. Angew. Chem., Int. Ed. 2006,
45, 5000–5002. (j) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org.
Lett. 2006, 8, 4755–4758. (k) Villar, F.; Equey, O.; Renaud, P. Org. Lett.
2000, 2, 1061–1064.
Supporting Information. Copies of H and 13C NMR
1
S
b
spectra of all new compounds, 27a, and 6. Copies of NOESY
spectra of 10, 18, 19, and 23. This material is available free of
charge via the Internet at http://pubs.acs.org.
(6) Ishiuchi, K.; Kubota, T.; Morita, H.; Kobayashi, J. Tetrahedron
Lett. 2006, 47, 3287–3289.
’ AUTHOR INFORMATION
(7) (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991–5994.
(b) DeLorbe, J. E.; Lotz, M. D.; Martin, S. F. Org. Lett. 2010, 12,
1576–1579.
Corresponding Author
*E-mail: hiroya@mail.pharm.tohoku.ac.jp.
(8) The stereochemistry of methoxymethyloxy group at C4 in 10
was determined by NOESY spectrum, which is shown in the Supporting
Information.
(9) Hughes, D. L. Org. React. 1992, 42, 335–656.
(10) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26–31.
’ ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research (C) 19590001 and 21590001 from the Japan Society
for the Promotion of Science (JSPS).
(11) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976,
41, 1485–1486.
(12) Sisu, E.; Sollogoub, M.; Mallet, J.-M.; Sinay, P. Tetrahedron
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