Diastereoselective Total Synthesis of (-)-Galiellalactone

Article abstract of DOI:10.1021/acs.joc.5b02121

An enantioselective total synthesis of (-)-galiellalactone has been accomplished. The key features of the synthesis involve the highly stereoselective construction of the cis-trisubstituted cyclopentane intermediate by a Pd(0)-catalyzed cyclization, the stereospecific introduction of an angular hydroxyl group by Riley oxidation, and the efficient construction of the tricyclic system of (-)-galiellalactone via a combination of diastereoselective Hosomi-Sakurai crotylation and ring-closing metathesis (RCM)

Full text of DOI:10.1021/acs.joc.5b02121

Article
pubs.acs.org/joc
Diastereoselective Total Synthesis of (−)-Galiellalactone
Taewoo Kim,† Young Taek Han,‡ Hongchan An,† Kyeojin Kim,† Jeeyeon Lee,† and Young-Ger Suh*,†
†College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea
‡College of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan 330-714, Korea
S
* Supporting Information
ABSTRACT: An enantioselective total synthesis of (−)-ga-
liellalactone has been accomplished. The key features of the
synthesis involve the highly stereoselective construction of the
cis-trisubstituted cyclopentane intermediate by a Pd(0)-
catalyzed cyclization, the stereospecific introduction of an
angular hydroxyl group by Riley oxidation, and the efficient
construction of the tricyclic system of (−)-galiellalactone via a combination of diastereoselective Hosomi−Sakurai crotylation
and ring-closing metathesis (RCM)
angular hydroxyl group, which is essential for the biological
activity of 1.8 Sterner and Johansson reported the first and
efficient synthesis of (−)-galiellalactone and established the
absolute configuration of the natural product.9 However, the
stereoselective introduction of a tertiary hydroxyl group
remains a formidable task10 because introduction of an epoxide,
as a precursor of the tertiary hydroxyl group, into the
hydrindane system of 1 has only been reported with moderate
diastereoselectivity.9a In addition, chemical hydroxylation at the
central angular position could not directly elaborate the tertiary
hydroxyl group.10a
INTRODUCTION
(−)-Galiellalactone (1), a fungal metabolite originally isolated
from the ascomycete Galiella rufa1 (Figure 1), has been
■
Recently, we have been interested in studies on (−)-galiella-
lactone, particularly on the cyclohexene system for which the
role in its biological activity has not been explored much;
however, the [3.3] bicyclic lactone system has been extensively
studied.10c,11 Thus, we envisioned a unique and versatile
synthetic strategy, in which the [3.3] bicyclic lactone system
and the cyclohexene moiety are sequentially constructed
starting from cyclopentane 4 because most of the previous
synthetic studies pursued the strategy. From the viewpoint of
medicinal chemistry, we realized that the structural variation of
the cyclohexene system is restricted because early construction
of the hydrindane system would limit late steps of the synthesis.
Herein, we report our enantioselective total synthesis of
(−)-galiellalactone (1).
Figure 1. Structure of (−)-galiellalactone (1).
reported to be a potent and specific inhibitor of signal
transducer and activator of transcription 3 (STAT3), which is
involved in numerous signaling pathways.2 (−)-Galiellalactone
covalently binds to one or more cysteine residues in STAT3
and subsequently blocks the DNA binding of phosphorylated
STAT3 without inhibition of phosphorylation and dimeriza-
tion.3 Importantly, persistent and aberrant activation of STAT3
has been detected in several human solid and hematological
cancer cells,2,4 whereas it is tightly regulated in normal cells,5
which supports STAT3 as a promising molecular target for
cancer therapy. (−)-Galiellalactone also induces apoptosis and
growth inhibition of human prostate cancer cells expressing
constitutively active STAT3 both in vitro and in vivo6 and
suppresses stem cell-like ALDH+ prostate cancer cells.7 For
these reasons, (−)-galiellalactone has recently been considered
to be a potential therapeutic agent against hormone-refractory
prostate cancer.
RESULTS AND DISCUSSION
■
Our synthetic approach for 1 is outlined in Scheme 1, which
includes stereoselective construction of the tricyclic intermedi-
ate containing three contiguous stereocenters as well as a
methyl substituent. (−)-Galiellalactone (1) was anticipated to
be obtained from homoallylic alcohol 2, which comprises all
four stereocenters of the natural product, by ring-closing
metathesis (RCM) and subsequent Barton−McCombie deox-
The structure of (−)-galiellalactone (1) features a unique
and highly congested [5,5,6]-tricyclic ring system that consists
of a reactive α,β-unsaturated lactone functionality and four
stereocenters. The tertiary stereogenic center possesses an
Received: September 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02121
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of diene 9 in the presence of a second generation Grubbs
catalyst afforded a cyclic bis-alkoxysilane 10 in a quantitative
yield. Cleavage of the silicon tether of 10 resulted in a
spontaneous lactonization of the resulting dihydroxy ester,
followed by TBS-protection of the allylic alcohol to produce δ-
valerolactone 6.
Scheme 1. Retrosynthetic Analysis of (−)-Galiellalactone (1)
After intensive optimization of the cyclization conditions
including various ligands and solvents as summarized in Table
1, it was determined that the intramolecular allylic alkylation of
a
Table 1. Pd(0)-Catalyzed Cyclization of δ-Valerolactone 6
b
c
entry
catalyst
solvent
yield (%)
ratio (5:5′)
1
2
3
4
5
6
7
8
9
Pd(dppf)2
Pd(dppf)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dppe)2
Pd(dppe)2
Pd(dppp)2
Pd(dppb)2
CH2Cl2
THF
99
80
90
85
76
90
82
73
61
7.2:1
1:1
CH2Cl2
DCE
5:1
3:1
d
ygenation of the secondary hydroxyl group at the final stage.
The C5a-side chain of 2 can be installed into the key bicyclic
intermediate 3 by oxidation of the alcohol followed by a
substrate-controlled stereoselective crotylation. The stereo-
chemistry of the C7b-stereocenter was predicted based on
the stereospecific introduction of an angular hydroxyl group by
a substrate-controlled oxidation of the cis-fused 5,5-bicyclic
lactone system, which can be efficiently produced from the cis-
trisubstituted cyclopentanetriol 4. Cyclopentanetriol 4 is
accessible by reduction of the [2.2.1] bridged bicyclic lactone
5, which can be efficiently prepared by a diastereoselective
Pd(0)-catalyzed cyclization of δ-valerolactone 6 that was
developed by our group although the substituents are quite
different.12 δ-Valerolactone 6 was expected to be conveniently
prepared from the known alcohol 7.
The synthesis commenced with the preparation of bicyclic
lactone 5, as shown in Scheme 2. Tosylation of the known
alcohol 713 and PMB deprotection with DDQ afforded the
allylic alcohol 8, which was converted to bis-alkoxysilane 9 via a
sequence of double silylation with another allylic alcohol
fragment and tosylate substitution with the anion of
benzenesulfonyl acetate.14 Ring closing metathesis (RCM)15
DMSO
CH2Cl2
THF
3:1
1.3:1
1.3:1
1:1.5
2:1
THF
THF
a
All reactions were conducted with 5 mol % catalyst in 0.05 M
b
solution under reflux conditions except entry 5. Isolated yield of the
c
diastereomeric mixture. Determined by 1H NMR spectra of the
d
diastereomeric mixtures. Reaction was conducted at 80 °C. dppe: 1.2-
bis(diphenylphosphino)ethane. dppp: 1,3-bis(diphenylphosphino)-
propane. dppb: 1,4-bis(diphenylphosphino)butane. dppf: 1,1′-
ferrocenediyl-bis(diphenylphosphine).
6 in the presence of Pd(dppf)2 in CH2Cl2 afforded the bicyclic
lactone 5 in an 87% yield with the best diastereoselectivity
(entry 1), which was determined by the isolation of each
isomer. Cyclization of 6 in the presence of Pd(PPh3)4 resulted
in low stereoselectivity regardless of the solvents (entries 3−5).
Cyclization in the presence of Pd(OAc)2 with dppe or dppb
also showed a disappointingly low stereoselectivity (entries 6−
7, 9). Interestingly, the cyclization in the presence of Pd(dppp)2
showed the opposite diastereoselectivity, although the yield was
slightly lower (entry 8). The observed high diastereoselectivity
is presumably due to the Pd(0)-catalyzed cyclization through
the transition state with the least steric interaction between the
benzenesulfonyl group and the π-allylpalladium complex
(Figure 2).12b,16
Scheme 2. Synthesis of [2.2.1] Bridged Bicyclic Lactone 5
Having successfully prepared the optically pure bicyclic
intermediate 5, we executed the construction of the cis-fused
5,5-bicylic lactone 12 and the stereoselective introduction of
the angular hydroxyl group as shown in Scheme 3. To the best
of our knowledge, direct introduction of the angular hydroxyl
group to the bicyclic or tricyclic backbone of 1 has not been
reported. Thus, we undertook the stereoselective construction
of the functionalized cis-fused 5,5-bicyclic lactone system. We
first transformed the bridged bicyclic lactone 5 into the cis-
1,2,3-trisubstituted cyclopentanetriol 4, which is difficult to
access by conventional cyclization procedures.17
Desulfonylation of 5 with 5% Na/Hg in the presence of
B(OH)3 afforded the desulfonylated bridged bicyclic lactone 11
in a 93% yield.18 Reduction of 11 with LiBH4 in the presence of
MeOH and subsequent TBS deprotection afforded the
B
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Figure 2. Plausible mechanism for Pd(0)-catalyzed cyclization.
Scheme 3. Synthesis of Dihydroxy Bicyclic Lactone 3
Table 2. Diastereoselective Hosomi−Sakurai Crotylation of
a
Aldehyde 13
b
c
entry
Lewis acid
yield (%)
ratio (2:14)
1:5
1
2
3
4
5
6
BF3·Et2O
TiCl4
88
78
97
5:1
1:1
NR
NR
SnCl4
d
MgBr2·Et2O
Et2AlCl
AlCl3
complex mixture
thermodynamically less favorable cis-1,2,3-trisubstituted cyclo-
pentanetriol 4. Allylic oxidation of 4 with excess MnO2
19
a
All reactions were conducted with (E)-crotyltrimethylsilane (10
equiv) and Lewis acid (2 equiv) in 0.1 M solution at −78 °C for 12 h.
followed by spontaneous lactonization of the resulting lactol
effectively produced the bicyclic lactone 12. For the pivotal
introduction of the angular hydroxyl group, we envisioned the
stereoselective oxidation of the exo-methylene moiety of the cis-
fused bicyclic lactone system because of its inherent convex-
face selectivity. Indeed, Riley oxidation20 of 12 with SeO2 in
1,4-dioxane provided the dihydroxy bicyclic lactone 3 as a
single diastereomer in a 90% yield (Scheme 3).
b
c
Isolated yield of the diastereomeric mixture. Determined by isolation
d
of each isomer after TES protection (See Scheme 4). No reaction.
Next, we turned our attention to the stereoselective
elaboration of the C5a-side chain as summarized in Table 2.
To our delight, Dess-Martin oxidation21 of 3 afforded aldehyde
13 without epimerization of the labile C5a stereocenter. We
originally anticipated an efficient elaboration of the C5a-side
chain unit that utilized the Brown22 or Roush23 crotylation
procedure. However, our attempts to directly install the C5a-
side chain unit were not successful. The aldehyde was
unexpectedly intact under those conditions. Thus, we employed
the diastereoselective Hosomi−Sakurai crotylation24 to directly
introduce the C5a-side chain unit, which contains both the C4
unit and a requisite terminal alkene for RCM at a later stage.
We expected a diastereoselective coupling in a chelation-
controlled fashion to elaborate the C4-stereocenter of 1.
Interestingly, the treatment of 13 with (E)-crotyltrimethyl-
silane and BF3·Et2O in CH2Cl2 afforded the isomer 14 as a
major product, along with the desired isomer 2, in an 88% yield
(entry 1). The undesired diastereoselectivity can be explained
by Felkin−Anh control as shown in Figure 3. However,
diastereoselective Hosomi−Sakurai crotylation in the presence
of TiCl4 provided a reversed diastereoselectivity with a ratio of
Figure 3. Diastereoselectivity in the Hosomi−Sakurai crotylation of
aldehyde 13.
5:1 presumably via chelation-controlled asymmetric induction
as we anticipated (entry 2). Crotylation in the presence of
SnCl4 resulted in low diastereoselectivity (entry 3), although
the yield was quantitative. The variation in diastereoselectivity
is likely due to complexation of the lactone moiety with Lewis
acids, although it is not clear at this stage.
The structure of the C4-stereocenter was confirmed by
comparison of its spectral data with that of the natural
(−)-galiellalactone after completion of the synthesis.
The diastereomeric mixture of homoallylic alcohols 2 and 14,
which were prepared in the presence of TiCl4 and inseparable
by column chromatography, was purified after TES protection
of the alcohol to afford optically pure RCM precursor 1525 in a
59% yield in three steps (Scheme 4). The tricyclic lactone 17
was obtained in a high yield from 15 by RCM in the presence
C
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(methanol-d4). Chemical shifts are expressed in parts per million
(ppm, δ) downfield from tetramethylsilane and are referenced to the
deuterated solvent (CDCl3 or CD3OD). 1H NMR data were reported
in the order of chemical shift, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; quint, quintet; dd, doublet of doublets; dt, doublet
of triplet; td, triplets of doublets; ddd, doublet of doublet of doublets;
dddd, doublet of doublet of doublet of doublets; qtd, quartet of triplet
of doublets; br, broad; m, multiplet and/or multiple resonance),
number of protons, and coupling constant in hertz (Hz).
Scheme 4. Completion of (−)-Galiellalactone (1) Synthesis
(R)-3-Hydroxypent-4-en-1-yl 4-methylbenzenesulfonate (8).
To a mixture of alcohol 7 (4.09 g, 18 mmol) and triethylamine (5.1
mL, 36.8 mmol) in CH2Cl2 (46 mL) were added p-toluenesulfonyl
chloride (5.27 g, 27.6 mmol) and 4-dimethylaminopyridine (674 mg,
5.5 mmol) at 0 °C. After stirring for 3 h at ambient temperature, the
reaction mixture was quenched with saturated NH4Cl solution (30
mL) and diluted with CH2Cl2 (50 mL). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (2 × 50
mL). The combined organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc/n-hexane = 1:6) to
afford p-methoxybenzyl ether (6.44 g, 93%) as a colorless oil:
of a second generation Grubbs catalyst, followed by TES
deprotection of the resulting tricyclic lactone 16 with CSA in
MeOH. We originally anticipated facile deoxygenation of the
secondary hydroxyl group right after stereoselective crotylation
reaction. However, preparation of the deoxygenation precursor
under a variety of reaction conditions was not successful
because of the steric congestion on the concave face. Thus, we
carried out the deoxygenation reaction after constructing the
tricyclic lactone system of 1. After intensive screening of the
deoxygenation conditions, deoxygenation of 17 with the
Barton−McCombie reaction26 via careful acylation with
pentafluorophenyl chlorothionoformate27 and n-Bu3SnH treat-
ment of the resulting xanthate finally furnished (−)-galiella-
lactone (1) in a 76% yield in two steps. Synthetic 1 was
identical to the natural product in all aspects, including optical
rotation.9a,10a,28
1
[α]2D0+11.46 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.76 (d,
2H, J = 8.3 Hz), 7.30 (d, 2H, J = 8.1 Hz), 7.14 (d, 2H, J = 8.5 Hz),
6.83 (d, 2H, J = 8.6 Hz), 5.65 (m, 1H), 5.21 (d, 1H, J = 1.7 Hz), 5.18
(d, 2H, J = 9.5 Hz), 4.43 (d, 1H, J = 11.0 Hz), 4.18 (m, 1H), 4.14 (d,
1H, J = 11.1 Hz), 4.06 (dt, 1H, J = 9.7 Hz, J = 5.6 Hz), 3.84 (td, 1H, J
= 7.7 Hz, J = 5.3 Hz), 3.78 (s, 3H), 2.41 (s, 3H), 1.89−1.82 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 159.1, 144.7, 137.7, 133.0, 130.2,
129.8, 129.3, 127.8, 117.9, 113.7, 70.0, 67.1, 55.2, 34.8, 21.5; IR (neat)
νmax 2957, 1613, 1514, 1465, 1361, 1303, 1249, 1189, 1177, 1097,
1035, 916, 817, 770, 664 cm−1; LR-MS (FAB+) m/z 376 (M+); HR-
MS (FAB+) calcd for C20H24O5S (M+) 376.1344, found 376.1351.
To a solution of p-methoxybenzyl ether (5.30 g, 14.1 mmol) in
CH2Cl2/pH 7.2 buffer solution (9:1, 140 mL) was added 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (6.39 g, 28.2 mmol) in one portion at
ambient temperature. After stirring for 3 h, the reaction mixture was
filtered and quenched with a saturated NaHCO3 solution (100 mL).
The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 50 mL). The combined organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (EtOAc/n-
hexane = 2:3) to afford allylic alcohol 8 (3.57 g, 99%) as a colorless oil:
CONCLUSION
■
In summary, we have achieved the enantioselective total
synthesis of (−)-galiellalactone (1). Our unique strategy based
on substrate-controlled stereocontrol involves the diastereose-
lective construction of the contra-thermodynamic tri-cis-
substituted cyclopentanetriol, the stereospecific introduction
of an angular hydroxyl group, and its efficient transformation
into the tricyclic system of (−)-galiellalactone via a sequence of
stereoselective Hosomi−Sakurai crotylation and RCM of the
resulting diene. Our versatile and straightforward procedure is
widely applicable to the syntheses of (−)-galiellalactone and its
structural variants including the cyclohexene-modified analogs,
which are quite useful in terms of synthetic and medicinal
chemistry.
[α]2D0 +3.50 (c 2.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.73 (d,
1
2H, J = 8.2 Hz), 7.30 (d, 2H, J = 8.0 Hz), 5.74 (m, 1H), 5.14 (d, 1H, J
= 17.2 Hz), 5.04 (d, 1H, J = 10.5 Hz), 4.20−4.14 (m, 2H), 4.08−4.03
(m, 1H), 2.39 (s, 3H), 2.21 (br, 1H), 1.87−1.70 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ 144.8, 139.7, 132.7, 129.8, 127.8, 115.3, 68.8,
67.3, 35.7, 21.5; IR (neat) νmax 3412, 2961, 1599, 1496, 1424, 1358,
1308, 1293, 1190, 1176, 1142, 1098, 1068, 996, 969, 916, 832, 816,
766, 664 cm−1; LR-MS (FAB+) m/z 257 (M + H+); HR-MS (FAB+)
calcd for C12H17O4S (M + H+) 257.0848, found 257.0860.
Methyl (12R)-10,10-Diisopropyl-7-methylene-4-oxo-15-
(phenylsulfonyl)-12-vinyl-3,5,9,11-tetraoxa-10-silahexadecan-
16-oate (9). To a solution of imidazole (5.88 g, 86.4 mmol) in
CH2Cl2 (140 mL) was added dichlorodiisopropylsilane (5.8 mL, 31.7
mmol) at 0 °C. After stirring for 10 min, a solution of allylic alcohol 8
(7.38 g, 28.8 mmol) in CH2Cl2 (20 mL) was added dropwise. After
stirring for 10 min at the same temperature, a solution of another
allylic alcohol (5.53 g, 34.6 mmol) in CH2Cl2 (20 mL) was added at 0
°C. The reaction mixture was warmed to ambient temperature and
stirred for 12 h. The resulting mixture was quenched with a saturated
NH4Cl solution (30 mL). The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The combined
organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 1:8) to afford bis-
alkoxysilane (14.62 g, 96%) as a colorless oil: [α]2D0 −7.68 (c 2.0,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, 2H, J = 8.3 Hz), 7.29
(d, 2H, J = 8.2 Hz), 5.68 (m, 1H), 5.21 (s, 1H), 5.13 (s, 1H), 5.03 (dd,
2H, J = 18.3 Hz, J = 10.4 Hz), 4.58 (s, 2H), 4.36 (q, 1H, J = 6.2 Hz),
EXPERIMENTAL SECTION
■
General Experimental Procedure. Unless noted otherwise, all
starting materials and reagents were obtained from commercial
suppliers and were used without further purification. Tetrahydrofuran
and diethyl ether were distilled from sodium benzophenone ketyl.
Dichloromethane, triethylamine, and pyridine were freshly distilled
from calcium hydride. All solvents used for the routine isolation of
products and chromatography were reagent grade and glass distilled.
Reaction flasks were dried at 100 °C. Air and moisture sensitive
reactions were performed under an argon atmosphere. Flash column
chromatography was performed using silica gel (230−400 mesh) with
the indicated solvents. Thin-layer chromatography was performed
using 0.25 mm silica gel plates. Optical rotations were measured with a
digital polarimeter at ambient temperature using a 100 nm cell of 2 mL
capacity. Infrared spectra were recorded on a FT-IR spectrometer.
Mass spectra were obtained with a double focusing mass spectrometer
(electrostatic analyzer and magnetic analyzer). 1H and 13C NMR
spectra were recorded on a 300, 400, 500, or 600 MHz spectrometers
as solutions in deuteriochloroform (CDCl3) or tetradeuteromethanol
D
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Article
4.20 (s, 2H), 4.16 (q, 2H, J = 7.2 Hz), 4.11−4.02 (m, 2H), 2.40 (s,
3H), 1.89−1.78 (m, 2H), 1.26 (t, 3H, J = 7.1 Hz), 0.94−0.93 (m,
14H); 13C NMR (CDCl3, 100 MHz) δ 154.9, 144.6, 142.2, 139.6,
133.0, 129.7, 127.8, 115.2, 113.2, 70.1, 67.6, 67.0, 63.9, 63.3, 36.8, 21.5,
17.2, 14.2, 12.1; IR (neat) νmax 2946, 2868, 1748, 1599, 1466, 1367,
1259, 1189, 1178, 1097, 1000, 920, 885, 816, 664 cm−1; LR-MS (FAB
+) m/z 529 (M + H+); HR-MS (FAB+) calcd for C25H41O8SSi (M +
H+) 529.2291, found 529.2297.
7.69−7.65 (m, 1H), 7.56 (td, 2H, J = 7.9 Hz, J = 2.9 Hz), 5.83 (d,
0.5H, J = 8.8 Hz), 5.72 (d, 0.5H, J = 8.7 Hz), 5.46−5,41 (m, 0.5H),
5.34−5.27 (m, 0.5H), 4.79 (dd, 1H, J = 12.7 Hz, J = 3.7 Hz), 4.65 (dd,
1H, J = 12.7 Hz, J = 7.4 Hz), 4.22−4.00 (m, 5H), 2.90−2.86 (m,
0.5H), 2.72−2.64 (m, 0.5H), 2.47−2.38 (m, 0.5H), 2.36−2.13 (m,
1H), 1.99−1.93 (m, 0.5H), 1.86−1.70 (m, 1H), 1.33−1.27 (m, 3H);
13C NMR (CDCl3, 100 MHz, a mixture of diastereomers) δ 162.9,
162.7, 154.9, 139.0, 138.6, 138.0, 137.5, 134.5, 134.3, 129.3, 129.2,
129.1, 129.0, 128.4, 127.7, 77.2, 76.3, 68.6, 68.4, 64.4, 63.4, 58.6, 27.4,
25.9, 20.0, 19.5, 14.2; IR (neat) νmax 2994, 1758, 1374, 1246, 1059
cm−1; LR-MS (FAB+) m/z 399 (M + H+); HR-MS (FAB+) calcd for
C18H23O8S (M + H+) 399.1114, found 399.1105.
To a suspension of 60% sodium hydride (727 mg, 18.2 mmol) in
DMF (38 mL) was added methyl phenylsulfonylacetate (3.89 g, 18.2
mmol) in DMF (10 mL) at 0 °C. After stirring for 1 h at 0 °C, a
solution of bis-alkoxysilane (3.95 g, 7.48 mmol) in DMF (10 mL) was
added. The reaction mixture was heated to 80 °C, stirred for 9 h, and
cooled to ambient temperature. The resulting mixture was quenched
with a saturated NH4Cl solution (30 mL) and diluted with ethyl
acetate (100 mL). The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (3 × 50 mL). The combined
organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 1:4) to afford
To a mixture of hydroxyl valerolactone (260 mg, 0.7 mmol) and
imidazole (67 mg, 1.0 mmol) in DMF (7 mL) was added tert-
butyldimethylsilyl chloride (148 mg, 1.0 mmol) at 0 °C. After stirring
for 10 min at ambient temperature, the reaction mixture was quenched
with H2O (10 mL) and diluted with ethyl acetate (10 mL). The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate (3 × 20 mL). The combined organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (EtOAc/n-
hexane = 1:2) to afford δ-valerolactone 6 (334 mg, 89%) as a colorless
1
benzenesulfonyl bis-alkoxysilane 9 (3.32 g, 78%) as a colorless oil: H
NMR (CDCl3, 400 MHz, a mixture of diastereomers) δ 7.82 (d, 2H, J
= 7.3 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.52 (t, 2H, J = 11.9 Hz), 5.73−
5.64 (m, 1H), 5.21 (d, 1H, J = 0.9 Hz), 5.13−5.08 (m, 2H), 5.04−5.00
(m, 1H), 4.58 (s, 2H), 4.29−4.20 (m, 3H), 4.15 (q, 2H, J = 7.1 Hz),
3.96 (ddd, 1H, J = 25.6 Hz, J = 11.2 Hz J = 4.0 Hz), 3.63 (d, 3H, J =
0.9 Hz), 2.08−1.87 (m, 2H), 1.53−1.45 (m, 2H), 1.26 (t, 3H, J = 7.1
Hz), 0.98−0.90 (m, 14H); 13C NMR (CDCl3, 100 MHz, a mixture of
diastereomers) δ 166.2, 154.9, 142.2, 139.8, 139.6, 137.1, 136.9, 134.1,
129.2, 128.9, 115.1, 115.0, 113.2, 72.5, 72.4, 70.6, 67.6, 64.0, 63.2, 52.8,
34.5, 34.4, 22.4, 22.1, 17.3, 17.2, 14.2, 12.2, 12.1; IR (neat) νmax 2947,
2868, 1746, 1448, 1375, 1328, 1260, 1150, 1085, 1011, 924, 884, 772,
724, 689 cm−1; LR-MS (FAB+) m/z 571 (M + H+); HR-MS (FAB+)
calcd for C27H43O9SSi (M + H+) 571.2397, found 571.2383.
Methyl 4-((R)-6-(((Ethoxycarbonyl)oxy)methyl)-2,2-diiso-
propyl-4,7-dihydro-1,3,2-dioxasilepin-4-yl)-2-(phenylsulfonyl)-
butanoate (10). To a refluxing solution of benzenesulfonyl bis-
alkoxysilane 9 (765 mg, 1.6 mmol) in toluene (160 mL, 0.01 M) was
added a second generation Grubbs catalyst (135 mg, 0.2 mmol). After
stirring for 30 min, the reaction mixture was cooled to ambient
temperature and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (EtOAc/n-hexane = 1:4) to
afford the cyclic bis-alkoxysilane 10 (720 mg, 100%) as a colorless oil:
1H NMR (CDCl3, 400 MHz, a mixture of diastereomers) δ 7.85 (d,
2H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.4 Hz), 7.54 (t, 2H, J = 7.7 Hz), 5.55
(s, 1H), 4.66 (d, 1H, J = 18.4 Hz), 4.56 (d, 1H, J = 15.6 Hz), 4.44 (t,
2H, J = 15.3 Hz), 4.26 (dd, 1H, J = 15.5 Hz, J = 4.8 Hz), 4.17 (m, 2H),
4.09−4.02 (m, 1H), 3.67 (d, 3H, J = 6.8 Hz), 2.28−1.85 (m, 2H),
1.62−1.53 (m, 2H), 1.28 (td, 3H, J = 7.1 Hz, J = 1.5 Hz), 0.99 (s,
14H); 13C NMR (CDCl3, 100 MHz, a mixture of diastereomers) δ
170.9, 166.3, 166.2, 154.7, 137.1, 137.0, 136.6, 136.5, 134.1, 133.6,
133.4, 129.2, 128.9, 70.5, 70.4, 70.3, 69.9, 69.3, 64.1, 62.8, 62.7, 60.2,
52.8, 34.7, 34.5, 23.8, 22.9, 20.9, 17.3, 17.2, 17.1, 16.9, 14.1, 12.1, 12.0;
IR (neat) νmax 2949, 1746, 1259, 1220, 1149, 772, 688 cm−1; LR-MS
(FAB+) m/z 543 (M + H+); HR-MS (FAB+) calcd for C25H39O9SSi
(M + H+) 543.2084, found 543.2077.
(Z)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-((2R)-6-oxo-5-
(phenylsulfonyl)tetrahydro-2H-pyran-2-yl)allyl Ethyl Carbo-
nate (6). To a solution of the cyclic bis-alkoxysilane 10 (10.04 g,
18.5 mmol) in THF (185 mL) was added tetra-n-butylammonium
fluoride (1.0 M solution in THF, 37.0 mL, 37.0 mmol) at ambient
temperature. After stirring for 12 h, the reaction mixture was quenched
with a saturated NH4Cl solution (50 mL) and diluted with ethyl
acetate (100 mL). The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (2 × 50 mL). The combined
organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 3:1) to afford
hydroxyl valerolactone (5.83 g, 79%) as a colorless oil: 1H NMR
(CDCl3, 400 MHz, a mixture of diastereomers) δ 7.93−7.90 (m, 2H),
1
oil: H NMR (CDCl3, 400 MHz, a mixture of diastereomers) δ 7.90
(m, 2H), 7.67−7.63 (m, 1H), 7.56−7.52 (m, 1H), 5.74 (dd, 0.5H, J =
34.3 Hz, J = 8.8 Hz), 5.60 (dd, 0.5H, J = 38.5 Hz, J = 8.5 Hz), 5.46−
5.38 (m, 0.5 H), 5.29 (td, 0.5H, J = 9.5 Hz, J = 3.7 Hz), 4.73 (dd,
0.5H, J = 12.5 Hz, J = 3.7 Hz), 4.68−4.53 (m, 1.5H), 4.30−4.00 (m,
5H), 2.83−2.78 (m, 0.5H), 2.67−2.59 (m, 0.5H), 2.44−2.08 (m, 2H),
1.95−1.90 (m, 0.5H), 1.77−1.66 (m, 0.5H), 1.30−1.24 (m, 3H),
0.88−0.85 (m, 9H), 0.08−0.02 (m, 6H); 13C NMR (CDCl3, 100
MHz, a mixture of diastereomers) δ 171.0, 162.7, 154.8, 138.9, 138.6,
138.4, 138.1, 137.6, 134.3, 129.3, 129.0, 126.9, 126.1, 125.9, 77.4, 76.2,
68.2, 68.0, 64.3, 63.8, 63.5, 62.5, 60.3, 59.4, 27.5, 25.9, 25.8, 20.9, 20.0,
19.5, 18.2, 14.1, −5.5; IR (neat) νmax 2955, 1745, 1448, 1321, 1255,
1147, 1085, 838, 773, 724, 688 cm−1; LR-MS (FAB+) m/z 513 (M +
H+); HR-MS (FAB+) calcd for C24H37O8SSi (M + H+) 513.1978,
found 513.1967.
(1R,4R,7R)-7-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-
4-(phenylsulfonyl)-2-oxabicyclo[2.2.1]heptan-3-one (5). To a
refluxing solution of δ-valerolactone 6 (5.38 g, 10.5 mmol) in CH2Cl2
(210 mL) was added a mixture of palladium acetate (118 mg, 0.5
mmol) and 1,1′-bis(diphenylphosphino)ferrocene (582 mg, 1.1
mmol) in CH2Cl2 (2 mL). After stirring for 6 h, the reaction mixture
was cooled to ambient temperature and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(EtOAc/n-hexane = 1:3) to afford [2.2.1] bridged bicyclic lactone 5
(3.84 g, 87%) as a colorless oil and the minor product 5′ (533 mg,
12%) as a white solid: [α]D20 −44.13 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 8.11 (d, 2H, J = 7.9 Hz), 7.65 (t, 1H, J = 7.4 Hz), 7.53 (t,
1H, J = 8.0 Hz), 5.34 (d, 2H, J = 19.1 Hz), 4.82 (s, 1H), 4.17 (q, 2H, J
= 13.6 Hz), 3.20 (s, 1H), 2.54 (td, 1H, J = 12.0 Hz, J = 4.6 Hz), 2.08
(m, 1H), 1.89 (m, 1H), 1.69 (m, 1H), 0.89 (s, 9H), 0.06 (s, 6H); 13C
NMR (CDCl3, 100 MHz) δ 169.1, 139.8, 137.2, 134.4, 130.2, 128.8,
116.1, 83.2, 73.0, 65.7, 57.1, 29.1, 28.0, 25.9, 18.3, −5.4; IR (neat) νmax
2954, 2929, 2856, 1791, 1463, 1448, 1326, 1256, 1158, 1119, 1076,
1037, 924, 839, 782, 759, 717, 688, 604 cm−1; LR-MS (FAB+) m/z
423 (M + H+); HR-MS (FAB+) calcd for C21H31O5SSi (M + H+)
423.1661, found 423.1663.
(1R,4R,7S)-7-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-
4-(phenylsulfonyl)-2-oxabicyclo[2.2.1]heptan-3-one (5′). [α]D20
1
+40.16 (c 2.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 8.02 (d, 2H,
7.6 Hz), 7.67 (t, 1H, J = 7.5 Hz), 7.53 (t, 1H, J = 7.9 Hz), 5.65 (s, 1H),
5.50 (s, 1H), 4.84 (s, 1H), 4.12 (q, 2H, J = 13.0 Hz), 3.10 (s, 1H),
2.90−2.84 (m, 1H), 2.39−2.33 (m, 1H), 2.08−1.96 (m, 2H), 0.87 (s,
9H), 0.05 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 169.4, 139.0,
137.3, 134.4, 130.2, 128.8, 116.6, 81.1, 74.2, 67.2, 55.6, 28.8, 25.9, 23.2,
18.3; IR (neat) νmax 2954, 2857, 1794, 1471, 1448, 1326, 1254, 1155,
1119, 1055, 1008, 943, 838, 779, 720, 688, 603 cm−1; LR-MS (FAB+)
m/z 423 (M + H+); HR-MS (FAB+) calcd for C21H31O5SSi (M + H+)
423.1661, found 423.1666.
E
DOI: 10.1021/acs.joc.5b02121
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1R,4S,7R)-7-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-2-yl)-
2-oxabicyclo[2.2.1]heptan-3-one (11). To a mixture of [2.2.1]
bridged bicyclic lactone 5 (324 mg, 0.8 mmol) and boric acid (475 mg,
7.7 mmol) in MeOH (8 mL) was added 5% sodium mercury amalgam
(2.35 g, 6.1 mmol) at ambient temperature. After stirring for 3 h, the
reaction mixture was decanted with diethyl ether and quenched with a
saturated NH4Cl solution (30 mL). The organic layer was separated,
and an aqueous layer was extracted with diethyl ether (2 × 20 mL).
The combined organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc/n-hexane = 1:6) to
afford desulfonylated bicyclic lactone 11 (200 mg, 93%) as a white
solid: [α]2D0 −8.35 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 5.18
(s, 1H), 5.04 (s, 1H), 4.86 (s, 1H), 4.13 (t, 2H, J = 14.7 Hz), 2.94 (d,
1H, J = 3.4 Hz), 2.66 (s, 1H), 2.05−1.92 (m, 3H), 1.81−1.75 (m, 1H),
0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 177.7,
142.4, 113.1, 82.0, 66.1, 53.7, 45.5, 29.0, 25.8, 23.1, 18.3, −5.4; IR
(neat) νmax 2954, 2857, 1789, 1471, 1333, 1255, 1149, 1097, 1047,
955, 907, 839, 778 cm−1; LR-MS (FAB+) m/z 283 (M + H+); HR-MS
(FAB+) calcd for C15H27O3Si (M + H+) 283.1729, found 283.1736.
(1R,2R,3S)-3-(Hydroxymethyl)-2-(3-hydroxyprop-1-en-2-yl)-
cyclopentan-1-ol (4). To a solution of desulfonylated bicyclic
lactone 11 (212 mg, 0.8 mmol) in diethyl ether (8 mL) were added
lithium borohydride (3.0 M in THF, 1.0 mL, 3.0 mmol) and methanol
(0.18 mL, 4.5 mmol) at 0 °C. After stirring for 4 h, the reaction
mixture was quenched with H2O (10 mL) and diluted with diethyl
ether (10 mL). The organic layer was separated, and the aqueous layer
was extracted with diethyl ether (2 × 10 mL). The combined organic
layer was washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatography on
silica gel (EtOAc/n-hexane = 1:2) to afford cyclopentane silyl ether
(206 mg, 96%) as a colorless oil: [α]2D0 −5.00 (c 1.0, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 5.28 (s, 1H), 5.13 (s, 1H), 4.30−4.26 (m, 1H),
4.18 (d, 1H, J = 12.2 Hz), 4.10 (d, 1H, J = 12.2 Hz), 3.62 (dd, 1H, J =
12.5 Hz, J = 3.4 Hz), 3.35 (dd, 1H, J = 11.1 Hz, J = 5.5 Hz), 2.69 (dd,
1H, J = 8.6 Hz, J = 4.3 Hz), 2.40 (m, 1H), 1.89−1.73 (m, 4H), 0.90 (s,
9H), 0.09 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 145.0, 116.4, 74.0,
68.2, 62.4, 51.0, 43.2, 33.6, 25.8, 24.5, 18.3, −5.3; IR (neat) νmax 3278,
2954, 2858, 1472, 1255, 1083, 1022, 837, 775 cm−1; LR-MS (FAB+)
m/z 287 (M + H+); HR-MS (FAB+) calcd for C15H31O3Si (M + H+)
287.2042, found 287.2038.
+ H+); HR-MS (FAB+) calcd for C9H13O3 (M + H+) 169.0865, found
169.0874.
(3aS,4R,6aR)-3a-Hydroxy-4-(hydroxymethyl)-3-methylene-
hexahydro-2H-cyclopenta[b]furan-2-one (3). To a refluxing
solution of bicyclic lactone 12 (27.0 mg, 0.1 mmol) in 1,4-dioxane
(2 mL) was added selenium dioxide (178.0 mg, 1.6 mmol). After
stirring for 24 h, the reaction mixture was filtered through a pad of
Celite and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc only) to afford
dihydroxy bicyclic lactone 3 (26.5 mg, 90%) as a colorless oil: [α]D20
1
+16.25 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 6.60 (s, 1H),
6.20 (s, 1H), 4.70 (d, 1H, J = 2.0 Hz), 3.83 (dd, 1H, J = 10.1 Hz, J =
5.0 Hz), 3.58 (t, 1H, J = 10.0 Hz), 2.81 (s, 1H), 2.44−2.36 (m, 1H),
2.06−2.01 (m, 2H), 1.78−1.72 (m, 1H), 1.60 (br, 1H), 1.17−1.13 (m,
1H); 13C NMR (CDCl3, 125 MHz) δ 169.5, 138.4, 128.4, 89.8, 85.1,
62.1, 53.3, 31.0, 25.7; IR (neat) νmax 3420, 2967, 1748, 1408, 1300,
1220, 1193, 1146, 1089, 1024, 984, 819, 772 cm−1; LR-MS (FAB+) m/
z 185 (M + H+); HR-MS (FAB+) calcd for C9H13O4 (M + H+)
185.0814, found 185.0810.
Diastereomeric Mixture of (3aS,4R,6aR)-3a-Hydroxy-4-
((1S,2R)-1-hydroxy-2-methylbut-3-en-1-yl)-3-methylenehexa-
hydro-2H-cyclopenta[b]furan-2-one (2) and (1R,2S) Isomer
(14). To a solution of dihydroxy bicyclic lactone 3 (23.0 mg, 0.1
mmol) in CH2Cl2 (1 mL) was added Dess-Martin periodinane (106.0
mg, 0.3 mmol) at ambient temperature. After stirring for 30 min, the
reaction mixture was filtered through a pad of anhydrous sodium
sulfate and concentrated in vacuo. The residue was used in the next
step without further purification.
To a solution of crude aldehyde 13 in CH2Cl2 (1.3 mL, 0.1 M) were
added titanium tetrachloride (0.25 mL, 0.3 mmol) and (E)-
crotyltrimethylsilane (160 mg, 1.3 mmol) at −78 °C. After stirring
for 6 h, the reaction mixture was quenched with a saturated Na2S2O3
solution (5 mL) and diluted with ethyl acetate (10 mL). The organic
layer was separated, and the aqueous layer was extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (EtOAc/n-
hexane = 1:2) to afford a diastereomeric mixture of homoallylic
alcohol 2/14 (23.2 mg, 78%, dr 5:1) as a colorless oil. The
diastereomeric ratio was determined after the separation of each
diastereomer as the silyl ethers 15 and 15′ followed by desilylation.
Major Product 2. [α]D20 +50.16 (c 0.25, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 6.33 (s, 1H), 5.86 (s, 1H), 5.67 (ddd, 1H, J = 17.9 Hz, J =
9.6 Hz, J = 8.4 Hz), 5.09−5.03 (m, 2H), 4.52 (d, 1H, J = 4.3 Hz), 3.51
(m, 1H), 2.35 (td, 1H, J = 10.7 Hz, J = 2.8 Hz), 2.26 (q, 1H, J = 7.2
Hz), 2.13−2.09 (m, 1H), 1.96−1.89 (m, 1H), 1.83−1.77 (m, 1H),
1.76 (s, 1H), 1.33 (d, 1H, J = 5.2 Hz), 1.23 (s, 1H), 1.05 (d, 3H, J =
1.7 Hz); 13C NMR (CDCl3, 150 MHz) δ 168.7, 142.7, 140.7, 122.4,
115.5, 90.4, 85.6, 72.2, 54.5, 43.2, 29.7, 22.5, 16.2; IR (neat) νmax 3503,
2926, 1749, 1220, 773 cm−1; LR-MS (FAB+) m/z 239 (M + H+); HR-
MS (FAB+) calcd for C13H19O4 (M + H+) 239.1283, found 239.1290.
Minor Product 14. [α]2D0 +23.28 (c 0.25, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 6.60 (s, 1H), 6.24 (s, 1H), 5.86 (m, 1H), 5.24
(d, 1H, J = 10.7 Hz), 5.15 (d, 1H, J = 7.6 Hz), 4.72 (s, 1H), 3.57 (d,
1H, J = 10.4 Hz), 3.39 (s, 1H), 2.32 (s, 1H), 2.20 (ddd, 1H, J = 13.6
Hz, J = 7.0 Hz, J = 5.8 Hz), 2.05−2.02 (m, 1H), 1.78 (s, 1H), 1.71−
1.68 (m, 1H), 1.25−1.13 (m, 1H), 1.02 (d, 3H, J = 7.0 Hz); 13C NMR
(CDCl3, 125 MHz) δ 169.7, 140.2, 138.6, 128.7, 116.8, 88.8, 85.2,
72.9, 54.5, 39.5, 31.3, 25.1, 9.7; IR (neat) νmax 3472, 2970, 1702, 1284,
1197, 1144, 1099, 987 cm−1; LR-MS (FAB+) m/z 239 (M + H+); HR-
MS (FAB+) calcd for C13H19O4 (M + H+) 239.1283, found 239.1282.
(3aS,4R,6aR)-3a-Hydroxy-4-((1S,2R)-2-methyl-1-((triethyl-
silyl)oxy)but-3-en-1-yl)-3-methylenehexahydro-2H-cyclo-
penta[b]furan-2-one (15). To a solution of a diastereomeric mixture
of homoallylic alcohol 2/14 (5:1) (23.2 mg, 0.1 mmol) in pyridine (1
mL) was added triethylsilyl trifluoromethanesulfonate (0.1 mL, 0.3
mmol) at −40 °C. After stirring for 30 min, the reaction mixture was
quenched with H2O (1 mL) and diluted with ethyl acetate (5 mL).
The organic layer was separated, and the aqueous layer was extracted
with ethyl acetate (2 × 5 mL). The combined organic layer was
To a solution of cyclopentane silyl ether (206 mg, 0.7 mmol) in
THF (15 mL) was added tetra-n-butylammonium fluoride (1.0 M
solution in THF, 0.8 mL, 0.8 mmol) at ambient temperature. After
stirring for 30 min, the reaction mixture was concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel
(CH2Cl2/MeOH = 9:1) to afford cyclopentanetriol 4 (124 mg, 100%)
1
as a colorless oil: [α]2D0 +37.84 (c 0.5, MeOH); H NMR (CD3OD,
400 MHz) δ 5.25 (d, 2H, J = 18.4 Hz), 4.26 (q, 1H, J = 4.4 Hz), 4.01
(s, 2H), 3.51 (m, 2H), 2.63 (dd, 1H, J = 8.2 Hz, J = 4.5 Hz), 2.40−
2.38 (m, 1H), 1.89−1.82 (m, 2H), 1.79−1.69 (m, 2H); 13C NMR
(CD3OD, 100 MHz) δ 147.8, 114.7, 76.2, 68.4, 64.3, 51.3, 44.0, 35.4,
26.6; IR (neat) νmax 3313, 2942, 1648, 1472, 1338, 1129, 1019, 945,
908, 798 cm−1; LR-MS (FAB+) m/z 173 (M + H+); HR-MS (FAB+)
calcd for C9H17O3 (M + H+) 173.1178, found 173.1177.
(3aR,4S,6aR)-4-(Hydroxymethyl)-3-methylenehexahydro-
2H-cyclopenta[b]furan-2-one (12). To a solution of cyclopentane-
triol 4 (52.5 mg, 0.3 mmol) in THF (12 mL) was added manganese
dioxide (1.06 g, 12.2 mmol) at ambient temperature. After stirring for
12 h, the reaction mixture was filtered through a pad of Celite and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 2:1) to afford cis-
fused 5,5-bicyclic lactone 12 (46.7 mg, 91%) as a colorless oil: [α]D20
+39.36 (c 0.25, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 6.39 (d, 1H, J
= 1.8 Hz), 5.85 (d, 1H, J = 1.0 Hz), 5.00 (t, 1H, J = 5.9 Hz), 3.69 (dd,
1H, J = 10.5 Hz, J = 5.6 Hz), 3.64−3.56 (m, 2H), 2.32−2.24 (m, 1H),
2.14 (dd, 1H, J = 13.4 Hz, J = 6.4 Hz), 1.79−1.69 (m, 2H), 1.29−1.18
(m, 1H); 13C NMR (CDCl3, 125 MHz) δ 171.1, 134.7, 125.6, 83.5,
62.2, 46.2, 44.3, 32.9, 25.9; IR (neat) νmax 3460, 2962, 1757, 1313,
1268, 1220, 1158, 1026, 985, 772 cm−1; LR-MS (FAB+) m/z 169 (M
F
DOI: 10.1021/acs.joc.5b02121
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The Journal of Organic Chemistry
Article
washed with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(EtOAc/n-hexane = 1:10 to 1:6) to afford the bicyclic lactone silyl
ether 15 (25.7 mg, 75%) as a white solid and the minor (1R, 2S)
isomer 15′ (5.2 mg, 15%) as a white solid.
mmol) at ambient temperature. After stirring for 3 h, the reaction
mixture was quenched with H2O (1 mL) and diluted with CH2Cl2 (1
mL). The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 5 mL). The combined organic layer was
washed with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(EtOAc/n-hexane = 1:2) to afford the crude xanthate.
Major Product 15. [α]D20 +37.60 (c 0.5, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 6.48 (s, 1H), 5.90 (s, 1H), 5.87 (m, 1H), 5.04−4.97 (m,
2H), 4.57 (d, 1H, J = 3.5 Hz), 3.69 (dd, 1H, J = 7.0 Hz, J = 2.0 Hz),
2.55−2.51 (m, 1H), 2.26−2.20 (m, 1H), 2.03−1.99 (m, 1H), 1.92−
1.83 (m, 2H), 1.83 (s, 1H), 1.49−1.43 (m, 1H), 1.01 (d, 3H, J = 6.8
Hz), 0.90 (t, 9H, J = 8.0 Hz), 0.53 (q, 6H, J = 8.0 Hz); 13C NMR
(CDCl3, 150 MHz) δ 168.6, 141.6, 140.2, 126.3, 114.1, 91.1, 84.8,
74.6, 53.9, 41.6, 29.9, 26.8, 12.6, 7.0, 5.5; IR (neat) νmax 3434, 2958,
1749, 1261, 1220, 1011, 772 cm−1; LR-MS (FAB+) m/z 353 (M +
H+); HR-MS (FAB+) calcd for C19H33O4Si (M + H+) 353.2148, found
353.2138.
To a mixture of tributyltin hydride (13 μL, 0.05 mmol) and
azobis(isobutyronitrile) (0.4 mg, 2 μmol) in toluene (0.5 mL) was
added the crude xanthate in toluene (0.5 mL) at 80 °C. The reaction
mixture was heated to 100 °C. After stirring for 1 h, the resulting
mixture was cooled to ambient temperature and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel
(EtOAc/n-hexane = 1:3) to afford (−)-galiellalactone 1 (3.5 mg, 76%
in 2 steps) as a white solid: [α]2D0 −47.56 (c 0.25, CHCl3) (lit.1,2[α]2D0
−52.80 (c 0.20, CHCl3)); 1H NMR (CDCl3, 500 MHz) δ 7.03 (d, 1H,
J = 3.0 Hz), 4.76 (dd, 1H, J = 7.5 Hz, J = 2.0 Hz), 2.62 (qdt, 1H, J =
14.6 Hz, J = 7.4 Hz, J = 3.1 Hz), 2.43 (dddd, 1H, J = 10.5 Hz, J = 7.4
Hz, J = 7.2 Hz, J = 4.8 Hz), 2.24 (dt, 1H, J = 14.0 Hz, J = 7.4 Hz), 2.07
(dddd, 1H, J = 14.6 Hz, J = 11.2 Hz, J = 7.6 Hz, J = 7.3 Hz), 1.93 (s,
1H) 1.85 (dddd, 1H, J = 13.2 Hz, J = 7.2 Hz, J = 7.2 Hz, J = 2.9 Hz),
1.74 (m, 1H), 1.18 (1H, m), 1.18 (d, 3H, J = 7.4 Hz), 1.07 (ddd, 1H, J
= 13.6 J = 8.0 Hz, J = 4.7 Hz); 13C NMR (CDCl3, 125 MHz) δ 169.5,
150.2, 130.6, 89.7, 81.9, 43.1, 33.0, 31.3, 29.0, 20.9; IR (neat) νmax
2959, 2931, 1759, 1744, 1188, 1017, 971, 896 cm−1; LR-MS (FAB+)
m/z 195 (M + H+); HR-MS (FAB+) calcd for C11H15O3 (M + H+)
195.1021, found 195.1013.
Minor Product 15′. [α]2D0 −29.78 (c 0.5, CHCl3); 1H NMR
(CDCl3, 600 MHz) δ, 6.54 (s, 1H), 6.03 (ddd, 1H, J = 17.4 Hz, J =
10.8 Hz, J = 4.6 Hz), 5.99 (s, 1H), 5.16 (dt, 1H, J = 11.0 Hz, J = 1.4
Hz), 5.09 (dt, 1H, J = 17.4 Hz, J = 1.8 Hz), 4.62 (d, 1H, J = 5.5 Hz),
3.81 (dd, 1H, J = 9.6 Hz, J = 2.8 Hz), 3.69 (s, 1H), 2.55−2.50 (m,
1H), 2.17 (m, 1H), 1.97−1.86 (m, 2H), 1.68 (quint, 1H, J = 6.0 Hz),
1.18−1.10 (m, 1H), 1.00−0.97 (m, 12H), 0.74−0.65 (m, 6H); 13C
NMR (CDCl3, 150 MHz) δ 169.6, 139.8, 137.9, 127.1, 115.2, 88.2,
85.2, 77.9, 55.9, 42.3, 31.4, 25.1, 14.6, 7.0, 6.0; IR (neat) νmax 3442,
2959, 2877, 1747, 1415, 1338, 1113, 1007, 977, 914, 819, 741 cm−1;
LR-MS (FAB+) m/z 353 (M + H+); HR-MS (FAB+) calcd for
C19H33O4Si (M + H+) 353.2148, found 353.2155.
(2aR,2a1S,4aR,5S,6R)-2a1-Hydroxy-6-methyl-5-((triethyl-
silyl)oxy)-2a1,3,4,4a,5,6-hexahydroindeno[1,7-bc]furan-1-
(2aH)-one (16). To a refluxing solution of bicyclic lactone silyl ether
15 (6.5 mg, 0.02 mmol) in CH2Cl2 (2 mL, 0.01 M) was added a
second generation Grubbs catalyst (0.9 mg, 0.9 μmol). After stirring
for 6 h, the reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 1:5) to afford the
tricyclic lactone 16 (6.0 mg, 99%) as a white solid: [α]2D0 −22.84 (c 0.5,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 6.75 (d, 1H, J = 2.4 Hz), 4.81
(d, 1H, J = 8.4 Hz), 3.95 (d, 1H, J = 2.5 Hz), 3.83 (s, 1H), 2.65−2.60
(m, 1H), 2.46 (ddd, 1H, J = 12.4 Hz, J = 6.7 Hz, J = 3.0 Hz), 2.14−
2.06 (m, 1H), 1.76−1.67 (m, 2H), 1.30−1.21 (m, 1H), 1.15 (d, 3H, J
= 8.1 Hz), 0.96 (t, 9H, J = 7.9 Hz), 0.63 (q, 6H, J = 8.0 Hz); 13C NMR
(CDCl3, 125 MHz) δ 169.9, 141.6, 129.6, 88.3, 80.0, 74.6, 48.4, 39.2,
30.8, 26.5, 19.1, 6.6, 4.6; IR (neat) νmax 3414, 2958, 2877, 1761, 1673,
1459, 1283, 1221, 1193, 1096, 1051, 1029, 836, 745 cm−1; LR-MS
(FAB+) m/z 325 (M + H+); HR-MS (FAB+) calcd for C17H29O4Si
(M + H+) 325.1835, found 325.1840.
(2aR,2a1S,4aR,5S,6R)-2a1,5-Dihydroxy-6-methyl-
2a1,3,4,4a,5,6-hexahydroindeno[1,7-bc]furan-1(2aH)-one (17).
To a solution of tricyclic lactone 16 (17.7 mg, 0.1 mmol) in MeOH (1
mL) was added camphor-10-sulfonic acid (β) (1.3 mg, 5 μmol) at
ambient temperature. After stirring for 1 min, the reaction mixture was
quenched with a saturated NaHCO3 solution (1.0 mL) and diluted
with ethyl acetate (5.0 mL). The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate (5 × 5.0 mL). The
combined organic layer was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/n-hexane = 4:1) to afford
hydroxygaliellalactone 17 (9.5 mg, 83%) as a white solid: [α]2D0 −39.44
(c 0.5, MeOH); 1H NMR (CD3OD, 500 MHz) δ 6.81 (d, 1H, J = 3.2
Hz), 4.62 (t, 1H, J = 4.7 Hz), 3.06 (dd, 1H, J = 7.0 Hz, J = 5.0 Hz),
2.59 (m, 1H), 2.23 (dd, 1H, J = 10.7 Hz, J = 4.5 Hz), 2.18−2.11 (m,
1H), 2.09−2.04 (m, 1H), 1.58−1.48 (m, 1H), 1.25 (d, 3H, J = 5.7
Hz); 13C NMR (CD3OD, 125 MHz) δ 177.6, 149.1, 134.5, 92.1, 84.5,
82.1, 54.5, 39.3, 33.0, 30.8, 18.0; IR (neat) νmax 3413, 2928, 1743,
1220, 1047, 772 cm−1; LR-MS (FAB+) m/z 211 (M + H+); HR-MS
(FAB+) calcd for C11H15O4 (M + H+) 211.0970, found 211.0971.
(−)-Galiellalactone (1). To a mixture of hydroxygaliellalactone 17
(5.0 mg, 0.02 mmol) and pyridine (10 μL, 0.1 mmol) in CH2Cl2 (0.5
mL) was added pentafluorophenyl chlorothionoformate (13 μL, 0.1
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02121.
■
S
1H and 13C NMR spectra of all novel compounds and
synthetic natural product (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: ygsuh@snu.ac.kr.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation of
Korea (NRF) grant for the Global Core Research Center
(GCRC) funded by the Korean government (MSIP) (No.
2011-0030001) and by a National Research Foundation of
Korea (NRF) grant funded by the Korean government (2009-
0083533).
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