Stereoselective total synthesis of (±)-peribysin e

Article abstract of DOI:10.1021/jo2021604

Radical cyclization of iodoketone 3 afforded cis-hydrindanone 8. Compound 8 was converted into key intermediate 5 via conventional transformations. Annulation of a spiro-lactal unit to 5 was pursued with three different approaches. In the first approach, radical cyclization of propargyl ester 17 provided spiro-lactone 18 with an undesired stereochemistry. Attempts to invert the stereochemistry at the spiro-center via retro-aldol and aldol condensation of compound 20 failed. In the second approach, key intermediate 5 was transformed into 23. Acylation of compound 23 gave 24 as a single diastereomer with the desired stereochemistry but in low yield. NBS bromination of 24 followed by lactone formation gave 26 in low yield. Alternatively, allylic oxidation of 24 with SeO₂ followed by lactonization gave 26 also in low yield. Finally, a third approach employing a semipinacol-type rearrangement of epoxy-alcohol 33 gave aldehyde 34 with the desired stereochemistry. Treatment of compound 34 with HCl in MeOH effected spiro-lactal formation and provided (±)-peribysin E. The overall yield of our synthesis is 3.2% from 2-methylcyclohenen-1-one.

Full text of DOI:10.1021/jo2021604

Article
pubs.acs.org/joc
Stereoselective Total Synthesis of ( )-Peribysin E
Hung-Yi Lee and Chin-Kang Sha*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan, ROC
S
* Supporting Information
ABSTRACT: Radical cyclization of iodoketone 3 afforded cis-
hydrindanone 8. Compound 8 was converted into key
intermediate 5 via conventional transformations. Annulation
of a spiro-lactal unit to 5 was pursued with three different
approaches. In the first approach, radical cyclization of
propargyl ester 17 provided spiro-lactone 18 with an undesired
stereochemistry. Attempts to invert the stereochemistry at the
spiro-center via retro-aldol and aldol condensation of compound 20 failed. In the second approach, key intermediate 5 was
transformed into 23. Acylation of compound 23 gave 24 as a single diastereomer with the desired stereochemistry but in low
yield. NBS bromination of 24 followed by lactone formation gave 26 in low yield. Alternatively, allylic oxidation of 24 with SeO2
followed by lactonization gave 26 also in low yield. Finally, a third approach employing a semipinacol-type rearrangement of
epoxy-alcohol 33 gave aldehyde 34 with the desired stereochemistry. Treatment of compound 34 with HCl in MeOH effected
spiro-lactal formation and provided ( )-peribysin E. The overall yield of our synthesis is 3.2% from 2-methylcyclohenen-1-one.
Scheme 1
INTRODUCTION
■
Peribysin E (1) and related metabolites were isolated by
Yamada and co-workers from a strain of Periconia byssoides
OUPS-N133 originally separated from the sea hare, Aplysia
kurodai.1 These natural products, especially peribysin E (1),
Figure 1, were reported to inhibit adhesion of leukemia HL-60
Figure 1. Structure of peribysin E.
Radical cyclization of 3 would give cis-hydrindanone 4. After
several conventional transformations, compound 4 could be
converted into key intermediate 5. The spiro-annulation of a β-
methylene lactal unit to 5 could furnish peribysin E (1).
Our synthesis thus began with 2-methylcyclohexen-1-one
(2), Scheme 2. CuI-mediated conjugate addition of 4-
(trimethylsilyl)-3-butynylmagnesium chloride (6) to 2, fol-
lowed by trapping the resulting enolate with chlorotrimethylsi-
lane, generated TMS-enol ether 7. Treatment of 7 with a
mixture of NaI and m-CPBA gave α-iodoketone 3. Photolysis of
α-iodoketone 3 with a sunlamp in the presence of
hexamethylditin, followed by reduction with tributyltin hydride,
gave compound 8. Hydrodesilylation of compound 8 with
trifluoroacetic acid followed by reduction with sodium
borohydride cleanly afforded alcohol 9 as a single diastereomer.
Dihydroxylation of the exocyclic double bond of 9 with OsO4
cells to human-umbilical-vein endothelial cells (HUVEC).2
Because of its potent cell-adhesion inhibitory activity and its
scarcity, peribysin E has become a target for total synthesis.
Danishefsky and co-workers achieved the first total synthesis of
both enantiomers of peribysin E and thereby reassigned the
absolute configuration (shown as 1). In their elegant synthesis,
a Diels−Alder reaction followed by semipinacol-type ring
contraction served to secure the stereochemistry of peribysin E
(1).3
In our laboratories, we developed a radical cyclization of α-
iodoketones to prepare cis-hydrindanones.4 This method was
applied to total synthesis of various natural products.5 We
envisioned that our method would be also applicable for the
total synthesis of peribysin E.
RESULTS AND DISCUSSION
■
Our synthetic planning was shown in Scheme 1. According to
our method,4 2-methylcyclohexen-1-one (2)6 could be
converted into α-iodoketone 3 with an alkynyl side chain.
Received: October 21, 2011
Published: November 17, 2011
© 2011 American Chemical Society
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Scheme 2
Scheme 3
acetonitrile, generated diol 20.11 Attempted retro-aldol and
aldol reactions of 20 with several bases, such as TBAF, LDA,
LHMDS, or with acids, such as HCl, Et2AlH, failed to produce
the desired compound 21.
Scheme 4
and N-methylmorpholine-N-oxide, followed by treatment of
the diol intermediate with 2,2-dimethyloxypropane, gave
acetonide 10. Dehydration of 10 with POCl3 at 70 °C afforded
compound 11. Allylic oxidation of 11 with Pd(OH)2 and tert-
butyl hydroperoxide gave enone 12.7 CuI mediated conjugate
addition of methyllithium to enone 12 afforded ketone 13 as a
single diastereomer. Reduction of ketone 13 with NaBH4, or
DIBAL, or L-selectride gave a mixture of epimeric alcohols. The
desired alcohol 14 was obtained only with Li/NH3 reduction.
Removal of the acetonide group in 14 followed by oxidative
cleavage with NaIO4 afforded ketone 15. The stereochemistry
of 15 was determined with single-crystal X-ray analysis.8
Protection of the alcohol group in 15 with a tert-
butyldimethylsilyl (TBS) group afforded the key hydrindanone
5.
We then devoted our effort to stereoselective annulation of
the spiro-lactal unit to hydrindanone 5, Scheme 3. Compound
5 was first treated with lithium diisopropylamide and then ethyl
cyanoformate to give ethyl ester 16. Trans-esterification of 16
with propargyl alcohol in the presence of p-toluenesulfonic acid
gave propargyl ester 17. Treatment of 17 with manganese
triacetate effected a radical cyclization to afford spiro
compound 18.9 A single-crystal X-ray analysis indicated that
18 had the undesired stereochemistry at the spiro-center.10 We
then attempted a retro-aldol and aldol condensation according
We then tried an alternative route, Scheme 4. Compound 5
was treated with lithium diisopropylamide and then acetone to
give β-hydroxy ketone 22. Dehydration of 22 followed by
isomerization of the double bond with DBU afforded enone 23.
Enone 23 was first deprotonated with lithium bis-
(trimethylsilyl)amide and then acylated with methyl cyano-
formate to afford exclusively keto-ester 24 but only in 31%
yield. A single-crystal X-ray analysis indicated that 24 has the
desired stereochemistry at the spiro-center.12 Compound 24
was then brominated with NBS to give compound 25.
́
to Depres’ procedure to invert the undesired stereochemistry at
the spiro-center.9 Samarium(II) iodide reduction of 18,
followed by removal of the TBS group with 50% HF in
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Treatment of crude 25 with silver(I) oxide gave compound 26
in low yield (25% in two steps from 24).13 Alternatively, allylic
oxidation of 24 with SeO2 in 1,4-dioxane at 85 °C followed by
lactonization gave compound 26 in 46% yield. Our effort to
optimize the yields of this second approach was not successful.
EXPERIMENTAL SECTION
■
2-Iodo-2-methyl-3-[4-(trimethylsilyl)but-3-yn-1-yl]-
cyclohexanone (3). To magnesium turnings (4.54 g, 181.56 mmol)
suspended in anhydrous THF (10 mL), 1,2-dibromoethane (0.20 mL)
was added. The reaction mixture was heated to reflux. A solution of 4-
chloro-1-trimethylsilyl-1-butyne (16.05 g, 99.86 mmol) and 1,2-
dibromoethane (0.10 mL) in THF (50 mL) was added dropwise
over a period of 1 h. After an additional reflux for 2 h, the reaction
mixture was cooled to −30 °C. CuI (12.97 g, 68.06 mmol) was added.
To the resulting mixture, 2-methyl cyclohexen-1-one 2 (5.00 g, 45.39
mmol) in anhydrous THF (60 mL) was added dropwise.
Chlorotrimethylsilane (11.46 mL, 90.78 mmol) and triethylamine
(12.58 mL, 90.78 mmol) was then added. The reaction mixture was
stirred at −30 °C for 16 h and then warmed up to room temperature.
After filtration, water was added. The filtrate was extracted with ether
(3 × 200 mL). The combined organic layer was washed with saturated
NH4Cl (100 mL) and brine (100 mL) and dried over MgSO4.
Concentration gave crude 7. It was immediately used for the next
reaction. To a solution of NaI (20.41 g, 136.17 mmol) and crude 7 in
THF (250 mL) was added dropwise m-CPBA (70%, 23.50 g, 136.17
mmol) in THF (150 mL) at 0 °C. The reaction mixture was stirred for
3 h. Water was added. The mixture was extracted with ether (3 × 100
mL). The combined organic layer was washed with saturated Na2S2O3
(150 mL), saturated NaHCO3 (150 mL), and brine (150 mL) and
dried over MgSO4. Concentration and silica gel flash column
chromatography (EtOAc/hexane, 1:50) afforded 3 (12.83 g, 78%) as
a yellow oil. Data for the major diastereomer: IR (neat) v 2956, 2864,
Scheme 5
1
2174, 1706, 1443, 1248 cm−1; H NMR (400 MHz, CDCl3) δ 3.52
(td, J = 14.4, 6.5 Hz, 1H), 2.44−2.31 (m, 2H), 2.32−2.18 (m, 1H),
2.04 (s, 3H), 2.03−1.95 (m, 1H), 1.95−1.81 (m, 2H), 1.59−1.36 (m,
3H), 0.43−0.33 (m, 1H), 0.10 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ 205.0 (C), 106.3 (C), 85.7 (C), 60.4 (C), 49.0 (CH), 35.7 (CH2),
34.2 (CH2), 28.7 (CH2), 27.7 (CH3), 24.8 (CH2), 17.7 (CH2), 0.0
(CH3); HRMS (FAB) m/z calcd for C14H23O Si I 362.0563, found
362.0559.
[3(E and Z),3aS*,7aS*]-3a-Methyl-3-[(trimethylsilyl)-
methylene]octahydro-4H-inden-4-one (8). To a solution of 3
(23.73 g, 65.49 mmol) in anhydrous benzene (600 mL) was added
(Bu3Sn)2 (6.55 mL, 13.09 mmol). The reaction mixture was heated to
reflux and irradiated with a sunlamp for 2 h. The sunlamp was
removed. AIBN (2.15 g, 13.09 mmol) and Bu3SnH (19.35 mL, 72.04
mmol) were added. The reaction mixture was heated to reflux for 2 h.
Concentration and silica gel flash column chromatography (EtOAc/
hexane, 1:50) gave 8 (13.76 g, 89%) as a mixture of E and Z isomers
(pale yellow oil). Data for the major isomer: IR (neat) v 2951, 2930,
2864, 1705, 1608, 1246 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.40 (t,
J = 2.1 Hz, 1H), 2.77− 2.64 (m, 1H), 2.56−2.45 (m, 2H), 2.29−2.18
(m, 1H), 2.12−2.02 (m, 1H), 1.98−1.77 (m, 2H), 1.69−1.53 (m, 2H),
1.52−1.39 (m, 2H), 1.15 (s, 3H), −0.01 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 213.5 (C), 165.2 (C), 122.3 (CH), 60.9 (C), 54.0
(CH), 40.3 (CH2), 35.1 (CH2), 28.7 (CH2), 28.5 (CH2), 26.6 (CH2),
22.6 (CH3), 0.8 (CH3); HRMS (EI) m/z calcd for C14H24OSi
236.1596, found 236.1590.
We then decided to pursue a third approach using
semipinacol-type rearrangement as the key step, Scheme 5.
Reduction of ketone ester 16 with NaBH4 gave compound 27.
Dehydration of 27 afforded α,β-unsaturated ester 28.
Reduction of the ester group in 28 with DIBAL gave allylic
alcohol 29. Stereoselective epoxidation of allylic alcohol 29 with
m-CPBA gave compound 30. Dess−Martin oxidation of alcohol
30 gave aldehyde 31. Reaction of 31 with the dianion generated
from 2-iodopropen-1-ol (32) and n-BuLi gave epoxy-alcohol
33.14 Treatment of 33 with 2,6-lutidine and TMSOTf effected a
semipinacol-type rearrangement to afford the unstable
intermediate 34.15 Treatment of 34 with HCl/MeOH
successfully afforded ( )-peribysin E (1) with the correct
stereochemistry. The 1H and 13C NMR spectra of our synthetic
peribysin E agree satisfactorily with those reported by
Danshefsky’s group.
(3aS*,7aS*)-3a-Methyl-3-methyleneoctahydro-4H-inden-4-
one (4). To a solution of 8 (13.76 g, 58.29 mmol) in CH2Cl2 (300
mL) was added CF3COOH (15.09 mL, 196.47 mmol) at 0 °C. The
reaction mixture was stirred for 1 h and then neutralized with saturated
NaHCO3 (75 mL). The reaction mixture was extracted with CH2Cl2
(3 × 100 mL). The combined organic layer was washed with brine (50
mL) and dried over MgSO4. Concentration gave a crude product 4 as
a pale yellow oil, which was used for the next reaction: IR (neat) v
1
2928, 2864, 1702, 1648, 1250 cm−1; H NMR (400 MHz, CDCl3) δ
CONCLUSION
■
4.89 (t, J = 2.1 Hz, 1H), 4.67 (t, J = 2.5 Hz, 1H), 2.61−2.42 (m, 2H),
2.41−2.32 (m, 1H), 2.31−2.23 (m, 1H), 2.14−2.05 (m, 1H), 1.96−
1.84 (m, 2H), 1.76−1.67 (m, 1H), 1.63−1.50 (m, 2H), 1.49−1.37 (m,
1H), 1.16 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 212.9 (C), 155.5
(C), 107.3 (CH2), 59.9 (C) 50.3 (CH), 38.7 (CH2), 29.1 (CH2), 28.9
(CH2), 28.1 (CH2), 24.6 (CH2), 23.4 (CH3); HRMS (EI) m/z calcd
for C11H16O 164.1201, found 164.1201.
In summary, we achieved a stereoselective total synthesis of
( )-peribysin E via α-carbonyl radical cyclization and semi-
pinacol-type rearrangement. Our synthesis provided ( )-peri-
bysin E in 3.2% overall yield from 2-methylcyclohexen-1-one
and is adaptable for preparation of analogues and derivatives of
peribysin E for anticancer study.
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(3aS*,4S*,7aS*)-3a-Methyl-3-methyleneoctahydro-1H-
inden-4-ol (9). To a solution of the crude product 4 in methanol
(400 mL), NaBH4 (4.95 g, 130.98 mmol) was added portionwise at 0
°C. After stirring for 0.5 h, water (50 mL) and CH2Cl2 (200 mL) were
added. The organic layer was separated, washed with saturated
NaHCO3 (50 mL) and brine (30 mL), and dried over MgSO4.
Concentration and silica gel flash column chromatography (EtOAc/
hexane, 1:50) furnished 9 (7.55 g, 78% from 8) as a colorless oil: IR
mL, 93.9 mmol) was added compound 11 (8.35 g, 37.56 mmol). The
reaction mixture was vigorously stirred at room temperature. After
stirring for 24 h, a mixture of 20% Pd(OH)2/C (1.32 g, 1.88 mmol),
K2CO3 (1.29 g, 9.39 mmol), and 70% t-BuOOH in water (12.89 mL,
93.9 mmol) was added. The reaction mixture was stirred at room
temperature for 24 h. The reaction mixture was then filtered through a
short pad of silica gel. The short pad of silica gel was washed with
CH2Cl2 (200 mL). The combined organic layer was washed with brine
(50 mL), dried over MgSO4, and concentrated. Silica gel flash column
chromatography (EtOAc/hexane, 1:10) afforded the enone 12 (6.66 g,
75%) as a pale yellow oil: IR (neat) v 2983, 2938, 1678, 1457, 1237,
1237 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.37 (dd, J = 10.3, 2.0 Hz,
1H), 5.90 (dd, J = 10.3, 0.9 Hz, 1H), 4.09 (d, J = 8.9 Hz, 1H), 3.90 (d,
J = 8.9 Hz, 1H), 2.58 (dd, J = 16.6, 4.8 Hz, 1H), 2.52−2.45 (m, 1H),
2.42 (ddd, J = 16.7, 2.8, 0.9 Hz, 1H), 2.12−2.00 (m, 1H), 1.96−1.88
(m, 1H), 1.67−1.56 (m, 1H), 1.40 (d, J = 0.6 Hz, 3H), 1.37 (d, J = 0.6
Hz, 3H), 1.37−1.27 (m, 1H), 1.18 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 198.9 (C), 152.0 (CH), 129.5 (CH), 109.6 (C), 92.4 (C),
67.7 (CH2), 48.0 (C), 41.6 (CH), 38.2 (CH2), 37.0 (CH2), 26.8
(CH3), 26.3 (CH3), 26.1 (CH2), 17.7 (CH3); HRMS (EI) m/z calcd
for C14H20O3 236.1412, found 236.1409.
1
(neat) v 3399, 2932, 2860, 1648, 1458 cm−1; H NMR (400 MHz,
CDCl3) δ 5.05 (ddd, J = 2.6, 1.9, 0.9 Hz, 1H), 4.94 (t, J = 2.3 Hz, 1H),
3.52 (dd, J = 4.1, 3.2 Hz, 1H), 2.51−2.29 (m, 2H), 1.92−1.68 (m,
5H), 1.66−1.46 (m, 4H), 1.31−1.19 (m, 1H), 1.08 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 160.3 (C), 106.0 (CH2), 75.3 (CH), 47.9 (C)
45.5 (CH), 32.5 (CH2), 28.8 (CH2), 28.3 (CH2), 25.1 (CH2), 24.7
(CH3), 16.2 (CH2); HRMS (EI) m/z calcd for C11H18O 166.1358,
found 166.1353.
(3a′S*,4S*,7′S*,7a′R*)-2,2,7a′-Trimethyloctahydrospiro[1,3-
dioxolane-4,1′-inden]-7′-ol (10). To a mixture of N-methyl
morpholine-N-oxide (42.80 mL, 182.64 mmol, 50% in water), water
(18 mL), acetone (60 mL), and osmium tetroxide (0.05 M in t-
butanol, 45.66 mL, 2.28 mmol) was added compound 9 (7.59 g, 45.66
mmol). The reaction mixture was stirred for 18 h at room
temperature. A slurry of sodium hydrosulfite (1 g) and magnesium
silicate (magnesol, 12 g) was added. The reaction mixture was filtered.
Acetone was removed under vacuum. The resulting mixture was
extracted with EtOAc (3 × 250 mL). The combined organic layer was
washed with brine (100 mL) and dried over MgSO4. Concentration
gave a crude product, which was used for the next reaction. To a
solution of the diol crude product in CH2Cl2 (220 mL) at room
temperature was added 2,2-dimethoxypropane (22.40 mL, 182.64
mmol) and p-toluenesulfonic acid (3.48 g, 18.26 mmol). The reaction
mixture was stirred for 1.5 h and quenched with saturated NaHCO3
(30 mL). The reaction mixture was extracted with CH2Cl2 (3 × 200
mL). The combined organic layer was washed with brine (50 mL),
dried over MgSO4, and concentrated. Silica gel flash column
chromatography (EtOAc/hexane, 1:10) gave alcohol 10 (9.77 g,
89%) as a white solid: mp 113−114 °C; IR (neat) v 3460, 2986, 2936,
2863, 1461, 1246, 1217 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.06 (d,
J = 9.0 Hz, 1H), 3.99 (d, J = 9.0 Hz, 1H), 3.57−3.48 (m, 1H), 2.21−
2.08 (m, 1H), 2.06−1.91 (m, 2H), 1.88−1.63 (m, 4H), 1.61−1.42 (m,
3H), 1.38 (d, J = 0.5 Hz, 3H), 1.32 (d, J = 0.5 Hz, 3H), 1.30−1.20 (m,
2H), 0.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 108.2 (C), 94.1
(C), 72.0 (CH), 69.6 (CH2), 48.1 (C), 42.8 (CH), 40.4 (CH2), 31.5
(CH2), 27.0 (CH2), 26.7 (CH3), 26.1 (CH3), 24.2 (CH2), 19.8 (CH3),
14.5 (CH2); HRMS (EI) m/z calcd for C14H24O3 240.1725, found
240.1717.
(3a′S*,4S*,7a′R*)-2,2,7a′-Trimethyl-2′,3′,3a′,4′,5′,7a′-
hexahydrospiro[1,3-dioxolane-4,1′-indene] (11). To a solution
of the alcohol 10 (8.89 g, 36.99 mmol) in anhydrous pyridine (120
mL) at room temperature was added phosphorus oxychloride (22.40
mL, 182.64 mmol). The reaction mixture was stirred at 70 °C for 4 h
and quenched with saturated NaHCO3 (100 mL). The organic layer
was separated. The aqueous layer was extracted with Et2O (3 × 200
mL). The combined organic layer was washed with brine (50 mL),
dried over MgSO4, filtered, and concentrated. Silica gel flash column
chromatography (EtOAc/hexane, 1:100) afforded the compound 11
(7.57 g, 92%) as a colorless oil: IR (neat) v 2982, 2948, 2924, 1649,
1456, 1368, 1212 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.64 (ddd, J =
10.2, 5.0, 2.6 Hz, 1H), 5.23 (ddt, J = 10.2, 2.7, 1.4 Hz, 1H), 3.94 (d, J =
8.6 Hz, 1H), 3.71 (d, J = 8.7 Hz, 1H), 2.16−2.07 (m, 1H), 2.07−1.95
(m, 1H), 1.91−1.73 (m, 3H), 1.73−1.55 (m, 2H), 1.53− 1.44 (m,
1H), 1.38−1.32 (m, 1H), 1.38 (s, 3H), 1.32 (s, 3H), 1.01 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 132.0 (CH), 128.2 (CH), 108.7 (C), 92.3
(C), 68.7 (CH2), 45.8 (C), 41.2 (CH), 36.5 (CH2), 27.3 (CH3), 26.3
(CH3), 24.2 (CH2), 22.6 (CH2), 20.9 (CH3), 20.6 (CH2); HRMS
(EI) m/z calcd for C14H22O2 222.1620, found 222.1620.
( 3 a ′ R * , 4 S * , 7 ′ R * , 7 a ′ S * ) - 2 , 2 , 7 ′ , 7 a ′ -
Tetramethylhexahydrospiro[1,3-dioxolane-4,1′-inden]-5′(4′H)-
one (13). To a slurry of copper iodide (16.65 g, 87.39 mmol) in
anhydrous Et2O (100 mL) was added methyllithium (2.23 M in Et2O/
hexane, 78.38 mL, 174.79 mmol) dropwise at 0 °C. The reaction
mixture was stirred for 60 min at 0 °C. A solution of the enone 12
(5.90 g, 24.97 mmol) in anhydrous Et2O (60 mL) was added over 0.5
h. The reaction mixture was stirred for 1 h and then quenched with
saturated NH4Cl (100 mL). The reaction mixture was extracted with
Et2O (3 × 200 mL). The combined organic layer was washed with
brine (50 mL), dried over MgSO4, and concentrated. Silica gel flash
column chromatography (EtOAc/hexane, 1:20) afforded the ketone
13 (5.29 g, 84%) as a colorless oil: IR (neat) v 2983, 2945, 2877, 1716,
1
1456, 1239, 1212 cm−1; H NMR (400 MHz, CDCl3) δ 3.91 (d, J =
8.4 Hz, 1H), 3.79 (d, J = 8.4 Hz, 1H), 2.56−2.37 (m, 2H), 2.26−2.14
(m, 2H), 2.04 (ddd, J = 14.7, 4.2, 2.0 Hz, 1H), 2.01−1.91 (m, 2H),
1.91−1.78 (m, 2H), 1.41 (s, 3H), 1.31−1.22 (m, 4H), 1.09 (s, 3H),
0.84 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 211.9 (C),
107.7 (C), 93.6 (C), 69.0 (CH2), 47.0 (CH), 46.8 (C), 46.4 (CH2),
41.1 (CH2), 34.9 (CH2), 33.7 (CH), 28.0 (CH3), 26.1 (CH3), 25.6
(CH2), 17.6 (CH3), 12.3 (CH3); HRMS (EI) m/z calcd for C15H24O3
252.1725, found 252.1731.
( 3 a ′ R * , 4 S * , 5 ′ S * , 7 ′ R * , 7 a ′ S * ) - 2 , 2 , 7 ′ , 7 a ′ -
Tetramethyloctahydrospiro[1,3-dioxolane-4,1′-inden]-5′-ol
(14). To a solution of ketone 13 (2.96 g, 11.73 mmol) in THF (100
mL) at −78 °C was added liquid ammonia (100 mL). Lithium (821
mg, 117.30 mmol) was added in small pieces. The reaction mixture
was stirred at −78 °C for 1 h. Solid NH4Cl (10 g) was added.
Ammonia was allowed to evaporate. Water (80 mL) was added. The
reaction mixture was extracted with CH2Cl2 (3 × 200 mL). The
combined organic layer was washed with brine (50 mL), dried over
MgSO4, and concentrated. Silica gel flash column chromatography
(EtOAc/hexane, 1:4) afforded the acetal alcohol 14 (2.39 g, 80%) as a
colorless oil: IR (neat) v 3399, 2982, 2927, 2878, 1465, 1240, 1214
cm−1; 1H NMR (400 MHz, CDCl3) δ 3.89−3.79 (m, 2H), 3.78 (d, J =
8.4 Hz, 1H), 2.26 (tdd, J = 10.0, 5.0, 2.5 Hz, 1H), 2.02−1.91 (m, 1H),
1.87−1.71 (m, 3H), 1.63−1.56 (m, 1H), 1.42 (s, 3H), 1.40−1.31 (m,
1H), 1.56−1.45 (m, 3H), 1.24 (s, 3H), 1.21−1.09 (m, 1H), 0.91 (s,
3H), 0.75 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 107.4
(C), 94.9 (C), 68.9 (CH2), 66.7 (CH), 46.7 (C), 45.6 (CH), 41.3
(CH2), 34.6 (CH2), 33.7 (CH2), 31.5 (CH), 28.3 (CH3), 26.1 (CH3),
24.1 (CH2), 17.9 (CH3), 11.8 (CH3); HRMS (EI) m/z calcd for
C15H26O3 254.1882, found 254.1872.
(3aR*,5S*,7R*,7aS*)-5-Hydroxy-7,7a-dimethyloctahydro-
1H-inden-1-one (15). To acetal alcohol 14 (2.39 g, 9.40 mmol) was
added a 2:1 mixture of MeOH/10% HCl (75 mL). The reaction
mixture was stirred 1 h and then neutralized with saturated NaHCO3.
Solid NaIO4 (4.02 g, 18.81 mmol) was added. The reaction mixture
was stirred for 2 h and then filtered through a short pad of silica gel.
(3a′R*,4S*,7a′R*)-2,2,7a′-Trimethyl-2′,3′,3a′,7a′-
tetrahydrospiro[1,3-dioxolane-4,1′-inden]-5′(4′H)-one (12).
To a mixture of 20% Pd(OH)2/C(1.32 g, 1.88 mmol), K2CO3 (1.29
g, 9.39 mmol), CH2Cl2 (160 mL), and 70% t-BuOOH in water (12.89
601
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The short pad of silica gel was washed with CH2Cl2 (150 mL). The
combined organic layer was washed with brine (50 mL), dried over
MgSO4, and concentrated. Silica gel flash column chromatography
(EtOAc/hexane, 1:2) afforded the hydroxyl ketone 15 (1.58 g, 92%)
as a white solid. Recrystallization from ether afforded colorless
needles: mp 104−105 °C; IR (neat) v 3410, 2960, 2925, 2876, 1730,
1464, 1277 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.92 (tt, J = 11.4, 4.6
Hz, 1H), 2.49−2.37 (m, 1H), 2.21−2.04 (m, 2H), 1.97 (ddt, J = 13.2,
4.4, 2.1 Hz, 1H), 1.89−1.79 (m, 2H), 1.79−1.70 (m, 1H), 1.70−1.46
(m, 3H), 1.19 (ABq, J = 12.1 Hz, 1H), 0.95 (s, 3H), 0.81 (d, J = 6.8
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 221.1 (C), 66.5 (CH), 49.6
(C), 45.2 (CH), 39.2 (CH2), 36.0 (CH2), 33.7 (CH2), 28.9 (CH),
22.9 (CH2), 15.3 (CH3), 13.5 (CH3); HRMS (EI) m/z calcd for
C11H18O2 182.1307, found 182.1302.
4.59 (m, 2H), 3.96−3.78 (m, 1H), 3.49 (dd, J = 10.0, 2.3 Hz, 0.3H),
3.21 (dd, J = 10.9, 8.9 Hz, 0.7H), 2.47−2.46 (m, 1H), 2.42−1.98 (m,
3H), 1.96−1.72 (m, 2H), 1.69−1.51 (m, 2H), 1.29−1.12 (m, 1H),
0.98 (s, 3H), 0.86 (s, 9H), 0.76 (m, 3H), 0.04 (s, 6H); 13C NMR (101
MHz, CDCl3) δ 210.7 (C), 174.6 (C), 145.4 (C), 106.9 (CH2), 71.4
(CH2), 66.4 (CH), 61.4 (C), 51.8 (C), 43.7 (CH), 39.5 (CH2), 33.7
(CH2), 33.6 (CH2), 27.9 (CH), 25.8 (CH3), 18.1 (C), 15.1 (CH3),
14.5 (CH3), −4.6 (CH3), −4.7 (CH3); HRMS (FAB) (M + H)+ m/z
calcd for C21H35O4Si 379.2305, found 379.2306.
(3S*,3a′R*,5′S*,7′R*,7a′S*)-5′-{[tert-Butyl(dimethyl)silyl]-
oxy}-7′,7a′-dimethyl-4-methyleneoctahydrospiro[furan-3,2′-
indene]-1′,2(3′H)-dione (18). To a solution of Mn(OAc)3 hydrate
(666 mg, 2.49 mmol) in absolute ethanol (10 mL) was added
dropwise a solution of 17 (376 mg, 0.99 mmol) in absolute ethanol
(10 mL). The reaction mixture was stirred for 3 h and then diluted
with ether (100 mL) and filtered through Celite. Concentration and
silica gel flash column chromatography (EtOAc/hexane, 20:1)
furnished 18 (278 mg, 74%) as a white solid. Recrystallization from
ether afforded colorless needles: mp 110−111 °C; IR (neat) v 2929,
2856, 2886, 1775, 1732, 1669, 1252 cm−1; 1H NMR (400 MHz,
CDCl3) δ 5.13−4.97 (m, 3H), 4.81−4.69 (m, 1H), 3.95 (tt, J = 11.2,
4.7 Hz, 1H), 2.65 (t, J = 13.6 Hz, 1H), 2.38−2.20 (m, 1H), 2.15−1.99
(m, 2H), 1.95−1.89 (m, 1H), 1.73−1.65 (m, 1H), 1.60 (ddd, J = 13.7,
11.3, 5.4 Hz, 1H), 1.22 (ABq, J = 12.2 Hz, 1H), 1.03 (s, 3H), 0.87 (s,
9H), 0.75 (d, J = 6.8 Hz, 3H), 0.06 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 212.0 (C), 169.2 (C), 75.2 (C), 66.9 (CH), 53.7 (CH), 52.9
(CH2), 50.5 (C), 43.1 (CH), 39.6 (CH2), 33.6 (CH2), 28.1 (CH),
27.9 (CH2), 25.8 (CH3), 18.2 (C), 15.1 (CH3), 13.8 (CH3), −4.6
(CH3), −4.6 (CH3); HRMS (FAB) m/z calcd for C21H34O4Si
378.2226, found 378.2221.
(3aR*,5S*,7R*,7aS*)-5-{[tert-Butyl(dimethyl)silyl]oxy}-7,7a-
dimethyloctahydro-1H-inden-1-one (5). To a solution of hydrox-
yl ketone 15 (1.10 g, 6.09 mmol) in anhydrous CH2Cl2 (60 mL) were
added triethylamine (2.40 mL, 17.25 mmol), 4-(dimethylamino)-
pyridine (372 mg, 3.05 mmol), and tert-butyldimethylsilyl chloride
(1.83 g, 12.18 mmol). The reaction mixture was stirred for 12 h and
then quenched with saturated NaHCO3 (30 mL). The reaction
mixture was diluted with CH2Cl2 (150 mL) and then washed with
brine (50 mL). The organic layers was dried over MgSO4 and
concentrated. Silica gel flash column chromatography (EtOAc/hexane,
1:50) afforded the ketone 5 (1.70 g, 94%) as a colorless oil: IR (neat)
1
v 2957, 2928, 2857, 1735, 1463, 1254 cm−1; H NMR (400 MHz,
CDCl3) δ 3.84 (tt, J = 11.1, 4.5 Hz, 1H), 2.45−2.31 (m, 1H), 2.18−
1.95 (m, 2H), 1.89−1.70 (m, 3H), 1.64−1.46 (m, 3H), 1.18 (td, J =
13.1, 11.1 Hz, 1H), 0.90 (s, 3H), 0.87−0.80 (m, 9H), 0.75 (d, J = 6.7
Hz, 3H), 0.01 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 221.0 (C),
67.3 (CH), 49.6 (C), 45.3 (CH), 39.6 (CH2), 35.9 (CH2), 34.2
(CH2), 29.0 (CH), 25.8 (CH3), 22.9 (CH2), 18.1 (C), 15.3 (CH3),
13.5 (CH3), −4.6 (CH3), −4.7 (CH3); HRMS (FAB) m/z calcd for
C17H32O2Si 296.2172, found 296.2172.
(3S*,3a′R*,5′S*,7′R*,7a′S*)-5′-{[tert-Butyl(dimethyl)silyl]-
oxy}-1′-hydroxy-7′,7a′-dimethyl-4-methylenedecahydrospiro-
[furan-3,2′-inden]-2-one (19). To a stirred solution of samarium
(437 mg, 2.90 mmol) in anhydrous and degassed THF (6 mL) under
argon was added 1,2-diiodomthane (0.18 mL, 2.20 mmol). The
reaction mixture was stirred for 2 h. Degassed water (0.18 mL) was
added. A solution of 18 (220 mg, 0.58 mmol) in anhydrous and
degassed THF (3 mL) was added dropwise. After stirring for 1 h, the
reaction mixture was extracted with ether (3 × 50 mL). The combined
organic layer was washed with water (20 mL), saturated NaHCO3 (10
mL), and brine (10 mL) and dried over MgSO4. Concentration and
silica gel flash column chromatography (EtOAc/hexane, 1:5) furnished
alcohol 19 (132 mg, 60%) as a white solid: mp 124−125 °C; IR (neat)
Ethyl (3aR*,5S*,7R*,7aS*)-5-{[tert-Butyl(dimethyl)silyl]oxy}-
7,7a-dimethyl-1-oxooctahydro-1H-indene-2-carboxylate
(16). To a solution of diisopropylamine (0.20 mL, 1.41 mmol) in
anhydrous THF (3 mL), was added n-BuLi (0.67 mL, 2.0 M solution
in hexane, 1.35 mmol) at −78 °C, followed by addition of a solution of
5 (200 mg, 0.67 mmol) dissolved in anhydrous THF (3 mL). The
reaction mixture was stirred for 1 h at −78 °C, and then ethyl
cyanoformate (141 mg, 1.42 mmol) was added dropwise. After stirring
for 1 h, the reaction mixture was quenched with saturated NaHCO3
(20 mL) and then extracted with ether (3 × 50 mL). The combined
organic layer was washed with brine (20 mL), dried over MgSO4, and
concentrated. Silica gel flash column chromatography (EtOAc/hexane,
1:50) afforded the ketone ester 16 (229 mg, 93%) as a colorless oil: IR
1
v 3489, 2955, 2928, 2856, 1756, 1671, 1255 cm−1; H NMR (400
MHz, CDCl3) δ 5.27 (t, J = 1.5 Hz, 1H), 5.20 (t, J = 1.9 Hz, 1H), 4.77
(dt, J = 12.6, 2.4 Hz, 1H), 4.68 (dt, J = 12.7, 1.8 Hz, 1H), 4.00 (d, J =
9.5 Hz, 1H), 3.87 (tt, J = 11.0, 4.6 Hz, 1H), 2.34 (dd, J = 14.2, 13.1 Hz,
1H), 2.21−2.12 (m, 1H), 1.92−1.83 (m, 1H), 1.83−1.76 (m, 3H),
1.66−1.59 (m, 1H), 1.53 (ddd, J = 13.6, 11.2, 5.3 Hz, 1H), 1.25 (q, J =
12.3 Hz, 1H), 0.90 (s, 3H), 0.85 (s, 9H), 0.82 (d, J = 6.7 Hz, 3H), 0.02
(s, 6H); 13C NMR (101 MHz, CDCl3) δ 180.9 (C), 146.0 (C), 109.2
(CH2), 84.5 (CH), 71.3 (CH2), 66.8 (CH), 57.1(C), 47.5 (C), 46.7
(CH), 40.3 (CH2), 38.6 (CH2), 33.9 (CH2), 32.1 (CH), 25.9 (CH3),
18.2 (C), 16.3 (CH3), 14.5 (CH3), −4.6 (CH3), −4.7 (CH3); HRMS
(ESI) (M + Na)+ m/z calcd for C21H36O4Si Na 403.2281, found
403.2274.
1
(neat) v 2957, 2929, 2857, 1750, 1724, 1252 cm−1; H NMR (400
MHz, CDCl3) δ 4.22−4.09 (m, 2H), 3.94−3.79 (m, 1H), 3.41 (dd, J =
9.9, 2.1 Hz, 0.3H), 3.14 (dd, J = 10.8, 8.8 Hz, 0.7H), 2.39−2.14 (m,
1H), 2.12−1.96 (m, 2H), 1.89−1.79 (m, 1H), 1.65−1.50 (m, 2H),
1.29−1.14 (m, 4H), 0.96 (s, 3H), 0.85 (s, 9H), 0.75 (d, J = 6.8 Hz,
3H), 0.04 (s, 1H), 0.02 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 212.7
(C), 169.9 (C), 67.0 (CH), 61.4 (CH2), 54.1 (CH), 50.4 (C), 43.1
(CH), 39.6 (CH2), 33.7 (CH2), 28.0 (CH), 27.9 (CH2), 25.8 (CH3),
18.1 (C), 15.1 (CH3), 14.1 (CH3), 13.8 (CH3), −4.6 (CH3), −4.6
(CH3); HRMS (ESI) (M + Na)+m/z calcd for C20H36O4SiNa
391.2281, found 391.2281.
(1′R*,3S*,3a′R*,5′S*,7′R*,7a′S*)-1′,5′-Dihydroxy-7′,7a′-di-
methyl-4-methylenedecahydrospiro[furan-3,2′-inden]-2-one
(20). To a solution of alcohol 19 (132 mg, 0.35 mmol) in CH3CN (4
mL) was added HF (0.5 mL, 50% aqueous solution). The reaction
mixture was stirred for 0.5 h, quenched with saturated NaHCO3 (2
mL), and extracted with ether (3 × 50 mL). The combined organic
layer was washed with brine (10 mL) and dried over MgSO4.
Concentration and silica gel flash column chromatography (EtOAc/
hexane, 1:1) furnished diol 20 (84 mg, 91%) as a white solid.
Recrystallization from CHCl3 afforded colorless crystals: mp 154−156
Prop-2-yn-1-yl (3aR*,5S*,7R*,7aS*)-5-{[tert-Butyl(dimethyl)-
silyl]oxy}-7,7a-dimethyl-1-oxooctahydro-1H-indene-2-carbox-
ylate (17). To a solution of the ketone ester 16 (487 mg, 1.32 mmol)
in anhydrous benzene (12 mL) were added propargyl alcohol (1.57
mL, 26.42 mmol) and p-toluenesulfonic acid (25 mg, 0.13 mmol). The
reaction mixture was stirred for 24 h at 105 °C, quenched with
saturated NaHCO3 (20 mL), and then extracted with Et2O (3 × 50
mL). The combined organic layer was washed with brine (20 mL),
dried over MgSO4, and concentrated. Silica gel flash column
chromatography (EtOAc/hexane, 1:50) afforded the ketone ester 17
(474 mg, 95%) as a colorless oil: IR (neat) v 3312, 2956, 2929, 2857,
1
°C; IR (neat) v 3412, 2958, 2925, 2856, 1754, 1672, 1275 cm−1; H
NMR (400 MHz, CDCl3) δ 5.27 (s, 1H), 5.19 (s, 1H), 4.76 (dt, J =
12.6, 2.3 Hz, 1H), 4.67 (dt, J = 12.8, 1.5 Hz, 1H), 3.98 (s, 1H), 3.92
(tt, J = 11.3, 4.5 Hz, 1H), 2.37−2.28 (m, 1H), 2.25−2.15 (m, 1H),
1
2131, 1753, 1730, 1253 cm−1; H NMR (400 MHz, CDCl3) δ 4.83−
602
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2.03−1.95 (m, 2H), 1.95−1.84 (m, 2H), 1.82−1.68 (m, 2H), 1.48
(ddd, J = 13.2, 11.7, 5.1 Hz, 1H), 1.21 (ABq, J = 12.2 Hz, 1H), 0.89 (s,
3H), 0.83 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 180.9
(C), 145.7 (C), 109.3 (CH2), 84.2 (CH), 71.3 (CH2), 66.0 (CH), 57.1
(C), 47.5 (C), 46.6 (CH), 40.0 (CH2), 38.5 (CH2), 33.1 (CH2), 31.8
(CH), 16.3 (CH3), 14.4 (CH3); HRMS (FAB) (M + H)+ m/z calcd
for C15H23O4 267.1596, found 267.1599.
97−99 °C; IR (neat) v 2954, 2928, 2856, 1750, 1724, 1643, 1460,
1
1250 cm−1; H NMR (400 MHz, CDCl3) δ 4.90 (dd, J = 1.3, 0.7 Hz,
1H), 4.78 (s, 1H), 3.79 (tt, J = 11.0, 4.6 Hz, 1H), 3.65 (s, 3H), 2.48
(dd, J = 12.9, 6.8 Hz, 1H), 2.27−2.20 (m, 1H), 1.95 (t, J = 13.0 Hz,
1H), 1.83 (ddt, J = 6.7, 4.2, 1.9 Hz, 1H), 1.73 (d, J = 0.6 Hz, 3H),
1.68−1.47 (m, 3H), 1.18 (ABq, J = 12.5 Hz, 1H), 0.97 (s, 3H), 0.84 (s,
9H), 0.75 (d, J = 6.7 Hz, 3H), 0.02 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 213.0 (C), 170.5 (C) 143.5 (C), 112.5 (CH2), 66.9 (CH),
66.1 (C), 52.9 (CH3), 50.9 (C), 42.0 (CH), 39.6 (CH2), 35.1 (CH2),
33.5 (CH2), 29.2 (CH), 25.8 (CH3), 20.9 (CH3), 18.1 (C), 15.2
(CH3), 14.4 (CH3), −4.6 (CH3); HRMS (FAB) m/z calcd for
C22H38O4Si 394.2539, found 394.2541.
(3aR*,5S*,7R*,7aS*)-5-{[tert-Butyl(dimethyl)silyl]oxy}-2-(1-
hydroxy-1-methylethyl)-7,7a-dimethyloctahydro-1H-inden-1-
one (22). To a solution of diisopropylamine (0.12 mL, 0.83 mmol) in
anhydrous THF (5 mL) was added n-BuLi (0.30 mL, 2.5 M solution in
hexane, 0.76 mmol) at −78 °C. A solution of 5 (200 mg, 0.67 mmol)
in anhydrous THF (2 mL) was then added. The reaction mixture was
stirred for 1 h at −78 °C. Acetone (0.11 mL, 1.38 mmol) was then
added dropwise. After stirring for 1 h, the reaction mixture was
quenched with saturated NH4Cl (10 mL) and then extracted with
ether (3 × 50 mL). The combined organic layer was washed with brine
(20 mL), dried over MgSO4, and concentrated. Silica gel flash column
chromatography (EtOAc/hexane, 1:50) afforded the β-hydroxyl
ketone 22 (188 mg, 78%) as a colorless oil: IR (neat) v 3492, 2929,
(3R*,3a′R*,5′S*,7′R*,7a′S*)-5′-{[tert-Butyl(dimethyl)silyl]-
oxy}-7′,7a′-dimethyl-4-methyleneoctahydrospiro[furan-3,2′-
indene]-1′,2(3′H)-dione (26). To a solution of compound 24 (235
mg, 0.60 mmol) was added SeO2 (265 mg, 2.38 mmol) in 1,4-dioxane
(20 mL). The reaction mixture was stirred at 85 °C for 14 h and then
concentrated. Silica gel flash column chromatography (EtOAc/hexane,
1:50) afforded the compound 26 (103 mg, 46%) as a colorless oil: IR
1
(neat) v 2927, 2856, 2856, 1776, 1733, 1670, 1462, 1254 cm−1; H
1
2857, 1714, 1462, 1376, 1256 cm−1; H NMR (400 MHz, CDCl3) δ
NMR (400 MHz, CDCl3) δ 5.18 (d, J = 1.6 Hz, 1H), 5.07 (dt, J =
12.6, 2.4 Hz, 1H), 5.03 (d, J = 1.5 Hz, 1H), 4.81 (dt, J = 12.5, 1.6 Hz,
1H), 3.88 (tt, J = 11.4, 4.4 Hz, 1H), 2.75−2.65 (m, 1H), 2.29 (dd, J =
13.4, 7.1 Hz, 1H), 2.08 (t, J = 13.3 Hz, 1H), 1.95−1.86 (m, 1H),
1.73−1.58 (m, 3H), 1.27 (ABq, J = 12.2 Hz, 1H), 1.04 (s, 3H), 0.88
(d, J = 2.9 Hz, 9H), 0.79 (d, J = 6.7 Hz, 3H), 0.06 (s, 6H); 13C NMR
(101 MHz, CDCl3) δ 212.1 (C), 174.5 (C), 144.3 (C), 107.7 (CH2),
71.8 (CH2), 66.8 (CH), 61.4 (C), 51.0 (C), 41.5 (CH), 39.6 (CH2),
33.2 (CH2), 33.0 (CH2), 29.8 (CH), 25.8 (CH3), 18.1 (C), 15.1
(CH3), 14.2 (CH3), −4.6 (CH3); HRMS (FAB) (M + H)+ m/z calcd
for C21H35O4Si 379.2305, found 379.2302.
4.50 (s, 1H), 3.87 (tt, J = 11.0, 4.5 Hz, 1H), 2.58 (dd, J = 10.6, 3.0 Hz,
1H), 2.16−1.97 (m, 2H), 1.86−1.75 (m, 1H), 1.69−1.56 (m, 3H),
1.51 (ddd, J = 13.6, 11.1, 5.0 Hz, 1H), 1.22−1.13 (m, 4H), 1.04 (s,
3H), 0.91 (s, 4H), 0.86 (s, 9H), 0.75 (d, J = 6.7 Hz, 3H), 0.04 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 225.3 (C), 73.4 (C), 67.1 (CH), 53.8
(CH), 51.5 (C), 43.3 (CH), 39.3 (CH2), 33.9 (CH2), 30.6 (CH), 28.8
(CH3), 26.8 (CH2), 25.9 (CH3), 25.3 (CH3), 18.2 (C), 15.5 (CH3),
12.9 (CH3), −4.6 (CH3), −4.6 (CH3); HRMS (FAB) (M − H)+ m/z
calcd for C20H37O3Si 353.2512, found 353.2508.
(3aR*,5S*,7R*,7aS*)-5-{[tert-Butyl(dimethyl)silyl]oxy}-7,7a-
dimethyl-2-(1-methylethylidene)octahydro-1H-inden-1-one
(23). To a solution of β-hydroxyl ketone 22 (4.00 g, 11.29 mmol) and
pyridine (4.10 mL, 50.81 mmol) in CH2Cl2 (220 mL), thionyl
chloride (1.63 mL, 22.58 mmol) was added dropwise at 0 °C. The
reaction mixture was stirred for 2 h and then neutralized with saturated
NaHCO3 (150 mL). The reaction mixture was extracted with Et2O (3
× 300 mL). The combined organic layer was washed with brine (150
mL) and dried over MgSO4. Concentration gave a crude product,
which was used for the next reaction. To a solution of crude product in
CH2Cl2 (110 mL) was added DBU (3.18 mL, 22.58 mmol) at room
temperature. The reaction mixture was stirred for 12 h and then
neutralized with saturated NH4Cl (50 mL). The reaction mixture was
extracted with CH2Cl2 (3 × 200 mL). The combined organic layer was
washed with brine (50 mL) and dried over MgSO4. Concentration and
silica gel flash column chromatography (EtOAc/hexane, 1:50)
afforded the enone 22 (3.61 g, 99%) as a pale yellow oil: IR (neat)
Ethyl (5S*,7R*,7aS*)-5-{[tert-Butyl(dimethyl)silyl]oxy}-1-hy-
droxy-7,7a-dimethyloctahydro-1H-indene-2-carboxylate
(27). To a solution of 16 (550 mg, 1.49 mmol) in MeOH (15 mL),
NaBH4 (113 mg, 2.99 mmol) was added portionwise at 0 °C. After
stirring for 0.5 h, water (10 mL) and CH2Cl2 (30 mL) were added.
The organic layer was separated, washed with saturated NaHCO3 (10
mL) and brine (10 mL), and dried over MgSO4. Concentration and
silica gel flash column chromatography (hexane/EtOAc, 20:1)
furnished hydroxyl ester 27 (482 mg, 87%) as a diastereomeric
mixture (colorless oil). One diastereomer (Rf = 0.63) was isolated with
silica gel flash column chromatography (EtOAc/hexane, 1:5): IR
1
(neat) v 3489, 2955, 2928, 2857, 1711, 1254 cm−1; H NMR (400
MHz, CDCl3) δ 4.16 (q, J = 7.1 Hz, 2H), 3.99−3.86 (m, 2H), 3.26 (d,
J = 5.9 Hz, 1H), 2.96 (ddd, J = 10.1, 8.9, 7.3 Hz, 1H), 2.05−1.92 (m,
2H), 1.92−1.80 (m, 1H), 1.79−1.68 (m, 1H), 1.68−1.58 (m, 2H),
1.52−1.43 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.17 (td, J = 13.3, 8.7 Hz,
1H), 0.93 (s, 3H), 0.91 (d, J = 6.7 Hz, 3H), 0.85 (s, 9H), 0.01 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 175.6 (C), 82.3 (CH), 67.1 (CH),
60.7 (CH2), 45.5 (C), 45.2 (CH), 42.4 (CH), 40.3 (CH2), 35.4
(CH2), 31.8 (CH2), 27.9 (CH), 25.9 (CH3), 19.3 (CH3), 18.2 (C),
17.7 (CH3), 14.2 (CH3), −4.6 (CH3), −4.7 (CH3); HRMS (ESI) (M
+ Na)+ m/z calcd for C20H38O4SiNa 393.2437, found 393.2431.
Another diastereomer (Rf = 0.45) was isolated with silica gel flash
column chromatography (EtOAc/hexane, 1:5): IR (neat) v 3489,
1
v 2957, 2928, 2856, 1704, 1634, 1461, 1254 cm−1; H NMR (400
MHz, CDCl3) δ 3.85 (tt, J = 11.1, 4.5 Hz, 1H), 2.50−2.28 (m, 2H),
2.19 (s, 3H), 2.01−1.91 (m, 1H), 1.87−1.76 (m, 4H), 1.64−1.48 (m,
3H), 1.20 (ABq, J = 12.4 Hz, 1H), 0.95 (s, 3H), 0.87 (s, 9H), 0.77 (d, J
= 6.7 Hz, 3H), 0.04 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 209.3
(C), 148.5 (C), 129.9 (C), 67.6 (CH), 51.0 (C), 41.6 (CH), 39.7
(CH2), 34.2 (CH2), 30.3 (CH), 30.2 (CH2), 25.8 (CH3), 24.4 (CH3),
20.7 (CH3), 18.2 (C), 15.7 (CH3), 13.7 (CH3), −4.6 (CH3), −4.6
(CH3); HRMS (FAB) m/z calcd for C20H36O2Si 336.2485, found
336.2479.
Methyl (2R*,3aR*,5S*,7R*,7aS*)-5-{[tert-Butyl(dimethyl)-
silyl]oxy}-2-isopropenyl-7,7a-dimethyl-1-oxooctahydro-1H-in-
dene-2-carboxylate (24). To a solution of enone 23 (1.00 g, 2.97
mmol) in anhydrous THF (5 mL) was added LHMDS (5.94 mL, 1.0
M solution in THF, 5.94 mmol) at −78 °C. The reaction mixture was
stirred for 1 h at −78 °C. HMPA (0.62 mL, 3.56 mmol) and methyl
cyanoformate (1.23 mL, 14.85 mmol) were added dropwise. After
stirring for 1 h, the reaction mixture was quenched with saturated
NaHCO3 (10 mL) and then extracted with ether (3 × 100 mL). The
combined organic layer was washed with brine (50 mL), dried over
MgSO4, and concentrated. Silica gel flash column chromatography
(EtOAc/hexane, 1:50) afforded the compound 24 (360 mg, 31%) as a
white solid. Recrystallization from ether afforded colorless needles: mp
1
2956, 2928, 2857, 1717, 1254 cm−1; H NMR (400 MHz, CDCl3) δ
4.14 (q, J = 7.1 Hz, 2H), 3.88 (dd, J = 9.8, 3.9 Hz, 1H), 3.77 (tt, J =
11.1, 4.5 Hz, 1H), 2.89−2.77 (m, 1H), 2.32 (d, J = 3.9 Hz, 1H), 1.90−
1.77 (m, 3H), 1.72−1.59 (m, 2H), 1.56−1.49 (m, 1H), 1.45−1.36 (m,
1H), 1.24 (t, J = 7.1 Hz, 3H), 1.17 (ABq, J = 12.2 Hz, 1H), 1.01 (d, J =
6.6 Hz, 3H), 0.99 (s, 3H), 0.85 (s, 9H), 0.02 (s, 6H); 13C NMR (101
MHz, CDCl3) δ 176.0 (C), 85.5 (CH), 67.1 (CH), 60.7 (CH2), 47.3
(CH), 44.1 (C), 43.6 (CH), 41.5 (CH2), 34.0 (CH2), 29.9 (CH), 27.5
(CH2), 25.9 (CH3), 18.3 (CH3), 18.2 (C), 17.6 (CH3), 14.3 (CH3),
−4.6 (CH3); HRMS (ESI) (M + Na)+ m/z calcd for C20H38O4SiNa
393.2437, found 393.2431.
Ethyl (3aR*,4R*,6S*,7aR*)-6-{[tert-Butyl(dimethyl)silyl]oxy}-
3a,4,7a-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-indene-2-car-
boxylate (28). To a stirred solution of the hydroxyl ester 27 (482
mg, 1.30 mmol) in anhydride pyridine (20 mL) at room temperature
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was added phosphorus oxychloride (798 mg, 5.21 mmol). The
reaction mixture was stirred for 4 h at 70 °C and then quenched with
saturated NaHCO3 (25 mL). The reaction mixture was extracted with
Et2O (3 × 50 mL). The combined organic layer was washed with brine
(10 mL), dried over MgSO4, and concentrated. Silica gel flash column
chromatography (EtOAc/hexane, 1:100) afforded the ester 28 (398
mg, 87%) as a colorless oil: IR (neat) v 2956, 2927, 2856, 1715, 1626,
1240 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 2.3 Hz, 1H),
4.16 (q, J = 7.1 Hz, 2H), 3.78 (tt, J = 10.8, 4.2 Hz, 1H), 2.55−2.39 (m,
2H), 2.19−2.08 (m, 1H), 1.89−1.78 (m, 1H), 1.55−1.44 (m, 3H),
1.27 (t, J = 7.1 Hz, 3H), 1.22−1.12 (m, 1H), 1.01 (s, 3H), 0.87 (s,
9H), 0.85 (d, J = 6.8 Hz, 3H), 0.04 (s, 6H); 13C NMR (101 MHz,
CDCl3) δ 165.8 (C), 153.7 (CH), 133.8 (C), 68.6 (CH), 60.1 (CH2),
48.7 (CH), 47.7 (C), 38.7 (CH2), 35.5 (CH), 35.2 (CH2), 34.3
(CH2), 25.9 (CH3), 18.2 (C), 17.1 (CH3), 16.9 (CH3), 14.2 (CH3),
−4.7 (CH3); HRMS (ESI) (M + Na)+ m/z calcd for C20H36O3SiNa
375.2331, found 375.2330.
((3aS*,4R*,6S*)-6-{[tert-Butyl(dimethyl)silyl]oxy}-3a,4-di-
methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-2-yl)methanol
(29). To a solution of the unsaturated ester 28 (330 mg, 0.94 mmol)
in CH2Cl2 (10 mL) at −78 °C was added DIBAL (2.35 mL, 1 M in
toluene) dropwise. The reaction mixture was stirred for 1 h and then
quenched with acetone (3 mL). A saturated aqueous solution of
Rochelle’s salt (sodium potassium tartrate, 20 mL) was added. The
reaction mixture was stirred for 30 min. The organic layer was
separated. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layer was washed with brine (10 mL), dried
over MgSO4, and concentrated. Silica gel flash column chromatog-
raphy (EtOAc/hexane, 1:10) afforded the allylic alcohol 29 (277 mg,
95%) as a colorless oil: IR (neat) v 3360, 2956, 2926, 2856, 1645, 1255
cm−1; 1H NMR (400 MHz, CDCl3) δ 5.66 (s, 1H), 4.09 (s, 2H), 3.76
(tt, J = 10.9, 4.3 Hz, 1H), 2.31−2.03 (m, 3H), 1.87−1.76 (m, 1H),
1.70 (s, 1H), 1.57−1.38 (m, 3H), 1.14 (td, J = 13.1, 10.8 Hz, 1H), 0.93
(s, 3H), 0.86 (s, 9H), 0.80 (d, J = 6.7 Hz, 3H), 0.03 (s, 6H); 13C NMR
(101 MHz, CDCl3) δ 141.6 (C), 136.8 (CH), 69.1 (CH), 62.3 (CH2),
48.4 (CH), 47.4 (C), 39.0 (CH2), 36.4 (CH2), 36.2 (CH), 34.7
(CH2), 25.9 (CH3), 18.3 (C), 17.7 (CH3), 17.1 (CH3), −4.6 (CH3);
HRMS (EI) m/z calcd for C18H34O2Si 310.2328, found 310.2325.
((1aR*,1bS*,2R*,4S*,5aS*,6aR*)-4-{[tert-Butyl(dimethyl)-
silyl]oxy}-1b,2-dimethyloctahydro-6aH-indeno[1,2-b]oxiren-
6a-yl)methanol (30). To a solution of m-CPBA (70%, 370 mg, 2.14
mmol) in CH2Cl2 (3 mL) was added a solution of the allylic alcohol
29 (332 mg, 1.07 mmol) in CH2Cl2 (12 mL). The reaction mixture
was stirred for 1 h at 0 °C and then quenched with saturated Na2SO3
(10 mL) and saturated NaHCO3 (10 mL). The organic layer was
separated. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layer was washed with brine (10 mL), dried
over MgSO4, and concentrated. Silica gel flash column chromatog-
raphy (EtOAc/hexane, 1:5) afforded the epoxide alcohol 30 (320 mg,
92%) as a colorless oil: IR (neat) v 3438, 2927, 2856, 1459, 1254
cm−1; 1H NMR (400 MHz, CDCl3) δ 3.88 (dd, J = 12.4, 3.1 Hz, 1H),
3.72 (dd, J = 12.4, 7.3 Hz, 1H), 3.63 (tt, J = 11.1, 4.3 Hz, 1H), 3.31 (s,
1H), 1.98−1.83 (m, 2H), 1.80−1.63 (m, 2H), 1.60−1.46 (m, 2H),
1.44−1.32 (m, 2H), 1.22−1.12 (m, 1H), 0.98 (s, 3H), 0.89 (d, J = 6.8
Hz, 3H), 0.85 (s, 9H), 0.02 (s, 6H); 13C NMR (101 MHz, CDCl3) δ
68.1 (CH), 67.6 (CH), 65.8 (C), 61.8 (CH2), 41.7 (C), 40.0 (CH),
39.7 (CH2), 33.1 (CH2), 32.2 (CH), 30.9 (CH2), 25.9 (CH3), 18.2
(C), 16.7 (CH3), 13.8 (CH3), −4.6 (CH3); HRMS (ESI) (M + Na)+
m/z calcd for C18H34O3SiNa 349.2175, found 349.2173.
2956, 2928, 2856, 1723, 1462, 1251 cm−1; 1H NMR (400 MHz,
CDCl3) δ 9.15 (s, 1H), 3.65 (tt, J = 11.1, 4.3 Hz, 1H), 3.60 (s, 1H),
2.05 (dd, J = 14.2, 11.5 Hz, 1H), 1.87 (dd, J = 14.2, 7.5 Hz, 1H), 1.76−
1.67 (m, 2H), 1.54−1.47 (m, 1H), 1.45−1.28 (m, 2H), 1.23−1.11 (m,
1H), 1.04 (s, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 197.6 (CH), 68.2 (CH), 67.7 (CH),
67.3 (C), 42.2 (C), 39.4 (CH2), 39.2 (CH), 32.8 (CH2), 31.7 (CH),
27.3 (CH2), 25.8 (CH3), 18.1 (C), 16.5 (CH3), 14.1 (CH3), −4.7
(CH3); HRMS (FAB) (M − H)+ m/z calcd for C18H31O3Si 323.2042,
found 323.2048.
1-((1aR*,1bS*,2R*,4S*,5aS*,6aR*)-4-{[tert-Butyl(dimethyl)-
silyl]oxy}-1b,2-dimethyloctahydro-6aH-indeno[1,2-b]oxiren-
6a-yl)-2-methylenepropane-1,3-diol (33). To a solution of n-
BuLi (0.20 mL, 2.5 M solution in hexane, 0.48 mmol) in Et2O (1.5
mL) at −78 °C was added iodo alcohol 32 (47 mg, 0.24 mmol) in
Et2O (1.5 mL) over a period of 0.5 h. A solution of aldehyde 31 (40
mg, 0.12 mmol) in Et2O (1 mL) was added. The reaction mixture was
stirred for 0.5 h and then quenched with saturated NH4Cl (5 mL).
The reaction mixture was extracted with EtOAc (3 × 15 mL). The
combined organic layer was washed with brine (5 mL), dried over
MgSO4, and concentrated. Silica gel flash column chromatography
(EtOAc/hexane, 1:2) afforded the diol 33 (22 mg, 47%, 78% based on
40% 31 recovered) as a diastereomeric mixture (colorless oil). One
diastereomer (Rf = 0.25) was isolated with silica gel flash column
chromatography (EtOAc/hexane, 1:2): IR (neat) v 3421, 2957, 2926,
1
2855, 1655, 1255 cm−1; H NMR (400 MHz, CDCl3) δ 5.25 (d, J =
0.6 Hz, 1H), 5.14 (s, 1H), 4.48 (s, 1H), 4.24 (d, J = 13.4 Hz, 1H), 4.15
(d, J = 13.6 Hz, 1H), 3.61 (tt, J = 11.1, 4.4 Hz, 1H), 3.33 (s, 1H), 2.65
(s, 1H), 2.53 (s, 1H), 1.83 (dd, J = 12.2, 6.6 Hz, 1H), 1.76−1.60 (m,
3H), 1.54−1.46 (m, 1H), 1.44−1.28 (m, 2H), 1.21−1.12 (m, 1H),
0.98 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 0.6 Hz, 9H), 0.02
(s, 6H); 13C NMR (101 MHz, CDCl3) δ 146.5 (C), 114.7 (CH2), 73.5
(CH), 68.1 (CH), 68.0 (CH), 67.3 (C), 63.9 (CH2), 41.8 (C), 39.9
(CH), 39.6 (CH2), 33.1 (CH2), 32.1 (CH), 29.8 (CH2), 25.9 (CH3),
18.2 (C), 16.5 (CH3), 13.7 (CH3), −4.6 (CH3); HRMS (ESI) (M +
Na)+ m/z calcd for C21H38O4SiNa 405.2437, found 405.2427. Another
diastereomer (Rf = 0.19) was isolated with silica gel flash column
chromatography (EtOAc/hexane, 1:2): IR (neat) v 3440, 2957, 2856,
1653, 1256 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.20 (dd, J = 2.4, 1.2
Hz, 1H), 5.18 (d, J = 0.6 Hz, 1H), 4.40 (s, 1H), 4.33 (d, J = 13.3 Hz,
1H), 4.20 (d, J = 13.4 Hz, 1H), 3.62 (tt, J = 11.2, 4.4 Hz, 1H), 3.42 (s,
1H), 1.81−1.70 (m, 3H), 1.69−1.62 (m, 2H), 1.59−1.46 (m, 2H),
1.44−1.34 (m, 2H), 1.11−1.23 (m, 1H), 0.99 (s, 3H), 0.91 (d, J = 6.8
Hz, 3H), 0.85 (s, 9H), 0.02 (d, J = 1.6 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 147.1 (C), 114.8 (CH2), 73.0 (CH), 68.1 (CH), 67.3 (C),
67.2 (CH), 64.3 (CH2), 41.8 (C), 40.2 (CH), 39.7 (CH2), 33.1
(CH2), 32.1 (CH), 30.8 (CH2), 25.9 (CH3), 18.2 (C), 16.7 (CH3),
13.8 (CH3), −4.6 (CH3); HRMS (ESI) (M + Na)+ m/z calcd for
C21H38O4SiNa 405.2437, found 405.2431.
( )-Peribysin E (1). To a solution of 33 (8.5 mg, 0.022 mmol) in
anhydrous CH2Cl2 (2 mL) at 0 °C were added 2,6-lutidine (0.036 mL,
0.314 mmol) and TMSOTf (0.028 mL, 0.157 mmol). After stirring for
0.5 h, saturated NaHCO3 (5 mL) was added. The reaction mixture was
extracted with CH2Cl2 (3 × 15 mL). The combined organic layer was
washed with brine (10 mL) and dried over MgSO4. Concentration
gave the crude product 34. To a solution of the crude product 34 in
MeOH (3 mL) was added 35% HCl (0.02 mL). The reaction mixture
was stirred for 0.5 h and then quenched with saturated NaHCO3 (5
mL). The reaction mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layer was washed with brine (5 mL), dried over
MgSO4, and concentrated. Silica gel flash column chromatography
(EtOAc/hexane, 1:2) afforded ( )-peribysin E (1) (3.8 mg, 61%) as a
colorless oil: IR (neat) v 3404, 2923, 2926, 2864, 1655, 1263 cm−1; 1H
NMR (600 MHz, CDCl3) δ 5.06 (s, 1H), 4.96 (t, J = 2.0 Hz, 1H), 4.92
(t, J = 2.5 Hz, 1H), 4.46 (dt, J = 13.0, 2.3 Hz, 1H), 4.38 (dt, J = 13.1,
2.2 Hz, 1H), 3.94−3.85 (m, 1H), 3.54 (d, J = 2.1 Hz, 1H), 3.36 (s,
3H), 2.13 (d, J = 2.7 Hz, 1H), 2.01−1.95 (m, 1H), 1.92 (ddt, J = 13.2,
4.5, 2.2 Hz, 1H), 1.87 (dd, J = 13.1, 6.0 Hz, 1H), 1.77−1.71 (m, 1H),
1.71−1.66 (m, 1H), 1.60−1.53 (m, 1H), 1.49 (ddd, J = 13.1, 11.5, 5.7
Hz, 1H), 1.34 (s, 1H), 1.30−1.19 (m, 1H), 0.91 (s, 3H), 0.84 (d, J =
(1aR*,1bS*,2R*,4S*,5aS*,6aS*)-4-{[tert-Butyl(dimethyl)silyl]-
oxy}-1b,2-dimethyloctahydro-6aH-indeno[1,2-b]oxirene-6a-
carbaldehyde (31). To a solution of epoxide alcohol 30 (320 mg,
0.98 mmol) in anhydride CH2Cl2 (10 mL) was added Dess−Martin
periodinane (6.50 mL, 1.96 mmol, 15 wt % in CH2Cl2). After stirring
for 1 h, saturated NaHCO3 (10 mL) and saturated Na2S2O3 (10 mL)
were added. After stirring for 0.5 h, the reaction mixture was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layer was washed
with brine (25 mL), dried over MgSO4, and concentrated. Silica gel
flash column chromatography (EtOAc/hexane, 1:30) afforded the
epoxide alcohol 31 (292 mg, 92%) as a pale yellow oil: IR (neat) v
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6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 152.7 (C), 105.6 (CH),
103.1 (CH2), 88.6 (CH), 69.0 (CH2), 67.1 (CH), 60.8 (C), 55.1
(CH3), 45.9 (CH), 40.0 (CH2), 35.5 (CH), 34.3 (CH2), 32.9 (CH2),
16.1 (CH3), 14.4 (CH3); HRMS (ESI) (M + Na)+ m/z calcd for
C16H26O4Na 305.1729, found 305.1727.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for compounds 2−5, 8−
20, 22−24, 26−31, 33, and ( )-peribysin E (1) and
crystallographic information (CIF files) for compounds 15,
18, 20, and 24. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cksha@mx.nthu.edu.tw.
■
ACKNOWLEDGMENTS
We thank the National Science Council of the Republic of
China (Taiwan) for financial support.
■
REFERENCES
■
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