A unified approach to trans -hydrindane sesterterpenoids

Article abstract of DOI:10.1021/jo300726z

A synthetic approach to several sesterterpenoids containing an isopropyl trans-hydrindane system is presented. Its most remarkable feature is the stereochemical diversification of a common precursor through the choice of different hydrogenation conditions.

Full text of DOI:10.1021/jo300726z

Note
pubs.acs.org/joc
A Unified Approach to trans-Hydrindane Sesterterpenoids
Daniel T. Hog, Peter Mayer, and Dirk Trauner*
Fakultat fur Chemie und Pharmazie, Ludwig-Maximilians-Universitat Munchen, and Munich Center of Integrated Protein Science,
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Butenandtstr. 5-13, 81377 Munchen, Germany
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* Supporting Information
ABSTRACT: A synthetic approach to several sesterterpe-
noids containing an isopropyl trans-hydrindane system is
presented. Its most remarkable feature is the stereochemical
diversification of a common precursor through the choice of
different hydrogenation conditions.
esterterpenoids account for many beautiful natural
has also been found in several natural products that possess a
further oxidized five-membered ring, such as nitidasin (3),7
astellatol (4),8,9 or YW3699 (5).10 Another structurally related
trans-hydrindane sesterterpenoid, variecolin (6),11 exhibits an
isopropenyl group and a different ring fusion pattern on the
hydrindane portion. To facilitate comparison, retigeranic acids
A (1) and B (2) as well as variecolin (6) are depicted in Figure
1 as their unnatural enantiomers. The absolute configurations
of nitidasin (3), astellatol (4), and YW3699 (5) have not been
established to date to the best of our knowledge.
Whereas retigeranic acid A (1) has been a popular synthetic
target, as evidenced through successful total syntheses by
Corey,12 Paquette,13,14 Hudlicky,15,16 and Wender,17 few
approaches toward the other molecules shown in Figure 1
have been published to date. Tori et al. recently disclosed the
preparation of the [5−8−6]-tricarbocyclic framework of
YW3699 (5), a potent inhibitor of GPI anchor biosynthesis.18
Furthermore, Piers19,20 and Molander21 have published studies
toward the total synthesis of variecolin (6).
S
products that continue to inspire synthetic chemists.1
Being of considerable size, these molecules often show intricate
ring systems and difficult to access oxygenation patterns, which
renders them quite challenging targets. As a consequence, only
a limited number of sesterterpenoids have been prepared by
total synthesis,2 and many attractive structures remain to be
investigated in this respect.
Within the sesterterpenoid class, a small number of
compounds contain a trans-hydrindane ring system bearing
an angular methyl and an isopropyl group (Figure 1). The latter
substituent either resides in a trans-relationship to the methyl
group, as in retigeranic acid A (1),3−5 or a cis-relationship,
which is present in retigeranic acid B (2).6 This configuration
We now report an approach to the isopropyl hydrindane
sesterterpenoids that involves a common bicyclic intermediate.
Our synthetic manifold, which can be carried out in either
enantiomeric series,22 provides access to three trans-hydrindane
building blocks, two of which could be incorporated into ent-
retigeranic acids A (1) and B (2). The remaining one shows the
correct oxygenation pattern to serve as a synthetic precursor to
nitidasin (3), astellatol (4), and YW3699 (5).
Our pathway started from the readily available enantiopure
diketone 7,23 which was converted into trans-hydrindane 824
containing ca. 6% of the cis-isomer (Scheme 1). HCl-mediated
cleavage of the tert-butyl ether, followed by protection of the
carbonyl functionality as an acetal, provided secondary alcohol
9, which in turn was oxidized with pyridinium chlorochromate
Figure 1. Molecular structures of selected sesterterpenoids bearing a
trans-hydrindane moiety. The retigeranic acids A (1) and B (2) and
variecolin (6) are depicted as their unnatural enantiomers.
Received: April 25, 2012
Published: May 31, 2012
© 2012 American Chemical Society
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Note
Scheme 1. Stereoselective Synthesis of Ketone 12
Figure 2. Crystal structures of hydrogenation products 13 and 14.
phenomenon has been observed before but has been rarely
associated with the almost complete inversion of a stereo-
center.29−31 The reason for the stereoselectivity of the
hydrogenation, which could occur at the stage of a
tetrasubstituted double bond or an enone, is currently under
investigation using theoretical calculations, as is the stereo-
selectivity of the initial conjugate addition. In both cases, the
stereochemical outcome is not obvious from inspecting
molecular models alone.
Realizing that double-bond migration might be avoided with
a different catalyst, we carried out the hydrogenation in the
presence of PtO2 (Scheme 2). Gratifyingly, a single
diastereomer, hydrindanone 14, was isolated under these
conditions, possessing distinctly different spectroscopic data
from the isomer obtained previously. This desired stereo-
chemical outcome was again confirmed by X-ray crystallog-
raphy, which unambiguously showed the isopropyl substituent
residing in a cis-relationship to the angular methyl group
(Figure 2).
With appreciable quantities of ketones 13 and 14 in hand, we
then proceeded to correct the oxidation pattern on the five-
membered ring. Trapping the potassium enolate of ketone 14
with PhNTf2 yielded enol triflate 15, which underwent facile
Pd-catalyzed reduction to give alkene 16 (Scheme 3). The
(PCC) to yield ketone 10.25,26 At this point, purification by
recrystallization was possible, removing any traces of the cis-
hydrindane. Ketone 10 was then oxidized under Saegusa−Ito
conditions21 to yield enone 11, the structure of which was
confirmed by X-ray crystallography (see the Supporting
Information).27
Exposure of enone 11 to the higher order cyanocuprate
prepared from isopropenylmagnesium bromide and CuCN
resulted in the formation of isopropenyl hydrindanone 12 in
81% yield and as a single diastereomer. Two-dimensional NMR
experiments indicated that this addition occurred from the re-
side, i.e., syn to the angular methyl group. This unexpected
stereochemical outcome was subsequently verified by X-ray
crystallography (see the Supporting Information). It should be
noted that Molander et al.21 as well as Bull and Loedolff28
observed similar stereoselectivities in synthetic studies directed
toward variecolin (6) and a derivative of estrone, respectively.
Notably, the conjugate addition of an isopropyl cuprate gave
only unsatisfactory results in our hands. Thus, we turned our
attention to the seemingly straightforward hydrogenation of
isopropenyl hydrindanone 12. Exposure of alkene 12 to
hydrogen in the presence of Pd/C gave rise to hydrindanone
13 (Scheme 2), which yielded suitable crystals for X-ray
analysis (Figure 2). To our considerable surprise, ketone 13
possessed the (R)-configuration at the former allylic ring
position. Presumably, this unexpected epimerization arises from
the tendency of Pd/C to isomerize double bonds into more
highly substituted positions prior to hydrogenation. This
Scheme 3. Synthesis of Building Block 20 Suitable for
Nitidasin (3), Astellatol (4), and YW3699 (5)
Scheme 2. Diastereoselective Synthesis of Epimeric Ketones
13 and 14 Utilizing Hydrogenation Catalysts as a Chemical
Switch
regio- and stereoselective hydroboration of cyclopentene 16,
however, proved to be more challenging than anticipated,
especially in terms of its regioselectivity. After an extensive
screen of conditions, we found that a matched chiral
hydroboration reagent gave the most satisfying results.
Treatment of alkene 16 with (+)-IpcBH2,32 followed by
oxidative workup, gave the two isomeric alcohols 17 and 18
in a 5.5:1 ratio. A subsequent two-step protocol consisting of
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Note
cm−1) 3420, 2951, 2872, 1702, 1417, 1200, 1124, 1044; [α]2D0 +75.6 (c
1.00, CH2Cl2); HRMS-EI calcd for C10H16O2 [M+] 168.1145, found
168.1147.
liberating the carbonyl functionality (→19) and protection of
the alcohol as a TBS ether provided ketone 20 in pure form.
The structure of this valuable building block for the synthesis of
nitidasin (3), astellatol (4), and YW3699 (5) was also
confirmed by X-ray crystallography (see the Supporting
Information).
A mixture of alcohol S1 (22.6 g, 131 mmol), ethylene glycol (63.0
mL, 1.13 mol), and p-TsOH (2.50 g, 14.5 mmol) in benzene (500
mL) was heated to reflux for 2 h using a Dean−Stark trap. The
reaction was quenched by addition of saturated aqueous NaHCO3
(400 mL) at rt, and the aqueous layer was extracted with EtOAc (3 ×
400 mL). The combined organic layers were washed with saturated
aqueous NaCl (300 mL) and dried (Na2SO4), and the solvents were
removed under reduced pressure. Purification by FCC (silica,
hexanes/EtOAc = 3:2) yielded alcohol 9 (27.2 g, 97%) as pale yellow
Next, we prepared building blocks suitable for ent-retigeranic
acids A (1) and B (2) (Scheme 4). Interestingly, and in
Scheme 4. Syntheses of Building Blocks 22 and 24 Suitable
for ent-Retigeranic Acids A (1) and B (2)
1
oil: Rf 0.45 (hexanes/EtOAc = 1:1); H NMR (CDCl3, 400 MHz) δ
4.00−3.84 (m, 4H), 3.71 (dd, J = 8.8, 7.9 Hz, 1H), 2.18−2.06 (m,
1H), 1.79−1.42 (m, 9H), 1.39−1.22 (m, 2H), 0.81 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 110.1, 81.1, 64.4, 64.3, 42.6, 42.5, 35.8, 33.8,
31.2, 31.0, 25.0, 9.7; IR (ν/cm−1) 3420, 2949, 2874, 1349, 1192, 1117,
1074, 1043, 944; [α]2D0 +18.8 (c 1.00, CH2Cl2); HRMS-EI calcd for
C12H20O3 [M+] 212.1407, found 212.1405.
(3a′S,7a′S)-7a′-Methylhexahydrospiro([1,3]dioxolane-2,5′-
inden)-1′(6′H)-one (10). To a suspension of PCC (68.0 g, 320
mmol) and NaOAc (52.0 g, 640 mmol) in CH2Cl2 (700 mL) at 0 °C
was added dropwise a solution of alcohol 9 (27.2 g, 128 mmol) in
CH2Cl2 (150 mL), and the mixture was stirred for 4 h at rt. After being
filtered over a plug of silica, the solvents were removed under reduced
pressure. Purification by FCC (silica, hexanes/EtOAc = 5:1) and
subsequent recrystallization from hexanes yielded trans-hydrindane 10
(19.0 g, 71%) as a colorless crystalline solid: Rf 0.61 (hexanes/EtOAc
contrast with our earlier experiences, hydrogenation of
cyclopentene 16 in the presence of PtO2 resulted in partial
epimerization. However, the use of diimide, generated in situ,33
resulted in clean conversion to afford dioxolane 21 that was
subsequently deprotected to yield ketone 22.
Its diastereomeric counterpart, ketone 24, was accessible
through an analogous reaction sequence. Transformation of
ketone 13 into alkene 23 was conducted utilizing the same two-
step protocol described above. Hydrogenation with Pd/C
proceeded without incident with this substrate, and subsequent
acetal cleavage gave hydrindanone 24, an intermediate
previously employed in both Corey’s and Hudlicky’s syntheses
of retigeranic acid A (1).34 The X-ray structure of compound
24 is presented in the Supporting Information.
In summary, we have synthesized three trans-hydrindane
building blocks that might serve as valuable intermediates in the
syntheses of several complex sesterterpenoids. Our study was
marked by a high degree of stereochemical serendipity and
emphasizes the importance of meticulous product analysis, even
with seemingly straightforward reactions. Our work demon-
states that the tenedency of double bonds to migrate during
hydrogenation reactions, which is often unnoticed or seen as a
nuisace, can be exploited in useful ways.
1
= 1:1); mp 76.0−77.0 °C (hexanes); H NMR (CDCl3, 600 MHz) δ
3.94 (mC, 4H), 2.45 (ddd, J = 19.3, 8.8, 1.3 Hz, 1H), 2.14 (ddd, J =
19.2, 9.2, 9.2 Hz, 1H), 2.01 (dddd, J = 18.9, 13.0, 5.8, 3.8 Hz, 1H),
1.86 (dddd, J = 12.4, 8.9, 5.8, 1.1 Hz, 1H), 1.79−1.69 (m, 5H), 1.62
(mC, 1H), 1.49 (mC, 1H), 0.93 (s, 3H); 13C NMR (CDCl3, 150 MHz)
δ 219.7, 109.6, 64.6, 64.4, 47.1, 42.8, 36.2, 35.6, 30.9, 28.7, 23.7, 12.3;
IR (ν/cm−1) 2924, 1730, 1118, 1066, 1036, 938; [α]2D0 +83.6 (c 1.00,
CH2Cl2); HRMS-EI calcd for C12H18O3 [M+] 210.1250, found
210.1249.
(3a′R,7a′S)-7a′-Methyl-3a′,4′,7′,7a′-tetrahydrospiro([1,3]-
dioxolane-2,5′-inden)-1′(6′H)-one (11). To a solution of freshly
prepared LDA (86 mmol) in THF/hexanes (3.5:1, 154 mL) at −78
°C was slowly added a solution of ketone 10 (6.00 g, 28.6 mmol) in
THF (30 mL). After the mixture was stirred for 45 min at −78 °C,
Et3N (18.0 mL, 129 mmol) was added followed by TMSCl (14.6 mL,
114 mmol). The solution was stirred for 30 min at −78 °C, and the
reaction was quenched by addition of saturated aqueous NaHCO3 (50
mL) at 0 °C. The mixture was diluted with pentane (100 mL), and the
aqueous layer was extracted with pentane (3 × 50 mL). The combined
organic layers were washed with saturated aqueous NaCl (50 mL) and
dried (Na2SO4). Evaporation of the solvent under reduced pressure
yielded crude silylenol ether S2.
To a solution of silylenol ether S2 in CH2Cl2/MeCN (3:1, 132 mL)
was added Pd(OAc)2 (7.67 g, 31.5 mmol), and the solution was stirred
at 37 °C for 4 h. The mixture was filtered over a plug of silica, and the
solvents were evaporated under reduced pressure. Purification by FCC
(silica, hexanes/EtOAc = 7:1 to 2:1) yielded enone 11 (4.10 g, 69%)
as colorless crystalline solid along with starting material 10 (1.30 g,
22%).
EXPERIMENTAL SECTION
■
(1′S,3a′S,7a′S)-7a′-Methyloctahydrospiro([1,3]dioxolane-
2,5′-inden)-1′-ol (9). A mixture of trans-hydrindane 8 (30.4 g, 136
mmol) in EtOH/6 N HCl (7:1, 354 mL) was heated to reflux for 4 h.
The pH was adjusted to 7 by addition of Na2CO3 at 0 °C, and the
solvent was evaporated under reduced pressure. The residue was
partitioned between CH2Cl2 (800 mL) and H2O (200 mL). The
organic layer was washed with saturated aqueous NaCl (200 mL) and
dried (Na2SO4). Having evaporated the solvent under reduced
pressure, purification by flash column chromatography (FCC) (silica,
hexanes/EtOAc = 1:1) yielded alcohol S1 (22.6 g, containing ca. 5%
A second cycle and additional reaction batches resulted in an overall
transformation from ketone 10 (18.8 g, 89.5 mmol) to enone 11 (15.2
g) in 82% yield: Rf 0.50 (hexanes/EtOAc = 1:1); mp 127.5−129.5 °C
1
(hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 7.38 (dd, J = 5.9,
1.8 Hz, 1H), 6.03 (dd, J = 5.9, 3.2 Hz, 1H), 4.00−3.92 (m, 4H), 3.04
(mC, 1H), 1.96−1.86 (m, 3H), 1.82−1.74 (m, 2H), 1.69 (ddd, J =
13.2, 4.8, 4.8 Hz, 1H), 1.13 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ
211.7, 160.6, 132.0, 109.7, 64.8, 64.3, 50.7, 48.1, 33.6, 31.7, 26.8, 19.4;
IR (ν/cm−1) 2963, 2934, 1699, 1180, 1134, 1092; [α]2D0 −67.2 (c 1.00,
CH2Cl2); HRMS-EI calcd for C12H16O3 [M+] 208.1094, found
208.1097.
1
EtOAc, 96%) as colorless oil: Rf 0.16 (hexanes/EtOAc = 2:1); H
NMR (CDCl3, 300 MHz) δ 3.74 (dd, J = 9.1, 8.2 Hz, 1H), 2.74−2.19
(m, 4H), 2.19−2.09 (m, 1H), 2.00 (mC, 1H), 1.86 (brs, 1H), 1.76
(mC, 1H), 1.69−1.34 (m, 4H), 0.98 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 211.7, 80.4, 44.8, 43.0, 42.5, 37.3, 34.8, 31.2, 25.4, 9.9; IR (ν/
(3′R,3a′R,7a′S)-7a′-Methyl-3′-(prop-1-en-2yl)-
hexahydrospiro([1,3]dioxolane-2,5′-inden)-1′(6′H)-one (12).
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Note
To a suspension of CuCN (1.45 g, 16.2 mmol) in Et2O (48 mL) at 0
°C was slowly added isopropenylmagnesium bromide (65 mL, 0.5 M
in THF, 32.4 mmol). The resulting mixture was stirred for 30 min and
subsequently cooled to −78 °C. A solution of enone 11 (1.50 g, 7.20
mmol) in THF (15 mL) was added slowly. After being stirred for 2 h,
the reaction was quenched by addition of saturated aqueous NH4Cl
(40 mL). The mixture was allowed to warm to rt and diluted with
Et2O (100 mL). After filtering over a pad of Celite, the aqueous layer
was extracted with Et2O (3 × 40 mL). The combined organic layers
were washed with saturated aqueous NaCl (50 mL) and dried
(MgSO4), and the solvents were evaporated under reduced pressure.
Purification by FCC (silica, hexanes/EtOAc = 7:1 to 5:1) yielded
alkene 12 as colorless solid.
additional 30 min at 0 °C. The reaction was quenched by addition of
saturated aqueous NH4Cl (40 mL), and the aqueous layer was
extracted with Et2O (3 × 40 mL). The combined organic layers were
washed with saturated aqueous NaCl (30 mL) and dried (MgSO4),
and the solvents were removed under reduced pressure yielding crude
enol triflate 15.
To a solution of enol triflate 15 in DMF (30 mL) was added n-
Bu3N (8.47 mL, 35.7 mmol), HCOOH (1.12 mL, 29.8 mmol), and
Pd(PPh3)2Cl2 (334 mg, 476 μmol), and the suspension was stirred for
1 h at 75 °C. The mixture was quenched by adding H2O (30 mL) at rt
and filtered over a pad of Celite (washings with Et2O). The aqueous
layer was extracted with Et2O (5 × 40 mL) and the combined organic
layers were washed with 10% aqueous NaCl (3 × 75 mL) and dried
(MgSO4). Having evaporated the solvents under reduced pressure,
purification by FCC (silica, pentane/Et2O = 49:1 to 19:1) yielded
alkene 16 (2.57 g, 92%) as colorless oil: Rf 0.32 (hexanes/EtOAc =
Combined FCC of several reactions batches resulted in an overall
transformation from enone 11 (11.9 g, 57.2 mmol) to ketone 12 (11.5
g) in 81% yield: Rf 0.43 (hexanes/EtOAc = 3:1); mp 69.0−70.5 °C
1
1
16:1); H NMR (CD2Cl2, 400 MHz) δ 5.86 (mC, 1H), 5.81 (dd, J =
(hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ 4.97 (s, 1H), 4.83
5.9, 2.8 Hz, 1H), 3.94−3.88 (m, 4H), 2.15 (ddd, J = 12.6, 7.6, 4.4 Hz,
1H), 2.06 (dddd, J = 9.9, 7.6, 2.8, 1.4 Hz, 1H), 1.90−1.84 (m, 2H),
1.79 (dd, J = 13.8, 5.1 Hz, 1H), 1.72 (dtt, J = 9.8, 6.6, 6.6 Hz, 1H),
1.64 (mC, 1H), 1.56 (ddd, J = 12.5, 5.2, 2.4 Hz, 1H), 1.45 (mC, 1H),
1.00 (d, J = 0.6 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.7 Hz,
3H); 13C NMR (CD2Cl2, 100 MHz): δ 142.2, 134.5, 110.8, 64.9, 64.7,
54.8, 48.8, 46.2, 35.4 (2×), 32.6, 30.3, 23.9, 22.6, 21.5; IR (ν/cm−1)
3045, 2952, 2932, 2868, 1465, 1185, 1085; [α]2D0 −75.8 (c 1.00,
CH2Cl2); HRMS-EI calcd for C15H24O2 [M+] 236.1771, found
236.1758.
(2′S,3′S,3a′R,7a′R)-3′-Isopropyl-7a′-methyloctahydrospiro-
([1,3]dioxolane-2,5′-inden)-2′-ol (17). To a solution of alkene 16
(550 mg, 2.33 mmol) in THF (60 mL) at 0 °C was added dropwise
(+)-IpcBH2 (3.5 mL, ca. 1 M in THF, 3.5 mmol),32 and the mixture
was stirred at rt for 30 min. MeOH (500 μL) was added at 0 °C
followed by aqueous NaOH (3 N, 10 mL) and aqueous H2O2 (30%,
10 mL). After the mixture was heated to 55 °C for 40 min, saturated
aqueous NH4Cl (20 mL) was added at rt. The aqueous layer was
extracted with Et2O (3 × 30 mL), and the combined organic layers
were washed with saturated aqueous NaCl (2 × 40 mL) and dried
(MgSO4). Having evaporated the solvents under reduced pressure,
purification by FCC (silica, hexanes/EtOAc = 4:1) yielded alcohols 17
and 18 (5.5:1, 502 mg, 84%) as colorless oil. Analytical samples
(colorless oils) were obtained by repeated FCC. The analytical sample
of alcohol 18 contained ca. 14% of alcohol 17.
(s, 1H), 4.03−3.89 (m, 4H), 2.86 (mC, 1H), 2.77 (dd, J = 19.7, 1.8 Hz,
1H), 2.49 (dd, J = 19.5, 9.2 Hz, 1H), 2.41−2.34 (m, 1H), 1.99−1.91
(m, 2H), 1.81 (s, 3H), 1.75 (ddd, J = 13.8, 13.8, 4.8 Hz, 1H), 1.68
(mC, 1H), 1.63 (ddd, J = 13.1, 4.6, 2.6 Hz, 1H), 1.43 (ddd, J = 13.5,
13.5, 3.9 Hz, 1H), 1.04 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ
220.6, 146.1, 112.3, 109.8, 64.7, 64.4, 47.1, 45.8, 42.2, 41.9, 35.7, 30.9
(2×), 24.9, 15.3; IR (ν/cm−1) 2954, 2879, 1737, 1350, 1095, 1053;
[α]2D0 +30.6 (c 1.00, CH2Cl2); HRMS-EI calcd for C15H22O3 [M+]
250.1563, found 250.1565.
(3′R,3a′R,7a′S)-3′-Isopropyl-7a′-methylhexahydrospiro-
([1,3]dioxolane-2,5′-inden)-1′(6′H)-one (13). To a solution of
alkene 12 (250 mg, 1.00 mmol) in MeOH (10 mL) was added Pd/C
(10% Pd, 20 mg, 19 μmol) and the solution was stirred under an
atmosphere of H2 (balloon, 1 atm) for 16 h. The reaction mixture was
filtered over a pad of Celite, and the solvents were evaporated under
reduced pressure. Purification by FCC (silica, hexanes/EtOAc = 4:1)
and subsequent recrystallization from n-pentane provided pure ketone
13 (230 mg, 91%) as colorless solid: Rf 0.46 (hexanes/EtOAc = 3:1);
1
mp 88.0−90.0 °C (hexanes/EtOAc); H NMR (CDCl3, 600 MHz) δ
3.94 (mC, 4H), 2.40 (mC, 1H), 1.98−1.88 (m, 2H), 1.87−1.77 (m,
3H), 1.76−1.67 (m, 3H), 1.62 (mC, 1H), 1.55−1.47 (m, 1H), 0.97 (s,
3H), 0.94 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H); 13C NMR
(CDCl3, 150 MHz) δ 219.0, 109.6, 64.6, 64.4, 48.8, 45.4, 41.9, 38.1,
33.9, 30.8, 29.0, 28.0, 22.0, 17.4, 13.5; IR (ν/cm−1) 2960, 2875, 1737,
1141, 1122, 1046, 938; [α]2D0 +65.0 (c 1.00, CH2Cl2); HRMS-FAB
calcd for C15H25O3 [(M + H)+] 253.1798, found 253.1793.
(3′S,3a′R,7a′S)-3′-Isopropyl-7a′-methylhexahydrospiro-
([1,3]dioxolane-2,5′-inden)-1′(6′H)-one (14). To a solution of
alkene 12 (3.98 g, 15.9 mmol) in EtOH (300 mL) was added PtO2
(181 mg, 800 μmol), and the suspension was purged with H2 (balloon,
1 atm) for 60 min. The mixture was filtered over a pad of Celite, and
the solvent was evaporated under reduced pressure. Purification by
FCC (silica, hexanes/EtOAc = 5:1) yielded ketone 14 as colorless
solid.
Alcohol 17: Rf 0.34 (hexanes/EtOAc = 2:1); 1H NMR (CDCl3, 600
MHz) δ 4.32 (mC, 1H), 3.98−3.90 (m, 4H), 2.25 (ddd, J = 14.1, 10.5
Hz, 3.3 Hz, 1H), 2.01 (dd, J = 11.6, 7.1 Hz, 1H), 1.85 (mC, 1H), 1.73−
1.62 (m, 3H), 1.58 (mC, 1H), 1.54 (ddd, J = 12.8, 4.7, 2.5 Hz, 1H),
1.48 (ddd, J = 10.4. 10.4, 4.3 Hz, 1H), 1.42 (mC, 1H), 1.37 (brs, 1H),
1.22 (mC, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.87
(s, 3H); 13C NMR (CDCl3, 150 MHz) δ 110.4, 77.9, 64.5, 64.4, 57.2,
50.1, 46.9, 41.2, 36.9, 34.8, 30.8, 29.9, 24.1, 22.0, 19.1; IR (ν/cm−1)
3418, 2950, 2876, 1457, 1289, 1193, 1111, 1095, 1035; [α]2D0 −1.3 (c
1.00, CH2Cl2); HRMS-EI calcd for C15H26O3 [M+] 254.1876, found
254.1879.
Combined FCC of several reactions batches resulted in an overall
transformation from alkene 12 (10.7 g, 42.3 mmol) to ketone 14 (9.90
g) in 93% yield: Rf 0.46 (hexanes/EtOAc = 3:1); mp 65.5−67.0 °C
Alcohol 18: Rf 0.31 (hexanes/EtOAc = 2:1); 1H NMR (CDCl3, 600
MHz) δ 3.99−3.92 (m, 4H), 3.74 (d, J = 5.1 Hz, 1H), 2.37 (ddd, J =
14.3, 9.8, 3.5 Hz, 1H), 2.00 (mC, 1H), 1.93 (mC, 1H), 1.85 (mC, 1H),
1.82−1.71 (m, 4H), 1.69−1.64 (m, 1H), 1.63−1.58 (m, 1H), 1.36−
1.27 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H), 0.82 (d, J = 6.6
Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 110.4, 79.0, 64.5, 64.4, 45.6,
44.9, 42.4, 38.5, 34.9, 30.8, 30.7, 29.6, 24.1, 22.3, 18.3; IR (ν/cm−1)
3446, 2954, 2872, 1461, 1190, 1086, 1036; [α]2D0 −46.0 (c 0.50,
CH2Cl2); HRMS-EI calcd for C15H26O3 [M+] 254.1876, found
254.1869.
(2S,3S,3aR,7aR)-2-Hydroxy-3-isopropyl-7a-methylhexahy-
dro-1H-inden-5(6H)-one (19). To a solution of alcohols 17 and 18
(5.5:1, 495 mg, 1.95 mmol) in acetone/H2O (10:1, 44 mL) was added
PPTS (635 mg, 2.53 mmol), and the mixture was heated to reflux for 3
h. The pH was adjusted to 7 by adding NaHCO3 at rt and the mixture
was freed of acetone. The residue was diluted with Et2O (80 mL) and
the organic layer was washed with saturated aqueous NaHCO3 (2 × 20
1
(CH2Cl2); H NMR (CDCl3, 600 MHz) δ 4.00−3.87 (m, 4H), 2.48
(dd, J = 19.7, 2.4 Hz, 1H), 2.37 (dd, J = 19.7, 8.9 Hz, 1H), 2.28 (ddd, J
= 13.8, 7.2, 3.2 Hz, 1H), 2.00 (dd, J = 13.7, 12.8 Hz, 1H), 1.91 (ddd, J
= 12.7, 3.2, 2.2 Hz, 1H), 1.89−1.79 (m, 2H), 1.74−1.62 (m, 3H), 1.44
(ddd, J = 13.3, 13.3, 4.8 Hz, 1H), 1.04 (s, 3H), 0.96 (d, J = 6.0 Hz,
3H), 0.87 (d, J = 6.1 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 220.7,
109.9, 64.6, 64.4, 46.5, 45.5, 43.5, 41.9, 35.8, 30.7, 30.6, 29.9, 23.7,
23.2, 15.9; IR (ν/cm−1) 2954, 2879, 1740, 1472, 1346, 1139, 1113,
1102, 1086, 1045, 942; [α]D20 +56.6 (c 1.00, CH2Cl2); HRMS-EI calcd
for C15H24O3 [M+] 252.1720, found 252.1722.
(3′R,3a′R,7a′R)-3′-Isopropyl-7a′-methyl-3′,3a′,4′,6′,7′,7a′-
hexahydrospiro([1,3]dioxolane-2,5′-indene) (16). To a solution
of ketone 14 (3.00 g, 11.9 mmol) in THF (120 mL) at −78 °C was
added dropwise KHMDS (33.4 mL, 0.5 M in toluene, 16.7 mmol),
and the solution was stirred for 15 min. After addition of PhNTf2 (6.37
g, 17.9 mmol), the mixture was stirred 10 min at −78 °C and an
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Note
mL), aqueous HCl (1 N, 2 × 20 mL) and saturated aqueous NaHCO3
(20 mL). The organic layer was dried (MgSO4), and the solvents were
removed under reduced pressure. Purification by FCC (silica,
hexanes/EtOAc = 4:1 to 2:1) yielded regioisomers 19 and S3 (12:1,
307 mg, 75%) as a colorless solid. Analytical samples were obtained by
repeated FCC.
the reaction was heated to reflux for 3 h. The pH was adjusted to 7 by
addition of NaHCO3 at rt, and the mixture was freed of acetone. The
residue was diluted with Et2O (10 mL), and the mixture was washed
with saturated aqueous NaHCO3 (3 mL), HCl (2 N, 2 × 3 mL), and
saturated aqueous NaHCO3 (2 × 3 mL). The organic layer was dried
(MgSO4), and the solvents were removed under reduced pressure.
Purification by FCC (silica, pentane/Et2O = 20:1 to 9:1) yielded
ketone 22 (80 mg, 99%) as colorless oil: Rf 0.29 (hexanes/EtOAc =
16:1); 1H NMR (CDCl3, 600 MHz) δ 2.58 (ddd, J = 15.0, 4.1, 1.8 Hz,
1H), 2.47−2.40 (m, 2H), 2.31 (dddd, J = 16.3, 5.7, 1.8, 1.8 Hz, 1H),
1.97−1.88 (m, 2H), 1.86 (ddd, J = 12.9, 7.3, 1.9 Hz, 1H), 1.81−1.68
(m, 2H), 1.65−1.57 (m, 2H), 1.49 (ddd, J = 13.0, 13.0, 5.8 Hz, 1H),
1.19 (ddd, J = 11.8, 11.8, 8.4 Hz, 1H), 1.04 (s, 3H), 0.88 (d, J = 6.4
Hz, 3H), 0.86 (d, J = 6.4 Hz, 3H; 13C NMR (CDCl3, 150 MHz) δ
213.2, 50.2, 46.5, 42.3, 41.1, 39.9, 37.9, 37.6, 30.5, 29.3, 24.1, 22.1,
17.8; IR (ν/cm−1) 2954, 2868, 1711, 1420, 1386, 1214, 1045; [α]2D0
+11.2 (c 0.25, CH2Cl2); HRMS-EI calcd for C13H22O [M+] 194.1665,
found 194.1674.
Ketone 19: colorless solid; Rf 0.22 (hexanes/EtOAc = 2:1); mp
52.5−54.5 °C (hexanes/EtOAc); 1H NMR (CDCl3, 600 MHz) δ 4.42
(ddd, J = 9.4, 7.0, 4.9 Hz, 1H), 2.58 (ddd, J = 14.3, 3.4, 1.7 Hz, 1H),
2.44−2.30 (m, 4H), 2.10 (dd, J = 11.7, 7.0 Hz, 1H), 1.84 (ddd, J =
13.0, 7.1, 2.1 Hz, 1H), 1.73−1.67 (m, 1H), 1.62−1.55 (m, 3H), 1.31
(dd, J = 11.7, 9.3 Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H), 1.04 (s, 3H), 0.94
(d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ 212.0, 77.7, 56.6,
49.4, 48.6, 41.6, 40.9, 37.7, 37.2, 29.2, 24.2, 21.7, 19.1; IR (ν/cm−1)
3406, 2955, 2932, 2871, 1703, 1462, 1388, 1034; [α]2D0 +72.0 (c 0.125,
CH2Cl2); HRMS-EI calcd for C13H22O2 [M+] 210.1614, found
210.1613.
1
Regioisomer S3: colorless oil; Rf 0.28 (hexanes:EtOAc = 2:1); H
NMR (CDCl3, 600 MHz) δ 3.84 (d, J = 4.8 Hz, 1H), 2.63 (mC, 1H),
2.54−2.36 (m, 4H), 2.06 (ddd, J = 14.7, 7.3, 4.7 Hz, 1H), 2.04−1.98
(m, 1H), 1.98−1.92 (m, 1H), 1.83 (dd, J = 14.8, 8.9 Hz, 1H), 1.64
(mC, 1H), 1.59 (ddd, J = 12.7, 7.1, 2.4 Hz, 1H), 1.41 (brs, 1H), 1.00
(d, J = 0.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H);
13C NMR (CDCl3, 150 MHz) δ = 212.6, 78.4, 45.5, 44.6, 44.2, 41.5,
(3′S,3a′R,7a′R)-3′-Isopropyl-7a′-methyl-3′,3a′,4′,6′,7′,7a′-
hexahydrospiro([1,3]dioxolane-2,5′-indene) (23). To a solution
of ketone 13 (380 mg, 1.51 mmol) in THF (25 mL) at −78 °C was
added dropwise KHMDS (4.83 mL, 0.5 M in toluene, 2.41 mmol),
and the solution was stirred for 15 min. After addition of PhNTf2 (755
mg, 2.11 mmol), the mixture was stirred for an additional 30 min. The
reaction was quenched by adding saturated aqueous NH4Cl (10 mL),
and the mixture was allowed to warm to rt. The aqueous layer was
extracted with Et2O (3 × 10 mL), and the combined organic layers
were dried (Na2SO4). The solvents were removed under reduced
pressure to yield crude enol triflate S4.
38.8, 37.1, 30.1, 30.0, 24.1, 22.0, 18.4; IR (ν/cm−1) 3434, 2957, 2894,
2874, 1698, 1466, 1386, 1234, 1171, 1031; [α]2D0 −9.2 (c 0.5, CH2Cl2);
HRMS-EI calcd for C13H22O2 [M+] 210.1614, found 210.1614.
(2S,3S,3aR,7aR)-2-((tert-Butyldimethylsilyl)oxy)-3-isopropyl-
7a-methylhexahydro-1H-inden-5(6H)-one (20). To a solution of
alcohols 19 and S3 (12:1, 100 mg, 480 μmol) in DMF (6 mL) at 0 °C
were added imidazole (122 mg, 1.80 mmol), DMAP (23 mg, 0.19
mmol), and TBSCl (181 mg, 1.20 mmol), and the mixture was stirred
at rt for 16 h. The reaction was quenched by adding H2O (15 mL) and
the mixture was extracted with Et2O (3 × 25 mL). The combined
organic layers were washed with 10% aqueous NaCl (3 × 15 mL) and
dried (MgSO4), and the solvents were evaporated under reduced
pressure. Purification by FCC (silica, hexanes/EtOAc = 70:1 to 30:1)
yielded ketone 20 (141 mg, 91%) as colorless solid: Rf 0.23 (hexanes/
EtOAc = 16:1); mp 49.5−51.0 °C (hexanes/EtOAc); 1H NMR
(CDCl3, 600 MHz) δ 4.36 (ddd, J = 8.8, 6.9, 4.2 Hz, 1H), 2.56 (ddd, J
= 14.7, 3.6, 1.7 Hz, 1H), 2.43−2.36 (m, 2H), 2.35−2.28 (m, 2H), 1.98
(dd, J = 11.8, 6.9 Hz, 1H), 1.81 (ddd, J = 12.9, 7.1, 2.0 Hz, 1H), 1.71−
1.63 (m, 2H), 1.58 (mC, 1H), 1.27 (dd, J = 11.7, 8.8 Hz, 1H), 1.02 (s,
3H), 0.98 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H), 0.87 (s, 9H),
0.06 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (CDCl3, 150 MHz) δ
212.3, 77.8, 56.5, 50.2, 48.1, 41.6, 40.9, 38.0, 37.3, 29.2, 26.0, 24.4,
21.9, 19.2, 18.0, −3.5, −4.7; IR (ν/cm−1) 2956, 2929, 2857, 1711,
1472, 1254, 1106, 1073, 836; [α]2D0 +59.7 (c 0.33, CH2Cl2); HRMS-EI
calcd for C19H36O228Si [M+] 324.2479, found 324.2482.
To a solution of enol triflate S4 in DMF (10 mL) was added n-
Bu3N (1.07 mL, 4.53 mmol), HCOOH (140 μL, 3.78 mmol), and
Pd(PPh3)2Cl2 (53 mg, 80 μmol), and the mixture was stirred for 2 h at
75 °C. The reaction was quenched by adding H2O (10 mL) at rt and
the mixture was extracted with Et2O (5 × 15 mL). The combined
organic layers were washed with 10% aqueous NaCl (3 × 15 mL) and
dried (Na2SO4), and the solvents were evaporated under reduced
pressure. Purification by FCC (silica, pentane/Et2O = 49:1 to 19:1)
yielded alkene 23 (310 mg, 87%) as colorless oil: Rf 0.52 (hexanes/
1
EtOAc = 7:1); H NMR (CD2Cl2, 400 MHz) δ 5.85 (dd, J = 5.8, 2.5
Hz, 1H), 5.66 (dd, J = 5.8, 1.5 Hz, 1H), 3.96−3.86 (m, 4H), 2.20 (mC,
1H), 1.83−1.59 (m, 7H), 1.56−1.47 (m, 1H), 0.98 (d, J = 6.9 Hz,
3H), 0.86 (d, J = 0.5 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); 13C NMR
(CD2Cl2, 100 MHz) δ 142.7, 132.9, 110.7, 64.8, 64.6, 52.2, 49.4, 46.5,
34.1 (2×), 32.2, 28.8, 22.3, 19.4, 16.8; IR (ν/cm−1) 3043, 2945, 2872,
1119, 1082, 1054, 943; [α]D20 +85.8 (c 1.00, CH2Cl2); HRMS-EI calcd
for C15H24O2 [M+] 236.1771, found 236.1778.
(3R,3aR,7aS)-3-Isopropyl-7a-methylhexahydro-1H-inden-
5(6H)-one (24). To a solution of alkene 23 (300 mg, 1.27 mmol) in
n-pentane (15 mL) was added Pd/C (10% Pd, 33 mg, 25 μmol), and
the suspension was stirred under an atmosphere of H2 (balloon, 1
atm) for 16 h. The reaction mixture was filtered over a pad of Celite,
and the solvents were removed under reduced pressure yielding crude
ketal S5.
To a solution of ketal S5 in acetone (15 mL) was added I2 (86 mg,
0.34 mmol). The reaction was stirred for 10 min at rt and was then
quenched by adding aqueous Na2S2O3 (5 wt %, 10 mL). The mixture
was extracted with CH2Cl2 (3 × 20 mL), and the combined organic
layers were dried (MgSO4). Having evaporated the solvents under
reduced pressure, purification by FCC (silica, pentane/Et2O = 24:1 to
19:1) yielded ketone 24 (234 mg, 95%) as colorless solid: Rf 0.55
(hexanes:EtOAc = 7:1); mp 64.5−66.0 °C (CH2Cl2); 1H NMR
(CDCl3, 600 MHz) δ 2.44−2.36 (m, 2H), 2.31 (dddd, J = 16.5, 5.7,
1.9, 1.9 Hz, 1H), 2.15 (mC, 1H), 1.90−1.79 (m, 2H), 1.67−1.58 (m,
2H), 1.57−1.44 (m, 4H), 1.21−1.14 (m, 1H), 0.99 (s, 3H), 0.87 (d, J
= 6.6 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 150 MHz)
δ 212.6, 50.2, 47.2, 42.8, 41.3, 38.3, 37.9, 37.2, 29.4, 25.1, 21.9, 18.1,
17.3; IR (ν/cm−1) 2950, 2870, 1703, 1465, 1412, 1387, 1278, 1214,
1140; [α]2D0 +92.8 (c 0.50, CH2Cl2); HRMS-EI calcd for C13H22O
[M+] 194.1665, found 194.1661.
(3′S,3a′R,7a′S)-3′-Isopropyl-7a′-methyloctahydrospiro([1,3]-
dioxolane-2,5′-indene) (21). To a solution of alkene 16 (140 mg,
590 μmol) and NaOAc (556 mg, 6.80 mmol) in THF/H2O (1:1, 18
mL) was added p-TsNHNH2 (631 mg, 3.39 mmol), and the mixture
was heated to 80 °C for 4 h. The reaction was quenched by addition of
saturated aqueous K2CO3 (2 mL) at rt, and the mixture was extracted
with Et2O (3 × 15 mL). The combined organic layers were dried
(MgSO4), and the solvents were evaporated under reduced pressure.
Purification by FCC (silica, pentane/Et2O = 19:1 to 9:1) yielded trans-
hydrindane 21 (130 mg, 93%) as a colorless oil: Rf 0.37 (hexanes/
1
EtOAc = 16:1); H NMR (CDCl3, 600 MHz) δ 4.02−3.88 (m, 4H,),
1.91−1.78 (m, 3H), 1.77−1.67 (m, 3H), 1.64−1.53 (m, 4H), 1.47 (dd,
J = 11.8, 7.6 Hz, 1H), 1.32 (mC, 1H), 1.13 (mC, 1H), 0.89 (d, J = 6.3
Hz, 3H), 0.86 (s, 3H), 0.82 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
150 MHz) δ 110.9, 64.4, 64.3, 48.4, 46.7, 41.0, 40.3, 37.2, 35.4, 31.3
(2×), 28.7, 24.1, 22.4, 17.9; IR (ν/cm−1) 2950, 2873, 1464, 1356,
1289, 1190, 1115, 1096, 947; [α]2D0 −24.8 (c 0.25, CH2Cl2); HRMS-EI
calcd for C15H26O2 [M+] 238.1927, found 238.1927.
(3S,3aR,7aS)-3-Isopropyl-7a-methylhexahydro-1H-inden-
5(6H)-one (22). To a solution of dioxolane 21 (100 mg, 420 μmol) in
acetone/H2O (9:1, 10 mL) was added PPTS (137 mg, 546 μmol), and
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Note
(24) Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland,
L. A.; Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem. 1975,
40, 675−681.
(25) For a related reaction sequence, see: Cao, L.; Sun, J.; Wang, X.;
Zhu, R.; Shi, H.; Hu, Y. Tetrahedron 2007, 63, 5036−5041.
(26) Ketone 10 has been prepared via an alternative route. However,
no analytical data has been reported; see: Kotoku, N.; Tamada, N.;
Hayashi, A.; Kobayashi, M. Bioorg. Med. Chem. Lett. 2008, 18, 3532−
3535.
(27) CCDC 865613−865619 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 9−14, 16−24,
S1, and S3 and X-ray data for compounds 10−14, 20, and 24.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dirk.trauner@cup.uni-muenchen.de.
Notes
■
(28) Bull, J. R.; Loedolff, M. C. J. Chem. Soc., Perkin Trans. 1 1996,
The authors declare no competing financial interest.
1269−1276.
(29) Smit, C.; Fraaje, M. W.; Minnaard, A. J. J. Org. Chem. 2008, 73,
9482−9485 and references cited therein.
ACKNOWLEDGMENTS
■
We are grateful to the Fonds der Chemischen Industrie e. V.
(Ph.D. scholarship to D.T.H.) for financial support. We thank
D. Hager, P. Stawski, S. Strych, and R. Webster for helpful
discussions as well as undergraduate researchers S. Rappen-
gluck, T. M. Wildenhof, and M. Rossa for skillful experimental
assistance.
(30) Siegel, S.; Smith, G. V. J. Am. Chem. Soc. 1960, 82, 6082−6087.
(31) For a report on the influence of pressure and catalyst on olefin
isomerization, see: Hudlicky, M. Reductions in Organic Chemistry.
ACS Monograph 1995, 188, 53−55.
(32) Brown, H. C.; Jadhav, P. K.; Mandal, A. K. J. Org. Chem. 1982,
47, 5074−5083.
(33) Webster, R.; Boyer, A.; Fleming, M. J.; Lautens, M. Org. Lett.
2010, 12, 5418−5421.
(34) Although different preparations of ketone 24 have been
described,15,16,35,36 no analytical data has been reported to date.
(35) Corey, E. J.; Engler, T. A. Tetrahedron Lett. 1984, 25, 149−152.
(36) Attah-Poku, S. K.; Chau, F.; Yadav, V. K.; Fallis, A. G. J. Org.
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̈
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