Stereoselective transformations of (+)-abietic acid into (+)-vitedoin B and (+)-negundoin A

Article abstract of DOI:10.1021/jo5003533

The first synthesis of spirolactone (+)-vitedoin B (14 steps, 8.0% global yield) and spiro enol ether (+)-negundoin A (19 steps, 3.7% global yield), via a nor-labdane acetoxy ester, has been achieved starting from commercial (+)-abietic acid.

Full text of DOI:10.1021/jo5003533

Article
pubs.acs.org/joc
Stereoselective Transformations of (+)-Abietic Acid into (+)-Vitedoin
B and (+)-Negundoin A
†
Ruben
́
Tapia, Hanane Bouanou, Esteban Alvarez, Ramon
́
Alvarez-Manzaneda, Rachid Chahboun,*
and Enrique Alvarez-Manzaneda*
́
Departamento de Química Organica, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
*
S Supporting Information
ABSTRACT: The first synthesis of spirolactone (+)-vitedoin B (14
steps, 8.0% global yield) and spiro enol ether (+)-negundoin A (19
steps, 3.7% global yield), via a nor-labdane acetoxy ester, has been
achieved starting from commercial (+)-abietic acid.
INTRODUCTION
■
Over recent decades, a large number of terpenoids with a
spiroether or a spirolactone moiety in their structure have been
isolated from diverse natural sources. Among the spiroethers,
spirodihydrobenzofuran derivatives, such as corallidictyal D
1
2
3
4
(
1), K-76 (2), F1839-A (3), or stachybotrylactam (4), must
be highlighted. These compounds and others structurally
related to them are characterized by a potent and diverse
biological activity. Recently, some trinorlabdane-type spirolac-
5
6
tones, such as isoambreinolide (5) and vitedoin B (6), whose
biological activities have not yet been investigated, have been
isolated from different vegetal species. A third type of
spiroterpenoids includes a series of nor-diterpenes, with a
characteristic tricyclic structure containing a spiro enol ether
group with an α,β-unsaturated aldehyde, acid, or ester, which
have recently been isolated from different vegetal species widely
used in folk medicine in some Asian countries. Representative
examples are the antiinflammatory negundoin C (7),
negundoin B (8), and negundoin A (9), isolated from Vitex
Figure 1. Natural spiroethers and spirolactones.
7
synthetic routes toward these substances. Having obtained
efficient methods to achieve spiroannulation processes, it is
now necessary to prepare appropriate A ring functionalized
synthetic precursors, which allow us to access metabolites such
as compounds 2−4 and 6−9 and other structurally related
compounds, with functionalities in this ring, and which possess
potent biological activities.
negundo (Figure 1).
So far, only a few syntheses have been reported for some of
these spirodihydrobenzofuran derivatives, such as K-76 (2) and
stachybotrylactam (4); in all cases, the spiroannulation was
achieved after treatment of the suitable drimane (bicyclic
2b,c,8
sesquiterpene) phenol with a protic acid or a cationic resin.
Our group recently has reported efficient processes of
spirocyclization, mediated by NIS−PPh and I −PPh , which
In this paper we report the use of commercial abietic acid
14) to achieve this purpose and its application to the synthesis
3
2
3
(
allow the obtention of spirodihydrobenzofurans, such as
9
10
of (+)-vitedoin B (6) and (+)-negundoin A (9).
aldehyde 1, spirolactones, such as compounds 5 and 6,
11
and spiro enol ethers, such as ester 9.
The important biological activities of the above-mentioned
metabolites make it very interesting to consider developing
Received: February 13, 2014
Published: April 15, 2014
©
2014 American Chemical Society
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Article
RESULTS AND DISCUSSION
Scheme 1 shows the retrosynthesis of (+)-vitedoin B (6) from
+)-abietic acid (14). Compound 6 will be obtained directly
and hydrolysis of isopropylidene ketal. Ketone 13 can be
obtained from acid 14 after the regioselective syn-dihydrox-
ylation of the C13−C14 double bond, hydrogenation of the
C7−C8 double bond, oxidative decarboxylation of acid, and
allylic oxidation of the resulting alkene.
■
(
13
Scheme 1. Retrosynthesis of (+)-Vitedoin B (6)
Isopropyl ester 10 is also a suitable precursor for preparing
(
+)-negundoin B (9), as shown in the retrosynthesis depicted
in Scheme 2. Hydroxy ketone 16, which as a racemic mixture
has been previously transformed into the spiro compound 9,
11
is obtained after hydrolysis of diester 10 and further treatment
with methyllithium of the resulting hydroxy acid.
Scheme 3 shows the synthesis of unsaturated ketone 13 from
abietic acid (14). Compound 14 underwent regioselective
14
dihydroxylation, affording diol 17, when it was treated with
OsO , Me NO, and pyridine in t-BuOH under reflux.
4
3
Hydrogenation of this compound gave dihydroxy acid 18 as
the only diastereoisomer; the observed diastereoselectivity,
which led to a trans-fused tricyclic system, may be the result of a
15
hydroxyl-directed heterogeneous hydrogenation. After pro-
tection of the diol group, the carboxylic acid was transformed
into the aldehyde 21, which was converted successively into the
formate 22 and then into the alkene 23, utilizing procedures
Scheme 2. Retrosynthesis of (+)-Negundoin A (9)
1
6,17
previously developed in our laboratory.
Treatment of
compound 23 with PCC, pyridine, and Celite in 2:1 benzene−
dichloromethane under reflux led to α,β-enone 13.
Alkene 23 was obtained in an alternative way from acid 19
Scheme 4). Treatment of this compound with Pb(OAc)4,
(
Scheme 4. Direct Transformation of Acid 19 into Alkene 23
after the I −PPh -mediated cyclization of ester 10. This can be
2
3
prepared from ketoaldehyde 11 after chemoselective reduction
Cu(OAc) , and pyridine in refluxing benzene gave a mixture of
2
1
2
of aldehyde and elimination of the corresponding derivative
of the resulting alcohol and the Baeyer−Villiger oxidation of the
isopropyl ketone. The diol 12, the immediate precursor of
compound 11, will be formed after methylation of the enolate
resulting from the Birch reduction of unsaturated ketone 13
alkene regioisomers, which were reacted with I and PPh in
2
3
dichloromethane, affording the most stable tetrasubstituted
alkene 23 in 64% global yield.
The transformation of unsaturated ketone 13 into diol 12,
which possesses the acetyloxy and gem-dimethyl groups of the
Scheme 3. Synthesis of Ketone 13
4
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Scheme 5. Synthesis of Diol 12 from Enone 13
Scheme 6. Synthesis of (+)-Vitedoin B (6)
target compounds, was then addressed. Scheme 5 shows two
alternative procedures to achieve this purpose. Unsaturated
ketone 24 resulted when ketone 13 was treated with MeI and t-
complete stereoselectivity after treatment with I −PPh . The
2
3
spectroscopic properties of the latter were identical to those
previously described for the natural compound; the optical
rotation of synthetic vitedoin B (6) ([α]2 = +5.2, c = 1.0,
5
BuOK in THF. Reduction of 24 with NaBH and further
4
D
acetylation gave the expected acetate 26. Hydrogenation of the
latter in the presence of PtO2 and HClO4 gave the
simultaneous reduction of the carbon−carbon double bond
CHCl ) was similar to that reported for the natural product
3
([α]2 = +4.7, c = 0.9, CHCl3).
5
6
D
The above diester 10 was also transformed into (+)-ne-
gundoin A (9) (Scheme 7). The treatment of hydroxy acid 33
with MeLi gave hydroxyl ketone 16, which after methox-
ycarbonylation was converted into ketoester 15. This was
transformed into the spiro enol ether 34 with complete regio-
and stereoselectivity when it was treated with I and PPh .
18
and ketal deprotection, providing compound 12.
Alternatively, successive treatment of a solution of enone 13
in THF−t-BuOH with Li and NH and then with MeI gave
3
ketone 27. Diol 12 was obtained after reduction of the ketone
group, acetylation of the resulting alcohol, and ketal
deprotection.
2
3
Subsequent alkaline hydrolysis of the carbonate group and
acetylation of the resulting hydroxyl group finally afforded
(+)-negundoin A (9). The optical rotation of synthetic
negundoin A (9) ([α]2 = +12.1, c = 3.5, CHCl ) was similar
Finally, the transformation of diol 12 into (+)-vitedoin B (6)
was undertaken (Scheme 6). Treatment of compound 12 with
Pb(OAc)4 in dichloromethane at room temperature gave
ketoaldehyde 11 in high yield. This compound was also
obtained directly from ketal 29 when it was reacted with CuCl2
and NaIO4 in CH CN−H O. The ketoaldehyde 11 was
5
D
3
25
to that reported for the natural product ([α]D = +8.9, c = 0.2,
MeOH); the spectroscopic properties were identical to those
7
previously described.
3
2
12
chemoselectively reduced after treatment with Raney Ni to
the hydroxy ketone 30, which was tosylated and then subjected
to Baeyer−Villiger oxidation, affording diester 32. The latter
was heated with NaI in HMPA to give the exocyclic alkene 10,
which was converted into (+)-vitedoin B (6) in high yield with
Scheme 8 shows a possible mechanism for the trans-
formation of β-ketoester 15 into spiro compound 34. The
stereoselectivity observed reveals that the cyclization must take
place through an anti concerted process. In the presence of the
I −PPh system, the exocyclic carbon−carbon double bond of
2
3
4
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solution of 10 (146 mg, 0.4 mmol) in dry CH Cl (4 mL) was added.
The resulting mixture was stirred at room temperature for 15 h, after
which TLC showed no starting material. The solvent was removed
Scheme 7. Synthesis of (+)-Negundoin A (9)
2
2
under vacuum, the crude product was diluted with Et O−water (90−
2
3
0 mL), and the phases were shaken and separated. The organic phase
was washed with water and brine and dried over anhydrous Na SO .
2
4
Removal of the solvent under vacuum afforded a crude product which
was directly purified by flash chromatography on silica gel (20% ether/
hexanes) to give 6 (117 mg, 91%) as a colorless solid. Mp: 94−95 °C
2
5
7
29
(
=
hexane−EtOAc). [α] = +5.2 (c = 1.0, CHCl ) [lit. [α] = +4.7 (c
D
3
D
1
0.9, CHCl )]. H NMR (CDCl , 500 MHz): δ 0.85 (d, J = 6.6 Hz,
3
3
3
1
1
1
8
H), 0.87 (s, 3H), 0.88 (s, 3H), 0.95 (s, 3H), 1.25 (br s, 2H), 1.40−
.47 (m, 2H), 1.50−1.66 (m, 5H), 1.70−1.84 (m, 1H), 1.86 (ddd, J =
3.7, 11.6, 5.0 Hz, 1H), 2.04 (s, 3H), 2.18 (ddd, J = 13.4, 11.8, 8.1 Hz,
H), 2.46 (ddd, J = 18.7, 11.7, 5.0 Hz, 1H), 2.54 (ddd, J = 18.7, 11.3,
.0 Hz, 1H), 4.48 (dd, J = 11.5, 4.4 Hz, 1H). 13C NMR (CDCl , 125
3
MHz): δ 15.4 (CH ), 15.8 (CH ), 16.6 (CH ), 20.9 (CH ), 21.3
3
3
3
2
(
(
(
1
CH ), 23.2 (CH ), 24.9 (CH ), 27.8 (CH ), 29.36 (CH ), 29.44
3 2 2 3 2
CH ), 30.7 (CH ), 36.7 (CH), 37.7 (C), 41.8 (C), 46.1 (CH), 80.0
2
2
CH), 93.3 (C), 170.7 (C), 177.3 (C). IR (film): 1767, 1733, 1462,
−1
366, 1242, 1199, 1177, 1111, 1281, 1091, 1032, 972, 954, 668 cm .
+
HRMS (APcI): m/z calcd for C H O (M + H ) 323.2222, found
19
31
4
3
23.2214.
+)-Negundoin A (9). To a solution of 35 (140 mg, 0.42 mmol) in
CH Cl (4 mL) at 0 °C were added pyridine (0.6 mL) and acetic
(
2
2
anhydride (0.3 mL), and the reaction mixture was stirred at room
temperature for 1 h, at which time TLC showed no starting material.
Then the reaction mixture was cooled at 0 °C, water (0.6 mL) was
added to quench the reaction, and the mixture was stirred for an
additional 5 min. Then it was diluted with ether (25 mL) and washed
with water (3 × 5 mL), 2 N HCl (3 × 6 mL), water (3 × 5 mL) again,
Scheme 8. Possible Mechanism for the Transformation of β-
Ketoester 15 into Spiro Enol Ether 34
satd aq NaHCO (6 mL), and brine, and the organic phase was dried
3
over Na SO . Removal of the solvent under vacuum afforded a crude
2
4
product which was purified by flash chromatography on silica gel (15%
2
5
ether/hexanes) to yield 9 (152 mg, 96%) as a colorless syrup. [α]
=
D
9
29
1
+
12.1 (c = 3.5, CHCl ). [lit. [α] = +8.9 (c = 0.2, MeOH)]. H NMR
3 D
(
CDCl , 500 MHz): δ 0.77 (d, J = 6.6 Hz, 3H), 0.86 (s, 3H), 0.89 (s,
3
3
H), 0.95 (s, 3H), 1.34−1.44 (m, 4H), 1.54−1.73 (m, 5H), 1.75−1.83
(
(
m, 2H), 2.04 (s, 3H), 2.05−2.09 (m, 1H), 2.95−3.15 (m, 2H), 3.65
s, 3H), 4.47 (dd, J = 11.7, 4.5 Hz, 1H), 5.29 (t, J = 1.8 Hz, 1H).
1
3
C
NMR (CDCl , 125 MHz): δ 15.5 (CH ), 16.6 (CH ), 16.8 (CH ),
3
3
3
3
2
0.9 (CH ), 21.3 (CH ), 23.3 (CH ), 26.7 (CH ), 28.0 (CH ), 29.3
2 3 2 2 3
(
CH ), 31.0 (CH ), 31.6 (CH ), 36.5 (CH), 37.7 (C), 42.0 (C), 46.2
2 2 2
(
CH), 50.5 (CH ), 80.2 (CH), 87.3 (CH), 97.7 (C), 169.5 (C), 170.8
3
(
7
C), 178.5 (C). IR (film): 1735, 1707, 1633, 1365, 1244, 1127, 1033,
−1
+
94, 755 cm . HRMS (FAB): m/z calcd for C H O Na (M + Na )
compound 15 undergoes isomerization to the most stable
22 34 5
19
401.2304, found 401.2313.
tetrasubstituted derivative. The enol hydroxyl group, activated
by the phosphonium ion +PPh I, acts simultaneously as a
Isopropyl 3-((1S,4aR,6S,8aR)-6-Acetoxy-5,5,8a-trimethyl-2-
methylenedecahydronaphthalen-1-yl)propanoate (10). To a
solution of 32 (367 mg, 0.68 mmol) in HMPA (5 mL) was added NaI
3
proton donor and a nucleophile. The OH group of a molecule
transfers the proton by the β side on the less hindered carbon 2
of the olefinic bond of the adjacent molecule, which
simultaneously undergoes the intramolecular nucleophilic O-
attack on carbon 1, leading to intermediate I. The proton
transference takes place preferably by the β side probably due
to the steric hindrance exerted by the ketoester moiety on the α
side.
(
123 mg, 0.82 mmol), and the reaction mixture was stirred at 150 °C
for 1 h, at which time TLC showed no starting material. Then ether
40 mL) was added, and the organic phase was washed with brine (8 ×
15 mL) and dried over anhydrous Na SO . Removal of the solvent
(
2
4
under vacuum afforded a crude product which was directly purified by
flash chromatography on silica gel (10% ether/hexanes) to yield 10
209 mg, 84%) as a colorless syrup. [α]2 = +22.0 (c = 7.1, CHCl ). H
5
1
(
D
3
NMR (CDCl , 500 MHz): δ 0.71 (s, 3H), 0.84 (s, 3H), 0.86 (s, 3H),
In summary, the first synthesis of spirolactone (+)-vitedoin B
6) (14 steps, 8.0% global yield) and spiro enol ether
+)-negundoin A (9) (19 steps, 3.7% global yield), via acetoxy
3
1
1
2
4
1
.13−1.45 (m, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H),
.52−1.68 (m, 2H), 1.68−1.77 (m, 2H), 1.77−1.89 (m, 2H), 1.90−
.00 (m, 1H), 2.04 (s, 3H), 2.02−2.15 (m, 2H), 2.35−2.45 (m, 2H),
.51 (s, 1H), 4.52−4.54 (m, 1H), 4.86 (s, 1H), 4.99 (h, J = 6.2 Hz,
(
(
ester 10, from commercial (+)-abietic acid (14) has been
achieved. These results corroborate the absolute stereo-
chemistry of these natural spiroterpenoids.
13
H). C NMR (CDCl , 125 MHz): δ 14.4 (CH ), 16.5 (CH ), 19.2
3
3
3
(
(
3
CH ), 21.3 (CH ), 21.87 (CH ), 21.91 (CH ), 23.8 (CH ), 24.3
2
3
3
3
2
CH ), 28.2 (CH ), 33.4 (CH ), 36.6 (CH ), 37.9 (CH ), 38.0 (C),
2
3
2
2
2
EXPERIMENTAL SECTION
+)-Vitedoin B (6). To a solution of triphenylphosphine (105 mg,
9.2 (C), 54.7 (CH), 55.8 (CH), 67.4 (CH), 80.6 (CH), 107.0 (CH2),
■
(
147.2 (C), 170.9 (C), 173.5 (C). IR (film): 1732, 1372, 1243, 1109,
−1
0
.4 mmol) in dry CH Cl (4 mL) was added iodine (51 mg, 0.4
1029, 773, 669 cm . HRMS (FAB): m/z calcd for C H O Na (M +
2
2
22 36 4
+
mmol). The mixture was stirred at room temperature for 5 min, and a
Na ) 387.2511, found 387.2509.
4
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(
2S,4aR,5S,8aR)-6-Formyl-1,1,4a-trimethyl-5-(4-methyl-3-
gel (20% ether/hexanes) to yield 12 (104 mg, 91%) as a colorless
syrup.
oxopentyl)decahydronaphthalen-2-yl Acetate (11). Lead(IV)
acetate (598 mg, 1.35 mmol) was added to a solution of 12 (415 mg,
1
(3aS,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,9a-tetramethyl-
.13 mmol) in dry CH Cl (15 mL), and the mixture was stirred at
room temperature for 5 min, at which time TLC showed no 12. The
reaction was filtered through a silica gel pad and washed with ether (30
mL). The organic phase was then washed with 5% aq NaHSO (10
mL), satd aq NaHCO (3 × 10 mL), and brine and dried over
4,5,9,9a,9b,10,11,11a-octahydrophenanthro[2,1-d][1,3]dioxol-
2 2
7(3aH,3bH,8H)-one (13). Pyridinium chlorochromate (PCC) (1.55
g, 7.20 mmol), pyridine (0.62 g, 7.80 mmol), and Celite (1 g) were
added to a stirred solution of 23 (0.4 g, 1.20 mmol) in benzene−
3
CH Cl (30−15 mL), and the mixture was stirred at reflux under an
2
2
3
argon atmosphere for 4 days, at which time TLC showed no remaining
starting material. Following the same workup used to prepare 21, a
crude product was obtained which by chromatography on silica gel
(30% ether/hexanes) gave 13 (270 mg, 65%) as a colorless syrup.
Na SO . Removal of the solvent in vacuum gave a crude product
2
4
which was directly purified by flash chromatography on silica gel (15%
ether/hexanes) to yield 11 (396 mg, 96%) as a colorless oil. [α]
7.9 (c = 33.1, CHCl ). H NMR (CDCl , 500 MHz): δ 0.80−0.98
m, 3H), 0.85 (s, 6H), 0.86 (s, 3H), 1.00−1.07 (m, 2H), 1.04 (d, J =
.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 1.10−1.47 (m, 3H), 1.60 (ddd, J
25.1, 13.2, 3.5 Hz, 1H), 1.62−1.87 (m, 3H), 2.03 (s, 3H), 2.25−2.39
m, 2H), 2.45−2.57 (m, 2H), 4.47 (dd, J = 11.8, 4.5 Hz, 1H), 9.54 (d,
J = 4.0 Hz, 1H). C NMR (CDCl , 125 MHz): δ 14.0 (CH ), 16.5
CH ), 18.1 (CH ), 18.2 (CH ), 19.8 (CH ), 21.2 (CH ), 22.9 (CH ),
3.5 (CH ), 26.8 (CH ), 28.1 (CH ), 36.4 (CH ), 37.6 (C), 37.7 (C),
2 2 3 2
0.7 (CH), 41.0 (CH ), 50.0 (CH), 53.5 (CH), 53.8 (CH), 80.4
CH), 170.8 (C), 204.8 (CH), 213.8 (C). IR (film): 1731, 1711, 1465,
369, 1246, 1032, 751 cm . HRMS (FAB): m/z calcd for
2
5
=
D
1
+
(
6
=
3
3
2
5
1
[
α] = +5.6 (c = 7.6, CHCl ). H NMR (CDCl , 500 MHz): δ 0.85−
D
3
3
0
1
5
.87 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 1.07−
.09 (m, 1H), 1.13 (s, 3H), 1.33−1.35 (m, 1H), 1.46 (s, 3H), 1.52−1.
4 (m, 2H), 1.53 (s, 3H), 1.68 (ddd, J = 13.1, 13.1, 5.5 Hz, 1H), 1.78
(
13
(s, 3H), 1.79−1.93 (m, 2H), 1.97−2.06 (m, 2H), 2.12 (ddd, J = 14.3,
3
3
1
4.3, 4.3 Hz, 1H), 2.27 (ddd, J = 12.8, 7.0, 2.8 Hz, 1H), 2.35−2.47 (m,
H), 2.77 (ddd, J = 14.7, 3.3, 3.3 Hz, 1H), 3.59 (d, J = 8.2 Hz, 1H).
(
2
4
(
1
3 3 3 2 3 2
2
13
C NMR (CDCl , 125 MHz): δ 11.1 (CH ), 15.7 (CH ), 17.9 (CH ),
3
3
3
3
2
1
9.2 (CH ), 20.1 (CH ), 25.7 (CH ), 27.4 (CH ), 29.6 (CH ), 30.3
3 2 2 2 3
−
1
(CH ), 32.0 (CH ), 33.6 (CH ), 33.7 (CH), 34.7 (CH ), 39.0 (C),
3 2 2 2
+
40.4 (CH), 48.8 (CH), 84.1 (CH), 85.4 (C), 108.5 (C), 128.4 (C),
C H O Na (M + Na ) 387.2511, found 387.2508.
2
2
36
4
1
7
3
62.4 (C), 198.7 (C). IR (film): 1669, 1376, 1366, 1237, 1214, 1039,
Synthesis of 11 from 29. CuCl (62 mg, 0.46 mmol) and NaIO4
98 mg, 0.46 mmol), dissolved in water, were added to a solution of 29
150 mg, 0.37 mmol) in acetonitrile (10 mL), and the mixture was
2
−1
+
72, 668 cm . HRMS (FAB): m/z calcd for C H O Na (M + Na )
(
(
22 34
3
69.2406, found 369.2411.
Methyl 5-((1S,4aR,6S,8aR)-6-((Methoxycarbonyl)oxy)-5,5,8a-
stirred at room temperature for 15 h, at which time TLC showed no
9. Then the solvent was removed under vacuum, and ether−water
40:10 mL) was added. The phases were shaken and separated, and
the organic phase was washed with brine (3 × 10 mL) and dried over
anhydrous Na SO . Removal of the solvent under vacuum afforded a
crude product which was directly purified by flash chromatography on
silica gel (10% ether/hexanes) to yield 11 (112 mg, 84%) as a colorless
syrup.
trimethyl-2-methylenedecahydronaphthalen-1-yl)-3-oxopen-
tanoate (15). NaH (60%, 130 mg, 3.2 mmol) and dimethyl carbonate
2
(
(1.2 mg, 13 mmol) were added to a stirred solution of 16 (186 mg,
0
.65 mmol) in benzene (17 mL), and the mixture was stirred at reflux
2
4
under an argon atmosphere overnight, at which time TLC showed no
remaining starting material. Then water (2 mL) was slowly added at 0
°
C, ether−water (50:20 mL) was added, and the phases were shaken
and separated. The organic phase was washed with water and brine
and dried over anhydrous Na SO . Removal of the solvent under
(
2S,4aR,4bS,7S,8S,10aR)-7,8-Dihydroxy-7-isopropyl-1,1,4a-
2
4
trimethyltetradecahydrophenanthren-2-yl Acetate (12). PtO
2
vacuum afforded a crude product which was directly purified by flash
chromatography on silica gel (15% ether/hexanes) to give pure 15
(
80 mg, 0.35 mmol) and HClO (1.5 mL, 22.9 mmol) were added to a
4
solution of 26 (650 mg, 1.61 mmol) in dry AcOH (8 mL), and the
mixture was stirred at room temperature for 12 h under a hydrogen
atmosphere (3 atm). Then it was filtered through a silica gel pad and
washed with ether (60 mL). The filtrate was washed with water (5 ×
5 mL), aq NaHCO (5 × 15 mL), and brine (3 × 10 mL) and dried
over anhydrous Na SO . Removal of the solvent under vacuum
25
1
(
218 mg, 88%) as a colorless syrup. [α]D = +33.7 (c = 8.1, CHCl ). H
3
NMR (CDCl , 500 MHz): δ 0.71 (s, 3H), 0.85 (s, 3H), 0.93 (s, 3H),
3
1
2
3
.13−1.46 (m, 3H), 1.51−1.75 (m, 3H), 1.80−2.02 (m, 4H), 2.36−
.48 (m, 2H), 2.64−2.80 (m, 2H), 3.41 (s, 2H), 3.73 (s, 3H), 3.77 (s,
H), 4.36 (dd, J = 12.0, 4.2 Hz, 1H), 4.45 (br s, 1H), 4.85 (br s, 1H).
1
3
13
2
4
C NMR (CDCl , 125 MHz): δ 14.3 (CH ), 16.4 (CH ), 17.4 (CH ),
3
3
3
2
afforded a crude product which was directly purified by flash
chromatography on silica gel (25% ether/hexanes) to yield 12 (418
2
3.7 (CH ), 24.2 (CH ), 28.1 (CH ), 36.5 (CH ), 37.9 (CH ), 38.2
2 2 3 2 2
(
(
C), 39.3 (C), 42.0 (CH ), 49.1 (CH ), 52.3 (CH ), 54.5 (CH ), 54.6
mg, 74%) as a colorless syrup. [α]2 = −15.5 (c = 14.2, CHCl ). H
5
D
1
2 2 3 3
3
CH), 55.5 (CH), 85.1 (CH), 107.0 (CH ), 147.2 (C), 155.7 (C),
2
NMR (CDCl , 500 MHz): δ 0.66 (ddd, J = 11.7, 11.7, 3.4 Hz, 1H),
3
1
67.6 (C), 202.8 (C). IR (film): 1745, 1718, 1442, 1271, 974, 793
0
3
4
1
2
9
.76−1.04 (m, 2H), 0.86 (s, 3H), 0.87 (s, 3H), 0.87 (d, J = 6.9 Hz,
H), 0.88 (s, 3H), 0.92 (d, J = 6.9 Hz, 3H), 1.10 (ddd, J = 13.6, 13.6,
.0 Hz, 1H), 1.17 (ddd, J = 13.4, 4.1 Hz, 1H), 1.24−1.47 (m, 3H),
.48−1.72 (m, 7H), 1.75 (ddd, J = 13.2, 3.5, 3.5 Hz, 1H), 2.04 (s, 3H),
.05−2.10 (m, 1H), 2.22 (ddd, J = 12.7, 7.0, 3.7 Hz, 1H), 3.16 (d, J =
.6 Hz, 1H), 4.48 (dd, J = 11.7, 4.6 Hz, 1H). C NMR (CDCl , 125
MHz): δ 14.3 (CH ), 16.3 (CH ), 16.7 (CH ), 17.7 (CH ), 18.8
CH ), 20.9 (CH ), 21.3 (CH ), 23.9 (CH ), 27.1 (CH ), 28.2 (CH ),
1.4 (CH ), 33.5 (CH), 36.4 (C), 37.0 (CH ), 37.8 (C), 38.6 (CH),
2 2
3.1 (CH), 54.3 (CH), 75.0 (CH), 77.1 (C), 81.0 (CH), 171.0 (C).
IR (film): 3475, 1731, 1457, 1368, 1247, 1031, 977 cm . HRMS
FAB): m/z calcd for C H O Na (M + Na ) 389.2668, found
89.2670.
−1
+
cm . HRMS (FAB): m/z calcd for C H O Na (M + Na ) 417.2253,
22
34
6
found 417.2244.
-((1S,4aR,6S,8aR)-6-Hydroxy-5,5,8a-trimethyl-2-methylene-
decahydronaphthalen-1-yl)butan-2-one (16). To a solution of 33
100 mg, 0.36 mmol) in dry Et O (10 mL) was added MeLi in
4
(
2
13
3
dimethoxymethane (3.0M, 0.5 mL, 1.5 mmol), and the reaction
mixture was stirred at room temperature for 48 h, at which time TLC
showed no starting material. Then water (0.5 mL) was slowly added at
3
3
3
3
(
3
5
2 2 3 2 2 3
0 °C, later Et O−water (30:15 mL) was added, and the phases were
2
shaken and separated. The organic phase was washed with water and
brine and dried over anhydrous Na SO . Removal of the solvent under
−1
2
4
+
(
3
vacuum afforded a crude product which was directly purified by flash
chromatography on silica gel (20% ether/hexanes) to give pure 16 (84
22
38
4
mg, 85%) as a colorless syrup. [α]2 = +5.0 (c = 3.0, CHCl ). H NMR
5
1
Synthesis of 12 from 29. To a solution of 29 (127 mg, 0.31
D
3
mmol) in THF (8 mL) were added trifluoroacetic acid (1 mL, 13.5
mmol) and water (1 mL), and the reaction mixture was stirred under
reflux for 18 h, at which time TLC showed no starting material. Then
the solvent was removed under vacuum, and ether−water (40:10 mL)
was added. The phases were shaken and separated, and the organic
phase was washed with brine (3 × 10 mL) and dried over anhydrous
Na SO . Removal of the solvent under vacuum afforded a crude
(CDCl , 500 MHz): δ 0.69 (s, 3H), 0.77 (s, 3H), 0.99 (s, 3H), 1.08
3
(dd, J = 12.5, 2.8 Hz, 1H), 1.15−1.34 (m, 3H), 1.39 (ddd, J = 25.9,
13.0, 4.4 Hz, 1H), 1.53−1.77 (m, 3H), 1.77−1.88 (m, 2H), 1.95 (ddd,
J = 12.9, 12.9, 4.2 Hz, 1H), 2.10 (s, 3H), 2.28−2.32 (m, 1H), 2.40
(ddd, J = 12.8, 4.2, 2.4 Hz, 1H), 2.56−2.60 (m, 1H), 3.24−3.26 (m,
1H), 4.45 (s, 1H), 4.84 (s, 1H). 13C NMR (CDCl , 125 MHz): δ 14.3
3
(CH ), 15.4 (CH ), 17.5 (CH ), 24.0 (CH ), 27.9 (CH ), 28.3 (CH ),
2
4
3
3
2
2
2
3
product which was directly purified by flash chromatography on silica
30.1 (CH ), 36.9 (CH ), 38.1 (CH ), 39.1 (C), 39.5 (C), 42.7 (CH ),
3 2 2 2
4
409
dx.doi.org/10.1021/jo5003533 | J. Org. Chem. 2014, 79, 4405−4413

The Journal of Organic Chemistry
Article
5
4.6 (CH), 55.9 (CH), 78.8 (CH), 106.7 (CH ), 147.7 (C), 209.2
(CH ), 19.5 (CH ), 21.1 (CH ), 25.9 (CH ), 29.5 (CH ), 30.2 (CH ),
2
3
2
2
2
3
3
−
1
(
(
3
C). IR (film): 3422, 1712, 1456, 1363, 1163, 889, 670 cm . HRMS
FAB): m/z calcd for C H O Na (M + Na ) 301.2143, found
01.2139.
1R,4aR,4bS,7S,8S,8aS,10aR)-7,8-Dihydroxy-7-isopropyl-
,4a-dimethyltetradecahydrophenanthrene-1-carboxylic Acid
33.3 (CH ), 33.7 (CH), 35.4 (CH ), 36.7 (C), 37.6 (C), 38.7 (CH ),
2
2
2
+
40.1 (CH), 47.6 (CH), 51.0 (CH), 71.9 (CH ), 85.2 (CH), 85.5 (C),
2
18
30
2
−1
108.2 (C). IR (film): 3453, 1716, 1457, 1381, 1239, 1038, 771 cm .
+
(
HRMS (FAB): m/z calcd for C H O Na (M + Na ) 387.2875,
23
40
3
1
found 387.2869.
3aS,5aR,6R,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,9a-tetra-
(
18). To a solution of 17 (10 g, 29.72 mmol) in dry AcOH (100 mL)
(
was added 10% Pd/C (1 g), and the mixture was stirred at room
temperature under a hydrogen atmosphere (3 atm) for 12 h. Then the
mixture was filtered through a silica gel pad and washed with ether
methyltetradecahydrophenanthro[2,1-d][1,3]dioxole-6-carbal-
dehyde (21). PCC (5 g, 13.29 mmol) and Celite (4 g) were added to
a stirred solution of 20 (3.71 g, 10.18 mmol) in dry CH Cl (70 mL),
2
2
(
150 mL). The filtrate was washed with water (5 × 30 mL), aq 5%
and the mixture was stirred at room temperature under an argon
atmosphere for 1 h, at which time TLC showed no remaining starting
material. Then the reaction was worked up by the addition of ether
(40 mL), and the resulting mixture was filtered through a silica gel pad
and washed with ether (60 mL). The filtrate was washed with 2 N HCl
(3 × 30 mL) and brine. The solvent was evaporated to yield a crude
product, which was chromatographed on silica gel (10% ether/
NaHCO (5 × 30 mL), and brine. The solvent was evaporated to yield
1
MeOH). H NMR (CD COCD , 500 MHz): δ 0.76−0.78 (m, 1H),
3
2
5
8 (9.56 g, 95%) as a white solid. Mp: 148 °C. [α] = −9.8 (c = 17.9,
D
1
3
3
0
1
1
2
1
1
(
3
1
.84 (d, J = 7.0 Hz, 3H), 0.90 (s, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.93−
.04 (m, 2H), 1.16 (s, 3H), 1.16−1.18 (m, 1H), 1.22−1.30 (m, 2H),
.35−1.44 (m, 2H), 1.48−1.69 (m, 4H), 1.70−1.83 (m, 4H), 2.05−
.09 (m, 1H), 2.22−2.24 (m, 1H), 2.84 (br s, 2H), 3.13 (d, J = 9.6 Hz,
H). 13C NMR (CD COCD , 125 MHz): δ 15.1 (CH ), 16.9 (CH ),
2
5
hexanes) to yield 21 (3.02 g, 88%) as a colorless syrup. [α] = −34.5
D
1
(c = 51.6, CHCl ). H NMR (CDCl , 500 MHz): δ 0.68 (ddd, J =
3
3
3
3
3
3
7.4 (CH ), 18.2 (CH ), 19.0 (CH ), 19.6 (CH ), 24.9 (CH ), 27.8
11.6, 11.6, 6.0 Hz, 1H), 0.80−1.14 (m, 2H), 0.88 (s, 3H), 0.89 (d, J =
6.9 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H), 1.06 (s, 3H), 1.17−1.28 (m,
2H), 1.33−1.54 (m, 6H), 1.42 (s, 3H), 1.46 (s, 3H), 1.55−1.68 (m,
3
3
2
2
2
CH ), 32.3 (CH ), 34.3 (CH), 37.0 (C), 37.9 (CH ), 39.4 (CH ),
2
2
2
2
9.8 (CH), 47.8 (C), 52.6 (CH), 54.9 (CH), 75.3 (C), 77.4 (CH),
−
1
80.1 (C). IR (KBr): 3389, 1695, 1455, 1386, 1261, 692 cm . HRMS
3H), 1.76−1.86 (m, 2H), 1.98 (h, J = 6.9 Hz, 1H), 2.10−2.14 (m,
+
13
(
3
FAB): m/z calcd for C H O Na (M + Na ) 361.2355, found
1H), 3.55 (d, J = 8.3 Hz, 1H), 9.20 (s, 1H). C NMR (CDCl
3
, 125
), 19.2
(CH ), 19.4 (CH ), 23.9 (CH ), 25.7 (CH ), 29.5 (CH ), 30.2 (CH ),
20
34
4
61.2362.
MHz): δ 14.2 (CH ), 14.4 (CH ), 15.8 (CH ), 17.1 (CH
3 3 3 2
(
3aS,3bS,5aR,6R,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,9a-tetra-
3
2
2
2
3
3
methyltetradecahydrophenanthro[2,1-d][1,3]dioxole-6-car-
boxylic Acid (19). To a solution of 18 (3.85 g, 11.37 mmol) in dry
acetone (40 mL) were added 2,2-dimethoxypropane (2.54 g, 24.4
mmol) and p-toluenesulfonic acid (95 mg, 0.5 mmol), and the reaction
mixture was stirred under reflux for 4 h, at which time TLC showed no
starting material. Then the solvent was removed under vacuum, and
ether−water (90:20 mL) was added. The phases were shaken and
separated, and the organic phase was washed with brine and dried over
anhydrous Na SO . Removal of the solvent under vacuum afforded a
32.4 (CH ), 32.9 (CH ), 33.7 (CH), 35.8 (C), 38.1 (CH ), 40.3
2
2
2
(
(
CH), 46.8 (CH), 49.6 (C), 50.9 (CH), 84.9 (CH), 85.5 (C), 108.3
C), 206.5 (CH). IR (film): 1727, 1455, 1235, 1216, 1040, 864, 758
−
1
+
cm . HRMS (FAB): m/z calcd for C H O Na (M + Na ) 385.2719,
23
38
3
found 385.2723.
(
3aS,5aR,6R,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,9a-tetra-
methyltetradecahydrophenanthro[2,1-d][1,3]dioxol-6-yl For-
mate (22). m-Chloroperoxybenzoic acid (MCPBA) (70%; 7.38 g,
29.94 mmol) and NaHCO
stirred solution of 21 (3.62 g, 9.98 mmol) in CH
(2.51 g, 29.94 mmol) were added to a
Cl (300 mL), and
2
4
3
crude product which was directly purified by flash chromatography on
silica gel (20% ether/hexanes) to yield 19 (3.79 g, 88%) as a colorless
2
2
the reaction was stirred under reflux for 3 h, at which time TLC
indicated no starting material remaining. The reaction was quenched
syrup. [α]2 = +34.1 (c = 10.6, CHCl ). H NMR (CDCl , 500 MHz):
5
1
D
3
3
δ 0.69 (ddd, J = 12.3, 12.3, 3.5 Hz, 1H), 0.87 (s, 3H), 0.89 (d, J = 6.8
Hz, 3H), 0.96−1.11 (m, 2H), 0.94 (d, J = 6.9 Hz, 3H), 1.17 (s, 3H),
with satd aq Na
Then the organic solvent was removed under vacuum, and ether (100
mL) was added. The organic phase was washed with satd aq NaHCO
(8 × 30 mL) and brine, dried over Na SO , and concentrated to give
2 3
SO (30 mL) and stirred for an additional 15 min.
1
1
2
.18−1.31 (m, 2H), 1.39−1.54 (m, 2H), 1.43 (s, 3H), 1.47 (s, 3H),
.54−1.66 (m, 5H), 1.67−1.84 (m, 4H), 1.98 (h, J = 6.8 Hz, 1H),
3
2
4
1
3
25
.12−2.16 (m, 1H), 3.56 (d, J = 8.2 Hz, 1H). C NMR (CDCl , 125
22 (3.25 g, 86%) as a colorless syrup. [α]
D
= −52.8 (c = 20.3, CHCl
H NMR (CDCl , 500 MHz): δ 0.68 (ddd, J = 12.1, 12.1, 3.3 Hz, 1H),
3
3
).
3
1
MHz): δ 14.1 (CH ), 15.8 (CH ), 16.5 (CH ), 17.9 (CH ), 19.2
3
3
3
2
(
3
(
(
CH ), 19.3 (CH ), 24.1 (CH ), 25.7 (CH ), 29.5 (CH ), 30.1 (CH ),
0.84 (s, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.93−1.07 (m, 2H), 0.94 (d, J =
6.9 Hz, 3H), 1.20−1.24 (m, 1H), 1.33 (ddd, J = 25.6, 12.9, 3.9 Hz,
1H), 1.39−1.75 (m, 8H), 1.43 (s, 3H), 1.46 (s, 3H), 1.47 (s, 3H),
1.76−1.85 (m, 2H), 1.99 (h, J = 6.8 Hz, 1H), 2.20 (ddd, J = 12.8, 6.9,
3.7 Hz, 1H), 2.50 (br d, J = 12.4 Hz, 1H), 3.55 (d, J = 8.3 Hz, 1H),
8.02 (s, 1H). 13C NMR (CDCl , 125 MHz): δ 13.7 (CH ), 15.8
3
2
2
2
3
3
3.1 (CH ), 33.7 (CH), 36.3 (C), 37.1 (CH ), 38.1 (CH ), 40.3
2
2
2
CH), 47.2 (C), 48.9 (CH), 51.2 (CH), 85.0 (CH), 85.6 (C), 108.3
−1
C), 184.8 (C). IR (film): 1695, 1368, 1236, 1215, 1038, 757 cm .
+
HRMS (FAB): m/z calcd for C H O Na (M + Na ) 401.2668,
23
38
4
found 401.2676.
(3aS,5aR,6R,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,9a-tetra-
3
3
(
(CH ), 19.2 (CH ), 19.4 (CH ), 19.5 (CH ), 20.3 (CH ), 20.7 (CH ),
3 3 2 2 3 2
methyltetradecahydrophenanthro[2,1-d][1,3]dioxol-6-yl)-
25.7 (CH ), 29.5 (CH ), 30.2 (CH ), 32.7 (CH ), 33.7 (CH), 37.7
2 3 3 2
methanol (20). LiAlH (0.53 g, 14.04 mmol) was added at 0 °C to a
4
(CH ), 37.8 (C), 38.2 (CH ), 40.1 (CH), 51.0 (CH), 53.1 (CH), 84.9
2
2
stirred solution of 19 (4.43 g, 11.70 mmol) in dry diethyl ether (60
mL), and the mixture was stirred at room temperature under an argon
atmosphere for 5 min, at which time TLC showed no compound 19.
(
1
CH), 85.5 (C), 87.3 (C), 108.3 (C), 160.5 (CH). IR (film): 1721,
−1
448, 1385, 1189, 1040, 861, 772 cm . HRMS (FAB): m/z calcd for
+
C H O Na (M + Na ) 401.2668, found 401.2677.
23
38
4
Then acetone (0.5 mL) was slowly added at 0 °C, Et O−water (50:15
2
(3aS,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,9a-tetramethyl-
mL) was added, and the phases were shaken and separated. The
organic phase was washed with water and brine and dried over
anhydrous Na SO . Removal of the solvent under vacuum afforded a
3a,3b,4,5,7,8,9,9a,9b,10,11,11a-dodecahydrophenanthro[2,1-
d][1,3]dioxole (23). To a solution of triphenylphosphine (1.61 g,
6.16 mmol) in dry CH Cl (30 mL) was added iodine (1.56 g, 6.16
2
4
2
2
crude product which was directly purified by flash chromatography on
silica gel (20% ether/hexanes) to give pure 20 (3.74 g, 91%) as a
mmol), and the mixture was stirred at room temperature for 5 min.
Then a solution of 22 (2.12 g, 5.60 mmol) in dry CH Cl (20 mL) was
2
2
colorless syrup. [α]2 = −18.6 (c = 10.8, CHCl ). H NMR (CDCl ,
5
1
added, and the resulting mixture was stirred at room temperature for
D
3
3
5
0
6
1
00 MHz): δ 0.64 (ddd, J = 12.4, 12.4, 3.5 Hz, 1H), 0.77 (s, 3H),
.80−1.07 (m, 2H), 0.87 (s, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.94 (d, J =
.9 Hz, 3H), 1.10−1.35 (m, 4H), 1.36−1.67 (m, 7H) 1.43 (s, 3H),
.48 (s, 3H), 1.74 (br d, J = 13.0 Hz, 1H), 1.78−1.82 (m, 1H), 1.98 (h,
40 min. Then aq 5% NaHSO (5 mL) was added, and the mixture was
3
stirred for 5 min. The solvent was removed under vacuum, and the
crude product was diluted with ether−water (90−30 mL). The phases
were shaken and separated, and the organic phase was washed with
water and brine and dried over anhydrous Na SO . Removal of the
J = 6.9 Hz, 1H), 2.16−2.18 (m, 1H), 3.09 (d, J = 10.8 Hz, 1H), 3.41
2
4
13
(
d, J = 10.8 Hz, 1H), 3.54 (d, J = 8.3 Hz, 1H). C NMR (CDCl , 125
solvent under vacuum afforded a crude product which was directly
purified by flash chromatography on silica gel (5% ether/hexanes) to
3
MHz): δ 14.4 (CH ), 15.8 (CH ), 17.8 (CH ), 18.1 (CH ), 19.2
3
3
3
2
4
410
dx.doi.org/10.1021/jo5003533 | J. Org. Chem. 2014, 79, 4405−4413

The Journal of Organic Chemistry
Article
give 23 (1.34 g, 76%) as a colorless syrup. [α] 2D 5 = +12.5 (c = 29.1,
δ 0.89 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 1.04 (s, 3H), 1.06
(s, 3H), 1.09−1.11 (m, 1H), 1.15 (s, 3H), 1.35−1.60 (m, 2H), 1.44 (s,
3H), 1.49 (s, 3H), 1.66−1.92 (m, 8H), 1.99 (h, J = 6.9 Hz, 1H), 2.50−
2.58 (m, 1H), 3.23 (dd, J = 11.1, 5.0 Hz, 1H), 3.66 (d, J = 7.1 Hz, 1H),
1
CHCl ). H NMR (CDCl , 500 MHz): δ 0.71−0.73 (m, 1H), 0.86−
3
3
1.00 (m, 2H), 0.87 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.96
(
3
(
s, 3H), 1.19−1.30 (m, 2H), 1.44 (s, 3H), 1.45−1.60 (m, 2H), 1.52 (s,
H), 1.61 (s, 3H), 1.68−1.78 (m, 2H), 1.80−1.90 (m, 4H), 1.93−1.97
m, 1H), 1.99 (h, J = 6.9 Hz, 1H), 2.12 (ddd, J = 12.6, 6.9, 3.7 Hz,
5.62 (dd, J = 4.4, 2.4 Hz, 1H). 13C NMR (CDCl , 125 MHz): δ 15.8
3
(CH ), 19.1 (CH ), 19.3 (CH ), 20.8 (CH ), 23.5 (CH ), 25.9 (CH ),
3
3
2
3
3
2
1
H), 2.56 (ddd, J = 14.2, 3.4, 3.4 Hz, 1H), 3.55 (d, J = 8.3 Hz, 1H).
27.22 (CH ), 27.24 (CH ), 29.3 (CH ), 29.9 (CH ), 33.4 (CH ), 34.1
2 3 3 3 2
1
3
C NMR (CDCl , 125 MHz): δ 15.9 (CH ), 19.2 (CH ), 19.3 (CH ),
(CH), 35.6 (CH), 36.3 (CH ), 37.2 (C), 41.5 (C), 47.1 (CH), 77.4
3
3
2
3
2
1
9.7 (CH ), 19.9 (CH ), 20.7 (CH ), 25.0 (CH ), 26.0 (CH ), 29.7
(CH), 85.8 (C), 85.9 (CH), 108.5 (C), 120.0 (CH), 149.1 (C). IR
3
3
2
2
2
−1
(
CH ), 30.3 (CH ), 33.0 (CH ), 33.2 (CH ), 33.8 (CH), 37.5 (C),
(film): 3470, 1467, 1367, 1238, 1040, 866, 756 cm . HRMS (FAB):
3
3
2
2
+
3
1
7.9 (CH ), 41.0 (CH), 49.3 (CH), 84.9 (CH), 85.6 (C), 108.2 (C),
m/z calcd for C23H O Na (M + Na ) 385.2719, found 385.2724.
38 3
2
24.4 (C), 136.0 (C). IR (film): 1457, 1377, 1367, 1236, 1038, 773
(3aS,3bS,7S,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,6,9a-penta-
methyl-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecahydro-
phenanthro[2,1-d][1,3]dioxol-7-yl Acetate (26). To a solution of
−1
+
cm . HRMS (FAB): m/z calcd for C H O Na (M + Na ) 355.2613,
found 355.2621.
22
36
2
2
5 (376 mg, 1.04 mmol) in pyridine (5 mL) at 0 °C was added acetic
Synthesis of 23 from 19. To a solution of 19 (840 mg, 2.22
anhydride (2 mL), and the reaction mixture was stirred at room
temperature for 2 h, at which time TLC showed no starting material.
Then the reaction mixture was cooled at 0 °C, water (5 mL) was
added to quench the reaction, and the mixture was stirred for an
additional 10 min. Then it was diluted with ether−water (40:10 mL),
and the phases were shaken and separated. The organic phase was
washed with water (10 mL), 2 N HCl (4 × 10 mL), water (10 mL)
mmol) in benzene (25 mL) were added lead(IV) acetate (1.28 mg,
2.89 mmol), cooper(II) acetate (22 mg, 0.11 mmol), and pyridine
(
668 mg, 8.44 mmol), and the reaction mixture was stirred under
reflux for 15 min, at which time TLC showed no 19. Then it was
diluted with ether (40 mL) and washed with 2 N HCl (3 × 10 mL),
water (10 mL), satd aq NaHCO (3 × 10 mL), and brine, and the
3
organic phase was dried over Na SO . Removal of the solvent under
2
4
again, satd aq NaHCO (4 × 10 mL), and brine, and the organic phase
vacuum afforded a crude product (837 mg) which was used in the next
step without purification. To a stirred solution of this crude (837 mg)
in dry CH Cl (15 mL) was added a solution of triphenylphosphine
3
was dried over Na SO . Removal of the solvent under vacuum afforded
2
4
a crude product which was purified by flash chromatography on silica
gel (10% ether/hexanes) to give 26 (399 mg, 95%) as a colorless
syrup. [α]2 = −46.6 (c = 32.8, CHCl ). NMR (CDCl , 500 MHz): δ
2
2
(
755 mg, 2.88 mmol) and iodine (731 mg, 2.88 mmol) in dry CH Cl2
2
5
D
(30 mL), and the resulting mixture was stirred at room temperature
3
3
0
.89 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 1.02 (s, 3H), 1.06
for 2 h. Following the same workup used for 23 from 22, a crude
product was obtained which was directly purified by flash
chromatography on silica gel (5% ether/hexanes) to give 23 (472
mg, 64%) as a colorless syrup.
(
3
=
s, 3H), 1.12 (s, 3H), 1.16−1.18 (m, 1H), 1.36−1.38 (m, 1H), 1.43 (s,
H), 1.47 (s, 3H), 1.54−1.56 (m, 1H), 1.68−1.92 (m, 8H), 1.98 (h, J
6.8 Hz, 1H), 2.05 (s, 3H), 2.50−2.55 (m, 1H), 3.66 (d, J = 7.2 Hz,
H), 4.47 (dd, J = 11.3, 4.7 Hz, 1H), 5.61 (dd, J = 4.5, 2.6 Hz, 1H).
1
(
3aS,3bS,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,6,9a-penta-
methyl-3b,4,9,9a,9b,10,11,11a-octahydrophenanthro[2,1-d]-
1,3]dioxol-7(3aH,6H,8H)-one (24). Potassium tert-butoxide (155
13
C NMR (CDCl
, 125 MHz): δ 15.9 (CH ), 19.1 (CH ), 19.4 (CH ),
3
3 3 2
[
20.9 (CH ), 21.3 (CH ), 23.7 (CH ), 24.8 (CH ), 25.9 (CH ), 27.2
3
3
2
3
2
mg, 1.38 mmol) was added to a stirred solution of 13 (400 mg, 1.15
mmol) in dry THF (20 mL) under an argon atmosphere, and the
reaction mixture was stirred at room temperature for 20 min. Then
methyl iodide (0.072 mL, 1.38 mmol) was added, and the reaction
mixture was stirred at room temperature for an additional 1 h, at which
time TLC showed no starting material. The mixture was concentrated
in vacuo to give a crude product, which was diluted with ether−water
(CH ), 29.4 (CH ), 30.0 (CH ), 33.4 (CH ), 34.1 (CH), 35.7 (CH),
3 3 3 2
35.9 (CH ), 37.2 (C), 40.3 (C), 47.0 (CH), 79.4 (CH), 85.9 (CH),
2
85.9 (C), 108.6 (C), 120.6 (CH), 148.3 (C), 170.7 (C). IR (film):
−1
1736, 1468, 1367, 1241, 1035, 757 cm . HRMS (FAB): m/z calcd for
+
C H O Na (M + Na ) 427.2824, found 427.2831.
25
40
4
(3aS,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,6,9a-pentamethyl-
decahydrophenanthro[2,1-d][1,3]dioxol-7(3aH,3bH,8H)-one
(
40:10 mL), and the phases were shaken and separated. The organic
(27). A solution of enone 13 (253 mg, 0.73 mmol) in THF/t-BuOH
phase was washed with water and brine and dried over anhydrous
(5:1 mL) was added under argon to liquid NH at −78 °C, and the
3
Na SO . Removal of the solvent under vacuum afforded a crude
mixture was stirred for 10 min. Then Li (51 mg, 7.3 mmol) was added,
the mixture was stirred at −40 °C for 3 h, MeI (136 μL, 2.19 mmol)
was added, and the mixture was stirred for 1 h. After this time the
2
4
product which was purified by flash chromatography on silica gel (5%
ether/hexanes), affording 340 mg of 24 (82%) as a colorless syrup.
2
5
1
[
(
3
(
2
2
α] = −19.9 (c = 22.6, CHCl ). H NMR (CDCl , 500 MHz): δ 0.81
mixture was heated to room temperature to evaporate the NH , then
3
D
3
3
s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 1.22 (s,
H), 1.24 (s, 3H), 1.35−1.59 (m, 4H), 1.45 (s, 3H), 1.49 (s, 3H), 1.68
the mixture was diluted with ether and water, and the organic phase
was washed with water (3 × 25 mL) and brine (1 × 25 mL) and dried
ddd, J = 13.5, 11.3, 8.5 Hz, 1H), 1.75−1.91 (m, 4H), 1.97−2.08 (m,
over Na
SO . Removal of the solvent under vacuum afforded a crude
2 4
H), 2.43−2.61 (m, 2H), 3.70 (d, J = 7.3 Hz, 1H), 5.60 (dd, J = 4.9,
product which was purified by flash chromatography on silica gel (10%
.0 Hz, 1H). 13C NMR (CDCl , 125 MHz): δ 15.8 (CH ), 18.8
25
ether/hexanes) to give 27 (225 mg, 85%) as a colorless syrup. [α] =
D
3
3
1
(
CH ), 19.3 (CH ), 20.1 (CH ), 25.5 (CH ), 27.2 (CH ), 29.5 (CH ),
−39.8 (c = 19.5, CHCl ). H NMR (CDCl , 500 MHz): δ 0.63 (ddd, J
3
3
3
3
2
2
3
3
3
0.07 (CH ), 30.09 (CH ), 31.8 (CH ), 32.6 (CH ), 33.7(CH ), 34.1
= 12.1, 12.1, 3.4 Hz, 1H), 0.85−1.13 (m, 2H), 0.88 (d, J = 6.8 Hz,
3H), 0.94 (d, J = 6.8 Hz, 3H), 1.01 (s, 3H), 1.03 (s, 3H), 1.06 (s, 3H),
1.20−1.34 (m, 3H), 1.34−1.54 (m, 2H), 1.43 (s, 3H), 1.48 (s, 3H),
1.55−1.67 (m, 2H), 1.79 (ddd, J = 14.3, 4.5, 4.5 Hz, 1H), 1.94−2.07
(m, 2H), 2.23 (ddd, J = 11.0, 7.0, 3.5 Hz, 1H), 2.32 (ddd, J = 15.4, 5.1,
3.6 Hz, 1H), 2.62 (ddd, J = 15.3, 13.2, 6.3 Hz, 1H), 3.56 (d, J = 8.3 Hz,
1H). 13C NMR (CDCl , 125 MHz): δ 13.5 (CH ), 15.8 (CH ), 19.2
3
3
2
2
2
(
(
2
CH), 36.3 (CH), 37.4 (C), 44.9 (CH), 48.6 (C), 85.3 (CH), 85.9
C), 108.7 (C), 119.8 (CH), 149.1 (C), 216.2 (C). IR (film): 2961,
873, 1710, 1464, 1380, 1238, 1040, 668 cm . HRMS (FAB): m/z
−1
+
calcd for C H O Na (M + Na ) 383.2562, found 383.2555.
23
36
3
(
3aS,3bS,7S,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,6,9a-penta-
methyl-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecahydro-
phenanthro[2,1-d][1,3]dioxol-7-ol (25). Sodium borohydride (84
mg, 2.22 mmol) was added to a stirred solution of 24 (323 mg, 0.90
mmol) in EtOH (5 mL), and the reaction mixture was stirred at room
temperature for 15 min, at which time TLC showed no 24. The
reaction mixture was quenched with water (1 mL), and the solvent was
evaporated. The crude product was diluted with ether−water (30:10
mL), and the phases were shaken and separated. The organic phase
was washed with water and brine, and the organic phase was dried over
Na SO and concentrated to give 25 (292 mg, 90%) as a colorless
3
3
3
(CH ), 19.9 (CH ), 21.9 (CH ), 22.3 (CH ), 25.7 (CH ), 25.8 (CH ),
3
2
3
2
2
3
29.5 (CH ), 30.2 (CH ), 33.1 (CH ), 33.7 (CH), 34.5 (CH ), 36.5
3
3
2
2
(C), 37.8 (CH ), 40.2 (CH), 47.7 (C), 50.3 (CH), 54.6 (CH), 84.8
2
(CH), 85.6 (C), 108.3 (C), 216.9 (C). IR (film): 1707, 1457, 1366,
−
1
1241, 1039, 667 cm . HRMS (FAB): m/z calcd for C H O Na (M
2
3
38
3
+
+ Na ) 385.2719, found 385.2724.
(3aS,7S,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,6,9a-penta-
methyltetradecahydrophenanthro[2,1-d][1,3]dioxol-7-ol (28).
Sodium borohydride (89 mg, 2.36 mmol) was added to a stirred
solution of 27 (345 mg, 0.95 mmol) in EtOH (5 mL), and the reaction
2
4
2
5
1
syrup. [α] = −84.0 (c = 20.6, CHCl ). H NMR (CDCl , 500 MHz):
D
3
3
4
411
dx.doi.org/10.1021/jo5003533 | J. Org. Chem. 2014, 79, 4405−4413

The Journal of Organic Chemistry
Article
mixture was stirred at room temperature for 15 min, at which time
1.060 (d, J = 6.9 Hz, 3H), 1.49−1.63 (m, 4H), 1.64−1.75 (m, 3H),
1.78 (ddd, J = 13.2, 3.5, 3.5 Hz, 1H), 2.03 (s, 3H), 2.30−2.38 (m, 1H),
2.43−2.45 (m, 1H), 2.45 (s, 3H), 2.51 (h, J = 6.9 Hz, 1H), 3.95 (ddd, J
= 12.5, 9.6, 4.0 Hz, 2H), 4.44 (dd, J = 11.8, 4.4 Hz, 1H), 7.34 (d, J =
TLC showed no 27. Following the same workup used to prepare 25,
2
5
2
=
8 (292 mg, 90%) was obtained as a colorless syrup. [α] = −32.8 (c
D
1
4.5, CHCl ). H NMR (CDCl , 500 MHz): δ 0.55 (ddd, J = 12.3,
3
3
3
=
.7 Hz, 1H), 0.76−1.08 (m, 2H), 0.79 (s, 3H), 0.83 (s, 3H), 0.88 (d, J
8.0 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H). 13C NMR (CDCl , 125 MHz):
3
6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.98 (s, 3H), 1.20 (ddd, J =
δ 13.8 (CH ), 16.5 (CH ), 18.1 (CH ), 18.2 (CH ), 20.5 (CH ), 21.2
3
3
3
3
2
2
4.0, 10.8, 3.5 Hz, 1H), 1.34 (ddd, J = 25.9, 13.1, 3.7 Hz, 1H), 1.39−
(CH ), 21.6 (CH ), 22.0 (CH ), 23.6 (CH ), 28.0 (CH ), 30.2 (CH ),
3 3 2 2 3 2
1
.68 (m, 7H), 1.43 (s, 3H), 1.47 (s, 3H), 1.74−1.83 (m, 2H), 1.91 (h,
36.5 (CH ), 37.7 (C), 38.0 (C), 39.1 (CH), 40.8 (CH), 41.6 (CH ),
2
2
J = 6.9 Hz, 1H), 2.14 (ddd, J = 12.7, 7.1, 3.7 Hz, 1H), 3.14 (dd, J =
51.0 (CH), 53.8 (CH), 73.2 (CH ), 80.6 (CH), 127.8 (CH), 127.8
2
13
11.6, 4.5 Hz, 1H), 3.47 (d, J = 8.3 Hz, 1H). C NMR (CDCl , 125
(CH), 129.8 (CH), 129.8 (CH), 133.0 (C), 144.8 (C), 170.8 (C),
3
−1
MHz): δ 13.9 (CH ), 15.5 (CH ), 15.8 (CH ), 19.2 (CH ), 19.5
214.1 (C). IR (film): 1731, 1713, 1363, 1246, 1177, 667 cm . HRMS
3
3
3
3
+
(
CH ), 21.1 (CH ), 25.8 (CH ), 27.4 (CH ), 28.2 (CH ), 29.5 (CH ),
(FAB): m/z calcd for C H O SNa (M + Na ) 543.2756, found
2
2
2
2
3
3
29 44
6
3
4
1
0.2 (CH ), 33.6 (CH ), 33.7 (CH), 36.7 (C), 37.3 (CH ), 38.9 (C),
543.2757.
3
2
2
0.0 (CH), 51.0 (CH), 53.9 (CH), 79.0 (CH), 85.1 (CH), 85.5 (C),
Isopropyl 3-((1S,4aR,6S,8aR)-6-Acetoxy-5,5,8a-trimethyl-2-
((tosyloxy)methyl)decahydronaphthalen-1-yl)propanoate
(32). MCPBA (70%; 555 mg, 2.25 mmol) and trifluoroacetic acid (256
mg, 2.25 mmol) were added to a stirred solution of 31 (393 mg, 0.75
mmol) in CH Cl (20 mL), and the reaction was stirred under reflux
for 20 h, at which time TLC indicated no starting material remaining.
The reaction was quenched with satd aq Na SO (5 mL) and stirred
for an additional 15 min. Then the organic solvent was removed under
vacuum, and ether (40 mL) was added. The organic phase was washed
with satd aq NaHCO
concentrated to give 32 (505 mg, 90%) as a colorless syrup. [α]
−4.5 (c = 10.2, CHCl ). H NMR (CDCl , 500 MHz): δ 0.70−0.72
−1
08.2 (C). IR (film): 3438, 1637, 1367, 1237, 1037, 756 cm . HRMS
+
(
FAB): m/z calcd for C H O Na (M + Na ) 387.2875, found
23 40 3
387.2868.
(
3aS,7S,9aR,9bS,11aS)-11a-Isopropyl-2,2,6,6,9a-penta-
2
2
methyltetradecahydrophenanthro[2,1-d][1,3]dioxol-7-yl Ace-
tate (29). To a solution of 28 (376 mg, 1.03 mmol) in pyridine (5
mL) at 0 °C was added acetic anhydride (2 mL), and the reaction
mixture was stirred at room temperature for 2 h, at which time TLC
showed no starting material. Following the same workup used to
prepare 26, a crude product was obtained which was purified by
chromatography on silica gel (10% ether/hexanes) to give 29 (385 mg,
2
3
(5 × 15 mL) and brine, dried over Na SO , and
3
2 4
2
5
=
D
1
3
3
2%) as a colorless syrup. [α]2 = 26.7 (c = 4.0, CHCl ). H NMR
5
D
1
9
(m, 1H), 0.79 (s, 3H), 0.81−0.91 (m, 2H), 0.83 (s, 6H), 1.03−1.38
(m, 3H), 1.22 (d, J = 6.3 Hz, 6H), 1.50−1.86 (m, 8H), 2.03 (s, 3H),
2.04−2.22 (m, 2H), 2.45 (s, 3H), 3.88 (dd, J = 9.6, 6.1 Hz, 1H), 4.07
(dd, J = 9.6, 3.1 Hz, 1H), 4.44 (dd, J = 11.7, 4.5 Hz, 1H), 4.96 (h, J =
3
(
CDCl , 500 MHz): δ 0.57 (ddd, J = 12.1, 12.1, 3.5 Hz, 1H), 0.86 (s,
3
6
0
1
H), 0.87 (s, 3H), 0.89 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H),
.40−1.41 (m, 4H), 1.43 (s, 3H), 1.48 (s, 3H), 1.40−1.70 (m, 7H),
.73−1.85 (m, 2H), 1.98 (h, J = 6.9 Hz, 1H), 2.04 (s, 3H), 2.18−2.22
1
3
6.3 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H).
NMR (CDCl , 125 MHz): δ 13.9 (CH ), 16.5 (CH ), 20.5 (CH
21.2 (CH ), 21.6 (CH ), 21.8 (CH ), 21.9 (CH
(CH ), 28.0 (CH ), 30.3 (CH ), 35.8 (CH
C
),
(
m, 1H), 3.54 (d, J = 8.2 Hz, 1H), 4.48 (dd, J = 11.6, 4.5 Hz, 1H). 13
C
3
3
3
2
NMR (CDCl , 125 MHz): δ 14.0 (CH ), 15.8 (CH ), 16.7 (CH ),
1
3
3
3
3
), 23.5 (CH
2
), 23.6
3
3
3
3
9.2 (CH ), 19.5 (CH ), 21.0 (CH ), 21.3 (CH ), 23.8 (CH ), 25.8
2
3
2
2
), 36.5 (CH
2
), 37.7 (C),
37.9 (C), 39.1 (CH), 51.2 (CH), 53.8 (CH), 67.6 (CH), 73.3 (CH ),
2
3
2
2
3
2
(
CH ), 28.2 (CH ), 29.5 (CH ), 30.2 (CH ), 33.5 (CH ), 33.7 (CH),
2
3
3
3
2
3
8
1
6.6 (C), 36.9 (CH ), 37.8 (C), 40.0 (CH), 50.9 (CH), 54.0 (CH),
80.6 (CH), 127.9 (CH), 127.9 (CH), 129.8 (CH), 129.8 (CH), 133.1
2
0.9 (CH), 85.0 (CH), 85.6 (C), 108.2 (C), 170.9 (C). IR (film):
(C), 144.7 (C), 170.8 (C), 172.6 (C). IR (film): 1731, 1364, 1246,
−1
−1
734, 1456, 1366, 1240, 1031 cm . HRMS (FAB): m/z calcd for
1177, 1109, 954, 816, 667 cm . HRMS (FAB): m/z calcd for
+
+
C H O Na (M + Na ) 429.2981, found 429.2979.
C
29
H
44
O
7
SNa (M + Na ) 559.2705, found 559.2698.
25
42
4
(
2S,4aR,5S,8aR)-6-(Hydroxymethyl)-1,1,4a-trimethyl-5-(4-
3-((1S,4aR,6S,8aR)-6-Hydroxy-5,5,8a-trimethyl-2-methylene-
methyl-3-oxopentyl)decahydronaphthalen-2-yl Acetate (30).
To a solution of 11 (387 mg, 1.06 mmol) in THF (20 mL) was added
a 50% aqueous solution of Raney nickel (2 mL), and the mixture was
stirred at room temperature for 20 min. At this time TLC showed no
decahydronaphthalen-1-yl)propanoic Acid (33). KOH (2 N) in
MeOH (1 mL) and water (0.1 mL) was added to a solution of 10 (197
mg, 0.54 mmol) in MeOH (5 mL), and the mixture was stirred at
room temperature for 2 h, at which time TLC showed no remaining
starting material. Then the solvent was removed in vacuum, ether−
water (30:10 mL) was added, and the phases were shaken and
separated. HCl (2 N) (2 mL) was added slowly to the aqueous phase,
and the mixture was diluted with ether (30 mL). The organic phase
1
1. Then the reaction mixture was filtered through a silica gel−Na SO
2
4
pad (10:2 g), washed with acetone (10 mL), and concentrated to give
pure 30 (366 mg, 94%) as a colorless syrup. [α] = −0.9 (c = 8.8,
CHCl ). H NMR (CDCl , 500 MHz): δ 0.65−0.96 (m, 3H), 0.77 (s,
2
5
D
1
3
3
3
1
2
1
H), 0.79 (s, 6H), 0.98−1.40 (m, 4H), 1.01 (d, J = 6.9 Hz, 6H), 1.46−
.69 (m, 4H), 1.70−1.81 (m, 2H), 1.97 (s, 3H), 2.36−2.40 (m, 1H),
.44−2.57 (m, 2H), 3.48−3.59 (m, 2H), 4.39 (dd, J = 11.7, 2.5 Hz,
H). 13C NMR (CDCl , 125 MHz): δ 14.1 (CH ), 16.5 (CH ), 18.2
was washed with water and brine, dried over Na
SO , and
2 4
concentrated to afford pure 33 (109 mg, 72%) as a colorless syrup.
[α]2
5
= +26.1 (c = 4.2, CHCl ). H NMR (CDCl , 500 MHz): δ 0.70
1
D 3 3
(s, 3H), 0.77 (s, 3H), 0.99 (s, 3H), 1.09 (dd, J = 12.1, 2.3 Hz, 1H),
1.18−1.44 (m, 3H), 1.54−1.92 (m, 6H), 1.96 (ddd, J = 13.0, 13.0, 5.0
Hz, 1H), 2.10−2.30 (m, 1H), 2.41 (ddd, J = 12.8, 4.1, 2.4 Hz, 1H),
2.52 (ddd, J = 16.5, 8.9, 4.4 Hz, 1H), 3.26 (dd, J = 11.8, 4.3 Hz, 1H),
3
3
3
(
CH ), 18.3 (CH ), 20.9 (CH ), 21.3 (CH ), 21.8 (CH ), 23.7 (CH ),
3 3 2 3 2 2
2
4
8.1 (CH ), 30.5 (CH ), 37.0 (CH ), 37.8 (C), 38.1 (C), 40.9 (CH),
3 2 2
1.2 (CH), 41.9 (CH ), 51.3 (CH), 54.2 (CH), 65.6 (CH ), 80.5
2
2
4.51 (s, 1H), 4.87 (s, 1H). 13C NMR (CDCl
, 125 MHz): δ 14.3
), 27.8 (CH ), 28.3 (CH ),
), 39.1 (C), 39.4 (C), 54.5(CH),
), 147.2 (C), 179.2 (C). IR (film):
2
(
1
CH), 170.9 (C), 215.3 (C). IR (film): 3490, 1733, 1715, 1458, 1367,
3
−1
246, 1031 cm . HRMS (FAB): m/z calcd for C H O Na (M +
(CH
32.7 (CH
55.8 (CH), 78.8 (CH), 106.9 (CH
3
), 15.4 (CH
3
), 18.9 (CH
), 38.0 (CH
2
2
), 23.9 (CH
2
2
3
22
38
4
+
Na ) 389.2668, found 389.2673.
2S,4aR,5S,8aR)-1,1,4a-Trimethyl-5-(4-methyl-3-oxopentyl)-
-((tosyloxy)methyl)decahydronaphthalen-2-yl Acetate (31).
2
), 36.9 (CH
2
(
−1
6
3446, 1704, 1652, 1457, 1029, 770, 668 cm . HRMS (FAB): m/z
+
To a solution of 30 (320 mg, 0.87 mmol) in pyridine (5 mL) was
added p-toluenesulfonyl chloride (215 mg, 1.13 mmol), and the
reaction mixture was stirred at room temperature for 6 h, at which
time TLC showed no starting material. Then it was diluted with ether
calcd for C H O Na (M + Na ) 303.1936, found 303.1941.
17
28
3
3-De-O-acetyl-3-O-(methoxycarbonyl)negundoin A (34). To
a solution of triphenylphosphine (13 mg, 0.05 mmol) in dry CH Cl
2
2
(5 mL) was added iodine (13 mg, 0.05 mmol), and the mixture was
stirred at room temperature for 5 min. Then a solution of 15 (197 mg,
0.5 mmol) in dry CH Cl (3 mL) was added, and the resulting mixture
(
40 mL) and washed with 2 N HCl (3 × 20 mL) and brine, and the
organic phase was dried over Na SO . Removal of the solvent under
2
4
2
2
vacuum afforded a crude product which was purified by flash
chromatography on silica gel (15% ether/hexanes) to yield 31 (391
was stirred at room temperature for 5 h, at which time TLC showed
no remaining starting material. The solvent was removed under
vacuum, and the crude product was directly purified by flash
chromatography on silica gel (15% ether/hexanes) to give compound
mg, 86%) as a colorless syrup. [α]2 = −3.5 (c = 10.9, CHCl ). H
5
1
D
3
NMR (CDCl , 500 MHz): δ 0.73−0.91 (m, 3H), 0.80 (s, 3H), 0.825
3
34 (177 mg, 90%) as a colorless syrup. [α]2 = +23.0 (c = 6.0, CHCl3).
5
(
s, 3H), 0.833 (s, 3H), 1.03−1.37 (m, 2H), 1.055 (d, J = 6.9 Hz, 3H),
D
4
412
dx.doi.org/10.1021/jo5003533 | J. Org. Chem. 2014, 79, 4405−4413

The Journal of Organic Chemistry
Article
1
H NMR (CDCl , 500 MHz): δ 0.77 (d, J = 6.6 Hz, 3H), 0.87 (s, 3H),
Prod. 1994, 57, 1543−1548. (b) Grube, A.; Assmann, M.; Lichte, E.;
3
0
1
(
.95 (s, 3H), 0.96 (s, 3H), 1.30−1.46 (m, 4H), 1.51−1.74 (m, 5H),
̈
Sasse, F.; Pawlik, J. R.; Kock, M. J. Nat. Prod. 2007, 70, 504−509.
.75−1.85 (m, 2H), 2.08 (ddd, J = 13.5, 11.8, 7.6 Hz, 1H), 2.99−3.05
(2) For the isolation of K-76 see: (a) Miyazaki, W.; Tamaoka, H.;
Shinohara, M.; Kaise, H.; Izawa, T.; Nakano, Y.; Kinoshita, T.; Hong,
K.; Inoue, K. Microbiol. Immunol. 1980, 24, 1091−1098. For the
synthesis of K-76 see: (b) Corey, E. J.; Das, J. J. Am. Chem. Soc. 1982,
104, 5551−5553. (c) McMurry, J. E.; Erion, M. D. J. Am. Chem. Soc.
1985, 107, 2712−2720. For a recent review concerning K-76 and
structurally related compounds see: (d) Larghi, E. L.; Kaufman, T. S.
ARKIVOC 2011, vii, 49−102.
m, 1H), 3.10−3.16 (m, 1H), 3.65 (s, 3H), 3.77 (s, 3H), 4.31 (dd, J =
1
1.9, 4.5 Hz, 1H), 5.30 (t, J = 1.8 Hz, 1H). 13C NMR (CDCl , 125
3
MHz): δ 15.5 (CH ), 16.4 (CH ), 16.8 (CH ), 20.8 (CH ), 23.2
3
3
3
2
(
3
8
CH ), 26.7 (CH ), 27.9 (CH ), 29.3 (CH ), 31.0 (CH ), 31.5 (CH ),
2 2 3 2 2 2
6.5 (CH), 37.9 (C), 41.9 (C), 46.2 (CH), 50.5 (CH ), 54.6 (CH ),
3 3
4.6 (CH), 87.3 (CH), 97.7 (C), 155.7 (C), 169.5 (C), 178.4 (C). IR
−1
(
film): 1746, 1706, 1633, 1441, 1273, 1128, 1108, 968, 956, cm .
+
HRMS (FAB): m/z calcd for C H O Na (M + Na ) 417.2253,
found 417.2262.
(3) Sakai, K.; Watanabe, K.; Masuda, K.; Tsuji, M.; Hasumi, K.;
Endo, A. J. Antibiot. 1994, 48, 447−456.
22
34
6
3-De-O-acetylnegundoin A (35). KOH (2 N) in MeOH (1.5
(4) (a) Roggo, B. E.; Petersen, F.; Sills, M.; Roesel, J. L.; Moerker, T.;
Peter, H. H. J. Antibiot. 1996, 49, 13−19. (b) Roggo, B. E.; Hug, P.;
Moss, S.; Stampfli, A.; Kriemler, H. P.; Peter, H. H. J. Antibiot. 1996,
49, 374−379.
mL) was added to a solution of 34 (158 mg, 0.41 mmol in MeOH (12
mL), and the mixture was stirred at room temperature for 18 h, at
which time TLC showed no remaining starting material. Then the
solvent was removed in vacuum, ether−water (50:15 mL) was added,
and the phases were shaken and separated. The organic phase was
washed with water and brine, dried over Na SO , and concentrated to
(5) Ono, M.; Yanaka, T.; Yamamoto, M.; Ito, Y.; Nohara, T. J. Nat.
Prod. 2002, 65, 537−541.
2
4
(6) Ono, M.; Nishida, Y.; Masuoka, C.; Li, J.-C.; Okawa, M.; Ikeda,
T.; Nohara, T. J. Nat. Prod. 2004, 67, 2073−2075.
afford a crude product which was directly purified by flash
chromatography on silica gel (25% ether/hexanes) to give 35 (120
(7) Zheng, C.-J.; Huang, B.-K.; Wang, Y.; Ye, Q.; Han, T.; Zhang, Q.-
Y. Bioorg. Med. Chem. 2010, 18, 175−181.
mg, 90%) as a colorless syrup. [α]2 = +11.5 (c = 6.7, CHCl ). H
5
D
1
3
NMR (CDCl , 500 MHz): δ 0.77 (d, J = 6.6 Hz, 3H), 0.79 (s, 3H),
0
1
Hz, 1H), 3.00 (ddd, J = 11.4, 7.5, 2.0 Hz, 1H) 3.03 (ddd, J = 11.5, 7.6,
2
(8) (a) Kende, A. S.; Deng, W.-P.; Zhongand, M.; Guo, X.-C. Org.
Lett. 2003, 5, 1785−1788. (b) Deng, W.-P.; Zhong, M.; Guo, X.-C.;
Kende, A. S. J. Org. Chem. 2003, 68, 7422−7427.
3
.93 (s, 3H), 1.01 (s, 3H), 1.25−1.50 (m, 4H), 1.52−1.69 (m, 4H),
.79 (ddd, J = 13.5, 11.3, 4.6 Hz, 1H), 2.09 (ddd, J = 13.4, 11.7, 7.5
(9) Cano, M. J.; Bouanou, H.; Tapia, R.; Alvarez, E.; Alvarez-
.0 Hz, 1H), 3.11 (ddd, J = 11.7, 4.6, 1.7 Hz, 1H), 3.14 (ddd, J = 11.8,
.6, 1.7 Hz, 1H), 3.21 (dd, J = 11.6, 4.5 Hz, 1H), 3.65 (s, 3H), 5.28 (t,
Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. J. Org. Chem.
013, 78, 9196−9204.
4
2
13
J = 1.8 Hz, 1H). C NMR (CDCl , 125 MHz): δ 15.4 (CH ), 15.5
3
3
(10) Bouanou, H.; Tapia, R.; Cano, M. J.; Ramos, J. M.; Alvarez, E.;
Boulifa, E.; Dahdouh, A.; Mansour, A. I.; Alvarez-Manzaneda, R.;
Chahboun, R.; Alvarez-Manzaneda, E. Org. Biomol. Chem. 2014, 12,
667−672.
(
CH ), 16.8 (CH ), 21.1 (CH ), 26.6 (CH ), 26.8 (CH ), 28.0 (CH ),
3 3 2 2 2 3
2
4
1
9.5 (CH ), 31.1 (CH ), 31.6 (CH ), 36.5 (CH), 38.8 (C), 42.1 (C),
2 2 2
6.0 (CH), 50.5 (CH ), 78.3 (CH), 87.0 (CH), 98.0 (C), 169.5 (C),
3
78.8 (C). IR (film): 1667, 1630, 1364, 1126, 1045, 961, 815, 756
(
11) Tapia, R.; Cano, M. J.; Bouanou, H.; Alvarez, E.; Alvarez-
Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. Chem. Commun.
013, 49, 10257−10259.
12) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
Meneses, R. Synlett 2000, 197−200.
13) Tapia, R.; Guardia, J. J.; Alvarez, E.; Haidour, A.; Ramos, J. M.;
−1
+
cm . HRMS (FAB): m/z calcd for C H O Na (M + Na ) 359.2198,
found 359.2192.
20
32
4
2
(
ASSOCIATED CONTENT
■
* Supporting Information
(
S
General experimental procedures and H NMR and 13C NMR
1
Alvarez-Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. J. Org.
Chem. 2012, 77, 573−584 and references therein.
spectra for compounds 6, 9, 10−13, 15, 16, and 18−35. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(14) Alvarez-Manzaneda, E. J.; Chahboun, R.; Bentaleb, F.; Alvarez,
E.; Escobar, M. A.; Sad-Diki, S.; Cano, M. J.; Messouri, I. Tetrahedron
007, 63, 11204−11212.
15) Hydroxyl-directed homogeneous hydrogenation is well-known,
2
(
AUTHOR INFORMATION
Corresponding Authors
E-mail: rachid@ugr.es.
E-mail: eamr@ugr.es.
but the heterogeneous equivalent has also been reported. For some
examples, see: (a) Baldwin, J. E.; Fryer, A. M.; Spyvee, M. R.;
Whitehead, R. C.; Wood, M. E. Tetrahedron 1997, 53, 5273−5290.
■
*
(
b) Hill, B.; Jordan, R.; Qu, Y.; Assoud, A.; Rodrigo, R. Can. J. Chem.
*
2
011, 89, 1457−1468.
Present Address
(16) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Alvarez-Manzaneda, R.;
†
́
Chahboun, R.; Meneses, R.; Aparicio, B. M. Synlett 1999, 713−716.
R.A.M.: Area de Quım
Quımica y Fısica, Universidad de Almerıa
Spain.
Notes
́
ica Organ
́
ica, Departamento de
(17) Alvarez-Manzaneda, E. J.; Chahboun, R.; Cabrera Torres, E.;
́
́
́
, 04120 Almerıa,
́
Alvarez, E.; Alvarez-Manzaneda, R.; Haidour, A.; Ramos, J. M.
Tetrahedron Lett. 2005, 1075−1077.
5
(
18) Hydrogenation of the Δ bond in this type of compound leads
The authors declare no competing financial interest.
in most cases to the more stable trans-fused isomer. This could be
attributed to the steric hindrance that the axial C-4 and C-10 methyl
ACKNOWLEDGMENTS
groups exert on the β face. For some recent examples, see: (a) Mu
̈
ller,
edi, P. Helv. Chim. Acta 2003, 86, 439−456. (b) K. Hatzellis, K.;
■
(
R.; Ru
̈
We thank the Spanish Ministry of Science and Innovation
Project CTQ2009-09932) and the Regional Government of
Andalucia (Projects P07-FQM-03101 and P11-CTS-7651, and
assistance for the FQM-348 group) for financial support. R.T.
thanks the Spanish Ministry of Science and Innovation for the
predoctoral grant provided.
Pagona, G.; Spyros, A.; Demetzos, C.; Katerinopoulos, H. E. J. Nat.
Prod. 2004, 67, 1996−2001. (c) Sauer, A. M.; Crowe, W. E.;
Henderson, G.; Laine, R. A. Synlett 2010, 445−448.
(19) For a similar isomerization see ref 9.
REFERENCES
■
(
1) (a) Chan, J. A.; Freyer, A. J.; Carte, B. K.; Hemling, M. E.;
Hofmann, G. A.; Mattern, M. R.; Mentzer, M. A.; Westley, J. W. J. Nat.
4
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dx.doi.org/10.1021/jo5003533 | J. Org. Chem. 2014, 79, 4405−4413