Construction of AE ring system for the C19-diterpenoid alkaloids with a 5β-hydroxyl group

Article abstract of DOI:10.1016/j.tet.2011.04.062

An AE azabicyclic fragment, with a β-hydroxyl group at C-5 and a substituent at C-1, of the C₁₉-diterpenoid alkaloids, was synthesized. The key reactions include an intramolecular Claisen-type condensation, double Mannich reaction, and stereose

Full text of DOI:10.1016/j.tet.2011.04.062

Tetrahedron 67 (2011) 4192e4195
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Construction of AE ring system for the C19-diterpenoid alkaloids
with a 5b-hydroxyl group
*
Zhan-Kun Yang, Qiao-Hong Chen, Feng-Peng Wang
Department of Chemistry of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, No. 17, Duan 3, Renmin Nan Road, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2011
Received in revised form 2 April 2011
Accepted 15 April 2011
Available online 21 April 2011
An AE azabicyclic fragment, with a
terpenoid alkaloids, was synthesized. The key reactions include an intramolecular Claisen-type con-
densation, double Mannich reaction, and stereoselective nucleophilic addition of carbonyl group with the
b-hydroxyl group at C-5 and a substituent at C-1, of the C19-di-
assistance of steric effect of 1b-substituent.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
C19-diterpenoid alkaloid
AE azabicyclic fragment
Intramolecular Claisen-type condensation
Double Mannich reaction
1. Introduction
Diterpenoid alkaloids, the largest and most complex group of
terpenoid alkaloids, could be divided into three broad categories:
C20-diterpenoid alkaloids, C19-diterpenoid alkaloids, and C18-diter-
penoid alkaloids. The structural diversity and complexity, as well as
the important pharmacological activities, of the diterpenoid alka-
loids pose an alluring target for synthetic chemists and medicinal
chemists. Of them, the C19-diterpenoid alkaloids (674 in total by the
end of July 2008), a class of highly substituted alkaloids composed of
one seven-, three six-, and two five-memberedrings, may be divided
into six types, including 13 subtypes and 19 groups.1 So far, only
three C19-diterpenoid alkaloids belonging to one type have been
totally synthesized, all of which were contributed by the Wiesner
group.2e4 The challenge of the synthesis of C19-diterpenoid alkaloids
is mostly because of its polycyclic and highly bridged core structure
and heavily substituted feature. The diversity of substituent makes it
Fig. 1. Representatives of 5
b
-hydroxyl-containing C19-diterpenoid alkaloids.
There is no report yet on the total synthesis of 5
containing C19-diterpenoid alkaloids. Even though the 5
b-hydroxyl-
b
-hy-
droxyl-containing AE fragments have been synthesized by Kraus
et al. and Brimble et al.,9,10 these fragments do not contain a sub-
stituent at C-1. Considering that most of the naturally occurring 5b-
hydroxyl-containing C19-diterpenoid alkaloids do contain an
oxygenated group at C-1, we selected the C19-diterpenoid alkaloids
that contain an oxygenated group at C-1 and a hydroxyl group at C-
5b as our first synthetic targets. Here, we report the construction of
AE fragment with a substituent at C-1 and a hydroxyl group at C-5.
very difficult to explore a general synthetic approach to the C19
-
diterpenoid alkaloids with same core structure. However, it should
be feasible to build a general synthetic route to the C19-diterpenoid
alkaloids with some unique substituents.
It is not common for the C19-diterpenoid alkaloids to possess
a 5b-hydroxyl group, which were so far isolated from four species of
2. Results and discussion
plants.5e8 Two representatives of this type C19-diterpenoid alka-
loids were listed in Fig. 1. Among them, bonvalol represents the first
example, which was isolated by Jiang and Sung in 1984.5a
We planned to introduce an oxygenated substituent at C-1 of ring
A of C19-diterpenoid alkaloids prior to the construction of ring E. As
shown in Scheme 1, our synthesis started with Michael addition of
cyclohex-2-enone (3) with vinylmagnesium bromide, using the
procedure described in the literature.11 The ketone carbonyl in olefin
* Corresponding author. Tel./fax: þ86 28 85501368; e-mail address: wfp@scu.
edu.cn (F.-P. Wang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.062

Z.-K. Yang et al. / Tetrahedron 67 (2011) 4192e4195
4193
4 was protected as ketal, which can also avoid the rapid evaporation
of volatile 4 at room temperature. The olefinic double bond in 4 was
then oxidized with ozone to furnish the corresponding aldehyde,
which is readily reduced with NaBH4 to generate alcohol 5. In-
troduction of carbonate followed by deprotecting ketone carbonyl
furnished ethyl carbonate 6. At this stage, a lactone moiety was in-
stalled through an intramolecular Claisen-type condensation with
a pendent carbonate moiety. Initially, the procedure described in the
literature12 was employed to make the lactone 7, leading to only 35%
yield with 12 equiv of sodium hydride. Considering that excess so-
dium hydride might cause decomposition of the product or starting
material, we explored the effect of amount of sodium hydride on
yield. It was observed that yield was significantly increased to 93%
when the amount of sodium hydride was reduced to 2 equiv. Having
Fig. 3. Key NOESY correlations of 9.
made the
b-keto lactone 7 in high yield, the methyl group at the
future C-4 position was readily introduced via methylation of 1,3-
dianion of 7 at the g
carbon.13 Note that the optimal temperature for
the formation of dianion of our substrate was ꢀ20 ꢁC instead of 0 ꢁC
as reported in the literature.
Scheme 1. Synthesis of AE ring analog 9. Reagents and conditions: (a) (i) CH2CHMgBr,
CuI, (ii) ethylene glycol, TsOH, 60% for two steps; (b) (i) ꢀ78 ꢁC, O3, CH2Cl2, (ii) NaBH4,
75% for two steps; (c) (i) ClCO2Et, Py, (ii) PPTS, acetone, H2O, 95% for two steps; (d) 60%
NaH, THF, 93%, dr¼100:0; (e) ꢀ20 ꢁC, LDA, CH3I, 85% based on 42% conversion,
dr¼100:0; (f) 37% formaldehyde, BnNH2, EtOH, 30%, dr¼100:0.
With 1,4-disubstituted ring A analog 8 in hand, next step is to
construct ring E. Double Mannich reaction has been proved to be
a reliable strategy to construct azabicyclo[3.3.1]-nonane core struc-
ture, corresponding to the AE part of C19-diterpenoid alkaloids.14e16
Fig. 4. ORTEP drawing of 9.
Treatment of
in ethanol under reflux generated the racemic bicyclic compound 9
with a 1 -substituent in 30% yield (Scheme 1). It is worth noting that
b-keto lactone 8 with formaldehyde and benzylamine
5b
-substituent (Scheme 2). This inspired us to envision that the 5
hydroxyl group might be introduced through the nucleophilic
addition of the carbonyl group at C-5 in the presence of 1 -sub-
stituent. Consequently, compound 9 was treated with the enolate of
ethyl acetate (Scheme 3), which gave the desired AE ring analog 12,
b-
b
no diastereoisomer of 9 was observed in this reaction. The structure
of 9 was established based on the interpretation of its 2D NMR
spectra (Fig. 2), and its relative configuration was deduced from the
key NOESY correlations (Fig. 3). Both of them were confirmed by its
X-ray crystallographic analysis (Fig. 4).
b
possessing a 5
The hydroxyl group at C-5 was established as
on the NOE correlations between the hydroxyl proton and H-10, and
between the hydroxyl proton and H-3 (Fig. 5).
b
-hydroxyl group, of the C19-diterpenoid alkaloids.
b
orientation based
We next proceeded to stereoselectively introduce a 5
group. During the course of our investigation on AE ring analogs of
C18-diterpenoid alkaloids, it was observed that 1 -substituent in
b-hydroxyl
b
b
compound 10 could hinder the approach of borane from Si face,
leading to exclusive formation of compound 11 that contains a
Scheme 2. Hydroborylation of the double bond between C-5 and C-6.
Fig. 2. Key 1He1H COSY and HMBC correlations of 9.
Scheme 3. Synthesis of AE ring analog 12.

4194
Z.-K. Yang et al. / Tetrahedron 67 (2011) 4192e4195
4.3. Preparation of alcohol 5
A solution of olefin 4 (4.00 g, 24 mmol) in CH2Cl2 (150 mL) at
ꢀ78 ꢁC was flushed with ozone until the reaction mixture turned to
blue. Dimethyl sulfide (3.50 mL, 48 mmol) was then added to
quench the reaction. The subsequent mixture was allowed to warm
to room temperature and washed with water (100 mLꢂ2). The
organic layer was concentrated in vacuum to give a crude residue,
which was dissolved in CH3OH (100 mL) followed by the addition of
NaBH4 (1.83 g, 48 mmol) at 25 ꢁC. The resultant mixture was stirred
at the same temperature for 2 h prior to being quenched with
saturated NH4Cl solution (100 mL). The mixture was extracted with
ether (100 mLꢂ3), the combined organic layers were dried over
Na2SO4, and the solvent was evaporated in vacuo. The obtained
residue was chromatographed over silica gel, using petroleum
ether/ethyl acetate (1:1) as eluent, to afford 5 (colorless oil, 3.08 g,
Fig. 5. NOEDS correlations of 12.
3. Conclusion
75%). IR (KBr) nmax: 3407, 2926, 1450 cmꢀ1
CDCl3) 0.89e0.99 (1H, m), 1.17e1.26 (1H, m), 1.39e1.48 (1H, m),
1.48e1.59 (1H, m), 1.50e1.58 (1H, m), 1.71e1.84 (5H, m), 3.45e3.47
(2H, m), 3.91e3.95 (4H, m); 13C NMR (100 MHz, CDCl3)
22.7 (t),
;
1H NMR (400 MHz,
d
In conclusion, the AE analog, with a heavily substituted ring A
and a 5 -hydroxyl group, of the C19-diterpenoid alkaloids was
b
d
synthesized from cyclohex-2-enone. The key reactions include: (i)
installation of the lactone moiety at C-1 and C-11 through an
intramolecular Claisen-type condensation; (ii) construction of ring
E by double Mannich reaction; and (iii) stereoselective introduction
28.0 (t), 34.9 (d), 37.9 (t), 38.3 (t), 64.1 (t), 64.2 (t), 67.7 (t), 109.1 (s);
HRMS calcd for C9H17O3: 173.1172. Found: 173.1180.
4.4. Preparation of carbonate 6
of a hydroxyl group at 5b through nucleophilic addition of carbonyl
group with the assistance of steric effect of 1
b-substituent.
To a solution of alcohol 5 (3.44 g, 20 mmol) in CH2Cl2 (150 mL) at
0
ꢁC were sequentially added pyridine (4.59 mL, 60 mmol) and
4. Experimental section
ethyl chloroformate (3.82 mL, 40 mmol), and the reaction was
allowed to proceed with stirring at room temperature for 5 h prior
to being rinsed with 1 N HCl (100 mLꢂ2). The organic layer was
concentrated under reduced pressure to furnish a residue, which
was dissolved in acetone (70 mL) and water (3.5 mL). To this
mixture was added pyridine p-toluenesulfonate (1.69 g, 6 mmol),
and the mixture was refluxed for 24 h before being concentrated in
vacuo. The obtained residue was purified over chromatography
eluting with petroleum ether/ethyl acetate (20:1) to give com-
pound 6 (colorless oil, 3.80 g, 95%). IR (KBr) nmax: 2930, 1745, 1713,
4.1. General information
Melting points were determined on a Kofler block (uncorrected);
IR spectra were recorded on a Nicolet 200 SXV spectrometer; HRMS
were obtained with a Bruker BioTOFQ mass spectrometer; 1H and
13C NMR spectra were acquired on a Varian INOVA-400/54 spec-
trometer, with TMS as internal standard; silica gel GF254 and H
(10e40 mm, Qingdao Marine Chemical Factory, China) were used for
TLC and CC. Tetrahydrofuran (THF) was freshly distilled from so-
dium/benzophenone. Unless otherwise noted, all reactions were
carried out under an atmosphere of argon or nitrogen.
1450 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.30 (3H, t, J¼7.2 Hz),
1.42e1.52 (1H, m), 1.61e1.72 (2H, m), 1.92e1.95 (1H, m), 2.05e2.11
(1H, m), 2.14e2.18 (1H, m), 2.20e2.30 (1H, m), 2.36e2.45 (2H, m),
4.04 (2H, d, J¼5.2 Hz), 4.18 (2H, d, J¼7.2 Hz); 13C NMR (100 MHz,
4.2. Preparation of olefin 4
CDCl3) d 14.2 (q), 24.7 (t), 27.6 (t), 38.2 (d), 41.1 (t), 44.2 (t), 64.1 (t),
70.9 (t), 155.0 (s), 210.1 (s); HRMS calcd for C10H16NaO4: 223.0941.
Found: 223.0954.
To a solution of vinylmagnesium bromide (90 mL, 1.0 M in THF,
90mmol), CuI(1.44 g, 7.6 mmol)wasaddedunderargonatꢀ5 ꢁC, and
theresultingblackmixturewasstirredat0ꢁCfor20min. Asolutionof
2-cyclohexen-1-one (4.30 g, 45 mmol) in THF (50 mL) was slowly
addeddropwise over30min. The solutionwas stirredat 5 ꢁC for1 h. A
cold aqueous solution of ammonia and NH4Cl (pH 8.0, 100 mL) was
added and the mixture was extracted with ether (150 mLꢂ2). The
combined extracts were dried over MgSO4 and concentrated. The
crude residue was dissolved in THF (100 mL), to which was added
ethylene glycol (11.2 g, 180 mmol) and TsOH (0.774 g, 9 mmol). The
reaction solution was stirred at 25 ꢁC for 8 h prior to being diluted
with water (100 mL). The subsequent mixture was extracted with
dichloroform (100 mLꢂ2). The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography eluting with petroleum ether/ether (30:1)
to afford compound4 (colorless oil, 4.54 g, 60%fortwo steps). IR (KBr)
4.5. Preparation of lactone 7
To a solution of carbonate 6 (1.50 g, 7.5 mmol) in THF (250 mL)
was added NaH (60%, 0.60 g, 15 mmol), and the resulting mixture
was refluxed for 10 h prior to being quenched with saturated NH4Cl
(100 mL) and 3 N HCl solution (15 mL). The mixture was extracted
with ethyl acetate (100 mLꢂ3), the combined extracts were dried
over MgSO4 and concentrated in vacuo to furnish a residue, which
was purified by column chromatography eluting with petroleum
ether/ethyl acetate (2.5:1) to afford lactone 7 (pale yellow solid,
1.07 g, 93%). The lactone 7 exists as a mixture of ketone form and
enol form with a ratio of 10:2. IR (KBr) nmax: 2937, 2870, 1770,
1712 cmꢀ1; 1H NMR (400 MHz, CDCl3) ketone/enol¼10:2,
d (ketone
nmax: 3079,1640, 1448 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.80e0.86
form) 1.59e1.80 (2H, m), 2.02e2.06 (2H, m), 2.28e2.35 (1H, m),
2.45e2.50 (1H, m), 2.94e3.01 (1H, m), 3.47 (1H, d, J¼7.2 Hz), 4.14
(1H, m), 0.95e1.05 (1H, m),1.30 (1H, t, J¼12.8 Hz),1.36e1.44 (1H, m),
1.48e1.59 (1H, m), 1.69e1.78 (3H, m), 2.25e2.28 (1H, m), 3.89e3.94
(4H, m), 4.88 (1H, d, J¼10.4 Hz), 4.95 (1H, d, J¼17.2 Hz), 5.74 (1H, ddd,
(1H, d, J¼8.8 Hz), 4.30 (1H, dd, J¼8.8, 5.2 Hz);
d (typical signals for
enol form) 3.84 (1H, t, J¼8.8 Hz), 4.57 (1H, t, J¼8.4 Hz), 8.95 (1H, br
J¼17.2,10.4, 6.8 Hz); 13C NMR (100 MHz, CDCl3)
d
22.9 (t), 31.2 (t), 34.5
s, enol-H); 13C NMR (100 MHz, CDCl3)
d
23.2 (t), 26.2 (t), 39.4 (d),
(t), 39.3 (d), 40.5 (t), 64.1 (t), 64.2 (t), 108.9 (s), 112.2 (t), 143.1 (d);
HRMS calcd for C10H17O2: 169.1223. Found: 169.1231.
39.8 (t), 54.1 (d), 71.8 (t), 172.1 (s), 203.2 (s); these data are con-
sistent with those reported in the literature.16

Z.-K. Yang et al. / Tetrahedron 67 (2011) 4192e4195
4195
4.6. Preparation of lactone 8
J¼10.8, 2.0 Hz, H2-19), 2.32e2.40 (1H, m, H-2
a
), 2.53e2.61 (1H, m,
H-1), 3.27 (3H, s, OCH3), 3.37, 3.56 (each 1H, ABq, J¼13.6 Hz,
NCH2Ph), 3.60, 3.92 (each 1H, ABX, J¼11.6, 7.2 Hz, H-6), 3.55, 4.09
(each 1H, ABX, J¼9.6, 8.8 Hz, H-10), 7.22e7.31 (5H, m, aromatic
A solution of 7 (1.00 g, 6.49 mmol) in THF (10 mL) was added to
lithium diisopropylamide solution (14.2 mL,1.0 M inTHF,14.2 mmol)
at ꢀ20 ꢁC. After 30 min, CH3I (0.48 mL, 7.71 mmol) was slowly added
dropwise at ꢀ20 ꢁC. The reaction solution was stirred at 0 ꢁC for 2 h,
and diluted with water (20 mL). The mixture was extracted with
CH2Cl2 (30 mLꢂ2), and the combined extracts were dried over
Na2SO4 and concentrated under reduced pressure to give a residue.
This residue was purified by column chromatography, using petro-
leum ether/ethyl acetate (4:1) as eluent, to give lactone 8 (colorless
oil, 0.39 g, 85% based on 42% conversion). IR (KBr) nmax: 2970, 2935,
protons); 13C NMR (100 MHz, CDCl3):
d 21.3 (t, C-2), 21.9 (t, C-3),
30.6 (d, C-4), 38.7 (d, C-1), 45.9 (d, C-5), 47.5 (s, C-11), 54.6 (q,
OCH3), 60.5 (t, C-19), 61.2 (t, C-17), 64.1 (t, C-6), 73.8 (t, C-1), 108.1
(d, C-10), 126.7, 128.2, 128.6, 139.4 (CH2Ph); HRMS calcd for
C19H27NNaO3: 340.1883. Found: 340.1880.
4.9. Preparation of compound 12
1767,1712,1454,1372 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 1.09 (3H, d,
A solution of ethyl acetate (23.5 mL, 0.24 mmol) in THF (3 mL)
J¼6.0 Hz), 1.40e1.49 (1H, m), 1.69e1.79 (1H, m), 2.03e2.07 (2H, m),
2.34e2.40 (1H, m), 2.91e2.97 (1H, m), 3.46 (1H, d, J¼7.2 Hz), 4.15 (1H,
d, J¼9.2 Hz), 4.28 (1H, dd, J¼9.2, 4.8 Hz); 13C NMR (100 MHz, CDCl3):
was added to lithium diisopropylamide solution (1.0 mL, 1.0 M in
THF, 0.25 mmol) at ꢀ78 ꢁC. After stirring at the same temperature
for 30 min, a solution of 9 (59.8 mg, 0.20 mmol) in THF (3 mL) was
added and the mixture was stirred for 15 h at ꢀ40 ꢁC. The reaction
solution was quenched with saturated NH4Cl (10 mL) and extracted
with ethyl acetate (25 mLꢂ2). The combined organic layers were
dried (Na2SO4) and concentrated in vacuum. Column chromatog-
raphy of the residue, using petroleum ether/ethyl acetate (2:1) as
eluent, gave 12 (white solid, 63 mg, 82%): mp: 151e153 ꢁC; IR (KBr)
d
14.2 (q), 26.9 (t), 32.5 (t), 40.7 (d), 44.0 (d), 54.4 (d), 72.1 (t),172.2 (s),
204.3 (s); HRMS calcd for C9H12NaO3: 191.0679. Found: 191.0685.
4.7. Preparation of compound 9
To a solution of 8 (0.20 g, 1.2 mmol) in EtOH (300 mL) was added
aqueous formaldehyde solution (37%, 0.29 mL, 3.6 mmol) and
phenylmethanamine (0.2 mL, 1.8 mmol), and the reaction mixture
was refluxed for 48 h before cooling down to room temperature.
After removing the solvents, the crude residue was purified by col-
umn chromatography, employing petroleum ether/ethyl acetate
(10:1) as eluent, to afford 9 (white solid, 107 mg, 30%): mp:
119e161 ꢁC; IR (KBr) nmax: 3028, 2923,1778,1715,1455, 754 cmꢀ1; 1H
nmax: 3443, 3026, 2913, 1753, 1703, 1469, 757 cmꢀ1
(400 MHz, CDCl3):
0.75 (3H, s, H-18), 1.27 (3H, t, J¼7.2 Hz,
OCH2CH3), 1.30e1.36 (1H, m), 1.56e1.62 (1H, m), 2.16e2.24 (1H, m,
H-3
;
1H NMR
d
b
), 2.31 (1H, d, J¼12.0 Hz), 2.31, 2.65 (each 1H, ABq, J¼12.0 Hz),
2.43e2.50 (1H, m), 2.50, 2.59 (each 1H, ABq, J¼11.2 Hz), 2.67e2.73
(1H, overlapped), 2.83, 3.12 (each 1H, ABq, J¼16.8 Hz, H-6), 3.39,
3.54 (each 1H, ABq, J¼13.2 Hz, NCH2Ph), 4.15e4.19 (1H, overlapped,
H-10
H-10
a
b
), 4.16 (2H, t, J¼7.2 Hz, OCH2CH3), 4.39 (1H, dd, J¼11.6, 7.6 Hz,
NMR (400 MHz, CDCl3): d 0.99 (3H, s), 1.39e1.44 (1H, m), 1.87e1.92
), 5.87 (1H, s, OH), 7.25e7.33 (5H, m, aromatic protons); 13C
(1H, m), 2.20e2.26 (1H, m), 2.38, 3.05 (each 1H, ABX, J¼12.0, 2.4 Hz),
2.81e2.75 (1H, m), 2.85, 3.07 (each 1H, ABq, J¼11.2 Hz), 3.12e3.14
(1H, m), 3.51, 3.61 (each 1H, ABq, J¼13.0 Hz), 3.83 (1H, dd, J¼10.4,
9.2 Hz), 4.29 (1H, t, J¼9.2 Hz), 7.27e7.37 (5H, m); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3): d 13.9 (q), 19.9 (t), 22.1 (d), 31.5 (t), 32.1 (t),
39.0 (s), 42.5 (d), 50.7 (s), 57.5 (t), 61.2 (t), 62.2 (t), 62.7 (t), 72.7 (t),
75.3 (s), 127.1 (d), 128.3 (d), 128.5 (d), 138.3 (s), 174.7 (s), 179.0 (s);
HRMS calcd for C22H29NNaO5: 410.1938. Found: 410.1928.
CDCl3): d 20.7 (q), 22.0 (t), 39.2 (t), 46.1 (s), 47.5 (d), 58.6 (s), 59.8 (t),
61.5 (t), 65.8 (t), 69.2 (t),127.5 (d),128.5 (d),128.7 (d),137.7 (s),173.4
(s), 210.7 (s); HRMS calcd for C18H21NNaO3: 322.1414. Found:
322.1418. The X-ray crystallography data of 9 are listed below:
a colorless orthorhombic crystal from petroleum ether/ethyl acetate
(4:1) was mounted on a P4 four circle diffractometer and exposed to
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 30472075) for financial support of this research.
graphite-monochromated Mo Ka irradiation. The unit cell parame-
ꢀ
ꢀ
ꢀ
ters are a¼10.795 (2) A, b¼14.386 (3) A, c¼9.797 (2) A, V¼1521.5
References and notes
3
ꢀ
3
(5) A , Z¼4, dx¼1.307 g/cm , in space group Pna21, of the 10,268
ꢃ26.00ꢁ scan, 1584 were independently ob-
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measured with 2.50ꢃ
q
served at the level of F0>4s (F0). The structure was solved by the
directed method using the program SHELXLꢀ97 and the atomic
parameters were refined by the full-matrix least squares on F2
method. The final R indices [I>2
CCDC reference number: CCDC 801408.
s
(I)] was R1¼0.067, WR2¼0.167.
4.8. Preparation of compound 11
To a solution of 10 (0.30 g, 1.0 mmol) in THF (25 mL) was added
borane methyl sulfide complex (0.29 mL, 5.0 mmol) at ꢀ15 ꢁC, and
the reaction mixture was stirred for 48 h. Aqueous H2O2 solution
(30%, 1.02 mL, 10.0 mmol) and aqueous NaOH solution (1N, 10.0 mL,
10.0 mmol) were added, and the resulting mixture was stirred for
an additional 4 h at room temperature. The mixture was extracted
with ethyl acetate (50 mLꢂ2), and the combined extracts were
dried (MgSO4) and concentrated in vacuo. The obtained residue
was purified by column chromatography, eluting with petroleum
ether/ethyl acetate (2.5:1) to afford 11 (colorless oil, 190 mg, 92%
based on 65% conversion). IR (KBr) nmax: 3406, 3027, 2920, 1452,
741 cmꢀ1
H-3 ), 1.64e1.71 (2H, m, H-3
2.97 (each 1H, ABq, J¼10.4 Hz, H2-17), 2.18, 2.85 (each 1H, ABX,
;
1H NMR (400 MHz, CDCl3):
d 1.36e1.47 (2H, m, H-2b,
b
a
, H-5), 1.89e1.94 (1H, m, H-4), 2.10,
16. Coates, P. A.; Blagbrough, I. S.; Rowan, M. G.; Potter, B. V. L.; Pearson, D. P. J.;
Lewis, T. Tetrahedron Lett. 1994, 35, 8709e8912.