Construction of A/E/F ring systems of C19-diterpenoid alkaloids with both C-1 and C-6 oxygen functions

Article abstract of DOI:10.1016/j.tet.2011.10.073

An tricyclic AEF fragment of C₁₉-diterpenoid alkaloid bearing an angular methyl group and the oxygen function groups at C-1 and C-6 was successfully synthesized. The synthesis features a stereoselective intramolecular Diels-Alder reaction and a

Full text of DOI:10.1016/j.tet.2011.10.073

Tetrahedron 68 (2012) 159e165
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Tetrahedron
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Construction of A/E/F ring systems of C19-diterpenoid alkaloids with both C-1
and C-6 oxygen functions
*
*
Zhi-Gang Liu, Liang Xu , 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:
An tricyclic AEF fragment of C19-diterpenoid alkaloid bearing an angular methyl group and the oxygen
function groups at C-1 and C-6 was successfully synthesized. The synthesis features a stereoselective
intramolecular DielseAlder reaction and a highly efficient intramolecular Mannich reaction as well as
efficient functional groups transformations.
Received 4 September 2011
Received in revised form 11 October 2011
Accepted 21 October 2011
Available online 28 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
C19-diterpenoid alkaloids
AEF ring system
Intramolecular DielseAlder reaction
Intramolecular Mannich reaction
1. Introduction
alkaloid, almost invariably functionalized by oxygenation. Con-
struction of this subunit can be regarded as one of the key points for
C19-diterpenoid alkaloids comprise a large class of structurally
complex natural products mainly distributing in plants of Aconitium
and Delphinium genera, which display a range of biological activi-
ties including antiinflammatory, analgesic, antiarrhythmic, anti-
pyretic, anti-epileptic, hypotensive, and bradycardic properties.1
Until now, over 674 members of these compounds have been
identified, with new alkaloids ongoing to be isolated. The structures
of C19-diterpenoid alkaloids are characterized by a congested hex-
acyclic ring system containing 9e16 stereogenic centers and 5e9
oxygen functions involving hydroxyl, methoxy, and acyloxy groups.
Differences among the numerous members of these alkaloids are
determined by type, number, and position of the substituents on
the basic skeleton, which is mostly represented by the carbon
frame work of the aconane-type diterpene.
total synthesis of this family of alkaloids.8e10 In connection with an
interest in total synthesis of royleinine,1,11 one of the aconitine-type
C19-diterpenoid alkaloids bearing an unique C-18 angular methyl
group as well as C-1 and C-6 methoxyl groups, we planned to de-
velop a new methodology for construction of the A/E/F ring system
with both C-l and C-6 oxygen substituents. We now wish to de-
scribe a synthetic procedure leading to tricyclic amine 2 as the
model for A/E/F ring system of royleinine using stereoselective
intramolecular DielseAlder reaction and intramolecular Mannich
cyclization as the key steps.
OMe
16
13
C
OMe12
O
14
17
10
CO2CH3
1
OH
D
2
3
9
B
The total synthesis of C19-diterpenoid alkaloids is a conspicuous
A N F
15
11
A N F
8
E
challenge due to their intricate structures. So far, only three C19
-
E
OH
7
5
diterpenoid alkaloids have been practically synthesized, all of
4
6
which were contributed by Wiesner and co-workers in 1970s.2e4
19
OMe
18
OMe
Royleinine
Accordingly, partial ring systems synthesis of the six rings of C19
-
2
1
diterpenoid alkaloids has attracted much attention of synthetic
chemists, resulting in many elegant synthetic works and useful
methodologies.5e7 The unique nitrogen-containing A/E/F tricycle
section is the commonly observed subunit in the C19-diterpenoid
2. Results and discussion
The intramolecular Mannich reaction is a highly efficient ap-
proach to assemble of nitrogen-containing complex ring systems.
Despite the pioneering application of this methodology by Taber10
* Corresponding authors. Tel./fax: þ86 28 85501368 (F.-P. Wang.); tel./fax: þ86
28 85503046 (L. Xu.); e-mail addresses: liangxu@scu.edu.cn (L. Xu), 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.2011.10.073

160
Z.-G. Liu et al. / Tetrahedron 68 (2012) 159e165
in construction of A/E/F ring of the C18-diterpenoid alkaloid con-
taining an oxygenated quaternary carbon at C-4,12 we planned to
employ the similar reaction as the key step to form the E/F rings by
With the desired triol 9 in hand, the selective protection of 1,3-diol
and installation of C-6 methoxyl group were addressed next.
a
Treatmentof 9 withBn(OMe)2 inDCM inpresenceof catalytic amount
of CSA gave rise to 1,3-benzylidene acetal 10 in 86% yield based on90%
conversion. The remaining primary alcohol in 10 was then oxidized
withPCC/Na2CO3 inDCMto furnish an aldehyde, whichwassubjected
to a mild zinc powder promoted allylation in saturated aqueous
NH4Cl/THF (5:1)16 and in turn methylation of resulting homoallylic
generation of a highly reactive b-ketoester 3 (4/2, Scheme 1). The
polysubstituted six-membered ring-A 5 should be available by
intramolecular DielseAlder reaction followed by facile functional
group transformations.
alcohol with CH3I, affording the desired
a methyl ether 11 as a single
diastereoisomer in 84% yield over three steps. Careful analysis of the
plausible stereo transition state of allyation reaction reveals that the
bulky TBS group may hinder the Re face of carbonyl group, leading to
exclusive nucleophilic attack of allyl anion from Si face (Fig. 1). The
stereochemistry of the methoxyl group in 11 was confirmed at last E/F
ring closure stage based on NOE difference experiments.
Scheme 1. Retrosynthetic analysis for A/E/F ring 2.
Following the work of Sherburn and co-workers,13 the intra-
molecular DielseAlder reaction of the ester 6 that prepared from
the facile condensation of known (E)-2,4-pentadien-1-ols and (Z)-
2-methylbut-2-enedioic acid 1-(4-methoxybenzyl) ester,14 was
conducted in xylene at 130 ꢀC to give the cycloadduct as a 5:1
mixture of the exo and endo isomers in 97% yield, which could be
easily separated by column chromatography (Scheme 2). The rel-
ative stereochemistry of exo-adduct 5 was established by the ob-
served large coupling constant (J5,11¼13.6 Hz) in 1H NMR spectrum
and the NOE correlation between the angular methyl protons and
H-5. Subsequently, selective hydrolysis of PMB ester with TFA in
DCM delivered an acid, which was reduced to an alcohol 7 by in situ
formation of active mixed anhydride and then reduction with
NaBH4 in 90% yield over two steps. The alcohol function of 7 was
then protected as a TBS ether by using standard conditions and the
olefin was subjected to m-CPBA/NaHCO3 to give the epoxide 8 as
a single stereoisomer in 91% yield over two steps. After screening
various bulky nucleophilic hydride reagents and reaction condi-
tions, regioselective opening of epoxide with simultaneous re-
duction of lactone was effected by treatment with LiBHEt3 in THF to
deliver the desired triol 9 in 81% separated yield,15 along with
a small amount of unwanted regioisomer with hydroxyl at C-2.
Fig. 1. Stereochemical analysis of allylation of aldehyde 10a.
The next phase of the synthesis is outlined in Scheme 3.
Regioselective cleavage of the 1,3-benzylidene acetal 11 was ach-
ieved under classical conditions (DIBAL-H/DCM) to give primary
alcohol 12. The alcohol was then converted into methyl carboxylate
13 in three steps: (1) oxidation of alcohol 12 with PCC/NaOAc to the
aldehyde; (2) the aldehyde was further oxidized to carboxylic acid
with NaClO2; (3) conversion of carboxylic acid to the methylate 13
in 86% yield over three steps. With one single ester group in place,
attention turned to installation of nitrogen at C-19 position. Thus,
after a clean removal of TBS group with 5% HF/CH3CN, the resulting
alcohol was oxidized to aldehyde 14 by DesseMartin periodinane
reagent in 96% yield over two steps. Treatment of 14 with ethyl
amine in methanol followed by reduction in situ with NaBH(OAc)3
furnished the secondary amine, which was further protected with
Boc2O to give 15 in 88% yield over two steps.
OBn OH
H
OBn O
OCH3
a
b
H
11
OCH3
OCH3
13
TBSO
TBSO
12
OBn O
OBn O
OCH3
OCH3
c
d
H
H
OCH3
NBoc
OCH3
14
O
15
Scheme 2. Synthesis of intermediate 11. Reagents and conditions: (a) DIC, DMAP,
CH2Cl2, 89%; (b) xylene, BHT, 130 ꢀC, 97%; (c) (i) TFA, CH2Cl2, (ii) Et3N, ClCO2Et, THF,
then NaBH4, 90% for two steps; (d) (i) TBSCl, Et3N, DMF, (ii) m-CPBA, NaHCO3, CH2Cl2,
91% for two steps; (e) LiBHEt3, THF, 81%; (f) Bn(OMe)2, CSA, CH2Cl2, 86% based on 90%
conversion; (g) (i) PCC, Na2CO3, 4 A MS, CH2Cl2, (ii) Zn, allyl bromide, aq NH4CleTHF,
(iii) NaH, CH3I, THF, 84% for three steps.
Scheme 3. Synthesis of intermediate 15. Reagents and conditions: (a) DIBAL-H, CH2Cl2,
ꢀ
89%; (b) (i) PCC, NaOAc, 4 A MS, CH2Cl2, (ii) NaClO2, NaH2PO4, 2-methyl-2-butene,
tBuOH/H2O, iii) K2CO3, CH3I, DMF, 86% for three steps; (c) (i) 5% aq HF/CH3CN, (ii) DMP,
CH2Cl2, 96% for two steps; (d) (i) EtNH2, MeOH, then NaBH(OAc)3, (ii) (Boc)2O, Na2CO3,
THF, 88% for two steps.
ꢀ

Z.-G. Liu et al. / Tetrahedron 68 (2012) 159e165
161
The final stage of the synthesis involved in the key intra-
Colorless oil; IR (film) nmax
:
2956, 2838, 1722, 1652, 1613,
molecular Mannich reaction (Scheme 4). Thus, oxidative cleavage
of terminal olefin 15 with OsO4/NaIO4 gave an aldehyde 4 that
was subsequently hydrogenated to an alcohol 16. Oxidation of
alcohol 16 with DesseMartin periodinane formed the key keto
ester intermediate. Without further purification, this keto ester
intermediate was exposed to 5% TFA in DCM at room temperature
to remove the Boc group. To our surprise, it was found that the
Mannich cyclization occurred simultaneously upon removal of
the Boc group, giving the desired A/E/F ring 2 in 73% yield. The
relative configuration of the methoxy group at C-6 could be
confirmed by NOE difference experiments of compound 2, which
show the correlations between protons of angular methyl group
1445 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.32 (d, J¼8.1 Hz, 2H), 6.89
(d, J¼8.1 Hz, 2H), 6.41e6.19 (m, 2H), 5.87 (s, 1H), 5.79e5.65 (m, 1H),
5.26 (d, J¼16.0 Hz, 1H), 5.17 (s, 2H), 5.16 (d, J¼12.1 Hz, 1H), 4.59 (d,
J¼6.3 Hz, 2H), 3.81 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
168.1, 164.2, 159.3, 145.1, 135.5, 134.7, 129.9, 127.2, 126.2, 120.6,
118.5, 113.5, 66.0, 65.0, 54.8, 29.9; HRMS calcd for C18H20NaO5
339.1208, found 339.1202.
4.3. Preparation of compound 5
A solution of ester 6 (20.9 g, 66 mmol) in xylene (550 mL) was
heated to 130 ꢀC under Ar in the presence of BHT (1.45 g, 6.6 mmol)
for 48 h. The mixture was concentrated in vacuo to leave a brown
oil, which was purified by silica gel chromatography with PE/EtOAc
(5:1) to afford exo-5: 16.9 g, 81%; endo-5: 3.3 g, 16%. For exo-5:
white solid; mp: 69e71 ꢀC; IR (KBr) nmax: 2961, 1771, 1716, 1613,
(
d
1.20) and C-6 methoxy (
d
3.31), as well as between H-5 (
d
2.72)
and H-6 (d 3.62).
OBn O
OH
O
O
1517, 1468 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.27 (d, J¼8.3 Hz, 2H),
5
11
11
OCH3
OCH3
6.87 (d, J¼8.3 Hz, 2H), 5.70 (s, 2H), 5.15 (d, J¼12.0 Hz, 1H), 5.04 (d,
J¼12.0 Hz, 1H), 4.36 (t, J¼7.5 Hz, 1H), 3.81 (s, 3H), 3.76 (dd, J¼11.3,
8.0 Hz, 1H), 2.94 (d, J¼18.8 Hz, 1H), 2.94e2.90(m, 1H), 2.14 (d,
J¼13.5 Hz, 1H), 2.05 (dd, J¼18.8, 3.7 Hz, 1H), 1.61 (s, 3H); 13C NMR
CO2CH3
a
c
b
H
H
6
O
6
15
5
O
O
N
OCH3
NBoc
4
OCH3
NBoc
16
2
(100 MHz, CDCl3)
d 174.2, 173.8, 159.5, 129.8, 129.0, 127.6, 123.5,
Scheme 4. Synthesis of A/E/F ring 2. Reagents and conditions: (a) OsO4, NMO, 1,4-
dioxane/H2O, then NaIO4, 85%; (b) Pd(OH)2/C, H2, 95% EtOH, 94%; (c) DMP, Na2CO3,
CH2Cl2, then 5% TFA/CH2Cl2, 73%.
113.8, 69.8, 66.5, 55.2, 48.8, 43.0, 38.5, 37.8, 23.7; HRMS calcd for
C18H20NaO5 339.1208, found 339.1202. For endo-5: white solid; mp:
53e55 ꢀC; IR (KBr) nmax: 2965, 2914, 1767, 1725, 1613, 1517 cmꢁ1; 1H
NMR (400 MHz, CDCl3)
d
7.30 (d, J¼8.3 Hz, 2H), 6.89 (d, J¼8.3 Hz,
3. Conclusion
2H), 5.89e5.78 (m, 1H), 5.57 (d, J¼10.0 Hz, 1H), 5.14 (q, J¼11.9 Hz,
2H), 4.34 (dd, J¼8.7, 5.8 Hz, 1H), 4.12 (d, J¼8.7 Hz, 1H), 3.81 (s, 3H),
3.23 (d, J¼7.2 Hz, 1H), 3.15e3.00 (m, 1H), 2.58 (d, J¼18.2 Hz, 1H),
In conclusion, the desired tricycle amine 2 containing C-1 and C-
6 oxygen functions as the model of A/E/F ring system of royleinine
has been successfully synthesized from the commercial available
2,4-pentadien-1-ols. The synthesis features: (a) stereoselective
synthesis of the model intermediate polysubstituted six-
membered ring A through an intramolecular DielseAlder reaction
and efficient functional group transformations; (b) stereoselective
2.19e1.98 (m, 1H), 1.28 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 175.9,
175.5, 159.4, 129.9, 128.2, 127.9, 124.0, 113.7, 71.6, 66.4, 55.1, 45.4,
39.9, 35.2, 29.4, 23.4; HRMS calcd for C18H20NaO5 339.1208, found
339.1202.
4.4. Preparation of alcohol 7
installation of C-6a hydroxyl group through nucleophilic allylation
of carbonyl group with the assistance of steric effect of neighboring
bulky TBS group; (c) highly efficient construction of E/F ring by
To a stirred solution of exo-5 (14.2 g, 45 mmol) in CH2Cl2
(250 mL) was added trifluoroacetic acid (17.2 mL, 0.225 mol) at
0 ꢀC. After stirring at the same temperature for 2 h, the red reaction
mixture was concentrated in vacuo. The residue was dissolved in
100 mL EtOAc and adjusted to pH¼8 with saturated aqueous
NaHCO3. The organic layer was separated and discarded. The
aqueous layer was acidified using 3 N aqueous HCl and extracted
twice with EtOAc. The combined organics were dried over MgSO4,
evaporated to give the pure acid 5a. White solid; mp 184e186 ꢀC; IR
intramolecular Mannich reaction of
action conditions.
b-ketoester under mild re-
4. Experimental section
4.1. General information
(KBr) nmax: 3437, 2896, 2249, 2091, 1781, 1705 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
Melting points were determined on
a Kofler block (un-
corrected); IR spectra were recorded on a Nicolet 200 SXV spec-
trometer; HRMS were obtained with a Bruker BioTOFQ mass
spectrometer; 1H and 13C NMR spectra were acquired on a Varian
INOVA-400/54 spectrometer, 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 sodium/benzophenone. Unless otherwise noted, all
reactions were carried out under an atmosphere of argon or
nitrogen.
d
5.86e5.66 (m, 2H), 4.48 (t, J¼7.4 Hz, 1H), 3.82 (t,
J¼10.4 Hz, 1H), 3.37e3.11 (m, 1H), 2.94 (d, J¼19.0 Hz, 1H), 2.16 (d,
J¼13.9 Hz, 1H), 2.12 (d, J¼19.0 Hz, 1H), 1.67 (s, 3H); 13C NMR
(100 MHz, CDCl3þCD3OD)
d 176.4, 175.0, 128.4, 122.8, 69.8, 48.2,
42.2, 38.0, 37.4, 23.2; HRMS calcd for C10H12NaO4 219.0633, found
219.0631.
To a stirred solution of the crude acid 5a in THF (200 mL) at 0 ꢀC
were added Et3N (7.5 mL, 54 mmol) and ethyl chloroformate
(5.2 mL, 54 mmol). After stirring at the same temperature for
20 min, the inorganic salts were filtered off and washed with cold
THF (50 mL). The filtrate was placed in a 500 mL flask, followed by
addition of NaBH4 (3.4 g, 90 mmol) in portions and CH3OH (10 mL)
dropwise at ꢁ40 ꢀC. The reaction mixture was allowed to stir for 3 h
at the same temperature and quenched by addition of water. The
layers were separated, and the aqueous layer was extracted with
EtOAc. The combined organics were washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude residue was purified
by silica gel chromatography with PE/EtOAc (4:1) to yield alcohol 7
(7.4 g, 90% for two steps). White solid; mp 105e107 ꢀC; IR (KBr)
4.2. Preparation of ester 6
To
a solution of (Z)-2-methylbut-2-enedioic acid 1-(4-
methoxybenzyl) ester (40.2 g, 0.16 mol) and (E)-2,4-pentadien-1-
ols (13.5 g, 0.16 mol) in CH2Cl2 (400 mL) were added dropwise
DIC (22.2 g, 0.176 mol) and DMAP (980 mg, 8 mmol) in one portion
at 0 ꢀC. After stirring for 3 h, the mixture was filtered and the sol-
vent was removed in vacuo. The residue was purified by silica gel
chromatography with PE/EtOAc (15:1) to give ester 6 (45 g, 89%).

162
Z.-G. Liu et al. / Tetrahedron 68 (2012) 159e165
nmax: 3471, 2957, 2887, 1766 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
4.7. Preparation of compound 10
d
5.91e5.39 (m, 2H), 4.47 (t, J¼8.0 Hz, 1H), 3.82 (dd, J¼11.3, 8.0 Hz,
1H), 3.66 (d, J¼11.2 Hz, 1H), 3.47 (d, J¼11.2 Hz, 1H), 3.21e3.01 (m,
1H), 2.16 (d, J¼13.7 Hz, 1H), 2.05 (d, J¼18.8 Hz, 1H), 1.95 (d,
Benzaldehyde dimethylacetal (2.15 mL, 14.3 mmol) and CSA
(139.4 mg, 0.6 mmol) were added to a solution of triol 9 (3.8 g,
11.9 mmol) in CH2Cl2 (120 mL) at 0 ꢀC. The reaction mixture was
stirred for 1 h at the same temperature and then quenched with
saturated aqueous NaHCO3 (30 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc. The com-
bined organics were dried over MgSO4 and concentrated in vacuo.
The residue was purified by silica gel chromatography with PE/
EtOAc (10:1) to afford compound 10 (3.7 g, 86% based on 90%
J¼18.8 Hz, 1H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 176.0,
129.7, 123.3, 70.2, 66.9, 49.3, 37.9, 37.0, 35.7, 23.0; HRMS calcd for
C10H14NaO3 205.0841, found 205.0846.
4.5. Preparation of epoxide 8
To a stirred solution of alcohol 7 (7.4 g, 40.6 mmol) in DMF
(60 mL) were added Et3N (6.8 mL, 48.7 mmol), DMAP (249 mg,
2.0 mmol), and TBSCl (6.7 g, 44.7 mmol) at 0 ꢀC. After stirring at
room temperature for 2 h, the reaction mixture was diluted with
EtOAc (600 mL), washed with water (3ꢂ100 mL) and brine. The
organics were dried over MgSO4 and concentrated in vacuo to give
crude product 7a, which was directly used in next step. A small
portion was purified for characterization of 7a. White solid; mp
conversion). Colorless oil; IR (film) nmax
:
3466, 2930, 2885,
1459 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
7.50 (d, J¼7.1 Hz, 2H),
7.42e7.30 (m, 3H), 5.57 (s, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.18 (s, 1H),
4.11 (d, J¼11.4 Hz, 1H), 4.06 (d, J¼10.6 Hz, 1H), 4.00e3.91 (m, 2H),
3.86e3.72 (m, 1H), 3.23 (d, J¼10.6 Hz, 1H), 2.15 (dd, J¼11.9, 2.9 Hz,
1H), 1.96 (d, J¼11.9 Hz, 1H), 1.87e1.74 (m, 2H), 1.71e1.63 (m, 1H),
1.34e1.21 (m, 1H), 1.05 (s, 3H), 0.93 (s, 9H), 0.12 (s, 6H); 13C NMR
(100 MHz, CDCl3)
d 138.8, 128.8, 128.3, 126.1, 102.0, 75.8, 69.1, 66.9,
41e43 ꢀC; IR (KBr) nmax: 2953, 2855, 1776, 1472 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
57.4, 41.9, 37.6, 34.2, 32.1, 27.1, 25.7, 25.5, 18.2, ꢁ5.5, ꢁ5.7; HRMS
d
5.78e5.63 (m, 2H), 4.40 (t, J¼7.3 Hz, 1H), 3.74
calcd for C23H38NaO4Si 429.2437, found 429.2435.
(dd, J¼11.6, 8.0 Hz, 1H), 3.54 (d, J¼9.8 Hz,1H), 3.44 (d, J¼9.8 Hz, 1H),
3.15e2.94 (m, 1H), 2.13 (d, J¼19.0 Hz, 1H), 2.09 (d, J¼13.7 Hz, 1H),
1.88 (d, J¼19.0 Hz, 1H), 1.33 (s, 3H), 0.87 (s, 9H), 0.02 (s, 6H); 13C
4.8. Preparation of compound 11
NMR (100 MHz, CDCl3)
d 174.6, 130.2, 123.4, 69.7, 66.3, 49.4, 37.6,
To a stirred solution of 10 (3.8 g, 9.3 mmol) in CH2Cl2 (100 mL)
37.3, 35.8, 25.7, 23.4, 18.1, ꢁ5.7, ꢁ5.8; HRMS calcd for C16H28NaO3Si
ꢀ
were sequentially added Na2CO3 (3.0 g, 27.9 mmol), 4 A MS (7.6 g),
319.1705, found 319.1702.
and PCC (6.0 g, 27.9 mmol) at 0 ꢀC. After 10 min, the ice bath was
removed and stirring was continued for 1 h at room temperature.
Then ether (100 mL) was added and the mixture was filtered over
a pad of silica, washed with ether. The filtrate was concentrated in
vacuo to give crude product 10a, which was directly used in next
step. A small portion was purified for characterization of 10a. Col-
To a stirred solution of crude 7a in CH2Cl2 (250 mL) at 0 ꢀC
were added NaHCO3 (5.0 g, 60 mmol) and m-CPBA (14.8 g, 70%,
60 mmol) in portions. After 10 min, the ice bath was removed and
stirring was continued for 10 h at room temperature. The reaction
was quenched with saturated aqueous Na2S2O3 (30 mL), and the
resulting mixture was stirred until it became clear. The organic
phases were washed with water, dried over Na2SO4, and evapo-
rated to leave a residue, which was purified by silica gel chro-
matography with PE/EtOAc (20:1) to yield epoxide 8 (11.6 g, 91%
for two steps). White solid; mp 108e110 ꢀC; IR (KBr) nmax: 2927,
orless oil; IR (film) nmax: 2930, 2857, 1717, 1468 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
9.91 (s,1H), 7.49 (d, J¼6.9 Hz, 2H), 7.42e7.34 (m,
3H), 5.52 (s, 1H), 4.32e4.08 (m, 2H), 4.03 (d, J¼12.0 Hz, 1H), 3.70 (d,
J¼10.0 Hz, 1H), 3.33 (d, J¼10.0 Hz, 1H), 3.04 (d, J¼11.7 Hz, 1H), 2.02
(d, J¼11.7 Hz, 1H), 1.88e1.63 (m, 3H), 1.42 (d, J¼10.8 Hz, 1H), 1.29 (s,
2855, 1781, 1472 cmꢁ1
; d 4.41 (t,
1H NMR (400 MHz, CDCl3)
3H), 0.88 (s, 9H), 0.02 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 203.7,
J¼7.3 Hz, 1H), 3.96 (dd, J¼11.6, 8.0 Hz, 1H), 3.57 (d, J¼10.1 Hz, 1H),
3.32 (d, J¼10.1 Hz, 1H), 3.30e3.26 (m, 1H), 3.23e3.12 (m, 2H), 2.35
(d, J¼13.9 Hz, 1H), 1.96 (dd, J¼16.0, 3.7 Hz, 1H), 1.73 (d, J¼16.0 Hz,
1H), 1.19 (s, 3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz,
138.5, 128.9, 128.3, 126.1, 101.6, 74.4, 69.7, 66.0, 53.2, 39.8, 31.1, 30.7,
26.8, 25.9, 25.8, 18.2, ꢁ5.7, ꢁ5.8; HRMS calcd for C23H36NaO4Si
427.2281, found 427.2286.
Zinc powder (2.35 g, 36 mmol) was successively added in por-
tions to a stirred solution of the crude 10a and allyl bromide
(3.1 mL, 36 mmol) in saturated NH4Cl solution (100 mL) and THF
(20 mL). The mixture was continued stirring for 1 h at room tem-
perature, then extracted with CH2Cl2. The combined organics were
dried on Na2SO4 and concentrated in vacuo to give crude alcohol
10b, which was directly used in next step. A small portion was
purified for characterization of 10b. White solid; mp 58e60 ꢀC; IR
CDCl3)
d 174.8, 67.9, 67.6, 51.8, 51.2, 42.7, 38.6, 34.4, 34.1, 25.7, 23.8,
18.0, ꢁ5.7, ꢁ5.8; HRMS calcd for C16H28NaO4Si 335.1655, found
335.1651.
4.6. Preparation of triol 9
To a stirred solution of epoxide 8 (6.0 g, 19.2 mmol) in dry THF
(200 mL) at ꢁ20 ꢀC was added dropwise LiBHEt3 (77 mL, 1 M in
THF, 77 mmol). The reaction mixture was slowly warmed to 15 ꢀC
and stirred overnight. Then 50 mL water was added dropwise to
quench the reaction, followed by addition of 1 N aqueous NaOH
(40 mL) and 30% H2O2 (40 mL). The mixture was stirred over
additional 30 min before extracting with EtOAc. The combined
organics were dried over MgSO4 and concentrated in vacuo. The
residue was purified by silica gel chromatography with PE/EtOAc
(2:1) to yield triol 9 (4.9 g, 81%). White solid; mp 65e67 ꢀC; IR
(KBr) nmax: 3512, 3040, 2931, 2851, 1470 cmꢁ1
;
1H NMR (400 MHz,
CDCl3)
d
7.51 (d, J¼7.7 Hz, 2H), 7.41e7.33 (m, 3H), 5.94e5.75 (m,
1H), 5.59 (s, 1H), 5.12 (d, J¼17.1 Hz, 1H), 5.06 (d, J¼10.1 Hz, 1H), 4.69
(d, J¼12.0 Hz, 1H), 4.21 (td, J¼7.3, 3.2 Hz, 1H), 4.12 (s, 1H), 4.01e3.89
(m, 2H), 3.32 (d, J¼10.6 Hz, 1H), 3.26 (d, J¼3.3 Hz, 1H), 2.65e2.50
(m, 1H), 2.50e2.38 (m, 1H), 2.27 (d, J¼11.7 Hz, 1H), 1.88 (d,
J¼11.7 Hz, 1H), 1.73e1.62 (m, 3H), 1.32e1.21 (m, 1H), 1.00 (s, 3H),
0.92 (s, 9H), 0.10 (d, J¼3.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
139.0, 136.5, 128.9, 128.2, 126.4, 116.8, 102.4, 77.2, 70.5, 68.5, 67.1,
(KBr) nmax: 3298, 2930, 2857, 1470 cmꢁ1
;
1H NMR (400 MHz,
43.1, 42.5, 38.0, 33.3, 33.0, 27.2, 26.0, 25.8, 18.3, ꢁ5.6, ꢁ5.7; HRMS
CDCl3þD2O)
d
4.24 (s, 1H), 4.05 (d, J¼11.1 Hz, 1H), 3.99e3.84 (m,
calcd for C26H43O4Si 447.2931, found 447.2920.
3H), 3.74 (d, J¼12.3 Hz, 1H), 3.22 (d, J¼10.5 Hz, 1H), 1.90 (s, 2H),
1.83e1.71 (m, 1H), 1.61e1.52 (m, 2H), 1.28e1.22 (m, 1H), 1.04 (s,
3H), 0.91 (s, 9H), 0.09 (d, J¼3.7 Hz, 6H); 13C NMR (100 MHz,
To a stirred solution of crude 10b in dry THF (90 mL) was added
NaH (1.5 g, 60% in oil, 36.8 mmol) in one portion. After stirring at
room temperature for 20 min, CH3I (1.2 mL, 18.4 mmol) was added
and the suspension was heated to reflux for 3 h. The reaction
mixture was cooled to 0 ꢀC, and quenched with water. The organic
layer was separated and the water layer was extracted with EtOAc.
CDCl3)
d 72.0, 66.6, 65.3, 59.1, 41.8, 39.2, 37.8, 32.7, 29.2, 25.8,
25.4, 18.2, ꢁ5.6, ꢁ5.6; HRMS calcd for C16H35O4Si 319.2305, found
319.2303.

Z.-G. Liu et al. / Tetrahedron 68 (2012) 159e165
163
The combined organics were washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by silica gel
chromatography with PE/EtOAc (50:1) to give 11 (4.15 g, 84% for
three steps). Colorless oil; IR (film) nmax: 3069, 2931, 2856,
EtOAc. The combined organics were dried over MgSO4, and con-
centrated to give crude acid 12b, which was directly used in next
step. A small portion was purified for characterization of 12b. White
solid; mp 82e84 ꢀC; IR (KBr) nmax: 3458, 2936, 2855, 1717,
1469 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.51 (d, J¼7.0 Hz, 2H),
1462 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.38e7.31 (m, 5H),
7.41e7.29 (m, 3H), 5.84e5.68 (m,1H), 5.56 (s, 1H), 5.14 (d, J¼17.1 Hz,
1H), 5.09 (d, J¼10.1 Hz, 1H), 4.46 (d, J¼11.9 Hz, 1H), 4.07 (s, 1H), 3.87
(d, J¼11.9 Hz, 1H), 3.79 (d, J¼10.1 Hz, 1H), 3.43 (dd, J¼9.7, 3.9 Hz,
1H), 3.31 (s, 3H), 3.23 (d, J¼10.1 Hz, 1H), 2.63e2.52 (m, 1H),
2.40e2.31 (m, 2H), 1.81 (d, J¼11.8 Hz, 1H), 1.74e1.63 (m, 3H),
1.43e1.32 (m, 1H), 0.91 (s, 3H), 0.90 (s, 9H), 0.04 (s, 6H); 13C NMR
5.82e5.66 (m, 1H), 5.08 (d, J¼19.4 Hz, 1H), 5.04 (d, J¼11.7 Hz, 1H),
4.67 (d, J¼11.4 Hz, 1H), 4.53 (d, J¼11.4 Hz, 1H), 4.13 (s, 1H), 3.52 (s,
1H), 3.48e3.35 (m, 2H), 3.28 (s, 3H), 2.92 (s, 1H), 2.58e2.37 (m, 2H),
2.20e2.08 (m, 1H), 1.91e1.45 (m, 4H), 0.92 (s, 3H), 0.89 (s, 9H), 0.03
(s, 6H); 13C NMR (100 MHz, CDCl3)
d 178.1, 137.9, 135.8, 128.3, 127.6,
127.5, 116.7, 79.9, 74.9, 70.6, 69.2, 57.7, 44.6, 37.4, 28.8, 25.8, 25.2,
23.9, 18.2, 16.4, ꢁ5.6, ꢁ5.7; HRMS calcd for C27H45O5Si 477.3036,
found 477.3040.
(100 MHz, CDCl3)
d 139.2, 135.7, 128.9, 128.3, 126.5, 117.6, 102.5,
79.3, 77.1, 70.7, 63.4, 56.6, 42.4, 39.0, 38.3, 32.5, 28.5, 27.2, 26.0, 25.9,
18.3, ꢁ5.5, ꢁ5.6; HRMS calcd for C27H44NaO4Si 483.2907, found
483.2897.
To a stirred solution of crude acid 12b in DMF (75 mL) at 0 ꢀC
were added K2CO3 (2.15 g, 15.6 mmol) and CH3I (1.9 mL,
31.2 mmol). The reaction mixture was stirred at the same temper-
ature for 2 h. Then EtOAc (500 mL) was added, and the mixture was
washed with H2O (3ꢂ100 mL) and brine. The organic layer was
dried on MgSO4 and concentrated in vacuo. The residue was puri-
fied by silica gel chromatography with PE/EtOAc (60:1) to afford
ester 13 (3.3 g, 86% for three steps). White solid; mp 52e54 ꢀC; IR
4.9. Preparation of alcohol 12
DIBAL (29.6 mL, 1.0 M in Tol, 29.6 mmol) was added dropwise to
a stirred solution of 11 (3.4 g, 7.4 mmol) in CH2Cl2 (150 mL) at 0 ꢀC.
The reaction mixture was warmed to 10 ꢀC and stirred overnight.
With cooling (0 ꢀC), saturated potassium sodium tartrate solution
(100 mL) was added, and the suspension was stirred until it became
clear. The organic layer was washed with water, dried over Na2SO4,
and concentrated to give a residue, which was purified by silica gel
chromatography with PE/EtOAc (25:1) to afford alcohol 12 (3.0 g,
(KBr) nmax: 3029, 2931, 2859, 1750,1434 cmꢁ1
CDCl3)
;
1H NMR (400 MHz,
7.47e7.27 (m, 5H), 5.97e5.73 (m, 1H), 5.10 (d, J¼17.1 Hz,
d
1H), 5.02 (d, J¼10.1 Hz, 1H), 4.56 (d, J¼12.4 Hz, 1H), 4.34 (d,
J¼12.4 Hz, 1H), 3.86 (s, 1H), 3.65 (d, J¼10.0 Hz, 1H), 3.59 (s, 3H), 3.35
(d, J¼10.0 Hz, 1H), 3.33e3.28 (m, 1H), 3.24 (s, 3H), 2.75 (dd, J¼12.1,
2.8 Hz, 1H), 2.62e2.45 (m, 1H), 2.34e2.20 (m, 2H), 1.91e1.78 (m,
1H), 1.66e1.59 (m, 1H), 1.53e1.34 (m, 2H), 0.90 (s, 3H), 0.89 (s, 9H),
89%). Colorless oil; IR (film) nmax
:
3512, 3031, 2930, 2856,
7.39e7.28 (m, 5H),
1470 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
5.82e5.59 (m, 1H), 5.14 (d, J¼17.0 Hz, 1H), 5.05 (d, J¼10.1 Hz, 1H),
4.63 (d, J¼11.7 Hz, 1H), 4.35 (d, J¼11.7 Hz, 1H), 3.88e3.78 (m, 3H),
3.74 (d, J¼10.2 Hz,1H), 3.61 (d, J¼8.2 Hz,1H), 3.41 (dd, J¼9.5, 4.6 Hz,
1H), 3.31 (s, 3H), 3.19 (d, J¼10.2 Hz, 1H), 2.57e2.36 (m, 2H),
2.03e1.90 (m, 2H), 1.87 (dd, J¼14.0, 3.2 Hz, 1H), 1.69 (d, J¼13.1 Hz,
1H), 1.43 (t, J¼14.0 Hz, 1H), 1.34e1.21 (m, 1H), 0.89 (s, 12H), 0.03 (s,
0.03 (d, J¼1.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 174.0, 138.7,
136.5, 128.1, 127.5, 127.3, 116.3, 79.7, 74.6, 70.2, 64.1, 58.2, 51.1, 44.9,
44.8, 41.0, 37.4, 28.5, 25.8, 25.3, 23.7, 18.2, ꢁ5.5, ꢁ5.6; HRMS calcd
for C28H46NaO5Si 513.3012, found 513.2996.
4.11. Preparation of aldehyde 14
6H); 13C NMR (100 MHz, CDCl3)
d 138.4, 135.8, 128.4, 127.6, 127.5,
117.4, 80.1, 80.0, 69.8, 66.3, 63.7, 56.2, 43.0, 39.1, 38.3, 37.0, 27.4, 26.1,
25.9, 23.4, 18.3, ꢁ5.6, ꢁ5.6; HRMS calcd for C27H46NaO4Si 485.3063,
found 485.3059.
To a stirred solution of ester 13 (1.5 g, 3.06 mmol) in CH3CN
(120 mL) at 0 ꢀC was added aqueous HF (6.0 mL, 40% in H2O). After
stirring at 20 ꢀC for 4 h, saturated aqueous NaHCO3 (30 mL) was
added dropwise to quench the reaction. The mixture was extracted
with EtOAc, and the combined organics were dried on MgSO4,
concentrated to give crude alcohol 13a, which was directly used in
next step. A small portion was purified for characterization of 13a.
Colorless oil; IR (film) nmax: 3487, 3028, 2934, 1746, 1436 cmꢁ1; 1H
4.10. Preparation of ester 13
To a stirred solution of 12 (3.6 g, 7.8 mmol) in CH2Cl2 (100 mL)
ꢀ
were sequentially added 4 A MS (7.2 g), NaOAc (1.92 g, 23.4 mmol),
and PCC (5.0 g, 23.4 mmol) at 0 ꢀC. After 10 min, the ice bath was
removed and stirring was continued for 1 h at room temperature.
Then ether (100 mL) was added and the mixture was filtered over
a pad of silica, washed with ether. The filtrate was concentrated in
vacuo to give crude aldehyde 12a, which was directly used in next
step. A small portion was purified for characterization of 12a. Col-
orless oil; IR (film) nmax: 3068, 2931, 2857,1718,1468 cmꢁ1; 1H NMR
NMR (400 MHz, CDCl3) d 7.36e7.28 (m, 5H), 5.96e5.70 (m, 1H), 5.13
(d, J¼17.1 Hz, 1H), 5.05 (d, J¼10.1 Hz, 1H), 4.57 (d, J¼12.4 Hz, 1H),
4.34 (d, J¼12.4 Hz, 1H), 3.88 (s, 1H), 3.65 (d, J¼11.4 Hz, 1H), 3.59 (s,
3H), 3.51e3.38 (m, 2H), 3.29 (s, 3H), 2.87 (dd, J¼12.1, 3.1 Hz, 1H),
2.59e2.44 (m, 1H), 2.36 (d, J¼12.1 Hz, 1H), 2.34e2.25 (m, 1H), 2.01
(s, 1H), 1.87 (dd, J¼13.6, 3.2 Hz, 1H), 1.78e1.43 (m, 3H), 0.90 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 173.8, 138.6, 136.0, 128.1, 127.5, 127.3,
(400 MHz, CDCl3)
d
9.78 (d, J¼3.4 Hz, 1H), 7.37e7.27 (m, 5H),
116.9, 79.7, 74.5, 70.2, 66.5, 57.5, 51.1, 44.9, 43.8, 39.0, 37.2, 29.8,
25.5, 23.9; HRMS calcd for C22H32NaO5 399.2147, found 399.2136.
To a stirred solution of crude alcohol 13a in CH2Cl2 (60 mL) was
added DesseMartin periodinane (1.95 g, 4.6 mmol) at 0 ꢀC. The
reaction mixture was stirred at room temperature for 1 h, followed
by addition of saturated aqueous NaHCO3 (15 mL) and saturated
aqueous Na2S2O3 (15 mL) to quench the reaction. After being vig-
orously stirred for 30 min, the mixture was extracted with CH2Cl2.
The combined organics were dried on Na2SO4 and concentrated in
vacuo. The residue was purified by silica gel chromatography with
PE/EtOAc (15:1) to afford aldehyde 14 (1.1 g, 96% for two steps).
5.90e5.66 (m, 1H), 5.16e5.03 (m, 2H), 4.54 (d, J¼11.8 Hz, 1H), 4.33
(d, J¼11.8 Hz, 1H), 4.00 (d, J¼2.8 Hz, 1H), 3.56 (d, J¼10.0 Hz, 1H),
3.52e3.45 (m, 1H), 3.42 (d, J¼10.0 Hz, 1H), 3.22 (s, 3H), 2.60e2.52
(m, 1H), 2.49e2.39 (m, 2H), 2.26e2.14 (m, 1H), 1.90e1.78 (m, 1H),
1.65e1.59 (m, 1H), 1.54e1.48 (m, 1H), 1.41 (td, J¼12.4, 3.6 Hz, 1H),
0.93 (s, 3H), 0.89 (s, 9H), 0.03 (d, J¼1.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) d 205.4,138.5, 134.8, 128.2, 127.4, 127.3, 117.4, 79.5, 76.9, 70.3,
65.3, 57.0, 50.7, 44.3, 40.0, 37.3, 29.4, 25.9, 25.8, 23.9, 18.2, ꢁ5.7,
ꢁ5.6; HRMS calcd for C27H44NaO4Si 483.2907, found 483.2897.
To a stirred solution of crude aldehyde 12a in tBuOH/H2O
(125 mL, 3.5/1) were added sequentially 2-methyl-2-butene
(16.6 mL, 156 mmol), NaH2PO4$2H2O (6.1 g, 39 mmol), and NaC1O2
(3.5 g, 39 mmol) at 0 ꢀC. The mixture was stirred at room temper-
ature for 2 h, followed by addition of saturated aqueous Na2S2O3
(30 mL) to quench the reaction. The mixture was extracted with
Colorless oil; IR (film) nmax: 3029, 2934, 1746, 1705, 1436 cmꢁ1
;
1H
NMR (400 MHz, CDCl3) 9.63 (s, 1H), 7.43e7.27 (m, 5H), 5.99e5.60
d
(m, 1H), 5.09 (d, J¼17.1 Hz, 1H), 5.03 (d, J¼10.1 Hz, 1H), 4.55 (d,
J¼12.3 Hz, 1H), 4.35 (d, J¼12.3 Hz, 1H), 3.93 (d, J¼2.5 Hz, 1H), 3.61
(s, 3H), 3.29 (s, 3H), 3.24e3.16 (m, 1H), 3.08 (dd, J¼12.2, 3.2 Hz, 1H),

164
Z.-G. Liu et al. / Tetrahedron 68 (2012) 159e165
2.62e2.45 (m, 1H), 2.41 (dd, J¼12.2, 3.0 Hz, 1H), 2.30e2.12 (m, 1H),
2.01e1.88 (m, 1H), 1.81 (td, J¼14.1, 3.7 Hz, 1H), 1.65e1.56 (m, 1H),
0.94 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 201.9 (201.3), 173.9
(173.7), 156.6 (156.1), 139.3 (139.2), 128.2, 127.7, 127.5, 80.0 (79.1),
74.0, 73.7 (73.4), 70.1, 58.2, 52.4 (52.2), 51.2, 47.7, 46.1, 44.7, 44.6
(43.8), 38.8, 29.4, 28.4, 26.3 (25.5), 23.8, 13.2 (12.5); HRMS calcd for
C28H44NO7 506.3118, found 506.3123.
1.51e1.39 (m, 1H), 1.13 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 205.7,
173.6, 138.3, 135.9, 128.2, 127.6, 127.5, 116.7, 81.0, 74.0, 70.4, 58.8,
51.2, 48.5, 45.4, 44.0, 40.8, 28.5, 24.3, 23.1; HRMS calcd for
C22H30NaO5 397.1991, found 397.1995.
4.14. Preparation of compound 16
4.12. Preparation of compound 15
Pd(OH)2 on carbon (20%) (45 mg) was added to a solution of
aldehyde 4 (898 mg, 1.8 mmol) in 95% EtOH (20 mL). The mixture
was stirred under hydrogen for 20 h at room temperature. Filtration
of the reaction product through Celite and evaporation of the sol-
vent afforded compound 16 (690 mg, 94%), which was used in next
step without purification. A small portion was purified for charac-
terization of 16. Colorless oil; IR (film) nmax: 3433, 2931, 1723, 1690,
To a solution of aldehyde 14 (1.8 g, 4.8 mmol) in dry MeOH
(60 mL) was added 30% EtNH2 in methanol (28.9 mL, 192 mmol).
After stirring at room temperature for 5 h, the TLC analysis showed
the complete consumption of 14. Then the mixture was cooled at
0 ꢀC, and NaBH(OAc)3 (2.0 g, 9.6 mmol) was added. The reaction
mixture was stirred for another 30 min, and quenched with satu-
rated aqueous NaHCO3. The mixture was extracted with EtOAc, and
the combined organics were dried on MgSO4, concentrated to give
crude amine 14a, which was directly used in next step. A small
portion was purified for characterization of 14a. Colorless oil; IR
1415 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 9.79 (s, 1H), 4.08e3.99 (m,
2H), 3.71 (s, 3H), 3.66e3.58 (m, 1H), 3.55e3.44 (m, 1H), 3.29 (s, 3H),
3.23e3.02 (m, 2H), 2.92e2.50 (m, 3H), 2.19 (d, J¼12.1 Hz, 1H),
2.03e1.69 (m, 3H), 1.46 (s, 10H), 1.11 (s, 3H), 0.96 (s, 3H); 13C NMR
(film) nmax: 3328, 3028, 2928, 1748, 1727, 1435 cmꢁ1
;
1H NMR
(100 MHz, CDCl3)
d 201.2 (200.7), 176.5 (176.3), 156.6 (156.1), 80.1
(400 MHz, CDCl3) 7.37e7.24 (m, 5H), 5.94e5.76 (m, 1H), 5.10 (d,
d
(79.2), 73.6 (73.4), 66.9, 58.0, 51.9, 51.1, 47.5, 46.3, 44.6, 44.4, 38.8,
29.2, 28.4, 27.5, 26.3 (25.6), 13.1 (12.4); HRMS calcd for
C21H37NNaO7 438.2468, found 438.2465.
J¼17.1 Hz, 1H), 5.02 (d, J¼10.1 Hz, 1H), 4.57 (d, J¼12.4 Hz, 1H), 4.34
(d, J¼12.4 Hz, 1H), 3.87 (s, 1H), 3.59 (s, 3H), 3.39e3.29 (m, 1H), 3.26
(s, 3H), 2.80e2.51 (m, 5H), 2.39 (d, J¼11.8 Hz, 1H), 2.35e2.22 (m,
2H), 1.85 (d, J¼11.2 Hz, 1H), 1.60e1.35 (m, 3H), 1.10 (t, J¼7.1 Hz, 3H),
4.15. Preparation of compound 2
0.94 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 173.9, 138.7, 136.6, 128.1,
127.5, 127.3, 116.3, 79.7, 74.5, 70.3, 58.3, 51.0, 50.6, 46.3, 45.3, 44.9,
41.4, 36.0, 29.0, 26.1, 23.8, 15.3; HRMS calcd for C24H38NO4
404.2801, found 404.2809.
To a stirred solution of crude 14a in THF (80 mL) were added
Na2CO3 (1.53 g, 14.4 mmol) and (Boc)2O (1.57 g, 7.2 mmol). After
stirring at room temperature for 10 h, the mixture was diluted with
EtOAc, and washed with water and brine. The organic layer was
dried on MgSO4, concentrated in vacuo. The residue was purified by
silica gel chromatography with PE/EtOAc (20:1) to afford com-
To a stirred solution of 16 (491 mg, 1.2 mmol) in CH2Cl2 (24 mL)
wasaddedDesseMartinperiodinane(1.02 g, 2.4 mmol)andNaHCO3
(403 mg, 4.8 mmol) at 0 ꢀC. The reaction mixturewas stirred at room
temperature for 2 h, then quenched with saturated aqueous Na2S2O3
(5 mL). After being vigorously stirred for 30 min, the mixture was
extracted with CH2Cl2. The combined organics were dried on Na2SO4
and concentrated. The residue was dissolved in CH2Cl2 (20 mL), and
TFA (0.92 mL,1.2 mmol) was added dropwise to the solution at 0 ꢀC.
The mixture was stirred at room temperature for 2 h, and then the
solvent was removed in vacuo. The residue was diluted with CH2Cl2
and washed with saturated aqueous NaHCO3. The organic layer was
dried on Na2SO4, concentrated to give the crude product, which was
purified by silica gel chromatography with PE/EtOAc (20:1) to afford
compound 2 (259 mg, 73%). Colorless oil; IR (film) nmax: 2921, 2850,
pound 15 (2.1 g, 88% for two steps). Colorless oil; IR (film) nmax
:
3067, 2930, 1749, 1692, 1454 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
7.38e7.27 (m, 5H), 5.98e5.68 (m, 1H), 5.12 (d, J¼17.0 Hz, 1H), 5.03
(d, J¼10.0 Hz, 1H), 4.56 (d, J¼12.4 Hz, 1H), 4.34 (d, J¼12.4 Hz, 1H),
3.86 (s, 1H), 3.59 (s, 3H), 3.53e3.32 (m, 2H), 3.30 (s, 3H), 3.26e2.97
(m, 3H), 2.78e2.55 (m, 2H), 2.49e2.33 (m, 1H), 2.29 (d, J¼12.5 Hz,
1H), 1.93e1.80 (m, 1H), 1.64e1.54 (m, 1H), 1.52e1.39 (m, 11H), 1.09
1742,1700,1457 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 3.72 (s, 3H), 3.70
(d, J¼6.0 Hz,1H), 3.66e3.58 (m, 1H), 3.31 (s, 3H), 3.09e2.92 (m, 1H),
2.72 (d, J¼5.1 Hz, 1H), 2.62 (d, J¼11.6 Hz, 1H), 2.51 (d, J¼11.6 Hz, 1H),
2.42 (dd, J¼17.9, 6.8 Hz, 1H), 2.37e2.20 (m, 2H), 2.08e1.95 (m, 1H),
1.94e1.80 (m, 1H), 1.78e1.65 (m, 2H), 1.20 (s, 3H), 0.99 (t, J¼7.1 Hz,
(t, J¼6.5 Hz, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 173.8,
156.6, 138.7, 136.5, 128.2, 127.5, 127.3, 116.6, 80.1 (79.7), 79.0, 74.4,
70.3, 58.1, 51.1, 46.1 (45.8), 45.0, 44.8, 44.4(43.8), 40.9(40.6), 38.6,
29.5, 28.6 (28.4), 26.4 (25.8), 24.2, 13.2 (12.5); HRMS calcd for
C29H45NNaO6 526.3145, found 526.3150.
3H); 13C NMR (100 MHz, CDCl3)
d 209.5, 171.5, 83.1, 67.7, 64.0, 58.2,
56.8, 52.4, 50.6, 48.3, 40.2, 38.6, 33.5, 26.8, 26.1,12.9; HRMS calcd for
C16H25NNaO4 318.1681, found 318.1684.
4.13. Preparation of aldehyde 4
Acknowledgements
OsO4 (0.64 mL, 5 wt % in 1,4-dioxane, 0.125 mmol) and NMO
(588 mg, 5.0 mmol) were added to a stirred solution of olefin 15
(1.24 g, 2.5 mmol) in 1,4-dioxane/H2O (50 mL, 3:1). After stirring at
room temperature for 2 h, the TLC analysis showed the complete
consumption of 15. Then NaIO4 (1.07 g, 5.0 mmol) was added, and
the mixture was stirred overnight. The reaction was quenched with
saturated aqueous Na2S2SO3 (10 mL) and saturated aqueous
NaHCO3 (10 mL). The mixture was extracted with CH2Cl2, and the
combined organics were dried on Na2SO4, concentrated in vacuo.
The residue was purified by silica gel chromatography with PE/
EtOAc (5:1) to afford aldehyde 4 (1.06 g, 85%). Colorless oil; IR (film)
nmax: 2930, 1746, 1722, 1693, 1455 cmꢁ1; 1H NMR (400 MHz, CDCl3)
We are grateful to the National Natural Science Foundation of
China (No. 30873147 and No. 20902061) for financial support of
this research.
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.073.
References and notes
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