PIDA-promoted intramolecular transannular aziridination to synthesize bridged azatricyclic amines related to methyllycaconitine

Article abstract of DOI:10.1016/j.tet.2013.04.102

A synthetic strategy for the modeling construction of the A/E/F ring system of lycoctonine-type C₁₉-diterpenoid alkaloids bearing a featuring oxygen functional group at C-7 has been successfully developed. The key steps involved a diastereoselective gold(I)-catalyzed annulation to form cis-fused cyclopentene and a PIDA-promoted intramolecular transannular aziridination followed by regioselective ring cleavage to give the azatricyclic amine.

Full text of DOI:10.1016/j.tet.2013.04.102

Tetrahedron 69 (2013) 5431e5437
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
PIDA-promoted intramolecular transannular aziridination to
synthesize bridged azatricyclic amines related to methyllycaconitine
*
Zhi-Gang Liu, Hang Cheng, Meng-Jia Ge, Liang Xu , Feng-Peng Wang
Key Laboratory of Drug Targeting, Ministry of Education, and 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 2013
Received in revised form 14 April 2013
Accepted 23 April 2013
Available online 28 April 2013
A synthetic strategy for the modeling construction of the A/E/F ring system of lycoctonine-type C19-di-
terpenoid alkaloids bearing a featuring oxygen functional group at C-7 has been successfully developed.
The key steps involved a diastereoselective gold(I)-catalyzed annulation to form cis-fused cyclopentene
and a PIDA-promoted intramolecular transannular aziridination followed by regioselective ring cleavage
to give the azatricyclic amine.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Methyllycaconitine
C19-diterpenoid alkaloids
A/E/F ring system
Intramolecular transannular aziridination
PIDA
1. Introduction
the principle toxic component.2,3 Methyllycaconitine acts at the
neuromuscular junction, inhibiting neurotransmission and in-
Methyllycaconitine 1 (Fig. 1), a representative member of
lycoctonine-type C19-diterpenoid alkaloids,1 was first extracted
from Delphinium brownii by Manske in 1938 and later recognized as
ducing paralysis,4 and it has been found to be the most potent non-
protein antagonist of neuronal nicotinic acetylcholine receptors
(nAChRs).5 Researchers have proposed that methyllycaconitine or
analogs therefore could be useful for the treatment of diseases
affecting memory or for antiepileptic drug development.6
This alkaloid contains a unique and highly strained cage-like
skeleton, which includes six rings and 13 stereogenic centers. Its
potential medicinal value and intriguingly azahexacyclic structure
are very attractive to a number of synthetic chemists.7 However,
synthesis of C19-diterpenoid alkaloid is a conspicuous challenge
due to its intricate structure. So far, only three aconitine-type
C19-diterpenoid alkaloids have been practically synthesized by
the Wiesner and co-workers in 1970s.8e10 As to the lycoctonine-
type C19-diterpenoid alkaloids (about 280 natural compounds),
which differ from aconitine-type alkaloids (about 350 natural
compounds) in the substitution pattern at C-7 and possess an extra
oxygen-containing functionality at this position (Fig. 1),1 no
chemical preparation of any member of lycoctonine-type alkaloids
has been described. Although several partial ring systems, such as
A/E,11e18 A/E/F,19 and A/B/E/F20 subunits have been reported in the
synthesis toward methyllycaconitine in the past decades, none of
these systems has been constructed with the featuring C-7 oxygen
function. In collection with our long-standing interests toward the
total synthesis of C19-diterpenoid alkaloids,21,22 we planned to
develop a new and efficient methodology for constructing the A/E/F
Fig. 1. The structures of C19-diterpenoid alkaloids.
* Corresponding author. Tel./fax: þ86 28 85503046; e-mail address: liangxu@
scu.edu.cn (L. Xu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.102

5432
Z.-G. Liu et al. / Tetrahedron 69 (2013) 5431e5437
ring system with a key C-7 oxygen substituent, which would be one
of the crucial points for the total synthesis the lycoctonine-type
C19-diterpenoid alkaloids. We now describe a novel synthetic pro-
cedure leading to tricyclic amine 2 as the model for A/E/F ring
system of methyllycaconitine using an intramolecular transannular
aziridination and a subsequent regioselective ring cleavage as the
key steps.
2. Results and discussion
The retrosynthetic analysis (Scheme 1) involved an initial CeN
bond connection from 2 to a bridged, polycyclic aziridine 3, which
could be expected to arise from a transannular intramolecular
aziridination by oxidation of unsaturated primary amine 4. Ap-
propriate functional group interconversions suggest that 4 could
be derivable from ketone 5. In turn, the bicycle A/F ring could be
assembled by a cyclopentene annulation onto
a,b-unsaturated
ketoester 6.
Scheme 2. Synthesis of intermediate 18. Reagents and conditions: (a) (i) BH3$SMe2,
THF, (ii) (CH3)2CH(OCH3)2, p-TsOH, Tol, 75% for two steps; (b) tBuOK, THF, 95%; (c) DDQ,
1,4-dioxane, 89%; (d) TiCl4, allenyltriphenylstannane, CH2Cl2, 30%; (e) FeCl3$6H2O,
Ac2O, AcOH, 96%; (f) (i) TiCl4, allenyltriphenylstannane, CH2Cl2, 87%, (ii) cat. AuCl(PPh3),
Scheme 1. Retrosynthetic analysis for A/E/F ring 2 (P¼protecting group).
ꢀ
cat. AgOTf, CH2Cl2, 100%; (g) (i) NaBH4, CH3OH, 95%, (ii) Ag2O, CH3I, SMe2, 4 A MS, THF,
Our synthesis began with the known 2,2-bis(3-methoxy-3-
oxopropyl) malonic acid 7 (Scheme 2), readily available in two
steps from dibenzyl malonate.23 Selectively reduction of malonic
acid function with BH324 followed by protection of resulting 1,3-diol
furnished the acetonide 8. Then Dieckmann condensation25 by
treatment of 8 with potassium tert-butoxide in THF afforded the
88%; (h) K2CO3, CH3OH, 98%; (i) TBSCl, Et3N, DMAP, DMF, 16a (70%), and 16b (23%); (j)
i
ꢀ
PCC, Na2CO3, 4 A MS, CH2Cl2, 92%; (k) Ti(O Pr)4, NH3/EtOH, then NaBH4, 85%.
NaBH4 in MeOH, followed by methylation with MeI/Ag2O gave the
exclusive C-1
The stereochemistry of C-1 methoxy group was assigned as b ori-
b
-methoxy product 14 in 84% yield over two steps.31
b
-ketoester 9 in 95% yield. Oxidation of 9 with DDQ in 1,4-dioxane
gave the conjugate enone 10 smoothly.26,27 With the enone ester in
hand, the crucial cyclopentene annulation was attempted. Toste
et al. had found with the similar substrate an efficient conjugate
addition of allenyltriphenylstannane followed by gold(I)-catalyzed
entation based on NOE difference experiment, which shows
through-space interaction between H-1 (3.14 ppm) and olefin
proton H-17 (6.03 ppm). This stereochemistry presumably arises
due to the kinetic attack of hydride from the less encumbered
a face
cyclization of resulting acetylenic
b
-ketoester afforded cis-fused
(the face was seriously hindered by the ester group). After re-
b
cyclopentene as a single diastereomer.28 In this case, the first step
for introduction of propargyl group by conjugate addition of 10
with allenyltriphenylstannane in presence of TiCl4 was partially
successful, presumably due to the presence of acid sensitive ace-
tonide group in 10. 11 was isolated, but only in 30% yield. The fol-
lowing annulation of 11 under the Toste’s gold-catalysis condition
was also totally failed. These factors led us to reconsider the ap-
propriateness of the acetonide protecting group. Thus, direct acet-
ylation of the spiroketal group with catalytic FeCl3 in AcOH30 gave
diacetyl ester 12 in 96% yield. With this substrate, the conjugate
propargylation29 and the following gold(I)-catalyzed cyclization by
Toste’s procedure28 proceeded smoothly, delivering the cyclo-
pentene 13 as a single diastereomer in 87% yield over two steps.
With the key A/F ring precursor in place, we then turned our
attention to installation of methoxy group at C-1 and realization of
the C-4 quaternary stereocenter by desymmetrization of the pro-
chiral diol (Scheme 2). Accordingly, reduction of ketone 13 with
moval of the acetyl group of 14 under basic condition, regiose-
lective monoprotection of resulting 1,3-diol was effected by
treatment with TBSCl/TEA/DMAP in DMF, delivering the silyl ether
on the b-face to give 16a as the major product in 70% yield, along
with 23% yield of separable diastereoisomer 16b. The unwanted
16b could be easily recycled to diol 15 by treatment with TBAF in
THF. The relatively good regioselectivity of this reaction could be
attributed to the more severe steric hindrance of
a-face caused by
the fused cyclopentene moiety than that of -face. The remaining
b
primary alcohol in 16a was then oxidized with PCC/Na2CO3 in
dichloromethane to furnish an aldehyde 17, which subsequently
underwent reductive amination by treatment with ammonia in
ethanol and titanium (IV) isopropoxide, followed by reduction in
situ with NaBH4, affording primary amine 18 in 85% yield.32
With the key intermediate 18 in hand, our effort was focused on
the construction of the challenging bridged polycyclic aziridine. As
shown in Table 1, initial attempt to direct cyclization of 18 by the

Z.-G. Liu et al. / Tetrahedron 69 (2013) 5431e5437
5433
Table 1
Intramolecular transannular aziridination of primary amine 18
Entry
Conditions
Yield of
19 (%)
1
2
Pb(OAc)4 (2 equiv), K2CO3 (4 equiv), PhH, rt/60 ꢀ
NCS (2 equiv), CH2Cl2, rt, 12 h
C
0a
0b
3
4
5
6
7
8
9
10
11
NBS (2 equiv), acetone, rt, 2 h
NBS (2 equiv), DMF, rt, 2 h
NBA (2 equiv), DMF, rt, 2 h
NIS (2 equiv), DMF, rt, 2 h
PIDA (2 equiv), K2CO3 (2 equiv), DCE, 50 ꢀC, 2 h
PIDA (2 equiv), MgO (2 equiv), DCE, 50 ꢀC, 2 h
PIDA (2 equiv),Cu(OTf)2, (0.5 equiv), DCE, 50 ꢀC, 2 h
PIDA (1.2 equiv), K2CO3 (2 equiv), SiO2, DCE, 50 ꢀC, 1 h
PIFA (1.2 equiv), K2CO3 (2 equiv), SiO2, DCE, 50 ꢀC, 1 h
10
30c
24c
20c
40
33
35
70
38
Fig. 2. ORTEP diagram from the X-ray crystal structure of methyl quaternary amine
salt of 19 (CCDC 927430).
Significance of bold value indicates that the condition in entry 10 is the best result.
a
All of the amine 18 was recovered.
Mono- or di-chloramine was observed.
With almost same amount of byproduct 20 was isolated.
b
c
Nagata’s intramolecular aziridination method33,34 (entry 1) was un-
successful. Treatment of 18 with NCS still did not afford the desired
product, yielding only fairly stable mono- or di-chloramine (entry 2).
Encouragingly, when applying NBS in acetone, a small amount of
desired aziridine 19 was isolated from the reaction mixture (entry
3).35 Further optimization of reaction conditions provided aziridine
in up to 30% yield (entry 4), but with almost same quantities of major
allylic amination byproduct 20 and some unidentified low polar
compounds. Screening of other halogenated reagents, such as N-
bromoacetamide (NBA) and N-iodosuccinimide (NIS) got worse re-
sults (entry 5 and 6). It has been widely reported that the hypervalent
iodine reagents could promote nitrene transfer to olefin giving
aziridine in high yields,36e38 despite mostly using electron with-
drawing group substituted amine, such as sulfonamides39 or carba-
mates40 as substrates. To our delight, when 18 was treated with
phenyliodine(III) diacetate (PIDA) and K2CO3 in 1,2-dichloroethane at
50 ꢀC for 2 h, 19 was obtained in 40% yield without allylic amination
byproduct found (entry 7). After a series of experiments (entry
8e10), we found that treatment of 18 with PIDA and K2CO3 using
silica gel as additive gave the best result (entry 10), delivering 19 in up
to 70% yield. To the best of our knowledge, it was the first time that
PIDA was used as a sole promoter for intramolecular aziridination of
primary amine. Additionally, the use of more potent oxidant phe-
nyliodine(III) bistrifluoroacetate (PIFA) resulted in lower yield (entry
11). It is worthy to note that the aziridine 19 is fairly stable and could
be stored at rt even at neat liquid state. The structure of 19 was fur-
ther confirmed by single-crystal X-ray analysis of the corresponding
methyl quaternary amine salt (Fig. 2).
Scheme 3. Regioselective ring cleavage of aziridine 19. Reagents and conditions: (a)
Ac2O, CH2Cl2, 90%, inseparable; (b) EtI, DMF, then NaOAc 22a (77%), 22b (20%).
3. Conclusion
In conclusion, the synthesis of desired tricyclic amine 22a
modeling the A/E/F ring system of lycoctonine-type C19-diterpe-
noid alkaloids has been successfully accomplished by using gold(I)-
catalyzed annulation reaction and unprecedented PIDA-promoted
transannular aziridination of primary amine followed by regiose-
lective ring cleavage as the key steps. The development of this
methodology thus should provide a basis for the total synthesis of
methyllycaconitine.
Having achieved the synthesis of bridged aziridine, regiose-
lective ring cleavage and installation of oxygen function at C-7 were
next addressed (Scheme 3). Initial treatment of 19 with acetic an-
hydride in dichloromethane provided a 2:1 inseparable mixture of
regioisomers 21a and 21b in which the desired product 21a could
be identified as the major isomer by the 1H NMR spectrum.41
Pleasingly, reaction with ethyl iodide in DMF at rt generated
a more reactive quaternary amine salt, which was in turn treated
with sodium acetate in one pot at an elevated temperature, pro-
viding a 3.8:1 separable mixture of regioisomers 22a and 22b from
which the desired major isomer 22a was isolated in 77% yield.
The structure of 22a was further unambiguously established by its
X-ray crystallography.
4. Experimental section
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 13
C
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/benzo-
phenone. Unless otherwise noted, all reactions were carried out
under an atmosphere of argon or nitrogen.

5434
Z.-G. Liu et al. / Tetrahedron 69 (2013) 5431e5437
4.2. Preparation of acetonide 8
concentrated, and then taken up in 6 mL Et2O and treated with
3 mL std KF solution. The resulting suspension was stirred at rt for
1 h, filtered, and extracted with EtOAc. The combined organics were
dried over MgSO4, concentrated to yield a residue, which was pu-
rified by silica gel chromatography with PE/EtOAc (8:1) to yield
alkyne 11 (70 mg, 30%). Colorless oil; IR (film) nmax: 2934, 1733,
To a stirred solution of 2,2-bis(3-methoxy-3-oxopropyl) malonic
acid (16.6 g, 60 mmol) in THF (500 mL) at 0 ꢀC was added dropwise
BH3$SMe2 (10.7 g, 70.5 mmol). The reaction mixture was slowly
warmed to 25 ꢀC and stirred overnight. Then 80 mL CH3OH was
added dropwise to quench the reaction and the mixture was con-
centrated in vacuo. The resultant residue was dissolved in 200 mL
toluene and TsOH (516 mg, 3 mmol), 2,2-dimethoxypropane
(12.5 g, 0.12 mol) were added in one portion. After being stirred
at rt for 8 h, the reaction was quenched with std NaHCO3 solution
and the organic layer was washed with brine, dried over MgSO4,
concentrated to give a residue, which was purified by silica gel
chromatography with PE/EtOAc (20:1) to give acetonide 8 (13.0 g,
75% for two steps). Colorless oil; IR (film) nmax: 2951, 2869, 1738,
1649, 1476 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 12.51 (s, 1H), 3.78 (s,
3H), 3.60e3.52 (m, 2H), 3.51e3.38 (m, 2H), 2.81 (d, J¼4.7 Hz, 1H),
2.61e2.49 (m, 1H), 2.46e2.38 (m, 2H), 2.38e2.29 (m, 2H), 1.95 (s,
1H), 1.72e1.61 (m, 1H), 1.31 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
173.4, 172.7, 98.4, 83.5, 80.7, 70.8, 68.8, 67.2, 51.5, 40.0þ, 30.8, 25.4,
25.0, 24.6, 21.2, 20.3; HRMS (ESI) calcd for C16H22NaO5 [MþNa]þ
317.1365, found 317.1358.
4.6. Preparation of diacetyl ester 12
1438, 1375, 1202, 1085 cmꢁ1
; d 3.68
1H NMR (400 MHz, CDCl3)
(s, 6H), 3.57 (s, 4H), 2.39e2.19 (m, 4H), 1.79e1.60 (m, 4H), 1.40
To a stirred solution of 10 (7.0 g, 27.6 mmol) in AcOH (55 mL)
was added FeCl3$6H2O (2.2 g, 8.3 mmol). After 2 h, Ac2O (11 mL)
was added and stirring was maintained for another 3 h. Then EtOAc
(600 mL) was added and the organics were washed successively
with H2O (2ꢂ150 mL), std NaHCO3 solution (2ꢂ100 mL), and dried
over MgSO4, concentrated to give a residue, which was purified by
silica gel chromatography with PE/EtOAc (4:1) to yield diacetyl
(s, 6H); 13C NMR (100 MHz, CDCl3)
d
173.3, 97.7, 66.9, 51.2, 33.7, 27.5,
þ
26.7, 23.2; HRMS (ESI) calcd for C14H24NaO6 [MþNa]þ 311.1471,
found 311.1469.
4.3. Preparation of b-ketoester 9
To a stirred solution of 8 (13.7 g, 47.5 mmol) in THF (300 mL)
ester 12 (7.9 g, 96%). White solid; mp: 81e83 ꢀC; IR (KBr) nmax
:
t
at ꢁ20 ꢀC was added BuOK (6.4 g, 57 mmol). The reaction was
2958, 2854, 1743, 1686, 1367, 1236, 1042 cmꢁ1; 1H NMR (400 MHz,
completed in 1.5 h and quenched with std NH4Cl solution. 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 (30:1) to yield
CDCl3)
d
4.23 (d, J¼11.3 Hz, 2H), 4.08 (d, J¼11.3 Hz, 2H), 3.83 (s, 3H),
2.62 (t, J¼6.8 Hz, 2H), 2.10 (s, 6H), 2.02 (t, J¼6.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d
193.1, 170.3, 164.4, 153.1, 134.3, 64.8, 52.4, 40.2,
þ
34.0, 26.1, 20.6; HRMS (ESI) calcd for C14H18NaO7 [MþNa]þ
321.0950, found 321.0954.
b
-ketoester 9 (11.5 g, 95%). White solid; mp: 67e69 ꢀC; IR (KBr)
nmax: 3422, 2945, 2856, 1666, 1614, 1448, 1357, 1280, 1222,
1058 cmꢁ1 1H NMR (400 MHz, CDCl3)
12.16 (s, 1H), 3.76 (s, 3H),
3.61 (s, 4H), 2.32 (t, J¼6.7 Hz, 2H), 2.18 (s, 2H), 1.69 (t, J¼6.7 Hz, 2H),
1.44 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3)
172.6, 170.6,
4.7. Preparation of cyclopentene 13
;
d
To a stirred solution of 12 (6.2 g, 20.8 mmol) in CH2Cl2 (130 mL)
at ꢁ78 ꢀC was added dropwise a solution of TiCl4 (27 mL, 1 M in
CH2Cl2, 27 mmol). After 10 min, a solution of allenyltriphenyl-
stannane (12.1 g, 31.2 mmol) in 40 mL CH2Cl2 was added. The
mixture was allowed to reach rt gradually and stirred for another
2 h. The reaction was quenched with 80 mL water and extracted
with CH2Cl2. The combined organics were dried over Na2SO4,
concentrated, and then taken up in 150 mL Et2O and treated with
75 mL std KF solution. The resulting suspension was stirred at rt for
1 h, filtered, and extracted with EtOAc. The combined organics were
dried over MgSO4, concentrated to yield a residue, which was pu-
rified by silica gel chromatography with PE/EtOAc (10:1) to yield an
intermediate 12S (6.1 g, 87%). White solid; mp: 57e59 ꢀC; IR (KBr)
nmax: 3281, 2954, 1740, 1653, 1615, 1441, 1238, 1043 cmꢁ1; 1H NMR
d
98.2, 94.8, 67.6, 51.3, 31.3, 28.2, 25.9, 24.9, 23.8, 23.2; HRMS (ESI)
þ
calcd for C13H20NaO5 [MþNa]þ 279.1208, found 279.1213.
4.4. Preparation of ene-ketoester 10
To a solution of 9 (7.2 g, 28 mmol) in 1,4-dioxane (140 mL) was
added DDQ (6.7 g, 29.5 mmol), and the mixture was stirred at rt for
1 h. Then hexane (200 mL) was added and the solid filtered. The
filtrate was concentrated to give a residue, which was dissolved in
CH2Cl2 and washed with 5% NaHCO3 solution, and the aqueous
layer 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 (3:1) to yield ene-
ketoester 10 (6.3 g, 89%). White solid; mp: 100e102 ꢀC; IR (KBr)
nmax: 2952, 2873, 1732, 1675, 1380, 1366, 1267, 1076, 1034 cmꢁ1; 1H
(400 MHz, CDCl3)
d
12.46 (s, 1H), 4.17 (d, J¼11.5 Hz, 1H), 4.01
(d, J¼11.5 Hz, 1H), 3.96 (s, 2H), 3.80 (s, 3H), 2.69 (s, 1H), 2.57 (ddd,
J¼17.5, 5.5, 2.3 Hz, 1H), 2.45e2.23 (m, 3H), 2.22e2.12 (m, 1H), 2.09
(s, 3H), 2.06 (s, 3H), 1.96 (s, 1H), 1.66e1.55 (m, 1H); 13C NMR
NMR (400 MHz, CDCl3)
d
7.63 (s, 1H), 3.86 (d, J¼11.8 Hz, 2H), 3.82
(s, 3H), 3.78 (d, J¼11.8 Hz, 2H), 2.53 (t, J¼6.9 Hz, 2H), 2.00
(100 MHz, CDCl3) d 172.7, 172.0, 170.7, 170.6, 97.8, 82.2, 70.8, 65.2,
(t, J¼6.9 Hz, 2H),1.49 (s, 3H),1.48 (s, 3H); 13C NMR (100 MHz, CDCl3)
63.4, 51.4, 38.6, 33.0, 24.8, 20.6, 20.1; HRMS (ESI) calcd for
þ
d
193.5, 164.5, 156.1, 132.6, 98.4, 66.2,þ52.0, 36.2, 33.8, 27.1, 23.7,
C17H22NaO7 [MþNa]þ 361.1263, found 361.1274.
22.8; HRMS (ESI) calcd for C13H18NaO5 [MþNa]þ 277.1052, found
To a solution of intermediate 12S (2.6 g, 7.7 mmol) in CH2Cl2
(50 mL) were added AuCl(PPh3) (38 mg, 0.077 mmol) and AgOTf
(20 mg, 0.077 mmol). The reaction mixture was stirred at rt for 6 h,
then concentrated. The residue was directly purified by silica gel
chromatography with PE/EtOAc (5:1) to give cyclopentene 13 (2.6 g,
100%). White solid; mp: 64e66 ꢀC; IR (KBr) nmax: 2955, 1743, 1703,
277.1050.
4.5. Preparation of alkyne 11
To a stirred solution of 10 (203 mg, 0.8 mmol) in CH2Cl2 (5 mL) at
ꢁ78 ꢀC was added dropwise a solution of TiCl4 (0.96 mL, 1 M in
CH2Cl2, 0.96 mmol). After 10 min, a solution of allenyltriphenyl-
stannane (467 mg, 1.2 mmol) in 1.2 mL CH2Cl2 was added. The
mixture was allowed to reach rt gradually and stirred for another
2 h. The reaction was quenched with 4 mL water and extracted
with CH2Cl2. The combined organics were dried over Na2SO4,
1441, 1384, 1222, 1040 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 5.99
(d, J¼5.4 Hz, 1H), 5.86 (d, J¼5.4 Hz, 1H), 4.24 (d, J¼11.6 Hz, 1H), 4.18
(d, J¼11.6 Hz, 1H), 4.05 (d, J¼11.4 Hz, 1H), 3.91 (d, J¼11.4 Hz, 1H),
3.77 (s, 3H), 3.14 (t, J¼8.6 Hz, 1H), 2.74e2.59 (m, 1H), 2.52 (dd,
J¼16.4, 8.6 Hz, 1H), 2.44e2.29 (m, 2H), 2.09 (s, 3H), 2.06 (s, 3H),
1.98e1.84 (m, 1H), 1.81e1.70 (m, 1H); 13C NMR (100 MHz, CDCl3)

Z.-G. Liu et al. / Tetrahedron 69 (2013) 5431e5437
5435
d
207.3, 172.5, 170.4, 170.4, 132.9, 130.5, 68.8, 65.7, 64.1, 53.0, 47.1,
washed with brine (3ꢂ50 mL), and dried over MgSO4, concentrated
in vacuo. The residue was purified by silica gel chromatography
with PE/EtOAc (10:1e3:1) to yield silyl ether 16a (2.0 g, 70%) and
16b (650 mg, 23%). Data for 16a: colorless oil; IR (film) nmax: 3411,
þ
38.0, 34.3, 33.3, 24.8, 20.5; HRMS (ESI) calcd for C17H22NaO7
[MþNa]þ 361.1263, found 361.1274.
4.8. Preparation of methyl ether 14
2932, 2856, 1726, 1466, 1437, 1254, 1099, 1047 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
6.03 (d, J¼5.3 Hz, 1H), 5.89 (d, J¼5.3 Hz, 1H),
To a solution of 13 (2.9 g, 8.7 mmol) in MeOH (145 mL) at 0 ꢀC
was added NaBH4 (395 mg, 10.4 mmol). After being stirred for 1 h,
the reaction was quenched with std NH4Cl solution. The mixture
was extracted with CH2Cl2 and the combined organics were dried
over Na2SO4, concentrated to give a residue, which was purified by
silica gel chromatography with PE/EtOAc (2:1) to give an in-
termediate 13S (2.8 g, 95%). Colorless oil; IR (film) nmax: 3526, 2950,
3.93 (d, J¼9.8 Hz, 1H), 3.73 (d, J¼9.8 Hz, 2H), 3.68 (s, 3H), 3.58 (dd,
J¼10.6, 4.2 Hz, 1H), 3.49 (dd, J¼10.6, 6.4 Hz, 1H), 3.33 (s, 3H), 3.24
(t, J¼5.4 Hz, 1H), 3.10 (dd, J¼10.8, 3.9 Hz, 1H), 2.65 (t, J¼9.0 Hz, 1H),
2.55 (dd, J¼15.2, 8.2 Hz, 1H), 2.30 (dd, J¼15.2, 10.3 Hz, 1H),
2.10e1.89 (m, 1H), 1.81e1.70 (m, 1H), 1.71e1.60 (m, 1H), 1.36e1.22
(m, 1H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 174.7, 136.2, 130.2, 84.9, 71.4, 68.6, 60.2, 57.8, 51.6, 45.8,
1739, 1367, 1241, 1046 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
6.07
39.8, 33.3, 25.7, 24.4, 21.3, 17.9, ꢁ5.7, ꢁ5.9; HRMS (ESI) calcd for
(d, J¼5.5 Hz, 1H), 6.00 (d, J¼5.5 Hz, 1H), 4.05e3.91 (m, 3H), 3.81 (d,
J¼11.1 Hz, 1H), 3.75 (s, 3H), 3.65 (d, J¼11.7 Hz, 1H), 3.39 (td, J¼11.7,
4.2 Hz, 1H), 2.83 (t, J¼9.7 Hz, 1H), 2.47e2.24 (m, 2H), 2.07 (s, 3H),
2.06 (s, 3H),1.95e1.68 (m, 3H), 1.40 (td, J¼13.7, 3.8 Hz,1H); 13C NMR
C20H37O5Siþ [MþH]þ 385.2410, found 385.2410.
Data for 16b: white solid; mp: 55e57 ꢀC; IR (KBr) nmax: 3521,
2928, 2855, 1733, 1470, 1254, 1094 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
6.02 (d, J¼5.3 Hz, 1H), 5.88 (d, J¼5.3 Hz, 1H), 3.81 (dd, J¼11.1,
(100 MHz, CDCl3)
d
176.6, 170.7, 170.5, 136.2, 131.3, 75.8, 67.1, 63.3,
6.7 Hz, 1H), 3.72 (s, 3H), 3.61 (dd, J¼11.1, 5.0 Hz, 1H), 3.55 (d,
J¼9.5 Hz, 1H), 3.45 (d, J¼9.5 Hz, 1H), 3.32 (s, 3H), 3.09 (dd, J¼10.2,
3.6 Hz, 1H), 2.93 (t, J¼6.0 Hz, 1H), 2.80 (t, J¼9.4 Hz, 1H), 2.39 (dd,
J¼15.2, 8.5 Hz, 1H), 2.33e2.19 (m, 1H), 2.12e1.92 (m, 1H), 1.75e1.61
(m, 1H), 1.48 (dt, J¼13.7, 4.5 Hz, 1H), 1.32e1.19 (m, 1H), 0.89 (s, 9H),
59.2, 52.3, 47.5,þ38.2, 32.1, 26.9, 25.3, 20.8, 20.7; HRMS (ESI) calcd
for C17H24NaO7 [MþNa]þ 363.1420, found 363.1414.
To a solution of intermediate 13S (2.0 g, 6.0 mmol) in THF
ꢀ
(80 mL) at rt were added successively 4 A MS (3.0 g), Ag2O (6.9 g,
30 mmol), Me2S (2.2 mL, 30 mmol), and CH3I (7.5 mL, 0.12 mol). The
resulting suspension was kept in dark place and stirred overnight,
then filtered over a pad of silica, washed with EtOAc, and concen-
trated to give a residue, which was directly purified by silica gel
chromatography with PE/EtOAc (5:1) to give methyl ether 14 (1.9 g,
88%). Colorless oil; IR (film) nmax: 2946, 2828,1740, 1457,1436,1368,
0.07 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 175.1, 136.1, 130.3, 84.1,
70.7, 65.9, 60.7, 57.6, 51.8, 44.1, 39.9, 33.5, 25.7, 23.8, 21.0, 18.0, ꢁ5.8,
ꢁ5.9; HRMS (ESI) calcd for C20H37O5Siþ [MþH]þ 385.2410, found
385.2410.
4.11. Preparation of aldehyde 17
1240, 1103, 1045 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.03 (d,
J¼5.5 Hz, 1H), 5.87 (d, J¼5.5 Hz, 1H), 4.34 (d, J¼11.3 Hz, 1H), 4.14 (d,
J¼11.3 Hz,1H), 4.03 (d, J¼11.1 Hz,1H), 3.81 (d, J¼11.1 Hz,1H), 3.71 (s,
3H), 3.33 (s, 3H), 3.14 (d, J¼8.0 Hz, 1H), 2.66 (t, J¼9.1 Hz, 1H),
2.47e2.27 (m, 2H), 2.15e1.95 (m,1H), 2.04 (s, 6H),1.74 (d, J¼10.8 Hz,
To a stirred solution of 16a (1.2 g, 3.1 mmol) in CH2Cl2 (30 mL)
were added 4 A MS (2.4 g), Na2CO3 (660 mg, 6.2 mmol), and PCC
ꢀ
(1.3 g, 6.2 mmol) at 0 ꢀC. After 10 min, the ice bath was removed and
stirring was continued for 1 h at rt. Then ether (60 mL) was added
and the mixture was filtered over a pad of silica, washed with ether.
The filtrate was concentrated in vacuo to give a residue, which was
purified by silica gel chromatography with PE/EtOAc (30:1) to yield
aldehyde 17 (1.1 g, 92%). Colorless oil; IR (film) nmax: 2932, 2857,
2H), 1.37e1.21 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 174.3, 170.7,
170.4, 136.1, 129.7, 83.7, 67.1, 64.0, 60.4, 57.6,þ51.7, 45.7, 37.9, 33.3,
23.8, 20.7; HRMS (ESI) calcd for C18H26NaO7 [MþNa]þ 377.1576,
found 377.1568.
1734, 1466, 1254, 1207, 1100 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 9.53
4.9. Preparation of diol 15
(s, 1H), 5.87 (d, J¼5.6 Hz, 1H), 5.81 (d, J¼5.6 Hz, 1H), 3.93 (d,
J¼10.1 Hz, 1H), 3.87 (d, J¼10.1 Hz, 1H), 3.70 (s, 3H), 3.43e3.34 (m,
1H), 3.31 (s, 3H), 2.81 (t, J¼7.3 Hz, 1H), 2.45 (dd, J¼16.5, 7.8 Hz, 1H),
2.26 (dd, J¼16.5, 6.8 Hz, 1H), 2.01e1.88 (m, 1H), 1.87e1.77 (m, 1H),
1.73e1.57 (m, 2H), 0.85 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz,
To a solution of 14 (2.6 g, 7.2 mmol) in MeOH (120 mL) at 0 ꢀC,
was added K2CO3 (2.5 g, 18 mmol). After being stirred for 2 h, the
reaction was quenched with 1 N HCl solution (40 mL). The mixture
was concentrated to about 30 mL, then diluted with water, and
extracted with EtOAc. The combined organics were dried over
MgSO4 and concentrated in vacuo. The residue was purified by
silica gel chromatography with PE/EtOAc (1:1) to yield diol 15 (1.9 g,
98%). Colorless oil; IR (film) nmax: 3419, 2944,1729, 1456,1437,1253,
CDCl3)
d 204.6, 173.6, 134.7, 131.3, 81.8, 66.4, 62.4, 57.2, 51.8, 42.8,
34.6, 25.7, 20.4, 19.3, 18.1, ꢁ5.6, ꢁ5.7; HRMS (ESI) calcd for
C20H34NaO5Siþ [MþNa]þ 405.2073, found 405.2068.
4.12. Preparation of primary amine 18
1099,1047 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
5.84 (d, J¼5.3 Hz,1H),
5.77 (d, J¼5.3 Hz, 1H), 4.28 (d, J¼11.8 Hz, 1H), 4.06 (s, 1H), 3.87
(s, 1H), 3.76 (s, 3H), 3.67 (d, J¼10.6 Hz, 1H), 3.54 (d, J¼10.6 Hz, 1H),
3.44 (d, J¼11.8 Hz, 1H), 3.32 (d, J¼3.8 Hz, 1H), 3.25 (s, 3H), 3.18
(t, J¼9.2 Hz, 1H), 2.68 (dd, J¼16.7, 9.0 Hz, 1H), 2.29 (dd, J¼16.7,
9.5 Hz, 1H), 1.79 (ddd, J¼14.8, 10.1, 5.0 Hz, 1H), 1.44e1.31 (m, 1H),
To a solution of 17 (575 mg, 1.5 mmol) in std NH3/EtOH solution
(130 mL) at 0 ꢀC was added Ti(OiPr)4 (470 mg, 1.65 mmol). The
mixture was warmed to rt and stirred for 3 h. Then NaBH4 (113 mg,
3 mmol) was added and stirring was continued for another 30 min.
The reaction was then quenched with 20 mL concd ammonia so-
lution. The resulting precipitate was filtered and the filtrate was
concentrated to about 30 mL, then diluted with water and extracted
with EtOAc. The organics were dried over MgSO4 and concentrated.
The residue was purified by silica gel chromatography with CHCl3/
CH3OH (20:1) to give amine 18 (490 mg, 85%). Colorless oil; IR (film)
nmax: 3396, 2931, 2855, 1735, 1465, 1253, 1198, 1097 cmꢁ1; 1H NMR
1.04 (dd, J¼8.8, 4.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 176.1,
133.9, 131.3, 81.4, 72.7, 69.0, 62.0, 57.0,þ51.9, 39.5, 38.2, 35.0, 22.0,
19.7; HRMS (ESI) calcd for C14H22NaO5 [MþNa]þ 293.1365, found
293.1368.
4.10. Preparation of silyl ether 16a and 16b
(400 MHz, CDCl3)
d
6.05 (d, J¼5.2 Hz, 1H), 5.88 (s, 1H), 3.75 (d,
To a solution of 15 (2.0 g, 7.4 mmol) in DMF (25 mL) at 0 ꢀC were
added Et3N (1.5 mL, 11.1 mmol), DMAP (450 mg, 3.7 mmol), and
TBSCl (1.2 g, 7.8 mmol). The mixture was warmed to rt and stirred
for 2 h. Then EtOAc (200 mL) was added and the organics were
J¼10.1 Hz, 1H), 3.68 (s, 3H), 3.53 (d, J¼10.1 Hz, 1H), 3.33 (s, 3H), 3.04
(d, J¼8.8 Hz, 1H), 2.70 (d, J¼13.0 Hz, 1H), 2.55e2.46 (m, 2H),
2.44e2.35 (m, 1H), 2.35e2.24 (m, 1H), 2.03 (q, J¼12.0 Hz, 1H), 1.75
(d, J¼11.0 Hz, 2H), 1.13 (t, J¼11.5 Hz, 1H), 0.89 (s, 9H), 0.06 (s, 3H),

5436
Z.-G. Liu et al. / Tetrahedron 69 (2013) 5431e5437
0.05 (s, 3H); 13C NMR (100 MHz, CDCl3)
63.2, 60.1, 57.9, 51.6, 47.9, 40.5, 33.2, 25.8, 25.6, 21.6, 18.0, ꢁ5.6,
ꢁ5.7; HRMS (ESI) calcd for C20H38NO4Siþ [MþH]þ 384.2570, found
384.2573.
d
174.9, 137.0, 130.0, 85.4,
reflections measured with 2.8070ꢃ
q
ꢃ28.9366ꢀ scan, 4561 unique
(Rint¼0.0335), which were used in all calculations. The final wR2
was 0.0901 (all data) and R1 was 0.0385 (>2s(I)). CCDC reference
number: CCDC 927430.
4.13. Preparation of aziridine 19 with NBS/DMF
4.16. Preparation of inseparable 21a and 21b
To a solution of 18 (153 mg, 0.40 mmol) in DMF (2 mL) at rt was
added NBS (142 mg, 0.80 mmol). The mixture was stirred for 2 h,
then quenched with 20 mL std Na2S2O3 solution and extracted with
EtOAc. The combined organics were dried over MgSO4 and con-
centrated in vacuo. The residue was purified by silica gel chroma-
tography with PE/EtOAc (1:1e1:2) to yield aziridine 19 (45 mg, 30%)
and byproduct 20 (42 mg, 28%). Data for 19: colorless oil; IR (film)
nmax: 2928, 2854, 1741, 1465, 1250, 1091 cmꢁ1; 1H NMR (400 MHz,
To a solution of 19 (40 mg, 0.10 mmol) in CH2Cl2 (1 mL) at 0 ꢀ
was added Ac2O (20 mL, 0.21 mmol). The mixture was stirred for 1 h,
C
then quenched with std NaHCO3 solution and extracted with EtOAc.
The combined organics were dried over MgSO4 and concentrated to
give a residue, which was purified by silica gel chromatography
with PE/EtOAc (8:1) to yield an inseparable mixture of 21a and 21b
(45 mg, 95%). For the mixture: 1H NMR (400 MHz, CDCl3)
d 5.40 (s,
1H), 4.79e4.65 (m, 2H), 4.44 (s, 1H), 4.13e4.03 (m, 2H), 3.89e3.78
(m, 1H), 3.74 (s, 6H), 3.70 (s, 1H), 3.47 (d, J¼9.8 Hz, 1H), 3.42e3.28
(m, 6H), 3.25 (s, 3H), 3.23 (s, 3H), 2.92 (d, J¼13.4 Hz, 1H), 2.71 (d,
J¼6.8 Hz, 1H), 2.57 (t, J¼7.7 Hz, 1H), 2.50e2.29 (m, 4H), 2.20 (s, 3H),
2.10 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.92e1.82 (m, 2H), 1.80e1.46
(m, 6H), 0.89 (s, 18H), 0.03 (s, 12H).
CDCl3)
d
3.95 (s, 1H), 3.72 (s, 3H), 3.40 (d, J¼9.7 Hz, 1H), 3.28 (s, 3H),
3.25 (d, J¼9.7 Hz, 1H), 2.87 (s, 2H), 2.51 (s, 1H), 2.33 (s, 1H), 2.14 (d,
J¼5.1 Hz, 1H), 2.06e1.97 (m, 2H), 1.86 (t, J¼14.4 Hz, 1H), 1.77 (dd,
J¼13.3, 5.0 Hz, 1H), 1.44 (td, J¼13.6, 3.2 Hz, 1H), 1.29e1.15 (m, 1H),
0.87 (s, 9H), 0.02 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 173.6, 79.0,
69.7, 56.8, 55.8, 51.8, 49.4, 39.4, 37.2, 33.0, 31.5, 28.1, 25.9, 25.2, 20.4,
18.3, ꢁ5.5; HRMS (ESI) calcd for C20H36NO4Siþ [MþH]þ 382.2414,
found 382.2346.
4.17. Preparation of tricyclic amine 22a and 22b
Data for 20: colorless oil; IR (film) nmax: 2935, 2821, 1755,
1487 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
5.65 (d, J¼5.2 Hz, 1H), 5.57
To a solution of 19 (438 mg,1.15 mmol) in DMF (6 mL) was added
iodoethane (0.18 mL, 2.3 mmol). The mixture was stirred at 30 ꢀC
for 1 h, then NaOAc (470 mg, 5.75 mmol) was added and stirring
was continued for another 5 h. The mixture was poured into 100 mL
EtOAc and washed with brine (3ꢂ20 mL). The organics were dried
over MgSO4 and concentrated to give a residue, which was purified
by silica gel chromatography with PE/EtOAc (15:1e5:1) to yield 22a
(415 mg, 77%) and 22b (108 mg, 20%). Data for 22a: white solid; mp:
140e142 ꢀC; IR (KBr) nmax: 2924, 2851, 1741, 1464, 1373, 1243,
(d, J¼5.2 Hz, 1H), 4.59 (d, J¼6.7 Hz, 1H), 3.83 (d, J¼3.7 Hz, 1H), 3.69
(s, 3H), 3.42 (d, J¼9.3 Hz, 1H), 3.32 (d, J¼9.3 Hz, 1H), 3.26 (s, 3H),
2.95 (d, J¼6.7 Hz, 1H), 2.88 (d, J¼12.0 Hz, 1H), 2.44 (d, J¼12.0 Hz,
1H), 1.91e1.76 (m, 1H), 1.51e1.35 (m, 1H), 1.34e1.17 (m, 2H), 0.90 (s,
9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 174.5,
136.1, 133.6, 77.6, 72.3, 72.2, 63.7, 56.2, 53.1, 52.0, 45.0, 44.9, 25.9,
20.8, 18.8, 18.1, ꢁ5.5, ꢁ5.6; HRMS (ESI) calcd for C20H35NNaO4Siþ
[MþNa]þ 404.2233, found 404.2228.
1083 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 4.96e4.78 (m, 1H),
3.76e3.70 (m, 1H), 3.69 (s, 3H), 3.41 (d, J¼14.1 Hz, 1H), 3.31 (d,
J¼9.7 Hz, 1H), 3.25 (d, J¼9.7 Hz, 1H), 3.24 (s, 3H), 2.67e2.32 (m, 5H),
2.20e2.08 (m, 1H), 1.94 (s, 3H), 1.93e1.76 (m, 3H), 1.58e1.49 (m,
2H), 1.04 (t, J¼7.1 Hz, 3H), 0.87 (s, 9H), 0.00 (s, 6H); 13C NMR
4.14. Preparation of aziridine 19 with PIDA
To a solution of 18 (865 mg, 2.2 mmol) in DCE (180 mL) were
added silica gel (1.7 g), K2CO3 (608 mg, 4.4 mmol), and PIDA
(870 mg, 2.7 mmol). The mixture was stirred at rt for 30 min,
and heated to 50 ꢀC for 1 h. Then directly filtered and wash with
CHCl3/MeOH (5:1). The filtrate was concentrated in vacuo to give
a residue, which was purified by silica gel chromatography with
PE/EtOAc (1:1) to yield aziridine 19 (600 mg, 70%).
(100 MHz, CDCl3)
d 173.4, 170.4, 79.9, 78.5, 71.6, 69.2, 68.6, 56.9,
53.2, 51.3, 48.7, 39.2, 37.3, 31.5, 28.6, 25.9, 24.0, 21.2, 18.3, 13.2, ꢁ5.5;
HRMS (ESI) calcd for C24H44NO6Siþ [MþH]þ 470.2938, found
470.2940. Crystal data: C24H43NO6Si, M¼469.68, monoclinic,
ꢀ
3
ꢀ
ꢀ
ꢀ
b
a¼7.8927(3) A, b¼28.7461(14) A, c¼12.5666(8) A,
¼106.681(6)ꢀ,
V¼2731.2(2) A , T¼293.15, space group P21/n, Z¼4,
m
(Mo K
a
)¼0.121,
11,894 reflections measured with 2.8239ꢃ
q
ꢃ29.1888ꢀ scan, 5575
4.15. Preparation of methyl quaternary ammonium salt of 19
unique (Rint¼0.0250), which were used in all calculations. The final
wR2 was 0.2042 (all data) and R1 was 0.0736 (>2s(I)). CCDC refer-
To a solution of 19 (38 mg, 0.1 mmol) in CH2Cl2 (1 mL) was added
CH3I (31 mL, 0.5 mmol). After being stirred at rt for 30 min, the
ence number: CCDC 927431.
Data for 22b: white solid; mp: 86e88 ꢀC; IR (KBr) nmax: 2936,
reaction mixture was concentrated in vacuo to get nearly pure
methyl quaternary ammonium salt of 19 (52 mg, 100%). Further
purification was completed through flash silica gel chromatography
with CHCl3/CH3OH (5:1) or by recrystallization. Data for methyl
quaternary ammonium salt of 19: white solid; mp: 173e175 ꢀC; IR
(KBr) nmax: 2931, 2860, 1724, 1632, 1463, 1253, 1101 cmꢁ1; 1H NMR
2890, 1722, 1532, 1355 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 5.02 (s,
1H), 3.91 (s, 1H), 3.67 (s, 3H), 3.49 (d, J¼9.3 Hz, 1H), 3.30 (d,
J¼9.3 Hz, 1H), 3.20 (s, 3H), 2.84 (d, J¼3.4 Hz, 1H), 2.66 (d, J¼11.9 Hz,
1H), 2.57e2.37 (m, 3H), 2.14 (d, J¼11.9 Hz, 1H), 2.07 (d, J¼15.7 Hz,
1H), 1.99 (s, 3H), 1.93 (d, J¼12.5 Hz, 1H), 1.86e1.74 (m, 2H), 1.50 (d,
J¼13.7 Hz, 1H), 1.33e1.27 (m, 1H), 1.02 (t, J¼7.1 Hz, 3H), 0.88 (s, 9H),
(400 MHz, CDCl3)
d
4.30 (d, J¼4.7 Hz, 1H), 4.23 (s, 1H), 4.18 (d,
0.03 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 173.1, 169.9, 79.6, 78.4,
J¼4.7 Hz, 1H), 3.88 (d, J¼13.2 Hz, 1H), 3.81 (s, 3H), 3.56 (d,
J¼10.0 Hz, 1H), 3.47 (s, 3H), 3.39 (d, J¼10.0 Hz, 1H), 3.30 (s, 3H), 3.24
(d, J¼13.2 Hz, 1H), 2.75 (d, J¼15.2 Hz, 1H), 2.50 (d, J¼5.2 Hz, 1H),
2.26e2.13 (m, 2H), 1.79 (t, J¼14.7 Hz, 1H), 1.65e1.52 (m, 1H), 1.43 (d,
J¼13.6 Hz, 1H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR
71.6, 64.6, 61.7, 56.3, 53.6, 51.4, 51.0, 39.4, 38.3, 30.8, 26.9, 25.9, 21.1,
19.7, 18.2, 12.5, ꢁ5.5, ꢁ5.5; HRMS (ESI) calcd for C24H44NO6Siþ
[MþH]þ 470.2938, found 470.2940.
(100 MHz, CDCl3)
d
169.2, 76.0, 68.3, 56.9, 56.7, 56.3, 54.6, 53.1, 50.1,
Acknowledgements
49.3, 36.3, 30.4, 27.2, 26.1, 25.8, 20.7, 18.1, ꢁ5.4, ꢁ5.6; HRMS (ESI)
calcd for C21H38NO4Siþ [MꢁI]þ 396.2570, found 396.2289. Crystal
This paper is dedicated to professor Guo-Qiang Lin on the oc-
casion of his 70th birthday. Financial support for this work was
provided by the National Natural Science Foundation of China
(No. 30873147, No. 20902061, and No. 21272163).
ꢀ
data: C21H40INO5Si, M¼541.53, monoclinic, a¼7.2844(2) A,
3
ꢀ
ꢀ
ꢀ
ꢀ
b¼33.8783(9) A, c¼10.5399(2) A,
b
¼97.380(2) , V¼2579.52(12) A ,
T¼135.00(10), space group P21/c, Z¼4,
m
(Mo K
a
)¼1.316, 10,405

Z.-G. Liu et al. / Tetrahedron 69 (2013) 5431e5437
5437
18. Kraus, G. A.; Andersh, B.; Su, Q.; Shi, J. Tetrahedron Lett. 1993, 34, 1741e1744.
19. Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J. A.; Whiting, D. A. J. Chem.
Soc., Perkin Trans. 1 1998, 4047e4055.
20. Kraus, G. A.; Kesavan, S. Tetrahedron Lett. 2005, 46, 1111e1113.
21. Liu, Z. G.; Xu, L.; Chen, Q. H.; Wang, F. P. Tetrahedron 2012, 68, 159e165.
22. Cheng, H.;Xu,L.;Chen,D.L.;Chen, Q.H.;Wang,F. P. Tetrahedron2012, 68,1171e1176.
23. Bariyanga, J.; Johnson, M. T.; Mmutlane, E. M.; Neuse, E. W. J. Inorg. Organomet.
Polym. Mater. 2005, 15, 335e340.
Supplementary data
1H and 13C NMR spectra for all new compounds and NOEDS for
compound 14. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.04.102.
24. Priefer, R.; Farrell, P. G.; Harpp, D. N. Synthesis 2002, 18, 2671e2673.
25. Tsuchida, H. ,; Tamura, M.; Hasegawa, E. J. Org. Chem. 2009, 74, 2467e2475.
26. Rouillard, A.; Bonin, M. A.; Deslongchamps, P. Helv. Chim. Acta 2003, 86,
3730e3739.
References and notes
1. Wang, F. P.; Chen, Q. H. In The Alkaloids: Chemistry and Biology; Cordell, G. A.,
Ed.; Elsevier Science: USA, 2010; Vol. 69, pp 1e577.
2. Manske, R. H. F. Can. J. Res. 1938, 16B, 57e60.
3. Pelletier, S. W.; Mody, N. V.; Varughese, K.; Maddry, J. A.; Desai, H. K. J. Am.
Chem. Soc. 1981, 103, 6536e6538.
4. Drasdo, A.; Caulfield, M.; Bertrand, D.; Bertrand, S.; Wonnacott, S. Mol. Cell.
Neurosci. 1992, 3, 237e243.
5. Wonnacott, S.; Alberquerque, E. X.; Bertrand, D. Methods in Neurosciences;
27. Meyer, W. L.; Sigel, C. W.; Hoff, R. J.; Goodwin, T. E.; Manning, R. A.; Schroeder,
P. G. J. Org. Chem. 1977, 42, 4131e4136.
28. Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43,
5350e5352.
29. Haruta, J. I.; Nishi, K.; Matsuda, S.; Akai, S.; Tamura, Y.; Kita, Y. J. Org. Chem. 1990,
55, 4853e4859.
30. Sharma, G. V. M.; Mahalingam, A. K.; Nagarajan, M.; Ilangovan, A.; Radhak-
rishna, P. Synlett 1999, 1200e1202.
31. Werz, D. B.; Seeberger, P. H. Angew. Chem., Int. Ed. 2005, 44, 6315e6318.
32. Miriyala, B.; Bhattacharyya, S.; Williamson, J. S. Tetrahedron 2004, 60,
1463e1471.
33. Nagata, W.; Hirai, S.; Kawata, K.; Aoki, T. J. Am. Chem. Soc. 1967, 89, 5045e5046.
34. Nagata, W.; Hirai, S.; Kawata, K.; Okumura, T. J. Am. Chem. Soc. 1967, 89,
5046e5048.
35. Carman, R. M.; Derbyshire, R. P. C. Aust. J. Chem. 2003, 56, 319e322.
36. Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656e3665.
37. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523e2584.
38. Dauban, P.; Dodd, R. H. Synlett 2003, 1571e1586.
39. Dauban, P.; Dodd, R. H. Org. Lett. 2000, 2, 2327e2329.
40. Padwa, A.; Stengel, T. Org. Lett. 2002, 4, 2137e2139.
41. The multiplicity of the signal of proton on the carbon attached the acetoxyl
group can be used to differentiate the two isomers, since the signal of the
1993; Vol. 12263.
6. Loscher, W.; Potschka, H.; Wlaz, P.; Danysz, W.; Parsons, C. G. Eur. J. Pharmacol.
2003, 466, 99e111.
7. Goodall, K. J.; Barker, D.; Brimble, M. A. Synlett 2005, 1809e1827.
8. Wiesner, K.; Tsai, T. Y. R.; Huber, K.; Bolton, S. E.; Vlahov, R. J. Am. Chem. Soc.
1974, 96, 4990e4992.
9. Wiesner, K.; Tsai, T. Y. R.; Nambiar, K. P. Can. J. Chem. 1978, 56, 1451e1454.
10. Wiesner, K. Pure Appl. Chem. 1979, 51, 689e703.
11. Ismail, K. A.; Bergmeier, S. C. Eur. J. Med. Chem. 2002, 37, 469e474.
12. Goodall, K. J.; Brimble, M. A.; Barker, D. Tetrahedron 2012, 68, 5759e5778.
13. Grangier, G.; Trigg, W. J.; Lewis, T.; Rowan, M. G.; Potter, B. V. L.; Blagbrough, I. S.
Tetrahedron Lett. 1998, 39, 889e892.
14. Davies, A. R. L.; Hardick, D. J.; Blagbrough, I. S.; Potter, B. V. L.; Wolstenholme, A.
J.; Wonnacott, S. Biochem. Soc. Trans. 1997, 25, 545s.
15. Callis, D. J.; Thomas, N. F.; Pearson, D. P. J.; Potter, B. V. L. J. Org. Chem. 1996, 61,
4634e4640.
proton at C-17 of 21b appears as a broadened singlet at
d
¼5.40 ppm due to the
16. Coates, P. A.; Blagbrough, I. S.; Rowan, M. G.; Pearson, D. P. J.; Lewis, T.; Potter, B.
dihedral angle between H-7 and H-17 is ca. 90ꢀ based on observation of mo-
V. L. J. Pharm. Pharmacol. 1996, 48, 210e213.
17. Barker, D.; McLeod, M. D.; Brimble, M. A.; Savage, G. P. Tetrahedron Lett. 2002,
43, 6019e6022.
lecular model of 21b, while the corresponding proton signal of 21a shows as
a multiplet at
d
¼4.72 ppm.