Synthetic approach to the functionalized tricyclic core of atropurpuran

Article abstract of DOI:10.1016/j.tet.2015.11.050

A strategy for synthesizing the tricyclic fragment 5 of atropurpuran 1 is reported. Rings A and C of atropurpuran were assembled stereoselectively via two intramolecular Michael additions. The advanced tricyclic skeleton 5 shows the correct functionality and stereochemistry for atropurpuran 1, so the skeleton may serve as a key intermediate in its total synthesis.

Full text of DOI:10.1016/j.tet.2015.11.050

Tetrahedron 72 (2016) 347e353
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic approach to the functionalized tricyclic core of
atropurpuran
*
*
Huan Chen, Xiao-Huan Li, Jing Gong, Hao Song , Xiao-Yu Liu, Yong Qin
Key Laboratory of Drug Targeting of Ministry of Education, West China School of Pharmacy and State Key Laboratory of Biotherapy, Sichuan University,
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 16 October 2015
Received in revised form 19 November 2015
Accepted 23 November 2015
Available online 26 November 2015
A strategy for synthesizing the tricyclic fragment 5 of atropurpuran 1 is reported. Rings A and C of
atropurpuran were assembled stereoselectively via two intramolecular Michael additions. The advanced
tricyclic skeleton 5 shows the correct functionality and stereochemistry for atropurpuran 1, so the
skeleton may serve as a key intermediate in its total synthesis.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Atropurpuran
Diterpene
Michael addition
Organocatalyst
1. Introduction
stereocenters. Here we describe a substantial advance toward the
total synthesis of atropurpuran 1 by constructing the tricyclic
The genus Aconitum, an important source of traditional medi-
cines, is widely used in China to treat various diseases, including
rheumatic and neurological disorders as well as pain symptoms.1
Most compounds isolated from Aconitum species are structurally
classified as C18-, C19- and C20-diterpenoid alkaloids.2 In 2009,
Wang et al. reported the isolation of a novel non-alkaloidal diter-
pene, atropurpuran 1, from the roots of A. hemsleyanum var.
atropurpureum.3
framework (fragment D) via intramolecular Michael addition. This
fragment may serve as a key intermediate in a future synthetic
approach.
2. Results and discussion
We devised
a retrosynthetic analysis of atropurpuran 1
(Scheme 1) based on the biosynthetic pathway proposed by Wang
and co-workers.3,7 We envisioned that 1 could be accessed via
functional group transformations from the advanced intermediate
2. The critical ring D of atropurpuran could be forged through an
Atropurpuran 1 features an unprecedented cage-like skeleton
containing an unusual tetracyclo[5.3.3.04,9.04,12]-tridecane unit
(rings BeE) fused to a highly functionalized cyclohexene fragment
(ring A) with two adjacent chiral quaternary centers (Fig. 1). Be-
cause of its intriguing structure, atropurpuran has been an attrac-
tive target for synthetic chemists around the world. The groups of
Kobayashi4 and Hsung5 reported elegant approaches, respectively,
to the pentacyclic core (fragment A) and to rings BeD (fragment B)
of atropurpuran 1. Work from our group led to the preparation of
ring A (fragment C) via an organocatalytic asymmetric intra-
molecular Michael addition.6 Despite these advances and con-
tinuing efforts, the total synthesis of atropurpuran 1 has not yet
been reported. This reflects the difficulty in constructing its rigid
pentacyclic structure and in installing its three quaternary
* Corresponding authors. Tel./fax: þ86 28 85503842; e-mail addresses:
songhao@scu.edu.cn (H. Song), yongqin@scu.edu.cn (Y. Qin).
Fig. 1. Structure of atropurpuran 1 and synthesized intermediates.
http://dx.doi.org/10.1016/j.tet.2015.11.050
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

348
H. Chen et al. / Tetrahedron 72 (2016) 347e353
Table 1
intramolecular Michael addition of enone 3, while rings B and E
could be constructed via a DielseAlder cycloaddition and meth-
ylenation from compound 4. Several functional group manipula-
tions of 4 would simplify it to the tricycle 5. Transformation of the
bicyclic intermediate 6 into 5 could be achieved via an intra-
molecular Michael addition. Compound 6 could be generated
from the decalin 7, containing four contiguous stereogenic cen-
ters, which could be derived stereoselectively from aldehyde 8 via
an intramolecular organocatalytic Michael addition.8
The organocatalytic Michael addition reaction of 8a
Entry
Solvent
Catalyst
Time (h)
Yield (%)b
ee (%)c
drc
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
DME
Et2O
CH3CN
DMF
cat. I
10
12
>5 days
>5 days
20d
40
<5
<5
dd
20
40
26
35
30
de
de
cat. II
cat. III
cat. IV
cat. V
cat. II
cat. II
cat. II
cat. II
cat. II
>99%
>19:1
de
de
de
de
1
de
de
10
10
72
24
48
94.5
>99%
96.6%
95.8%
85.4%
>19:1
5:1
7.5:1
4.7:1
1.3:1
10
a
Unless otherwise noted, reactions were performed with 1 equiv of 8 and 20 mol
% of catalyst at 25 ꢀC.
b
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H).
Complex mixtures.
The ee and dr values were not determined.
c
d
e
Scheme 1. Retrosynthetic analysis of atropurpuran 1.
Our synthetic endeavors began with the preparation of cyclo-
hexadienone 8 from the known compound 10 (Scheme 2), which
was accessed in three steps from the commercially available acid 9.9
Reduction of the ketone carbonyl group in 10 using NaBH4, fol-
lowed by silyl protection of the resulting alcohol afforded ester 12
in high yield. This ester was then converted into aldehyde 13 in the
presence of DIBAL-H. After removal of the benzyl group via hy-
drogenation, phenol 14 was mixed with PhI(OAc)2/AcOH, generat-
ing dearomatization product 8 in 60% yield.10
6e10), affording the highest stereoselectivity (ee%>99%,
dr>19:1) and moderate yield (40%) (entry 2). We speculated that
the racemic starting aldehyde 8 might undergo a kinetic reso-
lution during the reaction. Except for generation of the desired
product 7, the other enantiomer of 8 was surprisingly converted
to phenol 15 as a main byproduct in most cases. Since its for-
mation involves a reductive CeC bond cleavage, future studies
are needed to explain how it forms under these reaction
conditions.
The stereochemistry of aldehyde 7 was established by analyzing
its methyl ester derivative 16 (Scheme 3). This derivative was ob-
tained efficiently by oxidizing the aldehyde to carboxylic acid, fol-
lowed by treatment with EDCI/DMAP/MeOH. Extensive NOE
experiments (Scheme 3) clearly indicated a cis-fused decalin sys-
tem, as well as trans relationships between aldehyde and OTIPS
substituents on the newly formed ring.
Scheme 2. Synthesis of the Michael addition precursor 8.
The organocatalytic Michael addition has proven to be a ver-
satile approach for stereocontrolled synthesis of complex mole-
cules with multiple stereocenters.8 With precursor 8 in hand, we
investigated its organocatalytic Michael addition using several
proline-type catalysts (Table 1, entries 1e5). Only catalyst II
afforded the desired addition product 7 as a major stereoisomer,
while the other screened catalysts gave low conversion (<5%, cat.
III and IV), required long reaction time (>5 days), or generated
complex mixtures (cat. I and V). Screening various additives, such
as phthalimide, picric acid, and p-toluenesulfonic acid, failed to
improve yield (not shown in Table 1).11 Screening various sol-
vents showed that CH2Cl2 gave the best results (Table 1, entries 2,
Scheme 3. Structural determination of 7.
Having successfully assembled ring C of atropurpuran, we con-
tinued the synthesis as planned, but encountered several chal-
lenges while attempting to forge ring A (Scheme 4). The aldehyde
functionality in compound 7 was selectively protected via treat-
ment with 1,3-propanediol and BF3$Et2O in CH2Cl2. Efforts to get
enone 17 to undergo DielseAlder cycloaddition with diene 18 were
unsuccessful.12 Attempts to achieve double Michael addition be-
tween 17 and enone 20 also failed,13 possibly due to steric hin-
drance of the methyl groups and the protected alcohol.

H. Chen et al. / Tetrahedron 72 (2016) 347e353
349
inseparable diastereoisomers (5 and 32) in a 1:1.4 ratio. The re-
action appears to proceed via two transition states 30 and 31, which
resulted in a cis relationship between H-5 and C19 in both products
5 and 32 based on the E geometric character in alkene 6. We con-
sidered the stereochemistry at C5, C8, and C10 unimportant at this
stage, since it could be eliminated later during assembling rings B
and E via DielseAlder reaction in the planned total synthesis.
Scheme 4. Attempts to construct ring A.
We then focused on forming ring A via an intramolecular Mi-
chael addition, in which the first task was to introduce an aldehyde-
terminated side chain at C10. The acetoxyl group in 17 was used as
a handle to incorporate the C10 stereogenic center. Intramolecular
Michael addition of 17 using LDA/HMPA at ꢁ78 ꢀC provided 22 in
73% yield (Scheme 5). The cis stereochemical outcome was assigned
on the basis of the obtained kinetic product under the reaction
conditions, where attacking of the enolate to the enone was sup-
posed to proceed from the less hindered convex face. Protecting the
ketone carbonyl group of 22 using neopentyl glycol with TsOH
afforded the desired 23. The lactone ring of 23 was then opened by
reduction with LiAlH4, followed by selective mono-protection of
the primary alcohol with a benzyl group, finally leading to the in-
termediate 24. Treating this compound with SOCl2 in pyridine at
0 ꢀC and eliminating the tertiary alcohol in 24 smoothly furnished
alkene 25. Simultaneous benzyl deprotection and alkene reduction
in the presence of H2 over Pd/C in MeOH gave compound 26 as
a single isomer; hydrogenation occurred exclusively from the less
hindered convex face. Alcohol oxidation using IBX gave the antic-
ipated aldehyde 27.
Scheme 6. Successful assembly of ring A.
3. Conclusion
In summary, we have synthesized the tricyclic fragment 5 of
atropurpuran (1) in 18 linear steps from the known keto ester 10.
Our strategy features the first application of an oxidative dear-
omatization/organocatalytic Michael addition approach to bicyclic
compound 7, thereby establishing three chiral centers in one pot.
Ring A of atropurpuran 1 was assembled via another intramolecular
Michael addition of diketone 6. The functionalized tricyclic core 5
may serve as a later-stage intermediate in a future total synthesis of
atropurpuran, and such efforts are underway in our laboratory.
4. Experimental section
4.1. General
All commercially available reagents were used without further
purification. All solvents were dried and distilled before use; THF
and Et2O were distilled from sodium/benzophenone ketyl;
dichloromethane was distilled from calcium hydride; CHCl3 was
distilled from P2O5. Chromatography was conducted by using
200e300 mesh silica gel. All new compounds gave satisfactory
spectroscopic analyses (1H NMR, 13C NMR, HRMS). NMR spectra
were recorded on 400 MHz NMR spectrometer. HRMS spectra were
obtained by the FAB method. Chiral HPLC analysis was performed
on HP Agilent 1260 apparatus.
4.2. Ethyl 5-(4-(benzyloxy)phenyl)-3-hydroxypentanoate (11)
Scheme 5. Establishment of the C10 chiral center.
The final steps of ring A synthesis are shown in Scheme 6. The
organolithium species was generated in situ from tributylstannane
28 using n-BuLi, and then added to aldehyde 27 to afford 29 in 68%
yield.14 Subsequent deacetalization with TsOH in acetone and IBX
oxidation of 29 gave the desired ketone 6 in 88% yield over two
steps. The E-alkene was confirmed based on NOE correlations ob-
served between H-3 and H2-19. Ultimately, ring A of atropurpuran
was generated in 76% yield via an intramolecular Michael addition
of 6 in the presence of t-BuOK in THF, leading to a pair of
To a dry round-bottom flask flushed with argon was added the
known compound 10 (320 mg, 1.0 mmol) and MeOH (25 mL). The
solution was cooled to 0 ꢀC, and was added NaBH4 (36.6 mg,
1.0 mmol) in small portions at 0 ꢀC. The reaction mixture was fur-
ther stirred for 1 h before it was quenched by addition of saturated
NH4Cl (10 mL) at 0 ꢀC. The MeOH was concentrated in vacuo. Then
the aqueous layer was extracted with EtOAc (3ꢂ20 mL). The com-
bined organic layers were dried over MgSO4 and concentrated in
vacuo. The crude product was subjected to a silica gel column

350
H. Chen et al. / Tetrahedron 72 (2016) 347e353
eluting with EtOAc: petroleum ether (1: 5) to give 11 (287 mg, 89%)
as pale solid. 1H NMR (400 MHz, CDCl3)
50.32, 68.07, 115.28, 129.24, 133.39, 153.89, 203.12 ppm; HRMS
d
1.26 (t, J¼7.2 Hz, 3H), 1.68
(MþNaþ) calcd for C20H34NaO3Si 337.2175, found 337.2143.
(m, 1H), 1.80 (m, 1H), 2.46 (d, J¼15.6 Hz, 1H), 2.48 (d, J¼9.6 Hz, 1H),
2.62 (m, 1H), 2.76 (m, 1H), 3.07 (s, 1H), 3.99 (m, 1H), 4.15 (q,
J¼7.2 Hz, 2H), 5.03 (s, 2H), 6.89 (d, J¼8.8 Hz, 2H), 7.10 (d, J¼8.8 Hz,
4.6. 4-Oxo-1-(5-oxo-3-((triisopropylsilyl)oxy)pentyl)cyclo-
hexa-2,5-dien-1-yl acetate (8)
2H), 7.31e7.43 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)
d 14.09,
30.76, 38.23, 41.23, 60.65, 67.07, 69.92, 114.69, 127.39, 127.81,
128.48, 129.30, 133.98, 137.08, 156.96, 172.97 ppm; HRMS (MþNaþ)
calcd for C20H24NaO4 351.1572, found 351.1566.
(Diacetoxyiodo)benzene (377 mg, 1.2 mmol) was added to
a solution of phenol 14 (410 mg, 1.2 mmol) in AcOH (15 mL) at 25 ꢀC
and the resulting solution stirred for 20 min. The reaction was
added saturated NaHCO3 until the pH¼7. Then the aqueous layer
was extracted with EtOAc (3ꢂ20 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The crude
product was subjected to a silica gel column eluting with EtOAc:
petroleum ether (1: 3) to give 8 (287 mg, 60%) as yellow oil. 1H NMR
4.3. Ethyl 5-(4-(benzyloxy)phenyl)-3-((triisopropylsilyl)oxy)
pe-ntanoate (12)
Under argon, to a 50 mL flask was added 11 (330 mg, 1.0 mmol),
dry CH2Cl2 (30 mL) and 2,6-lutidine (292
m
L, 2.5 mmol). The solu-
L, 2.0 mmol) was
(400 MHz, CDCl3)
d
1.04 (s, 21H), 1.59 (m, 2H), 1.89 (td, J¼12.0,
tion was cooled to 0 ꢀC, and then TIPSOTf (540
m
7.6 Hz 2H), 2.06 (s, 3H), 2.61 (dd, J¼6.0, 2.0 Hz, 2H), 4.36 (m, 1H),
added dropwise, the reaction mixture was further stirred for 1 h
before it was quenched by addition of saturated NH4Cl (10 mL) at
0 ꢀC. Then the aqueous layer was extracted with CH2Cl2 (3ꢂ20 mL).
The combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The crude product was subjected to a silica gel
column eluting with EtOAc: petroleum ether (1: 60) to give 12
6.27 (d, J¼10.0 Hz, 2H), 6.79 (d, J¼10.4 Hz, 2H), 9.81 (s, 1H) ppm; 13
C
NMR (100 MHz, CDCl3)
d 12.33, 17.63, 18.00, 21.14, 30.99, 34.08,
50.37, 67.21, 76.37, 115.21, 129.04, 148.06, 169.35, 185.07,
201.14 ppm; HRMS (MþNaþ) calcd for C22H36NaO5Si 431.2230,
found 431.21954.
(463 mg, 95%) as pale oil. 1H NMR (400 MHz, CDCl3)
d 0.85 (m, 3H),
4.7. (1R,2R,4aR,8aS)-1-Formyl-7-oxo-2-((triisopropylsilyl)
oxy)-1,2,3,4,4a,7,8,8a-octahydronaphthalen-4a-yl acetate (7)
and 4-hydroxyphenyl acetate (15)
1.06 (s, 18H), 1.27 (t, J¼7.2 Hz, 3H), 1.85 (m, 2H), 2.52 (d, J¼2.8 Hz,
1H), 2.55 (d, J¼3.6 Hz, 1H), 2.61 (m, 2H), 4.12 (q, J¼7.2 Hz, 2H), 4.35
(m, 1H), 5.03 (s, 2H), 6.90 (d, J¼8.4 Hz, 2H), 7.10 (d, J¼8.4 Hz, 2H),
7.25e7.43 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)
d 12.48, 17.70,
Catalyst II (12.7 mg, 0.04 mmol) was added a solution of 8
(80 mg, 0.2 mmol) in CH2Cl2 (15 mL) at 0 ꢀC. The resulting mixture
was stirred at 0 ꢀC for 12 h before it was quenched by addition of
saturated NH4Cl (10 mL) at 0 ꢀC. Then the aqueous layer was
extracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The crude
product was subjected to a silica gel column eluting with EtOAc:
petroleum ether (1: 5) to give 7 (11.8 mg, 40%) and 15 (10.4 mg,
18.04, 29.97, 39.46, 42.22, 60.26, 69.08, 69.90, 114.69, 127.34, 127.77,
128.45, 129.12, 134.39, 137.13, 156.92, 171.54 ppm; HRMS (MþNaþ)
calcd for C29H44NaO4Si 507.2907, found 507.2901.
4.4. 5-(4-(Benzyloxy)phenyl)-3-((triisopropylsilyl)oxy)penta-
nal (13)
Under argon, to a 50 mL flask was added 12 (520 mg, 1.2 mmol)
and dry CH2Cl2 (30 mL). The solution was cooled to ꢁ78 ꢀC, and
then DIBAL-H (1M in toluene) (1.76 mL, 1.8 mmol) was added
dropwise, the reaction mixture was further stirred for 1 h before it
was quenched by addition of MeOH (10 mL) at ꢁ78 ꢀC. After stirring
at ꢁ78 ꢀC for 10 min, added saturated C4O6H4KNa (30 mL). Then the
aqueous layer was extracted with CH2Cl2 (3ꢂ20 mL). The combined
organic layers were dried over MgSO4 and concentrated in vacuo.
The crude product was subjected to a silica gel column eluting with
EtOAc: petroleum ether (1: 50) to give 13 (445 mg, 86%) as col-
35%) as colourless oil.
20
7:[
a]
¼þ 93 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d 1.06 (s,
D
21H), 1.75 (m, 2H), 2.00 (m, 2H), 2.13 (s, 3H), 2.37 (dd, J¼17.6,
13.2 Hz, 1H), 2.69 (m, 2H), 3.42 (m, 1H), 4.40 (m, 1H), 5.92 (d,
J¼10.4 Hz, 1H), 7.11 (d, J¼10.4 Hz, 1H), 9.92 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3)
d 12.31, 18.01, 21.72, 29.56, 30.05, 36.68, 38.23,
55.29, 66.18, 78.36, 127.39, 152.58, 169.79, 195.76, 203.21 ppm;
HRMS (MþNaþ) calcd for C22H36NaO5Si 431.2230, found 431.2224.
HPLC: DAICEL AD-H Chiralpak, 97:3 Hexane/isopropanol, flow
1.0 mL/min; retention time: major enantiomer 8.52 min, minor
enantiomer 10.04 min.
ourless oil. 1H NMR (400 MHz, CDCl3)
d 1.01 (m, 3H), 1.05 (s, 18H),
1.89 (m, 2H), 2.62 (m, 4H), 4.37 (m, 1H), 5.04 (s, 2H), 6.91 (d,
15: 1H NMR (400 MHz, CDCl3)
d 2.28 (s, 3H), 5.09 (s, 1H), 6.77 (d,
J¼8.8 Hz, 2H), 7.08 (d, J¼8.8 Hz, 2H), 7.33e7.43 (m, 5H), 9.86 (t,
J¼8.8 Hz, 2H), 6.92 (d, J¼8.8 Hz, 2H) ppm; 13C NMR (100 MHz,
J¼2.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d
12.46, 18.08, 30.30,
CDCl3) d 21.07, 115.96, 122.44, 144.09, 153.28, 170.18 ppm; HRMS
39.73, 50.38, 68.03, 69.96, 114.81, 127.39, 127.84, 128.51, 129.13,
(MþNaþ) calcd for C8H8O3 152.0473, found 152.0477.
133.88, 137.09, 157.03, 202.10 ppm; HRMS (MþNaþ) calcd for
C
27H40NaO3Si 463.2644, found 463.2600.
4.8. (1R,2R,4aR,8aS)-Methyl 4a-acetoxy-7-oxo-2-((triiso-
propyl-silyl)oxy)-1,2,3,4,4a,7,8,8a-octahydronaphthalene-1-
carboxy-late (16)
4.5. 5-(4-Hydroxyphenyl)-3-((triisopropylsilyl)oxy)pentanal
(14)
To a 50 mL flask was added 7 (100 mg, 0.24 mmol) and CH2Cl2
(30 mL). The mixture was added NaHCO3 (41.2 mg, 0.49 mmol) and
m-CPBA (84.6 mg, 0.49 mmol). The solution was further stirred for
4 h at 25 ꢀC before it was quenched by addition of saturated NH4Cl
(10 mL) at 0 ꢀC. Then the aqueous layer was extracted with CH2Cl2
(3ꢂ20 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. The crude product was subjected to
13 (520 mg, 1.2 mmol), EtOAc (15 mL) and palladium on carbon
(10% Pd/C, wet, 52 mg) was added under a balloon of hydrogen for
24 h. The mixture was then filtrated through Celite. The filtrate was
concentrated in vacuo and purified by silica gel column chroma-
tography eluting with EtOAc: petroleum ether (1: 5) to afford 14
(352 mg, 85%) as colourless oil. 1H NMR (400 MHz, CDCl3)
d 1.01 (m,
3H), 1.05 (s, 18H), 1.89 (m, 2H), 2.62 (m, 4H), 4.37 (m, 1H), 4.94 (s,
a silica gel column eluting with EtOAc: petroleum ether (1: 2) to
20
1H), 6.74 (d, J¼8.4 Hz, 2H), 7.03 (d, J¼8.4 Hz, 2H), 9.87 (t, J¼2.0 Hz,
give S1 (84.2 mg, 81%) as brown oil.15
[
a
]
D
¼þ 50 (c 0.5, CHCl3). 1H
1H) ppm; 13C NMR (100 MHz, CDCl3)
d
12.44, 18.05, 30.30, 39.74,
NMR (400 MHz, CDCl3) d 1.00 (s, 21H), 1.64 (m, 2H), 1.91 (m, 1H),

H. Chen et al. / Tetrahedron 72 (2016) 347e353
351
2.11 (s, 3H), 2.21 (d, J¼11.2 Hz, 1H), 2.41 (dd, J¼18.0, 14.0 Hz, 1H),
(100 MHz, CDCl3)
d
12.89, 18.18, 25.95, 31.48, 32.15, 35.00, 37.09,
2.55 (dd, J¼9.0, 5.2 Hz, 1H), 2.80 (dd, J¼10.2, 4.4 Hz, 1H), 3.28 (dt,
J¼8.0, 5.6 Hz, 1H), 4.24 (m, 1H), 5.88 (d, J¼10.0 Hz, 1H), 7.03 (d,
38.83, 39.72, 41.95, 45.97, 66.54, 67.04, 84.95, 100.33, 174.55,
209.89 ppm; HRMS (MþNaþ) calcd for C25H42NaO5Si 489.2651,
found 489.2642.
J¼10.4 Hz,1H) ppm; 13C NMR (100 MHz, CDCl3)
d 12.50,18.03, 21.71,
29.35, 29.49, 29.57, 37.19, 39.23, 50.07, 66.54, 78.55, 127.20, 152.59,
169.88,176.40,196.32 ppm; HRMS (MþNaþ) calcd for C22H35NaO6Si
423.2206, found 423.2208. To a 50 mL flask was added S1 (150 mg,
0.35 mmol) and PhMe (30 mL). The mixture was added EDCI
(203 mg, 1.06 mmol), DMAP (8.6 mg, 0.07 mmol) and MeOH
4.11. (3a0S,6a0S,70R,80R,10a0R)-70-(1,3-Dioxan-2-yl)-5,5-
dimethyl-80-((triisopropylsilyl)oxy)octahydrospiro[[1,3]di-
oxane-2,50-naphtho[8a,1-b]furan]-20(30H)-one (23)
(143
m
L, 3.5 mmol) at 25 ꢀC. The mixture was further stirred for 4 h
To a 50 mL flask was added 22 (320 mg, 0.68 mmol), 2,2-
dimethyl-1,3-propanediol (107 mg, 1.0 mmol), trimethoxy-
methane (15 mL, 0.13 mmol), Ts-OH (23.6 mg, 0.13 mmol) and tol-
at 70 ꢀC before it was quenched by addition of saturated NH4Cl
(10 mL). Then the aqueous layer was extracted with EtOAc
(3ꢂ20 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. The crude product was subjected to
uene (20 mL). The reaction mixture was further stirred at 25 ꢀC for
1 h before it was quenched by addition of saturated NaHCO3
(20 mL). Then the aqueous layer was extracted with EtOAc
(3ꢂ20 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. The crude product was subjected to
a silica gel column eluting with EtOAc: petroleum ether (1: 10) to
20
give 16 (130 mg, 84%) as colourless solid. [
a
]
¼þ 46 (c 0.5, CHCl3).
D
1H NMR (400 MHz, CDCl3)
d
1.05 (s, 21H), 1.74 (m, 2H), 1.95 (m, 2H),
2.15 (s, 3H), 2.26 (m, 1H), 2.82e2.86 (dd, J¼4.8, 0.4 Hz, 2H), 3.27 (m,
a silica gel column eluting with EtOAc: petroleum ether (1: 8) to
20
1H), 3.66 (s, 3H), 4.29 (m, 1H), 5.91 (d, J¼10.4 Hz, 1H) 7.05 (d,
give 23 (320 mg, 85%) as pale white oil. [
a
]
¼ꢁ 18.33 (c 0.5, CHCl3).
D
J¼10.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d
12.55, 18.08,
1H NMR (400 MHz, CDCl3)
d 0.81 (s, 3H), 1.05 (s, 21H), 1.14 (s, 3H),
21.80, 29.47, 29.64, 37.54, 39.37, 50.35, 51.64, 66.68, 78.69, 127.35,
1.21 (m, 2H), 1.40 (d, J¼13.2 Hz, 1H), 1.66 (dd, J¼14.4, 6.4 Hz, 2H),
1.80 (m, 1H), 1.88 (m, 1H), 2.01 (m, 3H), 2.16 (m, 1H), 2.32 (m, 1H),
2.42 (m, 2H), 3.19 (dd, J¼16.8, 12.4 Hz, 1H), 3.38 (m, 2H), 3.59e3.80
(m, 4H), 4.01 (td, J¼10.8, 4.4 Hz, 1H), 4.10 (td, J¼12.4, 5.6 Hz, 2H),
152.61, 169.95, 172.17, 196.46 ppm; HRMS (MþNaþ) calcd for
C
23H38NaO6Si 438.2438, found 438.2441.
4.9. (1R,2R,4aR,8aS)-1-(1,3-Dioxan-2-yl)-7-oxo-2((triisopro-
pylsilyl)oxy)-1,2,3,4,4a,7,8,8a-octahydronaphthalen-4a-yl ace-
tate (17)
4.98 (d, J¼4.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d 12.89,
18.02, 22.35, 23.16, 26.54, 27.04, 29.72, 29.98, 32.41, 33.86, 34.07,
34.46, 40.57, 45.42, 66.50, 66.86, 66.94, 69.37, 70.28, 85.45, 98.00,
101.04, 176.28 ppm; HRMS (MþNaþ) calcd for C30H52NaO5Si
575.3327, found 575.3374.
Under argon, to a 25 mL flask was added 7 (230 mg, 0.56 mmol),
1,3-propanediol (86 mg, 1.12 mmol) and dry CH2Cl2 (15 mL). The
solution was cooled to 0 ꢀC and then added BF3$Et2O (15
mL,
4.12. (40R,4a0R,70R,80R,8a0S)-40-(2-(Benzyloxy)ethyl)-80-(1,3-
dioxan-2-yl)-5,5-dimethyl-70-((triisopropylsilyl)oxy)octahy-
dro-10H-spiro[[1,3]dioxane-2,20-naphthalen]-4a0-ol (24)
0.11 mmol), then warm to 25 ꢀC for 8 h before it was quenched by
addition of saturated NH4Cl (10 mL) at 0 ꢀC. Then the aqueous layer
was extracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The crude
product was subjected to a silica gel column eluting with EtOAc:
Under argon, to a 50 mL flask was added 23 (350 mg, 0.63 mmol)
and dry THF (20 mL). The solution was cooled to 0 ꢀC, and was
added LAH (29 mg, 0.76 mmol) in small portions at 0 ꢀC. The re-
action mixture was further stirred for 1 h before it was quenched by
addition of saturated NH4Cl (10 mL) at 0 ꢀC. The mixture was then
filtrated through Celite. The filtrate was concentrated in vacuo and
purified by silica gel column chromatography eluting with EtOAc:
petroleum ether (1: 8) to give 17 (200 mg, 76%) as colourless oil.
20
[
a]
¼þ 148 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d 1.07 (s, 21H),
D
1.28 (m, 2H), 1.68 (m, 2H), 1.88 (m, 1H), 2.05 (m, 1H), 2.10 (s, 3H),
2.24 (m, 1H), 2.36 (dd, J¼18.4, 13.6 Hz, 1H), 3.19 (dd, J¼18.4, 5.2 Hz,
1H), 3.35 (dt, J¼13.6 Hz, 1H), 3.60 (td, J¼11.2 Hz, 1H), 3.71 (td,
J¼11.6, 2.4 Hz, 1H), 4.08 (m, 3H), 4.95 (d, J¼3.6 Hz, 1H), 5.91 (d,
J¼10.4 Hz, 1H), 7.11 (d, J¼10.4 Hz, 1H) ppm; 13C NMR (100 MHz,
petroleum ether (1: 2) to afford S2 (335 mg, 95%) as pale white oil.15
20
[a
]
¼þ 44.28 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d 0.82 (s,
D
CDCl3)
d
12.43, 17.95, 21.53, 25.73, 29.40, 30.32, 36.99, 38.53, 45.76,
3H), 1.06 (s, 21H), 1.08 (s, 3H), 1.24 (m, 2H), 1.35 (d, J¼13.2 Hz, 2H),
1.69 (m,1H),1.73e1.83 (m, 4H),1.93e2.10 (m, 4H), 2.19 (m, 2H), 2.45
(s, 1H), 3.21 (dt, J¼14.8 Hz, 1H), 3.35 (t, J¼8.8 Hz, 2H), 3.63e3.70 (m,
5H), 3.77 (td, J¼10.8, 4.0 Hz, 1H), 4.07 (dd, J¼9.6, 5.2 Hz, 2H), 4.15
(dd, J¼6.8, 5.6 Hz, 1H), 4.98 (d, J¼3.6 Hz, 1H) ppm; 13C NMR
66.33, 66.86, 79.51, 102.40, 126.86, 153.23, 169.69, 198.52 ppm;
HRMS (MþNaþ) calcd for C25H42NaO5Si 489.2609, found 489.2642.
4.10. (3aS,6aS,7R,8R,10aR)-7-(1,3-Dioxan-2-yl)-8-((triiso-
propyl-silyl)oxy)octahydro-2H-naphtho[8a,1-b]furan-2,5(3H)-
dione (22)
(100 MHz, CDCl3)
d 12.87, 18.09, 22.45, 22.99, 26.52, 29.20, 29.55,
29.72, 31.44, 31.54, 31.64, 34.55, 35.89, 42.78, 45.10, 62.25, 66.45,
66.98, 67.19, 69.29, 70.14, 71.88, 98.34, 101.58 ppm; HRMS (MþNaþ)
calcd for C30H56NaO5Si 579.3642, found 579.3687. Under argon, to
a 50 mL flask was added S2 (340 mg, 0.61 mmol) and dry DMF
(25 mL). The solution was cooled to 0 ꢀC, and was added NaH
(17.6 mg, 0.73 mmol) in small portions at 0 ꢀC. The reaction mixture
Under argon, to a 50 mL flask was added 17 (450 mg, 0.96 mmol)
and dry THF (25 mL). The solution was cooled to ꢁ78 ꢀC, and then
LDA (1M in THF, 3.84 mL, 3.84 mmol) was added dropwise, the
reaction mixture was further stirred for 30 min before it was
quenched by addition of saturated NH4Cl (20 mL). Then the aque-
ous layer was extracted with EtOAc (3ꢂ20 mL). The combined or-
ganic layers were dried over MgSO4 and concentrated in vacuo. The
crude product was subjected to a silica gel column eluting with
was further added BnBr (145 mL, 1.2 mmol) after stirring for 10 min.
The reaction mixture was further stirred for 1 h at 25 ꢀC before it
was quenched by addition of saturated NH4Cl (10 mL) at 0 ꢀC. Then
the aqueous layer was extracted with EtOAc (3ꢂ25 mL). The com-
bined organic layers were dried over MgSO4 and concentrated in
vacuo. The crude product was subjected to a silica gel column
EtOAc: petroleum ether (1: 3) to give 22 (328 mg, 73%) as yellow oil.
20
[
a]
¼þ 117 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d 0.83 (m, 3H),
D
1.06 (s, 18H), 1.33 (m, 2H), 2.01 (m, 2H), 2.16 (dd, J¼4.4 Hz, 1H), 2.23
(m, 1H), 2.23 (d, J¼6.4 Hz, 1H), 2.42 (m, 1H), 2.47 (d, J¼5.4 Hz, 1H),
2.56 (m, 1H), 2.78 (dt, J¼14.4 Hz, 2H), 2.87 (d, J¼8.8 Hz, 1H), 3.17
(dd, J¼4.8 Hz, 2H), 3.62 (td, J¼11.2 Hz, 1H), 3.74 (td, J¼11.2 Hz, 1H),
4.04 (m, 2H), 4.09 (m, 1H), 4.99 (d, J¼3.6 Hz, 1H) ppm; 13C NMR
eluting with EtOAc: petroleum ether (1: 10) to give 24 (367 mg,
20
93%) as pale white oil. [
CDCl3)
a
]
D
¼þ 41 (c 0.5, CHCl3). 1H NMR (400 MHz,
d
0.83 (s, 3H), 1.05 (s, 3H), 1.06 (s, 21H), 1.24 (m, 2H), 1.33 (d,
J¼13.2 Hz, 2H), 1.61 (m, 2H), 1.64 (d, J¼5.6 Hz, 1H), 1.75e1.82 (m,
3H), 1.85e2.11 (m, 4H), 2.27 (m, 2H), 2.52 (s, 1H), 3.16 (d, J¼14.4 Hz,

352
H. Chen et al. / Tetrahedron 72 (2016) 347e353
1H), 3.33 (t, J¼9.6 Hz, 2H), 3.43 (td, J¼9.2, 4.0 Hz, 1H), 3.57 (q,
J¼5.2 Hz, 1H), 3.64 (t, J¼12.4 Hz, 2H), 4.05 (m, 2H), 4.15 (d, J¼9.6 Hz,
combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The crude product was subjected to a silica gel
1H), 4.47 (s, 2H), 4.99 (d, J¼3.6 Hz, 1H), 7.26e7.40 (m, 5H) ppm; 13
C
column eluting with EtOAc: petroleum ether (1: 12) to give 27
20
NMR (100 MHz, CDCl3)
d
12.97, 18.19, 22.58, 23.14, 26.63, 29.34,
(286 mg, 87%) as pale white oil. [
a
]
¼þ 15.5 (c 0.5, CHCl3). 1H
D
29.80, 31.70, 32.05, 34.91, 36.52, 42.69, 45.18, 66.53, 67.04, 67.37,
69.30, 70.26, 70.52, 71.60, 72.79, 98.40, 101.71, 127.45, 127.62,
128.27, 138.25 ppm; HRMS (MþNaþ) calcd for C37H62NaO5Si
669.4110, found 669.4157.
NMR (400 MHz, CDCl3) d 0.85 (s, 3H), 0.96 (s, 3H), 1.05 (s, 21H),
1.30 (m, 3H), 1.61 (m, 5H), 1.82 (m, 1H), 2.04 (m, 2H), 2.17 (m, 2H),
2.43 (m, 1H), 2.54 (dd, 1H, J¼17.6, 5.6 Hz), 2.68 (dd, J¼17.6, 8.0 Hz,
1H), 3.33 (d, J¼11.6 Hz, 1H), 3.41 (q, J¼5.2 Hz, 2H), 3.58 (d,
J¼11.2 Hz, 1H), 3.68 (m, 2H), 4.06 (t, J¼6.4 Hz, 2H), 4.37 (s, 1H),
4.53 (d, J¼5.6 Hz, 1H), 9.83 (s, 1H) ppm; HRMS (MþNaþ) calcd for
4.13. (((40R,70R,80R,8a0S)-40-(2-(Benzyloxy)ethyl)-80-(1,3-
dioxan-2-yl)-5,5-dimethyl-30,40,60,70,80,8a0-hexahydro-10H spiro
[[1,3] dioxane-2,20-naphthalen]-70-yl)oxy)triisopropylsilane
(25)
C
30H54NaO5Si 561.3587, found 561.3538.
4.16. (E)-1-((40R,4a0S,70R,80R,8a0R)-80-(1,3-Dioxan-2-yl)-5,5-
dimethyl-70-((triisopropylsilyl)oxy)octahydro-10H-spiro[[1,3]
dioxane-2,20-naphthalen]-40-yl)-5-((4-methoxybenzyl)oxy)-4-
methylpent-3-en-2-ol (29)
Under argon, to a 50 mL flask was added 24 (360 mg, 0.55 mmol)
and dry pyridine (20 mL). The solution was cooled to 0 ꢀC, and was
added SO2Cl (80.7 m
L, 1.11 mmol) at 0 ꢀC. Then the reaction mixture
was further stirred for 2 h at 25 ꢀC before it was quenched by ad-
dition of saturated NaHCO3 (10 mL) at 0 ꢀC. Then the aqueous layer
was extracted with EtOAc (3ꢂ25 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The crude
product was subjected to a silica gel column eluting with EtOAc:
Under argon, to a 50 mL flask was added 27 (723.3 mg,1.5 mmol)
and dry THF (20 mL). The solution was cooled to ꢁ78 ꢀC, and was
added n-BuLi (2.5 M in hexane, 0.6 mL, 1.5 mmol) at ꢁ78 ꢀC. The
solution was stirred for 10 min at ꢁ78 ꢀC, then 27 (161 mg,
0.3 mmol) in dry THF (10 mL) was added. The reaction mixture was
further stirred for 2 h at ꢁ78 ꢀC before it was quenched by addition
of saturated NH4Cl (10 mL). Then the aqueous layer was extracted
with EtOAc (3ꢂ20 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The crude product was
subjected to a silica gel column eluting with EtOAc: petroleum
ether (1: 3) to give 29 (a mixture 1: 1) (148.5 mg, 68%) as colourless
petroleum ether (1: 15) to give 25 (273 mg, 78%) as yellow oil.
20
[
a]
¼þ 113 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d 0.88 (s, 3H),
D
1.03 (s, 3H), 1.06 (s, 21H), 1.14 (m, 1H), 1.33 (d, J¼13.2 Hz, 1H), 1.63
(dd, J¼13.6, 6.4 Hz, 1H), 1.71 (m, 1H), 1.98 (m, 4H), 2.33 (dt, J¼16.4,
4.4 Hz, 1H), 2.51 (m, 1H), 2.73 (d, J¼13.6 Hz, 1H), 3.04 (d, J¼12.4 Hz,
1H), 3.34 (m, 4H), 3.62 (m, 3H), 3.76 (t, J¼10.8 Hz, 1H), 4.12 (m, 4H),
4.55 (q, J¼12.0 Hz, 2H), 4.87 (d, J¼4.4 Hz, 1H), 5.17 (s, 1H), 7.24e7.33
oil. 1H NMR (400 MHz, CDCl3)
d 0.76 (m, 3H), 0.87 (m, 6H), 1.03 (m,
(m, 5H) ppm; 13C NMR (100 MHz, CDCl3)
d
12.73,18.14, 22.68, 23.03,
3H), 1.04 (m, 21H), 1.20e1.32 (m, 4H), 1.67 (s, 3H), 1.96e2.14 (m,
4H), 2.27 (d, J¼14.0 Hz, 1H), 2.35 (d, J¼13.6 Hz, 1H), 3.22e3.41 (m,
3H), 3.44e3.54 (m, 1H), 3.63e3.74 (m, 4H), 3.81 (s, 3H), 3.89 (s, 2H),
4.07 (m, 2H), 4.37 (m, 2H), 4.55 (d, J¼4.8 Hz, 1H), 4.62 (s, 1H), 5.50
(m, 1H), 7.24 (m, 2H), 7.33 (m, 2H) ppm; HRMS (MþNaþ) calcd for
26.31, 29.14, 29.88, 33.06, 35.12, 35.38, 38.67, 39.26, 47.46, 65.78,
66.43, 67.06, 68.81, 69.60, 70.20, 72.80, 98.89, 101.73, 117.39, 127.33,
127.71, 128.21, 138.72, 140.93 ppm; HRMS (MþNaþ) calcd for
C
37H60NaO5Si 651.4057, found 651.4061.
C42H70NaO9Si 753.4738, found 753.4752.
4.14. 2-((40R,4a0S,70R,80R,8a0R)-80-(1,3-Dioxan-2-yl)-5,5-
dimethyl -70-((triisopropylsilyl)oxy)octahydro-10H-spiro[[1,3]
dioxane-2,20-naphthalen]-40-yl)ethanol (26)
4.17. (4S,4aS,7R,8R,8aR)-8-(1,3-Dioxan-2-yl)-4-((E)-5-((4-
meth-oxybenzyl)oxy)-4-methyl-2-oxopent-3-en-1-yl)-7 ((trii-
sopropyl-silyl)oxy)octahydronaphthalen-2(1H)-one (6)
25 (290 mg, 0.46 mmol), MeOH (20 mL), and palladium on
carbon (10 wt % Pd/C, wet, 29 mg) was added under a balloon of
hydrogen for 24 h. The mixture was then filtrated through Celite.
The filtrate was concentrated in vacuo and purified by silica gel
To a 50 mL flask was added 29 (263 mg, 0.3 mmol), acetone/
H2O¼20/1 (21 mL). The mixture was added Ts-OH (62 mg,
0.36 mmol). Then the reaction mixture was further stirred for 1 h
at 25 ꢀC before it was added H2O (10 mL). The acetone was con-
centrated in vacuo. Then the aqueous layer was extracted with
EtOAc (3ꢂ10 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude product was dis-
solved in DMSO (25 mL). The mixture was added IBX (300 mg,
1.07 mmol). Then the reaction mixture was further stirred for 3 h
at 25 ꢀC before it was quenched by addition of saturated Na2SO3.
Then the aqueous layer was extracted with EtOAc (3ꢂ25 mL). The
combined organic layers were dried over MgSO4 and concentrated
in vacuo. The crude product was subjected to a silica gel column
column chromatography eluting with EtOAc: petroleum ether (1:
20
5) to afford 26 (225 mg, 90%) as colourless oil. [
a
]
¼þ 55 (c 0.5,
D
CHCl3). 1H NMR (400 MHz, CDCl3)
d
0.76 (s, 3H),1.05 (s, 21H),1.09 (s,
3H), 1.18 (d, J¼13.2 Hz, 1H), 1.26 (t, J¼7.2 Hz, 1H), 1.29 (d, J¼13.2 Hz,
1H), 1.52 (dd, J¼14.0, 5.2 Hz, 1H), 1.55 (m, 3H), 1.68 (m, 2H), 1.77 (m,
3H), 2.03 (m, 1H), 2.10 (m, 1H), 2.20 (d, J¼14.0, 5.2 Hz, 1H), 2.34 (d,
J¼13.6 Hz, 1H), 2.93 (s, 1H), 3.35 (d, J¼11.6 Hz, 2H), 3.53 (d,
J¼11.6 Hz, 1H), 3.63e3.81 (m, 5H), 4.06 (m, 2H), 4.36 (s, 1H), 4.55 (d,
J¼5.6 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d 12.23, 18.10, 22.10,
22.50, 22.92, 25.79, 27.65, 29.63, 29.92, 30.00, 32.94, 36.54, 38.24,
39.33, 49.58, 62.32, 66.38, 66.84, 67.05, 69.38, 69.78, 99.23,
101.74 ppm; HRMS (MþNaþ) calcd for C30H56NaO5Si 563.3731,
found 563.3738.
eluting with EtOAc: petroleum ether (1: 5) to give 6 (202 mg, 88%
20
for two steps) as pale white oil. [
NMR (400 MHz, CDCl3)
a
]
¼þ 26.85 (c 0.5, CHCl3). 1H
D
d
0.83 (m, 2H), 1.03 (s, 21H), 1.30 (d,
J¼12.8 Hz, 2H), 1.59 (m, 2H), 1.83 (m, 1H), 2.04 (s, 3H), 2.08e2.34
(m, 5H), 2.51 (d, J¼16.0 Hz, 1H), 2.59 (td, J¼18.4, 5.6 Hz, 2H), 2.75
(m, 1H), 3.64 (m, 2H), 3.81 (s, 3H), 3.93 (s, 2H), 4.09 (td, J¼13.0,
4.4 Hz, 2H), 4.33 (s, 1H), 4.46 (s, 2H), 4.60 (d, J¼5.6 Hz, 1H), 6.29 (s,
1H), 6.88 (d, J¼8.4 Hz, 2H), 7.26 (d, J¼6.8 Hz, 2H) ppm; 13C NMR
4.15. 2-((40R,4a0S,70R,80R,8a0R)-80-(1,3-Dioxan-2-yl)-5,5-
dimethyl-70-((triisopropylsilyl)oxy)octahydro-10H-spiro[[1,3]
dioxane-2,20-naphthalen]-40-yl)acetaldehyde (27)
To a 50 mL flask was added 26 (330 mg, 0.61 mmol) and
DMSO (25 mL). The mixture was added IBX (684 mg, 2.44 mmol).
Then the reaction mixture was further stirred for 8 h at 25 ꢀC
before it was quenched by addition of saturated Na2SO3. Then the
aqueous layer was extracted with EtOAc (3ꢂ25 mL). The
(100 MHz, CDCl3) d 12.15, 16.41, 18.10, 22.76, 25.68, 27.79, 29.28,
32.89, 36.20, 38.44, 42.21, 45.78, 47.34, 48.96, 55.20, 66.10, 66.78,
67.08, 72.22, 73.73, 101.68, 113.79, 122.22, 125.24, 128.18, 129.26,
129.77, 153.28, 199.73, 212.87 ppm; HRMS (MþNaþ) calcd for
C
37H58NaO7Si 665.3798, found 665.3844.

H. Chen et al. / Tetrahedron 72 (2016) 347e353
353
4.18. (1R,4aS,4bR,7R,8R,8aR,10aR)-8-(1,3-Dioxan-2-yl)-1-(((4-
References and notes
methoxybenzyl)oxy)methyl)-1-methyl-7-((triisopropylsilyl)
oxy) decahydrophenanthrene-3,10(2H,4bH)-dione (5) and
(1S,4aS, 4bR,7R,8R,8aR,10aS)-8-(1,3-dioxan-2-yl)-1-(((4-
methoxybenz-yl)oxy)methyl)-1-methyl-7 ((triisopropylsilyl)
oxy)decahydro-phenanthrene-3,10(2H,4bH)-dione (32)
1. Benn, M. H.; Jacyno, J. M. In Alkaloids: Chemical and Biological Perspective; Pel-
letier, S. W., Ed.; John Wiley and Sons: New York, NY, 1983; Vol. 1, pp 153e210.
2. For reviews, see: (a) Wang, F. P.; Liang, X. T. In The Alkaloids: Chemistry and
Biology; Cordell, G. A., Ed.; Elsevier: New York, NY, 2002; Vol. 59, pp 1e280; (b)
Wang, F. P.; Chen, Q. H.; Liang, X. T. In The Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; Elsevier: New York, NY, 2009; Vol. 67, pp 1e78; (c) Wang, F.
P.; Chen, Q. H. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Elsevier: New York, NY, 2010; Vol. 69, pp 1e577.
Under argon, to a 10 mL flask was added 6 (20 mg, 0.03 mmol)
and dry THF (3 mL). The mixture was added t-BuOK (1 M in THF).
The solution was further stirred for 2 h at 25 ꢀC before it was
quenched by addition of saturated NH4Cl (10 mL). Then the
aqueous layer was extracted with EtOAc (3ꢂ20 mL). The com-
bined organic layers were dried over MgSO4 and concentrated in
vacuo. The crude product was subjected to a silica gel column
eluting with EtOAc: petroleum ether (1: 4) to give 5 and 32 as an
inseparable mixture (15 mg, 1:1.4, 76%) as colourless oil. 1H NMR
(400 MHz, CDCl3, all signals for both diastereomers are listed)
3. Tang, P.; Chen, Q. H.; Wang, F. P. Tetrahedron Lett. 2009, 50, 460.
4. Suzuki, T.; Sasaki, A.; Egashira, N.; Kobayashi, S. Angew. Chem., Int. Ed. 2011, 50,
9177.
5. Hayashi, R.; Ma, Z. X.; Hsung, R. P. Org. Lett. 2012, 14, 252.
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7. For a new biosynthetic proposal, see: Weber, M.; Owens, K.; Sarpong, R. Tet-
rahedron Lett. 2015, 56, 3600.
ꢀ
8. For a related review, see: (a) Maertens, G.; Menard, M.-A.; Canesi, S. Synthesis
2014, 46, 1573 For selected examples, see: (b) Hayashi, Y.; Gotoh, H.; Tamura, T.;
Yamagushi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028; (c) Vo, N.
T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 404; (d)
Calter, M. A.; Wang, J. Org. Lett. 2009, 11, 2205; (e) Bournaud, C.; Marchal, E.;
ꢀ
Quintard, A.; Sulzer-Mosse, S.; Alexakis, A. Tetrahedron: Asymmetry 2010, 21,
d
0.88 (m, 1H), 1.04 (s, 21H), 1.25 (s, 3H), 1.30 (m, 3H), 1.67 (m,
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1H), 1.84 (s, 1H), 2.04 (m, 1H), 2.17e2.37 (m, 5H), 2.56 (m, 3H),
2.76 (m, 1H), 3.42/3.48 (d, J¼12.0 Hz, 1H), 3.56 (s, 1H), 3.58 (d,
J¼11.6 Hz, 1H), 3.64 (m, 2H), 3.81 (s, 3H), 4.06 (td, J¼13.6, 3.6 Hz,
2H), 4.34 (s, 1H), 4.48 (s, 2H), 4.58 (d, J¼5.2 Hz, 1H), 6.87 (d,
J¼8.4 Hz, 2H), 7.24 (d, J¼8.8 Hz, 2H) ppm; 13C NMR (150 MHz,
ꢀ
ꢀ
9. Peuchmaur, M.; Saïdani, N.; Botte, C.; Marechal, E.; Vial, H.; Wong, Y.-S. J. Med.
Chem. 2008, 51, 4870.
CDCl3, all signals for both diastereomers are listed)
d 12.14, 13.78,
10. For selected reviews on dearomatization reactions, see: (a) Zhuo, C.-X.; Zhang,
W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662; (b) Ding, Q.; Ye, Y.; Fan, R.
Synthesis 2013, 45, 1 For recent examples, see: (c) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-
X.; Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 4455; (d) Yin,
Q.; Wang, S.-G.; Liang, X.-W.; Gao, D.-W.; Zheng, J.; You, S.-L. Chem. Sci. 2015, 6,
4179; (e) Huang, S.; Kotzner, L.; De, C. K.; List, B. J. Am. Chem. Soc. 2015, 137,
3446.
11. For details, see Supporting Information.
13.96, 18.13, 22.62, 22.68, 22.78, 25.69, 29.20, 29.69, 32.97, 35.70,
35.96, 38.24, 38.28, 38.81, 38.87, 45.79, 47.21, 47.25, 48.89, 55.25,
61.31, 61.58, 62.37, 66.04, 66.83, 67.12, 71.79, 72.12, 76.78, 101.64,
113.78, 129.41, 129.44, 129.65, 159.27, 204.72, 205.10,
212.46 ppm; HRMS (MþNaþ) calcd for C37H58KO7Si 681.3589,
found 681.3593.
€
12. For selected reviews, see: (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650;
(b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew.
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Y.; Deng, J.; Liu, H.; Bian, M.; Li, A. Sci. China Chem. 2014, 57, 926; (f) Mackay, E.
G.; Sherburn, M. S. Synthesis 2015, 47, 1.
Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (21321061, 21132006 and 21572140).
13. For related examples, see: (a) Jung, M. E.; Ho, D. G. Org. Lett. 2007, 9, 375; (b)
Kanoh, N.; Sakanishi, K.; Iimori, E.; Nishimura, K.; Iwabuchi, Y. Org. Lett. 2011, 13,
ꢀ
2864; (c) Amat, M.; Arioli, F.; Perez, M.; Molins, E.; Bosch, J. Org. Lett. 2013, 15,
2470; (d) Jin, J.; Qiu, F. G. Adv. Synth. Catal. 2014, 356, 340.
14. (a) Angoh, A. G.; Clive, D. L. J. J. Chem. Soc., Chem. Commun. 1984, 8, 534; (b)
Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1986, 108, 5655; (c) Yajima, A.;
Qin, Y.; Zhou, X.; Kawanishi, N.; Xiao, X.; Wang, J.; Zhang, D.; Wu, Y.; Nukada, T.;
Yabuta, G.; Qi, J.-H.; Asano, T.; Sakagami, Y. Nat. Chem. Biol. 2008, 4, 235.
15. The structures of S1 and S2, see Supporting Information.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.11.050.