A flexible enantioselective synthesis of (+)-centrolobine and 5-epi-diospongin-A using asymmetric transfer hydrogenation/tandem Grubbs cross-metathesis/oxy-Michael reaction as key steps

Article abstract of DOI:10.1016/j.tetasy.2013.01.005

An efficient enantioselective synthesis of (+)-centrolobine and 5-epi-diospongin-A was achieved by the use of asymmetric transfer hydrogenation (ATH)/tandem Grubbs cross-metathesis/oxy-Michael reaction. Furthermore, this strategy allows for diastereodiver

Full text of DOI:10.1016/j.tetasy.2013.01.005

Tetrahedron: Asymmetry 24 (2013) 196–201
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A flexible enantioselective synthesis of (+)-centrolobine and
5-epi-diospongin-A using asymmetric transfer hydrogenation/tandem
Grubbs cross-metathesis/oxy-Michael reaction as key steps
⇑
Gullapalli Kumaraswamy , Dasa Rambabu
Organic & Biomolecular Chemistry Division, CSIR—Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 November 2012
Accepted 4 January 2013
An efficient enantioselective synthesis of (+)-centrolobine and 5-epi-diospongin-A was achieved by the
use of asymmetric transfer hydrogenation (ATH)/tandem Grubbs cross-metathesis/oxy-Michael reaction.
Furthermore, this strategy allows for diastereodivergent access to every representative member of the
family.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
1,4-addition and asymmetric transfer hydrogenation strategy.11
Herein, we report another alternative unified synthetic strategy
The functionalized tetrahydropyran motif is prevalent in numer-
ous biologically active natural products. Many of these natural
products have been reported to have potent biological activity
which is attributed to the presence of the functionalized tetrahy-
dropyran core.1 Among them, 2,6-disubstituted glycoside natural
products, such as (+)-centrolobine 4, diospongin-A 1 and B 2, have
shown an array of therapeutical activities such as anti-osteopo-
rotic,2 anti-cancer,3 anti-inflammatory, anti-bacterial and
anti-leishmanial activities.4
Moreover, regardless of their structural similarities, they exhibit
noteworthy differences in their biological profiles. Diospongin B
displays a potent inhibitory activity on bone resorption induced
by parathyroid hormone, while diospongin A does not show any
activity for the same.5 (+)-Centrolobine 4 is an antibiotic, isolated
from the heartwood of Centrolobium robustum,6 while its enantio-
mer with similar activity occurs in a different origin, that is,
Centrolobium tomentosum (Fig. 1).7
for the synthesis of (+)-centrolobine and 5-epi-diospongin-A by
means of asymmetric hydogenation/tandem Grubbs cross-
metathesis/oxyMichael reactions. Our retrosynthetic approach is
shown in Scheme 1.
In principle, 5-epi-diospongin-A 3, could be obtained from a
tandem Grubbs cross-metathesis/oxy-Michael reaction of 1,3-anti
diol 5 and phenylvinylketone. The 1,3-anti diol 5 could be gener-
ated via an indium catalysed allylation of b-hydroxyphenyl acetal-
dehyde, which in turn could be obtained from 6. The stereogenic
centre in 6 could be accessed through a catalytic enantioselective
asymmetric transfer hydrogenation that is either (S) or (R) by using
the corresponding prochiral keto substrate. In a similar manner,
(+)-centrolobine, 4 could be obtained by employing olefin tethered
OH
OH
O
O
O
2. Results and discussion
O
Due to the biological activity of 1–4, synthetic approaches have
been recorded.8,9 To date, most strategies rely on asymmetric
induction resulting from either chiral auxiliaries, resident chirality
or catalytic asymmetric synthesis with privileged ligands with high
catalyst loading. Due to our interest in developing catalytic routes
to bioactive small molecules,10 we recently developed a flexible
enantioselective synthesis for diospongin-A 1 and B 2, and their
diospongin B 2
diospongin A 1
OH
O
O
O
enantiomers using
a catalytic hetero-Diels–Alder/Rh-catalysed
MeO
OH
centralobin 4
5-epi-diospongin A 3
⇑
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193275.
E-mail address: gkswamy_iict@yahoo.co.in (G. Kumaraswamy).
Figure 1. Bioactive glycoside natural products 1–4.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.005

G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201
197
OH
O
diastereoselective
allylation
OH
OH
O
O
tandem Grubbs-cross
metathesis/Michael reaction
O
OEt
+
OH
6
5
catalytic asymmetric
transfer hydrogenaion
3
catalytic asymmetric
transfer hydrogenaion
tandem Grubbs-cross
metathesis/Michael reaction
O
OH
+
O
MeO
OTBS
MeO
OH
4
7
Scheme 1. Retro synthetic analysis of 5-epi-diospongin-A 3 and (+)-centrolobine 4.
secondary alcohol
(Scheme 1).
7
and TBS-protected phenylvinylketone
the intended tandem Grubbs cross-metathesis-oxy-Michael reac-
tion14 of 5 with vinylacetophenone employing a second-generation
Grubbs catalyst led smoothly to the desired 5-epi-diospongin-A 3
in 88% isolated yield and with >99% diastereomeric ratio.
Accordingly, the readily available b-ketoester 8 was subjected
to Noyori’s protocol using 1 mol % of (S,S)-RuCl[N-tosyl)-1,2-
diphenylethylenediamine](p-cymene) in the presence of 10 mol %
K2CO3 in 2-propanol and stirring at ambient temperature for 48 h
to afford b-hydroxyl compound 6 in 98% yield and with 96%
enantioselectivity.
The chirooptical data of 3 were in full agreement with those re-
ported in the literature8f {½a D23
ꢀ
¼ ꢁ11:3 (c 0.6, CHCl3), lit.8f
½
a 2D3
ꢀ
¼ ꢁ11:6 (c 0.54, CHCl3)} (Scheme 2).
Next, we initiated the synthesis of (+)-centrolobine, 4 employ-
The enantiopurity was analysed by HPLC (Chiralpak OD-H, 5%
isopropanol in hexane at a flow rate of 0.8 mL/min) and the abso-
lute configuration was assigned by chemical correlation.12b Next,
the secondary hydroxyl in 6 was protected as a silyl ether to give
9 in 99% yield. The reduction of 9 with DIBAL-H gave the aldehyde
and the corresponding crude residue was subjected to deprotec-
tion of the TBS group using PPTS in an aprotic solvent at 0 °C to give
the b-hydroxyl aldehyde. Next, without purification, the residue of
b-hydroxyl aldehyde, was submitted to a b-chelation-controlled
indium-mediated allylation.13 After work-up purification, the
anti-diol 5 (9:1) was obtained in 81% yield as the major compound
(75% over three steps). Finally, after considerable experimentation,
ing strategic steps used in the above synthesis. The reduction of
10 with 1 mol % of (R,R)-RuCl[N-tosyl)-1,2-diphenylethylenedi-
amine](p-cymene) in the presence of 10 mol % K2CO3 in 2-propanol
and stirring at ambient temperature for 48 h resulted in no trace of
the desired compound 11 (Table 1, entry 1). The same reaction
with heating at 80 °C under otherwise identical conditions gave
hydroxyl compound 11 in 10% yield with 65% ee (Table 1, entry
2). When the reduction was carried out with 1 mol % of
(R,R)-RuCl[N-tosyl)-1,2-diphenylethylenediamine](p-cymene) in
the presence of HCO2H:Et3N (5:2) in EtOAc and heating at 80 °C
for 24 h, 11 was obtained in low yield and with moderate ee
(Table 1, entry 3). However, when the same substrate was exposed
1 mol%
Ts
Ph
N
Ru
OH
O
N
H
O
O
Ph
TBSCl
OEt
OEt
imadazole
DCM, 12 h
10 mol% K2CO3
2-propanol
rt, 48 h
98%yield; 96%ee
OH OH
6,
8
i) DIBAL-H
-78 °C
OTBS O
DCM, 20 min
OEt
ii) PPTS, MeOH
0 °C,1 h
5
, 75% (over 3 steps)
iii) In0, H2O
9, 99%
dr = 9:1
Br
OH
O
rt, 4 h
O
Grubbs 2nd gen
O
dr = > 99
88%
3,
DCM, 12 h, reflux
Scheme 2. Synthesis of 5-epi-diospongin-A 3.

198
G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201
Table 1
Asymmetric reduction of d-keto compound 10 employing various conditions
1 mol%
Ph
Ts
N
Ru
N
OH
O
O
O
Ph
H
OEt
OEt
MeO
MeO
11, 98%yield; 88%ee
10
Entry
1
Conditions
Time (h)
% Yield
%ee
10 mol % K2CO3
2-Propanol, rt
10 mol % K2CO3
2-Propanol, 80 °C
HCO2H:Et3N (5:2)
EtOAc, 80 °C
HCO2H:Et3N (5:2)
80 °C
HCO2H:Et3N (5:2)
40 °C
48
48
24
24
24
No reaction
2
3
4
5
10
40
95
98
65
60
72
88
to HCO2H:Et3N (5:2) as the hydrogen source as well as the solvent
and heating at 80 °C, the expected product 11 was obtained with
good yield and ee (Table 1, entry 4). Reducing temperature to
40 °C gave the target compound 11 with acceptable ee (88%) and
high yield (Table 1, entry 5).15
phy.16 Initially, the benzylic deoxygenation of 14 was attempted by
employing H2–Pd/C under balloon pressure with a trace of HCl.9k
However, the reaction mixture showed a multitude of products
and no trace amount of the desired compound 4 was observed.
Consequently, the deoxygenation and deprotection of TBS group
were achieved by reduction with NaBH4 following acid-catalysed
elimination of the resulting secondary alcohol and subsequent
reduction with NaBH4 to give (+)-centralobine 4 in 75% isolated
yield.9v The enantiomeric purity and analytical data (1H and 13C
NMR) were in agreement with those reported for the natural prod-
With the enantioenriched compound 11 in hand, we proceeded
further. The stereogenic secondary hydroxyl group in 11 was pro-
tected as TBS–ether 12 (98%). Upon exposure of 12 to DIBAL-H in
DCM at ꢁ78 °C the aldehyde was obtained, which without purifica-
tion was submitted to Wittig olefination (Ph3P+CH3Iꢁ, t-BuOK, THF,
ꢁ78 °C to rt) to give the terminal olefin 13 in 81% yield (over two
steps). Fluoride induced desilylation resulted in secondary alcohol
7 in 90% isolated yield. Finally, the tandem Grubbs CM-oxyMichael
reaction between terminal olefin 7 and p-t-butyldimethylsilyloxy
vinylacetophenone using Grubbs 2nd generation catalyst in DCM,
heated at reflux for 12 h gave 2,6-disubstituted pyrone 14 in 90%
yield with an 88:12 diastereomeric ratio. The major cis-configured
diastereomer 14 was separated by silica gel column chromatogra-
uct4b {½a 2D3
ꢀ
¼ þ95:3 (c 0.12, MeOH), lit.4b
½
a 2D3
ꢀ
¼ þ97:5 (c 0.1,
MeOH)} (Scheme 3).
3. Conclusion
In conclusion, we have accomplished a unified enantioselective
route for the synthesis of (+)-centrolobine and 5-epi-diospongin-A
by combining two efficient catalytic processes, that is, an asym-
OTBS
i) DIBAL-H
-78 °C
DCM, 20min
OTBS
CO2Et
TBSCl
11
imadazole
ii) Ph3PCH3I
MeO
MeO
O
DCM, 12 h
t-BuOK, THF
13, 81% (over 2 steps)
12, 98%
-78°C to rt; 12 h
OH
TBSO
TBAF, THF
Grubbs 2nd gen
DCM, 12 h, reflux
0 °C to rt, 4 h
MeO
7, 90%
O
i) NaBH4
MeOH, 0 °C to rt,1 h
4
O
ii) THF, NaBH4
TFA, rt , 1 h
(+)-centrolobine
75%
MeO
OTBDMS
14, dr = 88:12
90%
Scheme 3. Synthesis of (+)-centrolobine, 4.

G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201
199
metric transfer hydrogenation (ATH) and tandem Grubbs cross-
metathesis/oxy-Michael reaction. The genesis of chirality installed
via ATH offers an attractive alternative to high pressure molecular
hydrogen methods. Additionally, this methodology uses a low level
of catalyst loading and gives high enantioselectivity with opera-
tional simplicity. This is a flexible approach that provides access
to the synthesis of each representative member of diospongin
and centrolobine family. Further work is currently in progress.
(c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 7.30–7.24 (m, 5H), 5.14
(dd, J = 4.1 Hz, J = 9.2 Hz, 1H), 4.10 (q, J = 7.1 Hz, J = 14.3 Hz, 2H),
2.72 (dd, J = 9.2 Hz, J = 14.5 Hz, 1H), 2.67 (dd, J = 4.1 Hz,
J = 14.5 Hz, 1H), 1.25 (t, J = 7.1 Hz, J = 14.3 Hz, 3H), 0.84 (s, 9H),
0.01 (s, 3H), ꢁ0.17 (s, 3H); 13C NMR (75 MHz, CDCl3): 171.1,
144.0, 128.2, 127.4, 125.8, 72.2, 67.7, 60.4, 45.4, 25.6, 21.8, 18.0,
14.1, ꢁ2.9, ꢁ4.7, ꢁ5.3; IR
m
(cmꢁ1): 3448, 3031, 2955, 2893,
2857, 1738, 1467, 1092, 1049, 954, 834, 777, 699, 667, 533;
ESI-MS: m/z 331 (M+Na)+; ESI-HRMS: calcd for C17H28O3NaSi
331.16999, found 331.17031.
4. Experimental
4.1. General
4.1.3. (1S,3R)-1-Phenylhex-5-ene-1,3-diol 5
To a stirred solution of 9 (750 mg, 2.43 mmol) in CH2Cl2 (15 mL)
was added DIBAL-H (346 mg, 2.43 mmol, 1 M solution in toluene)
at ꢁ78 °C. The reaction mixture was stirred for 30 min at the same
temperature and then quenched with a saturated sodium potas-
sium tartarate solution. The aqueous layer was then extracted with
CH2Cl2 (3 ꢂ 30 mL). The combined organic layers were washed
with brine solution, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure to give the corresponding crude
aldehyde. The aldehyde was subjected to next step without further
purification. To a 0 °C cooled solution of aldehyde (574 mg) in
MeOH (5 mL) was added PTSA (413 mg, 2.17 mmol), and then stir-
red at 0 °C for 1 h, then quenched with water and extracted with
EtOAc (3 ꢂ 20 mL). The combined organic layers were washed with
NaHCO3 (3 ꢂ 10 mL) followed by brine (3 ꢂ 10 mL). The contents
were dried over anhydrous Na2SO4 and concentrated under
reduced pressure, to give the crude hydroxy-aldehyde which was
subjected to next step without further purification.
All reactions were conducted under an atmosphere of nitrogen
(IOLAR, Grade I). Apparatus used for reactions were oven dried.
THF was distilled over sodium benzophenone ketyl before use,
2-propanol and dichloromethane were distilled over calcium
hydride. All other chemicals used were commercially available.
Progress of the reactions was monitored by TLC on Silica Gel 60
F-254 pre-coated. Evaporation of the solvents was performed at re-
duced pressure on a rotary evaporator. Column chromatography
was carried out with silica gel grade 60–120, and 100–200 mesh.
1H NMR spectra were recorded at 300 and 500 MHz and 13C
NMR 75 MHz in CDCl3. J values are recorded in Hertz and abbrevi-
ations used are s-singlet, d-doublet, t-triplet, q-quartet, m-multi-
plet and br-broad. Chemical shifts (d) are reported relative to
TMS (d = 0.0) as the internal standard. IR spectra were recorded
on FT/IR-5700. Mass spectra data were compiled using MS (ESI),
HRMS mass spectrometers. Optical rotations were recorded on a
highly sensitive polarimeter with 10 mm cell.
To the above residue, water (14 mL) and indium powder
(343 mg, 2.98 mmol) were sequentially added at 23 °C. To this, al-
lyl bromide (0.25 mL, 2.98 mmol) was added and the reaction flask
was sealed with a rubber septum. After vigorous stirring for 1 h at
the same temperature, the reaction mixture was concentrated. To
the resulting residue, ethyl acetate (30 mL) was added and stirred
and filtered. The filtrate was dried over Na2SO4 and concentrated
under reduced pressure. The crude residue was passed through a
silica gel column chromatography (50% EtOAc in hexane) to afford
the separable diastereomers in a 9:1 ratio [major (311 mg) and
minor (34 mg)]. The major isomer was found to be a white semi
4.1.1. (S)-Ethyl 3-hydroxy-3-phenylpropanoate 6
To a solution of 8 (500 mg, 2.60 mmol) in anhydrous 2-propanol
(5 mL) under argon was added (S,S)-Ru-catalyst (15.8 mg,
0.026 mmol, 1 mol %), which was pre-dissolved in CH2Cl2
(2 ꢂ 1 mL). Then, K2CO3 (36 mg, 0.260 mmol) was added and the
resulting reaction mixture was stirred at ambient temperature
for 48 h. The reaction mixture was then diluted with water and ex-
tracted with EtOAc (3 ꢂ 10 mL). The combined organic layers were
washed with brine (3 ꢂ 5 mL), dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure to give the residue
which was subjected to silica gel flash column chromatography
(20% EtOAc in hexane) to afford 495 mg (98%) of compound 6 as
solid 5 (311 mg, 75% yield over three steps). ½a D23
¼ ꢁ31:0 (c 2.2,
ꢀ
CHCl3); 1H NMR (300 MHz, CDCl3): 7.28–7.18 (m, 5H), 5.76–5.62
(m, 1H), 5.07–4.94 (m, 3H), 3.87–3.81 (m, 1H), 2.64 (br s, 2H),
2.21–2.16 (m, 2H), 1.84–1.73 (m, 2H); 13C NMR (75 MHz, CDCl3):
144.3, 134.3, 128.3, 127.2, 125.4, 118.2, 71.4, 67.9, 43.9, 41.8; IR
a colourless liquid. ½a D23
ꢀ
¼ ꢁ43:0 (c 1, CHCl3) {lit.12b
½
a 2D3
ꢀ
¼ ꢁ50:1
(c 1.50, CHCl3)}; 1H NMR (300 MHz, CDCl3): 7.36–7.25 (m, 5H),
5.12 (dd, J = 4.5, J = 8.4 Hz, 1H), 4.17 (q, J = 7.1 Hz, J = 14.3 Hz, 2H),
2.74–2.70 (m, 2H), 1.23 (t, J = 6.9 Hz, J = 14.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): 172.3, 142.4, 128.4, 127.7, 125.6, 70.2, 60.8,
m
(cmꢁ1): 3380, 2927, 2852, 1717, 1453, 1054, 765, 700, 420;
ESI-MS: m/z 215 (M+Na)+; ESI-HRMS: calcd for C12H16O2Na
215.10425, found 215.10431.
43.2, 14.0; IR
m
(cmꢁ1): 3452, 3031, 2982, 1728, 1298, 1194,
4.1.4. 5-epi-Diospongin-A 3
1161, 1033, 914, 760, 700, 539; ESI-MS: m/z 217 (M+Na)+; ESI-
A 50 mL flame-dried two-neck round bottom flask equipped
with a magnetic stirrer bar and reflux condenser was charged with
(1S,3R)-1-phenylhex-5-ene-1,3-diol 5 (50 mg, 0.26 mmol), 1-phe-
nylprop-2-en-1-one (69 mg, 0.52 mmol) and anhydrous dichloro-
methane (11 mL) under an atmosphere of argon, and degassed
for 5 min. Second generation Grubbs’ catalyst (23 mg, 0.026 mmol)
was then added in a single portion resulting in an orange solution,
which was refluxed for 12 h. The reaction mixture was then al-
lowed to cool to room temperature, and concentrated in vacuo to
afford a dark brown oil, which was purified by silica gel column
chromatography (eluting with 30% ethyl acetate/hexanes) fur-
nished the title compound 3 as a white solid (68 mg, 88% yield).
HRMS calcd for C11H14O3Na 217.08352, found 217.08324.
4.1.2. (S)-Ethyl 3-(tert-butyldimethylsilyloxy)-3-phenylpropan-
oate 9
To a stirred solution of 6 (495 mg, 2.55 mmol) in CH2Cl2 (10 mL)
was added imidazole (348 mg, 5.10 mmol) at 0 °C. After stirring the
solution for 15 min, tert-butyldimethyl silyl chloride (575 mg,
3.82 mmol) and catalytic DMAP were added sequentially at the
same temperature. The resulting reaction mixture was stirred at
ambient temperature for 12 h, then quenched with a saturated
NH4Cl solution and extracted with CH2Cl2 (3 ꢂ 25 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude residue was puri-
fied by silica gel column chromatography (5% EtOAc in hexane) to
½
a 2D3
ꢀ
¼ ꢁ11:3 (c 0.6, CHCl3) lit.8f
½
a 2D3
ꢀ
¼ ꢁ11:6 (c 0.54, CHCl3); 1H
NMR (500 MHz, CDCl3):
d 7.97 (d, J = 7.8 Hz, 2H), 7.56 (t,
J = 7.8 Hz, 1H), 7.45(t, J = 7.0 Hz, 2H), 7.30–7.29 (m, 5H), 4.37 (d,
J = 12.0 Hz, 1H), 4.22–4.17 (m, 1H), 4.07–4.02 (m, 1H), 3.47 (dd,
afford the product 9 (780 mg, 99%) as a colourless oil. ½a D23
¼ ꢁ41:5
ꢀ

200
G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201
J = 5.2 Hz, J = 15.7 Hz, 1H), 3.10 (dd, J = 6.1 Hz, J = 16.6 Hz, 1H), 2.23
(d, J = 11.3 Hz, 2H), 1.55(br, 1H), 1.36–1.29 (m, 3H); 13C NMR
(150 MHz, CDCl3): d 198.0, 141.6, 137.2, 133.2, 128.5, 128.3,
THF (15 mL) and stirred at room temperature for 4 h. The resulting
yellow colour solid precipitate was allowed to settle down. Next,
the clear supernatant orange-yellow liquid was cannulised into
the above crude aldehyde (552 mg), which was dissolved in dry
THF (5 mL) at ꢁ78 °C after which the reaction mixture was allowed
to return to ambient temperature (ꢃ12 h). Next, the reaction mix-
ture was quenched with an aq satd NH4Cl and the aqueous layer
was extracted with diethyl ether (3 ꢂ 30 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude residue was purified by silica
gel column chromatography using (10% EtOAc in hexane) to afford
product 13 as a colourless oil (496 mg, 81% over two steps).
128.2, 127.5, 125.9, 77.5, 72.4, 68.1, 60.4, 44.7, 42.4, 40.9; IR
m
(cmꢁ1): 3448, 2924, 2853, 1725, 1599, 1453, 1072, 750; ESI-MS:
m/z 297 (M+H)+; ESI-HRMS: calcd for C19H20O3Na 319.13047,
found 319.13037.
4.1.5. (R)-Ethyl 5-hydroxy-5-(4-methoxyphenyl)pentanoate 11
To a mixture of ethyl 5-(4-methoxyphenyl)-5-oxopentanoate
10 (500 mg, 2 mmol) and HCOOH:Et3N (5:2) was added Ru-
catalyst (12.2 mg, 0.02 mmol, 1 mol %) which was pre-dissolved
in DCM. The resulting reaction mixture was heated at 40 °C for
24 h. After cooling the reaction mixture to room temperature,
water was added and the aqueous layer extracted with EtOAc
(3 ꢂ 10 mL). The organic solution was washed with aqueous NaH-
CO3 and brine successively. The organic layer was dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The
resulting residue was subjected to silica gel flash column chroma-
tography (30% EtOAc in hexane) to afford 11 as a colourless liquid
½
a 2D3
ꢀ
¼ þ39:1 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.81 (d,
J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 5.78–5.72 (m, 1H), 4.93
(dd, J = 17.0 Hz, J = 28.0 Hz, 2H), 4.59–4.56 (m, 1H), 3.78 (s, 3H),
2.04–2.0 (m, 2H), 1.71–1.66 (m, 1H), 1.60–1.57(m, 1H), 1.47–1.42
(m, 1H), 1.36–1.25 (m, 1H), 0.87 (s, 9H), 0.00 (s, 3H), ꢁ0.15 (s,
3H); 13C NMR (75 MHz, CDCl3): d 158.4, 138.8, 138.0, 126.8,
114.3, 113.2, 74.5, 55.1, 40.4, 39.2, 33.6, 29.6, 25.8, 24.9, 18.2,
ꢁ4.6, ꢁ4.9; IR (neat): 3451, 3074, 2931, 2857, 1639, 1511, 1248,
(497 mg, 98%). ½a D23
ꢀ
¼ þ22:5 (c 1, CHCl3); 1H NMR (300 MHz,
1085, 910, 833, 774,667, 555 cmꢁ1
.
CDCl3): d 7.19–7.18 (m, 2H), 6.8 (d, J = 7.9 Hz, 2H), 4.57–4.54 (m,
1H), 4.04 (q, J = 6.9, 14.9 Hz, 2H), 3.73 (s, 3H), 2.25–2.23 (m, 2H),
1.75–1.55 (m, 4H), 1.23 (t, J = 6.9, 13.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 173.5, 158.8, 136.6, 126.9, 113.6, 73.5, 60.2,
55.1, 38.1, 33.9, 21.1, 14.1; ESI-MS: m/z 275 (M+Na)+; ESI-HRMS:
calcd for C14 H20O4Na 275.12538, found 275.12554.
4.1.8. (R)-1-(4-Methoxyphenyl)hex-5-en-1-ol 7
To a stirred solution of 13 (496 mg, 1.61 mmol) in THF (10 mL)
was added TBAF (2.42 mL, 2.42 mmol, 1 M solution in THF) at 0 °C
after which the reaction mixture was allowed to return to ambient
temperature and stirred for further 4 h. The reaction mixture was
then quenched with H2O and extracted with EtOAc (3 ꢂ 20 mL).
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The crude residue was purified by silica gel column chromatogra-
phy using (20% EtOAc in hexane) to afford product 7 as a colourless
4.1.6. (R)-Ethyl 5-(tert-butyldimethylsilyloxy)-5-(4-methoxyphen-
yl)pentanoate 12
To a stirred solution of 11 (490 mg, 1.95 mmol) in CH2Cl2
(10 mL) was added imadazole (265 mg, 3.882 mmol) at 0 °C. After
stirring the solution for 15 min, tert-butyldimethyl silyl chloride
(0.438 mg, 2.91 mmol) and catalytic DMAP were added sequen-
tially at the same temperature. The resulting reaction mixture
was stirred at room temperature for 12 h, and quenched with a sat-
urated NH4Cl solution. Next, the aqueous layer was extracted with
CH2Cl2 (3 ꢂ 20 mL) and the combined organic layers were dried
over anhydrous Na2SO4. The contents were filtered and concen-
trated under reduced pressure. The resulting crude residue was
purified by silica gel column chromatography (5% EtOAc in hexane)
to afford the product 12 as a colourless oil (698 mg, 98%).
liquid (301 mg, 90%).
½
a 2D3
ꢀ
¼ þ25:0 (c 0.7, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.41 (d, J = 8.32 Hz, 2H), 7.03 (d, J = 8.32 Hz,
2H), 5.97–5.88 (m, 1H), 4.78–4.75 (m, 1H), 3.90 (s, 3H), 2.20–2.0
(m, 2H), 1.99–1.92 (m, 1H), 1.88–1.81 (m, 1H) 1.69–1.61 (m, 1H),
1.53–1.46 (m, 1H) 13C NMR (75 MHz, CDCl3): d 158.9, 138.5,
136.8, 127.0, 114.6, 113.7, 74.0, 55.2, 38.3, 33.5, 29.6. 25.1; IR
m
(cmꢁ1): 3417, 3072, 2931, 2858, 1639, 1611, 1512, 1460, 1300,
1246, 1176, 1034,831, 762, 638.
4.1.9. 1-(4-(tert-Butyldimethylsilyloxy)phenyl)-2-((2S,6R)-6-(4-
methoxyphenyl)tetrahydro-2H-pyran-2-yl)ethanone 14
½
a 2D3
ꢀ
¼ þ29:5 (c 2.1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.35 (d,
J = 7.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 4.77–4.75 (m, 1H), 4.25 (q,
J = 6.9, 14.8 Hz, 1H), 3.94 (s, 3H), 2.4–2.41 (m, 2H), 1.87–1.74 (m,
4H), 1.38 (t, J = 6.9, 14.8 Hz, 3H), 1.03 (s, 9H), 0.17 (s, 3H), 0.0 (s,
3H); 13C NMR (75 MHz, CDCl3): d 173.6, 158.4, 137.5, 135.9,
126.8, 113.3, 74.2, 60.1, 65.4, 55.1, 40.2, 34.1, 25.8, 21.8, 14.2,
ꢁ4.6, ꢁ5.0; IR (neat): 3451, 2954, 2932, 2857, 1736, 1612, 1248,
1088, 835, 554 cmꢁ1; ESI-MS: m/z 389 (M+Na)+; ESI-HRMS: calcd
for C20H34O4NaSi 389.21186, found 389.21276.
A 50-mL flame-dried two-neck round bottom flask equipped
with a magnetic stirrer bar and reflux condenser was charged with
(R)-1-(4-methoxyphenyl) hex-5-en-1-ol (50 mg, 0.24 mmol), 11-
(4-(tert-butyldimethylsilyloxy)phenyl)prop-2-en-1-one (128 mg,
0.48 mmol) and anhydrous dichloromethane (10 mL) under an ar-
gon atmosphere, and degassed for 5 min. Second generation Grub-
bs’ catalyst (21 mg, 0.024 mmol) was then added in a single
portion resulting in an orange solution, which was refluxed for
12 h. The reaction mixture was then allowed to return to room
temperature, after which the reaction mixture was concentrated
in vacuo to afford a dark brown oil, which was purified by silica
gel column chromatography (10% ethyl acetate in hexanes) to give
the cyclic compound 14 (84 mg, major) in an 88:12 ratio of separa-
4.1.7. (R)-tert-Butyl(1-(4-methoxyphenyl)hex-5-enyloxy)dimeth-
ylsilane 13
To a stirred solution of 12 (698 mg, 1.90 mmol) in CH2Cl2
(10 mL) was added DIBAL-H (299 mg, 2.1 mmol, 1 M solution in
toluene) at ꢁ78 °C. The resulting reaction mixture was stirred for
30 min at the same temperature and then quenched with a satu-
rated sodium potassium tartarate solution. The aqueous layer
was extracted with CH2Cl2 (3 ꢂ 25 mL). The combined organic lay-
ers were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give the corresponding
aldehyde. The aldehyde was subjected to the next step without fur-
ther purification.
ble diastereomers (12 mg, minor). ½a D23
ꢀ
¼ þ9:5 (c 1.1, CHCl3); 1H
NMR (400 MHz, CDCl3):
d 7.89 (d, J = 7.5 Hz, 2H), 7.21 (d,
J = 7.5 Hz, 2H), 6.83 (dd, J = 8.8 Hz, J = 17.6 Hz, 4H), 4.36 (d,
J = 11.3 Hz, 1H), 4.15–4.10 (m, 1H), 3.77 (s, 3H), 3.32 (dd,
J = 6.3 Hz, J = 16.4 Hz, 1H), 2.97 (dd, J = 6.3 Hz, J = 16.4 Hz, 1H),
1.96–1.93 (m, 1H), 1.84–1.81 (m, 2H), 1.75–1.70 (m, 1H),
1.56–1.47 (m, 1H), 1.40–1.32 (m, 1H), 0.99 (s, 9H), 0.23 (s, 6H);
13C NMR (75 MHz, CDCl3): d 197.1. 160.1, 158.6, 135.3, 131.0,
130.5, 127.0, 119.7, 113.5, 79.4, 75.0, 55.1, 45.2, 32.9, 31.3, 29.6,
Potassium t-butoxide (443 mg, 3.94 mmol) and methyl triphen-
ylphosphonium iodide (1.60 g, 3.94 mmol) were dissolved in dry
25.5, 23.7, ꢁ4.4; IR
m
(cmꢁ1): 3448, 2930, 2856, 1741, 1678,

G. Kumaraswamy, D. Rambabu / Tetrahedron: Asymmetry 24 (2013) 196–201
201
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centrolobine as a white solid (42 mg, 75%). ½a D23
¼ þ95:3 (c 0.12,
ꢀ
MeOH) {lit.4b
½
a 2D3
ꢀ
¼ þ97:5 (c 0.1, MeOH)}; 1H NMR (400 MHz,
CDCl3): 7.30 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 6.89 (d,
J = 9.0 Hz, 2H), 6.73 (d, J = 9.0 Hz, 2H), 4.65 (br s, 1H), 4.29 (d,
J = 10.0 Hz, 1H), 3.8 (s, 3H), 3.45–3.42 (m, 1H), 2.74–2.76 (m, 2H),
1.93–1.81 (m, 2H), 1.74–1.7 (m, 1H), 1.64–1.59 (m, 2H),
1.53–1.45 (m, 1H), 1.36–1.28 (m, 1H); 13C NMR (75 MHz, CDCl3):
158.6, 153.4, 135.8, 134.6, 129.5, 127.0, 115.0, 113.6, 79.0, 77.1,
55.2, 38.2, 33.3, 31.2, 30.7, 24.0 IR
m
(cmꢁ1): 3406, 3013, 2931,
2853, 1613, 1513, 1447, 1246, 1176, 1035, 828, 765, 544;
ESI-MS: m/z 335 (M+Na)+; ESI-HRMS: calcd for C20H24O3Na
335.16177, found 335.16237.
Acknowledgments
We are grateful to Dr. J. S. Yadav, Director, IICT, for his encour-
agement. Financial support was provided by the DST, New Delhi,
India (Grant No.: SR/S1/OC-08/2011) and the fellowship provided
to D.R.B. by CSIR (New Delhi) is gratefully acknowledged. Thanks
are also due to Dr. G. V. M. Sharma for his support.
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