Stereoselective synthesis of 1,6-dioxaspiro[4.5]decane chiral spiroketal skeleton via C2-symmetric approach using crossmetathesis

Article abstract of DOI:10.1016/j.tetasy.2008.07.010

A common asymmetric approach for the synthesis of a 1,6-dioxaspiro[4.5]decane chiral spiroketal system, which is a subunit of various natural products, is described and the key aspects of the synthesis are self-crossmetathesis and exploitation of C_2<

Full text of DOI:10.1016/j.tetasy.2008.07.010

Tetrahedron: Asymmetry 19 (2008) 1820–1823
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of 1,6-dioxaspiro[4.5]decane chiral spiroketal
skeleton via C2-symmetric approach using crossmetathesis
*
Errabelli Ramu, B. Venkateswara Rao
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A common asymmetric approach for the synthesis of a 1,6-dioxaspiro[4.5]decane chiral spiroketal sys-
tem, which is a subunit of various natural products, is described and the key aspects of the synthesis
are self-crossmetathesis and exploitation of C2-symmetric of the metathesis product 5 to obtain the
required chiral spiroketal.
Received 6 June 2008
Accepted 8 July 2008
Available online 9 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
biologists and synthetic organic chemists, and several approaches
have been developed for their synthesis.3 It was recently reported
Spiroketals are widely distributed in nature1 and exist in a wide
range of natural products of varying complexity. Spiroketals,
particularly 1,7-dioxaspiro[5.5]undecane and the 1,6-dioxa-
spiro[4.5]decane systems, are subunits of many biologically active
compounds such as polyether ionophores, insect pheromones, and
antibiotic macrolides. The sources of these include insects, mi-
crobes, plants, fungi, and marine organisms.2 The novel structural
features of these spiroketals have attracted the attention of both
that even poorly substituted spiroketals exhibit biological effects
such as tublin modulation4 (Spiket P) and cytotoxicity against tu-
mor cell lines5 (Fig. 1).
Due to the wide occurrence of such structures, a rapid and reli-
able entry into spirocyclic structure is highly desirable. In continu-
ation of our ongoing work in the synthesis of important acetals
such as brevicomins,6 spiroperoxides,6e and also in metathesis
reaction,7 we recently undertook the synthesis of (+)-spirolaxine
HO
1
2
1
R
R
R
O
OH
H
Me
Me
Et
O
O
O
Me
Me
Et
2
R
Me
1,6-dioxaspiro[4,5]decane3,10
Spiket P
OH
O
O
O
O
O
OH
O
(+)-spirolaxine methyl ether
1
Figure 1.
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. V. Rao).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.07.010

E. Ramu, B. V. Rao / Tetrahedron: Asymmetry 19 (2008) 1820–1823
1821
methyl ether (Fig. 1) an anti-helicobacter pylori agent,8 which
contains a 1,6-dioxaspiro[4.5]decane system. We envisaged that
1,6-dioxaspiro[4.5]decane unit 19 can be a precursor of natural
spiroketal class of compounds such as spirolaxine methyl ether
and pheromones3,10 and it could be synthesized from crossmetath-
esis11 (self-metathesis of 4) and acid-catalyzed cyclization
reactions via C2-symmetric substrate. This strategy of making C2-
symmetric compounds from a single substrate in a single step
has an advantage over conventional approach, which requires
more than one substrate thus leading to more manipulations.
chiral spiroketal system from only one starting material using
self-metathesis and acid-catalyzed cyclization. Extention studies
for the synthesis of natural spiroketals are under progress.
4. Experimental
TLC was performed on Merck Kiesel Gel 60, F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on
silica gel (60–120 mesh) using ethyl acetate and hexane mixture
as eluent. Melting points were determined on a Fisher John’s melt-
ing point apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer RX-1 FT-IR system. 1H NMR and 13C NMR spec-
tra were recorded using Varian Gemini-200 MHz or Bruker
Avance-300 MHz spectrometer.1H NMR data are expressed as
chemical shifts in ppm followed by multiplicity (s-singlet; d-dou-
blet; t-triplet; q-quartet; m-multiplet), number of proton(s) and
coupling constant(s) J (Hz). 13C NMR chemical shifts are expressed
in ppm. Optical rotations were measured with Horiba-SEPA-300
digital polarimeter. Accurate mass measurement was performed
on Q STAR mass spectrometer (Applied Biosystems, USA).
2. Results and discussions
The synthesis of 1 was initiated from the known epoxide 2,
which is commercially available. The regioselective opening of
epoxide 2 using allylmagnesiumbromide gave alcohol 3; the alco-
hol functionality was protected as methoxymethyl ether to get the
olefin precursor 4 using methoxymethyl chloride and diisopropyl-
ethylamine in dichloromethane. The key crossmetathesis reaction
of olefin 4 using Grubbs’ first generation olefin metathesis catalyst
(10 mol %) afforded the C2-symmetric dimer compound 5 as an
inseparable E, Z mixture with a ratio of E:Z = 9:1, which was iden-
tified by proton integration values in 1H NMR and was used in the
next step without their separation. Hydroboration of olefin 5
yielded alcohol 6. This was converted to keto compound 7 using
Dess–Martin periodinane. The spiroketalization of ketone 7 by
treatment with concd HCl in MeOH gave cyclized compound 8. Fi-
nally, the deprotection of benzyl group was achieved by Na/liq.
NH3 to afford the desired compound 1, as a colorless liquid in
90% yield, whose physical and spectroscopic data were in good
agreement with the reported values.9
4.1. (S)-((2-(Methoxymethoxy)hex-5-enyloxy)methyl)benzene
4
To an ice-cooled stirred solution of alcohol 3 (2 g, 9.7 mmol) in
DCM (20 mL) were added DIPEA (6.6 mL, 38.8 mmol), MOMCl
(1.5 mL, 19.4 mmol), and DMAP (5 mg). The reaction mixture was
allowed to warm to room temperature, then stirred for 4 h. The
reaction mixture was extracted with DCM (3 ꢀ 30 mL) and water
(30 mL). The combined organic layers were washed with brine
dried over Na2SO4, and concentrated under reduced pressure. The
OR
OR
O
a
c
BnO
BnO
BnO
2
OBn
5
R = H
3
4
OR
b
E
:
Z
= 9 :1
R = MOM
OR
OH
OR
O
e
d
BnO
BnO
OBn
OBn
6
7
OR
OR
OBn
O
OH
O
f
g
O
O
OBn
OH
8
1
Reagents and conditions: (a) CH2=CH-CH2MgBr, CuI, Ether, -20 oC, 12 h, 87%; (b) MOM-Cl, DIPEA,
o
o
DMAP, DCM, 0 C to rt, 4 h, 90%; (c) 10 mol% Grubbs 1st generation catalyst, DCM, 40 C, 12 h, 94%;
(d) BH3-DMS, H2O2, NaOH, THF, 0 oC to rt, 8 h, 85%; (e) Dess-Martin periodinane, DCM, 0 C to rt, 3 h,
o
88%; (f) Conc. HCl, MeOH, 40 oC, 10 min 92%; (g) Na in liq. NH3, THF, -78 oC, 5 h, 85%.
crude product was purified by column chromatography using ethyl
3. Conclusions
acetate: petroleum ether (1:7) to afford compound 4 (2.2 g, 91%) as
a liquid. ½a 3D2
ꢁ
¼ ꢂ42 (c 1, CHCl3); IR mmax 2926, 1639, 1450, 1364,
In conclusion, we have demonstrated a short asymmetric and
versatile approach for the synthesis of 1,6-dioxaspiro[4.5]decane
1211, 1101, 1035 cmꢂ1
;
1H NMR (CDCl3, 200 MHz) d 7.3 (m, 5H),

1822
E. Ramu, B. V. Rao / Tetrahedron: Asymmetry 19 (2008) 1820–1823
5.8 (m, 1H), 5 (m, 2H), 4.72 (d, H, J = 7.2 Hz), 4.62 (d, H, J = 7.2 Hz)
4.52 (s, 2H), 3.72 (m, 1H), 3.47 (m, 2H), 3.35 (s, 3H), 2.13 (m, 2H),
1.65 (m, 2H); 13C NMR (75 MHz) in CDCl3: d 138.1, 128.2,
127.4, 114.6, 95.9, 75.6, 73.1, 72.4, 55.3, 31.1, 29.5; LC–MS: 273
[M+Na]+.
31.5, 25.9, 19.5; LC–MS: 511 [M+Na]+; HRMS: calcd for C28H40O7
[M+Na]+ 511.2671, found 511.2670.
4.5. (2S,5R,7S)-2,7-Bis(benzyloxymethyl)-1,6-dioxaspiro[4.5]-
decane 8
4.2. (5R,12S,E)-5,12-Bis(benzyloxymethyl)-2,4,13,15-tetra-
oxahexadec-8-ene 5
To a stirred solution of ketone 7 (0.5 g, 0.96 mmol) in methanol
was added two drops of concd HCl, then the reaction mixture was
heated to 40 °C. Stirring was continued for another 10 min after
which methanol was removed under reduced pressure. The mix-
ture was extracted with ethyl acetate (2 ꢀ 25 mL) and water
(25 mL). The combined organic layers were dried over Na2SO4
and evaporated under reduced pressure. The crude product was
purified by column chromatography using ethyl acetate–petro-
leum ether (1:6) to afford the compound 8 (0.33 g, 92%) as a color-
The olefin 4 (1 g, 3.75 mmol) was dissolved in dry CH2Cl2
(10 mL). Grubbs’ 1st generation catalyst (0.15 g, 0.18 mmol) was
added. The reaction mixture was stirred at 40 °C temperature for
12 h, and then concentrated under reduced pressure after which
the residue was purified by column chromatography using ethyl
acetate–petroleum ether (1:6) to afford the compound 5 (0.89 g,
94%) as a viscous liquid (cis–trans mixture, 9:1). ½a D32
ꢁ
¼ ꢂ9:2 (c
less liquid. ½a 3D2
ꢁ
¼ þ18:2 (c 1.1, CHCl3); IR mmax 3029, 2866, 1612,
1.25, CHCl3); IR mmax 2926, 2855, 1619, 1451, 1304, 1146, 1103,
1501, 1304, 1113 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 7.3–7.25 (m,
;
1035 cmꢂ1
;
1H NMR (CDCl3, 200 MHz) d 7.28 (m, 10H), 5.4-5.32
10H), 4.55 (s, 2H), 4.53 (s, 2H), 4.25 (m, 1H), 3.99 (m, 1H), 3.48–
3.32 (m, 4H), 2.18–2.07 (m, 1H), 1.95–1.83 (m, 2H), 1.73–1.56
(m, 5H), 1.36–1.21 (m, 2H); 13C NMR (75 MHz) in CDCl3: d 138.7,
138.6, 128.3, 127.6, 127.57, 127.51, 127.4, 106.6, 77.1, 73.7, 73.2,
73.1, 72.7, 69.6, 37.4, 33.1, 27.5, 26.5, 20; LC–MS: 405 [M+Na]+;
HRMS: calcd for C24H30O7 [M+Na]+ 405.2041, found 405.2032.
(m, 2H), 4.7 (d, 2H, J = 6.8 Hz), 4.6 (d, 2H, J = 6.8 Hz) 4.5 (s, 4H),
3.7 (m, 2H), 3.44 (m, 4H), 3.34 (s, 6H), 2.05 (m, 4H), 1.58 (q, 4H,
J = 7.5 and 11.4 Hz); 13C NMR (75 MHz) in CDCl3: d 137.9, 129.7,
129.2, 127.9, 127.1, 95.6, 75.5, 75.3, 72.8, 72.2, 54.9, 31.6, 31.5,
22.8; LC–MS: 495 [M+Na]+; HRMS: calcd For C28H40O6 [M+Na]+
495.2722, found 495.2703.
4.6. (2S,5R,7S)-1,6-Dioxaspiro[4.5]decane-2,7-diyldimethanol 1
4.3. (5R,12S)-5,12-Bis(benzyloxymethyl)-2,4,13,15-tetra-
oxahexadecan-8-ol 6
A solution of compound 8 (0.2 g, 0.52 mmol) in THF (10 mL) was
added to a solution of liq. ammonia (20 mL) and sodium (0.25 g,
10.47 mmol) at ꢂ78 °C. The reaction was then stirred for 5 h. After
evaporation of ammonia, the reaction mixture was neutralized
with saturated aqueous NH4Cl solution and extracted with ethyl
acetate (2 ꢀ 25 mL). The combined organic layers were washed
with water and brine, and dried over Na2SO4. The solvent was re-
moved under reduced pressure and residue was purified by col-
umn chromatography using ethyl acetate–petroleum ether (2:3)
to afford the desired compound 1 (0.08 g, 85%) as a colorless liquid.
To a solution of 5 (0.8 g, 1.58 mmol) in THF (10 mL), BH3ꢃMe2S
(1.6 mL, 1.58 mmol) was added dropwise at ꢂ10 °C. Stirring con-
tinued for 8 h at room temperature. The reaction mixture was
quenched by the addition of 10% NaOH (2 mL) followed by 30%
H2O2 (4 mL) at 0 °C and allowed to warm to room temperature,
stirring continued for another 2 h. The reaction mixture was ex-
tracted with ethyl acetate (2 ꢀ 50 mL) and water (50 mL). The
combined organic layers were washed with brine dried over
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography using ethyl acetate–
petroleum ether (2:5) to afford compound 6 (0.7 g, 85%) as a syrup.
½
a 2D7
ꢁ
¼ þ70:0 (c 1.25, CHCl3), {lit.,9
[a]D = +70.9 (c 1.38, CHCl3)}; IR
mmax cmꢂ1 (neat): 3447, 2927, 1450, 1123, 1141, 968; 1H NMR
(300 MHz) in CDCl3: d 4.2 (dtd, 1H, J = 8.7, 5.5, 3.1 Hz), 3.9 (ddt,
1H, J = 11.9, 6.3, 3.1 Hz), 3.72 (dd, 1H, J = 11.1, 3.1 Hz), 3.58 (dd,
1H, J = 11.9, 3.9 Hz), 3.53 (dd, 1H, J = 12.7, 7.9 Hz), 3.49 (dd, 1H,
J = 12.8, 7.9 Hz), 2.3 (br s), 2.1 (m, 1H), 1.96 (m, 1H), 1.82 (m,
1H), 1.7 (m, 5H), 1.5 (dq, 1H, J = 16.6, 3.1 Hz), 1.3 (qd, 1H,
J = 16.6, 3.9 Hz), 13C NMR (75 MHz) in CDCl3: d 106.6, 78.3, 71.0,
66.0, 64.8, 37.7, 33.05, 26.3, 25.3, 19.6; FABMS: 203 [M+1]+; HRMS:
calcd for C10H18O4 [M+Na]+ 225.1102, found 225.1099.
½
a 3D2
ꢁ
¼ ꢂ7:6 (c 1.2, CHCl3); IR mmax 3482, 2906, 1613, 1501, 1451,
1300, 1142, 1037 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 7.32–7.23
;
(m, 10H), 4.73 (d, 1H, J = 7.1 Hz), 4.71 (d, 1H, J = 7 Hz), 4.62 (d,
1H, J = 7.1 Hz),4.61 (d, 1H, J = 7.0 Hz), 4.51 (s, 4H), 3.71 (m, 2H),
3.6–3.4 (m, 5H), 3.3 (s, 6H), 1.7–1.3 (m, 10H); 13C NMR (75 MHz)
in CDCl3: d 138.4, 138.3, 128.2, 127.5, 96., 76.4, 76.3, 73.2, 72.8,
71.3, 71.1, 55.4, 37.5, 33.1, 32.9, 32, 28.3, 28.21, 21.4; LC–MS:
513 [M+Na]+; HRMS: calcd For C28H42O7 [M+Na]+ 513.2828, found
513.2852.
Acknowledgments
4.4. (5R,12S)-5,12-Bis(benzyloxymethyl)-2,4,13,15-tetra-
oxahexadecan-8-one 7
E.R. thanks the CSIR-New Delhi for research fellowship. The
author also thanks Dr. J. S. Yadav, Dr. A. C. Kunwar and Dr. N. W.
Fadnavis for their help and encouragement, and IFCPAR (Indo-
French project) for financial support.
To a stirred solution of alcohol 6 (0.6 g, 1.14 mmol) in CH2Cl2
(10 mL) at 0 °C was added Dess–Martin periodinane (0.63 g,
1.49 mmol) and stirred for 3 h. The reaction mixture was diluted
with ether (20 mL) followed by washing with saturated NaHCO3
solution (2 ꢀ 25 mL) and brine (2 ꢀ 25 mL). The organic layer
was dried over Na2SO4 and evaporated under reduced pressure.
The crude product was purified by column chromatography using
ethyl acetate–petroleum ether (2:11) to afford compound 7 (0.52 g,
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