Formal total synthesis of aspergillides A and B

Article abstract of DOI:10.1016/j.tetasy.2012.02.009

The formal total synthesis of the cytotoxic 14-membered macrolides, aspergillides A and B is described. A combination of a chiron approach and an asymmetric synthesis is adopted for the synthesis of the target macrolides. The required 2,6-syn and 2,6-anti

Full text of DOI:10.1016/j.tetasy.2012.02.009

Tetrahedron: Asymmetry 23 (2012) 252–263
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Tetrahedron: Asymmetry
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Formal total synthesis of aspergillides A and B
⇑
Gangavaram V.M. Sharma , Vennampalli Manohar
Organic and Biomolecular Chemistry Division, CSIR-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:
The formal total synthesis of the cytotoxic 14-membered macrolides, aspergillides A and B is described. A
combination of a chiron approach and an asymmetric synthesis is adopted for the synthesis of the target
macrolides. The required 2,6-syn and 2,6-anti tetrahydropyrans were constructed via a tandem Sharpless
asymmetric epoxidation and 6-exo cyclization on d-hydroxy allylic alcohols, as the key steps. The requi-
Received 19 January 2012
Accepted 14 February 2012
Available online 14 March 2012
site chiral synthon was prepared from L-ascorbic acid.
Ó 2012 Elsevier Ltd. All rights reserved.
(13
S
)
(13S)
1. Introduction
O
O
O
O
O
O
1
Aspergillides A, B and C (1, 2 and 3, Fig. 1), the first examples of
14-membered macrolactones embedded with a 2,3,6-trisubsti-
tuted tetrahydropyran (THP) moiety, were isolated from the
marine fungus Aspergillus ostianus strain 01F313 by Kusumi
et al.1 in 2008. Aspergillides 1–3 possess good cytotoxic properties
against mouse lymphocytic leukemia cells (L1210).1 Initially, the
9
8
O
(3S) O
(3R) O
(7R)
(7R)
HO
Aspergillide C 3
(4
S
)
HO
HO (4
)
S
Aspergillide A 1
Aspergillide B 2
stereochemistry of aspergillides
A and B was reported as
(3S,4S,7R,13S) and (3S,4S,7R,13R), respectively,1 which upon their
total synthesis by Uenishi et al.2 in 2009, proved to be incorrect. La-
ter, the structures of aspergillides A and B were revised by X-ray
crystallographic studies of their m-bromo benzoate derivatives.3
Only two examples were found in the recent literature,4 where
the tetrahydropyran (THP) was not part of a hemiacetal or acetal
Figure 1. Corrected and revised structures.
lective oxocarbenium allylation for the construction of the desired
trans- or cis-THPs in a stereoselective manner.
In continuation of our program on the synthesis of lactone-con-
taining biologically active natural products,8 we herein report the
formal total synthesis of aspergillides A 1 and B 2 by the combina-
tion of a chiron approach and the stereoselective construction of
the tetrahydropyran via a tandem Sharpless asymmetric epoxida-
tion (SAE)/6-exo cyclization.
moiety. Aspergillide
A
1
contains four stereocenters
(3R,4S,7R,13S) with a 3,7-cis-bridged THP, while aspergillide B 2
contains four stereocenters (3S,4S,7R,13S) with a 3,7-trans-bridged
THP. The structural complexity and biological activity of 1 and 2
have attracted the attention of synthetic chemists.5–7 The main
synthetic challenge in these molecules is the construction of the
cis- and trans- bridged THP in a stereoselective fashion. In previous
reports, Uenishi et al.2 applied the Pd(II)-catalyzed cyclization of a
6-hydroxy allylic alcohol. Marco et al.5b,c,6a and She et al.7a em-
ployed C-glycosidation, while Kuwahara et al.5a,6b used a Ferrier-
type reaction on a cyclic acetal and a silyl ketene acetal. Fuwa
et al.5d,e used intramolecular oxa-conjugate cyclization, while Sab-
itha et al.5f and Takahashi et al.5h used SmI2-induced intramolecu-
lar cyclization. Likewise, Shishido et al.5g used a transannular oxy-
Michael reaction, whereas, Jennings et al.7b utilized a diastereose-
2. Results and discussion
The retrosynthetic analysis (Scheme 1) of macrolide 2 revealed
that it could be realized via macrolactonization from the seco-acid
4, which in turn could be obtained from alcohol 5 and acid 6 via
cross metathesis. Acid 6 was obtained from tetrahydropyran diol
7, which could be formed stereoselectively using a tandem SAE/
6-exo cyclization from d-hydroxy allylic alcohol 8. The required
diol 8 in turn could be obtained from epoxide 9, an L-ascorbic acid
derivative.
2.1. Synthesis of the acid (C1–C8) segment 6
The known8i,9 epoxide 9 (Scheme 2), derived from
acid, upon regioselective opening with vinylmagnesium bromide
L-ascorbic
⇑
Corresponding author. Tel.: +91 40 2719 3154; fax: +91 40 2716 0387x0757.
E-mail address: esmvee@iict.res.in (G.V.M. Sharma).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.009

G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
253
in THF in the presence of CuI10 gave 10 in 84% yield. Alcohol 10 on
subsequent reaction with PMBBr in the presence of NaH in THF
gave ether 11 (75%). Ozonolysis of olefin 11 in CH2Cl2 at ꢀ78 °C fol-
lowed by reduction of the resultant aldehyde with NaBH4 at room
temperature in MeOH gave alcohol 12 (74%).
Treatment of alcohol 12 with TBDPSCl and imidazole in CH2Cl2
gave 13 in 91% yield. Deprotection of the acetonide in 13 with
CuCl2ꢁ2H2O in CH3CN afforded diol 14 (85%), which upon further
chemoselective tosylation in the presence of Bu2SnO11 and Et3N
in CH2Cl2 furnished monotosylate 15 in 90% yield. Nucleophilic
cyclization of tosylate 15 in the presence of K2CO3 in MeOH at
room temperature afforded epoxide 16 in 73% yield.
Regioselective opening of epoxide 16 upon reaction with allyl-
magnesium chloride in dry ether in the presence of CuI10 gave alco-
hol 17 (90%), which upon subsequent masking of the hydroxy
group in 17 with BnBr in THF in the presence of NaH gave ether
18 in 89% yield. Ozonolysis of olefin 18 (Scheme 2) in CH2Cl2 gave
aldehyde 19, which upon subsequent Wittig olefination with
(methoxycarbonylmethylene)triphenyl phosphorane in benzene
at reflux gave
a,b-unsaturated ester 20 (82%). Selective reduction
of the ester in 20 with DIBAL-H in CH2Cl2 furnished allylic alcohol
21 in 84% yield.
At this stage, we planned to synthesize the required tetrahydro-
pyran via
a Sharpless asymmetric epoxidation followed by
Yamaguchi macrolactonization
cross metathesis
O
OH
OH
OH
O
OH
O
O
O
O
+
O
BnO
5
6
BnO
HO
4
2
tandem SAE/
6-exo cyclization
TBDPSO
OH
OH
O
OH
O
L-Ascorbic
acid
TBDPSO
OH
O
O
BnO
OBn
7
9
8
Scheme 1. Retrosynthesis of aspergillide B (2).
OR
O
OPMB
OPMB
OH
O
e
a, b
O
c, d
TBDPSO
RO
O
OR
O
O
O
9
14 R = H (85%)
15 R = Ts (90%)
12 R = H (74%)
10
R = H (84%)
13 R = TBDPS (91%)
11 R = PMB (75%)
OPMB
g, h
O
OPMB
OPMB
f
i
TBDPSO
TBDPSO
TBDPSO
19
R
OR
OBn
R = O
16, (73%)
17 R = H (90%)
20
R = CHCO2CH3 (82%)
18
R = Bn (89%)
OPMB
OPMB
O
j
k
TBDPSO
OH
TBDPSO
PMBO
OH
OBn
OBn
21 (84%)
21a expected
OH
PMBO
O:PMB
O:Bn
δ+
O
OH
Ti
O
O
OH
TBDPSO
O
OH
TBDPSO
22 (80%)
formed exclusively
Ti
TBDPSO
favoured 5-exo
Scheme 2. Reagents and conditions: (a) vinylmagnesium bromide, dry THF, CuI, ꢀ40 °C to rt, 4 h; (b) PMBBr, NaH, dry THF, 0 °C to rt, 6 h; (c) (i) O3, CH2Cl2, dimethylsulfide,
ꢀ78 °C, 15 min; (ii) NaBH4, MeOH, 0 °C to rt, 1 h; (d) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 2 h; (e) (i) CuCl2ꢁ2H2O, CH3CN, 0 °C to rt, 45 min; (ii) Bu2SnO, TsCl, Et3N, rt, 30 min;
(f) K2CO3, MeOH, rt, 1 h; (g) allylmagnesium chloride, CuI, dry ether, ꢀ40 °C to rt, 2 h; (h) BnBr, NaH, dry THF, 0 °C to rt, 5 h; (i) (i) O3, CH2Cl2, dimethylsulphide, ꢀ78 °C,
15 min; (ii) Ph3P=CHCO2Me, benzene, reflux, 2 h; (j) DIBAL-H, CH2Cl2, 0 °C, 1 h; (k) (+)-DIPT, Ti(Oi-Pr)4, cumene hydroperoxide, 4 Å MS, CH2Cl2, ꢀ20 °C to rt, 8 h.

254
G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
OH
OH
H
O
H
a
b
TBDPSO
21
OH
TBDPSO
OH
OBn
8 (88%)
OBn
8a
OH
6-exo
TBDPSO
O
OH
cyclization
BnO
7 (85%)
Scheme 3. Reagents and conditions: (a) DDQ, CH2Cl2:H2O (19:1), 0 °C to rt, 1 h; (b) Sharpless asymmetric epoxidation, Table 1.
deprotection of the PMB ether and acid mediated 6-exo cycliza-
tion.12,13Accordingly, 21 was subjected to a Sharpless asymmetric
epoxidation with (+)-DIPT, cumene hydroperoxide and Ti(Oi-Pr)4
in CH2Cl2. The epoxidation reaction resulted in the 5-exo cyclized
furan derivative 22 (80%) as the only distinguishable product, in-
stead of giving 21a. It was assumed that due to chelation of the tita-
nium, the thermodynamically more stable and more favoured 5-exo
cyclization resulted in the cleavage of the benzyl ether after forma-
tion of the epoxide, wherein the epoxide opening protocol was gov-
erned by Baldwin rules.14 The Ti(Oi-Pr)4 was believed to be acting as
an internal acid in activating the epoxide for cyclization. Similar
observations were reported by Takahashi et al.,15 in which the
MOM group migrated from the d-position to the furan diol.
Due to this unexpected result, we decided to investigate the
tandem Sharpless asymmetric epoxidation and 6-exo cyclization
on the d-hydroxy allylic alcohol 8 rather than allylic alcohol 21.
Accordingly, 21 (Scheme 3) upon selective cleavage of the PMB
ether with DDQ in aq CH2Cl2 gave allylic alcohol 8 in 88% yield.
The tandem Sharpless asymmetric epoxidation (SAE)/6-exo cycli-
zation16 of 8 gave the desired tetrahydropyran 7. As can be seen
from Table 1, the use of tert-butyl hydroperoxide (TBHP), and cat-
alytic (entry 1) and stoichiometric amounts (entry 2) of Ti(Oi-Pr)4
and (ꢀ)-DIPT gave 7 in poor yields.
4 under the Yamaguchi protocol20 by using 2,4,6-trichlorobenzoyl
chloride, followed by cyclization in the presence of DMAP under
high dilution conditions in toluene afforded the E-macrolactone
26 in 52% yield. Finally, since the conversion of 26 into aspergillide
B 2 has already been reported in the literature,6a the synthesis of
26 formally constitutes the synthesis of 2. The spectroscopic data
of 26 and the specific rotation value, ½a D25
¼ ꢀ54:5 (c 0.6, CHCl3);
ꢂ
Lit.6a
[
a]
D = ꢀ56.3 (c 1.5, CHCl3) are in good agreement with the
data reported by Marco et al.6a
2.3. Formal total synthesis of aspergillide A 1
Aspergillide A 1 is the C3-epimer of aspergillide B 2, which pos-
sesses a 2,3,6-trisubstituted tetrahydropyran with a cis-ring junc-
tion. The retrosynthetic analysis of 1 (Scheme 6) revealed that
bis-olefin 27 could be a late stage intermediate, which, upon
RCM reaction19 would generate the macrolide ring structure. The
bis-olefin 27 in turn could be realized by the esterification of acid
28 with alcohol 5, while acid 28 could be obtained from pyran diol
29.
The cis-2,3,6-trisubtituted tetrahydropyran moiety was envis-
aged to come from d-hydroxy allylic alcohol 30 by tandem asym-
metric epoxidation and stereo- and regioselective openings
through a 6-exo cyclization under Sharpless asymmetric epoxidation
conditions. The d-hydroxy allylic alcohol 30 could be realized from
olefin 18, a synthetic intermediate of aspergillide B 2, by inverting
the C-3 stereocenter under Mitsunobu21 reaction conditions.
The use of cumene hydroperoxide (CHP) gave better results,
although low yields were observed with catalytic amounts of re-
agents. Better results were achieved when stoichiometric amounts
of reagents (Table 1, entries 4, 5, and 6) were used. Work-up under
basic, neutral, and acidic conditions gave similar results and entry
5 was found to be the best reaction condition to give 7 in 85% yield.
We believed that due to the ready availability of the nucleophile
(free hydroxy) for the cyclization, the kinetically controlled 6-exo
cyclization was favoured to result in 7 where Ti(Oi-Pr)4 acted as
an internal acid.
Diol 7 (Scheme 4) upon olefination under Masayoshi condi-
tions16a as well as under PPh3, imidazole and I2 conditions16b gave
olefin 24 in poor yields. However, in a two-step procedure, diol 7
was subjected to oxidative cleavage with NaIO4 in aq acetone to give
aldehyde 23, which upon further treatment with (methylene)tri-
phenylphosphonium iodide and t-BuOK gave olefin 24 in 76% yield.
Deprotection of the silyl group in the olefin with TBAF in THF at
room temperature gave alcohol 25 (74%), which upon oxidation with
TEMPO and BIAB17 in aq CH2Cl2 afforded acid 6 in 70% yield.
2.4. Synthesis of macrolactone 1
The PMB ether 18 (Scheme 7) was treated with DDQ in aq
CH2Cl2 to give the hydroxy olefin 31 (93%). The Mitsunobu21 reac-
tion of alcohol 31 upon treatment with p-nitrobenzoic acid, PPh3
and DIAD in THF at room temperature afforded 32 (81%), which
upon base mediated hydrolysis in the presence of K2CO3 in MeOH
gave 33 in 84% yield. The reaction of alcohol 33 with PMBBr in the
presence of NaH in THF furnished ether 34 in 86% yield.
Olefin 34 was subjected to ozonolysis in CH2Cl2 and Wittig olef-
ination of aldehyde 34a with (methoxycarbonylmethylene)tri-
phenylphosphorane in benzene at reflux gave the
a,b-
unsaturated ester 35 (87%). Reduction of the ester 35 with DI-
BAL-H in CH2Cl2 afforded the alcohol 36 (86%), which upon oxida-
tive cleavage with DDQ in aq CH2Cl2 gave d-hydroxy allylic alcohol
37 in 80% yield. Alcohol 37 underwent an SAE/6-exo cyclization un-
der standard reaction conditions without adding an external acid
to furnish tetrahydropyran diol 29 (83%), with epoxidation and
concomitant opening of the epoxide.
Diol 29 upon oxidative cleavage with NaIO4 in aq acetone gave
aldehyde 38, which upon Wittig olefination with (methylene)tri-
phenylphosphonium iodide and t-BuOK in THF afforded olefin 39
2.2. Synthesis of macrolactone
Acid 6 (0.36 mmol) and alcohol 518 (1.8 mmol) were subjected
to cross metathesis19,6a in the presence of Grubbs second genera-
tion catalyst G-II (0.07 mmol) in CH2Cl2 at 40 °C to give hydroxy
acid 4 (Scheme 5) in 48% yield, along with 4a in 25% yield, a
homodimer of 5. Macrolactonization of the resulting hydroxy acid

G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
255
Table 1
Tandem SAE/6-exo cyclization
Entry
Reagents and conditionsa
Time
Work-up
Yield (%)
1
2
3
4
5
6
(+)-DIPT (0.2 equiv), Ti(Oi-Pr)4 (0.1 equiv), TBHP (1.2 equiv), ꢀ20 °C
2 h at ꢀ20 °C then ꢀ10 °C for 48 h
2 h at ꢀ20 °C then ꢀ10 °C for 12 h
1 h at ꢀ20 °C then ꢀ10 °C for 12 h
1 h at ꢀ20 °C then ꢀ10 °C for 5 h
1 h at ꢀ20 °C then ꢀ10 °C for 5 h
1 h at ꢀ20 °C then ꢀ10 °C for 5 h
1 g NaOH in 1 mL brine/1 g of 8
1 g NaOH in 1 mL brine/1 g of 8
1 g NaOH in 1 mL brine/1 g of 8
1 g NaOH in 1 mL brine/1 g of 8
Aq sat. Na2SO4
15
55
60
85
85
80
(+)-DIPT (1.0 equiv), Ti(Oi-Pr)4 (1.0 equiv), TBHP (2.0 equiv), ꢀ20 °C
(+)-DIPT (0.2 equiv), Ti(Oi-Pr)4 (0.1 equiv), CHP (1.5 equiv), ꢀ20 °C
(+)-DIPT (1.2 equiv), Ti(Oi-Pr)4 (1.2 equiv), CHP (2.0 equiv), ꢀ20 °C
(+)-DIPT (1.2 equiv), Ti(Oi-Pr)4 (1.2 equiv), CHP (2.0 equiv), ꢀ20 °C
(+)-DIPT (1.2 equiv), Ti(Oi-Pr)4 (1.2 equiv), CHP (2.0 equiv), ꢀ20 °C
4 M HCl, aq sat. Na2SO4
a
All reactions were performed under pre-dried 4 Å molecular sieves in dry CH2Cl2.
OTBDPS
OR
OTBDPS
O
OH
O
OH
a
O
O
CHO
HO2C
c, d
b
BnO
BnO
BnO
BnO
7
24 R = TBDPS (76%)
25 R = H (74%)
6 (70%)
23
Scheme 4. Reagents and conditions: (a) NaIO4, acetone:H2O (9:1), rt, 30 min; (b) PPh3CH3I, t-BuOK, dry THF, ꢀ10 °C to rt, 6 h; (c) TBAF, dry THF, rt, 1 h; (d) TEMPO, BIAB,
H2O:CH2Cl2, (1:1), 0 °C, 1 h.
OH
N
N
O
O
Mes
Mes
Ph
O
O
O
Cl
HO2C
BnO
2
Ru
PCy3
O
ref: 6a
b
Cl
O
a
4
(48%; E/Z)
5
6
+
G-II:
2
nd generation
Grubb's catalyst
HO
BnO
+
OH
2
26 (52%)
4a
(25%)
3
3
OH
Scheme 5. Reagents and conditions: (a) G-II, CH2Cl2, reflux, 2 h; (b) (i) 2,4,6-trichlorobenzoyl chloride, Et3N, 0 °C to rt, THF, 2 h; (ii) DMAP, dry toluene, 60 °C, 6 h.
Esterification
13
5
OH
O
O
O
O
RCM
+
1
3
O 8
Mitsunobu
reaction
O
O
7
HO2C
BnO
BnO
4
HO
tandem SAE/
27
28
1
6-exo cyclization
OH
OH
TBDPSO
O
OH
TBDPSO
18
OH
OBn
30
BnO
29
Scheme 6. Retrosynthetic analysis of aspergillide A (1).
(77%). Treatment of 39 with TBAF in THF at room temperature fur-
nished alcohol 40 (85%), which upon subsequent oxidation with
TEMPO and BIAB17 in aq CH2Cl2 gave acid 28 in 75% yield.
In a further study on the synthesis of 1, both fragments 28 and 5
(Scheme 8) were subjected to cross metathesis to give very low
yield of the expected product. In order to increase the yield, instead
of a cross metathesis/macrolactonization protocol, we decided to
use an esterification/RCM protocol. Accordingly, esterification of
acid 28 with alcohol 5 in the presence of EDCI and DMAP gave
bis-olefin 27 in 61% yield.22 The bis-olefin upon RCM in the pres-
ence of Grubbs first generation catalyst G-I gave macrolactone 41
in 84% yield. The observed 1H, 13C NMR and specific rotation data,
½
a 2D5
ꢂ
¼ þ68:1 (c 0.27, CHCl3), Lit:5b
½
a 2D5
ꢂ
¼ þ67:5 (c 1.13, CHCl3) for
Z-olefin 41, were in accordance with the reported data by Marco
et al.5b Since, the conversion of 41 into 1 has already been reported,
the synthesis of 41 constitutes the formal total synthesis of 1.

256
G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
OR
OR
d
c
TBDPSO
TBDPSO
OBn
OBn
O
18 R = PMB
a
b
= PNB
31 R = H (93%)
O2N
33
34
R = H (84%)
32
R = PNB (81%)
R = PMB (86%)
OPMB
OR
g
e, f
TBDPSO
TBDPSO
R
TBDPSO
OH
OBn
OBn
36 R = PMB (86%)
34a R = O
37 R = H (80%)
35 R = CHCO2Me (87%)
OH
O
TBDPSO
O
R
O
OH
i, j
R
h
BnO
BnO
38
39
BnO
R = O
R = CH2 (77%)
40
28
R =CH2OH (85%)
R = CO2H (75%)
29 (83%)
Scheme 7. Reagents and conditions: (a) DDQ, CH2Cl2:H2O (19:1), 0 °C to rt, 1 h; (b) p-NO2PhCO2H, PPh3, DIAD, dry THF, 0 °C to rt, 2 h; (c) (i) K2CO3, MeOH, rt, 2 h; (ii) PMBBr,
NaH, dry THF, 0 °C to rt, 5 h; (d) (i) O3, CH2Cl2, dimethylsulphide, ꢀ78 °C, 15 min; (ii) Ph3P@CHCOOMe, benzene, reflux, 2 h; (e) DIBALH, CH2Cl2, 0 °C, 1 h; (f) DDQ, CH2Cl2:H2O
(19:1), 0 °C to rt, 1 h; g) (+)-DIPT, Ti(Oi-Pr)4, CHP, 4 Å MS, CH2Cl2, ꢀ20 °C, 5 h; (h) (i) NaIO4, acetone:H2O (5:1), rt, 30 min; (ii) PPh3CH3I, t-BuOK, dry THF, ꢀ10 °C to rt, 6 h; (i)
TBAF, dry THF, rt, 1 h; (j) TEMPO, BIAB, CH2Cl2, 0 °C, 1 h.
HO
O
a
28 + 5
PCy3
Ru
O
H
OH
Cl
Cl
Ph
BnO
28a
(34%)
PCy3
O
O
O
O
G-I: 1st generation
Grubb's catalyst
c
ref: 5b
b
1
28 + 5
O
O
BnO
BnO
27
(61%)
41
(84%)
Scheme 8. Reagents and conditions: (a) 20 mol % G-II, dry CH2Cl2, reflux, 6 h; (b) EDCI, DMAP, CH2Cl2, 0 °C to rt, 5 h; (c) 10 mol % G-I, dry CH2Cl2, reflux, 5 h.
300 MHz, Varian Inova 400 MHz, and Varian Unity Inova-
500 MHz with tetramethylsilane as an internal standard for solu-
tions in deuteriochloroform. J values are given in hertz. IR spectra
were recorded on Perkin–Elmer IR-683 spectrophotometer with
NaCl optics. Optical rotations were measured with JASCO DIP 300
digital polarimeter at 25 °C. Mass spectra were recorded on CEC-
21–11013 or Fannigan Mat 1210 double focusing mass spectrom-
eters operating at a direct inlet system or LC/MSD Trap SL (Agilent
Technologies).
3. Conclusion
In conclusion, the formal total synthesis of two tetrahydropyran
(THP) 14-membered macrolides, aspergillides A 1 and B 2 has been
achieved by a combination of a chiron approach and asymmetric
synthesis. The THP ring construction was achieved via a tandem
SAE/6-exo cyclization of the epoxide. Thus, 2,3,6-trisubstituted
THP was very efficiently formed in a one pot procedure without
adding an external acid catalyst in good yields.
4.1.1. (S)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-en-1-ol
10
4. Experimental
To a stirred solution of 9 (12.0 g, 83.33 mmol) in dry THF
(60 mL), copper (I) iodide (7.93 g, 41.67 mmol) was added and
cooled to ꢀ40 °C. A solution of vinylmagnesium bromide (2.0 N
solution in THF; 83.33 mL, 166.66 mmol) was added dropwise.
After 4 h, the reaction mixture was treated with aq NH4Cl solution
(30 mL) dropwise. It was then filtered through Celite and the
filtrate was extracted with ethyl acetate (2 ꢃ 50 mL). The organic
layers were dried (Na2SO4), evaporated under reduced pressure
and the residue was purified by column chromatography (Silica
gel, 60–120 mesh, 20% EtOAc in pet. ether) to afford 10 (12.0 g,
4.1. General methods
Solvents were dried over standard drying agents and freshly
distilled prior to use. Chemicals were purchased and used without
further purification. All column chromatography separations were
performed using silica gel (Acme0s 60–120 mesh). Organic solu-
tions were dried over anhydrous Na2SO4 and concentrated below
40 °C in vacuo. 1H NMR (200 MHz, 300 MHz, and 500 MHz) and
13C NMR (50 MHz, 75 MHz and 100 MHz) spectra were measured
with a Varian Gemini FT-200 MHz spectrometer, Bruker Avance

G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
257
84%) as a colorless liquid. ½a D25
ꢂ
¼ ꢀ11:2 (c 1.2, CHCl3); 1H NMR
38.11 mmol) were added at 0 °C and stirred at room temperature
for 2 h. The solvent was evaporated and the residue purified by col-
umn chromatography (silica gel, 60–120 mesh, 5% EtOAc in pet.
(300 MHz, CDCl3): d 5.83 (m, 1H, olefinic), 5.10 (m, 2H, olefinic),
3.97 (dd, 2H, J = 6.0, 6.8 Hz, –OCH2), 3.72 (ddd, 1H, J = 1.5, 4.5,
11.3 Hz, –OCH2), 3.54 (m, 1H, –OCH2), 2.22 (dt, 2H, J = 1.5, 6.8 Hz,
–CH2=CHCH2), 2.07 (d, 1H, J = 5.3 Hz, –OH), 1.41 (s, 3H, –CMe2),
1.34 (s, 3H, –CMe2); 13C NMR (75 MHz, CDCl3): d 134.0, 117.9,
78.4, 71.5, 65.9, 38.1, 26.5, 25.2; IR (neat): 3452, 3076, 2985,
2929, 1640, 1375, 1213, 854 cmꢀ1; ESIMS: (M+Na)+ 195.
ether) to give 13 (15.5 g, 91%) as a colorless oil. ½a D25
¼ ꢀ33:3 (c
ꢂ
0.64, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.60 (m, 4H, ArH-
TBDPS), 7.42–7.29 (m, 6H, ArH-TBDPS), 7.12 (d, 2H, J = 8.7 Hz,
ArH-PMB), 6.74 (d, 2H, J = 8.7 Hz, ArH-PMB), 4.61 (dd, 1H,
J = 11.3 Hz, benzylic), 4.44 (d, 1H, J = 11.3 Hz, benzylic), 4.15 (dd,
1H, J = 6.8, 13.6 Hz, –OCH), 3.89 (dd, 1H, J = 6.8, 8.3 Hz, –OCH),
3.77 (s, 3H, –OCH3), 3.80–3.70 (m, 4H, –OCH2), 3.68–3.54 (m, 2H,
–OCH2), 1.58 (m, 2H, –CH2), 1.40 (s, 3H, –CH3), 1.33 (s, 3H, CH3),
1.04 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 159.2, 135.6,
133.8, 129.7, 129.5, 127.7, 113.7, 109.3, 96.2, 78.5, 76.3, 72.7,
66.0, 60.1, 55.1, 33.9, 26.9, 25.6, 19.3; IR (neat): 3455, 3069,
4.1.2. (S)-4-((S)-1-(4-Methoxybenzyloxy)but-3-enyl)-2,2-dimethyl-
1,3-dioxolane 11
A cooled (0 °C) solution of 10 (12.0 g, 69.77 mmol) in dry THF
(120 mL), was treated with NaH 60% in wax (6.98 g, 174.42 mmol)
and stirred for 30 min. A solution of PMBBr (16.74 g, 83.72 mmol)
[prepared from p-methoxybenzyl alcohol (12.0 g, 86.96 mmol)
and PBr3 (4.09 mL, 43.48 mmol) in ether] in dry THF (40 mL) was
added dropwise and stirred at room temperature for 6 h. The reac-
tion mixture was treated with aq NH4Cl solution (20 mL) and ex-
tracted with EtOAc (2 ꢃ 50 mL). The combined organic layers
were washed with water (2 ꢃ 30 mL), brine (50 mL) and dried
(Na2SO4). The solvent was evaporated under reduced pressure
and the residue purified by column chromatography (silica gel,
60–120 mesh, 15% EtOAc in pet. ether) to furnish 11 (15.4 g, 75%)
2931, 2858, 1612, 1512, 1427, 1373, 1246, 1104, 1076, 701 cmꢀ1
;
HRMS (ESI): calcd. for C32H42O5NaSi [M+Na]+ 557.2699; found
557.2707.
4.1.5. (2S,3S)-5-(tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyl-
oxy)pentane-1,2-diol 14
To a stirred solution of 13 (15.2 g, 28.43 mmol) in acetonitrile
(75 mL) at 0 °C, CuCl2ꢁ2H2O (5.82 g. 34.12 mmol) was added and
stirred at room temperature for 45 min. It was then neutralized
with aq NaHCO3 (20 mL) and the resulting greenish mixture was
filtered through Celite. The filtrate was extracted with ethyl acetate
(2 ꢃ 50 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue by column chromatography (silica gel,
60–120 mesh, 40% EtOAc in pet. ether) afforded 14 (12.01 g, 85%)
as
a
yellow liquid.
½
a 2D5
ꢂ
¼ ꢀ26:9 (c 3.75, CHCl3); 1H NMR
(500 MHz, CDCl3): d 7.20 (d, 2H, J = 8.3 Hz, ArH-PMB), 6.81 (d, 2H,
J = 8.3 Hz, ArH-PMB), 5.81 (dddd, 1H, J = 6.8, 9.8, 13.6, 16.2 Hz, ole-
finic), 5.10–5.01 (m, 2H, olefinic), 4.58 (d, 1H, J = 11.3 Hz, benzylic),
4.56 (d, 1H, J = 11.3 Hz, benzylic), 4.12 (q, 1H, J = 6.0 Hz, –OCH), 3.91
(dd, 1H, J = 6.8, 8.3 Hz, –OCH), 3.79 (s, 3H, –OCH3), 3.65 (m, 1H, –
OCH), 3.44 (m, 1H, –OCH), 2.19 (m, 2H, –CH2), 1.40 (s, 3H, –CH3),
1.33 (s, 3H, –CH3); 13C NMR (100 MHz, CDCl3): d 159.0, 134.5,
130.6, 129.3, 117.1, 113.7, 109.2, 78.7, 77.8, 72.1, 71.3, 65.7, 55.1,
35.2, 26.4, 25.3; IR (neat): 3072, 2985, 2935, 1611, 1513, 1248,
1071 cmꢀ1; HRMS (ESI): calcd. for C17H24O4Na [M+Na]+ 315.1572;
found 315.1573.
as a colorless oil. ½a D25
¼ þ31:3 (c 4.4, CHCl3); IR (neat): 3450,
ꢂ
3069, 2932, 2859, 1612, 1513, 1465, 1247, 1079, 936, 701 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 7.62 (m, 4H, ArH-TBDPS), 7.38 (m,
6H, ArH-TBDPS), 7.12 (d, 2H, J = 8.7 Hz, ArH-PMB), 6.78 (d, 2H,
J = 8.7 Hz, ArH-PMB), 4.52 (d, 1H, J = 11.0 Hz, benzylic), 4.33 (d,
1H, J = 11.0 Hz, benzylic), 3.78 (s, 3H, –OCH3), 3.75 (d, J = 6.0 Hz,
2H, –OCH2), 3.70–3.64 (m, 1H, –OCH), 3.63–3.50 (m, 3H, –OCH),
2.60 (br s, 2H, –OH), 1.83 (m, 2H, –CH2), 1.05 (s, 9H, t-butyl); 13C
NMR (75 MHz, CDCl3): d 159.3, 135.5, 133.3, 130.0, 129.7, 129.6,
127.7, 113.8, 76.6, 73.0, 72.0, 64.0, 60.1, 55.2, 33.2, 26.8, 19.1;
HRMS (ESI): calcd. for C29H38O5NaSi [M+Na]+ 517.2386; found
517.2392.
4.1.3. (S)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-methoxy-
benzyloxy)-propan-1-ol 12
A solution of 11 (15.0 g, 51.37 mmol) in CH2Cl2 (100 mL) was
cooled to ꢀ78 °C and then bubbled with ozone gas for 15 min
and quenched with (CH3)2S (50 mL). The solvent was evaporated
to give aldehyde 11a, which was used for further reaction.
To a solution of the above aldehyde 11a (14.1 g, 43.25 mmol) in
MeOH (70 mL), NaBH4 (0.5 g, 12.75 mmol) was added at 0 °C and
stirred at room temperature for 1 h. Next, MeOH was evaporated
under reduced pressure, the residue was diluted with water
(50 mL) and extracted with ethyl acetate (2 ꢃ 50 mL). The organic
layers were washed with brine (10 mL), dried (Na2SO4), evaporated
and the residue purified by column chromatography (silica gel, 60–
120 mesh, 20% EtOAc in pet. ether) to afford 12 (10.5 g, 74%) as a
4.1.6. (2S,3S)-5-(tert-Butyldiphenylsilyloxy)-2-hydroxy-3-(4-
methoxybenzyloxy)pentyl 4-methoxy benzenesulfonate 15
To a stirred solution of 14 (12.0 g, 24.26 mmol) in CH2Cl2
(120 mL), Et3N (6.57 mL, 48.52 mmol) and Bu2SnO (94.0 mg,
0.49 mmol) were added. After 5 min, p-TsCl (5.12 g, 26.69 mmol)
was added and stirred for 30 min. The reaction mixture was diluted
with CH2Cl2 (50 mL), washed with water (2 ꢃ 50 mL), brine
(50 mL) and dried (Na2SO4). The organic layer was evaporated un-
der reduced pressure and the residue purifed by column chroma-
tography (60–120 silica gel, 10% EtOAc in pet. ether) to give 15
(14.2 g, 90%) as a colorless liquid. 1H NMR (300 MHz, CDCl3): d
7.78 (d, 4H, J = 8.3 Hz, ArH-tosyl), 7.62 (m, 4H, ArH-TBDPS), 7.43–
7.28 (m, 6H, ArH-TBDPS), 7.10 (d, 2H, J = 8.7 Hz, ArH-PMB), 6.76
(d, 2H, J = 8.7 Hz, ArH-PMB), 4.45 (d, 1H, J = 11.0 Hz, benzylic),
4.29 (d, 1H, J = 11.0 Hz, benzylic), 3.96 (dd, 1H, J = 1.9, 5.7 Hz, –
OCH), 3.80 (s, 3H, –CH3), 3.80–3.69 (m, 3H, –OCH), 3.03 (br s, 1H,
–OH), 2.50–2.40 (m, 2H, –CH2OTBDPS), 2.44 (s, 3H, –CH3), 1.78
(m, 2H, –CH2), 1.04 (s, 9H, t-butyl); IR (neat): 3447, 2930, 2858,
1739, 1610, 1513, 1362, 1178, 1035, 819, 703 cmꢀ1; HRMS (ESI)
calcd. for C36H44O7NaSiS [M+Na]+ 671.2474; found 671.2469.
colorless liquid.
½
a 2D5
ꢂ
¼ ꢀ119:4 (c 0.69, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.22 (d, 2H, J = 8.5 Hz, ArH-PMB), 6.82 (d,
2H, J = 8.5 Hz, ArH-PMB), 4.67 (d, 2H, J = 11.3 Hz, benzylic), 4.54
(d, 1H, J = 11.3 Hz, benzylic), 4.18 (dd, 1H, J = 6.6, 13.8 Hz, –OCH),
3.94 (dd, 1H, J = 6.6, 8.3 Hz, –OCH), 3.79 (s, 3H, –OCH3), 3.63 (m,
4H, 2ꢃ –OCH2), 2.03 (br s, 1H, –OH), 1.60 (m, 2H, –CH2), 1.42 (s,
3 H, –CH3), 1.36 (s, 3H, –CH3); 13C NMR (75 MHz, CDCl3): d 159.3,
130.4, 129.7, 113.8, 109.4, 78.4, 77.5, 72.5, 65.9, 59.7, 55.1, 33.0,
26.5, 25.5; IR (neat): 3431, 2985, 2934, 1611, 1512, 1374, 1246,
1037, 846, 819 cmꢀ1; HRMS (ESI): calcd. for C16H24O5Na [M+Na]+
319.1521; found 319.1512.
4.1.4. tert-Butyl ((S)-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
(4-methoxybenzyloxy)pro- poxy) diphenyl silane 13
4.1.7. tert-Butyl ((S)-3-(4-methoxybenzyloxy)-3-((S)-oxiran-2-
yl)propoxy)diphenylsilane 16
To a stirred solution of 12 (9.4 g, 31.76 mmol) in CH2Cl2
(100 mL), imidazole (5.40 g, 79.4 mmol) and TBDPSCl (10.48 g,
A solution of tosylate 15 (14.0 g, 21.53 mmol) in MeOH (70 mL)
was treated with K2CO3 (7.42 g, 53.82 mmol) and stirred at room

258
G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
temperature for 1 h. The reaction mixture was treated further with
aq NH4Cl solution (20 mL). Next, MeOH was evaporated under re-
duced pressure and the residue was extracted with solvent ether
(3 ꢃ 75 mL). The organic layer was washed with water (75 mL),
brine (75 mL), dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (silica gel, 60–120 mesh,
10% EtOAc in pet. ether) to furnish 16 (7.52 g, 73%) as a colorless
1613, 1512, 1247, 1105, 1083, 765, 701 cmꢀ1; HRMS m/z calculated
for C39H48O4NaSi (M+Na)+ 631.3219, found 631.3240.
4.1.10. (6S,7S,E)-Methyl 6-(benzyloxy)-9-(tert-butyldiphenyl-
silyloxy)-7-(4-methoxybenzy- loxy)non-2-enoate 20
A solution of 18 (3.0 g, 4.93 mmol) in CH2Cl2 (30 mL) was cooled
to ꢀ78 °C and bubbled with ozone gas for 15 min and treated with
(CH3)2S (5 mL). The solvent was evaporated to give aldehyde 19 as
a colorless liquid, which was used for further reaction.
liquid. ½a 2D5
ꢂ
¼ ꢀ23:2 (c 3.1, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.60 (dd, 4H, J = 1.3, 7.7 Hz, ArH-TBDPS), 7.41–7.28 (m, 6H, ArH-
TBDPS), 7.17 (d, 2H, J = 8.5 Hz, ArH-PMB), 6.76 (d, 2H, J = 8.5 Hz,
ArH-PMB), 4.74 (d, 1H, J = 11.3 Hz, benzylic), 4.46 (d, 1H,
J = 11.3 Hz, benzylic), 3.77 (s, 3H, –OCH3), 3.80–3.64 (m, 2H, –
OCH2), 3.26 (td, 1H, J = 4.3, 9.3 Hz, –OCH), 2.98 (m, 1H, epoxy),
2.69 (t, 1H, J = 7.4 Hz, 1H, epoxy), 2.40 (dd, 1H, J = 2.6, 4.9 Hz,
epoxy), 1.75 (m, 2H, –CH2), 1.01 (s, 9H, t-butyl); 13C NMR
(75 MHz, CDCl3): d 159.0, 135.5, 133.7, 130.7, 129.6, 129.6, 129.3,
127.6, 113.7, 77.1, 71.6, 59.8, 55.1, 43.1, 35.2, 26.8, 19.1; IR (neat):
3451, 3068, 2932, 2858, 1735, 1612, 1512, 1464, 1247, 1106, 1036,
821, 703 cmꢀ1; HRMS m/z (M+Na)+calculated for C29H36O4NaSi
499.2280, found 499.2259.
Aldehyde 19 (2.9 g, 4.76 mmol) was dissolved in benzene
(30 mL) and treated with (methoxycarbonylmethylene)triphenyl-
phosphorane (1.96 g, 5.72 mmol) at reflux. After 2 h, the solvent
was evaporated and the residue was purified by column chroma-
tography (silica gel, 60–120 mesh, 5% EtOAc in pet. ether) to fur-
nish 20 (2.61 g, 82%) as a colorless oil. ½a D25
¼ ꢀ55:1 (c 3.75,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.62 (m, 4H, ArH-TBDPS),
7.40–7.16 (m, 11H, ArH-TBDPS+Bn), 7.11 (d, 2H, J = 8.7 Hz, ArH-
PMB), 6.87 (dt, 1H, J = 6.8, 15.7 Hz, olefinic), 6.77 (d, 2H,
J = 8.7 Hz, ArH-PMB), 5.69 (d, 1H, J = 15.7 Hz, olefinic), 4.57 (d,
1H, J = 11.5 Hz, benzylic), 4.42 (br s, 2H, benzylic), 4.36 (d, 1H,
J = 11.5 Hz, benzylic), 3.85 (m, 1H, –OCH), 3.78 (s, 3H, –OCH3),
3.77–3.67 (m, 2H, –OCH2), 3.70 (s, 3H, –OCH3), 3.38 (m, 1H,
–OCH), 2.37–2.03 (m, 2H, –CH2), 1.93–1.62 (m, 2H, –CH2), 1.53
(m, 2H, –CH2), 1.05 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d
167.0, 159.1, 149.4, 138.3, 135.4, 133.8, 133.6, 130.7, 129.5,
129.4, 128.3, 127.9, 127.6, 120.9, 113.7, 78.6, 75.1, 72.5, 72.2,
60.3, 55.2, 51.3, 32.6, 28.6, 28.0, 26.8, 19.1; IR (neat): 3428, 3431,
2949, 2859, 1722, 1655, 1612, 1512, 1432, 12349, 1104, 821,
4.1.8. (3S,4S)-1-(tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyl-
oxy)oct-7-en-4-ol 17
To a stirred solution of epoxide 16 (7.5 g, 15.76 mmol) in dry
diethyl ether (100 mL), copper (I) iodide (1.50 g, 7.88 mmol) was
added and the mixture was cooled to -40 °C. A solution of allyl-
magnesium chloride in ether (generated from Mg 1.13 g,
47.28 mmol and allyl chloride 3.87 mL, 47.28 mmol in 50 mL
ether) was added. After 2 h, it was worked up as described for 10
and purified by column chromatography (silica gel, 60–120 mesh,
12% EtOAc in pet. ether) to afford 17 (7.41 g, 90%) as a colorless li-
;
702 cmꢀ1 HRMS m/z calculated for C41H50O6NaSi (M+Na)+
689.3274, found 689.3299.
quid. ½a 2D5
ꢂ
¼ þ8:4 (c 3.6, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.62
4.1.11. (6S,7S,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy)-7-
(4-methoxybenzyloxy)non-2-en-1-ol 21
(br m, 4H, ArH-TBDPS), 7.44–7.31 (br m, 6H, ArH-TBDPS), 7.12 (d,
2H, J = 8.7 Hz, ArH-PMB), 6.77 (d, 2H, J = 8.7 Hz, ArH-PMB), 5.76
(m, 1H, olefinic), 4.95 (m, 2H, olefinic), 4.49 (d, 1H, J = 11.0 Hz,
benzylic), 4.36 (d, 1H, J = 11.0 Hz, benzylic), 3.78 (s, 3H, –OCH3),
3.78–3.70 (m, 2H, –OCH2), 3.46 (m, 2H, –OCH2), 2.28–2.03 (m,
2H, –CH2allylic), 1.89–1.67 (m, 2H, –CH2), 1.52–1.37 (m, 2H,
–CH2), 1.05 (s, 9H, t-butyl); 13C NMR13C NMR (75 MHz, CDCl3): d
159.2, 138.5,135.5, 133.5, 130.4, 129.7, 129.5, 127.7, 114.7, 113.8,
78.9, 72.4, 60.3, 55.2, 33.6, 32.6, 30.0, 26.8, 19.1; IR (neat): 3450,
To a solution of 20 (2.51 g, 3.77 mmol) in CH2Cl2 (15 mL),
DIBAL-H (1.0 M solution in hexanes, 7.54 mL, 7.54 mmol) was
added at 0 °C. The resultant solution was stirred at 0 °C for 1 h
and treated with MeOH (5 mL). The reaction mixture was diluted
with EtOAc (20 mL), followed by aq potassium sodium tartrate
(5 mL) and stirred vigorously at room temperature for an addi-
tional 1 h. It was then filtered through Celite, after which the fil-
trate was dried (Na2SO4), evaporated and the residue purified by
column chromatography (silica gel, 60–120 mesh, 15% EtOAc in
3070, 2932, 2858, 1611, 1513, 1427, 1248, 1107, 1083, 703 cmꢀ1
;
HRMS m/z (M+Na)+calculated for C32H42O4NaSi: 541.2750, found:
pet. ether) to give 21 (2.06 g, 84%) as a colorless oil. ½a D25
¼ ꢀ41:3
ꢂ
541.2736.
(c 3.1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.62 (m, 4H, ArH-
TBDPS), 7.40–7.27 (m, 6H, ArH-TBDPS), 7.27–7.20 (m, 5H, ArH-
Bn), 7.09 (d, 2H, J = 8.4 Hz, ArH-PMB), 6.78 (d, 2H, J = 8.7 Hz, ArH-
PMB), 5.62–5.46 (m, 2H, olefinic), 4.56 (d, 1H, J = 11.7 Hz, benzylic),
4.47–4.38 (m, 3H, benzylic), 3.97 (d, 2H, J = 4.5 Hz, –CH2allylic),
3.87–3.79 (m, 1H, –CHOPMB), 3.79–3.68 (m, 2H, –CH2OTBDPS),
3.76 (s, 3H, –OCH3), 3.41 (m, 1H, –CHOBn), 2.22–2.11 (m, 1H,
–CH2), 2.05–1.82 (m, 2H, –CH2), 1.70–1.35 (m, 3H, –CH2), 1.05 (s,
9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 159.2, 138.6, 135.5,
133,8, 133.8, 132.6, 130.9, 129.6, 129.4, 128.3, 127.9, 127.6,
127.5, 113.7, 78.8, 75.4, 72.4, 72.2, 63.6, 60.4, 55.5, 32.8, 29.1,
28.6, 26.9, 19.3; IR (neat): 3448, 3067, 2929, 2857, 1611, 1511,
1245, 1081, 699 cmꢀ1; HRMS m/z calculated for C40H50O5NaSi
(M+Na)+ 661.3325, found 661.3357.
4.1.9. ((3S,4S)-4-(Benzyloxy)-3-(4-methoxybenzyloxy)oct-7-
enyloxy)(tert-butyl) diphenylsilane 18
To a cooled (0 °C) solution of 17 (7.40 g, 14.29 mmol) in dry THF
(45 mL), 60% NaH in paraffin wax (1.43 g, 35.72 mmol) was added
and stirred for 30 min. The reaction mixture was treated with a
solution of BnBr (2.05 mL, 17.15 mmol) in dry THF (40 mL), and
stirred at room temperature for 5 h. It was then worked up as de-
scribed for 11 and purified by column chromatography (silica gel,
60–120 mesh, 6% EtOAc in pet. ether) to furnish 18 (7.7 g, 89%)
as
a
colorless oil.
½
a 2D5
ꢂ
¼ ꢀ39:9 (c 1.65, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.62 (m, 4H, ArH-TBDPS), 7.40–7.18 (m, 11H,
ArH-TBDPS+Bn), 7.09 (d, 2H, J = 8.3 Hz, ArH-PMB), 6.74 (d, 2H,
J = 8.3 Hz, ArH-PMB), 5.72 (m, 1H, olefinic), 4.93 (m, 2H, olefinic),
4.57 (d, 1H, J = 11.5 Hz, benzylic), 4.57–4.45 (m, 2H, benzylic),
4.40 (d, 1H, J = 11.5 Hz, benzylic), 3.84 (s, 3H, –OCH3), 3.77 (s, 3H,
–OCH3), 3.73 (m, 2H, –OCH2), 3.45 (m, 1H, –OCH), 2.07–1.80 (m,
2H, –CH2), 1.74–1.45 (m, 2H, –CH2), 1.37–1.21 (m, 2H, –CH2),
1.05 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 159.2, 138.8,
138.7, 135.6, 133.9, 131.0, 129.6, 129.4, 128.3, 128.3, 127.9,
127.7, 127.5, 114.8, 113.7, 96.2, 78.8, 75.5, 72.4, 72.3, 60.5, 55.1,
32.9, 30.2, 29.0, 27.1, 19.4; IR (neat): 3450, 3069, 2931, 2858,
4.1.12. (R)-1-((2R,5R)-5-((S)-3-(tert-Butyldiphenylsilyloxy)-1
-(4-methoxybenzyloxy)propyl) tetrahydrofuran-2-yl)ethane-
1,2-diol 22
To a slurry of 4 Å molecular sieves powder (1.50 g) in CH2Cl2
(10 mL), (+)-DIPT (0.22 g, 0.94 mmol) was added and cooled to
ꢀ20 °C. Next, Ti(Oi-Pr)4 (0.22 mL, 0.78 mmol) was added and stir-
red at ꢀ20 °C for 30 min. To this mixture, cumene hydroperoxide
(0.22 mL, 1.56 mmol) was added and stirred at the same

G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
259
temperature for 30 min. A solution of 21 (0.50 g, 0.78 mmol) in
CH2Cl2 (2 mL) was added to the reaction mixture and stirred at
ꢀ20 °C for 1 h. The reaction mixture was stored at ꢀ10 °C for 8 h
and treated with NaOH in brine (1 g in 1 mL brine/1 g of 21) solu-
tion. It was then allowed to warm to room temperature with vig-
orous stirring for 3 h, diluted with ethyl acetate (10 mL) and
filtered through Celite. The filtrate was extracted with EtOAc
(3 ꢃ 15 mL) and the combined organic layers were washed with
brine (15 mL), dried (Na2SO4) and evaporated under reduced pres-
sure. Purification of the residue by column chromatography (silica
gel, 60–120 mesh, 30% EtOAc in pet. ether) gave diol 22 (0.35 g,
OCH), 3.49–3.33 (br m, 4H, –OCH), 2.15 (br, 2H, –OH), 1.94–1.81
(m, 4H, 2 ꢃ –CH2), 1.79–1.52 (m, 2H, –CH2), 1.05 (s, 9H, t-butyl);
13C NMR (50 MHz, CDCl3): d 135.6, 133.8, 129.6, 128.4, 127.7,
127.6, 127.5, 74.4, 72.8, 70.7, 70.4, 70.3, 63.5, 60.1, 27.2, 26.9,
25.6, 24.0, 19.2; IR (neat): 3422, 3067, 2932, 2859, 1631, 1428,
1105, 702 cmꢀ1; HRMS m/z calculated for C32H42O5NaSi (M+Na)+
557.2699, found 557.2672.
4.1.15. (2-((2S,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-
pyran-2-yl)ethoxy) (tert-butyl) diphenylsilane 24
To a cooled (0 °C) solution of 7 (0.95 g, 1.78 mmol) in H2O:ace-
tone (1:9, 10 mL), NaIO4 (0.46 g, 2.14 mmol) was added and stirred
at room temperature for 30 min. Acetone was removed under re-
duced pressure below 30 °C and the residue extracted with CH2Cl2
(2 ꢃ 20 mL). The organic layer was washed with water (20 mL),
brine (20 mL), dried (Na2SO4) and evaporated under reduced pres-
sure to give aldehyde 23 in quantitative yield.
To a solution of (methyl)triphenylphosphonium iodide (2.50 g,
6.20 mmol) in dry THF (30 mL), potassium tert-butoxide (0.50 g,
4.43 mmol) was added at -5 °C and stirred for 6 h below 0 °C. A
solution of aldehyde 23 (0.89 g, 1.77 mmol) in dry THF (10 mL)
was added to the reaction mixture and stirred at room temperature
for 2 h. It was then treated with saturated aq NH4Cl (15 mL) and
extracted with EtOAc (3 ꢃ 20 mL). The organic layers were washed
with water (25 mL), brine (25 mL) and dried (Na2SO4). Evaporation
of the solvent and purification of the residue by column chroma-
tography (silica gel, 60–120 mesh, 5% EtOAc in pet. ether) fur-
80%) as a colorless oil. ½a D25
ꢂ
¼ ꢀ3:8 (c 1.2, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.60 (d, 4H, J = 6.8 Hz, ArH-TBDPS), 7.41–
7.31 (m, 6H, ArH-TBDPS), 7.13 (d, 2H, J = 8.3 Hz, ArH-PMB), 6.76
(d, 2H, J = 8.3 Hz, ArH-PMB), 4.52 (d, 1H, J = 11.0 Hz, benzylic),
4.42 (d, 1H, J = 11.0 Hz, benzylic), 3.94–3.82 (m, 2H, –OCH2), 3.78
(s, 3H, –OCH3), 3.81–3.69 (m, 2H, –OCH2), 3.58–3.46 (m, 3H, –
OCH), 3.21 (m, 1H, –OCH), 2.12 (br, 1H, –OH), 1.94–1.67 (m, 6H,
3 ꢃ –CH2), 1.05 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d
159.1, 135.5, 133.6, 130.1, 129.7, 129.6, 127.6, 113.7, 80.8, 80.6,
77.4, 73.4, 72.3, 63.6, 60.3, 55.1, 34.2, 28.0, 26.8, 26.1, 19.1; IR
(neat): 3759, 3421, 3068, 2931, 2858, 1612, 1512, 1247, 1105,
1078, 702 cmꢀ1; HRMS m/z calculated for C33H44O6NaSi (M+Na)+
587.2804, found 587.2830.
4.1.13. (6S,7S,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy)
non-2-ene-1,7-diol 8
To a solution of 21 (1.7 g, 2.66 mmol) in H2O:CH2Cl2 (20 mL,
1:19), DDQ (0.72 g, 3.19 mmol) was added and stirred at room
temperature for 1 h. The reaction mixture was treated with aq
NaHCO3 (5 mL), filtered and washed with CH2Cl2 (20 mL). The fil-
trate was washed with water (10 mL), brine (10 mL), dried
(Na2SO4) and evaporated under reduced pressure. The residue
was purified by column chromatography (silica gel, 60–120 mesh,
30% EtOAc in pet. ether) to furnish 8 (1.21 g, 88%) as a colorless oil.
nished olefin 24 (0.68 g, 76%) as
a colorless gummy oil.
½
a 2D5
ꢂ
¼ ꢀ45:75 (c 1.10, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.63
(m, 4H, ArH-TBDPS), 7.38–7.28 (m, 6H, ArH-TBDPS), 7.28–7.23
(m, 5H, ArH-Bn), 5.76 (ddd, 1H, J = 4.9, 10.8, 15.7 Hz, olefinic),
5.11 (dd, 2H, J = 10.8, 17.7 Hz, olefinic), 4.53 (d, 1H, J = 11.8 Hz,
benzylic), 4.44 (d, 1H, J = 11.8 Hz, benzylic), 4.16 (m, 1H, –CHOpy-
ran), 4.07 (m, 1H, –CHOpyran), 3.81 (td, 1H, J = 5.4, 8.8 Hz, –OCH2),
3.69 (td, 1H, J = 5.4, 10.8 Hz, –OCH), 3.44 (m, 1H, –OCH), 2.01–1.88
(m, 2H, –CH2), 1.81–1.68 (m, 3H, –CH2 and –CH02), 1.47–1.38 (m,
1H, –CH2), 1.04 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d
138.6, 135.7, 134.1, 133.9, 129.6, 128.3, 127.7, 127.6, 127.5,
115.4, 74.1, 70.6, 70.3, 69.9, 60.4, 30.2, 29.8, 27.1, 23.8, 19.4; IR
(neat): 3449, 2926, 2856, 1637, 1463, 1213, 1107, 762 cmꢀ1; HRMS
½
a 2D5
ꢂ
¼ ꢀ11:3 (c 1.35, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.65 (d,
4H, J = 7.0 Hz, ArH-TBDPS), 7.43–7.22 (m, 11H, ArH-TBDPS+Bn),
5.71–5.53 (m, 2H, olefinic), 4.57 (d, 1H, J = 11.7 Hz, benzylic),
4.54 (d, 1H, J = 11.7 Hz, benzylic), 4.03 (d, 2H, J = 4.5 Hz, –CH2Oal-
lylic), 3.94–3.74 (m, 3H, –OCH+–OCH2), 3.79–3.68 (m, 2H, –
CH2OTBDPS), 3.76 (s, 3H, –OCH3), 3.41 (m, 1H, –CHOBn), 3.32 (dt,
J = 4.3, 7.4 Hz, 1H, –OCH), 2.75 (br s, 1H, –OH), 2.14 (td, 2H,
J = 5.9, 14.5 Hz, –CH2allylic), 1.82–1.50 (m, 4H, 2 ꢃ –CH2), 1.05 (s,
9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 138.5, 135.6, 132.4,
129.8, 129.6, 128.4, 127.8, 127.8, 127.7, 96.2, 81.2, 72.4,
70.9, 63.6, 62.5, 34.7, 29.2, 28.2, 27.0, 19.2; IR (neat): 3421,
3067, 2928, 2857, 1656, 1460, 1421, 1105, 1002, 701 cmꢀ1; HRMS
m/z calculated for
C
32H40O3NaSi (M+Na)+ 523.2644, found
523.2656.
4.1.16. 2-((2S,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-
pyran-2-yl)ethanol 25
To a cooled (0 °C) solution of 24 (0.66 g, 1.32 mmol) in dry THF
(5 mL) under a nitrogen atmosphere, a 1.0 M solution of TBAF in
THF (1.58 mL, 1.58 mmol) was added and stirred for 1 h. It was then
diluted with water (5 mL) and extracted with EtOAc (2 ꢃ 20 mL).
The combined organic layers were washed with water
(2 ꢃ 10 mL), brine (10 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue by column chromatography
(silica gel, 60–120 mesh, 20% EtOAc in pet. ether) afforded 25
m/z calculated for
C
32H42O4NaSi (M+Na)+ 541.2750, found
541.2727.
4.1.14. (R)-1-((2R,5S,6S)-5-(Benzyloxy)-6-(2-(tert-butyldiphenyl-
silyloxy)ethyl)-tetrahydro-2H-pyran-2-yl)ethane-1,2-diol 7
To a slurry of 4 Å molecular sieves powder (2.0 g) in CH2Cl2
(10 mL), (+)-DIPT (0.10 g, 0.43 mmol) was added and cooled to
ꢀ20 °C. Next, Ti(Oi-Pr)4 (0.06 mL, 0.22 mmol) and cumene hydro-
peroxide (0.58 mL, 4.16 mmol) were added with an interval of
30 min. A solution of allylic alcohol 8 (1.12 g, 2.16 mmol) in CH2Cl2
was added and stirred at ꢀ20 °C for 1 h. The reaction mixture was
then stored at -10 °C for 5 h. Work up as described for 22 and puri-
fication of the residue by column chromatography (silica gel, 60–
120 mesh, 30% EtOAc in pet. ether) afforded diol 7 (0.98 g, 85%)
(0.25 g, 74%) as a colorless liquid. ½a D25
ꢂ
¼ ꢀ39:8 (c 0.55, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.37–7.24 (m, 5H, ArH-Bn), 5.81 (ddd,
1H, J = 6.4, 10.6, 17.0 Hz, olefinic), 5.12 (dd, 2H, J = 10.6, 17.4 Hz,
olefinic), 4.61 (d, 1H, J = 11.3 Hz, benzylic), 4.45 (d, 1H, J = 11.3 Hz,
benzylic), 4.27 (dt, 1H, J = 5.3, 6.8 Hz, –CHOpyran), 4.04 (dt, 1H,
J = 3.8, 7.6 Hz, –CHOpyran), 3.75 (t, 2H, J = 5.3 Hz, –OCH2), 3.48–
3.43 (dt, 1H, J = 3.8, 5.3 Hz, –OCH), 2.34–1.92 (m, 3H, –CH2), 1.80
(m, 1H, –CH2), 1.75–1.56 (m, 1H, –CH2); 13C NMR (75 MHz, CDCl3):
d 137.8, 134.8, 128.4, 127.7, 127.6, 116.2, 73.9, 73.5, 71.1, 70.7, 61.4,
30.5, 26.5, 23.2; IR (neat): 3425, 2927, 2856, 1653, 1512, 1456,
1378, 1249, 1025, 699 cmꢀ1; HRMS m/z calculated for C16H22O3Na
(M+Na)+ 285.1466, found 285.1478.
as a colorless oil. ½a D25
ꢂ
¼ ꢀ63:7 (c 2.0, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.63 (m, 4H, ArH-TBDPS), 7.43–7.33 (m, 6H, ArH-TBDPS),
7.33–7.22 (br m, 5H, ArH-Bn), 4.50 (m, 2H, benzylic), 4.29 (dt, 1H,
J = 4.9, 14.4 Hz, –OCHpyran), 3.73 (m, 2H, –OCH), 3.56 (m, 1H, –

260
G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
4.1.17. 2-((2S,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-
pyran-2-yl)acetic acid 6
stirred at 60 °C for 1 h. It was then cooled to room temperature and
concentrated under reduced pressure. Purification of the residue
by column chromatography (silica gel, 60–120 mesh, 8% EtOAc in
pet. ether) furnished lactone 26 (24.5 mg, 52%) as a colorless oil.
To a stirred solution of 25 (0.22 g, 0.84 mmol) in CH2Cl2:H2O
(1:1, 1 mL), TEMPO (39.1 mg, 0.25 mmol) and BIAB (80.5 mg,
2.5 mmol) were added at 0 °C and stirred for 1 h. The reaction mix-
ture was diluted with water (5 mL) and extracted with CH2Cl2
(2 ꢃ 20 mL). The organic layers were washed with brine (10 mL),
dried (Na2SO4), evaporated and the residue purified by column
chromatography (silica gel, 60–120 mesh, 20–25% EtOAc in pet.
ether) to give acid 6 (0.16 g, 70%) as a colorless gummy oil.
½
a 2D5
ꢂ
¼ ꢀ54:5 (c 0.6, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.36–
7.25 (br m, 5H, ArH-Bn), 6.18 (dddd, 1H, J = 1.8, 4.6, 10.9, 15.5 Hz,
H-9), 5.64 (dd, 1H, J = 4.1, 15.5 Hz, H-8), 5.06 (m, 1H, H-13), 4.72
(d, 1H, J = 12.3 Hz, benzylic), 4.48 (m, 1H, H-7), 4.39 (d, 1H,
J = 12.3 Hz, benzylic), 4.18 (br d, 1H, J = 10.9 Hz, H-3), 3.32 (br s,
1H, H-4), 2.64 (dd, 1H, J = 10.9, 14.1 Hz, H-2), 2.25–2.15 (m, 2H,
H-6, H-10), 2.10 (dd, 1H, J = 1.4, 14.1 Hz, H-20), 2.05–1.90 (m, 2H,
H-5, H-100), 1.85–1.75 (m, 2H, H-11, H-12), 1.70–1.55 (br m, 2H,
H-50, H-120), 1.45–1.30 (br m, 2H, H-60, H-110), 1.17 (d, 3H,
J = 6.5 Hz, Me–C13); 13C NMR (100 MHz, CDCl3): d 170.5, 138.5,
137.6, 128.6, 128.2, 127.8, 127.5, 73.0, 71.2, 70.4, 69.9, 68.9, 39.9,
31.7, 30.6, 24.8, 23.0, 22.9, 19.1; IR (neat): 3450, 2938, 1730,
1646, 1377, 1207, 1096, 1044, 869 cmꢀ1; HRMS m/z calculated
for C21H28O4Na (M+Na)+ 367.1885, found 367.1878.
½
a 2D5
ꢂ
¼ ꢀ31:0 (c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.34–
7.20 (m, 5H, ArH-Bn), 5.80 (dt, 1H, J = 4.6, 11.0 Hz, olefinic), 5.27–
5.14 (m, 2H, olefinic), 4.60 (d, 1H, J = 11.9 Hz, benzylic), 4.47 (d,
1H, J = 11.9 Hz, benzylic), 4.35 (m, 1H, –CHOpyran), 4.27 (m, 1H,
–CHOpyran), 3.50 (m, 1H, –CHOBn), 2.72 (dd, 1H, J = 8.5, 15.7 Hz,
–CaH), 2.61 (dd, 1H, J = 5.1, 15.7 Hz, –Ca
H0), 2.04–1.94 (m, 1H, –
CH2), 1.79 (m, 1H, –CH20 ), 1.51–1.25 (m, 2H, –CH2); 13C NMR
(75 MHz, CDCl3): d 176.7, 138.0, 137.4, 128.4, 127.6, 116.4, 72.9,
71.5, 70.7, 70.1, 34.4, 29.5, 25.7; IR (neat): 3450, 2928, 2855,
1737, 1639, 1438, 1363, 1277, 1075, 1040, 921, 699 cmꢀ1; HRMS
m/z calculated for C16H20O4Na (M+Na)+ 299.1259, found 299.1260.
4.1.20. (3S,4S)-4-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)oct-
7-en-3-ol 31
To a solution of 18 (3.20 g, 5.26 mmol) in aq CH2Cl2 (30 mL,
19:1), DDQ (1.43 g, 6.31 mmol) was added and stirred at room
temperature for 1 h. Work-up as described for 8 and purification
of the residue by column chromatography (silica gel, 60–120 mesh,
30% EtOAc in pet. ether) furnished 31 (2.39 g, 93%) as a yellow li-
4.1.18. 2-(2R,3S,6R)-3-(Benzyloxy)-6-[(6S)-hydroxyhept-1-E,Z-
enyl]tetrahydropyran-2-yl} acetic acid 4
Grubbs second generation catalyst G-II (59 mg, ca. 0.07 mmol)
and alcohol 5 (0.205 g, 1.8 mmol) were dissolved in dry, deoxygen-
ated CH2Cl2 (30 mL) under an N2 atmosphere. After heating the
solution to reflux, acid 6 (0.10 g, 0.36 mmol) dissolved in dry deox-
ygenated CH2Cl2 (8 mL) was added. The mixture was then stirred at
reflux for 2 h. After cooling to room temperature, it was quenched
through the addition of DMSO (0.64 mL, 9.0 mmol) followed by stir-
ring for 12 h. The volatiles were evaporated under reduced pressure
and the residue purified by column chromatography (silica gel, 60–
120 mesh). First eluted (25% EtOAc in pet. ether) was (2S,11S,E)-do-
dec-6-ene-2,11-diol 4a (44.5 mg, 25%) as a colorless liquid. 1H NMR
(500 MHz, CDCl3): d 5.74 (dddd, 1H, J = 6.8, 10.2, 13.2, 16.9 Hz, ole-
finic), 4.95 (m, 2H, olefinic), 3.76 (sextet, 1H, J = 6.0 Hz, –OCH), 2.06
(td, 2H, J = 6.4, 13.2 Hz, –CH2), 1.61–1.31 (m, 4H, 2 ꢃ –CH2), 1.51 (d,
6H, J = 6.0 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 138.6, 114.7, 68.0,
38.8, 33.8, 33.7, 25.2, 23.5; IR (neat): 3341, 2936, 2827, 1535, 1460,
quid. ½a 2D5
ꢂ
¼ ꢀ7:3 (c 1.47, CHCl3); 1H NMR (500 MHz, CDCl3): d
7.63 (m, 4H, ArH-TBDPS), 7.39–7.32 (br m, 6H, ArH-TBDPS),
7.30–7.20 (m, 5H, ArH-Bn), 5.77 (m, 1H, olefinic), 4.96 (m, 2H, ole-
finic), 4.60 (d, 1H, J = 11.3 Hz, benzylic), 4.50 (d, 1H, J = 11.3 Hz,
benzylic), 3.89 (m, 2H, –OCH2), 3.77 (m, 1H, –OCH), 3.32 (dt, 1H,
J = 4.9, 7.2 Hz, –CHOBn), 2.66 (d, 1H, J = 3.8 Hz, –OH), 2.15 (m,
2H, –CH2 allylic), 1.81–1.54 (m, 4H, 2 ꢃ –CH2), 1.05 (s, 9H, t-butyl);
13C NMR (75 MHz, CDCl3): d 138.5, 135.5, 134.7, 133.3, 129.7,
129.5, 128.3, 127.8, 127.6, 114.7, 81.5, 72.5, 70.9, 62.3, 34.9, 29.7,
29.2, 26.9, 19.1; IR (neat): 3451, 2929, 2851, 1608, 1527, 1273,
1105, 918, 702 cmꢀ1; HRMS m/z calculated for C31H40O3NaSi
(M+Na)+ 511.2644, found 511.2618.
4.1.21. (3R,4S)-4-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)oct-
7-en-3-yl-4-nitrobenzoate 32
1134, 1015 cmꢀ1
.
The second eluted (40% EtoAc in pet. Ether) was 4 (62.2 mg,
48%) as an inseparable 4:1 E/Z mixture of olefins as a brown col-
ored oil. 1H NMR (500 MHz, CDCl3): (signals from major isomer)
d 7.33 (m, 5H, ArH-Bn), 5.75–5.44 (m, 2H, olefinic), 4.62 (d, 1H,
J = 11.7 Hz, benzylic), 4.44 (d, 1H, J = 11.7 Hz, benzylic), 4.33 (sex-
tet, 2H, J = 6.0 Hz, –OCH), 3.50 (dd, 1H, J = 4.5, 8.3 Hz, –OCH), 2.79
To a solution of 31 (2.35 g, 4.82 mmol), Ph3P (4.42 g,
16.87 mmol) and p-nitrobenzoic acid (3.38 g, 20.24 mmol) in dry
THF (25 mL), DIAD (3.32 mL, 16.87 mmol) was added at 0 °C and
stirred under an N2 atmosphere for 2 h. The solvent was evaporated
under reduced pressure and the residue purified by column chro-
matography (silica gel, 10% EtOAc in pet. ether) to afford 32
(m, 1H, –C
a
H), 2.53 (dd, 1H, J = 4.2, 15.5 Hz, –C
a
H0), 2.14–1.97
(2.49 g, 81%) as a colorless oil. ½a D25
ꢂ
¼ ꢀ15:95 (c 1.03, CHCl3); 1H
(m, 4H, 2 ꢃ –CH2), 1.81 (m, 2H, –CH2), 1.53–1.38 (m, 4H, 2 ꢃ –
CH2), 1.18 (d, 3H, J = 6.0 Hz, –CH3); 13C NMR (75 MHz, CDCl3): (sig-
nals for major isomer) d 175.2, 138.1, 133.5, 132.0, 129.1, 128.4,
127.7, 73.1, 71.6, 70.7, 70.1, 68.0, 38.4, 32.1, 29.7, 26.0, 25.0, 23.2,
22.9; IR (neat): 3450, 2928, 2855, 1737, 1639, 1438, 1363, 1277,
1075, 1040, 921, 699 cmꢀ1; HRMS (ESI): calcd. for C21H30O5Na
[M+Na]+ 385.1990; found 385.1974.
NMR (300 MHz, CDCl3): d 8.23 (d, 2H, J = 8.7 Hz, ArH-PNB), 8.07
(d, 2H, J = 8.7 Hz, ArH-PNB), 7.70–7.53 (m, 4H, ArH-TBDPS), 7.44–
7.29 (m, 6H, ArH-TBDPS), 7.27–7.17 (m, 5H, ArH-Bn), 5.75 (m, 1H,
olefinic), 5.60 (m, 1H, –OCHPNB), 4.98 (m, 2H, olefinic), 4.61 (d,
1H, J = 11.3 Hz, benzylic), 4.46 (d, 1H, J = 11.3 Hz, benzylic), 3.81–
3.71 (m, 1H, –OCHBn), 3.77–3.62 (m, 2H, –OCH2), 2.60 (m, 1H, –
CH2), 2.35–2.20 (m, 1H, –CH2), 2.19–1.93 (m, 2H, –CH2), 1.86–
1.57 (m, 2H, –CH2), 1.03 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3):
d 164.1, 150.4, 138.2, 137.9, 135.7, 135.5, 130.7, 129.6, 128.3, 127.9,
127.6, 127.6, 123.4, 115.2, 79.5, 73.8, 72.4, 60.0, 32.0, 30.0, 30.0,
26.8, 19.1; IR (neat): 3416, 3068, 2932, 2859, 1722, 1608, 1527,
1462, 1427, 1273, 1105, 918, 702 cmꢀ1; HRMS m/z calculated for
4.1.19. (1S,5S,11R,14S)-14-(Benzyloxy)-5-methyl-4,15
dioxabicyclo[9.3.1] pentadec-9E-en-3-one 26
A solution of hydroxy acid 4 (50 mg, 0.14 mmol, E/Z mixture) in
dry THF (1 mL) at 0 °C under an N2 atmosphere was treated with
Et3N (0.6 mL, 0.42 mmol) and 2,4,6-trichlorobenzoyl chloride
(102.4 mg, 0.42 mmol) sequentially. After stirring at room temper-
ature for 2 h, it was diluted with toluene (20 mL). Next, this mix-
C
38H43NO6NaSi (M+Na)+ 660.2761, found 660.2718.
4.1.22. (3R,4S)-4-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)oct-
7-en-3-ol 33
ture was added dropwise over 5 h to
a solution of DMAP
(0.171 g, 1.4 mmol) in dry toluene (150 mL) preheated at 60 °C.
After completion of the addition, the reaction mixture was further
A solution of 32 (2.40 g, 3.77 mmol) in MeOH (25 mL) was trea-
ted with K2CO3 (1.56 g, 11.31 mmol) and stirred at room tempera-

G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
261
ture for 2 h. Next, MeOH was evaporated under reduced pressure
and the residue was extracted with solvent ether (3 ꢃ 50 mL).
The organic layers were washed with water (75 mL), brine
(75 mL), dried (Na2SO4), and evaporated. The residue was purified
by column chromatography (silica gel, 60–120 mesh, 25% EtOAc in
3430, 3031, 2949, 2859, 1720, 1649, 1612, 1511, 1432, 1249,
1104, 821, 702 cmꢀ1
; HRMS (ESI): calcd. for C41H50O6NaSi
[M+Na]+ 689.3274; found 689.3299.
4.1.25. (6S,7R,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy)-7-
(4-methoxybenzyloxy)non-2-en-1-ol 36
pet. ether) to afford 33 (1.55 g, 84%) as
a colorless liquid.
½
a 2D5
ꢂ
¼ ꢀ15:2 (c 1.88, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.64
To a solution of 35 (1.40 g, 2.1 mmol) in CH2Cl2 (10 mL), DIBAL-
H (1.0 M solution in hexanes, 5.25 mL, 5.25 mmol) was added at
0 °C and stirred for 1 h. Work-up as described for 21 and purifica-
tion of the residue by column chromatography (silica gel, 60–120
mesh, 10 to 15% EtOAc in pet. ether) gave allylic alcohol 36
(m, 4H, ArH-TBDPS), 7.44–7.31 (m, 6H, ArH-TBDPS), 7.29–7.17
(m, 5H, ArH-Bn), 5.77 (m, 1H, olefinic), 4.95 (m, 2H, olefinic),
4.58 (d, 1H, J = 11.7 Hz, benzylic), 4.56 (d, 1H, J = 11.7 Hz, benzylic),
3.97 (m, 1H, –CHOH), 3.90–3.77 (m, 2H, –CH2OTBDPS), 3.38 (m, 1H,
–OCHBn), 2.89 (br m, 1H, –OH), 2.36–2.02 (m, 2H, –CH2allylic),
1.80–1.65 (m, 2H, –CH2), 1.62–1.33 (m, 2H, –CH2), 1.05 (s, 9H, t-bu-
tyl); 13C NMR (100 MHz, CDCl3): d 138.6, 135.5, 135.5, 129.7, 128.3,
127.8, 127.7, 127.5, 123.5, 114.7, 81.5, 72.2, 71.7, 62.8, 34.0, 29.6,
28.9, 26.8, 19.0; IR (neat): 3451, 3072, 2928, 2859, 1600, 1512,
1427, 1248, 1108, 1083, 703 cmꢀ1; HRMS m/z calculated for
(1.15 g, 86%) as a colorless oil. ½a D25
ꢂ
¼ ꢀ2:8 (c 4.5, CHCl3); 1H
NMR (500 MHz, CDCl3): d 7.61 (m, 4H, ArH-TBDPS), 7.39–7.20
(m, 11H, ArH-TBDPS+Bn), 7.11 (d, 2H, J = 8.7 Hz, ArH-PMB), 6.75
(d, 2H, J = 8.7 Hz, ArH-PMB), 5.55 (m, 2H, olefinic), 4.67 (d, 1H,
J = 11.9 Hz, benzylic), 4.55 (d, 1H, J = 11.4 Hz, benzylic), 4.45 (d,
1H, J = 11.9 Hz, benzylic), 4.39 (d, 1H, J = 11.4 Hz, benzylic), 4.09
(m, 1H, –CHO), 3.99 (m, 2H, –OCH2), 3.83–3.73 (m, 2H, –OCH),
3.77 (s, 3H, –OCH3), 3.47 (m, 1H, –OCHBn), 2.23–1.18 (m, 2H,
–CH2allylic), 1.77–1.64 (m, 3H, CH2), 1.51–1.40 (m, 1H, –CH2),
1.05 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 159.0, 138.7,
136.8, 135.5, 133.8, 132.6, 130.9, 129.6, 129.3, 128.3, 127.8,
127.6, 127.5, 113.7, 80.0, 76.9, 72.9, 66.1, 63.6, 60.6, 55.2, 33.8,
29.7, 28.7, 26.9, 19.2; IR (neat): 3450, 2931, 2859, 1736, 1617,
C
31H40O3NaSi (M+Na)+ 511.2644, found 511.2619.
4.1.23. ((3R,4S)-4-(Benzyloxy)-3-(4-methoxybenzyloxy)oct-7-
enyloxy)(tert-butyl)diphenyl- silane 34
To a cooled (0 °C) and stirred solution of 33 (1.50 g, 3.07 mmol)
in dry THF (10 mL), NaH (0.307 g, 7.67 mmol) was added and stir-
red for 30 min. It was then treated with a solution of PMBBr
(0.74 g, 3.68 mmol) in dry THF (5 mL). After 5 h, it was worked
up as described for 11 and purified by column chromatography
(silica gel, 60–120 mesh, 15% EtOAc in pet. ether) to furnish 34
1458, 1246, 1102, 970, 701 cmꢀ1
40H50O5NaSi [M+Na]+ 661.3325; found 661.3357.
; HRMS (ESI): calcd. for
C
(1.60 g, 86%) as a yellow liquid. ½a D25
ꢂ
¼ þ1:4 (c 2.3, CHCl3); 1H
4.1.26. (6S,7R,E)-6-(Benzyloxy)-9-(tert-butyldiphenylsilyloxy)-
non-2-ene-1,7-diol 37
NMR (500 MHz, CDCl3): d 7.61 (m, 4H, ArH-TBDPS), 7.39–7.18 (br
m, 11H, ArH-TBDPS+Bn), 7.11 (d, 1H, J = 8.2 Hz, ArH-PMB), 6.74
(d, 2H, J = 8.2 Hz, ArH-PMB), 5.73 (m, 1H, olefinic), 4.93 (m, 2H, ole-
finic), 4.66 (d, 1H, J = 11.9 Hz, benzylic), 4.55 (d, 1H, J = 11.9 Hz,
benzylic), 4.45 (d, 1H, J = 11.9 Hz, benzylic), 4.37 (d, 1H,
J = 11.9 Hz, benzylic), 3.83–7.72 (m, 2H, –OCH2), 3.76 (s, 3H, –
OCH3), 3.50 (m, 1H, –OCH), 3.46 (br m, 1H, –OCH), 2.26–2.02 (m,
2H, –CH2), 1.78–1.66 (m, 3H, –CH2), 1.51–1.41 (m, 1H, –CH2),
1.04 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3): d 159.0, 138.8,
138.5, 135.5, 133.9, 130.9, 129.6, 129.3, 128.3, 127.8, 127.6,
127.4, 114.7, 113.7, 80.0, 77.0, 72.2, 72.0, 60.6, 55.2, 33.7, 30.2,
30.0, 26.9, 19.2; IR (neat): 3452, 3069, 2928, 2860, 1613, 1502,
1240, 1101, 1082, 701 cmꢀ1; HRMS m/z calculated for C39H48O4N-
aSi (M+Na)+ 631.3219; found 631.3240.
To a solution of 36 (1.1 g, 1.72 mmol) in H2O:CH2Cl2 (10 mL,
1:19), DDQ (0.47 g, 2.06 mmol) was added and stirred at room
temperature for 1 h. Work-up was as described for 8 and the resi-
due purified by column chromatography (silica gel, 60–120 mesh,
30% EtOAc in pet. ether) to furnish 37 (0.71 g, 80%) as a colorless
oil. ½a 2D5
ꢂ
¼ ꢀ22:9 (c 2.1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.63
(m, 4H, ArH-TBDPS), 7.41–7.34 (m, 6H, ArH-TBDPS), 7.30–7.22
(m, 5H, ArH-Bn), 5.73 (m, 1H, olefinic), 5.52 (m, 1H, olefinic),
4.58 (d, 1H, J = 11.4 Hz, benzylic), 4.52 (d, 1H, J = 11.4 Hz, benzylic),
4.46 (d, 2H, J = 6.4 Hz, –CH2OH), 3.95 (m, 1H, –OCH), 3.90–3.80 (m,
2H, –CH2OTBDPS), 3.35 (m, 1H, –CHOBn), 2.89 (br, 1H, –OH), 2.28–
2.06 (m, 2H, –CH2), 1.74–1.67 (m, 2H, –CH2), 1.60–1.52 (m, 1H,
–CH), 1.43–1.33 (m, 1H, –CH), 1.06 (s, 9H, t-butyl); 13C NMR
(75 MHz, CDCl3): d 138.5, 135.5, 133.1, 133.0, 132.8, 129.8, 129.3,
128.4, 127.7, 127.6, 81.4, 72.2, 71.8, 63.7, 62.9, 34.0, 29.1, 28.1,
26.8, 19.1; IR (neat): 3450, 3055, 2919, 2825, 1601, 1501, 1235,
1061, 702 cmꢀ1; HRMS (ESI): calcd. for C32H42O4NaSi [M+Na]+
541.2750; found 541.2727.
4.1.24. (6S,7S,E)-Methyl-6-(benzyloxy)-9-(tert-butyldiphenyl-
silyloxy)-7-(4-methoxybenzy- loxy) non-2-enoate 35
A solution of 34 (1.60 g, 2.63 mmol) in CH2Cl2 (15 mL) was
cooled to ꢀ78 °C and bubbled with ozone gas for 15 min. It was
then quenched with (CH3)2S (2 mL) and the solvent evaporated
to give aldehyde 34a as a colorless oil in quantitative yield.
The crude aldehyde 34a was dissolved in benzene (30 mL) and
treated with (methoxycarbonylmethylene)triphenylphosphorane
(1.83 g, 5.33 mmol) at reflux. After 2 h, the solvent was evaporated
and the residue purified by column chromatography (silica gel, 60–
120 mesh, 5% EtOAc in pet. ether) to furnish 35 (1.52 g, 87%) as a
4.1.27. (S)-1-((2R,5S,6R)-5-(Benzyloxy)-6-(2-(tert-butyldiphenyl-
silyloxy)ethyl)-tetrahydro-2H-pyran-2-yl)ethane-1,2-diol 29
To a slurry of 4 Å molecular sieves powder (1.0 g) in CH2Cl2
(10 mL), (+)-DIPT (0.20 g, 0.97 mmol) was added and cooled to
ꢀ20 °C. Next, Ti(Oi-Pr)4 (0.28 mL, 0.97 mmol), cumene hydroper-
oxide (0.27 mL, 1.94 mmol) and a solution of allylic alcohol 37
(0.50 g, 0.97 mmol) in CH2Cl2 (2 mL) were added sequentially with
an interval of 30 min and stirred at ꢀ20 °C for 1 h. The reaction
mixture was then kept at ꢀ20 °C for 5 h. Worked up as described
for 7 and purified the residue by column chromatography (silica
gel, 60–120 mesh, 30% EtOAc in pet. ether) to afford diol 29
colorless oil. ½a D25
ꢂ
¼ ꢀ10:95 (c 2.4, CHCl3); 1H NMR (300 MHz,
CDCl3):
d 7.61 (br m, 4H, ArH-TBDPS), 7.41–7.30 (m, 6H,
ArH-TBDPS), 7.27–7.23 (m, 5H, ArH-Bn), 7.10 (d, 2H, J = 8.5 Hz,
ArH-PMB), 6.88 (dd, 1H, J = 6.8, 13.8 Hz, -olefinic), 6.74 (d, 1H,
J = 8.5 Hz, ArH-PMB), 5.71 (d, 1H, J = 15.7 Hz, olefinic), 4.68–4.55,
4.41, 4.38 (4 ꢃ d, 4H, benzylic), 3.84–3.73 (m, 2H, –CH2OTBDPS),
3.77 (s, 3H, –OCH3), 3.72–3.68 (m, 1H, –CHOPMB), 3.70 (s, 3H, –
OCH3), 3.45 (m,1H, –CHOBn), 3.39–2.11 (br m, 2H, –CH2), 1.84–
1.62 (m, 3H, –CH2), 1.58–1.44 (m, 1H, CH2), 1.05 (s, 9H, t-butyl);
13C NMR (75 MHz, CDCl3): d 167.0, 159.0, 149.2, 136.4, 135.5,
133.8, 130.8, 129.6, 129.3, 128.3, 127.8, 127.6, 121.0, 113.7, 80.0,
76.7, 72.2, 60.5, 55.2, 51.3, 32.6, 28.6, 28.0, 26.9, 19.2; IR (neat):
(0.43 g, 83%) as a colorless oil. ½a D25
ꢂ
¼ þ80:6 (c 2.0, CHCl3); 1H
NMR (500 MHz, CDCl3): d 7.62 (m, 4H, ArH-TBDPS), 7.40–7.29
(m, 6H, ArH-TBDPS), 7.30–7.22 (m, 5H, ArH-Bn), 4.60 (d, 1H,
J = 11.6 Hz, benzylic), 4.40 (d, 1H, J = 11.6 Hz, benzylic), 3.75 (m,
2H, –CH2OH), 3.54 (m, 2H, –CH2OTBDPS), 3.45 (dd, 1H, J = 5.3,
10.1 Hz, –CHOpyran), 3.37 (td, 1H, J = 2.4, 9.2 Hz, –CHOpyran),
3.29 (m, 1H, –CHOH), 3.01 (td, 1H, J = 4.3, 10.1 Hz, –CHOBn),

262
G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
2.27–2.19 (m, 2H, –CH), 1.79 (m, 1H, –CH2), 1.49 (m, 1H, –CH2),
1.38 (m, 2H, –CH2), 1.05 (s, 9H, t-butyl); 13C NMR (75 MHz, CDCl3):
d 138.4, 135.5, 133.9, 129.5, 128.3, 127.7, 127.6, 127.6, 78.4, 77.6,
77.2, 73.5, 70.78, 63.6, 60.3, 35.3, 28.8, 26.8, 26.4, 19.2; IR (neat):
16.6 Hz, olefinic), 5.23 (dd, 1H, J = 11.1, 17.7 Hz, olefinic), 4.63 (d,
1H, J = 11.6 Hz, benzylic), 4.43 (d, 1H, J = 11.6 Hz, benzylic), 3.91
(dd, 1H, J = 5.0, 10.5 Hz, –OCHpyran), 3.74 (td, 1H, J = 3.3, 7.7 Hz,
–OCHpyran), 3.18 (td, 1H, J = 4.4, 10 Hz, –OCHBn), 2.90 (dd, 1H,
3566, 3448, 3064, 2922, 2829, 1612, 1502, 1264, 1081, 703 cmꢀ1
;
J = 3.9, 15.5 Hz, –CaH), 2.51 (dd, 1H, J = 7.7, 15.5 Hz, –CaH), 2.31
HRMS (ESI): calcd. for C32H42O5NaSi (M+Na)+ 557.2699; found
557.2679.
(qd, 1H, J = 3.3, 7.2 Hz, –CH2), 1.82 (qd, 1H, J = 3.3, 5.5 Hz, –CH2),
1.49 (m, 2H, –CH2); 13C NMR (75 MHz, CDCl3): d 176.5, 137.9,
137.8, 128.3, 127.7, 127.6, 115.2, 77.8, 77.0, 76.3, 70.8, 38.1, 30.5,
26.7 IR (neat): 3450, 2928, 2855, 1737, 1639, 1438, 1363, 1277,
1075, 1040, 921, 699 cmꢀ1; HRMS (ESI): calcd. for C16H20O4Na
[M+Na]+ 299.1259; found 299.1260.
4.1.28. (2-((2R,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-
pyran-2-yl)ethoxy) (tert-butyl) diphenylsilane 39
The diol 29 (0.40 g, 0.75 mmol) was treated with NaIO4 (0.19 g,
0.9 mmol) in acetone:H2O (5:1, 6 mL) at room temperature for
30 min. Work-up as described for 23 gave (2R,5S,6R)-5-(benzyl-
oxy)-6-(2-(tert-butyldiphenylsilyloxy)ethyl)-tetrahydro-2H-pyr-
an-2-carba- ldehyde 38, which was used for further reaction.
To a solution of (methyl)triphenylphosphonium iodide (1.05 g,
2.59 mmol) in dry THF (10 mL), potassium tert-butoxide (0.21 g,
1.85 mmol) was added at -10 °C and stirred for 6 h. A solution of
38 (0.37 g, 0.74 mmol) in THF (10 mL) was added dropwise to
the above solution and stirred at room temperature for 1 h.
Work-up as described for 24 and purification of the residue by col-
umn chromatography (silica gel, 60–120 mesh, 5% EtOAc in pet.
4.1.31. (S)-Hept-6-en-2-yl-2-((2R,3S,6R)-3-(benzyloxy)-6-vinyl-
tetrahydro-2H-pyran-2-yl)- acetate 27
To a stirred solution of acid 28 (50.0 mg, 0.18 mmol) in dry
CH2Cl2 (2 mL) at °C, under an N2 atmosphere, EDCI (51.8 mg,
0.27 mmol) and DMAP (33.0 mg, 0.27 mmol) were added. After
10 min, alcohol 5 (25.0 mg, 0.22 mmol) in dry CH2Cl2 (2 mL) was
added and stirred for 5 h. The reaction mixture was treated with
an aq NH4Cl solution (10 mL) and extracted with CH2Cl2
(3 ꢃ 10 mL). The organic layer was sequentially washed with 1 M
HCl (10 mL), water (10 mL), brine (10 mL) and dried (Na2SO4).
The solvent was evaporated and the residue purified by column
chromatography (silica gel, 60–120 mesh, 5% EtOAc in pet. ether)
ether) furnished 39 (0.28 g, 77%) as a colorless oil. ½a D25
¼ þ96:0
ꢂ
(c 1.75, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.64 (m, 4H, ArH-
TBDPS), 7.38–7.22 (m, 11H, ArH-TBDPS+Bn), 5.76 (ddd, 1H,
J = 4.8, 10.6, 15.5 Hz, olefinic), 5.08 (dd, 2H, J = 10.6, 17.4 Hz, ole-
finic), 4.58 (d, 1H, J = 11.6 Hz, benzylic), 4.42 (d, 1H, J = 11.6 Hz,
benzylic), 3.86 (m, 1H, –OCHpyran), 3.81–3.73 (m, 2H, –OCH2),
3.46 (m, 1H, –OCHpyran), 3.06 (m, 1H, –OCHBn), 2.29–2.19 (m,
2H, –CH2), 1.76 (m, 1H, –CH2), 1.58 (m, 1H, –CH2), 1.50–1.29 (m,
2H, –CH2), 1.04 (s, 9H, t-butyl); 13C NMR (100 MHz, CDCl3): d
138.6, 135.6, 134.1, 132.0, 129.4, 128.3, 127.6, 127.5, 127.5,
114.5, 77.3, 77.3, 77.0, 70.8, 60.2, 35.3, 30.7, 29.3, 26.8, 19.2; IR
(neat): 3440, 2928, 2841, 1615, 1442, 1213, 1107 cmꢀ1; HRMS
(ESI): calcd. for C32H40O3NaSi [M+Na]+ 523.2644; found 523.2655.
to furnish 27 (41.0 mg, 61%) as a colorless oil. ½a D25
¼ þ100:8 (c
ꢂ
0.49, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.35 -7.27 (m, 5H,
ArH-Bn), 5.83–5.73 (m, 2H, olefinic), 5.22–4.93 (m, 4H, olefinic),
4.92 (m, 1H, –CHOester), 4.63 (d, 1H, J = 11.9 Hz, benzylic), 4.44
(d, 1H, J = 11.1 Hz, benzylic), 3.86 (m, 1H, –OCH), 3.76 (td, 1H,
J = 4.0, 9.0 Hz, –OCH), 3.18 (td, 1H, J = 4.5, 9.5 Hz, –OCH), 2.86
(dd, 1H, J = 4.0, 14.9 Hz, –CaH), 2.41 (dd, 1H, J = 9.0, 14.9 Hz, –
CaH), 2.28 (m, 1H, –CH), 2.02 (dd, 2H, J = 5.0, 11.9 Hz, –CH2),
1.80 (m, 1H, –CH), 1.60–1.24 (br m, 6H, 3 ꢃ –CH2), 1.17 (d, 3H,
J = 6.0 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 171.2, 138.5, 138.1,
128.3, 127.8, 127.7, 127.6, 114.8, 114.6, 77.6, 77.6, 76.5, 70.7,
70.5, 38.6, 35.4, 33.4, 30.6, 28.9, 24.6, 19.9; IR (neat): 3450, 2928,
2855, 1730, 1639, 1448, 1353, 1270, 1075, 1040 cmꢀ1; HRMS
(ESI): calcd. for C23H32O4Na [M+Na] 395.3192; found 395.2197.
4.1.29. 2-((2R,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-
pyran-2-yl)ethanol 40
To a cooled (0 °C) solution of 39 (0.25 g, 0.5 mmol) in dry THF
(15 mL) under a nitrogen atmosphere, TBAF (0.6 mL, 0.6 mmol)
was added and stirred for 1 h. Work-up as described for 25 and
purification of the residue by column chromatography (silica gel,
60–120 mesh, 25% EtOAc in pet. ether) gave 40 (0.11 g, 85%) as a
4.1.32. (1R,5S,11R,14S,Z)-14-(Benzyloxy)-5-methyl-4,15-dioxa-
bicyclo[9.3.1]-pentadec-9-en-3-one 41
To a stirred solution of 10 mol % of Grubbs first generation
ruthenium catalyst G-I in deoxygenated dry CH2Cl2 (100 mL) at re-
flux, a solution of diene 27 (20.0 mg, 0.05 mmol) in CH2Cl2 (20 mL)
was added slowly over a period of 1 h and stirred for 3 h under an
N2 atmosphere at the same temperature. The reaction mixture was
cooled to room temperature and stirring was continued for a fur-
ther 2 h. Next, DMSO (0.20 mL, 2.5 mmol) was added and allowed
to stir for an additional 10 h. The reaction mixture was concen-
trated to give a brown residue, which was purified by column chro-
matography (silica gel, 60–120 mesh, 4–5% EtOAc in pet. ether) to
liquid. ½a 2D5
ꢂ
¼ þ152:5 (c 0.81, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.35–7.23 (m, 5H, ArH-Bn), 5.77 (ddd, 1H, J = 5.3, 10.6, 17.4 Hz,
olefinic), 5.18 (td, 1H, J = 1.5, 17.4 Hz, olefinic), 5.06 (td, 1H,
J = 1.5, 17.4 Hz, olefinic), 4.60 (d, 1H, J = 11.7 Hz, benzylic), 4.45
(d, 1H, J = 11.7 Hz, benzylic), 3.85, (m, 1H, –CHO), 3.74 (t, 2H,
J = 5.3 Hz, –OCH2), 3.47 (td, 1H, J = 3.0, 8.7 Hz, –CHO), 3.14 (td,
1H, J = 4.2, 9.8 Hz, –CHOBn), 2.63 (br s, 1H, –OH), 2.27 (m, 1H, –
CH), 2.12 (m, 1H, –CH), 1.74 (m, 2H, –CH2), 1.44 (m, 2H, –CH2);
13C NMR (75 MHz, CDCl3): d 138.1, 134.8, 128.4, 127.8, 127.8,
115.2, 81.5, 77.9, 76.5, 70.8, 61.6, 34.3, 30.6, 28.9; IR (neat):
afford 41 (15.5 mg, 84%) as a colorless oil. ½a D25
¼ þ68:1 (c 0.27,
ꢂ
CHCl3); 1H NMR (500 MHz, CDCl3):
d 7.33–7.23 (br m, 5H,
3420, 2929, 2850, 1655, 1512, 1456, 1378, 1249, 1025, 699 cmꢀ1
;
HRMS (ESI): calcd. for C16H22O3Na [M+Na]+ 285.1466; found
285.1478.
ArH-Bn), 5.55 (tdd, 1H, J = 2.6, 5.6, 10.8 Hz, olefinic), 5.11 (dd, 1H,
J = 2.0, 11.3 Hz, –CH–CHOester), 5.00 (m, 1H, olefinic), 4.61 (d,
1H, J = 11.8 Hz, benzylic), 4.41 (d, 1H, J = 11.8 Hz, benzylic), 4.06
(br d, 1H, J = 11.3 Hz, –CHOpyran), 3.67 (td, 1H, J = 2.6, 11.8 Hz,
–CHOpyran), 3.11 (m, 1H, –CHOBn), 2.85 (dd, 1H, J = 2.6, 11.8 Hz,
4.1.30. 2-((2R,3S,6R)-3-(Benzyloxy)-6-vinyl-tetrahydro-2H-
pyran-2-yl)acetic acid 28
–CaH), 2.24 (m, 3H, –CaH and –CH2allylic), 1.82–1.76 (m, 1H,
To a stirred solution of 40 (0.09 g, 0.34 mmol) in CH2Cl2:H2O
(1:1) (1 mL), TEMPO (16 mg, 0.1 mmol) and BIAB (0.33 g,
1.02 mmol) were added at 0 °C and stirred for 1 h. Work-up as de-
scribed for 6 and purification by column chromatography (silica
gel, 60–120 mesh, 25% EtOAc in pet. ether) gave 33 (70.5 mg,
–CH2alkyl), 1.70–1.40 (br m, 7H, –CH2alkyl), 1.22 (d, 3H,
J = 6.2 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 173.3, 138.2, 135.4,
128.3, 128.1, 127.6, 127.6, 80.0, 76.5, 75.0, 70.4, 69.6, 39.2, 34.4,
31.7, 29.4, 28.0, 25.8, 20.9; IR (neat): 3450, 2926, 2851, 1720,
1431, 1366, 1277, 1075, 1040, 921 cmꢀ1; HRMS (ESI): calcd. for
75%) as a liquid. ½a D25
ꢂ
¼ þ153:2 (c 1.8, CHCl3); 1H NMR (300 MHz,
C21H28O4Na [M+Na] 367.1885; found 367.1884.
CDCl3): d 7.35–7.23 (m, 5H, ArH-Bn), 5.81 (ddd, 1H, J = 5.0, 10.5,

G. V. M. Sharma, V. Manohar / Tetrahedron: Asymmetry 23 (2012) 252–263
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Acknowledgments
The authors are thankful to MLP-0010, for financial support. V.
M. thanks the Council of Scientific and Industrial Research (CSIR),
India, for financial support in the form of a fellowship.
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