Studies directed toward the first total synthesis of acremodiol and acremonol

Article abstract of DOI:10.1016/j.tetasy.2009.10.030

Studies directed toward the synthesis of acremodiol and acremonol resulted in the synthesis of two macrodiolides 1, 1a, and 2 besides 3. The attempted synthesis of 1 and 2 confirmed that the absolute stereochemistry defined in the earlier report is incorr

Full text of DOI:10.1016/j.tetasy.2009.10.030

Tetrahedron: Asymmetry 20 (2009) 2513–2529
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Studies directed toward the first total synthesis of acremodiol and acremonol
*
Gangavaram V. M. Sharma , Samala Mallesham, Chirutha Chandra Mouli
Organic Chemistry 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:
Studies directed toward the synthesis of acremodiol and acremonol resulted in the synthesis of two
macrodiolides 1, 1a, and 2 besides 3. The attempted synthesis of 1 and 2 confirmed that the absolute
stereochemistry defined in the earlier report is incorrect. Compound 1 was synthesized by RCM-mediated
macrocyclization. Attempted synthesis of 2 failed to give good yields in the cyclization, and 1a and 2 were
synthesized by the Yamaguchi macrolactonization method.
Received 25 August 2009
Accepted 7 October 2009
Available online 24 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Acremodiol 1 and acremonol 2, two 14-membered bis-macro-
lides, were isolated by Berge et al.1 from a soil sample of the Bermuda
Islands, Acremonium-like anamorphic fungus. The structure of these
two macrolides was assigned based on the NMR, ESI-MS, and FAB-
MS spectroscopy.1 Compound 1 has four stereocenters (5R, 6R,
Retrosynthetic analysis of 1 (Scheme 1) revealed bis-olefin 4 as
a late stage intermediate which could be made by the acryloylation
of 5. Ester 5 could in turn be prepared by the esterification of acid 6
and alcohol 7, while 6 and 7 were envisioned to derive from 8
and 9.
11R, and 14R) with a 5,6-vic diol and an
ety. Similarly, 2 has three asymmetric centers (6R, 11R, and 14R)
with a carbonyl group at C-5 and two ,b-unsaturated esters. Struc-
a,b-unsaturated ester moi-
2.1. Synthesis of the C-2 to O-7 segment
a
turally, these compounds are closely related to clonostachydiol,2,3
while the relative stereochemistry was reported1 to be the same
for colletodiol.4,5 Macrolides 1 and 2, unlike colletodiol have shown
activity against a series of Gram positive bacteria and fungi. In con-
tinuation of our studies on the synthesis of macrodiolides,6 macro-
triolides6 herein, we report our attempts on the first synthesis of 1
and 2, to determine their absolute stereochemistry. The synthesis
of 1 was achieved by RCM-mediated macrocyclization, while 1a
and 2 were synthesized by macrolactonization method.
Accordingly, ester 8 (Scheme 2) upon asymmetric dihydroxyla-
tion7a with AD-mix-b and methane sulfonamide afforded the
known diol 107b (61%), which on reaction with TBSCl, Et3N, and
8
cat. DMAP in CH2Cl2 gave 11a (major, 50%) and 11b (minor,
12%). Alcohol 11a on treatment with MEMCl and DIPEA in CH2Cl2
furnished 12 in 84% yield. Catalytic hydrogenation of ester 12 with
PtO2 in EtOAc under an H2-atmosphere gave ester 13 in 94%, which
on subsequent hydrolysis with 0.5 N NaOH in MeOH/H2O (1:1)
afforded acid 6 in 87% yield.
O
O
O
O
O
O
14
11
14
11
HO
5
14
11
5
HO
O
R
R1
O
6
O
O
6
6
OH
OH
O
O
O
acremodiol 1 R1=OH, R=H
(5R,6R,11R,14R)
acremonol 2
(6R,11R,14R)
epi clonostachydiol 3
(5R,6R,11R,14R)
acremodiol 1a R1=H, R=OH
(5R,6R,11S,14R)
* Corresponding author.
E-mail address: esmvee@iict.res.in (G.V.M. Sharma).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.030

2514
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
Chiron approach from
D-glyceraldehyde
O
O
O
O
Jacobsen's hydrolytic
kinetic resolution
O
O
O
O
(R)
(R)
(R)
HO
MEMO
MEMO
OH
(R)
OH
OPMB
OPMB
O
O
5
RCM (Grubb's-I)
Sharpless asymmetric
dihydroxylation
4
1
O
HO
OH
O
O
MEMO
+
CHO
OTBS
OPMB
7
9
6
Sharpless-AD
protocol
O
Ot-Bu
8
Scheme 1. Retrosynthesis of acremodiol 1.
OR
OH
O
O
O
b
a
Ot-But
Ot-But
Ot-But
8
OR'
OH
10
11a R = TBS, R' = H
11b R' = TBS, R = H
OTBS
O
OTBS
O
OTBS
O
c
e
d
OH
Ot-But
Ot-But
OMEM
6
OMEM
12
OMEM
13
Scheme 2. Reagents and conditions: (a) AD-mix-b, methane sulfonamide, t-BuOH/H2O (1:1), 0 °C to rt, 27 h; (b) TBSCl, Et3N, cat. DMAP, CH2Cl2, 0 °C to rt, 12 h; (c) MEMCl,
DIPEA, CH2Cl2, rt, 24 h; (d) H2, PtO2, EtOAc, 40 psi, rt, 4 h; (e) NaOH, 0.5 N, MeOH, rt, 18 h.
2.2. Synthesis of the C-9 to O-1 segment
Having successfully synthesized both the fragments 6 and 7,
acid 6 was subjected to esterification with alcohol 7 under Yamag-
uchi10 conditions to furnish ester 25 (Scheme 4) in 82% yield.
Desilylation of 25 using ZrCl4 in CH3CN11 gave alcohol 5 (68%),
which on further treatment with acryloyl chloride and DIPEA in
CH2Cl2 afforded 4 in 88% yield. The bis-olefin 4 was subjected to
RCM with Grubbs first generation catalyst12 in CH2Cl2 at reflux to
furnish the bis-lactone 26 in 60% yield. Finally, removal of PMB
Reaction of the alcohol 14 (Scheme 3) prepared from 9 with
p-TsCl and Et3N in CH2Cl2, followed by deoxygenation of tosylate
15 with LAH in dry THF afforded 16 in 87% yield. The terminal
olefin 16 upon treatment with m-CPBA was converted into racemic
epoxide 17 in 75% yield.
The kinetic resolution of 17 with (S,S)-Jacobsen catalyst,9 gave
the diol 18 (39%) and epoxide 18a (43%). The reaction of diol 18
with anisaldehyde dimethyl acetal gave cyclic derivative 19 (73%,
dr 5:4), which on reductive opening with DIBAL-H in CH2Cl2 fur-
nished the alcohol 20 in 76% yield. Oxidation of 20 under Swern
conditions followed by Wittig olefination of 21 in THF at 0 °C to
room temperature afforded olefin 22 in 50% yield. Acid (60% aq
AcOH)-catalyzed hydrolysis of acetonide 22 furnished the diol 23
(88%), which on tosylation (p-TsCl, Et3N, DMAP) in CH2Cl2 afforded
24 in 73% yield. Further, treatment of tosylate 24 with LAH gave
deoxy compound 7 in 95% yield, constituting the synthesis of the
C-9 to O-1 segment.
13
and MEM groups in 26, on treatment with TiCl4 in CH2Cl2 affor-
ded 1 in 69% yield. The synthetic compound 1 was fully character-
ized by 1H, 13C, ESI-MS, and IR spectra. The spectral analysis data of
compound 1 was found to be not matching with those reported for
1. Similarly the specific rotation value of synthetic 1 [
0.15, CHCl3)] was not corresponding with that reported1 for 1
{[ D = +98 (c 0.3, MeOH)}. Thus, the synthesis of 1 has amply indi-
a]D = ꢀ35.3 (c
a]
cated that the structure originally assigned to the natural product
acremodiol1 is incorrect.
Having been unsuccessful in achieving the synthesis of
acremodiol 1, next we aimed at the synthesis of acremonol 2

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2515
O
O
O
a
b
O
O
O
OTs
O
OH
O
14
15
16
O
O
O
O
d
c
O
OH
O
OH
O
+
18
17
18a
O
O
f, g, h
e
R
i
O
O
18
O
H
19
OPMB
20 R = CH2OH
21 R = CHO
22 R = CH = CH2
OCH3
RO
HO
OH
j
k
HO
TsO
23 OPMB
7
OPMB
24 R = H
24a R = Ts
OPMB
Scheme 3. Reagents and conditions: (a) p-TsCl, Et3N, cat. DMAP, CH2Cl2, rt, 24 h; (b) LAH, dry THF, 0 °C-reflux,12 h; (c) m-CPBA, CHCl3, rt, 24 h; (d) S,S(+)-N,N-bis(3,5-ditert-
butyl salicylidine)-1,2-cyclo hexane diamino cobalt(II), AcOH, toluene, rt, 1 h; H2O, 15 °C to rt, 12 h; (e) anisaldehyde dimethylacetal, PPTS, CH2Cl2, rt, 2 h; (f) DIBAL-H, CH2Cl2,
0 °C to rt, 12 h; (g) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 3 h; (h) Ph3P+CH3 Iꢀ, n-BuLi, THF, 0 °C to rt, 12 h; (i) 60% aq AcOH, rt, 12 h; (j) p-TsCl, Et3N, cat. DMAP, CH2Cl2, 0 °C to rt,
14 h; (k) LiAlH4, dry THF, 0 °C to rt, 12 h.
O
O
O
O
OTBS
O
c
b
7, a
MEMO
TBSO
MEMO
OH
OH
OMEM
OPMB
OPMB
25
5
6
O
O
O
O
O
O
O
O
e
d
HO
MEMO
MEMO
O
O
OH
OPMB
OPMB
O
O
4
1
26
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 7, DMAP, toluene, rt, 14 h; (b) ZrCl4, dry CH3CN, 0 °C, 20 min; (c) acryloyl chloride, DIPEA,
CH2Cl2, 0 °C to rt, 2 h; (d) Grubbs’ catalyst—I, CH2Cl2, reflux, 48 h; (e) TiCl4, CH2Cl2, 0 °C to rt, 6 h.
since the C5–OH group of 1 was in keto form in 2. Thus, 2 is
devoid of a stereocenter at C-5. Hence, it was presumed that
the synthesis of 2 would well define the stereochemistry at
C-6, C-11, and C-14, so that C-5 stereochemistry could be rede-
fined later.
2.4. Synthesis of the C-8 to O-1 segment
Opening of the known epoxide 319 (Scheme 6) with allyl magne-
sium chloride in ether and subsequent silylation of the secondary
alcohol 32 with TBSCl and imidazole in CH2Cl2 gave 32a in 70% yield.
Ozonolysis of 32a and olefination of the resulting aldehyde with
(ethoxycarbonylmethylene)triphenyl phosphorane gave 33 in 72%
yield. Reduction of ester 33 with DIBAL-H furnished allylic alcohol
34 in 77% yield. Sharpless epoxidation14 of 34 with (ꢀ)-DIPT in
CH2Cl2 afforded epoxide 35 in 75% yield. Treatment of epoxy alcohol
35 with Ph3P and NaHCO3 in CCl4 gave chloride 35a (71%), which on
further treatment with Na in dry ether afforded 36 in 73% yield.
Benzylation of 36 with BnBr and Ag2O in CH2Cl2 gave 37 (78%). Ozon-
olysis of olefin 37 in CH2Cl2 followed by the olefination with (p-tol-
2.3. Synthesis of acremonol 2
The retrosynthetic analysis of acremonol
2 is shown in
Scheme 5. Compound 2 could be realized by macrolactonization
from the seco-acid 27, which in turn could be made from acid
28 and alcohol 29. The acid was envisioned to come from D-man-
nitol derivative 30, while 29 was planned from chiral propylene
oxide 31.

2516
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
Yamaguchi esterification
O
O
O
1
O
O
14
(R)
(R)
11
PMBO
5
O
(R)
OH
HO
8
6
OBn
OH
27
O
O
2
Sharpless epoxidation
Yamaguchi Macrolactonisation
OTBS
OH
O
O
O
SO2Tol
+
O
OH
OBn
OMPM
31
29
28
O
OH
O
O
O
OH
30
Scheme 5.
OR
OTBS
O
OTBS
b
a
c
O
OH
31
32 R = OH
32a R = OTBS
33
O
34
OTBS
OTBS
OTBS
f
g
d, e
h
R
O
36
OH
35
37 OBn
35 R = OH
35a R= Cl
OTBS
O
OH
O
i
SO2Tol
SO2Tol
O
O
38
OBn
OBn 29
Scheme 6. Reagents and conditions: (a) (i) allyl chloride, Mg, dry ether, ꢀ78 °C, 2 h; (ii) TBSCl, imidazole, CH2Cl2, rt, 4 h; (b) (i) O3, CH2Cl2, ꢀ78 °C, 30 min; (ii) Ph3P@CHCOOEt,
CH2Cl2, rt, 4 h; (c) DIBAL-H, CH2Cl2, ꢀ78 °C, 2 h; (d) (ꢀ)-DIPT, 4 Å, cumene hydroperoxide, Ti(OiPr)4, CH2Cl2, ꢀ20 °C, 3 h; (e) Ph3P, NaHCO3, CCl4, reflux, 30 min; (f) Na, ether, rt,
12 h; (g) Ag2O, BnBr, CH2Cl2, reflux, 12 h; (h) (i) O3, CH2Cl2, ꢀ78 °C, 30 min; (ii) Ph3P@CHCOOC2H4SO2Tol, CH2Cl2, rt, 4 h; (i) TMSCl, H2O, CH3CN, rt, 1 h.
uenesulfonylethoxycarbonylmethylene)triphenyl phosphorane15
afforded 38 in 71% yield. Finally, desilylation of 38 with TMSCl
(cat.) and H2O in CH3CN gave 29 in 88% yield.
subsequent olefination with (ethoxycarbonylmethylene)triphenyl
phosphorane gave the unsaturated ester 46 in 72% yield. Treatment
of 46 with TBSCl gave 47 (90%), which finally on hydrolysis with
0.5 M NaOH in MeOH gave acid 28 in 94% yield.
2.5. Synthesis of the C-2 to O-7 segment
Acid 28 was subjected to esterification with alcohol 29 under
Yamaguchi reaction conditions10 to give 48 in 77% yield (Scheme 8).
Desilylation of 48 with TMSCl (cat.) and H2O in CH3CN furnished 49
(87%), which on selective hydrolysis of the sulfonyl ester with DBN
in dry benzene15 afforded 27 in 78% yield. Macrolactonization of
the resulting seco-acid 27 was then realized under the Yamaguchi
protocol6,10 with 2,4,6-tirchlorobenzoyl chloride, under high dilu-
tion conditions in toluene to afford 50 in 52% yield. The oxidative
deprotection of 50 with DDQ in aq CH2Cl2 gave 51 in 68% yield.
Oxidation of secondary alcohol 51 with Dess–Martin periodinane18
in CH2Cl2 afforded 52 in 80% yield. Finally, 52 on debenzylation
with TiCl4 in CH2Cl2 at room temperature for 2 h gave 2 in 79%
Diol 30 was benzoylated with BzCl and Et3N in CH2Cl2 to give 39
in 78% yield. Selective acetonide deprotection and oxidative cleav-
age with H5IO6 in ether16 and subsequent reduction with LAH
afforded 40 in 42% yield in three steps (see Scheme 7).
Reaction of triol 40 with anisaldehyde dimethyl acetal and PPTS
in CH2Cl2 gave acetal 41 in 71% yield (dr 3:2). Reductive opening of
the PMB acetal from the less hindered side with DIBAL-H in CH2Cl2
gave the diol 42 (75%), which on selective tosylation gave 43 (71%).
Reduction of tosylate 43 with NaBH4 in DMSO17 at 160 °C fur-
nished 44 (92%), which on acetonide deprotection with 60% aq
AcOH afforded triol 45 in 88% yield. Oxidative cleavage of 45 and
yield. [
a]
D = ꢀ55.3 (c 0.22, MeOH); lit.1
[a]D = +40 (c 0.3, MeOH).

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2517
HO
HO
HO
O
a
c
O
b
O
BzO
OBz
O
OH
O
O
O
O
O
O
O
O
O
OH
OH
O
40
H
41
30
39
OCH3
HO
HO
HO
O
O
d
HO
OH
O
OTs
g
e
f
O
O
HO
O
HO
OPMB
OPMB
OPMB
43
42
OPMB
44
45
HO
TBSO
O
O
TBSO
h
O
i
j
C2H5O
C2H5O
HO
OPMB
OPMB
46
47
OPMB
28
Scheme 7. Reagent and conditions: (a) BzCl, CH2Cl2, Et3N, 0 °C to rt, 12 h; (b) (i) H5IO6, ether, rt, 6 h; (ii) LAH, THF, 0 °C to rt, 12 h; (c) anisaldehyde dimethylacetal, PPTS,
CH2Cl2, rt, 2 h; (d) DIBAL-H, CH2Cl2, 0 °C to rt, 2 h; (e) TsCl, Et3N, CH2Cl2, rt, 14 h; (f) DMSO, NaBH4, 160 °C, 10 min; (g) 60% aq AcOH, rt, 12 h; (h) (i) NaIO4, MeOH/H2O (5:1),
0 °C to rt, 3 h; (ii) Ph3P@CHCOOEt, CH2Cl2, 0 °C to rt, 4 h; (i) TBSCl, imidazole, CH2Cl2, rt, 4 h; (j) 0.5 N NaOH, MeOH, rt, 24 h.
O
O
OTBS
O
O
O
OH
O
PMBO
PMBO
OPMB
a
b
28
TBSO
OBn
O
HO
OBn
O
+
OH
O
O
49
SO2Tol
SO2Tol
SO2Tol
48
O
OBn 29
O
O
O
O
O
O
O
PMBO
PMBO
HO
e
d
c
OH
O
O
OBn
O
OBn
O
OBn
O
O
50
OH
27
51
O
O
O
O
g
f
O
O
OBn
OH
O
O
52
2
Scheme 8. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h, 29, DMAP, toluene, rt, 1 h; (b) cat. TMSCl, H2O, CH3CN, rt, 1 h; (c) DBN, dry
benzene, rt, 12 h; (d) 2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h, DMAP, toluene, 90 °C, 10 h; (e) DDQ, CH2Cl2/H2O (19:1), rt, 3 h; (f) Dess–Martin periodinane, dry
CH2Cl2, rt, 12 h; (g) TiCl4, dry CH2Cl2, rt, 2 h.
However, the spectral data7 and specific rotation value7
obtained for synthetic 2 and the data reported in the literature1
did not correspond to each other. Thus, it is indeed evident from
the synthesis of 2 that the structure proposed in the literature
for natural 2 is also incorrect.
yield as white solid, mp 165–168 °C; [
a
]D = ꢀ15.7 (c 0.23, CHCl3);
lit.7b
[a]D = ꢀ31 (c 1.0, MeOH).
2.7. Synthesis of macrolide 1a
From the literature data on the macrodiolide class of natural
products 1 and 2, it was assumed that the stereochemistry at C-6
and C-14 of 1 and 2 is the same. From the synthetic studies on acre-
monol 2, it was proposed to synthesize the (5R, 6R, 11S, 14R)
diastereomer of the originally proposed structure of acremodiol.
2.6. Synthesis of epi-clonostachydiol
Bis-lactone 50 (Scheme 9) was treated with TiCl4 in CH2Cl2 at
room temperature for 2 h to afford epi-clonostachydiol 3 in 78%

2518
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
further purification. All column chromatographic separations were
O
O
O
O
performed using silica gel (Acme’s, 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 400 MHz) and
13C NMR (50 MHz and 75 MHz) spectra were measured with a Var-
ian Gemini FT-200 MHz spectrometer, Bruker Avance 300 MHz,
Varian Inova 400 MHz, and Varian Unity Inova-500 MHz with tet-
ramethylsilane as an internal standard for solutions in deuterio-
chloroform. J values are given in hertz. IR spectra were recorded
on Perkin–Elmer IR-683 spectrophotometer with NaCl optics. Opti-
cal rotations were measured with JASCO DIP 300 digital polarime-
ter at 25 °C. Mass spectra were recorded on CEC-21–11013 or
Fannigan Mat 1210 double focusing mass spectrometers operating
at a direct inlet system or LC/MSD Trap SL (Agilent Technologies).
O
a
PMBO
HO
O
OBn
OH
O
O
3
50
Scheme 9. Reagents and conditions: (a) TiCl4, dry CH2Cl2, rt, 2 h.
Accordingly, allylic alcohol 34 on reaction with (+)-DIPT and
Ti(Oipr)4 in CH2Cl2 gave the epoxy alcohol 53 in 72% yield
(Scheme 10). The epoxy alcohol 53 on reaction with Ph3P and NaH-
CO3 (cat.) in refluxing CCl4 was converted into epoxy chloride 53a
in 66% yield. Treatment of 53 with Na in dry ether afforded olefin
54 (75%), which on reaction with BnBr and Ag2O in CH2Cl2 at reflux
furnished ether 55 (70%). Ozonolysis of 55 in CH2Cl2 to give an
aldehyde and subsequent olefination with (p-toluenesulfonyleth-
oxycarbonylmethylene) triphenyl phosphorane15 gave 56 in 70%
yield. Finally, desilylation of 56 with TMSCl (cat.) and H2O in
CH3CN afforded 57 in 85% yield.
Catalytic hydrogenation of the ester 48 (Scheme 11) with PtO2
in EtOAc afforded 58 (94%), which on hydrolysis with 0.5 M NaOH
in MeOH gave acid 59 (90%).
Condensation of acid 59 with alcohol 57 through its mixed
anhydride gave the ester 60 in 72% yield (Scheme 12). Desilylation
of 60 with HF–pyridine complex in THF afforded 61 (73%), which
on hydrolysis of 61 with DBN gave the seco-acid 62 (68%). Macrol-
actonization of 62 under Yamaguchi high dilution conditions affor-
ded 63 in 58% yield. Finally, bis-lactone 63 was treated with TiCl4
4.1.1. (4R,5R,E)-tert-Butyl 4,5-dihydroxyhex-2-enoate 10
A well-stirred solution of AD-mix-b (4.63 g, 5.95 mmol) in t-
BuOH/H2O (1:1, 20 mL) was treated with methane sulfonamide
(0.28 g, 2.97 mmol) at room temperature. After 30 min, the clear
yellow solution was cooled to 0 °C and ester 8 (0.50 g, 2.97 mmol)
was added. The reaction mixture was stirred vigorously at 0 °C for
27 h, and then the reaction was quenched with solid Na2SO4 (5 g),
and the reaction mixture was warmed to room temperature, and
stirred for another 50 min. The resultant mixture was extracted
with CH2Cl2 (3 ꢁ 10 mL) and the combined extracts were dried
(Na2SO4), filtered, and concentrated. The residue was purified by
column chromatography (60–120 silica gel, 3:7 EtOAc/n-hexane)
to afford 10 (0.37 g, 61%) as a yellow syrup. [
a]D = +10.5 (c 0.92,
CHCl3), lit.7b D = +11.0 (c 0.9, CHCl3); 1H NMR (200 MHz, CDCl3):
[a]
d 6.74 (dd, 1H, J = 5.2, 15.6 Hz, olefinic), 6.03 (dd, 1H, J = 1.50,
15.6 Hz, olefinic), 3.97 (m, 1H, –CH), 3.66 (m, 1H, –CH), 3.12 (br
s, 2H, 2 ꢁ –OH), 1.47 (s, 9H, 3CH3 t-Bu), 1.22 (d, 3H, J = 5.90 Hz,
–CH3); IR (neat): 3433, 1715, 1370, 1160 cmꢀ1; EIMS (m/z%): 203
(M++1) (4), 188 (3), 156 (10), 103 (95), 85(30), 58 (100).
in CH2Cl2 to give 1a in 80% yield, [
a]
D = ꢀ52.7 (c 0.23, MeOH);
lit.1
[a]
D = +98 (c 0.33, MeOH).
The spectroscopic data of 1a did not match with those of acremo-
diol1 andhencethestructureofthenaturalproductisstillunresolved.
3. Conclusion
4.1.2. (4R,5R,E)-tert-Butyl 5-(tert-butyldimethylsilyloxy)-4-
hydroxyhex-2-enoate 11a
Thus, in conclusion, we have synthesized three bis-macrolides
1, 2, and 1a and epi-clonostachydiol 3, while attempting the first
synthesis of acremonol and acremodiol. The spectral (1H, 13C,
ESI-MS, and IR) analysis data of synthetic 1, 1a, and 2, besides
the specific rotation values were found not to match with the data
reported for the natural products. Thus, all efforts in the direction
of the first synthesis19 of acremodiol and acremonol met with fail-
ure in the synthesis of these natural products.
A
solution of diol 10 (0.36 g, 1.78 mmol), DMAP (0.01 g,
0.09 mmol), and TBSCl (0.58 g, 3.92 mmol) in CH2Cl2 (5 mL) was
cooled to 0 °C and Et3N (0.43 g, 4.27 mmol) was added. The reac-
tion mixture was stirred at room temperature for 12 h, and
quenched with H2O (5 mL). The mixture was then extracted with
CHCl3 (3 ꢁ 10 mL) and the combined extracts were washed with
brine (10 mL), dried (Na2SO4), and concentrated to give the residue,
which was purified by column chromatography (60–120 silica gel,
1:19 EtOAc/n-hexane). First eluted was 11a (0.28 g, 50%) (70% yield
based on recovered 10) as a yellow syrup. [
a
]
D = ꢀ5.7 (c 0.69,
4. Experimental
CHCl3); 1H NMR (200 MHz, CDCl3):
d
6.76 (dd, 1H, J = 4.4,
15.6 Hz, olefinic), 6.0 (dd, 1H, J = 2.2, 15.6 Hz, olefinic), 3.96 (m,
1H, –CH), 3.73 (m, 1H, –CH), 2.42 (d, 1H, J = 5.2 Hz, –OH), 1.47 (s,
9H, 3CH3 t-Bu), 1.21 (d, 3H, J = 5.9 Hz, –CH3), 0.89 (s, 9H, 3 ꢁ –
CH3), 0.08 (s, 3H, CH3–Si), 0.06 (s, 3H, CH3–Si); IR (neat): 3434,
4.1. General methods
Solvents were dried over standard drying agents and freshly
distilled prior to use. Chemicals were purchased and used without
OTBS
OTBS
OTBS
c
a
b
R
OH
O
54
OH
34
53 R = OH
53a R = Cl
OTBS
OTBS
O
OH
O
d
e
SO2Tol
SO2Tol
O
O
OBn
OBn
56
55
57
OBn
Scheme 10. Reagents and conditions: (a) (+)-DIPT, 4 Å, cumene hydroperoxide, Ti(OiPr)4, CH2Cl2, ꢀ20 °C, 3 h; (b) (i) Ph3P, NaHCO3, CCl4, reflux, 30 min; (ii) Na, ether, rt, 12 h;
(c) BnBr, Ag2O, CH2Cl2, rt, 12 h; (d) (i) O3, CH2Cl2, ꢀ78 °C, 2 h; (ii) Ph3P@CHCOOC2H4SO2Tol, CH2Cl2, 0 °C to rt, 4 h; (e) cat. TMSCl, H2O, CH3CN, rt, 1 h.

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2519
O
O
OTBS
OTBS
O
OTBS
b
a
OH
O
O
OPMB
OPMB
48
OPMB 58
59
Scheme 11. Reagents and conditions: (a) PtO2, H2, EtOAc, rt, 4 h; (b) 0.5 N NaOH, MeOH, rt, 24 h.
O
OTBS
O
O
O
O
OH
b
PMBO
PMBO
TBSO
a
OPMB
59
O
O
HO
OBn
SO2Tol
OBn
SO2Tol
+
OH
O
61
O
O
60
SO2Tol
O
OBn
57
O
O
O
O
O
O
O
e
d
c
HO
PMBO
PMBO
O
OH
O
OH
OBn
OBn
1a
O
O
63
OH
62
Scheme 12. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h, 57, DMAP, toluene, rt, 1 h; (b) HF–pyridine complex, dry THF, rt, 6 h; (c) DBN,
dry benzene, rt, 12 h; (d) 2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h, DMAP, toluene, 90 °C 10 h; (e) TiCl4, dry CH2Cl2, rt, 2 h.
2980, 2856, 1716, 1371, 1159, 1096 cmꢀ1; FABMS (m/z%): 317
(M++1) (30), 299 (39), 261 (35), 185 (16), 159 (67), 137 (14), 73
(100).
through Celite and the filtrate was evaporated to afford 13 (0.17 g,
94%) as a liquid. [
D = +21.7 (c 0.45, CHCl3); 1H NMR (300 MHz,
a
]
CDCl3): d 4.70 (dd, 2H, J = 6.9, 21.1 Hz, –OCH2O– MEM), 3.89 (m,
1H, –CH), 3.66 (m, 2H, –OCH2 MEM), 3.51 (m, 2H, –OCH2 MEM),
3.36 (m, 4H, –CH, –OCH3 MEM), 2.29 (m, 2H, –CH2), 1.88–1.60
(2 m, 2H, –CH2), 1.43 (s, 9H, 3CH3 t-Bu), 1.10 (d, 3H, J = 6.4 Hz,
–CH3), 0.87 (s, 9H, 3 ꢁ –CH3), 0.05 (s, 6H, 2 ꢁ –CH3); IR (neat):
2924, 2854, 1731, 1463, 1514, 1368, 1254, 1152, 1043 cmꢀ1; FABMS
(m/z%): 407 (M++1) (7), 331 (12), 293 (5), 275 (44), 187 (12), 154
(30), 89 (100), 59 (64).
The second eluted was 11b (0.07 g, 12%) as a yellow syrup. 1H
NMR (200 MHz, CDCl3): d 6.73 (dd, 1H, J = 6.0 Hz, 15.7 Hz, olefinic),
5.86 (d, 1H, J = 15.7 Hz, olefinic), 3.97 (m, 1H, –CH), 3.60 (m, 1H,
–CH), 2.30 (m, 1H, –OH), 1.48 (s, 9H, 3CH3, t-Bu), 1.14 (d, 3H,
J = 6.0 Hz, –CH3), 0.90 (s, 9H, 3 ꢁ –CH3), 0.08 (s, 3H, CH3–Si), 0.06
(s, 3H, CH3–Si).
4.1.3. (4R,5R,E)-tert-Butyl 5-(tert-butyldimethylsilyloxy)-4-((2-
methoxyethoxy) methoxy)hex-2-enoate 12
4.1.5. (4R,5R)-5-(tert-Butyldimethylsilyloxy)-4-((2-methoxyeth-
oxy) methoxy)hexanoic acid 6
A solution of alcohol 11a (0.27 g, 0.85 mmol) and DIPEA (0.44 g,
3.42 mmol) in CH2Cl2 (5 mL) was treated with MEMCl (0.21 g,
1.71 mmol) and stirred at room temperature for 24 h. The reaction
was quenched with water (2 mL) and the reaction mixture was ex-
tracted with CH2Cl2 (3 ꢁ 10 mL). The combined extracts were
washed with brine (10 mL), dried (Na2SO4), and concentrated.
The residue was purified by column chromatography (60–120 sil-
ica gel, 1:19 EtOAc/n-hexane) to afford 12 (0.29 g, 84%) as a yellow
A mixture of 13 (0.16 g, 0.39 mmol) and 0.5 M NaOH (2 mL) in
MeOH (5 mL) was stirred at room temperature for 18 h and then
neutralized with HCl (0.5 M, 2 mL). The reaction mixture was
extracted with CHCl3 (3 ꢁ 15 mL) and the combined extracts were
dried (Na2SO4) and concentrated. The residue was purified by col-
umn chromatography (60–120 silica gel, 1:1 EtOAc/n-hexane) to
give 6 (0.12 g, 87%) as a colorless oil. [a]D = +93.5 (c 0.28, CHCl3);
syrup. [
a
]
D = +5.8 (c 1.39, CHCl3); 1H NMR (200 MHz, CDCl3): d 6.75
1H NMR (300 MHz, CDCl3): d 4.68 (2d, 2H, J = 6.7, Hz, –OCH2O–
MEM), 3.90 (m, 1H, –CH), 3.68 (m, 2H, –OCH2 MEM), 3.52 (m, 2H,
–OCH2 MEM), 3.39 (m, 4H, –CH, –OCH3 MEM), 2.45 (m, 2H, –CH2),
1.96–1.65 (2 m, 2H, –CH2), 1.10 (d, 3H, J = 6.0 Hz, –CH3), 0.87 (s,
9H, 3 ꢁ –CH3), 0.05 (s, 6H, 2 ꢁ –CH3); IR (neat): 3435, 2958, 2855,
1727, 1614, 1520, 1369, 1299, 1174, 1012 cmꢀ1; FABMS (m/z%):
373 (M++23) (10), 349 (5), 307 (5), 275 (40), 245 (32), 154 (28), 89
(60), 73 (100), 59 (74).
(dd, 1H, J = 5.20, 15.6 Hz, olefinic), 5.91 (d, 1H, J = 15.6 Hz, olefinic),
4.69 (m, 2H, –OCH2O– MEM), 4.09 (m, 1H, –CH), 3.89 (m, 1H, –CH),
3.73–3.60 (2 m, 2H, –OCH2 MEM), 3.50 (m, 2H, –OCH2 MEM), 3.36
(s, 3H, –OCH3 MEM), 1.49 (s, 9H, 3CH3, t-Bu), 1.09 (d, 3H, J = 5.9 Hz,
–CH3), 0.89 (s, 9H, 3 ꢁ –CH3), 0.06 (s, 6H, 2 ꢁ –CH3); IR (neat):
3436, 2958, 2933, 2856, 1716, 1368, 1253, 1155, 1104 cmꢀ1; FAB-
MS (m/z,%): 405 (M++1) (4), 329 (6), 299 (14), 273 (20), 159 (44),
111 (22), 89 (100), 59 (66).
4.1.6. (S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-enyl 4-
methylbenzenesulfo-nate 15
To a cooled (0 °C) solution of alcohol 14 (5.8 g, 33.72 mmol),
DMAP (0.41 g, 3.37 mmol), and Et3N (6.8 g, 67.44 mmol) in CH2Cl2
(25 mL), p-TsCl (7.06 g, 37.1 mmol) was added portionwise and
stirred at room temperature for 24 h. The solvent was evaporated
4.1.4. (4R,5R)-tert-Butyl 5-(tert-butyldimethylsilyloxy)-4-((2-
methoxyethoxy) methoxy) hexanoate 13
To a suspension of PtO2 (0.02 g, 0.09 mmol) in EtOAc (2 mL),
unsaturated ester 12 (0.18 g, 0.44 mmol) was added and subjected
to hydrogenation at 40 psi for 4 h. The catalyst was filtered off

2520
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
and the residue was purified by column chromatography (60–120
4.1.10. (S)-4-(2-((4R)-2-(4-Methoxyphenyl)-1,3-dioxolan-4-
yl)ethyl)-2,2-dimethyl-1,3-dioxolane 19
silica gel, 1:9 EtOAc/n-hexane) to afford 15 (9.0 g, 82%) as a syrup.
[a
]
D = +12.5 (c 1.5, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.80, 7.30
To a stirred solution of 18 (0.83 g, 4.36 mmol) and PPTS (0.02 g,
0.09 mmol) in dry CH2Cl2 (10 mL), anisaldehyde dimethylacetal
(1.20 g, 6.55 mmol) was added at 0 °C and the mixture was stirred
at room temperature for 2 h. The reaction mixture was neutralized
with Et3N, the solvent was evaporated, and the residue was puri-
fied by column chromatography (60–120 silica gel, 1:9 EtOAc/n-
(2d, 4H, J = 8.0 Hz, Ar), 5.64 (m, 1H, olefinic), 5.03 (m, 2H, ole-
finic), 4.55 (m, 1H, –CH), 4.00 (m, 2H, –CH), 3.75 (m, 1H, –CH),
2.40 (m, 5H, –CH2, CH3 Ar), 1.30, 1.28 (2s, 6H, 2 ꢁ –CH3); IR
(neat): 2850, 1550, 1360, 1145 cmꢀ1
; FABMS (m/z,%): 349
(M++23) (20), 311 (30), 245 (15), 101 (40), 89 (100), 73, (80),
59 (74).
hexane) to give 19 (0.98 g, 73%) as an oil, [a]D = +1.3 (c 0.31, CHCl3);
1H NMR (200 MHz, CDCl3): d 7.36, 6.84 (2d, 4H, J = 6.0 Hz, Ar), 5.83,
5.71 (2s, 1H, –CH Ar), 4.25–3.95 (m, 4H, 2 ꢁ –CH2), 3.80 (s, 3H, –
OCH3 Ar), 3.69–3.44 (m, 2H, 2 ꢁ –CH), 1.70 (m, 4H, 2 ꢁ –CH2),
1.38, 1.32 (2s, 6H, 2 ꢁ –CH3); IR (neat); 3050, 2950, 1600, 1580,
1126, 1073, 750 cmꢀ1; FABMS (m/z%): 309 (M++1) (10), 265 (15),
150 (30), 122 (45), 89 (25), 57, (26), 55 (100).
4.1.7. (S)-4-(But-3-enyl)-2,2-dimethyl-1,3-dioxolane 16
To a stirred suspension of LAH (1.39 g, 36.8 mmol) in dry THF
(30 mL) a solution of 15 (6.0 g, 18.4 mmol) in dry THF (30 mL)
was added dropwise at 0 °C under nitrogen atmosphere and the
mixture was stirred at reflux for 12 h. The reaction mixture was
cooled to 0 °C, treated with saturated aq Na2SO4 solution
(25 mL), filtered, and the filtrate was dried (Na2SO4) and evapo-
rated (below 30 °C). The crude residue was distilled under vacuum
at 100 °C/12 mm to give 16 (2.5 g, 87%) as a colorless liquid.
4.1.11. (R)-4-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(4-meth-
oxybenzyloxy)butan-1-ol 20
To a stirred solution of 19 (0.97 g, 3.15 mmol) in dry CH2Cl2
(10 mL), DIBAL-H (2.36 mL, 4.72 mmol, 2 M solution in toluene)
was added at 0 °C and stirred at the same temperature for 12 h.
Methanol (2 mL) was added to the reaction mixture at 0 °C and
stirred for 10 min. Saturated aq solution of sodium potassium tar-
trate (5 mL) was added and after 10 min, the methanol was evap-
orated. It was diluted with water (10 mL) and extracted with
CH2Cl2 (2 ꢁ 25 mL). The combined organic layers were washed
with brine (10 mL), dried (Na2SO4), concentrated, and the residue
was purified by column chromatography (60–120 silica gel, 1:3
EtOAc/n-hexane) to afford 20 (0.74 g, 76%) as a gummy syrup.
[a]
D = +15.9 (c 2.85, CHCl3); 1H NMR (200 MHz, CDCl3): d 5.80
(m, 1H, olefinic), 5.00 (m, 2H, olefinic), 4.02 (m, 2H, –CH2), 3.47
(m, 1H, –CH), 2.15 (m, 2H, –CH2), 1.79–1.51 (m, 2H, –CH2), 1.37,
1.34 (2s, 6H, 2 ꢁ –CH3); IR (neat): 2948, 1620, 1540, 1454, 1248,
1036 cmꢀ1; EIMS (m/z%): 157 (M++1) (32), 89 (65), 73, (50), 59
(80), 43 (100).
4.1.8. (S)-2,2-Dimethyl-4-(2-(oxiran-2-yl)ethyl)-1,3-dioxolane
17
To a stirred solution of olefin 16 (2.4 g, 15.38 mmol) in CHCl3
(25 mL), m-CPBA (3.98 g, 23.07 mmol) was added and stirred at
room temperature for 24 h. The reaction mixture was filtered
and the filtrate was washed with saturated NaHCO3 solution
(20 mL), dried (Na2SO4), concentrated, and the residue was purified
by column chromatography (60–120 silica gel, 1:9 EtOAc/n-hex-
ane) to furnish 17 (1.98 g, 75%) as a colorless liquid. 1H NMR
(200 MHz, CDCl3): d 4.02 (m, 2H, –CH2), 3.48 (m, 1H, –CH), 2.90
(m, 1H, –CH), 2.70 (m, 1H, –CH), 2.44 (m, 1H, –CH), 1.66 (m, 4H,
2 ꢁ –CH2), 1.39, 1.28 (2s, 6H, 2 ꢁ CH3); IR (neat): 3050, 2932,
1620, 1452, 1034, 950, 860 cmꢀ1; EIMS (m/z%): 173 (M++1) (22),
154, (30), 89 (72), 73 (50), 59 (100), 43 (60).
[a]
D = +42.0 (c 0.50, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.21,
6.83 (2d, 4H, J = 7.3 Hz, Ar), 4.50 (m, 2H, –OCH2 Ar), 4.01 (m, 2H,
–CH2), 3.80 (s, 3H, –OCH3, Ar), 3.65 (m, 1H, –CH), 3.49 (m, 3H, –
CH2, –CH), 1.84 (br s, 1H, –OH), 1.44–1.70 (m, 4H, 2 ꢁ –CH2),
1.39, 1.33 (2s, 6H, 2 ꢁ –CH3); IR (neat); 3448, 2985, 2933, 1613,
1514, 1373, 1176, 1060 cmꢀ1; FABMS (m/z%): 311 (M++1) (7),
252 (40), 196 (45), 121 (70), 90 (30), 57, (100).
4.1.12. (S)-4-((R)-3-(4-Methoxybenzyloxy)pent-4-enyl)-2,2-
dimethyl-1,3-dioxolane 22
To a stirred solution of oxalyl chloride (0.62 g, 3.53 mmol) in
dry CH2Cl2 (5 mL), DMSO (0.55 g, 7.06 mmol) was added at
ꢀ78 °C and stirred at the same temperature for 0.5 h. A solution
of alcohol 20 (0.73 g, 2.35 mmol) in CH2Cl2 (2 mL) was added at
ꢀ78 °C and stirred for another 2.5 h at the same temperature. Then
Et3N (1.42 g, 14.12 mmol) was added at 0 °C and stirred for further
45 min. The reaction mixture was diluted with water (5 mL) and
extracted with CH2Cl2 (2 ꢁ 10 mL). The combined organic layers
were washed with brine (10 mL), dried (Na2SO4), and concentrated
to give 21 in quantitative yield as a pale yellow syrup, which was
used as such for the next reaction.
4.1.9. (R)-4-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)butane-1,2-
diol 18
A mixture of (S,S)-Jacobsen’s catalyst (0.01 g, 0.02 mmol) and
AcOH (0.02 g, 0.04 mmol) in toluene (1 mL) was stirred in open
air at room temperature for 1 h. The solvent was removed by rotary
evaporator, and the brown residue was dried under vacuum. To
this catalyst, epoxide 17 (1.95 g, 11.33 mmol) was added in one
portion and the stirred mixture was cooled in an ice-water bath.
H2O (0.11 g, 6.23 mmol) was slowly added keeping the bath tem-
perature at 15 °C. After 1 h, ice-water bath was removed and the
reaction mixture was stirred at room temperature for 12 h. The
crude reaction mixture was purified by column chromatography
(60–120 silica gel, 1:1 EtOAc/n-hexane). First eluted was 18a
(0.850 g, 43% yield) as a yellow liquid. 1H NMR (200 M Hz, CDCl3):
d 4.12 (m, 1H, –CH), 4.01 (m, 1H, –CH), 3.49 (m, 1H, –CH), 2.91 (m,
1H, –CH), 2.72 (m, 1H, –CH), 2.44 (m, 1H, –CH), 1.66 (m, 4H, 2 ꢁ –
CH2), 1.38, 1.32 (2s, 6H, 2 ꢁ CH3).
To
a solution of (methylenetriphenyl)phosphonium iodide
(1.88 g, 4.67 mmol) in dry THF (10 mL), n-BuLi (2.92 mL,
4.675 mmol, 1.6 N) was added at 0 °C and the mixture was stirred
for 1 h. Aldehyde 21 (0.72 g, 2.33 mmol) in dry THF (2 mL) was
added at 0 °C and the mixture was stirred for an additional 12 h.
The reaction was quenched with saturated NH4Cl (5 mL) solution
and the reaction mixture was extracted with ether (2 ꢁ 20 mL).
The combined extracts were washed with brine (20 mL), dried
(Na2SO4), concentrated, and the crude residue was purified by col-
umn chromatography (60–120 silica gel, 1:19 EtOAc/n-hexane) to
Second eluted was 18 (0.84 g, 39%) as
a yellow syrup.
[a]
D = +17.4 (c 0.63, CHCl3); 1H NMR (200 MHz, CDCl3): d 4.03
afford 22 (0.35 g, 50%) as a yellow syrup. [
a]D = +33.0 (c 0.50,
CHCl3); 1H NMR (200 MHz, CDCl3):
d
7.20, 6.84 (2d, 4H,
(m, 2H, –CH2), 3.75–3.30 (m, 6H, 2 ꢁ –CH, –CH2, 2 ꢁ OH), 1.80–
1.40 (m, 4H, 2 ꢁ –CH2), 1.39, 1.32 (2s, 6H, 2 ꢁ –CH3); IR (neat):
3450, 3310, 2935, 1642, 1375, 1125, 1075 cmꢀ1; FABMS (m/z%):
191 (M++1) (18), 175 (8), 154 (100), 137 (78), 89 (28), 69, (29),
55 (36).
J = 8.2 Hz, Ar), 5.70–5.61 (m, 1H, olefinic), 5.24–5.10 (m, 2H, ole-
finic), 4.45, 4.25 (2d, 2H, J = 11.7 Hz, –OCH2 Ar), 4.10–3.65 (m,
3H, –CH, –CH2) 3.71 (s, 3H, –OCH3 Ar), 3.49 (m, 1H, –CH), 1.78–
1.48 (m, 4H, 2 ꢁ –CH), 1.38–1.33 (2s, 6H, 2 ꢁ –CH3); IR (neat);

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2521
3049, 2932, 1614, 1512, 1454, 1375, 1090, 824 cmꢀ1; FABMS (m/
z%): 307 (M++1) (8), 252 (20), 193 (5), 121 (100), 91 (30), 77
(25), 57 (70).
mixture was filtered and the filtrate was evaporated. The resulting
anhydride was dissolved in toluene (2 mL) and treated with
alcohol 7 (0.07 g, 0.31 mmol) and DMAP (0.07 g, 0.62 mmol) in
toluene (3 mL). It was stirred at room temperature for 12 h, filtered
through Celite, and evaporated. The residue was purified by col-
umn chromatography (60–120 silica gel, 1:4 EtOAc/n-hexane) to
4.1.13. (2S,5R)-5-(4-Methoxybenzyloxy)hept-6-ene-1,2-diol 23
A mixture of 22 (0.35 g, 1.14 mmol) in 60% aq AcOH (5 mL) was
stirred at room temperature for 12 h. The reaction mixture was
neutralized with NaHCO3 and extracted with EtOAc (3 ꢁ 20 mL).
The combined organic layers were dried (Na2SO4) and evaporated.
The residue was purified by filtration through a small pad of silica
gel with 1:1 EtOAc/n-hexane to afford 23 (0.27 g, 88%) as a color-
afford 25 (0.15 g, 82%) as an oil. [a]
D = +35.5 (c 1.08, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.17, 6.79 (2d, 4H, J = 8.3 Hz, Ar), 5.69
(m, 1H, olefinic), 5.19 (m, 2H, olefinic), 4.86 (m, 1H, –CH), 4.69
(m, 2H, –OCH2O– MEM), 4.46, 4.21 (2d, 2H, J = 11.3 Hz, –OCH2
Ar), 3.89 (m, 1H, –CH), 3.79 (s, 3H, –OCH3 Ar), 3.65 (m, 3H, –CH,
–OCH2 MEM), 3.50 (m, 2H, –OCH2 MEM), 3.35 (m, 4H, –CH,
–OCH3 MEM), 2.33 (m, 2H, –CH2), 1.91 (m, 1H, –CH), 1.57 (m,
less syrup. [a]
D = +41.3 (c 0.65, CHCl3). 1H NMR (200 MHz, CDCl3):
d 7.20, 6.84 (2d, 4H, J = 8.0 Hz, Ar), 5.75 (m, 1H, olefinic), 5.22 (m,
2H, olefinic), 4.52, 4.25 (2d, 2H, J = 12.0 Hz, –OCH2 Ar), 3.84–3.71
(m, 4H, –CH, –OCH3 Ar), 3.70–3.50 (m, 2H, –CH2), 3.40 (m, 1H,
–CH), 1.70, 1.53 (2 m, 4H, 2 ꢁ –CH2); IR (neat): 3448, 3310, 3049,
2932, 1612, 1512, 1451, 1398, 1075 cmꢀ1; EIMS (m/z%): 267
(M++1) (7), 229 (15), 155 (30), 121 (20), 91 (100), 57 (70).
5H, 2 ꢁ –CH2, –CH), 1.20 (d, 3H, J = 6.8 Hz, –CH0 ), 1.10 (d, 3H,
3
J = 6.8 Hz, –CH3), 0.87 (s, 9H, 3 ꢁ –CH3), 0.04 (s, 6H, 2 ꢁ CH3); IR
(neat): 2948, 2860, 1726, 1614, 1511, 1456, 1370, 1248,
822 cmꢀ1; FABMS (m/z%): 583 (M++1, 10), 393 (5), 307, (7), 275
(5), 229 (8), 154 (30), 137 (27), 121 (100), 89 (18), 77 (15), 59 (50).
4.1.14. (2S,5R)-2-Hydroxy-5-(4-methoxybenzyloxy)hept-6-enyl
4-methylbenzene sulfonate 24
4.1.17. (4R,5R)-((2R,5R)-5-(4-Methoxybenzyloxy)hept-6-en-2-
yl) 5-hydroxy-4-((2-methoxyethoxy)methoxy)hexanoate 5
To a solution of 25 (0.10 g, 0.17 mmol) in dry CH3CN (1 mL),
ZrCl4 (0.008 g, 0.03 mmol) in dry CH3CN (0.5 mL) was added at
0 °C. The reaction mixture was stirred for 20 min at the same tem-
perature, the reaction was quenched with saturated NaHCO3 solu-
tion (1 mL), and the reaction mixture was extracted with EtOAc
(2 ꢁ 10 mL). The combined organic layers were washed with brine
(10 mL), concentrated, and the residue was purified by column
chromatography (60–120 silica gel, 3:7 EtOAc/n-hexane) to afford
To a cooled (0 °C) solution of diol 23 (0.26 g, 0.97 mmol), DMAP
(cat.), and Et3N (0.19 g, 1.95 mmol) in CH2Cl2 (15 mL), p-TsCl
(0.18 g, 0.97 mmol) was added portionwise at 0 °C and the mixture
was stirred at room temperature for 14 h. Worked up as described
for 15 and purified by column chromatography (60–120 silica gel,
1:4 EtOAc/n-hexane). First eluted was 24a (0.05 g, 8%) as a yellow
syrup. 1H NMR (200 MHz, CDCl3): d 7.78, 7.32 (2 m, 8H, SO2Ph),
7.18, 6.84 (2d, 4H, J = 7.7 Hz, Ar), 5.70 (m, 1H, olefinic), 5.21 (m,
2H, olefinic), 4.58 (m, 1H, –CH), 4.51–4.23 (2d, 2H, J = 11.5 Hz,
–OCH2 Ar), 3.88–3.65 (m, 6H, –CH2, –CH, –OCH3 Ar), 2.45, 2.44
(2s, 6H, 2 ꢁ –CH3 Ar), 1.71–1.39 (m, 4H, 2 ꢁ –CH2).
5 (0.05 g, 68%) as a yellow syrup. [a]
D = +19.7 (c 0.9, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.17, 6.82 (2d, 4H, J = 8.5 Hz, Ar), 5.69
(m, 1H, olefinic), 5.20 (m, 2H, olefinic), 4.86 (m, 1H, –CH), 4.74
(dd, 2H, J = 6.9, 26.2 Hz, –OCH2O– MEM), 4.46, 4.24 (2d, 2H,
J = 11.5 Hz, –OCH2 Ar), 3.79 (m, 4H, –CH, –OCH3 Ar), 3.65 (m, 3H,
–CH, –OCH2 MEM), 3.52 (m, 2H, –OCH2 MEM), 3.36 (s, 3H,
–OCH3 MEM), 3.27 (m, 1H, –CH), 2.33 (m, 2H, –CH2), 1.89 (m,
1H, –CH), 1.60 (m, 5H, 2 ꢁ –CH2, –CH), 1.19 (d, 3H, J = 6.2 Hz,
Second eluted was 24 (0.3 g, 73%) as a yellow syrup. [a]D = +39.7
(c 0.79, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.76, 7.31 (2d, 4H,
J = 7.7 Hz, SO2Ph); 7.17, 6.83 (2d, 4H, J = 7.7 Hz, Ar), 5.70 (m, 1H,
olefinic), 5.21 (m, 2H, olefinic), 4.50, 4.22 (2d, 2H, J = 11.5 Hz,
–OCH2 Ar), 3.88 (m, 7H, 2 ꢁ –CH, –CH2 –OCH3 Ar), 2.45 (s, 3H,
–CH3 Ar), 1.70–1.40 (m, 4H, 2 ꢁ –CH2); IR (neat): 3444, 2924,
2855, 1610, 1512, 1457, 1351, 1247, 1149 cmꢀ1; FABMS (m/z%):
421 (M++1) (5), 391 (10), 229 (13), 154 (32), 137 (46), 121 (100),
77 (24), 69 (50), 57 (76).
–CH0 ), 1.12 (d, 3H, J = 6.4 Hz, –CH3); IR (neat): 3449, 2931, 1727,
3
1612, 1513, 1454, 1375, 1299, 1176, 1036, 929, 823 cmꢀ1; FABMS
(m/z%): 469 (M++1) (5), 393 (3), 307, (5), 256 (3), 229 (4), 154 (29),
137 (27), 121 (100), 107 (10), 89 (18), 77 (15), 59 (12).
4.1.15. (2R,5R)-5-(4-Methoxybenzyloxy)hept-6-en-2-ol 7
4.1.18. (4R,5R)-((2R,5R)-5-(4-Methoxybenzyloxy)hept-6-en-2-
yl) 5-(acryloyloxy)-4-((2-methoxyethoxy)methoxy)hexanoate 4
To a stirred solution of alcohol 5 (0.05 g, 0.11 mmol) and DIPEA
(0.07 g, 0.53 mmol) in dry CH2Cl2 (1 mL), acryloyl chloride (0.04 g,
0.43 mmol) was added at 0 °C under nitrogen atmosphere. After
stirring at room temperature for 2 h, the reaction mixture was di-
luted with CH2Cl2 (20 mL), washed sequentially with H2O (5 mL),
10% HCl (5 mL), saturated NaHCO3 (5 mL), and brine (5 mL). The
combined extracts were dried (Na2SO4), concentrated, and the res-
idue was purified by column chromatography (60–120 silica gel,
1:4 EtOAc/n-hexane) to afford 4 (0.05 g, 88%) as a colorless syrup.
To a stirred suspension of LAH (0.05 g, 1.38 mmol) in dry THF
(3 mL), a solution of 24 (0.29 g, 0.69 mmol) in dry THF (2 mL)
was added dropwise at 0 °C under a nitrogen atmosphere and
the mixture was stirred at room temperature for 12 h. The reaction
mixture was worked-up as described for 16 and the residue was
purified by column chromatography (60–120 silica gel, 1:3
EtOAc/n-hexane) to give 7 (0.16 g, 95%) as a colorless syrup.
[a]
D = +28.1 (c 0.49, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.19,
6.82 (2d, 4H, J = 10.7 Hz, Ar), 5.72 (m, 1H, olefinic), 5.20 (m, 2H, ole-
finic), 4.51, 4.24 (2d, 2H, J = 13.6 Hz, –OCH2 Ar), 3.82–3.65 (m, 5H,
2 ꢁ –CH, –OCH3 Ar), 1.70, 1.40 (m, 4H, 2 ꢁ –CH2), 1.14 (d, 3H,
J = 8.7 Hz, –CH), 13C NMR (50 MHz, CDCl3): d 138.8, 129.2, 116.9,
113.7, 80.2, 69.8, 67.7, 55.2, 35.0, 31.7, 23.3; IR (neat): 3448,
2932, 1611, 1513, 1455, 1374, 1093, 928 cmꢀ1; EIMS (m/z%): 251
(M++1) (28), 154 (10), 137 (32), 121 (100), 95 (12), 69 (14), 57 (20).
[a]
D = +25.5 (c 0.16, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.19,
6.79 (2d, 4H, J = 8.3 Hz, Ar), 6.38 (d, 1H, J = 17.3 Hz, olefinic), 6.07
(dd, 1H, J = 10.5, 17.3 Hz, olefinic), 5.81–5.63 (m, 2H, olefinic),
5.19 (m, 2H, olefinic), 5.05 (m, 1H, –CH), 4.84 (m, 1H, –CH), 4.71
(m, 2H, –OCH2O– MEM), 4.50, 4.24 (2d, 2H, J = 12.0 Hz, –OCH2
Ar), 3.78 (s, 3H, –OCH3 Ar), 3.64 (m, 4H, 2 ꢁ –CH, –OCH2 MEM),
3.50 (m, 2H, –OCH2 MEM), 3.35 (s, 3H, –OCH3 MEM), 2.35 (m,
2H, –CH2), 1.89, 1.74 (2 m, 2H, –CH2), 1.55 (m, 4H, 2 ꢁ CH2), 1.23
(d, 3H, J = 6.0 Hz, –CH3), 1.18 (d, 3H, J = 6.0 Hz, –CH3); IR (neat):
2950, 1728, 1613, 1550, 1453, 1390, 1292, 1175, 1038, 925,
825 cmꢀ1; FABMS (m/z%): 523 (M++1) (5), 391 (7), 307, (4), 289
(3), 185 (5), 154 (30), 137 (30), 121 (100), 107 (12), 89 (26), 77
(12), 69 (26), 57 (40).
4.1.16. (4R,5R)-((2R,5R)-5-(4-Methoxybenzyloxy)hept-6-en-2-
yl) 5-(tert-butyl dimethylsilyloxy)-4-((2-methoxyethoxy)-
methoxy)hexanoate 25
To a solution of acid 6 (0.11 g, 0.31 mmol) and Et3N (0.063 g,
0.628 mmol) in dry THF (5 mL), 2,4,6-trichlorobenzoyl chloride
(0.07 g, 0.314 mmol) was added and the reaction mixture was stir-
red at room temperature for 2 h under nitrogen atmosphere. The

2522
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
4.1.19. (5R,6R,11R,14R,E)-11-(4-Methoxybenzyloxy)-5-(2-meth-
oxyethoxy) methoxy)-6,14-dimethyl-1,7-dioxacyclotetradec-9-
ene-2,8-dione 26
and concentrated. The residue was purified by column chromatog-
raphy (60–120 silica gel, n-Hexane) to furnish 32a (7.5 g, 70%) as a
colorless liquid, [
a]
D = ꢀ57.4 (c 0.76, CHCl3); 1H NMR (200 MHz,
Ester 4 (0.04 g, 0.07 mmol) was dissolved in freshly distilled and
CDCl3): d 5.72 (m, 1H, olefinic), 4.89 (q, 2H, J = 17.3, 3.7 Hz,
olefinic), 3.76 (q, 1H, J = 6.0 Hz, –CH), 2.02 (m, 2H, allylic –CH2),
1.44 (m, 2H, –CH2), 1.07 (d, 3H, J = 6.0 Hz, –CH3), 0.84 (s, 9H,
3 ꢁ –CH3), 0.00 (s, 6H, 2 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d
139.5, 114.2, 77.1, 32.0, 29.5, 26.2, 22.9, 14.2, ꢀ3.2; IR (neat):
2956, 2858, 1467, 1370, 1254, 1135, 1053, 997 cmꢀ1; ESIMS: 237
(M+Na)+.
degassed anhydrous CH2Cl2 (160 mL) and Grubbs’
I catalyst
(0.013 g, 0.02 mmol) was added. The mixture was heated at reflux
for 48 h under a nitrogen atmosphere. Most of the solvent was then
distilled off and the concentrated solution was left to stir at room
temperature for 2 h under air bubbling in order to decompose the
catalyst. Evaporation to dryness gave a brown residue which on
purification by column chromatography (60–120 silica gel, 1:3
EtOAc/n-hexane) afforded 26 (0.02 g, 60%) as a brown syrup.
4.1.22. (R,E)-Ethyl 6-(tert-Butyldimethylsilyloxy)hept-2-enoate 33
Ozone was bubbled through a cooled (ꢀ78 °C) solution of 32a
(7.4 g, 34.57 mmol) in CH2Cl2 (70 mL) until the pale blue color per-
sisted. Excess ozone was removed with Me2S (2 mL) and stirred for
30 min at 0 °C. The reaction mixture was concentrated under re-
duced pressure to give aldehyde, which was used for a further
reaction.
[a
]
D = ꢀ10.9 (c 0.86, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.18,
6.79 (2d, 4H, J = 8.3 Hz, Ar), 6.67 (dd, 1H, J = 3.0, 15.8 Hz, olefinic),
5.98 (d, 1H, J = 15.8 Hz, olefinic), 5.05 (m, 1H, –CH), 4.76 (m, 3H,
–CH, –OCH2O– MEM), 4.47 (m, 2H, –OCH2 Ar), 4.17 (m, 1H, –CH),
3.93 (m, 1H, –CH), 3.79 (s, 3H, –OCH3 Ar), 3.70 (m, 2H, –OCH2
MEM), 3.54 (m, 2H, –OCH2 MEM), 3.37 (s, 3H, –OCH3 MEM), 2.70,
2.29 (2 m, 2H, CH2–CO), 1.83 (m, 5H, 2 ꢁ –CH2, –CH), 1.49 (m,
1H, –CH), 1.26 (d, 3H, J = 6.8 Hz, –CH3), 1.14 (d, 3H, J = 6.8 Hz, –
CH3); IR (neat): 2935, 1722, 1612, 1548, 1451, 1399, 1296, 105,
925 cmꢀ1; FABMS (m/z%): 495 (M++1) (23), 440 (18), 353, (5),
281 (16), 154 (68), 137 (60), 121 (82), 81 (43), 69 (68), 55 (100).
To a solution of the above-mentioned aldehyde in dry CH2Cl2
(50 mL)
(ethoxycarbonylmethylene)triphenyl
phosphorane
(7.82 g, 0.79 mmol) dissolved in dry CH2Cl2 (20 mL) was added at
0 °C. After the addition, the reaction mixture was stirred at room
temperature for 4 h. The reaction was quenched with water
(10 mL). The organic layer was separated, dried (Na2SO4), and
evaporated. Purification of the residue by column chromatography
(60–120 silica gel, 0.4:9.6 EtOAc/n-hexane) afforded 33 (6.8 g, 72%)
4.1.20. (5R,6R,11R,14R,E)-5,11-Dihydroxy-6,14-dimethyl-1,7-
dioxacyclotetradec-9-ene-2,8-dione 1
To a stirred solution of 26 (0.02 g, 0.04 mmol) in CH2Cl2 (1 mL),
TiCl4 (0.02 g, 0.08 mmol) in CH2Cl2 (1 mL) was added at 0 °C and
stirred at room temperature for 6 h. Saturated NaHCO3 solution
(10 mL) was added and extracted with CHCl3 (3 ꢁ 10 mL). The
combined organic layers were washed with water (10 mL), brine
(10 mL), dried (Na2SO4), and concentrated. The residue was puri-
fied by column chromatography (60–120 silica gel, 1:1 EtOAc/n-
as
a
colorless liquid.
[
a]
D = ꢀ21.5 (c 1.66, CHCl3). 1H NMR
(300 MHz, CDCl3): d 6.88 (m, 1H, olefinic), 5.70 (d, 1H, J = 6.7 Hz,
olefinic), 4.10 (q, 2H, J = 6.7 Hz, –OCH2), 3.76 (q, 1H, J= 6.0 Hz,
–CH), 2.20 (m, 2H, allylic –CH2), 1.50 (m, 2H, –CH2), 1.24 (m, 3H,
–CH3), 1.08 (d, 3H, J = 6.0 Hz, –CH3), 0.84 (s, 9H, 3 ꢁ –CH3), 0.01
(s, 6H, 2 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d 149.6, 120.9, 67.7,
51.5, 37.8, 28.4, 25.3, 25.2, 23.9, ꢀ4.4, ꢀ4.3; IR (neat): 3457,
2949, 1722, 1656, 1440, 1277, 1196, 1045, 844 cmꢀ1; HRMS m/z
[M+Na]+: calculated for C14H28O3SiNa, 309.1705; found: 309.1703.
hexane) to afford 1 (8 mg, 69%) as a colorless syrup. [
a
]
D = ꢀ35.3
(c 0.15, CHCl3); 1H NMR (300 MHz, DMSO-d6): d 6.83 (dd, 1H,
J = 3.0, 15.8 Hz, H-10), 5.78 (dd, 1H, J = 2.2, 15.8 Hz, H-9), 5.15 (d,
1H, J = 3.7 Hz, OH-5), 4.95 (d, 1H, J = 6.0 Hz, OH-11), 4.83 (dq, 1H,
J = 3.0, 6.7 Hz, H-6), 4.65 (m, 1H, H-14), 4.47 (m, 1H, H-11), 3.80
(m, 1H, H-5), 2.72, 2.66 (2dd, 1H, J = 3.0, 11.3 Hz, H0-3), 2.34, 2.28
(2dd, 1H, J = 3.6, 6.7 Hz, H-3), 1.78 (m, 1H, H-4), 1.72 (m, 2H, H-
12), 1.64, 1.43 (2 m, 3H, H-13, H-4), 1.17 (d, 3H, J = 6.0 Hz,
CH3–15), 1.07 (d, 3H, J = 6.0 Hz, CH3-16); 13C NMR (75 MHz,
DMSO-d6): d 172.2, 164.2, 152.8, 118.4, 72.7, 68.6, 67.3, 67.0,
28.2, 28.1, 27.7, 26.5, 19.5, 13.7; IR (neat): 3424, 2931, 1722,
1653, 1648, 1535, 1399 1027, 1002 cmꢀ1; FABMS (m/z%): 287
(M++1) (26), 269 (20), 154 (46), 81 (43), 69 (66), 55 (100).
4.1.23. (R,E)-6-(tert-Butyldimethylsilyloxy)hept-2-en-1-ol 34
To a stirred solution of ester 33 (6.7 g, 24.63 mmol) in dry
CH2Cl2 (30 mL) at ꢀ78 °C, DIBAL-H (35 mL, 49.26 mmol, 20 mol %
in toluene) was added and stirred at the same temperature for
2 h. The reaction was quenched with few drops of MeOH and aq so-
dium potassium tartrate (5 mL) and the reaction mixture was fil-
tered through Celite. It was dried (Na2SO4), evaporated, and the
residue was purified by column chromatography (60–120 silica
gel, 1:9 EtOAc/n-hexane) to give 34 (4.7 g, 77%) as a colorless li-
quid. [
a
]
D = ꢀ30.6 (c 1.07, CHCl3); 1H NMR (300 MHz, CDCl3): d
5.78 (m, 1H, olefinic), 5.03 (q, 1H, J = 17.3, 42.3 Hz, olefinic), 4.0
(m, 1H, –CH), 3.82 (m, 2H, –CH2), 2.2 (d, 1H, J = 6.7 Hz, –CH2),
1.46 (m, 2H, –CH2), 1.07 (d, 3H, J = 6.0 Hz, –CH2), 0.83 (s, 9H,
3 ꢁ –CH3), 0.01 (s, 6H, 2 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d
133.4, 128.9, 68.3, 63.8, 38.8, 28.5, 25.7, 23.1, 17.9, ꢀ4.9, ꢀ4.2;
IR: 3363, 2926, 2856, 1496, 1443 cmꢀ1; HRMS m/z [M+Na]+: calcu-
lated for C13H28O2SiNa, 267.1756; found: 267.1765.
4.1.21. (R)-tert-Butyl(hex-5-en-2-yloxy)dimethylsilane 32
A suspension of Mg (3.97 g, 165.5 mmol) and dry ether (30 mL)
was treated with allyl chloride (6.8 mL, 82.55 mmol) at room tem-
perature and stirred for 30 min. It was cooled to ꢀ78 °C and a solu-
tion of 31 (4 mL, 55.17 mmol) in dry ether (10 mL) was added
dropwise and the mixture was stirred at the same temperature
for 2 h. The reaction was quenched with aq NH4Cl solution
(10 mL), and the reaction mixture was extracted with ether
(2 ꢁ 50 mL). The combined extracts were washed with brine
(30 mL), dried (Na2SO4), and concentrated to afford the crude alco-
hol 32 (5.0 g, 90%) as a colorless liquid. It is used as such for next
reaction.
A mixture of the above-mentioned alcohol 32 (5 g, 50 mmol)
and imidazole (10.2 g, 150 mmol) in dry CH2Cl2 (50 mL) was trea-
ted with TBSCl (8.29 g, 55 mmol) at 0 °C under nitrogen atmo-
sphere and stirred at room temperature for 4 h. The reaction was
quenched with aq NH4Cl solution (10 mL) and the reaction mixture
was extracted with CH2Cl2 (2 ꢁ 50 mL). The combined extracts
were washed with water (30 mL), brine (30 mL), dried (Na2SO4),
4.1.24. ((2R,3R)-3-((R)-3-(tert-Butyldimethylsilyloxy)butyl)oxi-
ran-2-yl)methanol 35
To a cooled (ꢀ20 °C) suspension of activated powdered 4 Å MS
(1.5 g) in CH2Cl2 (20 mL), (ꢀ)-DIPT (0.57 g, 2.45 mmol) in dry
CH2Cl2 (2 mL),) Ti(OiPr)4 (0.36 mL, 1.22 mmol), and cumene hydro-
peroxide (4.4 M, 3.8 mL, 24.59 mmol) were added sequentially and
stirred for 20 min. A solution of alcohol 34 (3.0 g, 12.29 mmol) in
CH2Cl2 (10 mL) was added at ꢀ20 °C. The resulting mixture was
stirred at the same temperature for 3 h. The reaction was quenched
with 10% NaOH-saturated NaCl solution (30 mL) and the reaction
mixture was stirred at room temperature for 4 h. It was filtered
through Celite, dried (Na2SO4), and evaporated. The residue was

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2523
purified by column chromatography (60–120 silica gel, 1:9 EtOAc/
n-hexane) to give 35 (2.4 g, 75%) as a colorless liquid. [ D = +20.5
The above-mentioned aldehyde in dry CH2Cl2 (5 mL) was trea-
ted with (p-toluenesulfonyl-ethoxycarbonylmethylene)triphenyl
phosphorane (2.44 g, 6.58 mmol) dissolved in dry CH2Cl2 (5 mL)
at 0 °C and stirred at room temperature for 4 h. Worked up as de-
scribed for 33 and purification by column chromatography (60–
120 silica gel, 1:9 EtOAc/n-hexane) afforded 38 (1.32 g, 71% for
a
]
(c 0.31, CHCl3); 1H NMR (300 MHz, CDCl3): d 3.80 (m, 2H, –CH2),
3.56 (m, 1H, –CH), 2.85 (d, 2H, J = 14.3 Hz, 2 ꢁ –CH), 1.84 (t, 1H,
J = 6.7 Hz, –OH), 1.64–1.41 (m, 4H, 2 ꢁ –CH2), 1.07 (d, 3H,
J = 6.0 Hz, –CH3), 0.83 (s, 9H, 3 ꢁ –CH3), 0.01 (s, 6H, 2 ꢁ –CH3);
13C NMR (75 MHz, CDCl3): d 68.1, 61.6, 58. 56.0, 36.0, 28.0, 25.9,
23.7, ꢀ4.3, ꢀ4.8; IR (KBr): 3423, 2955, 2931, 2858, 1465, 1253,
1045, 835 cmꢀ1; HRMS m/z [M+Na]+: calculated for C13H28O3SiNa,
283.1705; found: 283.1718.
two steps) as a colorless liquid, [a]
D = +22.8 (c 0.43, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.75 (d, 2H, J = 8.3 Hz, –C6H4), 7.27 (m,
7H, –C6H5, –C6H4), 6.63 (dd, 1H, J = 6.0, 15.8 Hz, olefinic) 5.72 (d,
1H, J = 15.8 Hz, olefinic), 4.46 (d, 1H, J = 12.0, benzylic –CH2) 4.42
(t, 2H, J = 6.0 Hz, –OCH2), 4.30 (d, 1H, J = 11.3 Hz, benzylic –CH2),
3.82 (q, 1H, J = 5.2, 11.3 Hz, –CH) 3.69 (m, 1H, –CH), 3.39 (t, 2H,
J = 6.7 Hz, –CH2SO2), 2.38 (s, 3H, –CH3) 1.70–1.40 (m, 4H, 2 ꢁ
–CH2), 1.09 (d, 3H, J = 6.7 Hz, –CH3), 0.84 (s, 9H, 3 ꢁ –CH3) 0.00
(s, 6H, 2 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d 149.9, 129.95,
128.4, 128.1, 127.6, 120.4, 71.1, 68.3, 67.8, 57.4, 55.1, 35.0, 30.8,
25.8, 23.8, 21.6, –4.4; IR (Neat): 2924, 2855, 1723, 1655, 1459,
1266, 1179, 1045, 980 cmꢀ1; HRMS m/z [M+Na]+: calculated for
C30H44O6SSiNa, 583.2525; found 583.2536.
4.1.25. (3R,6R)-6-(tert-Butyldimethylsilyloxy)hept-1-en-3-ol 36
To a stirred solution of 35 (2.3 g, 8.84 mmol) in CCl4, Ph3P
(4.63 g, 17.69 mmol) and NaHCO3 (0.2 g/g) were added and stirred
at reflux for 30 min. The reaction mixture was evaporated and the
residue was purified by column chromatography (60–120 silica
gel, 0.2:9.8 EtOAc/n-hexane) to afford 35a (1.77 g, 71%) as a color-
less syrup. 1H NMR (300 MHz, CDCl3): d 3.85 (q, 1H, J = 6.0, 11.3 Hz,
–CH), 3.61 (q, 1H, J = 5.2 Hz, –CH), 3.39 (q, 1H, J = 6.0, 11.3 Hz, –CH),
2.94 (m, 1H, –CH), 2.83 (t, 1H, J = 4.5 Hz, –CH), 1.69–1.45 (m, 4H,
2 ꢁ –CH2), 1.13 (d, 3H, J = 6.0 Hz, –CH3) 0.89 (s, 9H, 3 ꢁ –CH3),
0.05 (s, 6H, 2 ꢁ –CH3).
4.1.28. (4R,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-hydroxyoct-2-
enoate 29
To a solution of 35a (1.7 g, 6.10 mmol) in dry ether, sodium me-
tal pieces (0.56 g, 24.40 mmol) were added and stirred at room
temperature for 12 h. The reaction was quenched with a few drops
of MeOH, evaporated, and the reaction mixture was extracted with
EtOAc (2 ꢁ 50 mL). It was washed with water (20 mL), brine
(20 mL), dried (Na2SO4), and evaporated. Purification of the residue
by column chromatography (60–120 silica gel, 0.6:9.4 EtOAc/n-
To a solution of 38 (1.25 g, 2.23 mmol) in CH3CN (10 mL), TMSCl
(0.04 g, 0.44 mmol) in CH3CN (2 mL) was added followed by H2O
(0.04 g, 2.23 mmol) at 0 °C and stirred at room temperature for
1 h. The reaction was quenched with NaHCO3 (0.2 g), and the reac-
tion mixture was diluted with water (5 mL), and extracted with
EtOAc (2 ꢁ 25 mL). The combined organic layers were washed with
brine (10 mL), dried (Na2SO4), evaporated, and the residue was
purified by column chromatography (60–120 silica gel 2.5.:7.5
hexane) afforded 36 (1.1 g, 73%) as a colorless oil. [
a
]
D = ꢀ37.4 (c
0.18, CHCl3); 1H NMR (300 MHz, CDCl3): d 5.89 (m, 1H, olefinic),
5.11 (q, 2H, J = 14.8 Hz, olefinic), 4.02 (m, 1H, –CH), 3.83 (m, 1H,
–CH), 1.60–1.37 (m, 4H, 2 ꢁ –CH2), 1.06 (d, 3H, J = 5.4 Hz, –CH3),
0.84 (s, 9H, 3 ꢁ –CH3), 0.01 (s, 6H, 2 ꢁ –CH3); 13C NMR (75 MHz,
CDCl3): d 141.5, 114.3, 73.1, 68.6, 35.1, 32.9, 26.0, 23.3, 18.0,
ꢀ4.4, ꢀ4.8; IR (KBr): 3386, 2929, 2857, 1465, 1373, 1253, 1134,
1048, 833 cmꢀ1; HRMS m/z [M+Na]+: calculated for C13H28O2SiNa,
267.1756; found: 267.1759.
EtOAc/n-hexane) to furnish 29 (0.88 g, 88%) as a syrup.
[a
]
D = ꢀ19.6 (c 0.93, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.76 (d,
2H, J = 8.3 Hz, –C6H4), 7.36–7.23 (m, 7H, –C6H5, –C6H4), 6.65 (dd,
1H, J = 6.0, 15.8 Hz, olefinic), 5.76 (dd, 1H, J = 1.1, 15.8 Hz, olefinic),
4.49 (d, 1H, J = 11.7 Hz, benzylic –CH), 4.43 (t, 1H, J = 6.2, 12.2 Hz, –
OCH2), 4.34 (d, 1H, J = 11.8 Hz, benzylic –CH), 3.90 (q, 1H, J = 5.2,
1.7 Hz, –CH), 3.77–3.67 (m, 1H, –CH), 3.42 (t, 2H, J = 6.0, 12.2 Hz,
–OCH2), 2.40 (s, 3H, –CH3), 1.76–1.32 (m, 4H, 2 ꢁ –CH2), 1.14 (d,
3H, J = 6.2 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 165.2, 149.5,
145.0, 137.6, 136.3, 129.9, 128.4, 128.0, 127.7, 127.6, 120.7, 77.5,
71.0, 67.5, 57.7, 55.0, 34.4, 30.8, 23.5, 21.5; IR (neat): 3375, 3059,
2925, 1722, 1656, 1596, 1491, 1318, 1143, 1086, 817 cmꢀ1; HRMS
m/z [M+Na]+: calculated for C24H30O6SNa, 469.1660; found:
469.1681.
4.1.26. ((2R,5R)-5-(Benzyloxy)hept-6-en-2-yloxy)(tert-butyl)-
dimethylsilane 37
To a stirred solution of 36 (1.05 g, 4.30 mmol) in dry CH2Cl2,
Ag2O (1.99 g, 8.60 mmol) was added and stirred at room tempera-
ture for 30 min. It was treated with BnBr (0.6 mL, 4.73 mmol) and
stirred at reflux for 12 h. The reaction mixture was filtered through
a pad of Celite, evaporated, and the residue was purified by column
chromatography (60–120 silica gel, 0.4:9.6 EtOAc/n-hexane) to af-
4.1.29. (1R,2R)-1,2-Bis((R)-2,2-dimethyl-1,3-dioxolan-4-yl)eth-
ane-1,2-diyl-dibenzoate 39
ford 37 (1.12 g, 78%) as a colorless liquid. [
a
]
D = ꢀ23.6 (c 0.9,
To a stirred solution of diol 30 (10 g, 37.87 mmol) and Et3N
(27 mL, 189.39 mmol) in dry CH2Cl2 (100 mL), benzoyl chloride
(11.7 g, 83.33 mmol) was added at 0 °C under a nitrogen atmo-
sphere. After stirring at room temperature for 12 h, the reaction
mixture was diluted with CH2Cl2 (100 mL) and washed sequen-
tially with H2O (50 mL), 10% HCl (50 mL), saturated NaHCO3
(50 mL), and brine (50 mL). The combined extracts were dried
(Na2SO4), concentrated, and the residue was purified by column
chromatography (60–120 silica gel, 1:9 EtOAc/n-hexane) to afford
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.59–7.12 (m, 5H, –C6H5),
5.77–5.61 (heptet, 1H, J = 7.5, 10.3 Hz, olefinic), 5.19 (q, 2H,
J = 4.1, 10.3 Hz, olefinic), 4.54, 4.30 (2d, 2H, J = 11.8 Hz, –OCH2
Ar), 3.76–3.62 (m, 2H, 2 ꢁ –CH), 1.61–1.32 (m, 4H, 2 ꢁ –CH2),
1.20 (d, 3H, J = 6.0 Hz, –CH3), 0.85 (s, 9H, 3 ꢁ –CH3) 0.00 (s, 6H,
2 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d 149.0, 131.5, 128.5,
128.2, 127.6, 121.0, 72.7, 57.80, 55.60, 35.3, 30.2, 25.8, 23.8, 22.4,
ꢀ4.4; IR (KBr): 3427, 2926, 2858, 1722, 1456, 1268, 1106 cmꢀ1
;
HRMS m/z [M+Na]+: calculated for C20H34O2SiNa, 357.2225; found:
39 (13.85 g, 78%) as a white solid, mp: 82–85 °C; [
a]
D = ꢀ112.7 (c
357.2232.
3.37, CHCl3); 1H NMR (300 MHz, CDCl3): d 8.0 (t, 4H, J = 6.7 Hz,
13.5 Hz, –C6H5), 7.53 (t, 2H, J = 6.7, 14.3 Hz, –C6H5), 7.41 (t, 4H,
J = 7.5, 15.1 Hz, –C6H5), 5.48 (d, 1H, J = 5.2 Hz, –CH), 4.88 (p, 1H,
J = 6.0, 10.5 Hz, –CH), 4.37 (q, 2H, J = 6.0, 12.8 Hz, benzylic –CH2),
4.11 (dd, 1H, J = 5.2, 11.3 Hz, –CH), 3.96 (p, 2H, J = 9.0, 15.8 Hz, ben-
zylic –CH2), 3.70 (q,1H, J = 6.7, 11.3 Hz, –CH), 1.52 (s, 3H, –CH3),
1.44 (s, 3H, –CH3), 1.34 (s, 3H, –CH3), 1.31 (s, 3H, –CH3); 13C
NMR (75 MHz, CDCl3): d 165.5, 165.4, 133.1, 129.8, 129.6, 129.
128.3, 128.3, 108.9, 99.8, 74.5, 70.5, 69.8, 66.2, 66.1, 62.1, 26.9,
4.1.27. (4R,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-(tert-butyldimeth-
ylsilyloxy)oct-2-enoate 38
Ozone was bubbled through a cooled (ꢀ78 °C) solution of 37
(1.1 g, 3.29 mmol) in CH2Cl2 (10 mL) until the pale blue color per-
sisted. Excess ozone was removed with Me2S (0.5 mL) and stirred
for 30 min at 0 °C. The reaction mixture was concentrated under
reduced pressure to give the aldehyde.

2524
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
26.5, 25.4, 20.4; IR (neat): 3433, 3062, 2991, 2896, 1727, 1600,
1453, 1378, 1206, 1112, 1067 cmꢀ1; HRMS m/z [M+Na]+: calcu-
lated for C26H30O8Na, 493.1838; found, 493.1835.
4.1.33. (2S,3S)-3-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-
hydroxy3-(4-methoxybenzyloxy)-propyl benzenesulfonate 43
To a cooled (0 °C) solution of diol 42 (4.0 g, 12.82 mmol) and
Et3N (3.88 g, 38.46 mmol) in CH2Cl2 (60 mL), p-TsCl (2.77 g,
14.10 mmol) was added in a single portion at 0 °C and the mixture
was stirred at room temperature for 14 h. The reaction was worked
up as described for 15 and purified by column chromatography
(60–120 silica gel, 1:4 EtOAc/n-hexane). First eluted was ditosylate
43a (0.05 g, 8%) as a yellow syrup. 1H NMR (200 MHz, CDCl3): d
7.80, 7.75 (2d, 4H, J = 8.0 Hz, 2 ꢁ –C6H4), 7.30 (m, 4H,, 2 ꢁ –C6H4)
7.22 (t, 2H, J = 12.4 Hz, –C6H4), 6.75 (d, 2H, J = 8.8 Hz, –C6H4),
4.42 (s, 2H, benzylic –CH2), 4.28 (d, 1H, J = 8.0 Hz, –CH), 4.11 (p,
2H, J = 6.6, 12.4 Hz, –CH2), 3.66 (s, 3H, –OCH3), 3.54 (d, 2H,
J = 6.6 Hz, –CH2), 3.48 (dd, 1H, J = 2.2, 10.2 Hz, –CH), 3.42 (dd, 1H,
J = 5.2, 9.5 Hz, –CH), 2.44, 2.40 (s, 6H, 2 ꢁ Ar–CH3), 1.58 (s, 3H, –
CH3), 1.33 (d, 3H, J = 2.2 Hz, –CH3).
4.1.30. (1S,2R)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)propane-
1,2,3-triol 40
To a solution of diester 39 (13.8 g, 30.94 mmol) in dry ether
(140 mL), H5IO6 (9.17 g, 40.22 mmol) was added at 0 °C and the
reaction mixture was stirred for 6 h at room temperature for 6 h.
Then, it was neutralized with NaHCO3 (10 g), stirred for 30 min, fil-
tered through a pad of Celite, and evaporated to give the crude
aldehyde, which was used as such for the next reaction.
To a stirred suspension of LAH (2.35 g, 61.88 mmol) in dry THF
(100 mL) a solution of the above-mentioned aldehyde in dry THF
(30 mL) was added dropwise at 0 °C under a nitrogen atmosphere
and the mixture was stirred at room temperature for 12 h. The
reaction mixture was cooled to 0 °C, treated with saturated aq
Na2SO4 (10 mL) solution, filtered, and the filtrate was dried
(Na2SO4). It was evaporated and the residue was purified by col-
umn chromatography (60–120 silica gel, 7:3 EtOAc/n-hexane) to
Second eluted was 43 (4.3 g, 71%) as
a yellow syrup,
[a]
D = ꢀ24.5 (c 0.2, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.77 (d,
2H, J = 8.0 Hz, –C6H4), 7.26 (t, 4H, J = 12.4, 19.1 Hz, –C6H4), 6.92
(d, 2H, J = 8.8 Hz, –C6H4), 4.48 (s, 2H, benzylic –CH2), 4.29 (d, 1H,
J = 8.0 Hz, –CH), 4.14 (p, 2H, J = 6.6, 12.4 Hz, –CH2), 3.81 (s, 3H,
–OCH3), 3.74 (d, 2H, J = 6.6 Hz, –CH2), 3.61 (dd, 1H, J = 2.2,
10.2 Hz, –CH), 3.47 (dd, 1H, J = 5.1, 9.5 Hz, –CH), 2.43 (s, 3H,
Ar–CH3), 1.58 (s, 3H, –CH3), 1.33 (d, 3H, J = 2.2 Hz, –CH3); 13C
NMR (75 MHz, CDCl3): d 159.3, 144.7, 132.8, 129.7, 129.4, 128.0,
113.8, 110.0, 76.6, 76.0, 73.1, 71.6, 70.7, 69.8, 55.2, 26.9, 26.7,
21.6; IR (neat): 3444, 2924, 2855, 1610, 1512, 1457, 1351, 1247,
1149 cmꢀ1; ESIMS: 489 (M+Na)+.
give 40 (2.4 g, 42%) as a white solid, mp: 65–67 °C, [a]D = +11.1 (c
0.35, CHCl3); 1H NMR (300 MHz, CDCl3): d 4.54–4.19 (br s, 3H,
3 ꢁ –OH), 4.11 (m, 2H, –CH2), 3.98 (m, 1H, –CH), 3.80 (s, 1H,
–CH), 3.70 (s, 2H, –CH2), 3.56 (s, 1H, –CH), 1.38 (d, 6H, J =
15.4 Hz, 2 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d 109.5, 75.5, 72.4,
71.0, 66.7, 64.2, 26.8, 25.2; IR (neat): 3433, 3063, 2996, 2896,
1727, 1603, 1453, 1318, 1204, 1170, 1067 cmꢀ1; HRMS m/z
[M+Na]+: calculated for C8H16O5Na, 215.0895; found: 215.0900.
4.1.31. (4S,5R)-4-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(4-
methoxyphenyl)-1,3-dioxan-5-ol 41
4.1.34. 1(1S,2R)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-(4-
methoxybenzyloxy) propan-2-ol 44
To a stirred solution of 40 (4.75 g, 24.73 mmol) and PPTS
(0.02 g, 0.08 mmol) in dry CH2Cl2 (50 mL), anisaldehyde dimethyl-
acetal (9 g, 49.47 mmol) was added at 0 °C and stirred at room
temperature for 2 h. The reaction mixture was neutralized with
Et3N, the solvent was evaporated, and the residue was purified
by column chromatography (60–120 silica gel, 2:8 EtOAc/n-hex-
To a stirred solution of 43 (4.2 g, 8.89 mmol) in dry dimethyl
sulfoxide (20 mL), NaBH4 (0.67 g, 17.79 mmol) was added at 0 °C
and the reaction mixture was stirred for 10 min at 160 °C. It was
neutralized with H2O (10 mL) and stirred for another 10 min at
room temperature. The reaction mixture was diluted with EtOAc
(100 mL), washed with water (30 mL), brine (30 mL), dried
(Na2SO4), and evaporated. The crude residue was purified by col-
umn chromatography (60–120 silica gel, 8.5:1.5 EtOAc/n-hexane)
ane) to give 41 (5.5 g, 71%) as a yellowish red syrup, [a] =
D
+16.6 (c 0.54, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.33 (d, 2H,
J = 8.3 Hz, –C6H4), 6.85 (t, 2H, J = 8.3, 12.8 Hz, –C6H4), 5.83 (s,
1H, benzylic –CH) 4.21 (p, 2H, J = 7.5, 12.8 Hz, –CH2), 4.07 (m,
3H, 3 ꢁ –CH), 3.98 (q, 2H, J = 5.2, 11.3 Hz, –CH2), 3.78 (s, 3H,
–OCH3), 3.46 (br s, –OH), 1.37 (s, 3H, –CH3), 1.31 (s, 3H, –CH3);
IR (neat): 3050, 2950, 1600, 1580, 1126, 1073, 750 cmꢀ1; HRMS
m/z [M+Na]+: calculated for C16H22O6Na, 333.1314; found:
333.1317.
to afford 44 (2.42 g, 92%) as a colorless syrup. [a]D = +21.8 (c
0.25, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.18 (d, 2H, J = 9.0 Hz,
–C6H4), 6.81 (d, 2H, J = 8.3 Hz, –C6H4), 4.47 (s, 2H, benzylic –CH2),
4.02 (p, 1H, J = 6.0, 12.0 Hz, –CH), 3.79 (s, 3H, –OCH3), 3.75–3.64
(m, 1H, –CH), 3.59 (dd, 1H, J = 3.0, 9.0 Hz, –CH), 3.43 (p, 2H,
J = 6.0, 9.8 Hz, –CH2), 2.29 (d, 1H, J = 6.0, –OH),1.35 (s, 3H, –CH3),
1.31 (s, 3H, –CH3), 1.21 (d, 3H, J = 6.0, –CH3); 13C NMR (75 MHz,
CDCl3): d 159.6, 129.6, 114.1, 75.4, 73.2, 71.1, 71.0, 66.8, 55.2,
29.6, 19.3; IR (neat): 3470, 2983, 2927, 1612, 1513, 1458, 1374,
1248, 1173, 1090, 1042 cmꢀ1; HRMS m/z [M+Na]+: calculated for
C16H24O5Na, 319.1521; found: 319.1527.
4.1.32. (2R,3S)-3-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-
methoxy-benzyloxy)-propane-1,2-diol 42
To a stirred solution of 41 (5.4 g, 17.41 mmol) in dry CH2Cl2
(30 mL), DIBAL-H (25 mL, 34.83 mmol, 20% solution in toluene)
was added dropwise at 0 °C and stirred at the same temperature
for 2 h. The reaction mixture was worked up as described for 34
and purified by column chromatography (60–120 silica gel, 4:6
4.1.35. (2R,3S,4R)-3-(4-Methoxybenzyloxy)pentane-1,2,4-triol
45
A mixture of 44 (2.35 g, 7.93 mmol) in 60% aq AcOH (20 mL)
was stirred at room temperature for 12 h. It was neutralized with
anhydrous NaHCO3, extracted with EtOAc (2 ꢁ 50 mL), dried
(Na2SO4), evaporated, and the residue was purified by column
chromatography (60–120 silica gel, 8:2 EtOAc/n-hexane) to afford
EtOAc/n-hexane) to afford 42 (4.07 g, 75%) as
[a]
a
syrup.
D = +55.4 (c 0. 1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.19 (d,
2H, J = 7.5 Hz, –C6H4), 6.84 (d, 2H, J = 8.3 Hz, –C6H4), 4.58 (q, 1H,
J = 6.0, 14.3 Hz, –CH), 4.47 (s, 1H, –CH), 4.07–3.87 (m, 2H, benzylic
–CH2), 3.78 (s, 3H, –OCH3), 3.69 (m, 4H, 2 ꢁ –CH2), 3.45 (q, 1H,
J = 6.0, 9.0 Hz, –CH), 2.97 (br s, –OH), 2.7 (br s, –OH), 1.34 (q, 6H,
J = 5.2, 7.5 Hz, 2 ꢁ –CH3), 13C NMR (75 MHz, CDCl3): d 159.0,
130.2, 129.9, 114.2, 80.7, 78.2, 73.1, 71.7, 71.2, 55.0, 27.3, 27.0;
IR (neat): 3412, 2924, 2855, 1610, 1512, 1487, 1376, 1275, 1170,
1114, 1067 cmꢀ1; HRMS m/z [M+Na]+: calculated for C16H24O6Na,
335.1470; found: 335.1454.
45 (1.8 g, 88%) as a colorless syrup. [a]
D = +8.75 (c 0.57, CHCl3); 1H
NMR (200 MHz, CDCl3): d 7.25 (d, 2H, J = 8.0 Hz, –C6H4), 6.86 (d,
2H, J = 8.0 Hz, –C6H4), 4.47 (s, 2H, benzylic –CH2), 3.95 (m, 1H,
–CH), 3.83 (m, 2H, –CH2), 3.82 (s, 3H, –OCH3), 3.64–3.55 (m, 2H,
–CH2), 3.14 (s, 1H, –OH), 2.92 (br d, 2H, 2-OH), 1.20 (d, 3H,
J = 6.5 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 175.3, 137.5, 128.8,
128.1, 127.8, 127.1, 87.3, 83.2, 80.1, 77.0, 73.9, 71.3, 35.9; HRMS

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2525
m/z [M+Na]+: calculated for C13H20O5Na, 279.1208; found:
279.1200.
–CH3); 13C NMR (75 MHz, CDCl3): d 149.6,129.9, 128.4, 128.1,
127.7, 120.7, 77.8, 71.1, 67.7, 57.7, 55.0, 34.5, 30.9, 23.5, 21.6; IR
(neat): 3435, 2930, 2856, 1714, 1607, 1512, 1462, 1170, 1105,
1033 cmꢀ1; HRMS m/z [M+Na]+: calculated for C20H32O5SiNa,
403.1916; found: 403.1929.
4.1.36. (4R,5R,E)-Ethyl 5-hydroxy-4-(4-methoxybenzyloxy)hex-
2-enoate 46
To a solution of triol 45 (1.75 g, 6.83 mmol) in MeOH/H2O (5:1,
20 mL), NaIO4 (2.92 g, 13.67 mmol) was added and stirred at room
temperature for 3 h. MeOH was removed and the residue was ex-
tracted with CH2Cl2 (2 ꢁ 50 mL). It was dried (Na2SO4) and concen-
trated to give aldehyde (1.53 g) in quantitative yield as a yellow
liquid, which was used as such for the next reaction
4.1.39. (4R,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-((4R,5R,E)-5-
(tert-butyldimethyl silyloxy)-4-(4-methoxybenzyloxy)hex-2-
enoyloxy)oct-2-enoate 48
To a solution of acid 28 (0.75 g, 1.99 mmol) and Et3N (0.50 g,
4.97 mmol) in dry THF (6 mL), 2,4,6-trichlorobenzoyl chloride
(0.60 g, 2.48 mmol) in dry THF (2 mL) was added and the reaction
mixture was stirred at room temperature for 2 h under nitrogen
atmosphere. It was filtered and the filtrate was evaporated. The
resulting anhydride was dissolved in toluene (3 mL), treated with
alcohol 29 (0.75 g, 1.65 mmol) in toluene (3 mL) and DMAP
(0.40 g, 3.31 mmol) in toluene (2 mL). The mixture was stirred at
room temperature for 1 h. The reaction mixture was filtered
through Celite and the filtrate was evaporated to afford a residue,
which was purified by column chromatography (60–120 silica
gel, 1.5:8.5 EtOAc/n-hexane) to give 48 (1.05 g, 77%) as an oil,
To
a solution of the above-mentioned aldehyde (1.53 g,
5.12 mmol) in dry CH2Cl2 (10 mL) (ethoxycarbonylmethylene)tri-
phenyl phosphorane (3.36 g, 10.24 mmol) dissolved in dry CH2Cl2
(5 mL) was added at 0 °C and stirred at room temperature for
4 h. Then the organic layer was evaporated and the residue was
purified by column chromatography (60–120 silica gel, 1.5:8.5
EtOAc/n-hexane) to afford ester 46 (1.45 g, 72%) as a colorless
liquid. [
a]
D = ꢀ197.5 (c 1.2, CHCl3) 1H NMR (300 MHz, CDCl3): d
7.17 (d, 2H, J = 8.0 Hz, –C6H4), 6.82 (d, 1H, J = 8.8 Hz, –C6H4), 6.76
(dd, 1H, J = 5.1 Hz, olefinic), 6.07 (d, 1H, J = 15.4 Hz, olefinic), 4.53
(d, 1H, J = 11.0 Hz, benzylic –CH), 4.22 (sextet, 3H, J = 6.6,
13.9 Hz, benzylic –CH, –CH2), 3.79 (s, 3H, –OCH3), 3.68 (q, 2H,
J = 5.1, 11.0 Hz, 2 ꢁ –CH), 2.66 (s, 1H, –OH), 1.32 (t, 3H, J = 7.3,
14.6 Hz, –CH3), 1.10 (d, 3H, J = 5.8 Hz, –CH3); 13C NMR (75 MHz,
CDCl3): d 165.8, 159.4, 144.3, 129.6, 124.6, 114.2, 83.1, 71.2, 69.4,
60.6, 55.2, 18.3, 14.1; IR (neat): 3479, 2978, 2935, 1717, 1655,
1513, 1461, 1249, 1176, 1035, 987 cmꢀ1; HRMS m/z [M+Na]+: cal-
culated for C16H22O5Na, 317.1388; found: 317.1395.
[a
]
D = ꢀ50.6 (c 0.05, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.80 (d,
2H, J = 8.1 Hz, –C6H4), 7.31 (q, 7H, J = 7.9, 14.7 Hz, –C6H5, –C6H4),
7.19 (d, 2H, J = 8.4 Hz, –C6H4), 6.87 (dd, 1H, J = 4.1, 15.8 Hz, ole-
finic), 6.82 (d, 2H, J = 8.6 Hz, –C6H4), 6.65 (dd, 1H, J = 6.0, 16.9 Hz,
olefinic), 6.01 (d, 1H, J = 15.8 Hz, olefinic), 5.77 (d, 1H, J = 15.8 Hz,
olefinic), 4.93 (sext., 1H, J = 6.2, 11.8 Hz, –CH), 4.45 (t, 2H, J = 6.0,
12.0 Hz, benzylic –CH2), 4.37–4.30 (m, 4H, benzylic –CH2, 2 ꢁ
–CH), 3.99–3.82 (m, 3H, –OCH2, –CH), 3.79 (s, 3H, –OCH3), 3.43
(t, 2H, J = 6.2, 12.4 Hz, –CH2SO2), 2.41 (s, 3H, –CH3), 1.70–1.52
(m, 4H, 2 ꢁ –CH2), 1.25 (d, 1H, J = 6.4 Hz, –CH3), 1.06 (d, 1H,
J = 5.6 Hz, –CH3), 0.87 (s, 9H, 3 ꢁ –CH3), 0.00 (s, 6H, 2 ꢁ –CH3);
13C NMR (75 MHz, CDCl3): d 166.6, 166.0, 149.1, 145.53, 129.9,
129.2, 128.4, 128.1, 127.7, 127.6, 123.0, 120.8, 113.7, 96.1, 81.5,
77.4, 71.3, 71.0, 70.6, 69.7, 57.7, 55.1, 31.5, 30.6, 25.8, 21.6, 20.0,
18.8, –4.7; IR (neat): 3423, 2924, 2854, 1726, 1604, 1510, 1458,
1382, 1250, 1216, 1143, 1084, 1032, 812, 757 cmꢀ1; HRMS m/z
[M+Na]+: calculated for C44H60O10SSiNa, 831.3574; found:
831.3587.
4.1.37. (4R,5R,E)-Ethyl 5-(tert-Butyldimethylsilyloxy)-4-(4-
methoxybenzyloxy) hex-2-enoate 47
To a mixture of alcohol 46 (1.4 g, 4.76 mmol) and imidazole
(0.97 g, 14.28 mmol) in dry CH2Cl2 (15 mL), TBSCl (0.78 g,
5.23 mmol) was added at 0 °C under a nitrogen atmosphere and
stirred at room temperature for 4 h. The reaction mixture was con-
centrated under reduced pressure and the residue was purified by
column chromatography (60–120 silica gel, 5:95 EtOAc/n-hexane)
to furnish 47 (1.75 g, 90%) as a yellow syrup. [
a
]
D = ꢀ6.8 (c 0.91,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.18 (d, 2H, J = 8.3 Hz,
–C6H4), 6.85 (dd, 1H, J = 4.5, 15.8 Hz, olefinic), 6.81 (d, 2H,
J = 8.3 Hz, –C6H4), 6.05 (d, 1H, J = 15.8 Hz, olefinic), 4.55–4.31 (q,
2H, J = 11.3, 59.6 Hz, benzylic –CH2), 4.22 (sextet, 2H, J = 6.6,
13.9 Hz, –CH2)3.85 (p, 2H, J = 6.0, 11.3 Hz, 2 ꢁ –CH), 3.79 (s, 3H,
–OCH3), 1.30 (t, 3H, J = 7.3, 14.6 Hz, –CH3), 1.07 (d, 3H, J = 6.0 Hz,
–CH3), 0.86 (s, 9H, 3 ꢁ –CH3), 0.01 (d, 6H, J = 5.2 Hz, 2 ꢁ –CH3);
13C NMR (75 MHz, CDCl3): d 166.6, 159.1, 145.7, 130.0, 129.2,
122.5, 113.7, 81.6, 71.2, 69.6, 55.3, 51.6, 25.9, 18.7, 17.9, ꢀ4.8,
ꢀ4.8; IR (neat): 2952, 2890, 1726, 1658, 1513, 1464, 1378, 1170,
1105, 1035 cmꢀ1; HRMS m/z [M+Na]+: calculated for C22H36O5SiNa
431.2073; found: 431.2085.
4.1.40. (4R,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-((4R,5R,E)-5-
hydroxy-4-(4-methoxy benzyloxy)hex-2-enoyloxy)oct-2-enoate
49
To a solution of 48 (1.0 g, 1.23 mmol) in CH3CN (8 mL) TMSCl
(0.26 g, 2.47 mmol) in CH3CN (2 mL) followed by H2O (0.02 g,
1.23 mmol) was added at 0 °C and stirred at room temperature
for 1 h. Worked up as described for 29 and purified by column
chromatography (60–120 silica gel, 3:7 EtOAc/n-hexane) to furnish
49 (0.75 g, 87%) as a syrup, [
a
]
D = ꢀ36.5 (c 1.11, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.78 (d, 2H, J = 8.3 Hz, –C6H4), 7.29 (q, 7H,
J = 8.12, 15.67 Hz, –C6H5, –C6H4), 7.18 (d, 2H, J = 7.5 Hz, –C6H4),
6.81 (d, 2H, J = 8.6 Hz, –C6H4), 6.75 (dd, 1H, J = 6.6, 15.8 Hz, ole-
finic), 6.67 (dq, 1H, J = 2.0, 5.8 Hz, olefinic), 5.99 (d, 1H,
J = 15.6 Hz, olefinic), 5.78 (d, 1H, J = 16.0 Hz, olefinic), 4.92 (m,
1H, –CH), 4.54 (t, 2H, J = 11.5, 21.7 Hz, benzylic –CH2), 4.43 (t,
2H, J = 6.0, 12.2 Hz, –OCH2), 4.31 (t, 2H, J = 3.0, 11.8 Hz, benzylic
–CH2), 3.90 (sext, 1H, J = 3.9, 9.4 Hz, –CH), 3.78 (s, 3H, –OCH3),
3.66 (p, 2H, J = 7.1, 10.1 Hz, 2 ꢁ –CH), 3.40 (t, 1H, J = 6.2, 12.4 Hz,
–CH2SO2), 2.14 (s, 3H, –CH3), 1.73–1.53 (m, 4H, 2 ꢁ –CH2), 1.25
(t, 3H, J = 6.2, 12.2 Hz, –CH3), 1.11 (d, 3H, J = 5.4 Hz, –CH3); 13C
NMR (75 MHz, CDCl3): d 165.2, 159.8, 149.4, 144.7, 137.9, 137.1,
129.8, 129.4, 128.4, 128.2, 127.8, 127.6, 124.6, 121.0, 113.9, 96.2,
83.1, 77.1, 71.3, 71.0, 70.9, 69.4, 57.7, 55.1, 55.0, 31.4, 30.7, 21.6,
20.1, 18.5; IR (neat): 3505, 2925, 2856, 1717, 1654, 1513, 1456,
1380, 1249, 1173, 986 cmꢀ1; HRMS m/z [M+Na]+: calculated for
C38H46O10SNa, 717.2709; found: 717.2711.
4.1.38. (4R,5R,E)-5-(tert-Butyldimethylsilyloxy)-4-(4-methoxy-
benzyloxy)hex-2-enoic acid 28
A mixture of 47 (0.9 g, 2.20 mmol) and 0.5 N NaOH (10 mL) in
MeOH (10 mL) was stirred at room temperature for 24 h and then
neutralized with HCl (0.5 M, 10 mL). The reaction mixture was ex-
tracted with EtOAc (3 ꢁ 30 mL), the combined extracts were dried
(Na2SO4), concentrated, and the residue was purified by column
chromatography (60–120 silica gel, 2:8 EtOAc/n-hexane) to give
28 (0.79 g, 94%) as a colorless oil. [
a
]
D = ꢀ84.8 (c 4.05, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.19 (d, 2H, J = 8.3 Hz, –C6H4), 6.99 (dd,
1H, J = 4.5, 15.8 Hz, olefinic), 6.84 (d, 2H, J = 9.0 Hz, –C6H4), 6.03
(d, 1H, J = 15.8 Hz, olefinic), 4.53, 4.34 (2d, 2H, J = 11.3 Hz, benzylic
–CH2), 3.87 (q, 2H, J = 4.5, 9.0 Hz, 2 ꢁ –CH), 3.8 (s, 3H, –OCH3), 1.05
(d, 3H, J = 6.0 Hz, –CH3), 0.86 (s, 9H, 3 ꢁ –CH3), 0.00 (s, 6H, 2 ꢁ

2526
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
4.1.41. (4R,7R,E)-4-(Benzyloxy)-7-((4R,5R,E)-5-hydroxy-4-(4-
methoxybenzyloxy) hex-2-enoyloxy)oct-2-enoic acid 27
the residue, which was purified by column chromatography (60–
120 silica gel, 1:3 EtOAc/n-hexane) to afford 51 (0.06 g, 68%) as a
To a solution of 49 (0.7 g, 1.0 mmol) in dry benzene (5 mL), a
solution of DBN (0.12 g, 1.0 mmol) in dry benzene (2 mL) was
added and the mixture was stirred at room temperature for 12 h
under nitrogen atmosphere. The reaction mixture was poured into
ether and water (1:1, 20 mL) and the aqueous layer separated was
acidified with 1 M HCl and extracted with ethyl acetate
(2 ꢁ 50 mL). The combined organic layers were washed with brine
(25 mL), dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by column chromatography (60–120 sil-
ica gel, 4.5:5.5 EtOAc/n-hexane) to afford 27 (0.39 g, 78%) as a yel-
white solid, mp: 139–141 °C; [a]
D = +31.0 (c 0.12, CHCl3); 1H
NMR (200 MHz, CDCl3): d 7.34–7.19 (m, 5H, –C6H5), 6.85 (d, 1H,
J = 5.8 Hz, olefinic), 6.70 (dt, 2H, J = 5.8, 4.1 Hz, olefinic), 6.01 (dq,
1H, J = 1.6 Hz, olefinic), 5.29 (dq, 2H, J = 1.6, 6.6 Hz, –CH), 5.15
(hept, 1H, J = 2.4, 5.8 Hz, –CH), 4.45 (q, 2H, J = 11.6, 30.7 Hz, ben-
zylic –CH2), 4.37 (s, 1H, –CH), 4.22 (t, 1H, J = 4.9 Hz, –CH), 2.18–
1.71 (m, 2H, –CH2), 1.64–1.48 (m, 2H, –CH2), 1.42 (d, 3H,
J = 6.6 Hz, –CH3), 1.17 (d, 3H, J = 6.6 Hz, –CH3); 13C NMR (75 MHz,
CDCl3): d 165.6, 150.6, 146.7, 137.9, 128.3, 127.6, 127.3, 122.2,
121.8, 96.1, 73.2, 71.0, 70.6, 69.4, 27.2, 26.0, 17.4,15.9; IR (KBr):
3404, 2923, 2853, 1717, 1459, 1257, 1172, 1052 cmꢀ1; HRMS m/z
[M+Na]+: calculated for C21H26O6Na, 397.1621; found: 397.1627.
low syrup. [
a]
D = ꢀ46.8 (c 0.24, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.29 (s, 5H, –C6H5), 7.25 (d, 2H, J = 8.0 Hz, –C6H4), 6.90 (dd, 1H,
J = 5.8, 15.4 Hz, olefinic), 6.80 (d, 2H, J = 8.8 Hz, –C6H4), 6.74 (dd,
1H, J = 5.1, 15.4 Hz, olefinic), 5.97 (dd, 2H, J = 2.9, 15.4 Hz, olefinic),
4.92 (q, 1H, J = 9.5, 15.4 Hz, –CH), 4.60 (dd, 2H, J = 2.9, 11.7 Hz, ben-
zylic –CH2), 4.30 (q, 2H, J = 11.7, 18.3 Hz, benzylic –CH2), 3.97 (m,
1H, –CH), 3.78 (s, 3H, –OCH3), 3.66 (d, 2H, J = 4.4 Hz, 2 ꢁ –CH),
1.72–1.55 (m, 4H, 2 ꢁ –CH2), 1.25 (t, 3H, J = 5.8 Hz, –CH3), 1.11
(d, 3H, J = 4.4 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 171.2,
165.2, 159.2, 149.9, 144.2, 137.6, 129.5, 129.3, 128.2, 127.5,
124.5, 121.6, 113.7, 82.8, 77.4, 71.1, 69.3, 55.0, 31.2, 30.4, 19.8,
18.1; IR (neat): 3540, 3020, 2978, 1713, 1655, 1514, 1452, 1176,
1069, 1034 cmꢀ1; HRMS m/z [M+Na]+: calculated for C29H36O8Na,
535.2307; found: 535.2305.
4.1.44. (3E,6R,9E,11R,14R)-11-(Benzyloxy)-6,14-dimethyl-1,7-
dioxacyclotetradeca-3,9-diene-2,5,8-trione 52
To a stirred solution of 51 (0.05 g, 0.13 mmol) in dry CH2Cl2
(2 mL) Dess–Martin periodinane (0.08 g, 0.20 mmol) was added
at 0 °C and stirred at room temperature for 12 h. The reaction mix-
ture was neutralized with saturated aq NaHCO3 solution (5–6
drops), stirred for another 10 min, and diluted with CH2Cl2
(50 mL). The organic layer was washed with H2O (10 mL), brine
(10 mL), dried (Na2SO4), and concentrated under reduced pressure.
The resulting residue was purified by column chromatography
(60–120 silica gel, 1.5:8.5 EtOAc/n-hexane) to give 52 (0.04 g,
80%) as a white semi solid. [
a]
D = ꢀ31.2 (c 0.3, CHCl3); 1H NMR
4.1.42. (3E,5R,6R,9E,11R,14R)-11-(Benzyloxy)-5-(4-
methoxybenzyloxy)-6,14-dimethyl-1,7-dioxacyclotetradeca-
3,9-diene-2,8-dione 50
(200 MHz, CDCl3): d 7.38 (s, 5H, –C6H5) 7.32 (d, 1H, J = 16.1 Hz, ole-
finic), 7.00 (dd, 1H, J = 4.4, 16.1 Hz, olefinic), 6.47 (d, 1H, J = 16.1 Hz,
olefinic), 6.14 (d, 1H, J = 15.4 Hz, olefinic), 5.30 (q, 1H, J = 7.3, 14.6,
–CH), 5.05 (t, 1H, J = 6.6, 13.2, –CH), 4.51 (q, 2H, J = 11.7, 19.1 Hz.,
benzylic –CH2), 4.51 (d, 1H, J = 7.4 Hz., –CH), 4.22 (d, 1H,
J = 3.6 Hz, –CH), 1.96–1.78 (m, 4H, 2 ꢁ –CH2), 1.52 (d, 3H,
J = 7.3 Hz, –CH3), 1.25 (d, 3H, J = 5.8 Hz, –CH3); 13C NMR (75 MHz,
CDCl3): d 199.4, 166.7, 164.0, 150.4, 137.7, 135.2, 131.1, 128.4,
127.7, 120.7, 77.4, 76.5, 75.5, 71.9, 70.7, 28.0, 27.9, 18.4, 16.3; IR
(neat): 3446, 2923, 2853, 1719, 1633, 1454, 1260, 1078,
To a stirred solution of 27 (0.35 g, 0.70 mmol) and Et3N (0.21 g,
2.11 mmol) in dry THF (3 mL), a solution of 2, 4, 6-trichlorobenzoyl
chloride (0.25 g, 1.05 mmol) in dry THF (1 mL) was added. The
resulting mixture was stirred for 2 h at room temperature under
nitrogen atmosphere and evaporated to afford the mixed anhy-
dride. It was diluted with toluene (10 mL) and filtered quickly
through Celite. The filtrate was added dropwise to a stirred solu-
tion of DMAP (0.07 g, 0.63 mmol) in toluene (490 mL) (total vol-
ume used for this operation was 500 mL) at 90 °C over a period
of 8 h. After the complete addition, the reaction mixture was stir-
red at 100 °C for 2 h. It was cooled, washed with 7% aq NaHCO3
(40 mL), 2 M aq HCl (40 mL), and brine (40 mL), and dried
(Na2SO4). The organic layer was evaporated and the obtained res-
idue was purified by column chromatography (60–120 silica gel,
1.5:8.5 EtOAc/n-hexane) to give 50 (0.17 g, 52%) as a syrup.
;
982 cmꢀ1 HRMS m/z [M+Na]+: calculated for C21H24O6Na,
395.1460; found: 395.1470.
4.1.45. (3E,6R,9E,11R,14R)-11-Hydroxy-6,14-dimethyl-1,7-
dioxacyclotetradeca-3,9-diene-2,5,8-trione 2
To a stirred solution of 52 (0.02 g, 0.06 mmol) in CH2Cl2 (1 mL),
TiCl4 (0.01 g, 0.06 mmol) in CH2Cl2 (1 mL) was added at 0 °C and
stirred at room temperature for 2 h. The reaction mixture was trea-
ted with saturated NaHCO3 solution (5 mL) and extracted with
CHCl3 (3 ꢁ 10 mL). The combined organic layers were washed with
water (10 mL), brine (10 mL), dried (Na2SO4), and concentrated.
The residue was purified by column chromatography (60–120 sil-
ica gel, 1:3 EtOAc/n-hexane) to afford 2 (0.02 g, 79%) as a colorless
[a
]
D = ꢀ52.6 (c 0.16, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.25
(m, 5H, –C6H5), 7.23 (d, 2H, J = 8.3 Hz, –C6H4), 6.90 (dd, 1H,
J = 5.8, 15.4 Hz, olefinic), 6.85 (d, 2H, J = 8.3 Hz, –C6H4), 6.72 (dq,
2H, J = 3.3, 15.7 Hz, olefinic), 5.98 (q, 1H, J = 15.7, 39.8 Hz, olefinic),
5.32–5.00 (m, 2H, 2 ꢁ –CH), 4.61 (d, 1H, J =11.6 Hz, –CH), 4.39 (q,
2H, J =12.4, 31.5 Hz, benzylic –CH2), 4.20 (d, 2H, J = 11.6 Hz, ben-
zylic –CH2), 4.01 (s, 1H, –CH), 3.79 (s, 3H, –OCH3), 2.15–1.49 (m,
4H, 2 ꢁ –CH2), 1.34 (d, 3H, J = 6.6 Hz, –CH3), 1.18 (d, 3H,
J = 6.6 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 165.6, 159.4, 150.2,
144.0, 137.9, 129.7, 129.2, 128.2, 127.5, 127.2, 123.5, 121.9,
113.7, 78.3, 76.9, 76.4, 71.3, 70.5, 70.2, 69.4, 55.1, 27.2, 26.2,
17.5, 16.1; IR (neat): 3429, 2924, 2854, 1719, 1611, 1513, 1458,
1170, 1063 cmꢀ1; HRMS m/z [M+Na]+: calculated for C29H34O7Na,
517.2202; found: 517.2213.
syrup, [
a]
D = ꢀ55.3 (c 0.25, MeOH); 1H NMR (400 MHz, CDCl3): d
7.33 (d, 1H, J = 16.6 Hz, H-3), 7.06 (dd, 1H, J = 3.7, 15.8 Hz, H-4),
6.40 (d, 1H, J = 15.8 Hz, H-10), 6.10 (dd, 1H, J = 15.8 Hz, H-9), 5.29
(q, 1H, J = 7.5, 14.3 Hz, H-6), 5.00 (p, 1H, J = 4.5, 10.5 Hz, H-14),
4.49 (d, 1H, J = 6.0 Hz, H-11), 2.02–1.69 (m, 2H, H-13) 1.67–1.36
(m, 2H, H-12), 1.53 (d, 3H, J = 7.5 Hz, H-15), 1.27 (d, 3H,
J = 6.7 Hz, H-16); 13C NMR (75 MHz, CDCl3): d 199.4, 165.5, 163.2,
151.3, 135.7, 130.8, 119.6, 75.5, 72.2, 70.3, 31.0, 29.6, 28.2, 18.9;
IR (neat): 3448, 2853, 1722, 1642, 1456, 1338, 1220, 1165,
1066 cmꢀ1
;
HRMS m/z [M+Na]+: calculated for C14H18O6Na,
4.1.43. (3E,5R,6R,9E,11R,14R)-11-(Benzyloxy)-5-hydroxy-6,14-
dimethyl-1,7-dioxacyclotetradeca-3,9-diene-2,8-dione 51
To a solution of 50 (0.12 g, 0.24 mmol) in a mixture of CH2Cl2
(1.9 mL) and H2O (0.1 mL), DDQ (0.08 g, 0.32 mmol) was added
and stirred at room temperature for 3 h. The reaction mixture
was filtered through Celite, dried (Na2SO4), and evaporated to give
305.1001; found: 305.1001.
4.1.46. (3E,5R,6R,9E,11R,14R)-5,11-Dihydroxy-6,14-dimethyl-
1,7-dioxacyclotetra deca-3,9-diene-2,8-dione 3
To a stirred solution of 50 (0.04 g, 0.08 mmol) in CH2Cl2 (1 mL),
TiCl4 (0.02 g, 0.08 mmol) in CH2Cl2 (1 mL) was added at 0 °C and

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2527
stirred at room temperature for 2 h. It was worked up as described
for 2 and the residue was purified by column chromatography (60–
120 silica gel, 2:3 EtOAc/n-hexane) to afford 3 (0.02 g, 78%) as a
raphy (60–120 silica gel, 0.4:9.6 EtOAc/n-hexane) to afford 55
(0.48 g, 70%) as a colorless oil. [
a
]
D = ꢀ69.9 (c 0.57, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.59–7.12 (s, 5H), 5.77–5.61 (m, 1H, ole-
finic), 5.19 (d, 2H, J = 4.1 Hz, olefinic), 4.54, 4.30 (d, 1H, J = 12.0 Hz,
benzylic –CH2), 3.76–3.62 (m, 2H, 2 ꢁ –CH), 1.61–1.32 (m, 4H,
2 ꢁ –CH2), 1.2 (d, 3H, J = 6.0 Hz, –CH3), 0.85 (s, 9H, 3 ꢁ –CH3),
0.04 (s, 6H, 2 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d 149.03,
137.49, 130.56, 128.27, 127.69, 127.35, 120.11, 72.32, 57.82,
55.17, 35.31, 31.81, 25.86, 23.80, 22.74, ꢀ4.44; IR (KBr): 3428,
2932, 2861, 1720, 1454, 1375, 1266, 1069,836 cmꢀ1 HRMS m/z
[M+Na]+: calculated for C20H34O2SiNa, 357.2225; found: 357.2213.
white solid, m. p: 165–168 °C; [
a]
D = ꢀ15.7 (c 0.3, CHCl3); 1H
NMR (400 MHz, CDCl3): 6.81 (t, 1H, J = 4.3, 7.3 Hz, H-10), 6.77 (t,
1H, J = 4.3, 7.3 Hz, H-4), 6.16 (dd, 1H, J = 1.4, 16.1 Hz, H-3), 5.90
(dd, 1H, J = 2.1, 16.1 Hz, H-9), 5.26 (dq, 1H, J = 2.1, 6.5 Hz, H-6),
5.24–5.17 (m, 1H, H-14), 4.63 (s, 1H, H-5), 4.45 (s, 1H, H-11),
3.70 (br s, 2-OH), 2.06–1.96 (m, 2H, H-13), 1.75–1.48 (m, 2H, H-
12), 1.44 (d, 3H, J = 6.5 Hz, H-15), 1.20 (d, 3H, J = 6.5 Hz, H-16);
13C NMR (100 MHz, MeOH-d4): d 167.8, 167.6, 153.4, 149.4,
122.9, 121.5, 73.8, 72.8, 70.9, 70.5, 29.2, 26.8, 17.6, 16.3; IR (neat):
3423, 2933, 1725, 1691, 1655, 1453, 1393, 1206, 1143, 1055 cmꢀ1
;
4.1.50. (4S,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-(tert-butyldimeth-
ylsilyloxy)oct-2-enoate 56
HRMS m/z [M+Na]+: calculated for C14H20O6Na, 307.1152; found:
307.1154.
Ozone was bubbled through a cooled (ꢀ78 °C) solution of 55
(0.45 g, 1.34 mmol) in CH2Cl2 (5 mL) until the pale blue color per-
sisted, excess ozone was quenched with Me2S (0.5 mL), and stirred
for 2 h. at 0 °C. The reaction mixture was concentrated under re-
duced pressure and used as such without further purification.
To the above-mentioned aldehyde (0.45 g, 1.34 mmol) in dry
CH2Cl2 (4 mL) (p-toluenesulfonylethoxycarbonylmethylene)tri-
phenyl phosphorane (1.0 g, 2.0 mmol) in dry CH2Cl2 (2 mL) was
added dropwise at 0 °C and worked up as described for 38 and
purified by column chromatography (60–120 silica gel, 1.2:8.8
EtOAc/n-hexane) to afford 56 (0.52 g, 70%) as a colorless liquid.
4.1.47. ((2S,3S)-3-((R)-3-(tert-Butyldimethylsilyloxy)butyl)oxiran-
2-yl)methanol 53
To a cooled (ꢀ20 °C) suspension of activated, powdered 4 Å MS
(0.75 g) in CH2Cl2 (10 m), (+) DIPT (0.30 g, 1.31 mmol), Ti(OiPr)4
(0.18 g, 0.65 mmol), and cumene hydroperoxide (2.01 g,
13.11 mmol) were added sequentially and stirred for 20 min. A
solution of alcohol 34 (1.6 g, 6.55 mmol) in CH2Cl2 (5 mL) was
added at ꢀ20 °C and the resulting mixture was stirred at the same
temperature for 3 h. The reaction was worked up as described for
35 and purified by column chromatography (60–120 silica gel,
1.5:8.5 EtOAc/n-hexane) to give 53 (1.23 g, 72%) as a colorless li-
[a
]
D = ꢀ61.2 (c 3.5, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.79 (d,
2H, J = 8.3 Hz, –C6H4), 7.31–7.25 (m, 7H, –C6H4, –C6H5), 6.64 (dd,
1H, J = 6.0, 15.8 Hz, olefinic), 5.74 (d, 1H, J = 15.8 Hz, olefinic),
4.49, 4.30 (2d, 2H, J = 12.0 Hz, benzylic –CH2), 4.44 (t, 2H, J = 6.0,
12.0 Hz, –OCH2), 3.84 (q, 1H, J = 5.2, 11.3 Hz, –CH), 3.70 (sext, 1H,
J = 6.0, 12.8 Hz, –CH), 3.42 (t, 2H, J = 6.7, 12.8 Hz, –CH2-SO2), 2.4
(s, 3H, Ar–CH3), 1.72–1.31 (m, 4H, 2 ꢁ –CH2), 1.07 (d, 3H, J = 6.0,
–CH3), 0.86 (s, 9H, 3 ꢁ –CH3), 0.04 (s, 6H, 2 ꢁ –CH3); 13C NMR
(75 MHz, CDCl3): d 165.3, 149.9, 129.9, 128.4, 128.1, 127.6, 120.5,
77.6, 70.9, 68.0, 57.8, 55.1, 34.6, 30.5, 25.8, 23.7, 21.6, –4.3, –4.6;
quid. [
a
]
D = ꢀ84.1 (c 0.62, CHCl3); 1H NMR (300 MHz, CDCl3): d
3.83 (m, 2H, –CH2), 3.54 (m, 1H, –CH), 2.85 (d, 2H, J = 14.3 Hz,
2 ꢁ –CH), 1.84 (t, 1H, J = 6.7 Hz, –OH), 1.64–1.41 (m, 4H, 2 ꢁ –
CH2), 1.07 (d, 3H, J = 6.0 Hz, –CH3), 0.83 (s, 9H, 3 ꢁ –CH3), 0.01 (s,
6H, 2 ꢁ –CH3); IR (neat): 3430, 2939, 2861, 1462, 1373, 1252,
1134, 1045, 834 cmꢀ1
;
HRMS m/z [M+Na]+: calculated for
C13H28O3SiNa, 283.1729; found: 283.1717.
4.1.48. (3S,6R)-6-(tert-Butyldimethylsilyloxy)hept-1-en-3-ol 54
To a solution of 53 (1.2 g, 4.61 mmol) in CCl4 (6 mL), Ph3P
(1.81 g, 6.92 mmol) and NaHCO3 (0.2 g/g.) were added and stirred
at reflux for 30 min. The reaction was worked up as described for
35a and purified by column chromatography (60–120 silica gel,
0.2:9.8 EtOAc/n-hexane) to afford 53a (0.85 g, 66%) as a colorless
syrup. 1H NMR (200 MHz, CDCl3): d 3.85 (q, 1H, J = 6.0, 11.3 Hz,
–CH), 3.61 (q, 1H, J = 5.2, 11.3 Hz, –CH), 3.39 (q, 1H, J = 6.0,
11.3 Hz, –CH), 2.94 (t, 1H, J = 5.2 Hz, –CH), 2.83 (t, 1H, J = 4.5 Hz,
–CH), 1.67–1.43 (m, 4H, 2 ꢁ –CH2), 1.13 (d, 3H, J = 6.0 Hz, –CH3),
0.89 (s, 9H, 3 ꢁ –CH3), 0.05 (s, 6H, 2 ꢁ –CH3).
IR (KBr): 2954, 2928, 1725, 1461, 1322, 1256, 1144, 1086 cmꢀ1
ESIMS: 583 [M+Na]+.
;
4.1.51. (4S,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-hydroxyoct-2-
enoate 57
To a solution of 56 (0.5 g, 0.89 mmol) in CH3CN (4 mL) TMSCl
(0.02 g, 0.17 mmol) in CH3CN (1 mL) followed by H2O (0.02 g,
0.89 mmol) was added at 0 °C and stirred at room temperature
for 1 h. The reaction was worked up as described for 29 and puri-
fied by column chromatography (60–120 silica gel, 1:3 EtOAc/n-
hexane) to furnish 57 (0.34 g, 85%) as a syrup. [
a
]
D = ꢀ35.9 (c
To a solution of epoxy chloride 53a (0.8 g, 2.87 mmol) in dry
ether (10 mL), sodium metal pieces (0.25 g, 11.48 mmol) were
added at room temperature and stirred for 12 h. It was worked
up as described for 36 and purified by column chromatography
(60–120 silica gel, 0.6:9.4 EtOAc/n-hexane) to afford 54 (0.52 g,
3.13, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.79 (d, 2H, J = 7.5 Hz,
–C6H4), 7.27 (q, 7H, J = 5.2, 12.0 Hz, –C6H5, –C6H4), 6.65 (dd, 1H,
J = 6.0, 15.8 Hz, olefinic), 5.79 (d, 1H, J = 15.8, olefinic), 4.51, 4.29
(2d, 2H, J = 12.0 Hz, benzylic –CH2), 4.44 (t, 2H, J = 6.2, 12.2 Hz, –
OCH2), 3.90 (q, 1H, J = 6.7, 14.3 Hz, –CH), 3.77–3.67 (m, 1H, –CH),
3.42 (t, 2H, J = 6.0, 12.2 Hz, –CH2SO2), 2.40 (s, 3H, Ar–CH3), 1.76–
1.32 (m, 4H, 2 ꢁ –CH2), 1.14 (d, 3H, J = 6.2 Hz, –CH3); 13C NMR
(75 MHz, CDCl3): d 165.3, 149.5, 145.0, 137.6, 136.3, 129.9, 128.4,
128.0, 127.8, 127.7, 120.6, 77.7, 71.1, 67.6, 57.7, 55.0, 34.5, 30.9,
23.5, 21.5; IR (neat): 3754, 3448, 2924, 2854, 1721, 1654, 1597,
1457, 1380, 1318, 1289, 1141, 1082 cmꢀ1; HRMS m/z [M+Na]+: cal-
culated for C24H30O6SNa, 469.1660; found: 469.1652.
75%) as a colorless oil. [
a
]
D = ꢀ22.5 (c 0.57, CHCl3); 1H NMR
(300 MHz, CDCl3): d 5.83 (m, 1H, olefinic), 5.11 (q, 2H, J = 14.8,
10.6 Hz, olefinic), 4.08 (br s, 1H, –CH), 3.82 (m, 1H, –CH), 1.85 (br
s, –OH), 1.62–1.45 (m, 4H, 2 ꢁ –CH2), 1.12 (d, 3H, J = 6.0 Hz,
–CH3), 0.88 (s, 9H, 3 ꢁ –CH3), 0.04 (s, 6H, 2 ꢁ –CH3); IR (neat):
3386, 2929, 2857, 1465, 1253, 1048, 833 cmꢀ1
; HRMS m/z
[M+Na]+: calculated for C13H28O2SiNa, 267.1756; found: 267.1768.
4.1.49. ((2R,5S)-5-(Benzyloxy)hept-6-en-2-yloxy)(tert-
butyl)dimethylsilane 55
4.1.52. (4R,5R)-Ethyl 5-(tert-butyldimethylsilyloxy)-4-(4-
methoxybenzyloxy)hexanoate 58
To a solution of 54 (0.5 g, 2.04 mmol) in dry CH2Cl2, Ag2O
(1.99 g, 4.09 mmol) was added and stirred for 30 min at room
temperature, then BnBr (0.38 g, 2.25 mmol) was introduced. The
reaction mixture was stirred at reflux for 12 h. The reaction was
worked up as described for 37 and purified by column chromatog-
To a suspension of PtO2 (0.02 g, 0.09 mmol) in EtOAc (1 mL),
ester 47 (0.8 g, 1.96 mmol) in EtOAc (1 mL) was added and then
subjected to hydrogenation at 40 psi for 4 h. The catalyst was fil-
tered off through Celite and the solvent was evaporated to afford
58 (0.75 g, 94%) as a liquid. [a]
D = +61.9 (c 1.53, CHCl3); 1H NMR

2528
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
(200 MHz, CDCl3): d 7.14 (d, 2H, J = 8.5 Hz, –C6H4), 6.76 (d, 2H,
J = 7.8 Hz, –C6H4), 4.50 (q, 2H, J = 10.9, 26.5 Hz, benzylic –CH2),
4.38 (q, 2H, J = 10.9 Hz, –OCH2), 3.87 (p, 1H, J = 6.2, 11.7 Hz,
–CH), 3.75 (s, 3H, –OCH3),, 3.21 (p, 1H, J = 3.9, 8.5 Hz, –CH), 2.28
(sext, 1H, J = 7.8, 14.8 Hz), 1.94–1.74,1.71–1.49 (2 m, 3H, –CH,
–CH2), 1.12 (t, 3H, J = 10.9 Hz, –CH3) 1.05 (d, 3H, J = 6.2 Hz,
–CH3), 0.84 (s, 9H, 3 ꢁ –CH3) 0.02 (s, 6H, 3 ꢁ –CH3); 13C NMR
(75 MHz, CDCl3): d 179.8, 159.3, 130.6, 129.6, 113.7, 81.2, 72.0,
68.7, 55.2, 51.4, 30.6, 25.7, 23.8, 17.1, –4.6; IR (neat): 2924,
2854, 1731, 1514, 1463, 1368, 1254, 1152, 1043 cmꢀ1; HRMS
m/z [M+Na]+: calculated for C22H38O5SiNa, 433.2386; found:
433.2376.
4.1.55. (4S,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-((4R,5R,E)-5-
hydroxy-4-(4-meth-oxy-benzyloxy)hex-2-enoyloxy)oct-2-
enoate 61
To a cooled (0 °C) solution of 60 (0.35 g, 0.43 mmol) in dry THF
(2 mL), HF–pyridine complex (0.04 g, 0.43 mmol) was added and
then stirred at room temperature for 6 h. The reaction was quenched
with CuSO4 solution (1 mL) and the reaction mixture was extracted
with EtOAc (2 ꢁ 25 mL). The combined organic layers were washed
with water (10 mL), brine (10 mL), dried (Na2SO4), concentrated,
and the residue was purified by column chromatography (60–120
silica gel, 3:7 EtOAc/n-hexane) to furnish 61 (0.22 g, 73%) as a yellow
syrup. [
a
]
D = ꢀ71.7 (c 1.76, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.76
(d, 2H, J = 8.3 Hz, –C6H4), 7.26 (q, 7H, J = 9.0, 5.2 Hz, –C6H5, –C6H4),
7.19 (d, 2H, J = 8.3 Hz, –C6H4), 6.8 (d, 2H, J = 8.3 Hz, –C6H4), 6.65
(dd, 1H, J = 6.0, 15.8 Hz, olefinic), 5.76 (d, 1H, J = 15.8 Hz, olefinic),
4.82 (m, 1H, –CH), 4.55 (dd, 2H, J = 3.7, 10.5 Hz, benzylic –CH2),
4.43 (t, 2H, J = 6.0,12.8 Hz, –OCH2), 4.30 (q, 2H, J = 12.0 Hz, benzylic
–CH2), 3.88 (q, 1H, J = 5.2, 10.5 Hz, –CH), 3.78 (s, 3H, –OCH3), 3.65 (p,
1H, J = 6.0, 12.8 Hz, –CH), 3.41 (t, 2H, J = 6.0, 12.8 Hz, –CH2–SO2), 3.20
(q, 1H, J = 6.0, 10.5 Hz, –CH), 2.41 (s, 3H, –CH3), 2.33 (t, 2H, J = 7.5,
12.8 Hz, –CH2CO), 2.20 (br s, –OH), 2.05–1.87 (m, 3H, –CH2, –CH),
1.80–1.68 (m, 1H, –CH), 1.15 (d, 3H, J = 6.7 Hz, –CH3), 1.11 (d, 3H,
J = 6.0, 12.8 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 173.3, 165.2,
159.8, 149.0, 144.9, 137.8, 129.9, 129.3, 128.4, 127.8, 128.1, 127..6,
121.8, 113.7, 81.6, 72.2, 71.6, 70.2, 69.4, 69.1, 57.8, 55.1, 31.8, 31.2,
30.4, 25.8, 24.4, 21.6, 20.0 18.0; IR (KBr): 3521, 2927, 2859, 1724,
1690, 1520, 1470, 1143 cmꢀ1; HRMS m/z [M+Na]+: calculated for
C38H48O10SNa, 719.2865; found: 719.2896.
4.1.53. (4R,5R)-5-(tert-Butyldimethylsilyloxy)-4-(4-methoxyben-
zyloxy)hexanoic acid 59
A mixture of 58 (0.70 g, 1.71 mmol) and 0.5 M NaOH (10 mL) in
MeOH (10 mL) was stirred at room temperature for 24 h. The
reaction was worked up as described for 28 and the residue was
purified by column chromatography (60–120 silica gel, 2:8
EtOAc/n-hexane) to give 59 (0.59 g, 90%) as a colorless oil.
[a]
D = +15.2 (c 0.75, CHCl3); 1H NMR (300 MHz, CDCl3): d 8.23
(br s, 1H, –COOH), 7.19, 6.83 (2d, 4H, J = 8.3 Hz, –C6H4), 4.41 (q,
2H, J = 11.3, 36.2 Hz, benzylic –CH2), 3.9 (p, 1H, J = 6.0, 12.0 Hz,
–CH), 3.76 (s, 3H, –OCH3), 3.27–3.22 (m, 1H, –CH), 2.39–2.25
(m, 2H, –CH2), 2.01–1.82 (m, 1H, –CH), 1.69–1.57 (m, 1H, –CH),
1.07 (d, 3H, J = 6.0 Hz, –CH3), 0.85 (s, 9H, 3 ꢁ –CH3), 0.00 (s, 6H,
3 ꢁ –CH3); 13C NMR (75 MHz, CDCl3): d 170.0, 159.3, 129.5,
128.4, 127.8, 113.8, 70.9, 70.5, 67.9, 55.4, 34.7, 30.8, 25.4, 19.9,
–4.3; IR (neat): 3435, 2958, 2855, 1727, 1614, 1520, 1369, 1299,
1174, 1012 cmꢀ1; HRMS m/z [M+Na]+: calculated for C20H34O5Si-
Na, 405.2073; found: 405.2060.
4.1.56. (4S,7R,E)-4-(Benzyloxy)-7-((4R,5R)-5-hydroxy-4-(4-
methoxybenzyloxy) hexanoyloxy)oct-2-enoic acid 62
To a solution of 61 (0.2 g, 0.28 mmol) in dry benzene (2 mL) a
solution of DBN (0.03 g, 0.28 mmol) in dry benzene (2 mL) was
added and stirred at room temperature for 12 h under nitrogen
atmosphere. Worked up as described for 27 and purified by column
chromatography (60–120 silica gel, 5:5 EtOAc/n-hexane) to afford
4.1.54. (4S,7R,E)-2-Tosylethyl 4-(benzyloxy)-7-((4R,5R)-5-(tert-
butyldimethyl silyl-oxy)-4-(4-methoxybenzyloxy)hexanoyloxy)-
oct-2-enoate 60
D = ꢀ57.58 (c 0.96, CHCl3); 1H
To a solution of acid 59 (0.3 g, 0.8 mmol) and Et3N (0.20 g,
2.01 mmol) in dry THF (3 mL) 2, 4, 6-trichlorobenzoyl chloride
(0.24 g, 1.0 mmol) was added and the reaction mixture was stirred
at room temperature for 2 h under nitrogen atmosphere. The reac-
tion mixture was filtered and the filtrate was evaporated. The
resulting anhydride was dissolved in toluene (2 mL), treated with
alcohol 57 (0.3 g, 0.67 mmol) in toluene (2 mL) and DMAP
(0.16 g, 1.34 mmol) in toluene (1 mL), and stirred at room temper-
ature for 1 h. The reaction was worked up as described for 48 and
purified by column chromatography (60–120 silica gel, 1.5:8.5
62 (0.1 g, 68%) as a yellow syrup. [
a
]
NMR (200 MHz, CDCl3): d 7.28 (s, 5H, –C6H5), 7.22 (d, 2H,
J = 8.3 Hz, –C6H4), 6.87 (dd, 1H, J = 6.0, 15.8 Hz, olefinic), 6.83 (d,
1H, J = 8.3 Hz, –C6H4), 5.96 (d, 1H, J = 15.8 Hz, olefinic), 4.83 (d, 1H,
J = 5.2 Hz, –CH), 4.56 (t, 2H, J = 12.0, 24.1 Hz, benzylic –CH2), 4.37
(q, 2H, J = 10.5, 25.6 Hz, benzylic –CH2), 3.95 (d, 1H, J = 5.2 Hz,
–CH), 3.80 (s, 3H, –OCH3), 3.68 (t, 1H, J = 6.0, 12.0 Hz, –CH), 3.22
(q, 1H, J = 6.0, 10.5 Hz, –CH), 2.23 (t, 2H, J = 6.0, 13.5 Hz, –CH2CO),
2.07 (s, 1H, –OH), 2.0–1.89 (m, 1H, –CH), 1.79–1.51 (m, 5H, 2 ꢁ
–CH2, –CH), 1.14 (t, 6H, J = 5.2, 9.8 Hz, 2 ꢁ –CH3); 13C NMR
(75 MHz, CDCl3): d 170.6, 164.0, 150.1, 129.5, 129.2, 128.4, 127.8,
121.4,113.8, 82.2, 78.7, 71.8, 70.7, 70.4, 68.7, 55.2, 34.4, 30.8. 25.1,
23.4, 19.9, 17.2; IR (neat): 2924, 2854, 1720, 1655, 1611, 1513,
1458, 1376, 1249, 1176, 1075 cmꢀ1; HRMS m/z [M+Na]+: calculated
for C29H38O8Na, 537.2464; found: 537.2451.
EtOAc/n-hexane) to give 60 (0.39 g, 72%) as an oil. [
a]
D = ꢀ7.9 (c
0.24, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.78 (d, 2H, J = 8.3 Hz,
–C6H4), 7.28 (q, 7H, J = 8.3, 17.3 Hz, –C6H5, –C6H4), 7.16 (d, 2H,
J = 8.3 Hz, –C6H4), 6.77 (d, 2H, J = 8.3 Hz, –C6H4), 6.60 (dd, 1H,
J = 6.0, 15.8 Hz, olefinic), 5.77 (d, 1H, J = 15.8 Hz, olefinic), 4.79 (q,
1H, J = 4.5, 10.5 Hz, –CH), 4.45 (q, 2H, J = 11.3, 27.9 Hz, benzylic –
CH2), 4.44 (d, 2H, J = 8.3 Hz, benzylic –CH2), 4.32 (t, 2H, J = 12.0,
27.2 Hz, 2 ꢁ –CH), 3.83 (d, 2H, J = 5.2 Hz, –OCH2), 3.76 (s, 3H, –
OCH3), 3.40 (t, 2H, J = 6.0, 12.0 Hz, –CH2–SO2), 3.21 (p, 1H, J = 3.7,
9.0 Hz, –CH), 2.39 (s, 3H, –CH3), 2.39–2.18 (m, 2H, –CH2-CO),
1.86 (m, 1H, –CH), 1.67–1.43 (m, 3H, –CH2, –CH), 1.25 (t, 2H,
J = 6.7, 14.3 Hz, –CH2), 1.12 (d, 3H, J = 6.0 Hz, –CH3), 1.07 (d, 3H,
J = 6.0 Hz, –CH3), 0.86 (s, 9H, 3 ꢁ –CH3), 0.018 (s, 6H, 2 ꢁ –CH3);
13C NMR (75 MHz, CDCl3): d 173.2, 165.1, 159.0, 149.2, 144.8,
137.7, 136.4, 129.8, 129.2, 128.3, 128.0, 127.7, 127.5, 120.7,
113.6, 81.5, 77.1, 72.1, 71.0, 69.9, 68.67, 57.7, 55.1, 55.0, 31.1,
30.3, 28.1, 25.7, 24.3, 21.5, 19.9, 17.9, –4.7; IR (neat): 3415, 2923,
2853, 1717, 1630, 1460, 1384, 1251, 1080, 758 cmꢀ1; HRMS m/z
[M+Na]+: calculated for C44H62O10SSiNa, 833.3730; found:
833.3726.
4.1.57. (3E,5R,6R,9E,11S,14R)-11-(Benzyloxy)-5-(4-methoxyben-
zyloxy)-6,14-dimethyl-1,7-dioxacyclotetradeca-3,9-diene-2,8-
dione 63
To a solution of 62 (0.08 g, 0.15 mmol) and Et3N (0.04 g,
0.46 mmol) in dry THF (2 mL), 2, 4, 6-trichlorobenzoyl chloride
(0.05 g, 0.23 mmol) in dry THF (1 mL) was added. The resulting
mixture was stirred at room temperature for 2 h under nitrogen
atmosphere. It was evaporated to afford the mixed anhydride,
which was diluted with toluene (10 mL) and filtered quickly
through Celite. The filtrate was added dropwise to a stirred solu-
tion of DMAP (0.15 g, 1.24 mmol) in toluene (90 mL) (total volume
used for this operation was 100 mL) at 90 °C for 10 h. The reaction
was worked up as described for 50 and purified by column chro-
matography (60–120 silica gel, 1.5:8.5 EtOAc/n-hexane) to give

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 20 (2009) 2513–2529
2529
63 (0.04 g, 58%) as an oil. [
a]
D = ꢀ10.4 (c 0.21, CHCl3); 1H NMR
References
(200 MHz, CDCl3): d 7.35–7.25 (m, 7H, –C6H5, –C6H4), 6.83 (d, 2H,
J = 8.3 Hz, –C6H4), 6.55 (q, 1H, J = 9.0, 15.8 Hz, olefinic), 5.82 (d,
1H, J = 15.8 Hz, olefinic), 5.19 (dd, 1H, J = 2.2, 6.7 Hz, –CH), 4.77
(q, 1H, J = 6.0, 10.5 Hz, –CH), 4.55, 4.31 (2d, 2H, J = 12.0 Hz, benzylic
–CH2), 4.55 (s, 2H, benzylic –CH2), 3.81 (s, 3H, –OCH3), 3.74 (m, 2H,
2 ꢁ –CH), 2.72 (dq, 1H, J = 2.2, 10.5 Hz, –CHCO), 2.33 (dq, 1H,
J = 3.0, 6.7 Hz,, –CHCO), 2.11–1.93 (m, 1H, –CH), 1.88–1.45 (m,
5H, 2 ꢁ –CH2, –CH), 1.33 (d, 3H, J = 6.7 Hz, –CH3), 1.16 (d, 3H,
J = 6.0 Hz, –CH3); 13C NMR (75 MHz, CDCl3): d 172.4, 164.2, 159.2,
147.6, 137.7, 130.4, 129.3, 128.4, 127.65, 124.7, 113.7, 78., 77.0,
75.6, 71.5, 70.4, 68.9, 55.2, 29.2, 28.8, 28.3, 23.9, 19.4, 14.0; IR
(neat): 3435, 2925, 2854, 1728, 1645, 1611, 1512, 1459, 1374,
1. Berg, A.; Notni, J.; Dorfelt, H.; Grafe, U. J. Antibiot. 2002, 55, 660–662.
2. Grove, J. F.; Speake, R. N.; Ward, G. J. Chem. Soc. 1966, 230–234.
3. (a) Mac Millan, J.; Simpson, T. J. J. Chem. Soc., Perkin Trans. 1 1973, 1487–1493;
(b) Schnubr Renberger, P.; Hungerbuhler, E.; Seebach, D. Tetrahedron Lett. 1984,
25, 2209–2212.
4. Grabley, S.; Hamman, P.; Thiericke, R.; Wing, J.; Philipp, S.; Zeeck, A. J. Antibiot.
1993, 46, 343–345.
5. (a) Rao, A. V. R.; Murthy, V. S.; Sharma, G. V. M. Tetrahedron Lett. 1995, 36, 139–
142; (b) Rao, A. V. R.; Murthy, V. S.; Sharma, G. V. M. Tetrahedron Lett. 1995, 36,
143–146.
6. (a) Sharma, G. V. M.; Chandramouli, Ch. Tetrahedron Lett. 2002, 43, 9159–
9161; (b) Sharma, G. V. M.; Chandramouli, Ch. Tetrahedron Lett. 2003, 44,
8161–8163; (c) Sharma, G. V. M.; Goverdhan Reddy, C. Tetrahedron Lett.
2004, 45, 7483–7485; (d) Sharma, G. V. M.; Janardhan Reddy, J.; Laxmi
Reddy, K. Tetrahedron Lett. 2006, 47, 6531–6535; (e) Sharma, G. V. M.;
Laxmi Reddy, K.; Janardhan Reddy, J. Tetrahedron Lett. 2006, 47, 6537–6540;
(f) Sharma, G. V. M.; Veera Babu, K. Tetrahedron: Asymmetry 2007, 18,
2175–2184; (g) Sharma, G. V. M.; Veera Babu, K. Tetrahedron: Asymmetry
2008, 5, 575–583.
7. (a) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570–
7571; (b) Han, J.; Su, N.; Jiang, T.; Xu, Y.; Huo, X.; She, X.; Pan, X. J. Org. Chem.
2009, 74, 3930–3932.
8. Sunazuka, T.; Hirose, T.; Harigaya, Y.; Takamatsu, S.; Hayashi, M.; Komiyama,
K.; Omura, S.; Sprenpelet, P. A.; Smith, A. B. J. Am. Chem. Soc. 1997, 119, 10247–
10248.
9. (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould,
A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315; (b)
Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936–
938; (c) Louis, J. T.; Nelson, W. L. J. Org. Chem. 1987, 52, 1309–1315.
10. Inagawa, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
11. Sharma, G. V. M.; Reddy, Ch. G.; Radha Krishna, P. J. Org. Chem. 2003, 68, 4574–
4575.
12. Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942–3943.
13. Gurjar, M. K.; Nagaprasad, R.; Ramana, C. V. Tetrahedron Lett. 2003, 44, 2873–
2875.
14. (a) Sharpless, K. B.; Katsuki, T. J. Am. Chem. Soc. 1980, 102, 5974–5976; (b) Gao,
Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765–5780.
15. Colvin, E. W.; Purcell, T. A.; Raphael, R. A. J. Chem. Soc., Perkin Trans. 1 1976,
1718–1722.
16. Wu, W.; Wu, Y. J. Org. Chem. 1993, 58, 3586–3588.
17. Mehta, G.; Mohal, N.; Lakshminath, S. Tetrahedron Lett. 2000, 41, 3505–
3508.
18. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
19. Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012–1044.
;
1251, 1176, 1068 cmꢀ1 HRMS m/z [M+Na]+: calculated for
C29H36O7Na, 519.2358; found: 519.2353.
4.1.58. (5R,6R,11S,14R,E)-5,11-Dihydroxy-6,14-dimethyl-1,7-
dioxacyclotetradec-9-ene-2,8-dione 1a
To a stirred solution of 63 (0.03 g, 0.07 mmol) in CH2Cl2 (1 mL),
TiCl4 (0.01 g, 0.07 mmol) in CH2Cl2 (1 mL) was added at 0 °C and
then stirred at room temperature for 2 h. The reaction was worked
up as described for 3 and purified by column chromatography (60–
120 silica gel, 4:6 EtOAc/n-hexane) to afford 1a (0.02 g, 80%) as a
white solid, mp: 118–120 °C; [
a]
D = ꢀ52.7 (c 0.23, MeOH); 1H
NMR (400 MHz, DMSO): d 6.53 (q, 1H, J = 7.8, 15.7 Hz, H-10),
5.74 (d, 1H, J = 15.7 Hz, H-9), 5.10 (d, 1H, J = 3.9 Hz, H-6), 4.97 (d,
1H, J = 4.9 Hz, H-14), 4.80 (q, 1H, J = 3.9, Hz, H-11), 4.60 (q, 1H,
J = 5.8, 9.8 Hz, H-5), 3.98 (s, 1H, OH-5), 3.79 (d, 1H, J = 3.9 Hz,
OH-11), 2.64 (q, 1H, J = 1.9, 10.7 Hz, H-3), 2.30 (dd, 1H, J = 2.9,
7.8 Hz, H-3), 1.77 (t, 1H, J = 13.7 Hz, H-4), 1.64–1.57 (m, 4H, H-4,
H-13, H-12), 1.41–1.47 (m, 1H. H-12), 1.16 (d, 3H, J = 5.8 Hz, –H-
15), 1.05 (d, 3H, J = 6.8 Hz, H-16); 13C NMR (75 MHz, DMSO): d
172.4, 164.5, 151.1, 120.9, 73.2, 69.9, 68.7, 67.0, 30.6, 29.2, 28.4,
26.6, 19.7, 13.7; IR (KBr): 3435, 2925, 2854, 1715, 1642, 1358,
1263, 770 cmꢀ1; HRMS m/z [M+Na]+: calculated for C14H22O6Na,
309.1308; found: 309.1312.
Acknowledgment
One of the authors (S.M.) thanks the CSIR, New Delhi, India, for
financial support in the form of a fellowship.