Stereoselective synthesis of C1-C9 and C9-C17 fragments of (+)-13-deoxytedanolide

Article abstract of DOI:10.1016/j.tet.2010.01.023

An efficient and highly stereoselective asymmetric synthesis of C1-C9 and C9-C17 fragments of (+)-13-deoxytedanolide have been achieved. Utilization of desymmetrization technique to prepare the triol with five stereogenic centers, regioselective Sharpless asymmetric dihydroxylation, Evans' aldol reaction, chiral methylation, and Wittig olefination are highlights of the synthesis.

Full text of DOI:10.1016/j.tet.2010.01.023

Tetrahedron 66 (2010) 3265–3274
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of C1–C9 and C9–C17 fragments of
(þ)-13-deoxytedanolide
*
J.S. Yadav , N. Rami Reddy
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500607, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2009
Received in revised form 30 December 2009
Accepted 6 January 2010
Available online 11 January 2010
An efficient and highly stereoselective asymmetric synthesis of C1–C9 and C9–C17 fragments of (þ)-13-
deoxytedanolide have been achieved. Utilization of desymmetrization technique to prepare the triol with
five stereogenic centers, regioselective Sharpless asymmetric dihydroxylation, Evans’ aldol reaction,
chiral methylation, and Wittig olefination are highlights of the synthesis.
Ó 2010 Published by Elsevier Ltd.
Keywords:
(þ)-13-Deoxytedanolide
Cytotoxicity
Evans’ aldol
Chiral auxiliary
Cross-metathesis
Yamaguchi macrolactonization
Regioselective Sharpless asymmetric
dihydroxylation
1. Introduction
stereoselective synthesis of C1–C9 and C9–C17 fragments of 1. From
the retrosynthetic strategy of 1 as shown in Scheme 1, we envisaged
Tedanolide, an anti-tumor macrolide was isolated from a Carib-
bean sponge Tedania ignis in 1984 by Schmitz et al.1 A closely related
macrolide, 13-deoxytedanolide (1) was also isolated from Mycale
adhaerens by Fusetani et al. in 1991.2 While these two polyketides
exhibited remarkable cytotoxicity at pico to nanomolar ranges,
13-deoxytedanolide was found highly cytotoxic with a reported IC50
of 94 pg/mL against P388 murine Leukemia cells.2 Recently Fusetani
et al. reported3 that 1 bound to 60S large ribosomal subunit of the
budding yeast Saccharomyces cerevisiae, inhibits polypeptide elon-
gation. Although, many protein synthesis inhibitory natural products
are known to bind to the prokaryotic large subunit, 1 is the first
macrolide inhibitor that binds to the eukaryotic ribosome. Owing to
the structural complexity and bioactivity, tedanolides have gener-
ated wide interest on their synthesis. Consequently, total synthe-
ses4,5 and several approaches toward their synthesis have been
reported by various research groups.6
that 1 could be obtained by coupling the macrolactone 2 and side
chain 3 via aldol reaction. The macrolactone 2 could be prepared by
coupling the fragments 4 and 5 by cross-metathesis8 and Yama-
guchi macrolatonisation.9 Carboxylic acid 4, in turn could be
derived from lactone 6 and alcohol 5 could be prepared from 1,5-
pentanediol using Evans’ aldol reaction, Wittig olefination, and
Reformatsky reaction as key steps.
2.1. Synthesis of the C1–C9 fragment 4
The synthesis of C1–C9 fragment 4 was obtained by (Scheme 2)
reductive opening of the lactone 6 with LiAlH4 in dry THF, which fur-
nished triol 7 with five chiral centers straight away.7a,d The triol 7 was
converted to its corresponding acetonide derivative 8 (90% yield) by
treating with 2,2-dimethoxypropane and PPTS in CH2Cl2. After pro-
tectingtheprimary–OHgroupof8, acetonidegroupwas cleaved using
p-TSA in methanol to afford 10 in 92% yield. Initial attempts to obtain
monoprotected mesylate derivative ended up with low yield of the
required compound. Silylation of 10 with TBDMSCl and imidazole in
CH2Cl2 followed by treatment with MOMCl and DIPEA in CH2Cl2
afforded compound 12, which was desilylated using TBAF in THF and
mesylated with MsCl and Et3N in CH2Cl2 to obtain 14 in high yield.
Compound 14 was heated with NaI in DMF followed by treatment with
DBU to obtain olefin 15.10 Initial efforts to generate the triol 17 by
2. Results and discussion
In continuation of our efforts in the synthesis of marine natural
products,7 especially polypropionates, we report herein the
* Corresponding author. Fax: þ91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.01.023

3266
J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
Yamaguchi
esterification
OH
OH
5
OH
O
OH
O
1
7
OMe
O
O
O
O
OMe
O
O
O
9
+
O
17
13
OH
cross-metathesis/
RCM
O
O
OH
aldol reacion
3
2
1
(+)-13-Deoxytedanolide
O
O
O
O
HOOC
OH
OH
O
OTIPS
OR
OH
OTES
OPMB
OBn
6
4
5
R=PMB
Scheme 1. Retrosynthetic analysis of (þ)-13-deoxytedanolide 1.
deprotection of triply benzylated system and MOM protected com-
pound 14 lead to migration of the double bond, therefore, it was
considerednecessary tohaveallylichydroxygroup free. Hencepriorto
debenzylation, 15 was treated with phosphomolybdic acid (adsorbed
on silica gel) under solvent-free conditions to obtain 16 in 95% yield.
Debenzylation of 16 under Birch reduction11 conditions gave
the corresponding triol in 90% yield. The crude triol 17 was con-
verted to PMB acetal using p-methoxybenzyldimethyl acetal and
catalytic CSA in CH2Cl2. Silylation of 18 with TIPSOTf and DIPEA in
CH2Cl2 gave compound 19, which on reduction with DIBAL-H12 in
CH2Cl2 followed by Swern oxidation13 of the alcohol 20 followed
by Wittig olefination14 of the corresponding aldehyde 21 with
stabilized ylide Ph3P]CHCOOtBu in benzene under reflux gave
asymmetric dihydroxylation15 (Scheme 3) with AD-mix-
a
(2.0 mol % based on OsO4) gave C2,C3-syn diols (23/24¼9.5/0.5,
separated on silica gel column).16 Acetonide protection of compound
23 and saponification by LiOH$H2O in THF/MeOH/H2O (4/1/2)
completed the synthesis of C1–C9 fragment 4 of (þ)-13-deoxy-
tedanolide (Scheme 3).
2.2. Synthesis of the C9–C17 fragment 5
The synthesis of C9–C17 fragment 5 started with benzylation of
1,5-pentanediol by NaH and BnBr in THF. Swern oxidation of the
alcohol 26 followed by further oxidation with aq NaClO2, H2O2 in
CH3CN resulted in the formation of corresponding carboxylic acid17
27 (73% over two steps). Auxiliary 42 was coupled to carboxylic acid
trans-
a
,
b
-unsaturated ester 22. Compound 22 on Sharpless
O
O
O
d
a
b
OBn
10 R1 = R2 = H
OR2
OR1
OBn
OH
OH
OH
OBn
O
OR
O
OBn
OBn
6
7
e
8
9
R = H
R = Bn
11 R1 = H, R2 = TBDMS
12 R1 = MOM, R2 = TBDMS
13 R1 = MOM, R2 = OH
c
f
g
OMs
i
h
k
OBn
OBn
OBn OMOM
OBn
OR
OH
OH
OH
14
15 R = MOM
16 R = H
17
j
o
l
n
OHC
OR2
OH
OR1
20
R1 = PMB, R2 = TIPS
OR2
OR1
O
O
OR
21
PMP
18
18 R = H
m
19 R = TIPS
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 0 ꢀC to rt, 4 h, 90%; (b) 2,2-DMP, PPTS, DCM, rt, 5 h, 90%; (c) NaH, BnBr, dry THF, 0 ꢀC to rt, 5 h, 95%; (d) MeOH, PPTS, rt,
overnight, 84%; (e) TBDMSCl, imidazole, DCM, rt, 2 h, 92%; (f) MOMCl, DIPEA, DCM, 0 ꢀC to rt, 6 h, 90%; (g) TBAF, dry THF, rt, 2 h, 92%; (h) MsCl, Et3N, dry DCM, 0 ꢀC to rt, 1 h, 93%;
(i) NaI, dry DMF, 50 ꢀC, 5 h then DBU, 80 ꢀC, 3 h, 88%; (j) PMA/SiO2, Solvent-free, rt, 15 min, 91%; (k) Li metal, liq. NH3, ꢁ45 ꢀC, 10 min; (l) PMB dimethylacetal, CSA cat., DCM, rt, 2 h,
after two steps 85%; (m) TIPSOTf, DIPEA, DCM, 0 ꢀC to rt, 2 h, 95%; (n) DIBAL-H, DCM, 0 ꢀC, 1 h, 93%; (o) DMSO, (COCl)2, DCM, Et3N, ꢁ78 ꢀC, 96%.

J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
OH
3267
b
ROOC
a
ROOC
21
OH
23
OR1
OR2
OR2
OR1
22
OH
R = t-Bu
R1 = PMB
R2 = TIPS
ROOC
+
OR2
OR1
OH
24
O
d
c
ROOC
23
4
OR1
O
OR2
25
Scheme 3. Reagents and conditions: (a) Ph3P^CHCOOtBu, benzene, reflux, 2 h, 87%; (b) AD-mix-
cat., DCM, rt, 5 h, 93%; (d) LiOH$H2O, THF/MeOH/H2O (4/1/2), rt, 18 h, 88%.
a, t-BuOH–H2O (1/1), MeSO2NH2, rt, 24 h, (23/24¼9.5/0.5) 90%; (c) 2,2-DMP, p-TSA
27 under standard conditions to form the N-acylated oxazolidi-
none18 28, which was methylated using NaHMDS and CH3I in THF.
Compound 29 on treatment with NaBH4 in ethanol and silylation of
the resulting alcohol 30 with TBDPSCl and imidazole, followed by
debenzylation using 10% Pd/C under H2 gas pressure, afforded the
alcohol 32 in high yield (Scheme 4).
d
b, c
e
HOOC
O
N
OR
R = H
OH
OBn
27
OBn
O
7
O
O
a
NH
28
42
26 R = Bn
O
f
j
i
CHO
O
N
OR2
OR1
TBDPSO
33
N
O
OBn
O
O
O
O
30 R1 = H, R2 = Bn
43
g
h
29
31 R1 = TBDPS, R2 = Bn
32 R1 = TBDPS, R2 = OH
k
l
N
O
O
O
OTBDPS
36
OH
OH
OTBDPS
O
O
OH
34
OTBDPS
PMP
35
OH
p
n, o
m
OPMB
OH
OPMB
OTBDPS
EtOOC
OPMB
OTBDPS
38
39
37
q, r
t
OPMB
OTES
OH
OR
OPMB
5
40 R = H
41 R = TES
s
Scheme 4. Reagents and conditions: (a) NaH, BnBr, dry THF, 0 ꢀC to rt, 3 h, 80%; (b) DMSO, (COCl)2, DCM, Et3N, ꢁ78 ꢀC; (c) NaClO2, NaH2PO4$2H2O, H2O2, acetonitrile, 0 ꢀC to rt, 6 h,
after two steps 73%; (d) (i) 42, n-BuLi, dry THF, ꢁ78 ꢀC, (ii) pivaloyl chloride, Et3N, dry THF, 0 ꢀC to rt, 2 h, 85%; (e) NaHMDS, dry THF, ꢁ78 ꢀC, MeI, 2 h, 81%; (f) NaBH4, EtOH, 0 ꢀC,
15 min, 85%; (g) TBDPSCl, imidazole, DCM, rt, 4 h, 95%; (h) H2, 10% Pd/C, EtOAc, rt, 2 h, 95%; (i) DMSO, (COCl)2, DCM, Et3N, ꢁ78 ꢀC; (j) 43, Bu2BOTf, DIPEA, DCM, ꢁ78 ꢀC to rt, after
two steps 82%; (k) NaBH4, EtOH, 0 ꢀC, 15 min, 85%; (l) PMB dimethylacetal, CSA cat., DCM, rt, 2 h, 87%; (m) DIBAL-H, dry DCM, 0 ꢀC, 1 h, 90%; (n) DMSO, (COCl)2, DCM, Et3N, ꢁ78 ꢀC;
(o) Ph3PCH3Br, NaHMDS, dry THF, 0 ꢀC, 1 h, after two steps 76%; (p) TBAF, dry THF, rt, 4 h, 92%; (q) DMSO, (COCl)2, DCM, Et3N, ꢁ78 ꢀC to rt; (r) BrCH2COOEt, Zn–Cu couple, dry THF,
reflux, 1 h, after two steps 70%; (s) TESOTf, DIPEA, dry DCM, rt, 1 h; 93%; (t) DIBAL-H, dry DCM, 0 ꢀC, 1 h, 92%.

3268
J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
Swern oxidation of 32 followed by Evans aldol reaction19a,b
HRMS: m/z calcd for
319.1833.
C
17H28O4Na [MþNa]þ 319.1837, found
employing N-acylated oxazolidinone 43 provided aldol adduct 34
with desired chirality and the stereochemical outcome was con-
ceived as reported on similar substrate.19c Reduction of 34 with
NaBH4 in EtOH gave 35, which was protected as its p-methox-
ybenzyl acetal derivative 36. Reduction of PMB acetal 36 with
DIBAL-H in CH2Cl2 afforded the primary alcohol 37, which on Swern
oxidation followed by Wittig olefination with nonstabilized ylide
Ph3P]CH2 gave 38 in 90% yield.20 Desilylation and Swern oxidation
followed by Reformatsky reaction21 using BrCH2COOEt and Zn/Cu
4.1.2. (2R,3S,4R)-3-(Benzyloxy)-2-methyl-4-[(4R,5S)-2,2,5-trimethyl-
1,3-dioxan-4-yl]pentan-1-ol (8). To solution of (10.5 g,
a
7
35.5 mmol) in dry DCM (100 mL), 2,2-dimethoxypropane (6.5 mL,
53.2 mmol) and PPTS (0.42 g, 1.77 mmol) were added. The mixture
was stirred at ambient temperature for 5 h. Saturated aqueous so-
lution of sodium bicarbonate was added to the reaction mixture.
The aqueous layer was extracted with DCM (2ꢂ100 mL) and the
combined organic layer was dried over Na2SO4 and evaporated
under reduced pressure to afford the crude product, which on
purification by column chromatography on silica gel gave acetonide
couple in refluxing THF afforded the b-hydroxy ester 40 in 70% yield
over two steps. Compound 40 was protected as its silyl ether using
TESOTf and DIPEA in CH2Cl2 followed by treatment with DIBAL-H in
CH2Cl2 and completed the synthesis of C9–C17 fragment 5.
8 as a white solid; (10.7 g, 90%), Rf¼0.60 (1/1 EtOAc/hexane); mp:
25
96–97 ꢀC; [
a
]
þ116.5 (c 0.5, CHCl3); IR (neat): 3479, 2923, 1617,
D
1031 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 7.37–7.23 (m, 5H, ArH),
3. Conclusion
4.74–4.55 (ABq, 2H, J¼11.7, 27.4 Hz, benzylic CH2), 3.92–3.79 (m,
1H), 3.65 (dd, J¼10.9, 4.7 Hz, 1H), 3.59–3.39 (m, 3H), 2.64 (dd, J¼7.8,
2.3 Hz,1H) 2.07–1.76 (m, 3H, 3ꢂCH),1.34 (s, 6H, 2ꢂCH3),1.21 (d, 3H,
J¼7.0 Hz, CH3), 0.87 (d, 3H, J¼7.0 Hz, CH3), 0.73 (d, 3H, J¼7.0 Hz,
In summary, we have demonstrated a highly stereoselective
syntheses of C1–C9 and C9–C17 fragments of (þ)-13-deoxy-
tedanolide. Studies toward completing the total synthesis of 1 by
coupling the two fragments and introduction of the side chain 3 is
now under progress.
CH3); 13C NMR (CDCl3, 75 MHz):
d 138.5, 128.5, 127.7, 127.3, 98.0,
85.6, 75.4, 73.8, 66.2, 64.3, 87.5, 36.3, 30.3, 29.8, 19.8, 16.5, 12.5, 9.9;
ESI HRMS: m/z calcd for C20H32O4Na [MþNa]þ 359.2198, found
359.2205.
4. Experimental
4.1. General
4.1.3. (4R,5S)-4-[(1R,2S,3R)-2,4-Di(benzyloxy)-1,3-dimethylbutyl]-
2,2,5-trimethyl-1,3-dioxane (9). To a stirred suspension of NaH (60%
suspension in mineral oil) (1.57 g, 32.7 mmol) in THF (80 mL) was
added a solution of alcohol 8 (10.0 g, 29.7 mmol) in dry THF (20 mL)
at 0 ꢀC. The reaction mixture was stirred at room temperature for
30 min. It was cooled to 0–5 ꢀC and benzyl bromide (3.5 mL,
32.7 mmol) was added dropwise. The reaction mixture was stirred
at room temperature for 4 h. The reaction mixture was cooled to
0–5 ꢀC and water was added slowly to dissolve the solids. The
temperature was raised to 25 ꢀC and the reaction mixture was
extracted with diethyl ether (3ꢂ100 mL). The combined organic
extract was washed with saturated NH4Cl, water, brine, dried over
Na2SO4, evaporated under reduced pressure, and purification by
Commercial reagents were used without further purification
and all the solvents were purified by standard techniques. All re-
actions were monitored by TLC (silica-coated plates and visualizing
under UV light). Air sensitive reagents were transferred by syringe
or double-ended needle. Evaporation of solvents was performed at
reduced pressure on a Buchi rotary evaporator. Infrared spectra
were recorded on a Perkin–Elmer 683 spectrometer. Optical rota-
tions were obtained on a Perkin–Elmer Model 343 polarimeter
preparing the samples in CHCl3. Melting points are uncorrected. 1H
NMR and 13C NMR spectra were recorded in CDCl3 on Varian
Gemini 200, Bruker 300, Varian 400, and 500 NMR spectropho-
column chromatography on silica gel afforded 9 as a colorless oil
25
tometers. Chemical shifts (
d) are quoted in parts per million and are
(12.0 g, 95%), Rf¼0.80 (1/4 EtOAc/hexane); [
a]
þ77.93 (c 0.5,
D
referred to tetramethylsilane (TMS) as internal standard. Coupling
constants (J) are quoted in Hertz. Column chromatographic sepa-
rations were carried out on silica gel (60–120 or 100–200 mesh)
using ethyl acetate and hexane as eluents. ESI HRMS were recorded
on ‘High Resolution QSTAR XL hybrid MS/MS system, Applied Bio-
systems’ under Electron Spray Ionization conditions by preparing
the sample solutions in MeOH.
CHCl3); IR (neat): 1456, 1096 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
7.32–7.18 (m, 10H, ArH), 4.60 (ABq, J¼11.7 Hz, 2H, benzylic CH2),
4.46 (s, 2H, benzylic CH2), 3.83 (dd, J¼10.4, 1.5 Hz, 1H, CH), 3.68–
3.59 (m, 2H, CH2), 3.44 (d, J¼11.1 Hz, 1H, CH), 3.39–3.33 (m, 2H,
CH2), 2.1 (m, 1H, CH), 2.02–1.74 (m, 2H, 2ꢂCH), 1.38 (s, 3H, C(CH3)2),
1.36 (s, 3H, C(CH3)2), 1.12 (d, J¼7.0 Hz, 3H, CH3), 0.87 (d, J¼7.0 Hz,
3H, CH3), 0.66 (d, J¼6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d
139.3, 138.8, 128.2, 127.3, 127.1, 126.7, 97.9, 83.1, 74.7, 73.4, 72.9,
4.1.1. (2S,3R,4S,5S,6R)-5-(Benzyloxy)-2,4,6-trimethylheptane-1,3,7-
triol (7). To a stirred suspension of LiAlH4 (4.9 g,129.2 mmol) in dry
THF (150 mL) at 0 ꢀC was added dropwise a solution of lactone 6
(15 g, 51.7 mmol) in dry THF (30 mL). The reaction mixture was
allowed to warm to 25 ꢀC and stirred for 4 h. Reaction mixture was
cooled to 0 ꢀC and quenched with dropwise addition of saturated
aqueous NH4Cl. The precipitate formed was filtered and washed
with ethyl acetate (2ꢂ100 mL). The combined organic extracts were
dried over Na2SO4, concentrated in vacuo, and the crude was pu-
rified by silica gel flash chromatography (3/2, EtOAc/hexane) to get
71.8, 66.2, 36.9, 36, 30.3, 29.8, 19.4, 16.6, 12.4, 9.8; ESI HRMS: m/z
calcd for C27H38O4Na [MþNa]þ 449.2667, found 449.2681.
4.1.4. (2S,3R,4S,5S,6R)-5,7-Di(benzyloxy)-2,4,6-trimethylheptane-
1,3-diol (10). PPTS (0.31 g, 1.29 mmol) was added to a stirring
solution of 9 (11.0 g, 25.8 mmol) in methanol (100 mL) at room
temperature. After stirring overnight, the reaction mixture was
quenched with saturated aqueous NaHCO3 solution. Methanol was
removed and the aqueous layer was extracted with DCM
(3ꢂ50 mL). The combined organic layer was washed with brine and
dried over Na2SO4. The filtrate was evaporated under reduced
pressure and the crude was purified by column chromatography on
7 (12.75 g, 85%) as a colorless syrup; Rf¼0.40 (3/2 EtOAc/hexane);
27.2
[
a]
ꢁ3.1 (c 1.35, CHCl3); IR (neat): 3508, 1462, 1036 cmꢁ1
;
1H
D
NMR (300 MHz, CDCl3):
d
7.35–7.25 (m, 5H, ArH), 4.63–4.72 (q, 2H,
silica gel to afford 10 as an oily liquid (8.36 g, 84%). Rf¼0.40 (1/1
25
J¼7.5 Hz, benzylic CH2), 3.72–3.91 (m, 2H, OCH2), 3.50–3.69 (m, 4H,
2ꢂOCH, OCH2), 3.39 (br s, OH), 1.76–2.08 (m, 3H, 3ꢂCH), 1.57 (br s,
OH) 1.12 (d, 3H, J¼7.5 Hz, CH3), 0.96 (d, 3H, J¼7.5 Hz, CH3), 0.73 (d,
EtOAc/hexane); [
a]
ꢁ58.05 (c 0.6, CHCl3); IR (neat): 3431, 1456,
D
1063 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 7.36–7.22 (m, 10H, ArH),
4.60 (ABq, J¼10.9 Hz, 2H, benzylic CH2), 4.47 (s, 2H, benzylic CH2),
3.96 (br s, 1H, OH), 3.8 (d, J¼9.8 Hz, 1H, CH), 3.68 (dd, J¼8.7, 4.1 Hz,
1H, CH), 3.63–3.50 (m, 3H, CH2, CH), 3.44 (dd, J¼9.0, 3.0 Hz,1H, CH),
3H, J¼7.5 Hz, CH3); 13C NMR (CDCl3, 75 MHz):
d 137.6, 128.3, 127.7,
127.5, 87.3, 75.9, 75.7, 68.1, 64.2, 37.5, 37.1, 35.3, 14.4, 12.9, 10.9; ESI

J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
3269
2.1 (m, 1H, CH), 1.92–1.75 (m, 2H, CH2), 1.12 (d, J¼7.5 Hz, 3H, CH3),
1.0 (d, J¼6.8 Hz, 3H, CH3), 0.73 (d, J¼6.8 Hz, 3H, CH3); 13C NMR
CH), 1.1 (d, J¼7.5, Hz, 3H, CH3), 0.95 (d, J¼6.8, Hz, 3H, CH3), 0.88 (d,
J¼7.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 138.5, 128.2, 127.4,
(75 MHz, CDCl3):
d
128.5, 128.3, 127.9, 127.7, 127.6, 87.3, 76, 73.2,
127.3, 98.3, 84.7, 81.6, 74.4, 73, 72.2, 65.3, 55.8, 38.8, 37.6, 36.2, 15.7,
14.5, 11.7; ESI HRMS: m/z calcd for C26H38O5Na [MþNa]þ 453.2616,
found 453.2624.
72.2, 69.2, 37.2, 36.8, 34.7, 14.9, 13.3, 11.7; ESI HRMS: m/z calcd for
C24H34O4Na [MþNa]þ 409.2354, found 409.2362.
4.1.5. (2S,3R,4S,5S,6R)-5,7-Di(benzyloxy)-1-[1-(tert-butyl)-1,1-dimethyl-
silyl]oxy-2,4,6-trimethylheptan-3-ol (11). To a stirring solution of 10
(8 g, 20.7 mmol) in DCM (80 mL), imidazole (2.81 g, 41.4 mmol) and
tert-butyldimethylsilylchloride (3.42 g, 22.77 mmol) were added. The
reaction mixture was stirred for 2 h at room temperature and
quenched with saturated aqueous NH4Cl. The reaction mixture was
extracted with DCM (3ꢂ50 mL), the combined layer was washed with
water, brine, dried over Na2SO4, and concentrated under reduced
4.1.8. (2S,3R,4R,5S,6R)-5,7-Di(benzyloxy)-3-(methoxymethoxy)-
2,4,6-trimethylheptyl methanesulfonate (14). To a stirred solution of
13 (5.8 g, 13.5 mmol) in dry DCM (50 mL), triethylamine (9.4 mL,
67.5 mmol) was added at room temperature. Methane sulfonyl
chloride (1.2 mL, 16.2 mmol) was added at 0 ꢀC and stirred at 25 ꢀC
for 1 h, quenched with water, and extracted with DCM (3ꢂ50 mL).
The combined organic layer was washed with saturated aqueous
NH4Cl and brine, dried (Na2SO4), and evaporated. The residue was
pressure. The residue was chromatographed on silica gel column to
purified by silica gel chromatography to give 14 (6.3 g, 93%);
25
25
give 11 (9.5 g, 92%) as a colorless oil. Rf¼0.80 (1/4 EtOAc/hexane); [
a
]
Rf¼0.75 (3/7 EtOAc/hexane); [
a]
þ16.38 (c 0.7, CHCl3); IR (neat):
D
D
þ3.53 (c 0.5, CHCl3); IR (neat): 3431, 1456, 1063 cmꢁ1
;
1H NMR
1456, 1355, 1175, 1032 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 7.36–7.19
(300 MHz, CDCl3):
d
7.34–7.18 (m, 10H, ArH), 4.60 (ABq, J¼10.9 Hz, 2H,
(m, 10H, ArH), 4.61–4.48 (m, 4H, benzylic 2ꢂCH2), 4.46 (s, 2H, CH2,
MOM), 4.20 (dd, J¼9.4, 3.7 Hz, 1H, CH), 4.12 (dd, J¼9.0, 5.6 Hz, 1H,
CH), 3.67 (d, J¼7.9 Hz,1H, CH), 3.58 (dd, J¼9.0, 5.6 Hz,1H, CH), 3.45–
3.39 (m, 2H, CH2), 3.34 (s, 3H, CH3, MOM), 2.85 (s, 3H, CH3, mesyl),
2.18 (m, 1H, CH), 1.99 (m, 1H, CH), 1.89 (m, 1H, CH), 1.12 (d, J¼6.8 Hz,
3H, CH3), 0.95 (d, J¼7.5, Hz, 3H, CH3), 0.90 (d, J¼6.8, Hz, 3H, CH3);
benzylic CH2), 4.46 (s, 2H, benzylic CH2), 3.76–3.63 (m, 3H, CH, CH2),
3.62–3.47 (m, 3H, CH, CH2), 2.10 (m, 1H, CH), 1.84 (m, 1H, CH), 1.70 (m,
1H, CH), 1.42 (br s, 1H, OH), 1.03 (d, J¼7.2 Hz, 3H, CH3), 1.0 (d, J¼6.8, Hz,
3H, CH3), 0.88 (s, 9H, 3ꢂCH3, tert-butyl/Si), 0.76 (d, J¼6.8 Hz, 3H, CH3),
0.04 (s, 6H, 2ꢂSiCH3); 13C NMR (75 MHz, CDCl3):
d 138.7, 136.8, 128.3,
128.1, 127.5, 127.3, 86.2, 76.0, 73.1, 72.7, 72.1, 67.1, 38.3, 36.4, 35.6, 25.9,
18.27, 15.5, 13.0, 10.7, ꢁ5.5; IR (neat): 3497, 1459, 1083 cmꢁ1; ESI
HRMS: m/z calcd for C30H48O4NaSi [MþNa]þ 523.3219, found
523.3241.
13C NMR (75 MHz, CDCl3):
d 128.2, 127.4, 127.2, 98.3, 84.1, 80.4, 74.2,
73.1, 72.4, 72.2, 55.7, 37.9, 36.9, 36.0, 16.1, 14.3, 11.1; ESI HRMS: m/z
calcd for C27H40O7NaS [MþNa]þ 531.2392, found 531.2411.
4.1.9. (3S,4R,5S,6R)-5,7-Di(benzyloxy)-3-(methoxymethoxy)-2,4,6-
trimethyl-1-heptene (15). A mixture of 14 (6 g, 11.8 mmol) and NaI
(8.85 g, 59 mmol) in DMF (60 mL) was heated at 50 ꢀC for 5 h. The
mixture was cooled to room temperature, DBU (2.1 mL, 14.2 mmol)
was added and the reaction mixture was heated at 80 ꢀC for 3 h. The
mixture was cooled to room temperature and poured into chilled
water and extracted with diethyl ether (3ꢂ100 mL). The combined
organic extract was washed with water, saturated aqueous NH4Cl
and brine, dried over Na2SO4, and evaporated. The residue was
4.1.6. tert-Butyl[(2S,3R,4R,5S,6R)-5,7-di(benzyloxy)-3-(methoxy-
m e t h o x y ) - 2 , 4 , 6 - t r i m e t h y l h e p t y l ] o x y d i m e t h yl s i l a n e
(12). Diisopropylethylamine (6.2 g, 36 mmol) and methoxymethyl
chloride (MOMCl) (1.7 mL, 21.6 mmol) were added to a stirred so-
lution of 11 (9.0 g, 18 mmol) in DCM (50 mL) at 0 ꢀC under nitrogen
atmosphere. After stirring for 6 h at room temperature, the reaction
mixture was quenched with saturated aqueous NH4Cl and extrac-
ted with DCM (3ꢂ50 mL). The extracted organic layer was washed
with saturated aqueous NH4Cl, brine, dried over Na2SO4, and con-
centrated under reduced pressure. The residue was chromato-
purified by silica gel column chromatography to give 15 (4.3 g, 88%)
25
as a colorless liquid. Rf¼0.55 (0.5/9.5 EtOAc/hexane); [
(c 0.25, CHCl3); IR (neat): 1633, 1454, 1032 cmꢁ1
(300 MHz, CDCl3):
a
;
]
þ122.53
D
graphed on silica gel column to give 12 (8.8 g, 90%) as colorless oil;
1H NMR
25
Rf¼0.60 (1/9 EtOAc/hexane); [
a
]
D
þ38.47 (c 0.45, CHCl3); IR (neat):
d
7.36–7.22 (m, 10H, ArH), 4.93 (s, 1H, olefinic),
1459, 1092, 1034 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
7.36–7.16 (m,
4.92 (s, 1H, olefinic), 4. 66 (ABq, J¼11.3 Hz, 2H, benzylic CH2), 4.50
(d, J¼6.4 Hz, 2H, benzylic CH2), 4.45 (s, 2H, CH2, MOM), 4.17 (d,
J¼3.7 Hz, 1H, CH), 3.62 (dd, J¼9.0, 4.5 Hz, 1H, CH), 3.40 (d, J¼7.5 Hz,
1H, CH), 3.36 (m, 1H, CH), 3.37 (s, 3H, CH3, MOM), 2.12 (m, 1H, CH),
1.93 (m, 1H, CH),1.62 (s, 3H, CH3),1.12 (d, J¼7.2 Hz, 3H, CH3), 0.91 (d,
10H, ArH), 4.72–4.53 (m, 4H, benzylic 2ꢂCH2), 4.46 (s, 2H, CH2,
MOM), 3.71 (d, J¼9.0 Hz, 1H, CH), 3.64–3.50 (m, 3H, CH, CH2), 3.48–
3.38 (m, 2H, CH2), 3.34 (s, 3H, CH3, MOM), 2.18 (m, 1H, CH), 1.86 (m,
1H, CH), 1.72 (m, 1H, CH), 1.14 (d, J¼6.8, Hz, 3H, CH3), 0.9–0.8 (m,
15H, 3ꢂCH3, tert-butyl, 2ꢂCH3), 0.01 (s, 6H, 2ꢂCH3, TBDMS); 13C
J¼6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 143.2, 139.1, 138.7,
NMR (75 MHz, CDCl3):
d
139.4, 128.2, 128.1, 127.4, 127.3, 127.1, 98.4,
128.2, 127.3, 127.2, 113.2, 94.6, 83.2, 80.2, 73.6, 73, 72.3, 55.8, 38.5,
35.9, 18.8, 16.6, 10.4; ESI HRMS: m/z calcd for C26H36O4Na [MþNa]þ
435.2511, found 435.2532.
84.0, 81.0, 74.3, 73.0, 72.3, 64.9, 55.4, 39.1, 38.0, 36.0, 29.7, 25.9, 16.4,
14.6, 10.9, ꢁ5.4; ESI HRMS: m/z calcd for C32H52O5Na Si [MþNa]þ
567.3481, found 567.3480.
4.1.10. (3S,4S,5S,6R)-5,7-Di(benzyloxy)-2,4,6-trimethyl-1-hepten-3-
ol (16). Compound 15 (3.8 g, 9.2 mmol) was mixed with phos-
phomolybdic acid (0.08 g, 0.045 mmol, adsorbed on 7.2 g of silica
gel) and stirred vigorously at room temperature. After stirring for
30 min, DCM (50 mL) was added to the mixture and filtered-off the
catalyst. The filtered cake was washed with DCM (2ꢂ20 mL) and
the combined filtrate was concentrated in vacuo and purified by
4.1.7. (2S,3R,4R,5S,6R)-5,7-Di(benzyloxy)-3-(methoxymethoxy)-
2,4,6-trimethylheptan-1-ol (13). 1.0 M solution of TBAF in THF
(18.7 mL, 18.7 mmol) was added to a stirred solution of 12 (8.5 g,
15.6 mmol) in THF (68 mL) at room temperature. The solution was
stirred for 4 h and quenched with water (50 mL). The reaction
mixture was extracted with EtOAc (3ꢂ60 mL), the combined or-
ganic layer was washed with brine, dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel to give 16 (3.0 g, 91%) as a
28
colorless viscous liquid. Rf¼0.65 (1/4 EtOAc/hexane); [
(c 0.6, CHCl3); IR (neat): 3439, 1494, 1605 cmꢁ1
(300 MHz, CDCl3): 7.38–7.20 (m, 10H, ArH), 5.0 (s, 1H, olefinic),
a
]
þ3.2
D
silica gel chromatography to obtain 13 (6.1 g, 92%). Rf¼0.70 (3/7
;
1H NMR
25
EtOAc/hexane); [
a
]
ꢁ29.37 (c 0.4, CHCl3); IR (neat): 3447, 1455,
d
D
1032 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
7.36–7.19 (m, 10H, ArH),
4.88 (s, 1H, olefinic), 4.59 (ABq, J¼11.3 Hz, 2H, benzylic CH2), 4.48
(s, 2H, benzylic CH2), 4.36 (br s, 1H, OH), 3.66 (dd, J¼9.0, 4.5 Hz,
1H, CH),3.58 (dd, J¼9.0, 3.0 Hz, 1H, CH), 3.50 (dd, J¼9.0, 3.7 Hz,
1H, CH), 3.40 (s, 1H, CH), 2.16 (m, 1H, CH), 1.92 (m, 1H, CH), 1.64
(s, 3H, CH3), 1.06 (d, J¼6.8 Hz, 3H, CH3), 0.95 (d, J¼7.5 Hz, 3H,
4.64–4.48 (m, 4H, benzylic 2ꢂCH2), 4.46 (s, 2H, CH2, MOM), 3.75–
3.62 (m, 2H, CH2), 3.56 (dd, J¼8.7, 4.9 Hz, 1H, CH), 3.47(dd, J¼8.7,
6.4 Hz, 1H, CH), 3.37–3.32 (m, 2H, CH2), 3.35 (s, 3H, CH3, MOM),
2.68 (br s, 1H, OH), 2.15 (m, 1H, CH), 1.89 (m, 1H, CH), 1.75 (m, 1H,

3270
J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
CH3); 13C NMR (75 MHz, CDCl3):
d
145.05, 138.4, 138.0, 128.4,
chromatography on silica gel to give 20 (0.932 g, 93%) as a colorless
28
128.3, 128.1, 127.7, 127.5, 127.3, 110.1, 84.9, 74.8, 73.1, 72.7, 71.8,
36.8, 35.7, 18.03, 14.4, 10.9; ESI HRMS: m/z calcd for C24H32O3Na
[MþNa]þ 391.2249, found 391.2288.
oil. Rf¼0.60 (1/4 EtOAc/hexane); [
a
]
D
þ2.6 (c 1.5, CHCl3); IR (neat):
3448,1613,1460,1248,1172 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.19
(d, J¼8.7 Hz, 2H, ArH), 6.82 (d, J¼8.5 Hz, 2H, ArH), 4.89 (s, 1H, ole-
finic), 4.87 (s, 1H, olefinic), 4.48 (ABq, J¼10.6 Hz, 2H, benzylic CH2),
4.23 (d, J¼6.8 Hz, 1H, CH), 3.79 (s, 3H, OCH3), 3.75 (d, J¼11.7 Hz, 1H,
CH), 3.49 (m, 1H, CH), 3.34 (t, J¼4.3 Hz, 1H, CH), 2.60 (m, 1H, CH),
2.01 (m, 1H, CH), 1.73 (s, 3H, CH3), 1.12–0.12 (m, 27H, 3ꢂHC(CH3)2,
2ꢂCH3); ESI HRMS: m/z calcd for C27H48O4Na Si [MþNa]þ 487.3219,
found 487.3231.
4.1.11. (3S,4S)-4-[(4S,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-di-
oxan-4-yl]-2-methyl-1-penten-3-ol (18). To the blue solution, pre-
pared by addition of lithium metal (1.0 g, 152 mmol) to liquid NH3
(100 mL), was added a solution of 16 (2.8 g, 7.6 mmol) in dry THF
(5 mL) at ꢁ40 ꢀC. The reaction mixture was stirred for 10 min and
quenched by addition of NH4Cl (8.1 g, 152 mmol). After removal of
NH3 by a stream of N2, ethyl acetate (50 mL) was added, stirred
vigorously, and filtered-off the solids. The filtrate was concentrated
under reduced pressure and the residue (compound 17) was used
for the next step without further purification.
Compound 17 (1.4 g, 7.4 mmol), camphorsulfonic acid (0.085 g),
and p-anisaldehyde dimethylacetal (2 mL, 11.1 mmol) in DCM
(15 mL) were stirred for 2 h at room temperature. Triethylamine
(4 mL) was added and the reaction mixture stirred for further
10 min. Solvent was removed under reduced pressure and the
residue was purified by silica gel flash column chromatography to
4.1.14. tert-Butyl(2E,4R,5S,6R,7S)-5-[(4-methoxybenzyl)oxy]-4,6,8-
trimethyl-7-[(1,1,1-triisopropylsilyl)oxy]-2,8-nonadienoate
(22). A
solution of dimethyl sulfoxide (DMSO) (0.4 mL, 5.9 mmol) in DCM
(20 mL) was added to a stirring solution of (COCl)2 (0.4 mL,
5.4 mmol) in DCM (20 mL) at ꢁ78 ꢀC. After 20 min, a solution of 20
(1.25 g, 2.69 mmol) in DCM (20 mL) was added at the same tem-
perature. The mixture was stirred for 20 min at ꢁ78 ꢀC and trie-
thylamine (2.0 mL, 13.4 mmol) was added at the same temperature.
Dry ice bath was removed and stirring was continued at room
temperature for 30 min. The reaction was quenched with saturated
aqueous NH4Cl (50 mL) and the mixture was extracted with DCM
(2ꢂ50 mL). The organic extract was washed with brine, dried over
Na2SO4, concentrated in vacuo, and the crude product was used for
the next step without further purification.
(tert-Butoxycarbonylmethylene) triphenyl phosphorane (1.21 g,
3.22 mmol) was added to a stirring solution of the above aldehyde
in benzene (50 mL) at room temperature under N2. After refluxing
for 2 h, the reaction mixture was diluted with n-hexane (100 mL)
and filtered through a Celite pad. The filtrate was evaporated in
vacuo and the residue was chromatographed on silica gel column to
give 18 (1.9 g, 85%) as a white semi-solid. Rf¼0.55 (1/4 EtOAc/hex-
26
ane); [
a]
þ88.33 (c 0.3, CHCl3); IR (neat): 3349, 1637, 1453,
D
1261 cmꢁ1; 1H NMR (200 MHz, CDCl3):
d
7.31 (d, J¼8.9 Hz, 2H, ArH),
6.83 (d, J¼8.5 Hz, 2H, ArH), 5.34 (s, 1H, PMP), 5.07 (s, 1H, olefinic),
4.88 (s, 1H, olefinic), 4.43 (br s, 1H, OH), 4.14 (dd, J¼11.2, 4.6 Hz, 1H,
CH), 3.79 (s, 3H, CH3, OCH3), 3.57 (dd, J¼10.0, 1.5, 1H), 3.47 (m, 2H,
CH2), 2.29 (m, 1H, CH), 2.0 (m, 1H, CH), 1.67 (s, 3H, CH3), 0.98 (d,
J¼7.0 Hz, 3H, CH3), 0.82(d, J¼6.6 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3):
d 161.1, 151.7, 127.1, 124.3, 113.8, 110.7, 102.1, 87.1, 79.8, 72.8,
55.5, 33.4, 31.0, 20.1, 12.4, 10.5; ESI HRMS: m/z calcd for C18H26O4Na
[MþNa]þ 329.1728, found 329.1760.
obtain the trans-
as a colorless liquid. Rf¼0.75 (1/4 EtOAc/hexane); [
0.12, CHCl3); IR (neat, cmꢁ1): 1713, 1648, 1614, 1460, 1248, 1144; 1H
NMR (300 MHz, CDCl3):
7.36 (d, J¼8.3 Hz, 2H, ArH), 7.17 (dd,
J¼15.8, 8.3 Hz, 1H, conjugated olefinic ), 6.98 (d, J¼8.3 Hz, 2H,
ArH), 5.83 (d, J¼15.8 Hz, 1H, conjugated olefinic ), 5.08 (s, 1H,
a,b-unsaturated ester 22 (1.325 g, with 87% yield)
25
a]
þ26.0 (c
D
4.1.12. Triisopropyl[((1S)-1-(1R)-1-[(4S,5R)-2-(4-methoxyphenyl)-
5-methyl-1,3-dioxan-4-yl]ethyl-2-methyl-2-propenyl)oxy]silane
(19). To a solution of 18 (1.0 g, 3.25 mmol) in CH2C12 (20 mL) were
added DIPEA (1.1 mL, 6.5 mmol) and the triisopropylsilyl triflate
(1.1 mL, 4.2 mmol) at 0 ꢀC under nitrogen. After 5 min, the cooling
bath was removed and the mixture stirred for 2 h at room tem-
perature. Water (50 mL) was added and the aqueous layer extracted
with DCM (3ꢂ30 mL). The combined organic layer was washed
with water, brine, dried (Na2SO4), evaporated in vacuo, and the
residue was purified by column chromatography on silica gel to
d
b
a
olefinic), 5.01 (s, 1H, olefinic), 4.63 (AB q, J¼11.3 Hz, 2H, benzylic
CH2), 4.44 (d, J¼5.3 Hz, 1H, CH), 3.96 (s, 3H, OCH3), 3.44 (dd, J¼6.0,
2.2 Hz, 1H, CH), 2.79 (m, 1H, CH), 2.05 (m, 1H, CH), 1.85 (s, 3H, CH3),
1.65 (s, 9H, t-butyl), 1.28 (d, J¼6.8 Hz, 3H, CH3), 1.22 (m, 21H,
3ꢂHC(CH3)2), 1.07 (d, J¼6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d
166.1, 158.9, 150.7, 146.8, 128.7, 128.0, 122.2, 113.6, 112.2, 83.1, 79.9,
give 19 (1.51 g, 95%) as a colorless liquid. Rf¼0.70 (1/9 EtOAc/hex-
72.1, 67.4, 55.2, 40.4, 38.5, 28.2, 18.3, 12.9, 10.5; ESI HRMS: m/z calcd
for C33H56O5Na Si [MþNa]þ 583.3794, found 583.3808.
25
ane); [
a
]
þ28.0 (c 0.13, CHCl3); IR (neat): 1614, 1461, 1247,
1168 cmꢁD1; 1H NMR (300 MHz, CDCl3):
d
7.32 (d, J¼8.4 Hz, 1H, ArH),
7.24 (d, J¼8.4 Hz, 1H, ArH), 6.81 (d, J¼8.8 Hz, 1H, ArH), 6.78 (d,
J¼8.8 Hz, 1H, ArH), 5.31 (s, 1H, PMP), 4.92 (s, 1H, olefinic), 4.90 (s,
1H, olefinic), 4.42 (d, J¼6.6 Hz, 1H, CH), 4.11–3.95 (m, 2H, CH2), 3.79
(s, 3H, OCH3), 3.36 (m, 1H, CH), 2.78 (dd, J¼14.3, 6.9 Hz, 1H, CH),
2.01 (m, 1H, CH), 1.73 (s, 3H, CH3), 1.13–0.89 (m, 24H, 3ꢂHC(CH3)2,
4.1.15. tert-Butyl(2S,3R,4R,5R,6S,7S)-2,3-dihydroxy-5-[(4-methox-
ybenzyl)oxy]-4,6,8-trimethyl-7-[(1,1,1-triisopropylsilyl)methyl]-8-
nonenoate (23). CH3SO2NH2 (0.11 g, 1.16 mmol) was added to
a stirring solution of AD-mix-a (8.5 g) in a mixture of t-BuOH and
H2O (1/1, 20 mL) at room temperature. After 5 min, solution of 22
(0.65 g, 1.16 mmol) in t-BuOH (1.0 mL) was added at 0 ꢀC and stir-
ring was continued for 28 h at room temperature. The reaction
mixture was quenched with Na2SO3 (8.0 g) at 0 ꢀC and extracted
with EtOAc (3ꢂ50 mL). The combined organic layer was washed
with saturated aqueous NH4Cl, brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was chromatographed on a silica
gel column to afford two diastereomers 23 and 24 in the ratio (9.5/
CH3), 0.79 (d, J¼6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 169.2,
143.8, 132.0, 127.2, 114.2, 113.4, 101.0, 81.5, 79.3, 73.2, 55.5, 41.0,
35.6, 17.6, 16.0, 15.2, 12.3, 11.8; ESI HRMS: m/z calcd for C27H46O4Na
Si [MþNa]þ 485.7313, found 485.7309.
4.1.13. (2R,3S,4R,5S)-3-[(4-Methoxybenzyl)oxy]-2,4,6-trimethyl-5-
[(1,1,1-triisopropyl silyl)oxy]-6-hepten-1-ol (20). A 20% solution of
DIBAL-H in toluene (4.6 mL, 9.0 mmol) was added dropwise to
a stirring solution of 19 (1.0 g, 2.16 mmol) in DCM (50 mL) at 0 ꢀC,
and the mixture was stirred for 1 h at 0 ꢀC. The reaction was
quenched with saturated aqueous potassium sodium tartrate so-
lution (40 mL). The reaction mixture was diluted with DCM (60 mL)
and vigorously stirred for 30 min. The aqueous layer was extracted
with DCM (3ꢂ30 mL). The combined organic layer was dried over
Na2SO4, concentrated in vacuo. The residue was purified by column
0.5) with overall yield (0.62 g, 90%) as a colorless liquids. Rf¼0.65
28
(3/7 EtOAc/hexane); 23: [
a]
þ21.0 (c 0.17, CHCl3); IR (neat): 3452,
D
1743, 1604, 1460, 1248, 1163 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
7.22 (d, J¼8.7 Hz, 2H, ArH), 6.84 (d, J¼8.7 Hz, 2H, ArH), 4.96 (s, 1H,
olefinic), 4.92 (s, 1H, olefinic), 4.53 (AB q, J¼10.6 Hz, 2H, benzylic
CH2), 4.35 (d, J¼6.0 Hz, 1H, CH), 4.03 (m, 2H, 2ꢂCH), 3.81 (s, 3H,
OCH3), 3.49 (m, 1H, CH), 3.01 (br s, 1H), 2.11–1.94 (m, 2H, 2ꢂCH),
1.76 (s, 3H, CH3), 1.50 (s, 9H, tert-butyl), 1.13 (d, J¼7.2 Hz, 3H, CH3),

J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
3271
1.09 (m, 21H, 3ꢂHC(CH3)2), 1.02 (d, J¼7.2 Hz, 3H, CH3); 13C NMR
J¼6.5 Hz, 2H, CH2), 3.44 (t, J¼6.5 Hz, 2H, CH2), 1.79–1.29 (m, 6H,
3ꢂCH2); ESI MS: 195 [Mþþ1].
(75 MHz, CDCl3): d 172.6, 159.6, 147.0, 128.9, 114.0, 113.0, 84.9, 82.4,
77.5, 73.4, 72.9, 72.5, 55.2, 40.6, 37.5, 27.9, 18.3, 18.2, 13.5, 12.9, 10.5;
ESI HRMS: m/z calcd for C33H58O7Na Si [MþNa]þ 617.3849, found
617.3871.
4.1.19. 5-(Benzyloxy)pentanoic acid (27). A solution of dimethyl
sulfoxide (DMSO) (11.2 mL,158.7 mmol) in DCM (30 mL) was added
to a stirring solution of (COCl)2 (10 mL,114.3 mmol) in DCM (30 mL)
at ꢁ78 ꢀC. After 20 min, a solution of 26 (14.0 g, 72.16 mmol) in
DCM (140 mL) was added at the same temperature. The reaction
mixture was stirred for 20 min and triethylamine (50 mL,
360.8 mmol) was added at ꢁ78 ꢀC. Dry ice bath was removed and
the stirring was continued at room temperature for 30 min. Satu-
rated aqueous NH4Cl (60 mL) was added to quench the reaction
mixture and extracted with DCM (3ꢂ100 mL). The combined
organic layer was washed with water, brine, dried over Na2SO4,
concentrated in vacuo, and used in the next step without
purification.
4.1.16. tert-Butyl(4R,5R)-5-(1S,2S,3R,4S)-2-[(4-methoxybenzyl)oxy]-
1,3,5-trimethyl-4-[(1,1,1-triisopropylsilyl)oxy]-5-hexenyl-2,2-di-
methyl-1,3-dioxolane-4-carboxylate (25). To a solution of 23 (0.3 g,
0.5 mmol) in dry DCM (10 mL) 2,2-demethoxy propane (1.0 mL,
0.75 mmol) and p-TSA (50 mg) were added. The mixture was stir-
red at ambient temperature for 5 h. After completion of the re-
action (monitored by TLC), the reaction mixture was washed with
saturated aqueous NaHCO3. The organic layer was washed with
water, dried over Na2SO4, and concentrated in vacuo. The residue
was chromatographed on a silica gel column to afford the acetonide
25 (0.29 g, 93%) as a colorless liquid. Rf¼0.70 (1/4 EtOAc/hexane);
A solution of NaClO2 (80% assay) (12.25 g, 108.2 mmol) in
water (112 mL) was added to a solution of above aldehyde in
acetonitrile (70 mL), NaH2PO4$2H2O (2.25 g, 14.4 mmol), and 35%
H2O2 (7.7 mL, 79.37 mmol). The reaction mixture was stirred at
room temperature for 6 h, cooled to 0–5 ꢀC and Na2SO3 was
added to quench the unreacted NaClO2 and H2O2 at 0 ꢀC. The
reaction mixture was acidified with 10% aqueous HCl and
extracted with DCM (3ꢂ50 mL). The combined organic layer was
dried (Na2SO4), concentrated in vacuo, and the residue was
purified by silica gel flash chromatography to provide the car-
boxylic acid 27 (7.8 g, 73%) as a colorless viscous oil. Rf¼0.35 (1/1
EtOAc/hexane); IR (neat): 3032, 1709, 1452 cmꢁ1; IR (neat): 3032,
25
[
a]
þ5.0 (c 0.25, CHCl3); IR (neat): 1721, 1617, 1460, 1249,
D
1163 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.22 (d, J¼8.7 Hz, 2H, ArH),
6.80 (d, J¼8.7 Hz, 2H, ArH), 4.91 (s, 1H, olefinic), 4.83 (s, 1H, ole-
finic), 4.61–4.33 (m, 3H, CH, benzylic CH2), 4.08 (d, J¼6.8 Hz, 1H,
CH), 3.79 (s, 3H, OCH3), 3.78 (m, 1H, CH), 3.47 (dd, J¼7.9, 2.3 Hz, 1H,
CH), 2.09–1.78 (m, 2H, 2ꢂCH), 1.67 (s, 3H, CH3), 1.46–1.33 (m, 18H,
6ꢂCH3), 1.09–1.01 (m, 21H, 3ꢂHC(CH3)2), 0.96 (d, J¼7.2 Hz, 3H,
CH3); ESI HRMS: m/z calcd for C36H62O7Na Si [MþNa]þ 657.4162,
found 657.4165.
4.1.17. (4R,5R)-5-(1S,2R,3R,4S)-2-[(4-Methoxybenzyl)oxy]-1,3,5-tri-
methyl-4-[(1,1,1-triisopropylsilyl)oxy]-5-hexenyl-2,2-dimethyl-1,3-di-
oxolane-4-carboxylic acid (4). A solution of lithium hydroxide
(0.09 g, 2.14 mmol in 10 mL of water) was added to a solution of 25
(0.14 g, 0.22 mmol) in THF/MeOH (4/1, 25 mL) at room temperature
and the reaction mixture was stirred for 18 h. The reaction mixture
was concentrated in vacuo. The residue was diluted with ethyl
acetate (30 mL) and 2 N HCl (3.0 mL) was added to adjust the pH of
the reaction mixture to 5. The organic layer was separated and the
aqueous layer was further extracted with ethyl acetate (3ꢂ30 mL).
The combined organic layer was washed with water, brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified
1709, 1452 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 8.2 (br s, 1H,
COOH), 7.25 (m, 5H, ArH), 4.46 (s, 2H, benzylic CH2), 3.45 (t,
J¼6.0 Hz, 2H, CH2), 2.36 (t, J¼6.8 Hz, 2H, CH2), 1.78–1.60 (m, 4H,
2ꢂCH2); ESI HRMS: m/z calcd for C12H16O3Na [MþNa] 231.0997,
found 231.1005.
4.1.20. (4R)-3-[5-(Benzyloxy)pentanoyl]-4-isopropyl-1,3-oxazolan-
2-one (28). A solution of n-BuLi in hexane (2.5 M, 23.0 mL,
57.6 mmol) was added dropwise to a stirring solution of 42 (6.2 g,
48 mmol) in anhydrous THF (100 mL) at ꢁ78 ꢀC. The mixture was
stirred at this temperature for 30 min. Acid 27 (12 g, 57.69 mmol)
was taken in THF (120 mL) in a separate flask and cooled to 0 ꢀC.
Triethylamine (11.36 mL, 81.6 mmol) and pivaloyl chloride
(7.52 mL, 62.4 mmol) were slowly added and after stirring for
30 min at 0 ꢀC, the lithio-(4R)-4-isopropyl-2-oxazolidinone was
added to this mixed anhydride. The mixture was warmed to room
temperature over a period of 2 h. The reaction was quenched with
aqueous NH4Cl solution and extracted with EtOAc (3ꢂ50 mL). The
organic layer was washed with saturated NaHCO3 solution, satu-
rated NH4Cl solution, and brine. The organic layer was dried
(Na2SO4), concentrated in vacuo, and the residue was purified by
by silica gel chromatography to give 4 (0.11 g, 88%) as a colorless
25
viscous liquid. Rf¼0.45 (2/3 EtOAc/hexane); [
a]
ꢁ5.0 (c 0.19,
D
CHCl3); IR (neat): 3449, 1719, 1617, 1460, 1250, 1170 cmꢁ1; 1H NMR
(500 MHz, CDCl3):
d
7.17 (d, J¼8.5 Hz, 2H, ArH), 6.78 (d, J¼8.5 Hz,
2H, ArH), 4.91 (s, 1H, olefinic), 4.87 (s, 1H, olefinic), 4.51–4.43 (m,
3H, CH, benzylic CH2), 4.30 (d, J¼7.7 Hz, 1H, CH), 4.13 (d, J¼7.7 Hz,
1H, CH), 3.77 (s, 3H), 3.26 (dd, J¼7.2, 3.0 Hz, 1H, CH), 2.19 (m, 1H,
CH), 2.01 (m, 1H, CH),1.73 (s, 3H, CH3), 1.25 (s, 6H, 2ꢂCH3), 1.10–1.01
(m, 24H, 3ꢂHC(CH3)2, CH3), 0.98 (d, J¼6.8 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3):
d 172.3, 160.1, 143.3, 128.9, 126.34, 113.8, 107.4,
104.1, 82.3, 80.37, 77.8, 72.8, 68.0, 55.2, 40.0, 36.2, 26.8, 18.3, 18.2,
12.8, 12.0, 11.37; ESI HRMS: m/z calcd for C32H54O7Na Si [MþNa]þ
601.3536, found 601.3543.
flash chromatography on silica gel to provide 28 (15.5 g, 85%) as
25
a colorless oil. Rf¼0.55 (3/7 EtOAc/hexane); [
a]
ꢁ39.0 (c 0.2,
D
CHCl3); 1H NMR (300 MHz, CDCl3):
d
7.29 (m, 5H, ArH), 4.47 (s, 2H,
CH2), 4.36 (m,1H, CH), 4.23–4.13 (m, 2H, CH2), 3.48 (t, J¼6.0 Hz, 2H),
3.03–2.81 (m, 2H, CH2), 2.36 (m, 1H, CH), 1.81–1.62 (m, 4H, 2ꢂCH2),
0.92 (d, J¼7.2 Hz, 3H, CH3), 0.87 (d, J¼6.8 Hz, 3H, CH3); 13C NMR
4.1.18. 5-(Benzyloxy)-1-pentanol (26). A solution of 1,5-pentane-
diol (10 g, 96.15 mmol) in THF (10 mL) was added to a flask con-
taining NaH (60% suspension in mineral oil, 5.5 g, 115.38 mmol) in
THF (90 mL) at room temperature. The mixture was stirred at room
temperature for 30 min and cooled to 0 ꢀC. Benzyl bromide
(11.5 mL, 96.15 mmol) was added slowly dropwise and the mixture
was stirred for 3 h at room temperature. Water was added slowly to
quench the reaction and extracted with ether (3ꢂ100 mL). The
organic layer was dried (Na2SO4) and concentrated under reduced
pressure and the residue was purified by flash chromatography on
silica gel to provide 26 (14.9 g, 80%) as a colorless oil. Rf¼0.40 (1/1
(75 MHz, CDCl3): d 172.9, 153.9, 138.4, 128.2, 127.4, 127.3, 72.7, 69.8,
63.2, 58.2, 35.0, 28.9, 28.2, 21.0, 17.7, 14.5; IR (neat): 1780, 1701,
1456 cmꢁ1
342.1681, found 342.1684.
;
ESI HRMS: m/z calcd for C18H25NO4Na [MþNa]
4.1.21. (4R)-3-[(2S)-5-(Benzyloxy)-2-methylpentanoyl]-4-isopropyl-
1,3-oxazolan-2-one (29). The solution of 28 (10.0 g, 31.3 mmol) in
THF (50 mL) was cooled to ꢁ78 ꢀC and 1 M solution of NaHMDS
(34.5 mL, 34.48 mmol) was added dropwise. The mixture was
stirred at ꢁ78 ꢀC for 1 h and iodomethane (9.75 mL, 156.5 mmol)
was added in to the reaction mixture. After stirring for 30 min, the
EtOAc/hexane); IR (neat): 3381, 1453, 1096 cmꢁ1
;
1H NMR
7.28 (m, 5H, ArH), 4.47 (s, 2H, benzylic), 3.60 (t,
(300 MHz, CDCl3):
d

3272
J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
solution was allowed to warm to room temperature. The mixture
was quenched with aqueous NH4Cl solution and extracted with
ether (3ꢂ50 mL). The organic extract was washed with saturated
NH4Cl solution, saturated NaHCO3, brine, dried over (Na2SO4), and
concentrated in vacuo. The residue was purified by chromatog-
29.8, 27.1, 25.8, 19.5, 16.6; ESI HRMS: m/z calcd for C22H32O2NaSi
[MþNa] 379.2069, found 379.2077.
4.1.25. (4S)-3-((2R,3S,6S)-7-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-3-
hydroxy-2,6-dimethylheptanoyl)-4-isopropyl-1,3-oxazolan-2-one
(34). A solution of dimethyl sulfoxide (DMSO) (1.3 mL, 18.5 mmol)
in DCM (15 mL) was added to a stirring solution of (COCl)2 (1.47 mL,
16.84 mmol) in DCM (15 mL) at ꢁ78 ꢀC. After 20 min, a solution of
32 (3.0 g, 8.42 mmol) in DCM (30 mL) was added at the same
temperature. After stirring the mixture for 20 min, triethylamine
(5.86 mL, 42.1 mmol) was added at ꢁ78 ꢀC. The reaction was
brought to room temperature and stirring was continued for
30 min at the same temperature. Saturated aqueous NH4Cl (30 mL)
was added and the mixture was extracted with DCM (3ꢂ50 mL).
The organic extract was washed with brine, dried over Na2SO4,
concentrated in vacuo, and the crude product was used in the next
step without further purification.
raphy on silica gel column to obtain 29 (8.4 g, 81%) as a colorless
25
oil. Rf¼0.60 (3/7 EtOAc/hexane); [
a
]
ꢁ46.0 (c 0.25, CHCl3); IR
D
(neat): 1778, 1699, 1456 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d 7.28
(m, 5H, ArH), 4.45 (s, 2H, CH2), 4.35 (m, J¼3.7 Hz, 1H, CH), 4.16–
4.04 (m, 2H, CH2), 3.49–3.39 (m, 2H, CH2), 2.34 (m, 1H, CH), 1.80
(m, 1H, CH), 1.67–1.35 (m, 4H, 2ꢂCH2), 1.2 (d, J¼6.8 Hz, 3H, CH3),
0.91 (d, J¼6.8 Hz, 3H, CH3), 0.87 (d, J¼6.8 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3):
d 176.8, 153.5, 138.5, 129.4, 128.2, 127.4, 127.3,
72.7, 70.1, 63.0, 58.2, 37.4, 29.6, 28.3, 27.2, 17.8, 17.7, 14.5; ESI
HRMS: Calculated m/z for C19H27NO4Na [MþNa] 356.1837, found
356.1842.
4.1.22. (2S)-5-(Benzyloxy)-2-methylpentan-1-ol (30). To a solution
of 29 (7.0 g, 21 mmol) in EtOH (70 mL), NaBH4 (1.59 g, 42 mmol)
was added at 0 ꢀC and stirred at the same temperature for
15 min. The reaction mixture was quenched with saturated
NH4Cl solution. EtOH was removed and the aqueous layer
extracted with EtOAc (3ꢂ50 mL). The organic layer was washed
with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by chromatography on silica gel column to
To the auxiliary 43 (1.48 g, 8 mmol) in DCM (15 mL) under
nitrogen, was added Bu2BOTf (8.4 mL, 8.42 mmol) followed by
DIPEA (1.72 mL, 10.1 mmol) at 0 ꢀC. The reaction mixture was stir-
red at 0 ꢀC for 30 min and then cooled to ꢁ78 ꢀC. The solution of
aldehyde in DCM (15 mL) was added and stirred for 30 min at
ꢁ78 ꢀC. The reaction mixture was stirred for 2 h further at room
temperature. The boron–aldolate complex was quenched with pH 7
phosphate buffer (15 mL) followed by addition of 30% H2O2–MeOH
(1/1, 30 mL) at 0 ꢀC and stirred for 1 h. The reaction mixture was
extracted with ether (3ꢂ40 mL) and the combined organic layer
was washed with water, brine, dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by silica gel column chromatog-
give 30 (3.7 g, 85%) as a colorless oil. Rf¼0.45 (1/1 EtOAc/hex-
26
ane);
[
a
]
þ31.0 (c 0.1, CHCl3); IR (neat): 3449, 1457,
1099 cmꢁ1D
; d 7.24 (m, 5H, ArH), 4.47
1H NMR (300 MHz, CDCl3):
(s, 2H, CH2), 3.48–3.36 (m, 4H, 2ꢂCH2), 1.73–1.42 (m, 5H, 2ꢂCH2
and CH), 0.91 (d, J¼6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
raphy gave pure Evan’s aldol adduct 34 (3.7 g, 82%) as a colorless
26
d
138.4, 128.3, 127.6, 72.9, 70.6, 67.9, 35.5, 29.5, 27.0, 16.5; ESI
liquid. Rf¼0.55 (2/3 EtOAc/hexane); [
a
;
]
ꢁ15.0 (c 0.25, CHCl3); IR
HRMS: m/z calcd for C13H20O2Na [MþNa] 231.1360, found
(neat): 3447, 1782, 1696, 1109 cmꢁ1
1DH NMR (200 MHz, CDCl3):
231.1362.
d 7.67–7.58 (m, 4H, ArH), 7.40–7.30 (m, 6H, ArH), 4.41 (m, 1H, CH),
4.30–4.14 (m, 2H, CH2), 3.83 (br s, 1H, OH), 3.66 (m, 1H, CH), 3.42
(m, 2H, CH2), 2.86 (m, 1H, CH), 2.33 (m, 1H, CH), 1.76–1.28 (m, 4H,
2ꢂCH2),1.24 (m,1H, CH),1.20 (d, J¼7.0 Hz, 3H, CH3),1.05 (s, 9H, tert-
butyl), 0.94 (d, J¼6.6 Hz, 3H, CH3), 0.93 (d, J¼7.3 Hz, 3H, CH3), 0.89
4.1.23. [(2S)-5-(Benzyloxy)-2-methylpentyl]oxy(tert-butyl)dipheny-
lsilane (31). To a solution of 30 (3.0 g, 14.4 mmol) in DCM (50 mL),
imidazole (1.95 g mL, 28.8 mmol) and TBDPSCl (4.35 g,
15.84 mmol) were added sequentially at room temperature. After
being stirred for 4 h at room temperature, the reaction mixture
was quenched with saturated aqueous NH4Cl solution and
extracted with DCM (3ꢂ50 mL). The combined organic layer was
dried (Na2SO4) and concentrated in vacuo. Purification of the
residue by column chromatography on silica gel gave compound
(d, J¼7.3 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3):
d 177.9, 153.4,
135.5, 133.9, 129.4, 127.5, 71.5, 68.6, 63.2, 58.1, 41.8, 35.7, 31.0, 29.4,
28.2, 26.8, 19.2, 17.8, 16.8, 10.5; ESI HRMS: m/z calcd for
C31H45NO5NaSi [MþNa] 562.2964, found 562.2973.
4.1.26. (2S,3S,6S)-7-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-2,6-dimethyl-
31 (6.1 g, 95%) as a colorless liquid. Rf¼0.75 (1/9 EtOAc/hexane);
heptane-1,3-diol (35). Compound 34 (3.0 g, 5.5 mmol) was reduced
25
[
a]
þ22.0 (c 0.17, CHCl3); IR (neat): 1463, 1108 cmꢁ1
;
1H NMR
to 35 (2.3 g, 85%) by following the procedure as enumerated in 4.1.22.
D
25
(300 MHz, CDCl3):
d
7.62 (d, J¼7.5 Hz, 4H, ArH), 7.38–7.19 (m, 11H,
Rf¼0.40 (6/4 EtOAc/hexane); [
a
]
þ10.0 (c 0.24, CHCl3); IR (neat):
D
ArH), 4.45 (s, 2H, benzylic CH2), 3.53–3.36 (m, 4H, 2ꢂCH2), 1.71–
3436, 1464, 1109 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d [ppm] 7.62 (d,
1.44 (m, 4H, 2ꢂCH2), 1.20 (m, 1H, CH), 1.04 (s, 9H, tert-butyl), 0.93
J¼7.5 Hz, 4H, ArH), 7.42–7.29 (m, 6H, ArH), 3.78–3.59 (m, 3H, CH2 and
CH), 3.54–3.40 (m, 2H, CH2), 1.77–1.50 (m, 3H, CH2 and CH), 1.40 (m,
1H, CH), 1.09 (m, 2H, CH2), 1.05 (s, 9H, tert-butyl), 0.94 (d, J¼6.8 Hz,
3H, CH3), 0.88 (d, J¼6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
(d, J¼6.8 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3):
d 135.6, 134.0,
132.7, 129.4, 128.3, 127.5, 127.4, 76.5, 72.8, 68.6, 35.6, 29.6, 26.8,
26.2, 19.3, 16.8; ESI HRMS: m/z calcd for C29H38O2NaSi [MþNa]
469.2538, found 469.2551.
d
[ppm] 135.6,133.9,129.5,127.5, 75.0, 68.6, 67.3, 38.8, 35.7, 31.4, 29.6,
26.8, 19.2, 16.9, 9.9; ESI HRMS: m/z calcd for C25H38O3NaSi [MþNa]
4.1.24. (4S)-5-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-4-methylpentan-
1-ol (32). To a solution of 31 (5.0 g, 11.2 mmol) in EtOAc (25 mL),
10% Pd/C (0.595 g, 0.56 mmol in terms of Pd) was added and the
reaction mixture was hydrogenated for 2 h. Palladium was filtered
through Celite bed and the filter cake washed with EtOAc (10 mL).
The combined organic solvent was concentrated in vacuo. The
residue was purified by chromatography on silica gel column to
437.2487, found 437.2505.
4.1.27. tert-Butyl((2S)-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-
1,3-dioxan-4-yl]-2-methylbutyloxy)diphenylsilane (36). Compound
35 (2.0 g, 4.8 mmol), camphorsulfonic acid (0.056 g, 0.24 mmol),
and p-anisaldehyde dimethylacetal (1.05 mL, 5.76 mmol) in DCM
(20 mL) were stirred for 2 h at room temperature. Triethylamine
(2.0 mL) was added and the solution was stirred for additional
10 min, the solvent was removed and the residue was purified by
afford 32 (3.79 g, 95%) as a colorless oil. Rf¼0.60 (2/3 EtOAc/hex-
26
ane); [
a]
þ8.1 (c 0.5, CHCl3); IR (neat): 3418, 1466, 1108 cmꢁ1; 1H
D
NMR (300 MHz, CDCl3):
d
7.62 (d, J¼7.5 Hz, 4H, ArH), 7.42–7.30 (m,
silica gel flash column chromatography to obtain 36 (2.2 g, 87%) as
25
6H, ArH), 3.60–3.41 (m, 4H, 2ꢂCH2), 1.71–1.40 (m, 4H, 2ꢂCH2), 1.17
a white semi-solid. Rf¼0.30 (1/9 EtOAc/hexane); [
CHCl3); IR (neat): 1462, 1247, 1110, 1035 cmꢁ1
CDCl3):
7.61 (d, J¼6.0 Hz, 4H, ArH), 7.42–7.28 (m, 8H, ArH), 6.8 (d,
a
]
þ5.0 (c 0.22,
D
(m, 1H, CH), 1.05 (s, 9H, tert-butyl), 0.93 (d, J¼6.8 Hz, 3H, CH3); 13
C
;
1H NMR (300 MHz,
NMR (50 MHz, CDCl3):
d
136.0, 132.1, 128.6, 128.1, 72.8, 61.2, 33.8,
d

J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
3273
25
J¼9.0 Hz, 2H, ArH), 5.37 (s, 1H, benzylic), 4.04–3.91 (m, 2H, CH2),
3.78 (s, 3H, OCH3), 3.77 (m, 1H, CH), 3.46 (m, 2H, CH2), 1.70–1.31 (m,
6H, 2ꢂCH2 and 2ꢂCH), 1.13 (d, J¼6.8 Hz, 3H, CH3), 1.05 (s, 9H, tert-
butyl), 0.92 (d, J¼6.0 Hz, 3H, CH3); ESI HRMS: m/z calcd for
C33H44O4NaSi [MþNa] 555.2906, found 555.2930.
hexane); [
a]
þ3.1 (c 0.5, CHCl3); IR (neat): 3439, 1615, 1460, 1247,
D
1037 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.20(d, J¼8.4 Hz, 2H, ArH),
6.81 (d, J¼8.8 Hz, 2H, ArH), 5.78 (m, 1H, olefinic CH), 5.05–4.96 (m,
2H, olefinic CH2), 4.43 (m, 2H, benzylic CH2), 3.79 (s, 3H, OCH3),
3.47–3.55 (m, 2H, CH2), 3.19 (m, 1H, CH), 2.46 (m, 1H, allylic CH),
1.64–1.22 (m, 5H, 2ꢂCH2, and CH), 1.02 (dd, J¼6.8, 3.6 Hz, 3H, CH3),
0.90 (dd, J¼6.6, 2.8 Hz, 3H, CH3); ESI HRMS: m/z calcd for
C18H28O3Na [MþNa] 315.4164, found 315.4161.
4.1.28. (2S,3S,6S)-7-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-3-[(4-me-
thoxybenzyl)oxy]-2,6-dimethylheptan-1-ol (37). Compound 37
(0.9 g, 90%) was prepared from compound 36 (1.0 g, 1.87 mmol) as
a colorless oil by the procedure as described in 4.1.13. The product
4.1.31. Ethyl(4S,7S,8S)-3-hydroxy-7-[(4-methoxybenzyl)oxy]-4,8-di-
methyl-9-decenoate (40). A solution of dimethyl sulfoxide (DMSO)
(0.6 mL, 9.0 mmol) in DCM (5.0 mL) was added to a stirring solution
of (COCl)2 (0.7 mL, 8.2 mmol) in DCM (5.0 mL) at ꢁ78 ꢀC. After
20 min, a solution of 39 (1.20 g, 4.1 mmol) in DCM (20 mL) was
added at the same temperature. After stirring the mixture for
20 min at ꢁ78 ꢀC, triethylamine (30 mL, 21.5 mmol) was added. The
reaction mixture was brought to room temperature and stirring
was continued for 30 min. Saturated aqueous NH4Cl (25 mL) solu-
tion was added to quench the reaction, extracted with DCM
(3ꢂ50 mL). The organic layer was washed with water, brine, and
dried over Na2SO4, concentrated in vacuo, and proceeded to next
step without purification.
To a warm (60 ꢀC) mixture of acetic acid (20 mL) and cupric
acetate dihydrate (0.082 g, 0.41 mmol) was added zinc dust (1.57 g,
24.6 mmol) while stirring the reaction mixture vigorously, over
a period of 2 min. Instantaneously, a reddish black solid (zinc/
copper couple) was formed with an exothermic reaction. The re-
action was cooled to room temperature and acetic acid was dec-
anted. The solid was washed with acetic acid (2ꢂ20 mL) followed
by ether (3ꢂ50 mL) and the wet Zn/Cu couple was used for the
reaction immediately.
was purified by silica gel chromatography. Rf¼0.55 (3/7 EtOAc/
25
hexane); [
a
]
D
þ19.0 (c 0.25, CHCl3); IR (neat): 3446, 1465, 1247,
1109, 1035 cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 7.67–7.58 (m, 4H,
ArH), 7.41–7.12 (m, 7H, ArH), 6.81 (m, 3H, ArH), 4.43 (s, 2H, benzylic
CH2), 3.78 (d, J¼4.4 Hz, 2H, CH2), 3.77 (s, 3H, OCH3), 3.50–3.34 (m,
3H, CH2, and CH), 1.98 (br s, 1H, OH), 1.71–1.38 (m, 3H, CH2, and CH),
1.37–1.20 (m, 3H, CH2, and CH), 1.05 (s, 9H, tert-butyl), 0.93 (d,
J¼6.2 Hz, 3H, CH3), 0.83 (d, J¼7.0 Hz, 3H, CH3); ESI HRMS: m/z calcd
for C33H46O4NaSi [MþNa] 534.8073, found 557.8079.
4.1.29. tert-Butyl((2S,5S,6S)-5-[(4-methoxybenzyl)oxy]-2,6-di-
methyl-7-octenyloxy) diphenylsilane (38). A solution of dimethyl
sulfoxide (DMSO) (0.2 mL, 2.88 mmol) in CH2Cl2 (3 mL) was added
to a stirring solution of (COCl)2 (0.23 mL, 2.62 mmol) in CH2Cl2
(3 mL) at ꢁ78 ꢀC. After 20 min, a solution of 37 (0.7 g, 1.31 mmol) in
CH2Cl2 (5 mL) was added at the same temperature. After stirring
the reaction mixture for 20 min, triethylamine (0.9 mL, 6.55 mmol)
was added at ꢁ78 ꢀC. The reaction was brought to room tempera-
ture and stirring was continued for 30 min. Saturated aqueous
NH4Cl (30 mL) was added, and the mixture was extracted with
DCM (3ꢂ25 mL). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo proceeded to
the next step without purification.
Methyltriphenylphosphonium bromide (1.4 g, 3.93 mmol) in
THF (20 mL) at 0 ꢀC was treated with sodium bis-
(trimethylsilyl)amide (2.6 mL, 1 M in THF, 2.62 mmol), and the
resulting solution was stirred at 0 ꢀC for 30 min. The aldehyde in
THF (5.0 mL) was added at 0 ꢀC, and the mixture was allowed to
warm to room temperature and stirred at this temperature for 1 h.
The reaction was quenched with saturated aqueous NH4Cl and
extracted with Et2O (3ꢂ25 mL). The combined ether fractions were
washed with brine and dried over Na2SO4, filtered, and concen-
trated. The residue was purified by flash chromatography on silica
To the Zn/Cu couple in THF (20 mL), the solution of aldehyde and
2-bromoethyl acetate (0.5 mL 4.5 mmol) in THF (10 mL) was added
under N2 atmosphere at room temperature. The reaction mixture
was refluxed gently for 1 h, allowed to cool to room temperature.
After quenching the reaction mixture with saturated aqueous
NH4Cl (10 mL), it was filtered on Celite. The Celite cake was washed
with diethyl ether (20 mL) and the filtrate was dried over Na2SO4,
and concentrated. The residue was purified by flash chromatogra-
phy on silica gel to afford the
b-hydroxyl ester (diastereomeric
mixture) 40 (1.09 g, 70% after two steps) as a colorless oil. Rf¼0.65
25
(3/7 EtOAc/hexane); [
a]
þ15.7 (c 0.5, CHCl3); IR (neat): 3451, 1730,
1613, 1460, 1247 cmꢁD1
;
1H NMR (200 MHz, CDCl3):
d
7.21
gel to afford compound 38 (0.53 g, 76%) as a colorless liquid.
(d, J¼8.4 Hz, 2H, ArH), 6.81 (d, J¼8.4 Hz, 2H, ArH), 5.79 (m, 1H,
olefinic CH), 5.0 (m, 2H, olefinic CH2), 4.43 (s, 2H, benzylic CH2), 4.15
(q, J¼7.0 Hz, 2H, ethyl CH2), 3.87 (m,1H, CH), 3.79 (s, 3H, OCH3), 3.18
(m, 1H, CH), 2.53–2.21 (m, 3H, CH2, and allylic CH), 1.69–1.34 (m,
5H, 2ꢂCH2, and CH), 1.28 (t, J¼7.0 Hz, 3H, CH3), 1.02 (dd, J¼6.6,
1.8 Hz, 3H, CH3), 0.88 (d, J¼5.9 Hz, 3H, CH3); ESI HRMS: m/z calcd
for C22H34O5Na [MþNa] 401.2303, found 401.2291.
25
Rf¼0.75 (1/9 EtOAc/hexane); [
a]
þ5.0 (c 0.25, CHCl3); IR (neat):
D
1618, 1461, 1247, 1110 cmꢁ1
;
1H NMR (200 MHz, CDCl3):
d 7.62 (d,
J¼6.0 Hz, 4H, ArH), 7.43–7.29 (m, 6H, ArH), 7.18 (d, J¼8.3 Hz, 2H,
ArH), 6.8 (d, J¼8.3 Hz, 2H, ArH), 5.76 (m, 1H, olefinic CH), 4.98 (m,
2H, olefinic CH2), 4.40 (s, 2H, benzylic CH2), 3.77 (s, 3H, OCH3),
3.51–3.36 (m, 2H, CH2), 3.16 (m, 1H, CH), 2.42 (m, 1H, allylic CH),
1.59 (m, 2H, CH2), 1.46–1.33 (m, 3H, CH2 and CH), 1.04 (s, 9H, t-
butyl), 0.99 (d, J¼6.8 Hz, 3H, CH3), 0.91 (d, J¼5.6 Hz, 3H, CH3); 13C
4.1.32. Ethyl(4S,7S,8S)-7-[(4-methoxybenzyl)oxy]-4,8-dimethyl-3-
[(1,1,1-triethylsilyl) oxy]-9-decenoate (41). To a solution of 40
NMR (75 MHz, CDCl3):
d
158.9, 140.9, 135.5, 134.0, 129.4, 129.2,
127.5, 114.3, 114.1, 113.6, 82.8, 71.3, 68.7, 55.2, 40.7, 35.8, 29.3, 28.9,
28.3, 27.9, 26.8, 19.3, 16.9, 15.5; ESI HRMS: m/z calcd for
C34H46O3NaSi [MþNa] 553.3113, found 553.3116.
(0.44 g, 1.12 mmol) in DCM (20 mL) were added DIPEA (0.56 mL,
3.36 mmol) and the triethylsilyltriflate (0.24 mL, 13.6 mmol) at 0 ꢀC
under nitrogen. After 5 min the cooling bath was removed and the
mixture stirred for 1 h at room temperature. Water was added to
quench the reaction and separated the layers. The aqueous layer
was extracted with DCM (2ꢂ30 mL) and the combined organic
layers were dried (Na2SO4), evaporated, and purified by chroma-
4.1.30. (2R,5S,6S)-5-[(4-Methoxybenzyl)oxy]-2,6-dimethyl-7-octen-
1-ol (39). To a solution of 38 (0.6 g, 1.13 mmol) in dry THF (20 mL),
TBAF (1.5 mL, 1 M in THF, 1.5 mmol) was added at 0 ꢀC. The reaction
mixture was warmed to room temperature and stirred for 4 h. It
was quenched with saturated aqueous NH4Cl solution (30 mL),
extracted with EtOAC (3ꢂ25 mL), and the combined organic extract
was washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by silica gel column chromatography to
obtain 39 (0.202 g, 92%) as a colorless liquid. Rf¼0.55 (4/7 EtOAc/
tography on silica gel column to get 41 (0.532 g, 93%) as a colorless
25
liquid. Rf¼0.65 (1/9 EtOAc/hexane); [
a]
þ19.2 (c 0.12, CHCl3); IR
D
(neat): 1730, 1613, 1460, 1247, 1108 cmꢁ1
CDCl3):
;
1H NMR (300 MHz,
d
7.20 (d, J¼8.3 Hz, 2H, ArH), 6.80 (d, J¼8.6 Hz, 2H, ArH),
5.78 (m, 1H, olefinic CH), 5.0 (m, 2H, olefinic CH2), 4.41 (s, 2H,
benzylic CH2), 4.09 (m, 3H, CH2 and CH), 3.79 (s, 3H, OCH3), 3.17 (m,

3274
J.S. Yadav, N. Rami Reddy / Tetrahedron 66 (2010) 3265–3274
5. (a) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2005, 127,
6186–6187; (b) Joshua, R. D.; Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am.
Chem. Soc. 2008, 130, 16407–16416.
1H, CH), 2.52–2.24 (m, 3H, CH2, and allylic CH), 1.60–1.32 (m, 2H,
CH2), 1.26 (m, 6H, CH3, CH2, and CH), 1.02 (dd, J¼6.8, 3.8 Hz, 3H,
CH3), 0.93 (t, J¼7.9 Hz, 9H, 3ꢂCH3), 0.89–0.80 (m, 3H, CH3), 0.56 (q,
6. (a) Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O. Tetrahedron Lett.
1996, 37, 385–388; (b) Matsushima, T.; Mori, M.; Nakajima, N.; Maeda, H.;
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1873–1876; (d) Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R. Tetrahedron Lett. 1998, 39,
9361–9364; (e) Rousch, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95–98; (f)
Matsushima, T.; Mori, M.; Zheng, B. Z.; Maeda, H.; Nakajima, N.; Uenishi, J.;
Yonemitsu, O. Chem. Pharm. Bull. 1999, 47, 308–321; (g) Jung, M. E.; Karama, U.;
Marquez, R. J. Org. Chem. 1999, 64, 663–665; (h) Matsushima, T.; Zheng, B. Z.;
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Smith, A. B., III; Lodise, S. A. Org. Lett. 1999, 1, 1249–1252; (j) Zheng, B. Z.;
Maeda, H.; Mori, M.; Kusaka, S. I.; Yonemitsu, O.; Matsushima, T.; Nakajima, N.;
Uenish, J. Chem. Pharm. Bull. 1999, 47, 1288–1296; (k) Jung, M. E.; Marquez, R.
Tetrahedron Lett. 1999, 40, 3129–3132; (l) Matsushima, T.; Nakajima, N.; Zheng,
B. Z.; Yonemitsu, O. Chem. Pharm. Bull. 2000, 48, 855–860; (m) Zheng, B. Z.;
Yamauchi, M.; Dei, H.; Kusaka, S. I.; Matsui, K.; Yonemitsu, O. Tetrahedron Lett.
2000, 41, 6441–6445; (n) Zheng, B. Z.; Yamauchi, M.; Dei, H.; Yonemitsu, O.
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Org. Lett. 2000, 2, 1669–1673; (p) Jung, M. E.; Lee, C. P. Org. Lett. 2001, 3,
333–336; (q) Loh, T. P.; Feng, L. C. Tetrahedron Lett. 2001, 42, 6001–6005; (r) Loh,
T. P.; Feng, L. C. Tetrahedron Lett. 2001, 42, 3223–3226; (s) Matsui, K.; Zheng,
B. Z.; Kusaka, S. I.; Kuroda, M.; Yoshimoto, K.; Yamada, H.; Yonemitsu, O. Eur. J.
Org. Chem. 2001, 3615–3624; (t) Hearn, B. R.; Ciavarri, J. P.; Taylor, R. E. Org. Lett.
2002, 4, 2953–2955; (u) Iqbal, J.; Nyavanandi, V. K.; Nanduri, S.; Vasudev, R.;
Naidu, A. Tetrahedron Lett. 2006, 47, 6667–6672.
J¼7.9 Hz, 6H, 3ꢂCH2); 13C NMR (75 MHz, CDCl3):
d 173.3, 146.8,
138.3, 130.9, 128.3, 113.7, 113.5, 83.09, 71.5, 67.6, 60.3, 55.2, 40.8,
40.3, 34.3, 30.1, 29.6,16.3,15.6,14.1, 6.8, 4.9; ESI HRMS: m/z calcd for
C28H48O5NaSi [MþNa] 515.3168, found 515.3161.
4.1.33. (4S,7S,8S)-7-[(4-Methoxybenzyl)oxy]-4,8-dimethyl-3-[(1,1,1-
triethylsilyl)oxy]-9-decen-1-ol (5). Compound 41 (0.25 g, 0.5 mmol)
in DCM (20 mL), under N2 atmosphere, was cooled to 0 ꢀC, and
diisobutylaluminum hydride (20% solution in toluene, 1.7 mL,
2.1 mmol) was slowly added over 10 min. After addition was
complete, stirring was continued for 1 h at 0 ꢀC. The reaction
mixture was carefully quenched with methanol (10 mL). Saturated
aqueous solution of potassium sodium tartrate solution (20 mL)
and ethyl acetate (20 mL) was added. The mixture was stirred
vigorously for 1 h to get the clear separation of organic and aqueous
layers. Separated the layers and the aqueous layer was extensively
extracted with ethyl acetate (3ꢂ50 mL). The combined organic
layers were dried (Na2SO4) evaporated to dryness and purified by
flash chromatography on silica gel to obtain 5 (0.21 g, 92%) as
7. (a) Yadav, J. S.; Rao, C. S.; Chandrashekar, S.; Ramarao, A. V. Tetrahedron Lett.
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Ravinder, K.; Reddy, B. V. S. Synlett 2007, 1957–1960.
25
a colorless liquid. Rf¼0.55 (5/8 EtOAc/hexane); [
a
]
D
þ28.0 (c 0.1,
CHCl3); IR (neat): 3448, 1613, 1462, 1247, 1109 cmꢁ1
;
1H NMR
7.20 (d, J¼8.3 Hz, 2H, ArH), 6.80 (dd, J¼8.6,
(300 MHz, CDCl3):
d
2.2 Hz, 2H, ArH), 5.79 (m, 1H, olefinic CH), 5.0 (m, 2H, olefinic CH2),
4.51–4.34 (m, 2H, benzylic CH2), 3.79 (s, 3H, OCH3), 3.75–3.64 (m,
3H, CH2, and CH), 3.16 (m,1H, CH), 2.43 (m,1H, allylic CH),1.71–1.44
(m, 3H, CH2, and CH), 1.34–1.20 (m, 4H, 2ꢂCH2), 1.05–0.79 (m, 15H,
3ꢂCH3), 0.60 (q, J¼7.9 Hz, 6H, 3ꢂCH2); 13C NMR (75 MHz, CDCl3):
8. Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140.
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d
158.1, 136.2, 128.6, 129.8, 115.0, 113.3, 80.2, 74.3, 71.5, 65.2, 54.1,
10. Wolf, S.; Esperanza, H. M.; Agosta, C. W. J. Org. Chem. 1982, 47, 4358–4359.
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15. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.;
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44.7, 39.9, 31.3, 29.8, 16.3, 13.2, 8.7, 4.4; ESI HRMS: m/z calcd for
C26H46O4NaSi [MþNa] 473.3063, found 473.3066.
Acknowledgements
NRR thanks CSIR, New Delhi for the financial support.
References and notes
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