Formal total synthesis of (-)-salicylihalamides A and B

Article abstract of DOI:10.1016/j.tetasy.2003.10.038

Formal total synthesis of (-)-salicylihalamides A and B is described starting with a nonracemic chiral epoxide obtained from Jacobsen's kinetic resolution. Sharpless asymmetric epoxidation, Diels Alder reaction, Mitsunobu coupling and ring closing metathe

Full text of DOI:10.1016/j.tetasy.2003.10.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 81–89
Formal total synthesis of ())-salicylihalamides A and B
J. S. Yadav* and P. Srihari
Organic Division, I, Indian Institute of Chemical Technology, Hyderabad 500-007, India
Received 28 August 2003; revised 9 October 2003; accepted 18 October 2003
Dedicated to Prof. G. Mehta on his 60th birthday
Abstract—Formal total synthesis of ())-salicylihalamides A and B is described starting with a nonracemic chiral epoxide obtained
from Jacobsenꢀs kinetic resolution. Sharpless asymmetric epoxidation, Diels Alder reaction, Mitsunobu coupling and ring closing
metathesis are the other key steps involved.
ꢀ 2003 Published by Elsevier Ltd.
H
1. Introduction
N
17
16
OH
O
O
Even though marine sponges supply compounds with
high diversity and architectural complexity, the ability
to obtain the same natural product repeatedly is highly
uncertain. This is even more so when the natural prod-
uct is isolated from an unidentified natural sponge.
Salicylihalamide is one such macrolide isolated1 from
Haliclona genus (South-Western Australian coast),
which exhibited cytotoxicity against a 60-cell line human
tumor assay with GI50 of 15 nM. The mechanism of
action of this compound has no correlation with known
compounds and thus occupies an important status.
Total synthesis was the only solution for this very
important molecule and to study further the biological
properties six syntheses have already been reported.2;3
This clearly indicates that this target molecule has gen-
erated tremendous activity in the synthetic chemistry
and medicinal chemistry groups not only as a complex
target but also as a promising lead molecule. Our long
standing interest in development of strategies for total
synthesis of natural products having cytotoxic proper-
ties prompted us to look at the total synthesis of ())-
salicylihalamides A and B. Our retrosynthetic analysis
revealed two key fragments viz., the functionalized
benzoic acid derivative 2 and the chiral aliphatic frag-
ment 3 (Scheme 1).
15
3
OH
4
5
1
O
9
13
12
CH3
8
6
10
11
1
OMe
O
OMOM OH
OTBDMS
OH
+
3
2
Scheme 1.
using Jacobsenꢀs complex, Sharpless asymmetric epoxi-
dation and regioselective opening of an epoxide for
elaborating the aliphatic part and a Diels Alder strategy
for the aromatic part as the key steps. All these reactions
are high yielding, clean, regio- and stereoselective and
with this strategy by manoeuvering the reagents, other
diastereomers/enantiomers would be easily synthesiz-
able.
Herein, we report full details on the formal total syn-
thesis of title compound involving a kinetic resolution
2. Results and discussion
Kinetic resolution of 2-(benzyloxyethyl)oxirane using
Jacobsenꢀs catalyst4
butylsalicylidene)-1,2-cyclohexanediaminocobalt (II) and
(R,R)-())-N-N0-bis(3,5-di-tert-
* Corresponding author. Tel.: +91-40-27193434; fax: +91-40-271605-
12; e-mail: yadav@iict.res.in
water yielded (R)-2-(benzyloxyethyl)oxirane 4 in 44%
0957-4166/$ - see front matter ꢀ 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2003.10.038

82
J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
20
yield and 99% ee. {½aŠ ¼ þ16:8 (c 2.75, CHCl3) Lit5
The absolute stereochemistry of this new stereogenic
center was also unequivocally confirmed at a later stage
after destroying the anomeric center.
D
½aŠ ¼ þ16:9 (c 2.51, CHCl3)}.
D
Epoxide 4 was opened with propargyl alcohol –O-THP
ether employing the Yamaguchi protocol6 to produce
the 2-heptyne-triol derivative 5 (Scheme 2). Protection
of the alcohol 5 as its benzyl ether 6 followed by
deprotection of the THP moiety afforded propargylic
alcohol 7, which was reduced to allyl alcohol 8 using
LiAlH4 in THF under reflux. Sharpless asymmetric
epoxidation7 of allyl alcohol 8 yielded epoxyalcohol 9,
which was converted to the corresponding iodide 10 by
treating with I2, TPP, and imidazole8 at 0 ꢁC. The
compound 10 on treating with Zn, NaI in MeOH at
reflux, yielded the secondary alcohol 11.9
The hydrolysis of ethyl acetal 13 using 80% acetic acid
under reflux conditions afforded the lactol 14, which on
one carbon Wittig olefination furnished the homolo-
gated triol derivative 15 in 85% yield. 13C data and
HPLC analysis of 15 ascertained the homogeneity of the
new stereogenic center created during the free radical
cyclization. The free hydroxyl group in 15 was protected
as methoxymethylether to afford 16. Selective debenzyl-
ation of 16 without affecting the olefinic functionality
was achieved by lithium/liq. NH3 to afford diol 17 in
90% yield. The diol 17 was monoprotected using
TBDMSCl to furnish the required chiral aliphatic moi-
ety 3.
OBn
OTHP
OH OBn NaH, BnBr
THF, 97%
O
The aryl part was synthesized starting from 1-benzyl-
oxy-3-butyne 18 (Scheme 4). This procedure involved a
novel Diels Alder-retro Diels Alder sequence hitherto
not reported for this fragment (Scheme 4). Treatment of
alkyne 18 with ethyl magnesium bromide resulted in an
acetylide that was quenched with ethylchloroformate to
furnish the carboxylic ester 19. Diels Alder reaction
between 19 and 1-methoxy cyclohexa-1,4-diene12 20
using catalytic dichloromaleic anhydride13 at 280 ꢁC
produced the disubstituted benzoic acid ethyl ester 21 in
74% yield.
THPO
n-BuLi, BF3.OEt2
-78o C, 90%
5
4
OBn OBn
OB OBn
LiAlH4, THF
reflux, 90%
PTSA, MeOH
r.t, 96%
THPO
HO
7
6
I2, TPP,
Imidazole
D(-)DIPT,
Ti(OiPr)4
OBn OBn
OBn OBn
O
HO
HO
TBHP, DCM
-20 oC, 90%
CH3CN:Et2O(1:3)
0o C, 90%
9
8
OH OBn OBn
OBn OBn
O
Zn, NaI
I
MeOH, reflux
92%
10
11
Scheme 2.
CO2Et
EtMgBr, ClCO2Et
OBn
Treatment of 11 with NBS and ethylvinylether in
dichloromethane yielded the prerequisite bromo acetal 12
for further manipulation (Scheme 3).10 We anticipated a
standard 5-exo trig cyclization on 11 with preferential
anti-geometry of the resulting new stereogenic center
using n-Bu3SnH in refluxing toluene with catalytic
AIBN as radical initiator to yield cyclic ethyl acetal 13.11
THF, 0 oC to r.t, 85%
OBn
18
19
OMe
OMe
CO2Et
DCMA
280 oC
74%
Diels Alder reaction
+
OBn
20
OMe
19
OMe
OEt
CO2Et
CO2Et
retro Diels Alder
-C2H4
nBu3SnH, AIBN
OH OBn OBn
O
OBn OBn
NBS, EVE
Br
Toluene, reflux
93%
°
OBn
OBn
DCM/0 C
90%
21
11
12
OEt
OH
Scheme 4.
O
OBn OBn
O
OBn OBn
Ph3PCH3I
80% AcOH,
reflux, 88%
n-BuLi, THF
-78 oC, 85%
Functional group manipulation involving debenzylation
of compound 21 with Pd(OH)2 under a hydrogen
atmosphere and oxidation of the resulting alcohol 22
under Dess Martin conditions14 yielded the aldehyde 23.
The aldehyde 23 on 1C Wittig homologation afforded
allyl derivative 24, which was hydrolyzed with lithium
hydroxide to obtain the key fragment allyl anisic acid 2.
Mitsunobu15 reaction between chiral aliphatic alcohol 3
and allyl anisic acid 2 produced the ester 25, which is set
for ring closing metathesis reaction (Schemes 5 and 6).
RCM with Grubbꢀs catalyst16 furnished the advanced
E-intermediate 26 in 85% yield (9:1, E=Z) toward total
synthesis of salicylihalamide.
CH3
CH3
14
13
OMOM OBn OBn
OH OBn OBn MOMCl,
DIPEA
Li, Liq.NH3
°
THF,-33 C
°
DCM, 0 C, 95%
CH3
CH3
16
15
90%
OMOM OH OTBDMS
OMOM OH OH
TBDMSCl, Imidazole
°
DCM, 0 C, 92%
CH3
CH3
3
17
Scheme 3.

J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
83
carried out using a Varian Gemini 200 or Varian Unity
400 or Varian Inova 500 MHz or Bruker Avance
300 MHz spectrophotometer using TMS as an internal
standard in CDCl3. Mass spectra were recorded on
Micro mass VG-7070H for EI, VG Autospec M for
FABMS, and Kompact SEQ MALDITOF MS for
MALDI mass spectrometers. The progress of all the
reactions was monitored by thin-layer chromatography
(TLC) using glass plates precoated with silica gel 60F254
to a thickness of 0.5 mm (Merck). Column chromato-
graphy was conducted by elution of columns with silica
gel 60–120 mesh using ethyl acetate and hexane as the
eluents. All reactions were carried out under inert
atmosphere unless mentioned following standard
syringe septa techniques. All the solvents were dried
using a standard procedure.
OMe
OMe
CO2Et
CO2Et
CHO
Pd(OH)2
21
EtOH, r.t.,
72%
DCM, r.t., 95%
OH
22
23
OMe
OMe
CO2Et
CO2H
LiOH, THF, H2O,
85%
Ph3PCh3I, n-BuLi,
-78 oC THF, 50%
2
24
Scheme 5.
OTBDMS
OMe
O
OMOM OH OTBDMS
OMOM
CH3
2, DEAD, TPP
O
Benzene, r.t. 75%
CH3
3
4.2. 2-(2-Benzyloxyethyl)-(2R)-oxirane 4
25
OTBDMS
A mixture of (R,R)-())-N-N0Bis(3,5-ditert-butyl salicy-
O
OMe
(Cy3P)2Cl2Ru=CHPh
10 mol%
OMOM
CH3
lidene)-1,2-cyclohexanediaminocobalt
II
(0.695 g,
Z isomer
O
+
1.15 mmol) toluene (2 mL) and acetic acid (0.130 mL,
2.25 mmol) was stirred while open to the air for 1h at
room temperature. The solvent was removed by rotary
evaporator under reduced temperature and the brown
residue was dried over vacuum. The racemic 2-(2-benz-
yloxyethyl)-oxirane (41g, 230 mmol) was added in one
portion, and the stirred mixture was cooled in an ice
water bath. Water (2.5 mL, 139 mmol) was slowly added
and the temperature of the reaction mixture was main-
tained such a way that it never rises more than 20 ꢁC.
After 1h, addition was complete. The icebath was re-
moved and the reaction mixture was stirred for 24 h. The
product 4 was isolated by column chromatography
DCM, r.t, 85%(9:1)
26
OH
O
OMe
Ref. 2e
OMOM
CH3
TBAF, THF
0°C, 92%
O
1
27
Scheme 6.
Deprotection of silyl ether 26 with TBAF proceeded
uneventfully to furnish the known alcohol 27, which has
already been converted to the target molecule by
Furstner et al.2e Thus the present strategy completes the
formal total synthesis.
1
(18.0 g, 44%). ½aŠ ¼ þ16:8 (c 2.75, CHCl3). H NMR
D
(CDCl3, 200 MHz) d 7.38–7.20 (m, 5H, aromatic-H),
4.50 (s, 2H, –OCH2Ph), 3.60 (t, 2H, J ¼ 7:3 Hz,
–CH2CH2OBn), 3.05–2.95 (m, 1H, CH2(O)CHCH2
CH2ꢀ), 2.75 (pseudo t, 1H, J ¼ 4:9 Hz, one
–CH2CH(O)CH2), 2.50–2.40 (m, 1H, one –CH2CH(O)
CH2), 2.00–1.65 (m, 2H, –CH2CH2OBn). 13C NMR
(CDCl3, 50 MHz): d ¼ 138:8, 128.2, 127.4, 72.9, 66.9,
49.8, 46.8, 32.8. IR (neat) cmꢀ1: 3033, 2860, 1603, 1495,
1258, 1100, 1013, and 911. MS (EI): m=z 178 (Mþ).
3. Conclusions
Our synthesis enabled us to prepare intermediate 27 in
multiple 100-mg quantity for introduction of modified
sidechains, which is currently underway. Also intro-
duction of stereogenic centers was achieved via Jacob-
senꢀs kinetic resolution and Sharpless epoxidation,
which should allow us to synthesize other stereoisomers.
4.3. 1-Benzyloxy-7-tetrahydro-2H-2-pyranyloxy-(3S)-
5-heptyn-3-ol 5
Under nitrogen atmosphere, a solution of n-butyl lith-
ium in hexane (43.2 mL, 112 mmol, 2.6 M solution in
hexane) was added to a solution of THP ether of
propargyl alcohol (18.4 g, 112 mmol) in THF (80 mL) at
)78 ꢁC, and the mixture was stirred for 15 min. Then,
BF3ÆOEt2 (7 mL, 56 mmol) was added to the solution
and the stirring was continued for 15 min at )78 ꢁC.
Finally a solution of epoxide 4 (10 g, 56 mmol) in dry
THF (20 mL) was added, and after stirring the reaction
mixture for 3 h at )78 ꢁC, the reaction was quenched by
adding saturated aqueous NH4Cl solution (40 mL). The
reaction mixture was extracted with ethyl acetate and
dried over anhydrous Na2SO4. Evaporation of the
4. Experimental
4.1. General methods
Melting point was determined with a melting point
apparatus (Polmon) and is uncorrected. Optical rota-
tions were measured with an Jasco DIP-360 Polarimeter
at 20 ꢁC and IR spectra were recorded with a Perkin
1
Elmer FTIR spectrophotometer. H NMR spectra were

84
J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
solvents resulted in crude alcohol, which was purified by
column chromatography to afford pure alcohol 5
3.75–3.60 (m, 1H, –CH(OBn)–), 3.60–3.45 (m, 2H,
–CH2OBn), 2.50–2.38 (m, 2H, –CH2CHC(OBn)–), 1.95–
1.80 (m, 2H, –CH2CH2OBn), 1.60–1.40 (br s, 1H, –OH).
IR (neat) cmꢀ1: 3418, 3032, 2923, 2237, 1963, 1603,
1453, 1360, 1274 and 1099. MS (FABMS): m=z 325
(Mþ+1).
(15.45 g, 90% yield) as a colorless liquid. ½aŠ ¼ þ3:1 (c
D
11.65, CHCl3). 1H NMR (CDCl3, 200 MHz):
d ¼ 7:40–7:20 (m, 5H, aromatic-H), 4.80–4.76 (m, 1H,
–OCHO–
of
THP
ring),
4.51(s,
2H,
–OCH2Ph), 4.21–4.19 (m, 2H, –CH2OTHP), 3.99–3.40
(m, 5H, –CH2CH2OBn, –CH2CHC(OH)– and –OCH2
of THP ring), 3.00–2.91(br s, 1H, O H), 2.41–2.39 (m,
2H, –CH(OH)CH2CBC–), 1.90–1.42 (m, 8H, 3 · CH2 of
THP ring and –CH2CH2OBn). IR (neat) cmꢀ1: 3420,
2922, 2231, 1602, 1498, 1352, 1078, 905. MS (FABMS):
m=z 319 (Mþ+1). Anal. Calcd for C19H26O4: C, 71.67; H,
8.23. Found C, 71.71; H, 8.21%.
4.6. 5,7-Di(benzyloxy)-(E,5S)-2-hepten-1-ol 8
Under nitrogen atmosphere, propargylic alcohol 7 (12 g,
37.0 mmol) was added to the suspension of LiAlH4
(4.2 g, 110 mmol) in dry THF (80 mL) at 0 ꢁC and the
mixture was heated to reflux for 8 h. The reaction mix-
ture was cooled to 0 ꢁC and quenched by ice-cooled
water (5 mL), 20% NaOH solution (5 mL) and again
water (15 mL). The mixture was filtered over a small pad
of Celite to afford the crude allyl alcohol that was
purified by column chromatography to afford pure 8 as
4.4. 2-[5,7]-Di(benzyloxy)-(5S)-2-heptynyloxy]tetrahy-
dro-2H-pyran 6
To a suspension of NaH (1.6 g, 66 mmol, 60% dispersion
in mineral oil) in dry THF (35 mL) was added dropwise
a solution of alcohol 5 (10.0 g, 32.6 mmol) in THF
(20 mL) at 0 ꢁC. To this reaction mixture TBAI (0.05 g)
and benzyl bromide (4.3 mL, 35.9 mmol) were added
subsequently and stirring was continued for 2 h at same
temperature and overnight at room temperature. The
reaction mixture was quenched by crushed ice flakes
until a clear solution (biphasic) has been formed. The
reaction mixture was extracted with ethyl acetate
(2 · 100 mL). The organic extracts were washed with
water (1 · 50 mL) brine (1 · 50 mL) and dried over
anhydrous Na2SO4. Evaporation of the solvents fol-
lowed by column chromatography afforded the pure
product 6 (12.5 g, 97% yield) as a colorless liquid.
a colorless liquid (10.8 g, 89.6% yield). ½aŠ ¼ þ34:1
D
(c 3.7, CHCl3). 1H NMR (CDCl3, 200 MHz):
d ¼ 7:40–7:20 (m, 10H, aromatic-H), 5.70–5.59 (m, 2H,
olefinic-H), 4.60–4.39 (m, 4H, 2 · –OCH2Ph), 4.02–3.98
(m, 2H, –CH2OH), 3.70–3.41(m, 3H, –CH 2CH2OBn
and –CH2CH(OBn)–), 2.40–2.20 (m, 2H, –CH2CH
(OBn)–), 1.80 (q, 2H, J ¼ 6:8, 12.0 Hz, –CH2CH2OBn),
1.26 (s, 1H, OH). 13C NMR (CDCl3, 75 MHz):
d ¼ 139:9, 139.8, 133.2, 129.7, 129.2, 129.0, 128.0, 127.8,
76.8, 74.4, 72.7, 68.1, 66.4, 38.4, 35.8. IR (neat) cmꢀ1
:
3438, 2862, 1641, 1452, 1095, and 918. MS (EI): m=z 326
(Mþ+1).
4.7. 3-[2,4-Di(benzyloxy)-(2R)-butyl]-(2R,3R)-oxiran-
2-yl methanol 9
½aŠ ¼ þ29:0 (c 9.2, CHCl3). 1H NMR (CDCl3,
D
200 MHz): d ¼ 7:40–7:20 (m, 10H, aromatic-H), 4.81–
4.79 (m, 1H, –OCHO of THP), 4.70–4.20 (m, 6H, 2 ·
To a freshly flame dried double necked round bottomed
flask equipped with activated molecular sieves
(4 AA)(ꢁ5 g) and dry CH2Cl2 (120 mL) at )20 ꢁC were
–OCH2Ph,
–CH2OTHP),
3.90–3.40
(m,
5H,
–CH2CH2OBn, –CH2CH(OBn)– and –OCH2 of THP
ring), 2.52–2.40 (m, 2H, –CH2CH(OBn)–), 1.98–1.41
(m, 8H, 3 · –CH2 of THP ring and –CH2CH2OBn).
IR(neat) cmꢀ1: 2921, 2230, 1606, 1496, 1357, 1080,
903. MS (FABMS): m=z 409 (Mþ+1). Anal. Calcd
for C26H32O4: C, 76.44; H, 7.89. Found: C, 76.49; H,
7.86%.
added Ti(OiPr)4 (1mL, 4.6 mmol),
D
())-diisopropyl
tartrate (1.2 mL, 4.0 mmol) and the mixture was stirred
for 20 min. Allyl alcohol 8 (10.5 g, 32.2 mmol) followed
by an interval of 20 min. TBHP (23.6 mmol, 70.8 mmol,
3 M solution in isooctane) were added and stirring was
continued for completion of the reaction (12 h). The
reaction mixture was warmed to 0 ꢁC and quenched by
water (30 mL) and stirred vigorously for 30 min. Whole
reaction mixture was filtered through sintered funnel
and the filtrate was again stirred along with 20% aq
NaOH solution (5 mL) saturated with solid NaCl. The
biphasic solution was separated and aqueous layer was
extracted with CH2Cl2 (2 · 50 mL). The combined or-
ganic extracts were dried over anhydrous Na2SO4 and
concentrated under vacuum. The crude residue was
purified by column chromatography to afford pure
epoxide 9 as a colorless oil (9.9 g, 89.8% yield).
4.5. 5,7-Di(dibenzyloxy)-(5S)-2-heptynyl alcohol 7
The compound 6 (12.0 g, 30.3 mmol) in MeOH (50 mL)
was stirred along with the catalytic amount of para-
toluenesulphonic acid (ꢁ200 mg) for 2 h. The mixture
was quenched by addition of saturated aqueous
NaHCO3 solution (10 mL). MeOH was evaporated
under reduced pressure and the aqueous phase was
extracted with ethyl acetate (2 · 30 mL). The organic
extracts were washed by brine (1 · 30 mL) dried over
anhydrous Na2SO4. After evaporating the solvent the
product was purified by column chromatography to
afford pure alcohol 7 (9.5 g, 96.8% yield) as a colorless
½aŠ ¼ þ35:2 (c 7.2, CHCl3). 1H NMR (CDCl3,
D
200 MHz): d ¼ 7:30–7:10 (m, 10H, aromatic-H), 4.50–
4.32 (m, 4H, 2 · –OCH2Ph), 3.80–3.60 (m, 2H,
–CH2OH), 3.58–3.39 (m, 3H, –CH2OBn and
–CH(OBn)–), 3.00–2.90 (m, 1H, one epoxide-H), 2.80–
2.70 (m, 1H, one epoxide-H), 2.50–2.20 (br s, 1H, –OH),
1.90–1.60 (m, 4H, –CH2CH2CH(OBn)–). 13C NMR
1
liquid. ½aŠ ¼ þ27:9 (c 7.0, CHCl3). H NMR (CDCl3,
D
200 MHz): d ¼ 7:32–7:15 (m, 10H, aromatic-H), 4.60–
4.38 (m, 4H, 2 · –OCH2Ph), 4.15 (s, 2H, –CH2OH),

J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
85
(CDCl3, 50 MHz): d ¼ 138:3, 137.1, 129.2, 127.9, 127.5,
4.10. 5,7-Di(benzyloxy)-3-(2-bromo-1-ethoxyethoxy)-
(3R,5R)-1-heptene 12
75.0, 73.9, 66.9, 63.9, 62.8, 48.9, 37.3, 35.9. IR (neat)
cmꢀ1: 3460, 2929, 2860, 1602, 1453, 1276, 1096, 912,
and 699. MS (FABMS): m=z 343 (Mþ+1). Anal. Calcd
for C21H26O4: C, 73.66; H, 7.65. Found: C, 73.58; H,
7.66%.
Freshly recrystallised NBS (7.6 g, 42.6 mmol) was added
to a stirred solution of ethylvinylether (9.2 g, 127 mmol)
and allyl alcohol 11 (14.0 g, 42.9 mmol) in anhydrous
CH2Cl2 (120 mL) at 0 ꢁC. After stirring the mixture for
5 h, the mixture was washed with water (2 · 30 mL)
followed by brine (1 · 30 mL) and dried over anhydrous
Na2SO4. Filtration followed by evaporation of the sol-
vent and chromatographic purification of he crude res-
idue afforded pure bromo acetal 12 (18.4 g, 89.8% yield)
as a colorless liquid. 1H NMR (CDCl3, 300MHz):
d ¼ 7:32–7:18 (m, 10H, aromatic-H), 5.80–5.60 (m, 1H,
–CH@CH2), 5.21–5.02 (m, 2H, –CH@CH2), 4.69–4.60
(m, 1H, –CHCH2Br), 4.50–4.40 (m, 4H, 2 · –OCH2Ph),
4.22–4.00 (m, 1H, –CH2CH(O)CH@CH2), 3.70–3.40
(m, 4H, –CH2OBn, –OCH2CH3), 3.30–3.25 (d, 2H,
J ¼ 4:9 Hz, –CH2Br), 2.01–1.60 (m, 4H, –CH(O)CH2-
CH(OBn)–, –CHCH2CH2OBn), 1.18 (t, 3H, J ¼ 7:5 Hz,
–OCH2CH3). IR (neat) cmꢀ1: 2959, 2925, 2872, 1456,
1376, 1101, and 876. MS (EI): m=z 478 (Mþ+1).
4.8. 2,4-Di(benzyloxy)-1-[3-iodomethyl-(2R,3S)-oxiran-
2-yl]-(2R)-butane 10
To a solution of alcohol 9 (10 g, 29.2 mmol) in acetoni-
trile: ether (1:3, 400 mL) at 0 ꢁC under nitrogen atmo-
sphere were added imidazole (4.9 g, 71.9 mmol), iodine
(14.8 g, 58.2 mmol), and triphenylphosphine (15.3 g,
58.6 mmol) successively. The mixture was stirred for
20 min. The resulting solution was diluted by cool ether
(200 mL) and was filtered over a sintered funnel. The
residue was washed by anhydrous ether (2 · 50 mL). The
combined filtrate was concentrated under reduced
temperature and the crude was passed through a pad of
silica gel to afford pure iodo product 10 (12.5 g, 95%) as
1
a colorless liquid. ½aŠ ¼ þ6:5 (c 5.1, CHCl3). H NMR
D
(CDCl3, 200 MHz): d ¼ 7:34–7:20 (m, 10H, aromatic-
H), 4.59–4.42 (m, 4H, 2 · –OCH2Ph), 3.80–3.78 (m, 1H,
–CH(OBn)–), 3.60–3.50 (m, 2H, –CH2OBn), 3.20–3.18
(m, 1H, CH2I), 3.00–2.92 (m, 2H, one –CH2I, one
epoxy-H), 2.36–2.30 (m, 1H, one epoxy-H), 2.00–
1.78 (m, 4H, –CH2CH(OBn)–, –CH2CH2OBn). IR
(neat) cmꢀ1: 3087, 2921, 1496, 1455, 1092, 1027, and
894.
4.11. 5-[2,4-Di(benzyloxy)-(2R)-butyl]-2-ethoxy-4-methyl-
(4S,5R)-2H,3H,4H-furan 13
To a solution of bromo acetal 12 (8.0 g, 16.7 mmol) in
dry toluene (50 mL) at reflux temperature under nitro-
gen atmosphere was added a solution of n-tributyltin-
hydride (4.5 mL, 16.7 mmol), azobisisobutyronitrile
(0.04 g, 0.16 mmol) in toluene (15 mL). After 2 h, the
solution was cooled to room temperature and passed
through a pad of silica gel to afford pure cyclic acetal 13
as colorless oil (6.2 g, 93%). 1H NMR (CDCl3,
200 MHz): d ¼ 7:40–7:20 (m, 10H, aromatic-H), 5.10–
4.94 (m, 1H, –CH2CH(OEt)O–), 4.60–4.40 (m, 4H, 2 ·
–OCH2Ph), 3.80–3.62 (m, 3H, –OCH2CH3, –CH(CH3)
CH(O)CH2–), 3.60 (t, 2H, J ¼ 7:0 Hz, –CH2OBn), 3.45–
3.32 (m, 1H, –CH(OBn)CH2–), 2.02–1.60 (m, 6H,
–CHCH2CH(CH3)–, –CHCH2CH(OBn)–, CHCH2CH2
OBn), 1.20 (t, 3H, J ¼ 6:2 Hz, –OCH2CH3), 1.10–0.98
(m, 3H, –CH(CH3)–). IR (neat) cmꢀ1: 2929, 2870, 1606,
1455, 1372, 1097, 991, 795, and 697. MS (FABMS): m=z
353 (Mþ)OEt). Anal. Calcd for C25H34O4: C, 75.34; H,
8.60. Found: C, 75.39; H, 8.51%.
4.9. 5,7-Di(benzyloxy)-(3R,5R)-1-hepten-3-ol 11
A mixture of iodo compound 10 (20 g, 44.2 mmol), NaI
(13.2 g, 88 mmol) and freshly activated zinc (7.2 g,
110 mmol) in anhydrous MeOH (120 mL) was refluxed
for 8 h under nitrogen atmosphere. The solution was
filtered and the residue was washed with MeOH
(2 · 25 mL). The filtrates were combined and concen-
trated. The residue was taken in ethylacetate (50 mL)
and washed with water (2 · 30 mL), brine (1 · 30 mL)
and dried over anhydrous Na2SO4. Evaporation of the
solvent and purification by column chromatography
afforded pure alcohol 11 (13.2 g, 91.6% yield) as a col-
orless liquid. ½aŠ ¼ ꢀ23:8 (c 5.0, CHCl3). 1H NMR
D
(CDCl3, 400 MHz): d ¼ 7:38–7:20 (m, 10H, aromatic-
H), 5.83–5.72 (m, 1H, –CH(OH)CH@CH2), 5.20 (d, 1H,
J ¼ 15:0 Hz, olefinic-H), 5.01(d, 1H, J ¼ 8:6 Hz, ole-
finic-H), 4.60 (d, 1H, J ¼ 14:2 Hz, one from 2ꢁ
–OCH2Ph), 4.50–4.40 (m, 3H, –CH2OCH2Ph and one
from 2ꢁ –OCH2Ph), 4.30–4.20 (m, 1H, –CH(OH)–),
3.89–3.80 (m, 1H, –CH(OBn)–), 3.60–3.42 (m, 2H,
–CH2OBn), 2.00–1.80 (m, 2H, –CHCH2CH(OBn)–),
1.78–1.61 (m, 2H, –CH2CH2OBn). 13C NMR (CDCl3,
50 MHz): d ¼ 139:9, 136.9, 136.7, 127.7, 126.8, 126.2,
113.8, 74.9, 74.0, 70.1, 64.3, 62.9, 42.6, 36.4. IR (neat)
cmꢀ1: 3440, 3031, 2862, 1954, 1602, 1493, 1207, and
1091. MS (FABMS): m=z 327 (Mþ+1). Anal. Calcd
for C21H26O3: C, 77.27; H, 8.03. Found: C, 77.32; H,
8.06%.
4.12. 5-[2,4-Di(benzyloxy)-(2R)-butyl]-4-methyl-(4S,5R)-
2H,3H,4H-2-furanol 14
The solution of ethyl acetal 13 (3.0 g, 7.5 mmol) in 80%
aq AcOH (30 mL) solution was refluxed for 4 h. The
mixture was cooled to 0 ꢁC, neutralized by solid
NaHCO3 and extracted with ethyl acetate (2 · 50 mL).
The organic extracts were washed by water (2 · 25 mL)
followed by brine (1 · 25 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation of the solvent fol-
lowed by purification (column chromatography) affor-
ded pure lactol 14 (2.5 g, 89.9% yield) as a syrupy liquid.
1H NMR (CDCl3, 200 MHz): d ¼ 7:32–7:20 (m, 10H,
aromatic-H), 5.45–5.30 (m, 1H, –CH2CH(OH)O–),
4.60–4.36 (m, 4H, 2 · –OCH2Ph), 3.80–3.62 (m, 1H,

86
J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
–CH(CH3)CH(O)CH2–), 3.60–3.42 (m, 3H, –CH2OBn,
–CH(OBn)–), 2.80–2.60 (br m, 1H, OH), 2.40–1.62
(m, 6H, –CHCH2CH(CH3)–, –CHCH2CH(OBn)–,
CHCH2CH2OBn), 1.60–1.40 (m, 1H, –CH(CH3)-
CH(O)–), 1.00 (t, 3H, J ¼ 7:1Hz, CH(C H3)–). IR (neat)
cmꢀ1: 3421, 3030, 2926, 1496, 1095, and 989. MS
MOM), 3.60–3.42 (m, 3H, –CH(OBn)–, –CH2OBn),
3.30 (s, 3H, –OCH3), 2.10–1.90 (m, 1H, –CH(CH3)–),
1.89–1.46 (m, 6H, –CHCH2CH(CH3)–, –CHCH2CH
(OBn)–, –CHCH2-CH2OBn), 0.86 (d, 3H, J ¼ 6:6 Hz,
–CH(CH3)–). IR (neat) cmꢀ1: 3064, 2931, 2882, 1640,
1496, 1098, 1039, and 916. MS (FABMS): m=z 413
(Mþ+1).
þ
(FABMS): m=z 371(M +1). Anal. Calcd for C23H30O4:
C, 74.57; H, 8.16. Found: C, 74.49; H, 8.14%.
4.15. 5-Methoxymethoxy-6-methyl-(3R,5R,6S)-8-nonene-
1,3-diol 17
4.13. 7,9-Di(benzyloxy)-4-methyl-(4S,5R,7R)-1-nonen-
5-ol 15
To a solution of lithium (0.51g, 72.8 mmol) in liq. NH 3
(50 mL) was added compound 16 (1.5 g, 3.6 mmol) in
dry THF (4 mL). The mixture was stirred for 1h, after
cooling the mixture to )78 ꢁC solid NH4Cl (1.6 g) was
added. NH3 was allowed to evaporate and the residual
mixture was taken in ethylacetate (20 mL) and washed
with water (2 · 10 mL), brine (1 · 20 mL) and dried over
anhydrous Na2SO4. Evaporation of the solvent and
chromatography of the crude afforded pure diol 17
To methyltriphenylphosphoniumiodide (8.75 g, 21.6
mmol) in dry THF (40 mL) under nitrogen atmosphere
at )78 ꢁC was added n-BuLi (6.3 mL, 21.5 mmol, 3.4 M
solution in hexane). After 30 min, to the resulting orange
yellow turbid mixture was added lactol 14 (2.0 g,
5.4 mmol) in dry THF (5 mL) via a canula and stirring
was continued for 8 h allowing the temperature to warm
to 0 ꢁC. The reaction mixture was quenched with satu-
rated aqueous NH4Cl solution (15 mL). The mixture
was filtered over a sintered funnel and the residue was
washed with ether (3 · 25 mL). The combined organic
filtrates were evaporated after washing with water
(1 · 25 mL), brine (1 · 25 mL), and drying over anhy-
drous Na2SO4. The product 15 was purified by column
chromatography to afford a colorless liquid (1.7 g,
(0.510 g, 90.6% yield) as a colorless liquid. ½aŠ ¼ þ43:4
D
(c 8.75, CHCl3). 1H NMR (CDCl3, 300 MHz):
d ¼ 5:80–5:60 (m, 1H, –CH@CH2), 5.00–4.90 (m, 2H,
–CH@CH2), 4.72 (d, 1H, J ¼ 6:8 Hz, one –OCH2OCH3),
4.61(d, 1H, J ¼ 6:4 Hz, one –OCH2OCH3), 4.02–3.97
(m, 1H, –CHOH), 3.80–3.65 (m, 3H, –CHOMOM,
–CH2OH), 3.40 (s, 3H, –OCH3), 1.98–1.80 (m, 3H,
@CHCH2CH(CH3)–), 1.70–1.40 (m, 4H, –CH2CH2OH,
–CH(OMOM)CH2CH–), 0.90 (d, 3H, J ¼ 6:0 Hz,
–CH(CH3)–). IR (neat) cmꢀ1: 3390, 3077, 2934, 1640,
1442, 1378, 1215, 1150, 1097, 1038, and 915. MS (EI):
m=z 232 (Mþ). Anal. Calcd for C12H24O4: C, 62.04; H,
10.41. Found: C, 62.08; H, 10.40%.
85.8%). ½aŠ ¼ þ31:1 (c 0.75, CHCl3). 1H NMR (CDCl3,
D
200 MHz): d ¼ 7:40–7:20 (m, 10H, aromatic-H), 5.90–
5.68 (m, 1H, –CH2CH@CH2), 5.10–4.92 (m, 2H,
–CH@CH2), 4.66–4.40 (m, 4H, 2 · –OCH2Ph), 3.90–
3.80 (m, 1H, –CHCH(OH)CH2–), 3.62–3.58 (m, 3H,
–CH(OBn), –CH2CH2OBn), 2.30–2.16 (m, 1H,
–CH(CH3)–), 2.00–1.80 (m, 4H, –CH(CH3)CH2CH@),
–CH(OH)CH2CH(OBn)–),
1.70–1.50
(m,
2H,
4.16. 1-(tert-Butyldimethylsilyloxy)-5-methoxymethoxy-
6-methyl-(3R,5R,6S)-8-nonen-3-ol 3
–CH(OBn)CH2–), 0.90 (d, 3H, J ¼ 5:5 Hz, –CH(CH3)–).
13C NMR (CDCl3, 50 MHz): d ¼ 138:2, 137.9, 137.5,
128.3, 127.7, 127.5, 115.6, 77.8, 74.3, 73.8, 71.5, 66.5,
38.7, 36.9, 34.1, and 14.9. IR (neat) cmꢀ1: 3480, 2926,
1640, 1454, and 1093. MS (FABMS): m=z 369 (Mþ+1).
Anal. Calcd for C24H32O3: C, 78.22; H, 8.75. Found: C,
78.16; H, 8.74%.
To a solution of diol 17 (0.5 g, 2.15 mmol) in dry CH2Cl2
(5 mL) and imidazole (0.29 g, 4.26 mmol) at 0 ꢁC under
nitrogen atmosphere was added TBDMSCl (0.32 g,
2.15 mmol) and stirred for 6 h allowing the mixture to
warm to room temperature. The reaction mixture was
diluted with water (3 mL) and extracted with CH2Cl2
(2 · 5 mL). The combined organic layers was washed
with brine (1 · 5 mL), dried over anhydrous Na2SO4,
filtered and concentrated under vacuum to afford the
crude product. Column chromatography of the crude
product afforded 3 as a colorless liquid (0.685 g, 91.9%).
4.14. 7,9-Di(benzyloxy)-5-methoxymethoxy-4-methyl-
(4S,5R,7R)-1-nonene 16
To alcohol 15 (1.6 g, 4.3 mmol) in anhydrous CH2Cl2
(12 mL) at 0 ꢁC were added diisopropylethyl amine
(1.4 g, 10.8 mmol) and MOMCl (0.46 g, 5.6 mmol) suc-
cessively and the mixture was stirred for 3 h. The reac-
tion mixture was quenched by adding water (4 mL) and
extracted with CH2Cl2. The organic extracts were wa-
shed with brine, dried over anhydrous Na2SO4 and
concentrated under vacuum to yield the crude product,
which was purified by column chromatography to afford
½aŠ ¼ þ22:3 (c 3.0, CHCl3). 1H NMR (CDCl3,
D
200 MHz): d ¼ 5:80–5:58 (m, 1H, –CH@CH2), 5.07–
4.85 (m, 2H, –CH@CH2), 4.60 (q, 2H, J ¼ 6:8, 13.6 Hz,
–OCH2OCH3), 3.97–3.54 (m, 4H, –CH2OTBDMS,
–CHCH(OMOM)–, –CH(OH)CH2–), 3.31(s, 3H,
–OCH3), 2.12–1.77 (m, 3H, @CHCH2CH(CH3)–), 1.70–
1.48 (m, 2H, –CH(OMOM)CH2–), 1.40–1.20 (m, 2H,
–CH(OH)CH2–), 0.94–0.79 (m, 12H, –C(CH3)3),
–CH(CH3)–), 0.06 (s, 6H, –Si(CH3)2C(CH3)3). 13C NMR
(CDCl3, 300 MHz) d 137.1, 115.9, 95.5, 80.1, 69.5, 55.9,
39.0, 37.4, 36.7, 35.4, 25.8, 18.2, 14.1, )5.2. IR (neat)
cmꢀ1: 3514, 2933, 1468, 1754, 1095, 1039, and 915. MS
(FABMS): m=z 347 (Mþ+1).
the pure product 16 (1.65 g, 92.2%). ½aŠ ¼ þ34:3 (c 5.4,
D
CHCl3). 1H NMR (CDCl3, 200 MHz): d ¼ 7:38–7:15
(m, 10H, aromatic-H), 5.80–5.60 (m, 1H, –CH@CH2),
5.00–4.90 (m, 2H, –CH@CH2), 4.60–4.32 (m, 6H,
–OCH2O–, 2 · –OCH2Ph), 3.80–3.60 (m, 1H, –CHO-

J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
87
4.17. 1-(3-Butynyloxymethyl)benzene 18
(FABMS): m=z 315 (Mþ+1). Anal. Calcd for C19H22O4:
C, 72.59; H, 7.05. Found: C, 72.53; H, 7.07%.
Product 18 was prepared using similar procedure as
given to compound 6 to afford 21.7 g in 95.1% yield as
1
a colorless liquid from 10 g of 3-butyne-1-ol. H NMR
4.20. Ethyl 2-(2-hydroxyethyl)-6-methoxybenzoate 22
(CDCl3, 200 MHz): d ¼ 7:40–7:20 (m, 5H, aromatic-H),
4.59 (s, 2H, –OCH2Ph), 3.60 (t, 2H, J ¼ 6:4 Hz,
–CH2OBn), 2.55–2.40 (m, 2H, –CH2CH2OBn), 0.98–
0.92 (m, 1H, acetylene-H). IR (neat) cmꢀ1: 3031, 2862,
2121, 1455, 1104, 909. MS (EI): m=z 160 (Mþ).
To compound 21 (2.0 g, 6.36 mmol) in absolute ethanol
(20 mL) was added Pd(OH)2 (0.15 g) and stirred at room
temperature under hydrogen atmosphere for 20 h. The
mixture was diluted by adding CHCl3 (5 mL) and fil-
tered through a small pad of Celite. Evaporation of the
solvent and purification of the crude mixture by column
chromatography afforded pure alcohol 22 (1.02 g,
71.5%) as a colorless liquid. 1H NMR (CDCl3,
300 MHz): d ¼ 7:27 (t, 1H, J ¼ 7:9 Hz, one aromatic H),
6.84 (d, 1H, J ¼ 7:6 Hz, one aromatic H), 6.77 (d, 1H,
J ¼ 7:6 Hz, one aromatic H), 4.38 (q, 2H, J ¼ 7:2,
14.3 Hz, –OCH2CH3), 3.85–3.76 (m, 5H, –OCH3,
–CH2OH), 2.79 (t, 2H, J ¼ 6:4 Hz, –CH2CH2OH), 1.90
(br s, 1H, –OH), 1.39 (t, 3H, J ¼ 7:2 Hz, –OCH2CH3).
IR (neat) cmꢀ1: 3418, 2946, 2842, 1730, 1588, 1469,
1266, 1189, 1072, and 952. MS (EI): m=z 224 (Mþ).
4.18. Ethyl 5-benzyloxy-2-pentynoate 19
To a freshly prepared ethyl magnesium bromide solu-
tion [from ethyl bromide (9.3 mL, 124 mmol) and mag-
nesium (3.0 g, 125 mmol) in dry THF (100 mL)] under
nitrogen atmosphere at 0 ꢁC was added alkyne 18
(10.0 g, 62.5 mmol) and allowed to stir at room tem-
perature for 1h. To this reaction mixture, at 0 ꢁC freshly
distilled ethyl chloroformate (12 mL, 125 mmol) was
added slowly. After the addition was complete, the
mixture was further stirred overnight at room temper-
ature. The reaction mixture was quenched with satu-
rated aqueous NH4Cl solution (25 mL) and extracted
with ethyl acetate. The organic extract was washed with
water (2 · 50 mL), brine (1 · 50 mL), dried over anhy-
drous Na2SO4, filtered and concentrated under vacuum.
Purification of the crude by column chromatography
afforded the ester 19 (12.3 g, 84.8% yield) as a colorless
syrupy liquid. 1H NMR (CDCl3, 200 MHz):
d ¼ 7:40–7:22 (m, 5H, aromatic-H), 4.58 (s, 2H,
–OCH2Ph), 4.20 (q, 2H, J ¼ 6:7 Hz, –OCH2CH3), 3.62
(t, 2H, J ¼ 7:4 Hz, –CH2OBn, 1.34 (t, 2H, J ¼ 6:7 Hz,
–OCH2CH3). IR (neat) cmꢀ1: 2983, 2870, 2241, 1711,
1454, 1366, 1255, 1076, 1019, and 746. MS (EI): m=z 232
(Mþ).
4.21. Ethyl 2-formylmethyl-6-methoxybenzoate 23
Dess Martin Periodinane (0.22 g, 0.53 mmol) was added
to a solution of alcohol 22 (0.1g, 0.44 mmol) in dry
CH2Cl2 (15 mL) at 0 ꢁC under nitrogen atmosphere. The
turbid solution was allowed to warm to room temper-
ature and stirred for 14 h. The reaction was diluted with
ethyl acetate (17 mL) and quenched with saturated
aqueous NaHCO3 (20 mL), and saturated aqueous
Na2S2O3 (20 mL). The mixture was vigorously stirred
until a clear solution resulted. The aqueous layer was
extracted with ethyl acetate (2 · 25 mL). The combined
organic extracts were washed with brine (1 · 20 mL),
dried over anhydrous Na2SO4 and concentrated to give
the crude aldehyde. Purification by column chroma-
tography afforded the pure aldehyde 23 (0.094 g, 94.9%)
as a colorless oil. 1H NMR (CDCl3, 200 MHz): d ¼ 9:60
(m, 1H, –CHO), 7.28–7.20 (m, 1H, one aromatic-H),
6.90–6.78 (m, 2H, aromatic-H), 4.38 (q, 2H, J ¼ 7:2,
14.2 Hz, –OCH2CH3), 3.80 (s, 3H, –OCH3), 3.60 (s, 2H,
–CH2CHO), 1.40 (t, 3H, J ¼ 7:3 Hz, –OCH2CH3). IR
(neat) cmꢀ1: 2981, 2841, 2728, 1729, 1706, 1586, 1471,
1266, 1072, and 795.
4.19. Ethyl 2-(2-benzyloxyethyl)-6-methoxybenzoate 21
A neat solution of 1-methoxycyclohexa-1,4-diene 20
(4.75 g, 43.1mmol) and ester 19 (5.0 g, 21.5 mmol) along
with a catalytic amount of dichloromaleic anhydride
(5 mg) was heated at 280 ꢁC for 8 h in a sealed tube. The
reaction mixture was cooled to room temperature
diluted with ethylacetate (25 mL) and washed with 20%
NaHCO3 solution followed by brine (1 · 25 mL). The
organic layer was dried over anhydrous Na2SO4, filtered
and evaporated to give the crude oil which was purified
by column chromatography to afford 21 (5.0 g, 73.9%)
4.22. Ethyl 2-allyl-6-methoxybenzoate 24
To a mixture of methyltriphenylphosphonium iodide
t
(0.109 g, 0.26 mmol) and BuOK (0.020 g, 0.178 mmol)
1
as a pale yellow liquid. H NMR (CDCl3, 200 MHz):
d ¼ 7:38–7:20 (m, 6H, 5 from phenyl, one subs.aryl-H),
6.82 (d, 2H, J ¼ 7:8 Hz, sub.aryl-H), 6.75 (d, 1H,
J ¼ 7:8 Hz, sub.aryl-H), 4.48 (s, 2H, –OCH2Ph), 4.32 (q,
2H, J ¼ 7:4 Hz, –OCH2CH3), 3.80 (s, 3H, –OCH3), 3.60
(t, 2H, J ¼ 7:4 Hz, –CH2OBn), 2.86 (t, 2H, J ¼ 7:4 Hz,
–CH2CH2OBn), 1.36 (t, 3H, J ¼ 7:4 Hz, –OCH2CH3).
13C NMR (CDCl3, 50 MHz): d ¼ 167:9, 156.2, 138.2,
136.9, 130.0, 128.1, 127.4, 127.3, 122.1, 109.0, 72.7, 70.5,
60.9, 55.7, 33.7, 14.1. IR (neat) cmꢀ1: 3030, 2859, 1727,
1599, 1585, 1471, 1364, 1267, 1072, 1028, and 913. MS
in dry THF (5 mL) at )78 ꢁC was added 18 crown 6
(ꢁ3 mg) and the solution was stirred for half an hour.
Aldehyde 33 (0.050 g, 0.225 mmol) in dry THF (1mL)
was added to this solution and stirring was continued
until the starting material had been consumed. The
reaction mixture was quenched by addition of water
(1mL) and the solvent was evaporated. The residue was
taken in ethyl acetate and the organic layer was washed
with water (1 · 5 mL) followed by brine (1 · 5 mL)
and dried over anhydrous Na2SO4. The solvent was

88
J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
evaporated under reduced pressure. Purification by flash
chromatography afforded the pure product 24 (0.025 g,
1586, 1469, 1265, 1098, 1039, and 913. MS (MALDI): m=z
543 (Mþ+Na).
1
50% yield). H NMR (CDCl3, 200 MHz): d ¼ 7:30–7:18
(m, 1H, aromatic-H), 6.82–6.72 (m, 2H, aromatic-H),
6.10–5.70 (m, 1H, –CH@CH2), 5.10–4.98 (m, 2H,
–CH@CH2), 4.38 (q, 2H, J ¼ 7:3, 14.1 Hz, –OCH2CH3),
3.80 (s, 3H, –OCH3), 3.34 (d, 2H, J ¼ 6:8 Hz,
–CH2CH@CH2), 1.40 (t, 3H, J ¼ 7:3 Hz, –OCH2CH3).
IR (neat) cmꢀ1: 2923, 2853, 1715, 1599, 1580, 1470,
1265, 1109, and 1072. MS (EI): m=z 220 (Mþ).
4.25. 3-[2-(tert-Butyldimethylsilyloxy)ethyl]-14-methoxy-
5-methoxymethoxy-6-methyl-(3S,5R,6S)-1H,4H,5H,6H,
7H,10H-benzo[c]oxacyclododecin-1-one 26
To a solution of the Grubbꢀs catalyst (Cy3P)2Cl2
Ru ¼ CHPh (0.025 g, 0.03 mmol) in dry CH2Cl2 (40 mL)
was added a solution of compound 25 (0.130 g,
0.25 mmol) in CH2Cl2 (2 mL). The reaction mixture was
stirred for 3 h at ambient temperature and poured into
water (20 mL). The organic phase was washed with brine
(1 · 20 mL), dried over anhydrous Na2SO4, filtered and
concentrated. Column chromatography of the crude
residue afforded pure product 26 (0.104 g, 85% yield
(9:1) E : Z isomer) as a light brown colored viscous
4.23. 2-Allyl-6-methoxybenzoic acid 2
To a solution of ester 24 (1.0 g, 4.5 mmol) in MeOH/
water (3:1; 10 mL) was added LiOHÆH2O (1.6 g,
36.3 mmol) and the mixture was heated to 70 ꢁC for 48 h.
The solvent was evaporated and the residue in water was
washed with ether (2 · 5 mL). The aqueous solution was
acidified by 2 N HCl (20 mL) and extracted with ethyl
acetate. The organic layer was washed with brine, dried
over Na2SO4 and concentrated to get the crude acid.
The product was purified over silica gel column chro-
matography to afford colorless solid 2 (0.74 g, 85%
yield). Melting point 105–107 ꢁC. 1H NMR (CDCl3,
200 MHz): d ¼ 7:32 (t, 1H, J ¼ 16:3 Hz, aromatic-H),
6.80 (t, 2H, J ¼ 16:3 Hz, aromatic-H), 6.00–5.80 (m, 1H,
–CH@CH2), 5.20–5.00 (m, 2H, ACH@CH2), 3.90 (s,
3H, –OCH3), 3.50 (d, 2H, J ¼ 6:2 Hz, Aryl-CH2–), 1.25
(s, 1H, acid-OH). 13C NMR (CDCl3, 75MHz):
d ¼ 162:8, 157.1, 139.6, 136.0, 131.5, 122.5, 121.6, 116.5,
108.9, 55.8, 37.2. IR (KBr) cmꢀ1: 2940, 1704, 1598, 1471,
1267, 1219, 1077, and 910. MS (EI): m=z 192 (Mþ).
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C,
68.72; H, 6.27%.
1
liquid. ½aŠ ¼ ꢀ58:5 (c 3.0, MeOH). H NMR (CDCl3,
D
500 MHz): d ¼ 7:22 (t, 1H, J ¼ 7:8 Hz, aromatic-H),
6.77 (dd, 2H, J ¼ 8:4, 22.5 Hz, aromatic-H), 5.52–5.42
(m, 2H, –CH(OCO)–, one olefinic-H), 5.37–5.30 (q, 1H,
J ¼ 9:5, 15.2 Hz, olefinic-H), 4.92 (d, 1H, J ¼ 6:2 Hz,
one –OCH2OCH3), 4.79 (d, 1H, J ¼ 6:7 Hz, one
–OCH2OCH3), 4.15 (dd, 1H, J ¼ 3:4, 9.0 Hz, –CH(O-
MOM)–), 3.80–3.65 (m, 6H, –OCH3, –OCH2OTBDMS,
one Ar–CH2–CH@CH–), 3.45 (s, 3H, –OCH2OCH3),
3.31(d, 1H, J ¼ 16:3 Hz, one Ar–CH2–CH@CH–), 2.30
(d, 1H, J ¼ 13:5 Hz, one –CH2CH2OTBDMS), 2.18–
2.09 (m, 1H, –CH(CH3)–), 2.00–1.90 (m, 1H, one
–CH2CH2OTBDMS), 1.82–1.65 (m, 3H, @CH–CH2–
CH(CH3)–, one –CH2–CH(OMOM)–), 1.51–1.41 (m,
1H, one –CH2CH(OMOM)–), 0.90 (s, 9H, tert.butyl-H),
0.87 (d, 3H, J ¼ 6:7 Hz, –CH(CH3)–), 0.06 (s, 6H,
–SiCH3)2–). 13C NMR(CDCl3, 50 MHz): d ¼ 168:1,
156.6, 139.1, 131.3, 129.8, 128.5, 122.7, 109.2, 96.9, 79.3,
72.0, 59.3, 55.4, 39.5, 37.7, 37.6, 35.7, 34.1, 25.8, 18.1,
13.3, )5.2. IR (neat) cmꢀ1: 2954, 2928, 2856, 1725, 1597,
1584, 1469, 1438, 1275, 1254, 1088, 1041, 970, and 951.
MS (FABMS): m=z 493 (Mþ+1).
4.24. 1-[2-(tert-Butyldimethylsilyloxy)ethyl]-3-methoxy-
methoxy-4-methyl-(1S,3R,4S)-6-heptenyl 2-allyl-6-meth-
oxybenzoate 25
To
a well-stirred solution of alcohol 3 (0.15 g,
0.60 mmol) and triphenylphosphine (0.24 g, 0.91mmol)
in dry benzene (4 mL) at room temperature was added
prestirred solution of acid 2 (0.117 g, 0.60 mmol) and
DEAD (0.160 g, 0.91 mmol) in benzene (4 mL). The
mixture was stirred for 14 h. Solvent was evaporated and
the residue was washed with dry ether and filtered
through a sintered funnel. The filtrates were dried over
anhydrous Na2SO4 and evaporation of the solvent fol-
lowed by chromatography of the crude residue afforded
pure ester 25 (0.235 g, 74.3% yield) as a pale pink col-
4.26. 3-(2-Hydroxyethyl)-14-methoxy-5-methoxymeth-
oxy-6-methyl-(3S,5R,6S)-1H,4H,5H,6H,7H,10H-benzo-
[c]oxacyclododecin-1-one 27
TBAF (0.44 mL, 0.44 mmol, 1M in THF) was added at
0 ꢁC to a solution of TBDMS ether 26 (0.12 g,
0.24 mmol) in THF (4 mL). After stirring the mixture for
3 h at ambient temperature the mixture was quenched
with water (3 mL). The aqueous layer was extracted with
ethyl acetate (2 · 5 mL). The combined organic phases
were dried over anhydrous Na2SO4 and evaporated.
Column chromatography of the crude residue afforded
the pure alcohol 27 (0.085 g, 92.4%) as a viscous liquid.
ored viscous liquid. ½aŠ ¼ ꢀ3:5 (c 4.0, CHCl3). 1H
D
NMR (CDCl3, 200 MHz): d ¼ 7:30–7:20 (m, 1H, aro-
matic-H), 6.76 (t, 2H, J ¼ 8:9 Hz aromatic-H), 6.00–
5.60 (m, 2H, 2 · –CH@CH2), 5.40–5.30 (m, 1H,
–CH(OCO)–), 5.10–4.84 (m, 4H, –CH@CH2), 4.73–4.65
(m, 2H, –OCH2OCH3), 3.83 (s, 3H, –OCH3), 3.78–3.62
(m, 2H, –CH2OTBDMS), 3.41–3.30 (m, 4H,
–CH2OCH3, –CH(OMOM)–), 1.95–1.79 (m, 4H, ArCH2-
CH@CH2, –CH2CH2OTBDMS), 1.74–1.65 (m, 2H,
–CH(CH3)CH2CH@CH2), 0.92–0.82 (m, 12H, tert-butyl-
H), 0.05 (s, 6H, –Si(CH3)2–). IR (neat) cmꢀ1: 2931, 1725,
½aŠ ¼ ꢀ52:6 (c 5.5, MeOH), )38.8 (c 1.0, CHCl3), lit.2e
D
½aŠ ¼ ꢀ34:5 (c 1.0, CHCl3). 1H NMR (CDCl3,
D
300 MHz): d ¼ 7:24–7:15 (m, 1H, aromatic-H), 6.81–
6.73 (m, 2H, aromatic-H), 5.53–5.41(m, 2H, one ole-
finic-H and –CH(OCO)–), 5.37–5.26 (m, 1H, olefinic-H),
4.82 (Ab quartet, 2H, J ¼ 6:8, 18.1 Hz, –OCH2OCH3),
4.18–4.10 (m, 1H, –CHOMOM), 3.84 (s, 3H, –OCH3),
3.78–3.66 (m, 4H, –CH2OH, aryl-CH2CH@CH2), 3.43

J. S. Yadav, P. Srihari / Tetrahedron: Asymmetry 15 (2004) 81–89
89
Org. Lett. 2000, 2, 4241; (c) Bhattacharjee, A.; De
Brabander, J. K. Tetrahedron Lett. 2000, 41, 8069; (d)
Feutrill, J. T.; Holloway, G. A.; Hilli, F.; Hugel, H. M.;
Rizzacasa, M. A. Tetrahedron Lett. 2000, 41, 8569; (e)
Furstner, A.; Oliver, R.; Blanda, G. Org. Lett. 2000, 2,
3731; (f) Scheufler, F.; Maier, M. E. Synlett 2001, 1221; (g)
Bauer, M.; Maier, M. E. Org. Lett. 2002, 4, 2205.
4. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 277(5328), 936.
5. Liu, C.; Coward, J. K. J. Org. Chem. 1991, 56, 2262.
6. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
7. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765.
(s, 3H, –OCH2OCH3), 2.35–2.23 (m, 2H, CH(CH3)-
CH2CH@CH2–), 2.15–2.05 (m, 1H, –CH(CH3)–), 1.93–
1.62 (m, 4H, –CH(OCO)CH2CH(OMOM)–, –CH2-
CH2OH), 0.85 (d, 3H, J ¼ 6:8 Hz, –CH(CH3)–). 13C
NMR (CDCl3, 75 MHz): d ¼ 168:2, 156.0, 139.0, 131.0,
129.9, 128.2, 124.2, 122.9, 109.1, 96.7, 79.3, 72.7, 59.1,
55.5, 55.4, 38.8, 37.6, 35.7, 33.9, and 13.2. IR (neat)
cmꢀ1: 3438, 2924, 1722, 1585, 1467, 1275, 1039, 973, 913,
and 731. MS (FABMS): m=z 379 (Mþ+1). Anal. Calcd
for C21H30O6: C, 66.65; H, 7.99. Found: C, 66.59; H,
8.01%.
8. Garegg, P. J.; Samuelson, B. J. Chem. Soc., Perkin Trans.
1 1980, 2866.
Acknowledgements
9. Similar alcohol with opposite center at C3 position was
prepared earlier by our group using (S) epoxide as given in
Yadav, J. S.; Bandyopadhyay, A.; Kunwar, A. C. Tetra-
hedron Lett. 2001, 42, 4907.
P.S.H. thanks CSIR, New Delhi for financial assistance.
10. Ueno, Y.; Chino, K. J. Chem. Soc., Perkin Trans. 1 1986,
1351.
References and Notes
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12. The compound was prepared from anisole as given in
Vogel’s Text Book of Practical Organic Chemistry; 5th ed.;
1989, p 1117.
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3. Partial syntheses and model studies: (a) George, G. I.;
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