Towards the synthesis of Palmerolide A: asymmetric synthesis of C1-C14 fragment

Article abstract of DOI:10.1016/j.tetasy.2007.10.011

The synthesis of a C1-C14 fragment of a marine cytotoxic natural product Palmerolide A is described. The key steps involved in this synthesis are deoxygenative rearrangement of an alkynol followed by an asymmetric dihydroxylation of a diene ester and CBS-

Full text of DOI:10.1016/j.tetasy.2007.10.011

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2473–2478
Towards the synthesis of Palmerolide A: asymmetric synthesis
of C1–C14 fragment
S. Chandrasekhar,* K. Vijeender, G. Chandrashekar and Ch. Raji Reddy
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 August 2007; accepted 8 October 2007
Dedicated to the memory of Professor Charles Mioskowski, UniVersite’ Louis Pasteur, BP 24, 67 401 Illkirch, France, who has passed away recently
Abstract—The synthesis of a C1–C14 fragment of a marine cytotoxic natural product Palmerolide A is described. The key steps involved
in this synthesis are deoxygenative rearrangement of an alkynol followed by an asymmetric dihydroxylation of a diene ester and CBS-
reduction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Palmerolide A is a 20-membered macrolide with a side
chain containing an enamide, five stereogenic centres and
a 1,3-diene system. The interesting structure and biological
profile have attracted the synthetic organic chemists.
Recently, the structure of Palmerolide A has been revised 1a
(Fig. 1),3 while two total syntheses and one partial synthesis
have been reported.3,4 We were interested in developing new
structural analogues of potent cytotoxic agents5 especially
related to melonoma. Herein we report a reagent controlled
synthesis of the C1–C14 fragment of Palmerolide A.
A marine natural product Palmerolide A 1 (Fig. 1) was re-
cently isolated from the Antarctic marine tunicate synoicum
adareanum by Baker et al.1 It exhibits unusual selectivity
against a number of cell lines in the 60 cell panel of the
National Cancer Institute (NCI) that correlates to vacuolar
ATPase inhibitors. In particular, Palmerolide A was found
to exhibit potent activity against the melanoma cell line
UACC-62 (LC50 = 18 nm), which is of particular impor-
tance. Further biological studies confirmed that Palmero-
lide A is indeed a potent inhibitor of bovine brain
V-ATPase (IC50 = 2 nM).2
The C1–C14 fragment of Palmerolide A (from a revised
structure) should be accessible from alkynol 5, through
O
O
1
1
O
O
H
H
19
19
20
20
N
N
7
7
O
O
OH
OH
HO
HO
14
10
14
10
O
O
11
11
O
O
NH2
NH2
Originally proposed (7R,10R,11R,19R,20R)-1
Revised structure (7S,10S,11S,19R,20R)-1a
Figure 1. Structure of Palmerolide A.
*
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512; e-mail: srivaric@iict.res.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.011

2474
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 18 (2007) 2473–2478
O
1
HO
HO
H
N
palmerolide A, 1a
7
+
SnBu3
HO
OH
O
2
I
14
10
O
O
11
3
NH2
O
1
MeO
BnO
OH
1,5-pentane
diol
BnO
7
OEt
5
OTBS
O
10
O
14
11
O
4
Scheme 1. Retrosynthesis of Palmerolide A.
deoxygenative rearrangement followed by an asymmetric
dihydroxylation. Alkynol 5 was further synthesized from
commercially available 1,5-pentane diol (Scheme 1).
using 9-BBN in THF to give compound 16 in 82% yield.
The alcohol was oxidized using IBX to furnish the alde-
hyde, which was immediately exposed to the two carbon
Wittig ylide, methoxycarbonylmethylenetriphenylphospho-
rane, to furnish the target C1–C14 fragment 4 in 93% yield
(Scheme 2).
2. Results and discussion
5-Benzyloxy-1-pentanal 6 (synthesized from 1,5-pentane
diol in two steps)6 was exposed to lithiated ethylpropiolate
to realize the formation of hydroxy alkynoate 5 in 85%
yield. The critical diene ester intermediate 7 has been
obtained from hydroxy alkynoate 5 by triphenylphosphine
mediated deoxygenative rearrangement via an allene5a,7 as
the key step. This key rearrangement allowed us to obtain
diene ester 7 ready for the stereoselective incorporation of
hydroxyl groups via a Sharpless asymmetric dihydroxy-
lation. The enantio and regioselective Sharpless asym-
metric dihydroxylation8 of diene ester 7 with ADmix-a,
3. Conclusions
In conclusion, we have achieved a highly efficient stereo-
selective synthesis of a functionalized C1–C14 fragment
of a marine metabolite Palmerolide A allowing us to
synthesize other structural analogs. The synthetic ease of
this approach allows us to prepare multigram of the key
fragment, which will enable us to design closely related
analogs for SAR studies. The work is presently being
pursued.
t
in BuOH/H2O (1:1) provided diol 8, which was masked
as its acetonoide 9 using 2,2-dimethoxy propane and cata-
lytic camphorsulfonic acid (CSA) in 85% yield with 96%
ee.9 Compound 9 was converted into the a,b-unsaturated
aldehyde 11 in two steps. Initially 9 was treated with
2 equiv of DIBAL-H to furnish alcohol 10, which was fur-
ther oxidized with IBX10 to aldehyde 11. This aldehyde was
exposed to magnesium homoallyl bromide to realize the
formation of allyl alcohol 12, which was formed as an
inseparable mixture (1:1) in 80% yield. Allyl alcohol 12
was converted into a,b-unsaturated ketone 13 using
IBX. The a,b-unsaturated ketone 13 was treated with
(R)-(ꢀ)-2-methyl-CBS-oxazaborolidine11 and BH3ÆDMS
at ꢀ40 ꢁC to furnish allyl alcohol 14 with an (S)-configura-
tion in 90% yield with 97% de.12 The newly created alcohol
functionality was masked as its TBDMS ether 15 using
TBDMSCl, imidazole as a base in 95% yield. The terminal
olefin in 15 was selectively hydroborated to a 1ꢁ-alcohol
4. Experimental
4.1. General
All solvents and reagents were purified by standard tech-
niques. Crude products were purified by column chromato-
graphy on silica gel of 60–120 mesh. IR spectra were
recorded on Perkin–Elmer 683 spectrometer. Optical rota-
tions were obtained on Jasco Dip 360 digital polarimeter.
1H and 13C NMR spectra were recorded in CDCl3 solution
on a Varian Gemini 200 and Brucker Avance 300. Chemi-
cal shifts were reported in parts per million with respect to
internal TMS. Coupling constants (J) are quoted in Hz.
Mass spectra were obtained on an Agilent Technologies
LC/MSD Trap SL.

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 18 (2007) 2473–2478
2475
OH
O
O
c
a
b
BnO
BnO
H
BnO
BnO
OEt
OEt
5
6
8
7
O
O
OH
O
O
OH
g
d
R
BnO
BnO
OEt
OH
O
O
12
9 R=COOEt
e
f
10 R=CH2OH
11 R=CHO
O
OR
O
O
h
i
k
BnO
BnO
O
O
13
14 R=H
15 R=TBDMS
OTBDMS
j
OTBDMS
O
O
O
l
BnO
BnO
OH
OMe
16
O
4
O
Scheme 2. Reagents and conditions: (a) LHMDS, ethyl propiolate, THF, ꢀ78 ꢁC, 3 h, 85%; (b) TPP, Benzene, rt, 2 h, 73%; (c) AD-mix-a, CH3SO2NH2,
tBuOH: H2O (1:1), 0 ꢁC, 24 h, 78%, 96% ee; (d) 2,2-DMP, CSA, DCM, 0 ꢁC, 3 h, 85%; (e) DIBAL-H, CH2Cl2, 0 ꢁC, 5 h, 90%; (f) IBX, DMSO, THF, rt,
2 h, 82%; (g) Mg, THF, homoallyl bromide 0 ꢁC, 80%; (h) IBX, DMSO, THF, rt, 1 h, 85%; (i) R-CBS catalyst, THF, ꢀ40 ꢁC, BH3ÆDMS, 3 h, 90%, 97%
de; (j) TBDMSCl, imidazole, CH2Cl2, 0 ꢁC to rt, 5 h, 94%; (k) 9-BBN, THF, 0 ꢁC, 4 h, then 20% NaOH, 30% H2O2, 3 h, 82%; (l) (i) IBX, DMSO, THF,
2 h; (ii) Ph3P@CHCO2CH3, 3 h, 93%.
4.1.1. Ethyl 8-(benzyloxy)-4-hydroxyoct-2-ynoate 5. To a
stirred solution of ethyl propiolate (1.93 mL, 22.91 mmol)
in THF (100 mL) at ꢀ78 ꢁC was slowly added LiHMDS
(1.06 M in hexanes, 28.76 mL, 34.44 mmol) and the whole
mixture was stirred at ꢀ78 ꢁC for 1 h. Aldehyde 6 (4 g,
20.83 mmol) in THF (30 mL) was then added dropwise
to the reaction mixture at ꢀ78 ꢁC and the stirring contin-
ued for 30 min. The reaction was quenched with aqueous
saturated NH4Cl (20 mL) before warming to room temper-
ature. The reaction mixture was diluted with water (15 mL)
and extracted with diethyl ether (2 · 20 mL), the combined
organic layers were washed with brine (20 mL), dried on
over Na2SO4 and evaporated in vacuo. The residue was
purified by column chromatography on silica gel eluted
with hexanes/EtOAc (8:2) to give alkynol 5 (5.13 g, 85%
yield) as a colourless oil: IR (neat): m 3407, 2931, 2861,
ester 7 (2.07 g, 73% yield): IR (neat): m 2926, 2855, 1711,
1641, 1252, 1136, 1104, 753 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 7.30–7.14 (m, 6H), 6.13–6.07 (m, 2H), 5.72
(d, J = 15.4 Hz, 1H), 4.46 (s, 2H), 4.17 (q, J = 7.1 Hz,
2H), 3.43 (t, J = 6.0 Hz, 2H), 2.26 (q, J = 6.7 Hz, 2H),
1.77–1.68 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 167.0, 144.7, 143.5, 138.3, 128.6,
128.2, 127.4, 127.4, 119.3, 72.7, 69.1, 60.0, 29.5, 28.6,
14.1; ESIMS: m/z 275 (M+1)+, 297 (M+Na)+; HRMS
calcd for C17H22O3Na: 297.1466 (M+Na)+; found,
297.1459.
4.1.3. (4S,5S,E)-Ethyl 8-(benzyloxy)-4,5-dihydroxyoct-2-
enoate 8. Into a 250 mL round-bottomed flask were
t
added 25 mL of BuOH, 25 mL of water and ADmix-a
(7 g, 1.4 g/mmol) and methanesulfonamide (0.47 g,
5.0 mmol). The mixture was stirred at room temperature
for about 5 min., and cooled to 0 ꢁC. To this cooled solu-
tion was added compound 7 (1.3 g, 5.0 mmol) and the mix-
ture was stirred for 24 h at 0 ꢁC. The reaction was
quenched with solid sodium sulfite (7 g) at room tempera-
ture. The reaction mixture was diluted with ethyl acetate
(50 mL) and after separation of the layers, the aqueous
layer was further extracted with ethyl acetate (3 · 30 mL).
The combined organic layers were washed with brine
(30 mL) and dried over anhydrous Na2SO4. After evapora-
tion of the solvent, the residue was purified on silica gel col-
2234, 1710, 1246, 1095, 747 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d 7.32–7.22 (m, 5H), 4.47 (s, 2H), 4.43–4.30
(m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.45 (t, J = 6.0 Hz,
2H), 1.80–1.50 (m, 6H), 1.31 (t, J = 7.1 Hz, 3H); 13C
NMR (CDCl3, 75 MHz): d 153.5, 138.2, 127.0, 127.5,
87.9, 76.3, 72.8, 69.9, 62.0, 61.6, 36.4, 29.0, 21.6, 13.8;
ESIMS: m/z 313 (M+Na)+; HRMS calcd for C17H22O4Na:
313.1415 (M+Na)+; found, 313.1410.
4.1.2. (2E,4E)-Ethyl 8-(benzyloxy) octa-2,4-dienoate 7.
A
mixture of alkynol 5 (3 g, 10.34 mmol) and TPP (3.52 g,
13.44 mmol) in benzene (30 mL) was stirred at room tem-
perature. After completion of the reaction (2 h, monitored
by TLC), the solvent was removed under vacuum and the
crude was purified on a silica gel column (eluting with
5% ethyl acetate in hexanes) to give the conjugated diene
umn eluting with hexanes/EtOAc (1:1) to give diol 8
25
(1.13 g, 78% yield) as a viscous liquid: ½aꢁD ¼ ꢀ12:2 (c
5.7, CHCl3): IR (neat): m 3418, 2923, 2855, 1713, 1273,
1
1096 cmꢀ1; H NMR (CDCl3, 300 MHz): d 7.34–7.22 (m,
5H), 6.87 (dd, J = 4.9, 15.67 Hz, 1H), 6.08 (dd, J = 1.5,

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S. Chandrasekhar et al. / Tetrahedron: Asymmetry 18 (2007) 2473–2478
15.6 Hz, 1H), 4.49 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.05–
4.01 (m, 1H), 3.65 (br s, 1H), 3.52–3.44 (m, 3H), 3.09 (br
s, 1H), 1.79–1.47 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H); 13C
NMR (CDCl3, 75 MHz): d 166.4, 147.0, 137.7, 128.3,
127.6, 122.0, 74.0, 73.6, 72.9, 70.1, 60.4, 30.2, 25.8, 14.0;
ESIMS: m/z 331 (M+Na)+; HRMS calcd for C17H24O5Na:
331.1521 (M+Na)+; found, 331.1518.
iodoxybenzoic acid (1.38 g, 4.93 mmol) in DMSO
(10 mL) was added alcohol 10 (1.0 g, 3.28 mmol) in THF
(80 mL) and allowed to stir for 3 h at room temperature.
After completion of the reaction, the reaction mixture
was filtered through a pad of Celite and washed with
ether (200 mL). The filtrate was washed with water
(50 mL), brine (50 mL, dried over anhydrous Na2SO4
and concentrated in vacuo. The crude product was puri-
fied by column chromatography on silica gel eluted
4.1.4. (E)-Ethyl 3-((4S,5S)-5-(3-(benzyloxy)propyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)acrylate 9. To a stirred solu-
tion of diol 8 (1.5 g, 4.87 mmol) in CH2Cl2 (10 mL) at
0 ꢁC was added CSA (0.112 g, 0.487 mmol) followed by
2,2-dimethoxypropane (1.01 mL, 9.74 mmol). The mixture
was stirred for 1 h and quenched with saturated aq NaH-
CO3 (30 mL). The organic layer was separated and the
aqueous layer further extracted with dichloromethane
(2 · 30 mL). The combined organic layers were washed
with water (25 mL), brine (20 mL), dried over Na2SO4
and the solvent was evaporated in vacuo. The residue
obtained was purified by column chromatography on silica
gel eluted with hexanes/EtOAc (9:1) to give the acetonide
with hexanes/EtOAc (9:1) to afford a,b-unsaturated alde-
25
hyde 11 (0.814 g, 82% yield): ½aꢁD ¼ ꢀ13:1 (c 0.7, CHCl3);
1H NMR (CDCl3, 300 MHz): d 9.56 (s, 1H), 7.30–7.25
(m, 5H), 6.6 (dd, J = 5.3, 15.6 Hz, 1H), 6.35 (dd, J = 1.3,
15.6 Hz, 1H), 4.47 (s, 2H), 4.24–4.19 (m, 1H), 3.76–
3.70 (m, 1H), 3.49–3.45 (m, 2H), 1.82–1.63 (m, 4H),
1.41 (s, 3H), 1.37 (s, 3H); ESIMS: m/z 327 (M+Na)+;
HRMS calcd for C18H24O4Na: 327.1572 (M+Na)+; found,
327.1561.
4.1.7. (E)-1-((4S,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-
1,3-dioxolan-4-yl) hepta-1,6-dien-3-ol 12. The homoallyl
bromide (0.635 g, 3.97 mmol) in THF (10 mL) was added
to a suspension of Mg (0.19 g, 7.94 mmol) in THF at room
temperature and stirred for 30 min. To this, aldehyde 11
(0.8 g, 2.64 mmol) was added in THF (10 mL) dropwise
at 0 ꢁC and stirring continued for 1 h. After completion
of the reaction (monitered by TLC), the mixture was
quenched with saturated aq NH4Cl (10 mL) and extracted
with ethylacetate (2 · 20 mL). The combined organic layers
were washed with water (15 mL), brine (15 mL), dried over
Na2SO4 and evaporated in vacuo. The crude product 12
(0.75 g, 80% yield) was obtained as inseparable mixture
and used it in the next step without further purification.
compound 9 (1.39 g, 85% yield) as a colourless oil:
25
½aꢁD ¼ ꢀ14:5 (c 4.6, CHCl3); IR (neat): m 2985, 2933,
2861, 1721, 1255, 1169, 1040, 756 cmꢀ1; 1H NMR (CDCl3,
300 MHz): d 7.32–7.23 (m, 5H), 6.80 (dd, J = 5.2 Hz,
15.4 Hz, 1H), 6.05 (dd, J = 1.5, 15.4 Hz, 1H), 4.46 (s,
2H), 4.17 (q, J = 7.1 Hz, 2H), 4.12–4.07 (m, 1H), 3.72–
3.4 (m, 1H), 3.48–3.44 (m, 2H), 1.82–1.57 (m, 4H), 1.39
(s, 3H), 1.36 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 165.7. 143.8, 138.3, 128.2, 127.4,
122.6, 109.2, 80.1, 80.0, 72.7, 69.6, 60.4, 28.5, 27.1, 26.5,
26.0, 14.0; ESIMS: m/z 371 (M+Na)+; HRMS calcd for
C20H28O5Na: 371.1834 (M+Na)+; found, 371.1823.
1
IR (neat): m 3449, 2926, 2857, 1638, 759 cmꢀ1; H NMR
4.1.5. (E)-4-((4S,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-
1,3-dioxolan-4-yl) but-3-en-1-ol 10. To a solution of
unsaturated ester 9 (1.5 g, 4.31 mmol) in CH2Cl2 (10 mL)
at 0 ꢁC was slowly added DIBAL-H (5.43 mL, 20% solu-
tion in toluene, 10.34 mmol) and the mixture was stirred
for 3 h at 0 ꢁC. The reaction was quenched with saturated
aq sodium potassium tartarate (30 mL) and the stirring
continued for 1 h. The organic layer was separated and
the aqueous layer extracted with dichloromethane
(2 · 30 mL). The combined organic layers were dried
over Na2SO4 and volatiles were removed under vacuum.
The crude product obtained was purified by column
chromatography on silica gel eluted with hexanes/EtOAc
(CDCl3, 300 MHz): d 7.37–7.28 (m, 5H), 5.87–5.53 (m,
3H), 5.05–4.92 (m, 2H), 4.47 (s, 2H), 4.16–4.05 (m, 1H),
3.94 (t, J = 8.0 Hz, 1H), 3.66–3.57 (m, 1H), 3.46–3.43 (m,
2H), 2.18–2.08 (m, 2H), 1.78–1.53 (m, 6H), 1.36 (s, 6H);
ESIMS: 383 (M+Na)+; HRMS: calcd for C22H32O4Na:
383.2198; found, 383.2193.
4.1.8. (E)-1-((4S,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-
1,3-dioxolan-4-yl) hepta-1,6-diene-3-one 13. To a solution
of iodoxybenzoic acid (0.63 g, 2.08 mmol) in DMSO
(10 mL) was added alcohol 12 (0.5 g, 1.38 mmol) in THF
(30 mL) and allowed to stir for 3 h at room temperature.
After completion of the reaction, the mixture was filtered
through a pad of Celite, and washed with ether (30 mL).
The filtrate was washed with brine (20 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica
gel eluted with hexanes/EtOAc (9:1) to afford a,b-unsatu-
(8:2) to give allyl alcohol 10 (1.187 g, 90% yield) as colour-
25
less oil: ½aꢁD ¼ ꢀ6:3 (c 3.15, CHCl3); IR (neat): m 3441,
2925, 2855, 1630, 759 cmꢀ1
;
1H NMR (CDCl3,
200 MHz): d 7.26–7.21 (m, 5H), 5.94–5.82 (m, 1H), 5.62
(dd, J = 7.3, 15.4 Hz, 1H), 4.45 (s, 2H), 4.07 (d,
J = 4.0 Hz, 2H), 3.95 (t, J = 8.0 Hz, 1H); 3.65–3.58 (m,
1H), 3.45–3.42 (m, 2H), 2.17 (br s, 1H), 1.76–1.50 (m,
4H), 1.35 (s, 6H); 13C NMR (CDCl3, 50 MHz): d 134.3,
128.2, 127.5, 127.4, 81.6, 80.3, 75.0, 74.0, 72.7, 69.8, 62.3,
29.9, 28.2, 27.1, 26.8, 26.0; ESIMS: m/z 329 (M+Na)+;
HRMS calcd for C18H26O4Na: 329.1728 (M+Na)+; found,
329.1714.
rated keto compound 13 (0.422 g, 85% yield):
25
½aꢁD ¼ ꢀ11:9 (c 5.1, CHCl3); IR (neat): m 2925, 2857,
1635, 11027, 758 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
;
7.29–7.25 (m, 5H), 6.64 (dd, J = 5.6, 15.8 Hz, 1H), 6.34
(d, J = 15.8 Hz, 1H), 5.85–5.72 (m, 1H), 5.04–4.94 (m,
2H), 4.46 (s, 2H), 4.10 (t, J = 7.5 Hz, 1H) 3.94–3.89 (m,
1H), 3.47–3.45 (m, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.34 (q,
J = 6.7 Hz, 2H), 2.03–1.60 (m, 4H), 1.40 (s, 3H), 1.37 (s,
3H); 13C NMR (CDCl3, 75 MHz): d 198.6, 141.3, 138.0,
136.5, 129.9, 127.9, 127.1, 127.1, 114.9, 109.0, 79.9, 72.4,
4.1.6. (E)-3-((4S,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-
1,3-dioxolan-4-yl) acrylaldehyde 11. To a solution of

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 18 (2007) 2473–2478
2477
69.3, 39.3, 28.3, 27.3, 26.8, 26.2, 25.7; ESIMS: m/z 381
(M+Na)+; HRMS calcd for C22H30O4Na: 381.2041
(M+Na)+; found, 381.2031.
tion mixture was stirred for 8 h at room temperature. The
mixture was treated with 20% aq NaOH (slow addition) at
0 ꢁC until the mixture was basic. To this, was added H2O2
(0.095 mL, 30% aq solution, 0.84 mmol) and the stirring
continued for 3 h. The reaction mixture was extracted with
ethyl acetate (6 · 10 mL), the combined organic layers were
washed with brine (25 mL), dried over Na2SO4, concen-
trated on rotary evaporator and the residue was purified
4.1.9. (S,E)-1-((4S,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)hepta-1,6-dien-3-ol 14. To a stirred solu-
tion of a,b-unsaturated keto compound 13 (0.30 g,
1.0 mmol) in THF (3 mL) was added (R)-(ꢀ)-2-methyl-
CBS-oxazaborolidine (1.0 M solution in toluene, 0.55 mL,
0.31 mmol) at ꢀ40 ꢁC and stirred for 30 min. To this
mixture was added BH3ÆDMS (0.08 mL, 1.10 mmol) drop-
wise and stirred at same temperature for 1 h. After comple-
tion of the reaction, the mixture was quenched with
MeOH (0.1 mL in 5 mL ether) followed by aq NaHCO3
(5 mL). The mixture was extracted with CH2Cl2 (2 ·
15 mL), and the combined organic layers were dried
and concentrated on rotary evaporator. The crude
by column chromatography to yield alcohol 16 (0.170 g,
25
82% yield): colourless liquid; ½aꢁD ¼ ꢀ79:7 (c 0.9, CHCl3);
IR (neat): m 3447, 2925, 2856, 763 cmꢀ1; 1H NMR (CDCl3,
300 MHz): d 7.28–7.26 (m, 5H), 5.77–5.41 (m, 2H), 4.47 (s,
2H), 4.20–4.10 (m, 1H), 3.94 (t, J = 8.1 Hz, 1H), 3.65–
3.44 (m, 5H), 1.74–1.33 (m, 16H), 0.88 (s, 9H), 0.03 (s,
3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 138.3,
137.9, 128.3, 127.6, 127.5, 126.5, 81.8, 80.5, 72.8, 72.4,
70.0, 62.7, 37.8, 37.6, 32.6, 28.5, 28.4, 27.2, 26.9, 26.2,
25.8, 21.2, 21.0, ꢀ4.3, ꢀ4.7; ESIMS: m/z 515 (M+Na)+;
HRMS calcd for C28H48O5NaSi: 515.3168 (M+Na)+;
found, 515.3158.
obtained was purified by flash column chromatography
25
to give product 14 (0.343 g, 90% yield): ½aꢁD ¼ ꢀ46:95
(c 1.45, CHCl3); IR (neat): m 3449, 2926, 2857, 1638,
759 cmꢀ1
;
1H NMR (CDCl3, 300 MHz):
d
7.29–
7.25 (m, 5H), 5.82–5.71 (m, 2H), 5.58 (dd, J = 7.1,
15.4 Hz, 1H), 5.04–4.93 (m, 2H), 4.46 (s, 2H), 4.11
(q, J = 6.0 Hz, 1H), 3.94 (t, J = 7.5 Hz, 1H), 3.64–
3.58 (m, 1H), 3.47–3.44 (m, 2H), 2.14–2.10 (m, 2H),
1.74–1.56 (m, 6H), 1.36 (s, 6H); 13C NMR (CDCl3,
75 MHz): d 138.0, 137.7, 137.6, 128.3, 127.6, 127.5,
127.4, 114.9, 198.5, 81.6, 80.4, 72.8, 71.2, 69.9, 35.9, 29.5,
28.4, 27.2, 26.9, 26.1; ESIMS: m/z 383 (M+Na)+; HRMS
calcd for C22H32O4Na: 383.2198 (M+Na)+; found,
383.2193.
4.1.12. (S,2E,8E)-Methyl 9-((4S,5S)-5-(3-(benzyloxy)prop-
yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-7-(tert-butyldimethylsilyl-
oxy)nona-2,8-dienoate 4. To
a
stirred solution of
2-iodoxybenzoic acid (0.085 g, 0.30 mmol) in DMSO
(1 mL) was added alcohol 16 (0.1 g, 0.20 mmol) in THF
(10 mL) at room temperature and the mixture was
stirred for 3 h. The solid materials were filtered through
a sintered funnel and the resulting filtrate was extracted
with diethyl ether (2 · 10 mL). The combined organic
layers were washed with brine (10 mL), dried over anhy-
drous Na2SO4 and concentrated under reduced pressure
to yield the aldehyde (0.089 g), which was used without
further purification. This aldehyde (0.089 g, 0.18 mmol)
was dissolved in benzene (15 mL), was added carbome-
4.1.10. (S,E)-1-(4S,5S)-5-(3-(Benzyloxy)propyl)-2-2-dimethyl-
1,3-dioxolan-4-yl)hepta-1,6-dien-3-yloxy)(tert-butyl)dimethyl-
silane 15. To a solution of alcohol 14 (0.20 g, 0.55 mmol)
in dry CH2Cl2 (10 mL), imidazole (0.094 g, 1.38 mmol) and
tert-butyldimethylsilyl chloride (0.21 g, 1.38 mmol) were
added at 0 ꢁC and stirred for 6 h at room temperature.
The reaction mixture was diluted with water and extracted
with CH2Cl2 (2 · 20 mL). The combined organic layers
were dried over anhydrous Na2SO4 and evaporated under
reduced pressure. The crude product was purified by col-
thoxy
methylenetriphenyl
phosphorane
(0.095 g,
0.27 mmol) and the resulting solution was stirred for 12 h
at room temperature. The solvent was removed under vac-
cum, and the residue obtained was diluted with dichloro-
methane (20 mL), washed with water (10 mL), brine
(10 mL), dried over Na2SO4 and concentrated on rotary
evaporator. The crude product was purified by column
umn chromatography using hexanes/EtOAc (9:1) as eluent
chromatography to yield a,b-unsaturated ester 4 (0.103 g,
25
to afford compound 15 (0.247 g, 94% yield): ½aꢁD ¼ ꢀ6:5 (c
25
93% yield): colourless oil; ½aꢁD ¼ ꢀ29:6 (c 2.85, CHCl3);
1
1.3, CHCl3); IR (neat): m 2925, 1632, 760 cmꢀ1; H NMR
IR (neat):
m 2928, 2856, 1724, 1653, 1253, 1094,
(CDCl3, 300 MHz): d 7.32–7.22 (m, 5H), 5.83–5.68 (m,
2H), 5.56–5.47 (m, 1H), 5.01–4.91 (m, 2H), 4.47 (s, 2H),
4.16–4.10 (m, 1H), 3.94 (t, J = 7.9 Hz, 1H), 3.64–3.58 (m,
1H), 3.46–3.45 (m, 2H), 2.11–2.04 (m, 2H), 1.79–1.52 (m,
6H), 1.38 (s, 3H), 1.36 (s, 3H), 0.88 (s, 9H), 0.08 (s, 3H),
0,03 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 138.4, 138.1,
137.6, 128.3, 127.5, 127.4, 126.8, 126.5, 114.4, 81.8, 81.6,
80.5, 72.7, 72.1, 70.0, 37.2, 29.3, 28.5, 27.2, 26.9, 26.2,
25.8, 25.6, ꢀ3.5, ꢀ4.2, ꢀ4.7; ESIMS: m/z 497 (M+Na)+;
HRMS calcd for C28H46O4NaSi: 497.3063; found:
497.3044.
835 cmꢀ1; H NMR (CDCl3, 300 MHz): d 7.28–7.26 (m,
5H), 6.98–6.8 (m, 1H), 5.8–5.45 (m, 3H), 4.47 (s, 2H),
4.12–4.10 (m, 1H), 3.9 (t, J = 7.7 Hz, 1H), 3.71 (s, 3H),
3.66–344 (m, 3H), 2.21–2.18 (m, 2H), 1.79–1.26 (m, 14H),
0.88 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz): d
167.1, 149.2, 138.0, 137.4, 128.2, 127.5, 127.8, 126.8,
126.5, 121.0, 81.7, 80.5, 72.7, 72.3, 71.9, 70.0, 51.3, 37.4,
32.0, 29.6, 28.5, 27.2, 26.8, 26.2, 25.7, 23.5, ꢀ4.3, ꢀ4.8;
ESIMS: m/z 569 (M+Na)+; HRMS calcd for C31H50O6N-
aSi: 569.3274 (M+Na)+; found, 569.3260.
1
4.1.11. (S,E)-7-((4S,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)-5-(tert-butyldimethylsilyoxy)hept-6-en-1-ol
16. To a solution of compound 15 (0.20 g, 0.42 mmol) in
dry THF, was added 9-BBN (0.077 g, 0.63 mmol) in THF
(10 mL) slowly over a period of 15 min, at 0 ꢁC. The reac-
Acknowledgement
K.V. and G.C.S. thank the CSIR, New Delhi, for financial
assistance.

2478
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 18 (2007) 2473–2478
Chandrasekhar, S. Angew. Chem., Int. Ed. 2003, 42, 3996–
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