Stereoconvergent synthesis of C1-C17 and C18-C25 fragments of bafilomycin A1

Article abstract of DOI:10.1016/j.tet.2007.11.091

The effective syntheses of the enantiomerically pure C1-C17 2 and C18-C25 3 fragments as promising synthetic intermediates of bafilomycin A₁, 1 have been achieved.

Full text of DOI:10.1016/j.tet.2007.11.091

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1971e1982
www.elsevier.com/locate/tet
Stereoconvergent synthesis of C1eC17 and C18eC25
fragments of bafilomycin A1
*
*
J.S. Yadav , K. Bhaskar Reddy, G. Sabitha
Organic Division, Indian Institute of Chemical Technology, Hyderabad 500007, Andhra Pradesh, India
Received 3 August 2007; received in revised form 31 October 2007; accepted 15 November 2007
Available online 3 December 2007
Abstract
The effective syntheses of the enantiomerically pure C1eC17 2 and C18eC25 3 fragments as promising synthetic intermediates of bafilo-
mycin A1, 1 have been achieved.
Ó 2007 Published by Elsevier Ltd.
Keywords: Bafilomycin A1; Intermediates; Bicyclic precursor; Aldol; Vinyl stannane; Vinyl iodide; Evans-aldol
1. Introduction
2. Results and discussion
Bafilomycin A1 1, is a 16-membered macrolide, first isolated
from a culture of Streptomyces griseus sp. by Werner et al. in
1983.1 It is a potent vacuolar Hþ-ATPase (V-ATPases) inhibi-
tor.2 The V-ATPases are known to participate in bone resorption
and inhibitors of such enzymes may potentially be used for the
treatment of osteoporosis.3 Furthermore, this compound dis-
played broad antibacterial, antifungal,4 and immunosuppressive
activities.5 Bafilomycin A1 contains an acid and base-sensitive
six-membered hemiketal that participates in a hydrogen-bond
network with the C9, C17 the hydroxyl group and the carbonyl
of the 16-membered lactone that is responsible for biological ac-
tivity. In light of its interesting chemical structure and profile of
biological activity, bafilomycin A1 has been an attractive target
for synthesis. Consequently, four total syntheses6 and several
partial contributions7 of bafilomycin A1 have been reported by
various research groups so far.
The retrosynthesis, we envisaged for the synthesis of bafi-
lomycin A1 is shown in Scheme 1. The macrolactone can be
opened and then disconnected between C11 and C12 via
a Stille-coupling reaction. As part of our interest in the synthe-
sis of bioactive natural products,8 herein we report the synthe-
sis of the C1eC11, C12eC17, and C18eC25 fragments of
bafilomycin A1, and also the coupling of C1eC11 fragment
with the C12eC17 fragment.
2.1. Synthesis of the C1eC11 fragment 4
The synthesis of the C1eC11 fragment 4 started with a known
triol8a,b 6 (Scheme 2). The 1,3-diol group in 6 was protected as
an acetonide employing 2,2-dimethoxy propane and PPTS in
CH2Cl2, and the free primary hydroxyl group was tosylated un-
der standard conditions to yield the tosylate 9. The tosyl com-
pound 9 was treated with lithium acetylideeethylenediamine
complex in DMSO to give the acetylenic compound and the
acetonide group was deprotected to yield the diol 10. Oxidation
of the primary alcohol in 10 with IBX furnished aldehyde 11.
When the secondary hydroxyl group in compound 11 was
acetylated using Ac2O, Et3N in the presence of DMAP,
*
IICT communication no.: 061108.
* Corresponding author. Tel.: þ91 40 27193434; fax: þ91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.11.091

1972
J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
OMe
12
18
OH
O
OMe
O
Si
OMe
OH
O
O
O
17
11
MeO2C
O
1
OH
+
HO
O
O
ODEIPS
2
O
3
25
OMe
Bafilomycin A1
1
OMe
O
OMe
I
+
Bu3Sn
MeO2C
ODEIPS
4
5
OBn OH OH
8
TPSO
CHO
7
OH OBn OH OH
6
Scheme 1. Retrosynthetic analysis of bafilomycin A1.
c,d
a,b
e
f
CHO
OH
OBn O
OTs
OH
O
OH
OBn
OH
OH
OBn OH
OBn
6
9
10
11
j,k
g
OH
h
OH
OR
CHO
OBn
ODEIPS
OR1
OBn
14 R1= H, R = H
12
13
16
i
15 R1 = H, R = Piv
OMe
m
n,o
OH
I
I
l
I
CHO
CO2Me
ODEIPS
ODEIPS
18
ODEIPS
17
4
Scheme 2. Reagents and conditions: (a) 2,2 DMP, PPTS, CH2Cl2, 0 ꢀC to rt, 3 h, 88%. (b) TsCl, NEt3, DMAP, CH2Cl2, 96%. (c) LiC^CH, H2N(CH2)2NH2,
DMSO, rt, 1 h, 80%. (d) PPTS, MeOH, 3 h, 84%. (e) IBX, DMSO, CH2Cl2, 0 ꢀC to rt, 3 h, 62%. (f) Et3N, Ac2O, DMAP, CH2Cl2, 0 ꢀC to rt, 85%. (g)
NaBH4, MeOH, 0 ꢀC to rt, 1 h, 92%. (h) Li, liq NH3, THF, 2 min, 88%. (i) PvCl, Et3N, CH2Cl2, 0 ꢀC to rt, 3 h, 94%. (j) DEIPSCl, imidazole, DMF, rt, overnight,
85%. (k) K2CO3, MeOH, rt, overnight, 85%. (l) Cp2ZrCl2, Me3Al, rt, 10 h then I2, THF, ꢁ25 ꢀC, 1 h, 82%. (m) MnO2, CH2Cl2, rt, 1 h, 96%. (n) CH2(OMe)-
CO2Me, LHMDS, THF, ꢁ78 ꢀC, 94%. (o) MeSO2Cl, Et3N, DBU, CH2Cl2, 0 ꢀC to rt, 80%.
b-elimination took place to give the unsaturated aldehyde 12.
The reduction of aldehyde functionality gave the corresponding
alcohol 13 in 92% yield. Treatment of alkyne 13 with Li in liq
NH3 resulted the debenzylated product 14 in 88% yield. Com-
pound 14 was selectively converted into mono pivalylated com-
pound 15. The free secondary hydroxyl group in compound 15
was silylated using diethylisopropylsilylchloride (DEIPSCl),9
imidazole in DMF and the subsequent removal of the pivaloyl
group furnished 16. Negishi’s methyl zirconation10 of com-
pound 16 led to the formation of compound 17.
Oxidation of the allylic alcohol 17 with MnO2 gave the cor-
responding a,b-unsaturated aldehyde 18. The aldol conden-
sation of 18 with lithium 2-methoxyacetate, followed by
mesylation of the resulting alcohol and b-elimination furnished
the C1eC11 fragment 4 of bafilomycin A1 1, which was found
to be identical with the compound reported by Hanessian et al.6g
2.2. Synthesis of the C12eC17 fragment 5
Our synthesis of vinyl stannane intermediate 5 was deve-
loped on the basis of Evans asymmetric aldol reaction. Thus,
asymmetric aldol reaction of oxazolidene 19 with the alde-
hyde11
7 using dibutylboronetriflate and triethylamine
provided syn-aldol product 20 in 82% yield as single diaste-
reoisomer (Scheme 3). After reduction with LiBH4, the diol
was converted to the corresponding acetonide 21 in 98% over-
all yield for two steps. Desilylation with TBAF in THF and
then exposure of the resulting alcohol to Sharpless epoxidation
afforded diastereomeric epoxy alcohols in 78% yield with 8:2
ratio, and were easily separated on silica gel column chromo-
tography. The required major epoxy alcohol 22, on treatment
with Ph3P/CCl4, followed by a base induced double elimina-
tion with Li/liq NH3 a protocol developed by our group12

J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
1973
O
O
OH
O
O
OTBDPS
b,c
a
OTBDPS
O
N
O
N
OTBDPS
OHC
O
O
7
Bn
Bn
19
20
21
OMe
OR
O
d,e
f,g
i
OH
SnBu3
O
O
O
O
O
h
O
22
5
R = H
23
24
R = Me
Scheme 3. Reagents and conditions: (a) n-Bu2BOTf, Et3N, CH2Cl2, 0 ꢀC to ꢁ78 ꢀC then 7, 1 h, 89%. (b) LiBH4, Et2O, H2O, 0 ꢀC, 1 h, 98%. (c) 2,2 DMP, PPTS,
CH2Cl2, 0 ꢀC, 1 h, 96%. (d) TBAF, THF, 0 ꢀC to rt, 2 h, 95%. (e) Ti(OiPr)4, (ꢁ)DIPT, TBHP, CH2Cl2, ꢁ20 ꢀC, 24 h, 78%. (f) TPP, CCl4, reflux, 1.5 h, 90%. (g) Li,
liq NH3, Fe(NO)3, ꢁ78 ꢀC, 2 h, 82%. (h) NaH, MeI, THF, 0 ꢀC to rt, 1 h, 98%. (i) Pd(PPh3)4, Bu3SnH, CH2Cl2, 0 ꢀC to rt, 0.5 h, 78%.
c
a,b
d
OH
8
CHO
OBn OPMB
26
OBn O
OR
PMB
OBn OPMB
25
27 R = H
28 R = Ac
e
g
i
f
O
OR
O
O
O
O
Si
Si
OH OH
OAc
3
29
30 R = Ac
31 R = H
h
Scheme 4. Reagents and conditions: (a) PPTS, PMP(OMe)2, CH2Cl2, rt, 1 h, 96%. (b) DIBAL-H, CH2Cl2, 0 ꢀC, 1 h, 85%. (c) IBX, DMSO, CH2Cl2, 0 ꢀC to rt, 3 h,
83%. (d) Mg/EtBr, THF, 2 h, 90%. (e) Ac2O, Et3N, CH2Cl2, 0 ꢀC to rt, 1 h, 94%. (f) 5% Pd/C, EtOAc, rt, 1 h, 90%. (g) (t-Bu)2Si(OTf)2, 2,6-lutidine, CH2Cl2, rt,
1 h, 85%. (h) NaOMe, THF, 1 h, 90%. (i) DMP, CH2Cl2, NaHCO3, 0 ꢀC to rt, 1 h, 88%.
afforded propargylic alcohol 23. The hydroxyl group in 23 was
protected as its methyl ether 24. Finally, treatment of 24 with
tributyltin hydride in the presence of a catalytic quantity of
bistriphenylphosphine palladium(II) chloride13 led to the de-
sired vinyl stannane C12eC17 subunit 5 (Scheme 3). The spec-
tral properties (1H, IR, mass HRMS) and specific rotation
[a]2D5 þ16.5 (c 1.10, CHCl3) {lit.6d [a]2D5 þ16.4 (c 1.01,
CHCl3)} of vinyl stannane 5 proved to be identical with the
reported compound.6d
gave a diol 29 in 90% yield. The diol 29 then was protected
with a di-tert-butylsilyl group,15 followed by deacetylation
of 30 afforded free hydroxyl compound 31. Oxidation of
31 using DesseMartin periodinane afforded the desired
C18eC25 fragment 3 as a white solid, mp 40e41 ꢀC {lit.6d
mp 40.0e40.5 ꢀC}. The spectral properties (1H, 13C NMR,
mass, IR, HRMS) and specific rotation [a]2D5 þ84.8 (c 0.9,
CHCl3) {lit.6d [a]D25 þ85.2 (c 0.89, CHCl3)} of ethylketo 3
are identical with reported compound.6d
2.3. Synthesis of the C18eC25 fragment 3
OMe
CO2Me
OMe
The synthesis of the intermediate 3 starts with the known
diol 8, which was reported by us.14 The diol 8, upon reaction
with p-methoxy benzaldehyde dimethyl acetal and p-toluene-
sulfonic acid (PPTS) resulted the protected compound, which
on subsequent regioselective reductive ring-opening reaction
with DIBAL-H in CH2Cl2 produced the free primary alcohol
25 (Scheme 4), which on oxidation with IBX then furnished
the aldehyde 26. The ethylenic alcohol was easily obtained
by reaction of 26 with EtMgBr in THF and the resulting alco-
hol 27 was converted into the acetyl derivative 28. Hydroge-
nolysis of the benzyl and PMB ethers using Pd/C in EtOAc
PdCl2(dppf)
4
+
5
DMF, 50 °C,
16 h, 60%
O
O
ODEIPS
2
OMe
O
CHO
1
PO
O
OMe
Scheme 5.

1974
J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
2.4. Coupling of fragments 4 and 5 to obtain 2
4.1.2. (2S,3S,4S)-3-(Benzyloxy)-2-methyl-4-[(4S,5S)-2,2,5-
trimethyl-1,3-dioxan-4-yl]pentyl 4-methyl-1-
benzenesulfonate (9)
The cross-coupling reaction between the vinyl iodide 4 cor-
responding to the C1eC11 fragment of 1 and the vinyl tributyltin
5 corresponding to the C12eC17 fragment of 1 by Stille16
method using a catalytic amount of PdCl2(dppf)17 in DMF at
50 ꢀC for 16 h afforded the desired E,E-diene 2 in 60% yield
(Scheme 5), which has been converted to 1 by coupling with 3.6d
To a stirred solution of alcohol (5 g, 14.88 mmol) in dry tri-
ethylamine(6.25 mL, 44.64 mmol)at 0 ꢀC was added p-toluene-
sulfonylchloride (3.12 g, 16.4 mmol). After the reaction mixture
was stirred at 25 ꢀC for 1.5 h, the reaction was quenched with
water (30 mL) and the resultant mixture was then extracted
with ethyl acetate (50 mLꢂ3). The extracts were washed with
saturated aqueous NaCl (30 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (SiO2, 12% EtOAc in hexane
as eluent) gave tosyl compound 9 (7 g, 96%) as a colorless vis-
cous liquid, Rf¼0.72 (1:1 EtOAc and hexane). [a]2D5 þ35.6 (c
3. Conclusion
Thus we have demonstrated the formal synthesis of bafilo-
mycin A1 1 by preparing two important intermediates, viz.
C1eC17 fragment 2 and C18eC25 fragment 3, which have
been utilized for synthesis of bafilomycin A1 1.6d
1
1.8, CHCl3); H NMR (CDCl3, 300 MHz): d 0.68 (d, 3H, J¼
6.8 Hz, CH3), 0.83 (d, 3H, J¼6.8 Hz, CH3), 1.05 (d, 3H, J¼
6.8 Hz, CH3), 1.31 (d, 6H, J¼6.8 Hz, 2ꢂCH3), 1.74e1.88 (m,
2H, 2ꢂCH), 2.12e2.24 (m, 1H, CH), 2.45 (s, 3H, ArCH3),
3.33 (dd, 1H, J¼1.5, 9.8 Hz, CH), 3.42 (t, 1H, J¼11.3 Hz,
CH), 3.62 (dd, 1H, J¼5.3, 11.3 Hz, CH), 3.74 (dd, 1H, J¼1.5,
10.6 Hz, CH), 3.87 (dd, 1H, J¼7.5, 9.8 Hz, CH), 4.23 (dd, 1H,
J¼5.3, 9.8 Hz, CH), 4.55 (s, 2H, benzylic CH2), 7.14e7.32
(m, 7H, ArH), 7.77 (d, 2H, J¼8.3 Hz, ArH); 13C NMR
(CDCl3, 75 MHz): d 144.2, 138.5, 132.9, 129.4, 127.9, 127.5,
126.9, 126.4, 97.6, 82.5, 74.6, 72.9, 71.6, 65.7, 36.7, 35.1, 29.9,
29.5, 21.1, 19.1, 15.8, 12.0, 9.3; IR (neat): 2972, 2852, 1626,
1359, 1174 cmꢁ1; ESIMS: 513.1 [MþNa]þ; HRMS (ESIMS)
m/z calcd for C27H38O4SNa [MþNa]þ 513.2286, found
513.2287.
4. Experimental
4.1. General
Commercial reagents were used without further purifica-
tion. All solvents were purified by standard techniques. Infra-
red (IR) spectra were recorded on a PerkineElmer 683
spectrometer. Optical rotations were obtained on a Jasco Dip
360 digital polarimeter. Melting points are uncorrected. NMR
spectra were recorded in CDCl3 on Varian Gemini 200, Bruker
300 or Varian Unity 400 NMR spectrometers. Chemical shifts
(d) are quoted in parts per million and are referenced to tetra-
methylsilane (TMS) as internal standard. Coupling constants
(J) are quoted in hertz. Column chromatographic separations
were carried out on silica gel (60e120 mesh). Mass spectra
were obtained on Finnegan MAT 1020B or micro mass VG
70-70H spectrometers operating at 70 eV using a direct inlet
system.
4.1.3. (4S,5S)-4-[(1S,2S,3S)-2-(Benzyloxy)-1,3-dimethyl-5-
hexynyl]-2,2,5-trimethyl-1,3-dioxane
To a stirred solution of 9 (4 g, 8.16 mmol) in dry dimethyl
sulfoxide (34.5 mL) was added lithium acetylide ethylene-
diaminecomplex(90%,4.18 g,40.8 mmol)at0 ꢀCinoneportion.
After the reaction mixture was stirred at 25 ꢀC for 1.5 h, the
reaction was quenched with saturated aqueous NH4Cl (30 mL)
under ice cooling, and the resultant mixture was then extracted
with ether (25 mLꢂ3). The extracts were washed with saturated
aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and con-
centrated in vacuo. Purification of the residue by flash column
chromatography (SiO2, 8% EtOAc in hexane as eluent) gave
alkyne compound (2.25 g, 80%) as a color oil, Rf¼0.80 (1:1
4.1.1. (2S,3S,4S)-3-(Benzyloxy)-2-methyl-4-[(4S,5S)-2,2,5-
trimethyl-1,3-dioxan-4-yl]entan-1-ol
To a solution of triol 68 (5.5 g, 16.4 mmol) in dry dichlorome-
thane (40 mL), 2,2-dimethoxy propane (14.8 mL, 114.6 mmol)
and PPTS (2.2 g, 14.1 mmol) were added. The mixture was
stirred at ambient temperature for 3 h. Sodium bicarbonate
was added to neutralize PPTS and filtered. Removal of solvent
and purification by silica gel column chromatography (20%
EtOAc in hexane as eluent) afforded the mono acetonide
(5.42 g, 88%) as a white solid, Rf¼0.60 (1:1 EtOAc and hexane).
1
EtOAc and hexane). [a]2D5 þ22.67 (c 1.0, CHCl3); H NMR
(CDCl3, 300 MHz): d 0.70 (d, 3H, J¼6.8 Hz, CH3), 0.88 (d, 3H,
J¼7.5 Hz, CH3), 1.20 (d, 3H, J¼6.8 Hz, CH3), 1.32 (s, 3H,
CH3), 1.34 (s, 3H, CH3), 2.02 (m, 1H, CH), 1.75e1.92 (m,
3H, CH and CH2), 2.13 (td, 1H, J¼2.3, 9.8 Hz, CH), 2.32 (dt,
1H, J¼3.0, 6.0 Hz, CH), 3.33 (dd, 1H, J¼1.5, 9.1 Hz, CH),
3.44 (t, 1H, J¼11.3 Hz, CH), 3.63 (dd, 1H, J¼4.5, 11.3 Hz, CH),
3.82 (dd, 1H, J¼1.5, 10.6 Hz, CH), 4.61 (ABq, 2H, J¼11.3,
15.9 Hz, benzylic CH2), 7.19e7.35 (m, 5H, ArH); 13C NMR
(CDCl3, 75 MHz): d 139.2, 128.2, 127.2, 126.6, 97.9, 96.2, 83.3,
75.0, 73.4, 69.0, 66.1, 36.9, 35.4, 30.4, 30.0, 19.6, 19.3, 18.6,
1
[a]2D5 þ32.77 (c 6.0, CHCl3); H NMR (CDCl3, 300 MHz):
d 0.73 (d, 3H, J¼6.8 Hz, CH3), 0.87 (d, 3H, J¼6.8 Hz, CH3),
1.21 (d, 3H, J¼6.8 Hz, CH3), 1.34 (s, 6H, 2ꢂCH3), 1.78e2.05
(m, 3H, 3ꢂCH), 2.63 (dd, 1H, J¼3.0, 8.3 Hz, CH), 3.42e3.59
(m, 3H, CH and CH2), 3.62 (dd, 1H, J¼5.3, 12.1 Hz, CH), 3.80
e3.90 (m, 2H, CH2), 4.64 (ABq, 2H, J¼11.3, 27.2 Hz, benzylic
CH2), 7.22e7.37 (m, 5H, ArH); 13C NMR (CDCl3, 75 MHz):
d 138.5, 128.5, 127.6, 127.0, 98.0, 85.6, 75.4, 73.4, 66.2, 64.3,
87.5, 36.3, 30.3, 29.8, 19.5, 16.4, 12.5, 9.8; IR (neat): 3478,
2921, 1617, 1031 cmꢁ1; FABMS: 337 [MþH]þ; HRMS
(ESIMS): m/z calcd for C20H32O4Na [MþNa]þ 359.2198,
found 359.2193.
12.6, 9.9; IR (neat): 2924, 2854, 1641, 1364, 1007, 995 cmꢁ1
;
FABMS: 345 [MþH]þ; HRMS (ESIMS): m/z calcd for
C22H32O3Na [MþNa]þ 367.2249, found 367.2249.

J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
1975
4.1.4. (2S,3S,4R,5S,6S)-5-(Benzyloxy)-2,4,6-trimethyl-8-
nonyne-1,3-diol (10)
aqueous NaCl (13 mL), dried over anhydrous Na2SO4, and con-
centrated in vacuo. Purification of the residue by flash column
chromatography (SiO2, 13% EtOAc in hexane as eluent) gave
12 (0.8 g, 85%) as a colorless oil, Rf¼0.62 (1:1 EtOAc and hex-
ane). [a]3D0 ꢁ41.24 (c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz):
d 0.99 (d, 3H, J¼7.0 Hz, CH3), 1.09 (d, 3H, J¼7.0 Hz, CH3),
1.76 (s, 3H, CH3), 1.95 (t, 1H, J¼2.3 Hz, acetylene), 2.28 (dt,
1H, J¼3.1, 7.0, 17.1 Hz, CH), 2.44 (ddd, 1H, J¼2.3, 6.2,
17.1 Hz, CH), 3.01 (tt, 1H, J¼3.1, 7.0 Hz, CH), 3.38 (dd, 1H, J¼
3.1, 7.0 Hz, CH), 4.54 (ABq, 2H, J¼11.7, 23.3 Hz, benzylic
CH2), 6.59 (d, 1H, J¼10.1 Hz, olefin), 7.32 (m, 5H, ArH),
9.38 (s, 1H, CHO); 13C NMR (CDCl3, 75 MHz): d 195.7,
155.7, 146.2, 138.7, 128.4, 128.3, 127.7, 127.5, 85.5, 82.5, 75.5,
70.2, 36.3, 22.2, 17.6, 16.1, 9.3; IR (neat): 2954, 2861, 1685,
1641, 989 cmꢁ1; HRMS (ESIMS): m/z calcd for C19H24O2
[M]þ 284.3971, found 284.3968.
To a stirred solution of acetonide (2.2 g, 6.4 mmol) in MeOH
(10 mL) at 0 ꢀC was added pyridinium p-toluenesulfonate
(1.6 g, 6.4 mmol). After the reaction mixture was stirred at
25 ꢀC for 3 h, the reaction was quenched with saturated aqueous
NaHCO3 (20 mL) under ice cooling, and the resultant mixture
was then extracted with ether (30 mLꢂ3). The extracts were
washed with saturated aqueous NaCl (12 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. Purification of the
residue by flash column chromatography (SiO2, 50% EtOAc
in hexane as eluent) gave 10 (1.71 g, 84%) as colorless oil,
Rf¼0.35 (1:1 EtOAc and hexane). [a]3D0 ꢁ22.58 (c 1.0, CHCl3);
1H NMR (CDCl3, 200 MHz): d 0.75 (d, 3H, J¼6.8 Hz, CH3),
1.03 (d, 3H, J¼6.8 Hz, CH3), 1.19 (d, 3H, J¼6.8 Hz, CH3), 1.50
(br s, OH), 1.71 (s, 3H, CH3), 1.74e1.96 (m, 2H, CH2), 2.00 (t,
1H, J¼3.0 Hz, acetylene), 2.07e2.33 (m, 1H, CH), 2.36 (dt, 1H,
J¼3.0, 6.0, 16.6 Hz, CH), 2.54 (ddd, 1H, J¼3.0, 6.0, 16.6 Hz,
CH), 3.38e3.65 (m, 1H, CH), 3.76e3.99 (m, 2H, CH2), 4.71
(s, 2H, benzylic CH2), 7.32 (m, 5H, ArH); 13C NMR (CDCl3,
75 MHz): d 137.6, 128.5, 128.0, 127.7, 88.8, 82.3, 76.7, 76.5,
70.5, 68.9, 37.3, 34.9, 34.8, 22.4, 16.2, 13.2, 11.6; IR (KBr):
3413, 3345, 2927, 2865, 1644, 1239, 995 cmꢁ1; FABMS 305
[MþH]þ; HRMS (ESIMS) m/z calcd for C19H28O3Na
[MþNa]þ 327.1936, found 327.1940.
4.1.7. (E,4R,5S,6S)-5-(Benzyloxy)-2,4,6-trimethyl-2-nonen-
8-yn-1-ol (13)
Sodiumborohydride (180 mg, 5.3 mmol) was added portion
wise to the stirred cold solution of unsaturated aldehyde 12
(1 g, 3.5 mmol) in 5 mL MeOH. After the reaction mixture
was stirred at 25 ꢀC for 1 h, MeOH was evaporated and the re-
sulted residue was quenched with water and extracted with ethyl
acetate (3ꢂ10 mL), combined extracts were washed with brine
solution, dried over anhydrous Na2SO4, and concentrated in va-
cuo. Purification of the residue by flash column chromatography
(SiO2, 40% EtOAc in hexane as eluent) gave 13 (0.925 g, 92%)
as colorless viscous liquid, Rf¼0.50 (1:1 EtOAc and hexane).
4.1.5. (2R,3R,4R,5S,6S)-5-(Benzyloxy)-3-hydroxy-2,4,6-
trimethyl-8-nonynal (11)
To a stirred solution of IBX (2.07 g, 7.4 mmol) in 4 mL dry
DMSO was added diol 10 (1.5 g, 4.93 mmol) in 15 mL dry
CH2Cl2 at 0 ꢀC. The resulting reaction mixture stirred at
25 ꢀC for 3 h. Solid was filtered and washed with diethyl ether.
The filtrate was extracted with ether, washed with water and
brine, and dried over anhydrous Na2SO4, the ether layer was
concentrated under reduced pressure and the crude product
was subjected to column chromatography (SiO2, 15% EtOAc
in hexane as eluent) to give aldehyde 11 (1.01 g, 62%) as a color-
less liquid, Rf¼0.58 (1:1 EtOAc and hexane). 1H NMR (CDCl3,
200 MHz): d 0.73 (d, 3H, J¼6.8 Hz, CH3), 1.04 (d, 3H, J¼
6.8 Hz, CH3), 1.17 (d, 3H, J¼7.2 Hz, CH3), 1.56 (br s, OH),
1.79e1.06 (m, 3H, CH2 and CH), 1.96 (t, 1H, J¼3.0 Hz, acety-
lene), 2.56 (m, 1H, CH), 2.59 (dd, 1H, J¼5.9, 15.4 Hz, CH), 3.44
(m, 1H, CH), 3.91 (dd, 1H, J¼3.4, 5.9 Hz, CH), 4.68 (s, 2H,
benzylic CH2), 7.32 (m, 5H, ArH), 9.77 (s, 1H, CHO); IR
(neat): 3453, 2928, 2846, 1698, 1641, 995 cmꢁ1; LCeMS:
325.1 [MþNa]þ; HRMS (ESIMS): m/z calcd for C19H26O3Na
[MþNa]þ 325.1779, found 325.1608.
[a]3D0 ꢁ14.21 (c 0.5, CHCl3); H NMR (CDCl3, 300 MHz): d
1
1.01 (d, 3H, J¼7.0 Hz), 1.09 (d, 3H, J¼7.0 Hz, CH3), 1.27 (q,
1H, J¼7.8, 9.3 Hz, CH), 1.42 (br s, OH), 1.68 (s, 3H, CH3),
1.81 (m, 1H, CH), 1.92 (t, 1H, J¼2.3 Hz, acetylene), 2.34 (m,
1H, CH), 2.72 (m, 1H, CH), 3.22 (dd, 1H, J¼3.9, 8.6 Hz, CH),
3.97 (s, 2H, CH2), 4.64 (q, 2H, J¼10.9, 13.3 Hz, benzylic CH2),
5.49 (d, 1H, J¼9.4 Hz, olefin), 7.30 (m, 5H, ArH); 13C NMR
(CDCl3, 75 MHz): d 138.8, 134.6, 128.3, 127.6, 127.5, 86.6,
83.3, 75.4, 69.7, 69.0, 35.8, 34.9, 22.0, 18.7, 16.4, 13.8; IR
(neat): 3423, 2927, 2859, 1639, 995 cmꢁ1; FABMS: 269
(Mꢁ18); HRMS (ESIMS): m/z calcd for C19H26O2Na
[MþNa]þ 309.3983, found 309.3667.
4.1.8. (E,4R,5S,6S)-2,4,6-Trimethyl-2-nonen-8-yne-1,5-diol
(14)
Lithium metal (51 mg, 7.3 mmol) was added to a stirred so-
lution of freshly distilled ammonia (10 mL) and compound 13
(0.7 g, 2.4 mmol) in dry THF (5 mL) in a 100 mL two neck
round bottom flask fitted with a cold finger condenser at
ꢁ33 ꢀC. The reaction mixture was then stirred for another
2 min at ꢁ33 ꢀC and quenched by the addition of solid ammo-
nium chloride and the ammonia was then allowed to evaporate.
The residue left was partitioned between water and ether and the
aqueous phase extracted with ether (3ꢂ30 mL). The combined
organic layers were washed with water and brine, dried over an-
hydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(SiO2, 60% EtOAc in hexane as eluent) to afford the pure 14
4.1.6. (E,4R,5S,6S)-5-(Benzyloxy)-2,4,6-trimethyl-2-nonen-
8-ynal (12)
To an ice-cold solution of 11 (1 g, 3.3 mmol) in dry CH2Cl2
(11.2 mL) and triethylamine (1.4 mL, 6.82 mmol) was added
dropwise acetic anhydride (0.37 mL, 3.97 mmol) and catalytic
amount of DMAP with stirring. After the reaction mixture was
stirred at 25 ꢀC for 14 h, the mixture was poured into ice-cooled
water (13 mL) and the resultant mixture was then extracted with
ether (3ꢂ10 mL). The extracts were washed with saturated

1976
J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
(0.422 mg, 88%) as a clear colorless liquid, Rf¼0.30. [a]D25
þ5.73 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d 1.01 (d,
3H, J¼6.6 Hz, CH3), 1.02 (d, 3H, J¼7.3 Hz, CH3), 1.41 (br s,
1H, OH), 1.69 (s, 3H, CH3), 1.67e1.69 (m, 2H, CH2), 1.88 (t,
1H, J¼2.2 Hz, acetylene), 2.21e2.37 (m, 2H, 2ꢂCH), 2.62 (m,
2H, 2ꢂCH), 3.27 (t, 1H, J¼5.9 Hz, CH), 4.00 (s, 2H, CH2), 5.37
(d, 1H, J¼9.5 Hz, olefin); 13C NMR (CDCl3, 75 MHz): d 135.8,
126.2, 83.5, 78.7, 69.3, 68.2, 35.2, 34.8, 20.9, 18.0, 16.6, 14.0;
IR (neat): 3403, 3350, 2924, 2854, 1641, 995 cmꢁ1; LCeMS:
219.1 [MþNa]þ; HRMS (ESIMS): m/z calcd for C12H20O2Na
[MþNa]þ 219.1360, found 219.1365.
69.7, 69.2, 38.8, 37.5, 35.7, 27.2, 21.9, 18.5, 17.7, 17.6, 16.4,
14.0, 13.5, 7.4, 7.3, 4.5; IR (neat): 3448, 2960, 1731, 1459,
1033 cmꢁ1; LCeMS: 431.2 [MþNa]þ; HRMS (ESIMS): m/z
calcd for C24H44O3SiNa [MþNa]þ 431.2957, found 431.2952.
4.1.11. (E,4R,5S,6S)-5-[(1,1-Diethyl-1-isopropylsilyl)oxy]-
2,4,6-trimethyl-2-nonen-8-yn-1-ol
To the solution of pivalate (0.7 g, 1.71 mmol) in 4 mL MeOH
was added K2CO3 (171 mg, 1.71 mmol). The reaction mixture
was stirred at room temperature for overnight. The resultant
mixture was filtered and washed with MeOH. The combined fil-
trate and washings were concentrated in vacuo. Purification of
the residue by column chromatography (SiO2, 25% EtOAc in
hexane as eluent) gave free alcohol 16 (0.47 g, 85%) as a color-
less liquid, Rf¼0.68 (1:1 EtOAc and hexane). [a]3D0 þ3.68 (c 1.9,
4.1.9. (E,4R,5S,6S)-5-Hydroxy-2,4,6-trimethyl-2-nonen-8-
ynyl pivalate (15)
Toanice-coldsolutionof14(0.4 g, 2.04 mmol)indryCH2Cl2
(11.2 mL) were added dropwise triethylamine (0.85 mL,
6.12 mmol) and pivaloyl chloride (0.38 mL, 3.06 mmol) with
stirring. After the reaction mixture was stirred at 25 ꢀC for 4 h,
the mixture was poured into ice-cooled water (13 mL), and the
resultant mixture was then extracted with ether (10 mLꢂ3).
The extracts were washed with saturated aqueous NaCl
(13 mL), dried over anhydrous Na2SO4, and concentrated in va-
cuo. Purification of the residue by flash column chromatography
(SiO2, 25% EtOAc in hexane as eluent) gave 15 (0.53 g, 94%) as
a colorless viscous liquid, Rf¼0.65 (1:2 EtOAc and hexane).
1
CHCl3); H NMR (CDCl3, 400 MHz): d 0.63e0.73 (m, 4H,
2ꢂCH2), 0.92e1.09 (m, 18H, 6ꢂCH3), 1.25 (br s, OH), 1.67
(s, 3H, CH3), 1.71e1.82 (m, 1H, CH), 2.10 (t, 1H, J¼2.5 Hz,
acetylene), 2.22e2.34 (m, 1H, CH), 2.58 (m, 1H, CH), 3.56
(dd, 1H, J¼3.4, 5.8 Hz, CH), 3.96 (s, 2H, CH2), 5.47 (d, 1H, J¼
9.4 Hz, olefin); 13C NMR (CDCl3, 75 MHz): d 133.8, 128.6,
83.7, 79.4, 69.2, 69.1, 37.4, 35.7, 22.0, 18.6, 17.6, 16.6, 13.8,
13.5, 7.4, 4.5; IR (KBr): 3441, 2945, 2878, 1452, 1248,
723 cmꢁ1; LCeMS: 347 [MþNa]þ; HRMS (ESIMS): m/z calcd
for C19H36O2SiNa [MþNa]þ 347.2382, found 347.2376.
1
[a]2D5 þ10.90 (c 1.25, CHCl3); H NMR (CDCl3, 400 MHz):
d 1.02 (d, 6H, J¼6.2 Hz, 2ꢂCH3), 1.21 (S, 9H, tert-butyl), 1.68
(s, 3H, CH3), 1.69e1.79 (m, 2H, CH2), 1.88 (t, 1H, J¼2.3 Hz,
acetylene), 2.20e2.37 (m, 2H, 2ꢂCH), 2.61 (m, 1H, CH), 3.27
(dd, 1H, J¼5.5, 7.0 Hz, CH), 3.38 (br s, OH), 4.45 (ABq, 2H,
J¼12.5, 23.4 Hz, CH2), 5.41 (d, 1H, J¼8.6 Hz, olefin); 13C
NMR (CDCl3, 75 MHz): d 184.7, 131.7, 129.6, 83.4, 78.5,
69.8, 69.3, 38.8, 35.3, 35.2, 26.9, 20.9, 17.6, 16.7, 14.1; IR
(neat): 3504, 3308, 2967, 1725, 1284, 992 cmꢁ1; LCeMS: 303
[MþNa]þ 321 [MþK]þ; HRMS (ESIMS): m/z calcd for
C19H24O2Na [MþNa]þ 280.4051, found 280.4047.
4.1.12. (2E,4R,5S,6S,8E)-5-[(1,1-Diethyl-1-
isopropylsilyl)oxy]-9-iodo-2,4,6,8-tetramethyl-2,8-
nonadien-1-ol (17)
To a stirred solution of Cp2ZrCl2 (0.9 g, 3.08 mmol) in dry
1,2-dichloroethane (10 mL) was added dropwise 2 M Me3Al/
n-hexane (2.31 mL, 4.62 mmol). After 0.5 h at 25 ꢀC, a solution
of 16 (0.5 g, 1.54 mmol) in dry 1,2-dichloroethane (2 mL) was
added to the reaction mixture. After 13 h, to the reaction mixture
at ꢁ30 ꢀC was added slowly a solution of I2 (3.92 g, 15.4 mmol)
in dry THF (18 mL), and the resultant mixture was stirred at
ꢁ30 ꢀC for 1.5 h. The reaction mixture was warmed to 0 ꢀC,
and ice-cooled saturated aqueous K2CO3 (40 mL) was added.
The resultant mixture was extracted with ether (3ꢂ30 mL).
The extracts were washed with saturated aqueous Na2S2O3
(2ꢂ30 mL) and saturated aqueous NaCl (30 mL), dried over an-
hydrous Na2SO4, and concentrated in vacuo. Purification of the
residue by flash column chromatography (SiO2, 12% EtOAc in
hexane as eluent) gave vinyliodo 17 (0.59 g, 82%) as a pale yel-
low viscous liquid, Rf¼0.52 (3:7 EtOAc and hexane). [a]D30
ꢁ8.82 (c 1.5, CHCl3); 1H NMR (CDCl3, 200 MHz): d 0.65 (q,
4H, J¼7.4, 14.8 Hz, 2ꢂCH2), 0.78 (d, 3H, J¼6.7 Hz, CH3),
0.92e1.09 (m, 17H, 5ꢂCH3 and CH2), 1.26 (m, 1H, CH),
1.67 (s, 3H, CH3), 1.80 (s, 3H, CH3), 1.97 (m, 1H, CH), 2.42
(dd, 1H, J¼3.7, 13.3 Hz, CH), 2.58 (m, 1H, CH), 3.43 (t, 1H,
J¼4.5 Hz, CH), 3.97 (s, 2H, CH2), 5.48 (d, 1H, J¼8.9 Hz, ole-
fin), 5.83 (s, 1H, olefin); 13C NMR (CDCl3, 75 MHz): d 147.0,
133.4, 129.1, 80.4, 75.1, 69.2, 42.9, 35.9, 35.6, 23.6, 18.9,
17.6, 16.1, 13.8, 13.5, 7.3, 4.5; IR (neat): 3437, 2958, 1453,
1248, 1097, 724 cmꢁ1; ESIMS: 489.1 [MþNa]þ; HRMS
(ESIMS): m/z calcd for C20H39O2SiINa [MþNa]þ 489.1661,
found 489.1657.
4.1.10. (E,4R,5S,6S)-5-[(1,1-Diethyl-1-isopropylsilyl)oxy]-
2,4,6-trimethyl-2-nonen-8-ynyl pivalate
To a stirred solution of 15 (0.5 g, 1.78 mmol) in dry DMF
(2 mL) and imidazole (730 mg, 10.7 mmol) was added drop-
wise diethylisopropylsilylchloride (0.58 mL, 3.57 mmol) at
0 ꢀC. After the reaction mixture was stirred at 25 ꢀC for 12 h,
the mixturewas poured into ice-cooled water (9 mL), and the re-
sultant mixturewas then extracted with ether (7 mLꢂ3). The ex-
tracts were washed with saturated aqueous NaCl (10 mL), dried
over anhydrous Na2SO4, and concentrated invacuo. Purification
of the residue by flash column chromatography (SiO2, 8%
EtOAc in hexane as eluent) gave protected compound (0.69 g,
85%) as a colorless liquid, Rf¼0.55 (1:4 EtOAc and hexane).
[a]3D0 ꢁ0.20 (c 1.3, CHCl3); 1H NMR (CDCl3, 300 MHz): d 0.63
e0.72 (m, 4H, 2ꢂCH2), 0.94e1.08 (m, 21H, 7ꢂCH3), 1.23 (s,
3H, CH3), 1.73e1.86 (m, 1H, CH), 1.89 (t, 1H, J¼2.3 Hz, acet-
ylene), 2.13 (ddd, 1H, J¼3.0, 8.3 Hz, CH), 2.28 (ddd, 1H,
J¼2.3, 5.3 Hz, CH), 2.61 (m, 1H, CH), 3.61 (dd, 1H, J¼3.0,
5.3 Hz, CH), 4.44 (s, 2H, CH2), 5.56 (d, 1H, J¼9.8 Hz, olefin);
13C NMR (CDCl3, 75 MHz): d 178.2, 130.6, 129.1, 83.7, 79.2,

J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
1977
4.1.13. (2E,4R,5S,6S,8E)-5-[(1,1-Diethyl-1-
isopropylsilyl)oxy]-9-iodo-2,4,6,8-tetramethyl-2,8-
nonadienal (18)
18.6, 17.6, 15.7, 14.8, 13.5, 7.4, 7.3, 4.5, 4.4; IR (neat): 3435,
2955, 1721, 1452, 1248, 720 cmꢁ1; LCeMS: 573.1 [MþNa]þ;
HRMS (ESIMS): m/z calcd for C24H43O4SiINa [MþNa]þ
573.1873, found 573.1871.
To a solution of 17 (0.5 g, 1.07 mmol) in dry CH2Cl2 (15 mL)
was added MnO2 (2.82 g, 32.1 mmol). After the reaction mix-
ture was stirred at 25 ꢀC for 2 h, the mixture was filtered through
Celite, and the filtered cake was washed with CH2Cl2. The fil-
trate and washings were combined and concentrated in vacuo.
Purification of the residue by flash column chromatography
(SiO2, 10% EtOAc in hexane as eluent) gave 18 (0.48 g, 96%)
as a colorless gummy liquid, Rf¼0.45 (3:7 EtOAc and hexane).
[a]3D0 ꢁ1.17 (c 1.5, CHCl3); 1H NMR (CDCl3, 300 MHz): d 0.67
(q, 4H, J¼7.5, 15.9 Hz, 2ꢂCH2), 0.76 (d, 3H, J¼6.8 Hz, CH3),
0.92e1.12 (m, 16H, 5ꢂCH3 and CH), 1.26 (m, 1H, CH), 1.75 (s,
3H, CH3), 1.80 (s, 3H, CH3), 1.98 (dd, 1H, J¼9.8, 12.8 Hz, CH),
2.36 (dd, 1H, J¼3.8, 12.8 Hz, CH), 2.86 (tt, 1H, J¼2.3, 6.8 Hz,
CH), 3.57 (m, 1H, CH), 5.86 (s, 1H, olefin), 6.65 (d, 1H,
J¼9.1 Hz, olefin), 9.38 (s, 1H, CHO); IR (neat): 2956, 2878,
1694, 1460, 1284, 1094, 720 cmꢁ1; ESIMS: 487.1 [MþNa]þ;
HRMS (ESIMS): m/z calcd for C20H37O2SiINa [MþNa]þ
487.1505, found 487.1487.
4.1.15. (4R)-4-Benzyl-3-((2R,3S,4E)-6-[1-(tert-butyl)-1,1-
diphenylsilyl]oxy-3-hydroxy-2-methyl-4-hexenoyl)-1,3-
oxazolan-2-one (20)
Di-n-butylboryltrifluoromethanesulfonate (17 mL, 1 M in
CH2Cl2, 16.97 mmol) was added to a solution of (S)-4-benzyl-
3-propionyloxazolidin-2-one 19 (3.96 g, 15.4 mmol) in 35 mL
of CH2Cl2 at such a rate as to maintain the internal temperature
below þ3 ꢀC. Triethylamine (2.7 mL, 18.5 mmol) was then
added dropwise (internal temperature below þ4 ꢀC). The result-
ing yellow solution was then cooled to ꢁ78 ꢀC and aldehyde 7
(5 g, 15.4 mmol) in 15 mL CH2Cl2 was added slowly (internal
temperature below ꢁ70 ꢀC). After 20 min, the solution was
warmed to 0 ꢀC and stirred at that temperature for 1 h. The reac-
tion was quenched by the addition of 15 mL aqueous phosphate
buffer solution of pH 7.0 and 50 mL of MeOH (internal temper-
ature below þ10 ꢀC). A solution of 30 mL of MeOH and 15 mL
of 30% aqueous H2O2 was added carefully (internal temperature
below þ10 ꢀC), and the resulting yellow solution was stirred at
0 ꢀC for 1 h. The reaction mixture was extracted with CH2Cl2
and the combined organic extracts were washed with 50 mL
of saturated aqueous NaHCO3 and 50 mL of saturated brine.
The organic solution was dried over anhydrous Na2SO4 and
purified by flash column chromatography (SiO2, 50% EtOAc
in hexane as eluent) to give syn-aldol adduct 20 as a colorless
oil (7.6 g, 89%, >95:5 diastereoselectively), Rf¼0.42 (1:1
4.1.14. Methyl(2Z,4E,6R,7S,8S,10E)-7-[(1,1-diethyl-1-
isopropylsilyl)oxy]-11-iodo-2-methoxy-4,6,8,10-
tetramethyl-2,4,10-undecatrienoate (4)
To a stirred solution of methyl methoxy acetate (217 mg.
2.15 mmol) in THF (3 mL) at ꢁ78 ꢀC was added LiHMDS
(1 M in THF 1.3 mL, 1.29 mmol). The mixture was stirred
at ꢁ78 ꢀC for 0.5 h before a solution of the 18 (200 mg,
0.43 mmol) in THF (2 mL) was added. The mixture was
then stirred at ꢁ78 ꢀC for 2 h, after which TLC indicated no
aldehyde remained. The mixture was quenched with dilute
aqueous ammonium chloride solution and extracted with ether
(3ꢂ15 mL). The combined ether extracts were dried over
Na2SO4 and concentrated in vacuo. Column chromatography
of the residue afforded the g-hydroxy ester (223 mg, 94%).
The mixture was used for the next step.
1
EtOAc and hexane). [a]2D5 ꢁ33.61 (c 2.4, CHCl3); H NMR
(CDCl3, 300 MHz): d 1.06 (s, 9H, tert-butyl), 1.22 (d, 3H,
J¼6.8 Hz, CH3), 2.73 (dd, 1H, J¼9.8, 13.6 Hz, PhCH), 3.27
(dd, 1H, J¼3.0, 13.6 Hz, PhCH), 3.80 (m, 1H, CH), 4.13 (d,
2H, J¼5.3 Hz, CH2), 4.22 (d, 2H, J¼3.8 Hz, CH2), 4.47 (t,
1H, J¼3.8 Hz, CH), 4.62 (m, 1H, CH), 5.72 (dd, 1H, J¼5.3,
15.1 Hz, olefin), 5.85 (dt, 1H, J¼3.8, 15.8 Hz, olefin), 7.15e
7.43 (m, 11H, ArH), 7.64 (m, 4H, ArH); 13C NMR (CDCl3,
50 MHz): d 176.6, 153.0, 135.4, 134.9, 133.5, 131.1, 129.6,
129.3, 129.0, 128.7, 127.6, 127.3, 71.9, 66.1, 63.6, 55.1, 42.7,
37.7, 26.7, 19.1, 11.0; IR (neat): 3449, 2931, 2856, 1780,
1696, 1384, 1029 cmꢁ1; LCeMS: 580.2 [MþNa]þ; HRMS
(ESIMS): m/z calcd for C33H39O5SiNa [MþNa]þ 580.2495,
found 580.2498.
To solution of the g-hydroxy ester (200 mg, 0.36 mmol) in
dry CH2Cl2 (4 mL) were added MsCl (82.5 mg, 0.72 mmol)
and triethylamine (109 mg, 1.08 mmol). The mixture was
stirred at room temperature for 3 h before DBU (109 mg,
0.72 mmol) was added. The mixture was stirred for another
2 h and then quenched with aqueous ammonium chloride solu-
tion. The mixture was extracted with diethyl ether (3ꢂ15 mL).
The combined extracts were dried over Na2SO4 and concen-
trated in vacuo. Column chromatography (SiO2, 20% EtOAc
in hexane as eluent) of the residue afforded the g-hydroxy ester
4 (184 mg, 80%) as a pale yellow viscous liquid, Rf¼0.60 (3:7
4.1.16. (2S,3S,4E)-6-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-2-
methyl-4-hexene-1,3-diol
To a stirred solution of 20 (7 g, 12.56 mmol) in Et2O (50 mL)
at 0 ꢀC, LiBH4 (0.414 g, 5.5 mmol) was added in one portion.
After the addition was complete, the reaction was allowed to
stir for 1 h at 0 ꢀC. After reaction was completed, the reaction
mixture was quenched with ice-cold water and extracted with
ethyl acetate (3ꢂ30 mL). The combined organic layers was
dried over anhydrous Na2SO4 and concentrated in vacuo. Puri-
fication by column chromatography (SiO2, 70% EtOAc in hex-
ane as eluent) yielded diol (4.73 g, 98%) as colorless oil,
Rf¼0.20 (1:1 EtOAc and hexane). [a]2D5 ꢁ0.58 (c 1.6, CHCl3);
EtOAc and hexane). [a]3D0 þ21.67 (c 1.5, CHCl3); H NMR
1
(CDCl3, 300 MHz): d 0.64 (q, 4H, J¼7.6, 15.8 Hz, 2ꢂCH2),
0.76 (d, 3H, J¼6.8 Hz, CH3), 0.94e1.08 (m, 16H, 5ꢂCH3 and
CH), 1.65e1.82 (m, 2H, CH2), 1.79 (s, 3H, CH3), 1.96 (s, 3H,
CH3), 2.41 (dd, 1H, J¼3.8, 12.8 Hz, CH), 2.68 (m, 1H, CH),
3.46 (m, 1H, CH), 3.65 (s, 3H, OCH3), 3.79 (s, 3H, CO2CH3),
5.83 (s, 1H, olefin), 5.90 (d, 1H, J¼9.1 Hz, olefin), 6.51 (s,
1H, olefin); 13C NMR (CDCl3, 75 MHz): d 165.5, 146.8, 142.8,
141.7, 130.0, 129.9, 80.2, 75.3, 60.2, 51.9, 43.2, 36.5, 36.0, 23.6,

1978
J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
1H NMR (CDCl3, 200 MHz): d 0.86 (d, 3H, J¼7.3 Hz, CH3),
1.07 (s, 9H, tert-butyl) 1.92 (m, 1H, CH) 3.63 (m, 2H, CH2),
3.64 (d, 1H J¼1.5 Hz, CH), 4.18e4.33 (m, 3H, CH2 and CH),
5.79 (m, 2H, olefinic), 7.28e7.43 (m, 6H, ArH), 7.58e7.70 (m,
4H, ArH); 13C NMR (CDCl3, 75 MHz): d 135.5, 133.7, 130.7,
130.0, 129.7, 127.7, 75.3, 66.2, 63.9, 39.9, 26.8, 19.2, 11.3; IR
(neat): 3412, 3069, 2856, 1638, 1029, 701 cmꢁ1; LCeMS:
407.1 [MþNa]þ; HRMS (ESIMS): m/z calcd for C23H32O3SiNa
[MþNa]þ 407.2018, found 407.2020.
with stirring and the resulting mixture was stirred for 30 min
at ꢁ20 ꢀC, allyl alcohol (1.2 g, 6.5 mmol) in dry CH2Cl2
(5 mL) was added and the resulting mixture was stirred for
another 30 min at ꢁ20 ꢀC. TBHP (3.3 M in toluene, 6 mL,
19.4 mmol) was then added and the reaction mixture was stirred
at the same temperature for 24 h. It was then warmed to 0 ꢀC,
quenched with 2 mL of water and stirred for 1 h at room temper-
ature. Aqueous NaOH solution (30%) saturated with NaCl
(6 mL) was then added and the reaction mixture was stirred vig-
orously for another 30 min at room temperature. The resulting
mixture was washed well with CH2Cl2. The organic phase was
separated and the aqueous phase was extracted with CH2Cl2.
Combined organic layers were washed with brine and dried
over anhydrous Na2SO4. The solvent was removed under re-
duced pressure and purified by silica gel column chromato-
graphy (SiO2, 60% EtOAc in hexane as eluent) to afford
compound 22 (1.0 g, 78%) as a colorless viscous liquid,
Rf¼0.55 (1:1 EtOAc and hexane). [a]2D5 ꢁ18.45 (c 1, CHCl3);
1H NMR (CDCl3, 300 MHz): d 1.17 (d, 3H, J¼6.8 Hz, CH3),
1.36 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.60e1.71 (m, 1H, CH),
2.14e2.43 (br s, OH), 2.92 (dd, 1H, J¼2.3, 5.3 Hz, CH),
3.12e3.17 (m, 1H, CH), 3.56 (dd, 1H, J¼1.5, 11.3 Hz), 3.62
(dd, 1H, J¼4.5, 12.8 Hz, CH), 3.84e3.93 (m, 2H, CH2), 4.07
(dd, 1H, J¼3.0, 11.3 Hz, CH); 13C NMR (CDCl3, 75 MHz):
d 98.8, 70.0, 66.1, 61.1, 56.8, 55.6, 30.2, 29.3, 18.8, 11.3; IR
(neat): 3414, 1616, 1381, 1219, 1009, 772 cmꢁ1; FABMS:
203 [MþNa]þ; HRMS (ESIMS): m/z calcd for C10H18O4Na
[MþNa]þ 225.1102, found 225.1105.
4.1.17. tert-Butyl(diphenyl)((E)-3-[(4S,5S)-2,2,5-trimethyl-
1,3-dioxan-4-yl]-2-propenyloxy)silane (21)
To a solution of diol (3 g, 7.8 mmol) in dry CH2Cl2 (40 mL),
2,2-dimethoxy propane (12 mL) and PPTS (1 g) was added. The
mixture was stirred at ambient temperature for 3 h. Sodium bi-
carbonate was added to neutralize PPTS and filtered. Removal
of solvent and purification by silica gel column chromatography
(SiO2, 20% EtOAc in hexane as eluent) afforded the mono ace-
tonide 21 (3.18 g, 96%) as a colorless liquid, Rf¼0.55 (1:2
EtOAc and hexane). [a]2D5 þ13.99 (c 1, CHCl3); H NMR
1
(CDCl3, 200 MHz): d 1.05 (d, 3H, J¼7.3 Hz, CH3), 1.07 (s,
9H, tert-butyl), 1.41 (s, 3H, CH3), 1.47 (s, 3H, CH3), 3.59 (dd,
1H, J¼1.5, 11.0 Hz, CH), 4.12 (dd, 1H, J¼2.9, 11.8 Hz, CH),
4.21 (d, 2H, J¼2.2 Hz, CH2), 4.52 (t, 1H, J¼2.2 Hz, CH), 5.71
(m, 2H, olefin), 7.29e7.44 (m, 6H, ArH), 7.61e7.72 (m, 4H,
ArH); 13C NMR (CDCl3, 75 MHz): d 135.5, 133.7, 130.0,
129.6, 128.9, 127.6, 98.7, 71.9, 66.4, 63.9, 33.0, 29.7, 26.8,
19.3, 19.2, 11.1; IR (neat): 3443, 2933, 2859, 1634, 1377,
705 cmꢁ1; LCeMS: 447.1 [MþNa]þ; HRMS (ESIMS): m/z
calcd for C26H36O3SiNa [MþNa]þ 447.2331, found 447.2330.
4.1.20. (4R,5S)-4-[(2S,3S)-3-(Chloromethyl)oxiran-2-yl]-
2,2,5-trimethyl-1,3-dioxane
4.1.18. (E)-3-[(4S,5S)-2,2,5-Trimethyl-1,3-dioxan-4-yl]-2-
propen-1-ol
To a stirred solution of compound 22 (0.7 g, 3.46 mmol) in
8 mL dry CCl4 were added triphenylphosphine (1.45 g,
5.2 mmol) and NaHCO3 (0.29 g, 3.46 mmol). The resulting
mixture was vigorously refluxed for 2 h. Solids were filtered
and washed with ether. The solvent was removed under reduced
pressure and purified by silica gel column chromatography
(SiO2, 25% EtOAc in hexane as eluent) to afford chloro com-
pound (0.69 g, 90%), as a colorless viscous liquid, Rf¼0.65
(2:3 EtOAc and hexane). [a]2D5 ꢁ21.83 (c 1, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 1.21 (d, 3H, J¼6.8 Hz, CH3), 1.40 (d,
6H, J¼9.8 Hz, 2ꢂCH3), 1.61e1.73 (m, 1H, CH), 2.87 (dd,
1H, J¼1.5, 4.5 Hz, CH), 3.28 (td, 1H, J¼1.5, 6.0 Hz, CH), 3.50
e3.69 (m, 3H, CH and CH2), 3.89e3.94 (m, 1H, CH), 4.10 (dd,
1H, J¼3.02, 11.3 Hz, CH); 13C NMR (CDCl3, 75 MHz): d 98.7,
69.5, 66.0, 58.4, 55.3, 44.2, 30.1, 29.2, 18.7, 11.2; ESIMS: 243.1
[MþNa]þ; HRMS (ESIMS): m/z calcd for C10H17O3ClNa
[MþNa]þ 243.0763, found 243.0775.
To a stirred solution of 21 compound (3 g, 7.0 mmol) in THF
(15 mL) and was added TBAF (8.5 mL (1 M in THF),
8.5 mmol) at 0 ꢀC. The reaction mixture was stirred for 1 h at
room temperature and the reaction mixture was concentrated
in vacuo. The crude product was purified by column chromatog-
raphy (SiO2, 40% EtOAc in hexane as eluent) on silica gel to
give the allyl alcohol (1.25 g, 95%) as a colorless liquid,
Rf¼0.55 (1:1 EtOAc and hexane). [a]2D5 þ10.25 (c 1.1,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.05 (d, 3H, J¼
6.6 Hz, CH3), 1.41 (d, 6H, J¼10.7 Hz, 2ꢂCH3), 3.56 (d, 2H, J¼
11.6 Hz, CH2), 4.13 (d, 2H, J¼4.1 Hz, CH2), 4.07 (d, 1H,
J¼2.5 Hz, CH), 4.44e4.55 (m, 1H, CH), 5.61 (dd, 1H, J¼5.0,
15.7 Hz, olefin), 5.83 (dt, 1H, J¼5.0, 15.7 Hz, olefin); 13C
NMR (CDCl3, 75 MHz): d 130.5, 130.4, 98.7, 71.8, 66.3, 32.8,
30.8, 29.6, 19.1, 11.0; IR (neat): 3443, 2933, 2859, 1634, 1377,
705 cmꢁ1; LCeMS: 209.1 [MþNa]þ; HRMS (ESIMS): m/z
calcd for C10H18O3Na [MþNa]þ 209.1153, found 209.1145.
4.1.21. (1S)-1-[(4R,5S)-2,2,5-Trimethyl-1,3-dioxan-4-yl]-2-
propyn-1-ol (23)
4.1.19. (2R,3S)-3-[(4R,5S)-2,2,5-Trimethyl-1,3-dioxan-4-
yl]oxiran-2-ylmethanol (22)
To freshly distilled ammonia (10 mL) in 100 mL two neck
round bottom flask fitted with a cold finger condenser was added
catalytic amount of ferric nitrate followed by the piecewise ad-
dition of lithium metal (0.2 g, 30 mmol) at ꢁ33 ꢀC and the re-
sulting gray colored suspension was stirred for 30 min. To this
reaction mixture compound, chloro compound was added
˚
Dry CH2Cl2 of 10 mL was added to 4A activated molecular
sieves powder and the suspension mixture was cooled to
ꢁ20 ꢀC. D-(þ) DET (0.302 g, 1.3 mmol) in dry DCM (2 mL)
and Ti(OiPr)4 (0.4 mL, 1.3 mmol) were added subsequently

J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
1979
(0.65 g, 3.0 mmol) in dry THF (4 mL) over a period of 5 min.
The reaction mixture was then stirred for 1 h at ꢁ33 ꢀC and
quenched by the addition of solid ammonium chloride (0.4 g)
and the ammonia was then allowed to evaporate. The reaction
mixture was extracted with water (2ꢂ10 mL) and ethyl acetate
(2ꢂ10 mL). The combined organic layers were washed once
with water and brine solution and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure.
The residue was purified on column chromatography (SiO2,
45% EtOAc in hexane as eluent) to afford the pure compound
23 (445 mg, 82%) as a clear colorless liquid, Rf¼0.50 (2:3
EtOAc and hexane). [a]2D5 ꢁ3.73 (c 1, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 1.14 (d, 3H, J¼6.8 Hz, CH3), 1.42 (d, 6H,
J¼14.4 Hz, 2ꢂCH3), 1.75e1.88 (m, 1H, CH), 2.38 (d, 1H, J¼
1.9 Hz, acetylene), 3.58 (dd, 1H, J¼1.3, 11.7 Hz, CH), 3.99
(dd, 1H, J¼2.5, 7.7 Hz, CH), 4.07 (dd, 1H, J¼2.6, 11.5 Hz, CH),
4.25 (d, 1H, J¼7.5 Hz, CH); 13C NMR (CDCl3, 50 MHz):
d 99.1, 82.8, 73.8, 66.8, 62.5, 29.4, 29.1, 24.8, 18.9, 11.0; IR
(neat): 3451, 2925, 2364, 1461, 1031, 767 cmꢁ1; LCeMS:
207 [MþNa]þ; HRMS (ESIMS): m/z calcd for C10H16O3Na
[MþNa]þ 207.0997, found 207.1002.
CHCl3)}; 1H NMR (CDCl3, 300 MHz): d 0.75e0.96 (m, 15H,
3ꢂCH3 and 3ꢂCH2), 1.07 (d, 3H, J¼6.8 Hz, CH3), 1.20e1.40
(m, 12H, 2ꢂCH3 and 3ꢂCH2), 1.40e1.56 (m, 6H, 3ꢂCH2),
1.72 (m, 1H, CH), 3.25 (s, 3H, OCH3), 3.35 (dd, 1H, J¼2.3,
9.1 Hz, CH), 3.56 (d, 1H, J¼12.8 Hz, CH), 3.74 (dd, 1H, J¼
2.3, 9.1 Hz, CH), 4.04 (dd, 1H, J¼3.0, 11.3 Hz, CH), 5.74 (d,
1H, J¼6.0, 18.9 Hz, olefin), 6.14 (d, 1H, J¼18.9 Hz, olefin);
ESIMS: 513.1 [MþNa]þ; HRMS (ESIMS): m/z calcd for
C23H46O3SnNa [MþNa]þ 513.2366, found 513.2357.
4.1.24. Methyl(2Z,4E,6R,7S,8S,10E,12E,14S)-7-[(1,1-
diethyl-1-isopropylsilyl)oxy]-2,14-dimethoxy-4,6,8,10-
tetramethyl-14-[(4R,5S)-2,2,5-trimethyl-1,3-dioxan-4-yl]-
2,4,10,12-tetradecatetraenoate (2)
To a solution of 4 (0.10 g, 0.18 mmol) and 56d (0.095 g,
0.18 mmol) in dry DMF (3 mL) was added [1,10-bis(diphen-
ylphosphino)ferrocene]palladium(II)chloride
(PdCl2(dppf))
(0.03 g, 0.04 mmol). After the reaction mixture was stirred at
50 ꢀC for 15 h under nitrogen, ice-cold water (4 mL) was added,
and the resultant mixture was then extracted with ether
(3ꢂ5 mL). The extracts were washed with saturated aqueous
NaCl (5 mL), dried over anhydrous Na2SO4, and concentrated
in vacuo. Purification of the residue by flash column chromato-
graphy(SiO2, 15%EtOAcinhexaneaseluent)gave 26d (0.067 g,
60%) as a colorless viscous liquid, Rf¼0.60 (3:7 EtOAc and hex-
ane). [a]3D0 þ32.12 (c 0.5, CHCl3); 1H NMR (CDCl3, 200 MHz):
d 0.65 (q, 4H, J¼7.3, 15.3 Hz, 2ꢂCH2), 0.78 (d, 3H, J¼5.9 Hz,
CH3), 0.82e1.14 (m, 14H, 4ꢂCH3 and 2ꢂCH), 1.16e1.49 (m,
6H, 2ꢂCH2 and 2ꢂCH), 1.33 (s, 3H, CH3), 1.37 (s, 3H, CH3),
1.64e1.87 (m, 2H, 2ꢂCH), 1.74 (s, 3H, CH3), 1.98 (s, 3H,
CH3), 2.28 (d, 1H, J¼8.1 Hz, CH), 2.71 (m, 1H, CH), 3.25 (s,
3H, OCH3), 3.32e3.37 (m, 3H, 3ꢂCH), 3.65 (s, 3H, OCH3),
3.75 (dd, 1H, J¼2.2, 8.1 Hz, CH), 3.79 (s, 3H, CO2CH3), 4.06
(dd, 1H, J¼2.2, 11.0 Hz, CH), 5.33 (dd, 1H, J¼7.3, 14.7 Hz,
CH), 5.81 (d, 1H, J¼11.0 Hz, olefin), 5.97 (d, 1H, J¼9.5 Hz,
olefin), 6.37 (dd, 1H, J¼11.0, 15.3 Hz, olefin), 6.52 (s, 1H, ole-
fin); 13C NMR (CDCl3, 200 MHz): d 165.6, 142.5, 142.4, 137.8,
130.3, 129.6, 128.7, 125.9, 116.1, 98.7, 80.8, 80.3, 73.9, 67.0,
60.3, 56.2, 52.0, 43.9, 36.9, 35.5, 29.7, 29.5, 29.4, 18.9, 18.8,
17.6, 16.5, 15.5, 14.7, 13.4, 11.1, 7.4, 7.3, 4.5, 4.4; IR (neat):
3435, 2927, 1720, 1456, 1381, 1250, 1199, 1104, 1018,
716 cmꢁ1; LCeMS: 645.3 [MþNa]þ and 681.1 [MþK]þ;
HRMS (ESIMS): m/z calcd for C35H62O7SiNa [MþNa]þ
645.4162, found 645.4147.
4.1.22. (4R,5S)-4-[(1S)-1-Methoxy-2-propynyl]-2,2,5-
trimethyl-1,3-dioxane (24)
To a stirred suspension of freshly activated sodium hydride
(187 mg, 8.15 mmol) in dry THF (3 mL) at 0 ꢀC, alcohol 23
(0.5 g, 2.7 mmol) in dry THF (3 mL) was added dropwise. After
stirring for 30 min, MeI (0.25 mL, 4.0 mmol) was added. After
completion of the reaction (1 h), the reaction mixture was
quenched with saturated aqueous NH4Cl solution and extracted
with EtOAc. The organic layer was washed with water and brine
solution, dried over anhydrous Na2SO4, and concentrated in va-
cuo, purification by silica gel column chromatography (SiO2,
30% EtOAc in hexane as eluent) afforded 24 (524 mg, 98%
yield) as colorless oil, Rf¼0.65 (2:3 EtOAc and hexane). [a]D25
1
ꢁ3.83 (c 1, CHCl3); H NMR (CDCl3, 300 MHz): d 1.04 (d,
3H, J¼6.8 Hz, CH3), 1.38 (s, 3H, CH3), 1.44 (s, 3H, CH3),
1.66e1.76 (m, 1H, CH), 2.32 (d, 1H, J¼1.9 Hz, acetylene), 3.41
(s, 3H, OCH3), 3.56 (dd, 1H, J¼1.51, 11.5 Hz, CH), 3.74 (dd,
1H, J¼1.9, 8.9 Hz, CH), 3.99 (dd, 1H, J¼2.5, 8.9 Hz, CH), 4.06
(dd, 1H, J¼2.8, 11.5 Hz, CH); 13C NMR (CDCl3, 75 MHz):
d 99.0, 81.3, 74.1, 73.2, 71.0, 66.6, 56.6, 29.5, 29.2, 18.9,
10.5; IR (neat): 3451, 2922, 2362, 1638, 1462, 1021, 771 cmꢁ1
;
LCeMS: 221 [MþNa]þ; HRMS (ESIMS): m/z calcd
for C11H18O3Na [MþNa]þ 221.1153, found 221.1156.
4.1.25. (4R)-4-[(1R,2R)-2-(Benzyloxy)-1,3-dimethylbutyl]-
2-(4-methoxyphenyl)-1,3-dioxane
4.1.23. Methyl(1S,2E)-3-(1,1,1-tributylstannyl)-1-[(4R,5S)-
2,2,5-trimethyl-1,3-dioxan-4-yl]-2-propenyl ether (5)
To a solution of diol 814 (2.5 g, 9.39 mmol) in CH2Cl2 (5 mL)
at ambient temperaturewere added p-methoxy benzaldehyde di-
methyl acetal (6.4 mL, 0.37 mmol) and pyridinium p-toluene-
sulfonate (PPTS, 0.05 g). The reaction mixture was stirred at
ambient temperature for 1 h before it was concentrated invacuo.
The remaining organic residue was purified by flash chromato-
graphy (SiO2, 25% EtOAc in hexane as eluent) to provide the de-
sired product (3.46 g, 96%) as colorless oil, Rf¼0.55 (2:3 EtOAc
To a solution of alkyne 24 (0.5 g, 2.5 mmol) in dry CH2Cl2
(3 mL) at 0 ꢀC was added Pd(PPh3)2Cl2 (356 mg, 0.5 mmol)
and Bu3SnH (0.2 mL, 7.5 mmol) was the added dropwise and
the mixture was stirred at 0 ꢀC for 1 h, TLC indicated that all
the starting materials reacted. The mixture was concentrated
in vacuo and the residue was subjected to column chromatogra-
phy (SiO2, 5% EtOAc in hexane as eluent) to give product 56d
(0.9 g, 78%) as a colorless oil, Rf¼0.90 (1:10 EtOAc and hex-
ane). [a]2D5 þ16.5 (c 1.10, CHCl3) {lit.6d [a]2D5 þ16.4 (c 1.01,
and hexane). [a]2D5 ꢁ92.15 (c 1, CHCl3); H NMR (CDCl3,
1
300 MHz): d 0.90 (d, 3H, J¼6.8 Hz, CH3), 0.94 (d, 3H,

1980
J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
J¼6.8 Hz, CH3), 1.06 (d, 3H, J¼7.5 Hz, CH3), 1.23 (dd, 1H,
J¼1.5, 12.8 Hz, CH), 1.58e1.71 (m, 1H, CH), 1.84e1.96 (m,
1H, CH), 1.97e2.15 (m, 1H, CH), 3.30e3.38 (dd, 1H, J¼2.3,
9.8 Hz, CH), 3.80 (s, 3H, OCH3) 3.87 (td, 1H, J¼2.23,
12.1 Hz, CH), 4.13e4.26 (m, 2H, CH2), 4.57 (ABq, 2H, J¼
11.3, 24.9 Hz, benzylic CH2), 5.29 (s, 1H, CH), 6.84 (d, 2H,
J¼9.1 Hz, ArH), 7.19e7.39 (m, 7H, ArH); 13C NMR (CDCl3,
75 MHz): d 159.8, 139.2, 131.8, 128.3, 127.5, 127.3, 127.4,
113.5, 100.8, 84.2, 75.9, 75.4, 67.3, 55.2, 40.8, 29.9, 28.5, 21.1,
CH3), 0.93 (d, 3H, J¼3.8 Hz, CH3), 1.04 (d, 3H, J¼7.5 Hz,
CH3), 1.62e1.75 (m, 1H, CH), 1.85e1.98 (m, 1H, CH), 2.55
(ddd, 1H, J¼2.3, 6.0, 16.6 Hz, CH), 2.78 (ddd, 1H, J¼2.3, 6.8,
16.6 Hz, CH), 3.27 (dd, 1H, J¼3.0, 9.1 Hz, CH), 3.77 (s, 3H,
OCH3), 4.23e4.62 (m, 5H, 2ꢂbenzylic CH2 and CH), 6.79 (d,
2H, J¼8.3 Hz, ArH), 7.14 (d, 2H, J¼8.3 Hz, ArH), 7.19e7.34
(m, 5H, ArH), 9.76 (t, 1H, J¼2.3 Hz, CHO); IR (neat): 2953,
2856, 1683, 1352, 772 cmꢁ1; HRMS (ESIMS): m/z calcd for
C24H32O4Na [MþNa]þ 407.2198, found 407.2004.
14.9, 10.6; IR (KBr): 3854, 3415, 1618, 1219, 772 cmꢁ1
;
ESIMS: 407 [MþNa]þ; HRMS (ESIMS): m/z calcd for
4.1.28. (5R,6R,7R)-7-(Benzyloxy)-5-[(4-methoxy-
benzyl)oxy]-6,8-dimethylnonan-3-ol (27)
C24H32O4Na [MþNa]þ 407.2198, found 407.2202.
Freshly prepared EtMgBr (prepared in situ from 390 mg
(15.62 mmol) of Mg and 1.42 g (15.62 mmol) of ethyl bromide
in 10 mL of dry THF) was added dropwise to a stirred solution of
aldehyde 26 (2 g, 5.2 mmol) in dry THF (10 mL) at 0 ꢀC. After
addition was completed, the reaction mixturewas allowed to stir
at room temperature for 2 h and then quenched with saturated
aqueous NH4Cl solution. The organic layer was separated and
the compound from aqueous layer was extracted with ethyl ac-
etate (2ꢂ20 mL). The combined organic layers were washed
with water and brine solution and dried over Na2SO4. Concen-
tration under reduced pressure and purification by column chro-
matography (SiO2, 15% EtOAc in hexane as eluent) afforded 27
(1.93 g, 90%) as a colorless viscous liquid, Rf¼0.60 (3:7 EtOAc
4.1.26. (3R,4R,5R)-5-(Benzyloxy)-3-[(4-methoxy-
benzyl)oxy]-4,6-dimethylheptan-1-ol (25)
To a solution of acetonide (4.0 g, 10.41 mmol) in dry CH2Cl2
(50 ml) at 0 ꢀC, a solution of DIBAL-H (9 mL, 1.4 M in toluene,
12.5 mmol) was added dropwise. After the addition was com-
plete, the reaction mixture was stirred at 0 ꢀC for 1 h. The reac-
tion mixture was slowly allowed to warm to room temperature,
stirred for 2 h for completion of the reaction, and was quenched
by the addition of MeOH (1 mL), followed by saturated aqueous
sodium potassium tartarate solution at 0 ꢀC and stirred for 0.5 h.
The aqueous layer was extracted with CH2Cl2 and washed with
brine, and dried over anhydrous Na2SO4 and concentrated inva-
cuo. The crude mixture on column chromatography (SiO2, 40%
EtOAc in hexane as eluent) afforded 25 (3.47 g, 85%) as color-
less liquid, Rf¼0.45 (1:1 EtOAc and hexane). [a]2D5 ꢁ31.39 (c 1,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 0.90 (d, 3H, J¼6.8 Hz,
CH3), 0.92 (d, 3H, J¼6.8 Hz, CH3), 1.04 (d, 3H, J¼6.8 Hz,
CH3), 1.43 (br s, OH) 1.58e1.81 (m, 2H, 2ꢂCH), 1.83e2.01 (m,
2H, 2ꢂCH), 3.23 (dd, 1H, J¼3.0, 8.3 Hz, CH), 3.55e3.67 (m,
2H, CH2), 3.72 (s, 3H, OCH3), 3.84 (td, 1H, J¼6.8, 1.5 Hz,
CH), 4.37 (dd, 1H, J¼6.8, 11.3 Hz, CH), 4.49 (ABq, 2H,
J¼10.8, 19.2 Hz, benzylic CH2), 4.52 (ABq, 2H, J¼11.3,
18.1 Hz, benzylic CH2), 6.79 (d, 2H, J¼8.3 Hz, ArH), 7.17 (d,
2H, J¼8.3 Hz, ArH), 7.20e7.33 (m, 5H, ArH); 13C NMR
(CDCl3, 75 MHz): d 159.4, 137.2, 128.6, 128.3, 128.0, 113.6,
88.6, 75.2, 72.6, 72.1, 58.6, 55.4, 42.8, 33.9, 27.6, 17.4, 9.7;
IR (KBr): 3414, 1617, 1353, 772 cmꢁ1; FABMS: 387
[MþH]þ; HRMS (ESIMS): m/z calcd for C24H34O4Na
[MþNa]þ 409.2722, found 409.2717.
1
and hexane). [a]2D5 ꢁ29.18 (c 1, CHCl3); H NMR (CDCl3,
300 MHz): d 0.83e0.98 (m, 9H, 3ꢂCH3), 0.99e1.08 (t, 3H, J¼
6.8 Hz, CH3), 1.33e1.63 (m, 2H, CH2), 1.68e2.02 (m, 2H,
CH2), 2.57 (br s, OH), 3.13e3.28 (m, 1H, CH), 3.47e3.69 (m,
1H, CH), 3.76 (s, 3H, OCH3), 3.82e3.94 (m, 1H, CH), 4.33e
4.60 (m, 5H, 2ꢂbenzylic CH2 and CH), 6.75e6.83 (m,
2H, ArH), 7.16 (d, 2H, J¼8.3 Hz, ArH), 7.12e7.34 (m, 5H,
ArH); IR (KBr): 3414, 1617, 1353, 772 cmꢁ1; FABMS: 415
[MþH]þ; HRMS (ESIMS): m/z calcd for C26H38O4Na
[MþNa]þ 437.2667, found 437.2680.
4.1.29. (3R,4R,5R)-5-(Benzyloxy)-1-ethyl-3-[(4-methoxy-
benzyl)oxy]-4,6-dimethylheptyl acetate (28)
To a solution of 27 (1.5 g, 3.62 mmol), CH2Cl2 (8 mL), Et3N
(1.52 mL, 10.86 mmol) were added DMAP (0.5 equiv) and ace-
tic anhydride (0.4 mL, 4.3 mmol) at 0 ꢀC. After the reaction
mixture was stirred at room temperature for 3 h, the reaction
mixturewas quenched with ice-cold water and the resultant mix-
ture was then extracted with CH2Cl2. The extracts were washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
(SiO2, 10% EtOAc in hexane as eluent) to afford 28 (1.55 g,
94%) as colorless oil, Rf¼0.68 (1:4 EtOAc and hexane). [a]D25
ꢁ40.62 (c 1, CHCl3); 1H NMR (CDCl3, 300 MHz): d 0.85 (d,
3H, J¼6.8 Hz, CH3), 0.86e0.94 (m, 6H, 2ꢂCH3), 1.04 (d, 3H,
J¼6.8 Hz, CH3), 1.05 (d, 3H, J¼6.8 Hz, CH3), 1.54e1.69 (m,
3H, 2ꢂCH2 and CH), 1.79 (s, 1/3ꢂCH3), 1.89 (s, 2/3ꢂCH3),
1.75e2.09 (m, 2H, CH2), 3.24 (m, 1H, CH), 3.69e3.85 (m,
1H, CH), 3.78 (s, 3H, OCH3), 4.17e4.60 (m, 4H, 2ꢂbenzylic
CH2), 4.80 (m, 1/3H, CH), 4.93 (m, 2/3H, CH), 6.80 (d, 2H,
J¼8.3 Hz, ArH), 7.18e7.33 (m, 7H, ArH); IR (neat): 3450,
2964, 1734, 1243, 1067, 761 cmꢁ1; LCeMS: 479.2 [MþNa]þ;
4.1.27. (3R,4R,5R)-5-(Benzyloxy)-3-[(4-methoxy-
benzyl)oxy]-4,6-dimethylheptanal (26)
To a stirred solution of IBX (5.36 g, 19.17 mmol) in 10 mL
dry DMSO was added diol 25 (3.7 g, 9.58 mmol) in 15 mL
dry CH2Cl2 at 0 ꢀC. After completion of addition, the reaction
mixture kept at room temperature for 3 h. After completion of
reaction by TLC indication, the reaction mixture was filtered
on a Celite using diethyl ether. The filtrate was washed with wa-
ter and brine and dried over anhydrous Na2SO4. The ether layer
was concentrated under reduced pressure and the crude product
was subjected to column chromatography (SiO2, 18% EtOAc in
hexaneas eluent) togivepure aldehyde 26(3.05 g, 83%) as avis-
cous liquid, Rf¼0.70 (3:7 EtOAc and hexane). [a]2D5 ꢁ47.34 (c 1,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 0.91 (d, 3H, J¼3.8 Hz,

J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
1981
HRMS (ESIMS): m/z calcd for C28H40O5Na [MþNa]þ:
d 0.76 (d, 3H J¼6.8 Hz, CH3), 0.86 (d, 3H, J¼6.8 Hz, CH3),
0.95 (t, 3H, J¼7.6 Hz, CH3), 1.00 (d, 3H, J¼6.8 Hz, CH3),
1.03 (s, 18H, 2ꢂtert-butyl), 1.55e1.36 (m, 3H, CH2 and CH),
1.56e1.80 (m, 2H, CH2), 2.15 (m, 1H, CH), 3.71 (dd, 1H, J¼
2.3, 9.1 Hz, CH), 3.73e3.81 (m, 1H, CH), 3.93 (br s, OH), 4.29
(ddd, 1H, J¼1.5, 5.3 Hz, CH); 13C NMR (CDCl3, 75 MHz): d
76.4, 73.6, 69.9, 38.9, 36.7, 30.5, 30.2, 27.5, 27.3, 21.6, 20.8,
20.1, 13.6, 13.1, 10.3; IR (KBr): 3471, 2965, 2364, 1463,
1041 cmꢁ1; LCeMS: 367.2 [MþNa]þ; HRMS (ESIMS): m/z
calcd for C19H40O3SiNa [MþNa]þ 367.2644, found 367.2643.
479.2773, found: 479.2771.
4.1.30. (3R,4S,5R)-1-Ethyl-3,5-dihydroxy-4,6-dimethyl-
heptyl acetate (29)
To a solution of compound 28 (1.2 g, 2.63 mmol) in dry
EtOAc (10 mL) was added catalytic amount of Pd/C (10%)
and the reaction mixture was stirred at room temperature under
hydrogen atmosphere for 2 h. The reaction mixture was filtered
off, washed with ethyl acetate, the filtrate was concentrated un-
der reduced pressure, and purified by silica gel column chroma-
tography (SiO2, 40% EtOAc in hexane as eluent) to afford
compound 29 (0.588 g, 90%) as a colorless liquid, Rf¼0.58
(1:1 EtOAc and hexane). [a]2D5 þ10.13 (c 1, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 0.82e1.02 (m, 12H, 4ꢂCH3), 1.35e
1.89 (m, 5H, 2ꢂCH2 and CH), 2.03 (s, 1/3ꢂCH3), 2.05 (s,
2/3ꢂCH3), 2.56 (m, 1/2H, OH), 2.96 (m, 1H, CH), 3.27 (q,
1H, J¼6.8, 11.3 Hz, CH), 3.41 (br s, 1/2H, OH), 3.77 (dd, 1/
2H, J¼1.5, 11.3 Hz, CH), 3.99 (m, 1/2H, CH), 4.79e5.00 (m,
1H, CH); IR (neat): 3427, 2966, 1377, 1022, 609 cmꢁ1; ESIMS:
269.1 [MþNa]þ; HRMS (ESIMS): m/z calcd for C13H26O4Na
[MþNa]þ 269.1728, found 269.1718.
4.1.33. 1-[(4R,5R,6R)-2,2-Di(tert-butyl)-6-isopropyl-5-
methyl-1,3,2-dioxasilinan-4-yl]-2-butanone (3)
To a solution of alcohol 31 (0.35 g, 1.08 mmol) in CH2Cl2
(5 mL) were added dry pyridine (0.620 mL, 5.08 mmol) and
DesseMartin periodinane (0.863 g, 2.03 mmol) at 0 ꢀC. After
stirring for 2 h at 25 ꢀC, the reaction mixture was quenched
with saturated aqueous Na2SO3 (10 mL) and the resultant mix-
turewas then extracted with Et2O (10 mLꢂ3). The extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography (SiO2, 10% EtOAc in hexane as eluent) to afford 36d
(306 mg, 88%) as a white solid, Rf¼0.80 (3:7 EtOAc and hex-
ane). Mp: 40e41 ꢀC {lit.6d mp: 40.0e40.5 ꢀC}; [a]2D5 þ84.8
4.1.31. 1-[(4R,5R,6R)-2,2-Di(tert-butyl)-6-isopropyl-5-
methyl-1,3,2-dioxasilinan-4-yl]methylpropyl acetate (30)
To a solution of 29 (450 mg, 1.83 mmol) in dry DMF (3 mL)
was added dropwise 2,6-lutidine (0.62 mL, 5.5 mmol, 98%) fol-
lowed by t-Bu2Si(OTf)2 (0.4 mL, 2.2 mmol, 97%) at 0 ꢀC. After
stirred at 25 ꢀC for 2 h, the reaction mixture was quenched with
saturated aqueous NaHCO3 (10 mL) at 0 ꢀC. The resultant mix-
turewas then extracted with Et2O (3ꢂ10 mL). The extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography (SiO2, 6% EtOAc in hexane as eluent) to afford 30
(0.6 g, 85%) as colorless oil, Rf¼0.62 (1:9 EtOAc and hexane).
[a]2D5 þ47.64 (c 1, CHCl3); 1H NMR (CDCl3, 400 MHz): d 0.72
(t, 3H, J¼7.8 Hz, CH3), 0.85 (d, 3H, J¼4.7 Hz, CH3), 0.92 (td,
3H, J¼3.12, 7.8 Hz, CH3), 1.01 (s, 18H, 2ꢂtert-butyl), 1.04 (d,
3H, J¼7.8 Hz, CH3), 1.46e1.93 (m, 5H, 2ꢂCH2 and CH), 2.03
(s, 3H, OCOCH3), 2.17 (m, 1H, CH), 3.67 (dd, 1H, J¼1.6,
9.4 Hz, CH), 4.02 (m, 1H, CH), 5.14 (m, 1H); IR (KBr): 3447,
2969, 2931, 2364, 1741, 1022 cmꢁ1; LCeMS: 409.3 [MþNa]þ;
HRMS (ESIMS): m/z calcd for C21H42O4SiNa [MþNa]þ
409.2750, found 409.2739.
1
(c 0.9, CHCl3) {lit.6d [a]D25 þ85.2 (c 0.89, CHCl3)}; H NMR
(CDCl3, 300 MHz): d 0.72 (d, 3H, J¼6.8 Hz, CH3), 0.86 (d,
3H, J¼6.8 Hz, CH3), 0.97 (s, 9H, tert-butyl), 0.99 (s, 9H, tert-
butyl), 1.00 (d, 3H, J¼6.8 Hz, CH3), 1.06 (t, 3H, J¼7.6 Hz,
CH3), 1.72 (dseptet, 1H, J¼6.8, 2.3 Hz, CH), 2.22 (m, 1H, CH),
2.35 (dd, 1H, J¼14.3, 3.1 Hz, CH), 2.51 (dq, 1H, J¼10.6,
7.5 Hz, CH2), 2.54 (dq, 1H J¼10.6, 7.5 Hz, CH2), 2.69 (dd,
1H, J¼14.3, 10.5 Hz, CH), 3.66 (dd, 1H, J¼9.8, 2.2 Hz, CH),
4.60 (ddd, 1H, J¼9.8, 6.0, 3.7 Hz, CH); 13C NMR (CDCl3,
75 MHz): d 210.3, 76.5, 73.7, 45.4, 38.7, 36.1, 30.3, 27.4,
27.2, 21.6, 20.8, 20.0, 13.7, 13.1, 7.6; IR (neat): 2965, 2859,
1717, 1469, 1038, 825 cmꢁ1; LCeMS: 343.1 [MþH]þ; HRMS
(ESIMS): m/z calcd for C19H38O3SiNa [MþNa]þ 365.2487,
found 365.2485.
Acknowledgements
KBR thanks UGC New Delhi for the financial support.
References and notes
4.1.32. 1-[(4R,5R,6R)-2,2-Di(tert-butyl)-6-isopropyl-5-
methyl-1,3,2-dioxasilinan-4-yl]-2-butanol (31)
1. (a) Werner, G.; Hagenmaier, H.; Drautz, H.; Baumgartner, A.; Zahner, H.
J. Antibiot. 1984, 37, 110e117; (b) Werner, G.; Hagenmaier, H.; Albert,
K.; Kohlshorn, H.; Drautz, H. Tetrahedron Lett. 1983, 24, 5193e5196.
2. Bowman, E. J.; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci. U.S.A.
1988, 85, 7972e7976.
3. (a) Suundquist, K. T.; Marks, S. C. J. Bone Miner. Res. 1994, 9, 1575e
1582; (b) Woo, J.-T.; Ohba, Y.; Tagami, K.; Sumitani, K.; Yamaguchi,
K.; Tsuji, T. Biol. Pharm. Bull. 1996, 19, 297e302.
To a solution of 30 (500 mg, 1.3 mmol) in dry MeOH (5 mL)
was added 5 M NaOMe/MeOH (0.8 mL, 3.9 mmol) at 0 ꢀC. Af-
ter the reaction mixture was stirred at 25 ꢀC for 2 h, the reaction
mixture was quenched with ion-exchange resin IR-120B. The
resultant mixture was filtered and the resin was washed with
MeOH. The combined filtrate and washings were concentrated
in vacuo. Purification of the residue by column chromatography
(SiO2, 12% EtOAc in hexane as eluent) gave 31 (0.4 g, 90%)
as a colorless viscous liquid, Rf¼0.55 (1:4 EtOAc and hex-
ane). [a]2D5 þ49.84 (c 1, CHCl3); 1H NMR (CDCl3, 400 MHz):
4. (a) Meyer, M.; Keller-Schierlein, W.; Drautz, H.; Blank, W.; Zahner, H.
Helv. Chim. Acta 1985, 68, 83e94; (b) Baker, G. H.; Brown, P. J.; Dorgan,
R. J. J.; Everett, J. R.; Ley, S. V.; Slawin, A. M. Z.; William, D. J. Tetra-
hedron Lett. 1987, 28, 5565e5568; (c) Deeg, M.; Hagenmaier, H.;
Kretschmer, A. J. Antibiot. 1987, 40, 320e328; (d) Baker, G. H.; Brown,

1982
J.S. Yadav et al. / Tetrahedron 64 (2008) 1971e1982
P. J.; Dorgan, R. J. J.; Everett, J. R. J. Chem. Soc., Perkin Trans. 2 1989,
1073e1079.
M. M.; Sabitha, G.; Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett.
2001, 42, 4713e4716; (c) Yadav, J. S.; Abraham, S.; Reddy, M. M.;
Sabitha, G.; Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett. 2002, 43,
3453; (d) Yadav, J. S.; Srinivas, R.; Sathaiah, K. Tetrahedron Lett.
2006, 47, 1603e1606.
5. (a) Siebers, A.; Altendorf, K. J. Biol. Chem. 1989, 264, 5831e5838; (b)
Droese, S.; Bindseil, K. U.; Bowman, E. J.; Siebers, A.; Zeeck, A.; Alten-
dorf, K. Biochemistry 1993, 32, 3902e3906.
6. (a) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871e6874;
(b) Toshima, K.; Jyojima, T.; Yamaguchi, H.; Murase, H.; Yoshida, T.;
Matsumura, S.; Nakata, M. Tetrahedron Lett. 1996, 37, 1069e1072; (c)
Toshima, K.; Yamaguchi, H.; Jyojima, T.; Noguchi, Y.; Nakata, M.;
Matsumura, S. Tetrahedron Lett. 1996, 37, 1073e1076; (d) Toshima,
K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida, T.; Murase, H.;
Nakada, M.; Matsumura, S. J. Org. Chem. 1997, 62, 3271e3284; (e)
Scheidt, K.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W. R.
Angew. Chem., Int. Ed. 1999, 38, 1652e1655; (f) Scheidt, K.; Bannister,
T. D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G. J.; Roush, W. R.
J. Am. Chem. Soc. 2002, 124, 6981e6990; (g) Hanessian, S.; Ma, J.;
Wang, W. J. Am. Chem. Soc. 2001, 123, 10200e10206.
9. (a) Toshima, K.; Tatsuta, K.; Kinoshiat, M. Tetrahedron Lett. 1986, 27,
4741e4744; (b) Toshima, K.; Mukaiyama, S.; Kinoshita, M.; Tatsuta,
K. Tetrahedron Lett. 1989, 30, 6413e6416; (c) Toshima, K.; Misawa,
M.; Ohta, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett. 1989, 30,
6417e6420; (d) Toshima, K.; Yanagawa, K.; Mukaiyama, S.; Tatsuta,
K. Tetrahedron Lett. 1990, 31, 6697e6698; (e) Toshima, K.; Nozaki,
Y.; Mukaiyama, S.; Tamai, T.; Nakata, M.; Tatsuta, K.; Kinoshita, M.
J. Am. Chem. Soc. 1995, 117, 3717e3727.
10. Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252e2254.
11. Roush, W. R.; Straub, J. A.; VanNieuwenhze, M. S. J. Org. Chem. 1991,
56, 1636e1648.
12. Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990, 46,
7033e7046.
7. (a) Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33, 3587e
3590; (b) Roush, W. R.; Bannister, T. D.; Wendt, M. D. Tetrahedron
Lett. 1993, 34, 8387e8390; (c) Paterson, I.; Bower, S.; McLeod, M. D.
Tetrahedron Lett. 1995, 36, 175e178; (d) Hanessian, S.; Wang, W.;
Gai, Y.; Olivier, E. J. Am. Chem. Soc. 1997, 119, 10034e10041; (e) Breit,
B.; Zahn, S. K. Tetrahedron Lett. 1998, 39, 1901e1904; (f) Marshall,
J. A.; Adams, N. D. Org. Lett. 2000, 2, 2897e2900.
13. Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857e
1867.
14. Yadav, J. S.; Reddy, K. B.; Sabitha, G. Tetrahedron Lett. 2004, 45, 6475e
6476.
15. Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871e4874.
16. Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813e817.
17. Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu,
K. S. J. Am. Chem. Soc. 1984, 106, 158e163.
8. (a) Yadav, J. S.; Rao, C. S.; Chandrashekar, S.; Ramarao, A. V. Tetra-
hedron Lett. 1995, 36, 7717e7720; (b) Yadav, J. S.; Abraham, S.; Reddy,