Asymmetric synthesis of (-)-tetrahydrolipstatin

Article abstract of DOI:10.1016/j.tet.2009.09.062

Attempts toward the asymmetric synthesis of (-)-tetrahydrolipstatin are described. A palladium catalyzed Wacker-type reaction to convert an alkene to a ketone, highly diastereoselective reduction of a β-hydroxy ketone, selective oxidation of a diol, and modular synthesis are the key features of the successful approach.

Full text of DOI:10.1016/j.tet.2009.09.062

Tetrahedron 65 (2009) 10083–10092
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of (ꢀ)-tetrahydrolipstatin
*
Sadagopan Raghavan , Kailash Rathore
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempts toward the asymmetric synthesis of (ꢀ)-tetrahydrolipstatin are described. A palladium catalyzed
Received 6 August 2009
Received in revised form
16 September 2009
Accepted 16 September 2009
Available online 18 September 2009
Wacker-type reaction to convert an alkene to a ketone, highly diastereoselective reduction of a b-hydroxy
ketone, selective oxidation of a diol, and modular synthesis are the key features of the successful approach.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Sulfoxide
Palladium
Tetrahydrolipstatin
Frater–Seebach alkylation
1. Introduction
derived from 5-substituted-3,5-dihydroxy-2-hexylpentanoic acid
having S,S,S absolute configuration. In view of the interesting
Tetrahydrolipstatin (THL) 1, a
b
-lactone antibiotic of microbial
structure and important biological activity in vivo, a number of
groups have reported the total synthesis of THL by a variety of
synthetic strategies.3
origin,1 functions as a potent and irreversible inhibitor of pancreatic
lipase. It is currently marketed as an anti-obesity drug under the
trade name of Xenical.Ò The biological activity is due to the trans
We report herein in full,4 our efforts toward the total synthesis of
1. The disconnective analysis shown in Scheme 1 is based on uti-
lizing the sulfinyl group in 5 as an intramolecular nucleophile to
prepare bromohydrin 4. Epoxide formation, hydroxyl directed
opening of epoxide followed by Pummerer and ene reactions would
substituted b-lactone, which reacts with serine hydroxy group to
form an ester bond in the active site of pancreatic lipase, thereby
slowing down the hydrolysis of triglycerides and absorption of
dietary fat by the small intestine.2 THL possesses a
b-lactone moiety
H
N
Me
Me
OP OH
O
OP OP
OHC
Me
Me
S
O
O
p-Tol
OP
O
O
O
10
Me
Me
Me
5
3
4
10
1
2
6
O
S
OH Br
O
S
OH
p-Tol
OP
p-Tol
OP
OH
4
5
P = Protecting group
Scheme 1.
yield triol derivative 3. The primary hydroxyl group in 3 can be
oxidized to the carboxylic acid and subsequent transformations
following previously established protocol would afford THL.3 Our
strategy differs from earlier approaches in that the sulfoxide
* Corresponding author.
E-mail address: sraghavan@iict.res.in (S. Raghavan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.062

10084
S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
chirality was to be utilized to introduce the allylic stereogenic center
and this in turn another stereocenter by asymmetric induction.
treatment of 10 with excess of 2,2-dimethoxypropane in the
presence of catalytic amounts of CSA afforded acetonide 11.14
Subjecting acetonide 11 to Pummerer reaction in the presence of
trifluoroacetic anhydride cleanly afforded the Pummerer in-
termediate 12, which without isolation was allowed to react with
an excess of 1-decene in the presence of stoichiometric amount of
anhydrous SnCl4.15 A complex mixture of products resulted from
which the desired product 13 could be isolated in poor yields only,
Scheme 3.
Since we had encountered difficulties in the reduction of epoxy
alcohol 9 and Pummerer followed by ene reaction on 11, we chose
to explore an alternate strategy wherein the decyl side chain would
be introduced at the initial stages of the synthesis. According to the
retrosynthetic plan depicted in Scheme 4, we decided to introduce
the decyl chain by alkylation of the dianion derived from 16 and
subject the resulting product 15 to further transformations.
Methyl phenyl sulfoxide5 was chosen instead of methyl p-tolyl
sulfoxide to avoid the potential deprotonation of the aromatic
methyl group by the second equivalent of the base, instead of the
methylene protons directly bonded to sulfur,16 after the first
equivalent of the base has abstracted the hydroxyl proton. In ad-
dition, 4-methoxy benzyl was chosen in lieu of the benzyl group
(compare with 5) to differentiate the secondary hydroxy groups in
2. Results and discussion
The synthesis began with the reaction of the organolithium
reagent derived from (R)-methyl p-tolyl sulfoxide5 6 with un-
saturated ester6 7 to furnish -keto sulfoxide 8.7 Diastereoselective
b
reduction of 8 following Solladie’s protocol8 using DIBAL-H in the
presence of anhydrous zinc chloride yielded the allylic alcohol 5
(P¼OBn, dr >95:<5). Treatment of 5 with freshly recrystallized N-
bromosuccinimide9 (NBS) afforded bromohydrin 4 (P¼OBn) as
a single isomer regio- and stereoselectively. We envisioned the
transformation of the 1,2-diol 4 to the 1,3-diol derivative 10, by
epoxide formation followed by hydroxyl directed reduction of the
epoxide using Red-Al.10 Thus treatment of 4 with anhydrous po-
tassium carbonate in dry acetonitrile yielded epoxide 9. The re-
duction of 9 using Red-Al in anhydrous THF was complicated due to
the competitive reduction of the sulfinyl moiety. The reduction was
non-chemoselective when attempted in a variety of solvents and at
different temperatures. While exploring other reducing agents, it
was observed that titanocene(III) chloride11 afforded the 1,3-diol 10
cleanly though the isolated yield was poor, Scheme 2.12,13
O
O
O
R1 R2
+
S
LDA, THF
60%
S
p -Tol
Me
EtO
OBn
p -Tol
OBn
6
7
8, R1, R2 = O
5, R1 = H, R2 = OH
DIBAL-H, ZnCl2,
THF, 73%
NBS, H2O,
Toluene, 81%
O
S
O
OH Br
OH
K2CO3, CH3CN,
80%
S
p-Tol
OBn
p-Tol
OBn
O
OH
4
9
Cp2TiCl2, Zn,
ZnCl2, THF, 41%
Red-Al
See text
O
S
OH OH
Mixture of Products
p-Tol
OBn
10
Scheme 2.
OMe
OMe
O
OH OH
O
S
O
O
S
p-Tol
OBn
p-Tol
OBn
O
Cat. CSA, CH2Cl2
89%
10
11
O
S
TFAA, CH2Cl2,
then
O
O
p-Tol
OBn
S
13
p-Tol
CF3(O)CO
OBn
7
12
SnCl4, 17%
6
Scheme 3.
Proceeding ahead, setting aside the issue of improving the yield
in the titanocene mediated reduction to be addressed later, the diol
10 was protected as its acetonide to attempt the one-pot Pummerer
followed by ene reaction to introduce the n-decyl side chain. Thus
14 by intramolecular acetal formation. The b-hydroxy sulfoxide 20,
prepared in a fashion analogous to 5, was subjected to treatment
with excess of LDA (3.5 equiv) and subsequently with 1-decyl io-
dide. A mixture of products was isolated in addition to recovered

S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
10085
O
S
OH OH
O
S
OH
THL, 1
Ph
Ph
O
OPMB
Ph
OPMB
14
15
9
9
O
OH
S
OPMB
16
Scheme 4.
O
O
S
R1 R2
LDA, THF
60%
+
S
Ph
Me
EtO
OPMB
Ph
OPMB
17
18
1
2
19
, R , R = O
DIBAL-H, ZnCl2,
THF, 66%
20, R1 = H, R2 = OH
LDA, n-C10H22I,
O
S
O
O
S
THF
9
+
See Text
Ph
OPMB Ph
OPMB
21
22
Scheme 5.
unreacted starting material. The crude 1H NMR spectrum indicated
the presence of O-allylated product 21 and the diene sulfoxide 22
along with unreacted starting material, Scheme 5. The result was
not better using methyl lithium,17 other bases (LiHMDS), varying
the temperature, and in the presence of additives (HMPA, TMEDA).
Having been unsuccessful in introducing the side chain, we were
forced to explore an alternate route to tetrahydrolipstatin. At this
juncture, we chose to exploit the Wacker-type reaction18 to prepare
of 24 using sodium borohydride in the presence of dieth-
ylmethoxyborane afforded 1,3-diol 25 (>95:<5 dr). Treatment of 25
with DDQ21 in anhydrous dichloromethane yielded the 4-methoxy
benzylidene acetal 26. The hydroxy group in 26 was protected as its
Mom-ether 27 by treatment with Mom-Cl in the presence of Hunig’s
base. Attempted one-pot Pummerer ene reaction afforded once
again a complex mixture of products, Scheme 7.
The diol 25 was converted to diacetate 28 and subjected to the
Pummerer ene reaction to yield a complex mixture of products. We
have earlier successfully executed15a,22 the Pummerer ene reaction
on 1,2-acetonides to prepare key intermediates en route to the
synthesis of target molecules. We believe the reason for our failure is
due to the competitive activation of the oxygens in 1,3-acetonide 11,
the acetal 27, and the 4-methoxy benzyl group in 28 leading to many
side reactions. Thus again we were unable to introduce the decyl
b
-hydroxy ketones from allylic alcohols in a key step of THL syn-
thesis. As illustrated in the retrosynthetic design, Scheme 6, we
planned hydroxyl directed reduction of the keto group and in-
troduction of the decyl side chain by Pummerer ene reaction.
The b-hydroxy sulfoxide 20 was subjected to palladium cata-
lyzed oxidative functionalization using a protocol recently reported
by us19 to furnish
b
-hydroxy ketone 24. Stereoselective reduction20
PMP
H
OP
O
O
O
S
OH
O
S
Ph
20
THL, 1
Ph
OPMB
23
24
6
Scheme 6.
O
OH
OPMB
O
OH
O
OPMB
O
S
OP OP OPMB
PdCl2, CuCl,
O2, Aq. DMF
NaBH4, Et2BOMe
S
S
Ph
Ph
Ph
70%
MeOH, THF, 73%
20
24
25, P = H,
28
Ac2O, Et3N,
Cat. DMAP,
CH2Cl2, 82%
, P = C(O)CH3
PMP
O
H
TFAA, CH2Cl2
DDQ, CH2Cl2, 61%
Complex mixture
of products
O
S
OP
O
Me
then
Ph
7
and SnCl4
Mom-Cl, iPr2NEt,
TBAI, CH2Cl2, 66%
26, P = H
27
, P = Mom
Scheme 7.

10086
S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
PMP
OH
H
O
PMP
OH
H
O
PMP
O
H
O
K2CO3,
CH3CN, 62%
O
O
S
O
TFAA, Et3N, CH2Cl2
O
PO
then aq. NaHCO3,
NaBH4, 50%
Ph
or
Ts
31
N
Ts-Cl, Et3N,
Bu2SnO
29, P = H
26
30
NaH, THF
, P = Ts
N
CH2Cl2, 75%
70% overall
yield for 3 steps
PMP
H
O
then Me (CH2)9MgBr,
cat. CuI, THF, 69%
OH
O
Me
10
32
Scheme 8.
PMP
OH
H
O
Cat. PPTS,
Aq. MeOH, 60%
PhI(OAc)2,
cat. TEMPO,
O
OBn OH OH
OBn OH
O
Me
Me
Me
CH2Cl2, 65%
10
10
10
34
35
32
, P = H
NaH, BnBr,
THF, 72%
33, P = Bn
LiHMDS, THF
then C6H13I,
HMPA, 70%
OBn OH
O
NaClO2, t-BuOH,
cyclohexene, H2O, 75%
OBn OH
O
Me
R
O
Me
10
OR
Me
36, R = H
4
2, R = Me
38, R = H
CH2N2, Et2O
90%
Aq. 1N LiOH,
THF, 70%
37, R = Me
H
N
Me
H
OHC
BOP-Cl, Et3N,
CH2Cl2, 65%
N
Me
O
O
41
OP
O
OHC
HO2C Me
Me
O
Me
Me
5
O
O
10
DCC, CH2Cl2,
72%
Me
39
40
, P = Bn
Me
5
H2, Pd(OH)2/C,
MeOH, 80%
10
1
, P = H
Scheme 9.
side chain using the sulfinyl moiety as the handle. The decyl chain
was introduced by a different strategy. -Hydroxy sulfoxide 26 was
Scheme 9. Hydrogenolysis of the benzyl ether afforded the alcohol
40, which was coupled29 to N-formyl leucine 41 using reported
conditions to furnish tetrahydrolipstatin 1. The physical data of 1
were in full agreement to those reported in the literature.3b
b
subjected to Pummerer reaction to afford an intermediate, which
without isolation was transformed to alcohol 29 in an one-pot op-
eration by treatment with saturated aq NaHCO3 followed by sodium
borohydride. The diol 29 was selectively monotosylated using p-
toluenesulfonyl chloride in the presence of Et3N and dibutyltin
oxide23 to furnish tosylate 30, which on treatment with anhydrous
potassium carbonate in acetonitrile yielded the epoxide 31. This on
treatment with an excess of decylmagnesium bromide in the
presence of catalytic quantities of CuI yielded the alcohol 32. The
alcohol 32 was more conveniently prepared in an one-pot operation
following the Forsyth protocol.24 Thus diol 29 on treatment with
tosyl imidazole using sodium hydride as the base furnished epoxide
31, which without isolation was reacted with an excess of decyl-
magnesium bromide as before to furnish 32, Scheme 8.
3. Conclusion
In summary, we have shown a chemoselective reduction of an
epoxide in the presence of a sulfinyl group using the titanocene
reagent. We were unable to introduce the decyl side chain by
a Pummerer ene reaction on a 1,3-acetonide and 4-methoxy benzyl
group containing substrates. The synthesis of tetrahydrolipstatin
was successfully accomplished taking advantage of the Wacker-
type oxidative functionalization reaction. The sulfur chirality has
been used initially to introduce the hydroxy stereogenic center and
the other centers have been introduced sequentially by substrate
control.
The alcohol 32 was protected as its benzyl ether 33 by treatment
with sodium hydride and benzyl bromide. Deprotection of the acetal
group using PPTS in methanolyielded the diol 34. Selective oxidation
of the primary hydroxy group using iodobenzene diacetate and
catalytic TEMPO25 yielded aldehyde 35. Oxidation of 35 using the
Pinnick protocol26 cleanly afforded the acid 36, which was converted
to the methyl ester 37 using ethereal diazomethane. Frater–Seebach
alkylation27 of 37 with hexyl iodide using LiHMDS as the base pro-
ceeded cleanly to afford the mono alkylated product 2 (P¼Bn). Hy-
drolysis of the ester using aq LiOH yielded the acid 38, which was
4. Experimental
4.1. General remarks
All air or moisture sensitive reactions were carried out under ni-
trogen atmosphere. Solvents were distilled over Na/benzophenone
ketyl for THF, over P2O5 followed by CaH2 for DCM, and over P2O5 for
toluene. Commercially available reagents were used without purifi-
cation except NBS, which was freshly recrystallized from hot water
converted to the b
-lactone 39 using BOP-Cl28 in the presence of Et3N,

S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
10087
before use. Thin layer chromatography was performed on precoated
silica gel plates. Column chromatography was carried out using silica
gel (60–120 mesh). NMR spectra were recorded on a 200, 300 or
400 MHz spectrometer. 1H and 13C NMR samples were internally
referenced to TMS (0.00 ppm). Melting points are uncorrected.
16.4 mmol) followed by N-bromosuccinimide (2.34 g, 13.1 mmol)
and the reaction mixture was stirred at room temperature for
15 min. The reaction was quenched by the addition of saturated
aqueous NaHCO3 solution (10 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (3ꢂ15 mL). The com-
bined organic layers were successively washed with water (20 mL),
brine (20 mL) and dried over Na2SO4. Evaporation of the solvent
afforded the crude product, which was purified by column chro-
matography using 45% EtOAc/hexane (v/v) as the eluent to afford
bromohydrin 4 (3.93 g, 8.9 mmol) as the sole product in 81% yield
as crystalline solid. Mp 112–113 ꢁC; TLC, Rf (60% EtOAc/hexane)
4.1.1. (E)-6-(Benzyloxy)-1-(Rs)-(p-tolylsulfinyl)hex-3-en-2-one [8]. To
a solution of LDA (0.08 M in solvents, 52.5 mmol) prepared from
diisopropylamine (7.7 mL, 55 mmol) and n-BuLi (1.6 M in hexane,
32.8 mL, 52.5 mmol) cooled at ꢀ40 ꢁC was added a solution of (R)-
methyl p-tolyl sulfoxide 6 (3.85 g, 25 mmol) in anhydrous THF
(330 mL) and stirred at the same temperature for 30 min. The re-
action mixture was gradually allowed to warm to 0 ꢁC and a solution
of the unsaturated ester 7 (5.85 g, 25 mmol) in THF (70 mL) was
added dropwise and stirred further for a period of 1 h. The reaction
was quenched by the addition of a saturated aqueous NH4Cl solution
(150 mL) and the pH adjusted to 2 by the addition of 5% aqueous
H2SO4 solution. The two layers were separated and the aqueous
phase extracted with Et2O (3ꢂ70 mL). The combined organic layers
were washed with water (120 mL), saturated brine (120 mL) and
dried over anhydrous Na2SO4. Evaporation of the solvent in vacuo
afforded the crude product, which was purified by column chro-
0.35; [
1706, 1363, 1178, 1081, 1028, 1004, 805, 738, 694, 632, 504 cmꢀ1
(200 MHz, CDCl3)
a
]
ꢀ104 (c 2.2, CHCl3); nmax (KBr) 3320, 2923, 2875, 1772,
D
;
dH
d
7.53 (d, J¼8.2 Hz, 2H), 7.35–7.23 (m, 7H),
4.66–4.58 (m, 1H), 4.51 (s, 2H), 4.37 (d, J¼5.2 Hz, 1H), 4.35–4.29 (m,
1H), 3.75–3.67 (m, 1H), 3.67–3.59 (m, 1H), 3.23 (dd, J¼9.6, 13.4 Hz,
1H), 2.68 (dd, J¼2.9, 13.4 Hz, 1H), 2.44 (s, 3H); dC (75 MHz, CDCl3)
d
141.7, 139.6, 137.7, 130.1, 128.4, 127.7, 124.0, 76.4, 73.3, 67.3, 66.1,
60.8, 52.7, 34.3, 21.4; m/z (FAB) 441 [MþH]þ; HRMS (FAB): [MþH]þ
found 441.0721. C20H26BrO4S requires 441.0735.
4.1.4. (R)-1-{(2R,3R)-3-[2-(Benzyloxy)ethyl]oxiran-2-yl}-2-(Ss)-(p-
tolylsulfinyl)ethanol [9]. Anhydrous K2CO3 (1.35 g, 9.8 mmol) was
added to a solution of bromohydrin 4 (3.93 g, 8.9 mmol) in dry
acetonitrile (90 mL) cooled at 0 ꢁC. The reaction mixture was then
allowed to warm to rt over a period of 15 min and stirred further for
8 h, when TLC examination revealed complete conversion of starting
material. Ether (60 mL) was then added to the reaction mixture and
after 10 min the precipitated solids were filtered through a plug of
Celite. The filtrate was evaporated to afford the crude product, which
was purified bycolumn chromatography using 50% EtOAc/hexane (v/
v) as the eluent to afford epoxy alcohol 9 (2.57 g, 7.1 mmol) in 80%
yield as a white crystalline solid. Mp 86–88 ꢁC; TLC, Rf (60% EtOAc/
matography using 8% EtOAc/CHCl3 (v/v) as the eluent to afford the
keto sulfoxide 8 (5.01 g,15 mmol) in 60% yield as a viscous yellow oil;
TLC, Rf (60% EtOAc/hexane) 0.42; [
þ81.5 (c 1.65, CHCl3); nmax
(KBr) 2922, 2859,1723,1662,1625,1492,1452,1363,1284,1177,1088,
1044, 810, 742, 699, 504 cmꢀ1
dH (300 MHz, CDCl3) 7.50 (d,
b-
a]
D
;
d
J¼7.9 Hz, 2H), 7.36–7.20 (m, 7H), 6.83 (td, J¼6.4,15.9 Hz,1H), 6.15 (dd,
J¼1.5, 15.9 Hz, 1H), 4.49 (s, 2H), 4.00 (d, J¼13.2 Hz, 1H), 3.81 (d,
J¼13.2 Hz, 1H), 3.55 (t, J¼6.4 Hz, 2H), 2.50 (q, J¼6.4 Hz, 2H), 2.41 (s,
3H); dC (75 MHz, CDCl3) d 190.5,147.9,141.9,137.8,131.4,129.9,128.3,
127.5, 124.1, 123.4, 72.9, 67.8, 66.3, 32.9, 21.2; m/z (ESI) 343 [MþH]þ;
HRMS (ESI): [MþH]þ found 343.1354. C20H23O3S requires 343.1367.
hexane) 0.32; [
2864, 1710, 1367, 1243, 1110, 1031, 811, 737, 698 cmꢀ1
CDCl3)
a
]
D ꢀ18.8 (c 2.5, CHCl3); nmax (KBr) 3292, 3030, 2924,
4.1.2. (2R,E)-6-(Benzyloxy)-1-(Rs)-(p-tolylsulfinyl)hex-3-en-2-ol
[5]. To a solution of anhydrous zinc chloride (2.45 g, 18 mmol) in
THF (100 mL) maintained at ambient temperature was added a so-
;
dH (200 MHz,
d
7.49 (d, J¼8.4 Hz, 2H), 7.35–7.21 (m, 7H), 4.46 (s, 2H),
4.16–4.09 (m,1H), 3.54 (t, J¼5.3 Hz, 2H), 3.47–3.42 (m,1H), 3.05–3.01
(m, 1H), 3.00 (dd, J¼9.1, 12.9 Hz, 1H), 2.79–2.75 (m, 1H), 2.69 (dd,
J¼2.3,12.9 Hz,1H), 2.44 (s, 3H),1.87–1.75 (m, 2H); dC (75 MHz, CDCl3)
lution of the b-keto sulfoxide 8 (5.01 g, 15 mmol) in anhydrous THF
(50 mL) and the mixture stirred for 15 min. The reaction mixture
was cooled to ꢀ78 ꢁC and a solution of DIBAL-H (1.4 M in toluene,
16 mL, 22.4 mmol) was added dropwise over a period of 10 min.
After 2 h of stirring at the same temperature, methanol (15 mL) was
added and the reaction mixture allowed to warm to rt. The solvent
was evaporated under reduced pressure and the residue was
treated with 5% aqueous HCl solution (50 mL). The aqueous layer
was extracted into CH2Cl2 (3ꢂ70 mL), the organic layer washed
once with 5% aqueous NaOH solution (25 mL), saturated brine
(25 mL), and dried over anhydrous Na2SO4. Removal of the solvent
in vacuo gave the crude product, which was purified by column
chromatography using 45% EtOAc/hexane (v/v) as the eluent to
afford the allyl alcohol 5 (3.68 g, 11 mmol) as a single diastereomer
in 73% yield as white crystals. Mp 74–75 ꢁC; TLC, Rf (60% EtOAc/
d
141.6, 139.9, 138.1, 130.0, 128.3, 127.7, 127.5, 123.9, 73.0, 66.7, 65.8,
60.6, 60.3, 53.8, 31.8, 21.3; m/z (FAB) 361 [MþH]þ; HRMS (FAB):
[MþH]þ found 361.1464. C20H25O4S requires 361.1473.
4.1.5. (2R,4R)-6-(Benzyloxy)-1-(Ss)-(p-tolylsulfinyl)hexane-2,4-diol
[10]. To a mixture of Cp2TiCl2 (2.65 g, 10.6 mmol) and activated Zn-
powder (1.39 g, 21.3 mmol) in dry THF (100 mL) at ambient tem-
perature was added freshly fused anhydrous ZnCl2 (1.47 g,
10.6 mmol) in one portion and stirred for 1 h. While stirring color of
the reaction mixture gradually changed from red to dark green. It
was then cooled to ꢀ23 ꢁC and a solution of epoxy alcohol 9 (2.57 g,
7.1 mmol) in dry THF (100 mL) was added slowly. The reaction
mixture was warmed to 0 ꢁC and the stirring continued for an ad-
ditional 6 h. The reaction mixture was then quenched by the slow
addition of saturated aqueous NH4Cl solution (50 mL). The layers
were separated and the aqueous layer extracted with ether
(3ꢂ30 mL). The combined organic layer was washed with 1 N
aqueous HCl solution (20 mL), water (20 mL), saturated aqueous
NaHCO3 solution (20 mL), saturated brine (20 mL) and dried over
anhydrous Na2SO4. Evaporation of the solvent in vacuo afforded the
crude product, which was purified by column chromatography
using 55% EtOAc/hexane (v/v) as the eluent to furnish the desired
1,3-diol 10 (1.06 g, 2.9 mmol) in 41% yield as a crystalline solid. Mp
hexane) 0.35; [
2856, 1596, 1492, 1447, 1406, 1364, 1305, 1115, 1009, 811, 735, 699,
623, 499, 455 cmꢀ1
dH (400 MHz, CDCl3)
a]
D þ70.3 (c 2.6, CHCl3); nmax (KBr) 3338, 3032, 2899,
;
d
7.51 (d, J¼8.7 Hz, 2H),
7.32–7.18 (m, 7H), 5.77 (td, J¼7.1, 15.8 Hz, 1H), 5.53 (dd, J¼6.3,
15.8 Hz, 1H), 4.65–4.56 (m, 1H), 4.45 (s, 2H), 3.46 (t, J¼7.1 Hz, 2H),
3.01 (dd, J¼8.7, 13.4 Hz, 1H), 2.73 (dd, J¼3.9, 13.4 Hz, 1H), 2.42 (s,
3H), 2.32 (q, J¼7.1 Hz, 2H); dC (75 MHz, CDCl3)
d 141.6, 140.3, 138.1,
131.9, 129.9, 129.3, 128.1, 127.4, 127.3, 123.9, 72.6, 69.2, 68.6, 63.2,
32.3, 21.2; m/z (ESI) 345 [MþH]þ; HRMS (ESI): [MþH]þ found
345.1531. C20H25O3S requires 345.1524.
70–73 ꢁC; TLC, Rf (60% EtOAc/hexane) 0.22; [
nmax (KBr) 3308, 3029, 2917, 2865, 2358, 1597, 1447, 1327, 1108,
1035, 848, 734, 697, 459 cmꢀ1
dH (200 MHz, CDCl3): 7.51 (d,
J¼8.1 Hz, 2H), 7.36–7.25 (m, 7H), 4.73–4.65 (br s, 1H), 4.50 (s, 2H),
a
]
D ꢀ118 (c 0.8, CHCl3);
4.1.3. (2R,3R,4S)-6-(Benzyloxy)-4-bromo-1-(Ss)-(p-tolylsulfinyl)hex-
ane-2,3-diol [4]. To a solution of the allylic alcohol 5 (3.68 g,
11 mmol) in dry toluene (55 mL) was added water (295 mL,
;
d

10088
S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
4.45 (t, J¼9.5 Hz, 1H), 4.09 (t, J¼9.5 Hz, 1H), 3.94–3.79 (br s, 1H),
3.71–3.58 (m, 2H), 2.97 (dd, J¼9.5, 13.2 Hz, 1H), 2.66 (dd, J¼2.2,
13.2 Hz, 1H), 2.44 (s, 3H), 1.83–1.61 (m, 4H); dC (75 MHz, CDCl3)
yield as a viscous yellow oil; TLC, Rf (10% EtOAc/CHCl3) 0.25; [
þ51 (c 0.7, CHCl3); nmax (KBr) 2925, 2856, 2362, 1723, 1660, 1615,
1512, 1446, 1247, 1174, 1087, 1035, 820, 748, 692, 495 cmꢀ1
dH
(200 MHz, CDCl3) 7.63–7.56 (m, 2H), 7.48–7.40 (m, 3H), 7.17 (d,
a]
D
;
d
141.5, 140.2, 137.8, 130.1, 128.5, 127.8, 127.7, 124.0, 73.4, 71.1, 68.5,
d
66.9, 63.4, 42.9, 36.9, 21.4; m/z (FAB) 363 [MþH]þ; HRMS (FAB):
J¼8.1 Hz, 2H), 6.88–6.70 (m, 3H), 6.09 (td, J¼1.5, 16.1 Hz, 1H), 4.37
(s, 2H), 4.04 (d, J¼13.2 Hz, 1H), 3.81 (d, J¼13.2 Hz, 1H), 3.73 (s, 3H),
3.46 (t, J¼6.6 Hz, 2H), 2.42 (q, J¼6.6 Hz, 2H); dC (75 MHz, CDCl3)
[MþH]þ found 363.1620. C20H27O4S requires 363.1630.
4.1.6. (4R,6R)-4-(2-(Benzyloxy)ethyl)-2,2-dimethyl-6-(Ss)-(p-tol-
ylsulfinylmethyl)-1,3-dioxane [11]. To a stirred solution of diol 10
(1.06 g, 2.9 mmol) in dichloromethane (15 mL), were added 2,2-
dimethoxypropane (1.8 mL, 14.6 mmol) and CSA (34 mg, 0.15 mmol)
successively and the reaction mixture was stirred at rt for 6 h. Et3N
(0.03 mL, 0.21 mmol) was then added and the reaction mixture was
concentrated under reduced pressure. The crude residue was puri-
fied by column chromatography using 15% EtOAc/hexane (v/v) as the
eluent to furnish the acetonide 11 (1.05 g, 2.6 mmol) in 89% yield, as
a crystalline solid. Mp 72–73 ꢁC; TLC, Rf (40% EtOAc/hexane) 0.32;
d 190.6, 159.3, 148.3, 131.5, 130.0, 129.4, 124.2, 113.9, 72.8, 67.6, 66.5,
55.3, 33.1; m/z (ESI) 381 [MþNa]þ; HRMS (ESI): [MþNa]þ found
381.1132. C20H22O4NaS requires 381.1136.
4.1.9. (2R,E)-6-(4-Methoxybenzyloxy)-1-(Rs)-(phenylsulfinyl)hex-3-
en-2-ol [20]. To a solution of anhydrous zinc chloride (4.9 g,
36 mmol) in THF (200 mL) maintained at ambient temperature was
added a solution of the b-keto sulfoxide 19 (10.74 g, 30 mmol) in
anhydrous THF (100 mL) and the mixture stirred for 15 min. The
reaction mixture was cooled to ꢀ78 ꢁC and a solution of DIBAL-H
(1.4 M in toluene, 32.2 mL, 45 mmol) was added dropwise over
a period of 10 min. After 2 h of stirring at the same temperature,
methanol (30 mL) was added and the reaction mixture allowed to
warm to rt. The solvent was evaporated under reduced pressure and
the residue was treated with 5% aqueous HCl solution (100 mL). The
aqueous layer was extracted into CH2Cl2 (3ꢂ150 mL), the combined
organic layers were washed once with aqueous 5% aqueous NaOH
solution (50 mL), saturated brine (50 mL), and dried over anhydrous
Na2SO4. Removal of the solvent in vacuo gave the crude product,
which was purified by column chromatography using 60% EtOAc/
hexane (v/v) as the eluent to afford the allyl alcohol 20 (7.13 g,
19.8 mmol) as a single diastereomer in 66% yield as a viscous pale
[a]
ꢀ108 (c 1.43, CHCl3); nmax (KBr) 2926, 2860, 1451, 1383, 1264,
D
1094, 1022, 935, 809, 747, 698, 460 cmꢀ1
; dH (200 MHz, CDCl3) d 7.52
(d, J¼7.4 Hz, 2H), 7.36–7.27 (m, 7H), 4.53–4.43 (m, 3H), 4.15–4.06 (m,
1H), 3.61–3.45 (m, 2H), 2.79–2.67 (m, 2H), 2.42 (s, 3H), 1.80–1.68 (m,
2H), 1.52 (s, 3H), 1.42 (s, 3H), 1.35–1.23 (m, 2H); dC (75 MHz, CDCl3)
d
141.6, 141.4, 138.5, 130.0, 128.4, 127.6, 124.0, 123.8, 99.3, 73.0, 66.0,
65.0, 63.6, 36.6, 36.5, 30.0, 21.0, 19.9; m/z (FAB) 403 [MþH]þ; HRMS
(FAB): [MþH]þ found 403.1936. C23H31O4S requires 403.1943.
4.1.7. (4R,6R,E)-4-[2-(Benzyloxy)ethyl]-2,2-dimethyl-6-[1-(p-tolylth-
io)undec-2-enyl]-1,3-dioxane [13]. TFAA (91
added to the solution of acetonide 11 (52 mg, 0.13 mmol) and
1-decene (49 L, 0.26 mmol) in dichloromethane (65 L) cooled at
0 ꢁC and the mixture stirred for 30 min. To the above reaction
mixture was added anhydrous SnCl4 (26 L, 0.15 mmol) dropwise
mL, 0.65 mmol) was
m
m
yellow oil; TLC, Rf (70% EtOAc/hexane) 0.32; [
nmax (KBr) 3379, 2927, 2856, 1720, 1611, 1512, 1443, 1246, 1175, 1089,
1031, 820, 752, 692, 468 cmꢀ1
dH (400 MHz, CDCl3) 7.65–7.61 (m,
a]D þ62.6 (c 2.3, CHCl3);
m
;
d
and the mixture stirred for a further 15 min. The reaction mixture
was quenched by the addition of saturated aqueous Na2CO3 solu-
tion (1 mL). The two layers were separated and the aqueous phase
was extracted with dichloromethane (3ꢂ2 mL). The combined or-
ganic layers were washed successively with water (2 mL), saturated
brine (2 mL) and dried over anhydrous Na2SO4. Evaporation under
reduced pressure afforded the crude product, which was purified
by column chromatography using 3% EtOAc/hexane (v/v) as the
eluent to furnish the pure sulfide 13 (11 mg, 0.02 mmol) in 17%
yield as a colorless oil; TLC, Rf (20% EtOAc/hexane) 0.82; dH
2H), 7.55–7.46 (m, 3H), 7.18 (d, J¼8.5 Hz, 2H), 6.79 (d, J¼8.5 Hz, 2H),
5.79 (td, J¼7.1, 15.6 Hz, 1H), 5.52 (dd, J¼6.4, 15.6 Hz, 1H), 4.75–4.68
(m, 1H), 4.38 (s, 2H), 4.04 (d, J¼13.2 Hz, 1H), 3.78 (s, 3H), 3.46 (t,
J¼6.4 Hz, 2H), 2.98 (dd, J¼9.2, 12.8 Hz, 1H), 2.77 (dd, J¼2.8, 12.8 Hz,
1H), 2.31 (q, J¼6.4 Hz, 2H); dC (75 MHz, CDCl3)
d 159.1, 143.8, 131.7,
131.3, 130.3, 129.8, 129.3, 129.2, 123.9, 113.7, 72.4, 69.2, 69.0, 62.8,
55.2, 32.5; m/z (ESI) 383 [MþNa]þ; HRMS (ESI): [MþNa]þ found
383.1287. C20H24O4NaS requires 383.1293.
4.1.10. (5R)-5-Hydroxy-1-(4-methoxybenzyloxy)-6-(Rs)-(phenyl-
sulfinyl)hexan-3-one [24]. A suspension of palladium(II)chloride
(352 mg, 1.98 mmol) and copper(I)chloride (1.96 g, 19.8 mmol) in
a mixture of N,N-dimethylformamide (DMF) and water (1:1, 20 mL)
was stirred under an oxygen atmosphere for 1 h. A solution of allyl
alcohol 20 (7.13 g, 19.8 mmol) in DMF and water (1:1, 10 mL) was
added to the above reaction mixture and was stirred at 50 ꢁC for
4 h. The reaction mixture was extracted with Et2O (3ꢂ75 mL),
washed successively with water (2ꢂ20 mL), saturated brine
(20 mL), and dried over anhydrous Na2SO4. Evaporation of the
solvent in vacuo afforded the crude product, which was purified by
column chromatography using 60% EtOAc/hexane (v/v) as the el-
(200 MHz, CDCl3)
d
7.33–7.18 (m, 7H), 7.03 (d, J¼8.1 Hz, 2H), 5.48–
5.32 (m, 2H), 4.47 (s, 2H), 4.32–4.03 (m, 1H), 3.85–3.69 (m, 1H),
3.62–3.49 (m, 1H), 3.57–3.49 (m, 1H), 3.05–2.95 (m, 1H), 2.50–2.37
(m, 2H), 2.31 (s, 3H), 2.02–1.90 (m, 2H), 1.78–1.44 (m, 2H), 1.40 (s,
3H), 1.36–1.21 (br s, 11H), 0.93–0.85 (distorted t, 3H).
4.1.8. (E)-6-(4-Methoxybenzyloxy)-1-(Rs)-(phenylsulfinyl)hex-3-en-
2-one [19]. To a solution of LDA (0.08 M in solvents, 35 mmol)
prepared from diisopropylamine (5.14 mL, 36.7 mmol) and n-BuLi
(1.6 M in hexane, 21.9 mL, 35 mmol) cooled at ꢀ40 ꢁC was added
a solution of (R)-phenyl methyl sulfoxide 17 (2.33 g, 16.7 mmol) in
anhydrous THF (220 mL) and stirred at the same temperature for
30 min. The reaction mixture was allowed gradually to warm to
0 ꢁC and a solution of the unsaturated ester 18 (4.4 g, 16.7 mmol) in
THF (45 mL) was added dropwise and stirred further for a period of
1 h. The reaction was quenched by the addition of saturated
aqueous NH4Cl solution (100 mL) and the pH adjusted to 2 by the
addition of 5% aqueous H2SO4 solution. The two layers were sepa-
rated and the aqueous phase extracted with Et2O (3ꢂ50 mL). The
combined organic layers were washed with water (80 mL), satu-
rated brine (80 mL) and dried over anhydrous Na2SO4. Evaporation
of the solvent in vacuo afforded the crude product, which was
purified by column chromatography using 8% EtOAc/CHCl3 (v/v) as
uent to furnish
yield as a viscous pale yellow oil; TLC, Rf (70% EtOAc/hexane) 0.15;
D þ84.9 (c 0.35, CHCl3); nmax (KBr) 3138, 2925, 2657, 1630, 1384,
1245, 1088, 1029, 754 cmꢀ1
dH (200 MHz, CDCl3) 7.67–7.59 (m,
b-hydroxy ketone 24 (5.21 g, 13.9 mmol) in 70%
[a]
;
d
2H), 7.56–7.48 (m, 3H), 7.16 (d, J¼8.8 Hz, 2H), 6.80 (d, J¼8.8 Hz, 2H),
4.52 (quintet, J¼5.9 Hz, 1H), 4.39 (s, 2H), 3.78 (s, 3H), 3.66 (t,
J¼5.9 Hz, 2H), 2.98–2.73 (m, 4H), 2.66 (t, J¼5.9 Hz, 2H); dC (50 MHz,
CDCl3)
d 208.6, 159.3, 143.6, 131.3, 129.9, 129.4, 129.4, 124.0, 113.9,
77.0, 72.9, 64.7, 62.0, 55.3, 49.0, 43.7; m/z (ESI) 399 [MþNa]þ; HRMS
(ESI): [MþNa]þ found 399.1240. C20H24O5NaS requires 399.1242.
4.1.11. (2R,4R)-6-(4-Methoxybenzyloxy)-1-(Rs)-(phenylsulfinyl)-
the eluent to afford the
b
-keto sulfoxide 19 (3.58 g, 10 mmol) in 60%
hexane-2,4-diol [25]. To a solution of b-hydroxy ketone 24 (5.21 g,

S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
10089
13.9 mmol) in THF (110 mL) cooled at ꢀ78 ꢁC was added dieth-
ylmethoxyborane (1 M in THF, 15.4 mL, 15.4 mmol) followed by
methanol (28 mL) and stirred for 30 min. Then solid sodium boro-
hydride (577 mg, 15.3 mmol) was added in three portions and the
mixture stirred for 2 h at the same temperature. The reaction was
quenched using a mixture of pH 7 phosphate buffer (20 mL),
methanol (30 mL), and 30% (w/v) hydrogen peroxide solution
(10 mL). This mixture was allowed to warm to rt and stirred further
at rt for 18 h. The organic solvent was evaporated in vacuo and the
aqueous layer was extracted with Et2O (3ꢂ75 mL). The combined
organic layers were washed with saturated brine (20 mL) and dried
over anhydrous Na2SO4. Evaporation of the solvent in vacuo yielded
the crude product, which was purified by column chromatography
using 65% EtOAc/hexane (v/v) as the eluent to afford the syn 1,3-diol
25 (3.82 g, 10.1 mmol) in 73% yield as a viscous colorless oil; TLC, Rf
3.85 (m, 1H), 3.79 (s, 3H), 3.75–3.64 (m, 2H), 3.64–3.54 (m,1H), 3.32
(s, 3H), 3.24 (dd, J¼6.0, 12.8 Hz, 1H), 2.89 (dd, J¼6.0, 12.8 Hz, 1H),
1.91–1.74 (m, 2H),1.70–1.50 (m, 2H); m/z (ESI) 443 [MþNa]þ; HRMS
(ESI): [MþNa]þ found 443.1500. C22H28O6NaS requires 443.1504.
4.1.14. (2R,4R)-6-(4-Methoxybenzyloxy)-1-(Rs)-(phenylsulfinyl)-
hexane-2,4-diyl diacetate [28]. To a solution of the diol 25 (137 mg,
0.39 mmol) in anhydrous CH2Cl2 (1.5 mL) at 0 ꢁC were added Et3N
(164 mL, 1.18 mmol), DMAP (2 mg), and acetic anhydride (111 mL,
1.18 mmol) successively and the mixture was stirred for 2 h at
ambient temperature. The reaction mixture was diluted with
CH2Cl2 (10 mL) and washed with 10% aqueous citric acid solution
(2ꢂ3 mL), water (3 mL), saturated brine (3 mL) and dried over an-
hydrous Na2SO4. Evaporation of the solvent under reduced pressure
afforded the crude product, which was purified by column chro-
matography using 45% EtOAc/hexane (v/v) as the eluent to afford
the diacetate 28 (148 mg, 0.32 mmol) in 82% yield as a viscous
(70% EtOAc/hexane) 0.22; [
2923, 2856, 2362, 1611, 1512, 1441, 1303, 1246, 1175, 1088, 1030, 820,
753, 691, 503 cmꢀ1
dH (300 MHz, CDCl3) 7.67–7.62 (m, 2H), 7.55–
a]D þ56 (c 2.25, CHCl3); nmax (KBr) 3386,
;
d
colorless oil; TLC, Rf (70% EtOAc/hexane) 0.42; [
CHCl3); nmax (KBr) 3457, 2927, 1736, 1513, 1371, 1244, 1032,
752 cmꢀ1
dH (400 MHz, CDCl3)
a
]
þ54 (c 1.05,
D
7.46 (m, 3H), 7.18 (d, J¼8.3 Hz, 2H), 6.82 (d, J¼8.3 Hz, 2H), 4.41 (s, 2H),
4.36–4.24 (m, 1H), 3.78 (s, 3H), 3.69–3.53 (m, 3H), 3.03 (dd, J¼7.6,
12.8 Hz, 1H), 2.80 (dd, J¼4.5, 12.8 Hz, 1H), 1.86–1.62 (m, 4H); dC
;
d
7.64 (d, J¼6.6 Hz, 2H), 7.57–7.48
(m, 3H), 7.20 (d, J¼8.8 Hz, 2H), 6.83 (d, J¼8.8 Hz, 2H), 5.17 (quintet,
J¼6.6 Hz, 1H), 5.06 (quintet, J¼6.6 Hz, 1H), 4.38 (d, J¼11.7 Hz, 1H),
4.35 (d, J¼11.7 Hz,1H), 3.80 (s, 3H), 3.48–3.36 (m, 2H), 3.14–3.07 (m,
2H), 1.99 (s, 3H), 1.95 (s, 3H), 1.79 (q, J¼5.9 Hz, 2H); m/z (ESI) 485
[MþNa]þ; HRMS (ESI): [MþNa]þ found 485.1595. C24H30O7NaS
requires 485.1609.
(75 MHz, CDCl3)
d 159.4, 143.9, 131.2, 129.8, 129.4, 124.1, 113.9, 77.0,
73.1, 71.5, 68.4, 63.4, 55.3, 42.7, 29.7; m/z (ESI) 401 [MþNa]þ; HRMS
(ESI): [MþNa]þ found 401.1405. C20H26O5NaS requires 401.1398.
4.1.12. (R)-1-[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-3-(Rs)-
(phenylsulfinyl)propan-2-ol [26]. DDQ (2.53 g, 11.1 mmol) was
added portionwise over a period of 10 min to a solution of diol 25
(3.82 g, 10.1 mmol) in anhydrous CH2Cl2 (55 mL) cooled at 0 ꢁC
under nitrogen atmosphere and stirred at the same temperature for
30 min. The reaction mixture was diluted with CH2Cl2 (100 mL) and
the precipitated solid was filtered off. The filtrate was washed
successively with aqueous saturated NaHCO3 solution (2ꢂ30 mL),
water (30 mL), saturated brine (30 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent in vacuo afforded the crude
product, which was purified by column chromatography using 60%
EtOAc/hexane (v/v) as the eluent to yield acetal 26 (2.32 g,
6.2 mmol) in 61% yield as a viscous colorless oil; TLC, Rf (70% EtOAc/
4.1.15. (R)-3-[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]pro-
pane-1,2-diol [29]. To a solution of acetal 26 (2.32 g, 6.17 mmol) in
anhydrous CH2Cl2 (35 mL) cooled at 0 ꢁC was added Et3N (2.6 mL,
18.5 mmol) followed by TFAA (3.6 mL, 18.5 mmol) under an atmo-
sphere of nitrogen and stirred for 15 min. Then a solution of NaBH4
(933 mg, 24.7 mmol) dissolved in 5% aqueous NaHCO3 solution
(50 mL) was added to the above reaction mixture at 0 ꢁC and stirred
for a further 20 min at the same temperature. The reaction mixture
was then extracted into CH2Cl2 (3ꢂ75 mL). The combined organic
layers were washed successively with water (2ꢂ40 mL), saturated
brine (40 mL) and dried over anhydrous Na2SO4. The solvent was
evaporated in vacuo and the residue was purified by column
chromatography using 70% EtOAc/hexane (v/v) as the eluent to
afford diol 29 (0.8 g, 3.1 mmol) in 50% yield as a viscous pale yellow
hexane) 0.32; [
1614, 1515, 1444, 1389, 1254, 1091, 1025, 802, 757, 692 cmꢀ1
(300 MHz, CDCl3) 7.62–7.57 (m, 2H), 7.53–7.47 (m, 3H), 7.24 (d,
a]
D þ34.4 (c 1.4, CHCl3); nmax (KBr) 3386, 2924, 2857,
;
dH
d
J¼9.1 Hz, 2H), 6.77 (d, J¼9.1 Hz, 2H), 5.42 (s, 1H), 4.47–4.37 (m, 1H),
4.24 (dd, J¼4.5, 11.3 Hz, 1H), 4.2–4.11 (m, 1H), 3.93 (dt, J¼2.3,
11.3 Hz, 1H), 3.78 (s, 3H), 3.06 (dd, J¼7.6, 12.8 Hz, 1H), 2.89 (dd,
oil; TLC, Rf (70% EtOAc/hexane) 0.15; [
(KBr) 3414, 2925, 1674, 1605, 1515, 1431, 1307, 1250, 1103, 1027, 830,
767, 599 cmꢀ1
dH (300 MHz, CDCl3)
a
]
D ꢀ21.8 (c 1.3, CHCl3); nmax
;
d
7.32 (d, J¼9.1 Hz, 2H), 6.83 (d,
J¼3.8, 12.8 Hz, 1H), 2.04–1.78 (m, 4H); dC (75 MHz, CDCl3)
d
160.0,
J¼9.1 Hz, 2H), 5.43 (s, 1H), 4.22 (dd, J¼4.5, 11.3 Hz, 1H), 4.13–3.99
(m, 1H), 3.98–3.85 (m, 2H), 3.78 (s, 3H), 3.54 (d, J¼10.6 Hz, 1H), 3.43
(dd, J¼5.3, 10.6 Hz, 1H), 1.90–1.72 (m, 2H), 1.69–1.55 (m, 1H), 1.54–
143.9, 131.2, 130.9, 129.4, 127.2, 124.0, 113.6, 101.0, 75.5, 66.9, 66.8,
63.3, 55.3, 42.1, 31.2; m/z (ESI) 399 [MþNa]þ; HRMS (ESI): [MþNa]þ
found 399.1247. C20H24O5NaS requires 399.1242.
1.43 (m, 1H); dC (100 MHz, CDCl3)
d 160.0, 130.7, 127.2, 113.7, 101.1,
76.7, 70.9, 66.9, 66.4, 55.3, 38.9, 31.3.
4.1.13. (2R,4R)-4-[(R)-2-(Methoxymethoxy)-3-(Rs)-(phenylsulfinyl)-
propyl]-2-(4-methoxyphenyl)-1,3-dioxane [27]. To a solution of the
acetal 26 (121 mg, 0.32 mmol) in anhydrous CH2Cl2 (2 mL) at 0 ꢁC
4.1.16. (R)-2-Hydroxy-3-[(2R,4R)-2-(4-methoxyphenyl)-1,3-dioxan-
4-yl]propyl 4-methylbenzenesulfonate [30]. To a solution of diol 29
(267 mg, 1.0 mmol) in anhydrous CH2Cl2 (5 mL) cooled at 0 ꢁC were
were added diisopropylethyl amine (167
mL, 0.96 mmol), TBAI
(2 mg), and Mom-Cl (48 L, 0.64 mmol) successively and the mix-
m
added Et3N (153 mL, 1.1 mmol) followed by p-toluenesulfonyl
ture stirred for 6 h at ambient temperature. The reaction mixture
was then quenched with water (2 mL) and the aqueous phase was
extracted into CH2Cl2 (2ꢂ5 mL). The combined organic extracts
were washed with saturated brine (3 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent under reduced pressure affor-
ded the crude product, which was purified by column chroma-
tography using 10% EtOAc/CHCl3 (v/v) as the eluent to afford the
Mom-ether 27 (88 mg, 0.21 mmol) in 66% yield as a viscous color-
chloride (262 mg, 1.1 mmol) and Bu2SnO (12 mg, 0.05 mmol). The
reaction mixture was then gradually allowed to warm to rt and
stirred for a period of 3 h. The reaction mixture was then quenched
with 10% aqueous citric acid solution (5 mL) and the aqueous layer
was extracted with dichloromethane (3ꢂ5 mL). The combined or-
ganic extracts were successively washed with water (5 mL), satu-
rated brine (5 mL) and dried over anhydrous Na2SO4. Evaporation
of the solvent afforded the crude product, which was purified by
column chromatography using 10% EtOAc/hexanes (v/v) as the el-
uent to afford tosylate 30 (312 mg, 0.75 mmol) in 75% yield as
a viscous yellow oil; TLC, Rf (70% EtOAc/hexane) 0.83; dH (200 MHz,
less oil; TLC, Rf (50% EtOAc/CHCl3) 0.51; [
nmax (KBr) 3413, 2925, 2853, 1727, 1443, 1253, 1028, 753 cmꢀ1
(300 MHz, CDCl3) 7.67–7.59 (m, 2H), 7.55–7.46 (m, 3H), 7.19 (d,
J¼9.1 Hz, 2H), 6.79 (d, J¼9.1 Hz, 2H), 5.36 (s, 1H), 4.56 (s, 2H), 4.05–
a]
þ26 (c 0.53, CHCl3);
D
;
dH
d
CDCl3)
d
7.75 (d, J¼8.1, 2H), 7.35–7.23 (m, 4H), 6.82 (d, J¼8.8 Hz, 2H),

10090
S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
5.41 (s, 1H), 4.21 (dd, J¼4.4, 11.7 Hz, 1H), 4.15–4.01 (m, 2H),
3.99–3.83 (m, 3H), 3.79 (s, 3H), 2.45 (s, 3H), 1.89–1.63 (m, 2H), 1.49
(d, J¼11.7 Hz, 1H), 1.35–1.20 (m, 1H).
[MþH]þ; HRMS (ESI): [MþNa]þ found 415.2804. C24H40O4Na re-
quires 415.2824.
4.1.19. (2R,4R)-4-[(S)-2-(Benzyloxy)butyl]-2-(4-methoxyphenyl)-1,3-
dioxane [33]. To a suspension of sodium hydride (60% in Nujol,
129 mg, 3.24 mmol) in anhydrous THF (2.5 mL) cooled at 0 ꢁC was
added n-tetrabutylammonium iodide (43 mg, 10 mol %, 0.21 mmol)
followed by the dropwise addition of carbinol 32 (846 mg,
2.16 mmol) in THF (2.5 mL) and stirred at the same temperature for
30 min. Neat benzyl bromide (0.38 mL, 3.24 mmol) was added
dropwise over a period of 10 min at 0 ꢁC. The reaction mixture was
allowed to gradually warm to rt and stirred further for 12 h under
an atmosphere of nitrogen. The reaction was quenched by the ad-
dition of saturated aqueous NH4Cl solution (3 mL). Two phases
were separated and the aqueous layer was extracted with EtOAc
(4ꢂ10 mL). The combined organic layers were washed successively
with water (2ꢂ5 mL), saturated brine (5 mL) and dried over anhy-
drous Na2SO4. The organic layer was evaporated under reduced
pressure to afford the crude product, which was purified by column
chromatography using 5% EtOAc/hexane (v/v) as the eluent to yield
benzyl ether 33 (749 mg, 1.6 mmol) in 72% yield as a colorless oil;
4.1.17. (2R,4R)-2-(4-Methoxyphenyl)-4-[(R)-oxiran-2-ylmethyl]-1,3-
dioxane [31]. To the solution of tosylate 30 (312 mg, 0.75 mmol) in
acetonitrile/methanol (19:1, 7 mL) was added potassium carbonate
(113 mg, 0.83 mmol) at rt and stirred for a period of 3 h. The re-
action mixture was then diluted with Et2O (20 mL) and the pre-
cipitated solids filtered through a plug of Celite. Evaporation of the
solvent under reduced pressure furnished the crude product, which
was purified by column chromatography using 15% EtOAc/hexane
(v/v) as the eluent to afford epoxide 31 (113 mg, 0.47 mmol) in 62%
yield as a viscous colorless oil; TLC, Rf (30% EtOAc/hexane) 0.35; [
ꢀ5.7 (c 3.5, CHCl3); nmax (KBr) 2924, 2853, 1614, 1516, 1461, 1364,
1247, 1103, 1030, 826, 777 cmꢀ1
dH (200 MHz, CDCl3) 7.35 (d,
a]
D
;
d
J¼8.8 Hz, 2H), 6.84 (d, J¼8.8 Hz, 2H), 5.43 (s, 1H), 4.26 (dd, J¼5.1,
11.8 Hz, 1H), 4.07–3.85 (m, 2H), 3.79 (s, 3H), 3.16–3.01 (m, 1H), 2.74
(t, J¼4.4, 1H), 2.54–2.46 (m, 1H), 2.07–1.76 (m, 4H); dC (50 MHz,
CDCl3)
d 159.9, 131.1, 127.3, 113.6, 101.1, 74.4, 66.9, 55.3, 48.9, 46.8,
38.4, 30.8; m/z (ESI) 250 [M]þ; HRMS (ESI): [MþNa]þ found
273.1108. C24H40O4Na requires 273.1102.
TLC, Rf (10% EtOAc/hexane) 0.35; [
3028, 2925, 2853, 2771, 1728, 1615, 1517, 1459, 1369, 1248, 1107,
1035, 825, 747, 698 cmꢀ1
dH (200 MHz, CDCl3) 7.36–7.24 (m, 7H),
a]
D ꢀ14 (c 0.3, CHCl3); nmax (KBr)
4.1.18. (S)-1-[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]tridecan-
2-ol [32]. The mixture of epoxide 31 (113 mg, 0.46 mmol) and CuCN
(2 mg, 0.02 mmol) in anhydrous THF (2.5 mL) was stirred at rt for
10 min. The reaction mixture was then cooled to ꢀ10 ꢁC and treated
with a freshly prepared solution of n-decylmagnesium bromide
(0.83 M in ether, 1.68 mL, 1.4 mmol). The reaction mixture was then
gradually warmed to 0 ꢁC and stirred for 2 h. It was quenched with
saturated aqueous NH4Cl solution (2 mL) and the aqueous layer was
extracted with EtOAc (3ꢂ5 mL). The combined organic layers were
washed with saturated brine (4 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Purification by column
chromatography using 10% EtOAc/hexane (v/v) as the eluent
afforded triol derivative 32 (125 mg, 0.32 mmol) in 69% yield as
a viscous colorless oil.
One-pot operation. To a suspension of sodium hydride (60% in
Nujol, 310 mg, 7.7 mmol) in anhydrous THF (10 mL) cooled at 0 ꢁC
was added a solution of diol 29 (810 mg, 3.1 mmol) in THF (20 mL)
dropwise. The mixture was gradually allowed to warm to rt and
further stirred for 1 h at the same temperature. It was then recooled
at 0 ꢁC and N-Ts-imidazole (686 mg, 3.1 mmol) was added in three
equal portions over a period of 20 min. The mixture was warmed to
rt and stirred for 40 min, then CuCN (55 mg, 0.61 mmol) was added
in one portion. After stirring for an additional 5 min, the mixture
was cooled to ꢀ10 ꢁC and a freshly prepared solution of n-decyl-
magnesium bromide (0.7 M in Et2O, 13.3 mL, 9.31 mmol) was
added via syringe. The reaction mixture was kept at the same
temperature for 2 h and then allowed to warm gradually to 0 ꢁC
over a period of 1 h. The reaction was quenched by the addition of
saturated aqueous NH4Cl solution (10 mL) and diluted with Et2O
(65 mL). The aqueous phase was re-extracted with Et2O (2ꢂ25 mL)
and the combined organic layers were washed with water
(2ꢂ25 mL), saturated brine (25 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent in vacuo furnished the crude
residue, which was purified by column chromatography using 10%
EtOAc/hexane (v/v) as the eluent to afford triol 32 (846 mg,
2.1 mmol) in 70% yield as a viscous colorless oil; TLC, Rf (20% EtOAc/
;
d
6.81 (d, J¼8.1 Hz, 2H), 5.39 (s, 1H), 4.51 (d, J¼11.7 Hz, 1H), 4.44 (d,
J¼11.7 Hz, 1H), 4.18 (dd, J¼4.4, 9.5 Hz, 1H), 4.01–3.83 (m, 2H), 3.79
(s, 3H), 3.54 (quintet, J¼5.9 Hz, 1H), 1.99 (quintet, J¼6.9 Hz, 1H),
1.87–1.50 (m, 4H), 1.46–1.20 (m, 19H), 0.89 (distorted t, J¼6.6 Hz,
3H); dC (75 MHz, CDCl3)
d 159.9, 139.0, 131.5, 128.3, 127.9, 127.5,
127.4, 113.5, 101.1, 75.1, 74.4, 70.5, 67.0, 55.1, 45.1, 40.3, 34.1, 32.1,
31.6, 30.0, 29.8, 29.7, 29.5, 25.3, 22.8, 14.3; m/z (ESI) 483 [MþH]þ;
HRMS (ESI): [MþNa]þ found 505.3318. C31H46O4Na requires
505.3293.
4.1.20. (3R,5S)-5-(Benzyloxy)hexadecane-1,3-diol [34]. To a stirred
solution of benzyl ether 33 (749 mg, 1.55 mmol) in methanol/water
(4:1) was added PPTS (39 mg, 0.16 mmol) and the mixture heated
at reflux for 4 h. The solvent was evaporated in vacuo and the crude
product was purified by column chromatography using 30% EtOAc/
hexane (v/v) as the eluent to afford the diol 34 (339 mg, 0.93 mmol)
in 60% yield as a colorless oil; TLC, Rf (30% EtOAc/hexane) 0.23; [
þ25.3 (c 2.65, CHCl3); nmax (KBr) 3440, 2924, 2853, 1640, 1456, 1217,
1057, 760, 696 cmꢀ1
dH (200 MHz, CDCl3) 7.37–7.28 (m, 5H), 4.67
a]
D
;
d
(d, J¼11.1 Hz, 1H), 4.42 (d, J¼11.1 Hz, 1H), 4.14–3.99 (m, 1H), 3.81 (t,
J¼5.9 Hz, 2H), 3.76–3.64 (m, 1H), 1.83–1.53 (m, 6H), 1.28–1.26 (br s,
18H), 0.89 (distorted t, J¼6.6 Hz, 3H); dC (75 MHz, CDCl3)
d 137.8,
128.6, 127.9, 80.3, 72.3, 70.6, 61.4, 41.0, 38.8, 33.3, 31.9, 29.8, 29.6,
29.3, 24.5, 22.7, 14.1; m/z (ESI) 365 [MþH]þ; HRMS (ESI): [MþNa]þ
found 387.2891. C23H40O3Na requires 387.2875.
4.1.21. (3S,5S)-5-(Benzyloxy)-3-hydroxyhexadecanal [35]. To a stir-
red solution of the diol 34 (339 mg, 0.93 mmol) in CH2Cl2 (18 mL)
was added TEMPO (44 mg, 0.28 mmol) followed by iodobenzene
diacetate (901 mg, 2.8 mmol). After stirring for 2 h at rt, the re-
action mixture was treated with 5% aqueous Na2S2O3 solution
(7 mL) and saturated aqueous NaHCO3 solution (7 mL). After
15 min, the organic phase was separated and the aqueous phase
was extracted with Et2O (3ꢂ25 mL). The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated under re-
duced pressure to furnish the crude residue, which was purified by
column chromatography using 20% EtOAc/hexane (v/v) as the el-
uent to afford the corresponding aldehyde 35 (219 mg, 0.61 mmol)
in 65% yield as a viscous pale yellow oil; TLC, Rf (50% EtOAc/hexane)
hexane) 0.52; [
a
]
D ꢀ14.9 (c 1.1, CHCl3); nmax (KBr) 3447, 2922, 2853,
1634, 1459, 558 cmꢀ1
;
dH (300 MHz, CDCl3)
d
7.31 (d, J¼9.1 Hz, 2H),
6.82 (d, J¼9.1 Hz, 2H), 5.45 (s, 1H), 4.22 (dd, J¼4.5, 12.1 Hz, 1H),
4.13–4.02 (m, 1H), 3.92 (dt, J¼2.3, 12.1 Hz, 1H), 3.86–3.80 (m, 1H),
3.78 (s, 3H), 1.92–1.23 (m, 24H), 0.88 (distorted t, J¼6.8 Hz, 3H); dC
0.72; [
1458, 1352, 1246, 1097, 743, 697 cmꢀ1
(t, J¼1.5 Hz, 1H), 7.38–7.28 (m, 5H), 4.65 (d, J¼11.0 Hz, 1H), 4.43 (d,
a]
þ2.6 (c 1.05, CHCl3); nmax (KBr) 3447, 2925, 2854, 1730,
D
(100 MHz, CDCl3)
d
159.8, 130.7, 127.2, 113.6, 101.1, 78.1, 71.4, 67.0,
; dH (400 MHz, CDCl3) d 9.81
55.3, 42.8, 37.7, 31.6, 29.8, 29.7, 29.4, 25.5, 22.8, 14.2; m/z (ESI) 393

S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
10091
J¼11.0 Hz, 1H), 4.36–4.28 (m, 1H), 3.76–3.68 (m, 1H), 2.58 (ddd,
1734, 1638, 1459, 1369, 1210, 1165, 1066, 760, 697 cmꢀ1
(300 MHz, CDCl3)
; dH
J¼2.2, 7.3, 16.8 Hz, 1H), 2.50 (ddd, J¼1.5, 4.3, 16.8 Hz, 1H), 1.81–1.48
(m, 4H), 1.41–1.15 (br s, 18H), 0.88 (distorted t, J¼6.6 Hz, 3H); dC
d
7.38–7.28 (m, 5H), 4.6 (d, J¼11.3 Hz, 1H), 4.43 (d,
J¼11.3 Hz, 1H), 3.95–3.85 (m, 1H), 3.73–3.63 (m, 4H), 2.48–2.37 (m,
(100 MHz, CDCl3)
d 202.1, 137.8, 128.6, 127.9, 79.5, 70.5, 67.1, 51.0,
1H), 1.74–1.44 (m, 6H), 1.33–1.22 (br s, 26H), 0.92–83 (m, 6H); dC
40.5, 33.2, 31.9, 29.8, 29.6, 29.6, 29.3, 24.5, 22.7, 14.1.
(75 MHz, CDCl3) d 175.5, 138.0, 128.4, 127.8, 127.7, 79.3, 72.2, 70.5,
51.9, 38.5, 33.3, 31.6, 29.8, 29.6, 29.3, 29.2, 28.7, 27.5, 24.6, 22.7, 22.5,
14.1, 14.0; m/z (ESI) 477 [MþH]þ; HRMS (ESI): [MþNa]þ found
499.3742. C30H52O4Na requires 499.3763.
4.1.22. (3S,5S)-5-(Benzyloxy)-3-hydroxyhexadecanoic acid [36]. To
a stirred solution of the aldehyde 35 (219 mg, 0.61 mmol) in cyclo-
hexene (0.6 mL) and t-BuOH (1.8 mL) cooled at 0 ꢁC was added
dropwise a solution of sodium chlorite (83 mg, 0.91 mmol) and
NaH2PO4$H2O (126 mg, 0.91 mmol) in water (0.6 mL). The mixture
was stirred for 30 min at the same temperature and then 3 h at rt.
The reaction mixture was then partitioned between Et2O (50 mL)
and water (5 mL). The aqueous phase was extracted with Et2O
(3ꢂ15 mL) and the combined organic layers were washed succes-
sively with water (5 mL), saturated brine (5 mL) and then dried over
anhydrous Na2SO4. Removal of solvent in vacuo furnished the crude
product, which was purified by base–acid treatment to afford acid
36 (172 mg, 0.45 mmol) in 75% yield as a colorless oil. TLC, Rf (50%
4.1.25. (2S,3S,5S)-5-(Benzyloxy)-2-hexyl-3-hydroxyhexadecanoic
acid [38]. To a solution of compound 2 (136 mg, 0.29 mmol) in THF
(3 mL) cooled at 0 ꢁC,1 M LiOH (1.4 mL,1.4 mmol) was added in one
portion and the mixture gradually warmed to ambient temperature
and then heated at 65 ꢁC for 2 h. The reaction mixture was cooled to
0 ꢁC and acidified using 1 N aqueous HCl solution to adjust pH to 2.
The aqueous layer was extracted with EtOAc (3ꢂ5 mL). The com-
bined organic layers were washed with water (3 mL), saturated
brine (2 mL) and dried over anhydrous Na2SO4. Evaporation of the
solvent under reduced pressure yielded the crude product, which
was purified by base–acid treatment to furnish acid 38 (92 mg,
0.2 mmol) in 70% yield as a viscous colorless oil; TLC, Rf (20% EtOAc/
EtOAc/hexane) 0.21; [
2925, 2854,1711,1580,1455,1065, 910, 737, 697 cmꢀ1
CDCl3)
a
]
þ29.4 (c 1.45, CHCl3); nmax (KBr) 3407,
D
;
dH (300 MHz,
d
7.39–7.27 (m, 5H), 4.62 (d, J¼11.3 Hz,1H), 4.42 (d, J¼11.3 Hz,
hexane) 0.15; [
a]
D þ14 (c 0.53, CHCl3) [lit.3c þ12.6 (c 0.92, CHCl3)];
1H), 4.26–4.12 (m, 1H), 3.77–3.65 (m, 1H), 2.54–2.40 (m, 2H), 1.86–
nmax (KBr) 3445, 2925, 2855, 1708, 14.58, 1215, 1064, 763, 697 cmꢀ1
;
1.45 (m, 4H), 1.27 (br s, 18H), 0.88 (distorted t, J¼6.6 Hz, 3H); dC
dH (300 MHz, CDCl3)
d
7.40–7.27 (m, 5H), 4.66 (d, J¼11.3 Hz, 1H),
(75 MHz, CDCl3)
d
137.7,128.6,127.9, 79.2, 70.6, 68.0, 40.0, 33.2, 31.9,
4.41 (d, J¼11.3 Hz, 1H), 3.97–3.85 (m, 1H), 3.77–3.66 (m, 1H), 2.41–
29.8, 29.6, 29.3, 24.5, 22.7, 14.1; m/z (ESI) 378 [M]þ; HRMS (ESI):
[MþNa]þ found 401.2675. C23H38O4Na requires 401.2667. Note:
signal for the carbonyl carbon not observed in 13C NMR.
2.29 (m, 1H), 1.84–1.48 (m, 4H), 1.39–1.15 (br s, 28H), 0.95–0.82 (m,
6H); dC (100 MHz, CDCl3) d 137.4, 128.6, 128.0, 127.9, 80.1, 72.2, 70.6,
51.7, 38.6, 33.1, 31.9, 31.6, 29.8, 29.6, 29.6, 29.3, 29.1, 27.3, 24.4, 22.7,
22.6, 14.1, 14.0; m/z (ESI) 463 [MþH]þ; HRMS (ESI): [MþNa]þ found
485.3595. C29H50O4Na requires 485.3606.
4.1.23. (3S,5S)-Methyl 5-(benzyloxy)-3-hydroxyhexadecanoate [37]. A
solution of acid 36 (172 mg, 0.45 mmol) in Et2O (5 mL) was ester-
ified by reaction with an ethereal solution of diazomethane. The
excess of diazomethane was quenched by adding few drops of
glacial acetic acid. Removal of the solvent in vacuo, followed with
purification by column chromatography using 10% EtOAc/hexane
(v/v) as the eluent afforded methyl ester 37 (161 mg, 0.41 mmol) in
Note: signal for the carbonyl carbon not observed in 13C NMR.
4.1.26. (3S,4S)-4-[(S)-2-(Benzyloxy)tridecyl]-3-hexyloxetan-2-one
[39]. To a solution of
CH2Cl2 (6 mL) was added Et3N (83
Cl (77 mg, 0.3 mmol) at rt. After 1 h, the resulting reaction mixture
was diluted with water (2 mL) and extracted with EtOAc (3ꢂ8 mL).
The combined organic phase was washed with water (4 mL), sat-
urated brine (4 mL) and dried over anhydrous Na2SO4 and con-
centrated in vacuo. The crude residue was purified by column
chromatography using 3% EtOAc/hexane (v/v) as the eluent to af-
b
-hydroxy acid 38 (92 mg, 0.2 mmol) in
L, 0.6 mmol) followed by BOP-
m
90% yield as a colorless oil; TLC, Rf (20% EtOAc/hexane) 0.32; [
þ27.5 (c 1.0, CHCl3); nmax (KBr) 3466, 2925, 2854, 1734, 1443, 1271,
1169, 1067, 743 cmꢀ1
dH (200 MHz, CDCl3) 7.39–7.19 (m, 5H), 4.59
a]
D
;
d
(d, J¼11.4 Hz, 1H), 4.44 (d, J¼11.4 Hz, 1H), 4.22–4.05 (m, 1H), 3.68 (s,
3H), 3.62–3.56 (m, 1H), 2.47 (dd, J¼6.8, 15.9 Hz, 1H), 2.36 (dd, J¼5.3,
15.9 Hz, 1H), 1.85–1.50 (m, 4H), 1.45–1.19 (br s, 18H), 0.89 (distorted
ford
b-lactone 39 (58 mg, 0.13 mmol) in 65% yield as a colorless oil;
t, J¼6.6 Hz, 3H); dC (75 MHz, CDCl3)
d
172.2,138.2,128.5,127.8,127.7,
TLC, Rf (20% EtOAc/hexane) 0.73; [
a
]
D ꢀ4 (c 0.97, CHCl3) [lit.3d ꢀ3.44
78.5, 70.6, 67.3, 51.4, 41.7, 40.5, 33.6, 32.0, 30.0, 29.8, 29.5, 24.8, 22.8,
14.3; m/z (ESI) 393 [MþH]þ; HRMS (ESI): [MþNa]þ found 415.2820.
C24H40O4Na requires 415.2824.
(c 0.93, CHCl3)]; nmax (KBr) 2926, 2855, 1823, 1741, 1460, 1378, 1119,
884, 736 cmꢀ1
; dH (400 MHz, CDCl3) d 7.36–7.27 (m, 5H), 4.55 (d,
J¼11.7 Hz,1H), 4.45–4.36 (m, 2H), 3.55–3.48 (m,1H), 3.23 (dt, J¼4.4,
8.1 Hz, 1H), 2.15 (td, J¼6.6, 14.7 Hz, 1H), 1.97–1.86 (m, 1H), 1.80–1.45
(m, 4H), 1.42–1.21 (br s, 26H), 0.93–0.84 (m, 6H); dC (300 MHz,
4.1.24. (2S,3S,5S)-Methyl 5-(benzyloxy)-2-hexyl-3-hydroxyhexadeca-
noate [2]. To a stirred solution of LHMDS (1 M in THF, 0.94 mL,
0.94 mmol) in THF (1 mL) cooled at ꢀ55 ꢁC was added a solution of
methyl ester 37 (161 mg, 0.41 mmol) in THF (1.4 mL). The reaction
CDCl3)
d 171.6, 138.2, 128.4, 127.7, 75.6, 75.2, 70.7, 56.5, 38.1, 33.3,
31.9, 31.4, 29.5, 29.5, 29.3, 28.9, 27.7, 26.6, 25.1, 22.6, 22.5, 14.1, 14.0;
m/z (ESI) 445 [MþH]þ; HRMS (ESI): [MþNa]þ found 467.3490.
C29H48O3Na requires 467.3501.
mixture was stirred at ꢀ55 ꢁC for 1 h and then hexyl iodide (90
mL,
0.61 mmol) in HMPA (0.36 mL, 2.05 mmol) was added dropwise at
the same temperature. The resulting mixture was stirred at ꢀ55 ꢁC
for 1 h, allowed to warm to ꢀ30 ꢁC, stirred at the same temperature
for another 1 h. It was then allowed to warm to ꢀ15 ꢁC and stirred
further at ꢀ15 ꢁC for 1 h. The yellow reaction mixture was diluted
with Et2O (20 mL) and poured into saturated aqueous NH4Cl solu-
tion (10 mL). Two phases were portioned and the aqueous layer
was extracted with Et2O (3ꢂ10 mL). The combined organic layers
were washed successively with water (4 mL), saturated brine
(5 mL) and dried over anhydrous Na2SO4. The solvent was removed
in vacuo. Purification by column chromatography using 4% EtOAc/
4.1.27. (3S,4S)-3-Hexyl-4-((S)-2-hydroxytridecyl)oxetan-2-one
[40]. Palladium hydroxide on carbon (5.8 mg,10 wt %) was added to
the solution of b-lactone 39 (58 mg, 0.13 mmol) in methanol (1 mL)
at ambient temperature and the mixture was stirred under an at-
mosphere of hydrogen at atmospheric pressure for 4 h. The solid
catalyst was filtered and washed with ethyl acetate. The combined
filtrates were concentrated under reduced pressure to afford the
crude residue, which was purified bycolumn chromatography using
10% EtOAc/hexane (v/v) as the eluent to furnish alcohol 40 (37 mg,
0.1 mmol) in 80% yield as white crystals. Mp 62–63 ꢁC [lit.3d 63–
hexane (v/v) as the eluent afforded compound
0.29 mmol) in 70% yield as a colorless oil; TLC, Rf (20% EtOAc/hex-
ane) 0.63; [
þ19.2 (c 1.25, CHCl3); nmax (KBr) 3459, 2926, 2855,
2
(136 mg,
64 ꢁC]; TLC, Rf (10% EtOAc/hexane) 0.11; [
a
]
D
ꢀ16 (c 1.75, CHCl3)
[lit.3c ꢀ16.3 (c 1.05, CHCl3)]; nmax (KBr) 3546, 2921, 2852,1812,1464,
a]
1382, 1125, 1088, 838, 759, 723, 574 cmꢀ1
; dH (300 MHz, CDCl3)
D

10092
S. Raghavan, K. Rathore / Tetrahedron 65 (2009) 10083–10092
Fidanze, S. Org. Lett. 2000, 2, 2405; (l) Bodkin, J. A.; Humphries, E. J.; McLeod,
d
4.44 (dt, J¼4.0, 6.4 Hz,1H), 3.80–3.73 (m,1H), 3.29 (ddd, J¼4.0, 6.8,
M. D. Aust. J. Chem. 2003, 56, 795; (m) Bodkin, J. A.; Humphries, E. J.; McLeod,
M. D. Tetrahedron Lett. 2003, 44, 2869; (n) Thadani, A. N.; Batey, R. A. Tetrahe-
dron Lett. 2003, 44, 8051; (o) Polkowska, J.; Lukaszewicz, E.; Kiegiel, J.; Jurczak,
J. Tetrahedron Lett. 2004, 45, 3873; (p) Yadav, J. S.; Vishweshwar Rao, K.; Sridhar
Reddy, M.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4393; (q) Yadav, J. S.; Vish-
weshwar Rao, K.; Prasad, A. R. Synthesis 2006, 3888; (r) Yadav, J. S.; Sridhar
Reddy, M.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4995; (s) Kumaraswamy, G.;
Markondaiah, B. Tetrahedron Lett. 2008, 49, 327; (t) Ghosh, A. K.; Shurrush, K.;
Kulkarni, S. J. Org. Chem. 2009, 74, 4508.
8.5 Hz,1H),1.93–1.66 (m, 4H),1.55–1.38 (m, 4H),1.38–1.21 (m, 24H),
0.95–0.83 (m, 6H); dC (100 MHz, CDCl3) d 171.1, 76.2, 69.3, 56.7, 41.2,
37.7, 31.9, 31.5, 29.7, 29.6, 29.4, 29.0, 27.9, 26.9, 25.5, 22.7, 22.6, 14.2,
14.1; m/z (ESI) 355 [MþH]þ; HRMS (ESI): [MþNa]þ found 377.3016.
C22H42O3Na requires 377.3031.
4.1.28. (1S)-1-[(2S,3S)-3-Hexyl-4-oxooxetan-2-yl]tridecan-2-yl (2S)-
2-formylamino-4-methylpentanoate [1]. A mixture of (S)-N-formyl-
4. Raghavan, S.; Rathore, K. Synlett 2009, 1285.
5. Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem., Int. Ed. 2005, 44, 7221.
6. The unsaturated ester 7 was prepared by a three step sequence involving (i)
selective mono protection of 1,3-propane diol as its benzyl ether followed by
(ii) Swern oxidation and (iii) Wittig olefination, in 40% overall yield.
7. Solladie, G.; Frechou, C.; Hutt, J.; Demailly, G. Bull. Soc. Chim. Fr. 1987, 827.
8. (a) Solladie, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985, 26, 435; (b) Sol-
ladie, G.; Frechou, C.; Demailly, G.; Greck, C. J. Org. Chem. 1986, 51, 1912; (c)
Carreno, M. C.; Garcia Ruano, J. L.; Martin, A. M.; Pedregal, C.; Rodriguez, J. H.;
Rubio, A.; Sanchez, J.; Solladie, G. J. Org. Chem. 1990, 55, 2120.
9. For the oxidative functionalization of allylic alcohols activated by NBS using
a sulfinyl moiety as the intramolecular nucleophile see: (a) Raghavan, S.;
Rasheed, M. A.; Joseph, S. C.; Rajender, A. Chem. Commun. 1999, 1845; (b) Ra-
ghavan, S.; Sreekanth, T. Tetrahedron Lett. 2008, 49, 1169.
L
-leucine (25 mg, 0.16 mmol), DCC (32 mg, 0.16 mmol), and DMAP
(3 mg, 0.02 mmol) in anhydrous CH2Cl2 (0.5 mL) was stirred at
ambient temperature for 10 min before a solution of the alcohol
40 (37 mg, 0.1 mmol) in anhydrous CH2Cl2 (0.5 mL) being in-
troduced dropwise. The mixture was then stirred at ambient
temperature for 24 h before being diluted with Et2O (10 mL). The
precipitate solid was filtered through a pad of Celite and the fil-
trate was washed successively with water (2ꢂ1 mL), saturated
brine (1 mL) and dried over anhydrous Na2SO4. After removal of
the solvent under reduced pressure the residue was purified
through column chromatography using 15% EtOAc/hexane (v/v) as
the eluent to afford (ꢀ) THL 1 (37 mg, 0.08 mmol) in 72% yield as
white crystals. Mp 41–42 ꢁC [lit.3b 40–42 ꢁC]; TLC, Rf (30% EtOAc/
10. (a) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719; (b) Ma, P.; Martin, V. S.;
Masamune, S.; Sharpless, K. B.; Viti, S. M. J. Org. Chem. 1982, 47, 1378.
11. RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J. Am. Chem. Soc. 1990, 112, 6408;
(b) Chakraborty, T. K.; Dutta, S. J. Chem. Soc., Perkin Trans. 1 1997, 1257.
12. The poor yield is probably because of loss during aq workup as a consequence
of the polarity of the product.
13. In an effort to improve theyield, titanocene mediated reductionwas attempted on
a, the silyl ether of 9. The reduction proceeded cleanly to afford a product, which
was subjected to desilylation with TBAF. A polar product b was obtained that did
not match with diol 10 and was therefore assumed to be the isomeric 1,2-diol.
hexane) 0.42; [
a
]
ꢀ31 (c 0.1, CHCl3) [lit.3b ꢀ33 (c 0.36, CHCl3)];
D
nmax (KBr) 2925, 2855, 1822, 1738, 1675, 1549, 1459, 1255,
1124 cmꢀ1
; dH (400 MHz, CDCl3) d 8.22 (s, 1H), 5.95–5.83 (m, 1H),
5.06–4.98 (m, 1H), 4.72–4.60 (m, 1H), 4.30–4.22 (m, 1H), 3.24–3.16
(m, 1H), 2.21–2.11 (m, 1H), 2.07–1.94 (m, 1H), 1.87–1.40 (m, 7H),
1.38–1.20 (m, 23H), 1.01–0.96 (m, 6H), 0.92–0.86 (m, 6H); dC
O
S
OP
O
S
OH
Cp2TiCl2, Zn,
ZnCl2, THF
(100 MHz, CDCl3) d 160.7, 74.8, 72.7, 57.0, 49.6, 41.5, 38.7, 34.0, 31.9,
p-Tol
OBn
p -Tol
OBn
31.4, 29.6, 29.5, 29.4, 29.3, 28.9, 27.6, 26.7, 25.5, 25.0, 24.9, 22.9,
22.7, 22.5, 21.7, 14.1, 14.0; m/z (ESI) 496 [MþH]þ; HRMS (ESI):
[MþNa]þ found 518.3821. C29H53NO5Na requires 518.3821.
Note: signals for the two carbonyl carbon not observed in 13C
NMR.
O
TBAF, THF
38% overall
OH
9, P = H
TBS-Cl, Imd.
CH2Cl2, 81%
b
a
, P = TBS
14. The resonances for the methyl groups of the acetonide in the 13C spectrum of 11
support the structure of diol 10 and therefore the bromohydrin 4. For the as-
signment of relative configuration of 1,3-diols see: (a) Rychnovsky, S. D.;
Rogers, B. N.; Richardson, T. I. Acc. Chem. Res. 1998, 31, 9; (b) Evans, D. A.; Rieger,
D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099.
Acknowledgements
15. (a) Raghavan, S.; Mustafa, S. Tetrahedron 2008, 64, 10055; (b) Ishibashi, H.;
Komatsu, H.; Ikeda, M. J. Chem. Res., Synop. 1987, 296.
16. Unpublished results from the laboratory. For the alkylation of dianions derived
S.R. is thankful to Dr. J.M. Rao, Head, Org. Div. I and Dr. J.S. Yadav,
Director, IICT for constant support and encouragement. K.R. is
thankful to the CSIR, New Delhi for fellowships. Financial assistance
from DST (New Delhi) is gratefully acknowledged. We thank Dr. A.C.
Kunwar for the NMR spectra and Dr. R. Srinivas for the mass spectra.
from
b-hydroxy tolyl sulfoxide, see: Cho, B. T.; Kim, D. J. Tetrahedron 2003, 59,
2457 For the alkylation of dianion derived from
b-hydroxy phenyl sulfoxide see:
Tanikaga, R.; Hosaya, K.; Hamamura, K.; Kaji, A. Tetrahedron Lett. 1987, 28, 3705.
17. Sato, T.; Itoh, T.; Fujisawa, T. Tetrahedron Lett. 1987, 28, 5677.
18. Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62, 9.
19. Raghavan, S.; Krishnaiah, V.; Rathore, K. Tetrahedron Lett. 2008, 49, 4999.
20. Chen, K.; Harttmann, G.; Prasad, K.; Repic, O.; Shapiro, H. J. Tetrahedron Lett.
1987, 28, 155.
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