A carbohydrate approach for the formal total synthesis of the prostacyclin analogue (16S)-iloprost

Article abstract of DOI:10.1016/j.tetasy.2012.03.005

The formal total synthesis of the synthetic and stable analogue of prostacyclin, (16S)- iloprost is described via a convergent synthesis starting from readily available d-glucose. Julia olefination and the aldol reaction are the key steps involved in the synthesis.

Full text of DOI:10.1016/j.tetasy.2012.03.005

Tetrahedron: Asymmetry 23 (2012) 388–394
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Tetrahedron: Asymmetry
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A carbohydrate approach for the formal total synthesis of the prostacyclin
analogue (16S)-iloprost
⇑
Srivari Chandrasekhar , Chirumarry Sridhar, Pabbaraja Srihari
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal total synthesis of the synthetic and stable analogue of prostacyclin, (16S)- iloprost is described
Received 14 February 2012
Accepted 6 March 2012
Available online 11 April 2012
via a convergent synthesis starting from readily available
tion are the key steps involved in the synthesis.
D
-glucose. Julia olefination and the aldol reac-
Ó 2012 Elsevier Ltd. All rights reserved.
1
1. Introduction
COOH
CO2Me
α
-side chain
α
-side chain
Prostacyclins play a major role in vascular, central nervous sys-
tem, and inflammatory disorders.1 However, since the activities of
prostacyclins are hampered by their low metabolic half-lives,2 re-
search is more focussed on designing new synthetic analogues as
alternatives to the natural prostacyclins.3 Iloprost (Fig. 1), a highly
potent and stable compound is an example of a synthetic analogue
for prostacyclin which is used in treatment of thrombo-angiitis
obliterans, ischemia, Raynaud’s disease, and pulmonary arterial
hypertension.4 Even though, iloprost suffers from low oral activity,
its potent biological activity has lead it to be utilized as a drug
which is administered either by inhalation or through infusion.
So far there are very few synthetic contributions5 for this com-
pound and majority of them rely on stereoselective keto reduction
(C15) resulting in the mixture of diastereomers.
A
6
ω
-sidechain
O
ω
-side chain
B
C
20
15
16
12
18
13
OH
OH
OH
HO
beraprost 2
Figure 1. Structures of (16S)-iloprost 1 and beraprost 2.
iloprost 1
followed by MOM and ketal deprotection. Aldehyde 4 in turn can
be obtained from bicyclic ketone 6 via an aldol reaction followed
by further manipulations in a five step sequence. Further, sulfone
Our group has taken up a program to design facile strategies to-
ward the total synthesis of potent prostaglandins and prostacyc-
lins. As a part of this program, we have recently published our
initial results on the formal total synthesis of anti-platelet drug
5 can be obtained from the commercially available D-glucose 7
(Scheme 1).
beraprost6 (Fig. 1) wherein the tricyclic ring with an
a-side chain
Our synthesis began with the preparation of bicyclic ketal 6
through a condensation reaction of the readily available glyoxal
and dimethyl-1,3-acetone dicarboxylate7 followed by selective
protection of the keto functionality as the corresponding ketal with
neopentyl glycol following the known literature procedures.8
Ketone 6 was converted into the chiral TES enolate with LiCl-
complexed lithium amide9 and TESCl, and then subjected to a
Mukaiyama aldol reaction with benzyl glyoxaldehyde 9 using
BF3ꢀOEt2 to afford a diastereomeric mixture 10 in a 4:1 ratio.10
Compound 11, when subjected to NaBH4 reduction in MeOH at
ꢁ45 °C, afforded diol 12 which was further treated with Pd/C to
afford triol 12. Triol 12 when treated with NaIO4, underwent oxida-
tive cleavage to yield the desired key fragment 4 (Scheme 2).
We next carried out the synthesis of the sulfone intermediate
has been accomplished. Herein we report the synthesis of the
x
-
side chain [which happens to be a common core for both beraprost
and (16S)-iloprost] and its utility toward formal total synthesis of
(16S)-iloprost following a chiron pool approach starting from the
inexpensive and readily available D-glucose.
2. Results and discussion
Retrosynthetically, (16S)-iloprost can be obtained from the
known intermediate 3. The key intermediate 3 can be obtained
via a Julia olefination reaction between aldehyde 4 and sulfone 5
⇑
Corresponding author. Tel.: +91 4027193210; fax: +91 4027160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
starting from commercially available D-glucose 7. Thus D-glucose
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.005

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 23 (2012) 388–394
389
O
O
O
O
S
N
N
N
N
(16S)-iloprost
CHO
1
O
OMOM
OH
OH
3
4
5
OH
OH
HO
O
O
OH
OH
O
O
HO
D-glucose 7
6
Scheme 1. Retrosynthetic analysis for (16S)-iloprost.
8
1.
Ph
N
Ph
H·HCl
n-BuLi, TESCl
dryTHF, −100
O
O
°
C
NaBH4
MeOH
6
°
9
− 45 C, 3 h
2. OHC
OBn
OBn
81%
BF3·OEt2., CH2Cl2,
°
-78 C, 3 h, 92% ee
OH
10
O
75%
O
O
O
O
O
O
NaIO4
THF:H2O, 30 min
91%
Pd/C
MeOH, 4 h
95%
OBn
OH
CHO
OH
11
OH
12
OH
OH
OH
4
Scheme 2. Synthesis of bicyclic aldehyde 4.
was converted into product 13 in four steps as reported earlier.11
Selective primary acetonide deprotection was achieved with 60%
AcOH to give diol 14, which upon oxidative cleavage by NaIO4 fol-
lowed by reduction with NaBH4 yielded alcohol 15. Alcohol 15 was
protected as the corresponding silyl ether 16 with TBDPSCl in the
presence of imidazole. Deprotection of the acetonide moiety12 with
BCl3 followed by oxidative cleavage of the acetal afforded the alde-
hyde which was reduced to 1,3-diol 17 with NaBH4 (Scheme 3).
The primary alcohol in 17 was selectively protected as the corre-
sponding silyl ether with TBSCl in the presence of TEA and then
to MOM ether with MOMCl to give the fully masked compound
18. Compound 18, when treated with pTSA in methanol, gave the
TBS-deprotected compound, which was converted into tosylate
19 with tosyl chloride in the presence of TEA and DMAP. Tosylate
19 was converted into the corresponding iodide and then coupled
with metallated propyne (generated in situ by treatment of propy-
ne with n-BuLi) to give 20.13 The coupled product 20 upon desily-
lation with TBAF afforded alcohol 21, which was converted into
thioether upon treatment with 1-phenyl-1H-tetrazole-5-thiol un-
der Mitsunobu conditions and then subjected to oxidation with
ammonium molybdate to give sulfone 514 (Scheme 3).
With the two key fragments, aldehyde 4 and sulfone 5, in hand,
we were ready to couple them under Julia olefination conditions to
obtain the core structure of iloprost. Thus, sulfone 5 was treated
with LiHMDS and to this was added aldehyde 4 to give olefin
22.15 Global deprotection was achieved with 6 M HCl to provide
the key intermediate 3 (Scheme 4). Compound 3 can be converted
into the target molecule in a few further manipulations.5d Thus, we
have accomplished the formal synthesis of (16S)-iloprost.
3. Conclusions
In conclusion, we have achieved a highly stereoselective formal
synthesis of (16S)-iloprost starting from commercially available
D-
glucose following a chiron approach. The key steps involved are the

390
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 23 (2012) 388–394
HO
O
O
ref 11
O
HO
HO
OH
OH
O
60% aq. AcOH
rt, 12 h, 75%
O
O
HO
O
7
13
HO
TBDPS-Cl,
Imidazole
i. NaIO4, MeOH,
1 h, rt
O
O
O
HO
CH2Cl2, rt,
1 h, 90%
ii. NaBH4, MeOH,
30 min, rt
81% for two steps
O
O
15
14
TBDPSO
i. BCl3, CH2Cl2, 2 min, rt
ii. NaIO4, MeOH:H2O
O
O
OH
TBDPSO
iii. NaBH4, MeOH, 30 min 78% for
3 steps
O
OH
17
16
i. pTSA, MeOH,
i. TBSCl, TEA,
CH2Cl2, 10 h
TBDPSO
°
0
C to rt, 30 min,
92%
OTBS
ii. MOM-Cl, TEA,
DMAP, CH2Cl2, 10 h
88% for 2 steps
ii. Ts-Cl, TEA, DMAP
CH2Cl2, 0 C to rt, 3 h,
90%
OMOM
°
18
TBDPSO
TBDPSO
i. NaI, NaHCO3
Me2CO, 89%
TBAF, THF
OTs
°
0
C to rt,
ii. propyne, n-BuLi
HMPA/THF, 1 h
70%
OMOM
OMOM
20
30 min, 98%
19
i.1-phenyl-1H-tetrazole
-5-thiol, PPh3, DIAD
°
THF, 0 C, 30 min
O
S
N
N
HO
N
ii. (NH4)6Mo7O24·4H2O
30% H2O2, EtOH, 20 h
rt, 89% for 2 steps
OMOM
N
O
OMOM
21
5
Scheme 3. Synthesis of 5.
Mukaiyama aldol reaction and the Julia–Kocienski olefination. The
strategy adopted paves the way for the synthesis of a key -branch
starting from a readily available inexpensive sugar which can also
be utilized for the total synthesis of beraprost. The application of
this strategy to the total synthesis of other prostacyclin analogues
is currently being investigated.
given in Hz. The chemical shifts are reported in ppm on a scale
downfield from TMS as the internal standard and signal patterns
are indicated as follows: s = singlet, d = doublet, t = triplet,
q = quartet, sex = sextet, m = multiplet, br = broad. FTIR spectra
were recorded on KBr pellets CHCl3/neat (as mentioned) and re-
ported in wave number (cmꢁ1). Optical rotations were measured
on digital polarimeter using a 1 mL cell with a 1 dm path length.
For low (MS) and high (HRMS) resolution, m/z ratios are reported
as values in atomic mass units. Mass analysis was done in ESI
mode. Column chromatography was carried out using silica gel
(60–120 or 100–200 mesh) packed in glass columns. Technical
grade ethyl acetate, and petroleum ether used for column chroma-
tography were distilled prior to use.
x
4. Experimental section
4.1. General
All reagents were of reagent grade and used without further
purification unless specified otherwise. Solvents for the reactions
were distilled prior to use: THF, toluene, and diethyl ether were
distilled from Na and benzophenone ketyl; MeOH from Mg and
I2; CH2Cl2 from CaH2. All air or moisture sensitive reactions were
conducted under a nitrogen atmosphere in flame-dried or oven-
dried glassware with magnetic stirring.1H NMR and 13C NMR spec-
tra were recorded in CDCl3 as solvent on a 200 or 300 MHz spec-
trometer at ambient temperature. The coupling constant J is
4.1.1. (3a0S,40S,6a0R)-40-(2-(Benzyloxy)-1-hydroxyethyl)-5,5-
dimethyltetrahydro-10H-spiro[[1,3]dioxane-2,20-pentalen]-
50(30H)-one 10
A suspension of (R,R)-bis(phenylethyl)ammonium chloride 8
(4.6 g, 17.6 mmol) in THF (50 mL) was cooled to ꢁ78 °C and n-BuLi
(1.6 M in hexane, 22.5 mL, 35.26 mmol) was added dropwise. The

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 23 (2012) 388–394
391
O
O
4, LiHMDA
6M HCl, rt, 10 h
81%
5
THF:HMPA (5:1),
°
- 78 C to rt, 6.5 h,
57%
OMOM
OH
22
COOH
O
ref 5e
OH
OH
OH
3
OH
iloprost 1
Scheme 4. Synthesis of key intermediate 3.
mixture was warmed to 0 °C, re-cooled to ꢁ105 °C and treated
dropwise with a solution of the ketone 6 (2.5 g, 11.15 mmol) in
THF (25 mL). After stirring the mixture for 30 min at ꢁ105 °C, it
was warmed to ꢁ78 °C and treated with ClSiEt3 (3.3 mL,
22.32 mmol). After stirring the mixture for 15 min, a saturated
aqueous NaHCO3 (50 mL) was added and the mixture was warmed
to ambient temperature and extracted with ether (80 mL). The or-
ganic phase was dried (MgSO4) and concentrated in vacuo. Chro-
matography (hexanes/EtOAc, 9:1) of the residue gave the silyl
enol ether (3.7 g, 94%). A solution of aldehyde 9 (1.8 g, 12.0 mmol)
in CH2Cl2 (40 mL) was treated at room temperature with BF3ꢀEt2O
(1.7 ml, 12.0 mmol), and the resulting mixture was cooled immedi-
ately to ꢁ95 °C. After the addition of a solution of the above silyl
enol ether (3.7 g, 10.9 mmol) (92% ee) in CH2Cl2 (50 mL), the resul-
tant orange mixture was stirred for 1 h. The mixture was treated
with a saturated aqueous NaHCO3 solution (60 mL), warmed to
ambient temperature and extracted with ether. The organic phase
was dried (MgSO4) and concentrated in vacuo. Chromatography
(hexanes/EtOAc, 1:1) of the residue provided a mixture of 10a
and 10b (3.07 g, 75%, ratio 4:1) as colorless oils. Rf = 0.33 (SiO2,
30% EtOAc in petroleum ether) 1H NMR of compound 10a
(300 MHz, CDCl3): d 7.31–7.36 (m, 5H), 4.52–4.60 (m, 2H), 3.43–
3.62 (m, 7H), 1.64–2.35 (m, 9H), 0.94 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 220, 137.7, 128.3, 127.8, 127.6, 109.6, 73.2, 72.4, 72.0,
69.5, 56.7, 44.9, 41.2, 41.0, 37.7, 35.1, 29.9, 22.3; IR (Neat) mmax
2.24 (m, 3H), 1.68–1.80 (m, 3H), 1.40–1.51 (m, 1H), 0.95 (d, 6H,
J = 3.6 Hz); 13C NMR (100 MHz, CDCl3): d 137.6, 128.4, 127.8,
127.7, 110.2, 75.0, 73.5, 73.3, 72.1, 71.8, 70.6, 56.6, 41.6, 40.7,
39.7, 38.7, 35.8, 30.0, 22.4; IR (Neat) mmax 3414, 2951, 2864,
1454, 1327, 1110, 1015, 746, 699 cmꢁ1; ESI/HRMS calcd for
C
22H32O5 [M+Na]+ 399.2152, found 399.2139.
4.1.3. ((3a0S,40R,50R,6a0R)-50-Hydroxy-5,5-dimethylhexahydro-
10H-spiro[[1,3]dioxane-2,20-pentalene]-40-yl)ethane-1,2-diol 12
To a stirred solution of benzyl ether 11 (2.4 g, 6.3 mmol) in
EtOAc (25 mL) was added 10% Pd/C (0.2 g) at room temperature
The flask was evacuated and pressurized with H2 (balloon) and
the mixture was then stirred for 4 h. The mixture was then filtered
through a pad of Celite. After washing thoroughly with EtOAc, the
filtrate was concentrated, and purified by column chromatography
using EtOAc:hexane (3:1) to afford triol 12 as a colorless solid
(1.7 g, 95%). Mp 84–90 °C; Rf = 0.24 (SiO2, 50% EtOAc in petroleum
ether) 1H NMR (300 MHz, CDCl3): d 4.18 (br s, 2H), 3.86–4.05 (m,
2H), 3.58–3.68 (m, 2H), 3.35–3.45 (m, 4H), 2.79 (br s, 1H), 2.27–
2.42 (m, 1H), 2.00–2.21 (m, 4H), 1.59–1.81 (m, 3H), 1.48 (q, 1H,
J = 10.7 Hz and 21.5 Hz), 0.95 (d, 6H, J = 13.7 Hz); 13C NMR
(75 MHz, CDCl3): d 110.1, 75.5, 74.9, 74.3, 65.3, 56.3, 44.5, 44.0,
41.2, 39.7, 35.4, 30.0, 29.6, 22.5; IR (Neat) mmax 3385, 2951, 2868,
1729, 1467, 1329, 1108, 1014, 757 cmꢁ1; ESIMS: m/z 287 [M+H]+.
3454, 2952, 2864, 1733, 1453, 1328, 1114, 1012, 739, 699 cmꢁ1
;
4.1.4. (3a0S,40R,50R,6a0R)-50-Hydroxy-5,5-dimethylhexahydro-
10H-spiro[[1,3]dioxane-2,20-pentalene]-40-carbaldehyde 4
ESI/HRMS calcd for C22H30O5 [M+Na]+ 397.1994, found 397.1983.
A solution of triol 12 (1.7 g, 5.9 mmol) in THF: H2O (3:1) (30 mL)
was treated with NaIO4 (3.8 g, 17.8 mmol) portion wise at 0 °C and
stirred at room temperature for 2 h. The reaction mixture was fil-
tered, the filtrate evaporated, and the residue obtained was dis-
solved in water (20 mL) and extracted with EtOAc (3 ꢂ 30 mL).
The combined organic layers were dried over anhydrous Na2SO4,
concentrated in vacuo, and purified by column chromatography
using EtOAc:hexane (1:1) as an eluent to afford aldehyde 4
(1.4 g, 96%) as a light yellow oil. Rf = 0.72 (SiO2, 50% EtOAc in petro-
leum ether). 1H NMR (300 MHz, CDCl3): d 9.75 (s, 1H), 4.30 (q, 1H,
J = 7.3 Hz and 14.7 Hz), 3.51 (s, 2H), 3.46 (s, 2H), 2.50–2.64 (m, 2H),
1.92–2.29 (m, 7H), 1.55–1.66 (m, 1H), 0.96 (d, 6H, J = 1.5 Hz); 13C
NMR (75 MHz, CDCl3): d 203.1, 128.2, 74.4, 72.3, 71.8, 66.3, 41.4,
40.0, 39.0, 38.7, 36.7, 30.0, 22.4; IR (Neat) mmax 3414, 2951, 2865,
4.1.2. (3a0S,40R,50R,6a0R)-40-(2-(Benzyloxy)-1-hydroxyethyl)-5,5-
dimethylhexahydro-10H-spiro[[1,3]dioxane-2,20-pentalen]-50-ol
11
A solution of 10 (3.0 g, 8.02 mmol) in EtOH (60 mL) was cooled
to ꢁ45 °C and treated with NaBH4 (0.603 g, 16.04 mmol). After stir-
ring the mixture for 3 h, the reaction mixture was concentrated
and to this was added a saturated aqueous NH4Cl solution
(20 mL). The mixture was warmed to ambient temperature and ex-
tracted with diethyl ether. The organic phase was dried (MgSO4)
and concentrated in vacuo. Silica gel column chromatography
(hexanes/EtOAc, 1:1) of the residue afforded 11 (2.4 g, 81%) as a
colorless solid. Mp 99–105 °C; Rf = 0.27 (SiO2, 30% EtOAc in petro-
leum ether). 1H NMR (400 MHz, CDCl3): d 7.26–7.40 (m, 5H), 4.56
(s, 2H), 3.91–4.02 (m, 2H), 3.58–3.64 (m, 1H), 3.48–3.52 (m, 1H),
3.46 (d, 4H, J = 6.5 Hz), 2.58 (br s, 2H), 2.33–2.44 (m, 2H), 2.13–
1717, 1468, 1328, 1110, 1014, 770 cmꢁ1; ½a D25
¼ þ15:0 (c 3.5,
ꢃ
MeOH); ESIMS: m/z 255 [M+H]+.

392
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 23 (2012) 388–394
4.1.5. (3aR,5S,6R,6aR)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-
2,2,6-trimethyl-tetrahydrofuro[2,3-d][1,3]dioxole 13
yield). Rf = 0.15 (SiO2, 50% EtOAc in petroleum ether) 1H NMR
(300 MHz, CDCl3): d 5.71 (d, J = 3.6 Hz, 1H), 4.55 (m, 1H), 3.84–
3.80 (m, 2H), 3.72–3.62 (m, 2H), 3.41 (br.s, 2H), 2.12–1.90 (m,
1H), 1.50 (s, 3H), 1.32 (s, 3H), 1.14 (d, J = 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 111.5, 104.5, 83.3 (2C), 73.0, 63.4, 40.3, 26.6,
26.2, 10.0; IR (KBr): mmax 3435, 2985, 2860, 1240, 1127,
To a well stirred solution of D-glucose 7 (100.0 g) in dry acetone
(2 L), anhydrous copper sulfate (100.0 g) was added, followed by
concentrated sulfuric acid (4 mL). The reaction mixture was then
stirred at room temperature for 16 h. The solvent was decanted
and the residue was washed with acetone (3 ꢂ 200 mL) and the
combined acetone layers were neutralized with solid sodium
bicarbonate (neutral to pH paper), and stirred for 2 h, then filtered
and the filtrate was concentrated. The residue was taken in chloro-
form (200 mL), washed with a saturated aqueous NaHCO3 solution
(150 mL), water (150 mL), brine (150 mL), and dried over anhy-
drous Na2SO4, concentrated in vacuo and recrystallized from dis-
tilled petroleum ether to give glucose diacetonide (75 g, 65%) as
a crystalline solid (m.p.: 109 °C). A mixture of diacetone glucose
(20.28 g, 78 mmol), pyridinium dichromate (35.20 g, 94 mmol),
and acetic anhydride (22 mL, 234 mmol) in CH2Cl2 (150 mL) was
heated at reflux for 1 h. The solvent was evaporated and the resi-
due was taken in ether and filtered through a small pad of silica
gel. The combined ether layers were washed with aqueous sodium
bicarbonate (60 mL), water (60 mL), dried over anhydrous Na2SO4,
and concentrated to give the ketone (16.10 g, 80%) as a white solid,
which was utilized as such without further purification. A suspen-
sion of methyltriphenylphosphonium iodide (50.10 g, 124 mmol)
in dry THF (100 mL) at ꢁ78 °C, n-BuLi (85.3 mL, 136 mmol) was
added slowly under a nitrogen atmosphere. The reaction mixture
became yellowish and it was stirred for 30 min at the same tem-
perature. The above ketone (16.0 g, 62 mmol) in THF (50 mL) was
added slowly to the yellow phosphorane solution. The reaction
mixture was allowed to warm to room temperature and stirred
for 12 h. The reaction mixture was then quenched with aqueous
saturated NH4Cl solution (100 mL), and extracted with EtOAc
(2 ꢂ 120 mL). The combined organic layers were washed with
brine (100 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel
chromatography using petroleum ether/EtOAc (98:2) to afford
the exo-methylene compound (13.02 g, 82% yield) as a colorless
oil. To a stirred solution of the above compound (11.78 g, 46 mmol)
in EtOH (100 mL) was added 10% Pd/C (2 g) at room temperature.
The flask was evacuated and pressurized with H2 (balloons) and
the mixture was then stirred for 2 h. The mixture was then filtered
through a pad of Celite, washed thoroughly with EtOAc (30 mL),
and the filtrate was concentrated in vacuo and the residue was
purified by column chromatography (eluent: EtOAc:petroleum
ether = 98:2) to afford 3-C-methyl-3-deoxy derivative 13
(11.27 g, 95% yield) as a colorless oil. Rf = 0.52 (SiO2, 20% EtOAc
1050 cmꢁ1; ESIMS: m/z 219 [M+H]+; ½a 2D8
¼ þ22:0 (c 2, CHCl3).
ꢃ
4.1.7. ((3aR,5S,6R,6aR)-2,2,6-Trimethyltetrahydrofuro[3,2-d]-
[1,3]dioxol-5-yl)methanol 15
A solution of diol 14 (6.10 g, 28 mmol) in methanol (60 mL) was
treated with NaIO4 (23.97 g, 112 mmol) portionwise at 0 °C and
stirred at room temperature for 2 h. The reaction mixture was fil-
tered, the filtrate evaporated, and the residue was dissolved in
water (50 mL) and extracted with EtOAc (3 ꢂ 80 mL). The com-
bined organic layers were dried over anhydrous Na2SO4, and con-
centrated in vacuo to afford the aldehyde, which was used
immediately for further reaction without purification. A solution
of the aldehyde (4.8 g, 2.61 mmol) in MeOH (60 mL) was cooled
to 0 °C and treated with NaBH4 (1.98 g, 5.22 mmol). After stirring
the mixture for 30 min, the reaction mixture was concentrated to
remove methanol and to this was added a saturated aqueous
NH4Cl solution (20 mL). The mixture was extracted with diethyl
ether and the organic phase was dried (MgSO4) and concentrated
in vacuo. Chromatography (hexanes/EtOAc, 1:1) of the residue
afforded alcohol 15 (3.9 g, 81%) as a colorless solid. Rf = 0.22
(SiO2, 30% EtOAc in petroleum ether) 1H NMR (300 MHz, CDCl3):
d 5.74 (d, 1H, J = 3.5 Hz), 4.52 (t, 1H, J = 4.1 Hz and 8.1 Hz), 3.74–
3.87 (m, 2H), 3.44–3.54 (m, 1H), 2.53 (br s, 1H), 1.95–2.08 (m,
1H), 1.45 (s, 3H), 1.28 (s, 3H), 1.01 (d, 3H, J = 6.9 Hz); 13C NMR
(75 MHz, CDCl3): d 111.3, 104.6, 83.0, 82.8, 61.1, 37.9, 26.5, 26.1;
IR (Neat) mmax 3439, 2935, 1377, 1216, 1112, 1017, 874 cmꢁ1
;
½
a 2D5
ꢃ
¼ þ29:2 (c 2.5, MeOH); ESI/HRMS calcd for C9H16O4 [M+Na]+
211.0945, found 211.0926.
4.1.8. tert-Butyldiphenyl(((3aR,5S,6R,6aR)-2,2,6-trimethyl-
tetrahydrofuro[3,2-d][1,3]dioxol-5-yl)methoxy)silane 16
To a stirred solution of alcohol 15 (3.9 g, 20.7 mmol) in dry
CH2Cl2 (45 mL) was added imidazole (4.23 g, 62.23 mmol) at 0 °C
and stirred for 15 min at the same temperature. Then TBDPSCl
(6.4 mL, 24.8 mmol) was added at 0 °C and the reaction mixture
was stirred for an additional 15 min at the same temperature.
The reaction was quenched with a saturated NH4Cl (aq.) (60 mL)
solution at 0 °C, the two layers were separated and the aqueous
layer was extracted with CH2Cl2 (3 ꢂ 50 mL). The combined organ-
ic fraction was dried over anhydrous Na2SO4. The solvent was re-
moved through a rotary evaporator under reduced pressure and
the residue was purified through silica gel column chromatography
using 8% EtOAc/petroleum ether to yield TBDPS ether 16 as a col-
orless oil (7.45 g, 90%). Rf = 0.9 (SiO2, 30% EtOAc in petroleum
ether) 1H NMR (300 MHz, CDCl3): d 7.68–7.78 (m, 4H), 7.36–7.48
(m, 6H), 5.84 (d, 1H, J = 3.3 Hz), 4.58 (t, 1H, J = 3.9 Hz and 7.9 Hz),
3.71–3.95 (m, 3H), 2.13–2.24 (m, 1H), 1.53 (s, 3H), 1.36 (s, 3H),
1.07–1.11 (m, 12H); 13C NMR (75 MHz, CDCl3): d 135.6, 135.5,
134.7, 129.5, 127.6, 104.9, 83.1, 83.0, 63.1, 39.0, 26.7, 26.5, 26.3,
in petroleum ether) 1H NMR (300 MHz, CDCl3):
d 5.60 (d,
J = 3.5 Hz, 1H), 4.41 (t, J = 4.1 Hz, 1H), 4.03–3.91 (m, 1H), 3.90–
3.75 (m, 2H), 3.60–3.48 (m, 1H), 1.88–1.73 (m, 1H), 1.41 (s, 3H),
1.31 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 1.09 (d, J = 6.7 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 111.4, 109.3, 104.8, 83.4, 82.7, 77.8,
67.4, 42.7, 26.8, 26.6, 26.4, 25.3, 10.0; IR (KBr): mmax 3033, 2860,
1603, 1495, 1258, 1100, 1013, 911 cmꢁ1
; ESIMS: m/z 259.1
[M+H]+. ½a 2D0
¼ þ36 (c 1.0, CHCl3).
ꢃ
4.1.6. (R)-1-((3aR,5S,6R,6aR)-2,2,6-Trimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethane-1,2-diol 14
9.3; IR (Neat) mmax 2933, 1377, 1111, 1024, 704, 505 cmꢁ1
;
½
a 2D5
ꢃ
¼ þ7:8 (c 2.9, MeOH); ESI/HRMS calcd for C25H34O4Si
Deoxy glucose diacetonide 13 (9.80 g, 38 mmol) was treated
with 60% aqueous acetic acid (50 mL) and stirred at room temper-
ature for 12 h. After completion of the reaction, chloroform was
added and stirred for a further 30 min and the mixture was ex-
tracted with chloroform (3 ꢂ 100 mL). The combined organic lay-
ers were neutralized with solid NaHCO3 and stirring was
continued for 1 h. Next, it was filtered and concentrated to afford
a residue, which was purified by column chromatography using
petroleum ether/EtOAc (40:60) to give pure diol 14 (6.21 g, 75%
[M+Na]+ 449.2116, found 449.2102.
4.1.9. (2S,3S)-4-(tert-Butyldiphenylsilyloxy)-2-methylbutane-
1,3-diol 17
To a stirred solution of TBDPS protected compound 16 in CH2Cl2
was added a BCl3 solution (20 mL) at 0 °C. After 2 min, the reaction
was quenched with water (75 ml). The compound was extracted
twice with CH2Cl2 (2 ꢂ 50 mL). The organic layer was separated,
dried over anhydrous Na2SO4, and then concentrated using a rotary

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 23 (2012) 388–394
393
evaporator to afford the diol. The diol so obtained without further
purification was dissolved in MeOH:H2O (8:2) 40 mL and cooled to
0 °C. To this was added NaIO4 (11.2 g, 52.5 mmol) and the mixture
was stirred for 30 min The reaction mixture was then filtered, the
filtrate was evaporated, and the residue was dissolved in water
(50 mL) and extracted with EtOAc (3 ꢂ 60 mL). The combined or-
ganic layers were dried over anhydrous Na2SO4 and concentrated
in vacuo to afford the di-aldehyde, which was taken in MeOH
(60 mL) and cooled to 0 °C and then treated with NaBH4 (2.6 g,
70.0 mmol). After stirring the mixture for 30 min, the methanol
was evaporated and a saturated aqueous NH4Cl (20 mL) was
added. The mixture was extracted with diethyl ether. The organic
phase was dried (MgSO4) and concentrated in vacuo. Chromatogra-
phy (hexanes/EtOAc, 1:1) of the residue afforded 17 (4.8 g, overall
yield 78%) as a colorless oil. Rf = 0.19 (SiO2, 30% EtOAc in petroleum
ether). 1H NMR (300 MHz, CDCl3): d 7.64–7.75 (m, 4H), 7.32–7.48
(m, 6H), 3.55–4.0 (m, 5H), 2.09–2.25 (m, 1H), 1.07 (d, 12H,
J = 4.9 Hz), 0.88 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d
135.5, 129.6, 127.6, 78.4, 67.4, 65.1, 31.5, 26.7, 19.2, 12.8; IR (Neat)
mary alcohol as a colorless oil. To an ice-bath cooled solution of
primary alcohol (3 g, 7.4 mmol) in anhydrous CH2Cl2 (30 mL) were
added successively TEA (1.6 mL, 11.1 mmol), a solution of p-TsCl
(1.56 g, 8.2 mmol) in anhydrous CH2Cl2 (15 mL), and a catalytic
amount of DMAP. After being stirred at room temperature for
3 h, the reaction mixture was diluted with CH2Cl2 (25 mL) and
water, and the aqueous phase was extracted with CH2Cl2
(2 ꢂ 50 mL). The combined organic phases were washed succes-
sively with
a saturated solution of NaHCO3 (50 mL), brine
(50 mL) and dried over Na2SO4. After purification by flash chroma-
tography (eluent: EtOAc:petroleum ether = 10:90), product tosyl-
ate 19 (3.7 g, 90%) was obtained as a colorless oil. Rf = 0.65 (SiO2,
20% EtOAc in petroleum ether) 1H NMR (300 MHz, CDCl3): d
7.58–7.81 (m, 6H), 7.26–7.46 (m, 8H), 4.58 (d, 1H, J = 6.6 Hz),
4.48 (d, 1H, J = 6.7 Hz), 4.00–4.18 (m, 2H), 3.58–3.73 (m, 2H),
3.42–3.51 (m, 1H), 3.23 (s, 3H), 2.42 (s, 3H), 2.16–2.28 (m, 1H),
1.02 (s, 9H), 0.93 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d
135.5, 135.4, 129.6, 127.8, 127.6, 96.2, 78.7, 72.4, 63.6, 55.6, 34.6,
26.7, 21.5, 19.1, 13.5; IR (Neat) mmax 3430, 2930, 2856, 1360,
m
max 3450, 2932, 1425, 1340, 1111, 703, 504 cmꢁ1; ½a D25
ꢃ
¼ þ10:9 (c
1176, 1111, 817, 703, 505 cmꢁ1; ½a D25
¼ þ3:4 (c 2.5, MeOH); ESI/
ꢃ
2.4, MeOH); ESIMS: m/z 381 [M+Na]+.
HRMS calcd for C30H40O6SSi[M+Na]+ 579.2198, found 579.2215.
4.1.10. (6S,7S)-6-(methoxymethoxy)-2,2,7,10,10,11,11-hepta-
methyl-3,3-diphenyl-4,9-dioxa-3,10-disiladodecane 18
4.1.12. (S)-5-((S)-Hex-4-yn-2-yl)-9,9-dimethyl-8,8-diphenyl-
2,4,7-trioxa-8-siladecane 20
To an ice-bath cooled solution of diol 17 (4 g, 11 mmol), and
TEA (3.5 ml, 24 mmol) in anhydrous CH2Cl2 (50 mL) were added
a solution of TBDMSCl (1.8 g, 12.2 mmol) in anhydrous CH2Cl2
(15 mL) and a catalytic amount of DMAP. The mixture was stirred
at room temperature for 3 h, then diluted with water (50 mL) and
extracted with CHCl3 (3 ꢂ 60 mL). The combined organic phases
were washed with brine (50 mL) and dried over anhydrous Na2SO4.
After filtration and concentration in vacuo, the product was puri-
fied by flash chromatography (eluent; EtOAc: petroleum
ether = 1:4) to give primary TBS ether as a colorless oil in 85% yield.
To a stirred solution of the above alcohol (4.4 g, 9.3 mmol) and
diisopropylethyl amine (4.86 mL, 27.9 mmol) in dry CH2Cl2
(30 mL) were added MOMCl (0.97 g, 12 mmol) under a nitrogen
atmosphere over 5 min, and a catalytic amount of DMAP at 0 °C
after which the mixture was allowed to warm to room tempera-
ture for 5 h. After cooling to 0 °C, the reaction mixture was
quenched with water (30 mL) and extracted with CH2Cl2
(3 ꢂ 40 mL). The combined organic extracts were washed with
water (3 ꢂ 40 mL) and brine (40 mL), dried over anhydrous Na2SO4
and concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (9:1) gave MOM protected
alcohol 18 (4.8 g, 95% yield) as a colorless syrupy liquid. Rf = 0.74
(SiO2, 50% EtOAc in petroleum ether) 1H NMR (300 MHz, CDCl3):
d 7.66–7.81 (m, 4H), 7.37–7.49 (m, 6H), 4.75 (dd, 2H, J = 6.7 Hz
and 31.7 Hz), 3.76–3.85 (m, 2H), 3.64–3.71 (dd, 2H, J = 4.53 Hz
and 9.8 Hz), 3.54–3.62 (m, 1H), 3.37 (s, 3H), 1.96 ꢁ 2.11 (m, 1H),
1.09 (s, 9H), 0.89–0.95 (m, 12H), 0.05 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 135.6, 133.5, 129.5, 127.6, 96.6, 79.7, 64.8, 64.7, 55.6,
37.7, 26.8, 25.9, 19.2, 18.2, 13.4, -5.4; IR (Neat) mmax 3015, 1469,
1172, 1254, 1059, 703, 504 cmꢁ1; ESIMS: m/z 539 [M+Na]+.
Sodium hydrogen carbonate (0.79 g, 9.4 mmol) and sodium io-
dide (1.1 g, 7.5 mmol) were added to a solution of tosylate 19
(3.5 g, 6.2 mmol) in dry acetone (25 mL). The mixture was stirred
and heated at reflux for 3 h and extracted with pentane. The ex-
tracts were washed with water, a 10% sodium thiosulfate solution,
saturated sodium hydrogen carbonate and brine, dried over mag-
nesium sulfate and concentrated in vacuo to give the crude iodide.
Propyne gas (2.2 g, 54.6 mmol) was dissolved in dry THF (10 ml)
below ꢁ40 °C under Ar. It was then stirred for 10 min below
ꢁ50 °C and then nBuLi in hexane (1.60 M, 3.8 ml, 6.0 mmol) was
added slowly to the solution in a dropwise manner. The mixture
was then stirred for 10 min below ꢁ50 °C, after which HMPA
(1.5 ml) was added dropwise, and the mixture was stirred for a fur-
ther 30 min below ꢁ50 °C. Next, a second portion of nBuLi in hex-
ane (1.60 M, 3.8 ml, 6.0 mmol) was slowly added to the solution,
after which it was stirred for 10 min below ꢁ50 °C. A solution of
crude iodide (2.8 g, 5.4 mmol) in dry THF (50 ml) was added drop-
wise to this solution at ꢁ50 °C to ꢁ40 °C and the temperature was
gradually allowed to return to room temperature. After stirring for
3 h at room temperature, the mixture was poured into an ice-
cooled satd. ammonium chloride solution and extracted with
diethyl ether. The ether extracts were washed with a saturated
aqueous ammonium chloride solution, a saturated aqueous sodium
hydrogen carbonate solution and brine, dried over magnesium sul-
fate, and concentrated in vacuo after filtration. The residue was
chromatographed on silica gel (30 g). Elution with pentane diethyl
ether (25:l) gave 1.62 g of alkyne 20 (70%) as a viscous liquid.
Rf = 0.64 (SiO2, 10% EtOAc in petroleum ether). 1H NMR
(300 MHz, CDCl3): d 7.56–7.64 (m, 4H), 7.26–7.36 (m, 6H), 4.53–
4.69 (m, 2H), 3.61–3.70 (m, 2H), 3.42–3.51 (m, 1H), 3.27 (s, 3H),
1.86–2.33 (m, 3H), 1.68 (s, 3H), 0.92–1.01 (m, 12H); 13C NMR
(75 MHz, CDCl3): d 135.6, 135.5, 129.6, 129.6, 127.6, 96.4, 80.8,
64.2, 55.7, 34.5, 26.8, 22.0, 19.1, 15.9, 3.4; IR (Neat) mmax 2931,
½
a 2D0
ꢃ
¼ ꢁ12:9 (c 1, CHCl3).
4.1.11. (2S,3S)-4-(tert-Butyldiphenylsilyloxy)-3-
(methoxymethoxy)-2-methylbutyl 4-methylbenzenesulfonate
19
1428, 1109, 1035, 703, 504 cmꢁ1; ½a D25
¼ ꢁ12:8 (c 1.0, MeOH);
ꢃ
ESIMS: m/z 425 [M+H]+
.
To an ice-bath cooled solution of the TBS ether 18 (4.5 g,
8.7 mmol) in MeOH (40 mL) was added p-TsOH (300 mg). The reac-
tion mixture was stirred at 15 °C for 30 min The reaction mixture
was then quenched with solid NaHCO3 (2 g) and filtered. The fil-
trate was concentrated under reduced pressure and the crude
product was purified by column chromatography (3:1 hex-
anes:EtOAc ? 2:1 hexanes:EtOAc) to afford 3.04 g (87%) of the pri-
4.1.13. (2S,3S)-2-(Methoxymethoxy)-3-methylhept-5-yn-1-ol 21
A solution of TBDPS ether 20 (1.5 g, 3.5 mmol) in THF (30 mL)
was treated with TBAF (1 M in THF) (8 mL, 7.1 mmol) at 0 °C and
stirred for 30 min at room temperature. After completion of the
reaction, the reaction mixture was washed with an aq. saturated
NaHCO3 solution (20 mL). The organic layer was separated, dried

394
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 23 (2012) 388–394
over anhydrous Na2SO4, concentrated in vacuo, and then purified
by silica gel chromatography using petroleum ether/EtOAc
(80:20) to give pure product 21 (0.65 g, 98% yield) as a colorless
oil. Rf = 0.13 (SiO2, 10% EtOAc in petroleum ether). 1H NMR
(300 MHz, CDCl3): d 4.66–4.80 (m, 2H), 3.66–3.78 (m, 1H), 3.39–
3.60 (m, 5H), 1.80–2.04 (m, 3H), 1.77 (s, 3H), 0.96–1.08 (m, 3H);
13C NMR (75 MHz, CDCl3): d 96.3, 78.7, 72.4, 63.6, 55.6, 34.6,
26.7, 21.5, 19.1, 13.5; IR (Neat) mmax 3448, 2929, 2172, 1429,
4.1.15. (3aS,4R,5R,6aR)-5-hydroxy-4-((3S,4S,E)-3-hydroxy-4-
methyloct-1-en-6-ynyl)hexahydropentalen-2(1H)-one 3
A solution of MOM ether 22 and 6 M HCl(10 ml) was stirred for
20 h at room temperature. After completion of the reaction, the
mixture was extracted using EtOAc (3 ꢂ 10 mL). The combined or-
ganic layer was washed with
a sat. aq. NaHCO3 solution
(2 ꢂ 20 mL), then with brine, dried over anhydrous Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification by
silica gel column chromatography using EtOAc:Hex (4:1) as eluent
gave keto diol 3 (42 mg, 81%) as a colorless oil. Rf = 0.23 (SiO2, 30%
EtOAc in petroleum ether). 1H NMR (300 MHz, CDCl3): d 5.54–5.62
(m, 2H), 3.91–4.07 (m, 2H), 2.03–2.78 (m, 10H), 1.53–1.83 (m, 5H),
0.94 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d 220.1, 134.0,
132.5, 77.8, 77.4, 77.2, 76.0, 57.8, 45.9, 43.1, 42.3, 41.2, 38.2,
34.8, 22.1, 15.8, 3.5; IR (Neat) mmax 3446, 2925, 2855, 1737, 1640,
1106, 1034, 701 cmꢁ1; ½a D25
¼ ꢁ15:2 (c 1.2, MeOH); ESIMS: m/z
ꢃ
187 [M+H]+.
4.1.14. (3a0S,40R,50R,6a0R)-40-((3S,4S,E)-3-(Methoxymethoxy)-4-
methyloct-1-en-6-ynyl)-5,5-dimethylhexahydro-10H-
spiro[[1,3]dioxane-2,20-pentalen]-50-ol 22
To a solution of alcohol 21 (200 mg, 1.07 mmol) in THF (10 mL)
cooled to 0 °C were added 1-phenyl-1H-tetrazole-5-thiol (287 mg,
1.6 mmol), Ph3P (422 mg, 1.6 mmol), and DIAD (0.25 mL,
1.6 mmol), and the resultant solution was stirred at room temper-
ature for 30 min The reaction was quenched with a sat. aq. NaHCO3
(15 ml) solution at 0 °C, and the resultant mixture was extracted
with EtOAc (3 ꢂ 20 ml). The combined organic layer was washed
with brine, dried (Na2SO4), filtered, and concentrated under re-
duced pressure. Purification of the residue by flash chromatogra-
phy (silica gel, 10–15% EtOAc/hexanes) gave a sulfide (407.0 mg),
which contained some impurities but was used in the next reaction
without further purification.
To a solution of the above material (sulfide) in EtOH (10 mL)
was added a portion (3 mL) of a stock solution of (NH4)6Mo7O24.4-
H2O (330.0 mg) and 30% H2O2 (5 mL). The reaction mixture was
then stirred at room temperature for 20 h. The resultant mixture
was then extracted with EtOAc (3 ꢂ 10 mL), and the combined or-
ganic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the residue
by flash chromatography (silica gel, 10–15% EtOAc/hexanes) gave
sulfone 5 (360 mg, 89% for two steps) as a colorless oil. The crude
sulfone without further purification was directly utilized for the Ju-
lia olefination reaction.
1461, 1260, 1093, 1022, 799 cmꢁ1; ½a D25
¼ þ9 (c 1.0, MeOH);
ꢃ
ESIMS: m/z 299 [M+Na]+.
Acknowledgment
ChS thanks the CSIR, New Delhi for financial assistance.
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To a solution of sulfone 5 (100 mg, 0.27 mmol) in THF/HMPA
(5:1, v/v, 1.0 mL) cooled to ꢁ78 °C was added LHMDS (1.0 M solu-
tion in THF, 0.24 mL, 0.238 mmol), and the resultant solution was
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(5:1, v/v, 0.350 mL), and the resultant solution was allowed to
warm to room temperature over a period of 6.5 h. The reaction
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organic layer was washed brine, dried (Na2SO4), filtered, and con-
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major isomer 95% de (E)-olefin 22 (65 mg, 57%) as a light yellow
oil. Rf = 0.53 (SiO2, 20% EtOAc in petroleum ether). 1H NMR
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4.64 (m, 1H), 3.65–4.30 (m, 2H), 3.42–3.52 (m, 4H), 3.33–3.41
(m, 3H), 1.98–2.50 (m, 8H), 1.76–1.82 (m, 3H), 1.51–1.69 (m,
4H), 0.90–1.01 (m, 9H); 13C NMR (75 MHz, CDCl3): d 136.4, 130.7,
127.8, 110.1, 94.3, 81.6, 81.4, 78.1, 72.0, 72.0, 71.9, 58.3, 57.3,
55.3, 40.2, 37.0, 35.6, 30.0, 29.6, 22.4, 15.5, 3.4; IR (Neat) mmax
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3424, 2925, 2854, 1732, 1456, 1375, 1152, 1099, 1032, 766 cmꢁ1
;
½
a 2D5
ꢃ
¼ þ2:8 (c 0.49, MeOH); ESIMS: m/z 429 [M+Na]+.