A radical mediated approach to the stereoselective formal total synthesis of (+)-Sch 642305

Article abstract of DOI:10.1016/j.tet.2009.06.059

A formal total synthesis of (+)-Sch-642305 is described. The synthesis, which commenced from a simple chiral synthon (5S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one, employed, as a key step, a radical mediated opening of a chiral epoxy alcohol intermediate with Cp₂Ti(III)Cl following an efficient method developed by us earlier. The resultant intermediate radical was intramolecularly trapped by the electron deficient double bond present in the molecule to give rise to its highly functionalized six-membered carbocyclic ring in stereoselective manner.

Full text of DOI:10.1016/j.tet.2009.06.059

Tetrahedron 65 (2009) 6925–6931
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A radical mediated approach to the stereoselective formal total
synthesis of (þ)-Sch 642305q
,
b
b
Tushar Kanti Chakrabortya , Rajarshi Samanta , Pulukuri Kiran Kumar
*
a Central Drug Research Institute, CSIR, Chattar Manzil Palace, Post Box No. 173, Lucknow 226 001, UP, India
b Indian Institute of Chemical Technology, CSIR, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2009
Received in revised form 14 June 2009
Accepted 16 June 2009
Available online 21 June 2009
A formal total synthesis of (þ)-Sch-642305 is described. The synthesis, which commenced from a simple
chiral synthon (5S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one, employed, as a key step, a radical me-
diated opening of a chiral epoxy alcohol intermediate with Cp2Ti(III)Cl following an efficient method
developed by us earlier. The resultant intermediate radical was intramolecularly trapped by the electron
deficient double bond present in the molecule to give rise to its highly functionalized six-membered
carbocyclic ring in stereoselective manner.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
to the construction of the highly functionalized six member car-
bocyclic ring of the molecule.
Since the discovery of triphenylmethyl radical by Moses Gom-
berg, radical chemistry became a very useful tool in the arsenal of
synthetic organic chemists.1 Development of many improved
methods thereafter for the generation of radicals under easy and
mild conditions and the high tolerance of functional groups have
made radical mediated reactions increasingly useful in the syn-
thesis of structurally complex natural products.2–4 The work de-
scribed here is such an example which shows new perspective in
Ti(III) mediated reactions for the synthesis of compounds with
several chiral centres.
OH
O
O
O
Sch 642305
1
Figure 1.
Our target here is Sch 642305 (1, Fig. 1) isolated from Penicillium
verrucosum as a potent inhibitor of bacterial DNA primase.5 Because
DNA primase is necessary for the replication of chromosomal DNA,
its inhibitors can have very useful applications as potent antimi-
crobials.6,7 Jayasuriya and co-workers recently reported that Sch
642305 potently inhibits HIV-1 Tat transactivation too.8 The func-
tionally enriched bicyclic macrolide framework of 1, composed of
a decalactone moiety fused to a 4-hydroxycyclohexenone ring, is
synthetically challenging, especially because of the additional
presence of four stereogenic centres. As a result, several total syn-
theses of this molecule have already appeared in the literature.9–14
We wish to report here a formal total synthesis of (þ)-Sch 642305,
which employs, as a key step, the radical mediated opening of chiral
epoxy alcohol followed by intramolecular trapping of the resultant
intermediate radical by the electron deficient double bond leading
The method has been recently developed by us for the syntheses of
trans-fused highly substituted six member carbocycles,15 oxacycles16
and azacycles17 via Ti(III) mediated chiral epoxy alcohol opening fol-
lowed by 6-exo-trig mode of cyclization as shown in Scheme 1. Syn-
thesis of (þ)-Sch 642305 was undertaken to demonstrate the
application of this method in the synthesis of complex natural products.
H
X
O
X
CO2R
CH3
Cp2Ti(III)Cl
CO2R
CH3
H
OH
X= CH2, O, NTs
OH OH
Scheme 1.
Our retrosynthetic approach to the synthesis of (þ)-Sch 642305
is shown in Scheme 2. The principle reaction was Ti(III) mediated
opening of chiral epoxy alcohol 4 followed by intramolecular
trapping of the intermediate radical to lead to the cyclohexane ring
of the molecule. Now compound 7 would be prepared via Wittig
q
CDRI Communication No. 7800.
* Corresponding author. Tel.: þ91 522 2623286; fax: þ91 522 2623405/3938.
E-mail address: chakraborty@cdri.res.in (T.K. Chakraborty).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.059

6926
T.K. Chakraborty et al. / Tetrahedron 65 (2009) 6925–6931
OH
O
OTBDMS
CO2Et
OBn
prepared from L-glutamic acid in two steps using known
methods.18 Protection of the primary hydroxyl group as TBDMS
ether, and subsequent reduction of the lactone using LiBH4 fur-
nished the diol 8.
O
OH
O
O
2
O
OAc
3
Chemoselective acylation of the primary hydroxyl group
followed by TBDMS protection of the secondary hydroxyl group
led to the formation of globally protected compound 9.
Deacylation followed by Swern oxidation19 of the resultant
primary alcohol afforded an aldehyde intermediate, which on
Horner–Wadsworth–Emmons reaction with the keto-phos-
1
CH3
Ph3P
6
OTES
I
+
OTBDMS
CO2Et
HO
OTBDMS
CO2Et
CHO
OTBDMS
phonate 1020 afforded the desired
a,b-unsaturated keto com-
CO2Et
OBn
pound 11 in 75% yield. Luche reduction21 of 11 furnished an
inseperable mixture (1:1) of diastereomeric alcohols, which
were protected as acetate to provide 12. Selective deprotection
of the primary TBS with HF/Py afforded a primary alcohol,
which on oxidation under Dowering–Parikh22 conditions fol-
O
Ti(III)
O
OH
5
OH
4
7
Scheme 2. Retrosynthetic approach.
lowed
by
Wittig
olefination with
stabilized
ylide
Ph3P]CHCO2Et afforded the formation of
a,b-unsaturated ester
olefination from the chiral aldehyde 5 and phosphonium salt 6.
Both 5 and 6 could be synthesized from the same starting material
2, which in turn could be synthesized from cheap commercially
compound 3. K2CO3 mediated acetate deprotection of 3 set the
stage for Sharpless kinetic resolution23 of the intermediate
available starting material
L
-glutamic acid.18
diastereomeric mixture of allylic alcohols.
L
-(þ)-DIPT mediated
Sharpless kinetic resolution of the resultant diastereomeric
allylic alcohol afforded chiral epoxy alcohol 4 in 42% yield.
However, the unwanted allylic alcohol was also serviceable
through recycling via Swern oxidation followed by Luche re-
duction. Now 4 was well equipped for implementing the cru-
cial Ti(III) mediated epoxide opening followed by cyclization.
Indeed, on exposure to the Cp2Ti(III)Cl reagent, generated in
situ from Cp2TiCl2 and Zn dust and freshly fused ZnCl2,24
compound 4 underwent epoxide opening at C2 position from
the hydroxy side25 and gave rise to a radical intermediate that
2. Results and discussion
Synthesis of (þ)-Sch 642305 commenced from (5S)-5-(hydroxy-
methyl)dihydrofuran-2(3H)-one (2) (see Scheme 3), which was
OH
a, b
c, d
OH
OTBDMS
HO
O
O
2
8
OTBDMS
OTBDMS
was intramolecularly trapped by the
a,b-unsaturated ester
OTBDMS
OTBDMS
e, f, g
h, i
moiety leading to the formation of the highly substituted
six-membered trans-fused carbocyclic scaffold as the major prod-
uct (along with some unidentified complex mixture of com-
pounds as minor products), which was debenzylated to give triol
moiety 13.
AcO
OBn
9
O
P
O
11
EtO
EtO
O
OBn
10
OTBDMS
Synthesis of 6, the Wittig salt fragment, commenced from the
same starting material 2 (see Scheme 4). Compound 2 was
converted by reported procedure26 into known compound 14
which could be selectively mono acylated with acetyl chloride
followed by the protection of the secondary hydroxyl group as
TES ether to lead to all protected compound 15. Next 15 was
transformed into 6 in three stepsdselective acetyl deprotection,
iodide formation and finally, Wittig salt preparation using excess
TPP.
OTBDMS
OTBDMS
j, k, l
m, n
CO2Et
OBn
OAc
OBn
3
12
OAc
OTBDMS
CO2Et
OH
OTBDMS
CO2Et
OBn
q, r, s
o, p
O
6
H
13
4
OH OH
OH
a, b
CH3
OH
CH3
ref. 26
HO
CH3
OTES
AcO
2
Ph3P
I
14
15
OTES
6
OH
c, d, e
OTBDMS
CH3
H
ref.13
CH3
OH
Ph3P
I
O
6
CO2Et
OTES
O
CH3
Scheme 4. Reagents and conditions: (a) AcCl, 2,4,6-collidine, CH2Cl2, ꢁ78 ꢀC, 1.5 h,
85%; (b) TESCl, Et3N, DMAP, CH2Cl2, 0 ꢀC to rt, 10 min, 92%; (c) DIBAL-H, CH2Cl2, ꢁ78 ꢀC,
0.5 h, 95%; (d) TPP, I2, imidazole, Et2O/CH3CN (4:1), 0 ꢀC to rt, 0.5 h, 72%; (e) TPP, K2CO3,
CH3CN, reflux, 6 h, 75%.
H
O
7
O
1
Scheme 3. Reagents and conditions: (a) TBDMSCl, Et3N, DMAP, CH2Cl2, 0 ꢀC to rt, 8 h,
90%; (b) LiBH4, THF/H2O (20:1), 0 ꢀC to rt, 3 h, 95%; (c) AcCl, 2,4,6-collidine, CH2Cl2,
ꢁ78 ꢀC, 7 h, 88%; (d) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 ꢀC to rt, 5 min, 98%; (e) DIBAL-
H, CH2Cl2, ꢁ78 ꢀC, 0.5 h, 95%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 ꢀC, 1.5 h; (g)
Ba(OH)2, THF/H2O (20:1), 2 h, 75% in two steps; (h) NaBH4, CeCl3, MeOH, 0 ꢀC, 10 min,
98%; (i) Ac2O, Et3N, CH2Cl2, DMAP, 15 min, 95%; (j) HF/Py, THF, 0 ꢀC to rt, 8 h, 78%; (k)
SO3/Py, Et3N, CH2Cl2/DMSO(1:1.6), 0 ꢀC to rt, 15 min; (l) Ph3P]CHCO2Et, CH2Cl2, rt, 2 h,
72% in two steps; (m) K2CO3, EtOH, 0 ꢀC to rt, 6 h, 82%; (n) L-(þ)-DIPT, Ti(OiPr)4, TBHP,
CH2Cl2, MS 4 (Å), ꢁ20 ꢀC, 2 h, 42%; (o) Cp2TiCl2, Zn, ZnCl2, THF, ꢁ20 ꢀC to rt, 48 h, 65%;
(p) H2/Pd(C), dry EtOAc, 24 h, 80%; (q) (i). NaIO4, THF/H2O (1:1), 0 ꢀC to rt, 6 h; (ii).
nBuLi, 6, THF, ꢁ78 ꢀC, 0.5 h, 30% in two steps (based on recovered aldehyde); (r) DMP,
NaHCO3, CH2Cl2, 0 ꢀC to rt, 3 h, 70%; (s) H2/Pd(C), EtOAc/EtOH (1:1), 12 h, 75%.
Now NaIO4 mediated oxidative cleavage of 13 followed by
Wittig olefination with 6 led to the intermediate mixture of cis-
trans olefinic alcohol which could be oxidized by Dess–Martin
periodinane27 and finally, double bond saturation and selective
desilylation of TES ether were done under hydrogenation condi-
tion28 in one pot to get the compound 7. The spectral and analytical
data of 7 were in good agreement with that reported in the liter-
ature.13 Synthesis of 1 from 7 has already been reported.13

T.K. Chakraborty et al. / Tetrahedron 65 (2009) 6925–6931
6927
3. Conclusions
saturated aqueous NH4Cl solution at 0 ꢀC and was extracted with
EtOAc. The combined organic extracts were washed with water,
brine, dried (Na2SO4), filtered and concentrated in vacuo. Purifi-
cation of the residue by column chromatography (SiO2, 8% EtOAc
in petroleum ether eluant) provided diol compound 8 (8.2 g, 95%)
In summary, we have accomplished the formal total synthesis of
bioactive natural product (þ)-Sch 642305 through a radical medi-
ated epoxide opening followed by intramolecular cyclization
strategy using Cp2Ti(III)Cl and syntheses of both the fragments
commenced from the same cheap starting material. As these bi-
cyclic macrolides are having interesting biological activities, we
hope our synthetic strategy would be useful for the further in-
vestigation in the related fields.
as a colorless oil.
25
Rf¼0.3 (silica gel, 60 % EtOAc in hexane); [
a]
þ3.6 (c 5.3,
D
CHCl3); IR (neat): nmax 3340, 2929, 2858, 1361, 1254 cmꢁ1; 1H NMR
(200 MHz, CDCl3):
3.75–3.53 (m, 4H), 3.39 (dd, J¼9.5, 8.1 Hz, 1H),
2.71 (br s, 1H), 1.79–1.20 (m, 4H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR
d
(75 MHz, CDCl3):
d
71.7, 67.1, 62.2, 29.6, 28.8, 25.7, 18.1, ꢁ5.5; MS
4. Experimental
(ESI): m/z (%) 235 (95) [MþH]þ, 252 (85) [MþNH4]þ; HRMS (ESI):
calcd for C11H26O3NaSi [MþNa]þ 257.1549, found 257.1537.
4.1. General procedures
4.1.2. (S)-4,5-Bis(tert-butyldimethylsilyloxy)pentyl acetate (9)
To the stirred solution of diol 8 (8 g, 34.18 mmol) in dry CH2Cl2
(100 mL) at ꢁ78 ꢀC were added 2,4,6-collidine (11.9 mL,
102.54 mmol) followed by freshly distilled acetyl chloride (2.7 mL,
37.6 mmol). After being stirred for 7 h at the same temperature, it
was quenched by adding saturated aqueous NH4Cl solution and
extracted with EtOAc, washed with water, brine, dried (Na2SO4) and
concentrated in vacuo. Column chromatography (SiO2, 10% EtOAc in
petroleum ether eluant) of the residue afforded pure mono acety-
All reactions were carried out in oven or flame-dried glassware
with magnetic stirring under nitrogen atmosphere using dry,
freshly distilled solvents, unless otherwise noted. Reactions were
monitored by thin layer chromatography (TLC) carried out on
0.25 mm silica gel plates with UV light, I2, 7% ethanolic phospho-
molybdic acid-heat and 2.5% ethanolic anisaldehyde (with 1% AcOH
and 3.3% concd H2SO4)-heat as developing agents. Silica gel finer
than 200 mesh was used for flash column chromatography. Yields
refer to chromatographically and spectroscopically homogeneous
materials unless otherwise stated. Melting points are uncorrected.
IR spectra were recorded as neat liquids or KBr pellets. Mass spectra
were obtained under electron impact ionisation (EI), liquid sec-
ondary ion mass spectrometric (LSIMS) technique, electron spray
ionisation (ESI) and MALDI techniques. Optical rotations were
measured with a digital polarimeter. NMR spectra were recorded
on 500, 400, 300 and 200 MHz spectrometers at 30 ꢀC with 2–
10 mM solutions in appropriate solvents using TMS as internal
standard or the solvent signals as secondary standards and the
lated compound (8.3 g, 88%) as colorless oil.
31
Rf¼0.6 (silica gel, 30% EtOAc in hexane); [
a
]
þ6.2 (c 2.9, CHCl3);
D
IR (neat): nmax 2931, 2859, 1737, 1246 cmꢁ1
;
1H NMR (200 MHz,
CDCl3): 4.08 (t, J¼6.6 Hz, 2H), 3.68–3.55 (m, 2H), 3.38 (dd, J¼10.3,
8.1 Hz, 1H), 2.04 (s, 3H), 1.92–1.57 (m, 2H), 1.52–1.35 (m, 2H), 0.91
(s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 171.0, 71.2, 67.0,
64.3, 29.1, 25.8, 24.7, 20.8, 18.2, ꢁ5.4, ꢁ5.5; MS (ESI): m/z (%) 277
(70) [MþH]þ, 294 (100) [MþNH4]þ; HRMS (ESI): calcd for
C13H28O4NaSi [MþNa]þ 299.1654, found 299.1650.
To a solution of mono acetylated compound (8.0 g, 28.98 mmol)
in CH2Cl2 (90 mL), 2,6-lutidine (6.75 mL, 57.97 mmol) and
TBDMSOTf (7.3 mL, 31.88 mmol) were added sequentially at 0 ꢀC,
under nitrogen atmosphere. The reaction mixture was stirred from
0 ꢀC to room temperature for 5 min and it was then quenched by
adding saturated aqueous NaHCO3 solution. The resulting mixture
was extracted with EtOAc and the organic extracts were washed
with saturated aqueous CuSO4 solution, water, brine, dried
(Na2SO4), filtered and concentrated in vacuo. Purification by col-
umn chromatography (SiO2, 5% EtOAc in petroleum ether eluant)
chemical shifts are shown in
d scales. Multiplicities of NMR signals
are designated as s (singlet), d (doublet), t (triplet), q (quartet), br
(broad), m (multiplet, for unresolved lines), etc. 13C NMR spectra
were recorded on 75 and 100 MHz spectrometers with complete
proton decoupling.
4.1.1. (S)-5-(tert-Butyldimethylsilyloxy)pentane-1,4-diol (8)
Et3N (12.01 mL, 86.2 mmol) and TBDMSCl (8.445 g, 56.03 mmol)
were added sequentially to a solution of compound 218 (5 g,
43.1 mmol) in dry CH2Cl2 (150 mL) at 0 ꢀC. After being stirred for
15 min at the same temperature, DMAP (525 mg, 4.3 mmol) was
added and stirring was continued for 8 h with slow warming to
room temperature. The reaction mixture was quenched with sat-
urated aqueous NH4Cl solution and extracted with EtOAc. The
combined organic extracts were washed with water, brine, dried
(Na2SO4), filtered and concentrated in vacuo. Purification of the
residue by column chromatography (SiO2, 15% EtOAc in petroleum
ether eluant) provided pure TBDMS ether compound (8.9 g, 90 %) as
furnished compound 9 (11.1 g, 98%) as a colourless liquid.
24
Rf¼0.7 (silica gel, 10% EtOAc in hexane); [
a
]
ꢁ19.5 (c 2.8,
D
CHCl3); IR (neat): nmax 2953, 2858, 1742, 1243 cmꢁ1
;
1H NMR
(300 MHz, CDCl3):
d
4.04 (t, J¼6.4 Hz, 2H), 3.66 (m, 1H), 3.51 (dd,
J¼9.8, 5.3 Hz, 1H), 3.37 (dd, J¼9.8, 6.8 Hz, 1H), 2.03 (s, 3H), 1.78–1.55
(m, 3H), 1.43 (m, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H), 0.05 (s,
6H); 13C NMR (75 MHz, CDCl3):
d 171.1, 72.5, 66.9, 64.7, 30.5, 25.9,
25.8, 24.1, 20.9, 18.3, 18.1, ꢁ4.3, ꢁ4.8, ꢁ5.3, ꢁ5.4; MS (ESI): m/z (%)
391 (50) [MþH]þ, 408 (100) [MþNH4]þ; HRMS (ESI): calcd for
C19H42O4NaSi2 [MþNa]þ 413.2519, found 413.2508.
a colorless oil.
30
Rf¼0.5 (silica gel, 30 % EtOAc in hexane); [
a
]
D
þ18.1 (c 1.5,
CHCl3); IR (neat): nmax 2934, 2859, 1774, 1255, 1173, 1118 cmꢁ1
NMR (400 MHz, CDCl3):
;
1H
4.1.3. (S,E)-1-(Benzyloxy)-7,8-bis(tert-butyldimethylsilyloxy)-
oct-3-en-2-one (11)
d
4.52 (m, 1H), 3.82 (dd, J¼11.2, 2.6 Hz, 1H),
3.65 (dd, J¼11.2, 3.5 Hz, 1H), 2.54 (ddd, J¼17.3, 10.4, 6.9 Hz,1H), 2.40
To a solution of compound 9 (10.0 g, 25.57 mmol) in dry CH2Cl2
(75 mL) at ꢁ78 ꢀC, DIBAL-H (1.2 M solution in toluene, 45 mL,
53.7 mmol) was added slowly with stirring under nitrogen atmo-
sphere. After stirring for 0.5 h, at the same temperature, the re-
action mixture was quenched with dry MeOH and stirred for 0.5 h,
then Na/K tartrate was added, the resulting mixture was brought to
room temperature and stirred for 1 h. It was then extracted with
EtOAc and extracts were washed with water, brine, dried (Na2SO4),
filtered and concentrated in vacuo. Purification of the residue by
column chromatography provided the deacylated product (SiO2,
10% EtOAc in petroleum ether eluant, 8.45 g, 95%).
(ddd, J¼17.3, 9.5, 6.0 Hz, 1H), 2.30–2.09 (m, 2H), 0.87 (s, 9H), 0.05 (s,
3H), 0.045 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 177.5, 80.0, 64.8,
28.5, 25.7, 23.5, 18.2, ꢁ5.5, ꢁ5.6; (ESI): m/z (%) 248 (100)
[MþNH4]þ; HRMS (ESI): calcd for C11H22O3NaSi [MþNa]þ 253.1235,
found 253.1237.
Now to
a solution of TBDMS ether compound (8.5 g,
36.9 mmol) in THF/H2O (100 mL:0.1 mL) at 0 ꢀC, LiBH4 (804 mg,
36.9 mmol) was added portion wise with stirring under nitrogen
atmosphere and stirring was continued for 3 h at room temper-
ature. The reaction mixture was carefully quenched with

6928
T.K. Chakraborty et al. / Tetrahedron 65 (2009) 6925–6931
23
Rf¼0.6 (silica gel, 20% EtOAc in hexane); [
IR (neat): nmax 3030, 2931, 2859, 1467, 1252 cmꢁ1
(300 MHz, CDCl3): 3.71 (m, 1H), 3.65–3.56 (m, 2H), 3.53 (dd,
a
]
ꢁ7.6 (c 1.1, CHCl3);
1.62 (m, 1H), 1.45 (m, 1H), 0.88 (s, 9H), 0.87 (s, 9H), 0.04 (s, 12H);
MS (ESI): m/z (%) 512 (100) [MþNH4]þ, 517 (60) [MþNa]þ; HRMS
(ESI): calcd for C27H50O4NaSi2 [MþNa]þ 517.3145, found
517.3135.
D
;
1H NMR
d
J¼9.8, 5.3 Hz, 1H), 3.43 (dd, J¼9.8, 6.8 Hz, 1H), 1.82 (br s, 1H), 1.71–
1.48 (m, 4H), 0.89 (s, 18H), 0.07 (s, 6H), 0.053 (s, 3H), 0.048 (s, 3H);
To a solution of diastereomeric allylic alcohol compounds (7.5 g,
15.15 mmol) in CH2Cl2 (45 mL), Et3N (6.3 mL, 45.45 mmol), Ac2O
(2.1 mL, 22.7 mmol) and DMAP (183 mg, 1.5 mmol) were added
sequentially at 0 ꢀC, under nitrogen atmosphere. After stirring for
15 min at that temperature, the reaction mixture was quenched by
saturated aqueous NaHCO3 solution and extracted with EtOAc. The
organic extracts were washed with water, brine, dried (Na2SO4),
filtered and concentrated in vacuo. Purification by column chro-
matography (SiO2, 5–6% EtOAc in petroleum ether eluant) fur-
nished 12 (7.7 g, 95%) as a colorless liquid.
13C NMR (75 MHz, CDCl3):
d 72.5, 66.6, 62.7, 30.5, 27.8, 25.7, 25.6,
18.1, 17.8, ꢁ4.6, ꢁ5.0, ꢁ5.6, ꢁ5.7; MS (ESI): m/z (%) 349 (100)
[MþH]þ; HRMS (ESI): calcd for C17H40O3NaSi2 [MþNa]þ 371.2437,
found 371.2410.
To a solution of oxalyl chloride (3.0 mL, 34.5 mmol) in dry
CH2Cl2 (80 mL) at ꢁ78 ꢀC, DMSO (5.2 mL, 73.57 mmol) was added
slowly, in drop wise manner, with stirring under nitrogen atmo-
sphere. After 15 min stirring, deacylated primary alcohol (8.0 g,
23 mmol, dissolved in 20 mL of dry CH2Cl2) was added to the re-
action mixture. After 0.5 h of stirring at ꢁ78 ꢀC, Et3N (16 mL,
115 mmol) was added and stirred for another 0.5 h at ꢁ78 ꢀC and
then for 0.5 h at 0 ꢀC. The reaction mixture was then quenched with
saturated aqueous NH4Cl and extracted with EtOAc. The combined
organic extracts were washed with water, brine, dried (Na2SO4),
filtered and concentrated in vacuo. The aldehyde thus obtained,
was directly used after one flash chromatography in the next re-
action, without any further characterization.
Rf¼0.5 (silica gel, 10% EtOAc in hexane); IR (neat): nmax 2930,
2857, 1743, 1472, 1236, 1115 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
7.34–7.19 (m, 5H), 5.76 (m, 1H), 5.48–5.36 (m, 2H), 4.55 and 4.49
(two d, J¼12.8 Hz, 2H), 3.62 (m, 1H), 3.55–3.43 (m, 3H), 3.36 (dd,
J¼9.8, 6.0 Hz, 1H), 2.20–1.19 (m, 2H), 2.05 (s, 3H), 1.62 (m, 1H), 1.45
(m, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.04 (br s, 12H); MS (ESI): m/z (%)
554 (100) [MþNH4]þ; HRMS (ESI): calcd for C29H52O5NaSi2
[MþNa]þ 559.3251, found 559.3242.
To a solution of the aldehyde and the keto phosphonate 10
(8.28 g, 27.6 mmol) in THF/H2O (100 mL:5 mL), Ba(OH)2$8H2O
(5.4 g, 17.2 mmol) was added portion wise at 0 ꢀC and the reaction
was continued for 2 h at the same temperature. Then the reaction
mixture was carefully quenched with saturated aqueous NaHCO3
solution at 0 ꢀC and filtered through sintered funnel. The filtrate
was extracted with EtOAc. The combined organic extracts were
washed with water, brine, dried (Na2SO4), filtered and concentrated
in vacuo. Purification of the residue by column chromatography
4.1.5. (4S,2E,7E)-Ethyl 9-acetoxy-10-(benzyloxy)-4-(tert-
butyldimethylsilyloxy)deca-2,7-dienoate (3)
The compound 12 was dissolved in THF (35 mL) in a plastic vial
and aqueous HF/Py (1.4 mL) was added to it. The reaction mixture
was stirred for 8 h at room temperature. The reaction mixture was
poured into cold saturated aqueous NaHCO3 solution (25 mL) and
extracted with EtOAc. The organic layers were washed with water,
brine, dried (Na2SO4) and concentrated in vacuo. Column chro-
matography (SiO2, 18–20% EtOAc in petroleum ether eluant) gave
pure primary alcohol compound (4.6 g, 78%) as colorless liquid.
Rf¼0.4 (silica gel, 30% EtOAc in hexane); IR (neat): nmax 3466,
2930, 2857,1736,1369,1237,1104 cmꢁ1; 1H NMR (400 MHz, CDCl3):
(SiO2, 5% EtOAc in petroleum ether eluant) provided
a,b-un-
saturated keto compound 11 (8.5 g, 75%) as a colorless oil.
25
Rf¼0.6 (silica gel, 10 % EtOAc in hexane); [
a]
ꢁ15.9 (c 1.2,
D
CHCl3); IR (neat): nmax 2954, 2929, 2857, 1697, 1624, 1472, 1254,
1100 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.34–7.25 (m, 5H), 6.97 (dt,
d 7.38–7.22 (m, 5H), 5.75 (m, 1H), 5.52–5.31 (m, 2H), 4.56 and 4.48
J¼15.9, 6.8 Hz, 1H), 6.32 (d, J¼15.9 Hz, 1H), 4.58 (s, 2H), 4.13 (s, 2H),
3.66 (m,1H), 3.51 (dd, J¼9.8, 5.3 Hz,1H), 3.36 (dd, J¼9.8, 6.8 Hz,1H),
2.38–2.17 (m, 2H), 1.79–1.47 (m, 2H), 0.89 (s, 9H), 0.88 (s, 9H), 0.04
(two d, J¼12.4 Hz, 2H), 3.68 (m, 1H), 3.58–3.33 (m, 4H), 2.30 (m,
1H), 2.16–1.97 (m, 4H), 1.66–1.49 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H);
MS (ESI): m/z (%) 445 (100) [MþNa]þ; HRMS (ESI): calcd for
C23H38O5NaSi [MþNa]þ 445.2386, found 445.2400.
(br s, 12H); 13C NMR (75 MHz, CDCl3):
d 196.9, 148.9, 137.3, 129.9,
128.5, 127.9, 125.9, 73.9, 73.3, 72.2, 66.9, 32.5, 28.2, 25.9, 25.8, 18.3,
18.1, ꢁ4.3, ꢁ4.7, ꢁ5.3, ꢁ5.4; MS (ESI): m/z (%) 493 (15) [MþH]þ, 510
(35) [MþNH4]þ; HRMS (ESI): calcd for C27H48O4NaSi2 [MþNa]þ
515.2988, found 515.3000.
To a solution of primary alcohol (4 g, 9.46 mmol) in dry CH2Cl2
(12 mL) and dry DMSO (19 mL), Et3N (6.6 mL, 47.3 mmol) followed
by SO3/Py complex (7.5 g, 47.3 mmol) were added portion wise at
0 ꢀC under nitrogen atmosphere. After 15 min of stirring at 0 ꢀC, the
reaction was quenched with saturated aqueous NH4Cl solution and
extracted with EtOAc. The combined organic extracts were washed
with saturated aqueous CuSO4 solution, water, brine, dried
(Na2SO4), and concentrated in vacuo. The aldehyde (Rf¼0.55, 20%
EtOAc in petroleum ether) thus obtained by flash chromatography
was directly used for the next reaction.
4.1.4. (7S,E)-1-(Benzyloxy)-7,8-bis(tert-butyldimethylsilyloxy)-
oct-3-en-2-yl acetate (12)
To a solution of compound 11 (8.0 g, 16.26 mmol) in dry MeOH
(45 mL), CeCl3$6H2O (9.05 g, 24.3 mmol) was added portion wise
at 0 ꢀC under nitrogen atmosphere. Stirring was continued for
15 min at the same temperature. Then NaBH4 (921 mg, 24.3 mmol)
was added portion wise to the reaction mixture and the stirring
was continued for 10 min. The reaction mixture was then
quenched with saturated aqueous NH4Cl solution and extracted
with EtOAc. The combined organic extracts were washed with
water, brine, dried (Na2SO4), filtered and concentrated in vacuo.
Purification of the residue by column chromatography (SiO2, 10%
EtOAc in petroleum ether eluant) provided the mixture of di-
astereomeric allylic alcohol compounds (7.87 g, 98%) as a colorless
oil.
To the stirred solution of the aldehyde (9.46 mmol) in CH2Cl2
(25 mL), stabilized ylide Ph3P]CHCO2Et (6.6 g, 18.9 mmol) was
added at room temperature under nitrogen atmosphere. After be-
ing stirred for 2 h, the reaction mixture was concentrated and the
residue was purified by column chromatography (SiO2, 8% EtOAc in
petroleum ether eluant) to give the compound 3 (3.3 g, 72% over
two steps) as a colorless oil.
Rf¼0.7 (silica gel, 20 % EtOAc in hexane); IR (neat): nmax 2934,
2857, 1721 (br), 1658, 1460, 1368, 1237 cmꢁ1 1H NMR (300 MHz,
;
CDCl3):
d
7.36–7.26 (m, 5H), 6.85 (dd, J¼15.7, 4.8 Hz, 1H), 5.92 (d,
Rf¼0.5 (silica gel, 20% EtOAc in hexane); IR (neat): nmax 2929,
J¼15.7 Hz, 1H), 5.75 (m, 1H), 5.49–5.35 (m, 2H), 4.55 and 4.51 (two
d, J¼12.3 Hz, 2H), 4.30 (m, 1H), 4.19 (qd, J¼6.8, 2.7 Hz, 2H), 3.55–
3.44 (m, 2H), 2.15–2.04 (m, 2H), 2.07 (s, 3H), 1.67–1.59 (m, 2H), 1.32
(t, J¼6.8 Hz, 3H), 0.93 (s, 9H), 0.07–0.03 (m, 6H); MS (ESI): m/z (%)
508 (100) [MþNH4]þ, 513 (40) [MþNa]þ; HRMS (ESI): calcd for
C27H42O6NaSi [MþNa]þ 513.2648, found 513.2647.
2857, 1463, 1253, 1108 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 7.35–
7.22 (m, 5H), 5.74 (dt, J¼15.3, 7.2 Hz, 1H), 5.40 (dd, J¼15.3, 6.4 Hz,
1H), 4.56 and 4.53 (two d, J¼12.1 Hz, 2H), 4.24 (m, 1H), 3.63 (m,
1H), 3.49 (dd, J¼9.7, 4.8 Hz, 1H), 3.46 (dd, J¼9.7, 3.2 Hz, 1H), 3.37
(dd, J¼9.7, 6.4 Hz, 1H), 3.30 (t, J¼9.7 Hz, 1H), 2.20–1.96 (m, 2H),

T.K. Chakraborty et al. / Tetrahedron 65 (2009) 6925–6931
6929
4.1.6. (S,E)-Ethyl 6-((2S,3S)-3-((S)-2-(benzyloxy)-1-
hydroxyethyl)oxiran-2-yl)-4-(tert-butyldimethylsilyloxy)-
hex-2-enoate (4)
and 4.53 (two d, J¼12.5 Hz, 2H), 4.22–4.08 (m, 3H), 4.03–3.88 (m,
3H), 3.86–3.68 (m, 2H), 3.61 (dd, J¼9.5, 5.1 Hz, 1H), 2.58 (m, 1H),
2.38 (dd, J¼8.8, 5.5 Hz, 2H), 1.98 (m, 1H), 1.85–1.40 (m, 4H), 1.27 (t,
J¼7.3 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3):
The a,b-unsaturated ester compound 3 was dissolved in EtOH
(20 mL) and K2CO3 (1.7 g, 12.2 mmol) was added at 0 ꢀC under ni-
trogen atmosphere and stirred for 6 h. The reaction mixture was
slowly allowed to come at room temperature. It was then quenched
with saturated aqueous NH4Cl solution and extracted with EtOAc.
The combined extracts were washed with water, brine, dried
(Na2SO4), and concentrated in vacuo. Purified by column chroma-
tography (SiO2, 15% EtOAc in petroleum ether eluant) to provide
allylic alcohol (2.02 g, 75%) as a colorless liquid.
d 175.1, 128.4, 127.7, 127.6, 73.5, 72.4, 71.3, 70.9, 67.1, 60.9, 40.6, 36.2,
33.6, 27.3, 26.7, 25.9, 18.1, 14.1, ꢁ4.2, ꢁ5.1; MS (ESI): m/z (%) 467 (80)
[MþH]þ, 484 (100) [MþNH4]þ; HRMS (ESI): calcd for C25H42O6NaSi
[MþNa]þ 489.2648, found 489.2635.
The 1,3-diol (300 mg, 0.64 mmol) was dissolved in dry EtOAc
(6 mL) and 10% Pd on charcoal (30 mg) was added and subjected to
hydrogenation under atmospheric pressure using a H2-filled bal-
loon. After 24 h, the reaction mixture was filtered through a short
pad of Celite and the filter cake was washed with EtOAc. The filtrate
and washings were combined, concentrated in vacuo and purified
by column chromatography (SiO2, 70% EtOAc in petroleum ether
eluant) to provide the pure triol compound 13 (193 mg, 80%) as
Rf¼0.5 (silica gel, 30% EtOAc in hexane); IR (neat): nmax 3461,
2954, 2930, 2857, 1721, 1258, 1103 cmꢁ1 1H NMR (200 MHz,
;
CDCl3):
d
7.38–7.23 (m, 5H), 6.85 (dd, J¼15.4, 4.4 Hz, 1H), 5.90 (dd,
J¼15.4, 1.5 Hz, 1H), 5.72 (dt, J¼14.7, 6.6 Hz, 1H), 5.40 (dd, J¼14.7,
5.1 Hz, 1H), 4.54 (s, 2H), 4.37–4.10 (m, 4H), 3.44 (dd, J¼9.5, 3.7 Hz,
1H), 3.28 (dd, J¼9.5, 8.1 Hz, 1H), 2.16–2.01 (m, 2H), 1.70–1.56 (m,
2H), 1.31 (t, J¼7.3 Hz, 3H), 0.91 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); MS
(ESI): m/z (%) 466 (100) [MþNH4]þ; HRMS (ESI): calcd for
C25H40O5NaSi [MþNa]þ 471.2542, found 471.2531.
a gummy liquid.
24
Rf¼0.3 (silica gel, 70% EtOAc in hexane); [
a]
þ32.0 (c 1.5,
D
CHCl3); IR (neat): nmax 3446, 2930, 1734, 1473, 1075 cmꢁ1; 1H NMR
(200 MHz, CDCl3): 4.32–4.07 (m, 4H), 3.95 (br s, 2H), 3.86 (m, 1H),
d
3.75–3.50 (m, 2H), 2.52 (m,1H), 2.36 (dd, J¼6.6, 3.7 Hz, 2H),1.99 (m,
To a suspension of activated 4 Å MS (340 mg, 20 mol %) in
1H), 1.83–1.40 (m, 4H), 1.30 (t, J¼6.6 Hz, 3H), 0.89 (s, 9H), 0.06 (s,
CH2Cl2 (10 mL), Ti(OiPr)4 (1.12 mL, 3.78 mmol) and
L-(þ)-DIPT
6H); 13C NMR (75 MHz, CDCl3):
d 175.4, 72.9, 71.2, 67.5, 65.1, 61.0,
(0.96 mL, 4.55 mmol) were added sequentially at ꢁ20 ꢀC under
nitrogen atmosphere. After 20 min of stirring, a solution of di-
astereomeric mixture of allylic alcohols (1.7 g, 3.78 mmol) in CH2Cl2
(5 mL) was added and stirring continued for 30 min at the same
temperature. Then TBHP (3.46 M in toluene, 1.27 mL, 4.38 mmol)
was added to the reaction mixture and stirred for another 1.5 h
at ꢁ20 ꢀC. The reaction was quenched with H2O (50 mL) and tem-
perature was allowed to come to 0 ꢀC and vigorously stirred for 1 h.
Then it was extracted with EtOAc. The combined organic extracts
were washed with water, brine, dried (Na2SO4), and concentrated
in vacuo. Purified by column chromatography (SiO2, 15% EtOAc in
petroleum ether eluant) to provide the pure chiral epoxy alcohol
40.9, 36.3, 33.7, 27.2, 26.7, 25.8, 18.1, 14.1, ꢁ4.3, ꢁ5.1; MS (ESI): m/z
(%) 377 (100) [MþH]þ, 394 (90) [MþNH4]þ; HRMS (ESI): calcd for
C18H36O6NaSi [MþNa]þ 399.2178, found 399.2181.
4.1.8. (R)-4-(Triethylsilyloxy)pentyl acetate (15)
To the stirred solution of diol 1426 (1.3 g, 12.5 mmol) in dry
CH2Cl2 (40 mL) at ꢁ78 ꢀC were added 2,4,6-collidine (4.37 mL,
37.5 mmol) followed by freshly distilled acetyl chloride (0.97 mL,
13.75 mmol). After being stirred for 1.5 h at the same temperature,
it was quenched by adding saturated aqueous NH4Cl solution and
extracted with EtOAc, washed with water, saturated CuSO4 solu-
tion, brine, dried (Na2SO4) and concentrated in vacuo. Column
chromatography (SiO2, 20% EtOAc in petroleum ether eluant) of the
residue afforded pure mono acetylated compound (1.55 g, 85%) as
colorless oil.
compound 4 (739 mg, 42%) as a colorless liquid.
25
Rf¼0.5 (silica gel, 30% EtOAc in hexane); [
a
]
ꢁ11.4 (c 1.1,
D
CHCl3); IR (neat): nmax 3473, 2931, 2858, 1717, 1657, 1461, 1365,
1260 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
d
7.38–7.27 (m, 5H), 6.84
Et3N (2.67 mL, 19.18 mmol) and TESCl (2.42 mL, 14.4 mmol)
were added sequentially to a solution of mono acetylated com-
pound (1.4 g, 9.6 mmol) in dry CH2Cl2 (40 mL) at 0 ꢀC. After being
stirred for 5 min at the same temperature, DMAP (117 mg,
0.96 mmol) was added and stirring was continued for 10 min with
slow warming to room temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl solution and extracted
with EtOAc. The combined organic extracts were dried (Na2SO4),
filtered and concentrated in vacuo. Purification of the residue by
column chromatography (SiO2, 3–5% EtOAc in petroleum ether el-
uant) provided pure TES ether compound 15 (2.3 g, 92 %) as a col-
(dd, J¼15.4, 4.4 Hz, 1H), 5.93 (dd, J¼15.4, 1.5 Hz, 1H), 4.57 (s, 2H),
4.38 (m, 1H), 4.19 (q, J¼7.4 Hz, 2H), 3.66 (m, 1H), 3.60–3.49 (m, 2H),
2.92 (m, 1H), 2.77 (dd, J¼5.1, 2.2 Hz, 1H), 1.76–1.48 (m, 4H), 1.32 (t,
J¼6.6 Hz, 3H), 0.93 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 166.5, 150.1, 137.6, 128.4, 127.8, 127.7, 120.4, 73.5,
71.3, 70.8, 69.5, 60.4, 58.0, 55.9, 33.1, 26.6, 25.8, 18.1, 14.2, ꢁ4.6,
ꢁ4.9; MS (ESI): m/z (%) 465 (10) [MþH]þ, 482 (100) [MþNH4]þ;
HRMS (ESI): calcd for C25H40O6NaSi [MþNa]þ 487.2491, found
487.2481.
4.1.7. Ethyl 2-((1R,2R,3S,6S)-6-(tert-butyldimethylsilyloxy)-2-
((R)-1,2-dihydroxyethyl)-3-hydroxycyclohexyl)acetate (13)
orless oil.
24
Rf¼0.6 (silica gel, 10% EtOAc in hexane); [
a
]
ꢁ11.9 (c 2.6,
D
Activated Zn powder (507 mg, 7.75 mmol), freshly fused ZnCl2
(524 mg, 3.87 mmol) and Cp2TiCl2 (963 mg, 3.87 mmol) were taken
in dry THF (35 mL) and stirred for 0.5 h at room temperature. The
color of the reaction mixture turned into deep green. Then it was
cooled to ꢁ20 ꢀC and epoxy alcohol 4 (600 mg, 1.29 mmol) in dry
THF (10 mL) was added. The reaction mixture was allowed to come
at room temperature slowly. Then it was stirred for 48 h. Reaction
was quenched with saturated aqueous NH4Cl solution and extrac-
ted with EtOAc. The combined organic layer was washed with H2O,
brine, dried (Na2SO4) and concentrated in vacuo. Purification by
column chromatography (SiO2, 25% EtOAc in petroleum ether elu-
CHCl3); IR (neat): nmax 2956, 2877, 1743, 1236, 1045, 1007 cmꢁ1; 1H
NMR (300 MHz, CDCl3):
d
4.03 (t, J¼6.8 Hz, 2H), 3.82 (sextet,
J¼6.0 Hz, 1H), 2.03 (s, 3H), 1.78–1.50 (m, 2H), 1.53–1.40 (m, 2H), 1.14
(d, J¼6.0 Hz, 3H), 0.96 (t, J¼7.5 Hz, 9H), 0.58 (q, J¼7.5 Hz, 6H); 13C
NMR (75 MHz, CDCl3):
d 171.1, 67.9, 64.6, 35.8, 24.9, 23.7, 20.9, 6.8,
4.9; MS (ESI): m/z (%) 283 (80) [MþNa]þ; HRMS (ESI): calcd for
C13H28O3NaSi [MþNa]þ 283.1705, found 283.1715.
4.1.9. (R)-Triphenyl(4-(triethylsilyloxy)pentyl)phosphonium
iodide (6)
To a solution of compound 15 (2.2 g, 8.44 mmol) in dry CH2Cl2
(35 mL) at ꢁ78 ꢀC, DIBAL-H (1.2 M solution in toluene, 15.5 mL,
18.56 mmol) was added slowly with stirring under nitrogen at-
mosphere. After stirring for 0.5 h, at the same temperature, the
reaction mixture was quenched with dry MeOH and stirred for
ant) provided the 1,3-diol as pure gummy liquid (391 mg, 65%).
24
Rf¼0.5 (silica gel, 30 % EtOAc in hexane); [
a]
þ26.5 (c 1.1,
D
CHCl3); IR (neat): nmax 3442, 2930, 2857, 1732, 1252, 1106,
1038 cmꢁ1 1H NMR (200 MHz, CDCl3):
7.39–7.29 (m, 5H), 4.63
;
d

6930
T.K. Chakraborty et al. / Tetrahedron 65 (2009) 6925–6931
0.5 h. Then Na/K tartrate was added and the resulting mixture was
brought to room temperature and stirred for 1 h. It was then
extracted with EtOAc and extracts were washed with water, brine,
dried (Na2SO4), filtered and concentrated in vacuo. Purification of
the residue by column chromatography provided the deacylated
starting material) as a colorless oil. (Rf¼0.5, 20% EtOAc in petroleum
ether).
To a stirred solution of olefins (15 mg, 0.028 mmol) in CH2Cl2
(2 mL), NaHCO3 (14 mg, 0.17 mmol) followed by Dess–Martin
periodinane (59 mg, 0.14 mmol) were added at 0 ꢀC under nitrogen
atmosphere, then allowed to come to room temperature and stirred
for 3 h. Saturated Na2S2O3 solution were added and the biphasic
mixture was stirred for 15 min and extracted with EtOAc. The or-
ganic extracts were washed with saturated NaHCO3 solution, water,
brine, dried (Na2SO4) and concentrated in vacuo. The keto com-
pound (Rf¼0.6, 20% EtOAc in petroleum ether), thus obtained in 70%
yield, was directly used after flash chromatography for the next
reaction without further characterization.
product (SiO2,12–13% EtOAc in petroleum ether eluant,1.75 g, 95%).
31
Rf¼0.5 (silica gel, 30 % EtOAc in hexane); [
a]
ꢁ8.5 (c 1.4, CHCl3);
D
IR (neat): nmax 3336, 2953, 2876, 1048, 1005 cmꢁ1
(300 MHz, CDCl3):
;
1H NMR
d
3.89 (sextet, J¼6.0 Hz, 1H), 3.68–3.52 (m, 2H),
1.94 (br s, 1H), 1.68–1.47 (m, 4H), 1.16 (d, J¼6.0 Hz, 3H), 0.96 (t,
J¼8.3 Hz, 9H), 0.60 (q, J¼8.3 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d
68.2, 63.0, 36.1, 28.4, 23.2, 6.8, 4.8; MS (ESI): m/z (%) 241 (100)
[MþNa]þ; HRMS (ESI): calcd for C11H26O2NaSi [MþNa]þ 241.1623,
found 241.1618.
To a solution of the mixture of olefinic-keto compound (10 mg,
0.018 mmol) in dry EtOH (1 mL),10% Pd/C (catalytic) was added and
the mixture was hydrogenated and selectively TES ether was
deprotected using a H2-filled balloon for 12 h. It was then filtered
through a short pad of Celite and the filter cake was washed with
EtOAc. The filtrate and washings were combined and concentrated
in vacuo. Purification by column chromatography (SiO2, 30% EtOAc
in petroleum ether eluant) eluted compound 7 (5.8 mg, 75%) as
colorless oil.
To
a solution of primary alcohol in dry Et2O/CH3CN
(16 mL:4 mL), imidazole (1.87 g, 27.52 mmol) was added slowly
with stirring at 0 ꢀC under nitrogen atmosphere. Then TPP (2.7 g,
10.32 mmol) followed by I2 (1.83 g, 7.224 mmol) were added to the
reaction mixture at the same temperature. After being stirred for
next 0.5 h, it was quenched with saturated NaHCO3 solution and
extracted with EtOAc, water, brine, dried (Na2SO4), filtered and
concentrated in vacuo. Purification of the residue by fast column
chromatography provided the primary iodide product (SiO2, only
petroleum ether eluant, 1.62 g, 72%) which was directly used for the
next reaction without further characterization.
Rf¼0.4 (silica gel, 40 % EtOAc in hexane); in literature13
[a]D for 7
þ22.2 (c 0.05, CHCl3); IR (neat):
31
þ19.3 (c 0.6, CHCl3), observed [
a
]
D
nmax 3338, 2924, 2855, 1734, 1714 cmꢁ1; 1H NMR (500 MHz, CDCl3):
The primary iodide (1.5 g, 4.57 mmol) was immediately taken in
dry CH3CN (20 mL) and TPP (3.6 g, 13.72 mmol) followed by K2CO3
(3.15 g, 22.85 mmol) were added to the reaction mixture. The re-
action mixture was refluxed for 6 h, then cooled to room temper-
ature and filtered through cotton to remove the K2CO3. Then it was
concentrated in vacuo. Purification of the residue by column
chromatography (SiO2, 4% MeOH in CHCl3 eluant) provided the
d
4.16 (m, 1H), 4.14 (q, J¼6.9 Hz, 2H), 3.79 (m, 1H), 2.62 (td, J¼12.8,
6.9 Hz, 1H), 2.56 (dd, J¼16.7, 8.8 Hz, 1H), 2.45 (m, 1H), 2.37–2.20 (m,
3H), 2.00 (m, 1H), 1.84 (m, 1H), 1.60–1.55 (m, 2H), 1.5–1.39 (m, 3H),
1.35–1.24 (m, 3H), 1.28 (t, J¼7.0 Hz, 3H), 1.17 (d, J¼6.9 Hz, 3H), 0.92
(s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); MS (ESI): m/z (%) 437 (100)
[MþNa]þ; HRMS (ESI): calcd for C22H42O5NaSi [MþNa]þ 437.2699,
found 437.2682.
solid Wittig salt 6 as a yellow solid (2.02 g, 75%).
26
Rf¼0.3 (silica gel, 10 % MeOH in CHCl3); [
a
]
ꢁ1.8 (c 2.9, CHCl3);
D
Acknowledgements
IR (neat): nmax 3405, 3051, 2955, 2876, 1437, 1341, 1112, 1009 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
7.90–7.65 (m, 15H), 4.01 (m, 1H), 3.82
The authors wish to thank DST, New Delhi for the Ramanna
Fellowship (SR/S1/RFOC-06/2006; T.K.C.) and CSIR, New Delhi for
the research fellowships (R.S. and P.K.R).
(m, 1H), 3.51 (m, 1H), 2.06–1.61 (m, 4H), 1.10 (d, J¼6.0 Hz, 3H), 0.81
(t, J¼7.5 Hz, 9H), 0.44 (qd, J¼7.5, 3.0 Hz, 6H); 13C NMR (75 MHz,
CDCl3):
d
135.0 (d, JP–C¼2.2 Hz), 133.5 (d, JP–C¼9.9 Hz), 130.4 (d, JP–
¼12.6 Hz), 118.0 (d, JP–C¼85.8 Hz), 67.7, 39.7 (d, JP–C¼15.4 Hz), 23.7,
C
References and notes
22.9 (d, JP–C¼50.1 Hz), 18.9 (d, JP–C¼3.8 Hz), 6.7, 4.8; MS (ESI): m/z
(%) 464 (100) [MþH]þ; HRMS (ESI): calcd for C29H40OSiP [M]þ
463.2586, found 463.2605.
1. Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-VCH: Weinheim,
2001.
2. McCarroll, A. J.; Walton, J. C. Angew. Chem. 2001, 113, 2282–2307; Angew. Chem.,
Int. Ed. 2001, 40, 2225–2250.
3. Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; Wiley-
VCH: Weinheim, 1996.
4.1.10. Ethyl 2-((1R,2R,6S)-6-(tert-butyldimethylsilyloxy)-2-
((R)-5-hydroxyhexyl)-3-oxocyclohexyl)acetate (7)
4. Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Synthesis; Wiley:
Chichester, UK, 1995.
A solution of the triol 13 (100 mg, 0.26 mmol) in THF:H2O (1:1,
2.0 mL) was treated with NaIO4 (114 mg, 0.53 mmol) at 0 ꢀC. After
6 h stirring from 0 ꢀC to room temperature, the reaction mixture
was extracted with CH2Cl2. The combined organic extracts were
washed with water, brine, dried (Na2SO4), filtered and concentrated
in vacuo. Purification by flash column chromatography (SiO2, 30%
EtOAc in petroleum ether eluant) afforded the aldehyde compound
as a white gummy liquid.
5. Chu, M.; Mierzwa, R.; Xu, L.; He, L.; Terracciano, J.; Patel, M.; Gullo, V.; Black, T.;
Zhao, W.; Chan, T.-M.; McPhail, A. T. J. Nat. Prod. 2003, 66, 1527–1530.
6. Bouche, J. P.; Zechel, K.; Kornberg, A. J. Biol. Chem. 1975, 250, 5995–6001.
7. Azai, K. I.; Kornberg, A. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 4308–4312.
8. Jayasuriya, H.; Zink, D. L.; Polishook, J. D.; Bills, G. F.; Dombrowski, A. W.;
Genilloud, O.; Pelacz, F. F.; Herranz, L.; Quamina, D.; Lingham, R. B.; Dan-
zeizem, R.; Graham, P. L.; Tomassini, J. E.; Singh, S. B. Chem. Biodivers. 2005, 2,
112–122.
9. (a) Mehta, G.; Shinde, H. M. Chem. Commun. 2005, 3703–3705; (b) Mehta, G.;
Shinde, H. M. Tetrahedron Lett. 2005, 46, 6633–6636.
10. Ishigami, K.; Katsuta, R.; Watanabe, H. Tetrahedron 2006, 62, 2224–2230.
11. Snider, B.; Zhou, J. Org. Lett. 2006, 8, 1283–1286.
12. Wilson, E. M.; Trauner, D. Org. Lett. 2007, 9, 1327–1329.
13. Fortanet, J. G.; Carda, M.; Marco, J. A. Tetrahedron 2007, 63, 12131–12137.
14. Fujioka, H.; Ohba, Y.; Nakahara, K.; Takatsuji, M.; Murai, K.; Ito, M.; Kita, Y. Org.
Lett. 2007, 9, 5605–5608.
15. Chakraborty, T. K.; Samanta, R.; Das, S. J. Org. Chem. 2006, 71, 3321–3324.
16. Chakraborty, T. K.; Samanta, R.; Ravikumar, K. Tetrahedron Lett. 2007, 48,
6389–6392.
Now nBuLi solution in hexane (1.6 M, 0.36 mL) was added to the
solution of the Wittig salt 6 (383 mg, 0.65 mmol) in freshly dried
THF at ꢁ78 ꢀC under nitrogen atmosphere. It was stirred for 30 min
at the same temperature and the colour of the solution changed
into reddish yellow. Next the aldehyde in THF was added to the
reaction mixture and allowed to warm up to 0 ꢀC with continuous
stirring. The reaction mixture was quenched with saturated aque-
ous NH4Cl solution and extracted with EtOAc. The combined or-
ganic extracts were dried (Na2SO4), filtered and concentrated in
vacuo. Purification of the residue by column chromatography (SiO2,
8 % EtOAc in petroleum ether eluant) provided the mixture of cis
and trans olefinic compounds (42 mg, 30% based on recovered
17. Chakraborty, T. K.; Samanta, R.; Roy, S.; Sridhar, B. Tetrahedron Lett. 2009, 50,
3306–3310.
18. (a) Gringore, O. H.; Rouessac, F. P. Org. Synth. 1985, 63, 121–126; (b) Hanessian,
S.; Murray, P. J. Tetrahedron 1987, 43, 5055–5072. [In literature18b
[
a
]D for 2 þ32.
28
5 (c 2.9, EtOH), observed [
a
]
þ33.3 (c 4.1, EtOH)].
D

T.K. Chakraborty et al. / Tetrahedron 65 (2009) 6925–6931
6931
19. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.
24. (a) Green, M. L. H.; Lucas, C. R. J. Chem. Soc., Dalton Trans. 1972, 1000–1003;
(b) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110, 8561–8562;
For reviews on Cp2TiCl see: (c) Barrero, A. F.; Quı´lez del Moral, J.; Sa´nchez,
E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627–1641; (d) Daasbjerg, K.;
Svith, H.; Grimme, S.; Gerenkamp, M.; Mu¨ck-Lichtenfeld, C.; Gansau¨ er, A.;
Barchuk, A. Top. Curr. Chem. 2006, 263, 39–69; (e) Gansa¨uer, A.; Rinker, B.
Tetrahedron 2002, 58, 7017–7026; (f) Gansa¨uer, A.; Bluhm, H. Chem. Rev.
2000, 100, 2771–2788.
20.
O
P
O
b
a
EtO
EtO
BnO
CO2Et
EtO
EtO
Br
CO2Et
OBn
O
P
CH3
Reagents and conditions: (a) BnOH, NaH, THF, TBAI, 0 °C to rt,
12 h, 70%; (b) nBuLi, THF, -78 °C- 0 °C, 2 h, 85%.
25. (a) Chakraborty, T. K.; Dutta, S. J. Chem. Soc., Perkin Trans.
1 1997,
1257–1259; (b) Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2002, 43,
2313–2315.
21. (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227; (b) Turner, D.; Vogel, P.
Synlett 1998, 304–306.
22. Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505–5507.
23. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765–5780.
26. Brunner, H.; Lautenschlager, H.-J. Synthesis 1989, 706–709. [In literature26
[a]
22
D
27
for 14 ꢁ11.0 (c 38.0, EtOH), observed [
a
]
D
ꢁ12.8 (c 1.6, EtOH)].
27. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
28. Rotulo-Sims, D.; Prunel, J. Org. Lett. 2002, 4, 4701–4704.