Stereoselective total synthesis of (-)-synrotolide diacetate from d-ribose

Article abstract of DOI:10.1016/j.tet.2007.03.011

Stereoselective total synthesis of synrotolide as its diacetate from d-ribose utilizing a diastereoselective Grignard reaction, preferential (Z)-Wittig olefination, asymmetric allylation, and ring closing metathesis as key steps is reported.

Full text of DOI:10.1016/j.tet.2007.03.011

Tetrahedron 63 (2007) 3995–3999
Stereoselective total synthesis of (L)-synrotolide diacetate
from D-ribose*
*
Palakodety Radha Krishna and P. Srinivas Reddy
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology,
Hyderabad 500 007, Andhra Pradesh, India
Received 29 November 2006; revised 14 February 2007; accepted 1 March 2007
Available online 6 March 2007
Abstract—Stereoselective total synthesis of synrotolide as its diacetate from D-ribose utilizing a diastereoselective Grignard reaction,
preferential (Z)-Wittig olefination, asymmetric allylation, and ring closing metathesis as key steps is reported.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
corresponding bis-olefin by the Grubbs’ catalyst assisted
RCM protocol.
Naturally occurring a,b-unsaturated lactones show varied
pharmacological properties, while some exhibits antitumor
activity, others posses interesting properties.1 Notable among
them contain a polyoxygenated chain connected with a,b-
unsaturated lactone moiety having antimicrobial activity,
antifungal activity, or cytotoxicity against human tumor
cells.2 (ꢀ)-Synrotolide 1,3 an a-pyrone-containing natural
product was isolated from Syncolostemon rotundifolius,
and shares structural similarities with (ꢀ)-spicigerolide.2a
Continuing our interest in the synthesis of lactone skeleton-
containing bioactive natural products,4 herein we report the
stereoselective total synthesis of synrotolide as its diacetate
(2) from D-ribose through a chiron approach.
2. Results and discussion
Thus, the synthesis (Scheme 1) began following the litera-
ture procedure. The known5 5-O-(tert-butyldimethyl-
silyl)-2,3-O-isopropylidene-D-ribofuranose 3, obtained
from D-ribose, on exposure to MeMgI in ether, resulted
in a 9:1 separable diastereomeric mixture via a chelation
controlled mode in favor of the desired diol 4 as the major
product (76%).6 Later, both the hydroxyl groups in 4 were
protected as PMB ethers (PMBBr/NaH/THF/rt) to furnish
5 (74%). Compound 5, on TBDMS deprotection (TBAF/
THF/rt), afforded 6 (92%) with a free primary alcohol,
which was oxidized to an aldehyde under Swern reaction
conditions and subjected to a Wittig olefination reaction7
[(F3CCH2O)2POCH2COOMe/KHMDS/18-crown-6/THF/
ꢀ78 ꢁC], to afford the corresponding a,b-unsaturated ester 7
in 88% yield predominantly as the (Z)-isomer, as charac-
OR
12
10
11
OR'
OR'
O
9
RO
1
4
2
3
O
8
7
5
terized by H and 13C NMR spectroscopy. The coupling
constant (J¼9.05 Hz) and the chemical shift values (d 6.18
and d 6.00) of the olefinic protons confirmed the (Z)-geo-
metry of the olefin.
1
6
1. R = COCH3, R' = H
2. R = R' = COCH3
The reported strategy derives stereocenters at C(2), C(3),
and C(4) from D-ribose translating as those of C(10), C(9),
and C(8) of 2, respectively. Additionally, chiral center at
C(11) was generated by a diastereoselective Grignard reac-
tion, and the one at C(5) by an asymmetric allylation reac-
tion. Finally, the a-pyrone moiety was built from the
With ester 7 in hand, our next task was the creation of an
additional chiral center that corresponds to C(5) of the tar-
get compound. Thus, 7 was subjected to reduction with
DIBAL–H in ether to afford the allylic alcohol 8 (95%),
which was converted to the a,b-unsaturated aldehyde under
Swern reaction conditions. This aldehyde, without further
purification, on Keck asymmetric allylation8 gave 9, albeit
in a low yield of w25%. However, Maruoka allylation9
afforded 9 in good yield (70%) as inseparable diastereomers
(de 90%). Acryloylation of 9 (CH2]CH–COCl/DIPEA/
CH2Cl2/0–rt) gave separable bis-olefin 10 as the major
*
IICT communication no. 060905.
Keywords: D-Ribose; Synrotolide diacetate; Diastereoselective Grignard re-
action; Wittig olefination; Asymmetric allylation; Ring closing metathesis.
* Corresponding author. Tel.: +91 40 27160123x2651; fax: +91 40
27160387; e-mail: prkgenius@iict.res.in
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.03.011

3996
P. R. Krishna, P. S. Reddy / Tetrahedron 63 (2007) 3995–3999
OH
O
TBSO
OH
ref. 5
b
a
HO
D-Ribose
O
3
O
O
O
OTBS
4
OPMB
O
OPMB
OPMB
O
PMBO
MeOOC
c
d
PMBO
PMBO
O
O
O
O
OH
OTBS
7
5
6
OPMB
O
OR
g
f
PMBO
OH OR
e
O
HO
O
O
8
9 (major isomer, de 90%)
R = PMB
OPMB
O
O
OR
O
O
PMBO
O
i
h
RO
O
O
O
10. R = PMB
11
OAc
OH
O
k
X
O
O
j
O
1
AcO
HO
O
O
O
O
OPri
13
12
O
O
Ti
O
O
l
Ti
PriO
O
2
Bis(((R)-binaphthoxy)(isopropoxy)titanium) Oxide I
Scheme 1. Reagents and conditions: (a) MeMgI, ether, ꢀ78 ꢁC, 6 h (76%); (b) PMBBr, NaH, THF, 0 ꢁC–rt, 10 h (74%); (c) TBAF, THF, rt, 14 h (92%); (d) (i)
(COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h (90%); (ii) (F3CCH2O)2POCH2COOMe, KHMDS, 18-crown-6, THF, ꢀ78 ꢁC,4 h (88%); (e) DIBAL–H, ether,
0 ꢁC–rt, 6 h (95%); (f) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h (80%); (ii) I, allyltributyltin, CH2Cl2, 0 ꢁC, 36 h (70%); (g) CH2]CH–COCl, DIPEA,
CH2Cl2, 0 ꢁC–rt, 10 h (90%); (h) 10% PhCH]RuCl2(PCy3)2, CH2Cl2, reflux, 8 h (85%); (i) AlCl3, EtSH, CH2Cl2, rt, 0.5 h (70%); (j) Ac2O, Et3N, DMAP,
CH2Cl2, 0 ꢁC–rt (90%); (k) CuCl2$2H2O, MeCN, rt, 5 h (88%); (l) (i) CuCl2$2H2O, MeCN, rt, 5 h; (ii) Ac2O, pyridine, rt, 12 h (66% over two steps).
isomer in 90% yield. The newly created stereocenter was ten-
tatively assigned as depicted in Scheme 1, based on literature
precedence but was conclusively proved later. The RCM of
10 using Grubbs’ catalyst10 [10% PhCH]RuCl2(PCy3)2/
CH2Cl2/reflux/8 h] gave the a,b-unsaturated lactone 11 in
85% yield. With the complete skeleton in hand, wherein all
the hydroxyl functionalities were present in their protected
form, a stepwise release was planned. Initially, deprotection
of PMB ethers was contemplated so that they in turn could be
acetylated. Thus, Lewis acid11 (AlCl3/EtSH/CH2Cl2) medi-
ated PMB deprotection of 11 gave 12 (70%), which on sub-
sequent acetylation (Ac2O/Et3N/DMAP/CH2Cl2) afforded
13 (90%). Next, selective deprotection12 of acetonide
(CuCl2$2H2O/MeCN/rt/5 h) resulted in a product in 88%
98–101 ꢁC; [a]D25 ꢀ10.60 (c 0.05, CHCl3);{lit.3 mp 102–
103 ꢁC; [a]D25 ꢀ11.00 (c 0.09, CHCl3)} in 66% yield over
two steps. The physical and spectroscopic data of 2 were
identical to the reported values of synrotolide diacetate.
The synthesis of 2 also established the assigned stereochem-
istry of 9. It is interesting to note that many bioactive natural
products like spicigerolide2a and anamarine13 are endowed
with tetraacetates on their skeletons.
In conclusion, a stereoselective total synthesis of synrotolide
diacetate was accomplished by a versatile strategy. A combi-
nation of diastereoselective Grignard reaction, preferential
(Z)-Wittig olefination, asymmetric allylation, and ring
closing metathesis was effectively utilized in accomplishing
the synthesis.
1
yield. However, H NMR, physical data, and [a]2D5 values
did not match with the reported values of the natural product.
At this point in the synthesis, all our efforts to isolate 1 in
homogeneous form did not bear fruit under different reaction
conditions of acetonide deprotection, due to the parallel
migration of allylic acetate. Hence it was decided to synthe-
size synrotolide as its diacetate derivative (2). Accordingly,
12 on acetonide deprotection (CuCl2$2H2O/MeCN/rt/5 h)
and acetylation (Ac2O/pyridine/rt/12 h), afforded 2, mp
3. Experimental
3.1. General methods
Solvents were dried over standard drying agents and freshly
distilled prior to use. Chemicals were purchased and used

P. R. Krishna, P. S. Reddy / Tetrahedron 63 (2007) 3995–3999
3997
without further purification. All column chromatographic
separations were performed using silica gel (Acme’s, 60–
120 mesh). Organic solutions were dried over anhydrous
1.15 (d, 3H, J¼5.5 Hz), 0.85 (s, 9H), 0.01 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 159.24, 130.85, 129.50, 113.60,
108.00, 79.00, 78.30, 76.18, 73.42, 71.56, 69.79, 64.17,
55.18, 26.78, 25.89, 25.67, 24.81, 18.38, 16.11, ꢀ5.41,
FABMS: 578 [M+NH4]+. Anal. Calcd for C31H48O7Si: C,
66.39; H, 8.63. Found: C, 66.42; H, 8.66%.
1
Na2SO4 and concentrated below 40 ꢁC in vacuo. H NMR
(200, 300, and 400 MHz) and 13C NMR (50 and 75 MHz)
spectra were measured with a Varian Gemini FT-200 MHz
spectrometer, Bruker Avance 300 MHz, and Unity
400 MHz with tetramethylsilane as an internal standard for
solutions in deuteriochloroform. J values are given in hertz.
IR spectra were recorded on a Perkin–Elmer IR-683 spectro-
photometer with NaCl optics. Optical rotations were mea-
sured with JASCO DIP 300 digital polarimeter at 25 ꢁC.
Mass spectra were recorded on CEC-21-11013 or Finnigan
Mat 1210 double focusing mass spectrometer operating at
a direct inlet system or LC/MSD Trap SL (Agilent Techno-
logies).
ꢀ5.47; IR (neat): 2931, 1514, 1248, 1082, 835 cmꢀ1
;
3.4. (2R)-2-[(4-Methoxybenzyl)oxy]-2-((4R,5S)-5-(1S)-
1-[(4-methoxybenzyl)oxy]ethyl-2,2-dimethyl-1,3-
dioxolan-4-yl)ethan-1-ol (6)
A stirred solution of 5 (0.86 g, 1.54 mmol) in anhydrous
THF (5 mL) was treated with TBAF (2.3 mL, 2.31 mmol,
1 M solution in THF) for 14 h at room temperature. The re-
action mixture was extracted with ethyl acetate (2ꢂ25 mL)
and the combined organic layers were washed with brine
(1ꢂ10 mL), dried (Na2SO4), concentrated, and the residue
was purified over silica gel (EtOAc/n-hexane, 1:45) to give
6 as light yellow syrup (0.63 g, 92%). [a]2D5 +57.25 (c
3.2. (1R)-2-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-
(4R,5S)-5-[(1S)-1-hydroxyethyl]-2,2-dimethyl-1,3-
dioxolan-4-ylethan-1-ol (4)
1
1.86, CHCl3); H NMR (300 MHz, CDCl3): d 7.11 (d, 4H,
To a solution of 2,3-O-isopropylidene-5-O-tert-butyl-
dimethyl silyl-a-D-ribofuranose 3 (6.00 g, 19.70 mmol) in
anhydrous ether (60.0 mL), MeMgI [prepared from Mg
(1.44 g, 59.21 mmol) and MeI (3.69 mL, 59.21 mmol)]
was added under an N2 atmosphere at ꢀ78 ꢁC and stirred
for 6 h. After the completion of the reaction, it was quenched
with saturated aq NH4Cl (15 mL) and extracted with ethyl
acetate (2ꢂ60 mL). The combined organic layers were
washed with brine, dried (Na2SO4), concentrated, and the
residue was purified over silica gel (EtOAc/n-hexane,
1:19) to give a separable diastereomeric mixture (dr 9:1)
of diol 4 (4.71 g, 76%) as the major product as a thick syrup.
[a]2D5 +39.19 (c 0.12, CHCl3); 1H NMR (300 MHz, CDCl3):
d 3.95–3.75 (m, 4H), 3.68 (dt, 1H, J¼3.0, 6.8, 9.8 Hz), 3.55
(dd, 1H, J¼6.7, 9.8 Hz), 1.29 (s, 3H), 1.25 (s, 3H), 1.19 (d,
3H, J¼6.0 MHz), 0.85 (s, 9H), 0.04 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 108.20, 82.00, 77.60, 70.00, 65.40,
64.60, 28.00, 26.00, 25.20, 20.20, 18.20, ꢀ5.50, ꢀ5.61; IR
(thin film): 3417, 2931, 2859, 1251, 1220, 1116, 1066,
836, 778 cmꢀ1; FABMS: 321 [M]+, 205 [MꢀTBS]+. Anal.
Calcd for C15H32O5Si: C, 56.21; H, 10.06. Found: C,
56.19; H, 10.08%.
J¼8.5 Hz), 6.74 (d, 4H, J¼8.5 Hz), 4.48ꢀ4.21 (m, 7H),
4.07 (t, 1H, J¼6.7 Hz), 3.75 (s, 6H), 3.71 (m, 2H), 1.42
(s, 3H), 1.33 (s, 3H), 1.25 (d, 3H, J¼5.8 Hz); 13C NMR
(75 MHz, CDCl3): d 158.40, 130.01, 129.83, 128.95,
113.33, 107.49, 79.07, 76.27, 72.6, 70.72, 69.41, 61.67,
54.80, 26.50, 26.29, 16.08; IR (neat): 3456, 1514, 1248,
1077, 1035, 821 cmꢀ1; LCMS: 464 [M+NH4]+. Anal. Calcd
for C25H34O7: C, 67.24; H, 7.67. Found: C, 67.22; H, 7.80%.
3.5. Methyl-(Z,4R)-4-[(4-methoxybenzyl)oxy]-4-
((4R,5S)-5-(1S)-1-[(4-methoxybenzyl)oxy]ethyl-
2,2-dimethyl-1,3-dioxolan-4-yl)-2-butenoate (7)
To a stirred solution of oxalyl chloride (0.37 mL,
3.36 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢁC, DMSO
(0.32 mL, 4.93 mmol) was added followed by compound 6
(1.00 g, 2.24 mmol) in CH2Cl2 (5 mL) and the contents
were stirred for 1 h at ꢀ78 ꢁC. Later, the reaction mixture
was quenched with Et3N (0.935 mL, 6.72 mmol) and
diluted with CH2Cl2 (25 mL). The combined organic layers
were washed with brine (1ꢂ15 mL), dried (Na2SO4),
concentrated, and the residue was passed through a pad of
silica gel to give the corresponding aldehyde (0.895 g,
90%), which was used as such for further reaction. To a
stirred solution of (F3CCH2O)2POCH2COOMe (0.56 mL,
2.66 mmol), 18-crown-6 (2.47 g, 9.36 mmol) in anhydrous
THF (2 mL) at ꢀ78 ꢁC followed by KHMDS (0.67 g,
2.93 mmol) was added and the reaction mixture was stirred
for 30 min. To the reaction mixture, the aldehyde (0.80 g,
1.80 mmol) dissolved in THF (5 mL) was added. The reac-
tion mixture was stirred for 4 h, quenched with saturated
aq NH4Cl, and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried (Na2SO4), con-
centrated, and the residue was purified over silica gel
(EtOAc/n-hexane, 1:9) to give the product 7 (0.79 g, 88%)
3.3. 2-(tert-Butyl)-2-[(2R)-2-[(4-methoxybenzyl)oxy]-2-
((4R,5S)-5-(1S)-1-[(4-methoxybenzyl)oxy]ethyl-2,2-di-
methyl-1,3-dioxolan-4-yl)ethyl]oxydimethylsilane (5)
To a suspension of diol 4 (1.58 g, 49.96 mmol) in anhydrous
THF (10 mL), NaH (0.41 g, 17.28 mmol) in anhydrous THF
(5 mL) was slowly added at 0 ꢁC followed by addition
of PMBBr (3.78 g, 17.28 mmol). The reaction mixture
was stirred at room temperature for 10 h, quenched with
saturated aq NH4Cl, and extracted with ethyl acetate
(2ꢂ30 mL). The combined organic layers were washed
with brine (1ꢂ10 mL), dried (Na2SO4), concentrated, and
the residue was purified over silica gel (EtOAc/n-hexane,
1:32) to afford the PMB ether 5 (2.05 g, 74%) as colorless
as colorless syrup. [a]2D5 +58.57 (c 0.78, CHCl3); H NMR
1
(300 MHz, CDCl3): d 7.14 (d, 2H, J¼8.3 Hz), 7.06 (d, 2H,
J¼8.3 Hz), 6.72 (dd, 4H, J¼5.2, 8.3 Hz), 6.18 (dd, 1H,
J¼9.0, 12.0 Hz), 6.00 (d, 1H, J¼11.3 Hz), 5.40 (dd, 1H, J¼
6.7, 9.0 Hz), 4.44 (d, 1H, J¼11.3 Hz), 4.30 (q, 2H, J¼8.3,
11.3 Hz), 4.22–4.08 (m, 3H), 3.77 (m, 1H), 3.75 (s, 6H),
3.72 (s, 3H), 1.39 (s, 3H), 1.29 (s, 3H), 1.26 (d, 3H,
1
syrup. [a]2D5 +26.29 (c 1.02, CHCl3); H NMR (200 MHz,
CDCl3): d 7.02 (d, 4H, J¼7.7 Hz), 6.65 (d, 4H, J¼7.7 Hz),
4.51 (d, 1H, J¼11.1 Hz), 4.29 (q, 2H, J¼6.6, 11.0 Hz),
4.20 (q, 2H, J¼6.6, 11.0 Hz), 4.09–4.01 (m, 2H), 3.85 (m,
1H), 3.68 (s, 6H), 3.65 (m, 2H), 1.35 (s, 3H), 1.24 (s, 3H),

3998
P. R. Krishna, P. S. Reddy / Tetrahedron 63 (2007) 3995–3999
J¼6.0 Hz); 13C NMR (75 MHz, CDCl3): d 166.34, 158.86,
145.90, 129.58, 129.09, 123, 113.60, 131.00, 130.33,
108.02, 79.73, 78.17, 72.70, 71.68, 70.37, 69.68, 55.17,
51.33, 26.65, 25.04, 16.28; IR (neat): 1726, 1514, 1248,
1078, 1035, 822 cmꢀ1; LCMS: 518 [M+NH4]+. Anal. Calcd
for C28H36O8: C, 67.18; H, 7.25. Found: C, 67.15; H, 7.30%.
with brine, dried (Na2SO4), concentrated, and the residue
was purified over silica gel (EtOAc/n-hexane, 1:3.5) to
give the allylated product 9 (0.88 g, 70%) as light yellow
syrup. [a]2D5 +12.86 (c 0.003, CHCl3); 1H NMR (200 MHz,
CDCl3): d 7.09 (dd, 2H, J¼3.7, 8.3 Hz), 7.03 (d, 2H,
J¼8.3 Hz), 6.76–6.72 (m, 4H), 5.85–5.46 (m, 3H), 5.14–
5.08 (m, 2H), 4.40 (dd, 2H, J¼6.0, 11.3 Hz), 4.23–4.05
(m, 5H), 3.90 (dq, 1H, J¼2.2, 6.0 Hz), 3.76 (s, 3H), 3.75
(s, 3H), 3.70 (dd, 1H, J¼2.2, 6.7 Hz), 2.29 (dd, 2H, J¼6.0,
12.0 Hz), 1.41 (s, 3H), 1.31 (s, 3H), 1.21 (d, 3H,
J¼6.0 Hz); 13C NMR (75 MHz, CDCl3): d 159.10, 137.24,
134.11, 130.37, 128.02, 127.32, 118.18, 113.73, 108.88,
79.61, 78.99, 72.39, 71.51, 69.26, 55.20, 41.90, 26.79,
25.01, 16.60; IR (neat): 3445, 2930, 1609, 1513, 1250,
1073, 1034, 822 cmꢀ1; FABMS: 530 [M+NH4]+. Anal.
Calcd for C30H40O7: C, 70.29; H, 7.86. Found: C, 70.26;
H, 7.82%.
3.6. (Z,4R)-4-[(4-Methoxybenzyl)oxy]-4-((4R,5S)-5-(1S)-
1-[(4-methoxybenzyl)oxy]ethyl-2,2-dimethyl-1,3-dioxo-
lan-4-yl)-2-buten-1-ol (8)
To a stirred solution of 7 (1.60 g, 3.20 mmol) in anhydrous
ether (10 mL), DIBAL–H (5.68 mL, 8.00 mmol, 20% solu-
tion in toluene) was added dropwise at 0 ꢁC and stirred for
6 h and diluted with methanol, sodium potassium tartrate,
and extracted with ethyl acetate. The combined organic
layers were washed with brine, dried (Na2SO4), concen-
trated, and the residue was purified over silica gel (EtOAc/
n-hexane, 1:3) to afford 8 (1.42 g, 95%) as thick syrup.
[a]2D5 +24.30 (c 2.96, CHCl3); 1H NMR (200 MHz,
CDCl3): d 7.15 (d, 2H, J¼8.4 Hz), 6.98 (d, 2H, J¼8.4 Hz),
6.75 (dd, 4H, J¼8.4, 12.9 Hz), 6.01 (td, 1H, J¼6.8,
10.6 Hz), 5.55 (t, 1H, J¼9.9 Hz), 4.47–4.30 (m, 4H), 4.24
(dd, 1H, J¼4.5, 6.1 Hz), 4.14–4.03 (m, 3H), 3.96 (dd, 1H,
J¼6.8, 12.9 Hz), 3.76 (s, 3H), 3.759 (s, 3H), 3.719 (dd,
1H, J¼4.5, 6.1 Hz), 2.35 (br s, 1H, OH), 1.44 (s, 3H), 1.32
(s, 3H), 1.16 (d, 3H, J¼6.1 Hz); 13C NMR (75 MHz,
CDCl3): d 158.79, 158.51, 133.61, 130.20, 129.28, 128.67,
113.17, 107.48, 78.88, 76.39, 72.21, 71.40, 69.16, 68.93,
57.97, 54.68, 25.97, 24.31, 15.71; IR (neat): 3448, 1612,
1514, 1248, 1076, 1034, 821 cmꢀ1; LCMS: 495 [M+Na]+.
Anal. Calcd for C27H36O7: C, 68.62; H, 7.68. Found: C,
68.65; H, 7.64%.
3.8. (Z,4R)-1-Allyl-4-[(4-methoxybenzyl)oxy]-4-
((4R,5S)-5-(1S)-1-[(4-methoxybenzyl)oxy]ethyl-2,2-
dimethyl-1,3-dioxolan-4-yl)-2-butenyl acrylate (10)
To a stirred solution of 9 (0.40 g, 0.78 mmol) and N-ethyldi-
isopropylamine (0.14 mL, 1.56 mmol) in CH2Cl2 (5 mL),
acryloyl chloride (0.07 mL, 1.09 mmol) was added dropwise
at 0 ꢁC and stirred at room temperature for 10 h. The re-
action mixture was treated with water (1ꢂ15 mL) and
extracted into CH2Cl2 (2ꢂ15 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and evapo-
rated under reduced pressure. The residue was purified by
column chromatography (silica gel, EtOAc/n-hexane, 1:9)
to afford the acrylate 10 (0.39 g, 90%) as thick yellow syrup.
[a]2D5 +16.13 (c 1.38, CHCl3); 1H NMR (200 MHz, CDCl3):
d 7.05 (dd, 4H, J¼8.5, 16.4 Hz), 6.74 (dd, 4H, J¼3.1,
8.5 Hz), 6.409 (dd, 1H, J¼1.5, 17.1 Hz), 6.09 (dd, 1H,
J¼10.1, 17.1 Hz), 5.84–5.643 (m, 3H), 5.50–5.31 (m, 2H),
5.13–5.04 (m, 2H), 4.39 (dd, 2H, J¼3.9, 10.9 Hz), 4.25–
4.00 (m, 4H), 3.89 (dt, 1H, J¼4.6, 7.8 Hz), 3.76 (s, 3H),
3.757 (s, 3H), 3.71–3.65 (m, 1H), 2.41 (m, 2H), 1.41 (s,
3H), 1.30 (s, 3H), 1.18 (d, 3H, J¼5.4 Hz); 13C NMR
(75 MHz, CDCl3): d 164.76, 158.66, 132.85, 132.36,
132.10, 131.81, 130.35, 130.14, 129.86, 128.17, 117.88,
117.23, 113.16, 107.28, 79.1, 78.98, 77.55, 72.55, 69.58,
69.38, 69.20, 68.78, 54.53, 38.30, 26.26, 24.40, 15.47; IR
3.7. (5Z,7R)-7-[(4-Methoxybenzyl)oxy]-7-((4R,5S)-5-
(1S)-1-[(4-methoxybenzyl)oxy]ethyl-2,2-dimethyl-
1,3-dioxolan-4-yl)-1,5-heptadien-4-ol (9)
To a stirred solution of oxalyl chloride (0.44 mL, 4.00 mmol)
in CH2Cl2 at –78 ꢁC, DMSO (0.38 mL, 5.33 mmol) was
added followed by compound 8 (1.26 g, 2.67 mmol) in
CH2Cl2 and the reaction mixture was stirred for 1 h at
ꢀ78 ꢁC, quenched with Et3N (1.11 mL, 8.0 mmol), and
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated to
give the corresponding aldehyde (1.00 g, 80%), which was
used directly for further reaction.
(neat): 2930, 1722, 1513, 1248, 1190, 1037, 817 cmꢀ1
;
LCMS: 584 [M+NH4]+. Anal. Calcd for C33H42O8: C,
69.94; H, 7.47. Found: C, 69.91; H, 7.44%.
To a stirred solution of TiCl4 (0.03 mL, 0.25 mmol) in
CH2Cl2 was added dried Ti(OiPr)4 (0.22 mL, 0.74 mmol)
at 0 ꢁC under N2. The solution was allowed to warm
to room temperature. After 1 h, (R)-binaphthol (0.28 g,
0.99 mmol) was added at room temperature and the solution
was stirred for 3 h. The mixture was cooled to 0 ꢁC, and
treated with silver(I) oxide (0.11 g, 0.49 mmol) at 0 ꢁC.
The reaction mixture was allowed to warm to room temper-
ature, and stirred there for 5 h under exclusion of direct light
to furnish chiral bisTi(IV) oxide (R,R)-I was treated
with compound 8 (1.16 g, 2.46 mol) and allyltributyltin
(0.85 mL, 2.71 mol) at ꢀ15 ꢁC. The whole mixture was
warmed to 0 ꢁC and allowed to stir for 36 h. The reaction
mixture was quenched with saturated NaHCO3, and ex-
tracted with CH2Cl2. The organic extracts were washed
3.9. (6R)-6-[(Z,3R)-3-[(4-Methoxybenzyl)oxy]-3-
((4R,5S)-5-(1S)-1-[(4-methoxybenzyl)oxy]ethyl-
2,2-dimethyl-1,3-dioxolan-4-yl)-1-propenyl]-
5,6-dihydro-2H-2-pyranone (11)
A solution of 10 (0.41 g, 0.72 mmol) and first generation
Grubbs’ catalyst (0.059 g, 0.07 mmol) in anhydrous
CH2Cl2 (15 mL) was stirred at reflux for 8 h. After the com-
pletion of the reaction, solvent was removed under reduced
pressure and the residue purified by column chromatography
(silica gel, EtOAc/n-hexane, 1:4) to afford 11 (0.33 g, 85%)
1
as thick syrup. [a]D25 +11.66 (c 0.02, CHCl3); H NMR
(300 MHz, CDCl3): d 7.12–7.02 (m, 4H), 6.82–6.72 (m,
5H), 6.00 (d, 1H, J¼9.8 Hz), 5.78 (m, 1H), 5.58 (ddd, 1H,
J¼5.2, 6.7, 6.0 Hz), 4.88 (q, 1H, J¼6.7 Hz), 4.46–4.38 (m,

P. R. Krishna, P. S. Reddy / Tetrahedron 63 (2007) 3995–3999
3999
2H), 4.21–4.15 (m, 3H), 4.07–3.93 (m, 2H), 3.76 (s, 6H),
3.70 (t, 1H, J¼6.7 Hz), 2.36 (m, 2H), 1.40 (s, 3H), 1.30 (s,
3H), 1.21 (d, 3H, J¼5.2 Hz); 13C NMR (75 MHz, CDCl3):
d 163.00, 159.00, 144.00, 131.00, 130.80, 129.00, 127.60,
121.20, 113.60, 108.00, 79.50, 77.00, 72.00, 69.60, 69.00,
55.00, 29.00, 26.50, 24.50, 16.40; IR (thin film): 3380,
121.40, 76.72, 71.90, 70.80, 68.50, 29.20, 21.10, 21.00,
20.80, 14.50; IR (KBr): 3432, 2924, 1739, 1714, 1633,
1383, 1259, 1022, 960 cmꢀ1; EIMS: 426 [M]+, 196, 178,
153, 136. Anal. Calcd for C20H26O10: C, 56.33; H 6.15.
Found: C, 56.30; H, 6.11%.
2926, 2856, 1722, 1514, 1379, 1247, 1033, 817 cmꢀ1
;
Acknowledgements
ESIMS: 556 [M+NH4]+. Anal. Calcd for C31H38O8: C,
69.13; H, 7.11. Found: C, 69.10; H, 7.07%.
One of the authors (P.S.R.) thanks the CSIR, New Delhi, for
financial support in the form of a fellowship.
3.10. (6R)-6-((Z,3R)-3-Hydroxy-3-(4R,5S)-5-[(1S)-1-
hydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl-1-
propenyl)-5,6-dihydro-2H-2-pyranone (12)
References and notes
To a stirred solution of 11 (0.22 g, 0.41 mmol) in anhydrous
CH2Cl2 (8 mL) was added EtSH (0.12 mL, 1.63 mmol) fol-
lowed by AlCl3 (0.03 g, 0.24 mmol) at 0 ꢁC. The reaction
mixture was stirred at room temperature for 30 min and
then quenched with saturated aq NaHCO3 solution. The or-
ganic layers were extracted with ethyl acetate, washed with
brine, and dried (Na2SO4). After evaporation of the solvent,
the crude residue was purified by column chromatography
on silica gel (EtOAc/n-hexane, 1:3) to afford 12 (0.085 g,
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Rojas, C. M. Tetrahedron 2001, 57, 47–53; (b) Carda, M.;
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(300 MHz): d 6.85 (ddd, 1H, J¼9.8, 6.0, 3.7 Hz), 6.00 (br
d, 1H, J¼9.8 Hz), 5.69 (dd, 1H, J¼7.5, 2.6 Hz), 5.33 (m,
1H), 4.56 (ddd, 1H, J¼12.0, 8.3, 2.0 Hz), 4.08 (q, 1H,
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To a solution of 12 (0.08 g, 0.27 mmol) in MeCN (2 mL)
was added CuCl2$2H2O (0.14 g, 0.80 mmol) at 0 ꢁC. After
5 h, the reaction was quenched by adding saturated aq
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5.86–5.82 (m, 2H), 5.44 (ddd, 1H, J¼7.2, 3.8, 1.7 Hz),
5.29 (dd, 1H, J¼7.9, 3.5 Hz), 5.23 (ddd, 1H, J¼7.9, 3.4,
1.2 Hz), 5.04 (dd, 1H, J¼6.8 Hz), 4.96 (m, 1H), 2.41 (m,
2H), 2.12 (s, 6H), 2.06 (s, 3H), 2.02 (s, 3H), 1.25 (d, 3H,
J¼6.4 Hz); 13C NMR (100 MHz, CDCl3): d 170.20,
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