Asymmetric synthesis of (+)-cardiobutanolide

Article abstract of DOI:10.1016/j.tet.2006.09.005

A formal total synthesis of (+)-cardiobutanolide has been accomplished from d-glucose, a readily available precursor.

Full text of DOI:10.1016/j.tet.2006.09.005

Tetrahedron 62 (2006) 11240–11244
Asymmetric synthesis of (D)-cardiobutanolide
*
Ashish Garg, Ravi P. Singh and Vinod K. Singh
Department of Chemistry, Indian Institute of Technology, Kanpur-208016, India
Received 19 July 2006; revised 14 August 2006; accepted 1 September 2006
Available online 25 September 2006
Abstract—A formal total synthesis of (+)-cardiobutanolide has been accomplished from D-glucose, a readily available precursor.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
from D-glucose. The chirality at the 5- and 6-carbon atoms
in the natural product would be directly translated from
D-glucose. The other two chiral centers at 3- and 4-carbon
atoms would be created by Sharpless asymmetric dihydrox-
ylation reaction.
(+)-Cardiobutanolide 1, a g-lactone was isolated in 2003
from Goniothalamus cardiopetalus of the family Annona-
ceae.1 The related natural products isolated from the same
tree have been used as a traditional medicine in Asia to treat
rheumatism, edema, and as a mosquito repellent. Because of
the structural complexity of having five contiguous chiral
centers in the molecule and potential pharmacological activ-
ity, (+)-cardiobutanolide 1 has recently attracted the atten-
tion of synthetic organic chemists. Two syntheses of the
molecule involving chiral starting materials have already
appeared in the literature.2 While this manuscript was in
preparation, a third synthesis appeared employing a chiron
strategy.3 For the last several years, we were involved in the
synthesis of bioactive natural products having lactone as
a sub-unit using sugars as cheap starting materials.4 In this
paper, we report our approach for asymmetric synthesis of
(+)-cardiobutanolide 1.
The synthesisof (+)-cardiobutanolide 1 involved 3-O-benzyl-
1,2-O-isopropylidene-a-D-xylopentodialdo-1,4-furanose 5,
which was readily synthesized from D-glucose using a litera-
ture procedure.5 The diastereoselective addition of PhMgBr
to the aldehyde 5 resulted in the unwanted chelation con-
trolled product 6a and the desired C-5 epimer 6b in a ratio
of 12:1 (Scheme 2). The diastereomeric ratio could be
improved by subjecting the mixture to an oxidation (PDC)–
reduction (NaBH4) sequence to obtain the desired isomer
6b in a ratio of 10:1, which could be separated by column
chromatography resulting in the pure 6b. After protecting
the benzylic hydroxyl group as a benzyl ether, the acetonide
of 7 was hydrolyzed with dilute sulfuric acid in dioxane
to provide a hemiacetal whose diol was oxidatively cleaved
with NaIO4 to give an aldehyde 8 that was directly subjected
to Wittig olefination reaction with a stabilized ylide
(Ph3P]CHCO2Et). This gave an inseparable mixture of
a,b-unsaturated ester 9 in favor of E-isomer (E/Z ratio¼3:1).
Our strategy required that the olefination product 9 should
have trans geometry for the subsequent incorporation of
chiral diol via Sharpless asymmetric dihydroxylation.
The retrosynthetic analysis of (+)-1 is shown in Scheme 1. It
was conceived that the five-membered lactone ring can be
constructed after Arndt–Eistert homologation of an ester 2,
which can be synthesized from a hemiacetal 3. The requisite
chirality at the 7-carbon of (+)-1 in the side chain of 3 would
be created by a diastereoselective addition of PhMgX to the
corresponding aldehyde 4, which in turn, could be derived
O
OR1
OH
OR2 OR3
O
O
O
OH
OH
OHC
H
Ph
O
Ph
Ph
COOEt
D-Glucose
OH OH OH
(+)-1
OR1 OR1 OR3
2
R1O
R1O
O
3
4
Scheme 1. Retrosynthetic analysis.
Keywords: Cardiobutanolide; Asymmetric dihydroxylation; Lactone; D-Glucose.
* Corresponding author. Tel.: +91 512 259 7291; fax: +91 512 259 7436; e-mail: vinodks@iitk.ac.in
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.005

A. Garg et al. / Tetrahedron 62 (2006) 11240–11244
11241
OH
OBn
H
OH
O
O
O
O
OHC
H
BnO
a
b, c
d
Ph
O
Ph
O
O
Ph
O
6b
H
BnO
H
BnO
+
O
O
O
BnO
O
5
6a
6b
7
12:1
O
OCHO
CHO
O
OCHO
OBn
OH
e, f
g
h
Ph
BnO
Ph
COOEt
Ph
BnO
COOEt Ph
+
OEt
OBn
BnO
OBn
10a
BnO
OBn
10b
8
(E:Z = 3:1)
9
ꢀ
˚
Scheme 2. Reagents and conditions: (a) PhMgBr, THF, 0 C–rt, 30 min (90%); (b) PDC, CH2Cl2, 4 A MS, catalytic amount of CH3CO2H, 6 h (82%);
(c) NaBH4, MeOH, 0 ꢀC–rt, 4 h (98%), dr¼10:1; (d) NaH, BnBr, TBAI, THF, 0 ꢀC–rt, 2 h (98%); (e) 0.4% H2SO4, dioxane, 100 ꢀC, 6 h (80%); (f) NaIO4,
H2O/MeOH, 98%; (g) Ph3P]CHCO2Et, CH2Cl2, rt, 2 h, 98%; (h) K2CO3, EtOH, 0 ꢀC–rt (96%).
Keeping this in mind, we envisaged that the cis-isomer of the
a,b-unsaturated ester, on exposure to K2CO3/EtOH, would
provide 10b after deprotection of the formate ester and lacto-
nization followed by 1,4-addition of an ethoxide group.
Under the above basic conditions, the trans-isomer of 9, after
deprotection of the formyl group, would remain as hydroxyl
ester 10a as it would not lactonize because of the geometrical
constraint.6 This was indeed the case. The required trans-
ester 10a could be obtained in pure form using the above
protocol (Scheme 2). The d-hydroxyl group of 10a was pro-
tected as the corresponding TIPS ether that was subjected
to Sharpless asymmetric dihydroxylation using AD-mix b
(Scheme 3). The desired diol 11 was obtained in 94% yield
with a ratio of 4:1. The minor isomer could be separated after
the formation of acetonide ester 12. Conversion of 12 to 14
was carried out using the Arndt–Eistert homologation proto-
col.7 Thus, the ester 12 was hydrolyzed with LiOH in aque-
ous methanol to obtain carboxylic acid that was converted
into a-diazoketone 13 via reaction of diazomethane with
the mixed anhydride. Wolff rearrangement of the 13 using
silver benzoate afforded the homologated ester 14 in 68%
yield. Exposure of the 14 to TFA/H2O (10:1) resulted in
deprotection of the TIPS ether as well as acetonide with in
situ lactonization to give 15 as a clean product (Scheme 3).
Since the conversion of 15 into the natural product (+)-1
has recently been carried out,3 we stopped our synthesis at
this stage.
2. Experimental
2.1. General methods
Chemicals were purchased and used without further purifi-
cation. 1H and 13C NMR spectra were recorded on a JEOL
JNM-LA400 spectrometer. All chemical shifts are quoted
on the d scale, TMS as internal standard, and coupling con-
stants are reported in hertz. Routine monitoring of reactions
were performed by TLC, and using 0.2 mm Kieselgel 60
F254 precoated aluminum sheets, commercially available
from Merck. Visualization was done by fluorescence
quenching at 254 nm, by exposure to iodine vapor. All the
column chromatographic separations were done by using sil-
ica gel (Acme’s, 60–120 mesh). Petroleum ether used was of
boiling range 60–80 ꢀC. Reactions that needed anhydrous
conditions were run under an atmosphere of nitrogen or
argon using flame-dried glassware. The organic extracts
were dried over anhydrous sodium sulfate. Evaporations of
solvents were performed at reduced pressure. Tetrahydro-
furan (THF) was distilled from sodium benzophenone
ketyl under nitrogen. Dichloromethane was distilled from
CaH2. AD-mix b and (DHQD)2PHAL were purchased from
Aldrich. MeSO2NH2, CSA, and 2,2-dimethoxypropane were
obtained from Lancaster.
2.1.1. 3-O-Benzyl-1,2-O-isopropylidene-5-C-phenyl-
a-L-idopentofuranose (6a and 6b). To a solution of
a-D-pentodialdose 5 (8.89 g, 32.0 mmol) in anhydrous
THF (160.0 mL), PhMgBr (48.0 mL, 1 M soln in THF,
48.0 mmol) was added under an N2 atmosphere at 0 ꢀC
and stirred at room temperature for 12 h. The reaction mix-
ture was quenched with saturated NH4Cl and extracted with
In conclusion, we have achieved a formal total synthesis of
(+)-cardiobutanolide 1 from D-glucose, which is a readily
available starting material. The key steps in the synthesis
are Sharpless asymmetric dihydroxylation, Arndt–Eistert
homologation, and lactonization reactions.
TIPSO
Ph
OH
TIPSO
Ph
O
TIPSO
Ph
O
O
COOEt
OBn OH
11
a, b
d, e
c
COOEt
N2
10a
BnO
O
BnO
OBn
O
BnO
OBn
13
12
O
TIPSO
Ph
O
OH
O
g
h
OCH3
f
(+)-1
Ph
BnO BnO
O
BnO
OBn
O
OH
14
15
Scheme 3. Reagents and conditions: (a) TIPSOTf, 2,6-lutidine, DCM, 0 ꢀC–rt (98%); (b) AD-mix b, (DHQD)2PHAL, MeSO2NH2, t-BuOH/H2O, 0 ꢀC, 24 h
(94%), dr 4:1; (c) 2,2-dimethoxy propane, CSA, DCM, 0 ꢀC–rt, 2 h (91%); (d) LiOH$H2O, MeOH/H2O (4:1) (91%); (e) Et3N, ClCOOEt, CH2N2, THF, 0 ꢀC–rt
(60%); (f) PhCOOAg, Et3N, MeOH, 2 h (68%); (g) TFA/H2O (10:1), DCM, 24 h (98%); (h) Ref. 3.

11242
A. Garg et al. / Tetrahedron 62 (2006) 11240–11244
ethyl acetate. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated.
The residue was purified over silica gel to give a separable
diastereomeric mixture (dr 12:1) of benzylic alcohol 6a
(9.45 g, 83%) and 6b (0.80 g, 7%). Compound 6a: IR (thin
film, cmꢁ1) 3548, 3020; 1H NMR (CDCl3, 400 MHz):
d 1.31 (s, 3H), 1.49 (s, 3H), 3.64 (d, J¼2.9 Hz, 1H), 4.31
(dd, J¼7.3, 4.1 Hz, 1H), 4.43 (ABq, J¼11.5 Hz, Dn¼
98.1 Hz, 2H), 4.61 (d, J¼3.7 Hz, 1H), 5.06 (d, J¼7.3 Hz,
1H), 6.02 (d, 3.4 Hz, 1H), 7.26–7.41 (m, 10H); 13C NMR
(CDCl3, 100 MHz): d 26.2, 26.8, 71.8, 72.4, 82.1, 82.2,
84.5, 105.2, 111.9, 127.1, 127.7, 128.0, 128.1, 128.4,
128.6, 136.9, 139.6. MS (FAB) 357 (M++1). Anal. Calcd
for C21H24O5: C, 70.77; H, 6.79; found: C, 70.71; H, 6.83.
100 MHz): d 26.3, 26.7, 53.4, 70.3, 72.4, 78.2, 81.8, 82.1,
82.9, 105.0, 111.5, 127.5, 127.6, 127.8, 128.1, 128.3, 128.4,
137.7, 138.2, 139.3. MS (FAB) 447 (M++1). Anal. Calcd
for C28H30O5: C, 75.31; H, 6.77; found: C, 75.23; H, 6.85.
2.1.4. (2S,3R,4R)-2,4-Bis-(benzyloxy)-3-formyloxy-4-
phenyl-1-butanal (8). A solution of the acetonide 7 (9.0 g,
20.17 mmol) in dioxane (60.0 mL) was treated with 0.4%
H2SO4 (21.0 mL) at 100 ꢀC for 20 h. The reaction mixture
was quenched with solid Na2CO3 and concentrated. The resi-
due was dissolved in ethyl acetate, washed with water and
brine, and dried over Na2SO4. The organic layer was concen-
trated and chromatographed over silica gel to give (6.55 g,
80%) hemiacetal as a white solid. The hemiacetal (4.3 g,
10.6 mmol) was dissolved in MeOH (305.0 mL) and treated
with 0.6 N NaIO4 aqueous solution (308.0 mL). The reac-
tion mixture was stirred at room temperature for 1 h and
then concentrated on rotavapor. The residue was diluted
with water and extracted with DCM. The combined organic
layers were washed with brine and dried over anhydrous
Na2SO4. The solvent was removed in vacuo and the residue
was chromatographed over silica gel to give formido alde-
hyde 8 (4.2 g, 98%) as an oily liquid; [a]2D5 ꢁ8.52 (c 0.68,
CHCl3); IR (thin film, cmꢁ1) 3040, 1720; 1H NMR
(CDCl3, 400 MHz): d 4.11 (d, J¼10.9 Hz, 1H), 4.38 (d,
J¼11.2 Hz, 1H), 4.47 (d, J¼2.7 Hz, 1H), 4.62 (ABq,
J¼11.7 Hz, Dn¼84.6 Hz, 2H), 4.65 (d, J¼9.0 Hz, 1H),
5.55 (dd, J¼9.0, 2.5 Hz, 1H), 7.17–7.40 (m, 15H), 7.62 (s,
1H), 9.58 (s, 1H); 13C NMR (CDCl3, 100 MHz): d 53.4,
70.5, 73.2, 73.7, 77.9, 82.1, 127.9, 128.0, 128.1, 128.33,
128.39, 128.4, 128.5, 128.6, 128.8, 137.2, 158.9, 199.8.
MS (FAB) 405 (M++1). Anal. Calcd for C25H24O5: C,
74.24; H, 5.98; found: C, 74.31; H, 5.92.
2.1.2. 3-O-Benzyl-1,2-O-isopropylidene-5-C-phenyl-
a-D-glucopentofuranose (6b). To a solution of alcohol 6a
and 6b (5.36 g, 15.05 mmol) in dry DCM (90.0 mL), PDC
˚
(8.49 g, 22.58 mmol), powdered 4 A MS (12.04 g), and gla-
cial acetic acid (600 mL) were added. The reaction was exo-
thermic, refluxing gently and the orange color of the solution
turned to dark brown within 5 min. The reaction mixture was
stirred for 6 h; Celite was added and again stirred for 10 min.
The reaction mixture was filtered over silica gel under vacuo
and washed with DCM. The organic layer was concentrated
to yield the ketone (4.37 g, 82%). The ketone (4.37 g,
12.34 mmol) was dissolved in MeOH (40.0 mL) and cooled
to 0 ꢀC. To this cooled solution NaBH4 (1.87 g, 49.39 mmol)
was added portion wise and stirred for 4 h. The reaction
mixture was quenched with saturated NH4Cl and MeOH
was removed ona rotavapor. The aqueouslayerwas extracted
with EtOAc. The combined organic layers were washed with
water and brine and placed over anhydrous Na2SO4. The or-
ganic layer was concentrated in vacuo and chromatographed
over silica gel to give a separable diastereomeric mixture
(10:1) of alcohol 6b (3.91 g, 89%) and 6a (0.38 g, 9%) as a
syrup. Compound 6b: [a]2D5 ꢁ85.18 (c 1.35, CHCl3); IR
(thin film, cmꢁ1) 3550, 3045; 1H NMR (CDCl3, 400 MHz):
d 1.31 (s, 3H), 1.46 (s, 3H), 4.00 (d, J¼2.4 Hz, 1H), 4.32
(dd, J¼5.9, 3.2 Hz, 1H), 4.57(ABq, J¼11.5 Hz, Dn¼90.6 Hz,
2H), 4.62 (d, J¼3.9 Hz, 1H), 5.10 (d, J¼6.1 Hz, 1H), 6.03 (d,
J¼3.9 Hz, 1H), 7.26–7.39 (m, 10H); 13C NMR (CDCl3,
100 MHz): d 26.1, 26.7, 71.9, 72.2, 81.6, 82.4, 82.7, 105.1,
111.6, 126.0, 127.6, 128.0, 128.4, 128.7, 136.6, 141.2. MS
(FAB) 357 (M++1). Anal. Calcd for C21H24O5: C, 70.77; H,
6.79; found: C, 70.84; H, 6.71.
2.1.5. (4R,5R,6R)-Ethyl-4,6-bis-(benzyloxy)-5-(formido-
hydroxy)-5-phenyl-(2E/Z)-hexenoate (9). To a solution
of formido aldehyde 8 (203.0 mg, 0.5 mmol) in dry DCM
(3.0 mL), ethoxycarbonylmethylenetriphenylphosphorane
(348 g, 1.0 mmol) was added and stirred at room tempera-
ture for 2 h. The reaction mixture was quenched with water
and extracted with DCM. The organic layer was washed with
water and brine and dried over anhydrous Na2SO4. The sol-
vent was removed under vacuo and purified over silica gel to
give an inseparable mixture (E/Z 3:1) of trans- and cis-
enoate 9 (238 mg, 98%). IR (thin film, cmꢁ1) 3048, 1645;
1H NMR (CDCl3, 400 MHz): d 1.24 (t, J¼7.3 Hz, 0.75H),
1.27 (t, J¼7.3 Hz, 2.75H), 4.09 (d, J¼11.2 Hz, 1H), 4.14–
4.21 (m, 2H), 4.35 (dd, J¼11.5, 2.7 Hz, 2H), 4.55–4.73
(m, 3H), 5.30 (dd, J¼8.8, 1.5 Hz, 0.75H), 5.44 (dd, J¼9.0,
1.7 Hz, 0.25H), 5.68 (d, J¼8.6 Hz, 0.25H), 5.91 (dd,
J¼11.7, 1.2 Hz, 0.25H), 6.11 (dd, J¼15.8, 1.4 Hz, 0.75H),
6.79 (dd, J¼15.8, 5.8 Hz, 0.75H), 7.15–7.14 (m, 15H),
7.65 (d, J¼2.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d 14.1, 53.4, 60.6, 70.6, 72.1, 75.2, 75.9, 78.4, 123.9,
127.7, 127.8, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5,
128.6, 137.2, 137.5, 143.7, 159.0, 165.6. MS (FAB) 475
(M++1). Anal. Calcd for C29H30O6: C, 73.40; H, 6.37; found:
C, 73.35; H, 6.47.
2.1.3. 3,5-Di-O-benzyl-1,2-O-isopropylidene-5-C-phenyl-
a-D-glucopentofuranose (7). To a suspension of NaH
(0.67 g, 16.8 mmol) in anhydrous THF (50.0 mL), alcohol
6b (3.0 g, 8.4 mmol) in anhydrous THF (10.0 mL) was
slowly added at 0 ꢀC, stirred for 30 min, followed by addition
of benzyl bromide (1.10 mL, 9.26 mmol) and a catalytic
amount of TBAI. The resulting mixture was stirred at room
temperature for 2 h, quenched with NH4Cl, and extracted
with ether. The organic layer was washed with brine, dried
over anhydrous Na2SO4, and concentrated invacuo. The resi-
due was purified over silica gel to give the benzyl ether 7
(3.68 g, 98%) as a white solid. Mp 68–69 ꢀC; [a]D25 ꢁ60.00
(c 0.80, CHCl3); IR (thin film, cmꢁ1) 3025, 1240; 1H NMR
(CDCl3, 400 MHz): d 1.26 (s, 3H), 1.40 (s, 3H), 4.23 (m,
2H), 4.36 (m, 2H), 4.59 (m, 2H), 4.72 (m, 2H), 5.85 (d,
J¼3.7 Hz, 1H), 7.20–7.46 (m, 15H); 13C NMR (CDCl3,
2.1.6. (4R,5R,6R)-Ethyl-4,6-bis-(benzyloxy)-5-(hydroxy)-5-
phenyl-(2E)-hexenoate (10a) and (5R,6R,7R)-4-ethoxy-5,7-
bis-(benzyloxy)-6-(1-phenylmethyl)-3,4,5,6-tetrahydro-
4H-pyran-2-one (10b). The mixture of a,b-unsaturated

A. Garg et al. / Tetrahedron 62 (2006) 11240–11244
11243
ester 9 (6.8 g, 14.3 mmol) was dissolved in EtOH (45.0 mL)
and cooled to 0 ꢀC. To this cooled solution, K2CO3 (2.96 g,
21.42 mmol) was added and stirred at room temperature for
1 h. The reaction mixture was quenched with 2 N HCl at
0 ꢀC and stirred for 2 h. The aqueous layer was extracted
with ethyl acetate, washed with brine, and placed over anhy-
drous Na2SO4. The solvent was removed under vacuo and
chromatographed to give the trans-ester 10a (4.78 g, 72%)
and the corresponding lactone 10b (1.51 g, 23%). Com-
pound 10a: [a]2D5 +56.18 (c 2.62, CHCl3); IR (thin film,
4.73 (d, J¼4.6 Hz, 1H), 7.09–7.47 (m, 15H); 13C NMR
(CDCl3, 100 MHz): d 12.6, 12.8, 14.1, 18.0, 18.1,
61.5, 70.1, 70.8, 73.0, 73.1, 76.0, 76.7, 82.7, 127.5,
127.6, 127.8, 127.9, 128.0, 128.1, 128.2, 128.7, 138.1,
138.2, 138.5, 173.8. MS (FAB) 638 (M++1). Anal.
Calcd for C37H52O7Si: C, 69.78; H, 8.23; found: C, 69.69;
H, 8.33.
2.1.8. (4S,5R)-Ethyl-5-((1R,2R,3R)-1,3-bis(benzyloxy)-3-
phenyl-2-(triisopropylsilyloxy)propyl)-2,2-dimethyl-1,3-
dioxolane-4-carboxylate (12). To the solution of diol 11
(2.34 g, 3.58 mmol) in DCM (12.0 mL), 2,2-dimethoxy pro-
pane (4.4 mL, 35.78 mmol) and catalytic amount of CSA
were added at 0 ꢀC. The reaction mixture was stirred at
room temperature for 2 h under nitrogen atmosphere,
quenched with water, and extracted with DCM. The com-
bined organic layer was washed with brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The residue was
purified on column chromatography to give ester 12
(2.26 g, 91%) as a separable mixture in a ratio of 4:1. [a]D25
ꢁ25.61 (c 2.15, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 0.77 (m, 3H), 0.97 (d, J¼7.3 Hz, 18H), 1.08 (m, 3H),
1.47 (d, J¼9.1 Hz, 6H), 3.96 (m, 2H), 4.14 (m, 2H), 4.34
(m, 2H), 4.50 (m, 3H), 4.68 (s, 2H), 7.27–7.44 (m, 15H);
13C NMR (CDCl3, 100 MHz): d 13.4, 13.8, 18.1, 18.3,
25.9, 27.1, 61.2, 70.3, 73.4, 75.8, 76.7, 78.1, 78.2, 79.8,
87.8, 111.4, 126.7, 126.9, 127.4, 127.8, 127.9, 128.1,
128.7, 138.2, 139.1, 139.3, 171.2. MS (FAB) 678 (M++1).
Anal. Calcd for C40H56O7Si: C, 70.97; H, 8.34; found: C,
70.87; H, 8.43.
1
cmꢁ1) 3452, 1740; H NMR (CDCl3, 400 MHz): d 1.28
(t, J¼7.1 Hz, 3H), 3.71 (dd, J¼8.3, 2.2 Hz, 1H), 4.08 (d, J¼
11.2 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 4.33 (dd, J¼15.1,
11.2 Hz, 2H), 4.41 (d, J¼8.3 Hz, 1H), 4.46 (dd,
J¼6.4, 1.2 Hz, 1H), 4.63 (d, J¼11.5 Hz, 1H), 6.09 (dd,
J¼15.9, 1.2 Hz, 1H), 6.97 (dd, J¼15.8, 6.6 Hz, 1H), 7.17
(d, J¼7.3 Hz, 1H), 7.23–7.39 (m, 15H); 13C NMR (CDCl3,
100 MHz): d 14.2, 60.5, 70.4, 71.7, 76.2, 76.8, 80.9, 123.5,
127.7, 127.91, 127.96, 128.0, 128.2, 128.3, 128.4, 128.5,
137.5, 137.8, 138.8, 145.4, 165.9. MS (FAB) 447 (M++1).
Anal. Calcd for C28H30O5: C, 75.31; H, 6.77; found: C,
75.25; H, 6.84. Compound 10b: [a]2D5 ꢁ8.00 (c 0.60,
CHCl3); IR (thin film, cmꢁ1) 3455, 1758; 1H NMR
(CDCl3, 400 MHz): d 1.14 (t, J¼6.8 Hz, 3H), 2.56
(dd, J¼17.8, 2.4 Hz, 1H), 2.84 (dd, J¼17.8, 4.9 Hz, 1H),
3.40–3.50 (m, 2H), 3.77 (ABq, J¼4.9 Hz, Dn¼6.6 Hz,
1H), 4.19 (d, J¼4.4 Hz, 1H), 4.71 (d, J¼8.6 Hz, 1H), 4.42
(d, J¼11.2 Hz, 1H), 4.60–4.73 (m, 4H), 7.24–7.48 (m,
15H); 13C NMR (CDCl3, 100 MHz): d 15.2, 32.6, 60.2,
64.5, 70.2, 71.3, 71.7, 72.6, 78.0, 80.2, 126.8, 127.5,
127.6, 127.7, 127.8, 128.1, 128.2, 128.3, 128.4, 137.6,
137.7, 138.2, 168.8. MS (FAB) 447 (M++1). Anal.
Calcd for C28H30O5: C, 75.31; H, 6.77; found: C, 75.42;
H, 6.65.
2.1.9. 1-[5-(1,3-Bis-benzyloxy-3-phenyl-2-triisopropyl-
silanyloxy-propyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-2-
diazo-ethanone (13). To a ice cooled solution of 12
(300 mg, 0.43 mmol) in methanol/water (5.0 mL, 4:1)
was added lithium hydroxide monohydrate (108.7 mg,
2.59 mmol) at 0 ꢀC. The mixture was brought to 25 ꢀC and
was further stirred for 2 h. The pH of the solution was
adjusted to 7.0 by addition of aqueous NH4Cl, the solvent
was evaporated and the residue so obtained was extracted
with chloroform to give an acid. To this acid (730.0 mg,
1.09 mmol) in THF (8.0 mL) at 0 ꢀC, triethylamine
(451.0 mL, 3.29 mmol) and ethylchloroformate (204.3 mL,
2.18 mmol) were added one after the other. After 15 min,
the reaction mixture was brought to room temperature
for 30 min and was filtered over Celite. To this filtrate
a freshly prepared solution of diazomethane in diethyl ether
[(prepared from N-nitrosomethyl urea (1.10 g) and KOH
(2.0 g)] was added dropwise over a period of 30 min. The
mixture was stirred for 1.5 h at room temperature. The
solvent was evaporated under reduced pressure, and the resi-
due was purified by column chromatography to give 13
(453.7 mg, 60%). [a]2D5 ꢁ21.96 (c 2.85, CHCl3); IR (thin
film, cmꢁ1) 3371, 3031, 2107, 1637, 1071; 1H NMR
(CDCl3, 400 MHz): d 0.77 (m, 3H), 0.93 (d, J¼7.3 Hz,
18H), 1.26 (d, J¼10.9 Hz, 6H), 3.83 (m, 1H), 4.19 (m,
1H), 4.35 (m, 3H), 4.51 (m, 2H), 4.67 (ABq, J¼11.7 Hz,
Dn¼41.0 Hz, 2H), 7.18–7.41 (m, 15H); 13C NMR (CDCl3,
100 MHz): d 13.3, 18.1, 18.3, 26.0, 26.9, 53.1, 70.5, 73.7,
75.4, 78.0, 79.9, 81.3, 83.1, 110.7, 127.1, 127.2, 127.3,
127.6, 127.8, 128.0, 128.09, 128.13, 128.6, 138.3, 138.9,
139.2, 193.8. MS (FAB) 674 (M++1). Anal. Calcd for
C39H52N2O6Si: C, 69.61; H, 7.79; found: C, 69.72; H, 7.65.
2.1.7. (4R,5R,6R)-Ethyl-4,6-bis(benzyloxy)-2,3-dihy-
droxy-6-phenyl-5-(triisopropylsilyloxy)-hexanoate (11).
To a solution of alcohol 10a (564 mg, 1.14 mmol) in dry
DCM (5.0 mL), 2,6-lutidine (400 mL, 3.43 mmol) was added
at 0 ꢀC. The solution was stirred for 30 min, and then TIP-
SOTf was added and was further stirred for 12 h at room
temperature. The reaction mixture was quenched with water
and diluted with DCM. The organic layer was washed with
water and brine and dried over anhydrous Na2SO4. The
organic layer was concentrated in vacuo. The residue was
chromatographed on silica gel to give the TIPS ether
(695 mg, 98%). After that to a 1:1 solution of t-BuOH and
H2O (10.0 mL), AD-mix b (4.12 g) was added and stirred
for 5 min. To this stirred solution (DHQD)2PHAL
(103.0 mg) and MeSO2NH2 (172.0 mg) was added at room
temperature. The reaction mixture was cooled to 0 ꢀC,
TIPS ether (1.03 g, 1.93 mmol) was added, and was further
stirred at same temperature for 24 h. The reaction mixture
was quenched with Na2SO3. After 30 min EtOAc was added
and organic phase was separated. The combined organic
layer was washed twice with 1 M KHSO4 solution, 5%
NaHCO3, brine and dried over anhydrous Na2SO4. The
organic layer was evaporated in vacuo and residue was
purified on silica gel to give a inseparable mixture of
diol 11 (1.12 g, 92%). 1H NMR (CDCl3, 400 MHz):
d 0.91 (m, 3H), 1.01 (m, 18H), 1.22 (t, J¼17.3 Hz, 3H),
2.96 (d, J¼8.5 Hz, 1H), 3.32 (d, J¼2.9 Hz, 1H), 3.87
(dd, J¼9.8, 3.4 Hz, 1H), 4.17–4.34 (m, 4H), 4.51 (m, 3H),

11244
A. Garg et al. / Tetrahedron 62 (2006) 11240–11244
2.1.10. Methyl 2-((4R,5S)-5-((1R,2R,3R)-1,3-bis(benzyl-
oxy)-3-phenyl-2-(triisopropylsilyloxy)propyl)-2,2-di-
methyl-1,3-dioxolan-4-yl)acetate (14). To a solution of
a-diazoketone 13 (316.0 mg, 0.45 mmol) in anhydrous
MeOH (6.0 mL) was added, dropwise, a solution of silver
benzoate (38.0 mg, 0.14 mmol) in triethylamine (731 mL)
under dry N2 at ꢁ10 ꢀC. The reaction mixture was further
stirred for 1.5 h. The solvent was evaporated and the residue
was purified by column chromatography to give 14 (217 mg,
68%) as a syrupy liquid. [a]2D5 ꢁ2.79 (c 3.25, CHCl3); IR (thin
(m, 3H), 4.55–4.60 (m, 3H), 4.81 (d, J¼11.2 Hz, 1H),
7.24–7.44 (m, 15H); 13C NMR (CDCl3, 100 MHz): d 39.4,
69.7, 70.4, 74.3, 75.1, 75.5, 80.9, 83.1, 127.9, 128.1,
128.2, 128.4, 128.6, 128.8, 137.4, 137.5, 138.3, 175.2. MS
(FAB) 450 (M++1). Anal. Calcd for C27H28O6: C, 72.30;
H, 6.29; found: C, 72.38; H, 6.22.
Acknowledgements
1
film, cmꢁ1) 3030, 2928, 1743, 1071; H NMR (CDCl3,
V.K.S. thanks the CSIR, India for a research grant. A.G.
thanks the CSIR, New Delhi for a research fellowship.
400 MHz): d 0.72 (m, 3H), 0.96 (d, J¼7.3 Hz, 18H), 1.29
(m, 6H), 2.41 (dd, J¼15.8, 9.5 Hz, 1H), 2.72 (dd, J¼15.8,
2.2 Hz, 1H), 3.62 (s, 3H), 3.80 (t, J¼9.0 Hz, 1H), 3.95 (dd,
J¼9.3, 1.5 Hz, 1H), 4.15 (d, J¼11.5 Hz, 1H), 4.31 (m, 3H),
4.45 (d, J¼7.3 Hz, 1H), 4.60 (ABq, J¼11.9 Hz,
Dn¼20.6 Hz, 2H), 7.24–7.43 (m, 15H); 13C NMR (CDCl3,
100 MHz): d 13.4, 13.8, 18.1, 18.3, 25.9, 27.1, 61.2,
70.3, 73.4, 75.8, 76.7, 78.1, 78.2, 79.8, 87.8, 111.4,
126.7, 126.9, 127.4, 127.8, 127.9, 128.1, 128.7, 138.2,
139.1, 139.3, 171.2. MS (FAB) 678 (M++1). Anal. Calcd
for C40H56O7Si: C, 70.97; H, 8.34; found: C, 70.92; H, 8.41.
References and notes
1. Hisham, A.; Toubi, M.; Shuaily, W.; Ajitha Bai, M. D.;
Fujimoto, Y. Phytochemistry 2003, 62, 597.
2. (a) Ruiz, P.; Murga, J.; Carda, M.; Marco, J. A. J. Org. Chem.
2005, 70, 713; (b) Matsuura, D.; Takabe, K.; Yoda, H.
Tetrahedron Lett. 2006, 47, 1371.
3. Radha Krishna, P.; Narshimha Reddy, P. V. Tetrahedron Lett.
2006, 47, 4627.
2.1.11. 5-(1,3-Bis-benzyloxy-2-hydroxy-3-phenyl-pro-
pyl)-4-hydroxy-dihydro-furan-2-one (15). To a stirred so-
lution of 14 (103 mg, 0.15 mmol) in CH2Cl2 (2.0 mL) was
added a mixture of water (1.0 mL) and TFA (0.1 mL). The
reaction mixture was stirred for 24 h. The reaction mixture
was quenched with solid NaHCO3, extracted with DCM,
washed with brine, and placed over anhydrous NaSO4, evap-
orated under reduced pressure to provide the lactonized
product 15 (69 mg, 98%) as a solid. Mp 136–138 ꢀC; [a]D25
ꢁ49.5 (c 1.2, CHCl3); IR (thin film, cmꢁ1) 3397, 3030,
4. (a) Raina, S.; Singh, V. K. Tetrahedron 1996, 52, 4479; (b)
Chandrasekhar, M.; Raina, S.; Singh, V. K. Tetrahedron Lett.
2000, 41, 4969; (c) Chandra, K. L.; Chandrasekhar, M.; Singh,
V. K. J. Org. Chem. 2002, 67, 4630; (d) Singh, R. P.; Singh,
V. K. J. Org. Chem. 2004, 69, 3425.
5. (a) Lemieux, R. U.; Howard, J. Can. J. Chem. 1963, 41, 308; (b)
Tronchet, J. M. J.; Grivet, C.; Grand, E.; Seman, M.; Dilda, P.
Carbohydr. Lett. 2000, 4, 5.
6. We have earlier executed the similar kind of transformation
during the total synthesis of dihydrokawainol (viz Ref. 4d).
7. (a) Bachmann, W. E.; Stuve, W. S. Org. React. (N.Y.) 1942, 1, 38;
(b) Ando, W. Chemistry of Diazonium and Diazo Groups;
Patai, S., Ed.; Wiley: New York, NY, 1978; pp 458–475.
1
2924, 1767, 1060; H NMR (CDCl3, 400 MHz): d 2.50 (d,
J¼17.3 Hz, 1H), 2.64 (dd, J¼17.6, 4.9 Hz, 1H), 3.88 (dd,
J¼8.6, 1.5 Hz, 1H), 4.13 (d, J¼8.5 Hz, 1H), 4.40–4.45