Towards the total synthesis of etnangien: Synthesis of C32-C42 fragment by using a desymmetrization strategy

Article abstract of DOI:10.1016/j.tetasy.2010.10.003

The construction of the C32-C42 fragment of etnangien is described using a desymmetrization strategy generating five stereogenic centers from a bicyclic lactone. Another notable feature includes the use of the Sharpless asymmetric epoxidation to generate

Full text of DOI:10.1016/j.tetasy.2010.10.003

Tetrahedron: Asymmetry 21 (2010) 2524–2529
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Towards the total synthesis of etnangien: synthesis of C32–C42 fragment by
using a desymmetrization strategy
⇑
Gowravaram Sabitha , Kurra Yadagiri, Martha Bhikshapathi, Gajangi Chandrashekhar, Jhillu Singh Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The construction of the C32–C42 fragment of etnangien is described using a desymmetrization strategy
generating five stereogenic centers from a bicyclic lactone. Another notable feature includes the use of
the Sharpless asymmetric epoxidation to generate a stereogenic center at C40.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 September 2010
Accepted 4 October 2010
Available online 8 November 2010
1. Introduction
2.1. Synthesis of the C32–C42 fragment of etnangien
The genus Sorangium has been found to produce interesting
structures,1 such as the antifungal soraphens,2 the antibacterial
sorangicins3, and thuggacins,4 as well as the anticancer epothil-
ones.5 Recently, a new macrolactone etnangien 1 was isolated by
Hofle et al. from the myxobacterium Sorangium cellulosum,6 and it
displays potent antibiotic activity against a range of Gram-positive
bacteria, by inhibition of RNA-polymerase, in vitro and in vivo.
Importantly, it retains activity against retroviral DNA polymerase,
and shows no cross-resistance to rifampicine, the only clinically
used RNA-polymerase inhibitor so far. It was also found to show
low cytotoxicity against mammalian cell cultures. Moreover, etnan-
gien displays a number of salient motifs comprising of a 22-mem-
The synthesis of the C32–C42 fragment of etnangien started from
the known bicyclic lactone 5,8 which was prepared using a desym-
metrization strategy.9 Lactone 5, upon allylation with allyl bromide
using NaHMDS afforded allylic lactone 6, which was reduced using
LAH to furnish triol 7 in 85% yield (Scheme 2). The 1,3-diol moiety
was protected as the acetonide 8 and the primary hydroxyl function-
ality was converted to its corresponding pivolylate 9 using pivolyl
chloride in the presence of NEt3 in DCM in 92% yield. The acetonide
group of 9 was hydrolyzed with PTSA in MeOH to afford diol 10 in
75% yield. The primary hydroxyl group in compound 10 was selec-
tively tosylated with TsCl in the presence of NEt3 and Bu3SnO in
DCM to affordtosylate 11in 87%yield. Thesecondaryhydroxyl group
wasprotectedasaTBSetherusingTBSTf inpresenceof2,6-lutidinein
DCM to afford 12 in 92% yield. The –CH2OTs group of compound 12
wastransformedintoamethylgroupandsimultaneousdeprotection
of the pivaloyl group was achieved by using LAH in refluxing THF to
give 4 in 86% yield. Compound 4, upon oxidation using IBX in DMSO
and DCM, furnished the aldehyde, which upon Wittig homologation
bered macrolactone with
a polyunsaturated side chain and
includes 12 stereogenic centers. Due to its biological importance,
and its structural challenge, the synthesis of etnangien 1 has at-
tracted our attention to take-up its synthesis. So far, only one report
has appeared on the total synthesis of etnangien.7 Herein, we report
the synthesis of the C32–C42 fragment using a desymmetrization
strategy.
with PPh3@CHCO2Et in benzene at room temperature afforded a,b-
unsaturated ester 13 in 73% yield. The ester group of compound 13
was reduced to allylic alcohol 3 using DIBAL-H at ꢀ78 °C in CH2Cl2
in 72% yield. Allylic alcohol 3 upon Sharpless asymmetric epoxida-
tion furnished epoxy alcohol 14 in 80% yield, which on treating with
Red-Al yielded 1,3-diol 15 in 82% yield. Deprotection of the benzyl
ether in compound 15 was achieved using lithium naphthalide in
dry THF to afford triol 16 in 76% yield. The 1,3-dihydroxy groups of
triol 16 were protected as its PMB acetal 17 using anisaldehyde
dimethyl acetal, and a catalytic amount of PPTS in CH2Cl2 in 84%
yield. Inversion of the hydroxyl functionality in compound 17 was
achieved using Mitsunobu conditions10 to afford 18, which was pro-
tected as its MOM ether 19 by treatment with Hunig’s base and
MOMCl in 78% yield. Compound 19 upon treatment with Dibal-H11
resulted in the C32–C42 fragment 2 of etnangien. The structure of 2
was characterized by spectroscopic and analytical data.
2. Results and discussion
The retrosynthetic analysis is represented in Scheme 1. The
intermediate 4 with five stereogenic centers could be obtained
from a known bicyclic lactone 5 employing LAH mediated reduc-
tion. Unit 3 could be made by Wittig homologation and the final
fragment 2 could be obtained by utilizing a Sharpless asymmetric
epoxidation reaction to generate the stereogenic center at C40.
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.003

G. Sabitha et al. / Tetrahedron: Asymmetry 21 (2010) 2524–2529
2525
HO
OH
42
O
1
OH
O
HO
13
O
32
31
14
OH
OH
OMe
OH
etnangien 1
OPMB
OP
OP1
OP
OBn
OH
OBn
OTBS
OH
OH
C32-C42 Fragment 2
4
3
P=TBS
P=TBS
P1= MOM
O
O
O
OBn
5
Scheme 1. The retrosynthetic analysis of etnangien.
ature and quenched with a saturated aqueous NH4Cl solution
(30 mL) and extracted with ether (3 ꢁ 150 mL). The organic ex-
tracts were washed with water and brine, and dried over anhy-
drous Na2SO4 (2 g), concentrated in vacuo, and purified by
column chromatography on silica gel to give the allylated lactone
3. Conclusion
In conclusion, the synthesis of the C32–C42 fragment of etnan-
gien has been achieved using a desymmetrization strategy.
6 (27.47 g, 80%) as a viscous liquid. ½a D25
ꢂ
¼ ꢀ34:6 (c 1, CHCl3);
4. Experimental
4.1. General
IR (neat) mmax 2926, 1725 1638, 1452, 1058 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.34–7.23 (m, 5H), 5.79–5.65 (m, 1H), 5.36
(d, 1H, J = 3.1 Hz), 5.14–5.07 (m, 2H), 4.57 (ABq, 2H, J = 11.3 Hz),
3.83 (dd, 1H, J = 6.7 Hz), 3.55 (t, 1H, J = 3.2 Hz), 2.66–2.57 (m,
2H), 2.52–2.38 (m, 1H), 2.25–2.16 (m, 1H), 2.07–1.97 (m, 1H),
1.15 (d, 3H, J = 7.5 Hz), 0.89 (d, 3H, J = 7.5 Hz); 13C NMR (75 MHz,
CDCl3): d 162.5, 129.8, 122.4, 121.7, 120.7, 114.4, 111.4, 68.6,
58.0, 56.0, 53.4, 46.6, 29.5, 26.7, 24.1, 23.0; ESIMS: 317 (M++1).
Reactions were conducted under N2 in anhydrous solvents, such
as CH2Cl2, THF, and EtOAc. All reactions were monitored by TLC (sil-
ica-coated plates and visualizing under UV light). Petroleum ether
(bp 60–80 °C) was used. Yields refer to chromatographically and
spectroscopically (1H and 13C NMR) homogeneous material. Air sen-
sitive reagents were transferred by syringe or double-ended needle.
Evaporation of solvents was performed at reduced pressure on a Bu-
chi rotary evaporator. 1H and 13C NMR spectra of samples in CDCl3
were recorded on Varian FT-200 MHz (Gemini) and Bruker UXNMR
FT-300 MHz (Avance) spectrometers. Chemical shifts d are reported
relative to TMS (d = 0.0) as an internal standard. Mass spectra were
recorded E1 conditions at 70 eV on LC-MSD (Agilent technologies)
spectrometers. Column chromatography was performed on silica
gel (60–120 mesh) supplied by Acme Chemical Co., India. TLC was
performedonMerck60F-254silicagel plates. Opticalrotationswere
measured with a JASCO DIP-370 Polarimeter.
4.3. (2R,3R,4S,5R,6R)-2-Allyl-5-(benzyloxy)-4,6
dimethylheptane-1,3,7-triol (7)
To a stirred suspension of LiAlH4 (4.77 g, 125.41 mmol) in dry
THF (30 mL) at 0 °C, a solution of lactone 6 (27 g, 83.85 mmol) in
dry THF (60 mL) was added dropwise. The reaction mixture was re-
fluxed for 3 h. It was then cooled to 0 °C, diluted with ether, and
quenched by the dropwise addition of saturated aqueous Na2SO4.
The solid material was filtered and washed thoroughly with hot
ethyl acetate several times. The combined organic layers were
dried over anhydrous Na2SO4. The solvent was removed in vacuo
and the residue was purified by silica gel column chromatogra-
phy to afford compound 7 (23.37 g, 85%) as a viscous liquid.
4.2. (4R)-7-(Benzyloxy)-4-allyl-6,8-dimethyl-2,9-
dioxabicyclo[3.3.1]nonan-3-one (6)
½
a 2D5
ꢂ
¼ þ1:3 (c 1, CHCl3); IR (neat) mmax 3408, 2926, 1638, 1452,
1058 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.33–7.25 (m, 5H),
;
To a stirred solution of lactone 5 (30 g, 108 mmol) in anhydrous
THF (150 mL) at ꢀ78 °C under a nitrogen atmosphere, was added
LHMDS (141 mL, 141.30 mmol, 1.0 M) dropwise. After 1-h stirring
at ꢀ78 °C, allylbromide (neat 27.9 mL, 326 mmol) was added drop-
wise. The reaction mixture was stirred for 3 h at the same temper-
5.79–5.65 (m, 1H), 5.05–4.97 (m, 2H), 4.67 (s, 2H), 3.98–3.89 (m,
1H), 3.81–3.71 (m, 2H), 3.69–3.59 (m, 2H), 3.52 (d, 1H, J = 3.1,
9.1 Hz), 2.01–1.85 (m, 3H), 1.84–1.76 (m, 2H), 1.15 (d, 3H,
J = 6.7 Hz), 0.97 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d

2526
G. Sabitha et al. / Tetrahedron: Asymmetry 21 (2010) 2524–2529
O
O
O
OH
OH
OH
OBn
a
c
b
O
O
O
O
OBn
OBn
5
7
6
OPiv
OBn
OH
OH
OBn OH
O
O
OBn OPiv
O
d
e
f
10
8
9
OPiv
OTs
OBn
OH
OBn OPiv
OTs OP
OBn OH
P = TBS
k
OP
g
h
i
12
4
11
P = TBS
OP
OBn
OP
OBn
j
CO2Et
OH
13
P = TBS
3
P = TBS
OH
OP
OBn
OBn
OP
O
l
m
OH
OH
14
P = TBS
15
P = TBS
OMe
OMe
HO
OH
OP
OH
o
n
O
O
OP
OH
O
O
OH
OP
17
18
16
OMe
OPMB
OP1
OP
O
O
q
p
OP
OP1
OH
P = TBS
19
P1 = MOM
2
P1 = MOM
P = TBS
Scheme 2. Reagents and conditions: (a) NaHMDS allylbromide; dry THF, ꢀ78 °C 4 h, 80%; (b) LAH, dry THF, 0 °C to rt, 3 h, 85%; (c) 2, 2 DMP, pPTS, 0 °C to rt, dry CH2Cl2, 12 h,
90%; (d) pivolyl chloride, Et3N, 0 °C to rt, 12 h, 92%; (e) pTSA, MeOH, 0 °C to rt, 12 h, 75%; (f) TsCl, Bu3SnO, Et3N, dry CH2Cl2, 0 °C to rt, 10 h, 87%; (g) TBSꢃTf., 2.6 lutidine, dry
CH2Cl2, 0 °C to rt, 2 h, 92%; (h) LAH, dry THF, 0 °C to rt, 3 h, 86%; (i) (i) dry DMSO, dry CH2Cl2, (COCl)2, Et3N, ꢀ78 °C; (ii) PPh3@CHCO2Et, dry benzene, rt, 15 h, 73%; (j) DIBAL, dry
CH2Cl2 ꢀ78 °C, 2 h, 72%; (k) (+) DET, Ti(OiPr)4, cummene hydroperoxide dry CH2Cl2, ꢀ23 °C, 6 h, 80%; (l) Red-Al, dry THF, 0 °C to rt, 2 h, 82%; (m) Li, naphthalene, dry THF, 0 °C
to rt, 1.5 h, 76%; (n) MeO–Ph–CH(OMe)2, dry CH2Cl2, PPTS, 0 °C to rt, 2 h, 84%; (o) DEAD, TPP, p-C6H4(NO2)COOH, dry THF, 0 °C to rt, then K2CO3, MeOH, 4 h, 65%; (p) MOMCl,
i-Pr2EtN, dry CH2Cl2, 0 °C rt, 4 h, 78%; (q) DIBAL-H, dry CH2Cl2, ꢀ78 °C, 1 h, 80%.

G. Sabitha et al. / Tetrahedron: Asymmetry 21 (2010) 2524–2529
2527
137.4, 135.7, 128.6, 128.2, 127.9, 116.7, 88.7, 76.4, 74.7, 65.8, 41.9,
37.9, 35.4, 32.8, 14.7, 11.8; ESIMS: 323 (M++1).
0 °C and treated with p-toluenesulphonyl chloride (8.839 g,
46.52 mmol) and a catalytic amount of Bu2SnO. The reaction mix-
ture was stirred at room temperature for 10 h, after which it was
diluted with water and extracted with DCM. The organic layer
was washed with brine and dried over anhydrous Na2SO4. Removal
of the solvent under reduced pressure and purification by silica gel
column chromatography afforded 11 (2.72 g, 87%) as a viscous li-
4.4. (2R,3R,4R)-4-[(4R,5R)-5-Allyl-2,2-dimethyl-1,3-dioxan-4-
yl]-3-(benzyloxy)-2-methylpentan-1-ol 8
To a solution of triol 7 (23 g, 71.42 mmol) in dry DCM (40 mL),
2,2-dimethoxy propane (10.6 mL, 85.67 mmol) and PTSA (1.1 g,
7.14 mmol)wereadded. Themixturewasstirredatambienttemper-
ature for12 h. Sodiumbicarbonatewas addedtoneutralizePTSA and
filtered. Removal of the solvent and purification by silica gel column
chromatography afforded the mono acetonide 8 (23.22 g, 90%) as a
quid. ½a 2D5
ꢂ
¼ þ10:9 (c 1, CHCl3); IR (KBr): 3489, 2927, 1725, 1458,
1359, 1176, 1092 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.75 (d, 2H,
J = 8.3 Hz), 7.33–7.23 (m, 7H), 5.72–5.57 (m, 1H), 5.06–4.97 (m,
2H), 4.57 (ABq, 2H, J = 10.5 Hz), 4.27–4.17 (m, 2H), 4.14–4.05 (m,
2H), 3.79–3.69 (m, 1H), 3.39 (dd, 1H, J = 3.2, 8.4 Hz), 3.11 (br s
1H), 2.40 (s, 3H), 2.15–1.99 (m, 2H), 1.93–1.86 (m, 1H), 1.93–
1.86 (m, 1H), 1.78–1.69 (m, 1H), 1.23 (s, 9H), 1.03 (d, 3H,
J = 6.7 Hz), 0.97 (d, 3H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3): d
178.3, 144.4, 137.2, 134.5, 129.6, 128.6, 128.1, 128.0, 127.9,
117.8, 87.0, 76.3, 69.2, 68.4, 65.9, 40.9, 35.7, 34.3, 31.0, 27.2,
21.5, 14.6, 11.3; ESIMS: 561 (M++1).
white solid. ½a 2D5
ꢂ
¼ ꢀ19:9 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3):
d 7.35–7.25 (m, 5H), 5.75–5.62 (m, 1H), 5.06–4.97 (m, 2H), 4.64
(ABq, 2H, J = 11.3 Hz), 3.98 (dd, 1H, J = 1.5, 10.5 Hz), 3.84 (dd, 2H,
J = 3.0, 11.3 Hz), 3.73 (dd, 1H, J = 4.5, 11.3 Hz), 3.52–3.43 (m, 3H),
2.61–2.56 (br s, 1H), 2.12–2.01 (m, 2H), 1.94–1.76 (m, 2H), 1.33 (s,
6H), 1.21 (d, 3H, J = 6.7 Hz), 0.88 (d, 3H, J = 6.7 Hz); 13C NMR
(75 MHz, CDCl3): d 138.3, 134.9, 128.4, 127.6, 126.9, 116.9, 97.8,
85.6, 75.4, 71.5, 64.2, 64, 37.3, 35.9, 34.6, 32.5, 29.5, 19.7, 16.3, 9.9;
ESIMS: 363 (M++1).
4.8. (2R,3R,4R,5R,6R)-3-(Benzyloxy)-5-[1-(tert-butyl)-1,1-
dimethylsilyl]oxy-2,4-dimethyl-6-([(4-
methylphenyl)sulfonyl]oxymethyl)-8-nonenyl pivalate 12
4.5. (2R,3R,4R)-4-[(4R,5R)-5-Allyl-2,2-dimethyl-1,3-ioxan-4-yl]-
3-(benzyloxy)-2-methylpentyl pivalate 9
tert-Butyldimethylsilyl triflouoromethanesulphonate (8.3 g,
35.55 mmol) was added to an ice-cold solution of compound 11
(20 g, 29.62 mmol) in dry DCM (50 mL) followed by the slow addi-
tion of 2,6-lutidine (10.31 g, 88.8 mmol). The reaction mixture was
stirred for 2 h at 0 °C before being diluted with DCM and washed
with saturated aqueous NH4Cl and brine solution. The organic
phase was dried over Na2SO4, and concentrated. Purification by col-
umn chromatography afforded the pure compound 12 (22.17 g,
To a stirred and cooled solution of alcohol 8 (23 g, 63.53 mmol)
and triethylamine (35.9 mL, 253 mmol) in dry DCM (40 mL), tri-
methyl acetyl chloride (23.5 ml, 190.60 mmol) was slowly added.
The mixture was stirred overnight at room temperature. The reac-
tion mixture was diluted with CH2Cl2 and washed with aqueouscop-
per sulfate solution, water, and brine solution, and dried over
anhydrous Na2SO4. The solvent was removed in vacuo and the resi-
duewaspurifiedbysilicagelcolumnchromatographytoaffordcom-
92%). ½a 2D5
¼ þ3:7 (c 0.5, CHCl3); IR(KBr): mmax 2958, 1726, 1640,
ꢂ
1461, 1365, 1177, 1061, 835, 774 cmꢀ1; 1H NMR (200 MHz, CDCl3):
d 7.69 (d, 2H, J = 8.3 Hz), 7.32–7.26 (m, 7H), 5.62–5.48 (m, 1H),
4.93–4.84 (m, 2H), 4.56 (s, 2H), 4.21 (dd, 1H, J = 5.2, 11.3 Hz),
4.05 (dd, 1H, J = 5.2, 9.8 Hz), 3.98–3.88 (m, 4H), 3.27 (dd, 1H,
J = 3.7, 8.3 Hz), 2.42 (s, 3H), 2.21–2.08 (m, 2H), 2.02–1.88 (m, 2H),
1.19 (s, 9H), 1.07 (d, 3H, J = 7.5 Hz), 0.88 (d, 3H, J = 6.7 Hz), 0.85
(s, 9H), 0.05 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3): d
178.5, 144.5, 138.4, 135.6, 133, 129.7, 128.3, 127.9, 127.4, 127.3,
117.2, 84.2, 74.2, 71.8, 70.1, 65.9, 44.0, 39.5, 34.8, 32.2, 27.2,
26.0, 21.5, 18.4, 15.9, 12.0, ꢀ3.2, ꢀ4.0; ESIMS: 693 (M++NH4+).
pound 9 (26.03 g, 92%) as a solid. ½a D25
ꢂ
¼ ꢀ18:4 (c 1, CHCl3); 1H NMR
(200 MHz, CDCl3): d 7.31–7.21 (m, 5H), 5.73–5.59 (m, 1H), 5.03–4.96
(m, 2H), 4.61 (ABq, 2H, J = 12 Hz), 4.28 (dd, 1H, J = 5.2, 10.5 Hz), 3.92–
3.87 (m, 2H), 3.71 (dd, 1H, J = 4.5, 11.3 Hz), 3.48 (dd, 1H, J = 9.8,
11.3 Hz), 3.88 (dd, 1H, J = 2.2, 9.8 Hz), 2.19–1.95 (m, 3H), 1.87–1.69
(m, 2H), 1.31 (d, 6H, J = 7.5 Hz), 1.19 (s, 9H), 1.11 (d, 3H, J = 6.7 Hz),
0.92 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d 178.7, 139.1,
134.9, 128.2, 127.2, 126.6, 116.8, 97.8, 82.7, 74.8, 71.4, 65.7, 64,
37.0, 34.9, 34.7, 32.4, 29.5, 27.2, 19.7, 16.2, 9.8. ESIMS: 447 (M++1).
4.6. (2R,3R,4S,5R,6R)-3-(Benzyloxy)-5-hydroxy-6-
(hydroxymethyl)-2,4-dimethyl-8-nonenyl pivalate 10
4.9. (2R,3R,4R,5R,6S)-3-(Benzyloxy)-5-[1-(tert-butyl)-1,1-
dimethylsilyl]oxy-2,4,6-trimethyl-8-nonen-1-ol 4
To a stirred solution of compound 9 (25.5 g 54.72 mmol) in
methanol (50 mL) was added a catalytic amount of PTSA. The reac-
tion mixture was stirred overnight at room temperature. Sodium
bicarbonate was added to neutralize the PTSA and filtered. The fil-
trate was concentrated under reduced pressure and purification by
silica gel column chromatography afforded 10 (17.40 g, 75%) as a
To a stirred suspension of LiAlH4 (1.56 g, 44.11 mmol) in dry
THF (20 mL) at 0 °C was added dropwise a solution of compound
12 (18.5 g, 27.40 mmol) in dry THF (30 mL). The reaction mixture
was refluxed for 3 h. It was then cooled to 0 °C, diluted with ether,
and quenched by the dropwise addition of saturated aqueous
Na2SO4. The solid material was filtered and washed thoroughly
with hot ethyl acetate for several times. The combined organic lay-
ers were dried over anhydrous Na2SO4. The solvent was removed in
vacuo and the residue was purified by silica gel column chroma-
tography to afford compound 4 (9.8 g, 86%) as a viscous liquid.
pure liquid. ½a 2D5
ꢂ
¼ þ9:8 (c 0.5, CHCl3); IR (neat): mmax 3447,
2971, 2928, 1727, 1640, 1459, 1285, 1158, 1092, 1061 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 7.37–7.24 (m, 5H), 5.79–5.66 (m, 1H),
5.05–4.97 (m, 2H), 4.57 (ABq, 2H, J = 10.5 Hz), 4.26 (dd, 1H,
J = 3.7, 10.5 Hz), 4.17–4.08 (m, 1H), 3.92 (d, 1H, J = 9 1 Hz), 3.72–
3.58 (m, 2H), 3.42 (dd, 1H, J = 2.2, 9.8 Hz), 2.26–2.15 (m, 1H),
1.99–1.89 (m, 2H), 1.87–1.73 (m, 2H), 1.23 (s, 9H), 1.15 (d, 3H,
J = 6.7 Hz), 0.97 (d, 3H, J = 6.7 Hz); ESIMS: 407 (M++1).
½
a 2D5
ꢂ
¼ ꢀ25:3 (c 0.5, CHCl3); IR(KBr): mmax 3353, 2928, 2264,
1713, 1536, 1222, 1044 cmꢀ1 1H NMR (200 MHz, CDCl3): d 7.33–
;
7.26 (m, 5H), 5.71–5.63 (m, 1H), 4.98–4.92 (m, 2H), 4.63 (ABq,
2H, J = 11.7 Hz), 3.81–3.78 (m, 2H), 3.55–3.51 (m, 1H), 3.32 (dd,
1H, J = 2.9, 7.8 Hz), 2.49–2.44 (br s, 1H), 2.31–2.24 (m, 1H), 2.03–
1.98 (m, 1H), 1.94–1.89 (m, 1H), 1.81–1.73 (m, 1H), 1.66–1.61
(m, 1H), 1.15 (d, 3H, J = 6.8 Hz), 0.92 (s, 9H), 0.90 (d, 3H,
J = 6.8 Hz), 0.85 (d, 3H, J = 5.8 Hz), 0.06 (d, 6H, J = 4.8 Hz); 13C
NMR (75 MHz, CDCl3): d 137.9, 128.4, 127.8, 127.5, 115.6, 88.1,
4.7. (2R,3R,4S,5R,6R)-3-(Benzyloxy)-5-hydroxy-2,4-dimethyl-6-
([(4-methylphenyl)sulfonyl]oxymethyl)-8-nonenyl pivalate 11
A solution of 10 (17 g, 41.87 mmol) in dry DCM (30 mL),
containing triethylamine (17.79 ml, 125.6 mmol), was cooled to

2528
G. Sabitha et al. / Tetrahedron: Asymmetry 21 (2010) 2524–2529
75.2, 75.0, 65.1, 39.7, 38.8, 37.4, 36.0, 26.1, 18.5, 16.6, 14.6, 12.4,
(0.573 g, 2.01 mmol) and L-(+)-DET (0.415 g, 2.01 mmol) in dry
ꢀ3.5, ꢀ3.6; ESIMS: 443 (M++Na).
DCM (5 mL) were added with stirring and the resulting mixture
was stirred for 30 min at ꢀ25 °C. Compound 3 (4.5 g, 10.08 mmol)
in dry DCM (15 mL) was then added and the resulting mixture was
stirred for another 30 min at ꢀ25 °C followed by the addition of cu-
mene hydroperoxide (1.78 mL, 12.10 mmol). The resulting mixture
was stirred at the same temperature for 6 h, after which it was
warmed to 0 °C, quenched with 10 mL of water, and stirred for
1 h at room temperature. After that 30% aqueous NaOH solution
saturated with NaCl (10 mL) was then added and the reaction mix-
ture was stirred vigorously for another 30 min at room tempera-
ture. The resulting mixture was then filtered through Celite
rinsing with DCM. The organic phase was separated and the aque-
ous phase was extracted with DCM. Combined organic phases were
washed with brine and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and purified by silica gel col-
umn chromatography to afford 14 (3.41 g, 75%) as a viscous liquid.
4.10. Ethyl (2E,4R,5R,6R,7R,8S)-5-(benzyloxy)-7-[1-(tert-butyl)-
1,1-dimethylsilyl]oxy-4,6,8-trimethyl-2,10-undecadienoate 13
In an oven-dried flask under an N2 atmosphere, DMSO (6.41 mL,
90.41 mmol) was dissolved in dry DCM (35 mL). The solution was
cooled to ꢀ78 °C, and (COCl)2 (5.69 g, 45.53 mmol) was added
dropwise. After 5 min, alcohol 4 (9.5 g, 22.61 mmol) in dry DCM
(20 mL) was added drop wise. The white slurry was stirred for
10 min at ꢀ78 °C, before Et3N (13.70 g, 135.66 mmol) was added
drop wise. The solution was allowed to warm to ambient temper-
ature before being diluted in Et2O (20 mL) and washed with aque-
ous NH4Cl (20 mL), NaHCO3 (15 mL), and brine (20 mL). The
organic phase was dried over anhydrous Na2SO4 and concentrated
in vacuo to give crude aldehyde 13 (8.82 g, 80%), which was used
directly for the next reaction.
½
a 2D5
ꢂ
¼ ꢀ12:8 (c 0.5, CHCl3); IR (KBr):
mmax 3422, 2931, 1718, 1460,
The mixture of the above prepared aldehyde (8.82 g,
21.11 mmol) and PPh3@CHCO2Et (14.68 g, 42.20 mmol) in dry
DCM (25 mL) was stirred for 15 h. at rt. The reaction mixture was
concentrated and the resultant residue was purified by column
1256, 1067 cmꢀ1 1H NMR (400 MHz, CDCl3): d 7.34–7.28 (m, 5H),
;
5.76–5.61 (m, 1H), 5.01–4.89 (m, 2H), 4.61 (ABq, 2H, J = 6.7 Hz),
3.89–3.78 (m, 2H), 3.62–3.51 (m, 1H), 3.27 (dd, 1H, J = 1.5,
9.0 Hz), 3.07 (dd, 1H, J = 2.2, 6.7 Hz), 2.87–2.83 (m, 1H), 2.33–
2.22 (m, 1H), 2.11–2.02 (m, 1H), 1.81–1.73 (m, 1H), 1.64–1.42
(m, 2H), 1.07 (d, 3H, J = 7.5 Hz), 0.91 (s, 9H), 0.9 (d, 3H,
J = 7.5 Hz), 0.86 (d, 3H, J = 6.1 Hz), 0.06 (d, 6H, J = 7.5 Hz); ESIMS:
463 (M++1).
chromatography to give
a
,b-unsaturated ester 13 (7.51 g, 73%) as
a viscous liquid. ½a D25
ꢂ
¼ ꢀ7:5 (c 1, CHCl3); IR(KBr): mmax 2957,
2929, 1720, 1691, 1642, 1460, 1253, 1095, 1064, 835, 772 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.33–7.28 (m, 5H), 7.06 (dd, 1H,
J = 8.3, 15.8 Hz), 5.78 (dd, 1H, J = 1.5, 15.8 Hz), 5.74–5.58 (m, 1H),
5.02–4.89 (m, 2H), 4.61 (ABq, 2H, J = 11.3 Hz), 4.18 (q, 2H, J = 6.7,
14.3 Hz), 3.82–3.79 (m, 1H), 3.26 (dd, 1H, J = 2.2, 9.0 Hz), 2.73–
2.63 (m, 1H), 2.29–2.19 (m, 1H), 1.86–1.68 (m, 2H), 1.63–1.54
(m, 1H), 1.31 (t, 3H, J = 7.5 Hz), 1.2 (d, 3H, J = 7.5 Hz), 0.91 (s, 9H),
0.81 (d, 3H, J = 5.2 Hz), 0.8 (d, 3H, J = 4.5 Hz), 0.03 (d, 6H,
J = 5.2 Hz); ESIMS: 489 (M++1).
4.13. (3R,4R,5R,6R,7R,8S)-5-(Benzyloxy)-7-[1-(tert-butyl)-1,1-
dimethylsilyl]oxy-4,6,8-trimethyl-10-undecene-1,3-diol 15
Asolutionof compound14(3.2 g, 4.92 mmol)indry DCM(10 mL)
was cooled to 0 °C and Red-Al (2.8 ml, 20% solution in hexane,
9.00 mmol) was added to it over a period of 2 h. The mixture was
quenched with NH4Cl. The organic layer was washed with brine,
dried over anhydrous Na2SO4, and purified by column chromatogra-
phy to give the required alcohol 15 (2.63 g 82%) as a viscous liquid.
4.11. (2E,4R,5R,6R,7R,8S)-5-(Benzyloxy)-7-[1-(tert-butyl)-1,1-
dimethylsilyl]oxy-4,6,8-trimethyl-2,10-undecadien-1-ol 3
½
a 2D5
ꢂ
¼ þ1:6 (c 1, CHCl3); IR (KBr): mmax 3423, 2926, 2360, 1721,
At ꢀ78 °C, 1.4 M solution of DIBAL-H (17.83 mL, 30.32 mmol)
1543, 1219, 772 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.34–7.27 (m,
;
was slowly added to a solution of
a,b-unsaturated ester 13 (7.4 g,
5H), 5.73–5.59 (m, 1H), 4.65 (ABq, 2H, J = 6.7 Hz), 3.86–3.66 (m,
3H), 3.51–3.45 (m, 1H), 3.29 (dd, 1H, J = 4.5, 6.7 Hz), 2.90–2.75 (m,
1H), 2.34–2.25 (m, 1H), 2.03–1.75 (m, 4H), 1.68–1.57 (m, 2H), 0.97
(d, 3H, J = 7.5 Hz), 0.91 (s, 9H), 0.92 (d, 3H, J = 4.5 Hz), 0.84 (d, 3H,
J = 6.7 Hz), 0.04 (d, 6H, J = 3.1 Hz); ESIMS: 465 (M++1).
15.16 mmol) in dry DCM (15 mL). The solution was stirred for
2 h at ꢀ78 °C before being quenched with EtOAc (5 mL). The mix-
ture was allowed to warm to ambient temperature before an aque-
ous solution of Rochelle’s salt was added (30 mL) and stirred for
1 h. The aqueous phase was extracted with DCM and the combined
organic extracts were dried over anhydrous Na2SO4, concentrated,
and purified by column chromatography on silica gel to afford the
4.14. (3R,4R,5R,6R,7R,8S)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-
4,6,8-trimethyl-10-undecene-1,3,5-triol 16
desired allylic alcohol 3 (4.86 g, 72%) as
¼ þ1:4 (c 1, CHCl3); IR (KBr): mmax 2956, 1720, 1459, 1254,
1093, 835, 772 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.31–7.23 (m,
a pale yellow oil.
½
a 2D5
ꢂ
To solution of naphthalene (5.51 g, 43.10 mmol) in dry THF
(15 mL) in a round bottom flask, lithium metal (0.362 g,
;
5H), 5.82–5.58 (m, 3H), 4.99–4.88 (m, 2H), 4.61 (ABq, 2H,
J = 11.1 Hz), 4.11–4.03 (m, 2H), 3.85–3.81 (m,1H), 3.18 (dd, 1H,
J = 2.2, 8.8 Hz) 2.52–2.47 (m, 1H), 2.31–2.22 (m, 1H), 1.83–1.68
(m, 2H), 1.63–1.53 (m, 1H), 1.15 (d, 3H, J = 6.9 Hz), 0.91 (s, 9H),
0.83 (d, 3H, J = 3.3 Hz), 0.8 (d, 3H, J = 3.7 Hz), 0.04 (d, 6H,
J = 5.6 Hz); 13C NMR (75 MHz, CDCl3): d 138.1, 138.0, 134.6,
130.4, 128.7, 128.5, 128.2, 115.4, 79.4, 75.0, 74.9, 68.1, 38.8, 38.6,
37.3, 36.3, 26.1, 17.7, 14.8, 13.9, 11.9, ꢀ3.5, ꢀ3.6; ESIMS: 479
(M++Na).
51.72 mmol) was added to it in fractions at 0 °C and the resulting
gray colored suspension was stirred for 30 min. To this was added
compound 15 (2 g, 4.31 mmol) in dry THF (10 mL) over a period of
10 min. The reaction mixture was then stirred for another 1 h at
0 °C and quenched by the addition of solid ammonium chloride.
The ammonia was then allowed to evaporate. The residue left
was partitioned between water and ether and the aqueous phase
extracted with ether. The organic layers were combined, washed
once with water, brine, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography to afford pure 16 (0.56 g, 76%) as a
4.12. [(2S,3S)-3-((1S,2R,3R,4R,5S)-2-(Benzyloxy)-4-[1-(tert-
butyl)-1,1-dimethylsilyl]oxy-1,3,5-trimethyl-7-octenyl)oxiran-
2-yl]methanol 14
clear colorless liquid. ½a D25
ꢂ
¼ ꢀ14:6 (c 1, CHCl3); IR (KBr): mmax
3421, 2926, 1633, 1383, 1219, 1051, 772 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 5.72–5.62 (m, 1H), 5.03–4.98 (m, 2H), 3.94–
3.84 (m, 2H), 3.85–3.76 (m, 2H), 3.52–3.48 (m, 1H), 2.23–2.15
(m, 1H), 2.08–2.01 (m, 1H), 1.91–1.76 (m, 3H), 1.75–1.76 (m,
2H), 0.97 (d, 3H, J = 7.8 Hz), 0.95–0.91 (m, 12H), 0.85 (d, 3H,
In a 250 mL two neck round bottomed flask, 50 mL of dry DCM
was added to 4 Å powdered activated molecular sieves and the
suspension mixture was cooled to ꢀ20 °C, after which Ti(OiPr)4

G. Sabitha et al. / Tetrahedron: Asymmetry 21 (2010) 2524–2529
2529
J = 6.8 Hz), 0.13 (d, 6H, J = 10.7 Hz); 13C NMR (75 MHz, CDCl3): d
137.5, 116.2, 82.2, 80.3, 76.4, 62.2, 41.0, 38.8, 38.3, 36.4, 35.8,
29.7, 25.8, 16, 14.8, 14.0, ꢀ3.7, ꢀ4.3; ESIMS: 375 (M++1).
(d, 2H, J = 8.4 Hz), 5.72–5.62 (m, 1H), 5.44 (s, 1H), 4.99–4.91 (m,
2H), 4.65 (ABq, 2H, J = 6.4 Hz), 4.24 (dd, 1H, J = 4.1, 11.7 Hz),
4.02–3.88 (m, 2H), 3.79 (s, 3H), 3.46–3.33 (m, 2H), 3.39 (s, 3H),
2.36–2.22 (m, 1H), 2.14–1.93 (m, 2H), 1.84–1.64 (m, 2H), 1.62–
1.46 (m, 2H), 1.00 (d, 3H, J = 7.1 Hz), 0.91–0.81 (m, 6H), 0.87 (s,
9H), 0.04 (s, 3H), ꢀ0.02 (s, 3H); 13C NMR (75 MHz, CDCl3): d
159.7, 138.2, 131.5, 127.3, 115.4, 113.4, 101.1, 98.1, 84.7, 77.7,
74.7, 67.1, 55.9, 55.2, 40.0, 39.8, 38.5, 37.6, 29.6, 28.5, 26.1, 18.4,
14.7, 12.5, 12.4, ꢀ3.6, ꢀ3.9; ESIMS: 559 (M++Na).
4.15. (2S,3R,4R,5R,6S)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2-
[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-4,6-dimethyl-8-
nonen-3-ol 17
A solution of triol compound 16 (1 g, 2.67 mmol) in dry DCM
(10 mL) was cooled to 0 °C and catalytic amount of PPTS followed
by PMB acetal (0.583 g, 20% solution in hexane, 3.20 mmol) was
added to it over a period of 2 h. The mixture was then quenched
with sodium bicarbonate. The organic layer was washed with
brine, dried over anhydrous Na2SO4, and purified by column chro-
matography to give the required alcohol 17 (1.10 g 84%) as a vis-
4.18. (3R,4R,5S,6R,7R,8S)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]
oxy-3-[(4-methoxybenzyl)oxy]-5-(methoxymethoxy)-4,6,8-
trimethyl-10-undecen-1-ol 2
A cold (ꢀ78 °C) solution of PMB acetal 19 (0.2 g, 0.40 mmol) in
DCM (10 mL) was treated with diisobutylaluminum hydride
(0.26 mL, 0.44 mmol). The reaction mixture was allowed to warm
to 0 °C for 1 h. Excess hydride was quenched by the dropwise addi-
tion of saturated aqueous sodium potassium tartrate (caution vig-
orous evolution of H2, may result) and the mixture was allowed to
warm to rt. After vigorous stirring for 1 h, the organic solution was
washed with brine. The aqueous layer was extracted with Et2O and
the combined organic phases were washed with brine and dried
over anhydrous Na2SO4. Filtration and concentration followed by
flash chromatography provided alcohol 2 (0.16 g, 80%) as a clear
cous liquid. ½a 2D5
ꢂ
¼ ꢀ9:4 (c 1, CHCl3); IR (KBr): mmax 3486, 1740,
1H NMR
7.55 (d, 2H, J = 8.6 Hz), 7.02 (d, 2H,
1615, 1517, 1463, 1248, 1103, 1037, 831, 772 cmꢀ1
;
(200 MHz, CDCl3):
d
J = 8.4 Hz), 5.92–5.82 (m, 1H), 5.62 (s, 1H), 5.17–5.1 (m, 2H), 4.43
(dd, 1H, J = 3.3, 10.9 Hz), 4.21–4.06 (m, 1H), 4.02–3.94 (m, 2H),
3.97 (s, 3H), 3.64–3.53 (m, 1H), 2.53–2.43 (m, 1H), 2.33–2.24 (m,
2H), 2.21–1.88 (m, 4H), 1.18 (d, 3H, J = 7.1 Hz), 1.10–0.99 (m,
6H), 1.05 (s, 9H), 0.22 (s, 3H), 0.16 (s, 3H); ESIMS: 493 (M++1).
4.16. (2S,3S,4R,5R,6S)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2-
[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-4,6-dimethyl-8-
nonen-3-ol 18
colorless liquid. ½a D25
¼ þ11:7 (c 0.5, CHCl3); IR (KBr): mmax 3449,
ꢂ
2928, 2855, 1724, 1614, 1513, 1463, 1249, 1034, 834, 772 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.22 (d, 2H, J = 8.1 Hz), 6.82 (d, 2H,
J = 8.3 Hz), 5.77–5.63 (m, 1H), 5.02–4.93 (m, 2H), 4.60 (s, 2H), 4.4
(ABq, 2H, J = 11.1 Hz), 3.89 (dd, 1H, J = 3.2, 7.9 Hz), 3.79 (s, 3H),
3.72–3.65 (m, 2H), 3.39–3.34 (m, 1H), 3.33 (s, 3H), 3.24 (t, 1H,
J = 5.6 Hz), 2.33–2.14 (m, 2H), 1.82–1.72 (m, 3H), 1.69–1.55 (m,
2H), 0.96–0.81 (m, 9H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 157.6, 138, 129.4, 115.6, 113.8, 98.3, 85.5,
78.6, 74.4, 70.5, 61.5, 55.9, 55.2, 39.4, 38.8, 37.8, 35.6, 31.9, 29.6,
26.1, 14.1, 13.0, 11.6, ꢀ3.5, ꢀ3.6; ESIMS: 561 (M++Na).
At 0 °C, a solution of compound 17 (0.60 g, 1.21 mmol) in THF
(10 ml) was treated with TPP (0.41 g, 1.58 mmol) and DEAD
(0.27 mL, 1.58 mmol) followed by para-nitro benzoic acid (0.26 g,
1.58 mmol) and stirring was continued for 2 h. The mixture was
concentrated and the resulting crude product was purified by silica
gel column chromatography.
At 0 °C, a solution of the above benzoate in dry methanol (15 mL)
was treated with Na (0.056 g, 2.43 mmol) and the resulting reaction
mixture was stirred at rt (monitored by TLC). After 2 h, the reaction
mixture was neutralized with AcOH at 0 °C, evaporated, and purified
by column chromatography to obtain inverted alcohol 18 (0.24 g,
Acknowledgments
78%). ½a 2D5
ꢂ
¼ ꢀ11:5 (c 0.5, CHCl3); IR (KBr): mmax 3486, 1740, 1615,
K.Y. and G.C. thank UGC, and M.B. thanks CSIR, New Delhi for
the award of fellowships.
1517, 1463, 1248, 1103, 1037, 831, 772 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 7.31 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.72–5.58
(m, 1H), 5.39 (s, 1H), 4.95 (m, 2H), 4.23 (dd, 1H, J = 3.5, 10.9 Hz),
4.14–4.06 (m, 1H), 3.92 (dt, 1H, J = 1.8, 11.3 Hz), 3.79 (s, 3H), 3.73
(t, 3H, J = 2.4 Hz), 3.51 (d, 1H, J = 9 4 Hz), 2.19–2.04 (m, 2H), 1.96–
1.79 (m, 4H), 1.78–1.68 (m, 2H), 0.99 (d, 3H, J = 7.1 Hz), 0.95 (d, 3H,
J = 6.7 Hz), 0.9 (s, 9H), 0.84 (d, 3H, J = 6.9 Hz), 0.02 (d, 6H,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): d 157.2, 137.6, 127.5, 127.3,
116.0, 113.4, 101.0, 78.8, 78.3, 67.3, 55.2, 40.5, 40.0, 39.9, 39.6,
34.7, 28.9, 25.9, 16.0, 14.2, 14.0, 13.8, ꢀ4.2, ꢀ4.3; ESIMS: 493 (M++1).
References
1. Gerth, K.; Pradella, S.; Perlowa, O.; Beyer, S.; Muller, R. J. Biotechnol. 2003, 106,
233.
2. (a) Bedorf, N.; Schomburg, D.; Gerth, K.; Reichenbach, H.; Hofle, G. Annalen
1993, 1017; (b) Gerth, K.; Bedorf, N.; Irschik, H.; Hofle, G.; Reichenbach, H. J.
Antibiot. 1994, 47, 23.
3. (a) Jansen, R.; Wray, V.; Irschik, H.; Reichenbach, H.; Hofle, G. Tetrahedron Lett.
1985, 26, 6031; (b) Irschik, H.; Jansen, R.; Gerth, K.; Hofle, G.; Reichenbach, H. J.
Antibiot. 1987, 40, 7; (c) Jansen, R.; Irschik, H.; Reichenbach, H.; Schomburg, D.;
Wray, V.; Hofle, G. Annalen 1989, 111; (d) Jansen, R.; Irschik, H.; Reichenbach,
H.; Wray, V.; Hofle, G. Annalen 1989, 213.
4.17. tert-Butyl[((1R,2S)-1-(1R,2S,3S)-2-(methoxymethoxy)-3-
[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]-1-methylbutyl-2-
methyl-4-pentenyl)oxy]dimethylsilane 19
4. Jansen, R.; Hofle, G.; Kunze, B.; Reichenbach, H.; Steinmetz, H.; Irschik, H. Chem.
Eur. J. 2007, 13, 5822.
5. (a) Hoefle, G.; Bedorf, N.;Steinmetz, H.;Schomburg, D.; Gerth, K.;Reichenbach, H.
Angew. Chem., Int. Ed. 1996, 35, 1567; (b) Gerth, K.; Bedorf, N.; Hofle, G.; Irschik,
H.; Reichenbach, H. J. Antibiot. 1996, 49, 560; (c) Hofle, G.; Reichenbach, H. In
Anticancer Agents from Natural Products; Cragg, G. M., Kingston, D. G. I., Newman,
D. J., Eds.; CRC Press, Taylor & Francis Group: Boca Raton, FL, 2005; p 413.
6. (a) Hofle, G.; Reichenbach, H.; Irschik, H.; Schummer, D. German Patent DE 196
30 980 A1: 1–7 (5.2. 1998).; (b) Irschik, H.; Schummer, D.; Hofle, G.;
Reichenbach, H.; Steinmetz, H.; Jansen, R. J. Nat. Prod. 2007, 70, 1060.
7. Li, P.; Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Am. Chem.
Soc. 2009, 131, 11678.
8. Yadav, J. S.; Reddy, K. B.; Sabitha, G. Tetrahedron Lett. 2004, 45, 6475.
9. (a) Yadav, J. S.; Padmavani, B.; Venugopal, Ch. Tetrahedron Lett. 2009, 50, 3772;
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10. Mitsunobu, O. Synthesis 1981, 1–28.
11. Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
To a stirred solution of compound 18 (0.3 g, 0.60 mmol) in
i
anhydrous dichloromethane (15 mL) at 0 °C under nitrogen, Pr2-
NEt (0.23 g, 1.82 mmol) was added followed by the dropwise addi-
tion of MOMCl (0.09 mL, 1.12 mmol). After stirring for 4 h at room
temperature, the reaction mixture was diluted with water, satu-
rated aqueous NH4Cl, and brine solution, and then dried over anhy-
drous Na2SO4. The residue was concentrated in vacuo and purified
by silica gel column chromatography to afford pure compound 19
(0.24 g, 75%) as a clear colorless liquid. ½a D25
¼ ꢀ3:3 (c 0.5, CHCl3);
ꢂ
IR(KBr): mmax 2926, 2854, 1735, 1621, 1458, 1248, 1100, 1033, 831,
772 cmꢀ1; 1H NMR (200 MHz, CDCl3): d 7.37 (d, 2H, J = 8.6 Hz), 6.84