Stereoselective synthesis of cytotoxic marine metabolite harzialactone a by three different routes

Article abstract of DOI:10.1055/s-0030-1260177

The cytotoxic marine metabolite harzialactone A has been synthesized stereoselectively starting from phenylacetaldehyde through three different routes. The key steps were: in the first approach Sharpless asymmetric dihydroxylation, in the second approach

Full text of DOI:10.1055/s-0030-1260177

3190
PAPER
Stereoselective Synthesis of Cytotoxic Marine Metabolite Harzialactone A by
Three Different Routes1
Synthesis of
Harzi
u
alactone
A
ddukuri Nandan Kumar, Cheruku Ravindra Reddy, Biswanath Das*
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received 21 June 2011; revised 14 July 2011
In the first approach (Scheme 2), phenylacetaldehyde (2)
Abstract: The cytotoxic marine metabolite harzialactone A has
been synthesized stereoselectively starting from phenylacetalde-
hyde through three different routes. The key steps were: in the first
approach Sharpless asymmetric dihydroxylation, in the second ap-
was subjected to an enantioselective Maruoka allylation8
using titanium complex (S,S)-I (Figure 1) and allyltribu-
tyltin to form the homoallylic alcohol 4.7c The hydroxyl
proach diastereoselective iodo carbonate preparation, and in the group of 4 was protected as its TBS ether by treatment
third approach Jacobsen’s hydrolytic kinetic resolution. In all these
three schemes the triol was successfully converted into the lactone
by using highly chemoselective oxidation with TEMPO and (di-
asymmetric dihydroxylation9 using b-admix at room tem-
acetoxyiodo)benzene.
with tert-butyldimethylsilyl chloride in the presence of
imidazole to afford 5. Compound 5 underwent Sharpless
perature to give the diol 6 along with its diastereomer in
Key words: harzialactone A, stereoselective synthesis, Maruoka
the ratio 62:38 (favoring 6) (total yield 86%). These two
allylation, Sharpless asymmetric dihydroxylation, stereoselective
products (6 and its diastereomer) were separated by re-
iodo carbonate preparation, Jacobsen’s hydrolytic kinetic resolution
peated column chromatography (silica gel, hexane–
EtOAc, 1:1) to furnish pure 6 (yield 50%). Deprotection
of the TBS group of 6 using 4-toluenesulfonic acid in
Bioactive compounds from marine organisms have at-
methanol produced the desired triol. When the hydroxy
tracted much attention in recent years due to their interest-
group of 4 was not protected and the compound was di-
rectly subjected to Sharpless asymmetric dihydroxylation,
compound 3 and its diastereomers were formed in almost
equal amount and their separation was also difficult.
ing structural features and important biological
properties.2 Harzialactone A (1), a marine metabolite, was
isolated from the culture broth of a strain of Trichoderma
harianium OUPS-N115;3 it showed cytotoxicity against
However, from the TBS ether 5 it was convenient to ob-
cultured P388 cells.3 The absolute configuration (3R,5R)
tain 3 in pure form. Finally, the chemoselective oxidation
of harzialactone A (1) was established by its synthesis
of this triol 3 with 2,2,6,6-tetramethylpiperidin-1-oxyl
from D-glucose and D-xylose.4 A few other syntheses of
and excess (diacetoxyiodo)benzene afforded the target
compound, harzialactone A (1). Monitoring of the reac-
compound 1 have also been reported5 but in some cases
the long synthetic steps and the low overall yields are the
tion showed the initial formation of the intermediate lactol
problem. The synthesis of compounds related to harzia-
species, which then underwent further oxidation to the
lactone A have also currently attracted the attention of or-
lactone.10
ganic chemists.6
In the second approach (Scheme 3) the homoallylic alco-
hol 4 was treated with di-tert-butyl dicarbonate in the
presence of 4-(dimethylamino)pyridine and triethylamine
In continuation of our recent work7 on the stereoselective
synthesis of bioactive compounds, we have developed an
efficient short synthesis of harzialactone A (1) starting
in acetonitrile to form the homoallylic tert-butyl carbon-
from readily available phenylacetaldehyde (2). The syn-
ate 7 in high yield. The treatment of 7 with N-iodosuccin-
thesis was achieved by three different routes. The ret-
imide in acetonitrile at 0 °C afforded the diastereo-
rosynthetic analysis (Scheme 1) indicates that 1 can be
selective iodo carbonate 8 (with required stereogenic cen-
prepared from the triol 3 by selective oxidation and this
ter) as the sole product.10 The iodo carbonate 8 was subse-
triol 3 can be obtained from the homoallylic alcohol 4,
quently reacted with potassium carbonate in methanol to
generated from phenylacetaldehyde (2).
produce the syn-epoxy alcohol 9,11 which on treatment
O
O
OH OH
OR
O
OH
OH
H
1
3
4
2
Scheme 1 Retrosynthetic analysis of harzialactone A (1)
SYNTHESIS 2011, No. 19, pp 3190–3194
x
x.
x
x
.
2
0
1
1
Advanced online publication: 18.08.2011
DOI: 10.1055/s-0030-1260177; Art ID: Z63311SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Harzialactone A
3191
O
O
OR OH
OR
O
e
a
c
OH
H
OH
1
2
6 R = TBS
3 R = H
4
5
R = H
d
b
R = TBS
Scheme 2 Synthesis of harzialactone A (1). Reagents and conditions: (a) (S,S)-I (10 mol%), Bu3SnCH2CH=CH2, CH2Cl2, –15 to 0 °C, 15 h,
84.5%; (b) TBSCl, imidazole, CH2Cl2, 0 °C to r.t., 2 h, 92%; (c) b-admix, t-BuOH–H2O, 12 h, 86% (total), 50% (6); (d) PTSA, MeOH, 0 °C
to r.t., 1 h, 95%; (e) TEMPO, PhI(OAc)2, CH2Cl2, 0 °C to r.t., 5 h, 74%.
steps were found to be somewhat lower. The acid-cata-
lyzed opening of the epoxide ring of 10 afforded the major
product 11, which was separated from its minor diastereo-
mer by column chromatography (as discussed earlier).
Deprotection of the TBDPS group of 11 using 4-toluene-
sulfonic acid in methanol furnished the triol 3 which was
subsequently converted into harzialactone A (1) as out-
lined above in Scheme 2.
O
Oi-Pr
Ti
O
O
O
Ti
i-PrO
O
(S,S)-
I
In the third approach (Scheme 4) the homoallylic alcohol
4 was treated with tert-butyldiphenylsilyl chloride in the
presence of imidazole and 4-(dimethylamino)pyridine to
produce the olefin 12. The epoxidation of this compound
12 was carried out with 3-chloroperoxybenzoic acid to
form the racemic epoxide 13. This epoxide 13 underwent
Jacobsen’s hydrolytic kinetic resolution12 by treatment
with (S,S)-Salen–Co(III)–OAc complex and water to af-
ford the diol 11 along with the less polar corresponding a-
epoxide, which was separated by column chromatogra-
phy. Deprotection of the TBDPS group of 11 using 4-tol-
uenesulfonic acid in methanol yielded the triol 3 which
was then converted into the desired molecule, harzialac-
tone A (1) as discussed above.
H
H
N
N
Co
t-Bu
O
O
t-Bu
OAc
t-Bu
t-Bu
(S,S)-Salen–Co(III)–OAc complex
Figure 1
with tert-butyldiphenylsilyl chloride using imidazole and
4-(dimethylamino)pyridine furnished the TBDPS-pro-
tected epoxide 10. The hydroxy group of 9 could also be
protected as TBS ether but the yields in the subsequent
O
OR OH
OR
b
O
O
OR
c
e
O
OH
I
11 R = TBDPS
4 R = H
8
9
R = H
f
a
d
3
R = H
7 R = Boc
10 R = TBDPS
g
O
O
OH
1
Scheme 3 Synthesis of harzialactone A (1). Reagents and conditions: (a) Boc2O, Et3N, DMAP, CH2Cl2, 0 °C to r.t., 2 h, 91%; (b) NIS, MeCN,
–40 to 0 °C, 1.5 h, 89%; (c) K2CO3, MeOH, r.t., 0.5 h, 91%; (d) TBDPSCl, imidazole, DMAP, CH2Cl2, r.t., 3.5 h, 93%; (e) 5% HClO4, H2O–
MeCN (1:3), r.t., 2 h, 71%; (f) TBAF, THF, 0 °C to r.t., 3.5 h, 89%; (g) TEMPO, PhI(OAc)2, CH2Cl2, 0 °C to r.t., 5 h, 74%.
O
O
OR OH
OR
OTBDPS
c
b
e
O
OH
OH
11 R = TBDPS
1
4
R = H
13
d
a
3
R = H
12 R = TBDPS
Scheme 4 Synthesis of harzialactone A (1). Reagents and conditions: (a) TBDPSCl, imidazole, DMAP, CH2Cl2, r.t., 2 h, 94%; (b) MCPBA,
CH2Cl2, 0 °C to r.t., 6 h, 94%; (c) (S,S)-Salen–Co(III)–OAc (0.5 mol%), distilled H2O (0.45 equiv), THF, 0 °C to r.t., 49%; (d) TBAF, THF,
0 °C to r.t., 3.5 h, 89%; (e) TEMPO, PhI(OAc)2, CH2Cl2, 0 °C to r.t., 5 h, 74%.
Synthesis 2011, No. 19, 3190–3194 © Thieme Stuttgart · New York

3192
D. N. Kumar et al.
PAPER
(2R,4R)-4-(tert-Butyldimethylsiloxy)-5-phenylpentane-1,2-diol
(6)
In conclusion we have developed the stereoselective syn-
thesis of harzialactone A starting from phenylacetalde-
hyde through three different simple and efficient
approaches.
To a 100-mL round-bottomed flask were added t-BuOH (15 mL),
H2O (15 mL), and ADmix-b (0.934 g, 1.2 mmol) and MsNH2 (0.38
g, 4.0 mmol). The mixture was stirred at r.t. for about 5 min, and
cooled to 0 °C. To this cooled soln was added 5 (1.104 g, 4.0 mmol)
and the mixture was stirred for 12 h at r.t. The reaction was
quenched with solid Na2SO3 (4 g). The mixture was diluted with
EtOAc (30 mL) and after separation of the layers, the aqueous layer
was further extracted with EtOAc (30 mL). The combined organic
layers were washed with brine (30 mL) and dried (anhyd Na2SO4).
After evaporation of the solvent, the residue was purified by repeat-
ed column chromatography (silica gel, hexane–EtOAc, 1:1) to give
diol 6 (0.654 g, 50%).
TLC used silica gel F254 plates with the spots were examined under
UV light and then developed by an I2 vapor. Column chromatogra-
phy was performed with silica gel (BDH 100–200 mesh). Solvents
were purified according to standard procedures. The spectra were
recorded with the following instruments; IR: Perkin-Elmer RX FT-
IR spectrophotometer; NMR: Varian Gemini 200 MHz (1H) and 50
MHz (13C) spectrometer; ESIMS: VG-Autospec micromass. Organ-
ic extracts were dried over anhyd Na2SO4. Optical rotations were
measured with Jasco DIP 300 digital polarimeter at 25 °C.
[a]D32 +18.2 (c 0.9, CHCl3).
IR (KBr): 1744, 1637, 1389, 1215 cm–1.
(S)-1-Phenylpent-4-en-2-ol (4)
1H NMR (200 MHz, CDCl3): d = 7.41–7.21 (m, 5 H), 4.19 (m, 1 H),
3.93 (m, 1 H), 3.62 (m, 1 H), 3.46 (m, 1 H), 3.08–2.82 (m, 2 H),
1.82–1.34 (m, 2 H), 1.01 (s, 9 H), 0.20 (s, 6 H).
13C NMR (50 MHz, CDCl3): d = 138.8, 128.4, 127.8, 127.7, 127.6,
126.3, 70.0, 69.0, 66.2, 45.3, 40.2, 25.8, 18.8, –5.6.
To a stirred soln of TiCl4 (0.380 g, 2 mmol) in CH2Cl2 (30 mL) was
added dried Ti(Oi-Pr)4 (1.716 g, 6 mmol) at 0 °C under a N2 atmo-
sphere and the mixture was allowed to warm to r.t.. After 1.5 h,
Ag2O (0.496 g, 4 mmol) was added and the reaction was continued
for 6 h under exclusion of direct light. The mixture was diluted with
CH2Cl2 (80 mL), treated with (S)-BINOL (2.184 g, 8 mmol) at r.t.
for 2.5 h to furnish the chiral bis-Ti(IV) oxide (S,S)-I. This complex
was cooled to –15 °C and treated sequentially with aldehyde 2 (2.40
g, 20 mmol) and allyltributyltin (17.21 g, 52 mmol) at the same tem-
perature. The mixture was allowed to warm to 0 °C and stirred for
15 h. The mixture was quenched with sat. aq NaHCO3 (50 mL) and
extracted with Et2O (3 × 100 mL). The combined organic extracts
were dried (anhyd Na2SO4). Evaporation of the solvents and purifi-
cation of the residue by column chromatography (EtOAc–hexane,
1:9) gave pure 4 (2.74 g, 84.5%) as a colorless liquid.
[a]D32 +12.6 (c 1.2, CHCl3).
IR (KBr): 3418, 1640, 1495, 1448 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.33–7.10 (m, 5 H), 5.83 (m, 1 H),
5.18–5.05 (m, 2 H), 3.78 (m, 1 H), 2.84–2.61 (m, 2 H), 2.38–2.10
(m, 2 H).
MS (ESI): m/z = 311 [M + H]+.
Anal. Calcd for C17H30O3: C, 65.76; H, 9.74. Found C, 65.78; H,
9.75.
(2R,4R)-5-Phenylpentane-1,2,4-triol (3)
To a stirred soln of 6 (0.640 g, 2 mmol) in MeOH (10 mL), PTSA
(cat.) was added at 0 °C and the mixture was stirred at r.t. for 1 h.
After completion of the reaction, the mixture was quenched with
sat. aq NaHCO3 (8 mL) and extracted with CH2Cl2 (3 × 50 mL). The
organic extracts were dried (anhyd Na2SO4). Evaporation of the sol-
vents and purification of the residue by column chromatography
(EtOAc–hexane, 7:3) gave pure 3 (0.374 g, 95%) as a colorless liq-
uid.
[a]D32 +16.5 (c 1.0, CHCl3).
IR (KBr): 3419, 1642, 1492, 1445 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.40–7.20 (m, 5 H), 4.25 (m, 1 H),
3.98 (m, 1 H), 3.70 (m, 1 H), 3.50 (m, 1 H), 3.10–2.82 (m, 2 H),
1.82–1.53 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 138.4, 134.7, 129.4, 128.4, 126.4,
117.8, 71.7, 43.3, 41.1.
MS (ESI): m/z = 163 [M + H]+.
Anal. Calcd for C11H14O: C, 81.44; H, 8.17. Found: C, 81.38; H,
8.12.
13C NMR (50 MHz, CDCl3): d = 139.1, 128.8, 128.0, 127.2, 71.1,
69.2, 66.4, 44.9, 40.0.
MS (ESI): m/z = 197 [M + H]+.
(S)-4-(tert-Butyldimethylsiloxy)-5-phenylpent-1-ene (5)
Imidazole (0.680 g, 10 mmol) was added to a stirred soln of alcohol
4 (0.81 g, 5.0 mmol) in CH2Cl2 (10 mL). TBDCl (1.00 g, 6.5 mmol)
was then added to this soln at 0 °C, and the mixture was stirred at
r.t. for 2 h. The reaction was quenched with sat. aq NH4Cl (5 mL)
and extracted with CH2Cl2 (3 × 10 mL). The organic extracts were
washed with brine, dried (Na2SO4), and then concentrated. Column
chromatography of the crude product (silica gel, EtOAc–hexane,
20:1) provided 5 (1.27 g, 92%) as a colorless liquid.
[a]D32 +13.4 (c 1.4, CHCl3).
IR (KBr): 3445, 1643, 1458, 1242 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.60–7.31 (m, 5 H), 6.11 (m, 1 H),
5.38–5.22 (m, 2 H), 4.05 (m, 1 H), 3.07–2.83 (m, 2 H), 2.54–2.40
(m, 2 H), 1.09 (s, 9 H), 0.20 (s, 6 H).
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.33; H,
8.25.
(3R,5R)-5-Benzyl-3-hydroxydihydrofuran-2(3H)-one (Harzia-
lactone A, 1)
To a stirred r.t. soln of triol 3 (0.372 g, 1.8 mmol) in CH2Cl2 (20 mL)
was added sequentially PhI(OAc)2 (0.044 g, 6.4 mmol) and TEMPO
(30 mg, 12 mmol%). After stirring at r.t. for 5 h, sat. aq Na2S2O3 and
Et2O (35 mL) were added. The separated organic phase was washed
with sat. aq NaHCO3 then H2O. The combined aqueous washes
were extracted with Et2O (3 × 25 mL) and the combined organic
fractions were washed with brine, dried (Na2SO4), filtered, and con-
centrated by rotary evaporation. The residue was purified by flash
column chromatography (hexanes–EtOAc, 5:5) to provide lactone
1 (0.269 g, 74%) as a white solid.
13C NMR (50 MHz, CDCl3): d = 138.2, 132.2, 128.1, 128.0, 127.8,
127.4, 126.2, 115.7, 72.4, 45.7, 42.8, 25.4, 18.2, –5.7.
[a]D32 +36.4 (c 0.9, CHCl3).
IR (KBr): 1742, 1638, 1388, 1217 cm–1.
MS (ESI): m/z = 277 [M + H]+.
1H NMR (200 MHz, CDCl3): d = 7.36–7.16 (m, 5 H), 4.91 (m, 1 H),
4.04 (t, J = 7.5 Hz, 1 H), 3.28 (b, 1 Hrs), 2.97 (d, J = 6.0 Hz, 2 H),
2.40–2.16 (m, 2 H).
Anal. Calcd for C17H28O: C, 73.85; H, 10.21. Found: C, 73.78; H,
10.23.
Synthesis 2011, No. 19, 3190–3194 © Thieme Stuttgart · New York

PAPER
Synthesis of Harzialactone A
3193
13C NMR (50 MHz, CDCl3): d = 177.6, 135.2, 129.5, 128.8, 127.1,
1H NMR (200 MHz, CDCl3): d = 7.33–7.12 (m, 5 H), 4.03 (m, 1 H),
3.07 (m, 1 H), 2.69 (d, J = 7.0 Hz, 2 H), 2.71 (m, 1 H), 2.48 (m, 1
H), 1.98 (br s, 1 H), 1.88 (m, 1 H), 1.52 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 138.0, 129.6, 128.8, 126.9, 71.1,
50.2, 46.9, 44.0, 38.9.
78.3, 67.0, 41.07, 34.4.
MS (ESI): m/z = 215 [M + Na]+.
Anal. Calcd for C11H12O3: C, 68.67; H, 6.33. Found C, 68.74; H,
6.29.
MS (ESI): m/z = 179 [M + H]+.
(S)-4-(tert-Butoxycarbonyloxy)-5-phenylpent-1-ene (7)
Anal. Calcd for C11H14O2: C, 74.16; H, 7.89. Found: C, 74.32; H,
7.81.
Alcohol 4 (0.810 g, 5 mmol) was dissolved in anhyd CH2Cl2 (20
mL) and stirred at 0 °C and then warmed to r.t. Boc2O (3.44 mL, 7.5
mmol) was added followed Et3N (1.39 mL, 2 mmol) and DMAP
(0.066 g, 0.1 mmol). The mixture was stirred for 2 h and then ex-
tracted with CH2Cl2 (2 × 30 mL). The combined organic layers
were dried (anhyd Na2SO4) and concentrated in vacuo. The residue
on purification by column chromatography (EtOAc–hexane, 1:9)
afforded pure 7 (1.274 g, 91%) as a colorless liquid.
[a]D32 +92 (c 1, CHCl3).
IR (KBr): 1739, 1642, 1454, 1368, 1277 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28–7.10 (m, 5 H), 5.67 (m, 1 H),
5.12–4.99 (m, 2 H), 4.82 (m, 1 H), 2.97–2.75 (m, 2 H), 2.38–2.21
(m, 2 H), 1.43 (s, 9 H).
(R)-2-(tert-Butyldiphenylsiloxy)-1-[(R)-oxiran-2-yl]-3-phenyl-
propane (10)
To a stirred soln of 9 (0.534 g, 3.0 mmol) in anhyd CH2Cl2 (20 mL)
were added imidazole (0.306 g, 4.5 mmol) and TBDPSCl (0.921
mL, 4.5 mmol) at r.t. and the mixture was stirred at this temperature
for 3.5 h. The solvent was removed and the residue was taken up in
EtOAc (20 mL) and washed with H2O and brine. The organic layer
was separated, dried (anhyd Na2SO4), and evaporated. Purification
by column chromatography (silica gel, hexane–EtOAc, 8:2) gave
10 (1.151 g, 93%) as a colorless liquid.
[a]D32 –21.1 (c 0.5, CHCl3).
IR (KBr): 1692, 1460, 1371, 1243, 1163 cm–1.
13C NMR (50 MHz, CDCl3): d = 153.0, 137.5, 133.7, 129.2, 128.4,
126.9, 118.2, 80.8, 76.8, 40.0, 38.1, 27.9.
MS (ESI): m/z = 285 [M + Na]+.
1H NMR (200 MHz, CDCl3): d = 7.72 (d, J = 8.0 Hz, 2 H), 7.61 (d,
J = 8.0 Hz, 2 H), 7.48–7.3 (m, 6 H), 7.18–7.09 (m, 3 H), 6.81 (d,
J = 8.0 Hz, 2 H), 4.10 (m, 1 H), 2.89 (m, 1 H), 2.82–2.60 (m, 3 H),
2.25 (m, 1 H), 1.53–1.46 (m, 2 H), 1.04 (s, 9 H).
13C NMR (50 MHz, CDCl3): d =138.2, 136.1, 134.1, 134.0, 130.0,
129.9, 129.8, 128.1, 127.6, 127.5, 126.1, 72.9, 49.8, 47.3, 44.4,
39.0, 27.0, 19.2.
Anal. Calcd for C16H22O3: C, 73.28, H, 8.40. Found: C, 73.34, H,
8.37.
(4R,6R)-4-Benzyl-6-(iodomethyl)-1,3-dioxan-2-one (8)
To a stirred soln of 7 (1.179 g, 4.5 mmol) in anhyd MeCN (15 mL)
under N2 at –40 °C was added NIS (3.426 g, 13.5 mmol) and the
temperature was raised to 0 °C. The mixture was stirred for 1.5 h.
After completion of the reaction, the mixture was quenched with a
sat. Na2S2O3 soln (15 mL) and workup with EtOAc (3 × 20 mL) and
H2O (15 mL). The combined organic layers were dried (anhyd
Na2SO4) and concentrated in vacuo. Purification of the residue by
column chromatography (EtOAc–hexane, 4:6) afforded pure 8
(1.32 g, 89%) as light-yellow color liquid.
[a]D32 +20.3 (c 0.5, CHCl3).
IR (KBr): 1744, 1637, 1389, 1215 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.08–6.77 (m, 5 H), 4.35 (m, 1 H),
4.08 (m, 1 H), 3.04 (dd, J = 12.0, 5.0 Hz, 1 H), 2.91 (dd, J = 12.0,
9.0 Hz, 1 H), 2.85 (dd, J = 14.0, 6.0 Hz, 1 H), 2.62 (dd, J = 14.0, 8.0
Hz, 1 H), 1.99 (m, 1 H), 1.32 (m, 1 H).
MS (ESI): m/z = 439 [M + Na]+.
Anal. Calcd for C27H32O2Si: C, 77.84; H, 7.74. Found: C, 77.86,
7.76.
(2R,4R)-4-(tert-Butyldiphenylsiloxy)-5-phenylpentane-1,2-diol
(11)
To a cold soln of 10 (0.868 g, 2.0 mmol) in MeCN (1 mL), H2O (350
mL) and 65% HClO4 were added. The mixture was stirred at 0 °C
for 2 h. After completion of the reaction the mixture was neutralized
with aq NaHCO3. The aqueous layer was extracted with EtOAc
(2 × 20 mL) and washed with sat. aq NaHCO3 (3 mL) and brine (3
mL). The combined organic layer was dried (anhyd Na2SO4) and
concentrated. The residue was purified by column chromatography
(hexane–EtOAc, 6:4) to give 11 (0.616 g, 71%) as a colorless liquid.
[a]D32 –8.1 (c 0.5, CHCl3).
IR (KBr): 1695, 1462, 1373, 1242, 1161 cm–1.
13C NMR (50 MHz, CDCl3): d = 148.2, 135.0, 129.7, 128.9, 127.2,
78.8, 77.0, 41.21, 32.5.
MS (ESI): m/z = 333 [M + H], 355 [M + Na]+.
1H NMR (200 MHz, CDCl3): d = 7.75 (d, J = 8.0 Hz, 2 H), 7.68 (d,
J = 8.0 Hz, 2 H), 7.50–7.32. (m, 6 H), 7.11–7.01 (m, 3 H), 6.65 (d,
J = 8.0 Hz, 2 H), 4.10 (m, 1 H), 3.82 (m, 1 H), 3.41 (m, 1 H), 3.22
(m, 1 H), 2.71 (m, 1 H), 2.60 (m, 1 H), 1.58 (m, 1 H), 1.41 (m, 1 H),
1.04 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 138.2, 136.1, 133.9, 133.1, 130.0,
129.9, 129.1, 129.0, 128.0, 127.9, 127.2, 126.1, 75.2, 73.8, 70.9,
44.4, 38.5, 27.0, 19.2.
Anal. Calcd for C12H13IO3: C, 43.37; H, 3.92. Found: C, 43.42; H,
3.89.
(R)-1-[(R)-Oxiran-2-yl]-3-phenylpropan-2-ol (9)
K2CO3 (1.44 g, 10.5 mmol) was added to a soln of cyclic carbonate
8 (1.16 g, 3.5 mmol) in anhyd MeOH (10 mL) at r.t. and the result-
ing mixture was stirred for 0.5 h. The mixture was diluted with Et2O
(10 mL) and quenched with a mixture of sat. aq Na2S2O3–sat. aq
NaHCO3 (1:1). The aqueous phase was extracted with Et2O (3 × 30
mL) and the organic extracts were washed with brine, dried
(Na2SO4), and then concentrated. Purification of the crude product
by column chromatography (silica gel, EtOAc–hexane, 4:6) afford-
ed pure epoxide 9 (0.566 g, 91%) as a colorless liquid.
MS (ESI): m/z = 457 [M + Na]+.
Anal. Calcd for C27H34O3Si: C, 74.65; H, 7.83. Found: C, 74.52; H,
7.87.
(2R,4R)-5-Phenylpentane-1,2,4-triol (3)
To an ice-cooled soln of 11 (0.616 g, 1.3 mmol) in anhyd THF (5
mL) was added 1 M TBAF in THF (0.75 mL, 1.95 mmol) and the
mixture was stirred at r.t. for 3.5 h. After completion of the reaction,
H2O (2 mL) was added to the mixture and THF was removed under
vacuum. The aqueous layer was extracted with EtOAc (2 × 15 mL)
[a]D32 –9.9 (c 0.5, CHCl3).
IR (KBr): 3422, 1637, 1492, 1458 cm–1.
Synthesis 2011, No. 19, 3190–3194 © Thieme Stuttgart · New York

3194
D. N. Kumar et al.
PAPER
and washed with sat. aq NaHCO3 (4 mL) and brine (4 mL). The
combined organic layers were dried (anhyd Na2SO4) and concen-
trated. The residue was purified by column chromatography (hex-
ane–EtOAc, 2:8) to give 3 (0.229 g, 89%) as a viscous liquid.
5 min and then distilled H2O (24 mL, 1.45 mmol) was added. After
stirring for 10 h, this mixture was concentrated and purified by col-
umn chromatography (silica gel, hexane–EtOAc 2:8) to afford 11
(0.744 g, 49%) as a colorless liquid.
[a]D32 +25.6 (c 0.5, CHCl3).
IR (KBr): 1690, 1462, 1372, 1245, 1161 cm–1.
Acknowledgment
1H NMR (200 MHz, CDCl3): d = 7.40–7.20 (m, 5 H), 4.25 (m, 1 H),
3.98 (m, 1 H), 3.70 (m, 1 H), 3.50 (m, 1 H), 3.10–2.82 (m, 2 H),
1.82–1.53 (m, 2 H).
The authors thank CSIR and UGC, New Delhi for financial assi-
stance.
13C NMR (50 MHz, CDCl3): d = 139.1, 128.8, 128.0, 127.2, 71.1,
69.2, 66.4, 44.9, 40.0.
References
MS (ESI): m/z = 197 [M + H]+.
(1) Part 38 in the series, ‘Synthetic studies on natural products’.
(2) (a) Sims, J. J.; Rose, A. F.; Izac, R. R. In Marine Natural
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Asymmetry 1999, 10, 2305. (b) Mereyala, H. B.; Joe, M.;
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(5) (a) Kotkar, S. P.; Suryavanshi, G. S.; Sudalai, A.
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20, 205. (c) Sabitha, G.; Srinivas, R.; Das, S. K.; Yadav, J.
S. Beilstein J. Org. Chem. 2010, 6, 8.
Anal. Calcd for C11H16O: C, 67.32; H, 8.22. Found: C, 67.33; H,
8.25.
(S)-4-(tert-Butyldiphenylsiloxy)-5-phenylpent-1-ene (12)
To a stirred soln of 4 (0.810 g, 5.0 mmol) in anhyd CH2Cl2 (25 mL)
were added imidazole (0.510 g, 7.5 mmol) and TBDPSCl (1.56 mL,
6.0 mmol) at r.t. and the mixture was stirred at this temperature for
2 h. The solvent was removed and the residue was taken up in
EtOAc (30 mL) and washed with H2O (10 mL) and brine (10 mL).
The organic layer was separated, dried (anhyd Na2SO4), and evapo-
rated. Purification by column chromatography (silica gel, hexane–
EtOAc, 8:2) gave 12 (1.88 g, 94%) as a colorless liquid.
[a]D32 +11.5 (c 0.5, CHCl3).
IR (KBr): 1691, 1465, 1374, 1240, 1161 cm–1.
(6) (a) Zard, S. Z. Synlett 2009, 333. (b) White, J. D.; Yang, J.
Synlett 2009, 1713. (c) Rosenberg, S.; Leino, R. Synthesis
2009, 2651. (d) Marcelli, T.; Hiemstra, H. Synthesis 2010,
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Synthesis 2010, 3217.
(7) (a) Das, B.; Laxminarayana, K.; Krishnaiah, M.; Kumar, D.
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Suneel, K.; Satyalakshmi, G. Tetrahedron: Asymmetry
2009, 20, 1536. (c) Das, B.; Laxminarayana, K.; Krishnaiah,
M.; Kumar, D. N. Helv. Chim. Acta 2009, 92, 1840.
(8) (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 1708. (b) Gupta, P.; Naidu, S. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 849.
(9) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.;
Wang, Z. M. J. Org. Chem. 1992, 57, 2768.
(10) Hanzen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.;
Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57.
(11) (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto,
A.; Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013.
(b) Duan, J. J.-W.; Smith III, A. B. J. Org. Chem. 1993, 58,
3703.
1H NMR (200 MHz, CDCl3): d = 7.66 (d, J = 8.0 Hz, 2 H), 7.52 (d,
J = 8.0 Hz, 2 H), 7.41–7.24 (m, 6 H), 7.19–7.08 (m, 3 H), 6.91 (d,
J = 8.0 Hz, 2 H), 5.80 (m, 1 H), 5.04–4.85 (m, 2 H), 3.93 (m, 1 H),
2.78–2.41 (m, 2 H), 2.19–1.94 (m, 2 H), 1.04 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 139.0, 136.1, 135.0, 134.2, 134.1,
129.9, 129.8, 129.7, 128.1, 128.0, 127.4, 127.3, 126.1, 117.2, 74.1,
42.9, 40.1, 27.0, 19.1.
MS (ESI): m/z = 423 [M + Na]+.
Anal. Calcd for C27H32OSi: C, 81.00; H, 8.00. Found: C, 81.19; H,
8.07.
(R)-2-(tert-Butyldiphenylsiloxy)-1-(oxiran-2-yl)-3-phenylpro-
pane (13)
To a stirred soln of olefin 12 (1.60 g, 4 mmol) in CH2Cl2 (50 mL) at
0 °C was added MCPBA (50%, 0.816 g, 4.8 mmol). The mixture
was stirred at r.t. for 6 h and then quenched with sat. NaHCO3 (5
mL) soln. The resulting mixture was extracted with CH2Cl2 (3 × 30
mL), washed with sat. NaHCO3 (6 mL) and brine (6 mL), dried
(Na2SO4), concentrated, and then purified by column chromatogra-
phy (silica gel, hexane–EtOAc, 7:3) to yield the epoxide 13 (1.564
g, 94%) as a colorless liquid; diastereomeric mixture.
(12) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 277, 939. (b) Schaus, S. E.; Brandes, B.
D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A.
E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 1307.
(2R,4R)-4-(tert-Butyldiphenylsiloxy)-5-phenylpentane-1,2-diol
(11)
A soln of epoxide 13 (1.456 g, 3.5 mmol) and (S,S)-Salen–Co(III)–
OAc (0.010 g, 1.75 mmol) in THF (0.3 mL) was stirred at 0 °C for
Synthesis 2011, No. 19, 3190–3194 © Thieme Stuttgart · New York