Stereoselective synthesis of (+)-diplodialides-B, C and a formal synthesis of (+)-diplodialide-A by ring-closing metathesis approach

Article abstract of DOI:10.1016/j.tetasy.2006.11.045

Stereoselective synthesis of diplodialides-B and C and the formal synthesis of diplodialide-A are reported. A combination of Jacobsen's hydrolytic kinetic resolution and Sharpless epoxidation is used for the creation of two stereogenic centers, while a ring-closing metathesis strategy was used for the construction of the lactone ring.

Full text of DOI:10.1016/j.tetasy.2006.11.045

Tetrahedron: Asymmetry 17 (2006) 3197–3202
Stereoselective synthesis of (+)-diplodialides-B, C and a formal
synthesis of (+)-diplodialide-A by ring-closing metathesis approachq
G. V. M. Sharma and K. Laxmi Reddy*
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 September 2006; revised 31 October 2006; accepted 24 November 2006
Available online 4 January 2007
Abstract—Stereoselective synthesis of diplodialides-B and C and the formal synthesis of diplodialide-A are reported. A combination of
Jacobsen’s hydrolytic kinetic resolution and Sharpless epoxidation is used for the creation of two stereogenic centers, while a ring-closing
metathesis strategy was used for the construction of the lactone ring.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
esterification of alcohol 6 and acid 8. Intermediate 6 was
envisaged from (R)-propylene oxide 7, while chiral vinyl
alcohol 8 could be produced from epoxy alcohol 9
(Scheme 1).
Diplodialide-A 1, diplodialide-B 2, diplodialide-C 3, and
diplodialide-D 4 (Fig. 1), the first 10-membered pentake-
tides, were isolated from the plant pathogenic fungus Diplo-
dia pinea (IFO 6472) by Wada and Ishida.1,2 Among the
four, diplodialide-A 1 showed a significant inhibitory activ-
ity against progesterone 11a-hydroxylase in vegetable cell
cultures of Rhizopus stolonifer at 125 ppm. Wada and Ishida
determined the absolute stereochemistry of (9R)-1, (3S,9R)-
2 and (3R,9R)-3.3 Some groups4 have already reported the
synthesis of diplodialides 1–3. Herein, we report the synthe-
sis of 2 and 3 and a formal synthesis of 1.
2. Results and discussion
The synthesis of fragment 6 began by the kinetic resolution
of 10 (Scheme 2) under Jacobsen reaction conditions5 using
the (R,R)-catalyst to give chiral epoxide 7 (42%) and diol
11. Epoxide 7, on treatment with protected 1-[(2-propynyl-
oxy)methyl]benzene A in the presence of n-BuLi and
BF3ÆEt2O in THF at ꢀ78 ꢁC for 3 h, afforded 12 (64%);
on reaction with TBDPSCl in CH2Cl2 at room temperature
gave TBDPS ether 13. Concomitant removal of the benzyl
protecting group and saturation of triple bond with 10%
Pd–C/H2 in MeOH at room temperature gave 14 (93%),
which on subsequent oxidation with IBX in DMSO at
room temperature afforded aldehyde 15 (90%). Wittig olefi-
nation of 15 furnished the corresponding olefin 16 (67%),
which on desilylation under neutral conditions using HF-
pyridine in THF at room temperature for 12 h afforded
6, [a]D = ꢀ15.2 (c 1.1, CHCl3).
Our retrosynthetic analysis revealed that 1 and 3 could be
prepared from 2 by simple oxidation and hydrogenation,
respectively. Hence, the retroanalysis of 2 indicated that it
could be prepared efficiently by RCM protocol from the
bis-olefin 5, which in turn could be realized by Yamaguchi
O
O
O
O
O
O
O
O
O
HO
HO
HO
O
The synthesis of alkene 8 began from the known epoxide
9.6 Accordingly, reaction of 9 (Scheme 3) with Ph3P in
CCl4 at reflux gave chloro epoxide 17 (86%), which was
subjected to fragmentation with sodium sand in dry ether
at room temperature to afford 18 (82%). Vinyl alcohol 18
was treated with TBDPSCl to afford 19 (89%), which was
subjected to debenzylation with DDQ in CH2Cl2–H2O to
1
2
3
4
Figure 1.
q IICT Communication No. 060906.
*
Corresponding author. Fax: +91 40 27160387/27160757; e-mail:
kattalreddy@gmail.com
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.045

3198
G. V. M. Sharma, K. L. Reddy / Tetrahedron: Asymmetry 17 (2006) 3197–3202
O
O
3
1
HO
2
O
OH
(
OH
O
O
O
CO2H
BnO
OH
)
3
9
SPTO
8
6
7
5
Scheme 1.
O
OH
OH
O
a
+
10
7 (42%)
11 (40%)
OR
OR
OTBDPS
O
b, c
f, g
d, e
R
OBn
7
A
14 R = CH2OH (93%)
15 R = CHO (90%)
16 R = TBDPS (67%)
6 R = H (82%)
OBn
12 R = H (64%)
13 R = TBDPS (94%)
Scheme 2. Reagents and conditions: (a) (R,R)-Jacobsen catalyst, H2O, rt, 12 h; (b) n-BuLi, BF3ÆOEt2, THF, ꢀ78 ꢁC, 3 h; (c) TBDPSCl, imidazole,
CH2Cl2, rt, 2 h; (d) 10% Pd–C, H2, MeOH, rt, 12 h; (e) IBX, DMSO, rt, 4 h; (f) CH3Ph3P+Iꢀ, n-BuLi, THF, ꢀ20 ꢁC, 2 h; (g) HF-pyridine, THF, rt, 12 h.
OR
OTBDPS
R
b, c
O
d, e, f
O
a
OBn
BnO
Cl
BnO
OH
20 R = CH2OH (84%)
21 R = CHO (85%)
8 R = CO2H (91%)
18 R = H (82%)
19 R = TBDPS (89%)
17 (86%)
9
Scheme 3. Reagents and conditions: (a) Ph3P, CCl4, relfux, 2 h; (b) Na sand, ether, rt, 6 h; (c) TBDPSCl, imidazole, CH2Cl2, rt, 2 h; (d) DDQ, CH2Cl2–
H2O (19:1) reflux, 4 h; (e) (COCl)2, DMSO, Et3N, ꢀ78 ꢁC, 2 h; (f) Na2ClO2, NaH2PO4, 2-methyl 2-butene, t-BuOH, 10 h.
give 20 (84%). Alcohol 20 on Swern oxidation furnished
aldehyde 21, which on further oxidation with NaClO2
and NaH2PO4 in t-BuOH gave acid 8 (91%).
reported in the literature.4b The synthesis of 2 thus formally
constitutes the total synthesis of diplodialide-A 1.
The esterification of the two fragments 6 and 8 (Scheme 4)
was achieved under Yamaguchi reaction conditions7 using
2,4,6-trichlorobenzoyl chloride to furnish diene ester 5
(83%). Treatment of 5 with Grubbs (first generation) cata-
lyst under high dilution in CH2Cl2 at reflux furnished the
unknown dimer as the major product 22. Hence in order
to avoid the formation of this unwanted product, the
TBDPS group in 5 was first deprotected using HF–pyridine
to give 23. Diene 23 was treated with Grubb’s (first gener-
ation) catalyst8 under high dilution to furnish a 10:1 E:Z
mixture, which on chromatographic purification gave
3. Conclusion
In conclusion, a convergent total synthesis of (+)-diplo-
dialide-B and -C has been achieved very efficiently. Both
the requisite segments with two stereogenic centers were
prepared from Jacobsen and Sharpless reactions, while
RCM was used to build the carbon framework.
4. Experimental
4.1. General
diplodialide-B 2, [a]D = ꢀ35.8 (c 0.2, CHCl3); {lit.3
28
½aꢁD ¼ ꢀ37:3 (c 0.93, CHCl3)}, whose spectral data were
in accordance with the literature data.3 Similarly, hydro-
All moisture sensitive reactions were performed under a
nitrogen atmosphere using flame-dried glassware. The sol-
vents were dried over standard drying agents and freshly
distilled prior to use. NMR spectra were recorded on Var-
ian Gemini FT-200 MHz, Unity-400 MHz (21 ꢁC), and In-
genation of the E/Z-mixture of 24 and 2, using 10%
Pd–C in EtOAc, gave diplodialide-C 3, [a]D = ꢀ39.75 (c
28
0.25, CHCl3); {lit.3 ½aꢁD ¼ ꢀ41:0 (c 0.61, CHCl3)}.
Likewise, the oxidation of 2 to give diplodialide-A 1 is

G. V. M. Sharma, K. L. Reddy / Tetrahedron: Asymmetry 17 (2006) 3197–3202
3199
O
O
O
O
b
TBDPSO
TBDPSO
a
+
8
6
TBDPSO
O
5 (83%)
O
22
O
O
O
O
c
O
b
5
O
d
O
O
+
HO
HO
HO
1:10
HO
3 (93%)
24
2
23 (75%)
O
Ref. 13
O
2
O
1
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, THF, Et3N, rt, 6 h, DMAP, toluene, rt, 14 h; (b) Grubb’s catalyst I, CH2Cl2,
reflux, 48 h; (c) HF-pyridine, THF, rt, 12 h; (d) 10% Pd–C, H2, EtOAc, rt, 4 h.
ova-500 MHz (30 ꢁC) spectrometers, with 7–10 mM solu-
tions in appropriate solvents using TMS as an internal
standard. 13C NMR spectra were recorded with complete
proton decoupling. Optical rotations were measured with
a JASCO DIP-370 instrument, and [a]D-values are in units
of 10ꢀ1 deg cm2 gꢀ1. IR spectra were taken with a Perkin–
Elmer 1310 spectrometer. Mass spectra were recorded on
CEC-21-11013 or Finnigan Mat 1210 double focusing mass
spectrometers operating at a direct inlet system and
FABMS were measured using VG AUTOSPEC mass spec-
trometers at 5 or 7 K resolution using perfluorokerosene as
an internal reference. Nomenclature mentioned in Section
3 was adopted from ACD/Name Version 1.0b, Advanced
Chemistry Development Inc., and Toronto, Canada.
Organic solutions were dried over anhydrous Na2SO4
and concentrated below 40 ꢁC in vacuo.
(q, 1H, J = 6.0 Hz, CH); IR (neat) 3440, 3387, 1025,
820 cmꢀ1; EIMS (m/z): 76 (M+).
4.1.2. (R)-6-Benzyloxy-hex-4-yn-2-ol 12. n-BuLi (24.77 mL,
41.37 mmol, 1.6 N hexane solution) was added dropwise
to
a
solution of 1-[(2-propynyloxy)methyl]benzene
(5.53 g, 37.93 mmol) in dry THF (40 mL) under an
N2 atmosphere at ꢀ78 ꢁC and stirred for 30 min. The reac-
tion mixture was sequentially treated with BF3ÆOEt2
(4.77 mL, 41.37 mmol) and a solution of (R)-propylene
oxide 7 (2.0 g, 34.48 mmol) in dry THF (10 mL) after
10 min interval and stirred for an additional 3 h at
ꢀ78 ꢁC. Saturated NaHCO3 solution (20 mL) followed
by saturated NH4Cl solution (20 mL) was added to the
reaction mixture at ꢀ78 ꢁC and allowed to warm to room
temperature. The reaction mixture was extracted with
EtOAc (3 · 50 mL), washed with water (1 · 20 mL), dried
over Na2SO4, evaporated, and the residue obtained was
purified by column chromatography (silica gel, EtOAc–
4.1.1. (R)-Propylene oxide 7 and (S)-propane 1,2-diol
11. A mixture of (S,S)-(ꢀ)-N-N-bis(3,5-di-tert-butylsali-
cylidene)-1,2-cyclohexanediaminocobalt(II) (0.241 g, 0.40
mmol) in toluene (0.5 mL) and acetic acid (0.48 g,
0.80 mmol) was stirred while open to the air for 1 h at
room temperature. The reaction mixture was concentrated
under reduced pressure and the brown residue was dried
under vacuum. The racemic epoxide 10 (11.6 g, 200 mmol)
was added in one portion at 0 ꢁC, and water (2.0 mL,
110 mmol) was added dropwise over 5 min. The reaction
mixture was allowed to warm to room temperature and
hexane, 1.5:8.5) to furnish 12 (4.5 g, 64%) as a yellow
27
syrup. ½aꢁD ¼ ꢀ5:9 (c 1.0, CHCl3). 1H NMR (CDCl3,
300 MHz): d 1.28 (d, 3H, J = 6.0 Hz, –CH3), 1.90 (br s,
1H, OH), 2.40 (m, 2H, CH2), 3.95 (sextet, 1H, J = 6.0 Hz,
CH), 4.16 (t, 2H, J = 6.0 Hz, CH2), 4.60 (s, 2H, –CH2Ph),
7.30–7.40 (m, 5H, Ar–H); IR (neat) 3447, 2930, 2857,
1465, 1381 cmꢀ1; EIMS (m/z, %): 204 (M+) (56), 113 (43),
91 (100).
stirred for 16 h. (R)-Propylene oxide 7 (5.0 g, 43%)
4.1.3.
(R)-6-Benzyloxy-hex-4-yn-2-yloxy-tert-butyldi-
27
[a]D = ꢀ10.8 (c 1.0, CHCl3) {lit.5a ½aꢁD ¼ ꢀ11:6 (neat)}
phenylsilane 13. To a cooled (0 ꢁC) solution of 12 (3.0 g,
14.70 mmol) in CH2Cl2 (20 mL), imidazole (1.49 g,
22.05 mmol) was added followed by TBDPSCl (4.43 g,
16.17 mmol) and stirred for 4 h at room temperature.
The reaction mixture was treated with saturated aqueous
NH4Cl solution (15 mL) and extracted with CH2Cl2
(2 · 20 mL). The organic layer was washed with water
was isolated by distillation from the reaction mixture at
atmospheric pressure and diol 11 was removed by vacuum
distillation (65 ꢁC) to furnish 40% as colorless liquid,
1
[a]D = +15.5 (neat) {lit.5b [a]D = +16.0 (neat)}, H NMR
(CDCl3, 300 MHz): d 1.27 (d, 3H, J = 6.0 Hz, –CH3),
2.05 (br s, 1H, OH), 3.55 (t, 2H, J = 6.0 Hz, CH2), 3.90

3200
G. V. M. Sharma, K. L. Reddy / Tetrahedron: Asymmetry 17 (2006) 3197–3202
(1 · 20 mL), brine (1 · 20 mL), dried over Na2SO4, evapo-
extracted with EtOAc (3 · 10 mL). The organic layer was
washed with water (5 mL), brine (5 mL), dried over Na2SO4,
evaporated, and the residue obtained was purified by
column chromatography (silica gel 60–120 mesh, EtOAc–
rated, and the residue obtained was purified by column
chromatography (silica gel, EtOAc–hexane, 0.2:9.8) to give
27
13 (6.1 g, 94%) as a colorless liquid. ½aꢁD ¼ þ18:75 (c 0.6,
CHCl3). 1H NMR (CDCl3, 300 MHz): d 1.10 (s, 9H,
3 · CH3), 1.25 (d, 3H, J = 6.2 Hz, –CH3), 2.40 (m, 2H,
CH2), 4.0 (sextet, 1H, J = 6.0 Hz, CH), 4.10 (d, 2H,
J = 6.2 Hz, CH2), 4.55 (s, 2H, CH2), 7.20–7.40 (m, 11H,
Ar–H), 7.60–7.70 (m, 4H, Ar–H); IR (neat): 3250, 2851,
1462, 1221, 1087 cmꢀ1; ESIMS (m/z, %): 443 (M++1, 56).
hexane, 0.1:9.9) to furnish 6 (0.160 g, 82%) as a pale yellow
27
liquid. ½aꢁD ¼ ꢀ13:2 (c 1.1, CHCl3), 1H NMR (CDCl3,
400 MHz): d 1.15 (d, 3H, J = 6.0 Hz, –CH3), 1.30–1.60
(m, 4H, 2 · CH2), 2.00–2.10 (m, 2H, CH2), 3.70–3.70 (m,
1H, CH), 4.90–5.05 (m, 2H, olefin), 5.70–5.80 (m, 1H, ole-
fin); IR (neat): 3435, 1635, 1455, 1130, 982 cmꢀ1; EIMS
(m/z, %): 137 (M++Na, 75); Anal. Calcd for C7H14O
(114): C, 73.63; H, 12.36. Found: C, 73.55; H, 12.30.
4.1.4. (R)-5-tert-Butyldiphenylsilyloxy-hexan-1-ol 14. To
a stirred solution of 13 (3.0 g, 6.78 mmol) in EtOAc
(10 mL), 10% palladium adsorbed on carbon (Pd–C) was
added and stirred under H2 atmosphere for 12 h at room
temperature. The reaction mixture was filtered through
4.1.7. (2S,3S)-1-Chloro-2,3-epoxy-5-4-benzyloxy-1-pentane
17. To a stirred solution of epoxide 9 (1.50 g, 7.21 mmol)
in dry CCl4 (10 mL), Ph3P (3.75 g, 14.42 mmol), and
NaHCO3 (0.30 g, 0.72 mmol) were added and heated at
reflux for 4 h. CCl4 was evaporated under reduced pressure
and the residue obtained was purified by column chro-
matography (silica gel, 60–120 mesh, EtOAc–hexane,
Celite and the filtrate was concentrated under reduced pres-
27
sure to furnish 14 (2.50 g, 93%) as a colorless syrup. ½aꢁD
¼
þ9:0 (c 1.0, CHCl3). 1H NMR (CDCl3, 200 MHz): d 1.05 (s,
9H, 3 · CH3), 1.10 (d, 3H, J = 5.4 Hz, –CH3), 1.20–1.50 (m,
6H, 3 · CH2), 3.50 (t, 2H, J = 5.4 Hz, CH2), 3.81 (sextet,
1H, J = 5.4 Hz, CH), 7.25–35 (m, 6H, Ar–H), 7.65–7.75
(m, 4H, Ar–H); IR (neat): 3368, 2934, 2859, 1428, 1108,
1055 cmꢀ1; ESIMS (m/z, %): 357 (M+, 42).
0.5:9.5) to afford 17 (1.40 g, 86%) as a colorless syrup.
27
½aꢁD ¼ þ19:5 (c 1.5, CHCl3), 1H NMR (CDCl3,
200 MHz): d 1.70–2.05 (m, 2H, CH2), 2.85–3.05 (m, 2H,
2 · CH), 3.40–3.60 (m, 4H, 2 · CH2), 4.44 (s, 2H,
–CH2Ph), 7.22–7.35 (m, 5H, Ar–H); IR (neat): 2920,
2860, 1700, 1520, 1220 cmꢀ1; EIMS (m/z, %): 227 (M+,
38), 173 (20), 161 (35), 107 (100).
4.1.5. (R)-6-tert-Butyldiphenylsilyloxy-hept-1-ene 16. To
a stirred solution of 14 (1.5 g, 4.21 mmol) in dry DMSO
(3 mL), IBX (1.77 g, 6.32 mmol) was added at 0 ꢁC and
stirred for 6 h at room temperature. The reaction mixture
was quenched with satd NaHCO3 solution (5 mL). The
crude reaction mixture was filtered and washed with
EtOAc (2 · 10 mL). The organic layer was washed with
water (2 · 10 mL), brine (2 · 10 mL), dried over Na2SO4,
and concentrated under reduced pressure to obtain (R)-5-
tert-butyldiphenylsilyloxy-hexanal 15.
4.1.8. (3S)-3-Hydroxy-5-4-benzyloxy-1-pentene 18.
A
solution of 17 (1.20 g, 5.30 mmol) in dry ether (10 mL)
was added dropwise to a stirred suspension of freshly
prepared sodium sand (0.24 g, 10.61 mmol) in dry ether
(10 mL) under an N2 atmosphere at room temperature for
4 h. After complete addition, the reaction mixture was
allowed to stir for further 2 h. Then it was carefully
quenched with MeOH (10 mL) at 0 ꢁC, diluted with brine
(5 mL), dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by column chromatogra-
To a solution of (methyl)triphenylphosphonium iodide
(3.0 g, 7.34 mmol) in dry THF (30 mL), n-BuLi (4.58 mL,
7.34 mmol, 1.6 M solution in n-hexane) was added at
ꢀ20 ꢁC and stirred for 30 min. A solution of 15 (1.30 g,
3.67 mmol) in THF (15 mL) was added dropwise and stir-
red for 2 h at room temperature. Saturated aqueous NH4Cl
solution (15 mL) was added and extracted with EtOAc
(3 · 20 mL). The organic layer was washed with water
(25 mL), brine (25 mL), dried over Na2SO4, evaporated,
and the residue obtained was purified by column chroma-
tography (silica gel 60–120 mesh, EtOAc–hexane, 0.1:9.9)
phy (silica gel, 60–120 mesh, EtOAc–hexane, 1:9) to give 18
27
(0.83 g, 82%) as a colorless syrup. ½aꢁD ¼ ꢀ9:0 (c 0.4,
CHCl3), 1H NMR (CDCl3, 200 MHz): d 1.60–1.90 (m,
2H, CH2), 2.70 (br s, 1H, OH), 3.55–3.75 (m, 2H, CH2),
4.40 (q, 1H, J = 6.0 Hz, CH), 4.50 (s, 2H, –CH2Ph), 5.00–
5.30 (m, 2H, olefin), 5.75–5.90 (m, 1H, olefin), 7.20–7.35
(m, 5H, Ar–H); IR (neat): 2950, 2865, 1650, 1560,
1240 cmꢀ1; EIMS (m/z, %): 192 (M+, 23); Anal. Calcd for
C12H16O2 (192): C, 74.97; H, 8.39. Found: C, 74.94; H, 8.30.
to furnish 16 (0.87 g, 67%) as a pale yellow liquid.
27
½aꢁD ¼ þ15:1 (c 1.15, CHCl3), 1H NMR (CDCl3,
4.1.9.
(3S)-3-tert-Butyldiphenylsilyloxy-5-4-benzyloxy-1-
200 MHz):
d
1.05 (s, 9H, 3 · CH3), 1.07 (d, 3H,
pentene 19. To a stirred solution of 18 (0.50 g, 2.60 mmol)
in CH2Cl2 (10 mL), imidazole (0.26 g, 3.90 mmol), and
TBDPSCl (0.85 g, 3.12 mmol) were added and stirred for
3 h. The reaction mixture was treated with satd NH4Cl
(10 mL) and extracted with CH2Cl2 (2 · 10 mL). The
organic layer was washed with water (2 · 10 mL), brine
(2 · 10 mL), dried over Na2SO4, evaporated, and the resi-
due obtained was purified by column chromatography
J = 6.0 Hz, –CH3), 1.30–1.50 (m, 4H, 2 · CH2), 1.95 (q,
2H, J = 6.4 Hz, CH2), 3.80 (sextet, 1H, J = 5.6 Hz, CH),
4.80–5.0 (m, 2H, olefin), 5.60–5.80 (m, 1H, olefin), 7.20–
7.40 (m, 6H, Ar–H), 7.60–7.70 (m, 4H, Ar–H); IR (neat):
3435, 3071, 2932, 1635, 1467, 1134 cmꢀ1; EIMS (m/z, %):
353 (M+, 45), 238 (76); Anal. Calcd for C23H32OSi (353):
C, 78.35; H, 9.15. Found: C, 78.26; H, 9.08.
(60–120 silica gel, 0.3:9.7 EtOAc–hexane) to furnish 19
28
4.1.6. (R)-Hept-6-en-2-ol 6. A solution of 16 (0.60 g,
1.70 mmol) in dry THF (2 mL) was treated with HF-pyri-
dine and stirred at room temperature for 12 h. The reaction
mixture was quenched with satd NaHCO3 solution and
(1.0 g, 89%) as a colorless syrup. ½aꢁD ¼ ꢀ21:2 (c 0.6,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.12 (s, 9H,
3 · CH3), 1.65–1.95 (m, 2H, CH2), 3.50–3.75 (m, 2H,
CH2), 4.38 (q, 1H, J = 5.4 Hz, CH), 4.50 (s, 2H, –CH2Ph),

G. V. M. Sharma, K. L. Reddy / Tetrahedron: Asymmetry 17 (2006) 3197–3202
3201
5.05–5.30 (m, 2H, olefin), 5.70–5.80 (m, 1H, olefin), 7.20–
7.45 (m, 11H, Ar–H), 7.60–7.70 (m, 4H, Ar–H); IR (neat):
2950, 2865, 1650, 1560, 1240 cmꢀ1; EIMS (m/z, %): 430
(M+, 42), 238 (78), 77 (100).
1.12 mmol) was added at room temperature and stirred
for 30 min. A solution of 2,4,6-trichlorobenzoyl chloride
(0.137 g, 0.56 mmol) in dry THF (2 mL) was added to
the reaction mixture and stirred for 5 h at room tempera-
ture. The solvent was evaporated, the residue diluted with
toluene (20 mL), and treated with DMAP (0.136 g,
1.12 mmol) and 6 (0.064 g, 0.56 mmol). After 14 h, toluene
was evaporated and the crude residue purified by column
chromatography (silica gel, 60–120 mesh, EtOAc–hexane,
4.1.10.
(3S)-3-tert-Butyldiphenylsilyloxy-5-4-hydroxy-1-
pentene 20. To a stirred solution of 19 (0.90 g, 2.94 mmol)
in dichloromethane–water (19:1, 10 mL), DDQ (3.33 g,
14.70 mmol) was added and stirred at reflux for 4 h. Satd
aq NaHCO3 solution (10 mL) was added to the reaction
mixture and extracted with CH2Cl2 (3 · 10 mL). The com-
bined organic layers were washed with water (10 mL),
brine (10 mL), dried over Na2SO4, and concentrated. The
crude residue was purified by column chromatography (sil-
0.4:9.6) to afford 5 (0.105 g, 83%) as a colorless syrup.
28
½aꢁD ¼ ꢀ22:0 (c 0.6, CHCl3); 1H NMR (CDCl3,
200 MHz):
d 1.05 (s, 9H, 3 · CH3), 1.15 (d, 3H,
J = 3.5 Hz, CH3), 1.25–1.50 (m, 4H, 2 · CH2), 2.00 (q,
2H, J = 6.0 Hz, CH2), 2.40 (dd, 1H, J = 3.5, 7.5 Hz,
CH), 2.50 (dd, 1H, J = 1.7, 8.5 Hz, CH), 4.55 (q, 1H,
J = 6.0 Hz, CH), 4.85 (sextet, 1H, J = 5.8 Hz, CH), 4.90–
5.05 (m, 4H, olefinic), 5.65–5.90 (m, 2H, olefinic), 7.30–
7.45 (m, 6H, Ar–H), 7.65 (t, 4H, J = 3.5 Hz, Ar–H); 13C
NMR (CDCl3, 300 MHz): d 171.35, 139.5, 138.4, 136.56,
130.0, 127.52, 116.5, 114.8, 72.10, 66.85, 44.40, 35.5, 33.2,
27.26, 20.85; IR (neat): 3540, 3025, 2910, 1777, 1580,
1425, 1240, 1058 cmꢀ1; FABMS (m/z, %): 451 (M+, 75),
107 (100); Anal. Calcd for C28H38O3Si (450): C, 74.62; H,
8.50. Found: C, 74.54; H, 8.42.
ica gel, 60–120 mesh, EtOAc–hexane, 0.8:9.2) to afford 20
28
(0.71 g, 84%) as a yellow syrup. ½aꢁD ¼ ꢀ12:1 (c 0.3,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.10 (s, 9H,
3 · CH3), 1.60–1.80 (m, 2H, CH2), 3.50–3.80 (m, 2H,
CH2), 4.40 (q, 1H, J = 6.1 Hz, CH), 5.00–5.25 (m, 2H, ole-
fin), 5.70–5.90 (m, 1H, olefin), 7.35–7.45 (m, 6H, Ar–H),
7.65 (m, 4H, Ar–H); IR (neat): 3035, 2860, 1635, 1542,
1244, 1087 cmꢀ1; EIMS (m/z, %): 363 (M++Na, 77), 238
(34), 161 (30), 107 (100).
4.1.11. (3S)-3-tert-Butyldiphenylsilyloxy-pent-5-enoic acid
8. To a stirred solution of oxalyl chloride (0.25 mL,
2.10 mmol), in dry CH2Cl2 (10 mL), DMSO (0.26 mL,
4.20 mmol) was added at ꢀ78 ꢁC and stirred at the same
4.1.13. Preparation of dimer 22. Ester
5 (0.020 g,
0.047 mmol) dissolved in freshly distilled degassed anhy-
drous CH2Cl2 (100 mL) was treated with Grubbs’ catalyst
I (0.048 g, 0.0589 mmol) and heated at reflux for 2 days
under a nitrogen flow until TLC (hexane–EtOAc; 80:20)
showed the complete disappearance of the starting mate-
rial. Most of the solvent was then distilled off and the con-
centrated solution left to stir at room temperature for 2 h
under air bubbling in order to decompose the catalyst.
The reaction mixture was evaporated to dryness to give a
brown residue, which was purified by column chromato-
graphy (silica gel, 60–120 mesh, EtOAc–hexane, 0.2:9.8)
temperature for 30 min.
A solution of 20 (0.60 g,
1.76 mmol) in dry CH2Cl2 (20 mL) was added at ꢀ78 ꢁC
to the reaction mixture and stirred for 2.5 h at the same
temperature. Et3N (2.52 mL, 8.40 mmol) was added at
0 ꢁC and stirred for an additional 30 min. The reaction
mixture was diluted with water (20 mL) and extracted with
CH2Cl2 (2 · 20 mL). The combined organic layers were
washed with brine (20 mL), dried over Na2SO4, and con-
centrated to give (3S)-3-tert-butyldiphenylsilyloxy-pent-5-
enal 21 (0.51 g, 85%) as a pale yellow syrup.
to furnish 22 (0.027 mg, 70%) as a colorless syrup.
28
½aꢁD ¼ þ18:5 (c 0.5, CHCl3); 1H NMR (CDCl3,
To a stirred solution of 21 (0.50 g, 1.47 mmol) in tert-
butanol–water (7:3, 10 mL), sodium chlorite (0.16 g,
1.77 mmol), NaH2PO4 (0.27 g, 1.77 mmol), and 2-methyl-
2-butene (0.5 mL) were added and stirred at room temper-
ature for 10 h. The reaction mixture was concentrated, the
residue dissolved in ethyl acetate (10 mL), washed with
water (5 mL), brine (5 mL), dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified
by column chromatography (silica gel, 60–120 mesh,
200 MHz): d 1.05 (s, 18H, 6 · CH3), 1.15 (d, 6H,
J = 6.4 Hz, 2 · CH3), 1.25–1.50 (m, 8H, 4 · CH2), 1.85–
2.05 (m, 4H, 2 · CH2), 2.40 (dd, 4H, J = 3.5, 7.5 Hz,
2 · CH2), 4.55 (q, 2H, J = 7.2 Hz, 2 · CH), 4.80 (sextet,
2H, J = 5.6 Hz, 2 · CH), 4.90–5.00 (m, 4H, olefinic),
5.22–5.35 (m, 2H, olefinic), 5.70–5.90 (m, 2H, olefinic),
7.25–7.40 (m, 6H, Ar–H), 7.60–7.70 (m, 4H, Ar–H); 13C
NMR (CDCl3, 300 MHz): d 170.5, 139.8, 138.4, 136.2,
131.0, 130.6, 128.6, 127.1, 71.10, 65.7, 45.5, 35.0, 33.1,
27.8, 20.9; IR (neat): 3542, 3020, 2925, 1770, 1610, 1425,
1245, 1052 cmꢀ1; FABMS (m/z, %): 873 (M+, 85); Anal.
Calcd for C54H72O6Si2 (873): C, 74.27; H, 8.31. Found:
C, 74.50; H, 8.25.
EtOAc–hexane, 2:8) to afford 8 (0.47 g, 91%) as a pale yel-
28
low syrup. ½aꢁD ¼ ꢀ10:0 (c 0.6, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.05 (s, 9H, 3 · CH3), 2.40 (dd, 1H, J = 3.5,
7.0 Hz, CH), 2.55 (dd, 1H, J = 3.0, 6.5 Hz, CH), 4.55 (q,
1H, J = 6.5 Hz, CH), 5.0–5.20 (m, 2H, olefin), 5.80–5.90
(m, 1H, olefin), 7.35 (m, 6H, Ar–H), 7.65 (m, 4H, Ar–H);
IR (neat): 3546, 3070, 2934, 2858, 1780, 1589, 1428,
1240 cmꢀ1; EIMS (m/z, %): 353 (M++1, 64), 107 (100);
Anal. Calcd for C21H26O3Si (352): C, 71.15; H, 7.39.
Found: C, 71.06; H, 7.32.
4.1.14. (3S)-(R)-Hept-6-en-2-yl 3-hydroxy pent-4-enoate
23. A solution of 5 (0.10 g, 1.66 mmol) in THF (1 mL)
was taken in a plastic bottle, and HF-pyridine (2–3 drops)
was added at 0 ꢁC and stirred at room temperature for
12 h. The reaction mixture was quenched with satd Na-
HCO3 solution (5 mL) at 0 ꢁC and extracted with EtOAc
(2 · 50 mL). The organic layer was washed with satd
CuSO4 solution (5 mL), dried over Na2SO4, and the resi-
due obtained was purified by column chromatography (sil-
4.1.12. (1R)-1-Methyl-5-hexenyl (3S)-3-tert-butyldiphenyl-
silyloxy-4-pentenoate 5. To a stirred solution of 8 (0.20 g,
0.56 mmol) in dry THF (5 mL), Et3N (0.114 mL,

3202
G. V. M. Sharma, K. L. Reddy / Tetrahedron: Asymmetry 17 (2006) 3197–3202
ica gel, 60–120 mesh, EtOAc–hexane, 2:8) to afford 23
4.1.16. Diplodialide-C 3. To a stirred solution of 2
(0.005 g, 6.78 mmol) in EtOAc (2 mL), 10% palladium
adsorbed on carbon (Pd–C) was added and stirred under
an H2 atmosphere for 4 h. The reaction mixture was filtered
through Celite and the filtrate was concentrated under
28
(0.035 g, 75%) as a colorless syrup. ½aꢁD ¼ ꢀ9:5 (c 0.6,
CHCl3); 1H NMR (CDCl3, 200 MHz): d 1.15 (d, 3H,
J = 3.5 Hz, CH3), 1.25–1.50 (m, 4H, 2 · CH2), 2.0 (q,
2H, J = 5.0 Hz, CH2), 2.40 (dd, 1H, J = 3.0, 6.5 Hz,
CH), 2.50 (dd, 1H, J = 3.5, 7.0 Hz, CH), 4.55 (q, 1H,
J = 5.2 Hz, CH), 4.85 (sextet, 1H, J = 5.6 Hz, CH), 4.90–
5.05 (m, 4H, olefin), 5.65–5.90 (m, 2H, olefin); IR (neat):
3546, 3070, 2934, 2858, 1780, 1589, 1428, 1240 cmꢀ1; EIMS
(m/z, %): 213 (M++1, 45).
reduced pressure to obtain 3 (0.004 g, 93%) as a colorless
28
syrup. [a]D = ꢀ39.7 (c 0.25, CHCl3); {lit.3 ½aꢁD ¼ ꢀ41:0 (c
0.61, CHCl3)} 1H NMR (CDCl3, 500 MHz): d 1.27 (d,
3H, J = 6.6 Hz, –CH3), 1.30–1.85 (m, 10H, 5 · –CH2),
2.47 (dd, 1H, J = 9.77, 15.78 Hz, –CH), 2.68 (dd, 1H,
J = 4.0, 15.78 Hz, –CH), 4.05–4.13 (m, 1H, H-3), 4.93–
5.03 (m, 1H, H-9); 13C NMR (CDCl3, 300 MHz): d
171.09, 72.41, 69.82, 44.11, 35.48, 31.33, 29.68, 26.70,
21.68, 20.32; IR (neat): 3642, 3435, 1726, 1264,
1140 cmꢀ1; FABMS (m/z, %): 168 (M+, 68), 150 (56),
124 (26).
4.1.15. Diplodialide-B 2 [(4S,10R)-4-hydroxy-10-methyl-
3,4,7,8,9,10-hexahydro-2H-2-oxecini-ne] and cis-isomer
24. Ester 23 (0.010 g, 0.047 mmol) dissolved in freshly dis-
tilled degassed anhydrous CH2Cl2 (100 mL) was treated
with Grubbs’ catalyst I (0.048 g, 0.0589 mmol) and heated
at reflux for 2 days under a nitrogen flow until TLC (hex-
ane–EtOAc; 80:20) showed the complete disappearance of
the starting material. Most of the solvent was then distilled
off and the concentrated solution left to stir at room temper-
ature for 2 h under air bubbling in order to decompose the
catalyst. The reaction mixture was evaporated to dryness
to give a brown residue, which was purified by column chro-
matography (silica gel, 60–120 mesh, EtOAc–hexane, 3:97)
to allow the separation of the desired trans stereoisomer
(E)-2 (5 mg) and cis isomer Z-24 (0.5 mg) as colorless syrups.
Acknowledgement
K.L.R. is thankful to the UGC, New Delhi, India, for the
financial support.
References
First eluted was (4S,5E,10R)-2 [a]D = ꢀ35.8 (c 0.2,
1. Wada, K.; Ishida, T. J. Chem. Soc., Chem. Commun. 1975,
209–210.
2. Wada, K.; Ishida, T. J. Chem. Soc., Chem. Commun. 1976,
340–341.
3. Wada, K.; Ishida, T. J. Chem. Soc., Perkin Trans. 1 1979,
1154–1158.
4. (a) Wakamatsu, T.; Kozo, A.; Ban, Y. J. Org. Chem. 1979, 44,
2008–2012; (b) Ashok Kumar, V.; Shenvi, B.; Hans, G. Helv.
Chim. Acta 1980, 63, 2426–2433; (c) Tsuji, J.; Mandai, T.
Tetrahedron Lett. 1978, 19, 1817–1820; (d) Wada, K.; Ishida,
T. J. Chem. Soc., Perkin Trans. 1 1979, 323–327; (e) Singh, V.
K.; Baktharaman, S.; Anand, R. V. J. Org. Chem. 2003, 68,
3356–3359.
28
CHCl3); {lit.3 ½aꢁD ¼ ꢀ37:3 (c 0.93, CHCl3)} 1H NMR
(CDCl3, 300 MHz): d 1.19 (d, 3H, J = 7.0 Hz, –CH3),
1.25 (br s, 1H, –OH), 1.40–2.0 (m, 4H, 2 · –CH2), 2.00
(q, 2H, J = 6.0 Hz, –CH2), 2.35 (dd, 1H, J = 3.5, 7.5 Hz,
CH), 2.70 (dd, 1H, J = 7.5, 15.86 Hz, –CH), 4.38–4.50
(m, 1H, H-3), 4.70–4.80 (m, 1H, H-9), 5.32–5.55 (m,
2H, H-4, H-5); 13C NMR (CDCl3, 300 MHz): d 20.85,
27.26, 33.2, 35.5, 44.4, 66.8, 72.1, 128.2, 132.1, 168.8; IR
(neat): 3545, 1720, 1250, 1144, 975 cmꢀ1; FABMS (m/z,
%): 185 (M++1, 25), 124 (37).
5. (a) 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, 1307–1315; (b) Louis, J. T.;
Nelson, W. L. J. Org. Chem. 1987, 52, 1309–1315.
6. Radhakrishna, P.; Krishna Rao, L.; Kannan, V. Tetrahedron
Lett. 2004, 45, 7847–7850.
7. Inanga, J.; Hirata, K.; Sacki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
8. (a) Tanaka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
Second eluted was (4S,4Z,10R)-24 [a]D = ꢀ15.8 (c 0.1,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.18 (d, 3H,
J = 7.0 Hz, –CH3), 1.40–1.95 (m, 4H, 2 · –CH2), 2.05 (q,
2H, J = 6.0 Hz, –CH2), 2.30 (dd, 1H, J = 3.0, 6.2 Hz,
CH), 2.75 (dd, 1H, J = 7.0, 12.1 Hz, –CH), 4.38–4.55 (m,
1H, H-3), 4.75–4.83 (m, 1H, H-9), 5.10 (m, 1H, H-5),
5.25 (m, 1H, H-4); 13C NMR (CDCl3, 300 MHz): d
20.15, 26.5, 35.0, 44.2, 66.2, 72.0, 128.50, 132.5, 168.0; IR
(neat): 3545, 1720, 1250, 1144, 975 cmꢀ1; FABMS (m/z,
%): 185 (M++1, 25), 124 (37).
18–29; (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 112,
¨
3012–3140.