Total synthesis of (+)-phomopsolide B

Article abstract of DOI:10.1016/j.tet.2012.06.002

An enantiospecific total synthesis of polyhydroxy δ-pyrone natural product phomopsolide B is accomplished. The main feature of the synthesis is the installation of the required E-olefin by Horner-Emmons-Wordsworth reaction and the formation of the lactone

Full text of DOI:10.1016/j.tet.2012.06.002

Tetrahedron 68 (2012) 7489e7493
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (þ)-phomopsolide B
*
Kavirayani R. Prasad , Phaneendra Gutala
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2012
Received in revised form 30 May 2012
Accepted 3 June 2012
Available online 12 June 2012
An enantiospecific total synthesis of polyhydroxy d-pyrone natural product phomopsolide B is accom-
plished. The main feature of the synthesis is the installation of the required E-olefin by Hor-
nereEmmonseWordsworth reaction and the formation of the lactone involving StilleGennari
olefination followed by lactonization.
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Sosale Chan-
drasekhar on the occasion of his 60th
birthday
Keywords:
Phomopsolide B
Polyhydroxy lactone
d-Pyrone
1. Introduction
Phomopsolides A (1) and B (2) are 5,6-dihydro-(2H)-pyran-2-
one ( -pyrone) containing natural products isolated by Grove
d
from a strain of Phomopsis oblonga.1 Phomopsolides A and B possess
antiboring/antifeeding activity against Scolytid beetles, which are
responsible for the Dutch elm disease, the disease, which destroys
the American elm tree.2 Incidentally, the same phomopsolides
were also isolated by Stierle et al. from the fungus Penicillium sp.
lying in the inner bark of pacific yew, Taxus brevifolia along with
other analogous phomopsolides 3e5.3 Phomopsolide B 2 was also
isolated along with other polyketides from the submerged cultures
of endophytic fungal strain Diaporthe sp. XZ-07 of Camptotheca
acuminate by Yuan et al.4 Interestingly, phomopsolide B 2 was also
shown to be moderately cytotoxic against the human tumor cell
Fig. 1. Phomopsolides 1e5.
line HeLa with an IC50 of 5.7
A solitary synthesis of phomopsolide B 2 was reported in the
-glucose, which involves an arduous 24-step se-
mg/mL Fig. 1.
as the key steps.7 We have been involved in the synthesis of bio-
literature from
D
active d
-pyrone natural products8 and in continuation of our ef-
quence that includes separation of diasteromers.5 Synthesis of the
analogs of phomopsolides A and B, 3e5 was reported by the group of
O’Doherty et al. using asymmetric dihydroxylation and Achmato-
wicz oxidation of furan as the key steps,6 while synthesis of 3 was
reported by Blechert using olefin cross metathesis and RCM reaction
forts, herein we report a facile total synthesis of phomopsolide B 2.
Our approach for the synthesis of phomopsolide B 2 is de-
lineated in Scheme 1. It was anticipated to install the required
pyrone unit by elaboration of the primary alcohol in the tetrol 7 by
selective oxidation of the primary alcohol followed by Z-selective
Wittig olefination and lactonization. Synthesis of the tetrol 7 is
envisaged from the extension of the b-keto phosphonate 8 derived
from (S)-lactic acid.
* Corresponding author. Fax: þ91 80 23600529; e-mail address: prasad@org-
chem.iisc.ernet.in (K.R. Prasad).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.002

7490
K.R. Prasad, P. Gutala / Tetrahedron 68 (2012) 7489e7493
Scheme 1. Retrosynthesis for phomopsolide B 2.
2. Results and discussion
Scheme 2. Synthesis of tetrol 7.
Accordingly, the sequence commenced with the synthesis of the
a
,
b
-unsaturated ketone 11 by reaction of the phosphonate 89 with
the aldehyde 10, derived from the alcohol 910 in 65% yield. Re-
duction of the ketone in 11 with NaBH4 in presence of CeCl3 fur-
nished the alcohol 12 as a single diastereomer in 92% yield.
Deprotection of the TBS group as well as the benzylidene acetal was
accomplished by treating 12 with PPTS in MeOH to furnish the
tetrol 7 in 83% yield. All our efforts to oxidize the primary alcohol in
tetrol 7 to the aldehyde 13 without affecting the other secondary
hydroxy groups were futile (Scheme 2).
reaction of 16 with p-TSA to afford the lactone 17 in 78% yield. At
this stage, deprotection of the benzyl group turned out to be dif-
ficult. After exhaustive experimentation, it was found that the
treatment of 17 with FeCl3 afforded the free alcohol,12 which was
transformed to the corresponding ketal 18 without further purifi-
cation by reaction with 2,2-dimethoxypropane (77% yield over two
steps). Esterification of the free alcohol in 18 with tiglic acid
afforded 6 in 87% yield. Deprotection of the acetonide with
amberlyst-15 in MeOH furnished phomopsolide B 2 in 83% yield,
the spectral and physical properties, of which are in complete
agreement with that reported in literature (Scheme 3).1,5b
Owing to the difficulty in the selective oxidation of the primary
hydroxy group in 7, a strategy involving the protection of the sec-
ondary hydroxy groups was undertaken. Thus, all hydroxy groups
in the tetrol 7 were transformed into the silyl ethers to yield the
tetrasilyloxy compound 14 in 92% yield. Selective deprotection of
the primary TBS group in 14 afforded 15 in 71% yield. Oxidation of
the primary alcohol in 15 with IBX yielded the aldehyde, which on
Wittig olefination with StilleGennari phosphonate11 furnished the
3. Conclusions
In conclusion, a facile synthesis of phomopsolide B 2 is accom-
(Z)-
a,b-unsaturated ester 16 in 82% yield. Deprotection of the silyl
plished in 13% overall yield in 12 linear steps. The synthesis
groups with concomitant lactone formation was accomplished by
showcased the use of
a combination of E and Z selective
Scheme 3. Total synthesis of phomopsolide B 2.

K.R. Prasad, P. Gutala / Tetrahedron 68 (2012) 7489e7493
7491
WittigeHorner and StilleGennari olefination reactions in the con-
struction of the polyol -pyrone.
temperature for further 30 min, it was poured into water (10 mL)
and was extracted with diethyl ether (3ꢁ25 mL). Combined organic
layers were washed with brine (2ꢁ10 mL) and dried over Na2SO4.
Evaporation of the solvent followed by silica gel column chroma-
tography of the resulting residue using petroleum ether:EtOAc
(4:1) as eluent furnished 12 (0.88 g, 92%) as a colorless oil. Rf 0.4
d
4. Experimental section
4.1. General procedures
[a
]Dþ9.4 (c 2.9, CHCl3); IR (Neat) 3463, 2954, 2857, 1454,
1095 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d
7.49e7.46 (m, 2H),
Column chromatography was performed on silica gel, Acme
grade 100e200 mesh. TLC plates were visualized either with UV, in
an iodine chamber, or with phosphomolybdic acid spray, unless
noted otherwise. Unless stated otherwise, all reagents were pur-
chased from commercial sources and used without additional pu-
rification. THF was freshly distilled over Na-benzophenone ketyl.
Melting points were uncorrected. Unless stated otherwise, 1H NMR
and 13C NMR spectra were recorded either on 300 MHz or 400 MHz
machine in CDCl3 as solvent with TMS as reference unless other-
wise indicated. Unless stated otherwise, all the reactions were
performed under inert atmosphere. All the specific rotations were
determined at 24 ꢀC.
7.31e7.15 (m, 8H), 5.94 (dd, 1H, J¼15.6, 5.7 Hz), 5.72 (dd, 1H, J¼15.6,
6.0 Hz), 5.53 (s,1H), 4.69 (d, 1H, J¼12.3 Hz), 4.49 (d, 1H, J¼12.3 Hz),
4.36 (d, 1H, J¼7.5 Hz), 4.32 (d, 1H, J¼13.5 Hz), 3.86 (d, 1H,
J¼12.6 Hz), 3.78 (dt,1H, J¼10.2, 5.4 Hz), 3.56 (qd,1H, J¼12.0, 6.3 Hz),
3.2 (bs, 1H), 2.53 (d, 1H, J¼4.5 Hz), 1.06 (d, 3H, J¼6.3 Hz), 0.82 (s,
9H), 0.00 (s, 3H), ꢂ0.016 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 138.0,
131.8, 129.1, 128.7, 128.2, 128.2, 128.0, 127.9, 127.6, 126.2, 101.1, 79.8,
76.3, 71.9, 71.7, 71.1, 68.4, 25.7, 19.9, 17.9, ꢂ4.2, ꢂ4.7; HRMS for
C28H40O5SiþNa calcd 507.2543; found 507.2544.
4.1.4. (2S,3S,6S,7S,E)-2-(Benzyloxy)oct-4-ene-1,3,6,7-tetraol (7). To
a stirred solution of 12 (0.85 g, 1.75 mmol) in MeOH (10 mL) was
added PPTS (1.31 g, 5.25 mmol) at room temperature and was
refluxed for 4 h. After completion of the reaction (indicated by TLC),
MeOH was evaporated under vacuum and the reaction mixture was
diluted with DCM (10 mL). Solid NaHCO3 (0.880 g, 10.5 mmol) was
added to the reaction mixture and was stirred for further 15 min.
The reaction mixture was then filtered through a short pad of Celite
and the Celite pad was washed with DCM (3ꢁ10 mL). Evaporation
of solvent followed by silica gel column chromatography of the
resulting residue using EtOAc:MeOH (9:1) as eluent yielded 7
4.1.1. (4R,5S)-5-(Benzyloxy)-2-phenyl-1,3-dioxane-4-carbaldehyde
(10). To a stirred solution of 9 (0.92 g, 3.06 mmol) in EtOAc (10 mL)
was added IBX (2.57 g, 9.18 mmol) at room temperature and was
refluxed for 4 h. After completion of the reaction (monitored by
TLC), it was filtered through a short pad of Celite and the Celite pad
was washed with diethyl ether (3ꢁ10 mL). The organic layer was
washed with saturated NaHCO3 solution (10 mL), brine (10 mL), and
dried over Na2SO4. The crude aldehyde obtained after evaporation
of the solvent was used in the next step without further
purification.
(0.41 g, 83%) as a colorless oil. Rf 0.5 [
(Neat) 3390, 2882, 1652, 1455, 1048 cmꢂ1
CDCl3) 7.32e7.25 (m, 5H), 5.82e5.68 (m, 2H), 4.62, and 4.56 (ABq,
a
]Dꢂ10.0 (c 0.6, CHCl3); IR
4.1.2. (4S,E)-1-((4S,5S)-5-(Benzyloxy)-2-phenyl-1,3-dioxan-4-yl)-4-
((tert-butyldimethylsilyl)oxy)pent-1-en-3-one (11). Cs2CO3 (2.98 g,
9.18 mmol) was added to a solution of 8 (0.95 g, 3.06 mmol) in
MeCN (5 mL), and was stirred for 45 min at room temperature. The
reaction mixture was cooled to ꢂ15 ꢀC and a solution of the alde-
hyde 10 (obtained above) in THF (5 mL) was added dropwise and
was stirred for 30 min at the same temperature. After completion of
the reaction (monitored by TLC), it was cautiously quenched by
addition of saturated citric acid (10 mL), poured into water (20 mL),
and extracted with diethyl ether (3ꢁ25 mL). Combined organic
layers were washed with brine (2ꢁ10 mL) and dried over Na2SO4.
Evaporation of solvent gave the crude residue, which was purified
by silica gel column chromatography using petroleum ether:EtOAc
(4:1) as eluent to furnish 11 (0.96 g, 65%) as a colorless oil. Rf 0.4;
;
1H NMR (300 MHz,
d
2H, J¼15.6 Hz), 4.28e4.27 (m, 2H), 4.13e4.10 (m, 1H), 3.81e3.78 (m,
1H), 3.73e3.69 (m, 1H), 3.59e3.55 (m, 2H), 3.41e3.39 (m, 2H), 1.08
(d, 3H, J¼6.0 Hz); 13C NMR (100 MHz, CDCl3)
d 137.8, 132.2, 131.5,
128.5, 128.0, 128.0, 81.5, 76.5, 72.7, 72.0, 70.4, 60.9, 18.9; HRMS for
C15H22O5þNa calcd 305.1365; found 305.1363.
4.1.5. (5S,6S,9S,10S,E)-10-(Benzyloxy)-6,9-bis(tert-butyldimethylsily-
loxy)-2,2,3,3,5,13,13,14,14-nonamethyl-4,12-dioxa-3,13-
disilapentadec-7-ene (14). Imidazole (1.156 g, 17 mmol), TBSCl
(1.065 g, 7.1 mmol) and DMAP (0.035 g, 0.284 mmol) were added to
a stirred solution of 7 (0.40 g, 1.42 mmol) in DCM (10 mL) at room
temperature and the reaction mixture was refluxed for 3 h. After
completion of the reaction (indicated by TLC), it was poured into
water (20 mL) and extracted with diethyl ether (3ꢁ25 mL). Com-
bined organic layers were washed with brine (2ꢁ5 mL) and dried
over Na2SO4. Evaporation of solvent followed by silica gel column
chromatography of the resulting residue using petroleum ether:-
EtOAc (19:1) as eluent furnished 14 (0.97 g, 92%) as a colorless oil. Rf
[
a
]Dþ4.8 (c 1.5, CHCl3); IR (Neat) 2955, 2858, 1697, 1633, 1344,
1097 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d
7.51e7.48 (m, 2H),
7.33e7.18 (m, 8H), 7.00 (dd, 1H, J¼15.6, 1.5 Hz), 6.86 (dd, 1H, J¼15.3,
3.3 Hz), 5.60 (s, 1H), 4.66 (d, 1H, J¼12.3 Hz), 4.6 (dt, 1H, J¼5.4,
1.8 Hz); 4.47 (d, 1H, J¼12.6 Hz), 4.36 (dd, 1H, J¼12.3, 1.5 Hz), 4.23 (q,
1H, J¼7.2 Hz), 3.94 (dd, 1H, J¼12.9, 1.5 Hz), 3.38 (d, 1H, J¼1.8 Hz),
1.25 (d, 3H, J¼7.2 Hz), 0.83 (s, 9H), ꢂ0.007 (s, 3H), ꢂ0.021 (s, 3H);
0.6 [
a
]Dꢂ33.4 (c 3.0, CHCl3); IR (Neat) 2954, 2886, 1471, 1254 cmꢂ1
;
13C NMR (100 MHz, CDCl3)
d
201.5, 142.9, 137.6, 128.8. 128.4, 128.4,
1H NMR (400 MHz, CDCl3)
d 7.39e7.26 (m, 5H), 5.77 (m, 2H), 4.78
128.1, 127.9, 127.8, 126.1, 124.0, 100.9, 78.6, 74.3, 71.3, 70.9, 68.5,
25.7, 20.9, 18.1, ꢂ4.7, ꢂ4.9; HRMS for C28H38O5SiþNa calcd
505.2386; found 505.2386.
(d, 1H, J¼12.2 Hz), 4.69 (d, 1H, J¼12.2 Hz), 4.31e4.30 (m, 1H),
4.10e4.09 (m, 1H), 3.83 (d, 1H, J¼11.0 Hz), 3.75 (qd, 1H, J¼11.9,
6.1 Hz), 3.58 (dd, 1H, J¼10.9, 7.4 Hz), 3.44e3.41 (m, 1H), 1.00 (d, 3H,
J¼6.2 Hz), 0.91 (s, 9H), 0.90 (s, 9H), 0.89 (s, 18H), 0.06e0.00 (m,
4.1.3. (3S,4S,E)-1-((4S,5S)-5-(Benzyloxy)-2-phenyl-1,3-dioxan-4-yl)-
24H) (4ꢁSiMe2); 13C NMR (100 MHz, CDCl3)
d 139.4, 129.8, 129.3,
4-((tert-butyldimethylsilyl)oxy)pent-1-en-3-ol
(12). CeCl.37H2O
128.1, 127.5, 127.2, 84.1, 75.3, 73.0, 72.2, 71.4, 63.8, 25.9, 25.8, 25.8,
25.8, 18.3, 18.2, 18.1, 18.0, 17.2, ꢂ4.6 (2ꢁC), ꢂ4.70, ꢂ4.74, ꢂ4.8, ꢂ5.0,
ꢂ5.3, ꢂ5.4; HRMS for C39H78O5Si4þNa calcd 761.4824; found
761.4822.
(1.1 g, 2.95 mmol) was added to a stirred solution of 11 (0.95 g,
1.97 mmol) in MeOH (10 mL) and was allowed to stir for 45 min at
room temperature. It was cooled to ꢂ78 ꢀC and NaBH4 (0.112 g,
2.95 mmol) was added portionwise for over 10 min and the re-
action mixture was stirred for an additional 1 h at the same tem-
perature. After completion of the reaction (monitored by TLC), it
was quenched by addition of water (1 mL) at ꢂ78 ꢀC and was slowly
allowed to warm up to room temperature. After stirring at room
4.1.6. (2S,3S,6S,7S,E)-2-(Benzyloxy)-3,6,7-tris(tert-butyldimethylsily-
loxy)oct-4-en-1-ol (15). To
a stirred solution of 14 (0.90 g,
1.22 mmol) in EtOH (8 mL) was added PPTS (0.61 g, 2.44 mmol) at
room temperature and was stirred for 8 h. After completion of the

7492
K.R. Prasad, P. Gutala / Tetrahedron 68 (2012) 7489e7493
reaction (monitored by TLC), EtOH was evaporated under vacuum
and the reaction mixture was diluted with DCM (5 mL). Solid
NaHCO3 (0.41 g, 4.88 mmol) was added to the reaction mixture and
was stirred for further 15 min. The reaction mixture was then fil-
tered through a short pad of Celite and the Celite pad was washed
with DCM (3ꢁ10 mL). Evaporation of solvent followed by silica gel
column chromatography of the resulting residue using petroleum
ether:EtOAc (4:1) as eluent yielded 15 (0.54 g, 71%) as a colorless oil
along with 0.08 g (9%) of the unreacted starting material (14). Rf 0.5
Celite pad was washed with DCM (3ꢁ10 mL). Evaporation of
solvent followed by silica gel column chromatography of the
resulting residue using EtOAc as eluent yielded 17 (0.14 g, 78%) as
a colorless oil. Rf 0.4 [
a
;
]Dþ117.8 (c 0.75, CHCl3); IR (Neat) 3427,
1723, 1253, 1051 cmꢂ1
1H NMR (400 MHz, CDCl3)
d
7.38e7.27
(m, 5H), 6.86 (dd, 1H, J¼9.8, 4.6 Hz), 6.12 (d, 1H, J¼10.0 Hz), 6.05
(dd, 1H, J¼15.7, 5.8 Hz), 5.95 (dd, 1H, J¼15.7, 5.7 Hz), 4.95 (t, 1H,
J¼4.7 Hz), 4.62, and 4.58 (ABq, 2H, J¼11.9 Hz), 4.12 (t, 1H,
J¼4.1 Hz), 3.93 (t, 1H, J¼6.0 Hz), 3.65 (qd, 1H, J¼12.5, 6.3 Hz), 2.66
(bs, 2H), 1.17 (d, 3H, J¼6.3 Hz); 13C NMR (100 MHz, CDCl3)
[
a]Dꢂ45.0 (c 3.1, CHCl3); IR (Neat) 3493, 2930, 2858, 1472,
1463 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
7.35e7.26 (m, 5H), 5.80
d 162.9, 143.5, 136.9, 135.0, 128.5, 128.2, 127.8, 125.6, 122.8, 79.6,
(dd, 1H, J¼15.8, 4.0 Hz), 5.74 (dd, 1H, J¼15.7, 4.8 Hz), 4.74 (d, 1H,
J¼11.7 Hz), 4.63 (d, 1H, J¼11.7 Hz), 4.35 (t, 1H, J¼5.0), 4.10 (t, 1H,
J¼4.3 Hz), 3.76 (qd, 1H, J¼11.5, 6.0 Hz), 3.70 (d, 1H, J¼4.9 Hz),
3.59e3.55 (m, 1H), 3.50 (dt, 1H, J¼11.0, 5.4 Hz), 1.00 (d, 3H,
J¼6.2 Hz), 0.90 (s, 18H), 0.89 (s, 9H), 0.06e0.04 (m, 18H) (3ꢁSiMe2);
76.2, 71.7, 70.3, 68.7, 18.8; HRMS for C17H20O5þNa calcd
327.1208; found 327.1210.
4.1.10. (5S,6S)-5-Hydroxy-6-((E)-2-((4S,5S)-2,2,5-trimethyl-1,3-
dioxolan-4-yl)vinyl)-5,6-dihydro-2H-pyran-2-one (18). Anhydrous
FeCl3 (0.066 g, 0.41 mmol) was added to a stirred solution of 17
(0.025 g, 0.082 mmol) in DCM (2 mL) at room temperature and
was stirred for 1 h. After completion of the reaction (indicated
by TLC), reaction mixture was diluted with EtOAc (5 mL) and
solid NaHCO3 (0.085 g, 1.0 mmol) was added and was stirred for
further 5 min. The reaction mixture was then filtered through
a short pad of Celite and the Celite pad was washed with EtOAc
(3ꢁ5 mL). Evaporation of solvent followed by short silica gel
column chromatography of the resulting residue using EtOAc:-
MeOH (9:1) as eluent yielded trihydroxylactone (Rf 0.4) as a red
color oil, which was used in the next step without
characterisation.
To a solution of the trihydroxylactone in DCM (1 mL) was added
2,2-dimethoxypropane (0.5 mL) and p-TSA (0.002 g, 0.0082 mmol)
at room temperature and was stirred for 1 h. After completion of
the reaction (indicated by TLC), reaction mixture was diluted with
DCM (5 mL) and solid NaHCO3 (0.004 g, 0.041 mmol) was added
and was stirred for further 5 min. The reaction mixture was then
filtered through a short pad of Celite and the Celite pad was washed
with DCM (3ꢁ5 mL). Evaporation of solvent followed by silica gel
column chromatography of the resulting residue using petroleum
ether:EtOAc (1:1) as eluent furnished 18 (0.016 g, 77% for two steps)
13C NMR (100 MHz, CDCl3)
d 138.5, 130.6, 129.5, 128.4, 127.7, 127.7,
82.5, 75.2, 73.7, 72.9, 71.4, 61.9, 25.8, 18.1, 18.0, 17.1, ꢂ4.70 (2ꢁC),
ꢂ4.75, ꢂ4.79, ꢂ4.9, ꢂ5.0; HRMS for C33H64O5Si3þNa calcd
647.3959; found 647.3955.
4.1.7. (2R,3S,6S,7S,E)-2-(Benzyloxy)-3,6,7-tris((tert butyldimethylsilyl)
oxy)oct-4-enal. To a stirred solution of 15 (0.52 g, 0.83 mmol) in EtOAc
(10 mL) was added IBX (0.70 g, 2.49 mmol) at room temperature and
was refluxed for 4 h. After completion of the reaction (indicated by
TLC), it was then filtered through a short pad of Celite and the Celite
pad was washed with diethyl ether (3ꢁ10 mL). The organic layer was
washed with satd NaHCO3 solution (10 mL), brine (10 mL), and dried
over Na2SO4, and concentrated. The crude aldehyde obtained was
used in the next step without further purification.
4.1.8. (2Z,4S,5S,6E,8S,9S)-Methyl 4-(benzyloxy)-5,8,9-tris((tert-bu-
tyldimethylsilyl)oxy)deca-2,6-dienoate (16). To a pre-cooled (0 ꢀC)
solution of StilleGennari phosphonate (0.39 g, 1.24 mmol) in THF
(5 mL), was added NaH (0.050 g, 1.24 mmol) and was stirred for
30 min at same temperature. The reaction mixture was cooled to
ꢂ78 ꢀC and a solution of aldehyde obtained above in THF (5 mL)
was added dropwise and was stirred for 2 h. After completion of
the reaction (monitored by TLC), it was cautiously quenched by
addition of saturated ammonium chloride (10 mL), poured into
water (10 mL) and extracted with diethyl ether (3ꢁ15 mL).
Combined organic layers were washed with brine (2ꢁ5 mL) and
dried over Na2SO4. Evaporation of solvent gave the crude residue,
which was purified on silica gel column chromatography using
petroleum ether: ether (9:1) as eluent to furnish 16 (0.46 g, 82%
as a colorless oil. Rf 0.5 [
a
]Dþ133.0 (c 0.75, CHCl3); IR (Neat) 3411,
2925, 1718, 1379, 1251, 1031 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
6.99
(dd, 1H, J¼9.7, 5.5 Hz), 6.12 (d, 1H, J¼9.7 Hz), 6.02e5.94 (m, 2H), 4.9
(s,1H), 4.21(bs,1H), 3.99 (dd,1H, J¼8.4, 3.0 Hz), 3.82 (qd,1H, J¼12.2,
6.0 Hz), 2.93 (bs, 1H), 1.42 (s, 3H), 1.40 (s, 3H), 1.27 (d, 3H, J¼6.0 Hz);
13C NMR (100 MHz, CDCl3)
d 164.1, 144.5, 132.0, 126.6, 122.7, 108.7,
82.5, 79.8, 76.7, 62.4, 27.3, 26.8, 16.4; HRMS for C13H18O5þNa calcd
for two steps) as a colorless oil. Rf 0.5 [
(Neat) 2930, 2858, 1729, 1255, 1104 cmꢂ1
CDCl3)
a
]Dꢂ18.6 (c 2.7, CHCl3); IR
277.1052; found 277.1054.
;
1H NMR (400 MHz,
d
7.33e7.24 (m, 5H), 6.10 (dd, 1H, J¼11.5, 10.0 Hz), 5.94 (d,
4.1.11. (E)-(2S,3S)-6-Oxo-2-((E)-2-((4S,5S)-2,2,5-trimethyl-1,3-
1H, J¼11.8 Hz), 5.83e5.75 (m, 2H), 5.12 (dd, 1H, J¼9.5, 5.4 Hz),
4.57, and 4.51 (ABq, 2H, J¼12.0 Hz), 4.33 (d, 1H, J¼4.0 Hz), 4.09 (d,
1H, J¼4.7 Hz), 3.73 (qd, 1H, J¼11.8, 7.8 Hz), 3.67 (s, 3H), 0.99 (d,
3H, J¼6.1 Hz), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.05e0.01 (m,
dioxolan-4-yl)vinyl)-3,6-dihydro-2H-pyran-3-yl
2-methylbut-2-
enoate (6). Tiglic acid (0.011 g, 0.11 mmol), DCC (0.023 g,
0.11 mmol), and DMAP (0.003 g, 0.022 mmol) were added to a so-
lution of 18 (0.014 g, 0.055 mmol) in DCM (2 mL) at room tem-
perature and reaction mixture was stirred for 3 h. After completion
of the reaction (indicated by TLC), reaction mixture was then fil-
tered through a short pad of Celite and the Celite pad was washed
with diethyl ether (3ꢁ5 mL). Evaporation of solvent followed by
silica gel column chromatography of the resulting residue using
petroleum ether:EtOAc (7:3) as eluent yielded 6 (0.016 g, 87%) as
18H) (3 x SiMe2); 13C NMR (100 MHz, CDCl3)
d 166.2, 146.4, 138.8,
130.5, 129.6, 129.0, 127.6, 127.3, 122.6, 77.3, 76.0, 74.8, 71.4, 71.3,
51.2, 25.8, 18.2, 18.1, 18.0, 17.2, ꢂ4.70, ꢂ4.75 (2ꢁCH3), ꢂ4.8, ꢂ4.90,
ꢂ4.93; HRMS for C36H66O6Si3þNa calcd 701.4065; found
701.4068.
4.1.9. (5S,6S)-5-(Benzyloxy)-6-((3S,4S,E)-3,4-dihydroxypent-1-en-1-
yl)-5,6-dihydro-2H-pyran-2-one (17). A stirred solution of 16
(0.40 g, 0.59 mmol) in DCM (5 mL) was treated with p-TSA
(0.56 g, 2.95 mmol) for 3 h at room temperature. After comple-
tion of the reaction (indicated by TLC), reaction mixture was
diluted with DCM (5 mL) and solid NaHCO3 (0.50 g, 6.0 mmol)
was added and was stirred for further 15 min. The reaction
mixture was then filtered through a short pad of Celite and the
a colorless oil. Rf 0.4 [
a
]Dþ184.4 (c 0.35, EtOH); IR (Neat) 2984,
2932,1732, 1715, 1380, 1248 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
6.98
(dd, 1H, J¼9.7, 5.5 Hz), 6.88 (q, 1H, J¼6.6 Hz), 6.23 (d, 1H, J¼9.7 Hz),
5.95 (dd, 1H, J¼16.0, 5.8 Hz), 5.86 (dd, 1H, J¼15.7, 5.0 Hz), 5.38 (dd,
1H, J¼5.4, 3.0 Hz), 5.09 (t, 1H, J¼4.0 Hz), 3.94 (t, 1H, J¼8.3 Hz), 3.70
(dq, 1H, J¼12.2, 6.1 Hz), 1.79 (s, 3H), 1.78 (d, 3H, J¼6.7 Hz), 1.40 (s,
3H), 1.36 (s, 3H), 1.22 (d, 3H, J¼6.0 Hz); 13C NMR (100 MHz, CDCl3)
d
166.6,162.4,140.8,139.7,131.8,127.4,125.3,124.6,108.7, 82.2, 78.2,

K.R. Prasad, P. Gutala / Tetrahedron 68 (2012) 7489e7493
7493
76.7, 63.2, 27.3, 26.7, 16.3, 14.5, 11.9; HRMS for C18H24O6þNa calcd
Supplementary data
General experimental procedures and copies of 1H NMR and 13
NMR spectra for all the new compounds synthesized are provided.
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.06.002.
359.1472; found 359.1471.
Phomopsolide B 2: Amberlyst-15 (0.050 g) was added to a so-
lution of 6 (0.015 g, 0.045 mmol) in MeOH (2 mL) at room tem-
perature and was stirred for 2 h. After completion of the reaction
(indicated by TLC), MeOH was evaporated under vacuum and the
reaction mixture was diluted with DCM (5 mL). The reaction mix-
ture was then filtered through a short pad of Celite and the Celite
pad was washed with DCM (2ꢁ5 mL). Evaporation of solvent fol-
lowed by silica gel column chromatography of the resulting residue
using petroleum ether:EtOAc (1:4) as eluent yielded phomopsolide
C
References and notes
1. Grove, J. F. J. Chem. Soc., Perkin Trans. 1 1985, 865.
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Noshita, T.; Sugiyama, T.; Yamashita, K.; Oritani, T. Biosci. Biotechnol. Biochem.
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G. A.; Li, M. Tetrahedron Lett. 2004, 45, 6407; (c) O’Doherty, G. A.; Li, M.; Scott, J.
Tetrahedron Lett. 2004, 45, 1005.
B 2 as a white solid. (0.011 g, 83%). Rf 0.5 [
a
]Dþ224.6 (c 0.2, EtOH);
Lit.1,5b
[a
]Dþ255 (c 0.17, EtOH); mp 93e95 ꢀC; Lit.1 mp 97 ꢀC; IR
(Neat) 3567, 3384,1723,1711,1252 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.0 (dd, 1H, J¼9.7, 5.5 Hz), 6.90 (q, 1H, J¼7.1 Hz), 6.23 (d, 1H,
J¼9.7 Hz), 6.0 (dd, 1H, J¼15.8, 5.5 Hz), 5.88 (dd, 1H, J¼15.6, 5.7 Hz),
5.37 (dd, 1H, J¼5.3, 3.0 Hz), 5.10 (dd, 1H, J¼5.3, 2.6 Hz), 3.92 (t, 1H,
J¼5.7 Hz), 3.60 (dq, 1H, J¼12.7, 6.3 Hz), 2.63 (bs, 1H), 2.50 (bs, 1H),
1.81 (s, 3H), 1.80 (d, 3H, J¼6.3 Hz), 1.16 (d, 3H, J¼6.3 Hz); 13C NMR
7. Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513.
8. (a) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 1146; (b)
Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2; (c) Prasad, K. R.; Pencha-
laiah, K. Tetrahedron: Asymmetry 2010, 21, 2853; (d) Prasad, K. R.; Penchalaiah,
K. J. Org. Chem. 2011, 76, 6889.
9. Shapiro, G.; Buechler, D.; Hennet, S. Tetrahedron Lett. 1990, 31, 5733.
10. (a) Takano, S.; Kurotaki, A.; Sekiguchi, Y.; Satoh, S.; Hirama, M.; Ogasawara, K.
Synthesis 1986, 811; (b) Dureault, A.; Portal, M.; Carreaux, F.; Depezay, J. C.
Tetrahedron 1993, 49, 4201; (c) Lee, E.; Park, C. M.; Yun, J. S. J. Am. Chem. Soc.
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(100 MHz, CDCl3)
d 166.7, 162.5, 141.0, 139.9, 134.9, 127.4, 124.8,
124.6, 78.6, 76.1, 70.5, 63.3, 18.7, 14.5, 11.9; HRMS for C15H20O6þNa
calcd 319.1158; found 319.1156.
Acknowledgements
11. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
12. The triol resulting from the deprotection of the benzyl group in 17 has con-
siderable solubility in water. No appreciable amount of triol was isolated after
usual aqueous workup, hence it is necessary to avoid aqueous workup for this
transformation.
We thank the Department of Science and Technology (DST),
New Delhi for funding. K.R.P. is a Swarnajayanthi fellow of DST, New
Delhi. P.G. thanks Council of Scientific and Industrial Research
(CSIR), New Delhi for a senior research fellowship.