A cross-metathesis approach to the synthesis of (+)-phomopsolide B

Article abstract of DOI:10.1016/j.tetlet.2015.05.032

Abstract The synthesis of phomopsolide B has been achieved using an olefin cross-metathesis (CM) reaction as key step. Two metathesis partners, enediol and 5-hydroxy vinyl lactone were prepared from l-ascorbic acid. This is the first report of using 5-hyd

Full text of DOI:10.1016/j.tetlet.2015.05.032

Accepted Manuscript
A cross-metathesis approach to the synthesis of (+)-phomopsolide B
D. Vasudeva Reddy, Gowravram Sabitha, J. S. Yadav
PII:
S0040-4039(15)00841-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.032
TETL 46304
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 March 2015
8 May 2015
9 May 2015
Please cite this article as: Vasudeva Reddy, D., Sabitha, G., S. Yadav, J., A cross-metathesis approach to the synthesis
of (+)-phomopsolide B, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.05.032
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D. Vasudeva Reddy, Gowravram Sabitha* and J. S. Yadav

1
Tetrahedron Letters
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A cross-metathesis approach to the synthesis of (+)-phomopsolide B
D. Vasudeva Reddy, Gowravram Sabitha* and J. S. Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
The synthesis of phomopsolide B has been achieved using an olefin cross-metathesis
(CM) reaction as a key step. Two metathesis partners, ene diol and 5-hydroxy vinyl
lactone were prepared from L-ascorbic acid. This is the first report of using 5-hydroxy
vinyl lactone in an olefin cross-metathesis reaction.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
phomopsolides
cross-metathesis
5-hydroxy vinyl lactone
L-ascorbic acid
first report
In 1985, Grove et al reported the isolation of phomopsolides A
and B (Figure 1, 1 & 2) from the fungus Phomopsis oblonga.
Both 1 and 2 have been found to show antiboring/antifeeding
activity against the elm bark beetle.1,2 Later in 1997,
phomopsolides A and B were isolated by Stierle3 along with
three new phomopsolides C, D and E (Figure 1, 1-5) from
Penicillium sp.,which was isolated from the inner bark of the
Pacific yew, Taxus brevifolia. They have shown potent
antimicrobial activity against S. aureus. Phomopsolide B (2) was
also isolated from the submerged cultures of the endophytic
fungal strain Diaporthe sp. XZ-07 of Camptotheca acuminate. It
significantly inhibited the growth of human-tumor HeLa cells
with an IC50 of 5.7 µg/ml by the MTT assay (MTT=3-(4,5-
(+)- Phompsolide B based on an olefin cross-metathesis approach
starting from L-ascorbic acid.
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide).4
Phomopsolides A, B, C, D, E (1-5) and related compounds5 have
been isolated recently from the alga-associated fungus,
Penicillium clavigerum, which was isolated from the green alga
Chlorella vulgaris Beyerinck [Beijerinck]. Phomopsolide A and
phomopsolide C were reported as potent inhibitors (IC50 < 10
microM) of specific and established human cancer cell lines.
Figure 1. Phomopsolides A-E (1-5)
The retrosynthetic analysis of (+)-2 is shown in Scheme 1. This
strategy derives C5, C6, C3' and C4' stereocenters of 2 from L-
ascorbic acid. The target molecule 2 could be obtained from 7 by
esterification followed by deprotection of acetonide group.
Compound 7 in turn could be obtained from olefin cross-
metathesis reaction between dihydroxy olefin 8 and 5-hydroxy
vinyl δ-lactone 9. The two metathesis partners 8 and 9 could be
synthesized from L-ascorbic acid via an intermediate 10.
Phomopsolides
possess
6-substituted
5,
6-dihydro-5-
hydroxypyran-2-one core. To date, only two syntheses6, 7 of (+)-
phompsolide B have been reported. In continuation of our
interest on the synthesis of biologically active δ-lactone
containing natural products8 using olefin cross-metathesis
reaction as a key step, we herein describe the total synthesis of
______
∗ Corresponding author. Tel.: +91-40-27191629; fax: +91-40-
27160512; e-mail: gowravaramsr@yahoo.com

2
column chromatography. The spectral data of compound 7
matched with the data of the compound reported.7
HO
O
O
TBSCl, Imidazole
O
HO
ref 9
O
CO2Me
OH
2, 0 oC- R.T
CH Cl
HO
OH
2
11
90%
L- Ascorbic Acid
1. DIBAL, Hexane, -78 o
c
CH Cl
50% TFA,
2
2
O
O
O
O
CO2Me
0 oC, 95%
2. Ph3P+-CH3 Br-, n-BuLi
THF, -78 o
59% for two steps
OTBS
OTBS
12
C
13
OH
RO
OR
NaH, BnBr, THF
PPTS, EtOH
TBSO
Scheme 1. Retrosynthetic analysis
0 o
83% for two products
C
OTBS
OR'
0 oC - R.T, 88%
10, R = H
TBSCl, Imidazole
15a, R = Bn, R'= TBS
15b, R = TBS, R'= Bn
Thus, the synthesis of 2 began starting from L-ascorbic acid.
Initially, the 5-hydroxy vinyl δ-lactone 9 was prepared as shown
in Scheme 2. The known hydroxy ester9 11 obtained from L-
ascorbic acid, was protected as its TBS ether 12 in 90% yield.
The subsequent ester reduction of 12 and Wittig olefination were
conducted in one pot due to the instability of the intermediate
aldehyde to get the olefinic compound 13. Deprotection of the
isopropylidene group with 50% TFA10 in CH2Cl2 provided the
diol 10 in 95% yield. The primary hydroxyl group of diol 10 was
selectively protected as its TBS ether by using TBSCl and
imidazole in CH2Cl2 to obtain 14 in 90% yield. Protection of the
secondary hydroxyl group as its benzyl ether resulted in a
mixture of two inseparable isomers 15a and 15b.11 Interestingly,
after removal of the primary silyl group with PPTS in EtOH, the
two resulting primary alcohols could be separated on silica gel
2, 0 oC, 90%
14, R = TBS
CH Cl
2
OBn
HO
OBn
1. IBX, CH3CN, Reflux
MeO2C
OTBS
16a
+
OTBS
2. NaH, (CF3CH2O)2P(O)CH2CO2Me,
30 min at 0 oC, then addition
OTBS
17
HO
of aldehyde at -78 oC,
82% for two steps
OBn
16b
(16a:16b, 7:3)
OBn
OH
CH Cl
PTSA,
CH Cl
TiCl4,
2
2
2
2
O
O
0 oC, 90%
R.T, 88%
O
O
1
18
9
giving 16a and 16b in 7:3 ratio (by H NMR). These results
revealed that the silyl protecting group in the present case was
labile to migration.
Abbreviations: TBSCl = tert-Butyldimethylsilyl chloride, THF=
Tetrahydrofuran, DIBAL= Diisobutylaluminum hydride, TFA=
Trifluoroacetic acid, PPTS = Pyridinium p-toluenesulfonate, IBX
= 2-Iodoxybenzoic acid, PTSA= p-Toluenesulfonic acid
Oxidation of the primary hydroxyl group in 16a with IBX in
CH3CN furnished the corresponding aldehyde which on further
treatment with Still-Gennari phosphonate afforded Z-α,β-
unsaturated ester 17 in 82% yield over two steps. Treatment of
ester 17 with PTSA/ CH2Cl2 at room temperature resulted in the
deprotection of TBS group with the simultaneous lactone ring
formation to afford 18 in 88% yield. Deprotection of benzyl
group in compound 18 was achieved with TiCl4 in CH2Cl2 at 0 oC
to complete the synthesis of 5-hydroxy vinyl lactone 912 in 90%
yield.
The other coupling partner, dihydroxy olefin 8 was synthesized
from an intermediate 10 (see Scheme 2), which was accessed
from L-ascorbic acid. Accordingly, regioselective tosylation on
the primary alcohol 10 using TsCl, Et3N and a catalytic amount
of n-Bu2SnO in CH2Cl2 at 0 °C afforded mono-tosyl compound
19, which on subsequent treatment with LAH furnished methyl
compound 88g in 85% yield (Scheme 3).
Scheme 2. Synthesis of 5-hydroxy vinyl lactone 9
HO
TsCl, Et3N,
OTBS
O
Bu2SnO(cat)
O
HO
Scheme 2
OH
CH2Cl2, 0 oC, 92 %
HO
HO
OH
10
L- Ascorbic Acid
OTBS
OH
LAH, THF
0 oC, 85 %
OTs
HO
OH
19
8
With the two desired precursors 8 and 9 in hand, we were now
ready to study the key cross-metathesis reaction. Thus olefin
cross-metathesis (CM) reaction between the dihydroxy olefin 8
and the 5-hydroxy vinyl lactone 9 using 2nd generation Grubbs
catalyst13 in CH2Cl2 at refux resulted in an unisolable mixture of
three products, i.e., two self dimers (15%) and the required
coupled product (80%). Since we were unable to isolate pure
product at this stage, it was protected as an acetonide by reaction
with 2,2-dimethoxypropane to give a pure product 7 after flash
Abbreviations: TsCl = p-Toluenesulfonyl chloride, LAH =
Lithium aluminium hydride
Scheme 3. Synthesis of ene diol 8
Esterification of the free hydroxy group in 7 with tiglic acid
afforded 20 in 90% yield. Finally, deprotection of the acetonide
group with a catalytic amount of PTSA in CH2Cl2/MeOH (2:1)
furnished the target lactone, (+)-phomopsolide B in 89% yield.
The spectroscopic and physical data (1 H and 13C NMR, & [α]D)

3
of (+)-phomopsolide B (2)14 was identical with the reported data
in the literature.1,6b,7
10. Ren, G. B; Huang, Y. X; Sun, Y. P; Li, Z. H and Wu, Y. J.
Org. Chem. 2010, 75, 5048-506.
In conclusion, we have performed a convergent, stereoselective
synthesis of (+)-phomopsolide B in 15 steps and in 9% overall
yield. Olefin cross-metathesis was the key step involved to
accomplish the synthesis of (+)-phomopsolide B.
11. Wu, J. Z; Gao, J; Ren, G. B; Zhen, Z. B; Zhang, Y; Wu, Y.
Tetrahedron 2009, 65, 289–299.
12. Michaelis, S and Blechert, S. Org. Lett. 2005, 7(24), 5513-
5516.
13. Grubbs, R. H; Lee, C. W; Ding, S; Scholl, M. Org. Lett.
1999, 1(6), 953-956.
14. Phomopsolide B (2): [α]D20 : +235.30 (c = 0.4, MeOH); [Lit.3
[α]D20 : +250 (c = 0.03, MeOH); Lit.1,6b,7 [α]D20 : +255, +250, 224
o
(EtOH)]; mp 94–96 C; [Lit.1 97 °C]; IR (neat): 3445, 2924,
2854, 1743, 1632, 1543, 1465, 1379, 1110 cm−1; 1H NMR
(CDCl3, 300 MHz): δ 7.01 (dd, J = 9.8, 5.5 Hz, 1H), 6.93–6.87
(m, 1H), 6.24 (d, J = 9.8 Hz, 1H), 6.01 (ddd, J = 15.7, 5.6, 1.2
Hz, 1H), 5.90 (ddd, J = 15.7, 6.0, 1.2 Hz, 1H), 5.38 (dd, J = 5.6,
3.0 Hz, 1H), 5.12–5.09 (m, 1H), 3.93 (t, J = 6.0 Hz, 1H), 3.62
(dq, 12.7, 6.3 Hz, 1H), 2.42 (br.s, OH), 1.83-1.79 (m, 6H), 1.68
(br.s, OH), 1.17 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 125
MHz): δ 166.7, 162.4, 140.9, 139.9, 134.8, 127.5, 124.9, 124.6,
78.5, 76.1, 70.5, 63.3, 18.8, 14.5, 12.0; ESI-MS (m/z): 319 [M
+Na]+; HRMS-ESI: m/z calcd for C15 H20 O6 Na: 319.11521,
found: 319.11474.
Abbreviations: 2,2-DMP = 2,2-Dimethoxypropane, DCC =
N,N'-dicyclohexylcarbodiimide, DMAP
pyridine.
= 4-Dimethylamino
Scheme 4. Synthesis of (+)-phomopsolide B.
Acknowledgements: DVR thank CSIR, New Delhi for the
award of fellowship. All the authors thank CSIR, New Delhi for
financial support as part of XII Five Year plan programme under title
ORIGIN (CSC-0108).
Supplementary Material: Experimental procedures, spectral
data, copies of 1H NMR, 13C NMR spectra available.
____________
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