An enantioselective total synthesis of phomopsolide C

Article abstract of DOI:10.1016/S0040-4039(02)01866-X

A flexible enantioselective route to highly functionalized α,β-unsaturated δ-lactones, has allowed for the synthesis of phomopsolide C. This approach derives its asymmetry from (S)-lactic acid and by applying the Sharpless catalytic asymmetric dihydroxylation to vinylfuran. The resulting diols are produced in high enantioexcess and can be stereoselectively transformed into α,β-unsaturated-δ-lactones via a short highly diastereoselective oxidation and reduction sequence. A Wittig olefination reaction was used to introduce the side chain in either cis or trans form that was further elaborated into phomopsolide C.

Full text of DOI:10.1016/S0040-4039(02)01866-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8195–8199
An enantioselective total synthesis of phomopsolide C
Joel M. Harris and George A. O’Doherty*
Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
Received 12 July 2002; accepted 31 July 2002
Abstract—A flexible enantioselective route to highly functionalized a,b-unsaturated d-lactones, has allowed for the synthesis of
phomopsolide C. This approach derives its asymmetry from (S)-lactic acid and by applying the Sharpless catalytic asymmetric
dihydroxylation to vinylfuran. The resulting diols are produced in high enantioexcess and can be stereoselectively transformed into
a,b-unsaturated-d-lactones via a short highly diastereoselective oxidation and reduction sequence. A Wittig olefination reaction
was used to introduce the side chain in either cis or trans form that was further elaborated into phomopsolide C. © 2002
Published by Elsevier Science Ltd.
1. Introduction
Because American elm trees thrive on a wide range of
soils and can endure root disturbance, drought and
extreme cold, they became the most widely-planted
street tree in North America over the past century.1
Unfortunately,
a completely healthy 100-year-old
American elm can be killed in as little as two weeks if
attacked by Dutch elm disease.2 Since the arrival of this
pandemic to North America, over 40 million elm trees
in the United States have been killed.3 It was not
uncommon for a city to lose 90% of its elms in as little
as ten years.4 For instance, Des Moines, Iowa, lost a
quarter of a million trees in 6 years.4 The fungus
responsible for Dutch elm disease would be quite
innocuous if it were not for its association with the elm
bark beetle (Scolytid beetle). Therefore, protecting the
trees from the elm bark beetle should prove to be an
effective strategy for fighting this suburban pandemic.
Figure 1.
Inspired by the potent biological activity, in addition to
the synthetic challenges the structure offers, we set out
to synthesize this class of substituted pyranone using
our furan diol chemistry.7 To date only one phomop-
solide has succumbed to total synthesis, that being
phomopsolide B by Noshita8 who synthesized it from
glucose in 24 steps. While Noshita’s route is significant
in that it established the relative and absolute stereo-
chemistry of phomopsolide B, because of its length and
poor stereocontrol, we deemed the approach to be too
inefficient to provide sufficient quantities of material for
further study. Thus, we desired a more expedient route
to the phomopsolides, which has better relative stereo-
control in addition to being amenable to the synthesis
of the many possible phomopsolides. Herein we report
our successful endeavors toward the first synthesis of
the densely functionalized pyranone natural product
phomopsolide C (1c), in enatiomerically pure form
(Fig. 1).
In search of natural compounds that have an effective
antiboring/antifeeding activity, Grove,5 and later
Stierle,6 found a series of related 6-substituted 5,6-dihy-
dro-5-hydroxypyran-2-ones, the phomopsolides, with
the desired deterrent activity for Scolytid beetles. In
1985, Grove isolated phomopsolide A and B from the
fungus Phomopsis oblonga, which co-habitate with the
elm tree. In 1997, Stierle re-isolated phomopsolide A
and B in addition to three new phomopsolides (C–E)
from fungi lying in the bark of the Pacific yew (Taxus
brevifolia) and found them to have potent antimicrobial
activity against S. aureus.
Previously, we have had success at enantioselectively
synthesizing various biologically important pyranones
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01866-X

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J. M. Harris, G. A. O’Doherty / Tetrahedron Letters 43 (2002) 8195–8199
mixture of alcohol 5a and phosphorane 8a were treated
with excess Dess–Martin’s reagent (60% yield). Similar
results were obtained with the t-butyl phosphorane 8b
(75% yield) which exclusively gave the trans isomer 9b.
As expected, the more stable trans double bond isomer
9a was easily obtained by a photochemical isomeriza-
tion (I2/hn, >95%). As with the Dess–Martin oxidation
of 5, the in situ oxidation/Wittig reaction of 5 was only
compatible with C-4 ether substitution. Hence, expo-
sure of benzoate 5b and carbonate 5c to the same
reaction sequence provided good yields of the alkene
9c, which presumably occurs via a base catalyzed elimi-
nation of the desired product.
Scheme 1.
Previously, we have prepared in either enantiomerically
pure form the four pyranones 5a through 5d prepared
from furfural in six steps and good overall yields.10 Key
to this transformation is the efficient production of
pyranone 10 from furyl alcohol 3 (Scheme 3). Treat-
ment of furyl alcohol 3 with NBS13 in aqueous THF
(Achmatowicz reaction),14 then Jones reagent gave a
ketolactone intermediate, which was taken on without
purification to a Luche reduction15 with NaBH4 and
CeCl3 in MeOH, to give d-lactone 1016 in 70% yield
from 3 and >92% ee.17 The C-4 hydroxyl group of 10
was readily protected as either a TBS ether (85%),
benzoyl ester (96%), PMB ether (85%), or ethoxycar-
bonate (92%). In each case, the primary TBS groups
were selectively deprotected with 5% HF in CH3CN to
give primary alcohols 5a through 5d (91, 96, 61, 96%
yield, respectively). Unfortunately, due to an ensuing
elimination reaction only the C-4 TBS and PMB ethers
could be carried forward.
from dienoates9 and furan alcohols.7,10 The furyl alco-
hols were enantioselectively prepared from the Sharp-
less asymmetric dihydroxylation of vinylfuran.11 At the
outset, we targeted a selective synthesis of the trans
phomopsolide isomers 1b and 1c from enone 2a
(Scheme 1), as we felt that trans isomer 2a could
provide phomopsolide C.12 Incorporation of chemo-
selective and stereoselective enone reductions should
produce the other phomopsolides (A, B, D and E) from
2a or its cis-double bond isomer 2b. We opted for a
degree of convergence by deriving the C-9 stereochem-
istry from lactic acid where as the C-4/C-5 stereochem-
istry would come from our furan to pyranone oxidation
strategy.7,10
Our approach to this class of natural products was
inspired by our recent synthesis of several altholac-
tones.7 During those studies we found the use of an in
situ Dess–Martin oxidation/Wittig olefination reaction
allowed for good yields of olefination products via an
unstable aldehyde 6 (Scheme 2). Thus, we planned to
use this approach for the production of the trans dou-
ble bond isomers of enone 2. Initially we planned to
install the C-4 tigilate group before the oxidation/Wit-
tig sequence, however we found that the corresponding
aldehydes generated from 5b, 5c, and 5d underwent
rapid elimination reactions to pyranone 7. This base
sensitivity proved to be problematic throughout the
synthesis (vide infra).
Following a protocol developed by Thomas18 the
desired ylide 4 was prepared from (S)-ethyl lactate 11 in
4 steps and 40% overall yield (Scheme 3). The hydroxyl
group of (S)-ethyl lactate 11 was protected with TBDP-
SCl to give 12a followed by ester hydrolysis to form the
acid 12b (75%). The carboxylic acid 12b was converted
into the thioester 13 with 2-thiopyridine and DCC
(70%), which in turn reacted with the Wittig reagent to
give ylide 4 in good yield (70%). Ylide 4 was remark-
ably stable to silica gel chromatography, but not to
long term storage (Scheme 4).
We initially investigated the Wittig olefination reaction
with more readily available reagents 8a and 8b. In
practice, we found that a mixture of double bond
isomers (cis and trans-9a) were produced when a 1:4
Treatment of aldehyde 6 generated from Dess–Martin
oxidation of lactone 5a with the ylide 4 in CH2Cl2 at rt
gave a mixture of trans- and cis-alkenes 2a and 2b in
Scheme 3. (a) i. NBS, NaHCO3, NaOAc, THF, H2O, 0°C; ii.
Jones reagent, acetone, 0°C, then NaBH4/CeCl3, MeOH/
CH2Cl2, −78°C; (b) TBSOTf, 2,6-lutidine, CH2Cl2; (c) BzCl,
Pyr; (d) PNBO(NH)CCl3, BF3·OEt2, CH2Cl2; (e) ClCO2Et,
Pyr; (f) 5% HF(aq.)/AN.
Scheme 2.

J. M. Harris, G. A. O’Doherty / Tetrahedron Letters 43 (2002) 8195–8199
8197
Scheme 4.
Scheme 6.
60% yield as a 3:1 mixture in favor of the trans alkene
(Scheme 5).19 The double bond isomers were easily
separated by silica gel chromatography. The minor
isomer d-lactone 2b was isomerized to the trans isomer
2a in a >95% yield using AIBN and PhSH in refluxing
benzene. A much higher yielding olefination procedure
for the trans isomer 2a resulted from an initial florisil
purification of aldehyde 6 before exposure to Wittig
reagent 4 in refluxing benzene, yielding 2a and 2b as a
9:1 ratio and 80% yield.
In conclusion, this highly enantio- and diastereocon-
trolled route to phomopsolide C (1c) was completed in
11 steps (longest linear sequence) and 15% overall yield.
Unfortunately, due to double bond isomerization we
were unable to prepare phomopsolide A. Future work
in this area will involve efforts to solve this double
bond isomerization problem and broadening this route
to include the stereoselective preparation of phomop-
solide B, D and E.
The two silylethers of 2a and 2b were easily differenti-
ated by a selective deprotection with BF3·OEt2 in
CH3CN at 0°C (Scheme 6). The trans-allylic alcohol
14a was isolated in a 91% yield were as the cis-allylic
alcohol 14b was isolated in a 78% yield. In the trans
series, the C-4 tigilate of the phomopsolides was intro-
duced by a DCC coupling of 14a and tiglic acid,
providing 15 in a good yield (75%). Unfortunately in
the cis series, when the cis-enone 14b was subjected to
the same DCC coupling procedure only the trans
acylated product 15 was detected.
The enone 15 was too base sensitive for TBAF medi-
ated deprotection of the TBDPS group (Scheme 7). For
example, exposure of 15 to 1 equiv. of TBAF in CH2Cl2
gave exclusively the elimination product 16. Modifying
the basicity of TBAF with acetic acid led to no reac-
tion. Finally resorting to excess Et3N·3HF in CH2Cl2 at
room temperature for 1-day lead to good yields of
phomopsolide C, the trans-enone natural product 1c.
While phomopsolide C was unstable to silica gel it
could be purified by chromatography on florisil,
providing 73% yield of a white solid with spectral data
that matched that of the isolated natural product (Rf,
Scheme 7.
2. Experimental section
2.1. (5S)-5-[tert-Butyldimethylsilanyloxy)-(6S)-6-[(4S)-
4-(tert-butyldiphenylsilanyloxy)-3-oxo-pent-1(E)-enyl]-
5,6-dihydropyran-2-one (2a)
1
optical rotation, IR, H NMR, and 13C NMR).
The crude aldehyde 6 (237 mg, 0.924 mmol) was dis-
solved in 10 mL of benzene and phosphorane 4 (813
mg, 1.4 mmol) was added to the solution. The reaction
was heated to reflux and stirred for 4 h. The reaction
was concentrated and the crude product was purified
silica gel chromatography eluting with (30% EtOAc/
hexanes) to give a 9:1 ratio of compounds 2a (378 mg,
0.669 mmol) and 2b (42 mg, 0.074 mmol) in an 80%
overall yield. Major trans isomer 2a: Rf (30% EtOAc/
hexanes)=0.15; [h]D21=+40.1 (c 2.82, CH2Cl2); IR (thin
film, cm−1) 3071, 2956, 2931, 2893, 2858, 1736, 1702,
1638, 1472, 1428, 1363, 1248, 1112, 1058; 1H NMR
(500 MHz, CDCl3) l 7.66 (dd, J=7.5, 1.5 Hz, 2H), 7.62
Scheme 5. (a) Dess–Martin periodinane, CH2Cl2, NaHCO3,
rt; (b) PhSH, 5 mol% AIBN, PhH, reflux.

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J. M. Harris, G. A. O’Doherty / Tetrahedron Letters 43 (2002) 8195–8199
(dd, J=8.0, 1.5 Hz, 2H), 7.45-7.33 (m, 6H), 7.04 (dd,
J=15.5, 2.0, Hz, 1H), 6.89 (dd, J=15.5, 4.0 Hz, 1H),
6.80 (dd, J=10.0, 5.0 Hz, 1H), 6.06 (d, J=10.0 Hz,
1H), 5.00 (ddd, J=4.0, 4.0, 2.0 Hz, 1H), 4.42 (dd,
J=4.5, 4.5 Hz, 1H), 4.31 (q, J=7.0 Hz, 1H), 1.23 (d,
J=6.5 Hz, 3H), 1.11 (s, 9H), 0.84 (s, 9H), 0.08 (s, 3H),
0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) l 199.7,
162.0, 145.0, 139.3, 135.7, 135.6 (2C), 133.4, 132.8,
129.8, 127.62, 127.58, 126.0, 121.8, 79.4, 74.9, 63.4,
26.8, 25.4, 20.5, 19.1, 17.9, −4.6, −5.0; FAB HRMS
Calcd for [C32H44O5Si2+Na]+: 587.2625, Found:
587.2636.
HRMS Calcd for [C31H36O6Si+Na]+: 555.2179, Found:
555.2184.
2.4. Phomopsolide C (1c)
Ester 15 (3.0 mg, 5.6 mmol), 0.15 mL of THF, and
triethylamine trihydrofluoride (10 mL, 5.6 mmol) were
added to a plastic vial and stirred at room temperature
for 24 h. The reaction was quenched with saturated
NaHCO3, the aqueous layer was extracted with ether,
and the organic layer was dried (MgSO4). The crude
product was purified by silica gel flash chromatography
eluting with Et2O to yield 1.2 mg (4.1 mmol, 73%) of
phomopsolide C 1c: Rf (100% Et2O)=0.15; [h]2D1=+175
(c 0.05, CH2Cl2); IR (thin film, cm−1) 3500, 2975, 2926,
1730, 1710, 1643, 1429, 1245, 1112; 1H NMR (500
MHz, CDCl3) l 7.05 (dd, J=9.5, 5.5, Hz, 1H), 6.93
(dd, J=16.0, 4.0 Hz, 1H), 6.83 (m, 1H), 6.72 (dd,
J=15.5, 2.0 Hz, 1H), 6.24 (d, J=10.0 Hz, 1H), 5.50
(dd, J=5.5, 3.5 Hz, 1H), 5.31 (ddd, J=3.5, 3.5, 2.0 Hz,
1H), 4.30 (m, 1H), 1.77 (m, 6H), 1.39 (d, J=7.0 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 201.0, 166.9, 161.9,
141.3, 140.6, 139.4, 127.6, 126.3, 125.0, 77.6, 72.4, 63.0,
20.2, 15.0. 12.3.
2.2. (6S)-6-[(4S)-4-(tert-Butyldiphenylsilanyloxy)-3-oxo-
pent-1(E)-enyl]-(5S)-5-hydroxy-5,6-dihydro-pyran-2-one
(14a)
Compound 2a (66 mg, 0.117 mmol) was dissolved in 1
mL of CH3CN and BF3OEt2 (15 uL, 0.12 mmol) was
added to the solution at 0°C. The reaction was stirred
for 1 h. The reaction was quenched with saturated
aqueous NaHCO3, extracted (3×25 mL) with Et2O, and
dried (Na2SO4). The crude product was purified by
silica gel flash chromatography eluting with 100% Et2O
to yield 48 mg (0.106 mmol, 91%) of 15a: Rf (100%
Et2O)=0.15; [h]2D1=+28.3 (c 0.4, CH2Cl2); IR (thin film,
cm−1) 3442, 2957, 2928, 2857, 1731, 1714, 1634, 1470,
1463, 1428, 1384, 1247, 1111; 1H NMR (300 MHz,
C6D6) l 7.78–7.71 (m, 4H), 7.25–7.20 (m, 6H), 7.12 (dd,
J=15.9, 2.1, Hz, 1H), 6.80 (dd, J=15.6, 3.9 Hz, 1H),
5.90 (dd, J=9.9, 5.4 Hz, 1H), 5.62 (d, J=9.9 Hz, 1H),
4.43 (q, J=6.9 Hz, 1H), 4.11 (ddd, J=3.6, 3.3, 2.1 Hz,
1H), 3.20 (dd, J=5.4, 3.0 Hz, 1H), 1.23 (s, 9H), 1.18 (d,
J=6.6, 3H); 13C NMR (125 MHz, C6D6) l 199.5,
161.8, 143.8, 139.5, 136.7, 136.5, 130.6, 128.5, 127.0,
122.9, 79.4, 75.8, 62.5, 27.6, 20.9, 19.9; FAB HRMS
Calcd for [C26H30O5Si+H]+: 473.1760, Found: 473.1759.
Acknowledgements
We thank the Arnold and Mabel Beckman Foundation
for their generous support of our program.
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Alcohol 14a (45 mg, 0.10 mmol), 1.5 mL of CH2Cl2,
DCC (41 mg, 0.2 mmol), DMAP catalytic amount, and
tiglic acid (20 mg, 0.2 mmol) were added to a round
bottom flask and stirred at room temperature for 6 h.
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1
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77.6, 74.9, 63.2, 26.9, 20.6, 19.2, 14.5, 11.9; FAB

J. M. Harris, G. A. O’Doherty / Tetrahedron Letters 43 (2002) 8195–8199
8199
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