Total syntheses of (+)-pestaphthalide A and (-)-pestaphthalide B

Article abstract of DOI:10.1055/s-0030-1260166

Total syntheses of (+)-pestaphthalide A and (-)-pestaphthalide B were achieved. Key steps are an iridium-mediated meta-selective arylborylation, a Suzuki-coupling/Jacobsen-epoxidation sequence, a stereodivergent epoxide opening and an anionic cyclic carbonate/-lactone rearrangement. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260166

PAPER
2929
Total Syntheses of (+)-Pestaphthalide A and (–)-Pestaphthalide B
Total
S
ynt
o
heses of (+)-
n
Pestaphthali
a
de A and (–
s
)-Pestaphthalide
S
B
chwaben, Jens Cordes, Klaus Harms, Ulrich Koert*
Fachbereich Chemie, Philipps Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax +49(6421)2825677; E-mail: koert@chemie.uni-marburg.de
Received 28 June 2011; revised 12 July 2011
8 and the 1,1-disubstituted alkene 9 which were not sepa-
rable by chromatography.
Abstract: Total syntheses of (+)-pestaphthalide A and (–)-pestaph-
thalide B were achieved. Key steps are an iridium-mediated meta-
selective arylborylation, a Suzuki-coupling/Jacobsen-epoxidation
sequence, a stereodivergent epoxide opening and an anionic cyclic
carbonate/g-lactone rearrangement.
HO
HO
O
O
7a
6
1
O
O
Key words: arylborylation, cyclic carbonate/g-lactone rearrange-
ment, natural products, total synthesis, pestaphthalide A and B
3
3a
HO
HO
4
8
9
HO
HO
Pestaphthalide A and B were isolated from the endophytic
fungus Pestalotiopsis foedan during a screening for anti-
fungal activity against Candida albicans (ATCC 10231),
Geotrichum candidum (AS2.498) and Aspergillus fumig-
atus (ATCC 10894).1 The structures of both natural prod-
ucts were determined on the basis of HRESIMS analysis
and NMR data while the absolute configuration was de-
duced by a comparison of CD data. The pestaphthalide
skeleton consists of a 3H-isobenzofuran-1-one with a hy-
droxyethyl side chain at C3 (Scheme 1). Pestaphthalide A
and B are epimers differing in the absolute configuration
at the C3 stereocentre. Herein, we report our results on an
efficient synthesis of both pestaphthalides.
pestaphthalide A
HO
pestaphthalide B
MeO
O
Li
O
O
O
HO
MeO
O
HO
2
1
MeO
MeO
Our synthetic plan for the pestaphthalide structure 1 relied
on the introduction of the g-lactone via an intramolecular
attack of an aryllithium function 2 at the carbonyl group
of a cyclic carbonate at the late stage of the synthesis
(Scheme 1). Compound 2 should be accessible by asym-
metric epoxidation or dihydroxylation of an alkene 3,
which could be prepared by a Suzuki cross-coupling from
the arylboronate 4. A meta-selective arylborylation
should be the reaction of choice for the preparation of the
arylboronate 4. Miyaura, Hartwig and co-workers intro-
duced the catalyst system [Ir(cod)OMe]2, 4,4¢-di-tert-
butyl-2,2¢-bipyridine (dtbpy), bis(pinacolato)diboron
[(BPin)2] to achieve a meta-selective arylborylation.2,3
The synthetic potential of the CH borylation of arenes was
expanded by Maleczka, Smith and Marder.4–6 Applica-
tions of this reaction in the total synthesis of natural
products7,8 and in bioorganic chemistry9 have been report-
ed. The reaction of the resorcine dimethyl ether 5 under
Miyaura’s borylation conditions gave the arylboronate 6
in very good yield (Scheme 2). Subsequent Suzuki cross-
coupling worked well with (Z)-1-bromoprop-1-ene to de-
liver the Z-alkene 7. In contrast, the reaction with (E)-1-
bromoprop-1-ene led to a mixture of the desired E-alkene
MeO
MeO
B(OR)2
3
4
Scheme 1 Structures and retrosynthetic analysis of the pestaphtha-
lides
(BPin)2
MeO
MeO
[Ir(cod)OMe]2
dtbpy
octane, 125 °C
O
93%
MeO
MeO
B
O
5
6
Pd(PPh3)4
K2CO3
EtOH, H2O
toluene, 45 °C
MeO
Br
+
6
MeO
91%
7
Pd(PPh3)4
K2CO3
EtOH, H2O
toluene, 45 °C
MeO
MeO
Br
+
6
+
78%
MeO
MeO
SYNTHESIS 2011, No. 18, pp 2929–2934
Advanced online publication: 09.08.2011
x
x.
x
x
.
2
0
1
1
8
2:1
9
DOI: 10.1055/s-0030-1260166; Art ID: T64711SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Arylborylation and Suzuki cross-coupling

2930
J. Schwaben et al.
PAPER
Having synthetic access to the pure Z-alkene 7 only, we bromine–lithium exchange using tert-butyllithium at
disfavoured dihydroxylation for the functionalisation of –78 °C gave the aryllithium intermediate 16, which rear-
the double bond, which is known to give low enantiose- ranged upon warming to 20 °C into the desired 3H-
lectivities under Sharpless conditions for these type of isobenzofuran-1-one 17. No formation of the six-mem-
substrates.10 In contrast, Z-alkenes such as 7 are ideal can- bered lactone was observed. Boron tribromide cleavage of
didates for the asymmetric Katsuki–Jacobsen epoxida- the two methyl ethers in 17 provided the target compound
tion.11,12 With the (R,R)-salen–Mn(III) catalyst and m- pestaphthalide A. The analytical data of synthetic pe-
chloroperoxybenzoic acid/N-methylmorpholine N-oxide staphthalide A (optical rotation, NMR) matched those re-
as oxidant, the epoxide 10 was obtained with 93% ee ported for the natural product.1
(Scheme 3). The acid-catalysed opening of the epoxide 10
NBS
MeCN
0 °C
MeO
in the benzylic position by aqueous perchloric acid led to
a 4:1-mixture of diols 11 and 12. Subsequent treatment of
the mixture of diols with triphosgene resulted in the cyclic
carbonates 13 and 14, which were separated by chroma-
tography. The epoxide opening of compound 10 with
aqueous 10-camphorsulfonic acid led to a 1:3 mixture of
diols 11 and 12, which after conversion into the cyclic car-
bonates resulted in compound 14 as the major product.
The stereodivergent opening of the epoxide gave access to
both precursors for pestaphthalide A and B.
Br
13
O
O
85%
MeO
O
15
t-BuLi
THF
–78 °C to r.t.
MeO
Li
O
50%
The final sequence of the syntheses consists of an anionic
rearrangement of the cyclic carbonate into a hydroxyeth-
yl-substituted g-lactone. For pestaphthalide A, the bromi-
nation of 13 gave the aryl bromide 15 (Scheme 4). A
MeO
O
O
16
MCPBA, NMO
(R,R)-salen-Mn(III) catalyst
CH2Cl2
OMe
BBr3
CH2Cl2
r.t.
MeO
HO
O
O
–78 °C to r.t.
7
O
O
75%
95%
93% ee
MeO
MeO
HO
O
HO
HO
pestaphthalide A
10
17
aq HClO4
acetone
–20 °C
Scheme 4 Synthesis of pestaphthalide A
60%
The cyclic carbonate 14 was the starting point for the final
sequence to pestaphthalide B (Scheme 5). N-Bromosuc-
cinimide bromination yielded the aryl bromide 18. Treat-
ment of 18 with tert-butyllithium at –78 °C resulted in a
bromine–lithium exchange. Upon warming to room tem-
perature the aryllithium group attacked the cyclic carbon-
ate intramolecularly and delivered the isobenzofuranone
19. The assignment of the relative configuration in com-
pound 19 was possible via an X-ray structure of com-
pound rac-19 (Scheme 5), which was obtained in the
racemic series (epoxidation of the Z-alkene 7 with MCPBA
only). The unambiguous structural assignment of 19 in the
pestaphthalide B series also allows the clear assignment of
the epimeric compound 17 in the pestaphthalide A series.
Deprotection of the two methyl ethers in 19 gave the tar-
get compound pestaphthalide B, which was identical with
respect to its spectroscopic and analytical data with the
natural product.1
OMe
OMe
+
OH
OH
OH
OH
MeO
MeO
12
11
triphosgene, py
CH2Cl2, –78 °C to r.t.
18%
77%
OMe
OMe
O
O
O
O
O
MeO
MeO
O
In conclusion, the first syntheses of pestaphthalide A and
B have been accomplished. Key steps were a meta-selec-
tive arylborylation, an asymmetric epoxidation/stereodi-
vergent epoxide opening and an anionic carbonate/
isobenzofuranone rearrangement. This work confirms the
13
14
Scheme 3 Asymmetric epoxidation and stereodivergent synthesis
of the carbonates
Synthesis 2011, No. 18, 2929–2934 © Thieme Stuttgart · New York

PAPER
Total Syntheses of (+)-Pestaphthalide A and (–)-Pestaphthalide B
2931
tra were recorded on a Finnigan MAT TSQ 700 or MAT 95S mass
spectrometer. Specific rotations were recorded on a Perkin-Elmer
241 polarimeter. X-ray crystallographic measurements were per-
formed at 100 K on a STOE IPDS 2T diffractometer using MoKa
radiation.
2-(3,5-Dimethoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (6)
[Ir(cod)OMe]2 (261 mg, 0.39 mmol), 4,4¢-di-tert-butyl-2,2¢-bipyri-
dine (dtbpy; 212 mg, 0.79 mmol) and bis(pinacolato)diboron
[(BPin)2; 13.3 g, 52.6 mmol] were dissolved in n-octane (526 mL)
and the resulting solution was stirred at r.t. for 15 min. 2,6-
Dimethoxytoluene (5; 8.00 g, 52.6 mmol) was added to the reaction
vessel and the reaction mixture was heated to reflux for 3 d. After
complete consumption of the starting material, the reaction mixture
was allowed to cool to r.t. and transferred into a separatory funnel
with MTBE (200 mL) and brine (100 mL). The organic phase was
removed and the aqueous phase was extracted with MTBE
(3 × 200 mL). The combined organic layers were dried (MgSO4)
and the solvents were removed under reduced pressure. The remain-
ing crude product was purified by flash column chromatography on
silica gel (n-pentane–Et2O, 10:1) to give the boronate 6.
Yield: 13.6 g (93%); colourless, crystalline solid; mp 108–109 °C.
Rf = 0.31 (n-hexane–MTBE, 10:1).
IR (film): 2983, 2841, 1574, 1461, 1443, 1400, 1357, 1325, 1294,
1263, 1240, 1212, 1182, 1165, 1130, 1003, 965, 914, 847, 830, 711,
691, 517, 402 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35 (s, 12 H, 4 × MeBPin), 2.12 (s,
3 H, 4Ar-Me), 3.87 (s, 6 H, 2 × OMe), 6.97 (s, 2 H, 2-H and 6-H).
13C NMR (125 MHz, CDCl3): d = 8.6 (4Ar-Me), 24.9 (4 C,
4 × MeBPin), 55.9 (2 C, 2 × OMe), 83.8 (2 C, CBPin4 and 5), 109.5
(2 C, C2 and 6), 118.4 (CAr4), 126.8 (C1), 158.1 (2 C, CAr3 and 5).
11B NMR (160 MHz, CDCl3): d = 31.1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H23BO4Na: 301.1584;
Scheme 5 Synthesis of pestaphthalide B and X-ray structure of rac-
1913
found: 301.1584.
structural assignment of the natural products and opens
synthetic access to derivatives with potential antifungal/
antibiotic applications.
1,3-Dimethoxy-2-methyl-5-[(Z)-prop-1-enyl]benzene (7)
Boronate 6 (1.00 g, 3.60 mmol), K2CO3 (12.7 g, 92.2 mmol) and
Pd(PPh3)4 (208 mg, 0.18 mmol) were dissolved in a mixture of tol-
uene (69.0 mL), EtOH (23.0 mL) and H2O (46.0 mL), and the mix-
ture was degassed twice by freezing in liquid N2 under vacuum. (Z)-
1-Bromoprop-1-ene (0.93 mL, 10.79 mmol) was added and the bi-
phasic reaction mixture was heated to 45 °C for 16 h under vigorous
stirring. Then, the reaction mixture was allowed to cool to r.t. and
poured into a mixture of H2O (100 mL) and MTBE (150 mL). The
organic phase was removed and the aqueous phase was extracted
with MTBE (3 × 100 mL). The combined organic layers were
washed with brine (50 mL) and dried (MgSO4). The solvents were
removed under reduced pressure and the remaining crude product
was purified by flash column chromatography on silica gel (n-pen-
tane–Et2O, 20:1) to give the olefin 7.
All nonaqueous reactions were carried out using flame-dried glass-
ware under argon atmosphere. All solvents were distilled by rotary
evaporation. Solvents for nonaqueous reactions were dried as fol-
lows prior to use: THF was dried with KOH and subsequently dis-
tilled from sodium/benzophenone, and Et2O similarly from a
potassium/sodium alloy (K–Na, 4:1). CH2Cl2 was distilled from
CaH2. n-Octane was dried by refluxing with sodium (5 g/L) and
subsequent distillation. All commercially available reagents and re-
actants were used without purification unless otherwise noted. Re-
actions were monitored by thin-layer chromatography (TLC) using
Merck silica gel 60 F245 plates and visualised by fluorescence
quenching under UV light. In addition, TLC plates were stained us-
ing a KMnO4 stain. Chromatographic purification of products was
performed on Merck silica gel 60 (230–400 mesh) using a forced
flow of eluents. Concentration under reduced pressure was per-
formed by rotary evaporation at 40 °C and the appropriate pressure.
Yields refer to purified and spectroscopically pure products unless
otherwise noted. IR spectra were recorded on a Bruker Alpha-P FT-
IR spectrometer. The absorption bands are given in wave numbers
(cm–1). NMR spectra were recorded on a Bruker DPX250,
AV300B, DRX400, or DRX500 spectrometer at room temperature.
Chemical shifts are reported in ppm with the solvent resonance as
internal standard. Data are reported as follows: s = singlet,
d = doublet, t = triplet, q = quartet, pq = pseudoquartet. Mass spec-
Yield: 0.63 g (91%); colourless oil.
Rf = 0.53 (n-hexane–MTBE, 9:1).
IR (film): 2998, 2834, 1601, 1580, 1451, 1412, 1400, 1235, 1182,
1133, 1047, 964, 893, 839, 713, 602, 586 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.96 (dd, J = 7.2, 1.7 Hz, 3 H, 3-
HPr), 2.13 (s, 3 H, 2Ar-Me), 3.85 (s, 6 H, 2 × OMe), 5.79 (dq,
J = 11.6, 7.2 Hz, 1 H, 2-HPr), 6.44 (dd, J = 11.6, 1.4 Hz, 1 H, 1-HPr),
6.52 (s, 2 H, 4-H and 6-H).
13C NMR (75.5 MHz, CDCl3): d = 8.1 (2Ar-Me), 14.7 (CPr3), 55.7
(2 C, 2 × OMe), 104.4 (2 C, C4 and 6), 113.1 (CAr), 126.2 (CPr2),
130.3 (CPr1), 135.8 (CAr), 158.0 (2 C, CAr1 and 3).
Synthesis 2011, No. 18, 2929–2934 © Thieme Stuttgart · New York

2932
J. Schwaben et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C12H17O2: 193.1223; found:
193.1224.
1H NMR (300 MHz, CDCl3): d = 1.12 (d, J = 5.4 Hz, 3 H, 3-HPr),
2.08 (s, 3 H, 4-Me), 3.32 (dq, J = 4.2, 5.4 Hz, 1 H, 2-HPr), 3.83 (s,
6 H, 2 × OMe), 4.04 (d, J = 4.2 Hz, 1 H, 1-HPr), 6.48 (s, 2 H, 2-HAr
and 6-H).
13C NMR (62.9 MHz, CDCl3): d = 8.1 (4-Me), 12.6 (CPr3), 55.2
(CPr2), 55.7 (2 C, 2 × OMe), 57.9 (CPr1), 101.8 (2 C, CAr2 and C6),
113.5 (C4), 133.9 (CAr1), 158.0 (2 C, CAr3 and C5).
1,3-Dimethoxy-2-methyl-5-[(E)-prop-1-enyl]benzene (8) and
1,3-Dimethoxy-2-methyl-5-(prop-1-en-2-yl)benzene (9)
In an argon atmosphere boronate 6 (200 mg, 0.72 mmol) was dis-
solved in a mixture of toluene (14.0 mL), EtOH (4.5 mL) and H2O
(9.0 mL). K2CO3 (2.49 g, 18.0 mmol) was added and the mixture
was degassed twice by freezing in liquid N2 under vacuum.
Pd(PPh3)4 (42.0 mg, 0.04 mmol) and (E)-1-bromoprop-1-ene
(0.22 mL, 2.5 mmol) were added and the reaction mixture was heat-
ed to 45 °C for 16 h under vigorous stirring. The reaction mixture
was then cooled to r.t. and poured into a mixture of H2O (12 mL)
and MTBE (20 mL). The aqueous phase was removed and extracted
with MTBE (3 × 20 mL). The combined organic layers were dried
(MgSO4) and the solvents were removed under reduced pressure.
The remaining crude product was purified by chromatography on
silica (n-pentane–Et2O, 19:1) to give the isomeric olefins 8 and 9 as
an inseparable 2:1 mixture (according to 1H NMR analysis).
HRMS (ESI): m/z [M + H]+ calcd for C12H17O3: 209.1172; found:
209.1176.
(1S,2S)-1-(3,5-Dimethoxy-4-methylphenyl)propane-1,2-diol
(11) and (1R,2S)-1-(3,5-Dimethoxy-4-methylphenyl)propane-
1,2-diol (12)
Oxirane 10 (50.0 mg, 0.24 mmol) was dissolved in acetone (5 mL)
and H2O (0.10 mL) was added. The resulting solution was cooled to
–20 °C and 5% aq HClO4 (0.10 mL, 0.05 mmol) was added. After
24 h, the reaction mixture was diluted with NaH2PO4/Na2HPO4
buffer (pH 6.5, 10 mL), acetone was removed under reduced pres-
sure and the aqueous phase was extracted with EtOAc (4 × 10 mL).
The combined organic layers were washed with brine (10 mL),
dried (MgSO4) and concentrated under reduced pressure. The crude
product was purified by flash column chromatography on silica gel
(EtOAc–n-pentane, 4:1) to yield diastereomeric diols 11 and 12 as
an inseparable 4:1 mixture (according to 1H NMR analysis).
Yield: 109 mg (78%); colourless oil.
Rf = 0.50 (n-hexane–MTBE, 9:1).
IR (film): 2933, 2836, 1691, 1584, 1464, 1408, 1370, 1314, 1279,
1248, 1181, 1124, 1024, 969, 915, 840, 764, 708, 588, 533, 496, 444
cm–1.
Yield: 32.5 mg (60%); white solid.
1H NMR (300 MHz, CDCl3): d (olefin 8) = 1.89 (dd, J = 6.4,
1.5 Hz, 3 H, 3-HPr), 2.07 (s, 3 H, 2Ar-Me), 3.83 (s, 6 H, 2 × OMe),
6.21 (dq, J = 15.6, 6.5 Hz, 1 H, 2-HPr), 6.38 (dq, J = 15.7, 1.5 Hz,
1 H, 1-HPr), 6.52 (s, 2 H, 4-H and 6-H).
1H NMR (300 MHz, CDCl3): d (olefin 9) = 2.09 (s, 3 H, 2Ar-Me),
2.16 (dd, J = 1.3, 0.8 Hz, 3 H, 3-HPr), 3.85 (s, 6 H, 2 × OMe), 5.06
(pq, J = 1.5 Hz, 1 H, 1-HPr,a), 5.33 (dq, J = 1.1, 0.6 Hz, 1 H, 1-HPr,b),
6.63 (s, 2 H, 4-H and 6-H).
13C NMR (125 MHz, CDCl3): d (olefin 8) = 8.3 (2Ar-Me), 18.5
(CPr3), 55.8 (2 C, 2 × OMe), 101.6 (2 C, C4 and 6), 113.6 (CAr2),
125.1 (CPr2), 131.6 (CPr1), 136.5 (C5), 158.5 (2 C, CAr1 and 3).
13C NMR (125 MHz, CDCl3): d (olefin 9) = 8.3 (2Ar-Me), 22.1
(CPr3), 55.8 (2 C, 2 × OMe), 101.5 (2 C, C4 and 6), 112.0 (CPr1),
113.5 (CAr2), 140.1 (C5), 143.9 (CPr2), 158.0 (2 C, CAr1 and 3).
Rf = 0.31 (EtOAc–n-hexane, 4:1).
IR (film): 3362, 2989, 2931, 2839, 1588, 1461, 1413, 1312, 1236,
1076, 1049, 1020, 975, 920, 829, 646, 547 cm–1.
1H NMR (250 MHz, CD3OD): d (diol 11) = 0.98 (d, J = 6.4 Hz,
3 H, 3-HPr), 2.01 (s, 3 H, 4-Me), 3.81 (s, 6 H, 2 × OMe), 3.81 (m,
1 H, 2-HPr), 4.30 (d, J = 6.9 Hz, 1 H, 1-HPr), 6.59 (s, 2 H, 2-HAr and
6-H).
1H NMR (250 MHz, CD3OD): d (diol 12) = 1.13 (d, J = 6.4 Hz,
3 H, 3-HPr), 2.16 (s, 3 H, 4-Me), 3.81 (s, 6 H, 2 × OMe), 3.81 (m,
1 H, 2-HPr), 4.46 (d, J = 5.4 Hz, 1 H, 1-HPr), 6.61 (s, 2 H, 2-HAr and
6-H).
13C NMR (62.9 MHz, CD3OD): d (diol 11) = 8.1 (4-Me), 18.8
(CPr3), 55.8 (2 C, 2 × OMe), 72.2 (CPr2), 79.8 (CPr1), 102.0 (2 C,
CAr2 and C6), 114.3 (C4), 139.5 (CAr1), 158.3 (2 C, CAr3 and C5).
HRMS (ESI): m/z [M + H]+ calcd for C12H17O2: 193.1223; found:
193.1227.
13C NMR (62.9 MHz, CD3OD): d (diol 12) = 8.1 (4-Me), 17.7
(CPr3), 55.8 (2 C, 2 × OMe), 71.4 (CPr2), 78.2 (CPr1), 101.8 (2 C,
CAr2 and C6), 114.0 (C4), 139.0 (CAr1), 158.3 (2 C, CAr3 and C5).
HRMS (ESI): m/z [M + Na]+ calcd for C12H18O4Na: 249.1097;
found: 249.1098.
(2R,3S)-2-(3,5-Dimethoxy-4-methylphenyl)-3-methyloxirane
(10)
Olefin 7 (100 mg, 0.52 mmol), (R,R)-(–)-N,N¢-bis(3,5-di-tert-butyl-
salicylidene)-1,2-cyclohexanediaminomanganese(III)
chloride
[(R,R)-salen–Mn(III) catalyst; 26.4 mg, 0.04 mmol] and 97% NMO
(132 mg, 1.13 mmol) were dissolved in CH2Cl2 (10 mL) and the so-
lution was cooled to –78 °C. Then, a soln of MCPBA (257 mg,
1.49 mmol) in a mixture of CH2Cl2 (5 mL) and EtOH (1 mL) was
added dropwise and the reaction mixture was allowed to warm to r.t.
and stirred for 24 h. CH2Cl2 (20 mL) was added and the mixture was
transferred into a separatory funnel. The organic phase was washed
with 1 M NaOH (3 ×) and dried (MgSO4), and the solvents were re-
moved under reduced pressure. The remaining crude product was
purified by flash column chromatography on silica gel (n-pentane–
Et2O, 19:1) to give the desired oxirane 10.
(4S,5S)-4-(3,5-Dimethoxy-4-methylphenyl)-5-methyl-1,3-diox-
olan-2-one (13) and (4R,5S)-4-(3,5-Dimethoxy-4-methylphe-
nyl)-5-methyl-1,3-dioxolan-2-one (14)
The diastereomeric mixture of diols 11 and 12 (658 mg, 2.91 mmol)
was dissolved in CH2Cl2 (50 mL) and pyridine (1.41 mL,
17.5 mmol) was added. The resulting solution was cooled to –78 °C
and a soln of triphosgene (432 mg, 1.45 mmol) in CH2Cl2 (5 mL)
was added dropwise. Once the addition was complete, the reaction
mixture was allowed to warm to r.t. and was then quenched with sat.
aq NH4Cl (50 mL). The aqueous phase was separated and extracted
with CH2Cl2 (3 × 20 mL). The organic extract was washed with 1 M
HCl (20 mL), sat. aq NaHCO3 (20 mL) and brine (20 mL), dried
(MgSO4) and concentrated under reduced pressure. The crude prod-
uct containing the two diastereomeric carbonates was purified and
separated by flash column chromatography (MTBE–n-pentane,
2:1).
Yield: 103 mg (95%); yellow oil; 93% ee [the enantioselectivity
was determined at the stage of the carbonate 13 (vide infra)].
Rf = 0.29 (n-hexane–MTBE, 9:1).
IR (film): 2996, 2959, 2936, 2869, 1692, 1587, 1453, 1407, 1356,
1233, 1133, 1059, 1021, 979, 935, 892, 846, 817, 685, 584, 390
cm–1.
IR (film): 3362, 2989, 2931, 2839, 1588, 1461, 1413, 1373, 1312,
1236, 1132, 1076, 1049, 1020, 975, 920, 829, 646, 547, 450 cm–1.
Synthesis 2011, No. 18, 2929–2934 © Thieme Stuttgart · New York

PAPER
Total Syntheses of (+)-Pestaphthalide A and (–)-Pestaphthalide B
2933
HRMS (ESI): m/z [M + Na]+ calcd for C13H16O5Na: 275.0891;
(S)-3-[(S)-1-Hydroxyethyl]-5,7-dimethoxy-6-methylisobenzofu-
found: 275.0892.
ran-1(3H)-one (17)
A soln of t-BuLi in n-pentane (1.6 M, 0.77 mL, 1.23 mmol) was
added slowly to a stirred soln of bromide 15 (325 mg, 0.98 mmol)
in THF (40.0 mL) at –78 °C, and the mixture was stirred for 3 h.
Then, the reaction mixture was allowed to warm to r.t. and sat. aq
NH4Cl (20 mL) was added. The mixture was stirred for 30 min, then
the THF was evaporated and the remaining aqueous mixture was
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (MgSO4). The solvent was removed under reduced pres-
sure and the crude product was purified by flash column chromatog-
raphy on silica gel (MTBE–n-pentane, 5:1) to yield the desired
isobenzofuranone 17.
Carbonate 13
Yield: 565 mg (77%); white solid; mp 131 °C.
[a]D20 +4.5 (c 1.0, CHCl3).
Rf = 0.50 (MTBE–n-hexane, 2:1).
HPLC: CHIRALPAK® IA (Daicel Chemical Industries), eluent:
i-PrOH–n-hexane (5:95), flow: 1.0 mL/min, l = 200–650 nm,
temperature = 25 °C, tR[RR] = 17.23 min and tR[SS] = 22.84 min.
1H NMR (300 MHz, CDCl3): d = 1.56 (d, J = 6.2 Hz, 3 H, 3-HPr),
2.08 (s, 3 H, 4-Me), 3.84 (s, 6 H, 2 × OMe), 4.60 (dq, J = 8.1,
6.2 Hz, 1 H, 2-HPr), 5.08 (d, J = 8.1 Hz, 1 H, 1-HPr), 6.48 (s, 2 H, 2-
Yield: 123 mg (50%); white solid; mp 113 °C.
[a]D22 +32.1 (c 1.03, CHCl3).
HAr and 6-H).
13C NMR (75.5 MHz, CDCl3): d = 8.2 (4-Me), 18.4 (CPr3), 55.9
(2 C, 2 × OMe), 80.8 (CPr2), 85.4 (CPr1), 101.0 (2 C, CAr2 and C6),
116.2 (C4), 133.3 (CAr1), 154.4 (CO3), 158.8 (2 C, CAr3 and C5).
Rf = 0.40 (MTBE–n-hexane, 5:1).
IR (film): 2968, 2928, 1740, 1600, 1470, 1454, 1419, 1319, 1236,
1133, 1045, 999, 974, 831, 780, 685, 523, 436 cm–1.
Carbonate 14
Yield: 129 mg (18%); white solid; mp 102 °C.
[a]D21 –43.3 (c 1.04, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.37 [d, J = 6.4 Hz, 3 H, 3-
CH(OH)CH3], 2.14 (s, 3 H, 6-Me), 3.92 (s, 3 H, 7-OMe), 4.03 (s,
3 H, 5-OMe), 4.15 [qd, J = 6.4, 3.9 Hz, 1 H, 3-CH(OH)CH3], 5.20
(d, J = 3.9 Hz, 1 H, 3-H), 6.68 (s, 1 H, 4-H).
13C NMR (125 MHz, CDCl3): d = 8.8 (6-Me), 18.9 [3-
CH(OH)CH3], 56.3 (7-OMe), 62.3 (5-OMe), 69.0 [3-CH(OH)CH3],
83.0 (C3), 99.2 (C4), 110.8 (C7a), 121.3 (C6), 148.5 (C3a), 157.9
(C7), 164.4 (C5), 168.3 (C1).
Rf = 0.34 (MTBE–n-hexane, 2:1).
HPLC: CHIRALPAK® IA (Daicel Chemical Industries), eluent:
i-PrOH–n-hexane (5:95), flow: 1.0 mL/min, l = 200–650 nm,
temperature = 25 °C, tR[RS] = 12.90 min and tR[SR] = 17.71 min.
1H NMR (300 MHz, CDCl3): d = 1.06 (d, J = 6.6 Hz, 3 H, 3-HPr),
2.08 (s, 3 H, 4-Me), 3.82 (s, 6 H, 2 × OMe), 5.06 (dq, J = 7.7,
6.6 Hz, 1 H, 2-HPr), 5.70 (d, J = 7.7 Hz, 1 H, 1-HPr), 6.38 (s, 2 H, 2-
HRMS (ESI): m/z [M + Na]+ calcd for C13H16O5Na: 275.0890;
found: 275.0893.
HAr and 6-H).
(+)-Pestaphthalide A
13C NMR (75.5 MHz, CDCl3): d = 8.2 (4-Me), 16.0 (CPr3), 55.9
(2 C, 2 × OMe), 77.2 (CPr2), 81.0 (CPr1), 101.1 (2 C, CAr2 and C6),
115.6 (C4), 131.5 (CAr1), 154.7 (CO3), 158.6 (2 C, CAr3 and C5).
To a soln of isobenzofuranone 17 (33.0 mg, 0.13 mmol) in CH2Cl2
(10 mL) was added 1 M BBr3 in CH2Cl2 (0.78 mL, 0.78 mmol) at
0 °C and the mixture was stirred at r.t. for 3 d. When TLC showed
complete consumption of the starting material, 1 M HCl (10 mL)
was added and the mixture was extracted with EtOAc (4 × 20 mL).
The combined extracts were dried (MgSO4) and the solvent was re-
moved under reduced pressure. The remaining crude product was
purified by flash column chromatography on silica gel (CHCl3–
MeOH, 12:1) to give (+)-pestaphthalide A.
Synthesis of (+)-Pestaphthalide A
(4S,5S)-4-(2-Bromo-3,5-dimethoxy-4-methylphenyl)-5-methyl-
1,3-dioxolan-2-one (15)
A soln of carbonate 13 (415 mg, 1.64 mmol) in MeCN (30 mL) was
cooled to 0 °C. NBS (439 mg, 2.47 mmol) was added and the result-
ing mixture was stirred at 0 °C for 4 h. The solvent was removed un-
der reduced pressure and the remaining crude product was purified
by flash column chromatography on silica gel (MTBE–n-pentane,
2:1) to give the desired bromide 15.
Yield: 22.0 mg (75%); brown oil.
[a]D21 +36.7 (c 0.06, MeOH) [Lit.1 [a]D +51 (c 0.05, MeOH)].
Rf = 0.24 (CHCl3–MeOH, 12:1).
Yield: 465 mg (85%); white solid; mp 102 °C.
[a]D24 +22.6 (c 1.07, CHCl3).
IR (film): 3301, 2967, 1708, 1617, 1460, 1346, 1292, 1258, 1131,
1089, 977, 798, 548 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 [d, J = 6.4 Hz, 3 H, 3-
CH(OH)CH3], 2.07 (s, 3 H, 6-Me), 4.14 [qd, J = 6.4, 3.5 Hz, 1 H, 3-
CH(OH)CH3], 5.26 (d, J = 3.5 Hz, 1 H, 3-H), 6.52 (s, 1 H, 4-H).
13C NMR (125 MHz, CDCl3): d = 7.9 (6-Me), 18.5 [3-
CH(OH)CH3], 68.8 [3-CH(OH)CH3], 85.5 (C3), 102.1 (C4), 105.0
(C7a), 112.8 (C6), 148.3 (C3a), 156.6 (C7), 164.7 (C5), 173.5 (C1).
Rf = 0.35 (MTBE–n-hexane, 3:1).
IR (film): 2937, 1800, 1570, 1451, 1386, 1364, 1319, 1185, 1159,
1116, 1075, 1027, 994, 902, 769, 580, 426 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.70 (d, J = 6.3 Hz, 3 H, 3-HPr),
2.20 (s, 3 H, 4-Me), 3.78 (s, 3 H, 3Ar-OMe), 3.84 (s, 3 H, 5-OMe),
4.59 (dq, J = 6.3, 5.1 Hz, 1 H, 2-HPr), 5.58 (d, J = 5.1 Hz, 1 H, 1-
HPr), 6.69 (s, 1 H, 6-H).
13C NMR (75.5 MHz, CDCl3): d = 9.7 (4-Me), 19.7 (CPr3), 56.0
(3Ar-OMe), 60.6 (5-OMe), 80.9 (CPr2), 82.5 (CPr1), 103.8 (C6),
107.2 (CAr2), 122.9 (C4), 134.0 (CAr1), 154.5 (CO3), 156.1 (CAr3),
158.6 (C5).
HRMS (ESI): m/z [M + Na]+ calcd for C11H12O5Na: 247.0577;
found: 247.0575.
Synthesis of (–)-Pestaphthalide B
(4R,5S)-4-(2-Bromo-3,5-dimethoxy-4-methylphenyl)-5-methyl-
1,3-dioxolan-2-one (18)
A soln of carbonate 14 (120 mg, 0.476 mmol) in MeCN (10 mL)
was cooled to 0 °C. NBS (127 mg, 0.714 mmol) was added and the
resulting mixture was stirred at 0 °C for 4 h. The solvent was re-
moved under reduced pressure and the remaining crude product was
purified by flash column chromatography on silica gel (MTBE–
n-pentane, 2:1) to give the desired bromide 18.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15BrO5Na: 354.9975;
found: 354.9979.
Synthesis 2011, No. 18, 2929–2934 © Thieme Stuttgart · New York

2934
J. Schwaben et al.
PAPER
Yield: 134 mg (85%); white solid; mp 132 °C.
[a]D24 –79.6 (c 1.08, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.17 [d, J = 6.5 Hz, 3 H, 3-
CH(OH)CH3], 2.07 (s, 3 H, 6-Me), 4.00 [qd, J = 6.5, 4.6 Hz, 1 H, 3-
CH(OH)CH3], 5.23 (d, J = 4.6 Hz, 1 H, 3-H), 6.54 (s, 1 H, 4-H).
13C NMR (100 MHz, CDCl3): d = 7.8 (6-Me), 18.0 [3-
CH(OH)CH3], 69.8 [3-CH(OH)CH3], 85.9 (C3), 102.3 (C4), 104.5
(C7a), 112.8 (C6), 148.2 (C3a), 156.7 (C7), 164.8 (C5), 173.5 (C1).
Rf = 0.4 (MTBE–n-hexane, 3:1).
IR (film): 2940, 2857, 1819, 1568, 1452, 1386, 1334, 1306, 1193,
1163, 1117, 1095, 1023, 998, 900, 837, 797, 749 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.03 (d, J = 6.6 Hz, 3 H, 3-HPr),
2.20 (s, 3 H, 4-Me), 3.77 (s, 3 H, 3Ar-OMe), 3.85 (s, 3 H, 5-OMe),
5.33 (dq, J = 7.7, 6.6 Hz, 1 H, 2-HPr), 6.01 (d, J = 7.7 Hz, 1 H, 1-
HPr), 6.77 (s, 1 H, 6-H).
HRMS (ESI): m/z [M + Na]+ calcd for C11H12O5Na: 247.0577;
found: 247.0577.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra of compounds 6, 7, 8 and 9, 10, 11 and
12, 13, 14, 15, 17, (+)-pestaphthalide A, 18, 19 and (–)-pestaphtha-
lide B.
13C NMR (62.9 MHz, CDCl3): d = 9.7 (4-Me), 16.1 (CPr3), 56.0
(3Ar-OMe), 60.6 (5-OMe), 76.2 (CPr2), 79.9 (CPr1), 104.5 (C6),
106.7 (CAr2), 122.4 (C4), 131.8 (CAr1), 154.2 (CO3), 156.0 (CAr3),
158.4 (C5).
HRMS (ESI): m/z [M + Na]+ calcd for C13H15BrO5Na: 354.9975;
found: 354.9965.
Acknowledgment
(R)-3-[(S)-1-Hydroxyethyl]-5,7-dimethoxy-6-methylisobenzo-
furan-1(3H)-one (19)
Generous support from the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged.
A soln of t-BuLi in n-pentane (1.6 M, 0.13 mL, 0.21 mmol) was
added slowly to a stirred soln of bromide 18 (55.0 mg, 0.17 mmol)
in THF (10.0 mL) at –78 °C, and the mixture was stirred for 3 h.
Then, the reaction mixture was allowed to warm to r.t. and sat. aq
NH4Cl (10 mL) was added. The mixture was stirred for 30 min, then
the THF was evaporated and the remaining aqueous mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were dried (MgSO4). The solvent was removed under reduced pres-
sure and the crude product was purified by flash column chromatog-
raphy on silica gel (MTBE–n-pentane, 5:1) to yield the desired
isobenzofuranone 19.
References
(1) Ding, G.; Liu, S.; Guo, L.; Zhou, Y.; Che, Y. J. Nat. Prod.
2008, 71, 615.
(2) (a) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N.
Angew. Chem. Int. Ed. 2002, 41, 3056. (b) Ishiyama, T.;
Takagi, J.; Nobuta, Y.; Miyaura, N. Org. Synth., Coll. Vol.
XI; John Wiley & Sons: New York, 2009, 1007; Org. Synth.
2005, 82, 126. (c) Mkhalid, I. A. I.; Barnard, J. H.; Marder,
T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110,
890.
(3) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi,
N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390.
(4) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E. Jr.;
Smith, M. R. III Science (Washington, D.C.) 2002, 295, 305.
(5) Maleczka, R. E. Jr.; Shi, F.; Homes, D.; Smith, M. R. III
J. Am. Chem. Soc. 2003, 125, 7792.
Yield: 31.0 mg (74%); white solid; mp 125 °C.
[a]D24 –18.8 (c 1.01, CHCl3).
Rf = 0.30 (MTBE–n-hexane, 7:1).
IR (film): 3422, 2949, 2891, 1728, 1599, 1414, 1394, 1324, 1235,
1135, 1099, 1065, 985, 770, 611 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 [d, J = 6.4 Hz, 3 H, 3-
CH(OH)CH3], 2.14 (s, 3 H, 6-Me), 3.91 (s, 3 H, 7-OMe), 4.02 (s,
3 H, 5-OMe), 4.06 [qd, J = 6.4, 4.9 Hz, 1 H, 3-CH(OH)CH3], 5.23
(d, J = 4.9 Hz, 1 H, 3-H), 6.71 (s, 1 H, 4-H).
(6) Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.;
Batsanov, A. S.; Howard, J. A. K.; Perutz, R. N.; Marder,
T. B. Angew. Chem. Int. Ed. 2006, 45, 489.
13C NMR (75.5 MHz, CDCl3): d = 8.7 (6-Me), 18.4 [3-
CH(OH)CH3], 56.3 (7-OMe), 62.3 (5-OMe), 69.7 [3-CH(OH)CH3],
83.1 (C3), 99.6 (C4), 110.4 (C7a), 121.3 (C6), 148.8 (C3a), 157.9
(C7), 164.4 (C5), 168.4 (C1).
HRMS (ESI): m/z [M + Na]+ calcd for C13H16O5Na: 275.0890;
found: 275.0893.
(7) Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010, 132,
5926.
(8) Cordes, J.; Wessel, C.; Harms, K.; Koert, U. Synthesis 2008,
2217.
(9) Meyer, F.-M.; Liras, S.; Guzman-Perez, A.; Perreault, C.;
Bian, J.; James, K. Org. Lett. 2010, 12, 3870.
(10) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114,
7568.
(–)-Pestaphthalide B
(11) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N.
To a soln of isobenzofuranone 19 (11.0 mg, 0.04 mmol) in CH2Cl2
(3.0 mL) was added 1 M BBr3 in CH2Cl2 (0.26 mL, 0.26 mmol) at
0 °C and the mixture was stirred at r.t. for 3 d. When TLC showed
complete consumption of the starting material, 1 M HCl (5.0 mL)
was added and the mixture was extracted with EtOAc (4 × 10 mL).
The combined extracts were dried (MgSO4) and the solvent was re-
moved under reduced pressure. The remaining crude product was
purified by flash column chromatography on silica gel (CHCl3–
MeOH, 12:1) to give (–)-pestaphthalide B.
J. Am. Chem. Soc. 1990, 112, 2801.
(12) Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahedron Lett.
1991, 32, 1055.
(13) The crystal data of compound rac-19 have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 831699. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44
(1223)336033; E-mail: deposit@ccdc.cam.ac.uk] or via
www.ccdc.cam.ac.uk/data_request/cif. Crystal data:
C13H16O5, M = 252.26, triclinic, P1, a = 8.5193 (5) Å,
b = 9.3779 (7) Å, c = 9.4830 (6) Å, a = 62.355 (5)°,
b = 66.112 (5)°, g = 67.335 (5)°, V = 595.13 (7) Å3, Z = 2,
Dcalcd = 1.408 Mg/m3, 6344 reflections collected, 2500
independent (Rint = 0.0306), R1 = 0.0325, wR2 = 0.0791 (all
data).
Yield: 7.6 mg (78%); brown oil.
[a]D21 –44.1 (c 0.05, MeOH) [Lit.1 [a]D –41 (c 0.05, MeOH)].
Rf = 0.30 (CHCl3–MeOH, 12:1).
IR (film): 3293, 2982, 2927, 1716, 1616, 1344, 1293, 1132, 1088,
773, 726, 640, 548 cm–1.
Synthesis 2011, No. 18, 2929–2934 © Thieme Stuttgart · New York