CN-assisted oxidative cyclization of cyano cinnamates and styrene derivatives: A facile entry to 3-substituted chiral phthalides

Article abstract of DOI:10.1039/c2ob25409c

The asymmetric dihydroxylation (AD) of o-cyano cinnamates and styrene derivatives leads to efficient construction of chiral phthalide frameworks in high optical purities. This unique reaction is characterized by unusual synergism between CN and osmate groups resulting in rate enhancement of the AD process. The method is amply demonstrated by the synthesis and the structural/stereochemical assignment of the natural products.

Full text of DOI:10.1039/c2ob25409c

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PAPER
CN-assisted oxidative cyclization of cyano cinnamates and styrene derivatives:
a facile entry to 3-substituted chiral phthalides†
R. Santhosh Reddy, I. N. Chaithanya Kiran and Arumugam Sudalai*
Received 24th February 2012, Accepted 7th March 2012
DOI: 10.1039/c2ob25409c
The asymmetric dihydroxylation (AD) of o-cyano cinnamates and styrene derivatives leads to efficient
construction of chiral phthalide frameworks in high optical purities. This unique reaction is characterized
by unusual synergism between CN and osmate groups resulting in rate enhancement of the AD process.
The method is amply demonstrated by the synthesis and the structural/stereochemical assignment of the
natural products.
The Sharpless’ asymmetric dihydroxylation (AD) of alkenes
has emerged as a most reliable method for the preparation of
Introduction
Chiral phthalides [isobenzofuran-1(3H)-ones] comprising of 5-
membered lactones are found in a large number of plant products
displaying broad and potent biological activities.1 Due to the
biological importance of 3-substituted phthalides 1–3 (Fig. 1),
their molecular architectures have become a platform for new
synthetic methodology development.2 Over the past two
decades, newer methods toward introducing C-3 chirality in
phthalides have been established, which include (i) hydrogen-
ation of ketones (Noyori et al.),3a (ii) addition of zinc reagent to
aldehydes (Butsugan et al.),3b (iii) asymmetric tandem process
(Lin et al.),3c (iv) transesterification followed by cycloaddition
(Tanaka and Yamamoto groups),3d,e (v) alkynylation of alde-
hydes (Trost et al.),3f (vi) cyclization approach (Cheng et al.),3g
(vii) organocatalytic aldol-lactonization process (Wang et al.),3h
and reductive cyclization of 2-acylarylcarboxylates (Xu and Lin
et al.).3i Unfortunately, many such processes employ either
expensive organometallic reagents in stoichiometric amounts,3b,f,
chiral 1,2-diols, widely found in bioactive compounds and phar-
maceuticals. Ligand acceleration is central to the efficiency and
selectivity of the AD catalytic process.6
Results and discussion
Herein, we report a single-step oxidative cyclization of cyanocin-
namates and styrene derivatives to afford 3-substituted phthalides
in high yields via synergetic acceleration of CN and osmate ester
groups present in proximity positions.
We have recently reported a novel protocol of AD process and
Co-catalyzed “one-pot” reductive cyclization (CoCl2–NaBH4) of
nitro cyclic sulfites that led to the construction of 3-substituted
tetrahydroquinolin-3-ols.7 In analogy with this, we reasoned that
subjecting cyano cyclic sulfites to the same reaction conditions
should afford synthetically useful benzazepines.8 To our sur-
prise, when ethyl 2-cyanocinnamate 4a was subjected to a
typical AD-mix-β process for 7 h, with THF as co-solvent for
better solubility, the corresponding chiral phthalide 5a was
obtained exclusively in 99% ee (Scheme 1).
or chiral auxiliaries4 and they often lack broad substrate scope
g
and higher reaction stereoselectivity; only a few are atom
economical.5
This unexpected transformation is characterized by high rate,
excellent yield and enantioselectivity which is attributed to
coordination assistance provided by the neighboring CN group
to the osmate ester, leading to faster hydrolysis of the osmate
ester in the catalytic cycle. Incidentally, the rate of AD process
for electron-deficient o-substituted cinnamates is generally
Fig. 1 Structures of naturally occurring 3-substituted phthalides 1–3.
Chemical Engineering and Process Development Division National
Chemical Laboratory, Pashan Road, Pune 411008, India. E-mail:
a.sudalai@ncl.res.in; Fax: (+)91-02025902675
†Electronic supplementary information (ESI) available: Experimental
details and spectral data of all the new compounds. See DOI: 10.1039/
c2ob25409c
Scheme 1 Os-catalyzed oxidative cyclization of cyano cinnamates.
Org. Biomol. Chem., 2012, 10, 3655–3661 | 3655
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Table 1 CN-assisted Os-catalyzed oxidative cyclization of cyano ethyl
cinnamates
Table 2 CN-assisted Os-catalyzed oxidative cyclization of cyano
styrene derivatives
Entry R1
R2
R3
R4
Yielda (%) eeb,c,d (%)
Entry
R1
R2
R3
Yielda (%)
eeb,c (%)
m
n
o
p
q
r
H
OMe
OMe OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
95
95
93
94
94
92
93
94
94
93
93
99
99
99
99
99
99
99
99
99
99
97
97
97
98
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
OMe
OMe
OMe
H
H
H
94
95
94
94
94
92
93
94
94
93
95
94
99
99
99
99
99
99
99
99
99
99
98
98
OMe
OMe
H
OMe
OMe
OTs
OBn
F
OMe
OMe
H
OMe
OMe
OMe
H
OMe OMe
OMe
OMe
H
OMe OMe OMe
s
t
OTs
OBn
F
–O–CH2–O–
H
OMe OMe
OMe OMe
OMe OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
u
v
w
x
y
z
H
H
j
k
l
NO2
–O–CH2–O–
(E)-Ethyl 3-(1-
cyanonaphthalen-2-yl)
acrylate
H
H
H
H
C3H7
CH2OTBS 94
Ph
n-C6H13
94
92
a Isolated yield after column chromatographic purification. b ee
determined by chiral HPLC analysis (see the ESI†). c ee determined by
Mosher’s ester analysis for entries t, u, w–z. d Reaction completed in 3 h
for entries m–v.
a Isolated yield after column chromatographic purification. b ee
determined by chiral HPLC analysis (see the ESI†). c ee determined by
Mosher’s ester analysis for entries h, i & l.
reported to be sluggish (48 h to 7 days) giving products invari-
ably with moderate enantioselectivity (88% ee).9
Encouraged by this result, we examined the scope of the reac-
tion with other cyano cinnamate esters 4a-l (Table 1). In every
case, the reaction proceeded rapidly in 7 h giving the desired
phthalides 5a-l in excellent yields and enantioselectivities (up to
99%). For instance, substrates having halogen (entry i), highly
electron-rich (entry f) or electron-deficient (entry j) substituents
on the aromatic ring including 2-naphthyl nuclear system (entry
l) underwent this oxidative cyclization smoothly affording the
corresponding phthalides 5a-l in excellent yields.
Scheme 2 Investigation on the mechanistic detail of oxidative
cyclization.
Subsequently, we extended our study to include other styrene
derivatives bearing different functionalities on the aromatic
nucleus as well as on the β-position of the styrene derivative side
chain (R4) (Table 2). It was again found that this oxidative cycli-
zation AD process displayed a wide substrate scope tolerating
alkyl, aryl, alkoxy, fluoro or tosyl groups. Excellent yields
(93–95%) and enantioselectivities (97–99% ee) were indeed rea-
lized in all cases. The stereochemistry of the cyclized products
was assigned according to the previously established absolute
configuration of phthalides as well as in accordance with AD
rules.10
Scheme 3 Mechanism of CN-assisted Os-catalyzed oxidative
cyclization.
In order to account for the course of the reaction, the follow-
ing experiments (Scheme 2) were conducted: (i) AD-mix-β of
substrates 6 & 7 for 36 h gave the corresponding cyanodiols 8 &
9 respectively, indicating that both CN and CvC groups must be
positioned in proximity for CN coordination assistance to take
place; (ii) asymmetric aminohydroxylation11 of 4a gave the
expected amino alcohol 10 (64%) with no phthalide formation,
suggesting that coordination of CN onto imino osmate ester is
thermodynamically less favorable, due to its reduced Lewis acid
character;12 (iii) in addition, imino intermediates 11a-b were
indeed isolated in 20% yield during the AD-mix-β of substrates
4a and 4w. This study clearly excludes the hydrolysis of CN to
CO2H followed by cyclization route, (iv) addition of benzonitrile
as an external source of CN-assistance resulted in no rate
enhancement for the AD process. On the basis of these results, a
mechanistic model is shown in species Awith a synergism invol-
ving co-ordination of CN to Os(VI) and concurrent attack of
osmate ester onto electropositive carbon of CN is shown that
probably helps to accelerate the hydrolysis of osmate ester. This
results in 5-exo-dig type cyclization13 to afford iminoesters 11a-
b, which finally lead to the formation of phthalides 5a or 5w
(Scheme 3).
3656 | Org. Biomol. Chem., 2012, 10, 3655–3661
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Table 3 Competitive experimentsa
and their structural analogues via AD process of cyano cinna-
mates and styrene derivatives. This reaction is highly practical in
the sense that the products were obtained in excellent yields and
optical purities (97–99% ee) and shows broad substrate scope
and good functional group tolerance. The synergism shown by
CN and osmate groups in proximity helps to enhance the rate of
this reaction. The synthetic potential of this protocol is further
illustrated with a concise “one-pot” synthesis of three natural
products in high optical purities. We believe that this oxidative
intramolecular cyclization AD strategy should find wide appli-
cations in the total synthesis of other bioactive phthalide
frameworks.
Entry
Substrates
Product
Yieldb,c
%
1
2
3
4
5
4a + ethyl cinnamate
12 + 3,5 dimethoxy stilbene
4m + styrene
4o + 3,5 dimethoxy styrene
4r + 3,4,5 trimethoxy styrene
5a
13
5m
5o
5r
92
93
94
92
92
a Reagents and conditions: 1 : 1 Molar equivalents of aromatics
substrates with and without cyano substitution (1 mmol each), AD-mix-
β (0.5 mol%), tBuOH–THF–H2O (0.5 : 0.5 : 1), 25 °C, 3 h for entries
3–5 and 7 h for entries 1 and 2. b Isolated yields. c 5–8% of 1,2-diol
from the corresponding substrates without cyano substitution was indeed
isolated.
Experimental
Typical procedure
A 50 mL RB flask was charged with K3Fe(CN)6 (0.988 g,
3 mmol), K2CO3 (0.414 g, 3 mmol), tert-BuOH (2.5 mL), THF
(2.5 mL) and H2O (5 mL) and stirred for 10 min. Subsequently,
(DHQD)2PHAL (0.008 g, 1 mol%) and K2OsO4·2H2O (0.002 g,
0.5 mol%) were added and the stirring continued for additional
30 min. To this reaction mixture, o-cyano alkene (1 mmol) was
added and allowed to stir for 7 h at 25 °C. After completion of
reaction (as monitored by TLC), sodium bisulphite (1 g) was
added slowly at 0 °C. The organic layer was separated, aqueous
layer extracted with ethyl acetate (3 × 10 ml) and the combined
organic layers washed with brine (15 mL), dried over anhydrous
sodium sulphate and concentrated under reduced pressure to
yield the crude product. Flash column chromatographic purifi-
cation [silica gel (230–400 mesh) and petroleum ether–EtOAc as
an eluent] gave 5a-z in pure form with high yields and ee.
Scheme 4 Concise synthesis of (+) and (−)-matteucen C (2a-b).
Scheme 5 Short synthesis of demethyl pestaphthalide (16).
The higher reactivity of cyano substituted cinnamates and styr-
enes were substantiated by carrying out several competitive
experiments involving 1 : 1 molar equivalents of aromatic sub-
strates with and without cyano substitution; the results of which
are presented in Table 3. The results clearly show that cyano sub-
stituted substrates react almost 10–12 times faster than the one
without cyano substitution, giving excellent yields of phthalides.
This protocol has subsequently been demonstrated in the
asymmetric synthesis of three natural products: (i) demethyl pes-
taphthalide 16, an intermediate in the biosynthesis of virgatolide
A (1),2a which shows cytotoxic activity against HeLa cells; (ii)
matteucen C (2a-b),2b a Chinese medicinal herb used in the
treatment of hemostatics and relieving ostalgia; (iii) 3-
butylphthalide (3), an anticonvulsant drug for the treatment of
stroke2c,f (Fig. 1). The reported routes to synthesise these natural
products obviously have several limitations.14 This methodology
has thus established a concise synthesis of 3, 2a-b and 16 in
high optical purities starting from 5w, 12 and 14 respectively in
2 steps of AD of alkenes followed by demethylation with BBr3
or deoxygenation using Barton–McCombie protocol15 (Schemes
4 and 5). Interestingly, the first asymmetric synthesis of two
stereoisomers of matteucen C (2a-b) has unambiguously estab-
lished the stereochemical syn relationship of C-3 and C-8
positions.
(S)-Ethyl-2-((R)-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydro-
xyacetate (5a). Yield: 94%; colorless solid; mp 146–148 °C;
99% ee by chiral HPLC analysis (Chiracel OJ-H, n-hexane–
iPrOH, 90 : 10, 0.5 mL min−1) retention time 12.16 (99.65%)
and 13.80 (0.35%); [α]2D5 −95.65 (c 1.24, CHCl3); IR (CHCl3):
762, 856, 968, 1027, 1068, 1078, 1210, 1298, 1349, 1467, 1611,
1652, 1720, 1768, 2924, 3014, 3440 cm−1; 1H NMR (200 MHz,
CDCl3): δ 1.29 (t, J = 7.17 Hz, 3H), 3.16 (d, J = 5.79 Hz, 1H),
4.30 (q, J = 7.17 Hz, 2H), 4.66 (dd, J = 2.12, 5.81 Hz, 1H), 5.79
(d, J = 2.12 Hz, 1H), 7.57 (t, J = 7.06 Hz, 2H), 7.68–7.75 (m,
1H), 7.90–7.93 (m, 1H); 13C NMR (CDCl3): δ 13.8, 62.4, 70.3,
80.4, 122.0, 125.3, 126.4, 129.3, 134.0, 145.7, 169.82, 170.7;
HRMS (ESI) calcd for C12H12O5 [M + H]+ 237.0763, found
237.0772.
(S)-Ethyl-2-((R)-1,3-dihydro-5-methoxy-1-oxoisobenzofuran-3-
yl)-2-hydroxyacetate (5b). Yield: 95%; colorless solid; mp
121–122 °C; 99% ee by chiral HPLC analysis (Chiracel OJ-H,
n-hexane–iPrOH, 90 : 10, 1 mL min−1) retention time 25.80
(99.55%) and 30.33 (0.45%); [α]D25 −94.49 (c 1.15, CHCl3); IR
(CHCl3): 724, 876, 1031, 1084, 1191, 1212, 1278, 1295, 1357,
1398, 1445, 1486, 1578, 1607, 1721, 1765, 2984, 3023,
3415 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.29 (t, J = 7.20 Hz,
3H), 3.14 (brs, 3H), 3.91 (s, 3H), 4.29 (q, J = 7.20 Hz, 2H), 4.63
(d, J = 1.74, 1H), 5.69 (d, J = 2.29 Hz, 1H), 6.96 (d, J = 2.11
Hz, 1H), 7.05 (dd, J = 2.11, 8.66 Hz, 1H), 7.80 (d, J = 8.66 Hz,
1H); 13C NMR (CDCl3): δ 14.0, 55.8, 62.7, 70.5, 79.6, 106.0,
Conclusion
We have demonstrated a novel CN-assisted oxidative cyclization
for the synthesis of a wide variety of 3-substituted phthalides
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117.0, 118.9, 127.1, 148.5, 164.8, 169.5, 170.9; HRMS (ESI)
calcd for C13H14O6 [M + H]+ 267.0869, found 267.0863.
CDCl3): δ 1.27 (t, J = 7.20 Hz, 3H), 2.48 (s, 3H), 3.07 (s, 1H),
3.78 (s, 3H), 4.26 (q, J = 7.20 Hz, 2H), 4.63 (d, J = 2.16 Hz,
1H), 5.67 (d, J = 2.16 Hz, 1H), 6.99 (s, 1H), 7.35 (d, J = 8.14
Hz, 2H), 7.49 (s, 1H), 7.76 (d, J = 8.14 Hz, 2H); 13C NMR
(DMSO-d6): δ 14.5, 21.8, 56.7, 61.4, 70.3, 71.6, 81.4, 107.4,
118.7, 119.7, 128.6, 130.1, 132.6, 139.5, 145.9, 147.9, 157.0,
168.8, 170.9; HRMS (ESI) calcd for C20H20O9S [M + H]+
437.0906, found 437.0912.
(S)-Ethyl-2-((R)-1,3-dihydro-5,6-dimethoxy-1-oxoisobenzofuran-
3-yl)-2-hydroxyacetate (5c). Yield: 94%; colorless solid; mp
144–146 °C; 99% ee by chiral HPLC analysis (Chiracel OJ-H,
n-hexane–iPrOH, 90 : 10, 0.5 mL min−1) retention time 23.18
(99.36%) and 27.60 (0.64%); [α]D25 −95.12 (c 1.12, CHCl3); IR
(CHCl3): 758, 945, 1125, 1297, 1507, 1722, 1764, 2925, 3010,
3341 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.30 (t, J = 7.20 Hz,
3H), 3.20 (d, J = 6.23 Hz, 1H), 3.94 (s, 3H), 3.98 (s, 3H), 4.29
(q, J = 7.25 Hz, 2H), 4.62 (dd, J = 2.42, 6.16 Hz, 1H), 5.66 (d, J
= 2.20 Hz, 1H), 6.93 (s, 1H), 7.27 (s, 1H); 13C NMR (DMSO-
d6): δ 14.4, 56.2, 56.4, 61.2, 70.2, 81.2, 105.2, 105.8, 118.2,
141.7, 150.5, 154.8, 170.2, 171.3; HRMS (ESI) calcd for
C14H16O7 [M + H]+ 297.0974, found 297.0979.
(S)-Ethyl-2-((R)-5-(benzyloxy)-1,3-dihydro-6-methoxy-1-oxoiso-
benzofuran-3-yl)-2-hydroxyacetate (5h). Yield: 94%, colorless
solid; mp 138–140 °C; [α]D25 −96.04 (c 1.21, CHCl3); IR
(CHCl3): 738, 856, 1025, 1078, 1130, 1184, 1195, 1336, 1395,
1494, 1645, 1765, 2942, 3035, 3413 cm−1; 1H NMR (200 MHz,
CDCl3): δ 1.28 (t, J = 7.05 Hz, 3H), 3.04 (d, J = 5.93 Hz, 1H),
3.94 (s, 3H), 4.27 (q, J = 7.05 Hz, 2H), 4.55 (dd, J = 2.59, 5.93
Hz, 1H), 5.22 (d, J = 3.59 Hz, 2H), 5.61 (d, J = 2.08 Hz, 1H),
6.94 (s, 1H), 7.26 (s,1H), 7.29–7.45 (m, 5H); 13C NMR
(DMSO-d6): δ 13.7, 55.7, 61.5, 70.3, 70.6, 79.9, 105.2, 105.8,
118.5, 127.0, 127.8, 128.3, 135.3, 139.9, 150.8, 153.6, 169.7,
170.4; HRMS (ESI) calcd for C20H20O7 [M + H]+ 373.1287,
found 373.1293.
(S)-Ethyl-2-((R)-1,3-dihydro-6,7-dimethoxy-1-oxoisobenzofuran-
3-yl)-2-hydroxyacetate (5d). Yield: 94%, colorless solid; mp
110–112 °C; 99% ee by chiral HPLC analysis (Chiracel OJ-H,
n-hexane–iPrOH, 90 : 10, 0.5 mL min−1) retention time 23.90
(99.44%) and 27.87 (0.56%); [α]D25 −95.28 (c 1.0, CHCl3); IR
(CHCl3): 762, 946, 1132, 1298, 1518, 1728, 1764, 2985, 3034,
3425 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.30 (t, J = 7.19 Hz,
3H), 3.19 (brs, 1H), 3.91 (s, 3H), 4.10 (s, 3H), 4.29 (q, J = 7.19
Hz, 2H), 4.57 (s, 1H), 5.65 (d, J = 2.09 Hz, 1H), 7.13 (d, J =
8.11 Hz, 1H), 7.23 (d, J = 8.11 Hz, 1H); 13C NMR (CDCl3): δ
14.1, 56.7, 62.2, 62.6, 70.7, 79.0, 116.4, 118.8, 119.3, 138.5,
148.4, 152.9, 167.2, 170.9; HRMS (ESI) calcd for C14H16O7
[M + H]+ 297.0974, found 297.0979.
(S)-Ethyl-2-((R)-5-fluoro-1,3-dihydro-1-oxoisobenzofuran-3-yl)-
2-hydroxyacetate (5i). Yield: 94%, colorless solid; mp
108–109 °C; [α]D25 −95.41 (c 1.15, CHCl3); IR (CHCl3): 756,
891, 1052, 1097, 1130, 1190, 1325, 1374, 1485, 1629, 1765,
2928, 3015, 3351 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.30 (t,
J = 7.27 Hz, 3H), 3.17 (d, J = 6.74 Hz, 1H), 4.31 (q, J = 7.27
Hz, 2H), 4.62 (dd, J = 2.25, 5.84 Hz, 1H), 5.74 (d, J = 7.25 Hz,
1H), 7.23 (d, J = 8.4 Hz, 2H), 7.91 ((dd, J = 5.84, 8.39 Hz, 1H);
13C NMR (CDCl3): δ 13.9, 62.2, 70.3, 79.8, 109.6 (d, J = 24.64
Hz), 117.7 (d, J = 24.64 Hz), 122.7, 127.7, 148.6 (d, J = 10.33
Hz), 166.4 (d, J = 256.30 Hz), 168.6, 170.5; HRMS (ESI) calcd
for C12H11FO5 [M + H]+ 255.0669, found 255.0660.
(S)-Ethyl-2-((R)-1,3-dihydro-5,7-dimethoxy-1-oxoisobenzofuran-
3-yl)-2-hydroxyacetate (5e). Yield: 94%, colorless solid; mp
154–156 °C; 99% ee by chiral HPLC analysis (Chiracel OJ-H,
n-hexane–iPrOH, 90 : 10, 0.5 mL min−1) retention time 18.37
(99.60%) and 21.74 (0.40%); [α]D25 −96.29 (c 1.15, CHCl3); IR
(CHCl3): 746, 985, 1130, 1287, 1514, 1723, 1762, 2954, 3085,
3414 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.32 (t, J = 7.22 Hz,
3H), 3.37 (brs, 1H), 3.91 (s, 3H), 3.94 (s, 3H), 4.30 (q, J = 7.22
Hz, 2H), 4.61 (s, 1H), 5.67 (s, 1H), 6.47 (s, 1H), 6.59 (s, 1H);
13C NMR (CD3OD): δ 14.6, 56.5, 56.9, 63.0, 71.9, 82.1, 99.9,
100.3, 108.1, 153.1, 160.9, 168.9, 170.6, 172.5; HRMS (ESI)
calcd for C14H16O7 [M + H]+ 297.0974, found 297.0979.
(S)-Ethyl-2-((R)-1,3-dihydro-5-nitro-1-oxoisobenzofuran-3-yl)-
2-hydroxyacetate (5j). Yield: 93%, colorless solid; mp
146–148 °C; [α]D25 −95.28 (c 1.0, CHCl3); IR (CHCl3): 738,
829, 967, 1037, 1106, 1346, 1540, 1740, 1779, 2853, 2918,
1
3009, 3444 cm−1; H NMR (500 MHz, CDCl3): δ 1.35 (t, J =
7.20 Hz, 3H), 3.21 (d, J = 6.15 Hz, 1H), 4.36 (q, J = 7.20 Hz,
2H), 4.71 (d, J = 3.60 Hz, 1H), 5.90 (s, 1H), 8.09 (d, J = 8.24
Hz, 1H), 8.42–8.46 (m, 2H); 13C NMR (CDCl3): δ 14.1, 63.3,
70.2, 80.2, 117.9, 125.3, 127.0, 131.8, 146.9, 151.7, 167.3,
170.2; HRMS (ESI) calcd for C12H11NO7 [M + H]+ 282.0614,
found 282.0612.
(S)-Ethyl-2-((R)-1,3-dihydro-5,6,7-trimethoxy-1-oxoisobenzo-
furan-3-yl)-2-hydroxyacetate (5f). Yield: 92%, colorless solid;
mp 111–112 °C; [α]D25 −94.65 (c 1.23, CHCl3); IR (CHCl3):
1012, 1094, 1140, 1254, 1350, 1475, 1602, 1765, 2954, 3085,
3408 cm−1; 1H NMR (200 MHz, CDCl3): δ 1.31 (t, J = 7.20 Hz,
3H), 3.09 (s,1H), 3.86 (s, 3H), 3.96 (s, 3H), 4.13 (s, 3H), 4.31
(q, J = 7.20 Hz, 2H), 4.58 (d, J = 2.16 Hz, 1H), 5.58 (d, J =
2.16 Hz, 1H), 6.70 (s, 1H); 13C NMR (CDCl3): δ 13.9, 56.3,
61.1, 62.0, 62.4, 79.1, 99.6, 111.0, 142.0, 143.5, 152.1, 159.7,
167.3, 176.8; HRMS (ESI) calcd for C15H18O8 [M + H]+
327.1080, found 327.1072.
(S)-Ethyl-2-((R)-5-1,3-dihydro-5,6-dioxomethyl-1-oxoisobenzo-
furan-3-yl)-2-hydroxyacetate (5k). Yield: 95%, colorless solid;
mp 150–153 °C; [α]D25 −95.74 (c 1.0, CHCl3); IR (CHCl3): 786,
891, 1015, 1054, 1122, 1183, 1196, 1356, 1395, 1489, 1618,
1
1755, 2942, 3021, 3410 cm−1; H NMR (200 MHz, CDCl3): δ
1.31 (t, J = 7.14 Hz, 3H), 3.10 (brs, 1H), 4.30 (qd, J = 1.40,
7.14 Hz, 2H), 4.56 (s, 1H), 5.62 (d, J = 2.19 Hz, 1H), 6.14 (dd,
J = 1.40, 4.44 Hz, 2H), 6.89 (s, 1H), 7.20 (s, 1H); 13C NMR
(CDCl3): δ 14.0, 62.6, 70.4, 79.6, 101.9, 102.7, 104.3, 120.4,
142.2, 149.6, 153.7, 169.3, 170.8; Analysis: C13H12O7 requires
C 55.72, H 4.32 found C 55.65, H 4.29%.
(S)-Ethyl-2-((R)-5-(p-toluenesulfonoyloxy)-1,3-dihydro-6-methoxy-
1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (5g). Yield: 93%, color-
less solid; mp 107–108 °C; [α]D25 −94.89 (c 1.15, CHCl3); IR
(CHCl3): 768, 819, 1025, 1050, 1120, 1180, 1190, 1330, 1374,
1494, 1614, 1767, 2924, 3012, 3371 cm−1; 1H NMR (200 MHz,
3658 | Org. Biomol. Chem., 2012, 10, 3655–3661
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1
3012, 3457 cm−1; H NMR (200 MHz, CDCl3): 2.24 (brs, 1H),
3.79–3.85 (m, 1H), 3.90 (s, 3H), 3.95 (s, 3H), 4.03–4.09 (m,
1H), 5.35–5.39 (m, 1H), 6.42 (s, 1H), 6.48(s, 1H); 13C NMR
(CDCl3): δ 56.6, 62.0, 63.7, 80.7, 116.8, 118.4, 119.4, 139.7,
148.0, 152.5, 168.2; HRMS (ESI) calcd for: C11H12O5 [M + H]+
225.0718, found 225.0715. HRMS (ESI) calcd for: C11H12O5
[M + H]+ 225.0763, found 225.0772.
(S)-Ethyl 2-((R)-1,3-dihydro-1-oxonaphtho[2,1-c]furan-3-yl)-2-
hydroxyacetate (5l). Yield: 94%, colorless solid; mp
107–109 °C; [α]D25 −95.69 (c 1.15, CHCl3); IR (CHCl3): 784,
865, 989, 1010, 1106, 1210, 1275, 1291, 1319, 1368, 1573,
1607, 1750, 2978, 3084, 3457 cm−1 1H NMR (200 MHz,
;
CDCl3): δ 1.28 (t, J = 7.45 Hz, 3H), 3.14 (d, J = 6.06 Hz, 1H),
4.31 (q, J = 7.45 Hz, 2H), 4.74 (dd, J = 2.14, 6.06 Hz, 1H), 5.85
(d, J = 2.14 Hz, 1H), 7.58 (d, J = 8.50 Hz, 1H), 7.63–7.78 (m,
2H), 7.97 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H) 8.97 (d,
J = 8.5 Hz, 1H); 13C NMR (CDCl3 + CD3OD): δ 13.2, 61.5,
69.8, 80.3, 118.2, 118.6, 120.3, 122.4, 126.8, 128.0, 128.4,
133.0, 135.2, 147.6, 170.4; Analysis: C16H14O5 requires C
67.13, H 4.93 found C 67.11, H 4.89%.
(R)-3-(Hydroxymethyl)-5,7-dimethoxyisobenzofuran-1(3H)-one
(5q). Yield: 94%, colorless solid; mp 152–153 °C; 99% ee by
chiral HPLC analysis (Chiracel OJ-H, n-hexane–iPrOH, 90 : 10,
0.5 mL min−1) retention time 18.27 (99.36%) and 20.40
(0.64%); [α]D25 −78.11 (c 1.0, CHCl3); IR (CHCl3): 695, 765,
950, 1030, 1058, 1232, 1331, 1365, 1463, 1615, 1751, 2982,
1
3010, 3443 cm−1; H NMR (200 MHz, CDCl3): 2.53 (brs, 1H),
(R)-3-(Hydroxymethyl)isobenzofuran-1(3H)-one (5m). Yield:
95%, colorless solid; mp 101–104 °C; 99% ee by chiral HPLC
analysis (Chiracel OJ-H, n-hexane–iPrOH, 90 : 10, 0.5 mL
min−1) retention time 8.03 (99.36%) and 9.24 (0.64%); [α]D25
−78.12 (c 1.23, CHCl3); IR (CHCl3): 744, 847, 968, 1025,
1067, 1089, 1211, 1288, 1349, 1467, 1607, 1640, 1756, 2924,
3.77–3.88 (m, 1H), 3.91 (s, 3H), 3.99–4.04 (m, 3H), 4.10 (s,
1H), 5.40–5.45 (m, 1H), 7.09 (dd, J = 084, 8.20 Hz, 1H), 7.22
(d, J = 8.20 Hz, 1H); 13C NMR (CDCl3): δ 54.7, 54.9, 62.2,
80.4, 97.6, 98.2, 105.9, 151.7, 158.9, 166.6, 168.9; HRMS (ESI)
calcd for: C11H12O5 [M + H]+ 225.0763, found 225.0772.
1
3012, 3440 cm−1; H NMR (200 MHz, CDCl3): 2.61 (s, 1H),
(R)-3-(Hydroxymethyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-
one (5r). Yield: 92%, colorless solid; mp 178–180 °C; [α]2D5
−78.05 (c 1.15, CHCl3); IR (CHCl3): 1014, 1097, 1254, 1345,
1483, 1600, 1754, 2947, 3017, 3444 cm−1; 1H NMR (200 MHz,
CDCl3): 2.62 (brs, 1H), 3.84–3.90 (m, 4H), 3.96 (s, 3H),
4.03–4.09 (m, 1H), 4.13(s, 3H), 5.35–5.39 (m, 1H), 6.69 (s,
1H); 13C NMR (CDCl3 + CD3OD): δ 56.4, 61.2, 62.1, 63.7,
80.6, 99.9, 110.7, 141.8, 144.8, 152.1, 159.7, 168.3; HRMS
(ESI) calcd for: C12H14O6 [M + H]+ 255.0869, found 255.0863.
3.90 (d, J = 11.80 Hz, 1H), 4.14 (d, J = 11.80 Hz, 1H),
5.54–5.59 (m, 1H), 7.55 (t, J = 7.79 Hz, 2H), 7.70 (td, J = 1.14,
7.42 Hz, 1H), 7.89 (d, J = 7.42 Hz, 1H); 13C NMR (CDCl3 +
CD3OD): δ 61.7, 81.6, 121.6, 124.2, 125.6, 128.4, 133.4, 146.8,
170.6; HRMS (ESI) calcd for C9H8O3 [M + H]+ 165.0552,
found 165.0559.
(R)-3-(Hydroxymethyl)-5-methoxyisobenzofuran-1(3H)-one (5n).
Yield: 95%, colorless solid; mp 137–140 °C; 99% ee by chiral
HPLC analysis (Chiracel OJ-H, n-hexane–iPrOH, 90 : 10, 1 mL
min−1) retention time 27.19 (99.36%) and 39.72 (0.64%); [α]D25
−78.36 (c 1.12, CHCl3); IR (CHCl3): 728, 868, 1026, 1256,
(R)-1,3-Dihydro-1-(hydroxymethyl)-5-methoxy-3-oxoisobenzo-
furan-6-yl-4-methylbenzenesulfonate (5s). Yield: 93%, colorless
solid; mp 152–154 °C; [α]D25 −77.79 (c 1.18, CHCl3); IR
(CHCl3): 734, 849, 973, 103, 1053, 1178, 1345, 1372, 1494,
1490, 1607, 1640, 1749, 2853, 2923, 3440 cm−1 1H NMR
;
1614, 1755, 2919, 3018, 3437 cm−1 1H NMR (200 MHz,
;
(200 MHz, CDCl3): 2.31 (brs, 1H), 3.84–3.91 (m, 4H),
4.06–4.14 (m, 1H), 5.46 (t, J = 5.30 Hz, 1H), 6.94 (d, J = 2.0
Hz, 1H), 7.04 (dd, J = 2.0, 8.60 Hz, 1H), 7.80 (d, J = 8.60 Hz,
1H); 13C NMR (CDCl3 + CD3OD): δ 54.9, 62.1, 81.1, 105.6,
116.4, 117.8, 126.1, 149.8, 164.5, 170.8; HRMS (ESI) calcd for:
C10H10O4 [M + H]+ 195.0657, found 195.0663.
CDCl3): 2.24 (brs, 1H), 2.48 (s, 3H), 3.80 (s, 3H), 3.92 (dd, J =
4.60, 12.36 Hz, 1H), 4.03 (dd, J = 4.73, 12.36 Hz, 1H), 5.44 (t,
J = 4.60 Hz, 1H), 6.97 (s, 1H), 7.35 (d, J = 8.28 Hz, 2H), 7.48
(s, 1H), 7.78 (d, J = 8.28 Hz, 2H); 13C NMR (CDCl3
+
CD3OD): δ 20.1, 55.1, 61.5, 81.0, 105.4, 117.4, 119.3, 127.7,
128.8, 131.9, 138.9, 145.2, 147.8, 156.6, 169.5; HRMS (ESI)
calcd for: C17H16O7S [M + H]+ 365.0695, found 365.0693.
(R)-3-(Hydroxymethyl)-5,6-dimethoxyisobenzofuran-1(3H)-one
(5o). Yield: 93%, colorless solid; mp 165–167 °C; 99% ee by
chiral HPLC analysis (Chiracel OJ-H, n-hexane–iPrOH, 90 : 10,
0.5 mL min−1) retention time 23.18 (99.36%) and 27.60
(0.64%); [α]D25 −77.89 (c 1.0, CHCl3); IR (CHCl3): 698, 828,
956, 102v7, 1056, 1225, 1266, 1309, 1335, 1474, 1508, 1612,
(R)-5-(Benzyloxy)-3-(hydroxymethyl)-6-methoxyisobenzofuran-
1(3H)-one (5t). Yield: 94%, colorless solid; mp 126–128 °C;
[α]D25 −78.22 (c 1.10, CHCl3); IR (CHCl3): 689, 825, 975, 1025,
1076, 1223, 1268, 1312, 1334, 1494, 1528, 1621, 1752, 2924,
1
1752, 2922, 3023, 3358 cm−1; H NMR (200 MHz, CDCl3):
1
3032, 3385 cm−1; H NMR (200 MHz, CDCl3): 2.31 (brs, 1H),
2.71 (t, J = 6.44 Hz, 1H), 3.81–3.90 (m, 1H), 3.93 (s, 3H), 3.99
(s, 3H), 4.04–4.15 (m, 1H), 5.42–5.47 (m, 1H), 6.93 (s, 1H),
7.25 (s, 1H); 13C NMR (DMSO-d6): δ 56.1, 56.3, 62.4, 81.7,
105.0, 105.8, 117.9, 142.4, 150.4, 154.6, 170.6; HRMS (ESI)
calcd for: C11H12O5 [M + H]+ 225.0763, found 225.0772.
3.75–3.85 (m, 1H), 3.92 (s, 3H), 3.98–4.06 (m, 1H), 5.22 (s,
2H), 5.36–5.41 (m, 1H), 6.92 (s, 1H), 7.28 (s, 1H), 7.32–7.45
(m, 5H); 13C NMR (CDCl3): δ 56.2, 64.1, 71.1, 81.0, 105.4,
106.6, 118.7, 127.3, 128.4, 128.8, 135.6, 140.9, 151.3, 154.0,
170.5; HRMS (ESI) calcd for: C17H16O5 [M + H]+ 301.1076,
found 301.1072.
(R)-3-(Hydroxymethyl)-6,7-dimethoxyisobenzofuran-1(3H)-one
(5p). Yield: 94%, colorless solid; mp 85–88 °C; 99% ee by
chiral HPLC analysis (Chiracel OJ-H, n-hexane–iPrOH, 90 : 10,
0.5 mL min−1) retention time 18.27 (99.36%) and 20.93
(0.64%); [α]D25 −78.21 (c 1.0, CHCl3); IR (CHCl3): 698, 798,
956, 1030, 1067, 1220, 1328, 1339, 1458, 1605, 1745, 2976,
(R)-5-Fluoro-3-(hydroxymethyl)isobenzofuran-1(3H)-one (5u).
Yield: 94%, gum; [α]2D5 −77.21 (c 1.21, CHCl3); IR (CHCl3):
689, 825, 975, 1025, 1076, 1223, 1268, 1312, 1334, 1494,
1528, 1621, 1752, 2924, 3032, 3385 cm−1; 1H NMR (500 MHz,
CDCl3): 2.87 (brs, 1H), 3.93 (dd, J = 4.04, 12.59 Hz, 1H), 4.11
This journal is © The Royal Society of Chemistry 2012
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(dd, J = 4.04, 12.59 Hz, 1H), 5.51–5.53 (t, J = 4.04 Hz, 1H),
7.21–7.27 (m, 2H), 7.88–7.91 (m, 1H); 13C NMR (CDCl3): δ
63.5, 80.9, 109.7 (d, J = 24.64 Hz), 117.7 (d, J = 24.64 Hz),
122.6, 128.2 (d, J = 9.48 Hz), 149.7 (d, J = 9.48 Hz), 167.3 (d, J
= 398.54 Hz), 167.9; HRMS (ESI) calcd for: C9H7FO3 [M +
H]+ 183.0457, found 183.0463.
Analysis: C18H26O6 requires C 63.89, H 7.74 found C 63.81, H
7.68%.
(S)-3-((S)-Hydroxy(phenyl)methyl)-5,7-dimethoxyisobenzofuran-
1-(3H)-one (13a). Yield: 93%; colorless solid; mp 170–172 °C;
[α]D25 + 78.02 (c 1.20, CHCl3), 99% ee (Mosher’s ester analysis);
IR (CHCl3): 695, 759, 953, 1045, 1073, 1205, 1331, 1463,
1625, 1754, 2981, 3014, 3440 cm−1 1H NMR (500 MHz,
;
(R)-3-(Hydroxymethyl)-5,6-dioxomethylisobenzofuran-1(3H)-
one (5v). Yield: 93%, colorless solid; mp 144–145 °C; [α]2D5
−78.11 (c 1.20, CHCl3); IR (CHCl3): 698, 852, 957, 1024,
1067, 1232, 1286, 1319, 1343, 1484, 1582, 1612, 1766, 2942,
MeOH-d4): δ 3.69 (s, 3H), 3.85 (s, 3H), 4.81 (d, J = 6.41 Hz,
1H), 5.48 (d, J = 6.41 Hz, 1H), 5.87 (d, J = 1.9 Hz, 1H), 6.39
(d, J = 1.9 Hz, 1H), 7.29–7.32 (m, 5H); 13C NMR (CDCl3 +
CD3OD): δ 56.3, 76.0, 84.1, 100.0, 100.2, 107.8, 128.3, 128.9,
129.2, 139.5, 152.3, 160.2, 167.4, 170.2; HRMS (ESI) calcd for:
C17H16O5 [M + H]+ 301.1076, found 301.1081.
1
3054, 3389 cm−1; H NMR (200 MHz, CDCl3): 2.40 (brs, 1H),
3.84 (dd, J = 4.05, 12.47 Hz, 1H), 4.06 (dd, J = 4.05, 12.47 Hz,
1H), 5.41 (m, 1H), 6.13 (d, J = 2.33 Hz, 2H), 6.87 (s, 1H), 7.20
(s, 1H); 13C NMR (DMSO-d6): δ 62.1, 81.3, 102.8, 103.3,
119.8, 144.5, 149.1, 153.3, 169.6; HRMS (ESI) calcd for:
C10H8O5 [M + H]+ 209.0450, found 209.0454.
(R)-3-((R)-Hydroxy(phenyl)methyl)-5,7-dimethoxyisobenzo-
furan-1-(3H)-one (13b). Yield: 93%; colorless solid; mp
170–172 °C; [α]D25 −77.56 (c 1.15, CHCl3), 99% ee (Mosher’s
ester analysis); IR (CHCl3): 698, 759, 947, 1041, 1077, 1204,
(R)-3-((R)-1-Hydroxybutyl)isobenzofuran-1(3H)-one (5w). Yield:
93%; colorless solid; mp 103–109 °C; [α]D25 −76.89 (c 1.0,
CHCl3); IR (CHCl3): 694, 728, 1080, 1212, 1287, 1467, 1618,
1336, 1461, 1625, 1754, 2981, 3018, 3444 cm−1 cm−1 1H
;
NMR (500 MHz, MeOH-d4): δ 3.61 (s, 3H), 3.84 (s, 3H), 4.77
(d, J = 6.41 Hz, 1H), 5.45 (d, J = 6.41 Hz, 1H), 5.78(d, J = 1.7
Hz, 1H), 6.35 (d, J = 1.7 Hz, 1H), 7.29–7.32 (m, 5H); 13C NMR
(CDCl3 + CD3OD): δ 56.1, 76.0, 83.9, 99.9, 102.9, 107.6,
128.2, 128.8, 129.0, 139.2, 152.0, 159.9, 167.1, 169.8; HRMS
(ESI) calcd for: C17H16O5 [M + H]+ 301.1076, found 301.1081.
1
1752, 2873, 2959, 3433 cm−1; H NMR (200 MHz, CDCl3): δ
0.93 (t, J = 6.86 Hz, 3H), 1.44–1.72 (m, 4H), 1.97 (brs, 1H),
3.99 (brs, 1H), 5.40 (d, J = 3.68 Hz, 1H), 7.51–7.57 (m, 2H),
7.65–7.73 (m, 1H), 7.87–7.92 (m, 1H); 13C NMR (CDCl3): δ
13.9, 18.8, 34.9, 71.9, 83.3, 122.5, 125.7, 126.6, 129.3, 134.0,
147.3, 170.5; Analysis: C12H14O3 requires C 69.88, H 6.84
found C 69.82, H 6.81.
(S)-3-((S)-1-Hydroxyethyl)-5,7-dimethoxyisobenzofuran-1(3H)-
one (15). Yield: 93%; colorless solid; mp 139–140 °C; [α]2D5
+
(R)-3-((R)-1-Hydroxy-2-tertiarybutyldimethylsilylethyl)-5,6-
dimethoxyisobenzofuran-1(3H)-one (5x). Yield: 94%, colorless
solid; mp 166–168 °C; [α]D25 −79.24 (c 1.10, CHCl3); IR
(CHCl3): 775, 837, 1060, 1137, 1471, 1503, 1740, 2855, 2926,
76.89 (c 1.10, CHCl3); IR (CHCl3): 692, 771, 954, 1036, 1063,
1237, 1329, 1361, 1454, 1611, 1725, 2986, 3008, 3447 cm−1
;
1H NMR (200 MHz, CDCl3): δ 1.33 (d, J = 6.4 Hz, 3H), 2.0
(brs, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 4.09–4.15 (m, 1H), 5.17(d,
J = 3.99 Hz, 1H), 6.42 (d, J = 1.8 Hz, 1H), 6.52 (d, J = 1.8 Hz,
1H); 13C NMR (CDCl3): δ 18.7, 55.9, 68.6, 82.6, 98.3, 99.1,
107.5, 151.9, 159.7, 166.7, 168.0; HRMS (ESI) calcd for:
C12H14O5 [M + H]+ 239.0919, found 239.0923.
1
3406 cm−1; H NMR (200 MHz, CDCl3): 0.08 (d, J = 5.45 Hz,
6H), 0.90 (s, 9H), 2.30 (d, J = 5.50 Hz, 1H), 3.62–3.82 (m, 2H),
3.94 (s, 3H), 3.98 (s, 3H), 4.05–4.12 (m, 1H), 5.51 (d, J = 3.49
Hz, 1H), 6.98 (s, 1H), 7.28 (s, 1H); 13C NMR (CDCl3): δ −5.0,
−4.5, 17.9, 25.6, 56.2, 63.2, 73.3, 80.2, 104.2, 106.0, 118.9,
141.6, 150.6, 154.6, 170.6; Analysis: C18H28O6Si requires C
58.67, H 7.66 found C 58.65, H 7.68%.
(+) Matteucen C (2a). Yield: 68%; colorless powder; [α]2D5
+
54.18 (c 1.0, MeOH); IR (CHCl3): 691, 710, 1169, 1615, 1684,
1
1725, 3364 cm−1; H NMR (500 MHz, DMSO-d6): δ 4.94 (t, J
(R)-3-((R)-Hydroxy(phenyl)methyl)-5,6-dimethoxyisobenzofuran-
1(3H)-one (5y). Yield: 94%, colorless solid; mp 113–115 °C;
[α]D25 −79.23 (c 1.15, CHCl3); IR (CHCl3): 756, 857, 974, 1026,
= 4.8 Hz, 1H), 5.44 (d, J = 4.0 Hz, 1H), 5.72 (d, J = 4.8 Hz,
1H), 6.23 (d, J = 1.8 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H),
7.24–7.36 (m, 5H), 10.29 (s, 1H), 10.31 (s, 1H); 13C NMR
(CDCl3): δ 72.6, 81.7, 101.1, 102.3, 104.2, 126.9, 127.2, 127.6,
140.7, 151.5, 157.6, 163.9, 167.7; HRMS (ESI) calcd for:
C15H12O5 [M + H]+ 273.0763, found 273.0766.
1064, 1158, 1216, 1334, 1604, 1743, 2858, 2928, 3430 cm−1
;
1H NMR (200 MHz, CDCl3): 3.05 (brs, 1H), 3.64 (s, 3H), 3.90
(s, 3H), 4.69 (d, J = 7.44 Hz, 1H), 5.47 (d, J = 7.44 Hz, 1H),
5.85 (s, 1H), 7.20 (s, 1H), 7.34–7.41 (m, 5H); 13C NMR (CDCl3
+ CD3OD): δ 54.7, 74.4, 83.0, 104.3, 117.4, 126.7, 127.4,
138.2, 140.6, 149.8, 153.6, 170.7; Analysis: C17H16O5 requires
C 67.99, H 5.37 found C 67.92, H 5.41%.
(−) Matteucen C (2b). Yield: 68%; colorless powder; [α]2D5
−54.16 (c 1.0, MeOH); IR (CHCl3): 691, 710, 1169, 1615,
1684, 1725, 3364 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 4.94
(t, J = 4.8 Hz, 1H), 5.44 (d, J = 4.0 Hz, 1H), 5.73 (d, J = 4.8 Hz,
1H), 6.23 (d, J = 1.8 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H),
7.27–7.36 (m, 5H), 10.30 (s, 1H), 10.33 (s, 1H); 13C NMR
(CDCl3): δ 72.6, 81.7, 101.1, 102.3, 104.2, 126.9, 127.3, 127.6,
140.7, 151.5, 157.6, 163.9, 167.7; HRMS (ESI) calcd for:
C15H12O5 [M + H]+ 273.0763, found 273.0766.
(R)-3-((R)-1-Hydroxyheptyl)-5,6,7-trimethoxyisobenzofuran-
1(3H)-one (5z). Yield: 92%, colorless solid; mp 113–115 °C;
[α]D25 −78.36 (c 1.08, CHCl3); IR (CHCl3): 796, 1089, 1130,
1254, 1326, 1465, 1543, 1749, 2898, 2974, 3988 cm−1 1H
;
NMR (200 MHz, CDCl3): 0.87–0.93 (m, 3H), 1.26–1.37 (m,
8H), 1.64–1.78 (m, 3H), 3.87 (s, 3H), 3.94–3.96 (m, 4H), 4.13
(s, 3H), 5.23 (d, J = 3.09 Hz, 1H), 6.68 (s, 1H); 13C NMR
(CDCl3): δ 14.1, 22.5, 25.7, 29.2, 31.7, 32.9, 56.4, 61.3, 62.2,
72.1, 81.7, 99.9, 111.2, 141.8, 145.3, 152.3, 159.6, 168.1;
3-Butylphthalide (3). Yield: 86%; Colourless oil; [α]D25 −62.1
(c 1.15, CHCl3, ee = 99%); lit.,2i [α]2D2 −62 (c 4.2, CHCl3, ee =
99%); IR (CHCl3): 780, 1346, 1465, 1526, 1716, 2932 cm−1; 1H
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NMR (200 MHz, CDCl3): δ 0.88–0.95 (m, 3H), 1.32–1.53 (m,
4H), 1.68–1.86 (m, 1H), 1.97–2.07 (m, 1H), 5.46 (q, J = 7.6 Hz,
1H), 7.42 (dd, J = 1.13, 7.6 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H),
7.66 (td, J = 1.13, 7.4 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H); 13C
NMR (CDCl3): δ 13.9, 22.4, 26.9, 34.4, 81.3, 121.9, 125.5,
129.0, 133.9, 150.1, 170.3; HRMS (ESI) calcd for: C12H14O2
[M + H]+ 191.1072, found 191.1069.
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Demethyl pestaphthalide (16)
Yield: 78%; colorless solid; mp 102–104 °C; [α]D25 + 61.4 (c
0.50, MeOH, ee = 99%); lit.,7b [α]1D9 + 60.7 (c 0.29, MeOH); IR
(CHCl3): 1060, 1164, 1220, 1280, 1330, 1360, 1480, 1620,
1
1710, 1730 cm−1; H NMR (400 MHz, DMSO-d6): δ 1.03 (d, J
= 6.4 Hz, 3H), 4.0 (m, 1H), 4.91 (brs, 1H), 5.13(d, J = 3.0 Hz,
1H), 6.27 (brs, 1H), 6.36 (brs,1H), 10.28 (br, 2H); 13C NMR
(DMSO-d6): δ 18.4, 66.3, 81.8, 100.9, 102.4, 104.2, 152.1,
157.8, 164.2, 168.0; HRMS (ESI) calcd for: C10H10O5 [M + H]+
211.0606, found 211.0612.
Acknowledgements
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We thank CSIR, UGC and DST, New Delhi (sanction no. SR/
S1/OC-67/2010) for financial support. Authors also thank Dr
V. V. Ranade, Head, CE-PD and Dr B. D. Kulkarni for their con-
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