Synthesis of chiral 3-substituted phthalides by a sequential organocatalytic enantioselective aldol-lactonization reaction. Three-step synthesis of (S)-(-)-3-butylphthalide

Article abstract of DOI:10.1021/jo902118x

(Chemical Equation Presented) The development of efficient methods for the facile construction of important molecular frameworks is an important goal in organic synthesis. Chiral 3-substituted phthalides are widely distributed in a large collection of natural products with broad, potent, and potentially path-pointing biological activities. In this investigation, we have uncovered an unprecedented organocatalytic asymmetric aldol-lactonization reaction of 2-formylbenzoic esters with ketones/aldehydes for convenient construction of the enantioenriched "privileged" scaffold. As a result of the sensitive nature of substrate structures of an organocatalytic enantioselective aldol reaction, after extensive optimization of reaction conditions, catalyst L-prolinamide alcohol IV is identified as the best promoter. Interestingly, it is found that in this reaction, addition of an acid additive PhCO₂H can significantly enhance reaction efficiency with use of only as low as 2.5 mol % IV for the process. Moreover, due to the sensitivity of reaction conditions toward a sequential aldol-lactonization process without affecting enantioselectivity and racemization, it is essential to remove the catalyst for the subsequent facile lactonization reaction in the presence of K ₂CO₃. The aldol-lactonization processes serve as a powerful approach to the preparation of synthetically and biologically important 3-substitued phthalides with a high level of enantioselectivities. A 3-step catalytic asymmetric synthesis of the natural product of 3-butylphthalide is reported.

Full text of DOI:10.1021/jo902118x

pubs.acs.org/joc
Synthesis of Chiral 3-Substituted Phthalides by a Sequential
Organocatalytic Enantioselective Aldol-Lactonization Reaction.
Three-Step Synthesis of (S)-(-)-3-Butylphthalide
Haoyi Zhang,† Shilei Zhang,†,§ Lu Liu,† Guangshun Luo,† Wenhu Duan,*,†,‡ and
Wei Wang*,†,‡,§
†Department of Pharmaceutical Sciences, School of Pharmacy, East China University of Sciences &
Technology, Shanghai 200237, China, ‡Shanghai Institute of Materia Medica, Shanghai Institutes of
Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China, and §Department of Chemistry
and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001
wwang@unm.edu
Received October 5, 2009
The development of efficient methods for the facile construction of important molecular frameworks
is an important goal in organic synthesis. Chiral 3-substituted phthalides are widely distributed in a
large collection of natural products with broad, potent, and potentially path-pointing biological
activities. In this investigation, we have uncovered an unprecedented organocatalytic asymmetric
aldol-lactonization reaction of 2-formylbenzoic esters with ketones/aldehydes for convenient con-
struction of the enantioenriched “privileged” scaffold. As a result of the sensitive nature of substrate
structures of an organocatalytic enantioselective aldol reaction, after extensive optimization of
reaction conditions, catalyst L-prolinamide alcohol IV is identified as the best promoter. Interest-
ingly, it is found that in this reaction, addition of an acid additive PhCO2H can significantly enhance
reaction efficiency with use of only as low as 2.5 mol % IV for the process. Moreover, due to the
sensitivity of reaction conditions toward a sequential aldol-lactonization process without affecting
enantioselectivity and racemization, it is essential to remove the catalyst for the subsequent facile
lactonization reaction in the presence of K2CO3. The aldol-lactonization processes serve as a
powerful approach to the preparation of synthetically and biologically important 3-substitued
phthalides with a high level of enantioselectivities. A 3-step catalytic asymmetric synthesis of the
natural product of 3-butylphthalide is reported.
Introduction
biological activities.1 Some representative examples are de-
scribed in Figure 1. 3-Butylphthalide (1a), a component in
the Chinese folk medicine extracted from celery seed oil,2a is
in phase II clinical trials in China and potentially can be used
for the treatment of stroke.2b Moreover, it is employed for
The discovery of new synthetic methodologies for the
facile construction of biologically interesting complex mole-
cular architectures in an efficient way from readily available
starting materials is of considerable significance in chemical
synthesis. The importance of chiral 3-substituted phthalide
(1(3H)-isobenzofuranone) frameworks is underscored by
their wide distribution in a large collection of natural pro-
ducts with broad, potent, and potentially path-pointing
(1) For recent reviews of synthesis and biological applications of phtha-
lides, see: (a) Lin, G.; Chan, S. S.-K.; Chung, H.-S.; Li, S. L. Stud. Nat. Prod.
Chem. 2005, 611. (b) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891. (c)
Xioang, M. J.; Li, Z. H. Curr. Org. Chem. 2007, 11, 833.
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Z.; Hu, G. Y.; Tan, G. S. Chin. J. Modern Med. 2004, 93. (c) Yu, S.; You, S.;
Chen, H. Yaoxue Xuebao 1984, 101, 486. (d) Sato, H.; Yorozu, H.; Yamaoka,
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*To whom correspondence should be addressed. Phone: (505) 277-0756.
Fax: (505) 277-2609.
368 J. Org. Chem. 2010, 75, 368–374
Published on Web 12/14/2009
DOI: 10.1021/jo902118x
r
2009 American Chemical Society

Zhang et al.
JOCArticle
FIGURE 1. Selected examples of natural occurring chiral 3-substituted phthalides with reported biological activities.
seasoning and flavoring purposes, shows anticonvulsant
action,2c increases the duration of anesthesia,2d and exhibits
cerebral antiischemic action.2e Fuscinarin (1b) is a potent
human CCR5 antagonist, effectively blocking HIV entry
into host cells.3 (-)-Hydrastine (1c) is active at the opioid
receptor.4 In addition, it possesses antipaclitaxel-resistant
human ovarian cancer activity through c-Jun kinase-
mediated apoptosis and it is in phase I clinical trials.5
Vermistatin (1d) and alcyopterosin E (1e) display cytotoxic
activity,6 whereas cytosporone E (1f)7 and CJ-12,954 (1g)8
and isoochracinic acid (1h) and herbaric acid (1i),9 crypho-
nectric acid (1j),10 and (-)-rubiginone-H (1k)11 are anti-
bacterial and/or antibiotic reagents. The bioactivities of
(-)-typhaphthalide (1l),12 spirolaxine (1m),13 and (þ)-mona-
scodilone (1n)14 are unknown. Furthermore, the absolute
configurations of a number of these natural products such as
1b, 1g, 1h, 1i, 1j, 1k, and 1n have not been established.
Accordingly, efficient asymmetric methods for the facile
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J. Org. Chem. Vol. 75, No. 2, 2010 369

Zhang et al.
JOCArticle
construction of the chiral 3-substituted phthalide architec-
tures can lead to convenient approaches to these biologically
intriguing natural products. Consequently their ready avail-
ability enables them to serve as effective chemical tools for
the elucidation of the functions of proteins/receptors. More-
over, these asymmetric strategies will afford useful methods
for establishing absolute configurations of these natural
products including 1b, 1g, 1h, 1i, 1j, 1k, and 1n.
conditions. We have successfully applied the powerful meth-
od for efficient synthesis of natural product (S) 3-butyl-
phthalide in three steps with high yields and high enantio-
selectivity.
Results and Discussion
Design Plan. Aldol reactions are a cornerstone of synthetic
organic chemistry.24 A wealth of imaginative reagents, cata-
lysts, and protocols have been devised for the synthesis of
structurally diversified building blocks and targets. In recent
years, considerable attention has been directed toward de-
veloping organocatalytic asymmetric aldol reactions.25,26
Given the biological importance of the chiral 3-substituted
phthalides, the molecular architectures have become a plat-
form for new synthetic methodology development.1 In spite
of significant progress being made, asymmetric syntheses of
the scaffolds are very limited.15 Chiral auxiliaries, precur-
sors, and resolutions have been intensively explored for such
purposes.16 Despite the fact that catalytic approaches are
particularly appealing, only a handful of examples relying on
the use of organometallics have been reported to date.
Noyori reported the first catalytic asymmetric method using
an enantioselective transfer hydrogenation reaction for the
generation of the chiral 3-substituted phthalides.17 A chiral
amine alcohol mediated addition of zinc reagent to alde-
hydes was illustrated by Butsugan et al.18 Lin and co-workers
reported a Ni(II)/(S)-BINAP complex catalyzed asymmetric
tandem process.19 Tanaka20 and Yamamoto21 indepen-
dently disclosed highly enantioselective Rh(I)-catalyzed
one-pot transesterification and [2þ2þ2] cycloaddition to
afford the chiral frameworks. Trost and Weiss described
an elegant prophenol-promoted enantioselective alkynyl-
ation as a key step for the formation of enantioenriched
phthalides.22 Recently, Cheng and co-workers reported a
CoI2(S,S)dipamp-catalyzed cyclization approach to the
chiral scaffold.23
In contrast to the use of the chiral organometallics as
promoters, the employment of organocatalysts for the synth-
esis of chiral 3-substituted phthalides has not been dis-
closed.24 Moreover, there is ample room for improvement
and new efficient methods are needed in this area, with
respect to safety of reagents, catalysts, catalyst loadings,
stereoselectivities, overall efficiency, atom economy, and
methods with generation of functional diversity. Toward
this end, we wish to detail a new highly efficient organo-
catalytic enantioselective aldol-lactonization process for
the facile preparation of chiral 3-substituted phthalides
from simple achiral starting materials under mild reaction
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SCHEME 1. Synthesis of Chiral 3-Substituted Phthalides by a New Organocatalytic Asymmetric Aldol-Lactonization Reaction
JOCArticle
We envision that through the design of specific substrates, a
new strategy with incorporation of an unprecedented orga-
nocatalytic asymmetric aldol-initiated lactonization reaction
can be implemented for the efficient preparation of biologi-
cally significant chiral 3-substituted phthalides (Figure 1 and
Scheme 1).27,28 To our knowledge, such an organocatalytic
asymmetric aldol-lactonization reaction for the synthesis of
the molecular architectures has not been reported.29,30 To
successfully develop an organocatalytic asymmetric aldol-
lactonization reaction, we surmise that the key issue is to
design a functionalized aldol acceptor. In the process, it is
imaged that the use of 2-formylbenzoic esters 3 as one of the
essential reactants is required. They have an amphiphilic
function (Scheme 1). They serve as an aldol acceptor for
the aldol reaction. They also function as the electrophile for
the subsequent lactonization. It is realized that although
organocatalytic asymmetric aldol reactions of aryl aldehydes
with ketones or aldehydes have been intensively studied,25,26
the asymmetric aldol reaction of 2-formylbenzoic esters 3
with ketones/aldehydes 4 has not been reported. Due to the
sensitive nature of substrate structures, the enantioselectivity
and reaction yield of an aldol reaction varies significantly.
We speculate that the steric and electronic effect posed by the
O-ester moiety would have a dramatic influence on the
outcome of the aldol process. It is realized that 2-alkyl aryl
aldehydes as substrates for organocatalytic aldol reactions
have been less studied.31 Moreover, generally poorer enan-
tioselectivities were observed, as compared with less hin-
dered meta- and para-substituted benzaldehydes. Therefore,
seeking an optimal promoter is critical for the specific highly
enantioselective aldol reaction. Furthermore, a reaction
condition, which can accommodate a subsequent facile
lactonization without affecting the enantioselectivity of the
aldol reaction and racemization, presents another significant
challenge. Finally, highly efficient organocatalytic aldol
reactions with low catalyst loading (<5 mol %) are in high
demand for practical applications and such examples are
rarely seen in the existing protocols.26f,g,n,o
Optimization of Reaction Conditions. As discussed above,
a critical issue, which needs to be addressed in developing a
catalytic asymmetric approach to the aldol-lactonization
reaction, is the identification of proper organocatalysts.
Consequently, our initial studies focus on screening different
amine-based organocatalysts. To prove the feasibility of the
proposed catalytic enantioselective aldol-lactonization pro-
cess, initially an aldol reaction of methyl 2-formylbenzoate
3a in acetone 4a was probed in the presence of L-proline, an
effective catalyst in aldol reactions (Table 1 and Figure 2).26a
It was found that under the reaction condition, the major
product was aldol adduct 5a, which did not undergo a
subsequent complete lactonization reaction in a one-pot
operation. After multiple attempts, we found that by simple
removal of the catalyst through a short silica gel pad, the
lactonization proceeded smoothly to give phthalide 2a in
an almost quantitative yield when the intermediate 5a was
treated with K2CO3 (1.5 equiv) in MeOH/acetone (1:10, v/v)
at rt for 15 min.
Under the reaction conditions, 2a was obtained in 56%
yield and with moderate enantioselectivity (65% ee, Table 1,
entry 1). The mediocre results prompted us to screen other
organocatalysts aimed at improving enantioselectivity to
reach a useful level with the specific methyl 2-formylbenzo-
ate 3a. Although a number of chiral pyrrolidines have been
used in asymmetric aldol reactions, we are particularly
interested in those displaying high catalytic activity and
enantioselectivity toward acetone as donor and aryl alde-
hydes as acceptor related reactions since such systems are
close to the current one. In the first attempt with (S)-
pyrrolidine sulfonamide II, surprisingly a racemic mixture
was obtained (Table 1, entry 2).26k C2-Symmetric bisproli-
namide III gave a high yielding but disappointing enantio-
merically enriched product (entry 3) despite the fact that it
exhibited high enantioselectivity with simple aryl aldehyde
aldol acceptors.26g These studies indicate that indeed the
O-methyl ester moiety has a pronounced effect on the aldol
reaction. Considering the steric effect of the specific sub-
strate 3a and high catalytic activity observed with pyrrolidine
amide III, we reasoned that a bulky pyrrolidine amide could
be a good choice for the aldol-lactonization reaction. Re-
cently, we have successfully identified catalyst IV as a
promoter, originally developed by Singh et al.,26l for the
aldol reaction of acetone with R-amino aldehydes in the
synthesis of antibiotic linezolid.32 Notably, good enantio-
selectivity (88% ee) was achieved. With these results in mind,
we examined its suitability for this reaction. To our delight,
encouraging results (86% yield and 80% ee, entry 4) are seen.
(29) For a recent review of aldol-lactonization reactions, see: (a) Purohit,
V. C.; Matla, A. S.; Romo, D. Heterocycles, 2008, 76, 949. For selected recent
examples see: (b) Mitchell, T. A.; Zhao, C.-X.; Romo, D. Angew. Chem., Int. Ed.
2008, 47, 5026. (c) Cho, S. W.;Romo, D. Org. Lett. 2007, 9, 1537. (d) Chiang, P. C.;
Kaeobamrung, M.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520. (e)
Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, S. J. Am. Chem. Soc. 2006, 128,
8736. (f) Ullah, E.;Appel, B.;Fischer, C.; Langer, P. Tetrahedron2006, 62, 9694. (g)
Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205. (h) Sohn, S. S.;
Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370. (i) Kongsaeree, P.;
Meepowpan, P.; Thebtaranonth, Y. Tetrahedron: Asymmetry 2001, 12, 1913. (j)
Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945. (k)
Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J. Synlett 1996, 343.
(30) An enantioselective synthesis of isotetronic acids in a one-pot aldol-
lactonization sequence catalyzed by a proline derivative has been reported:
Vincent, J.-M.; Margottin, C.; Berlande, M.; Cavagnat, D.; Buffeteau, T.;
Landais, Y. Chem. Commun. 2007, 4782.
(31) (a) Schwab, R. S.; Galetto, F. Z.; Azeredo, J. B.; Braga, A. L.;
€
~
Ludtke, D. S.; Paixao, M. W. Tetrahedron Lett. 2008, 49, 5094. (b) Huang, J.;
Zhang, X.; Armstrong, D. W. Angew. Chem., Int. Ed. 2007, 46, 9073. (c)
ꢀ
ꢀ
Meciarova, M.; Toma, S.; Berkessel, A.; Koch, B. Lett. Org. Chem. 2006, 3,
437.
(32) Song, L.-R.; Chen, X.-B.; Zhang, S.-L.; Zhang, H.-Y.; Li, P.; Luo,
G.-S.; Liu, W.-J.; Duan, W.-H.; Wang, W. Org. Lett. 2008, 10, 5489.
J. Org. Chem. Vol. 75, No. 2, 2010 371

Zhang et al.
JOCArticle
TABLE 1. Exploration of the Organocatalytic Asymmetric Aldol-Lactonization Reaction of 3a with 4aa
entry
cat.
additive
T (°C)
t (h)
% yieldb
% eec
1d
2
3
4
5
6
7
8
I
II
none
none
none
none
none
none
PhCO2H
AcOH
H3PO4
PhCO2H
PhCO2H
rt
rt
rt
rt
-10
-40
-40
-40
-40
-40
-40
36
36
24
12
12
36
6
20
60
14
24
56
44
91
86
80
71
78
86
32
81
81
65
0
III
IV
IV
IV
IV
IV
IV
IVe
IVf
40
80
85
90
94
89
90
93
96
9
10
11
aReaction conditions: unless specified, see the Experimental Section and the Supporting Information. bIsolated yields. cDetermined by chiral HPLC
analysis (Chiralcel OD-H). d20 mol % used. e5 mol % of IV and 5 mol % of PhCO2H used. f2.5 mol % of IV and 2.5 mol % of PhCO2H used.
TABLE 2. The scope of IV-Catalyzed Aldol-Lactonization Reactions of
Aldehydes 3 with Ketones/Aldehydes 4a
FIGURE 2. Structures of organocatalysts screened.
Lowering reaction temperature resulted in the enhancement
of enantioselectivity (entries 5 and 6).
entry
R1
R2
Me
Me
Me
Me
Me
Me
R3
2
t (h) % yieldb % eec
The general wisdom in bifunctional organocatalysis is that
no additives are needed; nevertheless we found that in this
reaction, addition of an acid additive could significantly
augment reaction efficiency (entries 7-10). Among them
probed, PhCO2H was the best one (entry 7). The reaction
time was dramatically shortened (6 h) in a good yield (78%)
and with high ee (94%). Remarkably, as low as 2.5 mol % of
IV was sufficient for the highly enantioselective aldol-lacto-
nization reaction at -40 °C (entry 11).
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
24
24
30
24
12
40
60
36
12
36
12
91
83
77
84
68
70
53
78
93
73
38
96
97
90
93
91d
96
95
74
94f
97
99i
5-F
5-Cl
5-Br
6-NO2
5-MeO
3,5-(MeO)2 Me
5-Ph
H
Me
(CH2)4
Et
9e
10g
11h
H
H
H 2j
Me 2k
H
aReaction conditions: unless specified, see the Experimental Section
and the Supporting Information. bIsolated yields. cDetermined by chiral
HPLC analysis (Chiralcel OD-H). dAt -20 °C. eThe yield refers to total
yields for all isomers and 10 mol % of IV and 10 mol % of PhCO2H at
0 °C. fOnly anti isomer observed. gThe yield refers to total yields for all
isomers and regioselectivity 20:3 and less substituted as the major one.
hPoor yield (26%) was obtained with IV. However, reaction was carried
out with 2k (3 mmol) and propionaldehyde (6 mmol) in the presence of
20 mol % of L-proline in DMF at 0 °C. iDetermined by converting to a
corresponding acetal for HPLC analysis.
Scope of the Aldol-Lactonization Reactions. The optimal
reaction conditions, uncovered in the exploratory effort, are
exploited to probe the scope of the organocatalyst IV catalyzed
aldol-lactonization reactions. As revealed in Table 2, the
process serves as a general approach to the preparation of
highly enantiomerically enriched, synthetically and biologi-
cally important 3-substituted phthalides 2 with significant
structural variations for both aldol donors and acceptors. A
wide range of substituted methyl o-formylbenzoates 3 with
acetone 4a react smoothly to give lactones 2 with high enantio-
selectivities ranging from 91% to 97% ee (entries 1-7). The
results show that electron-neutral (entry 1), withdrawing
(entries 2-5), and donating (entries 6 and 7) substituents on
the aromatic have little effect on the aldol processes, providing
phthalides 2 with high yields and excellent enantioselectivities
except for the 5-phenyl substrate 3h (entry 8). The steric effect
is limited as well (entry 5).
in 93% yield (entry 9). Unsymmetric ketones can also partici-
pate in the process smoothly, as represented by butanone (97%
ee and 73% yield, entry 10). It is noted that the process is
complicated by regioselectivity. However, a good regioselec-
tivity (20:3) is observed with a product formed at less sub-
stituted site dominantly. Finally, an aldehyde is also evaluated.
It is found that L-proline I is a better promoter for the reaction
of propionaldehyde affording excellent enantioselectivity
(99% ee), albeit low yield (entry 11).
The process is also applicable to a variety of aldol donors. In
addition to acyclic ketones, it is possible to use cyclic ketones as
well. For example, the reaction with cyclohexanone affords
highly enantio- (97% ee) and diastereoselective (anti/syn >
20:1) product 2i with generation of two new stereogenic centers
Three-Step Synthesis of Natural Product (S)-(-)-3-Bu-
tylphthalide (1a). As mentioned above, (S)-(-)-3-butylphtha-
lide 1a is a natural product isolated from celery with a broad
372 J. Org. Chem. Vol. 75, No. 2, 2010

Zhang et al.
JOCArticle
SCHEME 2. Total Synthesis of Natural Product 3-Butylphthalide (1a)
spectrum of intriguing pharmacological activities.1c,2 More-
over, it is in phase II clinical trials in China and potentially can
be used for the treatment of stroke. Therefore, methods for the
efficient synthesis of the natural product and its analogies
are of considerable synthetic and biological significance in
drug discovery. Despite the significant and interesting
biological activity of the simple chiral natural product,
a very limited number of asymmetric total synthesis
methods are available. Moreover, to our knowledge, these
synthetic strategies exclusively rely on the use of chiral
auxiliaries, precursors, or resolutions.16g,h,k-m,o,33 An
enantioselective catalytic approach has not been dis-
closed. Herein we have successfully employed the catalytic
enantioselective aldol-lactonization process as a key step
in the 3-step synthesis of (S)-(-)-3-butylphthalide 1a for
the first time (Scheme 2).
chiral 3-substituted phthalide-derived natural products. This
constitutes our future plan to utilize the powerful synthetic tool
in target-oriented synthesis.
Experimental Section
General Procedure for Aldol-Lactonization Reactions
(Table 2, entry 1 as an example). A mixture of 3a (25 mg,
0.15 mmol), PhCO2H (0.46 mg, 0.00375 mmol), and catalyst
IV (1.4 mg, 0.00375 mmol) in acetone (0.8 mL) was stirred
at -40 °C for 24 h. After completion, the reaction was
indicated by TLC and the reaction mixture was passed
through a 3-4 cm silica gel pad quickly to remove the catalyst,
eluting with acetone. The residue, after removal of solvent,
was treated with K2CO3 (32 mg, 0.18 mmol) in acetone/
methanol 10/1 (v/v, 1 mL), then stirred at rt for 15 min. The
crude product was directly purified by silica gel column eluting
with EtOAc/petroleum (1/10 to 1/2) and the desired product
2a and ee and dr were determined by chiral HPLC analysis and
1H NMR, respectively (see the Supporting Information for
details). 1H NMR (400 MHz, CDCl3, TMS) δ 7.90 (d, 1H, J=
9.5 Hz, ArH), 7.67 (ddd, 1H, J=9.5, 1.5 Hz, ArH), 7.54 (t, 1H,
J=9.5 Hz, ArH), 7.48 (dd, 1H, J=9.5, 1 Hz, ArH), 5.93 (t,1H,
J=8.5 Hz, OCH), 3.14 (dd, 1H, J=8.5, 22.0 Hz, CH2), 2.92
(dd, 1H, J=8.0, 22.0 Hz, CH2), 2.26 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3, TMS) δ 204.4, 170.0, 149.3, 134.3, 129.4,
125.8, 122.3, 76.7, 48.1, 30.6; HPLC (chiralpak OD-H
column) hexanes/iPrOH = 70:30, flow rate 1.0 mL/min, λ =
254 nm, tR = 8.78 (major) min, 11.39 (minor) min, ee 96%;
[R]27D -8.3 (c 1.10, CHCl3); MS (EI) m/z (%) [Mþ] 190.1, 175.0
(10), 147.0 (100), 133.0 (47), 105.0 (25), 77.0 (12); HRMS-ES
m/z [M þ Na]þ calcd for C11H10NaO3 213.0528, found
213.0532.
As shown in Scheme 2, we prepared 3-butylphthalide 1a
in a two-step process including simple thioacetalization34
and desulfurization35 in 66% overall yield from com-
pound ent-2j, which is obtained from an ent-IV-catalyzed
aldol-lactonization reaction (Scheme 2). The spectral data
of 1a are in full agreement with those described in the litera-
ture ([R]27 -66.2 (c 1.08, CHCl3); lit.16o [R]26 -64.7
D
D
(c 1.06, CHCl3, ee 99%); lit.16m [R]27D -71.3 (c 0.23, CHCl3,
ee >99%)). Moreover, this synthesis allows for the deter-
mination of the absolute configuration of the products
from the new asymmetric aldol-lactonization reactions with
catalyst IV.
Conclusion
In conclusion, a new organocatalytic, highly enantioselec-
tive aldol-lactonization process, catalyzed by chiral L-prolin-
amide alcohol IV, has been achieved. The simplicity and
practical nature of the asymmetric protocols presented here
is underscored by the use of simple starting materials and
the generation of synthetically useful, high optically active
3-substituted phthalides under mild reaction conditions.
Moreover, the value of the aldol-lactonization process is
demonstrated in an efficient 3-step synthesis of natural product
(S)-(-)3-butylphthalide in a catalytic asymmetric version for
the first time. It is expected that the synthetic strategy can be
explored in the total synthesis of other biologically interesting
Total Synthesis of Natural Product 3-Butylphthalide (1a).
Compound ent-2j was prepared by following the general proce-
dure of preparing 3-substituted phthalides on a 3 mmol scale
except that the catalyst ent-IV was used. The product was
isolated in 72% yield and with 96% ee.
To a solution of ent-2j (0.408 g, 2 mmol) in 2 mL of dry
CHCl3 were added 1,2-ethanedithiol (0.38 g, 4 mmol)
and TiCl4 (0.57 g, 3 mmol). The mixture was stirred at rt
under N2 for 12 h and then 0.5 mL of water was added at
0 °C to terminate the reaction. The reaction mixture
was diluted with water (20 mL) and extracted with CHCl3
(3 ꢀ 10 mL). The combined organic extracts were washed
with saturated NaHCO3 and dried over Na2SO4. Filtration
and removal of solvent under reduced pressure gave an oil.
The crude product was treated with Raney-Ni (3 g) in EtOH
(20 mL) under reflux for 4 h. The reaction mixture was cooled
to rt, filtered, and concentrated. The residue was purified
by flash silica gel column to give a colorless oil (0.25 g)
in 66% overall yield. 1H NMR (500 MHz, CDCl3, TMS)
δ 7.86 (d, 1H, J=7.5 Hz, ArH), 7.64 (t, 1H, J=7.5 Hz, ArH),
(33) (a) Asami, M.; Mukaiyama, T. Chem. Lett. 1980, 17. (b) Min, Z. L.;
Zhang, Y. H.; Lai, Y. S.; Peng, S. X. Chin. Chem. Lett. 2007, 18, 1361. (c)
Yang, H.; Hu, G.-Y.; Chen, J.; Wang, Y.; Wang, Z.-H. Bioorg. Med. Chem.
Lett. 2007, 17, 5210.
(34) Kumar, V.; Sukh, D. Tetrahedron Lett. 1983, 24, 1289.
(35) Oeveren, A. V.; Jansen, J. F. G. A.; Feringa, B. L. J. Org. Chem.
1994, 59, 5999.
J. Org. Chem. Vol. 75, No. 2, 2010 373

Zhang et al.
JOCArticle
7.49 (t, 1H, J=7.5 Hz, ArH), 7.39 (d, 1H, J=7.5 Hz, ArH),
5.44 (q, 1H, J = 7.8 Hz, OCH), 2.05-1.98 (m, 1H, CH2),
1.75-1.70 (m, 1H, CH2), 1.46-1.29 (m, 2H, CH2), 0.87
(m, 3H, CH3); 13C NMR (100 MHz, CDCl3, TMS) δ 170.6,
150.1, 133.9, 128.9, 125.6, 121.7, 81.4, 34.4, 26.8, 22.4, 13.8;
[R]27 -66.2 (c 1.08, CHCl3), lit.16o [R]26 -64.7 (c 1.06,
D
>99%); MS (EI) m/z [Mþ] (%) 190.1, 133.0 (100), 105.0 (17),
77.0 (7).
Acknowledgment. Financial support of this research is
supported by the School of Pharmacy, East China University
of Science and Technology and the China 111 Project (Grant
No. B07023).
Supporting Information Available: Experimental proce-
dures and 1H and 13C NMR spectra, and chiral HPLC analysis
data for compounds 2, 3, and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
D
D
CHCl3, ee 99%), lit.16m [R]27 -71.3 (c 0.23, CHCl3, ee
374 J. Org. Chem. Vol. 75, No. 2, 2010