Catalytic enantioselective synthesis of chiral phthalides by Sml 2-mediated reductive cyclization of 2-acylarylcarboxylates

Article abstract of DOI:10.1021/ja061114z

A significant new and efficient catalytic asymmetric approach for the highly enantioselective synthesis of chiral phthalides by SmI₂-induced reductive cyclization of 2-acylarylcarbonylates was developed. The combination of (4S,5R)-4,5-diphenyloxazolidin-2-one and 2,2,6,6-tetramethylpiperidine was found to be a very effective catalyst system in the reaction. This method provides a ready access to a broad range of enantiomerically enriched phthalides (up to 99% ee). Copyright

Full text of DOI:10.1021/ja061114z

Published on Web 04/08/2006
Catalytic Enantioselective Synthesis of Chiral Phthalides by SmI2-Mediated
Reductive Cyclization of 2-Acylarylcarboxylates
Ling-Lin Huang,† Ming-Hua Xu,*,†,‡ and Guo-Qiang Lin*,†
Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences, 354 Fenglin Road, Shanghai
200032, China, and Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, China
Received February 16, 2006; E-mail: xumh@mail.sioc.ac.cn
This paper was retracted on May 16, 2007 (J. Am. Chem. Soc. 2007, 129, 6662).
Scheme 1
Phthalide (1(3H)-isobenzofuranone) frameworks are present in
a large number of natural products and biologically active com-
pounds.1 Chiral 3-substituted phthalides therefore are very useful
molecules as valuable pharmacological compounds and versatile
building blocks for medicinal chemistry.2 Over the past two decades,
there have been considerable efforts in the asymmetric synthesis
Scheme 2
of chiral phthalides, and a variety of methods toward introducing
C-3 chirality have been developed.3,4 Although catalytic approaches
appear to be the best and thus are of particular interest, only a few
cases on the synthesis of chiral phthalides by catalytic hydrogenation
and transfer hydrogenation have been reported to date.4 Novel
strategies are still in high demand. In this communication, we report
an efficient and highly enantioselective SmI2-induced reductive
cyclization of 2-acylarylcarbonylates to the corresponding enan-
tiomerically enriched phthalides using a chiral oxazolidinone
catalyst. To our knowledge, this is a significant new example of
asymmetric reaction in carbonyl reduction chemistry5 and samarium
diiodide chemistry.6
We have recently been involved in the SmI2-induced highly
selective reactions toward the asymmetric synthesis of some
structurally important molecules, such as γ-butyrolactones,7a-d,g
vicinal diamines,7e,f and â-amino alcohols.7h In considering phthalide
frameworks, we envisioned that the possible chelation of Sm(III)
with the ortho-ester carbonyl of 2-acylarylcarbonylate substrates
might be able to effectively stabilize and organize the reaction
transition state, thereby allowing the enantioselective reduction to
be achieved using SmI2 in the presence of an appropriate chiral
protonating agent. Optically active phthalides thus could be formed
after the subsequent lactonization (Scheme 1).
Initial experiments were carried out by the reactions of ethyl
2-benzoylbenzoate (1a) with samarium diiodide in the presence of
tert-butyl alcohol. As expected, the reaction proceeded smoothly
under 2 equiv of SmI2 and converted 1a into the corresponding
phthalide product in one step in 88% yield within 2 h at room
temperature.8 Attempts using (R)-BINOL as proton donor instead
of tBuOH gave the product with 14% ee and in 67% yield at -78
°C. Despite a low enantioselectivity, it implies the potential of
asymmetric reduction as we hypothesized above (see Scheme 1).
To achieve high enantioselectivity, the reaction conditions were
carefully screened, and various chiral compounds, including chiral
alcohols, amines, amides, and amino alcohols, were examined as
proton sources. Eventually, we were pleased to find that the optically
active phthalide product 2a could be successfully obtained in high
yield (88%) and excellent enantiomeric excess (98% ee) when the
reaction was performed at -78 to -50 °C in the presence of a
stoichiometric amount of (4S,5R)-4,5-diphenyloxazolidin-2-one (3)9
(Scheme 2). Notably, the enantioselectivity was found be very
sensitive to the reaction temperature, only 39% ee could be attained
under similar conditions at -78 °C.
Having established that (4S,5R)-4,5-diphenyloxazolidin-2-one (3)
could serve as a highly enantioselective protonating agent, we began
to consider that a catalytic enantioselective process of this reaction
might be accomplished using a catalytic amount of 3 in the presence
of a proper achiral protonating agent. The achiral protonating agent
is a proton donor, which can selectively transfer proton to the
deprotonated chiral protonating agent to reproduce the original chiral
protonating agent in the catalytic cycle. Some advances concerning
this concept have recently been reported in the catalytic enanti-
oselective protonation of enolate substrates.10
Following the idea, we then focused our efforts on developing
a suitable achiral protonating agent. Several achiral alcohol, phenol,
and amine compounds were screened in the reaction of 1a with
SmI2.11 Among them, we found that 2,6-diisopropylphenol, diethyl-
amine, and piperidine provided very low yields (<15%) even at
room temperature. Specifically, when more sterically bulky diiso-
propylamine or 2,2,6,6-tetramethylpiperidine was used, no reaction
was observed. The results suggest that these achiral proton donors
are less reactive and should not compete with the chiral 3 if they
coexist in the same reaction. To see the possibility of the catalytic
process, a combination of tert-butyl alcohol (0.1 equiv) and 2,2,6,6-
tetramethylpiperidine (1 equiv) was tested in the reaction of 1a at
room temperature. To our delight, the reaction worked well and
gave the racemic product 2a in 85% yield, which demonstrates the
occurrence of the catalytic reaction.
Encouraged by this result, we further investigated the catalytic
enantioselective reaction using different combinations of proton
donors. Reaction of 1a with SmI2 in the presence of chiral
oxazolidinone 3 (0.1 equiv) and achiral protonating agent (1 equiv)
produced optically active 2a. As revealed in Table 1, 2,6-
diisopropylphenol, diethylamine, and piperidine provided moderate
stereocontrol (entries 1, 2, and 4). The enantioselectivity was found
to be largely influenced by the steric hindrance of the achiral proton-
ating agent. With more sterically bulky diisopropylamine or 2,2,6,6-
tetramethylpiperidine, much higher enantiomeric excess (94-96%)
was obtained (entries 3 and 5). In entry 5, the highest enantiomeric
excess (96%) as well as good yield (80%) was achieved. This result
† SIOC.
‡ SIMM.
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J. AM. CHEM. SOC. 2006, 128, 5624-5625
10.1021/ja061114z CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Screen of Achiral Protonating Agent for Catalytic
Scheme 3
Enantioselective Reaction
entry
achiral protonating agent
yield (%)a
eeb
1
2
3
4
5
6c
2,6-diisopropylphenol
diethylamine
diisopropylamine
piperidine
2,2,6,6-tetramethylpiperidine
2,2,6,6-tetramethylpiperidine
85
79
65
75
80
45
55
65
94
76
96
96
shown that no formation of 2a took place with 2,2,6,6-tetrameth-
ylpiperidine alone, thus suggesting that achiral 2,2,6,6-tetrameth-
ylpiperidine is responsible for the regeneration of chiral oxazoli-
dinone catalyst 3 in the catalytic cycle, as proposed.
a Isolated yield. b Determined by chiral HPLC analysis. c 0.5 equiv of
catalyst 3 was used.
In summary, we have discovered a novel catalytic asymmetric
approach for the highly enantioselective synthesis of chiral phtha-
lides (up to 99% ee) using samarium diiodide protocol. The
combination of chiral oxazolidinone 3 and achiral amine 4
constitutes an efficient catalyst system for the asymmetric reductive
cyclization of a wide range of 2-acylarylcarbonylates. This method
provides new insights to the asymmetric reduction of carbonyl as
well as the asymmetric protonation. Further mechanistic studies of
the new catalytic system and the extension of the method are
currently underway.
Table 2. The SmI2-Induced Catalytic Enantioselective Synthesis
of Chiral Phthalides
entrya
1
R1
R2
2
yield (%)b
eec
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
C6H5
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
80
81
82
83
85
75
72
83
65
62
76
76
80
76
83
80
96
94
96
97
92
97
97
95
96
97
97
95
98
97
99
97
4-CH3C6H4
4-OCH3C6H4
4-FC6H4
Acknowledgment. Financial support from the National Natural
Science Foundation of China (20402018, 203900506), Shanghai
Rising-Star Program (05QMX1467), and the Chinese Academy of
Sciences is acknowledged.
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
4-BrC6H4
3,4-(CH3)2C6H3
3,4-(OCH3)2C6H3
2-naphthyl
2-furanyl
2-thiophenyl
4-BrC6H4
4-Br
C6H5
4-OCH3
4,5-C4H4
4,5-(Cl)2
4-CH3
References
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
C6H5
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3,6-(CH3)2
a See Supporting Information for reaction details. b Isolated yield.
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is almost comparable to that obtained with a stoichiometric amount
of 3. Further decreasing the loading of 3 to 0.05 equiv resulted in
a dramatic decrease of the reaction yield (45%), though the enan-
tiomeric excess was retained (entry 6). Thus, 2,2,6,6-tetrameth-
ylpiperidine turned out to be the best achiral protonating agent
examined.
With the catalytic system optimized, we then turned our attention
to substrate generality. A wide variety of 2-acylarylcarbonylates
(1) were evaluated using the conditions in entry 5 of Table 1.
Gratifyingly, all the reactions afforded phthalide products 2 in
relatively good yields and excellent enantioselectivities (92-99%
ee) (Table 2). It is noteworthy that the enantioselectivity of the
reaction is generally not affected by the substitution of 1. R1 could
be a broad range of aromatic substituents, such as phenyl, naphthyl,
furanyl, or thiophenyl (entries 1-10). Substrates with either
electron-donating or electron-withdrawing groups (R2) on each
aromatic carbon were found to be efficient (entries 11-16).
Assuming an analogous reaction mechanism, the absolute config-
uration of the phthalides obtained was determined to be S by
comparison of optical rotation value11 with that reported for 2a.3h,i
To gain some information on the catalyst system, an experiment
using deuterated 2,2,6,6-tetramethylpiperidine as achiral protonating
agent was conducted. When substrate 1a was reacted under similar
reaction conditions in the combination of 10 mol % of catalyst 3,
formation of the corresponding phthalide product with high
deuterium incorporation at the 3-position (2a-d, ∼80%) was
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t
(8) No phthalide product was observed in the absence of BuOH.
(9) Easily accessible from (1S,2R)-2-amino-1,2-diphenylethanol; see: Kno¨lker,
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Ed. Engl. 1996, 35, 2566.
1
observed by H NMR spectral analysis11 (Scheme 3). This result
(11) For details, see Supporting Information.
strongly indicates that this proton is indeed transferred from the
ND proton of deuterated 2,2,6,6-tetramethylpiperidine. It has already
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