A highly efficient asymmetric synthesis of optically active α,γ-substituted γ-butyrolactones using a chiral auxiliary derived from isosorbide

Article abstract of DOI:10.1021/ol005978f

(equation presented) Using an easily accessible and inexpensive chiral auxiliary derived from isosorbide, optically active α,γ-substituted γ-butyrolactones were obtained in high enantiomeric purity (up to >99% ee for trans) by the Sml₂-induced

Full text of DOI:10.1021/ol005978f

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2229-2232
A Highly Efficient Asymmetric Synthesis
of Optically Active r,γ-Substituted
γ-Butyrolactones Using a Chiral
Auxiliary Derived from Isosorbide
Ming-Hua Xu, Wei Wang, and Guo-Qiang Lin*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenlin Lu,
Shanghai 200032, P. R. China
lingq@pub.sioc.ac.cn
Received April 23, 2000
ABSTRACT
Using an easily accessible and inexpensive chiral auxiliary derived from isosorbide, optically active r,γ-substituted γ-butyrolactones were
obtained in high enantiomeric purity (up to >99% ee for trans) by the SmI -induced reductive coupling of chiral methacrylate 7 with ketones
2
in the presence of (−)-sultam as a proton source.
Compounds bearing the substituted γ-butyrolactone moiety
are widespread in nature and have received much interest
because of their physiological properties.1 Moreover, func-
tionalized γ-butyrolactones are important intermediates for
the synthesis of many organic compounds.2 Much attention
has been focused on the asymmetric synthesis of γ-butyro-
lactones.3 The approach based on SmI2-mediated reductive
radical reactions recently introduced by Fukuzawa4 is one
of the most facile and effective methods for preparing chiral
γ-butyrolactones. However, there has been no report, to the
best of our knowledge, concerning highly enantioselective
synthesis of R,γ-substituted γ-butyrolactones.5 In a previous
paper, we described the asymmetric synthesis of optically
active γ-methyl-γ-phenyl-γ-butyrolactone using easily ac-
cessible and inexpensive chiral auxiliaries derived from
(1) (a) Drioli, S.; Felluga, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin,
E. J. Org. Chem. 1998, 63, 2385-2388. (b) Rodriguez, C. M.; Martin, T.;
Martin, V. S. J. Org. Chem. 1996, 61, 8448-8452.
V.; Prabhakaran, J.; George, T. G. Tetrahedron 1997, 44, 15061-15068.
(j) Taniguch, N.; Uemura, M. Tetrahedron Lett. 1997, 38, 7199-7202. (k)
Merlic, C. A.; Walsh, J. C. Tetrahedron Lett. 1998, 39, 2083-2086. For
catalysis mediated by chiral metal complexes, see: (l) Ohkuma, T.;
Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509-5512. (m)
Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L.; Bode, J. W. J. Org. Chem.
1995, 60, 6654-6655. (n) Yu, W. Y.; Bensimon, C.; Alper, H. Chem. Eur.
J. 1997, 3, 417-423. (o) Cao, P.; Zhang, X. J. Am. Chem. Soc. 1999, 121,
7708-7709. For ligand-controlled asymmetric synthesis, see: (p) Mikami,
K.; Yamaoka, M. Tetrahedron Lett. 1998, 39, 4501-4504.
(2) (a) Koch, S. S. C.; Chamberline, A. R. J. Org. Chem. 1993, 58, 2725-
2737. (b) Grimm, E. L.; Reissig, H. U. J. Org. Chem. 1985, 50, 242-244.
(3) For transformation of chiral natural products, see: (a) Suzuki, Y.;
Mori, W.; Ishizone, H.; Naito, K.; Honda, T. Tetrahedron Lett.1992, 33,
4931-4932. (b) Yoda, H.; Shirakawa, K.; Takabe, K. Chem. Lett. 1991,
489-490. (c) Yoda, H.; Shirakawa, K.; Takabe, K. Tetrahedron Lett.1991,
32, 3401-3404. For dehydration of chiral γ-hydroxyl acid, see: (d)
Ramachandran, P. V.; Krzeminski, M. P.; Venkat, M.; Reddy, R.; Brown,
H. C. Tetrahedron: Asymmetry, 1999, 10, 11-15. (e) Boly, V.; Vigneron,
J. P. Tetrahedron Lett. 1980, 21, 1735. (f) Brown, H. C.; Kulkarni, S. V.;
Racherla, U. S. J. Org. Chem. 1994, 59, 365-369. For induction of chiral
auxiliaries, see: (g) Yammamoto, Y.; Sakamoto, A.; Nishioka, T.; Oda, J.;
Fukazawa, Y. J. Org. Chem. 1991, 56, 1112-1119. (h) Nair, V.;
Prabhakaran, J. J. Chem. Soc., Perkin Trans. 1 1996, 593-594. (i) Nair,
(4) Fukuzawa, S.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem.
Soc. 1997, 119, 1482-1483.
(5) During the preparation of this manuscript, a method was reported
for the synthesis of cis-R,γ-dialkyl γ-lactones using chiral sec-dialkyl
bishomopropargylic alcohols as the reactant; see: Diaz, D.; Martin, V. S.;
Org. Lett. 2000, 2, 335-337.
10.1021/ol005978f CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000

isomannide and isosorbide.6 Herein, we wish to report a new
reaction system that can be easily and effectively used for
the synthesis of optically active R,γ-substituted γ-butyro-
lactones.
the product’s optical rotation is (-)] or 47% [(+)] and in
good yield, 89% or 83%, respectively. These results clearly
showed that the configuration of the product was largely
determined by the stereochemistry of the proton source
employed.
On the basis of the low or moderate level of enantiose-
lectivity of the asymmetric protonation, we turned our focus
on the asymmetric synthesis induced by a chiral auxiliary.
Recently, our group became interested in asymmetric reac-
tions based on the application of isomannide and isosorbide
derivatives as chiral auxiliaries 6,10 Isomannide and isosorbide
are inexpensive, and commercially available carbohydrate
derivatives, substrates 5-7 (Figure 2), were easily prepared
It has been found that, in the reaction of R,â-unsaturated
esters with ketones mediated by SmI2 as an electron-transfer
agent, the presence of an alcohol is essential for the formation
of the γ-butyrolactones. The effect of a proton source in the
reaction was examined by Fukuzawa and co-workers in
1988,7 and tert-butyl alcohol was found to give the most
satisfactory results. Deuterium exchange experiments con-
firmed the role of the alcohol as the proton donor and a
proton was introduced into the R-C of the lactone. So, it is
desirable to construct the R-C chiral center of the lactone
by asymmetric protonation. Moreover, it would be interesting
to study the asymmetric inductions when both chiral auxiliary
and chiral proton source are present in the reaction (Scheme
1).
Scheme 1
Figure 2.
from them. We first treated these substrates with benzophe-
none in the presence of t-BuOH from -78 °C to room
temperature. The reactions proceeded smoothly, and 7 gave
the highest enantioselectivity.11 It was also noticed that the
reaction temperature was very important. The enantioselec-
tivity increased when the reaction was quenched at a lower
temperature; for example, the reaction of benzophenone with
7 provided lactone with 79% ee when quenched at -10 °C
as opposed to 60% ee when quenched at room temperature
(Table 1, entries 3 and 4).
First, the enantioselective effect of N-isopropylephedrine
(2) as the chiral proton source in the reaction of methyl
methacrylate with benzophenone was examined. As a result
about 9% ee (53% yield) was obtained under the optimized
conditions at temperatures from -78 to -10 °C. Although
this ee value is low, it shows that asymmetric protonation
in this process is possible. Furthermore, it reveals that a
samarium enolate is formed as a key intermediate in this
reaction.8 To increase the enantioselectivity, various chiral
compounds were examined as proton sources, which resulted
in moderate enantioselectivity;9 some examples were shown
(Figure 1). The reaction afforded 16% ee and 63% yield of
Table 1. Enantioselective Synthesis of γ-Butyrolactone 1
proton
source
yield
(%)a
ee
[R]D
entry ester
temp
(%)b sign
1
2
3
4
5
6
7
8
9
5
6
7
7
7
7
7
7
7
7
-78 °C f rt
-78 °C f rt
-78 °C f rt
-78 f -10 °C t-BuOH
-78 f -10 °C
-78 f -10 °C
-78 f -10 °C (-)-4
-78 f -10 °C (+)-4
-78 f -10 °C (()-4
-78 f -10 °C TrOH
t-BuOH
t-BuOH
t-BuOH
51
68
55
55
43
51
66
67
60
53
50
8
(+)
(-)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
60
79
85
86
95
93
95
87
2
3
Figure 1.
10
product when compound 3 was the chiral proton source.
When optically active sultam (-)-4 or (+)-4 was employed,
the enantiomeric excess was elevated to 39% [the sign of
a Isolated yield. b The ee values were determined by HPLC analysis on
a chiralcel AD column [detected at 254 nm; eluent, n-hexane/2-propanol,
80/20 (v/v)].
(6) Xu, M.-H.; Lin, G.-Q.; Xia, L.-J.; Chin. J. Chem. 1998, 16, 561-
564.
(7) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc.,
Perkin Trans. 1 1988, 1669-1675.
In light of these results, the possibility of preparing chiral
γ-butyrolactones via double asymmetric induction was
2230
Org. Lett., Vol. 2, No. 15, 2000

explored employing both chiral substrate 7 and a chiral
proton source. As shown in Table 1, when compounds 2
and 3 were used as the chiral proton sources, better results
were obtained as expected, and the enantiomeric excesses
were 85% and 86%, respectively. Surprisingly, when (-)-4
was employed, the reaction also provided 1 with very high
ee (95%, entry 7). The configuration of the main product
induced only by chiral proton source (-)-4 (see above) was
different from that induced only by chiral substrate 7, a result
we did not expect. An equally high enantiomeric excess (93%
ee) was obtained when (+)-4 was used as the chiral proton
source (entry 8). These results led to the suggestion that the
enantioselectivity of the reaction may be unrelated to double
asymmetric induction. To confirm this consideration, the use
of racemic sultam [(()-4] was examined. A high degree of
enantioselectivity was attained (95% ee, entry 9), similar to
that with the achiral sterically bulky trityl alcohol (entry 10).
These two results supported the idea that double asymmetric
induction was not exerted in this reaction. Moreover, in all
cases, we found that the configurations of the main products
were the same (entries 3-10). Thus, it can be concluded
that the enantioselectivity of the reaction was strongly
controlled by the stereochemistry of the chiral substrate and
that the chirality of the proton source was not a factor. In
addition, the results suggest that chelation of samarium atom
and the oxygen atoms in the substrate may play an important
role in the asymmetric induction. The exact transition-state
model and mechanistic explanation of this study remain
unclear at this time.
Table 2. Highly Enantioselective Synthesis of
trans-R,γ-Substituted γ-Butyrolactones
trans
ee (%)b
cis
ee (%)b
yield
(%)c
entry
product
trans/cisa
1
2
3
4
5
6
8
9
10
11
12
13
79/21
61/39
76/24
77/23
68/32
69/31
>99
>99
95
96
98
d
19
24
14
52
75
74
73
81
61
84
58
97
a trans and cis were confirmed by 1H-1H NOESY in light of their NOE
effect, and the ratio of trans/cis was determined by GC. b The ee values
were determined by HPLC analysis on chiralcel OJ, AD column (detected
at 254 nm; eluent, n-hexane/2-propanol, 80/20 (v/v)). c Total isolated yield
of trans and cis products. d Not detected.
The success in synthesis of highly optically active 1
prompted us to extend this new reaction system to the
preparation of γ-butyrolactones with two chiral centers, the
R-C and the γ-C. Treatment of chiral methacrylate 7 with
unsymmetrical ketones under optimized conditions12 for
several hours afforded the isomeric trans and cis lactones,
which could be separated by column chromatography. Table
2 summarizes the results of the asymmetric coupling reaction.
The trans products of chiral R,γ-substituted γ-butyrolactones
were obtained with high ee values in all cases; extremely
high ee values (>99%) were achieved with acetophenone
and propiophenone (entries 1 and 2). When R-tetralone was
used, trans and cis spiro lactones 13 were obtained with very
good enantiomeric excesses (entry 6). The configuration of
this type of trans product was solved by X-ray diffraction.
Using 4′-bromoacetophenone as starting material, we ob-
tained the corresponding product trans-11 as a colorless
crystal, which was recrystallized from EtOAc-hexane. The
absolute configuration was then determined as (2S,4R) by
X-ray crystallographic analysis of trans-11,13 illustrated in
Figure 3.
(8) For a review of asymmetric protonation of enolates and enols, see:
(a) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566-2587. For
examples of asymmetric protonation of samarium enolates, see: (b)
Takeuchi, S.; Miyoshi, N.; Ohgo, Y. Chem. Lett. 1992, 551-554. (c)
Takeuchi, S.; Ohira, A.; Miyoshi, N.; Mashio, H.; Ohgo, Y. Tetrahedron:
Asymmetry 1994, 5, 1763-1780. (d) Nakamura, Y.; Takeuchi, S.; Ohira,
A.; Ohgo, Y. Tetrahedron Lett. 1996, 37, 2805-2808. (e) Nakamura, Y.;
Takeuchi, S.; Ohgo, Y.; Yomaoka, M.; Yoshida, A.; Mikami, K. Tetrahe-
dron Lett. 1997, 38, 2709-2712. (f) Takeuchi, S.; Nakamura, Y.; Ohgo,
Y.; Curran, D. P. Tetrahedron Lett. 1998, 39, 8691-8694.
(9) Xu, M.-H. Ph. D. dissertation, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, P. R. China, 1999.
The detailed and further investigations of the asymmetric protonations will
be published elsewhere.
(10) Wang, J.-Q.; Xu, M.-H.; Zhong, M.; Lin, G.-Q. Chin. Chem. Lett.
1998, 9, 325-328.
(11) In an effort to maximize the results, other chiral auxiliaries were
also surveyed. With N-isopropylephedrine (2) as chiral auxiliary, chiral
γ-butyrolactone 1 was obtained in only 30% ee. However, 2 is a good chiral
auxiliary in the synthesis of chiral 4-substituted- and cis-3,4-disubstituted-
γ-butyrolactones; see: note (12) of ref 4.
Figure 3. X-ray crystal structure of trans-11.
Org. Lett., Vol. 2, No. 15, 2000
2231

In summary, we have developed an efficient, novel method
for the synthesis of optically active R,γ-substituted γ-butyro-
lactones by using the SmI2-mediated coupling of ketones with
a chiral methacrylate derived from isosorbide. We found that
both the chiral auxiliary and the hindered proton source in
this system are important features providing for the observed
excellent ee values of the products, >99% in some cases.
Further investigations of this process to prepare other chiral
γ-butyrolactones are in progress. Based on this new system,
future work will be aimed at the asymmetric synthesis of
fully substituted γ-butyrolactones.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (297912045).
We thank Jie Sun for the X-ray structural determination and
Min-Hua Tang, Li-Jun Xia for chiral HPLC analysis.
(12) Since (-)-sultam (4) is commercially available and not expensive,
we still use it as the chiral proton source instead of (()-sultam.
(13) Data for the X-ray structure analysis of trans-11: crystals from
EtOAc-hexane, C12H13O2Br (Mr ) 269.14); colorless, prismatic; crystal
dimensions 0.20 × 0.20 × 0.30 mm3; orthorhombic; space group P212121
(#19); a ) 8.101(3), b ) 25.457(3), c ) 5.886(3) Å, Z ) 4, V ) 1213.8(8)
Å3, F(000) ) 544.00, Fcalcd ) 1.473 g/cm3; T ) 293 K; 2θmax ) 55.0 °C;
3348 reflections measured, 1674 were unique (Rint ) 0.066) and 1338
observed (I > 3σ(I)); Rigaku AFC7R diffractometer, Mo KR radiation (λ
) 0.71069 Å), graphite monochromator; Lorentz-polarization absorption
correction (µ ) 33.75 cm-1). The structure was solved by Patterson methods
and refined with the full-matrix least-squares method; R ) 0.054, wR )
0.061; reflection/parameter ratio 9.77; residual electon density +0.74/-
Supporting Information Available: General experimen-
tal details and characterization data of all new chiral lactones
1 and 8-13 are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
0.45 e Å-3
.
OL005978F
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Org. Lett., Vol. 2, No. 15, 2000