Base-catalyzed asymmetric diels-alder reaction of 3-hydroxy-2-pyrone and simple aryl vinyl sulfoxide: Asymmetric synthesis of carbaketopyranoses

Article abstract of DOI:10.1246/bcsj.20110257

A highly stereoselective base-catalyzed asymmetric DielsAlder reaction of 3-hydroxy-2-pyrone and simple aryl vinyl sulfoxide is reported. Furthermore, the synthetic utility of the resulting product was demonstrated by the efficient asymmetric synthesis of β-L-carbafructopyranose and β- Lcarbapsicopyranose.

Full text of DOI:10.1246/bcsj.20110257

Short Articles
Bull. Chem. Soc. Jpn. Vol. 85, No. 5, 631-633 (2012)
Table 1. Base-Catalyzed DA Reaction of 1 and 2a
631
O
SOAr
Base-Catalyzed Asymmetric Diels-
Alder Reaction of 3-Hydroxy-
2-pyrone and Simple Aryl Vinyl
Sulfoxide: Asymmetric Synthesis
of Carbaketopyranoses
O
O
6
O
1
7
+
SOAr
5
4
( )-2a: Ar = Ph
(+)-2b: Ar = p-Tol
HO
HO
SOAr
( )-3a, ( )-3a'
(+)-3b
O
( )-4a, ( )-4a'
(+)-4b'
O
base
OH
O
O
1
SOPh
+
HO
( )-5
Hiroaki Okamura,* Fumiya Urabe,
Toshiyuki Hamada, and Tetsuo Iwagawa
Catalyst,
equiv
Yield endo
/%a) /exob)
Entry
1
Conditions
% deb)
Graduate School of Science and Engineering,
Kagoshima University, 1-21-35 Korimoto,
Kagoshima 890-0065
Et3N,
1.0
Et3N,
1.0
Et3N,
1.0
Et2NH,
1.0
CH2Cl2, rt,
3 days
neat, rt,
3 days
neat, 50 °C
3 days
neat, 50 °C
3 days
0c)
®
®
2
3
4
5
6
7
8
9
80 (for 3a)
69 (for 4a)
>95 (for 3a)
73 (for 4a)
77 (for 3a)
51 (for 4a)
35d) 2.7/1.0
70d) 1.5/1.0
59d) 1.8/1.0
63d) 2.3/1
73 1.4/1
66 1.6/1
55 1/1.7
38 1.5/1
38 1.7/1
69 1/4.3
20 1/1.7
Received August 25, 2011
E-mail: okam@sci.kagoshima-u.ac.jp
A highly stereoselective base-catalyzed asymmetric
Diels-Alder reaction of 3-hydroxy-2-pyrone and simple aryl
vinyl sulfoxide is reported. Furthermore, the synthetic utility
of the resulting product was demonstrated by the efficient
asymmetric synthesis of ¢-L-carbafructopyranose and ¢-L-
carbapsicopyranose.
i-Pr2NEt, neat, 50 °C
65 (for 3a)
46 (for 4a)
1.0
DBU,
1.0
3 days
neat, 50 °C
3 days
>95 (for 3a)
>95 (for 4a)
85 (for 3a¤)
>95 (for 4a¤)
35 (for 3a¤)
80 (for 4a¤)
58 (for 3a¤)
14 (for 4a¤)
>95 (for 3a¤)
>95 (for 4a¤)
87 (for 3a¤)
>95 (for 4a¤)
>95 (for 3a¤)
>95 (for 4a¤)
Li salt of 1, THF, 50 °C
0.1 3 days
Na salt of 1, DMF, 50 °C
0.1 3 days
K salt of 1, DMF, 50 °C
0.1 3 days
10 Mg salt of 1, THF, rt
0.1 3 days
11 Mg salt of 1, THF, 50 °C
0.1 3 days
12 Mg salt of 1, THF, 50 °C
1.0 3 days
The base-catalyzed Diels-Alder (DA) reaction is a unique
cycloaddition, which comprises the combination of electron-
deficient dienophiles and dienes that are activated by a base.1,2 It
is quite the opposite of the well-known Lewis acid-catalyzed
DA reactions that include electron rich dienes and dienophiles
that are activated by a Lewis acid. Our research group has been
conducting studies to develop base-catalyzed DA reactions2 and
has reported several synthetic applications of these reactions.3
Vinyl sulfoxides are known as attractive chiral molecules for
asymmetric synthesis.4 They are easily available in optically
pure form,4b,4c and their sulfur stereogenic center, which is
close to the reactive vinyl group, can provide high stereo-
selectivity. Asymmetric DA reactions using vinyl sulfoxides
as dienophiles are also well known to give optically active
compounds, but in most cases, one or more activating groups,
such as a carbonyl group and/or a nitro group, are needed
to increase the reactivity of dienophiles.5 To the best of our
knowledge, there are very few reports on the asymmetric DA
reaction using simple aryl vinyl sulfoxide and the stereo-
selectivity of the reaction is moderate.6
a) Isolated yield of DA adducts mixture after SiO2 column
chromatography. b) The ratio was determined by 1H NMR.
c) The starting materials were recovered. d) Small amount
(2%-3%) of 5 was a contaminant.
dienophile,5b,6 no product was obtained by the reaction without
a base-catalyst. Even the reaction carried out in diluted
solutions (CH2Cl2, THF, etc.) with 1.0 equiv of Et3N, which
was successful for the reaction of 1 and methyl acrylate,2a,2c
gave no product (Entry 1). However, under a highly concen-
trated condition (neat condition), Et3N and other amine cata-
lysts were effective in affording a mixture of four or five DA
adducts8 (endo isomers, («)-3a and («)-3a¤ (a diastereomer of
the sulfur stereogenic center of («)-3a), exo isomers, («)-4a
and («)-4a¤ (a diastereomer of the sulfur stereogenic center
of («)-4a), and a small amount of regioisomer («)-5 in Entries
2-5) in moderate yields after 3 days (Entry 2). The yields of
the products were improved by gentle warming, but at higher
temperature (above 80 °C) both of the products and pyrone 1
were decomposed and gave only tarry product.
In this paper, we report a new efficient base-catalyzed
asymmetric DA reaction of 3-hydroxy-2-pyrone7 (1) and
simple aryl vinyl sulfoxides 2, and the concise enantioselec-
tive synthesis of two carbaketopyranoses 8 and 13 from the
homochiral DA adduct (+)-4b¤ as its application.
Results and Discussion
The results of the base-catalyzed DA reaction of 1 and
(«)-2a are listed in Table 1. Because («)-2a is a less reactive
Published on the web April 28, 2012; doi:10.1246/bcsj.20110257

632
Bull. Chem. Soc. Jpn. Vol. 85, No. 5 (2012)
© 2012 The Chemical Society of Japan
HO
O
The catalysts listed in the table as “[metal salts] of 1” were
prepared by mixing 1 and the corresponding metallic bases
such as n-BuLi, t-BuONa, t-BuOK, and MeMgBr in appro-
priate solvents (Entries 7-12). The reactions were carried
out with 0.1 equiv of catalyst and gave mixtures of DA adducts
in moderate to poor yields. By increasing the amounts of
catalysts, the yields of the products significantly dropped as
exemplified by Entry 12.
O
OH
O
O
SO2Tol
O
S
HO
c, d
a, b
OH
+
O
7a
Tol
HO
SO2Tol
OH
HO CO2Me
(+)-4b'
(+)-6
O
O
OR1
HO
SO2Tol
The stereochemistries of the exo products, («)-4a and
(«)-4a¤ were unambiguously determined as 1R*,4R*,8S*,SR*
and 1S*,4S*,8R*,SR*, respectively, by comparing their
1H NMR spectra with those of (+)-4b, which was established
as 1S,4S,8R,SR by the asymmetric synthesis of ¢-L-carba-
fructopyranose tetracetate (+)-910b (vide infra). For the endo
products, («)-3a and («)-3a¤, their stereochemistries were
ascertained as 1R*,4R*,8R*,SR* and 1S*,4S*,8S*,SR*, re-
spectively, by the chemical shift in the 1H NMR signals of
H7endo. The signal of H7endo in («)-3a¤ showed a remarkable
upfield shift compared to that in («)-3a, which was explained
by the shielding effect of the nearby phenyl group.8 The
structure of («)-5 was suggested to be a regioisomer by the
chemical shift of H7 that appeared at a lower field (¤ 3.97) and
R1O
R1O
e, f
OH
7b
OR2
OR1
8: R1 = H, R2 = H
g
(+)-9: R1 = Ac, R2 = H
10: R1 = Ac, R2 = Ac
Scheme 1.
O
O
O
O
a, b, c
d
O
O
(+)-4b'
O
SO2-p-Tol
O
OH
(+)-11
OH
(+)-12
OR
RO
RO
e
1
by the H1-H7 coupling in its H-1H COSY spectrum.8
The stereoselectivity of the reaction was predominantly
controlled by the catalyst and the reaction conditions. In the
amine-catalyzed reactions (Entries 1-5), the endo isomers were
slightly dominant over the exo isomers, and the diastereomers
(«)-3a and («)-4a were obtained as major stereoisomers.
Although the change in the diastereomeric excess of («)-3a
listed in Entries 2 and 3 seemed to suggest that the diastereo-
selectivity was improved by heating, it could be explained by
the decomposition of the products and isomerization of the
endo isomer to a sterically less hindered exo isomer. Indeed,
the Et3N treatment of the products that was obtained from the
reaction listed in Entry 2 at 50 °C for 3 days, decomposed
a considerable amount of the products. The diastereomeric
excesses of the recovered («)-3a and («)-4a were changed
to 91% de and 65% de, respectively, and the endo/exo ratio
dropped to 1.5/1.0.
In contrast, the reactions catalyzed by metal salts of
1 (Entries 7-12) gave («)-3a¤ and («)-4a¤ as major isomers.
The best diastereoselectivity was observed in the reactions
catalyzed by the Mg salt of 1. The reaction carried out at room
temperature (Entry 10) provided («)-3a¤ and («)-4a¤ in >95%
de, although yield and endo/exo ratio were low (38% and
1.7/1, respectively). The reaction at 50 °C (Entry 11) increased
the yield and the ratio of the exo isomer (69% and 1/4.3,
respectively) and gave («)-4a¤ in >95% de, which can again
be explained by the thermal decomposition and endo-exo
isomerization of the products.9 The reactions catalyzed by Et3N
or DBU gave the product(s) in high diastereoselectivity, but
their endo/exo ratio was low (Entries 3 and 5).
OR
OR
13:R = H
(+)-14:R = Ac
f
Scheme 2.
methanolysis to give an ester, and its olefin and sulfoxide
moieties were oxidized simultaneously by mCPBA to give
epoxysulfone (+)-6 as a single diastereomer. The stereo-
chemistry of the resulting oxirane ring was supposed to be ¢
because of the diastereomeric induction of the neighboring
secondary hydroxy group. The direct acidic hydrolysis of the
epoxide was very slow and gave a complex mixture, which
could be explained by the lactone formation through the free
hydroxy and carbomethoxy groups in (+)-6. The acetylation
of the secondary hydroxy group, which might prevent the
lactonization, improved the hydrolysis and gave a mixture of
lactones 7a and 7b in high yield. The reductive elimination
of the sulfone moiety and the subsequent LAH reduction of
the lactone carbonyl group in 7a and 7b afforded the desired
compound 8 that was isolated as its tetraacetate (+)-9 and
pentaacetate 10. By comparing the [¡]D value of (+)-9
18
24
(½¡ꢀD = 40 (c 0.33, CHCl3), literature value10b ½¡ꢀD = 46
(c 1, CHCl3)) and 1H NMR spectrum of 1010a with their
reported data, the stereochemistry of 8 has been established
as shown in Scheme 1. The overall yield of (+)-9 and 10
was 36%.
To demonstrate the synthetic utility of the resulting DA
adduct, the concise asymmetric synthesis of two carbaketo-
pyranoses were carried out as shown below. ¢-L-Carbafructo-
pyranose 810 was synthesized in six steps from an optically
pure (+)-4b¤ that was obtained in 49% isolated yield by
reacting 1 with (+)-2b11 using the Mg salt of 1 as a catalyst
(Scheme 1). The lactone ring of (+)-4b¤ was cleaved by
The synthesis of ¢-L-carbapsicopyranose 13 was carried
out as shown in Scheme 2. The sulfoxide (+)-4b¤ was first
converted into sulfone by mCPBA oxidation, which was further
transformed into (+)-11 exclusively by OsO4 oxidation of the
olefin moiety followed by acetonide protection of the product
diol. The reductive elimination of the sulfonyl group proceeded
smoothly by using Raney Ni to give lactone (+)-12. Finally,

H. Okamura et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 5 (2012)
633
Shen, T. T. Nguyen, Y.-P. Goh, W. Ye, X. Fu, J. Xu, C.-H. Tan,
J. Am. Chem. Soc. 2006, 128, 13692. e) T. Kitazawa, Y.
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the reduction of the lactone carbonyl group gave desired ¢-L-
carbapsicopyranose (13) that was isolated as its pentaacetate
(+)-14 after acetylation. The overall yield of (+)-14 was 45%.
In conclusion, we have developed a new base-catalyzed
asymmetric DA reaction of 1 and phenyl vinyl sulfoxide
(«)-2a, which gave («)-3a and («)-4a¤ selectively by changing
the catalyst. It is an exceptional example of highly stereo-
selective DA reaction using non-activated vinyl sulfoxide as a
dienophile. The synthetic utility of the homochiral DA adduct
(+)-4b¤ was demonstrated by the asymmetric synthesis of ¢-L-
carbafructopyranose 8 and ¢-L-carbapsicopyranose (13).
2
a) H. Okamura, T. Iwagawa, M. Nakatani, Tetrahedron Lett.
1995, 36, 5939. b) H. Okamura, Y. Nakamura, T. Iwagawa, M.
Nakatani, Chem. Lett. 1996, 193. c) H. Okamura, K. Morishige, T.
Iwagawa, M. Nakatani, Tetrahedron Lett. 1998, 39, 1211. d) H.
Okamura, T. Iwagawa, M. Nakatani, J. Synth. Org. Chem., Jpn.
1999, 57, 84. e) H. Okamura, H. Nagaike, T. Iwagawa, M.
Nakatani, Tetrahedron Lett. 2000, 41, 8317. f ) H. Okamura, H. Iiji,
T. Hamada, T. Iwagawa, H. Furuno, Tetrahedron 2009, 65, 10709.
Experimental
Typical Experimental Procedures of the DA Reaction of
1 and («)-2a.
Amine-Catalyzed Reaction:
A homo-
geneously mixed 1 (1.0 mmol), («)-2a (0.50 mmol), and amine
catalyst (1.0 mmol) in a tightly capped glass tube was left in an
oil bath (50 °C) for 3 days. The reaction mixture was diluted
with a small amount of CH2Cl2 and subjected to short SiO2
column chromatography to remove tarry by-products, the
amine catalyst, and the starting materials. The ratio of the
products in the resulting mixture was determined by 1H NMR.8
Metal Salt-Catalyzed Reaction: A catalytic amount of
metal-containing base described in the text (0.050 mmol) was
added to a solution of 1 (1.0 mmol) and («)-2a (0.50 mmol) in
the solvent listed in Table 1 (0.50 mL). The resulting suspended
mixture was heated at 50 °C in an oil bath for 3 days. The
reaction mixture was diluted with aq. H3PO4 (5%, 5 mL) and
extracted with AcOEt (5 mL, three times). The collected AcOEt
solution was dried with MgSO4 and concentrated to a crude DA
mixture that was purified by short SiO2 column chromatog-
raphy. The ratio of the products in the resulting mixture was
3
a) H. Okamura, H. Shimizu, Y. Nakamura, T. Iwagawa, M.
Nakatani, Tetrahedron Lett. 2000, 41, 4147. b) H. Shimizu, H.
Okamura, T. Iwagawa, M. Nakatani, Tetrahedron 2001, 57, 1903.
c) H. Shimizu, H. Okamura, N. Yamashita, T. Iwagawa, M.
Nakatani, Tetrahedron Lett. 2001, 42, 8649. d) H. Okamura, H.
Shimizu, N. Yamashita, T. Iwagawa, M. Nakatani, Tetrahedron
2003, 59, 10159. e) H. Okamura, H. Nagaike, N. T. Kipassa, T.
Iwagawa, M. Nakatani, Heterocycles 2006, 68, 2587. f ) N. T.
Kipassa, H. Okamura, K. Kina, T. Hamada, T. Iwagawa, Org. Lett.
2008, 10, 815.
4
a) As a review of asymmetric cycloaddition reactions using
chiral sulfoxides, see: J. L. G. Ruano, B. C. de la Plata, in
Organosulfur Chemistry I in Topics in Current Chemistry, ed. by
P. C. B. Page, Springer-Verlag, Berlin, 1999, Vol. 204, pp. 1-126.
doi:10.1007/3-540-48956-8_1. b) K. K. Andersen, W. Gaffield,
N. E. Papanikolaou, J. W. Foley, R. I. Perkins, J. Am. Chem. Soc.
1964, 86, 5637. c) J. E. Mulvaney, R. A. Ottaviani, J. Polym. Sci.,
Part A: Polym. Chem. 1970, 8, 2293.
1
determined by H NMR.8
For a detailed discussion of the stereochemistry of the
5
a) K. Fuji, K. Tanaka, H. Abe, A. Itoh, M. Node, T. Taga, Y.
1
products and their H and 13C NMR and IR spectra, see Sup-
Miwa, M. Shiro, Tetrahedron: Asymmetry 1991, 2, 179. b) J. L. G.
Ruano, J. C. Carretero, M. C. Carreno, L. M. M. Cabrejas, A.
Urbano, Pure Appl. Chem. 1996, 68, 925.
porting Information.
The authors are grateful to Professor Junji Inanaga, Kyushu
University, and Assistant Professor Hiroshi Furuno, for the
elemental analysis and HRMS measurements. This work was
partially supported by a Grant-in-Aid for Scientific Research
(No. 23550160) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and by the Cooperative
Research Program of “Network Joint Research Center for
Materials and Devices” (No. 2011287).
6
To the best of our knowledge, only one example of the DA
reaction using simple aryl vinyl sulfoxide as a dienophile, which
provided poor stereoselectivity, has been reported: C. Maignan,
R. A. Raphael, Tetrahedron 1983, 39, 3245.
7
For preparation of 3-hydroxy-2-pyrone, see: J. A. Profitt, T.
Jonse, D. S. Watt, Synth. Commun. 1975, 5, 457.
1
8
For the H and 13C NMR spectra of the DA adducts and
their assignments, see Supporting Information.
The lower de of («)-3a¤ also can be explained by the
9
thermal decomposition and isomerization, which may change
(«)-3a faster than («)-3a¤.
Supporting Information
Experimental details for the synthesis of carbaketopyranoses
and spectral data are provided in Supporting Information that
is available free of charge on the Web at http://www.csj.jp/
journals/bcsj/.
10 a) T. Suami, S. Ogawa, M. Takata, K. Yasuda, K. Takei,
A. Suga, Bull. Chem. Soc. Jpn. 1986, 59, 819. b) S. Ogawa, Y.
Uematsu, S. Yoshida, N. Sasaki, T. Suami, J. Carbohydr. Chem.
1987, 6, 471. c) I. Hubrecht, E. Van der Eycken, J. Van der Eycken,
Synlett 2000, 971.
11 Optically pure (+)-2b was prepared by the reaction of vinyl
magnesium bromide and commercially available (¹)-menthyl
p-toluenesulfinate, in according to literature method.4b,4c
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