Asymmetric synthesis of 2,3-dihydro-4-pyranones by reaction of chiral 3-alkoxycyclobutanone and aldehydes

Article abstract of DOI:10.1021/ol1021355

Chiral cyclobutanone which had ethyl l-lactate as a chiral auxiliary at the 3-position reacted with aldehydes to give 2,3-dihydro-4-pyranones in up to 93% ee by combined use of titanium(IV) chloride and tin(II) chloride.

Full text of DOI:10.1021/ol1021355

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4984-4987
Asymmetric Synthesis of
2,3-Dihydro-4-pyranones by Reaction of
Chiral 3-Alkoxycyclobutanone and
Aldehydes
Shoko Negishi, Hiroyuki Ishibashi, and Jun-ichi Matsuo*
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
jimatsuo@p.kanazawa-u.ac.jp
Received September 8, 2010
ABSTRACT
Chiral cyclobutanone which had ethyl L-lactate as a chiral auxiliary at the 3-position reacted with aldehydes to give 2,3-dihydro-4-pyranones
in up to 93% ee by combined use of titanium(IV) chloride and tin(II) chloride.
Chiral pyrans are versatile building blocks for the synthesis
of many biologically active compounds, such as pheromones,
antitumor agents, and terpenoids.1 Chiral dihydropyranones
1 (Figure 1, R1, R2 ) H) have been prepared by enantiose-
lective hetero-Diels-Alder (HDA) reactions2 between si-
loxydienes and aldehydes by using various chiral Lewis acid
catalysts such as BINOL-metal (Mg,3a Ti,3b Zn,3c or Al3d)
complexes, Cu(II)4a or Rh(II)4b carboxamidates, and salen-
metal (Cr(III) or Mn(III)) complexes.5a-c Chiral organo-
catalysts6 such as TADDOL (R,R,R′,R′-tetraaryl-1,3-dioxo-
(1) Smith, A. B.; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008, 41,
Figure 1. 2,3-Dihydro-4-pyranones (1-3) and synthetic intermedi-
ate of pederin.
675.
(2) For a representative review on the asymmetric HDA reaction, see:
Jørgensen, K. Angew. Chem., Int. Ed. 2000, 39, 3558.
(3) (a) Du, H.; Zhang, X.; Wang, Z.; Bao, H.; You, T.; Ding, K. Eur.
J. Org. Chem. 2008, 2248. (b) Mikami, K.; Motoyama, Y.; Terada, M.
J. Am. Chem. Soc. 1994, 116, 2812. (c) Du, H.; Long, J.; Hu, J.; Li, X.;
Ding, K. Org. Lett. 2002, 4, 4349. (d) Maruoka, K.; Itoh, T.; Shirasaka, T.;
Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310.
lane-4,5-dimethanol),7a,b BAMOL (1,1′-biaryl-2,2′-dimeth-
anol),7c or oxazolines,7d which activate aldehydes through
hydrogen bonds, have also promoted enantioselective HDA
reactions between 1-amino-3-siloxy-1,3-butadienes8 and al-
(4) (a) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jørgensen,
K. A. J. Am. Chem. Soc. 1998, 120, 8599. (b) Doyle, M. P.; Phillips, I. M.;
Hu, W. J. Am. Chem. Soc. 2001, 123, 5366.
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(6) Recent review: Merino, P.; Marque´s-Lo´pez, E.; Tejero, T.; Herrera,
R. P. Synthesis 2010, 1.
10.1021/ol1021355  2010 American Chemical Society
Published on Web 10/05/2010

dehydes. Synthesis of dihydropyranones 2 bearing alkyl
groups at their 3-position (R1 ) alkyl, R2 ) H) is more
difficult, and only a few methods have been reported for their
preparation by using dirhodium(II) chiral carboxamidate9a
catalysts, Cu(II) bisoxazoline,9b or BINOL-metal (Al3d or
Zr9c) complexes. Chiral dihydropyranones 3 having dialkyl
groups at their 3-position are seen in the structure of natural
products such as the pederin family of natural products.10
However, preparation of chiral dihydropyranones 3 needs
many steps which include asymmetric aldol reaction.11a,b
We have reported a Lewis acid-catalyzed reaction between
3-alkoxycyclobutanones 4 and aldehydes12 to afford various
types of 2,3-dihydro-4-pyranones 7 (Scheme 1). A zwitterionic
Table 1. Effect of Chiral Auxiliary on Diastereoselective
Cycloaddition between Cyclobutanone 8a-g and Benzaldehyde
Scheme 1. Lewis Acid-Catalyzed Reaction between
Cyclobutanone 4 and Aldehyde to Dihydropyranone 7
intermediate 5 was generated by Lewis acid-catalyzed ring
opening of 3-alkoxycyclobutanone 4. Compound 6 was formed
by reaction of 5 and aldehyde, and elimination of alcohol from
adduct 6 gave dihydro-4-pyranone 7. It was then thought that
introducing a chiral auxiliary into the 3-alkoxy group of
cyclobutanone 413 would give chiral dihydropyranone 7.
First, screening for an effective chiral auxiliary for
asymmetric induction between 3-alkoxycyclobutanone 4 and
aldehyde was carried out by reaction between cyclobutanone
8a-g and benzaldehyde in the presence of titanium(IV)
chloride (Table 1). Reaction of cyclobutanones 8a and 8b,
a Diastereomer ratios: 8a (49:51), 8b (45:55), 8c (60:40), 8d (36:64),
8e (31:69), 8f (36:64), 8g (15:85). b Isolated yield. c Determined by chiral
HPLC. For the absolute configuration, see the text. d The reaction was carried
out at -20 to 0 °C.
which were prepared from (-)-menthol and (S)-1-(benzoxy)-
propane-2-ol, respectively, gave dihydro-4-pyranone 9 in low
ee’s (7-3% ee, entries 1 and 2). Moderate to good asym-
metric induction was observed in the reaction of cyclobu-
tanones 8c-e, which were derived from L-lactic esters
(44-79% ee, entries 3-5). The reaction of cyclobutanones
8f and 8g, which were prepared from L-malic acid dimethyl
ester and D-pantolactone, afforded cycloadduct 9 in 58% and
19% ee, respectively (entries 6 and 7). Therefore, L-ethyl
lactate was chosen as a chiral auxiliary for the present
asymmetric reaction.
The chiral cyclobutanone 8c was prepared from L-ethyl
lactate in three steps (Scheme 2). 1-Ethoxyethyl ether of
L-ethyl lactate 10 was prepared in 92% yield by reaction of
L-ethyl lactate and ethyl vinyl ether in the presence of a
catalytic amount of TFA. Treating 10 with triethylamine and
TMSOTf gave vinyl ether 11 (79% yield).14 [2 + 2]
(7) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
2003, 424, 146. (b) Anderson, C. D.; Dudding, T.; Gordillo, R.; Houk, K. N.
Org. Lett. 2008, 10, 2749. (c) Unni, A. K.; Takenaka, N.; Yamamoto, H.;
Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336. (d) McManus, H. A.;
Guiry, P. J. Chem. ReV. 2004, 104, 4151.
(8) Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321.
(9) (a) Anada, M.; Washio, T.; Shimada, N.; Kitagaki, S.; Nakajima,
M.; Shiro, M.; Hashimoto, S. Angew. Chem., Int. Ed. 2004, 43, 2665. (b)
Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jørgensen, K. A. J. Am.
Chem. Soc. 1998, 120, 8599. (c) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. Org. Lett. 2002, 4, 1221.
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Matsunaga, S. J. Nat. Prod. 2005, 68, 472.
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K. A.; Ast, S.; Carlson, J. S.; Oliver, A. G.; Konopelski, J. P. J. Org. Chem.
2009, 74, 5405. (b) Kocienski, P.; Narquizian, R.; Raubo, P.; Smith, C.;
Farrugia, L. J.; Muir, K.; Boyle, F. T. J. Chem. Soc., Perkin Trans. 1 2000,
2357
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2008, 130, 11600.
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Lett. 2008, 10, 821. (b) Delair, P.; Kanazawa, A. M.; de Azevedo, M. B. M.;
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Org. Lett., Vol. 12, No. 21, 2010
4985

Scheme 2
.
Preparation of Cyclobutanone 8c
Scheme 3. Determination of the Absolute Configuration of 9
14 in 78% yield, and hydrolysis of 14 gave diol 15 in 99%
yield. The specific rotation of obtained 15 ([R]26D ) -18.4)
suggested that its absolute configuration was R.15
Cycloaddition by using vinyl ether 11, isobutyryl chloride,
and triethylamine afforded cyclobutanone 8c in 67% yield
as a mixture of two diastereomers (60:40).
Next, the scope and limitations of diastereoselective
reaction of 8c were investigated by using various aldehydes
(Table 3). When electron-withdrawing groups were substi-
Interestingly, it was proven that addition of some metal
chlorides in a titanium(IV) chloride-promoted asymmetric
reaction between 8c and benzaldeyde improved the enanti-
oselectivity of product 9 (Table 2). The use of copper(II)
Table 3. Diastereoselective Cycloaddition with Various
Aromatic Aldehydes
Table 2. Effect of Metal Chloride on Diastereoselective
Cycloaddition between Chiral Cyclobutanone 8c and
Benzaldehyde
entry
metal chloride
time (h)
yield (%)a
% eeb
1
2
3
4
none
3.0
6.0
1.5
8.0
60
26
58
70
79
81
83
88
CuCl2
ZnCl2
SnCl2
a Isolated yield. b Determined by chiral HPLC.
chloride and zinc(II) chloride slightly improved the ee of
adduct 9, but yields were decreased (entries 2 and 3). Among
the metal chlorides tested, the use of tin(II) chloride gave 9
in 70% yield with the best enantioselectivity (88% ee, entry
4). The role of tin(II) chloride in this reaction has not yet
been clarified. The use of each separated diastereomer of 8c
gave almost the same results as those obtained by employing
a mixture of two diastereomers of 8c.
The absolute configuration of 9 was determined by
comparison with the specific rotation of known diol 1515
(Scheme 3). Baeyer-Villiger oxidation of 12, which was
prepared by reaction of compound 9 (88% ee) with metha-
nolic hydrogen chloride,16 gave lactone 13 in 90% yield.
Reduction of 13 with lithium aluminum hydride gave diol
a Isolated yield. b Determined by chiral HPLC analysis. The absolute
configuration was deduced from compound (R)-9.
tuted at the para-position of the phenyl group of benzalde-
hyde 16a-e, the corresponding 2,3-dihydropyranones 17a-e
were obtained in good yields (64-78%) and with high ee’s
(15) Choudary, B. M.; Chowdari, N. S.; Kantam, M. L.; Raghavan, K. V.
J. Am. Chem. Soc. 2001, 123, 9220.
(16) Mori, K.; Mori, H. Tetrahedron 1987, 43, 4097.
4986
Org. Lett., Vol. 12, No. 21, 2010

(88-92% ee, entries 1-5). On the other hand, aldehydes
bearing a methyl or phenyl group at the para-position of the
phenyl group gave lower ee’s (77% ee, entries 6 and 7). In
comparison with 2-naphthylaldehyde 16h, which gave cy-
cloadduct 17h in 60% yield and 93% ee (entry 9), the
reaction with 1-naphthylaldehyde 16i gave the desired adduct
17i in a lower yield (58%) and with lower ee’s (75% ee,
entry 10). These results suggest that this reaction was
influenced by steric effects. Reactions between 8c and
aliphatic aldehydes 16j and 16k gave the desired products
17j and 17k in moderate yields (43% and 47%) and with
good ee’s (76% and 78% ee, entries 10 and 11).
and silyl enol ethers19 to afford the corresponding chiral
dihydropyranones and cyclohexanones.
Acknowledgment. This work was supported by a Grant
from Suntory Institute for Bioorganic Research and a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: Detailed experimen-
tal procedures and full spectroscopic characterization data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1021355
In summary, chiral 2,3-dihydro-4-pyranones were prepared
by a diastereoselective asymmetric reaction of aldehyde and
3-alkoxycyclobutanone bearing L-ethyl lactate as a chiral
auxiliary. It is expected that these chiral cyclobutanones will
be effective for other reactions with imines,17 allylsilanes,18
(17) Matsuo, J.; Okado, R.; Ishibashi, H. Org. Lett. 2010, 12, 3266.
(18) Matsuo, J.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H. Org. Lett. 2009,
11, 3822.
(19) Matsuo, J.; Negishi, S.; Ishibashi, H. Tetrahedron Lett. 2009, 50,
5831.
Org. Lett., Vol. 12, No. 21, 2010
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