Recyclable asymmetric cyclization in ionic liquid catalyzed by an amino acid, leading to a Wieland-Miescher ketone analogue

Article abstract of DOI:10.1055/s-2007-970740

A procedure for recyclable asymmetric cyclization leading to optically active Wieland-Miescher ketone analogue has been developed employing D-phenylalanine and D-CSA in [hmim]PF₆ and dimethylimidazolidinone in 81% chemical yield and 74% enantio

Full text of DOI:10.1055/s-2007-970740

LETTER
661
Recyclable Asymmetric Cyclization in Ionic Liquid Catalyzed by an Amino
Acid, Leading to a Wieland–Miescher Ketone Analogue
Synthesis of
a
W
ieland
a
–Miescher
s
K
etone
A
a
nalogue to Nozawa,a,1 Tetsuya Akita,a Takashi Hoshi,b Toshio Suzuki,b Hisahiro Hagiwara*a
a
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
b
Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
Received 4 December 2006
Miescher ketone 3 or Hajos–Wiechert ketone 4 analogues
was reinvestigated in an ionic liquid as a liquid support of
amino acid and CSA, which might enable recycle use of
the catalysts as well as the reaction medium.
Abstract: A procedure for recyclable asymmetric cyclization lead-
ing to optically active Wieland–Miescher ketone analogue has been
developed employing D-phenylalanine and D-CSA in [hmim]PF6
and dimethylimidazolidinone in 81% chemical yield and 74% enan-
tiomeric excess in average after five uses. A Hajos–Wiechert ketone
analogue was also synthesized in a similar manner.
Key words: amino acid, asymmetric catalysis, asymmetric synthe-
sis, enones, ionic liquids, supported catalysis
Wieland–Miescher ketone 3 and Hajos–Wiechert ketone
4 analogues are very versatile starting materials for the
synthesis of a variety of natural products.2 Due to the im-
portance of these compounds, there have been several
synthetic procedures employing amino acid as a chiral
catalyst,3 which has stimulated recent developments of the
chemistry of organomolecular catalysts.4
Scheme 1 Recyclable asymmetric cyclization leading to Wieland–
Miescher ketone 3 and Hajos–Wiechert ketone 4 analogues
A recycle experiment of the cyclization of triketone 1 was
attempted at first by simply replacing DMF5 into a com-
mon ionic liquid, [bmim]PF6 (Scheme 1 and Table 1).
The reaction was carried out in the presence of an equiva-
lent amount of D-Phe and a half-equivalent amount of D-
CSA at room temperature to 70 °C. The reaction temper-
ature was raised by 10 °C per hour. After trituration of the
product 3 with Et2O, the residue was evacuated and reused
for subsequent reaction. As shown in entry 3, the third use
resulted in decrease of enantiomeric excess (ee) of the
enone 3, probably due to loss of D-Phe during extraction.
This result was partially solved by employing more vis-
cous [hmim]PF6 (entries 4–6), since [hmim]PF6 was much
more separable from Et2O than [bmim]PF6. More rapid
heating than the original rate (10 °C per day)5 was not a
problem. In order to increase solubility of D-Phe, highly
polar co-solvents were tested. Among them, N,N-dimeth-
ylpyrrolidinone (DMI; entries 13–17; 81% yield and 74%
ee in average after five uses) and N-methyl-2-pyrrolidino-
ne (NMP; entries 18–21; 77% yield and 78% ee after four
uses) gave comparable and reproducible results in recycle
experiments.
We reported previously a synthetic method toward the
Wieland–Miescher ketone analogues 3 employing L/D-
phenylalanine (Phe) as a chiral source with D-camphor-
sulfonic acid (CSA) in DMF, in which the reaction tem-
perature was raised by 10 °C per day to 70 °C.5 Since that
time, the method has been utilized for preparation of com-
pound 3 as a starting material for many natural products
not only in our group6 but also in many other groups.7
In reexamining the method, we found that the optimum
reaction condition required use of an equivalent amount of
L/D-Phe and a half-equivalent amount of D-CSA. This
issue should be solved especially in the case that non-
natural and expensive D-Phe is used in a large-scale ex-
periment. Gradual warming of the reaction is another
issue, which results in longer reaction time.
Room temperature ionic liquid has played key roles as an
environmentally benign and recyclable reaction medium.8
The characteristic nature of the liquid, especially immis-
cibility with other organic solvents and water, is useful as
a support of not only organometallic catalysts but also
organomolecular catalysts.9
L-Proline provided low chemical yield (entry 12) due to its
decomposition. Amberlyst 15 as an alternative of D-CSA
gave a comparable result at the first run, though recycle
experiments gave discouraging yields. Chiral ionic liquid,
tetrabutylphosphonium L-phenylalaninate {[TPP]L-Phe}
was not a suitable chiral medium for the present cycliza-
tion (entry 22).
In order to make the cyclization more efficient, economi-
cally and environmentally benign, amino acid catalyzed
cylization of triketone 1 or 2 leading to Wieland–
SYNLETT 2007, No. 4, pp 0661–0663
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-970740; Art ID: U14506ST
© Georg Thieme Verlag Stuttgart · New York

662
M. Nozawa et al.
LETTER
Table 1 Recyclable Asymmetric Cyclization Leading to Wieland–
Miescher Ketone Analogue 310
In summary, we have developed a new procedure for the
synthesis of Wieland–Miescher ketone 3 and Hajos–
Wiechert ketone 4 by recycling the catalysts and the
reaction medium, which provided additional efficiency
for preparation of important substrates 3 and 4 for natural
product synthesis.
Entry
Ionic liquid
Cosolvent
Yield (%)
ee (%)a
d
1
[bmim]PF6
[hmim]PF6
–
–
–
81
80
68
84
68
53
2b
3
e
4
–
–
–
88
77
85
86
70
61
Acknowledgment
5b
6b
This work was partially supported by Grant-in-Aid for Scientific
Research on Priority Areas (17073007 for H.H. and T.H.) from The
Ministry of Education, Culture, Sports, Science and Technology
(MEXT), and Sasaki Environmental Technology Foundation (for
H.H). Thanks are also due to Katayama Seiyakusho Co. Ltd. for a
generous supply of [tbp]L-phe. M.N. thanks JSPS for promotion of
young chemists.
7
formamide
80
28
84
8
8b
9
DMF
88
77
85
86
70
72
10b
11b
12c
24
74
References and Notes
13
DMIf
87
85
81
73
79
86
73
71
71
68
(1) JSPS Research Fellow.
14b
15b
16b
17b
(2) (a) Hagiwara, H.; Kamat, V. P. Recent Res. Devel. Org.
Bioorg. Chem. 1997, 1, 25. (b) Banerjee, A. K.; Laya-
Mimo, M. Studies in Natural Products Chemistry: Bioactive
Natural Products, Part E, Vol. 24; Atta-ur-Rahman, Ed.;
Elsevier: New York, 2000, 175.
(3) Recent procedures: (a) Shigehisa, H.; Mizutani, T.; Tosaki,
S.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61, 5057.
(b) Inomata, K.; Barrague, M.; Paquette, L. A. J. Org. Chem.
2005, 70, 533. (c) Davies, S. G.; Sheppard, R. L.; Smith, A.
D.; Thomson, J. E. Chem. Commun. 2005, 2802.
18
NMPg
82
81
63
80
90
79
70
72
19b
20b
21b
22
[tbp]L-Pheh
–
trace
–
(4) For example, see: (a) List, B. Tetrahedron 2002, 58, 5573.
(b) Notz, W.; Tanaka, F.; Barbas, C. F. III Acc. Chem. Res.
2004, 37, 580. (c) Asymmetric Organocatalysis; Berkessel,
A.; Groger, H., Eds.; Wiley-VCH: Weinheim, 2005.
(5) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
(6) Our representative efforts in this area: (a) Hagiwara, H.;
Uda, H. J. Chem. Soc., Perkin Trans. 1 1991, 1803.
(b) Hagiwara, H.; Inome, K.; Uda, H. J. Chem. Soc., Perkin
Trans. 1 1995, 757. (c) Hagiwara, H.; Nagatomo, H.;
Kazayama, S.; Sakai, H.; Hoshi, T.; Suzuki, T.; Ando, M. J.
Chem. Soc., Perkin Trans. 1 1999, 457. (d) Hagiwara, H.;
Nagatomo, H.; Yoshii, F.; Hoshi, T.; Suzuki, T.; Ando, M. J.
Chem. Soc., Perkin Trans. 1 2000, 2645. (e) Hagiwara, H.;
Sakai, H.; Uchiyama, T.; Ito, Y.; Morita, N.; Hoshi, T.;
Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2002,
583. (f) Hagiwara, H.; Takeuchi, F.; Nozawa, M.; Hoshi, T.;
Suzuki, T. Tetrahedron 2004, 60, 1983. (g) Hagiwara, H.;
Hamano, K.; Nozawa, M.; Hoshi, T.; Suzuki, T.; Kido, F. J.
Org. Chem. 2005, 70, 2250.
a The ee was determined by HPLC analysis with chiral column
(Daicel AS-H).
b
D-Phe, D-CSA and ionic liquid in previous reaction was reused.
c
L-Proline was used.
d Butylmethylimidazolium hexafluorophosphate.
e Hexylmethylimidazolium hexafluorophosphate.
f N,N-Dimethylpyrrolidinone.
g N-Methyl-2-pyrrolidinone.
h Tetrabutylphosphonium L-phenylalaninate.
Employing DMI as a co-solvent, asymmetric cyclization
of triketone 2 with D-Phe and D-CSA in [hmim]PF6 was
recycled and the results are shown in Table 2. The
reaction proceeded with similar efficiency (74% yield and
69% ee in average after four uses) as the cyclization of
triketone 1 in recycle experiments.
(7) Representative total syntheses that employed the procedure
in ref. 5: (a) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc.
1997, 119, 12425. (b) Zhang, F.; Almsted, J. K.; DeMuth, T.
P. Jr.; Ledoussal, B. Tetrahedron: Asymmetry 1998, 9,
3179. (c) Danishefsky, S. J. Angew. Chem. Int. Ed. 2002, 41,
1434. (d) Iwasaki, K.; Nakatani, M.; Inoue, M.; Katoh, T.
Tetrahedron 2003, 59, 8763. (e) Patin, A.; Kanazawa, A.;
Philouze, C.; Greene, A. E. J. Org. Chem. 2003, 68, 3831.
(f) Cheung, A. K.; Murelli, R.; Snapper, M. L. J. Org. Chem.
2004, 69, 5712.
(8) (a) Rogers, R. D.; Seddon, K. R. In Ionic Liquids: Industrial
Applications to Green Chemistry; Rogers, R. D.; Seddon, K.
R., Eds.; ACS Symposium Series 818, American Chemical
Society: Washington DC, 2002. (b) Ionic Liquids in
Synthesis; Wasserscheid, P.; Welton, T., Eds.; Wiley-VCH:
Weinheim, 2003. (c) Green Industrial Applications of Ionic
Liquids; Rogers, R. D.; Seddon, K. R., Eds.; Kluwer:
Table 2 Recyclable Asymmetric Cyclization Leading to Hajos–
Wiechert Ketone Analogue 410
Entry
1
Yield (%)
ee (%)a
84
78
77
68
73
2b
70
3b
63
4b
58
a The ee was determined by HPLC analysis with chiral column
(Daicel AS-H).
b
D-Phe, D-CSA and ionic liquid in previous reaction was reused.
Synlett 2007, No. 4, 661–663 © Thieme Stuttgart · New York

LETTER
Dordrecht, 2003. (d) Welton, T. Chem. Rev. 1999, 99, 2071.
Synthesis of a Wieland–Miescher Ketone Analogue
663
(10) Typical Experimental Procedure.
(e) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A:
Chem. 2002, 182-183, 419. (f) Dupont, J.; de Souza, R. F.;
Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667.
To a solution of the triketone 1 (196 mg, 1 mM) in
[hmim]PF6 (1.8 mL) and DMI (1.2 mL) was added D-Phe
(165 mg, 1 mM) and D-CSA (116 mg, 0.5 mM) under
nitrogen atmosphere. Reaction temperature was raised from
r.t. to 70 °C by 10 °C at 1 h intervals. After being stirred at
70 °C overnight, the product was triturated with Et2O until
the spot of the product 3 in ionic liquid was not observed by
TLC monitoring (eluent: EtOAc–n-hexane = 1:1).
(9) Representative examples of proline-catalyzed asymmetric
aldol reaction in ionic liquid: (a) Kotrusz, P.; Kmentova, I.;
Gotov, B.; Toma, S.; Solcaniova, E. Chem. Commun. 2002,
2510. (b) Kitazume, T.; Jiang, Z.; Kasai, K.; Mihara, Y.;
Suzuki, M. J. Fluorine Chem. 2003, 121, 205.
(c) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F. III
Synlett 2003, 1906. (d) Córdova, A. Tetrahedron Lett. 2004,
45, 3949. (e) Guo, H.-M.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-
Q.; Jiang, Y.-Z. Chem. Commun. 2005, 1450.
Evaporation of Et2O followed by column chromatography
and subsequent medium pressure LC of the residue (eluent:
EtOAc–n-hexane = 1:1) afforded the enone 3 (167 mg,
87%). After evacuation of Et2O under reduced pressure, a
mixture of D-Phe and D-CSA in [hmim]PF6 was reused after
addition of DMI (1.2 mL). The ee of the product 3 was
determined to be 86% by HPLC analysis using chiral column
(Daicel AS-H column, eluent: n-hexane–i-PrOH = 9:1).
Synlett 2007, No. 4, 661–663 © Thieme Stuttgart · New York