New procedures for the Julia-Colonna asymmetric epoxidation: Synthesis of (+)-clausenamide

Article abstract of DOI:10.1039/a801450g

The oxidation of chalcone 1 to optically active epoxide 2 [a precursor of (+)-clausenamide (+)-3] may be effected using a 15-mer or 20-mer of L-leucine bound to a PEG based support; poly-L-leucines of this type may be used as immobilised catalysts in a fixed-bed reactor.

Full text of DOI:10.1039/a801450g

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New procedures for the Julia´–Colonna asymmetric epoxidation: synthesis of
(+)-clausenamide
Michael W. Cappi,a Wei-Ping Chen,b† Robert W. Flood,a Yong-Wei Liao,b Stanley M. Roberts,*a‡ John
Skidmore,a John A. Smithc and Natalie M. Williamsona
a Department of Chemistry, Liverpool University, Liverpool, UK L69 7ZD
b College of Pharmacy, Second Military Medical University, Shanghai 200433, PR China
c School of Biological Sciences, Liverpool University, Liverpool, UK L69 7ZB
O
The oxidation of chalcone 1 to optically active epoxide 2 [a
O
precursor of (+)-clausenamide (+)-3] may be effected using a
i
H
O
Ph
15-mer or 20-mer of L-leucine bound to a PEG based
support; poly-L-leucines of this type may be used as
immobilised catalysts in a fixed-bed reactor.
H
Ph
Ph
Ph
2
1
The polyamino acid catalysed asymmetric epoxidation of a,b-
unsaturated ketones was discovered by Julia´ and Colonna.1 The
reaction entailed taking a polyamino acid, such as poly-
l-leucine, and allowing it to swell to form a gel in the presence
of an organic solvent, 4 m aq. NaOH and H2O2. After several
hours, the substrate was added to the three-phase system
(insoluble polyamino acid, organic solvent–substrate, and
water–H2O2–NaOH). This system was used by Lantos2 and
Ferreira3 in the synthesis of selected target molecules.
Recently, it has been shown that the original three-phase
system used by Julia´ and Colonna can be replaced by a non-
aqueous two-phase system4 and this modified procedure has
been used to prepare diltiazem, TaxolTM side-chain5 and other
interesting structures.6
These recent advances in the utilisation of the Julia´–Colonna
oxidation focused our attention on three issues: (i) under-
standing the mechanism of the reaction; (ii) finding a suitable
methodology for conducting the reaction on a large scale; and
(iii) broadening the range of target molecules that can be made
by using the Julia´–Colonna technique as the key step. Some
progress has been made in each of these areas, as detailed
below.
Understanding the mechanism of the Julia´–Colonna oxida-
tion is the key to the application of the methodology to a broader
range of substrates. Typically the polyamino acid catalyst is
prepared by synthesis of the appropriate amino acid N-carboxy
anhydride (NCA) and then initiating polymerisation using a
nucleophile (water, an alcohol or an amine). Using l-leucine
and 1,3-diaminopropane this procedure gives a polymer with a
molecular weight range of 1500–3000;7 it was of interest to
determine whether the heterogeneous nature of the polymer
and/or the method of preparation8 were important with regard to
the intriguing catalytic properties of the system.
Thus, l-leucine NCA was polymerised using a polyethylene
glycol polystyrene based9 amino nucleophile as the initiator to
give CAT 1. At the same time a PEG-polystyrene supported
15-mer of l-leucine (CAT 2) and a PEG-polystyrene supported
20-mer of l-leucine (CAT 3) were prepared using a peptide
synthesiser. The effectiveness of these catalysts for the
conversion of chalcone 1 into the corresponding epoxide 2
(Scheme 1) is detailed in Table 1.
Scheme 1 Reagents and conditions: i, biphasic conditions: base, oxidant,
e.g. urea–H2O2, solvent, e.g. THF, room temp.
‘synthetic enzyme’10) is currently under way to help to elucidate
the mechanism of this fascinating reaction.
Under the biphasic reaction conditions the polypeptide does
not swell to any appreciable extent. This suggested that the
substrate in a suitable solvent might be passed through a column
of the catalyst mixed with the oxidant to furnish a fixed-bed
reactor convenient for a large scale continuous flow synthesis of
optically active epoxides. A miniature system was studied.
Poly-l-leucine, immobilised on cross-linked aminomethyl-
polystyrene11 (CLAMPS), was slurry packed into a Pasteur
pipette together with oxidant. A solution of chalcone 1
dissolved in a solvent containing DBU (0.5% v/v) was passed
through the column. Gratifyingly, good conversions of 1 to
epoxide 2 of good to excellent optical purity was observed. A
comparison of two oxidants and five solvents (Table 2)
suggested that DABCO–H2O212 and tert-butyl methyl ether are
the components of choice for further study.
The epoxide 2 was utilised to prepare (+)-clausenamide 3, an
antiamnaesic agent with potent hepatoprotective activity13
(Scheme 2). Oxidation of ketone 2 under the conditions
recommended by Flisak14 afforded the ester 4, which was
converted into the amide 5 using (±)-2-methylamino-1-phenyl-
ethanol. Oxidation of the hydroxy amide 5 and subsequent base-
catalysed cyclisation under prescribed conditions15 furnished a
1:1 mixture of diastereomeric lactams (+)-7 and (2)-8
[epimerisation of (2)-8 to provide further quantities of (+)-7
may be effected by base16]. Diastereoselective reduction of
(+)-7 with NaBH4 generated (+)-clausenamide (+)-3 in 89%
yield; the synthetic material had physical properties in accord
with those documented previously.17 This naturally occurring
compound is now available from chalcone 1 in six steps and
40% overall yield.
Table 1 Oxidation of chalcone 1 using polyleucine catalystsa
Conversion
(%)
Catalyst
t/h
Eeb (%)
It is clear that the homogeneous polymers of leucine behave
in a very similar manner to the material prepared in the usual
way from the N-carboxy anhydride. This is the first time that a
simple polyamino acid, prepared using a peptide synthesiser,
has been shown to catalyse the Julia´–Colonna asymmetric
epoxidation reaction. Variation in the amino acid content of the
homogeneous peptide chain (i.e. ‘point mutation’ of the
CAT 1
CAT 2
CAT 3
1.5
1.5
1.5
78
89
66
83
87
89
Typical reaction conditions: chalcone (25 mg) in THF (0.75 cm3) with
catalyst (50 mg), DBU (6 equiv.) and urea–H2O2 (4.8 equiv.). Ees
determined by chiral HPLC.
a
b
Chem. Commun., 1998
1159

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Present address: Department of Chemistry, Liverpool University,
Liverpool, UK L69 7ZD.
‡ E-mail: sj11@liv.ac.uk
Table 2 Oxidation of chalcone 1 using a fixed-bed of poly-l-leucinea
Notes and References
†
Residence
time/min
Conversion
(%)
Oxidant
Solvent
Eeb(%)
Urea–H2O2
Urea–H2O2
Urea–H2O2
DABCO–H2O2 THF
DABCO–H2O2 CH2Cl2
DABCO–H2O2 EtOAc
DABCO–H2O2 ButOMe
DABCO–H2O2 MeCN
THF
EtOAc
ButOMe
15
20
20
15
15
15
20
25
63
87
93
80
74
57
> 97
87
94
96
96
98
84
92
> 98
86
1 S. Banfi, S. Colonna, H. Molinari, S. Julia´ and J. Guixer, Tetrahedron,
1984, 40, 5207 and references cited therein. For recent reviews, see
M. E. Lasterra-Sa´nchez and S. M. Roberts, Curr. Org. Chem., 1997,
187; S. Ebrahim and M. Wills, Tetrahedron: Asymmetry, 1997, 8,
3163.
2 J. R. Flisak, K. J. Gombatz, M. M. Holmes, A. A. Jarmas, I. Lantos,
W. L. Mendelson, V. J. Novack, J. J. Remich and L. Snyder, J. Org.
Chem., 1993, 58, 6247.
3 J. A. N. Augustyn, B. C. B. Bezuidenhoudt, A. Swanepoel and
D. Ferreira, Tetrahedron, 1990, 46, 4429; H. van Rensburg, P. S. van
Heerden, B. C. B. Bezuidenhoudt and D. Ferreira, Chem. Commun.,
1996, 2747.
4 P. A. Bentley, S. Bergeron, M. W. Cappi, D. E. Hibbs, M. B. Hurst-
house, T. C. Nugent, R. Pulido, S. M. Roberts and L. E. Wu, Chem.
Commun., 1997, 739.
a
Reagents and conditions: immobilised poly-l-leucine (300 mg) was
packed in a column with oxidant (30 mg). Chalcone 1 (50 mg) in solvent
(0.5 cm3) was added and the column was eluted with the same solvent. b Ees
determined by chiral HPLC.
5 B. M. Adger, J. V. Barkley, S. Bergeron, M. W. Cappi, B. E. Flower-
dew, M. P. Jackson, R. McCague, T. C. Nugent and S. M. Roberts,
J. Chem. Soc., Perkin Trans. 1, 1997, 3501.
6 J. V. Allen, M. W. Cappi, P. D. Kary, S. M. Roberts, N. M. Williamson
and L. E. Wu, J. Chem. Soc., Perkin Trans. 1, 1997, 3297.
7 P. A. Bentley, W. Kroutil, J. A. Littlechild and S. M. Roberts, Chirality,
1997, 9, 198.
Ph
OH
Ph
OH
O
H
O
Ph
iv
Ph
Ph
+
H
O
O
N
N
O
O
R
Me
Me
2 R = Ph
(+)-7
(–)-8
i
ii
8 H. R. Kricheldorf, Comp. Polym. Sci., 1989, 3, 531.
9 The peptide chain is linked via a hydroxymethylphenoxyacetic acid
linker and via a polyethylene glycol graft to polystyrene particles of
75–150 mm in diameter. The density of attachment was 0.17 mmol
peptide per gram of starting resin.
4 R = OPh
5 R = NMeCH2CH(OH)Ph
6 R = NMeCH2COPh
v
iii
Ph
H
OH
10 S. Julia´, J. Masana and J. C. Vega, Angew. Chem., Int. Ed. Engl., 1980,
19, 929.
Ph
O
N
11 S. Itsuno, M. Sakakura and K. Ito, J. Org. Chem., 1990, 55, 6047.
12 A. A. Oswald and D. L. Guertin, J. Org. Chem., 1963, 28, 651.
13 Y. Liu, C. Z. Shi and J. T. Zhang, Yaoxue Xuebao, 1991, 26, 166;
T. G. Lin, G. T. Liu, K. J. Li, B. L. Zhao and W. J. Xin, Zhongguo
Yaolixue Yu Dulixue Zhazhi, 1992, 16, 97.
14 P. W. Baures, D. S. Eggleston, J. R. Flisak, K. Gombatz, I. Lantos,
W. Mendelson and J. J. Remich, Tetrahedron Lett., 1990, 31, 6501.
15 D. F. Huang and L. Huang, Tetrahedron, 1990, 46, 3135; J. Q. Wang
and W. S. Tian, J. Chem. Soc., Perkin Trans. 1, 1996, 209.
16 M. H. Yang, Y. Y. Chen and H. Liang, Huaxue Xuebao, 1987, 45,
1170.
OH
Me
(+)-3
Scheme 2 Reagents and conditions: i, MCPBA, CH2Cl2, reflux, 78%; ii,
(±)-2-methylamino-1-phenylethanol, CH2Cl2, 0 °C to room temp., 93%; iii,
KMnO4–CuSO4, CH2Cl2, room temp., 76%; iv, aq. LiOH, Et2O–THF,
room temp., 93%; v, NaBH4, MeOH, 0 °C to room temp., 83%
We thank the BBSRC for Fellowships (to W.-P. C. and
N. M. W.), the EPSRC (Studentship to R. W. F., Fellowship to
J. S.) and the Leverhulme Centre for Innovative Catalysis
(Fellowship to M. W. C.).
17 W. Hartwig and L. Born, J. Org. Chem., 1987, 52, 4352; M. H. Yang,
Y. Y. Chen and L. Huang, Phytochemistry, 1988, 27, 445.
Received in Cambridge, UK, 20th February 1998; 8/01450G
1160
Chem. Commun., 1998
Typeset and printed by Black Bear Press Limited, Cambridge, England