Novel conditions for the Juliá-Colonna epoxidation reaction providing efficient access to chiral, nonracemic epoxides

Article abstract of DOI:10.1016/j.tetlet.2004.04.188

The addition of a phase-transfer catalyst significantly accelerates the Juliá-Colonna epoxidation reaction yielding chiral, nonracemic epoxy ketones. Furthermore, a reliable procedure for the preparation of highly active poly-L-leucine catalyst is reported.

Full text of DOI:10.1016/j.tetlet.2004.04.188

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5065–5067
Novel conditions for the Juli ꢀa –Colonna epoxidation reaction
providing efficient access to chiral, nonracemic epoxides
a
b
b
c,
*
Thomas Geller, Arne Gerlach, Christa M. Kr u€ ger and H.-Christian Militzer
a
Bayer CropScience AG, Process Research, Alfred-Nobel-Str. 50, D-40789 Monheim, Germany
b
Bayer Chemicals AG, R&D, D-51368 Leverkusen, Germany
c
Bayer HealthCare AG, Chemical Development, D-42096 Wuppertal, Germany
Received 23 February 2004; revised 30 March 2004; accepted 30 April 2004
Abstract—The addition of a phase-transfer catalyst significantly accelerates the Juli ꢀa –Colonna epoxidation reaction yielding chiral,
nonracemic epoxy ketones. Furthermore, a reliable procedure for the preparation of highly active poly-L-leucine catalyst is
reported.
Ó 2004 Elsevier Ltd. All rights reserved.
Stereoselective catalysts of pure organic origin have
1
improved procedures are hampered by several factors,
for example, by the limited availability of the catalysts,
which are used in rather large quantities, long reaction
times and/or difficulties in the work-up process.
come sharply into focus in recent times. In one of the
early examples, the use of chiral polyamino acids as
organic catalysts was reported by Juli ꢀa et al. in the
epoxidation of chalcone with good enantioselectivity
2
(
Scheme 1). Since then several groups, including Juliꢀa
In a move to extend our chiral technologies we became
interested in the Juli ꢀa –Colonna reaction since chiral,
nonracemic epoxides may serve as building blocks for
the synthesis of a wide variety of optically active com-
and Colonna and later Roberts and co-workers, have
shown that with respect to the original triphasic method
(
excess of inorganic base and hydrogen peroxide in an
4
aqueous phase, the substrate dissolved in an organic
phase and the insoluble polyamino acid as a third phase)
pounds.
3
several improvements can be gained. Under the new
Understanding the reaction mechanism of the Juli ꢀa –
Colonna epoxidation should be key to further optimi-
zation and has been addressed by some research
conditions of the Juli ꢀa –Colonna epoxidation a broad
range of substrates bearing a substituted enone system
as a prerequisite can be selectively epoxidized. However,
from an industrial point of view even the various
5
groups. Even so, very little is known about the active
catalytic species. A key problem is that the most com-
mon and selective catalyst, poly-leucine, is virtually
insoluble in organic and aqueous media. As a hypothesis
we assumed that a phase-transfer catalyst (PTC) should
be able to accelerate the reaction since for all existing
Juli ꢀa –Colonna protocols the hydroperoxide anion is
formed in one phase and has to be transferred through
at least one phase interface in order to form the desired
O
O
H O , solvent, base,
2
2
R'
R'
R
R
poly-L-amino acid
up to 98% ee
O
6
epoxide.
Scheme 1. Juli ꢀa –Colonna epoxidation.
In the first set of experiments we tested whether the
addition of a PTC under triphasic conditions would
have any influence on the epoxidation of trans-chalcone
Keywords: Juli ꢀa –Colonna epoxidation; Epoxides; Asymmetric reac-
tions; Asymmetric synthesis; Polyamino acid; Peptide; Phase-transfer
catalysis.
7
(the standard test system, Scheme 2). We chose these
conditions for our first tests since unactivated poly-
*
Corresponding
bayer-ag.de
author.
E-mail:
hans-christian.militzer.hm@
L-
leucine (poly- -Leu) can be used as the catalyst and
L
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.188

5066
T. Geller et al. / Tetrahedron Letters 45 (2004) 5065–5067
Table 2. Epoxidation of trans-chalcone using an aqueous NaOCl-
solution
O
O
H O , base, solvent
Ph
2
2
a
Ph
Conditions
Result
Ph
Ph
cat. poly-
L-Leu, (PTC)
O
1.5 h, room temp
+TBAB, 1.5 h, room temp
1% conversion, ee not evaluated
32% conversion, ee ¼ 90%
1
2
a
See Ref. 8.
Scheme 2. Standard test reaction for the Juli ꢀa –Colonna epoxidation.
Following the original protocol no reaction was
Table 1. Comparison of PTC/triphasic-conditions with the triphasic
protocol on trans-chalcone 1
11
observed with NaOCl. However, considerable con-
version and good enantioselectivity was obtained on
using TBAB as a phase-transfer catalyst over the same
reaction time of 1.5 h (Table 2, entry 2).
a
Conditions
Result
1
.5 h, room temp
2% conversion, ee not evaluated
>99% conversion, ee ¼ 94%
+
TBAB, 1.5 h, room temp
a
See Ref. 8.
For all the Juli ꢀa –Colonna protocols developed so far,
the polyamino acid employed and the manner of its
12
aqueous hydrogen peroxide as the oxidant. To our
surprise the addition of tetrabutylammonium bromide
(TBAB) as co-catalyst resulted in a dramatic accelera-
tion of the reaction (Table 1).
preparation are of crucial importance. Poly-L-Leu has
been prepared in a conventional fashion by synthesis of
the corresponding N-carboxyanhydride 4 (Leu-NCA)
and subsequent amine induced polymerization.
The reaction proceeds with high enantioselectivity (94%
ee). Within 1.5 h, virtually complete conversion to the
desired epoxide 2 was observed while under standard
triphasic conditions only 2% of the product was
detected. Under these conditions the previously
In our hands some of the commercial poly-L-leucines
did not deliver the required catalytic activity, so we
investigated large-scale production of material for our
developmental work. We obtained Leu-NCA on a multi
100 g scale in very pure and crystalline form by phos-
9
described pre-activation time of P6 h is reduced to a
genation of L-leucine 3 in THF, using 2 equiv of leucine
as acid scavenger. Under these conditions the Leu-NCA
was not accompanied by a dark brown oil as described
few minutes. Our current understanding of the reaction
with the PTC is that it increases the available peroxide
10
12a
concentration in the organic phase. Additionally, we
could show that due to the very fast reaction, the
amount of oxidant and base could be reduced signifi-
cantly, from 30 equiv H O and about 4 equiv of NaOH
earlier. After some optimization it turned out that the
subsequent statistical polymerization induced by 1,3-
diaminopropane was preferably performed in refluxing
13
toluene. The required poly-L-Leu 5 was isolated by
2
2
initially to 1.3equiv of each.
precipitation with an alcohol or by centrifugation and
subsequent drying. This procedure allowed the reliable
preparation of several highly active poly-L-Leu types
with different chain lengths on a multi 100 g scale
(Scheme 3).
Under all the published conditions hydrogen peroxide
or a hydrogen peroxide generating agent is used as the
oxidant. We therefore tested whether a somewhat safer
and equally readily available aqueous NaOCl-solution
could be used as the oxidizing reagent under the new
PTC/triphasic-conditions.
To our surprise poly-L-Leu that had been polymerized
at higher temperatures (ht-poly-
L
-Leu) led to signifi-
O
NH2
HN
phosgene
THF, 50°C
O
O
O
O
3
4
O
1
/(n+m) eq.
HN
1,3-diaminopropane
O
O
O
H
N
H
N
H N
NH2
2
N
N
H
toluene, reflux
H
O
O
O
n
m
4
5
Scheme 3. Preparation of Leu-NCA and statistical polymerization to poly-L-Leu 5.

T. Geller et al. / Tetrahedron Letters 45 (2004) 5065–5067
5067
Table 3. Comparison of PTC/triphasic-conditions with the triphasic
protocol on trans-chalcone
additional effects on reaction time, selectivity and catalyst
loading have been reported.
a
7. For example: (a) Juli ꢀa , S.; Masana, J.; Vega, J. C. Angew.
Chem., Int. Ed. Engl. 1980, 19, 929; (b) Bentley, P. A.;
Bergeron, S.; Cappi, M. W.; Hibbs, D. E.; Hursthouse, M.
B.; Nugent, T. C.; Pulido, R.; Roberts, S. M.; Wu, L. E.
Chem. Commun. 1997, 739; (c) Geller, T.; Roberts, S. M.
Chem. Commun. 1999, 1397; (d) Takagi, R.; Manabe, T.;
Shiraki, A.; Yoneshige, A.; Hiraga, Y.; Kojima, S.;
Ohkata, K. Bull. Chem. Soc. Jpn. 2000, 73, 2115; (e)
Geller, T.; Gerlach, A.; Kr u€ ger, C. M.; Militzer, H.-C. EP-
A-02015587.
Catalyst
Conditions
1.5 h
Result
Standard poly-
L
-
2% conversion, ee not evaluated
Leu
Ht-poly-
L
L
-Leu
-
1.5 h
7 min
59% conversion, ee ¼ 91%
>99% conversion, ee ¼ 94%
Ht-poly-
Leu + TBAB
See Ref. 8.
a
8
. Poly-L-Leu. All poly-L-Leu-batches used were prepared
via statistical polymerization of Leu-NCA with 1,3-
cantly more active catalysts as compared to the standard
material.
12d
In the triphasic epoxidation of trans-chal-
cone (Scheme 2) almost no conversion (2%, ee not
evaluated) was observed after 1.5 h with standard poly-
diaminopropane (1,3-diaminopropane/Leu-NCA ¼ 1:66).
12d
The standard-poly-L-Leu was prepared in THF at room
temperature. For the preparation of ht-poly-L-Leu, 1,3-
L
-Leu while in the same time the ht-poly-
already led to a conversion of 59% and an ee of 91%
Table 3). Obviously, the new catalyst material does not
L-Leu had
diaminopropane and Leu-NCA were dissolved at room
temperature in toluene and subsequently heated to reflux
for 24 h.
(
9
need a prolonged pre-activation period. The combina-
tion of ht-poly- -Leu and TBAB led to full conversion
of 1 in less than 10 min (Table 3, entry 3).
Triphasic/PTC-conditions. Poly-
00 wt %), 50 mg (0.24 mmol) of trans-chalcone and 8.5 mg
11 mol %) of TBAB were mixed. Subsequently 0.8 mL
toluene, 4.2 equiv NaOH (5 M) and 28.5 equiv H (30%,
L-Leu (100 mg, 11 mol %,
2
(
L
2
O
2
aq) were added. This mixture was stirred for the indicated
time at a rate of approximately 1250 rpm. For work-up the
mixture was diluted with 1 mL of EtOAc and poured
In summary, a new and efficient protocol for the Juli ꢀa –
Colonna epoxidation has been developed. It was found
that the addition of specific PTCs results in a significant
acceleration of the reaction. One effect of the PTC is a
sharp reduction of the catalyst pre-activation period
that is otherwise needed. Thus under the triphasic con-
ditions the principle of co-catalysis is very beneficial
slowly into 4 mL of a stirred ice cold aqueous NaHSO
3
solution (20%). After 5 min the mixture was centrifuged.
The organic phase was separated and the solvent evapo-
rated under reduced pressure.
Triphasic/PTC-conditions, NaOCl. As before but with
6
2 2
mL NaOCl-solution (aq 7.5% NaOCl) instead of H O
since the active poly-
duced. Ongoing research indicates that improved poly-
-leucine quality enables the epoxidation of a broader
L-leucine can be used as it is pro-
and NaOH. This mixture was stirred at a rate of
approximately 1250 rpm for 1.5 h. For work-up of the
mixture see above.
Triphasic conditions. As Triphasic/PTC but without phase-
transfer catalyst.
General remarks. (1) The reactions were carried out at
room temperature; (2) during the reaction light has to be
excluded; (3) the reactions were monitored by TLC or
HPLC; (4) samples for the HPLC were prepared by
filtration of a solution of the material (EtOAc/pet. ether
1:2) through a small layer of silica (Pasteur pipette),
evaporation of the solvent and re-dissolving the material
in the HPLC-solvent; (5) enantiomeric excess determined
by chiral HPLC employing racemic epoxides as standards.
L
range of substrates and leads to significant reductions in
catalyst loadings yielding a virtually biphasic system.
These results are reported in the following publication.
References and notes
1
. See, for example: List, B. Synlett 2001, 11, 1675–1686;
List, B. Tetrahedron 2002, 58, 5573–5590; Adamo, M. F.
A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem. Soc. 2002,
9. Flisak, J. R.; Gassman, P. G.; Lantos, I.; Mendelson, W.
L. 1990, EP 403252 A2, CAN 115:71370 AN 1991:471370.
10. Geller, T.; Gerlach, A.; Kr u€ ger, C. M.; Militzer, H.-C.
Chim. Oggi 2003, 21, 6.
1
24, 11223–11223.
2
. Juli ꢀa , S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed.
Engl. 1980, 19, 929.
3
. Porter, M. J.; Roberts, S. M.; Skidmore, J. Bioorg. Med.
Chem. 1999, 7, 2145–2156, and references cited therein;
Porter, J.; Skidmore, J. Chem. Commun. 2000, 1215–1225,
and references cited therein.
. Lauret, C.; Roberts, S. M. Aldrichim. Acta 2002, 35, 47.
. (a) Takagi, R.; Shiraki, A.; Manabe, T.; Kojima, S.;
Ohkata, K. Chem. Lett. 2000, 4, 366–367; (b) Takagi, R.;
Manabe, T.; Shiraki, A.; Yoneshige, A.; Hiraga, Y.;
Kojima, S.; Ohkata, K. Bull. Chem. Soc. Jpn. 2000, 73,
11. Roberts, S. M.; 1998, personal communication.
12. (a) Baars, S.; Drauz, K.-H.; Krimmer, H.-P.; Roberts, S.
M.; Sander, J.; Skidmore, J.; Zanardi, G. Org. Proc. Res.
Dev. 2003, 7, 509; (b) Dhanda, A.; Drauz, K.-H.; Geller,
T.; Roberts, S. M. Chirality 2000, 12, 313–317; (c) Banfi,
S.; Colonna, S.; Molinari, H.; Juli, S.; Guixer, J. Tetra-
hedron 1984, 40, 5207–5211, and references cited therein;
(d) Bentley, P. A.; Kroutil, W.; Littlechild, J. A.; Roberts,
S. M. Chirality 1997, 9, 198–202, and references cited
therein.
4
5
2
115–2121; (c) Flood, R. W.; Geller, T. P.; Petty, S. A.;
Roberts, S. M.; Skidmore, J.; Volk, M. Org. Lett. 2001, 3,
83–686; (d) Bentley, P. A.; Flood, R. W.; Roberts, S. M.;
Skidmore, J.; Smith, C. B.; Smith, J. A. Chem. Commun.
001, 1616–1617; (e) Berkessel, A.; Gasch, N.; Glaubitz,
13. Geller, T.; Gerlach, A.; Vidal-Ferran, A.; Militzer, H.-C.;
Langer, R. PCT Int. Appl. 2003, WO 2003070808 (Prior-
ity: DE 2002-1020679320020219, Bayer AG). Later Baars
et al. also reported polymerizations of Leu-NCA at
6
2
1
2a
K.; Koch, C. Org. Lett. 2001, 3, 3839–3842.
elevated temperature.
the procedure described in this article is now available
Ht-poly-L-Leu made similar to
6
. PTCs have already been used for Juli ꢀa –Colonna reactions
in order to utilize sparingly water-soluble oxidants such as
Na-perborate or Na-percarbonate. However, no beneficial
from Fluka (Poly-
93197).
L-leucine-1,3-diaminopropane, Prod. no