Scoping the triphasic/PTC conditions for the Juliá-Colonna epoxidation reaction

Article abstract of DOI:10.1016/j.tetlet.2004.04.189

A new, highly efficient procedure for the Juliá-Colonna epoxidation is reported. Based on the original triphasic protocol it is shown that the co-catalysis of the reaction with phase transfer catalysts results in a dramatic increase of reactivity and some

Full text of DOI:10.1016/j.tetlet.2004.04.189

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5069–5071
Scoping the triphasic/PTC conditions for the Juli ꢀa –Colonna
epoxidation reaction
a,
b
c
*
Thomas Geller, 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 Health Care AG, Process Development, Chemical Development, D-42096 Wuppertal, Germany
Received 23 February 2004; revised 21 April 2004; accepted 30 April 2004
Abstract—A new, highly efficient procedure for the Juli ꢀa –Colonna epoxidation is reported. Based on the original triphasic protocol
it is shown that the co-catalysis of the reaction with phase transfer catalysts results in a dramatic increase of reactivity and sometimes
also in a higher enantiomeric excess of product. The required amount of polyamino acid can be significantly reduced under the new
conditions, such that large scale industrial application of the method is now feasible.
Ó 2004 Elsevier Ltd. All rights reserved.
We have reported previously, in brief, that the Juli ꢀa –
Colonna epoxidation can be co-catalysed with phase
transfer catalysts (PTCs) resulting in a dramatic increase
the epoxidation process (Scheme 1, Table 1). Note that
as test substrates, compounds were chosen, which either
exhibit low reactivity or were not epoxidisable at all
under the standard triphasic conditions.
1
in the rate of the reaction. In order to scope the new
conditions, some further epoxidation reactions were
carried out to broaden the substrate range and to draw
comparison to the results published in the literature for
As seen previously under the new triphasic/PTC condi-
tions the conversions were generally much faster than
NH2 O
O
O
O
O
O O
S
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
1
2
3
4
5
Scheme 1. Products.
2
Table 1. Comparison of the triphasic/PTC-conditions with other Juli ꢀa –Colonna epoxidation protocols
Entry
Epoxide formed
Time
H
2
O
2
[equiv]
NaOH [equiv]
Conv. [%]
Ee [%]
Ref. experiment
5
1
2
3
4
5
1
2
3
4
5
15 min
8 min
5 h
5
4.2
1.3
4.2
4.2
4.2
97 (81)
>99 (76)
40 (85)
64 (70)
82 (61)
93 (98)
92 (76)
90 (77)
77 (80)
68 (21)
(2 h, biphasic)
(15 h, triphasic)
(18 h, triphasic)
6
1.3
28
6
3
b
1 h
2 h
5
5
(4 h, biphasic)
Cond. not publ.
7
2
Conditions: procedure a, 11 mol % poly-L-Leu type 1, 11 mol % TBAB used; results of the reference experiments are given in brackets.
Keywords: Juli ꢀa –Colonna epoxidation; Epoxides; Asymmetric reactions; Asymmetric synthesis; Polyamino acid; Peptide; Phase transfer catalysis.
*
Corresponding author. Tel.: +49-2173-38-4409; fax: +49-2173-38-4880; e-mail: thomas.geller@bayercropscience.com
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.189

5070
T. Geller et al. / Tetrahedron Letters 45 (2004) 5069–5071
Table 2. Influence of pre-activation of the polyamino acid for selected PTC’s
Entry
Epoxide formed
PTC/procedure
Time [min]
H
2
O
2
[equiv]
NaOH [equiv]
Conv. [%]
Ee [%]
Ò
1
2
3
4
5
6
1
1
2
2
5
5
Aliquat336 , a
Ò
30
30
5
5
4.2
4.2
1.3
1.3
4.2
4.2
74
100
100
100
92
55
91
82
95
22
64
Aliquat336 , b
þ
À
(Oct
(Oct
4
N) Br , a
N) Br , b
15
15
1.3
1.3
5
þ
À
4
Ò
Aliquat336 , a
Ò
120
30
Aliquat336 , b
5
95
2
Conditions: 11 mol % poly-L-Leu type 1, 11 mol % PTC; procedure a: instant mix; procedure b: with pre-activation.
under the published conditions, even though the poly-
2
L
-
-Leu) was used as it was produced. The
O
O
leucine (poly-
L
H2O2, base, solvent
cat. poly-L-Leu, (PTC)
Ph
Ph
enantiomeric excess (ee) was at least in the same range as
the reported results, sometimes significantly higher. In
the cases of the epoxidation of the 1-alkyl enones (Table
Ph
Ph
O
Scheme 2. Standard test reaction for the Juli ꢀa –Colonna epoxidation.
1
, entries 3 and 4) some side reactions were observed,
especially in the case of the epoxidation of 3-phenyl-2-
butenone (Table 1, entry 4). However, it is noteworthy
that this substrate type has not been epoxidisable at all
types. Using the triphasic conditions, a reduction of
poly-
significant loss of enantiomeric excess. Even with poly-
-Leu amounts of just 0.1 wt %, a reasonable enantio-
meric excess could be achieved. Due to the reduction of
poly- -Leu, the mixing and work-up of the reaction
L-Leu by a factor of 100 was possible without
3b
under the triphasic conditions so far.
L
As reported for trans-chalcone, the type of PTC used
has a profound influence on the outcome of the reac-
L
1
tion. The use of a more lipophilic catalyst results in a
dramatic loss of enantiomeric excess. However, this
effect can be minimised if the polyamino acid is pre-
system was no longer a problem; the reaction mixture
appears as a ‘2-phase-system‘ with only a trace of the
catalyst at the phase boundary, rather than the usual
voluminous gel.
2
activated in the presence of the PTC, whereupon the
enone (or sulfone) is added later. In order to ascertain
whether this effect can also be observed with other
substrates further tests were carried out (Table 2).
In a further test (2E)-1-phenyl-3-pyridin-2-yl-prop-2-en-
1-one was epoxidised under the new conditions with just
0
.5 mol % (9 wt %) poly-
reaction with this substrate is known to be slow under
standard conditions (16 h, 115 wt % poly- -Leu, 84%
L-Leu type 1 (Scheme 3). The
For all the substrates epoxidised in the presence of a
lipophilic PTC a significant positive influence on the ee
L
8
was observed when pre-activation of poly-
performed.
L
-Leu was
conv., 72% ee, triphasic conditions). The outcome of
the reaction confirmed the observation achieved with
trans-chalcone.
Under the previously published conditions, the usual
amount of poly- -Leu needed for efficient catalysis was
in the range of ca. 10 mol %, which translates to ca.
00 wt %. Due to the very fast reaction under the tri-
L
The influence of the amount of the PTC on the rate of
reaction and the enantiomeric excess of the chalcone
epoxide was also tested using the standard test reaction
(Scheme 2). As expected it was found that the rate of
reaction decreases with a reduction in the amount of
PTC but the enantiomeric excess remains high. It is
interesting to note that even 0.1 mol % of the catalyst
was sufficient to co-catalyse the reaction. With no PTC,
less than 1% conversion to the epoxide was observed in
the same reaction time (Fig. 1).
2
phasic/PTC-conditions it was interesting to determine
whether the amount of the polyamino acid could be
reduced (Table 3). Chalcone was used in the standard
3
test reaction (Scheme 2).
Interestingly a significant reduction in the amount of
poly-L-Leu required was achieved for both poly-L-Leu
The principle of co-catalysis is also applicable to other
reaction conditions in the Juli ꢀa –Colonna epoxidation,
that is, biphasic conditions and protocols involving sil-
ica-supported polyamino acids (PaaSiCat). Normally
Table 3. Reduction of the amount of poly-
L-Leu required
Catalyst type Concentra- Concentra- Conversion Ee
tion [mol %] tion [wt %] [%]
[%]
for these conditions pre-activated poly-L-Leu is re-
9
quired. Of interest is the fact that, under the new PTC
co-catalysed conditions a reasonable enantiomeric
excess can be achieved even with unactivated poly-L-Leu
Poly-
L
L
-Leu type 1 0.28
5
96
93
52
97
89
77
61
90
90
83
93
90
84
80
0
0
.11
.03
2
0.5
2
Poly-
-Leu type 2 0.20
(i.e., as produced directly from the polymerisation
reaction). As under the triphasic conditions the reaction
time as well as the enantiomeric excess is enhanced by
the PTC (Table 4). This fact might be explained by a
0
0
0
.05
.02
.01
0.5
0.2
0.1
1
Conditions: procedure a, 3 mol % TBAB, 4.2 equiv NaOH, 5 equiv
2
faster formation of the ‘real’ catalyst and therefore a
reduced (unselective) background reaction.
H
2
O
2
, 1 h reaction time.

T. Geller et al. / Tetrahedron Letters 45 (2004) 5069–5071
5071
0
.5 mol% poly-L-Leu, 3 mol% TBAB
O
aq. H O (1.5 eq.), toluene,
O
2
2
NaOH (1.5 eq.), 30 min
99% conv., 84% ee
Scheme 3. Epoxidation of (2E)-1-phenyl-3-pyridin-2-yl-prop-2-en-1-one.
N
N
O
>
4
1
9
00
type 2 (1-amino butane/leu-NCA ¼ 1:18). Due to the
0
0
0
0
0
0
0
0
0
initiator used for the preparation of poly-L-Leu type 1,
8
7
6
5
4
3
2
1
two active centres per molecule were assumed for the
calculation of the mol % figures for this catalyst. ht-poly-
Leu made using a procedure similar to that described in this
article is now available from Fluka (Poly-
diaminopropane, Prod. no 93197).
Triphasic/PTC-conditions, procedure a, (instant mix): The
indicated amount of poly- -Leu, 0.24 mmol of the substrate
and the given amount of PTC were mixed. Subsequently
.8 mL toluene, the indicated amounts of NaOH (5 M) and
(30%, 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 slowly into 4 mL of a stirred ice-cold aqueous
L-leucine-1,3-
L
0
0
0.5
1
1.5
2
2.5
3
3.5
0
TBAB [mol%]
2 2
H O
conversion enantiomeric excess
Figure 1. Influence of the PTC concentration on the rate of reaction
2
and enantiomeric excess. Conditions : Standard test reaction, proce-
dure a, 0.3 mol % poly-L-Leu type 1, indicated amount of TBAB,
NaHSO
3
solution, 20%. After 5 min the mixture was
centrifuged. The organic phase was separated and the
solvent evaporated under reduced pressure.
1
2 2
.5 equiv H O , 1.5 equiv NaOH, 2 h reaction time.
Triphasic/PTC-conditions, procedure b (pre-activation):
The poly-Leu and the PTC were placed in a sample vial.
Subsequently toluene and NaOH (5 M) were added (ratios
see procedure a). This mixture was stirred at a rate of
approximately 1250 rpm for 1.5 h before the substrate was
added. After the indicated reaction time the work-up was
carried out as described above.
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 HPLC were prepared by filtration of
a solution of the material (EtOAc/petrol-ether 1:2) through
a small layer of silica (Pasteur pipette), evaporation of the
solvent and re-dissolving the material in the HPLC solvent;
Table 4. Influence of the PTC under biphasic- and PaaSiCat-condi-
tions using unactivated poly-
L
-Leu, standard test (epoxidation of
trans-chalcone)
Conditions
Results
Biphasic
>99% conversion, 53% ee
>99% conversion, 78% ee
>99% conversion, 86% ee
>99% conversion, 92% ee
Biphasic/PTC
PaaSiCat
PaaSiCat/PTC
3b
3c
Conditions: 30 min room temp; biphasic; PaaSiCat; biphasic/PTC
and PaaSiCat/PTC as before but with 11 mol % TBAB.
(
5) enantiomeric excess was determined by chiral HPLC or
1
H NMR (using Eu(hfc)
standards.
3
) employing racemic epoxides as
In summary, the PTC co-catalysed Juli ꢀa –Colonna
epoxidation is normally much faster and the enantio-
meric excess higher than under previously documented
conditions. The effect is generally observable under all
tested protocols for the Juli ꢀa –Colonna epoxidation. In
particular, under the triphasic conditions, the principle
of co-catalysis is very beneficial since downstream work-
up is very simple and only cheap ingredients are
3
. 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, 739–740; (c) Geller, T.; Roberts,
S. M. Chem. Commun. 1999, 1397–1398; (d) Takagi, R.;
Manabe, T.; Shiraki, A.; Yoneshige, A.; Hiraga, Y.;
Kojima, S.; Ohkata, K. Bull. Chem. Soc. Jpn. 2000, 73,
required. The necessary amount of poly-L-Leu can be
reduced significantly to 2–5 wt %, thus mixing and cat-
alyst recovery is no longer a limitation.
2
115–2121.
4
. Geller, T.; Gerlach, A.; Vidal-Ferran, A.; Militzer, H.-C.;
Langer, R. PCT Int. Appl. WO 2003070808, 2003 (Priority:
DE 2002-10206793 20020219, Bayer AG).
References and notes
5. Chen, W.-P.; Egar, A. L.; Hursthouse, M. B.; Malik, K. M.
A.; Mathews, J. E.; Roberts, S. M. Tetrahedron Lett. 1998,
39, 8495–8498.
6. Kroutil, W.; Mayon, P.; Lasterra-S ꢀa nchez, M. E.; Madd-
rell, S. J.; Roberts, S. M.; Thornton, S. R.; Todd, C. J.;
T u€ ter, M. Chem. Commun. 1996, 845–846.
7. Bentley, P. A.; Bickley, J. F.; Roberts, S. M.; Steiner, A.
Tetrahedron Lett. 2001, 42, 3741–3743.
8. Lasterra-S ꢀa nchez, M. E.; Felfer, U.; Mayon, P.; Roberts, S.
M.; Thornton, S. R.; Todd, C. J. J. Chem. Soc., Perkin
Trans. 1 1996, 343–348.
1
. Geller, T.; Gerlach, A.; Kr u€ ger, C. M.; Militzer, H.-C.
Chim. Oggi 2003, 21, 6–8; Geller, T.; Gerlach, A.;
Kr u€ ger, C. M.; Militzer, H.-C. Tetrahedron Lett. 2004,
4
5, preceding communication. doi:10.1016/j.tetlet.2004.04.
88.
1
. Poly-Leu: All poly-
statistical polymerisation of
2
L
-Leu-batches used were prepared via
-leucine-NCA (leu-NCA)
L
with an amine at high temperature. Two types of catalyst
were prepared, differing in the amine used to initiate
polymerisation and the amine/leu-NCA ratio: poly-
type 1 (1,3-diaminopropane/leu-NCA ¼ 1:66), poly-
L
-Leu
-Leu
9. Bentley, P. A.; Cappi, M. W.; Flood, R. W.; Roberts, S.
M.; Smith, J. A. Tetrahedron Lett. 1998, 39, 9297–9300.
L