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