thylpentanoic acid 2 and 2-methylhexanoic acid 3 were
explored. The CRL lipase has previously been shown10 to
discriminate enantiomers of the corresponding acids in ester-
ification reactions in organic solvents with moderate to good
enantioselectivities 52–93% ee.§
Scheme 1 Synthesis of alarm pheromone of (S)-(+)-4-methylheptan-3-one
6; i. CRL, Phosphate buffer, 0.2 M, pH 7; ii EtLi (2.2 equiv.), Et O,
2
5
4%.
resultant ketone (S)-6 was determined both by chiral GC
analysis and optical rotation.12
For this study 1, 2 and 3 were (trans)esterified with the highly
fluorinated decanol 4 to explore (trans)esterification between
In conclusion we have demonstrated that a perfluorocarbon–
hydrocarbon solvent system offers an excellent medium for
lipase catalysed (trans)esterification reactions. Further by
judicious choice of ‘organic’ and ‘fluorous’ compatible sub-
strates, products of different enantiomeric series are partitioned
between the two phases. The product esters recovered from the
fluorous phase had high enantiomeric purities and reactions can
be conducted on a gramme scale. Clearly an optimal system will
have reduced partitioning of the ‘fluorous’ esters into hexane
with no post reaction washing, and this remains to be achieved,
but there are good prospects now for the development of such
reactor systems. The authors thank the European Commission
for supporting a Studentship (PB) through Research Training
Network, ERBFM-RXCT9.
‘
organic’ compatible esters–acids with a ‘fluorous’ alcohol. The
two liquid phases (hexane–PFH) became homogenous at 30 °C
and the reactions were carried out at 40 °C (Table 1). In all cases
the reaction progress was monitored by GC-MS to approx-
imately a 50% conversion. After completion, all reactions were
filtered to remove the enzyme and the homogenous medium
cooled (0 °C) and the phases left to partition (30 min). In general
the enantiomeric excesses of the product esters were high. It is
interesting that the enantiomeric enrichment values (Table 1) of
the fluorous recovered products is generally higher to that from
previous studies10 for CRL esterification reactions in hexane,
indicating an improved stereoselectivity under these novel
conditions. It is also notable that the esterification reaction
between 2 and 4 generates a product with a higher enantiomeric
purity than that between the corresponding vinyl ester 1 and 4,
despite these being slower reactions. Efficient partitioning of
the unreacted (S)-acids 2 and 3, and the product (R)-esters of the
opposite enantiomeric series, is compromised to some extent by
some solubility of the product esters in hexane and trace
amounts of the unreacted acids in the fluorous phase. This was
overcome by washing the hexane layer with PFH for maximum
recovery of the ester. The little acid in the fluorous phase was
not problematical and could be removed by rotary evaporation
on work up. Enantiomeric analysis of the ester carboxylate
moiety was determined directly after ester hydrolysis of the
products recovered from each phase without recourse to
chromatographic separation.
Notes and references
‡
Lipase from Candida rugosa (CRL) was purchased from the Sigma
21
Chemical Co. and had a specific activity of 724 U mg solid. In all
experiments the lipase was used ‘straight from the bottle’.
§
Experimental procedure: Ester–acid (1 mmol), ‘fluorous’ alcohol (1
mmol), PFH (10 ml), hexane (10 ml) and CRL§ (0.2 g) were placed in a
conical flask with a rubber septum. The mixture was shaken at 200 rpm at
4
0 °C and periodically aliquots (5 ml) of the reaction solution were analysed
by GC-MS to determine the extent of conversion. For the calculation of
conversion, the calibration curves of starting and product esters and alcohols
were constructed. The enzyme was filtered, the solid on the filter was
washed with 2 ml of PFH and 2 ml of hexane. Liquid phases were collected,
cooled (0 °C, 30 min) and separated. The hexane phase was washed with
PFH (5 3 15 ml). The washed hexane phase contained unreacted ester–acid
and less than 2% of ‘fluorous’ ester. Unreacted vinyl ester 1 was hydrolysed
With these encouraging results a preparative scale experi-
ment was conducted with CRL between acid 2 (6 g) and alcohol
2 4
in an aqueous acid (dil. H SO ) solution of mercury(II) acetate. Combined
4
(21.3 g) in a hexane–PFH solvent mix (1+1) at 40 °C. In this
fluorous phases were concentrated under reduced pressure (100 °C, 20 torr
to remove traces of acid), hydrolysed with methanolic LiOH and then
acidified. The % ee values (including 6) of the resulting acids were
determined by GC-MS using a chiral column (b-DEX 120, Supelco).
case dry Na SO was added to absorb expelled water. The
2
4
reaction was worked up after it had progressed to about 50%
conversion. The product ester (S)-5 (94% ee) was recovered
after evaporation of the fluorous phase. The resultant acid 2 was
recovered (1.97 g, 66%) after enzymatic hydrolysis (CRL) and
extraction of the product from the buffer into hexane. The
enantiomeric purity of this (S)-2 was 96% ee. The unreacted
acid was recovered from the PFH washed hexane layer with a
1
2
I. T. Horváth and J. Rábai, Science, 1994, 266, 72.
I. T. Horváth, Acc. Chem. Res., 1998, 31, 641; I. T. Horváth, G. Kiss, R.
A. Cook, J. E. Bond, P. A. Stevens, J. Rábai and E. J. Mozeleski, J. Am.
Chem. Soc., 1998, 120, 3133; L. P. Barthel-Rosa and J. A. Gladysz,
Coord. Chem. Rev., 1999, 190–192, 587; B. Cornils, Angew. Chem., Int.
Ed. Engl., 1997, 36, 2057; D. P. Curran, Angew. Chem., Int. Ed. Engl.,
7
9% ee (R)-2 (1.81 g, 57%,) contaminated with less than 2% of
ester 5. Decanol 4 was also recovered (13.3 g, 62%) from the
fluorous phase and there was an 80% recovery of the fluorous
solvent.
1
998, 37, 1174; E. de Wolf, G. van Koten and B.-J. Deelman, Chem.
Soc. Rev., 1999, 28, 37; C. Rocaboy, D. Rutherford, B. L. Bennett and
J. A. Gladysz, J. Phys. Org. Chem., 2000, 13, 596.
3 R. H. Fish, Chem. Eur. J., 1999, 5, 1677; J. J. J. Juliette, D. Rutherford,
I. T. Horváth and J. A. Gladysz, J. Am. Chem. Soc., 1999, 121, 2696; G.
Pozzi, M. Cavazzini, F. Cinato, F. Montanari and S. Quici, Eur. J. Org.
Chem., 1999, 1947.
In order to demonstrate the synthetic utility of the resolution
process the (S)-5 ester which was hydrolysed in the second
enzymatic reaction was used to prepare a sample of (S)-
(
+)-4-methylheptan-3-one 6 (94% ee) the principal alarm
4
5
6
A. M. Klibanov, Acc. Chem. Res., 1990, 23, 114.
A. M. Klibanov, Chem.-Tech. (Heidelberg), June 1986, 354.
P. A. Fitzpatrick and A. M. Klibanov, J. Am. Chem. Soc., 1991, 113,
11
pheromone of the ant Atta texana. These transformations are
summarised in Scheme 1. The enantiomeric purity of the
3
166.
Table 1 CRL (trans)esterification reactions with alcohol 4 and esters–acids
7 V. F. Hogan, D. O’Hagan and J. Sanvoisin, Ind. J. Chem., Sect. B, 1992,
31, 883.
1
, 2 and 3
8
L. E. Kiss, I. Kövesdi and J. Rábai, J. Fluorine Chem., 2001, 108, 95.
(
S)-Ester
(R)-Ester–acid
9 B. Hungerhoff, H. Sonnenschein and F. Theil, Angew. Chem., Int. Ed.,
2001, 40, 2492; B. Hungerhoff, H. Sonnenschein and F. Theil, J. Org.
Chem., 2002, 67, 1781.
b
c
Reaction
Conversion product ee unreacted ee
a
Ester–acid
time/h
(%)
(%)
(%)
1
0 B-V. Nguyen and E. Hedenström, Tetrahedron: Asymmetry, 1999, 10,
1821; K.-H. Engel, Tetrahedron: Asymmetry, 1991, 2, 165; P. Berglund,
M. Holmquist, E. Hedenström, K. Hult and H.-E. Högberg, Tetra-
hedron: Asymmetry, 1993, 4, 1869.
1
2
3
44
95
149
48
53
49
72
95
95
44
79
94.5
a
Reaction temperature 40 °C. b Combined fluorous phase. c Hexane phase
11 R. G. Riley and R. M. Silverstein, Tetrahedron, 1974, 30, 1171.
2 Spectroscopic characterisation of (S)-6 was entirely consistent with the
1
after extractions.
24
11
27
literature. [a]
D
= +19.1° (c, 2.9, hexane); (lit. [a]
D
= +21.0°).
CHEM. COMMUN., 2002, 1680–1681
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