TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4261–4262
The use of liquefied petroleum gas (LPG) as a solvent for
yeast reactions
Melanie K. Johns, Andrew J. Smallridge* and Maurie A. Trewhella
School of Life Science and Technology, Victoria University of Technology, PO Box 14428, Melbourne 8001, Australia
Received 27 March 2001; accepted 19 April 2001
Abstract—The yeast mediated reduction of ethyl acetoacetate to ethyl (S)-3-hydroxy butyrate proceeds with good yield and high
enantioselectivity in liquefied petroleum gas (LPG). It was found that slightly more water (2 ml/g yeast) and more yeast (1.6
g/mmol substrate) were required to effect complete conversion than was the case with more conventional organic solvents, such
as petroleum spirit. © 2001 Published by Elsevier Science Ltd.
Yeast is becoming a widely utilized chiral reducing agent
in organic synthesis due to its low cost and high
efficiency. Recently it has been demonstrated that yeast
reactions can be carried out in a variety of organic
solvents rather than the more conventional aqueous
reaction systems; solvents such as benzene,1 petroleum
ether,2 toluene3 and carbon tetrachloride3 have all been
successfully employed. The main advantage with using
an organic solvent for the reaction is the ease with which
the product can be isolated and that generally superior
isolated yields and enantioselectivity can be achieved.4
The main drawback associated with the use of organic
solvents is their potential toxicity and problems associ-
ated with their disposal. It was thought that liquefied
hydrocarbon gases may prove to be a ‘greener’ alterna-
tive to organic solvents since they are cheap, non-toxic
and readily recyclable.
substrate is required. It has been shown that an enzyme
becomes fully hydrated when surrounded by a few layers
of water molecules and this hydration layer acts as a
microreactor for the enzyme and protects it from any
detrimental effects of the bulk organic solvent.6,7 Sol-
vents that interact with this water layer and either remove
or distort it, will have a detrimental effect upon the
activity of the enzyme(s) involved in the reaction. Sol-
vents which are hydrophilic or water miscible will have
the greatest effect and are generally unsuitable solvents
for enzymatic reactions. For yeast mediated reactions,
non-polar solvents have been shown to be the most
suitable whilst in polar solvents such as acetonitrile,
acetone or dimethyl formamide, yeast is inactive. LPG
is partially miscible with water and it is probable that the
LPG is partitioning some of this essential water away
from the yeast enzymes; more water is therefore required
to maintain the enzymic activity. The requirement for
more yeast is an indication that either the yeast is less
active in LPG than in petroleum spirit or that the yeast
enzyme system is deactivated faster in LPG than in
petroleum ether.8 Diethyl ether, which is also partially
miscible with water, shows a similar requirement for a
higher yeast:substrate ratio.4
Reduction of ethyl acetoacetate (1) with dry baker’s yeast
in LPG5 (116 psi) in a stainless steel reaction vessel using
the reaction conditions determined to be optimal for
reaction in petroleum ether (0.8 ml water/g yeast, 1 g
yeast/mmol substrate) gave ethyl (S)-3-hydroxy butyrate
(2) in 33% conversion after 12 h (Scheme 1).
The product from the reaction, conducted under optimal
conditions, was isolated to give ethyl (S)-3-hydroxy
butyrate in 74% yield and 95% ee. The ee was measured
on the trifluoroacetyl derivative using chiral gas chro-
The yeast:water and yeast:substrate ratios were altered
in order to determine the optimal conditions for the
reaction. It was found that with 2 ml water/g yeast and
1.6 g yeast/mmol substrate complete conversion of ethyl
acetoacetate to ethyl (S)-3-hydroxy butyrate was
obtained. This is slightly more water and yeast than is
required to effect complete conversion in petroleum spirit
where only 0.8 ml water/g yeast and 1 g yeast/mmol
O
O
OH
O
Yeast
LPG (116psi)
OEt
OEt
(1)
Scheme 1.
(2)
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00664-5