Table 1 Key figures for the syntheses of different (R)-alcohols
Table 2 Key figures for the synthesis of (R)-2-nonanol with increased
substrate and 10-fold increased biocatalyst concentrations
(
R)-3-
(R)-2-
Octanol
(R)-2-
Nonanol
(R)-2-
Decanol
2-nonanone/mmol L-
1
80
100
150
Octanol
c
STY/mmol L d-1
-
1
74.6
9.72
713
16.3
677
117
77.8
10.1
743
17.0
705
112
88.1
12.7
842
19.3
799
89
82.9
13.0
792
18.1
752
87
STY/mmol L d-1
-1
881
127
83.8
1.92
795
101
889
128
105
2.40
994
81
814
117
157
3.60
1 490
54
-1
-1
-1
-1
STY/g L
d
STY/g L d
3
3
TONADH/10
TONGDH/10
TONNADP+
E factor
TONADH/10
TONGDH/10
TONNADP+
E factor
3
3
1
2
-nonanone and 0.6 mmol L- for 2-decanone) and were
leading to reduced amounts of waste. When comparing the
obtained E factors of 87 to 117 to those found in industry, a high
potential for the development of an environmentally friendly
process is apparent.
Subsequently, for the synthesis of (R)-2-nonanol, reactions
therefore suitable for application as a non-reactive phase. The
product alcohols could be easily separated from the aqueous
phase by decantation. For analysis, all small-scale samples were
extracted with hexane to allow quantitative recovery.
11
Initial batch experiments were carried out with substrate
with 10-times increased biocatalyst concentrations and higher
-
1
-
1
amounts corresponding to a concentration of 80 mmol L
assuming the substrate would be dissolved in the overall
reaction volume) and compared on the basis of space time yields
STY = amount of product produced per litre of reaction volume
per day), turnover numbers (TON = amount of product per
amount of catalyst or cofactor, respectively) and environmental
factors (E factor = kg waste per kg product) (see Table 1). The
time course of the reactions is presented in Fig. 2.
substrate concentrations (80, 100 and 150 mmol L )were carried
out (Table 2). Within these batch experiments, conversions
of at least 99.4% and ee values of >99.9% were achieved.
Due to increased biocatalyst concentration, reduced TONs for
both enzymes were found; nevertheless, the achieved values
are still promising. Moreover, it was possible to improve the
(
(
STY and TONNADP to reach industrially relevant values. Also,
+
the E factors could be improved; by increasing the substrate
-
1
concentration to 150 mmol L , an E factor of 54 was pos-
sible, which is within an acceptable range for fine chemical
10
production.
Conclusions
In conclusion, the application of the substrate itself as a second
phase for biocatalytic reactions represents a straightforward
method to enable environmentally friendly conversions of
hardly-water soluble substrates. Applying this strategy to the
LbADH-catalyzed syntheses of chiral aliphatic alcohols led to
promising STYs, E factors and TONs for both the biocatalyst
and the nicotinamide cofactor. Reaction engineering could
further improve those syntheses.
Acknowledgements
Fig. 2 Reaction progress for the LbADH-catalysed syntheses of chiral
The authors thank the Federal Ministry of Economics and
Technology via ZIM and DECHEMA for funding, as well
as Prof. W. Leitner (RWTH Aachen University) for fruitful
discussions.
alcohols utilizing the substrate as the second phase (3-octanone
R)-3-octanol ꢀ, 2-octanone , (R)-2-octanol ᭡, 2-nonanone , (R)-
-nonanol ꢁ, 2-decanone and (R)-2-decanol ᭹).
,
(
2
Even though LbADH showed product inhibitions for all
10
the alcohols, it was possible to achieve conversions of 84.6%
for 3-octanone, 88.2% for 2-octanone, 99.9% for 2-nonanone
and 94.0% for 2-decanone. Notably, only for 2-octanone was
Notes and references
1
H. P. Meyer, A. Kiener, R. Imwinkelried and N. Shaw, Chimia, 1997,
51, 287–289.
M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Kesseler, R.
Sturmer and T. Zelinski, Angew. Chem., Int. Ed., 2004, 43, 788–
824.
10
a substrate surplus inhibition found. This is most probably
the reason for the low conversions compared to the other 2-
2
-
1
-1
ketones. Within all experiments, STYs of 75 to 83 mmol L d ,
respectively, and enantioselectivities (enantiomeric excess, ee)
of > 99.9% were reached. Remarkably, the achieved STYs are
similar to those obtained for syntheses with comparable TONs
3
P. Galatsis, in Named Reactions for Functional Group Transforma-
tions, ed. J. J. Li and E. J. Corey, John Wiley & Sons, New Jersey,
2
007, pp. 2–21; A. Hirau, J. Chem. Soc. Chem. Commun., 1981, 315–
317; E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen and V. K.
-
1
-1
of about 90 mmol L d , where a biocompatible ionic liquid was
Singh, J. Am. Chem. Soc., 1987, 109, 7925–7926.
10
4 T. Ohkuma, M. Koizumi, K. Muniz, G. Hilt, C. Kabuto and R.
Noyori, J. Am. Chem. Soc., 2002, 124, 6508–6509; T. Ohkuma, M.
Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E. Katayama,
T. Yokozawa, T. Ikariya and R. Noyori, J. Am. Chem. Soc., 1998, 120,
applied as a solubiliser. However, when applying the substrate
as a second phase, an additional organic component can be
avoided; hence, facilitating downstream processing and thereby
3
094 | Green Chem., 2011, 13, 3093–3095
This journal is © The Royal Society of Chemistry 2011