Cyanobacterium-catalyzed asymmetric reduction of ketones

Article abstract of DOI:10.1016/S0040-4039(00)01132-1

Synechococcus sp. PCC 7942, a cyanobacterium, acted as a biocatalyst to reduce aryl methyl ketones into the corresponding (S)-alcohols with excellent enantioselectivities under illumination. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01132-1

Tetrahedron Letters 41 (2000) 6799±6802
Cyanobacterium-catalyzed asymmetric reduction of ketones
a,
a
b
b
Kaoru Nakamura, * Rio Yamanaka, Keiko Tohi and Hiroki Hamada
aInstitute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
bFaculty of Science, Okayama University of Science, Okayama 700-0005, Japan
Received 5 June 2000; revised 27 June 2000; accepted 30 June 2000
Abstract
Synechococcus sp. PCC 7942, a cyanobacterium, acted as a biocatalyst to reduce aryl methyl ketones into
the corresponding (S)-alcohols with excellent enantioselectivities under illumination. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: asymmetric reduction; enantioselectivity; cyanobacteria; algae; phototroph.
The asymmetric reduction of prochiral ketones has been extensively explored by researchers
using chemical and biological methods. As the latter method, microbial reduction has been widely
1�3
used for the synthesis of chiral alcohols. On the contrary, the use of photosynthetic plant cells
�10
and algae for asymmetric reduction is relatively rare4
due to the diculty in their cultivation,
the low reactivity of plant cells, and the lack of knowledge on the stereochemical control of
reactions. Thus, a new photosynthetic biocatalyst with high reactivity and selectivity for reducing
ketones is now unavailable.
Here we report our ®nding that Synechococcus sp. PCC 7942, a cyanobacterium which belongs
to phototroph, could enantioselectively reduce several aryl methyl ketones to the corresponding
(
S)-alcohols with the aid of light (Fig. 1).
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When 2 ,3 ,4 ,5 ,6 -penta¯uoroacetophenone (1) was reacted in a suspension culture of
Synechococcus sp. PCC 7942 under illumination, it was completely consumed within 3 days, and
the corresponding (S)-alcohol was obtained in a good chemical yield (> 90%) with excellent
enantiomeric excess (ee) (> 99%).
Optically active alcohols having penta¯uorophenyl moiety are potentially useful chiral building
blocks for drugs, insecticides, and ferroelectric liquid crystals.11,12 Fluorine substitutions of
hydrogen atoms in the molecules tend to dramatically in¯uence the biological activity or the
molecular reactivity. The per¯uorinated phenyl group has a striking stacking ability with
electron-rich arenes. For example, hexa¯uorobenzene was reported to form an 1:1 molecular
*
Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01132-1

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Figure 1. Asymmetric reduction of 2 ,3 ,4 ,5 ,6 -penta¯uoroacetophenone by Synechococcus sp. PCC 7942. The alga
absorbs light and carbon dioxide and uses this energy to reduce 1 into optically pure 2
13
complex with benzene. In optically active penta¯uorophenyl compounds, the penta¯uorophenyl
group is reported to be stacked with a naphthalene ring.
As shown in Table 1, other aryl methyl ketones were also reduced by Synechococcus sp. PCC
11,14
7
942, and all the ketones were reduced with high enantioselectivities (> 96% ee). Although the
chemical yields on the reduction of several ketones were not satisfactory, the elongation of incu-
bation times enabled us to improve the chemical yields in the reduction of o- and p-chloro-
acetophenone by the alga.
Thus, the cyanobacterium is found to enantioselectively reduce various aryl methyl ketones.
The merits of using the cyanobacterium in biotransformation are summarized as follows:
(
a) Low biocatalyst/substrate (b/s) ratio: A large amount of a biocatalyst is usually required to
15
reduce a considerable amount of a substrate (the b/s for baker's yeast is about 50±350). On the
contrary, only 37 mg (dry weight) of the alga could reduce 0.57 mmol (120 mg) of 1 in 9 days.
Thus, a low b/s ratio (2.6 wet weight, 0.5 dry weight) could be achieved. The improvement in the
b/s ratio is caused by the fact that the cyanobacterium can utilize the power of light e€ectively to
reduce the substrate.
(b) High selectivity and wide substrate speci®city: Ketones used in this report are reduced by the
cyanobacterium with excellent enantioselectivities (> 96%). An enzyme exhibiting high enantio-
selectivity usually shows a relatively strict substrate speci®city; hence, there scarcely is a catalyst
that reacts with many kinds of substrates and also shows high selectivities. This alga can reduce a
wide variety of aryl methyl ketones and a€ord the corresponding alcohols with high enantio-
selectivities.
(c) Easy manipulation and high growth rate: Photosynthetic plant cell cultures typically grow
quite slowly. However, cyanobacteria grow much faster than plant cell cultures in spite of the fact
that the algae are types of phototroph. Thus, contamination with microbes during the cultivation
can be eliminated.
16
(
d) Ecological system: To date, cyanobacteria have been used for biomass production and
17
biologically produced electricity. We propose that cyanobacteria can also be used eciently as
biocatalysts; the algae have the ability to directly utilize sunlight and carbon dioxide for photo-
synthesis. Due to this activity, cyanobacteria may help to solve a global environmental problemÐ
the greenhouse e€ectÐwhich increasingly threatens mankind at the beginning of the 21st century.
Reduction of 1 with Synechococcus sp. PCC 7942: Mature cultured algae (1.5 mL) of
Synechococcus sp. PCC 7942 were transferred to 300 mL Erlenmeyer ¯asks containing BG-11

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801
Table 1
Reduction of acetophenone derivatives by Synechococcus sp. PCC 7942
medium (100 mL). After pre-cultivation for about 14 days under ¯uorescent lamp illumination
ꢀ
(1000 lux) at 20 C, 0.57 mmol of 1 was added to the ¯ask. The mixture was incubated for 3 days
under illumination at 20 C. The mixture was then extracted with ether three times. The conversion
ꢀ
(
(
90%) and enantiomeric excess (> 99%) of the alcohol were determined by using GC-analysis
ꢀ
GC conditions: CP-cyclodextrin-B-2,3,6-M-19; 25 m; He 2 mL/min, 120 C, ketone; 2.9 min,
R-alcohol; 5.8 min, S-alcohol; 6.3 min). The ether layer was concentrated under reduced pressure
and the residue was subjected to silica gel column chromatography (eluent: hexane:ethyl ace-
È
tate=10:1) followed by distillation with Kugelrohr apparatus a€ording pure 2 in a 50% chemical
yield with >99% ee.
The product was identi®ed with H NMR, IR, and an elemental analysis. The absolute
1
con®guration of the alcohol was determined to be S by comparing the optical rotational value
20
20
18
with that reported. ‰ꢀŠD ^6.40 (c 0.50, pentane) (lit. (S)-2, ‰ꢀŠD ^6.33 (c 1.01, pentane)).

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802
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