Enantioselective monoreduction of different 1,2-diaryl-1,2-diketones catalysed by lyophilised whole cells from Pichia glucozyma

Article abstract of DOI:10.1016/j.tet.2008.06.019

In this work we have studied the monoreduction of different 1,2-diaryl-ethanediones (benzils, 1) with lyophilised whole cells from Pichia glucozyma CBS 5766, using the diphenyl compound (benzil, 1a) as model substrate, and extended the enantioselective reduction to structurally different symmetric benzils for producing enantiomerically pure or enriched benzoins (α-hydroxyketones 2) in high yields and very short reaction times. In order to study the regio- and stereoselectivity of this biocatalyst, we examined the reduction of diaryldiketones formed from different aryl moieties, to obtain symmetric and asymmetric crossed-benzoins. This methodology is conducted under very mild reaction conditions (aqueous media with small amounts of DMSO for solubilising the substrates, T=28 °C), therefore constituting a green alternative compared to other reported procedures for obtaining homochiral benzoins.

Full text of DOI:10.1016/j.tet.2008.06.019

Tetrahedron 64 (2008) 7929–7936
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective monoreduction of different 1,2-diaryl-1,2-diketones
catalysed by lyophilised whole cells from Pichia glucozyma
a
b
a
b,
*
´
´
´
Pilar Hoyos , Giacomo Sansottera , Marıa Fernandez , Francesco Molinari
,
a,
c
a,c,
*
´
´
Jose Vicente Sinisterra , Andres R. Alcantara
a
´
´
´
Grupo de Biotransformaciones, Departamento de Quımica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense de Madrid,
Plaza de Ramo´n y Cajal, s/n. 28040 Madrid, Spain
b Dipartimento di Scienze e Tecnologie Alimentari e Microbiologiche, Universit‘a degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
c Unidad de Biotransformaciones Industriales, Parque Cient´ıfico de Madrid, PTM, C/ Santiago Grisol´ıa, 2. 28760 Tres Cantos, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2008
Received in revised form 3 June 2008
Accepted 6 June 2008
Available online 10 June 2008
In this work we have studied the monoreduction of different 1,2-diaryl-ethanediones (benzils, 1) with
lyophilised whole cells from Pichia glucozyma CBS 5766, using the diphenyl compound (benzil, 1a) as
model substrate, and extended the enantioselective reduction to structurally different symmetric
benzils for producing enantiomerically pure or enriched benzoins (a-hydroxyketones 2) in high yields
and very short reaction times. In order to study the regio- and stereoselectivity of this biocatalyst, we
examined the reduction of diaryldiketones formed from different aryl moieties, to obtain symmetric
and asymmetric crossed-benzoins. This methodology is conducted under very mild reaction conditions
(aqueous media with small amounts of DMSO for solubilising the substrates, T¼28 ꢀC), therefore
constituting a green alternative compared to other reported procedures for obtaining homochiral
benzoins.
Keywords:
a
-Diketones
Benzoins
Stereoselective reductions
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
fact, the use of these biocatalysts, mainly as whole cells, represents
an attractive alternative to classical chemical synthesis, due to the
Enantiomerically pure
a
-hydroxyketones are useful building
mild and eco-friendly conditions of the reactions, conducted in
aqueous media.12 More concretely, biocatalytic reduction of benzil
(1,2-diphenylethanedione 1a, Scheme 1) to chiral benzoin 2a (or
related structures) has been described by using different microor-
ganisms and operational conditions,13 leading in some cases to the
blocks in the synthesis of different pharmaceuticals and fine
chemicals, such as antitumoral antibiotics (Olivomycin A and
Chromomycin A31), inhibitors of farnesyltransferase (Kurasoin A
and B2), inhibitors of amiloid-
b
protein production3 or antide-
pressant drugs (bupropion and its metabolites4). More concretely,
benzoins (1,2-diaryl-2-hydroxyethanone structures, 2, Scheme 1)
are useful as urease inhibitors5 or as building blocks for the syn-
thesis of different heterocycles.6 Homochiral benzoins can be
obtained either chemically through benzoin condensation
(catalysed by chiral thiazolium or triazolium salts,7 chiral metal-
lophosphites8) or enzymatically, through benzoin condensation
starting from racemic benzoins and catalysed by several thiamine-
diphosphate-dependent enzymes,9 as well as by fungal deracem-
ization10 or dynamic kinetic resolution of racemic benzoins.11
Another enzymatic strategy arises via the enantioselective re-
desired
a
a-hydroxyketone and in other cases to the corresponding
-diol.13b In fact, this process was firstly reported with the most
classical bio-reduction catalyst (baker’s yeast, whole cells of Sac-
charomyces cerevisiae), although the reaction proceeded with no
enantioselectivity.13c More recent studies with this same bio-
catalyst13g show the production of (R)-2a with 50% ee, while the use
of organic cosolvents leaded to higher enantiopurity values.13j
Some other microorganisms have been also used for the bio-
reduction of benzils, always in a ‘fresh cells’ state, meaning with
this term the straight use of the cells after the fermentation pro-
cess; thus, the use of Rhizopus oryzae cells allowed good enantio-
selectivity, although at the expense of a low reaction rate and
furnishing hydrobenzoin (1,2-diphenyl-1,2-ethanediol) as well.13h
Cells from Xanthomonas oryzae and Bacillus cereus were shown to
be selective and reduce 1a only to 2a, the first one yielding only (R)-
2a also under low reaction rates,13a while the latest one shows a fair
stereopreference towards (S)-2a production.13e,f In this case the
enzyme responsible from this reaction (benzil reductase) from
duction of
a-diketones catalysed by alcohol dehydrogenases. In
* Corresponding authors. Tel.: þ39 02 5031 9148; fax: þ39 02 5031 6694 (F.M.);
tel.: þ34 91 394 1820; fax: þ34 91 394 1822 (A.R.A.).
E-mail addresses: francesco.molinari@unimi.it (F. Molinari), andresr@farm.
´
ucm.es (A.R. Alcantara).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.019

7930
P. Hoyos et al. / Tetrahedron 64 (2008) 7929–7936
O
O
P. glucozyma
Ar2
Ar2
OH
CBS 5766
Ar1
Ar1
O
2
1
Ar1 = Ar2 = Ph
1a
1b
1c
1d
1e
Ar1 = Ar2 = Ph
(S)-2a
(S)-2b
(S)-2c
(R)-2d
(S)-2e
Ar1 = Ar2 = 2-furanyl
Ar1 = Ar2 = 3-furanyl
Ar1 = Ar2 = 2-thienyl
Ar1 = Ar2 = 3-thienyl
Ar1 = Ar2 = 2-furanyl
Ar1 = Ar2 = 3-furanyl
Ar1 = Ar2 = 2-thienyl
Ar1 = Ar2 = 3-thienyl
Ar1 = Ar2 = 4-methoxyphenyl 1f
Ar1 = Ar2 = 4-methoxyphenyl (S)-2f
Ar1 = Ar2 = 4-methylphenyl
Ar1 = Ph, Ar2 = 1-naphthyl
Ar1 = Ph, Ar2 = 2-naphthyl
1g
1h
1i
Ar1 = Ar2 = 4-methylphenyl (R)-2g
Ar1 = Ph, Ar2 = 1-naphthyl
Ar1 = 1-naphthyl, Ar2 = Ph
Ar1 = Ph, Ar2 = 2-naphthyl
Ar1 = 2-naphthyl, Ar2 = Ph
(S)-2h
(S)-2h'
(S)-2i
(S)-2i'
Scheme 1. Stereoselective reduction of 1,2-diaryl-ethanediones (1) to the corresponding benzoins (2).
B. cereus was isolated, characterised and over-expressed in Escher-
ichia coli.13e Very recently, the use of fresh resting cells from As-
pergillus oryzae and Fusarium roseum has been also described.13k
On the other hand, lyophilised cells from Pichia glucozyma have
been described as easy-to-handle biocatalyst for stereoselective
reduction of aromatic ketones.14 In this work we have studied the
reduction of 1a with dry cells of P. glucozyma CBS 5766 and ex-
tended the stereoselective reduction to structurally different sym-
metric benzils for producing enantiomerically pure or enriched
benzoins (Scheme 1) in high yields and very short times. In order to
study the regio- and stereoselectivity of this biocatalyst, we ex-
amined the reduction of diaryldiketones formed from different aryl
moieties, to obtain symmetric and asymmetric crossed-benzoins.
Table 1
Reduction of benzil (1a) catalysed by different concentrations of lyophilised cells of
P. glucozyma CBS 5766
P. glucozyma CBS 5766
(lyophilised cells, g/L)
Reaction time (h)
Conversion (%)
ee (%) of (S)-2a
10
20
30
3
3
3
87
99
99
54
75
74
enantiopreferences, a direct correlation between substrate con-
centration and enantioselectivity can be observed.15 This can be
explained by the hypothesis that at higher substrate concentration
all the occurring enzymes are active, while at lower concentrations
only the ones with the higher affinity display their activity. As can
be seen in Table 1 under the optimal conditions, adding 20 or 30 g/L
of lyophilised cells to the medium, the reaction was complete after
3 h, yielding only (S)-2a as reaction product, with very high con-
versions (around 99%) and similar ee values (75%). The reduction of
1a was carried out again and the reaction progress was followed,
finding out that the highest conversion was reached after 2.5 h, not
detecting any diol (hydrobenzoin, 3).
As detailed in Section 1, (S)-2a had been previously obtained by
whole cells-catalysed reduction of 1a, but after long reaction times
(whole cells from B. cereus, 12 h,13f Baker’s yeast dry cells, 72 h;13g F.
roseum fresh cells, 24 h13k). Our new biocatalyst is able to reduce 1a
in just 3 h with high yields and enantiomeric excess. Furthermore,
only minimum traces of the corresponding diol (hydrobenzoin)
were observed when the reaction was allowed to reach 24 h. For
the other microorganism recently described by Demir et al.,13k As-
pergillus oryzae OUT5048 fresh cells, good enantioselectivity and
yield in (S)-2a are obtained also after 3 h, but no indication of the
amount of catalyst used in the bio-reduction of 1a is presented, so
no comparison can be drawn with our conditions.
2. Results and discussion
Benzil (1a, Scheme 2) was used as the standard substrate to
study the ability of different microorganisms towards the reduction
of this kind of aromatic diketones. Among the lyophilised yeasts
tested (Pichia minuta CBS 1708, Pichia fermentans DPVPG 2770, P.
glucozyma CBS 5766, Pichia etchellsii CBS 2011, Candida utilis CBS
621 and Kluyveromyces marxianus CBS 397), best results were
obtained with lyophilised cells from P. glucozyma.
Thus, lyophilised cells from P. glucozyma were suspended in
a volume of phosphate buffer (pH 7.0, 0.1 M) to reach a biomass
concentration of 10 g/L (dry cells). Substrate (42 mg) was dissolved
in DMSO (1 mL) and the solution obtained was added to the bio-
transformation medium to reach a final concentration of substrate
of 0.4 mg/mL.
Different concentrations of lyophilised cells were used, in order
to find the best conditions to carry out the reduction of different
diketones. The results are shown in Table 1; as can be seen, in-
creasing the amount of catalyst from 10 to 20 g/L, both the yield and
the ee value increased. The reason why the enantioselectivity is
lower with lower amounts of lyophilised cells can be due to the
higher concentration of substrate experienced by cells: it has been
previously described that, in the presence of multiple de-
Therefore, 20 g/L of lyophilised cells of P. glucozyma were
employed for further studying the asymmetric bio-reduction of
different diaryldiketones into the corresponding benzoins (Table 2).
Some of the substrates employed in the biotransformation
(shown in Table 2) such as benzil (1a) and 1,2-bis(4-
hydrogenases (as in
a
whole cell system) with different
O
O
OH
P. glucozyma
CBS 5766
O
OH
(S)-2a
OH
1a
3
Scheme 2. Stereoselective reduction of benzil (1a) to the homochiral S-benzoin(S-2a) and hydrobenzoin (3).

P. Hoyos et al. / Tetrahedron 64 (2008) 7929–7936
7931
Table 2
for this substrate could be explained taking into account the pos-
sible presence of more than one alcohol dehydrogenase (ADH) with
different enantioselectivity inside the cell, as has been described for
several microorganisms.18 If this is the case, for those substrates,
which are reduced more slowly (1f and 1g) it could be assumed that
they are not recognised by ADH that catalyses the reduction of the
compounds 1a–1e (working very quickly on these substrates), so
that after prolonged reaction time another ADH could start acting
on them.
Five member heteroaryl moieties (1b–e) were quite well toler-
ated. Thus, (S)-2c was obtained in high yield and enantiomeric
excess. Through lipase kinetic resolution of 2c, (S)-2c is obtained in
poor yields and enantiomeric excess, due to the spontaneous and
quick oxidation that this substrate suffers at high temperatures.9d
Nevertheless, by this methodology, (S)-2c can be isolated in very
good yield and enantiopurity, by using very mild reaction condi-
tions. In the literature it has been described how the antipode
enantiomer, (R)-2c, can be obtained through benzoin condensation
catalysed by BAL,9d,19 so that these two biocatalytical approaches
are complementary in the synthesis of both enantiomers of 2c.
In order to test the potential of this biocatalyst, we decided to
carry out the reduction of crossed-diaryldiketones, formed from
Substrates of the reduction catalysed by lyophilised cells of P. glucozyma CBS 5766
O
O
P. glucozyma
Ar
Ar
OH
Ar
CBS 5766
Ar
O
2
1
Substrate
Ar
Ph
Product
Reaction
time
Conversion
(%)
ee (%)
1a
1b
1c
1d
1e
1f
(S)-2a
(S)-2b
(S)-2c
(R)-2d
(S)-2e
(S)-2f
(R)-2g
2.5 h
2.5 h
2.5 h
2.5 h
5 h
99
99
99
86
97
7
75
84
98
62
57
99
76
2-Furanyl
3-Furanyl
2-Thienyl
3-Thienyl
4-Methoxyphenyl
4-Methylphenyl
7 days
7 days
1g
97
methylphenyl)ethane-1,2-dione (1g) are commercially available.
On the other hand, 1,2-di(furan-2-yl)ethane-1,2-dione (1b),
1,2-di(furan-3-yl)ethane-1,2-dione (1c), 1,2-di(thiophen-2-yl)-
ethane-1,2-dione (1d), 1,2-di(thiophen-3-yl)ethane-1,2-dione (1e)
and 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (1f) were
synthesised by oxidation of the corresponding benzoins (1,2-
di(furan-2-yl)-2-hydroxyethanone (2b), 1,2-di(furan-3-yl)-2-
hydroxyethanone (2c), 2-hydroxy-1,2-di(thiophen-2-yl)ethanone
(2d), 2-hydroxy-1,2-di(thiophen-3-yl)ethanone (2e) and 2-hy-
droxy-1,2-bis(4-methoxyphenyl)ethanone (2f)), following the
protocol described by Corey and Suggs,16 as described in Section 4.
Previously, 2c, 2d and 2e were synthesised following the procedure
formerly described.11a Biotransformation products were purified by
silica-gel chromatography and the optical rotations were measured.
The absolute configurations of these products were assigned
according to a correlation with data from the literature9a,17 and by
comparison of HPLC retention times with reference compounds.
The data depicted in Table 2 illustrate the conversions and ee
values obtained. The reduction of aryl-substituted benzoin de-
rivatives was different to non-substituted benzoins. In fact, for 1f,
only 7% conversion was reached after 2.5 h or longer reaction times.
Poor conversion values for this substrate have been previously
reported,13g,k showing how when the electron donating methoxy
group is present in the para position the reduction proceeds more
slowly. On the other hand, all reactions’ products were assigned to
be (S), except those ones coming from the reduction of 1d and 1g;
in the first case, the stereorecognition is similar, but the absolute
configuration is altered because of the preference of the sulfur
atom. Nevertheless, the reduction of 1g conducted to (R)-2g, the
opposite enantiomer to the expected one, and once again this re-
action was also slower than non-substituted benzoins: after 2.5 h,
only 6% conversion was reached; the reaction was not complete
until 7 days (97% conversion, 76% ee, Table 2). These results are
anyway better than those described for the reduction of 1g with
Baker’s yeast dry cells by Mahmoodi and Mohammadi13g (17% yield,
36% ee), although these authors did not observe any change in the
stereorecognition for this substrate, due to the fact that with Bak-
er’s yeast all the reduction products are R. The change in stereobias
non-identical aromatic moieties. The use of asymmetric
a-
hydroxyketones as substrates in lipase-metal combo catalysed
dynamic kinetic resolution (DKR) is not possible, due to the fact
that the intermediate diketone obtained in situ with the oxidising
action of the ruthenium catalyst11 would furnish a random mixture
of the corresponding benzoins. Very recently we have described
a methodology to get enantiopure acyloins,20 through a ‘hidden-
acyloin’ DKR employing lipase B from Candida antarctica (CAL-B);
but this process is not applicable in the case of benzoins, because of
the great size of the substrates, which would be too bulky for the
CAL-B recognition. For this reason, regio- and stereoselective re-
duction of asymmetric diaryldiketones would constitute an elegant
methodology to obtain enantiopure crossed-benzoins.
Crossed-diaryldiketone compounds were obtained by oxidation
of the correspondent benzoins previously synthesised. It is well
known that crossed-benzoins cannot be synthesised through the
classical benzoin condensation procedure, due to the formation of
four possible products in the reaction. Therefore we decided to use
another methodology of a-hydroxycarbonyl compounds synthesis
based on the use of 1,3-dithianes, as depicted in Scheme 3.
The results obtained in the reduction of these asymmetrical
diaryldiketones are shown in Table 3.
The reduction of 1h and 1i could lead to two pairs of enantio-
mers (Scheme 4), so that all the possible compounds were pre-
viously synthesised in order to identify correctly the
biotransformation products by HPLC and their UV absorption
spectra, as described in Section 4.
Analysing the reduction products obtained from 1h, (S)-2h0 was
obtained after 20 h and just traces of (S)-2h could be detected.
On the other hand, the reduction of 1i led to two different
products: (R)-2i and (S)-2i0. The biotransformation was carried out
following the same procedure as the one described for the re-
duction of symmetric benzoins. After 24 h, the major product was
O
O
O
1) BuLi
2) Ar2CHO
PCC
BF3OEt2
HgO
SH(CH2)3SH
CoCl2
S
Ar1
S
H
S
Ar1
S
Ar2
OH
rac-2
Ar2
Ar2
OH
Ar1
H
Ar1
Ar1
O
4
6
5
1
4a: Ar1 = Phenyl
4b: Ar1 = 1-Naphthyl
4c: Ar1 = 2-Naphthyl
5a: Ar1 = Phenyl
5b: Ar1 = 1-Naphthyl
5c: Ar1 = 2-Naphthyl
6a, 2h: Ar1 = Phenyl; Ar2 = 1-Naphthyl
6b, 2h' : Ar1 = 1-Naphthyl; Ar2 = Phenyl
6c, 2i: Ar1 = Phenyl; Ar2 = 2-Naphthyl
6d, 2i' : Ar1 = 2-Naphthyl; Ar2 = Phenyl
Scheme 3. Synthesis of diaryldiketones (1) from different aromatic aldehydes.

7932
P. Hoyos et al. / Tetrahedron 64 (2008) 7929–7936
Table 3
Biocatalysed reduction of assymetrical diaryldiketones
O
O
P. glucozyma
CBS 5766
Ar2
Ar2
OH
Ar1
Ar1
O
2
1
Ar1
Ar2
Crossed benzoin
Benzil
Reduction products
(S)-2h0/(S)-2h
Conversion (%)
76/4
ee (%)
91/99
Reaction time (h)
20
Phenyl
1-Naphthyl
Phenyl
1-Naphthyl
Phenyl
2-Naphthyl
Phenyl
rac-2h
rac-2h0
rac-2i
rac-2i0
1h
1i
(S)-2i0/(R)-2i
63/28
53/99
20
2-Naphthyl
O
O
O
OH
OH
Ar2
Ar2
Ar2
+
OH
Ar2
reduction
Ar2
Ar1
Ar1
Ar1
Ar1
+
Ar1
and
O
OH
O
O
Scheme 4. Possible products of reduction of asymmetric 1,2-diaryl-1,2-ethanediones.
(S)-2i0 (63% yield) and the minor one (R)-2i. To understand this
stereobias, it has to be considered that, as it has been described,14
the reductions of different compounds catalysed by this microor-
ganism generally follow the classical Prelog’s rule21 that predicts
the stereochemistry of the obtained alcohol according to the rela-
tive size of substituents, through a delivery of the equivalent hy-
dride from the re face, yielding the S-alcohol.
protocol represents a potential useful tool for a green and sus-
tainable synthesis of this kind of compounds.
4. Experimental
4.1. General
The mechanism of the reduction via alcohol dehydrogenases has
been studied.22 The enzyme, as well as a cofactor, requires a metal
divalent cation (normally Zn2þ) to fix the substrate in the active
site, through interaction with the carbonyl moiety of the substrate,
placing the re side of the substrate ready to suffer the hydride
transfer. Thus, we could assume that the dicarbonyl moiety of the
molecule should be placed approximately in the same position to
the carbonyl group of single ketones to interact with the Zn2þ
cation, and therefore the delivery of the hydride should be carried
out via the re side, as shown in a tentative Prelog model repre-
sented in Scheme 5. In the reduction of 1h, both aromatic moieties
(phenyl and 1-naphthyl) could be recognised both in the medium
(M) and in the large (L) sites around the diketone structure, leading
to a mixture of S-2h0 (major product, right fitting) and S-2h (minor
product, wrong fitting), obtained through the hydride delivery via
the re face. Nevertheless, the different geometry of the 2-naphthyl
moiety must hamper the wrong fitting, fixing the right fitting and
therefore allowing two different hydride transfers to both carbonyl
groups via the re face, leading to a mixture of S-20i and R-2i. For
sure, it is clear that this is a tentative model, supposing planarity in
the substrates geometry, which should be confirmed by more ex-
perimental data.
Benzil, 2-bis(4-methylphenyl)ethane-1,2-dione, benzoin, 1,2-
di(furan-2-yl)-2-hydroxyethanone, 2-hydroxy-1,2-bis(4-methoxy-
phenyl)ethanone, 1-naphthaldehyde, 2-naphthaldehyde, 1,3-pro-
panedithiol, 2-phenyl-1,3-dithiane, BF3OEt2 and PCC were
purchased from Sigma Aldrich, and used as-received.
P. glucozyma was obtained from (Centraal Bureau voor Schim-
melcultures, Utrecht, The Netherlands).
HPLC analyses were performed with a chiral column Chiracel
OD-H (cellulose carbamate, 25 cmꢁ0.46 cm i.d.) at room temper-
ature using HPLC (mobile phase of n-hexane/2-propanol, 90/10 at
a flow rate of 1 mL/min).
NMR spectra were recorded on a Bruker AC-250. Chemical shifts
(d
) are reported in parts per million (ppm) relative to CHCl3 (1H:
d
7.27 ppm) and CDCl3
Column chromatography purifications were conducted on silica
gel 60 (40–63 m). TLC was carried out on aluminium sheets pre-
coated with silica gel; the spots were visualised under UV light
¼254 nm).
( d 77.0 ppm).
13C:
m
(l
4.2. Microorganisms, media and culture conditions
P. glucozyma CBS 5766 was routinely cultured in 750 mL Erlen-
meyer flasks with 100 mL of malt broth pH 6.0 for 48 h, at 27 ꢀC on
a rotary shaker set at 200 rpm.
In fact, further experiments are being conducted in our labora-
tory to optimise this biocatalytic reduction, elucidate its full po-
tential and apply it to a more broad range of substrates.
Lyophilised cells were obtained from a culture performed in
3.0 L fermenters with 1.0 L of malt broth pH 6.0 for 48 h, at 27 ꢀC
and agitation speed 100 rpm. Fresh cells from submerged cultures
were centrifuged and washed with 0.1 M phosphate buffer, pH 7.0;
washed cells were lyophilised. The amounts of lyophilised cells
obtained were in the range 8.1–8.3 g.
3. Conclusion
In this paper we present the bio-reduction of different aromatic
diketones, as a clean methodology to obtain enantiomerically pure
benzoins. The advantages of using lyophilised cells to catalyse the
reduction of benzil and benzil derivatives in mild reaction condi-
tions are shown reaching very high yields and enantiomeric excess,
in less than 3 h in most cases. More important, not only stereo-
selective but also regioselective bio-reductions have been in-
vestigated. Significant developments have been done in the
formation of asymmetric crossed-benzoins through the microbial
reduction of aromatic diketones. This biocatalytic reduction
4.3. Biotransformation conditions
Reductions were carried out with a reaction volume of 10 mL
with cells (200 mg, 20 g/L) resuspended in 0.1 M phosphate buffer
with 5% glucose, pH 7.0. After 45 min of incubation, the substrate
(0.02 mmol, 4.2 mg) dissolved in 0.1 mL of dimethylsulfoxide was

P. Hoyos et al. / Tetrahedron 64 (2008) 7929–7936
7933
Scheme 5. Hypothetical application of Prelog’s rule to the reduction of crossed 1,2-diaryl-1,2-ethanediones.
added and the incubation continued for 24 h under magnetical
ethanone (500 mg, 1.83 mmol) solved in 300
m
L of CH2Cl2, was
stirring at 28 ꢀC.
added and the mixture was stirred. The reaction progress was
followed by TLC. After 6 h, 5 mL of ether was added and the
supernatant decanted from the black residue. This solid was
washed with ether (3ꢁ5 mL) and the combined organic solution
was evaporated under vacuum. The resulting oil was purified by
silica-gel column chromatography (CH2Cl2), collecting 300 mg
(1.11 mmol) of yellow solid (60% yield). IR (film): 3000,
1648 cmꢂ1. Anal. Calcd for C16H14O4: C, 71.10; H, 5.22. Found: C,
70.64; H, 5.15.
4.4. General procedure for the synthesis of aromatic
diketones (1b–f and 1h–i)
4.4.1. Synthesis of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (1f)16
Pyridinium chlorochromate (565 mg, 2.62 mmol) was sus-
pended in 3.5 mL of CH2Cl2 in a 50 mL round bottom flask fitted
with a reflux condenser. 2-Hydroxy-1,2-bis(4-methoxyphenyl)-

7934
P. Hoyos et al. / Tetrahedron 64 (2008) 7929–7936
(C50 and C500), 138.0 (C20 and C200), 139.01 (C30 and C300), 182.87 (C1
and C2).
5'
2'
O
6'
1'
O
1
4'
3'
2''
5''
1''
2
3''
4''
O
4.4.6. 1-(Naphthalen-1-yl)-2-phenylethane-1,2-dione (1h)
O
6''
1H NMR (250 MHz, CDCl3):
d 4.01 (s, 6H, OCH3), 7.24 (ddd, 4H,
5''
2''
7'
8'
3'
6'
5'
6''
1''
4''
3''
O
1
J¼9.7, J¼2.7, J¼2.1 Hz, H-30 and H-50, H-300 and H-500), 8.09 (ddd, 4H,
8'a
2
J¼9.7, J¼2.7, J¼2.1 Hz, H-20 and H-60, H-200 and H-600). 13C NMR
4'a
4'
1'
2'
d
56.08 (2CH3), 114.70 (C30, C50, C300 and C500),
O
(63 MHz, CDCl3):
132.82 (C20, C60, C200 and C600), 126.67 (C10 and C100), 165.27 (C40 and
C400), 193.96 (C1 and C2).
IR (film): 1654, 1660 cmꢂ1. Anal. Calcd for C18H12O2: C, 83.06; H,
4.65. Found: C, 82.40; H, 4.76. 1H NMR (250 MHz, CDCl3):
7.43 (m,
d
4.4.2. 1,2-Di(furan-2-yl)ethane-1,2-dione (1b)
3H, H-300, 400and 500), 7.56 (m, 2H, H-30 and H-60), 7.66 (m, 1H, H-70),
7.85 (td, 2H, J¼8.4, J¼1.0 Hz, H-200 and H-600), 7.94 (m, 1H, H-50), 7.97
(m, 1H, H-20), 8.05 (d, 1H, J¼8.1 Hz, H-40), 9.24 (d, 1H, J¼8.6 Hz, H-
4'
3'
O
1''
5'
1
2
O
O
2'
80). 13C NMR (63 MHz, CDCl3): 124.87 (C80), 126.37 and 127.57 (C30
d
2''
1'
5''
O
3''
and C60), 128.98 (C80a), 129.24 (C50), 129.49 (C200 and C600), 129.92
(C20), 130.47 (C300 and C500), 131.35 (C40a), 133.74 (C100), 134.49 (C10),
135.22 (C40), 135.60 (C70), 136.45 (C400), 195.06 (C2), 197.62 (C1).
4''
IR (CH2Cl2): 1643 cmꢂ1. Anal. Calcd for C10H6O4: C, 63.16; H, 3.18.
Found: C, 62.80; H, 3.00. 1H NMR (250 MHz, CDCl3):
d 6.58 (dd, 2H,
J¼3.7, J¼1.7 Hz, H-40 and H-400), 7.59 (dd, 2H, J¼3.7, J¼0.7 Hz, H-30
4.4.7. 1-(Naphthalen-2-yl)-2-phenylethane-1,2-dione (1i)
and H-300), 7.72 (dd, 2H, J¼1.7, J¼0.7 Hz,00H-50 and H-500). 13C NMR
(63 MHz, CDCl3):
d
113.55 (C40 and C4 ), 125.26 (C30 and C300),
5''
149.81 (C50 and C500), 149.87 (C20 and C200), 177.23 (C1 and C2).
6''
4''
3''
O
1
1'
4'
8'
5'
8'a
4'a
2'
3'
2
7'
6'
4.4.3. 1,2-Di(furan-3-yl)ethane-1,2-dione (1c)
1''
2''
O
1'
2'
O
4'
O
1
5'
4''
3''
2''
2
3'
IR (film): 3087, 1667 cmꢂ1. Anal. Calcd for C18H12O2: C, 83.06; H,
5''
O
4.65. Found: C, 82.00; H, 4.77. 1H NMR (250 MHz, CDCl3):
d 7.52 (m,
O
1''
5H, H-Ph), 7.83 (m, 3H, H-40, H-60 and H-70), 7.94 (m, 2H, H-50 and
H-80), 8.03 (dd, 1H, J¼8.6, J¼1.7 Hz, H-30), 8.33 (s, 1H, H-10). 13C NMR
Anal. Calcd for C10H6O4: C, 63.16; H, 3.18. Found: C, 62.50; H,
3.05. 1H NMR (250 MHz, CDCl3):
d
6.93 (d, 2H, J¼1.51 Hz, H-40 and
(63 MHz, CDCl3):
d
124.06 (C30), 127.64 (C70), 128.40 (C50), 129.50
H-400), 7.49 (t, 2H, J¼1.60 Hz, H-50 and H-500), 8.53 (s, 2H, H-20 and H-
(C40), 129.64 (C60), 130.01 and 130.38 (C200 and C600), 130.45 (C300,
C500 and C-80), 130.70 (C80a), 132.70 (C40a), 133.50 (C100), 134.06
(C10), 135.9 (C400), 136.82 (C20), 195.13 (C1 and C2).
200). 13C NMR (63 MHz, CDCl3): 109.5 (C40 and C400),123.35 (C30 and
d
C300), 144.37 (C50 and C500), 152.30 (C20 and C200), 184.49 (C1 and C2).
4.4.4. 1,2-Di(thiophen-2-yl)ethane-1,2-dione (1d) (64% yield)
4.5. General procedure for the synthesis of racemic crossed-
benzoins (2h, 2h0, 2i and 2i0)
4'
3'
O
1''
S
5'
1
2
4.5.1. Synthesis of 2-(naphthalen-2-yl)-1,3-dithiane (5c)
S
2'
2''
1'
5''
1,3-Propanedithiol (602 mL, 6 mmol) was added to a solution of
O
3''
4''
2-naphthaldehyde (781 mg, 5 mmol) in acetonitrile (15 mL). CoCl2
(30 mg, 5 mmol %) was added and the mixture was stirred at room
temperature. After 15 h the solvent was evaporated under reduced
pressure and the product was purified by column chromatography
on silica gel, yielding 1.131 g (4.6 mmol, 92% yield). IR (film): 3055,
2924, 2885, 1505, 1278 cmꢂ1. Anal. Calcd for C14H14S2: C, 68.25; H,
5.73; S, 26.03. Found: C, 68.10; H, 5.60; S, 25.85.
IR (CH2Cl2): 1652 cmꢂ1. Anal. Calcd for C10H6O2S2: C, 54.03; H,
2.72; S, 28.85. Found: C, 53.58; H, 2.60; S, 28.50. 1H NMR (250 MHz,
CDCl3):
d
7.24 (dd, 2H, J¼4.8, J¼4.0 Hz, H-40 and H-400), 7.88 (dd, 2H,
J¼4.9, J¼1.0 Hz, H-30 and H-300), 8.10 (dd, 2H, J¼3.9, J¼1.0 Hz, H-50
and H-500). 13C NMR (63 MHz, CDCl3): 129.14 (C40 and C400), 137.75
d
(C50 and C500), 137.99 (C30 and C300), 139.01 (C20 and C200), 182.86 (C1
and C2).
6
1
5
S
8'
1'
4'
2
8'a
4'a
2'
4
7'
6'
4.4.5. 1,2-Di(thiophen-3-yl)ethane-1,2-dione (1e) (70% yield)
S
3
3'
1'
2'
5'
S
4'
O
1
5'
4''
3''
2''
2
3'
1H NMR (250 MHz, CDCl3):
d 2.01 (m,1H, H-5), 2.24 (m, 1H, H-5),
5''
O
S
1''
2.98 (m, 2H, H-4 and H-6), 3.15 (m, 2H, H-4 and H-6), 5.37 (s, 1H, H-
2), 7.52 (ddd, 2H, J¼5.9, J¼2.9, J¼0.8 Hz, H-10 and H-30), 7.64 (dd,1H,
J¼8.6, J¼1.8, J¼2.1 Hz, H-60), 7.86 (m, 3H, H-40, H-70 and H-80), 8.0 (d,
IR (CH2Cl2): 1636 cmꢂ1. Anal. Calcd for C10H6O2S2: C, 54.03; H,
2.72; S, 28.85. Found: C, 53.70; H, 2.50; S, 28.50. 1H NMR (250 MHz,
1H, J¼1.4 Hz, H-50). 13C NMR (63 MHz, CDCl3):
d 25.58 (C5), 32.58
CDCl3):
d
7.24 (dd, 2H, J¼4.9, J¼4 Hz, H-40 and H-400), 7.88 (dd, 2H,
(C4 and C6), 51.99 (C2), 126.11 (C60), 126.73 (C70), 126.76 (C10),
127.27 (C40), 128.17 (C80), 128.50 (C50), 128.96 (C30), 133.67 (C40a),
133.72 (C80a), 133.87 (C20).
J¼4.9, J¼1.2 Hz, H-50 and H-500), 8.0 (dd, 2H, J¼3.9, J¼1.2 Hz, H-20
and H-200). 13C NMR (63 MHz, CDCl3): 128.14 (C40 and C400), 137.75
d

P. Hoyos et al. / Tetrahedron 64 (2008) 7929–7936
7935
4.5.2. 2-(Naphthalen-1-yl)-1,3-dithiane (5b) (90% yield)
(C4%), 128.56 (C3% and 5%), 128.78 (C40), 129.23 (C50), 131.63 (C2%
and 6%), 132.30 (C80a), 133.28 (C40a), 134.15 (C1%), 137.32 (C10).
5
6
4.5.5. (2-(Naphthalen-1-yl)-1,3-dithian-2-yl)phenylmethanol (6b)
4
(82% yield)
S
S
1
3
2
8'
1'
4'
5'
8'a
7'
6'
6'
S
4'
6'''
5'''
2'
3'
7''
8''
6''
5''
4'''
3'''
3'
1'
S
4'a
8''a
5'
1'''
2'
1
4''a
4''
2'''
1''
OH
IR (film): 3049, 2930, 2888, 1506, 1417, 1272 cmꢂ1. Anal. Calcd
for C14H14S2: C, 68.25; H, 5.73; S, 26.03. Found: C, 68.07; H, 5.55; S,
2''
3''
IR (film): 3056, 2923, 1587, 1454 cmꢂ1
21H20OS2: C, 71.55; H, 5.72; S, 18.19. Found: C, 71.10; H, 5.66; S,
. Anal. Calcd for
25.90. 1H NMR (250 MHz, CDCl3):
d 3.03 (m, 2H, H-5) and 3.25 (m,
4H, H-4 and H-6), 5.96 (s, 1H, H-2), 7.56 (m, 3H, H-20, H-30 and H-60),
C
17.70. 1H NMR (250 MHz, CDCl3):
d
2.62 (m, 6H, H-40, H-50 and H-
7.87 (m, 3H, H-40, H-50 and H-70), 8.34 (d, 1H, J¼8.4 Hz, H-80). 13C
60), 6.71 (d, 1H, J¼3.2 Hz, H-1), 6.80 (d, 1H, J¼3.2 Hz, OH), 6.98 (m,
5H, H-Ph), 7.19 (m, 1H, H-200), 7.40 (m, 2H, H-600 and H-300), 7.69 (m,
1H, H-700), 7.82 (m, 2H, H-400 and H-500), 9.05 (dd, 2H, J¼3, J¼2.1 Hz,
NMR (63 MHz, CDCl3):
d 25.91 (C5), 33.20 (C4 and C6), 48.75 (C2),
123.70 (C20), 126.01 (C80), 126.28 (C60), 126.61 (C70), 126.75 (C40),
129.38 (C30), 129.46 (C50), 130.59 (C80a), 134.28 (C40a), 135.34 (C10).
H-800). 13C NMR (63 MHz, CDCl3): 24.57 (C50), 27.55 and 28.13 (C40
d
and C60), 66.90 (C20), 78.16 (C1), 125.14 (C200), 125.34 (C800), 1265.78
(C600), 127.30 (C700), 127.59 (C400), 127.99 (C300), 128.22 (C2% and
C6%), 130.07 (C4%), 130.39 (C3% and C5%), 131.63 (C800a), 132.10
(C500), 133.87 (C400a), 135.91 (C100), 138.10 (C1%).
4.5.3. Synthesis of (2-(naphthalen-2-yl)-1,3-dithian-
2-yl)phenylmethanol (6d)
Compound 5c (522 mg, 2.12 mmol) was dissolved in 5 mL of
anhydrous THF and BuLi (1.39 mL, 2.22 mmol) was added drop
wise. The mixture was stirred at ꢂ78 ꢀC for 1 h and then benzal-
4.5.6. Naphthalen-2-yl(2-phenyl-1,3-dithian-2-yl)methanol (6c)
dehyde (280 mL, 2.75 mmol) was added. The reaction was left to
(82% yield)
warm to room temperature. After 5 h, the reaction was quenched
by addition of 5 mL of NH4Cl 0.5 M. The organic phase was collected
and dried with anhydrous NaSO4. The solution was filtered and the
solvent was evaporated. The product was purified by column
chromatography (SiO2, CH2Cl2), yielding 605 mg of a white solid
(1.71 mmol, 81% yield). IR (film): 3453, 3055, 3020, 2904, 1502,
1450, 1277, 1188 cmꢂ1. Anal. Calcd for C21H20OS2: C, 71.55; H, 5.72;
S, 18.19. Found: C, 69.68; H, 5.70; S, 17.30.
5''
4''
3'
4'
5'
6''
4'a
8'a
6'
7'
1''
3''
S
S
2'''
1
1'''
2'
2''
3'''
4'''
8'
1'
OH
6'''
5'''
IR (film): 3500, 2986, 3020,1500,1141,1159 cmꢂ1. Anal. Calcd for
21H20OS2: C, 71.55; H, 5.72; S, 18.19. Found: C, 71.57; H, 5.68; S,
5'
C
5'''
4'
6'''
6'
S
17.54. 1H NMR (250 MHz, CDCl3): 1.81 (m, 2H, H-500), 2.60 (m, 4H,
d
4'''
3'''
3'
1'
H-400 and H-600), 3.05 (s, 1H, OH), 5.06 (s, 1H, H-1), 6.80 (dd, 1H,
J¼8.5, J¼1.7 Hz, H-Ar), 7.17 (m, 3H, H-Ar), 7.25 (s, 1H, H-Ar), 7.32 (m,
2H, H-Ar), 7.47 (m, 1H, H-Ar), 7.58 (m, 3H, H-Ar), 7.67 (m, 1H, H-Ar).
S
1''
8''
5''
8''a
4''a
7''
6''
2'
1'''
1
2''
3''
2'''
OH
4''
13C NMR (63 MHz, CDCl3):
d
25.20 (C500), 27.42 and 27.72 (C400 and
C600), 67.05 (C200), 81.53 (C1),126.22 (C60),126.33 (C10),126.41 (C4%),
126.77 (C70), 127.94 (C40), 128.07 (C50 and C80), 128.63 (C30), 128.67
(C3% and C5%), 131.04 (C2% and C6%), 132.71 (C20), 133.54 (C80a),
135.19 (C40a), 137.76 (C1%).
1H NMR (250 MHz, CDCl3): 1.86 (m, 2H, H-50), 2.61 (m, 4H, H-40
d
and H-60), 5.01 (s, 1H, OH), 5.20 (s, 1H, H-1), 6.77 (m, 2H, H-2% and
H-60%0 ), 7.08 (m, 3H, H-3%, H-4% and H-5%), 7.41 (m, 2H, H-100 and
H-3 ), 7.71 (m, 4H, H-400, H-600, H-700 and H-800), 8.10 (d, 1H, J¼0.7 Hz,
H-500). 13C NMR (63 MHz, CDCl3): 25.17 (C50), 27.50 and 27.75 (C40
d
4.5.7. Synthesis of 2-hydroxy-1-(naphthalen-2-yl)-2-
phenylethanone (2i0)
and C60), 67.0 (C20), 81.63 (C1), 126.50 (C600), 126.94 (C700), 126.51
(C100), 126.94 (C400), 127.76 (C2% and C6%), 128.17 (C800), 128.33
(C4%), 128.64 (C500), 128.90 (C300), 131.03 (C3% and C5%), 132.89
(C400a), 133.50 (C800a), 135.25 (C200), 137.59 (C1%).
BF3OEt2 (389 mL, 3.1 mmol) was dissolved in 1 mL of THF/H2O
(85/15) and HgO (636 mg, 3.1 mmol) was added. This mixture was
stirred at 0 ꢀC for 5 min and a solution of 6d (477 mg, 1.357 mmol)
in 24 mL of THF/H2O (85/15) was added. The reaction was stirred at
room temperature under argon for 20 h. CH2Cl2 (25 mL) was added
and the solution was filtered and washed with brine. The organic
phase was collected and dried with anhydrous NaSO4. CH2Cl2 was
filtered and evaporated under reduced pressure. The product was
purified by column chromatography (SiO2, CH2Cl2) affording
301 mg of a white solid (1.15 mmol, 85% yield). IR (film): 3440,
3061, 3028, 1681 cmꢂ1. Anal. Calcd for C18H14O2: C, 82.42; H, 5.38.
Found: C, 80.39; H, 5.24.
4.5.4. Naphthalen-1-yl(2-phenyl-1,3-dithian-2-yl)methanol (6a)
(80% yield)
5''
4''
2'
3'
6''
1''
1'''
4'
4'a
5'
3''
S
S
2'''
1'
1
3'''
4'''
2''
8'a
8'
OH
6'
6'''
5'''
7'
3''
IR (film): 3480, 3049, 2899, 1443, 1420, 1061, 1272 cmꢂ1. Anal.
Calcd for C21H20OS2: C, 71.55; H, 5.72; S, 18.19. Found: C, 70.87; H,
2''
4''
O
1'
4'
8'
5'
8'a
2
2'
5''
1''
7'
6'
1
5.65; S, 17.77. 1H NMR (250 MHz, CDCl3):
d
2.60 (m, 6H, H-400, H-500
6''
OH
3'
and H-600), 3.11 (d, 1H, J¼3.7 Hz, H-1), 5.74 (d, 1H, J¼3.7 Hz, H-OH),
4'a
7.18 (m, 7H, H-Ar), 7.64 (m, 5H, H-Ar). 13C NMR (63 MHz, CDCl3):
d
25.27 (C500), 27.64 (C600), 27.91 (C400), 68.10 (C200), 68.40 (C1), 123.89
1H NMR (250 MHz, CDCl3):
d 5.22 (s, 1H, OH), 6.04 (s, 1H, H-2),
7.24 (m, 5H, H-Ph), 7.48 (qt, 2H, J¼8.0, J¼1.7 Hz, H-60 and H-70), 7.74
(C80), 124.67 (C20), 125.37 (C30), 125.76 (C60), 127.25 (C70), 127.88

7936
P. Hoyos et al. / Tetrahedron 64 (2008) 7929–7936
(m, 1H, H-80), 7.77 (m, 1H, H-50), 7.82 (dd, 1H, J¼8.7, J¼1.7 Hz, H-40),
7.89 (dd, 1H, J¼8.7, J¼1.7 Hz, H-30), 8.38 (s, 1H, H-10). 13C NMR
(C100), 127.97 (C400, and C800), 128.15 (C300 and C500), 128.51 (C30 and
C50), 129.16 (C20 and C60), 129.61 (C400a), 133.60 (C40), 133.83 (C800a),
134.43 (C200), 136.78 (C10), 199.33 (C1). HPLC analysis (n-hexane/2-
propanol, 90/10; flow 1 mL/min): retention time: (S)-2i¼15.7 min,
(R)-2i¼20.93 min. UV analysis: lmax¼223, 248 nm.
(63 MHz, CDCl3):
d
76.67 (C2), 124.67 (C30), 127.43 (C70), 128.19
(C400), 129.04 (C50), 129.06 (C60 and C40), 129.50 (C300 and C500),
129.60 (C80), 130.16 (C200 and C600), 131.13 (C80a), 131.83 (C10), 132.62
(C40a), 136.23 (C20), 139.55 (C100), 199.29 (C1). HPLC analysis (n-
hexane/2-propanol, 90/10; flow 1 mL/min): retention time: (S)-
2i0¼16.1 min, (R)-2i0¼22.6 min. UV analysis: lmax¼210, 249,
288 nm.
Acknowledgements
This work was supported by SOLVSAFE (FP6-2003-NMP-SME-3,
Proposal no. 011774-2) European Project and by CAM Project
‘ENZTEREDOX ’ (S-0505/PPQ/0344). One of the authors (P.H.)
thanks the UCM (Complutense University of Madrid) for her Ph.D.
grant.
4.5.8. 2-Hydroxy-2-(naphthalen-1-yl)-1-phenylethanone (2h)
(78% yield)
3''
2''
1''
4''
O
1
6'
3'
4''a
2
1'
2'
References and notes
5'
4'
5''
8''a
OH
6''
8''
1. Roush, W. R.; Briner, K.; Kessler, B. S.; Murphy, M.; Gustin, D. J. J. Org. Chem.
1996, 61, 6098–6099.
7''
2. Uchida, R.; Shiomi, K.; Sunazuka, T.; Inokoshi, J.; Nishizawa, A.; Hirose, T.;
Tanaka, H.; Iwai, Y.; Omura, S. J. Antibiot. 1996, 49, 886–889.
3. Wallace, O. B.; Smith, D. W.; Deshpande, M. S.; Polson, C.; Felsenstein, K. M.
Bioorg. Med. Chem. Lett. 2003, 13, 1203–1206.
4. Fang, Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayade, C. H.; Wald, S. A. Tet-
rahedron: Asymmetry 2002, 11, 3659–3663.
IR (film): 3459, 2911, 2840, 1683 cmꢂ1. Anal. Calcd for C18H14O2:
C, 82.42; H, 5.38. Found: C, 81.78; H, 6.32. 1H NMR (250 MHz,
CDCl3):
d
4.45 (d, 1H, J¼4.7 Hz, OH), 6.52 (d, 1H, J¼4.4 Hz, H-2), 7.21
(m, 4H, H-Ar), 7.46 (m, 3H, H-Ar), 7.76 (m, 4H, H-Ar), 8.27 (d, 1H,
J¼8.4 Hz, H-800). 13C NMR (63 MHz, CDCl3):
d 74.14 (C2), 123.71
5. Tanaka, T.; Kawase, M.; Tani, S. Bioorg. Med. Chem. 2004, 12, 501–505.
6. (a) Wildemann, H.; Dunkelmann, P.; Muller, M.; Schmidt, B. J. Org. Chem. 2003,
68, 799–804; (b) Singh, M. S.; Singh, A. K. Synthesis-Stuttgart 2004, 6, 837–839.
7. Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743–1745.
8. Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070–3071.
9. (a) Demir, A. S.; Du¨nwald, T.; Iding, H.; Pohl, M.; Mu¨ ller, M. Tetrahedron:
(C800), 125.86 (C600), 126.061 (C700), 127.26 (C200), 127.59 (C400 and C500),
129.10 (C300), 129.41 (C3 and C50), 129.99 (C20 and C60), 131.78 (C40),
134.39 (C100), 134.74 (C400a), 135.60 (C10), 136.96 (C800a), 200.50 (C1).
HPLC analysis (n-hexane/2-propanol, 90/10; flow 1 mL/min): re-
tention time: (S)-2h¼14.8 min, (R)-2h¼23.38 min. UV analysis:
lmax¼223, 248 nm.
¨
Asymmetry 1999, 10, 4769–4774; (b) Demir, A. S.; Sesenoglu, O.; Eren, E.; Hosrik,
B.; Pohl, M.; Janzen, E.; Kolter, D.; Feldmann, R.; Du¨nkelmann, P.; Mu¨ller, M. Adv.
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2005, 61, 7378–7383; (e) Domı´nguez de Marı´a, P.; Stillger, T.; Pohl, M.; Wallert,
S.; Drauz, K.; Gro¨ger, H.; Trauthwein, H.; Liese, A. J. Mol. Catal. B: Enzym. 2006,
38, 43–47.
4.5.9. 2-Hydroxy-1-(naphthalen-1-yl)-2-phenylethanone (2h0)
(65% yield)
3''
7'
10. Demir, A. S.; Hamamci, H.; Sesenoglu, O.; Neslihanoglu, R.; Asikoglu, B.;
Capanoglu, D. Tetrahedron Lett. 2002, 43, 6443–6449.
8'
8'a
1'
2''
4''
5''
6'
5'
O
1
11. (a) Hoyos, P.; Ferna´ndez, M.; Sinisterra, J. V.; Alca´ntara, A. R. J. Org. Chem. 2006,
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Devine, P. N. Acc. Chem. Res. 2007, 40, 1412–1419.
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2
1''
4'a
4'
6''
2'
OH
3'
IR (film): 3100, 3050, 2900, 2888, 1646 cmꢂ1. Anal. Calcd for
18H14O2: C, 82.42; H, 5.38. Found: C, 81.50; H, 5.24. 1H NMR
C
(250 MHz, CDCl3): d 4.35 (s,1H, OH), 6.52 (s,1H, OH), 7.24 (m, 5H, H-
Ph), 7.43 (m, 2H, H-30 and H-60), 7.66 (m, 1H, H-70), 7.94 (m, 1H, H-
50), 7.97 (m, 1H, H-20), 8.05 (d, 1H, J¼8.1 Hz, H-40), 9.24 (d, 1H,
J¼8.6 Hz, H-80). 13C NMR (63 MHz, CDCl3):
d
77.81 (C2), 124.87 (C80),
126.37 (C60), 127.57 (C30), 128.19 (C-400), 128.98 (C80a), 129.24 (C50),
129.50 (C300 and C500), 129.92 (C20), 130.16 (C200 and C600), 131.35
(C40), 134.49 (C10), 135.22 (C40a), 135.60 (C70), 139.55 (C100), 195.06
(C1). HPLC analysis (n-hexane/2-propanol, 90/10; flow 1 mL/min):
retention time: (S)-2h0¼16.0 min, (R)-2h0¼23.1 min. UV analysis:
lmax¼210, 249, 288 nm.
14. Molinari, F.; Gandolfi, R.; Villa, R.; Occhiato, E. G. Tetrahedron: Asymmetry 1999,
10, 3515–3520.
15. D’Arrigo, P.; Fuganti, C.; Pedrocchi Fantoni, G.; Servi, S. Tetrahedron 1998, 5,
15017–15026.
4.5.10. 2-Hydroxy-2-(naphthalen-2-yl)-1-phenylethanone (2i)
(87% yield)
16. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 31, 2647–2650.
17. Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1217–1221.
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2000, 41, 4135–4138; (c) Matsuda, T.; Harada, T.; Nakajima, N.; Itoh, T.; Naka-
mura, K. J. Org. Chem. 2000, 65, 157–163.
5''
4''
4''a
6''
7''
O
1
3''
6'
3'
2
1'
5'
4'
2''
8''a
8''
1''
OH
2'
19. Ansorge-Schumacher, M. B.; Greiner, L.; Schroeper, F.; Mirtschin, S.; Hischer, T.
Biotechnol. J. 2006, 1, 564–568.
20. Bo` gar, K.; Hoyos-Vidal, P.; Alca´ntara-Leo´ n, A. R.; Ba¨ckwall, J. E. Org. Lett. 2007, 9,
3401–3404.
21. Prelog, V. Pure Appl. Chem. 1964, 9, 119–130.
22. (a) Sanghani, P. C.; Davis, W. I.; Zhai, L. M.; Robinson, H. Biochemistry 2006, 45,
4819–4830; (b) Yin, S. J.; Chou, C. F.; Lai, C. L.; Lee, S. L.; Han, C. L. Chem.-Biol.
Interact. 2003, 143, 219–227; (c) Kim, K. J.; Howard, A. J. Acta Crystallogr. 2002,
D58, 1332–1334.
IR (film): 3453, 3052, 1677, 1077 cmꢂ1. Anal. Calcd for C18H14O2:
C, 82.42; H, 5.38. Found: C, 80.26; H, 5.27. 1H NMR (250 MHz,
CDCl3):
(m, 3H, H-Ar), 7.73 (m, 4H, H-Ar), 7.88 (m, 2H, H-Ar). 13C NMR
(63 MHz, CDCl3):
76.76 (C2), 125.24 (C600), 126.86 (C700), 126.96
d 4.05 (s, 1H, OH), 6.05 (s, 1H, H-2), 7.31 (m, 3H, H-Ar), 7.40
d