Substrate Scope Evaluation of the Enantioselective Reduction of β-Alkyl-β-arylnitroalkenes by Old Yellow Enzymes 1-3 for Organic Synthesis Applications

Article abstract of DOI:10.1002/cctc.201500958

The substrate scope of the old yellow enzyme catalyzed reduction of β-alkyl-β-arylnitroalkenes is investigated. Compounds bearing either alkyl chains of increasing length at the carbon atom in position β to the nitro group or different substituents on the aromatic ring are prepared and submitted to bioreduction, to define the synthetic potential of this enantioselective reaction in the preparation of chiral fine chemicals. The versatility of the resulting nitroalkanes as chiral building blocks is shown by reducing the nitro group into a primary amine and by converting it into a carboxylic acid moiety by Meyer reaction. An "explosion" of chiral products can be observed by combining the highly enantioselective ene-reductase-mediated reduction of nitroalkenes with the chemical versatility of the nitro group.

Full text of DOI:10.1002/cctc.201500958

DOI: 10.1002/cctc.201500958
Full Papers
Substrate Scope Evaluation of the Enantioselective
Reduction of b-Alkyl-b-arylnitroalkenes by Old Yellow
Enzymes 1–3 for Organic Synthesis Applications
Mattia Bertolotti,[a] Elisabetta Brenna,*[a, b] Michele Crotti,[a] Francesco G. Gatti,[a]
Daniela Monti,[b] Fabio Parmeggiani,[a] and Sara Santangelo[a]
The substrate scope of the old yellow enzyme catalyzed reduc-
tion of b-alkyl-b-arylnitroalkenes is investigated. Compounds
bearing either alkyl chains of increasing length at the carbon
atom in position b to the nitro group or different substituents
on the aromatic ring are prepared and submitted to bioreduc-
tion, to define the synthetic potential of this enantioselective
reaction in the preparation of chiral fine chemicals. The versa-
tility of the resulting nitroalkanes as chiral building blocks is
shown by reducing the nitro group into a primary amine and
by converting it into a carboxylic acid moiety by Meyer reac-
tion.
Introduction
Enantiomerically enriched nitroalkanes are valuable building
blocks in organic chemistry because they are precursors of
useful chiral intermediates for fine chemicals synthesis. The
nitro moiety can serve as a masked functionality to be further
converted,[1] for example, into an amino group by reduction,[2]
into a ketone or aldehyde by the Nef reaction,[3] into a carboxyl-
ic acid by the Meyer reaction,[4] or it can be displaced under
suitable conditions by a nucleophile.[5]
terest in developing alternative biocatalyzed procedures for
the synthesis of optically active nitro compounds.
Ene-reductases (ERs) from the old yellow enzyme (OYE)
family have shown great efficiency in the enantioselective re-
duction of nitroalkene (E)-1a (Scheme 1), which is often em-
A variety of chemical methods have been described for the
synthesis of b,b-disubstituted nitroalkanes, which are configu-
rationally more stable than the a-substituted ones (the strong
electron-withdrawing effect of the nitro group enhances the
acidity of the a-hydrogen atom). The most successful ap-
proaches are based on metal-catalyzed[6,7] or organocatalyzed[8]
transfer hydrogenations, enantioselective conjugate addi-
tions,[9–12] and rhodium-catalyzed enantioselective hydrogena-
tion.[13]
Scheme 1. Known enantioselective biocatalytic reductions of (E)-1a.
Most of the chemical procedures suffer either from poor en-
vironmental sustainability, owing to the nature of the catalysts,
or from the narrow substrate range that limits the synthesis of
desirable products. As a consequence, there is considerable in-
ployed as a model substrate in the characterization of new
ERs.[14] Highly enantioselective reactions have been reported
for the reduction of the model substrate (E)-1a by using either
whole cells of baker’s yeast (BY, Saccharomyces cerevisiae),[15] or
isolated ERs from Lycopersicon esculentum (OPR1 and OPR3),[16]
Saccharomyces carlsbergensis and cerevisiae (OYE1–3),[17] Zymo-
monas mobilis (NCR),[17] Bacillus subtilis (YqjM),[18] Enterobacter
cloacae PB2 (PETNR),[19] or crude extracts of Clostridium sporo-
genes.[20] The (R)-enantiomer of the reduced product 2a could
be obtained by reaction with BY, OYE1–3, OPR1, and C. sporo-
genes extract, whereas the use of NCR, OPR3, YqjM, and PETNR
afforded compound (S)-2a (Scheme 1).
The effects of substituents on conversion and enantioselec-
tivity have been described for the biotransformations with
C. sporogenes extracts, and only partially for the reductions
with fermenting BY and PETNR. Thus, herein we report on the
investigation of the BY and OYE1–3 mediated reductions of
a set of nitroalkenes (E)-1a–l, bearing sterically and electroni-
[a] M. Bertolotti, Prof. E. Brenna, M. Crotti,+ Prof. F. G. Gatti, Dr. F. Parmeggiani,
S. Santangelo+
Dipartimento di Chimica
Materiali ed Ingegneria Chimica “Giulio Natta” Politecnico di Milano
Via Mancinelli 7, 20131, Milano (Italy)
E-mail: mariaelisabetta.brenna@polimi.it
[b] Prof. E. Brenna, Dr. D. Monti
Istituto di Chimica del Riconoscimento Molecolare
C.N.R.
Via Mario Bianco, 9, 20131, Milano (Italy)
[+] These authors contributed equally to this work. The authors are listed in al-
phabetical order.
Supporting Information and ORCID(s) from the author(s) for this article
are available on the WWW under http://dx.doi.org/10.1002/
cctc.201500958.
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cally different substituents either on the aromatic ring or at
the carbon atom in b-position with respect to the nitro group.
The aim is to explore the substrate scope of OYE catalyzed re-
duction of b,b-disubstituted nitroalkenes, and define the syn-
thetic potential of this enantioselective reaction in the devel-
opment of manufacturing processes for chiral fine chemicals.
The versatility of the resulting nitroalkanes as chiral building
blocks will also be highlighted by converting the nitro group
into a primary amine by reduction, and into a carboxylic acid
moiety by Meyer reaction.
Table 1. Biotransformations of nitroalkenes (E)-1a–l.
Substrate Ar
R
OYE1
c [%][a] c [%] c [%] c [%]
OYE2 OYE3 BY[c]
BY [lit.][d]
c [%]
ee [%][b] ee [%] ee [%] ee [%] ee [%]
(E)-1a
(E)-1b
(E)-1c
(E)-1d
(E)-1e
(E)-1 f
(E)-1g
(E)-1h
(Z)-1h
(E)-1i
(E)-1j
(E)-1k
(E)-1l
C6H5
Me 95
99 (R)
Et 75
99 (R)
nPr 52
99 (R)
iPr 12
74 (R)
Me 99
99 (R)
88
99 (R) 99 (R) 99 (R) 98 (R)
75 99 99 64
99 (R) 99 (R) 99 (R) 97 (R)
66 95 95 23
99 (R) 99 (R) 99 (R) 89 (R)
99
99
50
C6H5
C6H5
Results and Discussion
C6H5
13
66 (R) rac
99 99
36
36
70 (R)
99
–
Synthesis of nitroalkenes (E)-1a–l
p-F-C6H4
o-Cl-C6H4
m-Cl-C6H4
p-Cl-C6H4
p-Cl-C6H4
p-I-C6H4
–
99 (R) 99 (R) 99 (R)
1-Nitro-2-arylalkene derivatives (E)-1a–l were obtained accord-
ing to the synthetic procedures reported in Scheme 2. The first
Me
–
–
–
29
–
99 (R)[e]
99
Me 13
75 (R)
Me 99
76 (R)
Me 99
62 (S)
Me 99
90 (R)
o-MeO-C6H4 Me 95
73 (R)
m-MeO-C6H4 Me 11
92 (R)
p-MeO-C6H4 Me 88
99 (R)
76
42
–
76 (R) 40 (R) 94 (R)
45 99 99
59 (R) 62 (R) 92 (R) 89 (R)
48
99
59 (S) 84 (S) 92 (S)
99 99 70
90 (R) 50 (R) 95 (R)
99 99 99
90 (R) 80 (R) 80 (R)
42 65
94 (R) 44 (R) 80 (R)
92 99 99
94 (R) 97 (R) 97 (R)
99
99
–
–
–
–
–
5
[a] Conversion calculated on the basis of GC analysis of the crude mixture
after 24 h reaction time (isolation yields for BY reactions are reported in
the Experimental Section). [b] Enantiomeric excess calculated on the basis
of GC or HPLC analysis (see Experimental Section) on a chiral stationary
phase. [c] This work. [d] Literature data [15a,b]; [e] Assigned by analogy
(see Experimental Section).
Scheme 2. Synthesis and bioreduction of nitroalkenes (E)-1a–l.
step consisted of the Wittig reaction of the suitable aryl
ketone with methyltriphenylphosphonium iodide and potassi-
um tert-butoxide in THF to prepare the corresponding a-sub-
stituted styrene. The m-substituted compounds were convert-
ed into nitroalkenes (E)-1g and k in one step, by the reaction
with cerium ammonium nitrate and sodium nitrite in acetic
acid. All the other styrene derivatives were treated with acetic
anhydride and 65% aqueous nitric acid to afford a 1-nitro-2-ar-
ylalk-2-yl acetate intermediate, which was then submitted to
elimination upon reaction with sodium hydroxide in dichloro-
methane/water, to give the (E)-stereoisomer of the correspond-
ing nitroalkene. In the case of the p-chloro derivative 1h also
the (Z)-isomer could be isolated.
(1b–d) or different substituents on the aromatic ring (1e–l), to
establish whether this kind of reduction could be considered
a reliable method for the stereoselective production of useful
chiral nitroalkanes, and a valid alternative to known chemical
procedures.
We could achieve higher conversion yields and enantioselec-
tivities by using dried BY (160 gLÀ1) in water medium with no
co-solvent, working with a substrate concentration of 3 gLÀ1
and prolonging the reaction time to 72 h. The same substrates
were submitted to OYE mediated reactions (using a glucose
dehydrogenase and glucose as a co-substrate for the regenera-
tion of the NADPH cofactor) at pH 7.0, obtaining very similar
results, that is, quantitative conversions and high ee values
(Table 1). The only exceptions were represented by the isopro-
pylnitroalkene (E)-1d, and the o- and m-chloro derivatives (E)-
1 f and g. Alkene (E)-1d was reduced with rather good ee
values by OYE1, OYE2 and BY, but it afforded a racemic mixture
with OYE3. (E)-1 f was not transformed by OYE1–3, whereas it
was converted into the enantiopure reduced nitroalkane with
modest yields by BY. Surprisingly, the other ortho-substituted
substrate (E)-1j was reduced in high yields and good enantio-
Biotransformations of nitroalkenes (E)-1a–l
The only data reported in the literature[15a,b] for the BY reduc-
tion of a few 1-nitro-2-arylalkenes are collected in Table 1.
Dried yeast (200 gLÀ1) was employed in tap water in the pres-
ence of 0.4% ethanol as a co-solvent, with a substrate concen-
tration of 2 gLÀ1 and a typical incubation time of 48 h. We con-
ducted our investigation on 1a as a model compound and
a panel of analogues bearing either alkyl chains of increasing
length at the carbon atom in position b to the nitro group
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meric excess values by OYE1–3 and BY. (E)-1g was converted
quantitatively by BY into the (R)-enantiomer showing 94% ee,
but lower conversions and enantioselectivity values were
obtained with OYE1–3.
hydride and proton anti addition, therefore, they afford re-
duced products with opposite configuration at the newly
created stereocenters.
The enantioselectivity of the bioreductions of substrates (E)-
10a–l is in agreement with some conclusions we have recently
drawn[22] on the stereochemical outcome of OYE1–3 mediated
transformations of a set of trisubstituted monofunctionalized
alkenes, bearing no substituents at the carbon atom linked to
the activating EWG. Most of literature data regarding these
substrates were referred to (E)-stereoisomers. Under the hy-
pothesis of anti hydrogen addition, we could define their reac-
tive mode by considering the absolute configuration of the
corresponding reduced products. All the substrates were
found to bind to the enzyme active site according to a classical
binding mode, in which the largest group at the prostereogen-
ic carbon atom is on the opposite side with respect to the
EWG (Scheme 4a).
The use of isolated enzymes shows advantages with respect
to BY fermentation in the reaction work-up and product recov-
ery, because the extraction procedure does not involve the
handling of a large amount of biomass. For the model com-
pound (E)-1a, substrate loading could be increased in the reac-
tions catalyzed by OYE1–3 from a concentration of 1.0 gLÀ1, in
the presence of 0.1 gLÀ1 of isolated enzyme, to 3.2 gLÀ1 with
0.2 gLÀ1 of biocatalyst. The latter conditions afforded quantita-
tive conversion with OYE2 and OYE3, but only 50% of reduced
product with OYE1 (in 48 h reaction time).
Our data show that the range of accepted substrates for this
reaction is rather wide: the steric hindrance of the alkyl sub-
stituent on the double bond becomes critical only with a rami-
fication, and the presence of a substituent at the para position
of the aromatic ring, either a halogen atom or a methoxy
group, has no negative effects on the reaction. The ortho and
meta positions may suffer from steric problems caused by the
clash between the substituent and the hydrophobic residues
that define the aromatic binding pocket in the active site.
The stereochemical outcome of the reaction is determined
by the stereospecificity of the hydrogen addition occurring
with an anti mechanism, and by the binding mode of the sub-
strate to the enzyme active site. The electron-withdrawing
group (EWG), in this case the nitro moiety, which has to be
present on the alkene bond to activate it towards bioreduc-
tion, establishes hydrogen bonds with two amino acid residues
within the enzyme binding pocket (His191 and Asn194 for
OYE1–3), resulting in two possible substrate binding modes:[21]
a “classical” one (Scheme 3a) and a “flipped” one (Scheme 3b).
Scheme 4. Stereoselectivity of the OYE mediated reductions of olefins acti-
vated by an EWG linked to the less substituted olefinic carbon atom
(S=small, L=large). The general model (a) for the classical binding mode
(from ref. [22]) allows one to rationalize the stereochemical outcome of the
reduction of (E)-1a–l (b) and (Z)-1h (c).
For nitroalkenes (E)-1a–l, this arrangement in the enzyme-
binding pocket causes the (R)-enantiomer of the correspond-
ing reduced products to be obtained (Scheme 4b), with the
aryl group as the bulkier substituent linked to the carbon
atom in b position to the EWG. This model can also rationalize
the lower ee obtained for the isopropyl derivative (E)-1d: be-
cause of the larger steric hindrance of the isopropyl group
with respect to the phenyl group, both binding modes can be
adopted (still with some preference for the classical one), re-
sulting in both enantiomers being produced. Furthermore, as
both substituents are rather bulky, the conversions for this
substrate are significantly lower.
Scheme 3. Mechanism of OYE mediated reduction shown with the substrate
bound to the enzyme active site either in a classical (a) or flipped (b) bind-
ing mode.
A hydride ion is transferred from the reduced flavin prosthetic
group (FMNH2) to the olefinic carbon atom in the b position to
the activating substituent, and a proton is delivered by a tyro-
sine residue (Tyr196 for OYE1–3) to the a carbon atom on the
other stereoheterotopic face of the alkene, thus affording anti
hydrogen addition. The two modes differ from one another
only by a switch of the faces of the alkene that are exposed to
The (Z)-stereoisomer of compound 1h maintained the same
classical binding mode (Scheme 4c), affording the (S)-enantio-
mer of nitroalkane 2h. The same inversion of configuration be-
tween (E)- and (Z)-stereoisomers was observed for substrates
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1a and 1h upon reduction with PETNR,[20] and for 1a with
NtDBR.[14c] This approach can be useful as a general strategy to
access the opposite enantiomer of the reduced products.
of amine (R)-4b is incorporated in aminoalkyl-1,4-diazepan-2-
one melanocortin-5 receptor antagonists[25] and in a series of
tropane derivatives showing potential as selective dopamine
transporter ligands.[26] In the latter, the chiral moiety is intro-
duced by amidation of a tropane derivative with (R)-2-phenyl-
butanoic acid followed by AlH3 reduction in THF.
Synthetic versatility of the optically pure nitroalkane
products
To assess the synthetic potential of this highly enantioselective
biotransformation, we investigated the conversion of the enan-
tiopure nitroalkanes (R)-2a–l recovered from biocatalyzed re-
ductions into valuable chiral building blocks by further manip-
ulation of the nitro moiety.
Conclusions
The experimental data herein reported show that the ene-re-
ductase-mediated hydrogenation of b,b-disubstituted nitroal-
kenes is characterized by wide substrate scope, high conver-
sion yields, and very satisfactory enantioselectivity values, es-
pecially if Baker’s yeast whole cells are employed. These key
requisites, combined with the inherent advantages already as-
cribed to biocatalysts and the synthetic versatility of the nitro
group, make this enantioselective procedure a good candidate
for application in fine-chemicals manufacturing processes. The
chemical manipulation of the nitro group to afford amines or
carboxylic acids widens the array of enantiomerically pure sub-
strates that can be obtained by application of this reaction
procedure. Furthermore, the one-pot conversion of the nitro
functionality into the corresponding amines by using
NiCl2·6H2O and NaBH4 telescopes the reaction sequence and
reduces time and costs connected with the purification of re-
action intermediates.
The treatment of the nitroalkane products with acetic acid
and sodium nitrite in DMSO at 358C affords the corresponding
carboxylic acids without loss of optical purity: this procedure
has been exploited for the conversion of compounds (R)-2c, e,
and i into carboxylic acids (R)-3c, e, and i, with 79–86% isola-
tion yields (Scheme 5). Compound (R)-3c, prepared by classical
Experimental Section
General methods
GC–MS analyses were performed by using an HP-5 MS column
(30 m”0.25 mm”0.25 mm, Agilent). The following temperature
program was employed: 608C (1 min)/68CminÀ1/1508C (1 min)/
128CminÀ1/2808C (5 min). The ee values of nitroalkanes 2a–l were
determined either by GC or HPLC analysis. Chiral GC analyses were
performed on a Chirasil DEX CB column (25 m”0.25 mm”0.25 mm,
Chrompack), carrier gas H2, constant flow 3.7 mLminÀ1, injector
temperature 2508C, detector temperature 2508C. Chiral HPLC anal-
yses were performed on a Chiralcel OD column (4.6 mm”250 mm,
Scheme 5. Synthetic versatility of the optically pure nitroalkane products.
resolution of diastereoisomeric salts, is employed in the prepa-
ration of orally active b-lactam inhibitors of human leukocyte
elastase.[23] The p-fluoro derivative (R)-3e is a key intermediate
in the synthesis of substituted triazolopyridines[24] having activ-
ity as MPS-1 inhibitors, employed in a new approach for the
treatment of proliferative disorders. The known synthesis con-
sists of the alkylation of methyl (4-fluorophenyl)acetate by re-
action with n-butyllithium and methyl iodide, followed by
saponification of the ester and classical resolution of the corre-
sponding acid with (S)-phenylethanamine, with loss of the un-
wanted enantiomer. The conversion of (R)-2i into 3i was em-
ployed to establish the absolute configuration of the starting
nitroalkane.
1
Daicel) installed on instruments with UV detector. H and 13C NMR
spectra were recorded on a 400 or 500 MHz spectrometer. The
chemical-shift scale was based on internal tetramethylsilane. TLC
analyses were performed on Merck Kieselgel 60 F254 plates. All the
chromatographic separations were performed on silica gel
columns.
General procedure for baker’s yeast mediated reduction
(preparative scale)
The reaction of the nitroalkane products with NiCl2·6H2O
and NaBH4 under aqueous conditions, instead, affords the cor-
responding enantiopure amines: in this case, the procedure
was exemplified with the conversion of products (R)-2b and
l to amines (R)-4b and l (Scheme 5). Remarkably, this kind of
reduction is compatible with the aqueous medium of OYE1–3
catalyzed reactions, thus it was performed in situ by addition
of the reagents to the biotransformation mixture (after com-
plete reduction of the C=C double bond mediated by OYE3),
without isolation of the intermediate nitroalkane. The structure
A mixture of baker’s yeast (40 g) and d-glucose (15 g) in tap water
(250 mL) was prepared. After 10 min stirring at 308C the suitable
nitroalkene derivative 1a–l (750 mg) was added in one portion.
The mixture was kept under stirring for 72 h at RT and then filtered
on a celite pad. The filtrate was extracted with EtOAc (3”100 mL).
The organic phase was dried over Na2SO4 and evaporated under
reduced pressure. The resulting crude product was purified by
column chromatography in n-hexane with increasing amounts of
EtOAc, to afford the corresponding nitroalkane (R)-2a–l.
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(R)-(1-Nitropropan-2-yl)benzene (2a): From (E)-1a (0.754 g,
4.63 mmol) derivative (R)-2a was obtained (0.577 g, 3.50 mmol,
76%): ee=99%, [a]D = +49.1 (c=1.0, CHCl3), lit. ref. [20] for (R)-2a
(ee>99%) [a]D = +52 (c=0.56, CHCl3). 1H NMR (CDCl3,
400 MHz):[20] d=7.38–7.18 (m, 5H, ArH), 4.88 (dd, J=12.1 Hz,
7.1 Hz, 1H, CHHNO2), 4.49–4.43 (dd, J=12.1 Hz, 8.2 Hz, 1H,
CHHNO2), 3.67 (m, CHCH3), 1.37 ppm (d, J=7.0 Hz, 1H, CHCH3);
13C NMR (CDCl3, 100.6 MHz):[20] d=140.1, 128.9, 127.5, 126.9, 81.8,
38.6, 18.7 ppm; GC-MS (EI) tR =14.30 min, m/z (%)=165 (M+, 2),
118 (100), 91 (90). Chiral GC (Chirasil DEX CB column): 808C/
18CminÀ1/1308C/508CminÀ1/1808C (2 min): (S)-2a tR =25.6 min,
(R)-2a tR =25.9 min
0.838 mmol, 22%): ee=99%, ½aŠ20 = +22.0 (c=1.3, CHCl3), only
D
a negative sign of the [a]D was reported in ref. [13a] for the enan-
tiomer of 2 f to which (S)-configuration had been assigned by anal-
1
ogy. H NMR (CDCl3, 400 MHz):[13a] d=7.45–7.20 (m, 4H, ArH), 4.64
(dd, J=12.2 Hz, 6.2 Hz, 1H, CHHNO2), 4.44 (dd, J=12.2 Hz, 8.2 Hz,
1H, CHHNO2), 4.14 (m, 1H, CH3CH), 1.38 ppm (d, J=7.0 Hz, 3H,
CH3CH); 13C NMR (CDCl3, 100.6 MHz):[13a] d=138.1, 133.8, 130.2,
128.7, 127.4, 127.3, 80.0, 35.5, 17.5 ppm; GC-MS (EI) tR =18.11 min,
m/z (%)=199 (5), 152 (75), 125 (100). Chiral GC (Chirasil DEX CB
column): 808C/18CminÀ1/1308C/508CminÀ1/1808C (2 min): (S)-2 f
tR =38.6 min, (R)-2 f tR =39.6 min.
(R)-1-Chloro-3-(1-nitropropan-2-yl)benzene (2g): From (E)-1g
(0.650 g, 3.30 mmol) derivative (R)-2g was obtained (0.531 g,
(R)-(1-Nitrobutan-2-yl)benzene (2b): From (E)-1b (0.957 g,
5.41 mmol) derivative (R)-2b was obtained (0.670 g, 3.75 mmol,
70%): ee=99%, [a]D = +38.7 (c=1.2, CHCl3), lit. ref. [27] for (R)-2b
2.68 mmol, 81%): ee=94%, ½aŠ20 = +35.8 (c=1.0, CHCl3), lit.
D
ref. [13b] for (R)-2g (ee=99%) ½aŠ20 = +37.1 (c=0.58, CHCl3).
D
(ee=97%) ½aŠ20 = +38.2 (c=1.1, CHCl3). 1H NMR (CDCl3,
1H NMR (CDCl3, 400 MHz):[13b] d=7.30–7.16 (m, 3H, ArH), 7.13–7.08
(m, 1H, ArH), 4.53 À4.43 (m, 2H, CH2NO2), 4.14 (sextet, J=7.5 Hz,
1H, CH3CH), 1.37 ppm (d, J=7.0 Hz, 3H, CH3CH); 13C NMR (CDCl3,
100.6 MHz):[13b] d=143.1, 135.0, 130.4, 128.0, 127.3, 125.3, 81.5,
38.5, 18.8 ppm; GC-MS (EI) tR =17.51 min, m/z (%)=199 (5), 152
(100), 125 (94). Chiral GC (Chirasil DEX CB column): 1058C/
0.38CminÀ1/1188C/508CminÀ1/1808C (2 min): (S)-2g tR =34.6 min,
(R)-2g tR =35.2 min.
D
400 MHz):[27] d=7.40–7.10 (m, 5H, ArH), 4.54 (m, 2H, CH2NO2), 3.35
(m, 1H, CHCH2), 1.72 (m, 2H, CHCH2), 0.83 ppm (t, J=7.4 Hz, 3H,
CH2CH3); 13C NMR (CDCl3, 100.6 MHz):[28] d=139.4, 128.8, 127.5,
125.9, 80.7, 46.0, 26.1, 11.4 ppm; GC-MS (EI) tR =16.20 min, m/z
(%)=179 (M+, 2), 132 (90), 91(100). Chiral GC (Chirasil DEX CB
column): 808C/18CminÀ1/1308C/508CminÀ1/1808C (2 min): (S)-2b
tR =30.7 min, (R)-2b tR =30.9 min.
(R)-(1-Nitropentan-2-yl)benzene (2c): From 1c (0.912 g, 4.77 mmol)
derivative (R)-2c was obtained (0.571 g, 2.95 mmol, 62%): ee=
(R)-1-Chloro-4-(1-nitropropan-2-yl)benzene (2h): From (E)-1h
(0.690 g, 3.50 mmol) derivative (R)-2h was obtained (0.571 g,
99%, ½aŠ20 = +37.3 (c=1.0, CHCl3), lit. ref. [15a] for (R)-2c (ee=
2.87 mmol, 82%): ee=92%, ½aŠ20 = +47.2 (c1.0, CHCl3), lit. [20] for
D
D
89%) ½aŠ20 = +33.4 (c=1.2, CHCl3). H NMR (CDCl3, 400 MHz):[7] d=
1
(S)- 2h (ee=99%) ½aŠ20 = +51.3 (c=0.60, CHCl3); 1H NMR (CDCl3,
D
D
400 MHz):[20] d=7.35–7.10 (m, 5H, ArH), 4.48 (m, 2H, CH2NO2), 3.60
(m, 1H, CH3CH), 1.35 ppm (d, J=7,1 Hz, 3H, CH3CH); 13C NMR
(CDCl3, 100.6 MHz):[20] d=139.4, 133.4, 129.1, 128.3, 81.5, 38.0,
18.7 ppm; GC-MS (EI) tR =18.85 min, m/z (%)=199 (40), 152 (100),
125 (83). Chiral HPLC (Chiralcel OD column): hexane/iPrOH 98:2,
222 nm, 0.9 mLminÀ1; (R)-2h tR =14.5 min; (S)-2h tR =20.8 min.
7.38–7.10 (m, 5H, ArH), 4.52 (m, 2H, CH2NO2), 3.44 (m, 1H, CH-Ph),
1.68 (m, 2H, CH3CH2CH2-), 1.22 (m, 2H, CH3CH2CH2), 0.87 ppm (t,
J=7.3 Hz, 3H, CH3CH2CH2); 13C NMR (CDCl3, 100.6 MHz):[29] d=
139.6, 128.9, 127.5, 125.6, 81.0, 44.1, 36.2, 20.0, 13.7 ppm; GC-MS
(EI) tR =18.10 min, m/z (%)=193 (M+, 1), 146 (50), 118 (100), 91
(95). Chiral GC (Chirasil DEX CB column): 658C/18CminÀ1/1308C/
508CminÀ1/1808C (2 min): (R)-2c tR =50.28 min, (S)-2c tR =
50.85 min;
(R)-1-Iodo-4-(1-nitropropan-2-yl)benzene (2i): From (E)-1i (0.730 g,
2.53 mmol) derivative (+)-2i was obtained (0.405 g, 1.39 mmol,
(R)-(3-Methyl-1-nitrobutan-2-yl)benzene (2d): From (E)-1d (0.970 g,
5.08 mmol) derivative (R)-1d was obtained (0.245 g, 1.27 mmol,
55%): ee=95%, ½aŠ20 = +23.2 (c=0.9, CHCl3); 1H NMR (CDCl3,
D
400 MHz):[13c] d=7.66 (d, J=8.5 Hz, 2H, ArH), 6.97 (d, J=8.5 Hz,
2H, ArH), 4.47 (m, 2H, CH2NO2), 3.58 (sextet, J=7.0 Hz, 1H, CHCH3),
1.35 ppm (d, J=7.0 Hz, 3H, CH3C); 13C NMR (CDCl3, 100.6 MHz):[13c]
d=140.6, 138.1, 128.8, 92.8, 81.4, 38.2, 18.6 ppm; GC-MS (EI) tR =
21.88 min, m/z (%)=291 (M+, 10), 244 (100), 217 (38). Chiral HPLC
25%): ee=70%, ½aŠ20 = +24.9 (c=2.0, CHCl3), lit. ref. [11] for (R)-2d
D
(ee=95%) ½aŠ20 = +34.3 (c=2.80, CHCl3); 1H NMR (CDCl3,
D
400 MHz):[11] d=7.35–7.10 (m, 5H, ArH), 4.78 (dd, J=12.3 and
5.8 Hz, 1H, CHHNO2), 4.63 (dd, J=12.3 and 9.8 Hz, 1H, CHHNO2),
3.23 (m, 1H, CHCH(CH3)2), 1.96 (m, 1H, CHCH(CH3)2), 1.00 (m, 3H,
CHCH3), 0.81 ppm (m, 3H, CHCH3); 13C NMR (CDCl3, 100.6 MHz):[11]
d=138.7, 128.6, 128.1, 127.4, 80.0, 51.0, 31.4, 20.6, 20.2 ppm; GC-
MS (EI) tR =17.68 min, m/z (%)=193 (1), 146 (60), 104 (100). Chiral
HPLC (Chiralcel OD column): hexane/iPrOH 95:5, 222 nm,
0.9 mLminÀ1; (R)-2d tR =6.12 min; (S)-2d tR =7.13 min.
(Chiralcel OD column): hexane/iPrOH 9:1, 222 nm, 0.6 mLminÀ1
;
(R)-2i tR =17.4 min; (S)-2i tR =29.1 min. The absolute configuration
of (+)-2i was assigned by converting it (0.100 g, 0.344 mmol) into
(R)-(À)-2-(4-iodophenyl)propanoic acid (0.082 g, 0.295 mmol, 86%)
by Meyer reaction (see paragraph “General procedure for the
Meyer reaction of the nitroalkane derivatives” hereafter reported):
½aŠ20 =À38.4 (c=1.80, CHCl3) (lit. ref. [29] ½aŠ20 = +40.8 (c=2.45,
(R)-1-Fluoro-4-(1-nitropropan-2-yl)benzene (2e): From (E)-1e
(0.590 g, 3.26 mmol) derivative (R)-2e was obtained (0.412 g,
D
D
CHCl3) for (S)-2-(4-iodophenyl)propanoic acid with ee=97%);
1H NMR (CDCl3, 400 MHz):[29] d=7.66 (d, J=8.5 Hz, 2H, ArH), 7.07
(d, J=8.5 Hz, 2H, ArH), 3.69 (q, J=6.7 Hz, CHCOOH), 1.50 ppm (d,
J=6.7 Hz, 3H, CH3C); GC-MS (EI) tR =20.18 min, m/z (%)=276 (70),
231 (100), 104 (54).
2.25 mmol, 69%): ee=99%, ½aŠ20 = +47.7 (c=1.0, CHCl3), lit.
D
ref. [20] for (R)-2e (ee=99%) [a]D = +48.4 (c=0.52, CHCl3, 308C);
1H NMR (CDCl3, 400 MHz):[20] d=7.30–7.15 (m, 2H, ArH), 7.04–6.95
(m, 2H, ArH), 4.48 (m, 2H, CH2NO2), 3.60 (m, 1H, CHCH3), 1.35 ppm
(d, J=7.0 Hz, 3H, CHCH3); 13C NMR (CDCl3, 100.6 MHz):[20] d=162.0
(d, J=245 Hz), 136.7, 128.5 (d, J=8.5 Hz), 115.6 (d, J=21.8 Hz),
81.7, 37.8, 18.7 ppm; GC-MS (EI) tR =14.82 min, m/z (%)=183 (M+,
2), 136 (100), 109 (95). Chiral HPLC (Chiralcel OD column): hexane/
iPrOH 9:1, 222 nm, 0.6 mLminÀ1; (R)-2e tR =11.4 min; (S)-2e tR =
11.9 min.
(R)-1-Methoxy-2-(1-nitropropan-2-yl)benzene (2j): From (E)-1j
(0.650 g, 3.40 mmol) derivative (R)-2j was obtained (0.380 g,
1.97 mmol, 58%): I=80%, ½aŠ20 = +5.7 (c1.0, CHCl3), lit. ref. [30] for
D
(R)-2j (ee=96%) ½aŠ20 = +6.4 (c=2.1, CHCl3); 1H NMR (CDCl3,
D
400 MHz):[30] d=7.30–7.20 (m, 1H, ArH), 7.15 (m, 1H, ArH), 7.00–
6.80 (m, 2H, ArH), 4.60 (dd, J=12.0 Hz, 6.7 Hz, 1H, CHHNO2), 4.46
(dd, J=12.0 Hz, 8.1 Hz, 1H, CHHNO2), 3.95 (m, 1H, CHCH3), 3.85 (s,
1H, CH3O), 1.37 ppm (d, J=7.1 Hz, 3H, CH3C); 13C NMR (CDCl3,
(R)-1-Chloro-2-(1-nitropropan-2-yl)benzene (2 f): From (E)-1 f
(0.750 g, 3.81 mmol) derivative (R)-2 f was obtained (0.167 g,
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Full Papers
100.6 MHz):[30] d=157.1, 128.8, 128.5, 127.7, 120.8, 110.9, 80.4, 55.3,
33.4, 17.1 ppm; GC-MS (EI) tR =18.61 min, m/z (%)=195 (M+, 30),
133 (94), 121 (93), 91 (100). Chiral HPLC (Chiralcel OD column):
hexane/iPrOH 98:2, 222 nm, 0.9 mLminÀ1; (R)-2j tR =11.0 min; (S)-
2j tR =12.6 min.
(CDCl3, 100.6 MHz):[32] d=179.8, 139.5, 128.5, 128.3, 127.0, 51.4,
35.4, 20.9, 13.8 ppm; GC-MS (EI) tR =18.05 min, m/z (%)=178 (M+,
5), 136 (33), 91 (100).
(R)-2-(4-Fluorophenyl)propanoic acid (3e): From (R)-2e (0.250 g,
1.37 mmol, ee=99%) derivative (R)-3e was obtained (0.273 g,
(R)-1-Methoxy-3-(1-nitropropan-2-yl)benzene (2k): From (E)-1k
(0.550 g, 2.84 mmol) derivative (R)-2k was obtained (0.283 g,
1.62 mmol, 84%): ½aŠ20 =À60.9 (c=1.0, CHCl3), lit. ref. [33] for (R)-
D
3e (ee=99%) [a]D =À61.5 (c=1.04, MeOH); 1H NMR (CDCl3,
400 MHz):[34] d=7.35–7.25 (m, 2H, ArH), 7.04–6.96 (m, 2H, ArH),
3.71 (m, 1H, CHCH3), 1.49 ppm (d, J=7.0 Hz, 3H, CHCH3); 13C NMR
(CDCl3, 100.6 MHz): d=180.1, 162.0 (d, J=245 Hz), 136.3 (d, J=
3 Hz), 129.1 (d, J=8.0 Hz), 115.3 (d, J=21 Hz), 44.7, 18.5 ppm; GC-
MS (EI) tR =14.73 min, m/z (%)=168 (M+, 22), 123 (100), 103 (52).
1.45 mmol, 51%): ee=80%, ½aŠ20 = +27.5 (c=1.0, CHCl3), lit.
D
ref. [20] for (R)-2k (ee=89%) ½aŠ20 = +30.9 (c=0.56, CHCl3);
D
1H NMR (CDCl3, 400 MHz):[20] d=7.25 (m, 2H, ArH), 6.90 (m, 1H,
ArH), 6.79 (m, 1H, ArH), 4.54 (dd, J=12.0 Hz, 7.0 Hz, 1H, CHHNO2),
4.46 (dd, J=12.0 Hz, 8.4 Hz, 1H, CHHNO2), 3.80 (s, 1H, CH3O), 3.60
(m, 1H, CHCH3), 1.37 ppm (d, J=7.0 Hz, 3H, CH3C); 13C NMR (CDCl3,
100.6 MHz):[20] d=160.2, 142.7, 132.1, 119.3, 113.3, 112.8, 82.0, 55.4,
38.8, 18.9 ppm; GC-MS (EI) tR =18.25 min, m/z (%)=195 (M+, 41),
148 (100), 121 (85). Chiral GC (Chirasil DEX CB column): 110 8C
(55 min)/908CminÀ1/1808C (2 min): (S)-2k tR =42.2 min, (R)-2k tR =
43.9 min.
General procedure for the one-pot reduction of the nitro
group to amine
The enantioselective reduction of the suitable nitroalkene was per-
formed on 50 mg scale in the presence of OYE3 as it has been al-
ready described for analytical scale biotransformations. The reac-
tion was monitored by GC–MS. When the reduction was complete,
NiCl2·6H2O (1 equiv.) and NaBH4 (3 equiv.) were added cautiously to
the reaction mixture under vigorous stirring. After 1 h, the mixture
was extracted with EtOAc (3”10 mL) and purified by column chro-
matography (n-hexane with increasing amount of EtOAc).
(R)-1-Methoxy-4-(1-nitropropan-2-yl)benzene (2l): From 1l (0.934 g,
4.84 mmol) derivative (R)-2l was obtained (0.689 g, 3.53 mmol,
73%): ee=97%, ½aŠ20 = +65.8 (c=0.5, CHCl3); lit. ref. [30] for (R)-2l
D
(ee=88%) ½aŠ20 = +60.5 (c1.2, CHCl3). H NMR (CDCl3, 400 MHz):[30]
1
D
d=7.13 (m, 2H, ArH), 6.86 (m, 2H, ArH), 4.46 (m, 2H, CH2NO2), 3.78
(s, 3H, CH3O), 3.58 (m, 1H, CH3CH), 1.35 ppm (d, J=7.0 Hz, 3H,
CH3CH); 13C NMR (CDCl3, 100.6 MHz):[30] d=159.0, 133.0, 127.9,
114.4, 82.1, 55.3, 37.9, 18.79 ppm; GC-MS (EI) tR =19.57 min, m/z
(%)=195 (M+, 15), 148 (100), 121 (71). Chiral GC (Chirasil DEX CB
column): 958C/0.808CminÀ1/1328C/508CminÀ1/1808C (2 min): (S)-
2l tR =40.9 min, (R)-2l tR =41.3 min.
(R)-2-Phenylbutan-1-amine (4b): From (R)-2b (0.050 g, 0.28 mmol,
ee=99%) derivative (R)-4b was obtained (0.031 g, 0.21 mmol,
74%): [a]D =À9.4 (c=1.0, Et2O), lit. ref. [35] for (S)-4b (optical
purity=94%) ½aŠ20 = +9.2 (c=1.0, Et2O). 1H NMR (CDCl3,
D
400 MHz):[36] d=7.35–7.10 (m, 5H, ArH), 2.85–2.80 (m, 2H, CH2NH2),
2.52 (m, 2H, CHPh), 1.65 (m, 1H, CHCH3), 1.52 (m, 1H, CHCH3),
0.80 ppm (t, J=7.4 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100.6 MHz):[36]
d=142.0, 128.8, 127.6, 126.5, 49.7, 46.5, 26.5, 11.6 ppm; GC-MS (EI)
tR =12.41 min, m/z (%)=149 (M+, 2), 118 (34), 91(100).
General procedure for the OYE mediated bioreduction (ana-
lytical scale)
A solution of the substrate in DMSO (10 mL, 500 mm) was added to
a potassium phosphate buffer solution (1.0 mL, 50 mm, pH 7.0)
containing glucose (20 mmol), NADP+ (0.1 mmol), GDH (4 U) and
the required purified OYE (80–120 mg). The mixture was incubated
for 24 h in an orbital shaker (160 rpm, 308C). The solution was ex-
tracted with EtOAc (2”250 mL), centrifuging after each extraction
(15000 g, 1.5 min), and the combined organic solutions were dried
over anhydrous Na2SO4. Two replicates were performed for each
biotransformation: no significant differences (less than 5%) were
observed for conversion and ee values.
(R)-2-(4-Methoxyphenyl)propan-1-amine (4l): From (R)-2l (0.050 g,
0.26 mmol, ee=97%), derivative (R)-4l was obtained (0.036 g,
2.2 mmol, 85%): ½aŠ20 = +11.7 (c=1.1, EtOH), Ref. [37] ½aŠ20 = +
D
D
10.0 (c=1.0, EtOH). 1H NMR (CDCl3, 400 MHz):[37] d=7.11 (m, 2H,
ArH), 6.85 (m, 2H, ArH), 3.78 (m, 2H, OCH3), 3.0–2.6 (m, 3H, CH+
CH2), 1.22 ppm (d, J=7.1 Hz, 3H, CH3C); 13C NMR (CDCl3,
100.6 MHz):[37] d=158.3, 137.1, 128.3, 114.2, 55.3, 49.5, 39.6,
19.5 ppm; GC-MS (EI) tR =16.64 min, m/z (%)=165 (M+, 4), 135
(100), 121 (23), 105 (30).
Keywords: biocatalysis · enantioselectivity · enzyme catalysis ·
reduction · substituent effects
General procedure for the Meyer reaction of the nitroalkane
derivatives[31]
The suitable (R)-nitroalkane derivative (R)-2a–l obtained by BY re-
duction (2.0 mmol), NaNO2 (6.0 mmol) and AcOH (1.0 mL) were dis-
solved in DMSO (3 mL). The resulting mixture was stirred at 358C
for 24 h, before being acidified with aqueous HCl (10%). The prod-
uct was then extracted with Et2O and the combined extracts dried
over Na2SO4 and concentrated under reduced pressure, to afford
the corresponding carboxylic acid derivative.
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Received: August 28, 2015
Published online on December 15, 2015
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