Highly efficient asymmetric bioreduction of 1-aryl-2-(azaaryl)ethanones. Chemoenzymatic synthesis of lanicemine

Article abstract of DOI:10.1039/c9ob01616c

Different ketoreductases (KREDs) have been used to promote a highly selective reduction of several 1-aryl-2-(azaaryl)ethanones (azaaryl = pyridinyl, quinolin-2-yl), the corresponding secondary alcohols being obtained with very high yields and enantiomeric excesses (ee > 99%). The absolute configuration of each optically active alcohol has been assigned by means of modified Mosher and Kelly methods, two shielding effects being evaluated: (1) the Mosher phenyl ring effect on the azaaryl protons and (2) the one of the azaaryl ring on the Mosher methoxy group. In addition, the biologically active amine lanicemine has been synthesized from (R)-1-phenyl-2-(pyridin-2-yl)ethanol, thus proving the utility of the secondary alcohols here prepared.

Full text of DOI:10.1039/c9ob01616c

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: R. Liz, E. Liardo
and F. Rebolledo-Vicente, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB01616C.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 8
View Article Online
DOI: 10.1039/C9OB01616C
ARTICLE
Highly efficient asymmetric bioreduction of 1-aryl-2-
(azaaryl)ethanones. Chemoenzymatic synthesis of lanicemine.
Ramón Liz,a Elisa Liardoa,b and Francisca Rebolledo*a
Received 00th January 20xx,
Accepted 00th January 20xx
Different ketoreductases (KREDs) have been used to promote
a highly selective reduction of several 1-aryl-2-
DOI: 10.1039/x0xx00000x
(azaaryl)ethanones (azaaryl = pyridinyl, quinolin-2-yl), the corresponding secondary alcohols being obtained with very high
yields and enantiomeric excesses (ee > 99%). The absolute configuration of each optically active alcohol has been assigned
by means of modified Mosher and Kelly methods, two shielding effects being evaluated: (1) the Mosher phenyl ring effect
on the azaaryl protons and (2) the one of the azaaryl ring on the Mosher methoxy group. In addition, the biologically active
amine lanicemine has been synthesized from (R)-1-phenyl-2-(pyridin-2-yl)ethanol, thus proving the utility of the secondary
alcohols here prepared.
Introduction
Several methods have previously been applied to the
synthesis of optically active 2a with varied efficiency.10 Whereas
Enantiopure alcohols are highly valuable compounds due to
their prevalent presence in natural products and to their utility
as building blocks in the synthesis of a wide range of
agrochemicals, flavours, fragrances, and pharmaceuticals.1 In
addition, those containing a pyridine group in their structure
have numerous applications as ligands in asymmetric metal
catalysis,2 as resolving agents3 or as starting materials for the
preparation of more advanced chiral ligands.4 Moreover, the
involvement of enantiopure pyridyl alcohols or their derivatives
in biologically active compounds5 is also of great interest. For
instance, optically active 1-phenyl-2-(pyridin-2-yl)ethanol 2a
(Scheme 1) has been used in the synthesis of sedamine,6 a
piperidine alkaloid7 being effective in the treatment of cognitive
disorders,8 and both piperidine and quinoline units are present
in the structure of the antimalarial drug mefloquine.9
some non-enzymatic kinetic resolution (KR) protocols were
applied to racemic 2a with moderate11 or low selectivity,12 the
porcine pancreatic lipase (PPL)-catalysed hydrolysis of its acetyl
derivative afforded the product (R)-2a with 40% degree of
conversion (C) and 96% of enantiomeric excess (ee).6b
Nevertheless, the KR methodology suffers of some limitations
such as the maximal theoretical 50% yield of the required
enantiomer and the need to carry out the separation of the
product and the remaining substrate. Dynamic kinetic
resolution (DKR) offers a noticeable improvement but, although
a lipase-mediated DKR has been applied to several 1,2-
diarylethanols analogues, no examples with azaaryl
substituents have been reported.13
Taking the easy accessibility of the ketone precursors into
account, a highly selective asymmetric reduction of the
prochiral carbonyl group would be desirable. For this purpose,
carbonyl reductases mediated reactions have many inherent
merits such as environmental compatibility, high
enantioselectivity, and mild reaction conditions.14 Regarding
this methodology, we have recently demonstrated the utility of
KREDs (from Codexis®) to catalyse the reduction of a series of
aryl methyl (or ethyl) ketones, some of them bearing a sterically
bulky aryl moiety. For this reason, we thought it would be
interesting to test the potential of these KREDs to promote the
reduction of 1-aryl-2-(azaaryl)ethanones 1 in which a pyridine
or quinoline ring is present. It is of note that the attempts to
enantioselectively reduce substrate 1a with Baker’s yeast were
unsuccessful.15
OH
OH
N
N
Me
(R)-2a
(+)-Sedamine
Scheme 1
a. Departamento de Química Orgánica e Inorgánica and Instituto Universitario de
Biotecnología de Asturias, Universidad de Oviedo, 33006-Oviedo (Asturias), Spain.
E-mail: frv@uniovi.es; Tel: +34 985 102982.
b. Current address: EVOTEC, Center of Drug Discovery and Development, 37135,
Verona, Italy.
† Electronic Supplementary Information (ESI) available: General experimental
procedures, chiral HPLC chromatograms, and NMR spectra. See
DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 8
ARTICLE
Journal Name
Table 1 (S)-Selective KRED-catalyzed bioreductions of ketones 1.[a]
Results and discussion
View Article Online
DOI: 10.1039/C9OB01616C
A series of ketones 1a-f (Figure 1) were prepared in high yields
by treatment of pyridinylmethyl- or quinolin-2-ylmethyllithium
with the appropriate N,N-diethylarenecarboxamide.16 Although
these ketones have been presented in their keto forms in Figure
1, the 1H-NMR spectra (CDCl3) of all these compounds revealed
the presence of the enol or enaminone forms in different
percentages. Thus, the enol form was present in a 13-37% for
1a-c and less of 5% for 1d and 1e. However, for the quinoline
derivative 1f only 3% of keto structure was observed, the major
component (97%) being not the enol but the enaminone
tautomer17 (Scheme S1†).
The bioreduction of each compound 1a-f was tested using
ketoreductases from the Codexis® KRED Screening Kit and
employing 17.5% v/v of isopropyl alcohol (IPA) for cofactor
recycling and as a co-solvent. The screenings were performed
under the standard conditions at pH 7.0 and a detailed
collection of the results is included in Tables S1-S6 (ESI†). Here,
separated in two tables for (S)- (Table 1) and (R)-selective
bioreductions (Table 2), we have included a selection of the
most significant results, that is, those of the reactions in which
both the degree of conversion (C) and enantiomeric excess (ee)
obtained were higher than 90%. For ketones 1a,b,d,e both
enantiomers of the corresponding alcohol 2 can be achieved by
choosing the adequate KRED, the R enantiomer being obtained
in all the cases with KRED-P2-G03. In general, 3- and 4-pyridinyl
derivatives were the best substrates for the KREDs collection as
a whole. Satisfactory results in the bioreductions of 1c and 1f
were only achieved for one enantiomer (R and S, respectively)
and, although several KREDs shown a moderate or very high
efficacy in the reduction of 1c (Table 2, entries 3 and 4; Table
S3†), only KRED-P1-B02 was efficient to enantioselectively
reduce 1f (Table 1, entry 12; Table S6†).
O
OH
AzaAr
AzaAr
KRED
R
R
1a-f
(S)-2a,b,d,e,f
NADPH + H+ NADP+
O
OH
Ketone
R
AzaAr[b] KRED[c] Alcohol[d] ee (%)[e]
Entry
1
2
3
4
5
6
7
8
9
1a
1a
1b
1d
1d
1d
1d
1e
1e
1e
1e
1f
H
H
F
2-Py
2-Py
2-Py
3-Py
3-Py
3-Py
3-Py
4-Py
4-Py
4-Py
4-Py
2-Q
P1-B10
P1-B12
P1-B12
P1-B02
P1-B10
P1-B12
P2-D11
P1-B02
P1-B10
P1-B12
P2-D11
P1-B02
(S)-2a
(S)-2a
(S)-2b
(S)-2d
(S)-2d
(S)-2d
(S)-2d
(S)-2e
(S)-2e
(S)-2e
(S)-2e
(S)-2f
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
H
H
H
H
H
H
H
H
H
10
11
12
>99
a Reactions were carried out in 125 mM phosphate buffer pH 7.0 (also containing
1.25 mM MgSO4) using the corresponding ketone 1 (11 mol, 20 mM), KRED (2
mg), NADP+ (1.0 mM), and propan-2-ol (17.5% v/v) as described in ESI†. Py =
pyridinyl; 2-Q = quinolin-2-yl. KRED identified according to the nomenclature of
the Screening Kit of Codexis. Degree of conversion (C) higher than 99% were
obtained in all the cases except in entry 3 (C = 95%). e The ee was determined by
b
c
d
HPLC (see ESI† for details).
Assignment of the absolute configurations
The R assignment for (+)-2a has previously been made by
chemical correlation with (+)-sedamine.6a An identical
assignment (R)-(+) was proposed for optically active 2c,f by
Once checked the activity of KREDs, preparative
bioreductions of 1 were carried out at 20-50 mM substrate
concentration and with significant lowering of the KRED/ketone
ratio. Thus, the amount of KRED of the screening was lowered
to 25%, enough to totally convert the corresponding ketone (at
a 20 mM concentration) into the optically active alcohol (ee ≥
98%). In all the cases, alcohols were isolated with very high
Table 2 (R)-Selective KRED-catalyzed bioreductions of ketones 1.[a]
O
OH
AzaAr
AzaAr
KRED
yields (90–95%) after
chromatography (CC).
a
simple purification by column
R
R
1a-f
(R)-2a-e
NADPH + H+ NADP+
O
OH
N
O
N
O
Ketone
R
AzaAr
KRED
Alcohol[b] ee (%)[c]
Entry
1a-c
R: H (a); F (b); OMe (c)
1d
1
2
3
4
5
6
1a
1b
1c
1c
1d
1e
H
F
OMe
OMe
H
2-Py
2-Py
2-Py
2-Py
3-Py
4-Py
P2-G03
P2-G03
P2-C02
P2-G03
P2-G03
P2-G03
(R)-2a
(R)-2b
(R)-2c
(R)-2c
(R)-2d
(R)-2e
>99
>99
>99
>99
94
R
O
N
O
N
H
91
1f
1e
a
b
Reactions conditions as indicated in Table 1. Degree of conversion (C) higher
than 99% were obtained in all the cases. The ee was determined by HPLC (see
ESI† for details).
c
Figure 1 1-Aryl-2-(azaaryl)ethanones 1a-f of this study.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
analogy with 2a, after having carried out the KR of racemic
2a,c,f by means of a dehydrogenative Si-O coupling with an
identical silicon-stereogenic silane.18 However, perhaps due to
a misprint, the assignment (R)-(–) was also proposed for
optically active 2f, when this alcohol was produced by a similar
KR using an achiral silane and an optically active ligand.19
In our case, the specific rotation of 2a [obtained with KRED-
P2-G03, Table 1, entry 3; []D20 = +37.1 (c 0.73, CHCl3)] allowed
us to assign the R configuration to this alcohol,6a and therefore
to know the selectivity of all the active KREDs towards the
ketone 1a. Thus, by assuming that each specific KRED shows the
same stereopreference towards all the tested ketones 1, the
absolute configuration of the other optically active alcohols 2b-f
could also tentatively be assigned. However, the diverse aryl
rings of 1a-c, the different nitrogen location in the pyridine rings
of 1d,e, and the structurally different quinoline heterocycle
present in 1f could alter the accommodation of the ketone
substrates 1 in the active site of the KRED, and could originate
changes in the enzyme stereopreference. In fact, such
inversions of stereopreference have been observed in the
bioreductions carried out with some of the KREDs (ESI†), the
most significant being the results attained with KRED-P1-B05.
This enzyme catalysed the formation of (S)-2a,d,e (all bearing a
phenyl substituent) with C and ee up to >99% and 98%,
respectively (Tables S1, S4, and S5†), but it promoted the
formation of (R)-1b,c with similar high C and ee values (Tables
S2 and S3†).
As a consequence, we took the decision to search for an
unambiguous absolute configuration assignment of 2b-f. For it,
we decided to apply modified versions of the known methods
of Mosher20 and Kelly21 to the (R)-MTPA ester derivatives of the
alcohols 2. Related to the Mosher’s method, and since the
absolute configuration of 2a is unambiguously known,6a we
chose this alcohol to test the validity of our methodology.
Racemic alcohol ()-2a, prepared by NaBH4 reduction of 1a, was
treated with (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl
chloride [(S)-MTPA-Cl], and the resulting diastereomeric
mixture of (R)-MTPA ester derivatives 3a (Figure 2) analysed by
1H-NMR.
In the Mosher method, the so-called working models for the
MTPA-esters [as those shown in figure 2 for the diastereomeric
esters (R,R)- an (R,S)- 3a] are analysed in the light of the well-
known global shielding effect that the phenyl group belonging
to the acyl region of the ester exerts on the syn-placed aliphatic
protons of the alcohol moiety. 22 Thus, analysing the  values for
the signals of the protons in adjacent carbons to the chiral
centre in both diastereomeric esters, the configuration of the
alcohol is established. For the diastereomeric mixture 3a, these
syn-positioned aliphatic protons correspond to the CH2
grouping, whose diastereotopicity leads to overlapped signals
that advises against their use for this purpose. However, the
most deshielded pyridine proton (i. e., HPy-6) of both Mosher
esters (R,R)- and (R,S)-3a resonate in a clean region of the
spectrum and they appear as two well separated signals at 8.53
and 8.61 ppm (Figure 2). Taking the mentioned shielding effect
of the phenyl group into account, the lowest  value (8.53 ppm)
has to be assigned to (R,R)-3a, with the syn-placed HPy-6.
View Article Online
DOI: 10.1039/C9OB01616C
8.61
N
3.30
3.23
Ph OMe
Ph OMe
Ph
O
O
N
Ph
F3C
F3C
R
R
8.53
R
S
O
H
O
H
(R,R)-3a
(R,S)-3a
1
Figure 2 Working models of the diastereomeric (R)-MTPA esters 3a and H-NMR
chemical shift (, ppm) of some selected signals.
Effectively, when the enantiopure alcohol (R)-2a was treated
with (S)-MTPA-Cl and the resulting MTPA ester (R,R)-3a was
analysed by 1H-NMR, only the signal at 8.53 ppm was observed.
This fact proves that our proposed modification of the Mosher
method works well for assigning the previously reported
absolute configuration of 2a,6a and that this rationale could be
applied to the other alcohols provided that two well separated
groups of signals are observed in their spectra.
1
As expected, very similar H-NMR spectra to those of 3a
were obtained for the MTPA esters 3b,c derived from the other
2-Py alcohols 2b,c, so that analogous analyses also allowed us
to assign their absolute configurations (section 7, ESI†). In
addition, the absolute configuration of the 4-Py alcohol 2e was
assigned by focusing on the equivalent, most deshielded HPy-2
and -6 protons: two well resolved signals at 8.39 and 8.51 ppm
1
were observed in the H-NMR spectrum of the diastereomeric
mixture of esters 3e, the former being assigned to (R,R)-3e. For
the MTPA ester derivatives 3d,f (Figure 3), a partial overlapping
was observed for some azaaryl signals in the 1H-NMR spectrum
of the diastereomeric mixtures. However, a series of selective-
1D TOCSY experiments allowed us to distinguish and assign the
signals of all the protons of the pyridine ring in the derivative
3d, as well as three out of the six quinoline protons for 3f.
Comparison of the two set of signals newly enabled us to assign
the lower  set to the (R,R) diastereomer.
After this study, the most important result is that the azaaryl
protons of all the (R,R)-MTPA esters are more shielded than
those of their (R,S)-counterparts, thus validating our method for
establishing the absolute configurations of all the alcohols 2.
Regarding the Kelly’s method,21 which focusses on the
shielding effect that suffers the methoxy group of the MTPA
ester by a syn-placed aryl group of the alcohol region, an
inspection of Figures 2 and 3 reveals that its application to our
alcohols could be conflictive, since in all cases two aromatic
rings, aryl and azaaryl, are present in the alcohol region.
Nevertheless, the analysis of the OMe values collected in the
Figures 2 and 3, as well as the inspection of these OMe values
for 3b,c,e (ESI†), indicate that the shielding effect of the
azaarylmethyl substituent is higher than the one exerted by the
aryl ring. This trend, common for all these derivatives,
represents an additional confirmation of our absolute
configuration assignment and, subject to further experimental
data, could be used for other complicated assignments.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 8
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C9OB01616C
8.50
OMs
N
7.20
N
MsCl / NEt3
THF, -15 ºC to RT
NaN3
(R)-2a
3.35
Ph OMe
3.30
Ph OMe
7.48
DMF, 70 ºC
8.42
(R)-4
Ph
8.26
7.09
O
O
Ph
F3C
F3C
R
R
S
R
N
NHR
N
O
H
O
H
N3
N
8.44
7.31
H2 / Pd-C
HCl
(R,R)-3d
(R,S)-3d
(S)-6 2 HCl
MeOH
MeOH, RT
(S)-5
(Boc)2O
MeOH
(S)-6 (R = H, Lanicemine)
(S)-7 (R = Boc)
8.12
8.04
7.24
N
Scheme 2 Synthesis of lanicemine 6 from (R)-2a.
3.30
Ph OMe
3.20
Ph OMe
Ph
8.07
O
O
as the only reaction product in very high yield, different reaction
conditions were checked by the following reaction with NaN3.
Thus, when the process was carried out at 40 °C in N,N-
dimethylformamide (DMF) as solvent, equimolar amounts of
azide 5 and 2-(2-phenylethenyl)pyridine [Ph-CH=CH-(2-Py),
which proceeded from a competitive elimination reaction] was
formed. Moreover, the azidolysis reaction was accompanied by
a high degree of racemization, judged by the low ee (34%) of the
obtained azide 5. This means that both bi- and unimolecular
mechanisms are acting in the substitution process.
Furthermore, the alkene is likely to mainly be produced by the
unimolecular mechanism taking the poor basicity of the anion
azide into account. When the temperature was increased to 52
°C, the amount of alkene diminished and the azide 5 was
isolated with 89% ee, higher than in the previous experiment
but still with a significant loss of ee. Keeping in mind that the
higher temperature is favouring the bimolecular mechanism,
the azidolysis was finally conducted at 70 °C. Under these
conditions a low amount (5%) of alkene continued appearing,
but the azide (S)-5 was isolated with a high 97% ee and 88% yield
after purification by CC, consequently demonstrating the
efficacy of this process.
Reduction of the azide group in (S)-5 was also checked under
different conditions. The Staudinger protocol with PPh3 was
unsuccessful. The reduction with LiAlH4 proceeded smoothly at
room temperature, the reaction crude consisting of the amine
(S)-6 with a very small amount of impurities. Finally, the best
results were obtained by hydrogenation with H2 and Pd/C as
catalyst, which led to lanicemine in 98% yield. The subsequent
treatment with HCl in methanol gave the lanicemine
dihydrochloride (S)-6 · 2 HCl, which can be recrystallized from a
methanol-ethyl acetate mixture. As the synthesis of the N-Boc
derivative is necessary to analyse the ee of both its amine
precursor and the azide, the crude lanicemine was also
converted into the N-Boc derivative (S)-7, which was isolated
with very high yield (90%, after CC purification) and 97% ee.
The same protocol was also applied to the synthesis of (R)-6
and (R)-7 (ee = 97%) starting from enantiopure (S)-2a.
N
Ph
F3C
F3C
R
R
S
R
O
H
O
H
7.10
7.90
(R,R)-3f
(R,S)-3f
Figure 3 Diastereomeric (R)-MTPA esters 3d and 3f and chemical shift (, ppm) of
some selected signals.
Finally, by comparing the above results with the information
contained in Table 1, it is concluded that most of the highly
efficient KREDs showed the same stereopreference towards all
the ketone substrates 1, which also reinforces our strategy for
the absolute configuration assignment of alcohols 2.
Chemoenzymatic synthesis of lanicemine
In addition to the already mentioned utility of this kind of
optically active alcohols in the synthesis of the biologically
active sedamine or other piperidine alkaloids, they also can be
useful precursors of their amine analogues by applying a very
simple strategy (vide infra). In order to prove the viability of this
transformation, we have planned the synthesis of lanicemine
[(S)-6, Scheme 2] from the optically active (R)-1-phenyl-2-
(pyridin-2-yl)ethanol, (R)-2a. Lanicemine (AZD-6765) is a low-
trapping N-methyl-D-aspartate receptor (NMDAR) antagonist
with clinical relevance in a range of therapeutic areas including
pain management, epilepsy, neurodegenerative disease and
depression.23
The strategy, indicated in Scheme 2, consisted of three
steps: (1) mesylation of the optically active alcohol (R)-2a (ee >
99%); (2) SN2 displacement of the mesylate group in (R)-4 with
sodium azide; and (3) reduction of the azide (S)-5. In addition,
to facilitate the storage of lanicemine, it could be converted into
its dihydrochloride salt [(S)-6 · 2 HCl] or, by means of tert-
butoxycarbonylation, into its N-Boc derivative (S)-7. The first
step –mesylation of 2a– was carried out with mesyl chloride
starting at 15 C and allowing the reaction to reach the room
temperature very slowly (12 h). This temperature control was
necessary to avoid the formation of 2-(2-chloro-2-
phenylethyl)pyridine as a side product. This chlorinated
derivative was observed when the reaction started at room
temperature. As this compound is formed from 4 by a
nucleophilic substitution reaction with anion chloride, its
presence in the reaction crude and the subsequent treatment
with NaN3 would lead to an azide compound 5 with a lowered
enantiomeric excess. Once mesyl derivative (R)-4 was isolated
Experimental
General experimental procedures (synthesis of ketones,
racemic samples, and Mosher’s ester derivatives) and
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
screenings for the enzymatic bioreductions are described in flash chromatography; 18.4 mg, 80.1 μmol). M.p. = 1V2i4ew.6A-r1ti2cl6e.O4nlinCe.
20
20
ESI† along with copies of the chiral HPLC chromatograms and [α]D = +18.6 (c 1.2, CHCl3), ee > 99% [lit.,18b [α]D = +13.4 (c 0.38,
DOI: 10.1039/C9OB01616C
NMR spectra.
CHCl3), ee = 92%]. 1H NMR (CDCl3, 300.13 MHz) δ (ppm): 8.51 (br d, J
= 4.7 Hz, 1H, HPy-6), 7.61 [dt, J = 1.9 (d) and 7.7 (t) Hz, 1H, HPy-4], 7.33
(d, J = 8.6 Hz, 2H), 7.17 (bdd, J = 5.2 and 7.0 Hz, 1H, HPy-5), 7.10 (d, J
= 7.7 Hz, 1H, HPy-3), 6.87 (d, J = 8.6 Hz, 2H), 5.4-4.6 (br s, 1H, OH),
5.11 (dd, J = 3.6 and 8.7 Hz, 1H, H-1), 3.22-3.02 (AB signals of an ABX
system, 3JA,X = 3.6, 3JB,X = 8.7, and 2JA,B = 14.9 Hz, 2H, CH2). 13C NMR
(CDCl3, 75.5 MHz) δ (ppm): 159.6 (C), 158.7 (C), 148.3 (CH), 136.8
(CH), 136.2 (C), 126.9 (CH), 123.8 (CH), 121.6 (CH), 113.6 (CH), 72.8
(CH), 55.2 (CH3), 45.7 (CH2). These NMR data are in agreement with
literature data.19
General procedure for the preparative
bioreduction of ketones 1
Reactions were carried out in 5 or 10 mL glass vials which were
initially charged with 20.0 mg of the corresponding ketone 1. Then
propan-2-ol (17.5% v/v), DMSO (if necessary to completely dissolve
1, up to a maximum of 3.5% v/v), 125 mM phosphate buffer at pH
7.0 (containing 1.25 mM MgSO4), the corresponding KRED (20 mg)
and the cofactor NADP+ (1 mM) were added to achieve a final 20 –
50 mM concentration of 1. The reaction mixture was incubated (S)-1-Phenyl-2-(pyridin-3-yl)ethanol (2d). [This compound was not
during 24 h (96 h for 1f) at 30°C and 250 rpm. After this time, the described as optically active in the literature]. The reaction was
mixture was extracted with ethyl acetate (4 × 4 mL), the organic carried out with 50 mM 1d, without DMSO and with KRED-P2-D11.
layers were separated by centrifugation (5 min, 4700 rpm) after each 2d was obtained as a white solid with 90% yield (after flash
20
extraction, combined, washed with brine (8 mL) and finally dried over chromatography; 18.2 mg, 91.3 μmol). M.p. = 123.7-125.1 C. [α]D
1
anh. Na2SO4. Evaporation of the solvent yielded the crude alcohol = –13.8 (c 0.85, CHCl3), ee > 99%. H NMR (CDCl3, 300.13 MHz) δ
which was purified by flash column chromatography (hexane-ethyl (ppm): 8.30 (br d, J = 4.9 Hz, 1H, HPy-6), 8.26 (br s, 1H, HPy-2), 7.43 [dt,
acetate as eluent). By this procedure the following optically active J = 2.0 (t) and 7.9 (d) Hz, 1H, HPy-4], 7.38-7.20 (m, 5H), 7.13 (dd, J =
alcohols 2 were obtained:24
4.9 and 7.9 Hz, 1H, HPy-5), 4.85 (dd, J = 5.6 and 7.5 Hz, 1H, H-1), 3.5-
3.0 (br s, 1H, OH), 3.06-2.90 (AB signals of an ABX system, 3JA,X = 5.6,
(R)-1-Phenyl-2-(pyridin-2-yl)ethanol (2a). The reaction was carried
out with 50 mM 1a, without DMSO and with KRED-P2-G03. 2a was
obtained as a white crystalline solid with 95% yield (after flash
chromatography; 19.2 mg, 96.3 μmol). M.p. = 131.6-133.0 C (lit.,6a
122-124 C). [α]D20 = +38.1 (c 0.72, CHCl3), ee > 99% [lit.,6a [α]D20 = +42
(c 1, CHCl3), ee > 96%; lit.,19 [α]D20 = +25.6 (c 0.65, CHCl3), ee = 88%].
1
3JB,X = 7.5, and 2JA,B = 13.8 Hz, 2H, CH2). These H-NMR data are in
agreement with literature data26 for the racemic compound. 13C
NMR (CDCl3, 75.5 MHz) δ (ppm): 150.3 (CH), 147.3 (CH), 143.6 (C),
137.4 (CH), 133.9 (C), 128.4 (CH), 127.7 (CH), 125.8 (CH), 123.1 (CH),
74.7 (CH), 42.8 (CH2).
1H NMR (CDCl3, 300.13 MHz) δ (ppm): 8.54 (ddd, J = 0.9, 1.6, and 5.1 (S)-1-Phenyl-2-(pyridin-4-yl)ethanol (2e). [This compound was not
Hz, 1H, HPy-6), 7.63 [dt, J = 1.6 (d) and 7.7 (t) Hz, 1H, HPy-4], 7.47-7.16 described as optically active in the literature]. The reaction was
(several m, 6H), 7.11 (d, J = 7.7 Hz, 1H, HPy-3), 5.17 (dd, J = 4.6 and carried out with 50 mM 1e, without DMSO and with KRED-P1-B12.
7.5 Hz, 1H, H-1), 5.0-4.2 (br s, 1H, OH), 3.22-3.07 (m, AB signals of an 2e was obtained as a white solid with 90% yield (after flash
20
ABX system, 2H, CH2). 13C NMR (CDCl3, 75.5 MHz) δ (ppm): 159.5 (C), chromatography; 18.3 mg, 91.3 μmol). M.p. = 107.8-109.5 C. [α]D
1
148.4 (CH), 143.9 (C), 136.7 (CH), 128.2 (CH), 127.1 (CH), 125.7 (CH), = –16.1 (c 0.83, CHCl3), ee > 99%. H NMR (CDCl3, 300.13 MHz) δ
123.7 (CH), 121.6 (CH), 73.2 (CH), 45.6 (CH2). These NMR data are in (ppm): 8.29 (br d, 2H, HPy-2/6), 7.39-7.20 (m, 5H) 7.06 (d, J = 5.5 Hz,
agreement with literature data.18b
2H, HPy-3/5), 4.90 (dd, J = 5.3 and 7.7 Hz, 1H, H-1), 3.61 (br s, 1H, OH),
3.09-2.89 (AB signals of an ABX system, 3JA,X = 5.3, 3JB,X = 7.7, and 2JA,B
= 13.5 Hz, 2H, CH2). 13C NMR (CDCl3, 75.5 MHz) δ (ppm): 148.9 (CH),
147.8 (C), 143.6 (C), 128.4 (CH), 127.7 (CH), 125.8 (CH), 125.0 (CH),
74.1 (CH), 45.1 (CH2). These 1H- and 13C-NMR data are in agreement
with literature data for the racemic compound.27

(R)-1-(4-Fluorophenyl)-2-(pyridin-2-yl)ethanol
(2b).
[This
compound was not described as optically active in the literature].
The reaction was carried out with 30 mM 1b, with DMSO (1.75% v/v)
and with KRED-P2-G03. 2b was obtained as a white crystalline solid
with 92% yield (after flash chromatography; 18.6 mg, 85.5 μmol).
20
1
M.p. = 142.8-144.5 C. [α]D = +40.1 (c 0.95, CHCl3), ee > 99%. H (S)-1-Phenyl-2-(quinolin-2-yl)ethanol (2f). The reaction was carried
NMR (CDCl3, 300.13 MHz) δ (ppm): 8.52 (br d, J = 4.9 Hz, 1H, HPy-6), out with 20 mM 1f, with DMSO (3.5% v/v) and with KRED-P1-B02. 2f
7.63 [dt, J = 1.8 (d) and 7.5 (t) Hz, 1H, HPy-4], 7.38 (m, 2H), 7.20 (dd, J was obtained as
a yelow solid with 91% yield (after flash
= 5.3 and 7.5 Hz, 1H, HPy-5), 7.10 (d, J = 7.8 Hz, 1H, HPy-3), 5.4-4.6 (br chromatography; 18.3 mg, 73.6 μmol). M.p. = 122.1-123.7 C (lit.,18b
s, 1H, OH), 5.14 (dd, J = 4.6 and 7.5 Hz, 1H, H-1), 3.22-3.00 (m, AB 115-117 C for a sample with ee = 82%). [α]D20 = –79.4 (c 0.90, CHCl3),
signals of an ABX system, 2H, CH2). These 1H-NMR data are in ee > 99% [lit.,18b [α]D = –59.0 (c 0.99, CHCl3), ee = 82%]. H NMR
20
1
agreement with literature data25 for the racemic compound.13C NMR (CDCl3, 300.13 MHz) δ (ppm): 8.13-8.05 [two partially overlapped
1
(CDCl3, 75.5 MHz) δ (ppm): 161.9 (d, JC,F = 244,5 Hz, C), 159.3 (C), doublets centered at 8.10 (J = 8.3 Hz) and 8.08 (J = 8.5 Hz) ppm, 2H],
148.3 (CH), 139.7 (d, 4JC,F = 3.0 Hz, CH), 137.0 (CH), 127.4 (d, 3JC,F = 8.1 7.81 (br d, J = 8.1 Hz, 1H), 7.73 (dd, J = 1.4, 6.9, and 8.4 Hz, 1H), 7.58-
2
Hz, CH), 123.8 (CH), 121.8 (CH), 115.0 (d, JC,F = 21.1 Hz, CH), 72.6 7.45 (several m, 3H), 7.42-7.25 (several m, 3H), 6.20 (br s, 1H, OH),
(CH), 45.5 (CH2).
5.34 (dd, J = 4.5 and 7.7 Hz, 1H, H-1), 3.41-3.25 (m, AB signals of an
ABX system, 2H, CH2). 13C NMR (CDCl3, 75.5 MHz) δ (ppm): 160.4 (C),
146.8 (C), 143.8 (C), 136.8 (CH), 129.8 (CH), 128.5 (CH), 128.3 (CH),
127.5 (CH), 127.2 (CH), 126.8 (C), 126.2 (CH), 125.8 (CH), 122.0 (CH),
(R)-1-(4-Methoxyphenyl)-2-(pyridin-2-yl)ethanol (2c). The reaction
was carried out with 20 mM 1c, without DMSO and with KRED-P2-
G03. 2c was obtained as a white crystalline solid with 91% yield (after
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 8
ARTICLE
Journal Name
72.9 (CH), 46.0 (CH2). These 1H- and 13C-NMR data are in agreement dihydrochloride salt, (S)-6 · 2HCl, can be recrystallyzed from a
View Article Online
1
with literature data.18b
mixture of methanol-ethyl acetate; m.p. 200.4-202.5 °C (dec.);
H
DOI: 10.1039/C9OB01616C
NMR (MeOH-d4, 300.13 MHz) δ (ppm): 8.75 (ddd, J = 0.8, 1.6, and 5.8
Hz, 1H, HPy-6), 8.50 [dt, J = 1.6 (d) and 7.9 (t) Hz, 1H, HPy-4], 8.00-7.90
(S)-2-(2-Azido-2-phenylethyl)pyridine 5
(m, 2H, HPy-5 and HPy-3), 7.55-7.38 (m, 5H, Ph), 4.98 (dd, J = 6.3 and
A solution of alcohol (R)-2a (54.0 mg, 0.271 mmol, ee > 99%) and
triethylamine (100 L, 0.72 mmol) in anhydrous THF (1.0 mL) was
treated with mesyl chloride (41.9 L, 0.542 mmol) at 15 C and the
reaction was allowed to slowly reach room temperature. After 12 h,
ethyl acetate was added and the organic solution was successively
washed with saturated aq. NaHCO3 and water. After drying the
organic layer on anh. Na2SO4, the solvent was eliminated and the
crude consisting of the mesyl derivative (R)-4 (such it was deduced
3
9.7 Hz, 1H, H-1), 3.98 and 3.78 (AB signals of an ABX system, JA,X
=
6.3, 3JB,X = 9.7, and 2JA,B = 14.3 Hz, 2H, CH2). These 1H-NMR data are
in agreement with literature29 data. 13C NMR (MeOH-d4, 75.5 MHz) δ
(ppm): 152.3 (C), 148.1 (CH), 143.3 (CH), 135.9 (C), 131.1 (CH), 130.7
(CH), 129.8 (CH), 128.6 (CH), 127.3 (CH), 55.6 (CH), 39.0 (CH2).
tert-Butyl [(S)-1-phenyl-2-(pyridin-2-yl)ethyl]carbamate (S)-7
from its 1H NMR spectrum) was used in the next step without To a solution of crude lanicemine (S)-6 (20.0 mg, 0.101 mmol) in
purification. Thus, the crude (R)-4 was dissolved in anh. DMF (1.1 mL) methanol (1.0 mL), di-tert-butyl dicarbonate (44 mg, 0.20 mmol) was
and NaN3 (88 mg, 1.35 mmol) was added. The mixture was heated at added. The mixture was maintained at room temperature during 4 h.
70 C during 5 h (TLC control, hexane:ethyl acetate 3:1; Rf for the Then, solvents were removed and the residue subjected to flash
azide, 0.26). Then, ethyl acetate and water were added, the organic column chromatography (hexane:ethyl acetate 5:1) to give pure (S)-
20
phase was separated and the aqueous layer extracted with ethyl 7 (27 mg, 90% yield) as a white solid. M.p. = 133.2-134.8 C. [α]D
=
acetate (2 × 6 mL). The joined organic layers were washed with water –49.8 (c 1.1, CHCl3), ee = 97%. 1H NMR (CDCl3, 300.13 MHz) δ (ppm):
and dried on anh. Na2SO4. Evaporation of the solvent yielded the 8.53 (br d, J = 4.6 Hz, 1H, HPy-6), 7.50 [dt, J = 1.8 (d) and 7.7 (t) Hz, 1H,
azide (S)-5 which was purified by flash column chromatography HPy-4], 7.33-7.15 (m, 5H, Ph), 7.11 (ddd, J = 1.0, 5.0, and 7.6 Hz, 1H,
(hexane:ethyl acetate 9:1). Light yellow oil (53,5 mg, 88% yield); HPy-5), 6.94 (br d, J = 7.8 Hz, 1H, HPy-3), 5.98 (br s, 1H, NH), 5.08 (br s,
[α]D20 = 94.4 (c 1.8, CHCl3), ee = 97%. 1H NMR (CDCl3, 300.13 MHz) 1H, H-1), 3.38-3.00 (m, 2H, CH2), 1.35 (s, 9H). 13C NMR (CDCl3, 75.5
δ (ppm): 8.59 (ddd, J = 0.9, 1.9, and 4.9 Hz, 1H, HPy-6), 7.57 [dt, J = 1.9 MHz) δ (ppm): 158.0 (C), 155.1 (C), 148.9 (CH), 142.2 (C), 136.3 (CH),
(d) and 7.7 (t) Hz, 1H, HPy-4], 7.43-7.23 (m, 5H, Ph), 7.15 (ddd, J = 1.2, 128.2 (CH), 126.9 (CH), 126.0 (CH), 123.9 (CH), 121.5 (CH), 79.2 (C),
4.9, and 7.6 Hz, 1H, HPy-5), 7.09 (dt, J = 1.1 (t), 7.8 (d) Hz, 1H, HPy-3), 54.8 (CH), 44.6 (CH2), 28.2 (CH3). HRMS-ESI+ calcd. for [C18H23N2O2]+
5.09 (dd, J = 5.9 and 8.8 Hz, 1H, H-1), 3.28-3.12 (AB signals of an ABX (M+H)+ 299.1754 m/z, found 299.1758.
system, 3JA,X = 5.9, 3JB,X = 8.8, and 2JA,B = 13.8 Hz, 2H, CH2). 13C NMR
(CDCl3, 75.5 MHz) δ (ppm): 157.4 (C), 149.3 (CH), 139.3 (C), 136.3
(CH), 128.7 (CH), 128.2 (CH), 126.7 (CH), 124.1 (CH), 121.7 (CH), 65.8
(CH), 45.1 (CH2). HRMS-ESI+ calcd. for [C13H13N4]+ (M+H)+ 225.1135
Conclusions
The utility of several commercially available ketoreductases has
m/z, found 225.1137.
been proved in the asymmetric reduction of different prochiral
aromatic ketones which also bear an (azaryl)methyl grouping.
In most of the cases, (R)- and (S)-selective KREDs were found,
thus allowing the preparation of both enantiomers of the
alcohol with ee > 99%. The assignment of the absolute
configuration of each optically active secondary alcohol here
prepared has been established using modified Mosher and Kelly
methods. These findings could be applied in the absolute
configuration assignment of other more complex alcohols.
Finally, as a proof of the usefulness of this kind of compounds,
one of them has been transformed into the biologically active
lanicemine by means of a very simple and efficient strategy.
(S)-1-phenyl-2-(pyridin-2-yl)ethanamine (S)-6 and its dihydro-
chloride salt (S)-6·2HCl
To a solution of (S)-5 (52,0 mg, 0.232 mmol) in methanol (9.0 mL),
palladium on carbon (Pd/C, 45 mg, 10% w/w) was added and the
reaction mixture was stirred under a H2 atmosphere at room
temperature for 45 min. Then, the suspension was filtered through a
celite® pad. The organic solution was concentrated to give the crude
lanicemine, (S)-6 (45 mg, 98% yield); 1H NMR (CDCl3, 300.13 MHz) δ
(ppm): 8.58 (ddd, J = 0.9, 1.7, and 4.9 Hz, 1H, HPy-6), 7.56 [dt, J = 1.9
(d) and 7.7 (t) Hz, 1H, HPy-4], 7.42-7.19 (several m, 5H), 7.13 (ddd, J =
1.1, 4.9, and 7.5 Hz, 1H, HPy-5), 7.05 (br d, J = 7.8 Hz, 1H, HPy-3) 4.48
(dd, J = 4.9 and 9.0 Hz, 1H, H-1), 3.20-2.96 (AB signals of an ABX
system, 3JA,X = 4.9, 3JB,X = 9.0, and 2JA,B = 13.6 Hz, 2H, CH2), 2.0-1.5 (br
s, 2H, NH2). 13C NMR (CDCl3, 75.5 MHz) δ (ppm): 159.3 (C), 149.3 (CH),
145.6 (C), 136.2 (CH), 128.4 (CH), 127.0 (CH), 126.3 (CH), 124.0 (CH),
121.3 (CH), 56.0 (CH), 48.2 (CH2). The crude amine (S)-6 (25.0 mg,
0.126 mmol) was redissolved in methanol (4.0 mL) and trimethylsilyl
chloride (TMSCl, 240 L 1.89 mmol) was added. After 6 hours at room
temperature, the solvent was eliminated under reduced pressure
and the residue was successively washed with small portions of THF
(4 × 1.5 mL), obtaining the lanicemine hydrochloride (S)-6 · 2HCl as a
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the Principado de Asturias (FC-
GRUPIN-IDI2018000181). We also thank Dr. Isabel Merino
(NMR Unit of the Scientific and Technological Resources of the
University of Oviedo) for advising and technical assistance on
selective-1D TOCSY experiments.
20
white solid (34 mg, >99% yield); [α]D = +81.0 (c 1.2, MeOH), ee =
20
97% [Lit.28 [α]D
= +87.1 (c 1.1, MeOH), ee > 99%]. The
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
Pharmacol. Exp. Ther., 1999; 288, 121-132; (b)VGiew. ASratincleacOonlrinae,
M. A. Smith, S. Pathak, H.-L. Su, P. H. Boeijinga, D. J. McCarthy,
M. C. Quirk, Mol. Psychiatry, 2014D, O1I:91,0.9107389-/9C895O.B0(c16)16DC.
Downey, A. Dutta, S. McKie, G. R. Dawson, C. T. Dourish, K.
Craig, M. A. Smith, D. J. McCarthy, C. J. Harmer, G. M.
Goodwin, S. Williams, J. F. W. Deakin, Eur.
Neuropsychopharmacol., 2016, 26, 994-1003.
Notes and references
1
(a) V. Farina, J. T. Reeves, C. H. Senanayake, J. J. Song, Chem.
Rev., 2006, 106, 2734-2793; (b) T. B. Adams, M. M. McGowen,
M. C. Williams, S. M. Cohen, V. J. Feron, J. I. Goodman, L. J.
Marnett, I. C. Munro, P. S. Portoghese, R. L. Smith, W. J.
Waddell, Food Chem. Toxicol., 2007, 45, 171-201; (c) A.
Lumbroso, M. L. Cooke, B. Breit, Angew. Chem., 2013, 125,
1942-1986; Angew. Chem. Int. Ed., 2013, 52, 1890-1932; (d) C.
R. Shugrue, S. J. Miller, Chem. Rev., 2017, 117, 11894-11951.
(a) C. Bolm, M. Ewald, Tetrahedron Lett., 1990, 31, 3457-3460;
(b) J. M. Hawkins, K. B. Sharpless, Tetrahedron Lett., 1987, 28,
2825-2828.
24 Following the rule to name alcohols 2, pyridine ring positions
are numbered starting from the nitrogen atom (N-1).
25 M. J. Percino, V. M. Chapela, O. Urzúa, L.-F. Montiel, C.
Rodríguez-Barbarín, Res. Chem. Intermed., 2007, 33, 623-629.
26 R. A. Kornfeld, Y. Houminer, J. Agric. Food Chem., 1982, 30,
668-672.
27 N. Di Blasio, M. T. Lopardo, P. Lupattelli, Eur. J. Org. Chem.,
2009, 938-944.
28 R. J. Murray, D. Mathisen, M. Balestra, (S)-alpha-Phenyl-2-
pyridineethanamine (S)-malate and its use as a medicament,
Patent WO1994022831A1, 1994.
2
3
4
H. Gärtner, U. Salz, C. Rüchardt, Angew. Chem. Int. Ed., 1984,
23, 162-164.
(a) E. Macedo, C. Moberg, Tetrahedron: Asymmetry, 1995, 6,
549-558; (b) K. Nordström, E. Macedo, C. Moberg, J. Org.
Chem., 1997, 62, 1604-1609; (c) J. Uenishi, S. Aburatani, T.
Takami, J. Org. Chem., 2007, 72, 132-138.
(a) A. P. Roszkowski, W. M. Govier, Pharmacologist, 1959, 1,
60-78; (b) V. Barouh, H. Dall, D. Patel, G. Hite, J. Med. Chem.,
1971, 14, 834−836; (c) M. Cussac, A. Boucherle, J. L. Pierre, J.
Hache, Eur. J. Med. Chem., 1974, 9, 651-657. …
29 I. Bastida, M. San Segundo, R. López, C. Palomo, Chem. Eur. J.
2017, 23, 13332-13336.
5
6
7
8
(a) C.-Y. Yu, O. Meth-Cohn, Tetrahedron Lett. 1999, 40, 6665-
6668; (b) O. Meth-Cohn, C. C. Yau, C.-Y. Yu, J. Heterocyclic
Chem., 1999, 36, 1549-1553.
(a) F.-X. Felpin, J. Lebreton, Tetrahedron, 2004, 60, 10127-
10153; (b) T. M. Shaikh, A. Sudalai, Eur. J. Org. Chem., 2010,
3437–3444 and references therein cited.
O. Meth-Cohn, C-Y. Yu, M-C. Lestage, D.-H. Lebrun, P.
Caignard, P. Renard, Pyridine and piperidine derivatives for
treating neurodegenerative diseases, Eur. Patent 1050531,
2000; Chem. Abstr., 2000, 133, 350144.
(a) C. J. Ohnmacht, A. R. Patel, R. E. Lutz, J. Med. Chem., 1971,
14, 926-928; (b) J. M. Karle, I. L. Karle, Antimicrob. Agents
Chemother., 2002, 46, 1529–1534.
9
10 G. Chelucci, Part I in Targets in Heterocyclic Systems; Eds.: O.
A. Attanasi, D. Spinelli, 2009, 13, 303-346.
11 S. Rendler, G. Auer, M. Oestreich, Angew. Chem. Int. Ed.,
2005, 44, 7620-7624.
12 X. Li, H. Jiang, E. W. Uffman, L. Guo, Y. Zhang, X. Yang, V. B.
Birman, J. Org. Chem., 2012, 77, 1722-1737.
13 M.-J. Kim, Y. K. Choi, S. Kim, D. Kim, K. Han, S.-B. Ko, J. Park,
Org. Lett., 2008, 10, 1295-1298.
14 (a) M. Hall, A. S. Bommarius, Chem. Rev., 2011, 111, 4088-
4110; (b) R. A. Sheldon, J. M. Woodley, Chem. Rev., 2018, 118,
801−838.
15 S. Rusman, B. Kojić-Prodić, Ž. Ružić-Toroš, V. Šunjić, Croat.
Chem. Acta, 1990, 63, 701-718.
16 R. P. Cassity, L. T. Taylor, J. F. Wolfe, J. Org. Chem., 1978, 43,
2286-2288.
17 (a) T. Wang, G. Ouyang, Y.-M. He, Q.-H. Fan, Synlett, 2001,
939-942; (b) J. Bai, P. Wang, W. Cao, X. Chen, J. Mol. Struct.,
2017, 1128, 645-652.
18 (a) H. F. T. Klare, M. Oestreich, Angew. Chem. Int. Ed., 2007,
46, 9335-9338; (b) S. Rendler, O. Plefka, B. Karatas, G. Auer, R.
Frölich, C. Muck-Lichtenfeld, S. Grimme, M. Oestreich, Chem.
Eur. J., 2008, 14, 11512-11528.
19 A. Weickgenannt, M. Mewald, T. W. T. Muesmann, M.
Oestreich, Angew. Chem. Int. Ed., 2010, 49, 2223-2226.
20 J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem., 1969, 34,
2543-2549.
21 D. R. Kelly, Tetrahedron: Asymmetry, 1999, 10, 2927-2934.
22 C. E. Johnson, F. A. Bovey, J. Chem. Phys., 1958, 29, 1012-
1014.
23 (a) G. C. Palmer, R. J. Murray, C. L. Cramer, M. L. Stagnitto, M.
K. Knowles, L. R. Freedman, M. S. Eismann, N. Mahmood, M.
Balestra, A. R. Borrelli, T. J. Hudzik, D. J. McCarthy, J.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Organic & Biomolecular Chemistry
Page 8 of 8
View Article Online
DOI: 10.1039/C9OB01616C
Table of contents information
1-Aryl-2-(azaaryl)ethanols with ee > 99% have been prepared by KRED-catalyzed reduction of
the ketone precursors. A chemoenzymatic synthesis of lanicemine is described.
O
OH
AzaAr Different KREDs
AzaAr
NADPH / Propan-2-ol
Buffer Pi pH 7.0
R = H, F, OMe
AzaAr = 2-, 3-, and 4-Pyridine, 2-Quinoline
R
R
N
(R) and/or (S)
C > 99%
ee > 99%
OH
N
NH2
2 HCl
ee > 99%
Lanicemine · 2 HCl
ee = 97%. Overall yield: 86%