Synthesis of α-Alkyl-β-Hydroxy Amides through Biocatalytic Dynamic Kinetic Resolution Employing Alcohol Dehydrogenases

Article abstract of DOI:10.1002/adsc.201900317

Chiral (α-substituted) β-hydroxy amides are interesting derivatives as they are useful building blocks of many biologically active compounds. Herein, the biocatalytic stereocontrolled synthesis of various acyclic syn-α-alkyl-β-hydroxy amides through a dynamic kinetic resolution is shown. Hence, a series of overexpressed alcohol dehydrogenases (ADHs) in Escherichia coli was used to reduce the corresponding racemic β-keto amides. Among them, ADH-A from Rhodococcus ruber and commercial evo-1.1.200 afforded the best activities and selectivities, giving access to the opposite enantiomers with high diastereomeric excess and excellent enantiomeric excess. Some of these compounds were obtained at semipreparative scale. (Figure presented.).

Full text of DOI:10.1002/adsc.201900317

Title: Synthesis of α-Alkyl-β-Hydroxy Amides through Biocatalytic
Dynamic Kinetic Resolution Employing Alcohol Dehydrogenases
Authors: Daniel Méndez-Sánchez, Ángela Mourelle-Insua, Vicente
Gotor-Fernández, and Ivan Lavandera
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900317
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10.1002/adsc.201900317
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of α-Alkyl-β-Hydroxy Amides through Biocatalytic
Dynamic Kinetic Resolution Employing Alcohol
Dehydrogenases
Daniel Méndez-Sánchez,a,b,† Ángela Mourelle-Insua,a,† Vicente Gotor-Fernández,a* and
Iván Lavanderaa*
a
Department of Organic and Inorganic Chemistry, University of Oviedo, Avenida Julián Clavería 8, 33006 Oviedo,
Spain
Fax: (+34) 985 103446; phone: (+34) 985 103454 (V.G.-F.) and (+34) 985 103452 (I.L.); e-mail: vicgotfer@uniovi.es
(V.G.-F.) and lavanderaivan@uniovi.es (I.L.)
Current address: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
b
† These authors have equally contributed.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
mediated by rhodium[12] or copper[13] complexes, the
Abstract. Chiral (α-substituted) β-hydroxy amides are
interesting derivatives as they are useful building blocks of regioselective ring-opening of α,β-epoxy amides with
many biologically active compounds. Herein, the
biocatalytic stereocontrolled synthesis of various acyclic
syn-α-alkyl-β-hydroxy amides through a dynamic kinetic
resolution is shown. Hence, a series of overexpressed
alcohol dehydrogenases (ADHs) in Escherichia coli was
used to reduce the corresponding racemic β-keto amides.
Among them, ADH-A from Rhodococcus ruber and
commercial evo-1.1.200 afforded the best activities and
selectivities, giving access to the opposite enantiomers with
high diastereomeric excess and excellent enantiomeric
excess. Some of these compounds were obtained at
preparative scale.
sodium bis(2-methoxyethoxy)aluminium hydride
(Red-Al),[5] the palladium-catalysed β-acyloxylation
of amides,[14] and the ruthenium-mediated reduction
of β-keto nitriles[15] have been shown as attractive
strategies.
However, the synthesis of α-substituted β-hydroxy
amides in diastereo- and enantioselective manner is
more challenging due to the formation of four
possible diastereoisomers. Again, various synthetic
protocols have been developed to successfully get
access to these compounds (Figure 1A). Aldol
additions have provided good results although at the
expense of using very low reaction temperatures.[16]
The opening of chiral epoxides with different
nucleophiles has also been demonstrated as another
powerful tool. However, enantiopure synthons must
be previously synthesised.[6,17] A very simple and
direct method is the stereoselective reduction of the
racemic α-substituted β-keto amides under dynamic
conditions.[18] Since these substrates can easily
racemise due to the high acidity of the α-hydrogen, a
dynamic kinetic resolution (DKR)[19,20] can be
achieved, thus providing in the ideal case one out of
four diastereoisomer products. Various chemical
agents such boranes[21] and hydrides[22] have afforded
the corresponding racemic β-hydroxy amides with
high diastereomeric excess (de), while the Ru-[3,23]
and Ir-mediated[24] hydrogenation of α-substituted β-
keto lactams gave the alcohols with excellent de and
ee. There is just one report demonstrating the
asymmetric hydrogen transfer of acyclic substrates
with a ruthenium complex, obtaining the final
compounds with very high de and ee values after
recrystallisation of the reaction crude.[25]
Keywords: Alcohol dehydrogenases; Biocatalysis; Chiral
synthesis; Dynamic kinetic resolutions; β-Hydroxy amides
Chiral β-hydroxy amides are highly interesting
derivatives as they are versatile and useful building
blocks of different biologically active compounds.
Among
them,
oxazolines,[1]
oxazoles,[2]
pyrrolidines,[3] azetidines,[4] and 1,3-amino alcohols
such as fluoxetine,[5] can be mentioned. They are also
present in the core structure of anticancer families
like bengamides,[6] and can be utilised as ligands to
induce chirality in organic transformations.[7]
Different synthetic approaches have been designed
in order to synthesise these derivatives (Figure 1A).
Hence, the aldol condensation between a (chiral)
amide and an aldehyde[4,8] or an acylsilane[9] has been
demonstrated as a valuable methodology to obtain
these compounds with high enantiomeric excess (ee).
Likewise, the hydrogenation of β-keto amide
precursors employing ruthenium[10] or iridium[11]
complexes, the hydroboration of unsaturated amides
1
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10.1002/adsc.201900317
Advanced Synthesis & Catalysis
Figure 1. A) Chemical approaches; and B) (chemo)enzymatic methodologies to synthesise chiral (α-substituted) β-
hydroxy amides.
From an enzymatic point of view (Figure 1B), the
kinetic resolution of racemic β-hydroxy esters
through lipase-catalysed aminolysis,[26] or β-O-
protected nitriles with Rhodococcus erythropolis
whole cells[27] and the reduction of β-keto amides
using yeasts or fungi,[28] have provided the chiral
alcohols but with low yields and/or selectivities. Very
recently, the combination of Rhodococcus
rhodochrous whole cells[29] or a ruthenium catalyst[30]
with alcohol dehydrogenases (ADHs)[31] delivered
different cyclic β-hydroxy amides starting from the
corresponding racemic β-keto nitriles through a DKR
process with excellent de and ee.
While the bioreduction under dynamic conditions
of α-substituted β-keto esters using whole cells or
isolated ADHs has been recurrently studied,[20,32] this
has not been the case for the amide analogues. Herein
(Figure 1B, red), a set of α-alkyl-β-keto amides has
been successfully reduced with different lyophilised
preparations containing overexpressed ADHs in E.
coli affording the corresponding β-hydroxy amides in
many cases with outstanding enantio- and
diastereoselectivities.
used as nucleophile in the biotransformations for the
synthesis of 2a and 2b. Later on, the β-keto amides
were alkylated at α-position by treatment with
different alkyl halides in basic medium using acetone
as solvent.[32] After purification by column
chromatography, α-alkylated β-keto amides 3a-h
were obtained in moderate yields (38-60%). Finally,
the racemic β-hydroxy amides (4a-d) and α-
substituted β-hydroxy amides (5a-h) were
synthesised by addition of sodium borohydride to a
solution of the corresponding keto amide in dry
dichloromethane, obtaining the products after
extraction in high yields (89-98%) and excellent
purities.
For this purpose, the chemical synthesis of a wide
panel of α-substituted β-keto amides was developed
(Scheme 1). They differed in the amide protecting
group and the substitution pattern at α-position. We
used as starting materials commercially available β-
keto esters 1a and 1b following two independent
synthetic methodologies in order to obtain the
corresponding β-keto amides 2a-d. Better results
were found for the synthesis of N-benzylated keto
amides 2a and 2b (89% yield) through the formation
of 1,3,2-dioxaborinane intermediates,[33] while to get
access to compounds 2c (91% yield) and 2d (90%
yield) the lipase-mediated approach was preferred,[34]
finding less than 20% yield when benzylamine was
Scheme 1. Synthesis of (α-substituted) β-keto amides and
racemic β-hydroxy amides.
2
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10.1002/adsc.201900317
Advanced Synthesis & Catalysis
In order to study the suitability of the DKR processes
with the α-substituted substrates, different ADHs
were tested first towards the bioreduction of β-keto
amides 2a-d. Thus, the effect of the amide protecting
group could be considered. This way, lyophilised E.
coli preparations containing overexpressed (S)-
selective ADHs from Rhodococcus ruber (ADH-
From these results, it was clear that even though these
substrates were suitable for some ADHs, the amide
moiety (R2 and R3) and the substitution pattern in R1
had an important influence in some ADHs behaviour.
For this reason, the next step was to study the
influence that the substitution pattern at the α-
position had in the bioreduction, and also to look if
DKR transformations were possible.
The α-methylated β-keto amide 3a was chosen as
model substrate (Table 2 and Table S2 in the
Supporting Information). Under the same reaction
conditions previously described, it was observed that
full conversion into 5a was achieved when using
ADH-A (entry 1), RasADH (entry 2) or evo-1.1.200
(entry 3). On the one hand, ADH-A and evo-1.1.200
led to very high diastereo- and enantioselectivity,
obtaining in both cases the syn diastereoisomer as the
major one. This way, (2R,3S)-5a was obtained with
90% de and 99% ee using ADH-A as biocatalyst and
evo-1.1.200 led to the formation of (2S,3R)-5a with
94% de and >99% ee. On the other hand, even though
RasADH showed good results in terms of conversion,
it achieved the synthesis of the anti-diastereoisomer
(2S,3S)-5a but with only 30% de and 28% ee.
After this screening, the influence of different alkyl
chains at α-position was studied. For this purpose, the
bioreduction of substrates 3b-e into the
corresponding alcohols (5b-e) was attempted, finding
remarkable results only with ADH-A and evo-1.1.200
(Tables S3 and S4 in the Supporting Information;
Table 2, entries 4-11). As observed with the model
substrate 3a, both enzymes favoured the formation of
the syn-alcohols. In this manner, (2R,3S)-enantiomers
were obtained with high conversions (78->99% conv)
and moderate to high diastereoselectivity (72-92%
de) and very high enantioselectivity (99% ee) with
ADH-A. Additionally, (2S,3R)-5b-d were synthesised
in moderate to high conversion values (60-98% conv)
and high diastereo- and enantioselectivities (90-92%
de and 99->99% ee) with evo-1.1.200. However, this
biocatalyst lost its activity towards the synthesis of
the α-benzylated β-hydroxy amide 5e (entry 11).
Encouraged by these results and looking for a
further exploitation of the synthetic approach, we
decided to undertake the ADH-catalysed DKR of
substrate 3f, bearing an ethyl group at R1 position.
Using the same reaction conditions, all enzymes were
screened (Table S5 in the Supporting Information and
Table 2, entries 12 and 13). Unfortunately, only evo-
1.1.200 led to the preferential formation of alcohol
(2S,3R)-5f with high conversion (98%), moderate de
(77%) and excellent ee (>99%) values.
A),[35]
Thermoanaerobacter
ethanolicus
(TeSADH),[36] Thermoanaerobium sp. (ADH-T),[37]
Sphingobium yanoikuyae (SyADH),[38] Ralstonia sp.
(RasADH),[39] and the (R)-selective ADH from
Lactobacillus brevis (LbADH)[40] were screened.
Also, commercially available evo-1.1.200[41] was
studied.
The bioreductions were performed at 25 mM
concentration of the substrate in a reaction mixture
containing Tris·HCl 50 mM pH 7.5 and 1 mM of the
nicotinamide cofactor NAD(P)H. DMSO was used as
cosolvent in all cases in a 2.5% v/v ratio, and either
large amounts of 2-propanol (iPrOH) or the
glucose/GDH system were employed to regenerate
the cofactor. All reactions were incubated at 30 ºC for
24 hours (Table 1). After this time, ADH-A and
ADH-T revealed good results with all substrates,
leading to the synthesis of the (S)-alcohols with high
conversions and ee values (entries 1, 2, 4, 5, 7, 8, 10
and 11). Furthermore, the commercial evo-1.1.200
fully converted 2a-c into the enantiopure (R)-alcohols
4a-c (entries 3, 6 and 9). However, it led to the
formation of enantiopure (R)-4d with a moderate
conversion value (entry 12). The other ADHs
afforded worse results (see SI, Table S1).
Table 1. ADH-catalysed bioreduction of β-keto amides 2a-
d.[a]
c [%][b] ee [%][c]
Entry Substrate ADH
1
2
3
4
5
6
7
8
ADH-A
ADH-T
evo-1.1.200 >99
ADH-A
ADH-T
evo-1.1.200 >99
ADH-A
ADH-T
evo-1.1.200 >99
ADH-A
ADH-T
evo-1.1.200 40
>99
>99
96 (S)
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
>99 (S)
>99 (R)
96 (S)
96
96
>99 (S)
>99 (R)
>99 (S)
>99 (S)
>99 (R)
>99 (S)
>99 (S)
>99 (R)
>99
>99
9
10
11
12
>99
>99
[a] For reaction conditions and the complete set of data, see
the Supporting Information.
[b] Conversion values were measured by GC analyses.
[c]
Enantiomeric excess values were measured by HPLC
analyses. Major enantiomer in parentheses.
3
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10.1002/adsc.201900317
Advanced Synthesis & Catalysis
Table 2. Dynamic kinetic resolution of α-substituted β-keto amides 3a-h bearing different pattern substitution at α-
position.[a]
c [%][b]
>99
>99
>99
>99
96
99
60
99
98
78
<1
<1
98
99
98
96
8
de [%][c],[d]
90
30
94
88
92
72
90
92
92
78
n.d.
n.d.
77
82
86
12
n.d.
ee anti [%][c]
n.d.
28 (2S,3S)
n.d.
n.d.
n.d.
99 (2S,3S)
n.d.
n.d.
n.d.
99 (2S,3S)
n.d.
n.d.
5 (2R,3R)
n.d.
n.d.
99 (2S,3S)
n.d.
ee syn [%][c]
99 (2R,3S)
30 (2R,3S)
>99 (2S,3R)
99 (2R,3S)
>99 (2S,3R)
99 (2R,3S)
99 (2S,3R)
99 (2R,3S)
>99 (2S,3R)
99 (2R,3S)
n.d.
Entry
1
2
3
4
5
6
7
8
Substrate
3a
3a
ADH
ADH-A
RasADH
evo-1.1.200
ADH-A
evo-1.1.200
ADH-A
evo-1.1.200
ADH-A
evo-1.1.200
ADH-A
evo-1.1.200
ADH-A
evo-1.1.200
ADH-A
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
3f
3g
3g
3h
3h
9
10
11
12
13
14
15
16
17
n.d.
>99 (2S,3R)
99 (2R,3S)
>99 (2S,3R)
99 (2R,3S)
n.d.
evo-1.1.200
ADH-A
evo-1.1.200
[a] For reaction conditions and the complete set of data, see the Supporting Information.
[b] Conversion values were measured by GC analyses.
[c] Diastereomeric and enantiomeric excess values were measured by HPLC analyses. Major diastereoisomer shown
in parentheses.
[d]
ADH-A and evo-1.1.200 produced preferentially the syn-diastereoisomer, while RasADH (entry 2) led
preferentially to the formation of the anti-diastereoisomer.
n.d. not determined.
At this point, the influence that different amide
moieties had in the process was studied. For this
reason, the bioreduction protocol was set up using α-
methylated substrates 3g and 3h (Table S5 in the
Supporting Information; Table 2, entries 14-17). On
the one hand, as previously observed with compound
3a, the keto amide 3g was a suitable substrate for
ADH-A and evo-1.1.200, being the syn-alcohol the
major product in both cases (entries 14 and 15).
Hence, (2R,3S)- and (2S,3R)-5g were obtained with
high conversion and selectivity (99% conv., 82% de
and 99% ee and 98% conv., 86% de and >99% ee,
respectively). On the other hand, 3h led to high
conversion and low de values, while high
enantioselectivity towards the formation of (2R,3S)-
5h (96% conv, 12% de and 99% ee, entry 16) when
using ADH-A as biocatalyst and a completely loss of
activity when utilising evo-1.1.200. From these
results it became clear that the N-protecting had a
large effect in the enzyme recognition, being the
benzyl and the allyl moieties the most appropriate
ones to perform these DKR transformations.
The relative syn configuration of the final products
was assigned based on the use of NMR homonuclear
decoupling experiments (see the Supporting
Information). This result was confirmed with the
Scheme 2. Semipreparative DKR of α-substituted β-keto
amides: A) 3a-e,g,h catalysed by overexpressed ADH-A;
and B) 3f catalysed by evo-1.1.200.
method showed by Kalaitzakis and Smonou with α-
alkyl-β-hydroxy carbonyl compounds,[42] together
3
with the measured JH2H3 for similar derivatives[25]
4
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10.1002/adsc.201900317
Advanced Synthesis & Catalysis
Preparative scale bioreduction of α-substituted β-keto
amides 3a-e,g,h using the alcohol dehydrogenase from
Rhodococcus ruber (ADH-A)
and the known diastereopreference with the same
enzymes with α-alkyl-β-keto esters.[32] The absolute
configuration was determined due to the known
stereospecificity of these ADHs.[32,35-41]
Lyophilised E. coli/ADH-A cells (100 mg for β-keto amide
3a and 50 mg for β-keto amides 3b-e,g,h), DMSO (2.5%
v/v), NADH (1 mM) and iPrOH (5% v/v) were
successively added into an Erlenmeyer flask containing β-
keto amide (100 mg for 3a and 20 mg for 3b-e,g,h, 25
mM) in Tris·HCl buffer 50 mM pH 7.5. The reaction was
shaken at 30 °C and 250 rpm for 24 h and then extracted
with EtOAc (3 x 15 mL). The organic layers were
separated by centrifugation (5 min, 4900 rpm), combined
and finally dried over Na2SO4. The solvent was
concentrated under vacuum, furnishing the α-substituted β-
hydroxy amides 5a-e,g,h in moderate to excellent isolated
yields (52-94%).
In order to demonstrate the applicability of the
method, ADH-catalysed DKR transformations were
performed at semipreparative scale. For this purpose,
ADH-A was the enzyme of choice as it was the most
efficient ketoreductase, providing good or excellent
results in the bioreduction of substrates 3a-e,g,h. This
way, 100 mg of model β-keto amide 3a and 20 mg of
the other compounds were transformed into the
corresponding enantioenriched alcohols. 2.5% v/v of
DMSO was employed as co-solvent and the reaction
media (50 mM Tris.HCl pH 7.5) was implemented
with NADH (1 mM). 2-Propanol (5% v/v) was
employed to regenerate the nicotinamide cofactor.
After 24 hours, similar results to those obtained at
analytical scale were found (Scheme 2). Thus, the
syn-(2R,3S)-diastereoisomers of the alcohols were
obtained as the major one in moderate to high yields
(52-94%) and excellent enantioselectivities (>99%
ee). The diastereoselectivity of ADH-A remained
high with the exception of β-hydroxy amide 5c (59%
de) and, especially, alcohol 5h (9% de). Finally, the
transformation of 3f (20 mg) with evo-1.1.200 was
performed, obtaining the enantiopure (2S,3R)-5f
diastereoisomer with 78% de.
Preparative scale bioreduction of α-substituted β-keto
amide 3f using the commercial alcohol dehydrogenase
evo-1.1.200.
20 mg of β-keto amide 3f (25 mM) was added in an
Erlenmeyer flask containing DMSO (2.5% v/v),
i
MgCl2·6H2O (1 mM), NADH (1 mM) and PrOH (5% v/v)
in Tris·HCl buffer 50 mM pH 7.5 (final volume: 3.6 mL).
Finally, 75 mg of lyophilised evo-1.1.200 were added and
the reaction was shaken at 30 ºC and 250 rpm for 24 h.
After this time, the reaction was extracted with EtOAc (3 x
5 mL). The organic layers were separated by centrifugation
(5 min, 4900 rpm), combined and finally dried over
Na2SO4. The solvent was concentrated under vacuum,
achieving the α-substituted β-hydroxy amide 5f in high
isolated yield (17 mg, 84%).
Overall, herein the reduction of various acyclic α-
alkyl-β-keto amides has been described, affording the
corresponding syn-α-alkyl-β-hydroxy amides with
high diastereo- and enantioselectivities through DKR
processes, employing lyophilised E. coli cells
containing overexpressed ADHs. The high acidity of
the α-proton ensured a fast substrate racemisation
yielding the enantioenriched products at conversions
close to 100% even at almost neutral pH.
Enantiocomplementary ADH-A from Rhodococcus
ruber and commercially available evo-1.1.200
afforded the best results. An important effect of the
alkyl chain at α-position and also of the amide
protecting group was observed in these bioreductions.
Thus, higher de values were obtained for short alkyl
moieties and N-benzylated amides. This methodology
allows to get access to a new family of compounds
with selectivities comparable to the ones obtained
with metal catalysts,[25] thus demonstrating the great
potential of enzymes to obtain valuable derivatives
under straightforward, simple, and environmentally-
friendly conditions.
Acknowledgements
We thank Prof. Wolfgang Kroutil (University of Graz) for
providing the overexpressed ADHs. Financial support from the
Spanish Ministry of Economy and Competitiveness (MINECO,
Project CTQ2016-75752-R) is gratefully acknowledged. A.M.-I.
thanks MINECO for a predoctoral fellowship inside the FPI
program.
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Experimental Section
Alcohol dehydrogenases from Ralstonia sp. (RasADH),
Lactobacillus brevis (LbADH), Sphingobium yanoikuyae
(SyADH), Thermoanaerobacter ethanolicus (TeSADH),
Thermoanaerobacter sp. (ADH-T), Rhodococcus ruber
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10.1002/adsc.201900317
Advanced Synthesis & Catalysis
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UPDATE
Synthesis of α-Alkyl-β-Hydroxy Amides through
Biocatalytic Dynamic Kinetic Resolution
Employing Alcohol Dehydrogenases
Adv. Synth. Catal. Year, Volume, Page – Page
Daniel Méndez-Sánchez, Ángela Mourelle-Insua,
Vicente Gotor-Fernández,* and Iván Lavandera*
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