Straightforward preparation of biologically active 1-aryl- and 1-heteroarylpropan-2-amines in enantioenriched form

Article abstract of DOI:10.1039/c0ob00800a

Because of the importance of developing stereoselective syntheses for single enantiomers, a selected panel of racemic biologically active 1-aryl- and 1-heteroarylpropan-2-amines has been prepared, followed by a study of their behavior in enzymatic kinetic resolution (KR) processes. For this purpose, lipase B from Candida antarctica (CAL-B) proved to be an ideal biocatalyst allowing the preparation of the corresponding enantioenriched (R)-amides and (S)-amines by aminolysis reactions. Likewise, dynamic kinetic resolutions (DKR) have been successfully achieved combining the use of CAL-B and Shvo's catalyst. This research constitutes the first example of a lipase-catalyzed DKR process of β-substituted isopropylamines.

Full text of DOI:10.1039/c0ob00800a

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PAPER
Straightforward preparation of biologically active 1-aryl- and
1-heteroarylpropan-2-amines in enantioenriched form†
Mar´ıa Rodr´ıguez-Mata,a Vicente Gotor-Ferna´ndez,a Javier Gonza´lez-Sab´ın,b Francisca Rebolledoa and
Vicente Gotora
Received 29th September 2010, Accepted 16th November 2010
DOI: 10.1039/c0ob00800a
Because of the importance of developing stereoselective syntheses for single enantiomers, a selected
panel of racemic biologically active 1-aryl- and 1-heteroarylpropan-2-amines has been prepared,
followed by a study of their behavior in enzymatic kinetic resolution (KR) processes. For this purpose,
lipase B from Candida antarctica (CAL-B) proved to be an ideal biocatalyst allowing the preparation of
the corresponding enantioenriched (R)-amides and (S)-amines by aminolysis reactions. Likewise,
dynamic kinetic resolutions (DKR) have been successfully achieved combining the use of CAL-B and
Shvo’s catalyst. This research constitutes the first example of a lipase-catalyzed DKR process of
b-substituted isopropylamines.
Despite the aforementioned applications of these amines and
Introduction
their well established stereochemistry–activity relationship, bio-
The family of 1-arylpropan-2-amines represents a subclass of
logical studies of single stereoisomers are still scarce, probably
chiral amines with interesting pharmacological properties. Most of
due to their limited availability. As far as we are aware no
them show central and peripheral stimulant activity by multiple ac-
reports of lipase-catalyzed stereoselective transformations of 1-
tions at serotonin (5-HT) receptor subtypes and their applications
heteroarylpropan-2-amines have been described yet. For that
cover, for instance, the treatment of sleep disorders, depression
reason, we wish to report a simple and highly efficient chemoen-
and obesity.1 Particularly, the isomeric 1- and 2-naphthylpropan-2-
zymatic approach to this class of amines with relevant therapeutic
amines are efficient monoamine oxidase (MAO) inhibitors2 and it
has been proved that the 2-naphthyl analogue lacks the side effects
associated with central nervous system stimulants. In addition,
the 1-heteroaryl analogues such as 1-(1H-indol-3-yl)propan-2-
uses. The enantioselective acylation of the corresponding race-
mates using the Candida antarctica lipase type B (CAL-B) as a
catalyst will be firstly investigated in order to optimize the kinetic
resolution (KR) of these substrates. Dynamic kinetic resolution
amine are precursors of potent b-adrenergic receptor agonists,
the activity being strongly dependent on the configuration of their
stereogenic centers.3 Among this family of amines is also found
a-methylhistamine, the reference histamine H3-receptor agonist
most extensively used, whose (R)-enantiomer is significantly more
potent than its (S)-counterpart.4 In recent years, a plethora of
analogues of a-methylhistamine have been synthesized by means
of changing the alkyl chain, attaching substituents to the amine
group and even replacing the imidazole moiety by other aromatic
rings.5 Furthermore, many prodrugs of a-methylhistamine have
also appeared, such as carbamates or azomethine, to overcome
pharmacokinetic problems ascribed to its insufficient oral absorp-
tion and poor brain penetration.6
(DKR) processes will be also attempted to look for methods to
prepare optically active amine derivatives in high yields.
Results and discussion
Racemic amines were synthesized from aldehydes 1a–e, com-
mercially available except 1e, selecting two isomeric aryl (1-
and 2-naphthyl) and three heteroaryl (3-indolyl, 3-pyridyl, and
4-imidazolyl) derivatives due to their pharmacological interest
(Scheme 1). Thus, all selected aromatic aldehydes, except 1H-
imidazole-4-carbaldehyde, were transformed into the correspond-
ing amines in a two-step sequence, which involves a Henry reaction
with nitroethane and ammonium acetate at 115 ◦C to produce the
(E)-nitropropene intermediates 2a–d,7 followed by reduction using
lithium aluminium hydride in refluxing THF. Racemic amines 3a–
d were isolated with overall yields ranging from 33 to 74% (Scheme
1). Specifically, moderate yields were achieved for isopropylamines
( )-3a–c bearing naphthyl and indolyl substituents, while a lower
yield was attained for the pyridyl analogue 3d.
aDepartamento de Qu´ımica Orga´nica e Inorga´nica, and Instituto Universi-
tario de Biotecnolog´ıa de Asturias, Universidad de Oviedo, 33006, Oviedo,
Spain. E-mail: vgs@uniovi.es; Fax: +34 985103448; Tel: +34 985103448
bEntrechem, SL, Edificio Cient´ıfico-Tecnolo´gico, Campus de El Cristo,
33006, Oviedo, Spain
† Electronic supplementary information (ESI) available: Synthesis of
aldehyde 1e and characterization data for new compounds are described.
See DOI: 10.1039/c0ob00800a
This protocol failed when applied to 1H-imidazole-4-
carbaldehyde, the protection of the imidazole ring being required
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Table 1 Kinetic resolution of amine ( )-3ca
Entry Enzyme Solvent
t /h EeP (%)b EeS (%)b c (%)c Ed
1
2
3
4
5
6
7
8
AK
THF
20
20
20
20
> 99
> 99
> 99
> 99
98
97
98
4
< 3
< 3
4
< 3
< 3
7
51
51
> 200
> 200
> 200
> 200
> 200
> 200
> 200
> 200
PSL IM THF
RML
PPL
THF
THF
7
CAL-B THF
3.5
> 99
> 99
> 99
> 99
CAL-B Dioxane
CAL-B TBME
CAL-B Toluene
3.5
3.5
3.5
Scheme 1 Synthesis of racemic amines 3a–e.
51
51
95
a Enzymatic reaction conditions: racemic amine 3c (50 mg), lipase (50 mg),
ester 4 (5 equiv.), solvent (0.10 M), 30 ◦C and 250 rpm. b Enantiomeric
excess of substrate (eeS) and enantiomeric excess of product (eeP) values
were determined by HPLC (see the Supporting Information†). c c =
eeS/(eeS + eep). d E = ln[(1 - c) ¥ (1 - eeP)]/ln[(1 - c) ¥ (1 + eeP)].14
in this case.8 After unsuccessful attempts with protecting groups
such as benzyl or Boc (due to the formation of regioisomeric
mixtures as well as the partial deprotection during the process),
the trityl group turned out to be adequate to perform the com-
plete synthetic sequence. Thus, the corresponding 1-N-trityl-a-
methylhistamine 3e was obtained with 44% overall yield (Scheme
1). In addition, and considering previous reports,9 the attachment
of such a bulkier group should ensure a high enantiodiscrimination
by the enzyme in the subsequent KR of ( )-3e.
of selectivity leading to the isolation of the enantiopure (S)-amine
after 3.5 h (entries 6–8).
Finally we decided to extend our results in the kinetic resolution
of racemic amines 3a–e. THF was selected as solvent because of the
high solubility of amines in this organic solvent, and the reactions
were performed using CAL-B as biocatalyst (Table 2). Biocatalytic
processes were regularly analyzed by HPLC and finally stopped
when conversion values reached close to 50%. Except for 1-(3-
pyridyl)propan-2-amine (3d, entry 4), all the amines were acylated
with excellent enantioselectivities. Meanwhile short reaction times
were required for naphthyl 3a,b (entries 1 and 2) and indolyl
3c (entry 3) derivatives, one day of reaction was necessary to
attain a 50% conversion with the a-methylhistamine derivative
3e. In all cases, the remaining (S)-amines and the produced (R)-
methoxyacetamides 5a–e were isolated with high to excellent
enantiomeric excesses. The (S)-configuration for the remaining
amines 3a–e was established by comparison of the optical rotation
sign for some of them with data reported in the literature.15
Consequently, this means that CAL-B follows Kazlauskas’ rule,16
the (R)-enantiomer of the amine being preferentially acylated. The
lower enantioselectivity found for 3d could be explained on the
basis of the active site empirical model established for CAL-B. Ac-
cording to that, the higher the size differences between substituents
attached to the stereocenter, the higher the enantiodiscrimination
produced. Moreover, as predicted, the attachment of the trityl
moiety to the imidazole ring in 3e significantly enhanced the size of
the bigger substituent, leading to an excellent enantioselectivity.8,17
Interestingly, it is also remarkable that our results represent
a complementary approach to the one described by Gil and
co-workers, allowing the production of (R)-amides of opposite
configuration to the ones previously obtained using an alkaline
protease in the KR of 3a,c.12
Biocatalytic processes are nowadays recognized as efficient
methods for the production of enantiopure compounds.10 In
this sense, enzymatic resolutions of amines present interesting
advantages over traditional diastereomeric salt resolutions. They
are based on the possibility of using eco-friendly catalysts, mild re-
action conditions and simple separation protocols. Transaminases
and hydrolases are the most commonly used enzymes to carry
out this type of transformation,11 with some efficient examples
involving chiral isopropylamines.8,12
We focused our attention on the lipase-catalyzed KR of ( )-3a–e
by means of aminolysis reactions using a non-activated ester such
as ethyl acetate as well as ethyl methoxyacetate (4), the best results
in terms of reactivity and enantioselectivity being found with the
last one (data not shown). This is not a surprising result as alkyl
methoxyacetates have been previously found to be excellent acyl
donors for the kinetic resolution of primary benzylic amines.13
First of all a set of lipases were tested in the stereoselective lipase-
mediated acylation of the racemic 1-(1H-indol-3-yl)propan-2-
amine (3c, Table 1). For most of them very low conversions
were achieved although with an excellent selectivity towards the
formation of methoxyacetamide (R)-5c. AK lipase (entry 1),
Pseudomonas cepacia lipase (PSL IM, entry 2), Rhizomucor miehei
lipase (RML, entry 3), and porcine pancreas lipase (PPL, entry
4) led to up to 7% of enantiopure (R)-5c in the corresponding
reaction with 5 equiv. of 4 in THF at 30 ◦C after 20 h. Interestingly,
Candida antarctica lipase type B (CAL-B, entry 5) exhibited a
higher activity in a shorter span (3.5 h), yielding both amide 5c
and amine 3c in almost enantiopure form (98% ee and >99% ee,
respectively).
Kinetic resolutions were also carried out in different organic
solvents such as 1,4-dioxane, tert-butyl methyl ether (TBME)
or toluene searching for optimal conditions in the resolution of
racemic amine 3c. All of them also occurred with excellent levels
Probably the most advantageous issue in a kinetic resolution
(KR) resides in the fact that both single enantiomers can be
attained starting from a racemic mixture. Unfortunately, the
maximum yield in one enantiomer is limited to 50% due to the
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Table 2 Kinetic resolution of amines ( )-3a–e catalyzed by CAL-Ba
(R)-5a–e
(S)-3a–e
Entry
Substrate
t /h
EeP (%)b
Yield (%)b
EeS (%)b
Yield (%)b
c (%)c
Ed
1
2
3
4
5
( )-3a
( )-3b
( )-3c
( )-3d
( )-3e
4
5
3.5
4
> 99
98
98
85
96
(99)
(99)
(88)
(96)
(83)
87
91
> 99
98
(81)
(96)
(81)
(36)
(71)
47
48
51
54
50
> 200
> 200
> 200
52
24
97
> 200
a Enzymatic reaction conditions: racemic amine ( )-3a–e (50 mg), CAL-B (50 mg), ester 4 (5 equiv.), THF (0.10 M), 30 ◦C and 250 rpm. b Ee values were
determined by HPLC (see the Supporting Information†), and isolated yields were calculated taking into account the degree of conversion. c c = eeS/(eeS
+ eep). d E = ln[(1 - c) ¥ (1 - eeP)]/ln[(1 - c) ¥ (1 + eeP)]. 14
Table 3 CAL-B-mediated DKR of ( )-3a–c,e using ethyl methoxyacetate
in dry toluene and the presence of Na2CO3 and 2,4-dimethylpentan-3-ol
at 100 ◦C after 24 h
obvious limitations of the technique. If only one enantiomer is de-
sired, DKR provides a remarkable yield improvement by combin-
ing the action of a biocatalyst with a racemization agent, usually at
high temperatures.18 This methodology has been efficiently applied
for example to secondary alcohols,19 primary20 and secondary
amines21 and amino acid amides.22 However, surprisingly this
methodology has not been extended to any 1-heteroarylpropan-
2-amines yet. In our case and taking into account the excellent
selectivities shown by CAL-B towards amines 3a–c,e in the lipase-
catalyzed kinetic resolutions, we decided to evaluate the possibility
of successfully carrying out DKR processes with these substrates.
We chose commercially available dimeric ruthenium Shvo’s cata-
lyst for the development of DKR processes because of its versatility
in organic synthesis.23 The main reason for its efficient catalytic
activity is based on its dissociation under thermal conditions.24
Initially THF and toluene were selected as solvents because
of the limited solubility of the organocatalyst in TBME and
1,4-dioxane.25 Before carrying out DKR reactions, racemization
experiments were performed using enantiomerically pure amine
(S)-3c obtained in the CAL-B catalyzed KR reactions. Sodium
carbonate was used as base and 2,4-dimethylpentan-3-ol as mild
hydrogen donor, in the reactions with THF at 70 ◦C and toluene
at 100 ◦C, both reaction temperatures close to the corresponding
solvent boiling point. Interestingly no appreciable racemization
was detected after 22 h in THF (3c was recovered with >95% ee)
while heating in toluene led to the racemic amine, thus probing the
possible applicability of the latter conditions in DKR processes.
Once the optimal conditions for the racemization of the
remaining enantioenriched amine of the biocatalyzed process
were found, we ensured that no background reaction occurs
in the absence of biocatalyst and metal complex under these
experimental conditions. For the enzymatic DKR processes, we
selected racemic amines 3a–c,e, that is, those that show the
best enantioselectivity values in the CAL-B catalyzed kinetic
resolutions. Ethyl methoxyacetate (4) was used as acyl donor, and
in order to favour the racemization reaction, the relative amount
of 4 was decreased in comparison with the KR experiments
from 5 to 2 equiv. In addition, the load of CAL-B with respect
to the amine was decreased from (1 : 1) in weight to (1 : 0.25),
Entry
Substratea
c (%)b
Yield (%)c
EeP (%)d
1
2
3
4
( )-3a
( )-3b
( )-3c
( )-3e
93
> 99
87
50
58
86
74
97
93
97
91
80
a Amines ( )-3a–c and CAL-B were used in a (1 : 0.25) ratio in weight
meanwhile for ( )-3e a ratio (1 : 1) was used. b Ratio calculated by GC for
3a–c and 1H NMR for 3e. c Isolated yields after flash chromatography.
d Determined by HPLC.
except for the less reactive amine, the imidazole derivative 3e
(Table 3).
Reactions starting from naphthylpropan-2-amines 3a,b led to
high or complete conversions (93->99%) after 24 h, the formation
of the corresponding methoxyacetamides (R)-5a,b (93–97% ee,
Table 3, entries 1 and 2) occurring with high selectivity. For the
indole and the imidazole derivatives ( )-3c,e good conversion
values were also achieved (80–87%), yielding the amides (R)-
5c,e in very high optical purity (91–97% ee, entries 3 and 4).
It must be mentioned that the DKR of racemic amine 3c was
also tried in THF at 70 ◦C. However under these conditions
only a 52% conversion of amide 5c was attained, this product
(R)-5c and the corresponding amine (S)-3c being isolated with
92% and 97% ee, respectively. This result is in agreement with
the previous observations in the racemization experiments. Side-
products as amine dimerization species were only detected in
individual cases, but in minor amounts. Although all amides were
achieved with over 90% ee, the lower enantiomeric excesses in
comparison with the KR processes can be explained because of
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the lower enantioselectivity displayed by CAL-B in toluene at this
higher reaction temperature.
the residue were separated using different methods depending
on the substrate. Compounds 5c–e and 3c–e were separated by
flash chromatography (different mixtures of MeOH/CH2Cl2 and
NH3 (32% aq. solution)/MeOH 2 : 98, respectively). However,
the mixtures of 5a,b and 3a,b were treated with 3 N aq. H2SO4
(5 cm3) and extracted with dichloromethane (3 ¥ 5 cm3). The
Conclusions
In summary, after developing the synthesis of a panel of valu-
able 1-(hetero)arylpropan-2-amines with current and potential
applications in medical treatments, we have taken advantage of
the stereodiscrimination shown by CAL-B for the production
of the corresponding (S)-amines and (R)-amides by means of
KR processes. Likewise, in those enzymatic aminolysis reactions
which occur with good enantiomeric ratios, we have tested the
combination of bio- and chemo-catalysts for the development
of DKRs, allowing the preparation of (R)-amides with high
yields and optical purities. Thus, the DKR of b-isopropylamines
has been reported for the first time taking advantage of the
compatibility of CAL-B and Shvo’s catalyst in the optimized
reaction conditions.
◦
aqueous phase was treated with solid NaOH at 0 C until basic
pH was reached, and extracted with dichloromethane (5 ¥ 5 cm3).
Both organic phases were dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure, affording optically
active methoxyacetamides 5a,b and amines 3a,b. Yields for both
compounds 5 and 3 were calculated taking into account the degree
of conversion attained in the reaction (see Table 1). In order to
determine the enantiomeric excesses of amines 3a–e, they were
treated with acetyl chloride and the resulting acetamides were
analyzed by HPLC.
General procedure for the dynamic kinetic resolution of amines
( )-3a–e
Experimental
A flame dried Schlenk flask was charged with the racemic amine
3 (50 mg, 0.10 M) and a magnetic stirrer, closed, evacuated and
backfilled with nitrogen three times. Then, under the same inert
atmosphere, Shvo’s catalyst (10 mol%), toluene, CAL-B [12.5 mg
for amines 3a–c or 50 mg for amine 3e], Na2CO3 (25 mg),
2,4-dimethylpentan-3-ol (0.5 equiv.) and ethyl methoxyacetate
(2 equiv.) were subsequently added. The reaction mixture was
stirred at 100 ◦C for 24 h. Then, after cooling at room temperature,
General procedure for the synthesis of racemic
1-(hetero)arylpropan-2-amines 3a–e
Nitroethane (5.9 cm3) was added to a mixture of the corresponding
aldehyde (3.0 mmol) and ammonium acetate (57 mg, 0.74 mmol),
and the resulting suspension was heated to reflux for 6 h. After
cooling at room temperature, the solvent was evaporated and
the crude material was extracted with water (30 cm3)—for the
nitropropene derivatives 2a,b—or with saturated aqueous solution
of NaHCO3 (30 cm3)—for the nitropropene derivatives 2c–e—and
dichloromethane (3 ¥ 30 cm3). The organic layers were combined,
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure to give the corresponding 2-nitropropene 2a–e in
quantitative yield. Spectroscopic data for 2a–e were in good agree-
ment with those previously published.26 These compounds were
used as crude materials in the following reduction reaction. Thus,
the corresponding nitropropene 2a–e (3.1 mmol) was dissolved in
anhydrous THF (62 cm3) and LiAlH4 (0.35 g, 9.3 mmol) was added
gradually under a nitrogen atmosphere. The reaction mixture
was refluxed overnight. After cooling at room temperature, water
was carefully added until total destruction of the hydride excess,
and then, a solution of aq. 4 N NaOH was added in order to
capture the aluminium salts. The resulting mixture was filtered
R
the reaction was filtered over celiteꢀ and washed with methanol
(5 ¥ 2 cm3). The solvent was removed in vacuo and the crude
material was purified by column chromatography, yielding the
corresponding methoxyacetamides 5a–c,e (see Table 2).
Acknowledgements
This work has been supported by the Spanish Ministry of Science
and Innovation (MICINN, CTQ 2007-61126). V. G.-F. (Ramo´n
y Cajal Program), and M. R.-M. (FPU fellowship) also thank
MICINN for personal funding.
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over celiteꢀ, washed with THF, dried over anhydrous Na2SO4,
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2278 | Org. Biomol. Chem., 2011, 9, 2274–2278
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