Direct asymmetric dynamic kinetic resolution by combined lipase catalysis and nitroaldol (Henry) reaction

Article abstract of DOI:10.1002/adsc.200700432

The asymmetric synthesis of β-nitroalkanol derivatives was simply achieved by a combined nitroaldol (Henry) reaction with lipase-catalyzed transesterification in high yield and enantiomeric purity (up to 92% and 99% ee) through a direct one-pot procedure.

Full text of DOI:10.1002/adsc.200700432

FULL PAPERS
DOI: 10.1002/adsc.200700432
Direct Asymmetric Dynamic Kinetic Resolution by Combined
Lipase Catalysis and Nitroaldol (Henry) Reaction
Pornrapee Vongvilai,a Rikard Larsson,a and Olof Ramstrçma,*
a
KTH – Royal Institute of Technology, Department of Chemistry, Teknikringen 30, S-10044 Stockholm, Sweden
Fax : (+46)-8-791-2333; e-mail: ramstrom@kth.se
Received: August 31, 2007; Revised: December 30, 2007; Published online: February 11, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The asymmetricsynthesis of b-nitroalkanol to 92% and 99% ee) through a direct one-pot proce-
derivatives was simply achieved by a combined nitro- dure.
aldol (Henry) reaction with lipase-catalyzed transes-
terification in high yield and enantiomeric purity (up Keywords: dynamickineticresolution; enzyme catal-
ysis; nitroaldol (Henry) reaction; secondary alcohols
Introduction
racemic secondary alcohol has proven to be a useful
method for the synthesis of chiral molecules with high
The nitroaldol, or Henry reaction, between a carbonyl optical purity.[5] This approach, however, suffers from
group and a nitroalkane, constitutes a powerful the limitation of attaining a reaction yield of maxi-
À
method for C C bond formation in organichcemis-
mally 50%. Fortunately, dynamickineticresolution
try.[1] Moreover, the diversity of further transforma- (DKR), that is, the combination of racemization of
tions of the nitroaldol adduct, for example oxidation, the undesired enantiomer with in situ kineticresolu-
reduction and reductive denitration, provide efficient tion (KR), is a powerful technique to address this
access to valuable functionalized structural motifs problem.[6]
such as 1,2-amino alcohols common in chemical and
Recently, we developed a method for self-screening
biological expressions.[1,2] In recent years, control of of dynamiccombinatorial nitroaldol libraries through
the enantioselectivity of this reaction has attracted in- kinetically controlled lipase-mediated transesterifica-
creasing interest. Most commonly, chiral metal com- tion.[7] To explore the scope of the reaction, we herein
plexes and other additives are used to obtain nitro al- report a novel asymmetricsynthesis of b-nitroalkanol
cohols with good to excellent optical purities.[3]
derivatives in good yield and high enantiomeric
Nevertheless, the most common way in industry to excess via a direct one-pot reaction combining a nitro-
achieve enantiomerically pure compounds is still by aldol (Henry) reaction and kinetic resolution (KR),
biotransformation processes due to economic efficien- lipase-catalyzed transesterification, of the correspond-
cy as well as environmental impact.[4] For the last two ing adduct at mild conditions (Scheme 1).
decades, kinetic resolution (KR) by lipase catalysis of
Scheme 1. General concept of one-pot reaction.
448
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Direct Asymmetric Dynamic Kinetic Resolution by Combined Lipase Catalysis
FULL PAPERS
Table 1. Kineticresolution of 1a using various enzymes.[a]
Results and Discussion
The nitroaldol reaction is thermodynamically con-
trolled. It is very useful for most aldehydes but re-
quires control of the equilibrium displacement to
obtain useful yields. In the present study this is, how-
ever, used as an advantage and the equilibrium reac-
tion is used as the racemization step of the undesired
enantiomer (Scheme 1). Moreover, this reaction can
be performed by many catalysts, for example, organic
Entry
Enzyme
Conversion [%][b]
ee [%][c]
E[d]
1
2
3
4
CALB
CRL[e]
PS
PS-CI
PS-CII
PF
5
0
78
0
0
99
90
93
99
99
8
0
1
bases, inorganicbases, quaternary ammonium salts or
[2,8]
using only ionicliquids as a solvent.
Therefore, sev-
10
11
10
7
29
46
>200
21
30
>200
>200
eral bases were initially screened to find optimized
conditions for the nitroaldol reaction. Principally, the
equilibration process should be rapid and stable and
should not interact with the enzymatic reaction. In
preliminary studies, the reactions were conducted in
the presence of one equivalent each of nitroalkane,
5
6
7[f]
8[g]
PS-CI
PS-CI
[a]
Reactions were carried out with 0.05 mmol (12 mg) of
rac-1a with 10 mg of enzyme and 5 equiv. of vinyl acetate
(VA) in 0.3 mL of toluene at room temperature under an
argon atmosphere for 24 h.
Determined by H NMR spectroscopy.
Determined by HPLC analysis using OD column.
Enantiomericratio
Two different preparations were used with the same
result: Sigma L1754/Fluka 62316.
30 mg of enzyme was used.
1
aldehyde and base, respectively. H NMR spectrosco-
py was used to follow the reactions by comparing the
signals of the aldehyde, 4-nitrobenzaldehyde (4a), and
the nitro alcohol adduct (1a). Of the various bases ini-
tially tested, the majority was either showing low re-
activity or was attacking the acyl donor. Triethylamine
was finally chosen as catalyst for the reactions, yield-
ing equilibration times of around three hours at room
temperature.
[b]
[c]
[d]
[e]
1
[f]
[g]
30 mg enzyme, the reaction was run at 408C for 24 h.
In the kinetic resolution (KR) process, achieved by
lipase-catalyzed transesterification, most enzymes
used recognize broad ranges of substrates.[9] A size resolution process supposedly proceeds at a lower
difference of the substituents at the secondary alcohol rate due to lower accessibility to the enzyme pocket
position of the substrates is, however, needed to and/or recognition of the right enantiomer. However,
[9,10]
obtain high enantiomericexecss.
In the present these experiments revealed high enantiospecificity of
case, the size occupancies around the stereogenic po- the transesterification product (over 90% ee, en-
sition of the nitro alcohol adduct are similar to each tries 4–6, Table 1), except for one biocatalyst, the
other. Initially, a series of enzymes were screened non-immobilized Pseudomonas cepacia (PS), which
using vinyl acetate (VA), commonly used for transes- exhibited no selectivity (entry 3, Table 1). Further-
terification, as an acyl donor, and pure racemic 2- more, the reaction conditions were optimized by ini-
methyl-2-nitro-1-(4-nitrophenyl) propan-1-ol (1a) as tially increasing the amount of enzyme, up to 30 mg
an alcohol substrate. The reactions were followed for for 0.05 mmol of substrate. Only Pseudomonas cepa-
24 h in dry toluene as a suitable solvent under argon cia lipase (PS-CI) exhibited a satisfactory enhance-
atmosphere (Table 1).
ment of reactivity, 29% yield in 24 h and 99% ee
From the enzymes tested, lipases from Pseudomo- (entry 7, Table 1). Attempts to change the reaction
nas cepacia (PS, PS-CI and PS-CII) and Pseudomo- solvents by using TBME, DIPE, cyclohexane and
nas fluorescens (PF) showed transesterification activi- hexane, all of which are compatible with the enzymes,
ty with high enantiosepecificity. In contrast, enzymes did not lead to significant improvement. Increasing
from different Candida species; Candida antarctica the temperature to 408C, resulted in almost complete
lipase B (Novozyme 435), and Candida rugosa kineticresolution in 24 h (46% yield, entry 8,
(CRL), showed low or no reactivity with this sub- Table 1). Temperatures above 408C, however, resulted
strate (entries 1 and 2, Table 1). However, the conver- in decreasing enantiospecificity and also slow decom-
sion yields using lipases from Pseudomonas sp. were position of the alcohol substrate.
relatively low, even though the amount of enzyme
After optimization of the kineticresolution, we
added was above the commonly used ratio (2.5 mg subsequently addressed the DKR process using PS-CI
enzyme: 0.05 mmol of substrate).[9] A possible explan- as enzyme and vinyl acetate as acylating agent. Due
ation for this effect is that the secondary alcohol posi- to the somewhat sluggish enzymaticreatcion, the
tion of the substrate is sterically congested with either equilibrium of the nitroaldol reaction was forced to
two methyl groups or phenyl groups. Thus, the kinetic the product side to increase the concentration of the
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Pornrapee Vongvilai et al.
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Table 2. Kineticresolution of 1a using various acyl donors.[a]
enzyme-substrate complex, the lipase-acyl donor-nitro
alcohol intermediate. Thus, an excess of nitro com-
pound was used together with the same amount of
enzyme as in the KR process. In the first attempt, the
reaction was examined with four equivalents of nitro-
alkane, two equivalents of base, one equivalent of 4-
nitrobenzaldehyde, 90 mg of PS-C I and five equiva-
lents of vinyl acetate in toluene at 408C for 2 days.
Compound 2a was isolated in 65% yield and 85% ee
together with compounds 5 and 6 in high amounts.
Compound 5 was obtained from the coupling between
acetaldehyde, the transesterification by-product, and
nitroalkane. Compound 5 then competed with com-
pound 1a in the enzymatic process yielding compound
6.
To address this problem, the effects from different
acyl donors were subsequently screened. In these ex-
periments, PS-CI lipase and racemic 2-methyl-2-nitro-
1-(4-nitrophenyl) propan-1-ol (1a) were selected as
biocatalyst and alcohol substrate, respectively
(Table 2). As expected, the results showed low con-
versions in the KR process when isopropyl acetate
and isopropenyl acetate were used as acyl donors (en-
tries 1 and 2, Table 2). Better conversion was ob-
served when ethoxyvinyl acetate was used. Unfortu-
nately, this acylating agent cannot be use in the DKR
process because of nitroalkane attack to the acyl posi-
tion of ethoxyvinyl acetate yielding 3-methyl-3-nitro-
butan-2-one and ethyl acetate. However, p-chloro-
phenyl acetate revealed satisfactory results similar to
[a]
Reactions were carried out with 0.05 mmol (12 mg) of
rac-1a with 30 mg of enzyme and 5 equiv. of acyl donor
in 0.3 mL of toluene at 408C under an argon atmosphere
for 24 h.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis using OD column.
Enantiomericratio
Vinyl acetate was used as a solvent.
p-Chlorophenyl acetate was used as a solvent.
vinyl acetate (entry 4, Table 2). According to experi- solvent and dried under vacuum without loss of activi-
ence in the literature,[10] increasing the concentration ty. This experiment demonstrated that the method is
of the enzyme-substrate complex using the acyl donor an alternative method for synthesizing nitroalkanol
as solvent can lead to improved results. Surprisingly, derivatives via a one-pot reaction in high yield and
this approach revealed no enhancement of the yield with high enantiospecificity. To our knowledge, DKR
in the case of vinyl acetate, and no reaction for p- of nitro alcohol adducts has not been reported but the
chlorophenyl acetate (entries 5 and 6, Table 2). There- KR of similar substrates is known.[11] Therefore, this
fore, five equivalents of p-chlorophenyl acetate were new one-pot synthesis was applied to a range of dif-
used instead, even though this donor revealed slower ferent aldehyde substrates (Table 3).
conversion compared to vinyl acetate. No side reac-
tions were observed in this case.
p-Cyanobenzaldehyde (4b) was used under the
same conditions as for p-nitrobenzaldehyde but the
Finally, the one-pot DKR synthesis was carried out results showed slightly lower enantiospecificity
using an excess amount of 2-nitropropane together (Table 3, entry 2). In the case of benzaldehydes 4c–f,
with p-nitrobenzaldehyde, in the presence of PS-CI five equivalents of 2-nitropropane were used. The re-
and p-chlorophenyl acetate in toluene at 408C for 2 sults also showed high yields as well as enantiospeci-
days without stirring. Compound 2a was in this case ficities (entries 3–5, Table 3) except for 3,5-bis(tri-
isolated in 92% yield and 99% ee (entry 1, Table 3). fluoromethyl)benzaldehyde (4f) where the enantio-
The biocatalyst, Pseudomonas cepacia (PS-CI), was specificity decreased to 80% ee (entry 6, Table 3).
easily recovered by filtration, washed with organic This effect may be due to the presence of two groups
450
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Direct Asymmetric Dynamic Kinetic Resolution by Combined Lipase Catalysis
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Table 3. One-pot combined nitroaldol (Henry) reaction and
several aliphaticaldehydes (butyraldehyde, isovalery-
laldehyde, and octylaldehyde) were examined, howev-
er, all resulting in unsatisfactory enantiospecificities
(cf. Supporting Information) Thus, diminishing the al-
dehyde ring size, or the use of aliphaticaldehydes,
leads to decreasing enantiospecificities. On the other
hand, this one-pot procedure results in high stereo-
specificities for all benzaldehydes tested, the reaction
yields depending on the different substituents. The ab-
solute configuration of the stereogenic position was
assigned by a modified Mosherꢁs method.[12] Com-
pound 1a (99% ee), left from the kineticresolution by
enzyme-lipase PS-CI, was subsequently treated with
(À) and (+)-MTPACl in pyridine followed by purifi-
cation gave the corresponding ester 7a and 7a’. Based
on the Dd [d(À)Àd(+)] value, the (R)-configuration
was established for compound 2a. According to this
experiment, we propose the (R)-configuration for
compounds 2b–i.
lipase-catalyzed transesterification.[a]
Entry R
Product Time
[d]
Yield
[%][b]
ee
[%][c]
1
2
4-O2N-C6H4
2a
2b
2c
2d
2e
2f
2
2
3
3
3
3
90
89
89
90
92
80
99
91
97
91
97
80
4-NC-C6H4
4-F3C-C6H4
3-O2N-C6H4
3-NC-C6H4
3[d]
4[d]
5[d]
6[d]
3,5-bis
C6H3
ACHTREUNG(F3C)-
7[e]
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
C6H5
4-CH3-C6H4
4-CH3O-C6H4 2l
2-Thiophene 2m
2g
2h
2i
2j
2k
4
4
4
4
4
4
4
85
83
81
79
35
28
68
98
97
96
91
93
99
46
8[e]
9[e]
10[f]
11[f]
12[f]
13[f]
Conclusions
In summary, we have demonstrated for the first time
that the asymmetricsynthesis of b-nitroalkanol deriv-
atives can be simply and efficiently achieved by a
combined lipase-catalyzed transesterification and ni-
troaldol (Henry) reaction in a direct one-pot reaction.
Simple tuning of the reaction conditions allows for
the isolation of the desired products in good to excel-
lent yield, together with high stereospecificity, in rea-
sonable reaction times. Furthermore, easy handling of
the chemicals employed and also recovery of biocata-
lysts makes this system suitable for upscaling.
[a]
Reaction conditions:
0.125 mmol
benzaldehyde,
0.5 mmol 3, 0.25 mmol TEA, 106 mg p-chlorophenyl
acetate, 90 mg PS-CI, 0.25 mL toluene, 408C.
Isolated yield.
Determined by HPLC analysis using OD and OD-H
column.
[b]
[c]
[d,e]
[f]
5 and 10 equivalents of 2-nitropropane and 2.5 and 5
equivalents of TEA were used, respectively.
Reaction
conditions:
0.125 mmol
benzaldehyde,
1.25 mmol 3, 0.625 mmol TEA, 106 mg p-chlorophenyl
acetate, 120 mg PS-CI, 0.1 mL toluene, 408C.
Experimental Section
of similar size next to the stereogenic center. To ach-
ieve a reasonable equilibration rate for less electron- General Procedure for Dynamic Kinetic Resolution
withdrawing benzaldehydes, 4g–i, the amount of ni-
tropropane was increased up to ten equivalents. After
In a typical experiment, a reaction mixture of 4-nitrobenzal-
dehyde (4a) (19 mg, 0.125 mmol), 2-nitropropane (3)
a reaction time of 4 days, compounds 2g–i were ob-
tained in good yields and high enantiospecificities
(entries 7–9, Table 3). Similar conditions as for ben-
zaldehydes 4g–i were also applied in the cases of un-
substituted benzaldehyde 4j, benzaldehydes 4k–l with
electron-donating substituents, and heteroaromatic
benzaldehyde 4m. In 4 days reaction time, compound
2j was obtained in high yield and high enantiospecific-
ity (entry 10, Table 3). In contrast, benzaldehydes 4k
and 4l resulted in rather low yields, as expected from
the lower nitroaldol reaction rates, but retained high
enantiospecificities (entries 11 and 12, Table 3). The
heteroaromatic2-thiopheneacrboxzaldehyde ( 4l) re-
sulted in a higher yield but considerably lower enan-
tiospecificity of the b-nitroalkanol product within the
same reaction time (entry 13, Table 3). In addition,
(44 mg, 0.5 mmol), triethylamine (25 mg, 0.25 mmol), and 5
equivalents of p-chlorophenyl acetate (106 mg) in dry tolu-
ene (0.25 mL) were added to a sealed-cap vial (1.75 mL)
containing Pseudomonas cepacia (PS-CI, immobilized on
ceramic, Sigma–Aldrich, EC 3.1.1.3, 90 mg) together with
ground molecular sieve 4 Š (20 mg). The reaction mixture
was flushed with argon and stirred at 408C. After 2 days the
mixture was cooled to room temperature, filtered and
washed with CH2Cl2 (3”5 mL). The solvent was removed
under vacuum and the crude product was purified by
column chromatography [hexane:CH2Cl2 (1:4) to pure
CH2Cl2] affording 2a as a white amorphous; yield: 32 mg
(90%); 99% ee.
Adv. Synth. Catal. 2008, 350, 448 – 452
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Pornrapee Vongvilai et al.
FULL PAPERS
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