Mechanochemical enzymatic resolution of N-benzylated-β3-amino esters

Article abstract of DOI:10.3762/bjoc.13.167

The use of mechanochemistry to carry out enantioselective reactions has been explored in the last ten years with excellent results. Several chiral organocatalysts and even enzymes have proved to be resistant to milling conditions, which allows for rather efficient enantioselective transformations under ball-milling conditions. The present article reports the first example of a liquid-assisted grinding (LAG) mechanochemical enzymatic resolution of racemic β³-amino esters employing Candida antarctica lipase B (CALB) to afford highly valuable enantioenriched N-benzylated-β³-amino acids in good yields. Furthermore the present protocol is readily scalable.

Full text of DOI:10.3762/bjoc.13.167

Mechanochemical enzymatic resolution of
N-benzylated-β3-amino esters
Mario Pérez-Venegas1, Gloria Reyes-Rangel1, Adrián Neri2, Jaime Escalante*2
and Eusebio Juaristi*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1728–1734.
1Departamento de Química, Centro de Investigación y de Estudios
Avanzados, Avenida I.P.N. 2508, Ciudad de México, 07360, Mexico,
2Centro de Investigaciones Químicas, Universidad Autónoma del
Estado de Morelos, Av. Universidad 1001, Cuernavaca, Morelos,
62210, Mexico and 3El Colegio Nacional, Luis Gonzáles Obregón 23,
Centro Histórico, Ciudad de México, 06020, Mexico
doi:10.3762/bjoc.13.167
Received: 29 May 2017
Accepted: 01 August 2017
Published: 18 August 2017
This article is part of the Thematic Series "Mechanochemistry".
Guest Editor: J. G. Hernández
Email:
Jaime Escalante* - jaime@uaem.mx; Eusebio Juaristi* -
juaristi@relaq.mx
© 2017 Pérez-Venegas et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
ball-milling; β3-amino acid; Candida antarctica lipase B; enzymatic
resolution; mechanochemistry
Abstract
The use of mechanochemistry to carry out enantioselective reactions has been explored in the last ten years with excellent results.
Several chiral organocatalysts and even enzymes have proved to be resistant to milling conditions, which allows for rather efficient
enantioselective transformations under ball-milling conditions. The present article reports the first example of a liquid-assisted
grinding (LAG) mechanochemical enzymatic resolution of racemic β3-amino esters employing Candida antarctica lipase B
(CALB) to afford highly valuable enantioenriched N-benzylated-β3-amino acids in good yields. Furthermore the present protocol is
readily scalable.
Introduction
β-Amino acids are rather interesting molecules that frequently numerous natural products [10]. These properties have gener-
exhibit exceptional biological properties [1-3]; for instance, ated great interest in the development of synthetic methods for
some of them are efficient inhibitors of several enzymes [4,5]. the preparation of β-amino acids, especially protocols leading to
Furthermore, β-amino acid residues can be used to protect products with high enantiomeric excess (ee), which are re-
peptides and proteins against the activity of proteolytic en- quired to test the pharmacological activity of each enantiomer
zymes [6,7], or are precursors of numerous active compounds [11-13]. In this regard, several methods for the asymmetric syn-
such as β-lactams [8,9]. Finally, β-amino acids are present in thesis of β-amino acids have been documented [14-22] includ-
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ing strategies based on organocatalysis [23-26] and kinetic reso- LAG additive (η = 1.63) and 40 mg of CALB (Novozym 435,
lution using enzymes such as Candida antarctica lipase B, Novozymes, recombinant, expressed in Aspergillus niger,
which was shown to be efficient in the resolution of racemic immobilized in acrylic resin, >10000 U/g) at 25 Hz during
β-amino acids under various conditions [27-30].
30 min. Gratifyingly, 55% conversion to the enantioenriched
(R)-N-benzylated-β3-amino acid (R)-2a was observed, recov-
Among recent developments in instrumentation for synthetic ering 51% of enantioenriched starting material. It could be
chemistry, mechanochemistry has proved a rather attractive and established by chiral HPLC that the ee of the product amounted
useful technique [31-37]. In particular, it has been demon- 80% (Table 1, entry 1). This assay demonstrated that enzymatic
strated that mechanochemistry allows for the generation of hydrolysis can indeed be carried out under HSBM conditions. A
products through catalysts that can be recovered and reused [38- second reaction was carried out under the same conditions but
44], so this converts mechanochemistry into a green technique, in the absence of the enzyme, which did not proceed and the
whose field of application is still very wide.
starting material was recovered in its totality. This result shows
that the observed hydrolysis is induced by CALB and not by the
In this context, the use of a minimal amount of solvent (LAG) milling process per se. Furthermore, it could be established that
enable the development of convenient ball-milling protocols. In the CALB enzyme and N-benzylated-β3-amino esters are stable
particular, LAG facilitates mechanochemical applications on a to the mechanical force caused by HSBM. We then focused our
large scale [45,46].
attention on the search of the best conditions for this enzymatic
mechanochemical resolution.
Very recently, Hernández, Frings, and Bolm developed a
method to carry out the kinetic resolution of secondary alcohols First of all, we examined the effect of the milling frequency,
through selective acylation using Candida antarctica lipase B, 15 Hz (Table 1, entry 2). Both yield and ee decreased substan-
under solvent-free ball-milling conditions [47,48]. Inspired by tially in comparison with the initial approach carried out at
this ground-breaking report, which is in line with our continu- 25 Hz (Table 1, entry 1). Nevertheless, when the reaction time
ous interest in developing new sustainable organocatalytic was increased from 30 min to 1 h at 15 Hz (Table 1, entry 3) the
protocols [39,49-51], and taking advantage of previous experi- yield of the N-benzylated-β3-amino acid reached 49%, and
ence with the enzymatic hydrolysis of a racemic mixture of presented high ee (95%, E > 200). These data represent an
N-protected-β3-amino acid methyl esters [52], we decided to ex- improvement both in ee and yield compared with the data re-
amine the use of CALB enzyme under high-speed ball-milling corded in solution [52]. Motivated by this result, we investigat-
(HSBM) conditions as a method to obtain enantiopure ed the effect of other LAG additives in the reaction (see Sup-
N-benzylated-β3-amino acids (Scheme 1).
porting Information File 1, Table S1, entries 4–10). When
2M2B was replaced with other LAG additives a lower yield was
observed (Table 1, entries 4–6). Nevertheless, the enantioselec-
Results and Discussion
A racemic mixture of substrate rac-1a (82 mg, 1 equiv) was tivity of the process is maintained (95% ee), except when
milled in an Agate jar (12 mm of diameter, 4.6 mL) with an hexane was used (Table 1, entry 7), where a higher yield was
Agate ball (6 mm of diameter, 480 mg weight) using water observed (60%) although with a lower enantiomeric excess
(3.6 μL, 0.5 equiv), 0.2 mL of 2-methyl-2-butanol (2M2B) as a (86% ee). In the absence of a LAG additive and using
Scheme 1: Enantioselective enzymatic hydrolysis of racemic β3-amino ester rac-1a using CALB in solution [52] (top) and under HSBM conditions
(button). 2M2B: 2-methyl-2-butanol.
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Beilstein J. Org. Chem. 2017, 13, 1728–1734.
Table 1: Search of the best parameters in the enzymatic enantioselective hydrolysis of rac-1a under ball milling.
entrya
LAG additiveb
yield (%)c (S)-1a/(R)-2a time (h)
ee (S)-1a (%)d
ee (R)-2a (%)d
ce (%)
Ef
1g
2
2M2B
2M2B
2M2B
AcOEt
IPA
51/49
70/30
51/49
86/13
82/21
65/29
40/60
58/41
58/42
68/31
0.5
0.5
1
99
89
99
69
48
65
97
95
93
74
80
77
95
95
95
95
86
92
86
80
55
54
51
42
34
41
53
51
52
48
46
23
3
>200
81
4
1
5
1
63
6
CH3CN
hexane
–
1
77
7
1
55
8
1
89
9g
10h
–
1
45
–
1
20
aReactions were carried out with 0.5 equivalents of water and 15 Hz of frequency. b0.2 mL of LAG additive was used. cDetermined after purification
by flash chromatography. dDetermined by HPLC with chiral stationary phase. eCalculated from c = ees/(ees + eep).
fE = ln[1 − c(1 + eep)]/ln[1 − c(1 − eep)]. g25 Hz of frequency was used. h0.25 equivalents of water were used.
0.25 equivalents of water (Table 1, entries 8–10) both yield and carried out in the absence of water only traces of product were
ee were lower.
detected (see Supporting Information File 1 Table S1).
Water plays an important role in the reaction controlling the ac- To determine the substrate scope, the conditions that led to the
tivity of the enzyme; for example, the use of 0.5 equivalents of best results in the enzymatic resolution of substrate rac-1a
water yielded 49% of product 2a (Table 1, entry 3). However, (Table 1, entry 3) were employed with other racemic N-benzyl-
when 1 equivalent of water was employed the yield of the prod- ated-β3-amino esters as substrates (Table 2). It can be appreci-
uct increased to 92%. By contrast, when the reaction was ated that reaction yields decrease when longer aliphatic chains
Table 2: Substrate scope for the enzymatic resolution of N-benzylated-β3-amino esters.
yield (%)b
(S)-1/(R)-2
absolute
configurationh
entrya rac
R
eec (S)-1 (%)
eec (R)-2 (%)
cf (%)
Eg
1
2
3
4
5
6i
7i
8
1b
CH3-(CH2)-
51/49
53/43
68/29
74/24
79/18
92/10
89/10
89/4
91
84
23
57
13
18
1
4.5
2.1
97
98
94
94
91
83
80
94
−36.5
−45.2
−35.3
−40.0
−39.7
−35.0
−31.7
12.8
48
46
20
15
13
18
1
>200
>200
40
R
R
R
R
R
S
S
S
1c CH3-(CH2)2-
1d CH3-(CH2)3-
1e CH3-(CH2)4-
2.0
0.2
38
1f
1g
1h
1i
CH3-(CH2)5-
Ph
0.8
24
3.4
13
4-MeO-Ph
t-Bu
−0.5
−0.6
9
4
4
34
aReactions were carried out with 0.5 equivalents of water and 0.2 mL of 2M2B at 15 Hz during 1 h. bDetermined after purification by flash chromato-
graphy. cDetermined by HPLC with chiral stationary phase. dc = 0.33 in CH3Cl. ec = 0.33 in MeOH. fCalculated from c = ees/(ees + eep).
gE = ln[1 − c(1 + eep)]/ln[1 − c(1 − eep)]. hAssigned by chemical correlation and by HPLC with chiral stationary phase.
i0.75 equivalents of water were used.
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Beilstein J. Org. Chem. 2017, 13, 1728–1734.
are present in the substrate (Table 2, entries 1–5), although the
ee in products 2b–f remained rather high (>90%). Notably, this
aliphatic chain-length effect has been studied in other systems
with similar results [53].
The introduction of an aromatic ring (either unsubstituted or
para-substituted) in the substrate resulted in diminished yields
(Table 2, entries 6 and 7) but good ee (≥80%). With bulky
groups, such as tert-butyl, the experimentally observed low
yield was accompanied nevertheless by high ee (Table 2,
entry 8). Other reaction conditions were tested aiming of in-
creasing both yield and ee (see Supporting Information File 1);
however, the best results continued to be obtained by using the
conditions indicated in Table 1, entry 3.
To establish the absolute configuration of product 2a, a sample
was crystallized to give a suitable single-crystal for X-ray
diffraction analysis. The resulting structure showed the
R configuration (Flack parameter = 0.154) in the stereocenter
Figure 1: X-ray crystallographic structure of product (R)-2a (50% of
probability ellipsoids). CCDC registry number 1552645.
delimited by the atoms marked as C1, N1 and C3 (Figure 1). not as good as the obtained with fresh catalyst (compare entries
The R configuration in hydrolyzed product 2a was confirmed 1 and 2 in Table 3). This might suggest that the enzyme under-
by comparison with literature data [52]. The configuration of goes partial denaturation and/or partial destruction of the
products 2b, 2g to 2i was also assigned by comparison with lit- support, within each cycle (Table 3, entry 3). Interestingly,
erature data [52,54,55]. Finally, in the case of products 2c–f, however, ee values of the isolated β-amino acid still resulted
comparison of the elution order for both enantiomers with the quite acceptable. On the other hand, no product was detected
tendency found in 2a and 2b suggested that the configuration is after the third cycle. To evaluate the denaturalization of the en-
the same in all of them (see Supporting Information File 1) zyme provoked by the milling process, a sample of fresh cata-
[56,57].
lyst was milled for 1 h at 15 Hz under solvent-free conditions
and in the presence of a LAG additive, finding that both reac-
The enzyme employed in these experiments was recovered by tion yield (38%) and ee (>90%) are higher (see Supporting
centrifugation of the reaction crude followed by drying under Information File 1, Table S3, entries 5 and 6), compared with
vacuum (90% of recovered enzyme; we will call it rCALB). results from the hydrolysis using the catalyst recovered after the
This recovered material was reused to evaluate the enzyme re- first cycle (Table 4, entry 2). The milling process carried out
cyclability after the mechanochemical protocol. When the reac- using the catalyst milled with 2M2B presents a slight decrease
tion was carried out using the recovered enzyme the yield was in ee compared with the resolution reaction using the milled en-
Table 3: Recycling capacity of immobilized CALB under HSBM conditions.
entrya
recycling cycle
yield (%)b (S)-1a/(R)-2a
eec (S)-1a (%)
eec (R)-2a (%)
cd (%)
Ee
1
2
3
4
–
1
2
3
51/49
65/37
80/20
100/0
49
35
6
95
88
80
–
51
59
51
–
>200
22
10
0
–
aReactions were carried out with 0.5 equivalents of water and 0.2 mL of 2M2B at 15 Hz during 1 h. bDetermined after purification by flash chromato-
graphy. cDetermined by HPLC with chiral stationary phase. dCalculated from c = ees/(ees + eep). eE = ln[1 − c(1 + eep)]/ln[1 − c(1 − eep)].
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Beilstein J. Org. Chem. 2017, 13, 1728–1734.
Table 4: Scaling-up of the enzymatic hydrolysis reaction under ball-milling using substrate rac-1a.
entrya catalyst/substrate (equiv) b
yield (%)c (S)-1a/(R)-2a
eed (S)-1a (%)
eed (R)-2a (%)
ce (%)
Ef
1g
2
1/1
1/3
1/6
1/9
51/49
52/48
61/42
59/40
>99
62
95
93
93
94
51
40
36
34
>200
52
3
53
47
4
49
53
aReactions were carried out with 0.5 equivalents of water at 15 Hz during 1 h. b1 equivalent of enzyme = 40 mg; 1 equivalent of susbtrate = 82 mg.
cDetermined after purification by flash chromatography. dDetermined by HPLC with chiral stationary phase. eCalculated from c = ees/(ees + eep).
fE = ln[1 − c(1 + eep)]/ln[1 − c(1 − eep)]. g0.2 mL of LAG additive were used.
zyme under solvent-free conditions. This observation suggests spite of a decrease in yield in the case of long aliphatic chains.
that the LAG additive increases to some extent the degree of This efficiency of the enzymatic process is also observed in
denaturation of the enzyme, reducing the enantiodiscrimination substrates with bulky aromatic groups (ee ≥ 80%). The reaction
(ee = 91%) although maintaining significant catalytic activity is best carried out in the presence of the LAG additive
(yield = 38%).
2-methyl-2-butanol when the concentration of the substrate is
low. The enzymatic process could be scaled-up to 9-fold
Finally, to test the scalability of the process, a set of reactions affording the hydrolyzed product with high ee (≥93%) and an
was carried out increasing the amount of substrate rac-1a under excellent yield (40% out of a 50% theoretical maximum).
the optimized reaction parameters. (Table 4).
Finally, the enzyme catalyst could be recovered and reused
several times affording the desired amino acids with good ee al-
Relative to the results obtained with 1 equivalent of rac-1a in though with a decrease in conversion due to a partial denatura-
the presence of LAG additive (Table 4, entry 1) a slight de- tion process and partial destruction of the enzyme support.
crease in yield was observed when 3 equivalents of substrate
(and no LAG additive) were used to carry out the reaction
Supporting Information
(Table 4, entry 2). Nevertheless, the hydrolysis still proceeds
with excellent ee (93%). This result confirms that under sol-
Supporting Information File 1
vent-free conditions a particular amount of enzyme can cata-
lyze a larger amount of substrate, even up to nine equivalents,
without loss of enantiodiscrimination (Table 4, entry 4). It
appears that this high efficiency is a consequence of the highly-
concentrated medium that is generated under solvent-free
mechanochemical conditions, an effect that is not possible to
reach in solution [52]. This effect also allows for an increase in
the amount of product per cycle of the enzymatic reaction.
Experimental section, NMR spectra, chromatograms and
X-ray diffraction data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-167-S1.pdf]
Acknowledgements
Financial support from CONACYT, via grant 256653, is grate-
fully acknowledged. M.P-V. thanks CONACYT for Ph.D.
scholarship 707667.
Conclusion
The capacity of immobilized CALB to carry out the enzymatic
hydrolytic resolution of N-benzylated-β3-amino esters under
mechanochemical conditions was demonstrated. The reaction
proceeds with an excellent yield (up to 49% of the theoretical
50% maximum) and high enantioselectivity (up to 98% ee). The
method proved to be efficient in the resolution of racemic mix-
tures of β3-amino esters with aliphatic chains of different
lengths, affording high ees of the resulting β-amino acids in
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