An efficient dynamic kinetic resolution of N-heterocyclic 1,2-amino alcohols

Article abstract of DOI:10.1002/adsc.201100466

A chemoenzymatic dynamic kinetic resolution (DKR) of N-heterocyclic amino alcohols is described. Various lipases were studied as biocatalysts for the kinetic resolution of N-heterocyclic 1,2-amino alcohols. The influence of the support of the enzymes on t

Full text of DOI:10.1002/adsc.201100466

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DOI: 10.1002/adsc.201100466
An Efficient Dynamic Kinetic Resolution of N-Heterocyclic
1,2-Amino Alcohols
Richard Lihammar,a Renaud Millet,a and Jan-E. Bꢀckvalla,*
a
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Fax : (+46)-8-154-908; e-mail: jeb@organ.su.se
Received: June 8, 2011; Published online: August 26, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100466.
Abstract: A chemoenzymatic dynamic kinetic reso-
lution (DKR) of N-heterocyclic amino alcohols is
described. Various lipases were studied as biocata-
lysts for the kinetic resolution of N-heterocyclic 1,2-
amino alcohols. The influence of the support of the
enzymes on the enantioselectivity in the resolution
of different substrates is highlighted. Various 3-ace-
toxypyrrolidines and -piperidines were obtained in
high yield and high enantiomeric excess in efficient
DKR reactions.
compounds to chiral ligands and organocatalysts in
asymmetric synthesis.[1,2,3] Various methods have been
described for the preparation of N-heterocyclic alco-
hols in an optically active form[4]; however, only a few
of those involve enzymatic resolution.[5]
Enzymatic kinetic resolution (KR) is a highly pow-
erful tool for obtaining enantiopure alcohols and
amines.[6] It remains however limited by a theoretical
maximum yield of 50%. To overcome this limitation,
in situ racemisation, using an additional catalyst, has
been integrated with the KR protocol (Scheme 1).
This integrated system, known as dynamic kinetic res-
olution (DKR)[7], enables the reaction to proceed
beyond the 50% yield barrier and reach a theoretical
yield of 100% with high enantiomeric excess. The
number of substrate classes suitable for chemoenzy-
matic DKR with transition metal racemisation cata-
Keywords: amino alcohols; biocatalysis; dynamic
kinetic resolution; enzymatic catalysis; lipase
N-Heterocyclic chiral molecules are highly attractive lysts has increased during the past decade from the
compounds for industry and academic research.[1] early examples of simple benzylic alcohols with ali-
Among them, molecules bearing chiral secondary al- phatic substituents to more functionalised substrates
cohols such as 3-hydroxypiperidines or 3-hydroxypyr- such as chlorohydrins,[8] cyanohydrins,[9] diols,[10]
rolidines constitute an important class of molecules. amines,[11] axially chiral allenes,[12] and amino alco-
They have a wide application scope ranging from in- hols.[13]
termediates for the synthesis of biologically active
Scheme 1. Two examples of ruthenium-based racemisation catalysts (C1 and C2) and a schematic picture of an (R)-selective
dynamic kinetic resolution (DKR).
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Table 1. Kinetic resolution of 1a with various enzymes.[a]
In order to further explore the limitations of che-
moenzymatic DKR, we have now investigated the use
of this method for transforming racemic 1,2-amino al-
cohols into enantiomerically pure forms.[14]
Tomori et al.[5c] reported highly selective enzymatic
hydrolysis and transesterification processes for the
KR of N-heterocyclic acetates and alcohols, respec-
tively, employing lipase PS. However, the transesteri-
fication reaction required a large amount of biocata-
lyst (500 wt%) making it unsuitable for large-scale
synthesis. Horiguchi et al.[5d] described a similar reso-
lution in a flow reactor employing supported lipase
PS, which increased the catalytic activity of the
enzyme. Inspired by these results we decided to inves-
tigate the possibility of applying dynamic kinetic reso-
lution to a variety of substituted N-heterocyclic alco-
hols.
To prove the utility of the DKR process we envi-
sioned to study substrates with various groups at-
tached to the nitrogen of the heterocycle. Electron-
withdrawing N-protecting groups, electron-donating
aliphatic substituents, and N-aryls were considered
valuable to investigate. This range of substrates would
illustrate the viability of the protocol both before and
after a desired synthetic transformation.
Entry Enzyme Conv.
[%][b]
eeOH
eeOAc
Evalue[d]
[%][c]
[%][c]
1
2
3
4
PS
PS-C
PS-IM 19
IL1-PS 48
0
13
–
–
–
20
25
>200
(290)
67
13
16
88
89
91
98
5
CALB 51
96
89
[a]
The reactions were run at room temperature for 20 h on
a 0.25-mmol scale under argon using 5 mg of enzyme,
2 equiv. of isopropenyl acetate in 1 mL of toluene.
Calculated from the eeOH and eeOAc according to the for-
mula: Conv.=eeOH/(eeOAc+eeOH).
[b]
[c]
[d]
Determined by chiral HPLC (see Supporting Informa-
tion for more details).
Calculated from the eeOH and eeOAc according to formu-
la.[15]
As a model substrate we chose to start by investi-
gating the kinetic resolution of N-benzylpiperidin-3-ol
(1a).
As previously reported,[5c] non-immobilized PS
(Burkholderia cepacia, previously Pseudomonas cepa-
cia) showed very low activity in the transesterification
of 1a (Table 1, entry 1). When an immobilised PS
enzyme was employed the activity was increased and
an enantioselective reaction was obtained. Commer-
cially available lipases PS-IM (Burkholderia cepacia
immobilised on diatomaceous earth) and PS-C (Bur-
kholderia cepacia immobilised on ceramic particles)
showed moderate enantioselectivity with E values
ranging from 20 to 25 (Table 1, entries 2 and 3). On
the other hand IL1-PS[16] (Burkholderia cepacia
Scheme 2. First DKR attempt employing C1 as racemisation
catalyst.
coated with ionic liquid) showed an E value of 290 ed acetate 4a with a dramatic drop in ee (4% ee at
determined at 48% conversion. This was the highest full conversion). During the reaction, N-benzylpyrrole
E value observed for this substrate in the study was formed in approximately 10%. The decrease in
(Table 1, entry 4). A high activity with a good enan- enantioselectivity was confirmed to be due to a
tioselectivity was observed in the KR with CALB severe loss of selectivity in the enzymatic resolution
(Candida antarctica lipase B immobilized on acrylic (vide infra, Table 2) and highlighted the importance
resin, Novozyme 435ꢂ), which afforded an E value of of looking for the most suitable enzyme for each sub-
67 at 51% conversion (Table 1, entry 5). Even though strate.
the selectivity was not as high as for IL1-PS this result
was promising since CALB was not known to be able smaller substituent on the nitrogen, PS-IM showed
to resolve these types of cyclic secondary alcohols. the best selectivity with an E value of >400 (810) at
For N-isopropylpiperidin-3-ol (1b), which has a
Next a dynamic kinetic resolution was set up using room temperature (Scheme 3, Table 2, entry 5). In the
Shvoꢃs catalyst C1 for the racemisation and IL1-PS case of the N-cyclohexyl alcohol 1c (Cy=cyclohexyl)
for the resolution (Scheme 2).
an E value of >600 (1143) was obtained with IL1-PS
The reaction proceeded to full conversion within (Table 2, entry 9). With a cyclohexylmethyl group on
24 h at 708C giving acetate 2a in 90% ee. Under the the nitrogen (1d), both PS-IM and IL1-PS lost all ac-
same conditions, N-benzylpyrrolidin-3-ol (3a) afford- tivity while CALB displayed high selectivity (Table 2,
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An Efficient Dynamic Kinetic Resolution of N-Heterocyclic 1,2-Amino Alcohols
Table 2. Kinetic resolution of various 1,2-cyclic amino alcohols employing different lipases.[a]
Entry
Substrate
Enzyme
Conv. [%][b]
eeOH [%][c]
eeOAc [%][c]
E value[d]
1
2
3
4
PS
0
–
–
–
25
PS-IM
IL1-PS
CALB
19
48
51
16
88
96
91
98
89
>200 (290)
67
5
6
7
PS-IM
IL1-PS
CALB
18
11
41
20
9
64
99.7
99.4
96
>400 (810)
>200 (363)
95
8
9
10
PS-IM
IL1-PS
CALB
26
48
50
36
93
94
99.0
99.4
93
>200 (283)
>600 (1143)
98
11
12
13
PS-IM
IL1-PS
CALB
5
5
42
nd[e]
nd[e]
nd[e]
–
–
98
–
–
>200
14
15
16
PS-IM
IL1-PS
CALB
9
34
47
12
50
90
99
99
99
200
>200 (327)
>300 (617)
17
PS-IM
PS-IM
IL1-PS
CALB
53
20.5
65
nd[e]
nd[e]
nd[e]
–
89
99.8
52
–
nd[f]
>600 (1285)
11
–
18[g]
19
20
100
21[g]
22[g]
PS-IM
IL1-PS
45
55
80
99.8
>98
82
>200 (244)
67
23
24
25
PS-IM
IL1-PS
CALB
20
51
73
23
92
46
94
90
-
40
62
10
[a]
Typical conditions: substrate (0.25 mmol), lipase (25 mgmmolÀ1), isopropenyl acetate (2 equiv.) in toluene (1 mL) at
room temperature for 20 h. Cy=cyclohexyl.
Calculated from both ee, Conv.=eeOH/(eeOAc+eeOH) or determined by H NMR.
Determined by chiral GC or chiral HPLC (see Supporting Information for more details).
Calculated from both ee or from conversion and ee according to formula.[15]
No chiral separation methods for the alcohol were found.
Conversion was too close to 50% to allow accurate determination of E value.
Reaction time 3 h.
[b]
[c]
[d]
[e]
[f]
1
[g]
entries 11–13). Substrate 1f seemed to be within the them (Table 2, entries 14–16). CALB was considered
optimal size range for all three biocatalysts screened as the best enzyme for the resolution of this substrate
since good enantioselectivity was observed for all of due to its high activity.
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Scheme 3. KR conditions of various cyclic amino alcohols.
Scheme 5. General scheme for DKR of N-substituted pyrro-
lidin-3-ols and piperidin-3-ols.
Turning our attention to the substituted 3-pyrrolidi-
nols, once again the support of the enzyme appeared
to play a major role in the activity and selectivity of peratures which is crucial for the PS selectivity and
the enzyme. IL1-PS showed a low selectivity for sub- stability.
strate 3a (E=11, Table 2, entry 19), thus explaining
The conditions used for resolution of alcohol 1a
the low ee obtained previously (vide supra). However, were applied in a first attempt for the DKR of alco-
in this case, lipase PS-IM showed the highest enantio- hol 1b, but full conversion was not reached within
selectivity with an E value of 125 (Table 2, entry 18). 24 h. The reaction also yielded a slightly lower ee
The N-Cbz-pyrrolidin-3-ol (3b) showed the same re- than expected.[17] Prolongation of the reaction time
sults with the lipase PS-IM being more selective than from 24 to 36 h did not bring the reaction to comple-
IL1-PS (Table 2, entries 21 and 22). Finally, the N- tion since the PS lipase loses its activity after long re-
phenylpyrrolidin-3-ol (3c) was resolved in more mod- action times at these temperatures. The reaction con-
erate enantioselectivity by both PS-IM and IL1-PS ditions for 1b and also for the remaining substrates
(Table 2, entries 23 and 24). The results from these ki- therefore needed to be optimised in terms of enzyme
netic resolutions also illustrate the general trend that loading, acyl donor amount, and temperature
IL1-PS displays a faster catalysis of the transesterifi- (Scheme 5).
cation than PS-IM.
For substrates bearing an aliphatic substituent on
These kinetic resolutions highlight the impact that the nitrogen (1b–1e) an increase of the amount of
the support of an enzyme can play in such processes. acyl donor was needed due to low reactivity, and this
The same lipase can show dramatic variations in resulted in a decrease in enantioselectivity under the
enantioselectivity for the same substrate simply due reaction conditions. This decrease was hypothesised
to the immobilisation technique used.
to occur due to chemical acylation facilitated by the
Both racemisation catalyst C1 and C2 were com- tertiary amine. However, a background experiment
pared in the DKR of 1a at 608C (Scheme 4). The re- run at 708C for substrate 1b failed to show any signifi-
action with C2 as racemisation catalyst gave a product cant chemical acylation. Furthermore, higher yield
with a higher ee (96% ee) than that with C1 (91% ee). and somewhat better ee were obtained when the reac-
This slight difference is due to a more efficient race- tion was run at 508C instead of 608C (Table 3, en-
misation with C2 as the catalyst. This is advantageous tries 3 and 4). N-Cyclohexyl-3-acetoxypiperidine (2c)
since it enables the reaction to be run at lower tem- was isolated in a 89% yield and an excellent ee of
99% (Table 3, entry 5). The resulting ee and conver-
sion of 1d was lower than expected under the opti-
mised conditions and further elaboration with the re-
action conditions failed to improve the results
(Table 3, entry 6).
Acetate 2e was obtained in a 1:1 diastereomeric
mixture with a high ee. In order to determine the ee
the double bond was reduced, affording the known
acetate 2c in an ee above 98% (Scheme 6).
N-Tosyl-3-acetoxypiperidine (2f) was obtained in
88% yield and 96% ee (Table 3, entry 9).
N-Benzyl- and Cbz-protected pyrrolidinols 3a and
3b were efficiently converted to the enantioenriched
acetates 4a and 4b, respectively, in more than 95% ee
and yields above 80% (Table 3, entries 10 and 11).
Scheme 4. DKR of substrate 1a. Method A: 1a (0.25 mmol),
C1 (6.6 mg), IL1-PS (10 mg), PCPA (3.5 equiv.); Method B:
1a (0.5 mmol), C2 (16 mg), t-BuOK (3.4 mg), Na2CO3
(53 mg), IL1-PS (12.5 mg), isopropenyl acetate (2 equiv.).
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An Efficient Dynamic Kinetic Resolution of N-Heterocyclic 1,2-Amino Alcohols
Table 3. Dynamic kinetic resolution of substrates 1a–f and 3a–3c.[a]
Entry
1
Substrate
Enzyme (x mgmmolÀ1)
IL1-PS (25 mgmmolÀ1)
Isopropenyl acetate
2 equiv.
Product
Yield [%][b]
eeOAc [%][c]
91
96
2[d]
3
PS-IM (40 mgmmolÀ1)
PS-IM (80 mmol)
2 equiv.
4 equiv.
4 equiv.
(84)
76
86
92
95.4
96.4
4[d]
PS-IM(80 mgmmolÀ1)
5[d]
PS-IM (80 mgmmolÀ1)
CALB (40 mgmmolÀ1)
6 equiv.
4 equiv.
89
73
99
90
6
7[d]
8[d]
PS-IM (80 mgmmolÀ1)
PS-IM (80 mgmmolÀ1)
4 equiv.
6 equiv.
(70)
(83)
nd
98.6[e]
9[f]
CALB (25 mgmmolÀ1)
PS-IM (25 mgmmolÀ1)
2 equiv.
2 equiv.
88
80
96
95
10
11
PS-IM (25 mgmmolÀ1)
2 equiv.
87
95
12
13
IL1-PS (40 mgmmolÀ1)
PS-IM (25 mgmmolÀ1)
2 equiv.
4 equiv.
N
28
86
[a]
Typical conditions: substrate (0.5 mmol), C2 (5 mol%), t-BuOK (6 mol%), Na2CO3 (1 equiv.), lipase (25–80 mgmmolÀ1),
isopropenyl acetate (2.6 equiv.) in toluene (1 mL). See Supporting Information for more details. Cy=cyclohexyl.
Isolated yield, in parenthesis H NMR conversion.
Determined by chiral GC or chiral HPLC (see Supporting Information for more details).
Reaction run at 508C.
The ee was determined after hydrogenation of a 1:1 mixture of diastereomers.
6 mol% of C2 used.
[b]
[c]
[d]
[e]
[f]
1
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PS-D) and Prof. Itoh for providing IL1-PS. The authors
thank INTENANT for financial support. R.M is gratefully
acknowledging the Swiss National Science Foundation for a
postdoctoral stipend.
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DKR for N-phenylpyrrolidin-3-ol (3c) was first con-
ducted with IL1-PS, which was the most selective
enzyme in the KR study. The result was discouraging
since the ee of the acetate 4c was as low as 28%.
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tate in 86% ee and 82% yield (Table 3, entry 13).
In summary, DKR has been successfully applied to
various vicinal amino alcohols with a 3-hydroxypyrro-
lidine or -piperidine structure. A variety of electron-
withdrawing and electron-donating substituents on
the cyclic amine can be used. We also pinpointed the
importance of the effect of the immobilisation tech-
nique on the outcome of the enzymatic resolution.
Experimental Section
General Procedure for Dynamic Kinetic Resolution
of N-Benzyl-3-hydroxypiperidine 1a
Ruthenium complex C2 (h5-C5Ph5)Ru(CO)2Cl (16 mg,
0.025 mmol), IL1-PS (12.5 mg, 25 mgmmolÀ1 substrate) and
Na2CO3 (53 mg, 0.5 mmol) were added to a dry Schlenk
tube. Dry toluene (0.5 mL) was added and the resulting
yellow solution was stirred. A THF solution of t-BuOK
(60 mL, 0.5M in dry THF, 0.03 mmol) was added to the reac-
tion mixture. The reaction mixture turned orange. After ap-
proximately 5 min of stirring, rac-1a (95,6 mg, 0.5 mmol) dis-
solved in dry toluene (0.5 mL), was added to the reaction
mixture. After an additional 5 min, isopropenyl acetate
(110 mL, 1 mmol) was added. The reaction mixture was
heated to 608C. After 24 h the reaction mixture was filtered
and concentrated. Purification by Kugelrohr distillation (0.6
mmHg, 1308C) afforded (R)-2a in 96% ee; yield: 106 mg
(46 mmol, 91%). Spectral data were in accordance with
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Acknowledgements
We gratefully acknowledge Dr. Allan Svendsen, Novozymes
A/S for a generous gift of CALB (Novozym 435). We also
thank Dr. Yoshihiko Hirose, Amano Enzyme Inc. Gifu R&D
Center for kindly providing us with enzymes (PS-IM, PS-C,
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An Efficient Dynamic Kinetic Resolution of N-Heterocyclic 1,2-Amino Alcohols
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[15] E=ln[(eeOAc ꢇ(1ÀeeOH)/(eeOAc+eeOH)]/ln[eeOAc ꢇ(1+
eeOH)/(eeOAc+eeOH)]=ln{1À
[conv.ꢇ
E
[conv.ꢇ
G
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