Enzymatic dynamic kinetic resolution of (±)-cis-N-(Alkoxycarbonyl) cyclopentane-1,2-diamines based on spontaneous racemization

Article abstract of DOI:10.1021/ol101378k

Lipase B from Candida antarctica is an excellent catalyst for the enantioselective acetylation of different (±)-cis-N-(alkoxycarbonyl) cyclopentane-1,2-diamines. Depending on the alkoxycarbonyl group, a simple kinetic resolution (Boc-derivative) or an interesting dynamic kinetic resolution (DKR with Cbz-, Alloc, and ethoxycarbonyl derivatives) has been developed. Racemization for the DKR occurred due to the N,N′ intramolecular migration of the alkoxycarbonyl group.

Full text of DOI:10.1021/ol101378k

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3602-3605
Enzymatic Dynamic Kinetic Resolution of
(()-cis-N-(Alkoxycarbonyl)cyclopentane-
1,2-diamines based on Spontaneous
Racemization
F. Javier Quijada, Vicente Gotor,* and Francisca Rebolledo*
Departamento de Qu´ımica Orga´nica e Inorga´nica, and Instituto UniVersitario de
Biotecnolog´ıa de Asturias, UniVersidad de OViedo, 33071 OViedo, Spain
Vgs@unioVi.es; frV@unioVi.es
Received June 16, 2010
ABSTRACT
Lipase B from Candida antarctica is an excellent catalyst for the enantioselective acetylation of different (()-cis-N-(alkoxycarbonyl)cyclopentane-
1,2-diamines. Depending on the alkoxycarbonyl group, a simple kinetic resolution (Boc-derivative) or an interesting dynamic kinetic resolution
(DKR with Cbz-, Alloc, and ethoxycarbonyl derivatives) has been developed. Racemization for the DKR occurred due to the N,N′ intramolecular
migration of the alkoxycarbonyl group.
Currently, the increasing demand for both enantiomerically
pure compounds and environmentally friendly procedures
is being largely satisfied by the use of biocatalysts.1 In this
context, lipase-catalyzed kinetic resolution (KR) of racemic
mixtures continues to be one of the easiest and most efficient
methods to produce optically active alcohols, amines, and
their derivatives.2 However, in those cases in which only
one enantiomer is required, dynamic kinetic resolution
(DKR) is the best choice as it allows the desired enantiomer
to be obtained with 100% theoretical yield, in contrast with
the maximum 50% yield of KR. For successful DKR,
efficient racemization of the substrate is required while its
kinetic resolution is proceeding.
Although some DKRs of amines have been developed in
the past decade,3 they still remain much less explored than
those of secondary alcohols. In most cases, they have been
accomplished by the coupling of a highly enantioselective
(1) (a) Andrews, I.; Cui, J.; DaSilva, J.; Dudin, L.; Dunn, P.; Hayler,
J.; Hinkley, B.; Hughes, D.; Kaptein, B.; Lorenz, K.; Mathew, S.;
Rammeloo, T.; Wang, L.; Wells, A.; White, T.; Zhang, F. Org. Process
Res. DeV. 2010, 14, 19–29. (b) Hudlicky, T.; Reed, J. W. Chem. Soc. ReV.
2009, 38, 3117–3132. For some book reviews, see: (c) Modern Biocatalysis.
StereoselectiVe and EnVironmentally Friendly Reactions; Fessner, W.-D.,
Anthonsen, T., Eds.; Wiley-VCH: Weinheim, 2009. (d) Asymmetric Organic
Synthesis with Enzymes; Gotor, V., Alfonso, I., Garc´ıa-Urdiales, E., Eds.;
Wiley-VCH: Weinheim, 2008.
(2) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic
Synthesis. Regio- and StereoselectiVe Biotransformations, 2nd ed.; Wiley-
VCH: Weinheim, 2006.
10.1021/ol101378k  2010 American Chemical Society
Published on Web 07/19/2010

lipase-catalyzed acylation with an in situ organometallic
complex (based on iridium or ruthenium)3 or palladium-
mediated4 racemization of the starting amine. The equilib-
rium between both enantiomers is thus established by the
metal-catalyzed reversible formation of an intermediate
imine. Likewise, in a few cases, racemization of the amine
is promoted by triethylamine and acetaldehyde (released in
situ from the vinyl ester used as acyl donor),5 by an
alkylsulfanyl radical,6 or even spontaneously.7
Here, we report the first DKR of a vicinal diamine, (()-
cis-N-(alkoxycarbonyl)cyclopentane-1,2-diamine, using li-
pase B from Candida antarctica (CAL-B) as catalyst. The
interest in the chemoenzymatic method developed here lies
in the great utility of optically active vicinal diamines in
asymmetric synthesis and as precursors of pharmaceuticals.8
Thus, despite the scarcity of approaches to optically active
cis-cyclopentane-1,2-diamine derivatives, these compounds
have promising applications as precursors of peptide nucleic
acids (PNAs).9
Kinetic resolution of (()-5a was performed by an ami-
nolysis reaction catalyzed by CAL-B,11 first using ethyl
acetate as acyl donor and solvent (Scheme 1, entry 1). Under
these conditions, the enzyme catalyzed the acetylation of the
amino group of 5a, though with moderate enantioselectivity
(E ) 48).12 In an attempt to improve this result, racemic
1-phenylethyl acetate and tert-butyl methyl ether (TBME)13
were employed as acyl donor and solvent, respectively. As
expected, acetamide 6a was obtained with higher enantio-
meric excess and the E value significantly increased (entry
2). In this reaction, (R)-1-phenylethanol stemming from the
aminolysis of the racemic ester was also produced.14 If
aminolysis were the only process catalyzed by the enzyme,
identical amounts of 6a and 1-phenylethanol should be
expected. However, analysis of the 1H NMR spectrum
of the crude material showed a much lower percentage of
acetamide than alcohol. This difference is a consequence of
the competing hydrolysis of the acyl donor, also catalyzed
by the enzyme.14 Thus, acetic acid is also released to the
reaction medium, which could critically affect the enanti-
oselectivity. Effectively, by carrying out the reaction in the
presence of 4 Å molecular sieves, the competitive hydrolysis
of the ester drastically diminished, the enantioselectivity
value increased, and both substrate 5a and product 6a were
obtained with very high enantiomeric excesses (ee) and yields
(entry 3).
Synthesis of racemic (()-cis-N-Boc-cyclopentane-1,2-
diamine [(()-5a] was carried out from the commercial (()-
trans-2-aminocyclopentanol (1) following the sequence
shown in Scheme 1. When mesylation of Boc-derivative (()-
Scheme 1. Synthesis and Enzymatic Resolution of (()-5a
(3) For some recent reviews, see: (a) Lee, J. H.; Han, K.; Kim, M.-J.;
Park, J. Eur. J. Org. Chem. 2010, 999–1015. (b) Pellissier, H. Tetrahedron
2008, 64, 1563–1601. (c) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord.
Chem. ReV. 2008, 252, 647–658. (d) Mart´ın-Matute, B.; Ba¨ckvall, J.-E.
Curr. Opin. Chem. Biol. 2007, 11, 226–232. For some specific examples,
see: (e) Stirling, M.; Blacker, J.; Page, M. I. Tetrahedron Lett. 2007, 48,
1247–1250. (f) Paetzold, J.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2005, 127,
17620–17621. (g) Thale´n, L. K.; Zhao, D.; Sortais, J.-B.; Paetzold, J.; Hoben,
C.; Ba¨ckvall, J.-E. Chem.sEur. J. 2009, 15, 3403–3410.
(4) For a recent example using Pd-nanoparticles, see: Choi, Y.-K.; Kim,
Y.; Han, K.; Park, J.; Kim, M.-J. J. Org. Chem. 2009, 74, 9543–9545.
(5) DKR of secondary heterocyclic amines as proline and pipecolic acid
methyl esters: Liljeblad, A.; Kiviniemi, A.; Kanerva, L. T. Tetrahedron
2004, 60, 671–677.
(6) In this case, a protease was used as catalyst for the acylation: El
Blidi, L.; Nechab, M.; Vanthuyne, N.; Gastaldi, S.; Bertrand, M. P.; Gil,
G. J. Org. Chem. 2009, 74, 2901–2903.
(7) DKR of 8-amino-5,6,7,8-tetrahydroquinoline: Crawford, J. B.; Skerlj,
R. T.; Bridger, G. J. J. Org. Chem. 2007, 72, 669–671.
(8) For some reviews, see: (a) Gonza´lez-Sab´ın, J.; Rebolledo, F.; Gotor,
V. Chem. Soc. ReV. 2009, 38, 1916–1925. (b) Kizirian, J.-C. Chem. ReV.
2008, 108, 140–205. (c) Douthwhite, R. E. Coord. Chem. ReV. 2007, 251,
702–717. (d) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug
Res. 2006, 67, 101–114. (e) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580–2627. (f) Bennani, Y. L.; Hanessian, S.
Chem. ReV. 1997, 97, 3161–3195.
(9) Govindaraju, T.; Kumar, V. A.; Ganesh, K. N. J. Org. Chem. 2004,
69, 5725–5734.
(10) This compound is the result of an intramolecular SN2 displacement
of the mesylate group by the carbonyl oxygen of the Boc group: Benedetti,
F.; Norbedo, S. Tetrahedron Lett. 2000, 41, 10071–10074.
(11) Thus far, CAL-B (Novozyme SP-435) has proven to be the most
effective catalyst for the aminolysis reaction in organic solvent. For a review,
see: Gotor-Ferna´ndez, V.; Busto, E.; Gotor, V. AdV. Synth. Catal. 2006,
348, 797–812.
2a was performed at 0 °C, the corresponding mesylate was
obtained with a very high yield (94%). Subsequent reaction
of the mesylate with sodium azide under the conditions
described by Kumar et al.9 (at 70 °C) yielded azide (()-3a
along with a significant amount of oxazolidinone (()-410
(the H NMR analysis of the crude material showed 3:4 in
a 73:27 ratio). Fortunately, the amount of 4 was reduced to
18% when the reaction was conducted at 50 °C.
(12) (a) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294–7299. (b) Program “Selectivity” by Faber,
K.; Hoenig, H. http://www.cis.TUGraz.at/orgc/.
(13) Gonza´lez-Sab´ın, J.; Gotor, V.; Rebolledo, F. Tetrahedron: Asym-
metry 2004, 15, 481–488.
1
(14) CAL-B showed very high enantioselectivity toward the R enanti-
omer of the ester (ee >97% for the produced (R)-1-phenylethanol). Thus,
although a racemic ester was used, CAL-B only catalyzed the reaction with
the R enantiomer.
Org. Lett., Vol. 12, No. 16, 2010
3603

Table 1. CAL-B-Catalyzed Resolution of (()-5b-d
remaining substrate (1R,2S)-5b-d
product (1S,2R)-6b-d
b
b
substratea
R
time (days)
amine
ees (%)
yieldc (%)
amide
eep (%)
yieldc (%)
(()-5b
(()-5c
(()-5d
benzyl
allyl
ethyl
6
5
5
5b
5c
5d
60
47
46
38
36
49
6b
6c
6d
97
99
99
51
50
34
a For conditions, see Scheme 1, entry 3. b Determined by chiral HPLC analysis. c Isolated yields.
In order to study the scope of this chemoenzymatic
method, we planned the synthesis of other racemic mono-
carbamates (()-5b-d similar to that reported in Scheme 1
(see the Supporting Information). CAL-B-catalyzed resolu-
tions of (()-5b-d were performed under the best conditions
found for (()-5a; i.e., using racemic 1-phenylethyl acetate
as acyl donor and TBME as solvent (Table 1). In all cases,
the produced acetamides 6b-d were obtained with very high
ee, which correspond to reactions with high enantioselectivity
values. However, some considerations should be highlighted
in regard to the results obtained in the reactions of 5b and
5c. First, as the isolated yields for products 6b and 6c were
51% and 50%, respectively, the minimum degree of conver-
sion obtained in these reactions should also be 51% and 50%.
Should both processes were considered simple KRs, the
expected ee for both substrates would be g99%. However,
experimental ee for the remaining 5b and 5c were much
lower (see Table 1). This means that optically active 5b and
5c are undergoing racemization, thus leading to dynamic
kinetic resolutions.
amount of acid is very high, most of amine precipitates as
its acetate and the aminolysis ceases. A further addition of
triethylamine allowed the amine 5b to dissolve, the ami-
nolysis reaction being thus restarted, and the ee of 5b
continued to decrease until it reached 8%.
Taking these results into account, we attempted the
enzymatic dynamic kinetic resolution of 5b using other
solvents (1,4-dioxane and THF), Et3N as cosolvent (a mixture
10:1 of TBME/Et3N), and a higher reaction temperature (50
°C). Under all of the tested conditions, racemization of 5b
took place, and 6b was obtained with very high ee (96-99%),
the higher conversion value (>95%) being obtained when
the reaction was conducted at 50 °C using TBME and Et3N
as cosolvent. Under these conditions, a very efficient dynamic
kinetic resolution of (()-5b was achieved, and 6b was
isolated with very high ee and yield (see Table 2).
Table 2. CAL-B-Catalyzed DKR of (()-5a-da
The racemization of these substrates is most likely
produced by an intramolecular migration of the alkoxycar-
bonyl group between both vicinal nitrogens.15 As the chiral
carbons supporting both nitrogen substituents have opposing
absolute configurations, racemization takes place but the
asymmetric centers remain unaltered throughout the entire
process. To study this spontaneous racemization, enzymatic
acetylation of (()-5b (see Table 1) was periodically analyzed
by chiral HPLC and 1H NMR (see the Supporting Informa-
tion for details). The most significant results are as follows:
(1) the ee of acetamide 6b remained very high (96-98%)
all along the process; (2) the aminolysis of the ester ceased
after 8 days (c ) 56% for 6b), but its hydrolysis continued
proceeding extensively; (3) the ee for the remaining 5b
decreased until 19% after 10 days of reaction. These results
indicate that slow racemization is operating, probably
catalyzed by the produced acetic acid. Moreover, when the
product (1S,2R)-6a-d
substrate
R
amide
ee (%)
yieldb (%)
(()-5a
(()-5b
(()-5c
(()-5d
tert-butyl
benzyl
allyl
6a
6b
6c
6d
96
96
97
95
54c
94
85
72
ethyl
a TBME/Et3N 10:1 was used. All reactions were carried out at 50 °C
and 200 rpm for 9 days. b Isolated yields. c The remaining substrate (1R,2S)-
5a (ee ) 56%) was isolated with 24% yield.
When these DKR conditions were applied to the other
monocarbamates (Table 2), good results were obtained with
the N-allyloxycarbonyl (Alloc) and N-ethoxycarbonyl deriva-
tives 5c and 5d, the corresponding optically active acetamides
being isolated with high yields. However, in the reaction with
(15) For some examples in which an acyl migration in 1,2- and 1,3-
diol monoacetates has been taken advantage of in dynamic asymmetric
transformations, see: (a) Edin, M.; Mart´ın-Matute, B.; Ba¨ckvall, J.-E.
Tetrahedron: Asymmetry 2006, 17, 708–715. (b) Edin, M.; Steinreiber, J.;
Ba¨ckvall, J.-E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5761–5766.
3604
Org. Lett., Vol. 12, No. 16, 2010

Scheme 2. Acid-base Catalyzed Migration of the
Alkoxycarbonyl Group in Amino Carbamates 5a
Scheme 3. Assignment of the Configuration of the
Enzymatically Prepared 5a and 6b
a AcOH + NEt3 f AcO-+NHEt3.
a Compounds isolated in the enzymatic KR of (()-5a. b See ref 9.
c Acetamide isolated in the enzymatic DKR of (()-5b.
the N-Boc derivative 5a, besides acetamide 6a, the remaining
substrate 5a was also isolated (ee ) 56%, yield ) 24%).
This means that migration of the tert-butoxycarbonyl is not
favored in this case, probably due to the steric hindrance of
the tert-butyl group. This is also the reason why the kinetic
resolution of 5a was particularly efficient (see Scheme 1).
Considering all of these observations, in Scheme 2 we
propose a plausible mechanism to explain the migration of
the alkoxycarbonyl group and thus the racemization of 5.
Both the acetic acid released in the reaction medium and
the triethylamine could catalyze the migration.16 This fact
was also supported by additional proofs of racemization of
5b performed in the absence of the lipase. Thus, when an
enantioenriched sample of 5b (ee ) 60%) was dissolved in
TBME and stored at 28 °C and 200 rpm for 7 days, 5b was
recovered with almost the same ee (58%). However, if a
mixture of acetic acid (1 equiv) and triethylamine (0.5 equiv)
was added, the ee of 5b decreased to 27% after 7 days.17
Absolute configuration of the enzymatically prepared
compounds was established as follows: amino carbamate 5a
[isolated as the remaining substrate in the KR of (()-5a,
see Scheme 1] was transformed into 7 (Scheme 3), and the
sign of its specific rotation was compared with the reported
value for (1R,2S)-7.9 Thus, configuration (1R,2S) was as-
signed to the remaining 5a, and hence, the produced
acetamide was (1S,2R)-6a. In addition, configuration (1S,2R)
for acetamide 6b, obtained in the CAL-B catalyzed DKR of
(()-5b, was assigned by chemical correlation with (1S,2R)-
6a. Catalytic hydrogenation of 6b in the presence of tert-
butyl pyrocarbonate yielded the N-Boc acetamide 6a with
the same sign of optical rotation as that prepared by KR of
(()-5a (Scheme 3). In both cases, CAL-B preferentially
catalyzed the acetylation of the R enantiomer of the amine,
thus following Kazlauskas’ rule.18 Taking into account the
structural resemblance between the amino carbamates re-
ported here, we have tentatively assigned the (1S,2R)
configuration to the other produced acetamides 6c and 6d.
In conclusion, we have developed a highly efficient
chemoenzymatic method to prepare optically active cis-
cyclopentane-1,2-diamine derivatives. The key step in this
strategy is the kinetic resolution or the dynamic kinetic
resolution of the corresponding racemic monocarbamate.
Further research work into the scope and synthetic utility of
the new DKR is in progress.
Acknowledgment. We thank the Spanish MICINN
(CTQ2007-61126) for financial support of this work. F.J.Q.
is the grateful recipient of a Spanish MICINN predoctoral
fellowship.
Supporting Information Available: Experimental pro-
cedures, characterization data, copies of the NMR spectra,
and HPLC chromatograms. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) For an example of acid-promoted migration of an ethoxycarbonyl
group to an aziridine nitrogen, see: Crawley, S. L.; Funk, R. L. Org. Lett.
2006, 8, 3995–3998.
OL101378K
(17) The addition of only acetic acid (1 equiv) caused the precipitation
of the acetate of 5b, and its ee remained unaltered.
(18) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656–2665.
Org. Lett., Vol. 12, No. 16, 2010
3605