Practical chemoenzymatic dynamic kinetic resolution of primary amines via transfer of a readily removable benzyloxycarbonyl group

Article abstract of DOI:10.1016/j.tetlet.2007.12.017

A practical method for chemoenzymatic dynamic kinetic resolution of primary amines using dibenzyl carbonate as acyl donor has been developed leading to benzyl carbamates, which can be deprotected under very mild reaction conditions to give the free amine.

Full text of DOI:10.1016/j.tetlet.2007.12.017

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Tetrahedron Letters 49 (2008) 977–979
Practical chemoenzymatic dynamic kinetic resolution of primary
amines via transfer of a readily removable benzyloxycarbonyl group
Christine E. Hoben, Lisa Kanupp, Jan-E. Ba¨ckvall *
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 30 September 2007; revised 24 November 2007; accepted 5 December 2007
Available online 8 December 2007
Abstract
A practical method for chemoenzymatic dynamic kinetic resolution of primary amines using dibenzyl carbonate as acyl donor has
been developed leading to benzyl carbamates, which can be deprotected under very mild reaction conditions to give the free amine.
Ó 2007 Elsevier Ltd. All rights reserved.
Chiral amines are useful synthetic intermediates and are
structural elements of many biologically active com-
pounds.1 Commonly used methods to prepare chiral
amines include hydrogenation of imines and enamines,2
alkylation of imines,3 and aminohydroxylation.4 Various
ligands have been utilized in these metal-catalyzed reac-
tions to obtain high enantioselectivity. More recently,
chemoenzymatic methods have been used to efficiently pre-
pare enantiomerically pure chiral amines.5–11 We recently
reported a dynamic kinetic resolution (DKR) of primary
amines using combined ruthenium (catalyst 1) and enzyme
catalysis that works on both benzylic and aliphatic
amines.6,12 Independent work by the Jacobs–de Vos group
showed that a palladium/enzyme catalyst combination can
be used for practical DKR of benzylic amines.7a Subse-
quent work has provided additional procedures for chemo-
enzymatic DKR of amines in which various racemization
methods are combined with enzymatic resolution.8–10
A drawback with the DKR procedures reported so far is
that the product is a chiral amide, from which the free
amine can only be liberated under harsh reaction condi-
tions.13 Therefore, there is a demand for acyl donors in
the DKR of amines that transfer a readily removable pro-
tecting group. We now report on a chemoenzymatic DKR
of primary amines where the products are benzyl carb-
amates that can be deprotected under very mild reaction
conditions to give the free amine.
We first studied the use of acyl donors that transfer
more electron deficient acyl groups in the DKR. This
would lead to amides that can be hydrolyzed under milder
conditions. Unfortunately, kinetic resolution with Candida
antarctica lipase B (CALB) using ethyl and isopropyl tri-
fluoroacetate as well as isopropyl chloroacetate as acyl
donors resulted in significant non-catalyzed background
reaction leading to low enantioselectivity under the reac-
tion conditions required for the DKR.14 We therefore
focused our attention on acyl donors that lead to carb-
amates, since there is well-documented methodology to
release the free amine from these compounds under mild
conditions.15 In particular, the protection of amines as
allyloxy, benzyloxy, or t-butyloxy carbamates is popular
since deprotection requires either mild Pd catalysis or weak
acid catalysis.
O
R
O
R
H
H
R
R
R
R
Ru
Ru
R
R
CO
OC
CO
OC
1 (R = p-MeO-C6H4)
For the enzyme-catalyzed reaction of amines to give
carbamates we considered diallyl, dibenzyl, and di-t-butyl
carbonates (2–4) as appropriate acyl donors since they gave
*
Corresponding author. Tel.: +46 8 6747178; fax: +46 8 154908.
E-mail address: jeb@organ.su.se (Jan-E. Ba¨ckvall).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.017

978
C. E. Hoben et al. / Tetrahedron Letters 49 (2008) 977–979
no non-catalyzed background reaction on stirring with 1-
phenylethylamine (5) in toluene at 90 °C for 24 h. Kinetic
resolution of amine 5 was carried out with CALB using
carbonates 2–4 as acyl donors (Scheme 1). Diallyl carbon-
ate (2) gave only a moderate enantioselectivity (E = 9)16
whereas dibenzyl carbonate (3) afforded a highly enantio-
selective reaction (E = 156). The di-t-butyl carbonate (4)
was completely inactive in the enzymatic reaction.
O
NH2
HN
O
Ph
1 mol% Pd/C (10%)
H2 (1 atm)
EtOH, 0.5 h, rt
quantitative
13
(93% ee)
5
(93% ee)
Scheme 2. Deprotection of carbamates obtained from DKR.
Dibenzyl carbonate (3) was therefore chosen as the acyl
donor for the DKR reaction. We were pleased to find that
carbonate 3 was compatible with the racemization catalyst
1, and reaction of racemic 5 and carbonate 3 in the pres-
ence of Ru-catalyst 1 and CALB in toluene afforded benzyl
carbamate in 90% yield and 93% ee (Table 1, entry 1). p-
Substituted phenylethylamines (6–8) were reacted under
the DKR conditions and gave the corresponding carba-
mates in good to high yields with high ee (97–99% ee,
entries 2–4). Also aliphatic amines worked well in the
chemoenzymatic DKR reaction to give the corresponding
carbamates in good to high ee (entries 6–8).
The benzyloxycarbonyl group of products 13–20 can be
removed easily via hydrogenolytic cleavage.15 Deprotec-
tion using 1 mol % palladium on charcoal (10%) under a
hydrogen atmosphere was demonstrated with carbamate
13 where liberation of the amine was complete within half
an hour at room temperature. The amine was obtained in a
quantitative yield and with full retention of ee (Scheme 2).
The H2 reaction was very clean giving only CO2 and tolu-
ene as side products. If the reaction was left too long or if a
larger amount of catalyst was employed some racemization
of the product was observed.
In conclusion, we have developed a practical procedure
for chemoenzymatic DKR of primary amines using dibenz-
yl carbonate as the acyl donor, which allows release of the
free amine from the carbamate products under very mild
conditions.
O
O
R
R
R
HN
O
NH2
O
O
2 - 4
CALB
toluene, 90 oC
R = allyl
R = PhCH2 32% yield, 98% ee E = 156
R = -butyl no reaction
5
25% yield, 76% ee, E = 9
t
Scheme 1. CALB-catalyzed kinetic resolution of 5 with aryl alcohols.
Acknowledgments
Table 1
Dynamic kinetic resolution of primary amines with dibenzyl carbonate
Financial support from the Swedish Foundation for
Strategic Research, the Swedish Research Council, and
the German Research Foundation (DFG) is gratefully
acknowledged (C.E.H.).
(3)a
O
O
O
Ph
Ph
O
4 mol% 1
References and notes
NH2
HN
O
Ph
CALB, Na2CO3
toluene, 90 °C
R
R'
R
R'
1. Breuer, M.; Dietrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.;
72 h
13-20
5-12
Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824.
¨
2. (a) Blaser, H. U.; Spindler, F. Hydrogenation of Imino Groups. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, pp 247–265; (b)
Singaram, B.; Goralski, C. T. The Reduction of Imines and Enamines
with Transition Metal Hydrides. In Transition Metals for Organic
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Vol. 2, pp 147–154.
Entry
Amine
R
R0
Product
Yieldb
% eec
1
2
3
4
5
6
7
8
Ph
Me
Me
Me
Me
13
14
15
16
90
93
98
99
97
p-Br–Ph
p-F–Ph
p-MeO–Ph
95
72d
74d
3. Denmark, S. E.; Nicaise, O. J. C. Alkylation of Imino Groups. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, pp 923–961.
4. Bolm, C.; Hildebrand, J. P.; Muniz, K. Recent Advances in
Asymmetric Dihydroxylation and Aminohydroxylation. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; pp 399–428.
5
9
17
64
99
6
7
8
a
10
11
12
Cyclohexyl
Heptyl
iso-Propyl
Me
Me
Me
18
19
20
92
89
60d
96
90
99
The reaction was carried out by stirring 0.5 mmol of the amine,
1.25 mmol of dibenzyl carbonate, 26.5 mg of catalyst 1 (0.02 mmol,
4 mol %), 20 mg of CALB (Novozyme-435), and 20 mg of Na2CO3 in dry
toluene (5 ml) at 90 °C for 72 h.
´
5. (a) Martın-Matute, B.; Ba¨ckvall, J. E. Curr. Opin. Chem. Biol. 2007,
´
11, 226–232; (b) Martın-Matute, B.; Ba¨ckvall, J. E. Chemoenzymatic
Deracemization Processes. In Organic Synthesis with Enzymes in
Nonaqueous Solvents, Riva S. Ed., Wiley-VCH, in press.
6. Paetzold, J.; Ba¨ckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620–
17621.
b
Isolated yield unless otherwise noted.
Enantiomeric excess determined by chiral HPLC (chiralcel ODH).
Determined by GC.
c
d

C. E. Hoben et al. / Tetrahedron Letters 49 (2008) 977–979
979
´
´
7. (a) Parvulescu, A.; De Vos, D.; Jacobs, P. Chem. Commun. 2005,
5307–5309; (b) Parvulescu, A.; Jacobs, P.; De Vos, D. Chem. Eur. J.
2007, 13, 2034–2043.
Eur. J. 2006, 12, 6053–6061; (c) Martın-Matute, B.; Edin, M.; Bogar,
K.; Kaynak, F. B.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817–
8825.
8. Gastaldi, S.; Escoubet, S.; Vanthuyne, N.; Gil, G.; Bertrand, M. P.
Org. Lett. 2007, 9, 837–839.
9. Kim, M.-J.; Kim, W.-H.; Han, K.; Choi, Y. K.; Park, J. Org. Lett.
2007, 9, 1157–1159.
10. (a) Stirling, M.; Blacker, J.; Page, M. I. Tetrahedron Lett. 2007, 48,
1247–1250; (b) Blacker, A. J.; Stirling, M. J.; Page, M. I. Org. Process
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11. Dunsmore, C. J.; Carr, R.; Fleming, T.; Turner, N. J. J. Am. Chem.
Soc. 2006, 128, 2224–2225.
13. For example, acidic hydrolysis of the acetamide of 1-phenylethyl-
amine requires reaction at 140 °C for 48 h in concentrated hydro-
chloric acid.
14. The racemization with catalyst 1 under the DKR conditions requires
a temperature of 90 °C (see Ref. 6).
15. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley Interscience: New York, 1999; pp 503–550.
16. It is not clear why the allyl carbonate gives only a moderate
enantioselectivity since there was no background reaction in the
control reaction. A likely explanation is that the enzyme itself has
some effect on the non-catalyzed reaction, increasing the reaction
pathway via direct acylation.
12. For related work on ruthenium- and enzyme-catalyzed DKR of
´
alcohols see: (a) Bogar, K.; Ba¨ckvall, J. E. Tetrahedron Lett. 2007, 48,
´
5471–5474; (b) Martın-Matute, B.; Edin, M.; Ba¨ckvall, J. E. Chem.