Chemoenzymatic dynamic kinetic resolution of secondary amines

Article abstract of DOI:10.1016/j.tetlet.2006.12.032

The kinetic resolution of amines using a novel iridium based catalyst coupled with an enzyme catalysed step is achieved on a large scale with high yields and ee.

Full text of DOI:10.1016/j.tetlet.2006.12.032

Tetrahedron Letters 48 (2007) 1247–1250
Chemoenzymatic dynamic kinetic resolution of secondary amines
Matthew Stirling,a,b John Blackerb and Michael I. Pagea,*
aDepartment of Chemical and Biological, Sciences, The University of Huddersfield, Huddersfield HD1 3DH, UK
bNPILPharma, Leeds Road, Huddersfield HD1 9GA, UK
Received 7 November 2006; revised 29 November 2006; accepted 8 December 2006
Abstract—The kinetic resolution of amines using a novel iridium based catalyst coupled with an enzyme catalysed step is achieved
on a large scale with high yields and ee.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Enantiomerically pure chiral amines are particularly
important to the pharmaceutical and agrochemical
industries. The common procedures for their prepara-
tion include resolution from the racemate,1 asymmetric
reductive amination,2 asymmetric hydrogenation3 and
alkylation of imines.4 Due to its operational simplicity
the majority of industrial scale syntheses employ a
kinetic resolution via a diastereomeric recrystallisation
or enzymatic acylation to separate the desired enantio-
mer from the racemic mixture. However, this methodol-
ogy has the inherent disadvantage of limiting the yield to
a maximum of 50% which has a considerable impact on
the economic viability of the procedure. To overcome
this drawback it is possible to combine the kinetic reso-
lution with a simultaneous racemisation to give a theo-
retical yield of 100% in a procedure known as dynamic
kinetic resolution (DKR) (Scheme 1). If the desired
enantiomer is R, then this requires krac > k1 > k2.
known methods for racemisation of amines7 require
harsh reaction conditions under which most enzymes
would be denatured making them unsuitable for
DKR. Recently, milder conditions for amine racemisa-
tion have been developed through the use of ruthenium8
and palladium9 based catalysts both of which have been
employed in the successful DKR of chiral amines.10
However, both systems have significant limitations that
restrict their industrial applicability including high cata-
lyst loading, limited substrate scope and high substrate
dilution.
Herein, we report an efficient process for the DKR of a
secondary amine using a novel iridium-based amine rac-
emisation catalyst under significantly milder conditions
than any previously reported. Pentamethylcyclopenta-
dienyliridium(III) iodide dimer, [IrCp*I2]2, successfully
racemises 1-methyl-1,2,3,4-tetrahydroisoquinoline, 1,
with a low catalyst loading11 (Scheme 2 and Fig. 1).
Racemisation is observed under extremely mild condi-
tions, t1/2 = 215 min at 40 ꢁC using only 0.2 mol %
[IrCp*I2]2.
This technique has been successfully utilised in the
synthesis of amino acid derivatives5 and alcohols.6 The
Z
Z
Enzyme +
k1
The drop in enantiomeric excess of 1 is accompanied
by the formation of a small amount of the correspond-
ing imine which increases with time indicating that
R
R
-Z
krac
Enzyme +
k2
0.2 mol% [IrCp*I2]2
S
S
-Z
NH
NH
0.5 M amine, toluene
o
40 C
Scheme 1.
Me
Me
)-1
(
S
*
Corresponding author. Tel.: +44 1484 472531; fax: +44 1484
473075; e-mail: m.i.page@hud.ac.uk
Scheme 2.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.032

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M. Stirling et al. / Tetrahedron Letters 48 (2007) 1247–1250
100.0
90.0
80.0
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
%Imine
%Impurities
%ee
0
50
100
150
200
250
300
350
400
450
Time / min
Figure 1. Racemisation of (S)-1-methyl-1,2,3,4-tetrahydroisoquinoline at 40 ꢁC, showing % ee and % composition.
hydrogen is lost from the catalyst concurrently with
imine hydrogenation. 1-Methylisoquinoline is also
formed in low levels (<5%) presumably due to dehydro-
genation of the intermediate imine by the racemisation
catalyst. In general, it was found with other amines that
a small amount of imine was formed during the
racemisation which indicates that the catalyst can lose
hydrogen during turnover. However, conducting the
racemisation under an atmosphere of hydrogen consid-
erably decreases the rate of racemisation. For example,
the racemisation of (S)-N-methyl-a-methylbenzylamine
2 was complete in 5 h at 80 ꢁC using 1 mol % [IrCp*I2]2
under an air atmosphere, but still had 80% ee after the
same time under a hydrogen atmosphere of 1 atm.
phenylpropyl carbonate 4 as an acyl donor (Scheme 3)
was carried out at 40 ꢁC (Fig. 2) to give 55% unreacted
3 in 70% ee (S) and 45% carbamoylated 3 in 91% ee (R)
in just over 8 h, corresponding to an E value of 27. For
the DKR to be successful both the racemisation and
resolution need to work under the same conditions in
the same reaction flask.
The racemisation process and the enzymatic resolution
were then combined in the hope of achieving a dynamic
kinetic resolution. Racemic amine 3 (0.48 M) was
reacted with 3-methoxyphenylpropyl carbonate
4
(0.72 M) in toluene with 0.2 mol % [IrCp*I2]2 and 50%
w/w immobilised C. rugosa lipase (1100 units/mg), at
40 ꢁC for 23 h (Fig. 3). This gave a 90% conversion to
the product carbamate in a 96% ee. The reaction was
performed at a 3 g scale and the product carbonate
was isolated in a 82% yield with a 96% ee.
NHMe
Me
The DKR was also undertaken using other acyl donors
and an interesting observation was made when using the
conditions above with racemic 1-methyl-1,2,3,4-tetra-
hydroisoquinoline, 1, and 3-methoxyphenyl allyl carbon-
ate.12 Although the corresponding allyl carbamate was
successfully formed in a high enantiomeric excess
(94%) in about 50% yield, the other major product
2
The next step, having found an efficient racemisation
catalyst for amines, was to couple racemisation to an en-
zyme-catalysed resolution. The enzymatic resolution of
racemic 3 using Candida rugosa lipase and 3-methoxy-
MeO
MeO
NH
O nPr
N
MeO
MeO
3
Candida rugosa lipase
toluene, 40 oC, 8 h
Me
O
Me
+
+
MeO
MeO
O nPr
MeO
O
NH
O
Me
4
Scheme 3.

M. Stirling et al. / Tetrahedron Letters 48 (2007) 1247–1250
1249
100.0
90.0
80.0
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
%ee of carbamate
at end-point = 91%
%ee Amine
%Amine
%Carbamate
0
50
100
150
200
250
300
350
400
450
Time / min
Figure 2. Enzymatic resolution of 3 using 3-methoxyphenylpropyl carbonate as the acyl donor, showing % ee and % composition.
100.0
%ee of carbamate
at end-point = 96%
%Carbamate
%Amine
90.0
80.0
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
0
100
200 300 400
500 600
700 800 900 1000 1100 1200 1300 1400
Time / min
Figure 3. DKR of 3 using 3-methoxyphenylpropyl carbonate as the acyl donor, showing % ee and % composition.
was identified by NMR and GCMS analysis as N-allyl-
1-methyl-1,2,3,4-tetrahydroisoquinoline. This product,
after an initial lag period, is formed with zero-order
kinetics, whereas carbamate formation shows a first-
order profile. The concentration of the carbamate levels
off at ꢀ50% conversion, despite the amine still being
present in 30% of its original concentration. The amine
concentration continues to decrease with only the N-allyl
amine being formed. Presumably amine 1 reacts with
the carbamate product to form the N-allyl amine. This
reaction must be catalysed by [IrCp*I2]2 as the N-allyl
amine is not formed in the enzymatic resolution of 1
under otherwise identical conditions in the absence of
the metal catalyst. The carbamate concentration increases
to the point at which the rate of its formation equals
the rate of the N-allyl amine formation and as a conse-
quence its measured concentration remains constant.
This unwanted reaction did not occur with alkyl aryl
carbonates. In conclusion, we have developed a highly
efficient, extremely mild process for the dynamic kinetic
resolution of isoquinoline-based chiral secondary
amines in a good yield and a high enantiopurity using
a simple, air-stable iridium-based amine racemisation
catalyst. This result constitutes the first example of a
chemoenzymatic dynamic kinetic resolution on a sec-
ondary amine. Work is ongoing to extend the scope of
the procedure towards the dynamic kinetic resolution
of primary amines.
Synthesis of the catalyst: Pentamethylcyclopentadienyl-
iridium(III) chloride dimer (4.38 g, 5.51 mmol) and
sodium iodide (8.46 g, 56.7 mmol) were added to a single
neck 1000 ml round-bottomed flask. A water condenser
was fitted to the flask, the remaining necks were stop-

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M. Stirling et al. / Tetrahedron Letters 48 (2007) 1247–1250
pered and argon was purged through the vessel at
500 ml/min for 30 min. The purge of argon was then
reduced to 20 ml/min and acetone (525 ml < 100 ppm
H2O) was added, the flask was then placed in an oil bath
at 60 ꢁC and the reaction stirred using a magnetic stirrer
resulting in a dark orange solution containing some
insoluble iridium dimer. The reaction was allowed to re-
flux under argon for 3 h before being cooled to room
temperature. The reaction was concentrated to dryness
under vacuum to yield a brown/red solid that was
dissolved in dichloromethane (500 ml) and washed with
water (3 · 250 ml), the organic layer was separated, dried
using sodium sulfate, filtered and concentrated to dry-
ness under vacuum to yield a brown solid. The solid
was crystallised from chloroform/methanol to yield
brown needle-like crystals, the filtrates were concen-
trated to dryness and the resulting residue was recrystal-
lised form chloroform/methanol, this was repeated a
third time and the three crops of catalyst combined to
yield 5.10 g (78% isolated yield). The crystals were ana-
lysed by carbon and proton NMR: dH (CDCl3) 1.83 (s,
Cp*-CH3), dC (300 MHz, solvent CDCl3, reference
SiMe4) 11.13 (Cp*-CH3), 89.3 (Cp*). Elemental Anal.
Calcd for Ir2I4C20H30: C, 20.7; H, 2.6. Found: C, 20.6;
H, 2.5.
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We thank the Royal Commission for the Exhibition of
1851 for their financial support of this research.