Dynamic kinetic resolution (DKR) using immobilized amine nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2004.02.004

The first example of a dynamic kinetic resolution (DKR) using immobilized amine nucleophiles is described. This approach utilizes a nucleophilic amine attached to a solid phase resin via an organic spacer. The optical purities of the N-substituted α-amino ester products are superior to the solution phase DKR with diastereomeric ratios ranging from 11:1 to 18:1 and chemical yields between 66% and 98%.

Full text of DOI:10.1016/j.tetlet.2004.02.004

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2545–2549
Dynamic kinetic resolution (DKR) using immobilized amine
nucleophiles
Yevgeny Valenrod, Jinnie Myung and Robert N. Ben*
Department of Chemistry, University of Ottawa, Ottawa, ON, Canada K1N 6N5
Received 15 December 2003; revised 30 January 2004; accepted 2 February 2004
Abstract—The first example of a dynamic kinetic resolution (DKR) using immobilized amine nucleophiles is described. This
approach utilizes a nucleophilic amine attached to a solid phase resin via an organic spacer. The optical purities of the N-substituted
a-amino ester products are superior to the solution phase DKR with diastereomeric ratios ranging from 11:1 to 18:1 and chemical
yields between 66% and 98%.
Ó 2004 Elsevier Ltd. All rights reserved.
During the last decade, there has been tremendous
interest in using polymeric supports for the preparation
of small molecules including polypeptides,1 oligosac-
charides,2 and nucleic acids3 using both soluble and
insoluble resin beads. Several excellent reviews have
been published describing these approaches.4 Despite
the enormous impact of this approach on the chemical
community, a relatively small number of polymer-sup-
ported asymmetric reactions have been reported. These
examples utilize cycloaddition reactions with resin-sup-
ported dienophiles or dipolarophiles,5;6 Diels–Alder
reactions of N-crotyl oxazolidinones,7 1,3-dipolar cyclo-
addition reactions using mesitonitrile oxide,8 and
photochemical [2 + 2] cycloadditions.9 More recently,
the preparation of structurally diverse and chirally
defined 1,3-oxazolidines has been described.10 To the
best of our knowledge, there have been no reports of
polymer-supported kinetic resolutions11 or dynamic
kinetic resolutions.12 This paper describes the first
example of a dynamic kinetic resolution using immobi-
lized amine nucleophiles.
The DKR reaction in this study was modeled after an
earlier system useful for the preparation of N-substituted
a-amino acid derivatives using a-bromo-(R)-pantolac-
tonyl esters and various amines.13 In our approach,
polymer-supported amines were employed as nucleo-
philes and substituted a-bromo-(R)-pantolactonyl esters
were used as electrophiles (Fig. 1). Preparation of the
substituted a-bromo-(R)-pantolactonyl ester derivatives
is outlined in Scheme 1.13b;d The resin-bound amines (4a–
c) were prepared by coupling Fmoc-protected amino
alkanoic acids to MBHA poly(chloromethylstyrene)
supports using standard solid phase protocols. Nucleo-
philic resins with 1, 3, and 10 carbon spacers were prepared.
Reaction of 1 (2.5 equiv) with 4a produced negative
Kaiser and TNBS tests after 2 days (Scheme 1) indicating
O
O
R1
+
spacer
H2N
O
O
Insoluble resin support
Br
R1 = H, alkyl, aryl
Figure 1.
Keywords: Solid phase; Dynamic kinetic resolution; Resin-bound amine; Immobilized amine.
* Corresponding author. Tel.: +1-613-5625800x6321; fax: +1-613-5625170; e-mail: robert.ben@science.uottawa.ca
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.004

2546
Y. Valenrod et al. / Tetrahedron Letters 45 (2004) 2545–2549
O
O
O
H
(n-Butyl)4N+I- (cat.)
O
O
O
TFA
H
H2N
+
R
N
O
O
O
DIPEA (3.0 equiv.),
DMF, RT, 2 days
O
H
n
Br
O
O
+
H
N
H
4a, n = 1
4b, n = 3
4c, n = 10
NH2
-
O
O
1, R = H (85% yield)
2, R = CH3 (79% yield)
3, R = Ph (87% yield)
CF3CO2
1) 20% piperidine/DMF
2) HBTU (2.5 equiv.),
DIPEA (3.0 equiv.), DMF
5 (92% yield)
DCC (1.0 equiv.), DMAP
CH2Cl2, RT, 12 hrs.
FmocHN
CO2H
n
(2.6 equiv.)
3) 20% piperidine/DMF
O
O
H
+
R
HO
O
OH
FmocHN
Br
Scheme 1.
that all of the amines on the resin bead had reacted.
Removal of the substrate from the resin by treatment
with TFA and characterization by NMR and mass
spectrometry confirmed formation of dialkylated prod-
uct 5 in 92% isolated yield. No trace of the monoalkyl-
ated product was detected. This result suggested that
while DKR using immobilized amine nucleophiles was
feasible, selective formation of mono- and bis-alkylation
products may be difficult to control. However, DKR
performed with a-substituted esters 2 and 3 furnished
only monoalkylated products (Table 1). The exclusive
formation of monoalkylated products is attributed to
the fact that the secondary amine of products 6–8
is sterically hindered and not prone to reaction with
another equivalent of electrophile.
The size of the a-substituent influences the diastereo-
meric ratios in the formation of products 6–8. For
instance, 6a (R ¼ CH3) is formed as a 14:1 diastereo-
meric ratio while 6b (R ¼ Ph) is produced as an 18:1
diastereomeric ratio. This trend is also observed as the
length of the organic spacer between the amino group
and the resin increases (Table 1, entries 3–6).
Typical DKR using a-substituted (R)-pantolactonyl
esters has been shown to favor formation of N-substi-
tuted a-amino-(R)-pantolactonyl esters with the (S,R)
configuration.13a The stereochemical configuration of
the major diastereomer in our DKR using immobilized
amine nucleophiles was determined by comparing the
1H NMR of products 6–8 with the same products pre-
Table 1. DKR using immobilized amine nucleophiles
-
CF3CO2
O
O
O
n
O
H
2 or 3 (2.0 equiv.)
H
+
TFA
H2N
H
N
N
NH2
O
(n-Butyl)4NI (cat.),
DIPEA (3.0 equiv.),
DMF, RT, 2d
O
H
n
4a-c
R
6 8
-
Entry
Nucleophile
Substrate
Product
% Yielda
Dr (S,R/R,R)b
1
2
3
4
5
6
4a (n ¼ 1)
4a (n ¼ 1)
4b (n ¼ 3)
4b (n ¼ 3)
4c (n ¼ 10)
4c (n ¼ 10)
2
3
2
3
2
3
6a (R ¼ CH3, n ¼ 1)
6b (R ¼ Ph, n ¼ 1)
7a (R ¼ CH3, n ¼ 3)
7b (R ¼ Ph, n ¼ 3)
8a (R ¼ CH3, n ¼ 3)
8b (R ¼ Ph, n ¼ 3)
66
91
14:1
18:1
11:1
15:1
10:1
15:1
89
84
>95
>95
O
9c;
2
3
6a (R ¼ CH3, n ¼ 1)
6b (R ¼ Ph, n ¼ 1)
95
92
3:1
4:1
+
7
8
NH3
Cl-
H2N
O
9c;
+
NH3
H2N
Cl-
a Yields are reported as crude yields.
b Diastereomeric ratios (S,R/R,R) were determined using 360 MHz 1H NMR.
c Typical DKR conditions; substrate was not immobilized on resin during DKR.

Y. Valenrod et al. / Tetrahedron Letters 45 (2004) 2545–2549
2547
O
Cl-
O
H3N
O
H
+
Ph
DMF,
O
O
+
NH2
(n-Butyl)4NI (cat.), DIPEA (3.0 equiv.),
Br
RT, 2d
9
-
3
Cl3CCO2
TFA
O
O
O
H
H
+
H
N
O
H2N
O
Ph
6b SR = Major diastereomer
O
O
O
H
H
N
Ph
+
H2N
1 ) DMF, (n-Butyl)4NI (cat.),
DIPEA (3.0 equiv.), RT, 2d
2) TFA
O
O
4a
Br
3
Scheme 2.
pared via traditional DKR as outlined in Scheme 2.
Comparison of the NMR spectra indicated that the
major diastereomer from DKR using resin-bound
amines possessed the (S,R) configuration, consistent
with typical DKR.
A typical DKR involves a product-forming reaction
between two diastereomeric starting materials however,
a key element of the DKR is that these starting materials
readily interconvert and this interconversion is much
faster than the product-forming reaction. In our case,
reaction of the immobilized amine with substrates 1–3
constitutes the product-forming reaction while, epimer-
ization of 1–3 occurs by reaction with tetra-N-butyl
ammonium iodide. DKR using an immobilized amine
nucleophile is a heterogeneous reaction as the polymer
support is insoluble in DMF while a traditional DKR is
homogeneous in nature. However, the epimerization
reaction is homogeneous in both cases. Given that the
rate of a heterogeneous product-forming reaction (SN2)
is expected to be considerably slower than that of a
homogeneous reaction, it is plausible that the observed
increase in diastereoselectivity associated with the
immobilized amine nucleophiles may be a result of this
fact. A related hypothesis centers on the fact that the
concentration of resin-bound amine is comparatively
low, resulting in a decreased rate for the product-
forming reaction relative to a typical DKR. This
decreased rate would allow for a more efficient epimer-
ization process and increased diastereoselectivities. To
explore this possibility, a syringe pump addition exper-
iment was performed to simulate the low concentration
of the resin-bound amine in the DKR reaction (Scheme
4). In this experiment, substrate 3 was dissolved in dry
DMF with DIPEA (1.3 equiv), n-butyl ammonium
iodide (cat.), and benzylamine (1.1 equiv) was added via
syringe pump over 3 days. This experiment furnished the
desired N-substituted a-amino-(R)-pantolactone ester in
a 6.5:1 diastereomeric ratio and quantitative yield. The
identical experiment performed without a syringe pump
The diastereoselectivities of DKR using resin-supported
amines are unexpectedly high when compared to typical
DKR. For instance, reaction of electrophiles 2 or 3 with
glycinamide hydrochloride 9 under typical DKR con-
ditions furnished compounds 6a and 6b in only 3:1 and
4:1 diastereomeric ratio (Table 1, entries 7 and 8). In
contrast, DKR using an immobilized amine nucleophile
(4a) with substrate 2 or 3 produced 6a (R ¼ CH3) and
6b (R ¼ Ph) as a 14:1 and 18:1 diastereomeric ratio,
respectively. This marked increase in diastereoselectivity
was initially attributed to the fact that the resin-bound
amine is sterically more demanding than the primary
amine in a typical DKR. However, the fact that resin-
bound amines with 3 and 10 carbon flexible spacers (4b
and 4c) yielded 7a/7b and 8a/8b with nearly identical
optical purities (Table 1, entries 3–6) was surprising
given that as the spacer length increases, the amine is
further from the resin bead and steric effects from the
bead would be significantly reduced. A plausible expla-
nation for this is that the flexible carbon spacer was not
adopting an extended conformation. With this in mind,
DKR using immobilized amines with rigid polyglycine
and polyalanine tripeptide spacers was performed
(Scheme 3). However, these spacers furnished 10a/10b in
a 12:1 and 17:1 diastereomeric ratio, respectively, con-
firming that steric effects from the resin bead were not
responsible for the increase in diastereoselectivity when
using immobilized amine nucleophiles.
-
CF3CO2
O
R
O
3 (2.0 equiv.)
O
O
O
R
O
H
H
N
H
TFA
H
N
H
H2N
N
N
H
N
H
O
N
H
NH2
+
O
(n-Butyl)4NI (cat.)
DIPEA (3.0equiv.),
DMF, 2d, RT
R
O
R
Ph
R
O
R
R = H or CH3
10a R = H, 12:1 dr (95% yield)
10b R = CH3 17:1 dr (96% yield)
Scheme 3.

2548
Y. Valenrod et al. / Tetrahedron Letters 45 (2004) 2545–2549
a fast interconversion between the (R,R) and (S,R)
diastereomers of 2 is still important when using immo-
bilized amine nucleophiles. Furthermore, the epimer-
ization is still faster than that of the heterogeneous
product-forming reaction.
BnNH2 (dropwise over 3d)
DIPEA, (n-Butyl)4NI (cat)
O
O
DMF, RT
H
Ph
O
O
O
O
NHBn
O
H
Ph
dr = 6.5:1
O
O
Br
In summary, we propose that the mechanism for the
DKR using immobilized amine nucleophiles (Fig. 2) is
very similar to that of the solution phase DKR. One of
the most unusual features of the typical DKR is that one
major product is formed in greater than 50% yield,
despite the fact that the a-bromo-(R)-pantolactonyl
ester is a racemate (S,R/R,R ¼ 1:1). This is explained
in that one of the a-bromo-(R)-pantolactonyl esters
undergoes SN2 reaction faster than the other and the
slower reacting diastereomer is epimerized to the faster
one in situ. As the major diastereomer from the DKR
using resin-bound amines is (S,R), we conclude that the
(R,R) diastereomer is the faster reacting diastereomer
and this is due to formation of an intermolecular
hydrogen bond that facilitates delivery of the amine
nucleophile.13b It is likely that the transition states for
the faster and slower reacting diastereomers in the SP–
DKR are similar to those of a typical DKR as outlined
in Figure 2.
O
O
H
3
Ph
O
NHBn
BnNH2, DIPEA,(n-Butyl)4NI (cat),
DMF, RT, 3d
dr = 2:1
Scheme 4.
addition of benzylamine produced a 2:1 diastereomeric
ratio, indicating that the low concentration of amine
nucleophile is contributing to the unusually high dia-
stereoselectivity observed in the DKR using immobi-
lized amine nucleophiles. Unfortunately, this experiment
does not preclude the possibility that multiple amines
may interact in a co-operative manner within the con-
fines of the resin. Furthermore, this experiment does not
elucidate the relative rate difference between a hetero-
geneous DKR and a homogeneous DKR.
We have demonstrated the first example of a DKR using
immobilized amine nucleophiles. Relative to traditional
DKR, the diastereoselectivities are superior ranging
from 11:1 to 18:1 dr with product yields nearly quanti-
tative in most cases. Our results suggest that the
unusually high diastereoselectivities are not attributed to
steric effects from the resin but the fact that this is a
heterogeneous reaction and the concentration of the
immobilized amine nucleophile on the resin is low. This
Much like in the typical DKR, a catalytic amount of
n-alkyl ammonium iodide is essential for high diastereo-
selectivity in the SP–DKR. Reaction of immobilized
amine 4a with 2 furnished 6a as a 14:1 diastereomeric
ratio (Table 1, entry 1). However, when the reaction is
performed in the absence of tetra-n-butyl ammonium
iodide, 6a is produced as a 6:1 diastereomeric ratio
(Scheme 5). Since the catalytic iodide ion epimerizes the
a-bromo-(R)-pantolactonyl ester, this result implies that
-
Cl3CO2
O
O
O
O
H
2 (2.5 equiv.)
+
H
TFA
H2N
H
N
N
NH2
O
O
DIPEA (3.0 equiv.),
DMF, RT, 2d
H
CH3
4a
6a, dr = 6:1 (90% yield)
Scheme 5.
H3C
H3C
Steric Interactions
Hydrogen Bond
o
o
H3C
H3C
H
H
O
O
o
o
o
o
H
N
H
N
R
R
c
c
Br
Br
n
n
H
H
O
O
H
H
Faster reacting (R,R)-diastereomer
Figure 2. Proposed transition states for substrates 2 and 3.
Slower reacting (S,R)-diastereomer

Y. Valenrod et al. / Tetrahedron Letters 45 (2004) 2545–2549
2549
G. J.; Scheeren, H. W. Tetrahedron Lett. 2000, 41, 515; (d)
Zhang, W.; Xie, W.; Fang, J.; Wang, P. G. Tetrahedron
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Tetrahedron Lett. 1999, 40, 7035.
approach constitutes a useful method for preparing
N-substituted a-amino acid derivatives with high optical
purities using solid phase synthesis. The scope of this
reaction and applications are currently being explored.
6. For solid supported dipolarophiles see: (a) Tan, D. S.;
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Markandu, J.; Sridharan, V.; Suganthan, S. Tetrahedron
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8. Faita, G.; Paio, A.; Quadrelli, P.; Rancati, F.; Seneci, P.
Tetrahedron 2001, 57, 8313.
Acknowledgements
The authors acknowledge the Ohio State University
Mass Spec Facility for mass spectral analysis. R.N.B.
currently holds a Canada Research Chair (CRC) in
Medicinal Chemistry and gratefully acknowledges the
Canada Research Chair Program for support.
9. Lysek, R.; Furman, B.; Cierpucha, M.; Grzeszczyk, B.;
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