Kinetic resolution of nitrogen heterocycles with a reusable polymer-supported reagent

Full text of DOI:10.1002/anie.201204991

Angewandte
Chemie
DOI: 10.1002/anie.201204991
Enantioenriched Amines
Kinetic Resolution of Nitrogen Heterocycles with a Reusable Polymer-
Supported Reagent**
Imants Kreituss, Yuta Murakami, Michael Binanzer, and Jeffrey W. Bode*
Enantioenriched N-heterocycles are commonly prepared by
resolution of their racemic mixtures.[1] Surprisingly, enzymatic
and other catalytic resolutions of these important building
blocks are less developed;[2,3] the state of the art remains
separations by diastereomeric salt formation or resolution by
chromatography on chiral stationary phases.[4] As an alter-
native, stoichiometric chiral acylating agents can be used for
enantioselective amidation of racemic amines. Researchers,
including Fu,[5] Mioskowski,[6] Atkinson,[7] and others,[8] have
reported progress on such methods but their widespread use
has been precluded by restricted substrate scope, inconven-
ient reaction procedures, and lengthy syntheses of the
reagents.
We have recently developed a method for the catalytic
kinetic resolution of cyclic secondary amines featuring the
in situ generation of chiral O-acyl hydroxamic acid 1.[9] This
enantioselective acylating agent is remarkably robust; it can
be purified by column chromatography and stored for
prolonged periods without decomposition. This suggests
that a solid-supported version of 1 could act as an easily
handled reagent for the resolution of amines and could be
reloaded and reused (Figure 1). In certain contexts, such as
the rapid resolution of a chiral amine with minimal reaction
optimization, the transfer of specialized acyl groups, or use in
a flow process, a reusable chiral reagent would offer
advantages over the catalytic system.[10,11]
We now document the synthesis of the robust and
reusable polystyrene-supported reagent 9 and its use for the
facile resolution of racemic amines. The resolutions are
conducted simply by mixing the racemic amine and this
reagent (ca. 0.6 equiv), followed by aqueous extraction or
column chromatography to separate the acylated product
from the enantioenriched recovered amine. The reagent can
be reused dozens of times without loss of efficiency or
selectivity. This approach is useful for obtaining enantiopure
amines from their racemates as well as preparing enantioen-
riched amides with groups that can be cleaved under mild
conditions. In contrast, our catalytic conditions are currently
Figure 1. Kinetic resolution of N-heterocycles with a reusable, solid-
supported reagent based on chiral stoichiometric reagent 1.
best suited to the formation of amides that are difficult or
impossible to cleave.
The synthesis of solid-supported reagent 9 commenced
from bromo-substituted hydroxamic acid 4, which is available
in three steps from inexpensive chiral aminoindanol 2.[12,13]
Heck coupling with benzylacrylate gave 5 in 65% yield.[14]
A
one-pot procedure consisting of temporary protection of the
hydroxamic acid moiety (Ac2O), reduction of the double
bond and the benzyl ester (10% Pd/C, H2), followed by basic
workup (1m LiOH) afforded carboxylic acid 6 in 73% yield.
Both enantiomers of hydroxamic acid 6 were prepared and
subsequently immobilized onto aminomethyl polystyrene
resin 7 using HATU and DMAP. Treatment of the polymer-
supported hydroxamic acid 8 with 3-phenylpropionic anhy-
dride generated the desired amine resolving agent
(Scheme 1).
9
We chose racemic 2-ethylpiperidine as a test substrate for
resolutions using solid-supported reagent 9. The best con-
versions and selectivities were obtained in CH2Cl2 owing to
the efficient swelling of the resin in this solvent. Optimal
conversion of about 60%, which resulted in highly enan-
tioenriched recovered amine, was achieved at 238C in 48 h.[15]
We also tested various resin loadings, and selected a reagent
with 1.0 mmolgÀ1 of transferable acyl groups for the majority
of our studies. Resolving N-heterocycles proved to be
remarkably easy: 1.0 equiv of the amine was shaken with
0.6–0.7 equiv 9 followed by filtration to recover resin-bound
reagent 8. The resolved amide and unreacted amine were
separated by an aqueous extraction or by column chroma-
tography. Reagent 8 was reused by treatment with 3-phenyl-
propionic anhydride to regenerate 9. A single batch of 8 has
been used for more than 20 cycles across different substrates
and acylating agents, and we have not, so far, observed any
loss of selectivity or reactivity. This resolution procedure was
[*] I. Kreituss, Y. Murakami, Dr. M. Binanzer, Prof. J. W. Bode
Laboratorium fꢀr Organische Chemie, Department of Chemistry
and Applied Biosciences, ETH-Zꢀrich
Wolfgang-Pauli-Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: bode@org.chem.ethz.ch
Homepage: http://www.bode.ethz.ch/
[**] This work was supported by ETH Zꢀrich. We are grateful to Sheng-
Ying Hsieh for helpful discussions and for providing racemic
amines.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204991.
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Table 1: (Continued)
Entry Racemic substrate Recovered amine
Acylated product
4
c=66%
s>14
>99:1 e.r.
23% yield
75:25 e.r.
52% yield
5
c=60%
s=13
96:4 e.r.
34% yield
81:19 e.r.
52% yield
Scheme 1. Preparation of solid-supported amine-resolving agent 9.
Reagents and conditions: a) TFA/H2SO4 (3:1) 08C, then NBS
(1.01 equiv), 80%; b) N,O-bis(trimethylsilyl)acetamide (1.1 equiv),
CH3CN, 238C to 758C, then MoO5·Py·HMPA (MoOPH) (1.2 equiv),
CH2Cl2, 238C, 73%; c) benzylacrylate (1.50 equiv), Pd(OAc)2
(0.10 equiv), P(o-tolyl)3 (0.21 equiv), Et3N (5.00 equiv), CH3CN, 238C
to 758C, 65%; d) Ac2O (1.10 equiv), EtOAc, 238C to 458C, then Pd/C
(10 wt%), H2; then 1m LiOH, 73%; e) 7(0.50 equiv), HATU
(0.95 equiv), DMAP (1.00 equiv), Hꢀnig’s base (3.00 equiv), DMF;
f) 3-phenylpropanoic anhydride, DMF, 458C. Abbreviations: TFA=tri-
fluoroacetic acid, NBS=N-bromosuccinimide, Py=pyridine, HMPA=
hexamethylphosphoric acid triamide, HATU=2-(1H-7-azabenzotriazol-
1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate, DMAP=4-
dimethylaminopyridine.
6
c=53%
s=20
93:7 e.r.
21% yield
88:12 e.r.
49% yield
7
c=59%
s=23
99:1 e.r.
37% yield
84:16 e.r.
58% yield
8[e]
applied to a diverse range of N-heterocycles, including
piperidines (Table 1, entries 1–3), piperazines (entries 4 and
5), morpholines (entry 6), tetrahydroisoquinolines (entries 7
and 8), and diazapenones (entry 9), all proceeding with high
selectivities and good product recovery.
90:10
64% yield
33% yield
9
Table 1: Kinetic resolution of amines using 9.
c=20%
s=19
62:38 e.r.
76% yield
94:6 e.r.
19% yield
[a] Calculated conversion.[16] [b] Selectivity.[16] [c] Enantiomeric ratio deter-
mined by SFC or HPLC on a chiral support. [d] Yield of isolated product.
[e] Reaction time 96 h; we have focused on the recovered amine in this
example (an important precursor of isoquinoline alkaloids).[17]
Entry Racemic substrate Recovered amine
Acylated product
1
After the resolution, the recovered enantioenriched
amine can always be used directly for further manipulations.
However, it is often desirable to gain access to both scalemic
amines in one single experiment by deprotecting the amide
product. This is especially true if the racemic amine is
valuable and is essential for the eventual development of
dynamic kinetic resolutions.[18] Our initial efforts to cleave the
hydrocinnamyl amide under mild conditions using hydro-
lases[19] or the Schwartz reagent,[20] or under harsher con-
ditions such as reflux with strong acids or bases,[21] were
unsuccessful.[22] We therefore sought to identify an easily
cleavable, but also readily available, acyl group that could be
used in combination with resin 8.
c=62%[a]
s=15[b]
98:2 e.r.[c]
80:20 e.r.[c]
56% yield[d]
19% yield[d]
2
3
c=54%
s=17
93:7 e.r.
21% yield
86:14 e.r.
51% yield
c=58%
s=17
96:4 e.r.
32% yield
84:16 e.r.
48% yield
Several amide-derived protecting groups for amines that
are removed under mild conditions have been disclosed.[23]
2
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Table 2: Kinetic resolution of amines using reagents 10 and 11.
We selected two examples based on the similarity of the acyl
groups to hydrocinnamic acid and the compatibility of the
deprotection conditions with our desired substrates. Entwistle
reported that 3-(2-nitrophenyl)propanoyl amides can be
reduced to the corresponding anilines which undergo sponta-
neous intramolecular cyclization and releases the amine.[24]
Alternatively, the pent-4-enoyl group is rapidly cleaved using
iodine.[25] Chiral acylating agents 10 and 11 bearing these
groups were easily generated from resin 8 and the corre-
sponding carboxylic acid.
Entry Racemic substrate Recovered amine
Acylated product
Upon testing these solid-supported reagents with several
of our most important substrates, we were pleased to find that
the resolutions proceeded under identical conditions to our
standard procedure, and with similar efficiencies (Table 2,
entries 1–5). With shorter reaction times, which led to lower
conversion, highly enantioenriched amides were obtained
(entry 2). The use of the removable group and an excess
amount of an inexpensive, racemic amine such as 2-ethyl-
piperidine can be used to easily produce enantioenriched
amides (entry 6). Although this approach is less atom-
economical, it is a straightforward method to access enan-
tioenriched material from a racemic sample.
Many N-heterocycles, particularly electron-rich tetrahy-
droisoquinolines, are sensitive to oxidation and epimeriza-
tion. To confirm that the pent-4-enoyl group can be depro-
tected without complication in such substrates, we allowed 12
to react with 3 equiv of I2 in aqueous THF under air, which
cleanly afforded the unprotected amine in good yield
(Scheme 2). Careful isolation and analysis of the resulting
amine product confirmed that neither oxidation nor epime-
rization occurred during the deprotection.
1
c=47%[a]
s=25[b]
87:13 e.r.[c]
92:8 e.r.[c]
50% yield[d]
43% yield[d]
2
c=26%[e]
s=18
65:35 e.r.
57% yield
93:7 e.r.
21% yield
3
4
c=62%
s>23
>99:1 e.r.
32% yield
80:20 e.r.
61% yield
c=49%
s=20
88:12 e.r.
41% yield
90:10 e.r.
44% yield
5
c=43%
s=17
80:20 e.r.
42% yield
90:10 e.r.
40% yield
Scheme 2. Cleavage of the pent-4-enoyl without racemization.
6[e,f]
In summary, we have developed a robust, reusable
polymer-bound reagent for the kinetic resolution of a wide
range of N-heterocycles. The reagent benefits from brevity of
synthesis, high selectivity, robustness, and ease of recovery
(more than 20 cycles without erosion of reactivity or
selectivity). We have established a simple resolution proce-
dure: shaking the reagent and the amine at room temper-
ature, followed by filtration to separate the reagent from the
resolved enantiomers. Importantly, and in contrast to our
current catalytic amine resolution, this method allows the
facile transfer of acyl groups that can be easily removed from
the enantioenriched amide products.
92:8 er[g]
[a] Calculated conversion.[16] [b] Selectivity.[16] [c] Enantiomeric ratio deter-
mined by SFC or HPLC on a chiral support. [d] Yield of isolated product.
[e] Reaction time 15 h. [f] Ca. 5 equiv amine was used (unreacted amine was
not recovered). [g] 0.3 mmol of the product was obtained.
a solution in CH2Cl2 (5 mL) was added to the beads and the mixture
was shaken for 48 h. The beads were filtered off and washed with
CH2Cl2 (7 ꢀ three times the bead volume). The solution was
concentrated under reduced pressure and the amide product and
unreacted amine were separated by column chromatography (hex-
anes/EtOAc 1:1 for the amide; EtOAc/Et3N 99.9:0.1 for the amine;
stationary phase used: silica). Recovered amine 140 mg (37% yield,
e.r. = 99:1), acylated product 340 mg (58% yield, e.r. = 84:16).
Calculated conversion c = 59%, s = 23.
Experimental Section
Resin-bound reagent 9 (1.00 g, ca. 1.00 mmolgÀ1, 0.6–0.7 equiv) was
swollen in CH2Cl2 for 1 h. 6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahy-
droisoquinoline (380 mg, 1.40 mmol, 1.00 equiv; Table 1, Entry 7) as
Received: June 26, 2012
Published online: && &&, &&&&
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Keywords: amines · functionalized resins · kinetic resolution ·
nitrogen heterocycles · solid-supported reagents
.
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Angewandte
Chemie
Communications
Enantioenriched Amines
Shake it up baby! Simply shaking a poly-
mer-supported reagent and the racemic
amine at room temperature kinetically
resolves a broad range of N-heterocycles
with good selectivity. The polymer-sup-
ported reagents are robust, easy to
regenerate, and can be reused dozens of
times. Cleavable acyl groups can be used
to give access to both amine enantiomers
in a single resolution.
I. Kreituss, Y. Murakami, M. Binanzer,
J. W. Bode*
&&&& — &&&&
Kinetic Resolution of Nitrogen
Heterocycles with a Reusable Polymer-
Supported Reagent
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