Catalytic kinetic resolution of cyclic secondary amines

Article abstract of DOI:10.1021/ja209472h

The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.

Full text of DOI:10.1021/ja209472h

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Catalytic Kinetic Resolution of Cyclic Secondary Amines
Michael Binanzer, Sheng-Ying Hsieh, and Jeffrey W. Bode*
Laboratorium f€ur Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Z€urich, 8093 Z€urich, Switzerland
S Supporting Information
b
Scheme 1. Catalytic Kinetic Resolution of Secondary Amines
ABSTRACT: The catalytic resolution of racemic cyclic
amines has been achieved by an enantioselective amidation
reaction featuring an achiral N-heterocyclic carbene catalyst
and a new chiral hydroxamic acid cocatalyst working in
concert. The reactions proceed at room temperature, do not
generate nonvolatile byproducts, and provide enantioen-
riched amines by aqueous extraction.
nantiomerically pure amines are key constituents of pharma-
ceuticals and agricultural chemicals;1 however, there are few
Scheme 2. Synthesis of Hydroxamic Acid 1
E
methods for the catalytic resolution of racemic amines by either
chemical reagents or biotechnological approaches.2 This is par-
ticularly true of secondary amines, where the state of the art
remains chromatography on chiral supports or classical resolu-
tion by diastereomer formation. In contrast, catalytic kinetic
resolution3 is often the method of choice for the preparation of
other important chiral compounds, including secondary alcohols,4
carboxylic acids,5 and epoxides,6 as kinetic resolutions have the
advantage of reliably delivering enantiopure materials. In this
report, we document the catalytic kinetic resolution of secondary
amines by an enantioselective amide formation featuring two
independent catalytic cycles that work in concert with comple-
mentary reactivity and chemoselectivity. Despite the complexity
of the reaction mechanism, the resolution is operationally simple,
proceeds at room temperature, produces no nonvolatile bypro-
ducts, and affords enantioenriched amines by aqueous extraction
(Scheme 1).
The strong nucleophilicity of amines toward typical acylating
reagents generally precludes the intervention of a chiral mod-
ulator necessary for achieving catalytic amine resolutions. There-
fore, most approaches to kinetic resolution of amines require
stoichiometric amounts of chiral acylating agents.7 Fu has re-
ported effective catalytic amine resolutions using bulky acylation
reagents,8 including the resolution of indolines.9 Birman10 and
Miller11 have resolved protected amine derivatives, including
oxazolidinones and thioformylamides, with excellent selectiv-
ities, but this strategy precludes the use of secondary amines.
Alternatively, low reaction temperatures and concentrations can
suppress the background acylation, a strategy employed by
Seidel12 in a promising kinetic resolution of primary amines
using standard acylating reagents and chiral cocatalysts; second-
ary amines, however, fail to react under these conditions.
Important biocatalytic approaches include enantioselective car-
bamate formation,13 amide formation,14 deracemization,15 and
dynamic kinetic resolution,16 but the application of these meth-
ods to cyclic secondary amines is limited to isolated examples;17
the resolution of morpholines, piperazines, and azepanes has not
been described.
The basis for our approach to amine resolution is the catalytic
generation of acyl azoliums.18 These species undergo rapid
acylations with water, alcohols, and thiols but do not acylate
amines.19 We have devised methods for the catalytic generation
of acyl azoliums from α-functionalized aldehydes by internal redox
reactions promoted by N-heterocyclic carbenes (NHCs).20 Cat-
alytic amide formation requires an additive such as imidazole or
1-hydroxy-7-azabenzotriazole (HOAt) to convert the acyl azolium
to a secondary activated species that acylates the amine.21 Com-
peting imine formation complicates the combination of aldehyde
and amine, but we have overcome this problem by using α0-
hydroxyenones as bench-stable surrogates for aldehydes to give
clean, catalytic amidation reactions without imine formation and
with no background rate in the absence of the additive.22 These
observations opened the possibility of catalytic kinetic resolutions
of amines using an achiral NHC working in concert with a chiral
acylation cocatalyst.
Using 2-methylpiperidine as a challenging substrate, we sought
to identify reaction conditions and cocatalysts for the kinetic
resolution of secondary amines. Chiral protic heterocycles,
including imidazoles and triazoles, offered little or no enantio-
selectivity.23 A search for alternative cocatalysts led us to hydro-
xamic acids.24 While an initial screen of commercially available or
previously reported chiral hydroxamic acids offered only modest
selectivities,25 the cis-(1R,2S)-aminoindanol-derived hydroxamic
acid 1 gave excellent results. This novel catalyst can be readily
prepared in two steps from either enantiomer of inexpensive amino
alcohol 4 via known lactam 5 (Scheme 2).26 Further optimization of
the catalytic resolution conditions, including the use of mesityl-
substituted α0-hydroxyenone 3 to deter NHC-catalyzed side
Received: October 8, 2011
Published: November 14, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja209472h J. Am. Chem. Soc. 2011, 133, 19698–19701
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Table 1. Catalytic Kinetic Resolution of 2-Substituted Pi-
peridines with Hydroxamic Acid 1
Table 2. Catalytic Kinetic Resolution of Piperazines, Mor-
pholines, Tetrahydroisoquinolines, and Azepanes
Conditions: Resolutions were carried out on a 0.25 mmol scale with
amine(1.0equiv), triazolium2(10mol%), hydroxamicacid1(10 mol %),
α0-hydroxyenone 3 (0.7 equiv), and DBU (0.2 equiv) in CH2Cl2 (0.1 M)
at 23 °C for 18 h. a Calculated conversion.28 b Isolated yield of amide.
c 1.0 equiv of 3 was used.
Conditions: Resolutions were carried out on a 0.25 mmol scale with
amine(1.0equiv), triazolium2(10 mol%), hydroxamicacid1(10 mol%),
α0-hydroxyenone 3 (0.7 equiv), and DBU (0.2 equiv) in CH2Cl2
(0.1 M) at 23 °C for 18 h. a Calculated conversion.28 b Isolated yield of
amide. c 10 mmol scale. d The enantiomer (ent-1) of the hydroxamic acid
cocatalyst was used. e 1.0 equiv of 3 was used.
reactions,27 led to a robust enantioselective amidation of 2-methyl-
piperidine with synthetically useful selectivity (s = 17).
Treatment of racemic amines (1.0 equiv) with α0-hydroxye-
none 3 (0.7 equiv), triazolium precatalyst 2 (10 mol %), chiral
cocatalyst 1 (10 mol %), and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU; 20 mol %) in CH2Cl2 (0.1 M) at 23 °C for 18 h produced
enantiomerically enriched amides; the unreacted scalemic
amines were recovered by extraction or carbamoylation. These
conditions were tested for a range of substituted piperidines
(Table 1), all of which gave good selectivities and the same sense
of enantioselectivity. In addition to 2-alkylpiperidines, the syn-
thetically important pipecolinic ester was resolved with excellent
selectivity (entry 12). The resolution could be easily conducted
on a gram scale (10.0 mmol of amine; entry 2) with quantitative
recovery of hydroxamic acid 1. As with any kinetic resolution, the
enantiopurity of the recovered unreacted amine can be improved
by higher conversions (entry 7).
We also evaluated other classes of cyclic amines. Substi-
tuted piperazines and morpholines, both of which are com-
ponents of chiral pharmaceuticals, were resolved with s factors
ranging from 11 to 23 (Table 2, entries 1ꢀ4). Tetrahydroi-
soquinolines (entries 6ꢀ8) were resolved with outstanding
levels of selectivity (up to s = 74). It is noteworthy that in all
cases the resolutions were conducted under identical reaction
Figure 1. Proposed synergistic catalytic cycles for the kinetic resolution
of amines and a stereochemical mnemonic.
conditions; only minor variations in the reaction workup
were made.
Under the standard conditions, modest selectivities were
observed in resolutions of 1-phenylethanamine, 2-methylpyrro-
lidine, 2-methylaziridine, and 3-methylpiperidine, and the reac-
tion did not proceed in a preliminary evaluation of an acyclic
secondary amine. It is probable that alternative catalyst designs
will address these other substrates classes.
1
Monitoring the reaction by H NMR spectroscopy showed
that acylated intermediate 8 (Figure 1) was formed within
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Scheme 3. Effect of the Acyl Substituent on the Selectivity
and crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
bode@org.chem.ethz.ch
’ ACKNOWLEDGMENT
This work was supported by ETH Z€urich. We thank Yoonjoo
Kim and Claudia Kleinlein for preliminary experiments. Kind gifts of
racemic amines were made by Sigma-Aldrich and BioBlocks, Inc.
minutes. We confirmed 8 to be the active acylating agent by
independently preparing this compound and employing it as a
stoichiometric reagent, an experiment aided by the fact that 8
could be isolated and purified by column chromatography.
Kinetic resolution of 2-methylpiperidine with 0.5 equiv of
isolated 8 gave identical selectivity (s = 18). These results led
us to propose the synergistic catalytic cycles shown in Figure 1.
Hydroxamic acid 1 can be regarded as a chiral variant of
commonly used N-acylation reagents such as N-hydroxysuccini-
mide or HOAt. Its success as a catalyst, however, depends on the
ability of the NHC to generate synergistically the acylated
hydroxamate via intermediate acylating agent 7 that does not
itself react with the amine.29
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