Kinetic Resolution of Amines by a Nonenzymatic Acylation Catalyst

Full text of DOI:10.1002/1521-3773(20010105)40:1<234::AID-ANIE234>3.0.CO;2-K

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[13] The stereochemistry of this intermediate was rigorously established by
a combination of chemical and spectral means. Details will be
provided in a full paper.
R2N
N
[14] G. E. Keck, C. A. Wager, Org. Lett. 2000, 2, 2307 ± 2309.
[15] This material was prepared in three steps from the known unsaturated
ester: D. L. Boger, T. T. Curran, J. Org. Chem. 1992, 57, 2235 ± 2244.
[16] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25, 2183 ± 2186.
[17] J. A. Lafontaine, PhD thesis, University of California at Berkeley
(USA), 1999.
Fe
R'
R'
R'
R'
R'
NR2 = dimethylamino, pyrrolidino
R' = Me, Ph
NR2 = pyrrolidino, R' = Me: (–)-PPY* (1)
work to the acylation of amines were stymied by the
nucleophilicity of the amineÐit appears that, rather than
awaiting the intervention of the enantiopure catalyst, the
amine instead reacts directly with the acylating agent. As
illustrated in Table 1, a variety of common reagents acylate
(Æ)-1-phenylethylamine with essentially no stereoselection in
the presence of (ꢁ)-PPY*.[9]
Kinetic Resolution of Amines by a
Nonenzymatic Acylation Catalyst**
Â
Shigeru Arai, Stephane Bellemin-Laponnaz, and
Gregory C. Fu*
Dedicated to Professor David A. Evans
on the occasion of his 60th birthday
Table 1. Reaction of (Æ)-1-phenylethylamine with common acylating
agents in the presence of (ꢁ)-PPY*.
During the past four years, several groups have reported a
diverse array of interesting approaches to the development of
nonenzymatic acylation catalysts for the kinetic resolution of
alcohols, and certain classes of alcohols can now be resolved
with useful levels of stereoselection (selectivity factor s ꢀ
10).[1±3] Amines comprise a second important family of
substrates,[4] but, unfortunately, there has been no significant
progress in the development of nonenzymatic acylation
catalysts for their kinetic resolution, although some advances
have recently been made in the discovery of enantioselective
stoichiometric acylating reagents.[5] Here we describe the first
effective nonenzymatic acylation catalyst for the kinetic
resolution of amines [Eq. (1)],[6, 7] and we present preliminary
mechanistic data.
O
NH2
HN
Ph
X
10% (–)-PPY*
acylating agent
Ph
Me
Me
CHCl3
0 °C
racemic
Acylating agent
s
O
O
1.0
R
O
O
R
R = Me, Ph, tBu
X = Me, OMe
1.0
Cl
X
O
(no reaction)
1.2
O
Me
O
O
O
MeO
O
OMe
O
OMe
O
R
NH2
R
10% (–)-PPY*
R'
H2N
Ar
OMe
(1)
O
Ar
CHCl3
–50 °C
N
As a fortunate consequence of our studies of enantioselec-
tive rearrangement processes,[8c] we discovered an acylating
agent, an O-acylated azlactone, that reacts much more rapidly
with PPY* than with a primary amine. With this acylating
agent, we observed a significant level of stereoselection in the
kinetic resolution of (Æ)-1-phenylethylamine catalyzed by
enantiopure PPY* [Eq. (2)].[10]
racemic
Ar'
kinetic resolution
In earlier studies, we established that planar-chiral DMAP
derivatives such as PPY* can serve as useful catalysts for
several different enantioselective acylation processes, includ-
ing the kinetic resolution of secondary alcohols (DMAP ˆ 4-
dimethylaminopyridine).[8] Our initial efforts to extend this
O
[*] Prof. Dr. G. C. Fu, Dr. S. Arai, Dr. S. Bellemin-Laponnaz
Department of Chemistry
O
OMe
O
NH2
10% (–)-PPY*
tBu
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax : (‡ 1)617-258-7500
(2)
O
HN
OMe
Me
s = 2.8
Ph
Me
CHCl3
0 °C
kinetic resolution
N
Ph
racemic
β-Naphthyl
E-mail: gcf@mit.edu
[**] We thank Michael M.-C. Lo, Dr. J. Craig Ruble, and Beata Tao for
helpful discussions and preliminary studies, and we also thank Dr.
George P. Luke (ARIAD Pharmaceuticals, Inc.) for providing the
primary amine illustrated in entry 8 of Table 1. Support has been
provided by Bristol-Myers Squibb, Merck, the National Institutes of
Health (National Institute of General Medical Sciences, R01-
GM57034), Novartis, Pfizer, and Pharmacia.
Optimization studies produced an enhancement in stereo-
selection, primarily as a result of the temperature dependence
of the selectivity. Thus, by conducting the reaction at ꢁ508C
and adding the acylating agent in two batches, we can resolve
234
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(Æ)-1-phenylethylamine with a selectivity factor of 12 (Ta-
ble 2, entry 1).[11] Other primary amines can also be kinetically
resolved with good stereocontrol by PPY*. Higher selectivity
factors are obtained for amines in which the aromatic group
bears an ortho substituent (entries 2 and 3 vs. entry 1).
O
O
R
O
OMe
PPY*
HN
OMe
R'
slow
fast
O
Ar
step 2
step 1
N
Ar'
NH2
R
O
O
O
R'
Ar
Table 2. Kinetic resolutions catalyzed by (ꢁ)-PPY*.
PPY*
OMe
N
O
Ar'
Scheme 1. Proposed mechanism for acylations catalyzed by PPY*.
O
OMe
O
R
NH2
R
10% (–)-PPY*
t Bu
HN
OMe
O
Ar
CHCl3
–50 °C
N
with this kinetic scheme is our observation that the rate of the
reaction is zero order in acylating agent and first order in
PPY* and in amine.[13]
Ar
racemic
β-Naphthyl
Entry
1
Amine
s
Received: September 28, 2000 [Z15872]
12
[1] a) E. Vedejs, O. Daugulis, S. T. Diver, J. Org. Chem. 1996, 61, 430 ±
431; E. Vedejs, O. Daugulis, J. Am. Chem. Soc. 1999, 121, 5813 ± 5814;
b) T. Oriyama, Y. Hori, K. Imai, R. Sasaki, Tetrahedron Lett. 1996, 37,
8543 ± 8546; T. Sano, K. Imai, K. Ohashi, T. Oriyama, Chem. Lett.
1999, 265 ± 266; c) T. Kawabata, M. Nagato, K. Takasu, K. Fuji, J. Am.
Chem. Soc. 1997, 119, 3169 ± 3170; d) S. J. Miller, G. T. Copeland, N.
Papaioannou, T. E. Horstmann, E. M. Ruel, J. Am. Chem. Soc. 1998,
110, 1629 ± 1630; E. R. Jarvo, G. T. Copeland, N. Papaioannou, P. J.
Bonitatebus, Jr., S. J. Miller, J. Am. Chem. Soc. 1999, 121, 11638 ±
11643; e) F. Iwasaki, T. Maki, W. Nakashima, O. Onomura, Y.
Matsumura, Org. Lett. 1999, 1, 969 ± 972; F. Iwasaki, T. Maki, O.
Onomura, W. Nakashima, Y. Matsumura, J. Org. Chem. 2000, 65,
996 ± 1002; f) A. C. Spivey, T. Fekner, S. E. Spey, J. Org. Chem. 2000,
65, 3154 ± 3159.
2
3
27
16
4
11
[2] a) J. C. Ruble, H. A. Latham, G. C. Fu, J. Am. Chem. Soc. 1997, 119,
1492 ± 1493; b) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem. 1998,
63, 2794 ± 2795; c) C. E. Garrett, M. M.-C. Lo, G. C. Fu, J. Am. Chem.
Soc. 1998, 120, 7479 ± 7483; d) B. Tao, J. C. Ruble, D. A. Hoic, G. C.
Fu, J. Am. Chem. Soc. 1999, 121, 5091 ± 5092; e) S. Bellemin-
Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem.
Commun. 2000, 1009 ± 1010.
5
6
13
22
[3] Selectivity factor s ˆ (rate of fast-reacting enantiomer)/(rate of slow-
reacting enantiomer). For a review of kinetic resolution, see: H. B.
Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249 ± 330.
[4] For a review of methods for the asymmetric synthesis of amines, see:
A. Johansson, Contemp. Org. Synth. 1995, 2, 393 ± 407.
[5] a) Y. Ie, G. C. Fu, Chem. Commun. 2000, 119 ± 120; b) A. G. Al-
Sehemi, R. S. Atkinson, J. Fawcett, D. R. Russell, Tetrahedron Lett.
2000, 41, 2239 ± 2242.
7
8
16
11
[6] A wide array of enantiopure a-arylamines display biological activity,
including Exelon, a Novartis compound approved in the US in 2000
for the treatment of Alzheimerꢁs disease. For reviews about Exelon,
see: a) M. W. Jann, Pharmacotherapy 2000, 20, 1 ± 12; b) M. D.
Gottwald, R. I. Roaznski, Expert Opin. Invest. Drugs 1999, 8, 1673 ±
1682.
[7] Enantiopure a-arylamines are widely used as reagents in asymmetric
synthesis. For example, see: E. Juaristi, J. L. Leon-Romo, A. Reyes, J.
Escalante, Tetrahedron: Asymmetry 1999, 10, 2441 ± 2495.
[8] a) For kinetic resolutions of secondary alcohols, see ref. [2]; b) J.
Liang, J. C. Ruble, G. C. Fu, J. Org. Chem. 1998, 63, 3154 ± 3155;
c) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532 ± 11533;
d) B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121,
2637 ± 2638.
Electronic effects due to para substitution do not appear to
impact significantly on stereoselection (entries 4 and 5 vs.
entry 1), although enhanced selectivity is observed for a meta-
methoxy-substituted amine (entry 6). An increase in the size
of the alkyl group also leads to a modest increase in
stereoselection (entry 7 vs. entry 1). Entry 8 provides an
example of a kinetic resolution of a more highly functional-
ized amine that has been employed in studies of peptide-
based Src SH2 inhibitors.[12]
We believe that these kinetic resolutions proceed through
the pathway outlined in Scheme 1. Catalyst PPY* reacts
rapidly with the acylating agent, producing an ion pair
(step 1), which is the resting state of the catalytic cycle. In
the subsequent, stereochemistry-determining step, the me-
thoxycarbonyl group is transferred to the amine, thus furnish-
ing the carbamate and regenerating PPY* (step 2). Consistent
[9] We obtain similar results with our other planar-chiral DMAP-derived
catalysts.
[10] We have examined the use of a number of O-acylated azlactones.
These results will be reported in a future full paper.
[11] Sample experimental: Catalyst (ꢁ)-PPY* (5.2 mg, 0.014 mmol),
1-phenylethylamine (17.0 mg, 0.140 mmol), and CHCl3 (2.5 mL) were
added to a Schlenk flask under argon. The resulting purple solution
was cooled in a ꢁ508C bath, and a solution of O-acylated azlactone
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(13.5 mg, 0.0420 mmol) in CHCl3 (0.15 mL) was added by syringe.
After 4 hours, additional O-acylated azlactone (13.5 mg,
0.0420 mmol) in CHCl3 (0.15 mL) was added. After 24 hours (total),
the carbamate was isolated by flash chromatography (25% EtOAc/
hexanes) (7.3 mg; HPLC analysis: 79% ee). For ee analysis, the
unreacted amine was acylated (NEt3, Ac2O, CH2Cl2, RT) and then
purified by flash chromatography (EtOAc) to furnish the amide
(11.4 mg; GC analysis: 42% ee). These ee values correspond to a
selectivity factor s of 13 at 35% conversion.
geometries in which more metal centers can be magnetically
coupled.[6] A simple strategy for achieving higher nuclearities
involves the use of a blocking ligand on just one of the
reaction components, thereby permitting cluster growth to
propagate further before a closed structure forms. Accord-
ingly, the reaction between [Ni(H2O)6]2‡ and [(Me3tacn)-
Cr(CN)3] (Me3tacn ˆ N,N',N''-trimethyl-1,4,7-triazacyclono-
nane) in aqueous solution generates [(Me3tacn)8-
Cr8Ni6(CN)24]12‡, a 14-metal cluster featuring a cube of eight
Cr3‡ ions with each square face spanned by a [Ni(CN)4]2ꢁ
unit.[7] In further pursuing reactions of this type, we have
discovered two new cluster geometries, including a 19-metal
species that represents the largest metal ± cyanide cluster
reported to date.
[12] G. P. Luke, D. A. Holt, Tetrahedron: Asymmetry 1999, 10, 4393 ± 4403.
[13] A study of stereoselectivity as a function of catalyst ee is consistent
with the presence of one catalyst molecule in the stereochemistry-
determining step of the process.
Reaction of NiI2 with [(Me3tacn)Cr(CN)3] in aqueous
solution does not lead to the face-centered cubic [(Me3tacn)8-
Cr8Ni6(CN)24]12‡ cluster obtained with chloride, bromide,
nitrate, or perchlorate as counteranions.[7] Instead, crystallo-
graphic analysis[8] of a red-brown crystal isolated from the
reaction mixture revealed a product of composition 1,
High-Nuclearity Chromium ± Nickel ± Cyanide
Clusters: An Open Cr8Ni5(CN)24 Cage and a
C3-Symmetric Cr10Ni9(CN)42 Cluster
Incorporating Three Forms of
[(Me3tacn)8Cr8Ni5(CN)24]I10 ´ 27H2O
1
Cyanonickelate**
featuring the open-cage cluster depicted in Figure 1. The core
structure of this [(Me3tacn)8Cr8Ni5(CN)24]10‡ cluster most
notably differs from the complete face-centered cubic geom-
etry by having a Ni2‡ ion missing from one of the cube faces.
Jennifer J. Sokol, Matthew P. Shores, and
Jeffrey R. Long*
High-nuclearity metal ± cyanide clusters may ultimately
provide a vehicle for the design of new single-molecule
magnet molecules possessing an energy barrier for magnetic
moment reversal.[1] This contention is partly supported by
recent work in which an understanding of the factors
influencing superexchange interactions across a bridging
cyanide ligand has led to the synthesis of Prussian blue type
solids[2] with magnetic ordering temperatures as high as
373 K.[3] Typically, such solids are obtained from aqueous
assembly reactions between octahedral [M(H2O)6]x‡ and
[M'(CN)6]yꢁ complexes. The synthesis of molecular clusters
with similarly adjustable magnetic properties is expected to
require inhibition of some reactive sites on the precursor
complexes through substitution of inert blocking ligands. For
example, the use of 1,4,7-triazacyclononane (tacn) as a face-
capping tridentate ligand on each metal complex can direct
the formation of [(tacn)8M4M'4(CN)12]z‡ clusters with core
structures consisting of a single cubic unit excised from the
Prussian blue type framework.[4, 5]
Figure 1. Structure of the [(Me3tacn)8Cr8Ni5(CN)24]10‡ cluster and associ-
ated Iꢁ anions, as observed in 1. Black, cross-hatched, shaded, white, and
hatched spheres represent Cr, Ni, C, N and I atoms, respectively; H atoms
are omitted for clarity. The cluster has maximal point group symmetry C2v.
Selected mean interatomic distances [Š] and angles [8]: Cr-NCN 2.05(6), Cr-
C 2.04(5), Ni-C 1.86(2), C-NCN 1.14(3), Ni ´´´ Iouter 2.91(3), Ni ´´´ Iinner 3.09(3);
NCN-Cr-NCN 87(2), NCN-Cr-C 93(3), Cr-N-CCN 170(4), Cr-C-N 172(4), C-Ni-
C 89(1), Ni-C-N 177(1).
However, to produce the exceptionally large spin states
desiredÐalong with magnetic anisotropyÐfor increasing the
spin reversal barrier in single-molecule magnets, it is neces-
sary to develop methods for constructing larger cluster
[*] Prof. J. R. Long, J. J. Sokol, M. P. Shores
Department of Chemistry
University of California
Berkeley, CA 94720-1460 (USA)
Fax: (‡1)510-642-8369
As with [(Me3tacn)8Cr8Ni6(CN)24]12‡ [7]
the thermal energy
,
E-mail: jlong@cchem.berkeley.edu
delivered in the course of forming the cluster is apparently
sufficient to reorient the cyanide ligands from the CrIII-C-N
connectivity of the reactant complex to the more stable CrIII-
N-C-NiII bridging arrangement. This, rather than the reverse
bridging cyanide orientation, was clearly favored in the crystal
[**] This work was supported by the National Science Foundation, the
University of California, Berkeley, the Hellman Family Faculty Fund,
and Elf-Atochem. We thank Dr. C. Crawford and Unilever for a
donation of N,N',N''-trimethyl-1,4,7-triazacyclononane (Me3tacn), and
Prof. A. M. Stacy and Prof. J. Arnold for use of instrumentation.
236
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Angew. Chem. Int. Ed. 2001, 40, No. 1