Copper-catalyzed asymmetric N-H insertion reactions: Couplings of diazo compounds with carbamates to generate α-amino acids

Article abstract of DOI:10.1021/ja074483j

A Cu/chiral bipyridine catalyst has been developed for the asymmetric insertion of α-diazocarbonyl compounds into the N-H bonds of carbamates to generate an array of easily deprotected arylglycines in good ee. With respect to the reaction partners, as wel

Full text of DOI:10.1021/ja074483j

Published on Web 09/18/2007
Copper-Catalyzed Asymmetric N-H Insertion Reactions: Couplings of Diazo
Compounds with Carbamates to Generate r-Amino Acids
Elaine C. Lee and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received June 19, 2007; E-mail: gcf@mit.edu
Table 1. Catalytic Asymmetric N-H Insertions: Effect of Reaction
The development of efficient methods for the preparation of
enantioenriched R-amino acids is of considerable importance in a
variety of fields, including chemistry and biology.1 For example,
phenylglycine or other arylglycines are subunits of bioactive
molecules such as amoxicillin and vancomycin.2,3 As a consequence,
a great deal of effort has been dedicated to the discovery of new
approaches to the asymmetric synthesis of R-amino acids.4
The enantioselective insertion of an R-diazocarbonyl compound
into an N-H bond represents a potentially attractive route to
R-amino acid derivatives.5-7 However, whereas catalytic asym-
metric insertions into C-H bonds have evolved into an extremely
powerful tool in organic synthesis,8 the development of corre-
sponding reactions of X-H bonds (X ) a heteroatom such as O
or N) is still in its infancy. Thus, the first efficient method for
catalytic enantioselective insertions into O-H bonds was just
described in 2006 (eq 1).9
Parameters
entry
variation from the “standard” conditions
yield (%)a,b
ee (%)a
1
2
none
74
69
81
70
<2
86
80
77
80
70
71
66
42
94
84
R1 ) i-Pr instead of t-Bu
R1 ) Bn instead of t-Bu
3
77
4
R1 ) Me instead of t-Bu
no AgSbF6
6.0% AgOTf instead of AgSbF6
no bpy*
12% bpy* instead of 8% bpy*
8.0% of a bis(oxazoline)c instead of bpy*
8.0% of BISAF instead of bpy*
CH2Cl2 instead of ClCH2CH2Cl
THF instead of ClCH2CH2Cl
toluene instead of ClCH2CH2Cl
70
5
-
6
87
7
0
8
92
9
<10
<10
88
10
11
12
13
69
74
a Average of two experiments. b Isolated yield. c Isopropylidenebis[(4R)-
4-tert-butyl-2-oxazoline].
glycine derivatives (eq 2). With regard to ligand structure and to
reaction partners, this method complements the studies of Jørgensen
and Zhou.
In view of the significance of nonracemic R-amino acids, we
decided to examine enantioselective N-H insertion reactions of
R-diazo esters. At the time that we initiated this program, the state-
of-the-art for catalytic asymmetric intermolecular N-H insertions
was defined by a pioneering study by Jørgensen, who demonstrated
that a chiral copper/bis(oxazoline) catalyst can furnish 28% ee (54%
yield) for the reaction of aniline with MeC(N2)CO2Et.10,11 Very
recently, Zhou has reported an impressive advance in this field,
specifically, that a different copper/bis(oxazoline) catalyst achieves
the insertion of MeC(N2)CO2R into an array of anilines (ArNH2)
with excellent enantioselectivity (up to 98% ee).12 The use of other
N-H sources led either to no reaction (e.g., a primary alkyl amine)
or to a racemic product (e.g., a carbamate). The Zhou study focused
almost exclusively on MeC(N2)CO2R, although it was noted that
the insertion of EtC(N2)CO2R proceeds in good ee (94%) and
modest yield (51%), whereas PhC(N2)CO2R affords very low
enantiomeric excess (8%).
The procedure that we had developed for catalytic asymmetric
insertions of R-diazo esters into the O-H bond of alcohols (eq 1)
provides modest enantioselectivity for the reaction of BocNH2 with
PhC(N2)CO2t-Bu (<50% ee). In contrast, a copper/planar-chiral
bipyridine13,14 catalyst accomplishes the desired N-H insertion in
good yield and ee (Table 1, entry 1).
The stereoselectivity diminishes as the steric demand of the ester
decreases (Table 1, entries 2-4).15 In the absence of AgSbF6, N-H
insertion does not occur (entry 5), which suggests that it is
advantageous to generate a halide-free copper complex. Silver salts
that bear poorly coordinating counteranions other than SbF6 can
be employed, although a slightly lower ee is obtained (entry 6).
Because N-H insertion proceeds in the absence of bpy* (entry 7),
we examined the possibility that a larger excess of bpy* might
improve the ee by decreasing the amount of bpy*-free copper.
However, additional bpy* does not lead to enhanced enantioselec-
tivity (entry 8), which indicates that the equilibrium constant for
complexation of bpy* to copper is high. A variety of other ligands,
including a bis(oxazoline) and a bis(azaferrocene), are not effective
In this report, we describe further progress in achieving asym-
metric N-H insertion reactions, in particular, the use of a chiral
copper/bipyridine catalyst to couple R-aryl-R-diazo esters with
readily deprotected carbamates, thereby furnishing access to aryl-
9
12066
J. AM. CHEM. SOC. 2007, 129, 12066-12067
10.1021/ja074483j CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric N-H Insertions: Synthesis of
the N-H bonds of carbamates to generate an array of easily
deprotected arylglycines in good enantiomeric excess. This process
complements the two earlier reports of catalytic asymmetric
intermolecular N-H insertion reactions, both of which focused on
the use of a chiral bis(oxazoline) as a ligand for copper-catalyzed
couplings of anilines with R-methyl-R-diazo esters.
Boc-Protected Arylglycines (for Reaction Conditions, See eq 2)
entry
Ar
yield (%)a,b
ee (%)a
1
2
3
4
5
6
7
8
9
Ph
75
71
75
61
77
86
89
73
74
94
(2-Me)C6H4
(3-Me)C6H4
(4-OMe)C6H4
(4-NHBoc)C6H4
(4-Br)C6H4
81
88
95
91
Acknowledgment. Support has been provided by the National
Institutes of Health (National Institute of General Medical Sciences,
R01-GM66960), Merck Research Laboratories, Novartis, and
Boehringer Ingelheim.
85 (95)c
85
(4-CF3)C6H4
2-naphthyl
91
90
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
10
3-thienyl
48
80
a Average of two experiments. b Isolated yield. c After one crystallization
from hexanes.
References
(1) For example, see: Wang, L.; Schultz, P. G. Angew. Chem., Int. Ed. 2005,
44, 34-66.
Table 3. Catalytic Asymmetric N-H Insertions: Synthesis of
Cbz-Protected Arylglycines
(2) (a) For leading references to the chemistry and biology of vancomycin,
see: Medical Chemistry of BioactiVe Natural Products; Liang, X.-T., Fang,
W.-S., Eds.; Wiley: Hoboken, NJ, 2006; pp 35-72. (b) For an example
of studies of vancomycin analogues, see: Christensen, B. G.; Judice, J.
K.; Mu, Y. Preparation of Glycopeptide Derivatives as Antibacterial
Agents. U.S. Patent Appl. 2003008812, 2003.
(3) For leading references to the asymmetric synthesis of arylglycines, see:
(a) Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45,
6360-6362. (b) Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92,
889-917.
(4) For leading references on the asymmetric synthesis of amino acids, see:
(a) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290-4299 (catalytic
processes). (b) Natchus, M. G.; Tian, X. Org. Synth.: Theory Appl. 2001,
5, 89-196. (c) Calmes, M.; Daunis, J. Amino Acids 1999, 16, 215-250.
(d) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon: Oxford, England, 1989.
entry
Ar
yield (%)a,b
ee (%)a
1
2
3
Ph
77
49
78
95
(4-OMe)C6H4
(4-CF3)C6H4
90
82 (98)c
a Average of two experiments. b Isolated yield. c After one crystallization
from hexanes.
(5) (a) For an early study of metal-catalyzed N-H insertions, see: Yates, P.
J. Am. Chem. Soc. 1952, 74, 5376-5381. (b) For an overview of catalyzed
insertions of diazo compounds into N-H bonds, see: Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds; Wiley: New York, 1998; Chapter 8.2.
(6) For a classic industrial application (thienamycin) of a metal-catalyzed
insertion of a diazo compound into an N-H bond, see: Salzmann, T. N.;
Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem. Soc.
1980, 102, 6163-6165.
under these conditions (entries 9 and 10). Finally, the use of solvents
such as CH2Cl2, THF, or toluene, rather than ClCH2CH2Cl, results
in a small to moderate loss in ee (entries 11-13).
This new method for catalytic asymmetric N-H insertions can
be applied to a range of R-aryl-R-diazo esters (Table 2).16 Thus,
the aromatic ring can be substituted in the 2, 3, or 4 position, and
the group can be electron-donating or electron-withdrawing (entries
2-7). A fused aromatic ring or a heterocycle can be present (entries
8-10), although the reaction proceeds in modest yield if Ar )
3-thienyl (entry 10). Finally, for an N-H insertion that occurs with
relatively low stereoselectivity, the ee of the product can be
enhanced through crystallization (entry 6).
The scope of this copper/bpy*-catalyzed asymmetric N-H
insertion is not limited to the synthesis of Boc-protected arylgly-
cines. As illustrated in Table 3, reactions of CbzNH2 generally
proceed with comparable ee as for BocNH2 (but in somewhat lower
yield), thereby providing access to Cbz-protected arylglycines.
In a competition experiment, we have determined that Cu/bpy*
has a considerable bias for N-H rather than N-D insertion (eq
3). In an earlier study of O-H insertion reactions catalyzed by
Cu/BISAF, we observed a similar preference.9,17
(7) For a pioneering investigation of diastereoselective N-H insertion to
generate R-amino acids, see: Nicoud, J.-F.; Kagan, H. B. Tetrahedron
Lett. 1971, 2065-2068.
(8) For reviews and leading references, see: (a) Davies, H. M. L.; Long, M.
S. Angew. Chem., Int. Ed. 2006, 45, 6422-6425. (b) ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; pp 513-603. (c) Davies, H. M. L.; Beckwith,
R. E. J. Chem. ReV. 2003, 103, 2861-2903. (d) Mu¨ller, P.; Fruit, C. Chem.
ReV. 2003, 103, 2905-2919.
(9) Maier, T. C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594-4595.
(10) Bachmann, S.; Fielenbach, D.; Jørgensen, K. A. Org. Biomol. Chem. 2004,
2, 3044-3049.
(11) For a seminal study of catalytic asymmetric intramolecular N-H
insertions, see: Garcia, C. F.; McKervey, M. A.; Ye, T. Chem. Commun.
1996, 1465-1466.
(12) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am. Chem. Soc.
2007, 129, 5834-5835.
(13) (a) For a recent application of bpy* as a ligand in asymmetric catalysis,
see: Son, S.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 1046-1047. (b)
For the initial report of bpy*, see: Rios, R.; Liang, J.; Lo, M. M.-C.; Fu,
G. C. Chem. Commun. 2000, 377-378.
(14) For reviews of chiral 2,2′-bipyridine ligands, see: (a) Malkov, A. V.;
Kocovsky, P. Curr. Org. Chem. 2003, 7, 1737-1757. (b) Fletcher, N. C.
J. Chem. Soc., Perkin Trans. 1 2002, 1831-1842.
(15) Interestingly, for catalytic asymmetric O-H insertion reactions, the
opposite trend is observed: stereoselectivity increases as the steric demand
of the ester decreases (ref 9).
(16) Notes: (1) An attempt to extend this catalytic asymmetric N-H insertion
process to an R-alkyl-R-diazo ester led to a 1,2-H shift, thereby generating
an R,â-unsaturated ester. (2) An R-pyridyl-R-diazo ester was unreactive.
(3) The reaction of an R-alkenyl-R-diazo ester (2-phenylethenyl) proceeded
in good ee (87%), but modest yield (25%). (4) An insertion into the N-H
bond of an amine occurred with low enantioselectivity. All of these
couplings were conducted under our standard conditions (eq 2) without
any optimization.
(17) We observe a small negative nonlinear effect. For a review of nonlinear
effects, see: Kagan, H. B.; Luukas, T. O. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New
York, 1999; Chapter 4.1.
In summary, we have developed a Cu/bpy*-catalyzed method
for the asymmetric insertion of R-diazocarbonyl compounds into
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