α-Amino acid synthesis via a Cu(II) chiral Lewis acid mediated addition of soft carbon nucleophiles to glycine cation equivalents

Article abstract of DOI:10.1016/j.tetasy.2004.04.018

A new method for the formation of α-amino acid derivatives via Lewis acid mediated additions of soft carbon nucleophiles to carbamate protected glycine cation equivalents is described. A number of derivatives have been prepared in moderate yields and up to 85% ee using a Cu(II)-diamine catalyst combination.

Full text of DOI:10.1016/j.tetasy.2004.04.018

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1681–1684
a-Amino acid synthesis via a Cu(II) chiral Lewis acid mediated
addition of soft carbon nucleophiles to glycine cation equivalents
Rick Attrill, Heather Tye* and Liam R. Cox
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received 7 April 2004; accepted 15 April 2004
Abstract—A new method for the formation of a-amino acid derivatives via Lewis acid mediated additions of soft carbon nucleo-
philes to carbamate protected glycine cation equivalents is described. A number of derivatives have been prepared in moderate yields
and up to 85% ee using a Cu(II)-diamine catalyst combination.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
situ and has the ability to control the stereoselectivity of
the addition of the nucleophile by forming a stable five-
membered chelate with the chiral Lewis acid by binding
through both the imine N and the carbonyl O. With this
in mind N-benzyloxycarbonyl-a-methoxy glycinate 1
was chosen as a suitable substrate to begin the investi-
gation.
Recently there have been many examples of Lewis acid
catalysed/mediated additions of nucleophiles to imines
in the context of chiral auxiliary chemistry.1–7 However
there have only been a few reported chiral Lewis acid
catalysed variants of this Mannich-type reaction.8–12 The
use of a-imino esters as substrates in Mannich-type
reactions leads to the formation of a-amino acids. More
specifically the use of silyl enol ethers as nucleophiles in
such reactions gives us access to c-oxo-a-amino acids
(aspartic acid analogues), which are an interesting and
useful class of biologically active a-amino acids.13–22
Although Lectka9–11 and Kobayashi12 have successfully
achieved the formation of a-amino acids by the addition
of soft carbon nucleophiles to imines using chiral Lewis
acids, both methods employ protecting groups that
require aggressive deprotection conditions. Herein we
report an asymmetric Lewis acid mediated addition of
soft carbon nucleophiles to imines bearing carbamate-
type protecting groups that can be removed under mild
conditions. Furthermore, the reactive imine is formed in
2. Results and discussion
In order to ascertain effective Lewis acid and solvent
combinations for catalysing/mediating the addition, an
initial screen was conducted (Scheme 1). Lewis acids and
solvents were chosen using score plots, resulting from
principal components analyses,23 so as to enable an
investigation of a range of chemical behaviours.
Encouragingly, six ‘hits’ were identified from this screen
using LC–MS analysis of the crude reaction mixtures
(Table 1). These six ‘hits’ were investigated further and
the ratios of the starting material to target molecule
were calculated from the crude 1H NMR spectrum. The
Cbz
OMe
TMSO
Cbz
HN
MeO2C
O
Lewis acid
N
H
CO2Me
Ph
Ph
Solvent
r.t, 4 h
1
2
3
Scheme 1. Lewis acid and solvent screen.
* Corresponding author at present address: Evotec OAI, 151 Milton Park, Abingdon OX14 4SD. Fax: +44-1235 441509; e-mail: heather.tye@
evotecoai.com
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.018

1682
R. Attrill et al. / Tetrahedron: Asymmetry 15 (2004) 1681–1684
Table 2. Ligand screen
Table 1. Lewis acid and solvent screen
ZnCl2 CuBr2 AlCl3 SnCl4 Cu(OTf)2 Yb(OTf)3
Entrya Ligand Solvent
Yield/% Eeb/%
Major isomerc
MeCN
U
U
U
1
2
3
4
5
6
7
8
None
None
7
DCM
MeCN
MeCN
DCM
DCM
MeCN
DCM
DCM
8
29
26
14
18
40
7
0
0
––
––
DCM
THF
Toluene
U
U
23
0
Faster
––
––
U
8
9
10
0
U ¼ Product identified by LC–MS.
4
Slower
Slower
Faster
10
11
44
21
8
best Lewis acid and solvent combinations were found to
be Cu(OTf)2 in DCM or MeCN.
a For the ligand/solvent combinations not represented in the table,
there was no reaction.
b Enantioselectivities were obtained by use of chiral HPLC after
removal of the N-protecting group using TMSI in MeCN.
c Refers to the slower (retention time 21.90 min) or faster (retention
time 17.53 min) running enantiomer when analysed by HPLC using a
Chiralcel OD column.
The next step was to introduce the asymmetry-inducing
element in the form of an enantiopure chiral ligand. The
introduction of a ligand into the system could have
profound effects on the catalytic system and so it was
important to screen a variety of ligands. From the lit-
erature, ligands for copper 4–11 (Fig. 1) were examined
first, with a view to designing new ligands if necessary at
a later stage. Again nucleophile 2 and substrate 1 were
used in the reaction with stoichiometric amounts of
copper(II) triflate and ligands 4–11 in both DCM and
MeCN (Scheme 2 and Table 2)27.
with no ligand, using acetonitrile as the solvent gave the
best yield (29%). However with some ligands (entries 4,
5 and 8) the reactivity was reversed and DCM became
the preferred solvent for obtaining a significant amount
of the product. This difference is likely to be due to the
fact that acetonitrile is a coordinating solvent and can
therefore behave as a ligand, whereas DCM is nonco-
ordinating. The best ligand and solvent combination
was clearly cyclohexyl diamine 10 in DCM. When the
reaction was performed with ligand 10 in MeCN, the
yield increased; however this combination gave very
little to no enantioselectivity. Since the use of cyclohexyl
The results show that certain ligands 7–11 influenced the
stereochemical outcome of the reaction to some extent.
The effect of using different solvents was also very
noticeable, not only in modulating the enantioselectivity
but also in altering the yield of the product obtained. It
is interesting to note that in the reactions performed
O
O
Me
O
O
Me
Ph
N
N
N
N
S
N
N
S
Ph
OH HO
5
4
6
Me
Me
N
N
N
TfHN
NHTf
OH
8
7
9
H2N
Me
Ph
Ph
Ph
OH
BnHN
NHBn
BnHN
NHBn
10
11
12
Figure 1. Ligands which can form copper(II) complexes.
Cbz
OMe
TMSO
1.0 eq. Cu(OTf)2, 1.0 eq. ligand
solvent, r.t, 18 h
HN
O
Cbz
N
H
CO2Me
Ph
*
MeO2C
Ph
1
2
3
Scheme 2. Chiral ligand screen.

R. Attrill et al. / Tetrahedron: Asymmetry 15 (2004) 1681–1684
1683
Table 3. Effect of changing the leaving group and protecting group
diamine 10 in DCM gave the highest ee, we decided to
investigate the use of the related ligand (1R,2R)-N,N0-
dibenzyl-1,2-diphenylethane-1,2-diamine 12 with DCM.
Kobayashi et al.24;25 and Kanemasa et al.26 have already
demonstrated the use of this diphenyl backbone to great
effect in asymmetric Lewis acid catalysis.
Ligand
R
P
Yield/%
Eea/%
10
12
12
12
12
Me
Me
H
Cbz
Cbz
Cbz
Cbz
Boc
7
13
8
44
52
45
62
73
Ac
Ac
31
58
Ligand 12 was synthesised via pinacol coupling (Fig. 2)
followed by successive recrystallisations of the tartaric
acid salt. Use of 12 as the ligand in DCM solvent gave a
yield of 13% and a corresponding ee of 52%, which was
marginally better than the result obtained when using
ligand 10 in this solvent.
a Enantioselectivities were obtained by chiral HPLC after removal of
the N-protecting group (Cbz using TMSI in MeCN, Boc using TFA
in DCM).
mal reaction conditions and substrate 19 (Scheme 4 and
Table 4). There appears to be good nucleophilic com-
patibility over the range of nucleophiles investigated. It
is interesting to note that the use of enamine 20 led to a
product ee of 85% compared to 73% when using silyl
enol ether 2, where the use of both nucleophiles gives the
same product.
Investigations into the effect on yield and enantioselec-
tivity of the reaction by changing the leaving group and
then the protecting group on the substrate using the
preferred Cu(OTf)2/DCM/12 combination were subse-
quently conducted (Scheme 3 and Table 3).
The use of silyl enol ether 21 would be expected to give a
lower yield due to the electron-withdrawing properties
of the para-nitro group thus decreasing the reactivity
with respect to silyl enol ether 2. This was indeed the
case with the yield being 32% with the use of nucleophile
21 and 58% with the use of 2. Unfortunately it was not
possible to develop chiral HPLC assays for the depro-
tected products resulting from the use of nucleophiles
21, 23 and 24 and so the enantioselectivity of these
reactions could not be determined.
Of all the leaving groups studied, the best results were
obtained when the superior acetate leaving group was
employed. By comparing the last two entries in Table 3
it would appear that the steric properties of the pro-
tecting group also play an important role in the selec-
tivity of the reaction. An increase of 11% in the
enantioselectivity in going from the Cbz to the Boc
protecting group shows that the bulky tert-butyl group
led to higher selectivity in the reaction when compared
to the benzyl group. The electronic properties of these
groups are very similar and there is no apparent reason
for the 27% increase in yield in going from the Cbz to
the Boc protecting group.
3. Conclusion
In summary, a new general methodology for forming a-
amino acids by the Lewis acid mediated addition of soft
carbon nucleophiles to a carbamate-protected glycine
To demonstrate the generality of the reaction, six other
soft carbon nucleophiles were employed using the opti-
O
DCM, r.t., 1 h
BnNH2
13
93%
Ph
15
BnN
4 Å molecular sieves
Ph
H
14
Ph
BnHN
Ph
HgCl2/Mg/THF, r.t., 20 min
TiCl4/0 oC
r.t., 12 h
65%
15%
Ph
15
BnN
NHBn
( )-16
Ph
Ph
NHBn
Ph
Ph
(+)-Tartaric acid resolution
BnHN
BnHN
NHBn
(-)-12
( )-16
Figure 2. Synthesis of (1R,2R)-N,N0-dibenzyl-1,2-diphenyl-ethane-1,2-diamine 12.
P
OR
TMSO
1.0 eq. Cu(OTf)2, 1.1 eq. ligand
DCM, r.t, 18 h
HN
O
P
N
H
CO2Me
Ph
*
MeO2C
Ph
2
1: R = Me, P = Cbz
17: R = H, P = Cbz
18: R = Ac, P = Cbz
19: R = Ac, P = Boc
Scheme 3. Assessment of leaving group and protecting group effects.

1684
R. Attrill et al. / Tetrahedron: Asymmetry 15 (2004) 1681–1684
O
OAc
CO2Me
O
Nuc
CO2Me
1.0 eq. Cu(OTf)2, 1.1 eq. 12
O
N
H
1.2 eq. Nuc, DCM, r.t, 18 h
O
N
H
19
Scheme 4. Test of nucleophile compatibility.
6. Kondo, K.; Seki, M.; Kuroda, T.; Yamanaka, T.; Iwasaki,
T. J. Org. Chem. 1997, 62, 2877.
7. Fuentes, L. M.; Shinkai, I.; Salzmann, T. N. J. Am. Chem.
Soc. 1986, 108, 4675.
8. Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc.
1998, 120, 2474.
Table 4. Test for nucleophile compatibility
Entry
1
Nucleophile
Yield/%
58
Eea/%
OTMS
73
9. Ferraris, D.; Dudding, T.; Young, B.; Drury, W. J., III;
Lectka, T. J. Org. Chem. 1999, 64, 2168.
10. Ferraris, D.; Young, B.; Cox, C.; Drury, W. J., III;
Dudding, T.; Lectka, T. J. Org. Chem. 1998, 63, 6090.
11. Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am.
Chem. Soc. 1998, 120, 4548.
12. Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
1997, 119, 7153.
13. Yamaki, H.; Yamaguchi, M.; Imamura, H.; Suzuki, H.;
Nishimura, T.; Saito, H.; Yamaguchi, H. Biochem.
Biophys. Res. Commun. 1990, 168, 837.
14. Uchida, I.; Shigematsu, N.; Ezaki, M.; Hashimoto, M.;
Aoki, H.; Imanaka, H. J. Antibiot. 1985, 38, 1462–
1468.
15. Reed, J. W.; Purvis, M. B.; Kingston, D. G. I.; Biot, A.;
Gossele, F. J. Org. Chem. 1989, 54, 1161.
16. Vanderhaeghe, H.; Parmentier, G. J. Am. Chem. Soc.
1960, 82, 4414.
17. Botting, N. P. Chem. Soc. Rev. 1995, 24, 401.
18. Kristensen, I.; Larsen, P. O.; Sørensen, H. Phytochemistry
1974, 13, 2803.
2
Ph
2
52
85
N
O
20
OTMS
3
4
32
27
Not determined
NO2
21
OTMS
28
StBu
22
TMS
5
6
25
28
Not determined
Not determined
23
SnBu3
19. Ichihara, A.; Hasegawa, H.; Sato, H.; Koyama, M.;
Sakamura, S. Tetrahedron Lett. 1973, 37.
20. Couchman, R.; Eagles, J.; Hegarty, M. P.; Laird, W. M.;
Self, R.; Synge, R. L. M. Phytochemistry 1973, 12.
21. Barry, G. T.; Roark, E. J. Biol. Chem. 1964, 239, 1541.
24
a Enantioselectivities were obtained by chiral HPLC after removal of
the N-protecting group using TFA in DCM.
ꢀ
22. Berree, F.; Chang, K.; Cobas, A.; Rapoport, H. J. Org.
Chem. 1996, 61, 715.
cation equivalent has been developed. Initial results
show that moderate yields and good levels of enantio-
selectivity can be obtained. Along with improving the
yield and selectivity of the reaction, studies are currently
being conducted towards lowering the catalyst loading
while further investigating the versatility of this reaction.
23. Carlson, R. Design and Optimisation In Organic Synthesis;
Elsevier; 1997, Chapter 15.
24. Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem.
Soc. 2002, 124, 5640.
25. Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett.
2002, 4, 143.
26. Kanemasa, S.; Hamura, S.; Harada, E.; Yamamoto, H.
Tetrahedron Lett. 1994, 35, 7985.
References and notes
27. Data for 2-amino-4-oxo-4-phenyl butyric acid methyl
ester: mmax(CHCl3)/cmꢀ1 3393 (NH), 3031, 2955, 1739,
1685; dH (300 MHz; CDCl3) 2.08 (2H, br s, NH2), 3.40
(1H, A of ABX, JAB 17.9, JAX 6.6, CHCH2), 3.49 (1H, B of
ABX, JAB 17.9, JBX 4.4, CHCH2), 3.72 (3H, s, CH3), 3.97
(1H, X of ABX, JAX 6.3, JBX 4.4, CH), 7.38–7.49 (2H, m,
Ph), 7.51–7.61 (1H, m, Ph) 7.87–7.96 (2H, m, Ph); dC
(100 MHz; CDCl3) 42.9, 50.7, 52.3, 128.0, 128.6, 133.4,
136.5, 175.2, 197.8; m=z (ES) 230 ([M+Na]þ, 100%), 246
([M+K]þ, 28%); HRMS: (ES) Found: [M+Na]þ 230.0786,
C11H13NO3Na requires: 230.0793; HPLC (20% water/
MeCN, 1 mL/min, C18) 2.96 min; chiral HPLC (10%
iPrOH/hexane, 1.0 mL/min) 17.53, 21.90 min.
1. Sinclair, P. J.; Zhai, D.; Reibenspies, J.; Williams, R. M.
J. Am. Chem. Soc. 1986, 108, 1103.
2. Williams, R. M.; Armstrong, R. W.; Maruyama, L. K.;
Dung, J. S.; Anderson, O. P. J. Am. Chem. Soc. 1985, 107,
3246.
3. Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. J. Am.
Chem. Soc. 1988, 110, 1547.
4. Bailey, P. D.; Clayson, J.; Boa, A. N. Contemp. Org.
Synth. 1995, 173.
5. Nagao, Y.; Kumagai, T.; Tamai, S.; Abe, T.; Kuramoto,
Y.; Taga, T.; Aoyagi, S.; Nagase, Y.; Ochiai, M.; Inoue,
Y.; Fujita, E. J. Am. Chem. Soc. 1986, 108, 4673.