Highly diastereoselective switchable enantioselective mannich reaction of glycine derivatives with imines

Article abstract of DOI:10.1021/ja804527r

Tuning of diastereoselectivity was realized in the Mannich reaction of glycine derivatives with aromatic and aliphatic N-Ts imines using CuClO₄-FcPHOX ligand 4b and 4f having an MeO group at the 4-position and F atom at the 3,5-position of the

Full text of DOI:10.1021/ja804527r

Published on Web 10/08/2008
Highly Diastereoselective Switchable Enantioselective Mannich Reaction of
Glycine Derivatives with Imines
Xiao-Xia Yan,† Qian Peng,‡ Qing Li,† Kai Zhang,‡ Jun Yao,‡ Xue-Long Hou,*,†,‡ and
Yun-Dong Wu*,‡,§
State Key Laboratory of Organometallic Chemistry, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China, and Department of Chemistry, The Hong Kong UniVersity of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong, China
Received June 13, 2008; E-mail: xlhou@mail.sioc.ac.cn; chydwu@ust.hk
Table 1. Reaction of 1 with 2a Using Different Ligands and Lewis
Chiral R,ꢀ-diamino acid derivatives are an important class of
compounds because of their biological activities and their usefulness
in organic synthesis.1 Many synthetic approaches have been developed
for them, as exemplified by an assemblage employing asymmetric
Mannich type reaction of glycine derivatives with imines and nitro
compounds under metallo-2 and organocatalysis.3 The chiral quarter-
nary carbon center at the R-position was also established.4 However,
only a few reports realized both diastereo- and enantioselectivities and
no paper dealt with the tuning of diastereoselectivity. In some cases
the substrates were limited. Thus, challenges still remain regarding
diastereo- and enantioselectivities and/or substrate scope for the
reaction. On the other hand, tuning of diastereoselectivity by using
different approaches have been well documented;5,6 few reports
accomplished it by changing the electronic factor of the ligand.7,8 In
the studies of chiral ligands in asymmetric catalysis,9 we found a
dramatic effect of the electronic property of ligands on the switch of
regio- and diastereoselectivities in the Heck reaction and 1,3-dipolar
cycloaddition.10 Here we report our preliminary results showing that
the same strategy can be applied to Lewis acid catalyzed Mannich
reaction of glycine esters with both aromatic and aliphatic imines,
achieving excellent diastereo- and enantioselectivities for both syn and
anti products.
Initially, the reaction of glycine methyl ester 1 with N-tosyl imine
2a was examined using different Lewis acids and ligand 4a11 (eq 1,
Table 1). Reaction afforded R,ꢀ-diamino acid derivatives 3a in favor
of the anti-isomer in high yields using CuClO4 (entry 1). Better
diastereoselectivity was given using Cu(OTf)2 than using AgOAc (entry
3 vs entry 2). Higher diastereo- and enantioselectivities were realized
when the reaction proceeded at -78 °C (entry 4). THF was a better
solvent over CH2Cl2, toluene, and Et2O, leading to the best yield and
diastereo- and enantioselectivities (not shown in Table 1).
Acidsa
entry
ligand
Lewis acid
yield%b
syn/antic
ee% (syn/anti)d
1
2
4a
4a
4a
4a
4b
4b
4c
4d
4e
4e
4f
CuClO4
AgOAc
Cu(OTf)2
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
CuClO4
97
93
97
93
96
92
95
94
89
19
96
97
96
15:85
47:53
14:86
8:92
12:88
4:96
27:73
43:57
91:9
94:6
91:9
95:5
80:20
-/97
Ndf
3
-/99
-/99
-/99
-/99
96/99
93/99
99/-
98/-
96/-
99/-
93/-
4e
5
6e
7
8
9
10e
11
12e
13
4f
4g
a Molar ratio of 1/2a/ligand/Lewis acid/Et3N ) 1:1.2:11 mol%:10
mol%:10 mol%. b Isolated yield. c Determined by 1H NMR.
d Determined by chiral HPLC. e Run at -78 °C. f Not determined.
having an electron-donating methoxy group at the para-position of
phenyl rings on the P atom, anti- and syn-3a in a ratio of 96:4 (99%
ee for anti-3a) resulted (entry 5). A lower reaction temperature (-78
°C) favored the formation of the anti-product (entries 1 and 5 vs entries
4 and 6). On the other hand, a more syn-product was produced when
ligand 4c having an electron-withdrawing CF3 group at the para-
position of phenyl on the P atom was used (entry 7 vs entry 1). The
amount of syn- and anti-products was almost equal when the ligand
was 4d with 3,5-diMeC6H3 on the P atom (entry 8). Finally, syn-3a in
99% ee became the major product (syn/anti ratio 91:9) in the reaction
using ligand 4e containing two strongly electron-withdrawing CF3
groups at the 3,5-positions of phenyl rings (entry 9).
Although the syn-selectivity was realized using ligand 4e, the
diastereoselectivity was moderate (syn/anti ) 72:28) for electron-
deficient aromatic imine 2f. When the reaction proceeded at -78 °C
the yields of 3f decreased sharply (<20%). This was observed for
several other substrates (see SI), indicating the reactivity of ligand 4e
was lower. To correlate the diastereoselectivity and to increase the
catalytic activity, a computational study was performed with the density
functional theory method B3LYP/6-31G*(Lanl2dz).12 The complexes
of 4-Cu with the anion of iminoester 1 were fully optimized, and the
structures adopt a distorted tetrahedral geometry (Figure 1B). As shown
in Figure 1A, charge distribution analysis using electrostatic potential
(ESP) calculations13 indicated that the phenyl rings of the phosphine
are more electron-deficient with 3,5-difluoro substitution in 4f than
3,5-bis(trifluoromethy) substitution in 4e and 3,5-dichloro substitution
in 4g (a in Figure 1A). Thus, ligand 4f might lead to a better syn-
selectivity than 4e and 4g. In addition, the calculated negative charge
at the CR (b in Figure 1A) of iminoester 1 is the least for the complex
In our previous work we have demonstrated that the diastereose-
lectivity is switchable via a change of the electronic factor of ligands
4b-e.10a When they were tested for the current reaction, a dramatic
change in diastereoselectivity was evident (Table 1). With ligand 4b
† State Key Laboratory of Organometallic Chemistry.
‡ Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis.
§ The Hong Kong University of Science and Technology.
9
14362 J. AM. CHEM. SOC. 2008, 130, 14362–14363
10.1021/ja804527r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Re-face is blocked by the iso-propyl group of the ligand (Figure 1B).
A working model is proposed to correlate the observed stereochemistry.
Imine approaches the CR anion center in a staggered conformation
with the N atom pointing to Cu. The Ts group occupies the valley
formed by the two arene groups if the two rings are electron-deficient
in ligand 4f, giving a (2S,3R) product (Si-face for imine). The imine
attacks the CR with its Re-face when the arene rings are electron-rich
in ligand 4b.
In summary, we have achieved the tuning of diastereoselectivity in
the Mannich reaction of glycine ester with N-tosyl imines through
electronic adjustment of the ligand. Either syn- or anti-diamino acid
derivatives can be obtained in excellent diastereo- and enantioselec-
tivities by ligand modification. Further investigations on the applications
of the electronic factor in asymmetric catalysis are in progress.
Figure 1. (A) ESP charge of different ligands: (a) total charge on the arene;
(b) the charge on the iminoester anion. (B) Calculated structure of 4f-Cu-1
complex and the working model for the reaction with 2.
Table 2. Diastereoselectivity Switch of Mannich Reaction of
Glycine Ester 1 with Imines 2
Acknowledgment. Financially supported by the Major Basic
Research Development Program (Grant 2006CB806106), National
Natural Science Foundation of China (20532050, 20672130), Chinese
Academy of Sciences, Shanghai Committee of Science and Technology
and Croucher Foundation of Hong Kong. Q.P., K.Z., and J.Y. gratefully
acknowledged the Hong Kong Croucher Foundation for a Studentship.
ligand 4b
ligand 4f
yield%
(syn/anti)a,b
yield%
(syn/anti)a,b
entry
2, R
ee%c
ee%c
1
2
3
4
5
6
7
8
9
a, Ph
92 (4:96)
92 (6:94)
96 (87:13)
94 (5:>95)
95 (9:91)
99
96
93
99
99
97
94
99
97
90
97 (>95: 5)
98 (93:7)
94 (83:17)
92 (93:7)
96 (95:5)
99 (93:7)
98 (>95: 5)
72 (>95: 5)
87 (>95: 5)
68 (>95: 5)
99
99
91
98
98
97
96
99
99
99
b, m-MeO-C6H4
c, o-Br-C6H4
d, m-Cl-C6H4
e, p-Br-C6H4
f, p-NO2-C6H4
g, 2-furan
h, Pri
Supporting Information Available: Procedure for the synthesis of
4f, general procedure for Cu-catalyzed Mannich reaction, NMR spectra
and HPLC data for 3, cif files of X-ray analysis of syn-3e and anti-3e.
The coordinates of calculated structures. Complete ref 12. This material
is available free of charge via the Internet at http://pubs.acs.org.
97 (7:93)
99 (10:90)
76 (5:>95)
89 (5:>95)
70 (5:>95)
i, Cy
10
j, Bun
References
a Isolated yield. b The number in parentheses is the ratio of syn/anti,
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The absolute configurations of the syn-3e and anti-3e were assigned
as (2S,3R) and (2S,3S) by X-ray diffraction analysis. The same (2S)
configuration for the two products indicates that the addition of N-Ts
imine is on the Si-face of the Cu-bound iminoester anion with both
4b and 4f ligands. This can be understood based on the fact that the
JA804527R
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J. AM. CHEM. SOC. VOL. 130, NO. 44, 2008 14363