Direct Mannich reaction of glycinate Schiff bases with N-(8-quinolyl) sulfonyl imines: A catalytic asymmetric approach to anti-α,β-diamino esters

Article abstract of DOI:10.1021/ja807583n

An efficient catalytic enantioselective direct Mannich reaction of glycinate Schiff bases with aryl imines leading to anticonfigured orthogonally protected α,β-diaminoesters has been realized. Keys to success in this new catalyst system are the use of Fesulphos/Cu(CH₃CN)₄PF₆ (3-5 mol%) as a Lewis acid catalyst and readily available N-(8-quinolyl)sulfonyl-protected aldimines as substrates, affording excellent levels of diastereo- (typically anti/syn >90:10) and enantiocontrol (typically ≥90% ee). A remarkable feature of this catalyst system is that it allows the construction of products with a tetrasubstituted carbon stereocenter at C-α in a highly diastereo- and enantiocontrolled manner. Copyright

Full text of DOI:10.1021/ja807583n

Published on Web 11/12/2008
Direct Mannich Reaction of Glycinate Schiff Bases with N-(8-Quinolyl)sulfonyl
Imines: A Catalytic Asymmetric Approach to anti-r,ꢀ-Diamino Esters
Jorge Herna´ndez-Toribio, Ramo´n Go´mez Arraya´s,* and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de Madrid, Madrid, Spain
Received September 24, 2008; E-mail: juancarlos.carretero@uam.es; ramon.gomez@uam.es
Table 1. Influence of Imine Protecting Group in the CuI-Catalyzed
The wide-range significance of optically active R,ꢀ-diamino acids
Mannich Reaction of Glycinate Schiff Base 2a with Imines 3a-ia
as key structural components in bioactive compounds, as well as
valuable synthetic intermediates,1 has prompted the need for new
general and efficient procedures for the asymmetric synthesis of
this simple, yet polyfunctional, motif. Despite the catalytic asym-
metric direct Mannich-type reaction of glycinate Schiff bases with
imines being one of the most convergent routes for accessing this
type of nonproteinogenic aminoacid derivatives,1a only a handful
of protocols have been so far described in the literature.2 Although
high levels of syn-diastereoselectivity and enantiocontrol were
achieved, this strategy had not been applied to the preparation of
R,ꢀ-diaminoester derivatives with anti-configuration3 or those with
an R-tetrasubstituted carbon stereocenter. To date, these limitations
have been overcome with indirect approaches, mainly the catalytic
asymmetric aza-Henry reaction, either between nitro compounds
and R-iminoesters4 or between R-nitro acetates and imines,5,6 upon
subsequent selective reduction of the nitro to amino group. Direct
reaction of an R-isothiocyanate N-acyl oxazolidine with N-tosyl
imines has also been reported to provide protected anti-R,ꢀ-diamino
acids.7 As a useful complementary method, herein we describe a
catalytic asymmetric approach to orthogonally protected anti-R,ꢀ-
diamino esters, including those with a tetrasubstituted carbon at
C-R,8 relying on the direct Mannich reaction of glycinate Schiff
bases. The combined use of a CuI complex of the commercially
available Fesulphos ligand (1)9 as catalyst and readily available
8-quinolylsulfonyl-protected aldimines as substrates is key to
attaining good reactivity, a broad scope, and high diastereo- and
enantiocontrol.
entry
PG (imine)
time (h)
syn-4/anti-4/5b
1
2
3
4
5
6
7
8
9
Boc (3a)
Ts (3b)
p-Nosyl (3c)
4-OMe(C6H4)SO2- (3d)
(2-Thienyl)SO2- (3e)
(2-Pyridyl)SO2- (3f)
o-Nosyl (3g)
(8-Quinolyl)SO2- (3h)
(1-Naphthyl)SO2- (3i)
6
3
5
2
3
2
5
2
2
60:40:--c
43:52:5c,d
38:37:25c,d
40:40:20c,d
17:48:35c,d,c
35:35:30c,d
30:70:--
8:92:--
complex mixture
a Conditions: 2a (1 equiv),
3 (1.1 equiv), Cu(CH3CN)4ClO4 (5
mol%), (()-Binap (5 mol%), Et3N (10 mol%), CH2Cl2, rt. b By NMR
from the crude reaction mixture. c syn/anti configuration not established.
d Imidazolines 5 were obtained as diastereomeric mixtures.
Table 2. Cul/Fesulphos-Catalyzed Enantioselective Direct Mannich
Reaction of Iminoester 2a with Sulfonyl Imine 3h
Facing the challenge of achieving high diastereoselection, we
first examined the influence of the protecting group at the iminic
nitrogen in the CuI/(()-Binap-catalyzed model reaction of N-
benzylideneglycine methyl ester (2a) with different imines of
benzaldehyde (3a-i) in the presence of Et3N (10 mol%) as base
(Table 1). Initial results were rather disappointing since the N-Boc-
protected imine 3a, as well as the para-substituted arylsulfonyl
imines 3b-d and the heteroarylsulfonyl10 derivatives 3e9a,b,10b and
3f,10a,c led to mixtures of (syn+anti)-4 with very poor diastereo-
selectivity (de ) 0-20%, entries 1-6). The competitive formation
of the 1,3-dipolar cycloaddition imidazolidine product 5 (as mixture
of diastereomers) was also observed with the sulfonyl imines 3b-f.
However, the bulkier o-nosyl imine 3g led cleanly to a mixture of
4g with encouraging anti-diastereocontrol (syn/anti ) 30:70, entry
7). Moreover, an excellent level of anti-diastereoselection was
attained with the 8-quinolylsulfonyl-protected imine 3h10a,c (8:92
mixture of syn/anti-4h, entry 8). Interestingly, the sterically similar
1-naphthylsulfonyl imine 3i afforded a complex mixture of four
products under identical conditions (entry 9), showing that the
presence of the nitrogen of the 8-quinolyl moiety is crucial for good
anti-diastereocontrol.
entry
CuI (x mol%)
solvent
t (°C) anti/syna yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
Cu(CH3CN)4ClO4 (5) CH2Cl2
CuOTf (5)
rt
rt
92:8
94:6
93:7
91:9
94:6
96:4
99:1
99:1
98:2
91:9
79
77
85
62
79
80
74
73
71
35
91
91
92
90
91
92
96
96
91
--
CH2Cl2
CH2Cl2
CH3CN
toluene
THF
Cu(CH3CN)4PF6 (5)
Cu(CH3CN)4PF6 (5)
Cu(CH3CN)4PF6 (5)
Cu(CH3CN)4PF6 (5)
Cu(CH3CN)4PF6 (5) THF
Cu(CH3CN)4PF6 (5) THF
rt
rt
rt
rt
-40
-78
-40
rt
Cu(CH3CN)4PF6 (3)
THF
THF
10d Cu(CH3CN)4PF6 (1)
a By NMR and/or HPLC. b Isolated yield. c By chiral HPLC. d 12 h
reaction time.
HPLC separation of products, in this study the resulting R-imino
ester 4h was reduced to its R-benzylamino derivative anti-6 upon
addition of NaBH4 (1.2 equiv)/EtOH to the crude reaction mixture.
Among 12 tested ligands,11 only Fesulphos (1)9,12 led to a high
anti-diastereo- (anti/syn ) 92:8) and enantioselectivity (91% ee,
Table 2, entry 1). Further refinement of reaction conditions by
exploring other solvents and copper salts led to improved catalyst
performance (entries 2-8). The highest diastereo- (anti/syn ) 99:
1) and enantiocontrol (96% ee) were attained in THF at -40 or
-78 °C with Cu(CH3CN)4PF6/(R)-1 (5 mol%, entries 7 and 8).
Asymmetric catalysis was then investigated by screening a
number of well established chiral ligands (5 mol%) in the reaction
of 2a with imine 3h under the previous conditions. For better chiral
9
16150 J. AM. CHEM. SOC. 2008, 130, 16150–16151
10.1021/ja807583n CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Catalyst loading could be reduced to 3 mol% while maintaining
high reactivity and stereocontrol (91% ee, entry 9). Further decrease
to 1 mol% led to a dramatic drop of reactivity (entry 10).
assignment established by X-ray diffraction analysis,15 was achieved
in good yield by treatment with triphosgene (CH2Cl2, 0 °C to rt,
2 h) followed by easy cleavage of the 8-quinolylsulfonyl group
with an excess of Mg turnings in MeOH, this latter step being
accelerated under sonication.
Table 3. Structural Variations at the R-iminoester and Sulfonyl
Iminea
In summary, we have developed a route to protected anti-R,ꢀ-
diamino esters compatible with the generation of a tetrasubstituted
carbon at C-R. The choice of Fesulphos-CuI as catalyst and N-(8-
quinolyl)sulfonyl as protecting group at the imine substrate are the
key elements for achieving efficient control of both diastereo- and
enantioselectivity (typically g90% ee). Further investigations to
understand the exact role of the 8-quinolyl group are underway.
entry
R1
R2 (sulfonyl imine)
product
anti/synb
yield (%)c
ee (%)d
1e
2e
3f
H
4-OMeC6H4 (7h)
4-ClC6H4 (8h)
2-MeC6H4 (9h)
2-Naph (10h)
2-Furyl (11h)
3-Pyridyl (12h)
Cinnamyl (13h)
16
17
18
19
20
21
22
23
24
25
26
98:2
98:2
98:2
97:3
95:5
98:2
85:15
90:10
97:3
94:6
89:11
72
92
80
75
71
72
64
55
65
52
61
95
93
99
94
85
90
25
89
87
96
92
Acknowledgment. This work was supported by the Ministerio
de Ciencia e Innovacio´n (MICINN, CTQ2006-01121) and UAM/
Consejer´ıa de Educacio´n de la Comunidad Auto´noma de Madrid
(CCG07-UAM/PPQ-1799). J.H.T. thanks the MICINN for a pre-
doctoral fellowship.
H
H
H
H
H
H
4e
5e
6e
7e
8e
9e
10e
11e
Supporting Information Available: Experimental procedures and
characterization data of new compounds, copies of NMR spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
Me Ph (3h)
Me 4-ClC6H4 (8h)
Me 2-thienyl (14h)
Me 2-BrC6H4 (15h)
References
a (8-Q) ) 8-Quinolyl; CuI ) Cu(CH3CN)4PF6. b By NMR and/or
HPLC. c Isolated yield. d By chiral HPLC. e Reaction at -78 °C.
f Reaction at -40 °C.
(1) For a review on synthesis and biological significance of R,ꢀ-diamino acids,
see: (a) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa, A.; Flores, A. Chem.
ReV. 2005, 105, 3167. Review on vicinal diamines: (b) Lucet, D.; Le Gall,
T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(2) (a) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2003, 68, 2583. (b) Ooi, T.; Kameda, M.; Fujii, J.-i.; Maruoka, K.
Org. Lett. 2004, 6, 2397. (c) Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu,
H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4564.
(d) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki,
M. Chem. Asian J. 2007, 2, 794. (e) Kobayashi, S.; Yazaki, R.; Seki, K.;
Yamashita, Y. Angew. Chem., Int. Ed. 2008, 47, 5613.
(3) During the reviewing process of this paper, a syn/anti diastereoselective
switchable asymmetric Mannich reaction of glycinate derivatives with
imines was reported: Yan, X.-X.; Peng, Q.; Li, Q.; Zhang, K.; Yao, J.;
Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc. 2008, 130, 14362.
(4) (a) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001,
40, 2995. (b) Rueping, M.; Antonchick, A. P. Org. Lett. 2008, 10, 1731.
(5) (a) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc.
2007, 129, 3466. (b) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2008, 130, 2170. (c) Uraguchi, D.; Koshimoto, K.;
Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878. (d) Singh, A.; Johnston, J. N.
J. Am. Chem. Soc. 2008, 130, 5866. (e) Han, B.; Liu, Q.-P.; Li, R.; Tian,
X.; Xiong, X.-F.; Deng, J.-G.; Chen, Y.-C. Chem.sEur. J. 2008, 14, 8094.
(6) For the aza-Henry reaction between R-nitro acetates and R-imino esters,
see: Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362.
(7) Cutting, G. A.; Stainforth, N. E.; John, M. P.; Kociok-Ko¨hn, G.; Willis,
M. C. J. Am. Chem. Soc. 2007, 129, 10632.
(8) For reviews on the importance of R,R-disubstituted R-aminoacids, see: (a)
Cativiela, C.; D´ıaz de Villegas, M. D. Tetrahedron: Asymmetry 1998, 9,
3517. (b) Ohfune, Y.; Shinada, T. Bull. Chem. Soc. Jpn. 2003, 76, 1115.
(9) For recent applications of Fesulphos in asymmetric catalysis, see: (a)
Salvador Gonza´lez, A.; Go´mez Arraya´s, R.; Carretero, J. C. Org. Lett. 2006,
8, 2977. (b) Garc´ıa Manchen˜o, O.; Go´mez Arraya´s, R.; Adrio, J.; Carretero,
J. C. J. Org. Chem. 2007, 72, 10294. (c) Salvador Gonza´lez, A.; Rogr´ıguez
Rivero, M.; Go´mez Arraya´s, R.; Carretero, J. C. Org. Lett. 2008, 10, 4335.
(d) Lo´pez-Perez, A.; Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2008,
130, 10084.
Table 3 summarizes the evaluation of the scope under the
optimized conditions. A survey of electronically and sterically varied
aryl and heteroaryl N-(8-quinolyl)sulfonyl aldimines13 revealed a
high degree of stereochemical fidelity in their reaction with glycinate
2a, showing excellent diastereoselectivity (95:5-98:2) and g90%
ee in most cases14 (entries 1-6, products 16-21). The R,ꢀ-
unsaturated imine 13h, from cinnamaldeyde, was the only exception
to this trend, providing moderate diastereocontrol and very low
asymmetric induction (25% ee, entry 7). Pleasingly, the reaction
was equally successful with the R-substituted imino ester derived
from L-alanine 2b, a kind of nucleophile not yet reported in this
reaction even though it generates R,ꢀ-diaminoacid derivatives
tetrasubstituted at C-R. In the four tested reactions (entries 8-11),
2b provided the corresponding Mannich product (23-26) with
similar diastereo- and enantioselectivity (87-96% ee) to that
observed from 2a, albeit the chemical yields were somewhat lower
(52-65%). The relative and absolute configuration of the Mannich
products was established by X-ray diffraction analysis of a crystal
of pure anti-615 (>99% ee) obtained by recrystallization (from
CH2Cl2-hexane) of a 98:2 anti/syn mixture formed in the reaction
of 2a with imine 3h (2 mmol scale) using 3 mol% of
CuI-Fesulphos.
(10) For some recent examples on the use of heteroarylsulfonyl imines in
asymmetric catalysis, see: (a) Esquivias, J.; Gome´z-Arraya´s, R.; Carretero,
J. C. J. Am. Chem. Soc. 2007, 129, 1480. (b) Morimoto, H.; Lu, G.;
Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129,
9588. (c) Nakamura, S.; Nakashima, H.; Sugimoto, H.; Sano, H.; Hattori,
M.; Shibata, N.; Toru, T. Chem.sEur. J. 2008, 14, 2145. (d) Nakamura,
S.; Nakashima, H.; Yamamura, A.; Shibata, N.; Toru, T. AdV. Synth. Catal.
2008, 350, 1209. and refs 9a-c.
Scheme 1. Orthogonal Deprotection of the Amino Groups and
Chemical Correlationa
(11) See Supporting Information for the results with other chiral ligands.
(12) For 1,3-dipolar cycloaddition of azomethine ylides catalyzed by Fesulphos
complexes, see: (a) Cabrera, S.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am.
Chem. Soc. 2005, 127, 16394. (b) Cabrera, S.; Go´mez Arraya´s, R.; Mart´ın-
Matute, B.; Coss´ıo, F. P.; Carretero, J. C. Tetrahedron 2007, 63, 6587,
and ref 9d.
(13) Aliphatic imines were not explored since we have not succeeded so far in
developing a method for the isolation of this more labile type of imines.
(14) See Supporting Information for a tentative stereochemical model accounting
for the observed enantioselectivity and anti-diastereocontrol.
(15) See Supporting Information for X-ray diffraction data of anti-6.
(16) Lee, S. H.; Yoon, J.; Chung, S. H.; Lee, Y. S. Tetrahedron 2001, 57, 2139.
Scheme 1 exemplifies the sequential amino deprotection of the
R,ꢀ-diaminoester adducts under mild conditions. The optically
active amino ester 27 was obtained in one pot from the reaction of
2a with 3h upon smooth acid hydrolysis of the crude resulting imino
ester (2S,3S)-anti-4h. The transformation of 27 into the known
enantiopure urea 28,16 confirming otherwise the stereochemical
JA807583N
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J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16151