New, readily available organocatalysts for the enantioselective reduction of α-imino- and β-imino esters

Article abstract of DOI:10.1055/s-0030-1259941

Novel metal-free, readily available chiral catalytic systems for the enantioselective reduction of keto imines are reported. Different β-imino esters were reduced by trichlorosilane in the presence of 10 mol% of a chiral Lewis base easily obtained in one

Full text of DOI:10.1055/s-0030-1259941

LETTER
1085
New, Readily Available Organocatalysts for the Enantioselective Reduction of
a-Imino- and b-Imino Esters
A
a
C
atalytic Synthesis
o
a
f
C
hiral
b
-
r
A
minoE
t
sters ina Bonsignore,a Maurizio Benaglia,*a Rita Annunziata,a Giuseppe Celentanob
b
Received 20 January 2011
Dedicated to Professor Alberto Brandi on the occasion of his 60th birthday
highly enantiomerically enriched b-lactams, was recently
Abstract: Novel metal-free, readily available chiral catalytic sys-
tems for the enantioselective reduction of keto imines are reported.
Different b-imino esters were reduced by trichlorosilane in the pres-
ence of 10 mol% of a chiral Lewis base easily obtained in one step
only from prolinol, in high yields and in up to 85% enantioselectiv-
ity; imines bearing an inexpensive and removable chiral auxiliary,
were reduced with complete control of the absolute stereochemis-
try. The methodology was successfully extended to the stereoselec-
tive synthesis of a-amino esters.
developed.9
In the attempt to further enlarge the number and types of
chiral coordinating Lewis bases suitable for HSiCl3-
promoted reductions we have decided to explore the use
of novel enantiomerically pure phosphoroamides. We
wish to report here the results of our preliminary investi-
gation that allowed us to select at least two new chiral or-
ganocatalysts, readily synthesized in one step from cheap,
commercially available sources, like prolinol, and em-
ployed with success in the reduction of a- and b-imino es-
ters.
Key words: trichlorosilane, Lewis base, b-imino esters, stereo-
selective reduction, imines
In our approach structurally simple chiral Lewis bases
should be obtained by modification of an inexpensive,
commercially available, enantiopure material whose ma-
nipulation must be kept to minimum. Indeed several de-
rivatives were synthesized in a single-step procedure, by
reaction of different enantiomerically pure amino alco-
hols, typically (S)-prolinol or similar derivatives, and
diphenyl phosphinoyl chloride (compounds 1–6, see sup-
porting information). Based on our previous studies3,8,9
also ephedrine was used as chiral scaffold for the prepara-
tion of derivative 7 (Figure 1).
Recently great efforts have been made to develop efficient
organocatalytic methods to perform enantioselective imi-
ne reductions and reductive amination processes.1 Bi-
naphthol-derived phosphoric acids were successfully
employed as catalytic activators in the reduction of
ketimines by using a dihydropyridine-based Hantzsch es-
ter-type reagent as the reducing agent.2 Alternatively in
the last few years trichlorosilane-mediated reductions
have encountered a constantly increasing attention; the
simple coordination of a chiral Lewis base to HSiCl3 al-
lows to generate a chiral catalytic species active in the
stereoselective keto imine reduction.3
In preliminary experiments the reduction of N-benzyl
enamine 8 of 3-oxo-3-phenylpropionic acid methyl es-
ter,10 was studied. In a typical procedure the reaction was
Already in 1999 in his pioneering works Matsumura re-
ported the use of N-formyl proline to promote enantiose-
lective reduction of ketones and imines.4 Since then
several chiral activators for trichlorosilane-mediated re-
duction have been developed. They may be classifieds
mainly in two classes: a) chiral N-formyl derivatives, usu-
ally prepared starting from a-amino acids, b) picolina-
mides derivatives, typically synthesized by reacting
picolinic acid with chiral amino alcohols.3 Less frequently
trichlorosilane has been used in the reduction of imines
derived from a-keto esters, leading to the synthesis of nat-
ural and unnatural a-amino acids,5 and in the reduction of
b-enamino esters,6 as valid alternative to the metal-cata-
lyzed hydrogenations.7 In the course of our studies on the
organocatalytic reduction of chiral ketimines,8 a method
for the synthesis of b-amino esters, easily converted into
Ph
Ph
SiMe2t-Bu
O
OH
N
N
P
O
P
O
Ph
Ph
Ph
Ph
1
2
Me
OH
O
N
N
P
O
P
O
Ph
Ph
Ph
Ph
3
4
Ph
P
Ph
Ph
Me
N
Ph
Ph
O
HN
P
Ph
N
N
P
O
O
P
O
P
O
O
Ph
Ph
Ph
Ph
OH
Ph
SYNLETT 2011, No. 8, pp 1085–1088
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.04.2011
5
6
7
DOI: 10.1055/s-0030-1259941; Art ID: B02211ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Novel chiral organocatalysts for keto imine reduction

1086
M. Bonsignore et al.
LETTER
R
performed at 0 °C in dichloromethane for 12 hours in the
presence of 10 mol% of chiral Lewis base (Scheme 1).
R
catalyst (10 mol%)
HN
HN
HSiCl3 (3 equiv)
CH2Cl2, 12 h
COOMe
COOMe
Ar
Ar
Bn
Bn
Ar = Ph
Ar = Ph
Ar = Ph
Ar = 4-MeOC6H4
Ar = 4-MeOC6H4
Ar = 4-F3CC6H4
Ar = 4-F3CC6H4
Ar = 4-BrC6H4
Ar = 4-O2NC6H4
Ar = 4-O2NC6H4
8
R = Bn
R = PMP
R = Ph
R = Bn
R = PMP
R = Bn
R = PMP
R = PMP
R = Bn
9
HN
catalyst (10 mol%)
HN
10
12
14
16
18
20
22
24
26
11
13
15
17
19
21
23
25
27
COOMe
COOMe
HSiCl3 (3 equiv)
CH2Cl2, 12 h
Ph
Ph
8
9
Scheme 1 Stereoselective reduction of enamines 8 and 9
A few selected results are collected in Table 1. All activa-
tors were able to promote the trichlorosilane addition, of-
ten in very high yield. As one may expect on the basis of
previous studies,3 monodentate organocatalysts 1–4 and 7
showed to be less efficient catalysts and afforded the
product generally in lower yield than biscoordinating sys-
tems, like compounds 5 and 6. At 0 °C only modest enan-
tioselectivities were observed; however, at lower
temperature (–40 °C, entries 8 and 9 of Table 1) good ste-
reoselectivities were achieved: by employing catalysts 5
and 6 the reduction of enamine 8 afforded the product in
75% ee and 85% ee, respectively.
R = PMP
Scheme 2 Stereoselective reduction of different b-enamino esters
The organocatalytic reduction of N-benzyl and N-PMP
imines of different b-aryl b-keto esters was accomplished.
The corresponding b-amino esters were obtained in very
good yields, especially when the aryl residue bears elec-
tron-withdrawing groups (see for example entries 8 and
10–12 in Table 3).
Table 2 HSiCl3-Mediated Reduction of Different of b-Enamino
Estersa
Table 1 Stereoselective Reduction of Enamine 8 Promoted by
Chiral Organocatalysts 1–7a
Entry
Temp (°C) Catalyst
Imine
8
Yield (%)b ee (%)c
1
2
3
4
5
–40
–40
–40
0
5
6
5
5
6
53
50
73
83
81
75
85
21
65
45
Entry
Temp. (°C)
Catalyst
Yield (%)b ee (%)c
8
1
2
3
4
5
6
7
8
9
0
0
1
2
3
4
5
6
7
5
6
41
70
98
47
99
98
47
53
50
21
7
10
12
12
0
5
0
0
7
a Reaction was run for 12 h in CH2Cl2.
b Determined by 1H NMR and confirmed after chromatographic puri-
fication.
0
35
31
11
75
85
0
c Determined by HPLC (see Supporting Information).
0
Based on the results it is not possible to clearly select a
protecting group of choice. For example N-benzyl enam-
ine 8 was reduced in enantioselectivites higher than those
of N-PMP derivative 10, while for enamines 14 and 16, N-
4-methoxyphenyl-substituted derivative 16 offered the
best results (entry 3, Table 3). Catalyst 6 did not confirm
the excellent result shown with substrate 8 and behaved
quite unpredictably in several attempted reactions. There-
fore (S)-prolinol derivative 5 was preferably employed
with other substrates.
–40
–40
a Reaction was run for 12 h in CH2Cl2.
b Determined by 1H NMR and confirmed after chromatographic puri-
fication.
c Determined by HPLC (see Supporting Information).
In the attempt to find the best protecting group at the ni-
trogen, the N-4-methoxyphenyl (PMP) enamine 10 was
reduced in different experimental conditions (Scheme 2).
Although good chemical efficiency was achieved, lower
enantioselectivities were observed even at –40 °C (entry
3, Table 2). At this time it is not possible to give an easy
explanation of this result. It is noteworthy that the ana-
logue N-phenyl derivative 12 was reduced by catalyst 5 at
0 °C with 65% ee. Therefore in further studies of the per-
formance of catalysts of choice 5 and 6 both N-benzyl and
N-aryl enamines of differently substituted substrates were
taken in consideration. The general applicability of the
methodology was thus investigated (Scheme 2).10
Generally PMP-substituted compounds were reduced in
higher enantioselectivities than N-benzyl derivatives, al-
ways affording b-amino esters with ee value higher than
70% and up to 83% in the case of enamine 26.11 Addition
of HSiCl3 to imines 24 and 26 afforded the products with
80% ee and 70% ee, respectively, even at 0 °C.
In the attempt to improve the selectivity of the process, we
decided to take advantage of the presence of a removable
chiral auxiliary at the imine nitrogen;5b therefore trichlo-
rosilane-mediated reduction9 of enamine 28 derived from
Synlett 2011, No. 8, 1085–1088 © Thieme Stuttgart · New York

LETTER
A Catalytic Synthesis of Chiral b-Amino Esters
1087
very recently metal-free catalytic reductions of acyclic
imino esters were reported.15 Both catalysts 5 and 6 pro-
moted the reduction of N-4-methoxyphenyl imino ester 32
in quantitative yield at 0 °C and with 81% and 70% enan-
tioselectivity, respectively (Scheme 3, equation 2).
Table 3 Stereoselective Reduction of Different of b-Enamino
Estersa
Entry
1
Temp (°C) Catalyst
Imine
14
16
16
16
18
20
22
22
24
24
24
26
26
Yield (%)b ee (%)c
0
0
5
5
5
6
5
5
5
5
5
5
6
5
5
87
99
71
70
73
55
99
77
99
75
90
99
85
43
50
70
21
60
63
70
75
80
78
40
70
83
In conclusion, we have developed novel, inexpensive,
easy to make, metal-free chiral catalysts, able to promote
the trichlorosilane-mediated stereoselective reduction of
a-imino and b-imino esters. Further studies on the new
catalytic systems and their application in the reduction of
heterocyclic rings are currently under way.
2
3
–40
–40
–40
–40
0
4
5
6
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
the synthesis and characterization of chiral catalysts, characteriza-
7
8
–40
0
1
tion of reaction products, H NMR spectra and HPLC chromato-
9d
10d
11d
12d
13d
grams of chiral amino esters.
–40
0
Acknowledgment
This work was supported by MIUR: ‘Nuovi metodi catalitici stereo-
selettivi e sintesi stereoselettiva di molecole funzionali’.
0
–40
References and Notes
a Reaction was run for 12 h in CH2Cl2.
b Determined by 1H NMR and confirmed after chromatographic puri-
fication.
(1) (a) For a recent review on chiral amine synthesis, see:
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imines, see: Fleury-Bregeot, N.; de le Fuente, V.; Castillon,
S.; Claver, C. Chem. Catal. Chem. 2010, 2, 1346. For
recent selected reports on metal-catalyzed enamides
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G.; Zhou, L.; Zou, Y.; Wu, W.; Zhang, X. Angew. Chem. Int.
Ed. 2009, 48, 6052. (d) Steinhuebel, D.; Sun, Y.;
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(2) (a) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407.
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c Determined by HPLC (see Supporting Information).
d Ethyl ester was used.
(R)-1-phenylethyl amine was studied12 (Scheme 3, equa-
tion 1). By running the reaction at 0 °C the chiral b-amino
ester 29 was obtained after 12 hours in 98% yield with a
total control of the stereoselectivity.13 Also N-a-methyl-
benzyl imine 30 was effectively reduced in quantitative
yield, to afford the product as a single stereoisomer, as de-
termined by NMR analysis.
Finally we decided to test our methodology in the prepa-
ration of a-amino acids. A very limited number of cyclic
a-imino esters were studied in organocatalysis14 and only
(4) (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 1999, 40, 7507.
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(6) For two recent contributions on the enantioselective
synthesis of b-amino acids involving the use of
5 (10 mol%)
(1)
HSiCl3 (3 equiv)
N
HN
CH2Cl2, 12 h, 0 °C
COOMe
COOMe
R
R
(R)-28
(R)-30
R = C6H4
R = Ph
(R,R)-29
(R,R)-31
98%, 99% ee
99%, 99% ee
OMe
OMe
trichlorosilane, see: (a) Malkov, A. V.; Stoncius, S.;
Vrankova, K.; Arndt, M.; Kocovsky, P. Chem. Eur. J. 2008,
14, 8082. (b) Zheng, H.-J.; Chen, W.-B.; Wu, Z.-J.; Deng,
J.-G.; Lin, W.-Q.; Yuan, W.-C.; Zhang, X.-M. Chem. Eur. J.
2008, 14, 9864; and references cited therein.
5 (10 mol%)
N
HN
(2)
HSiCl3 (3 equiv)
CH2Cl2, 12 h
OMe
OMe
O
O
(7) For a very recent review on the importance of b-amino acids,
see: Weiner, B.; Szymansky, W.; Janssen, D. B.; Minaard,
A. J.; Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656.
99%, 81% ee
33
32
Scheme 3 Stereoselective reduction of a-imino esters
Synlett 2011, No. 8, 1085–1088 © Thieme Stuttgart · New York

1088
M. Bonsignore et al.
LETTER
(8) (a) Guizzetti, S.; Benaglia, M. EP 2008010079, 2008.
(b) Guizzetti, S.; Benaglia, M. Eur. Patent Appl.
EP07023240.0, 2008. (c) Guizzetti, S.; Benaglia, M.; Cozzi,
F.; Annunziata, R. Tetrahedron 2009, 65, 6354.
(d) Guizzetti, S.; Biaggi, C.; Benaglia, M.; Celentano, G.
Synlett 2010, 134.
(9) Guizzetti, S.; Benaglia, M.; Bonsignore, M.; Raimondi, L.;
Celentano, G. Org. Biomol. Chem. 2011, 9, in press.
(10) For the preparation of different enamines and the assignment
of absolute stereochemistry of reduction products see the
details in Supporting Information.
(12) For the diastereoselective reduction of these chiral substrates
through hydrogenation with different catalytic systems, see:
Nugent, T. C.; El-Shazly, M.; Wachaure, V. N. J. Org.
Chem. 2008, 73, 1297; and references cited therein.
(13) The favorably match or mismatch combinations of chiral
amine auxiliary and catalysts have been already clarified in
ref. 5b.
(14) (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (b) Hoffmann, S.;
Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 2005, 44,
7424. (c) See also ref. 2.
(11) Deprotection of N-PMP was effectively accomplished with
CAN in MeCN at 0 °C (see Supporting Information for
experimental details).
(15) (a) Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007,
129, 5830. (b) See also ref. 5.
Synlett 2011, No. 8, 1085–1088 © Thieme Stuttgart · New York

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