Chemo- and enantioselective Bronsted acid-catalyzed reduction of α-imino esters with catecholborane

Article abstract of DOI:10.1002/adsc.201300352

The chemo- and enantioselective reduction of α-imino esters with catecholborane has been developed employing 10 mol% of an enantiopure BINOL-based phosphoric acid as organocatalyst. Various differently substituted aromatic α-amino acid derivatives can be

Full text of DOI:10.1002/adsc.201300352

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DOI: 10.1002/adsc.201300352
Chemo- and Enantioselective Brønsted Acid-Catalyzed Reduction
of a-Imino Esters with Catecholborane
Dieter Enders,a,* Andreas Rembiak,a and Bianca Anne Stçckela
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2127; e-mail: enders@rwth-aachen.de
Received: April 24, 2013; Revised: May 21, 2013; Published online: July 12, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300352.
Abstract: The chemo- and enantioselective reduc-
tion of a-imino esters with catecholborane has been
developed employing 10 mol% of an enantiopure
BINOL-based phosphoric acid as organocatalyst.
Various differently substituted aromatic a-amino
acid derivatives can be achieved in almost quantita-
tive yields and very good to excellent enantioselec-
tivities of up to 96% ee under mild reaction condi-
tions.
enantiomerically enriched a-arylglycines is the cata-
lytic asymmetric direct reduction of prochiral a-enam-
ides and a-imino esters, employing both metal-based
catalysts and organocatalysts. Although only few ex-
amples of metal-catalyzed hydrogenation reactions of
a-imino esters are known due to the low reactivity of
these substrates,[11] some organocatalytic protocols
have been developed employing Hantzsch esters,[12]
benzothiazolines[13] or trichlorosilane[14] as hydride
source. However, the reduction with Hantzsch esters
as well as with benzothiazolines occasionally suffers
from difficulties in the purification of the products,
albeit, in the latter case these problems have been
overcome by developing novel benzothiazolines bear-
ing hydroxy groups.[13] In contrast, the use of achiral
boron hydrides as reducing agents in organocatalysis
is less investigated. Whereas the Corey–Bakshi–Shi-
Keywords: amino acids; Brønsted acids; catechol-
borane; organocatalysis; phosphoric acids; reduc-
tion
Enantiomerically pure a-amino acids belong to one of bata (CBS) reduction is well known for the reduction
the most important classes of organic molecules and of ketones,[15] aromatic imines,[16] oximes,[17] stable N
ꢀ
as the building blocks of life play a key role in H imines[18] or cyclic N-sulfonylimines,[19] to the best
modern protein and peptide research.[1] Therefore of our knowledge, only the hydroboration of chiral a-
and due to their central role in organic chemistry the imino esters has been reported utilizing l-selec-
enantioselective synthesis of amino acids has gained tride.[20] To some extent this might result from the low
great attention and is still the focus of intensive cur- chemoselectivity of most of the common boron hy-
rent research.[2] Besides their application as enantio- drides. Hence, just recently catecholborane was suc-
pure substrates for auxiliaries, ligands and catalysts, cessfully utilized in the organocatalytic reduction of
a-amino acids are also utilized as chiral building ketones employing either thiourea catalysts or chiral
blocks in total synthesis.[3] An interesting class of such phosphoric acids[21] and in the reduction of ketimines
compounds is the chiral arylglycines because of their via Brønsted acid catalysis by our group.[22]
intriguing role in various pharmaceutical agents such
Chiral Brønsted acid catalysis has gained great at-
as glycopeptide antibiotics, ß-lactam antibiotics, anti- tention in the last decade since the pioneering work
bacterial agents and cardiovascular drugs.[4] Due to of Akiyama and Terada and is a rapidly growing sub-
their great importance, a variety of methodologies has field of organocatalysis. BINOL-based phosphoric
been developed,[5a] including asymmetric catalysis,[5] acids have successfully been employed in several or-
enzymatic resolution[6] and chiral auxiliary-mediated ganic transformations.[23] Because of the tremendous
induction.[7] In recent years especially asymmetric potential of this class of organocatalysts and the fact
Strecker reactions,[8] alkylations of glycine derivatives that catecholborane does not reduce ester groups
and a-imino esters have attracted great attention.[5c,9] even at elevated temperatures,[24] we envisaged
The organocatalytic biomimetic transamination of a- a Brønsted acid-catalyzed chemoselective reduction
keto esters has been published just recently.[10] of a-imino esters by applying catecholborane as hy-
Among these methods the most direct approach to dride source.
Adv. Synth. Catal. 2013, 355, 1937 – 1942
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1937

Dieter Enders et al.
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Table 1. Evaluation of the chiral Brønsted acids 4 in the re-
duction of imino ester 1a with catecholborane (2).[a]
borate formed in situ by the reaction of the acid with
catecholborane. Therefore, we then examined the
more acidic chiral acids 4d and 4e bearing a nitro
function or fluorine atoms at the aryl substituent of
the BINOL backbone (Table 1, entries 4 and 5). To
our delight this led to an increase in yield to more
than 90% as well as a slight increase of the enantiose-
lectivity to 45% (Table 1, entry 5). Further screening
of phosphoric acids showed that the well known
TRIP phosphoric acid 4f furnished the product 3a in
95% yield accompanied with an increased selectivity
of 77% ee (Table 1, entry 6).[26] In the reduction of
ketACTHUNRTGNEUNGimines, investigated by our group, the more acidic
N-triflylphosphoramide 4g gave the best results.[22] In
the case of the reduction of 1a, 4g also gave the
amino ester 3a in almost quantitative yield, albeit
with
a
dramatic decrease of enantioselectivity
(Table 1, entry 7). Use of a chiral lithium salt has
been reported in the reduction of ketones, furnishing
the corresponding alcohols in high yield and selectivi-
ty.[21b] In our case upon utilizing the chiral lithium salt
4h only racemic 3a was obtained (Table 1, entry 8).
Having identified chiral phosphoric acid 4f to be
the best catalyst we next examined the influence of
the aromatic N-protecting group on the yield and
enantioselectivity (Table 2). Although amino esters 3
could be isolated in high yields independently from
the N-protecting group, its effect on the selectivity of
the reduction was remarkable. In the presence of an
unsubstituted phenyl group on the imine moiety, 3b
was achieved with only moderate selectivity of 32%
ee (Table 2, entry 1). While the PMP-protecting group
gave the best result with 77% ee, moving the methoxy
group to the ortho position decreased the enantiose-
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
70
35
49
91
95
95
95
25
20
0
23
21
45
77
37
0
[a]
The reactions were performed on a 0.1-mmol scale of
imino ester 1a using 1.6 equiv. of catecholborane (2) and
5 mol% of catalyst 4 at ꢀ228C in 1.0 mL toluene for 2 d.
Before the addition of 1a the reaction mixture was pre-
cooled to ꢀ608C.
[b]
[c]
Yield of isolated 3a.
Determined by chiral stationary phase HPLC analysis.
Table 2. Influence of the N-protecting group on the asym-
metric reduction of a-imino esters 1.[a]
In continuation to our efforts in the asymmetric
synthesis of amino acids,[5c,25] herein we wish to report
the first chemo- and enantioselective hydroboration
of a-imino esters employing a chiral phosphoric acid
as catalyst. Preliminary experiments using achiral di-
phenyl phosphate as catalyst in the reduction of p-me-
thoxyphenyl (PMP)-protected ethyl imino ester 1a re-
vealed high reactivity and almost full conversion
within two hours at room temperature. Therefore we
started our investigations with a survey of different
chiral phosphoric acids at ꢀ228C with pre-cooling to
ꢀ608C before the addition of 1a (Table 1). Initial
tests with 5 mol% of sterically demanding chiral phos-
phoric acids 4a and 4b gave amino ester 3a only in
moderate yield and low enantioselectivity or even as
a racemic mixture (Table 1, entries 1 and 2). A
change to the less demanding acid 4c led to a slight
increase of the selectivity to 23% ee, however, still
with only moderate yield (Table 1, entry 3). We as-
sumed a low reactivity of the chiral phosphoric acid
Entry
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
Ph
3b
3c
3a
3d
90
88
95
84
32
19
77
4
OMP[d]
PMP
TMP[e]
[a]
Unless otherwise specified the reactions were performed
on a 0.1-mmol scale of imino ester 1a using 1.6 equiv. of
catecholborane (2) and 5 mol% of catalyst 4f at ꢀ228C
in 1.0 mL toluene for 2 d. Before the addition of 1a the
reaction mixture was pre-cooled to ꢀ608C.
Yield of isolated 3a.
Determined by chiral stationary phase HPLC analysis.
OMP=2-methoxyphenyl.
TMP=3,4,5-trimethoxyphenyl.
[b]
[c]
[d]
[e]
1938
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Chemo- and Enantioselective Brønsted Acid-Catalyzed Reduction of a-Imino Esters
Table 3. Evaluation of the solvent and the temperature in
the reduction of imino ester 1a with catecholborane (2).[a]
lectivity was increased to 72% (Table 3, entry 5). Con-
ducting the reaction in toluene under the same condi-
tions, instead, the selectivity clearly decreases to 39%
ee and even more at 08C and room temperature
(Table 3, entries 6–8). But we were pleased that the
enantioselectivity was increased to 77%, when the re-
action mixture was pre-cooled to ꢀ608C before the
addition of 3a and then further stirred at ꢀ228C for
48 h (Table 3, entry 9). While decreasing the concen-
tration of the imino ester led to a slight decrease in
enantioselectivity (Table 3, entry 10), increasing the
catalyst loading to 10 mol% provided the amino ester
3a in 98% yield and a very good enantioselectivity of
83%. A further increase of the catalyst loading had
no effect on the reaction (Table 3, entries 11 and 12).
During our investigations in the asymmetric reduc-
tion of imino esters we recognized a strong depend-
ence of the enantioselectivity on the pre-cooling tem-
perature. For this reason we finally did a survey of
the reaction temperature before adding 1a to the re-
action mixture. Interestingly pre-cooling to ꢀ708C
and ꢀ508C had a clear effect on the selectivity and
led to only 60% ee and 80% ee, respectively. It might
be assumed that at these temperatures the formation
of a borane imine adduct gets more favourable lead-
ing to a potential uncatalyzed and thus unselective re-
duction. To our delight we were able to improve the
conditions further by pre-cooling to ꢀ558C before the
addition of 1a and further stirring at ꢀ228C for 24 h.
Applying these conditions 3a is obtained in almost
quantitative yield and 86% ee (Table 4, entry 2).
Entry Solvent
T [8C]
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
DCM
Et2O
n-hexane
ꢀ60!ꢀ22 98
ꢀ60!ꢀ22 98
ꢀ60!ꢀ22 98
59
5
55
63
72
18
3
39
77
70
83
83
petroleum ether ꢀ60!ꢀ22 98
o-xylol
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ꢀ22
r.t.
0
ꢀ22
88
91
81
99
9
ꢀ60!ꢀ22 95
ꢀ60!ꢀ22 95
ꢀ60!ꢀ22 98
ꢀ60!ꢀ22 98
10[d]
11[e]
12[f]
[a]
Unless otherwise specified the reactions were performed
on a 0.1-mmol scale of imino ester 1a using 1.6 equiv. of
catecholborane (2) and 5 mol% of catalyst 4f at ꢀ228C
in 1.0 mL toluene for 2 d. Before the addition of 1a the
reaction mixture was pre-cooled to the given tempera-
ture.
[b]
[c]
[d]
[e]
[f]
Yield of isolated 3a.
Determined by chiral stationary phase HPLC analysis.
Reaction was performed in 2.0 mL solvent.
Reaction was performed with 10 mol% 4f for 24 h.
Reaction was performed with 15 mol% 4f for 24 h.
With the optimized conditions in hand we finally
investigated the substrate scope of the enantioselec-
lectivity to 19% (Table 2, entries 2 and 3). The intro- tive reduction of a-imino esters. Various electron-rich
duction of a more electron-rich arene as protecting as well as electron-deficient aromatic a-imino esters
group, such as TMP, furnished the corresponding with different substitution patterns were reduced with
amino ester 3d almost as a racemic mixture (Table 2, very good to excellent enantioselectivity and overall
entry 4). In the latter case it might be assumed that almost quantitative yield (Table 4). The absolute con-
the steric hindrance in the corresponding transition figuration of the amino esters 3a and 3e–3h has been
state is too big to allow a considerable enantiodiffer- determined to be (S) by comparing the optical rota-
entiation.
tion values with those reported in the literature.[12a,b,13]
Next we investigated the effect of the solvent and With small or flexible ester moieties like methyl or
the temperature on the reduction of a-imino esters benzyl esters only moderate enantioselectivities up to
1 (Table 3). Although the solvent seemed not to have 66% were obtained (Table 4, entries 1 and 5). In con-
any influence on the yield of isolated 3a, screening trast, the more sterically demanding tert-butyl ester
polar or coordinating solvents like DCM or diethyl delivered the corresponding amino ester 3g in almost
ether revealed inferior selectivities compared to tolu- quantitative yield and excellent enantioselectivity of
ene (Table 3, entries 1 and 2). Therefore, in all further 96% ee (Table 4, entry 4). Thus exclusively tert-butyl
experiments exclusively non-polar and non-coordinat- esters were used in the following experiments. Inter-
ing solvents are evaluated. Whereas n-hexane only estingly electron-rich 4-substituted imino esters only
leads to a moderate enantioselectivity of 55%, con- gave moderate enantioselectivties but still in excellent
ducting the reaction in petroleum ether furnished a- yield (Table 4, entries 6 and 7), whereas halogenated
amino ester 3a with 63% ee (Table 3, entries 3 and 4). substrates gave better results. With decreasing size of
However, aromatic non-polar solvents gave better re- the halogen atom in the 4-position of the aromatic
sults compared to the aliphatic ones. Although the re- moiety the enantioselectivity increased from 72% for
action mixture with o-xylol could only be cooled to bromine to 91% for fluorine substituted ester 1k
ꢀ228C due to its higher melting point the enantiose- (Table 4, entries 8–10). Assuming that the substituent
Adv. Synth. Catal. 2013, 355, 1937 – 1942
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1939

Dieter Enders et al.
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Table 4. Susbtrate scope for the enantioselective reduction
of a-imino esters.[a]
Entry R1
R2
3
Yield [%][b] ee [%][c]
Scheme 1. Enantioselective reduction of a-imino ester 1q in
a 1.0-mmol scale experiment.
1
C6H5
Me
Et
i-Pr
t-Bu 3g
Bn 3h
t-Bu 3i
3j
t-Bu 3k
t-Bu 3l
3e
3a
3f
93
93
97
87
86
97
88
94
97
63
86
92
96
66
67
70
91
78
72
77
84
89
94
92
90
84
86
57
2
C6H5
3
C6H5
4
C6H5
tative yield, but only moderate enantioselectivity
(Table 4, entry 19). In the end, the scalability of the
newly investigated method was proven with a 1.0-
mmol scale experiment (Scheme 1). a-Amino ester 3q
was obtained in 98% yield and excellent enantioselec-
tivity of 94%, which was further improved to >99%
ee by a single recrystallization from n-pentane.
In summary, we have developed the first enantiose-
lective reduction of a-imino esters with catecholbor-
ane employing a chiral phosphoric acid as catalyst.
Several electron-rich and halogenated aromatic sub-
strates with various substitution patterns have been
reduced in almost quantitative yields and very high
enantioselectivities.
5
C6H5
6
4-MeC6H4
7
4-MeOC6H4 tBu
8
4-FC6H4
9
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-ClC6H4
3-FC6H4
2-MeC6H4
2-FC6H4
2-ClC6H4
2-naphthyl
2-thienyl
cyclohexyl
10
11
12
13
14
15
16
17
18
19
t-Bu 3m 90
t-Bu 3n
t-Bu 3o
t-Bu 3p
t-Bu 3q
t-Bu 3r
t-Bu 3s
t-Bu 3t
t-Bu 3u
t-Bu 3v
97
91
97
97
99
97
92
81
95
[a]
The reactions were performed on a 0.1-mmol scale of
imino ester 1a using 1.6 equiv. of catecholborane (2) and
10 mol% of catalyst 4f at ꢀ228C in 1.0 mL toluene for
24 h. Before the addition of 1 the reaction mixture was
cooled to ꢀ558C.
Experimental Section
General Procedure for the Asymmetric Reduction of
a-Imino Esters
[b]
[c]
Yield of isolated 3.
Determined by chiral stationary phase HPLC analysis.
In a dry, argon-flushed Schlenk tube chiral phosphoric acid
4f (8 mg, 0.01 mmol, 10 mol%) was dissolved in dry toluene
(1.0 mL) and catecholborane 2 (19.7 mg, 0.16 mmol) was
added via syringe. After stirring at room temperature for
20 min the solution was cooled to ꢀ558C by a dry ice/ace-
tone bath and the solid a-imino ester was added in one por-
tion. After stirring at ꢀ228C for 24 h the reaction was
stopped with an ethanolamine/water mixture (1:2, 0.8 mL)
and was warmed to room temperature. After further addi-
tion of 1N NaOH (2.0 mL) the brown solution was extract-
ed three times with diethyl ether. The combined organic
phases were dried over Na2SO4 and filtered. After evapora-
tion of the solvent the residue was purified via flash column
chromatography over silica gel (diethyl ether:n-pentane=
1:10 to 1:4) to furnish the corresponding a-amino esters.
Racemic samples were prepared using diphenyl phosphate
(5 mol%) as catalyst in dry toluene for 1.5 h at room tem-
perature.
in the 4-position directly points to one of the TRIP
moieties in the transition state structure, resulting in
lower selectivities with increasing steric demand of
the substituent, other substitution patterns should
give better results. To our delight 3-substituted aro-
matic imino esters were reduced in high yield with
very good selectivities for both electron-rich and elec-
tron-deficient aromatic substrates in up to 89% ee
(Table 4, entries 11–13).
Furthermore, aromatic amino esters bearing a sub-
stituent in the 2-position were isolated in excellent
yield and enantioselectivities ranging from 90% to
94%, respectively (Table 4, entries 14–16). Particular-
ly this is the first time an enantioselective reduction
of ortho-substituted imino esters is reported giving
very good results. Similar reductions with trichlorosi-
lane as hydride source only gave moderate results in Acknowledgements
this case. Finally also the naphthyl moiety revealed to
We thank BASF SE for the donation of chemicals.
be a good substituent with 92% yield of isolated 3t
and 84% ee as well as heteroaromatic compounds like
thienyl with 86% enantioselectivity (Table 4, en-
tries 17 and 18). The reduction of alkyl-substituted
imino esters could also be achieved in almost quanti-
1940
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Adv. Synth. Catal. 2013, 355, 1937 – 1942

Chemo- and Enantioselective Brønsted Acid-Catalyzed Reduction of a-Imino Esters
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