A new family of cinchona-derived amino phosphine precatalysts: Application to the highly enantio- and diastereoselective silver-catalyzed isocyanoacetate aldol reaction

Article abstract of DOI:10.1021/ja110534g

A new class of readily accessible chiral amino-phosphine precatalysts derived from 9-amino(9-deoxy) epicinchona alkaloids has been developed. In combination with Ag(I) salts, these amino-phosphines performed as effective cooperative Brnsted base/Lewis aci

Full text of DOI:10.1021/ja110534g

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A New Family of Cinchona-Derived Amino Phosphine Precatalysts:
Application to the Highly Enantio- and Diastereoselective
Silver-Catalyzed Isocyanoacetate Aldol Reaction
Filippo Sladojevich,† Andrea Trabocchi,‡ Antonio Guarna,‡ and Darren J. Dixon*,†
†Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
‡Dipartimento di Chimica “U. Schiff”, Universitꢀa di Firenze, Via della Lastruccia, 13, 50019, Sesto Fiorentino, Italy
S Supporting Information
b
with commercially available aryl diphenylphosphino acids. As a
ABSTRACT: A new class of readily accessible chiral amino-
phosphine precatalysts derived from 9-amino(9-deoxy) epi-
cinchona alkaloids has been developed. In combination with
Ag(I) salts, these amino-phosphines performed as effective
cooperative Brønsted base/Lewis acid catalysts in the asym-
metric aldol reaction of isocyanoacetate nucleophiles. Under
optimal conditions, high diastereoselectivities (up to 98%)
and enantioselectivities (up to 98%) were obtained.
first application of this new family of precatalysts, we selected the
aldol reaction of isocyanoacetates with aldehydes.3 We hypothe-
sized that the acidity of the R-C-H of isocyanoacetates could be
enhanced after complexation with a suitably “soft” transition
metal ion (complex). This would allow deprotonation by the
bridgehead nitrogen, affording the bound and activated nucleo-
philic component poised for reaction with Lewis acid activated
aldehydes (Scheme 2). The reaction between tert-butyl isocya-
noacetate 5a and benzaldehyde 6a was chosen to probe reactivity
and stereocontrol.
From a screen of metal ion complexes, it was soon realized that
silver salts4 provided the best reactivity, by catalyzing smooth
conversion to oxazoline product 7a in the presence of all the pre-
catalysts (Table 1). Silver oxide was the most effective in terms of
reactivity and stereocontrol, allowing the reaction to be performed
at lower temperatures. The use of AcOEt and ethereal solvents
such as MTBE was also beneficial in terms of enantio- and dia-
stereoselectivity. Further adjustment of the tert-butyl isocyanoa-
cetate concentration to 0.3 M and addition of powdered 4 Å MS
allowed an enantiomeric excess of 96% to be reached for the major
diastereoisomer in a highly diastereoselective reaction (entry 10).
Finally, control experiments (entries 12 and 13) proved that the
presence of both the amino-phosphine 2 and Ag2O was required to
achieve optimal reactivity. A reaction in the absence of amino-
phosphine 2 required 5 days at -20 °C to reach completion, while
a reaction in the presence of the ligand 2 but without silver additive
gave only traces of product after 5 days at -20 °C. The scope of the
reaction with respect to the aldehyde was then probed (Table 2).
A variety of aromatic aldehydes (entries 1-5, Table 2) proved
effective, giving rise to excellent enantio- and diastereoselectivities
for the trans diastereomers. Aliphatic aldehydes were also effective
substrates (entries 6-8, Table 2), with thebest enantioselectivities
provided by hindered aldehydes such as pivaldehyde, while other
substrates gave rise to lower levels of enantiocontrol.5 The substi-
tution of amino-phosphine 2 with the pseudoenantiomeric 3 affor-
ded oxazoline (4R,5S)-7a with comparable yield and enantiocon-
trol (92%, entry 2, Table 2). The use of methyl isocyanoacetate 5b
was also possible, resulting in good levels of reactivity but a slightly
decreased diastereo- and enantioselectivity (entry 9, Table 2, 14:1
dr, 81% ee) when compared to tert-butyl isocyanoacetate. Pleas-
ingly, the new catalytic system was also effective with R-substituted
ooperative catalysis using multifunctional organic scaffolds
C
in combination with transition metal ions is emerging as
a powerful tool in asymmetric synthesis and has allowed the
development of unprecedented transformations in terms of re-
activity and stereocontrol.1 The design and synthesis of new,
readily accessible catalytic systems plays a pivotal role in this field
of research, allowing the discovery of useful synthetic pathways,
rapid optimization of the ligand canopy, and a better understand-
ing of the mechanism and origins of stereocontrol. To this end,
we recently reported the cooperative combination of Cu(I)OTf
and bifunctional, 9-amino(9-deoxy) epicinchona-derived urea
precatalysts as an efficient and effective catalytic system for the
enantioselective Conia-ene reaction of β-keto esters.2
To further advance our work in this field, we wanted to access
differently functionalized precatalysts based on the privileged and
easy-to-prepare 9-amino(9-deoxy) epicinchona scaffold. Specifi-
cally, we reasoned that the functionalization of the amino group
of 9-amino(9-deoxy) epicinchona alkaloids with appropriately
spaced diaryl phosphine ligands could provide a new class of chiral
amino-phosphines, with the potential to perform as effective asym-
metric precatalysts when used in combination with transition metal
ions. We envisaged that the differential in hard/soft character of
the two Lewis bases (Scheme 1) would allow a selective binding
of the phosphine to an appropriate (soft) metal ion, leaving the
amine partially free from complexation and therefore able to act
as an organic base in the reaction of interest. As well as enhancing
rates, this cooperativity between the phosphine-ligated metal ion
and the (Lewis/Brønsted) basic nitrogen could also lead to high
levels of stereocontrol through organized multipoint binding of
the reacting components in the transition structure. Herein we
wish to report our preliminary findings.
A small library of precatalysts 1-4 was readily formed by
reacting a selection of 9-amino(9-deoxy) epicinchona alkaloids
Received: November 23, 2010
Published: January 19, 2011
r
2011 American Chemical Society
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|

Journal of the American Chemical Society
COMMUNICATION
Scheme 1. Cooperative Catalysis Concept from Amino-
phosphines and Metal Ions and a Library of Cinchona-
Derived Precatalysts
Table 2. Scope of the Glycine-Derived Isocyanoacetate Aldol
Reaction
yield
ee
entry
R
5
R1
6
7
(%)a drb (%)c
1
2
3
4
5
6f
7
8f
9
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Me
a
a
a
a
a
a
a
a
b
a
Ph
Ph
a
a
b
c
d
e
f
(4S,5R)-7a
(4R,5S)-7a
(4S,5R)-7b
(4S,5R)-7c
(4S,5R)-7d
(4S,5R)-7e
(4S,5R)-7f
(4S,5R)-7g
(4S,5R)-7h
-
72d 21:1 96
76d 21:1 92e
3-Br-C6H4
69
77
60
89
10:1 92
15:1 92
13:1 89
16:1 81
4-F-C6H4
4-OMe-C6H4
C(Me)2-CO2Me
Scheme 2. Postulated Catalyst Activation Mode
tBu
iPr
81g 99:1 91
85g 48:1 61
g
a
o
Ph
73
14:1 81
10 tBu
Me
-
-
-
a Isolated yield of major diastereomer. b Determined by 1H NMR
analysis. c ee of the major diastereomer determined by chiral HPLC.
d Isolated yield after conversion to the corresponding N-benzoylated
amino-ester. e Opposite enantiomer obtained using pseudoenantiomeric
f
catalyst 3. Reaction run at 0 °C. g Isolated yield of the major diaste-
reoisomer after conversion to the corresponding formamide.
Table 1. Optimization of Reaction Conditions
Table 3. Scope of the Aldol Reaction with r-Substituted
Isocyanoacetates
T
time conva
eeb
dra (%)
entry precat
MLn
(°C) solvent (h)
(%)
yield ee
entry R
8
R1
6
9
dra (%)b (%)c
1
2
2
2
2
2
2
4
1
2
2
3
-
2
AgOAc
CuCl
25 CH2Cl2
25 CH2Cl2
25 CH2Cl2
25 CH2Cl2
25 CH2Cl2
-20 MTBE
-20 MTBE
-20 MTBE
-20 AcOEt
-20 AcOEt
-20 AcOEt
-20 AcOEt
-20 AcOEt
18
48
4
100
30
5:1 62
2
4:1
0
1
2
Ph 8a
Ph 8a
3-Br-C6H4
4-F-C6H4
b
(4R,5R)-9a 10:1 90 97
(4R,5R)-9b 11:1 78 94
(4R,5R)-9c 15:1 93 97
(4R,5R)-9d 18:1 85 98
(4R,5R)-9e 12:1 50 93
(4R,5R)-9f 11:1 56 96
(4R,5R)-9g 8:1 57 93
(4R,5R)-9h 4:1 72 71
3
Ag2CO3
Ag2O
Au(PPh3)Cl
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
100
100
100
5:1 64
6:1 71
2:1 44
c
h
i
3d Ph 8a
3-F-C6H4
4
3
5
48
24
36
24
24
24
24
120
4
5
6
7
8
Ph 8a
Ph 8a
Ph 8a
Ph 8a
Bn 8b
4-Br-C6H4
3-MeO-C6H4
4-Cl-C6H4
4-CO2Me-C6H4
4-Br-C6H4
6
100 19:1 90
100 13:1 76
100 11:1 76
100 13:1 94
100 21:1 96
100 21:1 91d
l
7
m
n
i
8
9
10c
11c
12
13
a Determined by H NMR analysis. b Isolated yield of major diaster-
eomer. c ee of the major diastereomer determined by chiral HPLC.
d Relative stereochemistry determined by single crystal X-ray analysis.
1
Ag2O
Ag2O
-
100
-
-
0
24 traces
-
a Determined by 1H NMR analysis of the crude reaction mixture.
b Determined by chiral HPLC analysis after conversion to the corre-
sponding N-benzoylated amino-ester. c Isocyanoacetate concentration
0.3 M and 4 Å MS added. d Opposite enantiomer obtained.
creation of two adjacent stereocenters, one of them being fully
substituted (Table 3). Notably, in all cases reported in Tables 2
and 3, complete conversion of the isocyanoacetates to products
was observed, and all yields in Tables 2 and 3 refer to isolated pure
major diastereomer.7 Interestingly, when R-substituted isocyanoa-
cetates 8a and 8b were used, the opposite facial selectivity in the
nucleophilic component was observed(incomparison to Table 2).
However, facial selectivity on the aldehyde remained the same.
Although the reason for the reversal in the observed selectivity is
isocyanoacetates 8a and 8b.6 When R-substituted isocyanoace-
tates 8 were reacted with aldehydes, the corresponding oxazolines
were obtained in high enantioselectivities (up to 98%) and good
diastereoselectivities (up to 18:1), allowing the simultaneous
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Journal of the American Chemical Society
COMMUNICATION
Table 4. Aldol Reaction at Low Catalyst Loadings
Scheme 3. Hydrolysis of Oxazolines
Scheme 4. Reductive Manipulation of Oxazoline 9d
2
Ag2O
time
conv
(%)a
yield
(%)b
ee
(%)c
entry (mol %) (mol %) (h)
dra
1
2
2
2
1
24
24
100
100
44
90
1:1
48
94
0.5
14:1
a Determined by H NMR analysis. b Isolated yield of major diaster-
1
eomer. c ee of the major diastereomer determined by chiral HPLC.
not apparent, this suggests that the mode of action of our catalytic
system differs from the seminal findings of Ito and Togni.4a,4b One
possible rationale for this observation could be that the diastereo-
mers are interconverting under the reaction conditions. However,
when an enantioenriched sample of (4R,5R)-9c was treated with
amino-phosphine 2 and Ag2O under the optimized conditions,
no epimerization or racemization was observed. When the minor
diastereomer obtained during the formation of (4R,5R)-9c was
treated in the same manner, no epimerization was observed.
We then turned our attention to the possibility of lowering the
catalyst loading. When oxazoline (4R,5R)-9c was prepared using
2 mol % of precatalyst2 and 1 mol % of Ag2O, the reaction occurred
smoothly, but the product was obtained in 48% enantiomeric excess
(entry 1, Table 4). In order to restore high levels of enantioselec-
tivity, the loading of Ag2O had to be further lowered to 0.5 mol %,
keeping the precatalyst loading at 2 mol % (entry 2, Table 4). We
postulate that at low catalyst loadings, isocyanoacetate 8a competes
with precatalyst 2 in the Agþ complexation and a non-asymmetric
pathway is occurring. In order to minimize the background and
restore high levels of enantioselectivity, the ratio of 2:Ag2Ohadtobe
changed from 2:1 to 4:1.
enantioselectivities. The possibility of lowering the catalyst loading
has been investigated, and good levels of reactivity and stereo-
control can be obtained with a combination of 2 mol % of ligand 2
and 0.5 mol % of Ag2O. Work to probe the origin of stereocontrol
and to uncover further catalytic applications of ligands 1-4 is
under investigation in our laboratories and will be reported in due
course.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for compounds 1-4, 7a-h, 9a-h, 11-13 and CIF
files for compounds 9c and 13. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
Darren.Dixon@chem.ox.ac.uk
’ ACKNOWLEDGMENT
To highlight the utility of the isocyanoacetate aldol reaction
products in synthesis, we explored their conversion to the
corresponding amino acid derivatives. For example, a mild
methanolysis allowed the conversion of oxazoline (4R,5S)-7a
directly to the corresponding tert-butyl ester 10, proving the
utility of our method for the direct preparation of protected
β-hydroxy-R-amino acid tert-butyl esters (Scheme 3). Hydrolysis
of 10 gave the parent amino acid in quantitative yield; this enabled
assignment of the absolute stereochemistry by comparison of its
specific rotationwith those reportedinthe literature.4a,8 Reduction
of 9d with LiAlH4 furnished amino alcohol 12, which was further
derivatized to oxazolidinone 13 (Scheme 4) in order to assign
absolute stereochemistry of 9a-h by single-crystal X-ray analysis.
In summary, we have developed a new class of chiral amino-
phosphine precatalysts that, in combination with an appropriate
transition metal ion, can perform as effective cooperative Brønsted
base/Lewis acid catalysts. This concept has been successfully
applied to the highly enantio- and diastereoselective aldol reaction
of isocyanoacetate nucleophiles in the presence of Ag(I) salts. The
protocol proved to be operationally simple and could be per-
formed by mixing together the ligand and Ag2O, without the need
to preform the active catalytic species. The catalytic system
proved particularly effective in inducing high levels of stereocon-
trol with aromatic and branched aliphatic aldehydes, while linear
aliphatic aldehydes furnished the desired products with lower
We thank the EPSRC (Leadership Fellowship to D.J.D.), the
EC [IEF to F.S. (PIEF-GA-2009-254068)], Andrew Kyle, of the
Department of Chemistry, University of Oxford, for X-ray
analysis, and the Oxford Chemical Crystallography Service for
the use of the instrumentation.
’ REFERENCES
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