Enantioselective one-pot synthesis of α-amino esters by a phosphine-catalyzed [3+2]-cycloaddition reaction

Article abstract of DOI:10.1002/chem.201103502

Phosphines go one-pot: The one-pot synthesis of cyclic α-amino esters from azlactones and allenes by a phosphine-catalyzed [3+2]-cycloaddition reaction followed by a ring opening of the azlactone moiety is presented. The products are isolated as single re

Full text of DOI:10.1002/chem.201103502

DOI: 10.1002/chem.201103502
Enantioselective One-Pot Synthesis of a-Amino Esters by a Phosphine-
Catalyzed [3+2]-Cycloaddition Reaction
Marianne Steurer, Kim L. Jensen, Dennis Worgull, and Karl Anker Jørgensen*[a]
Phosphine-catalyzed [3+2]-
cycloaddition reactions of elec-
tron-deficient allenes and al-
kynes with a,b-unsaturated car-
bonyl compounds can give
access to important highly func-
tionalized cyclopentenes.[1] The
seminal example of such
a
transformation was first report-
ed by Lu et al. in 1995,[2] and its
asymmetric version in 1997 by
the group of Zhang.[3] However,
it took another ten years before
the potential of this annulation
strategy using chiral phosphine
catalysts was studied more in-
tensively.[4] The last decade has
Scheme 1. Synthesis of optically active a-amino esters from allenes and olefinic azlactones.
witnessed considerable progress in the development of suit-
lenes. In general, two pathways are possible for this reac-
tion, affording regioisomers resulting from a- or g-addition.
Since b-substituted exocyclic enones preferentially undergo
g-addition,[3,5m,o] we assumed that the g-adduct would be fa-
vored, giving access to aspartic acid derivatives 5 after a
ring-opening reaction of the azlactone moiety.
ACHTUNGTRENNUNGable new chiral phosphine catalysts and their application in
asymmetric [3+2]-cycloaddition reactions.[5]
Recently, readily available olefinic azlactones have
emerged as amino acid precursors in organocatalysis.[6]
Therefore, we decided to develop a novel asymmetric phos-
phine-catalyzed [3+2]-cycloaddition reaction of olefinic
azlactones with allenes for the synthesis of highly functional-
ized chiral amino esters. The cycloaddition between olefinic
azlactones 1 and allenes 2 using a chiral phosphine catalyst
would thereby give access to enantioenriched cyclopentenyl
derivatives 3 and 4 (Scheme 1).
To the best of our knowledge, the optically active cyclo-
pentenyl derivatives 3 and 4 have until now only been syn-
thesized efficiently in a racemic manner.[7,8] Herein, we
report the results of our studies on the enantioselective one-
pot synthesis of cyclic a-amino esters by a phosphine-cata-
lyzed [3+2]-cycloaddition reaction of azlactones with al-
At the outset, a number of chiral phosphine catalysts
were evaluated for the [3+2]-cycloaddition reaction of (Z)-
olefinic azlactone 1a with ethyl buta-2,3-dienoate 2a (see
the Supporting Information). Among the catalysts tested,
(S)-BINEPINE[9] afforded the highest regio- and enantiose-
lectivities. As anticipated, it was found that the g-addition
was favored, providing a 12:1 regioisomeric ratio (i.r.) of
products 3a and 4a with an enantiomeric excess of 94% ee
of 3a (Scheme 2).[10] Additional screening of solvents and
concentrations showed that the best results were obtained in
toluene and a concentration of 0.1m provided a better solu-
bility of the azlactone. It should be noted that no difference
in the reaction outcome was observed when the reaction
was performed under air or inert conditions, which enhances
the practicability and usefulness of this phosphine-catalyzed
cycloaddition. A screening of different allenes showed that
the ethyl ester 2a in combination with an azlactone contain-
ing a phenyl group at the C2 position (R2 =Ph, see
Scheme 1), provided the highest, yet disappointing, conver-
sion and selectivities. The cycloaddition with Me-substituted
azlactone (R1 =Ph, R2 =Me) resulted in inferior results.
Since only partial conversion of the azlactone 1a, and
therefore a low combined yield of products 3a and 4a, was
[a] Dr. M. Steurer, K. L. Jensen, Dr. D. Worgull,
Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8619 6199
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103502.
Re-use of this article is permitted in accordance with the Terms and
Conditions set out at http://onlinelibrary.wiley.com/journal/10.1002/
TRENNUNG(ISSN)1521-3765/homepage/2111_onlineopen.html.
ACHTUNG-
76
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Chem. Eur. J. 2012, 18, 76 – 79

COMMUNICATION
Finally, the effect of the reac-
tion temperature was investi-
gated. Preliminary experiments
at lower temperatures showed
that at 58C almost the same
conversion was obtained as at
room temperature, whereas the
reaction was very slow at
À208C. Refluxing in toluene
for 2 h led to almost complete
consumption of 1a, providing a
significantly higher combined
yield of 72% of products 3a
and 4a (47% obtained at room
temperature, compare Table 1,
Scheme 2. ACHTUNGTRENNUNG[3+2]-Cycloaddition reaction of (Z)-olefinic azlactone 1a with ethyl buta-2,3-dienoate 2a catalyzed
by (S)-BINEPINE.
Table 1. Optimization of reaction conditions.[a]
Entry
(S)-7
[mol%]
Time/Temp
[h/8C]
Yield
[%][b]
i.r.
[3a:4a][c]
ee
G
G
N
[%][d]
1[e]
2[e]
3
4
5
10
20
20
20
20
10
20
22/RT
17/RT
2/110
21/60
21/80
28
47
72
55
66
25
83
12:1
ca. 10:1
4:1
94
94
85
92
7:1
5:1
5:1
4:1
89
6
7
22/80
n.d.[f]
91
3/RT then
21/110
3/RT then
21/80
8
20
77
5:1
93
[a] 1a (0.1 mmol), 2a (0.15 mmol), and (S)-7 in toluene (1.0 mL). [b] Iso-
lated yield of 3 and 4 after FC. [c] i.r.=regioisomeric ratio; determined
by 1H NMR spectroscopy of the crude reaction mixture. [d] Determined
on 5a by HPLC analysis using a chiral stationary phase. [e] Performed
under argon; with 2a (0.2 mmol) and toluene (0.5 mL). [f] n.d.=not de-
termined.
Scheme 3. Proposed mechanism for the phosphine-catalyzed [3+2]-cyclo-
addition reaction.
entries 2 and 3). While the regioselectivity dropped from
10:1 to 4:1, the enantioselectivity was, to our surprise, only
reduced to 85% ee. A screening of different reaction tem-
peratures showed that by performing the reaction at room
temperature followed by heating to 808C gave the best com-
bined results with respect to yield, regioselectivity, and
enantioselectivity (Table 1, entry 8). An attempt to reduce
the catalyst loading to 10 mol% resulted in low conversion
of 1a (Table 1, entry 6), and the following experiments were
observed in the cycloaddition (28%, Table 1, entry 1), an
optimization of the reaction conditions was performed. An
increase of the catalyst loading to 20 mol% resulted in a sig-
nificantly higher yield (47%), though still remaining unsatis-
factory low (Table 1, entry 2). Monitoring the reaction
showed that the degree of conversion of the azlactone to the
products 3a and 4a did not increase after three hours (per-
haps due to catalyst inhibition). Mechanistic studies on
phosphine-catalyzed [3+2]-cycloaddition reactions by Yu
et al. suggest the necessity of water to induce the 1,2-proton
transfer to release the catalyst from the intermediate ylide
species.[2,11] Scheme 3 outlines the mechanistic proposal for
the catalytic cycle. Therefore, several additives such as
water, alcohols, acids, as well as buffered systems, to pro-
mote this proton shift were tested. However, none of these
additives improved the conversion of the transformation (re-
sults not shown).
therefore performed with 20 mol% ofACHTNUTRGNEUNGBINEPINE (S)-7.
Based on the optimization of the first reaction step, we
next envisioned developing a one-pot [3+2]-cycloaddition/
methanolysis procedure that provides direct access to pro-
tected amino acid derivatives. Gratifyingly, treating the
crude reaction mixture with MeOH/TMSCl resulted in the
opening of azlactones 3 and 4 to give the products 5 and 6,
respectively. For the reaction of (Z)-olefinic azlactone 1a
with ethyl buta-2,3-dienoate 2a, pure major isomer 5a was
isolated in a good overall yield (58%, Scheme 4) in conjunc-
tion with a high enantioselectivity (93% ee). The scope of
Chem. Eur. J. 2012, 18, 76 – 79
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77

K. A. Jørgensen et al.
one-pot sequence to amino
esters 5 were comparable for all
substrates. Only in the case of
ortho-bromo
aryl-substituted
azlactone 1b, the enantioselec-
tivity dropped to 79% ee, whilst
the yield and the regioselectivi-
ty remained in the same range
as shown for the other sub-
strates.
This new one-pot reaction
can be classified as a TypeA-2-
2C2X[12] sequence and provides
an easy approach to enantioen-
riched amino acid derivatives
containing a quarternary stereo-
center.
The absolute configuration of
the major isomer 3a was deter-
mined to be (5S,9R) by single-
crystal X-ray analysis (see
Figure 1).[13] The stereochemis-
try of amino ester 5a was as-
signed according to 3a to be
(1S,5R)
and
assuming
a
common reaction pathway, the
configuration of the other de-
rivatives
analogy.
5 was assigned by
The obtained optically active
amino acid derivatives can un-
dergo a number of important
transformations. The amino
Scheme 4. Scope of the one-pot sequence to optically active amino esters. Yields are given for the major
isomer (i.r.=regioisomeric ratio of 3:4 determined after the first step).
acids 8 are readily available by hydrolysis of amino esters 5
as shown for derivative 8a, which was isolated as its HCl
salt in 76% yield (Scheme 5).[8] Functionalization of the a,b-
unsaturated ester moiety could be achieved by a Ru-cata-
lyzed ketohydroxylation of product 5a, and resulted in a-hy-
droxy-b-ketoester 9 in 72% yield.[14]
Figure 1. X-ray structure of the major isomer 3a.
the reaction was therefore studied, using this developed
one-pot sequence (Scheme 4). All optically active amino
acid derivatives were isolated as single regioisomers 5, and
the given regioisomeric ratios were determined after the
first step. Different b-aryl-substituted azlactones were evalu-
ated, including a variation of substituents containing elec-
tron-donating, as well as electron-withdrawing functionali-
ties on the aryl moiety (products 5b–i). Furthermore, a het-
eroaromatic azlactone was successfully employed, thereby
broadening the scope of the reaction (product 5j). In gener-
al, very high enantioselectivities (>90% ee) were obtained
with regioselectivities between 7:2 and 9:1. The yields of this
Scheme 5. Hydrolysis and oxidation of amino ester 5a.
78
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Chem. Eur. J. 2012, 18, 76 – 79

Synthesis of Functionalized Chiral Amino Esters
COMMUNICATION
In conclusion, we have developed a TypeA-2-2C2X[12]
one-pot synthesis of enantioenriched amino acid derivatives
containing a quarternary stereocenter. The sequence relies
on an asymmetric phosphine-catalyzed [3+2]-cycloaddition
reaction between ethyl buta-2,3-dienoate and (Z)-olefinic
azlactones, followed by an in situ ring opening of the azlac-
tone moiety. The products were generally obtained in good
overall yields and high enantioselectivities. Transformations
of the obtained amino esters to the respective amino acid
and to an a-hydroxy-b-ketoester have successfully been
demonstrated, giving access to further functionalizable com-
pounds.
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Acknowledgements
This work was made possible by grants from OChemSchool, Carlsberg
Foundation, and FNU. Thanks are expressed to Hao Jiang for inspiring
experiments and discussions. We thank Dr. Jacob Overgaard for perform-
ing X-ray analysis. M.S. thanks the Austrian Science Fund (FWF) for a
postdoctoral Erwin Schrçdinger fellowship (J 3053-N19).
Keywords: amino esters
·
asymmetric synthesis
·
cycloaddition · organocatalysis · phosphines
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were significantly elongated in one direction. However, using CuKa
radiation it is possible to determine the absolute configuration of
the molecule in the crystal structure: The Flack parameter is
0.04(30) and the Hooft y parameter (W. W. R. Hooft, L. H. Straver,
A. L. Spek, J. Appl. Crystallogr. 2008, 41, 96–103) is 0.06(12), while
the probability for the correct determination of the absolute config-
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mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Received: November 7, 2011
Published online: December 7, 2011
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