Proline-catalysed asymmetric amination of α,α-disubstituted aldehydes: Synthesis of configurationally stable enantioenriched α-aminoaldehydes

Article abstract of DOI:10.1039/b305465a

Proline-catalysed animation of α,α-disubstituted racemic aldehydes with azodicarboxylates proceeds smoothly to give configurationally stable scalemic aldehydes and oxazolidinones in up to 86% ee.

Full text of DOI:10.1039/b305465a

Proline-catalysed asymmetric amination of a,a-disubstituted aldehydes:
synthesis of configurationally stable enantioenriched a-aminoaldehydes†
Henning Vogt,a Sylvia Vanderheidena and Stefan Bräse*b
a Kekulé-Institut für Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universität
Bonn, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany
b Institut für Organische Chemie, Universität Karlsruhe, Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany.
E-mail: braese@ioc.uka.de; Fax: +49 721 608 8581
Received (in Cambridge, UK) 15th May 2003, Accepted 1st August 2003
First published as an Advance Article on the web 22nd August 2003
Proline-catalysed amination of a,a-disubstituted racemic
aldehydes with azodicarboxylates proceeds smoothly to give
configurationally stable scalemic aldehydes and oxazolidi-
nones in up to 86% ee.
The influence of the solvent was examined using DEAD with
hydratropaldehyde (1c) in different solvents (Table 1). While
the reaction does not proceed in ethyl acetate or DMF,
1,4-dioxane, acetonitrile or dichloromethane are suitable sol-
vents to furnish alcohol 3c-Et in moderate to good enantiose-
lectivities. Although in dioxane a maximal yield of 87% was
obtained, dichloromethane was used in subsequent studies as it
yielded 2c-Et in 80% ee.
With the notion in mind that a more bulky azodicarboxylate
would improve the stereoselectivity DBAD was used in the
reaction with 1c. In this case, the cyclization of alcohol 3c-Bn
to form oxazolidinone 4c-Bn proceeded quantitatively without
any additional basic treatment of the crude product, due to the
higher lability of the benzyloxycarbonyl group. With 81% ee
the reaction using DBAD shows similar enantioselectivity to
that using DEAD. This method was further examined using
chiral aldehydes 1a–h and alicyclic cyclohexanecarbaldehyde
1i with DEAD to yield a-alkyl-a-aryl aldehydes 2(c–h)-Et and
3,3-dialkyloxazolidinones 4(a,b,i)-Et, respectively (Scheme 1,
Table 2). As the product of the reduction of aldehyde 2c-Et
consisted of a mixture of uncyclised alcohol 3c-Et and
cyclization product 4c-Et, complete formation of the ox-
azolidinone was achieved by treating the crude product with
0.5 M methanolic NaOH prior to isolation.
While reaction of non-aromatic a-alkyl aldehydes 1a,b
displayed only moderate enantioselectivities up to 28% ee, a
remarkable improvement in terms of stereoselectivity was
observed when applying the reaction to the a-alkyl-a-aryl
substituted aldehydes 1c–h. Corresponding products 2(c–h)-Et
were obtained in good enantiomeric excess from 76% ee in
para-methoxyphenyl-substituted 2f-Et up to 86% ee in 2-naph-
thyl substituted 2e-Et. As the good enantioselectivity is
surprisingly consistent within the class of a-alkyl-a-aryl
substituted aldehydes, the presence of the aromatic a-sub-
stituent seems to play an important role, probably owing to its
bulkiness, thus improving the level of stereo-differentiation
between the two a-substituents. The deviation from the average
80% ee in the presence of the unsubstituted a-aryl substituent as
in aldehyde 2c-Et to higher and lower values when introducing
aromatic substitution patterns might be due to electronic effects
stabilizing or destabilizing certain transition states in the course
of the reaction. Further investigations towards the elucidation of
the mechanism are in progress.
The synthesis of a,a-disubstituted amino acids, aldehydes and
alcohols is due to their interesting properties a highly attractive
field. These compounds inhibit particular biological activity on
one hand, such as a-ethyl-4-carboxyphenylglycine which acts
as a group I/group II metabotropic glutamate receptor antago-
nist,1 and on the other hand can be found in a number of
peptides.2,3 Existing methods for the asymmetric approach to
this class of compounds include auxiliary-controlled and
catalytic Strecker syntheses,4 diastereoselective alkylation of
chiral phenylpyrazines5 or amino acid-derived oxazaborolidi-
none enolates,6 as well as a variety of asymmetric phase-
transfer catalysis reactions.7 In an ongoing project towards the
synthesis of biologically active peptides, we required the
asymmetric synthesis of a-aryl-a-methylglycines.
Recently, List et al. and Jørgensen et al. reported the
asymmetric proline-catalysed amination of achiral linear alde-
hydes to give, after reduction, the corresponding amino alcohols
in good yields and excellent enantioselectivities.8,9 Further-
more, Jørgensen et al. examined the direct amination of
a-substituted b-ketoesters catalysed by a chiral copper(II)-
bisoxazolidinone complex.10 Seeing the potential of the easy-
to-handle procedures and the good availability of -proline we
L
decided to investigate proline-catalysed asymmetric amination
of a,a-disubstituted racemic aldehydes with azodicarboxylates.
a,a-Disubstituted racemic aldehydes are either commercially
available or, in the case of a-aryl-substituted aldehydes 1d–h,
can easily be prepared from the corresponding acetophenones
(or propiophenone in the case of 1d) following known
procedures by Wittig reaction with methoxymethyltriphenyl-
phosphonium chloride in NaH/DMSO and cleavage of the
resulting enol ether with HBr in acetone/water 4 : 1.11
Proline-catalysed asymmetric amination reactions were ex-
amined for a-disubstituted aldehydes 1a–i using diethyl
azodicarboxylate (DEAD) and dibenzyl azodicarboxylate
(DBAD). Similar to the reaction of achiral aldehydes, 0.5 equiv.
of the amino acid as catalyst, either
L
-proline (5), or
L
-
azetidinecarboxylic acid (6) and 1.5 equiv. of a,a-disubstituted
aldehyde 1 were reacted with 1 equiv. of azodicarboxylate.‡8,9
After complete consumption, the yellow colour of the azodi-
carboxylate disappeared. To isolate aldehydes 2-R the reaction
was then quenched with water and the aqueous phase extracted
with organic solvents. Products 2-R were purified by column
chromatography. In contrast the oxazolidinones 4-R were
obtained by treatment of the initial reaction mixture with an
excess of NaBH4 to yield alcohols 3-R, which in most cases
underwent intramolecular substitution to form oxazolidinones
4-R. Aqueous workup followed by column chromatography
furnished the final products. Racemic samples rac-2-R or rac-
4-R were prepared using DL-proline.
The assumption that the use of the more rigid 4-membered
ring analogue to proline, -2-azetidinecarboxylic acid (6), as a
L
Table 1 Reaction of hydratropaldehyde 1c with DEAD using
yield alcohol 3c-Et in different solvents (0 °C, then rt, 60 h)
L-proline to
Solvent
Yield (%)a
ee (%)b
Acetonitrile
Dichloromethanec
1,4-Dioxane
77
62
87
66
80d
67
a After column chromatography. b Enantiomeric excess determined using
HPLC with a chiral stationary phase (Chiracel OD). c Product isolated as
aldehyde 2c-Et. d In single cases up to 86% ee were detected.
† Electronic supplementary information (ESI) available: experimental. See
http://www.rsc.org/suppdata/cc/b3/b305465a/
2448
CHEM. COMMUN., 2003, 2448–2449
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Scheme 1 Asymmetric a-amination of a,a-disubstituted aldehydes 1 with azodicarboxylates catalysed by L-proline (5) or L-azetidinecarboxylic acid (6),
followed by reduction of a-amino aldehydes 2-R and cyclisation of the corresponding alcohols 3-R to give oxazolidinones 4-R.
catalyst might lead to an even higher grade of stereoselectivity
was disproved by the fact that in all cases lower ee’s around
50% were observed, para-methoxycarbonyl derivative 2h-Et
being an exception to this rule, but with 78% ee still not
reaching the efficiency of the reaction catalysed by
(Table 2).
L
-proline (5)
Although not resulting in an asymmetric reaction, the
reaction of cyclohexanecarbaldehyde (1i) offers an interesting
route to spiroazoxaalkanes.
Scheme 2 Palladium-catalysed hydrogenation of the benzyloxycarbonyl
group and subsequent cleavage of the hydrazine with sodium nitrite.
The removal of the amino group was demonstrated on
oxazolidinone 4c-Bn (Scheme 2). Hydrogenation of 4c-Bn at
ambient pressure using 10% Pd/C in methanol/acetic acid at rt
resulted in cleavage of the benzyloxycarbonyl group.12 Cleav-
age of the hydrazine moiety was accomplished by treating
2-amino-3-methyl-3-phenyloxazolidinone (7c) with sodium
nitrite in 3 : 1 acetic acid/1 M aq. HCl within 30 min.13
The absolute configuration of oxazolidinone 8c was deter-
mined to be (R) after comparison to known optical rotation
values.§14
wide spectrum of a-substituted phenylglycine derivatives.11
This is the first example of the proline-catalysed reaction of
a,a-disubstituted aldehydes with electrophiles.
Financial support from the DFG (SFB 624) is gratefully
acknowledged.
Notes and references
Another class of great interest besides the a-amino aldehydes
and their corresponding alcohols presented above are the non-
proteogenic a-amino acids, which can be derived from those
substances. Oxidation of aldehyde 2c-Et with 1 M aq. KMnO4
in t-BuOH and 1 M aq. NaH2PO4 at rt delivered the
corresponding amino acid in non-optimised 25% yield.9
In summary we present an efficient route to a,a-disubstituted
configurationally stable scalemic a-amino aldehydes and
oxazolidinones in up to 86% ee starting from racemic
aldehydes. Especially the a-aryl-a-alkyl substituted amino acid
derivatives which can be synthesized in good enantioselectiv-
ities are due to their physiological activity of great interest.1 The
good accessibility to the aldehydes required as reagents opens a
‡ Reaction of the more valuable aldehydes 1d–i was carried out using 1
equiv. aldehyde with 1.1 equiv. azodicarboxylate.
§ Optical rotation of 8c: [a]D25
=
+107.2° (c
= 3, CH3OH), (S)-
enantiomer;14 found: [a]Dn = 284.3° (c = 1, CHCl3).
1 J. S. Bedingfield, M. C. Kemp, D. E. Jane, H. W. Tse, P. J. Roberts and
J. C. Watkins, Br. J. Pharmacol., 1995, 116, 3323; N. Sekiyama, Y.
Hayashi, S. Nakanishi, D. E. Jane, H. W. Tse, E. F. Birse and J. C.
Watkins, Br. J. Pharmacol., 1996, 117, 1493.
2 E. Katz, H. Schmitt, M. Aydin, W. A. König and G. Jung, Liebigs Ann.
Chem., 1985, 365; C. Auvin-Guette, S. Rebuffat, I. Vuidepot, M.
Massias and B. Bodo, J. Chem. Soc., Perkin Trans. 1, 1993, 249; Y. S.
Tsantrizos, S. Pischos, F. Sauriol and P. Widden, Can. J. Chem., 1996,
74, 165; I. Augeven-Bour, S. Rebuffat, C. Auvin, C. Goulard, Y. Prigent
and B. Bodo, J. Chem. Soc., Perkin Trans. 1, 1997, 1587.
3 For preparation of optically active amino acids, see: R. M. Williams,
Synthesis of Optically Active a-Amino Acids, Pergamon, Oxford, 1989;
R. M. Williams and J. A. Hendrix, Chem. Rev., 1992, 92, 889; M.
Ahrend, Angew. Chem., 1999, 111, 3047 (Angew. Chem., Int. Ed., 1999,
38, 2873); L. Yet, Angew. Chem., 2001, 113, 900 (Angew. Chem., Int.
Ed., 2001, 40, 875); K. L. Reddy and K. B. Sharpless, J. Am. Chem. Soc.,
1998, 120, 1207 and refs. therein.
Table 2 Reaction of aldehydes R1R2CHCHO 1 with DEAD or DBAD using
L
-proline (5) or
L-azetidinecarboxylic acid (6) as catalyst to give aldehydes
2-R or oxazolidinones 4-Ra
Yield
Reagent Product Time/dc (%)bc ee (%)c ee (%)d
R1 R2
1
4 D. Ma, H. Tian and G. Zou, J. Org. Chem., 1999, 64, 120; F. A. Davis,
S. Lee, H. Zhang and D. L. Fanelli, J. Org. Chem., 2000, 65, 8704; P.
Vachal and E. N. Jacobsen, Org. Lett., 2000, 2, 867.
5 S.-H. Lee and E.-K. Lee, Bull. Korean Chem. Soc., 2001, 22, 551.
6 E. Vedejs, S. C. Fields, R. Hayashi, S. R. Hitchcock, D. R. Powell and
M. R. Schrimpf, J. Am. Chem. Soc., 1999, 121, 2460.
7 For a review, see: K. Maruoka and T. Ooi, Chem. Rev., 2003, 103, 3013
and refs. therein.
8 B. List, J. Am. Chem. Soc., 2002, 124, 5656.
9 A. Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang and K. A.
Jørgensen, Angew. Chem., 2002, 114, 1868 (Angew. Chem., Int. Ed.,
2002, 41, 1790); for a review: R. O. Duthaler, Angew. Chem., 2003, 115,
1005 (Angew. Chem., Int. Ed., 2003, 42, 975).
10 M. Marigo, K. Juhl and K. A. Jørgensen, Angew. Chem., 2003, 115,
1405 (Angew. Chem., Int. Ed., 2003, 42, 1367).
11 S. Danishefsky and D. F. Harvey, J. Am. Chem. Soc., 1985, 107,
6647.
12 D. A. Niederer, J. T. Kapron and J. C. Vederas, Tetrahedron Lett., 1993,
34, 6859.
Me Et
Et Bu
Me Ph
Me Ph
Me Ph
Et Ph
1a DEAD 4a-Et
1b DEAD 4b-Et
1c DEAD 2c-Et
1c DEAD 4c-Ete
1c DBAD 4c-Bn
1d DEAD 2d-Etf
3
9
3
3
3
3
52
35
62
17
83
59
54
87
63
50
26
28g
4g
6g
ndj
ndj
51i
52i
49i
56i
ndj
53i
78i
—
80h
81i
81i
80i
86i
76i
85i
82i
—
Me 2-Naph
Me 4-OMe-Ph
Me 3,5-OMe-Ph 1g DEAD 2g-Etf
Me 4-CO2Me-Ph 1h DEAD 2h-Etf
1e DEAD 2e-Etf 2.5
1f DEAD 2f-Etf
5
6
6
4
-(CH2)5-
1i DEAD 4i-Et
a Experimental conditions: see ESI. b Yield determined after column
chromatography.
c
d
L
-Proline (5) used as catalyst.
L
-Azetidinecarboxylic
acid (6) used as catalyst. e Crude product treated with 0.5 M methanolic
NaOH before column chromatography. f 1 equiv. aldehyde 1 was reacted
with 1.1 equiv. azodicarboxylate. g ee determined by GC on a chiral
stationary phase. h ee determined by HPLC on a chiral stationary phase
(Chiralpack AS). i ee determined by HPLC on a chiral stationary phase
13 R. Milcent, M. Guevrekian-Soghomoniantz and G. Barbier, J. Hetero-
cycl. Chem., 1986, 23, 1845.
14 H. Pietsch, Tetrahedron Lett., 1972, 27, 2789.
(Chiracel OD). j Reaction was not carried out using
L-azetidinecarboxylic
acid (6) as a catalyst.
CHEM. COMMUN., 2003, 2448–2449
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