Tertiary aromatic amide for memory of chirality: Access to enantioenriched α-substituted valine

Article abstract of DOI:10.1021/ja801165z

A new methodology for the asymmetric synthesis of quaternary α-substituted amino acids using memory of chirality has been developed. This strategy employs dynamic axial chirality of tertiary aromatic amides to memorize the initial chirality of an α-amino acid during the enolization step. Starting from l-valine, an oxazolidin-5-one containing a tertiary aromatic amide was synthesized in one step and then alkylated with various electrophiles with good yield and enantioselectivity (up to 96%). Quaternary products can be obtained enantiomerically pure by recrystallization. One-step deprotection affords enantioenriched (S)-α-methyl valine (ee = 94%) or enantiopure (S)-α-isopropyl aspartic acid (ee >99%) in only three steps starting from L-valine. Copyright

Full text of DOI:10.1021/ja801165z

Published on Web 04/15/2008
Tertiary Aromatic Amide for Memory of Chirality: Access to
Enantioenriched r-Substituted Valine
Mathieu Branca, Didier Gori, Re´gis Guillot, Vale´rie Alezra,* and Cyrille Kouklovsky*
Laboratoire de Chimie des Proce´de´s et Substances Naturelles, ICMMO, CNRS UMR 8182,
Baˆt 410, UniVersite´ Paris-Sud, F-91405 Orsay, France
Received February 15, 2008; E-mail: valezra@icmo.u-psud.fr; cykouklo@icmo.u-psud.fr
Scheme 1. General Strategy to Enantioenriched Quaternary
R-Amino Acids
There is an ever-growing interest in the synthesis, pharmacology,
and conformational properties of nonproteinogenic amino acids,
and in particular R,R-disubstituted R-amino acids.1 Due to their
biological importance, many procedures have been developed for
the stereoselective synthesis of quaternary R-amino acids.2 Among
them, some procedures apply a new principle, memory of
chirality,3,4 in order to use the starting R-amino acid as the only
source of chirality. For instance, Fuji and Kawabata have performed
essentially methylation and intramolecular alkylation of various
R-amino acids with high enantiomeric excesses by using a
nonracemic enolate with a chiral C-N axis.5 Carlier used the
intrinsic chirality of the benzodiazepine-2-one ring to obtain R,R-
dialkyl amino acids enantioselectively.6
The high rotation barriers of tertiary aromatic amides have been
exploited as a new method for diastereoselection.7 We thought to
apply the properties of these amides to the concept of memory of
chirality, by introducing a hindered tertiary aromatic amide onto a
starting amino acid. The generation of a dynamic axial chirality
should allow stereoselective alkylation of the corresponding enolate
after deprotonation (Scheme 1). For this purpose, N-substituted,
amino acid derived, oxazolidin-5-ones were chosen as substrate
for enantioselective alkylation. Herein, we report highly enanti-
oselective synthesis of quaternary L-valine derivatives.
Scheme 2. Synthesis of Compound 1
Compound 1 was selected and synthesized without racemization
in one step from sodium L-valinate by modifying a procedure
described by Seebach8 (Scheme 2). The crystal structure of
compound 1 indicated that, in the solid state, it adopts a (P,cis)
conformation (Figure 1). This is consistent with the major
conformation adopted in CDCl3 at low temperature, according to
our 1H NMR and theoretical studies (trans conformers are
destabilized by a decrease of conjugation in amide bond9 and
(M,cis) conformer by naphthyl distortion10).
improve significantly the enantioselectivity, and increasing the
temperature was deleterious (-60 °C, entry 11). Dissolution of
crystals at -78 °C (entry 12) did not change enantioselectivity.
These results suggested the formation of a dynamic chiral enolate,
as expected.
We next attempted methylation of compound 1. Deprotonation
with KHMDS gave higher yields and enantioselectivities than with
LDA. Additives, solvents, electrophiles, and reaction conditions
(temperature, concentration, deprotonation time, or alkylation time)
were then screened (Table 1). Increased enolate formation time
improved yield but resulted in deterioration of the enantioselectivity.
Yields and enantioselectivities generally increased when a cosolvent
such as 1,2-dimethoxyethane (DME) was used. Using a crown ether
dramatically boosted conversion but was deleterious to the enan-
tiomeric excess (entry 5). Then, we replaced THF by the less polar
diethyl ether. Conversion was, not surprisingly, slightly decreased,
but racemization of the enolate was also slowed (entries 4 and 6).
Good conversion was restored by replacing methyl iodide by the
more reactive methyl triflate and increasing the concentration.
Finally, the best conditions were the following: deprotonation with
1.5 equiv of KHMDS (in toluene) in diethyl ether/DME for less
than 10 min and alkylation either with a very reactive electrophile
for 10 min (entry 9) or with a less reactive electrophile with DMPU
(entry 7). Lowering the temperature (-86 °C, entry 10) did not
We next applied the optimized conditions to other reactive
electrophiles (Table 2): enantioselectivities exceed 73%, and yields
range from 59 to 98%. Enantioselectivity can be enhanced by
recrystallization for all compounds. Moreover, analysis of deuter-
ated compound 2g by chiral stationary-phase HPLC indicated
retention of configuration.
Deprotection of compound 2a (ee ) 94%) or 2f (ee > 99%)
was achieved in one step: reflux in HBr 47% led quantitatively to
Figure 1. ORTEP plot of compound 1. Ellipsoids are drawn at the 50%
probability level.
9
5864 J. AM. CHEM. SOC. 2008, 130, 5864–5865
10.1021/ja801165z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Screening of Reaction Conditions for Methylation of
Compound 1a
Scheme 4. Alkylation of Compound 4
using our optimized conditions. Only racemic product 5 was
obtained in 59% yield (Scheme 4).
additive
(equiv)
t1
(min)
t2
(min)
conv
(%)b
ee
(%)b
entry
solvent
X (equiv)
1H NMR spectroscopy of 1 at 195 K in Et2O/toluene demon-
strates that the (P,trans) and (M,trans) conformers can be neglected
and that a 100:12 ratio of (P,cis):(M,cis) conformers is observed.
Since this ratio does not totally explain the conversion rates and
enantioselectivities, we suggest that a dynamic resolution process
also contributes to stereochemical induction: Ar-CO rotation in
compound 1 should be faster than metalation and lead to
preferential deprotonation of the (P,cis) conformer in which the
labile proton is more accessible. Racemization of this enolate
(Ar-CO rotation) should be relatively slow, and alkylation should
occur opposite to the second aromatic ring, leading to global
retention of configuration. Further NMR and theoretical studies
are under investigation to confirm this hypothesis.
1
2
3
4
5
6
7
THF
THF
THF
THF
THF
Et2O
Et2Od
0c I (6)
60
10
10
10
10
10
10
20
49
57
100
95
85
66
74
57
33
79
4
4
10
1
10
10
I (30)
I (30)
I (30)
I (30)
I (30)
I (5)
DME (6)
DME (6)
18-c-6 (3)
DME (6)
DME (3)
DMPU (3)e
DME (3)
DME (3)
87
88(74f) 78
8
9
10
11
12
Et2Od
Et2Od
3
8
8
8
8
OTf (3)
OTf (5)
OTf (5)
OTf (5)
OTf (5)
10
10
10
10
10
64
88
95(78f) 82
Et2Od,g DME (3)
Et2Od,h DME (3)
Et2Od,i DME (3)
93
99
82
85
54
83
a Unless specified, a mixture of KHMDS (3 equiv, 0.5 M in toluene)
We have described herein a utilization of chiral Ar-CO axis of
tertiary aromatic amides in the field of memory of chirality. Our
methodology gives access to enantioenriched quaternary valine in
only three steps. Future work will involve extension of this strategy
to aldolization and to other amino acids.
and additive was added via canula at -78 °C to a solution of 1;
concentration of enolate was 0.07 mol ·L-1 b Determined by chiral
.
stationary-phase HPLC. c Electrophile in situ. d Only 1.5 equiv of
KHMDS was added, and the concentration of the enolate was 0.15
mol·L-1
.
e Added with electrophile. f Isolated yield. g Reaction at
-86 °C. h Reaction at -60 °C. i Crystal dissolution at -78 °C.
Table 2. Alkylation of Compound 1
Acknowledgment. We are grateful to the CNRS and Ministe`re
de la Recherche et de l’Enseignement Supe´rieur (grant to M.B.).
Supporting Information Available: Crystallographic data and
1H NMR at low temperature of compound 1, experimental details and
characterization of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
yield
(%)
ee
(%)a
recrystallization ee
(%)a
entry
electrophile
E
product
yield (%)
(1) (a) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127–5143. (b) Kang,
S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Chem. ReV. 2005, 105, 4537–
4558.
(2) Recent reviews: (a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2007, 18, 569–623. (b) Vogt, H.; Bra¨se, S. Org. Biomol. Chem.
2007, 5, 406–430.
(3) Reviews: (a) Fuji, K.; Kawabata, T. Chem.—Eur. J. 1998, 4, 373–376. (b)
Kawabata T.; Fuji K. In Topics in Stereochemistry; Denmark, S. E., Ed.;
John Wiley & Sons: New York, 2003; Vol. 23, pp 175-205. (c) Eames,
J.; Suggate, M. J. Angew. Chem., Int. Ed. 2005, 44, 186–189. (d) Zhao,
H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1–16.
(4) Recent examples: (a) Kolaczkowski, L.; Barnes, D. M. Org. Lett. 2007, 9,
3029–3032. (b) Bonache, M. A.; Cativiela, C.; Garcia-Lopez, M. T.;
Gonzalez-Muniz, R. Tetrahedron Lett. 2006, 47, 5883–5887.
(5) (a) Kawabata, T.; Chen, J.; Suzuki, H.; Fuji, K. Synthesis 2005, 1368–
1377. (b) Kawabata, T.; Kawakami, S.-p.; Shimada, S.; Fuji, K. Tetrahedron
2003, 59, 965–974. (c) Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K.
Angew. Chem., Int. Ed. 2000, 39, 2155–2157. (d) Kawabata, T.; Moriyama,
K.; Kawakami, S.; Tsubaki, K. J. Am. Chem. Soc. 2008, 130, 4153–4157.
(6) (a) Carlier, P. R.; Zhao, H.; MacQuarrie-Hunter, S. L.; DeGuzman, J. C.;
Hsu, D. C. J. Am. Chem. Soc. 2006, 128, 15215–15220. (b) MacQuarrie-
Hunter, S. L.; Carlier, P. R. Org. Lett. 2005, 7, 5305–5308. (c) Carlier,
P. R.; Lam, P. C.-H.; DeGuzman, J. C.; Zhao, H. Tetrahedron: Asymmetry
2005, 16, 2999–3002.
1
2
3
4
5
6
7
MeIb
Me
Me
Et
2a 74
78
MeOTf
EtOTf
allyl-I
Bn-I
2a 78c
2b 59
2c 88c
82
91
88
60
80
67
85
83
89
94
>99
99
>99
98
allyl
Bnd
2d 72-98 73-91
4-OMeBn-I 4-OMeBn
ethyl
CH2CO2Et 2f 80c
iodoacetate
tBuOD
2e 98c
86
96
>99
8
D
2g 76e
93
a Determined by chiral stationary-phase HPLC. b DMPU (3 equiv)
added with MeI. c Complete conversion. d For unknown reasons, ee
varies from 73 to 91%. e Percent deuteration determined by 1H NMR
spectroscopy.
Scheme 3. Obtention of Enantioenriched R-Substituted Amino
Acids
(7) (a) Betson, M. S.; Clayden, J.; Helliwell, M.; Johnson, P.; Lai, L. W.; Pink,
J. H.; Stimson, C. C.; Vassiliou, N.; Westlund, N.; Yasin, S. A.; Youssef,
L. H. Org. Biomol. Chem. 2006, 4, 424–443. (b) Bragg, R. A.; Clayden,
J.; Morris, G. A.; Pink, J. H. Chem.—Eur. J. 2002, 8, 1279–1289. (c)
Clayden, J.; Stimson, C. C.; Keenan, M. Synlett 2005, 1716–1720.
(8) Seebach, D.; Fadel, A. HelV. Chim. Acta 1985, 68, 1243–1250.
(9) Branca, M.; Alezra, V.; Kouklovsky, C.; Archirel, P. Tetrahedron 2008,
64, 1743–1752.
(10) Unpublished results. Recent results indicate that the same major conformer
is obtained with an alanine derived oxazolidinone.
R-methyl valine 3a or R-isopropyl aspartic acid 3f (Scheme 3).
The S-configuration was confirmed by comparison with optical
rotation of known compounds.11,12
In order to confirm memory of chirality by dynamic axial
chirality, we performed an alkylation reaction on compound 4,
(11) Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A.; Lapena, Y. Tetra-
hedron 1995, 51, 5921–5928.
(12) Fadel, A.; Salau¨n, J. Tetrahedron Lett. 1987, 28, 2243–2246.
JA801165Z
9
J. AM. CHEM. SOC. VOL. 130, NO. 18, 2008 5865