Highly enantioselective synthesis of (S)-α-alkyl-α,β- diaminopropionic acids via asymmetric phase-transfer catalytic alkylation of 2-phenyl-2-imidazoline-4-carboxylic acid tert-butyl esters

Article abstract of DOI:10.1021/ol9013552

Image Presented An efficient enantioselective synthetic method for (S)-α-alkyl-α,β-diaminopropionic acid is reported. The asymmetric phase-transfer catalytic alkylation of N(1)-Boc-2-phenyl-2- imidazoline-4-carboxylic acid tert -butyl ester in the presenc

Full text of DOI:10.1021/ol9013552

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3738-3741
Highly Enantioselective Synthesis of
(S)-r-Alkyl-r,ꢀ-diaminopropionic Acids
via Asymmetric Phase-Transfer Catalytic
Alkylation of 2-Phenyl-2-imidazoline-4-
carboxylic Acid tert-Butyl Esters
Yohan Park,† Sukhoon Kang,† Young Ju Lee,† Taek-Soo Kim,†
Byeong-Seon Jeong,‡ Hyeung-geun Park,*,† and Sang-sup Jew*,†
Research Institute of Pharmaceutical Sciences and College of Pharmacy,
Seoul National UniVersity, Seoul 151-742, Korea, and College of Pharmacy,
Yeungnam UniVersity, Gyeongsan 712-749, Korea
hgpk@snu.ac.kr
Received June 16, 2009
ABSTRACT
An efficient enantioselective synthetic method for (S)-r-alkyl-r,ꢀ-diaminopropionic acid is reported. The asymmetric phase-transfer catalytic
alkylation of N(1)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid tert -butyl ester in the presence of chiral quaternary ammonium catalyst gave
the corresponding alkylated products (93-98% ee) which could be transformed to enantioenriched r-alkyl-r,ꢀ-diaminopropionic acids.
R,ꢀ-Diamino acids 1 have been regarded as attractive
synthetic targets in view of their various biological activities.
As nonnatural amino acids, they not only resist proteolysis,
but also form stabilized and specific conformations of the
peptides containing them.1,2 Chiral R,ꢀ-diaminocarbonyl
moieties can be found in several, naturally occurring cyclo-
peptidic antibiotics, such as bleomycin, capreomycin, vio-
mycin, and tuberactiomycin. Also, several imidazoline
compounds derived from chiral R-alkyl-R,ꢀ-diamino acids
have exhibited antitumor activity.3 Furthermore, optically
active R-alkyl-R,ꢀ-diamino acids can be easily cyclized to
ꢀ-lactams, which give rise to new, valuable ꢀ-lactam
antibiotics.4
A number of enantioselective synthetic methods for
R-alkyl-R,ꢀ-diaminopropionic acids have been reported thus
far,5 with most based on the diastereoselective R-alkylation
of chiral glycine equivalents,5b on the R-amination of chiral
R-cyanoesters,5c,d and on the chiral asparagines.5d Since most
of the reported methods employ chiral substrates or chiral
† Seoul National University.
‡ Yeungnam University.
(1) For a comprehensive review on synthetic approach and biological
significance of R,ꢀ-diamino acids, see: Viso, A.; Ferna´ndez de la Pradilla,
R.; Garcia, A.; Flores, A. Chem. ReV. 2005, 105, 3167
.
(3) (a) Sharma, V.; Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2006,
128, 9137. (b) Bon, R. S.; Sprenkels, N. E.; Koningstein, M. M.; Schmitz,
R. F.; de Kanter, F. J. J.; Do¨mling, A.; Groen, M. B.; Orru, R. V. A. Org.
Biomol. Chem. 2008, 6, 130.
(2) For recent papers on the catalytic asymmetric methods for the
nonproteinogenic R,ꢀ-amino acid derivatives, see: (a) Kuwano, R.; Okuda,
S.; Ito, Y. Tetrahedron: Asymmetry 1998, 9, 2773. (b) Robinson, A. J.;
Stanislawski, P.; Mulholland, D. J. Org. Chem. 2001, 66, 4148. (c) Nieger,
M. Chem. Commun. 2005, 2729. (d) Almodovar, I.; Ho¨velmann, C. H.;
Streuff, J.; Nieger, M.; K. Mun`iz, K. Eur. J. Org. Chem. 2006, 704. (e)
Guerrini, A.; Varchi, G.; Samor`ı, C.; Battaglia, A. Eur. J. Org. Chem. 2008,
(4) (a) Du¨rckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H.
Angew. Chem., Int. Ed. 1985, 24, 180. (b) van der Steen, F. H.; van Koten,
G. Tetrahedron 1991, 47, 7503. (c) Loewe, M. F.; Cvetovich, R. J.; Hazen,
G. G. Tetrahedron Lett. 1991, 32, 2299. (d) Murayama, T.; Kobayashi, T.;
Miura, T. Tetrahedron Lett. 1995, 36, 3703.
3834. (f) Arraya´s, R. G.; Carretero, J. C. Chem. Soc. ReV. 2009, 38, 1940
.
10.1021/ol9013552 CCC: $40.75
Published on Web 07/27/2009
 2009 American Chemical Society

auxiliaries, their applications in industry for large scale
production might prove difficult. In this letter, we report a
new efficient synthesis of (S)-R-alkyl-R,ꢀ-diaminopropionic
acids via asymmetric phase-transfer catalytic R-alkylation
of imidazoline-4-carboxylates which could be applied to
industrial process.6,7
protect the N(1)-H of the imidazoline. Five kinds of N(1)-
acyl protections with acid chlorides or acid anhydrides in
the presence of triethylamine gave N(1)-acylimidazolines
7a-e, which were then converted to the corresponding
tert-butyl esters 8a-e by transesterification using AlMe3
and tert-butanol in toluene8b (Scheme 2).
Very recently, we reported a series of new synthetic
methods for optically active R-alkylserines and R-alkylcys-
teines by the catalytic enantioselective R-alkylation of tert-
butyl 2-phenyloxazoline-4-carboxylate and tert-butyl 2-phe-
nylthiazoline-4-carboxylate under phase-transfer conditions,
respectively.8 These works demonstrated that the phase-
transfer catalytic conditions are very efficient for the R-alky-
lation of the oxazoline-4-carboxylate and the thiazoline-4-
carboxylate systems. On the basis of our previous results,
we attempted to apply the phase-transfer catalytic alkylation
of imidazoline-4-carboxylate system 3 for the enantioselec-
tive synthesis of chiral R-alkyl-R,ꢀ-diaminopropionic acids
1 (Scheme 1).
Scheme 2. Preparation of 2-Phenyl-2-imidazoline-4-carboxylates
Scheme 1. Synthetic Strategy for Optically Active
R-Alkyl-R,ꢀ-diaminopropionic Acids via Asymmetric
Phase-Transfer Catalysis
For asymmetric phase-transfer catalytic alkylation, we
adapted our previous reaction conditions.8 phase-transfer
catalytic benzylations of 8a-8e were performed using 5.0
mol % of the representative phase-transfer catalysts (PTCs)9
(10,9a 11,9b 129c) along with benzyl bromide (5.0 equiv) and
solid KOH (5.0 equiv) in toluene at 0 °C for 1.5-16 h.
First, the substrate, N(1)-protected-2-phenyl-2-imida-
zoline-4-carboxylic acid tert-butyl ester 3, was prepared
from commercially available R,ꢀ-diaminopropionic acid
(4) in four steps. The methyl esterification of 4 using
thionyl chloride in methanol, followed by coupling with
ethyl benzimidate, afforded methyl 2-phenyl-2-imidazo-
line-4-carboxylate (6). Before the transesterification of 6
to the corresponding tert-butyl ester, it was necessary to
(5) (a) Colson, P. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918. (b)
Jolles, R. C. F.; Crockett, A. K.; Rees, D. C.; Gilbert, I. H. Tetrahedron:
Asymmetry 1994, 5, 1661. (c) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez,
J. A. Tetrahedron: Asymmetry 1994, 5, 1465. (d) Badorrey, R.; Cativiela,
C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A. Tetrahedron: Asymmetry 1995,
6, 2787. (e) Castellanos, E.; Reyes-Rangel, G.; Juaristi, E. HelV. Chim. Acta
As shown in Table 1, the binaphthalene-derived PTC 12
(entry 3, 98% ee) showed the best enantioselectivity, while
the cinchona PTCs 10 (entry 1, 72% ee) and 11 (entry 2,
75% ee) afforded low and moderate enantioselectivity,
respectively. The chemical yields and enantioselectivities
were variable depending on the N(1)-protective group of the
imidazoline substrates. In terms of enantioselectivity, the tert-
butyl-possessing acyl groups (8e, 8c, 8d) gave very high
enantioselectivities (entry 3, 98% ee; entry 6, 98% ee; entry
7, 95% ee). The bulky tert-butyl groups might play an
2004, 87, 1016
.
(6) For recent reviews on the phase-transfer catalysis, see: (a) Maruoka,
K.; Ooi, T. Chem. ReV. 2003, 103, 3013. (b) O’Donnell, M. J. Acc. Chem.
Res. 2004, 37, 506. (c) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37,
518. (d) Hashimoto, T.; Maruoka, K. Chem. ReV. 2007, 107, 5656
.
(7) For our recent reports on the asymmetric phase-transfer catalytic
alkylation, see: (a) Jew, S.-s.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park,
H.-g. Chem. Commun. 2001, 1244. (b) Park, H.-g.; Jeong, B.-S.; Yoo, M.-
S.; Park, M.-k.; Huh, H.; Jew, S.-s. Tetrahedron Lett. 2001, 42, 4645. (c)
Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-k.; Lee, Y.-J.;
Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036. (d) Jew,
S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park, H.-g. Org. Lett. 2002, 4,
4245. (e) Yoo, M.-S.; Jeong, B.-S.; Lee, J.-H.; Park, H.-g.; Jew, S.-s. Org.
Lett. 2005, 7, 1129
.
(8) (a) Jew, S.-s.; Lee, Y.-J.; Lee, J.; Kang, M. J.; Jeong, B.-S.; Lee,
J.-H.; Yoo, M.-S.; Kim, M.-J.; Choi, S.-h.; Ku, J.-M.; Park, H.-g. Angew.
Chem., Int. Ed. 2004, 43, 2382. (b) Kim, T.-S.; Lee, Y.-J.; Jeong, B.-S.;
Park, H.-g.; Jew, S.-s. J. Org. Chem. 2006, 71, 8276. (c) Kim, T.-S.; Lee,
Y.-J.; Lee, K.; Jeong, B.-S.; Park, H.-g.; Jew, S.-s. Synlett 2009, 671.
(9) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414. (b) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, H.-g. Org. Lett. 2002,
4, 4245. (c) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 5139.
Org. Lett., Vol. 11, No. 16, 2009
3739

Table 1. Screening of Substrate and PTC
Table 3. Enantioselective Phase-Transfer Alkylation of 8e with
Various Alkyl Halides in the Presence of 12
entry
8
PTC
time (h)
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8e
8e
8e
8a
8b
8c
8d
10
11
12
12
12
12
12
4
4.5
16
1.5
2
49
43
95
70
92
77
79
72
75
98
93
89
98
95
6
5
a Isolated yields. b Enantiomeric excess was determined by HPLC
analysis of 9C using a chiral column (Chiralcel AD or OD) with hexanes/
2-propanol as the eluent.
integral role in the high enantioselectivities. Regarding
chemical yields, aliphatic acyl groups (entries 4, 6, and 7)
showed relatively lower chemical yields compared to those
of the benzoyl and Boc groups (entries 3 and 5). The Boc
group afforded the best results in both chemical yield and
enantioselectivity. Reaction conditions were optimized with
the best substrate (8e), by varying base and reaction
temperature (Table 2). Generally, high enantioselectivities
a Isolated yields. b Enantiomeric excess was determined by HPLC
analysis of 9e using a chiral column (Chiralcel AD or OD) with hexanes/
2-propanol as eluents. c Absolute configuration was assigned by the
comparison of the specific optical rotation value of the R-benzyl-R,ꢀ-
diaminopropionic acid prepared by hydrolysis of 9eC with the literature
value;5d other absolute configurations were tentatively assigned as S based
on the absolute configuration of 9eC.
lective phase-transfer catalytic alkylation with various alkyl
halides under optimal reaction conditions (entry 2 in Table
2). As shown in Table 3, very high chemical yields
(87-99%) and enantioselectivities (93-98% ee) were ob-
served for allylic, propargylic, and benzylic halides.10
Hydrolysis of 9eC (98% ee) with 6.0 M HCl was
performed in order to generate R-benzyl-R,ꢀ-diaminopropi-
onic acid (1C), interestingly, however, only the tert-butyl
group was removed (Scheme 3). Previous results on the
Table 2. Optimization of Reaction Conditions
entry
base
KOH
temp (°C) time (h) yield (%)a ee (%)b config.
1
2
3
rt
0
3.5
16
83
95
91
46
79
88
95 (S)d
98 (S)
96 (S)
79 (S)
98 (S)
97 (S)
KOH
KOH
-20
0
0
24
24
24
4
4c KOH
5
6
Scheme 3. Effect of N(1)-Substituent on the Acidic Hydrolysis
of the tert-Butyl 2-Phenyl-2-imidazoline Carboxylates in 9eC
and 9aC
50% KOH
CsOH
0
a Isolated yields. b Enantiomeric excess was determined by HPLC
analysis of 9eC using a chiral column (Chiralcel OD) with hexanes/2-
propanol as the eluent. c 2.5 mol % of PTC 12 was used. d Absolute
configuration was assigned by comparison of the specific optical rotation
value of the R-benzyl-R,ꢀ-diaminopropionic acid (1C) prepared by hy-
drolysis of 9eC with the literature value.5d
were observed regardless of the base conditions, but solid
KOH gave the highest chemical yield (entry 2, 95%; entry
5, 79%; entry 6, 88%). Reaction temperature seemed
insensitive to enantioselectivity, but the best chemical yield
was observed at 0 °C (entry 2, 95%). Notably, use of less
catalyst 12 decreased both chemical yield and enantioselec-
tivity (entry 4, 46%, 79% ee). Substrate 8e was chosen for
further investigation for scope and limitation in enantiose-
hydrolysis of the imidazoline group of iso-amarine revealed
that N(1)-acetylation should precede before the hydrolysis
3740
Org. Lett., Vol. 11, No. 16, 2009

of the imidazoline moiety because the protonated form 13
in acidic media is quite resistant to hydrolysis.11 Indeed, the
hydrolysis of 9aC (93% ee) under 6.0 M HCl in ethanol
readily provided 1C, which was in accord with previous
results (Scheme 4).
diaminopropionic acid with very high enantioselectivities as
well as high chemical yields.
In conclusion, an efficient synthetic methodology for
optically active R-alkyl-R,ꢀ-diaminopropionic acid, by the
asymmetric phase-transfer catalytic alkylation of N(1)-Boc-
2-phenyl-2-imidazoline-4-carboxylic acid tert-butyl ester (8e)
was developed. The facile preparation of the substrate, high
enantioselectivity, and mild asymmetric alkylation conditions
make this method a practical route for the preparation of
versatile synthetic intermediates, (S)-R-alkyl-R,ꢀ-diamino-
propionic acids, which can be applied to the synthesis of
biologically active ꢀ-lactams, peptidomimetics, and imida-
zoline natural products.
Scheme 4. Preparation of R-Benzyl-R,ꢀ-diaminopropionic Acid
Acknowledgment. This work was supported by the SRC/
ERC program of MOST/KOSEF (R11-2007-107-02001-0).
Supporting Information Available: Representative ex-
perimental procedures, as well as spectroscopic characteriza-
tions of all new compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
Finally, liberation of R-benzyl-R,ꢀ-diaminopropionic acids
(1C) from 9eC was accomplished by a two-step sequence;
(1) Removal of both N(1)-Boc and tert-butyl ester in 9eC in
refluxing EtOH-H2O (volume ratio ) 1:1) affording 14
quantitatively.11d (2) N(1)-Acetylation of 14 with acetic
anhydride followed by hydrolysis with 6.0 M HCl11e
providing (S)-1C in 54% yield {[R]D25 ) 12.06 (c 1.0, H2O);
[R]D25 ) 9.2 (c 0.8, H2O)5e}. To the best of our knowledge,
this is the first catalytic synthetic method for R-alkyl-R,ꢀ-
OL9013552
(10) In the cases of less reactive, aliphatic alkyl halides, the reaction
rates remarkably slowed down, so that the desired products were obtained
in less than 5% chemical yields even after 48 h stirring.
(11) (a) Williams, O. F.; Bailar, J. C., Jr. J. Am. Chem. Soc. 1959, 81,
4464. (b) Saigo, K.; Kubota, N.; Takebayashi, S.; Hasegawa, M. Bull. Chem.
Soc. Jpn. 1986, 59, 931. (c) Corey, E. J.; Ku¨hnle, F. N. M. Tetrahedron
Lett. 1997, 38, 8631. (d) Mitchell, J. M.; Finney, N. S. Tetrahedron Lett.
2000, 41, 8431. (e) Braddock, D. C.; Hermitage, S. A.; Redmond, J. M.;
White, A. J. P. Tetrahedron: Asymmetry 2006, 17, 2935.
Org. Lett., Vol. 11, No. 16, 2009
3741