Highly enantioselective synthesis of α-alkyl-alanines via the catalytic phase-transfer alkylation of 2-naphthyl aldimine tert-butyl ester by using O(9)-allyl-N(1)-2′,3′,4′-trifluorobenzylhydrocinchonidinium bromide

Article abstract of DOI:10.1021/jo034006t

Systematic investigations to develop an efficient enantioselective synthetic method for α-alkyl-alanine by catalytic phase-transfer alkylation were performed. The alkylation of 2-naphthyl aldimine tert-butyl ester, 1E, with RbOH and O(9)-allyl-N-2′,3′,4′t

Full text of DOI:10.1021/jo034006t

to be powerful enzymatic inhibitors (such as R-methyl-
dopa, R-methyltryptophan, and R-methylaspartic acid)3
and useful synthetic building blocks1 via chemical trans-
formations. Accordingly, the development of effective
synthetic methods for chiral RRAAs is a very important
and challenging subject in organic synthesis. Historically,
a number of the enantioselective synthetic methods have
been described for chiral RRAAs,4 but only a few are
practical.5
High ly En a n tioselective Syn th esis of
r-Alk yl-a la n in es via th e Ca ta lytic
P h a se-Tr a n sfer Alk yla tion of 2-Na p h th yl
Ald im in e ter t-Bu tyl Ester by Usin g
O(9)-Allyl-N(1)-2′,3′,4′-tr iflu or oben zylh yd r o-
cin ch on id in iu m Br om id e
Sang-sup J ew,* Byeong-Seon J eong, J eong-Hee Lee,
Mi-Sook Yoo, Yeon-J u Lee, Boon-saeng Park,
Myoung Goo Kim, and Hyeung-geun Park*
On the basis of the pioneering application of the
Cinchona-derived phase-transfer catalyst6 to the enan-
tioselective synthesis of R-amino acids, the O’Donnell
group adapted 4 to develop a new synthetic method for
RRAAs via the enantioselective catalytic phase-transfer
alkylation of aldimines 1 in 1992.7 However, relatively
low enantioselectivities were observed (ca. 30-50% ee).
In 1999, the Lygo group improved the enantioselectivities
up to 87% ee by using the more efficient catalyst 5.8 More
recently, the Maruoka group developed an even better
non-Cinchona phase-transfer catalyst, derived from (S)-
binaphthol, which was successfully applied to the syn-
thesis of RRAAs.9 As a part of our program to develop
new chiral building blocks, we were interested in devel-
oping a practical enantioselective synthetic method for
the preparation of RRAAs. In this note, we describe the
efficient enantioselective synthetic method of the syn-
thesis of R-alkyl-alanine by using O(9)-allyl-N-2′,3′,4′-
trifluorobenzylhydrocinchonidinium bromide 6. Through
systematic investigations of the electronic effect in the
phase-transfer catalytic reaction, we recently reported
that the ortho-F on the phenyl ring in 4 plays an integral
role in enantioselectivity enhancement.10,11 In particu-
lar, O(9)-allyl-N-2′,3′,4′-trifluorobenzylhydrocinchoni-
dinium bromide 6 was successfully applied for the
synthesis of an R-amino acid and showed the highest
Research Institute of Pharmaceutical Science and College of
Pharmacy, Seoul National University, Seoul 151-742, Korea
ssjew@plaza.snu.ac.kr
Received J anuary 3, 2003
Abstr a ct: Systematic investigations to develop an efficient
enantioselective synthetic method for R-alkyl-alanine by
catalytic phase-transfer alkylation were performed. The
alkylation of 2-naphthyl aldimine tert-butyl ester, 1E, with
RbOH and O(9)-allyl-N-2′,3′,4′-trifluorobenzylhydrocinchoni-
dinium bromide, 6, at -35 °C showed the highest enanti-
oselectivities, up to 96% ee.
Chiral R,R-dialkyl-R-amino acids (RRAAs), a class of
noncoded amino acids, have been extensively studied due
to their important role in the fields of synthetic and
biological chemistry.1 Their quaternary chiral centers
contribute not only to the molecular stability but also to
the conformational preference, by inducing a preferable
helical secondary structure of the peptide backbone, when
incorporated into a peptide.2 Moreover, the biological
activities of peptides containing RRAAs can be main-
tained longer because of their resistance against enzy-
matic hydrolysis. Also, the RRAAs themselves are known
(3) (a) Sourkers, T. L. Arch. Biochem. Biophys. 1945, 51, 444. (b)
Shirlin, D.; Gerhart, F.; Hornsperger, J . M.; Harmon, M.; Wagner, I.;
J ung, M. J . Med. Chem. 1988, 31, 30. (c) Kiick, D. M.; Cook, P. F.
Biochemistry 1983, 22, 375.
* Phone: 82-2-880-7872. Fax: 82-2-872-9129.
(1) (a) Bellier, B.; McCort-Tranchenpain, I.; Ducos, B.; Danasci-
mento, S.; Meudal, H.; Noble, F.; Garbay, C.; Roques, B. P. J . Med.
Chem. 1997, 40, 3947. (b) Mossel, E.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Broxterman, Q. B.; Boesten, W. H. J .; Kamphius, J .;
Quaedflieg, P. J . L. M.; Temussi, P. Tetrahedron: Asymmetry 1997, 8,
1305. (c) Dery, O.; J oisen, H.; Grassi, J .; Chassaing, G.; Couraud, J .
Y.; Lavielle, S. Biopolymers 1996, 39, 67. (d) Benedetti, E.; Gavuzzo,
E.; Santini, A.; Kent, D. R.; Zhu, Y.-F.; Zhu, Q.; Mahr, C.; Goodman,
M. J . Pept. Sci. 1995, 1, 349. (e) Toniolo, C.; Formaggio, F.; Crisma,
M.; Valle, G.; Boesten, W. H. J .; Schoemaker, H. E.; Kamphuis, J .;
Temussi, P. A.; Becker, E. L.; Pre´cigoux, G. Tetrahedron 1993, 49, 3641.
(f) Schiller, P. W.; Weltrowska, G.; Nguyen, T. M.-D.; Lemieux, C.;
Chung, N. N.; Marsden, B. J .; Wilkes, B. C. J . Med. Chem. 1991, 34,
3125.
(2) (a) Wipf, P.; Heimgartner, H. Helv. Chim. Acta 1988, 71, 258.
(b) Hodgkin, E. E.; Clark, J . D.; Miller, K. R.; Marshall, G. R.
Biopolymers 1990, 30, 533. (c) Di Blasio, B.; Pavone, V.; Lombardi, A.;
Pedone, C.; Benedetti, E. Biopolymers 1993, 33, 1037. (d) Toniolo, C.;
Crisma, M.; Formaggio, F.; Valle, G.; Cavicchioni, G.; Pre´cigoux, G.;
Aubry, A.; Kamphius, J . Biopolymers 1993, 33, 1061. (e) Toniolo, C.
J anssen Chim. Acta 1993, 11, 10. (f) Karle, I. L.; Rao, R. B.; Prasad,
S.; Kaul, R.; Balaram, P. J . Am. Chem. Soc. 1994, 116, 10355. (g)
Formaggio, F.; Pantano, M.; Crisma, M.; Bonora, G. M.; Toniolo, C.;
Kamphius, J . J . Chem. Soc., Perkin Trans. 2 1995, 1097. (h) Benedetti,
E. Biopolymers 1996, 40, 3. (i) Karle, I. L.; Kaul, R.; Rao, R. B.;
Raghothama, S.; Balaram, P. J . Am. Chem. Soc. 1997, 119, 12048.
(4) For recent reviews, see: (a) Cativiela, C.; Diazde-Villegas, M.
D. Tetrahedron: Asymmetry 1998, 9, 3517. (b) Wirth, T. Angew. Chem.,
Int. Ed. 1997, 36, 225. (c) Seebach, D.; Sting, A. R.; Hoffmann, M.
Angew. Chem., Int. Ed. 1996, 35, 2708. (d) Duthaler, R. O. Tetrahedron
1994, 50, 1539.
(5) (a) Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.;
Hayashi, T. Tetrahedron 1988, 44, 5253. (b) Ito, Y.; Sawamura, M.;
Matsuoka, M.; Matsumoto, Y.; Hayashi, T. Tetrahedron Lett. 1987, 28,
4849. (c) Belokon, Y. N.; North, M.; Kublitski, V. S.; Ikonnikov, N. S.;
Krasik, P. E.; Maleev, V. I. Tetrahedron Lett. 1999, 40, 6105. (d)
Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
Chesnokov, A. A.; Larionov, O. V.; Parmar, V. S.; Kumar, R.; Kagan,
H. B. Tetrahedron: Asymmetry 1998, 9, 851.
(6) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J . J . J . Am. Chem.
Soc. 1984, 106, 446. (b) O’Donnell, M. J .; Bennett, W. D.; Wu, S. J .
Am. Chem. Soc. 1989, 111, 2353. (c) Lygo, B.; Wainwright, P. G.
Tetrahedron Lett. 1997, 38, 8595. (d) Corey, E. J .; Xu, F.; Noe, M. C.
J . Am. Chem. Soc. 1997, 119, 12414. (e) Ooi, T.; Kaneda, M.; Maruoka,
K. J . Am. Chem. Soc. 1999, 121, 6519.
(7) O’Donnell, M. J .; Wu, S. Tetrahedron: Asymmetry 1992, 3, 591.
(8) Lygo, B.; Crosby, J .; Perterson, J . A. Tetrahedron Lett. 1999, 40,
8671.
(9) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J . Am. Chem.
Soc. 2000, 122, 5228.
(10) J ew, S.-s.; Yoo, M.-S.; J eong, B.-S.; Park, H.-g. Org. Lett. 2002,
4, 4245.
10.1021/jo034006t CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/02/2003
4514
J . Org. Chem. 2003, 68, 4514-4516

TABLE 1. En a n tioselective Ca ta lytic P h a se-Tr a n sfer
Ben zyla tion of th e Va r iou s Ald im in es (1A-F ) Usin g
Ca ta lyst 6a
SCHEME 1
time
(h)b
yield
(%)c
entry
aldimine 1
% eed (configuration)e
1
2
3
4
5
6
1A
1B
1C
1D
1E
1F
12
8
10
16
2
76
84
72
69
93
80
76 (S)
77 (S)
61 (S)
75 (S)
88 (S)
82 (S)
enantioselectivity for this reaction (from 94 to >99% ee).10
We planned to use 6 in the enantioselective phase-
transfer alkylation of aldimine for the synthesis of
R-alkyl-alanines.
10
a
Reaction was carried out with 5.0 equiv of benzyl bromide and
5.0 equiv of KOH in the presence of 10 mol % 6 in toluene under
the given conditions. Reaction conditions for the deprotection of 2
and the N-benzoylation of 3c are described in the Experimental
Although the optimization studies for the reaction were
already performed by the O’Donnell group (reaction
conditions: the mixed base, KOH + K2CO3; 4-chlorophe-
nyl aldimine 1B; room temperature), we needed to
reinvestigate the reaction conditions and the imine-
protecting groups of the aldimine for the best enantiose-
lectivity for the following three reasons. (1) The optimal
reaction condition could be different depending upon the
structure of phase-transfer catalyst. (2) There might be
some electronic effect depending upon the substituted
position of the chloride in the aromatic ring of the imine.
(3) There was no investigation of the optimal reaction
temperature. Six aldimines (1A-F ) were prepared from
L-alanine tert-butyl ester and the corresponding aromatic
aldehydes. The enantioselective benzylation reactions
with the prepared aldimines were performed by using
10 mol % catalyst 6, along with the aldimines, benzyl
bromide, and KOH in toluene at 0 °C for 2-16 h (Scheme
1). The enantioselectivities of 2 were determined by a
chiral HPLC analysis of the corresponding N-benzoyl
derivatives of 3, which were obtained by hydrolysis of 2
under acidic conditions.
As shown in Table 1, there was no considerable
electronic effect depending on the substituted position of
the chloride, but the dichloro group decreased the enan-
tioselectivity (1A, 76% ee; 1B, 77% ee; 1C, 61% ee). In
the case of the bulky aromatic substituents, the enanti-
oselectivity of the 2-naphthyl derivative (1E, 88% ee) was
higher than that of the 1-naphthyl derivative (1D, 75%
ee), which is consistent with the previous results.7
However, the bulkier 9-anthracenyl group (1F , 82% ee)
did not positively influence the enantioselectivity. The
4-chlorophenyl-derived aldimine 1B, which was mainly
used in the previous studies of this type of reaction, gave
lower enantioselectivity than 1E under our reaction
conditions.7-9 Compound 1E was chosen as a substrate
for alkylation, from the viewpoint of enantioselectivity
as well as chemical yield and reaction time. Further
investigations to optimize the reaction conditions are
summarized in Table 2.
b
Section. Reaction time for consumption of the aldimine 1 to
transform the benzylated aldimine 2. c Isolated yield of purified
d
3c for two steps from 1. Enantiopurity was determined by the
HPLC analysis of the N-benzoyl derivative of 3c, using a chiral
column (Chiral Technologies Inc., Chiralcel OD). e Absolute con-
figuration was assigned by the relative retention times of both
enantiomers determined previously.8,9
TABLE 2. En a n tioselective Ca ta lytic P h a se-Tr a n sfer
Ben zyla tion of 1Ea
temp time yield
(°C)
entry catalyst base
(h)
(%) % ee (configuration)
1
2
3
4
5
6
7
8
9
4
5
6
6
6
6
6
6
6
6
6
KOH
KOH
KOH
KOH
KOH
KOH
-15 10
91
94
96
93
91
61
93
96
93
91
67
75 (S)
83 (S)
84 (S)
88 (S)
90 (S)
64 (S)
92 (S)
87 (S)
93 (S)
95 (S)
89 (S)
-15
20
0
9
0.5
2
-15 10
-25 24
RbOH -15
CsOH -15
RbOH -25
4
2
6
10
11
RbOH -35 10
RbOH -45 40
a
Reaction conditions were the same as those for Table 1, except
for the catalyst, base, and temperature.
optimal. The efficiency of the catalysts for the alkylation
was then examined. Among the catalysts, the enantiose-
lectivity of N-trifluorobenzyl catalyst 6 (90% ee) was
higher than those observed with the N-benzyl catalyst 4
(75% ee, entry 1) and the N-anthracenyl catalyst 5 (83%
ee, entry 2) at -15 °C. To overcome the limitation of
temperature when using KOH as a base, stronger bases
were employed at temperatures below -15 °C. RbOH
(92% ee, entry 7) provided higher enantioselectivity than
those obtained with KOH (90% ee, entry 5) and CsOH
(87% ee, entry 8) at -15 °C. By varying the reaction
temperature, we finally obtained the best enantioselec-
tivity (95% ee, entry 10) with the following reaction
conditions: aldimine 1E, catalyst 6, RbOH, -35 °C.
Table 3 summarizes the results obtained for the
alkylation of 1E with various alkyl halides under the
optimal conditions. The high enantioselectivities (up to
96% ee) with satisfactory chemical yields indicate that
When KOH was employed as a base, lower tempera-
tures improved the enantioselectivity, -15 °C being the
(11) For our recent studies on chiral phase-transfer catalysts, see:
(a) J ew, S.-s.; J eong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-g. Chem.
Commun. 2001, 1244. (b) Park, H.-g.; J eong, B.-S.; Yoo, M.-S.; Park,
M.-k.; Huh, H.; J ew, S.-s. Tetrahedron Lett. 2001, 42, 4645. (c) Park,
H.-g.; J eong, B.-S.; Yoo, M.-S.; Lee, J .-H.; Park, M.-k.; Lee, Y.-J .; Kim,
M.-J .; J ew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036.
J . Org. Chem, Vol. 68, No. 11, 2003 4515

TABLE 3. En a n tioselective Ca ta lytic P h a se-Tr a n sfer Alk yla tion of 1E w ith Va r iou s Alk yl Ha lid es in th e P r esen ce of
Ca ta lyst 6a
alkyl halides
(RX)
time
(h)b
yield
(%)c
entry
% eed (configuration)
a
b
c
d
e
f
g
h
i
allyl bromide
propargyl bromide
benzyl bromide
20
12
10
24
40
24
12
10
8
87
89
91
89
86
90
91
92
93
87
89
85 (S)
84 (S)
95 (S)
90 (S)
90 (S)
88 (S)
90 (S)
96 (S)
95 (S)
92 (S)
86 (S)
4-bromobenzyl bromide
4-tert-butylbenzyl bromide
4-trifluoromethylbenzyl bromide
2-fluorobenzyl bromide
2,6-difluorobenzyl bromide
2,4-dichlorobenzyl bromide
3-methylbenzyl bromide
1-chloromethylnaphthalene
j
k
40
24
a
Reaction was carried out with 5.0 equiv of alkyl halide and 5.0 equiv of RbOH in the presence of 10 mol % 6 in toluene at -35 °C. The
b
reaction conditions for the deprotection of 2 and the N-benzoylation of 3 are described in the Experimental Section. Reaction time for
consumption of the aldimine 1E to transform the alkylated aldimine 2E. c Isolated yield of 3 for two steps from 1E. Enantiopurity was
d
determined by HPLC analysis of the N-benzoyl derivatives of 3, using a chiral column [Chiral Technologies Inc., Chiralcel OD (for 3a -
d ,f,g,i-k ) and Chiralpak AD (for 3e and 3h )]; in each case, it was established by analysis of the racemate that the enantiomers were
fully resolved.
these optimal phase-transfer reaction conditions and
catalyst 6 are very effective for the preparation of chiral
R-alkyl-alanine derivatives. In conclusion, we investi-
gated the optimal reaction conditions of the enantiose-
lective catalytic phase-transfer alkylation for R-alkyl-
alanines. The alkylation of 2-naphthyl aldimine tert-butyl
ester 1E with RbOH and O(9)-allyl-N-2′,3′,4′-trifluo-
robenzylhydrocinchonidinium bromide 6 at -35 °C showed
high enantioselectivities, up to 96% ee.
Exp er im en ta l Section
F IGURE 1. Cinchona-derived phase-transfer catalysts.
Rep r esen ta tive P r oced u r e of Ca ta lytic En a n tioselec-
tive Alk yla tion of 1E Usin g Ca ta lyst 6 Un d er P h a se-
Tr a n sfer Con d ition s (Ben zyla tion ). To a cooled (-35 °C)
mixture of aldimine 1E (70 mg, 0.25 mmol), catalyst 6 (14 mg,
0.025 mmol), and rubidium hydroxide (127 mg, 1.24 mmol) in
toluene (1.0 mL) was added benzyl bromide (0.15 mL, 1.24
mmol). The reaction mixture was stirred vigorously at -35 °C
until the starting material (1E) had been consumed (10 h). Then,
mL), and the extracts were washed with water. The dichl-
romethane solution was then dried (MgSO4) and concentrated
under reduced pressure. Purification of the residue by flash
column chromatography on silica gel (hexanes/EtOAc ) 30:1)
afforded the desired N-benzoyl derivative of 3c (55 mg, 95%
yield) as a white solid. The enantioselectivity was determined
by chiral HPLC analysis of N-benzoyl derivative of 3c (Chiral
Technologies, Inc., Chiralcel OD, hexanes/2-propanol ) 500:7.0,
water (5 mL) was added and the extraction was performed with
flow rate ) 0.7 mL/min, 23 °C, λ ) 254 nm; retention times R
dichloromethane (2 × 10 mL). The solvent was removed under
(minor) 15.9 min, S (major) 20.0 min, 95% ee). The absolute
reduced pressure, and the residue was dissolved in tetrahydro-
configuration was determined by comparison of the HPLC
furan (1.5 mL). Aqueous hydrochloric acid (1 N, 1.5 mL) was
retention time with that of the authentic sample synthesized
added, and the mixture was stirred at room temperature for 1
by the reported method.8,9
h. The resulting mixture was washed with hexanes (2 × 5 mL),
and then the aqueous phase was basified with solid sodium
Ack n ow led gm en t. This work was supported by a
bicarbonate and extracted with dichloromethane (3 × 10 mL).
grant (R01-2002-000-0005-0) from the Basic Research
Program of the KOSEF (2002).
The dichloromethane extracts were dried (MgSO4) and concen-
trated under reduced pressure. Purification of the residue by
column chromatography on silica gel (hexanes/EtOAc ) 1:2) gave
amine 3c (54 mg, 91% yield) as a colorless oil. The amine 3c (40
mg, 0.17 mmol) was dissolved in dichloromethane (0.5 mL), and
then triethylamine (0.05 mL, 0.34 mmol) and benzoyl chloride
(0.03 mL, 0.25 mmol) were added successively. The reaction
mixture was stirred at room temperature for 30 min. The
resulting mixture was extracted with dichloromethane (3 × 5
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic char-
acterization of 1E, 6, and N-benzoyl derivatives of 3a -k and
HPLC conditions. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O034006T
4516 J . Org. Chem., Vol. 68, No. 11, 2003