Enantioselective synthesis of -benzylalanine using trans -3,4-Dihydro-3,4-diaryldibenzo[ c, g ]phenanthrene-3,4-diols

Article abstract of DOI:10.1055/s-0030-1258520

Asymmetric benzylation of a benzophenone Schiffs base of alanine ethyl ester was successfully conducted using trans-3,4-dihydro-3,4-diaryldibenzo[c,g] phenanthrene-3,4-diol as a chiral source.

Full text of DOI:10.1055/s-0030-1258520

LETTER
2097
Enantioselective Synthesis of a-Benzylalanine Using trans-3,4-Dihydro-3,4-
diaryldibenzo[c,g]phenanthrene-3,4-diols
E
nantioselective Synth
i
e
sis of
t
a
-Benz
s
ylalanineuru Kitamura,* Daisuke Kitahara, Tatsuo Okauchi
Department of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata-ku, Kitakyushu-shi, Fukuoka, 804-8550 Japan
Fax +81(93)8843304; E-mail: kita@che.kyutech.ac.jp
Received 27 May 2010
cyclization of 2,2¢-biaryldicarbonyl compounds.9 In this
Abstract: Asymmetric benzylation of a benzophenone Schiff’s
reaction, where the starting biphenyl is configurationally
stable, the axial chirality of the dicarbonyl compounds is
base of alanine ethyl ester was successfully conducted using trans-
3,4-dihydro-3,4-diaryldibenzo[c,g]phenanthrene-3,4-diol as
a
stereospecifically transmitted onto two stereogenic cen-
ters of the product. By this method, various enantiomeri-
cally pure 3,4-dihydrodibenzo[c,g]phenanthrene-3,4-
diols 2 were synthesized (Equation 1).
chiral source.
Key words: amino acids, asymmetric synthesis, biaryls, diols,
phase-transfer catalysis
a,a-Disubstituted amino acids have attracted considerable
attention because of their potential as enzyme inhibitors,
pharmaceuticals, and tools of biochemical research.1 Var-
ious stereocontrolled syntheses of optically active a,a-di-
substituted amino acids have been reported.2 Among
them, enantioselective alkylation of enolates of amino
acid using phase-transfer catalysts has been an area of fo-
cus in recent years. In 1989, O’Donnell reported the first
enantioselective synthesis of a-amino acid derivatives us-
ing phase-transfer catalyst3 and the same group reported
the synthesis of a,a-disubstituted a-amino acids in 19924
using cinchona-derived quaternary ammonium catalysts
and the Schiff’s base of alanine. In addition to cinchona-
derived ammonium catalysts,5 several artificial quaterna-
ry ammonium catalysts have been developed recently for
the synthesis of a,a-disubstituted amino acids.6
SmI2
R
R
O
or
OH
OH
R
TiCl4, Zn
R
O
>99% ee
2a R = H
(P)-1 >99% ee
2b R = Ph
2c R = 4-MeC6H4
2d R = 3-MeC6H4
2e R = 3,5-Me2C6H3
2f R = 3-MeOC6H4
2g R = 3-F3CC6H4
Equation 1
The X-ray crystal structure of 2 shows the two substitu-
ents R placed at axial positions suggesting that the com-
plex of 2 with an appropriate metal constitutes an
effective asymmetric environment. That is, imagine the
complex of trans-diol 2, metal M, and substrate A–B
where A is the reaction point and both A and B coordinate
to metal M as shown in Figure 2. Reactant Y approaches
from the top face of the complex because the bottom face
is shielded by substituent R.10
Chiral alkoxides derived from chiral diol or amino alcohol
have also been found to catalyze C-alkylation of Schiff’s
bases of alanine under phase-transfer conditions. For
the chiral diol/amino alcohol, enantiomerically pure
TADDOL, NOBIN,7 and BINOLAM8 are used
(Figure 1).
NEt2
Ph
Ph
O
O
NH2
OH
OH
OH
OH
OH
R
Ph
Ph
NEt2
Y
OH
OH
M
(R,R)-TADDOL
(R)-NOBIN
(S)-BINOLAM
A
B
R
Figure 1
Y
We previously reported the synthesis of new optically ac-
tive C2-symmetric trans-diols by intramolecular pinacol
Figure 2
Based on the hypothesis, we examined the several reac-
tions and found that the trans-diol 2 could be used as a
chiral source in the enantioselective C-alkylation reaction
of the Schiff’s base of alanine ester for the synthesis of
SYNLETT 2010, No. 14, pp 2097–2100
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1258520; Art ID: U04710ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

2098
M. Kitamura et al.
LETTER
a-benzyl-a-methyl a-amino acids. In this communication, ester 3a. When simple diol 2a was used as a chiral source,
we describe the outcome of the investigation.
the starting Schiff’s base 3a was consumed within 15 min-
utes and the desired alkylated product 4a was obtained in
81% yield with an enantiomeric excess of 3% (entry 1).
When diol 2b, with phenyl groups as substituents R, was
used as a chiral source, 4a was obtained with an ee of 31%
(entry 2). The reaction of 4a became slower and the enan-
We began examining the alkylation of Schiff’s base
311with benzyl halide in toluene in the presence of a chiral
diol and potassium tert-butoxide as a base (Table 1).12 En-
tries 1–16 list the results using benzyl bromide. First, we
examined benzylation of Schiff’s base of alanine ethyl
Table 1 Enantioselective Benzylation of Schiff’s Base 3 Using Benzyl Halidesa
R
Ph
OH
chiral alcohol
t-BuOK
O
O
Ph
Ph
Ph
Ph
OH
OH
N
N
+
Ar
X
0 °C
toluene
OY
Ar
OY
OMe
Ph
R
4
3a Y = Et
3b Y = t-Bu
2
5
Entry
1
3
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
X
Chiral alcohol R
Time
15 min
5 min
1.5 h
40 min
1 hf
4
Yield (%)b ee (%)c,d
3a
3a
3a
3b
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
2a
2b
2b
2b
2b
2b
2b
2b
2b
2c
2d
2d
2e
2f
H
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
81
75
60
94
66
58
62
50
59
71
65
61
68
70
70
39
65
64
55
63
65
3
31
0
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3e
4
4
5
58
65
67
65
65
26
70
74
60
15
37
0
6
2 hf
7
3 hf
8
4.5 hf
6 hf
9
10
11
12
13
14
15
16
17
18
19
20
21
4-MeC6H4
3-MeC6H4
3-MeC6H4
3,5-Me2C6H3
3-MeOC6H4
3-F3CC6H4
–
1 hf
1 hf
3 hf
1 hf
3 hf
2g
5
1 hf
1 hf
2d
2b
2d
2d
2d
3-MeC6H4
Ph
3 hf
87
84
69g
90g
90g
3 hf
2-MeC6H4
3-MeC6H4
4-MeC6H4
3-MeC6H4
3-MeC6H4
3-MeC6H4
3 hf
3 hf
3 hf
a Reaction was conducted with 3, ArCH2X (1.5 equiv), and t-BuOK (3 mol) in the presence of chiral alcohol 2 or 5 (10 mol%) in toluene (0.15
M). The reaction mixture was a suspension because t-BuOK was insoluble in toluene.
b Isolated yield.
c The enantiomeric excess (ee) of 4 was determined by HPLC analysis using a chiral column (DAICEL CHIRALCEL AD-H, hexane–
i-PrOH = 99:1).
d The absolute configurations of all optically active products 4a were S. For information on how the absolute configuration was determined, see
ref. 13.
e t-BuONa was used instead of t-BuOK.
f ArCH2X was added slowly for the given time, after which the reaction was quenched.
g Absolute stereochemistry was undetermined.
Synlett 2010, No. 14, 2097–2100 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of a-Benzylalanine
2099
tioselectivity was not observed when sodium tert-butox-
ide was used instead of potassium tert-butoxide (entry 3).
Reaction of tert-butyl ester 3b was slower compared to
ethyl ester 3a and gave 4a in high yield but low ee (entry
4).
Ph
X
Ph
H
N
O
O
K
H
Ar
Ar
O
Next benzyl bromide was added slowly in order to react
with the enolate of the Schiff’s base 3a which was con-
structed in the asymmetric environment adequately, since
the reaction using potassium tert-butoxide, diol 2b and
Schiff’s base 3a proceeded very rapidly (within 5 min, en-
try 2). For an addition time of one hour, product 4a was
obtained with an ee of 58% (entry 5). For a longer addition
time of three hours, 4a was obtained with an ee of 67%
(entry 7). Further prolongation of the addition time did not
improve the ee (entries 8 and 9).
OEt
Figure 3
Acknowledgment
This research was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science, Sports and
Culture.
In a preliminary study of the effect of substituent R in diol
2 in giving product 4a, we found bulkier phenyl groups to
be more effective than hydrogen in increasing the value of
ee (entry 1 vs. entry 2). Therefore, we examined diol 2
with various substituted phenyl groups as substituents R
for alkylation of 3a with benzyl bromide under slow addi-
tion conditions. Diol 2c with para-tolyl groups gave 4a
with a low ee (entry 10). Diol 2d with meta-tolyl groups
gave 4a with ee = 74% (entry 12). Diol 2e with meta-
dimethylphenyl groups was unremarkable (entry 13) and
diols 2f and 2g with meta-methoxyphenyl and meta-triflu-
orophenyl groups, respectively, were ineffective (entries
14 and 15) in increasing the ee. For mono-ol 5, prepared
from diol 2b (Ag2O, MeI, DMF, 82%), enantioselectivity
was not observed, suggesting that the diol part in 2 is im-
portant for the induction of enantioselectivity.
References and Notes
(1) (a) Fesko, K.; Uhl, M.; Steinreiber, J.; Gruber, K.; Griengl,
H. Angew. Chem. Int. Ed. 2010, 49, 121. (b) Tanaka, M.
Chem. Pharm. Bull. 2007, 55, 349. (c) Venkatraman, J.;
Shankaramma, S. C.; Balaram, P. Chem. Rev. 2001, 101,
3131. (d) Horikawa, M.; Shigeri, Y.; Yumoto, N.;
Yoshikawa, S.; Nakajima, T.; Ohfune, Y. Bioorg. Med.
Chem. Lett. 1998, 8, 2027. (e) Khosla, M. C.; Stachowiak,
K.; Smeby, R. R.; Bumpus, F. M.; Piriou, F.; Lintner, K.;
Fermandjian, S. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 757.
(2) For reviews, see: (a) Maruoka, K. Org. Process Res. Dev.
2008, 12, 679. (b) Nájera, C.; Sansano, J. M. Chem. Rev.
2007, 107, 4584. (c) Vogt, H.; Bräse, S. Org. Biomol. Chem.
2007, 5, 406. (d) O’Donnell, M. J. Acc. Chem. Res. 2004,
37, 506. (e) Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37,
526.
Next, we changed the alkylating reagent from benzyl bro-
mide to benzyl chloride. Diol 2d gave 4a with an ee of
87% (entry 17). Diol 2b with phenyl groups gave 4a with
an ee of 84% (entry 18). Various tolymethyl chlorides
were also used in this reaction (entries 19–21); meta- and
para-methylbenzyl chloride gave a,a-disubstituted amino
acids 4 with an ee of 90% (entries 20 and 21).
(3) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353.
(4) O’Donnell, M. J.; Wu, S. Tetrahedron: Asymmetry 1992, 3,
591.
(5) (a) Jew, S.-S.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Lee,
Y.-J.; Park, B.-S.; Kim, M. G.; Park, H.-G. J. Org. Chem.
2003, 68, 4514. (b) Lygo, B.; Crosby, J.; Peterson, J. A.
Tetrahedron Lett. 1999, 40, 8671.
For all entries that gave optically active 4a, the absolute
configurations was S.13
(6) For spiro ammonium salts, see: (a) Ooi, T.; Takeuchi, M.;
Kato, D.; Uematsu, Y.; Tayama, E.; Sakai, D.; Maruoka, K.
J. Am. Chem. Soc. 2005, 127, 5073. (b)Ooi, T.;Tayama, E.;
Maruoka, K. Angew. Chem. Int. Ed. 2003, 42, 579. (c) Ooi,
T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228. (d) Ooi, T.; Uematsu, Y.; Maruoka,
K. Tetrahedron Lett. 2004, 45, 1675. (e) Ooi, T.; Takeuchi,
M.; Ohara, D.; Maruoka, K. Synlett 2001, 1185. (f) For
bisammonium salts, see: Ohshima, T.; Shibuguchi, T.;
Fukuta, Y.; Shibasaki, M. Tetrahedron 2004, 60, 7743.
(7) (a) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Singh,
I.; Parmar, V. S.; Vyskočil, Š.; Kagan, H. B. J. Org. Chem.
2000, 65, 7041. (b) Belokon, Y. N.; Kochetkov, K. A.;
Churkina, T. D.; Ikonnikov, N. S.; Vyskočil, Š.; Kagan,
H. B. Tetrahedron: Asymmetry 1999, 10, 1723.
The observed good enantioselectivity may be attributable
to selective formation of the rigid enolate fixed by square
planer K+ as shown in Figure 3.14 The Re-face of the eno-
late of 3a is shielded by the aryl group in trans-diol 2.
Therefore electrophilic attack of benzyl halide occurs on
the Si-face of the enolate to give (S)-4a. The lack of enan-
tioselectivity with mono-ol 5 can be attributed to the dif-
ficulty of forming a rigid enolate in an asymmetric
environment.
In conclusion, we have used trans-3,4-dihydro-3,4-di-
aryldibenzo[c,g]phenanthrene-3,4-diol as the chiral
source for enantioselective benzylation of a Schiff’s base
of alanine. In this reaction, use of benzyl chloride and its
slow addition were essential for high enantioselectivity of
the product.
(c) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.;
Parmár, V. S.; Kumar, R.; Kagan, H. B. Tetrahedron:
Asymmetry 1998, 9, 851.
Synlett 2010, No. 14, 2097–2100 © Thieme Stuttgart · New York

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M. Kitamura et al.
LETTER
THF at r.t. for 15 h) with the literature data. See: Green,
J. E.; Bender, D. M.; Jackson, S.; O’Donnell, M. J.;
McCarthy, J. R. Org. Lett. 2009, 11, 807.
(8) Casas, J.; Nájera, C.; Sansano, J. M.; González, J.; Saá,
J. M.; Vega, M. Tetrahedron: Asymmetry 2001, 12, 699.
(9) (a) Kitamura, M.; Shiomi, K.; Kitahara, D.; Yamamoto, Y.;
Okauchi, T. Synlett 2010, 1359. (b) Ohmori, K.; Kitamura,
M.; Suzuki, K. Angew. Chem. Int. Ed. 1999, 38, 1226.
(10) For the related structure of various combination of
TADDOLs and metals, see: Seebach, D.; Beck, A. K.;
Heckel, A. Angew. Chem. Int. Ed. 2001, 40, 92.
(11) Polt, R.; Peterson, M. A.; DeYoung, L. J. Org. Chem. 1992,
57, 5469.
(12) In an initial screening on bases (NaH, KH, CaH2, NaOH,
KOH, CsOH·H2O, CsCO3, t-BuONa, t-BuOK), t-BuOK was
good in terms of the yield and/or ee of the alkylated product
4.
O
(S)
H2N
OEt
Ph
6
Figure 4
(14) For the structure of coordinated potassium ion, see: Islam,
M. S.; Pethrick, R. A.; Pugh, D. J. Phys. Chem. A 1998, 102,
2201.
(13) The absolute configurations of product 4a were determined
by comparison of the optical rotation of amino ester 6
(Figure 4) derived by hydrolysis of 4a (1 M citric acid in
Synlett 2010, No. 14, 2097–2100 © Thieme Stuttgart · New York