Synthesis of optically active β-alkyl aspartate via [3,3] sigmatropic rearrangement of α-acyloxytrialkylsilane

Article abstract of DOI:10.1016/j.tetlet.2004.05.157

The synthesis of four types of optically active β-carbon-substituted analogs of threo-β-hydroxy aspartate (THA) and a β-carbon-substituted analog of threo-β-benzyloxy aspartate (TBOA), which are potent blockers of excitatory amino acid transporters in the

Full text of DOI:10.1016/j.tetlet.2004.05.157

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5869–5872
Synthesis of optically active b-alkyl aspartate via
[3,3] sigmatropic rearrangement of a-acyloxytrialkylsilane
Kazuhiko Sakaguchi,a,* Masahiro Yamamoto,a Tetsuo Kawamoto,a Takeshi Yamada,a
Tetsuro Shinada,a Keiko Shimamotob and Yasufumi Ohfunea,*
aGraduate School of Science, Department of Material Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
bSuntory Institute for Bioorganic Research, Wakayamadai, Shimamoto, Mishima, Osaka 618-8503, Japan
Received 16 April 2004; revised 12 May 2004; accepted 28 May 2004
Abstract—The synthesis of four types of optically active b-carbon-substituted analogs of threo-b-hydroxy aspartate (THA) and a b-
carbon-substituted analog of threo-b-benzyloxy aspartate (TBOA), which are potent blockers of excitatory amino acid transporters
in the mammalian central nervous system, via the chirality-transferring ester–enolate Claisen rearrangement of a-acyloxytrialkyl-
silane is described.
Ó 2004 Elsevier Ltd. All rights reserved.
L
-Glutamate acts as an excitatory neurotransmitter in
R1
3S
R1
3R
the mammalian central nervous system and is as well a
potent neurotoxin.1 For normal neurotransmission by
glutamate, it is necessary to maintain the extracellular
glutamate concentration below neurotoxic levels and,
therefore, glutamate transporters play an important role
for this purpose.2;3 To date, five subtypes of glutamate
transporters have been found in mammalian tissues.3
For elucidation of the intrinsic properties and physio-
logical roles of transporters, development of subtype-
selective inhibitors of glutamate transporters is required.
(2S,3S)-THA 1a4 and (2S,3S)-TBOA 1b5 are known as
representative inhibitors; in particular, the latter exhibits
potent nontransportable blocker activity to glutamate
transporters (Fig. 1). Therefore, b-substituted aspartates
are expected as a lead for developing useful blockers of
glutamate transporters.
CO2H
R2
CO2H
R2
2S
2S
HO2C
HO2C
NH2
NH2
1a: R1= OH, R2= H (THA)
1b: R1= PhCH2O, R2= H (TBOA)
1c: R1= Me, R2= H
2c: R1= Me, R2= H
2d: R1= Me, R2= Me
1d: R1= Me, R2= Me
1e: R1= PhCH2CH2, R2= H
Figure 1.
chirality that is, a carbon center attached to a tert-butyl-
dimethylsilyl (TBDMS) group to both the 2- and 3-
positions of the product. Conversion of the resulting
amino acids to the b-substituted aspartates will be
achieved by the oxidative cleavage of the C–C double
bond of the vinylsilane moiety. We wish to report herein
the synthesis of a b-carbon-substituted analog of THA
1c, its a-methyl-substituted analog 1d, their C3-epimers
2c and 2d, and a b-carbon-substituted analog of TBOA
1e in optically active form. According to the previous
research, the construction of each 2S,3S-threo configu-
ration for 1c–e and 2S,3R-erythro configuration for 2c,d
will be achieved by this method using E- and Z-(S)-a-
acyloxysilanes, respectively.
In a previous study, we reported the synthesis of opti-
cally active vinylsilane-containing a-amino acids via the
chirality-transferring ester–enolate Claisen rearrange-
ment of a-acyloxytrialkylsilane (Scheme 1).6 This
method is characterized by the complete transfer of the
Keywords: Ester–enolate Claisen rearrangement; a-Hydroxysilane;
a-Acyloxysilane; threo-b-Hydroxy aspartate; threo-b-Benzyloxy aspar-
tate; Glutamate transporter.
The synthesis of THA analog 1c was started with opti-
cally active amino acid, syn-(2S,3R)-5c, prepared from
* Corresponding authors. Tel.: +81-6-6605-2571; fax: +81-6-6605-
2522; e-mail: sakaguch@sci.osaka-cu.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.157

5870
K. Sakaguchi et al. / Tetrahedron Letters 45 (2004) 5869–5872
O
[3,3] sigmatropic
NHBoc
NH2
rearrangement
HO2C
NHBoc
HO2C
HO2C
R2
R2
O
2
3
2
*
*
R2
R1
3
R1
R1
*
*
TBDMS
TBDMS
*
oxydative cleavage
1c, 1d (THA analog)
1e (TBOA analog)
E olefin
Z olefin
2c 2d (THA analog)
Scheme 1.
O
R
R
MeO2C
NHBoc
ref 6a
HO2C
NH2
2S
NHBoc
OH
O
S
ref 6a
a, b
R
3R
TBDMS
syn-5c: R = H
syn-5d: R = Me
syn-6c: R = H
syn-6d: R = Me
E-4c : R = H
E-4d : R = Me
3
R
R
MeO2C
MeO2C
MeO2C
HO2C
e
c, d
NHBoc f, g
NHBoc
1c
1d
syn-8c: R = H
syn-8d: R =Me
syn-7c: R = H
syn-7d: R =Me
O
R
R
ref 6a
HO2C
OH
MeO2C
MeO2C
NHBoc
R
NH2
NHBoc
ref 6a
2c
2d
O
2S
3S
TBDMS
S
(anti : syn = 12 : 1)
9
anti-8c: R = H
anti-8d: R =Me
Z-4c : R = H
Z-4d : R = Me
anti-5c: R = H
anti-5d: R = Me
Scheme 2. Reagents and conditions: (a) Boc2O, Na2CO3, H2O–dioxane (1:2), rt, 2 h (for 5c), 72 h (for 5d); (b) CH2N2, Et2O, 0 °C, 30 min (67–94%,
two steps); (c) O3, AcOEt, )78 °C, 10 min, then Me2S, rt, 1 h; (d) Jones oxidation (47–57%, two steps); (e) CH2N2, Et2O, 0 °C, 15 min (quant); (f) 1 M
NaOH, THF, rt, 16 h; (g) TFA (50 equiv), CH2Cl2, 0 °C, 3 h (94–99%, two steps).
crotyl alcohol (3) via the ester–enolate Claisen rear-
rangement of a-acyloxysilane E-4c as reported (Scheme
2).6a Prior to carrying out an oxidative degradation of
the terminal olefin, the amino, and the carboxyl groups
of syn-5c were protected with a Boc group and a methyl
ester, respectively (94%, two steps). Ozonolysis of the
protected syn-6c followed by Jones oxidation of the
resulting mixture afforded carboxylic acid syn-7c in 47%
yield for two steps, which, upon treatment with CH2N2,
gave diester syn-8c in quantitative yield. Deprotection
of syn-8c was performed by the following sequence
of reactions: (1) 1 M NaOH in THF and (2) TFA
(50 equiv) in CH2Cl2. The desired 1c was obtained in
94% yield from syn-8c. a-Methyl-substituted analog 1d
of THA was synthesized by the use of syn-5d6a in the
same manner as for 1c.
propanal (10) (Scheme 3). The Wittig olefination of 10
with methyl (triphenylphosphoranylidene)acetate gave
ester 11 in 87% yield (E : Z ¼ 19 : 1). After separation
of the E=Z mixture, the pure E-11 was reduced with
DIBAL and the resulting allylic alcohol was converted
to TBDMS ether (94% from E-11). The reverse-Brook
rearrangement of the resulting silyl ether afforded a-
hydroxysilane 12 in 80% yield,9 which, upon Jones
oxidation, gave acylsilane 13 in quantitative yield.
Alternatively, this was prepared from 10 by the Horner–
Wadsworth–Emmons reaction with (a-phosphonoacyl)-
silane (14) in 75% yield.10 Enantioselective reduction of
13 with (+)-B-chloro diisopinocamphenylborane (DIP-
Cl)11 under reflux in THF afforded optically active 12,
whose optical purity and absolute configuration were
determined to be 88% ee and S by the modified Mosher
method using 1H NMR,12 respectively. Condensation of
(S)-12 with N-Boc-Gly gave a-acyloxysilane 15 (92%
from 13). According to Kazmaier’s13 and our protocol,6
a-acyloxysilane 15 was treated with LDA, ZnCl2 in
THF at )78 °C to room temperature to produce a
rearrangement product 16 in 86% yield as the sole dia-
stereomer. On treatment of 16 with 42% HBF4
(100 equiv) in 1,4-dioxane at 65 °C for 24 h, spontaneous
desilylation and removal of the Boc group proceeded to
give amino acid 17 in 68% yield. According to the
method for the synthesis of the THA analog, protection
of both the amino and the carboxyl groups gave 18
The 3S-epimers of the THA analog 2c and 2d were
synthesized by the use of anti-(2S,3S)-5c7 and 5d, which
were prepared from 2-butyn-1-ol (9) via the ester–eno-
late Claisen rearrangement of optically active a-acyloxy-
silane Z-4, in the same manner as that of the
3R-isomers, respectively.6a Thus, four types of the b-
carbon-substituted analogs of THA 1c, 1d, 2c, and 2d
were synthesized.8
According to our synthetic plan in Scheme 1, the syn-
thesis of TBOA analog 1e was started with 3-phenyl-

K. Sakaguchi et al. / Tetrahedron Letters 45 (2004) 5869–5872
5871
OH
O
e
a
b, c, d
Ph
O
TBDMS
g
Ph
MeO
f
Ph
10
11
12
p
O
NHBoc
OH
O
h
O
TBDMS
Ph
l
TBDMS
TBDMS
Ph
TBDMS
Ph
(S)-12 88% ee
R2O2C NHR1
Ph
13
15
NHBoc
Ph
MeO2C
R
HO2C
NHBoc
Ph
n, o
i, j, k
1e
17 : R1 = H, R2 = H
16
19 : R = CO2H
20 : R = CHO
m
18 : R1 = Boc, R2 = Me
Scheme 3. Reagents and Conditions: (a) Ph3P@CHCO2Me (1.5 equiv), benzene, reflux, 16 h (87%, E : Z ¼ 19 : 1, separable); (b) DIBAL (2.5 equiv),
CH2Cl2, )78 °C to rt, 1 h; (c) TBDMSCI (1.5 equiv), imidazole (1.5 equiv), CH2Cl2, )78 °C to rt, 1 h (94%, two steps); (d) sec-BuLi (4 equiv),
TMEDA (4.5 equiv), THF, )78 °C to rt, 1 h (80%); (e) Jones oxidation (quant); (f) (+)-DIP-CI (3 equiv), THF, reflux, 2 h; (g) N-Boc-Gly (2 equiv),
EDCI (2 equiv), DMAP (10 mol %), CH2Cl2, 0 °C, 2 h (92%, two steps); (h) LDA (3.0 equiv), ZnCl2 (1.2 equiv), THF, )78 °C to rt (86%); (i) 42%
HBF4 (100 equiv), 1,4-dioxane, 65 °C, 24 h (68%); (j) Boc2O (1 equiv), Na2CO3 (2 equiv), H2O–1,4-dioxane (1:2), rt; (k) CH2N2, Et2O (80%, two
steps); (l) OsO4 (0.01 equiv), NaIO4 (4 equiv), H2O–acetone (2:1), 0 °C to rt, 24 h; (m) Jones oxidation (96%, two steps); (n) 1 M NaOH (4 equiv),
THF, rt, 18 h; (o) TFA (50 equiv), CH2Cl2, 0 °C, 4 h, then recrystallization from EtOH (50% from 19); (p) (MeO)2POCH2COTBDMS (14, 1.2 equiv),
NaH (1 equiv), THF, 0 °C, 1 h (75%).
Table 1. Inhibition of glutamate uptake in MDCK cells
(80%, two steps). An attempt to cleave the terminal
olefin by ozonolysis was not satisfactory and the desired
carboxylic acid 19 was afforded in 37% yield together
with trace amounts of aldehyde 20. The yield was much
improved (80%) when 18 was treated with OsO4
(0.01 equiv) and NaIO4 (4 equiv) in H2O–acetone (2:1)
at room temperature for 24 h. The by-produced 20
(18%) was converted to 19 by Jones oxidation in
quantitative yield. Finally, after deprotection of 19 in
two steps [(i) 1 M NaOH, (ii) TFA], recrystallization of
the crude mixture from EtOH gave the TBOA analog
1e14 with >95% ee (50% yield from 19). The relative and
absolute configurations of 1e were determined to be
2S,3S by the following experiments: (1) Each J value
between Ha and Hb of the c-butyrolactone 21 or its C2-
epimer 22, which was prepared from 20 as shown in
Scheme 4, was 9.8 and 6.8 Hz, respectively. These results
indicate that 21 possesses 2,3-trans configuration. (2)
The absolute configuration of the C2-position of 1e was
determined to be S by comparison of the 1H NMR
spectral data of its (R)- and (S)-MTPA-amide.15
IC50 (M)
EAAT3
EAAT2
1a (THA)
1b (TBOA)
19 0.7
2.6 0.16
7.3 0.37
1.4 0.11
16 1.0
1c
1d
1e
2c
2d
28 2.0
a
a
35 2.7
79 5.1
15 1.2
16 0.7
a
a
a No inhibitory activity was observed at 100 lM.
of THA. On the other hand, 1d and 2d did not show any
inhibitory activity at 100 lM. These results suggest that
the oxygen function at the b-position of aspartate would
be one of the important factors for the inhibition of
glutamate transporters. In the previous studies on the
inhibitors of glutamate transporter, the active confor-
mations of both aspartate and TBOA were proposed to
be HO2C–C–C–CO2H anti (conformer A) (Fig. 2).5b;17
In this study, the small J value between Hc and Hd of 1e
(3.2 Hz) as well as that of TBOA (2.5 Hz) showed that
the Hc–C–C–Hd gauche conformers (A and/or C) are
predominant over the conformer B. Taking the gauche
effect18 between the NH2 group and the OR group and
the electrostatic effects into consideration, the con-
former A of TBOA would have the advantage over the
conformer C. The slightly larger J value of 1e compared
Inhibition of glutamate uptake by the synthetic aspar-
tate derivatives was preliminarily assessed in MDCK
cells stably expressing EAAT2 (glial transporter) or
EAAT3 (neuronal transporter).5b;16 The values of 50%
inhibitory concentration (IC50) are shown in Table 1.
The activity of 1e was about one-tenth of that of TBOA,
and activities of both 1c and 2c were about a half of that
6.8 Hz
2.83 ppm
2.43 ppm
9.8 Hz
NHBoc
NaBH4 (2.5 equiv)
THF-MeOH (1 : 1)
LDA (2.2 equiv)
THF, -78 o
then NH4Cl aq.
4.52 ppm
21
C
O
O
Ha
Hb
O
0
oC to rt, 30 min
b
O
H
+
20
2
2
NHBoc
3
90%
Ha
3
45%
PhCH2CH2
PhCH2CH2
4.19 ppm
(22 : 21 = 1 : 3.5)
2,3-cis
2,3-trans
22
21
Scheme 4.

5872
K. Sakaguchi et al. / Tetrahedron Letters 45 (2004) 5869–5872
anti
CO2H
Hc
CO2H
CO2H
CO2H
NH2
Hc
X
J = 2.5 Hz
(1b: TBOA)
J = 3.2 Hz
(1e)
H2N
HO2C
X
gauche
effect
Hd
Hd
Hd
CO2H
(A)
X
Hc
NH2
(B)
(C)
1b: X = PhCH2O (TBOA), 1e: X = PhCH2CH2
Figure 2.
as the diester 8c by silica-gel column chromato-
graphy.
to that of TBOA suggested that the loss of gauche effect
by exchange of an oxygen atom to a carbon atom in the
X group decreased the contribution of the conformer A
in 1e, which would result in a decrease of the inhibitory
activity. Therefore, our present results supported the
hypothesis that the active conformation is conformer A.
Further studies regarding the structure–activity rela-
tionship of glutamate transporters of the synthetic 1c,
1d, 2c, 2d, and 1e are in progress in our laboratories.
20
D
8. 1c (90% ee): mp 268 °C (decomposition); ½aꢀ +9.8 (c 2.03,
5 M HCl); 1H NMR (400 MHz, D2O):
d 4.00 (d,
J ¼ 2:1 Hz, 1H), 2.94 (dq, J ¼ 2:1, 7.1 Hz, 1H), 1.13 (d,
J ¼ 7:1 Hz, 3H). 1d (90% ee): mp 268 °C (decomposition);
22
D
½aꢀ +11.9 (c 0.91, 5 M HCl); 1H NMR (400 MHz, D2O): d
21
2.75 (q, J ¼ 7:4 Hz, 1H), 1.48 (s, 3H), 1.13 (d, J ¼ 7:4 Hz,
3H). 2c (>95% ee): mp 268 °C (decomposition); ½aꢀ +34.3
D
1
(c 2.05, 5 M HCl); H NMR (400 MHz, D2O): d 3.68 (d,
J ¼ 5:3 Hz, 1H), 2.90 (dq, J ¼ 5:3, 7.5 Hz, 1H), 1.25 (d,
22
J ¼ 7:5 Hz, 3H). 2d (>95% ee): mp 126 °C; ½aꢀ +28.0 (c
D
1.06, 5 M HCl); 1H NMR (400 MHz, D2O): d 2.87 (q,
J ¼ 7:6 Hz, 1H), 1.39 (s, 3H), 1.20 (d, J ¼ 7:6 Hz, 3H).
9. (a) Brook, A. G. Acc. Chem. Res. 1974, 77–84; (b)
Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y.-M.;
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Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y.-M.;
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Acknowledgements
This study was financially supported by a Grant-in-Aid
for Scientific Research (No 13680674) from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan, the Project for the Future Program (JSPS
99L01204), and a Grant from Suntory Institute for
Bioorganic Research (SUNBOR). We thank Professor
S. G. Amara (University of Pittsburgh) for providing
the cells expressing EAATs.
10. Nowick, J. S.; Danheiser, R. L. J. Org. Chem. 1989, 54,
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30
D
1
14. 1e (>95% ee): mp 194 °C; ½aꢀ +5.3 (c 0.95, 5 M HCl); H
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