Ester-enolate Claisen rearrangement of proline-containing α-acyloxy-α-vinylsilane. Synthesis of pyrrolidine-fused glutamate analogs

Article abstract of DOI:10.1016/j.tetlet.2007.05.066

The stereoselective syntheses of pyrrolidine-fused aspartate and glutamate analogs, (S)-α-carboxymethyl-proline 3 and (S)-α-2-carboxyethyl-proline 4, using a chirality-transferring ester-enolate Claisen rearrangement of α-vinyl-α-acyloxysilane having a Boc-Pro as an acyloxy group, are described. The stereochemical outcome of the proline ester-derived ester-enolate Claisen rearrangement is also disclosed.

Full text of DOI:10.1016/j.tetlet.2007.05.066

Tetrahedron Letters 48 (2007) 4821–4824
Ester-enolate Claisen rearrangement of proline-containing
a-acyloxy-a-vinylsilane. Synthesis of pyrrolidine-fused
glutamate analogs
Kazuhiko Sakaguchi,* Masahiro Yamamoto, Yusuke Watanabe and Yasufumi Ohfune*
Graduate School of Science, Department of Material Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Received 10 April 2007; revised 10 May 2007; accepted 11 May 2007
Available online 17 May 2007
Dedicated to the late Professor Yoshihiko Ito
Abstract—The stereoselective syntheses of pyrrolidine-fused aspartate and glutamate analogs, (S)-a-carboxymethyl-proline 3 and
(S)-a-2-carboxyethyl-proline 4, using a chirality-transferring ester-enolate Claisen rearrangement of a-vinyl-a-acyloxysilane having
a Boc-Pro as an acyloxy group, are described. The stereochemical outcome of the proline ester-derived ester-enolate Claisen rear-
rangement is also disclosed.
Ó 2007 Elsevier Ltd. All rights reserved.
The ester-enolate Claisen rearrangement is a powerful
method for the enantio- and diastereoselective carbon–
carbon bond forming reactions from an original chiral
ester.1 Its application to the synthesis of a-amino acids
was first reported by Kazmaier, which is performed by
the efficient control of the ester-enolate geometry by
Zn2+.2 As a part of our ongoing program for the synthe-
sis of biologically active natural products and related
amino acids, we also synthesized several glutamate and
aspartate analogs including their a-substituted deriva-
tives3 using the ester-enolate Claisen rearrangement of
a-acyloxy-a-alkenylsilanes in which various N-protected
a-amino acids were employed as the acyloxy group.4
This method is characterized by the masked chirality
of the carbon attached to the acyloxy and silyl groups
and its complete transfer to the newly formed carbon
center. In recent years, a-substituted-proline has
attracted significant attention because this substructure
was found in several natural products, such as oxazolo-
mycin (1)5 and kaitocephalin (2)6 (Fig. 1). Furthermore,
this group can be viewed as a conformational modifier
of glutamate which functions at many synapses in the
mammalian central nervous systems as an excitatory
neurotransmitter and is implicated in the construction
of memory and learning as well as in the pathogenesis
of neuron damage that causes various neuronal dis-
eases.7 In this Letter, we describe the novel ester-enolate
Claisen rearrangement of a-acyloxysilane possessing a
proline as an acyloxy group and its application to the
synthesis of the pyrrolidine-fused aspartate analog 3
and glutamate analog 4.
We considered that the ester-enolate derived from the
proline-containing a-acyloxy-a-alkenylsilane A would
undergo the Claisen rearrangement to give the a-substi-
tuted-proline derivative B, with transfer of the original
chirality of the ester counterpart to the rearranged prod-
uct.8 According to our previous studies, the use of Boc–
Gly, Boc–Ala, and Boc–Phe as the acyloxy group sug-
gested that the rearrangement proceeds through a
chair-like transition state with the ZnCl2-assisted dian-
ionic Z-enolate.4 However, the stereochemical outcome
of the proline-containing Claisen rearrangement is not
well-documented in which the enolate geometry could
not be controlled by Zn2+, since its base treatment pro-
duces a mono-anion enolate. Furthermore, the effects of
the sterically bulky Boc-Pro on the transition state struc-
ture to have either the chair- or boat-like conformation,
which controls the newly formed configuration of the
product, are unexplored.
Keywords: Ester-enolate Claisen rearrangement; a-Hydroxysilane; a-
Acyloxysilane; Z-Enolate; Proline; a-Substituted-proline; Chirality
transfer.
Initially, we examined the rearrangement of 6, prepared
from (S)-a-hydroxysilane 5 (>95% ee)9 by initial
*
Corresponding authors. E-mail: sakaguch@sci.osaka-cu.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.066

4822
K. Sakaguchi et al. / Tetrahedron Letters 48 (2007) 4821–4824
H
HO2C
HO2C
N
ester-enolate Claisen
rearrangement
R
N
O
R
N
b
c
*
HO2C
b
3
O
R3Si
c
*
a
R3Si
*
H
HO2C
N
A
B
O
HO2C
N
c
*
a
4
Cl
HO
Cl
O
O
MeO
HO
H
CO2H
O
N
NH2
HO
N
NMe
O
H
N
H
H
O
CO2H
OH
Oxazolomycin (1)
HO
CO2H
Kaitocephalin (2)
Figure 1.
coupling with Boc-L-Pro and subsequent hydrogenation
of the resulting ester with the Lindlar catalyst, according
to the conditions used in our previous studies3,4 where
Zn2+ played a key role in the highly diastereoselective
rearrangement. In this case, the addition of Zn2+
(1.2 equiv) was not effective at all to give the rearranged
product in 10% yield and the starting 6 (75%) was recov-
ered (Table 1, entry 1). In the absence of Zn2+, the yield
of the rearranged 7 was up to 50% (entry 2). After exam-
ining several bases, we found that the reaction using
be produced from the chair-E and/or boat-Z transition
state.
It was considered that destabilization of the ionic eno-
late by the addition of HMPA would affect the product’s
enantioselectivity. To our delight, the addition of
HMPA (23% in THF) was quite effective for the enan-
28
tioselective transformation to afford (S)-7, ½aꢀD ꢁ32.4
(c 0.90, CHCl3, >95% ee), with complete transfer of
the starting chirality (>95% ee) in 77% yield (Table 1,
entry 4). The highly polar HMPA would contribute
not only to the exclusive formation of the (Z)-enolate,11
but also to accelerating the rate of the rearrangement
from the chair-Z transition state. The preferential for-
mation of the Z-enolate in the presence of HMPA can
be explained as kinetic deprotonation from the sterically
less-hindered conformer D although it is not clear from
the present experiment whether an equilibrium between
the (Z)- and (E)-enolates is present under the reaction
conditions (Scheme 1).
LHMDS (3.0 equiv) gave the rearranged 7 in 70% yield
24
(entry 3). The optical purity of the rearranged 7, ½aꢀD
ꢁ22.2 (c 1.27, CHCl3), was determined to be 71% ee
and its absolute configuration was S (Supplementary
data). This result suggested that the rearrangement pro-
ceeded through the preferential formation of the Z-eno-
late with the chair-like transition state in which the
sterically bulky TBDMS group was located at an equa-
torial position to give (S)-7 as the major enantiomer
(S:R = 85.5:14.5) (Scheme 1). We estimated the activa-
tion energy of the model ester-enolate intermediate C
by the B3LPY/P6-31G* calculation (Fig. 2).10 This cal-
culation suggested that the chair-like transition state
with the (Z)-enolate is the most preferential pathway
for the formation of (S)-7, which is in good agreement
with the experimental result. Enantiomer (R)-7 would
Next, we turned our attention to the synthesis of a-carb-
oxymethyl-proline 3 and a-carboxyethyl-proline 4 from
(S)-7, which possesses a vinylsilane group that is con-
vertible to the requisite a-carboxymethyl and a-carboxy-
ethyl groups (Scheme 2). It has been reported that the
Table 1. Ester-enolate Claisen rearrangement of 6
1) N-Boc-L-Pro
EDCI, DMAP
CH2Cl2, rt, 2 h
Boc
Boc
N
O
HO2C
OH
N
conditions
O
S
Si
Si
THF, -78 oC, 30 min
then rt
2) H2, Lindlar cat.
AcOEt, rt, 2 h
Si
(S
)-5
(S)-7
6
>95% ee
Si = TBDMS
Entry
Base (equiv)
ZnCl2 (equiv)
7 (%, % ee)
Recovery of 6 (%)
a
a
1
2
3
4b
LDA
LDA
LHMDS
LHMDS
3.0
3.0
3.0
3.0
1.2
—
—
—
10
50
70
77
75
40
16
—
71
>95
a Not determined.
b 23% HMPA in THF.

K. Sakaguchi et al. / Tetrahedron Letters 48 (2007) 4821–4824
4823
Boc
O
without with
HMPA HMPA
N
Boc
HO2C
N
Si
Si
O
Si
Z-enolate
85.5
:
98
:
(S)-7
Boc
N
O
O
LHMDS
(HMPA)
N
O
S
Boc
Si
Boc
N
O
Si
HO2C
14.5
2
6
Z-enolate
O
> 95% ee
(R)-7
Si = TBDMS
O
Si
E-enolate
>95% ee
71% ee
N
Boc
(70% yield) (77% yield)
RO
H
O
O
OR
Boc
Z
-enolate
E-enolate
N
Boc
N
H
N
D
E
N
TMS
TMS
TMS
TMS
R =
TBDMS
Scheme 1.
AcN
Ac
N
Ac
O
O
O
N
O
O
N
O
Ac
O
H3Si
O
H3Si
N
H3Si
H3Si
O
O
Ac
H3Si
19.6 kcal/mol
22.1 kcal/mol
24.3 kcal/mol
27.4 kcal/mol
C
chair
boat
Chair
boat
Z-enolate
E-enolate
Figure 2. Activation energy of the ester-enolate Claisen rearrangement of C calculated by B3LYP/6-31G*.
R2
Boc
N
Boc
N
H
R1O2C
HO2C
HO2C
MeO2C
HO2C
RO2C
N
N
e
f,g
b
Si
a
9: R1 = H, R2 = H
(S)-3
11
(
S
)-7: R = H
c,d
8: R = Me
10: R1 = Me, R2 = Boc
h
Boc
N
Boc
Boc
N
H
HO2C
MeO2C
HO2C
MeO2C
MeO2C
f,g
N
j,k
N
i
H
Si
HO2C
Si
O
(S)-4
O
14
12 (1 : 1)
13 (1 : 1)
Si = TBDMS
Scheme 2. Reagents and conditions: (a) CH2N2, Et2O, quant. (b) HBF4 (200 equiv), 1,4-dioxane, 100 °C, 3 h, quant. (c) Boc2O (1 equiv), Na2CO3
(1.1 equiv), H2O-1,4-dioxane, rt, 2 h. (d) CH2N2, Et2O, rt, 10 min, 82% (2 steps). (e) OsO4 (0.01 equiv), NaIO4 (1 equiv), H2O–acetone, rt, 16 h, 60%.
(f) 1 M NaOH, THF, rt, 16 h. (g) TFA, CH2Cl2, rt, 3 h, 95% (2 steps). (h) mCPBA (2 equiv), NaHCO3 (2 equiv), CH2Cl2, rt, 16 h, 75%. (i) AcOH,
70 °C, 1 h, 83%. (j) TBAF (1.5 equiv), AcOH, THF, rt, 40 min, 78%. (k) Jones oxidation, 0 °C, 86%.
ozonolysis of the vinylsilane produced an a-peroxy alde-
hyde contrary to the normal oxidative cleavage of the
carbon–carbon double bond.12 Therefore, the synthesis
of (S)-3 was performed by the initial removal of the silyl
group and subsequent cleavage of the resulting vinyl
group. After esterification of (S)-7 with CH2N2, the
TBDMS group was removed using HBF4 to give a-allyl-
ated 9 in quantitative yield. Re-protection of 9 followed

4824
K. Sakaguchi et al. / Tetrahedron Letters 48 (2007) 4821–4824
Pereira, S.; Srebnik, M. Aldrichim. Acta 1993, 26, 17–29;
(d) Enders, D.; Knopp, M.; Scheiffers, R. Tetrahedron:
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by oxidative cleavage of the vinyl group of 10 with OsO4
and NaIO4 gave the protected 11, which, upon removal
19
of the protecting group, yielded (S)-3, ½aꢀD +122.0 (c
0.90, 5 M HCl). The synthesis of (S)-4 was started with
the initial epoxidation of 8 using mCPBA to give a 1:1
mixture of epoxysilane 12, which, upon treatment with
acetic acid, afforded a-silylaldehyde 13 (83%, 1:1 mix-
ture).13 Removal of the silyl group by TBAF (78%) fol-
lowed by Jones oxidation gave carboxylic acid 14 (86%),
which, upon deprotection, gave (S)-4, ½aꢀ2D0 +66.6 (c 0.90,
5 M HCl), in 95% yield.
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In summary, the ester-enolate Claisen rearrangement of
the optically active a-alkenyl-a-acyloxysilane possessing
a Boc-Pro as an acyloxy group was found to proceed
through the chair-like transition state with a Z-enolate
in the presence of HMPA to produce the vinylsilane-
containing a-substituted-proline with complete transfer
of the original chirality. The rearranged product (S)-7
was converted to both (S)-a-carboxymethyl-proline 3
and (S)-a-2-carboxyethyl-proline 4. Applications of the
present method for the ester-enolate rearrangement of
c-substituted a-alkenyl-a-acyloxysilane and neurobio-
logical evaluation of the synthetic aspartate analog 3
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4
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Acknowledgement
This study was financially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
8. Recently, the diastereoselective ester-enolate Claisen rear-
rangement of the 5-substituted-proline allyl ester was
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enolate Claisen rearrangement of crotyl pyroglutamate
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Supplementary data
Spectral data of (S)-7, (S)-3, and (S)-4. Determination
of the optical purity and absolute configuration of (S)-
7. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/
j.tetlet.2007.05.066.
References and notes
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