Catalytic Asymmetric Hydrogenation of Dehydroamino Acid Esters with Biscarbamate Protection and Its Application to the Synthesis of xCT Inhibitors

Article abstract of DOI:10.1002/chem.201900289

Catalytic asymmetric hydrogenation of dehydroamino acid esters with biscarbamate protection was examined for the first time to prepare optically active amino acids. The new method was successfully applied to the synthesis of new cystine–glutamate exchanger inhibitors.

Full text of DOI:10.1002/chem.201900289

A Journal of
Accepted Article
Title: Catalytic Asymmetric Hydrogenation of Dehydroamino Acid Ester
with Biscarbamate Protection and Its Application to Synthesis of
xCT inhibitor
Authors: Yoko Yasuno, Iho Mizutani, Yuki Sueuchi, Yuuka
Wakabayashi, Nozomi Yasuo, Keiko Shimamoto, and Tetsuro
Shinada
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To be cited as: Chem. Eur. J. 10.1002/chem.201900289
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Catalytic Asymmetric Hydrogenation of Dehydroamino Acid Ester
with Biscarbamate Protection and Its Application to Synthesis of
xCT inhibitor
Yoko Yasuno,[a] Iho Mizutani,[a] Yuki Sueuchi,[a] Yuuka Wakabayashi,[a] Nozomi Yasuo,[a] Keiko
Shimamoto,[b] and Tetsuro Shinada* [a]
Abstract: Catalytic asymmetric hydrogenation of dehydroamino acid
esters with biscarbamate protection was examined for the first time to
prepare optically active amino acids. The new method was
successfully applied to the synthesis of novel cystine-glutamate
exchanger inhibitors.
Z-DhaaE 3 has not been employed for the catalytic asymmetric
reduction, we expected that 3 would be acceptable as a substrate
for the Et-DuPHOS Rh catalyzed hydrogenation according to the
following consideration. Burk et al. proposed the reaction
mechanism of the asymmetric hydrogenation reaction of Z-1
using (2R,5R)-Et-DuPHOS Rh catalyst to give (R)-2 (model A).2
The hydride on the Rh center in A is selectively transferred to the
si-face of the coordinating enamide bond to give (R)-2.3It is
conceivable that Z-DhaaE 3 could bind to the Rh center to give
transition state model B in analogy with model A to undergo
Catalytic asymmetric hydrogenation of dehydroamino acid ester
(DhaaE) 1 has been recognized as a well-established synthetic
method to prepare optically active amino acids 2 (Scheme 1).1
Enormous application has been demonstrated in the synthesis of
biologically active nitrogen-containing compounds. In this study,
we envisioned a new synthetic variant using biscarbamate 3 in
the catalytic asymmetric hydrogenation with a chiral 1,2-Bis[(2,5)-
diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I)
trifluoromethanesulfonate [Et-DuPHOS Rh] catalyst. Although
selective hydrogenation reaction to provide (R)-4 in
a
stereoselective manner.
The above synthetic challenge is motivated by our original
design and synthesis of cystine-glutamate exchanger (xCT)
inhibitors4 using N-benzoyl diaminosuberic acid (DAS) as a new
template (Figure 1). xCTs are an amino acid transporter which
imports extracellular cystine coupled with the efflux of intracellular
glutamate (Figure 1, A).4,5 The cystine is converted to glutathione
via cysteine which play a crucial role in drug metabolism and
removal of active oxygen species in the cell. Recent studies
focusing on cancer metabolism suggest that xCTs are
overexpressed in many cancers to promote tumor survival and
enhancement of drug metabolism when cancer cells are exposed
Scheme 1. Catalytic asymmetric reduction of DhaaE 1 and 3 using chiral Et-
DuPHOS Rh catalyst. A: transition state model with Z-1.2 B: a hypothetical
transition state model with Z-3.
[a]
Dr. Y. Yasuno, I. Mizutani, Y. Sueuchi, Y. Wakabayashi, N. Yasuo,
Prof. Dr. T. Shinada
Graduate School of Science
Osaka City University
Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
E-mail: shinada@sci.osaka-cu.ac.jp
Dr. K. Shimamoto
[b]
Bioorganic Research Institute
Suntory Foundation for Life Sciences
8-1-1, Seikadai, Seika-cho, Soraku-gun, Kyoto 619-0284, Japan
Figure 1. A: a model for cystine uptake via xCT. B: Pharmacophore model
based on the 3D superposition of low energy conformation of substrates4c and
a proposed biding model of a newly designed N-Benzoyl DAS derivative (red).
Supporting information for this article is given via a link at the end of
the document.
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to anticancer drugs.4a,6 Therefore, xCTs are expected to be a
promising molecular target for drug discovery of new anticancer
drugs. Along this line, development of xCT inhibitors have been
extensively studied.4,6 Bridges et al. proposed a pharmacophore
model of xCT inhibitors based on the three-dimensional
superposition of low energy conformation of xCT inhibitors (Figure
1B).4c Inspired by their analysis, we envisioned structurally simple
N-benzoyl DAS derivatives 5–8 as a new inhibitor in which their
substituents could interact with the proposed aromatic biding site,
negative charge ion pair site, and head group L-amino acid site.
using (2R,5R)-Et-DuPHOS Rh catalyst is the same as those of
the previously reported asymmetric reduction of DhaaEs 1. These
results suggested that the hydrogenation stereoselectively
proceeded via the proposed transition state model B described in
Figure 1.
We emerged
a synthetic route to access all of the
diastereoisomers of 5-8 via common synthetic precursor 9 (Figure
2). The synthesis of 9 offers challenging opportunity to test the
feasibility of the proposed asymmetric hydrogenation. The distal
amino acid chiral centers with orthogonal protection would be
installed by the reduction of dehydroamino acid ester with mono-
or bis-carbamate protection.
Scheme 2. Catalytic asymmetric hydrogenation of bis-carbamate 11 and 17
using chiral Et-DuPHOS-Rh catalyst.
The above new methodology was successfully applied to the
synthesis of common synthetic precursors (2S,7S)-23 and
(2R,7S)-26 with orthogonal protection (Figure 2). The synthesis of
(2S,7S)- 23 was achieved by the simultaneous hydrogenation of
DhaaE 22 which was prepared from 17 by a series of sequential
transformations: (i) removal of the TBS group, (ii) TEMPO
oxidation, and (iii) olefination with 15 in good yield. DhaaE 22 was
subjected to the catalytic asymmetric hydrogenation in the
presence of (2S,5S)-DuPHOS Rh catalyst to give (2S,7S)-23 as
a single diastereoisomer.
The synthesis of (2R,7S)-26 was accomplished by a stepwise
introduction of the (R)- and the (S)-chirality starting from 17.
Biscarbamte 17 was converted to (R)-18 under the hydrogenation
conditions in the presence of (2R,5R)-Et-DuPHOS Rh catalyst.
The optical rotation value of (R)-18 was opposite in sign to that of
(S)-18. (R)-Carbamate 18 was converted dehydroamino acid
ester 25 in a similar manner to the synthesis of 22 from 17. The
asymmetric hydrogenation of 25 using (2S,5S)-Et-DuPHOS Rh
catalyst provided (2R,7S)-26 in 70% yield. We carefully examined
the diastereomeric ratio of (2S,7S)-23 and (2R,7S)-26 by 1H-NMR
analysis (Supporting information). The NMR signal patterns of 23
and 26 were distinguishable in C6D6, indicating that the distal
amino acid chiral centers of (2S,7S)-23 and (2R,7S)-26 were
selectively induced under the hydrogenation conditions.
Figure 2. Synthetic plan for 5–8.
To realize the new synthetic route, we initially investigated the
stereochemical outcomes of (2R,5R)-Et-DuPHOS Rh-catalyzed
hydrogenation reactions using DhaaEs 11 and 17 as substrates
(Scheme 2). Z-Bis-carbamate 11 was prepared from Z-10 by
treatment with Boc2O in the presence of 4-[N,N-
(dimethylamino)]pyridine (DMAP). Pleasingly, the key asymmetric
hydrogenation proceeded smoothly under the conditions [H2 (0.8
MPa), (2R,5R)-Et-DuPHOS Rh catalyst (5 mol%), THF, rt] to give
(R)-12 in
a stereoselective manner. The newly created
stereocenter was determined to be R by conversion of 12 to
amino acid 137 and comparison of the optical rotation with that of
the authentic 13. In a similar manner, Z-17, prepared from 14 by
olefination using the Schmidt reagent 15,8,9 followed by tert-
butoxycarbonylation of the resulting Z-DhaaE 16, underwent
stereoselective reduction in the presence of (2S,5S)-Et-DuPHOS
Rh catalyst to give (S)-18 in high yield. The chirality of 18 was
unambiguously determined to be S by comparison of the optical
rotation value of 1910 derived from 18 as well as inspection of the
MTPA amide 20a and 20 b derived from 19. Each amide revealed
dr
= >95:5 (Supporting Information) implying the minor
diastereomer was less than the analytical detection limit. It is
noteworthy that the observed R stereoselectivity from 11 and 17
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Global deprotection of the two methyl esters, Boc, and Bn groups
using AlCl3 and Me2S gave 30 in 41% yield. In our delight,
(2S,7S)-30 displayed potent xCT inhibitory effect at the IC50
values of 4.5 M. It is noteworthy that (2S,7S)-30 (4.5 M) is 1.6-
fold more potent than that of 4-(carboxyphenyl)glycine (4-CPG,
31) known to be one of the most potent xCT inhibitors.14 We
prepared other distereoisomers, (2R,7R)-30, (2S,7R)-32 and
(2R,7S)-32 from 17 to compare their biological activities (Figure
3). These diastereoisomers displayed much lower inhibitory
effects at the IC50 values of 50–80 M, indicating that the
stereochemistry of the designed molecules plays an important
role in the inhibitory effects.
Scheme 3. Stereoselective preparation of 23 and 26 with orthogonal protections.
N-benzoyl DAS derivatives were prepared from 9 via 17. A
typical example is displayed in Scheme 4 and Figure 3.12,13
Deprotection of the Cbz groups of 23 under the hydrogenation
conditions followed by acylation with 28 to give 29 in 75% yield.
Figure 3. Comparison of biological activities of 30and 32.
In summary, we have developed a new entry for the catalytic
asymmetric hydrogenation reaction using dehydroamino acids
with biscarbamate protection. The experimental results
demonstrated in the above revealed that the degree of
stereoselectivity and product yield were found to be the same as
those of the previously established catalytic asymmetric reduction
using Z-1.1 Successful application was demonstrated by the
synthesis of all of the optically active N-Benzoyl DAS derivatives
30 and 32. Among them, we found a potent xCT inhibitor (2S,7S)-
30 which was more potent to the powerful inhibitor 4-CPG (31).
Compound 30 would be a new lead compound to develop
anticancer agent based on the cysteine uptake inhibition.
Recently, DAS and its analogues have received significant
attention as a chemically stable and robust cystine surrogate.15,16
Previous synthetic methods to prepare DAS derivatives have
been mainly performed by chiral pool approach using amino acids
as a starting material and diastereoselective alkylation using
glycine derivatives with a chiral auxiliary.17 However, the previous
synthesis was performed in multi-steps to give a limited number
of the diastereoisomers. In contrast, the present catalytic
asymmetric hydrogenation reaction offers short and flexible
accesses to all of the stereoisomers. The new catalytic
hydrogenation reaction would open a new way to prepared not
Scheme 4. Synthesis of (2S,7S)-30. IC50 values was estimated by the
incorporation of extracellular 14C-glutamate by the C6 cells12 in which xCT is
expressed by the pretreatment with diethyl maleate. 4-Carboxyphenyl)glycine
(4S-CPG) was used for a positive control (IC50 = 7.1 M).14
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[13] The iodides of (2S, 3S)-30 play an important role in the inhibitory effects.
For example, (2S,3S)-N-Cbz DAS (112 M) and (2S, 3S)-
dichlorobenzoyl DAS (92M) showed moderate activities. Full details of
the structure activity relationship study will be reported in due course.
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Acknowledgements
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This work was supported by a grant in aid for KAKENHI
(18K14345 for YY, 17K08216 for TS, 16H01166 and 18H04433
for KS), the Osaka City University (OCU) Strategic Research
Grant for young researchers (2017 and 2018 for YY) and top
priority researchers (2017 and 2018 for TS), and JGC-S
Scholarship Foundation (for YY).
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Keywords: catalytic asymmetric hydrogenation• dehydroamino
acid • diaminosuberic acid • orthogonal protection • cystine-
glutamate exchanger
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Dehydroamino acid
esters with biscarbamate
protection were
employed for the catalytic
asymmetric
hydrogenation for the first
time to give optically
active amino acid esters.
The new method was
successfully applied to
the development of xCT
inhibitors.
Yoko Yasuno,[a] Iho
Mizutani,[a] Yuki Sueuchi,[a]
Yuuka Wakabayashi,[a]
Nozomi Yasuo,[a] Keiko
Shimamoto,[b] and Tetsuro
Shinada*
Page No. – Page No.
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