Concise Synthesis of Anserine: Efficient Solvent Tuning in Asymmetric Hydrogenation Reaction

Article abstract of DOI:10.1055/s-0035-1562796

A concise synthesis of anserine and related compounds was accomplished by Et-DuPhos-Rh-catalyzed asymmetric hydrogenation of dehydrohistidine derivatives in 2,2,2-trifluoroethanol, which played a key role in improving the yield and selectivity.

Full text of DOI:10.1055/s-0035-1562796

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–C
A
letter
Synlett
M. Yamashita et al.
Letter
Concise Synthesis of Anserine: Efficient Solvent Tuning in Asym-
metric Hydrogenation Reaction
Megumi Yamashitaa
Keita Shimizua
Yasuaki Koizumia
Toshiyuki Wakimotoa,b
Yoshitaka Hamashimaa
Tomohiro Asakawaa
Makoto Inaia
Toshiyuki Kan*a
Et
Et
P
P
H2
O
O
Me
Rh
Me
Et-DuPHOS-Rh
N
N
N
N
OMe
OMe
Et
Et
F3CCH2OH
NHX
TfO
NHR
O
>
90% ee
(R,R)-Et-DuPHOS-Rh
O
O
O
Me
N
N
N
N
N
a
OH
OH
OH
School of Pharmaceutical Sciences, University of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
NH
NH2
NH
NH2
NH
NH2
kant@u-shizuoka-ken.ac.jp
Faculty of Pharmaceutical Sciences, Hokkaido University,
Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan
N
H
b
Me
O
O
anserine
balenine
carnosine
Received: 28.06.2016
Accepted after revision: 29.07.2016
Published online: 23.08.2016
metric hydrogenation of a dehydrohistidine moiety as a key
step. We found that the condensation reaction of aldehyde
7
10,11
DOI: 10.1055/s-0035-1562796; Art ID: st-2016-u0417-l
4 with phosphonoacetate 5a or 5b
proceeded smoothly
in the presence of tetramethylguanidine (TMG) to provide
the corresponding dehydrohistidine derivative 6a or 6b
Abstract A concise synthesis of anserine and related compounds was
accomplished by Et-DuPhos-Rh-catalyzed asymmetric hydrogenation
of dehydrohistidine derivatives in 2,2,2-trifluoroethanol, which played a
key role in improving the yield and selectivity.
(Scheme 1).
O
Me
O
O
Me
CHO
TMG
THF
Key words anserine, DuPhos, rhodium catalysis, asymmetric cataly-
sis, hydrogenation, dehydrohistidine, trifluoroethanol
N
N
(
MeO)2P
N
N
+
OMe
OMe
·
HOTf
NHX
NHX
4
5a: X = Cbz
b: X = Boc
6a: X = Cbz, 66%
6b: X = Boc, 73%
Anserine (1; Figure 1), an N-(β-alanyl)-L-histidine deriv-
5
1
ative, is widely distributed in foods, including fish (tuna
Scheme 1 Synthesis of dehydrohistidine derivatives 6a and 6b
2
and bonito) and chicken. It has attracted much attention
3
due to its effect of decreasing lactate and uric acid levels,
4
and is a possible lead compound for drug development. For
For the asymmetric hydrogenation reaction, we selected
structure–activity studies and for investigations of its mode
Et-DuPhos-Rh (7; Table 1), developed by Burk and co-work-
ers,12 as the catalyst, because it can be used with various
enamides in which the amine is protected. The desired re-
action did not proceed in aprotic solvents such as CH Cl ,
of action, an efficient and flexible synthesis of 1 is required.
5
6
The analogues balenine (2) and carnosine (3) can be read-
ily synthesized by acylation of inexpensive histidine and by
alkylation of the 5′-nitrogen of imidazole, but the reported
synthesis of 1 requires laborious alkylation of the less-reac-
2
2
MeCN, EtOAc, or THF. The lack of reactivity in aprotic sol-
vents might be due to coordination of 1-methylimidazole to
the reactive site on Rh. In contrast, we found that the hy-
drogenation reaction proceeded in protic solvents (Table 1).
Compared with yields obtained in MeOH or AcOH (Ta-
ble, 1, entries 1 and 2), a dramatic improvement was ob-
7
tive nitrogen of N-(β-alanyl)-L-histidine derivatives.
8,9
Because aldehyde 4 is readily available, we aimed to
synthesize anserine (1) starting from 4 by using the asym-
1
2c,13
served in 2,2,2-trifluoroethanol (TFE) (entries 3–5).
Be-
O
O
Me
cause the pK values of MeOH, AcOH, and TFE are 15.5, 4.8,
a
N
N
N
N
OH
OH
and 12.4, respectively, AcOH might poison the catalyst as a
result of its stronger acidity, whereas less acidic TFE might
efficiently protonate the methylimidazole group to de-
NH
NH2
NH
NH2
R
O
O
14
crease its basicity. Additionally, the hydrogenation reac-
anserine (1)
balenine (2: R = Me)
carnosine (3: R = H)
tion in TFE could be carried out at a lower temperature and
a lower pressure of hydrogen than in MeOH or AcOH (en-
tries 3 and 4). This might contribute to the high selectivity.
Figure 1 Structures of N-(β-alanyl)-L-histidine amino acids 1, 2, and 3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C

B
Synlett
M. Yamashita et al.
Letter
Table 1 Asymmetric Hydrogenation Reactions of Dehydrohistidine
Derivatives 6a and 6b
O
O
N
N
N
N
CHO
OMe
OMe
N
O
NHX
NHX
Me
H2 (psi)
Et-DuPHOS-Rh (7) (10 mol%)
N
H
N
N
Y
Y
OMe
6a or 6b
10
11a: X = Cbz, Y = Me
11b: X = Boc, Y = H
12a: X = Cbz, Y = Me
12b: X = Boc, Y = H
NHX
solvent, Temp
8
8
a: X = Cbz
b: X = Boc
1) NaH, MeI
THF, 99%
H2 (150 psi)
7 (10 mol%)
1) H2, Pd(OH)2
MeOH
Et
Et
Et
P
P
10
11a
12a
2
Rh
2) 9, EDCI, Et N
2) 5a, TMG
TFE, 50 °C
92% ee
3
THF, 65%
CH2Cl2
55% (3 steps)
Et
TfO
3) aq NaOH, MeOH
aq HCl, 61%
(
R,R)-Et-DuPHOS-Rh (7)
1
) TrCl, pyridine
95%
H2 (100 psi)
7 (10 mol% )
1) SOCl2
MeOH
a
Entry Sub-
strate
H
2
(psi)
Solvent
Temp (°C) Yield (%) ee (%)
10
11b
12b
3
2
3
) 5b, TMG
THF
) HCO2H
F3CCH2OH, 50 °C
2) 9, DCC, HOBt
Et3N, CH2Cl2
21% (3 steps)
3) aq NaOH, MeOH
aq HCl, 39%
1
2
3
4
6a
6a
6a
6a
6b
1550
1200
1425
300
MeOH
AcOH
120
120
50
83
67
99
91
67
44
68
93
99
98
91% (2steps)
F
F
F
3
3
3
CCH
CCH
CCH
2
2
2
OH
OH
OH
50
Scheme 3 Syntheses of balenine (2) and carnosine (3)
5
100
50
a
Determined by chiral HPLC analysis (CHIRALPAK-IC)
On the other hand, the synthesis of carnosine (3) began
with trityl protection of 10 and olefination with the Boc-
protected phosphorane 5b. After selective deprotection of
the trityl group to give 11b, asymmetric hydrogenation to
give amino ester 12b was successfully accomplished, de-
spite the presence of the reactive amine functionality, by
prolongation of the reaction time. After removal of the Boc
group, selective monoacylation of 12b was accomplished
by treatment of the corresponding dihydrochloride salt and
BocNH(CH ) CO H (9) with DCC and benzotriazol-1-ol
Furthermore, the combination of DuPhos-Rh catalyst 7 and
TFE was applicable to the analogous Boc-protected deriva-
tive 6b (entry 5).
Conversion of 8a into anserine (1) was performed as
shown in Scheme 2. After deprotection of the Cbz group un-
der hydrogenolysis conditions followed by incorporation of
15
Boc-β-alanine 9, hydrolysis of the methyl ester and re-
moval of the Boc group provided 1. The spectral data for the
2
2
2
1
13
synthetic 1 ( H NMR, C NMR, IR, and HRMS) were in full
(HOBt). Hydrolysis of the methyl ester and deprotection of
6,17
agreement with those of the natural product.
the Boc group provided carnosine (3).1
In summary, we have developed a concise method for
the synthesis of anserine (1) by a Rh-catalyst-mediated
asymmetric hydrogenation reaction in the presence of re-
active methylimidazole as a key step. This protocol was also
applicable to the preparation of balenine (2) and carnosine
(3), which have different substitutions on the histidine
ring; it should also be suitable for syntheses of various ana-
logues by changing the alanine side-chain unit, and for the
preparation of organocatalysts or chiral ligands for transi-
tion-metal catalysts. Further applications of this method
are being examined in our laboratory.
O
1
) H2, Pd(OH)2
MeOH, 74%
Me
N
N
OMe
NHCbz
1
2) 9, EDCI, Et3N, CH2Cl2, 57%
3) aq NaOH, MeOH
aq HCl, 67%
8a
BocHN
CO2H
9
Scheme 2 Synthesis of anserine (1)
This protocol was also applicable to the syntheses of
balenine (2) and carnosine (3) from 1H-imidazole-4-carbal-
dehyde (10), as shown in Scheme 3. For the synthesis of 2,
methylation of 10 and Horner–Wadsworth–Emmons reac-
tion with 5a gave the enamide ester 11a. The hydrogena-
tion reaction of 11a mediated by DuPhos-Rh catalyst in TFE
proceeded smoothly to provide the corresponding amino
ester 12a. Conversion into balenine (2) was performed by a
similar procedure to that employed for anserine (1).
Acknowledgment
The authors thank Dr. Kazuhiro Watanabe and Dr. Yoshiharu Wata-
nabe (Yaizu Suisankagaku Industry Co., Ltd.) for valuable discussions.
This work was financially supported by Grants-in-Aid for Scientific
Research on Priority Areas 12045232 and 24105530 from the Minis-
try of Education, Culture, Sports, Science and Technology (MEXT) of
Japan, and by a grant for the Platform Project for Supporting Drug
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C

C
Synlett
M. Yamashita et al.
Letter
Discovery and Life Science Research (Platform for Drug Discovery, In-
formatics, and Structural Life Science) from the Japan Agency for
Medical Research and Development (AMED).
(11) Schmidt, U.; Meyer, R.; Leitenberger, V.; Griesser, H.;
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Supporting Information
Tetrahedron 1994, 50, 4399.
(
13) When TFE was used as the solvent, it was possible to decrease
the hydrogen pressure and the temperature; a slight increase in
the enantioselectivity was also observed.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562796.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
Asymmetric Hydrogenation of 6a; Typical Procedure
(
R,R)-Et-DuPHOS-Rh (7) (14 mg, 10 mol%) was added to a solu-
References and Notes
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as a pale-yellow oil; yield: 58 mg (91%); optical purity >99% ee
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chiral
HPLC
[CHIRALPAK-IC,
hexane–EtOH–Et NH
2
1
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–
1
(
; H
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13
Hz, 1 H), 6.76 (s, 1 H), 7.33–7.37 (m, 6 H). C NMR (125 MHz,
CDCl ): δ = 26.7, 31.3, 52.7, 53.4, 67.1, 126.4, 128.2, 128.3, 128.6,
1
(
(
(
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1
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+
34.1, 136.0, 138.5, 155.6, 171.3. HRMS (ESI): m/z [M + H] calcd
for C16H20N O : 318.1448; found: 318.1451.
3
4
1
(
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without any protection of the imidazole group. Boc protection
was therefore selected in the case of carnosine synthesis.
17) The optically rotation of the synthesized carnosine (3) matched
(
1
(
(8) Chen, B.-C.; Skoumbourdis, A. P.; Sundeen, J. E.; Rovnyak, G. C.;
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(
(
9) Preparation of 4 was performed by single protection of 1H-
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acid hydrolysis. Application of similar conditions to an N-acyl-
histidine resulted in N-methylation of the amide group.
(
25
6
25
that of natural carnosine: [α]D +21.0 (c 0.215, H O) [Lit. [α]
+
proceeded with high enantioselectivity.
2
D
20.5 (c 2.0, H O)]. The asymmetric reduction of 11b therefore
2
(10) Schmidt, U.; Liebenknecht, A.; Wild, J. Synthesis 1984, 53.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C