Facile synthesis of (S)-gizzerosine - A potent inducer of gizzard erosion in chicks - Using successive zinc-mediated and palladium-catalyzed coupling reactions

Article abstract of DOI:10.1055/s-2005-918447

Gizzerosine, a potent inducer of gizzard erosion in chicks, was synthesized using successive inc-mediated and palladium-catalyzed coupling reactions as the key steps. The piperonyl moiety was used as a novel N-protecting group. Georg Thieme Verlag Stuttga

Full text of DOI:10.1055/s-2005-918447

SHORT PAPER
3191
Facile Synthesis of (S)-Gizzerosine – A Potent Inducer of Gizzard Erosion in
Chicks – Using Successive Zinc-Mediated and Palladium-Catalyzed Coupling
Reactions
S
uccessive Zinc-M
a
ediated and
s
Palladiu
u
m-Catalyzed
h
Coupling
R
e
a
action
s
ru Shimasaki,a Hiromasa Kiyota,*a Minoru Sato,b Shigefumi Kuwaharaa
a
Division of Bioscience & Biotechnology for Future Bioindustry, Graduate School of Agricultural Science, Tohoku University,
1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Fax +81(22)7178783; E-mail: kiyota@biochem.tohoku.ac.jp
b
Division of Biological Resource Science, Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiya,
Aoba-ku, Sendai 981-8555, Japan
Received 15 September 2005
This paper is dedicated to Professor Steven V. Ley, FRS, CBE, on the occasion of his 60th birthday.
NHZ
Abstract: Gizzerosine, a potent inducer of gizzard erosion in
BnO
I
L-serine
chicks, was synthesized using successive zinc-mediated and palla-
dium-catalyzed coupling reactions as the key steps. The piperonyl
moiety was used as a novel N-protecting group.
4 steps
~87%
3
O
Key words: gizzerosine, gizzard erosion, chickens, total synthesis,
histamine
NHZ
NHZ
Br
BnO
BnO
ZnI
a)
‘Black vomit’ is a serious disease for chickens and is ac-
companied by gizzard erosion or ulceration.1 In 1983,
Naito et al. investigated the cause of this disease and iso-
lated an amino acid gizzerosine (1), a potent inducer of
gizzard erosion, which was generated during the heat
treatment of brown fish meal.2 The structure and absolute
stereochemistry of 1 was confirmed by Mori’s synthesis
of racemic3 and optically active forms.4 Since 1 is in great
demand as an important ulcerating agent for biologists, as
well as a standard for the quality control of fish meal, we
began to develop a practical synthesis of 1. Here we de-
scribe a short and efficient synthesis of 1.
At first, we targeted Mori’s synthetic intermediate 2,4
which could be simply prepared by a zinc-mediated 1,4-
addition reaction5a of the known iodide 3 with acrolein.
However, this reaction did not proceed as expected and
only the corresponding alanine derivative was formed.
Next we tried to prepare Mori’s other intermediate, alco-
hol 6, using the coupling reaction with allyl bromide5b and
hydroboration. Preparation of 5 was successful (98%) and
hydroboration–oxidation gave the desired 6, which could
then be utilized in the formal synthesis of 1. The yield for
this step was improved from 32% to 68% by applying
mildly alkaline conditions (NaOAc, H2O2, pH 7.5)6 dur-
ing the oxidation step to avoid concomitant hydrolysis of
the benzyl group.
O
O
4
5
b)
O
NHZ
NHZ
ref. 4
BnO
BnO
OH
O
O
O
2
6
ref. 4
N
NH2
HO
N
H
N
H
O
gizzerosine (S)-1
Scheme 1 Formal synthesis of 1. a) i. allyl bromide (1.2 equiv), Zn
(6.0 equiv), (CH2Br)2 (0.3 equiv), TMSCl (0.06 equiv), DMF, 60 °C,
50 min ii. CuCN (1.0 equiv), LiCl (2.0 equiv), –78 °C, 2 h (98%); b)
i. BH3·SMe2 (0.5 equiv), THF, 0 °C, 12 h. ii. H2O2 (30%, 3.3 equiv),
NaOAc (2.5 equiv) (68%).
derivatives were examined. Although histamine itself did
not react, its derivatives 10a–d8 (Table 1) with electron-
donating groups on the primary nitrogen atom were cou-
pled with 9 to give 11a (N-Bn), 11b (N-PMB), 11c [N-
(3,4-dimethoxybenzyl)], or 11d (N-piperonyl). Treatment
of 11a with Pd/C under hydrogen gave 7-N-benzylgizze-
rosine, however, deprotection of the N-benzyl group was
unsuccessful even in an acidic suspension and palladium
catalyst under 10 atm of hydrogen pressure. Deprotection
of 11b resulted in decomposition of the products. On the
other hand, hydrogenation and deprotection of piperonyl
derivative 11d smoothly afforded gizzerosine (1) as the
dihydrochloride salt using Pd/C in ethanol under a hydro-
gen atmosphere in 47% yield. As far as we know, this is
the first case of using the piperonyl group as an N-protect-
Next we aimed to improve the overall yield by changing
the strategy. As shown in Scheme 2, chain elongation
with 3-bromo-1-propenyl acetate 77 afforded SN2¢ product
9, exclusively in 98% yield, instead of 8. This allylic ace-
tate 9 was a good substrate for palladium-catalyzed cou-
pling reactions. Thus, reactions with histamine
SYNTHESIS 2005, No. 19, pp 3191–3192
x
x.
x
x
.
2
0
0
5
Advanced online publication: 25.10.2005
DOI: 10.1055/s-2005-918447; Art ID: C07305SS
© Georg Thieme Verlag Stuttgart · New York

3192
Y. Shimasaki et al.
SHORT PAPER
In summary, the short, efficient, and facile synthesis of
gizzerosine (S)-1, a potent inducer of gizzard erosion, was
achieved using successive zinc-mediated and palladium-
catalyzed coupling reactions as the key steps. The pipero-
nyl moiety was used as a novel N-protecting group.
NHZ
NHZ
AcO
not SN2
BnO
ZnI
BnO
O
O
4
8
AcO
a)
Br
7
SN2′
NMR spectra were conducted at 300 MHz (1H NMR) and 150 MHz
1
(13C NMR) with acetone as the reference (2.22 ppm, H NMR;
215.94 ppm, 13C NMR).
NHZ OAc
N
(+)-1·2HCl (9)
Amorphous solid; mp 250–251 °C (dec.) [Lit.4 251–252 °C (dec.)];
BnO
H
N
N
H
[a]D22 +9.45 (c 0.555, H2O) {Lit. [a]D22 +10.3 (c 1.28, H2O)}.
O
9
R
IR (ATR, Zn–Se): 3300–2300 (br s), 3116 (s), 2786 (s), 2450 (m),
1634 (s), 1601 (s), 1522 (s), 1462 (s), 1395 (s), 1348 (m), 1329 (m),
1235 (w), 1052 (w), 957 (w), 839 (w), 794 (w), 719 (w), 623 (m)
cm–1.
1H NMR (D2O): d = 1.35–1.60 (2 H, m), 1.74 (2 H, quint, J = 7.5
Hz), 1.89 (2 H, m, pseudo q, J = 7.4 Hz), 3.11 (4 H, pseudo t, J = 6.6
Hz), 3.37 (2 H, pseudo t, J = 7.2 Hz), 3.75 (1 H, t, J = 6.0 Hz,
CHC=O), 7.26 (1 H, br s), 8.30 (1 H, br s).
10a–d
b)
N
NHZ
BnO
N
H
N
R
O
11a: R = Bn
(50%)
(92%)
3,4-(OMe)2Bn (trace)
PMB
11b:
11c:
11d:
13C NMR (D2O): d = 22.04, 22.91, 25.65, 30.38, 46.86, 47.72,
54.99, 116.93, 131.45, 135.69, 175.08 (C=O).
c)
piperonyl
(71%)
HRMS-FAB: m/z calcd for C11H21N4O2 [M + H] +: 241.1665;
found: 241.1671.
N
NH2
HO
N
H
N
R
(S)-1
Acknowledgment
O
We thank Prof. Takeshi Sugai (Keio Univ., Japan) for useful advice
and Prof. Hidenori Watanabe (Tokyo Univ., Japan) for kindly
giving us the authentic sample. Financial support by grant-in-aid
from the Japan Society for the Promotion of Science (No.
17580092) is gratefully acknowledged.
Scheme 2 Synthesis of 1 by a palladium-catalyzed coupling reac-
tion. a) 7 (1.2 equiv), CuCN (1.0 equiv), LiCl (2.0 equiv), DMF, 2 h
(98%); b) 2¢-N-(p-R-C6H4CH2)histamine (1.2 equiv), Pd2(dba)3 (0.05
equiv), PPh3 (0.05 equiv), THF, 50 °C, 2 h; c) H2, Pd(OH)2/C, H2O–
THF–EtOH (1:1:3) (47% for 10d).
References
Table 1 Preparation of 2¢N-Protected Histamines
(1) Johnson, D. C.; Pinedo, C. Avian Dis. 1971, 15, 835.
(2) Okazaki, T.; Noguchi, T.; Igarashi, K.; Sakagami, Y.; Seto,
H.; Mori, K.; Naito, H.; Masumura, T.; Sugahara, M. Agric.
Biol. Chem. 1983, 47, 2949.
(3) Mori, K.; Okazaki, T.; Noguchi, T.; Naito, H. Agric. Biol.
Chem. 1983, 47, 2131.
N
N
a)
N
H
N
H
Ar
H2N
N
H
histamine
10a–d
(4) Mori, K.; Sugai, T.; Maeda, Y.; Okazaki, T.; Noguchi, T.;
Naito, H. Tetrahedron 1985, 41, 5307.
(5) (a) Dexter, C. S.; Jackson, R. F. W. J. Org. Chem. 1999, 64,
7579. (b) Dunn, M. J.; Jackson, R. F. W.; Pietruszka, J.;
Turner, D. J. Org. Chem. 1995, 60, 2210.
(6) Xue, C.-B.; Voss, M. E.; Nelson, D. J.; Duan, J. J.-W.;
Cherney, R. J.; Jacobson, I. C.; He, X.; Roderick, J.; Chen,
L.; Corbett, R. L.; Wang, L.; Meyer, D. T.; Kennedy, K.;
DeGrado, W. F.; Hardman, K. D.; Teleha, C. A.; Jaffee, B.
D.; Liu, R.-Q.; Copeland, R. A.; Covington, M. B.; Christ,
D. D.; Trzaskos, J. M.; Newton, R. C.; Magolda, R. L.;
Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2001, 44, 2636.
(7) Lombard, M.; Girotti, R.; Morganti, S.; Trombini, C. Org.
Lett. 2001, 3, 2981.
Entry ArCHO
Products
10a
Yields (%)
1
2
3
4
Benzaldehyde
Anisaldehyde
94
93
10
89
10b
3,4-Dimethoxybenzaldehyde
Piperonal
10c
10d
a Conditions: ArCHO (2.5 equiv), NaBH4 (2.0 equiv), MS 3Å,
MeOH.
ing group. This low yield was due to the instability of 1 in
the presence of palladium catalysts. The overall yield
from 3 was 33% in three steps (29% from L-serine in sev-
en steps). The spectroscopic data of 1 coincided with
those reported.3,4
(8) N-Benzylhistamine: Beke, G.; Szabó, L. F.; Podány, B. J.
Nat. Prod. 2002, 65, 649.
Synthesis 2005, No. 19, 3191–3192 © Thieme Stuttgart · New York