The first synthesis of kaitocephalin based on the structure revision

Article abstract of DOI:10.1016/S0040-4039(01)02255-9

A total synthesis of kaitocephalin (2), a glutamate receptor antagonist, was accomplished employing a novel stereoselective C-C bond forming reaction of a nitrone (8) and a halide (11) with zinc in aqueous solvent under sonication as a key step. The absolute configuration of kaitocephalin was confirmed to be 2R,3S,4R,7R,9S.

Full text of DOI:10.1016/S0040-4039(01)02255-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 861–864
The first synthesis of kaitocephalin based on the structure
revision
Hidenori Watanabe,* Masayuki Okue, Hiroyuki Kobayashi and Takeshi Kitahara*
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo,
1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
Received 1 November 2001; revised 21 November 2001; accepted 22 November 2001
Abstract—A total synthesis of kaitocephalin (2), a glutamate receptor antagonist, was accomplished employing a novel
stereoselective CꢀC bond forming reaction of a nitrone (8) and a halide (11) with zinc in aqueous solvent under sonication as a
key step. The absolute configuration of kaitocephalin was confirmed to be 2R,3S,4R,7R,9S. © 2002 Elsevier Science Ltd. All
rights reserved.
Kaitocephalin was isolated from Eupenicillium shearii
PF1191 by Shin-ya and Seto et al. in 1997.1 This
compound exhibits potent inhibitory activity against
neuronal cell death by the action of antagonist for
Herein, we report a total synthesis of kaitocephalin (2,
revised structure) employing a newly developed reaction
of a nitrone and an alkylhalide as a key step (Fig. 1).
NMDA (N-methyl-
D
-aspartic acid) and AMPA/KA (a-
Our strategy shown in Scheme 1 is to construct com-
pound A by a CꢀC bond forming reaction of nitrone B
and halide C. Nitrone B can be derived from an aldol
reaction between the known compounds (3 and 4)
followed by standard functional group manipulation.
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/
kainic acid) receptors. The initially proposed
stereochemistry (1) of kaitocephalin is depicted below.2
The first total synthesis of 1 was announced very
recently by Ma et al. and the spectroscopic data of their
synthetic 1 were reported to be identical with those of
natural kaitocephalin.3 However, after we had also
finished a synthesis of 1, we found that 1H NMR
spectral data of our synthetic 1 and its retention time
on HPLC were not identical with those of the natural
compound. Additionally, epimerization at C-2 of natu-
ral kaitocephalin during a derivatization was suggested
by model experiments, and a revised structure (2) was
proposed in the preceding paper.4
The preparation of nitrone 8 and iodide 11, precursors
of the key reaction, is shown in Scheme 2. The sequence
began from lactone 3 which was prepared from
line using Seebach’s method.5 Treatment of aldehyde 4
(prepared from
-serine by Garner’s method6) with the
L-pro-
L
lithium enolate of lactone 3 (THF, −78°C) provided
syn-alcohol 5a and anti-alcohol 5b (51% combined
yield, 5a/5b=2:3). The stereochemistries of 5a and 5b
were determined by NOESY experiments of derivatives
Cl
Cl
O
O
H2N
H2N
HO
HO
2
COOH
COOH
6
5
4
NH
NH
3
7
Cl
Cl
9
OH
COOH
OH
COOH
HOOC
HOOC
N
H
N
H
8
H
H
2R,3S,4R,7R,9S
Revised Structure (2)
2S,3S,4R,7R,9S
Kaitocephalin (1) (Proposed Structure)
Figure 1.
Keywords: kaitocephalin; total synthesis; NMDA antagonist; AMPA/KA antagonist.
* Corresponding authors. Fax: 81-3-5841-8019; e-mail: atkita@mail.ecc.u-tokyo.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02255-9

862
H. Watanabe et al. / Tetrahedron Letters 43 (2002) 861–864
R4
R4
H
HN
Cbz
R3
R5
O
HN
R3
N
N
+
2
NH
A
O
O
R5
OR2
COOR1
OHC
OR2
COOR1
N
O
But
R1OOC
NH
C
N
H
X
R1OOC
OH
4
B
3
Scheme 1. Synthetic plan.
O
O
BzlO
N
Cbz
N
N
Cbz
N
O
a
NHCbz
OTBDPS
d, e, f
3 + 4
+
OH
OH
O
O
O
N
But
6
O
O
But
But
b, c
5a
5b
Cbz
HN
Cbz
HN
g, h
i
OTBDPS
OTBDPS
OTMS
OTMS
COOBzl
7
N
O
N
H
COOBzl
8
Cl
Cl
Cl
O
O
NH3+Cl–
OH
j
k, l
BzlO
BzlO
NH
NH
BzlOOC
Cl
OH
I
L-Serine benzyl ester hydrochloride
BzlOOC
10
BzlOOC
11
Scheme 2. Synthesis of 8 (=B) and 11 (=C). (a) LDA, THF, −78°C, 51% (5a/5b=2:3); (b) Dess–Martin periodinane, CH2Cl2,
Py, 0°C; (c) NaBH4, EtOH/THF (5:1), 0°C, 31%; (d) 10% H2SO4, 1,4-dioxane, rt–80°C; (e) BzlBr, DBU, CH3CN, rt; (f)
TBDPSCl, Et3N, DMAP, CH2Cl2, rt, 84%; (g) 80% AcOH, 60°C, 52%; (h) TMSCl, imidazol, DMF, 0°C, 96%; (i) MeReO3,
Urea·H2O2, MeOH, rt, 84%; (j) 4-benzyloxy-3,5-dichlorobenzoic acid, BOP reagent, Et3N, CH2Cl2, 0°C–rt, 92%; (k) MsCl, Et3N,
CH2Cl2, 0°C, 74%; (l) NaI, acetone, rt, 84%.
9a and 9b (Scheme 3). The minor product 5a was
converted into desired diastereomer 5b by Dess–Martin
oxidation followed by reduction with NaBH4 (31%
from 5a). Treatment of 5b with 10% H2SO4 caused an
intramolecular transacetalization of t-butyloxazoline
and hydrolysis of dimethyloxazoline. Benzylation of the
carboxyl group followed by protection of the primary
alcohol with TBDPSCl gave 6 in 84% yield over three
steps. Hydrolysis of t-butyloxazoline with 80% AcOH
(52% yield) and subsequent protection of the secondary
alcohol as the TMS ether provided 7 (96% yield).
Oxidation of the secondary amine of 7 with MeReO3–
was then converted into iodide 11 via the mesylate in
62% yield. The iodide could be synthesized via the
tosylate as well, but the use of mesylate allowed an easy
purification of 11 by simple recrystallization.
The key CꢀC bond forming step of nitrone 8 and halide
11 with zinc under ultrasound irradiation is outlined in
Scheme 4. Treatment of nitrone 8 and iodide 11 with
zinc activated by CuI under irradiation of ultrasound
(THF/H2O=3.3:1,ambienttemperature)8 gavehydroxyl-
amine 12 in 75% yield as a single isomer. The stereo-
chemistry at C-7 of 12 was inferred from analogy with
2-epi-12 whose stereochemistry had already been deter-
mined.4 After reduction of hydroxylamine with zinc
and ammonium chloride (98% yield), protection of the
secondary amine with CbzCl followed by removal of
TBDPS and TMS groups by TMSCl–MeOH system
afforded diol 13 in 45% yield over two steps. Stepwise
oxidation of the primary alcohol of 13 proceeded selec-
7
urea·H2O2 afforded nitrone 8 (=B, 84% yield).
Meanwhile, another precursor [11 (=C)] for the key
coupling reaction was prepared from
L-serine benzyl
ester hydrochloride. Amidation with 4-benzyloxy-3,5-
dichlorobenzoic acid by BOP reagent in the presence of
triethylamine provided 10. The hydroxyl group of 10

H. Watanabe et al. / Tetrahedron Letters 43 (2002) 861–864
863
BzlO
BzlO
Cbz
Cbz
O
O
N
N
H
a, b
a, b
N
H
O
N
H
O
5b
5a
But
But
H
O
O
NOE
NOE
9b
9a
Scheme 3. NOEs of 9a and 9b. (a) 10% H2SO4, 1,4-dioxane, rt; (b) BzlBr, DBU, CH3CN, rt.
Cl
Cbz
Cbz
O
HN
HN
BzlO
a
b, c, d
OTBDPS
OTMS
NH
OTBDPS
OTMS
COOBzl
7
Cl
N
O
BzlOOC
N
COOBzl
H
OH
8
12
Cl
Cl
Cbz
O
O
HN
BzlO
H2N
HO
NH
e, f, g
OH
COOH
OH
NH
Cl
OH
COOBzl
Cbz
BzlOOC
N
Cl
H
HOOC
N
H
H
COOH
Kaitocephalin (2)
13
Scheme 4. Completion of the synthesis of 2. (a) 11, Zn (8 equiv.), CuI (3.6 equiv.), THF/H2O (3.3:1), ultrasound, rt, 75%; (b) Zn,
satd NH4Cl, EtOH, 90°C, 98%; (c) CbzCl, K2CO3, toluene/H2O; (d) TMSCl, MeOH, rt, 45%; (e) 4-methoxy-TEMPO, KBr, satd
NaHCO3, NaClO, CH2Cl2, 0°C; (f) NaClO2, 2-methyl-2-butene, NaH2PO4, ButOH/H2O (10:3), rt, 86%; (g) H2, 20% Pd(OH)2–C,
EtOH/CHCl3 (10:1), rt 27%, after preparative HPLC.
tively with 4-methoxy-TEMPO and co-oxidizing
reagent system9 followed by sodium hypochlorite to
give carboxylic acid (86%, two steps). Finally,
hydrogenolysis of the benzylic protective groups with
H2/20% Pd(OH)2–C afforded the target molecule,
kaitocephalin (2). In this step, chloroform was indis-
pensable as it minimized dechlorination of the aromatic
ported by a Grant-in-Aid for Scientific Research (Prior-
ity Area (A) ‘Exploitation of Multi-Element Cyclic
Molecules’ and General Research (B); No. 12460050)
from the Japanese Ministry of Education, Culture,
Sports, Science and Technology. We also thank Sankyo
Foundation of Life Science and Suntory Institute for
Bioorganic Research for financial support.
1
ring. H NMR spectral data, retention time on HPLC
and specific rotation of synthetic 2 were identical with
those of authentic natural kaitocephalin.10
References
In conclusion, the first total synthesis of the revised
structure of kaitocephalin (2) was accomplished starting
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tion of kaitocephalin has been proven to be
2R,3S,4R,7R,9S.
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Acknowledgements
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University of Tokyo for a kind gift of the H NMR
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1

864
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J=5.5, 6.4, 14.4 Hz), 3.65 (m, 1H), 4.11 (brs, 1H), 4.31
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−26.6° (c 0.19, H2O). [lit.1 1H NMR (500 MHz, D2O) l
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6.0, 14.0 Hz), 2.41 (ddd, J=6.0, 7.0, 14.5 Hz), 3.70 (m),
4.16 (brs), 4.35 (dd, J=6.0, 8.0 Hz), 4.41 (brs), 7.62 (s,
2H); [h]2D1 −31° (c 0.7, H2O)].
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