Total synthesis of (-)-kaitocephalin

Article abstract of DOI:10.1039/c3cc42365d

(-)-Kaitocephalin has been synthesized. With the C9 stereocenter from Garner's aldehyde, the C4 quaternary carbon was installed by the desymmetrization of the Cbz-protected serinol. The remaining stereogenic centers were generated through mercuriocyclizat

Full text of DOI:10.1039/c3cc42365d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Total synthesis of (À)-kaitocephalin†
Wonchul Lee,a Joo-Hack Younb and Sung Ho Kang*a
Cite this: Chem. Commun., 2013,
49, 5231
Received 1st April 2013,
Accepted 17th April 2013
DOI: 10.1039/c3cc42365d
www.rsc.org/chemcomm
(À)-Kaitocephalin has been synthesized. With the C9 stereocenter
from Garner’s aldehyde, the C4 quaternary carbon was installed by the
desymmetrization of the Cbz-protected serinol. The remaining stereo-
genic centers were generated through mercuriocyclization, epoxida-
tion and regioselective epoxide opening, in which the quaternary
carbon most likely played crucial roles in the stereoinduction.
(À)-Kaitocephalin (1), which is barely available, was isolated
from the filamentous fungus Eupenicillium shearii PF1191 by
Shin-ya et al. in 1997.1 It has a novel molecular architecture
assembled by three amino acids, alanine, proline and serine,
through carbon–carbon linkages. Its stereochemistry was initially
proposed to be (2S,3S,4R,7R,9S) based on NMR studies,2 and later
Scheme 1 Retrosynthetic analysis of kaitocephalin (1). Boc = tert-butoxycarbo-
nyl, Cbz = benzyloxycarbonyl, Bz = benzoyl.
revised to (2R,3S,4R,7R,9S) based on synthetic studies.3 The the protected serinol 4, mercuriocyclization of the olefinic
natural product turned out to be a pharmaceutically precious carbamate 3 could induce the desired C7 chiral center
molecule, displaying strong antagonism against NMDA (N-methyl- (Scheme 1). Previously, we reported a related desymmetrization
D-aspartate) and AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole method, which was found to be applied most effectively to the
propionic acid)/KA (kainic acid) receptors,1,2,4 which correspond N-benzoylated serinols.9 Since removal of the N-benzoyl group
to the three types of the ionotropic glutamate receptors implicated usually requires harsh conditions, its synthetic applicability
in various physiological functions such as learning, memory and was thought to be more reliable by extending the method to the
neuro-plasticity.5 Since kaitocephalin shows the same level of serinols with a readily removable protecting group. In the
potency as CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a repre- proposed mercuriocyclization, a Hg cation is expected to be
sentative antagonist against AMPA/KA receptors, and much less delivered from the a face opposite to the t-butyl carbamate
cytotoxicity than CNQX,1,2,4 this first naturally purified antagonist group to induce the requisite stereoselectivity. Furthermore, the
is regarded as a potential lead compound to develop therapeutic C4 stereocenter may work synergistically with the carbamate
agents for the treatment of neurological diseases such as stroke substituent because the larger conjugated ester group probably
and epilepsy.6 Its intriguing unique structural features and stays away from the Hg-bonded substituent in the transition
scarcity as well as beneficial biological properties have stimu- state. The C2 and C3 stereogenic centers were planned to be
lated synthetic organic chemists to engage in its synthetic settled by the substitution of the epoxide, formed from the
studies. Herein, we describe the asymmetric total synthesis of allylic alcohol 2 through the observed intrinsic stereoselectivity
kaitocephalin.3,7,8
in the related epoxidation8d and dihydroxylation,7b using an
Our synthetic analysis showed that while the C4 stereochemistry N nucleophile. The remaining asymmetric C9 carbon would be
would be installed by the stereoselective desymmetrization of delivered by employing the Garner’s aldehyde 7.10
Our synthesis began with preparation of 4. The Wittig
olefination of 7 with the known phosphonium salt 611 pro-
duced the cis-alkene 8 in 73% yield along with 9% of its trans-
isomer (Scheme 2). After desilylation of 8, the resulting alcohol
was converted to the iodide 9 as the alkylating partner to the
a MIRC, Department of Chemistry, KAIST, Daejeon 305-701, Korea.
E-mail: shkang@kaist.ac.kr; Fax: +82-42-350-2810; Tel: +82-42-350-2825
b Department of Chemical and Biochemical Engineering, Sun Moon University,
Asan-si, Chungnam 336-840, Korea
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc42365d malonate 5 in 95% yield. Alkylation of 5 with 9 proceeded
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5231--5233 5231

View Article Online
Communication
ChemComm
demasked primary alcohol, hydrogenolysis of the Cbz protecting
group with concomitant hydrogenation and cyclization of the
1
generated g-amino carboxylic acid. Since the H NMR spectral
signals of 15 are separated discretely, the related NOE experi-
ments could be readily conducted. The strong NOE crosspeaks
between H7 and H9 of 15 showed that C7s of 13 and 15 have the
requisite R configurations. The correct stereochemical assign-
ment of 13 was also corroborated by synthesizing kaitocephalin
1 (vide infra).
The remaining synthetic concerns for the target molecule 1
were installation of the amino alcohol functionality at the
olefinic double bond of 13, and adjustment of the oxidation
states of its functional groups. The previously reported methods
for the amino alcohol functionality harnessed aldol condensation–
oxidation–reduction,7a,c–e dihydroxylation–thiocarbonylation–
substitution,7b and carbamoylation–intramolecular nitrene
insertion.7f To capitalize on epoxide opening reaction for the
functionalization as proposed in our retrosynthetic analysis,
the initial epoxidation of the conjugated ester 13 was tried
under basic conditions to no avail. Consequently, 13 was
reduced to the allylic alcohol 2, which was subjected to mCPBA
or the Sharpless asymmetric epoxidation to provide a single
diastereomeric epoxide 16 efficiently (Scheme 3). In contrast to
the observation for a structurally closely related allylic alcohol
by Hatakeyama’s group,8d the Sharpless epoxidation of 13
Scheme 2 Preparation of the pyrrolidine 13. (a) 6, nBuLi, HMPA, THF, À78 1C to
0 1C, then 7, À40 1C to 0 1C, 73%; (b) nBu4NF, THF, 0 1C, 97%; (c) I2, Ph3P,
imidazole, CH2Cl2, 0 1C, 98%; (d) Cs2CO3, DMF, 0 1C to RT, then 9, RT; (e) NaBH4,
EtOH, RT, 68% (over 2 steps); (f) 11, BzCl, Et3N, THF, RT, 90% (90% de, 4% of SM);
(g) Dess–Martin periodinane, CH2Cl2, 0 1C, 90% (90% de, 5% of SM); (h) Ph3P =
CHCO2Et, CH2Cl2, reflux, 88% (one diastereomer); (i) Hg(tfa)2, NaHCO3, CH2Cl2, 0 1C,
then Et3B, LiBH4, THF, À78 1C, 82% (4% of SM); (j) 80% aq. AcOH, 50 1C; (k) AZADO,
PhI(OAc)2, pH 6.8 phosphate buffer, MeCN, RT, 82% (over 2 steps); (l) H2, 10 wt% Pd/C,
EtOH, 50 1C; (m) BOP, iPr2NEt, CH2Cl2, RT, 78% (over 2 steps). TBDPS = tert-
butyldiphenylsilyl, HMPA = hexamethylphosphoramide, DMF = N,N-dimethylformamide,
tfa = trifluoroacetate, AZADO = 2-azaadamantane N-oxyl, BOP = (benzo-triazol-
1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate.
smoothly in the presence of Cs2CO3 and the subsequent proceeded uneventfully. Since (MeO)3B is known to induce
reduction of the alkylated diester with NaBH4 afforded the the endo-mode epoxide-opening of 2,3-epoxy alcohols through
desymmetrization substrate 4 in 68% yield. When 4 was sub- intramolecular chelation,14 16 was substituted by an azide
jected to our previously reported benzoylation conditions using anion in the presence of (MeO)3B to give rise to the azido
the chiral catalyst 10,9 the monobenzoate 12 was obtained in alcohol 17 exclusively in 91% yield. Probably, the complete
88% yield with 76% de. After replacing the Cbz protecting regioselectivity was synergistically controlled by the steric
group of 4 with COOMe, COOPh, COOCH2CCl3, Boc etc., the bulkiness from the quaternary center. The epoxide opening
corresponding substrates were exposed to the desymmetriza-
tion conditions, which revealed that the highest diastereo-
selectivity could be attained with the Cbz protecting group.
To streamline the desymmetrization strategy for our total
synthesis, several bisoxazolines were scouted as chiral ligands
using 4 as the substrate which led to 11 as the best catalyst,
which delivered 12 in 90% yield with 90% de along with 4% of
the recovered 4. Two carbon elongation of 12 was conducted
through the Dess–Martin oxidation12 followed by the Wittig
olefination which gave the conjugated trans-ester 3 in 79% yield
after chromatographic removal of 4% of the diastereomeric
trans-ester and 4% of the corresponding cis-isomers. The next
issue, the stereoselective formation of the pyrrolidine ring, was
approached by electrophile-promoted cyclization. While the
initial attempt using iodocyclization was unsuccessful, mercurio- Scheme 3 Synthesis of kaitocephalin diethylamine salt (1ÁHNEt2) via the TBS-
protected triol 20. (a) DIBAL-H, THF, À78 1C, 87%; (b) mCPBA, CH2Cl2, À20 1C,
cyclization was found to be rewarding. Accordingly, 3 was treated
with Hg(tfa)2, and then reductively demercurated in situ with
LiBH4 in the presence of Et3B13 to furnish the required stereo-
chemical pyrrolidine 13 in 82% yield and 4% of its diastereomer
98%; or (–)-DIPT, Ti(OiPr)4, M.S. (4 Å), tBuO2H, À20 1C, 94%; (c) NaN3, (MeO)3B,
i
DMF, RT to 50 1C, 91%; (d) 3 M HCl, MeOH, 40 1C; (e) 18, BOP, Pr2NEt, CH2Cl2,
0 1C to RT, 83% (over 2 steps); (f) BzCl, Et3N, CH2Cl2, 0 1C, 89%; (g) TBSOTf,
2,6-lutidine, CH2Cl2, À78 1C to 0 1C, 97%; (h) K2CO3, MeOH, 0 1C, 95%; (i) AZADO,
along with 4% of the recovered 3. At this stage, it was not PhI(OAc)2, pH 6.8 phosphate buffer, MeCN, RT, then 6 M HCl, RT; (j) H2, 20 wt%
Pd(OH)2/C, CHCl3, EtOH, RT; (k) purification: Dowexs 50WX4 (H+ form) with 1 M
possible to elucidate the stereochemistry of 13 at the newly
installed C7 stereogenic center using NMR studies due to the
peak broadenings caused by various rotamers. Alternatively, it
was converted to pyrrolizidinone 15 efficiently by a sequence of
NH4OH, COSMOSIL 75C18-OPN with H2O, then HPLC (COSMOSIL 5C18-PAQ) with
5% MeOH in 20 mM Et2NH-CO2 buffer pH 7, 26% from 20. DIBAL-H
=
diisobutylaluminum hydride, mCPBA = m-chloroperbenzoic acid, DIPT = diisopro-
pyl tartrate, M.S. = molecular sieves, Bn = benzyl, TBS = tert-butyldimethylsilyl,
acidic hydrolysis of the acetonide group, oxidation of the Tf = trifluoromethanesulfonyl.
c
This journal is The Royal Society of Chemistry 2013
5232 Chem. Commun., 2013, 49, 5231--5233

View Article Online
ChemComm
Communication
reaction to implement the concurrent oxidation of the triol 23 to
the tri(carboxylic acid) 24. For the structural elucidation of 24, it
was converted to the tri(methyl ester) 25 in 74% yield, the 1H NMR
spectra of which show three methyl peaks as singlets at d 3.85, 3.81
and 3.77 ppm indicating the existence of three methyl esters. In
addition, the HRMS measurement of 25 was found ([M + Na]+ =
700.1199 (calcd: 700.1183)) to support the reliable formation of the
tri(carboxylic acid) 24 in the oxidation step. The crude 24 was
reacted with hydrogen gas in the presence of Pd(OH)2/C and CHCl3
for debenzylation as well as azide reduction. After filtration of the
generated amino tri(carboxylic acid) through an ion-exchange resin,
the semi-purified oxazolidinone-protected kaitocephalin ammonium
salt was heated at 40 1C with ethanolic NaOH. Heating at 70 1C
resulted in extensive decomposition. The subsequent purification
procedure of the crude kaitocephalin provided kaitocephalin
diethylamine salt 1ÁHNEt2 in 22% overall yield from 23, which
is identical to our prepared sample in all the aspects.
Scheme 4 Synthesis of kaitocephalin diethylamine salt (1ÁHNEt2) via the oxa-
zolidinone-protected triol 23. (a) NaH, THF, 0 1C, 86%; (b) 3 M HCl, MeOH, 40 1C;
(c) 18, BOP, iPr2NEt, CH2Cl2, 0 1C to RT, 84% (over 2 steps); (d) AZADO, PhI(OAc)2,
pH 6.8 phosphate buffer, MeCN, RT; (e) TMSCHN2, MeOH, PhMe, 0 1C, 74%;
(f) H2, 20 wt% Pd(OH)2/C, CHCl3, EtOH, RT, purified through Dowexs 50WX4
(H+ form) with 1 M NH4OH; (g) 2 M NaOH, EtOH, 40 1C; (h) purification: Dowexs
50WX4 (H+ form) with 1 M NH4OH, COSMOSIL 75C18-OPN with H2O, then HPLC
(COSMOSIL 5C18-PAQ) with 5% MeOH in 20 mM Et2NH-CO2 buffer pH 7, 22%
from 23. TMS = trimethylsilyl.
We have elaborated reliable asymmetric synthetic routes to
kaitocephalin from the readily prepared Garner’s aldehyde 7.
was observed to be susceptible to the neighboring functional The synthesis has evinced the crucial role of the enantio-
group. When the benzoxymethyl group of 16 was replaced by the selective desymmetrization of the serinol derivative 4 in installing
methoxycarbonyl group, the corresponding epoxy alcohol was the chiral quaternary center, which is believed to function as a
recalcitrant to the substitution reaction, which required higher guiding rudder to induce the remaining stereogenic centers. Other
reaction temperature and longer reaction time to offer the desired distinctive synthetic functionalizations include formation of the
opening product in 30–40% yield along with extensive decomposi- trisubstituted pyrrolidine by the stereoselective mercuriocycliza-
tion. After removal of the acid-labile protecting groups of 17, the tion and the tri(carboxylic acid) by the concurrent oxidation.
generated amino group was coupled with the benzoic acid 18 to
This research was supported by the NRF grant funded by the
procure the amide 19 in 83% overall yield. In the course of the MEST (2012-0000912 and 2012-0000098).
remaining synthetic study, it was recognized that the primary
hydroxyl group(s) could not be oxidized efficiently in the presence
of the secondary alcohol of several intermediates derived from 19.
Notes and references
1 K. Shin-ya, J.-S. Kim, K. Furihata, Y. Hayakawa and H. Seto,
Based on the recognition, the secondary hydroxyl group of 19 was
protected by a sequence of chemoselective benzoylation, silylation
and debenzoylation to render the silyl ether 20 in 82% yield. The
three primary hydroxyl groups of 20 were concurrently oxidized by
AZADO,15 and then the in situ acidic desilylation supplied the
tri(carboxylic acid) 21. The crude 21 was subjected to the
hydrogenolysis–hydrogenation process in the presence of Pearlman’s
catalyst and chloroform as reported to suppress the dechlorination.3
Purification of the crude product using an ion-exchange resin with
ammonium hydroxide produced kaitocephalin ammonium salt, the
1H NMR spectra of which are identical with the published data.7d
Further purification of the salt using the known protocol through
reverse phase column chromatography and HPLC afforded kaitoce-
phalin diethylamine salt 1ÁHNEt2 in 26% overall yield from 20, all
the spectral data of which match those previously reported, and
also its specific optical rotation measured by us, [a]2D2 = À29.9
(c 0.34, H2O), is in good agreement with the known values.7
Another two-step shorter synthesis has been developed by
switching the Cbz and silyl protecting groups of the afore-
mentioned intermediates to oxazolidinone, which was employed
similarly in the Ma synthesis.7e Treatment of 17 with NaH induced
its cyclization and concomitant debenzoylation, probably by the
Tetrahedron Lett., 1997, 38, 7079.
2 H. Kobayashi, K. Shin-ya, K. Furihata, Y. Hayakawa and H. Seto,
Tetrahedron Lett., 2001, 42, 4021.
3 M. Okue, H. Kobayashi, K. Shin-ya, K. Furihata, Y. Hayakawa, H. Seto,
H. Watanabe and T. Kitahara, Tetrahedron Lett., 2002, 43, 857.
4 K. Shin-ya, Biosci., Biotechnol., Biochem., 2005, 69, 867.
5 A. Limon, J. M. Reyes-Ruiz, R. G. Vaswani, A. R. Chamberlin and
R. Miledi, ACS Chem. Neurosci., 2010, 1, 175.
6 (a) M. J. Sheardown, E. P. Nielsen, A. J. Hansen, P. Jacobsen and
T. Honore, Science, 1990, 247, 571; (b) D. Bleakman and D. Lodge,
Neuropharmacology, 1998, 37, 1187; (c) G. J. Lee, Drugs, 2000, 59, 33.
7 Total synthesis: (a) H. Watanabe, M. Okue, H. Kobayashi and
T. Kitahara, Tetrahedron Lett., 2002, 43, 861; (b) M. Kawasaki,
T. Shinada, M. Hamada and Y. Ohfune, Org. Lett., 2005, 7, 4165;
(c) R. G. Vasawani and R. Chamberlin, J. Org. Chem., 2008, 73, 1661;
(d) M. Hamada, T. Shinada and Y. Ohfune, Org. Lett., 2009, 11, 4664;
(e) S. Yu, S. Zhu, X. Pan, J. Yang and D. Ma, Tetrahedron, 2011,
67, 1673; ( f ) K. Takahashi, D. Yamaguchi, J. Ishihara and
S. Hatakeyama, Org. Lett., 2012, 14, 1644.
8 Synthetic studies: (a) T.-P. Loh, Y.-K. Chok and Z. Yin, Tetrahedron
Lett., 2001, 42, 7893; (b) D. Ma and J. Yang, J. Am. Chem. Soc., 2001,
123, 9706; (c) K. V. Kudryavtsev, N. V. Nukolova, O. V. Kokoreva and
E. S. Smolin, Russ. J. Org. Chem., 2006, 42, 412; (d) K. Takahashi,
N. Haraguchi, J. Ishihara and S. Hatakeyama, Synlett, 2008, 671.
9 M. S. Hong, T. W. Kim, B. Jung and S. H. Kang, Chem.–Eur. J., 2008,
14, 3290.
10 P. Garner, Tetrahedron Lett., 1984, 25, 5855.
11 S. H. Kang and W. J. Kim, Synlett, 1991, 520.
12 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
detached benzyloxy anion, to deliver the oxazolidinone 22 in 86% 13 S. H. Kang, J. H. Lee and S. B. Lee, Tetrahedron Lett., 1998, 39, 59.
14 M. Sasaki, K. Tanino, A. Hirai and M. Miyashita, Org. Lett., 2003,
yield (Scheme 4). After removal of the acid-susceptible protecting
groups of 22, the resulting amino group was benzoylated with 18 to
5, 1789.
15 M. Shibuya, M. Tomizawa, I. I. Suzuki and Y. Iwabuchi, J. Am. Chem.
give the amide 23 in 84% yield. We used the AZADO oxidation
Soc., 2006, 128, 8412.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5231--5233 5233