Synthetic studies on poison-frog alkaloid 261C

Article abstract of DOI:10.1055/s-2005-921911

The synthesis of highly substituted indolizidine core for the synthesis of poison-frog alkaloid 261C has been achieved. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-921911

LETTER
3109
Synthetic Studies on Poison-Frog Alkaloid 261C
Synthetic Studies
o
a
n Poison-F
o
rog Alkaloid
k
261C i Toyooka,*a Masashi Kawasaki,b Hideo Nemoto,*a Suresh Awale,c Yasuhiro Tezuka,c Shigetoshi Kadotac
a
b
c
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
E-mail: toyooka@ms.toyama-mpu.ac.jp
Department of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, Kurokawa 5180, Kosugi-Machi,
Toyaama 939-0398, Japan
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
Received 22 September 2005
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Abstract: The synthesis of highly substituted indolizidine core for
the synthesis of poison-frog alkaloid 261C has been achieved.
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Me
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H
N
N
H
Key words: poison-frog alkaloid 261C, Mantella betsileo, 6,5,5-
tricyclic ring system, a7 nicotinic acetylcholine receptors, highly
substituted indolizidine core
Me
H
261C
205B
Figure 1
The alkaloid 261C (Figure 1), isolated from skin extracts
of a Madagascan poison frog Mantella betsileo, possesses
the unique 6,5,5-tricyclic ring system with six asymmetric
centers.1 The gross structure of this alkaloid was deter-
mined on the basis of CIMS, GC-FTIR, and extensive
NMR studies.1 Since a structurally related tricyclic poison
frog alkaloid 205B2 has been found to possess a selective
inhibition of a7 nicotinic acetylcholine receptors over
a4b2 or a3b4 receptors,3 the alkaloid 261C is expected to
have similar activity. However, only 0.9 mg of this alka-
loid was isolated from skins of 43 frogs, which hindered
further studies. Consequently, a total synthesis of this
natural product is required. In this communication, we
would like to report the synthesis of highly substituted in-
dolizidine core 14 for the synthesis of 261C.
(DHQD)2PYR ligand-induced Sharpless asymmetric di-
hydroxylation reaction5 to afford the corresponding diol 3
as a mixture of diastereoisomers. The primary hydroxyl
group in 3 was protected as a TBDPS ether followed by
mesylation of the secondary hydroxyl and a substitution
reaction of the resulting mesylate with NaN3 to provide
the azide 4. Removal of the THP group in 4 with acid, and
Swern oxidation followed by a Horner–Emmons reaction
gave the unsaturated ester 5. Hydrogenation of 5 over
10% Pd/C gave rise to the pure piperidone 6 in 60%
isolated yield. The piperidone 6 was converted to a methyl
urethane, which was treated with LiHMDS followed by
2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyr-
idine (Comins’ reagent)6 to afford the enol triflate 7. A
palladium-catalyzed CO insertion reaction under Cacchi’s
conditions7 furnished 8.
The key enaminoester 8 was prepared from known alco-
hol 1 (Scheme 1).4 The enantiopure alcohol 1 was con-
verted to terminal olefin 2, which was subjected to the
b
c
a
d
AcO
OH
OTHP
OTHP
OTHP
H
TBDPSO
TBDPSO
g
1
2
3
4
N3
OH
H
H
f
e
H
H
H
TBDPSO
CO2Et
TBDPSO
TBDPSO
TBDPSO
N
H
O
N
OTf
N
CO2Me
N3
CO2Me
CO2Me
5
6
7
8
Scheme 1 Reagents and conditions: a) 1. dihydropyran, PPTS, CH2Cl2, r.t.; 2. K2CO3, MeOH, r.t.; 3. 10% Pd/C, H2, EtOAc, 1 atm (60%); 4.
Swern oxidation, then n-BuLi, Ph3P+CH3Br–; THF. 0 °C to r.t. (70%); b) 1. (DHQD)2PYR, K2OsO4, K3Fe(CN)6, K2CO3, H2Ot-BuOH, 0 °C
(74%); 2. TBDPSCl, Et3N, DMAP, CH2Cl2, 0 °C to r.t. (99%); c) 1. MsCl, Et3N, CH2Cl2, 0 °C; 2. NaN3, DMF, 80 °C (80%); d) 1. PPTS, EtOH,
60 °C; 2. Swern oxidation, then (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C to r.t. (95%); e) 10% Pd/C, H2, EtOAc, 1 atm. (60%); f) 1. n-BuLi,
ClCO2Me, THF, –78 °C to 0 °C (97%); 2. LiHMDS, 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (Comins’ reagent), THF,
–78 °C to –40 °C (94%); g) Pd(Ph3P)4, CO, MeOH, Et3N, DMF, 75 °C (81%).
SYNLETT 2005, No. 20, pp 3109–3110
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Advanced online publication: 04.11.2005
DOI: 10.1055/s-2005-921911; Art ID: U27805SS
© Georg Thieme Verlag Stuttgart · New York

3110
N. Toyooka et al.
LETTER
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a
b
c
8
H
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H
H
H
TBDPSO
TBDPSO
OH
TBDPSO
N
CO2Et
N
N
CO2Me
CO2Me
10
CO2Me
11
CO2Me
9
H
H
H
H
H
H
H
d
e
f
H
H
H
H
H
HO
OTHP
MeO2C
14
N
N
MeO2C
N
CO2Et
Troc
Troc
13
H
12
CO2Et
Scheme 2 Reagents and conditions: a) (vinyl)2CuLi, Et2O, –78 °C to –10 °C (96%); b) 1. Super-Hydride® THF, 0 °C (95%); 2. Swern oxi-
dation, then NaH, (EtO)2P(O)CH2CO2Et, THF, 0 °C to r.t. (93%); c) 1. 10% Pd/C, H2 (4 atm) EtOAc; 2. Super-Hydride®, THF, 0 °C (98%);
d) 1. dihydropyran, PPTS, CH2Cl2, r.t.; 2. 2 M KOH/i-PrOH, 120 °C, sealed tube, then TrocCl, K2CO3, CH2Cl2–H2O (84%); e) 1. Swern oxi-
dation, then NaClO2, NaH2PO4, t-BuOH–H2O; 2. CH2N2, EtOAc (62%); 3. PPTS, EtOH, 60 °C, then Swern oxidation, then NaH,
(EtO)2P(O)CH2CO2Et, THF, 0 °C to r.t. (85%); f) 10% Cd/Pb, 1 N NH4OAc–THF, r.t. (70%), (7: 1).
A key Michael-type conjugate addition reaction of 8 with
divinyllithium cuprate afforded the adduct 9 as a single
stereoisomer.8 Reduction of the ester moiety in 9 followed
by Swern oxidation of the resulting alcohol and a Horner–
Emmons olefination gave rise to the a,b-unsaturated ester
10 as a mixture of E- and Z-olefin isomers. Hydrogenation
of both isomers of 10 and reduction of the resulting ester
with Super-Hydride® provided the alcohol 11. Protection
of the hydroxyl group in 11 with dihydropyran under acid-
ic conditions followed by hydrolysis of the methyl ure-
thane moiety afforded an amino alcohol, which was
treated with TrocCl to give 12. A two-step oxidation of 12
and esterification using diazomethane provided the
methyl ester, whose side chain at the other a-position was
modified to give rise to the a,b-unsaturated ester 13. With
the requisite 13 in hand, the stage was now set for the key
Michael-type cyclization reaction to afford the indolizi-
dine 14. Thus, treatment of 13 with 10% Cd/Pb under
Ciufolini’s conditions9 gave the cyclized product as a 7:1
mixture of the diastereomers, with the major product 14
being isolated in 70% yield. The stereochemistry of 14
was determined to be the desired indolizidine for the
synthesis of 261C by the NOE experiments shown in
Scheme 2.
Acknowledgment
This work was supported in part by The Research Foundation for
Pharmaceutical Sciences. We also would like to thank Drs. John W.
Daly, Thomas F. Spande, and H. Martin Garraffo, NIH, for very
valuable suggestions and discussions about this paper.
References
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Daly, J. W.; Andriamaharavo, N. R.; Andriantsiferana, M.
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(2) (a) Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H.
Angew. Chem. Int. Ed. 2003, 42, 3808. (b) Toyooka, N.;
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In summary, we achieved the construction of the indoliz-
idine core 14 possessing the desired stereochemistry for
our planned synthesis of the unique tricyclic poison-frog
alkaloid 261C. Further studies toward the completion of
total synthesis of 261C are now in progress.
Synlett 2005, No. 20, 3109–3110 © Thieme Stuttgart · New York