The enantioselective synthesis of poison-frog alkaloids (-)-203A, (-)-209B, (-)-231C, (-)-233D, and (-)-235B″

Article abstract of DOI:10.1016/j.tetlet.2005.11.047

The enantioselective synthesis of indolizidines (-)-203A, (-)-209B, (-)-231C, (-)-233D, and (-)-235B″ has been achieved and the absolute stereochemistry of both indolizidines 203A and 233D was established as 5S,8R,9S. The relative stereochemistry of natur

Full text of DOI:10.1016/j.tetlet.2005.11.047

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 577–580
The enantioselective synthesis of poison-frog alkaloids
(ꢀ)-203A, (ꢀ)-209B, (ꢀ)-231C, (ꢀ)-233D, and (ꢀ)-235B00
Naoki Toyooka,a,* Zhou Dejun,a Hideo Nemoto,*,a H. Martin Garraffo,b
Thomas F. Spandeb and John W. Dalyb
aFaculty of Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
bLaboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, DHHS, Bethesda, MD 20892, USA
Received 19 October 2005; revised 4 November 2005; accepted 4 November 2005
Available online 28 November 2005
Abstract—The enantioselective synthesis of indolizidines (ꢀ)-203A, (ꢀ)-209B, (ꢀ)-231C, (ꢀ)-233D, and (ꢀ)-235B00 has been
achieved and the absolute stereochemistry of both indolizidines 203A and 233D was established as 5S,8R,9S. The relative stereo-
chemistry of natural 231C was established by the present asymmetric synthesis.
Ó 2005 Elsevier Ltd. All rights reserved.
The 5,8-disubstituted indolizidines are one of a large
indolizidine subclass of alkaloids found in amphibian
skin.1 Recently, such indolizidines have been detected
in mixed arthropod collections.2 Poison-frog alkaloids
including these indolizidines continue to be of interest
as synthetic targets3 due to their intriguing biological
activities. Indeed, we found recently that the synthetic
indolizidine (ꢀ)-235B0, an alkaloid originally isolated
from poison-frog skin, acts as a selective and non-com-
petitive blocker of a4b2 nicotinic acetylcholine recep-
tors.4 The potency of (ꢀ)-235B0 for this receptor was
comparable with one of the best studied antagonists,
dihydro-b-erythroidine. As part of a program directed
at studying the synthesis of biologically active alka-
loids,5 we would like to report here the chiral synthesis
of (ꢀ)-203A, an alkaloid originally isolated from Dend-
robates auratus,6 and the determination of its absolute
stereochemistry. The total synthesis of 209B,7 231C,8
233D,8 and 235B009 has also been achieved starting from
a common chiral lactam 9.
3, which was subjected to a palladium catalyzed carbon-
ylation to give rise to the enaminoester 4. The methyl
substituent at the 3-position was introduced by our ori-
ginal Michael-type conjugate addition reaction12 of 4 to
afford 5 in a highly stereoselective manner. The carbon-
chain extension at the 2-position of 5 was performed by
reduction of 5 with lithium triethylborohydride (Super-
Hydride), Swern oxidation of the resulting alcohol 6
followed by a Horner–Emmons reaction to give the
a,b-unsaturated ester 7. Hydrogenation of 7 over Pearl-
manÕs catalyst and a trimethylaluminum-catalyzed cycli-
zation13 of the resulting aminoester yielded the lactam 8.
Cleavage of the silylether with TBAF provided the
corresponding alcohol 9, which was subjected to two-
step oxidation and the Arndt–Eistert sequence to afford
the homologated ester 10. Reduction of both lactam and
ester moieties with LiAlH4 and oxidation of the result-
ing alcohol with the Dess–Martin periodinane14 gave
rise to the aldehyde, which was transformed into
the Z-iodoolefin 11 under StorkÕs reaction conditions.15
The Sonogashira coupling16 reaction of 11 using the
trimethylsilylacetylene provided the eneyne derivative
12, whose trimethylsilyl group was removed with
The synthesis began with the enantiomerically pure pip-
eridone 1,10 which was converted to the Cbz-urethane 2
in good yield. Treatment of 2 with LiHMDS followed
by 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloro-
pyridine (CominsÕ reagent)11 provided the enol triflate
K2CO3 in MeOH to furnish the (ꢀ)-indolizidine 203A
26
(½aꢁD ꢀ94.5 (c 2.0, CHCl3), lit.6 [a]D ꢀ23.3 (c 0.30,
CHCl3)). The spectral data of synthetic (ꢀ)-203A were
identical with those of the natural product. This abso-
lute configuration is the same as that reported previ-
ously for levorotatory 205A and 207A. It should be
noted that in all cases of 5,8-disubstituted indolizidines,
*
Corresponding author. Tel.: +81 76 434 7532; fax: +81 76 434
4656; e-mail: toyooka@ms.toyama-mpu.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.047

578
N. Toyooka et al. / Tetrahedron Letters 47 (2006) 577–580
the rotations of the natural alkaloids were significantly
less than those of synthetic materials. The presence of
some naturally occurring racemic material is one possi-
ble explanation (Scheme 1).
5,9-Z by GC–MS and GC–FTIR comparison of syn-
thetic material with natural 231C in extracts from a
Panamanian dendrobatid frog, D. pumilio.8 The rotation
of the natural alkaloid is unknown.
Reduction of 9 with lithium aluminum hydride gave an
indolizidine, whose side chain at the 5-position was
elongated in two steps by Swern oxidation followed by
Wittig olefination to provide the indolizidine 13.
Hydrogenation of the double bond of 13 and treatment
of the resulting silyl ether with TBAF gave the alcohol
14. Swern oxidation of 14 and Wittig reaction of the
resulting aldehyde with iodomethyltriphenylphospho-
nium iodide15 gave rise to the Z-iodoolefin 15. A
cross-coupling reaction of 15 with vinylmagnesium bro-
mide in the presence of a phosphine–nickel catalyst17
provided the alkaloid (ꢀ)-233D previously isolated from
a Panamanian poison frog, Dendrobates pumilio.8 The
spectroscopic data of synthetic material were identical
In another synthesis, the lactam 9 was converted to ole-
fin 16 in three steps shown in Scheme 2. Hydrogenation
26
of 16 over 10% Pd–C afforded (ꢀ)-209B (½aꢁD ꢀ91.7 (c
28
1.06, MeOH), lit.18 ½aꢁD ꢀ91.3 (c 0.58, MeOH)). The
spectral data were identical with those previously
reported.18 The rotation of the natural material is
unknown.
Comins et al.19 reported the synthesis of 235B00 from the
alcohol 14. Thus, Wittig olefination of the aldehyde,
derived from Swern oxidation of 14, under high dilution
26
and Ôsalt freeÕ conditions gave rise to (ꢀ)-235B00 (½aꢁD
28
ꢀ80.9 (c 1.71, MeOH), lit.18 ½aꢁD ꢀ85.4 (c 0.79, MeOH),
24
lit.19 ½aꢁD ꢀ88.0 (c 1.0, MeOH)). The spectral data of
with those of natural 233D. Comparison of the optical
synthetic 235B00 were identical with reported values.
Remarkably natural 235B00 appears to be the (+)-enan-
tiomer with an [a]D +11.3 (c 1.0, MeOH).9 The presence
of some racemic alkaloid in that sample appears
possible.
26
rotation of synthetic (ꢀ)-233D (½aꢁD ꢀ93.6 (c 1.32,
26
CHCl3), HCl salt: ½aꢁD ꢀ48.9 (c 1.50, MeOH)) with that
of the natural alkaloid (lit.8 HCl salt: [a]D ꢀ3.4 (c 0.16,
MeOH)) suggests that the absolute stereochemistry of
natural 233D, like those of other levorotatory 5,8-disub-
stituted indolizidines, is 5R,8R,9S. The presence in the
natural material of a portion of the alkaloid as a race-
mate appears possible, if not likely.
In summary, we have achieved the first asymmetric syn-
thesis of indolizidine (ꢀ)-203A and, by the present
asymmetric synthesis, we unambiguously determined
its absolute stereochemistry to be 5S,8R,9S. The asym-
metric syntheses of poison frog-indolizidines (ꢀ)-209B,
(ꢀ)-231C, (ꢀ)-233D, and (ꢀ)-235B00 are also presented.
The absolute stereochemistry of natural 233D appears
to be likely 5R,8R,9S based on the present asymmetric
The Sonogashira coupling16 of 15 with trimethylsilyl-
acetylene followed by deprotection of the TMS group
with K2CO3 in MeOH furnished (ꢀ)-231C, whose rela-
tive stereochemistry was determined to be 5,8-E, and
H
Me
b
c
d
e
3
H
H
H
H
H
OTBDPS
OTBDPS
OTBDPS
OTBDPS
MeO2C
N
MeO2C 2 N
Cbz
O
N
R
TfO
N
Cbz
4
Cbz
3
5
1: R = H
R = Cbz
a
:
2
H
H
H
H
Me
H
Me
H
Me
H
Me
f
g
h
H
H
H
H
H
OH
HO
OTBDPS
OTBDPS
OTBDPS
N
N
N
EtO2C
N
Cbz
6
Cbz
7
O
O
9
8
H
H
H
H
Me
Me
H
Me
Me
H
i
j
k
l
8
H
H
N
H
H
H
H
CO2Me
N
N
N
9
5
I
O
10
11
12
(-)-203A
TMS
Scheme 1. Reagents and conditions: (a) n-BuLi, CbzCl, THF, ꢀ78 to 0 °C (86%); (b) LiHMDS, 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-
chloropyridine (CominsÕ reagent), THF, ꢀ78 to ꢀ40 °C (91%); (c) Pd(Ph3P)4, CO, MeOH, Et3N, DMF, 75 °C (78%); (d) Me2CuLi, Et2O ꢀ78 to
ꢀ10 °C (99%); (e) Super-Hydride, THF, 0 °C (92%); (f) Swern oxidation then NaH, (EtO)2P(O)CH2CO2Et, THF, 0 °C–rt (97%); (g) 20% Pd(OH)2/
C, MeOH, 4 atm then Me3Al, CH2Cl2, reflux (71%); (h) TBAF, THF, rt (99%); (i) (1) Swern oxidation; (2) NaClO2, NaH2PO4, t-BuOH/H2O, 0 °C–
rt; (3) ClCO2Et, Et3N, THF, 0 °C; (4) CH2N2, Et2O, rt; (5) PhCO2Ag, Et3N, MeOH, rt (69%); (j) (1) LiAlH4, THF, reflux; (2) 1,1,1-tris(acetyloxy)-
1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (Dess–Martin reagent), CH2Cl2, rt; (3) ICH2P+Ph3Iꢀ, NaHMDS, HMPA, THF, ꢀ78 °C to rt (60%); (k)
CuI, trimethylsilylacetylene, Pd(Ph3P)4, i-Pr2NH, THF, rt (93%); (l) K2CO3, MeOH, rt (91%).

N. Toyooka et al. / Tetrahedron Letters 47 (2006) 577–580
579
H
H
H
H
Me
H
Me
H
Me
H
Me
a
b
c
OTBDPS
H
H
H
H
H
OH
N
N
N
N
OH
I
O
13
14
15
9
f
g
e
d
H
H
H
H
H
Me
H
Me
H
Me
H
Me
H
Me
H
h
H
H
H
H
H
N
N
N
N
N
16
(-)-209B
(-)-235B''
(-)-231C
(-)-233D
Scheme 2. Reagents and conditions: (a) (1) Lithium aluminum hydride, THF, reflux; (2) Swern oxidation; (3) TBDPSO(CH2)3P+Ph3Brꢀ, n-BuLi,
THF, 0 °C–rt (83%); (b) (1) 10% Pd/C, H2, EtOAc, 1 atm; (2) TBAF, THF, rt (79%); (c) (1) Swern oxidation; (2) ICH2P+Ph3Iꢀ, NaHMDS, HMPA,
THF, ꢀ78 °C to rt (61%); (d) NiCl(dppp), vinylmagnesium bromide, Et2O, rt (86%); (e) (1) CuI, TMS–acetylene, Pd(Ph3P)4, i-Pr2NH, THF, rt
(90%); (2) K2CO3, MeOH, rt, (89%); (f) (1) Swern oxidation; (2) n-PrP+Ph3Brꢀ, NaHMDS, THF, ꢀ78 °C to rt (66%); (g) (1) Lithium aluminum
hydride, THF, reflux; (2) Swern oxidation; (3) n-BuP+Ph3Brꢀ, n-BuLi, THF, 0 °C–rt (78%); (h) 10% Pd/C, H2, EtOAc, 1 atm (95%).
´
Wrobleski, A.; Sahasrabudhe, K.; Aube, J. J. Am. Chem.
synthesis and analogies to other levorotatory indolizi-
dines, namely 203A, 205A, 207A, and 235B0. In addi-
tion, the relative stereochemistry of natural 231C was
also determined. These 5,8-disubstituted indolizidines
will likely provide useful compounds for selective and
non-competitive inhibition of nicotinic acetylcholine
receptors, widely distributed in the mammalian brain.
Such studies of these synthetic indolizidines are now in
progress, and the results will be published in due course.
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Acknowledgments
This work was supported in part by The Research Foun-
dation for Pharmaceutical Sciences. We gratefully
acknowledge financial support provided by grant-aid
(No. 17590004) for Scientific Research by the Ministry
of Education, Culture, Sports, Science, and Technology
of the Japanese Government. Work at NIH was sup-
ported by the intramural research program of NIDDK.
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