Enantioselective syntheses of poison-frog alkaloids: 219F and 221I and an epimer of 193E

Article abstract of DOI:10.1016/j.tetlet.2005.11.046

Enantioselective syntheses of indolizidines (-)-219F and (-)-221I have been achieved and the relative stereochemistries of natural 219F and 221I were determined by the present synthesis. A levorotatory indolizidine, corresponding to one proposed structure

Full text of DOI:10.1016/j.tetlet.2005.11.046

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 581–582
Enantioselective syntheses of poison-frog alkaloids:
219F and 221I and an epimer of 193E
a
a,
b
Naoki Toyooka,a,* Zhou Dejun, Hideo Nemoto, H. Martin Garraffo,
*
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 2004; revised 4 January 2005; accepted 4 November 2005
Available online 28 November 2005
Abstract—Enantioselective syntheses of indolizidines (ꢀ)-219F and (ꢀ)-221I have been achieved and the relative stereochemistries
of natural 219F and 221I were determined by the present synthesis. A levorotatory indolizidine, corresponding to one proposed
structure for 193E, was also synthesized, but was found to differ from 193E. It seems likely that natural 193E is the 8-epimer of
the synthesized indolizidine.
Ó 2005 Elsevier Ltd. All rights reserved.
In the preceding paper, we have reported the first total
syntheses of the poison-frog alkaloids 203A, 231C, and
233D. The absolute stereochemistry of 203A and
233D, and the relative stereochemistry of 231C were
determined by these total syntheses.1 Among 5,8-disub-
stituted indolizidines reported from frog skin, none of
the fifteen 8-ethyl substituted indolizidines have been
synthesized at the present time and in the stereochemis-
try of the C-8 ethyl group has not been assigned.2 In the
present letter, we report the first total synthesis and
determination of the relative stereochemistry of two
8-ethyl indolizidine poison-frog alkaloids, 219F2 and
221I2 starting from a common chiral lactam intermedi-
ate 5. An epimer of another 8-ethyl indolizidine 193E2
also was synthesized.
conditions4 gave rise to the key lactam 5. Removal of
the silyl group in 5 with TBAF yielded alcohol 6. A
two-step oxidation of 6 followed by Arndt–Eistert reac-
tion of the resulting carboxylic acid provided the homolo-
gated ester 7. Reduction of 7 with LiAlH4, Swern
oxidation of the resulting alcohol and Wittig olefination
afforded (ꢀ)-8. Coinjections of synthetic material 8 with
natural 193E, detected in a Madagascan mantellid frog,
Mantella viridis (unpublished results), indicated that the
synthetic material had a slightly longer GC retention
time than the natural alkaloid. Consequently, it is likely
that the natural alkaloid 193E is the 8-epimer of the syn-
thetic material 8. The GC–mass spectra of synthetic and
natural materials were virtually identical and their GC–
FTIR spectra were very similar in the Bohlmann band
region (indicating 5,9-Z configurations), although differ-
ing slightly in their fingerprint regions.
A Michael-type conjugate addition reaction of 1 with
lithium divinylcuprate generated in situ afforded the tri-
substituted piperidine 2 as a single isomer.3 Reduction
of the ester moiety with Super-Hydride provided alcohol
3, which was transformed into the a,b-unsaturated ester
4 using Swern oxidation of 3 followed by a Horner–
Emmons reaction of the resulting aldehyde. Hydrogena-
tion of 4 followed by treatment of the resulting amino
ester with trimethyl aluminum under WeinrebÕs reaction
Ester 7 was also converted to (ꢀ)-221I with a procedure
analogous to that used in the synthesis of (ꢀ)-8, as
shown in Scheme 1. The relative stereochemistry of nat-
ural 221I was determined by comparison of synthetic
material with natural product detected in a Madagascan
mantellid frog, Mantella viridis (unpublished results), on
GC–MS and GC–FTIR analysis. Alcohol 6, by another
sequence, was transformed into olefin 9 using Swern
oxidation followed by a Wittig olefination. Hydrogena-
tion of the double bond in 9 and removal of the silyl
group provided alcohol 10. Finally construction of the
*
Corresponding authors. 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.2005.11.046

582
N. Toyooka et al. / Tetrahedron Letters 47 (2006) 581–582
H
H
H
a
b
c
H
H
H
H
H
H
H
OTBDPS
OTBDPS
OTBDPS
HO
OTBDPS
MeO2C
N
MeO2C
N
EtO2C
N
N
Cbz
1
Cbz
2
Cbz
4
Cbz
3
H
Et
8
H
H
g
H
H
H
9 N
5
Et
H
Et
H
Et
H
d
e
f
H
H
H
(-)-8
OH
OTBDPS
CO2Me
N
N
N
H
Et
H
O
O
O
6
5
7
H
H
h
N
i
(-)-221I
H
H
H
Et
H
Et
H
Et
H
j
k
OTBDPS
H
H
N
N
OH
N
9
10
(-)219F
Scheme 1. Reagents and conditions: (a) (vinyl)2CuLi, Et2O, ꢀ78 °C to ꢀ10 °C (99%); (b) Super-Hydride, THF, 0 °C (92%); (c): (1) Swern oxidation;
(2) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C to rt (97%); (d): (1) 20% Pd(OH)2/C, H2, MeOH, 4 atm; (2) Me3Al, CH2Cl2, reflux (68%); (e): TBAF,
THF, rt (91%); (f): (1) Swern oxidation; (2) NaClO2, NaH2PO4, t-BuOH/H2O, 0 °C to rt; (3) ClCO2Et, Et3N, THF, 0 °C; (4) CH2N2, Et2O, rt; (5)
PhCO2Ag, Et3N, MeOH, rt (81%); (g): (1) LiAlH4, THF, reflux; (2) Swern oxidation; (3) MeP+Ph3Iꢀ, n-BuLi, THF, 0 °C to rt (63%); (h): (1) LiAlH4,
THF, reflux; (2) Swern oxidation; (3) n-PrP+Ph3Iꢀ, NaHMDS, THF, ꢀ78 °C to rt (62%); (i): (1) LiAlH4, THF, reflux; (2) Swern oxidation; (3)
TBDPSO(CH2)3P+PhBrꢀ, n-BuLi, THF, 0 °C to rt (72%); (j): (1) 10% Pd/C, H2, EtOAc, 1 atm; (2) TBAF, THF, rt (81%); (k): (1) Swern oxidation;
(2) (MeO)2P(O)CHN2, t-BuOK, THF, ꢀ78 °C to rt (64%).
terminal triple bond was performed by reaction of the
corresponding aldehyde, derived from 10, with the Sey-
ferth–Gilbert reaction5 to give rise to (ꢀ)-219F. The
GC–MS and GC-FTIR spectra of the synthetic alkaloid
were identical in every respect with those of natural
alkaloid detected in the Madagascan mantellid frog,
Mantella betsileo, and the relative stereochemistry of
natural 219F was thus determined by this total synthesis.
For alkaloids 221I and 219F, the relative configuration
of the 8-ethyl group is the same as in the levorotatory
8-methylindolizidines, (ꢀ)-203A, (ꢀ)-205A, (ꢀ)-207A,
(ꢀ)-233D, and (ꢀ)-235B0.6
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. Research at NIH was sup-
ported by the intramural program of NIDDK.
References and notes
1. Toyooka, N.; Dejun, Z.; Nemoto, H.; Garraffo, H. M.;
Spande, T. F.; Daly, J. W. Tetrahedron Lett. 2006, 47,
preceding paper doi:10.1016/j.tetlet.2005.11.047.
2. Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon Press: New York, 1999; Vol. 13, pp 1–161; Daly,
J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005,
68, 1556–1575. These reviews cite the structures of 193E,
219F and 221I as otherwise unpublished work.
3. Toyooka, N.; Nemoto, H. Recent Res. Devel. Organic
Chem. 2002, 6, 611–624.
In summary, we achieved the first asymmetric syntheses
of the following 8-ethyl substituted indolizidines: (ꢀ)-
219F, (ꢀ)-221I, and an epimer of 193E. The relative ste-
reochemistry of natural 219F and 221I was determined
unambiguously by the present synthesis. The relative
stereochemistry of natural 193E will likely correspond
to the 8-ethyl epimer of our synthetic material 8.
4. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 18, 4171–4174.
5. Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem.
1971, 36, 1379–1385.
Acknowledgements
6. Toyooka, N.; Nemoto, H.; Kawasaki, M.; Garraffo, H. M.;
Spande, T. F.; Daly, J. W. Tetrahedron 2005, 61, 1187–
1198; . Tetrahedron 2005, 61, 5139.
This work was supported in part by The Research Foun-
dation for Pharmaceutical Sciences. We gratefully