First enantioselective synthesis of a hydroxyindolizidine alkaloid from the ant Myrmicaria melanogaster

Article abstract of DOI:10.1055/s-2008-1078502

The first enantioselective synthesis of the recently reported ant alkaloid 1 has been achieved starting from commercially available lactam 3 in seven steps and 25% overall yield. The proposed structure of the natural product was confirmed by comparison with synthetic 1 and its absolute configuration established as 3S,5R,8S,9S. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078502

1894
LETTER
First Enantioselective Synthesis of a Hydroxyindolizidine Alkaloid from the
Ant Myrmicaria melanogaster
Enantioselective
S
a
ynthesis of
o
a
H
ydroxyin
k
dolizidine
A
i
lkaloid Toyooka,*a Dejun Zhou,a Hideo Nemoto,a Yasuhiro Tezuka,b Shigetoshi Kadota,b Tappey H. Jones,c
H. Martin Garraffo,d Thomas F. Spande,d John W. Dalyd
a
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
Fax +81(76)4344656; E-mail: toyooka@pha.u-toyama.ac.jp
Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
Department of Chemistry, Virginia Military Institute, Lexington, VA 24450, USA
b
c
d
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
DHHS, Bethesda, MD 20892, USA
Received 4 April 2008
tone 5 in a highly diastereoselective manner. Treatment of
Abstract: The first enantioselective synthesis of the recently re-
6 with DIBAL followed by addition of vinyl Grignard re-
ported ant alkaloid 1 has been achieved starting from commercially
agent to the resulting aldehyde provided the alcohol 7 as a
mixture of diastereomers. The cross-metathesis reaction
available lactam 3 in seven steps and 25% overall yield. The pro-
posed structure of the natural product was confirmed by comparison
with synthetic 1 and its absolute configuration established as of 7 with 1-hexen-3-one in the presence of the Grubbs sec-
ond-generation catalyst8 in refluxing methylene chloride
3S,5R,8S,9S.
afforded the homologated product 8. Exposure of 8 to hy-
drogenation in the presence of Pearlman’s catalyst fur-
nished the two indolizidines (–)-1 and 9. These
indolizidines were easily separated by column chroma-
tography to furnish (–)-19 as a major isomer and 910 as a
minor isomer in 62% and 19% isolated yields, respective-
ly. The stereochemistry of the synthetic major isomer
(–)-1 was determined by the NOE experiments indicated
in Scheme 1.
Key words: hydroxyindolizidine, venoms of ant, Myrmicaria mel-
anogaster, chelation control, new ant alkaloid
The bicyclic indolizidine skeleton has been found in nat-
ural sources such as skin extracts of poison frogs,1 venoms
of ants,2 and many of these natural products showed in-
triguing biological activities.3 The stereoselective con-
struction of the substituted indolizidine ring system
remains a substantial challenge in organic chemistry.4
Very recently, five new alkaloids, along with six known
indolizidines and three known pyrrolidines, have been de-
tected in the extracts of the ant Myrmicaria melanogaster
from Brunei in the Indonesian archipelago.5 Although the
structures of two new indolizidine alkaloids (1 and 2,
Figure 1) were proposed on the basis of a nonstereoselec-
tive synthesis and GC-FTIR analysis of each stereoiso-
mer,5 no stereoselective synthesis of 1 has yet been
reported. As part of our ongoing program of devising syn-
theses of biologically active alkaloids,6 we report here the
first enantioselective synthesis of the above venom alka-
loid 1 starting from the commercially available lactam 3
in seven steps and 25% overall yield.
The stereochemical course of the addition of the vinyl an-
ion to the aldehyde intermediate from 6 can be explained
by the chelation control model as shown in Figure 2. The
use of excess Grignard reagent (3 equiv) resulted in the
formation not of the Felkin–Anh type of transition state
but rather a chelated transition state, where the anticipated
preference for b-attack of the vinyl anion would yield the
major isomer. In the chelated transition state, steric hin-
drance of the a-hydrogen at the 3-position of pyrrolidine
ring would also favor b-attack of the vinyl anion.
[vinyl]–
[vinyl]–
H
H
H
Mg
O
O
H
H
O
N
The lactam 3 was converted to the Cbz-imide 4 in high
yield, which was subjected to Martin’s transformation7 to
produce the 2,5-cis-disubstituted pyrrolidine 6 via the ke-
N
BnO
Cbz
n-Bu
n-Bu
H
H
H
H
HO
H
N
N
HO
n-Bu
N
Cbz
H
1
2
Figure 2 Stereochemical course of the addition of vinyl anion
Figure 1
SYNLETT 2008, No. 12, pp 1894–1896
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1078502; Art ID: U02908ST
© Georg Thieme Verlag Stuttgart · New York
We found that synthetic (–)-1 had a retention time (tR) and
mass spectrum identical with the natural product from the
Myrmicaria melanogaster ant as well as the first eluting
isomer ( )-1 of the mixture of four components [( )-1 and
x
x
.x
x
.2
0
0
8

LETTER
Enantioselective Synthesis of a Hydroxyindolizidine Alkaloid
1895
a
b
c
H
H
H
O
O
O
MeO2C
MeO2C
N
N
MeO2C
NH
H
Cbz
Cbz
3
4
5
H
H
H
H
HO
H
d
H
e
N
HO
HO
5
2
MeO2C
N
N
Cbz
8
Cbz
Cbz
7
6
O
H
H
H
H
1.5%
f
HO
4.5%
3
9
+
H
N
5
N
H
3.6%
HO
H
N
H
H
H
1
9
6.4%
selected NOE data for 1
Scheme 1 Reagents and conditions: a) LiHMDS, CbzCl, THF, –78 to 0 °C (92%); b) n-BuMgBr, TMEDA, THF, –78 °C (65%); c) Ph3SiH,
BF3·OEt2, CH2Cl2, –78 °C to r.t. (98%); d) DIBAL, CH2Cl2, –78 °C then vinylMgBr (3 equiv), THF, –78 °C to r.t. (72%); e) 1-hexen-3-one,
Grubbs second-generation catalyst (0.1 equiv), CH2Cl2, reflux (97%); f) 20% Pd(OH)2, EtOH, 1 atm (1: 62%, 9: 19%).
Sinnwell, V.; Baumann, H.; Kaib, M.; Francke, W. Angew.
Chem., Int. Ed. Engl. 1997, 36, 77.
three ( )-diastereomers] synthesized earlier in a nonenan-
tioselective manner by Jones et al.5 The absolute configu-
ration of the natural product was shown identical to that of
(–)-1 by the correspondence of its tR after co-injection
with ( )-1 from Jones’ synthetic mixture and the crude ant
extract using a chiral permethylated b-cyclodextrin col-
umn.11 Thus the natural product has the same absolute
configuration as (–)-1, that is, 3S,5R,8S,9S. This is the
same configuration at C-3, C-5, and C-9 as the recently
synthesized natural (–)-monomorine from ants.12
(3) (a) Toyooka, N.; Kobayashi, S.; Zhou, D.; Tsuneki, H.;
Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H.
M.; Spande, T. F.; Daly, J. W. Bioorg. Med. Chem. Lett.
2007, 17, 5872. (b) Kobayashi, S.; Toyooka, N.; Zhou, D.;
Tsuneki, H.; Wada, T.; Sasaoka, T.; Sakai, H.; Nemoto, H.;
Garraffo, H. M.; Spande, T. F.; Daly, J. W. Beilstein J. Org.
Chem. 2007, 3, 30. (c) Tsuneki, H.; You, Y.; Toyooka, N.;
Kagawa, S.; Kobayashi, S.; Sasaoka, T.; Nemoto, H.;
Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004, 66, 1061.
(4) (a) Michael, J. P. Beilstein J. Org. Chem. 2007, 3, 27.
(b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191.
(5) Jones, T. H.; Voegtle, H. L.; Miras, H. M.; Weatherford, R.
G.; Spande, T. F.; Garraffo, H. M.; Daly, J. W.; Davidson, D.
W.; Snelling, R. R. J. Nat. Prod. 2007, 70, 160.
(6) (a) Toyooka, N.; Tsuneki, H.; Kobayashi, S.; Zhou, D.;
Kawasaki, M.; Kimura, I.; Sasaoka, T.; Nemoto, H. Curr.
Chem. Biol. 2007, 1, 97. (b) Toyooka, N.; Tsuneki, H.;
Nemoto, H. Yuki Gosei Kagaku Kyokaishi 2006, 64, 49.
(c) Toyooka, N.; Nemoto, H. New Methods for the
Asymmetric Synthesis of Nitrogen Heterocycles; Vicario, J.
L., Ed.; Research Signpost: India, 2005, 149–163.
(d) Toyooka, N.; Nemoto, H. Recent Research
In summary, we achieved the first enantioselective syn-
thesis of the new ant alkaloid, 3-butyl-5-propyl-8-hy-
droxyindolizidine, starting from lactam 3 in seven steps,
and the absolute configuration as well as the proposed rel-
ative structure of the natural ant alkaloid was confirmed
by comparison with synthetic (–)-1. The relative configu-
ration reported5 for the hydroxyindolizidine as structure
10a was arbitrarily depicted but fortuitously shows the
correct absolute configuration as this work indicates.
Acknowledgment
Developments in Organic Chemistry, Vol. 6; Pandalai, S. G.,
Ed.; Transworld Research Network: Trivandrum India,
2002, 611–624.
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science and
Tamura Foundation for Promotion of Science and Technology.
(7) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron
2004, 60, 7301.
(8) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(9) Spectral Data of 1
References and Notes
IR (neat): 3482, 2956, 2872, 1513, 1457, 1378, 1234, 1130,
1054, 970, 826 cm–1. 1H NMR (500 MHz, CDCl3): d = 0.90
(3 H, t, J = 7.2 Hz), 0.91 (3 H, t, J = 7.2 Hz), 1.17–1.49 (11
H, br m), 1.53–1.62 (4 H, m), 1.68–1.86 (3 H, m), 2.25 (1 H,
t-like, J = 9.8 Hz), 2.40 (1 H, m), 2.75 (1 H, t-like, J = 8.5
(1) (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod.
2005, 68, 1556. (b) Daly, J. W.; Garraffo, H. M.; Spande, T.
F. In Alkaloids: Chemical and Biological Perspectives, Vol.
13; Pelletier, S. W., Ed.; Pergamon Press: New York, 1999,
1–161.
(2) (a) Francke, W.; Schroder, F.; Walter, F.; Sinnwell, V.;
Baumann, H.; Kaib, M. Liebigs Ann. 1995, 965.
Hz), 3.03 (1 H, d, J = 10.3 Hz), 3.74 (1 H, d, J = 9.8 Hz). 13
C
NMR (75 MHz, CDCl3): d = 14.27 (q), 14.50 (q), 19.16 (t),
22.98 (t), 25.92 (t), 26.67 (t), 28.75 (t), 28.98 (t), 32.18 (t),
37.83 (t), 39.43 (t), 60.43 (d), 64.07 (d), 65.45 (d), 70.06 (d).
MS: m/z (%) = 239 [M+], 196 (100). HRMS: m/z calcd for
(b) Schroder, F.; Sinnwell, V.; Baumann, H.; Kaib, M.
Chem. Commun. 1996, 2139. (c) Schroder, F.; Francke, S.;
Francke, W.; Baumann, H.; Kaib, M.; Pasteels, J. M.;
Daloze, D. Tetrahedron 1996, 52, 13539. (d) Schroder, F.;
Synlett 2008, No. 12, 1894–1896 © Thieme Stuttgart · New York

1896
N. Toyooka et al.
LETTER
C15H29ON: 239.2103; found: 239.2121. [a]D26 –48.92
(c 0.62, CHCl3).
(10) Spectral Data of 9
both synthetic (–)-1 and natural product 10a coeluted and
had identical mass spectra. Synthetic (–)-1 also had a
retention time and mass spectrum identical to the first eluting
isomer, ( )-1, of the mixture of diastereomers synthesized in
a nonstereoselective manner by Jones et al.5 For the
determination of the absolute configuration of 10a, an HP
5890 GC with flame-ionization detection was used with He
carrier gas and a head pressure of 20 psi. This was fitted with
a chiral permethylated b-cyclodextrin column (SGE,
30 m × 0.22 mm i.d., 0.25 mm film thickness) operated with
a program of 100 °C at a rate of 1 °C/min. Using these
conditions, the Myrmicaria melanogaster ant
hydroxyindolizidine 10a and (–)-1 each coeluted with the
slightly more slowly eluting enantiomer (156.5 °C) of the
( )-1 racemate present in Jones’ synthetic mixture, whereas
the (+)-1 enantiomer, from Jones’ synthetic mixture eluted at
156.0 °C.
Mp 39–40 °C. IR (KBr): 3343, 2955, 2933, 2859, 2784,
1466, 1378, 1259, 1207, 1194, 1158, 1123, 1062, 1019 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.3 Hz),
0.91 (3 H, t, J = 7.3 Hz), 1.18–1.36 (8 H, m), 1.42 (1 H, m),
1.45–1.64 (4 H, m), 1.80–1.84 (2 H, m), 1.92–2.08 (3 H, m),
2.15 (1 H, br), 2.66 (1 H, t-like, J = 8.5 Hz), 3.43 (1 H, br).
13C NMR (75 MHz, CDCl3): d = 14.24 (q), 14.53 (q), 19.55
(t), 22.88 (t), 27.91 (t), 29.22 (t), 29.68 (t), 30.87 (t), 34.08
(t), 37.51 (t), 39.37 (t), 62.10 (d), 63.75 (d), 72.87 (d), 73.05
(d). MS: m/z (%) = 239 [M+], 182 (100). HRMS: m/z calcd
for C15H29ON: 239.2103; found: 239.2127; [a]D26 –53.55
(c 1.05, CHCl3).
(11) For proof of identity of (–)-1 with the natural ant alkaloid
(10a, see ref. 5), a Shimadzu QP-2010 GC/MS equipped
with an RTX-5 column (30 m × 0.25 mm i.d.) was used
employing a program of 60 °C to 250 °C at 10 °C/min. Here,
(12) Toyooka, N.; Zhou, D.; Nemoto, H. J. Org Chem. 2008,
DOI: 10.1021/jo800593n.
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