Enantiospecific synthesis of an indolizidine alkaloid, (+)-ipalbidine

Article abstract of DOI:10.1016/S0040-4039(03)00563-X

Enantiospecific total synthesis of an indolizidine alkaloid, ipalbidine, was achieved starting from (-)-pyroglutamic acid by employing an intramolecular McMurry coupling reaction with a low-valent titanium, as a key step.

Full text of DOI:10.1016/S0040-4039(03)00563-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3035–3038
Enantiospecific synthesis of an indolizidine alkaloid,
(+)-ipalbidine
Toshio Honda,* Hidenori Namiki, Hiromasa Nagase and Hirotake Mizutani
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
Received 3 February 2003; revised 24 February 2003; accepted 27 February 2003
Abstract—Enantiospecific total synthesis of an indolizidine alkaloid, ipalbidine, was achieved starting from (−)-pyroglutamic acid
by employing an intramolecular McMurry coupling reaction with a low-valent titanium, as a key step. © 2003 Elsevier Science
Ltd. All rights reserved.
Ipalbidine 1, isolated from the seeds of Ipomoea alba L.
as the aglycone of ipalbine 2 (Fig. 1), is a naturally
occurring indolizidine alkaloid, which contains a 1-
azabicyclo[4.3.0]-non-3-ene system with a phenolic sub-
stituent at the 3-position.1
our work on the synthesis of analgesic agents, we are
interested in a chiral synthesis of ipalbidine by forming
a carbonꢀcarbon double bond as a crucial step.
In order to construct the desired carbonꢀcarbon double
bond, we first planned to utilize an intramolecular
ring-closing metathesis7 along with our retrosynthetic
analysis as depicted in Scheme 1, where the optically
active key precursor might be prepared from (−)-pyro-
glutamic acid in relatively short steps.
Ipalbidine 1 was known as a nonaddictive analgesic,
and caused analgesia in mice which was not antago-
nized by naloxone.2 This alkaloid also showed
inhibitory effects on respiratory burst of leukocyte and
scavenged oxygen-free radicals.3
Thus, the alcohol 3,8 readily accessible from pyroglu-
tamic acid methyl ester, was reacted with p-toluenesul-
fonyl chloride to give the tosylate 4, which, on
treatment with a higher-order cuprate reagent afforded
the desired olefinic amide 5 in 93% yield. The bromide
9 was prepared from the ester 6 by condensation with
paraformaldehyde in the presence of tris[2-(2-
methoxyethoxy)ethyl]amine (TDA-1),9 followed by
Although a number of total synthesis for racemic ipal-
bidine have appeared by application of newly devel-
oped synthetic strategies or methodologies,4 only one
chiral synthesis has been reported to date,5 where,
however, the optical purity of the target compound has
not been mentioned, unfortunately.6 In the course of
Figure 1.
Keywords: (+)-ipalbidine; McMurry coupling; indolizidine alkaloid;
ring-closing metathesis; chiral synthesis.
* Corresponding author. Tel.: +81-3-5498-5791; fax: +81-3-3787-0036;
e-mail: honda@hoshi.ac.jp
Scheme 1. Retrosynthetic route for (+)-ipalbidine.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00563-X

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T. Honda et al. / Tetrahedron Letters 44 (2003) 3035–3038
With the pivotal starting material in hand, we
attempted a ring-closing metathesis (RCM) for the
diene 10 using Grubbs catalyst10 or Hoveyda catalyst11
under various reaction conditions; however, no cycliza-
tion product could be isolated, unfortunately. It is
recognized that the Schrock catalyst is usually more
effective than the Grubbs catalyst in the construction of
a poly-substituted olefin system in RCM; however,
none of the desired product could be obtained even by
the use of the Schrock catalyst.12
We therefore turned our attention to McMurry
coupling13 for constructing a tetra-substituted olefin
system. Ozonolysis of the diene 10, followed by reduc-
tive work-up with methyl sulfide, provided the corre-
sponding diketone 11, which, on treatment with
titanium(0), prepared from titanium(III) chloride THF
complex and ZnꢀCu couple, in DME at 80°C for 48 h
furnished the desired product 1214 in 30% yield together
with the cis-diol 13 and stereochemically unidentified
diol 14 in 15 and 15% yields, respectively. The structure
of the cis-diol 13 was determined by X-ray analysis
unambiguously as depicted in Figure 2.15
Scheme 2. Reagents and conditions: (i) TsCl, Et3N, DMAP,
CH2Cl2, rt (88%); (ii) THF–Et2O, −78 to 0°C (93%); (iii)
(CH2O)n, Cs2CO3, TDA-1, toluene, 85°C (54%); (iv) DIBAL,
CH2Cl2, −78°C; (v) CBr4, PPh3, CH2Cl2, rt (71% from 7).
Unidentified compound 14 seemed to have diol func-
tions based on consideration of the spectroscopic
data.16 Although we could not confirm its structure at
present, unfortunately, a diastereoisomeric b-cis-diol
structure would be assumed reasonably based on the
reaction mechanism. When this coupling was carried
out under the same reaction conditions for 5 h, the
cis-diol 13 was isolated in 66% yield in addition to the
diol 14 (6%) (Scheme 3).
Figure 2. ORTEP drawing of the diol 13.
reduction of the ester 7 with diisobutylaluminum
hydride and bromination of the resulting alcohol 8 with
CBr4 and Ph3P as shown in Scheme 2. Condensation of
the amide 5 with the bromide 9 was carried out in
THF–HMPA in the presence of NaH to give the diene
10 in 90% yield.
For completion of the synthesis of (+)-ipalbidine,
reduction of the amide function for 12 was achieved by
using lithium aluminum hydride to furnish the amine 15
in 86% yield.
Scheme 3. Reagents and conditions: (i) NaH, THF–HMPA, rt (90%); (ii) O3, MeOH, −78°C, then Me2S, −78°C to rt (99%); (iii)
TiCl3(thf)3, ZnꢀCu, DME, 80°C (30% for 12, 15% for 13, 15% for 14).

T. Honda et al. / Tetrahedron Letters 44 (2003) 3035–3038
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Finally, debenzylation of 15 under hydrogenolysis con-
Acknowledgements
ditions over 5% palladium hydroxide on carbon in
MeOH afforded the natural product 1. The spectro-
scopic data of 1, mp 76–78°C (from benzene–cyclohex-
ane) (lit.,4b mp 82–84°C), were in agreement with those
reported.4 Although some difference is observed
between the specific optical rotation of the synthesized
compound 1 {[h]D +158.6 (c 0.8, MeOH); +189.4 (c 1,
CHCl3)} and those reported {lit.,4b [h]D +190.5 (c 1,
MeOH); lit.,5 [h]D +54.1 (c 1, EtOH)} and the accurate
value is still obscure at present, we believe that our
compound has an almost optically pure form based on
the synthetic strategy (Scheme 4).
This work was supported in part by a grant from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan.
References
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Since the direct formation of the alkene function from
the diketone 11 by the McMurry coupling was found to
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elimination of the vic-diol function in 13 was involved
as the key reaction. Thus, the reaction of the diol 13
obtained from 11 by the McMurry coupling with a
shorter reaction time in 66% yield, with trimethyl
orthoformate and PPTS afforded the orthoformate 16,
which, on treatment with acetic anhydride17 brought
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olefin 12 in 75% yield from 13 (Scheme 5).
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In summary, we have disclosed an alternative total
synthesis of optically active (+)-ipalbidine 1, in which
intramolecular McMurry coupling of the diketone 11
with Ti(0) was employed, as the key reaction, forming a
carbonꢀcarbon double bond directly. Elimination of
the vic-diol of 13, obtained as the major product, from
the McMurry coupling of 11 under different reaction
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7. For recent reviews on metathesis, see: (a) Grubbs, R. H.;
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Scheme 4. Reagents and conditions: (i) LiAlH4, THF, rt
(86%); (ii) H2, 5% Pd(OH)2–C, MeOH, rt (100%).
11. (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.,
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Scheme 5. Reagents and conditions: (i) CH(OMe)3, PPTS,
CH2Cl2, rt; (ii) Ac2O, 140°C (75% from 13).

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T. Honda et al. / Tetrahedron Letters 44 (2003) 3035–3038
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data collection, had an average width at half-height of
0.18° with a take-off angle of 6.0°. Scans of (1.68+0.30
tan q)° were made at a speed of 16.0°/min (in v). The
weak reflections (I<10.0|(I)) were rescanned (maximum
of seven scans) and the counts were accumulated to
ensure good counting statistics. Of the 4267 reflections
that were collected, 4228 were unique (Rint=0.000);
equivalent reflections were merged. The intensities of
three representative reflections were measured after every
150 reflections. No decay correction was applied. The
structure was solved using MALTAN88. R=0.049, Rw=
0.056.
13. (a) McMurry, J. E. Chem. Rev. 1989, 89, 1513–1524; (b)
Lenoir, D. Synthesis 1989, 883–897.
14. Selected data for 12: mp 109–111°C (recrystallized from
benzene–hexane); [h]D +186.1 (c 1, CHCl3). 1H NMR
(CDCl3) l 1.63 (3H, s), 1.73 (1H, m), 2.13 (1H, m),
2.25–2.48 (4H, m), 3.58 (1H, d, J=18.2 Hz), 3.74 (1H,
dddd, J=5.1, 7.4, 10.4 and 12.5 Hz), 4.47 (1H, d, J=18.2
Hz), 5.07 (2H, s), 6.95 (2H, d, J=8.7 Hz), 7.10 (2H, d,
J=8.7 Hz), 7.30–7.47 (5H, m); 13C NMR (CDCl3) l 20.4,
24.9, 29.9, 38.2, 44.3, 52.9, 69.9, 114.4, 126.9, 127.4,
127.8, 128.2, 128.5, 129.7, 132.0, 136.8, 157.7, 173.7; IR
16. Selected data for 14: 1H NMR (CDCl3) l 0.99 (3H, s),
1.41 (1H, d, J=1.6 Hz), 1.67 (1H, m), 1.70 (1H, dd,
J=3.8 and 13.3 Hz), 1.96 (1H, ddd, J=1.6, 11.7 and 13.3
Hz), 2.24 (1H, m), 2.43 (1H, s), 2.43–2.51 (2H, m), 3.77
(1H, d, J=13.8 Hz), 3.84 (1H, d, J=13.8 Hz), 4.00 (1H,
dddd, J=3.8, 4.9, 8.7 and 11.7 Hz), 5.07 (2H, s), 6.97
(2H, d, J=9.1 Hz), 7.30–7.49 (7H, m); 13C NMR
(CDCl3) l 23.8, 24.6, 30.4, 41.2, 46.3, 52.8, 69.9, 72.9,
75.0, 114.1, 127.5, 127.9, 128.0, 128.5, 133.3, 136.9, 158.1,
175.2; IR (thin film) 3392, 1664, 1608, 1508, 1454, 1246,
1178 cm−1; HRMS m/z found: 367.1784 (calcd for
C22H25NO4: 367.1783).
(thin film) 1786, 1606, 1510, 1453, 1421, 1240 cm−1
;
HRMS m/z found: 333.1749 (calcd for C22H23NO2:
333.1729).
15. Crystal data for 13: mp 167–168°C (recrystallized from
EtOAc). C22H25NO4/3H2O, M=421.49, orthorhombic,
space group P212121, a=7.666(1), b=42.539(5), c=
3
6.7407(9) A, V=2198.2(5) A , Z=4, Dcalcd=1.27 g/cm3.
The data were collected at a temperature of 23 1°C using
the v scan technique to a maximum 2q value of 136.0°.
Omega scans of several intense reflections, made prior to
,
,
17. Ando, M.; Ohhara, H.; Takase, K. Chem. Lett. 1986,
879–882.