Intramolecular cyclodehydration of (4S)-(+)-4-carboxyethyl-4-(pyrrol-1-yl)butanal as the key step in the formal synthesis of (S)-(-)-Myrmicarin 217

Article abstract of DOI:10.1016/S0957-4166(03)00201-5

(S)-(-)-Myrmicarin 217, a tricyclic alkaloid recently discovered in the poison glands of Myrmicaria ants, has been formally synthesized. The intramolecular cyclodehydration of 4-carboxyethyl-4-(pyrrol-1-yl)butanal is the key step in the construction of the required six-membered ring.

Full text of DOI:10.1016/S0957-4166(03)00201-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1447–1449
Intramolecular cyclodehydration of
(4S)-(+)-4-carboxyethyl-4-(pyrrol-1-yl)butanal as the key step in
the formal synthesis of (S)-(−)-Myrmicarin 217
Roberta Settambolo,a Giuditta Guazzellib and Raffaello Lazzaronib,*
aICCOM-CNR, Sezione di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
bDipartimento di Chimica e Chimica Industriale, Universita` di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
Received 7 February 2003; accepted 20 February 2003
Abstract—(S)-(−)-Myrmicarin 217, a tricyclic alkaloid recently discovered in the poison glands of Myrmicaria ants, has been
formally synthesized. The intramolecular cyclodehydration of 4-carboxyethyl-4-(pyrrol-1-yl)butanal is the key step in the
construction of the required six-membered ring. © 2003 Elsevier Science Ltd. All rights reserved.
Myrmicarin 217 is a tricyclic alkaloid recently discov-
ered in the poison glands of Myrmicaria ants, a genus
of african Myrmicinae. The first synthesis of non
racemic M217 was reported by Valle´e et al.1 Schro¨der
and Francke described the synthesis of racemic M2172
and the same authors have previously isolated various
natural myrmicarins.
reactive or difficult to be prepared via traditional syn-
thetic chemistry. Encouraged by the success of our
protocol and attracted by the intriguing structure of the
above alkaloid, we tried to synthesize non racemic
Myrmicarin 217 via the cyclodehydration of a suitable
chiral 4-(pyrrol-1-yl)butanal (Scheme 1)
We chose -glutamic acid diethyl ester hydrochloride 1
L
to introduce the appropriate stereogenic center.
According to a well known procedure,5 1 was con-
densed with 2,5-dimethoxytetrahydrofuran under non-
racemizing conditions, namely, in a stirred mixture of
warm water and 1,2-dichloroethane to give the
pyrrolyldiester (2S)-(−)-diethyl-2-(pyrrol-1-yl)pentane-
dioate 2 in excellent yield. The reduction of 2 into 3 was
successfully accomplished by treatment of 2 with
DIBAH in hexane (1.8 equiv.) at −78°C. The
pyrrolylbutanal 3 was chemo- and regioselectively
obtained, only the distal ester group being reduced to
the corresponding carbonyl group. The (4S)-(+)-4-car-
boxyethyl-4-(pyrrol-1-yl)butanal 3 is stable enough to
be handled at room temperature and can be stored at
0°C for a few days without any decomposition.6 Over
longer times, 3 spontaneously cyclizes, presumably giv-
ing the bicyclic alcohol bearing the hydroxyl group on
C-8.7 A one pot ring closure/dehydration sequence was
carried out by heating the butanal 3 at 100°C in
anhydrous DMSO, a typical neutral dehydration agent
of benzyl alcohols.8 The 5,6-dihydroindolizine 4 bearing
an ester group on position 5 was obtained selectively.9
The product 4 was isolated by silica chromatography
by eluting with hexane/Et2O 2:1 and was transformed
As a pyrrolo[2,1,5-cd]indolizidine, Myrmicarin 217
belongs to the ‘izidine’ type alkaloids, widely present in
nature and characterized by a variety of physiological
activities.3 We recently found a new approach to 5,6-
dihydroindolizines via an in situ domino hydroformyla-
tion/cyclization/dehydration reaction sequence of
1-allylpyrroles.4 In this pathway an unprecedented
intramolecular electrophilic substitution by the car-
bonyl group of the produced 4-pyrrolylbutanals on the
C-2 pyrrole carbon is the key step to construct the
six-membered ring of the indolizine moiety. The 4-
pyrrolylbutanals are a class of compounds almost
unknown in literature, perhaps because they are very
* Corresponding author. Tel.: +39-050-918227; fax: +39-050-918260;
e-mail: lazza@dcci.unipi.it
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00201-5

1448
R. Settambolo et al. / Tetrahedron: Asymmetry 14 (2003) 1447–1449
Scheme 1. Reagents and conditions: (a) 2,5-dimethoxytetrahydrofuran, 1,2-dicloroethane/H2O (1:1), 80°C, 50 min, 80%; (b) 1 M
DIBAH in hexane (1.8 equiv.), −78°C, 3 h, 65%; (c) DMSO, 100°C, 2 h, 55%; (d) LiAlH4, THF, rt, 2 h, 85%; (e) H2, 5% Rh,
Et2O, 80%; (f) 5% Rh, Et2O, 75%; (g) LiAlH4, THF, rt, 2.5 h, 80%.
into
(5S)-(−)-5-hydroxymethyl-5,6,7,8-tetrahydro-
Acknowledgements
indolizine 6 using two different methods. In the first the
reduction of the ester group of 4 to the corresponding
hydroxymethyl group in 510 was achieved by treatment
of 4 with LiAlH4 at room temperature; subsequently
the double bond in 5 was reduced with H2 in the
presence of 5% rhodium on carbon catalyst to give 6
(d–e in Scheme 1). In an alternative sequence, the
unsaturated ester 4 was submitted to hydrogenation of
the double bond under the same experimental condi-
tions adopted in the case of 5 selectively giving 5% (f in
Scheme 1).11 Then 5% was transformed into 6 by treat-
ment with LiAlH4 (g in Scheme 1). Spectroscopic data
(1H and 13C NMR, MS) and specific rotation for the
resulting alcohol 6 are in full agreement with that
reported by Valle´e et al.: [h]2D0=−34.1 (c 1, CH2Cl2);
lit.1b [h]2D0=−33.7 (c 1, CH2Cl2).
Financial
acknowledged.
support
by
MIUR
is
gratefully
References
1. (a) Sayah, B.; Le´on-Pelloux, N.; Milet, A.; Guindet-Par-
dillos, J.; Valle´e, Y. J. Org. Chem. 2001, 66, 2522; (b)
Sayah, B.; Le´on-Pelloux, N.; Valle´e, Y. J. Org. Chem.
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2. Schro¨der, F.; Francke, W. Tetrahedron 1998, 54, 5259.
3. For an updated review on the indolizidine alkaloids, see:
Michael, J. P. Nat. Prod. Rep. 2001, 18, 520.
4. (a) Lazzaroni, R.; Settambolo, R.; Caiazzo, A.; Pon-
torno, L. J. Organomet. Chem. 2000, 601, 320; (b) Set-
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The
(5S)-(−)-5-hydroxymethyl-5,6,7,8-tetrahydro-
indolizine 6 has previously been converted by Valle´e
into (S)-(−)-M217 having 98% enantiomeric excess.1b
5. Jefford, C. W.; Sienkiewicz, K.; Thornton, S. R. Helv.
In summary, a formal synthesis of (S)-M217 has been
achieved by intramolecular cyclodehydration of the
(4S)-4-carboxyethyl-4-(pyrrol-1-yl)butanal 3 promoted
by the strong nucleophilic character of the pyrrole
carbon atom a to the nitrogen. The synthesis of 3
shows that pyrrolylbutanals4 can be prepared via tradi-
tional organic chemistry and they can be isolated and
fully characterized. The new intermediates 4 and 5 were
also isolated and characterized; they are two examples
of 5,6-dihydroindolizines, a class of compounds almost
unknown in literature, recently obtained by us under
Chim. Acta 1995, 78, 1511.
6. Selected data for 3: yellow liquid; [h]2D0=+53.2 (c 1,
1
benzene); H NMR (CDCl3, 200 MHz, TMS): l 9.66 (bs,
1H), 6.73 (t, J=2.0 Hz, 2H), 6.21 (t, J=2.0 Hz, 2H), 4.67
(m, 1H), 4.22 (m, 2H), 2.52–2.20 (m, 4H), 1.28 ( t, J=7.2
Hz, 3H).
7. 1H NMR spectra of pure samples of 3, carried out at
different times, showed a decrease of the CHO signal and
the corresponding increase of a structurated signal at 5.15
ppm, compatible with the CH
boxyethyl-8-hydroxyl-5,6,7,8-tetraidroindolizine.
ever, a GC–MS control of the same samples showed the
typical fragmentation of 5-carboxyethyl-5,6-dihydroind-
olizine 4.9
6
OH proton in the 5-car-
How-
rhodium
catalyzed
hydroformylation
of
1-
allylpyrroles.4 Synthesis of natural products of similar
structure via the above procedure are in progress.

R. Settambolo et al. / Tetrahedron: Asymmetry 14 (2003) 1447–1449
1449
8. Settambolo, R.; Lazzaroni, R.; Messeri, T.; Mazzetti, M.;
Salvadori, P. J. Org. Chem. 1993, 58, 7899.
1H NMR (CDCl3, 200 MHz, TMS): l 6.75 (s, 1H),
6.42 (dd, J=2.6, 9.8 Hz, 1H), 6.15 (t, J=3.0 Hz, 1H),
6.07 (m, 1H), 5.61 (m, 1H), 4.16 (m, 1H), 3.79–3.60 (m,
2H), 2.77 (m, 1H), 2.40 (m, 1H), 1.96 (bs, 1H); 13C NMR
( CDCl3): l 128.5, 121.2, 120.0, 117.4, 108.2, 106.6, 64.5,
56.1, 26.1; MS m/e 149 (M+ 37), 118 (100), 117 (79), 91
(14).
9. Selected data for 4: yellow oil; [h]2D0=−127.5 (c 0.35,
1
hexane); H NMR (CDCl3, 200 MHz, TMS): l 6.63 (dd,
J=1.5; 2.7 Hz, 1H), 6.45 (dt, J=9.6; 1.6 Hz, 1H), 6.17
(dd, J=2.7; 3.6 Hz, 1H), 6.08 (dd, J=1.5; 3.6 Hz, 1H),
5.60 (m, 1H), 4.71 (m, 1H), 4.15 (m, 2H), 2.83 (m, 2H),
1.24 (m, 3H); 13C NMR (CDCl3): l 14.1, 27.6, 56.5, 61.5,
106.8, 108.9, 116.1, 120.6, 121.6, 129.2, 171.0; MS m/e
191 (M+ 13), 118 (100), 90 (10).
11. The spectroscopic parameters (1H and 13C NMR, MS)
for 5% resulted in agreement with that reported in litera-
ture for the same compound prepared in an alternative
way.1b
10. Selected data for 5: yellow oil; [h]2D0=+69.6 (c 1, CH2Cl2);