Total synthesis of four Pandanus alkaloids: Pandamarilactonine-A and -B and their chemical precursors norpandamarilactonine-A and -B

Article abstract of DOI:10.1016/S0040-4039(02)01129-2

Norpandamarilactonine-A and -B are prepared from (S)-prolinol and converted into pandamarilactonine-A and -B.

Full text of DOI:10.1016/S0040-4039(02)01129-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5583–5585
Total synthesis of four Pandanus alkaloids:
pandamarilactonine-A and -B and their chemical precursors
norpandamarilactonine-A and -B
Fe´lix Busque´, Pedro de March, Marta Figueredo,* Josep Font and Elena Sanfeliu
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
Received 29 April 2002; revised 31 May 2002; accepted 13 June 2002
Abstract—Norpandamarilactonine-A and -B are prepared from (S)-prolinol and converted into pandamarilactonine-A and -B.
© 2002 Elsevier Science Ltd. All rights reserved.
Pandanus amaryllifolius Roxb. (Pandanaceae), com-
monly named screw pine, is a small species of about 50
cm characterised by very sweet smelling leaves. It is
cultivated extensively through tropical and subtropical
regions and traditionally used as a food flavouring
additive and in folk medicine for strengthening the
heart and as a diuretic.1 The two diastereoisomeric
pyrrolidine alkaloids pandamarilactonine-A (1) and -B
(2) (Fig. 1) were recently isolated by Takayama and
co-workers from this plant.2 The isolated erythro iso-
mer 1 was dextrorotatory with [h]2D3=+35 (c 4.37,
CHCl3), while the threo isomer 2 was optically inactive.
Besides their isolation and structural characterisation,
the authors described a total synthesis of racemic 1 and
2 passing through the key symmetrical amine 3, which
was considered as a plausible biogenetic precursor of
pandamarilactonines. A reinvestigation of the alka-
loidal fraction of the plant led to the isolation of
compound 3, which was named pandamine,3 reinforc-
ing the biogenetic hypothesis. Additionally, another
pair of diastereomeric alkaloids with a closely related
structure, norpandamarilactonine-A (4) and -B (5) were
also found in racemic form as minor bases in fresh
leaves of the plant4 and the threo isomer rac-5 was
synthesised from 2-pyrrolidone and 3-methyl-2(5H)-
furanone, following the protocol developed by Martin
et al.5 Here we present an alternative synthesis of both
norpandamarilactonines 4 and 5 and their conversion
into pandamarilactonines 1 and 2 by alkylation with
the suitable partner 6.
The preparation of 6 (Scheme 1) started from the
hydroxydithiane 7,6 which after silylation and removal
of the thioacetal function furnished the aldehyde 8 in
H
N
O
O
O
O
N
N
O
O
H H
H H
O
O
3
O
O
O
O
O
O
N
H
N
H
O
H H
H H
MsO
O
O
O
4
1
5
6
2
Figure 1.
Keywords: Pandanus alkaloids; total synthesis; norpandamarilactonine; pandamarilactonine.
* Corresponding author. Tel.: 34-935811853; fax: 34-935811265; e-mail: marta.figueredo@uab.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01129-2

5584
F. Busque´ et al. / Tetrahedron Letters 43 (2002) 5583–5585
c,
9
OTIPS
S
a, b
O
TBDPSO
CHO
HO
S
7
8
TBDPSO
d
e, f
O
O
O
O
O
O
HO
H H
TBDPSO
MsO
10, threo
11, erythro
12, Z
13, E
6, Z
14, E
Scheme 1. Reagents and conditions: (a) TBDPSCl, Im, DMF, rt, 96%; (b) CaCO3, MeI, CH3CN–H2O, rt, 92%; (c) BF3·Et2O,
CH2Cl2, −78°C, 2 h, 82%; (d) TMSCl, DBU, CHCl3, reflux, 1 h, 94%; (e) Bu4NF, THF, rt, 3 h, 86%; (f) MsCl, pyr, CH2Cl2, rt,
overnight, 74%.
88% yield. The vinylogous Mukaiyama reaction7 of 8
with the silyloxyfuran 9, prepared by Martin methodol-
ogy,5 delivered a 7:1 mixture of the threo and erythro
alcohols 10 and 11 in 82% yield. Treatment of a 6:1
mixture of these diastereomeric alcohols with TMSCl/
DBU in refluxing chloroform gave the olefins 12 and 13
in 94% yield after purification by silica gel chromato-
graphy. Provided that an antiperiplanar E2 type mecha-
nism is operating during the elimination step, the Z
olefin 12 should be formed from the threo alcohol 10
and the E olefin 13 from the erythro alcohol 11, but 12
and 13 were isolated in a ca. 3:1 ratio, denoting some
extent of Z/E isomerisation. The olefins were finally
converted by standard procedures into the sulfonates 6
and 14, which could be chromatographically separated.
Although interconversion between the two isomeric
sulfonates was not detected, their stability is quite
limited due to the easy hydrolysis of the lactone and the
sulfonate 6 should be transformed rapidly.
carbamate with TMSI in refluxing chloroform took
place with concomitant epimerisation of the stereogenic
centre of the lactone moiety, furnishing a ca. 1:1 mix-
ture of the two norpandamarilactonines, which were
separated by silica gel chromatography. The first and
1
second eluted diastereomers showed H NMR spectra
respectively identical to those reported for natural nor-
pandamarilactonine-B (5) and -A (4).4 The specific
rotation measured for 4 was [h]2D0=−7 (c 1.5, CHCl3)
and for 5 [h]2D0=−3 (c 2.6, CHCl3). We suspected that
the reason for such low optical activity values could be
that racemisation had occurred in some extent. Thus,
the configurational instability of these alkaloids was
confirmed when a mixture of 4 and 5 was treated with
an equimolar amount of freshly prepared mesylate 6 in
DMF in the presence of pyridine at 60°C. Under these
conditions, pandamarilactonines 1 and 2 were slowly
formed in a ca. 1:1 ratio. After 3 days, the reaction
mixture was treated and purified by flash chromatogra-
1
phy over silica gel. The first eluted isomer showed H
The synthesis of the pyrrolidine fragment (Scheme 2)
was accomplished starting from the carbamate 15, eas-
ily prepared from (S)-prolinol.8 Oxidation of 15 with
MCPBA produced the two oxiranes 16, [h]2D0=−13 (c
1.3, EtOH), and 17, [h]2D0=−42 (c 1.3, EtOH), in 77%
total yield and erythro/threo ratio 1.5:1. The oxiranes
were separated and the major isomer 16 was converted
into the erythro a-methyl butenolide 18, [h]2D0=−33 (c
0.9, EtOH), by a three-step protocol,9 consisting in
addition to the dianion of 2-phenylselenopropionic
acid,10 followed by acid induced lactonisation and oxi-
dation of the selenide function with consequent thermal
elimination, with an overall 61% yield. Cleavage of the
NMR spectrum identical to that reported for natural
pandamarilactonine-B (2), while the second matched
the spectral data reported for pandamarilactonine-A
(1).2 The overall isolated yield was 44%. Analysed pure
samples of each diastereomer exhibited no optical activ-
ity. Although it has been described that in acidic media
pandamarilactonine-A and -B do not interconvert and
that the former does not racemise either,2 pandamari-
lactonine-A isolated from natural sources shows a low
26% e.e. and pandamarilactonine-B is a racemate. In
neutral or basic media, a mechanism involving b-elimi-
nation–conjugate addition11 (Scheme 3) may easily
cause the configurational instability of these alkaloids.
b, c, d, e
H
a
f
g
O
4 + 5
1 + 2
O
O
N
N
N
H H
CO2Et
H H
CO2Et
CO2Et
15
16, erythro
17, threo
18
Scheme 2. Reagents and conditions: (a) MCPBA, CHCl3, rt, 24 h, 77%; (b) separation of diastereoisomers; (c) PhSeCHCH3CO2H,
LDA (2 equiv.), THF, 0°C to rt, 1.5 h; (d) AcOH, THF, reflux, 16 h; (e) H2O2, AcOH, 0°C, 45 min, 61% from 16; (f) TMSI,
CHCl3, reflux, 5 h, 84%; (g) 6, pyr, DMF, 60°C, 3 days, 44%.

F. Busque´ et al. / Tetrahedron Letters 43 (2002) 5583–5585
5585
O
O
O
O
O
O
N
R
NH
R
N
R
H
H
H
H
Scheme 3.
Acknowledgements
5. Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J.
Am. Chem. Soc. 1999, 121, 6990–6997.
6. Solladie´, G.; Ferna´ndez, I.; Maestro, C. Tetrahedron:
We gratefully acknowledge financial support of DGES
(project PB97-0215) and CIRIT (1999SGR-00091). We
also thank CIRIT for a grant to F.B.
Asymmetry 1991, 2, 801–809.
7. For a recent review on the vinylogous aldol reaction, see:
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929–1972.
8. Sato, T.; Tsujimoto, K.; Matsubayashi, K.; Ishibashi, H.;
Ikeda, M. Chem. Pharm. Bull. 1992, 40, 2308–2312.
9. Figueredo, M.; Font, J.; Virgili, A. Tetrahedron 1987, 43,
1881–1886.
10. (a) Petragnani, N.; Ferraz, H. M. C. Synthesis 1978,
476–478; (b) Reich, H. J.; Chow, F.; Shah, S. K. J. Am.
Chem. Soc. 1979, 101, 6638–6648.
11. (a) Cardellach, J.; Estopa`, C.; Font, J.; Moreno-Man˜as,
M.; Ortun˜o, R. M.; Sa´nchez-Ferrando, F.; Valle, S.;
Vilamajo´, L. Tetrahedron 1982, 38, 2377–2394;
(b) Camps, P.; Cardellach, J.; Corbera, J.; Font, J.;
Ortun˜o, R. M.; Ponsati, O. Tetrahedron 1983, 39, 395–
400.
References
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