Syntheses of lamellarins I and K by [3+2] cycloaddition of a nitrone to an alkyne

Article abstract of DOI:10.1055/s-2001-15143

Lamellarins I and K were obtained by a new approach based on the 1,3-dipolar cycloaddition of a nitrone to an alkyne. The key cycloaddition yields an isoxazoline which rearranges to afford the central pyrrole ring.

Full text of DOI:10.1055/s-2001-15143

1164
LETTER
Syntheses of Lamellarins I and K by [3+2] Cycloaddition of a Nitrone to an
Alkyne
Maite Díaz, Enrique Guitián,* Luis Castedo
Departamento de Química Orgánica y Unidad Asociada al CSIC,Universidad de Santiago, 15706 Santiago de Compostela, Spain
Fax 34 981 595012; E-mail: qoenrgui@usc.es
Received 23 March 2001
The first synthesis of lamellarins was published by Stegli-
Abstract: Lamellarins I and K were obtained by a new approach
ch’s group in 1997.4 Since then, new procedures for the
based on the 1,3-dipolar cycloaddition of a nitrone to an alkyne. The
preparation of lamellarins of general structure 1 have been
key cycloaddition yields an isoxazoline which rearranges to afford
the central pyrrole ring.
developed by Banwell5 and Ishibashi.6 Banwell’s synthe-
sis of lamellarin K is particularly interesting because it is
Key words: lamellarins, nitrone-alkyne 1,3-dipolar cycloaddition
convergent, versatile and high-yielding.5a The key step in
this approach is the formation of the central pyrrole ring
by an intramolecular 1,3-dipolar cycloaddition between
The lamellarin alkaloids are a group of approximately 35
an azomethine ylide and an alkyne.5 Here we present a re-
compounds isolated from the marine prosobranch mollusc
lated approach to lamellarins which relies on two known
Lamellaria sp., the marine ascidian Didemnum sp. and the
sponge Dendrilla cactos. Most of them have the basic
facts: a) nitrones add to alkynes to form isoxazolines,7 and
b) isoxazolines with a R-CH2- substituent at position 3 can
structure 1, although about a third have a double bond be-
be rearranged to pyrroles8 (Scheme 1).
tween carbons 8 and 9.1 The lamellarins have an interest-
ing range of pharmacological activities, including
antitumour and anti HIV-1 properties, reversal of multi-
drug resistance (MDR), and immunomodulatory activi-
N
N
R
R
N
ty.1,2 For example, it has been claimed that lamellarins I
O
O
+
R
(1a) and K (1b) not only exhibit potent cytotoxic activity
R
R
in vitro against multidrug-resistant cell lines, but also re-
R
2,3
verse their MDR at noncytotoxic concentrations,
and
Scheme 1
the results of in vivo tests of lamellarin K are consistent
with these claims.3
As synthetic targets we selected lamellarins I and K. Ap-
plication of our procedure to their synthesis requires prep-
aration of alkyne 2 and nitrones 3. Alkyne 2 was
synthesized from isovanillin (4) as shown in Scheme 2.
Protection of the hydroxyl group of 4 as an isopropyl ether
by treatment with K2CO3 and iPrBr, followed by treatment
with iodine and silver trifluoroacetate, afforded iodide 5,
which upon palladium-catalyzed coupling with trimethyl-
silylacetylene (TMSA) yielded 6. Treatment with MCP-
BA transformed the formyl group of 6 into a hydroxyl
group, which was then protected with K2CO3 and iPrBr
as above, with accompanying loss of the TMS group.
Finally, deprotonation of the resulting alkyne with LDA
O
N
O
R1
R2
O
O
HO
8 R8
MeO
N
9
OR
R7
RO
MeO
OMe
R3
MeO
R6
R4
R5
1a, Lamellarin I, R=Me
1b, Lamellarin K, R=H
1
Figure 1
CHO
OMe
TMS
CO2Et
CHO
CHO
iPrO
I
d, e, f
a, b
c
iPrO
iPrO
HO
iPrO
OMe
OMe
OMe
4
5
6
2
Scheme 2 a) K2CO3, 2-bromopropane/DMF, 100 C, 24 h, 98%; b) I2, F3C CO2 Ag, CHCl3, rt, 3 h, 80%; c) TMSA, PdCl2(PPh3)2, CuI, Et3N,
dioxane, 45 C, 3 h, 98%; d) MCPBA, NaHCO3, CH2Cl2, rt, 30 min, 73%; e) K2CO3, 2-bromopropane/DMF, 100 C, 24 h, 45%; f) LDA,
THF, –78 C, 15 min; then ClCO2Et, –78 C rt, 94%
Synlett 2001, No. 7, 1164–1166 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Syntheses of Lamellarins I and K by [3+2] Cycloaddition of a Nitrone to an Alkyne
1165
RO
RO
MeO
MeO
N
N
MeO
MeO
O
MeO
MeO
a, b
a, R= Me
b, R= iPr
RO
RO
7
3
Scheme 3 a) NaBH4, MeOH, rt, 1 h, 96-97%; b) H2O2, Na2WO4, MeOH, rt, 3 h, 45-49%
OR
O
N
OMe
OMe
MeO
MeO
120 C
2
+
3a, R= Me
3b, R= iPr
CO2Et
OiPr
OMe
OR
8a, R= Me
8b, R= iPr
OiPr
CO2Et
PrOi
N
AlCl3
MeO
1a, R= Me, 43%
1b, R= H, 45%
OR
OMe
OMe
OMe
9a, R= Me, 35%
9b, R= iPr, 61%
OR
Scheme 4
and carboxylation with ethyl chloroformate afforded 2 in
Acknowledgement
good yield.
Financial support from the DGES (PB96-0967) is gratefully ack-
nowledged. We also thank the Xunta de Galicia for the award of a
fellowship to M. Díaz.
N-Oxides 3 were obtained from dihydroisoquinolines 7,
which were prepared using standard isoquinoline alkaloid
procedures.9 Reduction of the imine double bond of 7 with
sodium borohydride, followed by a non-optimized oxida-
tion with sodium tungstate10 (45-49% yield), afforded N-
oxides 3.
References and Notes
(1) Urban, S.; Hickford, S. J. H.; Blunt, J. W.; Munro, M. H. G.
Current Organic Chemistry 2000, 4, 765-807. Lamellarins O,
P, Q and R have a different structure characterized by a non-
fused polysubstituted pyrrole nucleus.
(2) Andersen, R. J.; Faulkner, D. J.; Cun-heng, H.; Van Duyne, G.
D.; Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492. Quesada, A.
R.; Gravalos, M. D. G.; Puentes, J. L. F. Br. J. Cancer 1996,
74, 677. Boger, D.; Soenen, D. R.; Boyce, C. W.; Hedrick, C.
W.; Jin, Q. J. Org. Chem. 2000, 65, 2479. Reddy, M. V. R.;
Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.;
Bushman, F. D.; Venkateswarlu, Y.; Faulkner, D. J. J. Med.
Chem. 1999, 42, 1901.
(3) Puentes, J. L. F.; García, D.; Rodríguez, A. US Patent.
5,852,033, 1995.
(4) a) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem. Int. Ed.
Engl. 1997, 36, 155. b) Peschko, C.; Winklhofer, C.; Steglich,
W. Chem.–Eur. J. 2000, 6, 1147.
The key cycloaddition step was carried out by heating a
mixture of nitrone 3 and alkyne 2 under argon for 18 h at
120 C in a sealed tube. Under these conditions com-
pounds 9 were obtained in moderate yields.11 The cy-
cloaddition appears to take place with the expected
regiochemistry to form the isoxazoline 8, which upon
heating undergoes rearrangement to the corresponding
pyrrole 9.
Finally, lamellarins I and K were obtained from 9a and
9b, respectively, by removal of the isopropyl protecting
groups12 with concomitant acid-catalyzed lactonization.13
Synlett 2001, No. 7, 1164–1166 ISSN 0936-5214 © Thieme Stuttgart · New York

1166
M. Díaz et al.
LETTER
(5) a) Banwell, M.; Flyn, B.; Hockless, D. Chem. Commun. 1997,
2259. b) Banwell, M.; Flyn, B.; Hockless, D.; Longmore, R.
W.; Rae, D. Aust. J. Chem. 1999, 52, 755.
(6) Ishibashi, F.; Miyazaki, Y.; Ywao, M. Tetrahedron 1997, 53,
5951.
(7) a) Tufariello, J. J. in 1,3-Dipolar Cycloaddition Chemistry,
Padwa, A., Ed., John Wiley and Sons, New York, 1988, vol.
2, pp. 83-68. b) Breuer, R.; Aurich, H. G.; Nielsen, A. T. in
Nitrones, Nitronates and Nitroxides; Patai, S., Ed., John
Wiley and Sons, New York, 1989, pp. 139-312. c) Little, R. D.
in Comprehensive Organic Synthesis, Trost, B. M.; Fleming,
I.; Paquette, L.A., Eds., Pergamon Press, Oxford, 1991, pp.
239-270.
was chromatographed (silicagel, hexane/ether) to yield 9b (38
mg, 61% yield) as an oil. Spectroscopic data for 9b: UV
(EtOH), max: 304 nm. IR (NaCl), : 1694 cm-1. 1H NMR
(CDCl3), : 6.73 (m, 2H), 6.61 (s, 1H), 6.50 (s, 1H), 6.40 (m,
2H), 4.50-4.32 (m, 5H), 4.05-3.98 (m, 3H), 3.74 (s, 3H), 3.52
(s, 3H), 3.46 (s, 3H), 3.25 (s, 3H), 3.10-2.90 (m, 2H), 1.26-
0.78 (m, 27H) ppm. 13C NMR (CDCl3), 162.2 (C), 151.4 (C),
150.1 (C), 149.5 (C), 148.2 (C), 145.8 (C), 145.7 (C), 144.5
(C), 141.3 (C), 130.0 (C), 129.0 (C), 127.8 (C), 124.0 (C),
123.2 (CH), 122.0 (C), 120.1 (C), 119.8 (C), 119.6 (C), 115.9
(CH), 114.8 (CH), 107.4 (CH), 104.7 (CH), 75.5 (CH), 71.7
(CH), 71.6 (CH), 71.4 (CH), 60.5 (CH3), 59.7 (CH2), 56.1
(CH3), 55.7 (CH3), 55.1 (CH3), 42.6 (CH2), 23.0 (CH2), 22.7
(CH3), 22.2 (CH3), 21.9 (CH3), 15.2 (CH3), 13.7 (CH3) ppm.
LRMS, m/z (%):745 (M+, 34). HRMS, m/z calcd. for
C43H55NO10 745.382598, found 745.385468.
(8) a) Zhao, B-X.; Yu, Y.; Eguchi, S. Tetrahedron 1996, 52,
12049. b) Schmidt, G.; Stracke, H. U.; Winterfeldt, E. Chem.
Ber. 1970, 103, 3196.
(9) a) Shamma, M. The Isoquinoline Alkaloids, Academic Press,
New York, 1972. b) Shamma, M.; Moniot, J. M. Isoquinoline
Alkaloid Research 1972-1977, Plenum Press, New York,
1978.
(10) Murahashi, S.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S.
J. Org. Chem. 1990, 55, 1736.
(12) Banwell, M.; Flyn, B.; Stewart, S. G. J. Org. Chem. 1998, 63,
9139.
(13) Spectroscopic data for these synthetic compounds are
identical to those published for lamellarins I and K. Carrol, A.
R.; Bowden, B. F.; Coll, J. C. Aust. J. Chem. 1993, 46, 489.
(11) Experimental procedure for the cycloaddition. A solution of
3b (37 mg, 0.08 mmol) and 2 (38 mg, 0.12 mmol) in toluene
(1 mL) was heated under argon in a sealed tube for 18 h at 120
C. Then the solvent was evaporated in vacuo and the residue
Article Identifier:
1437-2096,E;2001,0,07,1164,1166,ftx,en;G06001ST.pdf
Synlett 2001, No. 7, 1164–1166 ISSN 0936-5214 © Thieme Stuttgart · New York