Synthetic studies on a model of cylindrospermopsin

Article abstract of DOI:10.1055/s-2007-980360

A new strategy for the synthesis of cylindrospermopsin is described using an intramolecular Mannich reaction to form ring A. Guanylation of the piperidine nitrogen and reaction on an activated double bond generates ring B. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980360

1446
LETTER
Synthetic Studies on a Model of Cylindrospermopsin
Synthetic Studies
o
e
n a Model
l
of
C
yli
e
ndrosperm
o
n
psin e Henon, Yves Troin*
Laboratoire de Chimie des Hétérocycles et des Glucides, EA 987, Ecole Nationale Supérieure de Chimie de Clermont-Ferrand,
Université Blaise-Pascal, BP187, 63174 Aubière Cédex, France
Fax +33(473)407008; E-mail: troin@chimtp.univ-bpclermont.fr
Received 23 February 2007
H
R2
N
R1
Abstract: A new strategy for the synthesis of cylindrospermopsin
is described using an intramolecular Mannich reaction to form ring
A. Guanylation of the piperidine nitrogen and reaction on an acti-
vated double bond generates ring B.
R1
H+
O
O
R2CHO
+
H2N
O
O
Key words: cylindrospermopsin, piperidines, intramolecular
Mannich reaction
Scheme 1
We decided to extend our methodology to more challeng-
ing targets and focused on the cylindrospermopsin alka-
loids. Our approach to cylindrospermopsin (1) is depicted
in Scheme 2. Displacement of the primary alcohol deriv-
atives in 4 would yield the tricyclic guanidine core. Syn-
thesis of 4 relies on forming the hydroxy function via a
stereoselective intramolecular opening of an appropriate
epoxide by a guanylated piperidine.9
Cylindrospermopsin (1) has been isolated from different
sources of cyanobacteria, predominantly Cylindro-
spermopsis raciborskii,1 but also Umezaki natans2 and
Aphanizomenon ovalisporum.3 This compound, together
with its diastereoisomer 2,4 exhibits hepatotoxic activity
when 7-deoxycylindrospermopsin (3) is devoid of
biological activity (Figure1).5
–
–
Therefore, a possible precursor of compound 4 could be 5,
which results from guanylation of the piperidine nitrogen
and a stereospecific epoxidation of the double bond of 6.
Compound 6 could be obtained by stuctural transforma-
tions on tetrasubstituted piperidine 7, generated by an in-
tramolecular Mannich-type reaction,8 with the ultimate
starting point being the correct stereoisomer of amine 8.
We wish to report our strategy and preliminary results
towards the stereoselective construction of the cylin-
drospermopsin framework.
OSO3
OSO3
12
13
O
O
A
H
10
H
14
N
NH
N
B
NH
H
7
C
H
HN
HN
8
N
H
N
H
O
N
H
N
H
O
H
OH
HO
H
cylindrospermopsin (1)
7-epi-cylindrospermopsin (2)
–
OSO3
O
H
In order to test the strategy, we chose to work on a simpler
model starting from amine 8 and benzaldehyde. Synthesis
of amine 8 was realized from commercial methyl-3-oxo-
pentanoate (9, Scheme 3). Protection of the keto function
of 9 with ethylene glycol, followed by reduction with lith-
ium aluminum hydride furnished the alcohol 10. Oxida-
tion with manganese dioxide and subsequent Wittig–
Horner olefination gave unsaturated ester 11. Diastereo-
selective conjugate addition of N-benzyl-N-methyl-
benzylamine to 11 (de>95%) led, after deprotection of the
amino group, to amine 8, in a 27% overall yield (six
steps).
N
NH
H
HN
N
H
N
O
H
7-deoxycylindrospermopsin (3)
Figure 1
Due to the various functionalities in the molecules and
their high toxicity, the synthesis of cylindrospermopsin
alkaloids in both their racemic6 and enantiomeric form7
has been attempted. Part of our research involves the
asymmetric synthesis of saturated N-heterocycles. We
have studied a simple and efficient Mannich-type cycliza-
tion permitting rapid and highly stereoselective access to
polysubstituted piperidine systems (Scheme 1), which
have been validated through the enantioselective synthe-
sis of various alkaloids.8
Intramolecular Mannich reaction of 8 and benzaldehyde
using our standard conditions cleanly afforded the ex-
pected piperidine 12 as a mixture of diastereoisomers
(12a:12b = 3:2), which were isolated in 62% yield and
separated by flash column chromatography (Scheme 4).
We have previously demonstrated that the potential
carbonyl functionality could be conveniently used to
quantitatively epimerize a substituent in the a-position.10
Furthermore, subsequent reduction of this carbonyl group
with L-Selectride® gave the desired alcohol with an axial
SYNLETT 2007, No. 9, pp 1446–1448
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980360; Art ID: G04107ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
7

LETTER
Synthetic Studies on a Model of Cylindrospermopsin
1447
OH
H
H
N
OMe
RO
1
N
N
NCbz
NHCbz
OMe
LG
N
4
O
H
H
N
OMe
OMe
RO
RO
H
N
N
N
N
NH
Cbz
OMe
OMe
NCbz
R'O
R'O
5
6
H
RO
CHO
O
H
CO2Me
+
CO2Me
NH
R'O
O
NH2
7
8
R'O
Scheme 2
O
1) (CH2OH)2,
toluene, PTSA
O
O
1) MnO2
CO2Me
OH
2) Ph3P=CHCO2Me
56%
2) LiAlH4, THF
85%
10
9
N
H
1)
NH2
O
BuLi, 0 °C
72%
O
O
O
CO2Me
CO2Me
2) H2, Pd(OH)2, 5 atm
MeOH–H2O–AcOH,
75%
11
8
Scheme 3
configuration and excellent diastereoselectivity.10 All the
subsequent reactions were done on major isomer 12a. At-
tempts to Boc-protect the amine functionality of the pipe-
ridine 12a were unsuccessful. However, Cbz-protection
and subsequent reduction of the N-protected piperidine
with DIBAL-H led to the corresponding aldehyde, which
could be used in the next step without purification.
Wittig–Horner olefination, using methyl triphenylphos-
phonium bromide, gave piperidine 13 in an overall yield
of 55% for three steps.
1) MgSO4, PhCHO
CH2Cl2, reflux
O
O
O
O
8
+
2) PTSA,
toluene, 65 °C
N
H
N
H
62%
CO2Me
CO2Me
12b
12a
12a/12b = 3:2
O
O
1) CbzCl, Na2CO3
12a
Heck cross-coupling11 of 13 with 4-bromo-2,6-dimeth-
oxypyrimidine (14)12 led to piperidine 15, albeit in poor
yield. Modifying the conditions of this reaction (reagents,
temperature and solvent) did not improve the yield.
Convenient N-deprotection of the Cbz using TMSI in
acetonitrile13 gave the expected piperidine 16 in an overall
yield of 67% (Scheme 5).
2) DIBAL-H (1M)
3) MePPh3–Br+
n-BuLi, THF, 0 °C
N
Cbz
13
55%
Scheme 4
In conclusion, we have developed a new approach to cy-
lindrospermopsin alkaloids by efficiently synthesizing the
A and B rings of their framework. We are now working on
the synthesis of piperidine 7, as well as the epoxidation
step, which must be realized before guanylation of the
piperidine nitrogen. This work is currently under investi-
gation and will be reported shortly.
Treatment of 16 with bis(benzyloxycarbonyl)methylthio-
pseudourea 17,14 using mercury(II) chloride and triethyl-
amine in N,N-dimethylformamide at 0 °C, conveniently
guanylated the hindered piperidine nitrogen, which spon-
taneously cyclized to 18 during purification (flash chro-
matography) in an unoptimized 45% yield (Scheme 6).
Synlett 2007, No. 9, 1446–1448 © Thieme Stuttgart · New York

1448
H. Henon, Y. Troin
LETTER
OMe
References and Notes
OMe
N
O
O
(1) Ohtani, I.; Moore, R. E.; Runnegar, M. T. C. J. Am. Chem.
Soc. 1992, 114, 7941.
(2) Harada, K.; Ohtani, I.; Iwamoto, K.; Suzuki, M.; Watanabe,
M. F.; Watanabe, M.; Terao, K. Toxicon 1994, 32, 73.
(3) Banker, R.; Teltsch, B.; Sukenik, A.; Carmeli, S.; Hadas, O.;
Porat, R. J. Phycol. 1997, 33, 613.
N
14
Br
N
OMe
13
N
N
OMe
Pd(OAc)2, PPh3,
Na2CO3, DMF
31%
Cbz
15
(4) Banker, R.; Teltsch, B.; Sukenik, A.; Carmeli, S. J. Nat.
Prod. 2000, 63, 387.
OMe
N
O
O
(5) (a) Norris, R. L.; Eaglesham, G. K.; Pierens, G.; Shaw, G.
R.; Smith, M. J.; Chiswell, R. K.; Seawright, A. A.; Moore,
M. R. Environ. Toxicol. 1999, 14, 163. (b) Runnegar, M. T.;
Xie, C.; Snider, B. B.; Wallace, G. A.; Weinreb, S. M.;
Kuhlenkamp, J. Toxicol. Sci. 2002, 67, 81.
TMSI, MeCN
67%
N
H
N
OMe
16
(6) For the racemic total synthesis of cylindrospermopsin and its
C-7 isomer, see: (a) Xie, C.; Runnegar, M. T. C.; Snider, B.
B. J. Am. Chem. Soc. 2000, 122, 5017. (b) Heintzelman, G.
R.; Fang, W.-K.; Keen, S. P.; Wallace, G. A.; Weinreb, S. M.
J. Am. Chem. Soc. 2002, 124, 3939.
Scheme 5
OMe
SMe
O
O
(7) For the enantioselective total synthesis of
17
NHCbz
N
cylindrospermopsin and its C-7 isomer, see: (a) White, J.
D.; Hansen, J. D. J. Am. Chem. Soc. 2002, 124, 4950.
(b) Looper, R. E.; Williams, R. M. Angew. Chem. Int. Ed.
2004, 43, 2930. (c) White, J. D.; Hansen, J. D. J. Org. Chem.
2005, 70, 1963. (d) Looper, R. E.; Runnegar, M. T. C.;
Williams, R. M. Tetrahedron 2006, 62, 4549. (e) For a
review on the synthesis and biological activities of
cylindrospermopsin alkaloids, see: Murphy, P. J.; Thomas,
C. W. Chem. Soc. Rev. 2001, 30, 303.
CbzN
16
N
N
OMe
Et3N, DMF
HgCl2, 0 °C
CbzN
NHCbz
O
O
OMe
N
(8) (a) Ciblat, S.; Besse, P.; Papastergiou, V.; Veschambre, H.;
Canet, J.-L.; Troin, Y. Tetrahedron: Asymmetry 2000, 11,
2221. (b) Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y.
J. Chem. Soc., Perkin Trans. 1 2000, 353. (c) Carbonnel, S.;
Troin, Y. Heterocycles 2002, 57, 1807. (d) Rougnon
Glasson, S.; Tratrat, C.; Canet, J.-L.; Chalard, P.; Troin, Y.
Tetrahedron:Asymmetry 2004, 15, 1561.
(9) SN2 displacement of the bromide derivative by the guanydyl
derivative in order to form cycle B of cylindrospermeopsin
has been described, see reference 6a.
H
45%
N
CbzN
N
N
OMe
Cbz
18
Scheme 6
(10) Rougnon Glasson, S.; Canet, J.-L.; Troin, Y. Tetrahedron
Lett. 2000, 41, 9797.
(11) (a) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320.
(b) For a recent review on Heck reactions, see: Link, J. T.
Organic Reactions, Vol. 60; Wiley: Hoboken, 2002, Chap.
2.
(12) White, J. D.; Hansen, J. D. J. Org. Chem. 2005, 70, 1963.
(13) Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc.
1987, 109, 442.
(14) McAlpine, I. J.; Armstrong, R. W. Tetrahedron Lett. 2000,
41, 1849; and references cited therein.
Synlett 2007, No. 9, 1446–1448 © Thieme Stuttgart · New York