Construction of the A-ring of cylindrospermopsin via an intramolecular oxazinone-N-oxide dipolar cycloaddition

Article abstract of DOI:10.1016/S0040-4039(00)01921-3

The efficient synthesis of an A-ring synthon for the marine hepatatoxin cylindrospermopsin has been achieved. The key step features an intramolecular oxazinone N-oxide/alkene dipolar cycloaddition resulting in the establishment of the three contiguous ste

Full text of DOI:10.1016/S0040-4039(00)01921-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 769–771
Construction of the A-ring of cylindrospermopsin via an
intramolecular oxazinone-N-oxide dipolar cycloaddition
Ryan E. Looper and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80524, USA
Received 26 September 2000; revised 26 October 2000; accepted 31 October 2000
Abstract—The efficient synthesis of an A-ring synthon for the marine hepatatoxin cylindrospermopsin has been achieved. The key
step features an intramolecular oxazinone N-oxide/alkene dipolar cycloaddition resulting in the establishment of the three
contiguous stereogenic centers in the A-ring from one pre-existing stereogenic center in a single step. © 2001 Elsevier Science Ltd.
All rights reserved.
Cylindrospermopsin (1) was first isolated in 1992, from
the marine cyanobacterium Cylindrospermopsis raci-
borskii.1a Following the initial discovery of 1 it has also
been isolated from Aphanizomenon ovalisporum1b and
Umezikia natans.1c The family has recently been ex-
panded with the isolation of 7-epi-cylindrospermopsin
(2)2a and deoxycylindrospermopsin (3).2b These com-
pounds have exhibited hepatotoxic activity (LD50=0.5–
0.2 mg/kg in mice for 1) and are partially responsible for
the acute toxicity of algae blooms.3 Much effort has been
dedicated to the detection of these toxins in water
supplies as outbreaks of both human and animal hepa-
toenteritis have become a serious problem.4a Cylindro-
spermopsin, along with mycrocrystin heptapeptides,
have been implicated in the death of at least 50 people
in Cararu, Brazil who consumed contaminated drinking
water.4b Although the exact mode of action has not been
elucidated for these compounds, it has been shown that
cultured rat hepatocytes experience an inhibition of
glutathione synthesis prior to cell death.3,5
1 has recently been accomplished6 and several synthetic
strategies have appeared in the literature.7 We envisioned
that the three contiguous stereogenic centers of the
4-hydroxypiperidine moiety in the A-ring of 1 could be
set in a single intramolecular cycloaddition reaction.
The intramolecular 1,3-dipolar cycloaddition (1,3-DC)
of nitrones has become a powerful tool to access archi-
tecturally complex heterocycles.8 Nonetheless, the use
of functionalized nitrone precursors, in particular a-
alkoxycarbonylnitrones, has found little application in
the synthesis of natural products.9 This is in part due to
poor stereoselectivity arising from nitrone E/Z isomer-
ization in acyclic systems. The ability of the 1,3-DC
reaction to set three contiguous stereogenic centers,
with the possibility of post cycloaddition manipulation
of the carbonyl functionality, makes a-alkoxycarbonyl-
nitrones functionally rich synthons for heterocyclic ring
construction. The development of geometrically (E/Z)
constrained nitrones, from chiral 1,4-oxazin-2-ones
(oxazinone N-oxides), have shown excellent regio- and
diastereoselectivity in intermolecular 1,3-DC reactions,
but have remained unexplored in an intramolecular
fashion.10
In addition to cylindrospermopsin’s intriguing biological
activity, the incorporation of six stereogenic centers, the
zwitterionic guanidinium and sulfate units, and a densely
functionalized tricyclic core have made these molecules
attractive synthetic targets. A racemic total synthesis of
The synthesis of the requisite oxazinone N-oxide 10,
began with the esterification of ( )-3-buten-2-ol (4) with
N-t-Boc-Gly to afford the allylic ester 5 (Scheme 1).11
* Corresponding author. E-mail: rmw@chem.colostate.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01921-3

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R. E. Looper, R. M. Williams / Tetrahedron Letters 42 (2001) 769–771
Scheme 1.
10 was surprising as no dimerization9b nor spontaneous
The dianion of 5, generated by the addition of sodium
bis(hexamethylsilyl)amide, smoothly underwent [3,3]-
sigmatropic Claisen rearrangement to give the crotyl
glycine derivative 6 in quantitative yield.12
cyclization was observed.
Exposure of the oxazinone-N-oxide 10 to elevated tem-
peratures cleanly effected the 1,3-dipolar cycloaddition
reaction to give the tricyclic isoxazolidine 13 in 78%
isolated yield (Scheme 2). As expected from Oppolzer’s
work with intramolecular N-alkenylnitrone cycloaddi-
tions,9b the nitrone 10 added suprafacially to the alkene
predominantly through the chair like exo-transition
state A‡ to give 13. Although the reaction produced 13
as a single diastereomer it was accompanied, as a 10:1
mixture, by the regioisomeric isoxazolidine 14 as evi-
denced by a quartet at 3.77 ppm (1H, J=6.3 Hz) in the
The optically active N-t-Boc crotylglycine13 derivative
6, could alternatively be prepared by enolate alkylation
of the commercially available oxazinone 11 affording
12 as a single stereoisomer in 64% yield.14 Birch reduc-
tion of 12 afforded 6 in 57% yield and >99:1 er.
Preliminary results have shown that rearrangement of
the ester 5 derived from R-(−)-3-buten-2-ol proceeds in
91.5:8.5 er.
Reduction of 6 with lithium aluminum hydride gener-
ated the protected amino alcohol 7 in 62–83% yield.15
Removal of the t-Boc group was effected by treatment
with boron tifluoride etherate.16 It should be noted that,
the use of traditional Brønsted and Lewis acids led
predominantly to urethane formation. Treatment of the
free amino alcohol 8 with a-bromophenyl acetate in
situ gave moderate yields of the oxazin-2-one 9.17
Oxidation of the secondary amine (9) with Davis’
oxaziridine led exclusively to the conjugated oxazinone-
N-oxide 10 in 75% yield.18 The dimerization of 9 to the
corresponding diketopiperazine was rapid in polar sol-
vents. Oxidation of the amine was therefore carried out
immediately after isolation of 9. The stability of nitrone
Figure 1. X-Ray structure for 13.
Scheme 2.

R. E. Looper, R. M. Williams / Tetrahedron Letters 42 (2001) 769–771
Soc. 2000, 122, 5017–5024.
771
1H NMR spectrum for the alkoxy-methine proton. The
stereochemistry of 13 was confirmed by single-crystal
X-ray diffraction (Fig. 1). Presumably severe eclipsing
interactions in the regioisomeric exo-transition state B‡
disfavor the formation of the tricyclic ring system in 14.
7. (a) Heintzelman, G. R.; Parvez, M.; Weinreb, S. M.
Synlett 1993, 8, 551–552. (b) Snider, B. B.; Harvey, T. C.
Tetrahedron Lett. 1995, 36, 4587–4590. (c) Heintzelman,
G. R.; Weinreb, S. M. J. Org. Chem. 1996, 61, 4594–
4599. (d) Snider, B. B.; Xie, C. Tetrahedron Lett. 1998,
39, 7021–7024. (e) McAlpine, I. J.; Armstrong, R. W.
Tetrahedron Lett. 2000, 41, 1849–1853. (f) Keen, S. P.;
Weinreb, S. M. Tetrahedron Lett. 2000, 41, 4307–4310.
(g) Djung, J. F.; Hart, D. J.; Young, E. R. R. J. Org.
Chem. 2000, 65, 5668–5676.
Hydrogenolysis of 13 in the presence of methanol led
directly to the ester 15. NO bond cleavage in 13 leads to
a highly strained bicyclic system. The resulting 1,3-diax-
ial disposition of the lactone renders the ensuing trans-
esterification a facile process.
8. (a) For reviews on the 1,3-DC reaction: Gothelf, K. V.;
Jorgenson, K. A. Chem. Rev. 1998, 863–909. (b) Con-
falone, P. N.; Huie, E. M. In Organic Reactions; Kende,
A. S., Ed.; John Wiley & Sons: New York, 1998; Vol. 36,
pp. 3–173.
9. (a) Tamura, O.; Mita, N.; Kusaka, N.; Suzuki, H.;
Sakamotao, M. Tetrahedron Lett. 1997, 38, 429–432. (b)
Oppolzer, W.; Snowden, R. L.; Bakker, B. H.; Petrzilka,
M. Tetrahedron 1985, 41, 3497–3509. (c) For an applica-
tion to the synthesis of 1,4- and 1,3-piperidinols, see:
Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.;
Naito, T. Tetrahedron 1998, 54, 15589–15606.
In summary, we have found that the use of a-alkoxy-
carbonylnitrones to be an efficient and highly stereose-
lective route to the 4-hydroxy piperidine moiety in the
A-ring of cylindrospermopsin. Current work in our
laboratory is directed toward the enantioselective total
synthesis of cylindrospermopsin utilizing this general
approach.
Acknowledgements
10. (a) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi,
M.; Miyawaki, T.; Sakamoto, M. Chem. Commun. 1996,
1861–1862. (b) Baldwin, S. W.; Young, B. G.; McPhail,
A. T. Tetrahedron Lett. 1998, 39, 6819–6822.
Financial support from the National Science Founda-
tion
(Grant
cCHE
9731947)
is
gratefully
acknowledged.
11. Martin, S. F.; Josey, J. A.; Wong, Y.; Dean, D. W. J.
Org. Chem. 1994, 59, 4805–4820.
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