Studies on total synthesis of cylindrospermopsin: New constructions of uracils from α,β-unsaturated esters

Article abstract of DOI:10.1016/S0040-4039(00)00633-X

Two different routes have been developed to prepare uracils related to that found in the marine hepatotoxin cylindrospermopsin starting from α,β- unsaturated esters. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00633-X

Tetrahedron Letters 41 (2000) 4307±4310
Studies on total synthesis of cylindrospermopsin: new
constructions of uracils from a,b-unsaturated esters
Stephen P. Keen and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Received 8 March 2000; revised 13 April 2000; accepted 14 April 2000
Abstract
Two di€erent routes have been developed to prepare uracils related to that found in the marine hepatotoxin
cylindrospermopsin starting from a,b-unsaturated esters. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cyclization; nitrogen heterocycles; uracils.
In 1992 Moore and co-workers described the isolation and characterization of the hepatotoxin
cylindrospermopsin (1) produced by the fresh water blue±green alga Cylindrospermopsis raciborskii.1a
This compound, which can be produced by algal blooms in drinking water, has been implicated in
a severe outbreak of hepatoenteritis in tropical Australia which hospitalized a number of people,
and appears to be a signi®cant public health problem. Recently, 7-epicylindrospermopsin (2),
which is also toxic, has been isolated from the cyanobacterium Aphanizomenon ovalisporum
collected from Lake Kinneret in Israel.1b
During the past few years we have been attempting to develop a total synthesis of cylindro-
spermopsin (1),2,3 and recently have focused on devising methodology for construction of the
uracil D-ring of this unique heterocyclic natural product. Our overall strategy requires that the
precursor for this ring be an a,b-unsaturated ester. Uracils like those found in metabolite 1,
however, are most commonly synthesized from b-keto esters, acetylenic esters, or related
compounds in this same oxidation state. Far less methodology has been described for preparing
* Corresponding author. Tel: (814) 863-0189; fax: (814) 863-8403; e-mail: smw@chem.psu.edu
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00633-X

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these heterocycles from compounds in the lower oxidation state.4 We now describe two new
approaches to construction of a uracil ring starting from an a,b-unsaturated ester.
Our initial route commenced using enoate 3 as a model for cylindrospermopsin. Based upon
work of Yamamoto et al.5 it was found that the silylated lithium amide reagent 4 undergoes
conjugate addition to unsaturated ester 3 (^78ꢀC±rt) to a€ord adduct 5 (Scheme 1).5 Compound 5
is a single stereoisomer, but its con®guration has not been determined.5b It should also be noted
that the isopropyl ester was necessary here since the corresponding methyl ester simply undergoes
1,2-addition with 4 to form the N-benzylamide.5a Treatment of amine 5 with trichloro-
acetylisocyanate, followed by basic hydrolysis produced the desired dihydrouracil 6 in high yield.
By analogy with work by Back on oxidation of lactams,6 it was possible to oxidize 6 with
diphenylseleninic anhydride to give uracil 7. Finally, the N-benzyl group of 7 could be removed
by transfer hydrogenolysis to give the desired uracil system 8.7
Scheme 1.
Although this route in fact proved successful, we considered the possibility of devising a more
ecient and shorter alternative sequence where both the oxidation step and nitrogen protection
could be avoided. It is known that hydroxylamine and its N-alkyl derivatives can be added
regioselectively to a,b-unsaturated esters8 and lactones9 to produce isoxazolidin-5-ones. We have
found that commercially available N,O-bis-(trimethylsilyl)hydroxylamine is a convenient source
of the free base of hydroxylamine in this type of reaction, and thus re¯uxing methyl ester 9 with
this reagent in ethanol a€ords adduct 10 as a 1:1 mixture of diastereomers (Scheme 2). It should
be noted that the addition reaction does not proceed in an aprotic solvent like THF unless some
ethanol is added.10 Treatment of isoxazolidin-5-one 10 with phenyl chloroformate presumably
leads to the intermediate N-acylation product 11, which upon ammonolysis a€ords the desired
N-hydroxy dihydrouracil 12.11 We recognized that 12 is in the correct uracil oxidation state, and
that a dehydration to imine 13 should a€ord the desired product 8 after tautomerization.
Eliminations of simple hydroxamic acid derivatives to N-acylimines are rare. Fowler, for example,
has reported that the acetate of a hydroxamic acid can be eliminated by high temperature, short
contact thermolysis to produce an N-acylimine.12 We were pleased to discover that simply treating
hydroxy compound 12 with tri¯ic anhydride/pyridine at room temperature led to the requisite
uracil 8. An interesting second product formed in this reaction has been tentatively assigned the

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rearranged uracil structure 14.13 Alternatively, treatment of hydroxy compound 12 with tosyl
chloride/DMAP in re¯uxing 1,2-dichloroethane a€ords uracil 8 in 81% yield without formation of
any of the rearrangement product 14.
Scheme 2.
Therefore, we have developed a direct, three step route to a uracil from an a,b-unsaturated
ester. Work is currently underway on optimizing this methodology and applying it in a total
synthesis of cylindrospermopsin.
Acknowledgements
We are grateful to the National Science Foundation (CHE-9732038) for ®nancial support of
this research, and Gerald Artman, III for conducting some related experiments.
References
1. (a) Ohtani, I.; Moore, R. E.; Runnegar, M. T. C. J. Am. Chem. Soc. 1992, 114, 7941. Moore, R. E.; Ohtani, I.;
Moore, B. S.; DeKoning, C. B.; Yoshida, W. Y.; Runnegar, M. T. C.; Carmichael, W. W. Gazz. Chim. Ital. 1993,
123, 329. (b) Banker, R.; Teltsch, B.; Sukenik, A.; Carmeli, S. J. Nat. Prod. 2000, 63, 387.
2. Heintzelman, G. R.; Parvez, M.; Weinreb, S. M. Synlett 1993, 551. Heintzelman, G. R.; Weinreb, S. M.; Parvez,
M. J. Org. Chem. 1996, 61, 4594.
3. For other studies on synthesis of cylindrospermopsin, see: Snider, B. B.; Harvey, T. C. Tetrahedron Lett. 1995, 36,
4587. Snider, B. B.; Xie, C. Tetrahedron Lett. 1998, 39, 7021. McAlpine, I. J.; Armstrong, R. W. Tetrahedron Lett.
2000, 41, 1849. White, J. D.; Hansen, J. D. Abstracts of Papers, 219th National Meeting of the American Chemical
Society: San Francisco, CA, 2000; ORGN 812.
4. For reviews on uracil synthesis, see: Wamho€, H.; Dzenis, J.; Hirota, K. Adv. Heterocycl. Chem. 1992, 55, 129.
Brown, D. J.; Evans, R. F.; Cowden, W. B.; Fenn, M. D. The Pyrimidines; Wiley Interscience: New York, 1994.

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5. (a) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.; Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y.
J. Org. Chem. 1997, 62, 6274 and references cited therein. See also: Sewald, N.; Hiller, K. D.; Korner, M.;
Findeisen, M. J. Org. Chem. 1998, 63, 7263. (b) In general, additions of lithio amide 4 to enoate systems like 3
were found by Yamamoto to produce predominantly the syn isomer.5a
6. Back, T. G. J. Org. Chem. 1981, 46, 1442.
7. Botta, M.; Summa, V.; Saladino, R.; Nicoletti, R. Synth. Commun. 1991, 21, 2181.
8. Baldwin, J. E.; Harwood, L. M.; Lombard, M. J. Tetrahedron 1984, 40, 4363. Niu, D.; Zhao, K. J. Am. Chem.
Soc. 1999, 121, 2456.
9. Maciejewski, S.; Pan®l, I.; Belzeki, C.; Chmielewski, M. Tetrahedron 1992, 48, 10363. Frelek, J.; Pan®l, I.;
Gluzinski, P.; Chmielewski, M. Tetrahedron: Asymmetry 1996, 7, 3415.
10. Cf. Reetz, M. T.; Rohrig, D.; Harms, K.; Frenking, G. Tetrahedron Lett. 1994, 35, 8765.
11. On the other hand, treatment of compound 10 with ethyl chloroformate, followed by ammonolysis gave amide i
(72% yield) which could not be cyclized to the dihydrouracil 12.
12. Hwang, Y. C.; Fowler, F. W. J. Org. Chem. 1985, 50, 2719 and references cited therein.
1
13. 6-(1-Methoxymethoxy-2-methylpropyl)-1H-pyrimidine-2,4-dione (8). IR (Nujol mull) 3110, 1724, 1657 cm^1; H
NMR (300 MHz, CDCl3) ꢀ 9.04 (br s, 1H), 8.80 (br s, 1H), 5.65 (s, 1H), 4.63 (s, 2H), 4.06 (d, J=6.8 Hz, 1H), 3.41
(s, 3H), 2.05±1.90 (m, 1H), 1.03 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) ꢀ 163.8,
154.3, 152.5, 100.7, 95.5, 80.0, 56.4, 32.3, 18.8, 18.1; MS (FAB+) m/z (relative intensity) 229 (MH+, 47), 197
(MH+^MeOH, 13). 1-(1-Methoxymethoxy-2-methylpropyl)-1H-pyrimidine-2,4-dione (14). IR (Nujol mull) 3166,
1
1708, 1683, 1625 cm^1; H NMR (300 MHz, CDCl3) ꢀ 8.77 (br s, 1H), 7.33 (d, J=7.9 Hz, 1H), 5.77 (dd, J=1.9,
7.9 Hz, 1H), 5.61 (d, J=8.3 Hz, 1H), 4.64 (d, J=6.8 Hz, 1H), 4.61 (d, J=6.8 Hz, 1H), 3.39 (s, 3H), 2.08±1.94 (m,
1H), 1.09 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) ꢀ 162.9, 150.9, 139.7, 102.7,
95.1, 86.5, 56.6, 33.1, 18.1, 17.4.