Asymmetric synthesis of epicylindrospermopsin via intramolecular nitrone cycloaddition. Assignment of absolute configuration

Article abstract of DOI:10.1021/ja012709r

A synthesis of (-)-epicylindrospermopsin (2) was completed that establishes its absolute configuration and corroborates the corrected structural assignment previously made to this toxin by Weinreb et al. The hydroxylamine 3, prepared from 4-bromobenzyloxy

Full text of DOI:10.1021/ja012709r

Published on Web 04/11/2002
Asymmetric Synthesis of Epicylindrospermopsin via Intramolecular Nitrone
Cycloaddition. Assignment of Absolute Configuration
James D. White* and Joshua D. Hansen
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
Received December 14, 2001
Scheme 1a
Cylindrospermopsin (1) and its C7 epimer 2 are potent naturally
occurring environmental toxins which contain a guanidinium unit
embedded in a unique tricyclic skeleton.1 The isolation of cylin-
a Conditions: (i) cis-2-butene, t-BuOK, n-BuLi, (+)-MeOB(Ipc)2, Et2O-
THF, 45%; (ii) Ms2O, pyr, CH2Cl2, 100%; (iii) NaN3, DMF, 85 °C; (iv)
Ph3P, THF-H2O, 56% from 7; (v) p-MeOC6H4CHO, MeOH, Na2CO3, 60
drospermopsin by Moore from the cyanobacterium Cylindrosper-
°C; (vi) m-CPBA, CH2Cl2, 0 °C f room temperature; (vii) HONH2‚HCl,
mopsis raciborskii was followed by a detailed structural investi-
MeOH, 0 °C f room temperature, 60% from 8.
gation based upon NMR evidence which concluded incorrectly that
the structure of this substance was represented by 2.2 Subsequent
Scheme 2a
isolation of cylindrospermopsin from the alga Umezakia natans
found in Japan3 and the isolation of both cylindrospermopsin4 and
an epimer5 from Aphanizomenon oValisporum present in a lake in
Israel did not rectify this misassignment, nor did a synthesis of
(()-cylindrospermopsin by Snider,6 which unfortunately failed to
distinguish between this substance and its C7 epimer. A recent
unambiguous synthesis of (()-2 by Weinreb has established
definitively that this is the structure of 7-epicylindrospermopsin;7
our approach, which was directed toward an asymmetric synthesis
of 2 in the belief that this structure corresponded to cylindrosper-
mopsin, thus became a prospective route to its natural C7 epimer.8
The key feature of our route is an intramolecular nitrone cycload-
dition9 that sets configuration at C10 and C12 of 2 from a precursor
assembled from the hydroxylamine 3 and aldehyde 4.
Asymmetric crotylation of p-bromobenzyloxyacetaldehyde (5)
with the reagent obtained from cis-2-butene and (+)-diisopinyl-
campheylmethoxyborane10 gave the syn homoallylic alcohol 6 in
94% enantiomeric excess, as determined by NMR analysis of its
Mosher ester11 (Scheme 1). Displacement of the mesylate 7 with
sodium azide, followed by reduction of the azide with triphenyl-
a Conditions: (i) 4-Bromo-2,6-dimethoxypyrimidine, n-BuLi, CeCl3,
Et2O-THF, -78 °C f room temperature, 97%; (ii) Ph3CCl, Et3N, DMAP,
phosphine, afforded the inverted primary amine 8, which was
condensed with p-anisaldehyde. The resulting imine was oxidized
in situ with m-chloroperbenzoic acid to give oxaziridine 9, and upon
treatment with hydroxylamine hydrochloride this substance fur-
nished 3.12
Synthesis of the aldehyde 4 commenced from (R)-methionine,
which upon exposure to excess benzyl bromide yielded (R)-2-(N,N-
dibenzyl)butyrolactone (10) (Scheme 2).13 The latter was reacted
with 4-lithio-2,6-dimethoxypyrimidine14 in the presence of cerium
trichloride to furnish a quantitative yield of lactol 11 as a mixture
of stereoisomers. Treatment of 11 with triphenylmethyl chloride
gave the primary trityl ether 12, and reduction of this ketone with
L-Selectride produced the syn amino alcohol 13 along with its anti
CH2Cl2, ∆, 93%; (iii) L-Selectride, THF, 84%; (iv) TBSOTf, Et3N, THF,
87%; (v) HCO2H, THF, 100%; (vi) H2, Pd(OH)2/C, EtOH, 81%; (vii)
Boc2O, Et3N, CH2Cl2, 68%; (viii) TPAP (cat.), NMO, mol. sieves, CH2Cl2,
91%.
isomer in the ratio 12:1. The secondary alcohol of 13 was protected
as its tert-butyldimethylsilyl ether 14, after which the trityl group
was removed quantitatively with formic acid. The N,N-dibenzyl
moiety was cleaved by hydrogenolysis to give primary amine 15,
which was then converted to its N-Boc derivative, and subsequent
oxidation of the primary alcohol with Ley’s reagent15 produced
aldehyde 4 in nine steps and 20% overall yield from (R)-methionine.
Condensation of hydroxylamine 3 with aldehyde 4 gave (Z)-
nitrone 16 in good yield (Scheme 3), and intramolecular cycload-
dition of 16 in refluxing toluene afforded the unstable oxazabicyclo-
[2.2.1]heptane derivative 17, accompanied by two unidentified
* Corresponding author. E-mail address: james.white@orst.edu.
9
4950
J. AM. CHEM. SOC. 2002, 124, 4950-4951
10.1021/ja012709r CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3a
Scheme 4a
a Conditions: (i) (a) (Cl3CO)2CO, THF; (b) NaN3, DMF, 49%; (ii)
TESOTf, Et3N, CH2Cl2, 99%; (iii) KHMDS, Me3O+ BF4-, CH2Cl2; (iv)
Pd/C, H2, MeOH; (v) HCl (conc.) ∆, 21% from 22; (vi) SO3‚pyr, DMF,
63%.
Acknowledgment. We are indebted to Hyunik Shin whose
insights created the initial impetus for this project, to Professor
Alexandre F. T. Yokochi for the X-ray crystal structure of 20, and
to Professor Steven Weinreb, Pennsylvania State University, for
helpful correspondence. Financial support was provided by the
National Science Foundation (0076103-CHE).
a Conditions: (i) MeOH mol. sieves, ∆, 60%; (ii) Toluene, mol. sieves,
∆; (iii) Zn, NH4Cl, THF-H2O; (iv) HCl, MeOH, 68% from 16; (v) CO(Im)2,
CH2Cl2, then K2CO3, MeOH, 85%; (vi) Dess-Martin periodinane, CH2Cl2;
(vii) L-Selectride, THF; (viii) H2/C, Pd(OH)2, EtOH, 55% from 19.
Supporting Information Available: Experimental procedures and
characterization data and X-ray crystallographic data for 20 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
stereoisomers in the ratio 10:5:1. As predicted from conformational
analysis of 16, the major product 17 arose from an exo cycloaddition
to the re face of the terminal alkene in the orientation shown.16 In
situ reduction of 17 with zinc and ammonium chloride followed
by acidic removal of the Boc group furnished piperidine 18 in which
five of the six stereocenters correspond to those of 2. Before
inverting the C12 hydroxyl group, it was decided to bridge the
piperidine nitrogen and the amino function at C8 via a urea, and
for this purpose 18 was treated with carbonyldiimidazole to produce
19. The secondary alcohol of 19 was oxidized to a ketone, and
subsequent reduction of this substance with L-Selectride afforded
the 12â alcohol as the major product (â:R > 15:1). Hydrogenolysis
of the primary p-bromobenzyl ether gave the crystalline diol 20
whose relative stereostructure was confirmed by X-ray crystal-
lographic analysis.
Diol 20 was converted to azide 21, and the remaining secondary
hydroxyl group was protected as its triethylsilyl ether 22 (Scheme
4). Exposure of 22 to trimethyloxonium tetrafluoroborate in the
presence of potassium hexamethyldisilazide gave the O-methylated
derivative 23 which was subjected to catalytic hydrogenation over
palladium-on-carbon. The resultant primary amine underwent
spontaneous cyclization to give guanidine 24, and subsequent
exhaustive hydrolysis in concentrated hydrochloric acid led to
cleavage of silyl ethers as well as methyl ethers attached to the
pyrimidine nucleus to yield 25. This diol was shown to be identical
by comparison of 1H and 13C NMR spectra with the corresponding
racemic substance prepared by Weinreb,7 and sulfation as previously
described6 gave (-)-7-epicylindrospermopsin (2) accompanied by
the bis sulfate of 25 (ca. 2.5:1, respectively). These substances were
separated by HPLC, and purified 2 was found to have spectral data
in good agreement with those recorded for both natural5 and
synthetic7 epicylindrospermopsin. The specific rotation of synthetic
material establishes that the absolute configuration of natural
epicylindrospermopsin is 7S, 8R, 10S, 12S, 13R, 14S, as represented
by 2.
References
(1) For a recent review of the biological properties and synthetic approaches
to cylindrospermopsin, see: Murphy, P. J.; Thomas, C. W. Chem. Soc.
ReV. 2001, 30, 303.
(2) (a) Ohtani, I.; Moore, R. E.; Runnegar, M. T. C. J. Am. Chem. Soc. 1992,
114, 7941. (b) 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.
(3) (a) Harada, K.; Ohtani, I.; Iwamoto, K.; Suzuki, M.; Watanabe, M. F.;
Watanabe, M.; Terav, K. Toxicon 1994, 32, 73. (b) Terav, K.; Ohmori,
S.; Igarashi, K.; Ohtani, I.; Watanabe, M. F.; Harada, K. I.; Ito, E.;
Watanabe, M. Toxicon 1994, 32, 833 and references therein.
(4) Banker, R.; Carmeli, S.; Hadas, O.; Teltsch, B.; Porat, R.; Sukenik, A. J.
Phycol. 1997, 33, 613.
(5) Banker, R.; Teltsch, B.; Sukenik, A.; Carmeli, S. J. Nat. Prod. 2000, 63,
387.
(6) Xie, C.; Runnegar, M. T. C.; Snider, B. B. J. Am. Chem. Soc. 2000, 122,
5017.
(7) Weinreb, S. M.; Heintzelman, G. R.; Fang, W. K.; Keen, S. P.; Wallace,
G. A. J. Am. Chem. Soc. 2001, 123, 8851.
(8) For earlier synthetic studies directed toward cylindrospermopsin, see: (a)
Heintzelman, G. R.; Parvez, M.; Weinreb, S. M. Synlett 1993, 551. (b)
Snider, B. B.; Harvey, T. C. Tetrahedron Lett. 1995, 36, 4587. (c)
Heintzelman, G. R.; Weinreb, S. M.; Parvez, M. J. Org. Chem. 1996, 61,
4594. (d) Snider, B. B.; Xie, C. Tetrahedron Lett. 1998, 39, 7021. (e)
McAlpine, I. J.; Armstrong, R. W. Tetrahedron Lett. 2000, 41, 1849. (f)
Keen, S. P.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 4307. (g) White,
J. D.; Hansen, J. D. Abstracts of Papers; 219th National Meeting of the
American Chemical Society, San Francisco, CA; American Chemical
Society: Washington, DC, 2000; ORGN 812. (h) Djung, J. F.; Hart, D.
J.; Young, E. R. R. J. Org. Chem. 2000, 65, 5668. (i) Looper, R. E.;
Williams, R. M. Tetrahedron Lett. 2001, 42, 769.
(9) (a) Jorgenson, K. A.; Gothelf, K. V. Chem. ReV. 1998, 98, 863. (b)
Confalone, P. N.; Huie, E. M. In Organic Reactions; Kende, A. S., Ed.;
Wiley: New York, 1998; Vol. 36, pp 3-173.
(10) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(11) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
(12) Grundke, G.; Keese. W.; Rimpler, M. Synthesis 1987, 1115.
(13) Reetz, M. T.; Schmitz, A.; Holdgru¨n, X. Tetrahedron Lett. 1989, 30, 5421.
(14) Langley, B. W. J. Am. Chem. Soc. 1956, 78, 2136.
(15) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(16) Precedent for this mode of cycloaddition can be found in: (a) Oppolzer,
W.; Siles, S.; Snowden, R. L.; Bakker, B. H.; Petrzilka, M. Tetrahedron
1985, 41, 3497. (b) Hoffmann, R. W.; Endesfelder, A. Justus Liebig Ann.
Chem. 1986, 1823.
JA012709R
9
J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 4951