Synthesis of an analogue of the marine polypropionate tridachiahydropyrone

Article abstract of DOI:10.1021/ol0478178

(Chemical Equation Presented) A novel approach to the formation of the unusual pyrone-containing ring systems as found in polypropionate metabolites from the Tridachia family of marine molluscs has been developed. This approach includes an intramolecular

Full text of DOI:10.1021/ol0478178

ORGANIC
LETTERS
2005
Vol. 7, No. 3
407-409
Synthesis of an Analogue of the Marine
Polypropionate Tridachiahydropyrone
David W. Jeffery,† Michael V. Perkins,*,† and Jonathan M. White‡
School of Chemistry, Physics and Earth Sciences, Flinders UniVersity,
G. P. O. Box 2100, S.A. 5001, Australia, and School of Chemistry,
The UniVersity of Melbourne, Victoria 3010, Australia
mike.perkins@flinders.edu.au
Received October 25, 2004
ABSTRACT
A novel approach to the formation of the unusual pyrone-containing ring systems as found in polypropionate metabolites from the Tridachia
family of marine molluscs has been developed. This approach includes an intramolecular cyclization of a
ring to afford a fused, bicyclic pyrone.
â-keto acid onto a cyclohexenone
Tridachiahydropyrone (1) was isolated in 1996 by Cimino
et al. from the sacoglossan mollusc, Tridachia crispata.1 This
compound is structurally interesting, possessing an unusual
fused, bicyclic, pyrone-containing ring system. The function
of such a polypropionate metabolite in the organism is
unknown, but it has been postulated that it may act as a
chemical defense agent against exposure to UV light.1
We have recently developed a method3 for the formation
of cyclohexenone derivatives that we require as synthons
for the total synthesis of tridachione marine natural prod-
ucts.1,2,4 We now report the extension of this methodology
to the synthesis of the analogue 4 of tridachiahydropyrone
(1), which lacks the vinyl side chain.
Subsequently, the metabolites tridachiahydropyrone-B (2)
and -C (3) were isolated from Placobranchus ocellatus.2
These peroxides appear to be photooxygenation products
from tridachiahydropyrone (1). The biological activity of
compounds 1-3 has not been evaluated and no syntheses
or attempted syntheses of these compounds have been
reported.
In the absence of any relevant literature precedent we
proposed the cyclization, dehydration, and methylation of
(1) Gavagnin, M.; Mollo, E.; Cimino, G.; Ortea, J. Tetrahedron Lett.
1996, 37, 4259-4262.
(2) Fu, X.; Hong, E. P.; Schmitz, F. J. Tetrahedron 2000, 56, 8989-
8993.
(3) Jeffery, D. W.; Perkins, M. V. Tetrahedron Lett. 2004, 45, 8667-
8671.
(4) (a) Ireland, C. M.; Scheuer, P. J. Science 1979, 205, 922-923. (b)
Ireland, C. M.; Faulkner, D. J. Tetrahedron 1981, 37 (Suppl. No. 1), 233-
240. (c) Ksebati, M. B.; Schmitz, F. J. J. Org. Chem. 1985, 50, 5637-
5642. (d) Dawe, R. D.; Wright, J. L. C. Tetrahedron Lett. 1986, 27, 2559-
2562. (e) Gavagnin, M.; Marin, A.; Mollo, E.; Crispino, A.; Villani, G.;
Cimino, G. Comp. Biochem. Physiol. 1994, 108B, 107-115. (f) Gavagnin,
M.; Mollo, E.; Castelluccio, F.; Montanaro, D.; Ortea, J.; Cimino, G. Nat.
Prod. Lett. 1997, 10, 151-156.
† Flinders University.
‡ The University of Melbourne.
10.1021/ol0478178 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/06/2005

Tandem addition/cyclization of enone 8 with methyl
cuprate, as previously described,3 gave cyclohexanone 7 in
70-80% yield (Scheme 2). The cyclic product existed as a
mixture of keto:enol tautomers, but as a single, detectable
diastereomer, indicating that the addition was highly facially
selective. Treatment of cyclic product 7 with a 2-fold excess
of NaH, followed by MeI as previously described3 afforded
a 3:2 mixture of trans:cis products 6 and 12 which were
inseparable by column chromatography. However, treatment
of cyclohexanone 7 with 1 equiv of NaH followed by MeI
and subsequent treatment of the reaction mixture with a
second portion of NaH to promote elimination of the OTBS
gave an improved 9:1 trans:cis (6:12) selectivity (determined
by GC/MS) in 83% yield.10 This method also gave a small
amount of the OPMB eliminated alkene 14. Intermediate 13
could also be isolated, and its stereochemistry and that of 6
were assigned by NOE experiments (Figure 1).
Scheme 1
acid 5 as the final pyrone ring-forming step (Scheme 1). We
envisaged the formation of acid 5 by deprotection and
oxidation of a suitable precursor 6. This precursor was
proposed to be formed by the tandem conjugate addition/
cyclization (to give 7) and methylation procedure we have
developed3 for the preparation of highly substituted cyclo-
hexenones of this type. The enone 8 required in this case
was to be formed by the H/W/E coupling of the phosphonate
9 with aldehyde 10 (Scheme 1).
Figure 1. NOE correlations for 6 and 13.
Phosphonate 9 (enantiomer known5) was prepared (90%)
by reaction of known chiral ester6 11 with the lithium anion
of dimethyl methylphosphonate7 in THF at -78 °C. A
H/W/E coupling of known3 aldehyde 10 with phosphonate
9 under Roush conditions (LiCl, DIPEA, MeCN, room
temperature)8 afforded enone 8 (64%) as a single detectable
E isomer on a multigram scale (Scheme 2).9
Primary alcohol 15 was obtained (96%) by deprotection
of PMB ether 6 with DDQ in CH2Cl2/pH 7 buffer at 0 °C.11
Alcohol 15 was very acid sensitive and cyclized/dehydrated
to afford pyrone 16 in CDCl3 (depending on its acidity) or
by treatment of an NMR sample with p-TsOH (Scheme 3).
Although we are interested in forming bicyclic, pyrone-
containing rings, 16 is at the wrong oxidation state for our
purposes.
Dess-Martin oxidation12 of alcohol 15 afforded aldehyde
17 (99%, crude, Scheme 3) with no apparent epimerization
of the stereocenter R to the aldehyde and no formation of
Scheme 2
(5) Mulzer, J.; Berger, M. Tetrahedron Lett. 1998, 39, 803-806.
(6) Walkup, R. D.; Kane, R. R.; Boatman, P. D., Jr.; Cunningham, R. T.
Tetrahedron Lett. 1990, 31, 7587-7590.
(7) (a) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88,
5654-5656. (b) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915-
930.
(8) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(9) All new compounds gave spectroscopic data in agreement with the
assigned structures and copies of NMR spectra and spectral data for all
new compounds are available in the Supporting Information.
(10) Subsequent reactions were performed on this 9:1 mixture but only
the major (trans) isomer is shown for simplicity. The proportion of trans
isomer 6 was enriched during chromatographic purifications of the products
of subsequent reactions such that cis isomer 12 was undetectable after
purification of acid 5.
(11) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535-9544.
(12) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
408
Org. Lett., Vol. 7, No. 3, 2005

and γ-pyrone 4 (34%) (Scheme 4). Resonances in the 13C
NMR spectrum of γ-pyrone 4 were consistent with typical
R-methoxy-â-methyl-γ-pyrone 13C resonances, and R-pyrone
19 lost CO2 as a fragment in its mass spectrum, which
γ-pyrone 4 did not. Both isomers displayed large, negative
optical rotations (4 had [R]D -780 and 19 had [R]D -806).
Furthermore, both 4 and 19 were crystalline and single-
crystal X-ray analysis confirmed their structures and relative
stereochemistry (Figure 2).
Scheme 3
pyrone 16. Aldehyde 17 was oxidized with NaClO213 to give
acid 5 (64%) as a 1:1 mixture of epimers.
Without specific precedent for the formation of the unusual
pyrone ring system required for pyrone 4, we investigated a
number of conditions used for the formation of normal
pyrone rings14 (which have readily enolizable, acyclic trione
precursors) without success. It was apparent that we required
mild, acidic, dehydrating conditions and to this end acid 5
was treated with freshly prepared Eaton’s reagent (1:10 w/w
P2O5-MeSO3H)15 in CH2Cl2 at room temperature. This gave
pyrone 18 (52%), predominantly in the keto form with
stereochemistry as shown (assigned by NOE experiments,
Scheme 4).
Figure 2.
In conclusion, we have applied our previously developed3
cyclohexenone strategy to install the cyclohexadiene moiety
into an enantiopure model pyrone that is analogous to
tridachiahydropyrone (1). We have also developed a novel
pyrone-forming reaction that affords fused, bicyclic, pyrone-
containing ring systems. We are currently applying this
strategy to the convergent synthesis of tridachiahydropyrone
(1) as a single enantiomer.
Scheme 4
Acknowledgment. We wish to thank the Australian
Research Council for funding and Flinders University for
its support and facilities.
Supporting Information Available: Copies of NMR
spectra and spectral data for all new compounds and
experimental procedures for compounds 4, 6, 13, 18, and
19. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0478178
Pyrone 18 was O-methylated with CH2N2 to give close to
a 1:1 mixture of the readily separable R-pyrone 19 (41%)
(14) (a) Ishibashi, Y.; Shigeru, O.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1996, 37, 2997-3000. (b) Arimoto, H.; Nishiyama, S.;
Yamamura, S. Tetrahedron Lett. 1990, 31, 5619-5620.
(15) Eaton, P. E.; Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 38,
4071-4073.
(13) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron Lett. 1980,
37, 2091-2096.
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