Synthesis of the cyclohexan subunit of baconipyrones A and B from furan.

Article abstract of DOI:10.1021/ol000334t

[figure: see text] The synthesis of the cyclohexan subunit of the siphonarlid metabolites baconipyrones A and B from furan is described. A key step included the alkylative ring opening of 7-oxanorbornenic sulfone 4 and oxidative desulfonylation of compoun

Full text of DOI:10.1021/ol000334t

ORGANIC
LETTERS
2
001
Vol. 3, No. 1
07-109
Synthesis of the Cyclohexan Subunit of
Baconipyrones A and B from Furan
1
Od o´ n Arjona,* Roberto Menchaca, and Joaqu ´ı n Plumet*
Departamento de Qu ´ı mica Org a´ nica I, Facultad de Qu ´ı mica,
UniVersidad Complutense, 28040 Madrid, Spain
plumety@eucmax.sim.ucm.es
Received November 2, 2000
ABSTRACT
The synthesis of the cyclohexan subunit of the siphonariid metabolites baconipyrones A and B from furan is described. A key step included
the alkylative ring opening of 7-oxanorbornenic sulfone 4 and oxidative desulfonylation of compound 8.
Pulmonate molluscs of the genus Siphonaria are a source
1
of secondary metabolites of the polypropionate class. Among
these, baconipyrones A and B isolated in 1989 by Faulkner
2
et al. (Figure 1), constitute an exception to the normal
polypropionic skeleton3 since they do not contain the
4
expected carbon sequence typical of this polyketide family.
To date no total synthesis of baconipyrones A anb B has
*
Additional corresponding author email: arjonao@eucmax.sim.ucm.es.
1) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998, 15,
77, and references therein.
2) Manker, C. D.; Faulkner, D. J.; Stout, J. T.; Clardy, J. J. Org. Chem.
989, 54, 5371.
3) For an interesting report on noncontiguous polypropionates from
(
4
(
1
(
marine molluscs, see: Brecknell, D. J.; Collet, L. A.; Davies-Coleman, M.
T.; Garson, M. J.; Jones, D. D. Tetrahedron 2000, 56, 2497.
3
(
4) According to Davies-Coleman et al. “baconipyrones are proposed
to be rearrangement products generated from a siphonariid precursor...” or
“
are generated as artifacts during the extraction.”
5) Paterson, I.; Chen, D. Y.; Ace n˜ a, J. L.; Franklin, A. S. Org. Lett.
000, 2, 1513.
(
Figure 1.
2
(
(
6) Paterson, I.; Franklin, A. S. Tetrahedron Lett. 1994, 35, 6925.
7) Black, K. A.; Vogel, P. J. Org. Chem. 1986, 51, 5341. Compound 1
has been synthesized in optically pure form ([R]D ) +235.0) starting from
+)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl camphanate. In this pre-
liminary account racemic 1 has been used.
(
been published, albeit the total synthesis of (-)-baconipyrone
C (Figure 1) has been recently reported by Paterson et al.5
(8) For a review on the use of 7-oxanorbornenic derivatives (Diels-
Alder adducts of furan) as synthetic intermediates, see: Arjona, O.; Cossy,
J.; Plumet, J.; Vogel, P. Tetrahedron 1999, 55, 13521
(
9) The referee suggests a possible improvement of the yield of this
(10) (a) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1357. (b) Hwu, J. R.; Leu, L.-C.; Robl, J. A.; Anderson, D. A.; Wetzel,
J. M. J. Org. Chem. 1987, 52, 188. (c) Hwu, J. R.; Wetzel, J. M. J. Org.
Chem. 1985, 50, 3946.
process by application of a procedure previously described: Warm, A.;
Vogel, P. J. Org. Chem. 1986, 51, 5348. We thank the referee for this
valuable suggestion, which will be tested soon.
1
0.1021/ol000334t CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/14/2000

Scheme 1
Previously, an enantiocontrolled synthesis of the γ-pyrone
gives ketone 2 in 40% overall yield. In this reaction 45% of
starting 1 was recovered and recycled. Using other reaction
9
subunit of these compounds was also reported by the same
6
authors.
conditions (t-BuOK, IMe), substantial amounts of R,R′-
dialkylated ketone were obtained as byproduct. Protection
of the carbonyl group as ethylenacetal using 1,2-bis-
In this paper we wish to account for the synthesis of the
cyclohexan subunit of baconipyrones A and B from furan
via the oxanorbornenic derivative 1 (Scheme 1). The
synthetic plan was designed as follows. Methylation of 1,
followed by protection of the carbonyl group, oxidation of
the phenylsulfenyl moiety and dehydrochlorination would
provide the vinyl sulfone 4. Stereoselective exo-alkylative
ring opening of 4, followed by 1,4-addition of MeLi to the
resulting cyclohenenyl sulfone will provide 6, with the
correct configuration of the three methyl groups. The relative
configuration of the ethyl group in 8, trans to the R,R′
dimethyl groups, could be obtained by oxidation of the
hydroxyl group followed by addition of ethylmagnesium
bromide. Finally, the oxidative desulfonylation of 8, followed
by stereocontrolled reduction of the resulting hydroxyl group
and deprotection of the ketal functionality would give rise
to the desired compound 11.
(
trimethylsilyloxy)-ethane in the presence of TMSOTf 10
affords 3, which after oxidation of the phenylsulfide moiety
with monoperoxyphthalic acid magnesium salt (MMPP)
followed by dehydrochlorination with DBU yields vinyl
N
sulfone 4 in 82% overall yield (two steps). The S 2′ ring
1
1
opening of 4 using MeLi in THF gives cyclohexenyl
sulfone 5, which after Michael addition of MeLi followed
4
by hydrolysis with a saturated aqueous NH Cl solution
1
2
affords sulfone 6 (Scheme 2).
With sulfone 6 in our hands, the synthetic sequence was
completed as follows (Scheme 3). Swern’s oxidation of 6
followed by addition of EtMgBr to the ketone 7 gives alcohol
8 with total stereoselectivity. Oxidative desulfonylation of
8
to afford ketone 9 appeared to be a critical step of this
synthetic route. After considerable experimentation, the best
conditions were those reported by Yamada et al.13 (LDA,
THF/DMPU, followed by treatment with oxygen). Under
these conditions 54% of ketone 9 was obtained. Reduction
Compound 1 was prepared in three steps (86% overall
yield) from furan according to the procedure previously
7
8
described by P. Vogel et al. starting from furan. Alkylation
of 1 with lithium bis(trimethylsilyl)amide (LHMDS) and IMe
3 2
of the carbonyl group with BH ‚SMe yielded the desired
Scheme 2
108
Org. Lett., Vol. 3, No. 1, 2001

Scheme 3
equatorial alcohol 10 as the only diastereomer. Finally,
on the aldol reaction, the way for the total synthesis of
baconipyrones A and B is now opened.
14
3 2
deprotection of 10 with CeCl ‚7H O in the presence of NaI
afforded 11.
Acknowledgment. Dedicated to Professor Kenneth L.
Rinehart. This work was supported by the DGICYT (Min-
isterio de Educaci o´ n y Cultura, Spain, Grant n×bc 96-0641).
Roberto Menchaca thanks Universidad Complutense de
Madrid for a Grant. We also thank ′Servicio de RMN′
In summary, the cyclohexan subunit of baconipyrones A
and B has been synthesized starting from furan in 15 steps
and 4% overall yield. Considering that the remaining
fragment of these compounds, conveniently functionalized,
5
was obtained by Paterson et al. using methodologies based
(UCM) for technical assistance.
(
11) Arjona, O.; de Dios, A.; Fern a´ ndez de la Pradilla, R.; Plumet, J.;
Viso, A. J. Org. Chem. 1994, 59, 3906.
12) This transformation can be achieved without isolation of the
Supporting Information Available: Copies of NMR
(
spectra for key compounds 6, 8, 9, 10 and 11 and description
of all experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
intermediate vinyl sulfone 5. In this case the overall yield for the
transformation of 4 into 6 is 59%.
(
13) Yamada, S.; Nakayama, K.; Takayama, H. Tetrahedron Lett. 1984,
5, 3239.
14) Marcantoni, E.; Nobili, F. J. Org. Chem. 1997, 62, 4183.
2
(
OL000334T
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