A novel anionic condensation, fragmentation, and elimination reaction of bicyclo[2.2.1]heptenone ring systems.

Article abstract of DOI:10.1021/ol990532o

[formula: see text] We have identified an unprecedented anionic condensation, fragmentation, and elimination sequence from the coupling of bicyclo[2.2.1]-heptenones with aldehydes. This reaction leads to the stereoselective formation of disubstituted five

Full text of DOI:10.1021/ol990532o

ORGANIC
LETTERS
1999
Vol. 1, No. 1
27-29
A Novel Anionic Condensation,
Fragmentation, and Elimination Reaction
of Bicyclo[2.2.1]heptenone Ring
Systems
Jon D. Rainier* and Qing Xu
Department of Chemistry, The UniVersity of Arizona, Tucson, Arizona 85721
rainier@u.arizona.edu
Received March 18, 1999
ABSTRACT
We have identified an unprecedented anionic condensation, fragmentation, and elimination sequence from the coupling of bicyclo[2.2.1]-
heptenones with aldehydes. This reaction leads to the stereoselective formation of disubstituted five-membered rings which are present in a
wide array of bioactive molecules.
Substituted furans are a key architectural feature in a wide
array of biologically active molecules. Our interest in the
2,5-disubstituted furan-containing marine natural products
gymnodimine1,2 and eleutherobin3,4 has directed our attention
to the synthesis of these structural units. As envisioned, our
approach to the synthesis of substituted furans included (a)
an aldol condensation between an oxabicyclo[2.2.1]heptenone5
and an aldehyde, (b) a subsequent fragmentation reaction,6
and (c) an elimination reaction to the corresponding olefin
(Scheme 1). As described in this Letter, in the course of these
(1) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.; Yasumoto,
T. Tetrahedron Lett. 1995, 36, 7093-7096. (b) Stewart, M.; Blunt, J. W.;
Munro, M. H. G.; Robinson, W. T.; Hannah, D. J. Tetrahedron Lett. 1997,
38, 4889-4890.
(2) For synthetic efforts to gymnodimine, see: Ishihara, J.; Miyakawa,
J.; Tsujimoto, T.; Murai, A. Synlett. 1997, 1417-1419.
Scheme 1. Sequential Diels-Alder, Condensation, and
Fragmentation Approach to 2,5-Disubstituted Furans
(3) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.;
Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744-8745.
(4) Two total syntheses of eleutherobin have appeared. See: (a) Nicolaou,
K. C.; van Delft, F.; Ohshima, T.; Vourloumis, D.; Xu, J. H., S.; Pfefferkorn,
J.; Kim, S.; Li, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2520-2524. (b)
Chen, X.-T.; Zhou, B.; Bhattacharya, S. K.; Gutteridge, C. E.; Pettus, T. R.
R.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 789-792.
(5) Available from a furan Diels-Alder reaction. For a relevant review,
see: Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179-14233.
(6) For other uses of oxabicyclo[2.2.1] fragmentation reactions in the
synthesis of substituted furans, see ref 5.
investigations we have uncovered an unprecedented anion-
mediated condensation, fragmentation, and elimination reac-
tion during which all of the goals outlined above were
accomplished in a single flask.7
To investigate the sequence depicted in Scheme 1, we
initially examined the condensation of oxabicyclo[2.2.1]-
(7) Acid-mediated Aldol-Grob fragmentations have been described.
See: (a) Kabalka, G. W.; Tejedor, D.; Li, N.-S.; Malladi, R. R.; Trotman,
S. J. Org. Chem. 1998, 63, 6438-6439. (b) Yamamoto, T.; Suemune, H.;
Sakai, K. Tetrahedron 1991, 47, 8523-8528.
(8) The trisubstituted olefin geometry was determined through the
identification of the appropriate NOESY cross-peaks (see the Supporting
Information for more details).
10.1021/ol990532o CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/17/1999

heptenone 4 with benzaldehyde (Table 1, entry 1). Surpris-
tion, fragmentation, and elimination reaction of 10 with
benzaldehyde and isobutyraldehyde proceeded smoothly to
give cyclopentenes 11 and 12, respectively. However, in
contrast to 4 and 7, the condensation of 10 with benzaldehyde
and isobutyraldehyde gave predominantly or exclusively the
E-alkene isomer.8
Table 1. Single Flask Condensation, Fragmentation, and
Elimination to 2,5-Disubstituted Dihydrofurans
In contrast to 8, 9, 11, and 12, the NOESY spectra of
substituted furans 5 and 6 were devoid of information.
However, we were able to determine the olefin geometry in
5 and 6 after derivatization of the furan (Scheme 2). That
Scheme 2. Determination of the Olefin Geometry in
Furans 5 and 6
ingly, rather than the simple condensation product, we
isolated disubstituted furan 5 exclusively as its Z-alkene
isomer in 83% yield after esterification. To our delight, we
had achieved the condensation, fragmentation, and elimina-
tion in a single flask.
With the notion that this reaction might lead to the efficient
synthesis of a number of substituted furans, we set out to
determine the scope. As is depicted in Tables 1 and 2, other
is, treatment of 5 and 6 with methanolic KOH resulted in
hydrolysis, decarboxylation, and aromatization to give 13
and 14, respectively. DIBAL reduction gave allyl alcohols
15 and 16.9 As depicted, NOESY cross-peaks were observed
between the isopropyl/phenyl hydrogens and the methylene
hydrogens of the hydroxy methyl group, thereby establishing
the trisubstituted olefin geometry.
Table 2. Single Flask Condensation, Fragmentation, and
Elimination to 1,4-Disubstituted Cyclopentenes
While any detailed mechanistic discussion requires further
experimentation, a reasonable working hypothesis is depicted
in Scheme 3. It is highly likely that aldol condensation to
Scheme 3. Possible Mechanism for the Condensation,
Fragmentation, and Elimination Reaction of
Bicyclo[2.2.1]heptenes
aldehydes and bicyclo[2.2.1] ring systems successfully
underwent the reaction. For example, the condensation of
isobutyraldehyde with 4 gave furan 6 exclusively as the
Z-alkene isomer in 78% yield (Table 1, entry 2). The reaction
is not specific to 4 as unsubstituted oxabicyclo[2.2.1]-â-keto
ester 7 also underwent the condensation, fragmentation, and
elimination reaction sequence. The unoptimized coupling of
7 with benzaldehyde and isobutyraldehyde gave furans 8 and
9, respectively (Table 1, entries 3 and 4). Interestingly, while
4 gave exclusively the Z-alkene isomer with both benzal-
dehyde and isobutyraldehyde, 7 gave a 3:1 E:Z alkene
mixture when condensed with benzaldehyde and a 1:2 E:Z
mixture when condensed with isobutyraldehyde.8
We have also examined the reaction between bicyclo-
[2.2.1]heptenone 10 and aldehydes (Table 2). As with the
synthesis of the furans mentioned previously, the condensa-
28
Org. Lett., Vol. 1, No. 1, 1999

give 18 precedes fragmentation as attempted aldol coupling
between furan 2110 and isobutyraldehyde resulted in the
recovery of 21. Lactol formation provides oxetane 19.7
Oxetane fragmentation then leads to furan 20. The nature of
the substrate dependence on the E,Z-olefin selectivity is not
readily apparent and is thus the focus of our current efforts.11
bicyclo[2.2.1]heptene ring systems. Our current efforts are
focusing on the nature of the selectivity in this reaction as
well as its use in the synthesis of furan-containing natural
products.
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (GM56677) for partial support of
this work. Support from the Department of Chemistry at The
University of Arizona as well as The University of Arizona
Foundation is also acknowledged. The authors would like
to thank Dr. Arpad Somogyi for help with mass spectra
analysis and Dr. Neil Jacobsen and Mr. Travis Gregar for
help with NMR experiments.
The bicyclo[2.2.1] ring systems used in this study are
readily accessible using a Diels-Alder cycloaddition reaction
between bromopropynoate 22 and the appropriate diene
(Scheme 4).12-14 A subsequent two-step hydrolysis of the
Scheme 4. Diels-Alder Approach to Bicyclo[2.2.1]heptenes
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 4-12, 15,
and 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL990532O
(9) Thus far, we have been unable to selectively reduce the ethyl ester
in 5 or 6.
(10) 21 is available from the reaction of 4 and NaOCH3.
(11) Thus far, our attempts to equilibrate the olefin in 5 with base have
been unsuccessful.
(12) Sherman, E.; Dunlop, A. P. J. Org. Chem. 1960, 25, 1309-1311.
(13) Chamberlin, P.; Rooney, A. E. Tetrahdedron Lett. 1979, 383-386.
(14) Leroy, J. Tetrahdedon Lett. 1992, 33, 2969-2972.
resulting bromoacrylate derivative gave â-keto esters 4, 7,
and 10.
To conclude, we have identified a novel anion-mediated
condensation, fragmentation, and elimination reaction of
Org. Lett., Vol. 1, No. 1, 1999
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