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B. E. Love et al. / Tetrahedron Letters 50 (2009) 5050–5052
previously described) provided a quantitative yield of 4 uncontam-
inated by 5. This product could then be treated with iron chloride
to give phoenicin 6 in 76% yield uncontaminated by 7, which then
provided pure oosporein 8 in 59% yield upon treatment with pyr-
rolidine and copper(II) acetate, followed by hydrolysis. Similarly,
treatment of pure 4 directly with pyrrolidine and copper(II) acetate
(once again followed by hydrolysis), provided 8 in 52% yield,
uncontaminated by 9. These results suggested that the source of
dibenzofuran diquinone 9 was isophoenicin 7, and that pure
oosporein 8 could indeed be prepared simply by starting from pure
biaryl 4, which in turn could be prepared from pure hexaacetate 2.
Thus, a synthesis of oosporein was achieved in four steps and 24%
overall yield starting from 2,5-dimethoxytoluene. Identity of the
product was confirmed by preparation of the tetraacetate via treat-
ment with acetic anhydride and sulfuric acid. Interestingly, the 13C
NMR spectrum of 8 obtained at room temperature in DMSO-d6
showed only two sharp peaks above 100 ppm (attributable to C-1
and C-4) along with a broad peak centered around 169 ppm, pre-
sumably caused by slow tautomerization between the carbonyl-
and hydroxyl-bearing carbons. Addition of excess triethylamine re-
solved this broad peak into two sharp peaks at 173.3 and
171.9 ppm, presumably through formation of the corresponding
anionic species.
Having found success in removing one step from the synthesis
of oosporein, we considered further shortening the synthetic se-
quence. As aryl acetates can be hydrolyzed under base-promoted
conditions, treatment of hexaacetate 2 with pyrrolidine and copper
acetate (followed by acidic hydrolysis) was investigated. While this
gave a 51% yield of product (yield essentially identical to that ob-
tained in the conversion of 4 into 8) the product was a mixture
consisting of approximately 85% 8 and 15% cyclized product 9. This
indicated that even pure hexaacetate 2 (or intermediates derived
from it) could lead to 9 under some conditions. Variation in reac-
tion conditions failed to improve the purity of 8 while still main-
taining comparable yields.19
Acknowledgments
A significant portion of this work was funded by PhytoMyco Re-
search Corporation, Greenville, NC, through funds provided by SBIR
Phase II-USDA Grant #2005-33610-16084. The PI for this grant is
Dr. Ven Subbiah, of PhytoMyco Research Corporation.
Supplementary data
Experimental procedures, characterization data and NMR spec-
tra for compounds 2, 4, 6 and 8. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
References and notes
1. (a) Vining, L. C.; Kelleher, W. J.; Schwarting, A. E. Can. J. Microbiol. 1962, 8, 931;
(b) Takeshita, H.; Anchel, M. Science 1965, 147, 152; (c) Strasser, H.; Vey, A.;
Butt, T. M. Biocontrol Sci. Technol. 2000, 10, 717; (d) Nagaoka, T.; Nakata, K.;
Kouno, K.; Ando, T. Z. Naturforsch. 2004, 59c, 302.
2. Brewer, D.; Jen, W. C.; Jones, G. A.; Taylor, A. Can. J. Microbiol. 1984, 30, 1068.
3. Terry, B. J.; Liu, W.-C.; Cianci, C. W.; Proszynski, E.; Fernandes, P.; Meyers, E. J.
Antibiot. 1992, 2, 286.
4. Seger, C.; Erlebach, D.; Stuppner, H.; Griesser, U. J.; Strasser, H. Helv. Chim. Acta
2005, 88, 802.
5. (a) Seger, C.; Laengle, T.; Pernfuss, B.; Stuppner, H.; Strasser, H. J. Chromatogr., A
2005, 1092, 254; (b) Seger, C.; Sturm, S.; Laengle, T.; Wimmer, W.; Stuppner, H.;
Strasser, H. J. Agric. Food Chem. 2005, 53, 1364; (c) Michelitsch, A.; Rueckert, U.;
Rittmannsberger, A.; Seger, C.; Strasser, H.; Likussar, W. J. Agric. Food Chem.
2004, 52, 1423; (d) Strasser, H.; Abendstein, D.; Stuppner, H.; Butt, T. M. Mycol.
Res. 2000, 104, 1227.
6. Kögl, F.; van Wessem, G. C. Recl. Trav. Chim. Pays-Bas 1944, 63, 5.
7. Posternak, T. Helv. Chim. Acta 1938, 21, 1326.
8. Dallacker, F.; Löhnert, G. Chem. Ber. 1972, 105, 614.
9. Kalamar, J.; Steiner, E.; Charollais, E.; Posternak, T. Helv. Chim. Acta 1974, 57,
2368.
10. A SciFinder ScholarÒ search failed to locate any newer syntheses of oosporein
than the one described by Posternak in Ref. 9.
11. Love, B. E.; Bonner-Stewart, J.; Forrest, L. A. Synlett 2009, 813.
12. Though commercially available, 2,5-dimethoxytoluene is moderately
expensive. If cost is a concern, however, it can readily be prepared in 97%
yield from inexpensive methylhydroquinone.13
While the synthesis described above was proceeding, the reac-
tion of pyrrolidine and copper acetate with ditoluquinone 1 was
also investigated in an attempt to achieve an even shorter syn-
thesis of oosporein 8. Treatment of 1 with copper(II) acetate
and an excess of pyrrolidine once again produced a fine green-
black precipitate which was difficult to isolate due to its ten-
dency to clog filter paper or fritted glass during filtration, though
hydrolysis of this material gave a 69% yield of benzofuran diqui-
none 9.20 All attempts to hydrolyze 9 to convert it into 8 were
unsuccessful.
Since a large loss of usable product occurred in the Thiele-Win-
ter transformation of 1 into 2, variations in the reaction protocol
were investigated in an attempt to improve the ratio of 2:3 in
the product mixture. Use of both triflic acid21 and boron trifluoride
etherate22 as substitutes for concentrated sulfuric acid was inves-
tigated, but the product ratio remained constant at approximately
1.2:1. (The lack of acid catalyst influence on product distributions
has been noted previously).14
13. Sudhir, U.; James, B.; Joly, S.; Nair, M. S. Res. Chem. Intermed. 2003, 29, 523.
14. McOmie, J. F. W.; Blatchly, J. M. Org. React. 1972, 19, 199.
15. More rapid isolation of the products (in approximately 80% yield) could be
accomplished by removal of most of the methanol under reduced pressure,
followed by dilution with water and isolation of the products by suction
filtration. Failure to remove most of the methanol prior to dilution with water
greatly diminished the yield of the product obtained.
16. (a) Baltzly, R.; Lorz, E. J. Am. Chem. Soc. 1948, 70, 861; (b) Luly, J. R.; Rapoport, H.
J. Org. Chem. 1981, 46, 2745.
17. Mixtures of quinones and tertiary amines have been observed to form stable
radical anion/radical cation pairs. See, for example: Dworniczak, M. React.
Kinet. Catal. Lett. 2003, 78, 65.
18. The ratio of solvent volume to mixture weight (10 mL of methanol per gram of
mixture) appeared to be more critical than the number of washings. For
identical one gram samples, one trituration with 10 mL of methanol produced
2 in 45% yield, two triturations with 5 mL each of methanol produced 2 in 49%
yield, and three triturations with 3 mL each of methanol produced 2 in 51%
yield, all uncontaminated by 3.
19. As yields for the conversion of 2 into 4 are quantitative, this modification, had
it been successful, would have only resulted in a saving of time, not an
improvement of yield.
20. While 6 equiv of pyrrolidine (relative to diquinone) were sufficient for the
conversion of
4 into 8, the conversion of 1 into 9 required 12 equiv of
pyrrolidine. Use of lesser amounts of pyrrolidine led to contamination of 9 with
an unidentified impurity.
21. Villemin, D.; Bar, N.; Hammadi, M. Tetrahedron Lett. 1997, 38, 4777.
22. (a) Fieser, L. J. Am. Chem. Soc. 1948, 70, 3165; (b) Blatchly, J. M.; Green, R. J. S.;
McOmie, J. F. W.; Searle, J. B. J. Chem. Soc. (C) 1969, 1353.
In summary, a short, efficient synthesis of oosporein 8 has been
developed, which provides this compound in 24% overall yield in
four steps from 2,5-dimethoxytoluene. No chromatography was
required during any step of the synthesis.