ORGANIC
LETTERS
2011
Vol. 13, No. 19
5136–5139
Three-Component Coupling Approach
to Trachyspic Acid
Daniel C. Schmitt, Leighann Lam, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
Received July 25, 2011
ABSTRACT
Three-component coupling of the lithium enolate of t-BuOAc, silyl glyoxylate, and an R,β-unsaturated ketone enables the rapid construction of the
trachyspic acid carbon skeleton. A 3,4-disubstituted isoxazole is utilized to mask the C7/C9 dicarbonyl. New enolsilane/nitrile-oxide
cycloadditions enable the preparation of various 3,4-disubstituted isoxazoles that are challenging to access by other means.
Trachyspic acid (1) was isolated from the culture broth
of Talaromyces trachyspermus SANK 12191.1 Trachyspic
acid possesses a substituted citric acid subunit and a
hydrophobic side chain, defining characteristics of the
2-alkyl citrate natural products, and as an inhibitor of
tumor heparanase (IC50 = 36 μM), it has inspired several
synthetic studies.2À6 The contiguous C3 and C4 chiral
centers and the efficient management of the unusual
C6ÀC9β,γ-diketoaldehydehaveproven tobetheprinciple
hurdles to synthesis. For construction of the former sub-
unit, previous syntheses of trachyspic acid have employed
either aldol2,3,6 or Ireland-Claisen rearrangement4,5 stra-
tegies. The occurrence of the fully substituted C3 glycolic
acid suggested the opportunity to develop a new silyl
glyoxylate-based three-component coupling7À13 that might
permit efficient access to the core substructure. This Letter
details experiments directed to this end.
The open chain form (2) of trachyspic acid reveals a 1,4-
relationship between the C3 glycolic acid and the C6
ketone, hinting at a potential Michael addition of a silyl
glyoxylate with an appropriately functionalized R,β-un-
saturated ketone (Scheme 1); however, a C6/C7/C9 tricar-
bonyl compound would pose an intractable chemo-
selectivity challenge in the projected three-component
(7) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127,
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(8) Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C.; Johnson, J. S.
J. Am. Chem. Soc. 2008, 130, 17281–17283.
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Soc. 2010, 132, 17393–17395.
(12) Greszler, S. N.; Malinowski, J. T.; Johnson, J. S. Org. Lett. 2011,
13, 3206–3209.
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Tanzawa, K.; Hosoya, T.; Furuya, K.; Takahashi, S.; Furihata, K.;
Seto, H. J. Antibiot. 1995, 48, 357–362.
(2) Morokuma, K.; Taira, Y.; Uehara, Y.; Shibahara, S.; Takahashi,
K.; Ishihara, J.; Hatakeyama, S. Tetrahedron Lett. 2008, 49, 6043–6045.
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(13) Schmitt, D. C.; Johnson, J. S. Org. Lett. 2010, 12, 944–947.
(14) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
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r
10.1021/ol202002r
Published on Web 08/31/2011
2011 American Chemical Society