Synthesis of (()-epi-Stegobinone UtilizingSilacyclopropanes as Synthetic IntermediatesStacie A. Calad, Jelena CÄ irakovic´, and K. A. Woerpel*Department of Chemistry, UniVersity of California,IrVine, California [email protected] September 28, 2006The synthesis of (()-1′-epi-stegobinone has been accom-plished in ten steps and 17% overall yield from a recentlyreported silacyclopropane-derived diol. All stereocenters ofthe final product were established relative to the stereochem-istry of the initial silacyclopropane. This synthesis representsthe first time silacyclopropane reactivity has been employedin a target-directed synthesis.Stegobinone (1) is the female-produced sex pheromone ofthe drugstore beetle, Stegobium paniceum,1,2and the furniturebeetle, Anobium punctatum.3Both species are economicallyimportant pests due to the damage they can cause to stored grainand wood products. The chemical structure of stegobinone2includes a dihydropyranone ring, a structural motif that iscommon to other polypropionate natural products.4-6The naturalisomer, (2S,3R,1′R)-stegobinone (1),7readily isomerizes to epi-stegobinone (2), which is repellent to the male species insteadof an attractant (Figure 1).8,9Due to its unique structure, severalapproaches toward the synthesis of stegobinone have beenundertaken.10-15In this paper, we describe an approach to stegobinone utilizingsilacyclopropanes as synthetic intermediates. The synthetic plan,which represents the first demonstration of silacyclopropanesas intermediates in target-directed synthesis, derives all thestereocenters in the final molecule from the stereochemistry ofthe starting silacyclopropane (Scheme 1). Disconnection of thedihydropyranone ring of 1 by an acid-promoted cyclizationprovides polypropionate fragment 3. The desired stereochemistryat the 1′-position could be established by an anti,syn-selectivealdol reaction of ethyl ketone 4 with propionaldehyde. Weenvisioned the 1,3-diol array of 3 arising through carbon-siliconbond oxidation of oxasilacyclopentane 4, which could be derivedfrom the silacyclopropane of cis-butene.We recently reported the diastereoselective synthesis of ethylketone 4, containing four contiguous stereocenters, in five stepsfrom cis-butene (Scheme 2).16Silver-catalyzed silylene transferfrom silacyclopropane 6 provided stereospecific formation ofsilacyclopropane 5. Treatment of the in situ formed cis-dimethylsilacyclopropane 5 with N-methyl-N-benzylformamideand a catalytic amount of copper iodide resulted in an N,O-acetal, which was hydrolyzed and acetylated to provide oxasi-lacyclopentane 7 in 74% yield over four steps. Nucleophilicsubstitution with silyl enol ether 817produced ketone 4 in 95%yield and high diastereoselectivity.18The observed stereochem-istry can be explained by approach of the silyl enol ether throughan antiperiplanar transition state.19,20(1) Kuwahara, Y.; Fukami, H.; Ishii, S.; Matsumura, F.; Burkholder,W. E. J. Chem. Ecol. 1975, 1, 413-422.(2) Kuwahara, Y.; Fukami, H.; Ishii, S.; Matsumura, F.; Burkholder,W. E. Tetrahedron 1978, 34, 1769-1774.(3) White, P. R.; Birch, M. C. J. Chem. Ecol. 1987, 13, 1695-1706.(4) Crossman, J. S.; Perkins, M. V. J. Org. Chem. 2006, 71, 117-124.(5) Manker, D. C.; Faulkner, D. J. J. Org. Chem. 1989, 54, 5374-5377.(6) Ciavatta, M. L.; Trivellone, E.; Villani, G.; Cimino, G. TetrahedronLett. 1993, 34, 6791-6794.(7) The absolute configuration of stegobinone was determined bystereocontrolled synthesis: (a) Hoffmann, R. W.; Ladner, W. TetrahedronLett. 1979, 4653-4656. (b) Mori, K.; Ebata, T.; Sakakibara, M. Tetrahedron1981, 37, 709-713. (c) Hoffmann, R. W.; Ladner, W.; Steinbach, K.; Massa,W.; Schmidt, R.; Snatzke, G. Chem. Ber. 1981, 114, 2786-2801.(8) Kodama, H.; Mochizuki, K.; Kohno, M.; Ohnishi, A.; Kuwahara, Y.J. Chem. Ecol. 1987, 13, 1859-1869.(9) For syntheses of 1′-epi-stegobinone, see: (a) Ebata, T.; Koseki, K.;Shimazaki, K.; Kawakami, H.; Chuman, T.; Matsushita, H.; Mori, K.Heterocycles 1990, 31, 581-585. (b) Ebata, T.; Mori, K. Agric. Biol. Chem.1990, 54, 527-530.(10) Ono, M.; Onishi, I.; Kuwahara, Y.; Chuman, T.; Kato, K. Agric.Biol. Chem. 1983, 47, 1933-1934.(11) Mori, K.; Ebata, T. Tetrahedron 1986, 42, 4413-4420.(12) Matteson, D. S.; Man, H.-W. J. Org. Chem. 1993, 58, 6545-6547.(13) Matteson, D. S.; Man, H.-W.; Ho, O. C. J. Am. Chem. Soc. 1996,118, 4560-4566.(14) Gil, P.; Razkin, J.; Gonza´lez, A. Synthesis 1998, 386-392.(15) Mori, K.; Sano, S.; Yokoyama, Y.; Bando, M.; Kido, M. Eur.J. Org. Chem. 1998, 1135-1141.(16) CÄ irakovic´, J.; Driver, T. G.; Woerpel, K. A. J. Org. Chem. 2004,69, 4007-4012.(17) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J.Tetrahedron 1987, 43, 2075-2088.(18) Addition of the corresponding allylic silane, which would producediol 9 after carbon-silicon bond oxidation, was not selective (58:42 dr).FIGURE 1. (2S,3R,1′R)-Stegobinone (1) and (2S,3R,1′S)-stegobinone(2).SCHEME 1. Retrosynthetic Analysis10.1021/jo0620011 CCC: $37.00 © xxxx American Chemical SocietyJ. Org. Chem. XXXX, XX, APAGE EST: 3.9Published on Web 12/29/2006The polypropionate functionality of the molecule was furtherrevealed through oxidation of the hindered carbon-silicon bond,as was previously reported.16Due to the strongly basic condi-tions necessary for the oxidation, a protecting group for theenolizable ketone moiety of 4 was required. Masking the ketoneas an alkene proved to be the best strategy (Scheme 2). Thesubsequent carbon-silicon bond oxidation21was achieved in94% yield at ambient temperature using the conditions optimizedin our laboratory.22-24Installation of the remaining polypropionate unit of the carbonskeleton was accomplished by an aldol reaction. To preventchelation of the diol oxygens in the aldol reaction,25-27thesterically hindered di-tert-butylsilyl protecting group was em-ployed (Scheme 3).28,29Subsequent ozonolysis of the doublebond afforded aldol precursor 10. Aldol reactions of β-silyloxylithium enolates have been reported to provide products contain-ing the desired anti,syn-stereochemistry.30The lithium enolateof ketone 10, however, gave aldol product 11 as a 68:32 mixtureof diastereomers. Other metal enolates were screened, and thereaction of Sn(OTf)2provided the highest yields and selectivities(Scheme 3).31The major isomer obtained from the tin aldolreaction was the same major diastereomer obtained from thelithium aldol reaction. Based on literature precedent,30,31wesurmised that the
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