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Synthesis 2011(17): 2751-2753  
DOI: 10.1055/s-0030-1260161
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© Georg Thieme Verlag Stuttgart ˙ New York

Triple Mukaiyama-Michael Cascade toward a Tricyclic Framework

Dina Shpasser, Moshe Kapon, Mark Botoshansky, Moris S. Eisen*
Schulich Faculty of Chemistry and Institute of Catalysis Science and Technology, Technion-Israel Institute of Technology, Haifa 32000, Israel
Fax: +972(4)8295705; e-Mail: chmoris@tx.technion.ac.il;

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Publication History

Received 28 April 2011
Publication Date:
05 August 2011 (online)

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Abstract

The intermolecular Mukaiyama-Michael addition between stoichiometric amounts of a bisketene acetal and methyl vinyl ketone is rapidly followed by a double cascade intramolecular Mukaiyama-Michael addition to form a fused tricyclic compound containing four-, five- and six-membered rings embellished with several functionalities.

Key words

Mukaiyama-Michael addition - cascade reaction - fused tricyclic framework - silyl enol ethers - bisketene acetals

Cuprous salts are well known to effectively catalyze the intermolecular [2n+2n] photocycloaddition of diallyl ethers or homoallyl vinyl ethers toward a large variety of multicyclic tetrahydrofurans. [¹] The concomitant oxidation of these multicyclic frameworks with ruthenium complexes provides a very elegant route for the production of multicyclic synthons containing fused cis-cyclobutanated butyrolactone motifs. [²] The synthesis of these multicyclic compounds is very interesting, providing an intermediate for the cyclobutyl-cyclopropylcarbinyl-type rearrangement of constrained polycyclic lactones and allowing the formation of more refined, elaborate compounds. [³] Here, we present a simple intermolecular Mukaiyama-Michael coupling followed by an intramolecular cascade Mukaiyama­-Michael reaction for the production of a tricyclic compound containing four-, five- and six-membered rings embellished with a variety of functional groups for further transformations.

More than a decade ago it was shown that the bisketene acetal 2 undergoes a double Mukaiyama-Michael reaction under mild Lewis acidic conditions [4] with anhydrous zinc iodide [5] to give an inseparable 1:1 mixture of the cis- and trans-diketo dilactones 3 in good yield. [6] The bisketene acetal 2 can be obtained from the corresponding lactide (1) after deprotonation and consecutive reaction with trimethylsilyl chloride at low temperature (-110 ˚C) [¹] (Scheme  [¹] ).

Interestingly, when the original conditions were employed for the addition of bisketene acetal 2 to methyl vinyl ketone, using the strong Lewis acid titanium(IV) chloride [7] rather than zinc iodide, the di- and tricyclic ke­tals 4 (two diastereomers) and 5 were obtained (Figure  [¹] ), in addition to the aforementioned product 3. [6]

Scheme 1 Synthesis of diketo dilactones 3 from lactide (1)

Figure 1 The di- and tricyclic ketals 4 (two diastereomers) and 5 obtained in the reaction of bisketene acetal 2 with methyl vinyl ketone catalyzed by titanium(IV) chloride [6]

Hence, it is clear that the Lewis acidity of the activator has an enormous effect in determining the product of the coupling between bisketene acetal 2 and methyl vinyl ketone. Although the intermolecular reaction of lactones with ketene acetals to produce β-ketal esters was the original reaction performed by Mukaiyama and co-workers, [8] the intramolecular protocols have been presented by others. [9] Interestingly, there are few reports on similar reactions using the less reactive silyl enol ethers. [¹0] We postulated that use of the mild Lewis acid, in addition to use of an equimolar amount of methyl vinyl ketone, would provide an intermolecular followed by an intramolecular cascade to give formation of the tricyclic product 6. Indeed, compound 6 was formed in good yield from the stoichiometric addition of bisketene acetal 2 to methyl vinyl ketone via a triple Mukaiyama-Michael cascade reaction, as presented in Scheme  [²] . Tricyclic compound 6 was obtained as a crystalline yellowish material by slow evaporation of the solvent. The structure of tricyclic product 6, exhibiting three interconnected fused rings, a four-, a five- and a six-membered ring, with many embellishing functional groups, was unambiguously confirmed by X-ray crystallographic studies (Figure  [²] ).

Scheme 2 Triple cascade Mukaiyama-Michael addition for the synthesis of tricyclic compound 6

Figure 2 ORTEP X-ray crystallographic representation of the tricyclic product 6

Interestingly, under the present reaction conditions, the cascade intramolecular activation of the vinyl methyl ketone is by far much faster than the intermolecular reaction with a second equivalent of methyl vinyl ketone, producing the tricyclic product in a chemoselective and regioselective fashion. Moreover, the unexpected difference in reactivity of the different trimethylsilyl groups under aqueous hydrogen fluoride solution is also worth noting; the trimethylsilyloxy group at the ipso carbon of the three cyclic rings was not protonated, in contrast to the trimethylsilyloxy group on the five-membered tetrahydrofuran ring.

Lactide (1) was purchased from Aldrich, placed in a Schlenk flask and dried overnight on a high-vacuum line. CH2Cl2 was purchased from Frutarom, distilled and stored over molecular sieves. Methyl vinyl ketone was purchased from Fluka and freshly distilled before use. ZnI2 was purchased from Aldrich and used without further purification. NMR spectra were recorded on a Bruker 400 MHz spectrometer. X-ray analysis was performed by mounting a single crystal on a Nonius Kappa CCD diffractometer, using graphite-monochromatized Mo Kα radiation. Data collection, cell refinement and reduction were carried out using the Nonius software packages ‘collect’, [¹¹] HKL Denzo and Scalepack. [¹²] Structure solution and refinement were carried out using maXus [¹³] and SHELXL-97 [¹4] program packages, respectively. The ORTEP program incorporated in the TEXRAY [¹5] package was used for molecular graphics. Non-hydrogen atoms were refined anisotropically until convergence was reached at R = 0.0334 and with R 2 = 0.0679 for I > 2σ(I). [¹6]

rel -(1 S ,3S,6S,8S,9R/1R,3R,6R,8R,9S)-9-Hydroxy-3,6,9-trimethyl-8-(trimethylsilyloxy)-4,7-dioxatricyclo[4.2.1.0 ³,8 ]nonan-5-one (6)

ZnI2 (283 mg, 0.887 mmol) was added to a soln of freshly distilled methyl vinyl ketone (1.4 mL, 16.8 mmol) and bisketene acetal 2 (4.8 mL, 16.8 mmol) in CH2Cl2 (10 mL) at 0 ˚C. The reaction mixture was vigorously stirred at 0 ˚C for 4 h. Then, the mixture was warmed to r.t. Acetone (30 mL) and 48% aq HF (0.4 mL, 26 mmol) were added and the mixture was left to stir at r.t. for 2 h. CH2Cl2 (200 mL) and H2O (30 mL) were then added. The organic layer was washed with sat. aq NaHCO3 (2 30 mL) and brine (2 30 mL), dried (MgSO4) and then concentrated to afford a yellow oil. Flash chromatography [silica gel, R f  = 0.46 (hexane-EtOAc, 3:2)] provided three separated materials, of which the main product was a single diastereomer of the yellow crystalline solid 6; yield: 4.18 g (87%); the mp was not determined since the solid decomposed upon heating over 90 ˚C, presumably owing to elimination of the TMS group. X-ray analysis was performed on crystals that were obtained from an aliquot of the solution after slow evaporation of the solvent. The other two products were not successfully characterized since they were mixtures of diastereomers and their amount was <3% of the conversion.

¹H NMR (400 MHz, CDCl3): δ = 2.50 (dd, ² J HH = 2.42 Hz, ³ J HH = 9.69 Hz, 1 H, CH 2 on four-membered ring), 2.23 (dd, ² J HH = 2.42 Hz, ³ J HH = 13.73 Hz, 1 H, CH 2 on four-membered ring), 1.95 (dd, ³ J HH = 9.69 Hz, ³ J HH = 13.73 Hz, 1 H, CH on four-membered ring), 1.45 (s, 3 H, CH 3 on four-membered ring), 1.38 (s, 3 H, CH 3COO), 1.33 (s, 3 H, CH 3COH), 0.19 [s, 9 H, Si(CH 3)3].

¹³C NMR (100 MHz, CDCl3): δ = 2.0, 17.3, 22.2, 29.9, 50.9, 72.0, 81.0, 86.2, 107.6, 169.9.

Anal. Calcd for C13H22O5Si (286.40): C, 54.52; H, 7.74. Found: C, 54.28; H, 7.56.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis. Included are the relevant X-ray tables and the checkCIF file.

Acknowledgment

This research was supported by the United States-Israel Binational Science Foundation under contract 2008283.

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Mackay, S.; Gilmore, C. J.; Edwards, C.; Tremayne, M.; Stuart, N.; Shankland, K. maXus: A Computer Program for the Solution and Refinement of Crystal Structures from Diffraction Data; University of Glasgow: Glasgow/Nonius BV: Delft/MacScience Co. Ltd.: Yokohama, 1998.

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Crystallographic data for the structure 6 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 821687. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk.

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Mackay, S.; Gilmore, C. J.; Edwards, C.; Tremayne, M.; Stuart, N.; Shankland, K. maXus: A Computer Program for the Solution and Refinement of Crystal Structures from Diffraction Data; University of Glasgow: Glasgow/Nonius BV: Delft/MacScience Co. Ltd.: Yokohama, 1998.

16

Crystallographic data for the structure 6 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 821687. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk.

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Scheme 1 Synthesis of diketo dilactones 3 from lactide (1)

Figure 1 The di- and tricyclic ketals 4 (two diastereomers) and 5 obtained in the reaction of bisketene acetal 2 with methyl vinyl ketone catalyzed by titanium(IV) chloride [6]

Scheme 2 Triple cascade Mukaiyama-Michael addition for the synthesis of tricyclic compound 6

Figure 2 ORTEP X-ray crystallographic representation of the tricyclic product 6