HETEROCYCLES

Communication | Special issue | Vol. 80, No. 2, 2010, pp. 863-872
Received, 12th August, 2009, Accepted, 9th November, 2009, Published online, 11th November, 2009.
DOI: 10.3987/COM-09-S(S)109

■ Synthesis of α-Alkylidene-δ-valerolactones via the Conjugate Addition of Ketone Enolates to Functionalized Allyl Acetates

P. Veeraraghavan Ramachandran* and Annyt Bhattacharyya

Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Dr.; BRWN 5131
West Lafayette, IN 47907-2084, U.S.A.

Abstract

Sequential addition of ketone enolates to allyl acetates bearing an ester, followed by reduction and cyclization provides a variety of substituted α-alkylidene-δ-valerolactones.

Butenolides, pyranones, α-alkylidene-γ-butyrolactones and -δ-valerolactones present in multitude of natural products display a variety of biological activities.1 Although not as prevalent as α-methylene-γ-butyrolactones, the corresponding δ-valerolactones are also essential components and characteristic features of a plethora of natural products.2 Several of these substrates possess novel pharmacological and interesting biological activities which range from antibiotic to antitumor activity.2 In addition to the biological significance, α-methylene-δ-valerolactones find applications in carbon-carbon bond forming reactions3 and methylene-bridged disaccharide synthesis.4

Among the α-alkylidene-δ-valerolactones, the synthesis of α-methylene δ-valerolactones is more common5 and among the several approaches known in the literature, the metal-mediated cyclization of homoallylic alkynoates6 and carbonylation7 are noteworthy. Other processes include synthesis via the Horner-Wadsworth-Emmons reaction of α-phosphonolactones8 and the trifluoromethanesulfonic acid mediated Friedel-Crafts reaction of diethoxyphosphorylacrylic acids.9 Shiozaki and coworkers reported the synthesis of α-alkylidene-δ-valerolactones from corresponding ketones via aldol condensation on a δ-valerolactone moiety for the preparation of certain rennin inhibitors.10 Recently Howell and coworkers reported the synthesis of α-alkylidene-γ-butyrolactones via a cross-metathesis reaction in the presence of Grubbs catalyst and 2,6-dichlorobenzoquinone.11 However, this process was not effective for the preparation of the corresponding δ-valerolactones. Singh and Batra reported the preparation of a series of β-aryl-δ-methyl-α-methylene-δ-valerolactones via a nucleophilic substitution (SN2 process) of Baylis-Hillman acetates (Scheme 1).12

As part of our ongoing projects on vinylalumination,13 we envisaged a terse general synthesis of variantly substituted α-alkylidene-δ-valerolactones via the conjugate addition-elimination of functionalized allylic acetates (an overall SN2' process) with enolate nucleophiles as delineated in Scheme 2. As can be seen, this process allows for the incorporation of substitutions at β, γ, and δ-positions. The successful synthesis of a variety of γ- and δ-substituted α-alkylidene-δ-valerolactones, including the construction of fused bicyclic valerolactone moieties14 is reported herein.

The required allyl acetates for the present study were prepared via the vinylalumination13 of acetaldehyde and benzaldehyde, followed by esterification of the resulting alcohols with acetic anhydride in the presence of pyridine (Scheme 3). These derivatives can be prepared via Baylis-Hillman reaction12,15 as well.

Initially, the enolates from various methyl ketones were generated under kinetic conditions (LDA, -78 oC), which was followed by the addition of a solution of 3a or 3b (Scheme 4). The conjugate addition- elimination process is only initiated at or above 0 oC. Subsequent warming of the reaction mixture to ambient condition and stirring overnight ensures complete consumption of 3a or 3b. It is to be noted that the reaction is prohibitively slow even at 0 oC. Extensive experimentation confirmed that the presence of excess base or HMPA does not have any beneficial effect on the reaction and that THF is the solvent of choice.

The oxoesters (4a-d and 5a-5c) from methyl ketones (R3=H, Scheme 4) were obtained in moderate (52-65%) yields. The 1H NMR analysis of all of the products (4a-d and 5a-c) indicated 90% E geometry for the olefin. The C2-symmetric bis-adducts derived from the deprotonation of 4 or 5 were also obtained in 10-20% yield. The availability of the base for the deprotonation of 4 or 5 could be presumably from the reversibility of the enolate formation. The formation of the bis adduct could be considerably controlled under optimum conditions (1.2 equivalent of LDA), although it could not be completely suppressed. The results are summarized in Table 1.

Compared to the methyl ketones, other classes of ketones such as ethyl, n-propyl, benzyl and alicyclic ketones generated keto esters in much better yields with similar E:Z ratio as observed for 4 and 5. The keto-adducts from propiophenone (6a,7a), n-butyrophenone (6b,7b), deoxybenzoin (6c,7c), cyclopentanone (6d,7d), and cyclohexanone (6e) are among the representatives. The alicyclic derivatives of keto esters (6d, 6e and 7d) could be successfully generated under analogous reaction conditions. The formation of the bisadducts, as observed for 4a-d and 5a-c, does not occur for keto-adducts 6a-d, 7a-d, presumably due to the steric congestion at the newly generated ternary stereocenter in these adducts. The results are summarized in Table 2.

Chemoselective reduction of the α-alkylidene oxoesters to the corresponding hydroxyesters could be effected quantitatively with Sodium borohydride. Substrates 6a-e and 7a, 7c and 7d underwent reduction with varied diastereoselectivity. The diastereoselectivity was not determined at this point since the alcohol has a tendency to lactonize during aqueous workup. Attempted silica-gel chromatography resulted in partial lactonization of the hydroxyl ester. As a consequence, they were submitted to an acidic environment without further purification and the cyclization to the lactones occurred instantaneously.

Thus, 4a-d, 5a-c, 6a-e and 7a, 7c, 7d generated the lactones 8a-d, 9a-c, 10a-e and 11a, 11c, 11d, respectively, in high yields over two steps (Scheme 5). The alkyl substituent at the α-position predominantly governs the hydride approach from the si face of the prochiral carbonyl carbon, thus favoring the formation of the syn-alcohol. Thus, while 10a and 10c were formed as 2:1 and 1:1 mixture of diastereomers respectively, lactones 10b and 11b were generated with high cis-selectivity. The diastereomeric ratio was determined from 1H NMR coupling constants. The lactone 11a and the cyclopentanone-derived lactones 10d and 11c were formed excusively as anti isomers.16 The lactone 10e, obtained from cyclohexanone, was an inseparable diastereomeric mixture in the ratio of 2:1.14 The yields and the diastereomeric ratios of the lactones are summarized in Table 3.

In conclusion we have demonstrated a highly convenient synthesis of a variety of α-alkylidene-δ-valerolactones from readily available synthons. The generality of the methodology has been demonstrated via the synthesis of a wide range of δ-alkyl/aryl valerolactones and studies on the stereochemistry at ring junction for fused bicyclic α-alkylidene δ-valerolactones. Current efforts focus on the enantio- and diastereoselective reduction of the keto esters for the preparation of chiral lactones. We are also examining ways to improve the yields in the conjugate addition-elimination step.

EXPERIMENTAL
General: Unless otherwise noted, reagents were purchased from commercial suppliers. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl under nitrogen. Diisopropylamine was distilled over calcium hydride or potassium hydroxide and stored over 4 Ǻ molecular sieves. n-Butyl lithium (2.5 M solution in hexanes) was procured from Aldrich. Thin layer chromatography was performed on Sorbent Technologies precoated silica gel w/UV254 glass backed (250μm) plates. Silica gel (Sorbent Technologies 230-400 mesh) was used for flash column chromatography. 1H NMR spectra was recorded on a Gemini (300 MHz) or Bruker (200 MHz) spectrometer. Spectra was referenced internally to the residual proton resonance in CDCl3 (δ 7.26 ppm) as the internal standard. Commercially available CDCl3 was stored under 4 Ǻ molecular sieves. Chemical shifts (δ) were reported as parts per million (ppm) in δ scale downfield from TMS. 13C NMR spectra were recorded on a Gemini 300 spectrometer and referenced to CDCl3 (δ 77.0 ppm). Coupling constants (J) were reported in Hertz. Spectroscopic data is presented for representative compounds.
Typical procedure for preparation of α-alkylidene-δ-valerolactone 8a.
Preparation of 4a: To a solution of diisopropylamine (0.33 mL, 2.4 mmoles) in anhydrous THF (1 mL) at -78 oC was added n-BuLi (0.96 mL, 2.4 mmol, 2.5 M soln. in hexanes) followed by the addition of a solution of acetophenone (0.24 g, 2 mmol dissolved in anhydrous THF (3mL) at the same temperature over a period of 10 minutes. To the resulting mixture was added a solution of 3a (0.34 g, 2 mmol) dissolved in anhydrous THF (3 mL) and stirred overnight, during which time the reaction mixture warmed upto ambient temperature. This was then quenched with saturated aqueous ammonium chloride, extracted with EtOAc, dried (Na2SO4) and concentrated to obtain crude 4a, which was purified by flash column chromatography using silica-gel (1:9:: EtOAc:hexanes) to obtain 0.30 g (65%) of pure 4a as an oil. δH(300 MHz; CDCl3): 7.99 (2H, d, J 6.0, ArH), 7.4-7.6 (3H, m, ArH), 6.9 (1H, q, J 7.2, CH3CH=C), 3.75 (s, 3H, OCH3), 3.13-3.08 (2H, m, CH2CH2), 2.76-2.71 (2H, m, CH2CO), 1.86 (d, 3H, J 7.14, CH3) δC(75 MHz; CDCl3): 199.4, 167.9, 138.9, 136.7, 133, 131.7, 128.5, 128, 51.6, 37.7, 21.4 14.3.
Preparation of 8a: To a solution of 4a (0.1 g, 0.43 mmol) in anhydrous MeOH (3 mL) was added solid NaBH4 (16.3 mg, 0.43 mmol) under ice-cooling and stirred for 2 h. The reaction mixture was quenched with water. Methanol was removed under reduced pressure and the aqueous layer was extracted with EtOAc, dried (Na2SO4) and concentrated. The contents in the flask was dissolved in CH2Cl2 (5 mL) and catalytic amount of p-toluenesulfonic acid was added and the solution was refluxed for 30 min. The reaction was quenched with water, extracted with CH2Cl2, dried (Na2SO4), and purified by flash column chromatography using silica-gel (1:9::EtOAc:hexanes) to obtain 0.064 g (74%) of 8a as a white crystalline solid. δH(300 MHz; CDCl3): 7.4-7.2 (6H, m, ArH, CH3CH=C), 5.28 (1H, dd, J 2.34, PhCH), 2.76-2.31 (2H, m, CH2CH2), 2.28-2.18 (1H, m, CH2CHO), 2.10-1.86(1H, m, CH2CHO), 1.83 (d, 3H, J 7.14, CH3). δC(75 MHz; CDCl3): 166.5, 141.5, 139.6, 128.6, 128.2, 125.9, 125.8 MS (EI) 202(M+), 104, 96, 77.

ACKNOWLEDGEMENTS
We thank the Herbert C. Brown Center for Borane Research for support of this work.

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