Chapter Chapter Enantioselective Catalytic Intramolecular Michael Additions: Asymmetric Synthesis of Chiral γ-Lactones 115 Chapter 5.1 Introduction γ-Lactones (γ-butyrolactones or GBL, Figure 5.1), which has been widely found in natural compounds, are interesting lead structures for new drugs due to the broad scope of their biological activities including antibiotic, antihelmetic, antifungal, antitumour, antiviral, anti-inflammatory and cytostatic properties.1 Thus their synthesis has become a continuously developing area in synthetic organic chemistry in recent years.1-3 The ring-closing method by C-C bond generation has been realized as one of the main synthetic approaches for γ-lactone rings. Figure 5.1 Structure of γ-lactone. Naito et al.4-5 successfully developed a novel tandam radical addition-cyclization method for the asymmetric synthesis of polyfuctionalized γ-lactones based on the formation of the C3-C4 bond. As shown in Scheme 5.1, the chiral substrate had two different radical acceptors (acrylate and oxime ether moieties) intermolecularly connected. In the presence of a bulky substituent CH2OTBDPS of chiral oxime ether, the tandam reaction provided various chiral γ-lactones with high diastereoselectivity. The remarkable feature of this reaction is the construction of two C-C bonds and two chiral centers via a tandom process. Scheme 5.1 Synthesis of γ-lactones via tandem radical addition-cyclization reaction. 4-5 116 Chapter Martín et al.6-7 reported a base-induced intramolecular Michael addition of enantiomerically enriched α-[(phenylthio)acyloxy]-α,β-unsaturated esters to obtain highly substituted γ-lactones with a high degree of stereocontrol (Scheme 5.2). The key step in the synthesis of α,β-unsaturated esters was the regioselective opening of 2,3-epoxy alcohols using thiophenyl acetic acid. Scheme 5.2 Synthesis of γ-lactones via intramolecular Michael addition. 6-7 Merey et al.8 reported a 1,5-electrocyclic ring closure reaction of carbonyl ylides from conjugated esters and diazo bis(carbonyl) compounds (Scheme 5.3). This is an easy and highly efficient method for the preparation of γ-lactones based on C4-C5 bond generation by the intramolecular Michael addition to conjugated esters. Scheme 5.3 Synthesis of γ-lactones via 1,5-electrocyclic ring closure reaction.8 As shown above, α,β-unsaturated carbonyl compounds have been widely used as carbon electrophiles for the preparation of γ-lactones. On the other hand the intramolecular Michael addition reaction from readily available acyclic precursors have been shown to be a general and useful shortcut for the preparation of a variety of 117 Chapter hetero- and carbocyclic compounds.9 Due to the important role of γ-lactones in the field of biological and pharmaceutical chemistry, we were interested in developing a novel and efficient stereoselctive synthetic method to chiral γ-lactones through an intramolecular Michael addition. 5.2 Synthesis of substrates The donor-acceptor functionalized substrates 102, with a 1,3-dicarbonyl nucleophile tethered to an α,β-unsaturated ester or ketone, were synthesized according to the reaction sequence shown in Scheme 5.4. The trans-γ-hydroxy-α,β-unsaturated carbonyl compounds 100 were prepared by the Wittig reactions of glycoaldehyde with the appropriate stabilized ylides in refluxing THF.10 Subsequently, the esterification reactions between the carboxylic acids 101 and alcohols 100 in the presence of one equivalent dicyclohexylcarbodiimide (DCC) afforded the desired α,β-unsaturated carbonyl compounds 102.11 Scheme 5.4 Synthesis of donor–acceptor functionalized substrates 102. 5.3 TBD catalyzed intramolecular Michael additions Our group reported that 1,5,7-triazabicyclo[4.4.0]dec-5-ene 103 (TBD), a bicyclic guanidine base, can efficiently catalyze the Michael addition reactions between 1,3-dicarbonyl donors and a range of alkenes.12 Inspired by these result, we decided to 118 Chapter investigate the inherent reactivity of α,β-unsaturated carbonyl compounds 102 towards base-catalyzed intramolecular Michael addition reactions by using TBD as the catalyst for the racemic reactions. Table 5.1 TBD catalyzed intramolecular Michael addition reactions. product time /h yield /%a 104a 0.5 85 104b 3.5 71 104c 10 85 104d 52 75 entry a substrate Isolated yield. dr = 6:1 (determined by 1HNMR). As shown in Table 5.1, various α,β-unsaturated carbonyl compounds 102a-d were examined by using 20 mol% of TBD in CH2Cl2. To our delight, all the reactions proceeded smoothly to afford the corresponding α,β-disubstituted γ-lactones 104a-d 119 Chapter in good yields with diastereomeric ratios of approximately 6:1. The cyclization of trans-enone 102a was complete after only 0.5 hour (entry 1). The replacement of ketoester with O,S-dialkyl thiomalonate led to slightly slower reaction rate (entry 2). tert-Butyl enone 102c provided the cyclized product with even longer reaction time than that of phenyl enone 102b (entry 3). The intramolecular Michael addition reaction of α,β-unsaturated ester 104d was also tolerable, albeit prolonged reaction time was required (entry 4). 5.4 Cinchona alkaloids catalyzed intramolecular Michael additions With the racemic results in hand, we then turned our attention to chiral organic basecatalyzed intramolecular Michael addition reactions. A series of chiral guanidines were first examined, resulting in very slow reaction rate. As we known, readily accessible Cinchona alkaloids have been identified as efficient organocatalysts for Michael addition reactions.13 Herein we envisioned that the employment of Cinchona alkaloids as catalysts for asymmetric intramolecular Michael addition reactions might lead to the enantioselective formation of γ-lactones. For the optimization screening, compound 102b was used as a model substrate. The decarboxylation of thioester at the C3 position of the cyclized product 104b could provide γ-lactone 105a in quantitative yield. The enantiomeric excess of 105a was determined; hence the diastereoselectivity of the intramolecular Michael addition reaction was not considered. Among the commercially available Cinchona alkaloids that were tested, cinchonine gave the best yield (76%) and enantioselectivity (77% ee, Table 5.3, entry 3). Solvent effect was then studied with cinchonine as the optimum catalyst. The use of non-polar solvents such as toluene and xylene afforded γ-lactone 120 Chapter 105a with faster reaction rates and similar enantioselectivities (entries 5-6). However, low yields were obtained due to some side reactions. Chlorobenzene provided the product in 76% yield with only 50% ee (entry 7). Inferior results were observed when THF and MeCN were utilized in the reactions (entries 8-9). Table 5.2 Optimization of the reaction conditions for intramolecular Michael addition reactions of α,β-unsaturated carbonyl compound 102b.a entry catalyst solvent time /h Quinine Quinidine Cinchonine Cinchonidine Cinchonine Cinchonine Cinchonine Cinchonine Cinchonine CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene xylene chlorobenzene THF MeCN 96 96 50 96 37 34 18 10 20 yield /%b 30 20 76 19 35 48 76 38 31 ee /%c 58 60 77 72 75 72 50 43 23 a All reactions were performed with 0.05 mmol of 102b in 1.0 mL of solvent. Overall isolated yield of two steps. c Enantiomeric excess of 105a was determined by chiral HPLC. b 121 Chapter Table 5.3 Preparation of various chiral γ-lactones by enantioselective intramolecular Michael addition reactions of α,β-unsaturated carbonyl compounds 102.a time /h yield /%b ee /%c SEt 50 76 77 2-naphthyl SEt 52 71 70 SEt 60 21 20 SEt 48 74 60 4-CNC6H4 SEt 45 67 66 entry 102 R1 R2 102b Ph 102e 102f biphenyl 102g 4-MeC6H4 102h a product All reactions were performed with 0.05 mmol of 102 in 1.0 mL of solvent. b Overall isolated yield of two steps. c Enantiometric excess of 105 was determined by chiral HPLC. 122 Chapter The optimal reaction conditions were then applied to the preparation of chiral γ-lactones 105a-e with a ketone functionality at the C4 position from various α,β-unsaturated ketones (Table 5.3). The intramolecular Michael addition reaction of naphthyl enone 102e provided the cyclized product 105b in 71% yield with 70% ee (entry 2). For the reaction of biphenyl enone 102f, the corresponding product was generated in low yield and enantioselectivity (entry 3). When 4-methyl-phenyl enone 102g was used as the substrate, γ-lactone 105d was obtained in 74% yield with 60% ee (entry 4). The introduction of nitrile group to the 4-position of phenyl enone led to a slightly faster reaction rate (entry 5); and γ-Lactone 105e was afforded in 67% yield with 66% ee. 5.5 Conclusion In this chapter, an efficient and practical organic base-catalyzed intramolecular Michael addition reaction was developed as a synthetic approach towards γ-lactones. The cyclization of α,β-unsaturated ketones tethered a 1,3-dicarbonyl nucleophile could be effectively catalyzed by cinchonine to afford chiral γ-lactones in moderated to good yields and enantioselectivities. However, there are still some unsolved problems of this methodology. For instance, the cyclization reaction of α,β-unsaturated ester was quite slow. In addition, the enantiometric purities of γ-lactones were still not excellent. Therefore expanding the substrate scope and improving the enantioselctivity could be the targets for future efforts. 123 Chapter 5.6 Experimental 5.6.1 General Procedures The general procedures of Chapter were followed. 5.6.2 Preparation of substrates 102a-h 5.6.2.1 General procedure for the synthesis of trans-γ-hydroxy-α,β-unsaturated carbonyl compounds 100 To a solution of the stabilized ylide (1.2 mmol, 1.2 eq.) in THF (5 mL) was added glycoaldehyde dimer (60 mg, 1.0 mmol, 1.0 eq.). The resulting solution was heated under reflux for hours. The solution was cooled and the solvent was evaporated in vacuo. The product was purified by flash column chromatography (Florisil, hexane/EA mixture, 1/1) and was used immediately. 5.6.2.2 General procedure for the synthesis of trans-α,β-unsaturated carbonyl compounds 102 To a solution of carboxylic acid 101 (0.75 mmol, 1.5 eq.) and trans-γ-hydroxyα,β-unsaturated carbonyl compounds 100 (0.5 mmol, 1.0 eq.) in THF (2.5 mL) was added a solution of DCC (0.5 mmol, 1.0 eq.) in THF (0.5 mL). The reaction mixture was stirred overnight, filtered, and the filtrate was evaporated. The residue was purified by flash column chromatography (silica gel, gradient elution with hexane/EA mixture, 8/1 to 2/1) to afford the product 102. 5.6.2.3 Characterization of substrates 102a-h 124 Chapter (102a) (E)-4-oxo-4-phenylbut-2-enyl 3-oxo-3-phenylpropanoate Colorless oil, 60% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 4.12 (s, 1H), 4.95 (dd, 1H, J = 1.9, 4.3 Hz), 4.99 (dd, 1H, J = 1.3, 3.7 Hz), 6.02 (dt, 1H, J = 3.7, 19.0 Hz), 7.14 (dd, 1H, J = 1.6, 15.6 Hz), 7.43-7.60 (m, 6H), 7.79-7.82 (m, 1H), 7.94-7.99 (m, 3H). 13 C NMR (75 MHz, CDCl3, ppm): δ 62.8, 86.6, 125.8, 126.1, 128.4, 128.5, 128.6, 128.7, 128.9, 131.5, 133.0, 133.1, 133.9, 140.1, 141.0, 172.4, 189.9. The compound existed as enolate form in CDCl3. FTIR (film): 1032, 1182, 1277, 1333, 1369, 1452, 1641, 1653, 1720, 3427 cm-1. LRMS (ESI) m/z 331.1 (M+Na+). (102b) (E)-4-oxo-4-phenylbut-2-enyl 3-(ethylthio)-3-oxopropanoate Colorless oil, 65% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 1.27 (t, 3H, J = 7.3 Hz), 2.93 (dd, 2H, J = 7.3, 15.0 Hz), 3.69 (s, 2H), 4.91 (dd, 2H, J = 1.7, 4.2 Hz), 6.95 (dt, 1H, J = 4.2, 15.7 Hz), 7.14 (dd, 1H, J = 1.7, 15.7 Hz), 7.45 (t, 2H, J = 7.5 Hz), 7.55 (t, 1H, J = 7.3 Hz), 7.95 (m, 2H). 13C NMR (75 MHz, CDCl3, ppm): δ 14.4, 24.1, 49.4, 64.0, 125.9, 128.7, 133.1, 137.3, 140.1, 153.4, 165.4, 189.6, 191.0. FTIR (film): 1016, 115582, 1218, 1286, 1380, 1452, 1519, 1656, 1681, 1751, 2858, 2935, 3020, 3350 cm-1. LRMS (EI) m/z 293.1 (M+H+). 125 Chapter (102c) (E)-5,5-dimethyl-4-oxohex-2-enyl 3-(ethylthio)-3-oxopropanoate Colorless oil, 70% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 1.12 (s, 9H), 1.24 (t, 3H, J = 7.5 Hz), 2.90 (dd, 2H, J = 7.5, 14.7 Hz), 3.61 (s, 2H), 4.80 (dd, 2H, J = 2.1, 4.5 Hz), 6.68 (dt, 1H, J = 1.7, 15.3 Hz), 6.81 (dt, 1H, J = 4.2, 15.3 Hz). 13C NMR (75 MHz, CDCl3, ppm): δ 14.3, 24.0, 25.9, 43.1, 49.3, 63.9, 124.6, 138.2, 165.3, 190.8, 203.4. FTIR (film): 1020, 1259, 1460, 1635, 1684, 1744, 2855, 2928, 2961, 3427 cm-1. LRMS (EI) m/z 272.1 (M+). (102d) (E)-4-ethoxy-4-oxobut-2-enyl ethyl malonate Colorless oil, 72% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (t, 6H, J = 7.3 Hz), 3.43 (s, 2H), 4.16-4.25 (m, 4H), 4.80 (dd, 2H, J = 2.0, 4.5 Hz), 6.02 (dt, 1H, J = 1.7, 15.7 Hz), 6.90 (dt, 1H, J = 4.5, 15.7 Hz). 13C NMR (75 MHz, CDCl3, ppm): δ 14.0, 14.1, 41.3, 60.6, 61.7, 63.3, 122.6, 140.2, 165.6, 165.8, 166.1. FTIR (film): 1032, 1182, 1277, 1333, 1369, 1452, 1641, 1653, 1720, 3427 cm-1. LRMS (EI) m/z 267.2 (M+Na+). (102e) (E)-4-(naphthalen-2-yl)-4-oxobut-2-enyl 3-(ethylthio)-3-oxopropanoate 126 Chapter Colorless oil, 70% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (m, 3H), 2.99 (m, 2H), 3.74 (s, 2H), 4.98 (t, 2H, J = 2.1 Hz), 7.06 (dt, 1H, J = 4.2, 15.5 Hz), 7.35 (dt, 1H, J = 1.5, 15.6 Hz), 7.52-7.62 (m, 2H), 7.88 (t, 2H, J = 8.2 Hz), 8.05 (q, 2H, J = 8.2, 19.2 Hz), 8.58 (s, 1H). 13C NMR (75 MHz, CDCl3, ppm): δ 14.4, 24.1, 49.4, 64.0, 124.3, 125.6, 126.7, 127.7, 128.5, 129.5, 130.5, 132.5, 134.5, 135.5, 140.0, 165.4, 189.3, 191.1. FTIR (film): 1020, 1182, 1228, 1271, 1456, 1525, 1645, 1692, 1745, 2856, 2934, 3057 cm-1. LRMS (EI) m/z 342.0 (M+). (102f) (E)-4-(biphenyl-4-yl)-4-oxobut-2-enyl 3-(ethylthio)-3-oxopropanoate Colorless oil, 70% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (t, 3H, J = 7.5 Hz), 2.95 (dd, 2H, J = 7.3, 15.0 Hz), 3.69 (s, 2H), 4.98 (dd, 2H, J = 1.7, 4.2 Hz), 7.01 (dt, 1H, J = 4.2, 15.3 Hz), 7.24 (d, 1H, J = 15.6 Hz), 7.39-7.48 (m, 3H), 7.63 (q, 4H, J = 8.4, 20.9 Hz), 8.05 (d, 2H, J = 8.4 Hz). 13C NMR (75 MHz, CDCl3, ppm): δ 14.4, 24.1, 49.4, 64.0, 125.8, 127.2, 128.2, 128.9, 129.3, 136.0, 139.8, 140.0, 145.8, 165.4, 189.1, 191.0. FTIR (film): 1031, 1149, 1282, 1328, 1633, 1747, 2856, 2933, 3419 cm-1. LRMS (EI) m/z 368.1 (M+). 127 Chapter (102g) (E)-4-oxo-4-p-tolylbut-2-enyl 3-(ethylthio)-3-oxopropanoate Colorless oil, 72% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 1.26 (t, 3H, J = 7.3 Hz), 2.39 (s, 3H), 2.95 (dd, 2H, J = 7.5, 15.0 Hz), 3.67 (s, 2H), 4.90 (dd, 2H, J = 1.8, 4.3 Hz), 6.94 (dt, 1H, J = 4.3, 15.5 Hz), 7.17 (dt, 1H, J = 1.8, 15.5 Hz), 7.24 (d, 2H, J = 8.1 Hz), 7.86 (d, 2H, J = 8.2 Hz). 13C NMR (75 MHz, CDCl3, ppm): δ 14.3, 21.6, 24.0, 49.3, 64.0, 125.8, 128.8, 129.3, 134.7, 139.5, 143.9, 165.4, 189.0, 190.9. FTIR (film): 1013, 1149, 1265, 1648, 1692, 1733, 2817, 2856, 2911, 3237, 3419 cm-1. LRMS (EI) m/z 306.1 (M+). (102h) (E)-4-(4-cyanophenyl)-4-oxobut-2-enyl 3-(ethylthio)-3-oxopropanoate Colorless oil, 72% yield. 1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (t, 3H, J = 7.3 Hz), 2.95 (dd, 2H, J = 7.5, 15.0 Hz), 3.68 (s, 2H), 4.92 (dd, 2H, J = 1.4, 3.8 Hz), 6.99 (dt, 1H, J = 4.0, 15.3 Hz), 7.11 (d, 1H, J = 15.7 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.85 (d, 2H, J = 8.7 Hz ). 13 C NMR (75 MHz, CDCl3, ppm): δ 14.3, 24.1, 49.4, 63.9, 125.2, 128.3, 130.2, 131.9, 136.0, 140.7, 165.3, 188.4, 191.1. FTIR (film): 1008, 1069, 1147, 1282, 1584, 1629, 1673, 1745, 2925 cm-1. LRMS (ESI) m/z 316.4 (M-H+). 128 Chapter 5.6.3 TBD catalyzed intramolecular Michael additions 5.6.3.1 General procedure for TBD catalyzed intramolecular Michael additions To a solution of the substrate 102 (0.1 mmol, 1.0 eq.) in CH2Cl2 (1 mL) under nitrogen was added TBD (2.8 mg, 0.02 mmol, 0.2 eq.). The reaction was stirred at room temperature and monitored by TLC. After starting material 102 disappeared, the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/EA mixture, 4/1). 5.6.3.2 Characterization of disubstituted γ-lactones 104a-d (104a) 3-benzoyl-4-(2-oxo-2-phenylethyl)dihydrofuran-2(3H)-one H NMR (300 MHz, CDCl3, ppm): δ 3.26 (dd, 1H, J = 8.0, 17.6Hz), 3.38 (dd, 1H, J = 6.1, 17.8 Hz), 3.78 (td, 1H, J = 6.3, 13.8 Hz), 4.20 (dd, 1H, J = 6.1, 9.1 Hz), 4.48 (d, 1H, J = 6.6 Hz), 4.90 (dd, 1H, J = 7.4, 9.2 Hz), 7.48-7.70 (m, 6H), 7.60 (d, 2H, J = 7.2 Hz), 7.85 (d, 2H, J = 7.2 Hz ). (104b) S-ethyl 2-oxo-4-(2-oxo-2-phenylethyl)tetrahydrofuran-3-carbothioate 129 Chapter H NMR (300 MHz, CDCl3, ppm): δ 1.31 (t, 3H, J = 7.5 Hz), 2.99 (dd, 2H, J = 7.3, 15.5 Hz), 3.17 (dd, 1H, J = 8.4, 17.8 Hz), 3.40 (dd, 1H, J = 4.8, 18.1 Hz), 3.52-3.59 (m, 2H), 4.02 (dd, 1H, J = 6.7, 9.1 Hz), 4.81 (dd, 1H, J = 7.0, 9.1 Hz), 7.49 (t, 2H, J = 7.8 Hz), 7.61 (d, 1H, J = 7.5 Hz), 7.92(d, 2H, J = 7.2 Hz ). (104c) S-ethyl 4-(3,3-dimethyl-2-oxobutyl)-2-oxotetrahydrofuran-3-carbothioate H NMR (300 MHz, CDCl3, ppm): δ 1.18 (s, 9H), 1.33 (t, 3H, J = 7.5 Hz), 2.72 (dd, 1H, J = 8.7, 18.1 Hz), 2.90 (dd, 1H, J = 5.1, 18.2 Hz), 3.00 (dd, 2H, J = 7.4, 18.0 Hz), 3.33 (td, 1H, J = 7.5, 14.4 Hz), 3.47 (d, 1H, J = 7.7 Hz), 3.92 (dd, 1H, J = 6.7, 9.2 Hz), 4.72 (dd, 1H, J = 7.6, 9.0 Hz). (104d) ethyl 4-(2-ethoxy-2-oxoethyl)-2-oxotetrahydrofuran-3-carboxylate H NMR (300 MHz, CDCl3, ppm): δ 1.24-1.34 (m, 6H), 2.47-2.66 (m, 2H), 3.33-3.36 (m, 2H), 4.03 (t, 1H, J = 7.7 Hz), 4.14 (dd, 2H, J = 6.9, 14.3 Hz), 4.26 (dd, 2H, J = 6.9, 14.3 Hz), 4.65 (dd, 1H, J = 7.5, 9.0 Hz). 130 Chapter 5.6.4 Cinchona alkaloids catalyzed intramolecular Michael additions 5.6.4.1 General procedure for Cinchona alkaloids catalyzed intramolecular Michael additions To a solution of the substrate 102 (0.05 mmol, 1.0 eq.) in CH2Cl2 (1 mL) under nitrogen was added Cinchona alkaloid (0.01 mmol, 0.2 eq.). The reaction was stirred at room temperature and monitored by TLC. After starting material 102 disappeared, the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/EA mixture, 4/1) to give the disubstitued γ-lactone 104. 5.6.4.2 General procedure for the synthesis of γ-lactones 105 by decarboxylation of thioester To a solution of disubstitued γ-lactone 104 in DMSO/H2O (10:1, V/V, mL) was added NaCl (solid, 3.0 eq.). The reaction mixture was stirred overnight at 110 oC. After cooling to room temperature, the mixture was diluted with water (2 mL) and extracted with ether (3 x mL). The combined organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel to give mono substituted γ-lactone 105 in quantitative yield. 5.6.4.3 Characterization of mono substituted γ-lactones 105a-e 131 Chapter (105a) 4-(2-oxo-2-phenylethyl)dihydrofuran-2(3H)-one White solid, 76% yield, 77% ee. Mp = 105-106 oC. 1H NMR (300 MHz, CDCl3, ppm): 2.27 (dd, 1H, J = 6.6, 17.4 Hz), 2.82 (dd, 1H, J = 7.7, 17.4 Hz), 3.16-3.29 (m, 3H), 4.03 (dd, 1H, J = 5.9, 9.4 Hz), 4.64 (dd, 1H, J = 6.6, 9.0 Hz), 7.49 (t, 2H, J = 7.5 Hz), 7.60(t, 2H, J = 7.2 Hz), 7.93 (d, 2H, J = 7.3 Hz). LRMS (ESI) m/z 227.2 (M+Na+), HRMS (ESI) m/z 227.0668 (M+Na+), calc. for C12H12O3Na 227.0679. The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 80/20; flow rate 1.0 mL/min; temp 25 °C; detection UV 210 nm; retention time: 23.6 (minor) and 26.0 (major). 132 Chapter (105b) 4-(2-(naphthalen-2-yl)-2-oxoethyl)dihydrofuran-2(3H)-one White solid, 70% yield, 70% ee. Mp = 106-108 oC. 1H NMR (300 MHz, CDCl3, ppm): δ 2.31 (dd, 1H, J = 7.0, 17.4 Hz), 2.84 (dd, 1H, J = 7.4, 17.4 Hz), 3.18-3.44 (m, 3H), 4.07 (dd, 1H, J = 6.3, 9.0 Hz), 4.67 (dd, 1H, J = 7.0, 9.0 Hz), 7.55-7.65 (m, 2H), 7.87-8.00 (m, 4H), 8.45 (s, 1H). 13C NMR (75 MHz, CDCl3, ppm): δ 31.2, 34.3, 41.9, 73.2, 123.4, 127.0, 127.8, 128.7, 128.8, 129.5, 129.8, 132.4, 133.5, 135.8, 176.6, 197.3. FTIR (film): 896, 1020, 1176, 1217, 1257, 1422, 1681, 1777, 2305, 2929, 2987, 3054 cm-1. LRMS (ESI) m/z 277.1 (M+Na+), HRMS (ESI) m/z 277.0844 (M+Na+), calc. for C16H14O3Na 277.0835. The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 80/20; flow rate 0.5 mL/min; temp 25 °C; detection UV 230 nm; retention time: 79.9 (minor) and 88.9 (major). 133 Chapter (105c) 4-(2-(biphenyl-4-yl)-2-oxoethyl)dihydrofuran-2(3H)-one White solid, 21% yield, 20% ee. Mp = 170-172 oC. 1H NMR (300 MHz, CDCl3, ppm): δ 2.29 (dd, 1H, J = 6.4, 17.7 Hz), 2.84 (dd, 1H, J = 8.0, 17.7 Hz), 3.23-3.35 (m, 3H), 4.05 (dd, 1H, J = 5.9, 9.4 Hz), 4.66 (dd, 1H, J = 6.7, 9.2 Hz), 7.39-7.50 (m, 3H), 7.62 (d, 2H, J = 8.7 Hz), 7.69 (d, 2H, J = 8.4 Hz), 8.00 (d, 2H, J = 8.4 Hz). 13C NMR (75 MHz, CDCl3, ppm): δ 31.1, 34.2, 41.9, 73.2, 127.2, 127.4, 128.4, 128.5, 129.0, 132.0, 132.1, 134.8, 139.6, 146.4, 176.6, 196.9. FTIR (film): 829, 1020, 1172, 1201, 1224, 1258, 1401, 1679, 1786, 2848, 2987, 3054 cm-1. LRMS (ESI) m/z 281.2 (M+H+). 134 Chapter The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 60/40; flow rate 1.0 mL/min; temp 25 °C; detection UV 254 nm; retention time: 34.4 (minor) and 50.2 (major). (105d) 4-(2-oxo-2-p-tolylethyl)dihydrofuran-2(3H)-one White solid, 74% yield, 60% ee. Mp = 90-92 oC. 1H NMR (300 MHz, CDCl3, ppm): δ 2.26 (dd, 1H, J = 6.6, 17.7 Hz), 2.42 (s, 3H), 2.79 (dd, 1H, J = 8.1, 17.7 Hz), 3.12-3.26 (m, 3H), 4.02 (dd, 1H, J = 5.9, 9.4 Hz), 4.63 (dd, 1H, J = 7.0, 9.4 Hz), 7.29 (d, 2H, J = 9.4 Hz), 7.82 (d, 2H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3, ppm): δ 21.6, 31.1, 34.2, 41.7, 73.2, 128.0, 129.5, 133.7, 144.6, 176.6, 196.9. FTIR (film): 810, 1016, 1180, 135 Chapter 1223, 1265, 1294, 1371, 1409, 1606, 1679, 1777, 2848, 2916, 3054 cm-1. LRMS (ESI) m/z 219.2 (M+H+). The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 80/20; flow rate 0.5 mL/min; temp 25 °C; detection UV 230 nm; retention time: 46.7 (minor) and 52.8 (major). (105e) 4-(2-(5-oxotetrahydrofuran-3-yl)acetyl)benzonitrile White solid, 67% yield, 66% ee. Mp = 82-84 oC. 1H NMR (300 MHz, CDCl3, ppm): δ 2.26 (dd, 1H, J = 6.6, 17.7 Hz), 2.81 (dd, 1H, J = 8.0, 17.4 Hz), 3.15-3.25 (m, 3H), 4.02 (dd, 1H, J = 5.6, 9.4 Hz), 4.63 (dd, 1H, J = 7.1, 9.2 Hz), 7.61 (d, 2H, J = 8.7 Hz), 7.78(d, 136 Chapter 2H, J = 8.4 Hz). 13C NMR (75 MHz, CDCl3, ppm): δ 30.9, 34.2, 41.8, 73.0, 129.0 129.4, 132.1, 134.8, 176.4, 196.3. FTIR (film): 815, 1010, 1071, 1175, 1396, 1483, 1585, 1686, 1770, 2910, 3054 cm-1. LRMS (EI) m/z 252.6 (M+Na+). The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OB-H (4.6 mm i.d. x 250 mm); hexane/2-propanol 70/30; flow rate 1.0 mL/min; temp 25 °C; detection UV 230 nm; retention time: 44.9 (minor) and 51.0 (major). 137 Chapter References: [1] Seitz , M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285. [2] Collins, I. J. Chem. Soc., Perkin Trans. I 1999, 1377. [3] El Ali, B.; Alper, H. Synlett 2000, 161. [4] Miyabe, M.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000, 2, 4071. [5] Miyabe, M.; Ueda, M.; Fujii, K.; Nishimura, A.; Naito, T. J. Org. Chem. 2003, 68, 5618. [6] Rodríguez, C. M.; Ravelo, J. L.; Martín, V. S. Org. Lett. 2004, 6, 4787. [7] Ravelo, J. L.; Rodríguez, C. M.; Martín, V. S. J. Organomet. Chem. 2006, 691, 5326. [8] Anac, O.; Güngör, F. S.; Merey, G. Helv. Chim. Acta. 2006, 89, 1231. [9] Recent examples: (a) Fustero, S.; Jiménez, S. D.; Moscardó, J.; Catalán, S.; del Pozo, G. Org. Lett., 2007, 9, 5283. (b) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter, R. G. J. Org. Chem. 2008, 73, 5155. (c) Saito, N.; Ryoda, A.; Nakanishi, W.; Kumamoto, T.; Ishikawa, T. Eur. J. Org. Chem., 2008, 2759. (d) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2008, 47, 1. (e) Greshock, T. J.; Funk, R. L. Tetrahedron Lett. 2006, 47, 5437. [10] Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink. E. R. T. J. Org. Chem. 2003, 68, 4239. [11] Shelkow, R.; Nahmany, M.; Melman, A. Org. Biomol. Chem. 2004, 2, 397. [12] Ye, W.; Xu, J.; Tan, C.-T.; Tan, C.-H. Tetrahedron Lett. 2005, 46, 6875. 138 Chapter [13] Selected examples of Michael reactions catalyzed by cinchona alkaloids: (a) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105. (b) Bella, M.; Jørgenson, K. A. J. Am. Chem. Soc. 2004, 126, 5672. (c) Vakulya, B.; Varga, S.; Csámpai A.; Soós, T. Org. Lett. 2005, 7, 1967.ctical Synthesis of 139 [...]... Hz), 6. 95 (dt, 1H, J = 4.2, 15. 7 Hz), 7.14 (dd, 1H, J = 1.7, 15. 7 Hz), 7. 45 (t, 2H, J = 7 .5 Hz), 7 .55 (t, 1H, J = 7.3 Hz), 7. 95 (m, 2H) 13C NMR ( 75 MHz, CDCl3, ppm): δ 14.4, 24.1, 49.4, 64.0, 1 25. 9, 128.7, 133.1, 137.3, 140.1, 153 .4, 1 65. 4, 189.6, 191.0 FTIR (film): 1016, 1 155 82, 1218, 1286, 1380, 1 452 , 151 9, 1 656 , 1681, 1 751 , 2 858 , 29 35, 3020, 3 350 cm-1 LRMS (EI) m/z 293.1 (M+H+) 1 25 Chapter 5 (102c)... Hz), 7. 35 (dt, 1H, J = 1 .5, 15. 6 Hz), 7 .52 -7.62 (m, 2H), 7.88 (t, 2H, J = 8.2 Hz), 8. 05 (q, 2H, J = 8.2, 19.2 Hz), 8 .58 (s, 1H) 13C NMR ( 75 MHz, CDCl3, ppm): δ 14.4, 24.1, 49.4, 64.0, 124.3, 1 25. 6, 126.7, 127.7, 128 .5, 129 .5, 130 .5, 132 .5, 134 .5, 1 35. 5, 140.0, 1 65. 4, 189.3, 191.1 FTIR (film): 1020, 1182, 1228, 1271, 1 456 , 152 5, 16 45, 1692, 17 45, 2 856 , 2934, 3 057 cm-1 LRMS (EI) m/z 342.0 (M+) (102f)... 15. 0 Hz), 3.68 (s, 2H), 4.92 (dd, 2H, J = 1.4, 3.8 Hz), 6.99 (dt, 1H, J = 4.0, 15. 3 Hz), 7.11 (d, 1H, J = 15. 7 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7. 85 (d, 2H, J = 8.7 Hz ) 13 C NMR ( 75 MHz, CDCl3, ppm): δ 14.3, 24.1, 49.4, 63.9, 1 25. 2, 128.3, 130.2, 131.9, 136.0, 140.7, 1 65. 3, 188.4, 191.1 FTIR (film): 1008, 1069, 1147, 1282, 158 4, 1629, 1673, 17 45, 29 25 cm-1 LRMS (ESI) m/z 316.4 (M-H+) 128 Chapter 5 5.6.3... = 7.0, 9.0 Hz), 7 .55 -7. 65 (m, 2H), 7.87-8.00 (m, 4H), 8. 45 (s, 1H) 13C NMR ( 75 MHz, CDCl3, ppm): δ 31.2, 34.3, 41.9, 73.2, 123.4, 127.0, 127.8, 128.7, 128.8, 129 .5, 129.8, 132.4, 133 .5, 1 35. 8, 176.6, 197.3 FTIR (film): 896, 1020, 1176, 1217, 1 257 , 1422, 1681, 1777, 23 05, 2929, 2987, 3 054 cm-1 LRMS (ESI) m/z 277.1 (M+Na+), HRMS (ESI) m/z 277.0844 (M+Na+), calc for C16H14O3Na 277.08 35 The enantiomeric... (102c) (E) -5, 5-dimethyl-4-oxohex-2-enyl 3-(ethylthio)-3-oxopropanoate Colorless oil, 70% yield 1H NMR (300 MHz, CDCl3, ppm): δ 1.12 (s, 9H), 1.24 (t, 3H, J = 7 .5 Hz), 2.90 (dd, 2H, J = 7 .5, 14.7 Hz), 3.61 (s, 2H), 4.80 (dd, 2H, J = 2.1, 4 .5 Hz), 6.68 (dt, 1H, J = 1.7, 15. 3 Hz), 6.81 (dt, 1H, J = 4.2, 15. 3 Hz) 13C NMR ( 75 MHz, CDCl3, ppm): δ 14.3, 24.0, 25. 9, 43.1, 49.3, 63.9, 124.6, 138.2, 1 65. 3, 190.8,... CDCl3, ppm): δ 1.28 (t, 3H, J = 7 .5 Hz), 2. 95 (dd, 2H, J = 7.3, 15. 0 Hz), 3.69 (s, 2H), 4.98 (dd, 2H, J = 1.7, 4.2 Hz), 7.01 (dt, 1H, J = 4.2, 15. 3 Hz), 7.24 (d, 1H, J = 15. 6 Hz), 7.39-7.48 (m, 3H), 7.63 (q, 4H, J = 8.4, 20.9 Hz), 8. 05 (d, 2H, J = 8.4 Hz) 13C NMR ( 75 MHz, CDCl3, ppm): δ 14.4, 24.1, 49.4, 64.0, 1 25. 8, 127.2, 128.2, 128.9, 129.3, 136.0, 139.8, 140.0, 1 45. 8, 1 65. 4, 189.1, 191.0 FTIR (film):... 203.4 FTIR (film): 1020, 1 259 , 1460, 16 35, 1684, 1744, 2 855 , 2928, 2961, 3427 cm-1 LRMS (EI) m/z 272.1 (M+) (102d) (E)-4-ethoxy-4-oxobut-2-enyl ethyl malonate Colorless oil, 72% yield 1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (t, 6H, J = 7.3 Hz), 3.43 (s, 2H), 4.16-4. 25 (m, 4H), 4.80 (dd, 2H, J = 2.0, 4 .5 Hz), 6.02 (dt, 1H, J = 1.7, 15. 7 Hz), 6.90 (dt, 1H, J = 4 .5, 15. 7 Hz) 13C NMR ( 75 MHz, CDCl3, ppm): δ 14.0,... 1 05 in quantitative yield 5. 6.4.3 Characterization of mono substituted γ-lactones 105a-e 131 Chapter 5 (105a) 4-(2-oxo-2-phenylethyl)dihydrofuran-2(3H)-one White solid, 76% yield, 77% ee Mp = 1 05- 106 oC 1H NMR (300 MHz, CDCl3, ppm): 2.27 (dd, 1H, J = 6.6, 17.4 Hz), 2.82 (dd, 1H, J = 7.7, 17.4 Hz), 3.16-3.29 (m, 3H), 4.03 (dd, 1H, J = 5. 9, 9.4 Hz), 4.64 (dd, 1H, J = 6.6, 9.0 Hz), 7.49 (t, 2H, J = 7 .5. .. 1 65. 6, 1 65. 8, 166.1 FTIR (film): 1032, 1182, 1277, 1333, 1369, 1 452 , 1641, 1 653 , 1720, 3427 cm-1 LRMS (EI) m/z 267.2 (M+Na+) (102e) (E)-4-(naphthalen-2-yl)-4-oxobut-2-enyl 3-(ethylthio)-3-oxopropanoate 126 Chapter 5 Colorless oil, 70% yield 1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (m, 3H), 2.99 (m, 2H), 3.74 (s, 2H), 4.98 (t, 2H, J = 2.1 Hz), 7.06 (dt, 1H, J = 4.2, 15. 5 Hz), 7. 35 (dt, 1H, J = 1 .5, 15. 6... mm i.d x 250 mm); hexane/2-propanol 80/20; flow rate 0 .5 mL/min; temp 25 ° C; detection UV 230 nm; retention time: 46.7 min (minor) and 52 .8 min (major) (105e) 4-(2- (5- oxotetrahydrofuran-3-yl)acetyl)benzonitrile White solid, 67% yield, 66% ee Mp = 82-84 oC 1H NMR (300 MHz, CDCl3, ppm): δ 2.26 (dd, 1H, J = 6.6, 17.7 Hz), 2.81 (dd, 1H, J = 8.0, 17.4 Hz), 3. 15- 3. 25 (m, 3H), 4.02 (dd, 1H, J = 5. 6, 9.4 Hz), . 1 25. 6, 126.7, 127.7, 128 .5, 129 .5, 130 .5, 132 .5, 134 .5, 1 35. 5, 140.0, 1 65. 4, 189.3, 191.1. FTIR (film): 1020, 1182, 1228, 1271, 1 456 , 152 5, 16 45, 1692, 17 45, 2 856 , 2934, 3 057 cm -1 . LRMS (EI). ( 75 MHz, CDCl 3 , ppm): δ 14.4, 24.1, 49.4, 64.0, 1 25. 9, 128.7, 133.1, 137.3, 140.1, 153 .4, 1 65. 4, 189.6, 191.0. FTIR (film): 1016, 1 155 82, 1218, 1286, 1380, 1 452 , 151 9, 1 656 , 1681, 1 751 , 2 858 ,. 7.3, 15. 0 Hz), 3.69 (s, 2H), 4.91 (dd, 2H, J = 1.7, 4.2 Hz), 6. 95 (dt, 1H, J = 4.2, 15. 7 Hz), 7.14 (dd, 1H, J = 1.7, 15. 7 Hz), 7. 45 (t, 2H, J = 7 .5 Hz), 7 .55 (t, 1H, J = 7.3 Hz), 7. 95 (m, 2H).