When the catalyzed addition of 1.58l to 1.49a was carried out in dioxane:D2O (10:1), partial deuterium incorporation was observed at both the − and −positions of 1.53l (Scheme 1-23). The fact that the product is obtained with less than 100% of 1H exchange carries implications for the mechanism
48
of the obligatory 1,3-prototropy, and suggests that it transpires at least in part via ion pair with [R3N- H]+, rather than D2O, as the partner that reacts with the dienolate.56b
Scheme 1-22. Secondary Transformations of 1.53a
Scheme 1-23. Reaction of 1.49a and 1.58l in D2O
1.8 Conclusions
In summary, we have developed an enantioconvergent 1,4-arylation of −substituted
−unsaturated butenolides. This reaction is one of the first dynamic kinetic resolutions that takes advantage of racemization of a −stereocenter through formation of a dienolate. A wide range of −aryl,
−substituted −butyrolactones can be accessed in good yields, excellent enantioselectivities, and as a single diastereomer. These lactones can be further manipulated to generate useful organic building
49
blocks, including 1,4-diols and 1,4-amino alcohols. Additionally, the products can be diastereoselectively alkylated to afford stereochemically complex trisubstituted lactones. Extension of this work to other classes of nucleophiles, as well as application of the DKR conjugate addition manifold to additional substrates is currently underway in our laboratory.
50
1.9 Experimental DetailsGeneral Methods
All air-free reactions were carried out under an atmosphere of nitrogen. Thin layer chromatography (TLC) was performed on Sorbtech plastic-backed 0.20 mm silica gel 60 plates. Visualization was accomplished with UV light and either an aqueous ceric ammonium molybdate (CAM) or potassium permanganate (KMnO4) solution, followed by heating. Flash chromatography was performed under positive air pressure using Siliaflash-P60 silica gel (40-63 μm) purchased from Silicycle. Yields and enantiomeric ratios reported for the enantioconvergent arylation reactions represents the average of two trials.
Instrumentation
1H NMR and 13C NMR spectra were recorded on either a Bruker model DRX 500 or 600 (cryoprobe equipped) spectrometer. The spectra were calibrated using residual solvent resonances: 1H NMR (CDCl3 at 7.26 ppm), 13C NMR (CDCl3 at 77.16 ppm). 1H NMR data are reported as follows: chemical shift, multiplicity (abbreviations: s = singlet, br s = broad singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of doublets, dt = doublet of triplets, t = triplet, td = triplet of doublets, tt = triplet of triplets, qt = quintet, and m = multiplet), coupling constant (Hz) and integration. High resolution mass spectrometry (HRMS) was performed using a Thermo Scientific LTQ FT Ultra mass spectrometer S2 with direct infusion in either the positive or negative ion mode. Samples were prepared in HPLC grade methanol. High performance liquid chromatography (HPLC) was performed on a Perkin Elmer Flexar® HPLC system equipped with PDA detector. Optical rotations were measured using a 2 mL cell with a 1 dm path length on a Jasco DIP 1000 digital polarimeter. Infrared (IR) spectra were obtained using a Jasco 260 Plus Fourier Transform Infrared Spectrometer.
Materials
Anhydrous 1,4-dioxane, 98% was purchased from Sigma Aldrich and stored under 4Å MS in a Schlenk flask in an N2-filled glovebox. All other solvents were purified by passage through a column packed
51
with activated aluminum under N2 pressure. Phenylboronic acid was recrystallized from water. All other boronic acids were used as received. All boronic acids were stored in an N2 filled glovebox. α- Angelica lactone was purchased from Oakwood Chemical and used as received. α-Angelica lactone was stored in an N2 filled glovebox. Hydroxy[-(S)-BINAP]-rhodium(I) dimer was purchased from Sigma Aldrich and used as received or prepared according to the method reported by Hayashi.81 Hydroxy[-(S)-BINAP]-rhodium(I) dimer was stored in an N2-filled glovebox. All other catalysts were prepared according to known literature procedures.78
Procedure for Optimization Experiments:
(Rh[(S)-BINAP]OH)2, boron source, and inorganic base were added to a flame-dried 1-dram vial in a N2-filled glovebox. Dry solvent and -angelica lactone were added via micropipette. The reaction was capped with a PTFE/silicone cap and removed from the glovebox. Organic base and water were added. The reaction was sealed with electrical tape and heated to 60 ºC for 24 h. After 24 h, the reaction was filtered through a silica gel plug with EtOAc, and concentrated in vacuo.
Procedure for Preparation of Racemic Standards:
[Rh(cod)Cl]2 (0.986 mg, 0.00200 mmol, 2 mol %), arylboronic acid (0.200 mmol, 2 equiv), and K2CO3 (41.5 mg, 0.300 mmol, 3 equiv) were added to a flame-dried 1-dram vial in a N2-filled glovebox. Dry toluene (0.5 mL), −substituted −unsaturated butenolides (0.100 mmol), and triethylamine (10.1 mg, 0.100 mmol, 1 equiv) were added via micropipette. The reaction was capped with a PTFE/silicone cap and removed from the glovebox. Water (0.05 mL) was added. The reaction was sealed with electrical tape and heated to 60 ºC for 24 h. After 24 h, the reaction was filtered through a silica gel plug with EtOAc, and concentrated in vacuo. The compounds were purified on silica gel via column chromatography using a gradient of 5% EtOAc:hexanes to 20% EtOAc:hexanes.
52
General Procedure A: Preparation of 5-Alkyl-2(3H)-furanone Starting Materials:
The substrates were prepared via a modified literature method.56b,82
Step 1: Methyl (triphenylphosphoranylidene)acetate (1 equiv) was dissolved in dry DCM (0.2 M) and 4Å molecular sieves (~0.5 g) were added. Triethylamine (1.09 equiv) was added to the flask. The acid chloride (0.90 equiv) was added slowly, and allowed to stir at room temperature. After 16 h, the reaction was filtered through cotton to remove molecular sieves, and concentrated in vacuo. The residue was triturated with pentane (~100 mL) twice, and the filtrates were concentrated in vacuo. The crude allene was purified on silica gel using a gradient of 2.5% EtOAc:hexanes to 10% EtOAc:hexanes to afford a mixture of allene and alkyne products.
Step 2: The allene/alkyne mixture was dissolved in a mixture of 1:1 THF:H2O (0.15 M). Lithium hydroxide (5 equiv) was added and the reaction was allowed to stir at room temperature. After 15 min, the reaction was diluted with water and extracted with diethyl ether (3x); the organic layers were discarded. The aqueous layer was then acidified to pH = 1 using 1 M HCl and extracted with diethyl ether. The organic layers were dried with anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to afford a mixture of the desired allene and alkyne. The mixture of products was taken onto the next step without further purification.
53
Step 3: The mixture of allene/alkyne was dissolved in acetone (0.17 M) in an aluminum foil-covered round bottom flask. Silver nitrate (0.2 equiv) was added and the reaction headspace was purged with nitrogen. The reaction was allowed to stir in the dark overnight at room temperature. The reaction was filtered through a pad of silica gel with diethyl ether. Some substrates are obtained as a mixture of isomers; the isomers can be separated by silica gel column chromatography.
5-heptylfuran-2(3H)-one (1.49c): The title compound was prepared according to General Procedure A using nonanoyl chloride (0.910 g, 5.15 mmol) affording 1.49c (0.425 g, 2.33 mmol, 45% yield over three steps) as a light-yellow oil. Analytical data for 1.49c: 1H
NMR (600 MHz, CDCl3) 5.13 (m, 1H), 3.20 (q, J = 2.4, 4.8 Hz, 2H), 2.32-2.29 (m, 2H), 1.60-1.55 (m, 2H), 1.35-1.28 (m, 8H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3): 177.2, 157.3,
98.2, 34.0, 31.7, 29.0, 29.0, 28.3, 25.7, 22.6, 14.1; IR (thin film): 3790, 3661, 2950, 1797, 1677, 1582, 1549, 1529, 1104, 930; TLC (hexane:EtOAc 70:30) Rf = 0.56; HRMS (ESI): Calcd. for C11H18O2+H2O: ([M+NH4]): 223.1310, Found: 223.1303.
5-(cyclopentylmethyl)furan-2(3H)-one (1.49d): The title compound was prepared according to General Procedure A using cyclopentanepropionyl chloride (2.89 g, 18.0 mmol) affording 1.49d (1.36 g, 8.15 mmol, 45% yield over three steps) as a light-yellow oil. Analytical data for 1.49d: 1H NMR (600 MHz, CDCl3) 5.14 (m, 1H), 3.20 (q, J = 2.1, 4.5 Hz,
2H), 2.31-2.29 (m, 2H), 2.15 (m, 1H), 1.85-1.79 (m, 2H), 1.67-1.54 (m, 4H), 1.23-1.17 (m, 2H); 13C
NMR (151 MHz, CDCl3): 177.2, 157.1, 98.7, 36.6, 34.5, 34.0, 32.4, 25.0; IR (thin film): 2951, 1798, 1266, 1105, 930, 744; TLC (hexane:EtOAc 70:30) Rf = 0.59; HRMS (ESI): Calcd. for C10H14O2+H2O: ([M+NH4]): 207.0997 Found: 207.0990.
General Procedure B: Rh-Catalyzed Arylation of 5-Substituted-2(3H)-furanones: A flame-dried 1-dram vial was cooled under a stream of N2, and charged with the appropriate lactone (0.200 mmol, 1 equiv). The vial was purged with N2, capped with a PTFE/silicone cap, and transferred to a N2-filled glovebox. The vial was then charged with hydroxy[-(S)-BINAP]-rhodium(I) dimer (5.95 mg, 0.02
54
equiv, 4.00 μmol), phenylboronic acid (48.8 mg, 2 equiv, 0.400 mmol), and K2CO3 (27.6 mg1 equiv, 0.200 mmol). 1,4-Dioxane (0.45 mL) was added, the vial was capped with a PTFE/silicone cap and removed from the glovebox. N-Methylpyrrolidine (170 mg,10 equiv, 2.00 mmol) and water (0.05 mL) were added, the vial was sealed with electrical tape, and the reaction was heated to 60 ºC for 1 h. The reaction mixture was filtered through a silica gel plug with EtOAc and concentrated.
General Procedure C: Rh-Catalyzed Arylation of -Angelica Lactone: A flame-dried vial was transferred to a N2-filled glovebox. The vial was then charged with hydroxy[-(S)-BINAP]-rhodium(I) dimer (2.97 mg, 0.02 equiv, 2.00 μmol), appropriate aryl boronic acid (2 equiv, 2.00 mmol), and K2CO3 (0.05-1 equiv; See Table 3). 1,4-Dioxane (0.225 mL) and -angelica lactone (9.81 mg, 1 equiv, 0.100 mmol) were added, the vial was capped with a PTFE/silicone cap and removed from the glovebox. N- Methylpyrrolidine (85.2 mg, 10 equiv, 1.00 mmol) and water (0.025 mL) were added, the vial was sealed with electrical tape, and the reaction was heated to 60 ºC for one h. The reaction mixture was filtered through a silica gel plug with EtOAc and concentrated.
(4S,5S)-5-methyl-4-phenyldihydrofuran-2(3H)-one (1.53a): The title compound was prepared according to General Procedure C using phenylboronic acid (0.049 g, 0.40 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.029 g (82%) 1.53a as an amorphous white solid. Analytical data for 1.53a: 1H NMR (600 MHz, CDCl3); 7.27-7.42 (m, 5 H), 4.59 (m, 1H), 3.28 (m,
1H), 2.97 (dd, J = 25.2, 12.6 Hz, 1H), 2.82 (dd, J = 27.0, 16.2 Hz, 1H), 1.45 (d, J = 9.0 Hz, 3H) 13C
NMR (151 MHz, CDCl3); 175.6, 138.2, 129.1, 127.8, 127.3, 83.2, 49.7, 37.5, 19.2; IR (thin film): 3853, 3734, 1782, 1541, 1507, 1457, 1204, 1070, 940, 774, 702; HRMS (ESI+): Calcd. for C11H12O2: ([M+Na]): 199.0735, Found: 199.0727; HPLC (87.5:12.5 hexanes:iPrOH, Daicel CHIRALCEL IC): 97:3 er, tR (minor) = 24.5 min, tR (major) = 25.7 min; []D = -8.4 (c = 0.01, CHCl3); TLC (hexane:EtOAc
55
(4S,5S)-5-ethyl-4-phenyldihydrofuran-2(3H)-one (1.53b): The title compound was prepared according to General Procedure B using 5-ethylfuran-2(3H)-one (0.022 g, 0.20 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.020 g (57%) 1.53b as a clear, colorless oil. Analytical data for 1.53b: 1H NMR (600 MHz, CDCl3); 7.46-7.38 (m, 2H), 7.3 (m, 1H), 7.29-7.26
(m, 2H), 4.43 (m, 1H), 3.34 (m, 1H), 2.97 (dd, J = 17.4, 8.7 Hz, 1H), 2.78 (dd, J = 17.4, 10.2 Hz), 1.83- 1.68 (m, 2H), 1.02 (t, J = 7.5 Hz); 13C NMR (151 MHz, CDCl3) 175.8, 139.1, 129.1, 127.7, 127.3,
88.3, 47.3, 37.6, 27.0, 10.0; IR(thin film): 2934, 1780, 1457, 1200, 969, 701; HRMS (ESI+): Calcd. for C12H14O2: ([M+Na]): 213.0892, Found: 213.0884; HPLC (98:2 hexanes:iPrOH, Daicel CHIRALCEL OJ-H): 90:10 er, tR (minor) = 33.4 min, tR (major) = 31.6 min; []D = -13.3 (c = 0.01, CHCl3);
TLC (hexane:EtOAc = 70:30): Rf = 0.50.
(4S,5S)-5-heptyl-4-phenyldihydrofuran-2(3H)-one (1.53c): The title compound was prepared according to General Procedure B using 5-heptylfuran-2(3H)-one (0.036 g, 0.20 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.037 g (71%) 1.53c as a clear, colorless oil. Analytical data for 1.53c: 1H NMR (600 MHz, CDCl3) 7.41-7.38 (m, 2H), 7.33
(m, 1H), 7.28-7.26 (m, 2H), 4.47 (m, 1H), 3.32 (m, 1H), 2.97 (dd, J = 17.4, 8.7 Hz, 1H), 2.77 (dd, J = 18.0, 10.5 Hz, 1H) 1.77-1.68 (m, 2H). 1.51 (m, 1H), 1.36 (m, 1H), 1.31-1.21 (m, 8H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.8, 139.1, 129.1, 127.7, 127.3, 87.1, 47.8, 37.6, 34.1, 31.7,
29.3, 29.1, 25.7, 22.6, 14.1; IR (thin film): 3853, 3421, 2928, 2856, 2360, 1782, 1653, 1541, 1497, 1457, 1419, 1339, 1203, 1097, 965, 760, 701; HRMS (ESI+): Calcd. for C17H24O2: ([M+Na]): 283.1674, Found; 283.1666; HPLC (87.5:12.5 hexanes:iPrOH, Daicel CHIRALCEL IC): 93:7 er, tR
(minor) = 23.8 min, tR (major) = 15.2 min; []D = -30.0 (c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30):
56
(4S,5S)-5-(cyclopentylmethyl)-4-phenyldihydrofuran-2(3H)-one (1.53d): The title compound was prepared according to General Procedure B using 5- (cyclopentylmethyl)furan-2(3H)-one (0.033 g, 0.20 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.037 g (76%) 1.53d as a clear, colorless oil. Analytical data for 1.53d: 1H NMR (600 MHz, CDCl3) 7.41-7.38 (m, 2H), 7.33 (m, 1H), 7.28-7.26 (m, 2H) 4.51 (m, 1H), 3.30 (m, 1H), 2.97 (dd, J = 8.7, 17.5 Hz, 1H), 2.76 (dd, 1H), 1.99 (m, 1H), 1.83-1.72 (m, 3H), 1.65-1.47 (m, 5H), 1.11 (m, 1H), 1.01 (m, 1H); 13C NMR (151 MHz, CDCl3) 175.8, 139.0, 129.2, 127.7, 127.3, 86.6, 48.2, 40.4, 37.6, 36.9,
33.0, 32.3, 25.0, 24.9; IR (thin film): 3432, 2949, 1773, 1647, 1541, 1497, 1456, 1204, 772, 701, 544; HRMS (ESI+): Calcd. for C16H20O2: ([M+Na]): 267.1261, Found: 267.1351; HPLC (99:1 hexanes:iPrOH, Daicel CHIRALCEL IA): 96:4 er, tR (minor) = 16.4 min, tR (major) = 15.2 min; []D =-40.2
(c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30): Rf = 0.57
(4S,5S)-5-benzyl-4-phenyldihydrofuran-2(3H)-one (1.53e): The title compound was prepared according to General Procedure B using 5-benzylfuran-2(3H)-one (0.035 g, 0.20 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.045 g (89%) 1.53e as a white solid. Analytical data for 1.53e: 1H NMR (600 MHz, CDCl3); 7.41-7.38 (m, 2H), 7.35-7.31
(m, 3H), 7.29-7.24 (m, 5H), 4.77 (m, 1H), 3.39 (m, 1H), 3.11 (dd, J = 14.4, 3.9 Hz, 1H), 2.96 (dd, J = 15.0, 6.9 Hz, 1H), 2.85 (dd, J = 18.0, 9.0 Hz), 2.72 (dd J = 17.4, 9.6 Hz, 1H); 13C NMR (151 MHz,
CDCl3) 175.5, 138.9. 136.0, 129.7, 129.2, 128.6, 127.8, 127.3, 127.0, 86.8, 46.2, 39.2, 27.4; IR (thin film): 3853, 3839, 3801, 3734, 3420, 1774, 1647, 1558, 1541, 1496, 1456, 1206, 1144, 999, 771, 700, 592; HRMS (ESI+): Calcd. for C17H16O2: ([M+Na]): 275.1048, Found: 275.1038; HPLC (87.5:12.5 hexanes:iPrOH, Daicel CHIRALCEL IC): 94:6 er, tR (minor) = 20.1 min, tR (major) = 23.8 min; []D = -
57
(4S,5S)-5-isopropyl-4-phenyldihydrofuran-2(3H)-one (1.53f): The title compound was prepared according to General Procedure B using 5-isopropylfuran-2(3H)-one (0.025 g, 0.20 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.027 g (66%) 1.53f as a clear, colorless oil. Analytical data for 1.53f: 1H NMR (600 MHz, CDCl3) 7.40-7.37 (m, 2H), 7.31
(m, 1H), 7.29-7.26 (m, 2H), 4.37 (m, 1H), 3.46 (m, 1H), 3.00 (dd, J = 18.0, 9.6 Hz, 1H), 2.72 (dd, J = 18.0, 9.0 Hz, 1 H), 1.95 (m, 1H), 0.99 (dd, J = 40.8, 6.9 Hz, 6H); 13C NMR (151 MHz, CDCl3) 175.9,
140.8, 129.2, 127.5, 127.2, 91.6, 44.4, 38.2, 31.9, 18.8, 17.3); IR (thin film): 3853, 3839, 3801, 3750, 3420, 2964, 1773, 1646, 1558, 1540, 1507, 1455, 1208, 998, 961, 772, 699; HRMS (ESI+): Calcd. for C13H16O2: ([M+Na]): 227.1048, Found: 227.1040; HPLC (87.5:12.5 hexanes:iPrOH, Daicel CHIRALCEL IC): 96:4 er, tR (minor) = 16.3 min, tR (major) = 14.9 min; []D = -2.1 (c = 0.01, CHCl3); TLC
(hexane:EtOAc = 70:30): Rf = 0.53.
(4S,5S)-5-methyl-4-(p-tolyl)dihydrofuran-2(3H)-one (1.53g): The title compound was prepared according to General Procedure C using p-tolylboronic acid (0.027 g, 0.20 mmol) and K2CO3 (691g, 5.00 mol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.008 g (42%) 1.53g as an amorphous white solid. Analytical data for 1.53g: 1H NMR (600 MHz,
CDCl3) 7.21 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 2H), 4.55 (m, 1H), 3.24 (m, 1H), 2.94 (dd, J = 17.4, 8.4 Hz, 1H), 2.79 (dd, J = 17.4, 11.1 Hz, 1H), 1.43 (d, J = 6.6 Hz, 3H); 13C NMR (151 MHz,
CDCl3) 175.7, 137.6, 135.1, 129.8, 127.1, 83.3, 49.4, 37.5, 21.1, 19.2; IR (thin film): 3853, 3734, 3649, 1781, 1541, 1507, 1457, 1219, 1074, 772; HRMS (ESI+): Calcd. For C12H14O2: ([M+Na]): 213.0892, Found: 213.0884; HPLC (95:5 hexanes:iPrOH, Daicel CHIRALCEL IA): 97:3 er, tR (minor) = 7.7 min, tR (major) = 7.0 min; []D = -8.3 (c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30): Rf = 0.47.
58
(4S,5S)-4-(4-methoxyphenyl)-5-methyldihydrofuran-2(3H)-one (1.53h): The title compound was prepared according to General Procedure C using 4- methoxyphenylboronic acid (0.030 g, 0.20 mmol) and K2CO3 (691g, 5.00 mol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.015 g (73%) 1.53h as a white solid. Analytical data for 1.53h: 1H NMR (600 MHz, CDCl3) 7.16 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 4.52
(m, 1H), 3.83 (s, 3H), 3.22 (m, 1H), 2.93 (dd, J = 17.4, 8.7 Hz, 1H), 2.77 (dd, J = 18, 11.4 Hz, 1H), 1.43 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.7, 137.6, 135.1, 129.8, 127.1, 83.3, 49.4,
37.5, 21.1, 19.2; IR (thin film): 3853, 3431, 1773, 1647, 1541, 1517, 1457, 1251, 773, 568; HRMS (ESI+): Calcd. For C12H14O3: ([M+Na]): 229.0841, Found: 229.0833; HPLC (96:4 hexanes:iPrOH, Daicel CHIRALCEL IA): 92:8 er, tR (minor) = 13.2 min, tR (major) = 12.4 min; []D = -3.4 (c = 0.01, CHCl3);
mp 113-115°C; TLC (hexane:EtOAc = 70:30): Rf = 0.36.
(4S,5S)-4-(4-chlorophenyl)-5-methyldihydrofuran-2(3H)-one (1.53i): The title compound was prepared according to General Procedure C using 4- chlorophenylboronic acid (0.031 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.009 g (42%) 1.53i as a white solid. Analytical data for 1.53i: 1H
NMR (600 MHz, CDCl3) 7.37 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.54 (m, 1H), 3.26 (m, 1H), 2.97 (dd, J = 8.4, 17.4 Hz, 1H), 2.76 (dd, J = 10.8, 17.4 Hz, 1H), 1.44 (d, J = 6.0 Hz, 3H); 13C
NMR (151 MHz, CDCl3) 175.1, 136.7, 133.7, 129.3, 128.6, 83.0, 49.1, 37.4, 19.2; IR (thin film): 3419, 1782, 1647, 1541, 1491, 1217, 1091, 1073, 943, 773, 553; HRMS (ESI+): Calcd. for C11H11ClO2: ([M+Na]): 233.0345, Found: 233.0338; HPLC (96:4 hexanes:iPrOH, Daicel CHIRALCEL IA): 94:6 er, tR (minor) = 13.3 min, tR (major) = 11.5 min; []D = -10.9 (c = 0.01, CHCl3); mp 104-107°C; TLC
59
(4S,5S)-4-(4-bromophenyl)-5-methyldihydrofuran-2(3H)-one (1.53j): The title compound was prepared according to General Procedure C using 4- bromophenylboronic acid (0.040 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.014 g (54%) 1.53j as a white solid. Analytical data for 1.53j: 1H
NMR (600 MHz, CDCl3) 7.53 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 4.53 (m, 1H), 3.25 (m, 1H), 2.97 (dd, J = 8.4, 17.4 Hz, 1H), 2.76 (dd, J = 10.8, 17.4 Hz, 1H), 1.44 (d, J = 6.0 Hz, 3H); 13C
NMR (151 MHz, CDCl3) 175.1, 1327.3, 132.3, 128.9, 121.8, 82.9, 49.1, 37.3, 19.2; IR(thin film): 3853, 3734, 3649, 1781, 1541, 1507, 1489, 1069, 772; HRMS (ESI+): Calcd. for C11H11BrO2: ([M+Na]): 276.9840, Found: 276.9831; HPLC (95:5 hexanes:iPrOH, Daicel CHIRALCEL IA): 94:6 er, tR (minor) = 12.8 min, tR (major) = 11.1 min; []D = -10.4 (c = 0.01, CHCl3); mp 110-114°C; TLC
(hexane:EtOAc = 70:30): Rf = 0.38.
(4S,5S)-4-(4-fluorophenyl)-5-methyldihydrofuran-2(3H)-one (1.53k): The title compound was prepared according to General Procedure C using 4- fluorophenylboronic acid (0.028 g, 0.20 mmol) and K2CO3 (691 g, 5.00 mol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.011 g (57%) 1.53k as a clear, colorless oil. Analytical data for 1.53k: 1H NMR (600 MHz, CDCl3) 7.25 (m, 2H), 7.09 (m, 2H), 4.54 (m, 1H), 3.27 (m, 1H), 2.96
(dd, J = 17.4, 8.4 Hz, 1H), 2.76 (dd, J = 18.0, 10.6 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H); 13C NMR (151
MHz, CDCl3) 175.2, 162.2, 133.9, 128.8, 116.1, 83.1, 49.0, 37.5, 19.1; IR (thin film): 3432, 1782, 16647, 1513, 1386, 1277, 1224, 1163, 1069, 939, 775, 546; HRMS (ESI+): Calcd. for C11H11FO2: ([M+Na]): 217.0641, Found: 217.0634; HPLC (90:10 hexanes:iPrOH, Daicel CHIRALCEL IA): 94:6 er, tR (minor) = 8.3 min, tR (major) = 7.3 min; []D = -3.8 (c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30):
60
Ethyl 4-((2S,3S)-2-methyl-5-oxotetrahydrofuran-3-yl)benzoate (1.53l): The title compound was prepared according to General Procedure C using 4- ethoxycarbonylphenylboronic acid (0.039 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.021 g (85%) 1.53l as a white solid. Analytical data for 1.53l: 1H NMR (600 MHz, CDCl3) 8.07 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 4.59
(m, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.34 (m, 1H), 3.00 (dd J = 8.7, 17.7 Hz, 2H), 2.82 (dd, J = 10.8, 17.4 Hz, 2H), 1.45 (d, J = 6.0 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.1,
166.1, 143.3, 130.4, 130.2, 127.3, 82.8, 61.2, 49.6, 37.3, 19.3, 14.4; IR (thin film): 3853, 3434, 3649, 1783, 1716, 1558, 1541, 1507, 1457, 1280, 1105, 770; HRMS (ESI+): Calcd. for C14H16O4: ([M+Na]): 271.0946, Found: 271.0937; HPLC (85:15 hexanes:iPrOH, Daicel CHIRALCEL OJ-H): 95:5 er, tR (minor) = 30.1 min, tR (major) = 28.0 min; []D = -3.9 (c = 0.01, CHCl3); mp 101-103°C; TLC
(hexane:EtOAc = 70:30): Rf = 0.31.
(4S,5S)-5-methyl-4-(m-tolyl)dihydrofuran-2(3H)-one (1.53m): The title compound was prepared according to General Procedure C using m-tolylboronic acid (0.027 g, 0.20 mmol) (0.028 g, 0.20 mmol) and K2CO3 (691g, 5.00 mol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.008 g (51%) 1.53m as a colorless, amorphous solid. Analytical data for 1.53m: 1H NMR (600 MHz, CDCl3) 7.29 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.07 (m, 1H), 4.58 (m,
1H), 3.23 (m, 1H), 2.95 (dd, J = 17.4, 8.4 Hz, 1H), 2.81 (dd, J = 17.4, 10.8 Hz, 1H), 2.39 (s, 3H), 1.44 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.7, 138.9, 138.2, 129.0, 128.6, 128.0, 124.3,
83.2, 49.6, 37.5, 21.5, 19.3; IR (thin film): 3431, 1647, 774, 568; HRMS (ESI+): Calcd for C12H14O2: ([M+Na]): 213.0892, Found: 213.0884; HPLC (93:7 hexanes:iPrOH, Daicel CHIRALCEL IA): 91:9 er, tR (minor) = 6.5 min, tR (major) = 6.0 min; []D = -1.7 (c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30):
61
(4S,5S)-4-(3-methoxyphenyl)-5-methyldihydrofuran-2(3H)-one (1.53n): The title compound was prepared according to General Procedure C using 3- methoxyphenylboronic acid (0.030 g, 0.20 mmol) and K2CO3 (691 g, 5.00
mol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.014 g (68%) 1.53n as a clear, colorless oil. Analytical data for 1.53n: 1H NMR (600 MHz, CDCl3) 7.31 (t, J = 7.8 Hz, 1H), 6.87-6.85 (m, 2H), 6.80 (m, 1H), 4.58
(m, 1H), 3.84 (s, 3H), 3.23 (m, 1H), 2.96 (dd, J = 18.0, 8.7 Hz, 1H), 2.80 (dd, J = 17.4, 11.1 Hz, 1H), 1.45 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.5, 160.1, 139.9, 130.2, 119.4, 113.5,
112.6, 83.1, 55.3, 49.7, 37.5, 29.7, 19.3; IR (thin film): 3431, 1773, 1647, 1457, 1206, 775, 700; HRMS (ESI+): Calcd. for C12H14O3: ([M+Na]): 229.0841, Found: 229.0832; HPLC (93:7 hexanes:iPrOH, Daicel CHIRALCEL IA): 96:4 er, tR (minor) = 9.3 min, tR (major) = 8.3 min; = 4.1 (c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30): Rf = 0.36.
(4S,5S)-4-(3-chlorophenyl)-5-methyldihydrofuran-2(3H)-one (1.53o): The title compound was prepared according to General Procedure C using 3- chlorophenylboronic acid (0.031 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.009 g (42%) 1.53o as a clear, colorless oil. Analytical data for 1.53o: 1H
NMR (600 MHz, CDCl3) 7.35-7.31 (m, 2H), 7.27 (m, 1H), 7.16 (m, 1H), 4.57 (m, 1H), 3.25 (m, 1H), 2.98 (dd, J = 8.4, 17.4 Hz, 1H), 2.78 (dd, J = 10.8, 18.0 Hz, 1H), 1.45 (d, J = 6.0 Hz, 3H); 13C NMR
(151 MHz, CDCl3) 175.0, 140.4, 135.0, 130.5, 128.1, 127.5, 125.4, 82;8, 49.3, 37.3, 19.3; IR (thin film): 3431, 2387, 1647, 775, 570; HRMS (ESI+): Calcd. for C11H11ClO2: ([M+Na]): 233.0345, Found: 233.0338; HPLC (95:5 hexanes:iPrOH, Daicel CHIRALCEL IA): 96:4 er, tR (minor) = 9.6 min, tR (major) = 8.7 min; []D = -7.8 (c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30): Rf = 0.41.
62
(4S,5S)-4-(2-methoxyphenyl)-5-methyldihydrofuran-2(3H)-one (1.53p): The title compound was prepared according to General Procedure C using 2- methoxyphenylboronic acid (0.030 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The reaction was stirred for 3 h. The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.014 g (68%) 1.53p as a clear, colorless oil. Analytical data for 1.53p: 1H NMR (600 MHz, CDCl3) 7.30 (m, 1H), 7.17 (dd, J = 1.8, 7.8 Hz,1H),
6.98-6.93 (m, 2H), 4.76 (m, 1H), 3.87 (s, 3H), 3.50 (m, 1H), 2.95 (dd, J = 9.6, 17.4 Hz, 1H), 2.88 (dd, J = 9.3, 17.7 Hz, 1H), 1.43 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.6, 160.0, 139.9,
130.2, 119.4, 113.5, 112.6, 83.1, 55.3, 49.7, 37.5, 19.3; IR (thin film): 3431, 1774, 1647, 1496, 1219, 773, 569; HRMS (ESI+): Calcd. for C12H14O3: ([M+Na]): 229.0841, Found: 229.0833; HPLC (95:5 hexanes:iPrOH, Daicel CHIRALCEL IA): 94:6 er, tR (minor) = 8.0 min, tR (major) = 7.4 min; []D = -4.6 (c
= 0.01, CHCl3); TLC (hexane:EtOAc = 70:30): Rf = 0.42.
(4S,5S)-5-methyl-4-(naphthalen-2-yl)dihydrofuran-2(3H)-one (1.53q): The title compound was prepared according to General Procedure C using 2-naphthylboronic acid (0.034 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.016 g (62%) 1.53q as a white solid. Analytical data for 1.53q: 1H NMR (600 MHz, CDCl3) 7.91-
7.84 (m, 3H), 7.73 (d, J = 1.8 Hz, 1H), 7.56-7.51 (m, 2H), 7.39 (dd, J = 8.4, 1.8 Hz, 1H), 4.70 (m, 1H), 3.45 (m, 1H), 3.04 (dd, J = 17.4, 8.4 Hz, 1H), 2.93 (dd, J = 18.0, 10.8 Hz, 1H), 1.49 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.6, 135.5, 133.4, 132.8, 129.1, 127.7, 127.7, 126.7, 126.4,
126.3, 124.7, 83.1, 49.9, 37.5, 29.7, 19.3; IR (thin film): 1778, 1219, 1069, 941, 820, 772, 547; HRMS (ESI+): Calcd. for C12H14O3: ([M+Na]): 249.0892, Found: 249.0883; HPLC (95:5 hexanes:iPrOH, Daicel CHIRALCEL IA): 91:9 er, tR (minor) = 10.9 min, tR (major) = 10.1 min; []D = -6.3 (c = 0.01,
63
(4S,5S)-4-(1H-indol-4-yl)-5-methyldihydrofuran-2(3H)-one (1.53r): The title compound was prepared according to General Procedure C using 5-indolylboronic acid (0.032 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.012 g (56%) 1.53r as an amorphous, colorless solid. Analytical data for 1.53r: 1H NMR
(600 MHz, CDCl3) 8.27 (s, 1H), 7.55 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (m, 1H), 7.10 (dd, J = 1.8, 8.4 Hz, 1H), 6.57 (m, 1H), 4.65 (m, 1H), 3.37 (m, 1H), 2.99 (dd, J = 8.4, 17.4 Hz, 1H), 2.89 (dd, J = 11.4, 17.4 Hz, 1H), 1.46 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 176.1, 135.2, 129.4,
128.3, 125.2, 121.1, 119.3, 102.5, 83.9, 50.0, 38.1, 19.2; IR (thin film): 3853, 3734, 3649, 3567, 1749, 1541, 1508, 1456, 1219, 772, 512; HRMS(ESI+): Calcd. for C12H14O3: ([M+Na]): 238.0844, Found: 238.0836; HPLC (87.5:12.5 hexanes:iPrOH, Daicel CHIRALCEL IA): 95:5 er, tR (minor) = 12.5 min, tR
(major) = 13.9 min; []D = -7.3 (c = 0.01, CHCl3); TLC (hexane:EtOAc = 70:30): Rf = 0.28.
(4S,5S)-4-(6-ethoxypyridin-3-yl)-5-methyldihydrofuran-2(3H)-one (1.53s): The title compound was prepared according to General Procedure C using 6-ethoxy-3- pyridinylboronic acid (0.033 g, 0.20 mmol) and K2CO3 (0.014 g, 0.10 mmol). The crude material was purified by silica gel column chromatography (95:5 hexanes:EtOAc to 80:20 hexanes:EtOAc) to afford 0.007 g (32%) 1.53s as a white solid. Analytical data for 1.53s: 1H NMR (600 MHz, CDCl3) 8.05 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 2.7, 8.7 Hz, 1H),
6.78 (d, J = 8.4 Hz, 1H), 4.51 (m, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.23 (m, 1H), 2.95 (dd, J = 8.4, 18.0 Hz, 1H), 2.74 (dd, J = 11.1, 17.7 Hz, 1H), 1.43 (m, 6H); 13C NMR (151 MHz, CDCl3) 175.1, 163.7,
145.9, 136.8, 126.0, 111.7, 82.8, 62.0, 46.4, 37.2, 19.0, 14.6; IR (thin film): 2434, 2349, 1496, 772, 573, 504; HRMS (ESI+): Calcd. for C12H14O3: ([M+Na]): 244.0950, Found: 244.0941; HPLC(93:7 hexanes:iPrOH, Daicel CHIRALCEL IA): 95:5 er, tR (minor) = 10.2 min, tR (major) = 9.5 min; []D = -7.2
64
Procedure for 1 mmol Scale Synthesis of 1.53a: A flame-dried scintillation vial was transferred to a N2-filled glovebox. The vial was then charged with hydroxy[-(S)-BINAP]-rhodium(I) dimer (14.9 mg, 0.01 equiv, 10.00 μmol), phenylboronic acid (0.244 g, 2 equiv, 2.00 mmol), and K2CO3 (0.138 g, 1 equiv, 1.00 mmol). 1,4-Dioxane (2.25 mL) and -angelica lactone (98.1 mg, 1 equiv, 1.00 mmol) were added, the vial was sealed with a rubber septum and removed from the glovebox. N-Methylpyrrolidine (0.852 g, 10 equiv, 10.0 mmol) and water (0.25 mL) were added, and the reaction was heated to 60 ºC for 1 h. The reaction mixture was filtered through a silica gel plug with EtOAc and concentrated. The crude mixture was purified via silica gel chromatography (5% EtOAc:hexanes to 20% EtOAc:hexanes) to afford 0.156 g (89%) of 1.53a.
Procedures for Secondary Transformations on (4S,5S)-5-methyl-4-phenyldihydrofuran-2(3H)- one:
(3R,4S)-3-phenylpentane-1,4-diol (1.74): (4S,5S)-5-Methyl-4- phenyldihydrofuran-2(3H)-one 1.53a (17.6 mg, 0.100 mmol) dissolved in THF (1 mL) was added to a flame-dried, N2-filled round bottom flask. A solution of LiAlH4, 2M in THF (20.1 mg, 0.27 mL, 0.530 mmol, 5.3 equiv), was added to the flask. The reaction was stirred at room temperature for 2 h. The reaction was then diluted with ether and cooled to 0 C. Water (0.02 mL) was added, followed by 15% aqueous sodium hydroxide (0.02 mL), and more water (0.06 mL). The reaction was warmed to room temperature and stirred for 15 min. Anhydrous MgSO4 (~0.5 g) was added, and the suspension was stirred for 15 min. The reaction was filtered through a silica plug with diethyl ether to afford 0.012 g (67 %) of the diol as an amorphous white solid. Analytical data for 1.74: 1H NMR (600 MHz, CDCl3) 7.34 (t, J = 7.8 Hz, 2H), 7.25 (t, 7.2 Hz, 1H), 7.19 (d, J = 7.8 Hz,
2H), 3.97 (m, 1H) 3.68 (m, 1H), 3.55 (m, 1H), 2.72 (m, 1H), 2.24 (m, 1H), 1.97 (m, 1H), 1.07 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 142.5, 128.7, 128.2, 126.7, 61.5, 51.4, 35.3, 21.4; IR (thin
film): 3853, 3434, 3649, 1698, 1541, 1507, 1457, 771; HRMS (ESI+): Calcd. for C11H16O2: ([M+H]): 181.1229, Found: 181.1223; []D = 20.8 (c = 0.01, CHCl3); TLC (Et2O): Rf 0.15.
65
(3S,4S)-4-hydroxy-3-phenylpentanamide (1.75): (4S,5S)-5-Methyl-4- phenyldihydrofuran-2(3H)-one 3a (59.9 mg, 0.300 mmol) was dissolved in MeOH (1 mL). Aqueous ammonium hydroxide (1 mL, 28% NH3) was added. The reaction was stirred at room temperature. After 5 h, the reaction was extracted thrice with DCM, dried with MgSO4, filtered, and concentrated. Purification via silica gel column chromatography (100% DCM to 90:10 DCM:MeOH) afforded 26.0 mg (45%) of the amino alcohol as an amorphous white solid. Analytical data for 1.75: 1H NMR (600 MHz, CDCl3) 7.33 (t, J = 7.5 Hz, 2H), 7.26 (m, 1H), 7.21
(m, 1H), 5.47 (br s, 1H), 5.43 (br s, 1H), 3.97 (m, 1H), 3.07 (m, 1H), 2.89 (dd, J = 6.0, 15.0 Hz, 1H), 2.81 (br s, 1H), 2.63 (dd, J = 6.6, 15.3 Hz, 1H), 1.09 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) 175.2, 142.4, 128.8, 127.9, 127.0, 71.8, 50.5, 39.5, 22.2; IR (thin film): 3853, 3450, 3649, 3392, 1654, 1558, 1541, 1507, 1457, 702; HRMS (ESI+): Calcd. for C11H15NO2: ([M+Na]): 216.1000, Found: 216.0993; []D = 14.9 (c = 0.01, CHCl3); TLC (Et2O): Rf = 0.22.
(2S,3R)-5-amino-3-phenylpentan-2-ol (1.76): Amide 1.75 (0.022 g, 0.11 mmol) and dry THF (2 mL) were added to a flame dried, N2-filled 2-neck round bottom flask equipped with reflux condenser. A solution of LiAlH4 (2 M in THF, 0.17 mL, 3 equiv) was added to the reaction flask. The reaction was stirred at reflux for 5 h. The reaction was then diluted with ether and cooled to 0 C. Water (0.01 mL) was added, followed by 15% aqueous sodium hydroxide (0.01 mL), and more water (0.04 mL). The reaction was warmed to room temperature and stirred for 15 min. Anhydrous MgSO4 (~0.5 g) was added, and the suspension was stirred for 15 min. The reaction was filtered through a Celite® plug with diethyl ether. Purification via silica gel column chromatography (50:50 MeOH:DCM, 1% aq. NH4OH to afford 9.00 mg (44 %) of the amino alcohol as a white amorphous solid. Analytical data for 1.76: 1H NMR (600 MHz, DMSO-d6) 7.27-
7.26 (m, 2H), 7.16-7.15 (m, 3H), 3.67 (m, 1H), 2.44 (m, 1H), 2.33 (m, 1H), 2.05 (m, 1H), 1.62 (m, 1H), 0.81 (d, J = 6 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) ; 144.1, 128.6, 128.6, 126.4, 79.6, 70.3, 52.2,
66
(3R,4S,5S)-3-allyl-5-methyl-4-phenyldihydrofuran-2(3H)-one (1.77): A stock solution of LDA was made: 0.17 mL of dry diisopropylamine and 3.00 mL dry THF were added to a flamed dried flask under N2. The flask was cooled to -78 °C in a dry ice/acetone bath and allowed to cool for ~5 min. Then 0.44 mL of 2.5M nBuLi in hexanes was added. The LDA solution was stirred for 30 min at -78 °C. In a separate flame dried, N2-filled round bottom flask, (4S,5S)-5-methyl-4-phenyldihydrofuran-2(3H)-one 1.53a (17.6 mg, 1 equivalent, 0.100 mmol) and dry THF (1.0 mL) added. The reaction was cooled to -78 °C, and LDA solution (0.36 mL) was transferred to the substrate-containing flask. The solution was stirred at -78 °C for 1 h. A solution of 3- iodoprop-1-ene (21.5 mg, 0.0117 mL, 1.28 equivalent, 128 µmol) in THF (0.1 mL) was added at -78 and stirred for 1 h, then warmed to 0 °C and stirred for an additional h. The reaction was diluted with Et2O and quenched with saturated aqueous ammonium chloride. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. on the crude material was purified by silica gel chromatography (2.5% EtOAc:hexanes to 10% EtOAc:hexanes) to afford 0.017 g (70%) of the stereotriad as a single diastereomer, as a clear, colorless oil. Analytical data for 1.77: 1H NMR