J. Am. Chem. Soc., 1997, 119(18), , DOI: /ja970079g

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1 J. Am. Chem. Soc., 1997, 119(18), , DOI: /ja970079g Terms & Conditions Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machinereadable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at Copyright 1997 American Chemical Society

2 ( 1997 American Chemical Society J. Am. Chem. Soc. V 119 Page43 17 Brzezinski Supplemental Page 1 The Asymmetric Baylis-Hillman Reaction Linda Joy Brzezinski, Sara Rafel, and James W. Leahy* Department of Chemistry, University of California Berkeley, California, Supplementary Material General. Unless otherwise noted, all compounds were obtained from Aldrich Chemical Company and were used without further purification. Dichloromethane was distilled from calcium hydride under nitrogen. Anhydrous methanol was distilled from magnesium turnings and iodine. Triethylamine was distilled and stored over potassium hydroxide. Analytical thin-layer chromatography was performed with E. Merck 250-mm precoated F-254 silica gel 60 plates. Flash chromatography was run under air pressure using mesh silica gel supplied by E. Merck (Darmstadt).1 'H and 1 3 C NMR spectra were recorded at 400 and 100 MHz, respectively, in CDCl 3 except where noted and coupling constants are reported in Hz. Infrared spectra were recorded as neat films on sodium chloride plates. Enantiomeric ratios were determined via gas chromatography on an HP 5890A gas chromatograph using a Cyclodex B column (J&W Scientific # , 30 m x 0.32 mm I.D.). Helium carrier gas was at 20 psi head pressure and a temperature program of 70 'C for 5 min followed by a ramp of 4 OC/min to 175 oc. Microanalyses were performed by MHW Laboratories, Phoenix, AZ. 2a 2(R), 6(R)-2,6-Dimethyl-5-methylene-1,3-dioxan-4-one (2a). 2 A stirred solution of acrylate 1 (1.00 g, 3.7 mmol) 3 in dichloromethane (5 ml) was cooled to 0 oc and acetaldehyde (2.38 g, 54 mmol) was added followed by DABCO (0.27 g, 1.85 mmol). The solution was stirred at 0 oc for 8 h, then concentrated under reduced pressure. S1

3 (G1997 American Chemical Society J. Am. Chem. Soc. V 119 Page4317 Brzezinski Supplemental Page 2 The residue was purified by flash column chromatography to provide Oppolzer's sultam (725 mg, 91 %) as a white solid and 2a (448 mg, 85 %) as a colorless oil. [a]d (c = 1.8, CHCl 3 ). IR 2965, 1725, 1630, 1465, 1410, 1285, 1200 cm H NMR (500 MHz) (d, 3, J = 6.3), 1.50 (d, 3, J = 5.1), 4.64 (m, 1), 5.50 (q, 1, J = 5.1), 5.60 (d, 1, J = 2.4), 6.50 (d, 1, J = 2.4). 1 3 C NMR (125 MHz) , 20.9, 74.1, 99.5, 125.5, 137.7, Anal. Calcd. for C 7 H, : C 59.14, H Found: C 58.74, H Retention time min (vs min for enantiomer). 2b 2(R), 6(R)-2,6-Diethyl-5-methylene-1,3-dioxan-4-one (2b). 4 Following the procedure described above with propionaldehyde, 2b was obtained as a colorless oil (98 %). [a]d = (c = 1.0, CHCl 3 ). 'H NMR (t, 6, J = 6.9), 1.55 (m, 2), 1.76 (m, 2), 4.43 (m, 1), 5.15 (t, 1, J = 5.3), 5.52 (d, 1, J = 2.2), 6.38 (d, 1, J = 2.3). 3 C NMR , 15.6, 34.2, 35.3, 78.1, 100.5, 124.9, 137.7, Retention time min (vs min for enantiomer). 2c 2(R), 6(R)-2,6-Dipropyl-5-methylene-1,3-dioxan-4-one (2c). Following the procedure described above with butyraldehyde, 2c was obtained as a colorless oil (70 %). [a]d = (c = 1.1, CHCl 3 ). IR 2970, 2720, 1720, 1630, 1440, 1390, 1280 cm-'. 1H NMR (500 MHz) (t, 6, J = 7.5), 1.46 (m, 4), 1.69 (m, 4), 5.50 (m, 1), 5.28 (t, 1, J = 5.2), 5.55 (d, 1, J = 2.1), 6.42 (d, 1, J = 2.4). 3 C NMR (125 MHz) , 13.7, 16.4, 17.8, 36.3, 36.9, 77.3, 101.8, 125.0, 137.2, Anal. Calcd. for C,,H, : C 66.64, H Found: C 66.38, H Retention time min (vs min for enantiomer). S2

4 I V / American fiemical Society J. Am. Uthem. soc. V 11 IPage4. I / brzezinski Supplemental vage.5 2d 2(R), 6(R)-2,6-Di-isopropyl-5-methylene-1,3-dioxan-4-one (2d). 4 Following the procedure described above with isobutyraldehyde, 2d was obtained as a colorless oil (33 %). [a]d = (c = 0.9, CHCl,). 'H NMR (300 MHz) 0.93 (m, 12), 1.40 (m, 2), 4.57 (m, 1), 5.02 (d, 1, J = 6.5), 5.50 (d, 1, J = 2.0), 6.42 (d, 1, J = 2.0). Retention time min (vs min for enantiomer). Ph"'Ni 0 PM 2e 2(R), 6(R)-2,6-Di-(2-phenylethyl)-5-methylene-1,3-dioxan-4-one (2e). Following the procedure described above with hydrocinnamaldehyde, 2e was obtained as a colorless oil (68 %). [a]d = (c = 1.1, CHCl 3 ). IR 2930, 2865, 1740, 1630, 1605, 1495, 1455 cm-'. 'H NMR (m, 4), 2.82 (m, 4), 5.51 (m, 1), 5.30 (t, 1, J = 5.1), 5.60 (d, 1, J = 2.2, 6.51 (d, 1, J = 2.4), 7.15 (m, 10). 1C NMR , 30.7, 35.8, 36.6, 76.5, 101.0, 125.6, 126.2, 128.4, 128.4, 128.5, 128.5, 136.8, 136.8, 140.5, 140.9, Anal. Calcd. for C 2 1 H2O 3 : C 78.23, H Found: C 78.57, H min for enantiomer). Retention time min (vs. Ac OAc 2f 2(R), 6(S)-2,6-Di-(acetoxymethyl)-5-methylene-1,3-dioxan-4-one (2f). Following the procedure described above with acetoxyacetaldehyde, 5 2f was obtained as a colorless oil (68 %). [a]d = (c = 1.2, CHC1 3 ). IR 2925, 2855, 1740, 1625, 1460, 1375 cm'. 'H NMR (500 MHz) (s, 3), 2.12 (s, 3), 4.29 (d, 2, J = 4.5), 4.31 (d, 1, J = 5.8, 4.38 (dd, 1, J = 12.1, 3.3), 4.92 (m, 1), 5.54 (t, 1, J = 4.5), 5.79 (d, 1, J = 2.1), 6.59 (d, 1, J = 2.4). "C NMR (125 MHz) , 20.6, 63.3, 65.2, 75.7, 94.7, 127.9, 132.6, 162.1, 170.2, S3

5 V I VV American fiemical Society J. Am. Uthem. soc. V II V Page4.5 I / brzezinski Supplemental Page Anal. Calcd. for C11H : C 51.16, H Found: C 51.41, H Retention time min (vs min for enantiomer). 2g 2(R), 6(R)-2,6-Di-isobutyl-5-methylene-1,3-dioxan-4-one (2g). Following the procedure described above with isovaleraldehyde, 2g was obtained as a colorless oil (67 %). [aid = (c = 7.5, CHCl 3 ). 'H NMR (m, 12), 1.50 (m, 2), 1.72 (m, 2), 1.91 (m, 2), 4.58 (m, 1), 5.35 (t, 1, J = 6.3), 5.59 (d, 1, J = 1.8), 6.46 (d, 1, J = 1.9). 'C NMR , 13.6, 13.7, 13.8, 28.4, 29.5, 34.1, 35.2, 78.5, 101.2, 124.6, 138.2, Anal. Calcd. for C1 3 H : C 68.99, H Found: C 69.24, H Retention time min (vs min for enantiomer). MeOQ 2 C OH 3 (R) Methyl 3-hydroxy-2-methylenepentanoate (3).6 A solution of acrylate 2b (1.00 g, 5.9 mmol) in anhydrous methanol (20 ml) was cooled to 0 oc and camphorsulfonic acid (2.6 mg) was added. The solution was stirred at 0 oc for 40 min and triethylamine (2 drops) was added. The solution was concentrated under reduced pressure and the residue was purified by flash column chromatography to give 3 (721 mg, 85 %) as a colorless oil. [aid = (c = 0.5, CHCl 3 ). H NMR (t, 3, J = 6.5), 1.64 (m, 2), 2.90 (br. s, 1), 3.75 (s, 3), 4.32 (t, 1, J = 6.3), 5/75 (s, 1), 6.19 (s, 1). C NMR , 22.3, 50.8, 68.6, 124.8, 144.1, MeO C~y 2 OH 3a (R) Methyl 3-hydroxy-2-methylenebutanoate (3a). 6 Following the procedure described above with 2a, 3a (80 %) was obtained as a colorless oil. [a] 0 = (c = S4

6 V I VV American fiemical Society J. Am. Uthem. soc. V II V Page4.5 I / brzezinski Supplemental Fage D 0.8, CHCl 3 ). IR 3350, 2950, 1725, 1445, 1380, 1160 cm. 'H NMR (500 MHz) (d, 3, J = 6.5), 2.76 (d, 1, J = 5.6), 3.79 (s, 3), 4.62 (quin, 1, J = 6.1), 5.84 (t, 1, J = 1.1), 6.22 (d, 1, J = 0.6). 1 3 C NMR (125 MHz) , 51.8, 67.1, 124.1, 143.5, Anal. Calcd. for C 6 H, : C 55.37, H Found: C 55.43, H MeQ2C OHY 3g (R) Methyl 3-hydroxy-5-methyl-2-methylenehexanoate (3g). 7 Following the procedure described above with 2g, 3g (76 %) was obtained as a colorless oil. [X]D = (c = 4.0, CHCl 3 ). H NMR (m, 6), 1.38 (m, 2), 1.75 (m, 1), 3.75 (s, 3), 4.40 (m, 1), 5.77 (d, 1, J = 1.6), 6.12 (d, 1, J = 1.7). 'C NMR , 14.2, 28.1, 30.4, 50.7, 67.7, 125.1, OH 4 2(R), 3(R) Methyl 3-hydroxy-2-methylpentanoate (4).8 A solution of acrylate 3 (1.00 g, 6.9 mmol) in anhydrous dichloromethane (10 ml) was degassed and [Rh(nbd)(diphos-4)]BF 4 (20 mg, 0.4 mol %)9 was added under a nitrogen atmosphere. The solution was then stirred under an atmosphere of hydrogen until the consumption of starting material was complete by thin layer chromatography (approximately 2 h). The solution was then concentrated under reduced pressure and triturated with a mixture of ether/petroleum ether (1:3). The mixture was filtered through a plug of silica gel and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 4 (861 mg, 85 %) as a colorless oil. [ajd = (c = 1.1, CHCl 3 ) [lit. [aid = (c = 1.28, CHCl 3 ). 8 'H NMR (t, 3, J = 7.1), 1.12 (d, 3, J = 6.9), 1.36 (m, 1), 1.50 (m, 1), 2.46 (quin, 1, J = 6.1), 2.65 (br. s, 1), 3.52 (m, 1), 3.62 (s, 3). S5

7 vi " I American onemicai zociety J. Am. k-nem. zoc. v i i!s rageei i / nrzezinski 3uppIemental rage o MeqC OH 4a 2(R), 3(R) Methyl 3-hydroxy-2-methylbutyrate (4a).1 0 Following the procedure described above with 3a, 4a (61 %) was obtained as a colorless oil. [c]d = (c = 2.0, CHCl 3 ). 'H NMR (d, 3, J = 6.7), 1.22 (d, 3, J = 6.5), 2.43 (m, 1), 3.61 (s, 3), , m). MeO 2 C 4g 2(R), 3(R) Methyl 2,5-dimethyl-3-hydroxyhexanoate (4g).11 Following the procedure described above with 3g, 4g (85 %) was obtained as a colorless oil. [CID = (c = 4.0, CHC1 3 ). 'H NMR (t, 6,1= 6.7), 1.12 (d, 3, J = 6.7), 1.16 (m, 2), 1.30 (m, 1), 1.80 (m, 1), 3.63 (s, 3), 3.65 (m, 1). MeqC OAc HO 5 (S) Methyl 4-acetoxy-3-hydroxy-2-methylenebutanoate (5).12 A solution of acrylate 2f (521 mg, 2.0 mmol) and triethylamine (0.1 ml) in anhydrous methanol (30 ml) was warmed to 45 oc for 10 min, then concentrated under reduced pressure in a warm water bath. The resulting residue was purified by flash column chromatography to yield 5 (283 mg, 75 %) as a colorless oil. [x]d = (c = 2.4, CHCl 3 ). IR 3470, 2955, 1725, 1630, 1440, 1380, 1160 cm'. 1H NMR (s, 3), 3.81 (s, 3), 4.20 (dd, 1, J = 11.5, 6.9), 4.31 (dd, 1, J = 11.5, 3.6), 4.74 (m, 1), 6.00 (d, 1, J = 1.1), 6.40 (d, 1, J = 0.8). 3 C NMR , 52.0, 67.4, 69.7, 127.3, 128.3, 138.5, 166.2, Anal. Calcd. for C 8 H : C 51.06, H Found: C 50.92, H o+ bh bac 6 7 S6

8 V I V / American fiemical Society J. Am. Uthem. soc. V II V Page4. I / brzezinski Supplemental vage / Tulipalin B (6) and acetyltulipalin B (7).12 A solution of 5 (247.2 mg, 1.3 mmol) in toluene (55 ml) containing water (0.1 ml) and camphorsulfonic acid (62 mg) was heated to reflux for 5 h, then concentrated under reduced pressure. The residue was purified by flash column chromatography to give 6 (38.0 mg, 25 %) and 7 (132.5 mg, 65%) as colorless oils. Data for 6: [a]d = (c = 0.9, CHCl 3 ). IR 3420, 2975, 2910, 1755, 1670, 1415, 1275 cm-1. 1H NMR (500 MHz) (br s, 1), 4.18 (dd, 1, J = 10.0, 3.6), 4.50 (dd, 1,J = 10.1, 6.6), 4.95 (t, 1,J = 2.1), 6.02 (d, 1,J = 1.7), 6.42 (d, 1,J = 2.0). "C NMR (125 MHz) , 73.5, 126.8, 137.6, Anal. Calcd. for CsH : C 52.63, H Found: C 52.41, H Data for 7: [ad = (c = 1.8, CHCl 3 ). IR 3105, 2975, 1765, 1670, 1410, 1375 cm-1. H NMR (s, 3), 4.30 (dd, 1, J = 10.9, 2.5), 4.59 (dd, 1, J = 10.9, 6.4), 5.82 (m, 1), 6.15 (d, 1, J = 1.5), 6.55 (d, 1, J = 1.8). C NMR , 68.9, 70.6, 129.8, 133.3, 168.2, Anal. Calcd. for C 7 H : C 53.85, H Found: C 54.01, H References 1. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, Drewes, S. E.; Emslie, N. D.; Karodia, N.; Khan, A. A. Chem. Ber. 1990, 123, Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, Khan, A. A.; Emslie, N. D.; Drewes, S. E.; Field, J. S.; Ramesar, N. Chem. Ber. 1993, 126, Bestmann, H. J.; Ermann, P.; Rueppel, H.; Sperling, W. Liebigs Ann. Chem. 1986, Adam, W.; Hoch, U.; Saha-Mbller, C. R.; Schreier, P. Angew. Chem. Int. Ed. Engl. 1993, 32, Scheuplein, S. W.; Kusche, A.; BrUckner, R.; Harms, K. Chem. Ber. 1990, 123, Meyers, A. I.; Yamamoto, Y. Tetrahedron 1984, 40, Brown, J. M.; Evans, P. L.; James, A. P. Org. Synth. Coll. Vol. VIII 1993, Kraft, P.; Tochtermann, W. Tetrahedron 1995, 51, Oppolzer, W.; Starkemann, C.; Rodriguez, I.; Bernardinelli, G. Tetrahedron Lett. 1991, Corbet, J.-P.; Benezra, C. J. Org. Chem. 1981, 46, S7