Total Synthesis of Echinopines A and B

Transcript

1 Total Synthesis of Echinopines A and B K. C. Nicolaou,* anfeng Ding, Jean-Alexandre Richard, and David Y.-K. Chen* Contribution from Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The elios Block, #03 08, Singapore kcn@scripps.edu; david_chen@ices.a-star.edu.sg I) Experimental Section Supporting Information Available II) III) IV) Abbreviations References 1 and 13 C NMR Spectra of Compounds I) Experimental Section Experimental Data for Compounds General Procedures. All reactions were carried out under a nitrogen or argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (TF), hexane, diethyl ether (Et 2 ), methylene chloride (C 2 Cl 2 ), toluene, diisopropylamine (i-pr 2 N) and triethylamine (Et 3 N) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Methanol (Me), benzene, acetonitrile (MeCN), N,N -dimethylformamide (DMF) and dimethylsulfoxide (DMS), were purchased in anhydrous form and used without further purification. Water, ethyl acetate (EtAc), diethyl ether (Et 2 ), methylene chloride (C 2 Cl 2 ), acetone and hexanes were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reagents were purchased at the highest

2 commercial quality and used without further purification, unless otherwise stated. Yields refer to chromatographically and spectroscopically ( 1 NMR) homogeneous materials, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of ammonium molybdate, anisaldehyde, and heat as developing agents. E. Merck silica gel (60, particle size mm) was used for flash column chromatography. NMR spectra were recorded on a Bruker AV-600 instrument and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, pent = pentet, hex = hexet, br = broad. IR spectra were recorded on a Perkin-Elmer Spectrum ne FTIR spectrometer with diamond ATR accessory. Melting points (m.p.) are uncorrected, and recorded on a Buchi B-540 melting point apparatus. igh-resolution mass spectra (RMS) were recorded on an Agilent ESI TF (time of flight) mass spectrometer at 3500 V emitter voltage. 2-bromo-2-cyclohexen-1-one (6): To a stirred solution of 2-cyclohexen-1-one (5) (6 ml, 62 mmol) in C 2 Cl 2 (160 ml) at 0 C was added a solution of bromine (3.24 ml, 63.2 mmol) in C 2 Cl 2 (160 ml) 6 Br over 1 h. Et 3 N (14.4 ml, mmol) was added and the resulting mixture was allowed to warm at room temperature and stirred for 1.5 h before it was quenched with Cl (1.0 M aq., 100 ml). The layers were separated and the organic layer was washed with brine (100 ml), dried (Na 2 S 4 ) and concentrated in vacuo to afford 2-bromo-2-cyclohexen-1-one (6) (10.63 g, 98%), where the 1 and 13 C NMR spectroscopic data matched those reported in literature. 1 (S)-2-bromo-cyclohex-2-en-1-ol (7): A solution of (R)-α,α-diphenylprolinol (1.11 g, 4.38 mmol) and B(Me) 3 (600 µl, 5.26 mmol) in TF (75 ml) was stirred at room temperature for 1 h before being cooled at 5 C and the addition of B 3 N,N-diethylaniline (7.76 ml, 43.8 mmol). A solution of 2- bromo-2-cyclohexen-1-one (6) (7.67 g, 43.8 mmol) in TF (75 ml) was added over 75 min and the S2

3 7 Br reaction mixture was allowed to warm to room temperature and stirred for 16 h before it was quenched by a slow addition of Me (50 ml) and Cl (1.0 M aq., 100 ml). The layers were separated, and the organic layer was extracted with Et 2 (2 100 ml), washed with brine (100 ml), dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 8:2) afforded (S)-2-bromo-cyclohex-2-en-1-ol (7) (6.96 g, 90%) as a colorless oil, whose 1 and 13 C NMR spectroscopic data matched those reported in the literature Enantiomeric purity was determined to be >95% ee by Mosher ester analysis. [α] = 77 (c = 1.74, CCl 3 ); Lit [α] = 85.2 (c = 1.89, CCl 3 ). D D (S)-cyclohex-2-en-1-ol (8): To a stirred solution of (S)-2-bromo-cyclohex-2-en-1-ol (7) (2.46 g, 13.9 mmol) in Et 2 (250 ml) at 78 C was added a solution of n-buli (2.0 M in cyclohexane, 24 ml, 48.7 mmol). The reaction mixture was stirred for 1 h and warmed to 10 C and stirred for further 1.5 h before it was quenched with 2 (100 ml). The layers were separated, and the organic 8 layer was washed with brine (100 ml), dried (Na 2 S 4 ) and concentrated in vacuo to afford (S)-cyclohex-2-en-1-ol (8) (1.09 g, 80%) as a colorless oil, whose 1 and 13 C NMR spectroscopic data matched those reported in the literature. 2 The enantiomeric purity was determined to be >95% ee by 25 Mosher ester analysis. [α] = 107 (c = 1.0, CCl 3 ); Lit [α] = (c = 1.03, CCl 3 ). D D Allylic alcohol 11: To a stirred solution of alcohol (S)-cyclohex-2-en-1-ol (8) (16.92 g, 172 mmol) in C 2 Cl 2 (250 ml) at room temperature were added a solution of TBSCl (33.8 g, 224 mmol) in C 2 Cl 2 11 (200 ml) and DMAP (2.1 ml, 17.2 mmol). Et 3 N (36 ml, 258 mmol) was then added and the resulting mixture was stirred for 6 h before it was quenched with Cl (1.0 M aq., 150 ml). The layers were separated and the organic layer was washed with NaC 3 (150 ml, sat. aq.), brine (150 ml), dried (Na 2 S 4 ) and concentrated in vacuo to afford the corresponding TBS ether 9 as a light yellow oil, which was used directly without further purification. A stirred solution of alkenyl TBS ether 9 (obtained above, 32.5 g, mmol) in C 2 Cl 2 (200 ml) at 78 C was saturated with ozone until a persistent blue color was observed. The reaction mixture S3

4 was quenched with PPh 3 (45 g, 172 mmol) and then warmed to room temperature over a period of 16 h. The resulting mixture was concentrated in vacuo, diluted with Et 2 (500 ml) and filtered through a pad of Celite. The combined filtrate was concentrated in vacuo to afford the corresponding crude dialdehyde as an orange oil, which was used directly without further purification. To a stirred solution of the dialdehyde (obtained above) in benzene (200 ml) at room temperature were added acetic acid (400 µl, 7 mmol) and piperidine (650 µl, 6.58 mmol). The resulting mixture was warmed to 90 C and heated for 1 h before it was cooled to room temperature. The resulting mixture was washed with Cl (2.0 M aq., ml), NaC 3 (150 ml, sat. aq.) and water (150 ml), and then dried (Na 2 S 4 ) and concentrated in vacuo to afford crude α,β-unsaturated aldehyde 10 as an orange oil, which was used directly without further purification. To a stirred solution of α,β-unsaturated aldehyde 10 (obtained above) in Me (500 ml) at 0 C was added NaB 4 (6.5 g, 172 mmol) over a period of 15 min. The resulting mixture was stirred for 0.5 h before it was diluted with water (250 ml) and extracted with C 2 Cl 2 (3 300 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 9:1 4:1) afforded allylic alcohol 11 (32.9 g, 84% over the four steps) as a yellow 25 oil. 11: R f = 0.35 (silica gel, hexanes:etac 4:1); [α] = 50 (c = 1.00, CCl 3 ); IR (film) ν max 3352, 2954, 2929, 2856, 1472, 1462, 1361, 1252, 1148, 1062, 1016, 901, 833, 773, 667 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 5.60 (s, 1 ), 4.90 (br s, 1 ), 4.18 (dq, J = 18.6, 5.4 z, 2 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 1.45 (t, J = 6.0 z, 1 ), 0.88 (s, 9 ), 0.06 ppm (s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 147.5, 128.0, 78.1, 62.4, 34.4, 31.0, 26.2 (3C), 18.6, 4.4 (2C) ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found γ,δ-unsaturated ester 12: To a stirred solution of alcohol 11 (2.24 g, 9.81 mmol) in xylenes (18 ml) at room temperature were added triethyl orthoacetate (18 ml, 98.1 mmol) and 2-nitrophenol (68 mg, 0.49 mmol). The resulting mixture was heated at 150 C for 21 h before it was cooled to room temperature and diluted with Et 2 (40 ml). The resulting mixture was washed with NaC 3 (40 ml, sat. aq.) and D S4

5 C 2 Et brine (40 ml), and the organic layer was dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 9:1) afforded γ,δ- 12 unsaturated ester 12 [2.57 g, 86%, ca. 1.5:1 mixture of anti:syn diastereoisomers by 1 NMR (anti isomer shown)] as a yellow oil. 12: R f = 0.70 (silica gel, hexanes:etac 20:1); IR (film) ν max 2955, 2929, 2857, 1736, 1655, 1472, 1463, 1410, 1371, 1323, 1292, 1251, 1165, 1117, 1068, 1037, 1004, 961, 938, 906, 871, 835, 774, 681 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 4.90 (d, J = 1.2 z, 0.33 ), 4.85 (d, J = 1.8 z, 0.67 ), 4.75 (d, J = 2.4 z, 0.67 ), 4.74 (d, J = 1.8 z, 0.33 ), (m, 0.33 ), (m, 2 ), (m, 0.67 ), 2.78 (br s, 0.33 ), 2.67 (br d, J = 5.4 z, 0.67 ), 2.55 (dd, J = 16.8, 9.0 z, 0.33 ), (m, 1.67 ), 2.42 (dd, J = 16.8, 5.4 z, 0.33 ), 2.34 (dd, J = 15.6, 7.2 z, 0.67 ), 2.25 (dquint, J = 8.4, 2.4 z, 0.33 ), (m, 0.67 ), (m, 1 ), (m, 1 ), (m, 3 ), 0.86 (s, 6 ), 0.83 (s, 3 ), 0.03 ( 0.02) ppm (3 s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 173.7, 172.9, 153.2, 151.8, 106.5, 105.8, 74.5, 60.5, 60.4, 49.2, 46.1, 36.2, 33.3, 33.0, 29.6, 29.4, 26.0, 18.2, 14.4, 4.3, 4.4, 4.6, 5.0 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found β-keto ester 15: To a stirred solution of ethyl ester 12 (4.41 g, 14.8 mmol, 1.5:1 mixture of anti:syn diastereoisomers) in TF/Me/ 2 (150 ml, 3:1:1) at room temperature was added Li 2 ( C 2 Me g, 29.6 mmol). The resulting mixture was stirred for 16 h before it was acidified with Cl (1.0 M aq.) until p = 6. The layers were separated, and the aqueous layer was extracted with Et 2 (3 80 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo to afford the crude carboxylic acid 13 as a yellow oil, which was used directly without further purification. To a stirred suspension of methyl potassium malonate (14) (6.93 g, 44.4 mmol) 3 in TF (50 ml) at room temperature was added MgCl 2 (4.23 g, 44.4 mmol). The resulting mixture was heated at 70 C for 3.5 h before it was cooled to room temperature. Independently, to a stirred solution of carboxylic acid 13 (obtained above) in TF (50 ml) at room temperature was added CDI (5.28 g, 32.6 mmol). The S5

6 resulting mixture was stirred for 3 h before it was added to the methyl potassium malonate/mgcl 2 solution at ambient temperature over a period of 0.5 h. The resulting mixture was stirred at the same temperature for 16 h before it was quenched with Cl (1.0 M aq., 100 ml). The layers were separated and the aqueous layer was extracted with Et 2 (3 100 ml). The combined organic layers were washed with brine (100 ml), dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 20:1) afforded β-keto ester 15 [3.78 g, 78% over the two steps, ca. 2.7:1 mixture of anti:syn diastereoisomers by 1 NMR (anti isomer shown)] as a yellow oil, and amide 5-epi-15a (15%) as a colorless oil. 15: R f = 0.40 (silica gel, hexanes:etac 9:1); IR (film) ν max 2954, 2930, 2857, 1749, 1718, 1633, 1436, 1361, 1314, 1251, 1123, 1065, 1038, 1004, 859, 835, 774, 670 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 4.89 (d, J = 1.8 z, 0.27 ), 4.82 (d, J = 1.8 z, 0.73 ), 4.71 (d, J = 1.8 z, 0.27 ), 4.67 (d, J = 1.8 z, 0.73 ), (m, 0.73 ), (m, 0.27 ), 3.72 (s, 3 ), (m, 1.73 ), 3.40 (d, J = 15.6 z, 0.27 ), (m, 0.27 ), (m, 0.27 ), (m, 0.73 ), (m, 0.73 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.84 (s, 6.6 ), 0.82 (s, 2.4 ), 0.02 ( 0.05) ppm (3 s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 202.4, 202.0, 167.9, 153.2, 151.4, 106.7, 105.9, 74.4, 52.4, 49.6, 49.3, 48.2, 45.3, 44.8, 42.3, 33.4, 33.1, 29.6, 29.3, 26.0, 18.3, 18.2, 4.2, 4.4, 4.6, 4.9 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found epi-15a: R f = 0.40 (silica gel, hexanes:etac 4:1); IR (film) ν max 2927, 2856, 1772, 1737, 1461, 1377, 1252, 1168, 1065, 1037, 1003, 964, 835, 774 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 8.18 (s, 1 ), 7.47 N (s, 1 ), 7.08 (s, 1 ), 4.99 (d, J = 1.8 z, 1 ), 4.81 (d, J = 1.8 z, 1 ), 4.42 (s, 1 ), (m, 1 ), 3.07 (br s, 1 ), 2.86 (dd, J = 17.4, 7.8 z, 1 ), N 5-epi-15a (m, 1 ), (m, 1 ), (m, 2 ), 0.75 (s, 9 ), 0.01 (s, 3 ), 0.17 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 169.5, 152.6, 136.4, 131.1, 116.2, 106.7, 74.2, 44.9, 34.7, 33.5, 29.8, 25.9 (3C), 18.1, 4.5, 5.2 ppm; RMS (ESI): calcd for C N 2 2 SiNa + [M + Na + ] , found S6

7 Stannane 25: To a stirred solution of alcohol 11 (245 mg, 1.07 mmol) in TF (3 ml) at room temperature were added Na (43 mg, 1.07 mmol) and a solution of n-bu 3 SnC 2 I (232 mg, 0.54 mmol) n-bu 3 Sn 25 in TF (3 ml). MPA (2 ml) was added, and the resulting mixture was stirred for 16 h before it was quenched with 2 (10 ml) and diluted with Et 2 (10 ml). The layers were separated, and the aqueous layer was extracted with Et 2 (3 10 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 100:1) afforded stannane 25 (228 mg, 80%) as a colorless oil. 25: R f = 0.50 (silica gel, hexanes:etac 30:1); IR (film) ν max 2955, 2926, 2854, 1731, 1463, 1360, 1250, 1150, 1054, 1023, 1005, 960, 902, 857, 833, 773, 728, 666, 598 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 5.56 (s, 1 ), 4.89 (br s, 1 ), 3.89 (dd, J = 13.2, 4.2 z, 2 ), 3.68 (dd, J = 10.2, 6.0 z, 2 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 6 ), (m, 6 ), (m, 24 ), 0.05 ppm (s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 144.8, 129.4, 78.0, 74.2, 61.8, 34.1, 31.1, 29.2 (3C), 27.3 (3C), 26.0 (3C), 18.4, 13.7 (3C), 9.0 (3C), 4.6 (2C) ppm; RMS (ESI): calcd for C SiSnNa + [M + Na + ] , found Alcohol 26: To a stirred solution of stannane 25 (67 mg, mmol) in TF (3 ml) at 78 C was added n-buli (1.4 M in TF, 0.13 ml, mmol). The resulting mixture was stirred for 0.5 h before it was quenched with 2 (10 ml) and diluted with EtAc (5 ml). The layers were separated, and the aqueous layer was extracted with EtAc (3 5 ml). The combined 26 organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 10:1) afforded alcohol 26 [15 mg, 49%, ca. 7:1 mixture of anti:syn diastereoisomers by 1 NMR (anti isomer shown)] as a colorless oil. 26: R f = 0.30 (silica gel, hexanes:etac 5:1); IR (film) ν max 2954, 2929, 2857, 1654, 1472, 1361, 1253, 1107, 1037, 860, 834, 775, 670 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 5.00 (d, J = 2.4 z, 0.88 anti syn), 4.95 (d, J = 1.8 z, 0.12 ), 4.89 (d, J = 2.4 z, 0.88 ), 4.49 (q, J = 6.0 z, 0.12 ), 4.12 (q, J = 7.2 z, 0.88 ), (m, 0.12 ), (m, 1.76 ), (m, 0.12 ), 2.92 (t, J = 6.0 z, 0.12 ), S7

8 (m, 0.12 ), (m, 1.88 ), (m, 0.88 ), (m, 0.88 ), (m, 1 ), (m, 0.12 ), (m, 1 ), 0.92 (s, 9 ), 0.12 (s, 3 ), 0.11 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = (syn), (anti), (syn), (anti), 76.2, 63.4 (syn), 62.8 (anti), 54.3, 33.3 (anti), 33.1 (syn), 29.8 (anti), 29.7 (syn), 25.8 (3C), 18.0, 4.3 (anti), 4.5 (syn), 4.8 (anti), 5.1 ppm (syn); RMS (ESI): calcd for C Si + [M + + ] , found Tosylate 27: To a stirred solution of alcohol 26 (12 mg, mmol) in C 2 Cl 2 (2 ml) at room temperature were added Et 3 N (55 µl, mmol), DMAP (6.0 mg, mmol) and para- Ts toluenesulfonyl chloride (37.7 mg, mmol). The resulting mixture was stirred for 8.5 h before it was quenched with 2 (10 ml) and diluted with Et 2 (5 ml). The 27 layers were separated, and the aqueous layer was extracted with Et 2 (3 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 30:1) afforded tosylate 27 (16.7 mg, 85%) as a colorless oil. 27: R f = 0.35 (silica gel, hexanes:etac 10:1); IR (film) ν max 2954, 2929, 2856, 1654, 1598, 1463, 1361, 1252, 1176, 1097, 949, 834, 775, 665 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.80 (dd, J = 18.0, 6.0 z, 2 ), 7.34 (d, J = 6.0 z, 2 ), 4.92 (dd, J = 4.5, 1.8 z, 1 ), 4.72 (dd, J = 4.5, 1.8 z, 1 ), 4.06 (dd, J = 5.4, 4.8 z, 1 ), (m, 2 ), (m, 1 ), (m, 1 ), 2.45 (s, 3 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.83 (s, 9 ), 0.02 (s, 3 ), 0.00 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 147.9, 144.7, 132.9, 129.8, 128.0, 108.1, 74.3, 69.6, 51.8, 33.3, 29.8, 25.7, 21.7, 17.9, 4.6, 4.9 ppm; RMS (ESI): calcd for C SSiNa + [M + Na + ] , found Nitrile 28: To a stirred solution of tosylate 27 (16.7 mg, mmol) in DMF (2 ml) at room temperature was added potassium cyanide (11 mg, 0.17 mmol). The resulting mixture was warmed to 60 C and stirred for 12 h before it was cooled to room temperature, quenched with 2 (10 ml) and diluted with Et 2 (5 ml). The layers were separated, and the aqueous layer was extracted with Et 2 (3 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column S8

9 CN chromatography (silica gel, hexanes:etac 40:1) afforded nitrile 28 (9.1 mg, 86%) as a colorless oil. 28: R f = 0.45 (silica gel, hexanes:etac 10:1); IR (film) ν max 2955, , 2857, 1658, 1472, 1463, 1378, 1361, 1253, 1142, 1120, 864, 836, 776, 669 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 5.04 (dd, J = 4.8, 1.8 z, 1 ), 4.96 (dd, J = 5.4, 2.4 z, 1 ), (m, 1 ), (m, 4 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.90 (s, 9 ), 0.11 (s, 3 ), 0.09 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 148.2, 118.4, 108.2, 76.7, 48.4, 32.7, 29.0, 25.9, 18.3, 18.1, 4.2, 4.7 ppm; RMS (ESI): calcd for C NSiNa + [M + Na + ] , found Aldehyde 29: To a stirred solution of nitrile 28 (9.1 mg, mmol) in C 2 Cl 2 (1 ml) at room temperature was added Dibal- (1.0 M in toluene, 0.11 ml, 0.11 mmol). The resulting mixture was C stirred for 1.5 h before it was quenched with N 4 Cl (10 ml, sat. aq.) and diluted with C 2 Cl 2 (5 ml). The layers were separated, and the aqueous layer was extracted with 29 C 2 Cl 2 (3 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 30:1) afforded aldehyde 29 (8.3 mg, 90%) as a colorless oil. 29: R f = 0.60 (silica gel, hexanes:etac 10:1); IR (film) ν max 2955, 2930, 2857, 1728, 1656, 1472, 1462, 1257, 1122, 1102, 884, 837, 776, 669 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 9.79 (s, 1 ), 4.87 (d, J = 2.4 z, 1 ), 4.72 (d, J = 2.4 z, 1 ), 3.76 (dd, J = 8.4, 6.0 z, 1 ), (m, 1 ), (m, 3 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.86 (s, 9 ), 0.03 (s, 3 ), 0.02 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 204.2, 152.3, 108.4, 79.4, 49.0, 47.1, 34.5, 30.7, 27.5 (3C), 19.6, 2.6, 3.2 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found S9

10 Carboxylic acid 13: To a stirred solution of aldehyde 29 (8.2 mg, mmol) and 2-methyl-2-butene (33 µl, 0.32 mmol) in t-bu/p 7 phosphate buffer (1:1, 0.8 ml) at room temperature was added 13 C 2 NaCl 2 (5.8 mg, mmol). The resulting mixture was stirred for 2 h before it was filtered through a short pad of anhydrous Na 2 S 4 /Si 2 and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 5:1) afforded carboxylic acid 13 (8.2 mg, 94%) as a colorless oil. 13: R f = 0.25 (silica gel, hexanes:etac 5:1); IR (film) ν max 2954, 2929, 2857, 1708, 1655, 1472, 1410, 1251, 1122, 1026, 862, 834, 774, 670 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = (br s, 1 ), 4.88 (d, J = 2.4 z, 1 ), 4.82 (d, J = 2.4 z, 1 ), 3.86 (dd, J = 13.8, 7.8 z, 1 ), 2.68 (br, 1 ), (m, 3 ), 2.26 (quintd, J = 8.4, 1.8 z, 1 ), (m, 1 ), (m, 1 ), 0.86 (s, 9 ), 0.05 (s, 3 ), 0.04 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 179.2, 152.4, 108.2, 79.3, 50.3, 37.4, 34.4, 30.7, 27.4 (3C), 19.6, 2.7, 3.2 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found α-diazo-β-keto ester 4: To a stirred solution of β-keto ester 15 (5.75 g, 17.6 mmol, 2.7:1 mixture of anti:syn diastereoisomers) in MeCN (180 ml) at room temperature were added p- 4 N 2 C 2 Me acetamidobenzenesulfonyl azide (6.35 g, 26.4 mmol) 4 and Et 3 N (4.9 ml, 35.2 mmol). The resulting mixture was stirred for 4 h before it was concentrated in vacuo. The resulting residue was diluted with C 2 Cl 2 (100 ml), filtered through a pad of Celite and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 9:1) afforded α-diazo-β-keto ester 4 [5.99 g, 97%, ca. 2.7:1 mixture of anti:syn diastereoisomers by 1 NMR (anti isomer shown)] as a yellow oil. 4: R f = 0.50 (silica gel, hexanes:etac 9:1); IR (film) ν max 2954, 2929, 2857, 2131, 1722, 1655, 1436, 1361, 1306, 1250, 1206, 1123, 1066, 1039, 1007, 864, 835, 775, 745 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 4.90 (d, J = 2.4 z, 0.27 ), 4.83 (d, J = 2.4 z, 0.73 ), 4.77 (d, J = 2.4 z, 0.27 ), 4.73 (d, J = 2.4 z, 0.73 ), (m, 0.27 ), (m, 0.73 ), 3.82 (s, 2.2 ), 3.81 (s, 0.8 ), (dd, J = 18.0, S10

11 9.0 z, 0.27 ), (m, 0.73 ), (m, 1.27 ), (m, 0.73 ), (m, 1 ), (m, 1 ), (m, 0.73 ), (m, 0.27 ), (m, 1 ), 0.83 (s, 6.6 ), 0.81 (s, 2.4 ), 0.02 ( 0.06) ppm (3 s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 192.5, 191.7, 162.0, 153.4, 152.2, 106.5, 105.9, 74.6, 52.4, 48.8, 45.3, 42.4, 39.6, 33.5, 33.3, 29.7, 29.5, 26.0, 18.2, 4.2, 4.4, 4.6, 5.0 ppm; RMS (ESI): calcd for C N 2 4 SiNa + [M + Na + ] , found Cyclopropane 16: To a stirred suspension of Rh 2 (Ac) 4 (75 mg, 0.17 mmol) in benzene (150 ml) at 90 C was added a solution of α-diazo-β-keto ester 4 (5.99 g, 17 mmol, 2.7:1 mixture of anti:syn 16 C 2 Me diastereoisomers) in benzene (450 ml) over a period of 40 min. The resulting mixture was heated for further 0.5 h before it was cooled to room temperature and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 4:1) afforded pure cyclopropane 16 (3.88 g, 70%) as a light yellow amorphous solid. 16: R f = 0.33 (silica gel, hexanes:etac 4:1); [α] 25 D = +102 (c = 1.00, CCl 3 ); IR (film) ν max 2953, 2930, 2857, 1729, 1462, 1437, 1360, 1336, 1277, 1250, 1218, 1169, 1124, 1081, 1023, 936, 912, 868, 837, 776, 671 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = (m, 1 ), 3.74 (s, 3 ), (m, 3 ), 2.18 (d, J = 5.4 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 1.56 (d, J = 5.4 z, 1 ), 0.85 (s, 9 ), 0.03 ppm (s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 207.4, 168.0, 79.1, 52.6, 49.9, 48.0, 44.4, 39.8, 34.2, 26.0 (3C), 24.8, 24.0, 18.2, 4.2, 4.5 ppm; RMS (ESI): calcd for C Si + [M + + ] , found Alcohol 17: To a stirred solution of TBS ether 16 (660 mg, 2.03 mmol) in TF (40 ml) at room 17 C 2Me temperature was added F py (2.6 ml, 30.5 mmol). The resulting mixture was stirred for 1.5 h before it was carefully poured into a solution of NaC 3 (20 ml, sat. aq.). The layers were separated, and the aqueous layer was extracted with C 2 Cl 2 (5 30 ml). The combined organic layers were washed with brine (30 ml), dried (Na 2 S 4 ) and concentrated in vacuo to afford alcohol 17 as a yellow oil, which was used directly S11

12 without further purification. For analytical purpose, crude alcohol 17 was purified by flash column chromatography (silica gel, hexanes:etac 4:1 1:1) to afford pure alcohol 17 as a light yellow oil : R f = 0.37 (silica gel, hexanes:etac 1:1); [α] = (c = 1.00, CCl 3 ); IR (film) ν max 3426, D 2954, 1717, 1437, 1335, 1275, 1219, 1070, 1024 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 3.85 (dd, J = 7.8, 7.2 z, 1 ), 3.72 (s, 3 ), (m, 2 ), (m, 2 ), 2.19 (d, J = 5.4 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 1.57 ppm (d, J = 5.4 z, 1 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 207.4, 167.9, 78.6, 52.7, 50.3, 47.5, 44.4, 39.7, 33.8, 25.5, 24.0 ppm; RMS (ESI): calcd for C Na + [M + Na + ] , found PMB ether 18: To a stirred solution of p-methoxybenzyl trichloroacetimidate 5 (1.44 g, 5.08 mmol) and alcohol 17 (crude, obtained above, 506 mg) in C 2 Cl 2 (50 ml) at room temperature was added PPTS PMB 18 C 2 Me (50 mg, 0.2 mmol). The resulting mixture was stirred for 24 h before it was quenched with NaC 3 (7 ml, sat. aq.). The layers were separated, and the aqueous layer was extracted with C 2 Cl 2 (2 15 ml). The combined organic layers were washed with brine (20 ml), dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 7:3 1:1) afforded PMB ether 18 (490 mg, 73% over the two steps from TBS ether 16) as a light yellow oil. 18: R f = 0.40 (silica gel, hexanes:etac 7:3); [α] 25 D = (c = 1.00, CCl 3 ); IR (film) ν max 2952, 1721, 1612, 1586, 1513, 1437, 1336, 1246, 1221, 1173, 1110, 1081, 1029, 822 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.22 (d, J = 9.0 z, 2 ), 6.86 (d, J = 9.0 z, 2 ), 4.48 (d, J = 11.4 z, 1 ), 4.38 (d, J = 11.4 z, 1 ), 3.79 (s, 3 ), 3.74 (s, 3 ), 3.62 (dd, J = 14.4, 7.2 z, 1 ), (m, 1 ), (m, 2 ), 2.21 (d, J = 5.4 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 1.57 ppm (d, J = 5.4 z, 1 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 207.4, 167.9, 159.5, 130.3, (2C), (2C), 85.4, 71.8, 55.5, 52.7, 50.4, 45.9, 44.3, 40.5, 31.0, 24.5, 24.4 ppm; RMS (ESI): calcd for C [M + + ] , found S12

13 Enol triflate 19: To a stirred solution of ketone 18 (117 mg, 0.35 mmol) in TF (3 ml) at 78 C was added LDA [0.51 M [prepared from a solution of n-buli (2.2 M in hexane, 800 µl, 1.76 mmol) and Tf diisopropylamine (250 µl, 1.77 mmol) in TF (2.4 ml) at 0 C], 0.71 PMB 19 CMe mmol, 1.4 ml]. The resulting mixture was stirred for 1 h before a solution of PhNTf 2 (206 mg, 0.53 mmol) in TF (2 ml) was added. The resulting mixture was stirred for 1 h and then warmed to 0 C and stirred for further 1 h. The reaction mixture was quenched with N 4 Cl (5 ml, sat. aq.), the layers were separated and the aqueous layer was extracted with Et 2 (3 10 ml). The combined organic layers were washed with brine (15 ml), dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 9:1) afforded enol triflate 19 (126 mg, 77%) as a light yellow oil. 19: R f = 0.40 (silica gel, hexanes:etac 9:1); [α] 25 D = (c = 1.00, CCl 3 ); IR (film) ν max 2989, 2870, 1729, 1613, 1514, 1423, 1290, 1248, 1211, 1139, 1095, 1035, 912, 817 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.23 (d, J = 8.4 z, 2 ), 6.87 (d, J = 8.4 z, 2 ), 5.54 (d, J = 3.0 z, 1 ); 4.43 (dd, J = 17.4, 10.8 z, 2 ), 3.79 (s, 3 ), (m, 1 ), 3.73 (s, 3 ), 2.81 (m, 1 ), (m, 1 ), 2.08 (d, J = 5.4 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 1.29 ppm (d, J = 5.4 z, 1 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 168.7, 159.5, 149.1, 130.3, (2C), (J C-F = 318 z), 119.0, (2C), 84.5, 71.4, 55.5, 53.5, 52.5, 46.1, 37.8, 31.1, 27.4, 25.7 ppm; RMS (ESI): calcd for C F 3 7 SNa + [M + Na + ] , found TBS ether 21: To a stirred solution of methyl ester 19 (126 mg, 0.27 mmol) in C 2 Cl 2 (3 ml) at 78 C was added Dibal- (1.0 M in toluene, 680 µl, 0.68 mmol). The resulting mixture was stirred for 1 h PMB Tf before it was diluted with C 2 Cl 2 (5 ml), quenched with sodium potassium tartrate (5 ml, sat. aq.), warmed to room temperature and stirred for 0.5 h. 21 TBS The layers were separated, and the aqueous layer was extracted with C 2 Cl 2 (3 10 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo to afford alcohol 20 as a yellow oil, which was used directly without further purification. S13

14 To a stirred solution of alcohol 20 (obtained above) in C 2 Cl 2 (3 ml) at 0 C were added 2,6- lutidine (125 µl, 1.08 mmol) and Tf (124 µl, 0.54 mmol). The resulting mixture was warmed to room temperature and stirred for 1 h before it was concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 100:1) afforded TBS ether 21 (132 mg, 89% over the two steps) as a light 25 yellow oil. 21: R f = 0.50 (silica gel, hexanes:etac 20:1); [α] = (c = 1.00, CCl 3 ); IR (film) ν max 2953, 2932, 2860, 1614, 1514, 1422, 1248, 1211, 1143, 1086, 838, 777, 604 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.24 (d, J = 8.4 z, 2 ), 6.86 (d, J = 8.4 z, 2 ), 5.46 (d, J = 2.4 z, 1 ), 4.44 (dd, J = 10.2, 5.4 z, 2 ), 4.15 (d, J = 11.4 z, 1 ), 3.79 (s, 3 ), 3.66 (dd, J = 19.2, 11.4 z, 1 ), 3.15 (d, J = 11.4 z, 1 ), 2.73 (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.99 (d, J = 5.4 z, 1 ), 0.83 (s, 9 ), 0.80 (d, J = 5.4 z, 1 ), 0.02 (s, 3 ), 0.00 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 159.4, 152.8, 130.6, (2C), (J C-F = 319 z), 116.2, (2C), 85.3, 71.3, 60.5, 55.5, 53.7, 36.4, 35.2, 31.1, 25.9 (3C), 25.4, 22.6, 18.3, 5.6 (2C) ppm; RMS (ESI): calcd for C F 3 6 SSiNa + [M + Na + ] , found D Allylic alcohol 23 (from enol triflate 21): To a stirred solution of enol triflate 21 (9.0 mg, mmol), Pd(PPh 3 ) 4 (1.0 mg, 0.87 µmol) and lithium chloride (2.1 mg, 0.05 mmol) in TF (1.5 ml) at 70 PMB C was added a solution of tri-n-butylstannylmethanol 24 6 (16.1 mg, 0.05 mmol) in TF (1 ml) over a period of 1 h. The resulting mixture was stirred for 1 h before it was quenched with 2 (5 ml) and diluted with EtAc (5 ml). The layers were 23 separated, and the aqueous layer was extracted with EtAc (3 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 10:1) afforded alcohol 23 (6.2 mg, 82%) as a colorless oil. Due to its moderate stability (TBS migration, especially when concentrated), allylic 25 alcohol 23 was used without prolonged storage. 23: R f = 0.40 (silica gel, hexanes:etac 3:1); [α] = (c = 1.00, CCl 3 ); IR (film) ν max 3458, 2953, 2930, 2857, 1613, 1514, 1464, 1389, 1342, 1302, 1248, 1172, 1072, 1036, 1005, 836, 775 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.25 (d, J = 8.4 z, 2 S14 D

15 ), 7.25 (d, J = 8.4 z, 2 ), 5.47 (s, 1 ), 4.44 (dd, J = 15.6, 11.4 z, 2 ), (m, 2 ), 3.78 (s, 3 ), (m, 3 ), (m, 1 ), 2.71 (br s, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.90 ppm (d, J = 4.8 z, 1 ), 0.87 (s, 9 ), 0.58 (d, J = 4.8 z, 1 ), 0.07 (s, 3 ), 0.05 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 159.3, 149.5, 130.9, (2C), 126.7, (2C), 85.5, 71.1, 64.3, 60.9, 58.6, 55.5, 38.3, 37.1, 31.9, 26.0 (3C), 25.6, 24.6, 18.4, 5.4 (2C) ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found α,β-unsaturated methyl ester 22: To a stirred solution of enol triflate 21 (132 mg, 0.24 mmol) in DMF/Me (14 ml, 5:9) at room temperature were added Et 3 N (100 µl, 0.72 mmol) and Pd(PPh 3 ) 4 Me 2 C (14 mg, mmol). The resulting mixture was warmed to 50 C and heated for 1 PMB 22 h under a C atmosphere (1 atm) before it was quenched with N 4 Cl (10 ml, sat. aq.). The resulting mixture was extracted with Et 2 (3 15 ml), and the combined organic layers were washed with brine (20 ml), dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 20:1) afforded α,β-unsaturated methyl ester 22 (93 mg, 85%) as a light yellow oil. 22: R f = 0.40 (silica gel, hexanes:etac 20:1); [α] 25 = (c = 1.00, CCl 3 ); IR (film) ν max 2952, 2931, 2857, 1717, 1613, 1514, 1464, 1437, 1393, 1301, 1248, 1228, 1206, 1147, 1109, 1079, 1036, 837, 777, cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.30 (d, J = 8.4 z, 2 ), 6.90 (d, J = 8.4 z, 2 ), 6.62 (d, J = 2.4 z, 1 ), 4.61 (d, J = 10.8 z, 1 ), 4.50 (s, 2 ), 3.83 (s, 3 ), (m, 1 ), 3.76 (s, 3 ), 3.11 (d, J = 10.4 z, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.94 (d, J = 5.4 z, 1 ), 0.84 (s, 9 ), 0.59 (d, J = 5.4 z, 1 ), 0.02 (s, 3 ), 0.00 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 165.1, 159.2, 142.5, 140.3, 130.6, (2C), (2C), 84.7, 71.0, 62.0, 58.7, 55.3, 51.3, 38.1, 36.2, 31.6, 25.7 (3C), 25.4, 22.0, 18.0, 5.7 (2C) ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found D S15

16 Allylic alcohol 23 (from methyl ester 22): To a stirred solution of α,β-unsaturated methyl ester 22 (1,09 g, 2.37 mmol) in C 2 Cl 2 (30 ml) at room temperature was added Dibal- (1.0 M in toluene, 5.9 PMB ml, 5.93 mmol). The resulting mixture was stirred for further 0.5 h before it was diluted with C 2 Cl 2 (15 ml), quenched with sodium potassium tartrate (20 ml, sat. aq.), warmed to room temperature and stirred for 0.5 h. The layers were separated, 23 and the aqueous layer was extracted with C 2 Cl 2 (3 20 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 7:3) afforded allylic alcohol 23 (1.02 g, 100%) as a colorless oil. Alcohol 30: To a stirred solution of allylic alcohol 23 (177 mg, 0.41 mmol) in benzene (20 ml) at room temperature was added Adam s catalyst (Pt 2 2, 106 mg, 60% wt/wt). The resulting mixture was stirred under an atmosphere of hydrogen (1 atm) for 2 h before it was filtered PMB 30 through a pad of Celite and the filtrate was concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 10:1) afforded alcohol 30 (123 mg, 69%) as a light yellow oil. Due to its moderate stability (TBS migration, especially when concentrated), alcohol 30 was used without prolonged storage. 30: R f = 0.45 (silica gel, hexanes:etac 3:1); [α] 25 D = (c = 1.00, CCl 3 ); IR (film) ν max 3469, 2932, 2858, 1613, 1514, 1463, 1360, 1302, 1248, 1172, 1065, 1038, 835, 777 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.24 (d, J = 9.0 z, 2 ), 6.84 (d, J = 9.0 z, 2 ), 4.41 (dd, J = 17.4, 11.4 z, 2 ), 3.92 (d, J = 11.4 z, 1 ), (m, 2 ), 3.64 (s, 3 ), (m, 1 ), (m, 1 ), 3.37 (d, J = 11.4 z, 1 ), (m, 2 ), (m, 2 ), (m, 2 ), (m, 1 ), (m, 1 ), 0.89 (s, 9 ), 0.57 (d, J = 4.8 z, 1 ), 0.51 (d, J = 4.8 z, 1 ), 0.08 (s, 3 ), 0.06 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 159.2, 131.3, (2C), (2C), 85.4, 71.1, 66.1, 65.4, 55.5, 53.1, 48.9, 42.2, 35.9, 33.6, 32.5, 26.0 (3C), 25.5, 22.1, 18.4, 5.4, 5.5 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found S16

17 Aldehyde 31: To a stirred solution of alcohol 30 (680 mg, 1.57 mmol) in C 2 Cl 2 (20 ml) at room temperature were added NaC 3 (793 mg, 9.44 mmol) and DMP (1.33 g, 3.14 mmol). The resulting mixture was stirred for 2 h before it was quenched with Na 2 S 2 3 (30 ml, sat. aq.) PMB 31 and diluted with Et 2 (30 ml). The layers were separated, and the aqueous layer was extracted with Et 2 (3 20 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 5:1) afforded aldehyde 31 (627 mg, 93%) as a white solid. 31: R f = 0.55 (silica gel, 25 hexanes:etac 3:1); m.p. = C (EtAc/hex); [α] = (c = 1.00, CCl 3 ); IR (film) ν max 2928, 2853, 2741, 1715, 1614, 1587, 1514, 1462, 1403, 1347, 1304, 1247, 1177, 1059, 1032, 1005, 965, 938, 835, 775, 669 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 9.66 (s, 1 ), 7.30 (d, J = 9.0 z, 2 ), 6.90 (d, J = 9.0 z, 2 ), 4.54 (d, J = 11.4 z, 1 ), 4.46 (d, J = 11.4 z, 1 ), 4.09 (d, J = 10.8 z, 1 ), 3.83 (s, 3 ), 3.72 (dd, J = 13.2, 6.6 z, 1 ), 3.21 (d, J = 10.8 z, 1 ), (m, 1 ), (m, 1 ), (m, 2 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.88 (s, 9 ), 0.66 (s, 2 ), 0.04 (s, 3 ), 0.03 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 203.0, 159.2, 130.8, (2C), (2C), 84.1, 71.2, 63.6, 57.5, 55.3, 53.0, 39.6, 38.0, 31.5, 27.9, 25.7 (3C), 24.1, 19.0, 18.1, 5.8 (2C) ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found D α,β-unsaturated ester 32: To a stirred solution of trimethyl phosphonoacetate (0.68 ml, 4.20 mmol) in TF (15 ml) at 0 C was added n-buli (2.2 M in hexane, 1.6 ml, 3.52 mmol). The resulting mixture was stirred for 45 min before a solution of aldehyde 31 (611 mg, 1.42 mmol) in PMB Me 2 C 32 TF (5 ml) was added. The resulting mixture was stirred for 1 h, warmed to room temperature and stirred for a further 1 h before it was diluted with Et 2 (20 ml) and quenched with N 4 Cl (20 ml, sat. aq.). The layers were separated and the aqueous layer was extracted with Et 2 (3 15 ml). The combined organic layers were washed with brine (20 ml), dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 4:1 S17

18 1:1) afforded α,β-unsaturated ester 32 (627 mg, 96%, ca. 4:1 mixture of E/Z isomers by 1 NMR 25 spectroscopic analysis) as a colorless oil. 32: R f = 0.60 (silica gel, hexanes:etac 3:1); [α] = (c = 1.00, CCl 3 ); IR (film) ν max 2950, 2856, 1722, 1651, 1613, 1586, 1513, 1463, 1436, 1390, 1350, 1301, 1247, 1171, 1063, 1038, 1006, 938, 835, 775, 667 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.24 (d, J = 9.0 z, 2 ), 7.08 (dd, J = 15.6, 10.2 z, 0.8 ), 6.85 (d, J = 9.0 z, 2 ), 6.39 (dd, J = 11.4, 10.8 z, 0.2 ), 5.72 (d, J = 15.6 z, 0.8 ), 5.60 (dd, J = 11.4, 1.2 z, 0.2 ), 4.45 (d, J = 12.0 z, 0.2 ), 4.44 (d, J = 11.4 z, 0.8 ), 4.38 (d, J = 11.4 z, 0.8 ), 4.37 (d, J = 11.4 z, 0.2 ), 3.78 (s, 3 ), (m, 5 ), 3.26 (d, J = 10.8 z, 0.8 ), 3.14 (d, J = 11.4 z, 0.2 ), (m, 0.8 ), 2.19 (dd, J = 12.0, 4.8 z, 1 ), (m, 1 ), (m, 1.2 ), (m, 1.8 ), (m, 1 ), (m, 1 ), (m, 0.2 ), 0.85 (s, 7.2 ), 0.83 (s, 1.8 ), 0.75 (d, J = 4.8 z, 0.8 ), 0.72 (d, J = 4.8 z, 0.2 ), 0.68 (d, J = 4.8 z, 0.2 ), 0.63 (d, J = 4.8 z, 0.8 ), 0.03 ( 0.05) ppm (3 s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 167.2, 159.3, 154.5, 152.7, 131.0, (2C), 120.1, 117.5, (2C), 85.1, 84.8, 70.9, 70.6, 64.8, 64.6, 55.5, 53.5, 53.4, 51.5, 51.2, 49.6, 41.0, 40.8, 39.3, 39.0, 37.7, 31.7, 31.5, 26.0 (3C), 25.5, 25.4, 22.8, 18.3, 5.5, 5.6 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found D Methyl ester 33: To a stirred solution of enoate 32 (611 mg, 1.26 mmol) in Me (20 ml) at 0 C was added NiCl (90 mg, 0.38 mmol) followed by NaB 4 (96 mg, 2.52 mmol). The resulting mixture was stirred at room temperature for 1 h before it was filtered through a short pad PMB Me 2 C 33 of Celite and the filtrate was concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 4:1) afforded methyl ester 33 as a colorless oil (602 mg, 98%). 33: R f = 0.60 (silica gel, hexanes:etac 3:1); [α] 25 D = (c = 1.00, CCl 3 ); IR (film) ν max 2951, 2856, 1738, 1612, 1586, 1512, 1462, 1436, 1360, 1301, 1246, 1170, 1066, 1037, 1006, 938, 833, 774, 666 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 7.29 (d, J = 9.0 z, 2 ), 6.89 (d, J = 9.0 z, 2 ), 4.49 (d, J = 11.4 z, 1 ), 4.42 (d, J = 11.4 z, 1 ), 3.82 (s, 3 ), 3.78 (d, J = 11.4 z, 1 ), 3.69 (s, 3 ), 3.66 (q, J = 4.8 z, 1 ), 3.41 (d, J = 11.4 z, 1 ), S18

19 (m, 1 ), (m, 1 ), (m, 2 ), (m, 2 ), (m, 3 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.90 (s, 9 ), 0.72 (d, J = 4.8 z, 1 ), 0.56 (d, J = 4.8 z, 1 ), 0.06 (s, 3 ), 0.04 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 174.3, 159.0, 131.0, (2C), (2C), 84.9, 70.4, 64.6, 55.3, 52.6, 51.5, 45.8, 40.9, 37.2, 37.0, 33.7, 31.5, 28.3, 25.9 (3C), 25.3, 23.7, 18.1, 5.6, 5.7 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found Diol 35: To a stirred solution of methyl ester 33 (310 mg, mmol) in C 2 Cl 2 (25 ml) at 78 C was added Dibal- (1.0 M in toluene, 1.59 ml, 1.59 mmol). The resulting mixture was stirred for min, warmed to 0 C and stirred for 40 min before it was quenched with EtAc (20 ml) and sodium potassium tartrate (20 ml, sat. aq.). The resulting mixture was warmed to room temperature and stirred for 1 h. The layers were separated, and the aqueous layer was extracted with EtAc (4 20 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo to afford alcohol 34, which was used directly without further purification. Alternatively, alcohol 34 could be obtained from α,β-unsaturated ester 32 as follows: To a stirred solution of α,β-unsaturated ester 32 (10.1 mg, mmol) in TF (1 ml) at 78 C was added lithium triethylborohydride (1.0 M in TF, 164 μl, mmol). The resulting mixture was stirred for 3 h before it was allowed to warm to room temperature, quenched with N 4 Cl (10 ml, sat. aq.) and diluted with EtAc (5 ml). The layers were separated, and the aqueous layer was extracted with EtAc (5 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 5:1) afforded alcohol 34 (6.0 mg, 63%), which was used directly in the next step. To a stirred solution of alcohol 34 (obtained above) in C 2 Cl 2 /p 7 phosphate buffer (27.5 ml, 10:1) at 0 C was added DDQ (222 mg, mmol). The resulting mixture was stirred for 40 min before a second batch of DDQ (222 mg, mmol) was added. The resulting mixture was stirred at 0 S19

20 C for further 40 min before it was quenched with NaC 3 (20 ml, sat. aq.). The layers were separated, and the aqueous layer was extracted with C 2 Cl 2 (6 20 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 2:1 1:2) afforded diol 35 (207 mg, 96% over the two steps) as a colorless oil. This compound could be stored at 20 C as a C 2 Cl 2 solution in the presence of two drops of 2 to avoid 25 TBS migration. 35: R f = 0.20 (silica gel, hexanes:etac 1:1); [α] = 2.2 (c = 1.00, CCl 3 ); IR (film) ν max 3327, 2929, 2857, 1471, 1462, 1436, 1389, 1360, 1250, 1059, 1005, 990, 938, 833, 772, 734, 665 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 3.98 (q, J = 4.8 z, 1 ), 3.75 (d, J = 11.4 z, 1 ), 3.66 (q, J = 6.4 z, 2 ), 3.46 (d, J = 11.4 z, 1 ), (m, 1 ), (m, 2 ), (m, 3 ), (m, 1 ), (m, 1 ), 1.63 (br s, 1 ) (m, 2 ), (m, 3 ), 0.90 (s, 9 ), 0.76 (d, J = 4.2 z, 1 ), 0.59 (d, J = 4.8 z, 1 ), 0.05 (s, 3 ), 0.04 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 78.7, 64.7, 63.3, 55.7, 46.1, 40.8, 37.3, 37.1, 34.9, 32.3, 28.9, 25.9, 24.9, 24.1, 18.2, 5.5, 5.6 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found D Keto aldehyde 3: To a stirred solution of diol 35 (50 mg, mmol) in C 2 Cl 2 (5 ml) at room temperature was added NaC 3 (198 mg, 2.36 mmol) followed by DMP (250 mg, mmol). The resulting mixture was stirred for 2 h before it was quenched with Na 2 S 2 3 (10 ml, 3 sat. aq.) and diluted with Et 2 (10 ml). The layers were separated, and the aqueous layer was extracted with Et 2 (4 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 10:1) afforded keto aldehyde 3 (40 mg, 81%) as a colorless oil. 3: R f = 0.60 (silica gel, 25 hexanes:etac 5:1); [α] = (c = 1.00, CCl 3 ); IR (film) ν max 2953, 2857, 1738, 1726, 1462, D 1390, 1361, 1252, 1150, 1058, 1006, 938, 835, 774, 666 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 9.74 (dd, J = 1.8, 1.2 z, 1 ), 3.82 (d, J = 11.4 z, 1 ), 3.65 (d, J = 11.4 z, 1 ), (m, 3 ), (m, 1 ), (m, 2 ), (m, 2 ), 1.85 (dd, J = 13.5, 8.4 z, 2 ), (m, 1 ), (m, 1 ), 0.89 (s, 9 ), 0.83 (d, J = 5.4 z, 1 ), 0.73 (d, J = 5.4 z, 1 ), 0.07 (s, S20

21 3 ), 0.06 ppm (s, 3 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 221.0, 202.4, 64.4, 54.6, 43.4, 42.9, 39.1, 38.1, 36.6, 29.4, 25.9, 25.4, 23.1, 19.3, 18.2, 5.5, 5.6 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found Diol 37: To a stirred solution of keto aldehyde 3 (111 mg, mmol) and MPA (1.15 ml, 6.63 mmol) in TF (degassed, 33 ml) at 78 C was added SmI 2 (0.1 M in TF, 16.6 ml, 1.66 mmol). The resulting mixture was stirred for 1 h, warmed to room temperature and stirred for further 0.5 h. The reaction mixture was quenched with NaC 3 (30 ml, sat. aq.) 37 and diluted with C 2 Cl 2 (30 ml). The layers were separated, and the aqueous layer was extracted with C 2 Cl 2 (6 10 ml), and the combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 8:1) afforded diol 37 (56 mg, 50%) as a white amorphous solid. 37: R f = 0.60 (silica gel, hexanes:etac 1:1); [α] 25 D = (c = 1.00, CCl 3 ); IR (film) ν max 3397, 2927, 2857, 1462, 1361, 1252, 1082, 996, 836, 774, 663 cm 1 ; 1 NMR (600 Mz, CD 3 CN, 67 C): δ = 4.02 (d, J = 10.8 z, 1 ), 3.62 (dd, J = 7.8, 3.6 z, 1 ), 3.31 (d, J = 10.8 z, 1 ), 3.06 (br s, 1 ), 3.03 (br d, J = 3.0 z, 1 ), (m, 1 ), 2.11 (d, J = 7.2 z, 1 ), (m, 2 ), (m, 2 ), (m, 2 ), (m, 1 ), (m, 1 ), (m, 1 ), (m, 1 ), 0.92 (s, 9 ), 0.58 (d, J = 4.8 z, 1 ), 0.52 (d, J = 4.8 z, 1 ), 0.07 ppm (s, 6 ); 13 C NMR (150 Mz, CD 3 CN, 67 C): δ = 84.4, 78.1, 65.8, 57.8, 41.3, 40.7, 40.2, 36.5, 28.6, 28.1, 27.1, 26.9, 24.8, 19.7, 17.7, 4.3, 4.5 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found Carbonate 37a: To a stirred solution of diol 37 (4.3 mg, mmol) in benzene (2 ml) at room temperature was added 1,1 -carbonyldiimidazole (CDI, 12.4 mg, mmol). The resulting mixture was heated at reflux for 3 h before it was concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 30:1) afforded carbonate 37a (4.0 mg, 87%) as a white amorphous solid. 37a: R f = 0.70 (silica gel, hexanes:etac 5: 1); IR (film) ν max 2923, 2852, 1807, 1726, 1463, 1259, 1072, 1023, 838, 778 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 4.72 (dd, J = 8.4, 1.8 z, 1 ), 3.77 (d, J = 10.8 z, 1 S21

22 ), 3.61 (d, J = 10.8 z, 1 ), 2.54 (d, J = 6.6 z, 1 ), (m, 2 ), (m, 1 ), (m, 2 ), (m, 1 ), (m, 1 ), 1.76 (d, J = 14.4 z, 1 ), (m, 2 ), 1.40 (quint, J = 7.2 z, 1 ), 0.92 (s, 9 ), 0.71 (d, J = 4.8 z, 1 ), 0.65 (d, J = 5.4 z, 1 ), 0.08 ppm (s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 37a 154.9, 92.2, 85.7, 64.1, 51.5, 38.9, 35.6, 35.4, 34.8, 26.9, 25.9, 25.3, 25.1, 21.3, 18.3, 16.9, 5.4, 5.5 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found Keto acetate 39: To a stirred solution of diol 37 (53.4 mg, mmol) in C 2 Cl 2 (3 ml) at room temperature was added DMP (100 mg, mmol), followed by NaC 3 (80 mg, mmol). The Ac resulting mixture was stirred for 45 min before it was quenched with Na 2 S 2 3 (10 ml, sat. aq.) and diluted with Et 2 (8 ml). The layers were separated, and the 39 aqueous layer was extracted with Et 2 (5 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo to afford the crude hydroxy ketone 38, which was used directly for the next step without further purification. To a stirred solution of crude hydroxy ketone 38 (obtained above) in C 2 Cl 2 (6 ml) at room temperature were added Et 3 N (0.22 ml, 1.58 mmol) and DMAP (19.4 mg, mmol), followed by Ac 2 (0.15 ml, 1.58 mmol). The resulting mixture was stirred for 24 h before a second batch of Et 3 N (0.22 ml, 1.58 mmol), DMAP (19.4 mg, mmol) and Ac 2 (0.15 ml, 1.58 mmol) were added. The resulting mixture was stirred for further 24 h before it was quenched with NaC 3 (15 ml, sat. aq.) and diluted with EtAc (10 ml). The layers were separated, and the aqueous layer was extracted with EtAc (4 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 20:1) afforded keto acetate 39 (48.5 mg, 81% 25 over the two steps) as a colorless oil. 39: R f = 0.56 (silica gel, hexanes:etac 5:1); [α] = (c = 1.00, CCl 3 ); IR (film) ν max 2928, 2856, 1751, 1715, 1463, 1365, 1241, 1060, 1007, 937, 835, 774, 663 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 3.89 (d, J = 10.8 z, 1 ), 3.45 (d, J = 10.8 z, 1 ), D S22

23 (m, 2 ), 2.54 (d, J = 7.8 z, 1 ), 2.38 (dd, J = 7.2, 3.9 z, 1 ), 2.35 (dd, J = 12.6, 6.6 z, 1 ), (m, 2 ), 2.12 (s, 3 ), (m, 1 ), 1.86 (td, J = 9.6, 3.3 z, 1 ), (m, 2 ), 1.42 (d, J = 15.0 z, 1 ), 0.91 (s, 9 ), 0.71 (d, J = 5.4 z, 1 ), 0.69 (d, J = 5.4 z, 1 ), 0.07 ppm (s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 205.8, 170.4, 94.5, 64.0, 53.6, 39.5, 38.8, 36.2, 34.8, 34.4, 30.7, 30.3, 25.9, 25.1, 21.3, 18.3, 15.7, 5.3, 5.4 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found Ketone 40: To a stirred solution of keto acetate 39 (45 mg, mmol) and Me (24 µl, mmol) in TF (2 ml, degassed) at 78 C was added SmI 2 (0.1 M in TF, 2.4 ml, 0.24 mmol). The resulting mixture was stirred for 15 min before it was quenched with N 4 Cl (10 ml, sat. aq.) and diluted with EtAc (5 ml). The layers were separated, and the aqueous 40 layer was extracted with EtAc (4 5 ml). The combined organic layers were dried (Na 2 S 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes:etac 60:1) afforded ketone 40 (35 mg, 92%) as a colorless oil. 40: R f = 0.60 (silica gel, hexanes:etac 5:1); [α] 25 = (c = 1.00, CCl 3 ); IR (film) ν max 2929, 2856, 1697, 1463, 1360, D 1251, 1063, 1006, 927, 834, 773, 660 cm 1 ; 1 NMR (600 Mz, CDCl 3 ): δ = 3.91 (d, J = 10.8 z, 1 ), 3.31 (d, J = 10.8 z, 1 ), 2.82 (t, J = 8.4 z, 1 ), 2.74 (td, J = 12.0, 5.4 z, 1 ), (m, 1 ), 2.37 (t, J = 8.4 z, 1 ), (m, 1 ), (m, 4 ), 1.79 (dd, J = 12.0, 7.8 z, 1 ), (m, 1 ), (m, 1 ), 1.34 (d, J = 14.4 z, 1 ), 0.91 (s, 9 ), 0.71 (d, J = 5.4 z, 1 ), 0.70 (d, J = 5.4 z, 1 ), 0.06 ppm (s, 6 ); 13 C NMR (150 Mz, CDCl 3 ): δ = 215.8, 64.2, 55.6, 47.0, 40.8, 39.8, 36.4, 34.5, 30.8, 29.2, 28.1, 25.9, 25.7, 18.3, 15.9, 5.2, 5.4 ppm; RMS (ESI): calcd for C SiNa + [M + Na + ] , found Alcohol 41: To a stirred solution of TBS ether 40 (100 mg, mmol) in Me/C 2 Cl 2 (15 ml, 1:1) at room temperature was added Ts 2 (60 mg, mmol). The resulting mixture was stirred for 1 h before it was quenched with NaC 3 (15 ml, sat. aq.) and diluted with C 2 Cl 2 (10 ml). The layers were separated, and the aqueous layer was extracted with C 2 Cl 2 (4 8 ml). The combined organic S23