Stereoselective Synthesis of the CDE Ring System of Antitumor Saponin Scillascilloside E-1

Stereoselective Synthesis of the CDE Ring System of Antitumor Saponin Scillascilloside E-1 Yoshihiro Akahori, Hiroyuki Yamakoshi, Shunichi Hashimoto, and Seiichi Nakamura*, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-603, Japan, and Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-012, Japan nakamura@phar.nagoya-cu.ac.jp Table of Contents 1. General Information S2 2. Experimental Procedures S3 3. Additional References S24 4. Copies of 1 H and C NMR Spectra S25 5. NESY Correlation Diagrams for Iodolactone, Enone 4 and Ketone 3, and Copies of NESY Spectra S50 S1

1. General Information ptical rotations were recorded on a digital polarimeter. Infrared (IR) spectra were recorded on an FT- IR spectrophotometer and absorbance bands are reported in wavenumber (cm 1 ). Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded with tetramethylsilane (δ H 0.00) or C 6 H 6 (δ H 7.16) as an internal standard. Coupling constants (J) are reported in hertz (Hz). Abbreviations of multiplicity are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data are presented as follows: chemical shift, multiplicity, coupling constants and integration. Carbon nuclear magnetic resonance ( C NMR) spectra were recorded with CDCl 3 (δ C 77.0) or C 6 D 6 (δ C 127.0) as an internal standard. Column chromatography was carried out on silica gel 60 N (63 210 μm or 40 50 μm) or NH silica gel (100 0 mesh). Analytical thin layer chromatography (TLC) was carried out with 0.25 mm silica gel plates. Visualization was accomplished with ultraviolet light and anisaldehyde or phosphomolybdic acid stain, followed by heating. Reagents and solvents were purified by standard means or used as received unless otherwise noted. Dehydrated dichloromethane (CH 2 Cl 2 ) and tetrahydrofuran (THF, stabilizer free) were purchased. Chlorotrimethylsilane (TMSCl) and diisopropylamine (i-pr 2 NH) were distilled from calcium hydride. thanesulfonyl azide (MsN 3 ), 26 2-iodoxybenzoic acid (IBX), 27 trimethylsilyldiazomethane (TMSCHN 2 ) 2 and Dess Martin periodinane 29 were prepared according to literature procedures. All reactions were conducted under an argon atmosphere unless otherwise noted. S2

2. Experimental Procedures H 11 diketene (1.1 equiv) DMAP (0.1 equiv) Et 2, 10 C rt 9 h 35 MsN 3 (1.5 equiv) Et 3 N (4. equiv) CN, 2 h % (2 steps) N 2 12 (R)-3-thylcyclohex-2-en-1-yl 2-Diazo-3-oxobutanoate (12). Diketene (1.50 ml, 19.6 mmol) was added to a solution of alcohol 11 5,6 (2.00 g,. mmol) and DMAP (2 mg, 1.79 mmol) in Et 2 (100 ml) at 10 C. After 9 h of stirring at room temperature, the reaction was quenched with 0. M aqueous KH (50 ml), and the resulting mixture was extracted with Et 2 (2 100 ml). The combined organic extracts were washed with brine (40 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (3.97 g), which was used without further purification. thanesulfonyl azide (3.24 g, 26. mmol) was added to a solution of the crude acetoacetate 35 (3.97 g) and Et 3 N (12.0 ml, 6.1 mmol) in acetonitrile (100 ml) at 0 C. After 2 h of stirring at room temperature, the reaction mixture was partitioned between AcEt (300 ml) and H 2 (0 ml), and the aqueous layer was extracted with AcEt (300 ml). The combined organic extracts were washed with brine (0 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (6.31 g), which was purified by column chromatography (silica gel 0 g, 10:1 n- hexane/acet) to give α-diazo-β-ketoester 12 (3.50 g, % for two steps) as a yellow oil. R f 0.66 (3:1 n-hexane/acet); [α] 25 D +146.9 (c 1.10, CHCl 3 ); IR (neat) 293, 29,, 1659, 66, 01, 1247, 17, 1060 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.63 1.6 (m, 4H), 1.73 (br s, 3H), 1. 2.05 (m, 2H), 2.4 (s, 3H), 5.3 (m, 1H), 5.51 (m, 1H); C NMR (125.7 MHz, CDCl 3 ) δ 1. (CH 2 ), 23.7 (CH 3 ), 2.0 (CH 2 ), 2.3 (CH 3 ), 29. (CH 2 ), 70.3 (CH), 119.3 (CH), 142.1 (C), 161.3 (C), 190.4 (C); HRMS (FAB) m/z [M + H] + calcd for C 11 H N 2 3 223.103; found 223.1101. N 2 12 LiH (3 equiv) THF/H 2 (1:1) 0 C, 30 min 6% 10 N 2 (R)-3-thylcyclohex-2-en-1-yl Diazoacetate (10). Lithium hydroxide (106 mg, 4.44 mmol) was S3

added to a solution of α-diazo-β-ketoester 12 (329 mg, 1.4 mmol) in THF/H 2 (1:1, 1 ml) at 0 C. After 30 min of stirring, the reaction mixture was partitioned between CH 2 Cl 2 (40 ml) and H 2 (10 ml), and the aqueous layer was extracted with CH 2 Cl 2 (3 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (309 mg), which was purified by column chromatography (silica gel 10 g, 10:1 n-hexane/acet with 3% Et 3 N) to give diazoacetate 10 (230 mg, 6%) as a yellow oil. R f 0.66 (3:1 n-hexane/acet); [α] 27 D +4.3 (c 1.21, CHCl 3 ); IR (neat) 3119, 293, 210, 16, 1435, 5, 1242, 116 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.64 1.2 (m, 4H), 1.71 (br s, 3H), 1. 2.02 (m, 2H), 4.72 (s, 1H), 5.33 (m, 1H), 5.49 (m, 1H); C NMR (125.7 MHz, CDCl 3 ) δ 1.9 (CH 2 ), 23.6 (CH 3 ), 2.1 (CH 2 ), 29. (CH 2 ), 46.2 (CH), 69.3 (CH), 119.9 (CH), 141.2 (C), 166.6 (C); Anal. Calcd for C 9 H 12 N 2 2 : C, 59.99; H, 6.71; N,.55. Found: C, 59.7; H, 6.69; N,.49. N 2 10 (1.2 equiv) + HC TBDPS LHMDS (1.2 equiv) 23 THF, 7 C, 30 min TES 9 %, dr = 1:1 TBDPS H 23 TES N 2 (R)-3-thylcyclohex-2-en-1-yl (S)-6-(tert-Butyldiphenylsilyl)oxy-2-diazo-5-(triethylsilyl)oxy-3- hydroxyhexanoate (). A solution of LHMDS [prepared from 1,1,1,3,3,3-hexamethyldisilazane (1.00 ml, 4.66 mmol) and butyllithium in n-hexane (1.65 M, 2.0 ml, 4.62 mmol)] in THF ( ml) was added to a solution of diazoacetate 10 (39 mg, 4.66 mmol) and aldehyde 9 7 (1.77 g, 3. mmol) in THF ( ml) at 7 C. After 30 min of stirring, the reaction was quenched with saturated aqueous NH 4 Cl (40 ml), and the resulting mixture was extracted with AcEt (2 100 ml). The combined organic extracts were washed with brine (30 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (2.91 g), which was purified by column chromatography (silica gel 100 g, :1 n-hexane/acet with 5% Et 3 N) to give alcohol (2. g, %, dr = 1:1) as a yellow oil. Diastereomers could be separated by flash column chromatography (silica gel 100 g, :1 27 n-hexane/acet with 5% Et 3 N). Data for the less polar isomer: R f 0.43 (5:1 n-hexane/acet); [α] D +4.2 (c 1.24, CHCl 3 ); IR (neat) 3466, 2953, 92, 167, 77, 12, 11, 107 cm 1 ; 1 H NMR (500 S4

MHz, CDCl 3 ) δ 0.49 (q, J = 7. Hz, 6H), 0.7 (t, J = 7. Hz, 9H), 1.05 (s, 9H), 1.61 2.06 (m, H), 1.70 (br s, 3H), 3.42 (br s, 1H), 3.57 (dd, J =.1, 9. Hz, 1H), 3.64 (dd, J = 4.7, 9. Hz, 1H), 4.01 (m, 1H), 4.96 (m, 1H), 5.34 (m, 1H), 5.49 (m, 1H), 7.34 7.46 (m, 6H), 7.62 7.69 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 4.7 (CH 2 ), 6.7 (CH 3 ), 1.9 (CH 2 ), 19.1 (C), 23.7 (CH 3 ), 26. (CH 3 ), 2.2 (CH 2 ), 29.9 (CH 2 ), 3.2 (CH 2 ), 63.4 (CH), 67.0 (CH 2 ), 69.4 (CH), 70.2 (CH), 1.1 (CH), 127.71 (CH), 127.73 (CH), 129.7 (CH), 129. (CH), 3.1 (C), 3.3 (C), 5.6 (CH), 141.1 (C), 166.1 (C); HRMS (ESI) m/z [M + Na] + calcd for C 35 H 52 N 2 5 Si 2 Na 659.3312; found 659.3305. Data for the more polar isomer: R f 0.3 (5:1 n-hexane/acet); [α] 29 D +45.7 (c 1.06, CHCl 3 ); IR (neat) 3466, 2953, 93, 162, 77, 12, 11, 1069 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.49 (q, J = 7. Hz, 6H), 0.6 (t, J = 7. Hz, 9H), 1.05 (s, 9H), 1.61 2.00 (m, 6H), 1.70 (br s, 3H), 1.7 (dt, J = 14.4,.1 Hz, 1H), 2.11 (dt, J = 14.4, 4. Hz, 1H), 3.39 (br s, 1H), 3.49 (dd, J = 7.5, 10.2 Hz, 1H), 3.61 (dd, J = 4.3, 10.2 Hz, 1H), 3.9 (m, 1H), 4. (dd, J = 4.,.1 Hz, 1H), 5.34 (m, 1H), 5.4 (m, 1H), 7.36 7.45 (m, 6H), 7.62 7.6 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 4. (CH 2 ), 6.7 (CH 3 ), 19.0 (CH 2 ), 19.2 (C), 23.7 (CH 3 ), 26.2 (CH 3 ), 2.2 (CH 2 ), 29.9 (CH 2 ), 39.2 (CH 2 ), 64. (CH), 67.7 (CH 2 ), 69.4 (CH), 71.3 (CH), 1.1 (CH), 127.7 (CH), 129.77 (CH), 129.0 (CH), 3.1 (C), 3.2 (C), 5.57 (CH), 5.59 (C), 141.0 (C), 166.0 (C); HRMS (ESI) m/z [M + Na] + calcd for C 35 H 52 N 2 5 Si 2 Na 659.3312; found 659.3331. TBDPS H 23 TES N 2 IBX (3 equiv) pyridine ( equiv) DMS/THF (1:1) 6 h 94% TBDPS 23 TES N 2 14 (R)-3-thylcyclohex-2-en-1-yl (S)-6-(tert-Butyldiphenylsilyl)oxy-2-diazo-3-oxo-5-(triethylsilyl)- oxyhexanoate (14). A solution of alcohol (4.02 g, 6.31 mmol) in THF (32 ml) was added to a solution of 2-iodoxybenzoic acid (5.36 g, 19.1 mmol) and pyridine (7.7 ml, 95.2 mmol) in DMS (32 ml). After 6 h of stirring, the reaction mixture was diluted with H 2 (100 ml) and passed through a Celite pad. The filtrate was extracted with n-hexane/acet (3:1, 2 0 ml), and the combined organic extracts were washed with brine (100 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (5.72 g), which was purified by column chromatography (silica S5

gel 0 g, :1 n-hexane/acet with 5% Et 3 N) to give α-diazo-β-ketoester 14 (3.75 g, 94%) as a pale yellow oil. R f 0.60 (5:1 n-hexane/acet); [α] 9 D +52.6 (c 1.00, CHCl 3 ); IR (neat) 2953, 21,, 1655, 1427, 126, 11, 1071, 1016 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.49 (q, J = 7.9 Hz, 6H), 0.5 (t, J = 7.9 Hz, 9H), 1.03 (s, 9H), 1.63 1.6 (m, 4H), 1.70 (br s, 3H), 1.90 2.02 (m, 2H), 3.14 (dd, J = 7.3,.9 Hz, 1H), 3.25 (dd, J = 5.0,.9 Hz, 1H), 3.54 (dd, J = 7.0, 10.0 Hz, 1H), 3.63 (dd, J = 4.9, 10.0 Hz, 1H), 4.35 (dddd, J = 4.9, 5.0, 7.0, 7.3 Hz, 1H), 5.3 (m, 1H), 5.50 (m, 1H), 7.36 7.45 (m, 6H), 7.65 7.69 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 4.6 (CH 2 ), 6.6 (CH 3 ), 1.7 (CH 2 ), 19.0 (C), 23.6 (CH 3 ), 26.7 (CH 3 ), 27.9 (CH 2 ), 29. (CH 2 ), 45.0 (CH 2 ), 67. (CH 2 ), 69.3 (CH), 70.0 (CH), 119.4 (CH), 127.6 (CH), 129.51 (CH), 129.54 (CH), 3.3 (C), 5.5 (CH), 141.7 (C), 160.9 (C), 191.0 (C); HRMS (ESI) m/z [M + Na] + calcd for C 35 H 50 N 2 5 SiNa 657.36; found 657.311. TBDPS 23 TES N 2 14 TFA (1 equiv) CH 2 Cl 2 /H (1:1) 0 C, 30 min % TBDPS 23 H N 2 (R)-3-thylcyclohex-2-en-1-yl (S)-6-(tert-Butyldiphenylsilyl)oxy-2-diazo-5-hydroxy-3-oxohexanoate (). Trifluoroacetic acid (0.23 ml, 3.10 mmol) was added to a solution of TES ether 14 (1.99 g, 3. mmol) in CH 2 Cl 2 /H (1:1, 30 ml) at 0 C. After 30 min of stirring, the reaction was quenched with saturated aqueous NaHC 3 (30 ml), and the resulting mixture was extracted with AcEt (2 100 ml). The combined organic extracts were washed with brine (30 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (2.01 g), which was purified by column chromatography (silica gel 100 g, 3:1 n-hexane/acet with 5% Et 3 N) to give α-diazo-δ-hydroxyester (1.44 g, %) as a pale yellow oil. R f 0.32 (5:1 n-hexane/acet); [α] 10 D +69.3 (c 0.7, CHCl 3 ); IR (neat) 3512, 3071, 3049, 2931, 256, 25,, 1645, 1427, 1290, 11, 101, 90 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.07 (s, 9H), 1.64 1.4 (m, 4H), 1.72 (br s, 3H), 1.90 2.02 (m, 2H), 2.99 (d, J = 5.3 Hz, 1H), 3.02 (dd, J = 3., 16.5 Hz, 1H), 3. (dd, J =.4, 16.5 Hz, 1H), 3.65 (dd, J = 5.5, 10.2 Hz, 1H), 3.69 (dd, J = 4.9, 10.2 Hz, 1H), 4.23 (ddddd, J = 3., 4.9, 5.3, 5.5,.4 Hz, 1H), 5.37 (m, 1H), 5.50 (m, 1H), 7.36 7.44 (m, 6H), 7.65 7.6 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 1.7 S6

(CH 2 ), 19.1 (C), 23.6 (CH 3 ), 26.7 (CH 3 ), 27.9 (CH 2 ), 29.7 (CH 2 ), 43.3 (CH 2 ), 67.1 (CH 2 ), 6.6 (CH), 70.3 (CH), 119.2 (CH), 127.6 (CH), 129.6 (CH), 3.0 (C), 3.1 (C), 5.4 (CH), 5.5 (CH), 142.0 (C), 160.9 (C), 191. (C); HRMS (ESI) m/z [M + Na] + calcd for C 29 H 36 N 2 5 SiNa 543.2291; found 543.2275. TBDPS 23 H N 2 Rh 2 (Ac) 4 (2 mol %) benzene, reflux 5 min 23 TBDPS 16 (Ph 3 P) 3 RhCl (5 mol %) Ph 3 P (1.5 equiv) TMSCHN 2 (2.5 equiv) i-prh ( equiv) dioxane, 60 C, 30 min 60% (2 steps) 23 TBDPS (R)-3-thylcyclohex-2-en-1-yl (S)-5-[(tert-Butyldiphenylsilyl)oxymethyl]-4,5-dihydro-3-methylfuran-2-carboxylate (). A solution of α-diazo-δ-hydroxyester (9 mg, 0.305 mmol) in benzene (3 ml) was added to a refluxing suspension of Rh 2 (Ac) 4 (2.7 mg, 6.1 μmol) in benzene (12 ml), and the mixture was stirred for 5 min. After cooling, the catalyst was filtered through a Celite pad, and the filtrate was evaporated in vacuo. The crude product (149 mg) was used without further purification for the next reaction. Trimethylsilyldiazomethane in n-hexane (1.7 M, 0.45 ml, 0.765 mmol) was added to a mixture of the crude β-ketoester 16 (149 mg), (Ph 3 P) 3 RhCl (14.1 mg,.2 μmol), triphenylphosphine (1 mg, 0.45 mmol) and 2-propanol (0.35 ml, 4.57 mmol) in 1,4-dioxane (6 ml) at 60 C, and the mixture was stirred for 30 min. After cooling, saturated aqueous NaHC 3 ( ml) and xone (0 mg, 0.305 mmol) were added, and the resulting mixture was vigorously stirred for 30 min. The mixture was extracted with n-hexane/acet (5:1, 2 70 ml), and the combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (301 mg), which was purified by column chromatography (NH silica gel 30 g, :1 n- hexane/acet) to give α,β-unsaturated ester (9.6 mg, 60% for two steps) as a colorless oil. R f 0.63 (5:1 n-hexane/acet); [α] 2 D +111.6 (c 3.11, CHCl 3 ); IR (neat) 3071, 2932, 257, 09, 1663, 1427, 77, 1263, 1140, 11, 910 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.03 (s, 9H), 1.62 (m, 1H), 1.69 (br s, 3H), 1.72 1.2 (m, 3H), 1.9 2.00 (m, 2H), 2.03 (br s, 3H), 2.75 (m, 1H), 2.5 (m, 1H), 3.73 (dd, J = 4.5, 10.9 Hz, 1H), 3.76 (dd, J = 5.4, 10.9 Hz, 1H), 4.62 (dddd, J = 4.5, 5.4, 7.0, 10.5 Hz, 1H), 5.3 (s, S7

1H), 5.51 (s, 1H), 7.35 7.43 (m, 6H), 7.66 7.6 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ.0 (CH 3 ), 19.1 (CH 2 ), 19.3 (C), 23.7 (CH 3 ), 26.7 (CH 3 ), 2.0 (CH 2 ), 29.9 (CH 2 ), 39.4 (CH 2 ), 65.6 (CH 2 ), 69.2 (CH), 7.6 (CH), 1.0 (CH), 123.2 (C), 127.6 (CH), 127.7 (CH), 129.6 (CH), 129.7 (CH), 3.3 (C), 3.5 (C), 5.6 (CH), 5.7 (CH), 140.6 (C), 141.0 (C), 161.1 (C); HRMS (ESI) m/z [M + Na] + calcd for C 30 H 3 4 SiNa 5.2437; found 5.2446. 23 TBDPS LDA (2 equiv) THF, 7 C, 5 min then TMSCl (2 equiv) 7 0 C, 30 min 23 C 2 H 19 TBDPS TMSCHN 2 (1.5 equiv) benzene/h (1:1) 0 C, 5 min 62% (2 steps) TBDPS 23 C 2 7b thyl [2S,2(1S),5S]-5-[(tert-Butyldiphenylsilyl)oxymethyl]-2-(1-methylcyclohex-2-en-1-yl)-3- methylenetetrahydrofuran-2-carboxylate (7b). Butyllithium in n-hexane (1.55 M, 0.25 ml, 0.39 mmol) was added to a solution of diisopropylamine (60 μl, 0.43 mmol) in THF (2.5 ml) at 7 C. After 30 min of stirring at 0 C, the solution was cooled to 7 C, and a solution of α,β-unsaturated ester (94.1 mg, 0.192 mmol) in THF (1.5 ml) was added dropwise. After 5 min of stirring, TMSCl (50 μl, 0.39 mmol) was added, and the resulting mixture was stirred at 7 C for 5 min. The mixture was allowed to warm up to 0 C and was stirred for 30 min. The mixture was quenched with saturated aqueous NH 4 Cl (10 ml), and the resulting mixture was extracted with AcEt (3 40 ml). The combined organic extracts were washed with brine (10 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (127 mg), which was chromatographed (silica gel 10 g, 4:1 n-hexane/acet) to give slightly impure carboxylic acid 19 (.4 mg). Trimethylsilyldiazomethane in n-hexane (1.7 M, 0. ml, 0.29 mmol) was added to a solution of carboxylic acid 19 (.4 mg) in benzene/h (1:1, 2 ml) at 0 C. After 5 min of stirring, the mixture was concentrated in vacuo, and the residual pale yellow oil (90.5 mg) was purified by flash column chromatography (silica gel 10 g, :1 n-hexane/acet) to give methyl ester 7b (60.0 mg, 62% for two steps) as a colorless oil. R f 0.57 (5:1 n-hexane/acet); [α] 22 D +61.7 (c 1.33, CHCl 3 ); IR (neat) 3071, 2932, 259, 34, 1430, 1242, 11 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.03 (s, 9H), 1.04 (s, 3H), 1.52 1.64 (m, 3H), 1.71 (m, 1H), 1.9 (m, 2H), 2.69 (m, 1H), 2.3 (m, 1H), 3.42 (dd, J =.7, 10.1 Hz, S

1H), 3.53 (s, 3H), 3.74 (dd, J = 4.0, 10.1 Hz, 1H), 4.35 (m, 1H), 5.25 (d, J = 1.6 Hz, 1H), 5.4 (d, J = 2. Hz, 1H), 5.61 (dd, J = 1.5, 10.4 Hz, 1H), 5.70 (dt, J = 10.4, 3.6 Hz, 1H), 7.34 7.43 (m, 6H), 7.61 7.63 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 19.0 (CH 2 ), 19.2 (C), 22.9 (CH 3 ), 24.7 (CH 2 ), 26. (CH 3 ), 30.5 (CH 2 ), 37.0 (CH 2 ), 43.4 (C), 51.7 (CH 3 ), 65.0 (CH 2 ), 7.6 (CH), 91.9 (C), 112.4 (CH 2 ), 127.2 (CH), 127.60 (CH), 127.63 (CH), 129.57 (CH), 129.63 (CH), 1.5 (CH), 3.5 (C), 5.5 (CH), 5.6 (CH), 144.9 (C), 2.3 (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 40 4 SiNa 527.2594; found 527.2566. 23 TBDPS LDA (2 equiv) THF, 7 C, 5 min then TMSCl (2 equiv) 7 0 C, 30 min TBDPS 23 C 2 H 19 I2 (1.1 equiv) sat. aq. NaHC 3 CN, 0 C, 6 h 59% (2 steps) TBDPS 23 I (1R,3S,3aʹS,4ʹS,7aʹS)-3-[(tert-Butyldiphenylsilyl)oxymethyl]-4ʹ-iodo-7aʹ-methyl-5-methylene-2,3ʹdioxaspiro[cyclopentane-1,1ʹ-hexahydroindan]-2ʹ-one (). The rearrangement was performed according to the above procedure employing α,β-unsaturated ester (4.0 mg, 1 μmol), butyllithium in n-hexane (1.55 M, 0.23 ml, 0.34 mmol), diisopropylamine (50 μl, 0.36 mmol) and TMSCl (40 μl, 0.34 mmol). The crude product (124 mg) was chromatographed (silica gel 10 g, 4:1 n-hexane/acet) to give slightly impure carboxylic acid 19 (47. mg). Iodine (27.0 mg, 0.107 mmol) was added to a solution of carboxylic acid 19 (47. mg, 97 μmol) in CN/saturated aqueous NaHC 3 (1:1, 1 ml) at 0 C. After 6 h of stirring, the reaction was quenched with 1 M aqueous Na 2 S 2 3 (10 ml), and the resulting mixture was extracted with AcEt (2 30 ml). The combined organic extracts were washed with brine (30 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (56.0 mg), which was purified by flash column chromatography (silica gel 25 g, 10:1 n-hexane/acet) to give iodolactone (45.2 mg, 59% for two steps) as a colorless oil. R f 0.63 (3:1 n-hexane/acet); [α] D +4.3 (c 1.6, CHCl 3 ); IR (neat) 2932, 257, 90, 1427, 1221, 1111, 10, 966 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.06 (s, 9H), 1.35 (s, 3H), 1.40 (m, 1H), 1.5 1.61 (m, 2H), 1.76 (m, 1H), 1.5 (m, 1H), 1.99 (m, 1H), 2.71 (m, 1H), 2.76 (m, 1H), 3.60 (dd, J = 9.0, 10.2 Hz, 1H), 3.4 (dd, J = 4.9, 10.2 Hz, 1H), 4.34 (m, 1H), 4.57 (d, J = 2.0 S9

Hz, 1H), 4.67 (m, 1H), 4.96 (s, 1H), 5.25 (s, 1H), 7.36 7.43 (m, 6H), 7.64 7.66 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ.6 (CH 2 ), 19.3 (C), 19.5 (CH 3 ), 23.4 (CH), 26.9 (CH 3 ), 29.3 (CH 2 ), 30.9 (CH 2 ), 36.2 (CH 2 ), 44.3 (C), 65.0 (CH 2 ), 79.0 (CH), 2.1 (CH), 92.3 (C), 110.6 (CH 2 ), 127.6 (CH), 127.7 (CH), 129.63 (CH), 129.64 (CH), 3.5 (C), 3.6 (C), 5.55 (CH), 5.56 (CH), 144.9 (C), 4.4 (C); HRMS (ESI) m/z [M + Na] + calcd for C 30 H 37 I 4 SiNa 639.1404; found 639.90. TBDPS 23 C 2 DIBALH (2.5 equiv) CH 2 Cl 2, 7 C, 3 h TBDPS 23 H 7b 5% 21 [2S,2(1S),5S]-[5-(tert-Butyldiphenylsilyloxy)methyl-2-(1-methylcyclohex-2-en-1-yl)-3-methylenetetrahydrofuran-2-yl]methanol (21). Diisobutylaluminum hydride in n-hexane (1.0 M, 2. ml, 2. mmol) was added to a solution of ester 7b (556 mg, 1.10 mmol) in CH 2 Cl 2 (11 ml) at 7 C. After 3 h of stirring, the reaction was quenched with methanol (0.5 ml), followed by addition of 1 M aqueous potassium sodium tartrate ( ml). The resulting mixture was vigorously stirred at room temperature for 30 min, and was extracted with AcEt (3 40 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (600 mg), which was purified by flash column chromatography (silica gel g, :1 n- hexane/acet) to give alcohol 21 (445 mg, 5%) as a colorless oil. R f 0.44 (5:1 n-hexane/acet); [α] 23 D +27.5 (c 1.11, CHCl 3 ); IR (neat) 3495, 3073, 3022, 2934, 260, 1472, 1427, 11, 103 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.04 (s, 3H), 1.06 (s, 9H), 1.47 (m, 1H), 1.57 (m, 1H), 1.65 (m, 1H), 1.77 (dt, J = 3.4, 12.9 Hz, 1H), 1.5 1.94 (m, 2H), 2.69 (dddd, J = 2.1, 2.4, 5.4, 16.3 Hz, 1H), 2.71 (dd, J = 2.5, 9.0 Hz, 1H), 2.0 (dddd, J = 2.1, 2.4,.7, 16.3 Hz, 1H), 3.52 (dd, J = 3.7, 10.9 Hz, 1H), 3.57 (dd, J = 9.0, 11.0 Hz, 1H), 3.1 (dd, J = 4.1, 10.9 Hz, 1H), 3. (dd, J = 2.5, 11.0 Hz, 1H), 4.25 (dddd, J = 3.7, 4.1, 5.4,.7 Hz, 1H), 5.01 (t, J = 2.4 Hz, 1H), 5.19 (t, J = 2.1 Hz, 1H), 5.5 (dd, J = 1.2, 10.6 Hz, 1H), 5.6 (m, 1H), 7.37 7.45 (m, 6H), 7.67 7.6 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 19.21 (C), 19.24 (CH 2 ), 23.3 (CH 3 ), 24. (CH 2 ), 26. (CH 3 ), 30.5 (CH 2 ), 36.5 (CH 2 ), 42.4 (C), 64. (CH 2 ), 66.5 (CH 2 ), 77. (CH), 92.1 (C), 107. (CH 2 ), 127.1 (CH), 127.70 (CH), 127.72 (CH), 129.7 (CH), S10

129. (CH), 2.1 (CH), 3.06 (C), 3.10 (C), 5.7 (CH), 5. (CH), 149.5 (C); HRMS (ESI) m/z [M + Na] + calcd for C 30 H 40 3 SiNa 499.2644; found 499.2622. TBDPS 23 H 21 Dess Martin periodinane (1.5 equiv) CH 2 Cl 2, 2 h 94% TBDPS 23 CH 22 [2S,2(1S),5S]-5-[(tert-Butyldiphenylsilyl)oxymethyl]-2-(1-methylcyclohex-2-en-1-yl)-3-methylenetetrahydrofuran-2-carbaldehyde (22). Dess Martin periodinane (199 mg, 0.469 mmol) was added to a solution of alcohol 21 (2 mg, 361 mmol) in CH 2 Cl 2 (4 ml) at 0 C. After 2 h of stirring at room temperature, the reaction was quenched with a mixture of 1 M aqueous Na 2 S 2 3 (10 ml) and saturated aqueous NaHC 3 (10 ml), and the resulting mixture was vigorously stirred for 30 min. The mixture was extracted with AcEt (2 60 ml), and the combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (19 mg), which was purified by column chromatography (silica gel 10 g, :1 n-hexane/acet) to give aldehyde 22 (161 mg, 94%) as a colorless oil. R f 0.59 (5:1 n-hexane/acet); [α] 22 D +34.5 (c 1.11, CHCl 3 ); IR (neat) 3071, 3024, 2932, 259, 2712, 32, 1653, 9, 1464, 1427, 62, 1111, 1047 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.02 (s, 9H), 1.05 (s, 3H), 1.51 1.71 (m, 4H), 1.9 1.94 (m, 2H), 2.64 (m, 1H), 2.4 (m, 1H), 3.41 (dd, J = 7.3, 10.3 Hz, 1H), 3.64 (dd, J = 4.1, 10.3 Hz, 1H), 4.37 (m, 1H), 5. (d, J = 2.4 Hz, 1H), 5.27 (dd, J = 1.2, 2.6 Hz, 1H), 5.6 (d, J = 10.4 Hz, 1H), 5.76 (m, 1H), 7.35 7.43 (m, 6H), 7.61 7.63 (m, 4H), 9.64 (s, 1H); C NMR (125.7 MHz, CDCl 3 ) δ 1.7 (CH 2 ), 19.2 (C), 22.6 (CH 3 ), 24.7 (CH 2 ), 26. (CH 3 ), 30.4 (CH 2 ), 37.1 (CH 2 ), 43.0 (C), 65.7 (CH 2 ), 7.5 (CH), 93.4 (C), 111.7 (CH 2 ), 127.6 (CH), 127.7 (CH), 12.5 (CH), 129.6 (CH), 129.7 (CH), 0.7 (CH), 3.3 (C), 3.4 (C), 5.57 (CH), 5.61 (CH), 144.7 (C), 2.1 (CH); HRMS (ESI) m/z [M + Na] + calcd for C 30 H 3 3 SiNa 497.24; found 497.2462. S11

TBDPS 23 CH 22 N 2 HN N 2 (0.1 equiv) N 2, 10 h 9%, dr = 1.7:1 SM recovery 10% TBDPS 23 H N 2 23 [2S,2(1S),5S]-1-[5-(tert-Butyldiphenylsilyloxy)methyl-2-(1-methylcyclohex-2-en-1-yl)-3-methylenetetrahydrofuran-2-yl]-2-nitroethanol (23). To a solution of aldehyde 22 (910 mg, 1.92 mmol) in nitromethane ( ml) was added 1,1,3,3-tetramethylguanidine (24 μl, 0.19 mmol), and the mixture was stirred for 10 h. The solvent was removed in vacuo, and the residual yellow oil (1.09 g) was purified by column chromatography (silica gel 50 g, 30:1 :1 n-hexane/acet) to give nitroalcohol 23 (9 mg, 9%, dr = 1.7:1) as a colorless amorphous, along with recovered aldehyde 22 (96.4 mg, 11%) as a colorless oil. R f 0.2 (5:1 n-hexane/acet); [α] 24 D +. (c 1.01, CHCl 3 ); IR (neat) 3524, 3071, 3026, 2932, 260, 1653, 9, 57, 1463, 1427, 73, 1290, 11, 11, 1049, 970, 24 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.04 (s, 1.9H), 1.05 (s, 5.7H), 1.06 (s, 3.3H), 1.10 (s, 1.1H), 1.64 1.74 (m, 3H), 1.93 2.10 (m, 3H), 2.6 (dd, J = 7.5, 16.7 Hz, 0.37H), 2.74 2.76 (m, 1.26H), 2.0 (m, 0.37H), 2.9 (d, J = 3.9 Hz, 0.63H), 3.03 (d, J = 4.9 Hz, 0.37H), 3.52 (dd, J = 3.7, 11.3 Hz, 0.63H), 3.56 (dd, J = 3.3, 11.3 Hz, 0.37H), 3.0 (dd, J = 3.2, 11.3 Hz, 0.63H), 3.3 (dd, J = 3.4, 11.3 Hz, 0.37H), 4.23 4.27 (m, 1H), 4.30 (dd, J = 10., 12.0 Hz, 0.63H), 4.37 (dd, J = 9.9, 12.2 Hz, 0.37H), 4.65 (m, 0.37H), 4.6 (m, 0.37H), 4.7 4.0 (m, 1.26H), 5.02 (s, 0.37H), 5.22 (s, 0.37H), 5.27 (s, 0.63H), 5.37 (s, 0.63H), 5.74 5.7 (m, 0.74H), 5.0 (dt, J = 10.6, 3.4 Hz, 0.63H), 5. (d, J = 10.6 Hz, 0.63H), 7.37 7.45 (m, 6H), 7.64 7.69 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 19. (C), 19.1 (C), 19.4 (CH 2 ), 19.5 (CH 2 ), 24.76 (CH 2 ), 24.7 (CH 2 ), 25.2 (CH 3 ), 25.3 (CH 3 ), 26. (CH 3 ), 30.4 (CH 2 ), 31.1 (CH), 79.0 (CH 2 ), 79.2 (CH 2 ), 79.3 (CH), 9.9 (C), 91.2 (C), 10.2 (CH 2 ), 109. (CH 2 ), 127.7 (CH), 127.1 (CH), 12.0 (CH), 12.3 (CH), 129.5 (CH), 129.6 (CH), 129.90 (CH), 2.6 (CH), 2.7 (CH), 2. (C), 2.90 (C), 2.92 (CH), 5.5 (CH), 5.6 (CH), 5.66 (CH), 5.70 (CH), 14.0 (C), 0.1 (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 41 N 5 SiNa 55.2652; found 55.2635. S12

TBDPS 23 H N 2 23 1. H 2 S 4 (0.1 equiv) Ac 2, 0 C, 2 h 2. Et 3 N (3.3 equiv) CH 2 Cl 2, 30 min 94% (2 steps) TBDPS 23 N 2 24 [2S,2(1S),5S]-5-[(tert-Butyldiphenylsilyl)oxymethyl]-2-(1-methylcyclohex-2-en-1-yl)-3-methylene- 2-(2-nitrovinyl)tetrahydrofuran (24). A 0.2 M solution of sulfonic acid in acetic anhydride (0.10 ml, 0.02 mmol) was added to a solution of nitroalcohol 23 (101 mg, 0. mmol) in acetic anhydride (2 ml) at 0 C. After 2 h of stirring, the reaction was quenched with saturated aqueous NaHC 3 ( ml), and the resulting mixture was extracted with AcEt (2 40 ml). The combined organic extracts were successively washed with saturated aqueous NaHC 3 ( ml) and brine ( ml), and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (142 mg), which was used without further purification. Et 3 N (0.10 ml, 0.72 mmol) was added to a solution of the crude acetate (142 mg) in CH 2 Cl 2 (2 ml) at room temperature. After 30 min of stirring, the reaction mixture was concentrated in vacuo, and the residual pale yellow oil (145 mg) was purified by column chromatography (silica gel 5 g, :1 n-hexane/acet) to give nitroalkene 24 (92.3 mg, 94% for two steps) as a pale yellow amorphous. R f 0.66 (5:1 n-hexane/et 2 twice); [α] 23 D 12.9 (c 1.0, CHCl 3 ); IR (neat) 3071, 3024, 2930, 259, 1651, 24, 1427, 4, 1265, 11, 1030, 24, 702 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.02 (s, 3H), 1.05 (s, 9H), 1.4 1.56 (m, 2H), 1.64 1.73 (m, 2H), 1.5 1.96 (m, 2H), 2.51 (m, 1H), 2.6 (ddt, J =., 16.0, 2.7 Hz, 1H), 3.45 (dd, J = 5., 10.6 Hz, 1H), 3.56 (dd, J = 5., 10.6 Hz, 1H), 4.31 (m, 1H), 5.06 (d, J = 2.7 Hz, 1H), 5.24 (s, 1H), 5.63 (d, J = 10.1 Hz, 1H), 5.0 (ddd, J = 2.7, 5.0, 10.1 Hz, 1H), 7.24 (d, J = 12. Hz, 1H), 7.37 7.46 (m, 6H), 7.42 (d, J = 12. Hz, 1H), 7.63 7.66 (m, 4H); C NMR (125.4 MHz, CDCl 3 ) δ 19.0 (C), 19.2 (CH 2 ), 22. (CH), 24. (CH 2 ), 26. (CH 3 ), 30.4 (CH 2 ), 36.4 (CH 2 ), 43.5 (C), 66.0 (CH 2 ), 7.1 (CH), 9.2 (C), 111.2 (CH 2 ), 127.70 (CH), 127.72 (CH), 129.0 (CH), 129.7 (CH), 129. (CH), 0.7 (CH), 3.2 (C), 3.3 (C), 5.55 (CH), 5.57 (CH),. (CH), 145.3 (CH), 14.2 (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 39 N 4 SiNa 540.2546; found 540.256. S

TBDPS 23 NaBH 4 (3 equiv) dioxane/et 2 (1:1) N 2 7 h 90% 24 TBDPS 23 N 2 6b TBDPS 23 PhNC (4 equiv) Et 3 N (4 equiv) benzene, reflux 6 h N 2 97% 6b TBDPS 23 H N 25 [2S,2(1S),5S]-5-[(tert-Butyldiphenylsilyl)oxymethyl]-2-(1-methylcyclohex-2-en-1-yl)-3-methylene- 2-(2-nitroethyl)tetrahydrofuran (6b). A solution of nitroalkene 24 (92.0 mg, 0. mmol) in dioxane (2 ml) was added to a stirred suspension of NaBH 4 (.2 mg, 0.534 mmol) in EtH (2 ml) at 0 C. After 7 h of stirring at room temperature, brine ( ml) and H 2 (5 ml) were added, and the mixture was extracted with AcEt (2 30 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (109 mg), which was purified by column chromatography (silica gel 10 g, :1 n-hexane/acet) to give cycloaddition precursor 6b (3.5 mg, 90%) as a colorless oil. R f 0.61 (5:1 n-hexane/et 2 twice); [α] 24 D +22.4 (c 0.9, CHCl 3 ); IR (neat) 3071, 3022, 2931, 259, 1655, 51, 1472, 1427, 3, 11, 1036 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.03 (s, 3H), 1.06 (s, 9H), 1.49 (m, 1H), 1.5 (m, 1H), 1.67 1.77 (m, 2H), 1.5 1.95 (m, 2H), 2. (ddd, J = 4.9, 10.6, 14.2 Hz, 1H), 2.53 2.59 (m, 2H), 2.4 (dddd, J = 2.1, 2.3,.,.2 Hz, 1H), 3.59 (d, J = 4. Hz, 2H), 4.16 (ddd, J = 4.9, 10.9,.0 Hz, 1H), 4.24 (m, 1H), 4.33 (ddd, J = 5.7, 10.6,.0 Hz, 1H), 4.94 (t, J = 2.3 Hz, 1H), 5.1 (t, J = 2.1 Hz, 1H), 5.51 (d, J = 10.3 Hz, 1H), 5.69 (ddd, J = 2.5, 5.1, 10.3 Hz, 1H), 7.36 7.43 (m, 6H), 7.65 7.66 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 19.1 (C), 19.3 (CH 2 ), 23.2 (CH 3 ), 24.7 (CH 2 ), 26. (CH 3 ), 30.2 (CH 2 ), 32.1 (CH 2 ), 36.2 (CH 2 ), 43.9 (C), 66.4 (CH 2 ), 72.7 (CH 2 ), 7.0 (CH), 90.2 (C), 10.3 (CH 2 ), 127.3 (CH), 127.57 (CH), 127.60 (CH), 129.6 (CH), 129.7 (CH), 1. (CH), 3.1 (C), 3.2 (C), 5.4 (CH), 5.5 (CH), 149.5 (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 41 4 SiNa 542.2703; found 527.2692. (1S,3S,3aʹR,4ʹR,7aʹS)-Perhydro-3-[(tert-butyldiphenylsilyl)oxymethyl]-7aʹ-methyl-5-methylene- S14

2-oxa-4ʹ,3ʹ-epoxynitrilospiro[cyclopentane-1,1ʹ-indene] (25). A mixture of nitroalkene 6b (624 mg, 1. mmol), phenyl isocyanate (0.52 ml, 4.7 mmol) and Et 3 N (0.67 ml, 4.0 mmol) in benzene (1 ml) was refluxed for 6 h. After cooling, the resulting yellow suspension was partitioned between Ac- Et (60 ml) and H 2 (30 ml), and the aqueous layer was extracted with AcEt (2 60 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (1.30 g), which was purified by column chromatography (silica gel 30 g, 5:1 n-hexane/acet) to give isoxazoline 25 (55 mg, 97%) as a pale yellow form. R f 0.45 (3:1 n-hexane/acet); [α] 25 D +7.2 (c 2.32, CHCl 3 ); IR (neat) 3071, 2959, 2934, 259, 1655, 1471, 1427, 11 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.05 (s, 9H), 1.06 (s, 3H), 1.14 (m, 1H), 1.23 1.32 (m, 2H), 1.52 1.54 (m, 2H), 1.95 (m, 1H), 2.67 (m, 1H), 2.76 (dd, J = 0.9, 19.4 Hz, 1H), 2.0 (ddt, J =.3, 16.1, 2. Hz, 1H), 2.7 (dd, J = 2.5, 19.4 Hz, 1H), 3.34 (br d, J =.4 Hz, 1H), 3.52 (dd, J = 6.0, 10.4 Hz, 1H), 3.62 (dd, J = 4.5, 10.4 Hz, 1H), 4.22 (m, 1H), 4.63 (q, J =.4 Hz, 1H), 4.76 (m, 1H), 5.09 (m, 1H), 7.36 7.44 (m, 6H), 7.65 7.66 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 1.1 (CH 2 ), 19.3 (C),. (CH 3 ), 26. (CH 3 ), 2.1 (CH 2 ), 30.1 (CH 2 ), 36.0 (CH 2 ), 36.5 (CH 2 ), 45.2 (C), 60.1 (CH), 66.0 (CH 2 ), 77.5 (CH), 77. (CH), 9.7 (C), 107.0 (CH 2 ), 127.7 (CH), 129.69 (CH), 129.71 (CH), 3.41 (C), 3.44 (C), 5.5 (CH), 5.60 (CH), 4.3 (C), 167.2 (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 39 N 3 SiNa 524.2597; found 524.2579. TBDPS DIBALH (1.5 equiv) 23 toluene, C min H N 97% 25 23 H NH 26 TBDPS (1S,3S,3ʹS,3aʹR,4ʹR,7aʹS)-Perhydro-3-[(tert-butyldiphenylsilyl)oxymethyl]-7aʹ-methyl-5-methylene-2-oxa-4ʹ,3ʹ-epoxyiminospiro[cyclopentane-1,1ʹ-indene] (26). DIBALH in n-hexane (1.0 M, 0.31 ml, 0.31 mmol) was added to a solution of isoxazoline 25 (102 mg, 0.4 mmol) in toluene (4 ml) at C. After min of stirring, the reaction was quenched with methanol (0.1 ml), and 1 M aqueous potassium sodium tartrate (10 ml) was added to the solution. After 1 h of vigorous stirring, the resulting mixture was partitioned between CHCl 3 (30 ml) and H 2 (10 ml), and the aqueous layer was ex- S

tracted with CHCl 3 (2 30 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (109 mg), which was purified by column chromatography (silica gel 5 g, 10:1 CHCl 3 /CN) to give isoxazolidine 26 (101 mg, 97%) as a pale yellow form. R f 0.52 (1:1 n-hexane/acet); [α] 25 D 14.3 (c 1.42, CHCl 3 ); IR (neat) 32, 3071, 2930, 257, 1655, 1472, 1427, 1111 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.97 (s, 3H), 1.04 (s, 9H), 1.3 (m, 1H), 1.47 (m, 1H), 1.6 1.3 (m, 3H), 1.93 (m, 1H), 2.07 (dd, J = 7.0,.9 Hz, 1H), 2.10 (dd, J =.0,.9 Hz, 1H), 2.47 (t, J =.0 Hz, 1H), 2.63 (m, 1H), 2.73 (m, 1H), 3.50 (dd, J = 6.4, 10.1 Hz, 1H), 3.62 (dd, J = 4.5, 10.1 Hz, 1H), 3.91 (m, 1H), 3.96 (m, 1H), 4.16 (m, 1H), 4.7 (m, 1H), 5.04 (m, 1H), 7.36 7.43 (m, 6H), 7.65 7.67 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ.1 (CH 2 ), 19.2 (C), 21.0 (CH 3 ), 23.9 (CH 2 ), 26. (CH 3 ), 27.1 (CH 2 ), 37.1 (CH 2 ), 43.4 (CH 2 ), 43. (C), 55.2 (CH), 63.9 (CH), 66.1 (CH 2 ), 76.9 (CH), 1.4 (CH), 96. (C), 105. (CH 2 ), 127.5 (CH), 127.60 (CH), 129.56 (CH), 129.59 (CH), 3.6 (C), 5.6 (CH), 2. (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 41 N 3 SiNa 526.2753; found 526.2742. TBDPS 23 H NH 26 H 2, Pt 2 (40 mol %) AcEt, 16 h H H TBDPS 23 27 NH2 ClC 2 (2 equiv) Na 2 C 3 (4 equiv) acetone, 30 min H H TBDPS 23 NHC2 2 Dess Martin periodinane (1.1 equiv) CH 2 Cl 2, 2 h 67% (3 steps) dr = 4.3:1 H TBDPS 23 NHC2 29 + C-epimer thyl (1S,3S,5R,3ʹS,3aʹR,7aʹS)-3-[(tert-Butyldiphenylsilyl)oxymethyl]-5,7aʹ-dimethyl-4ʹ-oxo-2- oxaspiro[cyclopentane-1,1ʹ-perhydroindan]-3ʹ-ylaminoformate (29). A mixture of isoxazolidine 26 (359 mg, 0.7 mmol) and platinum oxide (64.4 mg, 0.24 mmol) in AcEt (7 ml) was stirred under 1 atm of hydrogen for 16 h. Hydrochloric acid in AcEt (4 M, 0.2 ml, 0. mmol) was added and the mixture was vigorously stirred for min. The resulting mixture was diluted with H (30 ml), and the catalyst was filtered through a Celite pad. The filtrate was evaporated in vacuo, and the residual pale-yellow oil (424 mg) was used without further purification. To a solution of the crude aminoalcohol 27 (424 mg) in acetone (10 ml) was added methyl chloroformate (0.11 ml, 1.42 mmol), followed by addition of Na 2 C 3 (302 mg, 2.5 mmol). After 30 min of stirring, the reaction mixture was partitioned between AcEt (50 ml) and H 2 ( ml), and the S16

aqueous layer was extracted with AcEt (2 40 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (49 mg), which was used without further purification. Dess Martin periodinane (340 mg, 0.02 mmol) was added to a solution of the crude alcohol 2 (49 mg) in CH 2 Cl 2 (10 ml) at 0 C. After 2 h of stirring at room temperature, the reaction was quenched with a mixture of 1 M aqueous Na 2 S 2 3 (10 ml) and saturated aqueous NaHC 3 (10 ml), and the resulting mixture was vigorously stirred for 30 min. The mixture was extracted with AcEt (3 40 ml), and the combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (49 mg), whose 1 H NMR [integration of the angular methyl protons, desired product 29 (0.75 ppm), C-epimer (0.54 ppm)] revealed a diastereomeric ratio of 4.3:1. Purification of the crude product by column chromatography (silica gel 25 g, 4:1 n-hexane/acet) afforded ketone 29 (2 mg, 54%), along with its C- epimer (52.3 mg, %) as colorless oils. R f 0.27 (3:1 n-hexane/acet); [α] 19 D +2.0 (c 1.7, benzene); IR (neat) 3401, 3049, 2959, 2932, 257, 21, 0, 1466, 64, 1227, 11, 106, 1072 cm 1 ; 1 H NMR (500 MHz, C 6 D 6 ) δ 0.67 (d, J = 7.0 Hz, 3H), 0.75 (s, 3H), 1.00 (dd, J = 5.7, 11.6 Hz, 1H), 1.04 (m, 1H), 1.24 (s, 9H), 1.32 (m, 1H), 1.64 (m, 1H), 1.71 (m, 1H), 1.3 1.91 (m, 3H), 1.9 (d, J = 7.3 Hz, 1H), 2.11 (dd, J = 10.7, 14.5 Hz, 1H), 2. (m, 1H), 2. (dd, J = 7.3, 14.5 Hz, 1H), 3.45 (dd, J = 4.4, 10.9 Hz, 1H), 3.53 (s, 3H), 3.71 (dd, J = 3.1, 10.9 Hz, 1H), 3.95 (m, 1H), 4.60 (m, 1H), 7.26 7.36 (m, 4H), 7.41 7.44 (m, 2H), 7.3 7.9 (m, 5H); C NMR (125.7 MHz, C 6 D 6 ) δ 16.7 (CH 3 ), 19.4 (C), 22.2 (CH 2 ), 25.3 (CH 3 ), 27.1 (CH 3 ), 32.1 (CH 2 ), 35.6 (CH 2 ), 40.5 (CH 2 ), 41.4 (CH), 49.0 (CH 2 ), 49.7 (CH), 51.0 (C), 51.3 (CH 3 ), 59.4 (CH), 66.3 (CH 2 ), 7.5 (CH), 95.2 (C), 12.1 (CH), 12.3 (CH), 129.9 (CH), 0.00 (CH), 3.7 (C), 3. (C), 6.1 (CH), 6.2 (CH), 7.2 (C), 2.3 (C); HRMS (ESI) m/z [M + Na] + calcd for C 33 H 45 N 5 SiNa 56.2965; found 56.2951. Data for the C-epimer: R f 0.16 (3:1 n-hexane/acet); [α] D +1.2 (c 0., benzene); IR (neat) 3397, 304, 2959, 2930, 257, 24, 05, 05, 1462, 64, 1224, 1105, 1072 cm 1 ; 1 H NMR (500 MHz, C 6 D 6 ) δ 0.54 (s, 3H), 0.65 (d, J = 6.7 Hz, 3H), 0.91 1.00 (m, 2H), 1.1 (m, 1H), 1.21 (s, 9H), 1.40 (m, 1H), 1.53 (m, 1H), 1.64 1.70 (m, 2H), 1.4 1.94 (m, 2H), 1.94 (d, J = 7.4 Hz, 1H), 2. (m, 1H), 2.36 (dd, J = 10.2, 14.5 Hz, 1H), 3.43 (dd, J = 5.1, 10.7 Hz, 1H), 3.54 (s, 3H), 3.59 3.60 (m, 2H), S

4.65 (m, 1H), 7.27 7.41 (m, 6H), 7.3 7.4 (m, 5H); C NMR (125.7 MHz, C 6 D 6 ) δ 16.9 (CH 3 ), 19.1 (C), 22.7 (CH 2 ), 25. (CH 3 ), 26. (CH 3 ), 30.3 (CH 2 ), 36.3 (CH), 37.9 (CH 2 ), 40.6 (CH 2 ), 40. (CH 2 ), 50.5 (CH), 51.3 (CH 3 ), 52.9 (C), 5.0 (CH), 66.0 (CH 2 ), 7.4 (CH), 95.3 (C), 127.9 (CH), 12.0 (CH), 129.7 (CH), 3.5 (C), 3.6 (C), 5.9 (CH), 6.0 (CH), 7.0 (C), 2.3 (C); HRMS (ESI) m/z [M + Na] + calcd for C 33 H 45 N 5 SiNa 56.2965; found 56.292. H 23 29 TBDPS NHC2 5% TFA, toluene 60 C, h 6% TBDPS 23 4 (1S,3S,5R,7aʹS)-3-[(tert-Butyldiphenylsilyl)oxymethyl]-1ʹ,4ʹ,5ʹ,6ʹ,7ʹ,7aʹ-hexahydro-5,7aʹ-dimethyl- 2-oxaspiro[cyclopentane-1,1ʹ-2H-inden]-4ʹ-one (4). A solution of ketone 29 (6 mg, 0.365 mmol) in toluene/tfa (:1, 7.35 ml) was heated at 60 C for h. The reaction mixture was concentrated in vacuo, and the residual brown oil (19 mg) was purified by column chromatography (silica gel 5 g, 5:1 n-hexane/acet) to give enone 4 (4 mg, 6%) as a pale yellow oil. R f 0.53 (3:1 n-hexane/acet); [α] 19 D 6.7 (c 1.31, CHCl 3 ); IR (neat) 3071, 2959, 2932, 259, 162, 1614, 1427, 11 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.04 (s, 9H), 1. (d, J = 6.9 Hz, 3H), 1. (s, 3H), 1.60 1.64 (m, 2H), 1.9 1.95 (m, 2H), 2. 2.45 (m, 5H), 2.43 (dd, J = 1.,.9 Hz, 1H), 2.70 (dd, J = 3.7,.9 Hz, 1H), 3.64 (dd, J = 4.2, 10.9 Hz, 1H), 3.74 (dd, J = 4.1, 10.9 Hz, 1H), 4.29 (m, 1H), 6.42 (dd, J = 1., 3.7 Hz, 1H), 7.32 7.42 (m, 6H), 7.65 7.66 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 16.5 (CH 3 ), 19.2 (C),.3 (CH 2 ), 21.4 (CH 3 ), 26. (CH 3 ), 2.9 (CH 2 ), 36.0 (CH 2 ), 39.2 (CH), 40.0 (CH 2 ), 44.5 (CH 2 ), 51.1 (C), 66.7 (CH 2 ), 77.7 (CH), 9.4 (C), 127.59 (CH), 127.60 (CH), 129.5 (CH), 129.61 (CH), 3.45 (C), 3.46 (C), 4.2 (CH), 5.6 (CH), 5.7 (CH), 149.0 (C), 199.7 (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 40 3 SiNa 511.2644; found 511.2662. S1

23 4 TBDPS NaBH 4 (1.5 equiv) CeCl 3 7H 2 (1.5 equiv) H, 40 C, 30 min 91% 23 H 30 TBDPS (1S,3S,5R,4ʹR,7aʹS)-3-[(tert-Butyldiphenylsilyl)oxymethyl]-1ʹ,4ʹ,5ʹ,6ʹ,7ʹ,7aʹ-hexahydro-5,7aʹ-dimethyl-2-oxaspiro[cyclopentane-1,1ʹ-2H-inden]-4ʹ-ol (30). A solution of enone 4 (62.4 mg, 0.12 mmol) in H (1.5 ml) was added to a mixture of NaBH 4 (7.3 mg, 0.193 mmol) and CeCl 3 7H 2 (71.5 mg, 0.192 mmol) in H (1.5 ml) at 40 C. After 30 min of stirring, the reaction was quenched with 1 M aqueous HCl (1 ml), and the resulting mixture was partitioned between AcEt (40 ml) and brine ( ml). The aqueous layer was extracted with AcEt (30 ml), and the combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (9.1 mg), which was purified by column chromatography (silica gel 5 g, 5:1 n-hexane/acet) to give allyl alcohol 30 (57.3 mg, 91%) as a colorless amorphous. R f 0.44 (3:1 n-hexane/acet); [α] 19 D 9.4 (c 0.97, CHCl 3 ); IR (neat) 3399, 3049, 2932, 259, 1472, 1462, 1427, 1265, 11 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 1.05 (s, 9H), 1.07 (d, J = 7.0 Hz, 3H), 1.09 (s, 3H), 1.19 (m, 1H), 1.35 (m, 1H), 1.55 (tq, J = 3.3,.6 Hz, 1H), 1.63 (m, 1H), 1.73 (m, 1H), 2.02 (m, 1H), 2.09 (dt, J =.6, 4.3 Hz, 1H), 2. (m, 1H), 2.2 2.33 (m, 2H), 2.4 (ddd, J = 1.7, 3.0, 16.1 Hz, 1H), 3.69 (dd, J = 5.7, 10.5 Hz, 1H), 3.72 (dd, J = 4.4, 10.5 Hz, 1H), 4.14 (m, 1H), 4.24 (m, 1H), 5.33 (m, 1H), 7.35 7.43 (m, 6H), 7.66 7.70 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 16.6 (CH 3 ), 19.3 (C),.2 (CH 3 ), 21.0 (CH 2 ), 26.9 (CH 3 ), 29. (CH 2 ), 35.9 (CH 2 ), 36.9 (CH 2 ), 39.3 (CH), 44.2 (CH 2 ), 51.7 (C), 67.3 (CH 2 ), 69.0 (CH), 77.2 (CH), 97.1 (C), 1.3 (CH), 127.57 (CH), 127.5 (CH), 129.50 (CH), 129.55 (CH), 3.7 (C), 3. (C), 5.70 (CH), 5.72 (CH), 2.5 (C); HRMS (ESI) m/z [M + Na] + calcd for C 31 H 42 3 SiNa 5.1; found 5.270. TBDPS 23 H 30 CH 2 I 2 (4 equiv) Et 2 Zn (4 equiv) CH 2 Cl 2, 9 h 92% H 23 31 TBDPS (1S,3S,5R,1aʹS,3aʹS,7ʹR,7aʹR)-3-[(tert-Butyldiphenylsilyl)oxymethyl]-5,3aʹ-dimethyl-2-oxaspiro- S19

[cyclopentane-1,3ʹ-perhydrocyclopropa[c]inden]-7ʹ-ol (31). To an ice-cooled (0 C) solution of allyl alcohol 30 (55.4 mg, 0.1 mmol) in CH 2 Cl 2 (2 ml) was added diiodomethane (36 μl, 0.45 mmol), followed by addition of Et 2 Zn in n-hexane (1.05 M, 0.43 ml, 0.45 mmol). After 9 h of stirring, the reaction mixture was diluted with Et 2 (10 ml), and pyridine (0.10 ml) was added. The resulting suspension was vigorously stirred for 30 min, and was filtered through a Celite pad. The filtrate was partitioned between AcEt ( ml) and H 2 ( ml), and the aqueous layer was extracted with AcEt (30 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (79.5 mg), which was purified by column chromatography (silica gel 5 g, 5:1 n-hexane/acet) to give cyclopropane 31 (52.3 mg, 92%) as a colorless amorphous. R f 0.53 (5:1 benzene/et 2 ); [α] D 42.0 (c 1.6, CHCl 3 ); IR (neat) 3356, 2931, 259, 1472, 1427, 1265, 11 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.40 (dd, J = 2., 7.0 Hz, 1H), 1.03 (d, J = 6.7 Hz, 3H), 1.06 (s, 9H), 1.12 (s, 3H), 1. (m, 1H), 1.27 1.32 (m, 2H), 1.42 (m, 1H), 1.51 (dd, J = 6.3, 12.0 Hz, 1H), 1.61 1.1 (m, 4H), 1.9 2.01 (m, 2H), 1.95 (d, J =.3 Hz, 1H), 2.11 (m, 1H), 3.6 (d, J = 4. Hz, 2H), 4. 4. (m, 2H), 7.37 7.44 (m, 6H), 7.6 7.72 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ 7.7 (CH 2 ), 16.7 (CH),.0 (CH 3 ), 19.0 (CH 3 ), 19.3 (C), 21.2 (CH 2 ), 26. (CH 3 ), 2.2 (CH 2 ), 35.1 (CH 2 ), 36.7 (CH 2 ), 40.2 (CH 2 ), 40.7 (C), 42.1 (CH), 4.6 (C), 67.2 (CH), 67.3 (CH 2 ), 77. (CH), 94.2 (C), 127.61 (CH), 127.62 (CH), 129.6 (CH), 3.6 (C), 5.7 (CH); HRMS (ESI) m/z [M + Na] + calcd for C 32 H 44 3 SiNa 527.2957; found 527.2979. H 23 31 TBDPS Bu 4 NF (1.5 equiv) THF, 60 C, 30 min 96% H 23 32 H (1S,3S,5R,1aʹS,3aʹS,7ʹR,7aʹR)-3-(Hydroxymethyl)-5,3aʹ-dimethyl-2-oxaspiro[cyclopentane-1,3ʹperhydrocyclopropa[c]inden]-7ʹ-ol (32). Bu 4 NF in THF (1.0 M, 0. ml, 0. mmol) was added to a solution of TBDPS ether 31 (50.1 mg, 99.2 μmol) in THF (2 ml). After 30 min of stirring at 60 C, the mixture was partitioned between AcEt (30 ml) and H 2 ( ml), and the aqueous layer was extracted with AcEt (2 30 ml). The combined organic extracts were washed with brine ( ml) and S

dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (54.3 mg), which was purified by column chromatography (silica gel 5 g, 4:3 n-hexane/acet) to give diol 32 (26.6 mg, 96%) as a white solid. R f 0.32 (1:1 n-hexane/acet); mp 9 161 C (colorless needles from Et 2 ); [α] 22 D 63.4 (c 1.27, CHCl 3 ); IR (neat) 3275, 2937, 262, 144, 75, 1265 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.46 (dd, J = 3.5,.2 Hz, 1H), 1.05 (d, J = 6.7 Hz, 3H), 1.11 (t, J = 3.5 Hz, 1H), 1. (s, 3H), 1. (m, 1H), 1.35 (m, 1H), 1.42 (m, 1H), 1.49 (dd, J = 6.2, 11.9 Hz, 1H), 1.64 1.72 (m, 2H), 1.76 1.5 (m, 4H), 1.92 (m, 1H), 2.16 (m, 1H), 3.55 (dd, J = 6.9, 11.4 Hz, 1H), 3.66 (dd, J = 3.6, 11.4 Hz, 1H), 4.1 (dd, J = 3., 10.9 Hz, 1H), 4. (m, 1H); C NMR (125.7 MHz, CDCl 3 ) δ.1 (CH 2 ), 16.7 (CH),.0 (CH 3 ), 19.1 (CH 3 ), 21.1 (CH 2 ), 2.1 (CH 2 ), 35.0 (CH 2 ), 36.2 (CH 2 ), 40.79 (C), 40.2 (CH 2 ), 42.2 (CH), 4. (C), 67.0 (CH), 67.2 (CH 2 ), 7.1 (CH), 94.5 (C); HRMS (ESI) m/z [M + Na] + calcd for C 16 H 26 3 Na 29.0; found 29.7. H 23 32 H H 23 H 2, Pt 2, AcNa AcH, 40 C, 4 h 74% H 33 (1S,3S,5R,3aʹR,4ʹR,7aʹS)-3-(Hydroxymethyl)-5,3aʹ,7aʹ-trimethyl-2-oxaspiro[cyclopentane-1,1ʹ- hexahydroindan]-4ʹ-ol (33). A mixture of cyclopropane 32 (.0 mg, 56.3 μmol), Pt 2 (3. mg, 16.7 μmol) and AcNa (. mg, 0.163 mmol) in AcH (0.6 ml) was heated at 40 C under 1 atm of hydrogen. Two additional equal portions of Pt 2 (1.9 mg,.4 μmol) were added after 16 h and 32 h. After a total reaction time of 4 h, the catalyst was filtered through a Celite pad, and the filtrate was evaporated in vacuo. The residual gray solid was partitioned between AcEt (30 ml) and H 2 (10 ml), and the aqueous layer was extracted with AcEt (2 30 ml). The combined organic extracts were washed with brine (10 ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (40.1 mg), which was purified by flash column chromatography (silica gel 10 g, 1:1 n-hexane/acet) to give diol 33 (11.1 mg, 74%) as a white solid. R f 0.25 (1:1 n-hexane/ AcEt); [α] D 23 29.5 (c 0.54, CHCl 3 ); IR (neat) 3393, 297, 293, 27, 1474, 1, 12, 10 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.99 (s, 3H), 1.06 (d, J = 6.7 Hz, 3H), 1.11 (s, 3H), 1.30 (ddd, J = 2.1, S21

4.7,.5 Hz, 1H), 1.40 (m, 1H), 1.52 1.65 (m, 5H), 1.69 (ddt, J = 2.0, 12.5, 5.0 Hz, 1H), 1.73 1.1 (m, 2H), 1.92 2.04 (m, 2H), 2.21 (m, 1H), 3.57 (dd, J =.1, 11.1 Hz, 1H), 3.65 (dd, J = 3.7, 11.1 Hz, 1H), 3.96 (dd, J = 5.0, 11.3 Hz, 1H), 4.21 (m, 1H); C NMR (125.7 MHz, CDCl 3 ) δ 16.4 (CH 3 ), 16.6 (CH 3 ),.3 (CH 3 ),.2 (CH 2 ), 26.1 (CH 2 ), 29.6 (CH 2 ), 33.6 (CH 2 ), 35. (CH 2 ), 40.7 (CH 2 ), 43.5 (CH), 49. (C), 51.0 (C), 6.0 (CH 2 ), 73.6 (CH), 77.6 (CH), 96.7 (C); HRMS (ESI) m/z [M + Na] + calcd for C 16 H 2 3 Na 291.1936; found 291.1923. 23 H 33 H TBDPSCl (1.9 equiv) imidazole (3. equiv) DMF, 6 h 95% TBDPS 23 H 34 (1S,3S,5R,3a'R,4'R,7a'S)-3-[(tert-Butyldiphenylsilyl)oxymethyl]-5,3a',7a'-trimethyl-2-oxaspiro- [cyclopentane-1,1'-hexahydroindan]-4'-ol (34). A 0.35 M solution of tert-butylchlorodiphenylsilane in DMF (0.10 ml, 35.0 μmol) was added to a solution of diol 33 (4.9 mg, 1.3 μmol) and imidazole (4. mg, 0.071 mmol) in DMF (0.5 ml) at 0 C. After 6 h of stirring at room temperature, the reaction mixture was partitioned between n-hexane/acet (3:1, 30 ml) and H 2 ( ml), and the aqueous layer was extracted with n-hexane/acet (3:1, 2 30 ml). The combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (24.9 mg), which was purified by column chromatography (silica gel 5 g, 5:1 n-hexane/acet) to give TBDPS ether 34 (. mg, 95%) as a colorless oil. R f 0.40 (3:1 n-hexane/ AcEt); [α] D 23 27.6 (c 0.2, CHCl 3 ); IR (neat) 3419, 3071, 292, 255, 1462, 1427, 11, 10 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.91 (s, 3H), 0.976 (d, J = 5. Hz, 3H), 0.92 (s, 9H), 1.07 (s, 3H), 1.23 (ddd, J = 2.2, 4.6,.3 Hz, 1H), 1.34 (m, 1H), 1.43 1.64 (m, 7H), 1.6 (dt, J = 6.2,.3 Hz, 1H), 1.96 (dt, J = 5.6, 11.3 Hz, 1H), 2.07 2. (m, 2H), 3.62 (dd, J = 4.5, 10.5 Hz, 1H), 3.66 (dd, J = 4.9, 10.5 Hz, 1H), 3. (dd, J = 5.0, 11.3 Hz, 1H), 4. (m, 1H), 7.30 7.37 (m, 6H), 7.60 7.63 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ.9 (CH 3 ), 16.6 (CH 3 ),.3 (CH 3 ), 19.3 (C),.3 (CH 2 ), 26.1 (CH 2 ), 26. (CH 3 ), 29.6 (CH 2 ), 33.6 (CH 2 ), 36.1 (CH 2 ), 40.2 (CH 2 ), 43.3 (CH), 49. (C), 50.9 (C), 67.2 (CH 2 ), 73. (CH), 77.4 (CH), 96.5 (C), 127.6 (CH), 129.55 (CH), 129.57 (CH), 3.61 (C), 3.64 (C), 5.6 S22

(CH), 5.7 (CH); HRMS (ESI) m/z [M + Na] + calcd for C 32 H 46 3 SiNa 529.3114; found 529.3123. 23 H 34 TBDPS Dess Martin periodinane (1.6 equiv) CH 2 Cl 2, 30 min % TBDPS 23 3 (1S,3S,5R,3a'R,7a'S)-3-[(tert-Butyldiphenylsilyl)oxymethyl]-5,3a',7a'-trimethyl-2-oxaspiro[cyclopentane-1,1'-hexahydroindan]-4'-one (3). Dess Martin periodinane (9.5 mg, 22.4 μmol) was added to a solution of alcohol 34 (7.0 mg,. μmol) in CH 2 Cl 2 (1 ml) at 0 C. After 30 min of stirring at room temperature, the reaction was quenched with a mixture of 1 M aqueous Na 2 S 2 3 (7 ml) and saturated aqueous NaHC 3 (7 ml), and the resulting mixture was vigorously stirred for 30 min. The mixture was extracted with AcEt (2 30 ml), and the combined organic extracts were washed with brine ( ml) and dried over anhydrous Na 2 S 4. Filtration and evaporation in vacuo furnished the crude product (10.1 mg), which was purified by column chromatography (silica gel 5 g, :1 n-hexane/ AcEt) to give ketone 3 (6.2 mg, %) as a colorless oil. R f 0.59 (3:1 n-hexane/acet); [α] D 23 14.6 (c 0.64, CHCl 3 ); IR (neat) 2961, 2930, 259, 09, 1472, 1462, 1427, 11 cm 1 ; 1 H NMR (500 MHz, CDCl 3 ) δ 0.7 (s, 3H), 1.05 (s, 9H), 1.07 (d, J = 7.0 Hz, 3H), 1.36 (m, 1H), 1.3 (s, 3H), 1.53 1.5 (m, 2H), 1.6 (m, 1H), 1.5 (m, 1H), 1.93 2.06 (m, 3H), 2.11 2. (m, 3H), 2.32 (dt, J = 5.,.5 Hz, 1H), 2.60 (ddd, J =., 11.9,.7 Hz, 1H), 3.6 (dd, J = 4.7, 10.6 Hz, 1H), 3.73 (dd, J = 4.7, 10.6 Hz, 1H), 4.24 (m, 1H), 7.36 7.44 (m, 6H), 7.66 (m, 4H); C NMR (125.7 MHz, CDCl 3 ) δ.4 (CH 3 ), 19.0 (CH 3 ), 19.3 (C),.9 (CH 2 ), 23.5 (CH 3 ), 26.0 (CH 2 ), 26. (CH 3 ), 2.9 (CH 2 ), 35.9 (CH 2 ), 36.0 (CH 2 ), 39.5 (CH 2 ), 43.2 (CH), 51.7 (C), 60.9 (C), 67.2 (CH 2 ), 77. (CH), 96.5 (C), 127.63 (CH), 127.64 (CH), 129.60 (CH), 129.62 (CH), 3.5 (C), 3.6 (C), 5.61 (CH), 5.65 (CH), 216. (C); HRMS (ESI) m/z [M + Na] + calcd for C 32 H 44 3 SiNa 527.2957; found 527.2954. S23

3. Additional References (26) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. rg. Chem. 1990, 55, 1959 1964. (27) Frigerio, M.; Santagostino, M.; Sputore, S. J. rg. Chem. 1999, 64, 4537 453. (2) Shioiri, T.; Aoyama, T.; Mori, S. rg. Synth. 1990, 6, 1 7. (29) Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. rg. Synth. 00, 77, 141 2. S24

4. Copies of 1 H and C NMR Spectra N 2 12 S25

10 N 2 S26

TBDPS H 23 TES N 2 (less polar isomer) S27

TBDPS H 23 TES N 2 (more polar isomer) S2

TBDPS 23 TES N 2 14 S29

TBDPS 23 H N 2 S30

23 TBDPS S31

TBDPS 23 C 2 7b S32

TBDPS 23 I S33

TBDPS 23 H 21 S34

TBDPS 23 CH 22 S35

TBDPS 23 H N 2 23 S36

TBDPS 23 N 2 24 S37

TBDPS 23 N 2 6b S3

TBDPS 23 H N 25 S39

TBDPS 23 H NH 26 S40

23 29 TBDPS H NHC2 S41

23 TBDPS H NHC2 C-epimer of 29 S42

23 4 TBDPS S43

23 H 30 TBDPS S44

TBDPS 23 H 31 S45

H 23 H 32 S46

23 H 33 H S47

23 H 34 TBDPS S4

23 3 TBDPS S49

5. NESY Correlation Diagrams for Iodolactone, Enone 4 and Ketone 3, and Copies of NESY Spectra TBDPS 21 22 14 I 23 4 TBDPS 9 23 14 16 3 TBDPS I 14 H NESY H 21 22 H H H TBDPS NESY H TBDPS 23 H ax 11 9 H ax H TBDPS 14 23 16 H NESY J 9ax,11ax = 11.9 Hz TBDPS 21 22 14 I S50