Studies on the mechanism, selectivity and synthetic utility of. lactone reduction using SmI 2 and H 2 O

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1 Studies on the mechanism, selectivity and synthetic utility of lactone reduction using SmI 2 and H 2 O Dixit Parmar, a Lorna A. Duffy, a Dhandapani V. Sadasivam, b Hiroshi Matsubara, c Paul A. Bradley, d Robert A. Flowers II, b David J. Procter a * a School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK. b Department of Chemistry, Lehigh University, Seeley G. Mudd Building, Bethlehem, PA 18015, USA. c Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka , Japan. d Discovery Chemistry, Pfizer Global R & D, Ramsgate Road, Sandwich, Kent, . david.j.procter@manchester.ac.uk. CT13 9NJ, UK Contents S2 General Experimental S3 Preparation of Samarium Iodide S4 S49 Experimental S53 S80 1 H and 13 C NMR spectra of new compounds S81 X-ray crystal structure of 49: CCDC = S82 noe studies on S22 S83-S88 Stopped flow kinetic study S89-S94 DFT MO Calculations S1

2 General experimental All experiments were performed under an atmosphere of nitrogen, using anhydrous solvents, unless stated otherwise. THF was distilled from sodium / benzophenone, and when used in conjunction with SmI 2, deoxygenated by bubbling with N 2 for 15 minutes. Dichloromethane was distilled from CaH 2, and methanol was distilled from the corresponding magnesium alkoxide and stored under argon. Water was distilled before being deoxygenated by bubbling with N 2. 1 H NMR and 13 C NMR were recorded using 300, 400 and 500 MHz spectrometers, with chemical shift values being reported in ppm relative to residual chloroform (δ H = 7.27 or δ C = 77.2) as internal standards. All coupling constants (J) are reported in Hertz (Hz). Mass spectra were obtained using positive and negative electrospray (ES±) or gas chromatography (GC) methodology. Infra-red spectra were recorded as evaporated films or neat using a FT/IR spectrometer. Column chromatography was carried out using µ, 60A silica gel. Routine TLC analysis was carried out on aluminium sheets coated with silica gel 60 F254, 0.2 mm thickness. Plates were viewed using a 254 nm ultraviolet lamp and dipped in aqueous potassium permanganate or p-anisaldehyde. S2

3 For experimental details, characterisation data and calculations for Schemes 1, 3-6 and Figure 1, please see the Supporting Information section of our preliminary communication. 1 Preparation of samarium diiodide (SmI 2 ) Samarium diiodide was prepared by a modification of the procedure of Imamoto and Ono. 2 Samarium powder (2.00 g, 13.3 mmol, 1.2 eq) was added to an oven dried roundbottomed flask, the flask sealed, covered in aluminum foil and flushed with N 2 for 30 min. THF (110 ml) was added and the resulting suspension bubbled with N 2 for 15 min. Finally, iodine (2.80 g, 11.0 mmol, 1 eq) was added and the flask flushed again with N 2 for 10 min. The flask was heated at 60 ºC for 18 hours. The 0.1 M solution was allowed to cool to room temperature and then used directly. 1 Duffy, L. A.; Matsubara, H.; Procter, D. J. J. Am. Chem. Soc. 2008, 130, Imamoto, T.; Ono, M. Chem. Lett. 1987, 501. S3

4 Additional examples of SmI 2 -H 2 O lactone reduction Ethyl 5-hydroxy-2-(hydroxymethyl)pentanoate S1 As for general procedure A 1 (see preliminary communication), reaction of ethyl 2- oxotetrahydro-2h-pyran-3-carboxylate (82 mg, 0.48 mmol, 1 eq) with SmI 2 (0.1 M in THF, 38.0 ml, 3.81 mmol, 8 eq) and distilled H 2 O (9.50 ml) followed by stirring for 1 hour, after work up and purification by column chromatography on silica gel eluting with 80% EtOAc in petroleum ether (40 60 C), gave the title compound (80 mg, 0.45 mmol, 94%) as a yellow oil; ν max (neat)/cm (OH), 2942, 1718 (C=O), 1457, 1380, 1186, 1047, 856; δ H (400 MHz, CDCl 3 ) 1.28 (3H, t, J 7.1, CH 3 ), (2H, m, CH 2 CH 2 OH), (2H, m, CHCH 2 ), 2.01 (1H, br s, OH), (1H, m, CH), 2.66 (1H, br s, OH), 3.65 (2H, t, J 6.1, CH 2 OH), (2H, m, CHCH 2 OH), 4.17 (2H, q, J 7.1, CH 2 O); δ C (100 MHz, CDCl 3 ) 14.2 (CH 3 ), 24.7 (CH 2 ), 30.1 (CH 2 ), 47.1 (CH), 60.8 (OCH 2 ), 62.4 (CH 2 OH), 63.0 (CHCH 2 OH), (C(O)); m/z (ES+ mode) 199 ((M + Na), 100), 375 (20), 407 (8); (Found: (M + Na), C 8 H 16 O 4 Na requires M, ). Ethyl 3-hydroxy-2-(2-(hydroxymethyl)phenyl)propanoate S2 S4

5 As for general procedure A 1 (see preliminary communication), reaction of ethyl 3- oxoisochroman-4-carboxylate (66 mg, 0.30 mmol, 1 eq) with SmI 2 (0.1 M in THF, 24.0 ml, 2.40 mmol, 8 eq) and distilled H 2 O (6.00 ml) followed by stirring for 1 hour, after work up and purification by column chromatography on silica gel eluting with 60% EtOAc in petroleum ether (40 60 C), gave the title compound (45 mg, 0.20 mmol, 67% (97% based on starting material consumption)) as a colourless oil; ν max (neat)/cm (OH), 2918, 1723 (C=O), 1682, 1556, 1538, 1371, 1287, 1016, 665; δ H (400 MHz, CDCl 3 ) 1.13 (3H, t, J 7.1, CH 3 ), 2.75 (2H, s, 2 OH), 3.76 (1H, dd, J 9.6, 5.6, CH a H b OH), (2H, m, CH a H b OH + CH), 4.13 (2H, q, J 7.1, CH 2 O), 4.60 (1H, d, J 12.4, ArCH a H b OH), 4.72 (1H, d, J 12.4, ArCH a H b OH), (4H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 14.1 (CH 3 ), 48.9 (CH 2 O), 61.3 (CH), 63.6 (ArCH 2 OH), 64.2 (CH 2 OH), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-C), (Ar-C), (C(O)); m/z (ES+ mode) 247 ((M + Na), 100), 233 (31), 201 (24); (Found: (M + Na), C 12 H 16 O 4 Na requires M, ). Ethyl 2-(hydroxymethyl)-2-(3-hydroxypropyl)hept-6-enoate S3 As for general procedure A 1 (see preliminary communication), reaction of ethyl 2- oxo-3-(pent-4-enyl)tetrahydro-2h-pyran-3-carboxylate (58 mg, 0.24 mmol, 1 eq) with SmI 2 (0.1 M in THF, 19.0 ml, 1.93 mmol, 8 eq) and distilled H 2 O (4.80 ml) followed by stirring for 1 hour, after work up and purification by column chromatography on silica gel eluting with 80% EtOAc in petroleum ether (40 S5

6 60 C), gave the title compound (48 mg, 0.20 mmol, 81%) as a yellow oil; ν max (neat)/cm (OH), 2935, 1718 (C=O), 1653, 1638, 1559, 1458, 1194, 1054, 909; δ H (400 MHz, CDCl 3 ) 1.27 (3H, t, J 7.1, CH 3 ), (2H, m, CH 2 CH 2 CH=CH 2 ), (2H, m, CH 2 CH 2 OH), (2H, m, CH 2 CH 2 CH 2 CH=CH 2 ), (2H, m, CH 2 CH 2 CH 2 OH), 1.95 (1H, s, OH), 2.03 (2H, q, J 7.1, CH 2 CH=CH 2 ), 2.66 (1H, s, OH), 3.63 (2H, t, J 6.3, CH 2 OH), 3.65 (1H, d, J 11.6, CH a H b OH), 3.74 (1H, d, J 11.6, CH a H b OH), 4.18 (2H, q, J 7.1, OCH 2 ), (2H, m, CH=CH 2 ), (1H, m, CH=CH 2 ); δ C (100 MHz, CDCl 3 ) 14.3 (CH 3 ), 23.4 (CH 2 ), 27.0 (CH 2 ), 29.3 (CH 2 ), 33.1 (CH 2 ), 34.1 (CH 2 ), 50.5 (C), 60.6 (OCH 2 ), 63.0 (CH 2 OH), 64.7 (CCH 2 OH), (CH=CH 2 ), (CH=CH 2 ), (C(O)); m/z (ES+ mode) 267 ((M + Na), 100), 511 (58), 394 (38), 272 (18); (Found: (M + Na), C 13 H 24 O 4 Na requires M, ). S6

7 Experimental (Scheme 2) Methyl 5-hydroxypentanoate S4 3 To a stirred solution of γ-valerolactone (5.00 g, 50.0 mmol, 1 eq) in MeOH (50 ml) was added slowly, concentrated H 2 SO 4 (2 ml) and the reaction heated at 90 ºC for 24 hours. The reaction was cooled to room temperature and the ph adjusted to 7 with the addition of a saturated solution of NaHCO 3 (25 ml). The aqueous layer was separated and extracted with Et 2 O (3 30 ml) and the combined organics were dried (Na 2 SO 4 ) and concentrated in vacuo to give methyl 5-hydroxypentanoate (5.59 g, mmol, 95%) as a orange oil; δ H (500 MHz, CDCl 3 ) (2H, m, CH 2 CH 2 CH 2 OH), (2H, m, CH 2 CH 2 OH), 2.36 (2H, t, J 7.5 Hz, CH 2 C(O)), 3.65 (2H, t, J 6.3 Hz, CH 2 OH), 3.67 (3H, s, OCH 3 ); δ C (125 MHz, CDCl 3 ) 20.8 (CH 2 CH 2 CH 2 OH), 31.4 (CH 2 CH 2 OH), 33.2 (C(O)CH 2 ), 51.0 (OCH 3 ), 61.2 (CH 2 OH), (C(O)-ester); 1 H and 13 C NMR data is consistant with literature values. 3 Methyl 5-oxopentanoate S5 4 DMSO (0.12 ml, 1.70 mmol, 2 eq) in CH 2 Cl 2 (5 ml) was added to a stirred solution of oxalyl chloride (0.07 ml, 0.85 mmol, 1 eq) in CH 2 Cl 2 (10 ml) at 78 C and the resulting solution was stirred for 10 min. Methyl 5-hydroxypentanoate (0.10 g, 0.85 mmol, 1 eq) was then added as a solution in CH 2 Cl 2 (5 ml) and the resultant solution 3 Roche, D.; Greiner, J.; Aubertin, A.-M.; Vierling, P. Bioconjugate Chem. 2006, 17, Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.; Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, S7

8 stirred for a further 30 min. Triethylamine (0.59 ml, 4.25 mmol, 5 eq) was then added and the reaction mixture was allowed to warm to room temperature and stir for 3 hours. Aqueous saturated NaHCO 3 (20 ml) was then added, and the aqueous layer was separated and extracted with EtOAc (3 20 ml). The combined organic extracts were dried (MgSO 4 ), and concentrated in vacuo to give methyl 5-oxopentanoate (0.10 g, 0.85 mmol, 100%) as a yellow oil that was used without further purification; δ H (500 MHz, CDCl 3 ) 1.96 (2H, quintet, J 7.3 Hz, CH 2 CH 2 CHO), 2.39 (2H, apparent t, J 7.3 Hz, CH 2 CHO), 2.54 (2H, t, J 7.3 Hz, CH 2 C(O)), 3.68 (3H, s, OCH 3 ), 9.78 (1H, s, CHO); δc (125 MHz, CDCl 3 ) 24.3 (CH 2 CH 2 CHO), 34.2 (CH 2 C(O)), 43.2 (CH 2 CHO), 51.0 (OCH 3 ), (C(O)-ester), (CHO); 1 H and 13 C NMR data is consistent with literature values. 4 5-Benzyloxy-pentan-1-ol S6 5 To a stirred solution of 1,5-pentanediol (3.00 g, 28.9 mmol, 2.5 eq) in THF (40 ml) was added portionwise NaH (0.72 g, 30.0 mmol, 2.6 eq) at 0 ºC and the resulting slurry stirred for 30 min. A solution of benzyl bromide (1.97 g, 11.5 mmol, 1 eq) in THF (10 ml) was added and the solution was stirred at room temperature for 18 hours. The reaction was quenched by the addition of H 2 O (20 ml) at 0 ºC and aqueous saturated NaCl (10 ml) was then added, and the aqueous layer was separated and extracted with Et 2 O (3 50 ml). The combined organic extracts were dried 5 Thompson, A. M.; Delaney, A. M.; Hamby, J. M.; Schroeder, M. C.; Spoon, T. A.; Crean, S. M.; Showalter, H. D. H.; Denny, W. A. J. Med. Chem. 2005, 48, 4628 S8

9 (Na 2 SO 4 ), and concentrated in vacuo to give the crude product. Purification by column chromatography on silica gel eluting with 60% EtOAc in petroleum ether (40-60) gave 5-benzyloxy-pentan-1-ol (0.94 g, 4.84 mmol, 42%) as a clear oil; δ H (500 MHz, CDCl 3 ) (2H, m, CH 2 ), (2H, m, CH 2 ), (2H, m, CH 2 ), 3.50 (2H, t, J 6.5 Hz, CH 2 OH), 3.66 (2H, t, J 6.5 Hz, CH 2 OBn), 4.52 (2H, s, OCH 2 Ph), (5H, m, 5 Ar-CH); δ C (125 MHz, CDCl 3 ) 22.5 (CH 2 ), 29.7 (CH 2 ), 33.7 (CH 2 ), 62.9 (CH 2 OH), 70.3 (CH 2 OBn), 73.2 (OCH 2 Ph), (Ar-CH), (2 Ar-CH), (2 Ar-CH), (Ar-C); 1 H and 13 C data is consistent with literature values. 5 5-Benzyloxy-pentanal S7 A solution of DMSO (0.69 ml, 9.72 mmol, 2 eq) in CH 2 Cl 2 (10 ml) was added to a stirred solution of oxalyl chloride (0.60 ml, 4.86 mmol, 1 eq) in CH 2 Cl 2 (50 ml) at -78 C and he resulting solution was stirred for 30 min. 5-Benzyloxy-pentan-1-ol (0.94 g, 4.86 mmol, 1 eq) was then added as a solution in CH 2 Cl 2 (10 ml) and the resultant solution stirred for 1 hour. Triethylamine (3.39 ml, 24.3 mmol, 5 eq) was then added and the reaction mixture was allowed to warm to room temperature and stir for 2 hours. Aqueous saturated NaHCO 3 (35 ml) was then added, and the aqueous layer was separated and extracted with EtOAc (4 50 ml). The combined organic extracts were dried (MgSO 4 ), and concentrated in vacuo to give 5-benzyloxy-pentanal which required no purification and was used in the next step. S9

10 7-Benzyloxy-3-hydroxy-heptanoic acid ethyl ester S8 A solution of LDA was prepared by the addition of n-buli (2.07 M in hexanes, 1.01 ml, 2.08 mmol, 1 eq) to a stirred solution of diisopropylamine (0.29 ml, 2.08 mmol, 1 eq) in THF (30 ml) at -78 C and the resultant solution stirred for 1 hour. Anhydrous EtOAc (0.17 ml, 2.12 mmol, 1.02 eq) was then added and the reaction stirred for a further 30 min. Finally, 5-benzyloxy-pentanal (0.40 g, 2.08 mmol, 1 eq) was added via cannula and left to stir at -78 C for 20 min and then the reaction warmed to room temperature and left to stir overnight. Aqueous saturated NH 4 Cl (15 ml) was then added, and the aqueous layer was separated and extracted with Et 2 O (3 20 ml). The combined organic extracts were dried (Na 2 SO 4 ), and concentrated in vacuo to give the crude product. Purification by column chromatography on silica gel eluting with 30% EtOAc in petroleum ether (40-60) to give 7-benzyloxy-3-hydroxyheptanoic acid ethyl ester (0.48 g, 1.71 mmol, 70% over two steps) as a yellow oil: ν max (CH 2 Cl 2 /evaporated film)/cm (OH), 2860, 1733 (C(O)-ester), 1453, 1370, 1160 (C-O), 1098, 1027, 737, 698 and 605; δ H (500 MHz, CDCl 3 ) 1.20 (3H, t, J 7.0 Hz, CH 3 ), 1.38 (2H, m, CH 2 CH 2 CH), 1.47 (2H, m, CH 2 CH), 1.58 (2H, m, CH 2 CH 2 OH), 2.34 (1H, dd, J 16.4, 9.1 Hz, 1H from C(O)CH 2 CH), 2.44 (1H, dd, J 16.4, 3.3 Hz, 1H from C(O)CH 2 CH), 3.41 (2H, t, J 6.5 Hz, CH 2 OBn), 3.93 (1H, tt, J 8.2, 3.9 Hz, CH), 4.09 (2H, q, J 7.0 Hz, OCH 2 CH 3 ), 4.42 (2H, s, CH 2 Ph), 7.20 (1H, m, Ar-CH), 7.27 (4H, m, 4 Ar-CH); δ C (125 MHz, CDCl 3 ) 14.2 (CH 3 ), 22.2 (CH 2 ), 29.6 (CH 2 ), 36.4 (CH 2 ), 41.3 (CH 2 ), 60.7 (OCH 2 ), 67.9 (CH), 70.2 (OCH 2 ), 72.9 (OCH 2 Ph), (2 Ar-CH), (Ar-CH), (2 Ar-CH), (Ar-C), S10

11 173.1 (C(O)-ester); m/z (EI mode) 303 ((M + Na), 100%); Found: (M + Na), C 16 H 24 O 4 Na requires M + Na, ). 7-Benzyloxy-3-(tert-butyl-dimethyl-silanyloxy)-heptanoic acid ethyl ester S9 To a stirred solution of 7-benzyloxy-3-hydroxy-heptanoic acid ethyl ester (0.71 g, 2.48 mmol, 1 eq) in DMF (20 ml) at room temperature, was added imidazole (0.34 g, 4.96 mmol, 2 eq) and the reaction left to for 10 min, followed by addition of tertbutyl-chlorodimethyl-silane (0.56 g, 3.72 mmol, 1.5 eq) and then the reaction was left to stir for 18 hours. Aqueous saturated NaHCO 3 (15 ml) was then added and the aqueous layer was separated and extracted with Et 2 O (3 20 ml). The combined organics were then washed with H 2 O (5 20 ml) and then dried (MgSO 4 ) and concentrated in vacuo to give the crude product. Purification by column chromatography on silica gel eluting with 10% EtOAc in petroleum ether (40-60) gave 7-benzyloxy-3-(tert-butyldimethyl-silanyloxy)-heptanoic acid ethyl ester (0.63 g, 1.60 mmol, 64%) as a yellow oil: ν max (CH 2 Cl 2 /evaporated film)/cm , 2856, 1736 (C(O)-ester), 1461, 1375, 1254 (C-O), 1162, 1101, 956, 835, 776, 734, 697 and 665; δ H (500 MHz, CDCl 3 ) (3H, s, SiCH 3 ), 0.00 (3H, s, SiCH 3 ), 0.80 (9H, s, 3 CCH 3 ), 1.19 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), (2H, m, CH 2 CH 2 CH), (2H, m, CH 2 CH), 1.56 (2H, q, J 7.1 Hz, CH 2 CH 2 OBn), 2.36 (2H, m, C(O)CH 2 CH), 3.41 (2H, t, J 6.6 Hz, CH 2 OBn), 4.06 (2H, m, OCH 2 ), 4.44 (2H, s, CH 2 Ph), 7.23 (1H, m, Ar-CH), 7.28 (4H, m, 4 Ar-CH); δ C (125 MHz, CDCl 3 ) (SiCH 3 ), (SiCH 3 ), 14.2 (3 CCH 3 ), 17.9 (SiC), 21.0 (CH 2 ), 25.8 (CH 3 ), 29.8 (CH 2 ), 37.4 (CH 2 ), 42.7 (CH 2 ), 60.3 (OCH 2 ), 69.4 (CH), 70.3 (OCH 2 ), 72.9 S11

12 (OCH 2 Ph), (2 Ar-CH), (Ar-CH), (2 Ar-CH), (Ar-C), (C(O)-ester); m/z (CI mode) 412 (40), 395 ((M), 100%), 107 (40) and 91 (50); m/z (EI mode) 395 ((M), 1%), 337 (20), 245 (80), 145 (40), and 91 (100); Found: (M), C 22 H 39 O 4 Si requires M, ). 3-(tert-Butyl-dimethyl-silanyloxy)-7-hydroxy-heptanoic acid ethyl ester S10 To a stirred solution of 7-benzyloxy-3-(tert-butyl-dimethyl-silanyloxy)-heptanoic acid ethyl ester (0.485 g, 1.23 mmol, 1 eq) in EtOH (15 ml) was added Pd/C (10% activated on carbon, 0.12 g, 0.12 mmol, 0.1 eq). The flask was evacuated and filled with H 2 three times and the reaction left under H 2 for 18 hours at which point the solution was flushed through a plug of silica and washed with EtOAc (3 10 ml) and concentrated in vacuo to give 3-(tert-butyl-dimethyl-silanyloxy)-7-hydroxy-heptanoic acid ethyl ester (0.39 g, 1.23 mmol, 100%) as a dark oil: ν max (CH 2 Cl 2 /evaporated film)/cm (OH), 2927, 2859, 2335, 1952, 1737 (C(O)-ester), 1651, 1602, 1471, 1453, 1387, 1365, 1314, 1252 (C-O), 1176, 1099, 1027, 967, 938, 836, 776, 698, 650 and 607; δ H (400 MHz, CDCl 3 ) 0.05 (3H, s, SiCH 3 ), 0.07 (3H, s, SiCH 3 ), 0.87 (9H, s, 3 CCH 3 ), 1.26 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), (2H, m, C(O)CH 2 CH), 3.65 (2H, t, J 6.6 Hz, CH 2 OH), (3H, m, 2H from OCH 2 CH 3 and 1H from CHOSi); δ C (100 MHz, CDCl 3 ) (SiCH 3 ), (SiCH 3 ), 14.2 (CH 3 ), 18.0 (SiC), 21.1 (CH 2 ), 25.8 (3 CCH 3 ), 32.7 (CH 2 ), 37.2 (CH 2 ), 42.6 (CH 2 ), 60.4 (CH 2 OH), 62.8 (CH 2 O), 69.3 (CHOSi), (C(O)-ester); m/z (ES- mode) 479 (10), 429 (10), 400 (10), 370 (10), 369 (20) 355 (25), 353 (60), 339 (100), 197 (50) and 196 (45); m/z (ES+ mode) 364 (10), 328 (10), 327 ((M + Na), 100%), 322 ((M + NH 4 ), 15%), 305 S12

13 ((M + H), 90%), 303 (60) and 281 (10); (Found M + NH 4, C 15 H 36 O 4 NSi requires M + NH 4, ). 5-(tert-Butyldimethylsilyloxy)-7-ethoxy-7-oxoheptanoic acid S11 To a stirred solution of 3-(tert-butyl-dimethyl-silanyloxy)-7-hydroxy-heptanoic acid ethyl ester (0.57 g, 1.88 mmol, 1 eq) and sodium phosphate buffer (ph 7, 6.70 ml, 4.69 mmol, 2.5 eq) in MeCN (10 ml), was added 2,2,6,6-tetramethylpiperidine-1- oxyl (21 mg, 0.13 mmol, 0.07 eq) and the solution heated to 35 C and stirred for 5 min. A solution of sodium chlorite (0.42 g, 3.75 mmol, 2 eq) in H 2 O (1.90 ml) was added and the reaction stirred a 35 C for 1 hour. Finally, a solution of sodium hypochlorite (87 µl, 0.04 mmol, 0.02 eq) in H 2 O (1.05 ml) was added and the reaction left to heat at 35 C for a further 18 hours. The reaction was quenched by the addition of H 2 O (5 ml) and the aqueous layer was separated and extracted with EtOAc (3 20 ml). The combined organics were dried (Na 2 SO 4 ) and concentrated in vacuo to give 5-(tert-butyldimethylsilyloxy)-7-ethoxy-7-oxoheptanoic acid which required no further purification and was used in the next step. 3-(tert-Butyl-dimethyl-silanyloxy)-heptanedioic acid 1-ethyl ester 7-methyl ester S12 S13

14 To a stirred solution of 5-(tert-butyldimethylsilyloxy)-7-ethoxy-7-oxoheptanoic acid (0.15 g, 0.51 mmol, 1 eq) in PhMe (12 ml) was added MeOH (3 ml) and (trimethylsilyl)diazomethane (2.0 M in toluene, 0.56 ml, 1.12 mmol, 2.2 eq) and the reaction stirred for 3 hours. The solution was concentrated in vacuo to give 3-(tertbutyldimethyl-silanyloxy)-heptanedioic acid 1-ethyl ester 7-methyl ester (0.18 g, 0.54 mmol, 77% over two steps) as a yellow oil which required no further purification: ν max (CH 2 Cl 2 /evaporated film)/cm , 2961, 2095, 1653 (C(O)-ester), 1647 (C(O)- ester), 1517, 1490, 1473, 1465, 1458, 1436, 1374, 1259 (C-O), 1176 (C-O), 1093 (C- O), 1019, 663 and 459; δ H (400 MHz, CDCl 3 ) 0.03 (3H, s, SiCH 3 ), 0.05 (3H, s, SiCH 3 ), 0.85 (9H, s, C(CH3) 3 ), 1.25 (3H, t, J 7.2 Hz, OCH 2 CH 3 ), 1.51 (2H, m, CH 2 ), 1.65 (2H, m, CH 2 ), 2.31 (2H, m, CH 2 ), 2.43 (2H, m, CH 2 ), 3.65 (3H, s, OCH 3 ), (3H, m, 1H from OCH) and 2H from OCH 2 ); δ C (100 MHz, CDCl 3 ) (2 SiCH 3 ), 14.2 (C(CH 3 ) 3 ), 17.9 (OCH 2 CH 3 ), 20.4 (CH 2 ), 25.7 (3 C(CH 3 ) 3 ), 33.9 (CH 2 ), 36.8 (CH 2 ), 42.5 (CH 2 ), 51.5 (OCH 3 ), 60.3 (OCH 2 CH 3 ), 68.9 (CH), (C(O)), (C(O)); m/z (ES+ mode) 355 ((M + Na), 100%), 333 ((M + H), 10%), 241 (5) and 142 (15); Found: (M + H), C 16 H 33 O 5 Si requires M + H, ). 3-Hydroxy-heptanedioic acid 1-ethyl ester 7-methyl ester 10 To a stirred solution of 3-(tert-butyl-dimethyl-silanyloxy)-heptanedioic acid 1-ethyl ester 7-methyl ester (0.31 g, 0.92 mmol, 1 eq) in MeCN (2 ml) was added pyridine (4.38 ml, 55.4 mmol, 60 eq) and hydrogen fluoride (40% solution in H 2 O, 1.85 ml, 36.9 mmol, 40 eq) and the reaction left to stir for 18 hours. The reaction was S14

15 quenched by the slow addition of aqueous saturated NaHCO 3 (5 ml) and the aqueous layer was separated and extracted with EtOAc (3 10 ml). The combined organics were washed with aqueous saturated CuSO 4 (3 10 ml), then dried (Na 2 SO 4 ) and concentrated in vacuo to give 3-hydroxy-heptanedioic acid 1-ethyl ester 7-methyl ester as a clear oil which was used in the next step. (6-Oxo-tetrahydro-pyran-2-yl)-acetic acid ethyl ester S13 6 O O O EtO S13 A stirred solution of 3-hydroxy-heptanedioic acid 1-ethyl ester 7-methyl ester (15 mg, 0.07 mmol, 1 eq) in THF (5 ml) was treated with a catalytic amount of p- toluenesulfonic acid at room temperature and the reaction left to stir for 48 hours. The reaction was concentrated in vacuo followed by addition of a saturated solution of NaHCO 3 (5 ml) and the aqueous layer separated and extracted with Et 2 O (3 10 ml). The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo to give the crude product. Purification by flash column chromatography on silica gel eluting with a solvent gradient of 60% EtOAc in petroleum ether (40-60) gave (6-oxotetrahydro-pyran-2-yl)-acetic acid ethyl ester (10 mg, 0.05 mmol, 78% over two steps) as a yellow oil, product was not fully characterised at this step: δ H (400 MHz, CDCl 3 ) 1.20 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), (2H, m, CH 2 ), (2H, m, CH 2 ), (4H, m, 2 CH 2 ), 4.10 (2H, q, J 7.1 Hz, OCH 2 ), 4.67 (1H, m, CH); m/z (CI mode) 204 (10), 187 ((M + H), 100%), 169 (20), 140 (30), 99 (40), and 83 (30); m/z (EI mode) 187 ((M + H), 10%), 130 (10), 98 (30), 83 (65) and 48 (100); 6 Wang, S.; Chen, G.; Kayser, M. M.; Iwaki, H.; Lau, P. C. K.; Hasegawa, Y. Can. J. Chem. 2002, 80, 613. S15

16 Found: (M + H), C 9 H 15 O 4 requires M + H, ). Data is consistant with literature values. 6 3,7-Dihydroxy-heptanoic acid ethyl ester 11 As for general procedure E (see page S33), reaction of (6-oxo-tetrahydro-pyran-2-yl)- acetic acid ethyl ester (20 mg, 0.11 mmol, 1 eq) with SmI 2 (0.1 M in THF, 7.56 ml, 0.76 mmol, 7 eq) and distilled H 2 O (1.89 ml) followed by stirring for 5 hours gave, after work up and purification by column chromatography on silica gel eluting with a solvent gradient of 60% EtOAc in petroleum ether (40-60), 3,7-dihydroxy-heptanoic acid ethyl ester (17mg, 0.09 mmol, 83%) as a yellow oil: ν max (CH 2 Cl 2 /evaporated film)/cm (2 OH), 2095, 1651 (C(O)-ester), 1506, 1458, 1399, 1374, 1301, 1186 (C-O), 1073, 1021, 665 and 410; δ H (400 MHz, CDCl 3 ) 1.21 (3H, t, J 7.2 Hz, OCH 2 CH 3 ), (7H, m, 7H from CHCH 2 CH 2 CH 2 CH 2 OH), 2.34 (1H, dd, J 16.4, 9.1 Hz, 1H from CH 2 CO 2 Et), 2.44 (1H, dd, J 16.4, 3.0 Hz, 1H from CH 2 CO 2 Et), 2.97 (1H, s, OH), 3.60 (2H, t, J 6.2 Hz, CH 2 OH), 3.95 (1H, s, OH), 4.11 (2H, q, J 7.2 Hz, OCH 2 CH 3 ); δ C (100 MHz, CDCl 3 ) 14.2 (CH 3 ), 21.7 (CH 2 ), 32.5 (CH 2 ), 36.1 (CH 2 ), 41.2 (CH 2 ), 60.7 (CH 2 OH), 62.8 (CH 2 O), 67.8 (CHOH), (C(O)-ester); m/z (ES+ mode) 297 (10), 212 (100), 191 ((M + H), 40%) and 101 (10); Found: (M + H), C 9 H 19 O 4 requires M + H, ). S16

17 Claisen condensation using ethyl cyanoformate: General Procedure A Ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate S14 7 O O CO 2 Et S14 A solution of LDA was prepared by adding n-butyllithium (20.8 ml, 45.0 mmol, 1.5 eq, 2.16 M solution in hexane) to diisopropylamine (4.60 g, 45.0 mmol, 1.5 eq) in THF (90 ml) at -78 C under N 2 and stirring for 1 hour. The solution was warmed to 0 C for 10 min before cooling back down to -78 C. To this solution was added tetrahydro-2h-pyran-2-one (3.00 g, 30.0 mmol, 1 eq) dissolved in THF (30 ml) over 30 min via syringe pump and the resulting solution stirred for 1 hour. The reaction was once again warmed to 0 C for 10 min and cooled to -78 C before adding ethyl cyanoformate (4.46 g, 45.0 mmol, 1.5 eq) and allowing the resulting solution to warm to room remperature over 18 hours. The reaction was quenched by addition of aqueous saturated NH 4 Cl (15 ml) and the aqueous layer was separated and extracted with EtOAc (3 50 ml). The combined organic layers were washed with brine (50 ml), dried (Na 2 SO 4 ) and concentrated in vacuo to yield the crude product. Purification by column chromatography on silica gel eluting with 50% EtOAc in petroleum ether (40 60 C) gave the title compound (3.55 g, 21.0 mmol, 70%) as a yellow oil; ν max (neat)/cm , 2933, 1721 (C=O), 1462, 1372, 1249, 1152, 1078, 1062, 1032; δ H (400 MHz, CDCl 3 ) 1.31 (3H, t, J 7.2 Hz, OCH 2 CH 3 ), 1.91 (1H, m, CH 2 CH), 1.99 (1H, m, CH 2 CH), 2.19 (1H, m, CH 2 CH 2 O), 2.28 (1H, m, CH 2 CH 2 O), 4.13 (1H, t, J 9.0 Hz, CHC(O)), 4.25 (2H, m, -OCH 2 CH 3 ), 4.39 (2H, m, CH 2 O); δ C 7 Wright, J. L.; Caprathe, B. W.; Downing, D. M.; Glase, S. A.; Heffner, T. G.; Jaen, J. C.; Johnson, S. J.; Kesten, S. R.; MacKenzie, R. G. J. Med. Chem. 1994, 37, S17

18 (100 MHz, CDCl 3 ) 14.1 (OCH 2 CH 3 ), 20.9 (CH 2 ), 22.8 (CH 2 ), 47.4 (CH), 61.9 (OCH 2 CH 3 ), 69.3 (OCH 2 ), (C(O)), (C(O)); m/z (ES+ mode) 195 ((M + Na), 50), 439 (37), 407 (21), 399 (27), 367 (24), 296 (63), 267 (34), 227 (100). (Found: (M + Na), C 8 H 12 O 4 Na 1 requires M, ). Ethyl 3-oxoisochroman-4-carboxylate S15 O O CO 2 Et S15 As for general procedure A, 3-isochromanone (500 mg, 3.37 mmol, 1 eq) was deprotonated using LDA and reacted with ethyl cyanoformate (500 mg, 5.06 mmol, 1.5 eq). After workup and purification by column chromatography on silica gel eluting with 50% Et 2 O in petroleum ether (40 60 C) the title compound (647 mg, 2.94 mmol, 87%) was obtained as a yellow oil; ν max (neat)/cm , 1744 (C=O), 1457, 1391, 1142; δ H (400 MHz, CDCl 3 ) 1.21 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), 4.15 (2H, q, J 7.1 Hz, OCH 2 CH 3 ), 4.66 (1H, s, CH), 5.21 (1H, d, J 14.1, CH a H b O), 5.62 (1H, d, J 14.1, CH a H b O), (4H, m, Ph-H); δ C (100 MHz, CDCl 3 ) 14.0 (OCH 2 CH 3 ), 54.0 (CH), 62.6 (OCH 2 CH 3 ), 70.4 (OCH 2 ), (Ar-CH), (Ar-CH), (Ar- CH), (Ar-CH), (Ar-C), (Ar-C), (C(O)), (C(O)); m/z (ES+ mode) 221 ((M+H), 100 ), 243 (85), 275 (80), 259 (60), 207 (37), 229 (31), 291 (28). (Found: (M + H), C 12 H 13 O 4 requires M, ). S18

19 1-oxaspiro[5.5]undecan-2-one S16 8 O O S16 To oven-dried magnesium turnings (0.46 g, mmol, 4 eq) in THF (15 ml) was added 1,5-dibromopentane (1.11 g, 4.82 mmol, 1.1 eq) in THF (5 ml) via syringe pump over 1 h. The solution was stirred at room temp for 18 hours before the resultant grey solution was transferred to a separate flask. To this was added dropwise a solution of glutaric anhydride (0.50 g, 4.38 mmol, 1 eq) in THF (4 ml) and stirred for 18 hours. The reaction was quenched by dropwise addition of 3N HCl (20 ml) and warmed to 40 C for 1 h. The organic layer was separated and the aqueous layer was extracted with Et 2 O (2 15 ml). The combined organic layers were washed with brine (1 15 ml), dried (Na 2 SO 4 ) and the solvent removed in vacuo to yield the crude product. Purification by flash chromatography on silica gel eluting with a gradient system up to 50% EtOAc in petroleum ether (40 60 C) gave the title compound (381 mg, 2.27 mmol, 52%) as a yellow oil; ν max (neat)/cm , 1734 (C=O), 665; δ H (400 MHz, CDCl 3 ) (4H, m), (4H, m), (4H, m), (4H, m); δ C (100 MHz, CDCl 3 ) 16.1 (CH 2 ), 21.7 (CH 2 ), 25.4 (CH 2 ), 29.5 (CH 2 ), 32.9 (CH 2 C(O)), 37.3 (CH 2 ), 83.2 (CO), (C(O)); m/z (ES+ mode) 191 ((M + Na), 100), 359 (34); Found: (M + Na), C 10 H 16 O 2 Na 1 requires M, Canonne, P.; Belanger, D.; Lemay, G.; Foscolos, G. B. J. Org. Chem. 1981, 46, S19

20 Ethyl 2-oxo-1-oxaspiro[5.5]undecane-3-carboxylate S17 O O CO 2 Et S17 As for general procedure A, 1-oxaspiro[5.5]undecan-2-one (100 mg, 0.60 mmol, 1 eq) was deprotonated using LDA and reacted with ethyl cyanoformate (88 mg, 0.89 mmol, 1.2 eq). After workup and purification by column chromatography on silica gel eluting with 30% EtOAc in petroleum ether (40 60 C) the title compound (45 mg, 0.19 mmol, 32%) was obtained as a yellow oil; ν max (neat)/cm , 1722 (C=O), 1448, 1371, 1180; δ H (400 MHz, CDCl 3 ) 1.23 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), (8H, m, CH 2 ), (2H, m, CH 2 ), (2H, m), (1H, m, CH a H b CH), (1H, m, CH a H b CH), 3.39 (1H, t, J 7.3 Hz, CH), (2H, m, -OCH 2 CH 3 ); δ C (100 MHz, CDCl 3 ) 14.1 (OCH 2 CH 3 ), 20.6 (CH 2 ), 21.7 (CH 2 ), 25.3 (CH 2 ), 36.9 (CH 2 ), 37.8 (CH 2 ), 47.5 (CH), 61.8 (OCH 2 CH 3 ), 84.3 (OC), (C(O)), (C(O)); m/z (ES+ mode) 241 ((M+H), 100 ), 263 ((M+Na), 73). (Found: (M + H), C 13 H 21 O 4 requires M, ). S20

21 Synthesis of homoallyl halides: General procedure B 9 (E)-(4-Bromo-but-1-enyl)benzene ((E)-(4-Chloro-but-1-enyl)benzene) S18 9 To a 3-neck oven dried flask fitted with a reflux condenser was added Mg turnings (1.10 g, 45.0 mmol, 1 eq) in THF (44 ml). To this stirred mixture was added dropwise cyclopropyl bromide (6.05 g, 50.0 mmol, 1.1 eq) whilst gently warming to 30 C. At this point the reaction started to reflux, so heating was stopped whilst the rest of the bromide was added. Once the reaction had stopped refluxing, it was heated at 65 C for 1 hour and then allowed to cool back to room temperature to yield a 1 M solution of cyclopropylmagnesium bromide. Cyclopropylmagnesium bromide solution (22.0 ml, 22.0 mmol, 1.2 eq, 1 M in THF) was added to a separate flask and cooled to 0 C. Benzaldehyde (2.12 g, 20.0 mmol, 1 eq) was then added and the solution stirred for 15 min followed by the addition of acetyl chloride (1.88 g, 24.0 mmol, 1.2 eq). The reaction was heated to 50 C for 1 hour and then concentrated in vacuo. The crude residue was dissolved in a H 2 O/Et 2 O mixture and the organic layer separated, whilst the aqueous layer was extracted with Et 2 O (2 25 ml). The organic layers were combined, dried (Na 2 SO 4 ) and concentrated in vacuo to yield the crude product. Purification by column chromatography on silica gel eluting with 100% hexane gave the title compounds (2.43 g, 11.0 mmol, 58%) as a yellow oil and as an inseparable mixture of halides (3:1 Br:Cl); δ H (400 MHz, CDCl 3 ) 2.71 (0.5H, dt, J Hz, CH 2 CH 2 Cl), 2.81 (1.5H, dt, 9 Wong, K.-T.; Hung, Y.-Y. Tetrahedron Lett. 2003, 44, S21

22 J 7.0 and 1.4 Hz, CH 2 CH 2 Br), 3.50 (1.5H, t, J 7.1 Hz, CH 2 Br), 3.65 (0.5H, t, J 6.9 Hz, CH 2 Cl), 6.22 (1H, m, CH=CHPh), 6.52 (1H, d, J 15.9 Hz, CH=CHPh), (5H, m, Ph); δ C (100 MHz, CDCl 3 ) 32.3 (CH 2 Br), 36.3 (CH 2 CH 2 Br), (ArC-H), (ArC-H), (ArC-H), (ArC), (CH=CHPh), (CH=CHPh); m/z (EI+ mode) 212 (M Br ), 210 (M Br ), 166 (M Cl ), 131 (M-Br/Cl), 115, 117, 91; (Found: (M Cl ), C 10 H 11 Cl requires M, ); (Found: (M Br C 10 H 11 Br requires M, ). (4-Bromo-but-1-ene-1,1-diyl)dibenzene ((4-Chloro-but-1-ene-1,1-diyl)dibenzene) S19 9 As for general procedure B, a 1 M solution of cyclopropylmagnesium bromide (18.0 ml, 18.0 mmol, 1.2 eq) was prepared and added to benzophenone (2.73 g, 15.0 mmol, 1 eqv) followed by acetyl chloride (1.41 g, 18.0 mmol, 1.2 eq). After workup and purification by column chromatography on silica gel eluting with 2% EtOAc in petroleum ether (40 60 C), the title compound (0.78 g, 2.70 mmol, 18%) was obtained as a yellow oil and as an inseparable mixture of halides (3:1 Br:Cl); δ H (400 MHz, CDCl 3 ) 2.51 (0.5H, q, J 7.0, CH 2 CH 2 Cl), 2.61 (1.5H, q, J 7.0, CH 2 CH 2 Br), 3.35 (1.5H, t, J 7.0, CH 2 Br), 3.51 (0.5H, t, J 6.9, CH 2 Cl), 6.02 (1H, dt, J , CH=C), (10H, m, Ph); δ C (100 MHz, CDCl 3 ) 32.9 (CH 2 CH 2 Br(Cl)), 33.0 (CH 2 Cl), 44.5 (CH 2 Br), (CH=C), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-C), (Ar-C), (CH=C). S22

23 (E)-1-(4-Bromo-but-1-enyl)-4-methoxybenzene ((E)-1-(4-Chloro-but-1-enyl)-4- methoxybenzene) S20 9 As for general procedure B, a 1 M solution of cyclopropylmagnesium bromide (18.0 ml, 18.0 mmol, 1.2 eq) was prepared and added to 4-methoxybenzaldehyde (2.05 g, 15.0 mmol, 1 eq) followed by acetyl chloride (1.41 g, 18.0 mmol, 1.2 eq). After workup and purification by column chromatography on silica gel eluting with 50% CHCl 3 in petroleum ether (40 60 C), the title compound (1.99 g, 8.30 mmol, 55%) was obtained as a white solid and as an inseparable mixture of halides (3:1 Br:Cl); mp. 43 C ;δ H (400 MHz, CDCl 3 ) 2.59 (0.4H, dq, J , CH 2 CH 2 Cl), 2.68 (1.6H, dq, J , CH 2 CH 2 Br), 3.39 (1.6H, t, J 7.1, CH 2 Br), 3.54 (0.4H, t, J 5.6, CH 2 Cl), 3.73 (3H, s, OCH 3 ), 5.98 (1H, m, CH=CHAr), 6.36 (1H, d, J 15.8, CH=CHAr), 6.78 (2H, m, Ar-H), 7.23 (2H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 32.6 (CH 2 Br), 36.2 (CH 2 CH 2 Cl), 36.4 (CH 2 CH 2 Br), 44.3 (CH 2 Cl), 55.3 (OCH 3 ), (Ar-CH), (CH=CHAr), (Ar-CH), (Ar-C), (CH=CHAr), (Ar-C). (E)-1-Bromo-4-(4-bromobut-1-enyl)benzene S21 As for general procedure B, a 1 M solution of cyclopropylmagnesium bromide (18.0 ml, 18.0 mmol, 1.2 eq) was prepared and added to 4-bromobenzaldehyde (2.78 g, 15.0 mmol, 1 eq) followed by acetyl chloride (1.41 g, 18.0 mmol, 1.2 eq). After workup and purification by column chromatography on silica gel eluting with 100% S23

24 petroleum ether (40 60 C), the title compound (2.76 g, 9.6 mmol, 64%) was obtained as a white solid and as an inseparable mixture of halides (5:1 Br:Cl); mp. 36 C; δ H (400 MHz, CDCl 3 ) 2.69 (0.3H, dq, J , CH 2 CH 2 Cl), 2.79 (1.7H, dq, J , CH 2 CH 2 Br), 3.50 (1.7H, t, J 7.0, CH 2 Br), 3.65 (0.3H, t, J 6.9, CH 2 Cl), 6.22 (1H, m, CH=CHAr), 6.45 (1H, d, J 15.9, CH=CHAr), 7.25 (2H, m, Ar-H), 7.45 (2H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 32.1 (CH 2 Br), 36.2 (CH 2 CH 2 Br), (Ar-C), (CH=CHAr), (Ar-CH), (CH=CHAr), (Ar-CH), (Ar-C). S24

25 Alkylation of α-ethoxycarbonyl lactones: General procedure C 2-Oxo-3-((E)-4-phenyl-but-3-enyl)-tetrahydro-pyran-3-carboxylic acid ethyl ester 30 Ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate (494 mg, 2.90 mmol, 1 eq) was dissolved in DMF (25 ml) and cooled to 0 C. To this solution was added slowly NaH (83 mg, 3.40 mmol, 1.2 eq) and the reaction allowed to warm to room temperature. When the initial effervescence had subsided, the reaction was heated to 60 C for 1 hour then allowed to cool to room temperature before adding ((E)-4- bromo-but-1-enyl)-benzene (717 mg, 3.40 mmol, 1.2 eq). The reaction mixture was heated to 60 C for 18 hours then quenched with H 2 O (15 ml) and extracted with EtOAc (3 40 ml). The organic layers were combined and washed with H 2 O (3 40 ml) before being dried (Na 2 SO 4 ) and the solvent removed in vacuo to yield the crude product. Purification by column chromatography on silica gel eluting with 25% EtOAc in petroleum ether (40 60 C) gave the title compound (290 mg, 0.96 mmol, 33%) as a colourless oil; ν max (neat)/cm , 1729 (C=O), 1452, 1192; δ H (400 MHz, CDCl 3 ) 1.32 (3H, t, J 7.1, OCH 2 CH 3 ), 1.92 (1H, m, CH 2 ), 2.01 (1H, m, CH 2 ), (2H, m, CH 2 ), 2.26 (2H, m, CH 2 ), 2.37 (1H, m, CH 2 ), 2.49 (1H, m, CH 2 ), 4.27 (2H, q, J 7.1, OCH 2 CH 3 ), 4.34 (2H, dt, J 16.5, 5.1, OCH 2 ), 6.20 (1H, dt, J , CH=CHPh), 6.44 (1H, d, J 15.8, CH=CHPh), (5H, m, Ph); δ C (100 MHz, CDCl 3 ) 14.1 (OCH 2 CH 3 ), 20.6 (CH 2 ), 28.2 (CH 2 ), 28.3 (CH 2 ), 36.0 (CH 2 ), 53.9 (C), 62.2 (OCH 2 CH 3 ), 68.7 (CH 2 O), (Ar-CH), (Ar-CH=CH), (Ar- CH), (Ar-CH), (Ar-CH=CH), (Ar-C), (C(O)), (C(O)); S25

26 m/z (ES+ mode) 357 ((M + C 4 H 7 ), 100), 325 ((M + Na), 20); (Found: (M + Na), C 18 H 22 O 4 Na 1 requires M, ). Ethyl 3-(but-3-enyl)-2-oxotetrahydro-2H-pyran-3-carboxylate 28 As for general procedure C, reaction of ethyl 2-oxotetrahydro-2H-pyran-3- carboxylate (504 mg, 2.93 mmol, 1 eq) with NaH (84 mg, 3.51 mmol, 1.2 eq) and 4- bromobut-1-ene (474 mg, 3.51 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 30% EtOAc in petroleum ether (40 60 C) gave the title compound (474 mg, 2.10 mmol, 72%) as a colourless oil; ν max (neat)/cm , 1728 (C=O), 1641, 1450, 1399, 1265, 1241, 1199, 1023, 913, 857; δ H (400 MHz, CDCl 3 ) 1.22 (3H, t, J 7.1, OCH 2 CH 3 ), 1.78 (2H, m, CH 2 ), 1.87 (2H, m, CH 2 ), (2H, m, CH 2 ), 2.11 (1H, m, CH 2 ), 2.35 (1H, m, CH 2 ), 4.17 (2H, q, J 7.1, OCH 2 CH 3 ), 4.23 (2H, dt, J , OCH 2 ), 4.94 (2H, m, CH=CH 2 ), 5.72 (1H, m, CH=CH 2 ); δ C (100 MHz, CDCl 3 ) 14.0 (OCH 2 CH 3 ), 20.7 (CH 2 ), 28.0 (CH 2 ), 28.2 (CH 2 ), 35.5 (CH 2 ), 53.8 (C), 62.0 (OCH 2 CH 3 ), 68.7 (CH 2 O), (CH=CH 2 ), (CH=CH 2 ), (C(O)), (C(O)); m/z (ES+ mode) 227 ((M + H), 100), 244 ((M + NH 4 ), 81); (Found: (M + H), C 12 H 19 O 4 requires M, ). Ethyl 3-(4-methylpent-3-enyl)-2-oxotetrahydro-2H-pyran-3-carboxylate 29 S26

27 As for general procedure C, reaction of ethyl 2-oxotetrahydro-2H-pyran-3- carboxylate (396 mg, 2.30 mmol, 1 eq) with NaH (66 mg, 2.75 mmol, 1.2 eq) and 5- bromo-2-methylpent-2-ene (450 mg, 2.75 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 30% EtOAc in petroleum ether (40 60 C) gave the title compound (280 mg, 1.10 mmol, 48%) as a colourless oil; ν max (neat)/cm , 2933, 1729 (C=O), 1477, 1448, 1366, 1347, 1265, 1160, 1092, 858; δ H (400 MHz, CDCl 3 ) 1.21 (3H, t, J 7.1, OCH 2 CH 3 ), 1.53 (3H, s, CH 3 ), 1.60 (3H, s, CH 3 ), (6H, m, 3 CH 2 ), 2.01 (1H, m, from CH 2 ), 2.36 (1H, m, from CH 2 ), 4.15 (2H, q, J 7.1, OCH 2 CH 3 ), 4.23 (2H, m, OCH 2 ), 5.01 (1H, m, CH=C); δ C (100 MHz, CDCl 3 ) 14.0 (OCH 2 CH 3 ), 17.6 (CH 3 ), 20.6 (CH 2 ), 23.2 (CH 3 ), 25.6 (CH 2 ), 28.1 (CH 2 ), 36.3 (CH 2 ), 53.9 (C), 61.9 (OCH 2 CH 3 ), 68.6 (OCH 2 ), (CH=C), (CH=C), (C(O)), (C(O)); m/z (ES+ mode) 277 ((M + Na), 100), 255 ((M + H), 30), 531 (28), 309 (23), 278 (20), 532 (14); (Found: (M + Na), C 14 H 22 O 4 Na requires M, ). Ethyl 3-(4,4-diphenylbut-3-enyl)-2-oxotetrahydro-2H-pyran-3-carboxylate 31 As for general procedure C, reaction of ethyl 2-oxotetrahydro-2H-pyran-3- carboxylate (392 mg, 2.28 mmol, 1 eq) with NaH (66 mg, 2.73 mmol, 1.2 eq) and (4- bromo-but-1-ene-1,1-diyl)dibenzene (784 mg, 2.73 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 20% EtOAc in petroleum ether (40 60 C) gave the title compound (223 mg, 0.59 mmol, 26%) as a colourless oil; ν max (neat)/cm , 1728 (C=O), 1659, 1597, 1495, 1446, 1366, 1275, S27

28 1196, 1097, 763, 702; δ H (400 MHz, CDCl 3 ) 1.12 (3H, t, J 7.1, OCH 2 CH 3 ), 1.56 (1H, m, CH 2 ), 1.71 (1H, m, CH 2 ), 1.82 (1H, m, CH 2 ), 2.00 (2H, m, CH 2 ), 2.05 (1H, m, CH 2 ), 2.14 (1H, m, CH 2 ), 2.24 (1H, m, CH 2 ), 4.06 (2H, q, J 7.1, OCH 2 CH 3 ), 4.13 (2H, t, J 6.0, OCH 2 ), 5.96 (1H, t, J 7.2, CH=CPh 2 ), (10H, m, Ph-H); δ C (100 MHz, CDCl 3 ) 14.0 (OCH 2 CH 3 ), 20.5 (CH 2 ), 25.0 (CH 2 ), 27.8 (CH 2 ), 36.3 (CH 2 ), 53.9 (C), 62.1 (OCH 2 CH 3 ), 68.6 (CH 2 O), (CH=CPh 2 ), (2 Ar-CH), (Ar-CH), (CH=CPh 2 ), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-C), (Ar-C), (C(O)), (C(O)); m/z (ES+ mode) 401 (100), 438 (62), 402 (25), 439 (24), 379 (14); (Found: (M + H), C 24 H 27 O 4 requires M, ). Ethyl-3-((E)-4-(4-methoxyphenyl)but-3-enyl)-2-oxotetrahydro-2H-pyran-3- carboxylate 32 As for general procedure C, reaction of ethyl 2-oxotetrahydro-2H-pyran-3- carboxylate (411 mg, 2.39 mmol, 1 eq) with NaH (69 mg, 2.87 mmol, 1.2 eq) and (E)- 1-(4-bromo-but-1-enyl)-4-methoxybenzene (692 mg, 2.87 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 25% EtOAc in petroleum ether (40 60 C) gave the title compound (620 mg, 1.87 mmol, 78%) as a colourless oil; ν max (neat)/cm , 2838, 1725 (C=O), 1607 (C=O), 1510, 1445, 1245, 1173, 1107, 968; δ H (400 MHz, CDCl 3 ) 1.20 (3H, t, J 7.1, OCH 2 CH 3 ), (2H, m, CH 2 ), 1.88 (1H, m, CH 2 ), (2H, m, CH 2 ), 2.10 (1H, m, CH 2 ), 2.24 (1H, m, CH 2 ), 2.36 (1H, m, CH 2 ), 3.70 (3H, s, OCH 3 ), 4.15 (2H, q, J 7.1, S28

29 OCH 2 CH 3 ), 4.21 (2H, m, OCH 2 ), 5.94 (1H, dt, J , CH=CHAr), 6.27 (1H, d, J 15.8, CH=CHAr), 6.74 (2H, m, Ar-H), 7.17 (2H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 14.1 (OCH 2 CH 3 ), 20.6 (CH 2 ), 28.1 (CH 2 ), 28.2 (CH 2 ), 36.1 (CH 2 ), 53.9 (C), 55.3 (OCH 3 ), 62.1 (OCH 2 CH 3 ), 68.7 (CH 2 O), (Ar-CH), (Ar-C), (Ar- CH=CH), (Ar-CH=CH), (Ar-CH), (Ar-C), (C(O)), (C(O)); m/z (ES+ mode) 350 ((M + H 2 O), 100), 333 ((M + H), 15); (Found: (M + H), C 19 H 25 O 5 requires M, ). Ethyl -3-((E)-4-(4-bromophenyl)but-3-enyl)-2-oxotetrahydro-2H-pyran-3- carboxylate 33 As for general procedure C, reaction of ethyl 2-oxotetrahydro-2H-pyran-3- carboxylate (0.99 g, 5.72 mmol, 1 eq) with NaH (0.17 g, 6.86 mmol, 1.2 eq) and (E)- 1-halo-4-(4-bromobut-1-enyl)benzene (1.98 g, 6.86 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 30% EtOAc in petroleum ether (40 60 C) gave the title compound (1.56 g, 4.11 mmol, 72%) as a colourless oil; ν max (neat)/cm , 1728 (C=O), 1483, 1399, 1163; δ H (400 MHz, CDCl 3 ) 1.22 (3H, t, J 7.1, OCH 2 CH 3 ), (1H, m, CH 2 ), (1H, m, CH 2 ), (2H, m, CH 2 ), (1H, m, CH 2 ), (1H, m, CH 2 ), (2H, m, CH 2 ), 4.17 (2H, q, J 7.1, OCH 2 CH 3 ), 4.21 (2H, m, OCH 2 ), 6.10 (1H, dt, J 15.9, 6.8, CH=CHAr), 6.28 (1H, d, J 15.9, CH=CHAr), 7.11 (2H, m, Ar-H), (2H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 14.1 (OCH 2 CH 3 ), 20.6 (CH 2 ), 28.1 (CH 2 ), 28.3 (CH 2 ), 35.8 (CH 2 ), 53.8 (C), 62.2 (OCH 2 CH 3 ), 68.7 (CH 2 O), (Ar-CBr), S29

30 127.5 (Ar-CH), (ArCH=CH), (ArCH=CH), (Ar-CH), (Ar-C), (C(O)), (C(O)); m/z (ES+ mode) 405 ((M + Na), 100), 403 ((M + Na), 94), 296 (22), 279 (21), 511 (14); (Found: (M + Na), C 18 H 21 O 4 BrNa requires M, ). Ethyl 2-oxo-3-((E)-4-phenylbut-3-enyl)-1-oxaspiro[5.5]undecane-3-carboxylate 34 As for general procedure C, reaction of ethyl 2-oxo-1-oxaspiro[5.5]undecane-3- carboxylate (41 mg, 0.17 mmol, 1 eq) with NaH (5 mg, 0.21 mmol, 1.2 eq) and (E)- (4-bromo-but-1-enyl)-benzene (43 mg, 0.21 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 15% EtOAc in petroleum ether (40 60 C) gave the title compound (26 mg, 0.07 mmol, 41%) as a colourless oil; ν max (neat)/cm , 2359, 1723 (C=O), 1447, 1231, 1123; δ H (400 MHz, CDCl 3 ) 1.22 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), (7H, m), (5H, m), (2H, m, CH 2 CH 2 HC=C), (3H, m, CH 2 CH 2 HC=C + 1H), (1H, m), (2H, m, CH 2 O), 6.12 (1H, dt, J , CH=CHPh), 6.34 (1H, d, J 15.6, CH=CHPh), (5H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 14.1 (OCH 2 CH 3 ), 21.9 (CH 2 ), 25.3 (CH 2 ), 25.8 (CH 2 ), 28.4 (CH 2 ), 35.6 (CH 2 ), 36.8 (CH 2 ), 38.5 (CH 2 ), 53.8 (C), 61.9 (CH 2 O), 84.2 (CO), (CH=CHPh), (Ar-CH), (CH=CHPh), (Ar-CH), (Ar-CH), (Ar-C), (C(O)), (C(O)); m/z (ES+ mode) 371 ((M + H), 100), 114 (66), 388 (M + NH 4 ), 57), 392 ((M + Na), 24). (Found: (M + H), C 23 H 31 O 4 requires M, ). S30

31 Ethyl 3-((E)-4-(4-bromophenyl)but-3-enyl)-2-oxo-1-oxaspiro[5.5]undecane-3- carboxylate 35 As for general procedure C, reaction of ethyl 2-oxo-1-oxaspiro[5.5]undecane-3- carboxylate (88 mg, 0.37 mmol, 1 eq) with NaH (11 mg, 0.44 mmol, 1.2 eq) and (E)- 1-bromo-4-(4-bromobut-1-enyl)benzene (128 mg, 0.44 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 15% EtOAc in petroleum ether (40 60 C) gave the title compound (43 mg, 0.10 mmol, 27%) as a colourless oil; ν max (neat)/cm , 2860, 1738 (C=O), 1721 (C=O), 1486, 1447, 1231, 1207, 1124, 1093, 1071, 1007, 966, 932, 850; δ H (400 MHz, CDCl 3 ) 1.21 (3H, t, J 7.1, OCH 2 CH 3 ), (6H, m, 3 CH 2 ), (6H, m, 3 CH 2 ), (2H, m, CH 2 ), (2H, m, CH 2 CH 2 CH=CHAr), (1H, m, CH a H b CH=CHAr), (1H, m, CH a H b CH=CHAr), (2H, m, OCH 2 CH 3 ), 6.11 (1H, dt, J , CH=CHAr), 6.28 (1H, d, J 15.9, CH=CHAr), 7.11 (2H, d, J 8.6, Ar-H), 7.33 (2H, d, J 8.3, Ar-H); δ C (100 MHz, CDCl 3 ) 14.1 (OCH 2 CH 3 ), 21.9 (CH 2 ), 25.3 (CH 2 ), 25.8 (CH 2 CH 2 CH=CHAr), 28.4 (CH 2 ), 35.5 (CH 2 ), 36.8 (CH 2 ), 38.5 (CH 2 CH 2 CH=CHAr), 53.7 (C), 61.9 (OCH 2 CH 3 ), 84.2 (CO), (ArC-Br), (Ar-CH), (CH=CHAr), (CH=CHAr), (Ar- CH), (Ar-C), (C(O)), (C(O)); m/z (ES+ mode) 473 ((M + Na), 100), 471 ((M + Na), 77); 474 (31), 466 (29), 503 (18); (Found: (M + Na), C 23 H 29 O 4 Br 1 Na 1 requires M, ). S31

32 Ethyl 4-(but-3-enyl)-3-oxoisochroman-4-carboxylate 36 O O CO2 Et 36 As for general procedure C, reaction of ethyl 3-oxoisochroman-4-carboxylate (93 mg, 0.42 mmol, 1 eq) with NaH (12 mg, 0.51 mmol, 1.2 eq) and 4-bromobut-1-ene (68 mg, 0.51 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 15% EtOAc in petroleum ether (40 60 C) gave the title compound (29 mg, 0.11 mmol, 26%) as a yellow oil; ν max (neat)/cm , 2904, 1749 (C=O), 1731 (C=O), 1646, 1558, 1506, 1456, 1396, 1219, 1129, 1021; δ H (400 MHz, CDCl 3 ) 1.19 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), (2H, m, CH 2 CH=CH 2 ), 2.51 (1H, ddd, J 13.9, 10.9, 5.3, CH a H b CH 2 CH), 2.59 (1H, ddd, J 13.9, 10.9, 5.3, CH a H b CH 2 CH), 4.16 (2H, dq, J 14.1, 7.1, OCH 2 CH 3 ), 4.98 (2H, m, CH 2 CH=CH 2 ), 5.37 (1H, d, J 14.6, CH a H b O), 5.54 (1H, d, J 14.6, CH a H b O), (1H, m, CH=CH 2 ), (4H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 13.9 (OCH 2 CH 3 ), 28.6 (CH 2 CH=CH 2 ), 33.7 (CH 2 CH 2 CH), 57.3 (C), 62.4 (OCH 2 CH 3 ), 69.7 (CH 2 O), (CH=CH 2 ), (Ar- CH), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-C), (Ar-C), (CH=CH 2 ), (2 C(O)); m/z (ES+ mode) 297 ((M + Na), 100), 329 (36); 313 (15); (Found: (M + Na), C 16 H 18 O 4 Na 1 requires M, ). S32

33 Ethyl 3-oxo-4-((E)-4-phenylbut-3-enyl)isochroman-4-carboxylate 37 As for general procedure C, reaction of ethyl 3-oxoisochroman-4-carboxylate (86 mg, 0.39 mmol, 1 eq) with NaH (11 mg, 0.47 mmol, 1.2 eq) and (E)-(4-bromo-but-1- enyl)-benzene (99 mg, 0.47 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 30% EtOAc in petroleum ether (40 60 C) gave the title compound (21 mg, 0.06 mmol, 15%) as a yellow oil; ν max (neat)/cm , 1742 (C=O), 1637, 1597, 1451, 1238; δ H (400 MHz, CDCl 3 ) 1.12 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), 2.02 (2H, m, CH 2 CH=CHPh), 2.50 (1H, m, CH a H b CH 2 CH), 2.63 (1H, m, CH a H b CH 2 CH), 4.10 (2H, qd, J 14.1, 7.1, OCH 2 CH 3 ), 5.29 (1H, d, J 14.6, CH a H b O), 5.47 (1H, d, J 14.6, CH a H b O), 6.08 (1H, m, CH=CHPh), 6.25 (1H, d, J 15.9, CH=CHPh), (9H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 13.9 (OCH 2 CH 3 ), 28.0 (CH 2 CH=CH 2 ), 34.1 (CH 2 CH 2 CH), 57.3 (C), 62.5 (OCH 2 CH 3 ), 69.7 (CH 2 O), (Ar-CH), (Ar-CH), (Ar-CH), (Ar- CH), (Ar-CH), (Ar-CH), (CH=CHPh), (Ar-CH), (CH=CHPh), (Ar-C), (Ar-C), (Ar-C) (2 C(O)); m/z (ES+ mode) 373 ((M + Na), 100), 410 (40), 389 (15), 368 (12); (Found: (M + Na), C 22 H 22 O 4 Na requires M, ). S33

34 Ethyl 4-((E)-4-(4-bromophenyl)but-3-enyl)-3-oxoisochroman-4-carboxylate 38 As for general procedure C, reaction of ethyl 3-oxoisochroman-4-carboxylate (128 mg, 0.56 mmol, 1 eq) with NaH (16 mg, 0.67 mmol, 1.2 eq) and (E)-1-bromo-4-(4- bromobut-1-enyl)benzene (162 mg, 0.67 mmol, 1.2 eq) after workup and purification by column chromatography on silica gel eluting with 25% EtOAc in petroleum ether (40 60 C) gave the title compound (50 mg, 0.11 mmol, 20%) as a yellow oil; ν max (neat)/cm , 2357, 1743 (C=O), 1485, 1449, 1397, 1241, 1155, 1070; δ H (400 MHz, CDCl 3 ) 1.11 (3H, t, J 7.1 Hz, OCH 2 CH 3 ), (2H, m, CH 2 CH=CHAr), (1H, m, CH a H b CH 2 CH), (1H, m, CH a H b CH 2 CH), 4.08 (2H, m, OCH 2 CH 3 ), 5.28 (1H, d, J 14.6, CH a H b O), 5.47 (1H, d, J 14.6, CH a H b O), 6.06 (1H, td, J 15.9, 6.6, CH=CHAr), 6.17 (1H, d, J 15.9, CH=CHAr), 7.08 (2H, m, Ar-H), 7.13 (2H, m, Ar-H), (4H, m, Ar-H); δ C (100 MHz, CDCl 3 ) 13.9 (OCH 2 CH 3 ), 28.0 (CH 2 CH=CHAr), 33.9 (CH 2 CH 2 CH), 57.2 (C), 62.5 (OCH 2 CH 3 ), 69.7 (CH 2 O), (ArCBr), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-CH), (Ar-CH), (CH=CHAr), (CH=CHAr), (Ar-CH), (Ar-C), (Ar-C), (Ar-C), (C(O)), (C(O)); m/z (ES+ mode) 451 ((M + Na), 100), 453 (M + Na), 83). (Found: (M + Na), C 22 H 21 O 4 Br 1 Na 1 requires M, ). S34

35 Decarbalkoxylation of α-ethoxycarbonyl lactones: General Procedure D 3-(But-3-enyl)tetrahydro-2H-pyran-2-one 24a 10 O O H 24a Ethyl 3-(but-3-enyl)-2-oxotetrahydro-2H-pyran-3-carboxylate (137 mg, 0.61 mmol, 1 eq) was dissolved in DMSO (2 ml). LiCl (44 mg, 1.04 mmol, 1.7 eq) and H 2 O (0.036 ml) were added and the reaction mixture was heated to 180 C for 3 hours. After cooling to room temperature, saturated aqueous NaHCO 3 (3 ml) was added and the reaction diluted with H 2 O (10 ml). The aqueous layer was extracted with Et 2 O (3 20 ml) and the combined organic layers were washed with brine and dried (Na 2 SO 4 ). The solvent was removed in vacuo to yield the crude product. Purification by column chromatography on silica gel eluting with 35% EtOAc in petroleum ether (40 60 C) gave the title compound (92 mg, 0.60 mmol, 98%) as a colourless oil; ν max (neat)/cm , 2924, 2868, 1734 (C=O), 1640, 1444, 1392, 1344, 1258, 1154, 1071, 999, 912, 665; δ H (400 MHz, CDCl 3 ) (2H, m, CH 2 ), (2H, m, CH 2 CH 2 O), (2H, m, CH 2 ), (2H, m, CH 2 CH=CH 2 ), (1H, m, CH), (2H, m, CH 2 O), (2H, m, CH=CH 2 ), (1H, m, CH=CH 2 ); δ C (100 MHz, CDCl 3 ) 22.0 (CH 2 ), 24.5 (CH 2 ), 30.2 (CH 2 ), 30.9 (CH 2 ), 38.6 (CH), 68.3 (CH 2 O), (CH=CH 2 ), (CH=CH 2 ), (C=O); m/z (EI mode) 154 ((M), 3), 100 ((M CH 2 CH 2 CH=CH 2 ), 100), 41 (51), 55(42); (Found: (M), C 9 H 14 O 2 requires M, ). 10 Fry, A. J.; Little, R. D.; Leonetti, J. J. Org. Chem., 1994, 59, S35