Crossed Intramolecular Rauhut-Currier-Type Reactions via Dienamine Activation

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1 Crossed Intramolecular Rauhut-Currier-Type Reactions via Dienamine Activation Eugenia Marqués-López, Raquel P. Herrera, Timo Marks, Wiebke C. Jacobs, Daniel Könning, Renata M. de Figueiredo, Mathias Christmann* Organic Chemistry, Dortmund University of Technology, Otto-Hahn-Str. 6, Dortmund, 44227, Germany Fax: , Supporting Information Table of Contents General experimental methods 3 Synthesis of starting materials 4 (2E)-5-(3,3-Dimethyloxiranyl)-3-methylpent-2-enyl acetate (15) 4 (2E)-3-Methyl-6-oxohex-2-enyl acetate (16) 4 (2Z,6E)-3-Methyl-8-oxonona-2,6-dienyl acetate (18) 5 (2E,6E)-8-Hydroxy-3-methylnona-2,6-dienyl acetate (19) 5 (2E,6E)-3-Methylnona-2,6-dien-1,8-diol () 6 (2E,6E)-3-Methyl-8-oxonona-2,6-dienal (6a) 6 (2E,6E)-3-Methyl-8-oxo-8-phenylocta-2,6-dienyl acetate (22) 7 (2E,6E)-8-Hydroxy-3-methyl-8-phenylocta-2,6-dienyl acetate (23) 7 (2E,6E)-6-Methyl-1-phenylocta-2,6-dien-1,8-diol (24) 8 (2E,6E)-3-Methyl-8-oxo-8-phenylocta-2,6-dienal (6b) 9 [(p-nitrobenzyl)methylene]triphenylphosphoran (25) 9 (2E,6E)-3-Methyl-8-(4-nitrophenyl)-8-oxoocta-2,6-dienyl acetate (26) 10 (2E,6E)-8-Hydroxy-3-methyl-8-(4-nitrophenyl)octa-2,6-dienyl acetate (27) 10 (2E,6E)-6-Methyl-1-(4-nitrophenyl)octa-2,6-diene-1,8-diol (28) 11 (2E,6E)-3-Methyl-8-(4-nitrophenyl)-8-oxoocta-2,6-dienal (6c) 12 [(p-naphtylbenzyl)methylene]triphenylphosphoran (29) 12 (2E,6E)-3-Methyl-8-(naphthalen-2-yl)-8-oxoocta-2,6-dienyl acetate (30) 13 (2E,6E)-8-Hydroxy-3-methyl-8-(naphthalen-2-yl)octa-2,6-dienyl acetate (31) 13 (2E,6E)-6-Methyl-1-(naphthalen-2-yl)octa-2,6-diene-1,8-diol (32) 14 (2E,6E)-3-Methyl-8-(naphthalen-2-yl)-8-oxoocta-2,6-dienal (6d) 15 [(p-chlorobenzyl)methylene]triphenylphosphoran (33) 15 (2E,6E)-8-(4-Chlorophenyl)-3-methyl-8-oxoocta-2,6-dienyl acetate (34) 16 S-1

2 (2E,6E)-8-(4-Chlorophenyl)-8-hydroxy-3-methylocta-2,6-dienyl acetate (35) 16 (2E,6E)-1-(4-Chlorophenyl)-6-methylocta-2,6-diene-1,8-diol (36) 17 (2E,6E)-8-(4-Chlorophenyl)-3-methyl-8-oxoocta-2,6-dienal (6e) 18 [(p-methoxybenzyl)methylene]triphenylphosphoran (37) 18 (2E,6E)-8(4-Methoxyphenyl)-3-methyl-8-oxo-8-oxoocta-2,6-dienyl acetate (38) 19 (2E,6E)-8-Hydroxy-8-(4-methoxyphenyl)-3-methylocta-2,6-dienyl acetate (39) 19 (2E,6E)-1-(4-Methoxyphenyl)-6-methylocta-2,6-dien-1,8-diol () (2E,6E)-8-(4-Methoxyphenyl)-3-methyl-8-oxoocta-2,6-dienal (6f) 21 (E)-6-Hydroxy-3-methyl-7-nitrohept-2-enyl acetate (41) 21 (2E,6E)-3-Methyl-7-nitrohepta-2,6-dienyl acetate (42) 22 (2E,6E)-3-Methyl-7-nitrohepta-2,6-dienal (6g) 22 (2E,6E)-Methyl-8-acetoxy-6-methylocta-2,6-dienoate (45) 23 (2E,6E)-3-Methyl-octa-2,6-dien-1,8-diol (46) 24 (2E,6E)-3-Methylocta-2,6-diendial (6h) 24 Organocatalytic enantioselective cyclization of enals 7a-h 25 General procedure 25 (R)-2-Methyl-5-(2-oxopropyl)cyclopent-1-encarbaldehyde (7a) 25 (R)-2-Methyl-5-(2-oxo-2-phenylethyl)cyclopent-1-encarbaldehyde (7b) 26 (R)-2-Methyl-5-(2-(4-nitrophenyl)-2-oxoethyl)cyclopent-1-enecarbaldehyde (7c) 26 (R)-2-Methyl-5-(2-(naphthalen-2-yl)-2-oxoethyl)cyclopent-1-enecarbaldehyde (7d) 27 (R)-2-Methyl-5-(2-(4-chlorophenyl)-2-oxoethyl)cyclopent-1-enecarbaldehyde (7e) 27 (R)-5-(2-(4-Methoxyphenyl)-2-oxoethyl)2-methylcyclopent-1-encarbaldehyde (7f) 27 (S)-2-Methyl-5-(nitromethyl)cyclopent-1-enecarbaldehyde (7g) 28 (R)-Rotundial [(R)-2-methyl-5-(2-oxoethyl)cyclopent-1-enecarbaldehyde] (7h) 28 (R)-Rotundiol [(R)-2-(2-(hydroxymethyl)-3-methylcyclopent-2-enyl)ethanol] (47) 29 (R)-2-(3-Methyl-2-((4-nitrobenzyloxy)methyl)cyclopent-2-enyl)ethyl-4-nitrobenzoate (48) 29 X-ray structures 30 NMR Spectra 31 HPLC Analysis of products 7a-h 79 References and notes 89 S-2

3 GENERAL EXPERIMENTAL METHODS Solvents of HPLC grade were purchased from Fisher Scientific or VWR (Prolabo). Where dry solvents (Et 2 O, CH 2 Cl 2, toluene, DMF or THF) were required they were purified by Solvent Purification Systems M-BRAUN Glovebox Technology SPS-0. Technical quality solvents for column chromatography were used after short path distillation in a rotary evaporator. Catalysts I- VII were purchased from Alfa Aesar or Aldrich and used without further purification [L-Proline (I) (99%), (S)-( )-α,α-diphenylprolinol (II) (98%), (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2- pyrrolidinemethanol (III) (99%), (S)-( )-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether (IV) (95%), (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether (IV) (96%), (S)-α,α- Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether (V) (97%), (S)-2- (methoxydiphenylmethyl)pyrrolidine (VI) (95%) and (S)-( )-2-(diphenylmethyl)pyrrolidine (VII) (97%)]. Unless noted below, all other compounds were reported in literature or were supplied by Aldrich, Acros or AlfaAesar, and used without further purification. Thin-layer chromatography (SiO2, TLC) was performed on Merck TLC silica gel F 254. Column chromatography was performed on Merck silica gel ( nm), using standard flash chromatographic methods. Chiral HPLC analysis was performed using an Agilent 10 series HPLC with a diode array detector. Chiral columns include Daicel Chiralpak IA (Chiral Technologies Eur., 25 cm 4.6 mm I.D.), Daicel Chiralpak IB (Chiral Technologies Eur., 25 cm 4.6 mm I.D.) and Nucleocel Delta S (Macherey-Nagel, 25 cm 4.6 mm). Melting points were measured out on a Büchi B-5 block apparatus and are uncorrected. Optical rotations were recorded on a Perkin Elmer polarimeter 341 at 589 nm, and were reported as [α] D (concentration). The NMR spectra were recorded on Bruker DRX300 (300 MHz) DRX0 (0 MHz) or DRX500 (500 MHz) spectrometers and were referenced against the residual solvent peaks [CHCl 3 : δ 7.26 ppm ( 1 H NMR) and ppm ( 13 C NMR) and CD 3 OD: δ 3.31 ppm ( 1 H NMR) and 40 ppm ( 13 C NMR)] or using an external reference for 31 P NMR (H 3 PO 4, 0.0 ppm). Chemical shifts are reported in parts per million as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant, and integration. Infrared spectra were recorded on a Nicolet Impact 0D spectrometer on potassium bromide matrix (disk or film). Low resolution mass spectra were performed on a Thermo TSQ mass spectrometer for ESI-MS; or on a GC System, Hewlett Packard 6890 series/mass selective detector, Hewlett Packard 5973 (column: HP-5MS (J&W Scientific, Agilent); 25 m, 0.2 mm I.D., film 0.33 µm) for GC-EI-MS. High resolution mass spectra were recorded on a LTQ Orbitrap mass spectrometer coupled to an Accela HPLC-System (HPLC column: Hypersyl GOLD, 50 mm 1 mm, 1.9 µm) for HPLC-ESI-HRMS; or on a DFS-High resolution Magnetic Sector MS (Double Focusing Mass Spectrometer) for DI-EI-HRMS (Direct inlet EI-HRMS) or coupled to a Trace GC Ultra 00 (column: DB-5MS (J&W Scientific, Agilent); S-3

4 25 m, 0.25 mm I.D., film 0.1 µm) for GC-EI-HRMS and for GC-CI-HRMS. All instruments are from Thermo Electron. Elemental analyses were recorded on an automatic Leco CHNS-932 elemental analyzer. SYNTHESIS OF STARTING MATERIALS (2E)-5-(3,3-Dimethyloxiranyl)-3-methylpent-2-enyl acetate (15) [1] To a stirred solution of geranyl acetate 14 (9. g, 50.1 mmol) in CH 2 Cl 2 ( ml) at 0 C a solution of m-cpba (70-75%, Acros; 12.4 g, 50.3 mmol) was added and stirred for 1 h. After warming up the reaction mixture to r.t. an aqueous solution of NaOH ( M, 25 ml) was added. The aqueous phase was extracted with CH 2 Cl 2 (3 x 25 ml). The combined organic phases were washed with brine (2 x 30 ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, hexane/etoac 5:1) to afford 15 [1] (10.5 g, 99%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ (m, 1H), 4.58 (d, J = 7.2 Hz, 2H), 2.69 (t, J = 6.4 Hz, 1H), (m, 2H), 4 (s, 3H), 1.71 (s, 3H), (m, 2H), 1.29 (s, 3H), 1.25 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 171.1, 141.3, 118.8, 63.9, 61.2, 58.4, 36.1, 2, 24.8, 2, 18.7, (2E)-3-Methyl-6-oxohex-2-enyl acetate (16) [1] To a stirred solution of HIO 4 2H 2 O (13.7 g,.1 mmol) in H 2 O (50 ml) at 0 C a solution of (2E)- 5-(3,3-dimethyl-oxiranyl)-3-methyl-pent-2-enyl acetate 15 (11.4 g, 53.7 mmol) in THF ( ml) was added and stirred for 1 h. Then brine ( ml) was added, and the aqueous phase was extracted with Et 2 O (3 x ml). The combined organic phases were washed with a saturated aqueous solution of NaHCO 3 (3 x ml), and brine (3 x ml), dried over MgSO 4. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO 2, hexane/etoac 4:1) to afford 16 [1] (7. g, 85%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ 9.77 (t, J = 1.6 Hz, 1H), (m, 1H), 4.56 (d, J = 7.2 Hz, 2H), (m, 2H), 2.37 (t, J = 7.6 S-4

5 Hz, 2H), 4 (s, 3H), 1.71 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 1.7, 17,, 119.2, 6, 41.7, 31.4, 2, (2Z,6E)-3-Methyl-8-oxonona-2,6-dienyl acetate (18) To a stirred solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (0 g, 11.8 mmol) in THF ( ml), 1-(triphenylphosphoranylidene)acetone 17 (15.1 g, 4 mmol) was added in one portion and stirred for 16 h at C. After filtration of the white solid, the solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO 2, pentane/etoac 4:1) to afford 18 in (2. g, 96%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ 6.75 (dt, J = 1, Hz, 1H), 5 (d, J = 1 Hz, 1H), 5.35 (t, J = Hz, 1H), 4.56 (d, J = Hz, 2H), (m, 2H), 2.22 (s, 3H), (m, 2H), 3 (s, 3H), 1.70 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 198.6, 17, 147.2, 1.4, 131.5, 119.4, 61.1, 37.7, 30.4, 26.8, 2, IR (KBr film) (cm -1 ) ν 2967, 2925, 1735, 1674, 1629, 1371, 1259, 1097, 1021, 799. ESI-MS m/z (%) 233 () [M+Na] +. HPLC-ESI- HRMS ([M+H] + ) calcd for C 12 H 19 O , found (2E,6E)-8-Hydroxy-3-methylnona-2,6-dienyl acetate (19) [2] To a stirred solution of (2E,6E)-3-methyl-8-oxonona-2,6-dienyl acetate 18 (952 mg, 4.53 mmol) and CeCl 3 7H 2 O (2.10 g, 5.71 mmol) in MeOH (45 ml) at 0 C, NaBH 4 was added in three portions (2 mg, 6.25 mmol) and stirred for 2 h at r.t. After the addition of acetone (6 ml) and HCl (0.5 M, 50 ml) the aqueous phase was extracted with EtOAc (4 x ml). The combined organic phases were washed with brine ( ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, toluene/etoac 5:1) to afford 19 (749 mg, 78%) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), 5.29 (t, J = 7.5 Hz, 1H), (m, 2H), (m, 1H), (m, 4H), S-5

6 (s, 3H), (m, 1H), 1.65 (s, 3H), 1. (dd, J =, Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 17, 141.3, 134.8, 129.6, 118.8, 68.6, 61.3, 38.8, 30.0, 23.3,.9, IR (KBr film) (cm -1 ) ν 3431, 2971, 2929, 1738, 1448, 1367, 1233, 1062, 1024, 967. ESI-MS m/z (%) 235 [M+Na] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 12 H O 3 Na , found (2E,6E)-3-Methylnona-2,6-diene-1,8-diol () [1b] To a stirred solution of (2E,6E)-8-hydroxy-3-methylnona-2,6-dienyl acetate 19 (792 mg, 3.73 mmol) in MeOH (7.5 ml), K 2 CO 3 (4 mg, 370 µmol) was added and stirred for 4 h at r.t. Then H 2 O (5 ml) was added and extracted with EtOAc (4 x ml). The combined organic phases were washed with an aqueous solution of HCl ( M, ml), saturated aqueous solution of NaHCO 3 ( ml), and brine ( ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 2:1 1:1 1:4) to afford (533 mg, 84%) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ (m, 1H), (m, 1H), 5.37 (t, J = 7.5 Hz, 1H), (m, 1H), (m, 2H), (m, 6H), 1.65 (s, 3H), 1.23 (dd, J =, Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 138.5, 134.7, 129.9, 12, 68.7, 59.1, 38.9, 30.0, 23.3, IR (KBr film) (cm -1 ) ν 3474, 3338, 3290, 2971, 2927, 1668, 1448, 1370, 1300, 11, 1062, 7, 968, 936. ESI-MS m/z (%) 193 [M+Na] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 10 H 18 O 2 Na , found (2E,6E)-3-Methyl-8-oxonona-2,6-dienal (6a) [3] To a stirred solution of (2E,6E)-3-methylnona-2,6-diene-1,8-diol (195 mg, 1.15 mmol) in DMSO (5 ml), a solution of IBX (2.2 g, 7.75 mmol) in DMSO (5 ml) was added and stirred for 1 h at r.t. Then H 2 O ( ml) was added and the resulting cloudy suspension was filtered through a course fritted funnel and washed with EtOAc ( ml). The aqueous phase was also extracted with EtOAc (5 x 10 ml). The combined organic phases were washed with H 2 O ( ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The 1 H NMR of the crude product 6a shows a mixture of isomers (2E,6E):(2E,6Z) 87:13. The residue was purified by S-6

7 flash chromatography (SiO 2, pentane/etoac 1:1) to afford 6a (181 mg, 95% yield, dr 94:6) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 9.99 (d, J = Hz, 1H), 6.74 (dt, J = 1, Hz, 1H), 9 (d, J = 1 Hz, 1H), 5.88 (d, J = Hz, 1H), (m, 2H), (m, 2H), 2.23 (s, 3H), 2.18 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 19, 19, 161.2, 145.4, 13, 127.7, 38.6, 29.7, 2, IR (KBr film) (cm -1 ) ν 1672, 1629, 1431, 1362, 1255, 1192, 1124, 984. ESI-MS m/z (%) 189 [M+Na] +. GC-EI-HRMS ([M] + ) calcd for C 10 H 14 O ; found (2E,6E)-3-Methyl-8-oxo-8-phenylocta-2,6-dienyl acetate (22) To a stirred solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (0 mg, 1.18 mmol) in THF (2 ml), (phenacylidene)triphenylphosphorane 21 (1. g, 4.70 mmol) was added in one portion and stirred for 7 h at C. After filtration of the solid, the solvent was removed under reduced pressure. The residue was extracted with Et 2 O (4 x 10 ml). The combined organic phases were dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, toluene/etoac 19:1) to afford the product 22 (296 mg, 93%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ (m, 2H), (m, 1H), (m, 2H), 1 (dt, J = 15.6, 6.8 Hz, 1H), 6.88 (d, J = 15.6 Hz, 1H), (m, 1H), 4.59 (d, J = 7.2 Hz, 2H), (m, 2H), (m, 2H), 3 (s, 3H), 1.74 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 190.8, 171.1, 148.7, 1.6, 137.8, 132.6, 128.5, 126.2, 119.4, 61.1, 37.8, 30.8, 2, IR (KBr film) (cm -1 ) ν 2936, 1738, 1670, 1651, 1448, 1366, 1233, 1023, 951, 696. ESI-MS m/z (%) 295 () [M+Na] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 17 H 21 O , found Anal calcd for C 17 H O 3 : C, 7; H, 7.4; found: C, 74.6; H, 7.5. (2E,6E)-8-Hydroxy-3-methyl-8-phenylocta-2,6-dienyl acetate (23) [2] S-7

8 To a stirred solution of (2E,6E)-3-methyl-8-oxo-8-phenylocta-2,6-dienyl acetate 22 (770 mg, 2.83 mmol) and CeCl 3 7H 2 O (1.3 g, 3.58 mmol) in MeOH (18 ml) at 0 C, NaBH 4 was added in three portions (148 mg, 3.91 mmol) and stirred for 2 h at r.t. After the addition of acetone (6 ml) and HCl (0.5 M, 50 ml) the aqueous phase was extracted with EtOAc (4 x ml). The combined organic phases were washed with brine ( ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/et 2 O 2:3) to afford 23 (669 mg, 86%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ (m, 5H), (m, 2H), (m, 1H), 5.15 (br s, 1H), (m, 2H), (m, 2H), (m, 3H), 5 (s, 3H), 1.68 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 171.2, 143.2, 141.3, 132.9, 131.5, 128.4, 127.5, 126.3, 118.9, 75.1, 61.4, 38.8, 30.1, 21.1, IR (KBr film) (cm -1 ) ν 3434, 3028, 2930, 2863, 2844, 1736, 1451, 1382, 1366, 1233, 1023, 967, 700. ESI- MS m/z (%) 297 () [M+Na] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 17 H 22 O 3 Na , found Anal calcd for C 15 H 22 O 3 : C, 74.4; H, 8.1; found: C, 74.5; H, 8.2. (2E,6E)-6-Methyl-1-phenylocta-2,6-diene-1,8-diol (24) [1b] To a stirred solution of (2E,6E)-8-hydroxy-3-methyl-8-phenyl-octa-2,6-dienyl acetic acid ester 23 (2 mg, 0. mmol) in MeOH (3 ml), K 2 CO 3 (8 mg, 0.06 mmol) was added and stirred for 2 h at r.t. Then H 2 O (5 ml) was added and extracted with Et 2 O (4 x ml). The combined organic phases were washed with an aqueous solution of HCl ( M, ml), saturated aqueous solution of NaHCO 3 ( ml), and brine ( ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/et 2 O 1:3) to afford 24 (169 mg, 91%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ (m, 4H), (m, 1H), (m, 2H), (m, 1H), 5.15 (d, J = Hz, 1H), (m, 2H), (m, 3H), (m, 2H), 1.65 (s, 3H), 1. (br s, 1H). 13 C NMR ( MHz, CDCl 3 ) δ 143.3, 138.7, 132.9, 131.6, 128.4, 127.5, 126.1, 124.1, 75.1, 59.2, 38.7, 30.0, IR (KBr film) (cm -1 ) ν 3330, 3027, 2929, 2850, 1668, 1450, 1382, 1302, 1238, 1090, 4, 965, 756, 700. ESI-MS m/z (%) 255 () [M+Na] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 15 H O 2 Na , found Anal calcd for C 15 H O 2 : C, 77.6; H, 8.7; found: C, 77.4; H, 8.6. S-8

9 (2E,6E)-3-Methyl-8-oxo-8-phenylocta-2,6-dienal (6b) [3] To a stirred solution of (2E,6E)-6-methyl-1-phenyl-octa-2,6-dien-1,8-diol 24 (166 mg, 0.71 mmol) in DMSO (1 ml), a solution of IBX (1.2 g, 4.29 mmol) in DMSO (9 ml) was added and stirred for 1 h at r.t. Then H 2 O (10 ml) was added and the resulting cloudy suspension was filtered through a course fritted funnel and washed with Et 2 O ( ml). The aqueous phase was also extracted with Et 2 O (5 x 10 ml). The combined organic phases were washed with H 2 O ( ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/et 2 O 3:2) to afford 6b (114 mg, 70%) as light yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ (d, J = Hz, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), 2.21 (d, J = 0.8 Hz, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 19, 190.4, 161.6, 14, 137.6, 132.8, 128.6, 128.5, 127.7, 126.7, 38.7, 30.2, IR (KBr film) (cm -1 ) ν 2923, 2853, 1674, 1446, 1382, 1349, 1287, 1252, 1090, 1224, 1175, 1124, 4, 987, 851, 771, 696. ESI-MS m/z (%) 251 () [M+Na] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 15 H 17 O , found Anal calcd for C 15 H 16 O 2 : C, 78.9; H, 7.1; found: C, 78.4; H, 7.1. [(p-nitrobenzyl)methylene]triphenylphosphoran (25) [4] To a stirred solution of triphenylphosphine (21.2 g,.0 mmol) in acetone (130 ml) a solution of 2- bromo-1-(4-nitrophenyl)ethanone (.6 g,.0 mmol) in acetone (70 ml) was added. The mixture was stirred overnight at r.t. Then the solvent was removed under reduced pressure. The crude salt was solved in H 2 O/EtOH/acetone 1:1:, and then an aqueous solution of NaOH (5%) was added slowly until ph 10 ( ml) at 0 C. The precipitate was separated and dissolved in CHCl 3 (0 ml), and washed with three portions of H 2 O (3 x 50 ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The ylide 25 (1 g, 47% yield, 2 steps) was obtained after recrystallization from ethanol as yellow solid: mp C (lit C). 1 H NMR (0 MHz, CDCl 3 ) δ 8. (d, J = Hz, 2H), 8 (d, J = Hz, 2H), S-9

10 7.68 (m, 6H), (3H), (m, 6H), 4.50 (d, J = 2 Hz, 1H). 31 P NMR (121.5 MHz, CDCl 3 ) δ C NMR (125 MHz, CDCl 3 ) δ (d, J = 3.8 Hz), 148.4, (d, J = 15.3 Hz), (d, J = 10.5 Hz), (d, J = 2.9 Hz), (d, J = 12.5 Hz), 127.9, (d, J = 91.2 Hz), 123.3, 53.7 (d, J = Hz). IR (KBr disk) (cm -1 ) ν 1529, 14, 1436, 18, 1390, 1342, 1183, 1106, 1085, 8, 865, 750, 719, 693. ESI-MS m/z (%) 426 () [M+H] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 26 H 21 O 3 NP ; found (2E,6E)-3-Methyl-8-(4-nitrophenyl)-8-oxoocta-2,6-dienyl acetate (26) To a stirred solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (1 mg, 3.53 mmol) in THF (18 ml), [(p-nitrobenzyl)methylene]triphenylphosphorane 25 (0 g, 14.1 mmol) was added in one portion, under argon atmosphere, and stirred for h at C. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO 2, toluene/etoac :1) to afford 26 (4 mg, 36%) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 8.31 (d, J = Hz, 2H), 3 (d, J = Hz, 2H), 6 (dt, J = 15.4, 6.9 Hz, 1H), 6.84 (d, J = 15.4 Hz, 1H), 5. (t, J = 6.9 Hz, 1H), 4. (d, J = 6.9 Hz, 2H), 2.50 (q, J = 6.7 Hz, 2H), 2.28 (t, J = 7.5 Hz, 2H), 3 (s, 3H), 1.74 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 189.4, 171.2, 151.2, 150.1, 142.8, 1.4, 129.6, 12, 123.9, 119.8, 61.3, 37.8, 31.1, 21.1, IR (KBr film) (cm -1 ) ν 2937, 1735, 1673, 1621, 1525, 1347, 1233, 1024, 854, 828, 703. ESI-MS m/z (%) 318 (10) [M+H] +, 3 () [M+Na] +, 356 (10) [M+K] +, 381 (30) [M+Na+MeCN] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 17 H 19 O 5 NNa ; found (2E,6E)-8-Hydroxy-3-methyl-8-(4-nitrophenyl)octa-2,6-dienyl acetate (27) [2] To a stirred solution of (2E,6E)-3-methyl-8-(4-nitrophenyl)-8-oxoocta-2,6-dienyl acetate 26 (419 mg, 1.30 mmol) and CeCl 3 7H 2 O (630 mg, 1.69 mmol) in MeOH (13 ml) at 0 C, NaBH 4 was added in three portions (69 mg, 1.82 mmol) and stirred for 2 h at r.t. The reaction mixture poured S-10

11 into ice/h 2 O, and then a solution of citric acid (10%) was added. After addition of EtOAc ( ml) the phases were separated, and the aqueous phase was extracted with EtOAc (4 x 15 ml). The combined organic phases were washed with brine ( ml), dried over Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 4:1 2:1) to afford 27 (397 mg, 96%) as yellow solid: mp -62 C. 1 H NMR (500 MHz, CDCl 3 ) δ 8.18 (dd, J = 8.8, 1.5 Hz, 2H), 7.53 (d, J = 8.1, 2H), (m, 1H), 5.58 (ddd, J = 15.3, 7.2, 1.2 Hz, 1H), 5.31 (t, J = 6.9 Hz, 1H), 5.23 (d, J = 7.3 Hz, 1H), (m, 2H), 2.45 (br s, 1H), (m, 2H), (m, 2H), 4 (d, J = 1.5 Hz, 3H), 1.67 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 171.2, 150.4, 147.2, 1.7, 133.2, 132.1, 126.8, 123.6, 119.4, 74.3, 61.4, 38.5, 29.9, 2, IR (KBr film) (cm -1 ) ν 3446, 2936, 2853, 1735, 1521, 1348, 1236, 1024, 970, 856, 749, 701, 8. ESI-MS m/z (%) 242 (), 302 () [M-OH] +, 342 () [M+Na] +, 358 (10) [M+K] +, 383 () [M+Na+MeCN] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 17 H 21 O 5 NNa ; found (2E,6E)-6-Methyl-1-(4-nitrophenyl)octa-2,6-diene-1,8-diol (28) [1a] AcO NO 2 NO 2 Me Me K 2 CO 3,MeOH HO r.t.,3d 27 OH OH 82% 28 C 17 H 21 NO 5 (319.35) C 15 H 19 NO 4 (277.31) To a stirred solution of (2Z,6E)-8-hydroxy-3-methyl-8-(4-nitrophenyl)octa-2,6-dienyl acetate 27 (372 mg, 1.16 mmol) in MeOH (3 ml), K 2 CO 3 (81 mg, 0.58 mmol) was added at 0 C, under argon atmosphere, and stirred for 3 d at r.t. Then a saturated aqueous solution of NH 4 Cl (10 ml) was added, and after addition of EtOAc (10 ml) the phases were separated. The aqueous phase was extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with brine ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 2:1 1:2) to afford 28 (265 mg, 82%) as light yellow solid: mp C. 1 H NMR (500 MHz, CD 3 OD) δ 8.19 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), (m, 1H), 5. (dd, J = 15.3, 6.9 Hz, 1H), 5.36 (td, J = 6.5, 1.2 Hz, 1H), 5. (d, J = 6.9 Hz, 1H), 9-2 (m, 2H), (m, 2H), (m, 2H), 1.64 (s, 3H). 13 C NMR (125 MHz, CD 3 OD) δ 15, 148.4, 138.7, 133.4, 128.2, 125.4, 124.4, 74.9, 59.4,.0, 31.4, IR (KBr film) (cm -1 ) ν 3300, 3167, 29, 1667, 1599, 1519, 1448, 1344, 5, 967, 854, 742, 698. ESI-MS m/z (%) 279 (18), 312 (), 313 (24). HPLC-ESI-HRMS ([2M+Na] + ) calcd for C 30 H 38 O 8 N 2 Na ; found S-11

12 (2E,6E)-3-Methyl-8-(4-nitrophenyl)-8-oxoocta-2,6-dienal (6c) [3] HO Me 28 OH C 15 H 19 NO 4 (277.32) NO NO 2 Me 2 IBX O DMSO,r.t.,45min 6c O 85% C 15 H 15 NO 4 (273.28) To a stirred solution of (2E,6E)-6-methyl-1-(4-nitrophenyl)octa-2,6-diene-1,8-diol 28 (243 mg, 0.88 mmol) in DMSO (5 ml), a solution of IBX (1.5 g, 5.25 mmol) in DMSO (5 ml) was added and stirred for 45 min at r.t. Then H 2 O (15 ml) was added and the resulting cloudy suspension was filtered through a course fritted funnel and washed with EtOAc ( ml). The aqueous phase was also extracted with EtOAc (4 x 10 ml). The combined organic phases were washed with H 2 O ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The 1 H NMR of the crude product shows a dr of 90:10. The residue was purified by flash chromatography (SiO 2, pentane/et 2 O 2:1 1:2) to afford 6c (3 mg, 85%, dr 98:2) as yellow solid: mp C. 1 H NMR (500 MHz, CDCl 3 ) δ 1 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 3 (d, J = 8.8 Hz, 2H), 6 (dt, J = 15.3, 6.9 Hz, 1H), 6.89 (dt J = 15.3, 1.1 Hz, 1H), 5.91 (dd, J =, 1.2 Hz, 1H), (m, 2H), (m, 2H), 2.21 (d, J = 1.1 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 19, 18, 161.1, 150.3, 149.4, 142.6, 129.6, 127.9, 126.5, 123.9, 38.6, 30.4, IR (KBr disk) (cm -1 ) ν 29, 2890, 1669, 1619, 1599, 1518, 1344, 12, 1191, 1127, 7, 856, 827, 710. ESI-MS m/z (%) 296 () [M+Na] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 15 H 16 O 4 N ; found [(p-naphtylbenzyl)methylene]triphenylphosphoran (29) [5] To a stirred solution of 2-bromo-1-(naphthalen-2-yl)ethanone (9.70 g, 38.5 mmol) in CH 2 Cl 2 (27 ml) a solution of triphenylphosphine (10.9 g, 41. mmol) in CH 2 Cl 2 (27 ml) was added at 0 C and stirred overnight at r.t. Then the solvent was removed under reduced pressure. The crude salt was solved in CH 2 Cl 2 /H 2 O 150:150, and then an aqueous solution of Na 2 CO 3 (27.5 g in 1 ml of H 2 O) was added at r.t. and stirred overnight. Then the organic phase was separated, dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. After recrystallization from benzene, ylide 29 (12.1 g, 73%, 2 steps) was obtained as light yellow solid: mp C. 1 H NMR (0 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.15 (dd, J = 8.5, 1.5 Hz, 1H), S-12

13 7.92 (m, 1H), (m, 8H), (m, 11H), 4.64 (d, J = 24.6 Hz, 1H). 31 P NMR (121.5 MHz, CDCl 3 ) δ C NMR (125 MHz, CDCl 3 ) δ (d, J = 2.9 Hz), (d, J = 14.6 Hz), 13, (d, J = 9.7 Hz), 13, (d, J = 2.9 Hz), (d, J = 12.5 Hz), 127.5, 127.4, 127.1, (d, J = 81.6 Hz), 126.2, 12, 51.4 (d, J = Hz). IR (KBr disk) (cm -1 ) ν 15, 1521, 1479, 1433, 13, 1178, 1106, 881, 847, 748, 718, 692, 519. ESI-MS m/z (%) 431 () [M+H] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 30 H 24 OP ; found (2E,6E)-3-Methyl-8-(naphthalen-2-yl)-8-oxoocta-2,6-dienyl acetate (30) To a suspension of [(p-naphthylbenzyl)methylene]triphenylphosphoran 29 (7. g, 17.6 mmol) in CH 2 Cl 2 ( ml) a solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (0 g, 5.88 mmol) in CH 2 Cl 2 (24 ml) was added, under argon atmosphere, and stirred for 4 d at r.t. The solvent was removed under reduced pressure. The 1 H NMR of the crude product shows a dr of 96:4. The residue was purified by flash chromatography (SiO 2, pentane/etoac :1 4:1) to afford 30 (1. g, 73%) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 8. (br s, 1H), 7.98 (br d, J = 8.8 Hz, 1H), 7.92 (br d, J = Hz, 1H), 7.85 (br d, J = 8.8 Hz, 1H), 7.82 (br d, J = Hz, 1H), (m, 2H), (m, 2H), 5. (t, J = 7.1 Hz, 1H), 4.57 (d, J = 6.8 Hz, 2H), (m, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.98 (d, J = 1.1 Hz, 3H), 1.72 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 190.4, 170.9, 148.4, 1.5, 135.4, 135.2, 132.5, 130.0, 129.4, 128.4, 128.3, 127.8, 126.7, 126.3, 124.5, 119.5, 61.1, 37.8, 30.9,.9, IR (KBr film) (cm -1 ) ν 2932, 1736, 1667, 1619, 1364, 1234, 1023, 956, 821, 754. ESI-MS m/z (%) 263 () [M-CH 3 CO 2 ], 323 (78) [M+H] +, 345 (36) [M+Na] +, 386 (10) [M+Na+MeCN] +. DI-EI-HRMS ([M] + ) calcd for C 21 H 22 O ; found (2E,6E)-8-Hydroxy-3-methyl-8-(naphthalen-2-yl)octa-2,6-dienyl acetate (31) [2] To a stirred solution of (2E,6E)-3-methyl-8-(naphthalen-2-yl)-8-oxoocta-2,6-dienyl acetate 30 (0 g, 3.10 mmol) and CeCl 3 7H 2 O (1.50 g, 3 mmol) in MeOH (31 ml) at 0 C, NaBH 4 was added S-13

14 in three portions (164 mg, 4.34 mmol) and stirred for 90 min at r.t. The reaction mixture poured into ice/h 2 O, and then a solution of citric acid (10%) was added. After addition of EtOAc ( ml) the phases were separated, and the aqueous phase was extracted with EtOAc (4 x 30 ml). The combined organic phases were washed with brine (1 ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 4:1 2:1) to afford 31 (858 mg, 85%) as colorless oil: 1 H NMR (0 MHz, CDCl 3 ) δ (m, 4H), (m, 3H), (m, 2H), (m, 2H), (m, 2H), 2.52 (br s, 1H), (m, 2H), (m, 2H), 4 (s, 3H), 1.68 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 171.3, 141.4, 1.7, 133.4, 13, 132.9, 131.7, 128.2, 12, 127.7, 126.2, 125.9, 124.6, 11, 75.2, 61.5, 38.8, 30.2, 21.1, IR (KBr film) (cm -1 ) ν 3423, 2934, 2852, 1736, 1441, 1367, 1236, 1023, 967, 859, 8, 751. ESI-MS m/z (%) 247 (90), 307 (11) [M-OH] +, 347 () [M+Na] +, 388 (10) [M+Na+MeCN] +. DI-EI-HRMS ([M] + ) calcd for C 21 H 24 O ; found (2E,6E)-6-Methyl-1-(naphthalen-2-yl)octa-2,6-diene-1,8-diol (32) [1a] To a stirred solution of (2Z,6E)-8-hydroxy-3-methyl-8-(naphthalen-2-yl)octa-2,6-dienyl acetate 31 (783 mg, 2.41 mmol) in MeOH (6 ml), K 2 CO 3 (334 mg, 2.41 mmol) was added at 0 C, under argon atmosphere, and stirred for h at r.t. Then a saturated aqueous solution of NH 4 Cl ( ml) was added, and after addition of EtOAc ( ml) the phases were separated. The aqueous phase was extracted with EtOAc (3 x ml). The combined organic phases were washed with brine ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 2:1 1:1) to afford 32 (670 mg, 98%) as white solid: mp C. 1 H NMR (0 MHz, CDCl 3 ) δ (m, 4H), (m, 3H), (m, 2H), 5.35 (t, J = Hz, 1H), (br m, 1H), (m, 2H), 3.69 (br s, 1H), 2.75 (br s, 1H), (m, 2H), 9-5 (m, 2H), 1. (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 1.8, 138.1, 133.1, 132.9, 132.8, 131.6, 128.1, 12, 127.7, 12, 125.7, 124.7, 124.5, 124.2, 7, 5, 38.6, 30.0, IR (KBr disk) (cm -1 ) ν 3303, 3179, 2927, 1449, 1272, 1017, 965, 817, 738, 503, 470. ESI-MS m/z (%) 247 (), 265 () [M-OH] +, 305 (86) [M+Na] +. DI-EI-HRMS ([M] + ) calcd for C 19 H 22 O ; found S-14

15 (2E,6E)-3-Methyl-8-(naphthalen-2-yl)-8-oxoocta-2,6-dienal (6d) [3] To a stirred solution of (2E,6E)-6-methyl-1-(naphthalen-2-yl)octa-2,6-diene-1,8-diol 32 (434 mg, 1.54 mmol) in DMSO (8 ml), a solution of IBX (2.6 g, 9.22 mmol) in DMSO (8 ml) was added and stirred for 1 h 30 min at r.t. Then H 2 O ( ml) was added and the resulting cloudy suspension was filtered through a course fritted funnel and washed with EtOAc (50 ml). The aqueous phase was also extracted with EtOAc (4 x 10 ml). The combined organic phases were washed with H 2 O ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The 1 H NMR of the crude product shows a dr of 93:7. The residue was purified by flash chromatography (SiO 2, pentane/et 2 O 1:1) to afford 6d (417 mg, 97%, dr = 94:6) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 2 (dd, J =, 0.8 Hz, 1H), 8.43 (br s, 1H), (m, 4H), (m, 2H), (m, 2H), 5.96 (dd, J =, 1.1 Hz, 1H), (m, 2H), (m, 2H), 2.21 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 19, 190.2, 161.9, 146.9, 135.5, 13, 132.5, 130.1, 129.5, 128.7, 128.4, 127.8, 127.7, 126.8, 126.8, 124.4, 38.8, 30.2, IR (KBr film) (cm -1 ) ν 3017, 1668, 1618, 1296, 1216, 1189, 1127, 985, 864, 8, 753, 668. ESI-MS m/z (%) 279 () [M+H] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 19 H 19 O ; found [(p-chlorobenzyl)methylene]triphenylphosphoran (33) [4b,5] To a stirred solution of 2-bromo-1-(4-chlorophenyl)ethanone (15.3 g, 64.2 mmol) in CHCl 3 (90 ml) triphenylphosphine (1 g, 64.2 mmol) was added at 0 C and stirred overnight at r.t. Then the solvent was removed under reduced pressure. The crude salt was solved in CH 2 Cl 2 /H 2 O :70, and then an aqueous solution of Na 2 CO 3 (45.6 g in 130 ml H 2 O) was added at r.t. and stirred overnight. Then the organic phase was separated, dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. After recrystallization from ethanol, ylide 33 (12.1 g, 45% yield) was obtained as yellow solid: mp C (lit C). 1 H NMR (0 MHz, CDCl 3 ) δ 7.90 (d, J = 8.6 Hz, 2H), (m, 6H), (m, 3H), (m, 6H), 7.31 (d, J = 8.6 S-15

16 Hz, 2H), 4.39 (d, J = 24.1 Hz, 1H). 31 P NMR (121.5 MHz, CDCl 3 ) δ C NMR (125 MHz, CDCl 3 ) δ (d, J = 3.9 Hz), (d, J = 15.4 Hz), 135.3, (d, J = 9.6 Hz), (d, J = 2.9 Hz), 12 (d, J = 12.5 Hz), 128.5, 127.9, 12 (d, J = 91.2 Hz), 51.1 (d, J = Hz). IR (KBr disk) (cm -1 ) ν 1576, 1522, 1481, 1434, 1394, 1336, 1174, 1105, 898, 873, 754, 717, 691. ESI- MS m/z (%) 415 () [M+H] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 26 H 21 OClP ; found (2E,6E)-8-(4-Chlorophenyl)-3-methyl-8-oxoocta-2,6-dienyl acetate (34) To a suspension of [(p-chlorobenzyl)methylene]triphenylphosphorane 33 (7.30 g, 17.6 mmol) in CH 2 Cl 2 ( ml) a solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (0 g, 5.88 mmol) in CH 2 Cl 2 (24 ml) was added, under argon atmosphere, and stirred for 4 d at r.t. The solvent was removed under reduced pressure. The 1 H NMR of the crude product shows a conversion of %, and dr of 96:4. The residue was purified by flash chromatography (SiO 2, pentane/etoac :1 6:1) to afford 34 (990 mg, 55%, dr = 94:6) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 7.83 (dd, J = 8.8, 1.9 Hz, 2H), 7. (dd, J = 8.8, 2.3 Hz, 2H), 6.99 (dtd, J = 15.3, 6.8, Hz, 1H), 6.81 (dd, J = 15.7, 1.5 Hz, 1H), 5.37 (t, J = 7.6 Hz, 1H), 4.56 (d, J = 7.6 Hz, 2H), 2.43 (q, J = 7.3 Hz, 2H), 2.23 (t, J = 7.7 Hz, 2H), 0 (d, J = 2.2 Hz, 3H), 1.71 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 189.4, 17, 149.2, 1.5, 139.1, 136.3, 130.0, 128.9, 125.9, 119.7, 61.2, 37.8, 30.9, 2, IR (KBr film) (cm -1 ) ν 2936, 17, 1670, 1588, 1367, 1232, 1092, 1015, 956, 824. ESI-MS m/z (%) 247 (), 307 (10) [M+H] +, 329 (66) [M+Na] +, 370 (46) [M+Na+MeCN] +. DI-EI-HRMS ([M] + ) calcd for C 17 H 19 O 3 Cl ; found (2E,6E)-8-(4-Chlorophenyl)-8-hydroxy-3-methylocta-2,6-dienyl acetate (35) [2] AcO Cl Me Me NaBH 4,CeCl 3 7H 2 O AcO MeOH,r.t.,1h 34 O OH 92% 35 C 17 H 19 ClO 3 (306.78) C 17 H 21 ClO 3 (308.) Cl S-16

17 To a stirred solution of (2E,6E)-8-(4-chlorophenyl)-3-methyl-8-oxoocta-2,6-dienyl acetate 34 (8 mg, 2.67 mmol) and CeCl 3 7H 2 O (1.30 g, 3.47 mmol) in MeOH (27 ml) at 0 C, NaBH 4 was added in three portions (141 mg, 3.74 mmol) and stirred for 1 h at r.t. The reaction mixture poured into ice/h 2 O, and then a solution of citric acid (10%) was added. After addition of EtOAc (30 ml) the phases were separated, and the aqueous phase was extracted with EtOAc (4 x ml). The combined organic phases were washed with brine ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 4:1) to afford 35 (761 mg, 92%) as colorless oil: 1 H NMR (0 MHz, CDCl 3 ) δ (m, 4H), (m, 1H), (m, 1H), 5.29 (td, J =, Hz, 1H), 7 (br d, J = 6.5 Hz, 1H), (m, 2H), 2.58 (br s, 1H), (m, 2H), (m, 2H), 2 (s, 3H), 1.65 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 171.3, 141.8, 141.2, 13, 132.8, 131.9, 128.5, 127.6, 11, 74.3, 61.5, 38.8, 30.1, 21.1, IR (KBr film) (cm -1 ) ν 3428, 2932, 2854, 1736, 1669, 1489, 1441, 1369, 1233, 1089, 10, 969, 826. ESI-MS m/z (%) 331 () [M+Na] +. DI-EI-HRMS ([M] + ) calcd for C 17 H 21 O 3 Cl ; found (2E,6E)-1-(4-Chlorophenyl)-6-methylocta-2,6-diene-1,8-diol (36) [1a] To a stirred solution of (2E,6E)-8-(4-chlorophenyl)-8-hydroxy-3-methylocta-2,6-dienyl acetate 35 (636 mg, 6 mmol) in MeOH (5 ml), K 2 CO 3 (144 mg, 3 mmol) was added at 0 C, under argon atmosphere, and stirred for 42 h at r.t. Then a saturated aqueous solution of NH 4 Cl ( ml) was added and extracted with EtOAc (4 x ml). The combined organic phases were washed with brine ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 2:1 1:1) to afford 36 (538 mg, 98%) as white solid: mp -62 C. 1 H NMR (0 MHz, CDCl 3 ) δ (m, 4H), (m, 1H), 5.54 (dd, J = 15.3, Hz, 1H), 5.32 (t, J = Hz, 1H), 7 (d, J = Hz, 1H), (m, 2H), 2.92 (br s, 1H), (m, 5H), 1. (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 141.9, 138.5, 133.2, 132.9, 132.1, 128.6, 127.6, 124.3, 74.5, 59.3, 38.8, 30.1, IR (KBr film) (cm -1 ) ν 33, 2926, 1667, 1488, 1437, 18, 1089, 1010, 825. ESI-MS m/z (%) 231 (75) [M+Cl] +, 249 () [M+OH] +, 289 () [M+Na] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 15 H O 2 Cl ; found S-17

18 (2E,6E)-8-(4-Chlorophenyl)-3-methyl-8-oxoocta-2,6-dienal (6e) [3] To a stirred solution of (2E,6E)-1-(4-chlorophenyl)-6-methylocta-2,6-diene-1,8-diol 36 (4 mg, 1.72 mmol) in DMSO (9 ml), a solution of IBX (2.9 g, mmol) in DMSO (9 ml) was added and stirred for min at r.t. Then H 2 O ( ml) was added and the resulting cloudy suspension was filtered through a course fritted funnel and washed with EtOAc (50 ml). The aqueous phase was also extracted with EtOAc (4 x 10 ml). The combined organic phases were washed with H 2 O ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The 1 H NMR of the crude product shows a dr of 90:10. The residue was purified by flash chromatography (SiO 2, pentane/et 2 O/ 1:2) to afford 6e (430 mg, 95% yield, dr = 96:4) as light yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 0 (dd, J = 7.7, 1.9 Hz, 1H), 7.85 (dd, J = 8.8, 1.9 Hz, 2H), 7.44 (dd, J = 8.8, 1.9 Hz, 2H), (m, 1H), 6.89 (dd, J = 15.3, 1.2 Hz, 1H), 5.92 (d, J = 8.1 Hz, 1H), (m, 2H), (m, 2H), 2.21 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 19, 189.1, 161.6, 147.6, 139.3, 13, 130.0, 12, 127.7, 126.4, 38.7, 30.2, IR (KBr film) (cm -1 ) ν 2938, 1671, 1619, 1588, 1294, 1222, 1092, 1010, 843, 732. ESI-MS m/z (%) 245 (), 263 () [M+H] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 15 H 16 O 2 Cl ; found [(p-methoxybenzyl)methylene]triphenylphosphoran (37) [6] To a stirred solution of 2-bromo-1-(4-methoxyphenyl)ethanone (4. g,.0 mmol) in THF ( ml) triphenylphosphine (5.30 g,.0 mmol) was added at 0 C and stirred for 3 h, and then overnight at r.t. The suspension was concentrated under reduced pressure to half of its volume and was Et 2 O (10 ml) was added. The phosphonium salt was filtered off and washed with Et 2 O ( ml). An aqueous solution of Na 2 CO 3 ( M, 170 ml) was added and stirred overnight at r.t. The reaction mixture was extracted with EtOAc (2 x ml) and the combined organic phases were dried over MgSO 4, filtered and concentrated under reduced pressure. The ylide 37 (5.5 g, 82%) was S-18

19 obtained as white solid. The spectroscopical data of were identical to those described in the literature. (2E,6E)-8(4-Methoxyphenyl)-3-methyl-8-oxo-8-oxoocta-2,6-dienyl acetate (38) Ph 3 P O OMe Me 37 Me AcO O THF,70 C,8h AcO 16 84% 38 O C 9 H 14 O 3 (170.21) C 18 H 22 O 4 (302.36) OMe To a stirred solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (700 mg, 4.11 mmol) in THF (5 ml) [(p-methoxybenzyl)methylene]triphenylphosphorane 37 (3.4 g, 8.23 mmol) was added in one portion and stirred for 8 h at 70 C. The yellow solid was filtered off, washed with Et 2 O ( ml) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO 2, hexane/acetone 4:1) to afford 38 (1.1 g, 84%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ 7.94 (d, J = Hz, 2H), (m, 4H), (m, 1H), 4. (d, J = 7.1 Hz, 2H), 3.88 (s, 3H), (m, 2H), (m, 2H), 4 (s, 3H), 1.75 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 18, 171.1, 163.3, 147.6, 1.7, 130.8, 130.7, 125.9, 119.3, 113.7, 61.2, 55.4, 37.9, 30.8, 2, IR (KBr disk) (cm -1 ) ν 1736, 1669, 1622, 10, 1512, 1371, 1344, 1304, 1259, 1171, ESI-MS m/z (%) 303 (64) [M+H] +, 325 (64) [M+Na] +, 366 () [M+Na+MeCN] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 18 H 23 O , found Anal calcd for C 18 H 22 O 4 : C, 71.5; H, 7.3; found: C, 71.2; H, 7.4. (2E,6E)-8-Hydroxy-8-(4-methoxyphenyl)-3-methylocta-2,6-dienyl acetate (39) [2] To a stirred solution of (2E,6E)-8-(4-methoxyphenyl)-3-methyl-8-oxoocta-2,6-dienyl acetate 38 (9 mg, 3.24 mmol) and CeCl 3 7H 2 O (1.5 g, 4.10 mmol) in MeOH ( ml) at 0 C, NaBH 4 was added in three portions (184 mg, 4.86 mmol) and stirred for 2 h at r.t. After the addition of acetone (6 ml) and HCl (0.5 M, 50 ml) the aqueous phase was extracted with EtOAc (4 x ml). The combined organic phases were washed with brine ( ml), dried over MgSO 4 and the solvent was S-19

20 removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, hexane/acetone 4:1) to afford the product 39 (711 mg, 72%) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ 7.30 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), (m, 2H), (m, 1H), 5.12 (br s, 1H), (m, 2H), 3.81 (s, 3H), (m, 2H), (m, 2H), 6 (s, 3H), 0 (br d, J = 3.6 Hz, 1H), 1.68 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 171.2, 15, 141.4, 135.4, 13, 13, 127.4, 118.9, 113.8, 74.6, 61.4, 55.3, 38.8, 30.1, 21.1, IR (KBr film) (cm - 1 ) ν 3465, 2934, 2837, 1737, 1669, 1610, 1585, 1512, 1443, 1382, 1367, 1247, 1174, 1087, 1033, 970, 832. ESI-MS m/z (%) 327 () [M+Na] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 18 H 24 O 4 Na , found Anal calcd for C 18 H 24 O 4 : C, 7; H, ; found: C, 71.5; H,. (2E,6E)-1-(4-Methoxyphenyl)-6-methylocta-2,6-dien-1,8-diol () [1b] To a stirred solution of (2E,6E)-8-hydroxy-8-(4-methoxyphenyl)-3-methylocta-2,6-dienyl acetate 39 (6 mg, 2.10 mmol) in MeOH (15 ml), K 2 CO 3 (8 mg, 0.06 mmol) was added and stirred for 4 h at r.t. Then H 2 O (5 ml) was added and extracted with EtOAc (4 x 15 ml). The combined organic phases were washed with HCl ( M, 15 ml), saturated aqueous solution of NaHCO 3 ( ml), and brine ( ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, hexane/acetone 7:3) to afford the product (4 mg, %) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ 7.28 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), (m, 2H), (m, 1H), 5.15 (br d, J = 5.1 Hz, 1H), (m, 2H), 3.81 (s, 3H), (m, 4H), 1.66 (s, 3H), 1.44 (br s, 1H). 13 C NMR ( MHz, CDCl 3 ) δ , 135.5, 13, 131.2, 127.4, 124.1, 113.8, 74.7, 59.2, 55.3, 38.8, 30.1, IR (KBr film) (cm -1 ) ν 3353, 2932, 2837, 1667, 1610, 1585, 1511, 1442, 1382, 1302, 1247, 1174, 1086, 1034, 972, 832, 731. ESI-MS m/z (%) 245 (), 285 (62) [M+Na] +. HPLC-ESI- HRMS ([M+Na] + ) calcd for C 16 H 22 O 3 Na , found Anal calcd for C 16 H 22 O 3 : C, 73.3; H, 8.5; found: C, 73.2; H, 8.4. S-

21 (2E,6E)-8-(4-Methoxyphenyl)-3-methyl-8-oxoocta-2,6-dienal (6f) [3] To a stirred solution of (2E,6E)-1-(4-methoxyphenyl)-6-methylocta-2,6-diene-1,8-diol (0 mg, 1.53 mmol) in DMSO (1 ml), a solution of IBX (2. g, 9.15 mmol) in DMSO (10 ml) was added and stirred for 1 h at r.t. Then H 2 O (15 ml) was added and the resulting cloudy suspension was filtered through a course fritted funnel and washed with Et 2 O (1 ml). The aqueous phase was extracted with EtOAc (5 x 10 ml) and the combined organic phases were washed with brine (1 ml), dried over MgSO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/et 2 O 1:1) to afford the product 6f (268 mg, 68%, dr 98:2) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ (d, J = Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), (m, 4H), (m, 1H), 3.87 (s, 3H), (m, 2H), (m, 2H), 2. (d, J = 0.8 Hz, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 191.2, 188.8, 163.6, 16, 14, 13, 130.7, 127.8, 126.6, 113.9, 55.6, 38.9, 30.3, IR (KBr film) (cm -1 ) ν 3006, 2936, 2843, 2772, 1666, 1596, 1510, 14, 1305, 1256, 1169, 11, 1090, 1025, 847, 676, 634, 6. ESI- MS m/z (%) 259 () [M+H] +. HPLC-ESI-HRMS ([M+H] + ) calcd for C 16 H 19 O , found Anal calcd for C 16 H 18 O 3 : C, 74.4; H, ; found: C, 74.1; H, 7.2. (E)-6-Hydroxy-3-methyl-7-nitrohept-2-enyl acetate (41) [7] KO t Bu (126 mg, 1.12 mmol) was added to a stirred solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (1.90 g, 11.2 mmol), nitromethane (910 µl, 16.9 mmol), THF (2.8 ml) and tert-butanol (2.8 ml) at 0 C. The stirred mixture was allowed to warm to r.t. After 45 h the mixture was poured into water ( ml) and extracted with EtOAc (4 x ml). The combined organic layers were washed with water ( ml) and brine (50 ml), dried over anhydrous Na 2 SO 4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO 2, pentane/etoac 9:1 3:1) to afford the product 41 ( g, 79% yield) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ (m, 1H), 4.56 (d, J = 6.5 Hz, 2H), (m, 2H), 4.28 (br s, 1H), (m, 1H), (m, 1H), (m, 1H), 3 (d, J = 2.3 Hz, 3H), 1.70 (s, S-21

22 3H), (m, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ 171.4, 1.8, 119.7,.7, 68.2, 61.3, 35.1, 31.6, 21.1, IR (KBr film) (cm -1 ) ν 3854, 3484, 2924, 1711, 1552, 1432, 13, 1232, 1093, ESI-MS m/z (%) 254 () [M+Na] +. HPLC-ESI-HRMS ([M+Na] + ) calcd for C 10 H 17 O 5 NNa , found 251. (2E,6E)-3-Methyl-7-nitrohepta-2,6-dienyl acetate (42) [7] Trifluoroacetic anhydride (0.77 ml, 5.54 mmol) was added to a solution of β-nitro alcohol 41 (1. g, 4 mmol) in CH 2 Cl 2 (5.6 ml) at -10 C. The resulting solution was allowed to stir 5 min, and then triethylamine (1.4 ml, 10.1 mmol) was slowly added dropwise over 15 min and the reaction mixture stirred 16 min at 10 C. The resulting mixture was poured into CH 2 Cl 2 (50 ml) and washed with saturated aqueous NH 4 Cl solution (2 x 30 ml). The aqueous layers were backextracted with CH 2 Cl 2 (2 x 30 ml) and the combined organic layers were washed with brine ( ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 9:1 3:1) to afford the product 42 (830 mg, 77%) as yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ (m, 1H), 6.97 (dt, J = 13.4, 1.5 Hz, 1H), 5.38 (td, J = 6.9, 1.1 Hz, 1H), 4.58 (d, J = 6.9 Hz, 2H), (m, 2H), 2.25 (br t, J = 7.4 Hz, 2H), 4 (s, 3H), 1.72 (s, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ 171.1, 141.6,, 139.4, 1.5, 61.1, 37.4, 26.6, 21.1, IR (KBr film) (cm -1 ) ν 2928, 1735, 1649, 1525, 1448, 1353, 1235, 1024, 955. HPLC-ESI-HRMS ([2M+Na] + ) calcd for C H 30 O 8 N 2 Na , found (2E,6E)-3-Methyl-7-nitrohepta-2,6-dienal (6g) [9] To a stirred solution of (2E,6E)-3-methyl-7-nitrohepta-2,6-dienyl acetate 42 (1. g, 5.77 mmol) in dry CH 2 Cl 2 (250 ml), DIBAL-H (5.7 ml, 5.71 mmol, M in heptane) was added under argon atmosphere at -78 C, and stirred for 1 h. After dropwise addition of a saturated aqueous solution of NH 4 Cl and potassium sodium tartrate a white emulsion was formed. The phases were separated after 1 h of stirred. The aqueous phase was extracted with EtOAc (3 x ml). The combined S-22

23 organic phases were washed with brine (150 ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 1:1) to afford the product 43 and the corresponding reduced product (E)-3-methyl-7-nitrohept-2-en-1-ol (723 mg, dr = :) as yellow oil. To a stirred solution of this mixture in DMSO (18 ml), a solution of IBX (3.50 g, 12.7 mmol) in DMSO (9 ml) was added and stirred for 1 h at r.t. Then H 2 O (5 ml) was added and the resulting suspension was filtered through a course fritted funnel and washed with EtOAc ( ml). The aqueous phase was extracted with EtOAc (3 x 10 ml) and the combined organic phases were washed with brine (50 ml), dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography (SiO 2, pentane/etoac 2:1) to afford the product 6g (297 mg, dr = 72:28) and the corresponding reduced product (E)-3-methyl-7- nitrohept-2-enal as yellow oil. After second column chromatography the product 6g was obtained pure enough for the catalytic reaction: 1 H NMR (500 MHz, CDCl 3 ) δ 0 (d, J = 7.7 Hz, 1H), (m, 1H), 1 (d, J = 13.4, 1H), 5.88 (d, J = 7.6 Hz, 1H), (m, 2H), (m, 2H), 2. (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 190.9,, 1.4, 1.3, 12, 38.1, 25.9, IR (KBr film) (cm -1 ) ν 3703, 3498, 2964, 1670, 1522, 1437, 1352, GC-CI-MS m/z (%) 81 (), 95 (70), 123 (55), 138 (55), 170 (30) [M+H] +. HPLC-CI-HRMS ([M+H] + ) calcd for C 8 H 12 O 3 N , found (2E,6E)-Methyl-8-acetoxy-6-methylocta-2,6-dienoate (45) [8] To a stirred solution of (E)-3-methyl-6-oxohex-2-enyl acetate 16 (4.30 g, 25.1 mmol) in CH 2 Cl 2 (155 ml), methyl (triphenylphosphoranylidene)acetate 44 (10.6 g, 31.6 mmol) was added in one portion and stirred for 18 h at r.t. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, pentane/et 2 O 4:1) to afford the product 45 [8b] (5.4 g, 95%, dr = 95:5) as yellow oil: 1 H NMR (0 MHz, CDCl 3 ) δ 6.92 (dt, J = 15.6, 7.2 Hz, 1H), 5.81 (dt, J = 15.6, 1.2 Hz, 1H), (m, 1H), 4.57 (d, J = 6.8 Hz, 2H), 3.71 (s, 3H), (m, 2H), (m, 2H), 4 (s, 3H), 1.69 (s, 3H). 13 C NMR ( MHz, CDCl 3 ) δ 17, 166.9, 148.4, 1.5, 121.2, 119.3, 61.1, 51.4, 37.6, 30.2, 2, S-23