Supporting Information

Transcription

1 Supporting Information Total Synthesis of Cytospolide D and its Biomimetic Conversion to Cytospolides M, and Q Gunnar Ehrlich* and Christian B. W. Stark* Fachbereich Chemie, Institut für rganische Chemie, Universität Hamburg, Martin-Luther-King-Platz 6, Hamburg, Germany ehrlich@chemie.uni-hamburg.de stark@chemie.uni-hamburg.de SI 1

2 Table of Contents I. Materials and Methods 3 II. Characterization Data of all Compounds 4-19 III. Comparison of NMR-Spectroscopic Data of Synthesized Natural Products with Reported Data IV. Elucidation of the Stereoselectivity of the Grignard Addition V. 1 H and 13 C-NMR Spectra of all Compounds SI 2

3 I. Materials and Methods All reagents were used as purchased from commercial suppliers. Solvents were purified by conventional methods prior to use. Reactions were monitored by thin layer chromatography using Machery-Nagel precoated TLC-sheets ALUGRAM Xtra SIL G/UV 254 and visualized with potassium permanganate [(2.4 g KMn 4, 16 g K 2C 3, 4 ml NaH (5 %), 196 ml H 2)] or ceric ammonium molybdate [(phosphomolybdic acid (5 g), Ce(S 4) 2 2 H 2 (2 g), H 2S 4 conc (12 ml), H 2 (188 ml)]. Chromatographic purification was performed as flash chromatography on Fluka silica gel 60 (particle size mm). Yields refer to chromatographically purified and spectroscopically pure compounds. NMR spectra were recorded on a Bruker F-300 (operating at 300 MHz for 1 H and 75 MHz for 13 C acquisitions), a Bruker AV-400 (operating at 400 MHz for 1 H and 100 MHz for 13 C acquisitions) or a Bruker AV-600 (operating at 600 MHz for 1 H and 150 MHz for 13 C acquisitions). Chemical shifts are reported in ppm with the solvent resonance as the internal standard: chloroform-d 1: 7.26 ( 1 H-NMR), ( 13 C-NMR). Coupling constants J are given in Hertz (Hz). Multiplicities are classified as follows: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet and combinations thereof, or m = multiplet or br = broad signal. Two-dimensional NMR (H CSY, HSQC, HMBC) were used for the assignment of all compounds. Assignment of every single carbon atom of the alkyl side-chains was not always possible due to overlap of signals in 13 C NMR spectra. High resolution mass spectra were obtained on an Agilent 6224 ESI-TF. IR spectra were recorded on a Bruker ALPHA FT-IR Platinum ATR. Absorbance frequencies ṽ are reported in reciprocal centimeters (cm -1 ). ptical rotation data were measured with a Krüss ptronic P8000 at 598 nm using a 100 mm path-length cell in the solvent, at the concentration and temperature indicated. Melting Points were measured with a Büchi Melting Point M-565 and are uncorrected. All compounds were named according to IUPAC rules. For simplicity, the numbering of the carbon atoms of a given structure does not follow IUPAC rules. SI 3

4 II. Characterization Data of all Compounds (2S)-1,2-di--p-methoxybenzylidene-1,2,5-pentanetriol (28) (2S)-1,2,5-pentanetriol (16) 1 (3.66 g, 30.5 mmol) was dissolved in THF (30 ml). Then p-methoxybenzaldehyde dimethylacetal (5.55 g, 30.5 mmol) and CSA (0.10 g, 0.43 mmol) were added to the reaction. After stirring overnight, triethylamine (0.5 ml) was added and the solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes/etac 1:4 + 1% Et 3N) to give PMP acetal 28 (3.56 g, 14.9 mmol, 49%) as a colorless oil: dr = 2:1; [ ] 20 D = (c 0.26, CHCl 3); 1 H NMR (300 MHz, MeD) δ (m, 2H, H-8), (m, 2H, H-9), 5.80 (s, 0.4H, H-6), 5.79 (s, 0.6H, H-6), (m, 1.3H, 1*H-2, 0.3*H-1a), 4.07 (dd, J = 7.6, 6.8 Hz, 0.6H, 0.6*H-1a), 3.79 (s, 3H, H-11), 3.67 (dd, J = 7.6, 6.5 Hz, 0.6H, 0.6*H-1b), (m, 2.4H, 2*H-5, 0.4*H-1b), (m, 4H, H-3, H-4); 13 C NMR (75 MHz, MeD) δ (C-10), (C-10), (C-7), (C-7), (C-8), (C-8), (C-9), (C-6), (C-6), 78.2 (C-2), 77.6 (C-2), 71.8 (C-1), 71.0 (C-1), 62.7 (C-5), 55.7 (C-11), 31.1 (C-3/C-4), 30.8 (C-3/C-4), 29.9 (C-3/C-4), 29.8 (C-3/C-4) ppm; IR (ATR) 3415 (br), 2936 (m), 2873 (m), 1770 (w), 1613 (s), 1588 (w), 1516 (s), 1459 (m), 1434 (m), 1396 (m), 1379 (m), 1303 (s), 1245 (ss), 1170 (s), 1111 (w), 1065 (ss), 1029 (ss), 1009 (m), 932 (m), 828 (ss), 778 (w), 586 (m) cm -1 ; HRMS (ESI) m/z calcd for C 13H [M+H] , found (2S)-5-tert-butyldimethylsilyloxy-1,2-di--(p-methoxybenzylidene)-1,2-pentanediol (17) To a solution of alcohol 28 (2.56 g, 10.8 mmol) in CH 2Cl 2 (25 ml) were added imidazole (1.03 g, 15.1 mmol) and TBSCl (3.14 g, 11.9 mmol). Immediately, the formation of a white precipitate was observed. After 30 min the reaction was stopped by addition of sat. NaHC 3-solution (25 ml). The organic layer was separated and the aqueous layer was extracted twice with CH 2Cl 2. The combined organic layers were dried with MgS 4, filtered 1 (2S)-1,2,5-pentanetriol was prepared by diazotation of L-glutamic acid according to: Larcheveque, M.; Lalande, J. Tetrahedron 1984, 40, ; and reduction of the resulting 2-oxotetrahydrofuran carboxylic acid following: Kuehnert, S. M.; Maier, M. E. rg. Lett. 2002, 4, SI 4

5 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/etac 5:1 + 1% Et 3N) giving the TBS-protected alcohol 17 (3.53 g, 10.0 mmol, 93%) as a colorless liquid: [ ] 18 D = (c 1.02, CHCl 3); 1 H NMR (300 MHz, MeD) δ (m, 2H, H 8), 6.90 (d, J = 8.6 Hz, 2H, H-9), 5.80 (s, 0.3H, H-6), 5.69 (s, 0.7H, H-6), (m, 1.3H, 1*H-2, 0.3*H1a ), 4.05 (t, J = 7.2 Hz, 0.7H, 0.7*H-1a), 3.78 (s, 3H, H-11), (m, 2.7H, 2*H-5, 0.7*H-1b), (m, 0.3H, 0.3*H-1b), (m, 4H, H-3, H-4), 0.91 (s, 9H, (CH 3) 3CSi), 0.07 (s, 6H, (CH 3) 2Si); 13 C NMR (75 MHz, MeD) δ (C-10), (C-10), (C-7), (C-7), (C-8), (C-8), (C-9), (C-6), (C-6), 78.2 (C-2), 77.6 (C-2), 71.8 (C-1), 71.0 (C-1), 64.0 (C-5), 55.7 (C-11), 31.2 (C-3/C-4), 30.9 (C-3/C-4), 30.1 (C-3/C-4), 30.1 (C-3/C-4), 26.4 ((CH 3) 3CSi), 19.2 ((CH 3) 3CSi), -5.2 ((CH 3) 2Si) ppm; IR (ATR) 2950 (m), 2929 (m), 2856 (m), 1614 (m), 1588 (w), 1516 (m), 1462 (m), 1386 (m), 1302 (m), 1246 (ss), 1169 (m), 1074 (br, ss), 1034 (s), 1002 (s), 971 (m), 937 (w), 828 (br, ss), 773 (ss), 661 (w), 585 (w) cm -1 ; HRMS (ESI) m/z calcd for C 19H 32Na 4Si + [M+Na] , found (2S)-5-tert-butyldimethylsilyloxy-2-(p-methoxybenzyloxy)-pentan-1-ol (18) 5 TBS 1 6 H To a solution of PMP acetal 17 (3.43 g, 9.73 mmol) in dry toluene (10 ml) was added DIBAl-H-solution (9.7 ml, 1.2 M in toluene, 11.7 mmol) at 0 C. The conversion was monitored by TLC (hexanes/etac 4:1), and after 3 h a second amount of DIBAl-H-solution (1.0 ml, 0.83 mmol) was added. The reaction mixture was stirred overnight at 0 C and water (20 ml) was added to quench the reaction. The precipitate was dissolved by addition of potassium sodium tartrate. The organic layer was separated and the aqueous layer was extracted twice with EtAc. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. Chromatography (silica gel, hexanes/etac 4:1) yielded the desired regioisomer 18 (2.58 g, 7.28 mmol, 75%) and the less polar, primary PMB-ether (0.24 g, 0.67 mmol, 7%) as a colorless liquids: [ ] 21 D = (c 1.07, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 7.27 (d, J = 8.7 Hz, 2H, H-8), 6.88 (d, J = 8.7 Hz, 2H, H-7), 4.56 (d, J = 11.2 Hz, 1H, H-6a), 4.47 (d, J = 11.2 Hz, 1H, H-6b), 3.80 (s, 3H, H-11), (m, 1H, H-1a), 3.61 (t, J = 6.0 Hz, 2H, H-5), (m, 2H, H-1b, H-2), 1.97 (s, 1H, H), (m, 4H, H-3, H-4), 0.90 (s, 9H, (CH 3) 3CSi), 0.05 (s, 6H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-10), (C-7), (C-8), (C-9), 79.3 (C-2), 71.3 (C-6), 64.4 (C-1), 63.2 (C-5), 55.4 (C-11), 28.7 (C-3), 27.2 (C-4), 26.1 ((CH 3) 3CSi), 18.5 ((CH 3) 3CSi), -5.2 ((CH 3) 2Si) ppm; IR (ATR) 3439 (br), 2951 (m), 2928 (m), 2856 (m), 1612 (m), 1586 (w), 1512 (s), 1463 (m), 1388 (w), 1360 (w), 1301 (w), 1246 (ss), 1173 (m), 1087 (br, ss), 1035 (ss), 936 (w), 831 (br, ss), 773 (ss), 661 (w), 568 (w), 512 (w) cm -1 ; HRMS (ESI) m/z calcd for C 19H 34Na 4Si + [M+Na] , found SI 5

6 (2S)-5-tert-butyldimethylsilyloxy-2-(p-methoxybenzyloxy)-pentanal (12) Alcohol 18 (2.40 g, 6.78 mmol) was dissolved in CH 2Cl 2 (50 ml) and cooled to 0 C. Dess-Martin periodinane (3.45 g, 8.13 mmol) was added and the white suspension was stirred for 2 h at 0 C. Afterwards sat. NaHC 3- solution (30 ml) was added. The organic layer was separated and the aqueous layer was extracted twice with CH 2Cl 2. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. Column chromatography (silica gel, hexanes/etac 4:1) gave aldehyde 12 (1.81 g, 5.12 mmol, 76%) as a colorless liquid: [ ] 21 D = (c 1.13, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 9.62 (d, J = 2.2 Hz, 2H, H-1), 7.27 (d, J = 8.7 Hz, 2H, H-8), 6.88 (d, J = 8.7 Hz, 2H, H-7), 4.60 (d, J = 11.4 Hz, 1H, H-6a), 4.48 (d, J = 11.4 Hz, 1H, H-6a), 3.80 (s, 3H, H-11), 3.76 (ddd, J = 7.4, 5.2, 2.2 Hz, 1H, H-2), 3.59 (t, J = 6.0 Hz, 2H, H-5), (m, 4H, H- 3, H-4), 0.88 (s, 9H, (CH 3) 3CSi), 0.03 (s, 6H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-1), (C- 10), (C-8), (C-7), (C-9), 83.1 (C-2), 72.3 (C-6), 62.6 (C-5), 55.4 (C-11), 28.1 (C-3), 26.6 (C- 4), 26.1 ((CH 3) 3CSi), 18.5 ((CH 3) 3CSi), -5.2 ((CH 3) 2Si) ppm; IR (ATR) 2953 (m), 2928 (m), 2856 (m), 1732 (m), 1612 (m), 1586 (w), 1513 (s), 1443 (w), 1387 (w), 1361 (w), 1302 (w), 1247 (ss), 1173 (w), 1092 (ss), 1006 (s), 1006 (w), 937 (w), 832 (ss), 774 (ss), 711 (w), 661 (w) cm -1 ; HRMS (ESI) m/z calcd for C 19H 32Na 4Si + [M+Na] , found (4S,5S)-1-tert-butyldimethylsilyloxy-4-(p-methoxybenzyloxy)-decan-5-ol (13) To magnesium turnings (0.252 g, 10.5 mmol) in dry diethyl ether (11 ml) was slowly added 1-bromopentane (1.59 g, 10.5 mmol). During the addition, when the reaction proved to be too exothermic, the flask was cooled with ice water. After complete addition, the reaction mixture was stirred for 1 h until most of the magnesium turnings were dissolved. Then aldehyde 12 (1.85 g, 5.25 mmol), dissolved in dry diethyl ether (10 ml), was slowly added to the solution of ethyl magnesium bromide (c ~ 1 M) at 0 C. The reaction mixture was stirred at 0 C for 2 h and allowed to warm up to rt overnight. Sat. NH 4Cl-solution was added, until the magnesium hydroxide was dissolved. The organic layer was separated and the aqueous layer was extracted twice with EtAc. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. The crude SI 6

7 product 13 (2.23 g) proved sufficiently pure by 1 H NMR for the following oxidation reaction and no further purification was needed; analytical data of a purified sample (column chromatography on silica gel, hexanes/etac 8:1): [ ] 22 D = +9.5 (c 1.06, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 7.26 (d, J = 8.5 Hz, 2H, H- 12), 6.88 (d, J = 8.6 Hz, 2H, H-13), 4.59 (d, J = 11.0 Hz, 1H, H-11a), 4.42 (d, J = 10.9 Hz, 1H, H-11b), 3.80 (s, 3H, H-16), 3.62 (t, J = 5.9 Hz, 2H, H-1), 3.53 (td, J = 5.5, 3.2 Hz, 1H, H-5), 3.29 (q, J = 5.0 Hz, 1H, H-4), 2.25 (s, br, 1H, H), (m, 1H, H-3a), (m, 3H, H-3a, H-2), (m, 3H, 2x H-6, 1x H-7/8/9), (m, 5H, H-7, H-8, H-9), (m, 3H, H-10), 0.90 (s, 6H, (CH 3) 3CSi), 0.06 (s, 3H, (CH 3) 2Si), 0.05 (s, 3H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-15), (C-12), (C-13), (C-14), 82.0 (C-4), 72.8 (C-5), 72.1 (C-11), 63.3 (C-1), 55.4 (C-16), 33.5 (C-6), 32.1 (C-8), 28.4 (C-2), 26.6 (C-3), 26.1 ((CH 3) 3CSi), 25.6 (C-7), 22.8 (C-9), 18.5 ((CH 3) 3CSi), 14.2 (C-10), -5.1 ((CH 3) 2Si) ppm; IR (ATR) 3467 (m, br), 2952 (s), 2928 (s), 2856 (s), 1612 (w), 1586 (w), 1513 (s), 1463 (m), 1387 (w), 1360 (w), 1301 (w), 1247 (ss), 1172 (w), 1086 (ss, br), 1036 (ss), 938 (w), 832 (ss), 773 (ss), 661 (w), 575 (w), 517 (w) cm -1 ; HRMS (ESI) m/z calcd for C 24H 44Na 4Si [M+Na] +, found For the elucidation of the stereochemistry please refer to SI 24. (4S)-1-tert-butyldimethylsilyloxy-4-(p-methoxybenzyloxy)-decan-5-one (14) Crude alcohol 13 (2.23 g) was dissolved in CH 2Cl 2 (50 ml). Dess-Martin periodinane (2.45 g, 5.78 mmol) was added and the suspension was stirred for 2 h at rt. The reaction was stopped by adding sat. NaHC 3-solution (30 ml) and stirred for further 5 min. The organic layer was separated and the aqueous layer was extracted twice with CH 2Cl 2. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. After column chromatography (silica gel, hexanes/etac 6:1) ketone 14 (1.89 g, 4.48 mmol, 85% over 2 steps) was isolated as a colorless liquid: [ ] 22 D = (c 1.12, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 7.25 (d, J = 8.8 Hz, 2H, H-13), 6.87 (d, J = 8.6 Hz, 2H, H-14), 4.50 (d, J = 11.3 Hz, 1H, H-11a), 4.34 (d, J = 11.3 Hz, 1H, H-11b), 3.80 (s, 3H, H-16), (m, 1H, H-4), 3.57 (t, J = 6.1 Hz, 2H, H-1), 2.49 (t, J = 7.3 Hz, 2H, H-6), (m, 6H, H-2, H-3, H-7), (m, 4H, H-8, H-9), (m, 3H, H-10), 0.88 (s, 9H, (CH 3) 3CSi), 0.02 (s, 6H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-5), (C-15), (C-12), (C-13), (C-14), 84.4 (C-4), 72.1 (C-11), 62.7 (C-1), 55.4 (C-16), 37.8 (C-6), 31.6 (C-8), 28.7 (C-2/3), 28.6 (C-2/3), 26.1 ((CH 3) 3CSi), 23.1 (C-7), 22.6 (C-9), 18.5 ((CH 3) 3CSi), 14.1 (C-10), -5.2 ((CH 3) 2Si) ppm; IR (ATR) 2953 (s), 2928 (s), 2856 (s), 1714 (s), 1612 (m), 1586 (w), 1513 (s), 1463 (m), 1388 (w), 1360 (w), 1302 (w), 1247 (ss), 1173 (m), 1090 (ss, br), 1036 (s), 938 (w), 832 (ss), 774 (ss), 714 (w), 661 (w), 514 (w) cm -1 ;HRMS (ESI) m/z calcd for C 24H 42Na 4Si + [M+Na] , found SI 7

8 (4S,5R)-1-tert-butyldimethylsilyloxy-4-(p-methoxybenzyloxy)-decan-5-ol (15) A solution of ketone 14 (1.59 g, 3.77 mmol) in dry diethyl ether (20 ml) was cooled to -50 C and a solution of zinc borohydride (5.2 ml, c ~ 0.18 M, 0.94 mmol) was added. The reaction mixture was stirred for 1 h at this temperature. After adding acetone (2 ml), the solution was warmed to rt and 10 ml water was added. The organic layer was separated and the aqueous layer, containing white precipitates, were extracted twice with EtAc. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. The crude product 15 was subjected to the following reaction without purification; analytical data of a purified sample (column chromatography on silica gel, hexanes/etac 8:1): [ ] 21 D = -3.4 (c 0.99, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 7.26 (d, J = 8.7 Hz, 2H, H-13), 6.88 (d, J = 8.7 Hz, 2H, H-14), 4.53 (d, J = 11.1 Hz, 1H, H-11a), 4.47 (d, J = 11.1 Hz, 1H, H-11b), (m, 1H, H-5), 3.80 (s, 3H, H-16), (m, 2H, H-1), 3.35 (ddt, J = 6.8, 5.2, 3.5 Hz, 1H, H-4), 2.07 (s, br, 1H, H), (m, 1H, H-2a), (m, 6H, H-2b, H-3, H-6, 1x H-7/8/9), (m, 5H, H-7, H-8, H-9), (m, 3H, H-10), 0.89 (s, 9H, (CH 3) 3CSi), 0.05 (s, 6H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-15), (C-12), (C-13), (C-14), 81.8 (C-4), 71.7 (C-5), 71.5 (C-11), 63.3 (C-1), 55.4 (C-16), 32.2 (C-6/8), 32.1 (C-6/8), 29.1 (C-2), 26.1 ((CH 3) 3CSi), 26.0 (C-7), 24.9 (C-3), 22.8 (C-9), 18.5 ((CH 3) 3CSi), 14.2 (C-10), -5.1 ((CH 3) 2Si) ppm; IR (ATR) 3475 (m, br), 2952 (s), 2928 (s), 1856 (s), 1612 (m), 1586 (w), 1513 (s), 1463 (m), 1387 (w), 1360 (w), 1301 (m), 1246 (ss), 1172 (m), 1087 (ss, br), 1036 (ss), 1006 (w), 832 (ss), 773 (ss), 732 (m), 661 (w), 582 (w), 514 (w) cm -1 ; HRMS (ESI) m/z calcd for C 24H 44Na 4Si + [M+Na] , found (4S,5R)-5-acetoxy-1-tert-butyldimethylsilyloxy-4-(p-methoxybenzyloxy)-decane (29) TBS Crude alcohol 15 was dissolved in CH 2Cl 2 (30 ml). Then ethyldiisopropylamine (0.96 ml, 5.7 mmol), acetanhydride (0.54 ml, 5.7 mmol,) and DMAP (46 mg, 0.38 mmol) were added. After stirring overnight at rt, the brownish solution was directly concentrated in vacuo and the residue was purified by column chromatography (silica gel, hexanes/etac 8:1) yielding acetate 29 (1.57 g, 3.36 mmol, 89%) as a colorless SI 8

9 liquid: [ ] 22 D = -6.8 (c 1.06, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 7.25 (d, J = 8.5 Hz, 2H, H-13), 6.86 (d, J = 8.6 Hz, 2H, H-14), 5.09 (dt, J = 9.1, 3.6 Hz, 1H, H-5), 4.61 (d, J = 11.0 Hz, 1H, H-11a), 4.39 (d, J = 11.0 Hz, 1H, H-11b), 3.79 (s, 3H, H-16), (m, 2H, H-1), 3.43 (dt, J = 7.5, 3.8 Hz, 1H, H-4), 2.06 (s, 3H, H-18), (m, 6H, H-2, H-3, H-6), (m, 6H, H-7, H-8, H-9), (m, 3H, H-10), 0.89 (s, 9H, (CH 3) 3CSi), 0.03 (s, 6H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-17), (C-15), (C-12), (C-13), (C-14), 79.7 (C-4), 74.8 (C-5), 71.8 (C-1), 63.1 (C-1), 55.4 (C-16), 31.8 (C-8), 29.8 (C-6), 29.2 (C-2), 26.7 (C-3), 26.1 ((CH 3) 3CSi), 25.6 (C-7), 22.7 (C-9), 21.4 (C-18), 18.5 ((CH 3) 3CSi), 14.2 (C-10), -5.2 ((CH 3) 2Si) ppm; IR (ATR) 2953 (m), 2928 (m), 2856 (m), 1736 (s), 1612 (w), 1586 (w), 1513 (m), 1463 (m), 1369 (m), 1301 (w), 1240 (ss, br), 1172 (w), 1091 (s, br), 1036 (s), 832 (ss), 774 (s), 716 (w), 661 (w), 581 (w), 512 (w) cm -1 ; HRMS (ESI) m/z calcd for C 26H 46Na 5Si + [M+Na] , found (4S,5R)-5-acetoxy-4-(p-methoxybenzyloxy)-decan-1-ol (19) To a solution of TBS ether 29 (1.64 g, 3.51 mmol) in THF (20 ml) was added TBAF. 3H 2 (1.33 g, 4.21 mmol). The solution was stirred for 4 h at rt and stopped by the addition of water (20 ml). EtAc was added until a clear phase separation was achieved. The organic phase was separated and the aqueous phase was extracted twice with EtAc. The combined organic phases were dried over MgS 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/etac 2:1 to 1:1), giving alcohol 19 (1.10 g, 3.12 mmol, 89%) as a colorless liquid: [ ] 22 = (c 1.02, CHCl 3); 1 H NMR (400 MHz, CDCl 3) δ 7.25 (d, J = 8.6 Hz, 2H, H-13), 6.86 (d, J = 8.6 Hz, 2H, H-14), 5.12 (dt, J = 9.4, 3.4 Hz, 1H, H-5), 4.64 (d, J = 10.9 Hz, 1H, H-11a), 4.37 (d, J = 10.9 Hz, 1H, H-11b), 3.79 (s, 3H, H-16), 3.59 (t, 3 J = 5.7 Hz, 2H, H-1), 3.44 (dt, J = 7.2, 3.6 Hz, 1H, H-4), 2.06 (s, 3H, H-18), 1.79 (s, br, 1H, H), (m, 1H, H-2a), (m, 5H, H- 2b, H-3, H-6), (m, 6H, H-7, H-8, H-9), (m, 3H, H-10); 13 C NMR (101 MHz, CDCl 3) δ (C-17), (C-15), (C-12), (C-13), (C-14), 79.8 (C-4), 74.5 (C-5), 71.8 (C-11), 62.9 (C-1), 55.4 (C-16), 31.8 (C-8), 29.8 (C-6), 29.2 (C-2), 26.8 (C-3), 25.6 (C-7), 22.6 (C-9), 21.4 (C-18), 14.1 (C- 10) ppm; IR (ATR) 3434 (m, br), 2953 (m), 2931 (m), 2860 (m), 1733 (s), 1612 (m), 1586 (w), 1512 (s), 1464 (m), 1301 (w), 1239 (ss), 1173 (m), 1058 (s), 1029 (ss, br), 950 (m), 820 (w), 756 (s), 581 (w), 513 (w); HRMS (ESI) m/z calcd for C 20H 32Na + 5 [M+Na] , found SI 9

10 (4S,5R)-5-acetoxy-4-(p-methoxybenzyloxy)-decanal (20) To a solution of alcohol 19 (0.117 g, mmol) in CH 2Cl 2 (5 ml) was added Dess-Martin-periodinane (0.17 g, 0.40 mmol). Immediately, the solution turned slightly yellow and a white precipitate occurred. After 30 min the reaction was complete and sat. NaHC 3-solution (5 ml) was added. The organic phase was separated and the aqueous phase was extracted twice with CH 2Cl 2. The combined organic phases were dried over MgS 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/etac 2:1) yielding aldehyde 20 (0.108 g, mmol, 93%) as a colorless liquid: [ ] 21 D = (c 1.03, CHCl 3); 1 H NMR (400 MHz, CDCl 3) δ 9.69 (s, 1H, H-1), 7.22 (d, J = 8.4 Hz, 1H, H-13), 6.86 (d, J = 8.5 Hz, 1H, H-14), 5.14 (dt, J = 9.2, 3.7 Hz, 1H, H-5), 4.59 (d, J = 10.9 Hz, 1H, H-11a), 4.30 (d, J = 11.0 Hz, 1H, H- 11b), 3.79 (s, 3H, H-16), 3.40 (dt, J = 7.7, 3.6 Hz, 1H, H-4), 2.54 (dt, J = 17.3, 6.8 Hz, 1H, H-2), 2.45 (dt, J = 17.7, 7.2 Hz, 1H, H-2 ), 2.06 (s, 3H, H-18), (m, 2H, H-3), (m, 1H, H-6a), (m, 1H, H-6b), (m, 6H, H-7, H-8, H-9), (m, 3H, H-10); 13 C NMR (101 MHz, CDCl 3) δ (C-1), (C-17), (C-15), (C-12), 13.0 (C-13), (C-14), 78.6 (C-4), 73.6 (C-5), 71.6 (C-6), 55.5 (C-16), 40.3 (C-2), 31.7 (C-8), 30.1 (C-6), 25.5 (C-7), 22.6 (C3/9), 22.5 (C-3/9), 21.3 (C-18), 14.1 (C-10) ppm; IR (ATR) 2954 (m), 2931 (m), 2859 (m), 2732 (w), 1727 (s), 1612 (m), 1586 (w), 1513 (s), 1464 (m), 1369 (m), 1301 (w), 1237 (ss, br), 1174 (m), 1073 (s, br), 1030 (s, br), 948 (w), 820 (m), 579 (w), 515 (w) cm -1 ; HRMS (ESI) m/z calcd for C 20H 30Na + 5 [M+Na] , found (2E,6S,7R)-7-acetoxy-6-(p-methoxybenzyloxy)-dodec-2-enal (11) H Aldehyde 20 (0.530 g, 1.51 mmol) was dissolved in CDCl 3 (4 ml). Then (triphenylphosphoranylidene)- acetaldehyde 2 (0.690 g, 2.27 mmol) was added and the solution was stirred for 16 h at 50 C. As the starting 2 This reagent was prepared according to: Schmidt, A.; Hilt, G. rg. Lett. 2013, 15, SI 10

11 material 20 and the unsaturated aldehyde share the same R f-value, the reaction was monitored by 1 H-NMR. After 16 h the ratio s.m./product was calculated as 1:1.8 and no aldehyde signal of remaining (triphenylphosphoranylidene)-acetaldehyde could be detected. Therefore, an additional portion of (triphenylphosphoranylidene)-acetaldehyde (0.460 g, 1.51 mmol) was added and the solution was stirred for further 2 d at 50 C. After 1 H-NMR indicated almost full conversion, the brownish solution was concentrated and the residue was purified by column chromatography (silica gel, hexanes/etac 2:1), giving aldehyde 11 (0.465 g, 1.24 mmol, 82%) as a yellow liquid: [ ] 21 D = (c 1.00, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 9.45 (d, J = 7.9 Hz, 1H, H-1), 7.23 (d, J = 8.6 Hz, 2H, H-15), 6.87 (d, J = 8.6 Hz, 2H, H-16), 6.77 (ddd, J = 15.6, 7.1, 6.3 Hz, 1H, H-3), 6.05 (ddt, J = 15.6, 7.9, 1.5 Hz, 1H, H-2), 5.14 (ddd, J = 9.3, 3.9, 2.9 Hz, 1H, H-7), 4.64 (d, J = 11.0 Hz, 1H, H-13a), 4.33 (d, J = 11.0 Hz, 1H, H-13b), 3.80 (s, 3H, H-18), 3.42 (dt, J = 9.0, 3.3 Hz, 1H, H-6), (m, 1H, H-4a), 2.31 (ddtd, J = 15.6, 8.6, 6.9, 1.4 Hz, 1H, H-4b), 2.08 (s, 3H, H-20), (m, 3H, H-5, H-8a), (m, 1H, H-8 ), (m, 6H, H-9, H-10, H-11), 0.89 (t, J = 6.7 Hz, 3H, H- 12); 13 C NMR (75 MHz, CDCl 3) δ (C-1), (C-19), (C-17), (C-3), (C-2), (C- 14), (C-15), (C-16), 78.7 (C-6), 74.1 (C-7), 71.8 (C-13), 55.4 (C-18), 31.8 (C-10), 30.0 (C-8), 29.1 (C-4), 28.5 (C-5), 25.6 (C-9), 22.6 (C-11), 21.3 (C-20), 14.1 (C-12) ppm, IR (ATR) 2953 (m), 2929 (m), 2858 (m), 2734 (w), 1731 (s), 1687 (ss), 1636 (w), 1611 (m), 1585 (w), 1512 (s), 1463 (m), 1371 (m), 1301 (m), 1238 (br, ss), 1173 (m), 1070 (br, s), 1025 (ss), 974 (m), 820 (m), 602 (w), 515 (w) cm -1 ; HRMS (ESI) m/z calcd for C 22H 32Na + 5 [M+Na] , found (2S,4R,5R,6E,10S,11R)-11-acetoxy-2-benzoyloxy-5-hydroxy-10-(p-methoxybenzyloxy)-4- methylhexadec-6-en-4-one (22) (2S)-2-benzoyloxy-3-pentanone 3 (21) (0.439 g, 2.11 mmol) was dissolved in diethyl ether (13 ml) and cooled to -78 C, Then, chlorodicyclohexlborane (2.1 ml, c = 1 M in hexanes, 2.1 mmol) and N-ethyldimethylamine (0.38 ml, 3.5 mmol) were added. After stirring at -78 C for 30 min, the temperature was raised to 0 C for 4 h. During this time a white precipitate was formed. Again, the reaction mixture was cooled to -78 C and aldehyde 11 (0.530 g, 1.41 mmol), dissolved in diethyl ether (5 ml), was added. For completion of the reaction, the flask was stored overnight at -18 C. Then water (10 ml) was added at 0 C to dissolve the precipitate. The organic layer was separated and the aqueous layer was extracted twice with EtAc. The combined organic 3 This reagent was prepared according to: Paterson, I.; Steadman, V. A.; McLeod, M. D.; Trieselmann, T. Tetrahedron, 2011, 67, SI 11

12 phases were dried over MgS 4, filtered and concentrated in vacuo. Chromatography (silica gel, hexanes/etac 3:1) yielded aldol product 22 (0.656 g, 1.13 mmol, 80%) as a highly viscous oil. The excessive amount of used (2S)-2-benzoyloxy-3-pentanone (21) could also be recovered: [ ] 21 D = +3.2 (c 1.01, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 8.08 (d, J = 8.5 Hz, 2H, H-28), 7.58 (t, J = 7.4 Hz, 1H, H-30), 7.46 (t, J = 7.5 Hz, 2H, H-29), 7.25 (d, J = 8.3 Hz, 2H, H-20), 6.87 (d, J = 8.6 Hz, 2H, H-21), 5.64 (dt, J = 15.0, 6.6 Hz, 1H, H-7), 5.43 (q, J = 6.7 Hz, 1H, H-2), 5.40 (ddt, J = 14.9, 8.0 Hz, 1.3 Hz, 1H, H-6), 5.09 (dt, J = 9.4, 3.5 Hz, 1H, H-11), 4.62 (d, J = 11.0 Hz, 1H, H-18a), 4.35 (d, J = 11.0 Hz, 1H, H-18b), 4.19 (td, J = 7.9, 3.8 Hz, 1H, H-5), 3.79 (s, 3H, H-23), 3.40 (dt, J = 8.7, 3.5 Hz, 1H, H-10), 2.87 (dq, J = 8.3, 7.1 Hz, 1H, H-4),), (m, 1H, H-8a), 2.06 (s, 3H, H-25), (m, 1H, H-8b), (m, 4H, H-9, H-12), 1.56 (d, J = 7.1 Hz, 3H, H-1), (m, 6H, H-13, H-14, H-15), 1.14 (d, J = 7.1 Hz, 3H, H-17), (m, 3H, H-16); 13 C NMR (75 MHz, CDCl 3) δ (C-3), (C-24), (C-26), (C-22), (C-7), (C-30), (C-6), (C-27), (C-20/28), (C-20/28), (C-19), (C-29), (C-21), 79.1 (C-10), 75.1 (C-5), 75.0 (C-2), 74.7 (C-11), 71.8 (C-18), 55.4 (C-23), 48.2 (C-4), 31.8 (C-14), 29.9 (C-9/12), 29.6 (C-9/12), 28.6 (C-8), 25.6 (C- 13), 22.6 (C-15), 21.3 (C-25), 15.8 (C-1), 14.6 (C-17), 14.1 (C-16) ppm; IR (ATR) 3507 (m, br), 2932 (m), 2859 (m), 1716 (ss), 1611 (w), 1585 (w), 1513 (m), 1451 (m), 1369 (m), 1242 (ss), 1175 (m), 1112 (s), 1069 (s), 1025 (s), 997 (s), 820 (m), 711 (ss), 581 (w), 513 (w) cm -1 ; HRMS (ESI) m/z calcd for C 34H 46Na + 8 [M+Na] , found (2S,4R,5R,6E,10S,11R)-11-acetoxy-2-benzoyloxy-5-tert-butyldimethylsilyloxy-10-(pmethoxybenzyloxy)-4-methylhexadec-6-en-4-one (30) TBS Aldol product 22 (0.634 g, 1.09 mmol) was dissolved in CH 2Cl 2 (5 ml) and imidazole (0.22 g, 3.2 mmol) and TBSCl (0.49 g, 3.3 mmol) were added. The turbid suspension was stirred for 16 h. The reaction mixture was diluted with CH 2Cl 2 (15 ml) and water was added, until the precipitate was dissolved. The organic phase was separated and the aqueous phase was extracted twice with CH 2Cl 2. The combined organic phases were dried over MgS 4, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, hexanes/etac 4:1) yielded the TBS-ether 30 (0.675 g, mmol, 89%) as a colorless oil: [ ] 21 D = (c 1.30, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 8.08 (d, J = 7.1 Hz, 2H, H-28), 7.58 (t-like, 1H, H-30), 7.45 (t, J = 7.5 Hz, 2H, H- 29), 7.25 (d, J = 8.7 Hz, 2H, H-20), 6.87 (d, J = 8.7 Hz, 2H, H-21), 5.53 (dt, J = 15.6, 6.7 Hz, 1H, H-7), 5.41 (q, J = 6.9 Hz, 1H, H-2), 5.29 (ddd, J = 15.2, 8.3, 1.4 Hz, 1H, H-6), 5.10 (dt, J = 9.3, 3.5 Hz, 1H, H-11), 4.62 (d, J = 10.9 Hz, 1H, H-18a), 4.36 (d, J = 10.9 Hz, 1H, H-18b), 4.22 (t, J = 8.7 Hz, 1H, H-5), 3.80 (s, 3H, H-23), 3.41 (dt, J = 8.7, 3.5 Hz, 1H, H-10), 2.86 (dq, J = 9.1, 7.0 Hz, 1H, H-4), (m, 1H, H-8a), 2.06 (s, 3H, H-25), SI 12

13 (m, 1H, H-8b), (m, 4H, H-9, H-12), 1.52 (d, J = 6.9 Hz, 3H, H-1), (m, 6H, H-13, H-14, H-15), 1.00 (d, J = 7.0 Hz, 3H, H-17), (m, 3H, H-16), 0.82 (s, 9H, (CH 3) 3CSi), (s, 3H, (CH 3) 2Si), (s, 3H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-3), (C-24), (C-26), (C-22), (C-30), (C-7), (C-6), (C-27), (C-28), (C-19), (C-20), (C-29), (C-21), 79.4 (C-10), 76.5 (C-5), 75.4 (C-2), 74.6 (C-11), 72.0 (C-18), 55.4 (C-23), 49.0 (C-4), 31.8 (C-14), 30.0 (C-9/12), 29.7 (C-9/12), 28.5 (C-8), 26.0 ((CH 3) 3CSi), 25.6 (C-13), 22.6 (C-15), 21.3 (C-25), 18.1 ((CH 3) 3CSi), 15.3 (C-1), 14.5 (C-17), 14.1 (C-16), -3.9 ((CH 3) 2Si), -4.6 ((CH 3) 2Si) ppm; IR (ATR) 2953 (m), 2930 (m), 2856 (m), 1720 (ss), 1611 (w), 1585 (w), 1513 (m), 1452 (m), 1112 (s), 1066 (br, s), 1026 (br, s), 1002 (s), m), 1371 (m), 1242 (br, ss), 1175 (m), 834 (ss), 776 (s), 710 (ss), 578 (w), 512 (w) cm -1 ; HRMS (ESI) m/z calcd for C 40H 60Na 8Si + [M+Na] , found (2R,3R,4E,8S,9R)-3-tert-butyldimethylsilyloxy-9-hydroxy-8-(p-methoxybenzyloxy)-3- methyltetradec-4-enoic acid (10) To a solution of ketone 30 (0.449 g, mmol) in methanol (6 ml) was added NaBH 4 (24 mg, 0.64 mmol) in 2 portions within 10 min. After stirring for 30 min, sodium (15 mg, 0.87 mmol) was added and the solution was stirred for further 16 h. Then water (10 ml) was added and EtAc, until a phase separation was observed. The organic layer was separated and the aqueous layer was extracted twice with EtAc. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. After column chromatography (silica gel, hexanes/etac 2:1 to 1:1), the triol was isolated as a diastereomeric mixture (0.332 g, mmol, 93%). To a solution of the obtained triol (0.332 g, mmol) in CH 2Cl 2 (5 ml) was added NaI 4, immobilized on silica gel, (1.40 g, c = mmol/g, mmol). The suspension was vigorously stirred for 3 h and then filtered. The silica gel residue was washed twice with CH 2Cl 2 and the filtrate was concentrated in vacuo. The crude aldehyde was directly subjected to the oxidation to the carboxylic acid without further purification. The aldehyde was dissolved in t-butanol (8 ml) and NaH 2P 4-solution (7 M, 5 ml) solution was added. Then 2-methyl-2- butene (2.6 ml, 18 mmol, 1.3 g) was added, followed by NaCl 2 (0.67 g, c = 80%, 6.0 mmol). The slightly greenish colored biphasic solution was vigorously stirred for 30 min. Then water (10 ml) and CH 2Cl 2 (10 ml) were added. The organic layer was separated and the aqueous layer was extracted twice with CH 2Cl 2. The combined organic layers were dried over MgS 4 filtered and concentrated in vacuo. The purity of the crude carboxylic acid 10 (0.301 g, mmol, 96%), checked by NMR spectroscopy, was sufficiently high; analytical data of a purified sample (column chromatography on silica gel, hexanes/etac 3:1 + 1% HAc): [ ] 21 D = (c 1.07, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 7.26 (d, J = 8.6 Hz, 2H, H-18), 6.89 (d, J = 8.6 Hz, 2H, H- 17), 5.60 (dt, J = 15.2, 6.6 Hz, 1H, H-5), 5.35 (dd, J = 15.4, 7.6 Hz, 1H, H-4), 4.55 (d, J = 11.0 Hz, 1H, H-16a), SI 13

14 4.45 (d, J = 11.1 Hz, 1H, H-16b), 4.18 (t, J = 7.3 Hz, 1H, H-3), (m, 1H, H-9), 3.81 (s, 3H, H-21), 3.33 (dt, J = 9.0, 3.4 Hz, 1H, H-8), 2.52 (qui, J = 7.1 Hz, 1H, H-2), (m, 1H, H-6a), (m, 1H, H- 6b), (m, 1H, H-7a), (m, 3H, H-7b, H-10), (m, 6H, H-11, H-12, H-13), 1.09 (d, J = 7.1 Hz, 3H, H-15), (m, 3H, H-14), 0.87 (s, 9H, (CH 3) 3CSi), 0.05 (s, 3H, (CH 3) 2Si), 0.03 (s, 3H, (CH 3) 2Si); 13 C NMR (75 MHz, CDCl 3) δ (C-1), (C-20), (C-5), (C-4), (C-17), (C-18), (C-19), 81.3 (C-8), 76.0 (C-3), 71.7 (C-16), (C-9), 55.4 (C-21), 47.1 (C-2), 32.2 (C- 10/12), 32.0 (C-10/12), 28.5 (C-6), 28.1 (C-7), 26.0 (C-11), 25.8 ((CH 3) 3CSi), 22.7 (C-13), 18.2 ((CH 3) 3CSi), 14.2 (C-14), 13.7 (C-15), -3.8 ((CH 3) 2Si), ((CH 3) 2Si) ppm; IR (ATR) 2953 (s), 2929 (m), 2856 (s), 1709 (m), 1612 (w), 1513 (s), 1461 (m), 1376 (w), 1361 (w), 1301 (w), 1246 (ss), 1173 (w), 1058 (ss), 1036 (ss), 972 (w), 983 (w), 834 (ss), 775 (s), 732 (m), 668 (w) cm -1 ; HRMS (ESI) m/z calcd for C 29H 50Na 6Si + [M+Na] , found (2R,3R,4E,8S,9R)-3,9-dihydroxy-8-(p-methoxybenzyloxy)-3-methyltetradec-4-enoic acid (23) To a solution of the crude carboxylic acid 10 (0.301 g, mmol) in THF (5 ml) was added TBAF*3H 2 (0.22 g, 0.69 mmol). After stirring for 3 h, water (5 ml) and EtAc were added, until a phase separation was observed. The organic phase was separated and the aqueous phase was extracted twice with EtAc. The combined organic phases were dried over MgS 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/etac 1:1 + 1% HAc) to give the deprotected carboxylic acid 23 (0.220 g, mmol, 90%) as a colorless oil: [ ] 21 D = -8.5 (c 2.25, CHCl 3); 1 H NMR (300 MHz, CDCl 3) δ 7.25 (d, J = 8.6 Hz, 1H, H-18), 6.88 (d, J = 8.7 Hz, 1H, H-19), 5.67 (dt, J = 13.7, 6.7 Hz, 1H, H-5), 5.40 (dd, J = 15.4, 7.3 Hz, 1H, H-4), 4.54 (d, J = 11.2 Hz, 1H, H-16a), 4.43 (d, J = 11.1 Hz, 1H, H-16b), 4.11 (t, J = 7.5 Hz, 1H, H-3), (m, 1H, H-9), 3.79 (s, 3H, H-21), 3.32 (dt, J = 9.1, 3.4 Hz, 1H, H-8), 2.51 (qui, J = 7.2 Hz, 1H, H-2), (m, 1H, H-6), (m, 1H, H-6 ), (m, 1H, H-7a), (m, 9H, H-7b, H-10, H-11, H-12, H-13), 1.13 (d, J = 7.2 Hz, 3H, H-15), 0.89 (t, J = 6.8 Hz, 3H, H-14); 13 C NMR (75 MHz, CDCl 3) δ (C-1), (C-20), (C-5), (C-4/17), (C-17/4), (C-18), (C- 19), 81.2 (C-8), 74.7 (C-3), 71.8 (C-9), 71.6 (C-16), 55.4 (C-21), 45.5 (C-2), 32.1 (C-10/12), 32.0 (C-10/12), 28.5 (C-6), 28.2 (C-7), 26.0 (C-11), 22.7 (C-13), 14.2 (C-14/15), 14.1 (C-14/15) ppm; IR (ATR) 3400 (bs, s), 2932 (ss), 2858 (s), 1710 (s), 1612 (m), 1513 (s), 1459 (m), 1301 (m), 1247 (ss), 1174 (m), 1081 (m), 1033 (s), 972 (w), 821 (m) cm -1 ; HRMS (ESI) m/z calcd for C 23H 36Na + 6 [M+Na] , found SI 14

15 (2R,3S,6E,8R,9R)-8-hydroxy-3-(p-methoxybenzyloxy)-9-methyl-2-pentyl-2,3,4,5,8,9- hexahydrooxecin-10-one (24) H A solution consisting of DMAP (0.136 g, 1.12 mmol) and 2-methyl-6-nitrobenzoic anhydride (83 mg, 0.25 mmol) in toluene (56 ml) was prepared. Then dihydroxy acid 23 (76 mg, 0.19 mmol), first dissolved in CH 2Cl 2 (1 ml) for better solubility and then diluted with toluene (46 ml), was added via dropping funnel as slowly as possible over 36 h to the solution of the anhydride and DMAP. After complete addition, the reaction mixture was stirred for further 8 h and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, CH 2Cl 2/EtAc 10:1) yielding the desired macrolactone 24 (14.9 mg, 38.2 µmol, 21%) as colorless crystals as well as diene 25 (5.4 mg, 16 µmol, 8%) as a byproduct: [ ] 25 D = (c 0.30, CHCl 3); mp = 67.5 C; 1 H NMR (600 MHz, CDCl 3) δ 7.24 (d, J = 8.5 Hz, 2H, H-18), 6.88 (d, J = 8.6 Hz, 2H, H- 19), (m, 2H, H-4, H-5), 4.82 (td, J = 7.4, 3.9 Hz, 1H, H-9), 4.52 (d, J = 11.0 Hz, 1H, H-16a), 4.36 (d, J = 11.0 Hz, 1H, H-16b), 4.28 (d, J = 7.9 Hz, 1H, H-3), 3.81 (s, 3H, H-21), 3.31 (t, J = 7.6 Hz, 1H, H-8), 2.66 (qd, J = 7.0, 3.2 Hz, 1H, H-2), (m, 1H, H-6a), 2.25 (d, J = 8.9 Hz, 1H, H), (m, 2H, H-6b, H- 7a), (m, 2H, H-7b, H-10a), (m, 1H, H-10b), (m, 6H, H-11, H-12, H-13), 1.27 (d, J = 7.0 Hz, 3H, H-15), 0.86 (t, 3 J = 7.0 Hz, 3H, H-14); 13 C NMR (151 MHz, CDCl 3) (C-1), (C-20), (C-4), (C-17), (C-18), (C-5), (C-19), 80.7 (C-8), 76.9 (C-9), 72.4 (C-3), 71.3 (C- 16), 55.4 (C-21), 47.0 (C-2), 34.2 (C-7), 32.4 (C-10), 32.1 (C-12), 28.5 (C-6), 24.5 (C-11), 22.7 (C-13), 14.2 (C- 14), 12.7 (C-15) ppm; IR (ATR) 3507 (br, s), 2953 (s), 2925 (ss), 2854 (s), 1732 (s), 1612 (m), 1586 (w), 1513 (s), 1460 (m), 1375 (m), 1302 (m), 1248 (ss), 1212 (w), 1171 (ss), 1072 (s), 1035 (s), 1001 (s), 977 (w), 907 (w), 821 (m) cm -1 ; HRMS (ESI) m/z calcd for C 23H 34Na + 5 [M+Na] , found Cytospolide D (4) To a solution of PMB ether 24 (8.2 mg, 21 µmol) in CH 2Cl 2 (3 ml) were added water (0.5 ml) and DDQ (9.5 mg, 42 µmol). The biphasic reaction mixture was vigorously stirred for 4 h and then sat. NaHC 3-solution (3 ml) was added. Excessive amounts of DDQ were reduced by adding 5 mg Na 2S 3. The organic phase was separated and the aqueous phase was extracted twice with CH 2Cl 2. The combined organic phases were dried over SI 15

16 MgS 4, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, CH 2Cl 2/EtAc 3:1) yielded cytospolide D (4) (4.9 mg, 18 µmol, 86%) as colorless crystals: [ ] 25 D = (c 0.20, CHCl 3), lit (c 0.38 CHCl 3); mp = 60 C, lit. colorless oil; 1 H NMR (600 MHz, CDCl 3) δ (m, 2H, H-4, H-4), 4.77 (td, J = 7.4, 3.9 Hz, 1H, H-9), 4.30 (s, br, 1H, H-3), 3.65 (ddd, J = 8.6, 6.8, 1.7 Hz, 1H, H-8), 2.69 (qd, J = 7.0, 3.3 Hz, 1H, H-2), (m, 1H, H-6a), (m, 1H, H-6b), 1.98 (ddt, J = 13.8, 9.0, 2.3 Hz, 1H, H-7a), (m, 1H, H-7b), (m, 1H, H-10a), (m, 5H, H 2, H, H-10b), (m, 6H, H-11, H-12, H-13), 1.28 (d, J = 7.0 Hz, 3H, H-15), 0.87 (t, J = 6.7 Hz, 3H, H-14); 13 C NMR (151 MHz, CDCl 3) δ (C-1), (C-4), (C-5), 78.0 (C-9), 74.1 (C-8), 72.1 (C-3), 46.9 (C-2), 38.3 (low int., C- 7), 32.3 (C-10), 31.9 (C-12), 28.5 (low int., C-6), 24.6 (C-11), 22.7 (C-13), 14.2 (C-14), 12.6 (C-15) ppm; IR (ATR) 3484 (br, s), 2954 (w), 2926 (ss), 2855 (m), 1719 (s), 1457 (m), 1375 (m), 1262 (w), 1179 (s), 1102 (m), 1067 (w), 1013 (m) cm -1 ; HRMS (ESI) m/z calcd for C 15H 26Na + 4 [M+Na] , found Cytospolide M (6) Cytospolide D (4) (4.1 mg, 15 µmol) was dissolved in CH 2Cl 2 (1.5 ml) and cooled to -20 C. Then mcpba (6.3 mg, 30 µmol) was added and the solution was stirred for 16 h at -20 C. To induce complete epoxide opening and cyclization, CSA (1 mg) was added and the reaction was kept at -20 C for additional 1 h. The organic solution was diluted with CH 2Cl 2 (3 ml), washed with sat. NaHC 3-solution and separated. The aqueous phase was extracted twice with CH 2Cl 2 and the combined organic phases were dried over MgS 4, filtered and concentrated in vacuo. Column chromatography (silica gel, hexanes/etac 1:2) yielded cytospolide M (6) (3.7 mg, 13 µmol, 86%) as readily crystallizing substance: [ ] 22 D = (c 0.35, CHCl 3), lit (c 0.09, CHCl 3); mp = C, lit C; 1 H NMR (600 MHz, CDCl 3) δ 5.35 (dt, J = 9.3, 3.6 Hz, 1H, H- 9), 4.11 (dd, J = 9.1, 7.0 Hz, 1H, H-5), 4.03 (td, J = 8.2, 3.8 Hz, 1H, H-8), 3.89 (d, J = 2.6 Hz, 1H, H-3), 3.53 (d, J = 9.0 Hz, 1H, H-4), 2.75 (qd, J = 6.9, 2.6 Hz, 1H, H-2), 2.08 (dt, J = 12.3, 4.2 Hz, 1H, H-6a), 2.00 (tdd, J = 12.4, 9.5, 7.0 Hz, 1H, H-6b), (m, 2H, H-7), (m, 1H, H-10a), (m, 2H, H-10b, H), (m, 6H, H-11, H-12, H-13), 1.29 (d, J = 7.0 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H); 13 C NMR (151 MHz, CDCl 3) δ (low int., C-1), 82.0 (C-3), 81.4 (C-8), 80.7 (C-5), 76.6 (C-4), 75.2 (C-9), 45.7 (C-2), 31.8 (C- 12), 29.6 (C-6), 29.2 (C-10), 25.8 (C-11), 23.6 (C-7), 22.6 (C-13), 14.8 (C-15), 14.1 (C-14) ppm; IR (ATR) 3338 (s, br), 2925 (ss), 2854 (m), 1730 (ss), 1485 (w), 1378 (w), 1333 (w), 1288 (w), 1260 (w), 1183 (m), 1168 (m), 1130 (w), 1099 (m), 1065 (m), 1005 (w), 990 (w), 963 (w) cm -1 ; HRMS (ESI) m/z calcd for C 15H 25Na + 5 [M+Na] , found SI 16

17 Cytospolide Q (9) To a solution of cytospolide M (6) (3.5 mg, 12 µmol) in THF (1 ml) was added potassium trimethylsilanolate (1.9 mg, 15 µmol). After 2 h the reaction mixture was diluted with 3 ml EtAc and washed with 1M HCl (3 ml). The organic phase was separated and the aqueous phase was extracted twice with EtAc. The combined organic phases were dried over MgS 4, filtered and concentrated in vacuo. Recyclization to cytospolide Q (9) was observed during concentration. The residue was purified by column chromatography (silica gel, CH 2Cl 2/methanol 20:1) to give cytospolide Q (9) (2.2 mg, 7.7 µmol, 63%) as colorless crystals, accompanied by a diastereomer (1.0 mg): [ ] 21 D = +1.3 (c 0.19, CHCl 3), lit (c 0.04 CHCl 3); mp = C, lit C; 1 H NMR (600 MHz, CDCl 3) δ 4.52 (dd, J = 7.1, 3.6 Hz, 1H, H-3), 4.11 (dd, J = 8.0, 3.6 Hz, 1H, H-4), 3.94 (td, J = 7.5, 4.1 Hz, 1H, H-5), 3.90 (ddd, J = 8.5, 6.4, 3.2 Hz, 1H, H-8), 3.83 (ddd, J = 7.9, 4.5, 3.2 Hz, 1H, H-9), 2.81 (qui, J = 7.5 Hz, 1H, 2), 2.59 (s, br, 1H, H), (m, 1H, H-6a), (m, 1H, H-6b), (m, 1H, H-7a), (m, 1H, H-7b), 1.58 (m, 1H, H), (m, 1H, H-11a), (m, 2H, H-10), (m, 5H, H-11b, H-12, H-13), 1.27 (d, J = 7.6 Hz, 3H, H-15), 0.89 (t, J = 6.8 Hz, 3H, H-14); 13 C NMR (151 MHz, CDCl 3) δ (C-1), 85.2 (C-4), 83.5 (C-8), 78.7 (C-5), 71.6 (C-9), 71.3 (C-3), 39.4 (C-2), 33.2 (C- 10), 31.9 (C-12), 29.1 (C-6), 25.7 (C-11), 23.2 (C-7), 22.7 (C-13), 14.2 (C-14), 9.1 (C-15) ppm; IR (ATR) 3427 (m), 2953 (s), 2924 (ss), 2854 (s), 1760 (s), 1460 (m), 1377 (w), 1261 (w), 1181 (m), 1099 (m), 1021 (m) 985 (w) cm -1 ; HRMS (ESI) m/z calcd for C 15H 25Na + 5 [M+Na] , found (2R,3S,6E,9R)-3-(p-methoxybenzyloxy)-9-methyl-2-pentyl-2,3,4,5-tetrahydrooxecine-8,10-dione (26) Allylic alcohol 24 (10.3 mg, 26.4 µmol) was dissolved in CH 2Cl 2 (1 ml) and Dess-Martin reagent (17 mg, 40 µmol) was added. The white suspension was stirred for 2 h and then directly concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/etac 4:1) to give enone 26 (9.0 mg, 23 µmol, 88%) as a colorless oil: [ ] 22 D = (c 0.68, CHCl 3); 1 H NMR (600 MHz, CDCl 3) δ 7.18 (d, J = 8.6 Hz, 2H, H-18), (m, br, 1H, H-5), 6.86 (d, J = 8.6 Hz, 2H, H-19), 5.74 (d, br, J = 16.5 Hz, 1H, H-4), 5.21 (dt, J = 8.6, 4.7 Hz, 1H, H-9), 4.53 (d, J = 11.2 Hz, 1H, H-16a), 4.32 (d, J = 11.2 Hz, 1H, H-16b), 3.94 (s, br, 1H, H-2), 3.80 (s, 3H, H-21), 3.51 (d, J = 6.8 Hz, 1H, H-8), (m, 1H, H-6a), (m, br, 1H, SI 17

18 H-6b), (m, 2H, H-7), (m, 2H, H-10), (m, 6H, H-11, H-12, H-13), 1.32 (d, J = 6.8 Hz, 3H, H-15), (m, 3H, H-14); 13 C NMR (151 MHz, CDCl 3) δ (only visible in HMBC, C-3), (C-1), (C-20), (only visible in HMBC, C-4), (C-17), (C-18), (low int., C-4), (C-19), 79.0 (C-8), 75.2 (low int., C-9), 70.8 (C-16), 55.4 (C-21), 53.5 (C-2), 31.7 (C-10/12), 31.6 (C- 10/12), 28.8 (low int., C-6/7), 28.7 (low int., C-6/7), 25.4 (C-11), 22.6 (C-13), 14.2 (C-14) 10.8 (low int., C-15) ppm; IR (ATR) 2954 (m), 2931 (s), 2857 (m), 1735 (ss), 1690 (s), 1642 (w), 1612 (w), 1586 (w), 1513 (s), 1455 (m), 1376 (w), 1331 (w), 1302 (w), 1247 (ss), 1205 (m), 1174 (m), 1145 (m), 1126 (m), 1114 (m), 1074 (m), 1035 (m), 976 (w), 821 (w) cm -1 ; HRMS (ESI) m/z calcd for C 23H 32Na + 5 [M+Na] , found (2R,3S,6E,9R)-3-hydroxy-9-methyl-2-pentyl-2,3,4,5-tetrahydrooxecine-8,10-dione (27) To a solution of PMB-ether 26 (9.0 mg, 23 µmol) in CH 2Cl 2 (2 ml) were added water (0.3 ml) and DDQ (8.0 mg, 35 µmol). The biphasic reaction mixture was vigorously stirred for 3 h. Then CH 2Cl 2 (5 ml) and NaHC 3-solution (3 ml) were added and stirring was continued for 5 min. The organic layer was separated and the aqueous layer was extracted twice with CH 2Cl 2. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. After column chromatography (silica gel, hexanes/etac 4:1) hydroxyenone 27 was isolated as a colorless oil (5.6 mg, 21 µmol, 90%): [ ] 23 D = +8.8 (c 0.29, CHCl 3); 1 H NMR (600 MHz, Chloroform-d) δ 6.87 (m, 1H, H-5), 5.87 (d, J = 16.7 Hz, 1H, H-4), 5.05 (td, J = 6.7, 3.4 Hz, 1H, H-9), (m, 1H, H-6a), (m, 1H, H-6b), (m, 2H, H-7), (m, 2H, H-10), (m, 6H, H-11, H-12, H-13), 1.32 (d, J = 6.8 Hz, 3H, H-15), (m, 3H, H-14); 13 C NMR (151 MHz, CDCl 3) δ (only visible in HMBC, C-3), (only visible in HMBC, C-1), (only visible in HMBC, C-5), (only visible in HMBC, C-4) 79.5 (C-9), 73.8 (C-8), 53.7 (C-2), 31.6 (2C, C-10, C-12), 29.9 (C-7), 28.2 (C-6), 25.4 (C-11), 22.6 (C-13), 14.1 (C-14), 10.8 (only visible in HMBC, C-15) ppm; IR (ATR) 3488, (br), 2954 (s), 2929 (ss), 2856 (s), 1735 (ss), 1691 (s), 1641 (w), 1454 (m), 1377 (w), 1334 (w), 1245 (m), 1205 (m), 1145 (m), 1078 (w), 1052 (w), 1022 (w) cm -1 ; HRMS (ESI) m/z calcd for C 15H 24Na + 4 [M+Na] , found SI 18

19 Cytospolide (7) To a solution of hydroxyenone 27 (2.2 mg, 8.2 µmol) in THF (0.7 ml) was added LiHMDS (8 µl, c = 1.0 M in THF, 8 µmol). After stirring for 30 min at rt, water (2 ml) and EtAc were added, until a phase separation was achieved. The organic layer was separated and the aqueous layer was extracted twice with EtAc. The combined organic layers were dried over MgS 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/etac 4:1). Cytospolide (7) was obtained as readily crystallizing solid (1.4 mg, 5.2 µmol, 64%): [ ] 22 D = -1.6 (c 0.19, CHCl 3), lit (c 0.06, CHCl 3), mp = C, lit. colorless oil; 1 H NMR (600 MHz, CDCl 3) δ 5.33 (dt, J = 9.6, 3.7 Hz, 1H, H-9), 4.56 (ddd, J = 11.0, 6.8, 4.4 Hz, 1H, H-5), 4.07 (ddd, J = 9.3, 7.0, 3.9 Hz, 1H, H-8), 3.73 (q, J = 6.6 Hz, 1H, H-2), 3.14 (dd, J = 11.7, 10.7 Hz, 1H, H-4a), 2.34 (dd, J = 11.7, 4.4 Hz, 1H, H-4b), 2.10 (tdd, J = 12.0, 9.1, 6.8 Hz, 1H, H-7a), (m, 1H, H-6a), (m, 1H, H-7b), 1.78 (dd, J = 11.9, 7.0 Hz, 1H, H-6b), (m, 1H, H-10a), (m, 2H, H-10b, H-11a), (m, 5H, H-11b, H-12, H-13), 1.26 (d, J = 6.5 Hz, 3H, H-15), 0.90 (t, J = 7.0 Hz, 3H, H-14); 13 C NMR (151 MHz, CDCl 3) δ (C-3), (low int., C-1), 81.0 (C-8), 77.2 (ovl. by CDCl 3, C-5), 76.1 (C-9), 57.4 (C-2), 47.3 (C-4), 31.7 (C-12), 31.1 (C-6), 29.2 (C-10), 25.8 (C-11), 24.1 (C-7), 22.6 (C-13), 14.1 (C-14), 10.6 (C-15) ppm; IR (ATR) 2954 (s), 2927 (ss), 2856 (m), 1746 (ss), s), 1461 (w), 1430 (w), 1359 (w), 1337 (w), 1240 (m), 1206 (m), 1183 (s), 1166 (w), 1116 (s), 1100 (m), 1080 (m), 891 (w) cm -1 ; HRMS (ESI) m/z calcd for C 15H [M+H] , found SI 19

20 III. Comparison of NMR-spectroscopic data of synthesized natural products and reported data 4 cytospolide D H lit., m, J in Hz found c lit. found ppm a , dq, 7.0, , qd, 7.0, , br, s 4.30, br, s , ov , m , ov , m , m 2.38, m , m 1.85, m , m , m 1.98, ddt, 13.8, 9.0, , m , t, , ddd, 8.6, 6.8, , td, 7.4, , td, 7.4, a 1.72, m b 1.54, m , m , m a 1.29 m b 1.29, m 12 a 1.29, m b 1.29, m 13 a 1.28, m b 1.28, m , m , m , m , t, , t, , d, , d, a) The constant deviation of ca / ppm in the chemical shift of many carbon atoms may be caused by a different method for calibration of the entire spectrum. In our NMR spectra the CDCl 3 signal was calibrated to ppm and the chemical shifts of the other carbon atoms were rounded from two decimals to one decimal according to standard mathematic rules. 4 See: (a) Lu, S.; Kurtán, T.; Yang, G.; Sun, P.; Mándi, A.; Krohn, K.; Draeger, S.; Schulz, B.; Yi, Y.; Li, L.; Zhang, W. Eur. J. rg. Chem. 2011, (b) Lu, S.; Sun, P.; Li, T.; Kurtán, T.; Mándi, A.; Antus, S.; Krohn, K.; Draeger, S.; Schulz, B.; Yi, Y.; Li, L.; Zhang, W. J. rg. Chem. 2011, 76, SI 20

21 cytospolide M H lit., m, J in Hz found c lit. found ppm a low int b , dq, 6.9, , qd, 6.9, , br, s 3.89, d, , d, , d, , dd, 9.1, , dd, 9.1, , m 2.00, m 2.08, dt, 12.3, , tdd, 12.4, 9.5, , m 1.84, m , m , dt, 8.3, , td, 8.2, , dt, 9.1, , dt, 9.3, a 1.54, m b 1.45, m , m , m a 1.35 m b 1.35, m 12 a 1.32, m b 1.32, m 13 a 1.31, m b 1.31, m , m , m , m , t, , t, , d, , d, b) The discrepancy of ppm in the chemical shift of C-1 may be attributed to the broad signal shape and the low intensity in the NMR of the synthesized sample which makes the exact peak localization difficult. SI 21

22 cytospolide Q H lit., m, J in Hz found c lit. found ppm a , m, , qui, , dd, 7.0, , dd, 7.1, , dd, 8.0, , dd, 8.0, , dt, 7.5, , td, 7.5, , m 1.95, m , m 1.94, m , m , dt, 8.0, , ddd, 8.5, 6.4, , dt, 7.8, , ddd, 7.9, 4.5, a 1.38, m b 1.38, m 11 a 1.50 m b 1.33, m a 1.30, m b 1.30, m 13 a 1.32, m b 1.32, m , t, , t, , d, , d, SI 22

23 cytospolide H lit., m, J in Hz found c lit. found ppm a , q, , q, , dd, 11.7, , t, , dd, 11.7, , dd, 11.7, , m 4.56, ddd, 11.0, 6.8, , m 2.00, m , m 1.93, m 1.78, dd, 11.9, , m 2.10, tdd, 12.0, 9.1, , m , dt, 7.0, , ddd, 9.3, 7.0, , dt, 9.6, , dt, 9.6, a 1.60, m b 1.47, m 11 a 1.47 m b 1.38, m , m , m , m , m a 1.33, m b 1.33, m 13 a 1.30, m b 1.30, m , m , m , t, , t, , d, , d, SI 23