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Synthesis 2010(15): 2643-2651  
DOI: 10.1055/s-0029-1218825
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of the C1-C14 Fragment of Sarcoglaucol-16-one via Z-Selective Ando-Type Horner-Wadsworth-Emmons Olefination

Christoph Gastl, Sabine Laschat*
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: +49(711)68564285; e-Mail: sabine.laschat@oc.uni-stuttgart.de;

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Publication History

Received 26 March 2010
Publication Date:
18 June 2010 (online)

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Abstract

A synthetic strategy involving a Z-selective Horner-Wadsworth-Emmons olefination was developed for the preparation of the sarcoglaucolone precursor methyl (2Z,6E)-8-(methoxymeth­oxy)-6-methyl-2-[(3E)-4-methyl-5-oxopent-3-enyl]-9-[(trimethylsilyl)methyl]deca-2,6,9-trienoate. The target compound was isolated in a E/Z ratio of 17:83

Key words

Ando-type reaction - olefination - cembranolide - natural product - macrocycles

Cembranolides are macrocyclic diterpenes of marine origin that possess a variety of interesting biological activities, such as cytotoxic, anti-inflammatory, anti-bacterial and anti-viral activities, which make these natural products promising targets for synthetic approaches [¹-³] as pioneered by Marshall. [4] In 2004, Wright and König reported the isolation of the cembranolide sarcoglaucol-16-one (1) from a soft coral species belonging to the genus Sarcophyton (Scheme  [¹] ). [5] The structure of 1 was established by NMR analysis and the absolute stereochemistry was determined by the modified Mosher method. It was further shown that compound 1 displayed promising cytotoxic activity against MCF7 tumor cell lines. [5] From a synthetic point of view, sarcoglaucol-16-one (1) possesses the following structural features: (a) a 14-membered macrocycle with attached γ-butenolide unit, [6] (b) two stereogenic centres at C-6 and C-9 and (c) a methyl ester at a branching position of the diterpenoid, the latter being rather uncommon among the various cembranolides. Whereas the carbon skeleton of 1 can be biogenetically traced back to geranylacetone or geranylgeraniol, [¹] results by Dorta on furanocembranolides revealed that a genus-specific oxidation cascade leads from a methyl group to a carboxylic acid or ester. [²e] However, the regioselective C-H oxidation of the branching methyl groups in a terpene precursor is rather difficult to achieve by chemical means, [7] and even treatment of terpene derivatives with isolated cytochrome P450 monooxygenases often yields complex product mixtures with competing or sometimes strongly favoured epoxide formation rather than allylic oxidation. [8] [9] In order to develop a total synthesis of sarcoglaucol-16-one (1), we decided to first establish the C1-C14 carbon skeleton of the macrocycle 1 with correct configuration of the C=C double bonds, and to focus later on the installation of the stereogenic centres at C-6 and C-9. The results are reported below.

In our retrosynthetic approach, which is shown in Scheme  [¹] , a ring-closing metathesis (RCM) [¹0] [¹¹] of macrocyclic methacrylate 2 was planned as the final step. Methacrylate 2 should be obtained from allylic alcohol derivative 3 via deprotection and esterification. Macrocyclization towards 3 should be achieved via intramolecular Sakurai reaction [¹²] [¹³] of enal 4 which, in turn, could arise from the C7-C14 fragment 5 via deprotection of the primary alcohol, oxidation to the corresponding aldehyde, followed by Horner-Wadsworth-Emmons olefination with phosphonate 6 (i.e., C1-C6 fragment). We hoped to establish the stereogenic centre at C-9 via a Noyori-type addition [¹4] of an organozinc species derived from isopropenyl bromide 8 to the α,β-unsaturated aldehyde 7.

Scheme 1

The synthesis of the C7-C14 fragment commenced with protection of 5-hydroxypentan-2-one (9) with triethylsilyl chloride (TESCl) in the presence of triethylamine at room temperature in 96% yield, followed by olefination with phosphonate 10a in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and lithium chloride in acetonitrile at room temperature according to the procedure by Roush, [¹5] to yield the α,β-unsaturated ester 11 in 68% yield (E/Z = 74:26; Scheme  [²] ). Reduction of 11 to the corresponding allylic alcohol 12 was achieved with diisobutylaluminum hydride (DIBAL-H) [¹6] in tetrahydrofuran (THF) at -78 ˚C, from which the pure E-isomer 12 could be obtained after flash chromatography in 61% yield.

Scheme 2

Subsequent oxidation with tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO) in dichloromethane at 10 ˚C, yielded enal 7a in 61% yield. Next, Noyori-type 1,2-additions [¹4] [¹7] of an organozinc species to enal 7a were investigated in order to establish the stereochemistry at C-9 of sarcoglaucol-16-one (1). In a preliminary experiment, when enal 7a was treated with ethylisopropenylzinc, [¹8] employing N-morpholinoisoborneol 14 [¹9] as chiral ligand, in toluene at 0 ˚C, the desired allylic alcohol 13 was isolated in 78% yield and 82% ee. However, when enal 7a was treated with ethyl{1-[(trimethylsilyl)methyl]vinyl}zinc [²0] in the presence of ligand 14 under similar conditions, allylic alcohol 5a was isolated in 54% yield in racemic form. Then, the addition was performed with ligand 15 [²¹] instead of N-morpholinoisoborneol 14, yielding the allylic alcohol 5a in 54% yield with a disappointing 6% ee (see also Supporting Information for further experiments). Due to these unexpected difficulties, we decided to continue the synthetic efforts with the racemic material 5a, which was protected with chloromethyl methyl ether (MOMCl) in dichloromethane in the presence of Hünig’s base at room temperature to give the O-MOM-derivative 5b in 97% yield. Subsequent deprotection of the TES group with tetrabutyl­ammonium fluoride (TBAF) in THF at 0 ˚C gave 5c in 85% yield, which was oxidised with TPAP and NMO in dichloromethane at room temperature to yield aldehyde 16 in 70% yield.

For the synthesis of the C1-C6 fragment 6a, the Ando phosphonate 10b [²²] was deprotonated with sodium hydride in dimethylsulfoxide (DMSO) at room temperature, followed by addition of 4-bromobut-1-ene at 40 ˚C to yield the phosphonate derivative 17a in 79% based on recovered starting material 10b (Scheme  [³] ).

Scheme 3

Compound 17a was submitted to ozonolysis, the progress of which was monitored by addition of Sudanred III, [²³] followed by reductive work-up with triphenylphosphane to give the aldehyde 18a in 76% yield. Treatment with stabilized ylide 19 [²4] in a (3:1) mixture of benzene and toluene under reflux gave the enal-substituted phosphonate 6a in 65% yield. Compound 6a was protected either with 2,2-dimethoxypropane in the presence of 10-camphorsulfonic acid (CSA) in methanol at room temperature to give the dimethylacetal 20a in 98% yield, or with 1,3-propanedithiol and Montmorillonite K10 in dichloromethane at room temperature to give the corresponding dithioacetal 20b in 88% yield. Phosphonate 20a was deprotonated with sodium hydride in the presence of sodium iodide in THF at room temperature, followed by addition of the enal 16 in THF at -20 ˚C and warming to room temperature according to the procedure by Pikho, [²5] [²6] to give the desired olefin 21a in 79% crude yield, predominantly as the Z-isomer (E/Z = 17:83). Due to the fact that the crude product 21a already contained 15% of enal 4a, the mixture was treated with Dowex 50 × 8 ion-exchange resin in dichloromethane at room temperature in order to hydrolyze the dimethyl acetal; enal 4a was isolated in 78% yield (E/Z = 17:83). Dithioacetal 20b was treated in a similar manner with aldehyde 16 as described for phosphonate 20a, and the corresponding olefin 21b was isolated in 47% yield (E/Z = 17:83).

In order to check whether the Ando phosphonates 20a and 20b are required for the Z-selective Horner-Wadsworth-Emmons olefination, the structurally related diethyl phosphonate 22 was deprotonated with sodium hydride in the presence of sodium iodide in THF, followed by addition of aldehyde 16, and the corresponding alkenes 23 were isolated in 80% yield as a mixture of Z- and E-isomers (50:50, Scheme  [4] ). It should be noted that the Still-Gennari­ olefination [²7] was not considered as an alternative method due to the use of expensive (bistrifluoroethyl)phosphonate and [18]crown-6-ether.

Scheme 4

In conclusion, the acyclic C1-C14 carbon skeleton 4a of sarcoglaucol-16-one (1) has been established by a convergent approach in ten steps (for the longest linear sequence) and 4.7% overall yield from hydroxyketone 9, employing a Z-selective Ando-type Horner-Wadsworth-Emmons olefination of 20a and aldehyde 16 as the key step. Attempts to improve the enantioselectivity of the 1,2-addition of isopropenylzinc derivatives to enal 7a to gain access to the enantiomerically pure target molecule 4a are currently in progress in our laboratories.

Melting points were measured with a Mettler-Toledo DSC822e calorimeter and are uncorrected. IR spectra were recorded with a Bruker Vector 22 FT-IR spectrometer. ¹H and ¹³C NMR spectra were recorded­ with a Bruker Avance 300 or a Bruker Avance 500 spectrometer with TMS as an internal standard. Mass spectra were recorded with a Finnigan MAT 95 (CI) instrument with ammonia as reactant gas, a Varian MAT 711 (EI, 70 eV) and a Bruker Daltonics microTOF-Q (ESI) spectrometer with nitrogen as carrier gas. Flash chromatography was performed using Kieselgel 60, 40-63 µm (Fluka­). All solvents were dried, and reactions were performed in dried glassware using standard Schlenk techniques. Reaction monitoring was performed with a Trace GC 2000 Ultra Optima 5-MS column (30 m × 0.25 mm) with hydrogen as carrier gas using different temperature programs. The enantioselectivity was detected by gas chromatography on chiral stationary phases.

The following compounds were prepared according to literature procedures: 10b, [²²] 11, [4d] 19, [²4] diisopropenylzinc [¹8] and 2-bromo-3-trimethylsilylprop-1-ene. [²0] For details of the preparation of ligand 15 and phosphonate 22, see the Supporting Information.

(2 E )-3-Methyl-6-[(triethylsilyl)oxy]hex-2-en-1-ol (12)

To a solution of 11 (4.27 g, 15.7 mmol) in THF (80 mL), was dropwise added DIBAL-H (52 mL, 62.7 mmol, 1.2 M in toluene) at -78 ˚C and the mixture was stirred for 2 h. Sat. Seignette salt solution (20 mL) was added at -78 ˚C, and the mixture was warmed to r.t., the layers were separated, the aqueous layer was extracted with Et2O (5 × 100 mL) and the combined organic layers were dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on SiO2 (hexanes-EtOAc, 5:1) to yield 12.

Yield: 2.32 g (61%); pale-yellow oil; 100% E by ¹H NMR analysis; R f  = 0.34 (hexanes-EtOAc, 5:1).

FTIR (ATR): 3340 (w), 2952 (s), 2912 (s), 2876 (s), 1669 (w), 1458 (m), 1415 (m), 1382 (m), 1299 (w), 1238 (m), 1193 (w), 1095 (vs), 1003 (vs), 960 (s), 804 (s), 775 (m), 724 (vs), 669 (m) cm-¹.

¹H NMR (250 MHz, CDCl3): δ = 0.58 (q, J = 7.9 Hz, 6 H, CH2, TES), 0.96 (t, J = 7.9 Hz, 9 H, CH3, TES), 1.34 (br s, OH), 1.59-1.72 (m, 2 H, H-4), 1.68 (d, J = 1.3 Hz, 3 H, CH3), 2.03-2.11 (m, 2 H, H-5), 3.68 (t, J = 6.6 Hz, 2 H, H-6), 4.15 (dq, J = 6.9, 0.7 Hz, 2 H, H-1), 5.42 (tq, J = 6.9, 1.3 Hz, 1 H, H-2).

¹³C NMR (125 MHz, CDCl3): δ = 2.9 (CH3, TES), 5.3 (CH2, TES), 14.7 (C-4), 29.4 (C-5), 34.2 (CH3), 57.9 (C-3), 60.9 (C-1), 121.8 (C-2), 138.1 (C-3).

GC/MS (EI): m/z (%) = 340 (6), 307 (10), 294 (4), 266 (8), 262 (3), 239 (4), 220 (2), 215 (7), 199 (3), 191 (22), 180 (23), 165 (4), 153 (8), 147 (9), 134 (86), 119 (44), 106 (38), 103 (41), 93 (42), 90 (38), 87 (7), 73 (100, TMS), 67 (7), 59 (10), 51 (13).

Anal. Calcd for C13H28O2Si: C, 63.87; H, 11.56. Found: C, 63.78; H, 11.45.

(2 E )-3-Methyl-6-[(triethylsilyl)oxy]hex-2-enal (7a)

To a solution of 12 (500 mg, 2.04 mmol) in CH2Cl2 (30 mL), were added powdered molecular sieves 4 Å (1.00 g), NMO (1.44 g, 12.3 mmol) and TPAP (30 mg, 0.08 mmol) at 0 ˚C. After 10 min, the mixture was warmed to r.t., filtered through SiO2, evaporated and purified by flash chromatography (hexanes-EtOAc, 2:1) to yield aldehyde 7a.

Yield: 302 mg (61%); colourless oil; R f  = 0.30 (hexane-EtOAc, 10:1).

FTIR (ATR): 2953 (s), 2912 (s), 2876 (s), 1673 (vs), 1634 (m), 1458 (m), 1414 (m), 1383 (m), 1239 (m), 1192 (m), 1097 (vs), 1008 (s), 956 (m), 863 (m), 799 (s), 725 (vs), 670 (m), 599 (w), 551 (w), 516 (w) cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 0.59 (q, J = 7.9 Hz, 6 H, CH2, TES), 0.96 (t, J = 7.9 Hz, 9 H, CH3, TES), 1.67-1.79 (m, 2 H, H-5), 2.18 (d, J = 1.2 Hz, 3 H, H-7), 2.25-2.33 (m, 2 H, H-4), 3.63 (t, J = 6.2 Hz, 2 H, H-6), 5.89 (ddd, J = 8.0, 2.3, 1.2 Hz, 1 H, H-2), 10.00 (d, J = 8.0 Hz, 1 H, H-1).

¹³C NMR (125 MHz, CDCl3): δ = 4.5 (CH3, TES), 6.8 (CH2, TES), 16.5 (C-5), 31.5 (C-4), 41.9 (C-7), 59.6 (C-6), 125.2 (C-2), 135.1 (C-3), 202.2 (C-1).

GC/MS (EI): m/z (%) = 224 (3), 182 (4), 165 (3), 149 (8), 134 (12), 131 (7), 120 (10), 115 (22, TES), 108 (43), 105 (38), 102 (8), 92 (88), 83 (62), 75 (22), 73 (100, TMS), 59 (36), 50 (24).

HRMS (ESI): m/z [M + Na]+ calcd for C13H26NaO2Si+: 265.1594; found: 265.1587.

(3 R ,4 E )-2,5-Dimethyl-8-[(triethylsilyl)oxy]octa-1,4-dien-3-ol (13)

To a solution of diethylzinc (127 µL, 1.24 mmol) in toluene (3 mL), were added at r.t. over 15 min, diisopropenylzinc (413 µL, 0.41 mmol, 1 M in toluene) and ligand 14 (165 µL, 16.5 µmol, 0.1 M in toluene) and the mixture was cooled to 0 ˚C. Then, 7a (100 mg, 0.41 mmol) was added and the reaction mixture was stirred for 1 h at 0 ˚C, hydrolyzed with sat. NH4Cl (10 mL) and diluted with Et2O (10 mL). The organic layer was separated, dried (Na2SO4), evaporated and the crude product was purified by flash chromatography on SiO2 (hexanes-EtOAc, 12:1) to give 13.

Yield: 91 mg (78%); colourless oil; R f  = 0.26 (hexanes-EtOAc, 10:1); 82% ee (by GC on Bondex α un β); [α]D ²0 -36 (c = 1, CHCl3).

FTIR (ATR): 3340 (m), 2939 (m), 2903 (m), 2876 (m), 2702 (w), 2548 (w), 2346 (w), 2189 (w), 1942 (m), 1651 (m), 1465 (m), 1415 (m), 1382 (m), 1335 (w), 1232 (m), 1095 (s), 1005 (s), 960 (m), 895 (m), 832 (m), 725 (vs), 670 (m) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 0.61 (q, J = 7.9 Hz, 6 H, CH2, TES), 0.96 (t, J = 7.9 Hz, 9 H, CH3, TES), 1.54 (d, J = 3.9 Hz, 1 H, OH), 1.6-1.71 (m, 2 H, H-7), 1.65 (dd, J = 1.2, 0.8 Hz, 3 H, H-10), 1.73 (d, J = 1.4 Hz, 3 H, H-9), 1.97-2.13 (m, 2 H, H-6), 4.04-4.07 (m, 1 H, H-3), 4.17-4.19 (m, 2 H, H-8), 4.84-4.85 (m, 1 H, Ha-1), 4.94-4.95 (m, 1 H, Hb-1), 5.36 (tq, J = 6.5, 1.4 Hz, 1 H, H-4).

¹³C NMR (125 MHz, CDCl3): δ = 4.5 (CH3, TES), 6.8 (CH2, TES), 16.4 (C-10), 17.6 (C-9), 32.9 (C-7), 35.5 (C-6), 59.7 (C-8), 75.6 (C-3), 111.2 (C-1), 124.5 (C-4), 136.9 (C-5), 147.4 (C-2).

HRMS (ESI, positive): m/z [M + Na]+ calcd for C16H32O2SiNa: 307.2064; found: 307.2073.

(4 E )-5-Methyl-8-[(triethylsilyl)oxy]-2-[(trimethylsilyl)methyl]octa-1,4-dien-3-ol (5a)

To a solution of 2-bromo-3-trimethylsilylprop-1-ene (80 mg, 0.41 mmol) in Et2O (1 mL), was added t-BuLi (565 µL, 0.85 mmol, 1.5 M in toluene) at -78 ˚C. The mixture was warmed to -20 ˚C over 1 h and re-cooled to -78 ˚C. Then, ZnCl2 (207 µL, 0.21 mmol, 1 M in Et2O) was added and the mixture was warmed to r.t. over 3 h, followed by sequential addition of diethylzinc (22 µL, 0.21 mmol) and 7a (97 mg, 0.4 mmol) in Et2O (1 mL). After 1 h, the reaction mixture was hydrolyzed by addition of sat. NH4Cl (10 mL). The layers were separated and the organic layers were extracted with EtOAc (3 × 10 mL), dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on SiO2 (hexanes-EtOAc, 10:1) to give 5a.

Yield: 38 mg (54%); pale-yellow oil; R f  = 0.55 (hexanes-EtOAc, 10:1); 6% ee (by GC on Bondex α un β).

FTIR (ATR): 3370 (w), 2952 (s), 2912 (s), 2877 (s), 2568 (w), 2373 (w), 2181 (w), 1973 (m), 1635 (w), 1458 (m), 1415 (m), 1382 (m), 1247 (s), 1157 (m), 1096 (s), 1005 (s), 962 (m), 882 (s), 839 (vs), 796 (s), 724 (vs), 693 (s), 670 (m), 633 (m) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 0.04 (s, 9 H, TMS), 0.58 (q, J = 7.9 Hz, 6 H, CH2, TES), 0.95 (t, J = 7.9 Hz, 9 H, CH3, TES), 1.38 (ddd, J = 14.0, 1.1, 0.3 Hz, 1 H, Ha-10), 1.45 (d, J = 3.5 Hz, 1 H, OH), 1.59 (dd, J = 14.0, 1.1 Hz, 1 H, Hb-10), 1.63-1.69 (m, 2 H, H-7), 1.73 (d, J = 1.4 Hz, 3 H, H-9), 2.06-2.09 (m, 2 H, H-6), 3.59 (t, J = 6.7 Hz, 2 H, H-8), 4.65 (dq, J = 1.3, 1.04 Hz, 1 H, Ha-1), 4.65-4.69 (m, 1 H, H-3), 4.98 (t, J = 1.4 Hz, 1 H, Hb-1), 5.15 (dq, J = 8.8, 1.4 Hz, 1 H, H-4).

¹³C NMR (125 MHz, CDCl3): δ = 0.9 (TMS), 4.8 (CH3, TES), 7.1 (CH2, TES), 17.1 (C-9), 22.9 (C-10), 31.2 (C-7), 36.2 (C-6), 62.8 (C-8), 72.2 (C-3), 106.7 (C-1), 126.7 (C-4), 139.7 (C-5), 145.5 (C-2).

GC/MS (EI): m/z (%) = 338 (4) [M+ - H2O], 206 (10), 191 (6), 180 (24), 165 (9), 134 (39), 119 (34), 117 (26), 115 (18) [TES], 106 (15), 103 (16), 93 (20), 79 (6), 73 (100) [TMS], 59 (12).

HRMS (EI, 70 eV): m/z [M]+ calcd for C19H40O2Si2: 356.2567; found: 356.2578.

Anal. Calcd for C19H40O2Si2: C, 63.98; H, 11.30. Found: C, 63.97; H, 11.31.

Triethyl[{(4 E )-6-(methoxymethoxy)-4-methyl-7-[(trimethylsilyl)methyl]octa-4,7-dienyl}oxy]silane (5b)

To an ice-cooled solution of alcohol 5a (243 mg, 0.68 mmol) in CH2Cl2 (20 mL) were added sequentially DIPEA (2.56 mL, 14.3 mmol) and MOMCl (363 µL, 4.78 mmol). After 10 min, the mixture was warmed to r.t., stirred for 36 h and then diluted with H2O (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with 1.5 N HCl (20 mL), sat. NaHCO3 (20 mL), dried (Na2SO4) and the solvent was evaporated. The crude product was purified by flash chromatography on SiO2 (hexanes-EtOAc, 10:1) to give 5b.

Yield: 265 mg (97%); pale-yellow oil; R f  = 0.60 (hexanes-EtOAc, 10:1).

FTIR (ATR): 2952 (s), 2912 (m), 2877 (s), 1665 (w), 1637 (w), 1459 (m), 1416 (m), 1383 (m), 1247 (s), 1213 (m), 1149 (s), 1094 (vs), 1035 (vs), 958 (s), 917 (m), 884 (s), 840 (vs), 797 (s), 740 (vs), 726 (vs), 694 (s), 671 (m), 633 (m) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 0.04 (s, 9 H, TMS), 0.59 (q, J = 7.9 Hz, 6 H, CH2, TES), 0.96 (t, J = 7.9 Hz, 9 H, CH3, TES), 1.39 (dd, J = 14, 1 Hz, 1 H, Ha-3′), 1.57 (dd, J = 14, 1 Hz, 1 H, Hb-3′), 1.64-1.70 (m, 2 H, H-9), 1.72 (d, J = 1.3 Hz, 3 H, CH3), 2.06-2.1 (m, 2 H, H-8), 3.36 (s, 3 H, H-1), 3.58 (t, J = 6.9 Hz, 2 H, H-10), 4.56 (dd, J = 6.7, 0.3 Hz, 1 H, Ha-3), 4.61 (d, J = 6.7 Hz, 1 H, Hb-3), 4.62-4.65 (m, 1 H, H-5), 4.68 (ddd, J = 3.7, 1.8, 1.1 Hz, 1 H, Ha-1′), 4.96-4.97 (m, 1 H, Hb-1′), 5.07 (dq, J = 9.1, 1.3 Hz, 1 H, H-6).

¹³C NMR (125 MHz, CDCl3): δ = -1.1 (TMS), 4.4 (CH3-TES), 6.8 (CH2-TES), 16.7 (CH3), 22.6 (C-3′), 31.0 (C-9), 35.9 (C-8), 55.4 (C-1), 62.6 (C-10), 74.6 (C-5), 93.1 (C-3), 108.1 (C-1′), 124.1 (C-6), 140.2 (C-7), 146.4 (C-2′).

GC/MS (EI): m/z (%) = 338 (2) [M+ - OMOM], 309 (2), 266 (2), 237 (6), 210 (4), 206 (8), 179 (14), 165 (7), 148 (4), 146 (9), 133 (72), 118 (43), 115 (21) [TES], 105 (34), 92 (46), 90 (37), 88 (32), 75 (26), 73 (100) [TMS], 59 (28).

HRMS (EI, 70 eV): m/z [M]+ calcd for C21H44O3Si2: 400.2829; found: 400.2810.

(4 E )-6-(Methoxymethoxy)-4-methyl-7-[(trimethylsilyl)methyl]octa-4,7-dienal (16)

To a solution of 5b (151 mg, 0.38 mmol) in THF (2 mL) was added dropwise a solution of TBAF˙H2O (125 mg, 0.39 mmol) in THF (1 mL) at 0 ˚C, and the reaction mixture was stirred for 10 min. Then, sat. NH4Cl (10 mL) was added, the mixture was warmed to r.t. and the organic layer was extracted with EtOAc (3 × 10 mL), dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on SiO2 (hexanes-EtOAc, 10: 1) to give 5c.

Yield: 98 mg (90%); pale-yellow oil; R f  = 0.35 (hexanes-EtOAc, 10:1).

FTIR (ATR): 3346 (w), 2949 (m), 2884 (m), 2554 (w), 2367 (w), 1996 (w), 1636 (w), 1442 (w), 1417 (w), 1383 (w), 1247 (m), 1213 (w), 1145 (m), 1094 (m), 1033 (s), 957 (w), 917 (w), 884 (m), 839 (s), 771 (w), 726 (w), 694 (m), 634 (w) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 0.04 (s, 9 H, TMS), 1.38 (dd, J = 14.1, 1.0 Hz, 1 H, CH2TMSa), 1.58 (dd, J = 14.1, 1.0 Hz, 1 H, CH2TMSb), 1.68-1.76 (m, 2 H, H-2), 1.73 (d, J = 1.4 Hz, 3 H, CH3), 2.13 (td, J = 7.6, 1.3 Hz, 2 H, H-3), 3.36 (s, 3 H, OCH3), 3.62-3.66 (m, 2 H, H-1), 4.58 (dd, J = 6.7, 0.3 Hz, 1 H, Ha-2′), 4.62 (d, J = 6.7 Hz, 1 H, Hb-2′), 4.63-4.65 (m, 1 H, H-6), 4.68 (ddd, J = 3.7, 1.8, 1.1 Hz, 1 H, Ha-8), 4.96 (dd, J = 1.8, 1.1 Hz, 1 H, Hb-8), 5.08 (dq, J = 9.2, 1.3 Hz, 1 H, H-5).

¹³C NMR (125 MHz, CDCl3): δ = -1.1 (TMS), 16.6 (CH3), 22.5 (CH2TMS), 30.6 (C-2), 36.1 (C-3), 55.4 (OCH3), 62.7 (C-1), 74.8 (C-6), 93.3 (C-2′), 108.2 (C-8), 124.5 (C-5), 139.9 (C-4), 146.3 (C-7).

MS (EI): m/z (%) = 225 (3) [M+ - OMOM], 180 (4), 165 (3), 152 (5), 141 (6), 136 (12), 126 (5), 118 (36), 110 (14), 106 (25), 96 (16), 93 (58), 90 (48), 88 (18), 84 (12), 73 (100) [TMS], 66 (10), 58 (17).

HRMS (ESI): m/z [M + Na]+ calcd for C15H30O3SiNa+: 309.1856; found: 309.1858.

To a solution of 5c (72 mg, 0.24 mmol) in CH2Cl2 (10 mL) were sequentially added powered 4 Å molecular sieves (250 mg), NMO (170 mg, 1.43 mmol) and TPAP (6 mg, 0.02 mmol) at 0 ˚C. The reaction mixture was stirred for 1.5 h then warmed to r.t., filtered over a plug of SiO2 and evaporated. The crude product was purified by flash chromatography (hexane-EtOAc, 7:1) to yield 16.

Yield: 50 mg (70%); colourless oil; R f  = 0.35 (hexanes-EtOAc, 6:1).

FTIR (ATR): 2952 (m), 2890 (m), 2821 (w), 2721 (w), 2563 (w), 2367 (w), 2181 (w), 1965 (w), 1725 (s), 1668 (m), 1636 (m), 1444 (m), 1416 (m), 1386 (m), 1348 (w), 1247 (s), 1212 (w), 1148 (s), 1093 (s), 1031 (vs), 976 (m), 957 (m), 916 (m), 883 (s), 838 (vs), 772 (m), 723 (w), 693 (m), 621 (m) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 0.04 (s, 9 H, TMS), 1.36 (dd, J = 14.1, 1.0 Hz, 1 H, CH2TMSa), 1.57 (dd, J = 14.1, 1.1 Hz, 1 H, CH2TMSb), 1.74 (d, J = 1.4 Hz, 3 H, CH3), 2.38 (td, J = 7.5, 1.4 Hz, 2 H, H-3), 2.56-2.60 (m, 2 H, H-2), 3.35 (s, 3 H, OCH3), 4.57 (dd, J = 6.5, 6.0 Hz, 2 H, H-2′), 4.68-4.69 (m, 1 H, Ha-8), 4.95 (dt, J = 2.9, 1.0 Hz, 1 H, Hb-8), 5.1 (dq, J = 9.0, 1.4 Hz, 1 H, H-5), 9.77 (t, J = 1.7 Hz, 1 H, H-1).

¹³C NMR (125 MHz, CDCl3): δ = -1.1 (TMS), 16.8 (CH3), 22.4 (CH2TMS), 31.7 (C-3), 41.9 (C-2), 55.4 (OCH3), 74.6 (C-6), 93.2 (C-2′), 108.5 (C-8), 125.1 (C-5), 138.2 (C-4), 146 (C-7), 201.9 (C-1).

GC/MS (EI): m/z (%) = 222 (5), 204 (5), 187 (5), 181 (6), 165 (4), 149 (7), 135 (14), 132 (10), 117 (48), 106 (53), 95 (10), 93 (30), 92 (84), 90 (62), 88 (28), 79 (13), 74 (33), 73 (100) [TMS], 64 (8), 58 (33).

HRMS (ESI): m/z [M + Na]+ calcd for C15H28O3SiNa+: 307.1700; found: 307.1702.

Methyl 2-[Di( o -tolyl)oxyphosphoryl]hex-5-enoate (17a)

NaH (216 mg, 8.98 mmol, 60% suspension in mineral oil) was added to a solution of phosphonate 10b (3.00 g, 8.98 mmol) in DMSO (5 mL). After stirring for 30 min at r.t., 4-bromobut-1-ene (1.05 µL, 10.3 mmol) was added dropwise and stirring was continued for 1 h. The mixture was warmed to 40 ˚C and stirred for 16 h. After cooling to r.t., sat. NH4Cl (50 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layer was dried (Na2SO4), evaporated and the residue was purified by flash chromatography on SiO2 (hexanes-EtOAc, 2:1) to yield 10b (705 mg, 2.11 mmol, 24%) and 17a (2.08 g, 79% based on recovered 10b).

Yellow oil; R f  = 0.35 (hexanes-EtOAc, 2:1).

FTIR (ATR): 3064 (w), 2952 (w), 1966 (m), 1737 (s), 1641 (w), 1585 (m), 1490 (s), 1461 (m), 1435 (m), 1336 (m), 1274 (s), 1222 (s), 1182 (s), 1163 (s), 1106 (s), 1043 (m), 929 (vs), 833 (m), 843 (m), 756 (vs), 708 (m), 601 (m) cm-¹.

¹H NMR (250 MHz, CDCl3): δ = 2.07-2.48 (m, 4 H, H-2, H-4), 2.18 (s, 3 H, ArCH3), 2.24 (s, 3 H, ArCH3′), 3.34 (ddd, J = 23.4, 10.8, 3.3 Hz, 1 H, H-2), 3.76 (s, 3 H, OCH3), 5.02 (dd, J = 1.2, 0.3 Hz, 1 H, Ha-6), 5.05-5.11 (m, 1 H, Hb-6), 5.68-5.85 (m, 1 H, H-5), 7.05-7.11 (m, 4 H, H-4′, H-5′, H-4′′, H-5′′), 7.11-7.2 (m, 2 H, H-3′), 7.21-7.35 (m, 2 H, H-6′).

¹³C NMR (125 MHz, CDCl3): δ = 16.3 (ArCH3), 26.2 (d, J = 3.9 Hz, C-4), 32.3 (d, J = 16 Hz, C-3), 45.2 (d, J = 135.3 Hz, C-2), 52.6 (OCH3), 116.62 (C-5), 120.16 (d, J = 2.5 Hz, C-6′), 120.24 (d, J = 2.5 Hz, C-9′), 125.15 (C-4′), 125.17 (C-4′′), 127.04 (d, J = 1.3 Hz, C-5′), 127.06 (d, J = 1.3 Hz, C-5′′), 129.22 (d, J = 1.3 Hz, C-2′), 129.32 (d, J = 1.3 Hz, C-2′′), 131.41 (C-3), 131.43 (C-3′′), 136.3 (d, J = 0.5 Hz, C-6), 148.9 (d, J = 1 Hz, C-1′), 149.1 (d, J = 1 Hz, C-1′′), 168.3 (d, J = 5.5 Hz, C-1).

³¹P NMR (202 MHz, CDCl3): δ = 15.17-15.38 (m).

GC/MS (EI): m/z (%) = 388 (14) [M]+, 357 (16), 347 (100), 334 (8), 315 (43), 302 (16), 287 (19), 249 (11), 227 (15), 192 (10), 180 (23), 165 (9), 153 (10), 133 (7), 115 (11), 108 (48) [o-cresyl], 107 (22), 91 (78) [tolyl], 77 (21), 64 (19), 55 (22).

HRMS (ESI): m/z [M + Na]+ calcd for C21H25O5PNa+: 411.1332; found: 411.1337.

Methyl 2-[Di( o -tolyl)oxyphosphoryl]-5-oxopentanoate (18a)

A solution of 17a (768 mg, 1.98 mmol) and Sudanred III (3 mg) in CH2Cl2 (70 mL) was cooled to -78 ˚C. Then, ozone was bubbled through the solution until it turned colourless, followed by bubbling argon through the solution for 5 min. Ph3P (648 mg, 2.47 mmol) was added and the reaction mixture was warmed to r.t. over 7 h. Evaporation of the solvent followed by flash chromatography on SiO2 (hexanes-EtOAc, 1:1) yielded 18a.

Yield: 586 mg (76%); yellow oil; R f  = 0.30 (hexanes-EtOAc, 1:1).

FTIR (ATR): 2953 (w), 2728 (w), 1965 (w), 1735 (s), 1585 (m), 1490 (s), 1461 (m), 1436 (m), 1385 (w), 1328 (w), 1271 (s), 1222 (s), 1181 (m), 1162 (s), 1106 (s), 1043 (m), 930 (vs), 852 (m), 806 (m), 757 (s), 708 (m), 599 (m), 562 (m), 530 (m), 518 (m) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 2.2 (s, 3 H, ArCH3), 2.24 (s, 3 H, ArCH3′), 2.45-2.55 (m, 2 H, H-4), 2.63-2.8 (m, 2 H, H-3), 3.44 (ddd, J = 29.9, 8.8, 5.6 Hz, 1 H, H-2), 3.76 (s, 3 H, OCH3), 7.03-7.17 (m, 4 H, H-5′, H-5′′, H-4′, H-4′′), 7.15-7.20 (m, 2 H, H-3′, H-3′′), 7.22-7.25 (m, 1 H, H-6′), 7.28-7.32 (m, 1 H, H-6′′), 9.75 (s, 1 H, H-5).

¹³C NMR (125 MHz, CDCl3): δ = 16.3 (ArCH3), 19.7 (d, J = 4.8 Hz, C-4), 41.8 (d, J = 13.1 Hz, C-3), 44.8 (d, J = 134.6 Hz, C-2), 52.8 (OCH3), 120.1 (d, J = 2.4 Hz, C-6′), 120.2 (d, J = 2.1 Hz, C-6′′), 125.3 (C-4′), 127.1 (C-5′), 129.2 (d, J = 4.3 Hz, C-2′), 129.3 (d, J = 4.3 Hz, C-2′′), 131.5 (d, J = 3.9 Hz, C-3′), 148.8 (d, J = 9.6 Hz, C-1′), 168.3 (d, J = 5.5 Hz, C-1), 203 (C-5).

³¹P NMR (202 MHz, CDCl3): δ = 14.03-14.38 (m).

GC/MS (EI): m/z (%) = 391 (2) [M + H]+, 359 (6), 335 (11), 315 (24), 302 (18), 283 (100), 273 (5), 252 (26), 244 (7), 227 (28), 212 (14), 195 (10), 179 (23), 165 (12), 153 (15), 131 (12), 120 (6), 108 (61) [o-cresyl], 105 (13), 91 (74) [tolyl], 77 (32), 65 (26), 55 (17).

HRMS (ESI): m/z [M + H]+ calcd for C20H23O6PH+: 391.1305; found: 391.1301.

Anal. Calcd for C20H23O6P: C, 61.54; H, 5.94. Found: C, 61.62; H, 5.89.

Methyl (5 E )-2-[Di( o -tolyl)oxyphosphoryl]-6-methyl-7-oxohept-5-enoate (6a)

A solution of 18a (200 mg, 0.51 mmol) and ylide 19 (236 mg, 0.72 mmol) in benzene (3 mL) and toluene (1 mL) was heated at reflux for 15 h. Evaporation of the solvent followed by flash chromatography (hexanes-EtOAc, 1:1) yielded 6a.

Yield: 144 mg (65%); pale-yellow oil; R f  = 0.50 (hexanes-EtOAc, 1:1).

FTIR (ATR): 3060 (w), 2952 (w), 2864 (w), 2825 (w), 2714 (w), 2359 (w), 2339 (w), 1736 (s), 1683 (s), 1645 (m), 1585 (m), 1490 (s), 1460 (m), 1436 (m), 1382 (w), 1336 (m), 1273 (s), 1223 (s), 1164 (vs), 1107 (vs), 1042 (s), 934 (vs), 853 (m), 806 (s), 759 (vs), 708 (m), 602 (m), 561 (m), 520 (s), 507 (s) cm-¹.

¹H NMR (250 MHz, CDCl3): δ = 1.74 (d, J = 1.4 Hz, 3 H, CH3), 2.19 (s, 3 H, ArCH3), 2.25 (s, 3 H, ArCH3′), 2.45-2.68 (m, 4 H, H-2, H-4), 3.35 (ddd, J = 23.9, 10.2, 4 Hz, 1 H, H-2), 3.78 (d, J = 0.6 Hz, 3 H, OCH3), 6.42 (tq, J = 7.2, 1.4 Hz, 1 H, H-5), 7.04-7.12 (m, 4 H, H-5′, H-5′′, H-4′, H-4′′), 7.13-7.22 (m, 2 H, H-3′, H-3′′), 7.23-7.32 (m, 2 H, H-6′, H-6′′), 9.42 (s, 1 H, H-7).

¹³C NMR (125 MHz, CDCl3): δ = 9.3 (CH3), 16.31 (ArCH3), 16.33 (ArCH3′), 25.8 (d, J = 4.5 Hz, C-4), 27.5 (d, J = 15.9 Hz, C-3), 45.4 (d, J = 134.9 Hz, C-2), 52.8 (OCH3), 120.1 (d, J = 2.5 Hz, C-6′), 120.2 (d, J = 2.5 Hz, C-6′′), 125.34 (d, J = 1 Hz, C-4′), 125.35 (d, J = 1 Hz, C-4′′), 127.11 (d, J = 1.4 Hz, C-5′), 127.14 (d, J = 1.4 Hz, C-5′′), 129.18 (d, J = 5.9 Hz, C-2′), 129.24 (d, J = 5.9 Hz, C-2′′), 131.51 (d, J = 0.7 Hz, C-3′), 131.53 (d, J = 0.7 Hz, C-3′′), 140.79 (C-6), 148.82 (d, J = 1.3 Hz, C-1′), 148.9 (d, J = 1.3 Hz, C-1′′), 151.1 (C-5), 168.4 (d, J = 5.8 Hz, C-1), 194.9 (d, J = 2.2 Hz, C-7).

³¹P NMR (202 MHz, CDCl3): δ = 14.35-14.65 (m).

GC/MS (EI): m/z (%) = 431 (22) [M + H], 412 (8), 402 (10), 365 (7), 347 (51), 335 (12), 315 (33), 303 (16), 287 (8), 263 (72), 253 (12), 241 (28), 209 (26), 190 (14), 184 (27), 178 (28), 168 (21), 152 (12), 137 (25), 126 (32), 124 (14), 108 (32) [o-cresyl], 91 (100) [tolyl], 71 (28), 65 (18), 55 (38).

HRMS (ESI): m/z [M + H]+ calcd for C23H27O6PH+: 431.1618; found: 431.1614.

Methyl (5 E )-2-[Di( o -tolyl)oxyphosphoryl]-7,7-dimethoxy-6-methylhept-5-enoate (20a)

To a solution of 6a (250 mg, 0.53 mmol) in MeOH (8 mL) were added dimethoxypropane (1 mL, 8.16 mmol) and CSA (12 mg, 0.05 mmol) and the mixture was distilled to remove MeOH and acetone. Filtration through basic Al2O3 and evaporation gave 20a.

Yield: 257 mg (98%); pale-yellow oil.

FTIR (ATR): 3475 (w), 2974 (m), 2932 (m), 2829 (m), 1962 (w), 1738 (s), 1651 (m), 1585 (m), 1491 (s), 1453 (m), 1438 (m), 1382 (w), 1333 (m), 1273 (m), 1223 (s), 1181 (s), 1163 (s), 1106 (vs), 1071 (s), 1042 (s), 931 (vs), 859 (m), 806 (m), 757 (vs), 708 (m), 601 (m), 561 (m) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 1.58 (d, J = 1.4 Hz, 3 H, CH3), 2.14-2.40 (m, 3 H, H-2, H-4), 2.19 (s, 3 H, ArCH3), 2.24 (s, 3 H, ArCH3′), 3.27 (s, 3 H, OCH3), 3.28 (s, 3 H, OCH3′), 3.35 (ddd, J = 23.2, 11.2, 3.2 Hz, 1 H, H-2), 3.77 (d, J = 0.7 Hz, 3 H, CO2CH3), 4.45 (d, J = 0.6 Hz, 1 H, H-7), 5.53 (t, J = 6.7 Hz, 1 H, H-5), 7.02-7.12 (m, 4 H, H-5′, H-5′′, H-4′, H-4′′), 7.14-7.19 (m, 2 H, H-3′, H-3′′), 7.21-7.24 (m, 1 H, H-6′), 7.27-7.30 (m, 1 H, H-6′′).

¹³C NMR (125 MHz, CDCl3): δ = 11.2 (CH3), 16.3 (ArCH3), 16.4 (ArCH3′), 26.1 (d, J = 16.1 Hz, C-3), 26.6 (d, J = 4.8 Hz, C-4), 45.5 (d, J = 133.9 Hz, C-2), 52.7 (CO2CH3), 53.5 (OCH3), 53.6 (OCH3′), 107.4 (C-7), 120.1 (d, J = 2.6 Hz, C-6′), 120.2 (d, J = 2.1 Hz, C-6′′), 125.1 (C-4′), 125.2 (C-4′′), 126.8 (C-5), 127.0 (d, J = 1.3 Hz, C-5′), 127.1 (d, J = 1.3 Hz, C-5′′), 129.3 (d, J = 4.5 Hz, C-2′), 129.3 (d, J = 4.4 Hz, C-2′′), 131.4 (C-3′), 131.5 (C-3′′), 134.2 (C-6), 148.9 (d, J = 1.5 Hz, C-1′), 149 (d, J = 1.4 Hz, C-1′′), 168.6 (d, J = 5.8 Hz, C-1).

³¹P NMR (202 MHz, acetonitrile-d 3): δ = 15.77-16.14 (m).

GC/MS (EI): m/z (%) = 444 (12), 405 (3), 386 (2), 354 (3), 293 (4), 285 (2), 222 (7), 198 (3), 182 (36), 171 (5), 166 (5), 150 (12), 137 (3), 123 (100), 111 (22), 91 (22) [tolyl], 79 (18), 77 (17), 65 (4), 55 (6), 53 (10).

HRMS (ESI): m/z [M + Na]+ calcd for C25H33O7PNa+: 499.1856; found: 499.1849.

Methyl (5 Z )-2-[Di( o -tolyl)oxyphosphoryl]-6-(1,3-dithian-2-yl)hept-5-enoate (20b)

To a solution of 6a (100 mg, 0.21 mmol) in CH2Cl2 (10 mL), was added 1,3-propanedithiol (64 µL, 0.63 mmol) and Montmorillonite K10 (20 mg) and the mixture was stirred at r.t. for 6 h. Evaporation of the solvent yielded 20b.

Yield: 96 mg (88%); pale-yellow oil.

FTIR (ATR): 2948 (w), 2898 (w), 1738 (s), 1491 (s), 1461 (m), 1435 (m), 1274 (s), 1226 (s), 1166 (s), 1108 (s), 947 (s), 633 (s), 607 (w) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 1.78 (s, 3 H, CH3), 1.84 (dtt, J = 14, 12.2, 3.2 Hz, 1 H, Ha-2′), 2.10 (dtt, J = 14, 4.4, 2.5 Hz, 1 H, Hb-2′), 2.15-2.26 (m, 2 H, Ha-1′), 2.19 (d, J = 0.4 Hz, 3 H, Ar-CH3), 2.24 (d, J = 0.4 Hz, 3 H, Ar-CH3′), 2.3-2.38 (m, 2 H, Hb-1′), 2.82-2.88 (m, 2 H, H-3), 2.90-2.98 (m, 2 H, H-4), 3.36 (ddd, J = 23.4, 11, 3.1 Hz, 1 H, H-2), 3.77 (d, J = 0.4 Hz, 3 H, OCH3), 4.56 (d, J = 0.4 Hz, 1 H, H-7), 5.31 (tdd, J = 6.3, 1.3, 0.4 Hz, 1 H, H-5), 7.02-7.07 (m, 2 H, H-5′′, H-5′′′), 7.08-7.13 (m, 2 H, H-4′′, H-4′′′), 7.14-7.18 (m, 2 H, H-3′′, H-3′′′), 7.22-7.24 (m, 1 H, H-6′′), 7.27-7.29 (m, 1 H, H-6′′′).

¹³C NMR (125 MHz, CDCl3): δ = 15.1 (CH3), 16.4 (Ar-CH3), 16.4 (Ar-CH3′), 25.4 (C-2′), 26.5 (d, J = 4.8 Hz, C-4), 26.6 (d, J = 16.2 Hz, C-3), 31.5 (C-1′), 45.2 (d, J = 132 Hz, C-2), 52.7 (OCH3), 55.1 (C-7), 120.2 (d, J = 2.6 Hz, C-6′′), 120.3 (d, J = 2.6 Hz, C-6′′′), 125.15 (d, J = 1.3 Hz, C-4′′), 125.16 (d, J = 1.3 Hz, C-4′′′), 127.05 (d, J = 1.1 Hz, C-5′′), 127.06 (d, J = 1.1 Hz, C-5′′′), 127.24 (C-5), 129.29 (d, J = 1.4 Hz, C-2′′), 129.34 (d, J = 1.1 Hz, C-2′′′), 131.41 (C-3′′, C-3′′′), 135.42 (C-6), 148.92 (d, J = 3.0 Hz, C-1′′), 148.99 (d, J = 3.0 Hz, C-1′′′), 168.6 (d, J = 5.5 Hz, C-1).

³¹P NMR (202 MHz, CDCl3): δ = 14.91-15.43 (m).

GC/MS (EI): m/z (%) = 520 (2) [M]+, 461 (88), 445 (3), 413 (6), 401 (4), 381 (24), 353 (8), 315 (5), 303 (2), 273 (2), 245 (2), 230 (3), 227 (5), 197 (3), 183 (5), 167 (8), 151 (11), 147 (4), 127 (100), 111 (13), 99 (23), 91 (42), 79 (54), 77 (16), 65 (12), 60 (10), 55 (14).

HRMS (ESI): m/z [M + H]+ calcd for C26H33O5PS2H+: 521.1589; found: 521.1580.

Methyl (2 Z ,6 E )-8-(Methoxymethoxy)-6-methyl-2-[(3 E )-4-methyl-5-oxopent-3-enyl]-9-[(trimethylsilyl)methyl]deca-2,6,9-trienoate (4a)

To a solution of 20a (109 mg, 0.23 mmol) in THF (8 mL) were added NaI (45 mg, 0.29 mmol) and NaH (8 mg, 0.34 mmol) at 0 ˚C and the mixture was stirred at r.t. for 15 min. The yellow solution was cooled to -20 ˚C and a solution of 16 (65 mg, 0.23 mmol) in THF (2 mL) was added dropwise. The reaction mixture was warmed to r.t. over 7 h and quenched by addition of aqueous NaH2PO4/NaOH buffer (0.1 M, 5 mL, pH 7). The aqueous layer was extracted with CH2Cl2 (3 × 50 mL) and the combined organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on Florisil (hexanes-EtOAc, 6:1) to yield 21a (86 mg, 79% crude) as a colourless oil (E/Z = 17:83 by ¹H NMR analysis), which contained 4a (15% assessed by ¹H NMR analysis). The product mixture was dissolved in CH2Cl2 (10 mL), Dowex 50 × 8 (30 mg) was added and the mixture was stirred at r.t. for 10 min to give 4a after filtration and evaporation.

Yield: 78 mg (78%); colourless oil.

FTIR (ATR): 2951 (m), 2927 (m), 2709 (w), 2571 (w), 2365 (w), 2187 (w), 1967 (w), 1714 (s), 1686 (vs), 1643 (m), 1506 (w), 1436 (m), 1378 (m), 1246 (s), 1195 (s), 1149 (s), 1117 (s), 1093 (s), 1035 (s), 975 (m), 959 (m), 917 (w), 839 (vs), 770 (m), 694 (m), 634 (w), 525 (w) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 0.04 (s, 9 H, TMS), 1.38 (dd, J = 5.0, 1.1 Hz, 1 H, CH 2TMS-Ha), 1.57 (dd, J = 5.0, 1.1 Hz, 1 H, CH 2TMS-Hb), 1.71 (d, J = 1.4 Hz, 3 H, 4′-CH3), 1.72 (d, J = 1.4 Hz, 3 H, 6-CH3), 2.15 (td, J = 7.5, 0.9 Hz, 2 H, H-5), 2.41-2.39 (m, 4 H, H-1′, H-2′), 2.58-2.63 (m, 2 H, H-4), 3.36 (s, 3 H, OCH3), 3.75 (s, 3 H, CO2CH3), 4.58 (dd, J = 25.1, 6.6 Hz, 2 H, H-2′′), 4.67-4.68 (m, 1 H, H-8), 4.96 (dd, J = 1.9, 1.2 Hz, 2 H, H-10), 5.08 (dq, J = 9.2, 1.4 Hz, 1 H, H-7), 5.93 (tt, J = 7.3, 2.1 Hz, 1 H, H-3), 6.44 (tq, J = 7.3, 1.4 Hz, 1 H, H-3′), 9.39 (s, 1 H, H-5′).

¹³C NMR (125 MHz, CDCl3): δ = -1.2 (TMS), 9.2 (CH3′), 16.5 (CH3), 22.6 (CH2TMS), 27.8 (C-1′), 28.7 (C-4), 33.4 (C-2′), 39.1 (C-5), 51.4 (CO2 CH3), 55.3 (OCH3), 74.5 (C-8), 93.1 (C-2′′), 108.2 (C-10), 124.9 (C-7), 130.5 (C-2), 139.3 (C-6), 139.9 (C-4′), 143.2 (C-3), 146.2 (C-9), 153.2 (C-3′), 167.8 (C-1), 195.2 (C-5′).

HRMS (ESI): m/z [M + Na]+ calcd for C24H40NaO5Si+: 459.6467; found: 459.6470.

Methyl (2 Z ,6 E )-2-[(3 E )-4-(1,3-Dithian-2-yl)pent-3-enyl]-8-(methoxymethoxy)-6-methyl-9-[(trimethylsilyl)methyl]deca-2,6,9-trienoate (21b)

To a solution of 20b (56 mg, 0.09 mmol) in THF (5 mL) were added NaI (12 mg, 0.08 mmol) and NaH (2 mg, 0.09 mmol) at 0 ˚C and the mixture was stirred for 10 min. After warming to r.t. for 20 min, the yellow solution was cooled to -20 ˚C and a solution of 16 (23 mg, 0.09 mmol) in THF (3 mL) was added dropwise. The mixture was warmed to r.t. over 7 h and diluted with sat. NH4Cl (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on SiO2 (hexanes-EtOAc, 5: 1) to yield 21b.

Yield: 20 mg (47%); colourless oil (E/Z = 17:83 by ¹H NMR analysis); R f  = 0.50 (hexanes-EtOAc, 5:1).

FTIR (ATR): 2949 (m), 2897 (m), 2559 (w), 2371 (w), 2184 (w), 1966 (w), 1715 (s), 1683 (m), 1637 (w), 1506 (w), 1435 (m), 1379 (w), 1246 (s), 1195 (m), 1148 (s), 1093 (m), 1033 (vs), 977 (m), 957 (m), 914 (m), 881 (m), 839 (vs), 770 (m), 693 (m), 634 (w), 621 (w), 528 (w), 511 (w) cm-¹.

¹H NMR (500 MHz, CDCl3): δ = 0.04 (s, 9 H, TMS), 1.38 (ddd, J = 13.9, 1.1, 0.3 Hz, 1 H, CH 2TMS-Ha), 1.58 (ddd, J = 14.1, 1.1, 0.3 Hz, 1 H, CH 2TMS-Hb), 1.71 (d, J = 1.4 Hz, 3 H, CH3′), 1.75 (dt, J = 1.4, 0.8 Hz, 3 H, CH3), 1.78-1.87 (m, 1 H, Ha-8′), 2.07-2.13 (m, 1 H, Hb-8′), 2.14-2.18 (m, 4 H, H-5, H-1′), 2.26-2.30 (m, 2 H, H-2′), 2.56-2.62 (m, 2 H, H-4), 2.82-2.87 (m, 2 H, H-7′), 2.91-2.98 (m, 2 H, H-7′), 3.36 (s, 3 H, OCH3), 3.74 (s, 3 H, CO2CH3), 4.55 (s, 1 H, H-5′), 4.59 (dd, J = 26.2, 7.1 Hz, 2 H, H-2′′), 4.62-4.65 (m, 1 H, H-8), 4.68 (dd, J = 1.8, 0.8 Hz, 1 H, H-10a), 4.97 (dd, J = 1.8, 1.1 Hz, 1 H, H-10b), 5.09 (dq, J = 9.2, 1.3 Hz, 1 H, H-7), 5.6 (tdd, J = 7.2, 1.4, 0.7 Hz, 1 H, H-3′), 5.87 (tt, J = 7.3, 1 Hz, 1 H, H-3).

¹³C NMR (125 MHz, CDCl3): δ = -1.1 (TMS), 15.1 (CH3′), 16.5 (CH3), 22.5 (CH2TMS), 25.5 (C-8′), 27.7 (C-1′), 27.8 (C-4), 31.6 (C-7′), 34.1 (C-2′), 39.2 (C-5), 51.2 (CO2 CH3), 55.3 (C-5′), 74.5 (C-8), 93.1 (C-2′′), 108.1 (C-10), 124.7 (C-7), 128.7 (C-3′), 131.1 (C-4′), 133.8 (C-2), 139.6 (C-6), 142.6 (C-3), 146.3 (C-9), 168.2 (C-1).

GC/MS (CI, CH4): m/z (%) = 526 (5) [M]+, 495 (4), 481 (12), 465 (32), 375 (6), 359 (8), 285 (5), 225 (4), 179 (24), 173 (11), 149 (6), 119 (10), 106 (25), 89 (34), 73 (100) [TMS], 61 (32), 45 (62).

HRMS (ESI): m/z [M + H]+ calcd for C27H46O4S2Si+: 527.2680; found: 527.2670.

Ethyl (2 Z ,6 E )-2-[2-(1,3-Dioxan-2-yl)ethyl]-8-(methoxymeth­oxy)-6-methyl-9-[(trimethylsilyl)methyl]deca-2,6,9-trienoate (23)

A solution of 22 (43 mg, 0.16 mmol) in THF (1 mL) was added dropwise to a suspension of NaH (4 mg, 0.16 mmol) in THF (3 mL) at 0 ˚C and the mixture was stirred for 30 min. Then 16 (50 mg, 0.18 mmol) in THF (50 µL) was added and the mixture was kept at 0 ˚C for 4 h, then warmed to 15 ˚C over 8 h, hydrolyzed with sat. NH4Cl (10 mL) and diluted with EtOAc (20 mL). After warming to r.t. and extracting with EtOAc (3 × 20 mL), the organic layer was washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography (hexanes-EtOAc, 3:1) to yield 23.

Yield: 59 mg (86%); colourless oil (E/Z = 50:50 by ¹H NMR analysis); R f  = 0.48 (hexanes-EtOAc, 3:1).

FTIR (ATR): 2953 (m), 2849 (m), 1960 (w), 1708 (s), 1638 (m), 1447 (m), 1378 (m), 1243 (s), 1192 (s), 1138 (vs), 1091 (s), 1032 (vs), 976 (m), 945 (m), 917 (m), 885 (m), 839 (vs), 769 (m), 724 (w), 694 (m), 634 (m), 588 (w), 565 (w), 546 (m), 526 (m) cm-¹.

(2Z)-23

¹H NMR (500 MHz, CDCl3): δ = 0.4 (s, 9 H, TMS), 1.28 (t, J = 7.1 Hz, 3 H, CO2CH2CH 3), 1.33 (dq, J = 13.5, 1.3 Hz, 1 H, Ha-6′), 1.39 (ddd, J = 14.1, 5.1, 1.0 Hz, 1 H, CH 2TMS-Ha), 1.58 (dd, J = 14.1, 1.0 Hz, 1 H, CH 2TMS-Hb), 1.68-1.71 (m, 2 H, H-2′), 1.71 (d, J = 1.3 Hz, 3 H, CH3), 2.02-2.11 (m, 1 H, Hb-6′), 2.12-2.2 (m, 2 H, H-5), 2.56-2.61 (m, 4 H, H-1′, H-4), 3.36 (s, 3 H, OCH3), 3.70-3.77 (m, 2 H, Ha-5a′, Ha-5b′), 4.06-4.11 (m, 2 H, Hb-5a′, Hb-5b′), 4.18 (q, J = 7.1 Hz, 2 H, CO2CH2), 4.47 (t, J = 5.3 Hz, 1 H, H-3′), 4.56 (dd, J = 6.7, 1.7 Hz, 1 H, Ha-2′′), 4.62 (dd, J = 6.7, 4.1 Hz, 1 H, Hb-2′′), 4.62-4.66 (m, 1 H, H-8), 4.68 (dd, J = 1.9, 0.8 Hz, 1 H, H-10a), 4.96 (dd, J = 1.9, 1.2 Hz, 1 H, H-10b), 5.11 (dq, J = 9.2, 1.3 Hz, 1 H, H-7), 5.86 (tt, J = 7.4, 1.1 Hz, 1 H, H-3).

¹³C NMR (125 MHz, CDCl3): δ = 14.3 (CO2CH2 CH3), 16.5 (CH3), 22.6 (C-10), 25.8 (C-6′), 26.6 (C-1′), 27.8 (C-4), 34.3 (C-18), 39.3 (C-5), 55.4 (OCH3), 60.4 (CO2 CH2), 66.9 (C-20, C-22), 74.5 (C-8), 93.2 (C-12), 101.7 (C-19), 108.3 (C-11), 124.7 (C-7), 131.7 (C-2), 139.6 (C-6), 141.5 (C-3), 146.3 (C-9), 167.8 (C-1).

MS (ESI): m/z = 486.21, 407.26, 361.22, 331.21, 305.19, 285.17, 259.16, 213.13, 185.13, 159.12, 131.09, 113.06.

HRMS (ESI): m/z [M + Na]+ calcd for C25H44O6SiNa+: 491.2799; found: 491.2800.

(2E)-23

¹H NMR (500 MHz, CDCl3): δ = 0.42 (s, 9 H, TMS), 1.28 (t, J = 7.1 Hz, 3 H, CO2CH2CH 3), 1.33 (dq, J = 13.5, 1.3 Hz, 1 H, Ha-6′), 1.39 (ddd, J = 14.1, 5.1, 1.0 Hz, 1 H, CH 2TMS-Ha), 1.58 (dd, J = 14.1, 1.0 Hz, 1 H, CH 2TMS-Hb), 1.68-1.71 (m, 2 H, H-2′), 1.73 (d, J = 1.3 Hz, 3 H, CH3), 2.02-2.11 (m, 1 H, Hb-6′), 2.12-2.2 (m, 2 H, H-5), 2.30-2.37 (m, 2 H, H-4), 2.39 (t, J = 0.8 Hz, 2 H, H-1′), 3.37 (s, 3 H, OCH3), 3.7-3.77 (m, 2 H, Ha-5a′, Ha-5b′), 4.06-4.11 (m, 2 H, Hb-5a′, Hb-5b′), 4.19 (q, J = 7.1 Hz, 2 H, CO2CH2), 4.49 (t, J = 5.3 Hz, 1 H, H-3′), 4.56 (dd, J = 6.7, 1.7 Hz, 1 H, H-2a′′), 4.62 (dd, J = 6.7, 4.1 Hz, 1 H, H-2b′′), 4.62-4.66 (m, 1 H, H-8), 4.68 (dd, J = 1.9, 0.8 Hz, 1 H, H-10a), 4.97 (dd, J = 1.9, 1.2 Hz, 1 H, H-10b), 5.08 (dq, J = 9.2, 1.3 Hz, 1 H, H-7), 6.73 (tt, J = 7.4, 1.1 Hz, 1 H, H-3).

¹³C NMR (125 MHz, CDCl3): δ = 14.3 (CO2CH2 CH3), 16.6 (CH3), 21.4 (C-1′), 22.5 (CH2TMS), 25.8 (C-6′), 29.1 (C-4), 34.5 (C-2′), 38.6 (C-5), 55.3 (OCH3), 60.2 (CO2 CH2), 66.9 (C-5′a, C-5′b), 74.5 (C-8), 93.1 (C-2′′), 101.7 (C-3′), 108.1 (C-10), 124.9 (C-7), 132.1 (C-2), 139.2 (C-6), 142.0 (C-3), 146.2 (C-9), 167.6 (C-1).

Acknowledgment

We gratefully acknowledge the Deutsche Forschungsgemeinschaft (SFB 706), the Institute for Physical Chemistry and the Ministerium für Wissenschaft, Forschung und Kunst des Landes Baden-Württemberg (Landesgraduierten fellowship for C.G.) for generous financial support. We would like to thank Prof. Pikho, Helsinki University of Technology for helpful discussions and suggestions and Daniel Pötzsch and Markus Mansueto for skillful technical assistance.

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