Transmissive Olefination Route to Putative \xe2\x80\x9cMorinol I\xe2\x80\x9d Lignans
A series of morinol-type lignans were rapidly assembled using a Grignard-based transmissive olefination. In combination with palladium-catalyzed arylations, the strategy provides stereoselective access to (7Z, 7\xe2\x80\xb2E), (7E, 7\xe2\x80\xb2E), (7E, 7\xe2\x80\xb2Z) morinol diastereomers and the (7Z, 8\xe2\x80\xb2E) and (7E, 8\xe2\x80\xb2E) conjugated analogs. Critical for the E/Z-stereoselectivity is a new, general method for converting alkenenitriles to alkenemethanols that circumvents the enal E/Z isomerization commonly encountered during conventional i-Bu2AlH reduction.
<!>(2Z, 4E)-2-(3, 4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-4-enamide (24)<!>tert-Butyl(2Z,4E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-4-enoylcarbamate (25)<!>(2Z, 4E)-2-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-4-en-1-ol (7Z, 7\xe2\x80\xb2E)-7<!>(2Z, 4E)-2-(3, 4-Dimethoxybenzylidene)-5-(trimethylsilyl)pent-4-enenitrile (26)<!>(2Z, 4Z)-2-(3,4-Dimethoxybenzylidene)-5-iodopent-4-enenitrile (27)<!>(2Z, 4Z)-2-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-4-enenitrile (28)<!>(2Z, 4Z)-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-dimethoxyphenyl)pent-4-enamide (i)<!>tert-Butyl((2Z,4Z)-2-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-4-enoyl)carbamate (ii)<!>(1Z, 4Z)-1,5-Bis(3,4-dimethoxyphenyl)penta-1,4-dien-2-ol (7Z, 7\xe2\x80\xb2Z)-7<!>(2E,4Z)-4-cyano-5-(3,4-dimethoxyphenyl)penta-2,4-dien-1-yl acetate (29)<!>(2Z,3E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-3-enenitrile (31)<!>(2Z,4E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-4-enamide (iii)<!>tert-butyl ((2Z,3E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-3-enoyl)carbamate (iv)<!>(2Z,3E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-3-en-1-ol (7Z, 9\xe2\x80\xb2E)-32<!>(2E,3E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)pent-3-en-1-ol (7Z, 9\xe2\x80\xb2E)-32 and (7E, 9\xe2\x80\xb2E)-32
<p>Alkenenitrile pharmacophores are embedded within an array of pharmaceuticals1 and natural products2 (Figure 1). In many instances the nitrile plays a key role in receptor binding as with the potent anti-HIV agent3 rilpivirine (1) where the nitrile groups interact deep within the binding pocket.4 Consistent with the key role of the nitrile group, E/Z-alkenenitrile diastereomers often exhibit significantly different potencies as exemplified by the antitumor agent 2.5 A similar interplay of substitution and E/Z-geometry influences the antitumor activity6 of calyculins A-H (3), unusual E- and Z-tetraenenitriles from the marine sponges Discodermia calyx and Lamellomorpha strongylata.2</p><p>Selective access to diastereomeric E- and Z-alkenenitriles is challenging.7 In addressing this challenge, a stereoselective synthesis of Z-alkenenitriles 6 was developed that hinges on an intramolecular transmissive olefination through a highly ordered transition structure (Scheme 1).8 Addition of excess Grignard reagent to Baylis-Hilman-derived9 hydroxyalkenenitriles 4 triggers a displacement that selectively affords Z-alkenenitriles 6. Mechanistic probes are consistent with a concerted reorganization through the magnesiate 5 in which the slender10 nitrile group preferentially eclipses the carbinol substituent R1.</p><p>Rapid access to Z-alkenenitriles from three readily available components, an aldehyde, acrylonitrile, and a Grignard reagent, appeared ideal for synthesizing, and unraveling the structural ambiguity of, the neolignan morinol I. Morinol I is one of a series of neolignans11 (Figure 2, 8-19) that were isolated during a bioactivity guided isolation of extracts from the roots of the traditional Chinese medicinal herb Morina chinensis.12 Among morinol metabolites the proposed structure 7 for morinol I is unique in having a skipped diene. All morinols, except morinol I, formally have water added to the C7-C8 bond. The related neolignan galanganal (15), isolated from the Zingiberaceae plant Alpinia galangal, has the same olefin position as 7 but the opposite C7 alkene geometry.13</p><p>Intriguingly, the HMBC and NOESY correlations reported for morinol I are not consistent with the skipped diene structure 7 but require a conjugated C7-C8 C9′-C8′ diene. Adding to the structural ambiguity is the secure structural identification of morinols A to D, through synthesis,14 which do contain a C7′-C8′ olefin. Unfortunately neither a sample nor spectral data of morinol I are available, leaving synthesis as the most promising method for determining the correct structure.15</p><p>The putative structure 7 of morinol I was rapidly assembled through a five-step sequence featuring a transmissive olefination (Scheme 2).8 Addition of excess vinylmagnesium bromide to the veratraldehyde-derived nitrile 209,16 afforded the Z-alkenenitrile 21 that was subjected to a palladium-catalyzed arylation14a with (3,4-dimethoxyphenyl)boronic acid (22) to provide 23. Conventional i-Bu2AlH reduction17 of nitrile 23, imine hydrolysis, and aldehyde reduction was irreproducible18 and gave varying ratios of lignan (7Z, 7′E)-7 and the diastereomer (7E, 7′E)-7. Neither (7Z, 7′E)-7 nor (7E, 7′E)-7 exhibit spectral data matching that of the natural product, although the NMR chemical shifts, such as the 1H NMR shift for H7, appeared more consistent with the Z-configuration of the C7 olefin.</p><p>Using the transmissive olefination strategy to prepare Z-C7 lignans corresponding to that of morinol I, requires a reproducible, stereoselective alkenenitrile to alkenol conversion. The stereoselective reduction of alkenenitriles to allylic alcohols is challenging because olefin isomerization can occur during the i-Bu2AlH reduction-hydrolysis sequence,19 in reversed nitrile hydrolysis-reduction sequences,20 and through isomerization of the resulting enal.21</p><p>After some exploratory forays,22 a stereoselective hydrolysis, acylation, reduction sequence was developed (Scheme 3). The sequence exploits the facile platinum-catalyzed hydrolysis of nitriles23 (23 → 24) and the selective reduction of imides.24 Despite a lack of precedent for the reduction of alkeneamides,25 a brief survey of reducing agents and solvent identified LiBH4 in THF as effective for reducing imide 25 to (7Z, 7′E)-alkenol 7 without any trace of the 7E-diastereomer.26</p><p>Having developed a robust method for controlling the stereochemistry of the C7 olefin, (7Z, 7′Z)-7 was targeted because the data reported for morinol I suggested either the geometry or position of the 7′Z-olefin was incorrect (Scheme 4). Key to the synthesis of (7Z, 7′Z)-7 was the serendipitous27 discovery that the trimethylsilylalkene 26, obtained through the transmissive olefination of 20 with trimethylsilylvinylmagnesium bromide (52%), underwent an efficient trimethylsilyl-iodine interchange with inversion of stereochemistry.28 Treating vinylsilane 26 with N-iodosuccinimide in 1:1 dichloromethane:hexafluoroisopropanol29 afforded the Z-iodide 2730 that was subjected to palladium-catalyzed coupling31 with (3,4-dimethoxyphenyl)boronic acid (22) to afford 28 with retention of configuration. Subjecting 28 to the three-step hydrolysis, acylation, and reduction efficiently provided (7Z, 7′Z)-7 with no erosion of olefin configuration.</p><p>Although morinol analog (7Z, 7′Z)-7 did not exhibit spectral data corresponding to that of the target, during the palladium-catalyzed coupling of 27, traces of a conjugated dienenitrile were generated which exhibited a 1H NMR methylene signal very similar to that reported for morinol I (δ 3.47 and 3.55, respectively). Attempts to isomerize the dienes (7Z, 7′Z)-28 and (7Z, 7′Z)-7 proved fruitless inspiring a new strategy based on the oxidative acetylation32 of 21. Using the 'original' oxidative acetylation protocol,32b nitrile 21 was smoothly transformed into (7Z, 8′E)-29 (Scheme 5). Palladium-catalyzed arylation of 29 with (3,4-dimethoxyphenyl)boronic acid (22) to afford (7Z, 8′E)-dienenitrile 31 proceeded best by employing the hydrazine ligand 30.33 A slight modification of the hydrolysis, imide formation, and reduction was required because the conventional Boc anhydride-DMAP procedure afforded the bis-Boc acylimidodicarbonate.34 Deprotonating the intermediate amide with BuLi and adding Boc anhydride afforded the requisite imide that was reduced without incident to the (7Z, 8′E)-alcohol 32. As a point of comparison, the sequential i-Bu2AlH reduction, imine hydrolysis, and NaBH4 reduction of nitrile 31 gave a 1:1 mixture of (7Z, 8′E)-32 and (7E, 8′E)-32. Although (7Z, 8′E)-32 exhibited several 1H NMR resonances similar to that of morinol, significant spectral differences are evident.</p><p>Graphing the 1H and 13C chemical shift differences between morinol I and the lignan diastereomers (7Z, 7′E)-7, (7E, 7′E)-7, (7E, 7′Z)-7, (7Z, 8′E)-32, and (7E, 8′E)-32 highlights the regions having the greatest discrepancy (Figure 3). Large differences in the 13C chemical shift exist for C9 and C9′ in the pentadiene fragment and for C1 of the aromatic ring.35 The 1H chemical shift values for the aromatic protons are quite similar whereas H7, H7′, and H9′ show pronounced differences relative to those reported for morinol I.35 The lack of clear chemical shift correlations of regions within the synthetic lignans compared to values reported for morinol I leave the exact identity of the natural product in doubt.</p><p>Morinol-type lignans are readily assembled through sequential transmissive olefinations and palladium-catalyzed couplings. The sequence generates diaryl pentadienes with excellent control over the E/Z geometry and features a new strategy for converting Z-dienenitriles into Z-allylic alcohols. In contrast to the conventional i-Bu2AlH reduction, imine hydrolysis, NaBH4 reduction of alkenenitriles, the platinum-catalyzed hydrolysis, imide formation, and reduction smoothly generates allylic alcohols without any observable isomerization. The versatility of the transmissive olefination and the new reduction strategy is illustrated in the synthesis of five morinol-type lignans in the quest to determine the structure of the elusive natural product morinol I.</p><!><p>Solid Parkins23 catalyst [bis(dimethylphosphinous acid-kP)dimethylphosphinyl-kP-hydridoplatinum(II)] (0.5 mg, 0.0075 mmol) was added to an ethanol/water solution (1:1, 20 mL) of 23 (54.8 mg, 0.15 mmol) and then the reaction mixture was heated to reflux. After 15 h, the solution was cooled, the solvent was evaporated, and then the residue was purified by radial chromatography (70% EtOAc in hexanes) to afford 50.0 mg (87%) of the amide 24 as a white solid (mp: 108–109 °C): IR (solid) 3416, 3338, 2935, 1672, 1518 cm−1; 1H NMR (CDCl3, 500 MHz): δ 3.31 (d, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 6H), 3.91 (s, 3H), 5.42 (s, 2H), 6.14 (dt, J = 16.0, 7.2 Hz, 1H), 6.47 (d, J = 16.0 Hz, 1H), 6.57 (s, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 2H), 6.90–6.97 (m, 4H); 13C NMR (CDCl3, 100 MHz): δ 39.8, 55.9, 56.0, 108.7, 111.0, 111.1, 111.3, 119.3, 121.3, 124.3, 128.3, 130.2, 130.3, 132.3, 135.3, 148.7, 148.9, 149.0, 172.1 ppm; HRMS for C22H25NO5 [M+Na+] calculated: 406.1631 found: 406.1619.</p><!><p>Solid di-tert-butyldicarbonate (43.4 mg, 0.20 mmol) and 4-dimethyaminopyridine (1.2 mg, 0.01 mmol) were added to a rt, CH2Cl2 solution (5mL) of 24 (40 mg, 0.10 mmol). After 20 h, the reaction mixture was poured into dichloromethane (10 mL), the phases were separated, the organic phase was combined and was then washed sequentially with 1M HCl (10 mL) and water (10 mL). The solvent was evaporated and the residue was then purified by radial chromatography (30% EtOAc in hexanes) to afford 35.3 mg (73 %) of imide 25 as a light yellow oil: IR (neat) 2979, 1777, 1601 cm−1, 1H NMR (CDCl3, 500 MHz): δ 1.43 (s, 9H), 3.31 (d, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 6.22 (dt, J = 11.6, 7.2 Hz, 1H), 6.51 (d, J = 11.6 Hz, 1H), 6.51 (s, 1H), 6.80–7.02 (m, 7H); 13C NMR (CDCl3, 100 MHz): δ 27.8, 38.4, 55.8, 55.9, 84.6, 108.7, 110.8, 111.0, 111.1, 119.4, 124.0, 128.1, 130.5, 130.7, 132.7, 133.5, 148.6, 148.7, 149.0, 149.3, 170.7 ppm; HRMS for C27H33NO7 [M+H+] calculated: 484.2336, found: 484.2325.</p><!><p>A THF solution (0.13 mL) of lithium triethylborohydride (0.13 mmol, 1 M ) was added to a rt, THF solution (5 mL) of 25 (30 mg, 0.06 mmol). After 2 h, an aqueous solution (10 mL) of 30% H2O2 was added. After 30 min, the aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated, and purified by radial chromatography (30% EtOAc in hexanes) to afford 16.0 mg (72%) of alcohol (7Z, 7′E)-7 as a light yellow oil: IR (neat) 3520, 2935, 1598 cm−1; 1H NMR (CDCl3, 400 MHz): δ 1.59 (broad s, 1H), 3.20 (d, J = 7.1 Hz, 2H), 3.88 (s, 6H), 3.89 (s, 3H), 3.91 (s, 3H), 4.34 (s, 2H), 6.20 (dt, J1 = 15.8 Hz, J2 = 7.1 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 6.50 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.95 (dd, J1 = 8.1 Hz, J2 = 2.0, 1H), 6.98 (d, J = 2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 39.5, 55.8, 55.9, 55.9, 61.3, 108.6, 110.9, 111.1, 112.0, 119.1, 121.2, 126.0, 129.4, 129.8, 130.4, 131.7, 138.5, 148.1, 148.5, 148.6, 149.0 ppm; HRMS for C22H26O5 [M+Na+] calculated: 393.1678, found: 393.1696.</p><!><p>Neat 1, 2-dibromoethane (0.01 mL, 0.07 mmol) was added to a suspension of Mg (22.4 mg, 0.89 mmol) in cold (0°C) THF (0.8 mL). Neat (E)-(2-(trimethylsilyl)vinyl) bromide (0.09 mL, 0.69 mmol) was added dropwise and after 1 h at 0 °C the THF solution of the resulting Grignard reagent was added to a −20 °C, THF solution (3 mL) of 2-((3, 4-dimethoxyphenyl)(hydroxy)methyl) acrylonitrile 209,16 (50 mg, 0.23 mmol). After 3 h, the reaction mixture was poured into aqueous, saturated NH4Cl (2 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated and purified by radial chromatography (15% EtOAc in hexanes) to afford 36.8 mg (52%) of nitrile 26 as a light yellow oil: IR (neat) 2954, 2206, 1600 cm−1,1H NMR (CDCl3, 500 MHz): δ −0.01 (s, 9H), 3.16 (d, J = 6.6 Hz, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 5.88 (d, J = 18.0 Hz, 1H), 6.04 (dt, J = 18.0, 6.6 Hz, 1H), 6.84 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.8, 1.8 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ −1.32, 42.7, 55.9, 106.2, 110.1, 110.7, 119.4, 123.3, 126.6, 134.7, 140.3, 143.9, 148.8, 150.5 ppm; HRMS for C17H23NO2Si: [M+H+] calculated 302.1577, found 302.1563.</p><!><p>Solid N-iodo succinimide (146.3 mg, 0.65 mmol) was added to a 0 °C 1,1,1,3,3,3-hexafluoroisopropanol and dichloromethane (1:1) solution (1.6 mL) of 26 (130 mg, 0.43 mmol). After 10 min, the reaction mixture was poured into an aqueous, saturated NH4Cl solution (2 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated, and purified by radial chromatography (15% EtOAc in hexanes) to afford 125 mg (82%) of nitrile 27 as a light yellow oil. IR (neat) 2934, 2206, 1597 cm−1; 1H NMR (CDCl3, 500 MHz): δ 3.26 (d, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.94 (s, 3H), 6.39 (dt, J =7.6, 7.6 Hz, 1H), 6.57 (dt, J = 7.6 Hz, 1.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 7.21 (dd, J = 8.4, 2.4 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 40.8, 55.9 (2), 86.6, 104.0, 110.2, 110.7, 119.2, 123.4, 126.3, 135.6, 144.3, 148.8, 150.7 ppm; HRMS for C14H14NO2I [M+Na+] calculated: 377.9967, found: 377.9944.</p><!><p>Solid (3,4-dimethoxyphenyl) boronic acid (87.8 mg, 0.46 mmol), palladium acetate (14.0 mg,0.06 mmol) and triphenyl phosphine (32.5 mg, 0.12 mmol) were added to a rt, THF solution (8 mL) of 27 (100.0 mg, 0.31 mmol). After 12 h, the reaction mixture was poured into water (2 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated, and purified by radial chromatography (30% EtOAc in hexanes) to afford 88.3 mg (78%) of nitrile 28 as a light yellow oil: IR (neat) 2931, 2206 cm−1; 1H NMR (CDCl3, 500 MHz): δ 3.39 (d, J = 7.8 Hz, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 5.72 (dt, J = 11.4, 7.2 Hz, 1H), 6.67 (d, J = 11.4 Hz, 1H), 6.83 (s, 1H), 6.85–6.89 (m, 3H), 6.91 (s, 1H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H); NOESY correlations between δ 5.72 and 6.67 established the Z-configuration of the disubstituted olefin; 13C NMR (CDCl3, 100 MHz): δ 34.7, 55.9 (2), 106.8, 110.3, 110.8, 111.0, 111.9, 119.5, 121.1, 123.2, 124.9, 126.6, 129.3, 132.5, 143.6, 148.3, 148.7, 149.0, 150.7 ppm; HRMS for C22H23NO4 [M+Na+] calculated:388.1525, found:388.1512.</p><!><p>Solid Parkins23 catalyst [bis(dimethylphosphinous acid-kP)dimethylphosphinyl-kP-hydridoplatinum(II)] (0.6 mg, 0.01 mmol) was added to an ethanol/water solution (1:1, 20 mL) of 28 (80 mg, 0.22 mmol) and then the reaction was heated to reflux. After 15 h, the solvent was evaporated and the residue was purified by radial chromatography (70% EtOAc in hexanes) to afford 95.1 mg (92%) of amide i as a white solid (mp: 101–102 °C): IR (solid) 3411, 3339, 2934, 2836, 1677, 1601 cm−1; 1H NMR (CDCl3, 400 MHz): δ 3.48 (d, J = 7.6 Hz, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 5.43 (s, 2H), 5.75 (dt, J = 11.6, 7.6 Hz, 1H), 6.59 (s, 1H), 6.61 (d, J = 11.6 Hz, 1H), 6.80–7.00 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ 34.1, 55.9 (2), 111.0, 111.3, 111.9, 121.2 (2), 126.3, 128.3, 129.8 (2), 131.4, 135.2, 148.1, 148.7, 148.8, 172.3 ppm; HRMS for C22H25NO5 [M+Na+] calculated: 406.1631, found: 406.1618.</p><!><p>Solid di-tert-butyl dicarbonate (136.8 mg, 0.63 mmol) and 4-dimethyamino pyridine (2.9 mg, 0.02 mmol) were added to a CH2Cl2, rt, solution (5 mL) of i (90 mg, 0.24 mmol). After 20 h the reaction mixture was poured into dichloromethane (10 mL) and washed sequentially with 1M HCl (10 mL) and water (10 mL). The solvent was evaporated and the residue was then purified by radial chromatography (30% EtOAc in hexanes) to afford 88.3 mg (76 %) of imide ii as a light yellow oil: IR (neat) 3296, 2930, 1766, 1686 cm−1; 1H NMR (CDCl3, 500 MHz): δ 1.38 (s, 9H), 3.45 (d, J = 7.8 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 5.73 (dt, J = 11.4, 7.2 Hz, 1H), 6.61 (d, J = 6.0 Hz, 1H), 6.62 (d, J = 6.0 Hz, 1H), 6.80–6.92 (m, 7H); 13C NMR (CDCl3, 100 MHz): δ 27.8, 33.6, 55.8, 55.9 (2), 82.7, 110.7, 110.8, 110.9, 111.6, 121.2, 125.6, 127.8, 129.6, 131.8, 134.6, 148.1, 148.6, 148.8, 149.0, 149.1 ppm; HRMS for C 27H33NO7 [M+Na+] calculated: 506.2155, found: 506.2155.</p><!><p>A THF solution (0.34 mL) of lithium triethylborohydride (0.34 mmol, 1 M) was added to a rt, THF solution (5 mL) of ii (80 mg, 0.17 mmol). After 2 h, an aqueous 30% solution (10 mL) of H2O2 was added. After 30 min, the aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated and purified by radial chromatography (30% EtOAc in hexanes) to afford 43.4 mg (69%) of alcohol (7Z, 7′Z)-7 as a light yellow oil: IR (neat) 3517, 2925, 1514 cm−1; 1H NMR (CDCl3, 400 MHz): δ 1.28 (s, 1H), 3.36 (d, J = 7.6 Hz, 2H), 3.88 (s, 6H), 3.89 (s, 3H), 3.91 (s, 3H), 4.35 (s, 2H), 5.82 (dt, J1 = 11.6 Hz, J2 = 7.6 Hz, 1H), 6.51(s, 1H), 6.66 (d, J = 11.6 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.89 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.93 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 400 MHz): δ 34.7, 55.9 (3), 77.2, 110.9, 111.9, 112.0, 121.1, 121.2, 128.0, 129.0, 130.0, 131.0, 138.7, 148.0 ppm; HRMS for C22H26O5 [M+Na+] calculated: 393.1678, found: 393.1691.</p><!><p>Solid 1, 4 benzoquinone (37.7 mg, 0.35 mmol), palladium acetate (4.0 mg, 0.02 mmol) and 4Å MS were added to a DMSO/AcOH solution (1:1, 5 mL) of 21 (40 mg, 0.17 mmol). The reaction was maintained at 40 °C under an air atmosphere using an air-filled balloon to maintain a slight positive pressure. After 72 h the reaction mixture was poured into EtOAc (10 mL), the phases were separated, the organic phase was washed with water (3 × 5 mL), dried (Na2SO4), concentrated, and purified by radial chromatography (20% EtOAc in hexanes) to afford 203 mg (67%) of nitrile 29 as a light yellow oil: IR (neat) 2254 cm−1; 1H NMR (CDCl3, 400 MHz): δ 2.14 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 4.74 (d, J = 6.0 Hz, 2H), 6.25 (dt, J = 15.8 Hz, 6.0 Hz, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.74 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 7.01 (s, 1H), 7.27 (dd, J = 8.6 Hz, 2.2 Hz, 1H) 7.63 (d, J = 2.2 Hz, 1H); 13C NMR (CDCl3, 400 MHz): δ 21.0, 56.0, 63.8, 107.0, 110.6, 110.9, 116.2, 116.8, 124.5, 126.4, 127.0, 130.8, 144.4, 149.1, 151.4, 170.7 ppm; HRMS for C16H17NO4K [M+K+] calculated: 326.0789, found: 326.0820.</p><!><p>Solid (3,4-dimethoxyphenyl)boronic acid (115 mg, 0.63 mmol) was added to a rt, DMF (1.5 mL) and H2O (0.5 mL) solution of 29 (150 mg, 0.522 mmol), K2CO3 (144 mg, 1.044 mmol), Pd(OAc)2 (2.33 mg, 0.01 mmol), and ligand (N,N′E,N,N′E)-N,N′-(ethane-1,2-diylidene)bis(piperidin-1-amine)36 (2.31 mg, 0.01 mmol). After 1 h, the mixture was diluted with EtOAc and H2O (10 mL, 1:1). The organic layer was separated, the aqueous phase was extracted with EtOAc (2 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated, and purified by radial chromatography (30% EtOAc in hexanes) to afford 116 mg (61%) of 31 as a white solid (mp 102–104 °C): IR: 1025, 1144, 1265, 1514, 1554, 1627, 2214, 2836, 2934 cm−1; 1H NMR (CDCl3, 400 MHz): δ 3.49 (d, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 6.10 (d, J = 15.3 Hz, 1H), 6.38 (dt, J = 15.3, 6.8 Hz, 1H),6.72–6.77 (m, 2H), 6.83–6.89 (m, 3H), 7.22 (dd, J = 8.4, 2.3 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H) ppm; 13C NMR (CDCl3, 400 MHz): δ 38.4, 55.9, 56.0, 108.1, 110.5, 110.9, 111.4, 112.0, 117.2, 120.7, 123.9, 126.8, 128.4, 131.6, 133.9, 142.2, 147.7, 149.0, 150.9 ppm; HRMS for C22H23NO4 [M+Na+] calculated: 388.1519, found: 388.1521.</p><!><p>Solid Parkins23 catalyst (bis(dimethylphosphinous acid-kP)dimethylphosphinyl-kP-hydridoplatinum(II)) (4.5 mg, 0.5 mol%, 0.01 mmol) was added to an ethanol-water (1:1, 20 mL) solution of 31 (75 mg, 0.21 mmol) and then the reaction was heated to reflux. After 15 h, the solvent was evaporated and the residue was purified by radial chromatography (70% EtOAc in hexanes) to afford 74 mg (94%) of the amide iii as a white solid (mp: 144–146 °C): IR: 3412, 3338, 1677 cm−1; 1H NMR (CDCl3, 400 MHz): δ 3.45 (d, J = 4.8 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 3.88 (s, 6H), 5.56 (br, s, 1H), 5.60 (br, s, 1H), 6.08–6.14 (m, 2H), 6.39 (s, 2H), 6.72–6.75 (m, 2H), 6.80–6.82 (m, 2H), 6.99–7.04 (m, 2H) ppm; 13C NMR (CDCl3, 400 MHz): δ 38.8, 55.8, 55.9, 56.0, 111.0, 111.2, 111.3, 112.1, 120.7, 121.8, 128.1, 129.5, 130.2, 132.1, 135.0, 147.5, 148.8, 148.9, 149.1, 171.5 ppm; HRMS for C22H25NO5 [M+Na+] calculated: 406.1625, found: 406.1632.</p><!><p>A cyclohexane solution of BuLi (2.0 M, 0.156 mmol) was added, drop-wise, to a −78 °C, THF (3 mL) solution of iii (60 mg, 0.156 mmol). After 1 h, a THF (1.0 mL) solution of di-tert-butyl dicarbonate (34 mg, 0.156 mmol) was added, and the reaction mixture was then allowed to warm slowly to room temperature. After 16 h saturated, aqueous ammonium chloride (3 mL) was added followed by H2O (5 mL). The organic layer was separated, the aqueous phase was extracted with EtOAc (2 × 10 mL), and the combined organic phase was washed with brine, dried (Na2SO4), concentrated, and purified by radial chromatography (50% EtOAc in hexanes) to afford 52 mg (68%) of iv as a pale yellow gummy liquid: IR: 3280, 2934, 1767, cm−1; 1H NMR (CDCl3, 400 MHz): δ 1.39 (s, 9H), 3.44 (d, J = 5.8 Hz, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 5.94–6.0 (m, 1H), 6.13 (d, J = 15.6 Hz, 1H), 6.44 (s, 1H), 6.71–6.74 (m, 2H), 6.79–6.82 (m, 2H), 6.90–6.93 (m, 2H), 7.30 (s, 1H) ppm; 13C NMR (CDCl3, 400 MHz): δ 27.8, 38.8, 55.83, 55.89, 55.92, 55.98, 56.0, 82.9, 110.7, 111.1, 111.3, 112.1, 120.7, 132.0, 134.3, 136.0, 147.6, 148.9, 149.1, 149.3 ppm; HRMS for C27H33NO7 Na [M+Na+] calculated: 506.2149, found: 506.2142.</p><!><p>A THF solution (5 mL) of lithium triethylborohydride (0.17 mL, 0.17 mmol) was added to a 0 °C, THF solution (3 mL) of iv (40 mg, 0.083 mmol) and then the solution was allowed to warm slowly to rt. After 2 h, an aqueous 30% solution of H2O2 (6 mL) was added. After 30 min, the aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated and purified by radial chromatography (30% EtOAc in hexanes) to afford 19 mg (62%) of (7Z, 9′E)-32 as a light yellow oil: IR: 1023, 1138, 1232, 1258, 1511, 1593, 1709, 2835, 2932, 3510 cm−1; 1H NMR (CDCl3, 400 MHz): δ 3.47 (d, J = 6.5 Hz, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 4.47 (br, d, 2H), 6.11 (dt, J1 = 15.8 Hz, J2 = 6.5 Hz, 1H), 6.20 (d, J = 15.8 Hz, 1H), 6.58 (s, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.77 (dd, J1 = 8.0 Hz, J2 = 2.0, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.97 (dd, J1 = 8.3 Hz, J2 = 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H) ppm; 13C NMR (CDCl3, 400 MHz): δ 39.1, 55.87, 55.90, 55.92, 55.98, 58.3, 111.0, 111.3, 112.0, 112.2, 120.5, 121.7, 129.1, 129.6, 132.7, 133.1, 133.3, 136.4, 147.5, 148.5, 148.7, 149.0 ppm; HMBC correlation of the 1H NMR hydroxymethyl signal at δ 3.47 with the olefinic 13C signals at δ 133.3, 136.4 confirm that the olefins are conjugated; HRMS for C22H26O5Na [M+Na+] calculated: 393.1672, found: 393.1697.</p><!><p>A cyclohexane solution of diisobutylaluminum hydride (1.0 M, 0.58 mmol) was added drop-wise to a −78 °C, toluene (4 mL) solution of 31 (100 mg, 0.274 mmol). The cooling bath was removed and the reaction allowed to slowly warm to rt. After 3 h the reaction mixture was cooled to −78 °C and ethanol (1 mL) and aqueous acetic acid (50%, 1 mL) were added sequentially. After 15 min. the solution was allowed to warm to rt, the organic layer was separated, the aqueous phase was extracted with EtOAc (2 × 10 mL), the combined organic phase was washed with water, aqueous NaHCO3, and brine, and then dried (Na2SO4), and concentrated to give the corresponding aldehyde (96 mg). The crude aldehyde (96 mg) was dissolved in methanol (7 mg, 0.30 mmol) at room temperature and solid NaBH4 was then added portion-wise. After 15 min. saturated, aqueous ammonium chloride (2 mL) was added, followed by water. The crude mixture was extracted with EtOAc (2 × 10 mL), the combined organic phase was washed with brine, dried (Na2SO4), concentrated, and purified by radial chromatography (35% EtOAc in hexanes) to afford 57 mg (56%) of a 1:1 mixture of alcohols (7Z, 9′E)-32 and (7E, 9′E)-32 as a pale yellow oily liquid. For (7E, 9′E)-32: IR: 3504, 2933, 1592 cm−1; 1H NMR (CDCl3, 400 MHz): δ 3.42 (d, J = 6.9 Hz, 2H), 3.86 (s, 9H), 3.90 (s, 3H), 4.44 (br, d, J = 2.8 Hz, 2H), 6.12 (dt, J1 = 16.2 Hz, J2 = 6.9 Hz, 1H), 6.56 (d, J = 16.2 Hz, 1H), 6.58 (s, 1H), 6.71 (s, 1H), 6.73 (d, J = 8.5, 1H), 6.82 (d, J = 8.5, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.86 (s, 1H) ppm; 13C NMR (CDCl3, 400 MHz): δ 39.4, 55.8, 55.9, 55.9, 56.0, 110.86, 111.3, 111.9, 112.6, 120.4, 122.2, 126.9, 128.2, 129.7, 131.3, 132.6, 136.1, 147.5, 148.2, 149.0 ppm; HRMS for C22H26O5Na [M+Na+] calculated: 393.1672, found: 393.1704.</p>