Synthesis of 1,2-Dihydroisoquinolines by a Modified Pomeranz-Fritsch Cyclization
Isoquinolines (IQs) and their derivatives are present in many natural products and biologically active small molecules. Herein, we report a modified procedure for the classical Pomeranz-Fritsch protocol, which expands the scope of 1,2-dihydroisoquinoline (DHIQs) products. 1,2-DHIQs are an attractive branch point for the synthesis of IQs, but because of their innate reactivity, they have remained difficult to prepare. We demonstrate that the Fujioka/Kita conditions, combining trimethylsiyltriflate (TMSOTf) and an amine base, activate dimethylacetals required for Pomeranz-Fritsch cyclization under sufficiently mild conditions to prepare a broad range of 1,2-DHIQ products. We also demonstrate the synthetic value of these DHIQs by further functionalization to either reduced tetrahydroisoquinoline (THIQ) or fully aromatized IQ natural products.Scheme 2. Synthetic Derivatization. Conditions and reagents: a) 10 wt% Pd/C, H2 (10 psi), MeOH; b) LiAlH4 (3 equiv.), Et2O, reflux, 63% over 2 steps; c) KO t Bu (3 equiv.), DMSO, rt, 50%; d) OsO4 (2 mol%), NMO (1.5 equiv.), Me2CO/ t BuOH/H2O, rt, 76%, > 20:1 dr.Experimental procedures, characterization data, copies of NMR spectra (PDF)
<!>Supporting Information<!>General Experimental<!>Condition Optimization<!>/ 43<!>Characterization of 3:<!>Yield of Product:<!>Characterization:<!>Yield of Product:<!>Characterization:<!>Compound 2h<!>Yield of Product:<!>Characterization:<!>Compound 2i<!>Yield of Product:<!>Characterization:<!>Yield of Product:<!>Characterization:<!>Compound 2k<!>Yield of Product:<!>Characterization:<!>/ 43<!>Compound 2l<!>Yield of Product:<!>Characterization:<!>Yield of Product:<!>Characterization:<!>Compound 2n<!>Yield of Product:<!>Characterization:<!>Compound 2o<!>Modification (work up):<!>Compound 2p<!>Yield of Product:<!>Characterization:<!>b) Synthesis and Characterization of Compounds in Scheme 2 Compound 8<!>Characterization:<!>Compound 9<!>Characterization:<!>/ 43<!>Compound 1a<!>/ 43<!>Compound 1a-4-Ns<!>/ 43<!>Characterization:<!>Compound 1a-2-Ns<!>Characterization:<!>/ 43<!>Characterization:<!>Compound 1a-Cbz<!>/ 43<!>Compound 1a-Ac<!>Characterization:<!>/ 43 Compound S15<!>Characterization:<!>Compound S16<!>/ 43<!>Compound 1l<!>Yield of Product:<!>Characterization:<!>/ 43 Compound S17<!>Compound 1m<!>Amounts of Reagents:<!>Yield of Product:<!>Characterization:<!>Compound S18<!>Characterization:<!>Compound 1n<!>Amounts of Reagents:<!>Yield of Product:<!>Characterization:<!>/ 43 Compound 1o<!>Characterization:<!>Compound 1p<!>Characterization:<!>Compound 1q<!>Amounts of Reagents:<!>Yield of Product:<!>Characterization:<!>/ 43
<p>Isoquinoline alkaloids contain heterocyclic motifs that are commonly found in biologically active small molecules (Scheme 1A). 1 The scaffold appears most commonly in two discrete redox tautomeric forms that constitute a formal 4e  | 4H + redox couple. These are the fully saturated 1,2,3, or the aromatized isoquinonlines (IQs) (Scheme 1A). 2 The intermediary dihydroisoquinonlines (DHIQs) can exist as either 1,2-or 3,4-dihydro-isomers, and while they are less commonly encountered as natural products, both isomers have been the targets of previous synthetic studies. 3 3,4-DHIQs are immediate products from the classic Bischler-Napieralski synthesis, 4 and are well-known synthetic precursors to enantiomerically pure 1-substituted THIQs by asymmetric hydrogenation. 5 By comparison, the synthesis and isolation of 1,2-DHIQs is less well-developed, 6 despite their importance as intermediates in the synthesis of alkaloid natural products, including the pavines (Scheme 1B, right). 7  Classical methods for their preparation include the Pomeranz-Fritsch cyclization of benzylamine dimethyl acetals (Scheme 1C). 3,8 However, the enamine of the 1,2-DHIQ product can be unstable under these conditions, and it is common for either acid-mediated elimination 8c or disproportionation 6 to lead to mixtures of IQ and THIQ (Scheme 1B,left). This has limited the scope of the Pomeranz-Fritsch, which typically requires strong aqueous acid (6M) and reaction temperatures in excess of 100 o C under Jackson's typical conditions. 8c Modifications have been reported, including Perchonock's 9 use of excess aluminum trichloride (AlCl3, >4 equiv.) at room temperature, and Miranda's 10 use of triflouoroacetic acid as a solvent at 50 o C. However, in spite of these adjustments, Pomeranz-Fritsch reactions remain capricious, and 1,2-DHIQs are more commonly prepared by partial dearomatization of IQs, 11,12  or transition-metal mediated annulation reactions. 13 Each comes with its own set of limitations, including the need for a previously constructed IQ core, the potential for overreduction to the THIQ, or a carbonyl at C1 that leads to isoquinolinones. 14  Despite its limitations, the Pomeranz-Fritsch cyclization provides an attractive disconnection for preparing 1,2-DHIQs from readily available acyclic starting materials. 3  Recognizing that the use of strong acids presents challenges of chemoselectivity, we questioned whether conditions developed by Fujioka and Kita, 15 combining a silyl triflate and a sterically encumbered pyridine base, could be used in their place, to allow acetal activation under milder, more chemoselective conditions (Scheme 1c). Herein, we report the success of this hypothesis, and demonstrate the synthetic value of the resulting 1,2-DHIQs for the preparation of either IQ or THIQ derivatives. 2,6   As a point of departure, we selected substrate 1a for our optimization studies, anticipating a regioselective cyclization at C4′ (isoquinoline numbering) based upon steric effects (Table 1). The desired 1,2-DHIQ product 2a would possess a 5,6-dimethoxy substitution pattern that is widely found in isoquinoline alkaloid natural products. 3  Under Fujioka and Kita's 15 previously reported conditions, consisting of TMSOTf (3 equiv.) and 2,6-lutidine (10 equiv.) in 1,2-DCE at 80 o C, we obtained an encouraging yield of 50%, along with the formation of a complex mixture (Entry 1). The nature of the amine base has a profound impact on the course of the reaction, and using less sterically demanding pyridines resulted in the formation of non-cyclized pyridinium salts 4 (Entries 2 and 3), which have been observed previously. 15 While the use of 2,4,6-collidine provided some improvement (Entry 4), it was not until we evaluated sterically encumbered tertiary amines that we observed yields of 70% or higher (Entries 5 and 6). This stands in contrast to the literature, where pyridine bases have typically outperformed aliphatic amines in Fujioka/Kita protocols. 15-16 When using diisopropylethylamine (DIPEA), we also observed a dramatic increase in rate (4h to 15 min), allowing us to reduce the reaction temperature from 80 o C to room temperature ( Entry 7). Next, we explored the effects of the substituent on nitrogen, and observed an improved yield of 92% for the N-nosyl derivative (Entry 8). 17 More Lewisbasic carbonate groups, including Boc or Cbz, were incompatible with the reaction conditions, and led instead to competitive formation of cyclic carbamate 3 (Entries 9 and 10). While both tosyl-and nosyl-groups performed well, the resulting products were difficult to purify by standard chromatography, leading to diminished isolated yields. This complication was addressed by using the corresponding triflate and lowering the quantity of DIPEA to 6 equivalents (Entry 11), which allowed us to maintain NMR yields in excess of 95% with more straightforward purification (1.0 mmol scale, 80% isolated yield, 259.4 mg).</p><p>Since the Pomeranz-Fritsch cyclization follows wellestablished trends for electrophilic aromatic substitution (EArS), less electron-rich aromatic rings were more reluc- tant to undergo cyclization under our standard conditions. For example, naphthyl substrate 1b afforded only 7% yield of 2b, along with a mixture of the intermediate 5b and the elimination byproduct 6b (Entry 12). Notably, 6b is formed as a 5:1 mixture of olefin isomers in favor of the (Z)-configured vinyl ether. 18 Nevertheless, synthetically useful reactivity for this more recalcitrant substrate could be recovered by heating the reaction to 80 o C in 1,2-DCE, to provide the desired product in an improved yield of 63% (Entry 13). We observed similar amounts of premature elimination in both cases, suggesting that vinyl ethers 6b are not reaction intermediates, but rather products of an irreversible shunt that decreases selectivity. Benzylic ether 5b is a constructive intermediate that could be productively converted to the product at elevated temperatures. 19 As the aromatic nucleophile became less electron rich, we observed decreasing yields of the 1,2-DHIQ product, such that 3-methylphenyl substrate 1c afforded only a 34% yield of 2c under our more forcing conditions, and phenyl substrate 1d did not undergo cyclization at all. In both cases, elimination to the vinyl ether 6 was competitive, and accounted for the majority of the reaction's mass balance.</p><p>Relative to previous Pomeranz-Fritsch modifications, our variant demonstrated good chemoselectivity (Table 2). This included aromatic rings with electron releasing oxygen substituents (2e-2g, 2k), as well as a diaryl amine (2h). In addition to classical 1,2-DHIQ substructures, heterocyclic analogues could also be prepared from the corresponding thiophene (1i) or indole (1j) starting materials, demonstrating compatibility with these more acid sensitive functionalities. Finally, 7,8-substituted-1,2-DHIQ 2k, representative of the cularine alkaloids, 20 could be synthesized in 88% yield with complete regioselectivity. This has been a difficult substitution pattern to prepare by more conventional Pictet-Spengler or Bischler-Napieralski syntheses, since they preferentially cyclize to the undesired 6,7-isomers (not shown). 21  While the preparation of 1-or 3-substituted-1,2-DHIQs was also possible, these substrates were prone to competitive reduction to the corresponding THIQ under our standard reaction conditions. For example, using 3 equiv. of TMSOTf and 6 equiv. of DIPEA, 1-methyl-DHIQ 2l was obtained in only 60% yield, along with 20% of THIQ 2l'. The formation of 2l' was consistent with hydride transfer from DIPEA to para-quinone methide 7, which is not observed when using substrates lacking a C1-substituent. We speculate that the C1-substituent may increase the rate of cyclization, and thus the concentration of para-quinone methide 7, allowing hydride transfer to compete with the elimination. Therefore, to avoid this complication, we replaced DIPEA with the non-reducing amine base 2,6lutidine, and were pleased to see the yield of 2l improve to 78% on 1.0 mmol scale, and 85% on 10 mmol scale. This allowed us to prepare >3 g of 2l in a single pass. A range of synthetically useful functional handles are tolerated at C1, including a terminal alkene (2n), a 1 o alcohol (2o) and a primary alkyl iodide (2p). Additionally, 3-methyl-DHIQ 2q could also be prepared in 73% yield, although more forcing conditions, including a prolonged reaction time (18 h) and elevated reaction temperature (80 o C), were required. We attribute these changes to the increased steric demands of elimination, which involves deprotonation of a 3 o C-H bond.</p><p>Since 1,2-DHIQs are attractive synthetic intermediates, our modified Pomeranz-Fritsch conditions provide entry into IQ and THIQ derivatives (Scheme 2). For example, reduction of the double bond by hydrogenation over Pd/C followed by reductive removal of the triflate with lithium aluminum hydride (AlH4) provided THIQ (±)-salsolidine (8) in a 63% yield over two steps. 22 Alternatively, isohypsic elimination mediated by KO t Bu in DMSO afforded the aromatized IQ natural product nigellimine (9) in a 50% yield. 23 Finally, oxidation using standard Upjohn conditions for dihydroxylation provided the 3,4-THIQ diol 10 in 70% yield and > 20:1 d.r. 24 Taken together, these transformations demonstrate the synthetic value of 1,2-DHIQs for Table 1. Reaction Optimization and Substituent Effects. a [a] Unless otherwise noted, reactions were performed using 0.2 mmol of 1, CH2Cl2 as solvent and a 4h reaction time; [b] Yield determined by 1 H-NMR using hexamethylbenzene as internal standard; [c] Complete consumption of 1 was detected in all entries; [d] reaction performed in 1,2dichloroethane; [e] uncyclized pyridinium salts 4 were formed as the major products; [f] 15 min reaction time; [g] An inseparable 20:1 regio-isomeric mixture was obtained; [h] A 5:1 ratio of Z/E olefin isomers was observed; [i] An inseparable 5:1 regio-isomeric mixture was obtained. the synthesis of isoquinolines with complementary oxidation states and substitution patterns.</p><p>In conclusion, we have developed a new isoquinoline synthesis by modifying the classical Pomeranz-Fritsch protocol. We have shown that the strong acids and elevated temperatures used previously can be replaced by a combination of TMSOTf with a sterically encumbered amine, following the precedent of Fujioka and Kita. 15 This modification tolerates acid-sensitive functional groups and heterocycles, and should facilitate the synthesis of diverse 1,2-DHIQ family members. Given their synthetic utility for the preparation of downstream isoquinoline products, we anticipate a number of opportunities for their future implementation.</p><!><p>The Supporting Information is available free of charge on the ACS Publications website.  [a] Unless otherwise noted, reactions were performed using 1.0 mmol of 1 in the presence of TMSOTf (3 equiv.), DIPEA (6 equiv.) 1 and Table 2 .</p><!><p>Chemicals and solvents were purchased from Sigma Aldrich, Alfa Aesar, Strem Chemicals, TCI or Oakwood, and used as received without further purification. Solvents were dried and purified using a PureSolv MD 7 (from Innovative Technology) or MB SPS 800 (from MBraun). We have not observed differences in the reaction outcome using either of these solvent purifiers.</p><p>Proton nuclear magnetic resonance ( 1 H NMR) spectra were acquired using Bruker Ascend 500 MHz or 400 MHz spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) and are calibrated to the residual solvent peak.</p><p>Coupling constants (J) are reported in Hz. Multiplicities are reported using the following abbreviations: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet (range of multiplet is given); br = broad. Carbon nuclear magnetic resonance ( 13 C NMR) spectra were acquired using Bruker Ascend 125 MHz or 100 MHz spectrometers. Fluorine nuclear magnetic resonance ( 19 F NMR) spectra were acquired using a Bruker Ascend 470 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) and are calibrated to the residual solvent peak. High resolution mass spectra (HRMS) were recorded using a Bruker maXis Impact TOF mass spectrometer by electrospray ionization time of flight reflectron experiments. Gas chromatographymass spectra (GC-MS) were recorded using an Agilent 7820A GC System with an Agilent 5975 Series MSD electron ionization mass detector. Fourier-transform infrared (FT-IR) spectra were recorded on a Thermo Scientific Nicolet 6700 FT-IR spectrometer. Analytical thin-layer chromatography was performed on pre-coated 250 mm layer thickness silica gel 60 F254 plates (EMD Chemicals Inc.). Visualization was performed by ultraviolet light and/or by staining with potassium permanganate or cerium molybdate. Purifications by column chromatography were performed using standard column chromatography using silica gel (40-63 μm, 230-400 mesh).</p><!><p>a) General Procedure: A flame-dried, 5 mL microwave tube equipped with a Teflon-coated stir bar and a rubber septum was charged with the acetal (0.2 mmol, 1.0 equiv) and dry solvent (5 mL, 0.2 M) and purged with a steady stream of N2 for 5 min, prior to the addition of the appropriate base (4-20 equiv, see Table S1 -S6) and TMSOTf (0.6 mmol, 3.0 equiv). The resulting solution was stirred under N2 at the indicated temperature for 15 min -18 h. Then it was quenched by the addition of HCl (10 mL, 1M) and extracted with CH2Cl2 (3  20 mL). The combined organic fractions were then dried over Na2SO4, filtered and concentrated in vacuo. The yield of the reaction was detected by 1 H-NMR spectroscopy with hexamethylbenzene as an internal standard.</p><!><p>b) Table S1. The screening of base. a,b   [a] Reaction was performed using 0.2 mmol of 1. [b] Yield was detected using 1 H-NMR with hexamethylbenzene as internal standard.</p><p>[c] Uncyclized pyridinium salts 4 were formed as the major products. c) Table S2. Temperature Effect. a,b   [a] Reaction was performed using 0.2 mmol of 1. [b] Yield was detected using 1 H-NMR with hexamethylbenzene as internal standard.</p><p>4 / 43 d) Table S3. The Screening of Solvent. a,b   [a] Reaction was performed using 0.2 mmol of 1. [b] Yield was detected using 1 H-NMR with hexamethylbenzene as internal standard.</p><p>[c] NEt3 (10.0 equiv) was used as base at room temperature.</p><p>e) Table S4. The Screening of Lewis-acid. a,b   [a] Reaction was performed using 0.2 mmol of 1. [b] Yield was detected using 1 H-NMR with hexamethylbenzene as internal standard.</p><p>5 / 43 f) Table S5. The effect of protecting groups. a,b   [a] Reaction was performed using 0.2 mmol of 1. [b] Yield was detected using 1 H-NMR with hexamethylbenzene as internal standard.</p><!><p>Rf = (hexanes/ethyl acetate 2:1): 0.11; IR (neat) v = 2938, 2838, 1743, 1515, 1418, 1258, 1235, 1138, 1123 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.85 -6.75 (m, 3H), 5.32 (dd,J = 6.4,2.3 Hz,1H),4.38 (d,J = 14.9 Hz,1H),4.34 (d,J = 14.8 Hz,1H),3.86 (s,3H),3.85 (s,3H),3.50 (dd,J = 10.1,6.4 Hz,1H),3.49 (s,3H),3.18 (dd,J = 10.1,2.3 Hz,1H); 13 C NMR (126 MHz, CDCl3) δ 156. 7, 149.5, 148.9, 128.0, 120.6, 111.21, 111.15, 98.1, 56.3, 56.04, 56.02, 50.2, 47.7; HRMS: Calcd. for C13H17NO5 [M+Na] + = 290.0999 m/z, found = 290.0992 m/z. g) Table S6. Reoptimized conditions for the triflate protecting group. a,b   [a] Reaction was performed using 0.2 mmol of 1. [b] Yield was detected using 1 H-NMR with hexamethylbenzene as internal A flame-dried, 10 mL test tube equipped with a Teflon-coated stir bar and a rubber septum was charged with the triflamide (1.0 mmol, 1.0 equiv). It was purged with N2 for 5 min prior to the addition of dry and degassed CH2Cl2 or 1,2-DCE (5 mL, 2M).</p><p>DIPEA or 2,6-lutidine (4.0 -6.0 equiv) was added via syringe followed by dropwise addition of TMSOTf (3.0 equiv). The reaction was then stirred for 4 h at the indicated temperature and then quenched with 1M HCl (10 mL). The mixture was extracted with CH2Cl2 (3  20 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified on silica gel using hexanes/ethyl acetate as eluent to afford the dihydroisoquinoline product.  1 and Table 2 Compound 2a Procedure: The reaction was carried out according to the General Procedure A.</p><!><p>259.4 mg, 0.80 mmol, 80%, off-white solid.</p><!><p>Rf = (hexanes/ethyl acetate 2:1): 0.60; IR (neat) v = 2940, 2840, 1634, 1608, 1519, 1465, 1455, 1417, 1223, 1186, 1142 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.64 (s, 1H), 6.62 (s,1H),6.50 (d,J = 7.6 Hz,1H),6.10 (d,J = 7.6 Hz,1H),4.79 (s,2H),3.88 (s,3H), 3.87 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 149. 3,149.1,122.5,122.4,120.0 (q,JF = 324.3 Hz),119.9,115.0,109.0,109.0,56.3,56.2,48.4;</p><!><p>314.6 mg, 0.89 mmol, 89%, white solid.</p><!><p>Rf = (hexanes/ethyl acetate 4:1): 0.42; IR (neat) v = 2995, 2939, 2847, 1569, 1497, 1416, 1389, 1332, 1224, 1150 9,149.3,142.0,123.4,121.9,120.0 (q,JF = 324.2 Hz),116.7,110.0,105.1,61.6,61.1,56.3,48.4;</p><!><p>Procedure: The reaction was carried out according to the General Procedure A.</p><!><p>295.6 mg, 0.78 mmol, 78%, pale-yellow solid.</p><!><p>Rf = (hexanes/ethyl acetate 3:1): 0.45; IR (neat) v = 3400, 3331, 2216, 1596, 1515, 1441, 1390, 1274, 1188, 1128   0, 140.7, 134.0, 129.1, 126.9, 125.1, 123.1, 120.1, 119.9 (q, JF = 332.5 Hz), 119.7, 117.3, 115.9, 114.6, 102.9, 48.6; 19 F NMR (470 MHz, CDCl3) δ -75.2 (s, 3F); HRMS: Calcd. for C17H12F3N3O2S [M+Na] + = 402.0495 m/z, found = 402.0476 m/z.</p><!><p>Procedure: The reaction was carried out according to the General Procedure A at 80 o C for 4 h.</p><!><p>166.4 mg, 0.62 mmol, 62%, pale-orange oil.</p><!><p>Rf = (hexanes/ethyl acetate 20:1): 0.39; IR (neat) v = 3109, 2859, 1624, 1395, 1333, 1276, 1225, 1186, 1152, 1110 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 7.21 (d, J = 5.1 Hz, 1H), 6.89 (d,J = 5.1 Hz,1H),6.49 (d,J = 7.6 Hz,1H),6.19 (d,J = 7.6 Hz,1H), 5.04 (s, 2H); 13 C NMR (126 MHz, CDCl3) δ 131. 8,125.6,124.6,124.5,121.8,119.9 (q,JF = 324.2 Hz),110.6,46. 2,6-lutidine (695.0 µL, 6.0 mmol)   CH2Cl2 (5 mL, 0.2 M) Purification: 10% EtOAc in Hexane.</p><!><p>217.9 mg, 0.56 mmol, 56%, dark-red solid.</p><!><p>Rf = (hexanes/ethyl acetate 10:1): 0.49; IR (neat) v = 3120, 3057, 3031, 2923, 1740, 1453, 1330, 1199, 1149 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 7.49 (dd, J = 6.8, 1. 6 Hz,1H),4H),2H),7.10 (d,J = 6.8 Hz,2H) 8,137.2,130.2,129.0,127.9,126.3,124.4,124.3,122.7,120.8,120.0 (q,JF = 324.5 Hz),118.1,110.1,103.1,102.1,46.9,46.0; 19 F NMR (470 MHz, CDCl3) δ -74.9 (s, 3F); HRMS: Calcd. for C19H15F3N2O2S [M+Na] + = 415.0699 m/z, found = 415.0685 m/z.</p><!><p>Procedure: The reaction was carried out according to the General Procedure A.</p><!><p>284.4 mg, 0.88 mmol, 88%, pale-orange oil.</p><!><p>Rf = (hexanes/ethyl acetate 4:1): 0.45; IR (neat) v = 3104, 2944, 2840, 1636, 1605, 1495, 1273, 1186,1146 cm -1 ; 1 H NMR (500</p><!><p>MHz, CDCl3) δ 6.83 (d, J = 8.7 Hz, 1H), 6.81 (d,J = 8.8 Hz,1H),6.47 (d,J = 7.6 Hz,1H),6.10 (d,J = 7.6 Hz,1H),4.91 (s,2H),3.87 (s, 3H), 3.85 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 153. 1, 144.8, 123.0, 122.0, 122.0, 121.3, 120.0 (q, JF = 324.3 Hz), 114.8, 111.8,   60.9, 55.9, 43.6; 19 F NMR (470 MHz, CDCl3) δ -75.4 (s, 3F); HRMS: Calcd. for C12H12F3NO4S [M+Na] + = 346.0331 m/z, found = 346.0332 m/z.</p><!><p>Procedure: The reaction was carried out according to the General Procedure A.</p><!><p>1.0 mmol scale: 264.5 mg, 0.78 mmol, 78%, white solid. 10.0 mmol scale: 2.87 g, 8.51 mmol, 85%.</p><!><p>Rf = (hexanes/ethyl acetate 5:1): 0.26; IR (neat) v = 3006, 2982, 2960, 2936, 1636, 1515, 1384, 1268, 1137 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.65 (s, 1H), 6.59 (s,1H),6.40 (d,J = 7.4 Hz,1H),6.14 (d,J = 7.5 Hz,1H), 5.17 (q, J = 6.5 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 1.41 (d, J = 6.7 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ 149. 4,148.8,126.1,120.9,119.9 (q,JF = 324.3 Hz),119.6,114.9,109.1,108.5,56.2,56.1,55.7,22.8;</p><!><p>256.7 mg, 0.64 mmol, 64%, off-white solid.</p><!><p>Rf = (hexanes/ethyl acetate 5:1): 0.36; IR (neat) v = 3007, 2939, 2839, 1634, 1576, 1495, 1452, 1349, 1144, 1090 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 7.31 -7.26 (m, 3H), 7.19 (dd, J = 6.7, 2.7 Hz, 2H), 6.77 (s, 1H), 6.66 (s, 1H), 6.40 (d, J = 7.4 Hz, 1H), 6.25 (d, J = 7.4 Hz, 1H), 6.18 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 149. 6, 149.2, 139.0, 128.7, 128.6, 127.5,   122.9, 122.2, 120.4, 120.1 (q, JF = 324.9 Hz), 116.9, 109.9, 109.0, 61.1, 56.2, 56.1; 19 F NMR (470 MHz, CDCl3) δ -75.2 (s, 3F); HRMS: Calcd. for C18H16F3NO4S [M+H] + = 400.0845 m/z, found = 400.0821 m/z.</p><!><p>Procedure: The reaction was carried out according to the General Procedure A.</p><!><p>304.4 mg, 0.84 mmol, 84%, white solid.</p><!><p>Rf = (hexanes/ethyl acetate 5:1): 0.30; IR (neat) v = 3076, 3019, 2979, 2903, 1573, 1466, 1414, 1350, 1270, 1149   1, 148.9,   132.8, 124.2, 121.3, 119.9 (q, JF = 324.6 Hz), 119.9, 119.2, 116.1, 109.3, 109.0, 59.3, 56.1, 56.0, 40.2; 19 F NMR (470 MHz, CDCl3)   δ -75.8 (s, 3F); HRMS: Calcd. for C15H16F3NO4S [M+H] + = 364.0825 m/z, found = 364.0825 m/z.</p><!><p>Procedure: The reaction was carried out according to the General Procedure A.</p><!><p>The crude product (a mixture of -OH and -OTMS) after normal work up was dissolved in MeOH (10 mL), and added citric acid (1 M aq., 10 mL). The resulting mixture was stirred for 5 min at rt and concentrated in vacuo. The mixture was then extracted with EtOAc (3 × 20 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo to afford the crude alcohol product, which was then purified according to the general procedure.  3, 148.8, 125.0, 121.2, 120.0 (q, JF = 325.0 Hz), 119. 8, 116.6, 109.12, 109.10, 62.4, 59.6, 56.2, 56.1, 32.1, 28.6; 19 F NMR (470 MHz, CDCl3) δ -75.5 (s, 3F); HRMS: Calcd. for C15H18F3NO5S [M+Na] + = 404.0750 m/z, found = 404.0750 m/z.</p><!><p>Procedure: The reaction was carried out according to the General Procedure A.</p><!><p>365.9 mg, 0.74 mmol, 74%, pale-yellow oil.</p><!><p>Rf = (hexanes/ethyl acetate 5:1): 0.34; IR (neat) v = 3003, 2939, 2839, 1633, 1575, 1464, 1416, 1220, 1141 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.68 (s, 1H), 6.59 (s, 1H), 6.42 (d, J = 7.4 Hz, 1H), 6.23 (d, J = 7.4 Hz, 1H), 4.99 (t, J = 6.3 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.24 -3.12 (m, 2H), 1.96 -1.84 (m, 3H), 1.75 -1.65 (m, 1H); 13 C NMR (126 MHz, CDCl3) δ 149. 5, 149.0, 124.6, 121.2, 120.0 (q, JF = 324. 9 Hz),119.8,116.8,109.2,108.9,58.7,56.3,56.2,36.2,29.1,5. 99,148.96,133.0,123.9,121.7,119.8 (q,JF = 324.0 Hz),119.7,108.28,108.26,56.2,56.1,50.9,20.9; 19 F NMR (470 MHz, CDCl3) δ -75.9 (s, 3F); HRMS: Calcd. for C13H14F3NO4S [M+H] + = 338.0668 m/z, found = 338.0669 m/z.</p><!><p>Procedure: A flame-dried, 50 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with 2l (168.7 mg, 0.5 mmol), 10 wt% Pd/C (33.0 mg, 20 wt%) and purged with N2 for 5 min, and dissolved in dry and degassed MeOH (5 mL, 0.1 M). The resulting mixture was then purged with H2 for 5 min, and then pressurize to 10 psi, and stirred at rt 19 / 43 for 4 h. The mixture was then filtered through celite. The filtrate was then concentrated in vacuo to afford the crude hydrogenation product, which was used for the next step directly. To the crude product was added LiAlH4 (56.9 mg, 1.5 mmol, 3 equiv) and purged with N2 for 5 min, prior to the addition of dry and degassed Et2O (5 mL, 0.1 M). The resulting mixture was then refluxed for 12 h, and cooled to 0 o C in an ice bath. Water (0.3 mL), 15% NaOH solution (0.1 mL) was then added dropwise.</p><p>The mixture was then warmed to rt and stirred for 30 min, and filtered through celite. The filtrate was poured on 10 mL 15% NaOH and extracted with EtOAc (3  20 mL). The combined organic fractions were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then purified on silica gel (25% EtOAc in hexanes to 20% MeOH in EtOAc) to afford (±)-8 (65.2 mg, 0.31 mmol, 63%) as a brown oil.</p><!><p>1 H NMR (500 MHz, CDCl3) δ 6.60 (s, 1H), 6.55 (s, 1H), 4.05 (q, J = 6.6 Hz, 1H), 3.83 (s, 3H), 3.83 (s, 3H), 3.24 (dt, J = 12.5, 5.1 Hz, 1H), 2.99 (ddd, J = 13.0, 8.4, 4.6 Hz, 1H), 2.84 (br s, 1H), 2.79 (ddd, J = 15.1, 9.0, 6.1 Hz, 1H), 2.65 (dt, J = 16.1, 4.8 Hz, 1H), 1.44 (d, J = 6.7 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ 147. 5, 147.4, 132.1, 126.7, 111.8, 109.1, 56.1, 55.9, 51.2, 41.7, 29.3, 22.8. The characterization data matches the data that has been reported previously. 1</p><!><p>Procedure: A flame-dried, 5 mL microwave vial equipped with a Teflon-coated stir bar and a rubber septum was charged with 2l (168.7 mg, 0.5 mmol), KO t Bu (168.3 mg) and purged with N2 for 5 min, and dissolved in dry and degassed DMSO (0.5 mL, 1 M). The resulting mixture was stirred at rt for 4 h. The solution was then poured on 10 mL 15% NaOH and extracted with EtOAc (3  20 mL). The combined organic fractions were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then purified on silica gel using EtOAc/MeOH (5:1) as eluent to afford 9 (50.9 mg, 0.25 mmol, 50%) as a brown oil.</p><!><p>1 H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 5.7 Hz, 1H), 7.39 (d, J = 5.7 Hz, 1H), 7.24 (s, 1H), 7.04 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 2.88 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 155. 7, 153.0, 150.1, 140.1, 133.0, 123.3, 118.6, 105.4, 103.9, 56.2, 56.1, 22.0. The characterization data matches the data that has been reported previously. 2</p><!><p>Compound 10 Procedure: The literature procedure was followed: 3 A flame-dried, 25 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with 2l (168.7 mg, 0.5 mmol), NMO (87.9 mg, 0.75 mmol) and dissolved in Me2CO/ H2O (2 mL/0.5 mL). A solution of OsO4 (2.54 mg, 0.01 mmol) in t BuOH (1 mL) was added. The mixture was stirred at rt for 8 h.</p><p>It was then quenched by the addition of Na2S2O3 (satd., 20 mL) and extracted with EtOAc (3  20 mL). The combined organic fractions were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then purified on silica gel (30% EtOAc in hexanes) to afford (±)-10 (140.6 mg, 0.38 mmol, 76%) as a white solid. The relative stereochemistry was assigned based on literature precedent. 3   Characterization: Rf = (ethyl acetate/hexane 1:2): 0.13; IR (neat) v = 3512, 3442, 3328, 1615, 1518, 1469, 1445, 1383, 1370, 1351, 1330, 1296, 1258, 1225, 1198, 1183, 1160, 1102 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 7.15 (s, 1H), 6.57 (s, 1H), 5.74 (br s, 1H), 4.99 (br s, 1H), 4.79 (br s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.49 (br s, 1H), 2.64 (br s, 1H), 1.81 (d, J = 6.7 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ 149. 2, 149.1, 127.2, 124.3, 119.7 (q, JF = 322. 1 Hz),109.5,108.4,78.5,67.6,56.2,56.2,54.0,27.6;  Step 1: A flame-dried, 250 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with the aldehyde (20.0 mmol, 1.0 equiv) and dissolved in MeOH (40 mL, 0.5 M). Then AcOH (10 mmol, 0.5 equiv) and the amine (20.0 mmol, 1.0 equiv) were added via a syringe. The resulting mixture was stirred at room temperature for 2h, and cooled to 0 o C in an ice bath, prior to the portion-wise addition of NaBH4 (30.0 mmol, 1.5 equiv). The resulting solution was then warmed to room temperature and stirred for 12h. The solution was then concentrated in vacuo and diluted with sat.</p><p>NaHCO3 (50 mL) and extracted with EtOAc (3  100 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The crude product was directly used for the next step.</p><p>Step 2: A 250 mL round bottom flask containing the crude amine product was equipped with a Teflon-coated stir bar and a rubber septum. It was dissolved in CH2Cl2 (0.2 -0.5 M), followed by the addition of DIPEA (1.5 equiv). The solution was cooled down -78 o C with a dry ice/acetone bath. Tf2O (1.0 -1.2 equiv) was added to the solution dropwise. The reaction was then stirred for 30 min at -78 o C, warmed to rt and stir for another 30 min and then quenched with H2O and 1M HCl (10 mL / mmol).</p><p>The phases were then separated, and the aqueous phase was extracted with CH2Cl2 (3  10 mL / mmol). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified on silica gel using hexanes/ethyl acetate as eluent to afford the triflamide product.</p><p>22 / 43</p><!><p>Procedure: The reaction was carried out according to the General Procedure B.</p><!><p>Compound 1a-Ts Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S3 (used as crude, 5.0 mmol, 1.28 g, 1.0 equiv) and dissolved in CH2Cl2 (20 mL, 0.25 M). Then NEt3 (15 mmol, 2.08 mL, 3.0 equiv), DMAP (0.5 mmol, 61.1 mg, 10 mol%) and TsCl (7.5 mmol, 1.43 g, 1.5 equiv) were added. The resulting mixture was stirred at room temperature for 12h and quenched by the addition of HCl (50 mL, 1M). The phases were then separated, and the aqueous phase was extracted with CH2Cl2 (3  50 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 1a-Ts (1.96 g, 4.79 mmol, 96%) as a brown solid.  1, 148.7, 143.3, 137.8, 129.7, 128.6, 127.2, 121.2, 111.4, 110.8, 104.0, 55.9, 55.8, 54.7, 52.4, 48.4, 21.5. The characterization data matches the data that has been reported previously. 4</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S3 (used as crude, 10.0 mmol, 2.55 g, 1.0 equiv) and dissolved in CH2Cl2 (20 mL, 0.25 M). Then NEt3 (30 mmol, 4.16 mL, 3.0 equiv) and 4-NsCl (12 mmol, 2.66 g, 1.2 equiv) were added. The resulting mixture was stirred at room temperature for 12h and quenched by the addition of HCl (50 mL, 1M). The phases were then separated, and the aqueous phase was extracted with CH2Cl2 (3  50 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The</p><!><p>residue was then purified on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 1a-4-Ns (3.35 g, 7.61 mmol, 76%) as a white solid.</p><!><p>Rf = (ethyl acetate/hexane 1:2): 0.30; IR (neat) v = 2916, 2839, 1517, 1465, 1445, 1400, 1366, 1341, 1312, 1287, 1257, 1233, 1201, 1161, 1137, 1124, 1107 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 8.33 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H), 6.82 -6.69 (m, 3H), 4.47 (s, 2H), 4.33 (t, J = 4.9 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.31 (d, J = 4.9 Hz, 2H), 3.24 (s, 6H); 13 C NMR (126 MHz, CDCl3) δ 149. 8, 149.2, 149.0, 146.7, 128.4, 127.6, 124.1, 121.1, 111.5, 110.9, 103.3, 55.9, 55.8, 54.6, 52.3, 48.2; HRMS: Calcd.</p><p>for C19H24N2O8S [M+Na] + = 463.1146 m/z, found = 463.1156 m/z.</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S3 (used as crude, 10.0 mmol, 2.55 g, 1.0 equiv) and dissolved in CH2Cl2 (20 mL, 0.5 M). Then NEt3 (30 mmol, 4.16 mL, 3.0 equiv) and 2-NsCl (12 mmol, 2.66 g, 1.2 equiv) were added. The resulting mixture was stirred at room temperature for 12h and quenched by the addition of HCl (50 mL, 1M). The phases were then separated, and the aqueous phase was extracted with CH2Cl2 (3  50 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 1a-2-Ns (3.88 g, 8.80 mmol, 88%) as a pale-yellow oil.</p><!><p>Rf = (ethyl acetate/hexane 1:2): 0.18; IR (neat) v = 2938,2836,1541,1515,1464,1441,1421,1369,1343,1257,1238,1191,1159,1140, 1121 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 8.02 -7.96 (m, 1H), 7.70 -7.59 (m, 3H), 6.79 -6.72 (m, 3H), 4.59 (s, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.36 (d, J = 5.2 Hz, 2H), 3.28 (s, 6H); 13 C NMR (126 MHz, CDCl3) δ 149. 3, 148.9, 148.0, 134.5, 133.4, 131.7, 131.2, 128.0, 124.2, 121.2, 111.3, 111.0, 104.0, 56.0, 55.9, 55.0, 52.4, 48.2</p><!><p>Compound 1a-Boc Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S3 (used as crude, 5.0 mmol, 1.28 g, 1.0 equiv) and dissolved in THF (10 mL, 0.5 M). Then Boc2O (6.0 mmol, 1.31 g, 1.2 equiv) was added. The resulting mixture was stirred at room temperature for 12h and concentrated in vacuo. The residue was then purified on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 1a-Boc (1.29 g, 3.63 mmol, 73%) as a colorless oil.</p><!><p>Rf = (ethyl acetate/hexane 1:2): 0.31; IR (neat) v = 2935,2834,1687,1514,1460,1407,1318,1260,1234,1158, 1120 cm -1 ; 1 H NMR (500 MHz, CDCl3) mixture of rotamers δ 6.87 -6.67 (m, 3H), 4.56 -4.36 (m, 3H), 3.84 (s, 6H), 3.37 (s, 3H), 3.35 (s, 3H), 3.26 (br s, 1H), 3.17 (br s, 1H), 1.49 and 1.45 (s, 9H); 13 C NMR (126 MHz, CDCl3) mixture of rotamers δ 155.9, 149. 1, 148.2, 131.2, 131.0, 120.4, 119.7, 111.3, 111.0, 110.6, 104.4, 103.7, 80.0, 56.0, 55.9, 54.8, 51.5, 50.6, 48.2, 48.0, 28.5; GC-MS (EI) Rt = 24.16 min, m/z = 355.2, 299. 1, 267.1, 209.1, 151.1, 75.1, 56.1.</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S3 (used as crude, 5.0 mmol, 1.28 g, 1.0 equiv), K2CO3 (1.38 g, 10 mmol, 2.0 equiv) and dissolved in MeCN (10 mL, 0.5 M). Then CbzCl (7.5 mmol, 1.07 mL, 1.5 equiv) was added. The resulting mixture was stirred at room temperature for 4h and diluted with H2O (10 mL) and brine (10 mL). The mixture was extracted with EtOAc (3  50 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 1a-Cbz (1.09 g, 2.80 mmol, 56%) as a colorless oil.</p><!><p>Characterization: Rf = (ethyl acetate/hexane 1:2): 0.27; IR (neat) v = 2938, 2834, 1695, 1514, 1462, 1412, 1364, 1319, 1298, 1260, 1231, 1116 cm -1 ; 1 H NMR (500 MHz, CDCl3) mixture of rotamers δ 7.46 -7.26 (m, 5H), 6.85 -6.63 (m, 3H), 5.20 (d, J = 4.9 Hz, 2H), 4.60 -4.34 (m, 3H), 3.86 (s, 3H), 3.81 and 3.68 (s, 3H), 3.40 (s, 3H), 3.34 (d, J = 5.0 Hz, 1H), 3.30 (s, 3H), 3.26 (d, J = 4.9 Hz, 1H); 13 C NMR (126 MHz, CDCl3) mixture of rotamers δ 149. 2, 130.4, 128.6, 128.2, 128.1, 120.0, 111.4, 111.1, 110.8, 104.2, 103.6, 67.5, 56.0, 55.8, 54.8, 51.3, 48.6, 47.8; GC-MS (EI) Rt = 30.68 min, m/z = 389. 3, 209.1, 151.1, 91.1, 75.1.</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S3 (used as crude, 5.0 mmol, 1.28 g, 1.0 equiv) and dissolved in CH2Cl2 (10 mL, 0.5 M). Then NEt3 (15.0 mmol, 2.09 mL, 3.0 equiv) and Ac2O (7.5 mmol, 0.71 mL, 1.5 equiv) were added. The resulting mixture was stirred at room temperature for 12 h and quenched with HCl (1M, 20 mL). The mixture was extracted with EtOAc (3  50 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified on silica gel using hexanes/ethyl acetate (1:2) as eluent to afford 1a-Ac (1.32 g, 4.43 mmol, 89%) as a colorless oil.</p><!><p>Rf = (ethyl acetate/hexane 2:1): 0.20; IR (neat) v = 2937, 2835, 1641, 1514, 1441, 1412, 1259, 1233, 1125 cm -1 ; 1 H NMR (500 MHz, CDCl3) mixture of rotamers δ 6.86 -6.58 (m, 3H), 4.60 -4.23 (m, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.45 -3.39 (m, 1H), 3.36 (s, 3H), 3.31 (s, 3H), 3.31 -3.27 (m, 1H), 2.17 and 2.11 (s, 3H); 13 C NMR (126 MHz, CDCl3) mixture of rotamers δ 171. 5, 149.4, 149.2, 148.48, 148.46, 130.4, 129.3, 120.7, 118.4, 111.6, 111.4, 110.9, 109.5, 103.7, 103.3, 56.0, 55.9, 55.2, 54.8, 53.0, 50.1, 49.0, 47.8, 21.9, 21.8  3, 131.7, 129.0, 128.5, 128.1, 127.9, 126.7, 126.1, 120.2 (q, JF = 323.1 Hz), 103.9, 55.2, 53.6, 48.3; 19 F NMR (470 MHz, CDCl3) δ -75.3 (s, 3F); GC-MS (EI) Rt = 23.53 min, m/z = 377. 2, 314.2, 287.1, 244.2, 180.1, 141.1, 115.1, 75.1, 58.1.</p><!><p>Procedure: A flame-dried, 250 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S1 (8.31 g, 50.0 mmol) and MgSO4 (18.05 g, 150.0 mmol). Dry CH2Cl2 (100 mL) was added via syringe followed by S2 (5.45 mL, 50.0 mmol). The resulting mixture was stirred at room temperature overnight and filtered through celite. The filtrate was then concentrated in vacuo and dried under high vacuum to provide S15 (12.38 g, 98%) as a white solid.</p><!><p>1 H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.16 (dd, J = 8.2, 1.9 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 4.67 (t, J = 5.3 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.75 (dt, J = 5.3, 2.6 Hz, 2H), 3.42 (s, 6H); 13 C NMR (126 MHz, CDCl3) δ 163. 2, 151.6, 149.4, 129.5, 123.4, 110.5, 109.0, 104.1, 63.6, 56.1, 56.1, 54.3. The characterization data matches the data that has been reported previously. 4</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S15 (1.27 g, 5.0 mmol), purged with N2 for 5 min, and dissolved in dry and degassed THF (25 mL, 0.2 M). The resulting mixture was stirred and cooled to -78 o C in a dry ice bath, prior to the dropwise addition of MeLi (2.42 mL, 7.5 mmol, 3.1 M).</p><p>The resulting solution was stirred for 30 min and the dry ice bath was removed and the solution was stirred for another 5 mins and then quenched with H2O (10 mL) and sat. NH4Cl (10 mL). The solution was then extracted with EtOAc (3  50 mL).</p><p>The combined organic fractions were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then purified on silica gel using hexanes/ethyl acetate (1:1) as eluent to afford S16 (899.7 mg, 59%) as a pale-yellow oil.</p><!><p>Characterization: 1 H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 1.4 Hz, 1H), 6.83 (dd, J = 8.2, 1.6 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.43 (t, J = 5.5 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.71 (q, J = 6.6 Hz, 1H), 3.36 (s, 3H), 3.31 (s, 3H), 2.63 (dd, J = 12.1, 5.6 Hz, 1H), 2.56 (dd, J = 12.1, 5.3 Hz, 1H), 1.63 (s, 1H), 1.35 (d, J = 6.6 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ 149. 2, 148.1, 138.1, 118.9, 111.1, 109.6, 104.0, 58.2, 56.0, 56.0, 54.2, 53.8, 49.2, 24.6. The characterization data matches the data that has been reported previously. 6</p><!><p>Procedure: The reaction was carried out according to the General Procedure B, step 2.</p><!><p>3.38 g, 8.42 mmol, 64%, white solid.</p><!><p>Rf = (EtOAc : Hexanes 1:3): 0.27; IR (neat) v = 2992,2960,2941,2841,1605,1446,1345,1241, 1147 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.95 (br s, 1H), 6.94 (dd,J = 8.4,1.4 Hz,1H),6.84 (d,J = 8.3 Hz,1H), 5.17 (d, J = 6.3 Hz, 1H), 4.22 (br s, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 3.31 (s, 3H), 3.21 (s, 3H), 3.25 -3.16 (m, 1H), 3.15 -3.01 (m, 1H), 1.67 (d, J = 6.3 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ 149. 3,149.2,130.3,120.20 (q,JF = 319.5 Hz),120.19,111.6,110.8,103.4,58.9,56.0,55.9,55.4,54.7,47.1,17.4; 2, 311.1, 204.1, 165.1, 149.1, 121.1, 106.0, 91.1, 75.1, 51.1.</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S15 (1.27 g, 5.0 mmol), purged with N2 for 5 min, and dissolved in dry and degassed THF (25 mL, 0.2 M). The resulting mixture was stirred and cooled to -78 o C in a dry ice bath, prior to the dropwise addition of PhLi (5 mL, 9.5 mmol, 1.9 M). The resulting solution was stirred for 2 h with the temperature ramping from -78 o C to -40 o C and then quenched with H2O (10 mL) and sat. NH4Cl (10 mL). The solution was then extracted with EtOAc (3  50 mL). The combined organic fractions were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then purified on silica gel using hexanes/ethyl acetate (1:1) as eluent to afford S17 (1.19 g, 72%) as a pale-yellow oil.  148.0, 144.1, 136.6, 128.5, 127.2, 127.0, 119.4, 111.1, 110.3, 103.8, 67.0, 55.9, 55.9, 53.8, 53.7, 49.4; GC-MS (EI) Rt = 25.87 min, m/z = 331. 1, 299.1, 268.1, 227.2, 197.1, 165.1, 141.0, 115.1, 75.1.</p><!><p>Procedure: The reaction was carried out according to the General Procedure B, step 2.</p><!><p>S17 (1.66 g, 5 mmol) 39 / 43 Tf2O (841.2 µL,5 mmol) DIPEA (1.05 mL, 6 mmol) CH2Cl2 (25 mL, 0.2 M) Purification: 15% EtOAc in Hexanes.</p><!><p>700.1 mg, 1.51 mmol, 30%, pale-yellow oil.</p><!><p>Rf = (EtOAc : Hexanes 1:5): 0.17; IR (neat) v = 2938, 2837, 1594, 1515, 1418, 1222, 1182, 1140   138.1, 128.5, 128.2, 122.3, 120.1 (q, J = 324.5 Hz), 112.9, 110.9, 102.4, 67.5, 56.0, 55.9, 54.2, 54.0, 48.3; 19 F NMR (470 MHz, CDCl3) δ -74.0 (s, 3F); HRMS: Calcd. for C20H24F3NO6S [M+Na] + = 486.1169 m/z, found = 486.1157 m/z.</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with S15 (1.27 g, 5.0 mmol), Zn powder (653.8 mg, 10 mmol) and purged with N2 for 5 min, and dissolved in dry and degassed THF (10 mL, 0.5 M). The resulting mixture was stirred and cooled to 0 o C in an ice bath, prior to the dropwise addition of allyl bromide (649.1 µL, 7.5 mmol). The resulting mixture was stirred overnight at rt. The solution was then extracted with EtOAc (3  50 mL). The combined organic fractions were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then purified on silica gel using hexanes/ethyl acetate (1:1) as eluent to afford S18 (1.40 g, 95%) as a pale-yellow oil.</p><!><p>1 H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 1. 4 Hz,1H),6.83 (dd,J = 8.3,1.6 Hz,1H),6.81 (d,J = 8.2 Hz,1H),1H),5.09 (dd,J = 17.1,1.7 Hz,1H),1H),4.41 (t,J = 5.5 Hz,1H),3.89 (s,3H),3.87 (s,3H), 3.58 (t, J = 6.9 Hz, 1H), 3.34 (s,3H),3.30 (s,3H),2.58 (dd,J = 11.5,5.0 Hz,1H),2.55 (dd,J = 11.4,4.4 Hz,1H),2H),1.63 (s,1H); 13 C NMR (126 MHz, CDCl3) δ 149. 2, 148.2, 136.4, 135.5, 119.6, 117.6, 111.1, 109.9, 103.9, 62.6, 56.0, 56.0, 54.0, 53.7, 49.0, 43.2. The characterization data matches the data that has been reported previously. 7</p><!><p>40 / 43 Procedure: The reaction was carried out according to the General Procedure B, step 2.</p><!><p>S18 (8.15 g, 27.6 mmol) Tf2O (5.04 mL, 33.1 mmol) DIPEA (7.21 mL, 41.4 mmol) CH2Cl2 (60 mL, 0.5 M) Purification: 30% EtOAc in Hexanes.</p><!><p>6.55 g, 15.3 mmol, 56%, pale-yellow oil.</p><!><p>Rf = (EtOAc : Hexanes 1:3): 0.23; IR (neat) v = 2939, 2838, 1606, 1518, 1260, 1222, 1183, 1110 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.96 (d, J = 8.1 Hz, 1H), 6.96 (br s, 1H), 6.85 (d,J = 8.3 Hz,1H),5.66 (ddt,J = 17.1,10.2,6.8 Hz,1H),5.13 (dd,J = 17.1,1.3 Hz,1H), 5.05 (d, J = 10.2 Hz, 1H), 4.99 (dd, J = 9.8, 5.6 Hz, 1H), 4.32 (br s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.39 (br s, 3H), 3.27 (s, 3H), 3.23 (d,J = 15.8 Hz,1H),3.13 (dd,J = 12.5,5.4 Hz,1H),3.04 (ddd,J = 15.3,9.4,6.2 Hz,1H), 2.77 (br s, 1H); 13 C NMR (126 MHz, CDCl3) δ 149. 4, 149.2, 134.00, 121.5, 118.3, 112.7, 110.9, 104.2, 63.8, 56.0, 55.9, 55.7, 54.9, 47.6; 19 F NMR (470 MHz, CDCl3)   mixture of rotamers: δ -74. 1 & -75.7 (s, 3F); GC-MS (EI) Rt = 23.55 min,m/z = 427.3,354.2,337.2,181.1,159.1,115.1,91.1,75.1.</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with 1n (2.14 g, 5.0 mmol) and purged with N2 for 5 min, and dissolved in dry and degassed THF (10 mL, 0.5 M). Borane (2.5 mL, 2.5 mmol, 1 M in THF) was added dropwise via the syringe. The resulting solution was stirred at RT for 4 h, prior to the addition of H2O2 (2 mL, 20.0 mmol) and NaOH (10 mL, 1M aq.) and stirred for another 1 h. The solution was then extracted with EtOAc (3  50 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified on silica gel using hexanes/ethyl acetate (1:1) as eluent to afford 1o (1.21 g, 77%) as a colorless oil.</p><!><p>Rf = (EtOAc : Hexanes 1:1): 0.14; IR (neat) v = 3511, 2941, 2839, 1737, 1518, 1379, 1221, 1184, 1108 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.96 (d, J = 8.1 Hz, 1H), 6.96 (br s, 1 H), 6.85 (d,J = 8.3 Hz,1H),4.95 (dd,J = 9.4,6.1 Hz,1H), 4.32 (br s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.67 (t, J = 5.4 Hz, 2H), 3.37 (br s, 3H), 3.28 (s, 3H), 3.22 (d,J = 15.2 Hz,1H),3.13 (dd,J = 15.1,6.2 Hz,1H),1H), 2.09 (br s, 1H), 1.61 -1.51 (m, 2H), 1.46 (br s, 1H); 13 C NMR (126 MHz, CDCl3) δ 149. 5, 149.3, 121.4, 112.6,   111.0, 104.1, 63.9, 62.3, 56.02, 55.96, 55.7, 54.8, 47.4, 29.8; 19</p><!><p>Procedure: A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with 1o (1.34 g, 3.0 mmol) in dry CH2Cl2 (15 mL, 0.2 M). I2 (913.7 mg, 3.6 mmol), imidazole (306.4 mg, 4.5 mmol) and triphenylphosphine (944.2 mg, 3.6 mmol) was added. The resulting mixture was stirred at RT for 12 h. Hexanes (15 mL) was 42 / 43 added to the mixture to allow the precipitation of the triphenylphosphine oxide byproduct. The mixture was then filtered, and the filtrate was concentrated in vacuo. The crude product was then purified on silica gel using hexanes/ethyl acetate (3:1) as eluent to afford 1p (1.60 g, 96%) as a white solid.</p><!><p>Rf = (EtOAc : Hexanes 1:3): 0.38; IR (neat) v = 2938, 2837, 1606, 1517, 1421, 1383, 1221, 1127 cm -1 ; 1 H NMR (500 MHz, CDCl3) δ 6.95 (d, J = 8.6 Hz, 1H), 6.94 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 4.93 (dd, J = 9.9, 5.6 Hz, 1H), 4.36 (br s, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.44 (br s, 3H), 3.31 (s, 3H), 3.29 -3.02 (m, 4H), 2.48 (br d, J = 9.5 Hz, 1H), 2.06 (br s, 1H), 1.88 -1.63 (m, 2H); 13 C NMR (126 MHz, CDCl3) δ 149. 6, 149.3, 121.6, 112.5, 111.1, 104.6, 63.5, 56.0, 55.0, 47.4, 30.4;</p><!><p>Procedure: Step 1: The following literature procedure was followed: 8 A flame-dried, 100 mL round bottom flask equipped with a Teflon-coated stir bar and a rubber septum was charged with NaBH(OAc)3 (3.0 g, 14.0 mmol) and dissolved in 1,2-DCE (35 mL). Then AcOH (572 µL, 10 mmol), S19 (1.51 mL, 10 mmol) and S20 (1.21 mL, 10 mmol) were added via a syringe. The resulting mixture was stirred at room temperature overnight. The resulting solution was quenched with sat. NaHCO3 (30 mL) and extracted with CH2Cl2 (3  50 mL). The combined organic fractions were then dried over MgSO4, filtered and concentrated in vacuo. The crude product was directly used for the next step.</p><p>Step 2: The reaction was carried out according to the General Procedure B, step 2.</p><!><p>Tf2O (1.68 mL, 10.0 mmol) DIPEA (2.61 mL, 15.0 mmol) CH2Cl2 (50 mL, 0.2 M) Purification: 15% EtOAc in hexanes.</p><!><p>2.49 g, 6.2 mmol, 62%, pale-orange solid.</p><!><p>Rf = (EtOAc : Hexanes 1:5): 0.17; IR (neat) v = 3007, 2942, 2842, 1737, 1593, 1421, 1259, 1222, 1155, 1126 cm -1 ; 1 H NMR (500</p><!><p>MHz, CDCl3) δ 6.98 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.81 (d,J = 8.2 Hz,1H),3H),3.89 (s,3H),3.87 (s,3H),3.22 (br s, 6H), 1.21 (br s, 3H); 13 C NMR (126 MHz, CDCl3) δ 149. 3,149.1,128.6,121.0,δ 120.2 (q,JF = 327.5 Hz),111.7,110.9,105.4,57.0,56.0,56.0,54.</p>