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(27) Synthesis of 9. To 8 (2.2 g, 10 mmol, neat) was added a freshly prepared KOH solution (2.5% aqu. 50 mL). The reaction mixture was stirred at room temperature for 40 h. Then the solution was extracted with ether (50 mL) and the ether layer was discarded. The aqueous layer was cooled to 0 °C and acidified to pH~4 with cold sulphuric acid (1M). A white precipitate formed, which was taken into ether (50 mL). The aqueous layer was extracted with ether (2 × 20 mL). The combined ether extracts were dried over Na2SO4 and concentrated under reduced pressure, keeping the water bath at 20 °C. The crude acid (semi solid) was used immediately in the next step with out any purification (0.970 g, 50%). Synthesis of 10. To a solution of 9 (4.0 g, 20 mmol) in MeOH (10 mL) was added 1M phosphate buffer (5 mL) to a pH~7.5 and a freshly prepared solution of (di-(3,4-dihydro-2H-pyrrole))diiodozinc (4.57 g, 10 mmol in water (60 mL). The reaction mixture was stirred for 3 days at room temperature and then cooled to 0 °C and acidified using Congo red as the indicator. The reaction mixture was extracted with ether and the ether layer was discarded. The water layer was cooled to 0 °C and basified carefully to pH~8 using K2CO3 The water layer was extracted with CHCl3 (3 × 20 mL). The combined extracts were dried over Na2SO4 and concentrated to provide 10 as oil. The crude product (3 g, 75%) was used in the next step without additional purification. Synthesis of 11. To a solution of 10 (2.1 g, 10 mmol) in dry CH2Cl2 (10 mL), Et3N (1.5 mL, 15 mmol) was added and stirred for 5 min. To this solution phenylacetyl chloride (1.6 g, 15 mmol) was added slowly and stirred at room temperature for 12 h. The reaction mixture was extracted with CH2Cl2 (100 mL) washed with sat. NaHCO3 (20 mL), brine (10 mL) and water (10 mL), and dried over Na2SO4 The combined organic extracts were concentrated under reduced pressure. The crude product was purified twice by column chromatography on silica gel using 100% CH2Cl2 for the first column, followed by EtOAc: hexanes (7:3) for the second purification to provide 11 (2 g, 65%) as a semisolid. Synthesis of 12. To 11 (3.3 g, 10 mmol) was added ethanolic KOH (5%, 20 mL). After refluxing this reaction for 2 h, the solvent was removed under reduced pressure. The crude product was washed with 3% HCl and extracted with CH2Cl2 (2 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure. Column chromatography on silica gel, using EtOAc: hexanes (1:1) provided 12 (2.7 g, 80%, mp = 179-182 °C) as colorless crystals. 1H NMR (400 MHz, CDCl3) δ 1.75 (m, 1H), 1.88 (m, 1H), 2.06 (m, 1H), 2.29 (m, 1H), 2.82 (m, 2H), 3.63-3.72 (m, 2H), 3.75 (s, 3H), 3.95 (m, 1H), 6.67 (d, J = 7.4 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 7.19 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 23.59, 34.22, 37.96, 45.21, 55.54, 56.02, 113.69, 127.04, 127.96, 130.29, 131.54, 132.77, 136.75, 145.10, 159.23, 164.53. HRMS (ES+) m/z calc’d for [M+H]+ C21H22NO2: 320.1651, found 320.1635.
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(34) Synthesis of 19. With gentle heating and stirring, LC-biotin (0.070 g, 0.20 mmol) was solubilized in DMF (2 mL) after which was added EDCI (0.050g, 0.26 mmol). With the addition of DMAP (0.070 g, 0.57 mmol) the reaction mixture turned orange in color and the solution was stirred for 30 min. at ambient temperature. In a separate flask was dissolved aniline 23 (0.021 g, 0.063 mmol) in DMF (2 mL) and the LC-biotin mixture was subsequently added. The reaction was allowed to progress over 24 h after which it was quenched with the addition of water. EtOAc was added and used to extract the product into the organic phase. Equal amounts of water and EtOAc were added and the organic product was extract into the EtOAc layer. The aqueous and organic phases were separated and the aqueous phase was extracted an additional four times with EtOAc. The combined organic fractions were washed four times with water to remove excess DMF then once with brine. The organic phase was dried over sodium sulfate then condensed under reduced pressure. The biotinylated product 19 was purified via flash column chromatography using silica gel (9% MeOH/CH2Cl2) in 29% yield (0.029 g): 1H NMR (400 MHz, CDCl3) δ 1.20-2.35 (m, 20H), 2.60-2.95 (m, 4H), 3.10-3.35 (m, 3H), 3.60-3.73 (m, 2H), 3.73 (s, 3H), 4.00 (m, 1H), 4.28 (m, 1H), 4.42 (m, 1H), 6.36 (d, J = 19.58 Hz, 1H), 6.51 (d, J = 7.55 Hz, 1H), 6.65 (d, J = 7.56 Hz, 2H), 6.76 (d, J = 9.56 Hz, 1H), 6.96 (m, 4H), 7.39 (d, J = 9.73 Hz, 1H), 7.61 (m, 1H), 9.03 (d, J = 11.84, 1H); MS (FAB+) [M+H]+ C37H48N5O5S: m/z 674.