Supporting information for J. Med. Chem., 1992, 35(16), , DOI: /jm00094a025 BLOOM

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1 Supporting information for J. Med. Chem., 1992, 35(16), , DOI: /jm00094a025 BLOOM Terms & Conditions Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at Copyright 1992 American Chemical Society

2 M m) SUPPLEMENTAL MATERIAL- EXPERIMENTAL All compounds show an appropriate proton nmr spectrum. Melting points are uncorrected. Disodium (R,R)-5-[2-[[2-(3-Chlorophenyl)-2- hydroxyethyl]amino]propyl]-1.3-benzodioxole-2.2-dicarboxylate. 3 Carbamate 19 (10.0 g, 19.8 mmole) was heated to reflux in a solution of 2.5 sodium hydroxide (80 ml, 200 mmole). A white solid formed after 10 min, but disappeared upon prolonged heating. After heating for 24 h, the solution was cooled, acidified to ph 10 (3 HCl, 12 ml) and loaded onto a 47 cm x 5 cm column equipped with a scintered glass disk, packed with C18 silica (350 ml) which was first activated by washing with methanol (400 ml) and then dilute sodium hydroxide (ph 8.5, 400 ml). After loading, the inorganic impurities were eluted using 600 ml additional dilute sodium hydroxide (ph 8.5). eluted by washing with methanol (1000 ml). The product was then Evaporation of the methanol followed by addition of water (60 ml) and Celite filtration gave a clear brown solution. This solution was evaporated to a volume of ml and ethanol (500 ml) was added causing a white precipitate to form. ethanol, then ether, and dried in vacuo. The solid was collected, washed with fresh The yield of the white dry powder was 7.83 g (85%). [a]d26???=-26???± 1 (c=1.058, H2O). Anal. calcd. for C20H18NO7ClNa2 plus 1.9% H2O : C, 50.59;, 4.03; N, 2.95; Na, 9.68; Cl, 7.47 Found: C, 50.72; H, 4.39; N, 2.93; Na, 9.06; Cl, 7.44.

3 /A /. FABMS calcd for C20H19NO7ClNa2 (M+H) Chlorophenacyl chloride, 5 Sulfuryl chloride (121 ml; g; m/z , found 1.5 mole) was added in one portion to well stirred 3'-chloroacetophenone (260 ml; g, 2.0 mole) in a 4 L beaker. A period of vigorous gas evolution ensued. Stirring was continued for 30 min and then the reaction was diluted with 500 ml of methylene chloride and treated with about 1800 ml of saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was further treated with ml portions of the bicarbonate solution. After drying over anhydrous magnesium sulfate the methylene chloride solution was concentrated to an oil in vacuo. This oil was distilled through a 12 inch Vigreux column. The fraction coming over at C at 350µ was collected. This fraction was crystallized, then recrystallized from heptane to give g (41%) of product, mp C (lit ). EI low resolution mass spectrum, m/z 188. (R)-l-(3-Chlorophenyl)-2-chloroethanol, 6 To a solution of 3.6 g (0.013 mol) asymmetric reduction catalyst 8 in 200 ml of THF at 25 C was added simultaneously a solution of 25.0 g (0.13 mol) of 5 in 85 ml of THF, and a solution of borane-thf complex (84.0 ml, 1.0, mol) over 0.5 h. mixture was stirred at 25 C for 1 h, poured into water (1 L) and extracted with ether (400 ml). The ether solution containing the product was washed with aq. NaHCO3, then brine, dried (MgSO4) and concentrated. The resulting cloudy liquid was distilled through a The short path (95-97 C, 400µ) to give g (87%) of a colorless, clear

4 - - liquid. ester. The ee (85%) was determined by NMR analysis of the Mosher [a]d26 =-31 ±l (c=1.181%). (R)-3-Chlorostyrene oxide, 7 A mixture of (R)-1 -(3-chlorophenyl)-2-chloroethanol (6) (18.66 g, mole), powdered potassium carbonate (75 g) and acetone (500 ml) was heated at reflux for 48 h. The mixture was filtered through Celite, concentrated, and distilled through a path (50-60 C, 25-50µ) to yield the product, a colorless liquid, short g (89%). The epoxide was stable in the freezer for long periods of time. [a]d26 =+10±l (c=1.02%, EtOH). Anal, calcd. for C8H9ClO: C, 62.15; H, 4.56; Cl, Found: C, 62.18; H, 4.53; Cl, (S)-N-(t-Butyloxycarbonyl)-3.4-dihydroxyphenylalanine, 10 A mixture of g (0.916 mole) of L-DOPA and 200 g (0.916 mole) of di-t-butyl dicarbonate in 1 L of DMF was heated at 70 C for 20 h under argon. The mixture was cooled and unreacted DOPA was removed by filtration (48 g of recovered DOPA). The filtrate was washed with ethyl acetate and the filtrate evaporated to yield a yellow oil. The oil was partioned between ethyl acetate (300 ml) and 300 ml of 5% citric acid solution. The ethyl acetate extract was washed with 300 ml of 5% citric acid and the combined aqueous layer was reextracted with ethyl acetate. The combined ethyl acetate extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to yield 182 g of orange foam (contains DMF) which was used in the next step without further purification.

5 (S)-N-(t-Butyloxycarbonyl)-3,4-dimethoxyphenylalanine ester, 11 methyl A mixture of 182 g (0.67 mole) of 10, 303 ml (691.0 g, 4.87 mole) of iodomethane and 846 g (6.13 mole) of anhydrous potassium carbonate in 2.0 L of acetone was heated at reflux for 16 h. The mixture was cooled, filtered, and the filtrate concentrated. The residue was taken up in 700 ml of ethyl acetate, washed with water (500 ml), brine (2 x 300 ml), dried over anhydrous magnesium sulfate and evaporated to yield an orange oil which solidified on standing, yielding 185 g (81% in two steps from L- DOPA) of a yellow solid. (c=0.586%, A sample was crystallized from EtOAchexane to yield a white solid, m.p C; [a]d26 =+4 +2 MeOH). Anal, calcd. for C17H25NO6: C, 60.16; H, 7.42;, Found: C, 59.86; H, 7.65; N, (S)-N-(t-Butyloxycarbonyl)-3,4-dimethoxyphenylalaninol, 12 To a cold (5 C) solution of 11 (191 g, THF was added portions over a period of 20 min mole) in 1.1 L of 15.0 g (0.689 mole) of lithium borohydride in for 20 min and then at 25* for 3 h under argon. The mixture was stirred at 8-10 C The mixture was cautiously diluted with 1.5 L of water, stirred for 5 min, 1.0 L of ethyl acetate was added and stirred for 1 h. The layers were separated and the aqueous layer was extracted with 600 ml of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness to yield 171 g (98%) of a white solid. The solid was recrystallized from ethyl acetate-hexane to yield 158 g (90%) of a white solid, m.p C; [a]d26???= (c=1.019%,

6 fw3c6v-/r)s MeOH). Anal. calcd. for C16H25N05: C, 61.72;, 8.09;, C, 61.56; H, 7.98; N, (S)-N-(t-Butyloxycarbonyl)-3,4-dimethoxyphenylalaninyl methanesulfonate, 13 Found: To an ice cold (0-5 C) solution of 143 g (0.459 mole) of 12 and triethylamine (245 ml,178 g, 1.76 mole) in 1400 ml of tetrahydrofuran was added dropwise a solution of 73 ml (108 g, mole) of methanesulfonyl chloride in 100 ml of THF at 5-10 C over a period of 45 min, and the resulting mixture was stirred at 10 C for 1 h under argon. The mixture was diluted with 1 L of water and extracted with 2 x 700 ml of ethyl acetate. The ethyl acetate extract was washed twice with 600 ml of 2 HCl, twice with 500 ml of 1 NaOH, brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. The resulting solid was triturated with hexane, collected by filtration, washed with hexane and dried to yield 155 g (86%) of off-white solid. A sample was purified by flash chromatography to yield a white solid, m.p C; [a]d26 =-13 ±1 (c=1.006%, EtOH). Anal. calcd. for C17H27NSO4: C, 52.42; H, 6.99;, 3.60; S, Found: C, 52.37;, 7.07; N, 3.58; S, (R)-3,4-Dimethoxyamphetamine, 14 A solution of 13 (50 g, mole) in 200 ml of CH2Cl2 was passed through a pad of 200 g of Magnesol placed in Buchner funnel, and washed with an additional 4 x 200 ml portion of CH2Cl2. To this filtrate was added 100 ml of trifluoroacetic acid and the solution was stirred for 3 h. The solvent was evaporated in vacuo to

7 ft -3DMfo yield 77.0 g of thick oil which was taken up in absolute ethanol, treated with Darco, and filtered. The filtrate was added to 5 g of palladium hydroxide on carbon followed by 750 ml of absolute ethanol and 35 g of sodium acetate (ph 4). The resulting mixture was shaken on a Parr apparatus at 30 psi of hydrogen for 24 h, filtered through a pad of Celite, washed with ethanol and the filtrate was evaporated in vacuo to yield water, basified (ph 13) with 10 N an oil. The oil was taken up in NaOH and extracted with 3 x 150 ml of ether. The ether fraction was washed with brine, dried over anhydrous Na2SO4, and evaporated to yield 13.2 g (52%) of crude oil. The crude material from several such runs were combined and distilled on the Kugelrohr apparatus to yield a white solid, bp C/250u; [a]d26 =-31 ±1 (c=1.064%, EtOH). Anal. calcd. for C11H17NO2: C, 67.66; H, 8.78;, Found: C, 67.42; H, 8.63;, (R,R) 3-Chloro-(((2-(3,4-dimethoxyphenyl)-lmethylethyl)amino)methyl) benzenemethanol, 16 To a DMSO was added solution of g (0.748 mole) of 14 in 700 ml of 108 g (0.823 mole) of N-(trimethylsilyl)acetamide and the mixture was stirred at room temperature for 1 h under argon. A solution of R-3-chlorostyrene oxide ( g, mole) in 100 ml of DMSO was added and the resulting mixture was heated at C for 48 h. The mixture was poured into a mixture of ice and 150 ml of conc. HCl, stirred for 15 min and washed with 3 x 350 ml of ether. The aqueous solution was basified with 10 N of ether. anhydrous NaOH (200 ml) and extracted with 3 x 500 ml The ether extract was washed with brine, dried over Na2SO4,and evaporated to dryness to yield 247 g (94%) of

8 ZY)'3C6W7 a light yellow oil. step. The oil was used without purification in the next A sample was purified by flash chromatography to yield a colorless oil which solidified on standing to yield a white solid: m.p C; [a]d26 =-38 ±1 (c=1.041%, EtOH). Anal. calcd. for C19H24NClO3: C, 65.22;, 6.91;, 4.00; Cl, Found: C, 64.91; H, 6.99;, 3.70; Cl, (R,R)-5-(3-Chlorophenyl)-3-(2-(3,4-dimethoxyphenyl)-lmethylethyl)-2-oxazolidinone, 17 A mixture of 16 (245 g, 0.70 mole), 1,1'-carbonyldiimidazole (227 g,1.40 mole) and triethylamine (605 ml) in 1.3 L of THF was stirred at room temp, overnight under argon. The mixture was poured into 3.5 L of water and extracted with 3 x 800 ml of ether. The ether extract was thoroughly washed with 3 x 650 ml of 2 HCl, 3 x 600 ml of brine, dried over anhydrous MgSO4, filtered and the filtrate was evaporated to dryness to yield 234 g of beige oil. The oil was crystallized from a solution of ethyl acetate (220 ml) and hexane (200 ml) to yield 146 g of white crystalline material. The filtrate was concentrated to yield 80 g of oil, which was purified by preparative HPLC (EtOAc-hexane 1:4) of white crystalline material. to yield an additional 15 g The total purified yield was 161 g (57%), m.p C; [a]d26 =-39 ±l (c=0.858%, EtOH). Anal. calcd. for C20H22NClO4: C, 63.91;, 5.90; N, 3.73; Cl, Found: C, 64.21; H, 5.90;, 3.60; Cl, (R,R)-5-(3-Chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-lmethylethyl)-2-oxazolidinone, 18 To an ice cold (5 C) solution of (160 g,0.426 mole) of 17 in 1.2 L of CH2Cl2 was added dropwise a solution of 121 ml (320 g,

9 fw3c6«1.28 mole) of boron tribromide in 100 ml of CH2Cl2 over a period of 50 min (temp. 4-8 C), stirred at 6 C for 20 min and then at ambient temp for 45 min. The mixture was recooled and water was added cautiously (foaming), causing a solid to precipitate. mixture was stirred at 25 C for 1 of water and 2 L of CH2Cl2). The resulting h to obtain a clear solution (2.5 L The two layers were separated and the organic layer was washed with brine (white solid started to precipitate, which redissolved after addition of a small amount of ethyl acetate), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to an oil. white crystals, (110 g, 74%) m.p. Crystallization from ethyl acetate yielded C; [a]d26 =-62 ±l (c=1.018%, EtOH). Anal. calcd. for C18H18NClO4: C, 62.16; H, 5.22; N, 4.03; Cl, Found: C, 62.25;, 5.18; N, 3.94; Cl, (R,R)-5-(2-(5-(3-Chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3- benzodioxole-2,2-dicarboxylic acid, diethyl ester, 19 A mixture of 18 (117.0 g, mole), diethyl dibromomalonate (114.6 g, 0.36 mole), and anhydrous K2CO3 (234 g, 1.69 mole) in 1.6 L of acetone was stirred at 25 C overnight. The mixture was filtered and concentrated to yield a yellow oil. oil was purified by preparative HPLC (Waters PrepPAK-500 silica column, toluene-acetone 20:1, 250 ml/min) to yield g (64%) of a yellow oil which solidified on standing, giving a white solid. sample was recrystallized from ethyl acetate-hexane to yield a white solid, m.p C; [a]d26 =-64 ±1 (c=1.044%, EtOH). Anal. calcd. for C25H26NClO8: C, 59.69;, 5.20; N, 2.78; Cl, Found: C, 59.73; H, 5.23; N, 2.66; Cl, The The