"Exshperimental"

Name : Mooch

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Quote : "Yesh!"

Experimental procedure for (-)-72 to 73

3-Deoxy-3-chlorogalanthamine (73)*
To a solution of galanthamine ( 1 , 0.143 g, 0.479 mmol) in dichloromethane (5 ml) was added p-toluenesulfonyl chloride (0.227 g, 1.19 mmol) and pyridine (0.787 g, 0.800 ml, 9.94 mmol) at 0°C in an ice-water bath, under an argon atmosphere. The reaction mixture was brought to ambient temperature and stirred for 24 h. It was then diluted with dichloromethane, washed with saturated sodium chloride solution, filtered, and separated. The resulting organic layer was dried (Na 2 SO 4 ), concentrated under reduced pressure, and then purified by silica gel flash-column chromatography with acetone as an eluent to give compound 73* as a colorless oil (0.0810 g, 53% yield): TLC (MeOH:Me 2 CO, 1:3) R, 0.41; [a]i2-282.8� (c0.61, CHCl,); IR (CHCl,) 3040, 3010, 2940, 2840, 1630, 1510, 1440, 1325, 1290, 1260, 1240, 1195, 1165, 1120, 1065, 1050, 1035, 1010, 990, 890 cm-t; 1H NMR (CDCl 3 ) 6 1.74 (br dd, lH, J= 14.0, 2.1 Hz), 2.09 (ddd, lH, J= 13.8, 10.7, 2.4 Hz), 2.19 (dt, lH, J= 13.6, 2.7 Hz), 2.42 (s, 3H), 2.97 (m, lH), 3.11 (br d, IH, J = 14.4 Hz), 3.31 (br t, lH, J = 13.2 Hz), 3.70 (d, lH, J= 15.1 Hz), 3.85 (s, 3H), 4.11 (d, lH, J= 15.1 Hz), 4.57 (m, lH), 4.86 (ddd, lH, J = 10.8, 3.9, 1.9 Hz), 5.88 (br d, lH, J = 10.4 Hz), 6.06 (d, lH, J = 10.4 Hz), 6.60 (d, lH, J = 8.2 Hz), 6.66 (d, lH, J = 8.2 Hz); HRMS calcd for Ci7Hz,C1N02 (M+ + H) 306.125, found 306.123.

*Note that compound 73 corresponds to compound 10 in the Han article.

Han, S. Y.; Sweeney, M. E.; Bachman, E. S.; Schweiger, E. J.; Forloni, G.; Coyle, J. t.; Davis, B. M.; Joullie, M. M. Eur. J. Med. Chem. 1992 , 27 , 673.

Experimental section for 73 to (-)-20/74

From the reduction of chloride 73 : A solution of chloride 73 (397 mg, 1.50 mmol) in tetrahydrofuran (3.0 mL) at 0 ºC was treated with 1.0M lithium triethylborohydride (Super Hydride®) (3.0 mL, 3.0 mmol). After heating at 40 ºC for 8h, the solution was cooled to room temperature, quenched with 1M sodium hydroxide (25 mL), extracted with methylene chloride (3 x 25 mL), dried (MgSO4) and concentrated in vacuo to afford a yellow oil. Crude 1H-NMR shows a 2.5-3:1 mixture of olefin isomer 20 : 74 . The crude mixture was taken into methylene chloride (3 mL) and treated with a solution of phenylselenium chloride (200 mg, 1.04 mmol) in methylene chloride (10 mL). After heating at 40 ºC for 2h, the orange solution was cooled to room temperature and diluted with methylene chloride (25 mL), washed with 1M sodium hydroxide (25 mL), 1M sodium thiosulfate (25 mL), dried (MgSO4) and concentrated in vacuo . Flash chromatography eluting with 3:1 acetone: methanol afforded first selenide (39 mg, 6%) followed by amine 20 (129 mg, 37 %). [a]D = -118.1 (c = 1.0, CH2Cl2).

*Note: for definitions of underlined terms, see below.

Definitions:

chloride 73 (3-Deoxy-3-chlorogalanthamine)

galanthamine

dichrolormethane

another name for methylene chloride

sodium chloride

Na + Cl -

p-toluenesolfonyl chloride

pyridine

argon atmosphere

air sensitive reactions are typically run under atmospheres such as argon or nitrogen

ambient

room temperature

silica gel flash column chromatography

see flash chromatography

acetone

tetrahydrofuran

lithium triethylborohydride

Super Hydride

A trademark name for the Aldrich product of lithium triethylborohydride, an extremely powerful and selective reducing agent.

sodium hydroxide

NaOH

methylene chloride

, a common organic solvent also known as dichlormethane

in vacuo

in a vacuum

olefin isomer

The term olefin is another name referring to an alkene, or double bond. The olefin isomer in this case refers the two isomers, 20 and 74, that differ in the location of a double bond.

phenylselenium chloride

sodium thiosulfate

flash chromatography

A faster alternative to column chromatography, a way to separate compounds in a sample. A plastic column is typically filled with silica gel, the sample placed on top, and the solvent flushed through with the help of pressure.

methanol

 selenide

Se -2 , the anion form of selenium

amine 20

"Yeesh! That's a lot of definitions!"