* Step 3: 2-Carbomethoxy-7-(gamma-carbomethoxy-beta-hydroxypropyl)hexahydropyrrolo[1,2-b]isoxazole [3]
To 235 mg (1.27 mmol) of adduct [2] in 70 ml of dry CH2Cl2, while stirring in an ice bath under nitrogen, was added 284 mg (1.1 eq.) of 85 % m-chlorobenzoic acid. After 2 h, the solution was warmed to room temperature and extracted with wather. The aqueous layer was concentrated in vacuo to give a clear oil which was taken up in CH2Cl2, dried over sodium sulfate, and filtered. The solvent was removed and the residue was dissolved in 70 ml of dry benzene, to which was added 5 ml of methyl acrylate. The resulting light yellow solution was refluxed for 20 h, cooled to room temperature, and extracted with 1 N hydrochloric acid. The acid extract was basicified with sodium bicarbonate, then extracted with CH2Cl2 to give, after drying over sodium sulfate, 282 mg (77 %) of a mixture of adducts [3] as a light yellow oil.
Step 4: 2-carbomethoxy-7-(gamma-carbomethoxy-beta-methanesulfonylpropyl)hexahydropyrrolo[1,2-b]isoxazole [4]
Freshly distilled methanesulfonyl chloride (91 microliter, 2 eq.) was added dropwise via a syringe to a stirred solution of 170 mg (0.59 mmol) of hydroxy ester [3] in 25 ml of freshly distilled, dry pyridine under a nitrogen atmosphere in an ice bath. After 1 h, the solution was warmed to room temperature, stirred for an additional 3 h, then poured onto ice. Potassium carbonate was added and the aqueous solution was extracted with CH2Cl2. The organic extract was dried over sodium sulfate, filtered, and concentrated to give 204 g (95 %) of [4] as a light yellow oil.
Step 5: 2-carbomethoxy-7-(3'-carbomethoxy-2'-trans-propenyl)hexahydropyrrolo[1,2-b]isoxazole [5]
Under nitrogen, 204 mg (0.56 mmol) of methanesulfonate ester [4] was dissolved in 25 ml of dry benzene, to which was added 138 mg (2 eq.) of freshly distilled 1,5-diazabicyclo[4.3.0]non-5-ene via a syringe. The resulting suspension was stirred for 4h, washed with 25 ml of saturated sodium bicarbonate solution and twice with 25 ml of water, then dried over sodium sulfate. The solvent was removed in vacuo to give 130 mg (86 %) of trans olefin [5] as a light yellow oil.
Step 6: 2-carbomethoxy-(1S*,2R*,3R*,6S*)-7-aza-8-oxotricyclo[4.2.1.03.7]nonane [6]
A solution of 78 mg (0.29 mmol) of the crude trans olefin [5] in 50 ml of dry, distilled xylene was refluxed for 3h. The solution was extracted with 1 N HCl. The acid extracted was basicified with sodium bicarbonate, then backextracted with CH2Cl2. The CH2Cl2 extract was dried over sodium sulfate, filtered, and concentrated to give a light yellow oil. Sublimation at 70 °C (0.08 mm) gave a mixture of 9 mg of [5] and 31 mg (66 %) of [6]. Crystallization from pentane gave an analytical sample of [6] as white plates.
Step 7: Methiodide of methyl (1S*,2R*,3R*,6S*)-7-aza-8-oxatricyclo[4.2.1.03,7]nonane-2-carboxylate [7]
To a solution of 140 mg (0.77 mmol) of cycloadduct [6] in 10 ml of anhydrous ether and 3 ml of CH2Cl2 was added 2 ml of methyl iodide (32 mmol) and this mixture was stirred under nitrogen at room temperature for 12 h. The resulting mixture was refluxed for an additional 24 h. Concentration gave a yellow solid residue that was recrystallized form MeOH/Et20 giving 145 mg (58 %) of a white solid.
Step 8: Ecgonine methyl ester [8]
To a solution of 140 mg (0.77 mmol) of the methiodide [7] in 4 ml of 50 % aqueous acetic acid was added 0.6 g of activated zinc dust under a nitrogen atmosphere. The resulting mixture was warmed to 70 °C for 3.5. The remaining solids were filtered and washed with 8 ml of hot water (ca 70 °C) The filtrate was saturated with solid sodium carbonateand continuously extracted with CH2Cl2 for 18 h. The CH2Cl2 solution was dried (MgSO4), concentrated, and bulb to bulb distilled in a Kugelrohr apparatus giving 43 mg (47 %) of a colorless oil.
Step 9: dl-Cocaine [9]
Following the method of de Jong, 23 mg (0.12 mmol) of compound [8] in 1 ml of dry benzene was added to a mixture of 1 g (9.4 mmol) of anhydrous sodium carbonate, 0.5 ml (4.3 mmol) of benzoyl chloride, and 19 ml of dry benzene. The resulting mixture was worked up as reported [ref.: Recl. Trav. Chim. Pays-bas (1940), vol 59, p 27-30] to give 9.8 mg (37 %) of a colorless oil that solidified on standing.
So, fellow bees, this is the synthesis of cocaine. In retrospect, this synthesis is not very promessing because it is too difficult in comparison with a meth synthesis. But, as a chemist, I have to say that Tufariello and coworkers did some great work (whow)