Pictet-Spengler Reaction

1. Reaction between the amine and the aldehyde gives rise to an aminal. 2. The aminal is dehydrated under acidic conditions to give an iminium ion. 3. The iminium ion reacts with the aromatic ring in a 6-endo-trig cyclization to afford the six-membered heterocycle. 4. The loss of a proton restores the aromatic ring.

1. Formation of an iminium ion. 2. Electrophilic addition at the 3-position, in accordance with the expected nucleophilicity of indoles, gives an spirocycle intermediate. 3. Final migration of the best migrating group and deprotonation.

A round-bottom flask was charged with D-tryptophan methyl ester hydrochloride (39.0 mmol, 1.0 eq) and anhydrous MeOH (130 mL). Upon dissolution, 2,3-butadione (2.5 eq) was added, and the solution was stirred at 65 °C for 20 h. The reaction contents were then cooled to room temperature and partitioned between saturated aqueous NaHCO3 and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were then dried (Na2SO4), filtered, and concentrated. A portion of the major diastereomer was collected as white crystalline solid via trituration and washing with EtOAc (62% yield).