A gold(i)-catalysed approach towards harmalidine an elusive alkaloid from Peganum harmala

Upon gold catalysis, the 2,3-dihydropyrrolo[1,2-a]indole motif, encountered in few but interesting bioactive natural products, was efficiently obtained from N-aryl 2-alkynylazetidine derivatives. In an attempt to apply this methodology to the synthesis of harmalidine, isolated from the seeds of Peganum harmala, advanced amino 2,3-hydropyrrolo[1,2-a]indol(one) derivatives were readily obtained in only 11 steps from but-3-yn-1-ol. While the reported structure of harmalidine could not be reached from these intermediates, a surprising 12-membered diimino dimer was isolated. Extensive comparison of the reported harmalidine NMR data to the experimental and calculated data of our synthetic molecules, harmaline or the synthetised N-methylharmaline show discrepancies with the proposed natural product structure.


S2
Experimental and predicted 13 C NMR data of harmalidine & compound 13 Table S1. Comparison of experimental and predicted 13 C NMR data of harmalidine and experimental 13 C NMR data pyrrolo [1,2-a]

General Procedure 1 for preparation of alkynyl aldimines (GP1)
The appropriate ,-acetylenic aldehyde (5 mmol, 1 equiv) was dissolved in dry Et 2 O (10 mL) with MgSO 4 (15 mmol, 3 equiv) and the appropriate aniline derivative (5 mmol, 1 equiv) and vigorously stirred at room temperature for 16 hours. The mixture was then filtered through a pad of celite before being concentrated under vacuum. The crude imine 3 was used in the next step without purification (yields were assumed quantitative).

General Procedure 2 for enolate-imine condensation (GP2)
To a cooled solution of DIPA (4.4 mmol, 2.2 equiv) in toluene (8 mL) at -78 °C under argon was added n-BuLi dropwise (1.6 M in hexanes, 4.4 mmol, 2.2 equiv). After 10 min of stirring, ethyl isobutyrate (4 mmol, 2 equiv) previously dissolved in 2 mL of toluene was added dropwise and the mixture was warmed to 0 °C. After 30 min of stirring, the imine 3 (2 mmol, 2 equiv) previously dissolved in 2 mL of toluene was added dropwise. The mixture was then warmed to room temperature and stirred overnight. The reaction was quenched with 1N HCl (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water, NaHCO 3 , brine, and dried over MgSO 4 . After filtration and evaporation, the crude product was purified by flash chromatography (SiO 2 , Cyclohexane/EtOAc) to afford the title azetidinone 4.

General Procedure 3 for azetidinone reduction (GP3)
To a stirred solution of AlCl 3 (6 mmol, 3 equiv) in Et 2 O (5 mL) at room temperature under argon was added a solution of LiAlH 4 (6 mmol, 3 equiv) previously dissolved in Et 2 O (10 mL). The resulting mixture was refluxed for 30 min and the azetidinone 4 (2 mmol, 1 equiv) was added dropwise as a solution in Et 2 O (2 mL). After completion of the reaction (within a few minutes as monitored by TLC), the mixture was cooled to 0 °C, diluted with Et 2 O (at least 50 mL) and an aqueous sodium potassium tartrate solution (12 mmol, 6 equiv in 50 mL H 2 O) was added very carefully and dropwise until bubbling stopped. The mixture was then stirred vigorously for several hours until decantation was clean. After separation of the two layers, the aqueous layer was extracted with Et 2 O (3 x 10 mL), the combined organic layers were washed with water and brine, concentrated and the residue was stirred for 30 min in a 3:1 THF/water mixture (30 mL) in the presence of EDTA (4 mmol, 2 equiv). After partitioning the mixture between Et 2 O and brine (30 + 30 mL), layers were separated, and the aqueous layer was extracted again with Et 2 O (30 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated, and the residue was purified by flash chromatography (SiO 2 , Cyclohexane/EtOAc) to afford the title compound 5.

General Procedure 5 for the oxidation of pyrrolo[1,2-a]indoles using TFAA and DPSO or DMSO (GP5)
Anhydrous DMSO or DPSO was dissolved in dry DCM and cooled to -78 °C. Freshly distilled trifluoroacetic anhydride was then carefully added via syringe to the solution, which was then stirred for 15 min at -78 °C. Pyrroloindole 6 (1 equiv) was dissolved in DCM in a second flask, cooled to -78 °C and finally added to the first flask via cannula. In each case, a strong coloration was immediately observed and the reaction reached full conversion within minutes. (All the pyrroloindol-1-ones synthesized in this section strongly revealed under the UV lamp). In some cases, the reaction mixture was quenched via classical workup conditions, or filtered through alumina to yield the crude product. Purification of the product by column chromatography S13 (SiO 2 , cyclohexane/EtOAc) must be done immediately thereafter or the crude mixture has to be stored directly in the freezer to avoid degradation of the product.

General Procedure 6 for the oxidation of indoles using oxalyl chloride and DMSO (GP6)
Anhydrous DMSO (1.0 mmol, 6 equiv) was dissolved in dry DCM (0.6 mL) and cooled to -78 °C. Freshly distilled oxalyl chloride (0.5 mmol, 3 equiv) was then carefully added via syringe to the solution, which was then stirred for 15 min at -78 °C. Indole derivatives (0.17 mmol, 1 equiv) were dissolved in DCM (1 mL) in a second flask, cooled to -78 °C and finally added to the first flask via cannula. In each case, a strong coloration was immediately observed, and the reaction reached full conversion within minutes. (All the pyrroloindol-1-ones synthesized in this section strongly revealed under the UV lamp). The flask was then removed from the cooling bath but the mixture was directly filtered through a small pad of celite and finally evaporated without letting it reach room temperature. The delicious smell of Me 2 S will tell you if the reaction is successful or not! Purification of the product by column chromatography (SiO 2 , cyclohexane/EtOAc) must be done immediately thereafter or the crude mixture must be stored directly in the freezer to avoid degradation of the product.

Identification Code
Compound 12