## 3 Results and Discussion  
### Synthesis and Structure Elucidation of Aaptoline B  
The retrosynthetic analysis for **1** is depicted in Figure 2, which includes the 6-endo selective transition metal-catalyzed cycloisomerization of 4-propagylaminoindole **2**. Precursor **2** was expected to be readily synthesized from the known dinitrobenzoate **3** by Batcho-Leimgruber indole synthesis, a powerful synthetic method for the synthesis of indoles from ortho-nitrotoluenes, which proceeds via the formation of the enamine intermediates and subsequent reductive cyclization [12], followed by regioselective \(N\)-propagylation. As shown in Scheme 1, our synthesis commenced with the preparation of previously reported ethyl 4-methyl-3,5-dinitrobenzoate **3**. Thus, benzoic acid **4** was refluxed in anhydrous ethyl alcohol in the presence of sulfuric acid to afford ethyl benzoate **3**[11]. When \(N\),\(N\)-dimethylformamide dimethyl acetal was used, according to the literature [13] to obtain enamine **5** from **3**, followed by reductive cyclization, the indole ethyl carboxylate **6** was obtained as a mixture with the corresponding methyl ester **6\({}^{\prime}\)**. We supposed that methoxide or methanol, possibly generated from dimethylformamide dimethyl acetal, led to unexpected transesterification. Hence, we performed the Batcho-Leimgruber indole synthesis reaction of **3** using \(N\),\(N\)-dimethylformamide diethyl acetal instead of dimethyl acetal, and obtained ethyl indole carboxylate **6** in 74% (two steps from **3**) without methyl ester byproducts. To minimize side reactions, such as over-alkylation and \(N\)-alkylation of pyrrolic nitrogen atom, we intensively investigated the reaction conditions of \(N\)-propagylation of **6** into 4-propagylaminoindole **2** by altering the amount of reagents, reaction time, and temperature. The optimal yield (61% isolated yield; 71% brsm yield) was achieved without \(N\)-alkylation of aromatic pyrrolic amine when the DMF solution of **2** and 1.1 equivalents  
Figure 2: Retrosynthetic analysis of aaptoline B (**1**). of propargyl bromide was heated at 65 \({}^{\circ}\)C for 72 h with 2.2 equivalents of K2 CO3 and a catalytic amount of KI [14]. With the cyclohexomerization precursor **2** in hand, we tested diverse transition metal catalysts (Table 1) to find out the optimal reaction conditions. We initially carried out cyclohexomerization of **2** with 0.1 equivalent of CuI (entry 1), and obtained **1** with 56% yield. When the reaction was conducted with InCl3 (entry 2) or AuCl (entry 3), the yields (18% and 27%, respectively) were poorer. The use of AgSbF6 as catalyst resulted in the best yield (73%, entry 4), being superior to other catalysts of Ag(I), such as AgNO3 (61%; entry 5) and AgOTf (35%; entry 6). However, the NMR spectra of **1** differed from those reported when using the same deuterated solvent (CDCl3). Significant differences were observed in both the \({}^{1}\)H and \({}^{13}\)C \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Entry 1** & **Catalyst** & **Time (h)** & **Yield 2 (\%)** \\ \hline
1 & CuI & 2 & 56 \\
2 & InCl3 & 27 & 18 \\
3 & AuCl & 8 & 27 \\
4 & AgSbF6 & 4.5 & 73 \\
5 & AgNO3 & 5 & 61 \\
6 & AgOTf & 5 & 35 \\ \hline \hline \end{tabular} \({}^{1}\) 30 mg of **7** in DMSO (0.1 M solution) was reacted; 2 Isolated yields.  
\end{table} 
Table 1: Catalyst screening for the completion of synthesis of proposed structure of **1**. NMR spectra of our synthetic sample compared to those of the isolated product [4]. To precisely confirm the structure of synthetic **1**, we employed two-dimensional NMR analysis (700 MHz, CD\({}_{3}\)OD; see the Supplementary Materials). Proton at C-3 was clearly revealed by homonuclear correlation spectroscopy (\({}^{1}\)H-1-H COSY) by correlations with the neighboring aromatic protons on C-2 and C-4, which were confirmed by further investigation employing heteronuclear correlation spectroscopy.