Total synthesis of (+)-lentiginosine via a key Au catalysis

Abstract

Total syntheses of (+)-lentiginosine and its 8a-epimer using a gold-catalyzed oxidative cyclization as the key step were realized. The gold chemistry, reported previously in a [4+2] synthesis of piperidin-4-ones, tolerates functionalized structures and is compatible with several protecting strategies albeit with low diastereoselectivities.

CH Bond Functionalization through Intramolecular Hydride Transfer

“…However, the mechanism proposed above would require a less‐common 1,7‐hydride shift to account for the formation of seven‐membered rings. Later, this methodology was applied to the stereoselective total synthesis of the natural product (+)‐lentiginosine ( 250 ), a bioactive azasugar 81c. As shown in Scheme , readily available butynylpyrrolidine 248 is subjected to a protocol similar to that in the cermizine synthesis.…”

Synthesis of piperidine and quinolizidine alkaloids

“…In the case of (+)-7-epi-dendroprimine 1-147 (Scheme 1. dendroprimine was realised by means of transformations analogous to those described earlier for the syntheses of (-)-dendroprimine 1-145 and its 5-epimer 1-146. While spectral data of (-)-dendroprimine and (+)-7-epi-dendroprimine 1-147 were in agreement with those reported in literature, the 13 C NMR spectrum of (+)-5-epi-dendroprimine was different from the reported data by Gelas-Mialhe. 63 The authors hypothesised that the correct structure in Gelas-Mialhe's synthesis might have been the (+)-5,7-epi-dendroprimine instead.…”

“…12 Zhang and co-workers have synthesised (+)-lentiginosine and its 8aepimer, 1-5, using a gold-catalysed cyclisation as a key step, albeit with low diastereoselectivity. 13…”

“…Kim et al 71 have adopted a strategy similar to one published by Ma and Zhu 72 for the synthesis of (-)-lasubine II and demonstrated that removal of the Cbz protection group on the nitrogen of key precursor 1-175 triggered a sequential endo-type Michael addition followed by an S N 2 reaction to form the quinolizidine framework in (-)-lasubine II (1-174) (Scheme 1. [3][4][5][6][7][8][9][10][11][12][13][14]. Reduction of 1-175 was found to be most optimal with hydrogenation in refluxing methanol at atmospheric pressure in the presence of Pd/C to give (-)-2-epilasubine II 1-176 in 37% yield.…”

“…2:1) but were consistently found to be poorer (1:1) on larger scale reactions as could be seen by integration of the diagnostic peaks in the 1 H NMR spectra ( Figure 3.4-17 and Figure 3. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The reaction yield was also significantly higher on small scale (~65%) but yields on large scale reactions ranged between 30 to 40%.…”