Highly convergent total synthesis of (+)-anaferine and (−)-dihydrocuscohygrine

Abstract

The total synthesis of (+)-anaferine and (−)-dihydrocuscohygrine is described. Bidirectional cross metathesis/double intramolecular aza-Michael reactions were the key steps.

Two Decades of Progress in the Asymmetric Intramolecular aza‐Michael Reaction

“…Finally, our research group described in 2019 a double IMAMR of N-sulfinyl amines 90 as the key step in the synthesis of alkaloids anaferine and dihydrocuscohygrine. [93] Substrates 92 were assembled by a double direction cross metathesis reaction of sulfinyl amines 90 and divinyl ketone 91, generated in situ through oxidation of the corresponding alcohol. Cyclization of compounds 92 under basic conditions provided bis-piperidine 93a and bis-pyrrolidine 93b in very good yields and diastereoselectivities (Scheme 32).…”

Evolution of Strategies in Protecting‐Group‐Free Synthesis of Natural Products: A Recent Update

“…[ 60 ] Dihydrocuscohygrine having C 2 ‐symmetrical bis‐pyrroldine moiety, was isolated from Erythroxylon coco . [ 61 ] del Pozo and co‐workers [ 62a ] reported the chiral auxiliary‐based PGF‐synthesis of anaferine ( 164 ) and dihydrocuscohygrine ( 166 ) (Scheme 18). The synthesis began with the cross‐metathesis between divinyl ketone 161 and sulfinylamine 160a to deliver bis‐enone 162a along with mono‐cross‐metathesis product.…”

“…The concise PGF‐synthesis of anaferine ( 164 ) (3 steps) and dihydrocuscohygrine ( 166 ) (5 steps) was easily achieved taking advantage of C 2 ‐symmetry with the chiral auxiliary already masking the nitrogens and completed in 75 % and 45.3 % overall yields, respectively. The 2002 synthesis of anaferine by Blechert and Stapper [ 62b ] required 11 steps for completion (23 % overall yield). The same authors [ 62c ] in 2002 completed the first synthesis of (+)‐dihydrocuscohygrine in 9 steps and 30 % overall yield.…”

“…The 2002 synthesis of anaferine by Blechert and Stapper [ 62b ] required 11 steps for completion (23 % overall yield). The same authors [ 62c ] in 2002 completed the first synthesis of (+)‐dihydrocuscohygrine in 9 steps and 30 % overall yield. The later synthesis of (–)‐dihydrocuscohygrine in 2008 by Higashiyama [ 62d ] required 6 steps with protecting groups involvement and had 13.7 % overall yield.…”

Total Synthesis of (–)-Anaferine: A Further Ramification in a Diversity-Oriented Approach

“…The last total synthesis of (-)-anaferine was accomplished in 2002 by Stapper and Blechert [24], while del Pozo et al recently reported the preparation of the (+)-enantiomer [25] (Figure 3). Stapper and Blechert's strategy took advantage of an enantiopure cycloheptene precursor, accessed in five steps from the commercially available tropone.…”