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Total Synthesis of Meloscine by a [2+2]‐Photocycloaddition/Ring‐Expansion Route
Author(s) -
Selig Philipp,
Herdtweck Eberhardt,
Bach Thorsten
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802383
Subject(s) - enantioselective synthesis , stereocenter , claisen rearrangement , chemistry , cyclobutane , stereochemistry , metathesis , reductive amination , ring (chemistry) , total synthesis , salt metathesis reaction , bicyclic molecule , organic chemistry , polymer , polymerization , catalysis
The stereogenic centers at C3 and C12 of meloscine ( 3 ) can be established in the photochemical key step 1 → 2 . 1,2‐ retro ‐Benzilic acid rearrangement to a five‐membered ring, reductive amination, Claisen rearrangement, and ring‐closing metathesis are further key steps in the transformation of cyclobutane 2 into the target molecule 3 (14 steps, 9 % overall yield). Enantioselective access to (+)‐meloscine was possible when the [2+2]‐photocycloaddition was conducted in the presence of a chiral template.The unusual monoterpenoid indole alkaloid meloscine was synthesized starting from a protected aminoethylquinolone in 15 steps and an overall yield of 9 %, employing a [2+2]‐photocycloaddition as the stereochemistry defining key step. After the initial plan of a Wagner–Meerwein type rearrangement of a [4.2.0]‐ into a [3.3.0]‐bicyclic substructure could not be realized, the required ring enlargement of a cyclobutane was eventually achieved by a retro ‐benzilic acid rearrangement. Generation of the central pyrrolidine ring was possible by a three‐step reductive amination domino sequence. The final ring was built up by a ring‐closing metathesis after the last quaternary stereocenter had been constructed by a Johnson–Claisen rearrangement. The synthesis was concluded by a selenylation–elimination sequence to build up the exocyclic vinyl group of meloscine. Using our methodology for enantioselective [2+2]‐photocycloaddition mediated by a chiral complexation agent, the experimentally very simple synthesis could be performed in an enantioselective fashion (7 % overall yield). The enantioselective synthesis of (+)‐meloscine represents the first example of a natural product synthesis employing an enantioselective [2+2]‐photocycloaddition as its key step, and illustrates nicely the synthetic potential of photochemical transformations for the construction of complex heterocyclic structures.