Total Synthesis of (±)-meloscine via an Allenyl Azide Cycloaddition/diradical Cyclization Cascade.

Open Access
Antoline, Joshua F
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
June 20, 2012
Committee Members:
  • Ken S Feldman, Dissertation Advisor
  • Raymond Lee Funk, Committee Member
  • Steven M Weinreb, Committee Member
  • Michael Anthony Hickner, Committee Member
  • meloscine
  • diradical
  • total synthesis
  • cyclization cascade
  • alkaloid
  • allenyl azide
Model studies towards and the total synthesis of the Melodan alkaloid (±)-meloscine (2-1) are described. An allenyl azide cycloaddition/diradical cyclization cascade was employed to form the central azabicyclo[3.3.0]octane ring core of the natural product. A model study was conducted to explore approachs to forming the tetrahydropyridine E-ring of meloscine. Azabicyclo[3.3.0]octene 3-30 was synthesized from tetrasubstituted allenyl azide 3-31 via a thermal allenyl azide cycloaddition/diradical cyclization cascade. Bicycle 3-30 was converted to trialkenyl bicycle 3-25 in 10 steps, including a oxidation/Tollens aldol followed by a double oxidation/olefination sequence to install the C(20) 1,3-divinyl moiety. Ring-closing metathesis under acidic conditions afforded model system target 3-1. Introduction of an ortho bromine substituent on the aryl ring and a terminal OBO-protected orthoester on the vinyl appendage of allenyl azide cyclization precursor 4-30 incorporated the necessary functionality to form the lactam B-ring of meloscine. Thermolysis of 4-30 afforded azabicyclo[3.3.0]octene 4-31, which was elaborated to 1,3-diol 4-36 in 6 steps. Acidic hydrolysis of orthoester 4-36 and aminolysis of the resulting ester gave primary amide 4-44. Intramolecular Goldberg-type coupling followed by a water-promoted Dess-Martin oxidation/Wittig olefination sequence gave tetracycle 4-54, which was converted to (±)-meloscine (2-1) in 3 steps for a total of 19 linear steps with 2.2% overall yield.