Eine Totalsynthese von (±)‐Codein durch 1,3‐dipolare Cycloaddition

Chemoenzymatic Formal Total Synthesis of ent‐Codeine and Other Morphinans via Nitrone Cycloadditions and/or Radical Cyclizations. Comparison of Strategies for Control of C‐9/C‐14 Stereogenic Centers

“…In 1984 Parsons published a model study of an intramolecular nitrone cycloaddition, which produced the correct C‐9/C‐14 relationship,5 followed by a complete total synthesis of morphine by this strategy 6. In 2011 Metz reported a total synthesis of racemic codeine via a nitrone cycloaddition that yielded the correct relationship at C‐9/C‐14 7. In a recent publication by Trost describing the enantioselective synthesis of galanthamine and morphine, it was noted that all attempts to achieve C‐9C‐14 bond formation via carbonyl ene cyclization failed 8…”

“…The stereochemistry of the cycloadduct 12 was shown to have the incorrect C‐9/C‐14 relationship, resulting from a different transition state geometry than that operating on the substrate reported by Metz 7. We therefore converted the adduct 12 to styrene 13 to allow for the introduction of the C‐9 center by hydroamination at a later stage of the synthesis.…”

“…[7] In a recent publication by Trost describing the enantioselective synthesis of galanthamine and morphine, it was noted that all attempts to achieve C-9 À C-14 bond formation via carbonyl ene cyclization failed. [8] In this paper we report the results of the stereochemical course of a nitrone cycloaddition, nitrile oxide cycloaddition, and a radical cyclization approach to ent-codeine and other morphinans, as shown in Figure 1.…”

“…[7] We therefore converted the adduct 12 to styrene 13 to allow for the introduction of the C-9 center by hydroamination at a later stage of the synthesis. Thus, treatment of 12 with excess Meerwein salt, followed by addition of LiAlH 4 , [which reduced the acetate and also led to the base-catalyzed elimination of the resulting trialkylammonium salt] afforded the Hofmann elimination product 13.…”

Formal Synthesis of (−)-Codeine by Application of Temporary Thio Derivatization

“…In 2011 we disclosed a total synthesis of (±)-codeine ( 2 ) featuring an intramolecular nitrone cycloaddition to construct the ABC-ring system with simultaneous generation of four contiguous stereogenic centers . We recently turned to the enantioselective preparation of the key isoxazolidine 3 .…”