THE TOTAL SYNTHESIS OF (+,-)-MORPHINE (PHENANTHROFURAN)
Abstract
The total synthesis of racemic morphine is reported. The synthetic strategy is based on the tandem addition of an in situ generated aryl lithium to the terminus of a (beta)-substituted vinyl sulfone followed by intramolecular alkylation of the resulting (alpha)-sulfonyl anion. Piperidine ring formation is accomplished by the intramolecular 1,6-Michael addition of an amine to a dienone. Functional group conversion completes the synthesis. Preparation of the requisite (delta)-hydroxy-(gamma)-aryloxy-(beta)-(N-methyl-p-toluenesulfonamidoethyl)-vinyl sulfone cyclization substrates by the nucleophilic opening of the (delta),(gamma)-epoxy-(beta)-(TE)-vinyl sulfone with phenols was unsuccessful. Alternate approaches to these cyclization substrates are detailed. The most efficient route employs the modified Mitsunobu coupling of a phenol with a cis-(delta)-siloxy-(gamma)-hydroxy-(beta)-(TE)-vinyl sulfone. The product, possessing (delta),(gamma)-trans stereochemistry fails to cyclize under metal-halogen exchange conditions, as does its desilylated analog. An oxidation/reduction sequence produces the cis-(delta),(gamma)-cyclization substrates, which do cyclize. Synthesis of the proposed phenylsulfonamidoethyl dienone intermediate from thebaine is detailed. Attempts to remove the phenylsulfonyl protecting group in the presence of the dienone and dienyl alcohol moieties are unsuccessful. Synthesis of a carbamate protected dienone from thebaine, followed by hydrolysis produces an ammonium dienone which undergoes 1,6-Michael addition upon neutralization. The inability to remove the phenylsulfonyl protecting group in the presence of the dienone dictates the use of the allyl group as a latent (beta)-aminoethyl synthon. The previously developed chemistry is applied without complication to produce the desired allyl tetracyclic sulfone. Functional group conversions provide the carbamoylethyl dienone which upon deprotection and neutralization produces a mixture of codeinone and neopinone. Conversion of this mixture to racemic morphine follows literature precedent.
Degree
Ph.D.
Subject Area
Organic chemistry
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