Asymmetric Total Synthesis of (+)-Codeine

via Intramolecular Carbenoid Insertion

James D. White, Peter Hrnciar, and Frank Stappenbeck

Yiben Wang

2/28/2012

White, J.D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64, 7871-7884.

Education:

-B.A. Cambridge University (1959)

-M.Sc. University of British Columbia (1961)

-Ph.D. Massachusetts Institute of Technology (1965)

-Post-doctoral: Dr. George H. Buchi

-1965: Harvard

-Leroy Wade (Ph.D.)

-Distinguished Professor Emeritus at Oregon State University

Awards: -National Institutes of Health Predoctoral Fellowship, M.I.T. (1964-1965)

-National Institutes of Health Research Career Development Award (1976-1981)

-Japan Society for the Promotion of Science Fellowship (1983)

-Centenary Medal, Royal Society of Chemistry, U.K. (1999)

-Arthur C. Cope Senior Scholar Award, American Chemical Society (2003)

-Oregon Outstanding Scientist Award (2006)

Dr. James D. White

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Codeine:

-an alkaloid found in the opium poppy

-first isolated in 1832 by Pierre Robiquet in

France.

-used to treat mild pain, relieve cough, and treat

diarrhea. (tylenol, ibuprofen, & cough syrups)

-side effects: euphoria, itching, nausea, vomiting,

drowsiness, dry mouth, depression, and coughing.

-used to treat diabetes – the hypoglycaemic effect

could lead to cravings for sugar.

-Codeine -> Morphine -> Heroin

Papaver somniferum var. album

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Codeine cont:

-1970s:

-Increased demand

-poor poppy crops

-Soviet Union as a buyer

-Turkish ban on poppy cultivation

-1973: 45% of U.S. strategic supply of opium

had to released for domestic use.

January 22, 1979:

Dr. Kenner Rice (LMC – NIH)

-large scale production of totally synthetic

morphine, codeine, and thebaine.

-NIH Total Opiate Synthesis

A page from Dr. Rice’s Lab Journal

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Structure:

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Retrosynthetic Analysis:

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Synthesis: MOD-DIOP

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Synthesis cont.:

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Synthesis cont.:

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Synthesis cont.:

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Synthesis cont.:

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Synthesis cont.:

Conclusions

• In principle, either enantiomer of codeine and morphine can be synthesized

– appropriate enantiomer of the MOD-DIOP ligand.

• Single asymmetric center set the complete stereogenicity of the product.

• Pentacyclic ketone intermediates – provide entry points for the synthesis of

morphine derivatives.

• Erhard, T.; Ehrlich, G.; Metz, P. Angew. Chem. Int. Ed. 2011, 50, 3892-3894.

– Communications: A Total synthesis of (+)-Codeine by 1,3-Dipolar

Cycloaddition

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