Following is an outline of the stereospecific synthesis of the Corey lactone

Chapter 24, Problem 24.35

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Following is an outline of the stereospecific synthesis of the Corey lactone. ProfessorE. J. Corey (Harvard University) describes it this way. The first general synthetic routeto all the known prostaglandins was developed by way of bicycloheptene intermediates.The design was guided by the requirements that the route be versatile enough to allowthe synthesis of many analogs and also allow early resolution. This synthesis has beenused on a large scale and in laboratories throughout the world; it has been applied tothe production of countless prostaglandin analogs. Corey was awarded the 1990 NobelPrize in Chemistry for the development of retrosynthetic analysis for synthetic produc-tion of complex molecules. See E. J. Corey and Xue-Min Cheng, The Logic of ChemicalSynthesis, John Wiley & Sons, New York, 1989, p. 255. For the structure of the prosta-glandins, see Section 26.3. Note: The wavy lines in compound C indicate that the stereo-chemistry of !Cl and !CN groups was not determined. [The conversion of (D) to (E)involves an oxidation of the ketone group to a lactone by the Baeyer-Villiger reaction,which we have not studied in this text.] (a) What is the function of sodium hydride, NaH, in the first step? What is the pKa ofcyclopentadiene? How do you account for its remarkable acidity?(b) By what type of reaction is (B) converted to (C)?(c) What is the function of the carbon dioxide added to the reaction mixture in Step 2of the conversion of (E) to (F)? Hint: What happens when carbon dioxide is dis-solved in water? Why not just use HCl?(d) The tributyltin hydride, Bu3SnH, used in the conversion of (H) to (I) reacts via aradical chain reaction; the first step involves a reaction with a radical initiator toform (Bu)3Sn?. Suggest a mechanism for the rest of the reaction.(e) The Corey lactone contains four chiral centers with the relative configurationsshown. In what step or steps in this synthesis is the configuration of each chiralcenter determined? Propose a mechanism to account for the observed stereospeci-ficity of the relevant steps.(f) Compound (F) was resolved using (1)-ephedrine. Following is the structure of(2)-ephedrine, the naturally occurring stereoisomer. What is meant by resolu-tion? What is the rationale for using a chiral, enantiomerically pure amine for theresolution of (F)?