Following is an outline of the stereospecific synthesis of the "Corey
lactone." Professor E. J. Corey (Harvard University) describes it this way.
"The first general synthetic route to 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 allow the synthesis of many
analogs and also allow early resolution. This synthesis has been used on a
large scale and in laboratories throughout the world; it has been applied to
the production of countless prostaglandin analogs." Corey was awarded the 1990
Nobel Prize in Chemistry for the development of retrosynthetic analysis for
synthetic production of complex molecules. See E. J. Corey and Xue-Min Cheng,
The Logic of Chemical Synthesis, John Wiley \& Sons, New York, 1989, p. 255.
For the structure of the prostaglandins, see Section 26.3. Note: The wavy
lines in compound \(\mathrm{C}\) indicate that the stereochemistry of
\(-\mathrm{Cl}\) and \(-\mathrm{CN}\) 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, \(\mathrm{NaH}\), in the first step?
What is the \(\mathrm{p} K_{\mathrm{a}}\) of cyclopentadiene? 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 2 of the conversion of (E) to (F)? Hint: What happens when carbon
dioxide is dissolved in water? Why not just use \(\mathrm{HCl}\) ?
(d) The tributyltin hydride, \(\mathrm{Bu}_{3} \mathrm{SnH}\), used in the
conversion of (H) to (I) reacts via a radical chain reaction; the first step
involves a reaction with a radical initiator to form \(\mathrm{Bu}_{3}
\mathrm{Sn} \cdot\). Suggest a mechanism for the rest of the reaction.
(e) The Corey lactone contains four chiral centers with the relative
configurations shown. In what step or steps in this synthesis is the
configuration of each chiral center determined? Propose a mechanism to account
for the observed stereospecificity of the relevant steps.
(f) Compound (F) was resolved using (+)-ephedrine. Following is the structure
of (-)-ephedrine, the naturally occurring stereoisomer. What is meant by
"resolution"? What is the rationale for using a chiral, enantiomerically pure
amine for the resolution of (F)?
(g) You have not studied the Baeyer-Villiger reaction (D to E). The mechanism
involves nucleophilic reaction of the peroxyacid with the carbonyl followed by
a rearrangement much like that involved in the hydroboration reaction (Section
6.4). Write a mechanism for this reaction.
