Doxaprost, an orally active bronchodilator patterned after

Chapter 26, Problem 26.19

(choose chapter or problem)

Doxaprost, an orally active bronchodilator patterned after the natural prostaglandins (Section 26.3), is synthesized in the following series of reactions starting with ethyl 2-oxocyclopentanecarboxylate. Except for the Nef reaction in Step 8, we have seen examples of all other types of reactions involved in this synthesis. O Ethyl 2-oxocyclopentanecarboxylate COOEt COOEt (CH2)6COOCH3 O COOH (CH2)6COOH O O (CH2)6COOH (CH2)6COOH Br (CH2)6COOH O O 1 2 3 4 5 6 7 8 9 10 H CH2NO2 Nef (CH2)6COOCH3 reaction O (CH2)6COOCH3 O C"O (CH2)6COOCH3 O C (CH2)6COOCH3 O H C O H C (CH2)4CH3 C (CH2)6COOH O H C O H C (CH2)4CH3 C (CH2)6COOH O H Doxaprost (an orally active bronchodilator) C HO CH3 H C (CH2)4CH3 (a) Propose a set of experimental conditions to bring about the alkylation in Step 1. Account for the regioselectivity of the alkylation, that is, that it takes place on the carbon between the two carbonyl groups rather than on the other side of the ketone carbonyl. (b) Propose experimental conditions to bring about Steps 2 and 3. (c) Propose experimental conditions for bromination of the ring in Step 4 and dehydrobromination in Step 5. (d) Write equations to show that Step 6 can be brought about using either methanol or diazomethane (CH2N2) as a source of the !CH3 in the methyl ester. (e) Describe experimental conditions to bring about Step 7 and account for the fact that the trans isomer is formed in this step. (f) Step 9 is done by a Wittig reaction. Suggest a structural formula for a Wittig reagent that gives the product shown. (g) Name the type of reaction involved in Step 10. (h) Step 11 can best be described as a Grignard reaction with methylmagnesium bromide under very carefully controlled conditions. In addition to the observed reaction, what other Grignard reactions might take place in Step 11? (i) Assuming that the two side chains on the cyclopentanone ring are trans, how many stereoisomers are possible from this synthetic sequence?