Routes to Essential Medicines. Peter J. Harrington

is formed by reduction of an iminoether. The 6,9‐iminoether (the iminoether involving the hydroxyl group at C6 and carbon at C9) is formed by rearrangement of an (E)‐O‐arylsulfonyl oxime (Beckmann Rearrangement). The (E)‐O‐arylsulfonyloxime is formed from the (E)‐oxime and an arylsulfonyl chloride (List the arylsulfonyl chlorides and (O)‐arylsulfonyloxime yields). (E)‐Erythromycin A oxime is formed from erythromycin A. (How is (E)‐erythromycin A oxime separated from (Z)‐erythromycin A oxime?)

      Extended Discussion

      (Z)‐Erythromycin A oxime can be prepared from (E)‐erythromycin A oxime. Draw structures for the products formed as (Z)‐erythromycin A oxime is carried through the same sequence used to convert (E)‐erythromycin A oxime to azithromycin.

Aztreonam

      Anti‐Infective Medicines/Antibacterials/β‐Lactam Medicines

       A single‐enantiomer molecule with multiple chiral carbons is often formed by modification of a natural product which has most or all of the chiral carbons already in place.

      Discussion. In the final step, the carboxylic acid of aztreonam is released by hydrolysis of the tert‐butyl ester. The amide bond near the center of the molecule is formed by reaction of the amine of the ammonium sulfamate zwitterion with a thioester.

      The amine of the ammonium sulfamate zwitterion is released by cleavage of the protecting group. The β‐lactam ring is formed by displacement of the secondary methanesulfonate by the N‐acylsulfamate nitrogen. The N‐acyl sulfamate is formed from the amide. The methanesulfonate is formed from the alcohol. The amine of L‐threonine amide is protected (List the protecting groups. Select one protecting group to use in the analysis). L‐Threonine amide is formed from L‐threonine methyl ester. L‐Threonine methyl ester hydrochloride is formed from L‐threonine (Fischer Esterification). L‐Threonine is produced by fermentation.

      The thioester is formed from the carboxylic acid and 2,2′‐dithiobis(benzothiazole). The carboxylic acid is formed by hydrolysis of the ethyl ester. The O‐alkyloxime is formed by O‐alkylation of the oxime with tert‐butyl α‐bromoisobutyrate. The thiazole ring is formed by reaction of an α‐bromoketone with thiourea (Hantzsch Thiazole Synthesis). The α‐bromoketone is formed by bromination of the ketone. The oxime is formed by nitrosation of ethyl acetoacetate.

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of an alternative route to the ammonium sulfamate zwitterion. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List the pros and cons for both routes and select one route to the ammonium sulfamate zwitterion as the preferred route.

B

      Beclomethasone Dipropionate

      Medicines Acting on the Respiratory Tract/Antiasthmatic and Medicines for Chronic Obstructive Pulmonary Disease

       A single‐enantiomer molecule with multiple chiral carbons is often formed by modification of a natural product which has most or all of the chiral carbons already in place. A steroid with 16β‐methyl and 17α‐hydroxy substituents is often formed by ring‐opening of a 16α,17‐epoxide with a methylmagnesium halide.

      Discussion. Beclomethasone dipropionate is manufactured in 3 steps from beclomethasone, 12 steps from 16β‐methylpregnane‐3β,17α,21‐triol 21‐acetate, 19 steps from 16‐dehydropregnenolone acetate, and 22 steps from diosgenin. Diosgenin is a phytosteroid sapogenin isolated from the tubers of Dioscorea wild yam.

Beclomethasone 17α,21‐dipropionate is formed from the 17α‐propionate and propanoic anhydride. The 17α‐propionate is formed via the 17α,21‐orthoester. The 17α,21‐orthoester is formed by reaction of beclomethasone and trimethyl orthopropionate (1,1,1‐trimethoxypropane).

      

      Chlorine is introduced at C9 on the α–face by ring‐opening of the 9β,11‐epoxide with hydrogen chloride. The 9β,11‐epoxide is formed from the bromohydrin. The 11β‐alcohol of the bromohydrin is formed in situ by hydrolysis of the formate ester. The 21‐alcohol is also released by hydrolysis of the carbonate ester. The bromohydrin formate is formed from the 9(11)‐alkene. The 9(11)‐alkene is formed by dehydration of the 11α‐alcohol. The 21‐alcohol is protected as a carbonate.

      The 11α‐alcohol is formed by microbial oxidation. The C21 acetate ester is hydrolyzed during the microbial oxidation. The 1,4‐diene‐3‐one is formed from the 2α,4α‐dibromo‐3‐one by double elimination. The 2α,4α‐dibromo‐3‐one is formed by α‐bromination of the C3 ketone. The C3 ketone is formed by oxidation of the 3β‐alcohol of 16β‐methylpregnane‐3β,17α,21‐triol 21‐acetate.

The acetate ester is formed by displacement of bromide by acetate. The α‐bromoketone is formed by α‐bromination of the C20 ketone. The C20 ketone is released by acetal hydrolysis. The 16β‐methyl substituent is introduced by ring‐opening of the 16α,17‐epoxide with methylmagnesium bromide (Grignard Reaction). Methylmagnesium bromide is formed from bromomethane. The 5,6‐alkene is reduced by catalytic hydrogenation. (What is the stereochemistry of the new chiral carbon at C5? Add this stereochemical feature to the structures in the retrosynthetic analysis.) The C20 ketone is protected as an acetal by reaction with ethylene glycol. The 16α,17‐epoxide is formed by epoxidation of the 16‐alkene of 16‐dehydropregnenolone acetate. The acetate ester is hydrolyzed under the epoxidation conditions.

The 16‐alkene of 16‐dehydropregnenolone acetate is formed from diosone by β‐elimination. Diosone is formed by oxidation of the 20(22)‐alkene of pseudodiosgenin‐3,26‐diacetate.