Routes to Essential Medicines. Peter J. Harrington

Artemether

      Anti‐Infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment

       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. Artemether (β‐artemether) is semisynthetic, it is manufactured in two steps from artemisinin. The methyl acetal of β‐artemether is formed by the acid‐catalyzed reaction of the hemiacetal (dihydroartemisinin) with methanol. The hemiacetal of dihydroartemisinin is formed by reduction of the ester of artemisinin. Artemisinin is a natural product isolated from the plant Artemisia annua or sweet wormwood.

Artemisinin can also be manufactured in four steps from artemisinic acid. In the last step, a hydroperoxide is formed by α‐oxidation of an aldehyde with triplet oxygen. The aldehyde, hydroperoxide, ketone, and carboxylic acid then assemble to form artemisinin. The aldehyde and ketone are formed by cleavage of an allylic hydroperoxide (Hock Rearrangement). The allylic hydroperoxide is formed from dihydroartemisinic acid (Ene Reaction). Dihydroartemisinic acid is formed by reduction of artemisinic acid. Artemisinic acid is a natural product also isolated from the plant A. annua or sweet wormwood. Artemisinic acid is also produced by fermentation.

      Extended Discussion

      Draw the structures of four impurities which are likely to form in the conversion of dihydroartemisinin to artemether.

Artesunate

      Anti‐Infective Medicines/Antiprotozoal Medicines/Antimalarial Medicines/For Curative Treatment

       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. Artesunate is semisynthetic, and it is manufactured in two steps from artemisinin. The ester is formed by reaction of the hemiacetal (dihydroartemisinin) with succinic anhydride. The hemiacetal of dihydroartemisinin is formed by reduction of the ester of artemisinin. Artemisinin is a natural product isolated from the plant A. annua or sweet wormwood.

      Artemisinin is also manufactured in four steps from artemisinic acid. In the last step, a hydroperoxide is formed by α‐oxidation of an aldehyde with triplet oxygen. The aldehyde, hydroperoxide, ketone, and carboxylic acid then assemble to form artemisinin. The aldehyde and ketone are formed by cleavage of an allylic hydroperoxide (Hock Rearrangement). The allylic hydroperoxide is formed from the alkene (Ene Reaction). The alkene, dihydroartemisinic acid, is formed by reduction of artemisinic acid. Artemisinic acid is a natural product also isolated from the plant A. annua or sweet wormwood. Artemisinic acid is also produced by fermentation.

      Extended Discussion

      β‐Artemether and α‐artesunate are both formed from dihydroartemisinin. Draw the structures of a retrosynthetic analysis of β‐artesunate.

Ascorbic Acid

      Vitamins and Minerals

       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. Ascorbic acid (vitamin C) is semisynthetic. Ascorbic acid is formed from 2‐keto‐L‐gulonic acid. 2‐Keto‐L‐gulonic acid is produced by fermentation from L‐sorbose. L‐Sorbose is produced by fermentation from D‐sorbitol.

      Extended Discussion

      Draw the structures of the retrosynthetic analysis of an alternative non‐fermentation route to 2‐keto‐L‐gulonic acid from L‐sorbose.

Atazanavir

      Anti‐Infective Medicines/Antiviral Medicines/Antiretrovirals/Protease Inhibitors

       A β‐amino alcohol with a primary β‐C is often formed by ring‐opening of an epoxide by an amine.

      Discussion. Two amides are formed with expensive N‐(methoxycarbonyl)‐L‐tertleucine (Moc‐L‐tertleucine) in the final step. The amine and hydrazine needed to form the amides are released by hydrolysis of tert‐butoxycarbonyl (Boc) protecting groups. A key C─N bond near the center of the molecule is formed by ring‐opening of an epoxide with a Boc‐protected hydrazine.

      Moc‐L‐Tertleucine is formed from L‐tertleucine and methyl chloroformate. L‐Tertleucine is formed by an enzyme‐mediated reductive amination of trimethylpyruvic acid. The pyruvic acid is formed by oxidation of the α‐hydroxyacid. The α‐hydroxyacid is formed from 1,1‐dichloropinacolone by rearrangement and hydrolysis. 1,1‐Dichloropinacolone is formed by α–chlorination of pinacolone.

      The epoxide is formed from the chlorohydrin by nucleophilic displacement of chloride by oxygen. The chlorohydrin is formed by reduction of the α‐chloroketone, N‐(tert‐butoxycarbonyl)‐3(S)‐amino‐1‐chloro‐4‐phenyl‐2‐butanone. The α‐chloroketone is formed by reduction of the α,α‐dichloroketone. The α,α‐dichloroketone is formed from N‐(tert‐butoxycarbonyl)‐L‐phenylalanine methyl ester and dichloromethane.

The Boc‐protected hydrazine is formed by reduction of the hydrazone. The hydrazone is formed by reaction of the aldehyde with Boc‐hydrazine. The aldehyde, 4‐(2‐pyridyl)benzaldehyde, is formed from 2‐bromopyridine and 4‐formylbenzeneboronic acid (Suzuki–Miyaura Coupling). The boronic acid is formed from 4‐chlorobenzaldehyde and trimethylborate via an acetal.