Chiral 2hydroxy carboxylic acids

In contrast to 2-amino acids, only a few non-racemic 2-hydroxy acids are found in nature. Hydrolysis of non-racemic cyanohydrins offers an interesting general route to (R)- as well as (S)-2-hydroxy carboxylic acids.

(R)- and (S)-cyanohydrins are, respectively, hydrolyzed in hydrochloric acid to give the corresponding (R)- and (S)-2-hydroxy acids in excellent yields and with complete retention of configuration.313 Under milder reaction conditions (lower temperature, shorter reaction times), the corresponding 2-hydroxy acid amides can be obtained selectively (Scheme 4).19

Aromatic 2-hydroxy carboxylic acids are of special interest for applications.13 Among them, optically active mandelic acids are regarded as most important commercially.13 The synthetic potential of non-racemic 2-hydroxy acids lies in

osopc cooh

(R)-2-hydroxy acids cooh

(R)-2-hydroxy acids

chjnh.

(R)-1,2-amino alcohols

1. N-Nucleophile

(inversion)

2. Hydrolysis chjnh.

(S)-amino acids

(R)-1,2-amino alcohols

(S)-amino acids

Scheme 3: Stereoselective follow-up reactions of non-racemic cyanohydrins.9 12

Cone, HCI/HOAc

Cone. HCI i

CONH.

Scheme 4: Stereoselective synthesis of (R)-2-hydroxy acid amides and (R)-2-hydroxy acids by hydrolysis of (R)-cyanohydrins.

the possibility to activate the hydroxy group, for example, by sulfonylation.20 The O-activated 2-hydroxy acids can be reacted with any kind of nucleophile to give the corresponding substitution product under complete inversion of configuration without any racemization (Scheme 3).20

The industrial production of CLOPIDOGREL (PLAVIX®) is an interesting example which demonstrates the synthetic potential of non-racemic cyanohydrins (Scheme 5).21

In the first step, (R)-2-chlorobenzaldehyde cyanohydrin is prepared by the almond meal-catalyzed addition of HCN to 2-chlorobenzaldehyde. The cyanohydrin is then transformed into the corresponding 2-hydroxy ester by Pinner reaction. Subsequently, the hydroxy group is activated by sulfonylation and reacted with tetrahydrothieno[3.2-c]pyridine to give, under complete inversion of configuration, the (S) - a-amino acid derivative CLOPIDOGREL.21

Another important class of pharmaceuticals which is prepared from chi-ral 2-hydroxy acids is the angiotensin-converting enzyme (ACE) inhibitors.22 (R)-3-phenylpropionaldehyde cyanohydrin is transformed into the corresponding 2-hydroxy ester which after activation by sulfonylation reacts with dipetides to give, under inversion of configuration, ACE inhibitors known as "prils" (Scheme 6).22

Almond meal extract

Almond meal extract

MeOH/HCI

MeOH/HCI

(Reconfiguration quant, ee~90%

(Reconfiguration

Scheme 5: Stereoselective synthesis of Clopidogrel (Plavix®) starting from

2-chlorobenzaldehyde.21

Enalapril Lisinopril

Scheme 6: Stereoselective synthesis of ACE inhibitors from 3-phenylpropionaldehyde cyanohydrin.

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