Versatile methodology for the synthesis and α-functionalization of (2R,3aS,7aS)-octahydroindole-2-carboxylic acid

Abstract

An improved strategy for the effective synthesis of enantiomerically pure (2R,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic), based on the formation of a trichloromethyloxazolidinone derivative, has been developed. Additionally, the completely diastereoselective α-alkylation of such oxazolidinone provides a very convenient and concise route to enantiopure α-tetrasubstituted derivatives of this Oic stereoisomer.

Recent progress on the stereoselective synthesis of cyclic quaternary α-amino acids

“…Recently, we reported244 a versatile methodology for the synthesis of (2 R ,3a S ,7a S )-2-methyl-octahydroindole-2-carboxylic acid 605 . Treatment of ( S , S , S,R )- 603 , obtained in three steps from ( S )-indoline-2-carboxylic acid 602 , with LDA in THF at −78 °C followed by addition of several alkyl electrophiles produced the alkylated products 604a–c in good yield.…”

Efficient access to enantiomerically pure cyclic α-amino esters through a lipase-catalyzed kinetic resolution

“…Hydrogenation of racemic indoline-2-carboxylic acid rac - 1 following our previously described methodology,12a afforded rac - 5 , which was transformed into the corresponding methyl rac - 6a and benzyl rac - 6b esters using standard procedures. Reaction with allyl chloroformate led to carbamates rac - 7a and rac - 7b , respectively, which were analyzed by HPLC to find adequate conditions for the separation of their enantiomers.…”

“…For example, it is present in marine compounds with antithrombotic properties;9 in the dipeptide perindropil (a potent antihypertensive drug used in the prevention of cardiovascular disorders such as heart failure);10 and in the prolyl oligopeptidase inhibitor S 17092, a compound with antiamnesic and cognitive-enhancing properties 11. Recently, some of us reported12 the synthesis of enantiomerically pure (2 S ,3a S ,7a S )- and (2 R ,3a R ,7a R )-Oic derivatives using preparative chiral HPLC,12a and that of the (2 R ,3a S ,7a S ) isomer by selective formation of a trichloromethyloxazolidinone 12b. The only enzymatic process for producing optically active Oic derivatives was described by Hirata13 and is based on the enzymatic hydrolysis of N -protected octahydroindole-2-carboxylates.…”

Practical access to the proline analogs (S,S,S)‐ and (R,R,R)‐2‐methyloctahydroindole‐2‐carboxylic acids by HPLC enantioseparation

“…In fact, at variance with Oic, attention on the a-methylated counterpart (aMe)Oic has been focused only recently. Within this context, we have described the preparation of enantiopure (S,S,S)-(aMe)Oic 13 and its epimer at the a carbon (R,S,S)-(aMe)Oic 14 by means of stereoselective alkylation processes. To the best of our knowledge, these are, together with the preparation of (S,S,S)-(aMe)Oic described in a patent, 15 the only synthetic routes to (aMe)Oic reported to date.…”