Synthesis and reactions of a novel 3,4-didehydropyroglutamate derivative

Abstract

Some reactions such as catalytic hydrogenation, Diels-Alder reaction, cyclopropanation, dihydroxylation, and Michael addition of a novel 3,4-didehydropyroglutamate derivative, in which the carboxylic group is protected as an ABO ester, are examined and found to take place in a stereospecific manner giving 3- and/or 4-substituted pyroglutamate derivatives without loss of enantiomeric purity at the alpha-position.

Natural Occurrence, Syntheses, and Applications of Cyclopropyl-Group-Containing α-Amino Acids. 2. 3,4- and 4,5-Methanoamino Acids

“…100 The N-tert-butoxycarbonyl-protected dimethyl ester of L-CCG-III (2R,2′S,2′S)-99 was also synthesized as an intermediate en route to (S)-endo-3,4-methano-L-proline [(S)-endo-84] (see section 2.6, Scheme 14), which was converted into its fully deprotected form (2R,2′S,2′S)-127 by acid hydrolysis. 63,101 The cyclopropanation of the enantiopure 3,4-didehydro-4-pyroglutamine orthoester 95 with tert-butyl dimethylsulfuranylideneacetate provided the 3-aza-4-oxabicyclo[3.1.0]hexanedicarboxylic acid derivative 174 as a separable mixture of the two diastereomers exo,endo-174 and exo,exo-174. Chemoselective ring opening of the lactam in 174, subsequent Barton decarboxylation, and final hydrolysis gave rise to L-CCG-IV (2S,1′R,2′S)-127 starting from exo,endo-174 and L-CCG-II (2S,1′R,2′R)-127 from exo,exo-174, repectively (Scheme 29).…”

“…Chemoselective ring opening of the lactam in 174, subsequent Barton decarboxylation, and final hydrolysis gave rise to L-CCG-IV (2S,1′R,2′S)-127 starting from exo,endo-174 and L-CCG-II (2S,1′R,2′R)-127 from exo,exo-174, repectively (Scheme 29). 63,101 A Michael-induced ring closure (MIRC) reaction of the glycinate enolate generated from ethyl (diphenylmethyleneamino)acetate ( 176) with the enantiopure (-)-menthyl 4-bromocrotonate (175) furnished the cyclopropane derivative 177 as a single diastereomer. Successive acid-and base-catalyzed hydrolysis of the ester and Schiff-base functionalities led to enantiomerically pure L-CCG-I (2S,1′S,2′S)-127 (Scheme 30).…”

“…Hydrolysis of the O , N -acetal in (2 R ,1‘ S ,2‘ S )- 173 , subsequent oxidation of the two hydroxymethyl groups, and final esterification furnished the dimethyl ester of d -CCG-I in its N - tert -butoxycarbonyl-protected form (2 R ,1‘ S ,2‘ S )- 99 -Boc (Scheme ) . The N - tert -butoxycarbonyl-protected dimethyl ester of l -CCG-III (2 R ,2‘ S ,2‘ S )- 99 was also synthesized as an intermediate en route to ( S )- endo -3,4-methano- l -proline [( S )- endo - 84 ] (see section 2.6, Scheme ), which was converted into its fully deprotected form (2 R ,2‘ S ,2‘ S )- 127 by acid hydrolysis. ,

28 Synthesis of Protected d -CCG-I Employing a Simmons−Smith-Type Cyclopropanation on a Chirally Modified Allyl Alcohol Derivative 100

29 An Approach to l -CCG-II and l -CCG-IV Applying a Stereocontrolled Cyclopropanantion of the 3,4-Didehydro- l -pyroglutamic ABO (5-Methyl-2,7,8- trioxabicyclo[3.2.1]octane) Orthoester 63,101

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Synthesis of nonracemic hydroxyglutamic acids

“…To illustrate this strategy dihydroxylation of the orthoester 92 (derived from L-pyroglutamic acid [97]) was performed to afford a single diastereoisomer 93 since the bulky orthoester residue allows the osmylation to occur from the opposite side (less hindered face). After purification of the diacetate 94 the recovery of acid (2 S ,3 R ,4 R )- 4 was performed (Scheme 24) [98]. However, the hydrolysis was carried out under mild conditions to prevent decomposition of this stereoisomer including racemization at Cα.…”

Stereocontrolled routes to β,β′-disubstituted α-amino acids

“…Oba et al published concomitantly the same approach to 3-methyl glutamic acid using an ABO protecting group and observed also an excellent diastereoselectivity in 1,4-addition on the pyroglutamic acid. 211…”