127949-74-0Relevant articles and documents
Unusual stereoselectivity in the alkylation of pyroglutamate ester urethanes
Charrier, Jean-Damien,Duffy, James E.S.,Hitchcock, Peter B.,Young, Douglas W.
, p. 2367 - 2371 (2001)
Previous studies on the alkylation of pyroglutamate ester urethanes have led to a consensus that alkylation at C-4 occurs to give a mixture of diastereoisomers, the major isomer of which usually has the alkyl group trans to the ester group at C-2. We have now discovered that this generalisation is not invariably correct and that, although for SN1-type electrophiles stereoselectivity is in fact trans, SN2-type electrophiles can give the thermodynamically less stable cis compounds as the predominant products. Use of the bulky proton source 2,6-di-tert-butylphenol to quench these reactions yields the cis isomers as the only products in good yield, thus making direct alkylation of pyroglutamic acid derivatives a useful alternative to our hydrogenation approach to these synthons.
Stereospecific synthesis of naturally-occurring 4-alkylideneglutamic acids, 4-alkylglutamates and 4-alkylprolines
Moody, Claire M.,Young, Douglas W.
, p. 3519 - 3530 (1997)
The enaminone 4, prepared from (2S)-pyroglutamic acid, has been found to react in an apparent 1,4-manner with DIBAL and Grignard reagents to afford a variety of alkylidene derivatives 8 which, except for the vinyl derivatives 8e, are formed only as the (E
Design and Synthesis of Building Blocks for PPII-Helix Secondary-Structure Mimetics: A Stereoselective Entry to 4-Substituted 5-Vinylprolines
Chiha, Slim,Soicke, Arne,Barone, Matthias,Müller, Matthias,Bruns, Judith,Opitz, Robert,Neud?rfl, J?rg-Martin,Kühne, Ronald,Schmalz, Hans-Günther
, p. 455 - 460 (2018/02/09)
In the course of our studies towards the synthesis of proline-based secondary-structure mimetics, we developed a straightforward methodology for the diastereoselective preparation of 4-alkyl-5-vinyl-substituted proline derivatives. Starting from N-Boc-protected tert-butyl pyroglutamate, α-alkylation, lactam reduction and acid-catalyzed methanolysis afforded 4-alkyl-5-methoxyproline derivatives. After BF3-induced formation of an N-acyl-iminium intermediate, the introduction of the 5-vinyl side chain was achieved with high diastereoselectivity by using vinylmagnesium bromide in the presence of AlCl3 or CuBr·SMe2 to afford either the cis- or the trans-product, respectively. The utility of the method was demonstrated in the rapid and efficient construction of new diproline mimetics rigidified in a polyproline-type II helix (PPII) conformation.
Diastereospecific synthesis of new 4-substituted l-theanine derivatives
Sebih, Fatiha,Bellahouel, Salima,Rolland, Marc,Derdour, Aicha,Martinez, Jean,Rolland, Valerie
, p. 690 - 696 (2014/05/20)
Considering the biological activity of l-theanine as a potent agonist of NMDA receptors, impacting on glutamatergic synapse activity, we have developed an asymmetric synthesis of new enantiomerically pure 4-substituted l-theanine derivatives. The key step is a stereospecific alkylation on a previously synthesized and correctly protected (S)-pyroglutamate.
Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists
Ibrahim, Mohamed A.,Johnson, Henry W. B.,Jeong, Joon Won,Lewis, Gary L.,Shi, Xian,Noguchi, Robin T.,Williams, Matthew,Leahy, James W.,Nuss, John M.,Woolfrey, John,Banica, Monica,Bentzien, Frauke,Chou, Yu-Chien,Gibson, Anna,Heald, Nathan,Lamb, Peter,Mattheakis, Larry,Matthews, David,Shipway, Aaron,Wu, Xiang,Zhang, Wentao,Zhou, Sihong,Shankar, Geetha
, p. 1368 - 1381 (2012/04/04)
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P 1) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.
Reinvestigation of the alkylation of pyroglutamate ester urethanes
Charrier, Jean-Damien,Duffy, James E. S.,Hitchcock, Peter B.,Young, Douglas W.
, p. 2199 - 2202 (2007/10/03)
Previous studies by several groups on the alkylation of pyroglutamic acid derivatives have led to a consensus that the stereoselectivity of alkylation at C-4 is invariably trans to the ester group at C-2. We have now discovered that this generalisation is not invariably correct and that, although for S(N)1-type electrophiles stereoselectivity is in fact trans, S(N)2-type electrophiles can give the thermodynamically less stable cis products with high diastereoselectivity. Use of the bulky proton source 2,6- di-tert-butylphenol to quench these reactions yields cis isomers as the only products in good yield, thus making direct alkylation of pyroglutamic acid derivatives a useful starting point for the synthesis of homochiral target compounds.
Stereoselective Reactions of Lithium Enolates Derived from N-BOC Protected Pyroglutamic Esters
Ezquerra, Jesus,Pedregal, Concepcion,Rubio, Almudena,Yruretagoyena, Belen,Escribano, Ana,Sanchez-Ferrando, Francisco
, p. 8665 - 8678 (2007/10/02)
The lithium enolates of N-Boc protected pyroglutamic ethyl or tert-butyl esters react with electrophiles in good yield without epimerization of the chiral centre.With benzyl bromides the process is stereospecific, yielding exclusively the trans isomer.However, with other reactive electrophiles a 2:1 tans/cis diastereometric mixture was obtained, regardless of the steric bulk of the ester group.
Amino Acid Synthesis Using (L)-Pyroglutamic Acid as a Chiral Starting Material
Baldwin, Jack E.,Miranda, Tania,Moloney, Mark,Hokelek, Tuncer
, p. 7459 - 7468 (2007/10/02)
Deprotonation of protected pyroglutamates 1(c), 1(d), and 1(e) with lithium di-isopropylamine (LDA) or lithium hexamethyldisilazide (LiHDMS) in THF, followed by reaction with electrophiles, leads to the formation of 4-substituted pyroglutamates in good yield.This approach has been used for the synthesis of the novel amino acid (4).Key Words: pyroglutamic acid; chiral amino acid synthesis
