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Enantiodivergent Synthesis of Benzoquinolizidinones from L-Glutamic Acid.

ABSTRACT: Benzoquinolizidinone systems were synthesized in both enantiomeric forms from L-glutamic acid. The key chiral arylethylglutarimide intermediate was synthesized from dibenzylamino-glutamate and homoveratrylamine. Aldol reaction of the glutarimide afforded a mixture of syn and anti-aldol adducts. Subsequent regioselective hydride reduction of the glutarimide carbonyl followed by N-acyliminium ion cyclization afforded a product with opposite absolute configurations at C3 and C11b. Cope elimination of the dibenzylamino group then converted the two diastereomers into enantiomers.

SUBMITTER: Kuntiyong P

PROVIDER: S-EPMC8512815 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Enantiodivergent Synthesis of Benzoquinolizidinones from L-Glutamic Acid.

Kuntiyong Punlop P Namborisut Duangkamon D Phakdeeyothin Kunita K Chatpreecha Rungrawin R Thammapichai Kittisak K

Molecules (Basel, Switzerland) 20210928 19

Benzoquinolizidinone systems were synthesized in both enantiomeric forms from L-glutamic acid. The key chiral arylethylglutarimide intermediate was synthesized from dibenzylamino-glutamate and homoveratrylamine. Aldol reaction of the glutarimide afforded a mixture of syn and anti-aldol adducts. Subsequent regioselective hydride reduction of the glutarimide carbonyl followed by N-acyliminium ion cyclization afforded a product with opposite absolute configurations at C3 and C1 ...[more]

PMID: 34641410

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Project description:Surface expression of alpha-(2,8)-linked polymers of sialic acid in adult tissues has been correlated with metastasis of several human cancers. One approach to chemotherapeutic intervention against the spread of these cancers involves the development of immunogenic molecules that elicit an antibody response against alpha-(2,8)-linked polysialic acids. Naturally occurring polysialic acids are not viable candidates because they are present during embryonic development and are recognized as self by the immune system. These natural polymers also have poor pharmacokinetic properties because they are readily degraded by neuraminidase enzymes. We have been interested in developing structural surrogates of polysialic acids in an effort to overcome these limitations. Reported herein are microwave-assisted solid-phase peptide syntheses and structural characterization studies of a series of alpha/delta hybrid peptides derived from Fmoc-Neu2en and Fmoc-Glu(OtBu)-OH. Conformational experiments including circular dichroism, NH/ND exchange, and ROESY in aqueous solution were performed to study the secondary structures of these hybrid foldamers. ROESY data were analyzed with the assistance of XPLOR-NIH that was modified to include parameter and topology files to accommodate unnatural amino acids and the delta amide linkages. The results indicate that stable secondary structure is dependent upon both the amino acid sequence and the configuration of Glu. The most stable foldamer was composed of a total of 6 residues beginning with L-Glu at the carboxy terminus and alternating Neu2en and L-Glu residues. In water, this foldamer adopts a right-handed helical conformation with 3.7 residues per turn, 7.4 A pitch, 5.8 A diameter, and a length of 18.5 A, which is stabilized by both classical C=O...H-N backbone interactions and by pyranose ring O and L-Glu HN H-bonding. These structural features orient the L-Glu carboxylates along the helical backbone with a periodicity that matches the carboxylate positions along the reported G2(+) left-handed helix of alpha-(2,8)-polysialic acid. However, the charge density of the foldamer is one-half that of the natural polymer. These findings provide a fundamental understanding of the factors that influence stable secondary structure in hybrid Neu2en/Glu systems, and the tools we have developed establish a viable platform for the rational design of alpha-(2,8)-polysialic acid surrogates.

Dataset Information

Enantiodivergent Synthesis of Benzoquinolizidinones from L-Glutamic Acid.

Publications

Enantiodivergent Synthesis of Benzoquinolizidinones from L-Glutamic Acid.

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