Potential of (2E,7E)-Nonadienedioates in Asymmetric Synthesis: Construction of Homopipecolic Acid and an Aminoester Building Block for Peptide Nucleic Acids

Abstract

E , 7 E ) -N o n a d i e n e d i o a t e s i n A s y m m e t r i c S y n t h e s i sAbstract: A convenient, asymmetric synthesis of (R)-homopipecolic acid methyl ester and an homochiral peptide nucleic acid (PNA) monomer building block are described, starting from the orthogonally disubstituted (2E,7E)-nonadienedioate. The approach involves stereoselective Michael monoaddition of (R)-N-benzyl-Na-methylbenzylamide to the unsaturated ester as the key step, and subsequent transformation of the remaining double bond of the unsaturated acid.Every synthetic route starts from a particular substrate that lends itself to the retrosynthetic scheme planned. The capacity of a substrate to participate in a wide range of synthetic pathways depends on the potential of their structure: cycles, chains and functional groups. Molecules with functional groups that react selectively are attractive from this point of view: the better the chemical orthogonality of the functional groups, the larger the spectrum of synthetic transformations possible and, consequently, the range of accessible targets.Cyclic b-amino acids such as (R)-homopipecolic acid (Scheme 1) have a number of interesting features that have been used to develop synthons of natural products 1 and key intermediates in b-lactam structures. 2 Synthetic oligonucleotides (Scheme 1; DNA/RNA) have been considered as potential gene-targeted therapeutic agents (antisense and antigene). 3 Peptide nucleic acids (PNAs) were first reported in 1991 as DNA mimics 3c and, since this time, a vast number of studies have been reported covering their synthesis, properties and potential applications. Among the known oligonucleotide analogues, acyclic N-(2-aminoethyl)glycyl peptide nucleic acids (Scheme 1; PNA I) or those derived from base-containing d-amino acid derivatives 4 (Scheme 1; PNA II), are found to be very good mimics of DNA/RNA. Within this area, a steadily growing group of analogues in which the sugarphosphate backbone is replaced by a polyamide backbone, is emerging, mainly as a consequence of the intriguing base-pairing properties of their prototype PNA. In this context, we envisaged the synthesis of the amino acid building block mononer 2 in PNA III.We have demonstrated 5 the use of chiral lithium (a-methylbenzyl)benzylamide [(R)-3 or (S)-3] to initiate asymmetric conjugate addition cyclisation of octa-2,6-dienedioate and nona-2,7-dienedioate to generate chiral cyclopentane and cyclohexane derivatives 4 and 5, respectively. 5b-e We have also developed strategies to stereoselectively obtain double-(7) and mono-addition (6, 8, 9 and 10) products 5d (Scheme 2), where the Z-double bond Scheme 1 O base O O P HO O O O base O P O O HO HN N HN N HN O base O base O O DNA/RNA PNA I H(OH) H(OH) PNA I I ; n = 1, m = 3 PNA I I I ; n = 5, m = 1 NH O NH base H N N O O NHBoc EtO 2 C N H CO 2 H (R)-homopipecolic acid O base n m 1 ; n = 1, m = 3 2 ; n = 5, m = 1 n m Downloaded by: Rutgers University. Copyrighted material.

Synthesis and Modeling of Ezetimibe Analogues

“…We have demonstrated the use of chiral lithium amide (α-methylbenzyl)benzylamide ( R )- or ( S )-2 in different domino reactions [ 9 , 10 , 11 , 12 ]. Firstly, in 1997, we published an asymmetric conjugate addition cyclization of octa-2,6-diendioate I, initiated by a chiral lithium amide, to obtain, stereoselectively, the methyl 2-amino-5-(2-methoxy-2-oxoethyl)cyclopentane-1-carboxylate (II Scheme 1 ), [ 13 , 14 , 15 ] and applied it to the synthesis of ( R ) and ( S )-methyl (2-methoxycarbonylcyclopent-2-enyl)acetate (III and IV) and ( R )- and ( S )-2-(2-hydroxymethylcyclopent-2-enyl)ethanol, useful homochiral synthons for monoterpenes [ 13 ], and to the asymmetric synthesis of all the stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylic acid (V Scheme 1 ) [ 14 , 15 ].…”