New synthetic routes to the kainoids: a synthesis of kainic acid and its analogues

New approaches to the synthesis of kainic acid and its analogues are presented. Two distinctly different approaches are described; the former utilised an intermolecular nitrile oxide addition to a homochiral substrate to furnish epikainate models and the second utilised amino acid chemistry to secure kainic acid.     

Synthesis of novel neuroexcitatory amino acids derived from kainic acid

The synthesis of the novel epimeric amino acids $\text{5a}$ and $\text{7a}$ by oxidation of methyl ketones derived from kainic acid is described. On biological testing both compounds exhibit a strong neuroexcitatory activity.     

Parallel synthesis of prostaglandin E1 analogues

The first demonstration of the rapid parallel synthesis of diverse prostaglandin derivatives is reported. Upper (alpha-) side chain diversity was introduced to core 1 via the parallel Suzuki coupling of hydroborated alkenes. Conversion to the enones 3 and 9 was followed by the addition of the lower (omega-) side chains as higher-order cuprates 4. Upper side chains incorporating an N-acylsulfonamide protecting group were further transformed into prostaglandin amide analogues. Cleavage from support with HF/pyridine followed by scavenging provided 26 prostaglandin E1 analogues in high purity.     

Divergent synthesis of two novel muscarine analogues from D-glucose

A divergent synthesis of two new muscarine analogues bearing the (5S)-dioxolanyl isosteric group was achieved starting from d-glucose, enabling access to libraries of potential muscarinic agonists or antagonists. The key step of the synthesis involved a regioselective epoxide ring opening in 2,5:3,4-dianhydro derivatives 5 and 15 with LiAlH₄, whereby the natural stereochemistry of (+)-muscarine (1) and (−)-allo-muscarine (2) was efficiently established.     

Stereoselective synthesis of conformationally constrained omega-amino acid analogues from pyroglutamic acid

Bicyclic lactams derived from pyroglutamic acid provide a useful scaffold for synthesis of conformationally restricted analogues of lysine, ornithine and glutamine, as well as an Ala-Ala dipeptide analogue. Amino alcohol and carboxylic acid derivatives are accessible from a common intermediate. In this strategy, the bicyclic lactam system not only controls, but also facilitates the determination of the stereochemistry of the synthetic intermediates.     

Studies towards a total synthesis of kainic acid

The preparation of the fused bicycle 14 is reported together with its photocyclisation to the dioxinone 2. Base induced fragmentation of the photoadduct 15 formed exclusively in the aforementioned photocylisation, followed by Wittig methylenation gave the kainoid derivative 18.     

The synthesis of heteroaromatic nitro compounds from 3-nitrochromone

3-Nitrochromone ( 1 ) reacts with a series of nucleophiles by Michael addition followed by intramolecular condensation to yield pyrrolyl ( 2 ), phenyl ( 3 ), pyridyl ( 4 ), pyrido ( 5,6 ), pyrimidyl ( 7 ) and pyrazolyl ( 8 ) nitro derivatives. The reactions proceed under basic catalysis in 39–78% yields. Conversion of 4 to 3,4-dihydrobenzofuro[3,2-b]quinol-1-(2H)one ( 12 ) is also described. Carbon-13 data for 2, 5, 6 and 8 are discussed. The one bond C,H coupling constants in the nitropyridines are also reported and used as an analytical tool.     

Total synthesis of tetracyclic kynurenic acid analogues isolated from chestnut honey

A short and efficient synthesis of novel tetracyclic Kynurenic acid analogues, isolated from chestnut honey, is described. The crucial step of the strategy was a MW-assisted cyclization of enamines of ethyl dioxohexahydropyrrolizine and 2,3-dioxooctahydroindolizine carboxylates to obtain 2,3,6,11b-tetrahydro-1H-pyrrolizino[2,1-b]quinoline-5,11-dione and 5,8,91,011,11a-hexahydroindolizino[2,1-b]quinoline-6,12-dione, respectively. Because of its modular nature, the synthetic strategy can have value as a general method for the preparation of compounds containing these new heterocyclic scaffolds.     

Regioselective synthesis of folic acid conjugates from diether-type archaeal lipid analogues

A regioselective access to both α- and γ-folic acid conjugates derived from archaeal lipid analogues is described. The synthetic approach is based on conveniently protected glutamates that led first to α- and γ-glutamate derivatives. The final reconstruction of the folic acid moiety was achieved through the reaction of a protected/activated pteroate followed by a simple deprotection step. These α- and γ-folic acid conjugates would permit to establish the importance of a regiocontrolled introduction of folic acid on the folic acid/folate receptor interaction in the case of a targeted drug/gene delivery.     

Palladium-catalyzed synthesis of novel optically active tryptophan analogues

[reaction: see text] Both unsaturated proline derivatives and optically active tryptophan analogues have been obtained via Pd-catalyzed cyclization of aniline-containing acetylenic amino acids. The side chain length of the cyclization precursor determines which one of the two possible products will be formed.     

A new strategy for the synthesis of optically active benzylic fluorides and corresponding five-membered heteroaromatic analogues

Benzylic fluorides, as well as five-membered heterocycles, have been obtained in high ee’s through cycloaddition reactions starting from easily accessible optically active propargylic fluorides.     

Concise synthesis of ether analogues of lysobisphosphatidic acid

We describe a versatile, efficient method for the preparation of ether analogues of (S,S)-lysobisphosphatidic acid (LBPA) and its enantiomer from (S)-solketal. Phosphorylation of a protected sn-2-O-octadecenyl glyceryl ether with 2-cyanoethyl bis-N,N-diisopropylamino phosphine and subsequent deprotection generated the bisether LBPA analogues. By simply changing the sequence of deprotection steps, we obtained the (R,R)- and (S,S)-enantiomers of 2,2'-bisether LBPA. An ELISA assay with anti-LBPA monoclonal antibodies showed that the bisether LBPAs were recognized with the same affinity as the natural 2,2'-bisoleolyl LBPA. [reaction: see text]     

Asymmetric synthesis of phosphonic acid analogues for acylcarnitine

Phosphonic acid analogues of acylcarnitine were prepared in an optically active form expecting CPT I inhibitory activities. The synthetic methodology was based on catalytic asymmetric dihydroxylation of β,γ-unsaturated phosphonates and subsequent regioselective amination via the cyclic sulfates.     

Chemoenzymatic synthesis of conformationally rigid glutamic acid analogues

All stereomers of cyclohexane and cyclopentane-derived analogues of glutamic acid have been synthesized from the corresponding 3-keto-cycloalkyl carboxylic acid esters by a combination of microbial steps and standard chemical methods.     

Design of novel conformationally restricted analogues of glutamic acid

Stereomeric 3-carboxy-Δ²-isoxazoline-cyclopentane amino acids, which represent restricted conformations of glutamic acid, have been prepared through a strategy based on the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to a suitably protected 1-amino-cyclopent-2-enecarboxylic acid. These amino acids, assayed at iGluRs and mGluRs, proved to be inactive. The biological data have been accounted for through the comparison of their conformational profile with that of a 3-carboxy-Δ²-isoxazolinyl proline (CIP-A) and (±)-1-aminocyclopentane-1,3-dicarboxylic acid.     

Synthesis of jasplakinolide analogues containing a novel omega-amino acid

The synthesis of the omega-amino acid 4 is described utilizing a two-dimensional synthesis strategy combined with an enzymatic differentiation of homotopic ester groups. The amino acid 4 features two non-bonded interactions that result in conformational constraints on a cyclic construct. This amino acid was incorporated into the four macrolactams 17, 22, 31, and 37. The ring in 17 and 22 is 18-membered, whereas 31 and 37 have a 19-membered ring. The pairs with the same ring size differ in a N-methyl group. For the larger macrolactams (31 and 37) conformational analysis showed that the macrocyclic rings are somewhat more rigid than in the natural lead, the depsipeptide jasplakinolide. Nevertheless, their conformations are comparable to the natural product. There are no intramolecular hydrogen bonds, neither is the cis-rotamer populated in the N-methyl compound 37. Due to the increased flexibility of the smaller macrolactams 17 and 22 and signal overlap, a distinct solution structure could not be obtained for these compounds. The amino acid 4 should be useful for restricting the conformation of other small peptides.