*4.2. Some Recent Approaches to Syntheses*

These compounds represent a new structural group of amino acids containing a unique hexahydrofuro[3,3–b]pyrane core system. It was shown that **74** and **75**, as well as many their synthetic analogs, exhibit preferential binding to GluK1 kainate receptors and almost no activity towards AMPA receptors. In total more 35 syntheses of dysiherbaine and neodysiherbaine were reported. Most of them were reviewed in 2013 by Cachet and Poree [73]. In our review, we will only consider several additional syntheses which were developed later and published in 2013–2018.

Taking into account that several syntheses of dysiherbaine, reported earlier, were based on a known intermediate, obtained through 13 to 16 steps, a formal synthesis of **74** was carried out [74]. In this synthesis, D-mannitol diacetonide, an available initial compound, was converted into the same compound by a shorter synthetic pathway.

Gilbeston and co-authors [75] from the University of Houston, USA, proposed a new variant of enantioselective synthesis of **74** which differed in a later design of functionalities in the tetrahydropyran ring than in other known pathways. The scheme of this synthesis suggested, first, the creation of tetrahydrofuran derivative and then the formation of tetrahydropyran ring with the use of metathesis reaction. The following introduction of the necessary substituents and, finally, the attachment of glutamic acid moiety to the furan fragment completed the synthesis. The furan fragment of **74** was constructed from methylglycidate **76**. This compound was transformed by a series of reactions into α,β-unsaturated epoxide **77**. The palladium catalyzed opening of this epoxide yielded the furan derivative **78**. Then **78** was converted by allylation of free alcohol with allyl bromide and silver oxide to provide the diene metathesis substrate **79**, in which oxymethyl group was introduced by reaction with LDA and formaldehyde. The derivative **79** was obtained as a mixture of stereoisomers and one of them, suitable for further transformations, was isolated by column chromatography. Metathesis of **79** with protection of hydroxy group gave **80**, containing the bicyclic core system of dysiherbaine. The oxidation of the double bond in **80** with OSO4 and *N*-oxide of methylmorpholine (MMO) led to diol **81**. On the following stages of introduction of mesyl and azide groups in the pyrane cycle was carried out to obtain **82**. The treatment of **82** with PPh3 and *N*,*N*-diisopropylethylamine (DIPEA) successfully provided aziridine **83**, protected with Boc. The consequent reaction with copper (II)

triflate, methylation, and deprotection of oxymethyl group provided the rearranged production of **84**. Further steps were the transformation into aldehyde **85**, introduction of glutamic acid residue to obtain **86**. Asymmetric hydrogenation with rhodium DuPhos (DuPhos is a class of organophosphorus compounds that are used as ligands for asymmetric syntheses), followed by deprotection of amino group and alkaline hydrolysis gave the target compound **74** (Scheme 10).

**Scheme 10.** Enanthioselective synthesis of (–)-dysiherbaine.

A total synthesis of neodysiherbaine A (**75**) based on 1,3-dipolar cycloaddition of a chiral nitrone to sugar-derived product, containing tetrahydropyran moiety, has also been reported recently [76]. The pyran allylic alcohol was obtained from methyl-α-*D*-mannopyranoside (**87**) through conversion into derivative **88** by the previously known multistep procedure, and, after the Swern oxidation and Wittig reaction, gave **89**. The further hydrogenation and Mannich reaction with Eschenmoser's salt yielded aldehyde, which, after DIBAL-H reduction, gave the compound **90**. The bipolar addition of a nitrone, catalyzed by etherate of MgBr2, led to **91**. This cycloaddition constructed the C2 and C4 asymmetric centers in a single step. Further transformations resulting in reductive cleavage of O-benzyl, *N*−O, and *N*-benzyl bond, which occurred simultaneously, led to intermediate **92** which was converted by multistep transformations into another key product (**93**). The intramolecular SN2 reaction in **93** led to the compound **94** containing the required configurations of all six stereogenic centers of neodysiherbaine A. The multistep substitution and removal of protective groups and formation of tricyclic intermediate **95**, followed by hydrolysis with 6M HCl, completed this synthesis (Scheme 11).
