Synthesis of the dysiherbaine tetrahydropyran core employing a tethered aminohydroxylation reaction

Abstract

A stereocontrolled and scalable synthesis of an advanced intermediate of the dysiherbaine tetrahydropyran core has been achieved in 11 steps and 27% overall yield. The key feature of this synthetic approach is the application of the Donohoe tethered aminohydroxylation reaction to install the amino diol and establish the four contiguous syn stereocenters on the tetrahydropyran ring.Since its isolation in 1997, (-)-dysiherbaine (1) has attracted attention in the chemical and biological communities due to its interesting structure and unique biological activity. 1 The molecular architecture of dysiherbaine (DH), characterized by a cis fused hexahydrofuro [3,2-b]pyran ring system displaying a glutamic acid appendage, has generated a great deal of interest as a synthetic target. 2,3 Our own synthetic efforts were motivated by dysiherbaine's impressive biological profile. 4 Radioligand binding assays of DH activity at ionotropic glutamate receptors indicate that DH is a potent agonist of kainate receptors. Furthermore, DH induces epilepsy-like seizures in mice and has been shown to be the most potent epileptogenic excitatory amino acid yet identified.Both the kainate receptor selectivity and potency of DH make it a valuable pharmacological tool for investigating the physiological roles of the various glutamate receptors in the CNS. 4e Assays of dysiherbaine activity at ionotropic glutamate receptors have demonstrated that DH is a potent agonist of non-NMDA type glutamate receptors, with a particularly high affinity for the KA receptor: IC 50 = 33 and 230 nM for KA and AMPA, respectively. 1 When injected into mice, DH exhibited the most potent epileptogenic activity and neurotoxic symptoms among the known excitatory amino acids. 4a Both the receptor selectivity and potency of DH make it an excellent probe to elucidate the roles of KA receptor subtypes in the CNS. Furthermore, as a neurotoxin and potent convulsant, DH may also provide insight as to targets for therapeutic intervention in the treatment of seizures. The low natural abundance of DH, however, has limited its availability, thereby impeding further studies on its mode of action. As a consequence, total synthesis of DH is required for further physiological studies.Since the initial elucidation of the dysiherbaine structure, several research groups, including our own, have independently accomplished the total synthesis of DH. The synthesis of DH previously developed in our laboratory featured a Fleet-inspired ring contraction of the δ-* Corresponding author. Tel.: 1-949-824-7089; fax: 1-949-824-7089; e-mail: archambe@uci.edu.. Supplementary Material Complete experimental procedures, product characterization, and spectral data. Supplementary data associated with this article can be found, in the online version, at Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetti...

Tethered Aminohydroxylation Reaction and Its Application to Total Synthesis

“…[18] In a first approach, allylic alcohol 41 was subjected to the 1 st Generation Procedure to yield regioisomeric carbamates 42a and 42b in a 1:1 mixture. By treating the isolated isomers independently under basic conditions, a 1:1 mixture was formed, showing that the sodium hydroxide required in the 1 st Generation hydroxyamination was also capable of catalysing a carbamate equilibration.…”

Cinchona Alkaloids as Chiral Ligands in Asymmetric Oxidations

“…In this example, the product oxazolidinone undergoes equilibrium under the reaction conditions to give the two products, but the nitrogen is at the 4-position of the ring system in both [365]. Of course, this approach circumvents the regiochemical problem associated with the site of attack of the nucleophile.…”

The Influence of Exocyclic Stereochemistry on the Tethered Aminohydroxylation Reaction

“…When oxidizing carbamates derived from allylic or homoallylic alcohols were used, we were able to obtain stereochemically defined amino alcohols with good levels of syn (1) or anti (2) stereoselectivity. By using these principles, the TA reaction has been used as a key step in the stereoselective synthesis of a range of biologically active compounds and natural products that uses aspects of both cyclic [11][12][13][14][15][16] and acyclic stereocontrol. [17][18][19][20] Attention was then turned to the possibility of inducing diastereoselectivity by using a stereocenter that is located outside (exo) of the heterocycle formed in the reaction (see 3!4).…”