Total Synthesis of Kaitocephalin, the First Naturally Occurring AMPA/KA Receptor Antagonist

Abstract

Excitatory neuronal transmission within the central nervous system (CNS) is mediated predominantly by L-glutamate, which plays a role of utmost importance in many physiological processes such as neural plasticity, memory, and learning. 1 However, excessive of L-glutamate release can result in neuronal cell death, a phenomenon that has been termed excitotoxcity. 2 It is now commonly accepted that excitotoxic cell death substantially contributes to the pathophysiology of both acute and chronic neurodegenerative disorders in the CNS. These disorders include epilepsy, focal and global ischaemia, stroke, pain, and neurodegenerative diseases. 3 These observations have stimulated considerable research efforts on the development of selective and potent antagonists for glutamate receptors, particularly compounds acting at the N-methyl-D-aspartate (NMDA), R-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainic acid (KA) receptor subtypes. 4 Some AMPA/KA receptor antagonists have shown promising usage for treatment of epilepsy and cerebrovascular ischemia. 5 In 1997, kaitocephalin, the first natural AMPA/KA antagonist, was isolated from Eupenicillium shearii. In the models of chick primary telencephalic and rat hippocampal neurons, this compound showed protection from kainate toxicity at 500 µM with EC 50 values being 0.68 and 2.4 µM, respectively, and from AMPA/cyclothiazide (500 µM/50‚M) toxicity with EC 50 values 0.6 and 0.4 µM, respectively. Unlike the known AMPA/KA antagonists with a quinoxalinedione skeleton, kaitocephalin does not have any cytotoxic effect. 6 Thus, SAR studies on this compound may open a new avenue to the development of therapeutic tools for protection of excitotoxicity. However, before comprehensive SAR studies become a reality, an efficient route to kaitocephalin is required. Toward this goal we report here the first total synthesis of kaitocephalin.On the basis of the proposed stereochemistry of kaitocephalin, 7 we described a synthetic plan as shown in Scheme 1. The 2,5-disubstituted pyrrolidines A were envisioned to be ideal building blocks for synthesizing the target molecule because its 2-position could be lithiated and then coupled with (R)-Garner aldehyde to assemble the right-hand part of kaitocephalin, and its C-C double bond could be converted into the left-hand moiety through Sharpless asymmetric dihydroxylation. 8 The detailed studies were outlined in Scheme 2. Protection of the acid and amide groups of (S)-pyroglutamic acid under ordinary conditions followed by reduction with DIBAL-H provided 1a and 1b. 9 Treatment of 1 with allyltrimethylsilane and TiCl 4 in methylene chloride afforded cis-2 as the major product, together with some separable transisomer. 10 The aldol condensation reaction was obviously a key step for this synthesis and therefore tested under many conditions. Initially, lithiation of 2a with LDA at -78°C followed by trapping the resultant anion with (R)-Garner aldehyde gave the condensation products quantitatively. However, it was found that four ...

Stereoselective Synthesis of Quaternary Proline Analogues

“…In 2001, Ma et al reported a highly diastereoselective aldol reaction between an -proline benzyl ester bearing an allyl substituent at its 5-position and (R)-Garner aldehyde, [49] with the objective being to assemble the right-hand part of kaitocephalin, which is the first naturally occurring AMPA/KA antagonist without cytotoxic effects. The allyl substituent did not seem to influence the diastereoselectivity of the aldol reaction, with treatment of 48 with LDA providing four isomers in almost equal amounts.…”

Enantio‐ and Diastereoselective Construction of α,α‐Disubstituted α‐Amino Acids for the Synthesis of Biologically Active Compounds

“…The structure was originally assigned to have a (2S,3S,4R,7R,9S)-configuration. [21] Recently, the Ma [82] and Kitahara [45] groups have reported the total synthesis of 6, independently. Kitahara's work has proven the structure revision at C2 to have an (R)-configuration, [45] while Ma's work concerned the synthesis of the (2S)-isomer of kaitocephalin.…”

“…Kitahara's work has proven the structure revision at C2 to have an (R)-configuration, [45] while Ma's work concerned the synthesis of the (2S)-isomer of kaitocephalin. [82] Kitahara and co-workers employed Seebach's aldol condensation of chiral oxazolone 80 with the (S)-configured Garner aldehyde [83] for the construction of the (2R,3S)-2-amino-3-hydroxy moiety. The stereoselectivity upon formation of (3S)-3-hydroxypyrrolidine (81a) was only 60 %, but the undesired (3R)-81b could be converted into (3S)-81a by oxidation of the 3-hydroxy group followed by reduction of the resulting ketone.…”

“…A sequence of reduction, protection, desilylation, oxidation, and deprotection gave (-)-kaitocephalin (6; Scheme 14). [45] Ma's synthesis [82] is characterized by the use of an allyl group pre-installed on the pyrrolidine compound 84 at its C5, which is an alanine precursor as well as a stereochemical directing group for the aldol condensation at C2. Reaction between the (R)-configured Garner aldehyde and LHMDS gave the (3R,4S)-aldol adduct 85 in 84 % yield, while LDA gave an equal mixture of four diastereomers.…”

Transition-metal-free synthesis of imidazobenzothiazines via domino C-S/C-N bond formation

“…Heterocycles bearing C-S and C-N bond, for example, imidazobenzothiazines, have been found with a broad range of uses in drugs, such as anti-inflammatory [16,17], antimicrobial [18,19], antitubercular [20][21][22][23], antifungal [24,25], antagonist [26][27][28][29][30], and in functional material additives [31][32][33]. In the synthesis of these compounds, tandem C-S/C-N formation shows obvious advances over other methods due to their facile one-pot procedure [34][35][36][37].…”