L -Muscarine

The presence of a dichloromethylene group at the anomeric center of 82 facilitates proton abstraction at C-3 by a strong base (77), aifording the 4-deoxyglycos-3-ulose derivative 83. Reduction of the dichloromethylene group by Raney nickel gave a 1-C-methyl derivative with high stereospecificity, which opens the way to a series of 2,5-anhydro-l-deoxyalditols. Compound 83 was the key intermediate for the synthesis (78) of tosyl L-(+)-epi-muscarine (84a) and tosyl L-(+)muscarine (84b). 

Muscarine is a tetrahydrofuran derivative with the structure shown in Figure 3.7a. Because of the three chirality centers present in the molecule, muscarine exists in eight isomers, of which only one, L-(- -)-muscarine, is active. The remaining isomers also have been detected in toxic fungi, but because of their low biological activity and low concentration they do not contribute to toxicity. 

Amino-3-tetrahydrofurancarboxylic acid 17, an oxygen cycloleucine analog, has been synthesized from D,L-homoserine by an intramolecular Mukaiyama aldol condensation in six steps (89TL1181). From o-Thr, l-muscarine 18 was synthesized in eight steps. The synthesis is highly stereoselective (85T5321). 

Anhydro-l,3,6-trideoxy-L-rtbo-hexitol-l-yl)-trimethyl-ammonium chloride [L-(+)-Muscarine chloride] 2,5-Anhydro-/3-D-arabinofuranose 179-80... 

L(+)-Muscarine, a cholinergic agonist from the mushroom Amanita muscaria... 

An elegant stereospecific synthesis of (+)-muscarine (2 R = NMe3) has been achieved by reduction of the epoxide (1) (easily produced from D-mannitol) with sodium bis-(2-methoxyethoxy)aluminium hydride to give predominantly (2 R = OH) on monotosylation, this forms (2 R = OTs). Chromatographic resolution and treatment with trimethylamine yielded (-l-)-muscarine (2 R = NMea).1... 

Li Z, Huang M, Ichikawa J, Dai J, Meltzer HY. 2005. N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M(l) muscarinic receptors. Neuropsychopharmacology 30 1986-1995. 

Bandzouzi, A, Chapleur, Y, Dichloromethylenation of sugar lactones a stereospecific synthesis of L-(+)-muscarine and L-(+)-epimuscarine toluene-p-sulphonates, J. Chem. Soc., Perkin. Trans. 1, 661-664, 1987. 

The (+)-cis isomer of (108) was the most potent muscarinic of the series. It demonstrated a eudismic ratio of the same high order of magnitude as that for muscarine and the dioxolanes. This (+)-cis enantiomer has the same absolute configuration as the muscarini-cally most active L-(+)-muscarine (2) and the (+)-cis-dioxolane (109). The other isomers represented by structure (108), although much less potent than the (+)-cis isomer, also demonstrated a degree of muscarinic agonist effect. All four isomers of structure (108) showed similar nicotinic potency and activity, close to that of carbamyl choline, and eudismic ratios were small. 

All stereoisomers of (221) and (233) are feeble nicotinics. X-ray analysis of (+)-trans-ACTM (221) (282) established the Tg angle as 137" (which is within the anticlinal range), and because of the rigidity of the cyclopropane ring, this value probably closely approaches the solution conformation. The (IS, 2S) absolute configuration of (+)- raras-ACTM superimposes on the equivalent centers in the potent muscarinic agonists (S)-(-l-)-acetyl-/3-methylcholine (31) (see Table 2.2) and (2S,4R,5S)-(-l-)-muscarine (3) (283). A racemic cyclobutane analog (234) of trans-ACTM is mueh less potent than ( )-trans-ACTM (284). 

Thus, eight optical isomers (tour enantiomeric pairs) are possible. Of these, only the naturally occurring alkaloid, (2S,3R,5S)-(+)-muscarine (also called L-(+)-muscarine), is correctly referred to as muscarine. The 05 carbon of (+)-muscarine has the same absolute configuration as the analogous chiral p carbon in S-(+)-methacholine. 

Following the previously reported synthesis of racemic muscarine from methyl vinyl ketone (28), Amouroux et al. (29) prepared both l-(+)-muscarine and its enantiomer in eight steps from d- and L-threonine, respectively, via the highly stereoselective iodocyclization of a y,8-unsat-urated 2,4-dichlorobenzylether, each being carried out separately (Scheme 4). A similar approach to tetrahydrofuran ring closure in the... 

A concise enantioselective synthesis of (-l-)-muscarine from (R)-benzyloxymethyloxirane was recently reported by Takano et al. (36) (Scheme 10). The starting oxirane was coupled with lithium acetylide-ethylenediamine, forming the hydroxyalkyne, which was converted to the acid-sensitive 2,3-dihydrofuran by methylation and subsequent treatment with base. The dihydrofuran derivative was hydroborated and oxidized in... 

Values for the equipotent ratios of L-muscarine (relative to acetylcholine), at various postganglionic cholinergic receptors, vary from about 0.1 to 5.4. Marked activity (among isomers and analogues of muscarine) is restricted to those substances in which the arrangement of the methyl, the hydroxyl, and the onium side-chain groups is the same as in muscarine. 

VoLLE, R. L., Muscarinic and Nicotinic Stimulant Actions at Autonomic Ganglia, in International Encyclopedia of Pharmacology. Pergamon Press, Oxford, 1966. 

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