Muscarines synthesis

Quaternary salts of the substances represented by tliese formulae have been prepared by Kogl, Veldstra and van der Laan as well as of the next lower homologues, the substituted butyraldehydes, and the methyl ethers of both series. Their pharmacological activities were negligible in comparison with that of muscarine, but as six stereoisomeric forms may be produced in each synthesis, the inactivity may be due to stereoisomerism, just as in the case of threonine (a-amino-)3-hydroxy-butyric acid) where West and Carter found that only the d —) form is... 

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

In view of the preponderance of muscarinic receptors in the CNS and the conceived need to augment the muscarinic actions of ACh in the treatment of Alzheimer s disease, much attention has been given recently to the synthesis of agonists that penetrate the blood-brain barrier, especially those that act specifically on M] receptors. 

In the periphery, some of the primary triggers for these processes have been identified. Acetylcholine seems to be one such factor because stimulation of preganglionic nerves in vivo increases enzyme activity. However, nicotinic and muscarinic receptor antagonists do not completely prevent this increase. The residual activation is attributed to peptides of the secretin-glucagon subgroup, including VIP and secretin both these peptides activate cAMP synthesis. Purinergic transmitters could also be involved. 

The aqueous Barbier-Grignard-type reaction has also been used in the synthesis of natural products. Chan and Li used the zinc mediated allylation as a key step in a total synthesis of (+)-muscarine (Scheme 8.5).72 The strategy was based on the observation that the diastereoselectivity of the allylation reaction in water can be reversed through the protection of the a-hydroxyl group. 

Scheme 6.156 Synthesis of muscarinic receptor antagonist analogues.

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

Thus, cholinergic receptor classification can be considered in terms of three stages of development. Initially, Dale [2] distinguished nicotinic and muscarinic receptor subtypes with crude alkaloids. Then, chemical synthesis and structure-activity relationships clearly revealed that nicotinic and muscarinic receptors were heterogeneous, but chemical selectivity could not come close to uncovering the true diversity of receptor subtypes. Lastly, analysis of subtypes came from molecular cloning, making possible the classification of receptors on the basis of primary structure (Fig. 11-2). 

This transmembrane signaling system involves a complex consisting of several functional proteins (Figure 7) stimulatory (e.g. P-adrenergic, dopamine Dp serotonin, vasopressin) [124] and inhibitory (e.g. a2-adrenergic, dopamine D2, opiod, and muscarinic) [125] receptors, stimulatory (Gs) and inhibitory (G ) G-proteins, and the catalytic protein, adenylate cyclase. On stimulation of a receptor, an associated G-protein binds GTP and the resulting receptor/G-protein/GTP complex then activates, or inhibits, adenylate cyclase in the catalysis of the synthesis... 

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). 

Wolf-Pflugmann M, Lambrecht G, Wess J, Mutschler E. (1989). Synthesis and muscarinic activity of a series of tertiary and quaternary N-substituted guvacine esters structurally related to arecoline and arecaidine propargyl ester. Arzneimittelforschung. 39(5) 539-44. 

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). 

Both [2- F] and [4- F]fluorobenzaldehydes are key intermediates in the synthesis of N-[ F]fluorobenzylamines via reductive aminations. This methodo o-gy has been successfully appHed to the preparation of a potential ace y -cholinesterase inhibitor [143] and of fluoro analogues of dexetimide, potent ligand of muscarinic cholinergic receptor [144] (Scheme 23). 

The Mannich reaction was used for the first synthesis of tropine, the parent alcohol of the tropane alkaloids. One of the natural tropane alkaloids used medicinally is hyoscyamine, sometimes in its racemic form atropine. Hyoscyamine is an anticholinergic, competing with acetylcholine for the muscarinic site of the parasympathetic nervous system, and thus prevendng the passage of nerve impulses. 

The formation of numerous ring-substituted spirolactams (53b) employed this methodology, which to date has also found application in a number of natural product syntheses. For example, the critical spirane junction-forming step in the synthesis of the muscarinic Mj receptor antagonist (—)-TAN1251A (58) from L-tyrosine involves PIFA-induced cyclization of the hydroxamic ester 56 to 57 according to Scheme 12 °. 

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

D.R. Hwang, C.S. Dence, Z.A. McKinnon, C.J. Mathias, M.J. Welch, Positron labeled muscarinic acetylcholine-receptor antagonist—2-[F-18]Fluorodexetimide and 4-[F-18]fluorodexetimide—Synthesis and biodistribution, Nucl. Med. Biol. 18 (1991) 247-252. 

---