Synthesis of -muscarine

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.

Regtosdective reduction of an epoxide. A key step in a short synthesis of (+)-muscarine (6) from the dibenzoate of 2,5-anhydro-D-glucitol (1) involves reduction of the epoxide 2. Use of SMEAH gives a 12 1 mixture of 3 and 4 use or LiAlH4 gives the same diols in the ratio 3 1. ... 

V. Popsavin, O. Beric, L. Radic, M. Popsavin, V. Cirin-Novta, and D. Miljkovic, Stereospecific synthesis of (+ )-muscarine from D-glucose, suitable for preparation of 5-substituted analogues, Collect. Czech. Chem. Commun., 63 (1998) 1522-1527. 

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... 

The heterocyclic ring, also, has been subjected to aminomethylation, as reported for the reaction of the furane sub.strate 454 (Fig. 172) with dimethylamine and formaldehyde, which represents a key step in the synthesis of muscarines. This is one of the few examples in alkaloid chemistry of the Mannich reaction not involving cyclization. 

Recently, similar conditions were applied to the deprotection of a Boc-peptide phenacyl ester fragment (1 1) during successful combined solid-phase and solution synthesis of muscarinic toxin 1 (MTX1)J 1... 

The photoisomerization of cyclobutanones to transient car-benes has been used as part of an interesting synthesis of muscarine (Pirrung and DeAmicis). Intramolecular oxetan formation has been used as part of novel syntheses of medium-ring ethers (1) and the tricyclo-octane (2) (Carless et al. Gleiter and Kissler). Cossy et al. have employed the photoreductive cycliza-... 

The first case of an mrramolecular C-H carbenoid insertion was reported by Cane and Thomas in 1984 [12], with the special diazoacetate 17 forming the spirocyclic 5-lactone 18 in 45 % yield according to eq. (8). Doyle et al. recognized that this is a general methodology for the synthesis of y-butyrolactones [16], The reactivity of the C-H bond toward carbene insertion is increased in the vicinity of an ether functionality. Thus, the 3(2H)-furanone 20, as a useful building block in the total synthesis of (+)-muscarine, results in 40% yield from the diazo precursor compound 19 [17],... 

Scheme 7.6 Protecting group-free synthesis of muscarine from 1957.

The situation with 3-hydroxyfurans was rather uncertain until recently. As a result of new work, the situation has been clarified. The so-called 3-hydroxyfuran was often discussed in the literature. -Thus, it has been described as a phenolic, crystalline compound, m.p. 58°, which allegedly gives a normal adduct with maleic anhydride. However, these observations were considered unreliable, as Bailey and Waggoner could not reproduce the results. Support for the latter workers was given also by Mabry, who again failed to reproduce the results. In the course of work on the synthesis of muscarine, the whole problem was undertaken on a broader basis. Intermediates were obtained which could have been 3-hydroxy-furans, but they were unequivocally described as a,jS-unsaturated ketones. ... 

A stereospecific synthesis of muscarines and allomuscarines of the D- and L- series has been achieved using 2-deoxy-2-ribose as starting material. Treatment of the ditoluoyl ester (1) with methanolic HCl gave a dimethyl ester which was converted to the dimethylamide (2) by heating to 90°C with dimethylamine. 

Scheme 7. Bandzouzi and Cbapleur synthesis of muscarine and epimuscarine (32,33).

Scheme 8. Synthesis of muscarine and allomuscarine by Piming and DeAmicis(//).

The copper-catalyzed amination of bromopyridine 29 was reported by workers at Merck on route to the synthesis of muscarinic (M3) antagonist 31 <01TL3251>. Interestingly, an uncatalyzed amination of 3-nitropyridines has also been reported <01JCS(P1)376>. Other metal mediated processes have been used to access pyridines with important biological activity as well <0lJOC605x01TL6811>. 

The full details of a convenient synthesis of muscarine-type compounds (see Vol. 5, p. 265) have now appeared the use of a transition-metal carbonyl to aid the cyclocondensation of aa-dibromo-ketones with MV-dimethyl-carboxamides gives good yields of 3(2i/)-furanones, which can be converted into the appropriate muscarine. In this way 4-methylmuscarine iodide (1), as a mixture of its two stereoisomers, was synthesised in 17% overall yield. 

Ketone 64 has been synthesized from D-xylose and used to construct the tetrahydrofuranyl calcheamicin analogue 65. Last year, Reet described a synthesis of muscarine from L-rhamnose and this has now been extended to (3R)-hydroxymuscarine 66 (tosylate salt). Both syntheses (and full details of the muscarine work have also appeared) proceed without the necessity of functional group protection. 

The synthesis of muscarine analogues from hexitols has been reviewed. ... 

Zinc-mediated allylation in the Luche conditions (commercial zinc powder in a saturated aqueous NH4 Cl/THF mixture) was applied in a five-step synthesis of (+)-muscarine, wherein an aldehyde derived from ethyl-lactate was treated with allyl bromide. No chelation control was observed with the a-alkoxyaldehyde, as well (Chan and Li, 1992a). 

The diene (170) has been used to produce racemic compounds of the C-gItycofuranosyl type (e.g. 171) and a new synthesis of muscarine (a further C-gfycofuranoside) from L-rhamnose is referred to in Chapter 24. 

There has been a further carbohydrate-based synthesis of the epoxide (+)-disparlure, the gipsy moth pheromone, using 2-deoxy-D-ribose as starting material and epoxyalcohol intermediates. (14S, 15S)-Leukotriene A4 methyl ester (58) has been prepared using the synthon (57), derived from D-glucal, as precursor, and epoxy alcohols were again used as intermediates. A synthesis of (+)-muscarine (59) from L-rhamnose is outlined in Scheme 10.46... 

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