Synthesis of (+)-muscarine from (S)-(-)-5-hydroxymethyl-2(5H)-furanone

Article abstract of DOI:10.1016/S0040-4039(00)01435-0

(+)-Muscarine has been synthesized from (S)-(-)-5-hydroxy-2(5H)-furanone via rather a long pathway to provide easy access to a wide variety of its analogues. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01435-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8137–8140
Synthesis of (+)-muscarine from
(S)-(−)-5-hydroxymethyl-2(5H)-furanone
Kyung Ho Kang,a Mi Young Cha,a Ae Nim Pae,a Kyung Il Choi,a Yong Seo Cho,a
Hun Yeong Koha,* and Bong Young Chungb
aBiochemicals Research Center, KIST, PO Box 131, Cheongryang, Seoul 130-650, South Korea
bDepartment of Chemistry, Korea University, Seoul 136-701, South Korea
Received 25 August 2000; accepted 30 August 2000
Abstract
(+)-Muscarine has been synthesized from (S)-(−)-5-hydroxy-2(5H)-furanone via rather a long pathway
to provide easy access to a wide variety of its analogues. © 2000 Published by Elsevier Science Ltd.
Numerous synthetic methods of (+)-muscarine (I)1 and its analogues2 as muscarinic agonists
for the development of therapeutics for Alzheimer’s disease3 have been reported. But the
synthetic approaches for the analogues were very limited in their versatility, since they utilized
quite specific methods such as stereospecific cyclization, chemoenzymatic resolution, etc. In
order to study the substituent effect of muscarine analogues on binding to the muscarinic
receptors, we needed a new synthetic strategy for producing a large number of muscarine
derivatives. In this report, we describe a synthetic route to (+)-muscarine that opens the way to
various modifications.4 Commercially available (S)-(−)-5-hydroxymethyl-2(5H)-furanone,5,6
which has been utilized as an important precursor in natural product synthesis and as a template
in the synthesis of polypropiate-derived structural units, was used as the starting material.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01435-0

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Treatment of (S)-(−)-5-hydroxy-2(5H)-furanone 1 with chlorotriphenylmethane in pyridine at
70°C for 16 h gave tritylated butenolide 2 in 83% yield (Scheme 1). The a,b-unsaturated lactone
2 was hydrogenated at 2 bar using H2/Pd on CaCO3 to give the lactone 3 in 96% yield. Saturated
lactone 3 was reacted with 1.0 M LiHMDS at −78°C followed by the addition of freshly prepared
O-electrophile, MoOPH7 at −25°C to afford diastereomeric alcohols 4a and 4b in a ratio of 12:1.8
The high stereoselectivity must have resulted from the bulkiness of the trityl group.9
Scheme 1. Conditions: (a) TrCl, pyridine, 70°C, 83%; (b) H2/Pd on CaCO3, THF, 2 bar, 96%; (c) LiHMDS, −78°C,
MoOPH, −25°C for 30 min, 71% (4a/4b=12:1); (d) TMSCl, pyridine, 0°C–rt, 86%; (e) 0.5 M Tebbe reagent,
THF/toluene (1:3), pyridine, −40°C; (f) Raney Ni/H2 (2 bar), THF, 78% (6a/6b=44:56) (two steps)
The alcohol 4a with desired configuration was separated by flash column chromatography, and
the free hydroxyl group was protected (TMSCl/pyridine, 86%) to give 5. The carbonyl group of
the lactone 5 was transformed to methyl group via exo-methylene formation with 0.5 M Tebbe
reagent10 solution in toluene followed by catalytic hydrogenation. Catalytic hydrogenation using
Pd on CaCO3 followed by desilylation gave 6a and 6b in a ratio of 1:11. Presumably the
syn-addition of H2 from less-hindered a-face resulted in the predominant formation of undesired
diastereomer 6b with (2R,3R,5S)-configuration as a precursor of (−)-epiallo-muscarine. Alterna-
tively, Raney Ni mediated hydrogenation in EtOH gave a mixture of deprotected and protected
diastereomers in an overall yield of 78% (two steps). After desilylation by K2CO3 in MeOH, we
could obtain 6a and 6b in a ratio of 44:56. In situ generation of some deprotected alcohol during
the reaction might have led to hydroxy-directed hydrogenation of double bond to increase the
amount of 6a.11
(3S,5S)-Lactone 4b could efficiently be converted to 6a (Scheme 2). Protection by TMSCl in
pyridine produced lactone 7 in 85% yield. Treatment of 7 with Tebbe reagent followed by reduction
with Pd on CaCO3 under H2 and deprotection of TMS group gave exclusively the expected
(2S,3S,5S)-diastereomer 8 in 67% yield (three steps). Inversion of the alcohol at C-3 was achieved
in 67% yield (two steps) using Mitsunobu condition12 (DEAD, benzoic acid, PPh3, 0°C, THF)
and then hydrolysis to give 6a.
Scheme 2. Conditions: (a) TMSCl, pyridine, 0°C–rt, 85%; (b) 0.5 M Tebbe reagent, THF/toluene (1:3), pyridine,
−40°C; (c) H2/Pd on CaCO3, THF, 2 bar; (d) K2CO3 in MeOH, 67% (three steps); (e) DEAD, benzoic acid, PPh3,
0°C, THF; (f) 20% aqueous K2CO3 solution in MeOH, 67% (two steps)

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Thus obtained 6a having appropriate configuration was reacted with acetic anhydride in the
presence of sodium acetate at 60°C to yield the acetate 9. FeCl3·6H2O was a highly efficient
reagent for detritylation. To a solution of 9 in CH2Cl2 was added solid FeCl3·6H2O, stirred at
room temperature for 20 min, and purified.13 Activation of the primary hydroxyl group with
p-toluenesulfonyl chloride in pyridine at −20°C followed by iodination using NaI in 2-butanone
at 80°C gave the iodide 1014 in 56% yield (three steps). Finally, deacetylation by 20% aqueous
K2CO3 solution in MeOH followed by treatment with excess trimethylamine in EtOH gave
(+)-muscarine iodide (Scheme 3). All the spectroscopic data of prepared (+)-muscarine were
consistent with those reported in the literature.15,16
Scheme 3. Conditions: (a) Ac2O, NaOAc, 60°C, 70%; (b) FeCl3·6H2O, CH2Cl2; (c) TsCl, pyridine, −20°C; (d) NaI,
2-butanone, 80°C, 56% (three steps); (e) 20% aqueous K2CO3 solution in MeOH, 72%; (f) NMe3 in EtOH, reflux, 92%
In summary, the synthesis of (+)-muscarine from (S)-(−)-5-hydroxy-2(5H)-furanone has been
accomplished. Although the yield of each step was not so high, the whole process is meaningful
in that it opened a novel pathway to the muscarine derivatives. Preparation of muscarine
derivatives utilizing this strategy is now under progress.
Acknowledgements
This work was supported by grants from the Korea Ministry of Health and Welfare.
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