Stereospecific synthesis of (+)-muscarine from D-glucose, suitable for preparation of 5-substituted analogues

Article abstract of DOI:10.1135/cccc19981522

A stereospecific synthesis of (+)-muscarine iodide (1) has been achieved starting from D-glucose as a chiral precursor. The key steps of the synthesis involved a stereospecific cyclization of 3,5-di-O-mesyl derivative 3 into the 2,5-anhydride 4, the stereospecific catalytic hydrogenation of unsaturated derivative 6, and the C-4 epimerization of alcohol 12 by Mitsunobu reaction.

Full text of DOI:10.1135/cccc19981522

1522
Popsavin et al.:
STEREOSPECIFIC SYNTHESIS OF (+)-MUSCARINE FROM D-GLUCOSE,
SUITABLE FOR PREPARATION OF 5-SUBSTITUTED ANALOGUES
1
2
Velimir POPSAVIN , Ostoja BERIC, Ljubica RADIC, Mirjana POPSAVIN ,
3
4
Vera CIRIN-NOVTA and Dusan MILJKOVIC
Institute of Chemistry, Faculty of Sciences, University of Novi Sad, Trg D. Obradovica 3,
210 00 Novi Sad, Yugoslavia; e-mail: 1 vpops@eunet.yu, 2 popsavin@posejdon.ih.ns.ac.yu,
3 nnovta@eunet.yu, 4 milkovic@sprynet.com
Received September 9, 1998
Accepted September 11, 1998
Dedicated to Dr Jan Fajkos on the occasion of his 75th birthday.
A stereospecific synthesis of (+)-muscarine iodide (1) has been achieved starting from D-glucose as
a chiral precursor. The key steps of the synthesis involved a stereospecific cyclization of 3,5-di-O-
mesyl derivative 3 into the 2,5-anhydride 4, the stereospecific catalytic hydrogenation of unsaturated
derivative 6, and the C-4 epimerization of alcohol 12 by Mitsunobu reaction.
Key words: 2,5-Anhydro sugars; (+)-Muscarine, Stereospecific synthesis; Alkaloids, Carbohydrates.
(+)-Muscarine (1) is a principal alkaloid of the poisonous mushroom Amanita musca-
ria, which shows acetylcholine agonist activity towards the different subtypes of mus-
carinic receptors1. Recently, much progress has been made in the understanding of the
muscarinic receptor sites and agonists or antagonists, which have a potential in the
treatment of Alzheimer’s disease2. Hence, synthetic activity in this area has been con-
siderable and numerous syntheses of muscarine have been accomplished from different
precursors3. Major drawbacks of most of these approaches are either lack of selectivity
or the usage of relatively expensive reagents and/or starting compounds. Apart from a
single synthesis of (–)-muscarine from (S)-malic acid3d, none of the reported routes are
suitable for the preparation of higher muscarine homologues. In the course of our
studies related to preparation of optically pure muscarine stereoisomers by chirality
transfer from D-glucose, the syntheses of (+)-epiallomuscarine4, (–)-allomuscarine5 and
(+)-epimuscarine6 were already accomplished. Herein we wish to report the first stere-
ospecific synthesis of (+)-muscarine (1) based on D-glucose as a chiral precursor.
1,2-O-Isopropylidene-α-D-glucofuranose (2) readily available from D-glucose7 was
tritylated (TrCl, Py, rt, 72 h) and subsequently mesylated (MsCl, Py, +4 °C, 24 h) in a
“one pot” procedure to afford a quantitative yield of the corresponding 3,5-di-O-mesyl-
6-O-trityl derivative 3. Treatment of compound 3 with ethylene glycol and p-toluene-
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Stereospecific Synthesis of (+)-Muscarine
1523
sulfonic acid, in refluxing benzene with azeotropic removal of water for 2 h gave the
2,5-anhydro-L-idose derivative 4 (51% from 2). Reaction of 4 with 2,2-dimethoxypro-
pane, in the presence of catalytic amounts of p-toluenesulfonic acid (rt, 24 h), afforded
the corresponding 4,6-O-isopropyledene derivative 5 in 87% yield. Treatment of 5 with
tetrabutylammonium fluoride, in boiling acetonitrile for 48 h, gave the corresponding
2,3-unsaturated derivative 6 in 76% yield. Catalytic hydrogenation of 6 (PtO2, EtOH, rt,
24 h) took place stereospecifically (from the less hindered β-side) to afford the 3-deoxy
derivative 7 as the only stereoisomer in high yield (94%). Selective removal of the
4,6-O-isopropylidene protective group in 7 was achieved with 10% trifluoroacetic acid
in methanol (rt, 0.5 h) whereupon the corresponding diol 8 was obtained in 79% yield8.
Comparing with the target molecule 1, the intermediate 8 has the correct stereochem-
istry only at the C-2 and C-5 chiral centers. For the sake of better functional and stereo-
chemical resemblance to the target, the molecule 8 must be further subjected to a C-6
deoxygenation and a Walden inversion at the C-4. This would lead to the key chiral
HO
HO
TrO
O
MsO
O
O
OMs
O
MsO
ii
i
O
OH
O
O
HO
O
O
OH
4
2
3
iii
O
O
O
O
O
MsO
v
iv
O
O
O
O
O
O
O
O
O
O
6
5
7
vi
O
O
O
vii
+
Br
O
O
O
HO
Br
Br
OH
O
OH
O
O
10
8
9
o
(i) TrCl, Py, rt, then MsCl, +4 C (100%); (ii) Ethylene glycol, TsOH, benzene, reflux (51%); (iii) Me C(OMe)
2
2
TsOH, rt (87%); (iv)Bu NF, MeCN, reflux (76%); (v) H /PtO , EtOH, rt (94%); (vi) CF COOH, MeOH,
4
2
2
3
rt (79%); (vii) CBr , Ph P, Py, rt (23% of 9 + 24% of 10)
4
3
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1524
Popsavin et al.:
intermediate 14 with all stereocenters corresponding to (+)-muscarine. At first we have
planned to deoxygenate the C-6 via the corresponding 6-bromo-6-deoxy derivative 9. It
was assumed that the diol 8 could be transformed to the bromo derivative 9 by using
the CBr4/Ph3P/Py reagent system which selectively reacted with the hydroxymethyl
groups of certain sugar derivatives to give high yields of the corresponding primary
bromodeoxy sugars. Conversely, the secondary hydroxyl groups remain unchanged
under the recommended reaction conditions9. However, a treatment of the diol 8 with
tetrabromomethane and triphenylphosphine (Py, rt) gave a low yield of the expected
6-bromo-6-deoxy derivative 9 (23%) accompanied by an equal amount of the 4,6-di-
bromo derivative 10.
Obviously, the deoxy derivative 9 could be further converted to the advanced inter-
mediate 12, however a low yield of the preceding bromination forced us to use the
known6 but rather efficient two-step sequence for the preparation of compound 12. It
included previous conversion of diol 8 (TsCl, Py, 20 °C, 6 days) to the 6-O-tosyl deri-
O
O
O
ii
i
O
O
O
HO
TsO
Me
OH
O
OH
O
OH
O
12
11
8
v
iii
O
OBz
O
OBz
O
vi
iv
O
O
CHO
Me
Me
Me
O
O
OTs
15
14
13
vii
O
OBz
O
viii
O
2
I
x
5
OR
OH
CH OH
CH I
2
2
Me
ix
CH NMe
2
3
Me
Me
6
4
3
1
16
17 R = Bz
18 R = H
(+)-Muscarine
iodide (1)
o
o
(i) TsCl, Py, -20 C (80%); (ii) LiAlH , THF, reflux (90%); (iii) TsCl, Py, rt (80%); (iv) KOBz, DMF, 100 C (66%);
4
o
(v) PhCOOH, Ph P, DEAD, THF, rt; (vi)CF COOH, 6 M HCl, +4 C; (vii) NaBH , MeOH, RT (27% from 12);
3
3
4
o
(viii) I , Imidazole, Ph P, MePh, reflux (83%); (ix) K CO , MeOH, rt (83%); (x) Me N, EtOH, 80 C (76%)
2
3
2
3
3
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Stereospecific Synthesis of (+)-Muscarine
1525
vative 11 (80%), followed by reduction of 11 (LiAlH4, THF↑↓, 4 h) to the desired
intermediate 12 (90%).
Treatment of 12 with tosyl chloride (Py, rt, 48 h) gave the 4-O-tosyl derivative 13 in
80% yield. Compound 13 readily reacted with potassium benzoate (DMF, 100 °C, 24 h) to
give the compound 14 (ref.10) (66%), with an absolute configuration of all stereogenic
centers corresponding to (+)-muscarine. Compound 14 was alternatively prepared di-
rectly from 12 by using the standard Mitsunobu11 conditions (PhCOOH, Ph3P, DEAD,
THF, rt, 24 h). However, thus obtained sample 14 was slightly contaminated with un-
identified aromatic impurities that remained in the sample even after repeated chroma-
tographic purification. Fortunately, these impurities did not affect the course of the
following reaction directed to the hydrolytic removal of the dioxolane protective group.
Treatment of 14 with a mixture of trifluoroacetic and 6 M hydrochloric acid (4 : 1; +4 °C,
24 h) gave the unstable aldehyde 15 which was immediately reduced with sodium boro-
hydride (MeOH, rt, 24 h) to afford the corresponding primary alcohol 16 (ref.12) (27%
from 12). Reaction of 16 with iodine, imidazole and triphenylphosphine (MePh↑↓, 3 h)
gave the known13 iodo derivative 17 (ref.14) in 83% yield. O-Debenzoylation of 17 with
potassium carbonate (MeOH, THF, rt, 1.5 h) afforded the iodo alcohol 18 (ref.15) in
83% yield.
Finaly, compound 18 was converted to (+)-muscarine iodide (1) by treatment with
trimethylamine (EtOH, 80 °C, 3 h). The 1H and 13C NMR spectral data (Table I) as well
as physical constants of 1 thus obtained were in reasonable agreement with those al-
ready reported13.
In conclusion, a practical multistep synthesis of (+)-muscarine was developed start-
ing from D-glucose as a chiral precursor. Each step of the synthesis was realized in a
TABLE I
NMR Spectral data for (+)-muscarine iodide (1; in D2O)
Chemical shifts (δ) and J (Hz)
H-1a
3.48
3.39
H-1b
3.62
3.49
H-2
4.66
4.57
H-3a
2.01
1.91
H-3b
2.12
2.01
H-4
4.13
4.03
H-5
4.06
3.96
H-6
1.21
1.11
This work
Ref.13
J1a,1b
14.0
14.0
J1a,2
9.1
J1b,2
1.8
J2,3a
9.5
J2,3b
6.4
J3a,3b
13.7
13.7
J3a,4
5.9
J3b,4
2.4
J4,5
2.5
2.5
This work
Ref.13
9.2
1.8
9.6
6.3
5.7
2.3
C-1
C-2
C-3
C-4
C-5
C-6
NMe3
56.70
57.09
This work 73.21
Ref.13
73.51
74.66
74.85
40.23
40.53
77.87
78.13
86.77
86.91
21.89
22.11
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1526
Popsavin et al.:
fully regio- and stereospecific manner, using inexpensive reagents and a readily avail-
able starting material. This approach is potentially useful for the preparation of a variety
of 5-substituted (+)-muscarine analogues, by starting from D-glucose derivatives bearing
the appropriate functional groups at C-6.
The work was supported by the Ministry of Science and Technology of the Republic of Serbia.
REFERENCES AND NOTES
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Birdsall, Eds), Vol. 10, p. 80. Elsevier, Cambridge 1989; b) De Amici M., Dallanoce C., De
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40, p. 190. Accademic Press, New York 1990; c) Lewis J. R.: Nat. Prod. Rep. 1992, 9, 81; d)
Knight D. W., Show D., Fenton G.: Synlett, 1994, 295, and references therein.
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7. Vargha L.: Chem. Ber. 1933, 66, 706.
8. Compound 8 was synthesized earlier by an independent six-step route (ref.6) in 17.43% overall
yield in respect to the starting triol 2. The sequence presented here represents a more convenient
route towards the intermediate 8, because it provided higher overall yield of the desired product
(25.04% in 6 steps).
9. Whistler R. L., Anisuzzaman A. K. M.: Methods Carbohydr. Chem. 1980, 8, 227.
1
10. Compound 14 (syrup): [α]D +0.53 (c 1.7, CHCl3); H NMR (CDCl3): δ 1.34 d, 3 H, J(5,6) = 6.6 Hz
(Me-6), 2.15 ddd, 1 H, J(3a,3b) = 13.8, J(2,3a) = 6.3, J(3a,4) = 2.4 Hz (H-3a), 2.25 ddd, 1 H,
J(2,3b) = 9.4, J(3b,4) = 5.9 Hz (H-3b), 3.82–4.07 m, 4 H (dioxolane CH2), 4.14–4.29 m, 2 H,
J(1,2) = 5.5, J(4,5) = 2.7 Hz (H-2 and H-5), 4.93 d, 1 H (H-1), 5.15 m, 1 H (H-4), 7.40-8.10 m,
5 H (Ph); 13C NMR (CDCl3): δ 19.78 (C-6), 32.97 (C-3), 65.43 and 65.56 (dioxolane CH2),
79.07 (C-2), 79.88 (C-4), 81.01 (C-5), 104.73 (C-1), 128.45, 129.65, 129.97 and 133.22
(aromatic), 166.14 (C=O); CI MS (i-C4H10): m/e 278 (M+).
11. Mitsunobu O.: Synthesis, 1991, 1.
12. Alcohol 16 (syrup): [α]D –7.85 (c 1.1, CHCl3); H NMR (CDCl3): δ 1.35 d, 3 H, J(5,6) = 6.5 Hz
1
(Me-6), 2.04 ddd, 1 H, J(3a,3b) = 13.7, J(2,3a) = 5.6, J(3a,4) = 1.9 Hz (H-3a), 2.24 ddd,
overlapped with bs, 2 H, J(2,3b) = 10.2, J(3b,4) = 6.3 Hz (H-3b and OH), 3.59 m, after addition
of D2O dd, 1 H, J(1a,1b) = 11.9, J(1a,2) = 4.6 Hz (H-1a), 3.87 m, after addition of D2O dd, 1 H,
J(1b,2) = 2.9 Hz (H-1b), 4.22 dq, 1 H, J(4,5) = 2.6 Hz (H-5), 4.32 m, 1 H (H-2), 5.14 dt, 1 H
(H-4), 7.40-8.08 m, 5 H (Ph); 13C NMR (CDCl3): δ 19.79 (C-6), 33.04 (C-3), 63.79 (C-1), 79.06
(C-5), 80.36 (C-2), 80.64 (C-4), 128.37, 129.55, 129.87 and 133.16 (aromatic), 166.11 (C=O); CI MS
(i-C4H10): m/e 237 (M+ + H).
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Stereospecific Synthesis of (+)-Muscarine
1527
13. De Amici M., De Micheli C., Molteni G., Pitre D., Carrea G., Riva S., Spezia S., Zetta L.:
J. Org. Chem. 1991, 56, 67.
14. Iodo derivative 17: [α]D –7.57 (c 0.37, CHCl3); m.p. 68 °C (from hexane). Ref.13: [α]D –11.67 (c 0.93,
CHCl3); m.p. 68 °C (from hexane).
15. Iodo alcohol 18 (syrup): [α]D –33.26 (c 0.87, CHCl3). Ref.13: [α]D –30.72 (c 0.87, CHCl3).
Collect. Czech. Chem. Commun. (Vol. 63) (1998)