A concise asymmetric synthesis of (+)-muscarine from (S)-γ-hydroxymethyl-γ-butyrolactone

Article abstract of DOI:10.1016/j.tetlet.2007.03.014

A highly stereoselective synthesis of (+)-muscarine iodide has been achieved in eight steps and 20% overall yield from commercially available (S)-γ-hydroxymethyl-γ-butyrolactone.

Full text of DOI:10.1016/j.tetlet.2007.03.014

Tetrahedron Letters 48 (2007) 2971–2973
A concise asymmetric synthesis of (+)-muscarine from
(S)-c-hydroxymethyl-c-butyrolactone
John Boukouvalas* and Ioan-Iosif Radu
De´partement de Chimie, Universite´ Laval, Quebec City, Que., Canada G1K 7P4
Received 31 December 2006; revised 23 February 2007; accepted 1 March 2007
Available online 4 March 2007
Abstract—A highly stereoselective synthesis of (+)-muscarine iodide has been achieved in eight steps and 20% overall yield from
commercially available (S)-c-hydroxymethyl-c-butyrolactone.
Ó 2007 Elsevier Ltd. All rights reserved.
Few natural products have enjoyed the prominence of
the alkaloid (+)-muscarine (1, X = OH or halogen,
Scheme 1) in terms of history, biological activity, and
impact to modern pharmacology and drug design.1,2
Interest in the muscarinic field has been invigorated in
recent years with the discovery that potent muscarinic
agonists, such as 1, could alleviate the short memory
loss exhibited by Alzheimer’s disease (AD) patients.3
Although muscarine is not therapeutically useful due
to adverse side-effects2a and its inability to cross the
blood-brain barrier,3 it is widely used as a biochemical
tool for studying signal transduction pathways in cul-
tured cells as well as in living systems.4 The combination
of growing demand and limited availability, along with
a simple but stereochemically challenging structure have
made 1 a classic target for synthesis.5 Commendable ef-
forts over the years have led to approximately 30 synthe-
ses from carbohydrate and noncarbohydrate starting
materials.6,7 However, the majority of these syntheses
suffer from excessive length or lack of selectivity.
In continuation of our interest in the expedient con-
struction of substituted tetrahydrofurans,8,9 we now
report a comparatively short, highly stereoselective syn-
thesis of 1 from (S)-c-hydroxymethyl-c-butyrolactone
(3). The latter is commercially available or inexpensively
prepared in two steps from naturally abundant L-glu-
tamic acid.10 Notwithstanding the structural homology
between 1 and 3, there is currently only one, non-stereo-
selective 15-step synthesis of muscarine that makes use
of a derivative of 3 as an early intermediate.6a Our ap-
proach differs from this, and the retrosynthetic analysis
is shown in Scheme 1. Dihydrofuran 2 was viewed as a
key intermediate whose alkylation and subsequent
anti-Markovnikov hydration would install the conti-
guous methyl and hydroxyl substituents along with the
correct stereochemistry at C2 and C3. In contemplating
high diastereoface selectivity, the use of a bulky protect-
ing group (PG), such as trityl or the more robust tert-
butyldiphenylsilyl, was deemed essential.10,11
HO
3
5
2
NMe
X
OPG
3
O
O
1
2
CO H
2
OH
HO C
NH
2
O
2
O
The synthesis began with the two-step conversion of 3 to
lactol 5 according to established precedent12 (Scheme 2).
Exposure of 5 with mesyl chloride and triethylamine in
dichloromethane, followed by heating, accomplished
b-elimination to furnish dihydrofuran 613 in 77% yield
after purification by silica gel chromatography.14
Attachment of the methyl substituent at C2 was realized
with complete regioselectivity by taking advantage of
L-glutamic acid
3
Scheme 1. Retrosynthetic analysis of muscarine.
Keywords: 2,3-Dihydrofurans; Hydroboration; Lactones; Lithiation;
(+)-Muscarine; Stereoselectivity.
Corresponding author. Tel.: +1 418 656 5473; fax: +1 418 656
7916; e-mail: john.boukouvalas@chm.ulaval.ca
*
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.014

2972
J. Boukouvalas, I.-I. Radu / Tetrahedron Letters 48 (2007) 2971–2973
b
c
d
OR
OTBDPS
OTBDPS
OTBDPS
O
HO
HO
O
O
O
O
5
6
7
3 R = H
a
4 R = TBDPS
e
HO
HO
g
h
NMe
I
I
OR
3
O
O
O
(+)-muscarine iodide (1a)
10
8 R = TBDPS
9 R = H
f
Scheme 2. Reagents and conditions: (a) TBDPSCl, Et3N, DMAP, CH2Cl2, 0 °C ! rt, 3 h (86%); (b) DIBAL, CH2Cl2, ꢀ78 °C, 2 h (95%); (c) MsCl,
Et3N, CH2Cl2, ꢀ20 ! 40 °C, 2.5 h (77%); (d) t-BuLi (2 equiv), THF, ꢀ78 ! 0 °C, 45 min, then TMEDA (2 equiv) or HMPA (1 equiv), 10 min, then
MeI (10 equiv), rt, 12 h (85%); (e) ThxBH2 (2 equiv), THF, 0 °C, 16 h, then aq 3 N NaOH/aq 30% H2O2, rt, 6 h (59%); (f) TBAF, THF, 0 °C ! rt,
2 h (93%); (g) Ph3P (1.5 equiv), I2 (1.4 equiv), imidazole (3 equiv), PhMe, 70 °C, 3 h (74%); (h) Me3N, EtOH, reflux, 3 h (92%).
2. For recent reviews on biological aspects of 1 and other
muscarinic agonists, see: (a) Eglen, R. M.; Choppin, A.;
Dillon, M. P.; Hegde, S. Curr. Opin. Chem. Biol. 1999, 3,
426–432; (b) Felder, C. C.; Bymaster, F. P.; Ward, J.;
DeLapp, N. J. Med. Chem. 2000, 43, 4333–4353; (c)
the propensity of dihydrofurans to undergo kinetic
deprotonation at the vinylic center a to the oxygen
atom.15 Thus, sequential treatment of 6 with t-BuLi
and a 10-fold excess of methyl iodide in the presence
of either TMEDA or HMPA afforded 7 in 85% yield.16
´
Bikadi, Z.; Simonyi, M. Curr. Med. Chem. 2003, 10, 2611–
2620; (d) Eglen, R. M. Prog. Med. Chem. 2005, 43, 105–
136.
3. Wu, E. S. C.; Griffith, R. C.; Loch, J. T., III; Kover, A.;
Murray, R. J.; Mullen, G. B.; Blosser, J. C.; Machulskis,
A. C.; McCreedy, S. A. J. Med. Chem. 1995, 38, 1558–
1570, and references cited therein.
4. See for example: (a) Masoud, G.-L.; Bourgue, C. W. J.
Neurosci. 2004, 24, 7718–7726; (b) Chen, S.-R.; Pan, H.-L.
Neuroscience 2004, 125, 141–148; (c) Wenzel, B.; Kunst,
M.; Guenther, C.; Ganter, G. K.; Lakes-Harlan, R.;
Elsner, N.; Heinrich, R. J. Comp. Neurol. 2005, 488, 129–
139; (d) Michel, F. J.; Fortin, G. D.; Martel, P.; Yeomans,
J.; Trudeau, L.-E. Neuropharmacology 2005, 48, 796–809;
(e) Chen, S.-R.; Wess, J.; Pan, H.-L. J. Pharmacol. Exp.
Ther. 2005, 313, 765–770; (f) Loreti, S.; Vilaro, M. T.;
Visentin, S.; Rees, H.; Levey, A. I.; Tata, A. M. J.
Neurosci. Res. 2006, 84, 97–105; (g) Nangle, M. R.; Keast,
J. R. Br. J. Pharmacol. 2006, 148, 423–433.
With the carbon skeleton in place, attention focused on
the hydration of the vinyl ether moiety by means of hyd-
roboration–oxidation.17 Of the various reagents tried,
including BH3ÆDMS, dicyclohexylborane, 9-BBN, disi-
amylborane, and thexylborane (ThxBH2), the last two
proved the most effective giving 86e as the only detect-
able isomer in yields of 55% and 59%, respectively. Sub-
sequent removal of the silyl protecting group provided
diol 9 which was cleanly transformed to the relay iodide
1018a on heating with iodine and triphenylphoshine in
the presence of imidazole.19 Finally, heating 10 in a
sealed tube with trimethylamine in ethanol6b delivered
(+)-muscarine iodide (1a) whose spectral and physical
properties18b were in excellent agreement with those
reported in the literature.6a,7e
5. Jin, Z. Nat. Prod. Rep. 2005, 22, 196–229, and previous
reviews in this series.
In summary, a highly selective asymmetric synthesis of
(+)-muscarine has been achieved in eight steps and
20% overall yield from (S)-c-hydroxymethyl-c-butyro-
lactone. This straightforward synthetic route builds the
3-oxygenated cis-2,5-disubstituted THF unit with com-
plete regio- and stereoselectivity and should be readily
adaptable to the preparation of other natural and
unnatural products of biomedical importance.20
6. For syntheses from 2000 see: (a) Kang, K. H.; Cha, M. Y.;
Pae, A. N.; Choi, K. I.; Cho, Y. S.; Koh, H. Y.; Chung, B.
Y. Tetrahedron Lett. 2000, 41, 8137–8140; (b) Popsavin,
V.; Beric, O.; Popsavin, M.; Radic, L.; Csanadi, J.; Cirin-
Novta, V. Tetrahedron 2000, 56, 5929–5940; (c) Knight, D.
W.; Staples, E. R. Tetrahedron Lett. 2002, 43, 6771–6773;
(d) Hartung, J.; Kunz, P.; Laug, S.; Schmidt, P. Synlett
2003, 51–54; (e) Knight, D. W.; Shaw, D. E.; Staples, E. R.
Eur. J. Org. Chem. 2004, 1973–1982; For recent syntheses
of analogues and other muscarine alkaloids see: (f) De
Amici, M.; Dallanoce, C.; Angelli, P.; Marucci, G.;
Cantalamessa, F.; De Marceli, C. Farmaco 2000, 55,
535–543; (g) Angle, S. R.; El-Said, N. A. J. Am. Chem.
Soc. 2002, 124, 3608–3616; (h) Hartung, J.; Kneuer, J.
Tetrahedron: Asymmetry 2003, 14, 3019–3031; (i) Fernan-
dez de la Pradilla, R.; Manzano, P.; Viso, A.; Fernandez,
J.; Gomez, A. Heterocycles 2006, 68, 1429–1442.
Acknowledgments
We thank the Natural Sciences and Engineering
Research Council of Canada (NSERC), Merck Frosst
Canada and Eisai Research Institute (Andover, MA,
USA) for financial support. We also thank FQRNT
´
(Quebec) for a postgraduate scholarship to I.-I.R.
7. For select syntheses before 2000 see: (a) Mulzer, J.;
Angermann, A.; Munch, W.; Schlichtho¨rl, G.; Hentzschel,
¨
References and notes
A. Liebigs Ann. Chem. 1987, 7–14; (b) Bandzouzi, A.;
Chapleur, Y. J. Chem. Soc., Perkin Trans. 1 1987, 661–
664; (c) Adams, J.; Poupart, M.-A.; Grenier, L. Tetrahe-
dron Lett. 1989, 30, 1753–1756; (d) Takano, S.; Iwabuchi,
Y.; Ogasawara, K. Chem. Commun. 1989, 1371–1372; (e)
´
1. Wang, P.-C.; Joullie, M. M. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1984; Vol. 23, pp 327–
380.

J. Boukouvalas, I.-I. Radu / Tetrahedron Letters 48 (2007) 2971–2973
2973
De Amici, M.; De Micheli, C.; Molteni, G.; Pitre, D.;
Carrea, G.; Riva, S.; Spezia, S.; Zetta, L. J. Org. Chem.
1991, 56, 67–72; (f) Hopkins, M. H.; Overman, L. E.;
Rishton, G. M. J. Am. Chem. Soc. 1991, 113, 5354–5365;
(g) Mantell, S. J.; Fleet, G. W. J.; Brown, D. J. Chem.
Soc., Perkin Trans. 1 1992, 3023–3027; (h) Chan, T. H.; Li,
C. J. Can. J. Chem. 1992, 70, 2726–2729; (i) Knight, D.
W.; Shaw, D.; Fenton, G. Synlett 1994, 295–296; (j)
Ohshiba, Y.; Yoshimitsu, T.; Ogasawara, K. Chem.
Pharm. Bull. 1995, 43, 1067–1069.
1H), 1.14 (s, 9H); 13C NMR (75 MHz, CDCl3) d 145.1,
135.6, 133.6, 129.6, 127.6, 98.9, 81.1, 65.9, 31.2, 26.8, 19.3;
Anal. Calcd for C21H26O2Si: C, 74.51; H, 7.74. Found: C,
74.87; H, 7.76.
`
15. (a) Boeckman, R. K., Jr.; Bruza, K. J. Tetrahedron Lett.
1977, 18, 4187–4190; For recent reviews on a-metalated
vinyl ethers see: (b) Friesen, R. W. J. Chem. Soc., Perkin
Trans. 1 2001, 1969–2001; (c) Friesen, R. W.; Sturino, C.
F. Sci. Synth. 2006, 8a, 841–862.
16. Data for 7: ½aꢁD +33.7 (c 2, CHCl3); H NMR (300 MHz,
CDCl3) d 7.76–7.70 (m, 4H), 7.48–7.33 (m, 6H), 4.75–4.65
(m, 1H), 4.50 (m, 1H), 3.80 (dd, J = 10.5, 5.5, 1H), 3.73
(dd, J = 10.5, 4.9, 1H), 2.75–2.63 (m, 1H), 2.56–2.47 (m,
1H), 1.80 (s, 3H), 1.11 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 154.0, 135.5, 133.6, 129.5, 127.5, 93.8, 81.3, 66.1,
32.3, 26.7, 19.2, 13.4; Anal. Calcd for C22H28O2Si: C,
74.95; H, 8.00. Found: C, 75.03; H, 8.22.
20
1
8. Boukouvalas, J.; Fortier, G.; Radu, I.-I. J. Org. Chem.
1998, 63, 916–917.
9. Boukouvalas, J.; Pouliot, M.; Robichaud, J.; MacNeil, S.;
Snieckus, V. Org. Lett. 2006, 8, 3597–3599.
10. Boukouvalas, J. In Handbook of Reagents for Organic
Synthesis: Chiral Reagents for Asymmetric Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 2003; pp 216–219.
11. Ando, K. J. Am. Chem. Soc. 2005, 127, 3964–3972.
12. (a) Hanessian, S.; Grillo, T. A. J. Org. Chem. 1998, 63,
1049–1057; (b) Pilli, R. A.; Riatto, V. B. Tetrahedron:
Asymmetry 2000, 11, 3675–3686; (c) Jung, M. E.; Pontillo,
J. J. Org. Chem. 2002, 67, 6848–6851.
17. (a) Brown, H. C.; Prasad, J. V. N. V.; Zee, S.-H. J. Org.
Chem. 1985, 50, 1582–1589; (b) Burkhardt, E. R.; Matos,
K. Chem. Rev. 2006, 106, 2617–2650.
20
18. (a) Iodide 10: ½aꢁD ꢀ32.8 (c 1.8, CHCl3), lit.7e (ee 96%)
20
½aꢁD ꢀ30.7 (c 0.874, CHCl3); (b) (+)-Muscarine iodide
20
20
13. For an alternative dehydration procedure see: Paquette, L.
A.; Brand, S.; Behrens, C. J. Org. Chem. 1999, 64, 2010–
2025.
(1a): ½aꢁD +6.33 (c 0.30, EtOH), lit.7e ½aꢁD +6.36 (c 0.346,
EtOH).
19. (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin
Trans. 1 1980, 2866–2869; See also: (b) Zakrzewski, P.;
Lau, C. K. Synlett 2003, 215–218.
20. For a recent review on the stereoselective synthesis of
tetrahydrofurans see: Wolfe, J. P.; Hay, M. H. Tetra-
hedron 2007, 63, 261–290.
20
1
14. Data for 6: ½aꢁD +53.4 (c 2, CHCl3); H NMR (300 MHz,
CDCl3) d 7.78–7.75 (m, 4H), 7.50–7.40 (m, 6H), 6.33 (dd,
J = 5.0, 2.5, 1H), 4.90 (dd, J = 5.0, 2.5, 1H), 4.72 (dddd,
J = 9.8, 7.2, 5.8, 5.5, 1H), 3.82 (dd, J = 10.7, 5.3, 1H), 3.75
(dd, J = 10.7, 4.9, 1H), 2.75–2.65 (m, 1H), 2.57–2.48 (m,