S.G. Davies et al. / Tetrahedron 65 (2009) 8283–8296
8295
NaHCO3 (5 mL) was added and the mixture was extracted with
CHCl3 (4ꢂ20 mL), the combined organic extracts were dried, fil-
tered and concentrated in vacuo. Purification of the residue by
flash column chromatography (eluent MeOH/CHCl3, 1:19) gave 5
[83:17 mixture of (E):(Z) isomers] as a pale brown oil (186 mg,
70%).
Union Road, Cambridge CB2 1EZ, UK [fax: þ44(0) 1223 336033 or
Acknowledgements
The authors would like to thank Macfarlan Smith Ltd., Edin-
burgh, for financial support and providing an authentic sample of
(þ)-pilocarpine, and also the Oxford Chemical Crystallography
Service for the use of their X-ray diffractometers.
4.1.31. (3S,4R)-3-Ethyl-4-[(N(10)-methylimidazol-50-yl)methyl]-
g-
butyrolactone 1 [(þ)-pilocarpine 1]
Me
N
Et
N
References and notes
O
O
1. Hardy, E. Bull. Soc. Chim. Fr. 1875, 24, 497.
2. Gerrard, A. W. Pharm. J. 1875, 5, 86.
3. (a) Jowett, H. A. D. J. Chem. Soc., Chem. Commun. 1900, 77, 473; (b) Jowett, H. A. D.
J. Chem. Soc., Chem. Commun. 1900, 78, 851; (c) Pinner, A.; Kohlhammer, E. Ber.
Dtsch. Chem. Ges. 1900, 33, 2357; (d) Pinner, A.; Kohlhammer, E. Ber. Dtsch. Chem.
Ges. 1900, 33, 1424; (e) Jowett, H. A. D. J. Chem. Soc., Chem. Commun. 1901, 79,
580; (f) Jowett, H. A. D. J. Chem. Soc., Chem. Commun. 1901, 79, 1331; (g) Pinner,
A.; Kohlhammer, E. Ber. Dtsch. Chem. Ges.1901, 34, 727; (h) Pinner, A.; Schwarz, R.
Ber. Dtsch. Chem. Ges. 1902, 35, 192; (i) Pinner, A.; Schwarz, R. Ber. Dtsch. Chem.
Ges. 1902, 35, 2441; The absolute (3S,4R)-configuration of (þ)-pilocarpine 1 was
established in 1966, see: Hill, R. K.; Barcza, S. Tetrahedron 1966, 22, 2889.
4. (a) Battersby, A. R.; Openshaw, H. T. In The Alkaloids; Manske, R. H. F., Holmes,
H. L., Eds.; Academic: New York, NY, 1953; Vol. 3, p 201; (b) Maat, L.; Beyerman,
H. C. In The Alkaloids; Brossi, A., Ed.; Academic: New York, NY, 1983; Vol. 22,
p 281.
5. (a) Dreisbach, R. H. J. Pharmacol. Exp. Ther. 1961, 131, 257; (b) Levy, B.; Ahliquist,
R. P. J. Pharmacol. Exp. Ther. 1962, 137, 219; (c) Dreisbach, R. H. Am. J. Physiol.
1963, 204, 497.
6. (a) Watson, P. G. Br. J. Ophthalmol. 1972, 56, 145; (b) Schwartz, B. N. Engl. J. Med.
1978, 290, 182.
7. Talyor, P. In The Pharmacological Basis of Therapeutics, 6th ed.; Gilman, A. G.,
Goodman, L. S., Gilman, A., Eds.; Macmillan: New York, NY, 1980; p 96.
8. (a) Leopold, I. H.; Keates, E. Clin. Pharmacol. Ther. 1968, 6, 262; (b) Worthen, D.
M.; Zimmerman, T. J.; Wind, C. A. Invest. Ophthalmol. 1974, 13, 296; (c) Sanders,
H. J. Chem. Eng. News 1985, 63, 30.
Hydrogenation. A mixture of a-ethylidene lactone 5 (150 mg,
0.73 mmol, 83:17 (E):(Z) mixture) and PtO2 (10 mg) in
degassed MeOH (5 mL) was stirred under hydrogen (3 atm) for
24 h. The reaction mixture was then filtered through Celite
(eluent MeOH) and the filtrate was concentrated in vacuo.
Purification of the residue by flash column chromatography
(eluent MeOH/CHCl3, 3:97) gave a 72:28 mixture of (þ)-pilo-
carpine 1 and (þ)-isopilocarpine 1 as a colourless oil (150 mg,
quant).
Recrystallisation of hydrochloride salt.
A 72:28 mixture of
(þ)-pilocarpine 1 and (þ)-isopilocarpine 1 (450 mg, 2.16 mmol)
was dissolved in EtOH (1.0 mL) and the solution was cooled to 0 ꢀC.
12 M aq HCl (0.18 mL, 1.0 equiv) in EtOH (0.5 mL) was then added
dropwise and the resultant mixture was refrigerated for 16 h. The
crystals of pilocarpine hydrochloride 1$HCl were removed by fil-
tration and twice recrystallised from EtOH to give pure (þ)-pilo-
carpine hydrochloride 1$HCl as a white crystalline solid (122 mg,
9. Aboul-Enein, H. Y.; Al-Badr, A. A. Methods Find. Exp. Clin. Pharmacol. 1982, 4,
321.
20
23%); mp 201–202 ꢀC (lit.3a mp 204–205 ꢀC); [
a
]
þ90.1 (c 2.0,
D
10. (a) Preobrashenski, N. A.; Poljakowa, A. M.; Preobrashenski, W. A. Ber. Dtsch.
Chem. Ges. 1936, 69, 1835; (b) Dey, A. N. J. Chem. Soc., Chem. Commun. 1937, 1057;
(c) Chumachenko, A. V.; Zvonkova, E. N.; Evstigneeva, R. P. J. Org. Chem. U.S.S.R.
(Engl. Trans.) 1972, 8, 1112; (d) DeGraw, J. I. Tetrahedron 1972, 28, 967; (e) Link,
H.; Bernauer, K. Helv. Chim. Acta 1972, 55, 1053; (f) Noordam, A.; Maat, L.; Be-
yerman, H. C. Rec. J. R. Neth. Chem. Soc. 1981, 100, 441; (g) Compagnone, R. S.;
Rapoport, H. J. Org. Chem. 1986, 51, 1713; (h) Belletire, J. L.; Mahmoodi, N. O.
J. Nat. Prod. 1992, 55, 194; (i) Horne, D. A.; Fugmann, B.; Yakushijin, K.; Bu¨chi, G.
J. Org. Chem. 1993, 58, 62; (j) Dener, J. M.; Zhang, L.-H.; Rapoport, H. J. Org. Chem.
1993, 58, 1159.
11. (a) Shapiro, G.; Chengzhi, C. Tetrahedron Lett. 1992, 33, 2447; (b) Wang, Z.; Lu, X.
Tetrahedron Lett. 1997, 38, 5213; (c) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc.
2002, 124, 8198.
12. For additional references related to the synthesis of isopilocarpine 2, see: (a)
Preobrashenski, N. A.; Wompe, A. F.; Preobrashenski, W. A. Ber. Dtsch. Chem.
Ges. 1933, 66, 1187; (b) Poljakowa, A. M.; Preobrashenski, W. A.; Preobrashenski,
N. A. Ber. Dtsch. Chem. Ges. 1936, 69, 1314; (c) Zhu, G.; Lu, X. Tetrahedron:
Asymmetry 1995, 6, 1657; (d) Braun, M.; Buhne, C.; Cougali, D.; Schaper, K.;
Frank, W. Synthesis 2004, 2905.
13. For additional references related to the syntheses of various analogues, see: (a)
Gonzalez, F. B.; Baz, J. P.; Espina, M. I. R. Tetrahedron Lett. 1989, 30, 2145; (b)
Sauerberg, P.; Chen, J.; WoldeMussie, E.; Rapoport, H. J. Med. Chem. 1989, 32,
1322; (c) Holden, K. G.; Mattson, M. N.; Cha, K. H.; Rapoport, H. J. Org. Chem.
2002, 67, 5913.
14. Davies, S. G.; Roberts, P. M.; Stephenson, P. T.; Thomson, J. E. Tetrahedron Lett.
2009, 50, 3509.
15. (a) Jones, R. G. J. Am. Chem. Soc. 1949, 71, 644; (b) Jones, R. G.; McLaughlin, K. C.
J. Am. Chem. Soc. 1949, 71, 2444.
20
H2O) {lit.,10j
[a
]
þ88 (c 2.0, H2O)}.
D
Recrystallisation of nitrate salt. A 72:28 mixture of (þ)-pilocar-
pine 1 and (þ)-isopilocarpine 1 (450 mg, 2.16 mmol) was dissolved
in EtOH (1.0 mL) and the solution was cooled to 0 ꢀC. Aq HNO3 (6 M,
0.36 mL, 1.0 equiv) in EtOH (0.5 mL) was then added dropwise and
the resultant mixture was refrigerated for 16 h. The crystals of pi-
locarpine nitrate 1$HNO3 were removed by filtration and twice
recrystallised from EtOH to give pure (þ)-pilocarpine nitrate
1$HNO3 as a white crystalline solid (410 mg, 70%); mp 177–178 ꢀC
20
20
(lit.41 mp 178 ꢀC); [
H2O)}.
a
]
þ83.1 (c 1.0, H2O) {lit.10b
[a
]
þ81.3 (c 1.0,
D
D
4.1.31.1. X-ray crystal structure determination for 1$HNO3. Data
were collected using an Enraf-Nonius -CCD diffractometer with
graphite monochromated Mo K radiation using standard pro-
k
a
cedures at 150 K. The structure was solved by direct methods
(SIR92); all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at idealised po-
sitions. The structure was refined using CRYSTALS.42
X-ray crystal structure data for 1$HNO3 [C11H17N3O5]:
M¼271.27, monoclinic, space group
P
21, a¼6.0473(2) Å,
b¼9.5320(4) Å, c¼11.2321(5) Å,
b
¼92.1417(19)ꢀ, V¼647.00(5) Å3,
16. Bransma, L. Preparative Acetylenic Chemistry, 2nd ed.; Elsevier: Amsterdam,
1988; 231.
Z¼2,
m
¼0.111 mmꢁ1
,
colourless
plate,
crystal
dimen-
17. The formation of vinyl ether 15 was not entirely unexpected as the base-cat-
alysed cyclisation of simple acetylinic alcohols has been previously reported,
although more forcing conditions employing stronger bases (e.g., NaNH2) are
generally required for unactivated acetylenes. See: (a) Pflieger, D.; Muck-
ensturm, B. Tetrahedron 1989, 45, 2031; (b) Eglinton, G.; Jones, E. R. H.; Whiting,
M. C. J. Chem. Soc., Chem. Commun. 1952, 2873.
18. Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.; Roberts, S. M.
Tetrahedron Lett. 1979, 20, 3981.
19. Treatment of 9 under these conditions resulted in a change of colour of the
solution from deep red to yellow, followed by the formation of a light brown
precipitate.
sions¼0.05ꢂ0.05ꢂ0.2 mm3. A total of 1561 unique reflections were
measured for 5<q<27 and 1561 reflections were used in the re-
finement. The final parameters were wR2¼0.089 and R1¼0.063
[I>ꢁ3.0
s
(I)].
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 722773. Copies of the
data can be obtained, free of charge, on application to CCDC, 12