A short synthesis of (+)-hygrine

Article abstract of DOI:10.1016/j.tetlet.2008.04.098

The synthesis of the alkaloid hygrine in a series of six steps starting from readily available proline N-methyl derivative (5) is described.

Full text of DOI:10.1016/j.tetlet.2008.04.098

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Tetrahedron Letters 49 (2008) 3995–3996
A short synthesis of (+)-hygrine
a,b,
Enzo B. Arevalo-Garcıa *, Juan Carlos Q. Colmenares
c
´
´
a Department of Chemistry, Wright State University, Dayton, OH 45435, USA
b Department of Chemistry, C.W. Post. L.I.U, Long Island, NY 11548, USA
c Loker Hydrocarbon Research Institute, USC, Los Angeles, CA 90089, USA
Received 18 March 2008; revised 12 April 2008; accepted 15 April 2008
Available online 20 April 2008
Abstract
The synthesis of the alkaloid hygrine in a series of six steps starting from readily available proline N-methyl derivative (5) is described.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Hygrine; Alkaloid; Dess–Martin periodinane
Hygrine (1) is an alkaloid present in coca leaves as
well as in a variety of other plants. It has been the sub-
ject of several biological and pharmacological studies,1
especially since it is known that hygrine is the precursor
of hyoscyamine and scopolamine, both compounds are
used in the preparation of a vast number of pharmaceu-
tical products; consequently, there is an increased interest
in the development of synthetic routes to this alkaloid in
order to investigate structure–activity relationship.
Hygrine (1) has been prepared previously2 by rather
lengthy and tedious synthetic routes. We now present
an exceptionally simple synthesis route which provides
1 in good overall yield (Scheme 1); As a result, our
approach presents an advantage over a recently pub-
lished synthesis of hygrine.3
Thus, treatment of the readily available 54 with
DIBAL-H in CH2Cl2 at À30 °C afforded aldehyde 4.
This product, without further purification, was then
reacted with (methoxymethyl)triphenylphosphonium bro-
mide and with KO-t-Bu/THF to generate a methyl vinyl
ether. The subsequent acid hydrolysis of the vinyl ether
provided the homologated aldehyde 3; treatment of this
compound with methyl magnesium bromide afforded 2
in a mixture 2.5:1 (hygroline:pseudohygroline). Finally,
the transformation of 2 to hygrine 1 was carried out
by the Dess–Martin5 periodinane procedure; the final
product was then purified with flash column chromato-
graphy (hexane–AcOEt = 6:4) and its identification was
accomplished by comparison of the obtained data with
those previously described in the literature.2,3 All the
analytical data are in agreement with the values reported
for the optically pure compound, included: bp 87–88 °C
(23 mm); (lit.:2c,5 bp 83–84 °C (21 mm)); hygrineÁHCl6
[a]D +34.0 (c = 0.5, H2O); (lit.3 [a]D +34.5 (c = 0.5,
H2O)).
Me
O
N
1
Me
*
Thus, an efficient 6-step synthesis of hygrine was accom-
plished in 35% overall yield.
Corresponding author. Tel.: +1 516 4245959; fax: +1 516 2993944.
´
´
E-mail address: barevalo@excite.com (E. B. Arevalo-Garcıa).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.098

3996
E. B. Are´valo-Garcı´a, J. C. Q. Colmenares / Tetrahedron Letters 49 (2008) 3995–3996
Ph PCH OCH Br, THF
DIBAL, CH Cl , -30 ºC
H
3
2
3
OMe
2
2
10% HCl-THF
N
N
O
O
5
Me
Me
4
MeMgBr, THF
Dess-Martin
N
N
OH
O
Me
Me
Me
H
3
2
N
O
Me
Me
1
Scheme 1.
Pomilio, A. J. Ethnopharmacol. 1995, 49, 81; (f) Humam, M.; Munoz,
O.; Christen, P.; Hostettmann, K. Nat. Prod. Commun. 2007, 2, 743.
Acknowledgements
2. Some examples: (a) Nagasaka, T.; Yamamoto, H.; Hayashi, I.;
Watanabe, M.; Hamaguchi, F. Heterocycles 1989, 29, 155; (b)
Langenskioeld, T.; Lounasmaa, M. Heterocycles 1983, 20, 671; (c)
Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103,
1172; (d) Hill, R. K.; Loeffler, L. J. J. Org. Chem. 1960, 25, 2028.
3. Lee, J.-H.; Jeong, B.-S.; Ku, J.-M.; Jew, S.-s.; Park, H.-g. J. Org.
Chem. 2006, 71, 6690.
4. Commercially available. It is also easily synthesized from proline by
treatment with SOCl2/MeOH, and subsequent addition of MeI and
NaH.
The authors are grateful to Wright State University,
C.W. Post Long Island University Chemistry Departments,
and Loker Hydrocarbon Research Institute for partial sup-
port of this work.
References and notes
1. Some examples: (a) Berkov, S.; Zayed, R.; Doncheva, T. Fitoterapia
2006, 77, 179; (b) Jordan, M.; Humam, M.; Bieri, S.; Christen, C.;
Poblete, E.; Munoz, O. Phytochemistry 2006, 67, 570; (c) Doncheva, T.;
Berkov, S.; Philipov, S. Biochem. Syst. Ecol. 2006, 34, 478; (d) Berkov,
S.; Pavlov, A.; Georgiev, V.; Stanimirova, P.; Kovacheva, P.; Philipov,
S. Annuaire Univ. Sofia Fac. Biol. 2005, 96, 95; (e) Vitale, A.; Acher, A.;
5. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
6. Hygrine was readily transformed into its hydrochloride salt for
comparison with the literature data of the same compound (see Ref. 3).