Syntheses of (-)-hygrine and (-)-norhygrine via Wacker oxidation

Article abstract of DOI:10.1016/j.tetlet.2010.03.098

Hygrine is an important biosynthetic intermediate for tropane alkaloids. A synthesis of (-)-hygrine starting from l-proline is described. The acetonyl side chain of hygrine was fashioned through the Wittig reaction followed by regioselective Wacker oxidation. In addition, this Letter provides the first synthesis of (-)-norhygrine.

Full text of DOI:10.1016/j.tetlet.2010.03.098

Tetrahedron Letters 51 (2010) 2900–2902
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Tetrahedron Letters
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Syntheses of (ꢀ)-hygrine and (ꢀ)-norhygrine via Wacker oxidation
*
Mahesh S. Majik, Santosh G. Tilve
Department of Chemistry, Goa University, Taleigao-Plateau, Goa 403 206, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Hygrine is an important biosynthetic intermediate for tropane alkaloids. A synthesis of (ꢀ)-hygrine start-
Received 12 February 2010
Revised 22 March 2010
Accepted 24 March 2010
Available online 27 March 2010
ing from L-proline is described. The acetonyl side chain of hygrine was fashioned through the Wittig reac-
tion followed by regioselective Wacker oxidation. In addition, this Letter provides the first synthesis of
(ꢀ)-norhygrine.
Ó 2010 Elsevier Ltd. All rights reserved.
The tropane alkaloids have attracted considerable interest due
to their significant biological properties, hallucinogenic character-
istics, and their utility as pharmacological probes.1 Several
members of this class of heterocycles including (ꢀ)-hyoscyamine
2, (ꢀ)-scopolamine 3, and (ꢀ)-cocaine 4 (Fig. 1) are used in
medicine as antimuscarinic drugs2 and their biosynthesis has been
extensively studied over last few decades.3 Hygrine 1, the
prototype of pyrrolidine alkaloids has served as a precursor for
the tropane skeleton. It was isolated from several plants4 and it ap-
pears to have no detectable optical activity when isolated. Later,
So far, there is no report on the synthesis of (ꢀ)-hygrine. Hence,
in continuation of our interest in the synthesis of small bioactive
molecules,8 we describe herein an easy access to (ꢀ)-hygrine start-
ing from L-proline using Wittig olefination and Wacker oxidation
as the key steps. During this study, the synthesis of (ꢀ)-norhygrine
was also accomplished for the first time.
The requisite (S)-N-carbobenzyloxyprolinal 7 was prepared
from easily available L
-proline according to literature procedure.9
The commercially available ethyltriphenylphosphonium bromide
salt 8 was treated with n-BuLi to generate in situ the desired ylide.
The Wittig reaction of this ylide with (S)-N-carbobenzyloxyprolinal
7 afforded the corresponding olefin 9 in 56% yield (Scheme 1). The
double bond geometry of olefin was assumed to be cis based on 13C
NMR peak of allylic methyl carbon which appeared at d 12.8. The
stage was now set up to generate the carbonyl functionality. The
( )-hygrine was resolved with
D-(+)-tartarate to give diastereo-
meric purity of maximum 80% after several recrystallizations and
absolute configurations4a of (+)-hygrine and (ꢀ)-hygrine were
determined by the relative correlations with those of
D-proline
and L
-proline, respectively. Recently, Park and co-workers5 con-
firmed the absolute configuration of (+)-hygrine as ‘R’ by its first
asymmetric synthesis.
To the best of our knowledge, the racemic hygrine has been
synthesized three times in the 1980’s.6a–c Recently, Klussmann
and co-workers have disclosed a new method toward racemic
hygrine using a metal catalyst.6d In spite of the apparently simple
molecular structure of hygrine 1, only two asymmetric syntheses
are reported. This may be because of its tendency to racemize read-
ily in neutral or basic conditions.4a,4c The recent first enantioselec-
tive synthesis of (+)-hygrine reported by Park and co-workers5 is
based on asymmetric phase transfer catalytic alkylation, and there-
after a short and direct synthesis of (+)-hygrine is reported by
H3C
N
O
H
CH
N
3
O
O
CH
3
HO
2
1
(+)-hygrine
Ph
(-)-hyoscyamine
H3C
O
Garcia and Colmenares using D
-proline as a starting material.7
N
O
H C
3
Although only (+)-hygrine acts as a precursor for the tropane
alkaloids, both the enantiomers of the hygrine appeared to serve
equally well in the biosynthesis of the cuscohygrine as well as
for the incorporation studies of radiolabeled hygrine [14C] into
the tropane alkaloids.3b
N
OCH3
O
H
O
O
O
H
HO
Ph
Ph
4
(-)-cocaine
3
(-)-scopolamine
* Corresponding author. Tel.: +91 832 6519317; fax: +91 832 2452886.
E-mail addresses: stilve@unigoa.ac.in, santoshtilve@yahoo.com (S.G. Tilve).
Figure 1. Hygrine and medicinally important tropane alkaloids.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.098

M. S. Majik, S. G. Tilve / Tetrahedron Letters 51 (2010) 2900–2902
2901
O
O
OH
Ph
H2, Pd/C
81%
CHO
N
N
CH3
N
COOH
CH3
N
H
N
H
O
Ph
O
O
O
5
O
13
Ph
7
6
O
10
CH3
O
Scheme 2. Synthesis of (ꢀ)-norhygrine.
c
a
b
CH3
N
N
O
Ph
carbonyl furnished (ꢀ)-norhygrine 13 having ½a D33
ꢁ
ꢀ29.6 (c 0.14,
O
Ph
O
O
O
9
10
CHCl3).
In conclusion, we have accomplished a brief synthesis of (ꢀ)-
hygrineꢂHCl in five steps from carbobenzyloxyprolinal. The key fea-
ture of the present synthesis is the use of Wacker oxidation for the
generation of carbonyl functionality in a regioselective manner.
Moreover, we have demonstrated the utility of this approach for
the first asymmetric synthesis of (ꢀ)-norhygrine.
O
O
O
e
CH3
d
N
CH3
N
12
O
Ph
O
CH3
11
O
Acknowledgments
CH3
(-)-1
N
We thank IISc (Bangalore) for HRMS facility, National Institute
of Oceanography (Goa) for NMR facility and DST, CSIR (New Delhi),
for the financial support. M.S.M. is thankful to CSIR for awarding
Senior Research Fellowship.
HCl
CH3
Scheme 1. Synthesis of (ꢀ)-hygrine. Reagents and conditions: (a) ethyltriphenyl-
phosphonium bromide 8, n-BuLi, Et2O, 56%; (b) PdCl2, CuCl, O2, DMF–H2O, 76%; (c)
HOCH2CH2OH, pTsOH, 82%; (d) LAH, THF, 66%; (e) 6 N HCl, THF, 73%.
Supplementary data
Wacker oxidation has served as a versatile reaction that has found
broad applications in synthetic chemistry for the functionalization
of an alkene.10 Wacker oxidation is the method of choice for the
oxidation of terminal olefin to ketone. However, for its application
to internal olefin, the problem of regioselectivity is needed to be
considered. It was conjectured that the bulky phenyl group (Cbz)
as well as pyrrolidine ring would favor the regioselectivity in Wac-
ker oxidation.10c Hence, olefin 9 was treated with PdCl2/CuCl, O2 in
DMF:H2O at 70 °C for 48 h. The expected acetonyl carbamate 10
was obtained exclusively in good yield. The regioselectivity in
Wacker oxidation was also further inveterated by changing the
N-protecting group (carboethoxy protected olefin gave 31% yield
for Wacker oxidation).
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.03.098.
References and notes
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Now, the completion of the total synthesis of (ꢀ)-hygrine re-
quired the introduction of the methyl group on the nitrogen of
the pyrrolidine ring. The most direct route to achieve this transfor-
mation would be the use of protection/reduction/deprotection
strategy recently applied by Park and co-workers for the synthesis
of (+)-hygrine.5 Thus, the acetonyl carbamate 10 was subjected to
ketalization reaction using ethylene glycol, pTsOH in refluxing ben-
zene to give corresponding ketal 11. Further, the reduction of the
benzyloxycarbonyl group using LAH provided the corresponding
N-methyl pyrrolidine ketal 12 having ½a D29
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ꢁ
[lit.5
½
a 3D0
+33.3 (c 1.0, CHCl3) for R-isomer]. Finally, the deprotec-
ꢁ
tion of the ketal 12 with 6 N HCl in THF provided (ꢀ)-hygrineꢂHCl
having ½a 3D0
ꢁ
ꢀ32.1 (c 0.25, H2O); [lit.5 ½a D29
ꢁ
+34.5 (c 0.5, H2O) for R-
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The regioselective preparation of the acetonyl carbamate 10
from the olefin 9 was further exploited for the first asymmetric
synthesis of (ꢀ)-norhygrine 13 (Scheme 2). Norhygrine is found
in various plants4 and so far only one synthesis of its racemate
has appeared in the literature.11 Thus, the deprotection of benzyl-
oxycarbonyl group by hydrogenolysis without affecting the ketone

2902
M. S. Majik, S. G. Tilve / Tetrahedron Letters 51 (2010) 2900–2902
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