Synthesis of the isoquinoline alkaloid, crispine C

Article abstract of DOI:10.1016/j.tetlet.2012.05.113

The first total synthesis of the isoquinoline alkaloid, crispine C is described in seven steps using a Henry reaction and the Pictet-Gams variant of the Bischler-Napieralski reaction to effect the key transformations.

Full text of DOI:10.1016/j.tetlet.2012.05.113

Tetrahedron Letters 53 (2012) 4084–4086
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Synthesis of the isoquinoline alkaloid, crispine C
⇑
Adele Blair, Louise Stevenson, Andrew Sutherland
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of the isoquinoline alkaloid, crispine C is described in seven steps using a Henry
reaction and the Pictet–Gams variant of the Bischler–Napieralski reaction to effect the key
transformations.
Received 6 April 2012
Revised 16 May 2012
Accepted 23 May 2012
Available online 30 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Crispine C
Isoquinoline synthesis
Pictet–Gams cyclisation
Guanylation
MeO
MeO
MeO
MeO
Carduus crispus, a Mongolian thistle has long been used in Chi-
nese folk medicine for the treatment of colds, stomach problems
and rheumatism. In 2002, pharmacological screening of an extract
revealed significant cytotoxicity against some human cancer cell
lines.1 The search for the active compounds led to the discovery
of five novel alkaloids, crispines A–E (Fig. 1). (+)-Crispine A (1)
Cl-
N
N+
H
1
2
NH
3 N
H
NH2
MeO
MeO
and crispine
B (2) have pyrrolo[2,1-a]isoquinoline skeletons
MeO
whereas crispine C (3) and crispine D (4) are isoquinoline alkaloids
with guanidinyl side-chains. (+)-Crispine E (5) is a tetrahydroiso-
quinoline with a guanidine-derived propyl side-chain at the C-1
position. On isolation, testing of these compounds against SKOV3,
KB and Hela human cancer cell lines showed crispine B (2) to have
significant cytotoxic activity.1
N
NH
NH2
N
MeO
NH
NH2
N
H
3 N
H
3
4
MeO
Due to their novel structures and the potential of these com-
pounds as pharmaceutical agents, there has been much interest
in their synthesis.2–4 Crispine A (1) in particular has been prepared
using a variety of methods,2 including a lipase-catalysed kinetic
resolution of a C-1 substituted tetrahydroisoquinoline2n as well
as by a stereoselective electrochemical cyanation of a chiral tetra-
hydroisoquinoline.2r Crispine B (2) has been prepared using a Bis-
NH
MeO
NH
NH2
N
H
5
Figure 1. Structures of crispines A–E (1–5).
chler–Napieralski reaction,3 while (+)-crispine
E
(5) was
reaction to effect the key step, we now report the first total synthe-
sis of crispine C.
synthesised using asymmetric transfer hydrogenation as the key
step.4b To date, there have been no reported syntheses of crispine
C (3) or crispine D (4). Our research group has had a long-standing
interest in the synthesis of guanylated natural products and medic-
inally active agents using in particular, various protected pyrazole-
1-carboxamidines for the efficient incorporation of the guanidine
group.5 Using this approach in combination with a Pictet–Gams
Our strategy for the synthesis of crispine C (3) involved the
preparation of a suitably functionalised phenethylamine that
would be coupled with 4-aminobutyric acid (Scheme 1). The
resulting amide was to be used in a Bischler–Napieralski type reac-
tion to form the isoquinoline ring system and the synthesis would
then be completed by the incorporation of the guanidine moiety.
Our first attempt at the synthesis of crispine C (3) involved
using 3,4-dimethoxyphenethylamine (6) as a starting material
⇑
Corresponding author.
E-mail address: Andrew.Sutherland@glasgow.ac.uk (A. Sutherland).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.113

A. Blair et al. / Tetrahedron Letters 53 (2012) 4084–4086
4085
X
OH
MeO
CHO
X
MeO
MeO
i
MeO
MeO
MeO
MeO
HN
O
MeO
NO2
NH2
X= H, OH
9
10
ii
3
PHN
OH
OH
MeO
MeO
MeO
MeO
MeO
MeO
iii
MeO
MeO
N
N
HN
O
NH
NH2
NH2
3 N
3
NHP
PhthN
12
H
11
3
iv
Scheme 1. Synthetic approach for the synthesis of crispine C (3).
O
MeO
MeO
N
Phth =
and a Bischler–Napieralski reaction to form a C-1 substituted 3,4-
dihydroisoquinoline (Scheme 2). 3,4-Dimethoxyphenethylamine
(6) was coupled with Cbz-protected 4-aminobutyric acid6 using
EDCI as the coupling agent to give the corresponding amide 7 in
89% yield. Amide 7 was then treated with neat phosphorus oxy-
chloride to effect the Bischler–Napieralski reaction4b,7 and this
gave 3,4-dihydroisoquinoline 8 in 73% yield. The next stage of
the reaction sequence required dehydrogenation of 8 to complete
the synthesis of the isoquinoline ring system. A number of well-
precedented methods were investigated including heating 8 in di-
phenyl ether at 170 °C in the presence of palladium on carbon,8 as
well as oxidation of 8 with selenium dioxide9 and DDQ.10 However,
all attempts led to decomposition or returned only 3,4-dihydroiso-
quinoline 8.
While the oxidation of dihydroisoquinolines to give isoquino-
lines is well known, problems with electron-rich ring systems have
been reported.11 These issues have been overcome by using the
Pictet–Gams modification of the Bischler–Napieralski reaction.12
A suitable substrate for this reaction was prepared in three steps
from 3,4-dimethoxybenzaldehyde (9) (Scheme 3). Initially, 9 was
subjected to a Henry reaction13 with nitromethane which gave
b-nitro alcohol 10 in 85% yield. Hydrogenation under standard con-
ditions gave b-amino alcohol 11 in quantitative yield and this was
then coupled with phthalimido-protected butyric acid14 using
EDCI to give b-amido alcohol 12 in 75% yield.15 With b-amido alco-
hol 12 in hand, this was subjected to the key Pictet–Gams reaction
using phosphorus oxychloride. Although the reaction does proceed
when performed neat, the best yield of 66% for isoquinoline 13 was
obtained using toluene as the solvent. The phthalimido-protecting
group was then removed using hydrazine hydrate. The resulting
amine was coupled with commercially available N,N0-bis
O
NPhth
13
NBoc
N
v, vi
N
BocHN
14
MeO
MeO
N
NBoc
N
H
NHBoc
15
vii
MeO
MeO
N
NH
NH2
N
H
3
Scheme 3. Reagents and conditions: (i) CH3NO2, 4 Å MS, DMSO, 85%; (ii) H2, 10%
Pd/C, MeOH, 100%; (iii) 4-Phth-aminobutanoic acid, EDCI, DMAP, CH2Cl2, 75%; (iv)
POCl3,
D
, toluene, 66%; (v) NH2NH2ꢀH2O,
D, EtOH; (vi) 14, EtN(i-Pr)2, MeOH, 82%
over two steps; (vii) TFA, CH2Cl2, 73%.
(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (14) in the
presence of Hünig’s base which gave guanidine 15 in 82% yield
over the two steps.5,16 Treatment of 15 with TFA to remove the
Boc-protecting groups gave crispine C (3) in 73% yield. The spectro-
scopic data obtained for our synthetic material were in complete
agreement with those reported for the natural product by Zhao
and co-workers.1
In summary, the first total synthesis of crispine C is reported in
seven steps and 25% overall yield. Although a two-step strategy
involving a Bischler–Naperialski reaction followed by oxidation
was unable to yield the C-1 substituted electron-rich isoquinoline,
a more direct ring-forming process utilising a Pictet–Gams reaction
was successful. The flexible approach described here is currently
being used to prepare a wide range of isoquinoline ring systems
with C-1 substituted guanylated side-chains. The results of these
studies as well as biological evaluation of these novel compounds
will be communicated in due course.
MeO
MeO
MeO
i
HN
O
MeO
NH2
3
CbzHN
6
7
ii
MeO
MeO
N
Acknowledgements
NHCbz
8
The authors gratefully acknowledge financial support from the
Scottish Funding Council, SINAPSE (studentship to A.B.), BBSRC
(studentship to L.S.) and the University of Glasgow.
Scheme 2. Reagents and conditions: (i) 4-Cbz-aminobutanoic acid, EDCI, DMAP,
CH2Cl2, rt, 89%; (ii) POCl3, , 73%.
D

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A. Blair et al. / Tetrahedron Letters 53 (2012) 4084–4086
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