A high yielding synthesis of anthranilate esters from sterically hindered alcohols

Article abstract of DOI:10.1016/S0040-4039(00)02327-3

A high yielding and operationally simple synthesis of anthranilate esters derived from primary, secondary and tertiary alcohols is reported. Esterification of the alcohol with N-(trifluoroacetyl)anthranilic acid under Steglich conditions, followed by sodium borohydride mediated cleavage of the trifluoroacetyl group affords the anthranilate ester. This new method has application in the synthesis of the ester sidechains of the commonly occurring Delphinium and Aconitum alkaloids and their analogues.

Full text of DOI:10.1016/S0040-4039(00)02327-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1785–1788
A high yielding synthesis of anthranilate esters from sterically
hindered alcohols
David Barker,a Malcolm D. McLeod,a,* Margaret A. Brimbleb and G. Paul Savagec
aSchool of Chemistry, F11, University of Sydney, Camperdown, NSW, 2006 Australia
bDepartment of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
cCSIRO Molecular Science, Bag 10, Clayton South, Vic. 3169, Australia
Received 13 November 2000; accepted 21 December 2000
Abstract—A high yielding and operationally simple synthesis of anthranilate esters derived from primary, secondary and tertiary
alcohols is reported. Esterification of the alcohol with N-(trifluoroacetyl)anthranilic acid under Steglich conditions, followed by
sodium borohydride mediated cleavage of the trifluoroacetyl group affords the anthranilate ester. This new method has
application in the synthesis of the ester sidechains of the commonly occurring Delphinium and Aconitum alkaloids and their
analogues. © 2001 Elsevier Science Ltd. All rights reserved.
Diterpenoid alkaloids derived from Delphinium and
Aconitum species constitute a structurally diverse class
of biologically active natural products with a long
history of use as medicines, poisons and insecticides.1 A
strong determinant of the biological activity associated
with these alkaloids is the presence of an anthranilate
ester sidechain, or its N-substituted derivatives, linked
to the C-18 hydroxyl of the alkaloid skeleton. A dra-
matic example of the importance of this structural unit
for biological activity is given by comparison of methyl-
lycaconitine (1, MLA)2 and its parent alkaloid lycoc-
tonine 2 (Scheme 1). In competitive ligand binding
studies at neuronal nicotinic acetylcholine receptors,
antagonists of the a7-nicotinic acetylcholine receptor
known.4
It has been proposed5 that the tertiary amine and
anthranilate ester sidechain of MLA 1 form an acylated
homocholine structural array at physiological pH that
gives rise to the potent nicotinic acetylcholine receptor
binding. The pivotal nature of this sidechain and the
paucity of efficient procedures for its synthesis lead us
to disclose our recently developed procedure for the
introduction of this structural unit.
The most common direct method for the synthesis of
anthranilate esters like 3 (Scheme 1) is the reaction of
an alcohol with isatoic anhydride 4 and catalytic base
at elevated temperature.6 The reaction is reported to
proceed readily and in high yield (>95%) for unhin-
dered primary alcohols, with difficulty for secondary
MLA
1,
containing
the
2-(2%-methylsuccin-
imido)benzoate ester sidechain, displays ca. 103 times
more potent inhibition of a-bungarotoxin binding than
its unsubstituted counterpart, 2.3 In fact, MLA is
among the most potent, competitive small molecule
OMe R = H, lycoctonine (2)
R =
O
MeO
N
O
O
NH2
O
OMe
Me
DMAP, DMF
+
ROH
O
RO
N
∆
OH
OH
Me
methyllycoconotine (MLA, 1)
O
N
H
O
4
3
OMe
18
RO
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02327-3

1786
D. Barker et al. / Tetrahedron Letters 42 (2001) 1785–1788
alcohols, giving mixtures of the desired ester and unde-
sired isomeric carbamate by-product, and to fail com-
pletely in the case of tertiary alcohols.
These conditions have been developed by Blagbrough5
and adopted by other workers for the synthesis of
MLA analogues.7,8 In general, low yields (typically
O
NHCOCF3
O
a) DCC, DMAP, CH3CN
b) NaBH4, EtOH
HO
OH +
O
N
N
H2N
5
6
Scheme 2.
Table 1. Synthesis of anthranilate esters with N-(trifluoroacetyl)anthranilic acid 6

D. Barker et al. / Tetrahedron Letters 42 (2001) 1785–1788
1787
O
O
11, R =
OH
OH
OR
OR
a) 1eq. 6, DCC, DMAP
b) NaBH4
a) 2eq. 6, DCC, DMAP
b) NaBH4
OH
O
NH2
H2N
EtN
EtN
EtN
9
56%
10
48%
Scheme 3.
40–65%) of the desired anthranilate esters are obtained
which can be attributed to the hindered neopentyl
environment of the C-18 hydroxyl group present in
lycoctonine and many simpler analogues. The low
yields of ester formation by these methods have
prompted investigations into the introduction of this
sidechain by alternative procedures,7,8a,9 however, none
of these methods has offered a general and high yield-
ing solution to the problem of sidechain introduction.
have been reported to lead to poor regioselectivity or
possibly transesterification during reactions with diol
substrates.5a We therefore investigated the new proce-
dure to assess its potential for kinetic discrimination
leading to the selective esterification of diol substrates
(Scheme 3). To this end the reaction of bicyclic diol 9
with one equivalent of acid 6 favoured reaction at the
primary hydroxyl to give selective mono-anthranilate
ester 10 in 56% yield, together with a small quantity of
the diester 11 (10%). Reaction of 9 with 2 equivalents of
acid gave the diester 11 in a moderate 48% yield.
In connection with our studies towards MLA ana-
logues, we turned our attention to the coupling proce-
dure developed by Breslow10 as an alternative to the
isatoic anhydride mediated synthesis. Initial attempts to
repeat this coupling procedure on stoichiometric quan-
tities of the alkoxide salt derived from 1-methyl-3-pipe-
ridinemethanol (5, Scheme 2) did not result in practical
yields of the coupled product. However, reaction of 5
with three equivalents of N-(trifluoroacetyl)anthranilic
acid 6 under Steglich conditions11 (DCC/DMAP) fol-
lowed directly by sodium borohydride mediated cleav-
age of the crude amide gave a gratifying 81% yield of
the anthranilate ester.12,13 This compares favourably
with the base catalysed reaction of isatoic anhydride,
which in our hands proceeded in 72% yield (Table 1,
entry 1).6b This high yielding and operationally simple
anthranilate ester synthesis prompted us to explore the
scope of this coupling reaction as an alternative to
conventional approaches.
Finally, heating the anthranilate esters with 2 equiva-
lents of 2-methylsuccinic acid at 125°C according to the
procedure of Blagbrough5c cleanly afforded the succin-
imide derivatives 12 and 13 in good yield (Scheme 4).
This procedure therefore offers a simple two-step
method for the introduction of the 2-(2%-methylsuccin-
imido)benzoate ester sidechain present in methyllyca-
conitine 1 and other delphinium alkaloids.
In conclusion, we have developed a practical, high
yielding synthesis of anthranilate esters from primary
and
secondary
alcohols
using
N-(trifluoro-
acetyl)anthranilic acid 6. The reactions proceed under
mild conditions and offer a practical alternative to
existing procedures. This method should find wide
applicability for the synthesis of diterpenoid alkaloids
such as methyllycaconitine and their analogues. Syn-
thetic studies and biological activity data will be
reported in due course.
The reaction of a range of simple primary alcohols with
6 afforded good yields of the anthranilate esters in
comparison with the isatoic anhydride mediated synthe-
sis (Table 1, entries 2, 3 and 4). Extension of this
procedure to AE bicyclic analogues of MLA, 7 and 85d
(Table 1, entries 5 and 6) containing neopentyl substi-
tuted alcohols also afforded coupled product in
improved yield.
Acknowledgements
Generous financial assistance from Dunlena Pty. Ltd
and an Australian Postgraduate Award (Industry) to
D.B. (C29804582) supported this work.
Secondary alcohols were observed to react readily with
6 to afford high yields of the anthranilate ester (Table
1, entries 7 and 8). To our knowledge this procedure
represents the first direct, high yielding synthesis of
anthranilate esters derived from secondary alcohols
reported in the literature.6 Attempts to promote the
esterification of tertiary alcohols, however, afforded
lower yields of the coupled product, in line with the
synthesis of t-butyl benzoate ester derivatives initially
reported by Steglich.11 The use of di-2-pyridyl thiocar-
bonate,14 recently recommended for the synthesis of
esters derived from tertiary alcohols failed to give the
desired product.
O
O
O
O
O
O
O
O
70%
O
N
O
O
NH2
12
O
O
O
O
O
O
84%
EtN
EtN
N
H2N
13
O
The extreme conditions associated with the isatoic
anhydride mediated synthesis of anthranilate esters
Scheme 4.

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D. Barker et al. / Tetrahedron Letters 42 (2001) 1785–1788
Andersh, B.; Su, Q.; Shi, J. Tetrahedron Lett. 1993, 34,
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