Synthesis of 7-methoxybenzolactam-V8 using aminomercuration as a key reaction

Article abstract of DOI:10.1016/S0040-4039(01)00747-X

7-Methoxybenzolactam-V8 was synthesized using a short synthetic route that employs aminomercuration as a key reaction.

Full text of DOI:10.1016/S0040-4039(01)00747-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4317–4319
Synthesis of 7-methoxybenzolactam-V8 using aminomercuration
as a key reaction
Sukumar Sakamuri*
Drug Discovery Program, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington,
DC 20007-2197, USA
Received 28 March 2001; accepted 30 April 2001
Abstract—7-Methoxybenzolactam-V8 was synthesized using a short synthetic route that employs aminomercuration as a key
reaction. © 2001 Elsevier Science Ltd. All rights reserved.
Protein kinase C (PKC) is a ubiquitous signal transduc-
ing enzyme system that plays a marked role in diverse
cellular processes including regulation of ion channels,
neurotransmitter release, growth and differentiation,
apoptosis, and neuronal plasticity.1 This complex
enzyme system serves to mediate numerous signals orig-
inating from the induction of lipid hydrolysis. The
discovery of isozyme-selective activators and inhibitors
(modulators) of protein kinase C (PKC) is crucial to
both dissecting the role of the individual isozymes in
physiological and pathophysiological processes and to
manipulating these pathways. It has been our objective
to synthesize analogs of the tumor-promoting substance
indolactam V (ILV, 1) or of its structurally simpler
mimic benzolactam-V8 (2), and to assess the ability of
these new compounds to modulate the various isozymes
of PKC as well as to examine the effects of such agents
on cellular growth and differentiation.2 Toward this
goal we have recently shown that introduction of a
methoxy substituent at the C7-position of 8-(1-
decynyl)benzolactam-V8 leads to compound 5, which
retains potency at PKCa, PKCd and PKCo.3 We have
recently reported the synthesis of compounds 4 and 5
using two different synthetic routes.3,4 The first syn-
thetic route (14 steps, 4.2% overall yield)3 employs the
alkylation of a Schiff’s base derived from tert-butyl
glycinate under phase transfer conditions. This method
suffers from poor selectivity. The second approach4
uses a diastereoselective Strecker reaction to generate
the phenylalanine fragment and is a lengthy route with
22 steps and 2.1% overall yield. The total synthesis of
benzolactam-V8 analogs depends mainly on the effec-
tive construction of the eight-membered lactam ring.
The 1-decynyl group at the C8-position, which is
important for biological activity, can be introduced
easily in the final stage as reported previously.3 Our
continued quest to find a simple synthetic route for the
preparation of 7-Methoxybenzolactam (4) lead to the
present synthetic approach.
O
H
N
2
1
N
4
NH
Me
Me
3
N
OH
5
O
N
4
5
6
3
6
OH
2
7
R1
1
8
R2
7
H
R1 = H, R2 = H, Benzolactam-V8 (2)
Indolactam V (1)
C8H17-n (3)
R1 = OMe, R2 = H (4)
R1 = H, R2 =
R1 = OMe, R2 =
C8H17-n (5)
The sequence began with the introduction of an allyl
group in an ortho position to the hydroxy group using
the Claisen rearrangement (Scheme 1). Thus, 3-nitro-
phenol (6) was transformed into its allyl ether 7 using
allyl bromide and potassium carbonate in refluxing
acetone in 98% yield. Compound 7 was subjected to
Claisen rearrangement in ortho-dichlorobenzene at
150°C for 6 h to give a mixture of products 8 and 9 in
a 1:1 ratio in 38% yield, which were separated by
column chromatography. Several attempts to improve
the yield under different reaction conditions5 were not
successful. Higher temperature and longer reaction
times gave only polymerized products. Nevertheless, the
starting materials are readily accessible, and satisfactory
* Tel.: (202) 687-8265; fax: (202) 687-0738; e-mail: sukumar@
giccs.georgetown.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00747-X

4318
S. Sakamuri / Tetrahedron Letters 42 (2001) 4317–4319
NO2
NO2
NO2
NO2
a
b
+
OH
OH
OH
O
6
7
8
9
1 : 1
NO2
NO2
NO2
NO2
d
c
+
NHBOC
OH
OH
OMe
NHBOC
OH
OMe
NH2
OMe
8
10
11
12
NO2
f
e
HN
CO2Bn
g
OH
NHBOC
OH
NHBOC
NHBOC
OMe
OMe
OH
TfO
CO2Bn
11
13
OMe
14
15
O
O
S
S
Me
Me
HN
CO2H
N
NH
N
NH
h, i
+
NHBOC
S
R
OH
OH
OH
OMe
OMe
OMe
16
4
17
Scheme 1. Reagents and conditions: (a) allyl bromide, K2CO3, acetone, reflux, 98%; (b) o-dichlorobenzene, 150°C, 6 h, 38%; (c)
MeI, K2CO3, acetone, 87%; (d) i. Hg(NO3)2, BocNH2, CH2Cl2, reflux, 24 h, ii. aq. NaCl, rt, 3 h, (iii) NaBH4, O2, DMF, 43% for
three steps; (e) H2, Pd/C, EtOH, overnight, 85%; (f) 2,6-lutidine, 1,2-dichloroethane, 74%; (g) H2, Pd/C, EtOH, quantitative; (h)
i. N-hydroxysuccinimide/DCC, CH2Cl2, ii. trifluoroacetic acid, then NaHCO3, EtOAc, 68% for two steps; (i) HCHO, NaCNBH3,
AcOH, CH3CN, reflux, 86%.
quantities of the intermediate 8 were obtained without
difficulty. Compound 8 was protected as its methyl
ether 10 in 87% yield.
tive yield, which was subsequently converted to the
eight-membered lactam using the active ester method as
reported previously.2a The two isomers were easily sep-
arated at this stage and were individually subjected to
reductive N-methylation using HCHO–NaCNBH3–
HOAc to give compounds 4 and 17 in good yield.10 The
stereochemistry of 4 and 17 was confirmed by compar-
ing their optical rotations and NMR spectra with those
of (2S,5S)- and (2S,5R)-7-methoxybenzolactam-V8.3,4
The addition of different carboxamides and related
compounds such as urethane to olefins using mer-
cury(II) nitrate is well documented in the literature.
This sequence provides a general method for the
Markovnikov functionalization of alkenes. Compound
10 on treatment with Hg(NO3)2 and tert-butylcarba-
mate in refluxing dichloromethane for 24 h gave the
organomercuric nitrate, which on treatment with
aqueous sodium chloride provided the organomercuric
chloride.6,7 This intermediate on reaction with sodium
borohydride in dimethylformamide saturated with
molecular oxygen gave alcohols 11 and 12 in a 4:1 ratio
in 43% yield over the three steps.8 Steric factors may be
the reason for formation of the anti-Markovnikov
product 12. The amino alcohols 11 and 12 were easily
separated by column chromatography. Compound 11
on catalytic hydrogenation gave the aniline 13 in 85%
In conclusion, an improved synthesis of 7-methoxyben-
zolactam-V8 which makes use of an aminomercuration
reaction has been reported. This synthesis, which is
relatively short with 13 steps, gives an improved overall
yield (5.1%), and can be used to prepare a variety of
C7-substituted analogs.
Acknowledgements
yield. Aniline 13 was reacted with the
D
-valine derived
The author is grateful to Professor Alan P. Kozikowski
for his guidance and encouragement. Financial support
from the National Institutes of Health (CA 79601) is
highly appreciated.
triflate9 14 to give compound 15 in 74% yield as a
mixture of two diastereoisomers. Compound 15 on
hydrogenation gave the carboxylic acid 16 in quantita-

S. Sakamuri / Tetrahedron Letters 42 (2001) 4317–4319
4319
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