Rapid access to tetracyclic ring system of lennoxamine type natural product by combined use of a novel three-component reaction and Pummerer cyclization

Article abstract of DOI:10.1039/b207179g

From readily available allylamine, aldehyde and isocyano-acetamide, a three-component reaction followed by a Pummerer cyclization provided tetracyclic ring systems (6-7-5-6 and 6-6-5-6) in excellent overall yields.

Full text of DOI:10.1039/b207179g

Rapid access to tetracyclic ring system of lennoxamine type natural
product by combined use of a novel three-component reaction and
Pummerer cyclization
Rocio Gámez Montaño and Jieping Zhu*
Institut de Chimie des Substances Naturelles, 91198 Gif-sur-Yvette Cedex, France.
E-mail: zhu@icsn.cnrs-gif.fr; Fax: 33 1 69 07 72 47; Tel: 33 1 69 82 31 31
Received (in Cambridge, UK) 24th July 2002, Accepted 9th September 2002
First published as an Advance Article on the web 24th September 2002
From readily available allylamine, aldehyde and isocyano-
acetamide, a three-component reaction followed by a
Pummerer cyclization provided tetracyclic ring systems
(6-7-5-6 and 6-6-5-6) in excellent overall yields.
Benzazepines, tetrahydroisoquinolines and isoindolinones are
privileged structures in drug research due to their proven
biological properties. The tetracyclic ring systems incorporating
these entities such as isoindolobenzazepine (1) and iso-
indoloisoquinoline (2) are also known in nature, as exemplified
by lennoxamine (3) and neuvamine (4, Fig. 1).1 Evidently, such
structures are interesting from both a synthetic and pharmaco-
logical point of view. Therefore, various synthetic approaches
have been developed to reach these natural products as well as
their analogues.2,3 In connection with our interest in developing
new synthetic methodologies for the rapid access of drug-like
and natural product-like compound libraries,4 we report herein
the synthesis of compounds 5 and 6 by a combined use of a
novel three-component reaction5 and Pummerer cyclization.6
Compounds 5 could be considered as the aza-analogues of
lennoxamine.
A three-step synthesis of tetracycle 5 (6-7-5-6 fused ring
system) is shown in Scheme 1. Three-component condensation
of 7, 8, and 9 (Bn = benzyl) in MeOH (room temperature to 60
°C) gave low yield of oxabridged tricyclic compound 10 (Fig. 2)
due probably to the use of enolizable aldehyde 8.7 After a brief
Scheme 1
Fig. 1
Fig. 2
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examination of reaction parameters, it was found that addition
of a catalytic amount of camphorsulfonic acid (CSA) is highly
beneficial to this transformation. Thus stirring a solution of
allylamine (7) and aldehyde (8) in MeOH (0.5 M) for 1 h
followed by introduction of isocyanoacetamide (9) and CSA
(0.05 equiv., 50 °C, 8 h) provided the oxa-bridged intermediate
(10) in over 95% isolated yield. Five chemical bonds have been
created in this multicomponent domino process by the union of
3CR/intramolecular Diels–Alder (IMDA) cycloaddition.8 For
the present work, this oxo-compound (10) did not need to be
isolated and was fragmented directly to the pyrrolopyridine by
addition of TFA at 278 °C. Over all, the pyrrolopyridine 11 was
produced in over 90% yield from three readily available inputs
by the union of 3CR/IMDA/fragmentation process.
Oxidation of sulfide 11 under standard conditions (MCPBA,
CH2Cl2, 0 °C) proceeded smoothly to provide the correspond-
ing sulfoxide as a mixture of two diastereomers without the
concurrent formation of amine-oxides. Formation of the
7-membered benzazepine ring by Pummerer reaction proved to
be more challenging than expected. After a survey of different
reaction conditions varying electrophiles (TFFA, pTsOH,
TMSOTf), bases, temperature and stoichiometries, the optimal
conditions found consisted of using TMSOTf (5.0 equiv.) as an
activator in dichloromethane (0.1 M) in the presence of Hunig’s
base (DIEA, 5.2 equiv., 220 °C).9 Under these conditions, two
separable diastereoisomers of tetracycle 5 (ratio = 2+1) were
isolated in 88% yield.† The relative stereochemistry of the
major isomer (JH1-H2 = 5.7 Hz) was deduced to be (1S*, 2R*)
by comparison with the literature date.10 To the best of our
knowledge, this represents one of the rare examples wherein a
Pummerer-type cyclization was performed in the presence of
basic nitrogen atoms within the same molecule.11
The same sequence was applied to the synthesis of a
tetracycle (6-6-5-6 fused ring) containing both the tetra-
hydroisoquinoline and pyrrolopyridine systems (Scheme 2).
Compound 6 was obtained in the form of two separable
diastereomers in three steps with an excellent overall yield
(83%).
In conclusion, we developed a three-step synthesis of
lennoxamine type tetracyclic compounds from readily available
starting materials. The combined use of MCR and the
Pummerer reaction characterized the present synthetic ap-
proach. The synthesis creates three heterocycles and delivers at
least three elements of diversity into the final polycycles with
the introduction of two functional groups (ester and sulfide)
susceptible for additional chemical manipulations. Further
applications of such strategy in the synthesis of complex natural
product-like compound libraries are in progress.
Financial support from CONACYT to Dr R. G. M. and
CNRS are gratefully acknowledged. We thank Professor E.
González-Zamora for fruitful discussions.
Notes and references
† 5a (1S*, 2R*), yield 58%: IR (CHCl3) n 3017, 2938, 2856, 1725, 1603,
1515, 1465, 1264, 1113 cm21; 1H NMR (300 MHz, CDCl3) d 7.44-7.19 (m,
10H), 6.73 (s, 1H), 5.86 (s, 1H), 4.68 (d, J = 5.7 Hz, 1H), 4.47 (d, J = 14.0
Hz, 1H), 4.43-4.29 (m, 3H), 4.34 (d, J = 14.0 Hz, 1H), 4.23-4.18 (m, 2H),
3.88 (s, 3H), 3.77-3.65 (m, 5H), 3.46 (s, 3H), 3.53-3.40 (m, 1H), 3.15 (m,
1H), 2.87-2.99 (m, 4H), 2.75 (dd, J = 14.0 Hz, 5.9 Hz, 1H), 1.40 (t, J = 7.0
Hz, 3H); 13C NMR (62.5 MHz, CDCl3) d 166.9, 160.3, 159.3, 147.7, 146.5,
141.3, 140.4, 135.7, 134.4, 133.5, 130.8, 129.5, 129.2, 128.9, 128.6, 128.2,
128.0, 126.0, 113.6, 112.9, 68.5, 67.6, 61.9, 60.5, 56.4, 55.9, 55.4, 53.0,
51.0, 40.3, 32.4, 14.3; MS (ES+): m/z 652 (M+, 100%). 5b (1R*, 2R*), yield
31%. IR (CHCl3) n 2928, 2855, 1697, 1602, 1517, 1363, 1286, 1201, 909
cm21; 1H NMR (300 MHz, CDCl3) d 7.33–7.41 (m, 10H), 6.69 (s, 1H), 6.14
(s, 1H), 4.90 (s, 1H), 4.52 (d, J = 14.5 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H),
4.37 (m, 1H), 4.30 (d, J = 14.5 Hz, 1H), 4.02 (s, 1H), 3.85 (s, 3H), 3.76-3.60
(m, 5H), 3.53 (s, 3H), 3.38 (m, 1H), 3.11–2.72 (m, 7H), 1.40 (t, J = 7.0 Hz,
3H); 13C NMR (62.5 MHz, CDCl3) d 167.1, 159.7, 158.0, 147.2, 145.8,
141.7, 140.3, 135.9, 134.5, 133.9, 133.3, 132.9, 130.5, 128.6, 128.4, 128.4,
127.2, 126.0, 114.9, 114.0, 71.8, 67.7, 62.0, 59.9, 56.7, 55.9, 55.8, 54.2,
51.1, 40.3, 36.8, 14.4; MS (ES+): m/z 652 (M+, 100%).
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Scheme 2 Reagents and conditions: a) MeOH, CSA (0.1 equiv.), 50 °C, 8
h, then TFA, 278 °C, 94%; b) MCPBA, CH2Cl2, 0 °C, 98%; c) TMSOTf,
DIEA, CH2Cl2, 220 °C, 90%.
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