New methods for the synthesis of naphthyl amines; Application to the synthesis of dihydrosanguinarine, sanguinarine, oxysanguinarine and (±)-maclekarpines B and C

Article abstract of DOI:10.1039/c4cc05209a

A new method for preparing naphthyl amines from 1,5 unsaturated dicarbonyl precursors is described; the utility of this new method was proven in the syntheses of several natural products, all containing the benzo[c]phenanthridine core and enabled by a radical promoted cyclisation of the naphthyl amine products formed in the key cyclisation. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc05209a

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New methods for the synthesis of naphthyl amines;
application to the synthesis of dihydrosanguinarine,
sanguinarine, oxysanguinarine and
Cite this: Chem. Commun., 2014,
50, 11314
Received 7th July 2014,
Accepted 7th August 2014
(Æ)-maclekarpines B and C†
Matthew R. Tatton,a Iain Simpsonb and Timothy J. Donohoe*a
DOI: 10.1039/c4cc05209a
www.rsc.org/chemcomm
A new method for preparing naphthyl amines from 1,5 unsaturated
dicarbonyl precursors is described; the utility of this new method
was proven in the syntheses of several natural products, all containing
the benzo[c]phenanthridine core and enabled by a radical promoted
cyclisation of the naphthyl amine products formed in the key
cyclisation.
We have recently reported the results of a programme of research
aimed at expanding methods for the de novo construction of
aromatic rings from linear precursors.1 When we consider the
opportunities that exist for functionalisation of the non-aromatic
intermediates produced en-route to an arene, and the potential for
cross coupling and C–H activation on the aromatic products, then
an attractive situation emerges.
Scheme 1 De novo route to substituted naphthyl amines.
One of our previous endeavours focussed on preparing
benzenoid compounds from unsaturated 1,5 dicarbonyls A
and amines by using enamine chemistry (Scheme 1, the geometry
and position of the alkene between the carbonyls is unimportant).2
We consider that both Mannich and electrocyclic based mechanisms
are feasible for this transformation. Recently, we wanted to examine
if this method might be extended to allow the formation of naphthyl
amines via reaction of a keto-aldehyde containing an aromatic
spacer, see B. As an additional objective, we also wanted to explore
the possibility of adding extra functionality onto the cyclisation
product and forming another ring onto the new aromatic system.
This tactic is expected to greatly increase the utility of the method in
the area of natural products synthesis.
In the first instance, we used a combination of enolate
arylbromide cross coupling reactions3 and alkene oxidative
cleavage to prepare a set of three keto-aldehyde precursors (1–3)
on which to test our hypotheses, Scheme 2. The cyclisation of
Scheme 2 Amine promoted cyclisation of dicarbonyl compounds.
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: timothy.donohoe@chem.ox.ac.uk
b AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire,
SK10 4TG, UK
these three substrates was examined under a series of acidic
and Lewis acidic conditions, and we found that the most
general set of conditions involved heating in toluene with acetic
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for all novel compounds. See DOI: 10.1039/c4cc05209a
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acid in the presence of 5 equivalents of a primary or secondary
amine. Pleasingly, this sequence gave rise to the naphthyl amine
core with three sets of substitution patterns in reasonable yields
(see compounds 4–9). We also found that reaction with an amine
in the presence of zinc chloride at 55 1C provided a milder
alternative set of conditions (providing comparable yields for 8
(55%), 6 (68%) and 7 (58%)). At this point we choose not to
speculate on the mechanism of this cyclisation, beyond our
previously presented hypotheses for the synthesis of phenyl
amine compounds and which involve pericyclic and/or Mannich
type processes.2a
Having proven the viability of the basic methodology and
promoted the synthesis of substituted naphthyl amines under
these new conditions, we wished to apply the chemistry to the
synthesis of a set of natural products. As mentioned earlier, we
also wanted to use this synthesis to explore the formation of
new rings adjacent to the newly formed naphthyl amine. There-
fore, a set of natural product targets based on the fused hexacyclic
ring structure (benzo[c]phenanthridine) of dihydrosanguinarine4
was identified to provide an interesting and challenging test of the
methodology.
Scheme 3 The synthesis of dihydrosanguinarine.
product dihydrosanguinarine 16 in 58% yield by forming a new
C–C bond. In our hands the use of C–H activation methods or tin
hydride induced radical cyclisation were not effective for this
cyclisation.13 To summarise the route so far, the synthesis of
dihydrosanguinarine was competed in 6 linear steps and 18%
overall yield.
Our next objective was the synthesis of the more complex
targets maclekarpine B and C, which contain the dihydro-
sanguinarine core but with an exocyclic unsaturated butyrolactone
ring attached a-to the nitrogen.14 We set about preparing a suitable
amine precursor 20 to test in cyclisation reactions, Scheme 4.
This was accomplished by the addition of TMS–furan 18 into
the imine formed by reaction of 13 and 17, followed by oxidative
deprotection (20).15 The yields and diastereoselectivity (1: 1 dr)
of 19 and 20 remained unoptimised as we quickly sought to test
a significantly more bulky amine in the cyclisation regimen.
Unfortunately, all cyclisation conditions that were examined
between amine 20 and dicarbonyl 12 led to either a lack of
reactivity or decomposition of the substrates; so it was concluded
that this route to the maclekarpines was not a viable one.
It is appropriate to note here that other synthetic approaches
to the benzo[c]phenanthridine alkaloids have been published.
In early work, Bailey reported a successful synthesis of related
alkaloids utilising a key Friedel–Crafts acylation.5 Ninomiya
reported the use of an enamide photocyclisation in their
alkaloid synthesis.6 Diels–Alder cycloaddition reactions have
also been used effectively in both formal and completed
syntheses of the benzo[c]phenanthridine alkaloids.7 Cushman
reported a key condensation of a Schiff base with an anhydride
to prepare chelidonine.8 Cheng and co-workers utilised their
nickel catalysed cyclisation methodology in the synthesis of
three benzo[c]phenanthridine alkaloids.9 Xu and co-workers
completed their alkaloid synthesis using a key palladium-
catalyzed ring-opening coupling reaction,10 while Hibino con-
structed an aza-triene moiety which underwent a microwave
assisted 6p-electrocyclisation to give the core scaffold.11
Our synthesis of dihydrosanguinarine began from commercially
available ketone 10, which was subjected to addition/elimination
(11) and oxidative cleavage to provide the substituted keto-aldehyde
precursor 12 for the key cyclisation, Scheme 3. Next, the requisite
amine partner 14 was prepared in two steps from commercially
available aldehyde 13, via a reductive amination sequence. For
cyclisation, the application of a range of conditions was examined
and we found that naphthyl amine 15 could be produced in 61%
yield using 5 equivalents of amine 14 and zinc chloride as a
promoter. Reduced yields of 15 (20%) were obtained with the
more vigorous acetic acid conditions. We also decided to utilise a
lower number of equivalents of valuable amine 14, and optimisation
of a reaction using 1.5 equivalents and addition of the dicarbonyl
via a syringe pump, was able to produce naphthyl amine 15 in
54% yield.
The second key step in the sequence involved the formation
of a six membered ring attached to the naphthyl amine moiety.
This was accomplished by using base promoted cyclisation
conditions as reported by Shi,12 and which furnished the natural
Scheme 4 Attempted cyclisation of a complex amine towards a synthesis
of maclekarpines B and C.
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We thank the EPSRC and AstraZeneca for support.
Notes and references
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L. C. A. Barbosa, J. Am. Chem. Soc., 2011, 133, 16418.
2 (a) M. R. Tatton, I. Simpson and T. J. Donohoe, Org. Lett., 2014,
16, 1920; for related earlier work see: (b) I. W. Davies, J. Marcoux,
J. D. O. Taylor and P. G. Dormer, Org. Lett., 2002, 4, 439;
(c) T. Y. Lam, Y. Wang and R. L. Danheiser, J. Org. Chem., 2013,
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Y. Wang and R. L. Danheiser, J. Org. Chem., 2013, 78, 11450;
(e) X. Y. Mak, A. L. Crombie and R. L. Danheiser, J. Org. Chem.,
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3 For a review on enolate cross coupling: (a) C. C. C. Johansson and
T. J. Colacot, Angew. Chem., Int. Ed., 2010, 49, 676; for related studies
see: (b) T. J. Donohoe, B. S. Pilgrim, G. R. Jones and J. A. Bassuto,
Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 11605; (c) B. S. Pilgrim,
A. E. Gatland, C. T. McTernan, P. A. Procopiou and T. J. Donohoe,
Org. Lett., 2013, 15, 6190.
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5 A. S. Bailey and C. R. Worthing, J. Chem. Soc., 1956, 4535.
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J. Chem. Soc., Perkin Trans. 1, 1975, 762.
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Scheme 5 Completion of the syntheses of (Æ)-maclekarpines B and C,
and of sanguinarine and oxysanguinarine.
However, we were able to progress towards these targets by
altering the sequence of events and installing the lactone in the
final step, Scheme 5. Oxidation of 16 with DDQ gave another
natural product, sanguinarine (21),16 in 90% yield; the pyridinium
functionality in this molecule was then subject to regioselective
nucleophilic attack by the extended enolate formed from reaction
of lactone 22 with LDA. The addition products were formed as a
0.85 : 1 mixture of diastereoisomers in 73% yield (these were
inseparable by silica gel chromatography). The NMR data for
the two compounds matched exactly with that reported for the
9 C. Cheng and R. P. Korivi, Chem. – Eur. J., 2010, 16, 282.
10 P. Lv, K. Huang, L. Xie and X. Xu, Org. Biomol. Chem., 2011, 9, 3133.
natural products maclekarpine B (23) and C (24), and this 11 Y. Ishihara, S. Azuma, T. Choshi, K. Kohno, K. Ono, H. Tsutsumi,
T. Ishizu and S. Hibino, Tetrahedron, 2011, 67, 1320.
12 (a) C. Sin, Y. Gu, W. Huany and Z. Shi, Chem. Commun., 2011,
allowed us to confirm the first synthesis of these two targets,
albeit as a mixture. Finally, and as part of our studies towards
47, 9813; (b) S. De, S. Mishra, B. N. Kakde, D. Dey and A. Bisai, J. Org.
the oxidation of dihydrosanguinarine, we also found that it
could be transformed into another natural product, namely
oxysanguinarine (25), by reaction with manganese dioxide.17
The data for all natural products reported herein was a very
good match with that in the literature.
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15 G. Landelle, A. Claraz, S. Oudeyer and V. Levacher, Tetrahedron Lett.,
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To conclude, we have developed a new piece of methodology
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17 R. SanMartin, E. M. Marigorta, I. Moreno and E. Dominguez,
fashion from acyclic precursors. The scope of the method to
prepare naphthyl amines was explored and it was then tested in
the successful and efficient syntheses of several natural products.
Heterocycles, 1997, 45, 757.
11316 | Chem. Commun., 2014, 50, 11314--11316
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