Angewandte
Chemie
DOI: 10.1002/anie.201409164
Natural Product Synthesis
Short and Efficient Syntheses of Protoberberine Alkaloids using
Palladium-Catalyzed Enolate Arylation**
Alice E. Gatland, Ben S. Pilgrim, Panayiotis A. Procopiou, and Timothy J. Donohoe*
Abstract: A concise synthesis of the biologically active
alkaloid berberine is reported, and a versatile palladium-
catalyzed enolate arylation is used to form the isoquinoline
core. The overall yield of 50% is a large improvement over the
single, previous synthesis. By design, this modular route allows
the rapid synthesis of other members of the protoberberine
family (e.g., pseudocoptisine and palmatine) by substitution of
the readily available aryl bromide and ketone coupling
partners. Moreover, by combining enolate arylation with
in situ functionalization, substituents can be rapidly and
regioselectively introduced at the alkaloid C13 position, as
demonstrated by the total synthesis of dehydrocorydaline. The
avoidance of electrophilic aromatic substitution reactions to
Scheme 1. Retrosynthesis of berberine and skeletally related protober-
berine natural products. PG=protecting group.
make the isoquinoline allows direct access to analogues
possessing more varied electronic properties, such as the
fluorine-containing derivative synthesized here.
T
he isoquinoline skeleton is one of the most prevalent core
electron-rich scaffolds, those with more varied electronic
properties are not readily accessible.
structures in alkaloid natural product chemistry. A subdivi-
sion of this class is the protoberberine alkaloids, an important
group of secondary metabolites possessing significant biolog-
ical activities as a result of their ability to bind or intercalate
As we have previously reported, recent work in our
laboratories has culminated in the development of a versatile
[
4]
method for the synthesis of isoquinolines. This protocol
[
1]
[5]
DNA. Isolated from an extensive range of plants, all
members feature 5,6-dihydrodibenzo[a,g]quinolizinium
employed the palladium-catalyzed a-arylation of readily
a
available ketones (using aryl bromides bearing an ortho-
moiety (the protoberberine skeleton), typically functional-
ized with hydroxy, methoxy, and methylenedioxy substituents.
The parent compound, berberine (Scheme 1), is the most
widely distributed and intensely studied of such alkaloids,
thus having demonstrated antifungal, antibacterial, anti-
inflammatory, antimalarial, antidiabetic, and anticancer activ-
acetal) to generate masked 1,5-dicarbonyl intermediates,
which could be cyclized with a source of NH to provide an
3
[
6]
extensive array of isoquinolines in excellent yields. We
therefore sought to apply this approach to the short total
synthesis of berberine and related targets. Furthermore, an
extension of our initial isoquinoline-forming methodology
introduced functional groups at the C4 position of the
[
1,2]
ity.
Yet it has seen only one previous total synthesis, by
[
7]
Kametani and co-workers in 1969, which provided berberine
iodide in low yield from a commercially unavailable starting
isoquinoline skeleton. This method exploited the fact that
the product of enolate arylation is more acidic than the
starting ketone and therefore exists as an enolate in the
reaction mixture before quenching. Consequently, this enol-
ate may be trapped in situ by a variety of alkyl, allyl, benzyl,
[
3]
material. The majority of synthetic approaches to related
compounds rely on electrophilic aromatic substitution to form
the central rings. Whilst this allows access to analogues with
[8]
and heteroatom electrophiles, and these are carried through
to occupy the C4 position in the resulting isoquinoline. It was
anticipated that this highly effective methodology would be
well suited to the introduction of substituents at C13 in the
protoberberine alkaloids (Scheme 1). It was envisaged that
subsequent formation of the B ring of berberine could be
achieved through nucleophilic displacement of the leaving
group X (anticipated to be chloride) by the isoquinoline
[
*] A. E. Gatland, Dr. B. S. Pilgrim, Prof. T. J. Donohoe
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: timothy.donohoe@chem.ox.ac.uk
Dr. P. A. Procopiou
[9]
nitrogen atom. The isoquinoline A in question would be
generated by aromatization of the dicarbonyl compound B,
which is the product of a palladium-catalyzed coupling
between the aryl bromide C and the enolate of ketone D.
Trapping of the product enolate with an alkyl halide in situ
would install a functional group (R) at C13.
GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage, SG1 2NY (UK)
[
**] We thank the EPSRC, GlaxoSmithKline and the St. John’s College
Oxford for financial support.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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