Communications
DOI: 10.1002/anie.201103864
Alkaloid Synthesis
Catalytic Enantioselective Total Synthesis of Hodgkinsine B**
Robert H. Snell, Robert L. Woodward, and Michael C. Willis*
Hodgkinsine (1) and hodgkinsine B (2) belong to a large
family of polypyrrolidinoindoline alkaloids which are present
in a variety of flora and fauna.[1] These alkaloids have been
shown to exhibit a broad range of biological activities,
including antibacterial,[2] antifungal,[2] antiviral,[2] cyto-
toxic,[2,3] and analgesic properties.[4] The simplest member of
this family, meso-chimonanthine (5), consists of two cyclo-
tryptamine units fused at the C3a-position. The higher order
oligomers, such as hodgkinsine (1) and hodgkinsine B (2),
generally possess a chimonanthine-derived core decorated
with additional cyclotryptamine units at the C7-position(s).[5]
The natural products 1 and 2 possess six stereocenters, of
which four are contiguous and three quaternary, and feature a
number of basic sites. These features, combined with their
high degree of symmetry, make these natural products
challenging targets for total synthesis. The synthesis of
cyclotryptamine alkaloids in general has received consider-
able attention of late, with the publication of several elegant
routes. Selected benchmarks include: the synthesis of meso-
and (À)-chimonanthine (5),[6a,b] hodgkinsine (1), hodgkinsi-
ne B (2),[6c,d] and quadrigemine C[6e] by Overman and co-
Scheme 1. Selected examples of cyclotryptamine alkaloids, together
with retrosynthetic strategies for the synthesis of hodgkinsine (1) and
hodgkinsine B (2).
workers, (+)-chimonanthine[6f] and (+)-11,11’-dideoxyverti-
cillin A[6g] by Movassaghi and co-workers, and psychotrimi-
ne[6h] and (+)-psychotetramine[6i] by Baran and co-workers.
To date, the symmetry of the hodgkinsine core has not
been fully exploited in a total synthesis.[6c,d,7] Our own interest
in desymmetrization reactions[8] highlighted meso-chimonan-
thine (5) as an ideal building block to access such a strategy.
We envisaged that the prochiral amines present in 5 (see
Scheme 2) could be functionalized in a key symmetry-break-
ing operation. A subsequent palladium-catalyzed oxindole a-
arylation, developed in our laboratory,[9,10] should allow the
installation of the final cyclotryptamine functionality at the
C7-position (Scheme 1). Importantly, this type of desymmet-
rization/C7-functionalization strategy should also be adapt-
able to the synthesis of other high order oligomers such as
quadrigemine H.
Key to our synthesis was the availability of meso-
chimonanthine (5) in short order and on a large scale.
Accordingly, we selected the hypervalent iodine-mediated
oxidative dimerization strategy of Takayama and co-workers
for the preparation of the core of meso-chimonanthine (5).[11]
This protocol forms the complex alkaloid in two steps from
commercially available starting materials. However, in our
hands, the method suffered from scalability and purification
issues, requiring extensive flash chromatography to separate
the regio- and diastereoisomers generated during the dime-
rization. We attributed the scalability problems to poor mass
transfer, associated with the low solubility of PIFA.[12] By
simply employing vigorous overhead stirring we successfully
scaled the reaction to greater than 40 g. To our delight, we
also found that careful treatment of a supersaturated solution
of the crude products with crystals of the desired meso isomer
precipitated the product as a > 9:1 mixture of meso-4 and
undesired isomers (Scheme 2). Reduction of this meso-
enriched mixture with Red-Al and subsequent recrystalliza-
tion afforded meso-chimonanthine (5) on a multigram scale
with no chromatographic steps.
[*] R. H. Snell, Dr. M. C. Willis
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Dr. R. L. Woodward
AstraZeneca Global Medicines Development
Macclesfield Works, Hurdsfield Industrial Estate
Macclesfield, Cheshire, SK10 2NA (UK)
[**] This work was supported by the EPSRC, AstraZeneca, and the
University of Oxford. The NMR spectroscopy and mass spectrom-
etry services at the University of Oxford are also thanked for their
assistance.
The inherent reactivity of amines (compared to alcohols)
has minimized their use as prochiral nucleophiles in desym-
metrizing processes.[8a,13,14] Nevertheless, Taguchi and co-
workers[13a,b] have demonstrated that simple meso-diamines
(derivatized to sulfonamides) can be desymmetrized in high
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