J Chem Crystallogr (2012) 42:639–644
DOI 10.1007/s10870-012-0275-z
COMMUNICATION
Crystal Structures of (3R,3aR,4S,7R,7aS)-3-(Allyloxy)hexahydro-
4,7-epoxyisobenzofuran-1(3H)-one and (3S,3aR,4S,7R,7aS)-3-((E)-
But-2-en-1-yloxy)hexahydro-4,7-epoxyisobenzofuran-1(3H)-one:
Confirmation of NMR Predicted Stereocentre Geometry
•
Mark Tarleton Paul V. Bernhardt
•
Adam McCluskey
Received: 1 August 2011 / Accepted: 17 January 2012 / Published online: 8 February 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Crystal structures of two isomeric norcantha-
ridin derivatives (3R,3aR,4S,7R,7aS)-3-(allyloxy)hexahy-
dro-4,7-epoxyisobenzofuran-1(3H)-one (7b), and (3S,3aR,
4S,7R,7aS)-3-((E)-but-2-en-1-yloxy)hexahydro-4,7-epox-
yisobenzofuran-1(3H)-one (8a) have been determined.
In both instances the equivalent enantiomer was also
obtained. The crystal structures of these compounds clarify
the stereochemistry inferred only by NMR analysis before.
analogue, displays the favourable anti-cancer properties of
cantharidin but displays little to no nephrotoxicity [1, 5]. In
addition to the anti-cancer properties, both cantharidin and
norcantharidin are potent inhibitors of the serine/threonine
protein phosphatases PP1 and PP2A. Cantharidin is a 1.78
and 0.26 lM potent PP1 and PP2A inhibitor, respectively,
while norcantharidin returns IC50 values of 1.98 and
0.37 lM for PP1 and PP2A, respectively [6].
Over the past decade we and others have expended
considerable effort in the development of a better under-
standing of the key structural features that are required for
both protein phosphatase inhibition and the anti-cancer
effects of these analogues [6–22]. In the course of one such
study we re-discovered, Novo-6 (3) (Fig. 1), a product that
arose form the hydrogenation of 5,6-dehydronorcantharidin
first reported by Eggelte [23]. Novo-6 (3) is phosphatase
inactive, but does display remarkable anti-cancer selectiv-
ity with preferential cell death of colon cancer derived cell
lines [6]. Excited by this observation, we have been keen to
develop these analogues further, but our rational drug
design approaches have been significantly hampered by the
unknown stereochemistry at the C3-OH. The synthetic
chemistry utilised in the preparation of Novo-6 suggests
that there are two possible diastereomers, 3a and 3b
(Scheme 1, enantiomers shown in boxed section).
Keywords Norcantharidin ꢀ Conformation ꢀ Crystal
structure ꢀ Stereocentre
Introduction
Cantharidin (1) (Fig. 1) is a naturally occurring toxin found
in over 1,000 species of blister beetles. Used by the Chi-
nese as a natural remedy for the past 2,000 years, can-
tharidin has a long history as a therapeutic agent [1, 2]. The
anti-cancer potential of cantharidin (1), was first recorded
in 1,264 [1, 3]. Structurally simple, cantharidin (1) displays
a number of features amenable to lead development
including exhibiting no myelosuppresion and not being a
substrate for the P-glycoprotein efflux pump. Despite this,
the dose limiting nephrotoxicity has prevented canthari-
din’s entry into Western medicine [1, 2, 4]. Notwith-
standing this, norcantharidin (2) (Fig. 1), the demethylated
Our initial efforts revealed only one diastereomer by
TLC whereas those of Eggelte et al. showed the presence
of two diastereomers by TLC [23]. This suggested that we
could separate 3a (anti) from 3b (syn) by flash chroma-
tography. We also note that our and Eggelte’s efforts also
suggest the presence of a major and minor product [23].
This is in keeping with the expected approach of the
anhydride C=O to the surface of the Pd–C catalyst where
the 7-O bridgehead would prefer to be distal with respect to
the catalyst surface allowing a closer approach of the
M. Tarleton ꢀ A. McCluskey (&)
Chemistry, School of Environmental and Life Sciences,
University of Newcastle, Callaghan, NSW 2308, Australia
e-mail: Adam.McCluskey@newcastle.edu.au
P. V. Bernhardt
School of Chemistry and Molecular Biosciences,
University of Queensland, Brisbane, QLD 4072, Australia
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