Tetrahedron Letters 56 (2015) 5079–5081

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Model studies directed to the synthesis of cucurbitacin I C/D rings

Nicholas A. Eddy ⇑, Gabriel Fenteany
Department of Chemistry, University of Connecticut, Storrs, CT 06269, United States

a r t i c l e i n f o a b s t r a c t

Article history: Herein, we detail a synthetic strategy toward the C/D rings of cucurbitacin I, a naturally occurring triter-
Received 10 June 2015 penoid. This route utilized ring-opening/ring-closing metathesis of a norbornene derivative for the for-
Revised 14 July 2015 mation of the C/D ring advanced intermediates, allowing for stereocontrol of the chiral centers.
Accepted 15 July 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Available online 18 July 2015

Keywords:
Cucurbitacin I
Natural product
Oxidation
Metathesis

Cucurbitacins are naturally occurring triterpenoids from the

Cucurbitacae and Cruciferae families of gourds, have been found
in the Russela and Hebeloma families of mushrooms, and possess
potent anti-inflammatory and anti-cancer biological activities.1
Our interest in these molecules comes from their ability to inhibit
cell migration,2 which is involved in multiple biological pathways,
including tumor metastasis and invasion.3 Putatively, members of
this family of natural products target the Janus kinase 2
(JAK2)/signal transduction and transcription factor 3 (STAT3) sig- Figure 1. Cucurbitacin I with the hydrindane highlighted.
naling pathway, which has been implicated in oncogenesis.4 Only
one account detailing a partial synthesis toward any family mem-
through the use of chiral Lewis acids or chiral auxiliaries, and (2)
ber has been presented to date.5 The dense functionality and mul-
a short number of synthetic steps toward the final desired
tiple adjacent stereocenters presented in the C and D rings of the
intermediate.
cucurbitacins pose a significant synthetic challenge. The structure
Cycloaddition between citraconic anhydride and cyclopentadi-
of cucurbitacin I with the hydrindane highlighted is shown in
ene gave adduct 6 almost exclusively in the endo diastereomer
Figure 1.
(>99:1) in quantitative yield. Corey has described an enantioselec-
Of the methods for synthesizing hydrindanes previously
tive method for this cycloaddition, which provides the opposite
described in the literature,6 we decided to focus on utilizing the
enantiomer desired for our synthesis.9 Reduction of 6 with LAH
Diels–Alder norbornene derivatives for the synthesis of the hydrin-
gave diol 7 in 93% (see Scheme 2), followed by methylation
dane C/D rings of cucurbitacin I (see Fig. 1).7 Retrosynthetically
through the action of NaH and MeI in THF at room temperature
(see Scheme 1), we believe that hydrindane, 1, can come from nor-
gave a modestly selective reaction to yield the hydroxy ether 4 in
bornene 2. 2 should be available from norbornenyl nitrile, 3, which
51% as a 3:1 inseparable mixture of regioisomers, with the major-
is a simple transformation from 4. We envision 4 to come from the
ity being the desired isomer. Transformation of 4 into the chloride
lactone 5, analogous to the anhydride 6. Our last target is the
by NCS and PPh3 in DCM at room temperature afforded 8 in 70%,
cycloadduct between commercially available citraconic anhydride
which was homologated with NaCN in DMF to give nitrile 3 in
and cyclopentadiene. This route allows for two benefits: (1) stere-
59%. Under nucleophilic conditions (e.g., Grignard and organo-
oselectivity has been well studied for the cycloaddition,8,9 thus
lithium species), 3 was unable to be transformed into the desired
allowing for better stereocontrol of the subsequent reactions
diene for ROM/RCM, and these conditions could not be catalyzed
with copper salts or other Lewis acids.10 Reductive methods,
⇑ Corresponding author.
DIBAL-H and LAH, were also used in an attempt to further
E-mail address: Nicholas.eddy@uconn.edu (N.A. Eddy).

http://dx.doi.org/10.1016/j.tetlet.2015.07.044
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
5080 N. A. Eddy, G. Fenteany / Tetrahedron Letters 56 (2015) 5079–5081
Scheme 1. Retrosynthetic disconnection of target hydrindane.
Scheme 2. Reactions elaborating hydroxy ether 4. Reagents and conditions: (a)
cyclopentadiene, DCM, 23 °C; (b) LAH, THF, 0 °C; (c) MeI, NaH, THF, 23 °C; (d) NCS,
PPh3, DCM; (e) NaCN, DMF, 80 °C; (f) KOH, EtOH, reflux.
elaborate 3, but unfortunately provided no reaction with the
nitrile. Hydrolytic conditions were also explored. Initial attempts
with strongly acidic conditions caused hydration of the alkene,
which was unsurprising for its strain. Basic hydrolysis with 2 M
KOH in refluxing ethanol gave the tetrahydrofuran derivative 9
Scheme 3. Synthesis of 13 from 3.
through deprotection of the methyl ether and displacement of
the nitrile (see Scheme 2). Milder conditions were attempted with
Amberlyst IRA-400(OH) in refluxing water and methanol, but pro-
vided no hydrolysis of the nitrile.11
We turned to the use of Bobbitt’s salt,12 and found that 4
converted to the aldehyde 10 in 46% under basic conditions
(see Scheme 3). Treatment with 2-propenylmagnesium bromide
led to 11 in 90% yield, which was oxidized through Swern condi-
tions to give 12 in 59% yield. 12 was used for ring-opening/
ring-closing metathesis to generate an analogue of the cucur-
bitacin C/D rings, 13, in 26% yield as a mixture of isomers.13 The
work of Miura et al. has shown that the use of 1,6-heptadiene
works as a co-catalyst for the formation of ethylene, though the
use of Grubb’s 2nd generation catalyst gave similar yields to what
we have found with 1,5-hexadiene.7 These authors were able to
improve yields through the use of Grubbs’ 3rd generation catalyst,
which we expect will show similar results in our system.
Homologation of 13 to the epi-1 core was met with little success
through a modified Tiffeneau–Demjanov procedure,14 giving a
complex mix of products in low yield.
These investigations have provided a defined route toward the
elaboration of the hydrindane C/D rings of the cucurbitacin family.
Certainly, the strained system provides a unique study, as 3 was
labile toward basic conditions, and oxidation of 4 allowed us to
achieve a system for ring-opening/ring-closing metathesis.
Homologation of 4 proved to be difficult, the ring-opening
and -closing of 12 allowed for the facile generation of the fused
bicyclo[3.3.0] system. The work herein provides an entry into the
synthesis of the C/D rings of the cucurbitacin family of compounds.
We show that the desired functionality for the C/D rings was read-
ily achieved through ring-opening/ring-closing metathesis of the
norbornene derivative 12, which would facilitate the synthesis of
cucurbitacin I.
Acknowledgements
The authors would like to thank Dr. James Bobbitt (Univ. of
Connecticut) and Dr. William Bailey (Univ. of Connecticut) for
helpful discussions. This work was supported by the National
Institutes of Health (GM077622) to G.F.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
044.
 N. A. Eddy, G. Fenteany / Tetrahedron Letters 56 (2015) 5079–5081 5081

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