A brief synthesis of (-)-englerin A

Article abstract of DOI:10.1021/ja201921j

Englerins A and B are guaiane sesquiterpenes that were isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester-bearing stereogenic cent

Full text of DOI:10.1021/ja201921j

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A Brief Synthesis of (À)-Englerin A
Zhenwu Li,† Mika Nakashige,† and William J. Chain*,†,‡
†Department of Chemistry, 2545 The Mall, University of Hawaii at Manoa, Honolulu, Hawaii 96822, United States
‡University of Hawaii Cancer Center, 651 Ilalo Street, Honolulu, Hawaii 96813, United States
S Supporting Information
b
ABSTRACT: Englerins A and B are guaiane sesquiterpenes
that were isolated from the bark of Phyllanthus engleri, a
plant indigenous to east Africa. The englerins consist of a
5-6-5 fused tricyclic structure with an ether bridge and two
ester-bearing stereogenic centers, including a highly unusual
glycolate residue. Englerin A is a potent and selective
inhibitor of the growth of six human renal cancer cell lines.
We report herein an efficient, eight-step synthesis of engler-
in A that leverages simple carbonyl-enabled carbonÀcarbon
bond formations. Our route is amenable to the production
of a diverse series of analogues for structureÀfunction
Figure 1. Structures of englerin A (1), englerin B (2), and englerin B
acetate (3).
studies and determination of the mode of action of these
natural products.
Scheme 1. A Carbonyl-Enabled Cyclization Sequence To
Form the Core Structure of the Englerins
enal cancer is a critical medical problem in the United States,
R
affecting an estimated 58,240 new patients and causing
13,040 deaths in 2010 alone.1 The primary treatment for renal
cancer is surgery; however, for patients with nonresectable or
metastatic tumors, chemotherapy is brought to bear. An esti-
mated $1.9 billion is spent annually for renal cancer chemother-
apy, and currently available treatments can have serious adverse
side effects.2 Effective new chemotherapeutic drug leads for the
treatment of renal cancer are of great interest.
Englerin A is a guaiane sesquiterpene that was recently isolated
from the bark of Phyllanthus engleri, a plant indigenous to east
Africa (particularly Tanzania and Zimbabwe) and familiar to
many traditional medicines (Figure 1).3 In a screen against the
NCI 60-cell panel, englerin A was found to be a potent and
selective inhibitor of the growth of six renal cancer cell lines
(GI50 = 1À87 nM), and in several cases, englerin A was an order
of magnitude more potent than paclitaxel and 2À3-fold more
potent than the current standards of care, sunitinib and
sorafenib.4 Englerin A showed 1000-fold selectivity for the renal
cancer cell line panel (for most other cell lines, GI50 values
ranged from 10À20 μM), and according to the NCI COMPARE
analysis, englerin A appears to operate by a new and unknown
mechanism of action. A preliminary mouse toxicity study deter-
mined that englerin A is extremely well tolerated, suggesting the
possibility of a large therapeutic window. The outstanding
biological activity and the unique, drug-like5 architecture of
englerin A have made it an attractive target for the synthetic
organic chemistry community.6
englerin A problem have been described, and these studies have
established the absolute stereochemistry of the natural product
and provided preliminary biological screening data.6 In order to
fully explore the therapeutic potential of englerin A, a short and
flexible synthetic route is desirable. We describe herein a simple,
eight-step, modular synthesis of englerin A that is amenable to
the production of a diverse array of analogues for structure
Àfunction studies7 as well as the incorporation of fluorescent and
affinity probes for target identification studies.
Our synthetic strategy was enabled by considering the C6 and
C9 acyl-bearing stereogenic centers of the englerins at the
carbonyl oxidation level, as depicted in Scheme 1. In this
intermediate the carbonyls are placed in a 1,4-relationship in
one direction and a 1,5-relationship in the other, which suggests
The structure of englerin A consists of a 5-6-5 fused tricyclic
system containing an ether bridge, and two ester-bearing stereo-
genic centers at C6 and C9. Several elegant solutions to the
Received: March 2, 2011
Published: April 08, 2011
r
2011 American Chemical Society
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Scheme 2. (a) Synthesis of Englerin Aa and (b) Samarium-Mediated Reductive Reaction Pathways with Aldehyde 7
a Conditions: (a) LDA, THF, À78 °C, then 5, À78 f 23 °C, 75%, 2:1 dr desired:∑others. (b) SmI2, HMPA, THF, 23 °C, 43%. (c) Cinnamic acid, 2,4,6-
trichlorobenzoyl chloride, DMAP, Et3N, toluene, 23 °C, 86%. (d) NaBH4, CH3OH, 0 °C, 99%. (e) LiHMDS, (imid)2SO2, THF, À10 f 23 °C, 99%. (f)
Cesium hydroxyacetate, 18-crown-6, toluene, 110 °C, 74%.
that the core structure of the englerins could be established using
simple carbonyl-enabled bond formations that combine a 3-fur-
anone and an R,β-unsaturated aldehyde. However, several
challenges associated with this synthetic strategy are readily
apparent. First, it was unclear at the outset of our studies how
we might control the stereochemical outcome of a Michael
addition of a 3-furanone-derived enolate to an R,β-unsaturated
aldehyde. Although stereochemical models for similar additions
have been advanced by Seebach8 and Heathcock,9 the additional
functionality of our putative enolate substrate complicated the
analysis.10 Second, both the steric and electronic properties of the
3-furanone may render an intramolecular cyclization reaction
quite slow. Finally, we were mindful that a successful synthesis of
the diketone 6 would necessitate the differentiation of homo-
logous functionality; we would be faced with the task of
selectively manipulating ketones in five- and six-membered rings.
Our synthesis commenced with the union of the 3-furanone
411 and 5-methylcyclopentenecarboxaldehyde (5)12 by treat-
ment of 4 with lithium N,N-diisopropylamide in THF and
exposure of the resultant lithium enolate to 5 at low temperature
(Scheme 2a). Under these conditions, we observed clean,
diastereoselective formation of the Michael adduct 7. A transi-
tion-state assembly that is consistent with the observed stereo-
selectivity is shown in Scheme 2a. Here, the C4 methyl-bearing
stereogenic center serves as a key controlling element; one of
eight possible diastereomers is formed preferentially in good
yield (75% combined yield, 2:1 dr desired:∑others), establishing
the relative stereochemistry at C1, C4, C5, and C10 of the natural
product in a single operation. The isomers are inseparable by
flash column chromatography; however, the relative stereochem-
istry of C1, C4, and C5 of the major isomer was determined by
NOE studies. Clear correlations were observed between the
protons at C4 and C5, and between the aldehyde proton and the
proton at C1. The C10 stereochemistry of the major diaster-
eomer was unknown at this juncture but was inferred to be that
shown in Scheme 2a on the basis of the successful elaboration of
this material to the natural product. Consistent with this model,
we found the stereochemical outcome of the Michael addition to
be markedly sensitive to additives that might diminish or other-
wise disrupt the chelation between the enolate and the aldehyde.
Addition of either lithium chloride or hexamethylphosphora-
mide (HMPA) to an otherwise identically conducted Michael
addition reaction results in formation of the adduct 7, favoring
the opposite stereochemistry at C10.
With one of the two key carbonÀcarbon bonds formed, we set
about completing the core of the natural product. We were aware
of several examples of umpolung13 reactivity observed between
aliphatic aldehydes and vinylogous esters, so we approached our
problem with a high degree of confidence.14 We reasoned that a
carbon-centered radical would engage the furanone productively,
and moreover, if we could generate that radical directly from the
aldehyde function of the Michael adduct 7, we may obviate the
issue of differentiating two ketones in a cyclized product like 6.
After much experimentation, we found that the action of
samarium(II) iodide15 in the presence of HMPA in THF at
ambient temperature smoothly transformed the Michael adduct
into the ketoalcohol 8 (43% yield, Scheme 2a) in a reductive
carbonylÀalkene cyclization. The modest isolated yield of 8 is
acceptable given that this remarkable transformation forges the
second critical carbonÀcarbon bond to complete the core
structure of the englerins, establishes the correct oxidation level
and stereochemistry at C6, and achieves all this using a diaster-
eomeric mixture of starting aldehydes (∼66% maximum theore-
tical yield of 8). Other one-electron reducing agents such as
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titanium(III),16 vanadium(II),17 and lithium naphthalenide18 did
not offer any advantage over samarium(II) in reactions with the
aldehyde 7. The HMPA additive proved critical as well; other
additives commonly employed with samarium(II)-mediated re-
ductive cyclizations gave markedly different results (Scheme 2b).
For example, addition of lithium chloride resulted in pinacol-type
carbonyl coupling to give 12, and various proton sources (e.g.,
methanol, tert-butanol, or hexafluoroisopropanol) resulted in
reduction of the aldehyde to the corresponding primary alcohol
13, though analytically pure samples of 12 and 13 were not
rigorously isolated. We were also unable to locate a suitable
catalyst to effect an intramolecular Stetter19 reaction to convert
the aldehyde 7 to the diketone 6. Under a variety of conditions,
we observed none of the desired product and recovered only
unchanged starting material.
Upgrades of the NMR instrumentation were provided by
the CRIF program of the NSF (CH E9974921) and the Elsa
U. Pardee Foundation. The purchase of the LC-MS TOF
was funded by the DOD (W911NF-04-1-0344). We thank
W. Yoshida (UH) for assistance with NMR data collection. We
thank Materia, Inc. for a generous donation of ruthenium catalyst.
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Corresponding Author
chain@hawaii.edu
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’ ACKNOWLEDGMENT
Financial support of this work from the University of Hawaii,
the University of Hawaii Cancer Center, and the Victoria S. and
Bradley L. Geist Foundation (47030) is gratefully acknowledged.
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