Enantioselective formal synthesis of (-)-englerin A via a Rh-catalyzed [4 + 3] cycloaddition reaction

Article abstract of DOI:10.1021/ol1015652

An enantioselective formal synthesis of (-)-englerin A (1) is reported. Key to the strategy is a Rh-catalyzed [4 + 3] cycloaddition reaction between furan 10 and diazo ester 11 that, following an intramolecular aldol condensation, produces the tricyclic scaffold of englerin. This strategy also provides a rapid, efficient, and stereoselective access to the biologically significant core motif of the guaiane sesquiterpenes.

Full text of DOI:10.1021/ol1015652

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3708-3711
Enantioselective Formal Synthesis of
(-)-Englerin A via a Rh-Catalyzed
[4 + 3] Cycloaddition Reaction
Jing Xu, Eduardo J. E. Caro-Diaz, and Emmanuel A. Theodorakis*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093-0358
etheodor@ucsd.edu
Received July 7, 2010
ABSTRACT
An enantioselective formal synthesis of (-)-englerin A (1) is reported. Key to the strategy is a Rh-catalyzed [4 + 3] cycloaddition reaction
between furan 10 and diazo ester 11 that, following an intramolecular aldol condensation, produces the tricyclic scaffold of englerin. This
strategy also provides a rapid, efficient, and stereoselective access to the biologically significant core motif of the guaiane sesquiterpenes.
Renal cell carcinoma (RCC, also known as hypernephroma)
is a type of kidney cancer that originates in the small tubes
in the kidneys that filter the blood and remove waste
products. This cancer ranks among the 10 leading cancer
types in the United States, and only in 2009, it was
responsible for about 58 000 new cases and 13 000 deaths.1
Importantly, RCC is resistant to radiation and chemotherapy,
leaving partial or radical nephrectomy as the only means of
treatment. Therefore, the search for new compounds that can
safely and effectively block or reverse RCC remains a high
priority.
Efforts to identify new small molecule leads against RCC
led to the identification of englerin A (1) and B (2) (Figure
1) from the Tanzanian plant Phyllanthus engleri.2 From the
standpoint of biogenesis, the englerins are guaiane-type
sesquiterpenes that contain an uncommon oxygenated motif
Figure 1. Structures of englerin A and B and natural analogues.
(Figure 1). Structurally related members of this family
(1) Jemal, A.; Siegel, R.; Ward, E.; Hao, Y.; Xu, J.; Thun, M. J. Cancer
Statistics 2009. CA Cancer J. Clin. 2009, 59, 225–249.
include orientalols E (3) and F (4)3 and pubinernoid B (5)4
(Figure 1). Most likely, this motif originates from a more
common bicyclic sesquiterpene core via a sequence of
(2) (a) Ratnayake, R.; Covell, D.; Ransom, T. T.; Gustafson, K. R.;
Beutler, J. A. Org. Lett. 2009, 11, 57–60. (b) Beutler, J. A.; Ratnayake, R.;
Covell, D.; Johnson, T. R. WO 2009/088854, 2009.
10.1021/ol1015652  2010 American Chemical Society
Published on Web 07/29/2010

oxygenations and acid-induced oxo-cyclization reactions
highlighted in Scheme 1.3
Scheme 2. Retrosynthetic Analysis
Scheme 1. Proposed Biosynthetic Approach
Remarkably, englerin A (1) showed highly potent and
selective cytotoxicities against various renal cancer cell lines
at low nanomolar level.2 Preliminary biological investigations
also showed a significant drop of potency and selectivity of
englerin B (2), suggesting that the substitution at the C-9
position by the glycolate ester may be important for the
activity and selectivity of englerins.2
Due to its promising anticancer activity and its scarcity
from natural sources, englerin A has become an intriguing
target in synthetic and medicinal chemistry. The absolute
configuration of 1 was confirmed by Christmann et al. in
their first total synthesis of ent-1 in 2009.5 More recently,
three additional syntheses were reported by Ma,6 Echavar-
ren,7 and Nicolaou,8 the first two of which were enantiose-
lective. In addition, a stereoselective approach to the
guaianolide core of these sesquiterpenes has been disclosed.9
Inspired by the unusual tricyclic motif, we sought to design
a general approach leading not only to the structures of 1
and 2 but also to various guaiane analogues, such as
orientalols E (3) and F (4) and pubinernoid B (5). We
envisioned that 1 could be derived from diol 6 via reversion
of the C-6 stereocenter, hydrogenation, and two esterifica-
tions. The C-9 hydroxyl group of the diol 6 could be easily
obtained by the regio- and stereoselective hydroboration on
the disubstituted double bond of 7. Moreover, the cyclopen-
tene moiety of 7 could be constructed from an intramolecular
aldol condensation of diketone 8, which can be formed from
oxa-tricyclic compound 9. In turn, the key oxa-tricyclic
compound 9 could be achieved via the Davies Rh-catalyzed
ring formation,10 from readily available disubstituted furan
10 and chiral diazo ester 11 (Scheme 2).
Rhodium-triggered cyclization reactions have been
widely applied in synthetic chemistry.11 In 1996, Davies
et al. reported an elegant enantioselective Rh(II)-catalyzed
[4 + 3] cycloaddition reaction between furans and diazo
esters.10,12 With this in mind we prepared furan 10 from
2-methylfuran in 3 steps following the reported procedure;13
and diazo ester 11, which derived from (R)-pantolactone in
3 steps.10 Notably, both of these starting materials are readily
available in more than 50 g-scale. Slow addition of the chiral
diazo ester 11 into furan 10 in refluxing hexane catalyzed
with 2 mol % of rhodium(II) octanoate gave rise to key oxa-
tricyclic motif 9 in an excellent yield (90%, Scheme 3) with
moderate diastereoselectivity (dr ) 3:1).14 This diastereo-
meric mixture can be easily separated through silica gel
column chromatography. It is likely that a more bulky chiral
auxiliary could provide better diastereoselectivity, although
attempts at effecting this reaction under lower temperature
or using less catalyst loading led to significantly poorer yield
without any enhancement of diastereoselectivity.
Initial functionalization of this oxa-tricyclic compound 9
was successfully accomplished by removing the auxiliary.
This was achieved by treating 9 with DIBAL-H to afford
the corresponding unstable ꢀ-hydroxyl enol ether, followed
by the Lewis acid induced rearrangement15 to afford enone
12 in 59% yield. For the next step, attempts of R-hydroxy-
lation with Davis oxaziridines16 of enone 12 were not
(3) Peng, G.-P.; Tian, G.; Huang, X.-F.; Lou, F.-C. Phytochemistry 2003,
63, 877–881.
(4) Huang, S.-X.; Yang, J.; Xiao, W.-L.; Zhu, Y.-L.; Li, R.-T.; Li, L.-
M.; Pu, J.-X.; Li, X.; Li, S.-H.; Sun, H.-D. HelV. Chim. Acta 2006, 89,
1169–1175.
(10) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc.
1996, 118, 10774–10782.
(5) Willot, M.; Radtke, L.; Ko¨nning, D.; Fro¨hlich, R.; Gessner, V. H.;
Strohmann, C.; Christmann, M. Angew. Chem., Int. Ed. 2009, 48, 9105–
9108.
(11) For an excellent review, see: Jeong, N.; Robinson, J. E.; Wender,
P. A.; Gamber, G. G.; Williams, T. J.; Davies, H. M. L. Walji, A. M. In
Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005; Chapters
11-14, pp 215-340.
(6) Zhou, Q.-F.; Chen, X.-F.; Ma, D.-W. Angew. Chem., Int. Ed. 2010,
49, 3513–3516.
(7) Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem., Int.
Ed. 2010, 49, 3517–3519.
(12) For a recent application of this strategy on natural product synthesis,
see also: Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. J.
(8) Nicolaou, K. C.; Kang, Q.; Ng, S. Y.; Chen, D. Y.-K. J. Am. Chem.
Soc. 2010, 132, 8219–8222.
Angew. Chem., Int. Ed. 2009, 48, 2346–2350.
(13) Weyerstahl, P.; Brendel, J. Liebigs Ann. Chem. 1988, 1015–1016.
1
(9) (a) Jime´nez-Nu´n˜ez, E.; Claverie, C. K.; Nieto-Oberhuber, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5452–5455. (b)
Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2009, 45, 7327–
7329.
(14) Calculated via H NMR spectroscopy.
(15) Poirier, J.-M.; Hennequin, L. Tetrahedron 1989, 45, 4191–4202.
(16) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org.
Chem. 1984, 49, 3241–3243.
Org. Lett., Vol. 12, No. 16, 2010
3709

Scheme 3
Scheme 4
discover that treatment of diketone 8 with NaHMDS fol-
lowed by heating in NaOMe/MeOH could provide the
desired key tricyclic intermediate 7 in acceptable yield (43%
brsm).21 Reduction of enone 7 furnished the corresponding
allylic alcohol as a single diastereomer, which was then
directly protected with a benzyl group to give 15, paving
the way for the following hydroboration.
successful. Gratifyingly, Rubottom oxidation17 of enone 12
led to the desired R-hydroxyl enone 13 in very good yield
(87% brsm). Not surprisingly, the hydroxylation occurred
on the less hindered face of this molecule, leading exclusively
to the opposite stereochemistry at C-6. Nonetheless, the C-6
stereocenter can be easily reversed in a latter stage. Notably,
m-CPBA selectively oxidized the electronic richer TMS enol
ether without touching any of other double bonds of our
substrate. The absolute stereochemistry of R-hydroxyl enone
13 was confirmed by a single-crystal Cu-mediated X-ray
analysis,18 thus establishing the desired absolute stereochem-
istry of oxa-tricyclic compound 9.19
The next stage of the synthesis involved elaboration of
the enone system to the five-membered ring, which eventu-
ally forms the tricyclic englerin core. After a simple TBS
protection on the C-6 hydroxyl group, the enone Michael
system was subjected to a 1,4-addition with propanal
catalyzed by thiazolium salt 14 under basic conditions
(Scheme 4).20 The diketone 8 was cleanly obtained in good
yield (75% over two steps) as a single diastereomer. Having
the precursor 8 on hand, the ensuing aldol condensation
proved to be unexpectedly difficult. Extensive studies on this
intramolecular aldol condensation were then applied, with
different substituents on the C-6 hydroxyl (H-, MOM-, TES-,
etc.), various bases (tBuOK, KOH, NaOMe, LDA, etc.), and
several reaction conditions. Eventually, we were pleased to
The next task was the installation of a hydroxyl group at
the C-9 position. This was accomplished in a regio- and
stereoselective manner by treating 15 with borane•THF
complex followed by basic H2O2 oxidative cleavage to give
the desired C-9 ꢀ-alcohol in 60% yield (Scheme 5). After
removal of the minor (∼10%) C-8 regioisomer via column
chromatography, the C-9 ꢀ-alcohol was converted to the
corresponding di-TBS-ether. After removal of the benzyl
group, initial efforts to hydrogenate the tetrasubstituted
double bond met with failure presumably due to the steric
hindrance of this alkene.22 This prompted us to deoxygenate
the C-3 stereocenter under standard Barton-McCombie
conditions (40% yield).23 However, a more efficacious route
from 16 to 18 was achieved by the dehydration with Burgess
reagent24 followed by a simple hydrogenation (90% over 2
steps). While the cleavage of the di-TBS-ether gave only
messy results under regular deprotection conditions (TBAF/
THF, rt or 80 °C, overnight), a microwave-accelerated
deprotection proved efficient and produced 6 in excellent
yield (TBAF/THF, 80 °C, 45 min, 93%).
The final stages of this synthesis would require the
esterification of the C-9 hydroxyl group, reversion of the
stereocenter at C-6, hydrogenation, and esterification. In fact,
(17) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron
Lett. 1974, 15, 4319–4322.
(21) To our surprise, compared to regular intramolecular reactions, this
intramolecular aldol reaction requires quite high concentration (0.4-0.7
M).
(18) CCDC782508 contains the supplementary crystallographic data
for compound 13. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
products/csd/request/.
(22) The C4-C5 double bond stays untouched even under high pressure
(up to 130 bar) with Pd/C, Crabtree’s catalyst, or PtO2.
(23) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 16, 1574–1585.
(19) Hooft, W. W. R.; Straver, L. H.; Spek, A. L. J. Appl. Crystallogr.
2008, 41, 96–103.
(24) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744–
4745.
(20) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639–647.
3710
Org. Lett., Vol. 12, No. 16, 2010

synthesis of englerin and related natural products from the
key intermediate 7 (Scheme 6). The applications of this
Scheme 5
Scheme 6
strategy to the synthesis of natural and designed tricyclic
sesquiterpenes could facilitate the SAR and chemical biology
studies of this unexplored class of natural products.
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (NIH) for financial support of this
work through Grant No. R01 GM081484-01. We thank the
National Science Foundation for instrumentation Grants
CHE9709183 and CHE0741968. We also thank Dr. Anthony
Mrse (UCSD NMR Facility), Dr. Yongxuan Su (UCSD MS
Facility), and Dr. Arnold L. Rheingold and Dr. Curtis E.
Moore (UCSD X-ray facility). We also appreciate the
technical assistance from Weng K. Chang and Steven D. E.
Sullivan (UCSD, Theodorakis group).
during the course of our work, an alternative route to (+)-6
and its successful elaboration to (-)-englerin A was reported
by Ma et al.6 Our synthetic work to (+)-6 provided another
novel and facile access to the englerin core. This approach
with 15 steps from readily available compound 10 and 11
in 5% overall yield constitutes a formal synthesis of (-)-
englerin A. More importantly, this Rh-catalyzed [4 + 3]
cycloaddition, followed by an intramolecular aldol condensa-
tion, provides a unique and facile method for construction
of a common guaiane-type tricyclic sesquiterpene skeleton.
This strategy is broadly applicable to an enantioselective
Supporting Information Available: Experimental pro-
cedures and characteristic data of new compounds, as well
as X-ray data of compound 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL1015652
Org. Lett., Vol. 12, No. 16, 2010
3711