Asymmetric synthesis of the oxygenated polycyclic system of (+)-harringtonolide

Article abstract of DOI:10.1021/ol300133x

A straightforward asymmetric synthesis of the cage oxygenated structure of (+)-harringtonolide has been accomplished for the first time. The key steps involved (i) a templated stereoselective IMDA reaction to build a highly functionalized cyclohexene ring

Full text of DOI:10.1021/ol300133x

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1270–1273
Asymmetric Synthesis of the Oxygenated
Polycyclic System of (þ)-Harringtonolide
Hajer Abdelkafi,† Patrick Herson,‡ and Bastien Nay*,†
ꢀ
ꢀ
Museum National d’Histoire Naturelle, Molecules de Communication et Adaptation des
Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris,
France, and Institut Parisien de Chimie Moleculaire (IPCM), UMR CNRS 7201,
ꢀ
ꢀ
Centre de Resolution de Structure, Universite Pierre et Marie Curie-Paris 6,
4 place Jussieu, 75252 Paris cedex 05, France
bnay@mnhn.fr
Received January 18, 2012
ABSTRACT
A straightforward asymmetric synthesis of the cage oxygenated structure of (þ)-harringtonolide has been accomplished for the first time. The key
steps involved (i) a templated stereoselective IMDA reaction to build a highly functionalized cyclohexene ring D, (ii) functionalization of the
cycloadduct, (iii) ring-closing metathesis providing the five-membered ring C, and finally (iv) a challenging one-step cascade cyclization of an
epoxy-alcohol toward the target structure, whose mechanism was investigated.
(þ)-Harringtonolide (1, Figure 1) is a norditerpene
isolated in 1978 from the Asian plum yew Cephalotaxus
harringtonia,1 a tree which first attracted attention because
it contains antitumor alkaloids (i.e., homoharringtonine).2
It was described as a phytotoxic compound, leading to
plant growth inhibition on tobacco and beans. Later,
analogous compounds in this terpenoid series were iso-
lated from other Cephalotaxus species.3 During our work
aiming at discovering new terpenic and alkaloidic com-
pounds from Cephalotaxus, harringtonolide was retrieved
Figure 1. Structure of Cephalotaxus norditerpenes 1 and 2.
from the plant extract. The compound was found strongly
cytotoxic at IC50 = 43 nM on KB tumor cells, while X-ray
crystallography of a brominated derivative allowed for
determining the absolute stereochemistry (as shown).4
Hereafter, we describe the first asymmetric synthesis of the
simplified analogues were reported, featuring the tricarbo-
cyclic portion corresponding to the ABC ring system of 1.5
Yet neither the pharmacophoric moiety of 1 nor its
mechanism of action have been determined. Only recently,
(5) Hegde, V.; Campitelli, M.; Quinn, R. J.; Camp, D. Org. Biomol.
Chem. 2011, 9, 4570.
(6) (a) Evanno, L.; Deville, A.; Bodo, B.; Nay, B. Tetrahedron Lett.
2007, 48, 4331. (b) Evanno, L.; Deville, A.; Dubost, L.; Chiaroni, A.;
(1) Buta, J. G.; Flippen, J. L.; Lusby, W. R. J. Org. Chem. 1978, 43,
1002.
Bodo, B.; Nay, B. Tetrahedron Lett. 2007, 48, 2893. (c) Abdelkafi, H.;
Evanno, L.; Deville, A.; Dubost, L.; Chiaroni, A.; Nay, B. Eur. J. Org.
Chem. 2011, 2789. (d) Abdelkafi, H.; Evanno, L.; Herson, P.; Nay, B.
Tetrahedron Lett. 2011, 52, 3447.
(7) (a) Rogers, D. H.; Morris, J. C.; Roden, F. S.; Frey, B.; King,
G. R.; Russkamp, F. W.; Bell, R. A.; Mander, L. N. Pure Appl. Chem.
1996, 68, 515. (b) Frey, B.; Wells, A. P.; Rogers, D. H.; Mander, L. N. J.
Am. Chem. Soc. 1998, 120, 1914. (c) Frey, B.; Wells, A. P.; Roden, F.;
Au, T. D.; Hockless, D. C.; Willis, A. C.; Mander, L. N. Aust. J. Chem.
2000, 53, 819.
(2) First isolation of homoharringtonine: Powell, R. G.; Weisleder,
D.; Smith, C. R., Jr.; Rohwedder, W. K. Tetrahedron Lett. 1970, 11, 815.
(3) (a) Xue, Z.; Sun, N. J.; Liang, X. T. Acta Pharm. Sin. 1982, 17,
236. Chem. Abstr. 1982, 96, 177999r. (b) Du, J.; Chiu, M.-H.; Nie, R.-L.
J. Nat. Prod. 1999, 62, 1664. (c) Yoon, Y. D.; Jeong, D. G.; Hwang,
Y. H.; Ryu, J. M.; Kim, J. J. Nat. Prod. 2007, 70, 2029.
(4) Evanno, L.; Jossang, A.; Nguyen-Pouplin, J.; Delaroche, D.;
Seuleiman, M.; Bodo, B.; Nay, B. Planta Med. 2008, 870.
r
10.1021/ol300133x
Published on Web 02/17/2012
2012 American Chemical Society

oxygen-bridged CD ring system, as part of our ongoing
work toward the total synthesis of 1.6
Scheme 1. Retrosynthetic Analysis of 1
The racemic total synthesis of 1 was first reported by
Mander and co-workers in the 1990s,7 and an elegant
complementary strategy was later designed by the same
group.8 In fact during their work, Mander and co-workers
synthesized hainanolidol (2, Figure 1) and thus accom-
plished a formal synthesis of 17b since pseudobenzylic
oxidation of 2 (from natural origin) was known to promote
ether bridge formation, as previously demonstrated by
others.3a Their most recent report described the construc-
tion of the CD bicyclic system by the DielsꢀAlder reaction
between an indenone dienophile (also incorporating the
future A-ring) and a R-pyrone diene, thus introducing the
lactone bridge at the same time.8b
Our synthetic approach ensues from the following anal-
ysis of 1 (Scheme 1). The A-ring may be constructed via
intramolecular cycloaddition involving the advanced inter-
mediate i bearing an appropriate R group. The ether and
lactone bridges of this compound (i), which will be described
below with R = H, would be derived from cascade cycliza-
tion of the epoxide intermediate ii. This is expected to be
formed from the densely functionalized cyclohexene iii
through ring closing metathesis (RCM) and regioselective
epoxidation. This intermediate (iii) would be derived by
functional group interconversion (FGI) of cycloadduct iv
constructed by asymmetric intramolecular DielsꢀAlder
reaction (IMDA). In order to make the correct enantiomer
of the natural product, we designed a stereodirected IMDA
reaction based on the chiral dioxane template 3 available
from D-glucose.6b,c This allowed for installing the chirality of
1, which is indeed carried by central ring D.
In previous reports, the cycloadduct 4 was synthesized in
8 steps and 20% overall yield starting from D-erythrose
ethylidene acetal.6c,9 The asymmetric 1,3-dioxane ring was
used as a rigid template to promote stereocontrol in the
IMDA reaction leading to 4. The key stereogenic centers
were introduced by taking advantage of anticipated stereo-
electronic interactions within a 1,3,9-decatriene system
holding a (Z,E,E) geometry. Several tens of grams of the
expected product 4 were thus successfully prepared in a
diastereomerically pure form.6c
performed in 73% yield using Garegg and Samuelsson con-
ditions (PPh3, I2, imidazole, toluene, reflux).10 Subsequent
regioselective reduction of the lactone ring in the presence of
L-selectride allowed the formation of lactol 8 in 91% yield.
Finally, this intermediate was engaged in Wittig reactions.
The traceless R groups in 9aꢀd opened the way to several
alternatives. Four ylides were tested, with R = H, Me, Ph, or
CO2Me. We found that only the semistabilized ylide
Ph3PdCHPh gave satisfying results, with 96% yield of diene
9c (R = Ph). Poor yields of compounds 9a (R = H) and 9b
(R = Me) were attributed to instability of products upon
purification, while the reaction with R = CO2Me was
unsuccessful.11 The intermediate 9c was submitted to RCM
in the presence of the Grubbs catalyst (either first or second
generation, at reflux or room temperature in dichloro-
methane, 84 and 93%, respectively), providing the chiral
CD bicyclic system 10 (Scheme 3). Efforts were then engaged
to reach the retrosynthetic intermediate ii.
Scheme 2. Unraveling and Functionalization of Cycloadduct 4
A straightforward route was used to functionalize the
cycloadduct 4 toward the metathesis substrates 9aꢀc
(Scheme 2). Unraveling under acidic conditions (TFA,
H2O, 80 °C) led to diol 5 in 76% yield through acetal
hydrolysis and concomitant lactone ring contraction. The
rearranged acetal 6 was also isolated (15%) but was recycled
by acid hydrolysis into 5.6c The diol 5 holds all appropriate
functional groups to construct our metathesis substrate.
Indeed, the one-step conversion of 5 into alkene 7 was
(8) (a) Zhang, H.; Appels, D. C.; Hockless, D. C. R. Tetrahedron
Lett. 1998, 39, 6577. (b) O’Sullivan, T. P.; Zhang, H.; Mander, L. N. Org.
Biomol. Chem. 2007, 5, 2627.
(9) D-Erythrose ethylidene acetal (3) is available from D-glucose:
€
€
Fengler-Veith, M.; Schwardt, O.; Kautz, U.; Kramer, B.; Jager, V.
Org. Synth. 2002, 78, 123. Org. Synth. Coll. Vol. 2004, 10, 405.
(10) (a) Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469. (b) For
another example of this reaction: Riache, N.; Blond, A.; Nay, B.
Tetrahedron 2008, 64, 10853.
Org. Lett., Vol. 14, No. 5, 2012
1271

To prevent epoxidation at the C-ring, the allylic alcohol
was oxidized into the electron-deficient enone 11. The
cyclohexene double bond was then regio- and stereoselec-
tively epoxidized in the presence of DMDO in acetone at
0 °C, leading to the epoxide 12 (complete stereoselectivity).
At this stage, it was not possible to determine the stereo-
chemicaloutcomeof the reactionby classical spectroscopic
methods. Moreover, neither 11 nor 12 were stable upon
purification on silica gel, occasionally leading to epoxide
opening, giving 13 from 12. Purification was thus under-
taken after the final reduction of the ketone in the presence
of NaBH4 and CeCl3 in MeOH,12 performed with a
stereoselectivity of 6:1 in favor of the β-alcohol 14, as
expected. Overall, compound 14 was obtained in 48%
yield from 10 (three steps). Fortunately, 14 (β-OH) gave
crystals allowing the relative stereochemistry to be deter-
mined by X-ray crystallography (Scheme 3).13 In fact, we
were not expecting such a complete β-stereoselectivity for
the epoxidation. It was explained by possible steric inter-
actions of DMDO with the likely pseudoaxial methyl
group, as it was observed for 14 (see X-ray structure), of
compound 11 (Scheme 3).
Scheme 3. Construction of the Bicyclic CD Ring System (10)
and Setting-up of Oxygenated Functionalities (Top), Rational-
ization of the Stereochemical Outcome of Epoxidation
(Bottom)
For the final stage of this work, a challenging one-step
cyclization of intermediate 14 (1:6 mixture of R- and β-OH
epimers) was envisaged to get the oxygenated cage structure
of the natural product (Scheme 4). Although the epoxide
stereochemistry was inverted compared to our initial retro-
synthetic intermediate ii, it was reasoned that since the
methyl group was likely to have a shielding effect on the
R-face during epoxidation, it may also congest the nearest
carbon C-6 on the epoxide. Therefore, we believed that
hydrating the epoxide 14 would take place on the alternative
carbon C-7. In fact, the all cascade process could be acid-
activated, first leading to triol 16 and then to lactone closure
and ether bridge formation, necessarily through the allylic
cation 17, to form the targeted product 15.
Scheme 4. Final Step and Mechanism of the Cascade Cycliza-
tion Towards the Cage Structure 15 from 14
A profusion of conditions were attempted for acid-
catalyzed epoxide opening by water before finding that
treating the epoxy-alcohol 14 with a 1 M solution of
KHSO4 in water and in the presence of Yb(OTf)3 in
THF at 50 °C (condition 1) provided 39% yield of the
polycyclic system 15 (Table 1). The Lewis acid was used to
accelerate the reaction (still uncompleted after three days
with the sole presence of KHSO4). Increasing the tempera-
ture (80 °C) resulted in degradation, while changing the
Lewis acid occasionally gave the unexpected indene by-
product 18 (70% yield with CuF2 in condition 3), probably
resulting from successive dehydrations. This product was
also observed when 14 was heated (80 °C) with catalytic
amounts of pTSA (0.1 equiv) in toluene. Eventually, the
aqueous conditions developed by Hudlicky and co-workers,
using silica gel alone or associated to Lewis acids,14
were applied to 14 (condition 4(i): Yb(OTf)3 over SiO2 in
water at 120 °C). Although no trace of the aim product 15
could be detected, only the triol 16 with the desired
stereochemistry was selectively formed in 56% yield after
three days. It showed that hydration of the epoxide was
(11) In the case of 9a, the crude extract could be engaged in the next
metathesis step, leading to the expected product 10 in 35% yield (over
two steps from 8) after purification.
(12) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(13) Crystallographic data for structures of 14 and 15 were deposited
with the Cambridge Crystallographic Data Center as numbers CCDC
863114 and 863115, respectively. Copies of data can be obtained free of
charge at www.ccdc.cam.ac.uk/products/csd/request, or on application
to CCDC, 12 Union Road, Cambridge CB2 IEZ, U. K. (Fax: þ 44 1233
336033 or E-mail: deposit@ccdc.cam.ac.uk). ORTEP drawings in
Scheme 3 and Figure 2 were generated using Mercury software.
(14) Hudlicky, T.; Rinner, U.; Finn, K. J.; Ghiviriga, I. J. Org. Chem.
2005, 70, 3490.
1272
Org. Lett., Vol. 14, No. 5, 2012

Table 1. Reaction Conditions toward 15, 16, and 18 from 14
isolated yield (%)
conditions
15
16
18
a
b
a
b
(1) Yb(OTf)3 (0.2 equiv), 1 M aq KHSO4/ THF (v/v 1:4), 50 °C, 24 h
(2) Yb(OTf)3 (0.2 equiv), 1 M aq KHSO4/ THF (v/v 1:4), 80 °C, 24 h
39
b
(3) CuF2 2H2O (0.2 equiv), 1 M aq KHSO4/ THF (v/v 1:4), 50 °C, 24 h
(4) (i) Yb(OTf)3 (0.2 equiv) on activated silica gel, water, 120 °C, 72 h then:
12
0
0
56
0
70
0
3
(ii) BF3 OEt2 (10 equiv), CH2Cl2, ꢀ78 °C f rt, 6 h
27
57
0
3
a
or: (ii) Yb(OTf)3 (1 equiv), THF, 80 °C
0
a Traces observed on TLC. b Degradation.
In conclusion, we have designed and accomplished the
first asymmetric synthesis of the cage oxygenated structure
(15) found in the cytotoxic natural product (þ)-harrington-
olide (1). Showing no cytotoxicity against KB cells, this
structure alone does not account for the cytotoxic activity
of the natural product, for which the tropone ring may be
necessary. Cycles D and C were successively constructed with
minimum use of protecting groups, respectively by IMDA
and RCM reactions, while the oxygen bridges in 15 were
formed in one step during a regioselective tandem process
performed on the epoxy-alcohol 14 under acid catalysis. Our
work is still in progress toward the total synthesis of 1.
Acknowledgment. The Agence Nationale de la Re-
cherche (ANR) is gratefully acknowledged for funding
this project and the research grant for H.A. (Grant No.
ANR-09-JCJC-0085-01). We warmly thank Prof. Tomas
Hudlicky from Brock University for interesting discussion
and suggestions during the Gordon conference on Natural
Products in July, 2011.
Figure 2. X-ray structure of compound 15.
completely regioselective upon C-7, confirming hindrance
of the R-face at C-6. Last treatment of 16 in the presence of
boron trifluoride etherate even lead to product 15 in 27%
yield. This transformation was greatly improved by the use
of Yb(OTf)3 in refluxing THF (57% yield).
The structure of 15 was first confirmed by 2D NMR,
especially HMBC experiments, which clearly showed cor-
relations across the ether and lactone bridges (Scheme 4).
Remarkably, both proton and carbon spectra were closely
related to those of the natural product (1), especially in the
δ 3.5ꢀ5.5 and δ 80ꢀ90 ranges for atoms at positions 1, 6,
and 7 (see the Supporting Information). Finally, a crystal
of compound 15 was analyzed by X-ray crystallography,
which revealed the beautiful structure of this caged com-
pound (Figure 2).13
Note Added after ASAP Publication. The Supporting
Information was replaced on February 21, 2012 to correct
the information over the arrow in the Scheme on p S3.
Supporting Information Available. Experimental pro-
cedures, CIF files, full spectroscopic data, and copies of
NMR spectra for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
1273