Total synthesis of the marine diterpenoid blumiolide C

Article abstract of DOI:10.1002/anie.200804004

(Chemical Equation Presented) First bloom: The total synthesis of the cytotoxic marine natural product blumiolide C (1) features a ring-closing metathesis (RCM) for the closure of a nine-membered ring to give the trans-bicyclo[7.4.0]oxatridecene core (see scheme; PMB=para-methoxybenzyl, TBS=tert-butyldimethylsilyl). Attachment of the side chain at C4 of the bicyclic core was achieved in a highly stereoselective manner and excellent yield through an aldol reaction/elimination sequence.

Full text of DOI:10.1002/anie.200804004

Angewandte
Chemie
DOI: 10.1002/anie.200804004
Marine Natural Products
Total Synthesis of the Marine Diterpenoid Blumiolide C
Cotinica Hamel, Evgeny V. Prusov, Jꢀrg Gertsch, W. Bernd Schweizer, and Karl-Heinz Altmann*
Natural products of marine origin have become increasingly
important lead structures for drug discovery. Several such
compounds or analogues derived from marine natural prod-
uct leads have been advanced to clinical trials in humans.[1]
However, the structural diversity represented by natural
products from marine sources, whose molecular architectures
are often distinct from those obtained from terrestrial
organisms, have only been exploited for drug discovery
purposes to a limited degree.[1] In this context one of the
major limitations is the often insufficient availability of
material from the natural source, and in many cases the
development of an efficient total synthesis of a biologically
active marine natural product represents an important pre-
requisite for the comprehensive evaluation of its medical
potential.
Diterpenoids derived from soft corals of the genus Xenia
exhibit a wide range of biological activities, including
antiproliferative,[2] antiangiogenic,[3] or antibacterial[4] effects.
The common structural denominator of these compounds is a
nine-membered carbocyclic ring, which is generally fused to a
dihydropyran, a d-lactone, or a cyclobutane moiety, thus
leading to three major classes of Xenia diterpenoids which
have been termed the xenicins (or xenicans), xeniolides, and
xeniaphyllans, respectively.[5] Despite the interesting biolog-
ical activity of several Xenia diterpenoids, synthetic efforts in
this area have been sparse and the potential of Xenia
diterpenoids to serve as lead structures for drug discovery
has remained largely unexplored. To the best of our knowl-
edge total syntheses have only been reported for two different
members of the group, namely coraxeniolide A[6] and anthe-
liolide[7]. (Also see reference [8]).
To gain a better understanding of the biological potential
of Xenia diterpenoids and to establish a basis for future
structure-activity relationship (SAR) studies, we embarked
on the total synthesis of a number of these structurally unique
natural products. Herein we report on the first total synthesis
of the Xenia diterpenoid blumiolide C (1), which was isolated
in 2005 by El-Gamal et al. from the soft coral Xenia blumi and
reported to exhibit potent in vitro antiproliferative activity
(ED50 values of 1.5 mm and 0.6 mm against the human colon
cancer cell line HT-29 and the mouse P-388 leukemia line,
respectively).[9] Structurally, blumiolide C (1) is distinct from
the majority of Xenia diterpenoids because of the presence of
a Z, rather than the commonly found E, double bond as part
of the nine-membered ring.
As illustrated in Scheme 1 our retrosynthesis of 1 initially
led to the disconnection into the synthon I-5 and an
unsaturated C4-side chain aldehyde that would be connected
in an aldol reaction/elimination sequence (although the
stereochemical outcome of this process was unclear at this
point). The exocyclic double bond in I-5 was to be installed by
olefination of the corresponding C11-keto lactone. The latter
would be obtained from diene I-4 through ring-closing olefin
metathesis (RCM),[10] which represents the key strategic step
in our approach to blumiolide C (1). Whereas this RCM-
based strategy was highly appealing at the conceptual level,
the successful implementation of this approach was much less
certain as no literature precedent existed prior to our own
work, for the direct construction of trans-fused bicyclo[7.4.0]
systems by an RCM-mediated closure of a nine-membered
ring.[11,12] The stereogenic center at C4a was envisioned to be
created by substrate controlled 1,4-cuprate addition onto a,b-
unsaturated d-lactone I-3, which would be derived from diene
I-2 by a second RCM reaction. Lastly, the stereocenter at
C11a was to be set through a diastereoselective aldol reaction,
thus leading to O-protected 3-hydroxy-propanal I-1a and a
suitable chiral crotonyl derivative I-1b as the ultimate
precursors.
[*] Dr. C. Hamel,[+] Dr. E. V. Prusov, Dr. J. Gertsch, Prof. Dr. K.-H. Altmann
Swiss Federal Institute of Technology (ETH) Zꢀrich
Department of Chemistry and Applied Biosciences
Institute of Pharmaceutical Sciences, HCI H405
Wolfgang-Pauli-Strasse 10, 8093 Zꢀrich (Switzerland)
Fax : (+41)44-6331369
E-mail: karl-heinz.altmann@pharma.ethz.ch
Homepage: http://www.pharma.ethz.ch/institute_groups/
institute_groups/pharmaceutical_biology/
Dr. W. B. Schweizer
Swiss Federal Institute of Technology (ETH) Zꢀrich
Department of Chemistry and Applied Biosciences
Laboratory of Organic Chemistry, Zꢀrich (Switzerland)
[+] Current address: AC Immune SA, CH-1015 Lausanne (Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804004.
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Scheme 1. Retrosynthesis of blumiolide C (1). PG=protecting group
or H. Protecting groups may vary independently.
The departure point for the implementation of this
strategy was the diastereoselective aldol reaction of TBSO-
substituted propanal 2 with E-crotonyl-oxazolidinone 3,
which gave the desired aldol product in excellent yield
(95%)[13] (Scheme 2). After protection of the secondary
hydroxy group as a TBS ether (to give 4) the chiral auxiliary
was reductively cleaved with LiBH4, and the newly formed
primary alcohol was acylated with acryloyl chloride. Treat-
ment of the resulting ester 5 with the second generation
Grubbs catalyst in refluxing CH2Cl2 overnight[14] furnished
a,b-unsaturated lactone 6 as the substrate for the stereose-
lective attachment of the C5–C7 fragment. To our delight, the
substrate-controlled 1,4-addition of the mixed cuprate,
Scheme 2. a) Bu2BOTf, Et3N, CH2Cl2, ꢀ788C!RT, 1.5 h, 95%;
b) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 1 h, 93%; c) LiBH4, MeOH (1
=
equiv), Et2O, 08C!RT, 1.5 h, 77%; d) CH2 CHC(O)Cl, Et3N, DMAP,
CH2Cl2, 08C, 1 h, 75%; e) Grubbs II, CH2Cl2, reflux overnight, 92%;
=
f) CH2 C(CH3)CH2CH2MgI, CuI, Et2O, ꢀ788C, 90%; g) CSA, MeOH/
CH2Cl2 (1:1), 08C, 30 min, 90%; h) DMSO, (COCl)2, Et3N, ꢀ788C,
=
93%; i) CH2 CHMgCl, ZnCl2, THF, ꢀ308C, 18 h, 62%, d.r. 5:1;
=
j) PMBOC( NH)CCl3, cyclohexane, PPTS (3 mol%), 08C!RT, 20 h,
68%. Tf=trifluoromethanesufonyl, DMAP=4-dimethylaminopyridine,
CSA=(+)-camphorsulfonic acid, DMSO=dimethysulfoxide,
PMB=para-methoxybenzyl, PPTS=pyridinium p-toluenesulfonate.
=
derived from CH2 C(CH3)CH2CH2MgI and CuI, to lactone
6 in ether at ꢀ788C[15] proceeded with excellent diastereose-
lectivity to provide trans-product 7 in 90% yield as the only
isolable isomer. Subsequent deprotection of the primary
hydroxy group with CSA in a mixture of MeOH and CH2Cl2
(1:1) followed by Swern oxidation of the resulting free alcohol
gave aldehyde 8 (84% based on 7). Unexpectedly, the
attempted addition of vinyl Grignard reagents to 8 was low
yielding and accompanied by the formation of side products;
however, this problem was overcome by the use of in situ
prepared divinyl zinc,[16] which provided the desired allylic
alcohol 9 in satisfactory yield as a 5:1 mixture of isomers
(which was inconsequential, as C9 in the natural product,
which corresponds with the newly formed chiral center in 9, is
present in the keto oxidation state). Reaction of 9 with p-
methoxybenzyl trichloroacetimidate gave the bisprotected
diol 10.
(1). Given the lack of precedence for the RCM-based
formation of nine-membered rings in bicyclic[7.4.0] systems,
a number of preliminary experiments were conducted, in
order to establish a basis for the final optimization cycle.
These experiments clearly indicated a need for the protection
of the hydroxy group at C9 (blumiolide C numbering) for the
RCM step, as none of the desired cyclic products were
obtained from 9 under a variety of reaction conditions. The
most promising results were obtained with 10 in combination
with 50 mol% of the second generation Hoveyda–Grubbs
catalyst.[17] The final set of optimization experiments with this
catalyst loading are summarized in Table 1. The most
favorable results were obtained upon prolonged exposure of
diene 10 to the catalyst at elevated temperature in toluene,
which furnished the desired oxabicyclo[7.4.0]tridecene deriv-
ative 11 in 66% yield as a single isomer (Scheme 3, Table 1).
Having established efficient access to the oxabicyclic
framework of 1, the next challenge consisted in the introduc-
tion of the exocyclic methylene moiety at C11. Initial attempts
With dienes 9 and 10 in hand the stage was now set for the
investigation of the crucial ring closure reaction to establish
the oxabicyclo[7.4.0]tridecene framework of blumiolide C
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Table 1: Optimization of reaction conditions for the RCM-based cycliza-
tion of diene 10 (Scheme 3).
T [8C]
t
Solvent
Additive
Yield [%][a]
60
90
90
2 d
3 d
3 d
1.5 h
1 h
toluene
toluene
toluene
toluene
o-Cl2C6H4
o-Cl2C6H4
BQ[b]
0[d]
66
66
BQ[b]
–
–
–
–
160[c]
190[c]
100[c]
60
28[d]
0[d]
30 min
[a] Yields of isolated products. [b] BQ=p-benzoquinone. [c] Microwave
irradiation. [d] Varying amounts of starting material were isolated.
Scheme 3. a) [10]=1.5 mm, Hoveyda–Grubbs II catalyst, 50 mol%. For
other conditions see Table 1.
at the installation of this C11–C19 double bond involved the
direct methylenation of the ketone derived from 11 by
removal of the TBS ether and subsequent oxidation of the
resulting secondary hydroxy group. Unfortunately, the con-
version of the C11-keto group into the corresponding
exocyclic methylene moiety proved to be exceedingly difficult
and none of the different olefination methods investigated
(Wittig, Tebbe,[18] Nysted,[19] or the Huang[20] reagents)
delivered any of the desired olefin. Similar difficulties were
encountered by Leumann and co-workers in their synthesis of
coraxeniolide A;[6a] however, in the coraxeniolide A system
Tebbe methylenation of the C11-keto group in the nine-
membered ring was possible if the six-membered ring
included a methyl or silyl acetal rather than the natural
ester moiety. In contrast, TBS acetal 13 (Scheme 4) failed to
undergo methylenation either under Tebbe or Petasis[21]
conditions.
Scheme 4. a) TBAF, THF, 08C!RT, 85%; b) DIBAL-H, THF, ꢀ788C,
96%; c) TBSOTf, 2,6-lutidine, ꢀ788C, 85%; d) DMP, RT, 88%;
e) DIBAL-H, CH2Cl2, ꢀ788C; f) MeOH, PPTS (5 mol%), RT, 1 h, 73%
(two steps, d.r. 1:1); g) TBAF (2 equiv), THF, RT, overnight, 90%;
h) TPAP, NMO, 4 ꢁ M.S., CH2Cl2, 08C, 1 h, 80%; i) MeMgBr, Et2O,
ꢀ308C, 30 min, 75%; j) Martin’s sulphurane, CH2Cl2, 08C!RT,
30 min, 86%; k) 48% aq HF, MeCN/THF (5:1), RT, 2.5 h; l) TPAP,
NMO, CH2Cl2, 4 ꢁ M.S., RT, 30 min, 73% (two steps). TBAF=tetrabu-
tylammonium fluoride, DIBAL-H=diisobutylaluminum hydride,
DMP=Dess–Martin periodinane, TPAP=tetrapropylammonium
peruthenate, NMO=4-methylmorpholin-N-oxide, M.S.=molecular
sieves.
Gratifyingly, however, the investigation of indirect
methylenation methods revealed that 13 could be converted
into the desired olefin through an addition/elimination
sequence, and in subsequent experiments methyl acetal 15
(Scheme 4) was found to be an even more favorable substrate
in this process. Thus, addition of MeMgBr to 15 proceeded
cleanly and diastereoselectively to provide tertiary alcohol 16
in 75% yield.[22] Regioselective formation of the exocyclic
double bond was then achieved by treatment of 16 with
Martinꢀs sulphurane,[23] which produced the desired alkene 17
in excellent yield (86%). Subsequent restoration of the
lactone functionality proceeded smoothly and gave the key
bicyclic intermediate 18 (corresponding to I-5 in Scheme 1) in
73% yield for the two-step sequence from 17 (i.e. acetal
hydrolysis and oxidation of the resulting lactol).
no precedence for the stereoselective introduction of a C4–
C12 double bond in xeniolides exists in the literature, as the
coraxeniolide A side chain is connected to the bicyclic core by
ꢀ
a C C single bond).
As illustrated in Scheme 5, the attachment of the C4-side
chain to intermediate 18 involved an aldol reaction with
aldehyde 19,[24] which proceeded in a highly diastereoselective
manner, albeit in somewhat moderate yield (50%).[25] After
extensive optimization of the reaction, the stereospecific
syn dehydration of aldol adduct 20 was achieved in excellent
yield using DCC in the presence of CuCl2.[26] Subsequent
deprotection of the resulting diene 21 with DDQ and
followed by DMP oxidation of the secondary hydroxy group
delivered blumiolide C (1) in 58% yield (from 21).
The spectroscopic properties of synthetic (+)-1 were in
good agreement with the literature data for natural (+)-
blumiolide C (1H and 13C NMR, HRMS, IR, and optical
rotation).[27] Ultimate structural proof was established by a
single crystal X-ray crystallographic analysis of 1, which
confirmed both the Z, E geometry of the unsaturated side
After the successful construction of its bicyclic core
structure, including the incorporation of the exocyclic meth-
ylene moiety at C11, the final challenge in the synthesis of
blumiolide C (1) was the stereoselective introduction of the
a,b/d,g-unsaturated side chain at C4. (It should be noted that
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Communications
In summary, the first enantioselective total synthesis of
the Xenia diterpenoid blumiolide C (1) has been accom-
plished in a total of 27 steps (24 steps for the longest linear
sequence) and 1% overall yield. The synthesis is built around
the unprecedented construction of the [7.4.0]oxabicylic ring
system through the RCM-based formation of a nine-mem-
bered ring as the key enabling step. Other crucial elements of
our approach to 1 include an Evans aldol reaction, a highly
diastereoselective mixed cuprate addition to an a,b-unsatu-
rated d-lactone, and a stereospecific dehydration reaction
with DCC/CuCl2 to introduce the side chain at C4.
The chemistry developed in the course of our work on
blumiolide C (1) provides the foundation for the future
synthesis of other natural Xenia diterpenoids as well as the
preparation of synthetic analogs of 1 for SAR studies and
target finding.
Scheme 5. a) LDA (3 equiv), THF, ꢀ788C, then 19, 2 h, 50%; b) neat
Received: August 13, 2008
Published online: November 27, 2008
DCC, CuCl2, RT, overnight, 90%; c) DDQ, CH2Cl2/phosphate buffer
(20:1), RT, 68%; d) DMP, CH2Cl2, RT, 1 h, 85%. LDA=lithiumdiisopro-
pylamide, DCC=N,N’-dicyclohexylcarbodiimide, DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone.
Keywords: medium-sized rings · metathesis · natural products ·
.
terpenoids · total synthesis
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Figure 1. X-ray crystal structure of synthetic blumiolide C (1). Ellipsoids
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membered rings (Figure 1).[28]
On the basis of a preliminary assessment of its in vitro
antiproliferative activity in HCT-116 and A549 human cancer
cells, (+)-1 inhibits human cancer cell growth with mm activity
(HCT-116 cells: IC50 = 13.8 mm; A549 cells: 33% growth
inhibition at 10 mm), although the compound appears to be
somewhat less active than what has been reported in the
literature.[9] It remains to be seen, whether these differences
may be caused (at least partly) by differences in the
experimental conditions employed, including the specific
cell lines investigated. Future work will show whether other
Xenia diterpenoids or, in particular, synthetic analogues of 1
may possess enhanced antiproliferative activity.
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[16] R. L. Soucy, D. Kozhinov, V. Behar, J. Org. Chem. 2002, 67,
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[27] The 1H NMR spectrum of synthetic blumiolide C corresponds
exactly with the published data.[9] For the 13C NMR spectrum of
synthetic 1 17 out of 20 signals match with the literature data
within 0.1 ppm. Two carbonyl signals deviate by 0.6 ppm, which
could simply be a consequence of different measuring condi-
tions. (See the Supporting Information). For the signal at
130.3 ppm in our spectrum the corresponding literature signal
is reported at 133.0 ppm. We assume this to be a publication
error in reference [9]. 1: HRMS: calc. for [M+Na]+: 353.1723,
found 353.1728; lit. HRFABMS calc. for [M]: 331.1902, found
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6394.
[22] In control experiments the two separated anomers of ketone 15
were treated with MeMgBr individually. For each anomer only
one diastereoisomeric product was obtained in the addition
reaction; however, the relative and absolute configuration of
these products at C3 and C11 was not determined.
[23] R. J. Arhart, J. C. Martin, J. Am. Chem. Soc. 1972, 94, 5003 –
5010.
331.1905. [a]D25 = + 50.08 (c = 0.4 gcmꢀ3, CHCl3); lit. [a]2D5
=
+ 66.08 (c = 0.4 gcmꢀ3, CHCl3).
[24] Aldehyde 19 was obtained from the known propargylic alcohol
22 (THP = tetrahydropyranyl; D. Dꢃez Martꢃn, I. S. Marcos, P.
Basabe, R. E. Romero, R. F. Moro, W. Lumeras, L. Rodrꢃguez, J.
Urones, Synthesis 2001, 1013 – 1022) in a four step sequence
comprising PMB-protection of the tertiary hydroxyl group,
removal of the THP group with p-toluene sulfonic acid, RED-
[28] CCDC 703479 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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