Enantioselective assembly of the benzo[d]xanthene tetracyclic core of anti-influenza active natural products

Article abstract of DOI:10.1039/c002011g

A combination of an enantioselective conjugate addition/trapping sequence and a ruthenium(iii)-catalyzed domino cyclization provides a concise access to benzo[d]xanthenes found in several anti-influenza active sesquiterpene natural products.

Full text of DOI:10.1039/c002011g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective assembly of the benzo[d]xanthene tetracyclic core of
anti-influenza active natural products†‡
Duc Tran Ngoc, Martin Albicker, Lorenz Schneider and Nicolai Cramer*
Received 1st February 2010, Accepted 2nd March 2010
First published as an Advance Article on the web 11th March 2010
DOI: 10.1039/c002011g
A combination of an enantioselective conjugate addition/
trapping sequence and a ruthenium(III)-catalyzed domino
cyclization provides a concise access to benzo[d]xanthenes
found in several anti-influenza active sesquiterpene natural
products.
Emerging resistance to anti-influenza agents in combination with
the recent global pandemics are a severe threat. Therefore the
search for alternative treatments is an important task. A small class
of sesquiterpene natural products that possess promising activity
against the influenza A virus has been reported. Stachyflin,1 the
most potent congener displays an IC50 value of 3 nM against
influenza A virus strains and has been shown to act as a fusion
inhibitor.2 Other members of this family like podosporin,3 aureol4
and strongylin5 are anti-virally active as well. The common
structural feature of this compound family is their tetracyclic
benzo[d]xanthene scaffold 1, thus making it an attractive target
that warrants further attention (Fig. 1).
To explore the potential of this compound class we required a
flexible and efficient route to access skeleton 1. Our retrosynthetic
strategy is based on a transition-metal catalyzed domino cycliza-
Fig. 1 Benzo[d]xanthene sesquiterpene natural products.
tion of diene 3 (Scheme 1). First, the C-ring should be closed via
a trans-selective alkoxy-metalation forming 2. Subsequently, an
addition across the double bond should then build the A-ring. A
proto-demetalation or a reductive elimination would lead either to
the saturated or unsaturated version of 1. The required precursor 3
derives from ketone 4, which should be ultimately accessible from
enone 5 by an enantioselective conjugate addition/electrophilic
trapping sequence.
For the initial enantioselective conjugate addition reaction
we employed conditions developed by Alexakis and coworkers
forming aluminium enolate 6 with an ee-value of 90% (Table 1).6
However, aluminium enolates are well known for their notori-
ous poor reactivity, impeding most direct electrophilic trapping
reactions. Therefore, some optimization was required for an
effective one pot addition–alkylation sequence. The reactivity
of aluminium enolates is greatly enhanced by their conversion
into the corresponding the ate-complex with methyl lithium7 and
further by addition of highly polar solvent additives. HMPA
proved to be essential and alternatives like DMPU were not viable
Scheme 1 Synthetic strategy for the benzo[d]xanthene skeleton.
(Entries 2 and 3). The enolate trapping proceeds well for benzylic
Laboratory of Organic Chemistry, ETH Zurich, HCI H 304, Wolfgang-
and propargylic iodides, while the corresponding bromides are
unreactive (Entry 4). The obtained diastereoselectivities range
from 6 : 1 to 10 : 1 in favor of the depicted isomer 4. Remarkably,
the alkylation works equally well for sterically demanding ortho-
disubstitutedbenzyliodides andprovides 4din63%yield(Entry7).
Less reactive electrophiles e.g. 2,6-dichlorobenzyl iodide can be
Pauli-Strasse 10, 8093 Zurich, Switzerland. E-mail: nicolai.cramer@
org.chem.ethz.ch; Fax: +41 44 632 1328; Tel: +41 44 632 6412
† This article is part of an Organic & Biomolecular Chemistry web theme
issue which highlights work by participants in the 2009 EuCheMS young
investigators workshop.
‡ Electronic supplementary information (ESI) available: Experimental
details and spectra. See DOI: 10.1039/c002011g
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Table 1 Optimization of the one pot addition–alkylation process
Scheme 2 [2+2+2]-Cyclotrimerization opens access to higher substituted
derivatives.
Entry
1
Conditions
HMPA
RX
Ketone 4
Yield [%]a
Ketones 4a and 4b were converted into the vinyl triflates
8a and 8b (Scheme 3). The subsequent sp2–sp3 cross-coupling
reaction required some investigation. Although iron-catalyzed
cross-coupling reactions using vinyl triflates and alkyl Grignard-
reagents are well precedented for related systems,9 only traces
of desired product 9 were obtained with this specific substrate
pair. We attribute this to the hindered neopentylic nature of the
vinyl triflate and the moderate stability of the Grignard-reagent.
A palladium-catalyzed Suzuki-coupling using the alkyl boron
reagent generated in situ from 4-methyl pentadiene and 9-BBN was
delicate as well (Table 2). The classical conditions for this substrate
class, yielded, irrespective of the phosphine ligand employed,
predominantly tricyclic product 10 arising from a direct arylation
via a concerted deprotonation metalation mechanism (Entries
1–3).10 Replacing the phosphine ligand by its higher homolog
triphenylarsine, completely suppressed this reactivity and gave rise
to the desired cross-coupled product 9 in almost quantitative yield.
Removal of the phenolic protecting group proceeded either under
acidic conditions for R = MOM, or using lithium n-butylthiolate
in HMPA for R = Me giving phenol 3 in 40% and 81% yield,
respectively.
4a
< 5
2
3
MeLi, HMPA
MeLi,
DMPU
4a
4a
67
5
4
5
6
MeLi, HMPA
4a
4b
4c
< 5
MeLi, HMPA
MeLi, HMPA
80
78
7
MeLi, HMPA
MeLi, HMPA
4d
4e
63
33
8b
9
MeLi, HMPA
MeLi, HMPA
4f
61
69
10
4g
a Yield of isolated the diastereomer 4. b 48% of 2,3-dimethyl cyclohexanone
was isolated additionally.
Scheme 3 Synthesis of intermediate 3, Reagents and conditions: a) (R =
Me): 2 equiv. nBuSLi, HMPA, 100 ◦C, 2 h, 81%; b) (R = MOM): 1 M
HCl, MeOH, 23 ◦C, 12 h, 41%.
used, although 4e is obtained in diminished yield along with 2,3-
dimethyl ketone (Entry 8).
A ruthenium(II)-catalyzed [2+2+2]-cyclotrimerization reaction
with the propargyl substituted ketone 4f and the tethered diyne 7
can be used to access higher substituted derivatives, e.g. 4h for a
synthetic approach to stachyflin congeners (Scheme 2).8
With the free phenol 3, we then explored different metals
and conditions for the anticipated cascade cyclization (Table 3).
Classical trans-nucleo-palladation selective Wacker-type condi-
tions using palladium(II)-complexes11 resulted mainly in the slow
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Table 2 sp2–sp3 Cross-coupling vs. direct arylation
Entry
Conditions
9a
10a
1
2
3
4
5
5% PdCl2(dppf), K3PO4, THF, 65 ◦
C
< 5%(9a)
21%(9a)
< 5%(9a)
98%(9a)
99%(9b)
72%(10a)
63%(10a)
91%(10a)
0%(10a)
0%(10b)
5% Pd(OAc)2, 10% SPhos, K3PO4, THF, H2O, 55 ◦
C
5% Pd(PPh3)4, CsF, dioxane, 85 ◦
C
5% Pd(dba)2, 12% AsPh3, K3PO4, DMF, H2O, 55 ◦
5% Pd(dba)2, 12% AsPh3, K3PO4, DMF, H2O, 55 ◦
C
C
a Isolated yields.
Table 3 Exploration of the cascade cyclizationa
Entry
Conditions
cis-1b
trans-1b
11b
12b
1
2c
3
20% PdCl2(CH3CN)2, LiCl, Na2CO3, BQ, THF, 60 ◦C, 48 h
10% Pd(hfacac)2, Na2CO3, BQ, THF, 60 ◦C, 48 h
10% PtCl2, CH3NO2, 45 ◦C, 3 h
—
—
—
—
—
—
—
9%
< 5%
—
69%
11%
—
—
—
41%
54%
< 5%
9%
38%
—
< 5%
—
69%
5%
—
—
—
—
—
—
—
4
10% PtCl4, CH2Cl2, 23 ◦C, 1 h
5c
6
10% AgNTf2, CH3CN, 40 ◦C, 24 h
20% RuCl3, 60% AgOTf, 40% PPh3, 50% Cu(OTf)2, CH3CN, 80 ◦C, 5 h
20% Cp*RuCl2, 40% AgOTf, 20% PPh3, 50% Cu(OTf)2, CH3CN, 80 ◦C, 2 h
10% TFA, CH3CN, 23 ◦C, 18 h
< 5%
—
7
8c
9
—
—
—
10% TfOH, toluene, 80 ◦C, 10 min
< 5%
20%
10
10% TfOH, MeNO2, 23 ◦C, 18 h
—
a Reaction conditions: 14.9 mg (0.05 mmol) 3, 0.05 M in the indicated solvent; b Yields of isolated products; c Starting material 3 was recovered.
formation of product 12 arising from a preferred 5-exo-trig
ring closure of the A-ring (Entries 1–2). Platinum(II) as well as
platinum(IV) complexes exhibited good reactivity towards the first
cyclization,12 but were not competent for a ring closure of the
second carbacycle, thus yielding the tricyclic hydroalkoxylation
product 11 (Entries 3–4). Cationic silver(I) complexes were much
less reactive (Entry 5). The condition reported by Ohta and
coworkers using cationic ruthenium(III) complexes for the for-
mation of dihydrobenzofurans from 2-allylphenols,13 promoted
the cascade cyclization and formed the tetracycle 1 (Entries
6–7). trans-Fused decalin trans-1, as occurring in the sponge
secondary metabolite cyclosmenospongine (Fig. 1),14 was formed
predominantly. We further evaluated Brønsted acids instead of the
metal catalysts. Trifluoroacetic acid was not reactive (Entry 8), but
triflic acid caused rapid decomposition of the starting material
to polymeric products (Entry 9). Switching to nitromethane as
solvent, allowed for the isolation of trans-1 in modest yields
(Entry 10).
In summary, we showed a concise enantioselective assembly of
benzo[d]xanthenes illustrating in particular ruthenium-promoted
cyclizations. Further efforts to address the formation of the
corresponding cis-decalin system and applications to the synthesis
of anti-influenza active natural product analogs are ongoing.
Acknowledgements
We gratefully acknowledge ETH Zurich (ETH-16 08-3) and
Fonds der Chemischen Industrie (Liebig-Fellowship to N. C.) for
funding. We thank Prof. Dr E. M. Carreira for generous support.
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