Total synthesis of ascididemin via anionic cascade ring closure

Article abstract of DOI:10.1039/c2cc34725c

A new and convergent synthesis of ascididemin is presented. Using an anionic cascade ring closure as the key step, this natural product is obtained in 45% overall yield in just 6 steps starting from 2′-fluoroacetophenone. This new approach was extended to the synthesis of a new isomer of ascididemin.

Full text of DOI:10.1039/c2cc34725c

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COMMUNICATION
Total synthesis of ascididemin via anionic cascade ring closurew
Ida Nymann Petersen,z Francois Cresteyz and Jesper Langgaard Kristensen*
¸
Received 2nd July 2012, Accepted 20th July 2012
DOI: 10.1039/c2cc34725c
A new and convergent synthesis of ascididemin is presented.
Using an anionic cascade ring closure as the key step, this
natural product is obtained in 45% overall yield in just 6 steps
starting from 20-fluoroacetophenone. This new approach was
extended to the synthesis of a new isomer of ascididemin.
Ascididemin (1) belongs to the family of the pyridoacridines, a
group of marine alkaloids isolated from corals, tunicates,
sponges and marine invertebrates (Scheme 1).1 Ascididemin
was first isolated in 1988 by Kobayashi and co-workers2 from
the okinawan tunicate Didemnum sp. Many of these natural
products along with ascididemin like kuanoniamine A (2) and
amphimedine (3) exhibit significant in vitro and in vivo cytotoxic
activities against several tumor cell lines.3 Moreover, most of the
pyridoacridines are also known to have antimicrobial, antiviral,
antiparasitic and fungicidal properties.4 These biological profiles
are not only promising for developing anticancer drugs but also
potential replacements for some of today’s antibiotics. Small
modifications in the structures of these pyridoacridines could
have potentially a great effect on the biological activity. Therefore
synthetic routes which give easy access and significant amount of
ascididemin, other pyridoacridines and likely other new synthetic
derivatives are required for further biological evaluations.
Scheme 2 Retrosynthetic analysis of ascididemin (1) based on an
anionic cascade ring closure.
prolonged reaction times and the use of harsh conditions and
reagents. In addition, synthesis of analogues for structure
activity studies has been arduous.6
We have previously developed an anionic cascade for the
construction of tri- and pentacyclic ring systems.7 Herein we
wish to report the application of a closely related cascade
reaction to the synthesis of pyridoacridine natural products,
see Scheme 2.
We speculated that ascididemin (1) could be prepared from
12-deoxyascididemin (4), which is itself a potent natural
product,8 via a simple oxidation at the benzylic position.
Making the two indicated disconnections in 4, as outlined in
Scheme 2, leads to tricyclic derivative 5 as the key intermediate
for the anionic ring closure: Deprotonation at the benzylic
position followed by nucleophilic attack on the cyano group
should give the iminium intermediate which via intramolecular
SNAr would give 4. The key substrate 5 required for the anionic
ring closure could presumably be accessed via a cross-coupling
reaction between 2-chloropyridine 6 and a suitable metalated
picoline.
Ascididemin has previously been synthesized using different
approaches to construct the polycyclic framework.5 These
efforts have utilized thermally initiated radical cyclizations
and condensation reactions of suitably poised amino-ketone
intermediates. However, these methods have limitations due to
The required 2-chloropyridine building block 6 was prepared
in 81% yield over three steps on a multigram scale, as shown in
Scheme 3. Knoevenagel condensation of commercially available
20-fluoroacetophenone with malononitrile gave crude alkene 7
which was treated with an excess of N,N-dimethylformamide
dimethyl acetal to provide enamine 8. Exposure of 8 to HCl in
acetic acid furnished 2-chloropyridine 6.9
Scheme 1 Structure of representative pyridoacridines: ascididemin
(1), kuanoniamine A (2) and amphimedine (3).
Department of Drug Design and Pharmacology, Faculty of Health
and Medical Sciences, University of Copenhagen, Universitetsparken 2,
DK-2100 Copenhagen, Denmark. E-mail: jekr@farma.ku.dk;
Fax: +45 3533 6041; Tel: +45 3533 6487
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and copies of NMR-spectra for all com-
pounds. See DOI: 10.1039/c2cc34725c
The precursor for the anionic cascade (5) was obtained via
Negishi cross-coupling of 6 with commercially available
3-methylpyridin-2-ylzinc using PEPPSI-iPr as the catalyst,
see Scheme 4.10–12 With the key intermediate in hand several
z These authors contributed equally.
c
9092 Chem. Commun., 2012, 48, 9092–9094
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The strategy is noteworthy due to a number of points: it does
not involve any protection/deprotection steps, the sequence
does not contain any non-productive changes in the oxidation
state and all the steps are bond-constructing. Thus, according
to the definition by Gaich and Baran16 this procedure is close
to ideal. Further studies concerning construction of new
pyridoacridine derivatives via the anionic cascade strategy
are currently in progress in our laboratories.
Scheme 3 Synthesis of building block 6. (a) Malononitrile (2 equiv.),
NH4OAc (1 equiv.), PhMe–AcOH (15 : 1), reflux, 12 h; (b) N,N-
dimethylformamide dimethyl acetal (2 equiv.), dry CH2Cl2, rt, 12 h,
N2. (c) HCl gas, AcOH, rt, 3 h, 81% over 3 steps.
The authors wish to thank the Danish Research Council for
funding and Dr Nils T. Nyberg for helpful assistance with the
NMR spectra of 10.
Notes and references
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2 J. Kobayashi, J.-F. Cheng, H. Nakamura and Y. Ohizumi, Tetrahedron
Lett., 1988, 29, 1177.
Scheme 4 Cross-coupling reaction and anionic cascade ring closure
followed by final oxidation to synthesize ascididemin (1). (a) 3-Methyl-
pyridin-2-ylzinc bromide (1.4 equiv.), PEPPSI-iPr (2 mol%), THF,
MW, 120 1C, 1 h, 80%; (b) NaH (10 equiv.), dry DMF, MW, 95 1C, 25
min; (c) O2, rt, 3 h, 69% over two steps.
3 E. Delfourne and J. Bastide, Med. Res. Rev., 2003, 23, 234.
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different bases and solvents were screened to promote the anionic
cascade.13 After extensive experimentation, we found that NaH in
DMF under MW irradiation at 95 1C led to complete conversion
of bipyridine 5 to 12-deoxyascididemin (4), as judged by LC-MS
and NMR.14 However, this compound proved to be very difficult
to handle and we opted to try and oxidize the intermediate directly.
Several different oxidants were screened15 and eventually we found
that immediate bubbling of oxygen through the crude solution
containing 4 for 3 h at room temperature provided 1 in 69% yield
in a one-pot procedure over two steps.
To demonstrate the versatility of this new approach and
extend the scope of this protocol, an isomeric ring system was
synthesized for the first time following the same methodology, see
Scheme 5. Thus, Br–Mg exchange of 3-bromo-4-methylpyridine
followed by transmetalation with a solution of ZnCl2 provided
a pyridylzinc intermediate which underwent a Negishi cross-
coupling reaction with 6 under the same conditions described
above to lead to bipyridine 9 in 80% yield. A similar cascade
ring closure followed by oxidation at the benzylic position
allowed the construction of a novel pentacyclic derivative 10 in
65% yield over two steps.
In conclusion, a convergent and very efficient synthetic
pathway for the preparation of pyridoacridine 1 and a novel
isomer 10 has been developed.
Starting from 20-fluoroacetophenone both compounds were
obtained in only 6 steps in 45% and 42% overall yield, respectively.
9 (a) The synthesis of similar pyridines is described in: R. H. Prager,
C. Tsopelas and T. Heisler, Aust. J. Chem., 1991, 44, 277(b) R. Church,
R. Trust, J. D. Albright and M. Kobayashi, J. Org. Chem., 1995,
60, 3750.
10 (a) E. Negishi, L. F. Valente and M. Kobayashi, J. Am. Chem.
Soc., 1980, 102, 3298; (b) E. Negishi and M. Kobayashi, J. Org.
Chem., 1980, 45, 5223; (c) E. Negishi, Acc. Chem. Res., 1982,
15, 340.
11 (a) For recent examples of Negishi cross-coupling reactions using
PEPPSI-iPr as the catalyst, see: C. Valente, M. E. Belowich,
N. Hadei and M. G. Organ, Eur. J. Org. Chem., 2010, 4343 and
references cited therein(b) F. Crestey and P. Knochel, Synthesis,
Scheme 5 Synthesis of a new pentacyclic derivative 10. (a) (1) n-BuLi
(1.05 equiv.), i-PrMgCl (0.53 equiv.), ꢀ10 1C, dry THF, 30 min;
(2) ZnCl2 (1.05 equiv.), ꢀ10 1C to rt, 40 min; (3) 6 (0.7 equiv.),
PEPPSI-iPr (2 mol%), MW, 120 1C, 1 h, 80%; (b) (1) NaH (10 equiv.),
dry DMF, MW, 95 1C, 25 min; (2) O2, rt, 3 h, 65% over two steps.
c
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2010, 1097; (c) T. Blumke, Y.-H. Chen, Z. Peng and P. Knochel,
Nat. Chem., 2010, 2, 313; (d) T. Fujita, T. Ichitsuka, K. Fuchibe
and J. Ichikawa, Chem. Lett., 2011, 986; (e) S. Bernhardt,
G. Manolikakes, T. Kunz and P. Knochel, Angew. Chem., Int.
Ed, 2011, 50, 9205.
Negishi cross-coupling under identical conditions afforded 5 in
72% yield, see ESIw for details.
13 (a) L. Benesch, P. Bury, D. Guillaneux, S. Houldsworth, X. Wang and
V. Snieckus, Tetrahedron Lett., 1998, 39, 961; (b) C. B. de Koning,
J. P. Michael and A. L. Rousseau, Tetrahedron Lett., 1998, 39, 8725;
(c) C. Rochais, R. Yougnia, T. Cailly, J. Sopkova-de Oliveira Santos,
S. Rault and P. Dallemagne, Tetrahedron, 2011, 67, 5806.
14 12-Deoxyascididemin (4) is slowly oxidized by air to ascididemin
(1). Thus, attempts to isolate and fully characterize 4 were
unsuccessful.
12 (a) Alternatively, a similar metalated species could also be obtained
after halogen–metal exchange of 2-bromo-3-methylpyridine with
a mixture of n-BuLi–i-PrMgCl (2 : 1) at ꢀ10 1C followed by
transmetalation of the in situ generated magnesate complex with
ZnCl2: T. Iida, T. Wada, K. Tomimoto and T. Mase, Tetrahedron
Lett., 2001, 42, 4841(b) J. G. Sosnicki, Synlett, 2009, 2508;
(c) Ł. Struk and J. G. Sosnicki, Synlett, 2012, 735; Subsequent
15 See ESIw for details.
16 T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75, 4657.
c
9094 Chem. Commun., 2012, 48, 9092–9094
This journal is The Royal Society of Chemistry 2012