Acid-catalyzed synthesis of bicyclo[3. n.1]alkenediones

Article abstract of DOI:10.1021/ol102909t

An acid-catalyzed Dieckmann-type reaction has been developed to access functionalized bicyclo[3.2.1]alkenediones. This methodology has been successfully extended to more substituted and larger ring homologues, providing a new and efficient route to the core of numerous attractive natural products and their analogues.

Full text of DOI:10.1021/ol102909t

ORGANIC
LETTERS
2011
Vol. 13, No. 4
664–667
Acid-Catalyzed Synthesis of
Bicyclo[3.n.1]alkenediones
Iacovos N. Michaelides, Benjamin Darses, and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
darren.dixon@chem.ox.ac.uk
Received December 1, 2010
ABSTRACT
An acid-catalyzed Dieckmann-type reaction has been developed to access functionalized bicyclo[3.2.1]alkenediones. This methodology has been
successfully extended to more substituted and larger ring homologues, providing a new and efficient route to the core of numerous attractive
natural products and their analogues.
Densely substituted bicyclo[m.n.1]alkanones are com-
mon to numerous biologically interesting and synthetically
challenging natural products (Figure 1). Widely repre-
sented by the polyphenols and phloroglucinol derivatives,1
like the radical scavenger vitisinol D (1),2 or the potential
anti-Alzheimer agent garsubellin A (2),3 this framework is
also present in welwistatin (3),4 famous for its promising
anticancer activity.
sequential R,R0-double addition of a cyclic ketone to an
acrylate derivative or an Effenberger cyclization.6
Current methodologies to access the [3.n.1] carbon skele-
ton rely predominantly on [5 þ 2] cycloadditions5 or on
(1) Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963.
(2) Huang, Y.-L.; Tsai, W.-J.; Shen, C.-C.; Chen, C.-C. J. Nat. Prod.
2005, 68, 217.
Figure 1. Naturally occurring bicyclo[m.n.1]alkanone structures.
(3) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull.
1997, 45, 947.
More recent studies for the synthesis of these bicyclo
frameworks include, for example, gold-catalyzed cyclization
(4) (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am.
Chem. Soc. 1994, 116, 9935. (b) Smith, C. D.; Zilfou, J. T.; Stratmann,
K.; Patterson, G. M. L.; Moore, R. E. Mol. Pharmacol. 1995, 47, 241. (c)
Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996, 49, 288.
(5) (a) Walls, F.; Padilla, J.; Joseph-Nathan, P.; Giral, F.; Romo, J.
(6) (a) Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V. Angew. Chem., Int.
Ed. 2005, 44, 3895. (b) Schick, H.; Roatsch, B.; Schwarz, H.; Hauser, A.;
Schwarz, S. Liebigs Ann. Chem. 1992, 419. (c) Dauben, W. G.; Bunce, R. A.
€
Tetrahedron Lett. 1965, 6, 1577. (b) Buchi, G.; Mak, C.-P. J. Am. Chem.
€
€
J. Org. Chem. 1983, 48, 4642. Effenberger cyclization: (d) Schonwalder,
K.-H.; Kollat, P.; Stezowski, J. J.; Effenberger, F. Chem. Ber. 1984, 117,
3280. (e) Rodeschini, V.; Simpkins, N. S.; Wilson., C. J. Org. Chem. 2007,72,
4265. (f) Nuhant, P.; David, M.; Pouplin, T.; Delpech, B.; Marazano, C.
Org. Lett. 2007, 9, 287.
€
Soc. 1977, 99, 8073. (c) Buchi, G.; Chu, P.-S. Tetrahedron 1981, 37, 4509.
€
(d) Buchi, G.; Chu, P.-S. J. Org. Chem. 1978, 43, 3717. (e) Engler, T. A.;
Wei, D.; Letavic, M. A. Tetrahedron Lett. 1993, 34, 1429. (f) Engler,
T. A.; Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy, J. P. J. Org.
Chem. 1994, 59, 6588. (g) Engler, T. A.; Meduna, S. P.; LaTessa, K. O.;
Chai, W. J. Org. Chem. 1996, 61, 8598. (h) Engler, T. A.; Letavic, M. A.;
Iyengar, R.; LaTessa, K. O.; Reddy, J. P. J. Org. Chem. 1999, 64, 2391.
ꢀ
ꢀ
(7) Barabe, F.; Betournay, G.; Bellavance, G.; Barriault, L. Org. Lett.
2009, 11, 4236.
r
10.1021/ol102909t
Published on Web 01/19/2011
2011 American Chemical Society

of silyl enol ethers onto pendant alkyne functionality7 or
combined rhenium-TBAF catalysis in ketone to ester
addition reactions.8
Scheme 2. Preparation of the Model Substrate 9a
During recent work within our group focusing on the
synthesis of daphniyunnine D (4),9 we unexpectedly ob-
served the formation of this intriguing structural motif.
While attempting to protect the carbonyl of the isomeric
enone 9e with ethylene glycol under TsOH catalysis, we
observed the formation of the expected ketal only in
12% yield accompanied by 26% of the monoprotected
bicyclo[3.2.1]alkenedione 5. This compound was believed
to result from an acid promoted Dieckmann-type reaction
of the enol form of the cyclic enone onto the activated ester
moiety,10 followed by an in situ ketalization.11
To investigate and develop this appealing process we
chose the readily accessible model substrate 9a for an
optimization study. Following a modification of a pre-
viously published reaction,12 it was found that the keto
diester 8a could be obtained in good yield by reacting the
commercially available compounds 6aand 7 in the presence
of sodium hydride. Subsequent Krapcho dealkyloxycarbo-
nylation provided an isomeric mixture of the cyclization
substrate 9a.
Table 1. Optimization of the TsOH-Catalyzed Cyclization
entry
solvent conditions
yielda (%)
Scheme 1. Unexpected Observation of the Formation of 5 and
Proposed Mechanistic Pathway
1
2
toluene, reflux (0.2 M)
toluene, 90 °C (0.2 M)
1,4-dioxane, reflux (0.2 M)
m-xylene, reflux (0.2 M)
TCE,b reflux (0.2 M)
46
15
0
3
4
54
52
0
5
6
DMF or DMSO, 145 °C (0.2 M)
m-xylene, reflux (0.05 M)
m-xylene, reflux (0.025 M)
m-xylene, reflux (0.05 M)c
mesitylene, reflux (0.05 M)
m-xylene, reflux (0.05 M)d
7
80
73
71
60
0
8
9
10
11
a Yields after flash chromatography. b TCE = 1,1,2,2-tetrachloro-
ethane. c Using 5 mol % of TsOH. d Without TsOH.
ging 46% yield (Table 1, entry 1). Moreover, single-crystal
X-ray diffraction of 10a unambiguously confirmed its
structure (Figure 2).13
With our model substrate in hand, the development of
optimum cyclization conditions was addressed by examin-
ing various reaction parameters. We reasoned that if the
mechanistic pathway was as shown in Scheme 1, cyclization
should proceed in the absence of ethylene glycol. This was
the case: by refluxing 9a in toluene in the presence of 10 mol
% of TsOH, the diketone 10a was isolated in an encoura-
Lowering the temperature was deleterious to the yield
with only 15% of the product being isolated (entry 2). By
changing the solvent to 1,4-dioxane with a boiling point
similar to that of toluene, no product formation was
observed. Therefore, reactions were performed in higher
boiling point solvents and gave improved yields of 54%
and 52% for m-xylene and 1,1,2,2-tetrachloroethane, re-
spectively (entries 4 and 5). On the other hand, use of polar
(8) Kuninobu, Y.; Morita, J.; Nishi, M.; Kawata, A.; Takai, K. Org.
Lett. 2009, 11, 2535.
(9) Zhang, H.; Yang, S.-P.; Fan, C.-Q.; Ding, J.; Yue, J.-M. J. Nat.
Prod. 2006, 69, 553.
(13) Data were collected at low temperature [Cosier, J.; Glazer, A. M.
J. Appl. Crystallogr. 1986, 19, 105] using an Enraf-Nonius KCCD
diffractometer [Otwinowski, Z.; Minor, W. Processing of X-ray Diffrac-
tion Data Collected in Oscillation Mode Methods Enzymol; Carter, C. W.,
Sweet, R. M., Eds.; Academic Press: New York, 1997; p 276]. The crystal
structure of 10a was solved using SIR92 [Altomare, A.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M. J.
Appl. Crystallogr. 1994, 27, 435] and refined using the CRYSTALS software
suite [Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487], as per the Supporting Information
(CIF).
(10) Two independent cases of related acidic cyclization reactions
have been reported: (a) Askam, V.; Quazi, T. U. J. Chem. Soc., Chem.
Commun. 1975, 798. (b) Sedgeworth, J.; Proctor, G. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2677.
(11) Harding, K. E.; Clement, B. A.; Moreno, L.; Peter-Katalinic, J.
J. Org. Chem. 1981, 46, 940.
(12) (a) Lennon, M.; McLean, A.; McWatt, I.; Proctor, G. R.
J. Chem. Soc., Perkin Trans. 1 1974, 1828. (b) Frew, A. J.; Proctor, G. R.
J. Chem. Soc., Perkin Trans. 1 1980, 1245. (c) Frew, A. J.; Proctor, G. R.;
Silverton, J. V. J. Chem. Soc., Perkin Trans. 1 1980, 1251.
Org. Lett., Vol. 13, No. 4, 2011
665

Scheme 3. Preparation of Cyclization Substratesa
Figure 2. Single-crystal X-ray structure of 10a.
solvents like DMF or DMSO at 145 °C only resulted in
decomposition (entry 6).
Lowering the concentration was found to be beneficial
with the optimal reaction being performed at 0.05 M to
obtain a yield of 80% (entry 7). Decreasing the amount of
TsOH or increasing the temperature by using boiling
mesitylene proved to be less favorable, and a control
experiment without acid showed no product formation
whatsoever.14 After determination of the optimal reaction
conditions the scope of the reaction was explored by
preparing seven-membered ring substrates with various
β-substituents (R) (with respect to the ketone).
The two-step procedure developed for the preparation of
9a (Scheme 2) was successfully applied to the synthesis of
various cyclic 1,5-ketoesters 9 (Scheme 3). Aryl, alkenyl,
and alkyl substituents were introduced opening the route to
functionalized bicyclo[3.2.1]alkenediones. In the case of the
N-Boc-protected indole substituent of 8d, the conditions of
the employed Krapcho reaction also resulted in the removal
of the Boc group.15 Application of the optimized cycliza-
tion conditions to these new substrates allowed the pre-
paration of a range of new bicyclic products (Scheme 4).
Phenyl- and 4-trifluoromethyl phenyl-substituted sub-
strates both gave high yields of the product, while electron-
rich aryl substituents led to the expected product but with
slightly lower yields (67% and 63% for 10c and 10d,
respectively). Methyl- and n-butyl-substituted keto esters 9e
and 9f successfully led to the alkyl-substituted bicyclo-
[3.2.1]alkenediones 10e and 10f in 59% and 57% yields,
respectively. Disappointingly, when the same procedure was
applied to the benzyloxyethyl-substituted substrate 9g no
reaction was observed, and a longer reaction time only resulted
in slow degradation. More interestingly, product 10h was
formed with 78% yield giving a direct access to the core of
vitisinol D (1). Pleasingly, when the 8-membered ring analo-
gue of 9a was submitted to the optimized cyclization condi-
tions, the bicyclo[3.3.1]alkenone 10i was obtained in 53%
yield, proving the potential access to larger ring systems.16
The R-allylated product 10j isolated in 46% yield from 9j17
demonstrates the possibility of accessing more functionalized
(14) Since TBAF was described as a basic promoting agent for this
type of reaction (ref 8) TsOH was also replaced by TBAF, but only
decomposition of the starting material was observed in this case.
(15) Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987,
52, 19.
(16) However, the 9-membered cyclization substrate proved to be
unreactive under TsOH catalysis, and no product was observed.
(17) For the preparation of 9j from 9e, see the Supporting Informa-
tion.
a Yields after flash chromatography. b Used crude. c Yield over two
steps.
666
Org. Lett., Vol. 13, No. 4, 2011

Scheme 4. Synthesis of Bicyclo[3.n.1]alkenedionesa
Scheme 5. One-Pot Cyclization/Protectiona
a Yields after purification by flash chromatography.
complete conversion of the starting material 9a to its
cyclization product, ethylene glycol was injected into the
same pot, and the monoprotected bicyclic product 11a was
afforded in 71% yield (Scheme 5). When the same procedure
was applied to the keto ester 9c, the corresponding p-MeO
derivative was afforded in 54% yield for the sequence.
In summary we have described an efficient TsOH-cata-
lyzed route to functionalized bicyclo[3.n.1]alkenediones.
Products were typically isolated in good overall yield, and
it has been shown that a one-pot procedure allows access to
a monoprotected form of these products. This methodo-
lody is currently being applied to the total synthesis of
vitisinol D (1) and related compounds, and the results will
be reported in due course.
Acknowledgment. We thank the EPSRC (a PDRA Fel-
lowship to B.D. and a Leadership Fellowship to D.J.D.),
Andrew Kyle of the Department of Chemistry, University
of Oxford, for X-ray structure determination, and the
Oxford Chemical Crystallography Service for the use of
the instrumentation.
a Yields after flash chromatography. b Using 20 mol % of TsOH.
cores. This last result is of particular interest considering that
a large number of natural products bear subsituents in the
R-position, like the prenyl group of garsubellin A (2).
One benefit of this method, as indicated by our initial
discovery (Scheme 1), is that the reactive carbonyl groups
can be differentiated under the employed reaction conditions
by the staged addition of ethylene glycol. Following the
Supporting Information Available. Experimental details
and characterization data for all new compounds and CIF
file of 10a. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
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