Synthesis of (+/-)-clusianone: High-yielding bridgehead and diketone substitutions by regioselective lithiation of enol ether derivatives of bicyclo[3.3.1]nonane-2,4,9-triones

Article abstract of DOI:10.1021/ol0620592

A concise synthesis of the polyprenylated acylphloroglucinol natural product, clusianone, in racemic form, is described. An Effenburger cyclization generated a core bicyclo[3.3.1]nonane-trione structure, which was then elaborated by means of regioselectiv

Full text of DOI:10.1021/ol0620592

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5283-5285
Synthesis of (+/−)-Clusianone:
High-Yielding Bridgehead and Diketone
Substitutions by Regioselective
Lithiation of Enol Ether Derivatives of
Bicyclo[3.3.1]nonane-2,4,9-triones
Vincent Rodeschini, Nadia M. Ahmad, and Nigel S. Simpkins*
School of Chemistry, The UniVersity of Nottingham, UniVersity Park,
Nottingham, NG7 2RD U.K.
nigel.simpkins@nottingham.ac.uk
Received August 21, 2006
ABSTRACT
A concise synthesis of the polyprenylated acylphloroglucinol natural product, clusianone, in racemic form, is described. An Effenburger
cyclization generated a core bicyclo[3.3.1]nonane-trione structure, which was then elaborated by means of regioselective lithiation reactions.
Plants and trees of the family Clusiaceae (Guttiferae) are a
rich source of polyprenylated acylphloroglucinols (PPAPs),
characterized by a bicyclo[3.3.1]nonane-trione core structure
bearing additional acyl and prenyl substituents, e.g., garsu-
bellin A (1), hyperforin (2), and clusianone (3) (Figure 1).1
1997, due to its ability to induce choline acetyltransferase,
a key enzyme involved in acetylcholine biosynthesis.2
Hyperforin (2) is thought to be the major bioactive constitu-
ent from Hypericum perforatum (St. John’s wort (SJW)),
which has well-known antidepressant properties.3 The use
of SJW extracts for the treatment of mild to moderate
depression is widespread in Europe but remains controversial
in terms of efficacy, especially with regard to undesirable
prescription drug interactions.4 Clusianone (3) has been
known since 1976, the structure originally being determined
by X-ray crystallography,5 although more recently there was
some confusion of this compound with a C-7 epimer.6 Recent
(2) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997,
45, 947-949.
(3) (a) Structure: Bystrov, N. S.; Chernov, B. K.; Dobrynin, V. N.;
Kolosov, M. N. Tetrahedron Lett. 1975, 2791-2794. (b) Biosynthesis:
Adam, P.; Arigoni, D.; Bacher, A.; Eisenreich, W. J. Med. Chem. 2002,
45, 4786-4793.
(4) Madabushi, R.; Frank, B.; Drewelow, B.; Hartmut, D.; Butterweck,
V. Eur. J. Clin. Pharm. 2006, 62, 225-233.
(5) McCandlish, L. E.; Hanson, J. C.; Stout, G. H. Acta Cryst., Sect. B
1976, 32, 1793-1801.
Figure 1. Representative PPAPs.
Garsubellin A (1) has attracted significant synthetic
attention since its isolation from Garcinia subelliptica in
(1) (a) Ciochina, R.; Grossman, R. B. Chem. ReV. 2006, 106, 3963-
3986. (b) Verotta, L. Phytochem. ReV. 2002, 1, 389-407.
10.1021/ol0620592 CCC: $33.50
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screening has ascribed potent anti-HIV and cancer chemo-
preventive properties to this compound and close natural
relatives.6a,7
PPAPs have stimulated much synthetic activity; several
groups have described progress toward specific members of
the PPAP family,8 but only very recently has 1 succumbed
to total synthesis by the groups of Shibasaki9 and Danishef-
sky.10
bridgehead substituent. Direct substitution at the vinylic
position (C-3) by metalation also appeared viable.14 Here
we present preliminary results which serve to validate this
strategy and which enable a very concise synthesis of 3
(Scheme 2).
Scheme 2
The idea of constructing either naturally occurring PPAPs
or unnatural derivatives, by appending substituents to a
common [3.3.1]-trione core system, is an attractive one in
terms of accessing diverse structures for probing the SAR
in these systems. In this context, we noted the very rapid
access to an appropriate trione, described by Spessard and
Stoltz in their elegant approach to garsubellin A (Scheme
1).11
Scheme 1
They accomplished diastereoselective (at C-7) conversion
of enol silane 4 into the bridged trione 5 by reaction with
malonyl dichloride, in a modification of a procedure origi-
nally described by Effenburger and co-workers.12 The yield
of 5 was modest, but the ketone corresponding to 4 could
also be recovered. Unfortunately, enol derivatives having
additional R- and R′-substituents, destined to emerge as the
C-1 and C-5 bridgehead groups in 5, were even less
satisfactory participants in the cyclization.
On the basis of our successful bridgehead lithiation-
substitution results on related [3.3.1] systems,13 we antici-
pated adopting this method for appending appropriate
substituents onto a core structure 5 at either (or both)
As installation of a substituent at the very hindered C-1
position of 5 was considered an extreme test of our strategy,15
we instead opted to focus on substitution reactions at C-3
and C-5 of a core trione (or derivative thereof). With
clusianone in mind as the ultimate target, we prepared an
enol derivative incorporating the required C-1 prenyl sub-
stituent.
Prenylation of the known vinylogous ester 6 gave 7,16
which was then reacted with MeLi and hydrolyzed under
mildly acidic conditions to give enone 8. Copper-catalyzed
Grignard addition to this tetrasubstituted system proved more
effective than the use of stoichiometric cuprate reagents and
provided the ketone product as a mixture of diastereoisomers
9 and 10, with the former predominating. A regioisomeric
mixture of enol ethers 11 and 12 was then easily prepared
using established conditions.17
(6) (a) Piccinelli, A. L.; Cuesta-Rubio, O.; Chica, M. B.; Mahmood, N.;
Pagano, B.; Pavone, M.; Barone, V.; Rastrelli, L. Tetrahedron 2005, 61,
8206-8211. (b) Delle Monache, F.; Delle Monache, G.; Gacs-Baits, E.
Phytochemistry 1991, 30, 2003-2005.
(7) Ito, C.; Itoigawa, M.; Miyamoto, Y.; Onoda, S.; Sundar Rao, K.;
Mukainaka, T.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2003,
66, 206-209.
(8) For full listings of previous efforts, see refs 9 and 10 and also: (a)
Mehta, G.; Bera, M. K. Tetrahedron Lett. 2006, 47, 689-692. (b) Kraus,
G. A.; Jeon, I. Tetrahedron 2005, 61, 2111-2116. (c) Lavigne, R. M. A.;
Riou, M.; Girardin, M.; Morency, L.; Barriault, L. Org. Lett. 2005, 7, 5921-
5923.
Our explorations of the Effenburger-type cyclization
indicated rather similar effectiveness of methyl enol ethers
such as 11/12 and the corresponding enol silanes (OTBS),
and either regioisomer appears to participate in the process.
(9) Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 14200-14201.
(14) Miyata, O.; Schmidt, R. R. Tetrahedron Lett. 1982, 23, 1793-1796.
(15) The Danishefsky Garsubellin A synthesis features bridgehead
substitution at this position, which proved less than trivial, due to a 25-
36% yield in the key bridgehead iodination process (via lithiation-
silylation).
(16) Majetich, G.; Hull, K.; Casares, A. M.; Khetani, V. J. Org. Chem.
1991, 56, 3958-3973.
(17) Heiszwolf, G. J.; Kloosterziel, H. J. Chem. Soc., Chem. Commun.
1966, 51.
(10) Siegal, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128,
1048-1049.
(11) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943-1946.
(12) Scho¨nwa¨lder, K.-H.; Kollatt, P.; Stezowski, J. J.; Effenburger, F.
Chem. Ber. 1984, 117, 3280-3296.
(13) Giblin, G. M. P.; Kirk, D. T.; Mitchell, L.; Simpkins, N. S. Org.
Lett. 2003, 5, 1673-1675.
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In the event, cyclization under conditions similar to those
described by Effenburger was predictably low yielding but
provided viable quantities of material for completion of our
synthesis. Thus, reaction of the mixture 11/12 with malonyl
dichloride under the described conditions gave the desired
trione 13 (ca. 30% crude material), as a single diastereomer,
which could be separated by base extraction from recovered
ketones 9/10 (55% recovered) (Scheme 3).18
Scheme 4
Scheme 3
The synthesis described here generates the naturally
occurring PPAP in racemic form in only nine synthetic steps
and in 12% overall yield (even accounting for a 24% yield
for the crucial bridge-forming process) from 6. The synthesis
underlines the brevity imbued by teaming the powerful
Effenburger cyclization with regioselective lithiation pro-
cesses. The low yields that accompany the key cyclization
are not easily rectified by minor variations to reaction
conditions, and we are presently investigating a more
substantial redesign of this process as a means to substantially
improve its efficiency.
Trione 13 was O-methylated under acidic conditions prior
to purification, providing the single regioisomeric vinylogous
ester 14 in 24% overall yield from 11 and 12.19
The vinylogous ester, 14, was then converted into the
natural product clusianone, as shown in Scheme 4. First,
treatment of 14 with excess LDA, followed by alkylation
with prenyl bromide, gave 15, with bridgehead substitution
occurring in 91% yield.20 Acylation at C-3 by the action of
LTMP followed by benzoyl chloride was equally efficient.21
Finally, hydrolysis of the vinylogous ester, under conditions
akin to those described previously,11 gave clusianone, as a
mixture of enol tautomers spectroscopically identical with
the reported data.6a,22
Acknowledgment. We acknowledge DEFRA for support
of V.R. and GSK, Harlow, U.K., and the University of
Nottingham for support of N.M.A. N.S.S. and N.M.A. would
like to thank Dr. Simon E. Ward (GSK, Harlow) for his
support of this work. We also thank Prof. Luca Rastrelli
(University of Salerno) for kindly sending us copies of NMR
spectra of natural clusianone.
(18) The stereochemical assignment of 13 was initially made by analogy
with the result of Spessard and Stoltz. The assignment was validated by
the eventual conversion of this intermediate into the natural product. In
addition, certain intermediates show distinctive large J-values between H-7
and one of the C-6 CH2 protons in the 1H NMR, demonstrating the
pseudoaxial (therefore endo) nature of H-7.
(19) Methylation under basic conditions (K2CO3, Me2SO4, acetone)
furnished an equimolar mixture of 14 and the regioisomeric vinylogous
ester, methylated at C-2. Equilibration studies indicated that isomer 14 is
the thermodynamically favoured one.
Supporting Information Available: Complete experi-
mental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0620592
(20) The use of 2 equiv of base proved optimal, but we could find no
evidence for dianion formation.
(21) For a recent example of a similar metalation, see: Zapf, C. W.;
Harrison, B. A.; Drahl, C.; Sorensen, E. J. Angew. Chem., Int. Ed. 2005,
44, 6533-6537.
(22) Further evidence for the identity of our synthetic sample was
obtained by comparison of spectral data of intermediate 16 with those of a
previously reported methylated derivative of clusianone (see Supporting
Information): De Oliveira, C. M. A.; Porto, A. M.; Bittrich, V.; Vencato,
I.; Marsaioli, A. J. Tetrahedron Lett. 1996, 37, 6427-6430.
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