A New Synthetic Approach to the Polycyclic Polyprenylated Acylphloroglucinols

Article abstract of DOI:10.1021/ol0357907

(Equation presented) The three-carbon α,α′-annulation of a sterically hindered cyclic β-keto ester can be achieved by alkynylation with 3,3-dietnoxypropyne, syn reduction of the alkyne with Co ₂(CO)₈ and Et₃SiH, and an int

Full text of DOI:10.1021/ol0357907

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4619-4621
A New Synthetic Approach to the
Polycyclic Polyprenylated
Acylphloroglucinols
Roxana Ciochina and Robert B. Grossman*
Department of Chemistry, UniVersity of Kentucky, Lexington, Kentucky 40506-0055
robert.grossman@uky.edu
Received September 16, 2003
ABSTRACT
The three-carbon r,r′-annulation of a sterically hindered cyclic â-keto ester can be achieved by alkynylation with 3,3-diethoxypropyne, syn
reduction of the alkyne with Co2(CO)8 and Et3SiH, and an intramolecular aldol reaction. The method is potentially useful for the synthesis of
nemorosone, hyperforin, and other polycyclic polyprenylated acylphloroglucinols.
In recent years, widespread interest in the antidepressant
activity of Hypericum perforatum (St. John’s wort) has
stimulated much investigation into metabolites from the
Guttiferae. Studies of the plants from this family have
revealed a class of compounds, the polycyclic polyprenylated
acylphloroglucinols (PPAPs), with fascinating chemical
structures and intriguing biological activities. The PPAPs
feature a highly oxygenated and densely substituted bicyclo-
[3.3.1]nonane-2,4,9-trione core to which are attached an acyl
group at C(1) or C(3) and prenyl or C10H17 side chains.1
Secondary cyclizations may involve the â-diketone and
pendant olefinic groups, affording adamantanes, homoada-
mantanes, or pyrano-fused structures. Various PPAPs have
been found to be antibiotics against multidrug-resistant S.
aureus,2 stimulators of choline acetyltransferase,3 and inhibi-
tors of DNA topoisomerase I and II,4 tubulin depolymeri-
zation,5 and neurotransmitter reuptake.6
The combination of intriguing biological activity and
challenging structure makes the PPAPs appealing targets for
organic synthesis, but surprisingly few model studies and
no total syntheses of these compounds have appeared. The
five model studies that have appeared to date have used an
R,R′-annulation of a cyclohexanone derivative to construct
the key bicyclo[3.3.1]nonane skeleton. In their garsubellin
A model studies, Shibasaki used a complex sequence that
included C-C bond-forming addition-elimination and aldol
reactions,7 Nicolaou used a “biomimetic” selenocyclization
of a cyclic â-keto ester onto a pendant prenyl group,8 and
Stoltz used a tandem Claisen-Dieckmann reaction of ma-
lonyl dichloride.9 In their hyperforin model studies, Kraus
(4) Tosa, H.; Iinuma, M.; Tanaka, T.; Nozaki, H.; Ikeda, S.; Tsutsui,
K.; Tsutsui, K.; Yamada, M.; Fujimori, S. Chem. Pharm. Bull. 1997, 45,
418.
(5) Roux, D.; Hadi, H. A.; Thoret, S.; Gue´nard, D.; Thoison, O.; Pa¨ıs,
M.; Se´venet, T. J. Nat. Prod. 2000, 63, 1070.
(1) Cuesta-Rubio, O.; Velez-Castro, H.; Frontana-Uribe, B. A.; Ca´rdenas,
J. Phytochemistry 2001, 57, 279.
(2) Iinuma, M.; Tosa, H.; Tanaka, T.; Kanamaru, S.; Asai, F.; Kobayashi,
Y.; Miyauchi, K.; Shimano, R. Biol. Pharm. Bull. 1996, 19, 311. Schempp,
C. M.; Pelz, K.; Wittmer, A.; Scho¨pf, E.; Simon, J. C. Lancet 1999, 353,
2129.
(6) Chatterjee, S. S.; Bhattacharya, S. K.; Wonnemann, M.; Singer, A.;
Mu¨ller, W. E. Life Sci. 1999, 63, 499.
(7) Usuda, H.; Kanai, M.; Shibasaki, M. Org. Lett. 2002, 4, 859. Usuda,
H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 3621.
(8) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q.; Kim, S.; Kessabi, J.
Org. Lett. 1999, 1, 807. Nicolaou, K. C.; Pfefferkorn, J. A.; Kim, S.; Wei,
H. X. J. Am. Chem. Soc. 1999, 121, 4724.
(3) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997,
45, 947.
(9) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943.
10.1021/ol0357907 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/01/2003

Scheme 1
Scheme 2a
used an allylation followed by Mn-mediated oxidative
cyclization,10 and, in a very creative approach, Young used
an intramolecular allene-nitrile oxide cycloaddition.11 Nico-
laou’s disconnection was unique: he annulated the gem-
dimethyl-containing ring onto an existing cyclohexanone,
whereas the others annulated the â-diketone-containing ring
onto an existing one.
a (a) NaH, BuLi, DMPU, prenyl bromide, 67%. (b) SnCl4,
CH2Cl2, 84%. (c) (EtO)2CHCtCSnBu3, Pb(OAc)4, 48%. (d)
HCO2H, 71%. (e) Co2(CO)8, 87%. (f) Et3SiH, Me3SiCtCSiMe3,
94%. (g) cat. 6 N aq HCl, 72%, ca. 1:1 dr.
We decided to focus our own initial efforts in this area
on the type A PPAP, nemorosone (Scheme 1),1,12 because
we thought that its fairly simple structure relative to other
PPAPs would present fewer hurdles as we developed our
methodology. Our retrosynthetic analysis of nemorosone had
us mask the sensitive prenyl groups as more robust, tractable
allyl groups until the very end of the synthesis, when they
could be installed by Ru-catalyzed cross-metathesis of 1 with
Me2CdCHMe.9,13 We thought that the C(3) allyl group of 1
could be installed by alkylation of the â-diketone group, the
C(4-5) bond of 1 by an intramolecular aldol reaction of 2,
and the C(1-2) bond of 2 by alkylation of â-diketone 3.
Our previous experience with synthesizing sterically con-
gested compounds by the use of CN groups14 led us to
speculate that a 1-alkynyl group could be added to C(1) of
3 without much steric impedance from the adjacent gem-
dimethyl group. In fact, the Hashimoto and Moloney groups
developed Pb(OAc)4-mediated alkynylations of â-keto esters
in the late 1980s,15,16 although they did not investigate
substrates so hindered as 3. The C-selectivity of the Pb-
mediated alkynylations appealed to us, as did their irrevers-
ibility and neutral conditions, the latter because we did not
want any sterically compressed intermediates to fragment
by retro-Michael, -Claisen, or -Dieckmann reactions. We
decided to alkynylate 3 with commercially available 3,3-
diethoxypropyne; after syn reduction of the CtC bond15 and
acetal hydrolysis to give 2, the unmasked aldehyde could
then engage in an intramolecular aldol reaction at C(5).
We decided to begin our investigation with a model study
(Scheme 2). Addition of prenyl bromide to the dianion of
methyl 3-oxo-6-heptenoate17 in the presence of DMPU gave
diene 4 in 67% yield, and cyclization of 4 with SnCl4
provided cyclohexanone-2-carboxylate 5 in 84% yield.18 The
Pb(OAc)4-mediated R-alkynylation of â-keto ester 5 with
lithiated 3,3-diethoxypropyne failed;15 instead, the major
product was derived from oxidative dimerization of the
alkyne. However, when the corresponding tributylstannylated
alkyne was added to a mixture of 5 and Pb(OAc)4, the desired
alkynylated â-keto ester 6, which contained the two contigu-
ous quaternary centers of the PPAPs, was obtained in 48%
yield.16 Even after flash chromatography, ester 6 was
contaminated with some Bu3SnX residue, but this impurity
was removed in subsequent steps.
Catalytic hydrogenation of the CtC bond of 6 failed, even
at very high pressures (ca. 1000 psi). To reduce the steric
encumbrance around the alkyne, acetal 6 was hydrolyzed to
the aldehyde 7 in neat HCO2H in 71% yield.19 Although
hydrogenation of the CtC bond of 7 proceeded with several
catalysts, reduction of the allyl and formyl groups was often
competitive, and those catalysts that did not also reduce the
allyl group caused the nascent cis enal to isomerize to the
trans isomer.
(10) Kraus, G. A.; Nguyen, T. H.; Jeon, I. Tetrahedron Lett. 2003, 44,
659.
(11) Young, D. G. J.; Zeng, D. J. Org. Chem. 2002, 67, 3134.
(12) de Oliveira, C. M. A.; Porto, A. L. M.; Bittrich, V.; Vencato, I.;
Marsaioli, A. J. Tetrahedron Lett. 1996, 37, 6427. de Oliveira, C. M. A.;
Porto, A. L. M.; Bittrich, V.; Marsaioli, A. J. Phytochemistry 1999, 50,
1073. Cuesta-Rubio, O.; Cuellar Cuellar, A.; Rojas, N.; Velez Castro, H.;
Rastrelli, L.; Aquino, R. J. Nat. Prod. 1999, 62, 1013.
(13) Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002, 4,
1939.
A literature survey revealed very few alternatives to
Lindlar-type hydrogenation for the syn reduction of alkynes
(14) Grossman, R. B. Synlett 2001, 13.
(15) Hashimoto, S.; Miyazaki, Y.; Shinoda, T.; Ikegami, S. J. Chem.
Soc., Chem. Commun. 1990, 1100.
(17) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082.
(18) White, J. D.; Skeean, R. W.; Trammell, G. L. J. Org. Chem. 1985,
50, 1939.
(16) Moloney, M. G.; Pinhey, J. T.; Roche, E. G. J. Chem. Soc., Perkin
Trans. 1 1989, 333.
(19) Gorgues, A.; Simon, A.; Le Coq, A.; Hercouet, A.; Corre, F.
Tetrahedron 1986, 42, 351.
4620
Org. Lett., Vol. 5, No. 24, 2003

1,3-diketone moiety of nemorosone (Scheme 1) and several
other type A PPAPs.
To our knowledge, the conversion of 5 to 9 constitutes
the first application of 3,3-diethoxypropyne to R,R′-annula-
tion, in which it acts as a synthetic equivalent to cis-â-
chloroacrolein. Undoubtedly, Shibasaki was expecting a cis-
â-chloroacrylate to behave similarly when he combined it
with a 2-acylcyclohexanone,7 but in this case, reaction
occurred at the γ-position, not the R-position, of the
nucleophile, and the acrylate-derived π bond of the adduct
had isomerized to the trans configuration, necessitating a
lengthy, awkward, and technically difficult sequence of steps
to achieve the desired aldol reaction.
Figure 1. The polycyclic polyprenylated acylphloroglucinols
(PPAPs).
In conclusion, we have developed a short and efficient
synthetic approach to the bicyclo[3.3.1]nonane skeleton of
the PPAPs that involves a novel three-carbon R,R′-annulation
of a sterically hindered cyclic â-keto ester with 3,3-
diethoxypropyne. The alkynylation reaction permits the
construction of the two contiguous quaternary centers of the
PPAPs in reasonable yield and without complications from
O-alkylation or retro-Michael, -Claisen, or -Dieckmann
reactions. We have also successfully applied a recently
developed syn hydrosilylation20 to the very hindered product
of this alkynylation reaction. The greatest remaining obstacle
to the synthesis of a PPAP is probably the transformation of
the 2-silyl-2-alken-1-ol moiety of 9 into a 2-prenyl-1,3-
diketone. Studies along this line are underway.
in the presence of unhindered alkene and carbonyl groups.
Only one precedent stood out: an alkyne was syn hydrosi-
lylated with Et3SiH via its Co2(CO)6 complex, and terminal
alkenes in the substrate were unaffected.20 We obtained the
Co2(CO)6 complex of 7 in 87% yield, despite the steric
encumbrance around the CtC bond in 7, and treatment of
the complex with excess Et3SiH in the presence of Me3SiCt
CSiMe3 gave the (E)-R-silyl enal 8 in 94% yield with
complete regio- and stereoselectivity. Furthermore, acid-
catalyzed cyclization of 8 cleanly gave separable aldols 9a
and 9b in 72% combined yield (ca. 1:1 crude dr). The faster-
moving, crystalline diastereomer was initially proposed to
1
be 9a because its H NMR spectrum showed long-range
allylic coupling between H(2) and H(4), whereas that of the
slower, liquid diastereomer did not. The assignment of the
former compound as 9a was later confirmed by X-ray
crystallographic analysis. Also, a NOESY spectrum of the
latter compound showed a cross-peak between a resonance
attributed to H(4) and one attributed to H(6) or H(7),
confirming it as 9b. Aldols 9 not only contain the bicyclo-
[3.3.1]nonane skeleton and all three quaternary centers of
the type A PPAPs (Figure 1), but they also contain
functionality that is suitable for elaboration into the 2-prenyl-
Acknowledgment. We thank the NIH (GM61002) for
its support of this work. NMR instruments used in this
research were obtained with funds from NSF’s CRIF
program (CHE-997841) and the University of Kentucky’s
Research Challenge Trust Fund.
Supporting Information Available: Experimental details
for the preparation and full characterization of compounds
1
4-9, X-ray data for 9a, H and 13C NMR spectra of 5-7,
and NOESY spectrum of 9b. This material is available free
(20) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609. Kira,
K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai, S.; Isobe, M. Tetrahedron
2002, 58, 6485.
of charge via the Internet at http://pubs.acs.org.
OL0357907
Org. Lett., Vol. 5, No. 24, 2003
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