Progress toward the Synthesis of garsubellin A and related phloroglucins: the direct diastereoselective synthesis of the bicyclo[3.3.1]nonane core.

Article abstract of DOI:10.1021/ol025968+

[reaction: see text] A highly diastereoselective single-step cyclization reaction provides access to the bicyclo[3.3.1]nonane core of the polyprenylated phloroglucin natural product garsubellin A. Further elaboration to a more functionalized analogue involves a sequential Claisen rearrangement/Grubbs olefin cross-metathesis strategy. Additionally, this strategy was extended to the preparation of the bis-quaternary carbon array found at the bridgehead positions of the phloroglucin natural products.

Full text of DOI:10.1021/ol025968+

ORGANIC
LETTERS
2
002
Vol. 4, No. 11
943-1946
Progress toward the Synthesis of
Garsubellin A and Related
1
Phloroglucins: The Direct
Diastereoselective Synthesis of the
†
Bicyclo[3.3.1]nonane Core
Sarah J. Spessard and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, DiVision of
Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
stoltz@caltech.edu
Received April 3, 2002
ABSTRACT
A highly diastereoselective single-step cyclization reaction provides access to the bicyclo[3.3.1]nonane core of the polyprenylated phloroglucin
natural product garsubellin A. Further elaboration to a more functionalized analogue involves a sequential Claisen rearrangement/Grubbs
olefin cross-metathesis strategy. Additionally, this strategy was extended to the preparation of the bis-quaternary carbon array found at the
bridgehead positions of the phloroglucin natural products.
Alzheimer’s disease affects approximately 4 million Ameri-
cans and is the most common form of dementia. It afflicts
phloroglucin isolated from the wood of Garcinia subellip-
tica. Preliminary studies have shown that garsubellin A
1
4
47% of people over the age of 85, currently the fastest
growing group with respect to the rest of the population.
These statistics necessitate the expedient development of
effective therapeutic agents. Neurodegenerative diseases such
as Alzheimer’s have been attributed to deficiencies in levels
2
of the neurotransmitter acetylcholine (ACh). Thus, inducers
of the enzyme choline acetyltransferase (ChAT), which is
responsible for the biosynthesis of ACh, are potential
3
Alzheimer’s therapeutics. One such biologically active
molecule is garsubellin A (1, Figure 1), a polyprenylated
Figure 1. Structure of garsubellin A (1).
†
This paper is dedicated to our colleague Professor Robert H. Grubbs
on the occasion of his 60th birthday.
(
1) Alzheimer’s Association. Alzheimer’s Vital Statistics. (http://
www.alz.org/research/current/stats.htm).
2) Fundamental Neuroscience; Zigmond, M. J., Bloom, F. E., Landis,
increases in vitro ChAT activity in rat septal neurons by
4
1
54% at a 10 µM concentration.
(
S. C., Roberts, J. L., Squire, L. R., Eds.; Academic Press: San Diego, 1999;
Structurally, garsubellin A is characterized primarily by a
highly oxygenated and densely functionalized bicyclo[3.3.1]-
nonane-1,3,5-trione core. Critical to our retrosynthetic plan-
pp 216-219.
(3) Auld, D. S.; Mennicken, F.; Day, J. C.; Quirion, R. J. Neurochemistry
2
001, 77, 253.
1
0.1021/ol025968+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/04/2002

8
ning was the implementation of a concise and stereocon-
trolled transformation to construct this core system. Two
previous synthetic efforts toward garsubellin A have also
focused on the core: one route utilizes a selenium-mediated
core structure (Figure 2). Therefore, the development of a
facile route to the core structure present in garsubellin A
5
cyclization, the second employs a more traditional Michael/
6
aldol sequence. Described herein is an approach to garsu-
bellin A featuring the construction of the highly oxygenated
[
3.3.1] bicyclic core in a single, diastereoselective cyclization
reaction.
Our retrosynthetic analysis for garsubellin A is outlined
in Scheme 1. It was envisioned that the C(2) prenyl moiety
Scheme 1
Figure 2. Some bicyclic phloroglucin natural products.
could be introduced by either a direct C-alkylation or a late-
stage thermal Claisen rearrangement, followed by an olefin
cross-metathesis reaction. The functionalized bicyclo[3.3.1]-
nonane-1,3,5-trione core (2) could arise from a variety of
two-bond disconnections; however, we reasoned that a
suitably functionalized cyclohexanone enol ether (4) and
malonyl dichloride (3) would be the most direct coupling
partners for a single-step construction of the desired ring
system. This approach was based on the anticipation that
the relative stereochemistry about the core ring structure
would arise via remote induction from the C(8) stereocenter,
thus allowing for an eventual asymmetric synthesis from a
should have broad implications for the preparation of several
bicyclic phloroglucin natural products and synthetic ana-
logues.
In 1984, Effenberger reported the reaction between
1-methoxy-1-cyclohexene and malonyl dichloride to give the
parent bicyclo[3.3.1]nonane system (9) such as the one found
9
in garsubellin A. While this reaction was attractive in that
it provided an effective route to the core framework, it
required that a 4-fold excess of enol ether be employed,
which was to be the more complex subunit in our synthesis.
Furthermore, the cyclization reaction has not appeared in the
subsequent literature and remains a singular example.10
Owing to the potential utility of this cyclization in the context
of the phloroglucin [3.3.1] bicyclic natural products, we
chose to investigate the efficiency and diastereoselectivity
of such cyclizations in a more complex arena. We were
particularly interested in the resulting relative stereochemical
relationship between substitution at C(8) and the malonyl
subunit. Additionally, a more versatile enol ether (i.e.,
trialkylsilyl compared to methyl) would provide a more
convenient entry into the complex systems needed for the
phloroglucins. Therefore, silyl enol ether 14 was targeted as
a reasonable model system for cyclization to the phloroglucin
ring system.
7
single stereogenic center. For the purposes of preliminary
studies, it was expected that readily available racemic enol
ethers of the type 4 would reveal the diastereomeric bias of
such cyclizations.
Interestingly, garsubellin A is a member of a larger family
of biologically relevant prenylated phloroglucin natural
products, all of which possess a similar bicyclo[3.3.1]nonane
(
4) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997,
5, 947.
5) Nicolaou, K. C.; Pfefferkorn, J. A.; Kim, S.; Wei, H. X. J. Am. Chem.
Soc. 1999, 121, 4724.
4
(
(
6) Usuda, H.; Kanai, M.; Shibasaki, M. Org. Lett. 2002, 4, 859.
(7) For general reviews on remote diastereoselective induction in
alkylations of enolate derivatives see: (a) Caine, D. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New
York, 1991; Vol. 3, Chapter 1.1, pp 1-63. (b) Evans, D. A. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3,
Chapter 1, p 1.
The synthesis of silyl enol ether 14 (Scheme 2) com-
11
menced with readily available vinylogous ester 10, which
was enolized by LDA and alkylated with prenyl bromide to
1
2
give 11. Treatment of 11 with methyllithium followed by
(8) For references dealing with the isolation of the compounds 5-8
13
aqueous acid furnished enone 12. Conjugate addition with
shown in Figure 2, see: (a) Cuesta-Rubio, O.; Padron, A.; Castro, H. V.;
Pizza, C.; Rastrelli, L. J. Nat. Prod. 2001, 64, 973. (b) Gurevich, A. I.;
Dobrynin, V. N.; Kolosov, M. N.; Popravko, S. A.; Ryabova, I. D.; Chernov,
B. K.; Derbentseva, N. A.; Aizenman, B. E.; Garagulya, A. D. Antibiotiki
(9) Sch o¨ nw a¨ lder, K.-H.; Kollat, P.; Stezowski, J. J.; Effenberger, F. Chem.
Ber. 1984, 117, 3280.
(
Moscow) 1971, 16, 510. (c) Gustafson, K. R.; Blunt, J. W.; Munro, M. H.
(10) To our knowledge, there are no related cyclizations of more densely
functionalized substrates that utilize a bis-acyl bond construction.
(11) Hara, R.; Furukawa, T.; Kashima, H.; Kusama, H.; Horiguchi, Y.;
Kuwajima, I. J. Am. Chem. Soc. 1999, 121, 3072.
G.; Fuller, R. W.; McKee, T. C.; Cardellina, J. H., II.; McMahon, J. B.;
Cragg, G. M.; Boyd, M. R. Tetrahedron 1992, 48, 10093. (d) Winkelmann,
K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat. Prod. 2001, 64,
7
01.
(12) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.
1944
Org. Lett., Vol. 4, No. 11, 2002

Scheme 2
Scheme 3
Me
1
2
CuLi and subsequent silyl enol ether formation provided
4 in 84% overall yield.1
4,15
With multigram quantities of 14 readily available, we
began to investigate the critical cyclization chemistry with
malonyl dichloride. Following substantial experimentation,
it was found that the ratio of enol ether to acid chloride could
1
7.20,21 Completion of the prenyl installation was ac-
complished by an olefin cross-metathesis using the Grubbs
ruthenium catalyst 18 in the presence of 2-methyl-2-butene
9
be reversed relative to the Effenberger study and that indeed
a TBS enol ether could be employed instead of a methyl
enol ether. Both modifications resulted in considerably
cleaner cyclizations. Under our carefully optimized condi-
tions, treatment of silyl enol ether 14 with 2 equiv of malonyl
2
2
to furnish 19 in 88% yield. Finally, saponification of
vinylogous ester 19 proceeded in good yield to provide the
semifunctionalized garsubellin A core system 20. Overall,
the sequence produced the bis-prenylated bicyclic core of
garsubellin A in just 10 steps.
16
dichloride in CH
2 2
Cl at -10 °C, followed by addition of
aqueous KOH under phase transfer catalysis (-10 f 23 °C),
16
produced a 36% yield of desired bicycle 15. Although the
isolated yields were modest, unreacted enol ether could be
recovered as ketone 13, providing an overall yield of 95%.
Conversion of the recovered ketone to the silyl enol ether,
followed by cyclization, gave a 55% combined yield of trione
Scheme 4
1
1
5 over the 2 cycles. Gratifyingly, the cyclization of 14 to
5 proceeded with complete diastereoselectivity to produce
the desired anti isomer with respect to the malonyl subunit
and the remote prenyl substitution at C(8). The relative
stereochemistry in 15 was unambiguously confirmed by
17
single-crystal X-ray diffraction (Scheme 3).
With a rapid synthesis of bicycle 15 in hand, we turned
our attention to the installation of the C(2) prenyl group
(Scheme 4). While a variety of traditional methods proved
unsatisfactory (e.g., direct C-alkylation, Pd-mediated cou-
plings, etc.), a more stepwise route emerged as the most
effective method. Condensation of bicycle 15 with allyl
alcohol followed by a thermal Claisen rearrangement and
treatment with diazomethane produced the allylated bicycle
18
19
In an attempt to extend this methodology to substrates that
are more relevant to the bicyclic phloroglucins (i.e., direct
cyclizations that produce the bis-quaternary carbon array),
it was found that substituents at the R-positions of the enol
ether greatly affect the reactivity of this system. For example,
under our standard cyclization conditions, the TBS enol ether
derived from 2,6-dimethylcyclohexanone produced virtually
none of the desired cyclized product 22, even with prolonged
reaction times and elevated temperatures. After considerable
optimization, however, bicycle 22 was obtained in 25% yield
(
13) Johnson, W. S.; McCarry, B. E.; Markezich, R. L.; Boots, S. G. J.
Am. Chem. Soc. 1980, 102, 352.
14) Laval, G.; Audran, G.; Galano, J.-M.; Monti, H. J. Org. Chem. 2000,
5, 3551.
15) Duhamel, P.; Hennequin, L.; Poirier, J. M.; Tavel, G.; Vottero, C.
Tetrahedron 1986, 42, 4777.
(
6
(
(
16) Obtained as a 1:1 mixture of equilibrating enol isomers.
(17) Crystallographic data have been deposited at the Cambridge
Crystallographic Data Center under deposition number 173065.
18) Allyl ether 16 was obtained as a single enol ether isomer represented
by the structure shown in Scheme 4 (by NOE analysis).
19) (a) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, Chapter 7.2, pp
(
(
(20) Obtained as a 1:1 mixture of separable enol ether isomers.
(21) Isolated in addition to 30% yield of recovered enol ether 16.
(22) See the preceding article in this issue: Chatterjee, A. K.; Sanders,
D. P.; Grubbs, R. H. Org. Lett. 2002, 4, 1939.
8
27-873. (b) Blechert, S. Synthesis 1989, 71. (c) Ziegler, F. E. Chem. ReV.
1
988, 88, 1423. (d) Ireland, R. E. Aldrichimica Acta 1988, 21, 59.
Org. Lett., Vol. 4, No. 11, 2002
1945

(
47% yield based on recovered ketone 23) by employing the
in a single step. Successful elaboration of ketone 15 (Scheme
4) establishes a viable end-game strategy for the introduction
of the final prenyl group at C(2). We have also demonstrated
the feasibility of this strategy toward the preparation of the
bis-quaternary carbon array found at the bridgehead positions
of the phloroglucin natural products (see Figure 2). Current
efforts are focused on further optimizing this cyclization, as
well as expanding the substrate scope to include fully
elaborated systems relevant to the synthesis of garsubellin
A and related compounds.
methyl enol ether 21 and bis(cyclopentadienyl)hafnium
dichloride as a Lewis acid mediator followed by standard
workup and treatment of the crude reaction mixture with
diazomethane (Scheme 5). Although bicycle 22 is obtained
Scheme 5
Acknowledgment. The authors are grateful to the Cali-
fornia Institute of Technology, the Camille and Henry
Dreyfus Foundation (New Faculty Award to B.M.S.), Merck
Research Laboratories, and Pharmacia (graduate fellowship
to S.J.S.) for generous financial support. The Grubbs,
MacMillan, and Hsieh-Wilson labs are acknowledged for
helpful discussions and the use of chemicals and instrumen-
tation. We thank Larry Henling and Michael Day for solving
the X-ray crystal structure and John Greaves (UCI) for
obtaining high-resolution mass spectra. The authors would
also like to acknowledge Professors Gary Spessard and
Gretchen Hofmeister for helpful discussions and advice.
in modest yield, the direct cyclization to produce the two
bridgehead quaternary carbons present in the phloroglucins
compares well with lengthier procedures to form similarly
substituted systems.23 These results establish the feasibility
of a single-step strategy toward the synthesis of the bicyclic
phloroglucins.
In summary, we have developed a highly diastereoselective
direct cyclization reaction that delivers the bicyclo[3.3.1]-
nonane-1,3,5-trione core of the phloroglucin natural products
Supporting Information Available: Experimental details
and characterization data for all new compounds including
X-ray data for 15. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) For a recent review on the synthesis of [3.3.1] bicyclic compounds,
see: Butkus, E. Synlett 2001, 12, 1827.
OL025968+
1946
Org. Lett., Vol. 4, No. 11, 2002