Total synthesis of garsubellin A

Article abstract of DOI:10.1021/ja057418n

A concise approach to the laboratory synthesis of garsubellin A is described. Garsubellin A, an effective inducer of choline acetyltransferase (ChAT), has been shown to have potential as a therapeutic agent for the treatment of Alzheimer's disease. Starti

Full text of DOI:10.1021/ja057418n

Published on Web 12/30/2005
Total Synthesis of Garsubellin A
Dionicio R. Siegel and Samuel J. Danishefsky*
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue,
New York, New York 10021, and Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway,
New York, New York 10027
Received October 31, 2005; E-mail: s-danishefsky@mskcc.org
Scheme 1a
Our laboratory has recently directed considerable attention to
natural products with properties that might be exploitable in the
treatment of neurodegenerative diseases. We view such natural
products, obtained via total synthesis, as particularly valuable lead
structures around which to organize discovery research efforts with
a view to enhancing and optimizing biological function.
In this connection, the triterpene garsubellin A (1), first isolated
by Fukuyama and colleagues from the wood of Garcinia subel-
liptica (used as a windbreak on the island of Okinawa), has emerged
as a fascinating target for interactive chemical and biological
investigations.1 Garsubellin A enhances choline acetyltransferase
(ChAT) activity by 154% in P10 rat septal neurons relative to a
control.1 In principle, a “small molecule” enhancer of ChAT could
trigger enhanced cerebral acetylcholine levels in a clinical setting.
Recalling that Alzheimer’s disease is associated with a significant
a Key: (a) n-BuLi, Et2O, 0 °C then prenylbromide; (b) K2OsO4‚2H2O,
loss (60-90%) of ChAT activity in the hippocampus, the potential
K2CO3, K3Fe(CN)6, CH3SO2NH2, t-BuOH-H2O, 23 °C; (c) TsOH‚H2O,
of a small molecule enhancer of this enzyme warrants further study.3
2,2-dimethoxypropane, acetone, 23 °C; (d) TBAF, THF, 23 °C (70% from
2); (e) Pd(OAc)2, PPh3, Ti(i-PrO)4, allyl methyl carbonate, C6H6, 80 °C,
62%.
We note in passing that most of the “anti-Alzheimer” drugs in use
today are dedicated to the proposition of enhancing acetylcholine
levels by inhibiting the enzyme cholinesterase, thereby attenuating
dissipation of the ester bond.
From a strictly chemical perspective, garsubellin A mobilizes
formidable structural defenses against prospective total syntheses.
Even upon cursory inspection, one notes its trioxygenated bicyclo-
[3.3.1]nonane skeleton, bearing a gem dimethyl group at C9, two
prenyl functions at C2 and C8, a fused tetrahydrofuran function
with its own stereogenic issues at C18 and, finally, an isobutyryl
function at the bridgehead C6 (comprising a â,â′-bis-1,3-diketo
network with C1 and C5).
Not surprisingly, the goal of a garsubellin total synthesis has
caught the fancy of many research groups.4 Indeed several
components of the garsubellin problem had already been solved
by rather ingenious chemistry.4 However, as is often the case with
difficult puzzles, the complexity of the complete garsubellin
problem transcends the sum of the challenges provided by its local
sectors. Recently, Shibasaki and co-workers described the first total
synthesis of garsubellin A.5 Below we describe our total synthesis
of garsubellin A.6 While we report here the synthesis of the
racemate, as will be seen, the charted pathway enables a reagent-
controlled total synthesis of the natural antipode of 1.
Though the total synthesis described herein was not intended as
an exercise in biosimulation, we did take note that, hypothetically,
dearomatization of a substituted phloroglucinol matrix (vide infra)
could, with proper orchestration, serve to provide a pathway
allowing for rapid progress toward our goal. Assembly of phenol
5 was accomplished in a four-step sequence, as shown (Scheme
1). Thus, selective prenylation of the differentially protected
phloroglucinol derivative 2 was accomplished by ortho-metalation
between the methoxy groups, followed by alkylation with prenyl-
bromide.7 Dihydroxylation of the newly installed prenyl group8
followed by acetonide formation and TBAF desilylation provided
the required phenol 5 in 70% yield over the four-step sequence as
a crystalline solid (144 °C).
The next major challenge in our approach entailed generating a
formal para-aromatic Claisen product, or an equivalent dearomatized
system from phenol 5. This important goal was accomplished by
allylation of 5 at the para position, as shown (see compound 6).9
The driving force for this transformation likely lies in the stability
imparted by the doubly vinylogous carbonate moiety (see asterisks).
The most obvious pathway for this transformation would involve
direct allylation at the para carbon. An alternative pathway would
consist of O-allylation, soon followed in sequence by rapid
o-Claisen and Cope-like rearrangements to reach 6.10 The operative
route in the case at hand remains to be rigorously demonstrated.
In practice, treatment of acetonide 6 with perchloric acid in a
water-dioxane mixture at elevated temperature presumably led to
diol 7, which was, in fact, not isolated (Scheme 2). The first
detectable kinetic event was the formation of a mixture of Michael-
like cyclization products, 8a, 8b and 9a, 9b, which are equilibrating
during the experiment. A key finding was the discovery that after
extended time the 8, 9 mixture progressed to a single compound,
10. It seems reasonable that the positioning of the allyl and
2-propanol appendages on opposite faces of the tetrahydrofuran
ring (see compounds 9) would facilitate the â-elimination of
methanol providing 10,11 thereby driving the diastereoselective
cyclization process. Following prolonged reaction as shown, 10
underwent cleavage of the vinylogous methyl carbonate, yielding
11 in 71% yield. The first step in the fashioning of the bicyclo-
[3.3.1]-bridged ring system was accomplished by conversion of 11
to 12 via olefin cross metathesis (Scheme 3).4d,12 Iodocarbocycliza-
tion of 12 provided 13 using standard iodolactonization conditions
9
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J. AM. CHEM. SOC. 2006, 128, 1048-1049
10.1021/ja057418n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
cyclopropanation reaction occurred at -78 °C. Upon warming, a
second exchange with the vinyl iodide produced the corresponding
vinyl Grignard intermediate, which, in a second allylation, led to
15.15 Treatment of 15 with TMSI generated 16. Keck radical
allylation of the secondary iodide of 16 cleanly installed the
prerequisite allyl group of the required relative configuration
(Scheme 4).16 A second olefin cross metathesis converted both allyl
groups to prenyl moieties, yielding deisobutyryl garsubellin A (17)
in 73% yield.4d,12 Treatment of 17 with LDA and TMSCl followed
by iodination provided 18 in variable yields. A second magnesium-
iodine exchange14 cleanly generated the bridgehead nucleophile,
which upon treatment with isobutyraldehyde provided the aldol-
type adduct 19 as a mixture of isomers. Dess-Martin oxidation17
followed by cleavage of the TMS ether provided garsubellin A,
matching the reported spectra.1 With a practical route to garsubellin
A in hand, studies are underway to help identify the therapeutically
pertinent mode of action of this prospective agent. Similarly,
analogues of garsubellin A will be prepared in efforts to improve
biological performance.
Scheme 3a
Acknowledgment. This work was supported by the National
Institutes of Health (S.J.D. CA28824).
Note Added after ASAP Publication. The uncorrected proof
version of this paper was inadvertently published on the ASAP
Web site on December 30, 2005. The corrected final version was
published on January 5, 2006.
Supporting Information Available: Experimental procedures and
characterization for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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