Studies directed toward the synthesis of terreulactone A: Rapid construction of the A, B, C rings

Article abstract of DOI:10.1021/ol052618p

An efficient, rapid synthesis of the A, B, C rings of terreulactone A is described. Key steps in the synthesis include a diastereoselective benzylic acid rearrangement to create the desired quaternary center at C₂ and a mild bromolactonization

Full text of DOI:10.1021/ol052618p

ORGANIC
LETTERS
2006
Vol. 8, No. 3
423-425
Studies Directed toward the Synthesis
of Terreulactone A: Rapid Construction
of the A, B, C Rings
Haibo Liu,† Dionicio R. Siegel,† and Samuel J. Danishefsky*,†,‡
Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, New York, New York
10027, and Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer
Research, 1275 York AVenue, Box 106, New York, New York 10021
s-danishefsky@ski.mskcc.org
Received October 28, 2005
ABSTRACT
An efficient, rapid synthesis of the A, B, C rings of terreulactone A is described. Key steps in the synthesis include a diastereoselective
benzylic acid rearrangement to create the desired quaternary center at C2 and a mild bromolactonization to assemble the lactonic ring A.
Acetylcholine is a neurotransmitter that plays an essential
role in memory and learning. Markedly decreased levels
of acetylcholine are a hallmark of Alzheimer’s disease.1
Acetylcholinesterase (AChE), the enzyme that degrades
acetylcholine to its inactive form (choline), has thus emerged
as a promising molecular target in the treatment of Alz-
heimer’s disease.2 Presumably, inhibition of AChE would
result in increased levels of acetylcholine, which could lead
to improved neural functioning in Alzheimer’s patients.
Needless to say, while this approach certainly seems reason-
able, Alzheimer’s is a complex disease and the drugs
currently available which were developed on the basis of
this premise have not yet been established as clinically viable
agents.
potent and highly selective inhibitors of AChE, with IC50
values ranging from 0.06 to 0.42 µM.3 Terreulactone A (1)
is a sesquiterpene lactone type meroterpenoid (Figure 1). The
Figure 1. Structure of terreulactone A.
Terreulactones A-D, microbial metabolites isolated from
solid-state fermentation of Aspergillus terreus F000501, are
† Sloan-Kettering Institute for Cancer Research.
‡ Columbia University.
(1) (a) Davies, P.; Maloney, A. J. F. Lancet 1976, 2, 1403. (b)
Whitehouse, P. J.; Price, D. L.; Struble, R. G.; Clarke, A. W.; Coyle, J. T.;
DeLong, M. R. Science 1982, 215, 1237.
(2) (a) Davis, K. L.; Mohs, R. C. Am. J. Psychiatry 1982, 139, 1421. (b)
Thal, L. J.; Fuld, P. A.; Masur, D. M.; Sharpless, N. S. Ann. Neurol. 1983,
13, 491.
structural complexity of terreulactone A (1), combined with
its promising biological profile (IC50 of 0.23 µM), prompted
us to launch a program toward its total synthesis.
Our strategy toward the synthesis of terreulactone A (1)
is outlined in Scheme 1. Thus, intermediate 3, itself obtained
from the readily available Wieland-Miescher ketone (2),
10.1021/ol052618p CCC: $33.50
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would be subjected to a stereoselective ring contraction
protocol to afford 4.4 Lactonization followed by appropriate
functional group management could ultimately provide
intermediate 5, which we expected would be amenable to
conversion to 6 in a fairly straightforward fashion. Finally,
we hoped to couple 6 with a suitable E,F progenitor, 7 (for
instance, according to the [3 + 3] annulation strategy
developed by Hsung).5
ring contracted intermediate 10. Unfortunately, extensive
attempts to bring about the desired rearrangement in any
experimental mode were unsuccessful, resulting only in
decomposition or unproductive side reactions.
Fortunately, in the course of preparing intermediate 8, we
had serendipitously discovered that an attempted one-step
oxidation of 11 to 12 proceeded smoothly to provide the
ring-contracted intermediate 13 as a single diastereomer
(Scheme 3a). NOE analysis of the reduced diol congener of
13 revealed that the newly generated C2 stereocenter pos-
sessed the configuration required for the natural product. A
rationale for this stereochemical outcome is provided in
Scheme 3b. Thus, migration of the gem-dimethyl bearing
carbon (through intermediate A) is favored on the basis of
general considerations of migratory aptitude, which is
sensitive to stability of cationoid character. Moreover,
intermediate B would presumably be destabilized by 1,3,5-
triaxial abutments. Encouraged by this unexpected result, we
set out to modify the substrate to incorporate the requisite
C1 functionality.
Scheme 1
Scheme 3
We originally hoped that an epoxide of the type 8 might
be induced to undergo ring contraction to afford the 6,5-
fused bicyclic framework possessing the requisite function-
alization at C2 and C1.6 Thus, under acidic conditions, we
anticipated that C3 would migrate to open the epoxide,
affording an oxonium intermediate which would subse-
quently be trapped to afford 9 (Scheme 2). Alternatively,
Scheme 2
Our synthesis commenced with the chemo- and stereose-
lective reduction of the Wieland-Miescher ketone (2)
followed by protection of the resultant alcohol to afford 14
(Scheme 4). Dimethylation of 14 provided 15, which was
then subjected to a two-step oxidation sequence to afford
the enol intermediate 3. The next task would be the
introduction of the C1 functionality. We elected to install a
sulfur group, which would eventually be unmasked through
a Pummerer rearrangement to afford the requisite C1 carbo-
nyl. Thus, treatment of 3 with the electrophilic sulfurizing
reagent PhSO2SPh led to installation of the thiophenyl group
at C1. The crude intermediate was heated to 110 °C in
degassed aqueous KOH solution4 and then treated with MeI
and NaH to afford the ring-contracted intermediate 16 in 45%
overall yield for the three steps. The carboxylic acid was
then liberated under Gassman’s conditions7 to provide
under nucleophilic conditions, a tetrahedral intermediate
could be envisioned which, upon collapse, might afford the
(3) (a) Kim, W.-G.; Cho, K.-M.; Lee, C.-K.; Yoo, I.-D. Tetrahedron
Lett. 2002, 43, 3197. (b) Cho, K.-M.; Kim, W.-G.; Lee, C.-K.; Yoo, I.-D.
J. Antibiot. 2003, 56, 344. (c) Kim, W.-G.; Cho, K.-M.; Lee, C.-K.; Yoo,
I.-D. J. Antibiot. 2003, 56, 351.
(4) Georgian, V.; Kundu, N. Tetrahedron 1963, 19, 1037.
(5) (a) Zehnder, L. R.; Hsung, R. P.; Wang, J. S.; Golding, G. M. Angew.
Chem., Int. Ed. 2000, 39, 3876. (b) Cole, K. P.; Hsung, R. P.; Yang, X.-F.
Tetrahedron Lett. 2002, 43, 3341. (c) Cole, K. P.; Hsung, R. P. Tetrahedron
Lett. 2002, 43, 8791.
(6) (a) Matoba, K.; Karibe, N.; Yamazaki, T. Chem. Pharm. Bull. 1984,
32, 2639. (b) Grant, P. K.; Lynch, G. P.; Simpson, J.; Wong, G. Aust. J.
Chem. 1993, 46, 1125.
(7) Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42, 918.
Org. Lett., Vol. 8, No. 3, 2006
424

Scheme 4
Figure 2. ORTEP representation of the X-ray crystal structure of
18.
In conclusion, the synthesis of the fully functionalized
A,B,C ring system of terreulactone A has been accomplished.
A key transformation involves a distereoselective ring
contraction of the diketone (3) to afford a 6,5-fused bicyclic
system.10 Studies toward the completion of the synthesis of
terreulactone A (1) are under investigation.
intermediate 4. Upon examination of a number of lacton-
ization conditions, we found that treatment of 4 with NBS
at 0 °C afforded the bromolactone 17 in 91% yield. Attempts
to reduce the bromide were complicated by a competition
reaction involving regeneration of the alkene; however, this
problem was circumvented through recourse to neat SnBu3H
reaction conditions. We note, parenthetically, that when the
reaction was allowed to proceed for longer than ap-
proximately 5 min, significant amounts of sulfur-reduced side
product were observed. The structure of intermediate 18 has
been confirmed through X-ray crystallography (Figure 2).
Intermediate 18 was subjected to MOM deprotection
conditions followed by oxidation of the resultant alcohol to
afford ketone 20. The latter was converted to the vinyl iodide
21 according to the Barton protocol.8 Finally, 21 was
advanced to the key coupling partner, enal 8, through
palladium-mediated carbonylation.9
Acknowledgment. This work was supported by a grant
from the National Institutes of Health (HL25848).
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds,
including X-ray data for intermediate 18 (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
OL052618P
(9) Baillargeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452.
(10) For previous instances of ring contractions based on processes
mechanistically related to the benzylic acid rearrangement, see: (a) Stoltz,
B. M.; Wood, J. L. Tetrahedron Lett. 1996, 37, 3929 (b) Grieco, P. A.;
Collins, J. L.; Huffman, J. C. J. Org. Chem. 1998, 63, 9576.
(8) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron 1988,
44, 147.
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