Cyclic 1,2-Diketones as core building blocks: A strategy for the total synthesis of (-)-terpestacin

Article abstract of DOI:10.1002/chem.200903356

We report a full account of our work towards the total synthesis of (-)-terpestacin (1), a sesterterpene originally isolated from fungal strain Arthrinium sp. FA1744. Its promising anti-HIV and anti-cancer activity, as well as its novel structure, make terpestacin an attractive synthetic target. A strategy based on the unique reactivity of cyclic 1,2-diketones (diosphenols) was developed and total synthesis of 1 was achieved in 20 steps, in the longest linear sequence, from commercially available 2-hydroxy-3-methyl-2-cyclopenten-1- one. The key feature of our synthesis is the double usage of a "Pd AAA-Claisen" protocol (AAA = asymmetric allylic alkylation), first in the early stages to generate the C1 quaternary center and then in the late stages to install the side chain. In addition, a rather unusual ene-1,2-dione moiety was synthesized and utilized as an excellent Michael acceptor to attach the C15 substituent. Several possible routes towards the total synthesis have been examined and carefully evaluated. During our exploration many interesting chemoselectivity issues have been addressed, such as a highly selective ring-closing metathesis and a challenging oxidation of a disubstituted olefin in the presence of three trisubstiuted ones.

Full text of DOI:10.1002/chem.200903356

FULL PAPER
DOI: 10.1002/chem.200903356
Cyclic 1,2-Diketones as Core Building Blocks: A Strategy for the Total
Synthesis of (À)-Terpestacin
Barry M. Trost,* Guangbin Dong, and Jennifer A. Vance[a]
Abstract: We report a full account of
our work towards the total synthesis of
available 2-hydroxy-3-methyl-2-cyclo-
penten-1-one. The key feature of our
synthesis is the double usage of a “Pd
AAA-Claisen” protocol (AAA=asym-
metric allylic alkylation), first in the
early stages to generate the C1 quater-
nary center and then in the late stages
to install the side chain. In addition, a
rather unusual ene-1,2-dione moiety
was synthesized and utilized as an ex-
cellent Michael acceptor to attach the
C15 substituent. Several possible
routes towards the total synthesis have
been examined and carefully evaluated.
During our exploration many interest-
ing chemoselectivity issues have been
addressed, such as a highly selective
ring-closing metathesis and a challeng-
ing oxidation of a disubstituted olefin
in the presence of three trisubstiuted
ones.
(À)-terpestacin (1),
a sesterterpene
originally isolated from fungal strain
Arthrinium sp. FA1744. Its promising
anti-HIV and anti-cancer activity, as
well as its novel structure, make terpes-
tacin an attractive synthetic target. A
strategy based on the unique reactivity
of cyclic 1,2-diketones (diosphenols)
was developed and total synthesis of 1
was achieved in 20 steps, in the longest
linear sequence, from commercially
Keywords: alkylation · asymmetric
catalysis · Claisen rearrangement ·
terpenoids · total synthesis
um sp. FA1744 by a collaboration between Oka and Bristol-
Myers Squibb.[3] Terpestacin was shown to effectively inhibit
the formation of syncytia (giant-multinucleated cells that
are caused by the expression of gp120 on cell surfaces
during HIV infection),[3a] and its IC50 value is as low as
0.46 mgmLÀ1, which suggests that it could be a promising
drug lead in anti-HIV chemotherapeutics.[3a] Recently, ter-
pestacin has also been isolated from other fungal sources
such as Ulocladium[4] and Bipolaris sorokiniana.[5]
Introduction
Isolation and biology: In 2007, the World Health Organiza-
tion estimated that 30.6–36.1 million people worldwide were
living with HIV and 2.1 million people had died of AIDS
that year.[1] Over the past two decades significant effort has
been applied to identifying pathological targets for HIV and
exploring new drug candidates for its chemotherapy. One
important target for finding
treatments for HIV infection is
syncytium formation, which
A recent oncological study shows that, both in vitro and
in vivo, terpestacin is also able to inhibit angiogenesis with-
out affecting endothelial cell viability and inhibits extracel-
lular signal-regulated kinase activity in the cells.[6] This
result implies that terpestacin could be employed for the
treatment of cancer.
constitutes a major cause of the
death of human T4 cells.[2]
During the screening for syncy-
tium formation inhibitors in
1993, an attractive natural prod-
uct named terpestacin (1) was
Structure: Besides these stimulating biological properties,
found in fungal strain Arthrini-
the structure of terpestacin has been attractive to the syn-
thetic community. Terpestacin contains
a
trans-fused
[3.0.13]bicyclic skeleton that includes a 15-membered mac-
rocycle with three geometrically defined trisubstituted ole-
fins. Furthermore, it contains an uncommon diosphenol
functionality (a cyclic 1,2-diketone with one ketone existing
as an enol) within a heavily substituted five-membered ring.
Interestingly, the structure of terpestacin contains a 4+4+4
combination that includes four oxygen atoms, four carbon–
[a] Prof. B. M. Trost, G. Dong, J. A. Vance
Department of Chemistry, Stanford University
Stanford, California 94305-5080 (USA)
Fax : (+1)6507250002
E-mail: bmtrost@stanford.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903356.
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6265

carbon double bonds, and four stereogenic centers, one of
them quaternary. All of these features have posed significant
challenges for the total synthesis of terpestacin.
hol motif at C11 and a subsequent alkylation at the C1 posi-
tion of 8 to provide the desired macrocycle.[10] Very recently,
another racemic synthesis of 1 was completed by the Tius
group, who employed an allene ether Nazarov reaction as a
key step to construct the five-membered ring core and a
HWE reaction to close the macrocycle.[11] In this article, we
describe a full account of our work towards the enantiose-
lective total synthesis of (À)-terpestacin, as well as a journey
to the development of a unique strategy to stereoselectively
and programmatically alkylate 3-substituted cyclopentane-
1,2-diketones (Scheme 2).[12]
Previous efforts: Given its promising anti-HIV and anti-
cancer activities, along with its novel architecture, several el-
egant total syntheses of terpestacin have been reported to
date. In 1998, Tatsuta et al. described the first racemic syn-
thesis of 1[7] and, later that year, they also reported the first
enantioselective synthesis, starting from tri-O-acetyl-d-galac-
tal 3 and using a selective Horner–Wadsworth–Emmons
(HWE) reaction to close the macrocycle of the intermedi-
ate-compound 4 (Scheme 1).[8] The Myers group, in 2002,
Scheme 2. Programmatic alkylation of cyclic 1,2-diketones.
Diosphenols: Cyclic 1,2-diketones with one of the ketones
in an enol form have been named diosphenols due to their
similar reactivity to phenols.[13] Notably, 3-substituted cyclic
1,2-diketones exist as a single tautomeric species, which
raises the attractive prospect of diosphenols serving as a piv-
otal core onto which several carbon-chain substituents can
be installed in a stereoselective fashion. As with phenols,
the enol OH of cyclic 1,2-diketones exhibits substantial nu-
cleophilicity and, generally, only O-alkylation occurs when
they are treated with alkylating agents.[14] In 2000, Trost and
Schroeder developed an asymmetric allylic alkylation
(AAA) method using diosphenols as nucleophiles and O-al-
lylated products were obtained with high enantioselectivity
(as in the reaction of 9 with 10 to form compound 11;
Scheme 3).[15] Subsequent Claisen-rearrangement of these
AAA adducts then provided the C-alkylation products with
excellent chirality transfer (as in the formation of 12 from
11).
Scheme 1. Previous enantioselective total syntheses of terpestacin (1);
MOM=methoxymethyl, Ac=acetyl, Bn=benzyl, TIPS=triisopropylsil-
yl, TBS=tert-butyldimethylsilyl.
completed the second enantioselective synthesis of terpesta-
cin, as well as a closely related natural product fusaproliferin
(2).[9] They initiated their synthesis with pseudoephedrine-
derived chiral amide 5 and constructed the macrocycle
through a stereoselective alky-
Basic principle: This O-allylation, Claisen rearrangement se-
quence should provide a chemo- and regioselective enolate
lation of 6 at the C15 position.
Moreover, this synthesis unam-
biguously established the abso-
lute configuration of this natu-
ral product. In 2003, Jamison
reported the third enantioselec-
tive synthesis starting from
chiral dihydrofuran 7, in which
they discovered that siccanol is
not 11-epi-terpestacin, but ter-
pestacin itself. Jamisonꢁs synthe-
sis features a highly selective,
Ni-catalyzed, reductive coupling
Scheme 3. Pd-catalyzed AAA-Claisen rearrangement sequence; DBA=dibenzylideneacetone, FOD=
to afford the chiral allylic alco- 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate.
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(À)-Terpestacin
FULL PAPER
allylation that can be performed asymmetrically with respect
to the enolate, the allyl fragment, or both (Scheme 4, a).
During this transformation up to two stereogenic centers
could ultimately be derived from diosphenol 18. The C15
stereocenter of 18 could be generated either by a vinylogous
enolate alkylation, or through a stereoselective Sakurai al-
lylation of the corresponding enone and the C1 quaternary
center would arise from another “Pd AAA-Claisen” reac-
tion of the inexpensive and commercially available 3-
methyl-1,2-cyclopentanedione 19 and isoprene monoepoxide
20.
Pd-catalyzed AAA reactions between diosphenol 19 and
isoprene monoepoxide 20 [Eq. (1)]:
Scheme 4. Basic principle: the controlled substitution of cyclic 1,2-dike-
tones to enable the synthesis of terpestacin (1).
can be created, including all-carbon quaternary ones. More-
over, the Claisen rearrangement product (C) regains dios-
A
Initial attempts to effect the AAA reaction between 19
and 20 by using the published reaction conditions[15] gave
only moderate enantioselectivity (Table 1, entries 1 and 2).
Note that tetrabutylammonium chloride was employed as
an additive to promote the p–s–p equilibration required for
resolution of vinyl epoxide 20 (Scheme 6). In this case, the
naphtho-Trost ligand (LNA) gave slightly higher ee (Table 1,
entry 2; 57% ee) than the standard ligand (LST) (Table 1,
entry 1, 48% ee). Lowering the catalyst loading from 2.5 to
0.5 mol% did not hamper the yield; on the contrary, the
enantioselectivity increased from 57 to 67% ee (Table 1, en-
same sequence again to introduce another alkyl substituent
at the C5 position. On the other hand, oxidation of 3,3-dis-
ubstituted diosphenol A’ could provide a relatively un-
known, but highly electrophilic, cyclopentenedione species,
B’ (Scheme 4, b). Conjugate addition of alkyl nucleophiles
across B’ should install a third carbon chain at the C4 posi-
tion. Therefore, we envision that all the carbon substituents
on the five-membered-ring core of terpestacin could be pro-
grammatically introduced in a chemo-, regio-, and stereose-
lective manner.
Results and Discussion
Synthesis plan: From a retro-
synthetic viewpoint (Scheme 5),
we envisaged that the side
chain and the C23 stereocenter
would be accessed through the
“Pd AAA-Claisen” protocol
followed by oxidative alkene
cleavage and the 15-membered
macrocycle could be construct-
ed by a highly selective ring-
closing metathesis (RCM) to
form the C12–C13 olefin. The
RCM precursors 13 or 14 could
be formed by alkylation of sul-
fone 15 with the corresponding
allyl bromides (16 or 17), which Scheme 5. Retrosynthetic analysis; PMB=para-methoxybenzyl.
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6267

B. M. Trost et al.
Table 1. Selected optimization studies.[a]
Entry
L[b]
x[b]
y[b]
t
T
c
[M]
Yield
[%][c]
ee
[h]
[oC]
[%][d]
1
2
3
4
5
6
7
8
9
LST
2.5
2.5
0.8
0.5
0.5
0.5
0.5
0.5
2.0
30
30
35
30
50
30
30
50
50
1.0
1.0
1.0
0.3
1.0
0.3
40
40
40
40
40
RT
60
40
RT
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.08
0.07
72
85
79
88
83
48
57
66
67
74
66
67
90
LNA
LNA
LNA
LNA
LNA
LNA
LNA
LST
79
85
0.3
2.5[e]
6.0[e]
94
The compound [HoACTHNUTRGNE(UNG fod)3] (fod=heptafluorodimethyloc-
93–95[f]
88–96
tanedione) has been established as an excellent catalyst for
such rearrangements.[15] Indeed, treatment of TIPS ether 22
[a] The reaction was operated with 2 equivalents of 20 and 1 equivalent
of 19. [b] See Equation (1) for definitions of L, x, and y. [c] Isolated
yield. [d] Enantioselectivities were determined for the acetate derivatives
by chiral HPLC. [e] A solution of 19 was added slowly through a syringe
pump over the indicated amount of time. [f] Isolated yield after direct
conversion to TIPS ether 22.
with 10 mol% [HoACTHNUTRGNEUNG(fod)3] in chloroform at 35–458C for five
days did provide the rearranged product 23 in 20% yield
(Table 2, entry 1). The E/Z selectivity for the newly formed
Table 2. Selected optimization of the [3,3]-Claisen rearrangement reac-
tion.
Entry Additives
(10 mol%)
Solvent
T
[8C]
t
Yield
[%][a]
E:Z[b]
G
[h]
1
2
3
4
5
6
7
[Ho(fod)3]
[Eu(fod)3]
[Ho(fod)3]
none
none
none
none
N
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
none
35–45
35
120
360
40
40
120
20
20
4.1:1
G
N/A[c] N/A
55
55
45
33
50
37
89
5.8:1
6.3:1
8.3:1
4.8:1
4–5:1
70
CHCl3
100[d]
0.25 82–93
0.25
120[d]
100[d]
120[d]
100[d]
120[d]
100[d]
120[d]
160[d]
8
9
[Ho
N
CHCl3
0.25
0.25
0.25
0.25
0.25
0.25
3
74
5.0:1
4.0:1
Scheme 6. p–s–p Equilibration.
[Ho
AHCTUNGTRENNUNG
(tmhd)][e] CHCl3
34
N/A[c] N/A
tries 2 and 4). Raising the loading of chloride salt caused a
slight but noticeable increase on the enantioselectivity
(Table 1, entry 5). Further study suggested that temperature
did not play an important role on either the yield, or the
enantioselectivity (Table 1, entries 6 and 7). Under all the
test conditions the reaction was observed to proceed at an
extremely high rate. A high reaction rate with low ee sug-
gests that the p–s–p interconversion between the two dia-
10
none
purified CHCl3
11
none
DME
100[f] 2.7:1
[a] Isolated yield. [b] Determined by 1H NMR spectroscopy. [c] Incom-
plete conversion with byproduct formation. [d] Microwave heating.
[e] TMHD=2,2,6,6-tetramethyl-3,5-heptanedionate. [f] Complete conver-
sion.
1
stereomeric palladium–p-allyl species
X
and
Y
(see
alkene geometry in 23 was 4.1:1 (determined by H NMR
Scheme 6) is relatively slow compared with the nucleophilic
attack. Thus, by decreasing the nucleophile concentration,
the rate of nucleophilic addition should be lowered, allowing
the palladium–p-allyl intermediates (X and Y) enough time
to equilibrate, which should provide a high facial selectivity.
Indeed, slow addition of 19 through a syringe pump dramat-
ically improved the enantioselectivity to 90% ee (Table 1,
entry 8). From these studies emerged the most practical set
of conditions and, as shown in Table 1, entry 9, up to
96% ee could be achieved with the standard Trost ligand.
Pd-AAA adduct 21 was subsequently protected in the same
pot with a bulky TIPS (TIPS=triisopropylsilyl) group, and
the silylated product 22 was isolated in 93–95% yield.
spectroscopy), favoring the E isomer. Use of the related
[EuACTHNUGTRNENG(U fod)3] as the catalyst, however, gave incomplete conver-
sion and the formation of unidentified byproducts (Table 2,
entry 2). When warmed to 558C for 40 h, diosphenol 23 was
afforded in 33% yield and 5.8:1 E/Z selectivity (Table 2,
entry 3). Surprisingly, in the absence of the catalyst, this sig-
matropic rearrangement proceeded equally well, or even
slightly better, by simply heating 22 in a minimal amount of
chloroform (Table 2, entry 4). An increased E/Z ratio (8.3:1)
was observed when 22 was heated at a reduced reaction
temperature (458C); however, the reaction rate was signifi-
cantly diminished (Table 2, entry 5). In the absence of a sol-
vent, this Claisen rearrangement occurred with increased
yield (89%) and reasonably good E/Z selectivity (4.8:1), al-
though a long period of heating (708C, 20 h) was still re-
quired to allow the reaction to go to completion (Table 2,
entry 6). A more practical protocol was then developed as
shown in Table 2, entry 7. Replacement of conventional
Claisen rearrangement leading to C-alkylated product 23:
With AAA adduct 22 in hand, the stage was set for a Clais-
en rearrangement to transfer the chirality from the side
chain onto the ring [Eq. (2)].
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(À)-Terpestacin
FULL PAPER
heating with microwave irradiation (1008C for 15 min fol-
lowed by 1208C for 15 min) significantly increased the reac-
tion rate and the product (23) was isolated in 82–93% yield.
Attempts to enhance the E/Z selectivity by employing the
Lewis acid catalysts [HoACTHNURTGENN(UG fod)3] and [HoAHCTUNGTRNEN(UGN tmhd)] (H-tmhd=
2,2,6,6–tetramethylheptane-3,5–dione) proved to be unfruit-
ful (Table 2, entries 8 and 9).
It should be noted that the choice of chloroform as the
solvent is not arbitrary. When 1,2-dimethoxyethane (DME)
was used as solvent, a 3 h microwave heating reaction at
1608C was required and the E/Z selectivity of the product
was lower (2.7:1, Table 2, entry 11). Interestingly, under the
same conditions as in Table 2, entry 7, but utilizing chloro-
form freshly distilled from K2CO3, the Claisen rearrange-
ment failed to give full conversion and the product was con-
taminated with unidentified byproducts (Table 2, entry 10).
We hypothesized that a trace amount of water and HCl
present in “unpurified” chloroform may help to catalyze this
[3,3]-sigmatropic rearrangement. In the case of the solvent-
free conditions, the diosphenol product itself can act as the
acid catalyst due to the acidity of the enol OH. Chirality
transfer from 22 to 23 proved to be complete and, at this
point, the absolute configuration of 23 was tentatively as-
signed in analogy with our previous work.[15]
Scheme 7. Synthesis of the model substrates.
dione (27), which allows an allylic nucleophile to attack at
the C15 position as shown in Equation (4). Conjugated cy-
clopentene-1,2-diones containing no substituents at C3 or
C4, such as 27, are a rare and underutilized species[16] about
which limited chemistry is known. The reaction of the
model system, TIPS enol ether (Æ)-25, under Corey-modi-
fied Saegusa oxidation conditions[17] resulted in a messy re-
action mixture and incomplete conversion [as shown in
Eq. (5) in which TBHP=tert-butyl hydroperoxide]. 2-Iod-
AHCTUNGTRENNUNG
oxybenzoic acid (IBX) oxidation[18] of the unprotected
model diketone (Æ)-24 gave none of the desired enedione
compound, but caused decomposition of the starting materi-
al [as shown in Eq. (6) in which MPO=p-methoxypyridine-
N-oxide].
After extensive experimentation, we found that treatment
of (Æ)-24 with 1 equivalent of palladium acetate and
1.5 equivalents of cesium carbonate in acetonitrile at ambi-
ent temperature cleanly provided cyclopentene-a-dione
(Æ)-28 as a yellow oil, in 78% yield (Scheme 8). To the best
of our knowledge, this represents the first example of direct
Saegusa oxidation of unprotected diosphenols.[19] Surprising-
ly, this enedione compound is relatively stable towards aque-
Installation of the allyl group at the C15 position (terpesta-
cin numbering): Elaboration of diketone 23 to the natural
product requires installation of an allyl side chain at the C15
position. One possible route to this compound is to generate
a vinylogous enolate by deprotonation of a protected dike-
tone followed by quenching with an allylic electrophile [see
Eq. (3) in which Pg=protecting group].
To that end, a model system
was employed to examine the fea-
sibility of this method. Model sub-
strate (Æ)-24 was prepared in
88% yield over two steps from di-
osphenol 19.[14] Subsequent TIPS
or p-methoxybenzyl (PMB) pro-
tection of the enol provided the
corresponding silyl ether (Æ)-25
and benzyl ether (Æ)-26 in excellent yield (Scheme 7). How-
ever, treatment of both (Æ)-25 and (Æ)-26 with various
bases and electrophiles in different solvents failed to provide
any of the desired alkylation products. Instead, some O-al-
kylation byproducts and decomposition of the starting mate-
rial were observed, which can likely be attributed to the
fragileness of the vinylogous enolate intermediate.
Alternatively, an umpolung strategy can be envisioned.
Instead of using the diosphenol as a nucleophile, oxidation
of the diketone would create a “hot” electrophile, an ene-
ous workup and silica gel chro-
matography.
Attempts
to
reduce the amount of palladium
required were, unfortunately,
unfruitful. For example, using
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6269

B. M. Trost et al.
The synthesis of sulfone segment 15 is depicted in
Scheme 11. Commercially available geranyl bromide (31)
was used to prepare known allyl alcohol 32 two steps.[22]
Under Sharpless asymmetric epoxidation conditions allyl al-
cohol 32 was converted to chiral epoxide 33 with 98% ee. A
reductive epoxide rearrangement procedure was then adopt-
ed from Li et al.;[23] the epoxy alcohol was converted in situ
into the corresponding epoxy iodide with PPh3, iodine, and
Scheme 8. Model reactions for allylation at the C4 position of diosphenol
24; TMS=trimethylsilyl.
molecular O2 (in DMSO), ben-
zoquinone, or CuACHTUNGTRENNUNG(OAc)2 as the
stoichiometric oxidant failed to
turn over the Pd catalyst. A
subsequent
indium-catalyzed Scheme 10. Synthesis of allyl bromide 16; TBAF=tetrabutylammonium fluoride.
Sakurai allylation[20] was then
employed and the allyl group
was installed into (Æ)-28 in a diastereoselective fashion. Di-
osphenol (Æ)-29 was isolated in 75% yield, as a 6:1 mixture
of isomers. In the major diastereomer the two allyl groups
are in a trans-position relative to each other, which was de-
termined by 1D nOe experiments. Moreover, this transfor-
mation constitutes the first example of an intermolecular C-
1,4-addition into this type of enedione species.[21]
With successful installation of an allyl substituent at the
C4 position in the model system, we tested these conditions
on the real system. Treatment of the Claisen rearrangement
product generated from 22 under the newly developed Sae-
gusa oxidation conditions smoothly gave cyclopentene-a-
dione 27 in 78% yield over the two steps (Scheme 9). For
the subsequent allylation, although indium chloride was
Scheme 11. Synthesis of sulfone fragment 15; Py=pyridine, l-DET=l-
diethyl tartrate
pyridine, which upon addition of water underwent reductive
elimination of the iodide ion that is formed to afford chiral
allyl alcohol 15 in 74% yield.
With compounds 15 and 16 in
hand, the stage was set to
couple these two fragments to-
gether. After careful optimiza-
tion, treatment of a mixture of
15 and 16 with 2 equivalents of
LiHMDS in THF-HMPA at
À408C cleanly provided cou-
Scheme 9. Synthesis of diosphenol 18.
pling product 34, in very good
yield, as a 1:1 mixture of diaste-
reomers (Scheme 12). Notably,
protection of the allylic alcohol
used as the Lewis acid in the model system, the use of mag-
nesium bromide was more effective for the real system. Al-
lylation product 18 was isolated in 86% yield with 5.7:1 d.r.;
the relative stereochemistry and the d.r. were determined by
1D nOe experiments and H NMR spectroscopy, respective-
ly.
is not necessary and no O-alkylation product was isolated.
The choice of base seems to be critical; for example, use of
NaHMDS or KHMDS was much less effective than
LiHMDS. Solvent and temperature optimization studies re-
vealed that a THF/HMPA (3:1) mixed solvent and À408C
combination gave the best yield. A number of sulfone re-
moval methods were then attempted, and a Pd-catalyzed re-
ductive desulfonylation turned out to be the most efficient
1
An RCM approach to constructing the 15-membered carbo-
cycle: Next, the enol OH in diosphenol 18 was protected as
a PMB ether (30; Scheme 10). Subsequently, the TIPS pro-
tecting group was removed by using TBAF and treatment of
the resulting allyl alcohol with PPh3 and CBr4 provided allyl
bromide segment 16 in high yield.
method for substrate 34. By using PdACTHNUTRGENUG(N OAc)2–DPPP (1,3-
bis(diphenylphosphino)propane) as the catalyst and NaBH4
as the stoichiometric reductant in DMSO, this desulfonation
proceeded with high regioselectivity, almost no loss of olefin
geometry, and RCM precursor 13 was furnished in 77%
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(À)-Terpestacin
FULL PAPER
drogen bonding. In addition, a low reaction temperature
proved to be important, as various byproducts formed at
elevated temperatures. Moreover, the use of the less reac-
tive Grubbs first-generation catalyst[27] failed to provide any
macrocyclization product.
Initial approach to installing the side chain: The advance-
ment of bicycle 36 to terpestacin (1) requires installation of
a side chain at C16, along with the C23 stereogenic center.
Removal of the PMB group in 36 turned out to be nontrivi-
al. A large number of methods for PMB deprotection, such
as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, trifluoroacetic
acid, ceric ammonium nitrate, BF3, and so forth, proved un-
successful. In the end, a relatively unconventional method
was tried by using MgBr2 and dimethyl sulfide (DMS).[28]
We anticipated that the chelation of Mg2+ to both the enol
ether and the ketone could facilitate the subsequent deben-
zylation, either by the bromide or DMS present. Indeed,
under these conditions the PMB group was cleanly removed
in excellent yield (Scheme 14). We envisioned that, due to
control by the adjacent C15 stereocenter, the Claisen rear-
rangement of the O-crotylated diosphenol 38 should give
the C-alkylation product with the desired stereochemistry.
Indeed, treatment of 37 with trans-crotyl bromide and potas-
sium carbonate, followed by microwave heating in DME
provided adduct 39 containing the whole carbon framework
and all the stereocenters present in the natural product.[29]
At this point, the stereochemistry of the newly formed C23
center in 39 was tentatively assigned as that shown in
Scheme 14. The enol and the allylic alcohol were subse-
quently protected with TES (TES=triethylsilyl) groups in
one step. All efforts to selectively oxidize the terminal
olefin in compound 40 without touching any of the three tri-
substituted alkenes to form 41 remained unfruitful. For ex-
ample, under regular dihydroxylation or diboration/oxida-
tion conditions[30] a complex mixture was obtained without
any of the desired product. This result implies that the che-
moselective oxidation of the terminal olefin over the trisub-
stituted olefins is very challenging considering that the latter
are typically more susceptible to oxidation.
Scheme 12. Synthesis of macrocycle 36; HMDS=hexamethyl disilazide,
Cy=cyclohexyl, Mes=mesityl, HMPA=hexamethylphosphoramide,
DPPP=1,3-bis(diphenylphosphino)propane.
yield. It is worth noting that carefully dried DMSO (distilled
over CaH2, then stored over 4 ꢂ molecular sieves) was re-
quired for this desulfonylation reaction.
Since compound 13 contains five olefins, many outcomes
are possible for the following RCM reaction (Scheme 13).
For example, C13 and C3 could close to form a six-mem-
bered ring (pathway A), C8 and C12 could close to form a
five-membered ring (pathway B), and so forth. After careful
screening, we found that treatment of 13 with 10 mol% of
Grubbs second-generation catalyst (35, see Scheme 12)[24] in
benzene at room temperature produced the desired 15-
membered carbocycle 36 in a reasonably good yield[25] (35–
44% of the E isomer).[26] We also found that having the C11
hydroxyl group protected with a TBS group did not provide
any 15-membered ring product, which indicates that the free
allylic alcohol moiety could be critical for the success of this
challenging RCM. We rationalize that coordination of the
hydroxyl group with the ruthenium catalyst, or potential in-
tramolecular hydrogen bonding between the OH and the di-
ketone moiety might be key factors in the formation of the
macrocycle. Benzene was selected as the solvent for this
RCM reaction instead of dichloromethane, because a less
polar solvent would be beneficial for the intramolecular hy-
Alternate route: a second Pd AAA-Claisen sequence to in-
stall the side chain before the macrocyclization: Given the
difficulties discovered in cleaving the alkene in the side
chain at a very late stage, an alternate route is to furnish the
side chain first and then close the macrocycle at the very
end. Furthermore, instead of dealing with a less electron-
rich terminal olefin, installation of a disubstituted alkene
should significantly increase the chance of the desired oxida-
tive cleavage of the side chain. To this end, a second Pd-cat-
alyzed AAA reaction between diosphenol 18 and allyl car-
bonate 42 using the standard (S,S)-Trost ligand ((S,S)-LST)
provided O-allylated product 43 in 94% yield with over
1
10:1 diastereoselectivity, which was determined by H NMR
spectroscopy (Scheme 15). The stereochemistry of the newly
formed chiral center in 43 was assigned by analogy to other
AAA reactions with allyl carbonate 42.[15] Subsequent mi-
Scheme 13. Possible RCM pathways.
Chem. Eur. J. 2010, 16, 6265 – 6277
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6271

B. M. Trost et al.
key factors which allow this
chemoselective oxidation. Sub-
sequent periodate cleavage of
the diol followed by chemose-
lective reduction, in the pres-
ence of the ketone, of the alde-
hyde formed with NaBH4 at
À788C in
a
CH2Cl2/MeOH
mixed solvent completed the
construction of the side chain
and gave 47.
Scandium-catalyzed
PMB
protection of primary alcohol
47 followed by TBAF-mediated
desilylation gave allylic alcohol
48 in 78% yield over two steps
(Scheme 16). Treatment of 48
with PPh3 and CBr4 in a di-
chloromethane/pyridine mixed
solvent[32] at À208C afforded
allyl bromide 49, which was
then subjected to the sulfone-
coupling and desulfonation con-
ditions described previously.
Adduct 50, which is formed in
this reaction, was isolated in
56% yield over the two steps
and serves as the precursor for
the subsequent RCM reaction.
Unfortunately, treatment of 50
under the exact olefin metathe-
sis conditions disclosed earlier
for substrate 13 failed to pro-
vide any of the macrocycle
products. Instead, trans-fused
[3.0.4] bicycle 51 was obtained
in 94% yield as the only prod-
uct from the RCM reaction.
Scheme 14. Initial efforts to install the side chain in the presence of the macrocycle.
Scheme 15. Installation of the side chain before macrocyclization.
Why did substrates 13 and 50
(depicted here together) give
totally different reactivity in the
crowave-mediated Claisen rearrangement gave diosphenol
44, which was then protected as a PMB ether. The resulting
compound, 45, contains various olefins: one mono-, one di-,
and one trisubstituted olefin, as well as one tetrasubstituted
conjugated enol ether. Thus, to selectively oxidize the disub-
stituted olefin in the presence of the others is a challenge.
For example, treatment of 45 with meta-chloroperbenzoic
acid only gave an epoxide at the position of the trisubstitut-
ed olefin. Fortunately, after extensive screening, the desired
diol, 46, was obtained in 40% (unoptimized) yield under
Sharplessꢁ asymmetric dihydroxylation conditions.[31] It is
likely that the bulky (DHQD)2PHAL ligand (hydroquini-
RCM reaction? We rationalize that the major steric interac-
tion in the core of 13 is between the C15 allyl group and the
two substituents at the C1 quaternary stereocenter. This in-
teraction would likely push the two groups away from each
other, which ultimately results in a favorable macrocycliza-
tion. However, in compound 50, the C1–C15 interaction is
compromised by a strong repulsion between the C15 allyl
group and the C16 side chain. Moreover, formation of a six-
dine 1,4-phthalazinediyl diether) would have unfavorACTHNUTRGNEUNGable
steric interactions with the TIPS group and the C1 quaterna-
ry center that result in slow oxidation of the trisubstituted
alkene. Furthermore, the monosubstituted olefin is relatively
electron-poor. These stereoelectronic biases could be the
6272
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(À)-Terpestacin
FULL PAPER
newly formed stereocenter in
52 was assigned by analogy to
similar AAA reactions with
allyl carbonate 42.[15] The di-
osphenol OH was then protect-
ed as a PMB ether. An acetyl
group was selected as the pro-
tecting group for the allyl alco-
hol moiety, firstly, because it
can be easily removed by hy-
drolysis and, secondly, because
an electron-withdrawing group
like acetate should deactivate
Scheme 16. Unsuccessful macrocyclization.
the
adjacent
trisubstituted
olefin to oxidation. With tet-
raene 53 in hand, the remaining challenge was to selectively
cleave the 1,2-disubstituted olefin in the presence of the
three trisubstituted olefins. Lessons learned from the second
attempted synthetic route led us to explore the possibility of
using the Sharpless asymmetric dihydroxylation reaction to
solve this chemoselectivity issue. To our delight, treatment
of 53 with AD-mix-a[34]/CH3SO2NH2 gave the desired diol,
54, in 65% (80% based on recovered starting material)
yield, whereas the use of AD-mix b resulted in a much
lower yield (24%).[35] We rationalized that the chemoselec-
tivity of this reaction comes from the fact that the endocy-
clic trisubstituted olefins would have a facial bias owing to
their restricted rotation, whereas the disubstituted olefin is
more conformationally flexible. In addition, the crystal
structure of terpestacin[3b] indicates that within the macrocy-
cle the C3–C4 and C7–C8 olefins are oriented in a similar
fashion. Therefore, by using an asymmetric oxidation that is
mismatched for the trisubstituted alkenes, oxidation of the
disubstituted olefin would be
membered ring is thermodynamically favored. Thus, all
these factors led to the preferred cyclization of compound
50 being to form the six-membered ring in lieu of a macro-
cyclization.
Revised approach leading to the total synthesis of (1): En-
couraged by the success of the macrocycle formation in the
first route and the success of the side chain installation in
the second pathway, we decided to combine the merits of
both approaches and further revise the method. We envi-
sioned that a similar approach to that used in the second
route could be applied to installing the side chain onto mac-
rocycle 37 (Scheme 17). Indeed, application of the AAA-
Claisen rearrangement sequence to diosphenol 37 unevent-
fully formed the side chain containing a trans-alkene with
excellent diastereoselectivity. Note that AAA adduct 52 was
isolated as almost a single diastereomer, as determined by
1H NMR spectroscopy,[33] and the stereochemistry of the
kinetically favored. Advance-
ment of diol 54 to the natural
product was then achieved in a
straightforward manner. Period-
ate cleavage of the vicinal diol
followed by reduction of the re-
sulting aldehyde furnished com-
pound 55 with the desired the
side chain. Subsequent removal
of the acetate and PMB pro-
tecting groups ultimately af-
forded
(À)-terpestacin
(1),
which is spectroscopically iden-
tical to the compounds previ-
ously reported.[9,10]
Conclusion
As summarized in Scheme 18, a
unique strategy has been devel-
oped for the enantioselective
total synthesis of terpestacin (1)
Scheme 17. Total synthesis of (À)-terpestacin (1); DHQ=dihydroquinine.
Chem. Eur. J. 2010, 16, 6265 – 6277
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6273

B. M. Trost et al.
Scheme 18. Summary.
termediate alcohol. The ee was determined by HPLC OC column,
1.0 mLminÀ1, 90:10 heptane/isopropanol, tr (major): 29.32 min, tr (minor):
38.41 min).
based on the unusual reactivity of diosphenols. By multiple
usage of the a-diketone functionality, twice in the “Pd
AAA-Claisen” protocol and once by the employment of its
oxidized form, the ene-1,2-dione, stereoselective alkylation
of cyclopentane-1,2-diketones could be achieved in a pro-
grammatically controlled fashion. An unusual procedure for
direct oxidization of the diosphenol moiety to the ene-1,2-
dione was developed and this enedione species proved to be
an excellent Michael acceptor for a subsequent intramolecu-
lar 1,4-Sakurai allylation. The chemo- and regioselective de-
sulfonylation of an allylic sulfone catalyzed by Pd0 is also
noteworthy. Several possible routes towards the total syn-
thesis have been examined and carefully evaluated. During
our exploration many interesting chemoselectivity issues
have been addressed and discussed in detail, including a
chemoselective RCM to form the 15-membered carbocycle
and a dihydroxylation reaction to oxidize a disubstituted
olefin in the presence of various other more electronically
activated olefins. It is envisaged that this diosphenol-based
strategy, along with the issues resolved in this work, will
have the potential to shed new light on the total syntheses
of related terpenoid natural products.
For a larger scale: (7.14 mmol) In a flame-dried, argon-purged round-
bottom flask [Pd2ACHTNUTRGNEG(UN dba)3]·CHCl3 (140.9 mg, 0.136 mmol), (R,R)-LST
(297.7 mg, 0.431 mmol), and Bu4NCl (1.04 g, 3.73 mmol) were combined
and dissolved in dry, deoxygenated CH2Cl2 (100 mL). Isoprene monoep-
oxide (1.50 g, 17.8 mmol) was added to this solution. The resulting yellow
solution was stirred at room temperature for 15 min, at which time a so-
lution of 19 (800.1 mg, 7.14 mmol) in dry, deoxygenated CH2Cl2 (100 mL)
was slowly added by syringe pump, over 6 h. After completion of the
slow addition, the reaction was cooled to À788C. 2,6-Lutidine (2.02 g,
18.9 mmol) and TIPSOTf (4.56 g, 14.9 mmol) were added and the solu-
tion was slowly warmed to room temperature, over 16 h. Concentration
in vacuo and purification by flash column chromatography (petroleum
ether/diethyl ether=95:5, then 9:1) gave the product as a yellow oil
(2.39 g, 95%, 88% ee). Rf: 0.46 (petroleum ether/ethyl acetate=8:1);
[a]D: +7.2 (c=1.02 in CH2Cl2, in this case 88% ee); 1H NMR (CDCl3,
500 MHz): d=6.05 (dd, J=17.6, 10.9 Hz, 1H), 5.18 (dt, J=17.6, 0.61 Hz,
1H), 5.12 (dq, J=10.9, 0.61 Hz, 1H), 3.79 (s, 2H), 2.43–2.40 (m, 2H),
2.33–2.28 (m, 2H), 1.98 (d, J=0.61 Hz, 3H), 1.37 (s, 3H), 1.07–1.02 ppm
(m, 21H); 13C NMR (CDCl3, 125 MHz): d=204.4, 161.1, 150.7, 140.3,
115.6, 83.7, 70.1, 32.5, 27.5, 20.4, 18.0, 17.7, 16.0, 11.9 ppm; IR (film): n˜ =
2943, 2866, 1749, 1714, 1640, 1463, 1410, 1384, 1333, 1247, 1204, 1096,
996, 882, 810 cmÀ1; elemental analysis calcd (%) for C20H36O3Si: C 68.13,
H 10.29; found: C 68.36, H 10.10.
Compound 27: Compound 22 (1.468 g, 4.17 mmol) was transferred into a
microwave vial with CHCl3 (3 mL). The microwave vial was sealed and
heated to 1008C for 15 min, then
1208C for 15 min. The CHCl3 was re-
moved under reduced pressure, the
crude compound was then dissolved in
Experimental Section
CH3CN (20 mL), and then Cs2CO3
(2.0 g, 6.26 mmol) and [PdACTHNUTRGENUG(N OAc)2]
(1.03 g, 4.59 mmol) were added. The
resulting mixture was stirred at room
temperature for 30 min. Palladium
Selected experimental procedures for the preparation of 22, 27, 18, 34,
13, 36, 52–55 and 1 (terpestacin) appear below. Full experimental details
for all new compounds are given in the Supporting Information. The op-
tical rotation measurements were taken at 228C.
Compound 22: (on a 3.6 mmol scale) In a flame-dried, argon-purged
round-bottom flask [Pd2ACHTUNGTRENNUNG(dba)3]·CHCl3 (71.0 mg, 0.0685 mmol), (R,R)-LST
black was filtered out through
a
celite–silica gel cake and compound 27
(145.4 mg, 0.210 mmol), and Bu4NCl
(497.2 mg, 1.79 mmol) were combined
and dissolved in dry, deoxygenated
CH2Cl2 (100 mL). Isoprene monoepox-
ide (754 mg, 8.97 mmol) was added to
this solution. The resulting yellow so-
lution was stirred at room temperature
for 15 min, at which time a solution of
19 (403.6 mg, 3.60 mmol) in dry, de-
oxygenated CH2Cl2 (50 mL) was
slowly added by syringe pump, over
6 h. After completion of the slow addi-
was purified by silica gel flash column chromatography (petroleum ether/
ethyl acetate=9:1) and isolated as an orange-yellow oil (1.135 g, 78%; E/
Z=4:1). Rf: 0.35 (petroleum ether/ethyl acetate=9:1); [a]D: +68.9 (c=
0.5 in CH2Cl2); 1H NMR (CDCl3, 500 MHz): d=7.81 (d, J=7.5 Hz, 1H),
6.84 (d, J=7.0 Hz, 1H), 5.32 (m, 1H), 4.01 (d, J=1 Hz, 2H), 2.55 (dd,
J=14.5, 8.5 Hz, 1H), 2.33 (dd, J=14, 7.5 Hz, 1H), 1.53 (s, 3H), 1.27 (s,
3H), 1.00–1.05 ppm (m, 21H); 13C NMR (CDCl3, 125 MHz): d=202.8,
189.3, 168.3, 139.3, 136.0, 115.4, 67.4, 47.9, 34.7, 21.4, 18.0, 17.7, 13.4,
12.0 ppm; IR (film): n˜ =3431, 2940, 2866, 1763, 1719, 1570, 1459, 1382,
1226, 1115, 996 cmÀ1
307.172948; found: 307.172637.
;
HRMS: m/z calcd for C17H27O3Si [MÀiPr]+:
tion, the reaction was cooled to À78 8C. 2,6-Lutidine (0.92 g, 8.95 mmol)
and TIPSOTf (2.51 g, 8.18 mmol) were added and the solution was slowly
warmed to room temperature, over 16 h. Concentration in vacuo and pu-
rification by flash column chromatography (petroleum ether/diethyl
ether=95:5, then 9:1) gave the product as a yellow oil (1.16 g, 93%,
96% ee. The ee of this sample was assumed to be the same as the ee of
the acetate derivative prepared from a 1 mL aliquot of the unisolated, in-
Compound 18: Allyltrimethylsilane (0.14 mL, 0.91 mmol) was added to a
suspension of 27 (32 mg, 0.091 mmol) and MgBr2·Et2O (70.8 mg,
0.274 mmol) in CH2Cl2 at À788C. The resulting suspension was stirred at
À788C for 10 min before it was warmed to 08C. Next, the suspension was
stirred at 08C for 10 min and then it was slowly warmed to room temper-
ature. The mixture was then stirred at room temperature for 1 h before it
was poured into a precooled NaHCO3 solution. The mixture was extract-
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(À)-Terpestacin
FULL PAPER
ed with ethyl acetate (10 mLꢃ3) and
the combined organic fractions were
dried over Na2SO4. Compound 18 was
purified by silica gel flash column
chromatography (petroleum ether/
ethyl acetate=9:1) and isolated as a
5 Hz, 1H), 5.08 (m, 1H), 4.90 (dd, J=
24.5, 11.5 Hz, 2H), 4.04 (dd, J=10,
3 Hz, 1H), 3.80 (s, 3H), 2.75 (dt, J=
10.5, 3 Hz, 1H), 2.40 (dd, J=13.5,
10.5 Hz, 1H), 2.26–1.96 (m, 8H), 1.80
(m, 3H), 1.62 (d, J=4.0 Hz, 3H), 1.56
(s, 3H), 0.99 ppm (s, 3H); 13C NMR
(CDCl3, 125 MHz): d=207.8, 159.7,
153.7, 138.0, 136.4, 133.2, 131.7, 129.5,
128.5, 127.9, 124.4, 121.6, 114.0, 76.7,
71.5, 55.4, 49.5, 44.8, 40.2, 38.4, 34.9,
colorless oil (30.8 mg, 86%, d.r.=5.7:1). Rf: 0.35 (petroleum ether/ethyl
acetate=9:1); [a]D: À19.6 (c=1.56 in CH2Cl2); 1H NMR (CDCl3,
500 MHz): d=6.44 (d, J=3 Hz, 1H), 5.80 (m, 1H), 5.65 (brs, 1H), 5.35
(tt, J=7.5, 1.5 Hz, 1H), 5.07 (dt, J=15.5, 1.5 Hz, 2H), 4.04 (s, 3H), 2.61
(ddd, J=2.5, 5, 10.5 Hz, 1H), 2.37 (td, J=5.5, 14 Hz, 1H), 2.3–2.2 (m,
2H), 1.92 (m, 1H), 1.80 (s, 3H), 1.05–1.03 ppm (m, 24H); 13C NMR
(CDCl3, 125 MHz): d=208.9, 150.7, 137.8, 136.3, 131.4, 117.6, 117.0, 67.8,
48.8, 43.2, 36.1, 35.3, 19.6, 18.1, 13.8, 12.0 ppm; IR (film): n˜ =3355 (br),
2943, 2867, 1694, 1654, 1464, 1394, 1214, 1115, 1066 cmÀ1; HRMS: m/z
calcd for C20H33O3Si [MÀiPr]+: 349.219899; found: 349.217262.
Compound 34: LiHMDS (0.62 mL, 0.5m in THF) was added dropwise to
a solution of 16 (65 mg, 0.155 mmol) and 15 (45.7 mg, 0.155 mmol), in
THF (0.6 mL) and HMPA (0.2 mL) at À408C, under nitrogen. The re-
sulting solution was stirred at À408C
31.0, 30.0, 23.9, 16.9, 15.6, 15.3, 10.5 ppm; IR (film): n˜ =3480 (br), 2934,
1712, 1628, 1516, 1455, 1248, 1156, 1053, 1033 cmÀ1; HRMS: m/z calcd for
C30H40O4 [M]+: 464.292660; found: 464.290731.
Compound 52: In a flame-dried, argon-purged round-bottom flask [Pd2-
AHCTNUGTERN(GNUN dba)3]·CHCl3 (1.5 mg, 0.0015 mmol) and (S,S)-LST (3.0 mg, 0.0044 mmol)
were combined and dissolved in dry,
deoxygenated CH2Cl2 (0.5 mL). Com-
pound 42[35] (23.2 mg, 0.118 mmol) was
then added to this solution. The result-
ing yellow solution was stirred at room
temperature for 15 min, at which time
a solution of 37 (20.3 mg, 0.059 mmol)
in dry, deoxygenated CH2Cl2 (0.7 mL)
was added slowly over 1 h by syringe
pump. After this addition, the solution
was concentrated in vacuo and com-
for 5 min, before it was poured into an
ice-cold solution of NaH2PO4 (1m).
The mixture was extracted with ethyl
acetate (10 mLꢃ3) and the combined
organic fractions were dried over
Na2SO4. The sulfone adducts 34 (mix-
ture of diastereomers) were purified
by silica gel flash column chromatog-
pound 52 was purified by silica gel flash column chromatography (petro-
leum ether/ethyl acetate=4:1, then 7:3) to give a colorless oil (19.2 mg,
89%, d.r.>15:1). Rf: 0.35 (petroleum ether/ethyl acetate=4:1); [a]D:
raphy (petroleum ether/ethyl acetate=
7:3, then 1:1) to give a colorless oil
(83.7 mg, 85%).
1
À57.33 (c=0.85 in CH2Cl2); H NMR (CDCl3, 500 MHz): d=6.18 (d, J=
3H, 1H), 5.67 (m, 1H), 5.47 (m, 1H), 5.42 (dd, J=6, 4.5 Hz, 1H), 5.20
(dd, J=10, 5.5 Hz, 1H), 5.10 (dd, J=7.5, 5 Hz, 1H), 4.57 (m, 1H), 4.04
(m, 1H), 2.74 (dt, J=11, 3 Hz, 1H), 2.39 (dd, J=14, 10.5 Hz, 1H), 2.26–
1.95 (m, 7H), 1.82–1.76 (m, 3H), 1.71 (dd, J=6.5, 1.5 Hz, 3H), 1.63 (s,
3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.39 (s, 3H), 0.97 ppm (s, 3H); 13C NMR
(CDCl3, 125 MHz): d=208.5, 152.6, 137.9, 136.3, 133.1, 132.5, 131.2,
128.7, 128.4, 124.4, 121.7, 76.70, 76.67, 49.2, 44.9, 40.3, 38.5, 34.9, 31.1,
29.9, 23.9, 21.1, 17.7, 16.8, 15.6, 15.4, 10.5 ppm; IR (film): n˜ =3448 (br),
2934, 1708, 1625, 1438, 1376, 1309, 1245, 1157, 1050 cmÀ1; HRMS: m/z
calcd. for C27H40O3 [M]+: 412.297746; found: 412.297427.
Compound 13: DMSO (3 mL) was added to a mixture of the sulfone ad-
ducts 34 (242 mg, 0.38 mmol), [PdACHTNUTRGNENG(U OAc)2] (17.2 mg, 0.076 mmol) and
DPPP (37.6 mg, 0.091 mmol) at room
temperature, under N2. The resulting
solution was stirred at room tempera-
ture for 15 min before NaBH4
(17.3 mg, 0.46 mmol) was added. The
resulting dark mixture was stirred
overnight and then it was poured into
brine (ca. 25 mL). The mixture was ex-
tracted with ethyl acetate (25 mLꢃ3)
Compound 53: Compound 52 (9.1 mg, 0.022 mol) was dissolved with
DME (2.5 mL) in a microwave vial under N2. The solution was heated at
1508C under microwave irradiation for
1 h, before the solvent was removed
under vacuum. CsCO3 (14.3 mg,
and the combined organic fractions
were dried over Na2SO4. Compound
13 was purified by silica gel flash
column chromatography (petroleum ether/ethyl acetate=9:1, then 3:1)
to give a colorless oil (163 mg, 77%). Rf: 0.35 (petroleum ether/ethyl ace-
tate=7:3); [a]D: À11.82 (c=0.38 in CH2Cl2); 1H NMR (CDCl3,
500 MHz): d=7.29 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 6.29 (d,
J=2.5 Hz, 1H), 5.80 (m, 1H), 5.11–5.04 (m, 2H), 5.00 (t, J=7.5 Hz, 1H),
4.92 (s, 1H), 4.86 (s, 2H), 4.83 (s, 1H), 4.02 (t, J=6 Hz, 1H), 3.80 (s,
3H), 2.56 (ddd, J=10, 5, 2.5 Hz, 1H), 2.34 (dt, J=14, 5.5 Hz, 1H), 2.20–
2.18 (m, 2H), 2.06–1.96 (m, 6H), 1.88 (m, 1H), 1.72 (s, 3H), 1.69–1.61
(s, 2H), 1.59 (s, 3H), 1.02 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=
207.2, 159.6, 154.4, 147.5, 138.4, 136.6, 134.9, 130.2, 129.5, 127.9, 124.5,
119.5, 116.9, 113.9, 111.1, 75.7, 71.3, 55.3, 49.5, 43.0, 39.9, 36.6, 35.8, 35.6,
33.2, 26.6, 19.7, 17.7, 16.3, 16.0 ppm; IR (film): n˜ =3480 (br), 3073, 2935,
1715, 1622, 1515, 1455, 1372, 1249, 1034, 913, 824 cmÀ1; HRMS: m/z calcd
for C32H44O4 [M]+: 492.323960; found: 492.322332.
0.044 mmol),
0.0044 mmol) and DMF (0.22 mL)
were added to the residue at room
temperature, under N2. The resulting
mixture was stirred at room tempera-
ture for 15 min, before PMBCl
(5.2 mg, 0.033 mmol) was added. The
resulting suspension was then stirred in
Bu4NI
(1.6 mg,
the dark for 2 h before it was poured
into brine. The mixture was then ex-
tracted with ethyl acetate (10 mLꢃ3) and the combined organic fractions
were dried over Na2SO4. After it was purified by silica gel flash column
chromatography (10% v/v diethyl ether in petroleum ether, then 25% v/v
ethyl acetate in petroleum ether), this PMB ether (ꢀ11.6 mg) was dis-
solved with pyridine (0.1 mL) and acetic anhydride (0.1 mL) at 08C. The
resulting solution was stirred at room temperature for 3 h, before it was
concentrated under vacuum. Compound 53 was then purified by silica gel
flash column chromatography (petroleum ether/diethyl ether=9:1, then
petroleum ether/ethyl acetate=9:1) to give a light-yellow oil (8.7 mg,
69%, over three steps). Rf: 0.35 (petroleum ether/ethyl acetate=9:1);
[a]D: À89.58 (c=0.26 in CH2Cl2); 1H NMR (CDCl3, 500 MHz): d=7.29
(d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 5.43–5.32 (m, 3H), 5.25–5.11
(m, 5H), 3.80 (s, 3H), 3.15 (m, 1H), 2.60 (dd, J=11, 3 Hz, 1H), 2.36 (d,
Compound 36: Grubbs second-generation catalyst (8.5 mg, 0.01 mmol)
was added to a solution of 13 (50.7 mg, 0.10 mmol) in benzene (40 mL)
under N2 at room temperature. The resulting solution was stirred at room
temperature for 16 h before it was concentrated in vacuo. Compound 36
was directly purified by silica gel preparative TLC (petroleum ether/ethyl
acetate=1:4, then 2:3) and isolated as a colorless oil (21.1 mg, 44%). Rf:
0.30 (petroleum ether/ethyl acetate=2:3); [a]D: À42.38 (c=0.68 in
1
CH2Cl2); H NMR (CDCl3, 500 MHz): d=7.31 (d, J=8 Hz, 2H), 6.88 (d,
J=7.5 Hz, 2H), 6.24 (d, J=3.0 Hz, 1H), 5.43 (m, 1H), 5.19 (dd, J=10,
Chem. Eur. J. 2010, 16, 6265 – 6277
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6275

B. M. Trost et al.
J=17 Hz, 1H), 2.30–2.20 (m, 3H), 2.14–2.00 (m, 6H), 1.85–1.79 (m, 3H),
1.72–1.67 (m, 2H), 1.64 (s, 3H), 1.61 (s, 3H), 1.59 (d, J=5.5 Hz, 3H),
1.53 (s, 3H), 1.16 (d, J=7 Hz, 3H), 0.94 ppm (s, 3H); 13C NMR (CDCl3,
125 MHz): d=209.1, 170.4, 162.4, 159.5, 148.4, 137.7, 132.6, 132.4, 131.9,
131.6, 130.5, 129.6, 124.9, 124.3, 121.8, 113.7, 78.8, 71.1, 55.3, 49.7, 47.1,
40.2, 39.3, 37.1, 34.6, 29.5, 27.7, 23.9, 21.6, 17.88, 17.87, 16.2, 15.7, 15.5,
11.1 ppm; IR (film): n˜ =2920, 2851, 1732, 1698, 1634, 1613, 1514, 1463,
1370, 1247, 1019 cmÀ1; HRMS: m/z calcd for C37H50O5 [M]+: 574.365825;
found: 574.367201.
mixture was extracted with ethyl acetate (10 mLꢃ3) and the combined
organic fractions were dried over Na2SO4. Preparative silica gel TLC
(10% MeOH in CH2Cl2) afforded (À)-terpestacin 1 (1.7 mg, 74%). Rf:
1
0.3 (10% MeOH in CH2Cl2); [a]D: À17.7 (c=0.085 in MeOH); H NMR
(CDCl3, 500 MHz): d=5.89 (brs, 1H), 5.40 (m, 1H), 5.24 (dd, J=10,
5.0 Hz, 1H), 5.13 (m, 1H), 4.06 (dd, J=10, 3.5 Hz, 1H), 3.89 (dd, J=
10.5, 7.0 Hz, 1H), 3.82 (dd, J=10, 5.5 Hz, 1H), 2.71 (dd, J=11.5, 2.0 Hz,
1H), 2.68 (m, 1H), 2.44 (d, J=17.0 Hz, 1H), 2.39 (dd, J=13.5, 10.5 Hz,
1H), 2.29–2.21 (m, 2H), 2.13–2.08 (m, 2H), 2.04–1.89 (m, 2H), 1.79–1.67
(m, 3H), 1.64 (s, 3H), 1.63 (s, 3H), 1.57 (s, 3H), 1.29 (d, J=7.0 Hz, 3H),
1.00 ppm (s, 3H); IR (film): n˜ =3347 (br), 2923, 2853, 1694, 1645, 1455,
1029 cmÀ1; HRMS: m/z calcd for C25H38O4 [M]+: 402.277010; found:
402.275848.
Compound 55:
(0.05 mL) was added to
A
solution of 53 (6.5 mg, 0.011 mmol) in tBuOH
mixture of AD-a-mix (21.1 mg) and
a
CH3SO2NH2 (1.6 mg, 0.017 mmol) in H2O (0.1 mL) and tBuOH
(0.05 mL) at 08C. The resulting mixture was stirred at 48C for 2 days,
before it was quenched with Na2SO3
and brine. The mixture was extracted
with ethyl acetate (10 mLꢃ3) and the
combined organic fractions were dried
over Na2SO4. Diols 54 (mixture of dia-
stereomers) were purified by silica gel
Acknowledgements
flash column chromatography (petro-
leum ether/ethyl acetate=7:3, then
We thank the American National Institutes of Health (NIH) (GM33049)
for their generous support of our programs. Mass spectra were provided
by the Mass Spectrometry Regional Center of the University of Califor-
nia, San Francisco, supported by the NIH Division of Research Resour-
ces. G.D. is a Stanford Graduate Fellow. Palladium salts were generously
supplied by Johnson-Matthey.
1:1) to give
a colorless oil (4.5 mg,
65%; 1.2 mg of 53 was recovered).
NaIO4 (19 mg, 0.089 mmol) was added
to
a solution of diol 54 (9.0 mg,
0.015 mmol) in THF/H2O (4:1, 0.2 mL), at 08C. The resulting solution
was stirred at room temperature for 1 h, before it was quenched with
brine. The mixture was then extracted with ethyl acetate (10 mLꢃ3) and
the combined organic fractions were dried over Na2SO4. After the sol-
vent was removed in vacuo, the crude aldehyde was dissolved with a mix-
ture of CH2Cl2 (0.1 mL) and MeOH (0.1 mL). The resulting solution was
cooled to À788C before NaBH4 (3 mg, 0.065 mmol) was added. The mix-
ture was stirred at À788C for 0.5 h before it was quenched with a mixture
of acetone (0.05 mL) and brine (3 mL). The resulting mixture was ex-
tracted with ethyl acetate (3 mLꢃ3) and the combined organic fractions
were dried over Na2SO4. Compound 55 was purified by silica gel flash
column chromatography (petroleum ether/ethyl acetate=7:3, then 3:2)
to give a colorless oil (6.5 mg, 78%). Rf: 0.35 (petroleum ether/ethyl ace-
tate=7:3); [a]D: À57.36 (c=0.60 in CH2Cl2); 1H NMR (CDCl3,
500 MHz): d=7.29 (d, J=8 Hz, 2H), 6.87 (d, J=8 Hz, 2H), 5.44 (m,
1H), 5.35 (d, J=11 Hz, 1H), 5.21 (dd, J=10, 6 Hz, 1H), 5.12 (d, J=
11.5 Hz, 1H), 5.10 (m, 1H), 3.80 (s, 3H), 3.62 (m, 2H), 2.64–2.60 (m,
2H), 2.34–2.22 (m, 5H), 2.13–2.00 (m, 4H), 2.00 (s, 3H), 1.92–1.65 (m,
4H), 1.63 (s, 3H), 1.54 (s, 3H), 1.43 (s, 3H), 1.11 (d, J=7 Hz, 3H),
0.96 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=208.9, 170.5, 160.9,
159.7, 149.2, 138.0, 132.4, 131.9, 131.7, 130.6, 129.2, 124.5, 121.6, 113.8,
79.0, 66.1, 55.4, 49.8, 49.0, 40.2, 39.4, 37.7, 34.6, 28.9, 27.5, 23.9, 21.6, 16.5,
15.6, 15.5, 14.6, 11.1 ppm; IR (film): n˜ =3462 (br), 2923, 2851, 1734, 1700,
1637, 1612, 1515, 1248, 1035, 1019 cmÀ1; HRMS: m/z calcd for C25H36O3
[MÀPMBÀOAc]+: 384.266445; found: 384.262829.
[1] UNAIDS, WHO (December 2007). “2007 AIDS epidemic update”.
Retrieved on 12th March 2008.
[2] E. De Clercq, Design of Anti-AIDS Drugs, Vol. 14 (Ed.: E. De
Clercq), Elsevier, Tokyo, 1990, pp. 1–24.
[3] a) M. Oka, S. Iimura, O. Tenmyo, Y. Sawada, M. Sugawara, H.
Ohkusa, H. Yamamoto, K. Kawano, S. L. Hu, Y. Fukagawa, T. Oki,
J. Antibiot. 1993, 46, 367–373; b) S. Iimura, M. Oka, Y. Narita, M.
Konishi, H. Kakisawa, Q. Gao, T. Oki, Tetrahedron Lett. 1993, 34,
493–496; c) M. Oka, S. Iimura, Y. Narita, T. Furumai, M. Konishi,
T. Oki, Q. Gao, H. Kakisawa, J. Org. Chem. 1993, 58, 1875–1881.
[4] B. Schlegel, M. Schmidtke, H. Dorfelt, P. Kleinwachter, U. Grafe, J.
Basic Microbiol. 2001, 41, 179–183.
[5] Y. Nihashi, C.-H. Lim, C. Tanaka, H. Miyagawa, T. Ueno, Biosci.
Biotechnol. Biochem. 2002, 66, 685–688.
[6] H. J. Jung, H. B. Lee, C. J. Kim, J. R. Rho, J. Shin, H. J. Kwon, J. An-
tibiot. 2003, 56, 492–496.
[7] K. Tatsuta, N. Masuda, H. Nishida, Tetrahedron Lett. 1998, 39, 83–
86.
[8] K. Tatsuta, N. Masuda, J. Antibiot. 1998, 51, 602–606.
[9] A. G. Myers, M. Siu, F. Ren, J. Am. Chem. Soc. 2002, 124, 4230–
4232.
[10] a) J. Chan, T. F. Jamison, J. Am. Chem. Soc. 2003, 125, 11514–
11515; b) J. Chan, T. F. Jamison, J. Am. Chem. Soc. 2004, 126,
10682–10691.
[11] G. O. Berger, M. A. Tius, J. Org. Chem. 2007, 72, 6473–6480.
[12] For a preliminary report of a portion of our work, see: B. M. Trost,
G. Dong, J. A. Vance, J. Am. Chem. Soc. 2007, 129, 4540–4541.
[13] C. Straneo, Gazz. Chim. Ital. 1940, 70, 27–37.
[14] For an example, see: A. A. Ponaras, Tetrahedron Lett. 1980, 21,
4803–4806.
[15] B. M. Trost, G. M. Schroeder, J. Am. Chem. Soc. 2000, 122, 3785–
3786.
[16] Besides this work, there is only one other report of cyclopentene-
1,2-diones with no substituents at C3 and C4: H. D. Martin, M.
Kummer, G. Martin, J. Bartsch, D. Brueck, A. Heinrichs, B. Mayer,
S. Roever, A. Steigel, Chem. Ber. 1987, 120, 1133–1149.
[17] J.-Q. Yu, H.-C. Wu, E. J. Corey, Org. Lett. 2005, 7, 1415–1417.
[18] K. C. Nicolaou, T. Montagnon, P. S. Baran, Angew. Chem. 2002, 114,
1035–1038; Angew. Chem. Int. Ed. 2002, 41, 993–996.
[19] For a Seagusa oxidation of TMS ethers of diosphenols, see: M. Kim,
L. A. Applegate, K. Kawada, D. S. Watt, Synth. Commun. 1990, 20,
989–997.
Compound 1 (terpestacin): LiOH (0.06 mL, 1m) was added to a solution
of 55 (7.3 mg, 0.013 mmol) in THF (0.18 mL) and MeOH (0.06 mL) at
room temperature. The resulting solution was stirred at room tempera-
ture for 2 h, before it was quenched with NaH2PO4 (1m). The mixture
was extracted with ethyl acetate (10 mLꢃ3) and the combined organic
fractions were dried over Na2SO4. The diol was purified by silica gel
column chromatography (petroleum ether/ethyl acetate=1:1, then 3:7)
to give a colorless oil (6.0 mg, 89%). Dry DMS (0.015 mL) was added to
a mixture of the above diol (3.0 mg, 0.0057 mmol) and MgBr2·Et2O
(14.5 mg, 0.056 mmol) in CH2Cl2
(0.2 mL) at À788C. The resulting sus-
pension was stirred at À788C for
10 min, before it was warmed to 08C.
The suspension was stirred at 08C for
10 min and then slowly warmed to
room temperature. The mixture was
stirred at room temperature for
40 min, before it was poured into a
precooled NaCl solution (10 mL). The
6276
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6265 – 6277

(À)-Terpestacin
FULL PAPER
[20] For an example of indium-catalyzed Sakurai allylation, see: P. H.
Lee, K. Lee, S.-Y. Sung, S. Chang, J. Org. Chem. 2001, 66, 8646–
8649.
[21] Kishi has reported a single example of intramolecular 1,4-O addition
into 4-substituted-cyclopentene-1,2-dione in the total synthesis of
batrachotoxinin A: M. Kurosu, L. R. Marcin, T. J. Grinsteiner, Y.
Kishi, J. Am. Chem. Soc. 1998, 120, 6627–6628.
[22] I. J. S. Fairlamb, J. M. Dickinson, M. Pegg, Tetrahedron Lett. 2001,
42, 2205–2208.
[23] Z. Liu, J. Lan, Y. Li, Tetrahedron: Asymmetry 1998, 9, 3755–3762.
[24] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953–
956.
[28] T. Onoda, R. Shirai, S. Iwasaki, Tetrahedron Lett. 1997, 38, 1443–
1446.
[29] The yield for both steps was not optimized.
[30] For an example of Pt-catalyzed diboration of simple alkenes, see: T.
Ishiyama, M. Yamamoto, N. Miyaura, Chem. Commun. 1997, 689–
690.
[31] H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev.
1994, 94, 2483–2547.
[32] The use of CH3CN as the solvent gave a large amount of decompo-
sition.
[33] When a racemic Trost ligand was used, the d.r. was observed to be
about 1:1.
[25] For a recent example of constructing a polyunsaturated macrocycle
through RCM, see: A. Fꢄrstner, C. Nevado, M. Tremblay, C. Chevri-
[34] The AD-mix was freshly prepared by mixing all the required ingre-
dients.
´
er, F. Teply, C. Aꢅssa, M. Waser, Angew. Chem. 2006, 118, 5969–
[35] For a related example, see: M. B. Andrus, S. D. Lepore, J. A. Sclafa-
ni, Tetrahedron Lett. 1997, 38, 4043–4046.
[36] For the preparation of 42, see: A. R. Haight, E. J. Stoner, M. J. Pe-
terson, V. K. Grover, J. Org. Chem. 2003, 68, 8092–8096.
5974; Angew. Chem. Int. Ed. 2006, 45, 5837–5842.
[26] The geometry of the newly formed E olefin was determined by an
NMR 1D nOe experiment between the C13 vinyl proton and the
C11 proton. Isolation of the minor Z isomer proved difficult due to
contamination by other byproducts.
[27] S. T. Nguyen, L. K. Johnson, R. H. Grubbs, J. W. Ziller, J. Am.
Chem. Soc. 1992, 114, 3974–3975.
Received: December 8, 2009
Published online: April 21, 2010
Chem. Eur. J. 2010, 16, 6265 – 6277
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6277