Electrophilic aromatic prenylation via cascade cyclization

Article abstract of DOI:10.1016/j.tet.2013.08.056

To gain access to prenylated hexahydroxanthenes, tandem cascade cyclization-electrophilic aromatic substitution reactions have been studied on substrates bearing allylic and propargylic substituents. Both BF ₃·OEt₂ and TMSOTf can be used to initiate this reaction sequence, resulting in different ratios of the C-2 and C-6 substitution products. Even though allylic transposition is observed in some cases, the results of a crossover experiment are consistent with an intramolecular reaction sequence. Taken together, these studies now allow preparation of either the C-2 or C-6 prenylated hexahydroxanthene products.

Full text of DOI:10.1016/j.tet.2013.08.056

Tetrahedron 69 (2013) 9212e9218
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electrophilic aromatic prenylation via cascade cyclization
*
John G. Kodet, Joseph J. Topczewski, Kevyn D. Gardner, David F. Wiemer
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2013
Received in revised form 19 August 2013
Accepted 20 August 2013
Available online 28 August 2013
To gain access to prenylated hexahydroxanthenes, tandem cascade cyclizationeelectrophilic aromatic
substitution reactions have been studied on substrates bearing allylic and propargylic substituents. Both
BF3$OEt2 and TMSOTf can be used to initiate this reaction sequence, resulting in different ratios of the C-2
and C-6 substitution products. Even though allylic transposition is observed in some cases, the results of
a crossover experiment are consistent with an intramolecular reaction sequence. Taken together, these
studies now allow preparation of either the C-2 or C-6 prenylated hexahydroxanthene products.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cationic
Cyclization
Electrophilic aromatic substitution
Prenylation
Tandem reactions
1. Introduction
substitution on resorcinols bearing allylic and propargylic sub-
stituents, some of which are isoprenoid and others that might be
Prenylated aromatic compounds are common natural products
and individual examples are known to possess a wide variety of
biological properties. Various compounds in the broad family dis-
play activity as anti-proliferative,1,2 anti-oxidant,3e5 chemo-pre-
ventative,6 CNS modulating,7,8 or immunosuppressant agents,9 and
as insect repellents.10,11 Common methods for incorporation of
a prenyl moiety into an aromatic system include the use of lithiated
intermediates,12e15 an approach which displays limited functional
group tolerance, FriedeleCrafts alkylation,12,16e18 which often
proceeds in modest yield even with an excess of the arene, or
Claisen rearrangements,19e22 where the regiochemistry both about
the allylic system and in the arene can be difficult to control. Our
preliminary account23 of a new reaction sequence based on cascade
cyclization with tandem electrophilic aromatic substitution (Fig. 1)
suggested a route to prenylated aromatic compounds with the
potential to overcome at least some of these limitations. Further-
more, cascade cyclization via an epoxide intermediate allows for-
mation of several new bonds in a single reaction,24 with the A- and
B-ring absolute stereochemistry ultimately derived from the re-
agents employed for epoxide formation. The value of this approach
is only enhanced to the extent that it can be coupled with a regio-
selective electrophilic aromatic substitution reaction,25 because
different isoprenoid substituents often are found at specific posi-
tions on the aromatic ring.26e30 This report describes efforts to
bring about cascade cyclization with electrophilic aromatic
viewed as precursors to isoprenoid groups, and delineates strate-
gies that allow preparation of different prenylated regioisomers.
In the initial description of this sequence,23 epoxide 1 was
converted to the tricyclic compound 2 through a process initiated
by treatment with BF3$OEt2. The product was elaborated to the
natural product (þ)-angelichalcone (3).23 A subsequent effort
employed the aromatic system 4, demonstrated transformation of
the tandem reaction product 5 to a phenol, and ultimately to
(þ)-schweinfurthin A (6).25 Those results suggested that the ability
of the phenolic substituent to stabilize at least a partial positive
charge was central to its participation in the tandem sequence.
Given the delocalization available in a prenyl cation,31 and the roles
that such cations play in biosynthesis,32 there was reason to believe
that a parallel process might be observed with a prenyl ether.
However, nothing was known about the regiochemistry of the
process either with respect to the site of EAS or that within
a resulting prenyl substituent. Our studies of these questions are
the subject of this report.
2. Results and discussion
To this point only one allylic substituent has been examined for
participation in this tandem reaction sequence, the diallyl ether 7
(Scheme 1).25 Brief treatment of epoxide 7 with BF3$OEt2 gave the
tandem product 8 in low yield (8%) along with a significant amount
of the cyclic ether 9 (32%).25 Because the C-allyl substituent can be
viewed as a precursor to a prenyl group (vide infra), our interest
was drawn to procedures that might optimize the formation of
* Corresponding author. Tel.: þ1 319 335 1365; fax: þ1 319 335 1270; e-mail
address: david-wiemer@uiowa.edu (D.F. Wiemer).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.056

J.G. Kodet et al. / Tetrahedron 69 (2013) 9212e9218
9213
H3CO
OCH3
OCH3
O
O
O
O
BF3 OEt2
71%
O
O
HO
HO
OMOM
H
H
H
OMOM
OBn
OH
1
2
3 ((+)-angelichalcone)
OBn
OH
O
HO
O
O
BF3 OEt2
50%
OH
HO
HO
6 ((+)-schweinfurthin A)
H
OCH3
OCH3
5
H
4
2
OH
Fig. 1. Applications of cascade cyclizations with tandem electrophilic aromatic substitution.
compound 8. One strategy for increasing the yield of the desired
hexahydroxanthene products would be to diminish formation of
the bridged A-ring ether by-products. Because these side products
presumably are formed from attack of the A-ring oxygen on a ter-
tiary carbocation, we hypothesized that opening the epoxide with
a Lewis acid that hindered this capture might increase the forma-
tion of hexahydroxanthene products. While some Lewis acids other
than BF3$OEt2 have been studied with limited success,33 one which
fit this new hypothesis and had not been studied was TMSOTf.34
the A-ring ether 9 was isolated as a 3:2 mixture of diastereomers.
This partial epimerization may indicate an appreciably long-lived
carbocation or some degree of reversibility in the cascade.35 Fur-
thermore, the elimination product 11 also became significant,
which may support the concept of a long-lived carbocation. Finally,
in striking contrast to the BF3$OEt2 mediated reactions of com-
pound 7, upon treatment with TMSOTf the regiochemistry of the
product hexahydroxanthene varied and the distal isomer 10 now
was found as the major product. Unfortunately, further efforts to
optimize use of TMSOTf went unrewarded.
It is possible that a more highly substituted allylic system would
afford the tandem product in better yield than the allyl case, es-
pecially if the substituent(s) would provide more stabilization to
a cationic intermediate. However, incorporation of substituents
that would afford unsymmetrical allyl cations also would present
issues of regiochemistry and/or stereochemistry that do not trouble
the parent allyl ether, and may afford still more complex product
mixtures. The crotyl derivative was examined based on the hy-
pothesis that the added methyl group would stabilize the putative
cationic intermediate relative to the parent allyl group. After
preparation of the epoxide 12 through standard methods,25,36 ex-
posure of this epoxide to BF3$OEt2 resulted in facile cyclization
(Scheme 2). In this case, the predominant product had undergone
hexahydroxanthene formation with concurrent aromatic sub-
stitution, and it had done so in a reasonably attractive yield (58%).
This reaction furnished the substitution product 13 as a mixture of
diastereomers (w2:1) at the new benzylic position. The observed
regiochemistry of the substituent can be explained through
electrophilic aromatic substitution via the more substituted
allylic terminus, and the linear isomer was not detected in any
measurable amount. To determine if the olefin stereochemistry was
involved in the transfer of stereochemical information to the new
benzylic position, commercial crotyl chloride also was employed to
prepare the substrate 12 as a w3:1 mixture of olefin isomers. When
this material was treated with BF3$OEt2 under standard conditions,
the only product observed was the C-2 substituted hexahydrox-
anthene, and it was isolated as a w2.5:1 mixture of the branched
diastereomers. Because both the pure E-olefin 12 and the mixed E/Z
material gave the branched product as a mixture of diastereomers
in a similar ratio, it appears likely that formation of this center is not
determined directly by the olefin stereochemistry of the starting
material.
O
O
O
O
O
HO
H
(+)-8 (8%)
(+)-9 (32%)
.
BF3 OEt2
O
O
O
(+)-7
TMSOTf
(+)-8 (10%)
(+)-9 (18%; dr 3:2)
O
O
O
O
HO
HO
H
H
(+)-11 (17%)
(+)-10 (32%)
Scheme 1. Tandem reactions of allyl ether 7.
To this end, the allyl epoxide 7 was treated with TMSOTf and
four major products were isolated (Scheme 1). As one might an-
ticipate, formation of the A-ring ether was affected, and it was
impacted in several ways. First of all, under the TMSOTf conditions
Several related systems also were examined in an effort to gauge
the scope of this process. A known two-step method was used to
introduce the propargyl groups of the bis ethers 14 and 17.37,38
When epoxide 14 was subjected to the standard cascade

9214
J.G. Kodet et al. / Tetrahedron 69 (2013) 9212e9218
CH3 NMR). While prenylation at either C-2 or C-6 could be useful, for-
CH3
CH3
mation of a mixture of the two regioisomeric products, with one
product further complicated as a mixture of olefin isomers, was less
attractive. However, compound 10 undergoes cross-metathesis
with 2-methyl-2-butene in 83% yield to give the prenyl derivative
25, a product that was not available as a pure isomer by direct
cyclization of the prenyl epoxide 22. Thus, both the C-2 and C-6
prenyl arenes 23 and 25 can be obtained selectively by this general
methodology, although different reaction sequences appear to be
required.
H3C
O
O
O
O
.
BF3 OEt2
HO
O
(+)-12
(+)-13 (58%)
Scheme 2. Tandem reaction of crotyl ether 12.
conditions (Scheme 3), the major product was the bridged A-ring
ether 15 (47%) although it was accompanied by the hexahydrox-
anthene 16 in low yield (14%). The parallel reaction of the propargyl
ether 17 gave only the bridged A-ring ether 18 (47%), and the
hexahydroxanthene 19 was not detected in this reaction mixture. A
standard reduction of compound 14 over Lindlar’s catalyst gave the
corresponding ‘reversed’ prenyl compound 20. When epoxide 20
was subjected to cascade conditions, the bridged A-ring ether 21
was isolated in low yield (12%) as the only identifiable product from
a very complicated mixture.
2
O
O
O
O
O
.
BF3 OEt2
1
HO
H
O
(+)-22
(+)-7
(+)-23 (33%)
+
O
Grubbs 2nd
53%
1
HO
HO
6
H
(+)-24 (18%)
R
R
R
+
R
O
O
O
Grubbs 2nd
O
O
O
O
1
HO
6
H
H
H
R
R
R
(+)-10
(+)-25 (11%)
(+)-15 R = CH3 (47%)
(+)-18 R = H (47%)
R
Scheme 4. Synthesis and tandem reaction of prenyl ether 22.
O
O
.
BF3 OEt2
+
R
R
O
O
O
In contrast to the reaction with BF3$OEt2, treatment of com-
pound 22 with 1 equiv of TMSOTf resulted in a 20% yield of
a mixture of compounds 24 and 25 in a ratio of 5:2, respectively.
Although compound 23 was not observed under these condi-
tions, it was obtained when the TMSOTf was used in excess
(2.6 equiv gave a 14% yield of 23) while amounts of compounds
24 and 25 decreased and more undesired side products were
observed.
(+)-14 R = CH3
(+)-17 R = H
HO
H
(+)-16 R = CH3(14%)
(+)-19 R = H (--)
H2
73%
Lindlar
The various allylic and propargylic systems examined yield
a number of different product types, and they also lead to in-
creased understanding of this complicated reaction sequence. One
might consider two explanations for the absence of the linear
isomer from the crotyl epoxide 12. The more straightforward one
is that the branched product is the result of enhanced cationic
character at the more substituted terminus of the allylic system. A
second potential explanation would be that the mechanism of this
process with allylic substrates is based upon a Claisen rearrange-
ment pathway.41,42 However, if the Claisen mechanism were op-
erative in all cases, then one would expect a reversed prenyl group
at the C-2 position in the product obtained from compound 22,
and that was not observed.
The selectivity observed for the normal prenylated product 23
at the C-2 position (Scheme 4), and the observed mixture of
isomers found in the C-6 substituted product (24 and 25), sug-
gested that the C-6 products might arise from an intermolecular
process while the C-2 product might result from an intra-
molecular process. Previous studies have shown that another C-2
substituted hexahydroxanthene results from an intramolecular
transfer,23 but the nature of substitution at the C-6 position has
not yet been examined. To explore the process leading to for-
mation of the C-6 product, a new type of crossover experiment
O
O
O
O
O
.
BF3 OEt2
O
H
(+)-20
(+)-21 (12%)
Scheme 3. Reactions of propargyl ethers 14 and 17.
To extend this study further in the prenyl series, epoxide 22 was
prepared from epoxide 7 through a metathesis reaction with 2-
methyl-2-butene and Grubbs’ second generation catalyst under
Lipshutz’s conditions (Scheme 4).39,40 Cyclization of the resulting
prenyl epoxide 22 upon treatment with BF3$OEt2 provided three
hexahydroxanthene products, and all of those had undergone ar-
omatic substitution. Based on the 1H NMR spectrum, it was clear
that the major product 23 bears a ‘normal’ prenyl substituent at the
C-2 position. The other two compounds had undergone sub-
stitution at the C-6 position, which might be expected from a more
stabilized cation,25 and were obtained as an inseparable mixture of
allylic isomers with the reversed prenyl compound 24 dominating
over the normal prenyl isomer 25 (18% and 11%, respectively, by 1H

J.G. Kodet et al. / Tetrahedron 69 (2013) 9212e9218
9215
was conducted (Scheme 5). Highly deuterated isoprenoids have
been employed in a variety of studies of terpene biosynthesis,43
and they commonly have been prepared through Wittig chem-
istry.44e46 To begin this study, the deuterium labeled prenyl ep-
H3C
CH3
CH3
H3C
CH3
H3C
CH3
H3C
O
2
O
O
O
oxide 28 was synthesized through
a metathesis strategy.
Hexadeutero-2-methyl-2-butene (27)47,48 was prepared by
Wittig condensation of acetone-d6 (26) with ethylidene triphe-
nylphosphorane prepared in situ from the corresponding phos-
phonium bromide. Due to the volatility of the deuterated olefin
27, it was prepared as a solution in THF and then used directly in
the cross metathesis reaction to provide labeled epoxide 28. After
a w60:40 mixture of epoxides 28 and 22 was subjected to
standard cyclization conditions, the hexahydroxanthene prod-
ucts were isolated and analyzed by GCeMS in comparison to
authentic samples. This analysis revealed that D0 and D12 com-
pounds were present, but little D6 product was observed (Table
1). The near absence of any crossover products suggested that
both the C-2 and C-6 substituted compounds arise from an
intramolecular process (or processes), despite the loss of selec-
tivity about the allylic system.
6'
2'
BF3
6
F3BO
O
H
22
29
CH3
CH3
CH3
23
CH3
H3C
CH3
+
24
and
25
O
O
F3BO
H
30
Scheme 6. A possible mechanistic rationale.
Br-
+
CD
3. Conclusion
3 D3C
O
CD3
7
(C6H5)3PCH2CH3
CH3
CD3
Grubbs 2nd
O
C6H5Li
CD3
O
In conclusion, these studies have expanded the scope of cascade
cyclizations terminated by electrophilic aromatic substitution in
several ways. For the first time TMSOTf has been shown to serve as
a Lewis acid able to bring about the tandem cascade cycliza-
tioneelectrophilic aromatic substitution sequence, and its use has
provided a unique product distribution. Through variations of these
procedures, it now is possible to obtain the regioisomeric prenyl-
substituted hexahydroxanthenes 23 and 25. During the course of
this work, a crossover experiment established that both the C-2 and
the C-6 substitution products are formed at least predominantly
through an intramolecular process, which increases the mecha-
nistic understanding of this tandem sequence. Thus it appears
likely that further studies of this reaction sequence will unveil
additional applications.
53%
D3C
CD3
D3C
26
27
O
(+)-28
(+)-28
.
BF3 OEt2
(+)-23
+
(+)-24 + (+)-25
+
(+)-22
Scheme 5. A crossover experiment.
Table 1
Distribution of deuterium in attempted crossover experiments
4. Experimental
Trial
Starting material (%)
Product
Isotopic distribution (%)
22 (D0)
28 (D12
)
D0
D6
D12
4.1. General experimental
1
2
41
59
23
24/25
23
27
29
27
28
8
8
10
7
65
63
63
65
Tetrahydrofuran and ether were freshly distilled from sodium/
benzophenone. Methylene chloride and triethylamine were dis-
tilled from calcium hydride prior to use. All other reagents and
solvents were purchased from commercial sources and used
without further purification. All reactions in nonaqueous solvents
were conducted in flame dried glassware under a positive pressure
of argon and with magnetic stirring. NMR spectra were obtained at
300e500 MHz for 1H, and 75e125 MHz for 13C with CDCl3 or
40
60
24/25
A single mechanism that would unify these data is difficult to
envision. With phenolic substituents that contain an allylic sys-
tem, for example, compound 22 (Scheme 6), an initial cyclization
might afford the oxonium ion 29 where [3,3] rearrangements
clearly would be possible. However, with the prenyl system
found in compound 22, such a rearrangement of intermediate 29
to provide the C-2 product would be expected to occur with al-
lylic transposition, contrary to the retention of the olefinic po-
sition that is observed. At the same time, rearrangement to the C-
6 substituted product would require two allylic transpositions, or
net retention,49 which is contrary to the mixture of compounds
24 and 25 that is formed. Thus it may be more likely that dis-
sociation of intermediate 29 to an allylic cation and compound
30 is followed by electrophilic aromatic substitution to afford the
observed mixture of products 23e25, and the lack of significant
crossover products suggests that the substitution would have to
be fast.
CD3OD as solvent, and (CH3)4Si (1H, 0.00 ppm) or CDCl3 13C,
(
77.0 ppm) or CD3OD (13C, 49.0 ppm) as internal standards unless
otherwise noted. High resolution mass spectra were obtained at the
ꢀ
University of Iowa Mass Spectrometry Facility. Silica gel (60 A,
0.040e0.063 mm) was used for flash chromatography.
4.2. General procedure for cascade cyclizations with BF3$OEt2
To a solution of the epoxide (w0.20 mmol) in CH2Cl2 (25 mL)
at ꢀ78 ꢁC was added BF3$OEt2 (0.20 mL, 1.6 mmol). After 10 min,
the reaction was quenched by addition of triethylamine (0.5 mL),
diluted with HCl, and extracted with CH2Cl2. The organic phase
was washed with water followed by brine, dried (MgSO4), fil-
tered, and concentrated in vacuo. Final purification by column

9216
J.G. Kodet et al. / Tetrahedron 69 (2013) 9212e9218
chromatography (ethyl acetate in hexanes) afforded products as
indicated below, generally as colorless oils.
38.9, 36.6, 25.9, 25.7, 23.8, 19.0; HRMS (EI) m/z calcd for C22H26O3
(Mþ) 338.1882, found 338.1882.
4.2.1. (E)-6-(But-2-enyloxy)-5-(but-3-en-2-yl)-1,1,4a-trimethyl-
2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (13). According to the
general procedure, a solution of epoxide 1236 (114 mg, 0.31 mmol)
in CH2Cl2 (60 mL) at ꢀ78 ꢁC was treated with BF3$OEt2 (0.20 mL,
1.6 mmol). After 10 min, the reaction was quenched, and standard
work-up gave compound 13 as a 2.1:1 mixture of diastereomers
4.2.4. 2-(2,4-Bis(2-methylbut-3-en-2-yloxy)benzyl)-1,3,3-trimethyl-
7-oxabicyclo[2.2.1]heptane (21). According to the general pro-
cedure, epoxide 20 (65 mg, 0.16 mmol) in CH2Cl2 (32 mL) at ꢀ78 ꢁC
was treated with BF3$OEt2 (0.1 mL, 0.8 mmol). After 8 min, standard
work-up and purification by column chromatography gave ether 21
(8 mg, 12%): 1H NMR (CDCl3)
d
6.98 (d, J¼8.5 Hz, 1H), 6.69 (d,
(66 mg, 58%). For the major component: 1H NMR (CDCl3)
d
6.83 (dd,
J¼2.4 Hz, 1H), 6.49 (dd, J¼8.3, 2.5 Hz, 1H), 6.12 (dd, J¼10.9, 4.9 Hz,
1H), 6.06 (dd, J¼10.9, 4.9 Hz, 1H), 5.20e5.07 (m, 4H), 3.72 (d,
J¼5.2 Hz, 1H), 2.63e2.48 (m, 2H), 1.98e1.88 (m, 2H), 1.76e1.52 (m,
3H), 1.46 (s, 6H), 1.39 (s, 6H), 1.28 (s, 3H), 1.00 (s, 3H), 0.91 (s, 3H);
J¼8.5, 0.9 Hz, 1H), 6.43 (d, J¼8.4 Hz, 1H), 6.25 (ddd, J¼17.2, 10.1,
6.9 Hz, 1H), 5.85e5.76 (m, 1H), 5.74e5.66 (m, 1H), 4.99 (ddd, J¼17.3,
2.0, 1.6 Hz, 1H), 4.87 (ddd, J¼10.2, 2.1, 1.4 Hz, 1H), 4.41e4.39 (m, 2H),
4.16e4.08 (m, 1H), 3.42 (dd, J¼11.6, 4.1 Hz, 1H), 2.67e2.62 (m, 2H),
2.01 (dt, J¼12.6, 3.2 Hz, 1H), 1.87e1.58 (m, 7H), 1.53 (br s, 1H), 1.34
(d, J¼7.2 Hz, 3H), 1.17 (s, 3H), 1.07 (s, 3H), 0.85 (s, 3H); 13C NMR
13C NMR (CDCl3)
d 154.1,153.6,144.7,144.5,129.3,126.9,114.5,113.0,
113.0, 112.5, 86.9, 86.1, 79.3, 79.2, 53.9, 45.6, 39.0, 27.7, 27.3, 27.2,
26.9, 26.8, 25.9, 25.8, 23.8, 19.1; HRMS (EI) m/z calcd for C26H38O3
(Mþ) 398.2821, found 398.2820.
(CDCl3)
105.3, 78.1, 75.9, 69.7, 46.7, 38.2, 37.7, 33.5, 28.2, 27.2, 22.8,19.8,18.4,
17.9, 14.2. For the minor diastereomer: 1H NMR (CDCl3)
6.83 (dd,
d 155.3, 151.6, 143.4, 129.0, 127.1, 126.8, 121.8, 114.9, 111.8,
d
4.2.5. 1,1,4a-Trimethyl-5-(3-methylbut-2-enyl)-6-(3-methylbut-2-
enyloxy)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (23). According
to the general procedure, a solution of epoxide 22 (81 mg,
0.20 mmol) in CH2Cl2 (25 mL) at ꢀ78 ꢁC was treated with BF3$OEt2
(0.20 mL, 1.6 mmol). After 10 min, the reaction was quenched, and
standard work-up gave compound 23 (25 mg, 31%) along with
a mixture of compounds 24 and 25 (23 mg, 28% total, 3:2 24:25).
J¼8.5, 0.9 Hz, 1H), 6.43 (d, J¼8.4 Hz, 1H), 6.26 (ddd, J¼17.1, 10.1,
7.4 Hz, 1H), 5.85e5.76 (m, 1H), 5.74e5.66 (m, 1H), 4.98 (ddd, J¼17.2,
2.1, 1.4 Hz, 1H), 4.85 (ddd, J¼10.1, 2.1, 1.1 Hz, 1H), 4.41e4.39 (m, 2H),
4.16e4.08 (m, 1H), 3.42 (dd, J¼11.6, 4.1 Hz, 1H), 2.67e2.62 (m, 2H),
2.01 (dt, J¼12.6, 3.2 Hz, 1H), 1.87e1.58 (m, 7H), 1.53 (br s, 1H), 1.36
(d, J¼7.2 Hz, 3H), 1.19 (s, 3H), 1.07 (s, 3H), 0.85 (s, 3H); 13C NMR
(CDCl3)
d
155.3, 151.4, 143.2, 129.0, 127.1, 126.8, 121.7, 114.9, 111.9,
For compound 23: 1H NMR (CDCl3)
d
6.84 (d, J¼8.4 Hz, 1H), 6.44 (d,
105.4, 78.1, 75.9, 69.7, 46.7, 38.2, 37.8, 33.8, 28.2, 27.2, 22.8,19.6,18.7,
17.9, 14.2; HRMS (EI) m/z calcd for C24H34O3 (Mþ) 370.2508, found
370.2504.
J¼8.4 Hz, 1H), 5.48 (t, J¼6.4 Hz, 1H), 5.20 (t, J¼7.4 Hz, 1H), 4.47 (d,
J¼6.5 Hz, 2H), 3.42 (dd, J¼11.5, 7.4 Hz, 1H), 3.28 (d, J¼7.4 Hz, 2H),
2.65e2.62 (m, 2H), 2.00 (dt, J¼12.2, 3.2 Hz, 1H), 1.87e1.82 (m, 1H),
1.79e1.69 (m, 4H), 1.77 (s, 3H), 1.77 (s, 3H), 1.71 (s, 3H), 1.64 (s, 3H),
4.2.2. 2-(2,4-Bis(2-methylbut-3-yn-2-yloxy)benzyl)-1,3,3-trimethyl-
7-oxabicyclo[2.2.1]heptanes and 1,1,4a-trimethyl-6-(2-methylbut-
3-yn-2-yloxy)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (15 and
16). According to the general procedure, epoxide 1436 (51 mg,
0.13 mmol) in CH2Cl2 (26 mL) was treated with BF3$OEt2 (0.08 mL,
0.65 mmol). After 10 min, standard work-up and purification by
column chromatography gave compound 15 (24 mg, 47%) and
compound 16 (6 mg, 14%), both as colorless oils. For compound 15:
1.17 (s, 3H), 1.08 (s, 3H), 0.86 (s, 3H); 13C NMR (CDCl3)
d 155.6, 151.2,
136.6, 130.3, 126.6, 123.1, 120.7, 118.1, 114.4, 104.4, 78.2, 75.8, 65.5,
46.9, 38.3, 37.9, 28.3, 27.3, 25.9, 25.7, 22.7, 22.4, 20.0, 18.2, 17.9, 14.2;
HRMS (EI) m/z calcd for C26H38O3 (Mþ) 398.2821, found 398.2825.
4.2.6. 1,1,4a-Trimethyl-7-(3-methylbut-2-enyl)-6-(3-methylbut-
2-enyloxy)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol and 1,1,4a-tri-
methyl-6-(3-methylbut-2-enyloxy)-7-(2-methylbut-3-en-2-yl)-
2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (24 and 25). 1H NMR
1H NMR (CDCl3)
d
7.46 (d, J¼2.4 Hz, 1H), 7.06 (d, J¼8.4 Hz, 1H), 6.74
(dd, J¼8.4, 2.4 Hz, 1H), 3.73 (d, J¼5.3 Hz, 1H), 2.59e2.55 (m, 2H),
2.56 (s, 1H), 2.54 (s, 1H), 1.95e1.90 (m, 2H), 1.72e1.65 (m, 1H), 1.68
(s, 6H), 1.63 (s, 6H), 1.58e1.51 (m, 1H), 1.47e1.42 (m, 1H), 1.28 (s,
(CDCl3) d 6.92 (s, 1H), 6.79 (s, 0.7H), 6.31 (s, 1H), 6.31 (s, 0.7H), 6.21
(dd, J¼14.8, 10.7 Hz, 1H), 5.50 (m, 1.7H), 5.29 (m, 0.7H), 4.96 (dd,
J¼14.0 Hz, 1.6 Hz, 1H), 4.92 (dd, J¼7.0, 1.6 Hz, 1H), 4.42 (m, 3.4H),
3.41 (dd, J¼11.2, 4.2 Hz, 1.7H), 3.23 (d, J¼7.3 Hz, 1.4H), 2.61 (m,
3.4H), 1.99 (m, 1.7H), 1.84 (m, 1.7H), 1.75e1.65 (m, 6.8H), 1.78 (s,
5.1H), 1.74 (s, 2.1H), 1.70 (s, 5.1H), 1.68 (s, 2.1H), 1.43 (s, 6H), 1.22 (s,
3H), 1.21 (s, 2.1H), 1.09 (s, 3H), 1.08 (s, 2.1H), 0.87 (s, 3H), 0.86 (s,
3H), 1.00 (s, 3H), 0.93 (s, 3H); 13C NMR (CDCl3)
d 153.7, 153.5, 129.5,
127.7, 114.9, 112.0, 89.9, 86.4, 86.2, 86.1, 73.5, 73.4, 72.3, 71.7, 54.0,
45.6, 39.0, 29.7, 29.6, 29.6, 29.5, 27.5, 25.9, 25.8, 23.8, 19.1; HRMS
(EI) m/z calcd for C26H34O3 (Mþ) 394.2508, found 394.2504. For
compound 16: 1H NMR (CDCl3)
d
6.95 (d, J¼8.3 Hz, 1H), 6.70 (dd,
2.1H); 13C NMR (CDCl3)
d 156.7,155.7,151.7,151.4,148.5,136.9,136.4,
J¼8.3, 2.5 Hz, 1H), 6.66 (d, J¼2.4 Hz, 1H), 3.42 (dd, J¼11.5, 4.2 Hz,
1H), 2.67e2.63 (m, 2H), 2.55 (s, 1H), 2.01e1.97 (m, 1H), 1.87e1.82
(m, 1H), 1.78e1.60 (m, 4H), 1.62 (s, 3H), 1.61 (s, 3H), 1.27 (s, 3H), 1.09
131.7, 129.6, 128.5,127.8, 123.2,122.1, 120.3,112.8, 112.2, 109.4,101.5,
100.6, 78.1, 78.1, 76.3, 76.2, 65.1, 65.0, 47.3, 47.2, 40.0, 38.4, 38.3, 37.8,
28.2, 27.7, 27.4, 27.4, 27.3, 27.2, 25.9, 25.7, 25.6, 22.5, 22.3, 20.0, 19.9,
18.1, 17.7, 14.3, 14.2; HRMS (EI) m/z calcd for C26H38O3 (Mþ)
398.2821, found 398.2815.
(s, 3H), 0.87 (s 3H); 13C NMR (CDCl3)
d 154.7, 153.2, 129.5, 116.5,
113.7, 110.0, 86.3, 78.1, 76.3, 73.6, 72.2, 47.0, 38.4, 37.8, 29.6, 29.6,
28.3, 27.3, 22.6, 19.9, 14.3; HRMS (EI) m/z calcd for C21H28O3 (Mþ)
328.2038, found 328.2034.
4.3. Cyclization of epoxide 7 with TMSOTf
4.2.3. (E)-3-(5-(2,4-Bis(prop-2-ynyloxy)phenyl)-3-methylpent-3-
enyl)-2,2-dimethyloxirane (18). According to the general procedure,
epoxide 1736 (89 mg, 0.26 mmol) in CH2Cl2 (53 mL) at ꢀ78 ꢁC was
treated with BF3$OEt2 (0.17 mmol, 1.3 mmol). After 10 min, stan-
dard work-up and purification by column chromatography gave
4.3.1. 7-Allyl-6-(allyloxy)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-
1H-xanthen-2-ol (10). To
a solution of epoxide 7 (90 mg,
0.26 mmol) in CH2Cl2 (30 mL) at ꢀ78 ꢁC was added TMSOTf
(0.25 mL, 1.4 mmol). After 12 min, the reaction was quenched by
addition of 1 N HCl (10 mL), diluted with water, and extracted with
CH2Cl2. The organic phase was washed with brine, dried (MgSO4),
filtered, and the filtrate was concentrated in vacuo. Final purifica-
tion by column chromatography (20% ethyl acetate in hexanes)
afforded a mixture of compounds 9 (16 mg, 18%), 11 (15 mg, 17%), 10
(29 mg, 32%), and the known compound 824 (9 mg, 10%) as yellow
ether 18 (42 mg, 47%) as a colorless oil: 1H NMR (CDCl3)
d 7.10 (d,
J¼8.4 Hz, 1H), 6.60 (d, J¼2.4 Hz, 1H), 6.52 (dd, J¼8.3, 2.5 Hz, 1H),
4.68e4.66 (m, 4H), 3.74 (d, J¼5.3 Hz,1H), 2.59e2.57 (m, 2H), 2.54 (t,
J¼2.3 Hz, 1H), 2.50 (t, J¼2.4 Hz, 1H), 1.97e1.47 (m, 5H), 1.30 (s, 3H),
1.00 (s, 3H), 0.97 (s, 3H); 13C NMR (CDCl3)
d 156.4, 156.1, 130.1, 124.1,
105.6, 100.6, 86.9, 86.0, 78.6, 78.5, 75.5, 75.4, 55.9, 55.8, 54.2, 45.6,
oils. For the title compound 10: 1H NMR (CDCl3)
d 6.82 (s, 1H), 6.29

J.G. Kodet et al. / Tetrahedron 69 (2013) 9212e9218
9217
(s, 1H), 6.08e5.93 (m, 2H), 5.40 (m, 1H), 5.24 (m, 1H), 5.03 (m, 2H),
4.46 (m, 2H), 3.41 (dd, J¼11.4, 4.4 Hz, 1H), 3.32 (d, J¼6.2 Hz, 2H),
2.62 (m, 2H), 1.98 (dt, J¼12.4, 3.3 Hz, 1H), 1.85 (dq, J¼12.8, 3.8 Hz,
1H), 1.73 (td, J¼13.6, 3.2 Hz, 1H), 1.67e1.58 (m, 2H), 1.48 (br, 1H),
64.2, 58.3, 36.3, 27.8, 27.4, 25.8, 25.7, 24.8, 18.7, 18.2, 18.1, 16.0;
HRMS (EI) m/z calcd for C26H38O3 (Mþ) 398.2821, found 398.2816.
4.6. 1,1,4a-Trimethyl-7-(3-methylbut-2-enyl)-6-(3-methylbut-
2-enyloxy)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (25)
1.21 (s, 3H), 1.08 (s, 3H), 0.87 (s, 3H); 13C NMR (CDCl3)
d
155.4, 151.9,
137.6, 133.5, 130.2, 120.7, 116.7, 115.0, 113.3, 100.8, 78.1, 76.3, 68.7,
47.2, 38.4, 37.8, 33.8, 28.2, 27.4, 22.3, 19.8, 14.3; HRMS (EI) m/z calcd
for C22H30O3 (Mþ) 342.2195, found 342.2197.
To a suspension of compound 10 (28 mg, 0.082 mmol) in PTS
(0.3 mL, 2.5% w/v in water) in a screw-cap vial at rt was added 2-
methyl-2-butene (0.1 mL, 0.94 mmol) followed by Grubb’s second
generation catalyst (10 mg, 0.012 mmol). After 2 h, the reaction
mixture was diluted with ethyl acetate and filtered through Celite.
The filtrate was concentrated in vacuo and final purification by
column chromatography (20% ethyl acetate in hexanes) to afford
4.3.2. 2-(2,4-Bis(allyloxy)benzyl)-1,3,3-trimethyl-7-oxabicyclo[2.2.1]
heptane (9). Obtained as a 3:2 ratio of diastereomers. 1H NMR
(CDCl3)
d
7.05 (d, J¼8.4 Hz, 1H), 7.01 (d, J¼8.2 Hz, 0.65H), 6.45e6.40
(m, 3.3H), 6.09e6.01 (m, 3.3H), 5.44e5.39 (m, 3.3H), 5.30e5.25 (m,
3.3H), 4.52 (m, 6.6H), 3.79 (d, J¼5.3 Hz, 0.65H), 3.73 (d, J¼5.4 Hz,
1H), 2.64 (dd, J¼14.2, 7.0 Hz, 0.65H), 2.60 (d, J¼7.6 Hz, 2H), 2.42 (dd,
J¼14.2, 8.4 Hz, 0.65H), 1.95e1.42 (m, 8.5H), 1.30 (s, 3H), 1.09 (s, 2H),
1.02 (s, 2H), 1.01 (s, 3H), 0.94 (s, 3H), 0.90 (s, 2H).
compound 25 (27 mg, 83%) as a colorless oil: 1H NMR (CDCl3)
d 6.79
(s, 1H), 6.30 (s, 1H), 5.48 (m, 1H), 5.28 (t, J¼7.4 Hz, 1H), 4.43 (m, 2H),
3.41 (dd, J¼11.4, 4.2 Hz, 1H), 3.22 (d, J¼7.4 Hz, 2H), 2.65e2.59 (m,
2H),1.98 (dt, J¼12.6, 3.5 Hz,1H),1.84 (dq, J¼12.6, 3.6 Hz,1H),1.78 (s,
3H), 1.73 (s, 3H), 1.70 (s, 6H), 1.68e1.62 (m, 4H), 1.21 (s, 3H), 1.08 (s,
4.3.3. 5-(2,4-Bis(allyloxy)benzyl)-4,6,6-trimethylcyclohex-3-enol
3H), 0.86 (s, 3H); 13C NMR (CDCl3)
d 155.8, 151.5, 137.0, 131.7, 129.7,
(11). 1H NMR (CDCl3)
d
7.09 (d, J¼8.0 Hz, 1H), 6.45e6.43 (m, 2H),
123.3, 122.1, 120.3, 112.9, 100.7, 78.2, 76.2, 65.1, 47.3, 38.4, 37.9, 28.3,
27.8, 27.4, 25.9, 25.7, 22.4, 19.9, 18.2, 17.7, 14.3; HRMS (EI) m/z calcd
for C26H38O3 (Mþ) 398.2821, found 398.2805.
6.10e6.02 (m, 2H), 5.44e5.38 (m, 2H), 5.30e5.23 (m, 3H),
4.56e4.49 (m, 4H), 3.52 (dd, J¼7.7, 5.6 Hz, 1H), 2.86 (dd, J¼14.8,
4.2 Hz, 1H), 2.73 (dd, J¼14.8, 8.2 Hz, 1H), 2.36 (m, 1H), 2.24 (m, 1H),
2.06e2.00 (m, 1H), 1.52 (br s, 1H), 1.49 (s, 3H), 0.99 (s, 3H), 0.92 (s,
4.7. Crossover experiment
3H); 13C NMR (CDCl3)
d 157.7, 157.0, 137.5, 133.5, 133.4, 130.3, 124.4,
118.3, 117.6, 117.3, 105.2, 100.3, 75.1, 68.9, 68.9, 49.0, 38.3, 31.8, 28.4,
25.6, 23.1, 16.8; HRMS (EI) m/z calcd for C22H30O3 (Mþ) 342.2195,
found 342.2208.
4.7.1. Preparation of 1,1,1-trideutero-2-(1,1,1-trideuteromethyl)-2-
butene (27). To a suspension of EtP(Ph3)3Br (7.4 g, 20 mmol) in
THF (30 mL) cooled in an ice bath was added PhLi (12 mL, 1.6 M in
Et2O, 19 mmol). The ice bath was removed for 5 min to allow anion
formation and then the reaction was cooled with an ice bath. After
5 min, (CD3)2CO (0.9 mL,12 mmol) was added and the reaction flask
was fitted with a distillation apparatus. After 5 min, the ice bath
was removed and the reaction was slowly heated to 33 ꢁC. This
afforded 1.75 g of distillate in the receiving flask, which was a 1:8
mixture of compound 2746,47 (210 mg, 23%) and THF by 1H NMR
analysis. This mixture was used in the subsequent reaction without
4.4. (E)-3-(5-(2,4-Bis(2-methylbut-3-en-2-yloxy)phenyl)-3-
methylpent-3-enyl)-2,2-dimethyloxirane (20)
To epoxide 14 (95 mg, 0.24 mmol), in MeOH (3 mL) at 0 ꢁC was
added Lindlar catalyst (7 mg) and quinoline (2 drops) and the re-
action mixture was allowed to stir under H2 (1 atm). After 2 h, the
reaction mixture was filtered through Celite, the pad was washed
with ethyl acetate, and the filtrate was concentrated in vacuo. Final
purification of the residue by column chromatography (4% ethyl
acetate in hexanes) afforded epoxide 20 (73 mg, 76%) as a colorless
further purification: 1H NMR (CDCl3)
J¼6.8 Hz, 3H).
d
5.10 (q, J¼6.8 Hz, 1H),1.47 (d,
4.7.2. Preparation of deuterium-labeled epoxide 28. To a suspension
of epoxide 7 (62 mg, 0.18 mmol) in PTS (0.5 mL, 2.5% w/v in water)
in a screw-capped vial at rt was added labeled 2-methyl-2-butene
(27, 690 mg of an 8:1 THF:27 mixture, 83 mg) followed by Grubb’s
second generation catalyst (11 mg, 0.013 mmol). After 19 h, the
reaction mixture was diluted with ethyl acetate and filtered
through Celite. After the filtrate was concentrated in vacuo, final
purification by column chromatography (8% ethyl acetate in hex-
anes) afforded epoxide 28 (39 mg, 53%) as a colorless oil: 1H NMR
oil: 1H NMR (CDCl3)
d
6.92 (d, J¼8.3 Hz, 1H), 6.72 (d, J¼2.2 Hz, 1H),
6.51 (dd, J¼8.3, 2.4 Hz, 1H), 6.17e6.03 (m, 2H), 5.36e5.31 (m, 1H),
5.21e5.07 (m, 4H), 3.26 (d, J¼7.3 Hz, 2H), 2.71 (t, J¼6.3 Hz, 1H),
2.21e2.12 (m, 2H), 1.76e1.60 (m, 2H), 1.72 (s, 3H), 1.45 (s, 6H), 1.39
(s, 6H), 1.26 (s, 3H), 1.24 (s, 3H); 13C NMR (CDCl3)
d 153.9 (2C), 144.7,
144.4, 134.2, 128.7, 126.8, 124.0, 114.9, 113.0, 112.9, 112.6, 79.3, 79.1,
64.1, 58.3, 36.3, 28.2, 27.3, 27.2, 27.1, 26.8, 26.8, 24.8, 18.7, 16.1;
HRMS (EI) m/z calcd for C26H38O3 (Mþ) 398.2821, found 398.2811.
(CDCl3)
d
7.00 (d, J¼8.4 Hz, 1H), 6.48 (d, J¼2.4 Hz, 1H), 6.42 (dd,
4.5. (E)-3-(5-(2,4-Bis(3-methylbut-2-enyloxy)phenyl)-3-
methylpent-3-enyl)-2,2-dimethyloxirane (22)
J¼8.0, 2.4 Hz, 1H), 5.52e5.46 (m, 2H), 5.34e5.32 (m, 1H), 4.47 (d,
J¼6.4 Hz, 2H), 4.46 (d, J¼6.8 Hz, 2H), 3.26 (d, J¼7.2 Hz, 2H), 2.71 (t,
J¼6.8 Hz, 1H), 2.22e2.08 (m, 2H), 1.71 (s, 3H), 1.74e1.62 (m, 2H),
1.27 (s, 3H), 1.25 (s, 3H); HRMS (EI) m/z calcd for C26H26D12O3 (Mþ)
410.3574, found 410.3578.
To a suspension of epoxide 725 (85 mg, 0.25 mmol) in PTS
(0.6 mL, 2.5% w/v in water) in a screw-cap vial at rt was added 2-
methyl-2-butene (0.16 mL, 1.5 mmol) followed by Grubb’s second
generation catalyst (14 mg, 0.016 mmol). After 19 h, the reaction
mixture was diluted with ethyl acetate and filtered through Celite.
The filtrate was concentrated in vacuo and final purification of the
residue by column chromatography (12% ethyl acetate in hexanes)
afforded epoxide 22 (52 mg, 53%) as a colorless oil: 1H NMR (CDCl3)
4.7.3. Crossover experiment. To a solution of epoxide 22 (8 mg,
0.020 mmol) and deuterated epoxide 28 (12 mg, 0.029 mmol) in
CH2Cl2 (40 mL) at ꢀ78 ꢁC was added BF3$OEt2 (0.10 mL, 0.8 mmol).
After 10 min, the reaction was quenched by addition of triethyl-
amine (0.25 mL), diluted with HCl, and extracted with CH2Cl2. The
organic phase was washed with water and brine, dried (MgSO4),
filtered, and concentrated in vacuo. Final purification by column
chromatography (20% ethyl acetate in hexanes) afforded a mixture
of deuterium labeled products. These separate compounds were
analyzed by 1H NMR and displayed a spectrum identical to that
observed for compounds 23, 24, and 25 except that it showed
d
7.00 (d, J¼8.2 Hz,1H), 6.47 (d, J¼2.4 Hz,1H), 6.41 (dd, J¼8.2, 2.4 Hz,
1H), 5.47 (m, 2H), 5.33 (t, J¼7.2 Hz, 1H), 4.47 (d, J¼6.6 Hz, 4H), 3.26
(d, J¼7.3 Hz, 2H), 2.71 (t, J¼6.3 Hz, 1H), 2.20e2.12 (m, 2H), 1.79 (s,
3H), 1.78 (s, 3H), 1.74 (s, 3H), 1.72 (s, 3H), 1.72 (s, 3H), 1.69e1.60 (m,
2H), 1.27 (s, 3H), 1.25 (s, 3H); 13C NMR (CDCl3)
d
158.1, 157.3, 138.0,
137.1, 134.4, 129.3, 123.7, 122.4, 120.1, 119.7, 104.6, 100.2, 64.9, 64.7,

9218
J.G. Kodet et al. / Tetrahedron 69 (2013) 9212e9218
12. Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1974, 96, 8046.
13. Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048.
14. Topczewski, J. J.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2009, 74, 6965.
15. Neighbors, J. D.; Topczewski, J. J.; Swenson, D. C.; Wiemer, D. F. Tetrahedron Lett.
2009, 50, 3881.
16. Arkoudis, E.; Lykakis, I. N.; Gryparis, C.; Stratakis, M. Org. Lett. 2009, 11, 2988.
17. Helesbeux, J. J.; Duval, O.; Guilet, D.; Seraphin, D.; Rondeau, D.; Richomme, P.
Tetrahedron 2003, 59, 5091.
decreased intensity in the methyl region. This mixture was analyzed
by GCeMS using authentic samples of compounds 23, 24, and 25 as
standards. For the mixture of compound 23 and its labeled analogue,
GCeMS analysis showed 27% D0, 8% D6, and 65% D12. For the mixture
of compounds 24 and 25 and their labeled analogues, GCeMS
analysis showed 29% D0, 8% D6, and 63% D12, corresponding to an
intramolecular process. This experiment was repeated with epoxide
22 (10 mg, 0.025 mmol) and labeled epoxide 28 (15 mg, 0.037 mmol)
in a slightly different ratio. Analysis of the resulting mixtures by
GCeMS indicated 27% D0,10% D6, and 63% D12 for compounds 23 and
its labeled analogue, and 28% D0, 7% D6, and 65% D12 for the mixture
of compounds 24 and 25 with their deuterated analogues.
18. Neighbors, J. D.; Buller, M. J.; Boss, K. D.; Wiemer, D. F. J. Nat. Prod. 2008, 71,
1949.
19. Dauben, W. G.; Cogen, J. M.; Behar, V. Tetrahedron Lett. 1990, 31, 3241.
20. Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327.
21. Daskiewicz, J. B.; Bayet, C.; Barron, D. Tetrahedron Lett. 2001, 42, 7241.
22. Talamas, F. X.; Smith, D. B.; Cervantes, A.; Franco, F.; Cutler, S. T.; Loughhead, D.
G.; Morgans, D. J.; Weikert, R. J. Tetrahedron Lett. 1997, 38, 4725.
23. Topczewski, J. J.; Callahan, M. P.; Neighbors, J. D.; Wiemer, D. F. J. Am. Chem. Soc.
2009, 131, 14630.
Acknowledgements
24. Rolfe, A.; Samarakoon, T. B.; Hanson, P. R. Org. Lett. 2010, 12, 1216.
25. Topczewski, J. J.; Kodet, J. G.; Wiemer, D. F. J. Org. Chem. 2011, 76, 909.
26. Leao, M.; Gomes, S.; Pedraza-Chaverri, J.; Machado, N.; Sousa, E.; Pinto, M.;
Inga, A.; Pereira, C.; Saraiva, L. J. Nat. Prod. 2013, 76, 774.
27. Masullo, M.; Bassarello, C.; Bifulco, G.; Piacente, S. Tetrahedron 2010, 66, 139.
28. Ren, Y. L.; Lantvit, D. D.; de Blanco, E. J. C.; Kardono, L. B. S.; Riswan, S.; Chai, H.;
Cottrell, C. E.; Farnsworth, N. R.; Swanson, S. M.; Ding, Y. Q.; Li, X. C.; Marais, J.
P. J.; Ferreira, D.; Kinghorn, A. D. Tetrahedron 2010, 66, 5311.
29. Tao, S.-J.; Guan, S.-H.; Wang, W.; Lu, Z.-Q.; Chen, G.-T.; Sha, N.; Yue, Q.-X.; Liu,
X.; Guo, D.-A. J. Nat. Prod. 2009, 72, 117.
Financial support from the ACS Division of Medicinal Chemistry
(in the form of a predoctoral fellowship to J.J.T.), the University of
Iowa Graduate College (in the form of a Presidential Fellowship to
J.G.K.), the Roy J. Carver Charitable Trust, and the National Cancer
Institute (R41CA126020 via Terpenoid Therapeutics, Inc.) is grate-
fully acknowledged.
30. Sukpondma, Y.; Rukachaisirikul, V.; Phongpaichit, S. J. Nat. Prod. 2005, 68, 1010.
31. Maynor, M.; Scott, S. A.; Rickert, E. L.; Gibbs, R. A. Bioorg. Med. Chem. Lett. 2008,
18, 1889.
Supplementary data
32. Allemann, R. K. Pure Appl. Chem. 2008, 80, 1791.
The 1H and/or 13C NMR spectra for compounds 9e11, 13, 15, 16,
18, 20e25, 27, and 28 are available. Supplementary data associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2013.08.056.
33. Mente, N. R.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2008, 73, 7963.
34. Tong, R. B.; Valentine, J. C.; McDonald, F. E.; Cao, R.; Fang, X. K.; Hardcastle, K. I.
J. Am. Chem. Soc. 2007, 129, 1050.
35. Feducia, J. A.; Gagne, M. R. J. Am. Chem. Soc. 2008, 130, 592.
36. Kodet, J. G., PhD thesis, University of Iowa, 2010.
37. Godfrey, J. D.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.; Colandrea, V. J.
Tetrahedron Lett. 1994, 35, 6405.
38. Tisdale, E. J.; Vong, B. G.; Li, H. M.; Kim, S. H.; Chowdhury, C.; Theodorakis, E. A.
Tetrahedron 2003, 59, 6873.
References and notes
39. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
40. Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K. Org. Lett. 2008, 10,
1325.
41. Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
42. Tarbell, D. S. Chem. Rev. 1940, 27, 495.
1. Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. J. Nat. Prod. 1998, 61,
1509.
2. Yoder, B. J.; Cao, S.; Norris, A.; Miller, J. S.; Ratovoson, F.; Razafitsalama, J.;
Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. J. Nat. Prod. 2007, 70, 342.
3. Cerecetto, H.; Lopez, G. V. Mini-Rev. Med. Chem. 2007, 7, 315.
4. Xu, Y. J.; Lai, Y. H.; Imiyabir, Z.; Goh, S. H. J. Nat. Prod. 2001, 64, 1191.
5. Milligan, S. R.; Kalita, J. C.; Heyerick, A.; Rong, H.; De Cooman, L.; De Keukeleire,
D. J. Clin. Endocrinol. Metab. 1999, 84, 2249.
6. Maiti, A.; Cuendet, M.; Croy, V. L.; Endringer, D. C.; Pezzuto, J. M.; Cushman, M. J.
Med. Chem. 2007, 50, 2799.
7. Belofsky, G.; French, A. N.; Wallace, D. R.; Dodson, S. L. J. Nat. Prod. 2004, 67, 26.
8. Gaoni, Y.; Mechoulam, R. J. Am. Chem. Soc. 1964, 86, 1646.
9. Fulton, B.; Markham, A. Drugs 1996, 51, 278.
43. Lei, X. G.; Dai, M. J.; Hua, Z. H.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49,
6383.
44. Raptis, C.; Garcia, H.; Stratakis, M. Angew. Chem., Int. Ed. 2009, 48, 3133.
45. West, R.; Wang, Y. S.; Atkinson, J. J. Labelled Compd. Radiopharm. 2008, 51, 413.
46. Comeskey, D. J.; Rowan, D. D.; Matich, A. J. J. Labelled Compd. Radiopharm. 2006,
49, 47.
47. Atkinson., J. G.; Fisher, M. H.; Horley, D.; Morse, A. T.; Stuart, R. S.; Synnes, E.
Can. J. Chem. 1965, 43, 1614.
48. Stephenson, L. M.; Speth, D. R. J. Org. Chem. 1979, 44, 4683.
49. Maruoka, K.; Sato, J.; Banno, H.; Yamamoto, H. Tetrahedron Lett. 1990, 31, 377.
10. Green, T. P.; Treadwell, E. M.; Wiemer, D. F. J. Nat. Prod. 1999, 62, 367.
11. Ampofo, S. A.; Roussis, V.; Wiemer, D. F. Phytochemistry 1987, 26, 2367.