Exploiting the facile release of trifluoroacetate for the α-methylenation of the sterically hindered carbonyl groups on (+)-sclareolide and (-)-eburnamonine

Article abstract of DOI:10.1021/jo102114f

An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (-)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of ¹⁹F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (-)-eburnamonine with significant cytotoxicity (LC₅₀ = 14.12 ?M) in drug-resistant MDA-MB-231 breast cancer cells.

Full text of DOI:10.1021/jo102114f

ARTICLE
pubs.acs.org/joc
Exploiting the Facile Release of Trifluoroacetate for the
r-Methylenation of the Sterically Hindered Carbonyl Groups
on (þ)-Sclareolide and (ꢀ)-Eburnamonine
Mark V. Riofski,† Jinu P. John,† Mary M. Zheng,‡ Julia Kirshner,‡ and David A. Colby*,†,§
†Department of Medicinal Chemistry and Molecular Pharmacology, ‡Department of Biological Sciences, and
§Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
S Supporting Information
b
ABSTRACT: An efficient method for the R-methylenation of
carbonyl groups is reported, and this transformation is accom-
plished by a facile elimination of trifluoroacetate during the
formation of the olefin. This method represents an improvement
beyond existing protocol in cases of steric hindrance, and we have
demonstrated the utility of the process across a series of ketones,
lactams, and lactones. Additionally, we have applied this method
to produce semisynthetic derivatives of the natural products
(þ)-sclareolide and (ꢀ)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is
also provided from a time course of 19F NMR. Biological evaluation of the natural-product-derived enones led to the identification of
a derivative of (ꢀ)-eburnamonine with significant cytotoxicity (LC50 = 14.12 μM) in drug-resistant MDA-MB-231 breast
cancer cells.
’ INTRODUCTION
bulky groups are present and was readily applied to other carbonyl-
containing compounds and natural products. In addition to installing
the R-methylene to (þ)-sclareolide by trifluoroacetate release, an
R-methylene group was incorporated next to the carbonyl group of
the alkaloid, (ꢀ)-eburnamonine, and this synthetic derivative showed
potent biological activity in drug-resistant MDA-MB-231 breast
cancer cells.
Molecules, especially natural products, with electrophilic func-
tional groups that can covalently bind to nucleophiles are valuable
biological probes.1ꢀ4 Typical examples of these electrophilic groups
are R,β-unsaturated carbonyl groups and epoxides.2,3 One of the
most prominent types of R,β-unsaturated carbonyl groups in natural
products is the R-methylene-γ-lactone, as nearly 3% of the known
natural products contain this feature.5,6 A representative class of
natural products that commonly have the R-methylene-γ-lactone is
the sesquiterpene lactones, and some examples of members are
parthenolide (1) and helenalin (2) (Figure1). (þ)-Sclareolide(3) is
another member of the sesquiterpene lactone family of natural
products that has a γ-lactone, but no R-methylene group is present.
Sclareolide is a widely used as a building block in many synthetic
strategies because of its availability, but the natural product itself is not
biologically active.7ꢀ12 We hypothesized that incorporating an R-
methylene group onto the existing carbonyl group may generate new
biological activity and that such a synthetic and biological objective
may have significant applications to other natural products. However,
our efforts to extend this methodology to 3 and construct the
R-methylene next to the carbonyl group proved to be quite trouble-
some, presumably due to adjacent steric congestion from the flanking
axial methyl groups. Thus, efficiently accessing derivatives of sclar-
eolide became a challenge, yet modifying a carbonyl group on other
natural products would likely present a similar problem. To overcome
this synthetic obstacle, we have developed an efficient and high-
yielding method for the R-methylenation of carbonyl groups using a
facile release of trifluoroacetate. This olefination strategy avoids the
use of traditional phosphorus groups that are incompatible when
’ RESULTS AND DISCUSSION
Methods to install an R-methylene functional group on a
γ-butyrolactone are well-known,13ꢀ18 and representative examples
are an Eschenmoser methenylation,13 the HornerꢀWadsworthꢀ
Emmons approach of Wiemer,14 a deformylative olefination,15 and a
deacetylative olefination.17 We initiated our studies with the applica-
tion of the former two methods to (þ)-sclareolide (3),andunreacted
starting material was returned almost exclusively. However, the
application of Wiemer’s protocol14b to 3 gave a minor, crystalline
byproduct 4, which in turn provided the first X-ray crystal structure of
the skeleton of (þ)-sclareolide (Scheme 1). The highly congested
nature across the ring system is apparent, due to the positioning of the
three axial methyl groups. Thus, we abandoned other olefination
protocols that would require the attachment of a bulky group at the
carbon adjacent to the carbonyl group in 3, such as the preparation of
a precursor for a Wittig reaction,16 and focused our attention on
olefination by formyl group release.15 Our reactions using the defor-
mylative olefination with 3 were somewhat successful and provided
Received: October 25, 2010
Published: April 14, 2011
r
2011 American Chemical Society
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Table 1. Olefination by Trifluoroacetate Release
Figure 1. Sesquiterpene lactone natural products and the R-methylene-
γ-lactone group.
Scheme 1
the desired olefin 5, albeit in low yields (i.e., 4ꢀ28%) and despite
considerable attempts at optimization (see Scheme 1).
Three variants to the formyl group release protocol have been
reported to install olefins at the R-position of carbonyl groups:
deacetylative,17 decarboxylative,18 and deoxalative methylenations.19
The decarboxylative methylenations developed by Grieco18a and
Johnson18b are attractive due to the in situ release of carbon dioxide.
Unfortunately, the installation of a carboxylate at the R-position of a
carbonyl group can be difficult, and the resulting intermediate can
also be unstable. Deformylative methylenations15 are the ready
alternative due to stability of the intermediate formyl group, but
the release of formate is not a facile process. Using inspiration from
literature precedent of Danheiser and co-workers who described the
benefits of releasing trifluoroacetate rather than formate,20 we
decided to exchange the formyl group with a trifluoroacetyl group.
Indeed, the release of trifluoroacetate has been rarely examined in
synthesis.20,21 We hypothesized that this modification would drama-
tically enhance the utility of the R-methylenation process and extend
beyond the scope of the pioneering deacetylative work of Ueno and
co-workers,17 because each of the protons is exchanged with fluorine.
To determine the potential of the R-methylenation from trifluor-
oacetate release, we required a series of substrates that contain a 4,4,
4-trifluoromethyl-1,3-butanedione functional group. These systems
are known to exist more favorably in the enol tautomer (eq 1),22 and
the enolic proton is highly acidic (a typical pKa = 8ꢀ9).23 We
envisioned that the use of these substrates with a trifluoromethyl
group would not only require a milder base to promote addition to
formaldehyde (due to the enhanced acidity of the enolic proton), but
also it would be more prone to elimination, following addition, and
form the desired olefin. We examined 4,4,4-trifluoromethyl-1,3-
butanedione-containing substrates 6ꢀ11 and found that each con-
verted to the respective olefin12ꢀ17 in excellent yields using K2CO3
with paraformaldehyde in refluxing benzene (Table 1). Although
during our optimizations we found that other bases promote the
process, K2CO3 routinely provided superior conversions and was also
easily removed by aqueous workup. The mild reaction conditions of
this olefination strategy through trifluoroacetate release are critical to
the high isolated yields, because enones are quite sensitive, and for
a All yields refer to isolated, pure products. b The additive 18-crown-6
was used.
example, homopolymerization of R-aryl vinyl ketones is known.24
Furthermore, this strategy avoids the use of toxic selenium reagents,
which are a common choice for synthesizing vinyl ketones, such as
compound 12.25 Additionally, the vinyl naphthyl ketone 14 is highly
reactive and methods to prepare 14 require the use of harsh oxidants,
such as chromium, or are low-yielding.26 In the case of the nonaro-
matic substrates, we found that the camphor derivative 11 required
the additive 18-crown-6 to achieve 95% conversion to product 17.
With these data about the efficient conversion of 4,4,4-trifluorometh-
yl-1,3-butanedione-containing substrates to olefins, we proceeded to
more complex substrates and natural products that provide a requisite
carbonyl group.
The next step to implement our strategy was the R-trifluor-
oacetylation of carbonyl groups of substrates 18ꢀ26 that encompass
an array of ketones, lactams, and lactones (Table 2). We resorted
to Danheiser’s protocol for an efficient trifluoroacetylation with
LiHMDS and CF3CO2CH2CF3.20 In the cases of the ketone sub-
strates 18ꢀ22, we found that nearly quantitative conversions were
routinely obtained after warming the reaction mixture from 0 °C to rt
rather than performing the reaction at ꢀ78 °C. However, in the cases
of the lactam 24 and lactones 25 and 26, O-trifluoroacetylation was
a potential concern at 0 °C, so these reactions were conducted
at ꢀ78 °C. Next, we immediately subjected the unpurified trifluor-
oacetylated intermediates from substrates 18ꢀ26 to olefination by
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Table 2. Scope of Two-Step Conversion of Carbonyl Groups
to Enones by Trifluoroacetate Release
Table 3. Scope of Two-step Conversion of Carbonyl Groups
to Enones by Trifluoroacetate Release
b
a All yields refer to isolated, pure products. LiHMDS, CF3CO2CH2CF3,
THF, then K2CO3, (CH2O)n, 18-crown-6, benzene, reflux. c See ref 15b.
example, using the two-step protocol for olefination by trifluor-
oacetate release, the isolated yield of the desired sclareolide
derivative 5 was increased to 65%, which is more than double the
yield compared to formyl group release. An extreme case is the
diolefination of the tropinone derivative 36 whereby trifluoroa-
cetate release provided the diolefin in high 85% yield, but the
olefination by formate release failed to form any product. A
similar result occurred in the conversion of the natural product,
(ꢀ)-eburnamonine (39), to its olefin derivative 43. Even though
the isolated yield from trifluoroacetate release provided the
product in a low 28% yield, this alkaloid has a tertiary amine
(i.e., a nucleophile) that confounds the generation of the electro-
philic enone group. In the case of steroid 37, no epimerization of
the R-stereocenter was observed in enone 41 by 1H NMR. The
formation of the enone products from the natural products (þ)-
sclareolide 3 and (ꢀ)-eburnamonine 39 demonstrate the in-
tended utility of this approach by trifluoroacetate release, because
there is significant steric bulk at the positions neighboring the R-
position (see also Scheme 1).
a All yields refer to isolated, pure products. b Trifluoroacetylation was
conducted at ꢀ78 °C.
trifluoroacetate release, and again, good to high yields of the enones
27ꢀ35 were obtained. Additional evidence of the utility of this pro-
cess was found in the case of R-thujone 22, because no epimerization
1
of the R-stereocenter was observed by H NMR. Furthermore,
similar to the targeted substrate 3 (see Scheme 1), the formation of
the olefin product 31 from R-thujone 22 was significant due to the
steric bulk at the positions neighboring the R-carbon of 22. Good
yields from the two-step R-methylenation by trifluoroacetate release
were obtained with carbonyl groups in acyclic systems, five-, six-, and
seven-membered rings, and across ketones, lactams, and lactones.
Also, (R)-carvone 21 was converted to the triene 30 in 85% yield
without any evidence of olefin migration.
To obtain mechanistic information about the release of
trifluoroacetate, we monitored the progress of the conversion
1
of 6 to 12 by H and 19F NMR. The starting material 6 has a
trifluoromethyl group that provides a chemical shift of ꢀ73.5
ppm by 19F NMR (Figure 2). We subjected this substrate to the
olefination conditions promoted by trifluoroacetate release and
obtained 19F NMR spectra at 30 min intervals. The substrate 6
was completely consumed after 30 min. Because the reaction
solvent is benzene, the trifluoroacetate that is generated during
the formation of the olefin is not soluble. However, it can be
observed upon the addition of water prior to observation by 19F
NMR (data not shown). Using the mechanistic interpretation of
Murray and Reid for deformylative olefination,15b we propose a
With these successes, we turned our attention to more com-
plex natural products and further decided to compare the isolated
yields from deformylative olefination to detrifluoroacetylative
olefination. From the side-by-side comparisons, our olefination
via trifluoroacetate release provided significantly higher yields
than the respective deformylative olefination (Table 3). For
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Figure 2. 19F NMR spectroscopy of 6 in benzene with (CH2O)n and
K2CO3 across 90 min at 30 min intervals. The internal standard is C6H5CF3.
Figure 4. Antiproliferative assay with HL-60 cells. The HL-60 cells were
incubated with compound for 72 h at 5 and 50 μM concentrations. Each
test was performed in quadruplicate and the antiproliferative effects are
displayed as the average of the four values.
Figure 3. Plausible mechanism for olefination by trifluoroacetate release.
mechanism in which trifluoroacetate is rapidly released after the
formation of a four-membered ring intermediate (Figure 3). The
19F NMR at ꢀ83.0 ppm was quite interesting, and we obtained
additional structural detail to determine if this transient peak could be
attributed to a mechanistic intermediate depicted in Figure 3 or
another intermediate. Indeed, the compound responsible for this
rogue peak could not be isolated after aqueous workup and purifica-
tion. To determine its identity, we obtained 1H, 13C, HMBC, and
HMQC NMR data, and after our analysis, a 4-(trifluoromethyl)-1,
3-dioxan-4-ol structure was assigned (eq 2).27 Indeed, methods to
prepare compounds with a 4-(trifluoromethyl)-1,3-dioxan-4-ol struc-
ture are rare.28 This intermediate could be envisioned to form after
the addition of a second equivalent of formaldehyde and cyclization
on the trifluoromethyl ketone as in eq 2. Multiple additions of formal-
dehydetoasubstrateareknownintheliteratureduringtheformation
of 1,3-dioxanes29 and of 1,3,5-dioxathiocane.30 Because the com-
pound is only transiently formed, we assert that its formation is rever-
sible and has little effect on the overall process, which is quite rapid.
Figure 5. Cytotoxicity assay with MDA-MB-231 cells. The MDA-MB-231
cells were incubated with 39 or 43 for 96 h. All values were normalized to
cell viability of vehicle treated controls and each represents the average of
three independent experiments performed in triplicate.
On the other hand, the additional presence of an enone did not
always impart biological activity upon a molecule. In the cases of the
derivatives of thujone, pregnenolone, and androsterone, neither the
parent compounds 22, 37, or 38 nor the enone containing deriva-
tives 31, 41, or 42 showed inhibition of HL-60 proliferation in the
assay. (ꢀ)-Eburnamonine (39) has biological activity as a muscarinic
agonist,35 but previous tests showed no cytotoxicity against KB
(human oral epidemoid carcinoma) cells.36 In our antiproliferative
assay, it displays significant antiproliferative effects activity in HL-60
cells at 50 μM. The eburnamonine analogue 43 appears to be more
potent than 39 in HL-60 cells, because antiproliferative effects are
observed at both 5 and 50 μM. In order to further compare the
biological activity of 39 and 43, we conducted a more thorough
biological evaluation in MDA-MB-231 cells, which are metastatic
breast cancer cells with the multidrug-resistance phenotype. This
cell line is highly aggressive and is known to be resistant to multiple
chemotherapeutic agents.37 Thus, MDA-MB-231 cells were treated
with increasing concentrations of 39 and 43 (Figure 5). Both
compounds exhibited cytotoxicity with LC50 values of 41.78 μM
(95% confidence interval of 30ꢀ58 μM) and 14.12 μM (95%
confidence interval of 10ꢀ17 μM) for 39 and 43, respectively.
Based on ANOVA results, 43 was significantly more cytotoxic than
With theseries ofnatural productsand natural product derivatives
in hand, we performed a preliminary screen for biological activity in
an antiproliferative assay with HL-60 (human acute promyelocytic
leukemia) cells to compare the compounds 1, 3, 5, 21, 22, 30, 31, and
36ꢀ43 (Figure 4). Each compound was tested at 5 and 50 μM
concentration, as screening strategies using one concentration31 or
two concentrations32 can rapidly identify biologically active mol-
ecules. Parthenolide (1) served as a positive control and its activity in
our assay is similar to previous reports.33 This natural product has a
mechanism of action through covalent binding.34 (þ)-Sclareolide
(3) is weakly active at both test concentrations, but the derivative 5
with an R-methylene group has increased activity at 50 μM. Likewise,
the carvone derivative 30 is active in the assay at high concentration,
and tropinone analogue 40 is highly active at both concentrations,
but the parent compounds (i.e., 21 and 36, respectively) are inactive.
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39 (p = 0.0008), and at doses g30 μM, 43 was able to eliminate
nearly 100% of cells, while the cytotoxic effect of (ꢀ)-eburnamo-
nine 39 plateaued between 10 and 30 μM with resistance observed
to the doses as high as 1 mM (data not shown in Figure 5). Overall,
these biological data support that the added presence of an enone
may enhance biological activity, but this relationship is not universal
and the relative magnitude of the effects may depend on additional
factors. Furthermore, the selective incorporation of an enone may
also impart an additional mechanism of action through covalent
binding. Additional studies are underway to determine the increased
antiproliferative effects of the (ꢀ)-eburnamonine derivative 43.
under reduced pressure. Without purification, the crude mixture was
immediately subjected to general procedure B. SiO2 flash chromatog-
raphy (25% EtOAc in hexanes) afforded the 2-methlyene-1-indanone 29
as a yellow oil (28 mg) in 98% yield.38
Phenyl Vinyl Ketone (12). See representative reaction procedure
A. 1H NMR, 13C NMR, and LRMS data were identical with the reported
data.38,39
p-Chlorophenyl Vinyl Ketone (13). See representative reaction
procedure A. SiO2 flash chromatography (5% Et2O in hexanes) afforded
the title compound as a clear oil (27 mg) in 83% yield. 1H NMR and IR
data were identical with the reported data.38,40
Naphthyl Vinyl Ketone (14). See representative reaction proce-
dure A. SiO2 flash chromatography (20% Et2O in hexanes) afforded the
title compound as a yellow oil (27 mg) in 76% yield. 1H and 13C NMR
data were identical with the reported data.38,41
’ CONCLUSIONS
In conclusion, we have developed a novel method to install
methylene groups at the R-position of carbonyl groups using the
facile release of trifluoroacetate, which is rarely used in organic
synthesis. Our method represents an improvement beyond
existing protocol in cases of steric hindrance and sensitive
functional groups, and we have demonstrated the utility of the
process across a series of ketones, lactams, and lactones. We were
also successful in preparing semisynthetic derivatives of complex
natural products. Additionally, we have provided mechanistic
insight for the process using 19F NMR data that indicate that the
olefination proceeds very rapidly. Biological evaluation led to the
identification of a derivative of (ꢀ)-eburnamonine with signifi-
cant cytotoxicity in drug-resistant MDA-MB-231 breast cancer
cells. Future studies will describe new avenues for the use of
trifluoroacetate release in synthesis and provide additional
structureꢀactivity relationships for this novel semisynthetic
derivative of (ꢀ)-eburnamonine.
Thienyl Vinyl Ketone (15). See representative reaction procedure
A. SiO2 flash chromatography (10% Et2O in hexanes) afforded the title
1
compound as a colorless oil (26 mg) in 98% yield. H NMR, IR, and
LRMS data were identical with the reported data.38,42
1,3-Benzodioxoly Vinyl Ketone (16). See representative reac-
tion procedure B. SiO2 flash chromatography (15% EtOAc in hexanes)
afforded the title compound as a colorless oil (20.9 mg) in 61% yield: 1H
NMR (500 MHz, CDCl3) δ 7.57 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 1.5 Hz,
1H), 7.12 (dd, J = 17.0, 10.5 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.42 (dd, J =
17.0, 1.5 Hz, 1H), 6.06 (s, 2H), 5.87 (dd, J = 10.5, 2.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 188.8, 151.9, 148.3, 132.0 (2), 129.5, 125.1, 108.5,
107.9, 101.9; IR (film) νmax 2900, 1661, 1443, 1250 cmꢀ1; HRMS (EI) m/z
calcd for C10H8O3 (M)þ 176.0473, found 176.0470.
r-Methylene-camphor (17). See representative reaction proce-
dure B. 1H NMR and IR data were identical with the reported data.38,43
2-Methyl-1-phenylprop-2-ene-1-one (27). See representative
reaction procedure C. SiO2 flash chromatography (5% EtOAc in hexanes)
1
afforded the title compounds as a colorless oil (26 mg) in 92% yield. H
NMR, IR, and HRMS data were identical with the reported data.38,44
Adamantyl Vinyl Ketone (28). See representative reaction proce-
dure C. SiO2 flash chromatography (1% EtOAc in hexanes) afforded the
title compound as a colorless oil (30 mg) in 88% yield: 1H NMR (300 MHz,
CDCl3) δ 6.83 (dd, J = 17.1, 10.5 Hz, 1H), 6.32 (dd, J = 17.1, 2.4 Hz, 1H),
5.63 (dd, J = 10.5, 8.4 Hz, 1H), 2.06 (m, 3H), 1.81 (d, J = 2.7 Hz, 6H),
1.79ꢀ1.64 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 204.3, 130.7, 128.6,
45.6, 38.0 (3), 36.9 (3), 28.2 (3); IR (film) νmax 2905, 2851, 1687,
1017 cmꢀ1; HRMS (EI) m/z calcd for C13H18O (M)þ 190.1358, found
190.1356.
’ EXPERIMENTAL SECTION
General Procedure A for Detrifluoroacetylative Olefina-
tion. To a solution of 4,4,4-trifluoro-1-phenyl-1,3-butanedione 6
(42 mg, 0.19 mmol) in benzene (10 mL) were added K2CO3 (82 mg,
0.59 mmol) and paraformaldehyde (200 mg, 6.59 mmol), and the
mixture was heated to reflux (oil bath = 90 °C). After 2 h the reaction
mixture was allowed to cool to rt, saturated aqueous NH4Cl (10 mL) was
added, and the resulting mixture was extracted with EtOAc (3 ꢁ 10 mL).
The organics were dried over Na2SO4 and concentrated under reduced
pressure. SiO2 flash chromatography (15% EtOAc in hexanes) afforded the
phenyl vinyl ketone 12 as a yellow oil (24 mg) in 93% yield.38
General Procedure B for Detrifluoroacetylative Olefination.
To a solution of 3-(trifluoroacetyl)camphor 11 (45 mg, 0.19 mmol) in
benzene (10 mL) were added K2CO3 (82 mg, 0.59 mmol), 18-crown-6
(13 mg, 0.05 mmol), and paraformaldehyde (200 mg, 6.59 mmol). The
suspension was heated to 80 °C for 2 h and then heated to reflux (oil bath =
90 °C) for 4 h. The mixture was allowed to cool to rt, saturated
aqueous NH4Cl (10 mL) was added, and the resulting mixture was extracted
with EtOAc (3 ꢁ 10 mL). The organics were dried over Na2SO4
and concentrated under reduced pressure. SiO2 flash chromatography
(5% Et2O in hexanes) afforded the R-methylene camphor 17 as a pale
yellow oil (32 mg) in 95% yield.38
General Procedure C for Trifluoroacetylation/Detrifluor-
oaceylative Olefination. To a 0 °C solution of LiHMDS (0.65 mL,
0.6 M in THF) was added a solution of 1-indanone 20 (26 mg, 0.19
mmol) in THF (1.0 mL). The reaction mixture was allowed to warm to
rt over 20 min, and then CF3CO2CH2CF3 was added (55 μL, 0.41
mmol). After an additional 20 min at rt, saturated aqueous NH4Cl
(5 mL) was added, and the resulting mixture was extracted with EtOAc
(3 ꢁ 5 mL). The organics were dried over Na2SO4 and concentrated
2-Methylene-1-indanone (29). See representative reaction pro-
cedure C. 1H NMR, 13C NMR, IR, and HRMS data were identical with
the reported data.38,45
r-Methylene-(R)-carvone (30). See representative reaction pro-
cedure C. SiO2 flash chromatography (5% EtOAc in hexanes) afforded
the title compound as a pale yellow oil (26 mg) in 85% yield: 1H NMR
(500 MHz, CDCl3) δ 6.74 (tt, J = 5.0, 1.0 Hz, 1H), 6.06 (t, J = 1.8
Hz, 1H), 5.19 (t, J = 1.8 Hz, 1H), 4.92 (t, J = 1.5 Hz, 1H), 4.77 (m, 1H),
3.39 (t, J = 6.5 Hz, 1H), 2.57ꢀ2.43 (m, 2H), 1.82 (q, J = 1.8 Hz, 3H),
1.71 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.0, 145.1, 144.3,
144.0, 136.0, 120.6, 113.6, 48.6, 30.0, 20.5, 16.1; IR (film) νmax 2923,
1667, 1614, 1048 cmꢀ1; HRMS (EI) m/z calcd for C11H14O
(M)þ 162.1045, found 162.1048; [R]25D ꢀ31.2 (c 1.82, CH2Cl2).
r-Methylene-thujone (31). See representative reaction proce-
dure C. SiO2 flash chromatography (5% EtOAc in hexanes) afforded the
title compound as a colorless oil (27 mg) in 82% yield: 1H NMR (500
MHz, CDCl3) δ 5.60 (s, 1H), 5.31 (s, 1H), 2.35 (q, J = 7.5 Hz, 1H), 1.97
(qu, J = 7.0 Hz, 1H), 1.30 (dd, J = 8.0, 4.5 Hz, 1H), 1.14 (d, J = 7.5 Hz,
3H), 1.13 (m, 1H), 1.03 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 0.36
(t, J = 5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 210.7, 148.5, 115.9,
45.7, 35.4, 29.7, 25.2, 20.6, 20.5, 19.1, 18.3; IR (film) νmax 2961, 2918,
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1749 cmꢀ1; HRMS (EI) m/z calcd for C11H16O (M)þ 164.1201, found
164.1199; [R]25D ꢀ26.1 (c 0.65, CHCl3).
r-Methylene-tert-butyl-dimethylsilyl-pregnenolone (41).
See representative reaction procedure C. The tert-butyl-dimethylsilyl
pregnenolone 37 was prepared according to the literature procedure.48
SiO2 flash chromatography (4% EtOAc in hexanes) afforded the title
compound as a colorless solid (55 mg) in 64% yield: mp 119ꢀ121 °C;
1H NMR (500 MHz, CDCl3) δ 6.43 (dd, J = 17.5, 10.5 Hz, 1H), 6.20 (dd,
J = 17.5, 1.5 Hz, 1H), 5.67 (dd, J = 10.5, 1.5 Hz, 1H), 5.32 (m, 1H),
3.51ꢀ3.45 (m, 1H), 2.79 (t, J= 9.0 Hz, 1H), 2.32ꢀ2.14 (m, 4H), 2.03ꢀ1.93
(m, 2H), 1.80 (dt, J = 13.0, 3.5 Hz, 1H), 1.75ꢀ1.60 (m, 4H), 1.53ꢀ1.39
(m, 6H), 1.30ꢀ1.17 (m, 2H), 0.99 (s, 3H), 0.89 (s, 9H), 0.60 (s, 3H), 0.06
(s, 6H); 13C NMR (125 MHz, CDCl3) δ 201.2, 141.9, 137.5, 127.4, 121.2,
72.9, 61.2, 57.6, 50.4, 45.1, 43.1, 39.4, 37.7, 37.0, 32.4, 32.3, 32.2, 26.3 (3),
25.0, 23.1, 21.4, 19.8, 18.6, 13.8, ꢀ4.2 (2); IR (film) νmax 2931, 1667,
1087 cmꢀ1; HRMS (EI) m/z calcd for C28H46O2Si (M þ H)þ 443.3345,
found 443.3340; [R]25D þ43.6 (c 0.1, CHCl3).
N-tert-Butylcarbamate-2-methylene-ε-caprolactam (32).
See representative reaction procedure C. SiO2 flash chromatography
(50% EtOAc in hexanes) afforded the title compound as a colorless oil
(36.7 mg) in 83% yield: 1H NMR (500 MHz, CDCl3) δ 5.76 (s, 1H),
5.38 (s, 1H), 3.66 (t, J = 5.0 Hz, 2H), 2.42 (t, J = 5.0 Hz, 2H), 1.79ꢀ1.68
(m, 4H), 1.52 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 172.5, 152.7,
147.2, 123.2, 82.6, 46.0, 32.5, 29.1, 28.1 (3), 28.0; IR (film) νmax 2934,
1761, 1707, 1180, 1141 cmꢀ1; HRMS (CI) m/z calcd for C12H19NO3
(M þ H ꢀ C4H8)þ 170.0817, found 170.0814.
(3S-cis)-(þ)-Tetrahydro-3-isopropyl-7a-methyl-6-methyl-
enepyrrolo[2,1-b]oxazol-5(6H)-one (33). See representative reaction
procedure C. The trifluoroacetylation step was conducted at ꢀ78 °C. SiO2
flash chromatography (15% EtOAc in hexanes) afforded the title compound
1
as a colorless oil (31.5 mg) in 82% yield: H NMR (500 MHz, CDCl3)
r-Methylene-tert-butyl-dimethylsilyl-andosterone (42).
See representative reaction procedure C. The tert-butyl-dimethylsilyl
androsterone 38 was prepared according to the literature procedure.49
SiO2 flash chromatography (2% EtOAc in hexanes) afforded the title
compound as a colorless solid (47 mg) in 59% yield: mp 150ꢀ152 °C;
1H NMR (500 MHz, CDCl3) δ 6.04 (m, 1H), 5.35 (m, 1H), 3.54 (tt, J =
10.8, 5.0 Hz, 1H), 2.55 (dd, J = 15.5, 6.5 Hz, 1H), 2.19ꢀ2.12 (m, 1H),
1.87ꢀ1.83 (m, 1H), 1.77ꢀ1.54 (m, 6H), 1.48ꢀ1.24 (m, 9H),
1.12ꢀ0.91 (m, 4H), 0.88 (s, 9H), 0.83 (s, 3H), 0.75ꢀ0.67 (m, 1H),
0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 209.3, 144.9, 118.8, 72.3,
54.9, 49.0, 48.3, 45.3, 38.9, 37.4, 36.1, 34.9, 32.2, 31.9, 31.4, 29.6, 28.8,
26.3 (3), 20.8, 18.6, 14.5, 12.7, ꢀ4.2 (2); IR (film) νmax 2927,
2854, 1728, 1641, 1091 cmꢀ1; HRMS (EI) m/z calcd for C26H44O2Si
(M þ H)þ 417.3189, found 417.3186; [R]25D þ11.9 (c 2.1, CHCl3).
r-Methylene-(ꢀ)-eburnamonine (43). See representative re-
action procedure C. SiO2 PTLC (79% EtOAc; 29% hexanes; 1% Et3N)
afforded the title compound as a yellow oil (17 mg) in 28% yield: 1H NMR
(500 MHz, CDCl3) δ 8.45 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H),
7.36ꢀ7.28 (m, 2H), 6.66 (s, 1H), 5.73 (s, 1H), 4.14ꢀ4.12 (m, 1H), 3.36
(dd, J = 14.0, 6.5 Hz, 1H), 3.28ꢀ3.22 (m, 1H), 2.98ꢀ2.91 (m, 1H),
2.64ꢀ2.60 (m, 1H), 2.57ꢀ2.47 (m, 2H), 2.36 (sextet, J = 7.5 Hz, 1H),
1.93ꢀ1.83 (m, 2H), 1.45ꢀ1.40(m, 1H), 1.38ꢀ1.25 (m, 2H), 1.01 (t, J=7.5
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.5, 145.2, 134.8, 131.5, 130.7,
125.8, 124.7, 124.4, 118.4, 116.9, 113.1, 54.4, 51.3, 44.5, 43.2, 32.2, 24.6, 21.3,
16.9, 8.8; IR (film) νmax 2936, 1692, 1455, 1092 cmꢀ1; HRMS (EI) m/z
δ 7.70 (dd, J = 5.5, 3.5 Hz, 1H), 7.52 (dd, J = 5.5, 3.5 Hz, 1H), 4.21 (m, 2H),
1.68 (septet, J = 6.0 Hz, 1H), 1.48ꢀ1.37 (m, 2H), 1.33ꢀ1.25 (m, 4H), 0.92
(t, J = 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 167.7, 132.3, 130.8,
128.7, 68.0, 38.6, 30.2, 23.6, 22.9, 14.0, 10.9; IR (film) νmax 2918, 1729,
1272 cmꢀ1; HRMS (EI) m/z calcd for C11H17NO2 (M)þ 195.1259, found
195.1262; [R]20D ꢀ0.007 (c 0.78, CHCl3).
5-Hexyl-3-methylenedihydrofuran-2(3H)-one (34). See re-
presentative reaction procedure C. The trifluoroacetylation step was
conducted at ꢀ78 °C. 1H and 13C NMR were identical with the reported
data.38,46
(1S,5R)-r-Methylene-2-oxabicyclo[3.3.0]oct-6-en-3-one
(35). See representative reaction procedure C. The trifluoroacetylation
step was conducted at ꢀ78 °C. SiO2 flash chromatography (25% EtOAc
in hexanes) afforded the title compound as a colorless oil (20 mg) in 66%
yield: 1H NMR (500 MHz, CDCl3) δ 6.20 (d, J = 2.0 Hz, 1H), 5.76 (td,
J = 4.9, 2.4 Hz, 1H), 5.68 (d, J = 1.7 Hz, 1H), 5.54 (dt, J = 4.9, 2.1 Hz,
1H), 5.10 (t, J = 6.2 Hz, 1H), 4.03 (ddt, J = 5.9, 3.8, 1.9 Hz, 1H),
2.85ꢀ2.76 (m, 1H), 2.74ꢀ2.65 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 170.1, 136.4, 130.2, 129.6, 121.9, 80.1, 50.8, 39.4; IR (film) νmax 2923,
1762, 1665, 1400, 1016 cmꢀ1; HRMS (EI) m/z calcd for C8H8O2 (M)þ
136.0524, found 136.0526; [R]20D = ꢀ25.3 (c 0.14, CHCl3)
11-Methylene-(þ)-sclareolide (5). See representative reaction
procedure C. SiO2 flash chromatography (15% EtOAc in hexanes)
1
afforded the title compound as a yellow oil (32 mg) in 65% yield: H
calcd for C20H22N2O (M)þ 306.1732, found 306.1736; [R]25 ꢀ31.4
NMR (500 MHz, CDCl3) δ 6.13 (d, J = 3.5 Hz, 1H), 5.47 (d, J = 3.5
Hz, 1H), 2.51 (t, J = 3.0 Hz, 1H), 2.10 (dt, J = 12.0, 3.5 Hz, 1H), 1.96
(dtd, J = 13.0, 3.5, 1.5 Hz, 1H), 1.89 (ddd, J = 14.5, 4.0, 3.0 Hz, 1H),
1.78ꢀ1.66 (m, 2H), 1.52ꢀ1.33 (m, 3H), 1.29 (s, 3H), 1.25ꢀ1.15 (m,
2H), 1.08 (dd, J = 13.0, 3.0 Hz, 1H), 1.05 (s, 3H), 0.89 (s, 3H), 0.85 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 171.5, 137.6, 118.4, 84.8, 64.2,
57.2, 42.3, 39.1, 38.2, 37.6, 33.7, 33.6, 23.8, 21.3, 20.7, 18.4, 15.6; IR (film)
νmax 2949, 1765, 1020, 930 cmꢀ1; HRMS (EI) m/z calcd for C17H26O2
(M þ H)þ 263.2011, found 263.2002; [R]25D þ15.0 (c 1.45, CHCl3).
2,7-Dimethylene-tropinone (40). See representative reaction
procedure C. N-ethyl carbamate tropinone (36) was prepared according
to the literature procedure.47 LiHMDS (4 equiv) and CF3CO2CH2CF3
(4 equiv) were used for trifluoroacetylation. For the olefination protocol,
after heating to reflux for 4 h, the reaction mixture was cooled to 80 °C,
and an additional portion of paraformaldehyde (200 mg) was added. After
heating at this temperature for 4 h, the reaction mixture was heated to
reflux (oil bath = 90 °C) for2 h. SiO2 flashchromatography (5% EtOAc in
hexanes) affordedthe title compoundasa yellow oil(37mg) in85%yield:
1H NMR (500 MHz, CDCl3) δ 6.13 (s, 2H), 5.37 (s, 2H), 4.95 (s, 2H),
4.11 (q, J = 7.0 Hz, 2H), 2.32 (m, 2H), 1.76 (dd, J = 8.0, 6.5 Hz, 2H), 1.21
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 187.4, 171.5, 154.3,
146.1, 146.0, 128.7, 61.8, 60.7, 59.0, 23.0, 21.4, 14.5; IR (film) νmax
2981, 1705, 1692, 1105 cmꢀ1; HRMS (ESI) m/z calcd for C12H15O3
(M þ Na)þ 244.0950, found 244.0948.
D
(c 0.34, CH2Cl2); UV (CH3CN) λmax (log ε) 255 (1.71), 265 (1.65) nm.
Cell Culture for HL-60 Cells33. HL-60 (human promyelocytic
leukemia) cells were obtained from ATCC. The cell culture was transition
into and then maintained in phenol red free RPMI-1640, supplemented
with 10% fetal bovine serum, and filter sterilized. Cells were cultured at
37 °C in a humidified incubator under 5% CO2 in air and passaged as
recommended.
Cell Proliferation Assay in HL-60 Cells33. The values for HL-60
cell proliferation in the presence of enone 1, 3, 5, 21, 22, 30, 31, and
36ꢀ43 were determined by MTT assay. HL-60 cells were plated into a
96-well plate at 5,000 cells per well in 80 μL. The cells were treated with
20 μL of a solution of test compound for a final concentration of 5 and 50 μM
in 0.5% DMSO in growth medium. Each concentration was repeated in
quadruplicate, and the plate was incubated at 37 °C in a humidified incubator
under 5% CO2 in air. After incubation for 72 h, 20 μL of MTT solution (2.5
mg/mL) in serum-free RPMI-1640 was added to each well, and the plate was
incubated further for 4 h. Next, 100 μL of acidic isopropyl alcohol (10%
Triton X-100 plus 0.1 N HCl in anhydrous isopropyl alcohol) was added and
allowed to dissolve for 16 h. The OD was measured at 570 nm, and the values
for HL-60 cell proliferation were calculated by GraphPad Prism 5 software.
Cell Culture for MDA-MB-231 Cells. MDA-MB-231 cells were
obtained from ATCC and cultured in complete media [DMEM supple-
mented with 4500 mg/L glucose, L-glutamine, NaHCO3, pyridoxine HCl,
3
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ARTICLE
and 10% fetal bovine serum]. Cells were cultured at 37 °C in a humidified
incubator under 5% CO2 in air and passaged as recommended.
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Cytotoxicity Assay in MDA-MB-231 Cells. The LC50 values for
MDA-MB-231 cells in the presence of enone 39 and 43 were deter-
mined by MTS assay. MDA-MB-231 cells were seeded in 96-well plate at
20,000 cells/well and treated for 96 h with either DMSO vehicle control
or various doses of 39 and 43. MTS assay was performed using the
CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay (MTS)
assay kit (Promega) per manufacturer instructions. Briefly, 20 μL of the
combined MTS/PMS solution was added to each well and incubated for
90 min at 37 °C under 5% CO2 in air. The OD was subsequently read at
492 nm on a Thermo Multiscan Asent plate reader. Data are presented as
mean ( SEM of at least 3 independent experiments performed in
triplicate. LC50 values were calculated by four-parameter logistic regres-
sion applied to log-transformed percent viability measurements. Sig-
nificance was analyzed by a two-way analysis of variance (ANOVA) and
Bonferroni’s correction as post-test to compare experiments with multi-
ple parameters. P-values below 0.05 were considered statistically sig-
nificant. All analyses were performed using Prism 5.0 software
(GraphPad Software).
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’ ASSOCIATED CONTENT
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Supporting Information. 1H and 13C NMR spectra,
S
b
X-ray data, and preparation of compound 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
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(26) (a) Flynn, G. A.; Lee, S. A.; Faris, M.; Brandt, D. W.; Charkravarty,
S. Patent WO 2007136790, November 29, 2007. (b) Augelli-Szafran, C. E.;
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(27) Diagnostic NMR data: 1H NMR (500 MHz, C6D6) δ 5.10 (d, J =
6.1 Hz, 1H), 4.70 (d, J= 6.2 Hz, 1H), 4.28 (t, J= 8.2 Hz, 1H), 3.54 (d, J=8.3
Hz, 2H); 13C NMR (125 MHz, C6D6) δ 200.9, 137.8, 135.0, 129.3 (2),
128.8 (2), 123.0 (q, J = 284 Hz, 1C); 93.9 (q, J = 33 Hz, 1C), 87.1 (CH2),
Corresponding Author
*E-mail: dcolby@purdue.edu.
’ ACKNOWLEDGMENT
Funding for this work was provided by Purdue University and
a grant from the Elk Charities through the Purdue University
Center for Cancer Research. Also, the authors acknowledge
Phillip E. Fanwick and the X-ray Crystallography Center, Purdue
University and Huaping Mo and the Purdue Interdepartmental
NMR Facility for assistance with structural elucidation. Biologi-
cal testing was conducted with assistance from the Purdue
University Center for Cancer Research through the Molecular
Discovery and Evaluation Shared Resource.
13
65.3 (CH2), 42.3 (CH); HMBC 1Hꢀ C 5.10/93.9, 5.10/65.3, 5.10/42.3,
4.70/93.9, 4.70/65.3, 4.70/, 4.28/93.9, 4.28/87.1, 4.28/65.3, 3.54/93.9,
3.54/87.1, 3.54/42.3.
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