Synthesis and chemical diversity analysis of bicyclo[3.3.1]non-3-en-2-ones

Article abstract of DOI:10.1016/j.tet.2010.04.112

Functionalized bicyclo[3.3.1]non-3-en-2-ones are obtained from commercially available phenols by a hypervalent iodine oxidation, enone epoxidation, epoxide thiolysis, and intramolecular aldol reaction sequence. Reaction optimization studies identified room temperature as well as microwave-mediated procedures, providing moderate to good yields (57-88%) in the thiophenol-mediated epoxide opening and intramolecular aldol reaction. In addition, the isolation of a key intermediate and in situ NMR studies supported the mechanistic hypothesis. The bicyclic ring products occupy novel chemical space according to ChemGPS and Chemaxon chemical diversity and cheminformatics analyses.

Full text of DOI:10.1016/j.tet.2010.04.112

Tetrahedron 66 (2010) 5852e5862
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and chemical diversity analysis of bicyclo[3.3.1]non-3-en-2-ones
,
b
Jared T. Hammill a, Julia Contreras-García b, Aaron M. Virshup b, David N. Beratan a
,
,
,
*
Weitao Yang a b, Peter Wipf a
a Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA
b Department of Chemistry, Duke University, Durham, NC 27708, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized bicyclo[3.3.1]non-3-en-2-ones are obtained from commercially available phenols by
a hypervalent iodine oxidation, enone epoxidation, epoxide thiolysis, and intramolecular aldol reaction
sequence. Reaction optimization studies identified room temperature as well as microwave-mediated
procedures, providing moderate to good yields (57e88%) in the thiophenol-mediated epoxide opening
and intramolecular aldol reaction. In addition, the isolation of a key intermediate and in situ NMR studies
supported the mechanistic hypothesis. The bicyclic ring products occupy novel chemical space according
to ChemGPS and Chemaxon chemical diversity and cheminformatics analyses.
Received 7 April 2010
Accepted 25 April 2010
Available online 22 May 2010
Keywords:
Bicyclo[3.3.1]nonenones
Chemical diversity analysis
Ring-opening
Ó 2010 Elsevier Ltd. All rights reserved.
Epoxyketone rearrangement
1. Introduction
been structurally defined to date.10 A more practical question that
must be addressed before the total number can be computed is how
Inspired by the steady advancements in genomics, proteomics,
and other omics,1 as well as the vast strides that have been made in
our understanding of signaling pathways,2 the National Institutes
of Health (NIH) have launched an ambitious Molecular Libraries
Program (MLP; an NIH Roadmap Initiative),3 aiming to enhance
chemical biology efforts through High Throughput Screening (HTS).
HTS followed by focused chemical library syntheses are expected to
yield small molecule probes effective at modulating a given
biological process or disease state. The MLP is supported by five
Centers for Chemical Methodologies and Library Development
(CMLD),4 who are charged with the validation of efficient, general,
state-of-the-art methodologies for the design, synthesis, analysis,
and handling of chemical diversity libraries. We are particularly
interested in developing new synthetic approaches toward che-
motypes that are currently underrepresented in the NIH Libraries
(MLSMR),5 a collection of ca. 340,000 small organic molecules
whose structures and biological annotation are conveniently
accessible through the PubChem web interface.6
to design new small-molecules with novel structures and proper-
ties while populating mainly the biologically relevant regions of
chemical space.11 As it is often the case in organic chemistry, nat-
ural products, specifically the development of natural product-like
libraries, might offer one opportunity to expand current chemical
diversity in meaningful directions.12 Our strategy focused on di-
versifying the highly functionalized bicyclo[3.3.1]non-3-en-2-one
core of the natural products gymnastatins F and Q (Fig. 1).13
The discussion of what constitutes diversity-oriented synthesis
(DOS) and probe-relevant chemical space has led to a growing
number of cheminformatics and structural analysis tools, sup-
porting chemists in their assessment of chemical diversity.7,8 Esti-
mates of the expanse of the chemical universe vary greatly, from
1023 to >1060 possible compounds,9 but only ca. 109 molecules have
Figure 1. Structures of the bicyclo[3.3.1]non-3-en-2-ones gymnastatin F and Q.
Gymnastatins F and Q were isolated from the extract of the
Halichondria sponge-derived fungus Gymnascella dankaliensis, and
found to exhibit potent growth inhibition against murine P388
lymphocytic leukemia and other human cancer cell lines.
* Corresponding author. E-mail address: pwipf@pitt.edu (P. Wipf).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.112

J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
5853
Furthermore, gymnastatin Q showed appreciable growth inhibition
in BSY-1 (breast) and MKN7 (stomach) human cancer cell lines.13
During the course of our total synthesis of aranorosin,14 we
discovered that the treatment of spirodiepoxyketone intermediate
1 with thiophenol in the presence of base initiated a novel ring-
opening/rearrangement cascade, resulting in the formation of the
bicyclic core present in the gymnastatins (Fig. 2).15
presence of PIDA provided quinone monoketal 4 in quantitative
yield. In situ generation of butenylmagnesium bromide followed by
addition to 4 and ketal hydrolysis led to the desired bis-a,b-un-
saturated ketone 5. Diepoxidation of 5 with basic hydrogen per-
oxide proceeded smoothly in methanol to afford the all syn-
oxygenated diepoxyketone 6 in 72% yield. Finally, ozonolysis in
CH2Cl2 at ꢀ78 ꢁC followed by treatment with an excess of DMS for
several days to ensure decomposition of the unusually stable
ozonide intermediate20 provided the diepoxyketone lactol 7 in 95%
yield on 1 g scale as a 1:1 mixture of lactols, as determined by 1H
NMR.
2.1. Reaction optimization for bicycle formation
When spirolactol 7 was treated with 5 equiv of thiophenol and
10 equiv of sodium hydride in THF, according to our previously
described procedure,21 a disappointing 28% yield of the desired
bicyclo[3.3.1]non-3-en-2-one 8 was isolated (Table 1, entry 1).
Screening bases of various strengths (not shown) revealed that
treatment of 7 with 10 equiv of potassium carbonate and 5 equiv of
thiophenol in THF provided the desired product 8 in 72% yield
(Table 1, entry 2). A solvent screen further increased the yield of the
desired product to 84% in diethyl ether (Table 1, entry 3); however
a significant increase in reaction time was required for complete
conversion. Ultimately, methylene chloride was found to be the
optimal solvent, providing 8 in 84% yield over 5 h reaction time.
Figure 2. Rearrangement of spirolactol 1 to bicyclic enone 2.
Inspired by this process, we sought to access new regions of
biologically relevant space with this methodology and prepare
bicyclo[3.3.1]non-3-en-2-one derivatives from commercially
available thiophenols through hypervalent iodine oxidation.16
2. Results and discussion
Table 1
The utility of hypervalent iodine reagents in organic synthesis
has been well documented.17 In particular, phenyl iodosobenzene
diacetate (PIDA) has been shown to facilitate the oxidative addition
of nucleophiles to phenols to give the corresponding substituted
dienones.18 The large scale production of the spirolactol 1, however,
was hampered by the low (20e30%) yield in the PIDA oxidation of
tyrosine, most likely due to the presence of the amide functionality
in this precursor.14,19 During their investigation of the total syn-
thesis of aranorosin, the McKillop group synthesized the de-
aminated spirolactol 7, which we used as a more synthetically
tractable starting point for our core diversifications (Scheme 1).20
Oxidative addition of MeOH to p-methoxy phenol (3) in the
Optimization of ring-opening/rearrangement reaction of spirolactol 7, forming bi-
cycle 8
Entry PhSH
(equiv)
Base (equiv) Temperature Solvent Time
Yielda (%)
1
2
3
4
5
6
7
8
5
NaH (10)
rt
THF
6 h
28
72
84
84
83
70
5
5
5
3
2
3
3
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
Cs2CO3 (5)
Cs2CO3 (2)
Cs2CO3 (5)
Cs2CO3 (5)
rt
rt
rt
rt
THF
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
THF
8 h
23 h
5 h
1.5 h
3 h
15 min 70
2 min 88
rt
66 ꢁ
60 ꢁC (MW)
C
CH2Cl2
a
Isolated yields.
O
1. 4-Bromo-1-butene,
Mgº, THF, then, 4,
THF, -78 ºC
OH
O
4
PhI(OAc)2
MeOH
Next, the effect of the counter cation on the carbonate base was
probed. Cesium carbonate proved the most advantageous, affording
both decreased reaction times and a reduction in necessary
equivalents of both the base and nucleophile. A slight excess of
thiophenol (3 equiv) and cesium carbonate (5 equiv) for 1.5 h at rt
provided 8 in 83% yield (Table 1, entry 5). The use of stoichiometric
amounts of both base and nucleophile led to a slight decrease in
yield to 70% (Table 1, entry 6). In order to further reduce reaction
times, the reaction was also performed at elevated temperatures
(THF, 66 ꢁC) to afford the desired product in only 15 min, albeit in
slightly reduced 70% yield (Table 1, entry 7). Finally, to decrease the
reaction time while minimizing decomposition during thermal
exposure, microwave conditions were investigated. Gratifyingly,
stirring 7 with 3 equiv of thiophenol and 5 equiv of cesium car-
bonate in the microwave at 60 ꢁC for 2 min afforded 8 in 88% yield
(Table 1, entry 8).
99%
2. Acetone/10%
acetic acid (1:1)
OH
OMe
MeO
O
3
43% (2 steps)
5
O
O
H2O2,
NaOH
Ozone, CH2Cl2
-78 ºC, then
O
O
O
O
MeOH
72%
DMS, rt, 3 d
95%
O
OH
OH
6
7
OH
2.2. Mechanistic investigation
OH
Table 1
SPh
13C NMR studies allowed for a further refinement of our previous
mechanistic hypothesis (Scheme 2).15 An initial reversible nucleo-
philic attack of thiophenol at the carbonyl group generates the
observed mixed O,S-acetals, which under basic conditions, undergo
a 1,2-migration to open the epoxide, giving ketone A. Next, prior to
HO
8
O
PhS
Scheme 1. Synthesis of diepoxyketone lactol 7 and conversion to bicycle 8 after
reaction optimization.

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J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
200.0 ppm
O
OH
OH
SPh
PhSH, Cs2CO3, CH2Cl2
O
O
191.1 ppm
-H2O
7
HO
OH
PhSH
O
80.4 ppm
DMSO-d6
O
PhS
79.8 ppm
79.1 ppm
78.9 ppm
OH
7
8
HO
O
SPh
OH
HO
OH
SPh
SPh
SPh
OH
SPh
OH
O
O
O
11
H
O
O
PhSH
OH
OH
OH
CHO
SPh
O
HO
O
O
O
HO
HO
PhS
HO
O
4
H
O
OH
OH
OH
A
B
Scheme 2. Proposed mechanism for the ring-opening and intramolecular aldol reaction of
diepoxyketone 7 with thiophenol.
Table 2
the addition of a second equivalent of thiophenol, a base catalyzed,
intermolecular aldol reaction with the hemiacetal occurs to give the
Scope of the rearrangement reaction of epoxyketone 7
isolated intermediate B. Finally, opening of the epoxide
a to the
carbonyl group with a second equivalent of thiophenol, followed by
dehydration, provides product 8. Specifically, incubation of spi-
rolactol 7 with 3 equiv of thiophenol in DMSO-d6 leads to a com-
plete conversion of the carbonyl carbon (200.0 ppm) to all four
possible diastereomeric acetals (new 13C peaks at 80.4, 79.8, 79.1,
and 78.9 ppm). Upon addition of 5 equiv of Cs2CO3, these acetal
CH2Cl2, rt, 1-2 h
Entry
R-SH
Product
Yielda,c (%)
peaks converge to a single a,b-unsaturated carbonyl resonance at
191.1 ppm, characteristic of bicyclo[3.3.1]non-3-en-2-one 8. Moni-
toring of the reaction mixture by 1H NMR revealed the complete
disappearance of the lactol hydrogen at C4 (5.76 ppm) and two of
the epoxide hydrogens (3.40e3.36 ppm) in 7, as well as the
appearance of a doublet of doublets corresponding to the hydrogen
at C11 of B (3.34 ppm), prior to the formation of product 8 (as
indicated by the alkene hydrogen at C7 of 8, 5.96 ppm). When
spirolactol 7 was subjected to the optimized room temperature
conditions and the mixture was quenched after only 5 min reaction
time, epoxyketone B was isolated in 18% yield along with a 53% yield
of 8. As expected, upon resubmission of B to the reaction conditions,
bicyclo[3.3.1]non-3-en-2-one 8 was formed in 77% yield.
1
8
83 (88)
73 (74)
72 (84)
74 (80)
74 (71)
74 (77)
87 (83)
2
9
3
10
11
12
13
14
4
5b
6
2.3. Scope and limitations of the ring-opening rearrangement
reaction
2.3.1. Survey of aryl thiol nucleophiles. Since 2 equiv of aryl thiol are
introduced in the product bicyclo[3.3.1]non-3-en-2-one, these re-
agents are important for structural diversification. Therefore, we
probed the electronic and steric limitations of the aryl thiol nu-
cleophiles. Alkyl substitution at the p-position (Table 2, entries 2
and 3) was well tolerated and provided the desired bicycles in good
yields. The presence of an electron-donating p-methoxy group had
little effect and provided similar yields (Table 2, entry 4). Electron-
withdrawing substituents on the arene, including the m-fluoro and
p-trifluoromethyl groups, also proceeded smoothly and provided
the corresponding products in good yields (Table 2, entries 5 and 6).
The o-bromo derivative was the highest yielding reagent under rt
conditions and provided a handle for subsequent cross-coupling
reactions (entry 7). The more sterically demanding 2-naphthyl
derivative exhibited a slightly lower yield (57%), possibly due to the
reduced solubility of both thiol reagent and product bicycle in
methylene chloride (entry 8). Furthermore, after 2 min at 60 ꢁC
in the microwave, the desired products were obtained in all cases in
comparable yields to the rt conditions, and the naphthyl derivative
provided the desired product 15 in improved 74% yield.
7
8
15
57 (74)
a
Yields in parentheses correspond to microwave heating of R-SH (3 equiv) and
Cs2CO3 (5 equiv) in CH2Cl2 for 2 min at 60 ꢁC.
b
Product contained a minor intractable aromatic impurity (<4% by 1H NMR).
c
Isolated yields.
with the hydroxyl substituents in the equatorial orientation. Fur-
thermore, the structure of analogue 14 was unambiguously estab-
lished via X-ray crystallography (Fig. 3).
2.3.2. Investigation of diepoxyketone substitution. In order to access
more highly substituted bicyclo[3.3.1]non-3-en-2-ones, the effect
of substituents on the diepoxyketone was also probed. The required
precursors were obtained by the addition of MeOH to commercially
available phenols in the presence of PIDA.
The structure assignments of the bicyclic products were sup-
ported by 1D and 2D NMR analyses. A single diastereomer was
observed, representing the thermodynamically favored product
The known quinone monoketals 16 and 21 were synthesized in
good yields on multi-gram scale (Schemes 3 and 4).20a,22 Addition of

J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
5855
Figure 3. ORTEP drawing of o-bromo-bicyclo[3.3.1]non-3-en-2-one 14 (with 50%
probability atomic displacement parameters).
1. 4-Bromo-1-butene,
Mgº, Et2O, reflux,
then 16, Et2O, rt
OH
O
PhI(OAc)2
MeOH
85%
2. Acetone/14%
acetic acid (1:1)
OMe
16
MeO
OMe
O
40%
(over 2 steps)
O
Ozone, CH2Cl2
-78 ºC, then
H2O2,
NaOH
O
DMS, rt, 2 d
100%
MeOH
75%
OH
OH
Scheme 4. Synthesis of m-cresol quinone monoacetal 21 by hypervalent iodine oxi-
dation and rearrangement to bicycle 25.
17
18
generation of pentenylmagnesium bromide followed by addition to
quinone monoketal 4 and ketal hydrolysis provided the desired bis-
a,b-unsaturated ketone 26 in 55% yield. Diepoxidation proceeded
O
OH
smoothly to give 27 in 89% yield, and subsequent ozonolysis gave
a 10:1 ratio of lactol 28 and aldehyde 29. However, in the presence of
thiophenol and base, a complex mixture formed, and none of the
desired bicyclo[3.4.1]dec-3-en-2-one 30 was isolated. It is likely that
intermolecular aldol processes leading to undesired side products
are more favored in this series than the intramolecular seven-
membered ring formation.
SH
OH
SPh
O
O
Cs2CO3
CH2Cl2
HO
O
OH
80%
19
20
Scheme 3. Synthesis of naphthoquinone monoacetal 16 by hypervalent iodine oxi-
dation and rearrangement to bicycle 20.
1. 4-Bromo-1-butene,
O
then, 4, Et2O, rt
in situ generated butenylmagnesium bromide to the monoketal 16
followed by ketal hydrolysis provided 17 in 40% yield over two steps.
Diepoxidation and ozonolysis proceeded in 75% and 100% yield,
respectively, to give 19 as a 2:1 mixture of lactol epimers by 1H NMR.
In the presence of thiophenol and cesium carbonate base, 19
rearranged to provide 20 in 80% yield. The structure of 20 was also
confirmed by X-ray analysis; all hydroxyl groups again assumed the
equatorial orientation on the cyclohexane chair (see
Supplementary data).
In an analogous fashion to the naphthyl derivatives, the quinone
monoacetal 21 and the methylated spirolactol 24 were prepared
(Scheme 4). Upon treatment of 24 with thiophenol under the
previously optimized conditions, 53% of the epoxy ketone 25 was
isolated as the major product. Even under forcing microwave
conditions (10 equiv of thiophenol and 10 equiv of Cs2CO3, CH2Cl2,
80 ꢁC, for 3 h), none of the expected bicyclo[3.3.1]non-3-en-2-one
was formed. Apparently, the presence of the axial methyl group in
25 decreases the flexibility of the bicyclic system sufficiently to
prevent an endo-addition of the second equivalent of thiophenol to
the remaining epoxide moiety in 25. However, this apparent re-
sistance of the epoxide moiety toward nucleophilic attack bodes
well for the use of more rigid epoxyketones in biological assays.
An attempt to extend the methodology towards the formation of
bicyclo[3.4.1]dec-3-en-2-ones was unsuccessful (Scheme 5). In situ
Mgº, Et2O, reflux,
H2O2,
NaOH
4
MeOH
89%
2. Acetone/14%
acetic acid (1:1)
HO
55%
26
(over 2 steps)
O
O
O
Ozone, CH2Cl2
-78 ºC, then
O
O
+
O
O
O
O
DMS, rt, 2 d
86%
O
OH
HO
OH
O
27
10:1
OH
28
29
SH
OH
SPh
HO
Cs2CO3, CH2Cl2
30
O
PhS
Scheme 5. Attempted preparation of bicyclo[3.4.1]dec-3-en-2-one 30.

5856
J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
2.4. Contribution to chemical diversity
chemical space. They are generally less flexible than the MLSMR
reference compounds, decreasing the likelihood of non-specific
binding in ligand-receptor interactions. PC5 and PC6 (Fig. 5b) are
greatly influenced by the electronegative atom content and the
aliphatic electropositive ratio, respectively. As might be expected,
the new compounds occupy open space on the negative PC5 axis
clustered around the origin of the PC6 axis, respectively.
The molecular diversity of the newly synthesized structures was
analyzed using the ChemGPS-NP map of chemical space (Fig. 4).23
ChemGPS-NP provides a coordinate system tuned for exploration
of biologically relevant compounds, derived from principal compo-
nent analysis of the physiochemical properties of known bioactive
and natural product molecules. The first three principle components
(PC1, PC2, and PC3) roughly correspond to the molecular size,
numberof p electrons(aromaticity)and lipophilicityof a compound.
Figure 4. ChemGPS-NP coordinates of the newly synthesized bicyclic products (blue
circles) and the bicyclo[3.3.1]-nonanes in the MLSMR library3 (crosses). Also shown are
the coordinates of bicyclo[3.3.1]non-3-en-2-ones with all hydroxyl groups removed
(yellow boxes).
The newly synthesized bicyclic products were compared to the
space spanned by the bicyclo[3.3.1]-nonanes already contained in
the MLSMR library (1907 compounds). The new compounds occupy
a simultaneously more aromatic and less lipophilic region of
chemical space than this reference collection (Fig. 4). The greater
degree of aromaticity is due to the benzene rings introduced
through the aryl thiol moieties. In particular, the two naphthyl
groups of structure 15 move this compound far outside the space of
known bicyclo[3.3.1.]nonanes (see number of aromatic rings in
Table 3). The dense hydroxylation pattern is responsible for the
compounds’ lower lipophilicity and increased polarity; as shown in
Figure 4, without the hydroxyl groups, the compounds’ lipophilicity
is greatly increased.
Figure 5. ChemGPS-NP coordinates of the newly synthesized bicyclic products (blue)
and the bicyclo[3.3.1]-nonanes in the MLSMR library (crosses). (a) PC1 and PC4
highlight size and flexibility, respectively. (b) PC5 and PC6, showing electronegative
and electropositive atomic content, respectively.
Physiochemical descriptors for each compound were computed
using the OpenEye toolkit (Table 3) as well as ChemAxon (not
shown).24 All but two of the compounds obey Lipinski’s rule of 5;25
in each case the number of hydrogen bond acceptors is well below
10, and the number of hydrogen bond donors is <5. These prop-
erties provide a measure of the efficiency of drug transport across
biological membranes. All but two of the compounds also have an
XLogP value of <5.0, indicating low lipophilicity and promising
bioavailability. The two compounds with high LogP (10 and 15)
contain large hydrocarbon R-groups, which increase their solubility
in non-polar solvents. Drugs are often significantly more potent
and selective than lead compounds, which can be accomplished by
increasing molecular weight and modulating lipophilicity, while
preserving the parent scaffold.26
The present analysis demonstrates that the highly hydroxylated
substitution pattern of 8e25 allows these compounds to expand
into new regions of the bicyclononane chemical space. With com-
paratively little variation in shape and volume and easy synthetic
access and modification, 8e25 are more hydrophilic than existing
bicyclononanes, while meeting Lipinski rules and exhibiting
reduced potential for non-specific binding.
Table 3
Selected physiochemical properties of new bicyclic products 8e15.24
Product
MW
XLogP
Lipinski
HBD
Lipinski
HBA
Lipinski
violations
Aryl
rings
B
8
9
308.35
400.51
428.56
512.72
460.56
536.51
436.49
558.30
500.63
342.41
322.38
ꢀ0.27
3.06
3.65
6.20
2.77
4.87
3.33
4.66
5.16
1.92
0.12
3
3
3
3
3
3
3
3
3
3
3
5
4
4
4
6
4
4
4
4
4
5
0
0
0
2
0
1
0
1
2
0
0
1
2
2
2
2
2
2
2
4
2
1
10
11
12
13
14
15
20
25
In terms of size and shape, the new derivatives do not appear to
occupy significantly new space, as shown by projection into the
first and fourth ChemGPS-NP principle components (Fig. 5a).
However, these compounds occupy lead-like portions of the
3. Conclusions
The aromatic thiol-mediated ring-opening, intramolecular
rearrangement reaction of epoxyketones can be used for the

J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
5857
preparation of densely functionalized bicyclo[3.3.1]non-3-en-ones.
4.2. General procedure A
The key synthetic intermediates are readily available from com-
mercially available phenols by hypervalent iodine oxidations.
Specifically, after scaleup of diepoxyketone 7, two optimized
procedures were developed for the diversity-generating trans-
formations. The mild room temperature conditions provided the
desired products in 1.5 h and 57e87% yield, while microwave
conditions were found to shorten the reaction time to 2 min at
60 ꢁC, providing the bicyclic products 8e15 in comparable yields
(71e88%). Both sets of conditions were shown to tolerate electron-
donating as well as electron-withdrawing substituents on the
aromatic thiol. Although the reaction conditions proved not to be
amenable to the formation of bicycl[3.4.1]decenones, the process
was tolerant of fused bicyclic systems. Methyl substitution on the
diepoxyketone was found to significantly decrease the rate of
addition of the second equivalent of thiophenol; however, this
reaction provided access to an interesting epoxyketone derivative
with a relatively inert epoxy functionality. Finally, a brief mecha-
nistic investigation led to a refinement of our mechanistic hy-
pothesis as well as the isolation of an intermediate in the pathway,
which might be useful for the selective addition of two different
thiol nucleophiles. A ChemGPS-NP based chemical diversity anal-
ysis revealed substantial structural difference between the new set
of bicyclo[3.3.1]non-3-en-2-ones and the related bicyclic scaffolds
currently available in the MLSMR collection. Studies to further
extend the scope of the reaction to include a greater variety of
thiol nucleophiles, more highly substituted diepoxyketones, and
selective thiol additions are in progress.
Addition/Rearrangement to bicyclo[3.3.1]nonane Scaffold. To
a stirred solution of 7 (0.0500 g, 0.252 mmol, 1 equiv) in dry,
degassed CH2Cl2 (12 mL) was added Cs2CO3 (0.411 g, 1.26 mmol,
5 equiv) and the thiol nucleophile (0.757 mmol, 3 equiv). The
reaction mixture was allowed to stir at rt for 1e2 h, diluted with
EtOAc (40 mL), and washed with brine. The organic layer was
separated and the aqueous layer was extracted with EtOAc
(2ꢂ10 mL). The combined organic layers were washed with brine,
dried (MgSO4), filtered, and concentrated under reduced pressure.
The crude mixture was dissolved in CH2Cl2 and purified by chro-
matography on SiO2.
4.3. General procedure B
Microwave Assisted Addition/Rearrangement to Bicyclo[3.3.1]
nonane Scaffold. To a stirred solution of 7 (0.0100 g, 0.0505 mmol,
1 equiv) in dry, degassed CH2Cl2 (2 mL) was added Cs2CO3
(0.0822 g, 0.252 mmol, 5 equiv) and the thiol nucleophile
(0.151 mmol, 3 equiv). The reaction mixture was heated in the
microwave reactor for 2 min at 60 ꢁC, diluted with CH2Cl2 (10 mL),
and washed with brine. The organic layer was separated and the
aqueous layer was extracted with EtOAc (2ꢂ10 mL). The combined
organic layers were washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude mixture was dis-
solved in CH2Cl2 and purified by chromatography on SiO2.
4.3.1. 4,4-Dimethoxycyclohexa-2,5-dienone (4)12. To a stirred solu-
tion of 4-methoxyphenol (10.0 g, 80.6 mmol, 1 equiv) in dry MeOH
(200 mL) at 0 ꢁC under a nitrogen atmosphere was added phenyl-
iodonium diacetate (PIDA; 25.9 g, 80.6 mmol, 1 equiv), and the
resulting solution was stirred for 45 min. After 45 min, the mixture
was quenched with a saturated aqueous solution of NaHCO3
(300 mL) and extracted with Et2O (3ꢂ). The combined organic
layers were washed with brine, dried (MgSO4), filtered, and con-
centrated under reduced pressure. The reaction mixture was
purified by chromatography on SiO2 (deactivated with 0.1% Et3N;
EtOAc/hexanes 1:5 to 1:1) to give 4 (12.3 g, 99% yield) as a colorless
oil: Rf 0.41 (EtOAc/hexanes, 1:3); IR (neat) 2991, 2941, 2830, 1685,
4. Experimental part
4.1. General
All moisture sensitive reactions were performed using syringe-
septum techniques under an atmosphere of either dry N2 or dry
argon unless otherwise noted. All glassware were dried in an oven
at 140 ꢁC for a minimum of 6 h or flame-dried under an atmosphere
of dry nitrogen prior to use. Reactions carried out at ꢀ78 ꢁC
employed a CO2(s)/acetone bath. Diethyl ether and tetrahydrofuran
were dried by distillation over sodium/benzophenone under an
argon atmosphere. Dry methylene chloride was purified by filtra-
tion through an activated alumina column. Methylene chloride was
degassed using the freeze/pump/thaw method (3ꢂ). Methanol was
1671, 1636, 1178, 1105, 1083, 1059, 1034, 1034, 958, 853 cmꢀ1
NMR (300 MHz, CDCl3) 6.84e6.79 (m, 2H), 6.29e6.24 (m, 2H),
3.37 (s, 6H); 13C NMR (75 Hz, CDCl3)
185.1, 143.2, 130.0, 92.4, 50.4;
HRMS (EIþ) m/z calcd for C8H10O3 154.0630, found 154.0628.
;
1H
d
d
ꢀ
stored over molecular sieves (3 A). Deuterated chloroform
was stored over anhydrous potassium carbonate. Reactions were
monitored by TLC analysis (pre-coated silica gel 60 F254 plates, 250
4.3.2. 4-(But-3-enyl)-4-hydroxycyclohexa-2,5-dienone
(5)12. To
m
m layer thickness) and visualized by using UV lamp (254 nm) or
a dry, 100 mL, three-necked, round-bottom flask equipped with an
addition funnel and reflux condenser was added magnesium
turnings (2.27 g, 93.4 mmol, 1.2 equiv) and a crystal of iodine. Heat
(Bunsen burner flame) was applied to the stirred turnings until
a purple gas coated the interior of the flask. The sample was
allowed to cool under argon and suspended in dry THF (30 mL). To
the stirred solution was added via an addition funnel a solution of
4-bromo-1-butene (9.48 mL, 93.4 mmol, 1.2 equiv) in dry THF
(10 mL) at a rate so that the solution maintained a gentle reflux.
After the addition was completed, the reaction mixture was
allowed to stir at reflux for 45 min, cooled to rt and cannulated over
30 min into a pre-cooled (ꢀ78 ꢁC) solution of 4 (12.0 g, 77.8 mmol,
1 equiv) in dry THF (150 mL). The reaction mixture was allowed to
stir at ꢀ78 ꢁC for 3 h and quenched with a saturated aqueous
solution of NH4Cl, warmed to rt, and extracted with EtOAc
(3ꢂ150 mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated under reduced pressure. The
resulting oil was diluted with H2O/acetone (1:1, 500 mL) and glacial
acetic acid (50 mL) was added. The reaction mixture was allowed to
stir at rt for 3 h, and extracted with EtOAc (3ꢂ150 mL). The
by staining with either Vaughn’s reagent (4.8 g of
(NH4)6Mo7O24$4H2O and 0.2 g of Ce(SO4)2 in 100 mL of a 3.5 N
H2SO4) or a potassium permanganate solution (1.5 g of KMnO4 and
1.5 g of K2CO3 in 100 mL of a 0.1% NaOH solution). Flash column
chromatography was performed with 40e63 mm silica gel (Sili-
cycle). Microwave reactions were performed on a Biotage Initiator
microwave reactor. Infrared spectra were measured on a Smiths
Detection IdentifyIR FT-IR spectrometer (ATR). Unless otherwise
indicated, all NMR data were collected at room temperature in
CDCl3 on a 300, 500, 600, or 700 MHz Bruker instrument. Chemical
shifts (
CHCl3
d
) are reported in parts per million (ppm) with internal
(d
7.26 ppm for 1H and 77.00 ppm for 13C), internal acetone
(
(
d
d
2.05 ppm for 1H and 29.85 ppm for 13C), or internal DMSO
2.50 ppm for 1H and 39.52 for 13C) as the reference. 1H NMR data
are reported as follows: chemical shift, multiplicity (s¼singlet, br
s¼broad singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
dd¼doublet of doublets, dt¼doublet of triplets, td¼triplet of dou-
blets, qd¼quartet of doublets, sep¼septet), integration, and cou-
pling constant(s) (J) in hertz (Hz).

5858
J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
combined organic layers were washed with brine, dried (MgSO4),
filtered, and concentrated under reduced pressure to give a yellow
oil, which was purified by chromatography on SiO2 (EtOAc/hexanes,
1:3) to give 5 (7.05 g, 43% yield) as a volatile pale yellow oil: Rf 0.24
(EtOAc/hexanes, 1:3); IR (neat) 3339, 3276, 2937, 1662, 1606, 1396,
1.27 mmol, 1 equiv) in CH2Cl2 (25 mL) were added thiophenol
(0.391 mL, 3.82 mmol, 3 equiv) and Cs2CO3 (3.46 g, 6.37 mmol,
5 equiv). The reaction mixture was allowed to stir at rt for 5 min
then quenched with a saturated aqueous solution of NH4Cl and
extracted with EtOAc (3ꢂ). The combined organic layers were
washed with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude mixture was purified by chromatog-
raphy on SiO2 (EtOAc/hexanes, 1:1) to give B (0.070 g, 18% yield) as
a colorless film: Rf 0.45 (EtOAc); IR (CDCl3) 3465, 2943, 2877, 1709,
1052, 1018, 991, 859, 716 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
6.86e6.81 (m, 2H), 6.21e6.16 (m, 2H), 5.77 (dddd, 1H, J¼6.3, 6.3,
10.2, 16.5 Hz), 5.06e4.96 (m, 2H), 2.52 (s, 1H), 2.09e2.01 (m, 2H),
1.88e1.83 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 185.5, 150.9, 137.1,
128.4, 115.4, 69.8, 38.8, 27.8; HRMS (EIþ) m/z calcd for C10H12O2
1274, 1437, 1326, 1111, 1085, 1025, 904, 729, 703 cmꢀ1
;
1H NMR
164.0837, found 164.0829.
(300 MHz, CDCl3)
d
7.64 (d, 2H, J¼7.5 Hz), 7.50e7.36 (m, 3H), 3.69
(d, 1H, J¼3.3 Hz), 3.62 (d, 1H, J¼2.1 Hz), 3.47 (d, 2H, J¼4.2 Hz), 3.36
(s, 1H), 3.32 (s, 1H), 2.92 (d, 1H, J¼12.3 Hz), 2.14e2.07 (m, 2H),
4.3.3. 4-(But-3-enyl)-4-hydroxycyclohexa-2,5-dioxirane
(6)12. To
a stirred solution of enone 5 (4.25 g, 25.9 mmol, 1 equiv) in meth-
anol (100 mL) and 30% aqueous hydrogen peroxide (7.93 mL,
77.6 mmol, 3 equiv) at 0 ꢁC was added 6 M NaOH (2.16 mL,
7.00 mmol, 0.5 equiv) dropwise. The reaction mixture was allowed
to stir at 0 ꢁC for 2 h, poured onto DI water and thoroughly
extracted with EtOAc (7ꢂ100 mL). The combined organic layers
1.50e1.38 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 198.3, 138.2, 130.4,
129.3, 126.0, 73.6, 71.7, 70.7, 70.6, 60.8, 56.6, 29.9, 27.7; HRMS (EIþ)
m/z calcd for C15H16O5S 308.0718, found 308.0713.
4.3.7. (1S,8R,9S)-5,8,9-Trihydroxy-1,3-bis(p-tolylthio)bicyclo[3.3.1]
non-3-en-2-one (9). Prepared according to general procedure A
utilizing 7 (0.0500, 0.252 mmol, 1 equiv), Cs2CO3 (0.411 g,
ꢀ
were washed with brine, poured onto activated 4 A molecular
sieves, and allowed to stir at rt for 3 h. The mixture was filtered and
concentrated under reduced pressure to give 6 (3.68 g, 72% yield) as
an off-white solid: Rf 0.62 (EtOAc/CH2Cl2, 1:1); IR (neat) 3459, 3028,
1.26 mmol, 5 equiv), and p-thiocresol (0.0940 mL, 0.757 mmol,
3 equiv). The crude reaction mixture was purified by chromatog-
raphy on SiO2 (EtoAc/hexanes, 1:1) to give 9 (78.6 mg, 73% yield) as
a white solid: Rf 0.29 (EtOAc/hexanes, 1:1); mp 191e193 ꢁC; IR
(neat) 3496, 3345, 3060, 2942, 1664, 1578, 1472, 1420, 1314, 1217,
2976, 2940,1702,1366, 1328, 1239, 1090, 1060, 1025, 926, 917 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
5.09e5.01 (m, 2H), 3.50 (s, 4H), 3.03 (s, 1H), 2.27e2.15 (m, 2H),
d
5.79 (dddd, 1H, J¼6.6, 10.2, 16.8 Hz),
1100, 1031, 868, 731 cmꢀ1
;
1H NMR (300 MHz, acetone-d6)
1.96e1.90 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
198.9, 136.7, 115.9,
d
7.64e7.62 (m, 2H), 7.40e7.38 (m, 2H), 7.28 (d, 2H, J¼8.1 Hz), 7.23
68.9, 63.9, 57.0, 35.6, 26.9; HRMS (ESIþ) m/z calcd for C10H12O4
(d, 2H, J¼8.1 Hz), 5.84 (d, 1H, J¼2.4 Hz), 4.44 (br s, 1H), 3.99 (s, 1H),
3.37 (dd, 1H, J¼6.0, 10.8 Hz), 3.17 (d, 1H, J¼2.4 Hz), 2.36 (s, 3H), 2.35
(s, 3H), 1.99e1.92 (m, 1H), 1.58e1.51 (m, 1H), 1.48e1.32 (m, 2H); 13C
196.0736, found 196.0726.
4.3.4. 1-Oxaspiro[4.5.]deca-6,9-diepoxy-2,8-lactol (7)12. A solution
of 6 (1.00 g, 5.10 mmol, 1 equiv) in CH2Cl2 (30 mL) was cooled to
ꢀ78 ꢁC. Ozone was passed through the stirred solution for 3.5 h fol-
lowed by O2 for 1 min.27 Dimethylsulfide (7.54 mL, 102 mmol,
20 equiv) was then added dropwise at ꢀ78 ꢁC. The reaction mixture
was allowed to stir at ꢀ78 ꢁC for 1 h and then allowed to warm to rt
and stirred at rt for 3 days. The solvent was removed under reduced
pressure. The crude product was purified by chromatography on SiO2
(EtOAc) to give 7 (0.962 g, 95% yield) as an off-white solid: Rf 0.45
(EtOAc); mp164e166 ꢁC;IR (neat)3369, 3440, 2965,1722,1459,1431,
1349, 1243, 1202, 1038, 976, 919 cmꢀ1; 1H NMR (500 MHz, acetone-
NMR (75 MHz, acetone-d6) d 190.9, 143.1, 140.8, 140.0, 139.9, 139.1,
135.6, 131.4, 130.6, 128.1, 126.1, 77.5, 75.8, 74.2, 69.2, 31.4, 28.4, 21.2,
21.2; HRMS (EIþ) m/z calcd for C23H24O4S2 428.1116, found 428.1101.
4.3.8. (1S,8R,9S)-1,3-Bis(4-tert-butylphenylthio)-5,8,9-trihydrox-
ybicyclo[3.3.1]non-3-en-2-one (10). Prepared according to general
procedure A utilizing 7 (0.0500, 0.252 mmol, 1 equiv), Cs2CO3
(0.411 g, 1.26 mmol, 5 equiv), and 4-tert-butylthiophenol, (0.13 mL,
0.76 mmol, 3 equiv). The crude reaction mixture was purified by
chromatography on SiO2 (EtOAc/hexanes, 5:1 to 3:1) to give 10
(0.0935 g, 72% yield) as a white solid: Rf 0.86 (EtOAc/hexanes, 1:1);
mp 203e207 ꢁC; IR (neat): 3475, 2956, 2902, 2866,1674,1591,1489,
1265, 1099, 1034, 1012, 831, 729 cmꢀ1; 1H NMR (300 MHz, acetone-
d6)
d
5.69(d,1H, J¼1.8 Hz), 5.53(brs,1H), 3.62(t,1H,J¼2.4 Hz),3.49 (t,
1H, J¼2.1 Hz), 3.35 (t, 1H, J¼2.4 Hz), 3.31 (t, 1H, J¼2.4 Hz), 2.35e2.27
(m, 1H), 2.19e2.11 (m, 2H), 2.05e2.00 (m, 1H); 13C NMR (125 Hz,
d6)
d 7.71e7.69 (m, 1H), 7.68e7.67 (m, 1H), 7.52e7.41 (m, 6H), 5.94
acetone-d6)
d
200.5,100.6, 80.3, 65.2, 63.6, 56.1, 55.9, 33.9, 31.1; HRMS
(d, 1H, J¼2.4 Hz), 4.62 (br s, 1H), 4.48 (br s, 1H), 4.04 (d, 1H,
J¼1.8 Hz), 3.40 (dd, 1H, J¼6.0, 11. 1 Hz), 3.19 (d, 1H, J¼2.1 Hz),
2.01e1.93 (m, 1H), 1.61e1.54 (m, 1H), 1.49e1.35 (m, 2H), 1.33 (s, 9H),
(EIþ) m/z calcd for C9H10O5 198.0528, found 198.0523.
4.3.5. (1S,8R,9S)-5,8,9-Trihydroxy-1,3-bis(phenylthio)bicyclo[3.3.1]
1.32 (s, 9H); 13C NMR (75 MHz, acetone-d6)
d 190.9, 153.7, 152.8,
non-3-en-2-one (8). Prepared according to general procedure A
143.8, 139.5, 138.9, 134.9, 128.4, 127.6, 126.9, 126.1, 77.7, 75.8, 74.2,
69.3, 35.3, 35.2, 31.5, 31.4, 28.3; HRMS (EIþ) m/z calcd for
C29H36O4S2 512.2055, found 512.2076.
utilizing
7 (0.025 g, 0.126 mmol, 1 equiv), Cs2CO3 (0.205 g,
0.631 mmol, 5 equiv), and thiophenol (0.039 mL, 0.38 mmol,
3 equiv). The crude mixture was purified by chromatography on
SiO2 (EtOAc/hexanes 1:2 to 1:1) to give 8 (0.0416 g, 83% yield) as
a white solid: Rf 0.33 (EtOAc/hexanes, 1:1); mp 185e188 ꢁC; IR
(neat) 3502, 3335, 3051, 2945, 2879, 1666, 1590, 1472, 1439, 1310,
4.3.9. (1S,8R,9S)-5,8,9-Trihydroxy-1,3-bis(4-methoxyphenylthio)bi-
cyclo[3.3.1]non-3-en-2-one (11). Prepared according to general
procedure A utilizing 7 (0.0500, 0.252 mmol, 1 equiv), Cs2CO3
(0.411 g, 1.26 mmol, 5 equiv), and 4-methoxythiophenol (0.093 mL,
0.76 mmol, 3 equiv). The crude reaction mixture was purified by
chromatography on SiO2 (EtOAc/hexanes, 1:1) to give 11 (0.0857 g,
74% yield) as a white solid. Rf 0.29 (EtOAc/hexanes, 1:1); mp
105e107 ꢁC; IR (neat) 3487, 2937, 2911, 2903, 1670, 1588, 1491,
1228, 1100, 1032, 954, 738, 689 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
7.52e7.51 (m, 2H), 7.46e7.41 (m, 5H), 7.33e7.32 (m, 3H), 5.96 (d,
1H, J¼0.9 Hz), 3.85e3.83 (m, 1H), 3.48 (s, 1H), 3.32 (s, 1H), 3.24 (s,
1H) 2.27 (s, 1H), 2.06e2.03 (m, 1H), 1.89 (dd, 1H, J¼1.5, 6.6 Hz), 1.76
(dt, 1H, J¼2.1, 8.1 Hz), 1.67 (s, 1H), 1.38 (dq, 1H, J¼3.0, 8.1 Hz); 13C
NMR (125 MHz, CDCl3)
d
193.0,143.3,141.9,134.9,133.4,133.1,130.1,
1285, 1243, 1172, 1101, 1025, 950, 829 cmꢀ1
;
1H NMR (300 MHz,
129.9, 129.5, 129.2, 128.4, 73.0, 69.9, 63.4, 58.4, 33.3, 29.1; HRMS
acetone-d6) 7.69e7.65 (m, 2H), 7.45e7.42 (m, 2H), 7.06e7.02 (m,
d
(EIþ) m/z calcd for C21H20O4S2 400.0803, found 400.0822.
2H), 6.99e6.95 (m, 2H), 5.70 (d, 1H, J¼2.4 Hz), 4.55 (br s, 1H), 4.37
(s, 1H), 3.97 (d, 1H J¼2.1 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 3.36 (dd, 1H,
J¼6.0, 10.8 Hz), 3.15 (s, 1H), 1.98e1.91 (m, 1H), 1.56e1.50 (m, 1H),
4.3.6. (1R,2R,4S,6S,7R,10S)-1,7,10-trihydroxy-6-(phenylthio)-3-oxa-
tricyclo[4.3.1.02,4]decan-5-one (B). To a stirred solution of 7 (0.250 g,
1.46e1.32 (m, 2H); 13C NMR (75 MHz, acetone-d6)
d 191.1, 162.0,

J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
5859
161.7, 141.7, 140.9, 140.5, 137.9, 121.4, 119.9, 116.3, 115.4, 77.4, 75.8,
74.1, 69.1, 55.8, 55.7, 31.5, 28.3; HRMS (EIþ) m/z calcd for C23H24O6S2
460.1014, found 460.1009.
chromatography on SiO2 (EtOAc/hexanes, 1:1) to give 15 (0.0357 g,
57% yield) as a white solid: Rf 0.44 (EtOAc/hexanes, 1:1); mp
230e233 ꢁC; IR (neat) 2509, 3351, 3047, 2984, 2871, 1662, 1584,
1129, 1099, 1032, 954, 857, 820, 745 cmꢀ1 1H NMR (300 MHz,
;
4.3.10. (1S,8R,9S)-5,8,9-Trihydroxy-1,3-bis(4-(trifluoromethyl)phe-
nylthio)bicyclo[3.3.1]non-3-en-2-one (12). Prepared according to
general procedure A utilizing 7 (0.0500, 0.252 mmol, 1 equiv),
DMSO-d6) d 8.39 (s, 1H), 8.09 (s, 1H), 8.00e7.88 (m, 6H), 7.83 (d, 1H,
J¼8.4 Hz), 7.59e7.57 (m, 4H), 7.49 (d, 1H, J¼8.1 Hz), 6.05 (d, 1H,
J¼1.8 Hz), 5.62 (d, 1H, J¼3.6 Hz), 5.51 (s, 1H), 5.22 (d, 1H, J¼3.9 Hz),
3.03 (s, 1H), 1.83e1.81 (m, 1H), 1.46e1.38 (m, 2H),1.22e1.14 (m, 1H);
Cs2CO3
(0.411 g,
1.26 mmol,
5 equiv),
and
4-tri-
fluoromethylthiophenol (0.135 g, 0.757 mmol, 3 equiv). The crude
reaction mixture was purified by chromatography on SiO2 (EtOAc/
hexane, 1:1) to give 12 (0.100 g, 74% yield) as a foam: Rf 0.21 (EtOAc/
hexanes, 1:1); mp 145e148 ꢁC; IR (neat) 3498, 1685, 1604, 1319,
1163, 1120,1103, 1062, 1013, 839 cmꢀ1; 1H NMR (300 MHz, acetone-
13C NMR (75 MHz, DMSO-d6)
d 190.7, 146.7, 138.5, 136.0, 134.6,
133.5, 132.9, 132.4, 132.3, 129.8, 129.3, 128.7, 128.0, 127.9, 127.7,
127.6, 127.2, 127.0, 126.9, 126.5, 76.6, 74.7, 74.0, 68.1, 30.6, 28.4;
HRMS (ESIþ) m/z calcd for C29H24O4NaS2 523.1014, found 523.1017.
d6)
d
8.00 (d, 2H, J¼8.1 Hz), 7.74 (d, 2H, J¼8.1 Hz), 7.69 (d, 2H,
4.3.14. 4,4-Dimethoxynaphthalen-1(4H)-one (16)15. To a stirred so-
lution of 4-methoxynapthol (5.00 g, 28.7 mmol, 1 equiv) in MeOH
(150 mL) was added PIDA (11.1 g, 34.4 mmol, 1.2 equiv), and the
resulting solution was stirred at rt for 1 h. The mixture was
quenched with a saturated aqueous solution of NaHCO3 and
extracted with CH2Cl2 (3ꢂ). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude mixture was purified bychromatography on SiO2 (deactivated
with 0.1% Et3N; EtOAc/hexanes, 1:3) to give 16 (5.00 g, 85% yield) as
a blue semi-solid: Rf 0.52 (EtOAc/hexanes, 1:3); IR (CDCl3) 2935,
J¼8.4 Hz), 7.60 (d, 2H, J¼8.4 Hz), 6.69 (d, 1H, J¼2.7 Hz), 4.84 (br s,
1H), 4.28 (s, 1H), 3.54 (dd, 1H, J¼5.7, 10.5 Hz), 3.32 (d, 1H, J¼2.4 Hz),
2.03e1.96 (m, 1H), 1.80e1.47 (m, 3H); 13C NMR (75 MHz, acetone-
d6)
d
190.0, 152.8, 139.6, 135.8, 135.4, 131.9, 126.8 (q, J¼3.75 Hz),
126.4 (q, J¼3.75 Hz), 78.0, 76.0, 75.0, 69.6, 31.0, 28.8. HRMS (ESIþ)
m/z calcd for C23H18O4F6NaS2 559.0448, found 559.0490.
4.3.11. (1S,8R,9S)-1,3-Bis(3-fluorophenylthio)-5,8,9-trihydroxy-
bicyclo[3.3.1]non-3-en-2-one (13). Prepared according to general
procedure A utilizing 7 (0.0500, 0.252 mmol, 1 equiv), Cs2CO3
(0.411 g, 1.26 mmol, 5 equiv), and 3-fluorothiophenol (0.064 mL,
0.76 mmol, 3 equiv). The crude reaction mixture was purified by
chromatography on SiO2 (EtOAc/hexanes, 1:1) to give 13 (0.110 g,
74% yield) as a white solid: Rf 0.46 (EtOAc/hexanes, 1:1); mp
190e192 ꢁC; IR (neat) 3349, 3345, 3060, 2942, 2918, 1664, 1578,
2827, 1668, 1629, 1597, 1455, 1297, 1056, 974, 764 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) 8.01 (d, 1H, J¼7.5 Hz), 7.67 (d, 1H, J¼7.2 Hz), 7.59
(t, 1H, J¼8.1 Hz), 7.43 (t, 1H, J¼8.1 Hz), 6.88 (d, 1H, J¼10.5 Hz), 6.53
(d,1H, J¼10.5 Hz), 3.13 (s, 6H); 13C NMR (75 Hz, CDCl3)
d 183.6,144.0,
139.5, 133.3, 132.4, 131.4, 129.1, 126.5, 126.1, 94.8, 51.0; HRMS (ESIþ)
m/z calcd for C12H13O3 [MþH] 205.0865, found 205.0870.
1472, 1420, 1472, 1314, 1217, 1155, 1099, 868, 731 cmꢀ1
;
1H NMR
(300 MHz, acetone-d6) 7.63e7.56 (m, 2H), 7.51e7.41 (m, 2H),
d
4.3.15. 4-(But-3-enyl)-4-hydroxynaphthalen-1(4H)-one
(17). To
7.30e7.21 (m, 3H), 7.16e7.09 (m, 1H), 6.39 (d, 1H, J¼2.4 Hz), 4.76 (br
s, 1H), 4.19 (s, 1H), 3.48 (dd, 1H, J¼6.0, 11.1 Hz), 3.29 (d, 1H, 2.4 Hz),
2.06e1.98 (m, 1H), 1.72e1.63 (m, 1H), 1.58e1.42 (m, 2H); 13C NMR
a dry, 250 mL round-bottom flask equipped with an addition funnel
was added magnesium turnings (0.714 g, 29.4 mmol, 1.2 equiv) and
a crystal of iodine. Heat (Bunsen burner flame) was applied to the
stirred turnings until a purple gas coated the interior of the flask.
The sample was allowed to cool under argon and suspended in dry
ether (20 mL). To the stirred solution was added via an addition
(75 MHz, acetone-d6)
d
190.3, 165.1 (d, J¼48.8 Hz), 161.8 (d,
J¼48.8 Hz), 149.3, 137.0, 135.9 (d, J¼8.3 Hz), 135.2 (d, J¼3.0 Hz),
132.3 (d, J¼7.5 Hz), 132.0 (d, J¼9.0 Hz), 131.3 (d, J¼8.3 Hz), 129.1 (d,
J¼3.0 Hz), 125.5 (d, J¼21.0 Hz), 119.7 (d, J¼22.5 Hz), 117.6 (d,
J¼21.0 Hz), 115.7 (d, J¼21.0 Hz), 77.8, 76.0, 74.7, 69.4, 31.2, 28.6;
HRMS (EIþ) m/z calcd for C21H19F2O4S2 436.0615, found 436.0633.
funnel
a solution of 4-bromo-1-butene (2.98 mL, 29.4 mmol,
1.2 equiv) in dry ether (20 mL). The reaction mixture was allowed to
stir at reflux for 1 h, allowed to cool to rt, and a solution of 16
(5.00 g, 24.5 mmol, 1 equiv) in dry ether (40 mL) was added and
quantitatively transferred with dry ether (20 mL). The heteroge-
neous reaction mixture was allowed to stir at rt for 15 min, cooled
to 0 ꢁC, quenched with a saturated aqueous solution of NH4Cl and
extracted with ether (ꢂ3). The combined organic layers were
washed with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude oil was suspended in acetone/water
(1:1, 200 mL) and glacial acetic acid (14 mL) was added. The re-
action mixture was allowed to stir at 0 ꢁC for 2 h and extracted with
Et2O (ꢂ2). The combined organic layers were washed with a satu-
rated aqueous solution of NaHCO3, brine, dried (MgSO4), filtered,
and concentrated under reduced pressure. The crude mixture was
purified by chromatography on SiO2 (EtOAc/hexanes, 1:10 to 5:1 to
1:1) to give 17 (2.09 g, 40% yield) as a yellow oil: Rf 0.68 (EtOAc/
hexanes, 1:1); IR (CDCl3) 3407, 3066, 2937, 1657, 1597, 1456, 1297,
4.3.12. (1S,8R,9S)-1,3-Bis(2-bromophenylthio)-5,8,9-trihydroxy-
bicyclo[3.3.1]non-3-en-2-one (14). Prepared according to general
procedure A utilizing 7 (0.0500, 0.252 mmol, 1 equiv), Cs2CO3
(0.411 g, 1.26 mmol, 5 equiv), and 2-bromobenzenethiol (0.091 mL,
0.76 mmol, 3 equiv). The crude reaction mixture was purified by
chromatography on SiO2 (EtOAc/hexanes 1:3 to 1:1) to give 14
(0.121 g, 87% yield) as a white solid. A small portion was recrys-
tallized (acetone/Et2O) to give colorless crystals for X-ray analysis:
Rf 0.28 (EtOAc/hexanes, 1:1); mp 171e173 ꢁC; IR (neat) 3427, 3468,
2937, 2883, 2868, 1659, 1599, 1446, 1420, 1331, 1272, 1248, 1110,
1019, 954, 760, 732 cmꢀ1 1H NMR (300 MHz, acetone-d6)
; d 8.06
(dd, 1H, J¼2.4, 7.2 Hz), 7.79 (dd, 1H, 2.1, 7.2 Hz), 7.75 (dd, 1H, J¼0.9,
8.1 Hz), 7.56 (dd, 1H, J¼1.5, 7.8 Hz), 7.45e7.29 (m, 4H), 6.19 (d, 1H,
J¼2.7 Hz), 4.86 (br s, 1H), 4.63 (s, 1H), 3.79 (d, 1H, J¼2.1 Hz), 3.47
(dd, 1H, J¼5.7, 10.2 Hz), 3.43 (d, 1H, J¼2.1 Hz), 1.74e1.55 (m, 4H); 13C
1150, 1051, 1014, 911, 762 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.99 (d,
NMR (75 MHz, acetone-d6)
d
190.0, 148.5, 141.6, 135.8, 135.6, 134.5,
1H, J¼7.8 Hz), 7.70 (d, 1H, J¼7.5 Hz), 7.60 (t, 1H, 6.6 Hz), 7.40 (t, 1H,
8.1 Hz), 6.92 (d, 1H, J¼10.2 Hz), 6.31 (d, 1H, J¼10.2 Hz), 5.62 (dddd,
1H, J¼6.3, 6.3, 10.5, 12.6 Hz), 4.91e4.85 (m, 2H), 2.81 (s, 1H),
2.12e1.96 (m, 2H), 1.96e1.82 (m, 1H), 1.58e1.45 (m, 1H); 13C NMR
134.4, 134.3, 133.2, 132.4, 131.5, 130.8, 129.6, 129.1, 127.6, 78.1, 76.2,
70.0, 69.9, 31.3, 28.4; HRMS (ESIþ) m/z calcd for C21H18O4NaS2Br2
578.8911, found 578.8945.
(75 Hz, CDCl3)
d 184.6, 151.9, 146.0, 137.0, 133.4, 130.2, 128.4, 128.1,
4.3.13. (1S,8R,9S)-5,8,9-Trihydroxy-1,3-bis(naphthalen-2-ylthio)bi-
cyclo[3.3.1]non-3-en-2-one (15). Prepared according to general
procedure A utilizing 7 (0.0250, 0.126 mmol, 1 equiv), Cs2CO3
(0.206 g, 0.631 mmol, 5 equiv), and napthalene-2-thiol (0.0606 g,
0.378 mmol, 3 equiv). The crude reaction mixture was purified by
126.3, 126.1, 115.0, 71.0, 42.0, 28.1; HRMS (ESIþ) m/z calcd for
C14H14O2Na 237.0891, found 237.0900.
4.3.16. (1aS,7S,7aR)-7-(But-3-enyl)-7-hydroxy-7,7a-dihydronaphtho
[2,3-b]oxiren-2(1aH)-one (18). To a stirred solution of 17 (1.90 g,

5860
J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
8.87 mmol, 1 equiv) and 30% aqueous hydrogen peroxide (2.72 mL,
26.6 mmol, 3 equiv) in methanol (80 mL) at 0 ꢁC was added 6 M
NaOH (0.74 mL, 4.4 mmol, 0.5 equiv) dropwise. The reaction mix-
ture was allowed to stir at 0 ꢁC for 2 h, poured onto a saturated
aqueous NH4Cl solution and extracted with EtOAc (ꢂ2). The com-
bined organic layers were checked for peroxides, dried (MgSO4),
filtered, and concentrated under reduced pressure to give 18
(1.53 g, 75% yield) as a light green powder: Rf 0.73 (EtOAc/hexanes,
1:1); mp 76e78 ꢁC; IR (neat) 3437, 3004, 2953, 1675, 1597, 1452,
solution of Na2CO3, and extracted with Et2O (ꢂ2). The combined
organic layers were washed with brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The crude residue was pu-
rified by chromatography on SiO2 (deactivated with 0.1% Et3N;
EtOAc/hexanes, 1:4) to give 21 (13.1 g, 85% yield) as a yellow oil: Rf
0.38 (EtOAc/hexanes, 1:3); IR (CDCl3) 2937, 1674, 1640, 1616, 1439,
1385, 1107, 1057, 965 cmꢀ1; 1H NMR (300 MHz, CDCl3)
J¼10.2 Hz), 6.23 (dd, 1H, J¼1.8, 10.5 Hz), 6.06 (s, 1H), 3.08 (s, 6H),
d 6.62 (d, 1H,
1.78 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 184.5, 155.6, 143.5, 131.9,
1334, 1293, 1062, 1010, 868, 773, 742 cmꢀ1
CDCl3)
;
1H NMR (300 MHz,
129.4, 95.0, 50.6, 16.3; HRMS (EIþ) m/z calcd for C9H12O3 168.0786,
d
7.86e7.83 (m, 1H), 7.69e7.62 (m, 2H), 7.42 (td, 1H, J¼2.7,
found 168.0785.
6.0 Hz), 5.71e5.58 (m, 1H), 4.94e4.87 (m, 2H), 3.79 (d, 1H,
J¼4.2 Hz), 3.75 (d, 1H, J¼4.2 Hz), 2.75 (s, 1H), 1.98e1.81 (m, 4H); 13C
4.3.20. 4-(But-3-en-1-yl)-4-hydroxy-3-methylcyclohexa-2,5-dien-
one (22). To a dry, 25 mL round-bottom flask equipped with an
addition funnel was added magnesium turnings (0.0305 g,
1.26 mmol, 1.2 equiv) and a crystal of iodine. Heat (Bunsen burner
flame) was applied to the stirred turnings until a purple gas coated
the interior of the flask. The sample was allowed to cool under
argon and suspended in dry ether (6 mL). To the stirred solution
was added via an addition funnel a solution of 4-bromo-1-butene
(0.13 mL, 1.26 mmol, 1.2 equiv) in dry ether (2 mL). The reaction
mixture was allowed to stir at reflux for 40 min, allowed to cool to
rt, and a solution of 21 (0.176 g, 1.05 mmol, 1 equiv) in dry ether
(3 mL) was added. The heterogeneous mixture was allowed to stir
at rt for 15 min, cooled to 0 ꢁC and quenched with a saturated
aqueous solution of NH4Cl and extracted with Et2O (ꢂ3). The
combined organic layers were washed with brine, dried (MgSO4),
filtered, and concentrated under reduced pressure. The crude am-
ber oil was suspended in acetone/water (1:1, 20 mL) and glacial
acetic acid (1.4 mL) was added. The reaction mixture was allowed to
stir at 0 ꢁC for 4 h and extracted with Et2O (ꢂ2). The combined
organic layers were washed with a saturated aqueous solution of
NaHCO3, brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude mixture was purified by chromatog-
raphy on SiO2 (EtOAc/hexanes, 1:5 to 1:3) to give 22 (0.0813 g, 44%)
as a yellow oil: Rf 0.35 (EtOAc/hexanes, 1:2); IR (CDCl3) 3420, 2920,
NMR (75 MHz, CDCl3) d 193.5, 143.3, 136.9, 134.4, 128.5, 128.3, 126.7,
126.6, 115.2, 72.4, 58.8, 55.5, 40.6, 27.4; HRMS (EIþ) m/z calcd for
C14H14O3Na 253.0841, found 253.0862.
4.3.17. (1a0R,2S,7a0S)-5-Hydroxy-4,5-dihydro-1a0H,3H-spiro[furan-
2,20-naphtho[2,3-b]oxiren]-70(7a0H)-one (19). A solution of 18
(1.10 g, 4.99 mmol,1 equiv) in CH2Cl2 (40 mL) was cooled to ꢀ78 ꢁC.
Ozone was passed through the stirred solution for 1.5 h, which was
then purged with O2 for 1 min.27 Dimethylsulfide (7.39 mL,
99.9 mmol, 20 equiv) was then added dropwise at ꢀ78 ꢁC. The
reaction mixture was allowed to stir at ꢀ78 ꢁC for 1 h and then
allowed to warm to rt and stirred at rt for 3 days. The solvent was
removed under reduced pressure and the crude mixture was puri-
fied by chromatography on SiO2 (EtOAc/hexanes, 1:2 to 1:1) to give
19 (1.18 g, 100% yield) as a 2:1 mixture of diastereomers as an off-
white solid: Rf 0.43 (EtOAc/hexanes, 1:1); IR (CDCl3) 3446, 2984,
1685, 1599, 1456, 1338, 1297, 1047, 1027, 986, 755, 732 cmꢀ1
NMR (300 MHz, CDCl3)
;
1H
d
7.84 (d,1H, J¼7.5 Hz), 7.63 (d,1H, J¼9.0 Hz),
7.44e7.38 (m, 2H), 6.02 (d, 1H, J¼3.5 Hz), 4.04 (d,1H, J¼4.2 Hz), 3.79
(br s, 1H), 3.74 (d, 1H, J¼4.5 Hz), 2.55e2.45 (m, 1H), 2.22e2.08 (m,
2H), 1.77 (ddd, 1H, J¼3.0, 8.1, 11.4 Hz); 13C NMR (75 Hz, CDCl3)
d
194.2, 142.8, 134.4, 128.3, 127.2, 126.5, 125.2, 100.3, 82.8, 58.4, 54.1,
35.8, 32.0; HRMS (EIþ) m/z calcd for C13H12O4 232.0736, found
232.0735. NMR data are for the major diastereomer only.
1666, 1633, 1446, 1431, 1394, 1375, 1243, 1049, 1001, 893 cmꢀ1
NMR (300 MHz, CDCl3)
;
1H
d
6.76 (dd, 1H, J¼3.0, 10.2 Hz), 6.57 (s, 1H),
4.3.18. (5R,8S,9R,11R)-5,8,11-Trihydroxy-9-(phenylthio)-6,7,8,9-tet-
rahydro-5,9-methanobenzo[8]annulen-10(5H)-one (20). To a stirred
solution of 19 (0.0500 g, 0.215 mmol, 1 equiv) in dry CH2Cl2 (5 mL)
were added Cs2CO3 (0.351 g, 1.08 mmol, 5 equiv) and thiophenol
(0.066 mL, 0.646 mmol, 3 equiv). The reaction was allowed to stir at
rt for 1 h. The crude mixture was diluted with CH2Cl2 (4 mL),
washed with brine, dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by chromatography on
SiO2 (EtOAc/hexanes, 10:1 to 1:1) to give 20 (59.0 mg, 80% yield) as
a white solid. A small portion was recrystallized (acetone/Et2O) to
give colorless crystals for X-ray analysis: Rf 0.32 (EtOAc/hexanes,
1:1); mp 180e182 ꢁC; IR (CDCl3) 3489, 1675, 1597, 1286, 1271, 1228,
6.07 (d, 1H, J¼9.9 Hz), 5.71 (dddd, 1H, J¼6.0, 6.0, 10.2, 16.5 Hz),
4.98e4.90 (m, 2H), 3.34 (s, 1H) 2.00e1.92 (m, 2H), 1.80 (s, 3H),
1.80e1.74 (m, 2H); 13C NMR (75 Hz, CDCl3)
d 186.6, 151.4, 147.0,
137.3, 134.5, 127.8, 115.0, 69.8, 38.8, 27.8, 15.5; HRMS (EIþ) m/z calcd
for C11H14O2 178.0994, found 178.0994
4.3.21. (1R,3S,5R,6S,7S)-6-(But-3-en-1-yl)-6-hydroxy-5-methyl-4,8-
dioxatricyclo[5.1.0.03,5]octan-2-one (23). To a stirred solution of 22
(1.00 g, 5.61 mmol, 1 equiv) and 30% aqueous hydrogen peroxide
(5.73 mL, 56.1 mmol, 10 equiv) in methanol 50 mL at rt was added
6 M NaOH (0.935 mL, 5.61 mmol, 1 equiv) dropwise. After 5 h, the
reaction mixture was quenched with a saturated aqueous NH4Cl
solution and extracted with EtOAc (ꢂ2). The combined organic
layers were checked for peroxides, dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude residue was pu-
rified by chromatography on SiO2 (EtOAc/hexanes, 1:2) to give 23
(0.800 g, 68% yield) as a pale yellow oil: Rf 0.66 (EtOAc/hexanes,
1:1); IR (CDCl3) 3483, 2976, 2933, 2859, 1705, 1640, 1437, 1159,
1055,1027, 760, 767 cmꢀ1; 1H NMR (300 MHz, acetone-d6)
d 7.92 (d,
1H, J¼7.8 Hz), 7.80 (d, 2H, J¼7.8 Hz), 7.75 (s, 1H), 7.71 (t, 1H,
J¼6.9 Hz), 7.54e7.42 (m, 4H), 4.62 (br s, 1H), 4.49 (s, 1H), 4.04 (s,
1H), 3.52 (dd, 1H, J¼5.7, 11.7 Hz), 3.42 (s, 1H), 1.89e1.83 (m, 1H),
1.72e1.57 (m, 2H), 0.99 (dq, 1H, J¼5.7, 12.3 Hz); 13C NMR (75 MHz,
acetone-d6)
d 193.9, 146.8, 139.2, 135.4, 133.5, 130.6, 129.9, 129.9,
128.2, 127.3, 125.8, 77.5, 75.2, 74.6, 69.8, 35.1, 28.6; HRMS (EIþ) m/z
1085, 1023, 919, 841 cmꢀ1; 1H NMR (700 MHz, CDCl3)
d 5.78 (dddd,
calcd for C19H18O4S 342.0926, found 342.0925.
1H, J¼6.3, 6.3, 10.5, 12.6 Hz), 5.06e5.01 (m, 2H), 3.51 (d, 1H,
J¼4.2 Hz), 3.49 (t, 1H, J¼4.2 Hz), 3.29 (d, 1H, J¼3.5 Hz), 2.94 (br s,
1H), 2.17e2.08 (m, 2H), 1.96e1.89 (m, 2H), 1.43 (s, 3H); 13C NMR
4.3.19. 4,4-Dimethoxy-3-methylcyclohexa-2,5-dienone
(21)14. To
a stirred solution of m-cresol (9.67 mL, 92.5 mmol, 1 equiv) in
MeOH (300 mL) at 0 ꢁC was added PIDA (44.7 g, 139 mmol,
1.5 equiv). The reaction mixture was allowed to warm to rt and
stirred for 1 h. At this point, an additional batch of PIDA (20.0 g,
62.1 mmol, 0.7 equiv) was added. The mixture was allowed to stir at
rt for an additional 1 h, and quenched with a saturated aqueous
(176 Hz, CDCl3) d 199.9, 136.6, 116.0, 70.3, 69.0, 63.8, 62.3, 57.2, 35.6,
27.1, 15.7; HRMS (ESIþ) m/z calcd for C11H14O4Na 233.0790, found
233.0797.
4.3.22. (10R,2S,30S,50R,70S)-5-Hydroxy-10-methyldihydro-3H-40,80-di-
oxaspiro[furan-2,20-tricyclo[5.1.0.03,5]octan]-60-one (24). A solution

J.T. Hammill et al. / Tetrahedron 66 (2010) 5852e5862
5861
of 23 (0.0700 g, 0.333 mmol, 1 equiv) in CH2Cl2 (3 mL) was cooled
to ꢀ78 ꢁC. Ozone was passed through the stirred solution for 1.5 h,
which was then purged with O2 for 1 min.27 Dimethylsulfide
(0.49 mL, 6.7 mmol, 20 equiv) was then added dropwise at ꢀ78 ꢁC.
The reaction mixture was stirred at ꢀ78 ꢁC for 1 h and then allowed
to warm to rt and stirred for 3 days. The solvent was removed under
reduced pressure and the crude mixture was purified by chroma-
tography on SiO2 (EtOAc/hexanes, 1:1) to give 24 (0.0710 g, 100%
yield) as a colorless oil and as a 1:1 mixture of lactols: Rf 0.22
(EtOAc/hexanes, 1:1); IR (CDCl3) 3496, 2976, 1705, 1442, 1457, 1204,
CDCl3) d 6.84e6.79 (m, 2H), 6.19e6.14 (m, 2H), 5.73 (dddd, 1H,
J¼6.6, 6.6, 10.2, 16.8 Hz), 5.02e4.94 (m, 2H), 2.43 (s, 1H), 2.04 (q, 2H,
J¼7.2 Hz), 1.78e1.73 (m, 2H), 1.40e1.29 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 185.7, 151.3, 137.7, 128.2, 115.3, 69.9, 39.1, 33.6, 22.8; HRMS
(ESIþ) m/z calcd for C11H14O2K 217.0631, found 217.0639.
4.3.25. 5-(Pent-4-enyl)-4-hydroxycyclohexa-2,5-dioxirane (27). To
a stirred solution of 26 (1.00 g, 5.61 mmol, 1 equiv) and 30% aque-
ous hydrogen peroxide (1.72 mL, 16.8 mmol, 3 equiv) in methanol
(50 mL) at 0 ꢁC was added 6 M NaOH (0.467 mL, 2.81 mmol,
0.5 equiv) dropwise. The reaction mixture was allowed to stir at
0 ꢁC for 2 h, poured onto a saturated aqueous NH4Cl solution and
extracted with EtOAc (ꢂ3). The combined organic layers were
1159, 1094, 1034, 982, 915, 868, 795 cmꢀ1
CDCl3)
5.82 (s, 1H), 4.44 (br s, 1H), 3.69 (t, 0.5H, J¼3.6 Hz), 3.55 (d,
0.5H, J¼3.3 Hz), 3.44e3.38 (m, 1.5H), 3.21 (d, 0.5H, J¼3.3 Hz),
2.37e1.95 (m, 4H), 1.37 (s, 3H); 13C NMR (75 Hz, CDCl3)
200.1
;
1H NMR (300 MHz,
d
ꢀ
d
washed with brine, poured onto activated 4 A molecular sieves, and
(200.1), 99.8 (99.8), 79.6, (79.6), 70.6, (69.0), 64.3, (62.7), 61.1,
(60.7), 55.9, (55.5), 33.0, (33.0), 30.5, (30.4), 15.5, (15.5); HRMS (EIþ)
m/z calcd for C10H12O5 212.0685, found 212.0680. 13C NMR data for
a diastereomer are listed in parenthesis.
allowed to stir at rt for 3 h. The mixture was filtered and concen-
trated under reduced pressure to give 27 (1.05 g, 89% yield) as
a yellow oil: Rf 0.43 (EtOAc/hexanes, 1:1); IR (neat) 3481, 2935,
1702, 1638, 1435, 1435, 1239, 1084, 995, 926, 887, 788 cmꢀ1 1H
;
NMR (300 MHz, CDCl3)
d
5.75 (dddd, 1H, J¼6.6, 6.6, 10.2, 13.5 Hz),
4.3.23. (1S,2R,4S,6S,7R,10S)-1,7,10-Trihydroxy-10-methyl-6-(phenyl-
thio)-3-oxatricyclo[4.3.1.02,4]decan-5-one (25). To a stirred solution
of 24 (0.0500 g, 0.236 mmol, 1 equiv) in dry CH2Cl2 (2 mL) were
added Cs2CO3 (0.384 g, 1.18 mmol, 5 equiv) and thiophenol
(0.072 mL, 0.707 mmol, 3 equiv). The reaction was allowed to stir at
rt for 2 h. The crude reaction mixture was diluted with EtOAc, and
washed with brine. The aqueous layer was extracted with EtOAc
(ꢂ2), the organic layers were combined, washed with brine, dried
(MgSO4), filtered, and concentrated under reduced pressure. The
crude mixture was purified by chromatography on SiO2 (EtOAc/
hexanes, 1:3 to 1:1) to give 25 (40.0 mg, 53% yield) as a colorless
film: Rf 0.29 (EtOAc/hexanes, 1:1); IR (CDCl3) 3476, 2933, 2877,
5.05e4.99 (m, 2H), 3.50 (s, 4H), 3.09 (s, 1H), 2.11 (q, 2H, J¼6.9 Hz),
1.84e1.78 (m, 2H), 1.53e1.42 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
199.0, 137.2, 115.8, 69.0, 64.0, 57.0, 35.8, 33.7, 21.9; HRMS (ESIþ) m/
z calcd for C11H14O4Na 233.0790, found 233.0785.
4.3.26. (10R,2S,30S,50R,70S)-6-Hydroxytetrahydro-40,80-dioxaspiro[py-
ran-2,20-tricyclo[5.1.0.03,5]octan]-60-one (28). A solution of 27
(0.92 g, 4.38 mmol, 1 equiv) in CH2Cl2 (22 mL) was cooled to
ꢀ78 ꢁC. Ozone was passed through the stirred solution for 2 h,
which was then purged with O2 for 1 min.27 Dimethylsulfide
(6.47 mL, 87.5 mmol, 20 equiv) was then added dropwise at ꢀ78 ꢁC.
The reaction mixture was allowed to stir at ꢀ78 ꢁC for 1 h and then
allowed to warm to rt and stirred at rt for 3 days. The solvent was
removed under reduced pressure. The crude product was purified
by chromatography on SiO2 (EtOAc/hexanes, 1:2 to 1:1) to give 28
(0.803 g, 86% yield) as a 10:1 mixture of the open and closed forms
of the lactol, as an off-white solid: Rf 0.25 (EtOAc/hexanes, 1:1); mp
112e115 ꢁC; IR (CDCl3) 3424, 2961, 2913, 1698, 1442, 1251, 1101,
1720, 1437, 1426, 1360, 1113, 1081, 1032, 752, 729 cmꢀ1
;
1H NMR
(300 MHz, CDCl3)
d
7.65 (t, 1H, J¼1.8 Hz), 7.63 (d, 1H, J¼1.5 Hz),
7.48e7.35 (m, 3H), 3.48e3.47 (m, 1H), 3.42 (app t, 2H, J¼2.4 Hz),
3.33 (dd, 1H, J¼5.4, 11.7 Hz), 2.92 (dd, 1H, J¼2.4 Hz, 12.3 Hz),
2.18e2.02 (m, 2H), 1.54 (s, 3H), 1.51e1.25 (m, 2H); 13C NMR
(75 MHz, CDCl3)
d 199.0, 138.2, 130.2, 129.2, 126.4, 73.9, 72.1, 70.6,
70.6, 67.2, 62.3, 29.6, 27.6, 14.8; HRMS (EIþ) m/z calcd for C16H18O5S
1010, 988, 956, 902, 868, 788 cmꢀ1
5.60 (s, 1H), 4.32 (br s, 1H), 4.17 (t, 1H, J¼4.2 Hz), 3.50 (t, 1H,
J¼3.6 Hz), 3.42e3.40 (m, 2H), 2.14e2.06 (m, 1H), 1.85e1.81 (m, 2H),
;
1H NMR (600 MHz, CDCl3)
322.0875, found 322.0880.
d
4.3.24. 4-Hydroxy-4-(pent-4-enyl)cyclohexa-2,5-dienone (26). To
a dry, 25 mL, two-necked, round-bottom flask equipped with an
addition funnel was added magnesium turnings (0.341 g,
14.0 mmol, 1.2 equiv) and a crystal of iodine. Heat (Bunsen burner
flame) was applied to the stirred turnings until a purple gas coated
the interior of the flask. The sample was allowed to cool under
argon and suspended in THF (4 mL). To the stirred solution was
added via an addition funnel a solution of 5-bromo-1-pentene
(1.7 mL, 14 mmol, 1.2 equiv) in THF (8 mL). The reaction mixture
was allowed to stir at ca. 40 ꢁC for 1 h, allowed to cool to rt, and
added via dropwise addition to a solution of 4 (1.80 g, 11.7 mmol,
1 equiv) in THF (20 mL) at ꢀ78 ꢁC. The reaction mixture was
allowed to stir at ꢀ78 ꢁC for 1 h and quenched with a saturated
aqueous solution of NH4Cl, warmed to rt, and extracted with EtOAc
(ꢂ3). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The crude
residue was suspended in acetone/water (1:1, 100 mL), glacial
acetic acid (10 mL) was added, and the reaction mixture was
allowed to stir at rt for 2 h. The reaction mixture was concentrated
under reduced pressure. The remaining aqueous layer was extrac-
ted with EtOAc (ꢂ3) and the combined organic layers were washed
with brine, dried (MgSO4), and concentrated under reduced pres-
sure. The crude residue was purified by chromatography on SiO2
(EtOAc/hexanes, 1:5 to 1:3) to give 26 (1.14 g, 55% yield) as a yellow
oil: Rf 0.2 (EtOAc/hexanes, 1:3); IR (neat) 3403, 2935, 2860, 1664,
1.79e1.71 (m, 3H); 13C NMR (151 Hz, acetone-d6)
d 199.1, 91.9, 69.7,
64.0, 62.9, 56.2, 55.5, 29.5, 29.3, 13.8; HRMS (EIþ) m/z calcd for
C10H12O5 212.0685, found 212.0691. Only the major lactol di-
astereomer is listed.
Acknowledgements
The authors thank Dr. Steven Geib (University of Pittsburgh) for
the X-ray structure analyses of 14 and 20, and NIH/NIGMS
(P41GM081275; P50GM067082) for financial support.
Supplementary data
1H NMR and 13C NMR spectra of all new compounds. Supple-
mentary data associated with this article can be found, in the online
version, at doi:10.1016/j.tet.2010.04.110. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
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27. Inadvertently, purging the reaction mixture with N2 for 15e20 min was omit-
ted from this experimental protocol. However, it is strongly recommended that
the solution is purged with N2 gas in order to remove residual ozone and O2
before the dimethylsulfide is added.