Synthesis of a functionalized oxabicyclo[2.2.1]-heptene-based chemical library

Article abstract of DOI:10.2174/138620712798280835

The 7-oxabicyclo[2.2.1]heptene ring system is a common structural motif in many pharmacologically interesting molecules. We recognized the potential to employ this highly oxygenated and conformationally-restricted scaffold in diversity-oriented synthesis to generate a library of non-chiral but topologically complex compounds. Herein, we report the synthesis and biological evaluation of two 96-member tricyclic libraries containing the oxabicyclo[2.2.1]heptene framework using acetal formation as the key step.

Full text of DOI:10.2174/138620712798280835

Combinatorial Chemistry & High Throughput Screening, 2012, 15, 81-89
81
Synthesis of a Functionalized Oxabicyclo[2.2.1]-Heptene-Based Chemical
Library
Sarah B. Luesse1, Gregg Wells1, Jeanne Miller2, Erin Bolstad1, Stephen C. Bergmeier*,2,
Mark C. McMills1, Nigel D. Priestley1 and Dennis L. Wright1
1Promiliad Biopharma, 340 W. State Street Athens, Ohio 45701, USA and Promiliad Biopharma, P.O. Box 10, Alberton,
Montana 59820, USA
2Department of Chemistry & Biochemistry, Ohio University, Athens, Ohio 45701, USA
Abstract: The 7-oxabicyclo[2.2.1]heptene ring system is a common structural motif in many pharmacologically
interesting molecules. We recognized the potential to employ this highly oxygenated and conformationally-restricted
scaffold in diversity-oriented synthesis to generate a library of non-chiral but topologically complex compounds. Herein,
we report the synthesis and biological evaluation of two 96-member tricyclic libraries containing the
oxabicyclo[2.2.1]heptene framework using acetal formation as the key step.
Keywords: Acetal, antibacterial, oxabicyclo[2.2.1]heptene.
INTRODUCTION
Cantharidin and heterocyclic substituted analogs, which
involve the 7-oxabicyclo[2.2.1]heptene based anhydride
system, have been evaluated as anti-cancer agents (3) [7-11].
and as inhibitors for serine/threonine protein phosphatases
(4) [12]. Conformationally restricted heterotricyclic systems
have also shown promise as potent orthopox egress
inhibitors [13].
Natural products have long been of great significance in
drug discovery. For example, screening and isolation studies
have lead to the identification of many antibiotics and
anticancer compounds that have either achieved clinical
significance or have served as leads that motivate further
drug development. Natural product development, however,
can be complicated as natural product leads are often
produced in limited quantities or the structures are not
readily modified to generate analogs. The goal of efficiently
incorporating natural product structural motifs into
combinatorial libraries is, therefore, a compelling one. Our
work in this area started with the natural product nonactin,
specifically with the adaptation of the fermentation-derived
nonactin precursors (+)- and (–)-nonactic acid. The natural
scaffolds allowed us to generate cis-2,5-substituted
tetrahydrofuran-based libraries that were stereochemically
complex [1]. As an extension of this work, we became
interested in generating a diverse library of furan-related,
structurally rigid, oxabicyclo[2.2.1]heptene analogs.
OH
O
O
O
R
Ar
Ar
SO2Ph
2
CO2H
1
O
O
O
O
N
BzO
O
O
(
)
9
O
OBz
3
4
Bicyclo[2.2.1]heptane ring systems are common motifs
in many natural products and pharmacologically interesting
molecules (Fig. 1) [2]. Analogs of endo-peroxide prosta-
glandin intermediates PGG and PGH, containing the
oxabicyclo[2.2.1]heptane scaffold, have been found to
possess interesting biological activities [3]. Also, 7-
oxabicyclo[2.2.1]heptane derivatives (1) have been reported
to be potent thromboxane A2 antagonists [4, 5]. A series of
bridged oxabicycles (2) were targeted and synthesized due to
recognition that the three-dimensional topology of a 7-
oxabicyclo[2.2.1]hept-5-ene system was deemed an
appropriate hydrophobic core element for estrogen receptor
ligands [6].
Fig. (1). Oxabicyclo[2.2.1]heptane analogs.
Due to the numerous reports of known biologically active
molecules which incorporate this scaffold, we hypothesized
that a library of related tricyclic compounds with multiple
points of structural and functional diversification would
provide an interesting class of new molecules with potential
for significant pharmacological activity. In this report, we
describe our straightforward synthesis of a library of tricyclic
oxabicyclo[2.2.1]heptene-derived acetals with two points of
structural diversification.
Our approach to the preparation of the library of tricyclic
heterocycles involved the synthesis of stable acetals (5) to
provide a structurally rigid framework which utilized the
oxabicyclo[2.2.1]heptene scaffold (Scheme 1). We envis-
oned a complexity generating reaction, via symmetrical
substitution of the ethylene moiety, that would introduce an
*Address correspondence to this author at the Department of Chemistry &
Biochemistry, Ohio University, Athens, Ohio 45701, USA;
Tel: +1-740-597-9649; Fax: +1-740-593-0148;
E-mail: bergmeis@ohio.edu
1386-2073/12 $58.00+.00
© 2012 Bentham Science Publishers

82 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1
Luesse et al.
additional element of topological diversity to provide acetal
6.
21.4, 11.6; HRMS (electrospray with Na) m/z [M+Na]+
C14H22NaO3 predicted 261.1467, found 261.1470.
O
O
Acetal 5{87}
R'
R'
1H NMR (CDCl3, 300 MHz) ꢀ 7.35-7.26 (m, 2H), 7.24-
7.17 (m, 3H), 6.43 (s, 2H), 4.56 (s, 2H), 4.46 (t, J = 5.3 Hz,
1H), 4.28 (dd, J = 12.2, 4.4 Hz, 2H), 3.68 (dd, J = 12.2, 12.2
Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.21 (dddd, J = 12.3, 10.1,
7.7, 5.0 Hz, 2H), 2.00-1.91 (m, 2H); 13C (CDCl3, 75 MHz)
141.7, 135.8, 128.5, 128.4, 125.3, 108.7, 80.6, 72.5, 43.4,
36.8, 30.9.
O
O
O
O
R
R
6
5
Scheme 1.
MATERIALS AND METHODS
General Methods
General Procedure for the Synthesis of Epoxide 10
THF and CH2Cl2 were dried using a column purification
system. IRs were obtained neat. Rf's were obtained by thin
layer chromatography on aluminum backed, silica coated,
TLC plates containing a fluorescent (254 nm) indicator.
Spots were visualized via UV or staining with
ninhydrin/ethanol mixture followed by heating. Compounds
were purified by either an automated flash purification
system utilizing silica gel or by flash chromatography using
32-63D 60Å silica gel according to the method of Still [14].
Silica gel plug filtrations and column chromatography were
performed using 32-63D 60Å silica gel. Aldehydes, acid
chlorides, and isocyanates were purchased from Aldrich and
used without additional purification. Diol 8[4] and 3-
furanmethanol [15] were synthesized according to standard
procedures. NMRs were obtained at 300 (1H) or 75 MHz
(13C). Chemical shifts are reported in “ppm” and coupling
constants are reported in “Hz”.
Solid mCPBA (600 mol%) was added in several portions
to acetal 5 (0.20 M in CH2Cl2) at 0°C. The mixture was
allowed to stir at 24°C for 20 h. After dilution, aq. sodium
disulfite was added and the mixture stirred for 30 min. The
organic phase was collected and washed with sat. aq.
NaHCO3 (3x), dried (MgSO4) and concentrated to provide
the pure epoxide. Further purification via flash
chromatography (SiO2, 20% ethyl acetate in hexanes) was
performed, when needed.
Epoxide 10{1}
1
18.6 mg, 99%, Rf 0.33 (50% EtOAc in hexanes); H
NMR (CDCl3, 300 MHz) ꢀ 7.45-7.27 (m, 5H), 5.36 (s, 1H),
4.32-4.15 (m, 4H), 3.94-3.83 (m, 2H), 3.34 (s, 2H), 2.36-
2.23 (m, 2H); 13C (CDCl3, 75 MHz) 138.1, 127.9, 127.5,
125.2, 107.5, 75.6, 70.3, 49.2, 46.4.
Epoxide 10{79}
General Procedure for the Synthesis of Acetal 5
1
87%, H NMR (CDCl3, 300 MHz) ꢀ 4.18 (d, J = 4.0 Hz,
Catalytic p-toluenesulfonic acid (~1-3 mg) was added to
diol 8 (150 mol%, 0.20 M in CH2Cl2). Aldehyde 9 (100
mol%) was added via syringe, or as a solid, and the resulting
reaction mixture was stirred at room temperature for 30
hours. The reaction mixture was treated with saturated
aqueous NaHCO3, and the organic extracts collected through
a Biotage phase separator. Purification via silica gel
chromatography in a disposable glass pipette (10-40% ethyl
acetate in hexanes) provided the desired product in >80%
purity.
1H), 3.98 (s, 2H), 3.93 (dd, J = 12.6, 4.5 Hz, 2H), 3.53 (dd, J
= 12.3, 12.3 Hz, 2H), 3.22 (s, 2H), 2.25 (dddd, J = 12.8,
10.6, 8.2, 5.7 Hz, 2H), 1.42-1.11 (m, 5H), 0.74 (t, J = 7.0 Hz,
6H); 13C (CDCl3, 75 MHz) 111.5, 76.4, 70.9, 50.0, 47.1,
45.9, 21.4, 11.5.
Epoxide 10{87}
1
92%, H NMR (CDCl3, 300 MHz) ꢀ 7.31-7.11 (m, 5H),
4.33 (t, J = 5.5 Hz, 1H), 4.03 (s, 2H), 4.03-3.97 (m, 2H),
3.60 (dd, J = 12.4, 12.4 Hz, 2H), 3.26 (s, 2H), 2.68 (t, J = 7.9
Hz, 2H), 2.39-2.27 (m, 2H), 1.94-1.84 (m, 2H); 13C (CDCl3,
75 MHz) 141.6, 128.5, 128.4, 126.0, 108.6, 76.4, 70.9, 50.1,
47.2, 36.7, 30.9.
Representative Acetal Data
Acetal 5{1}
1
Rf 0.27 (30% EtOAc in hexanes); H NMR (CDCl3, 300
Anhydride 11
MHz) ꢀ 7.51-7.44 (m, 2H), 7.35-7.29 (m, 3H), 6.42 (s, 2H),
5.47 (s, 1H), 4.61 (s, 2H), 4.40 (dd, J = 12.2, 4.4 Hz, 2H),
3.92 (dd, J = 12.5, 12.5 Hz, 2H), 2.29 (dddd, J = 12.2, 10.1,
7.9, 4.8 Hz, 2H); 13C (CDCl3, 75 MHz) 139.6, 135.8, 128.6,
128.2, 125.6, 108.4, 80.6, 72.7, 43.5.
A solution of (O-tBuMe2Si)-3-furanmethanol (1.46 g, 6.9
mmol) and maleic anhydride (1.4 g, 14.1 mmol) were
stirrred in Et2O (8.0 mL) at rt for 48 h. The reaction was
concentrated and chromatographed (25% EtOAc in hexanes)
to provide 1.87 g (61%) of anhydride 11. Rf 0.47 (25%
1
Acetal 5{79}
EtOAc in hexanes): H NMR (CDCl3, 300 MHz) ꢀ 6.25 (dt,
1H NMR (CDCl3, 300 MHz) ꢀ 6.38 (s, 2H), 4.52 (s, 2H),
4.36 (d, J = 3.9 Hz, 1H), 4.22 (dd, J = 12.5, 4.6 Hz, 2H),
3.63 (dd, J = 12.5, 12.5 Hz, 2H), 2.14 (dddd, J = 12.3, 10.1,
7.8, 5.1 Hz, 2H), 1.53-1.23 (m, 5H), 0.86 (t, J = 7.1 Hz, 6H);
13C (CDCl3, 75 MHz) 135.9, 111.3, 80.6, 72.5, 45.9, 43.4,
J = 1.8, 1.8 Hz, 1H), 5.42 (m, 1H), 5.33 (s, 1H), 4.37 (dddd,
J = 14.7, 14.7, 14.7, 1.8 Hz, 2H), 3.24 (s, 2H), 0.91 (s, 9H),
0.094 (s, 3H), 0.086 (s, 3H); 13C-NMR (75 MHz, CDCl3) ꢀ
170.0, 169.9, 151.7, 129.5, 83.1, 83.0, 58.7, 50.1, 48.8, 25.8,
18.3, -5.4; HRMS calcd for C15H22O5Si•Na 333.1129, found
333.1128.

Oxabicyclo[2.2.1]-Heptene-Based Chemical Library
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1 83
0.05 (s, 6H); 13C (CDCl3, 75 MHz) 151.3, 150.5, 142.3,
128.5, 110.2, 107.0, 102.9, 81.4, 81.1, 72.9, 72.8, 59.2, 45.5,
43.7, 25.9, 18.3, -5.3, -5.4.
Diol 12
To a 0 °C solution of anhydride 11 (3.22 g, 10.4 mmol)
in THF (20 mL) was added LiAlH4 (2.30 g, 60.5 mmol)
portionwise. The reaction was warmed to rt and stirred for an
additional 6 h. The reaction was quenched by the addition of
saturated aq. Na2SO4 solution. The resulting precipitate was
filtered and washed with EtOAc. The solution was
concentrated and chromatographed (30% EtOAc in hexanes)
to provide 1.86 g (60%) of diol 12 as a white solid, mp 105.1
TBS-Substituted Acetal 13{89}
1
Rf 0.20 (10% EtOAc in hexanes); H NMR (CDCl3, 300
MHz) ꢀ 7.38-7.13 (m, 5H), 6.06 (m, 1H), 4.49-4.27 (m, 4H),
4.26-4.07 (m, 3H), 3.51 (ddd, J = 12.2, 12.2, 2.7 Hz, 2H),
2.91 (dq, J =7.5, 7.0 Hz, 1H), 2.30-2.14 (m, 2H), 1.86 (dd, J
= 7.5, 7.5 Hz, 2H), 1.25 (d, J = 7.5 Hz, 3H), 0.89 (s, 9H),
0.05 (s, 6H).
1
– 106.6°C: Rf 0.30 (100% EtOAc): H NMR (CDCl3, 300
MHz) ꢀ 6.07 (dt, J = 1.8, 1.8 Hz, 1H), 4.64 (s, 1H), 4.55 (s,
1H), 4.34 (dddd, J = 14.7, 14.7, 14.7, 1.8 Hz, 2H), 3.90-3.73
(m, 4H), 3.64 (br s, 2H), 2.10-1.96 (m, 2H), 0.89 (s, 9H),
0.06 (s, 6H); 13C-NMR (75 MHz, CDCl3) ꢀ 150.5, 128.6,
82.2, 81.8, 62.89, 62.87, 59.2, 44.5, 42.8, 25.9, 18.3, -5.3, -
5.4; HRMS calcd for C15H28O4Si•Na 323.323.1649, found
323.1646.
Acetal 14{1}
1
Rf 0.46 (100% EtOAc); H NMR (CDCl3, 300 MHz) ꢀ
7.50-7.44 (m, 2H), 7.40-7.29 (m, 3H), 6.21 (dt, J = 1.8, 1.8
Hz, 1H), 5.48 (s, 1H), 4.60 (s, 1H), 4.58 (s, 1H), 4.46-4.33
(m, 4H), 3.93 (ddd, J = 12.2, 12.2, 2.5 Hz, 2H), 2.45-2.30
(m, 2H), 1.56 (br s, 1H); 13C (CDCl3, 75 MHz) 150.3, 139.0,
129.6, 128.6, 128.3, 125.9, 108.4, 81.4, 81.0, 72.61, 72.56,
58.8, 45.4, 43.6.
One Step Procedure for the Synthesis of Acetal 14
Aldehydes 9{1}, 9{61}, 9{76}, or 9{87} (150 mol%)
were added to an ice cooled solution of diol 12 (100 mol%),
p-toluenesulfonic acid (10 mol%), and 4Å molecular sieves
(50 wt%) in CH2Cl2 (0.15 M). The reaction was warmed to rt
and stirred for 18 h. The reaction was washed with saturated
aq. NaHCO3 solution, dried over MgSO4, filtered,
concentrated and chromatographed to provide the expected
product.
Acetal 14{20}
1
Rf 0.50 (80% EtOAc in hexanes); H NMR (CDCl3, 300
MHz) ꢀ 7.62-7.51 (m, 6H), 7.47-7.30 (m, 3H), 6.21 (dt, J =
1.8, 1.8 Hz, 1H), 5.54 (s, 1H), 4.61 (s, 1H), 4.59 (s, 1H),
4.48-4.32 (m, 4H), 3.96 (ddd, J = 12.2, 12.2, 2.6 Hz, 2H),
2.46-2.30 (m, 2H), 1.69 (br s, 1H); 13C (CDCl3, 75 MHz)
148.7, 139.9 (2C), 128.0 (2C), 127.1, 125.7, 125.5, 125.4,
124.7, 106.6, 79.8, 79.3, 70.9, 57.1 (2C), 43.8, 42.0.
Two Step Procedure for the Synthesis of Acetal 14
Acetal 14{50}
Aldehydes 9{20}, 9{50}, or 9{89} (150 mol%) were
added to an ice cooled solution of diol 12 (100 mol%), p-
toluenesulfonic acid (10 mol%), and 4Å molecular sieves
(50 wt%) in CH2Cl2 (0.15 M). The reaction was warmed to rt
and stirred for 18 h. The reaction was washed with saturated
aq. NaHCO3 solution, dried over MgSO4, filtered,
concentrated and chromatographed to provide the expected
product. A solution of nBu4NF (1.0 M in THF, 150 mol%)
was added to an ice-cooled solution of TBS-protected acetal
(100 mol%) in THF (1 M). The reaction was stirred for 2 h at
0 °C, diluted with EtOAc, washed with H2O, brine, dried
over MgSO4, concentrated and chromatographed to provide
alcohol 14.
1
Rf 0.43 (80% EtOAc in hexanes); H NMR (CDCl3, 300
MHz) ꢀ 7.61-7.49 (m, 1H), 7.46-7.29 (m, 1H), 6.40-6.33 (m,
1H), 6.19-6.15 (m, 1H), 5.52 (s, 1H), 4.60-4.51 (m, 2H),
4.45-4.27 (m, 4H), 3.98-3.89 (m, 2H), 2.43-2.27 (m, 2H),
1.97 (br s, 1H); 13C (CDCl3, 75 MHz) 156.6, 148.7, 139.9,
136.5, 128.0, 127.1, 125.6, 125.5, 124.7, 106.5, 79.8, 79.3,
71.0, 57.2 (2C), 43.8, 42.0.
Acetal 14{61}
1H NMR (CDCl3, 300 MHz) ꢀ 7.66 (s, 1H), 7.53 (d, J =
7.4 Hz, 1H), 7.32-7.19 (m, 2H), 6.62 (d, J = 3.3 Hz, 1H),
6.49 (d, J = 3.3 Hz, 1H), 6.22 (m, 1H), 5.58 (s, 1H), 4.60 (d,
J = 7.1 Hz, 2H), 4.48-4.33 (m, 4H), 3.91 (ddd, J = 12.3, 12.3,
2.3 Hz, 2H), 2.46-2.31 (m, 2H), 1.26 (br s, 1H).
TBS-Substituted Acetal 13{20}
1
Rf 0.43 (20% EtOAc in hexanes); H NMR (CDCl3, 300
Acetal 14{76}
MHz) ꢀ 7.60-7.51 (m, 6H), 7.46-7.29 (m, 3H), 6.11 (dt, J =
1.8, 1.8 Hz, 1H), 5.53 (s, 1H), 4.57 (s, 1H), 4.51 (s, 1H),
4.45-4.33 (m, 4H), 3.99-3.88 (m, 2H), 2.45-2.31 (m, 2H),
0.91 (s, 9H), 0.09 (s, 6H); 13C (CDCl3, 75 MHz) 150.5,
141.0, 138.2, 128.8, 128.6, 127.4, 127.2, 127.1, 126.4, 108.2,
81.5, 81.2, 72.8, 72.7, 59.3, 53.5, 45.6, 43.8, 25.9, 18.4, -
5.25, -5.32.
1H NMR (CDCl3, 300 MHz) ꢀ 6.17 (m, 1H), 4.52 (d, J =
7.6 Hz, 2H), 4.33 (dd, J = 5.9, 5.9 Hz, 2H), 4.29-4.16 (m,
3H), 3.66 (ddd, J = 12.3, 12.3, 2.7 Hz, 2H), 2.31-2.15 (m,
2H), 1.83-1.71 (m, 1H), 1.62 (br s, 1H), 0.91 (d, J = 6.9 Hz,
6H).
Acetal 14{87}
TBS-Substituted Acetal 13{50}
1H NMR (CDCl3,300 MHz) ꢀ 7.36-7.24 (m, 2H), 7.23
(m, 3H), 6.15 (m, 1H), 4.52 (d, J = 7.0 Hz, 1H), 4.44 (dd, J =
5.5, 5.5 Hz, 2H), 4.30 (m, 2H), 4.28-4.18 (m, 2H), 3.65 (ddd,
J = 12.2, 12.2, 2.5 Hz, 2H), 2.72 (dd, J = 7.5, 7.5 Hz, 2H),
2.35-2.17 (m, 3H), 2.01-1.88 (m, 2H).
1
Rf 0.31 (20% EtOAc in hexanes); H NMR (CDCl3, 300
MHz) ꢀ 7.39-7.33 (m, 1H), 6.41-6.30 (m, 2H), 6.09-6.07 (m,
1H), 5.22 (m, 2H), 4.53 (s, 1H), 4.48 (s, 1H), 4.41-4.27 (m,
4H), 3.90-3.79 (m, 2H), 2.41-2.27 (m, 2H), 0.89 (s, 9H),

84 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1
Luesse et al.
reduction [16]. The MIC value was taken as the lowest
concentration of test compound that inhibits growth such that
less than 1% reduction of the blue resazurin (ꢁmax 570 nm)
component of the Alamar blue to the pink resorufin (ꢁmax
600 nm) was observed.
Acetal 14{89}
1
Rf 0.19 (50% EtOAc in hexanes); H NMR (CDCl3, 300
MHz) ꢀ 7.36-7.27 (m, 2H), 7.24-7.16 (m, 3H), 6.14 (m, 1H),
4.47 (dd, J = 7.5, 7.0 Hz, 2H), 4.30-4.27 (m, 2H), 4.27-4.09
(m, 3H), 3.53 (ddd, J = 12.2, 12.2, 2.5 Hz, 2H), 2.93 (dq, J =
7.5, 7.0 Hz, 1H), 2.36 (br s, 1H), 2.29-2.14 (m, 2H), 1.87
(dd, J = 7.5, 7.5 Hz, 2H), 1.26 (d, J = 7.5 Hz, 3H).
RESULTS AND DISCUSSION
The straightforward synthesis of benzaldehyde-derived
acetal 5{1} is shown in Scheme 2. Reduction of
commercially available exo-3,6-epoxy-1,2,3,6-tetrahydroph-
thalic anhydride 7 with lithium aluminum hydride in THF
provided diol 8 (82%) [4]. 1,4-Diol 8 in CH2Cl2 was treated
with benzaldehyde (9{1}) in the presence of catalytic p-
toluenesulfonic acid to afford acetal 5{1} in 70% yield [18].
General Procedure for the Synthesis of Acylated Acetal
16
To a solution of hydroxy acetal 14 (100 mol% 0.20 M in
CH2Cl2) was added catalytic dimethylaminopyridine (~10
mol%), 4 Å molecular sieves, and Et3N (300 mol%) The
solution was cooled to 0 °C and acid chloride or isocyanate
15 (130 mol%) was added and the resulting reaction mixture
stirred at room temperature for 6-12 hours. The reaction
mixture was filtered through a Celite plug, and then treated
with H2O, saturated aqueous NaHCO3, and the organic
extracts collected through a Biotage phase separator.
Compounds were purified via silica gel plug in disposable
glass pipettes. A forerun of hexanes removed nonpolar
impurities; desired products were eluted with 50% EtOAc in
hexanes.
O
O
H
LiAlH4
82%
OH
OH
O
O
H
O
8
7
O
PhCHO 9{1}
pTSA, 70%
O
O
General Method for Antifungal Assays
Ph
5{1}
Candida glabrata was stored as a suspension in 50%
glycerol at -78°C. For susceptibility testing, a streak of stock
culture was made on SDA agar and grown at 30°C for 48 hr.
One pure colony of the test organism was recovered from the
plate, suspended in appropriate media, and grown in a 5 mL
shake flask culture. A sample of the shake flask culture was
diluted to 1.3ꢀ105 cells/mL in media and added to 96-well
test plates (100 μL per well) containing test compounds
dispensed in DMSO (1 μL). Amphotericin and ketoconazole
were used as controls. After an incubation period determined
from the strain-specific doubling time, Alamar blue (10 μL)
was added and allowed to incubate; each well was scored for
dye reduction [16]. The MIC value was taken as the lowest
concentration of test compound that inhibits growth such that
less than 1% reduction of the blue resazurin (ꢁmax 570 nm)
component of the Alamar blue to the pink resorufin (ꢁmax
600 nm) was observed.
Scheme 2. Synthesis of oxabicyclo[2.2.1]heptene acetal 5{1}.
We recognized the inherent problems with the stability of
acetals for biological applications. Therefore, tricycle 5{1}
was evaluated under a range of solution conditions to
evaluate the durability of the acetal. Under dilute aqueous
acid workup, acetal 5{1} is stable. However, prolonged
exposure (5 hours) to 1 M HCl in acetonitrile/water (1:1)
leads to reversion to diol 8. Ultimately, the acetal was found
to be quite stable and was resilient upon exposure to a wide
range of reaction conditions.
To produce
a
96-member oxatricyclic library,
commercially available aldehydes were selected to provide a
range of sterically and electronically diverse acetal
substitutions. Reaction of diol 8 with this series of aldehydes
9{1-96} provided a library of acid-stable acetals 5{1-96}.
Table 1 presents the results of this library generation for all
aldehydes from which pure acetal products were obtained.
Compounds were purified by silica gel chromatography and
all products were analyzed by 1H NMR analysis. In all cases,
a single product was observed with high purities (80-95%).
General Method for Antibacterial Assays
Bacterial strains were stored as a suspension in 50%
glycerol at -78°C. For susceptibility testing, a streak of stock
culture was made on appropriate agar [17] and grown at
either 30°C or 37°C for 48 hr. One pure colony of the test
organism was recovered from the plate, suspended in
appropriate media, and grown in a 5 mL shake flask culture.
A sample of the shake flask culture was diluted to 1.3ꢀ105
cells/mL in media and added to 96-well test plates (100 μL
per well) containing test compounds dispensed in DMSO (1
μL). Kanamycin, gentamycin, neomycin, carbenicillin,
vancomycin, hygromycin, chloramphenicol, streptomycin,
apramycin, spectinomycin and trimethoprom were used as
controls. After an incubation period determined from the
strain-specific doubling time, Alamar blue (10 μL) was
added and allowed to incubate; each well was scored for dye
Diol 8 is very insoluble in common organic solvents, and
therefore an excess of diol was used in most reactions to
achieve acceptable acetal formation. Several trends were
observed in regard to the ease of acetal formation with a
variety of substituted aldehydes. Alkyl aldehydes worked
well, as did most substituted benzaldehydes. A wide range of
substituted 2-furaldehydes also generated the desired acetals.
While we had success with furyl-based acetals, these
compounds required tedious purification via silica gel
chromatography. The presence of a double bond led to low
yields in the case of cinnamaldehyde-based acetal
(5{96}), or no product formation in attempts with

Oxabicyclo[2.2.1]-Heptene-Based Chemical Library
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1 85
Table 1. Oxabicyclo[2.2.1]Heptane-Derived Acetal Library
Aldehyde, ID
C6H5CHO, 9{1}
Product
Yield (%) b,c
Aldehyde, ID
3-Furaldehyde, 9{49}
Product
Yield (%)b,c
5{1}
5{2}
34
11
61
80
26
83
99
58
47
47
39
64
87
11
9
5{49}
5{50}
5{51}
5{52}
5{53}
5{54}
5{55}
5{56}
5{57}
5{58}
5{59}
5{60}
5{61}
5{62}
5{63}
5{64}
5{65}
5{66}
5{67}
5{68}
5{69}
5{70}
5{71}
5{72}
5{73}
5{74}
5{75}
5{76}
5{77}
5{78}
5{79}
5{80}
5{81}
5{82}
5{83}
5{84}
5{85}
5{86}
5{87}
5{88}
5{89}
5{90}
5{91}
5{92}
5{93}
5{94}
5{95}
5{96}
45
43
99
10
58
82
22
16
81
38
18
41
21
23
20
99
32
45
25
12
89
55
87
82
99
96
75
25
78
70
41
58
72
98
86
53
22
79
84
77
99
58
57
89
71
62
11
21
2-NO2C6H4CHO, 9{2}
2-Furaldehyde, 9{50}
5-NO2C5H3O2,a 9{51}
5-(CH3CH2)C5H3O2,a 9{52}
5-(CH3O2CCH2)C5H3O2,a 9{53}
2-Benzofurancarboxaldehyde, 9{54}
5-(C6H5)C5H3O2,a 9{55}
5-(2-NO2C6H4)C5H3O2,a 9{56}
5-(4-NO2C6H4)C5H3O2,a 9{57}
5-(2-CF3C6H4)C5H3O2,a 9{58}
5-(3-CF3C6H4)C5H3O2,a 9{59}
5-(2-ClC6H4)C5H3O2,a 9{60}
5-(3-ClC6H4)C5H3O2,a 9{61}
5-(4-ClC6H4)C5H3O2,a 9{62}
5-(4-BrC6H4)C5H3O2,a 9{63}
5-(2-NO2,4-ClC6H3)C5H3O2,a 9{64}
5-(2-Cl,5-CF3C6H3)C5H3O2,a 9{65}
5-(2,4-Cl2C6H3)C5H3O2,a 9{66}
5-(2,5-Cl2C6H3)C5H3O2,a 9{67}
5-(3,4-Cl2C6H3)C5H3O2,a 9{68}
CH3CHO, 9{69}
3-NO2C6H4CHO, 9{3}
5{3}
4-NO2C6H4CHO, 9{4}
5{4}
2-CF3C6H4CHO, 9{5}
5{5}
3-CF3C6H4CHO, 9{6}
5{6}
4-CF3C6H4CHO, 9{7}
5{7}
4-CNC6H4CHO, 9{8}
5{8}
4-FC6H4CHO, 9{9}
5{9}
2-ClC6H4CHO, 9{10}
5{10}
5{11}
5{12}
5{13}
5{14}
5{15}
5{16}
5{17}
5{18}
5{19}
5{20}
5{21}
5{22}
5{23}
5{24}
5{25}
5{26}
5{27}
5{28}
5{29}
5{30}
5{31}
5{32}
5{33}
5{34}
5{35}
5{36}
5{37}
5{38}
5{39}
5{40}
5{41}
5{42}
5{43}
5{44}
5{45}
5{46}
5{47}
5{48}
3-ClC6H4CHO, 9{11}
4-ClC6H4CHO, 9{12}
4-BrC6H4CHO, 9{13}
2-CH3C6H4CHO, 9{14}
3-CH3C6H4CHO, 9{15}
4-CH3C6H4CHO, 9{16}
64
35
97
54
38
63
34
59
16
29
45
33
33
16
40
18
44
48
99
86
70
30
47
57
44
36
49
22
28
89
93
85
42
4-iPrC6H4CHO, 9{17}
4-tBuC6H4CHO, 9{18}
2-C6H5C6H4CHO, 9{19}
4-C6H5C6H4CHO, 9{20}
3-(4-(CO2Me)C6H4)C6H4CHO, 9{21}
4-(4-(CO2Me)C6H4)C6H4CHO, 9{22}
2-SCH3C6H4CHO, 9{23}
2-CH3OC6H4CHO, 9{24}
4-CH3OC6H4CHO, 9{25}
4-((CH3)2N)C6H4CHO, 9{26}
4-(1-pyrrolidinyl)C6H4CHO, 9{27}
4-(1-piperidinyl)C6H4CHO, 9{28}
4-(4-morpholinyl)C6H4CHO, 9{29}
4-(N-Boc-piperazin-1-yl)C6H4CHO, 9{30}
4-(C6H5)2NC6H4CHO, 9{31}
2,3-F2C6H3CHO, 9{32}
CH3CH2CHO, 9{70}
CH3(CH2)2CHO, 9{71}
CH3(CH2)3CHO, 9{72}
CH3(CH2)5CHO, 9{73}
CH3(CH2)6CHO, 9{74}
(CH3)2CHCH2CHO, 9{75}
(CH3)2CHCHO, 9{76}
CH3CH2(CH3)CHCHO, 9{77}
CH3CH2CH2(CH3)CHCHO, 9{78}
(CH3CH2)2CHCHO, 9{79}
(CH3)3CCHO, 9{80}
2,5-F2C6H3CHO, 9{33}
CH3CH2CH2CH2(CH3CH2)CHCHO, 9{81}
(CH3)3CCH2CHO, 9{82}
2,6-F2C6H3CHO, 9{34}
3,4-F2C6H3CHO, 9{35}
(CH3)3CCH2(CH3)CHCH2CHO, 9{83}
CH3SCH2CH2CHO, 9{84}
3,5-F2C6H3CHO, 9{36}
2,3-(CH3)2C6H3CHO, 9{37}
2,4-(CH3)2C6H3CHO, 9{38}
2,5-(CH3)2C6H3CHO, 9{39}
2,6-(CH3)2CHO, 9{40}
3-(5-Methyl-2-furyl)butanal, 9{85}
C6H5CH2CHO, 9{86}
C6H5CH2CH2CHO, 9{87}
C6H5(CH3)CHCHO, 9{88}
C6H5(CH3)CHCH2CHO, 9{89}
C6H5CH2OCH2CHO, 9{90}
Cyclopropanecarboxaldehyde, 9{91}
Cyclopentanecarboxaldehyde, 9{92}
Cyclohexanecarboxaldehyde, 9{93}
5-Norbornene-2-carboxaldehyde, 9{94}
3-Cyclohexene-1-carboxaldehyde, 9{95}
3,4-(CH3)2C6H3CHO, 9{41}
3-F,4-C6H5C6H3CHO, 9{42}
2,5-(CH3O)2C6H3CHO, 9{43}
3,4-(CH3O)2C6H3CHO, 9{44}
2-Cl,3,6-F2C6H2CHO, 9{45}
2,6-F2,3-ClC6H2CHO, 9{46}
2,3,4,5,6-F5C6CHO, 9{47}
2-Thiophenecarboxaldehyde, 9{48}
Cinnamaldehyde, 9{96}
aC5H3O2 refers to 2-furaldehyde. bCompounds were all determined to be >80% pure by 1H NMR analysis. Yields refer to combined fractions of pure pdt (>80%) isolated after one
c
silica gel purification.

86 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1
Luesse et al.
trans-p-methoxycinnamaldehyde, 2,6-dimethyl-5-heptenal,
and trans, trans-2,4-hexadienal. The presence of multiple
electron-donating substituents (ie 3,4-dimethoxybenzal-
dehyde) was detrimental to the formation of the
corresponding acetal. A number of heterocyclic aldehydes,
such as 2-thiophenecarboxaldehyde (9{48}) and the
furaldehyde derivatives (9{49-68}), were successfully
applied in this acetal formation. However, aldehydes
containing an electron-rich nitrogen-based heterocycle, such
as 2-pyridine, indole, and pyrrole-carboxaldehyde
derivatives, resulted in recovery of unreacted starting
material and no observation of the desired acetal.
Additionally, ketal formation was attempted with
acetophenone and 4-heptanone, but only starting materials
were recovered.
The low reactivity of the alkene and epoxide
functionality on the acetals led to an alternative approach to
library synthesis. There have been numerous reports of the
preparation of oxabicyclic bridged compounds via Diels-
Alder reaction of substituted furans with various dienophiles
[6, 8, 10, 12, 30]. The resulting oxabicyclo[2.2.1]heptene
scaffolds are adorned with a pendent arm on the ethylene
unit. We saw this as an opportunity to introduce an easily
diversifiable functional group that would overcome the
limitations we encountered with reactions of the alkene unit
as well as to increase the complexity of our library by
introducing a second point of diversification.
As shown in Scheme 4, synthesis of the desired
substituted oxabicyclo[2.2.1]heptene scaffold commenced
with reduction of 3-furaldehyde to the corresponding alcohol
[15] Silylation of the primary alcohol with tert-
butyldiphenylsilyl chloride (imidazole, DMF, 25°C, 24 h)
provided the protected alcohol in good yield (81%).
Anhydride 11, the key starting material for our substituted
tricyclic library, was readily synthesized from an exo-
selective Diels-Alder cycloaddition of the protected furan
alcohol and maleic anhydride (87%) [6, 8, 10, 12, 30].
We planned to increase the complexity and variety of the
oxabicyclo[2.2.1] scaffold by adding a second point of
diversification. Towards this goal, acetal 5{1} was submitted
to a series of substitution reactions to react the alkene and
produce
a
symmetrically substituted functionalized
oxabicyclo[2.2.1]heptene product.
To our disappointment, dihydroxylation attempts with
AD-mix, OsO4, or KMnO4 were unsuccessful, with only
starting materials recovered or very messy reactions with
low yields of products (<20%). While there have been
reports of successful substitution attempts on the
oxabicyclo[2.2.1]heptene scaffold through desymmetrization
reactions such as hydroboration [19, 20] and
hydrophenylation [21-23], these were unsuccessful in all
cases for tricylic acetal 5{1} and primarily led to recovery of
unchanged acetal starting materials.
O
OHC
H
1) NaBH4
O
94%
O
O
2) TBS-Cl, imidazole
81%
3) maleic anhydride
87%
TBSO
H
O
11
O
OH
OH
LiAlH4
60%
In a further attempt to increase the diversity of these
tricyclic molecules, we also explored generation of an
epoxide and evaluated its potential for epoxide-opening
reactions to produce the additional point of diversification.
Reaction of m-chloroperoxybenzoic acid with acetal 5{1} in
CH2Cl2 at room temperature provided epoxide 10{1} in 99%
yield (Scheme 3) [4, 24]. Similarly, epoxides 10{79} and
10{87} were generated from the corresponding acetal 5 in
87% and 92% yields, respectively.
OTBS
12
Scheme 4. Synthesis of oxabicyclo[2.2.1]heptene anhydride 11.
An initial attempt at reducing 11 using excess sodium
borohydride (500 mol%) provided the two possible half-
reduced lactones, with only a trace of the desired diol 12 [3,
4]. The use of 400 mol% of lithium aluminum hydride gave
a 2:1:1 mixture of the desired diol and the two possible half-
reduced lactones [31]. A larger excess of lithium aluminum
hydride (600 mol%) provided the desired diol 12 in 60%
yield.
O
O
mCPBA
O
5
O
R
10
With the substituted diol in hand, synthesis of a library of
substituted acetals began with the large scale synthesis of
several acetals to produce chemset 14 as shown in Scheme 5.
Seven acetal derivatives (14) were prepared in larger
quantities (300-500 mg), employing aldehydes used
previously to generate the non-substituted acetal library.
These aldehydes were selected based on their previous
success and with the aim towards diversification of the
resulting acylated library. Removal of the silyl group with
tert-butylammonium fluoride (THF, 0°C, 1.5 h) provided
alcohol 14. For the examples using aldehydes 9{1}, 9{61},
9{76}, and 9{87}, the corresponding deprotected alcohol 14
was recovered directly from the acetal formation, and no
deprotection step was required. It is unclear why this
deprotection was observed for these select acetals.
NaN3
MW 140 °C
R'Li
CuCN
PhMgBr
CuCN
NR
NR
NR
Scheme 3. Substitution Reactions with Epoxide 10.
Grignard additions to epoxide 10 with no catalyst gave
only starting materials. Attempted copper-catalyzed
Grignard additions to oxabicyclic alkenes gave either no
reaction or were messy and gave low yielding rearrangement
products. Starting material was recovered in most cases,
unlike the previously reported ring opening rearrangements
observed for other oxabicycle systems with copper catalysts
[25, 26] or other transition metals [27-29].

Oxabicyclo[2.2.1]-Heptene-Based Chemical Library
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1 87
O
agents as shown in Scheme 6. A set of 21 commercially
available acid chlorides and isocyanates 15{1-21} were
selected (Fig. 2). These acylating agents were selected to
provide a range of sterically and electronically diverse
substitutions for the resulting library. Variations in chain
length, steric influence of branched chains, and variety in
substituted aromatic side chains were included in this series
of acylating agents.
9, pTsOH
O
O
12
TBSO
R
13
or
Bu4NF, THF
As shown in Scheme 6, reaction of the chemset 14 with the
set of acylating agents (15) provided a diverse library of
acylated acetals 16. Table 2 presents the results for the synthesis
of the 96 substituted tricycle library members (34-99%).
O
O
O
14{1}
66%, one step
HO
R
14{61} 34%, one step
14
All library members were purified by silica gel
chromatography and 30 compounds were analyzed by 1H
NMR analysis. In all cases, a single product was observed
with high purities (>80%). Most acylations proceeded with
ease and low isolated yields were primarily due to difficulty
in separating the product from an impurity with a similar Rf
according to TLC.
14{76} 34%, one step
14{87} 20%, one step
14{20} 46%, two steps
14{50} 39%, two steps
14{89} 58%, two steps
Scheme 5. Synthesis of hydroxymethyl-substituted oxabicyclo
[2.2.1] acetals (14).
All library members were evaluated as antibacterial
agents against a B. subtilis, S. aureus, and E. coli. In
To produce a 96-member acylated tricyclic acetal library,
we planned to react chemset 14 with a range of acylating
COCl
Ph
Ph
COCl
COCl
Ph
O
COCl
COCl
COCl
COCl
O
5
Cl
1
2
3
4
6
COCl
BnO
BnO
COCl
COCl
COCl
Ph
COCl
O2N
Cl
OMe
OBn
7
8
9
10
11
COCl
12
COCl
COCl
COCl
COCl
MeO
Cl
Me
13
14
NCO
15
16
NCO
17
NCO
NCO
Ph
O2N
H3COC
MeO
18
19
20
21
Fig. (2). Acylating agents 15{1-21} used in chemset 16 library synthesis.
O
O
O
O
R2
R1
O
O
16{1-17}
R2COCl, 15{1-17}
O
O
or
O
HO
R1
R2NCO, 15{18-21}
O
O
14
H
O
N
R1
R2
O
16{18-21}
Scheme 6. Acylation of hydroxymethyl-substituted oxabicyclic acetals (16).

88 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1
Luesse et al.
Table 2. Synthesis of Substituted Oxabicyclo[2.2.1]Heptene Acetal Library
Product
Yield (%)
Product
Yield (%)
Product
Yield (%)
Product
Yield (%)
Product
Yield (%)
16{1,1}
16{1,3}
16{1,4}
16{1,5}
16{1,6}
16{1,7}
16{1,8}
16{1,9}
16{1,11}
16{1,12}
16{1,13}
16{1,14}
16{1,16}
16{1,17}
16{1,18}
16{20,1}
16{20,2}
16{20,3}
16{20,4}
16{20,5}
63
83
34
34
81
80
34
64
93
89
77
85
86
72
59
53
99
91
99
94
16{20,6}
16{20,7}
16{20,8}
16{20,10}
16{20,11}
16{20,12}
16{20,13}
16{20,16}
16{20,17}
16{50,1}
16{50,2}
16{50,3}
16{50,4}
16{50,6}
16{50,7}
16{50,8}
16{50,10}
16{50,11}
16{50,12}
16{50,13}
94
78
83
99
89
85
85
83
78
80
95
74
82
73
73
75
94
77
73
82
16{50,14}
16{50,16}
16{50,17}
16{61,1}
16{61,3}
16{61,4}
16{61,5}
16{61,6}
16{61,7}
16{61,8}
16{61,9}
16{61,10}
16{61,11}
16{61,12}
16{61,13}
16{61,14}
16{61,15}
16{61,16}
16{61,17}
16{76,1}
70
63
82
85
89
99
80
79
73
70
90
84
93
93
92
82
69
82
60
37
16{76,3}
16{76,4}
16{76,5}
16{76,6}
16{76,7}
16{76,10}
16{76,11}
16{76,12}
16{76,13}
16{76,14}
16{76,16}
16{76,17}
16{76,18}
16{76,19}
16{76,20}
16{76,21}
16{87,1}
16{87,3}
16{87,4}
16{87,5}
67
70
63
76
35
69
66
73
48
55
86
82
98
99
99
60
72
78
64
73
16{87,6}
16{87,7}
16{87,8}
16{87,10}
16{87,12}
16{87,14}
16{89,1}
16{89,2}
16{89,3}
16{89,4}
16{89,6}
16{89,7}
16{89,8}
16{89,10}
16{89,11}
16{89,13}
92
79
99
82
69
71
88
97
89
91
81
89
85
98
45
95
Table 3. MIC Values in μM of Compounds Showing Antibacterial or Antifungal Activity
Compound ID B. subtilis S. aureus E. coli
Gentamycin
C. glabrata
0.125
0.125
500
1
1
Inactive
Neomycin
5{51}
1
1
16
Inactivea
1000
500
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
5{57}
250
5{59}
62
5{60}
250
Inactive
Inactive
Inactive
1000
1000
5{61}
62
16{20,4}
16{20,10}
1000
1000
Inactive
16{50,10}
aNo activity at 1000 μM.
addition, all compounds were evaluated as antifungal agents
against C. glabrata. Only 8 compounds showed any activity
in these assays. As shown in Table 3, none of the library
members showed any activity against E. coli or C. glabrata.
All activity was focused in the gram positive bacteria
B. subtilis and S. aureus. Unfortunately none of the library
members had sufficient activity to justify the synthesis of
further derivatives.
CONCLUSIONS
A library of functionally diverse and conformationally
restricted tricyclic compounds was produced which
employed the biologically significant 7-oxabicyclo[2.2.1]
heptene ring system. These novel substituted tricyclic
scaffolds provide a range of sizes, functionalities, and
structural flexibilities to probe the potential biological
activity of the oxabicyclo[2.2.1]heptene motif. We have also

Oxabicyclo[2.2.1]-Heptene-Based Chemical Library
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 1 89
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[15]
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Still-Wittig rearrangement. Tetrahedron, 2004, 60(48), 10921-
10926.
shown that acetal formation and the acetal motif can be
useful in the preparation of small molecule libraries.
ACKNOWLEDGMENTS
Davey, K.G.; Szekely, A.; Johnson, E.M.; Warnock, D.W.
We thank the National Science Foundation for support through
a Partnerships for Innovation grant (EHR-0227907) and Ohio
University through support of the BioMolecular Innovation and
Technology project (SCB, JM). We also thank the National
Institutes of Health for support through awards CA77347 (NDP)
and AI070248 (DLW). We also thank Promiliad Biopharma for
support (SBL, GW, MCM, NDP, DLW).
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a new commercial colorimetric microdilution
method with a standard method for in-vitro susceptibility testing of
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[18]
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norbornene-2-carboxaldehyde, for meso-1,3- and meso-1,4-Diols.
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Received: January 3, 2011
Revised: April 26, 2011
Accepted: June 19, 2011