Lewis acid mediated diastereoselective synthesis of fused fluorinated spiroketal as potential biologically active compounds

Article abstract of DOI:10.1016/j.tetlet.2011.08.004

A series of substituted dibenzalacetones prepared using standard procedures were condensed with 5-methyl, 5-phenyl, and 5-trifluoromethyl-1,3- cyclohexanediones respectively, in toluene containing BF₃·OEt as the Lewis acid catalyst. The reaction was found to be highly diastereoselective (dr, 9:1). The resulting spiroketals 1a-r were formed in moderate to good yields. In addition, a synthetically and biologically useful by-product identified as chromenone 7 was observed.

Full text of DOI:10.1016/j.tetlet.2011.08.004

Tetrahedron Letters 52 (2011) 5297–5300
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lewis acid mediated diastereoselective synthesis of fused fluorinated spiroketal
as potential biologically active compounds
⇑
Oluropo C. Agbaje, Olugbeminiyi O. Fadeyi, Cosmas O. Okoro
Department of Chemistry, Tennessee State University, 3500 John A. Merritt Blvd., Nashville, TN 37209-1561, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of substituted dibenzalacetones prepared using standard procedures were condensed with 5-
methyl, 5-phenyl, and 5-trifluoromethyl-1,3-cyclohexanediones respectively, in toluene containing
BF3ꢀOEt as the Lewis acid catalyst. The reaction was found to be highly diastereoselective (dr, 9:1). The
resulting spiroketals 1a–r were formed in moderate to good yields. In addition, a synthetically and bio-
logically useful by-product identified as chromenone 7 was observed.
Received 5 April 2011
Revised 27 July 2011
Accepted 1 August 2011
Available online 17 August 2011
Published by Elsevier Ltd.
1. Introduction
Research on their synthesis and chemical reactivity has at-
tracted considerable attention in recent years, due to their increas-
The increased interest in fluorinated pharmaceutical and medic-
inalagents has led to thedevelopmentofnovel agents and newstrat-
egies in drug discovery and development. The synthesis of
fluorinated compounds and their derivatives provide unlimited po-
tential for creating novel biologically active lead compounds for use
as therapeutics. The selective introduction of one or more fluorine
atoms into specific positions in an organic molecule changes the
molecules’ physicochemical properties, including its stability, lipo-
philicity and bioavailability. The above behavior could be explained
by the unique physical, chemical, and biological properties of
fluorine.
The carbon–fluorine bond is generally stronger than the carbon–
hydrogen bond. Thus many fluorine-containing compounds are sta-
ble and often avoid undesirable metabolic transformations. In addi-
tion, the increased lipophilicity often leads to ease of absorption and
transportation of molecules within biological membranes, thereby
improving their overall pharmacokinetic and pharmacodynamic
properties. However, prediction of sites in a molecule at which fluo-
rine substitution will result in optimal desired effects is still chal-
lenging. Therefore, the synthesis of fluorinated derivatives
provides a diverse array of building blocks and chemical substruc-
turesfornovelprocesses. Anillustrativeexampleoftheeffectoffluo-
rine is the 1,2,5-thiadiazole-based structure with muscarinic
activity shown below in Figure 1. The replacement of hydrogen
atoms on an oxidizable site by fluorine atoms protects the molecule
from hydroxylation processes mediated by P450 cytochrome
enzymes.1
ing pharmacological importance.3 In continuation of our interest in
the synthesis of fluorinated compounds as potential biologically ac-
tive molecules,4,5 herein, we report a diastereoselective synthesis of
fused fluorinated and non-fluorinated spiroketals 1a–r (Table 3).
2. Results and discussion
The synthesis of spiroketal 1 was inspired from previous work
by Giasuddin and co-workers, where dimedone and diarylideneac-
etones were refluxed in a mixture of toluene and n-heptane in the
presence of ZnCl2 to give spiroketal 4 in 70–76% yield as a single
diastereomer after separation (Scheme 1).3 Fluorinated cyclic b-
diketone 8 was obtained utilizing a known procedure reported
by our group,6 while the formation of diarylideneacetones 3a–k
was achieved (Table 1) using standard procedures.7 The trans–trans
configuration of the dienes 3a–k was confirmed by 1H NMR (cou-
pling constant, J = 12.8 Hz) as previously reported.7,8 Higher yield
of dibenzalacetones 3a–k and faster reactions were observed,
when the starting aldehyde contained less powerful electron-with-
drawing groups (Table 1, entries 1–6).
In an attempt to reproduce the previous work reported by Gia-
suddin and co-workers,3 dimedone 2 (2.2 equiv), diarylideneace-
tone 3a (1.0 equiv) in toluene/n-heptane in the presence of
20 mol % of ZnCl2 were refluxed for 16 h. The desired spiroketal 4
was obtained as a mixture of diastereomers in <30% yield, along
with chromenone 7 as a by-product (Scheme 2). The formation of
the by-product 7 was not reported by Giasuddin and co-workers.3
These unexpected results prompted us to further investigate
other Lewis acids and reaction conditions (Table 2). After surveying
a variety of reaction conditions, we found that increasing the
equivalent of diketone 2 (2.2–2.5 equiv) eliminated the formation
of the by-product chromenone 7.
Spiroketals are secondary metabolites found in numerous natu-
ral products. Many simple spiroketals exhibit a range of biological
activities.2
⇑
Corresponding author.
E-mail address: cokoro@tnstate.edu (C.O. Okoro).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.08.004

5298
O. C. Agbaje et al. / Tetrahedron Letters 52 (2011) 5297–5300
Plamatic concentration
Ki (nM)
(M receptor)
(ng/Kg)
(after 1 h , 30mg/Kgp.o.)
S
N
N
N
0.45
21
S
N
(5S, 6S)exo
S
N
F
F
0.40
805
S
F
N
(5S, 6S)exo (LY316108)
Figure 1. Protective effects of fluorine substitution on oxidative metabolisms. Effect of fluorination on plasmatic concentration of the muscarinic analgesic LY316108.1
Table 1
Synthesis of dibenzalacetone derivatives 3a–k
O
CHO
O
NaOH, H2O
R1
+
R1
R1
EtOH, rt
3a-k
6a-k
5
Entrya
R1
5
6
Yieldb (%)
1
2
3
4
5
6
7
8
H
4-F
4-CN
4-OMe
6-Br
4-CI
4-CF3
3-CF3
3,5-CF3
4-OCF3
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
94
90
80
89
85
83
75
70
65
60
85
9
10
11
j
k
j
k
3,4-(OCH20
)
a
All reactions were carried out in 95% EtOH and (2.5 M) NaOH at room temperature.
Yields refer to isolated pure products. All products were characterized by 1H NMR spectra.
b
Table 2
Effect of lewis acid
O
Ph
20 mol%
O
O
Lewis acid
toluene-n-heptane
or toluene
Me
O
+
Ph
Ph
Me
Me
O
Me
reflux ,48 h
Me
O
3a
4
Me
Ph
O
2
Entry
Lewis acid
Convb (%)
dra
1
2
3
4
5
6
7
8
9c
ZnCI2
SnCI4
TFA
AICI3
49
48
45
45
55
87
43
44
94
1:1
3:2
1:1
3:2
3:1
7:1
1:1
1:1
9:1
TiCI4
BF3ꢀOEt2
TsOH/AcOH
EtAICI2
BF3ꢀOEt2
a
b
c
Diastereomeric ratios were measured using 1H NMR.
Conversion determined by LC/MS and 1H NMR.
Reaction was also carried out in toluene.

O. C. Agbaje et al. / Tetrahedron Letters 52 (2011) 5297–5300
5299
Table 3
give moderate conversion in 3:1 dr. The origin of high diastereose-
lectivity observed using BF3ꢀOEt2 (Table 2, entry 6) is unclear but it
is likely due to its ability to coordinate tightly with the carbonyl
oxygen of the substituted Michael acceptor (dibenzyalacetone 3a).
It is noteworthy to mention that extending the reaction time to
48 h plays a significant role, which could be due to equilibration of
the minor diastereomer to the more stable major diastereomer.9
Also, the solvent effect on the conversion and selectivity of the
reaction was evaluated using different solvents. For this study,
BF3ꢀOEt2 was maintained as the Lewis acid under 48 h reflux and
using various solvents (THF, DMF, methanol, DMSO, pyridine, tolu-
ene, 2-(methoxy)ethyl-ether, 1,2-dimethoxyethane, n-heptane,
dichloromethane). Clearly, toluene is the optimal solvent to facili-
tate spiroketalization with 9:1 diastereoselectivity (Table 2, entry
9) and greater than 94% conversion. No product was formed when
the following solvents: DMSO, DMF, MeOH and DCE were used.
Since the reaction is facilitated by loss of water, the azeotropic ef-
fect of toluene appears to explain the result obtained.
Synthesis of spiroketal derivatives 1a–r
H
R2
O
Ar
O
H
O
H
O
H
R2
O
BF3. Et2O, 48 h
reflux, toluene
+
O
Ar
Ar
Ar
1a-r
O
R2
3
8
Enrtya
R2
Ar
Product
dra
Yieldb (%)
1
2
3
4
5
6
7
8
CH3
CF3
Ph
CH3
CH3
Ph
CH3
CF3
Ph
CH3
CF3
Ph
CH3
CF3
Ph
CH3
CF3
Ph
C6H5–
C6H5–
C6H5–
3,4-(OCH20)–C6H3–
3,4-(OCH20)–C6H3–
3,4-(OCH20)–C6H3–
4-F–C6H4–
4-F–C6H4–
4-F–C6H4–
4-CI–C6H4–
4-CI–C6H4–
1a
1b
1c
1d
1e
1f
1g
1h
1i
9:1
9:1
9:1
9:2
9:1
9:1
9:1
9:2
9:2
9:2
9:1
9:1
9:2
9:1
9:2
9:1
9:2
9:1
90
89
92
86
87
89
74
71
76
73
70
72
85
88
87
85
80
90
Next, we employed the observed optimal catalytic condition
using differently substituted dibenzalacetone 3 and various 5-
substituted diketones 8, as shown in Table 3.
9
10
11
12
13
14
15
16
17
18
1j
1k
11
1m
1n
1o
1p
1q
1r
4-CI–C6H4–
The nature of the groups in the 5 position of the cyclic b-dike-
tones 8, did not affect the reactivity or selectivity. As shown in Ta-
ble 3, various derivatives of the spiroketal were obtained in 70–92%
yield. It was observed that the electron withdrawing substitution
on the dibenzalacetone (entries 7–12) tends to give lower but
moderate yields (70–76%), while electron donating substitution
on the dibenzalacetone (entries 4–6, and 13–18) gave excellent
yields (80–92%). In all cases, high diastereomeric ratios in which
both pendant aryl groups are in pseudoequatorial positions were
obtained (Table 3). Though conformational studies showed that
three possible diastereomers may be possible for spiroketal 1,
two diastereomers were observed by 1H NMR in the course of
our studies and we only isolated the major diastereomer, which
is the diequatorial.
4-OCF3–C6H4–
4-OCF3–C6H4–
4-OCF3–C6H4–
4-OMe–C6H4–
4-OMe–C6H4–
4-OMe–C6H4–
a
Diastereomeric ratios were measured using 1H NMR.
lsolated yield.
b
Table 2 summarizes the result obtained utilizing various Lewis
acids, where BF3ꢀOEt2 gave good a diastereoselectivity ratio of 7:1
and 87% conversion (Table 2, entry 6). Using toluene as the solvent
(entries1–9), BF3ꢀOEt2, gave better selectivity and conversion (9:1
dr and 94% conversion, Table 2, entry 9). TiCl4 was also found to
The plausible mechanism for the formation of the observed
chromenone 7 is shown in Scheme 2. Further studies on the scope
O
Ar
O
O
O
O
O
ZnCl2 (20 mole %)
Toluene-n-Heptane
Reflux, 16 h
O
Me
Me
Ar
Ar
+
Me
Me
3
4
Me Me
Ar
2
Scheme 1. Synthesis of fused spiroketal 4.
LA
O
OH
O
Ar
O
LA
OH Ar
O
O
Ar
Ar
Ar
Ar
H
O
Me
Me
O
Me
Me
Ar
O
3
OH
10
Me
Me
Me
Me
2
O2H
9
O
Ar
O2H
Ar
O
Ar
O
Ar
O
Ar
H
H
H
OH
OH
Me
Me
Me
Me
O
Ar
O
O
14
O
Ar
Me
OH2
Me
Me
Me
13
12
H
11
O
Ar
H2O
Me
Ar
O
Me
7
Scheme 2. Proposed mechanism for the formation of chromenone 7.

5300
O. C. Agbaje et al. / Tetrahedron Letters 52 (2011) 5297–5300
8. Satya, P.; Monika Gupta Synth. Commun. 2005, 35, 213–222.
9. General procedure for the synthesis of fused spiroketal (8a–r)
and synthetic applications of chromenone 7 are in progress and
will be described in due course.
A
mixture of diketone 7 (2.5 mmol), trans–trans-dibenzalacetone 3a–k
In conclusion, a simple and efficient method for the diastereose-
lective synthesis of fused fluorinated and non-fluorinated spiroke-
tals has been developed. Furthermore, the biological evaluation of
the fluorinated spiroketals and chromenones derivatives is under-
way, and results will be reported in due course.
(1 mmol) and 20 mol % BF3ꢀEt2O (0.028 g, 0.2 mmol) in toluene (30 mL) was
refluxed for 48 h under Dean–Stark trap. The progress of the reaction was
monitored by TLC and GC/MS. After cooling the reaction mixture was reduced in
volume and neutralized with saturated aqueous NaHCO3 solution and then
extracted with ether (5 ꢁ 20 mL). The combined ether extracts was dried over
anhydrous sodium sulfate and evaporated in vacuo. The crude product was
recrystallized from methanol to give 1a–r.
7,70-Dimethyl-4,40-diphenyl-3,30,4,40,7,70,8,80-octahydro-2,20-spirobi[chromene]-
5,50(6H,60H)-dione 1a: 1H NMR (400 MHz, CDCl3) d (ppm): 3.81–3.90 (dd, 2H,
J = 12.5, 7.3 Hz), 3.78–3.80 (d, 2H), 7.21–7.41 (m, 10H), 1.21–1.40 (s, 12H), 2.55–
2.65 (m, 2H), 2.67–2.80 (m, 2H), 3.41–3.55 (m, 2H), 1.10–1.51 (dd, 2H,
Acknowledgment
We are thankful to the U.S. Department of Education Title III
Grant, Tennessee State University, for the financial support.
J = 8.0 Hz), 1.22–1.25 (dd, 2H, J = 8.0 Hz). 13C NMR (100.6 MHz, CDCl3)
d
(ppm): 21.2, 103.4, 45.6, 31.8, 196.8, 47.4, 29.8, 40.1, 164.2, 111.3, 126.8,
128.8, 127.9, 141.7. LC/MS m/z; 597 (M+H)+.
4,40-Diphenyl-7,70-bis(trifluoromethyl)-3,30,4,40,7,70,8,80-octahydro-2,20-
spirobi[chromene]-5,50(6H,60H)-dione 1b: 1H NMR (400 MHz, CDCl3) d (ppm):
4.01–4.04 (dd, 2H, J = 12.4, 7.3 Hz), 3.47–3.50 (m, 2H), 7.05–7.42 (m, 10H), 2.85–
2.93 (m, 2H), 2.67–2.76 (m, 4H), 2.53–2.65 (m, 2H), 2.35–2.40 (ddd, 2H, J = 2H,
J = 4.0, 8.0, 16.0 Hz), 1.81–1.89 (ddd, 2H, J = 2H, J = 4.0, 8.0, 16.0 Hz). 13C NMR
(100.6 MHz, CDCl3) d (ppm): 140.7, 103.4, 45.6, 31.8, 196.8, 28.2, 30.1, 17.1,
164.2, 111.3, 126.8, 128.8, 127.9, 141.7. LC/MS m/z; 593 (M+Na)+.
4,40,7,70-Tetraphenyl-3,30,4,40,7,70,8,80-octahydro-2,20-spirobi[chromene]-
5,50(6H,60H)-dione 1c: 1H NMR (400 MHz, CDCl3) d (ppm): 2.93–2.98 (dd, 2H,
J = 12.5, 7.3 Hz), 3.12–3.35 (m, 4H), 7.22–7.35 (m, 20H), 3.42–3.56 (m, 2H), 2.73–
2.82 (m, 2H), 2.47–2.61 (m, 2H), 1.78-1.85 (ddd, 2H, J = 4.0, 8.0, 16.0 Hz), 2.32–
2.40 (ddd, 2H, J = 4.0, 8.0, 16.0 Hz). 13C NMR (100.6 MHz, CDCl3) d (ppm): 103.4,
45.6, 31.8, 196.8, 28.2, 30.1, 20.7, 164.2, 111.3, 126.8, 128.8, 127.9, 141.7, 126.2,
140.9. LC/MS m/z; 594 (M+H)+.
References and notes
1. Edwards, P. N. Principles and Commercial Applications. In Organofluorine
Chemistry; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: N-Y,
1994; pp 505–509.
2. Raju, B. R.; Saikia, A. K. Molecules 2008, 13, 1942–2038.
3. Giasuddin, A. M.; Syeda, A. A.; Khabir Uddin, Md.; Taifur Rahman, Md.
Tetrahedron Lett. 2005, 46, 8217–8220.
4. Agbaje, C. O.; Fadeyi, O. O.; Adamson, F. S.; Myles, E. L.; Okoro, C. O. Bioorg. Med.
Chem. Lett. 2011, 21, 989–992.
5. Fadeyi, O. O.; Adamson, S. T.; Myles, E. L.; Okoro, C. O. Bioorg. Med. Chem. Lett.
2008, 18, 4172–4176.
6. Fadeyi, O. O.; Okoro, C. O. Tetrahedron Lett. 2008, 49, 4725–4727.
7. Organic Chemistry laboratory textbooks and online editions, Dibenzalacetone by
aldo condensation.