Synthesis of Functionalized Chiral Carbocyclic Cleft Molecules Complementary to Troeger's Base Derivatives

Article abstract of DOI:10.1021/jo991741p

The synthesis of optically pure functionalized cleft molecules derived from dibenzobicyclo[b,f][3.3.1]-nona-5a,6a-diene-6,12-dione is reported. These clefts are reminiscent of Troeger's base but contain clefts with different dimensions and additional carbonyl (or alcohol) groups that may be utilized in molecular recognition studies. The 2,8-dimethyl and 2,8-dibromo derivatives were synthesized via an intramolecular Friedel-Crafts acylation and were resolved by chiral HPLC. The 2,8-dinitro derivative was prepared by regiospecific nitration of dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione. The dibromo and dinitro derivatives allow direct access to a range of functionalized molecular clefts. Palladium-catalyzed coupling of the dibromo derivative afforded the disubstituted phenyl, anisole, and acetylene derivatives, while reduction of the dinitro derivative and acetylation provided amino-dione and amide-hydroxyl derivatives. X-ray crystal structures of the dimethyl 12, dibromo 13, di(p-methoxyphenyl) 16, dinitro 18, and dimethyl dinitro 22 derivatives show cleft angles between the planes between the aromatic rings of 84-104°. The synthetic route, structural features, and potential for molecular recognition studies of this class of clefts are compared with those of the more widely studied Troeger's base cleft molecules.

Full text of DOI:10.1021/jo991741p

3042
J . Org. Chem. 2000, 65, 3042-3046
Syn th esis of F u n ction a lized Ch ir a l Ca r bocyclic Cleft Molecu les
Com p lem en ta r y to Tr o1ger ’s Ba se Der iva tives
Marc C. Kimber, Andrew C. Try, Leoni Painter, Margaret M. Harding,* and Peter Turner
School of Chemistry, University of Sydney, New South Wales 2006, Australia
Received November 8, 1999
The synthesis of optically pure functionalized cleft molecules derived from dibenzobicyclo[b,f][3.3.1]-
nona-5a,6a-diene-6,12-dione is reported. These clefts are reminiscent of Tro¨ger’s base but contain
clefts with different dimensions and additional carbonyl (or alcohol) groups that may be utilized in
molecular recognition studies. The 2,8-dimethyl and 2,8-dibromo derivatives were synthesized via
an intramolecular Friedel-Crafts acylation and were resolved by chiral HPLC. The 2,8-dinitro
derivative was prepared by regiospecific nitration of dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-
6,12-dione. The dibromo and dinitro derivatives allow direct access to a range of functionalized
molecular clefts. Palladium-catalyzed coupling of the dibromo derivative afforded the disubstituted
phenyl, anisole, and acetylene derivatives, while reduction of the dinitro derivative and acetylation
provided amino-dione and amide-hydroxyl derivatives. X-ray crystal structures of the dimethyl
12, dibromo 13, di(p-methoxyphenyl) 16, dinitro 18, and dimethyl dinitro 22 derivatives show cleft
angles between the planes between the aromatic rings of 84-104°. The synthetic route, structural
features, and potential for molecular recognition studies of this class of clefts are compared with
those of the more widely studied Tro¨ger’s base cleft molecules.
In tr od u ction
racemic cleft molecules.8-10,17 However, optically pure
porphyrin-based receptors incorporating Tro¨gers base
have been shown to selectively bind chiral amines and
amino acids,21 and enantioselective recognition of DNA
by acridine-substitiuted Tro¨ger’s base systems has been
demonstrated.22
A chiral cavity, similar to that found in Tro¨ger’s base
1, is also present in a number of related systems in-
cluding dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-
dione 2, dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene 3,23
Kagan’s ether 424,25 and the tricyclic dibenzo[b,f][1,5]-
diazocine ring system 5.26 These skeletons differ from
Tro¨gers base in the atoms involved in formation of the
Molecules featuring convergent functional groups in
cleftlike shapes have emerged as useful receptors for
small molecules.1,2 The combination of a well-defined
semirigid cavity to which tunable functional groups can
be appended in predictable geometries has allowed the
design of a number of host systems for molecular recogni-
tion studies and for the controlled assembly of complex
molecular architectures. These concepts have been well
illustrated in, for example, clefts derived from Kemp’s
acid for the recognition of nucleic bases,3 the design of
molecular tweezers,4,5 and a number of acyclic hosts.2,6
The rigid cleftlike shape of Tro¨ger’s base 1 combined
with the chirality conferred by the diazocine bridge, has
resulted in incorporation of this framework into a number
of macrocyclic host systems, and as a scaffold to which
convergent functional groups can be appended to gener-
ate nonmacrocyclic synthetic receptors.7-18 The resultant
receptors have been used to allow recognition and binding
of guest molecules including biotin, adenine and ami-
nopyrimidines19,20 via convergent directional hydrogen-
bonding interactions and to develop water-soluble mac-
rocyclic hosts.9,11 In most host-guest studies involving
Tro¨ger’s base, the chirality of the cleft has not been
exploited for the discrimination between chiral substrates
but has been used to position functional groups in a
predictable geometry, and hence, most studies have used
(7) Becker, D. P.; Finnegan, P. M.; Collins, P. W. Tetrahedron Lett.
1993, 34, 1889.
(8) Wilcox, C. S. Tetrahedron Lett. 1985, 26, 5749.
(9) Wilcox, C. S.; Cowart, M. D. Tetrahedron Lett. 1986, 27, 5563.
(10) Adrian, J . C., J r.; Wilcox, C. S. J . Am. Chem. Soc. 1992, 114,
1398.
(11) Sucholeiki, I.; Lynch, V.; Phan, L.; Wilcox, C. S. J . Org. Chem.
1988, 53, 98.
(12) Yashima, E.; Akashi, M.; Miyauchi, N. Chem. Lett. 1991, 1017.
(13) Cudero, J .; Pardo, C.; Ramos, M.; Gutierrez-Puebla, E.; Monge,
A.; Elguero, J . Tetrahedron 1997, 53, 2233.
(14) Tatiboue¨t, A.; Demeunynck, M.; Lhomme, J . Synth. Commun.
1996, 26, 4375.
(15) Tatiboue¨t, A.; Fixler, N.; Demeunynck, M.; Lhomme, J . Tetra-
hedron 1997, 53, 2891.
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Kirsch-De Mesmaeker, A. Tetrahedron Lett. 1997, 38, 1567.
(17) Wilcox, C. S.; Greer, L. M.; Lynch, V. J . Am. Chem. Soc. 1987,
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8055.
(20) Adrian, J . C., J r.; Wilcox, C. S. J . Am. Chem. Soc. 1991, 113,
678.
(21) Crossley, M. J .; Hambley, T. W.; Mackay, L. G.; Try, A. C.;
Walton, R. J . Chem. Soc., Chem. Commun. 1995, 1077.
(22) Tatiboue¨t, A.; Demeunynck, M.; Anraud, C.; Collet, A.; Lhomme,
J . J . Chem. Soc., Chem. Commun. 1999, 161.
(23) Prasad, R. S.; Roberts, R. M. J . Org. Chem. 1991, 56, 2998.
(24) Kagan, J .; Chen, S.-Y.; Agdeppa, D. A., J r. Tetrahedron Lett.
1977, 51, 4469.
* To whom correspondence should be addressed. Fax: +61 2 9351
3329. Phone: +61 2 9351 2745. E-mail: harding@chem.usyd.edu.au.
(1) Lehn, J .-M. Supramolecular Chemistry, Concepts and Perspec-
tives; VCH: Weinheim, 1995.
(2) Comprehensive Supramolecular Chemistry; Atwood, J . L., Davies,
J . E., MacNicol, D. D., Vo¨gtle, F., Eds.; Elsevier Science: London, 1996;
Vol. 6.
(3) Rebek, J ., J r. Angew. Chem., Int. Ed. Engl. 1990, 29, 245.
(4) Zimmerman, S. C.; Zeng, Z.; Wu, W.; Reichert, D. E. J . Am.
Chem. Soc. 1991, 113, 183.
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Welch, C. J . Tetrahedron Lett. 1997, 50, 8655.
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Tetrahedron Lett. 1991, 32, 5309.
(25) Chen, J . S.; Watson, W. H.; Kagan, J .; Agdeppa, D. A., J r.; Chen,
S.-A. Acta Crystallogr. 1978, B34, 3627.
10.1021/jo991741p CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/22/2000

Synthesis of Functionalized Chiral Carbocyclic Cleft Molecules
J . Org. Chem., Vol. 65, No. 10, 2000 3043
Sch em e 1
bridgehead structure, which confer different bite angles
on the clefts. However, in contrast to Tro¨gers base, they
have been not been widely incorporated into the design
of supramolecular systems. Dione 2 has been used to
generate a chiral crown ether based receptor,27-29 while
4 has been elaborated to give a number of rigid cleft
systems and molecular tweezers.30-33 More recently,
functionalization of Kagan’s ether34 has afforded entry
into metallomacrocycles.35
In this paper, we describe the synthesis, resolution and
X-ray crystallographic analysis of a range of derivatives
of the chiral dione 2. Preliminary data on two of these
analogues has been communicated previously.36 In con-
trast to the synthesis of Tro¨ger’s base systems, which are
restricted to electron-donating groups on the primary
aromatic amine which is condensed with formalde-
hyde,11,37,38 both electron-withdrawing and electron-
donating groups can be directly incorporated into the
structure of 2. These derivatives, which may be readily
resolved and elaborated to incorporate a range of differ-
ent functionality, provide access to a range of new chiral
molecular clefts that contain complementary, yet unique
features, compared with Tro¨ger’s base-containing clefts.
as precursors in the synthesis of more complex chiral
clefts, and also to assess whether different substituents
influence the dimensions of the cleft. In particular,
incorporation of a halogen was desirable as these deriva-
tives provide an excellent handle for further modification
through metal-catalyzed cross-coupling reactions.40,41
Furthermore, symmetrically substituted halogen deriva-
tives of Tro¨ger’s base cannot be prepared, although the
preparation of unsymmetrical derivatives containing a
single halogen is possible.38
Racemic dimethyl and dibromo derivatives, 12 and 13,
respectively, were prepared in three steps from benzyl-
cyanides 6 and 7 respectively, via the same route
described by Tatemitsu et al (Scheme 1).39 The interme-
diate mixture of dinitrile stereoisomers, 8 and 10,
respectively, were not separated and characterized but
converted directly to the corresponding mixtures of
diacids 9 and 11, respectively. Treatment of these diacids
afforded racemic dimethyl dione 12 and dibromo dione
13 respectively. While chromatography was required to
purify the dimethyl derivative 12, the dibromo dione 13
crystallized directly from the final acid catalyzed cycliza-
tion step, and no chromatography was required to isolate
gram amounts of pure material.
To illustrate the potential of the dibromo dione 13 as
a building block for the construction of new supramo-
lecular hosts, a number of aryl derivatives were prepared.
Thus, palladium-mediated coupling of racemic 13 under
Suzuki conditions40,42 with phenyl, o- or p-methoxyphen-
ylboronic acid generated the corresponding bis-aryl di-
ones 14, 15, and 16, respectively, in >90% yield. Simi-
larly, treatment of dibromo dione 13 with trimethylsily-
lacetylene in the presence of PdCl2(PPh3)2, copper iodide,
Resu lts a n d Discu ssion
Syn th esis. The synthesis of the parent cleft 2 has been
reported by Tatemitsu et al. (Scheme 1, R ) H).39 The
key step in the synthesis is a double acid mediated
Friedel-Crafts acylation that generates the bicyclo ring
system. The only derivatives of 2 that have been reported
have involved reduction of the carbonyl groups to the diol
or a Wittig reaction to the bisalkene.27 Both strongly basic
conditions and acidic conditions are required in steps (b)
and (c) (Scheme 1) which limits the type of substitution
tolerated on the ring, and directive effects will influence
the ring closure in step (c).
Our initial studies focused on establishing the func-
tional groups that could be tolerated in the ring closure
steps, to provide derivatives that could be easily be used
(26) Molina, P.; Arques, A.; Tarraga, A.; del Rosario Obon, M.
Tetrahedron 1998, 54, 997.
(27) Naemura, K.; Fukunaga, R.; Komatsu, M.; Yamanaka, M.;
Chikamatsu, H. Bull. Chem. Soc. J pn. 1989, 62, 83.
(28) Naemura, K.; Fukunaga, R.; Yamanaka, M. J . Chem. Soc.,
Chem. Commun. 1985, 1560.
(29) Naemura, K.; Fukunaga, R. Chem. Lett. 1985, 1651.
(30) Harmata, M.; Murray, T. J . Org. Chem. 1989, 54, 3761.
(31) Harmata, M.; Barnes, C. L. Tetrahedron 1990, 31, 1825.
(32) Harmata, M.; Barnes, C. L. J . Am. Chem. Soc. 1990, 112, 2.
(33) Harmata, M.; Barnes, C. L.; Rao Karra, S.; Elahmad, S. J . Am.
Chem. Soc. 1994, 116, 8392.
(34) Harmata, M.; Kahraman, M. J . Org. Chem. 1999, 64, 4949.
(35) Harmata, M.; Kahraman, M. Tetrahedron Lett. 1999, 40, 4133.
(36) Try, A. C.; Painter, L.; Harding, M. M. Tetrahedron Lett. 1998,
39, 9809.
(38) Webb, T. H.; Wilcox, C. S. J . Org. Chem. 1990, 55, 363.
(39) Tatemitsu, H.; Ogura, F.; Nakagawa, Y.; Nakagawa, M.;
Naemura, K.; Nakagawa, M. Bull. Chem. Soc. J pn. 1975, 48, 2473.
(40) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(41) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(42) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(43) Zabel, V.; Watson, W. H.; Kagan, J .; Agdeppa, D. A., J r.; Chen,
S.-A. Cryst. Struct. Commun. 1978, 7, 727.
(37) Tro¨ger, J . J . Prakt. Chem. 1887, 36, 225.

3044 J . Org. Chem., Vol. 65, No. 10, 2000
Kimber et al.
Sch em e 2
F igu r e 1. Circular dichroism spectra (CH3CN), corrected to
enantiomeric purity, of (-)-12 (solid line) and (+)-12 (0.8 mM).
and triethylamine, followed by deprotection, afforded the
bisacetylene derivative 17.
Preparation of the dinitro dione 18 was also highly
desirable as a key building block that allows introduction
of hydrogen bond donor and acceptor groups into the
resultant clefts via amide and amino functional groups.
However, the route shown in Scheme 1 (R ) NO2) was
not followed as the strongly deactivating nitro groups
would not allow the final ring closure step to occur.
Instead, direct nitration of the parent dione 2 was carried
out which resulted in regioselective nitration at the 2-
and 8-positions to yield 18 in 75% yield. The 2,8-
disubstitution pattern was established by NOE experi-
ments from the benzylic protons to the ortho-coupled
aromatic doublet and was independently confirmed by
X-ray crystallography (see below). Similar nitration of the
dimethyl dione 12 afforded exclusively the dimethyl
dinitro dione 22 in 61% yield.
F igu r e 2. ORTEP plot of dinitro dione 18.
ration of crystalline diastereomeric derivatives of the
diones 12 and 13 could be carried out, we chose to
investigate chiral HPLC to generate optically pure mate-
rial directly. Racemic diones 12 and 13 were resolved
successfully by HPLC on a chiral column. The absolute
configuration of each of the enantiomers was determined
by circular dichroism (CD) spectroscopy on comparison
with the previously assigned CD data for the parent
compound 1.39 The CD spectra of each of the enantiomers
(-)-12 and (+)-12 (Figure 1) show features similar to
those of the dibromo dione enantiomers (-)-13 and (+)-
13.36 While the dinitroderivative was not resolved, it can
be readily obtained in optically pure form by using either
(-)-2 or (+)-2; these diones may be readily prepared by
dehydrative cyclization of optically pure isomers of 1,3-
diphenylglutaric.27
X-r a y Cr ysta llogr a p h y. Crystals suitable for diffrac-
tion of the dimethyl 12, dibromo 13, diphenyl 14, di(p-
anisole) 16, dinitro 18, and dimethyl dinitro 22 deriva-
tives were obtained, and X-ray structures of these five
derivatives were determined. Figure 2, which shows the
ORTEP view of the dinitro dione 18, illustrates the rigid
cleft shape of the molecule and the position of the two
carbonyl groups that are orientated toward the interior
of the cleft.
The dinitro dione 18 exhibited limited solubility in
most organic solvents except DMF and hence was con-
verted to the more soluble diacetamide derivative for
characterization. Catalytic hydrogenation of 18 in the
presence of palladium on charcoal catalyst resulted in
reduction of both the nitro groups and the stereoselective
reduction of the dione to the very polar amino diol 19
which was characterized as the acetamide derivative 20
(Scheme 2). The 1H NMR spectrum of 20 showed a
doublet (J ) 5.2 Hz) at δ 6.09 ppm confirming the
stereochemistry at the new chiral centers in which the
acetate groups in 20 (and hydroxyls in 19) are psuedo-
axial and oriented toward to interior of the cleft; similar
stereoselective reduction of the dione 2 has been reported
previously.39 Selective reduction of nitro groups at the
2- and 8-positions of dione 18 to give the bisaminodione
21 was achieved using iron-acetic acid.
Table 1 shows the variation in the interplanar angle
between the two aromatic rings, or cleft angle, as the R
substituents on the aryl rings are varied. For comparison,
the analogous interplanar angles in related cleft mol-
ecules including Tro¨ger’s base 1 and Kagan’s ether 4 are
also included. In the case of Tro¨ger’s base 1, X-ray
crystallography has shown that there is a moderate
degree of flexibility in the dimensions of the cleft that
may be fine-tuned or exploited in the design of biomimetic
Resolu tion of Dion es. Resolution of the parent dione
2 has been previously carried out39 via reduction to the
racemic diol and subsequent conversion and resolution
of the resultant menthoxyacetates. While similar prepa-

Synthesis of Functionalized Chiral Carbocyclic Cleft Molecules
J . Org. Chem., Vol. 65, No. 10, 2000 3045
Ta ble 1. In ter p la n a r An gle θ betw een P la n es Defin ed by
dibromo dione 13 as both compounds allow a wide-range
of functionality to be introduced into the clefts. Elabora-
tion of diones 13 and 18 into new chiral clefts is currently
under investigation in these laboratories.
Ben zen e Rin gs in Cleft Molecu les
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points are
uncorrected. 1H NMR spectra were recorded at 200 or 400 MHz
and are referenced to residual solvent protons. Circular
dichroism (CD) measurements were recorded using a 0.1 cm
cell and the following parameters; range 300-600 nm, ac-
cumulation 10 scans, temperature 20 °C, step 0.5 nm, speed
50 nm min-1, response 2 s, and bandwidth 1.0 nm.
derivatives of 2
12
13
14
16
18
22
R
CH3
Br
Ph
p-MeOPh
NO2
CH3
type of bridge
diazocine
ether
R1
H
H
H
H
θ,a deg
104.3, 101.7
91.4
100.4
99.7
b
2,8-Dim eth yldiben zobicyclo[b,f][3.3.1]n on a-5a,6a-dien e-
6,12-d ion e 12. p-Methylphenylacetonitrile 6 (8.0 g, 0.061 mol)
and powdered sodium hydroxide (2.4 g, 0.061 mol) were
dissolved in diiodomethane (8.3 g, 0.031 mol), and the resultant
mixture was heated at 165 °C for 45 min. The reaction mixture
was cooled, and water and dichloromethane were added in
portions. The two-phase system was shaken vigorously, the
organic phase was separated, washed with brine, dried over
anhydrous sodium sulfate, and the solvent was removed to give
a mixture of crude (()- and meso-phenylpentanedinitrile 8 (8.1
g), which was hydrolyzed by heating at 80 °C for 18 h in a
mixture of ethanol and potassium hydroxide solution (40%).
Ethanol was removed under vacuum and the residue was
diluted with water and washed with dichloromethane. The
aqueous phase was acidified to pH < 1 by the addition of
hydrochloric acid (3 M) and extracted with ethyl acetate. The
combined organic extracts were dried over anhydrous sodium
sulfate, and the solvent removed to give a mixture of crude
(()- and meso-phenylpentanedioic acids 9 (6.2 g). The crude
acids were heated at 100 °C for 45 min in sulfuric acid (18 M),
poured onto ice, and extracted with ether. The organic layers
were combined, washed with potassium hydroxide solution
(3%), dried over anhydrous sodium sulfate, filtered and
evaporated to dryness to give crude 12. Purification by
chromatography over silica afforded pure 12 (0.99 g, 16%) as
H
NO2
83.9
102.7
related clefts
1
4
5
92.9, 97.411 b
9343
substituted amine
77.9,76.626 b
a
b
All data were obtained on crystalline racemates. Two types
of molecules in unit cell.
systems through substitution of the aryl rings, and clefts
with interplanar angles between 88 and 104° were
observed.11 Some variation in the bite angle of clefts
incorporating Kagan’s ether has also been noted.30,32 In
the case of the chiral diones derived from 2, the R
substituents were also observed to influence the dimen-
sions of the cavity, which vary from 84° with the electron-
withdrawing nitro groups, to 104° with the electron-
donating methyl groups. In the case of dione 22, which
contains both methyl and nitro substituents, the cleft
angle is very close to that of the dimethyl dione 12,
suggesting that the electronic effect of the 2,8-dimethyl
substituents, rather than the 1,7-dinitro groups, is more
significant in influencing the cleft angle. These variable
cleft angles need to be taken into account, and potentially
may also be utilized, in the design of new hosts incorpo-
rating molecular clefts based on dione 2.
1
a white solid: mp 183-186 °C; IR (film) 1660 cm-1; H NMR
(200 MHz; CDCl3) δ 7.75-7.77 (2 H, m), 7.32-7.35 (4 H, m),
3.96 (2 H, t, J ) 3.0 Hz), 2.96 (2 H, t, J ) 3.0 Hz), 2.31 (6 H,
s, CH3); UV λmax (CHCl3) 315 (ꢀ 1458), 341 (sh) (2255), 308
(4548), 300 (sh) (4328), 273 (15429), 262 (sh) (20137), 253
(30664), 245 (sh) (29184); CIMS m/z 276 (MH+, 100), 248 (60),
206 (42). Anal. Calcd: C, 82.58; H, 5.84. Found: C, 82.61; H,
5.83. Crystals suitable for X-ray diffraction were obtained by
recrystallization from CH2Cl2. The enantiomers were resolved
on a Pirkle type 1A chiral column (3 mL/min, 1.5% 2-propanol/
light petroleum). A sample of 12 (20 mg) was dissolved in
dichloromethane (approximately 0.5 mL) and this solution was
injected in 20 µL portions. (+)-12, the (5R,11R)-isomer, eluted
first (6.2 mg, 99.4% pure), retention time 20 min, [R]22D ) +480
(c 0.62, CH3CN); followed by (-)-12, the (5S,11S)-isomer, (4.1
mg, 97.3% pure), retention time 22 min. Fractions were passed
through a silica column Whatman Partisil 10 (10% ethyl
acetate/light petroleum) to remove an impurity that formed
during the chromatography.
Con clu sion s
The dibromo 13 and dinitro 18 diones are new chiral
building blocks that may be used in the design of
functionalized molecular clefts and related supramolecu-
lar structures. Compared with the synthesis of the
analogous Tro¨ger’s base derivatives, the synthesis of the
dione clefts has several advantages. First, synthesis of
Tro¨gers base 1 is restricted to electron-donating groups
para to the precursor amine used to form the diazocine
bridge, and the direct synthesis of the corresponding
dinitro and dibromo derivatives is not possible. Hence,
formation of the diazocine bridge is often the last step in
the synthetic scheme. Second, an important feature of
the diones that is not present in any of the related cleft
molecules 1 or 3-5 is the presence of the two carbonyl
groups within the chiral cavity. Stereoselective reduction
of these groups to hydroxyls36,39 provides a mechanism
whereby the recognition features of the cleft may be
further tailored to target recognition of chiral substrates.
Very recently, a bistriflate derivative of Kagan’s ether 4
has been synthesized34 and metal-catalyzed coupling to
a bispyridyl derivative communicated.35 This Kagan’s
ether bistriflate derivative shows similar potential to the
2,8-Dibr om odiben zobicyclo[b,f][3.3.1]n on a-5a,6a-dien e-
6,12-d ion e 13. Dione 13 was prepared from p-bromobenzyl-
cyanide 7 (5.0 g, 25.5 mmol) using the same method outlined
above to prepare 12. The crude product was recrystallized from
dichloromethane to yield pure 13 (0.73 g, 17%) as a colorless
1
crystalline solid: mp 259-262 °C; IR (Nujol) 1695 cm-1; H
NMR (200 MHz; CDCl3) δ 8.08 (2 H, d, J ) 2.3 Hz), 7.64 (2 H,
dd, J ) 11.1, 2.3 Hz), 7.30 (2 H, d, J ) 11.1 Hz), 2.97 (2 H, t,
J ) 3.0 Hz), (3.99, 2 H, t, J ) 3.0 Hz); UV λmax (CHCl3) 355
(1194), 441 (1549), 327 (sh) (1704), 311 (3827), 302 (sh) (3481),
280 (5846), 248 (13905), 243 (14313), 230 (16150); CIMS m/z
406 (MH+, 100). Anal. Calcd for C17H10O2Br2: C, 50.28; H, 2.48.
Found: C, 50.31; H, 2.57. Crystals suitable for X-ray diffraction
were obtained by recrystallization from CH2Cl2. The enanti-
omers were resolved on a Pirkle type 1A chiral column (3 mL/
min, 1.5% 2-propanol/light petroleum). A sample of 13 (40 mg)

3046 J . Org. Chem., Vol. 65, No. 10, 2000
Kimber et al.
was dissolved in dichloromethane (approximately 1.0 mL) and
this solution was injected in 30 µL portions. Dione (+)-13, the
(5R,11R) isomer, eluted first (8.3 mg, 99.8% pure), retention
ether. Recrystallization from DMF affforded the title compound
18 as a yellow crystalline solid (503 mg, 75%): mp >300 °C;
1
IR (Nujol) 1695, 1601, 1510, 1442, 1250, 1205 cm-1; H NMR
time 22 min, [R]22 ) +430 (c 0.13, CH3CN); followed by (-)-
(200 MHz, d6-DMSO/CDCl3) δ 8.53 (2H, d, J ) 2.5 Hz), 8.36
(2H, dd, J ) 2.5, 8.4 Hz), 7.76 (2H, d, J ) 8.4 Hz), 4.30 (2H,
m), 3.05 (2H, m); UV λmax (CHCl3) 375 (ꢀ 790), 358 (1395), 329
(1844), 344 (2072), 265 (sh) (25766), 248 (37048); CIMS m/z
338 (MH+, 100), 292 (23). Anal. Calcd for C17H10N2O6,: C,
60.36; H, 2.98; N, 8.28. Found: C, 60.21; H, 2.71; N, 8.30.
Crystals suitable for X-ray diffraction were obtained by re-
crystallization from DMF.
D
13, the (5S,11S) isomer, (8.7 mg, 93.5% pure), retention time
23.5 min.
Gen er a l Meth od for Su zu k i Cou p lin gs. Dione 13 (101
mg, 0.25 mmol), the aryl boronic acid (0.54 mmol), Na2CO3
(78 mg, 0.74 mmol), and PdCl2(PPh3)2 (7 mg, 0.001 mmol) in
DME (5 mL) and H2O (1 mL) were refluxed at 80 °C for 16 h
under an atmosphere of nitrogen. The reaction was cooled and
the reaction partitioned between CH2Cl2 and water. The
aqueous layer was extracted with CH2Cl2, the combined
organic layers were dried over anhydrous sodium sulfate, and
the solvent was removed to give the crude product, which was
purified by chromatography on silica gel eluting with CH2Cl2.
In this way, the following compounds were obtained.
(()-2,8-Dip h en yld iben zobicyclo[b,f][3.3.1]n on a -5a ,6a -
d ien e-6,12-d ion e 14. Chromatography (Rf 0.22, CH2Cl2)
yielded the title compound as a white crystalline solid (95 mg,
(()-2,8-Dim eth yl-1,7-d in itr od iben zobicyclo[b,f][3.3.1]-
n on a -5a ,6a -d ien e-6,12-d ion e 22. Dione 12 (200 mg, 0.724
mmol) was dissolved in H2SO4 (10 mL) and stirred at 0 °C
while KNO3 (366 mg, 3.619 mmol) was added in portions over
30 min. The solution was stirred at room temperature for 16
h. The mixture was poured onto ice and the white precipitate
collected and washed successively with cold water and diethyl
ether. The resultant solid was recrystallized from DMF to yield
the title compound 22 as white plates (162 mg, 61%): mp >300
96%): mp 259-261 °C; IR (Nujol) 1690 cm-1; H NMR (200
°C; IR (Nujol) 1695, 1610, 1525, 1282, 1205 cm-1 1H NMR
;
1
MHz, CDCl3) δ 8.22 (2H, d, J ) 2.0 Hz), 7.75 (2H, dd, J ) 2.0,
8.0 Hz), 7.58-7.53 (6H, m), 7.46-7.34 (6H, m), 4.10 (2H, m),
3.06 (2H, m); UV λmax (CHCl3) 371 (ꢀ 1156), 358 (2814), 327
(3198), 342 (3677), 255 (58952); CIMS m/z 400 (MH+, 100).
Anal. Calcd for C29H20O2: C, 86.98; H, 5.03. Found: C, 86.96;
H, 4.95.
(200 MHz, d6-DMSO): δ 7.78 (2H, d, J ) 8.0 Hz), 7.57 (2H, d,
J ) 8.0 Hz), 4.13 (2H, m), 3.03 (2H, m), 2.15 (6H, s); UV λmax
(CHCl3) 377 (ꢀ 269), 359 (927), 343 (1350), 329 (1491), 310
(3418), 254 (sh) (20513), 248 (22766); CIMS m/z 366 (MH+,
40), 318 (65). Anal. Calcd for C19H14N2O6: C, 62.30; H, 3.85;
N, 7.65. Found: C, 62.09; H, 3.73; N, 7.67.
(()-2,8-Bisa cet a m id ob isa cet oxyd ib en zob icyclo[b,f]-
[3.3.1]n on a -5a ,6a -d ien e 20. Dinitro dione 18 (100 mg, 0.29
mmol) was stirred in methanol (75 mL) under an atmosphere
of H2 in the presence of palladium-on-charcoal catalyst (10%,
5 mg) for 16 h. The solution was filtered through Celite and
the methanol removed under reduced pressure to yield a
colorless oil containing the crude amine 19. The oil was
dissolved in dry pyridine (5 mL) and cooled to 0 °C under a
nitrogen atmosphere while acetyl chloride was added (90 µL,
1.15 mmol). The solution was stirred overnight at room
temperature for 16 h and poured onto water (5.0 mL) and the
aqueous layer extracted with CH2Cl2. The resultant organic
layers were combined, washed with HCl (1 M, 70 mL), and
dried over anhydrous sodium sulfate, and the solvent was
removed to yield the title compound as a beige solid (100 mg,
(()-2,8-Bis(o-m eth oxyp h en yl)d iben zobicyclo[b,f][3.3.1]-
n on a -5a ,6a -d ien e-6,12-d ion e 15. Chromatography (Rf 0.55,
CH2Cl2) yielded the title compound as a white solid (110 mg,
1
97%): mp 103-105 °C; IR (Nujol) 1690 cm-1; H NMR (200
MHz, CDCl3) δ 8.13 (2H, d, J ) 2.0 Hz), 7.71 (2H, dd, J ) 2.0,
8.0 Hz), 7.50 (2H, d, J ) 8.0 Hz), 7.24-7.36 (2H, m), 6.93-
7.04 (4H, m), 4.06 (2H, m), 3.79 (6H, s), 3.02 (2H, m); UV λmax
(CHCl3) 372 (sh) (ꢀ 1168), 353 (2995), 341 (3473), 295 (sh)
(12844), 254 (44855); CIMS m/z 460 (MH+, 100), 354 (83). Anal.
Calcd for C31H24O4: C, 80.85; H, 5.25. Found: C, 80.65; H,
5.43.
(()-2,8-Bis(p-m eth oxyp h en yl)d iben zobicyclo[b,f][3.3.1]-
n on a -5a ,6a -d ien e-6,12-d ion e 16. Chromatography (Rf 0.59,
CH2Cl2) yielded the title compound as a white solid (105 mg,
1
93%): mp 248-250 °C; IR (Nujol) 1690 cm-1; H NMR (200
77%): mp >300 °C; IR (Nujol) 3410, 1735, 1675, 1620 cm-1
;
MHz, CDCl3) δ 8.15 (2H, d, J ) 2.2 Hz), 7.71 (2H, dd, J ) 2.2,
8.2 Hz), 7.51 (2H, d, J ) 8.2 Hz), 7.47 (4H, m), 6.93 (4H, m),
4.06 (2H, m), 3.82 (6H, s), 3.03 (2H, m); UV λmax (CHCl3) 370
(sh) (ꢀ 3000), 343 (4928), 358 (5246), 292 (sh) (24197), 264
(52677); CIMS m/z 460 (MH+, 42), 354 (18). Anal. Calcd for
1H NMR (200 MHz, d6-DMSO) δ 9.72 (2H, s), 7.45 (2H, dd, J
) 2.2, 8.4 Hz), 7.28 (2H, d, J ) 2.4 Hz), 6.91 (2H, d, J ) 8.4
Hz), 6.09 (2H, d, J ) 5.2 Hz), 3.31 (2H, m), 2.35 (2H, m), 2.15
(6H, s), 1.95 (6H, s); UV λmax (CHCl3) 290 (sh) (ꢀ 2385), 282
(sh) (3426), 249 (32078); CIMS m/z 450 (MH+, 100); HRMS
calcd for C25H26O6N2 450.1791, found 450.1799. Anal. Calcd
for C25H26N2O6‚H2O: C, 64.09; H, 6.02; N, 5.98. Found: C,
64.21; H, 5.87; N, 5.84.
C
31H24O4: C, 80.85; H, 5.25. Found: C, 80.95; H, 5.17. Crystals
suitable for X-ray diffraction were obtained by recrystallization
from CH2Cl2.
(()-2,8-Bisa cetylen ed iben zobicyclo[b,f][3.3.1]n on a -5a ,-
6a -d ien e-6,12-d ion e 17. Dione 13 (300 mg, 0.739 mmol),
trimethylsilylacetylene (726 mg, 7.39 mmol), PdCl2(PPh3)2 (52
mg, 0.074 mmol), and CuI (7 mg, 0.04 mmol) were heated to
60 °C in dry triethylamine (25 mL) under N2 for 3 days. The
reaction was cooled, the solvent removed, and the residue
dissolved in methanol (10 mL) and stirred with KOH (10%,
10 mL) for 3 h. The reaction was extracted with CH2Cl2, the
organic layers were combined and dried, and the solvent was
removed to give the crude product. Purification by chroma-
tography (Rf 0.45, CH2Cl2) afforded the title compound 17 as
a white solid (165 mg, 75%): mp 210-214 °C dec; IR (Nujol)
1675 cm-1; 1H NMR (200 MHz, CDCl3): δ 8.07 (2H, d, J ) 1.6
Hz). 7.61 (2H, dd, J ) 1.7, 8.0 Hz), 7.42 (2H, d, J ) 8.0 Hz),
4.02 (2H, m), 3.10 (2H, s), 2.98 (2H, m); UV λmax (CHCl3) 358-
(ꢀ 256), 341(1219), 310(4334), 270(sh) (11089), 244(66984);
CIMS m/z 296 (MH+, 100), 269 (50). Anal. Calcd for C21H12O2:
C, 85.12; H, 4.08. Found: C, 84.89; H, 4.07.
(()-2,8-Dia m in od ib en zob icyclo[b,f][3.3.1]n on a -5a ,6a -
d ien e-6,12-d ion e 21. Dinitro dione 18 (250 mg, 0.739 mmol),
iron powder (295 mg, 5.2 mmol), acetic acid (0.60 mL, 10.346
mmol), and ethanol (20 mL) were refluxed under an nitrogen
atmosphere for 6 h. The reaction was poured onto water and
the aqueous layer extracted with CH2Cl2. The combined
organic extracts were washed with NaHCO3 and dried over
anhydrous sodium sulfate, and the solvent was removed to give
the title compound 21 as a yellow solid (192 mg, 93%): mp
288-291 °C; IR (Nujol) 3450, 3340, 1682, 1645, 1620 cm-1
;
1H NMR (200 MHz, d6-acetone), 7.13 (2H, d, J ) 2.6 Hz), 7.08
(2H, d, J ) 8.3 Hz), 6.84 (2H, dd, J ) 2.6, 8.3 Hz), 3.71 (2H,
m), 2.86 (2H, m), 2.77 (4H, s); UV λmax (CHCl3) 358 (ꢀ 4614),
345 (4756), 244 (34796); CIMS m/z 278 (MH+, 71); HRMS calcd
for C17H14N2O2 (M•+) 278.1055, found 278.1058.
Ack n ow led gm en t. Financial support from the Aus-
tralian Research Council is acknowledged (M.M.H).
(()-2,8-Din itr od iben zobicyclo[b,f][3.3.1]n on a -5a ,6a -d i-
en e-6,12-d ion e 18. Dione 239 (500 mg, 2.014 mmol) was
dissolved in H2SO4 (15 mL) and stirred at 0 °C while KNO3
(1.02 g, 10.1 mmol) was added in portions over 30 min. The
solution was stirred at room temperature for 16 h. The mixture
was poured onto ice and the white precipitate collected by
filtration and washed successively with cold water and diethyl
Su p p or tin g In for m a tion Ava ila ble: Details of the X-ray
analyses of compounds 12, 13, 16, 18, and 22 are in available
in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O991741P