Synthesis, resolution, and VCD analysis of an enantiopure diazaoxatricornan derivative

Article abstract of DOI:10.1021/ja800262j

Using simple organic synthetic transformations, a novel diazaoxatricornan derivative, the 12c-methyl-12-phenyl-8-propyl-12,12c-dihydro-8H-4-oxa-8,12- diazadibenzo[cd,mn]pyrene (6a), was prepared. This novel chiral cup-shaped molecule was isolated in racemic form and in excellent yield after the addition of methyl lithium to the BF₄ salt of a novel unsymmetrical diazaoxatriangulenium cation. Compound 6a was found to be stable under classical laboratory conditions - something not obvious considering the extreme stability of the carbenium ion precursor, the electron-rich nature of the core, and the strain induced by the pyramidalization of the central carbon. The enantiomers were readily separated by chiral stationary phase chromatography, and the absolute configuration of (-)-(S)-6a was determined by a comparison of the experimental and theoretical vibrational circular dichroism (VCD) spectra. This isolation of (-)-(S)-6a and (+)-(R)-6a constitutes thus the first report of a nonracemic closed-capped chiral bowl molecule for which the chirality is due to the intrinsic dissymmetry of the central core of the structure only.

Full text of DOI:10.1021/ja800262j

Published on Web 04/16/2008
Synthesis, Resolution, and VCD Analysis of an Enantiopure
Diazaoxatricornan Derivative
Pierre Mobian,† Cyril Nicolas,† Eric Francotte,*,‡ Thomas Bu¨rgi,*,§ and
Je´roˆme Lacour*,†
Department of Organic Chemistry, UniVersity of GeneVa, 30 Quai Ernest-Ansermet,
CH-1211 GeneVa 4, Switzerland, Global DiscoVery Chemistry, NoVartis Institutes for Biomedical
Research, WKL-122.P.25 Postfach, CH-4002 Basel, Switzerland, and Institute of
Microtechnology, UniVersity of Neuchaˆtel, 11, Rue Emile-Argand, 158 Postfach,
CH-2009 Neuchaˆtel, Switzerland
Received January 14, 2008; E-mail: jerome.lacour@chiorg.unige.ch; eric.francotte@novartis.com; thomas.burgi@unine.ch
Abstract: Using simple organic synthetic transformations, a novel diazaoxatricornan derivative, the 12c-
methyl-12-phenyl-8-propyl-12,12c-dihydro-8H-4-oxa-8,12-diazadibenzo[cd,mn]pyrene (6a), was prepared.
This novel chiral cup-shaped molecule was isolated in racemic form and in excellent yield after the addition
of methyl lithium to the BF4 salt of a novel unsymmetrical diazaoxatriangulenium cation. Compound 6a
was found to be stable under classical laboratory conditions—something not obvious considering the ex-
treme stability of the carbenium ion precursor, the electron-rich nature of the core, and the strain induced
by the pyramidalization of the central carbon. The enantiomers were readily separated by chiral stationary
phase chromatography, and the absolute configuration of (-)-(S)-6a was determined by a comparison of
the experimental and theoretical vibrational circular dichroism (VCD) spectra. This isolation of (-)-(S)-6a
and (+)-(R)-6a constitutes thus the first report of a nonracemic closed-capped chiral bowl molecule for
which the chirality is due to the intrinsic dissymmetry of the central core of the structure only.
resolution.4–6 In this context, the isolation of an enantiopure
closed-capped bowl-shaped molecule would be an important
novelty, with the synthesis, resolution, and absolute configu-
ration assignment of the nonracemic structure being possibly a
challenging task.
Introduction
Construction of fully ring-closed polycyclic structures dis-
torted from planarity have long been regarded as remarkable
synthetic targets.1 These bowl-shaped molecules can exhibit
unusual molecular properties and/or abnormal chemical behav-
iors.1,2 Some of the edifices are potential intermediates for the
generation of fullerenes, carbon nanotubes, and other artificial
bent structures and receptors.1,3 To our knowledge, most of the
reported structures are achiral. The few chiral fully fused
polycyclic derivatives have been characterized in racemic form
only owing to their configurational lability or to a lack of
Previously, Siegel et al. have reported the synthesis of
trioxatricornan derivatives that constitute an interesting class
(3) (a) Mehta, G.; Rao, H. S. P. AdV. Strain Org. Chem. 1997, 6, 139–
187. (b) Mehta, G.; Rao, H. S. P. Tetrahedron 1998, 54, 13325–13370.
(c) Scott, L. T. Angew. Chem., Int. Ed. 2004, 43, 4994–5007. (d)
Tsefrikas, V. M.; Scott, L. T. Chem. ReV. 2006, 106, 4868–4884. (e)
Perez, E. M.; Sierra, M.; Sanchez, L.; Torres, M. R.; Viruela, R.;
Viruela, P. M.; Orti, E.; Martin, N. Angew. Chem., Int. Ed. 2007, 46,
1847–1851. (f) Sygula, A.; Fronczek, F. R.; Sygula, R.; Rabideau,
P. W.; Olmstead, M. M. J. Am. Chem. Soc. 2007, 129, 3842–3843.
(g) Hayama, T.; Wu, Y.-T.; Linden, A.; Baldridge, K. K.; Siegel, J. S.
J. Am. Chem. Soc. 2007, 129, 12612–12613.
† University of Geneva.
‡ Novartis Institutes for Biomedical Research.
§ University of Neuchaˆtel.
(1) (a) Kuck, D. Chem. ReV. 2006, 106, 4885–4925. (b) Makha, M.; Purich,
A.; Raston, C. L.; Sobolev, A. N. Eur. J. Inorg. Chem. 2006, 507–
517. (c) Sygula, A.; Rabideau, P. W. In Carbon-Rich Compounds:
From Molecules to Materials; Haley, M. M., Tykwinski, R. R., Eds.;
Wiley-VCH: Weinheim, Germany, 2006; pp 529-565. (d) Wu, J.;
Mu¨llen, K. In Carbon-Rich Compounds: From Molecules to Materials;
Haley, M. M., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim,
Germany, 2006; pp 90-139. (e) Wu, Y.-T.; Siegel, J. S. Chem. ReV.
2006, 106, 4843–4867. (f) Xu, Z. Coord. Chem. ReV. 2006, 250, 2745–
2757. (g) Amaya, T.; Mori, K.; Wu, H.-L.; Ishida, S.; Nakamura, J.-
i.; Murata, K.; Hirao, T. Chem. Commun. 2007, 1902–1904. (h)
Kawase, T. Synlett 2007, 2609–2626.
(4) In this study, we are only considering fully ring-closed polycyclic
structures devoid of preexisting stereogenic centers or elements. For
examples of such molecules, see: (a) Na, J. E.; Lee, K. Y.; Seo, J.;
Kim, J. N. Tetrahedron Lett. 2005, 46, 4505–4508. (b) Mascal, M. J.
Org. Chem. 2007, 72, 4323–4327. (c) Mori, T.; Grimme, S.; Inoue,
Y. J. Org. Chem. 2007, 72, 6998–7010. (d) Song, Q. L.; Ho, D. M.;
Pascal, R. A. J. Org. Chem. 2007, 72, 4449–4453.
(5) (a) Sygula, A.; Rabideau, P. W. J. Chem. Soc., Chem. Commun. 1994,
1497–1499. (b) Biedermann, P. U.; Pogodin, S.; Agranat, I. J. Org.
Chem. 1999, 64, 3655–3662. (c) Priyakumar, U. D.; Sastry, G. N. J.
Org. Chem. 2001, 66, 6523–6530. (d) Priyakumar, U. D.; Sastry, G. N.
J. Phys. Chem. A 2001, 105, 4488–4494. (e) Seiders, T. J.; Baldridge,
K. K.; Grube, G. H.; Siegel, J. S. J. Am. Chem. Soc. 2001, 123, 517–
525. (f) Narahari Sastry, G. THEOCHEM 2006, 771, 141–147. (g)
Wang, Y.; Stretton, A. D.; McConnell, M. C.; Wood, P. A.; Parsons,
S.; Henry, J. B.; Mount, A. R.; Galow, T. H. J. Am. Chem. Soc. 2007,
129, 13193–13200.
(2) (a) Aprahamian, I.; Eisenberg, D.; Hoffman, R. E.; Sternfeld, T.;
Matsuo, Y.; Jackson, E. A.; Nakamura, E.; Scott, L. T.; Sheradsky,
T.; Rabinovitz, M. J. Am. Chem. Soc. 2005, 127, 9581–9587. (b)
Petrukhina, M. A.; Scott, L. T. Dalton Trans. 2005, 2969–2975. (c)
Kawase, T.; Kurata, H. Chem. ReV. 2006, 106, 5250–5273. (d) Jackson,
E. A.; Steinberg, B. D.; Bancu, M.; Wakamiya, A.; Scott, L. T. J. Am.
Chem. Soc. 2007, 129, 484–485. (e) Mack, J.; Vogel, P.; Jones, D.;
Kaval, N.; Sutton, A. Org. Biomol. Chem. 2007, 5, 2448–2452.
(6) Lofthagen, M.; Vernonclark, R.; Baldridge, K. K.; Siegel, J. S. J. Org.
Chem. 1992, 57, 61–69.
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2008 American Chemical Society
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A R T I C L E S
Mobian et al.
However, close examination of the known properties of these
carbenium ions 5 was raising several issues about the feasibility
of the project. First of all, it was debatable whether these highly
stable carbenium ions (pKR+ 19.4 for 5 vs 9.1 for 1) would be
electrophilic enough to react with hydride or organometallic
reagents and afford products of type 6, diazaoxatricornan
derivatives. Then, if possible, it was unclear whether these
compounds 6 would actually be stable under air (oxidative) and
moisture conditions, with the very electron-rich nature of the
core favoring possible electron transfer and/or ionic decomposi-
tion pathways.10 Finally, it was uncertain whether two different
nitrogen substituents could be introduced at the periphery of 6
(e.g., Figure 2, R1 * R2),11 with this condition being an absolute
must for the creation of a central stereogenic sp3 center upon
the addition of the nucleophilic reagent. Herein, we report that
chiral compounds of type 6 can indeed be made as we detail
the synthesis, resolution, and vibrational circular dichroism
(VCD) analysis of a quasi-enantiopure diazaoxatricornan deriva-
tive (6a, Figure 2, R′ ) Me, R1 ) Ph, R2 ) n-Pr), with
compound 6 being furthermore the first nonracemic closed-
capped chiral bowl molecule for which the chirality is due to
the intrinsic dissymmetry of the central core only.
Figure 1. Trioxatriangulenium cation 1 and trioxatricornan derivatives 2, 3,
and 4. R ) H, tBu; R′ ) Me, vinyl, allyl, CH2COCH3; X ) NO2, Br, SiMe3.
of polyaromatic molecular cavities useful for the construction
of macrocyclic cages. The synthesis of these organic building
blocks is straightforward, versatile, and can be achieved on a
large scale through the simple addition of a hydride or an
organometallic reagent to salts of trioxatriangulenium cations
of type 1. Typical examples are compounds 2 detailed in Figure
1 (R ) H, t-Bu; R′ ) H, alkyl, allyl, vinyl, etc.).6,7
Results and Discussion
Such trioxatricornans are achiral by virtue of the symmetrical
distribution of the substituents at the periphery of the core
structure. However, any unsymmetrical pattern for functional
groups or side chains at the exterior of the molecule creates a
dissymmetry and the occurrence of molecular chirality. Regio-
isomeric derivatives 3 and 4 (Figure 1), prepared by electrophilic
substitution reactions onto compounds of type 2 (R ) H, R′ )
Me), are two typical examples of chiral analogues with C1- and
C3-symmetry, respectively. To the best of our knowledge,
compounds of type 3 and 4 have only been reported in racemic
form.
Recently, Laursen and Krebs have shown that nitrogen
analogues of the trioxatriangulenium cation 1 can also be readily
prepared and, for the interest of this study, diazaoxatriangule-
nium cations 5 in particular (Figure 2, R1 ) R2 ) n-Pr, n-Hex,
n-Oct).8,9 This novel family of carbenium ions, featuring both
aza and oxa bridge(s), have been studied for their photochemical
and photophysical properties. Their global chemical reactivity
is, however, undocumented. In terms of chirality, it occurred
to us that these planar achiral derivatives could actually
constitute an interesting platform for the formation of novel
closed-capped chiral bowl molecules. In fact, any addition of a
nucleophile to the central sp2 carbon of an unsymmetrical
diazaoxatriangulenium cation (5, R1 * R2) would generate a
curved diazaoxatricornan derivative that would be chiral due
to the symmetry-breaking presence of the different nitrogen
substituents.
Choice of a Target. Having decided that the target of the study
would be a chiral compound of type 6, the next task was the
choice of the substituents R′, R1, and R2 taking in consideration
the need for (1) two different substituents on the N atoms, (2)
apical and lateral side chains with minimal degrees of freedom
(to help the VCD characterization of the product), and (3)
efficient conditions to separate the enantiomers of the target
after its synthesis in racemic form. As just mentioned, diaza-
oxatricornan derivative 6a was chosen, and the selection process
of the three groups R′, R1, and R2 is detailed below.
First, it was decided to introduce a methyl as the apical group
R′. This alkyl group is devoid of any conformational issue and
possibly easily introduced as the last step of the synthesis by
nucleophilic addition of methyl Grignard or methyl lithium to
the central carbon of an appropriate diazaoxatriangulenium
precursor of type 5 (Figure 2 and Scheme 1). Next, a phenyl
group was selected as substituent R1, as the planar rigid nature
of this group was also fitting the second selection rule. In terms
of synthesis, its incorporation into the global framework was
considered to be trivial, as literature precedents indicated that
anilines react at elevated temperature with salts of the tris(2,6-
dimethoxyphenyl)carbenium ion 7 to afford in good yields aryl-
substituted acridinium derivatives of type 8 (vide infra,
Scheme 1).12
The choice of a n-propyl group as the final substituent R2
was straightforward. In terms of synthesis, it was quite clear
that only an aliphatic amine would react with an acridinium
moiety of type 8;8,12 the formation of the second nitrogen bridge
requires forcing conditions and nucleophilic amines (25 equiv,
110 °C, NMP). The n-propyl group was then selected for its
good literature precedents as nucleophile in this type of ring
(7) (a) Lofthagen, M.; Chadha, R.; Siegel, J. S. J. Am. Chem. Soc. 1991,
113, 8785–8790. (b) Lofthagen, M.; Siegel, J. S. J. Org. Chem. 1995,
60, 2885–2890. (c) Lofthagen, M.; Siegel, J. S.; Hackett, M.
Tetrahedron 1995, 51, 6195–6208.
(8) Laursen, B. W.; Krebs, F. C. Chem.—Eur. J. 2001, 7, 1773–1783.
(9) Compound 5 belongs to a whole family of novel stable carbenium
ions: (a) Laursen, B. W.; Krebs, F. C.; Nielsen, M. F.; Bechgaard,
K.; Christensen, J. B.; Harrit, N J. Am. Chem. Soc. 1998, 120, 12255–
12263. (b) Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. 2000,
39, 3432–3434. (c) Herse, C.; Bas, D.; Krebs, F. C.; Bu¨rgi, T.; Weber,
J.; Wesolowski, T.; Laursen, B. W.; Lacour, J. Angew. Chem., Int.
Ed. 2003, 42, 3162–3166. (d) Laursen, B. W.; Reynisson, J.;
Mikkelsen, K. V.; Bechgaard, K.; Harrit, N. Photochem. Photobiol.
Sci. 2005, 4, 568–576.
(10) Cations 5 are, most probably, strong electrofugal groups: (a) Laleu,
B.; Mobian, P.; Herse, C.; Laursen, B. W.; Hopfgartner, G.; Bernar-
dinelli, G.; Lacour, J. Angew. Chem., Int. Ed. 2005, 44, 1879–1883.
(b) Laleu, B.; Machado, M. S.; Lacour, J. Chem. Commun. 2006, 2786–
2788.
(11) Only symmetrical diazaoxatriangulenium derivatives with the same
substituents on the nitrogen atoms have been reported so far.
(12) Krebs, F. C. Tetrahedron Lett. 2003, 44, 17–21.
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Analysis of an Enantiopure Diazaoxatricornan Derivative
A R T I C L E S
Figure 2. Diazaoxatriangulenium cations 5 (R1 ) R2 ) n-Pr, n-Hex, n-Oct) and chiral diazaoxatricornan derivatives 6 (R′, R1 * R2).
Scheme 1a
a Conditions: (a) PhNH2 (22 equiv), NMP, 120 °C, 1.5 h, 95%; (b) n-PrNH2 (25 equiv), NMP, 110 °C, 2.5 h, 45%; (c) LiI (100 equiv), NMP, 180 °C,
1.5 h, 65%; (d) MeLi (1.3 equiv), THF, 20 °C, 16 h, 97%.
closure and despite a high probability of an occurrence of several
conformers in the final product, with the second aza ring closure
being deemed easier to perform with higher boiling n-PrNH2
than gaseous MeNH2.
Synthesis and Basic Optical Properties. With the selection
of substituents made, the synthesis was started. First, purple
tris(2,6-dimethoxyphenyl)carbenium tetrafluoroborate salt [7]-
[BF4] was synthesized using a procedure similar to that reported
by Wada et al.13 Then treatment of [7][BF4] with aniline (22
equiv, NMP, 120 °C) gave the red acridinium salt [8][BF4] in
an excellent yield (95%).12 After that, following classical
conditions,8 [8][BF4] was reacted with n-propylamine (25 equiv,
NMP, 110 °C) to afford the green quinacridinium salt [9][BF4],
albeit in modest yield (45%).14 Finally, conversion of [9][BF4]
into the hexacyclic diazaoxatriangulenium salt [5a][BF4] was
Figure 3. Absorption spectra of compounds [8][BF4] (black), [9][BF4]
achieved by reaction with LiI (NMP, 180 °C, 65% yield).
Subsequent addition of MeLi resulted in the formation of desired
(green), and [5a][BF4] (red) (CH2Cl2, 10-4 mol·L-1).
diazaoxatricornan 6a in racemic form and excellent yield (97%).
All the steps and compounds are detailed in Scheme 1.
Enantiomeric Chromatographic Separation on Chiral Sta-
tionary Phases. With targeted compound rac-6a in hand, we
Not surprinsingly, novel salts [8][BF4], [9][BF4], and [5a]-
turned our attention to its enantiomeric resolution. Preparative
[BF4] are also colorful dyes, and their electronic absorption
chromatographic resolution on chiral stationary phases is now
spectra are reported in the Supporting Information and as a brief
recognized as a very powerful and general method to separate
preview in Figure 3 (CH2Cl2, 10-4 mol·L-1).
and isolate enantiomers of racemic compounds in good yield
and high optical purity.15,16 This approach was applied to rac-
(13) Wada, M.; Mishima, H.; Watanabe, T.; Natsume, S.; Konishi, H.;
6a to gain the single pure enantiomers. In order to perform the
preparative resolution of rac-6a, we first developed an appropri-
ate separation method by screening a number of chiral stationary
phases with different mobile phase mixtures. Most of these chiral
Kirishima, K.; Hayase, S.; Erabi, T. Bull. Chem. Soc. Jpn. 1995, 68,
243–249.
(14) The relative low yield might be due to an aerobic photooxidative
decomposition of n-PrNH2 catalyzed by acridinium salt [8][BF4]. For
examples, see: (a) Shinkai, S.; Hamada, H.; Kuroda, H.; Manabe, O.
J. Org. Chem. 1981, 46, 2333–2338. (b) Nicolas, C.; Herse, C.; Lacour,
J. Tetrahedron Lett. 2005, 46, 4605–4608. (c) Ohkubo, K.; Nanjo,
T.; Fukuzumi, S. Bull. Chem. Soc. Jpn. 2006, 79, 1489-1500, and
references therein.
(15) Francotte, E. R. J. Chromatogr. A 2001, 906, 379–397.
(16) Cox, G. J. PreparatiVe EnantioselectiVe Chromatography, 1st ed.;
Blackwell Publishing: Ames, IA, 2005.
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A R T I C L E S
Mobian et al.
Figure 4. Analytical chromatographic resolution of rac-6a on (a) Chiralcel OJ-H, n-hexane/methanol 995:5, 0.5 mL ·min-1, 23 °C, λ ) 254 nm and (b)
Chiralpak AD-H, n-hexane/2-propanol 995:5, 1 mL ·min-1, 23 °C, λ ) 254 nm.
stationary phases were based on polysaccharide derivatives and
are commercially available. A good separation could be achieved
on the cellulose-based phase Chiralcel OJ using a mixture of
hexane/methanol 995:5 (volume) and on the amylose-based
phase Chiralpak AD using a mixture of hexane/2-propanol 995:5
(volume) (Figure 4).17
However, because the separation factor was much higher on
Chiralcel OJ (2.49 compared to 1.23 on Chiralpak AD), the
preparative separation was performed on the cellulose-based
phase. For that purpose, a larger (25 mm × 250 mm) in-house
packed column containing Chiralcel OJ was employed and the
same mobile phase mixture was applied. As the solubility of
the racemate 6a was very poor in the mobile phase (about
0.02%), the separation of 70 mg had to be carried out by
repetitive injections which were all fractionated in three major
Figure 5. Electronic absorption spectrum of 6a (black, bottom) and ECD
fractions. After pooling of the corresponding fractions from the
multiple injections, they were evaporated to dryness. Fractions
1 and 3, which contained highly enriched amounts of the first
spectra (top) of the most (blue) and least (red) eluted fractions (CH2Cl2,
10-4 mol·L-1), (+)-6a and (-)-6a, respectively.
and last eluting enantiomers, respectively, were redissolved in
The two enantiomers were obtained on preparative scale in very
the applied mobile phase and reinjected on the same column
high enantiomeric purity. From a batch of 70 mg of racemic
(Chiralcel OJ) to afford, after fractionation and evaporation, the
6a, two separated fractions were afforded in good yields, 26
desired enantiomers in high enantiomeric excesses. Interestingly,
mg (99.2% ee) and 19 mg (98.1% ee) for the first and second
the optically enriched materials obtained after the first chro-
eluted fractions, respectively. These fractions correspond to (+)-
matographic run are very soluble in the applied mobile phase.
6a and (-)-6a as indicated by the specific optical rotation values,
In summary, the two enantiomers could be separated analyti-
[R]20 ) +16.1 and -13.2 (CH2Cl2, c ) 0.1 g/100 mL),
D
cally by chromatography on chiral stationary phases (Figure 4).
respectively.
Electronic circular dichroism (ECD) spectra of these most
(17) The unusual peak shape and elution profile on Chiralcel OJ (Figure
and least eluted compounds displayed totally symmetrical curves
in the 250-350 nm region. The spectra are reported in Figure
5. At the lowest energy, positive and negative Cotton effects
(∆ꢀ328 ) +5.5 and -5.2) are observed for (+)-6a and (-)-6a,
respectively. If one follows the spectrum of one of the separated
4, top trace) of the enantiomers of 6a is a known phenomenon in
enantioselective chromatography and has been observed in some
instances in our laboratories and other research groups. Although we
have no clear explanation for this feature, it indicates that both
enantiomers exhibit quite different adsorption kinetics, suggesting that
they interact with different sites within the chiral polymer matrix.
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Analysis of an Enantiopure Diazaoxatricornan Derivative
A R T I C L E S
(S)-6a enantiomer.21 Prior to the calculation of VCD spectra,
we searched for the conformations of the molecule (vide infra,
Figure 7).
The tricornan skeleton is rigid and does not bring confor-
mational degrees of freedom. Also, concerning the phenyl
residue of the nitrogen-bridging atom in position 4, there is only
one possible conformation. Due to steric repulsion between the
diazaoxatricornan protons H3 and H5 and o,o′-protons of aniline,
the phenyl residue is perpendicular to the tricornan system.
Finally, concerning the linear propyl chain, there are two
important degrees of freedom corresponding to two dihedral
angles centered around the N-C and a C-C bond. This entails
overall 3 × 3 ) 9 plausible conformers. Two are unstable and
seven have energies according to the calculations, ranging from
0.0 to 2.91 kcal ·mol-1
.
Figure 6. VCD spectra of the most (first, blue) and least (second, red)
eluted fractions of 6a. The spectra were measured in CD2Cl2 at a
concentration of 11.3 mg/mL. Some parts of the spectra are missing due to
strong solvent absorption in these regions.
The most stable conformer (3, 0.0 kcal ·mol-1) is the one
where the propyl chain is in an antiperiplanar conformation and
points away from the tricornan skeleton. Then, IR and VCD of
all nine conformers were calculated.22 Figure 8 compares
calculated IR and VCD spectra of conformer 3 and of a
Boltzmann distribution of all stable conformers.
enantiomers, then a series of sequentially opposite Cotton effects
can be observed from 250 to 350 nm. Whereas the ꢀ/∆ꢀ ratio
is rather large at the highest energy and near the maximum of
the electronic absorption (ꢀ/∆ꢀ287 ∼ 20 000), a more classical
ratio is obtained around 328 nm (ꢀ/∆ꢀ ∼ 1000).
It revealed that only minor differences between VCD and IR
spectra of the Boltzmann average and conformer 3 were
observable due to the presence of the latter at 85% compared
to other conformers.
At last, comparison between simulated and experimental IR
and VCD spectra undoubtedly showed that the second eluted
(levoratory) fraction corresponds to (S)-6a enantiomer (vide
supra, Figures 9 and 10).23
Absolute Configuration Determination. Vibrational circular
dichroism (VCD) measures the tiny differences in absorption
of left and right circularly polarized infrared radiation by chiral
enantioenriched samples.18 The method is a sensitive probe of
chirality and was used in the past to determine the absolute
configuration of enantiomers and also the conformation of
molecules.19 VCD has become a valuable alternative tool for
absolute configuration determination especially in cases where
suitable single crystals cannot be grown for analysis by X-ray
crystallography. The structural information (absolute configu-
ration, conformation) contained in a VCD spectrum can be
extracted by comparison with spectra obtained from electronic
structure calculations. It has been demonstrated in the past that
VCD spectra calculated by density functional theory (DFT)
methods have predictive quality.20 This allows assignment of
the absolute configuration since enantiomers have mirror image
VCD spectra. A rather large variety of structurally different
chemical substances have been analyzed by VCD in the past.
To our knowledge, experimental and theoretical studies on
compounds similar to chiral tricornan derivative 6a have not
been reported to date.
Perspectives
Herein, using simple organic synthetic transformations, we
have reported the synthesis of a novel racemic diazaoxatricornan
derivative. The enantiomers of which were readily separated
by chiral stationary phase chromatography. The absolute con-
figuration of (-)-(S)-6a was determined by a comparison of
the experimental and theoretical VCD spectra. Many of the
chiroptical properties of compound 6a have been examined, and
apart from VCD, this compound has displayed rather strong
manifestations of molecular chirality. A posteriori, the initial
selection of Me, Ph, and n-Pr as substituents R′, R1, and R2
seems to have been ideal for the purposed study as it has allowed
us to establish the feasibility of the synthetic protocol, the
efficiency of CSP-HPLC as a resolution method, and the global
chemical stability of the chiral cup-like molecule 6a—things
that were not completely obvious at the start of the study. This
isolation of (-)-(S)-6a and (+)-(R)-6a constitutes thus the first
Figure 6 shows the VCD spectra of the enantiomers of 6a
separated by CSP HPLC. The measured signals are small, which
intuitively agrees with the fact that chirality is due to the intrinsic
dissymmetry of the central core of the structure only. The VCD
spectra of the two enantiomers are almost mirror images, and
deviations thereof are attributed mainly to noise.
In order to determine the absolute configuration of the
enantiomers in the two eluted fractions, DFT calculations at
the B3PW91,6-31G(d,p) level of theory were performed on the
(21) The CIP (Cahn-Ingold-Prelog) System has been used for the absolute
configuration assignment of the enantiomers of 6a. The prioritization
of the substituents around the central (and only) stereogenic quaternary
sp3 center has been performed according to the sequence rules detailed
in the following articles: (a) Cahn, R. S.; Ingold, C.; Prelog, V. Angew.
Chem., Int. Ed. Engl. 1966, 5, 385–415. (b) Prelog, V.; Helmchen, G.
Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583. In 6a, the three sp2
carbons adjacent to the central sp3 center are hierarchically ranked in
the following order (from the highest to the next lower rank) (i) the
sp2 carbon closer to the O atom and the NPh moiety, respectively,
then (ii) the carbon between the O atom and the NPr group, and finally
(iii) the carbon flanked by the NPh and NPr moities, with the apical
methyl group being the substituent with the lowest priority of all.
(22) IR and VCD spectra for all nine conformers of (S)-6a are reported in
the Supporting Information.
(18) (a) Nafie, L. A.; Keiderling, T. A.; Stephens, P. J. J. Am. Chem. Soc.
1976, 98, 2715–2723. (b) Stephens, P. J.; Lowe, M. A. Annu. ReV.
Phys. Chem. 1985, 36, 213–241.
(19) (a) Polavarapu, P. L.; Zhao, C.; Cholli, A.; Vernice, G. G. J. Phys.
Chem. B 1999, 103, 6127–6132. (b) Aamouche, A.; Devlin, F. J.;
Stephens, P. J. J. Am. Chem. Soc. 2000, 122, 7358–7367. (c) Freedman,
T. B.; Cao, X.; Dukor, R. K.; Nafie, L. A. Chirality 2003, 15, 743–
758. (d) Bu¨rgi, T.; Urakawa, U.; Behzadi, B.; Ernst, K.-H.; Baiker,
A. New J. Chem. 2004, 28, 332–334.
(23) Even if the agreement between calculated and experimental IR and
VCD spectra is not perfect, absolute configuration can be still
determined. Indeed, some characteristic bands such as modes 16,17,
21, 3, and 6 can be assigned without ambiguity.
(20) Devlin, F. J.; Stephens, P. J.; Cheeseman, J. R.; Frisch, M. J. J. Phys.
Chem. A 1997, 101, 9912–9924.
9
J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008 6511

A R T I C L E S
Mobian et al.
Figure 7. Structures and relative energies of possible conformers of enantiomer (S)-6a. All calculations were made at the B3PW91,6-31G(d,p) level of
theory by relaxing all degrees of freedom without constraint.
mL) afforded a green precipitate, which was filtered over a Bu¨chner
funnel, washed with water, several times with Et2O, and collected.
The title compound was further purified by (i) dissolution of crude
product in CH2Cl2 and (ii) selective precipitation by addition of
Et2O, affording the dimethoxyquinacridinium tetrafluoroborate salts
[9][BF4] (0.32 g, 44%): mp 332 °C; 1H NMR (CD3CN, 400 MHz)
δ ) 7.96 (m, 2H), 7.82 (m, 3H), 7.67 (t, J ) 8.1 Hz, 1H), 7.60-7.52
(br s, 1H), 7.54 (m, 2H), 7.48-7.40 (br s, 1H), 6.97 (d, J ) 8.1
Hz, 1H), 6.91 (d, J ) 7.8 Hz, 1H), 6.66 (d, J ) 8.3 Hz, 1H), 6.55
(d, J ) 8.8 Hz, 1H), 4.72-4.64 (m, 1H), 4.82-4.40 (m, 1H), 3.78
(s, 3H), 3.77 (s, 3H), 2.13-2.03 (m, 2H), 1.20 (t, J ) 7.3 Hz, 3H);
13C NMR (CD3CN, 100 MHz) δ ) 160.8 (C), 160.4 (C), 144.6
(C), 144.5 (C), 143.4 (C), 141.4 (C), 139.7 (C), 139.2 (C), 138.3
(CH), 137.5 (CH), 137.0 (CH), 131.5 (CH), 119.8 (C), 114.2 (C),
113.3 (C), 109.7 (CH), 108.6 (CH), 107.2 (CH), 106.0 (CH), 104.1
(CH), 104.0 (CH), 56.6 (CH3), 56.5 (CH3), 52.2 (CH2), 20.4 (CH2),
11.1 (CH3); 19F NMR (376 MHz, CD3CN) δ ) -151.7 (20%),
-151.8 (80%); UV/vis (CH2Cl2, 10-4 M, λmax (log ꢀ)) 624 (4.25),
580 (4.13), 446 (3.91); IR (neat) ν ) 2973, 2945, 2884, 2836, 1603,
1579, 1553, 1494, 1345, 1253, 1247, 1172, 1046, 1033, 814, 760
cm-1; MS m/z (ES) 401.3, 447.1; HRMS (ESI, m/z) calcd for
report of a nonracemic closed-capped chiral bowl molecule for
which the chirality is due only to the intrinsic dissymmetry of
the central core of the structure.
Materials and Methods
9-(2,6-Dimethoxyphenyl)-1,8-dimethoxy-10-phenylacridini-
um tetrafluoroborate salt or [8][BF4]. Compound [7][BF4] (0.72
g, 1.4 mmol) was dissolved in 1-methyl-2-pyrrolidone (NMP) (10
mL), and aniline (3 mL, 31 mmol) was added. The initially purple
reaction mixture was heated to 120 °C under dinitrogen atmosphere
for 1.5 h. After cooling to 25 °C, the crude mixture was poured
into ether (15 mL) and the resulting dark red precipitate was
collected by filtration over a Bu¨chner funnel. The title compound
was further purified by dissolution in acetone and selective
precipitation by addition of Et2O, affording the desired tetrafluo-
roborate salt [8][BF4] (0.73 g, 95%): mp 223 °C; 1H NMR (CD3CN,
400 MHz) δ ) 7.97 (d, J ) 7.8 Hz, 1H), 7.96 (d, J ) 8.1 Hz, 1H),
7.89 (t, J ) 3.3 Hz, 3H), 7.61 (m, 2H), 7.49 (t, J ) 8.6 Hz, 1H),
7.08 (d, J ) 8.1 Hz, 2H), 6.92 (d, J ) 9.1 Hz, 2H), 6.83 (d, J )
8.5 Hz, 2H), 3.62 (s, 6H), 3.58 (s, 6H); 13C NMR (CD3CN, 100
MHz) δ ) 160.2 (C), 155.8 (C), 143.0 (C), 139.5 (CH), 138.8 (C),
131.4 (CH), 131.4 (CH), 119.6 (C), 119.3 (C), 111.0 (C), 106.5
(C), 103.7 (C), 56.8 (CH3), 55.6 (CH); 19F NMR (282 MHz,
CD2Cl2) δ ) -151.5 (20%), -151.6 (80%); UV/vis (CH3CN, 10-4
M, λmax (log ꢀ)) 541 (3.65), 509 (3.7), 359 (3.56); IR (neat) ν )
2941, 2839, 1596, 1575, 1495, 1468, 1432, 1374, 1360, 1346, 1277,
1263, 1250, 1105, 1082, 1046, 980, 817, 783, 764, 730, 701, 681,
653 cm-1; MS m/z (ES) 406.1, 452.3; HRMS (ESI, m/z) calcd for
+
C30H27N2O2 [M+], 447.2067; found, 447.2072.
8-Phenyl-12-propyl-12,12c-dihydro-8H-4-oxa-8,12-diazadiben-
zo[cd,mn]pyrenium tetrafluoroborate salt or [5a][BF4]. At 25
°C, LiI (58.0 mmol) was added to a solution of racemic-5-phenyl-
9-propyl-1,13-dimethoxyquinacridinium tetrafluoroborate salt
[9][BF4] (0.3 g, 0.56 mmol) in NMP (10 mL). The reaction mixture
was heated at 180 °C for 1.5 h and then allowed to cool to room
temperature. Addition of water (∼25 mL) afforded a precipitate,
which was filtered over a Bu¨chner funnel, washed with water,
several times with Et2O, and collected. Purification by column
chromatography over silica gel (CH2Cl2/MeOH 99:1, 24 × 2.5 cm)
gave a red material corresponding to salt [5a][BF4] (0.46 g, 65%):
+
C29H26NO4 [M+], 452.1856; found, 452.1865.
Racemic-5-phenyl-9-propyl-1,13-dimethoxyquinacridinium tet-
rafluoroborate salt or [9][BF4]. At 25 °C, n-propylamine (2.5 mL,
58.0 mmol) was added to a solution of 9-(2,6-dimethoxyphenyl)-
1,8-dimethoxy-10-phenyl-9,10-dihydroacridinium tetrafluoroborate
salt [8][BF4] (0.72 g, 1.33 mmol) in NMP (10 mL). The reaction
mixture was heated at 120 °C under a dinitrogen atmosphere for
2.5 h and then allowed to cool to 25 °C. Addition of water (∼25
1
mp 298 °C; H NMR (CD3CN, 400 MHz) δ ) 8.14 (t, J ) 8.8
Hz, 1H), 8.05 (t, J ) 8.6 Hz, 1H), 7.95-7.81 (m, 4H), 7.69 (d, J
) 8.8 Hz, 1H), 7.55-7.50 (m, 3H), 7.39 (d, J ) 8.1 Hz, 1H), 7.31
9
6512 J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008

Analysis of an Enantiopure Diazaoxatricornan Derivative
A R T I C L E S
Figure 10. Experimental (red) and calculated (black) VCD spectra of the
least (second) eluted (levoratory) fraction and (S)-6a, respectively; T ) 298
K. The calculations were performed at the B3PW91,6-31G(d,p) level.
19.9 (CH2), 11.1 (CH3); 19F NMR (376 MHz, CD3CN) δ ) -151.7
(20%), -151.8 (80%); UV/vis (CH2Cl2, 10-4 M, λmax (log ꢀ)) 563
(4.13), 527 (3.88), 456 (3.66); IR (neat) ν ) 2963, 1607, 1583,
1523, 1488, 1453, 1338, 1303, 1247, 1189, 1167, 1147, 1098, 1071,
1054, 815, 765, 732, 703 cm-1; MS m/z (ES) 358.1, 401.3; HRMS
(ESI, m/z) calcd for C28H21N2O+ [M+], 401.1648; found, 401.165.
Racemic 12c-Methyl-12-phenyl-8-propyl-12,12c-dihydro-8H-
4-oxa-8,12-diazadibenzo[cd,mn]pyrene 6a. The reaction was
conducted under dinitrogen atmosphere. To a suspension of
8-phenyl-12-propyl-12,12c-dihydro-8H-4-oxa-8,12-diazadiben-
zo[cd,mn]pyrenium tetrafluoroborate salt [5a][BF4] (60 mg, 0.12
mmol) in THF (4 mL) at 0 °C was added an excess of MeLi in
ether (100 µL, 0.16 mmol). The red suspension progressively
disappeared to give an orange solution which was stirred overnight
(16 h). The reaction was quenched by addition of two drops of
ethanol and ether (10 mL). The organic layer was washed with
water, dried over Na2SO4, and concentrated in vacuo to give 6a as
a white glassy solid (50 mg, 97%): mp 201 °C; 1H NMR (CDCl3,
400 MHz) δ ) 7.61 (t, J ) 7.3 Hz, 2H), 7.51 (m, 1H), 7.35 (m,
2H), 7.19 (t, J ) 8.1 Hz, 1H), 6.95 (dt, J ) 8.3, 3.3 Hz, 2H), 6.74
(d, J ) 8.4 Hz, 1H), 6.70 (dd, J ) 8.1, 1 Hz, 1H), 6.66 (d, J ) 8.4
Hz, 1H), 6.53 (d, J ) 8.4 Hz, 1H), 5.96 (d, J ) 8.1 Hz, 1H), 5.88
(d, J ) 8.1 Hz, 1H), 3.87 (m, 2H), 1.85 (m, 2H), 1.44 (s, 3H), 1.07
(t, J ) 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ ) 151.9 (C),
151.7 (C), 141.7 (C), 141.5 (C), 140.8 (C), 140.3 (C), 140.0 (C),
131.0 (CH), 130.7 (CH), 128.4 (CH), 127.7 (CH), 127.2 (CH), 127.2
(CH), 108.4 (CH), 108.3 (CH), 108.1 (CH), 106.9 (CH), 106.7 (CH),
105.3 (CH), 47.8 (CH2), 29.8 (CH3), 27.1 (C), 18.7 (CH2), 11.3
(CH3); UV/vis (CH2Cl2, 10-4 M, λmax (log ꢀ)) 287 (4.49); IR (film)
ν ) 2953, 2924, 2868, 1621, 1607, 1593, 1480, 1455, 1353, 1335,
Figure 8. Calculated IR (top) and VCD (bottom) spectra: Comparison
between conformer 3 and Boltzmann average of all seven conformers for
T ) 298 K.
1320, 1293, 1242, 1151, 1042, 783, 762, 745, 730, 700, 652 cm-1
;
MS m/z (ES) 417.2, 401.3, 358.3; HRMS (ESI-TOF-MS) calcd (%)
for C29H25N2O [M + H+], 417.1966; found, 417.1953.
Preparative Enantiomeric Separation of rac-6a. Preparative
enantioselective chromatographic separation was performed using
a prep HPLC column (25 mm × 250 mm) packed with Chiralcel
OJ (20 µm particle size) and a mixture of n-hexane/methanol 995/5
(volume) as the mobile phase. The chromatography was carried
out at a flow rate of 20 mL/min under isocratic conditions and at
room temperature. Detection was carried out by UV at 254 nm.
Seventy milligrams of rac-6a was dissolved in 300 mL of hexane/
methanol 995/5. Portions of 50 mL of this solution were injected
repetitively (six times), and three fractions were isolated for each
run. Fractions 1 and 3 of each run were pooled and evaporated to
give highly enriched amounts of the first and last eluting enanti-
omers, respectively. Both enantiomerically enriched materials were
redissolved in the applied mobile phase and reinjected on the same
Figure 9. Experimental (red) and calculated (black) IR spectra of the least
(second) eluted (levoratory) fraction and (S)-6a, respectively; T ) 298 K.
The calculations were performed at the B3PW91,6-31G(d,p) level.
(d, J ) 8.4 Hz, 1H), 6.62 (d, J ) 8.6 Hz, 1H), 6.58 (d, J ) 8.6 Hz,
1H), 4.51 (t, J ) 8.3 Hz, 2H), 2.05-1.95 (m, 2H), 1.21 (t, J )
7.28 Hz, 1H); 13C NMR (CD3CN, 100 MHz) δ ) 153.9 (C), 153.4
(C), 143.7 (C), 142.3 (C), 141.7 (C),141.6 (C), 141.1 (C), 140.2
(CH), 139.8 (CH), 139.1 (CH), 138.5 (C), 133.0 (CH), 131.8 (CH),
129.3 (CH), 112.4 (C), 111.2 (CH), 110.5 (CH), 109.5 (CH), 109.5
(CH), 109.0 (C), 108.4 (C), 107.9 (CH), 107.1 (CH), 50.3 (CH2),
9
J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008 6513

A R T I C L E S
Mobian et al.
column (Chiralcel OJ) to afford, after fractionation and evaporation,
the desired enantiomers in high enantiomeric excesses.
Calculation of the IR and VCD spectra was performed using
Gaussian03.24 The B3PW91 hybrid functional25 was used with a
6-31G(d,p) basis set.26 Prior to the calculation of the IR and VCD
spectra, complete structural relaxation was performed on all
conformers. Normal mode analysis revealed that all stationary points
found were true minima. For the simulation of the spectra,
calculated IR and VCD intensities were convoluted with Lorentzian
(+)-(R)-6a (26 mg): ee > 99.2% as determined by HPLC
(Chiralpak AD-H, n-hexane/2-propanol 99:1, 0.2 mL min-1, 23
°C, λ ) 254 nm, tR ) 23.74 min); CD (CH2Cl2, 1 × 10-4 M, 20
°C) λ (∆ꢀ) 328 (5.5), 304 (-4.2), 282 (1.6); [R]D ) +16.1 ( 1.4
(c ) 0.1g/100 mL, CH2Cl2).
(-)-(S)-6a (19 mg): ee > 98.1% as determined by HPLC
(Chiralpak AD-H, n-hexane/2-propanol 99:1, 0.2 mL min-1, 23
°C, λ ) 254 nm, tR ) 26.95 min); CD (CH2Cl2, 1 × 10-4 M, 20
°C) λ (∆ꢀ) 328 (-5.20), 304 (3.9), 282 (-1.7); [R]D ) -13.2 (
1.6 (c ) 0.1g/100 mL, CH2Cl2).
line shapes with a full width at half-maximum of 6 cm-1
.
Acknowledgment. We are grateful for financial support of this
work by the Swiss National Science Foundation, the State Secre-
tariat for Education and Research, the Schmidheiny Foundation,
and the Socie´te´ Acade´mique de Gene`ve.
Vibrational Circular Dichroism. A Bruker PMA 50 accessory
coupled to a Tensor 27 Fourier transform infrared spectrometer was
used to measure IR and VCD spectra. Modulation of the handedness
of the circular polarized light was achieved by a photoelastic
modulator (Hinds PEM 90) set at 1/4 retardation, and a lock-in
amplifier (SR830 DSP) was used for demodulation. To enhance
the signal/noise ratio, an optical low-pass filter (<1800 cm-1) was
put before the photoelastic modulator. Solutions of 6a were prepared
in CD2Cl2 at a concentration of 11.3 mg/mL. All spectra were
measured at a resolution of 6 cm-1 in a cell equipped with CaF2
windows and a 0.5 mm Teflon spacer. The VCD spectrum of a
racemic mixture of 6a served as the reference. This spectrum was
subtracted from the VCD spectra of the enantiomers. Both samples
and reference were measured 4 h in time slices of 20 min,
corresponding to about 24 000 scans for each sample and reference,
respectively.
Supporting Information Available: 1H NMR, 13C NMR, 19
F
NMR, UV, LRMS, and HRMS spectra of salts [8][BF4], [9]-
[BF4], [5a][BF4], and chiral bowl 6a. Calculated IR and VCD
spectra for the different conformers of (S)-6a, and complete ref
24. This material is available free of charge via the Internet at
http://pubs.acs.org.
JA800262J
(24) Frisch, M. J.; In Gaussian 03, revision C.01; Gaussian, Inc.: Wall-
ingford, CT, 2003.
(25) (a) Perdew, J. P.; Chevary, J. A.; Vosko, S. H.; Jackson, K. A.;
Pederson, M. R.; Singh, D. J.; Fiolhais, C. Phys. ReV. B 1992, 46,
6671–6687. (b) Becke, A. D J. Chem. Phys. 1993, 98, 5648–5652.
(26) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54,
724–728.
9
6514 J. AM. CHEM. SOC. VOL. 130, NO. 20, 2008