Synthesis, resolution, and absolute configuration of difunctionalized Troeger's base derivatives

Article abstract of DOI:10.1002/chem.200701960

Two racemic derivatives of Troeger's base, the 2,8-diboronic acid ester 6 and the 3,9-dibromo-substituted derivative 5, were synthesized and successfully resolved by HPLC on a chiral stationary Whelk-01 phase on a semipreparative scale, thereby giving rise to both enantiomers in a pure form. These functionalized C2symmetric building blocks are valuable precursors for a variety of further applications. Their absolute configurations were determined by comparison of their quantum chemically calculated CD and UV/Vis spectra with the experimental ones and were independently confirmed by X-ray diffraction analysis.

Full text of DOI:10.1002/chem.200701960

DOI: 10.1002/chem.200701960
Synthesis, Resolution, and Absolute Configuration of Difunctionalized
Trçgerꢀs Base Derivatives
Ulf Kiehne,[a] Torsten Bruhn,[b] Gregor Schnakenburg,[c] Roland Frçhlich,[d]
Gerhard Bringmann,*[b] and Arne Lützen*[a]
Abstract: Two racemic derivatives of Trçgerꢀs base, the 2,8-diboronic acid ester 6
and the 3,9-dibromo-substituted derivative 5, were synthesized and successfully re-
solved by HPLC on a chiral stationary Whelk-01 phase on a semipreparative scale,
thereby giving rise to both enantiomers in a pure form. These functionalized C2-
symmetric building blocks are valuable precursors for a variety of further applica-
tions. Their absolute configurations were determined by comparison of their quan-
tum chemically calculated CD and UV/Vis spectra with the experimental ones and
were independently confirmed by X-ray diffraction analysis.
Keywords:
chiral resolution
·
circular dichroism · configuration
determination · quantum chemical
calculations · Trçgerꢀs base
Introduction
Trçgerꢀs base (1; Scheme 1) was first synthesized more than
120 years ago, in 1887, by Julius Trçger.[1] Still, it took an-
other 50 years to discover its N-based chirality.[2] Only a few
years later, in 1944, it became the first chiral tertiary amine
to be resolved into its enantiomers;[3] this was achieved by
chromatography on d-lactose, yet led to only about 5.5% of
resolved optically pure material. In the 1970s and 80s, more
fruitful resolutions were developed by means of column
chromatography on cellulose triacetate[4] and by various
Scheme 1. The two enantiomers of Trçgerꢀs base (1).
HPLC methods applying different chiral stationary phases.[5]
Today, racemic Trçgerꢀs base itself is a standard compound
for testing the efficiency of new chiral stationary phases.[6]
The absolute configuration of 1 was first investigated in
1966, on the basis of comparative optical rotational disper-
sion (ORD) curves of the two pure enantiomers and (À)-ar-
gemonine, an alkaloid with a related structure: the (+)-en-
antiomer of 1 was attributed the (5S,11S) configuration.[7]
Later work on the basis of circular dichroism studies, by
using the exciton chirality method,[8] came to the opposite
conclusion; this, however, proved to be incorrect due to an
erroneous assignment of the direction of polarization of the
considered transitions. This assignment was believed to be
true until 1991, when Wilen et al. finally proved by X-ray
diffraction on a diastereomeric salt of (+)-1 and (À)-1,1’-bi-
naphthyl phosphoric acid that the initial assignment made in
1966 was correct.[9] This salt formation was achieved in a
very elegant manner by a crystallization-induced asymmetric
transformation (CIAT). Trçgerꢀs base usually racemizes
under acidic conditions in solution;[10] the selective precipita-
tion of only one of the two diastereomers of the salt, howev-
[a] Dr. U. Kiehne, Prof. Dr. A. Lützen
KekulØ-Institut für Organische Chemie und Biochemie
Rheinische Friedrich-Wilhelms-Universität Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Fax : (+49)228-739608
E-mail: arne.luetzen@uni-bonn.de
[b] Dr. T. Bruhn, Prof. Dr. G. Bringmann
Institut für Organische Chemie
Julius-Maximilians-Universität Würzburg
Am Hubland, 97074 Würzburg (Germany)
Fax : (+49)31-888-4755
E-mail: bringman@chemie.uni-wuerzburg.de
[c] Dipl.-Chem. G. Schnakenburg
Institut für Anorganische Chemie
Rheinische Friedrich-Wilhelms-Universität Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
[d] Dr. R. Frçhlich
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
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FULL PAPER
er, shifted the equilibrium of the two enantiomers in solu-
tion towards (+)-1 in the precipitate. By using this method,
both enantiomers were accessible on a multigram scale. This
is also possible by “classical” diastereomeric salt formation
of racemic 1 and (+)- or (À)-di-O,O’-p-benzoyl tartaric acid
(DBTA), as shown recently.[11]
The resolution of functionalized analogues of Trçgerꢀs
base, however, is limited to only a few examples: application
of either enantiopure DBTA or di-O,O’-p-toluoyl tartaric
acid (DTTA) resulted in diastereomeric salt formations of
an acridine-substituted analogue of Trçgerꢀs base, an
ethano-bridged representative, and a naphthyl-substituted
derivative.[12] Following an earlier example,[13] and parallel to
our own work described in this paper, Sergeyev and Dieder-
ich published the first study on the enantioseparation of
some difunctionalized analogues of Trçgerꢀs base by HPLC
on a semipreparative scale in 2006;[14] these analogues were
then used for the regio- and stereoselective tether-directed
remote functionalization of fullerenes.[15]
sophisticated derivatives in an enantiomerically pure form.
As the key steps of most of our routes to the ligands are
transition-metal-catalyzed cross-coupling reactions, we were
particularly interested in the resolution of precursors that
can be applied in such reactions. Herein, we report the prep-
aration and separation of one pair of diastereomers and the
synthesis and resolution of a racemic 2,8-disubstituted dibor-
onic acid derivative of Trçgerꢀs base as a valuable substrate
for Suzuki cross-coupling reactions. Moreover, we describe
the resolution of a racemic 3,9-dibromo-substituted ana-
logue, which can also be used as a substrate for all sorts of
cross-couplings. Furthermore, we have succeeded in deter-
mining the absolute configuration of the resolved enantio-
mers by quantum chemical circular dichroism calculations
and comparison of the predicted CD spectra with the exper-
imental ones and, independently, through anomalous X-ray
diffraction.
In the course of our studies towards the formation of dia-
stereoselectively self-assembled metallosupramolecular ag-
gregates of helical shape from dissymmetrical ligands based
on either substituted 1,1’-binaphthyls (for example, 1,1’-bi-
naphthalene-2,2’-diol (BINOL)) or d-isomannide,[16] the V-
shaped rigid core of Trçgerꢀs base attracted our interest as
another potential C2-symmetric building block. Such com-
pounds have become even more valuable since Jensen and
Wärnmark succeeded in establishing an easy access to 2,8-
dihalo-substituted analogues of Trçgerꢀs base in 2001
(Scheme 2).[17] This prompted us and other groups to apply
various cross-coupling methodologies for the construction of
larger architectures with extended V-shaped cores.[18,19]
Results and Discussion
All of the Trçgerꢀs base analogues we work with possess
methyl groups at the C4- and C10-positions, that is, ortho
with respect to the nitrogen atoms. Initially, o-methyl-substi-
tuted anilines were used because a methyl function at this
position facilitates the reaction sequence consisting of con-
secutive Schiff base formations and two electrophilic aro-
matic substitutions,[17,22] which, as a consequence, provided
better yields and furthermore resulted in the formation of
only one (desired) regioisomer of the Trçgerꢀs base ana-
logue. Recently, DFT calculations have revealed that the
methyl functions at these positions provide an additional,
and equally important, advantage. Usually, Trçgerꢀs bases
are configurationally stable under basic and neutral condi-
tions but tend to racemize rapidly under acidic conditions.[10]
The introduction of the methyl groups, however, gives rise
to a dramatic increase of the racemization barrier in acidic
media due to steric hindrance of the inversion,[23] thereby
leading to a significantly increased configurational stability
in acidic solution of bis(o-methyl)-substituted Trçgerꢀs base
A
Scheme 2. Synthesis of 2,8-halogenated analogues 2 and 3 of Trçgerꢀs
base (1). TFA: trifluoroacetic acid.
analogues; this makes them much more valuable precursors
than derivatives devoid of this particular substitution pat-
tern.
Our group has succeeded in applying these disubstituted
analogues of Trçgerꢀs base for the synthesis of racemic bis-
Our initial attempts were aimed at the resolution of 2 and
3 through diastereomeric salt formation by following the
successful approaches for other derivatives mentioned
above. However, even with various conditions, such as dif-
ferent solvents, temperature, scale, etc., and with different
chiral resolving agents, such as DBTA, DTTA, or camphor
sulfonic acid, resolution of the 2,8-dibromo- or 2,8-diiodo-
substituted compounds could not be achieved.
Replacement of the halogen atoms by hydroxy groups
also leads to a versatile precursor for further functionaliza-
tion. As shown previously,[18] this can be achieved by means
of an Ullmann coupling. However, instead of preparing the
respective racemic 2,8-dihydroxy compound from 3 via its
2,8-dimethoxy derivative first and subsequently applying all
A
complexes through coordination to titanium(IV) ions[20] and
also for the preparation of racemic N-heterocyclic bis(bipyr-
idine) and bis(2-pyridylmethanimine) ligands, which were
demonstrated to form dinuclear double- and triple-stranded
helicates in a (mostly) diastereoselective manner upon coor-
[21]
dination to metal ions like Ag+, Cu+, Fe2+, and Zn2+
.
To further pursue this concept, the availability of enantio-
merically pure ligand strands is inevitably required. We have
thus embarked on the development of methods to resolve
racemic Trçgerꢀs base analogues at an early stage of the syn-
thesis, which would allow us to prepare a number of more
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A. Lützen, G. Bringmann et al.
of the procedures mentioned above, a rewarding alternative
was to prepare diastereomers 4 directly by diphenylether
Ullmann cross-coupling of 3 with (R)-1-phenylethanol, by
using a protocol published by Buchwald and co-workers.[24]
As shown in Scheme 3, this reaction occurred smoothly and
Scheme 3. Ullmann diphenylether cross-coupling of the racemic Trçgerꢀs
base analogue 3 with enantiopure 1-phenylethanol for the synthesis of
the two diastereomeric derivatives of 4.
Figure 1. a) Chromatographic separation of the two diastereomers of 4 by
HPLC on an analytical chiral phase, (S,S)-Whelk-01, with n-heptane/di-
chloromethane 2:1 as the eluent and a flow rate of 0.3 mLminÀ1; b) rele-
vant section of the 1H NMR spectra of the 1:1 diastereomeric mixture of
4 and of the separated diastereomers, 4a and 4b.
gave a 1:1 mixture of the diastereomeric products 4a and 4b
in 76% yield. However, these products could not be sepa-
rated by crystallization or by column chromatography on
silica gel. Although diastereomers, 4a and 4b were finally
best resolved by using methods of enantioresolution on a
chiral phase. Thus, by applying an analytical (S,S)-Whelk-01
phase (300”4 mm) with (3S,4S)-4-(3,5-dinitrobenzamido)-
1,2,3,4-tetrahydro-phenanthrene covalently attached to silica
gel as a chiral selector and by using a mixture of n-heptane/
dichloromethane (2:1) as the eluent at a flow rate of
0.3 mLminÀ1, the resolution of the two diastereomers was
achieved (Figure 1). This separation was successfully scaled
up to a semipreparative level by using the (S,S)-Whelk-01
phase (250”10 mm) with a 3:1 mixture of n-heptane and di-
to some extent unsatisfying and made alternative attempts,
involving the use of chiral HPLC techniques for the direct
enantioseparation of racemic Trçgerꢀs base analogues 2 and
3, a rewarding option. However, despite numerous experi-
ments, none of the chiral phases we evaluated proved to be
suitable to achieve the resolution with any of the eluent
mixtures and flow rates tested.[26] Nevertheless, the success-
ful separation of the diastereomeric mixture of 4 prompted
us to consider the enantioseparation of other racemic di-
functionalized Trçgerꢀs base derivatives. Our attempts to
achieve the desired enantioresolution, therefore, concentrat-
ed on the 3,9-dibromo-substituted analogue 5, which has a
different substitution pattern. Racemic 5 can be prepared in
one step from 3-bromo-2-methylaniline according to a pub-
lished procedure (Scheme 4).[27]
chloromethane as the eluent and
a
flow rate of
1.5 mLminÀ1. Under these conditions, approximately 15 mg
of the diastereomeric mixture of 4 can be resolved in a
single run. Figure 1 shows the chromatogram of the two dia-
1
stereomers, 4a and 4b, and the H NMR spectra of the dia-
stereomeric mixture and of the separated isomers.
By hydrogenolysis,[25] the stereoisomers of 4 should be
readily converted into the enantiomerically pure bisphenolic
parent compounds, which could then act as versatile precur-
sors for the elaboration of tailor-made molecular structures,
either directly or after transformation into the respective
O,O’-bistriflate derivatives.
The use of this Trçgerꢀs base derivative proved to be most
successful. In contrast to the 2,8-dibromo-substituted com-
pound above, an enantioseparation was now easily achieved
by using an analytical (S,S)-Whelk-01 phase with n-heptane/
dichloromethane (85:15) as the eluent and a flow rate of
0.5 mLminÀ1 (Figure 2).
Still, despite this successful diasteromeric resolution, the
use of such a relatively expensive chromatographic tool was
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Trçgerꢀs Base Derivatives
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Scheme 4. Synthesis of racemic 3,9-dibromo-4,10-dimethyl-6H,12H,5,11-
methanodibenzodiazocine (5).
Scheme 5. Synthesis of racemic diboronic acid ester 6.
Figure 2. Chromatographic separation of racemic 5 by analytical HPLC
with the (S,S)-Whelk-01 chiral phase, n-heptane/dichloromethane 85:15
as the eluent, and a flow rate of 0.5 mLminÀ1
.
Again, this separation proved to be transferable to a semi-
preparative scale by applying slightly different conditions
(same solvent mixture, but a flow rate of 1.5 mLminÀ1). By
using this method, approximately 10 mg of racemic 5 can be
resolved into the separate enantiomers in a single run. How-
ever, due to some chromatographic tailing that occurs on
the semipreparative scale, every run yields a small fraction
containing both enantiomers incompletely separated. Paral-
lel to our approach, a very elegant method for the separa-
tion of 5 has recently been developed by Kostyanovsky and
co-workers, based on the discovery that racemic 5 crystalli-
zes as a conglomerate from toluene and the enantiomor-
phous crystals can be isolated mechanically by manual sepa-
ration and subsequent separate recrystallization.[28]
Besides halides or pseudohalides, one could also think of
other functionalities that show a somehow orthogonal reac-
tivity in cross-coupling reactions, such as boronic acids and
their derivatives, which are valuable substrates for Suzuki
cross-couplings. As we still wanted to achieve the resolution
of a 2,8-difunctionalized analogue of Trçgerꢀs base, we
Figure 3. Chromatographic separation of racemic 6 by analytical HPLC
with the (S,S)-Whelk-01 chiral phase, n-heptane/dichloromethane (85:15)
as the eluent, and a flow rate of 0.5 mLminÀ1
.
be transferred to a semipreparative scale, with n-heptane/di-
chloromethane (85:15) as the eluent and a flow rate of
1.5 mLminÀ1, yet with a more pronounced tailing. Nonethe-
less, as much as 6–7 mg of racemic 6 can thus be enantiose-
parated in a single run, although the fraction containing the
unseparated enantiomers is larger than in the case of 5. By
using this method, however, around 12 runs can easily be
performed within approximately 6 h to give around 30–
40 mg of each of the two enantiomers, (À)-6a and (+)-6b,
in an enantiopure form.
therefore prepared the racemic bis
by bromine–lithium exchange with subsequent borylation
(Scheme 5).
The resolution of the enantiomeric bisboronates 6 could
finally be achieved by again using an analytical (S,S)-Whelk-
01 phase with a mixture of n-heptane/dichloromethane
(85:15) as the eluent at a flow rate of 0.5 mLminÀ1
(Figure 3). As Figure 3 indicates, substantial tailing occurs,
even on an analytical scale, probably due to the presence of
the boronic acid ester groups. Again, this procedure could
A
After the successful enantioseparation of 5 and 6, the con-
firmation of the absolute configurations of the enantiomers
of 5 and the determination of those of 6 was a rewarding
task, as these building blocks were planned to act as starting
materials for the formation of more sophisticated enantio-
merically pure molecular architectures.
Fortunately, we succeeded in growing crystals suitable for
X-ray crystal structure analysis from both enantiomers of 5
and from the more rapidly eluting enantiomer of 6, by slow
evaporation of the solvents from solutions in n-heptane/di-
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A. Lützen, G. Bringmann et al.
chloromethane (3:1). Figure 4 shows the results of the analy-
sis of the enantiomers of 5 obtained upon investigation with
MoKa radiation. Due to the presence of the two bromine
UV and CD spectra of (+)- and (À)-5 with the calculated
ones was found (Figure 6). A similar approach, yet only for
the longest-wavelength band and thus for the first Cotton
effect, has recently been pursued by Kostyanovsky and co-
workers.[28]
Figure 4. Crystal structures of (À)-(5S,11S)-5 and (+)-(5R,11R)-5 as de-
termined by X-ray diffraction analysis.
Figure 6. Calculated (B3LYP/6-31G*; a) and experimental (c) UV
spectra of 5 and corresponding experimental CD spectra of (À)-5 (c)
and calculated CD spectra of (6S,11S)-5.
atoms, the absolute configuration could be directly deduced
from these experiments by analysis of the Flack parameter
(x=À0.018(7) for (+)-5, and À0.017(6) for (À)-5). The re-
sults confirmed the (5R,11R) configuration of (+)-5 and the
(5S,11S) configuration of (À)-5, as previously assigned by
Kostyanovsky and co-workers (Figure 4).[28]
For a first stereochemical assignment of 6, we used CD
spectroscopy as an efficient tool to elucidate the absolute
configuration of our compounds. Figure 5 shows the spectra
obtained from solutions of the enantiomers of 5 and 6 in
Application of the same approach to (+)- and (À)-6, how-
ever, did not lead to a similarly good agreement of the cal-
culated spectra (10 nm red-shifted) with the experimental
curves (Figure 7). Although these calculations permitted an
unambiguous determination of the absolute configuration,
the deviation in the region below l=225 nm was substan-
tial.
Figure 5. CD spectra of the two enantiomers of 5 (a) and 6 (c), in
Figure 7. Calculated (TD B3LYP/6-31G*//B3LYP/6-31G*; a) and ex-
perimental (c) UV spectra of 6 and corresponding experimental CD
spectra of (À)-6 (c) and calculated CD spectra of (5R,11R)-6.
CH3CN, c=4”10À5 molLÀ1
.
acetonitrile. From a comparison, a simple assignment of the
configuration of (+)- and (À)-6 in analogy to (+)- and (À)-5
is not possible. Thus, quantum chemical calculations of the
UV spectra of 5 and 6 and of the CD spectra of their enan-
tiomers were performed to unambiguously assign the abso-
lute configurations.
First attempts at the use of semiempirical methods
(CNDO/S-CI[29] calculations for AM1-optimized structures)
showed that this level of theory is not suited for an accurate
assignment of the absolute configurations of our Trçgerꢀs
bases. Thus, we used time-dependent (TD) DFT calculations
with the B3LYP hybrid functional and the 6-31G* basis set
on B3LYP/6-31G*-optimized structures of 5 and 6. By using
this method, an excellent agreement of the experimental
Therefore, further calculations were performed at
a
higher level of theory to attain a better agreement between
the computed and experimental data. Interestingly, DFT/
MRCI[30] calculations gave even worse results in the region
below 250 nm, thereby indicating that DFT methods are not
well suited for the calculation of the rotational strengths of
6 in this wavelength region. However, MRCI calculations
(UV shift of 36 nm to longer wavelengths) do reproduce the
experimental data to a satisfying degree as only the first
Cotton effect at approximately 280 nm is somewhat overes-
timated (Figure 8). These results nicely complement the as-
signment of (À)-6 as having the 5R,11R configuration.
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Trçgerꢀs Base Derivatives
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Figure 8. Calculated (MRCI/SVP//B3LYP/6-31G*; a) and experimen-
tal (c) UV spectra of 6 and corresponding experimental CD spectra of
(À)-6 (c) and calculated CD spectra of (5R,11R)-6.
Scheme 6. Model structures of 7 and 8.
Independently, an X-ray diffraction analysis was per-
formed, and a first analysis of (À)-6 by employing MoKa ra-
diation provided an excellent structural data set.[31] Howev-
er, the most important question for us, regarding the assign-
ment of the absolute configuration, could not be answered
owing to the lack of heavy atoms in this compound, which
results in a nondefined Flack parameter in this case.
Therefore, we turned to CuKa radiation: even if the stan-
dard deviation of the Flack parameter (x=0.0(3)) was still
quite high, this analysis clearly confirmed that the former
determination of (À)-6 as having the (5R,11R) configuration
was correct (Figure 9).
Figure 10. Comparison of the calculated (TD B3LYP/6-31G*//B3LYP/6-
31G*) CD spectra of (5R,11R)-5 (g) and (5R,11R)-6 (c) with those
of (5R,11R)-7 (a)) and (5R,11R)-8 (g).
acid ester functions are in the same positions as the bromine
atoms in 5. The first Cotton effects of both 5 and 8 appear
at nearly the same wavelength (ꢀ290 nm), but the CD spec-
tra as a whole are, nonetheless, not comparable, although 5
and 8 have the same absolute configuration and, formally,
the same substitution pattern. As compared to the spectrum
of 6, the first Cotton effect of 8 has an opposite sign, clearly
evidencing that the spectral differences are not only a conse-
quence of the various substituents as such but result from a
combination of both the electronic character of the substitu-
ent and its position.
Figure 9. X-ray crystal structure of (À)-(5R,11R)-6.
This demonstrates the difficulties in elucidating absolute
configurations of Trçgerꢀs bases just by comparison of their
experimental CD spectra. Even structurally very similar de-
rivatives of Trçgerꢀs base give rise to noticeably different
CD spectra, thereby making an unambiguous elucidation
impossible. Thus, for an unequivocal interpretation of these
CD spectra, quantum chemical calculations constitute an in-
dispensible tool.
For a further explanation of these differences of the ex-
perimental CD spectra, a more in-depth computational
study of the first Cotton effect was performed. In the litera-
ture,[28] the first Cotton effect found for all Trçgerꢀs bases,
resulting from a highest occupied molecular orbital–lowest
unoccupied molecular orbital (HOMO–LUMO) transition,
has (for example, in the case of 5) been assigned to be an n–
p* transition, and it might be possible that the first excited
states in 6 result from different transitions. Computational
investigations on 5 and 7 showed that the LUMO is indeed
To find out whether the divergence in the CD spectra of 5
and 6 was due to the different substitution patterns in these
structures or to other reasons, the UV and CD spectra of a
tetramethyl-substituted model compound 7 and the bis(bor-
onic acid) diester 8 (Scheme 6), a regioisomer of 6, were
also calculated.
The calculated CD spectra of 5 and 7 were found to differ
only slightly, but the curve of 5 is 15 nm red-shifted in com-
parison to that of 7 (Figure 10). The CD spectra of 6 and 7
showed a similar deviation pattern to those of 5 and 6, with
an opposite first Cotton effect, a result suggesting that the
different positions of the substituents at the ring alone were
not enough to explain the divergent CD spectra. This was
further corroborated by the comparison with the calculated
CD spectrum of model structure 8, in which the boronic
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A. Lützen, G. Bringmann et al.
a p* orbital; however, a more detailed population analysis
indicated that the HOMO does not only have n character
from the lone pairs of the nitrogen atoms but also possesses
a substantial portion of p character from the p orbitals of
the aromatic rings, thereby hinting at a strong +M effect of
the nitrogen atoms. Thus, the HOMO–LUMO transition is
better described as an n,p–p* transition for compounds such
as 5 and 7 (Figure 11, top).
While the stereoisomers of a 2,8-dihydroxy derivative have
only been separated in the form of their diastereomeric de-
rivatives by using HPLC techniques on chiral stationary
(S,S)-Whelk-01 phases, the same chromatographic approach
was also applied to the resolution of the racemic 3,9-dibro-
mo-functionalized Trçgerꢀs base derivative 5 and the 2,8-di-
boronic acid ester derivative 6 on a semipreparative scale.
The 4,10-dimethyl substitution pattern of these compounds
prevents their racemization in acidic media, which makes
their successful enantioseparation even more attractive, as
they are configurationaly stable under basic conditions
anyway, for example, in Suzuki reactions. We were also able
to determine the absolute configuration of the resolved en-
antiomers by comparison of quantum chemically calculated
CD spectra with the experimental ones and, independently,
by X-ray diffraction techniques. The reliable knowledge of
the absolute stereostructures of these compounds is a re-
quired precondition for the construction of more sophisticat-
ed molecular architectures, which we are currently preparing
in enantiomerically pure form.
Experimental Section
Figure 11. Calculated HOMOs (a and c) and LUMOs (b and d) of 6
(bottom) and 7 (top) obtained from B3LYP/6-31G* calculations.
General information: All reactions were performed under an argon at-
mosphere by using standard Schlenk techniques and glassware that was
oven dried prior to use. TLC was performed on aluminum TLC plates
coated with silica gel 60 F254 (Merck). Detection was done under UV
light (254 and 366 nm). Products were purified by column chromatogra-
1
While the diboronic acid esters 6 and 8 still have similar
HOMOs, their LUMOs are different due to the boron
atoms and are mostly formed of the empty p orbitals of the
boron atoms; thus, the first Cotton effects in the CD spectra
of 6 and 8 are due to an n,p–p transition. This evidences the
assumption that the properties of the different substituents
also have an influence on the spectra.
Thus, we did not only succeed in elucidating the absolute
configurations of the two enantiomers of 6, but we could
also establish some reasons for the difference between the
spectra of the Trçgerꢀs base derivatives investigated here.
One of the most important findings of the theoretical inves-
tigations is that the absolute configuration of differently sub-
stituted Trçgerꢀs bases cannot be established by just compar-
ing their experimental CD spectra, due to the unexpectedly
strong effects of the substituents on the CD spectra. Al-
though the DFT method used here is not always able to
fully reproduce the experimental CD spectra (mainly in the
lower wavelength region of 6), it does fulfill the task of dis-
tinguishing between the different enantiomers. With com-
pound 6 as an example, this has been vigorously confirmed
by higher-level calculations with the MRCI approach.
phy on silica gel 60 (70–230 mesh; Merck). H and 13C NMR spectra were
recorded on a Bruker DRX 500 spectrometer at 300 K, at 500.1 and
125.8 MHz, respectively, on a Bruker AM 400 spectrometer at 298 K, at
400.1 and 100.6 MHz, respectively, or on a Bruker Avance 300 spectrom-
eter at 298 K, at 300.1 and 75.5 MHz, respectively. 1H and 13C NMR
chemical shifts are reported on the d scale (ppm) relative to residual non-
deuterated and deuterated solvent, resepectively, as the internal stand-
ards. Signals were assigned on the basis of 1H, 13C, HMQC, and HMBC
NMR experiments. Mass spectra were taken on a Finnigan MAT 212 in-
strument with an MMS-ICIS data system (EI) or an A.E.I. MS-50 instru-
ment (EI; high-resolution EI). Melting points were measured with a hot-
stage microscope SM-Lux apparatus from Leitz and are not corrected.
Elemental analyses were carried out with a Fisons Instrument EA1108 or
a Heraeus Vario EL instrument. HPLC was performed by using a Promi-
nence console from Shimadzu (binary system consisting of two pumps
(LC20-AT), degasser (DGU-20A)3, diode array detector (SPD-M20A),
and a fraction collector (FRC-10A)). Chiral analytical and semiprepara-
tive stationary phases ((S,S)-Whelk-01 phase from GAT) were applied
and solvent mixtures of n-heptane and dichloromethane (HPLC quality)
were used. CD spectroscopy was performed on a Jasco J-810 instrument.
Crystal structures were edited with the Diamond 3.0 software (Crystal
Impact GbR). Most solvents were dried, distilled, and stored under
argon according to standard procedures. All chemicals were used as re-
ceived from commercial sources. Racemic 3,9-dibromo-4,10-dimethyl-
6H,12H-5,11-methanodibenzodiazocine (5),[27] 2,8-dibromo-4,10-dimeth-
yl-6H,12H-5,11-methanodibenzodiazocine (2),[17] and 2,8-diiodo-4,10-di-
methyl-6H,12H-5,11-methanodibenzodiazocine (3)[20] were prepared ac-
cording to published procedures. The numbering system for the 1H and
13C nuclei is indicated in Scheme 1.
2,8-Bis[(R)-1-phenylethoxy]-4,10-dimethyl-6H,12H-5,11-methanodiben-
zodiazocine (4, mixture of two diastereomers): A solution of 3 (600 mg,
1.20 mmol), (R)-(+)-1-phenylethanol (584 mg, 4.78 mmol, 4 equiv),
cesium carbonate (1.56 g, 4.78 mmol, 4 equiv), copper(I) iodide (46 mg,
0.24 mmol, 20 mol%), and 1,10-phenanthroline (anhydrous; 86 mg,
0.48 mmol, 40 mol%) in toluene (10 mL) was refluxed for 18 h. It was
Conclusion
In summary, we have succeeded in synthesizing racemic di-
substituted derivatives of Trçgerꢀs base bearing versatile
functional groups for the synthesis of elaborated structures.
4252
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4246 – 4255

Trçgerꢀs Base Derivatives
FULL PAPER
then filtered through silica gel and the residue was washed with CH2Cl2
(150 mL). The filtrate was dried with Na2SO4, the solvents were evapo-
rated, and the residue was purified by column chromatography (petro-
leum ether (40/60)/ethyl acetate 4:1 with 0.5% Et3N, Rf =0.39). Yield:
H), 7.23 (s, 2H, 1-H; 7-H), 7.48 ppm (s, 2H; 3-H, 9-H); 13C NMR
(125.8 MHz, CDCl3): d=16.9 (PhCH3), 24.8 (B
N
N
C-12), 67.6 (C-13), 83.6 (B[O2C2(CH3)4]),127.2 (C-14, C-16), 131.3 (C-1,
A
ACHTREUNG
C-7), 132.0 (C-4, C-10), 135.4 (C-3, C-9), 148.9 ppm (C-15, C-17), as a
result of the high multiplicity through the 13C–11B coupling, the signal for
C-2 und C-8 was too weak to be detected; MS (EI): m/z (%): 502.2 (100)
442 mg (0.91 mmol, 76%); MS (EI): m/z (%): 490.3 (100) [C33H34N2O2]+
+
C
C
; HRMS (EI): m/z: calcd for [C33H34N2O2] : 490.2620; found: 490.2624;
[C29H40B2N2O4]+
;
HRMS (EI): m/z: calcd for [C29H40B2N2O4]+
:
C
C
elemental analysis: calcd (%) for C33H34N2O2·0.5H2O: C 79.33, H 7.06, N
520.3174; found: 502.3174; elemental analysis: calcd (%) for
C29H40B2N2O4·H2O: C 66.95, H 8.14, N 5.38; found: C 66.47, H 7.82, N
5.24; UV/Vis (CH3CN): lmax (De)=202 (2.0”104), 240 (0.6”104), 273 nm
(0.5·104 mÀ1 cmÀ1).
5.61; found: C 79.34, H 7.10, N 5.15.
Separation of the diastereomers of 4: HPLC: chiral phase (analytical):
(S,S)-Whelk-01; eluent: n-heptane/CH2Cl2 2:1; flow rate (f)=
0.3 mLminÀ1
.
Separation of the enantiomers of 6: HPLC: chiral phase (analytical):
Diastereomer 4a: Retention time=13.0 min; [a]2D4 =+3.9 (c=0.54 in
CH2Cl2); m.p. 64–668C; 1H NMR (400.1 MHz, CDCl3): d=1.47 (d, 3J=
6.4 Hz; OCH(Ph)CH3), 2.20 (s; PhCH3), 3.68 (d, 2J=À16.7 Hz, 2H; 6-
endo-H, 12-endo-H), 4.13 (s, 2H; 13-H), 4.36 (d, 2J=À16.7 Hz, 2H; 6-
(S,S)-Whelk-01; eluent: n-heptane/CH2Cl2 85:15; f=0.5 mLminÀ1
.
Enantiomer (+)-(5R,11R)-6: Retention time=9.3 min; [a]2D5 =À169.1
(c=0.13 in CH2Cl2); CD (CH3CN): l (De)=278 (À33.5), 236 (À41.8),
218 nm (À44.2 cm2 molÀ1); elemental analysis: calcd (%) for
C29H40B2N2O4·H2O: C 66.95, H 8.14, N 5.38; found: C 66.78, H 7.87, N
5.20.
Enantiomer (À)-(5S,11S)-6: Retention time=10.7 min; [a]2D5 =+160.8
(c=0.13 in CH2Cl2), 95% ee; CD (CH3CN): l (De)=278 (+30.1), 236
(+37.6), 218 nm (+39.5 cm2 molÀ1); elemental analysis: calcd (%) for
C29H40B2N2O4·H2O: C 66.95, H 8.14, N 5.38; found: C 66.78, H 8.04, N
5.01.
3
4
exo-H, 12-exo-H), 5.07 (q, J=6.4 Hz, 2H; OCH(Ph)CH3), 6.16 (d, J1,3
=
4J7,9 =2.6 Hz, 2H; 1-H, 7-H), 6.50 (d, 4J1,3 =4J7,9 =2.6 Hz, 2H; 3-H, 9-H),
7.14–7.18 (m, 2H; 4Ph-H), 7.21–7.28 ppm (m, 8H; 2Ph-H, 3Ph-H, 2’Ph-H,
3’Ph-H); 13C NMR (100.8 MHz, CDCl3): d=17.2 (PhCH3), 24.4
(OCH(Ph)CH3), 55.2 (C-6, C-12), 67.7 (C-13), 76.1 (OCH(Ph)CH3),
110.6 (C-1, C-7), 116.8 (C-3, C-9), 125.5 (C-2Ph, C-2’Ph), 127.4 (C-4Ph),
128.6 (C-3Ph, C-3’Ph), 128.9 (C-14, C-16), 134.2 (C-4, C-10), 139.3 (C-15,
C-17), 143.5 (C-1Ph), 154.3 ppm (C-2, C-8).
Diastereomer 4b: Retention time=15.3 min; [a]2D4 =+123.3 (c=0.48 in
CH2Cl2); m.p. 70–728C; 1H NMR (400.1 MHz, CDCl3): d=1.47 (d, 3J=
6.4 Hz, 6H; OCH(Ph)CH3), 2.23 (s, 6H; PhCH3), 3.69 (d, 2J=À16.8 Hz,
2H; 6-endo-H, 12-endo-H), 4.11 (s, 2H; 13-H), 4.30 (d, 2J=À16.8 Hz,
Computational details: All optimizations were performed with the soft-
ware package Gaussian 03,[32] by using the AM1[33] Hamiltonian or the
DFT functional B3LYP[34] and the basis set 6-31G*.[35] The Trçgerꢀs bases
are quite rigid structures, which could be seen by the fact that only one
conformer for each base was found. To identify the found structures as
energetic minima, frequency calculations were accomplished at the same
level of theory. Rotational-strength values for the electronic transitions
from the ground state to the singly excited states were obtained by time-
dependent (TD) DFT calculations (B3LYP/6-31G*) with the Gaussian 03
software. Additionally, an MRCI/SVP[36] approach was used (CAS 12,12)
to calculate these values for 6 with the ab initio software package
ORCA 2.6.0 developed by Prof. Dr. F. Neese (University of Bonn, Ger-
many).[37] De values were calculated by forming sums of Gaussian func-
tions (s=0.08 eV for the TD DFT calculation, s=0.1 eV for the MRCI/
SVP calculations) centered at the wavelengths of the respective electron-
ic transitions and multiplied by the corresponding rotational strengths.
The CD spectra thus obtained were UV corrected[38] and compared with
the experimental ones. The HOMO and LUMO graphics were construct-
ed by using the MOLDEN[39] and POVRAY 4.6 software packages.
3
2H; 6-exo-H, 12-exo-H), 5.09 (q, J=6.4 Hz, 2H; OCH(Ph)CH3), 6.13 (d,
4J1,3 =4J7,9 =2.7 Hz, 2H; 1-H, 7-H), 6.53 (d, 4J1,3 =4J7,9 =2.7 Hz, 2H; 3-H,
9-H), 7.15–7.18 (m, 2H; 4’Ph-H), 7.19–7.27 ppm (m, 8H; 2Ph-H, 3Ph-H,
2’Ph-H, 3’Ph-H); 13C NMR (100.8 MHz, CDCl3): d=17.2 (PhCH3), 24.5
(OCH(Ph)CH3), 55.3 (C-6, C-12), 67.8 (C-13), 75.8 (OCH(Ph)CH3),
110.4 (C-1, C-7), 116.9 (C-3, C-9), 125.5 (C-2Ph, C-2’Ph), 127.3 (C-4Ph),
128.6 (C-3Ph, C-3’Ph), 128.8 (C-14, C-16), 134.1 (C-4, C-10), 139.2 (C-15,
C-17), 143.5 (C-1Ph), 154.2 ppm (C-2, C-8).
3,9-Dibromo-4,10-dimethyl-6H,12H-5,11-methanodibenzodiazocine (5):
Racemic 5 was synthesized according to a published procedure.[27] The
analytical and spectroscopic data were in accordance with those pub-
lished.
Separation of the enantiomers of 5: HPLC: chiral phase (analytical):
(S,S)-Whelk-01; eluent: n-heptane/CH2Cl2 85:15; f=0.5 mLminÀ1
.
Enantiomer (À)-(5R,11R)-5: Retention time=9.8 min; [a]2D5 =+214.8
(c=0.13 in CH2Cl2); CD (CH3CN): l (De)=291 (+15.9), 260 (À25.4),
219 nm (À54.6 cm2 molÀ1).
Crystal structure determinations
X-ray crystallographic analyses of (À)-(5S,11S)-5 and (+)-(5R,11R)-5:
Data were collected on a Nonius KappaCCD diffractometer equipped
with a low-temperature device (Cryostream, Oxford Cryosystems) at
123(2) K by using graphite monochromated MoKa radiation (l=
0.71073 Š).
Enantiomer (+)-(5S,11S)-5: Retention time: 10.9 min; [a]2D5: À210.7 (c=
0.13 in CH2Cl2), 98% ee; CD (CH3CN): l (De)=291 (À15.9), 260 (+
25.4), 219 nm (+54.6 cm2 molÀ1).
2,8-Bis[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)]-4,10-dimethyl-
X-ray crystallographic analysis of (À)-(5R,11R)-6: Data were collected
on a Nonius KappaCCD diffractometer by using monochromated CuKa
radiation (l=1.54178 Š). Programs used: data collection: COLLECT
(Nonius B.V., 1998); data reduction: Denzo-SMN;[40] absorption correc-
tion: Denzo.[41] The structures were solved by direct methods (SHELXS-
97) and refined by full-matrix least squares on F2 (SHELXL-97).[42] All
non-hydrogen atoms were refined anisotropically. Hydrogen atoms on
carbon atoms were placed in calculated positions and refined isotropical-
ly by using a riding model. For some details of the crystallographic data,
see Table 1. CCDC 659372 ((À)-(5R,11R)-6, employing CuKa radiation),
659277 ((À)-(5R,11R)-6, employing MoKa radiation), 659278 ((+)-
(5R,11R)-5), and 659279 ((À)-(5S,11S)-5) contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
6H,12H-5,11-methanodibenzodiazocine (6):
A solution of 2 (1 g,
2.45 mmol) in THF (10 mL) was cooled to À788C. nBuLi (1.6m in n-
hexane; 3.66 mL, 5.87 mmol, 2.4 equiv) was added at this temperature
within 5 min and the resulting solution was stirred for another 5 min. Tri-
methylborate (0.82 mL, 7.35 mmol, 764 mg, 3 equiv) was added, and the
reaction mixture was warmed to room temperature and stirred for anoth-
er hour. The solvents were evaporated and the residue was suspended in
toluene (30 mL). Pinacol (1.16 g, 9.8 mmol, 4 equiv) was added, and the
resulting mixture was refluxed for 16 h. Water was added, the layers were
separated, and the aqueous layer was extracted three times with CH2Cl2.
The combined organic layers were dried with Na2SO4, and the solvents
were evaporated. The crude product was pure according to NMR spec-
troscopic analysis. If the product requires further purification, it can be
dissolved in CH2Cl2. Excessive n-hexane has to be added and the result-
ing solution has to be stored at À208C for 10 h. The white precipitate can
be collected and is pure 6. Yield: 970 mg (1.94 mmol, 79%); m.p.
>2508C; 1H NMR (500.1 MHz, CDCl3): d=1.29 (s, 24H;
(CH3)4]), 2.39 (s, 6H; PhCH3), 4.05 (d, 2J=À17.0 Hz, 2H; 6-endo-H, 12-
endo-H), 4.34 (s, 2H; 13-H), 4.59 (d, J=À17.0 Hz, 2H; 6-exo-H, 12-exo-
B[O2C2-
G
ACHTREUNG
2
Chem. Eur. J. 2008, 14, 4246 – 4255
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4253

A. Lützen, G. Bringmann et al.
Table 1. Crystallographic data for (À)-(5R,11R)-6, (+)-(5R,11R)-5, and
(À)-(5S,11S)-5.
[12] a) A. Tatibouet, M. Demeunynck, C. Andraud, A. Collet, J.
Lhomme, Chem. Commun. 1999, 161–162; b) Y. Hamada, S. Mukai,
Tetrahedron: Asymmetry 1996, 7, 2671–2674; c) E. Talas, J. Margit-
falvi, D. Machytka, M. Czugler, Tetrahedron: Asymmetry 1998, 9,
4151–4156.
(À)-(5R,11R)-6 (+)-(5R,11R)-5 (À)-(5S,11S)-5
formula
C29H40B2N2O4
C17H16Br2N2
C17H16Br2N2
Mr
502.25
408.14
408.14
[13] Y. Miyahara, K. Izumi, A. A. Ibrahim, T. Inazu, Tetrahedron Lett.
1999, 40, 1705–1708.
T [K]
223(2)
123(2)
123(2)
crystal system
space group
crystal dimensions
[mm]
orthorhombic
P212121
0.20”0.20”0.05 0.26”0.18”0.12 0.60”0.40”0.32
orthorhombic
P212121
orthorhombic
P212121
[14] S. Sergeyev, F. Diederich, Chirality 2006, 18, 707–712.
[15] a) S. Sergeyev, F. Diederich, Angew. Chem. 2004, 116, 1770–1773;
Angew. Chem. Int. Ed. 2004, 43, 1738–1740; b) S. Sergeyev, M.
Schaer, P. Seiler, O. Lukoyanova, L. Echegoyen, F. Diederich,
Chem. Eur. J. 2005, 11, 2284–2294; c) W. W. H. Wong, F. Diederich,
Chem. Eur. J. 2006, 12, 3463–3471.
[16] a) A. Lützen, M. Hapke, J. Griep-Raming, D. Haase, W. Saak,
Angew. Chem. 2002, 114, 2190–2194; Angew. Chem. Int. Ed. 2002,
41, 2086–2089; b) C. A. Schalley, A. Lützen, M. Albrecht, Chem.
Eur. J. 2004, 10, 1072–1080; c) U. Kiehne, A. Lützen, Org. Lett.
2007, 9, 5333–5336.
[17] J. Jensen, K. Wärnmark,Synthesis 2001, 1873–1877.
[18] U. Kiehne, A. Lützen, Synthesis 2004, 1687–1695.
[19] a) C. Solano, D. Svensson, Z. Olomi, J. Jensen, O. F. Wendt, K.
Wärnmark, Eur. J. Org. Chem. 2005, 3510–3517; b) F. Hof, M.
Schar, D. M. Scofield, F. Fischer, F. Diederich, S. Sergeyev, Helv.
Chim. Acta 2005, 88, 2333–2344.
[20] U. Kiehne, A. Lützen, Eur. J. Org. Chem. 2007, 5703–5711.
[21] a) U. Kiehne, T. Weilandt, A. Lützen, Org. Lett. 2007, 9, 1283–1286;
b) U. Kiehne, T. Weilandt, A. Lützen, Eur. J. Org. Chem. 2008, in
press (DOI 10.1002/ejoc.200701215).
a [Š], a [8]
b [Š], b [8]
c [Š], g [8]
V [Š3]
12.2311(4), 90
13.8425(4), 90
16.9817(5), 90
2875.15(15)
4, 1.160
10.3918(2), 90
11.5529(3), 90
12.4471(2), 90
1494.34(5)
4, 1.814
10.3918(2), 90
11.5541(3), 90
12.4454(3), 90
1494.29(6)
4, 1.814
Z, 1 [mgm3]
m [mmÀ1
]
0.595
5.419
5.419
q range [8]
4.12–67.97
93.9
15213
4736/3598
(0.0620)
2.55–31.00
99.9
43721
4762/3946
(0.0979)
3.10–30.99
99.8
21974
4756/4163
(0.0506)
completeness [%]
reflns measured
unique/observed
reflns (Rint
)
data/restraints/
parameters
Gof on F2
4736/0/345
4762/0/192
4756/0/193
1.029
0.964
0.990
final R indices
[I>2s(I)]
R indices (all data) R1 =0.081,
wR2 =0.1183
absolute structure
parameter x
R1 =0.052,
wR2 =0.100
R1 =0.028,
wR2 =0.053
R1 =0.040,
wR2 =0.056
À0.018(7)
R1 =0.023,
wR2 =0.043
R1 =0.030,
wR2 =0.044
À0.017(6)
[22] For a detailed insight into the mechanism of formation of Trçgerꢀs
bases, see: a) E. C. Wagner, J. Am. Chem. Soc. 1935, 57, 1296–1298;
b) E. C. Wagner, J. Org. Chem. 1954, 19, 1862–1881; c) C. A. M.
Abella, M. Benassi, L. S. Santos, M. N. Eberlin, F. Coelho, J. Org.
Chem. 2007, 72, 4048–4054.
0.0(3)
[23] D. A. Lenev, K. A. Lyssenko, D. G. Golovanov, V. Buss, R. G. Kos-
tyanovsky, Chem. Eur. J. 2006, 12, 6412–6418; for details concerning
the racemization process, see reference [10].
Acknowledgements
[24] M. Wolter, G. Nordmann, G. E. Job, S. L. Buchwald, Org. Lett. 2002,
4, 973–976.
[25] Hydrogenolysis of the benzyl ethers should be possible without de-
stroying the Trçgerꢀs base core according to: P. G. M. Wuts, T. W.
Greene, Protective Groups in Organic Synthesis, 4th ed., Wiley-
VCH, Weinheim, 2007.
Financial support for this work from the Deutsche Forschungsgemein-
schaft (grant nos.: SPP 1118 and SFB 624) and the Fonds der Chemischen
Industrie is gratefully acknowledged. G.S. thanks Prof. Dr. A. C. Filippou
for support.
[26] The following chiral phases were tested: (S,S)-Whelk-01 phase, silica
gel coated with a Daicel Chiralpak AS material (chiral selector:
[1] a) J. Trçger, J. Prakt. Chem. 1887, 36, 225–245; for recent reviews,
see: b) M. Valik, R. M. Strongin, V. Kral, Supramol. Chem. 2005, 17,
347–367; c) B. Dolensky, J. Elguero, V. Kral, C. Pardo, M. Valik,
Adv. Heterocycl. Chem. 2007, 93, 1–56.
[2] M. A. Spielman, J. Am. Chem. Soc. 1935, 57, 583–585.
[3] V. Prelog, P. Wieland, Helv. Chim. Acta 1944, 27, 1127–1134.
[4] G. Hesse, R. Hagel, Chromatographia 1973, 6, 277–280.
[5] For some examples, see: a) K. R. Lindner, A. Mannschreck, J. Chro-
matogr. 1980, 193, 308–310; b) H. Yuki, Y. Okamoto, I. Okamoto, J.
Am. Chem. Soc. 1980, 102, 6356–6358.
[6] For some examples, see: a) Y. Okamoto, E. Yashima, Angew. Chem.
1998, 110, 1072–1095; Angew. Chem. Int. Ed. 1998, 37, 1021–1043;
b) A. Kusuno, M. Mori, T. Satoh, M. Miura, H. Kaga, T. Kakuchi,
Chirality 2002, 14, 498–502.
[7] O. Cervinka, A. Fabryova, V. Novak, Tetrahedron Lett. 1966, 5375–
5377.
amylose-tris[(S)-a-methylbenzylcarbamate]),
a
Kromasil Chiral
DMB phase, a ReproSil 100 Chiral-1 phase (chiral selector in both
cases: O,O’-bis(3,5-dimethylbenzoyl)-N,N’-diallyl-l-tartaric acid
amide covalently attached to silica gel), and a Kromasil Chiral TBB
phase (chiral selector: O,O’-bis(4-tert-butylbenzoyl)-N,N’-diallyl-l-
tartaric acid amide covalently attached to silica gel).
[27] A. Hansson, J. Jensen, O. F. Wendt, K. Wärnmark, Eur. J. Org.
Chem. 2003, 3179–3188.
[28] D. A. Lenev, K. A. Lyssenko, D. G. Golovanov, O. R. Malyshev,
P. A. Levkin, R. G. Kostyanovsky, Tetrahedron Lett. 2006, 47, 319–
321.
[29] BDZDO/MCDSPD, J. W. Downing (modified by J. Fleischhauer, W.
Schleker, B. Kramer; ported to Linux by K.-P. Gulden), Department
of Chemistry and Biochemistry, University of Colorado, Boulder,
CO, 1992.
[30] S. Grimme, M. Waletzke, J. Chem. Phys. 1999, 111, 5645–5655.
[31] Structural data obtained from the X-ray crystal structure analysis of
(À)-6 employing MoKa radiation: C29H40B2N2O4; Mr =502.25; a=
12.0839(5), b=13.8472(4), c=16.8741(7) Š; a=b=g=908, V=
[8] a) S. F. Mason, K. Schofield, R. J. Wells, J. W. Whitehurst, G. W.
Vane, Tetrahedron Lett. 1967, 137–141; b) S. F. Mason, K. Schofield,
G. W. Vane, R. J. Wells, J. W. Whitehurst, J. Chem. Soc. B 1967,
553–556.
[9] S. H. Wilen, J. Z. Qi, P. G. Williard, J. Org. Chem. 1991, 56, 485–
487.
2823.51(18) Š3; Z=4; 1=1.182 mgmÀ3
;
orthorhombic; space
group=P212121. Data collection: Nonius-KappaCCD diffractometer
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(l=0.71073 Š); crystal dimensions: 0.60”0.40”0.08 mm; F
1080; qmax =288 (completeness 99.8%); À15<h<15, À15<k<18,
A
4254
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Chem. Eur. J. 2008, 14, 4246 – 4255

Trçgerꢀs Base Derivatives
FULL PAPER
À20<l<22; 25874 measured reflections, 6801 independent reflec-
tions (Rint =0.0775); m=0.077 mmÀ1; max. and min. transmissions=
0.9939 and 0.9555. Structural analysis and refinement: see the Ex-
perimental Section. GoF (F2)=0.886, final R indices ([I>2s(I)]):
R1 =0.0415, wR2 =0.0632; R indices (all data): R1 =0.0828, wR2 =
0.0712; max. and min. residual electron density: 0.176 and
À0.169 eŠ3; absolute structure parameters: 0.7(8).
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Received: December 11, 2007
Published online: March 20, 2008
Chem. Eur. J. 2008, 14, 4246 – 4255
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4255