Development of an axial chirality switch

Article abstract of DOI:10.1021/ol0700660

(Chemical Equation Presented) Switching axial chirality: The development and synthesis of a new axial chiral system, which shows solvent-dependent atropisomerism, is described. Control of axial chirality by the choice of solvent was studied by NMR and CD

Full text of DOI:10.1021/ol0700660

ORGANIC
LETTERS
2007
Vol. 9, No. 5
899-902
Development of an Axial Chirality
Switch
Stefan Reichert and Bernhard Breit*
Institut fu¨r Organische Chemie und Biochemie, Albert-Ludwigs-UniVersita¨t
Freiburg i. Brsg., Albertstr. 21, 79104 Freiburg i. Brsg., Germany
bernhard.breit@chemie.uni-freiburg.de
Received January 10, 2007
ABSTRACT
Switching axial chirality: The development and synthesis of a new axial chiral system, which shows solvent-dependent atropisomerism, is
described. Control of axial chirality by the choice of solvent was studied by NMR and CD spectroscopy.
In the past few years, there has been an increased interest in
the development and synthesis of systems capable of
performing a defined function on a molecular scale.1 This
includes molecular switches, characterized as systems which
due to the action of an external stimulus can change
reversibly between two distinct states. Known examples are
switchable rotaxanes and catechanes,2 conformational
switches,3 redox switches,4 as well as photo and chiroptical
switches.5 In many cases, processes known from nature have
served as role models for the design of artificial systems. In
this context, we became interested in the natural product FD-
594 which, dependent on the polarity of the solvent, can exist
in two conformations having opposite helicity (solvent-
dependent atropisomerism, Figure 1).6
A detailed conformational analysis of the aglycon of FD-
594 (1) revealed that the helicity of the biaryl axis is
connected to the preferred conformation in the central six-
membered ring C.6 Thus, the two hydroxy substituents at
carbon atoms 6 and 7 can occupy either a pseudobisequatorial
(biseq-1) or a pseudobisaxial position (bisax-1) (Figure 1)
which is a function of the solvent polarity. According to
proton NMR experiments in chloroform (µ ) 1.14 D, ꢀ )
(1) (a) Eelkema, R.; Pollard, M. M.; Vicario, J.; Katsonis, N.; Ramon,
B. S.; Bastiaansen, C. W. M.; Broer, D. J.; Feringa, B. L. Nature 2006,
440, 163. (b) Kinbara, K.; Aida, T. Chem. ReV. 2005, 105, 1377-1400. (c)
Feringa, B. L.; van Delden, R. A.; ter Wiel, M. K. J. Pure Appl. Chem.
2003, 75, 563-575. (d) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J.
F. Angew. Chem., Int. Ed. 2000, 39, 3348-3391. (e) Kelly, T. R.; de Silva,
H.; Silva, R. A. Nature 1999, 401, 150-152. (f) Koumura, N.; Zijlstra, R.
W. J.; van Delden, R. A.; Harada, N.; Feringa, B. L. Nature 1999, 401,
152-154.
(2) (a) Balzani, V.; Credi, A.; Silvi, S.; Venturi, M. Chem. Soc. ReV.
2006, 35, 1135-1149. (b) Qu, D.-H.; Wang, Q.-C.; Ren, J.; Tian, H. Org.
Lett. 2004, 6, 2085-2088. (c) Brouwer, A. M.; Frochot, C.; Gatti, F. G.;
Leigh, D. A.; Mottier, L.; Paolucci, F.; Roffia, S.; Wurpel, G. W. H. Science
2001, 291, 2124-2128.
(3) (a) Karle, M.; Bockelmann, D.; Schumann, D.; Griesinger, C.; Koert,
U. Angew. Chem., Int. Ed. 2003, 42, 4546-4594. (b) Yuasa, H.; Hashimoto,
H. J. Am. Chem. Soc. 1999, 121, 5089-5090.
(4) (a) Brayshaw, S. K.; Green, J. C.; Hazari, N.; McIndoe, J. S.; Marken,
F.; Raihby, P. R.; Weller, A. S. Angew. Chem., Int. Ed. 2003, 45, 6005-
6008. (b) Rathore, R.; Le Magueres, P.; Lindeman, S. V.; Kochi, J. K.
Angew. Chem., Int. Ed. 2000, 39, 809-812.
(5) (a) Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsma, E.
M. Chem. ReV. 2000, 100, 1789-1816. (b) Shinkai, S.; Minami, T.; Kusano,
Y.; Manabe, O. J. Am. Chem. Soc. 1983, 105, 1851-1856.
N
4.89, ET ) 0.259),7 FD-594 (1) prefers the biseq-1
conformation (3J6,7 ) 9.2 Hz)8 to allow the formation of a
stabilizing intramolecular hydrogen bond between the hy-
droxyl groups on C6 and C7.
However, when switching to methanol (µ ) 2.88 D, ꢀ )
N
32.66, ET ) 0.762)7 as the solvent, the intramolecular
hydrogen bond is broken, and minimization of gauche
(6) (a) Eguchi, T.; Kondo, K.; Kakinuma, K.; Uekusa, H.; Ohashi, Y.;
Mizoue, K.; Qiao, Y.-F. J. Org. Chem. 1999, 64, 5371-5376. (b) Qiao,
Y.; Okazaki, T.; Ando, T.; Mizoue, K.; Kondo, K.; Eguchi, T.; Kakinuma,
K. J. Antibiot. 1998, 51, 288-295.
(7) µ, dipole moment in debye; ꢀr, dielectricity constant; ETN, normalized
polarity parameter from: Reichardt, C. SolVents and SolVent Effects in
Organic Chemistry; Wiley-VCH: Weinheim, 2003.
(8) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870-2871.
10.1021/ol0700660 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/07/2007

able BINOL derivative with potentially manifold applications
in supramolecular chemistry and asymmetric catalysis.11
To get an idea about the influence of the ortho substituent
R on relative energies of biseq and bisax conformations, we
performed density functional gas-phase calculations for the
model systems 2-6 on the B3LYP/6-311+G(3df,2p)//
B3LYP/6-31G* level with Gaussian03.12 Thus, for all model
systems, geometry optimization for both distinguished
conformers was performed and the corresponding relative
energies were compared. For molecules 2 (Erel(zpe) ) 1.5 kcal/
mol), 3 (Erel(zpe) ) 1.4 kcal/mol), and 6 (Erel(zpe) ) 1.8 kcal/
mol), the biseq conformation was energetically favored.
Conversely, for molecules 4 (Erel(zpe) ) 2.2 kcal/mol) and 5
(Erel(zpe) ) 2.4 kcal/mol), the corresponding bisax conforma-
tion is preferred. Thus, with increasing steric demand of the
substituent R in the 1 position, the biseq conformation
becomes disfavored, which goes along with an increase of
A1,3-strain in the biseq conformation between the hydroxy
substituent at C10 and the R substituent at C1 (Scheme 1).
However, the situation for the methoxy-substituted system
6 is different.
Figure 1. Solvent-dependent atropisomerism of FD-594 (1, R )
H). Left: pseudobisequatorial hydroxyl substituents on C6 and C7
(biseq-1). Right: pseudobisaxial hydroxyl substituents on C6 and
C7 (bisax-1).
Here, the calculation suggests the possibility for an
additional stabilizing intramolecular hydrogen bond between
the hydroxy substituent at C10 and the methoxy substituent
at C1 (Figure 2). According to the gas-phase calculations,
interaction of the hydroxy substituents at C6/C7 now favors
the bisax-1 conformation (3J6,7 ) 3.6 Hz) and induces a
switch in helicity of the biaryl axis.
Intrigued by this interesting conformational behavior of
FD-594 (1), we became interested in the development of a
simplified artificial model system which could mimic the
solvent-dependent atropisomerism. As a minimal central core,
we identified the 9,10-dihydrophenanthren skeleton9 which
corresponds to the BCD-ring system of FD-594 (1, Scheme
1). The identification of the role of the methoxy substituent
Scheme 1. Minimal Model Systems Designed to Mimic
Solvent-Dependent Atropisomerism of FD-594
Figure 2. Optimized geometries (B3LYP/6-31G*) of (R,R)-6.
Left: biseq conformer with 2 hydrogen bonds. Right: bisax
conformer.
the stabilizing effect of this additional hydrogen bond
overcompensates the A1,3-strain.
To determine the preferred conformations of model
systems 2-6 in solution, compounds 2-6 were prepared
following a divergent strategy which allows the synthesis
of all compounds from a common precursor.
Thus, 3-methoxybenzaldehyde 7 was converted into the
corresponding cyclohexyl imine (Scheme 2). Position-
selective ortho metalation with LTMP13 and trapping of the
intermediate aryllithium species with iodine furnished iodide
8 in an almost quantitative yield. To effect a biaryl coupling
toward the sterically crowded tetra-ortho-substituted biaryl
at the D-ring in FD-594 (1) was an important aspect. We
speculated that the gauche orientation of the hydroxy substi-
tuents at C6 and C7 is disfavored by A1,3-strain10 exerted by
the ortho-methoxy substituent at ring D. Therefore, the influ-
ence of substituents R at carbon 1 of the model system (2-
6) should be explored. Furthermore, the hydroxyl groups at
positions 4 and 5 were incorporated into the model system
(protected as methyl ethers) because, if this concept was
successful, the system could behave and be used as a switch-
(9) For conformational investigations on 9,10-dihydrophenanthrene
derivatives, see: (a) Cobb, D. I.; Lewis, A.; Armstrong, R. N. J. Org. Chem.
1983, 48, 4139-4141. (b) Armstrong, R. N.; Lewis, D. A.; Ammon, H. L.;
Prasad, S. M. J. Am. Chem. Soc. 1985, 107, 1057-1058. (c) Darnow, J.
N.; Armstrong, R. N. J. Am. Chem. Soc. 1990, 112, 6725-6726.
(10) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860.
(11) (a) Kyba, E. B.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D. J.
J. Am. Chem. Soc. 1973, 95, 2692-2693. (b) Noyori, R.; Tomino, I.;
Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6709-6716.
(c) For a review, see: Brunel, J. M. Chem. ReV. 2005, 105, 857-897.
(12) Frisch, M. J. et al. Gaussian 03, revision B.04. See Supporting
Information for full citation.
900
Org. Lett., Vol. 9, No. 5, 2007

system 9, a mild variant of the Ullmann coupling with
copper(I) thiophenecarboxylate (CuTC) was chosen.14 After
acidic workup, the bisaldehyde 9 was obtained in good yield
(86%). Monobromination of 9 gave regioselectively biphenyl
system 10 (Scheme 2).
appropriate electrophile allowed us to install the desired sub-
stituents at carbon 1. Final pinacol coupling furnished the
model compounds 3-6 in moderate to good yields (Table 1).
With the thus-obtained model systems 2-6, NMR studies
were performed in methanol and in chloroform to determine
the preferred conformation in solution. It is known that the
barrier of rotation of biaryl systems is lowered, if they are
bridged by a six-membered ring.16 At room temperature,
molecules 2, 3, and 6 showed broadened signals due to an
exchange process. Therefore, the conformer population for
all diols 2-6 was determined by integration of the signals
for H9 and H10 in the proton NMR measured at T ) 240 K
(Table 2).17
Scheme 2. Synthesis of Bisaldehyde 9 and Key Intermediate
10a
Table 2. Conformer Equilibria for Diols 2-6 Determined by
NMR at 240 Ka
entry
compound
solvent
biseq (%)
bisax (%)
1b
2b
3
4
5
6
7
8
9
2
CD3OD
CDCl3
CD3OD
CDCl3
CD3OD
CDCl3
CD3OD
CDCl3
94
98
nd
32
nd
nd
nd
nd
nd
58
82
6
2
>99
68
>99
>99
>99
>99
>99
42
3
4
5
6
CuTC ) copper(I) thiophenecarboxylate; b.o.r.s.m. ) based on
recovered starting material.
CD3OD
CDCl3
toluene-d8
10
11
18
The unsubstituted model system 2 was obtained by
samarium diiodide mediated anti diastereoselective pinacol
coupling of bisaldehyde 9 (Table 1).15 After protection of
a
nd ) not detected. Assignment of the corresponding conformations
has been made on the basis of the size of the 3J9,10 coupling constant. b For
symmetrical compound 2, the J9,10 coupling constant was determined
3
employing a nondecoupled HSQC experiment.
Table 1. Synthesis of Model Compounds 2-6
In the case of the unsubstituted diol 2, the biseq conforma-
tion was preferred in chloroform as well as in methanol. For
the chlorine- and bromine-substituted derivatives 4 and 5,
only the bisax conformation was detectable in both methanol
and chloroform, which is in agreement with the calculations.
However, in the case of the fluorine- and methoxy-substituted
systems 3 and 6, respectively, a significant influence of the
nature of the solvent on the conformational equilibrium could
be observed. Thus, for 6 in methanol, the bisax conformation
is populated to more than 99% (Table 2, entry 9). However,
when going to CDCl3 as the solvent, a 58:42 equilibrium in
favor of the biseq conformer was detected (entry 10).
Interestingly, when using the even less polar solvent toluene
(µ ) 0.30 D, ꢀ ) 2.38, ETN ) 0.099), the equilibrium could
be shifted far toward the biseq conformer (Table 2, entry
11). Thus, in agreement with theory, the methoxy-substituted
biaryl system 6 seemed an appropriate candidate to imitate
product
(yield)
entry
conditions
substrate
1
2
(1) SmI2, THF, 0 °C
9
2 (88%)
3 (19%)
(1) CyNH2, MgSO4, CH2Cl2, rt
(2) n-BuLi, THF, - 78 °C, then
(PhSO2)2NF, HCl
10
(3) SmI2, THF, 0 °C
3
(1) CyNH2, MgSO4, CH2Cl2, rt
(2) n-BuLi, THF, - 78 °C then
C2Cl6, HCl
10
4 (36%)
(3) SmI2, THF, 0 °C
4
5
(1) SmI2, THF, 0 °C
10
10
5 (72%)
6 (44%)
(1) CyNH2, MgSO4, CH2Cl2, rt
(2) n-BuLi, THF, - 78 °C then
Davis oxaziridine, HCl
(3) dimethyl sulfate, DME
(4) SmI2, THF, 0 °C
(13) Flippin, L. A.; Muchowski, J. M.; Carter, D. S. J. Org. Chem. 1993,
58, 2463-2467.
(14) Liebeskind, L. S.; Zhang, S.; Zhang, D. J. Org. Chem. 1997, 62,
2312-2313.
(15) Ohmori, K.; Kitamura, M.; Suzuki, K. Angew. Chem., Int. Ed. 1999,
38, 1226-1229.
(16) Bringmann, G.; Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner,
J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384-5427.
(17) Temperature-dependent NMR experiments of 6: see Supporting
Information.
the bisaldehyde function in 10 as the corresponding bisimine,
bromine lithium exchange and subsequent trapping with an
Org. Lett., Vol. 9, No. 5, 2007
901

the helicity switch of the natural product FD-594 (1). Hence,
rac-6 was separated into its enantiomers employing prepara-
tive HPLC (Chiracel AD-H).
can be assigned as P-(R,R)-6 in n-hexane and as M-(R,R)-6
in methanol.18 Additionally, CD spectra of 6 were calculated
employing quantum chemical methods (TD-B3LYP/TZ-
VP).19 Comparison between calculated and experimental CD
curves confirmed the configurational assignment for 6
(Figure 3).12,19
For enantiomerically pure 6, CD spectra were recorded
N
in n-hexane (µ ) 0.0 D, ꢀ ) 1.88, ET ) 0.009) and in
methanol (µ ) 2.88 D, ꢀ ) 32.66, ETN ) 0.762), respectively
(Figure 3). As expected, the CD spectra behave like mirror
These experiments illustrate that the axial chirality of 6
can be controlled by choice of the solvent environment.
Hence, the solvent-dependent atropisomerism of the complex
natural product FD-594 (1) could be transferred to the much
simpler model system 6. Modification of 6 and its application
as a molecular switch as well as a switchable ligand for
asymmetric catalysis are the subjects of current research in
these laboratories.
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie and the Krupp Award for Young
University Teachers (B.B.). S.R. thanks the Fonds der
Chemischen Industrie for a Ke´kule´ fellowship. Preliminary
investigations by Dr. G. Stavrakov (Univ. Freiburg) are
acknowledged. We thank Prof. Dr. T. Koslowski (Univ.
Freiburg) for help with the calculations, Dr. M. Keller for
NMR experiments, and Dr. R. Krieger and G. Fehrenbach
for HPLC analysis (all Univ. Freiburg).
Figure 3. Experimental and calculated CD spectra for the (R,R)-
enantiomer of 6. Blue: exptl CD curve of P-(R,R)-6 in n-hexane
(c ) 1.3 × 10-5 M, rt). Magenta: calcd CD curve of P-(R,R)-6.
Red: exptl CD curve of M-(R,R)-6 in methanol (c ) 1.3 × 10-5
M, rt). Yellow: calcd CD curve of M-(R,R)-6.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0700660
images and thus confirm a complete helicity switch of the
biaryl chromophore as a consequence of change in solvent
environment. From comparison with known 9,10-dihydro-
phenanthene derivatives, the helicity of the biaryl chro-
mophore was assigned as P-6 in n-hexane and as M-6 in
methanol.9,18 With the known relative configuration at C9
and C10 from NMR experiments, the absolute configuration
(18) (a) Lakshman, M. K.; Xiao, W.; Sayer, J. M.; Cheh, A. M.; Jerina,
D. M. J. Org. Chem. 1994, 59, 1755-1760. (b) Gawron˜ski, J.; Grycz, P.;
Kwit, M.; Rychlewska, U. Chem.-Eur. J. 2002, 8, 4210-4215.
(19) (a) Furche, F.; Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski,
A.; Vo¨gtle, F.; Grimme, S. J. Am. Chem. Soc. 2000, 122, 1717-1724. (b)
Autschbach, J.; Ziegler, T.; van Gisbergen, S. J. A.; Baerends, E. J. J. Chem.
Phys. 2002, 116, 6930-6940. (c) Brown, A.; Kemp, C. M.; Mason, S. F.
J. Chem. Soc. A 1971, 751-755.
902
Org. Lett., Vol. 9, No. 5, 2007