Synthesis, conformational stability, and asymmetric transformation of atropisomeric 1,8-bisphenolnaphthalenes

Article abstract of DOI:10.1021/jo200309g

Highly congested, axially chiral 1,8-bisphenolnaphthalenes have been synthesized in 75% overall yield by palladium-catalyzed Suzuki coupling of 1,8-diiodonaphthalene and 4-methoxy-2-methylphenylboronic acid followed by regioselective formylation and deprotection. The C₂-symmetric anti-stereoisomers of 1,8-bis(2′-methyl-4′-hydroxy-5′- formylphenyl)naphthalene, 5, and its diimine analogues 9 and 10 were found to be significantly more stable than the corresponding syn-isomer. Crystallographic analysis revealed that this stereochemical preference results from a unique intramolecular hydrogen bonding motif and concomitant minimization of steric repulsion. Triaryl 5 proved stable to rotation about the chiral axes at room temperature and the enantiomers were isolated via formation of diastereomeric diimines with (R)-2-amino-1-propanol and (R)-2-amino-3-methyl-1-butanol, respectively, chromatographic separation, and mild hydrolysis. Slow syn/anti-interconversion of 5, 9, and 10 was observed at enhanced temperatures and the diastereomerization and enantiomerization processes were monitored by CD and NMR spectroscopy. The Gibbs activation energy, ΔG^?, for the isomerization of 5 was determined as 103.7 (102.4) kJ/mol for the conversion of the anti-(syn-) to the syn-(anti-)isomer at 45.0 °C. Condensation of 5 with two chiral amino alcohols generates diimines that undergo quantitative asymmetric transformation of the first kind toward the thermodynamically favored (P,P,R,R)- or (M,M,S,S)-atropisomer, respectively. The incorporation of two imino alcohol units controls the outcome of this unidirectional atropisomerization, i.e. the central chirality of the amino alcohol used induces a rigid, axially chiral triaryl scaffold with perfect stereocontrol. Accordingly, the rotational energy barrier for the conversion of (M,M,S,S)-9 to its syn-isomer is significantly increased and was determined as 115.7 kJ/mol at 58.0 °C.

Full text of DOI:10.1021/jo200309g

ARTICLE
pubs.acs.org/joc
Synthesis, Conformational Stability, and Asymmetric Transformation
of Atropisomeric 1,8-Bisphenolnaphthalenes
Marwan W. Ghosn and Christian Wolf *
Department of Chemistry, Georgetown University, Washington, D.C. 20057, United States
S Supporting Information
b
ABSTRACT: Highly congested, axially chiral 1,8-bisphenol-
naphthalenes have been synthesized in 75% overall yield by
palladium-catalyzed Suzuki coupling of 1,8-diiodonaphthalene
and 4-methoxy-2-methylphenylboronic acid followed by regio-
selective formylation and deprotection. The C2-symmetric anti-
stereoisomers of 1,8-bis(20-methyl-40-hydroxy-50-formylphenyl)
naphthalene, 5, and its diimine analogues 9 and 10 were found
to be significantly more stable than the corresponding syn-
isomer. Crystallographic analysis revealed that this stereochem-
ical preference results from a unique intramolecular hydrogen
bonding motif and concomitant minimization of steric repul-
sion. Triaryl 5 proved stable to rotation about the chiral axes at room temperature and the enantiomers were isolated via formation of
diastereomeric diimines with (R)-2-amino-1-propanol and (R)-2-amino-3-methyl-1-butanol, respectively, chromatographic
separation, and mild hydrolysis. Slow syn/anti-interconversion of 5, 9, and 10 was observed at enhanced temperatures and the
diastereomerization and enantiomerization processes were monitored by CD and NMR spectroscopy. The Gibbs activation energy,
ΔGq, for the isomerization of 5 was determined as 103.7 (102.4) kJ/mol for the conversion of the anti-(syn-) to the syn-(anti-)isomer
at 45.0 °C. Condensation of 5 with two chiral amino alcohols generates diimines that undergo quantitative asymmetric
transformation of the first kind toward the thermodynamically favored (P,P,R,R)- or (M,M,S,S)-atropisomer, respectively. The
incorporation of two imino alcohol units controls the outcome of this unidirectional atropisomerization, i.e. the central chirality of
the amino alcohol used induces a rigid, axially chiral triaryl scaffold with perfect stereocontrol. Accordingly, the rotational energy
barrier for the conversion of (M,M,S,S)-9 to its syn-isomer is significantly increased and was determined as 115.7 kJ/mol at 58.0 °C.
Scheme 1. Synthesis of 1,8-Bis(30-formyl-40-hydroxyphenyl)-
’ INTRODUCTION
naphthalene, 1
The intriguing structure and dynamic stereochemistry of
axially chiral compounds has fueled their use in asymmetric
synthesis, chiral recognition, the design of microscopic devices
such as molecular motors and switches, drug discovery, and other
areas.1 Undoubtedly, the exceptional diversity and the unique
stereochemical, electronic, and photochemical properties of both
conformationally stable and rapidly racemizing axially chiral
biaryls and polyaryls have led to a wide variety of applications.2
It is therefore not surprising that structural analysis along with
sensors,9 we recently prepared 1,8-bis(30-formyl-40-hydroxyphe-
nyl)naphthalene, 1, exhibiting two salicylaldehyde rings in the peri-
positions of naphthalene via Suzuki coupling of 1,8-diiodo-
the study of enantiomerization and diastereomerization pro-
cesses of mono- and disubstituted naphthalenes have received
significant attention.3 Alkyl,4 aryl,5 and heteroaryl6 groups have
naphthalene and boronic acid 2 followed by deprotection of
been introduced into the naphthalene framework to study the
dialdehyde 3 (Scheme 1).10
energy barrier to rotation about the naphthylꢀalkyl or
Triaryl 1 undergoes fast rotation about the two arylꢀaryl
bonds at room temperature, which results in the interconversion
of the enantiomeric anti-isomers via the thermodynamically less
stable meso syn-intermediate. We realized that imine formation
with amino alcohols disturbs this equilibrium and strongly favors
naphthylꢀaryl bond and intramolecular interactions between
proximate alkyl and aryl groups. In particular, the incorporation
of two phenol rings into a rigid C2-symmetric scaffold that is
reminiscent of the successful BINOL motif has been of general
interest due to potential applications in asymmetric catalysis and
enantioselective sensing for a long time.7
In continuation of previously conducted studies with stereodynamic
Received: February 11, 2011
Published: April 08, 2011
chiral biaryls and triaryls,8 and 1,8-diheteroarylnaphthalene-derived
r
2011 American Chemical Society
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Scheme 2. Central-to-Axial Chirality Induction upon Diimine Formation with Stereodynamic Triaryl 1
Scheme 3. Structures of 4 Exhibiting anti-Parallel (anti-Iso-
mer) and Parallel (syn-Isomer) 2-Methylphenyl Moieties and
of 5
of methyl groups into the ortho-positions of 1 would produce
conformational isomers that are stable to interconversion and
separable at room temperature (Scheme 3). We therefore
decided to prepare 1,8-bis(20-methyl-40-hydroxy-50-formylphe-
nyl)naphthalene, 5, exhibiting moderate bulk adjacent to the
chiral axes which should suffice to isolate and characterize the
stereoisomers of this atropisomer and its diimine derivatives
while racemization and diastereomerization reactions could be
studied at elevated temperatures.
’ RESULTS AND DISCUSSION
We began the synthesis of 5 with Suzuki coupling of 1,8-
diiodonaphthalene and commercially available 4-methoxy-2-
methylphenylboronic acid, 6 (Scheme 4). Initially, we screened
the effect of various catalysts, solvents, base, and temperature to
identify suitable reaction conditions for the construction of the
sterically congested scaffold of 5. We were pleased to find that 1,8-
bis(20-methyl-40-methoxyphenyl)naphthalene, 7, can be obtained
in quantitative amounts by using Pd(PPh3)4 as catalyst and K3PO4
as base in toluene. NMR analysis revealed that 7 was a 1:3 mixture
of the syn- and anti-isomers. The Vilsmeier reaction with an excess
of phosphorus oxychloride and dimethyl formamide then furn-
ished 1,8-bis(20-methyl-40-methoxy-50-formylphenyl)naphthalene,
8, with 99% yield in approximately the same diastereomeric
ratio. Finally, deprotection with boron tribromide gave 5 having a
syn- and anti-isomer ratio of 1:4 in 77% yield.
The diastereomers of 8 were separated by column chroma-
tography and the racemic anti-isomer was converted to anti-5
and then to (P,P,R,R)-9 and (M,M,R,R)-9 by condensation with
2 equiv of (R)-2-amino-1-propanol. The diimine formation
proceeds with quantitative yields and is completed at room
temperature within 1 h. Chromatographic purification on silica
gel then allowed isolation of the two diastereomeric products
(Scheme 5). Heating of the diastereomeric mixture of 9 to
establish thermodynamic equilibrium showed that the first eluted
diimine corresponds to the more stable diastereomer, see below.
The sense of amplification of asymmetric induction observed
with the diimines of 1 and CD and crystallographic analysis of 5
population of a single diastereomer that is stabilized by intramo-
lecular hydrogen bonding (Scheme 2). The diimine formed
displays strong Cotton effects at high wavelengths and NMR
and crystallographic analysis showed that the central chirality of
the amino alcohol substrate induces a rigid, axially chiral triaryl
scaffold with perfect stereocontrol: Condensation of 1 and (R)-
amino alcohols results in well-defined amplification of asym-
metric induction and the triaryl was found to adopt an (M,M)-
conformation. The opposite sense of chiral induction was
observed with (S)-amino alcohols. We were able to demonstrate
that the fast diimine formation, which is complete within 5 min,
followed by in situ CD measurements allows time-efficient
determination of the absolute configuration and the enantio-
meric purity of the substrate used. Similar results were obtained
with amino acids.11
We envisioned that a less fluxional analogue of 1 would
provide further insights into (a) the amplification of asymmetric
induction and (b) the effect of the intramolecular hydrogen
bonding on the conformational stability of the diimine deriva-
tives and provide (c) an entry to the potential use of these
compounds in enantioselective recognition and catalysis. Since
Clough and Roberts estimated the energy barrier to syn/anti-
diastereomerization of 1,8-bis(2-methylphenyl)naphthalene, 4,
as approximately 100 kJ/mol,12 we expected that incorporation
Scheme 4. Synthesis of 1,8-Bis(20-methyl-40-hydroxy-50-formylphenyl)naphthalene, 5
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Scheme 5. Isolation of Enantiopure 5
Figure 1. 1H NMR spectra of diimine diastereomers obtained from racemic 5 and (R)-2-amino-1-propanol and quantitative conversion toward (P,P,R,R)-9:
(A) 60 °C, 0 h, (B) 60.0 °C, 14 h; /, corresponds to (M,M,R,R)-9; q corresponds to (P,P,R,R)-9.
and 9 suggest that (P,P,R,R)-9 is the thermodynamically favored
atropisomer. Hydrolysis of (P,P,R,R)-9 with aqueous HCl at 0 °C
afforded enantiopure (P,P)-5 in 85% yield, with no trace of the
syn-diastereomer based on NMR analysis. The enantiopurity of 5
was confirmed by derivatization to the corresponding (P,P,R,R)-
diimine with (R)-2-amino-1-propanol and NMR analysis did not
show any signals of the diastereomeric (M,M,R,R)-isomer.
On the basis of our experience with stereolabile 1, which
spontaneously adopts a single conformation upon diimine for-
mation with enantiopure amino alcohols and the kinetic analysis
of 4 by Clough and Roberts, we investigated the possibility to
convert the atropisomeric mixture of 9 to a single isomer upon
heating. Such an asymmetric transformation of the first kind
would generate the thermodynamically favored diimine isomer
and thus facilitate the formation of enantiopure 5 with a theoretical
yield of 100% and without the need for an elaborate chromato-
graphic separation of the equimolar mixture of (M,M,R,R)- and
(P,P,R,R)-9. Several cases in which asymmetric transformation of
the first kind was used to manipulate the diastereomeric ratio of
axially chiral compounds have been reported. For example, Meyers
et al. found that the stereochemical outcome of the diastereoselective
oxazoline-mediated asymmetric Ullmann coupling of aryl bromides
is significantly improved upon heating of the product mixture.13 This
transformation favors the formation of the desired (P)-atropisomer,
a key intermediate for the total synthesis of permethylated
tellimagrandin.14 The same principle has been used for the derace-
mization of o-dihydroxylated biaryl ligands VANOL and VAPOL15
and for the preparation of the aglycon of vancomycin.16
We realized that (M,M,R,R)- and (P,P,R,R)-9, formed from
racemic 5 and (R)-2-amino-1-propanol at 25 °C, showed distinct
NMR spectra, for example two doublets at 1.26 and 1.40 ppm
corresponding to the imino alcohol methyl groups (Figure 1). We
therefore used NMR analysis to monitor the atropisomerization
process. Upon heating to 60.0 °C, the signals of the thermodynami-
cally less favored diastereomer decreased in intensity and (P,P,R,R)-9
with >98% de was obtained after 14 h.
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Figure 3. Different views of the crystal structure of (P,P)-5.
Figure 2. CD spectra of (P,P)-5 (blue), (P,P,R,R)-9 (red), and(P,P,S,S)-9
(green) at 5.0 ꢁ 10ꢀ5 M in CHCl3.
Scheme 6. Interconversion of the Stereoisomers of 5
We previously reported that condensation of stereolabile 1
and (R)-2-amino-1-propanol exclusively generates the (M,M,R,R)-
stereoisomer, which is the thermodynamically favored confor-
mer due to stabilization by intramolecular hydrogen bonding
and concomitant minimization of steric repulsion. Accordingly,
diimine formation with (S)-2-amino-1-propanol gave the (P,P,S,S)-
enantiomer, Scheme 2.10 These results are in perfect agreement
with the asymmetric transformation of a mixture of (M,M,R,R)-
and (P,P,R,R)-9 toward the latter diastereomer. In analogy to
the amplification of asymmetric induction observed with 1,
the central chirality of the imino alcohol moiety in 9 controls
the chiral amplification and induces the same sense of axial
chirality.17 Since the atropisomerization occurs with more than
99% de, it provides quantitative access to stereochemically pure 9
on the gram scale, which can then be hydrolyzed without
concomitant isomerization to enantiopure 5. Having developed
a convenient procedure producing (P,P)-5, we were able to
prepare (P,P,R,R)-9 and (P,P,S,S)-9, the thermodynamically less
stable diastereomer, via condensation with either enantiomer of
2-amino-1-propanol. Analyzing the CD spectra of the enantio-
meric (M,M,R,R)-and (P,P,S,S)-diimines of 1, we previously
speculated that the Cotton effects are predominantly controlled
by the sense of axial chirality while the chiral centers in the imino
alcohol units were expected to have little or no effect on the
chiroptical properties. Comparison of the CD spectra of (P,P)-5,
(P,P,R,R)-9, and (P,P,S,S)-9, all exhibiting the same sense of axial
chirality, now clearly shows that this assumption is correct
(Figure 2). The three atropisomers exhibit a pronounced positive
Cotton effect, and the incorporation of the diimino alcohol units
results in a significant red shift. Importantly, the diastereomeric
(P,P)-diimines of 9 show almost perfectly superimposable CD
spectra, which underscores the overwhelming or possibly ex-
clusive contribution of the relative orientation of the two cofacial
salicylidenimine rings to the observed CD activity.18
the large CD amplitudes of (P,P)-5 can be attributed to strong
exciton coupling of the cofacial chromophores.
We then turned our attention to the kinetic analysis of 5
(Scheme 6). Interconversion of the stereoisomers of 5 requires
one salicylaldehyde ring to rotate about the chiral naphthylꢀ
phenyl axis. Accordingly, the edge of the rotating ring points
toward the adjacent phenyl moiety in the transition state. In
general, this process can proceed via two T-shaped transition
states having the methyl group of the rotating phenyl ring either
directed toward or away from the other phenyl ring.19 The latter
orientation is expected to afford significantly less steric hindrance
and is therefore the favored interconversion pathway.
A solution of (P,P)-5 in chloroform was stirred at 45.0 °C and
small aliquots were taken at 1 h intervals and diluted to 5.0 ꢁ
10ꢀ5 M for CD analysis. After 10 h, the CD signals disappeared
indicating complete racemization (Figure 4). The syn/anti ratio
of 5 at 45.0 °C in chloroform at equilibrium was determined by
1H NMR spectroscopy as 23.4:76.6. The observed ratio corre-
sponds to a difference in Gibbs free energy of the anti- and syn-
isomers, ΔG, of 1.3 kJ/mol according to the Boltzmann eq 1.20
2Nsyn=Nanti ¼ expð ꢀ ΔGo=RTÞ
ð1Þ
Figure 5 shows the decrease of the mole fraction of (P,P)-5 as a
function of time. The mathematical solution for the kinetics of
consecutive, first-order, reversible reactions involving three species
such as the syn/antiinterconversion of 5 has been reported by
Vriens.21 Curve fit analysis with use of eq 2 allowed the determina-
tion of the rate constant for the anti- to syn-isomerization, k1.
Slow evaporation of a solution of enantiopure (P,P)-5 in chloro-
form gave single crystals suitable for X-ray studies (Figure 3). As
expected, crystallographic analysis shows that the two salicylaldehyde
rings reside in almost perfectly perpendicular orientation relative to
the naphthalene backbone, exhibiting a C2-symmetric structure with
a torsion angle of 5.32°. The splaying between the two phenyl rings
was determined as 20.51°, which results in a centroidal phenyl-to-
phenyl separation of 3.47 Å. On the basis of the enforced π-stacking
of the proximate salicylaldehyde rings, the positive Cotton effect and
R
x ¼ C1eD k t þ C2eD k t
þ
ð2Þ
1
1
2 1
K1K2E2
k1 = rate constant of the anti-tosyn-interconversion, K1 = equilibrium
constant for the formation of the syn-isomer, K2 = equilibrium
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Scheme 7. Interconversion of the Atropisomers of 9
Figure 4. Decrease of the CD signal of (P,P)-5 as a result of racemiza-
tion in chloroform (6.95 ꢁ 10ꢀ4 M) at 45.0 °C. The CD spectra were
collected at 25 °C at a concentration of 5.0 ꢁ 10ꢀ5 M in chloroform.
Figure 6. Analysis and curve fitting of the change in the mole fractions
of (P,P,S,S)-9 (red), (M,P,S,S)-9 (black), and (M,M,S,S)-9 (blue) upon
heating of (P,P,S,S)-9 to 58.0 °C in chloroform.
benzylic 1H NMR signals of the three diastereomers (see the SI
for details). Equilibrium was reached after 2 days, and the
atropisomeric ratio was determined as 94.4:3.9:1.7 [(M,M,S,S):
(P,P,S,S):(M,P,S,S)] (Figure 6). Accordingly, the thermodyna-
mically favored (M,M,S,S)-atropisomer is more stable than the
syn-intermediate by 11.2 kJ/mol while conversion of the latter to
(P,P,S,S)-9 is driven by only 2.4 kJ/mol. Comparison of the
relative amounts of the two anti-isomers of 9 reveals a difference
in Gibbs free energy of 8.8 kJ/mol. Crystallographic analysis of
syn-9 and (P,P,R,R)-10 shows that these results can be explained
by selective intramolecular hydrogen bonding and concomitant
optimization of steric repulsion in (M,M,S,S)-9, vide infra.
Following Vriens’ mathematical treatment for two consecutive
reversible reactions and curve fitting we then determined the
individual rotational energy barriers (see the SI for details). The
interconversion of (P,P,S,S)-9 to the syn-diastereomer has a
Gibbs activation energy, ΔGq(P,P,S,S)-9f(P,M,S,S)-9, of 108.7 kJ/mol.
The intermediate syn-isomer undergoes diastereomerization to
the two anti-conformers and the corresponding activation en-
ergies were calculated as 106.3 (ΔGq(M,P,S,S)-9f(P,P,S,S)-9) and
104.5 kJ/mol (ΔGq(M,P,S,S)-9f(M,M,S,S)-9). As expected from the
asymmetric transformation experiments discussed above, the
energy barrier for the conversion of (M,M,S,S)-9 to the syn-
isomer, ΔGq(M,M,S,S)-9f(M,P,S,S)-9, is significantly higher and was
determined as 115.7 kJ/mol. To confirm these data, we analyzed
the initial decay of (P,P,S,S)-9 at low conversion (less than 2%
completion), which can be approximately treated as an irreversible
first-order reaction (see the Experimental Procedures section). We
thus obtained a rotational energy barrier, ΔGq(P,P,S,S)-9f(M,P,S,S)-9, of
Figure 5. Change in the mole fraction of (P,P)-5 upon heating to 45.0 °C.
For conditions, see Figure 4.
constant for the formation of either anti-isomer, R = ratio of
forward rate constants (k2/k1) for the consecutive, reversible, first-
order reactions, k2 = rate constant for syn- to anti-interconversion,
and C1, C2, D1, D2, and E2 are constants.22
Having determined the syn/anti-ratio and thus the equilibrium
constant for the isomerization of 5, wewereabletodeterminetherate
constants for the reversible interconversion steps, k1 and k2, as 6.308
ꢁ 10ꢀ5 sꢀ1 for the anti f syn and as 1.038 ꢁ 10ꢀ4 sꢀ1 for the syn f
anti interconversion, respectively. As expected, the observed isomer-
izations proved to obey first-order kinetics. With use of the Eyring
equation, the Gibbs activation energy, ΔGq, for the atropisomeriza-
tion of 5was calculated as 103.7 (102.4) kJ/mol for the conversion
of the anti-(syn-) to the syn-(anti-)isomer (see the SI).
The analysis of the atropisomerization of 9 is more compli-
cated and involves four different rate constants (Scheme 7).
Because CD analysis does not provide quantitative information
about individual diastereomer concentrations we used NMR
spectroscopy to monitor the conversion of (P,P,S,S)-9, which
was prepared by condensation of (P,P)-5 with 2 equiv of (S)-2-
amino-1-propanol, to the thermodynamically stable atropisomer
(M,M,S,S)-9 via the intermediate (M,P,S,S)-isomer.
A solution of (P,P,S,S)-9 in deuterated chloroform was heated
to 58.0 °C and the isomerization was studied by integration of the
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undergo hydrogen bonding with the adjacent imines) while the
steric bulk of the imino alcohol moieties is placed outside of this ring
structure in the least crowded positions. The CdN HOCphenyl
3 3 3
and the CaliphOH OCphenyl hydrogen bond lengths are 1.861 and
2.178 Å, respectively.
3 3 3
In analogy to the results obtained with 9, we observed
quantitative asymmetric transformation of the first kind with 10,
which can be used to prepare either pure (M,M,S,S)- or (P,P,R,R)-
atropisomers of these diimines. The kinetic and thermodynamic
analyses of the unidirectional atropisomerization process of 9 and
10 discussed above and in the SI are in perfect agreement with the
crystallographic data showing distinct stabilization of the (P,P,R,R)-
isomer due to intramolecular hydrogen bonding and minimized
steric repulsion between the imine moieties.
We also found that (P,P)-5 can be used for the kinetic
resolution of the enantiomers of 2-amino-1-propanol. Diimine
formation of the enantiopure dialdehyde 5 and 4 equiv of the
racemic substrate at room temperature followed by extraction after
5 h allowed recovery of the remaining amino alcohol in 47% yield.
Chiral HPLC analysis showed that the (S)-amino alcohol was
enriched to 54% ee, which proves the expected favored formation
of (P,P,R,R)-9 (see the Experimental Procedures section).
In conclusion, we have synthesized the first examples of axially
chiral 1,8-bisphenolnaphthalenes that are stable to racemization
at room temperature. The incorporation of two ortho-substi-
tuted phenol moieties into a rigid C2-symmetric scaffold that is
reminiscent of the successful BINOL motif has been of general
interest due to potential applications in asymmetric catalysis and
enantioselective sensing for a long time. Stereochemical analysis
showed that the anti-stereoisomers of 1,8-bis(20-methyl-40-hy-
droxy-50-formylphenyl)naphthalene, 5, and its diimine analogues
9 and 10 are significantly more stable than the corresponding syn-
isomer. Slow syn/anti-interconversion, obeying reversible first-
order kinetics, of 5, 9, and 10 occurs at elevated temperatures and
this provides a convenient entry toward enantiopure bisphenols
that can be prepared on the gram scale via asymmetric transfor-
mation of the first kind. Spectroscopic NMR and CD analyses
supported by crystallography of syn- and anti-1,8-bisphenol-
naphthalenes showed that the incorporation of two imino
alcohol units into the triaryl scaffold controls the outcome of
the unidirectional atropisomerization with literally perfect
stereocontrol, resulting from a unique intramolecular hydrogen
bonding motif and concomitant reduction of steric repulsion.
While the stereochemical bias of the atropisomers studied
originates from the central chirality of the incorporated amino
alcohol units, the chiroptical properties are solely determined by
the sense of axial chirality. Chiral recognition studies using 1,8-
bisphenolnaphthalenes as UV, CD, and fluorescence sensors are
currently underway in our laboratories.
Figure 7. Single crystal structure of syn-9.
Figure 8. Different views of the crystal structure of (P,P,R,R)-10
showing the hydrogen bonding motif.
109.2 kJ/mol, which is in very good agreement with the value
determined by curve fitting.
Attempts to grow a single crystal of (P,P,R,R)- or (M,M,S,S)-9
for crystallographic analysis were unsuccessful. But we were able to
obtain a crystal structure of the syn-isomer (Figure 7). This
atropisomer hasa torsionangle of 18.33° and the splaying between
the two phenyl rings is 21.09° corresponding to a centroidal
phenyl-to-phenyl separation of 3.52 Å. The steric repulsion
between the two salicylidenimine rings explains the low relative
stability compared to the (P,P,R,R)- or the (M,M,S,S)-isomer.
To better understand the overwhelming thermodynamic
stability of the (P,P,R,R)- and the (M,M,S,S)-configuration, we
decided to prepare the corresponding diimine using (R)-2-
amino-3-methyl-1-butanol (see the SI for details on the synth-
esis, CD analysis, etc.). Fortunately, a crystal of (P,P,R,R)-10 was
obtained by crystallization from a hexane solution (Figure 8).
Crystallographic analysis revealed a torsion angle of 18.17° and
splaying between the two phenyl rings was calculated as only
13.46° resulting in a centroidal phenyl-to-phenyl separation of
3.33 Å. The significantly reduced splaying compared to syn-9 is
quite remarkable and results from reduced steric repulsion
between the imino alcohol units and additional hydrogen bond-
ing between the alcohol groups and the phenol units in the
opposite salicylidenimine ring. The arrangement of the two
salicylidenimines in (P,P,R,R)-10 allows formation of a total of
four intramolecular hydrogen bonds (the phenol groups also
’ EXPERIMENTAL PROCEDURES
All reagents and solvents were used without further purification.
Reactions were carried out under nitrogen atmosphere and under
anhydrous conditions. 1,8-Diiodonaphthalene was prepared from
1,8-diaminonaphthalene as described in the literature.23 Products were
purified by flash chromatography on SiO2 (particle size 0.032ꢀ0.063 mm).
NMR spectra were obtained at 400 (1H NMR) and 100 MHz (13C NMR),
using CDCl3 as solvent. Chemical shifts are reported in ppm relative to
TMS. For CD analysis, samples were diluted to 5.0 ꢁ 10ꢀ5 M with
anhydrous chloroform and the instrument was purged with nitrogen for
20 min. Spectra were collected between 245 and 540 nm at 25.0 °C with a
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standard sensitivity of 100 mdeg, a data pitch of 0.5 nm, a bandwidth of
1 nm, a scanning speed of 500 nm sꢀ1, and a response of 0.5 s using a quartz
cuvette (1 cm path length). The data were adjusted by baseline correction
and binomial smoothing.
was allowed to stir for 1 h at room temperature. The mixture was then
extracted with water, dried over MgSO4, and concentrated in vacuo.
Chromatographic purification with EtOAc:EtOH (99.5:0.5) as the
mobile phase allowed the isolation of the two diastereomeric products
(P,P,R,R)-9 and (M,M,R,R)-9 as yellow solids in quantitative yield.
1H NMR (P,P,R,R)-9: δ 1.26 (d, J = 6.4 Hz, 6H), 1.67 (s, 6H), 3.43 (t,
J = 6.4 Hz, 2H), 3.62 (m, 2H), 3.72 (dd, J = 2.0, 12.0 Hz, 2H), 6.50 (s,
2H), 6.56 (s, 2H), 7.16 (d, J = 7.0 Hz, 2H), 7.49 (dd, J = 7.0, 8.0 Hz, 2H),
7.95 (m, 4H). 13C NMR: δ 17.8, 20.8, 66.8, 67.2, 114.9, 117.8, 125.1,
129.0, 129.8, 130.8, 131.2, 133.4, 134.8, 138.0, 141.9, 161.8, 164.3. Anal.
Calcd for C32H34N2O4: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.05; H,
6.98; N, 5.14.
Hydrolysis of (P,P,R,R)-9 to (P,P)-5. Pure (P,P,R,R)-9 (43.2 mg,
0.08 mmol) was dissolved in 5 mL of 1 M NaOH, and 1 mL of aqueous
HCl (12.1 M) was added dropwise at 0 °C. The mixture was allowed to
stir for 10 min. The resulting suspension was extracted with CH2Cl2 and
the combined organic layers were dried over MgSO4 and concentrated
in vacuo. Purification by flash chromatography on silica gel (CH2Cl2)
afforded enantiopure (P,P)-5 (28.5 mg, 0.07 mmol) in 85% yield, with
no sign of the syn-diastereomer based on NMR analysis. The enantio-
purity of 5 was confirmed by derivatization to the corresponding
diimine, using (R)-2-amino-1-propanol. The NMR spectrum of the
condensation product showed the presence of a single diastereomer.
Diimine (P,P,R,R)-10. To racemic 5 (200 mg, 0.51 mmol) dissolved
in 15 mL of CHCl3 over molecular sieves (4 Å, beads, 8ꢀ12 mesh) was
added 2 equiv of (R)-2-amino-3-methyl-1-butanol (104 mg, 1.02 mmol)
and the mixture was allowed to stir at 70 °C for 16 h. Upon completion of
the asymmetric transformation, the mixture was cooled to room tem-
perature, extracted with water, dried over MgSO4, and concentrated in
vacuo. Chromatographic purification with CH2Cl2:EtOAc (1:1) as the
mobile phase gave (P,P,R,R)-10 (285 mg, 0.50 mmol) in 99.8% yield.
1H NMR (P,P,R,R)-10: δ 0.96 (d, J = 6.8 Hz, 12H), 1.64 (s, 6H), 1.91
(m, 2H), 3.05 (m, 2H), 3.68 (t, J = 10.5 Hz, 2H), 3.87 (m, 2H), 6.50 (s,
2H), 6.59 (s, 2H), 7.16 (d, J = 7.0 Hz, 2H), 7.50 (dd, J = 7.0, 8.0 Hz, 2H),
7.94 (m, 4H). 13C NMR: δ 18.6, 20.0, 20.8, 29.9, 64.2, 114.7, 118.1,
125.2, 128.9, 129.7, 130.9, 131.1, 133.2, 134.7, 138.1, 142.3, 163.0, 165.0.
Anal. Calcd for C36H42N2O4: C, 76.29; H, 7.47; N, 4.94. Found: C,
76.18; H, 7.28; N, 4.87.
The hydrolysis of (P,P,R,R)-10 to (P,P)-5 was conducted as described
above with (P,P,R,R)-9 and gave enantiopure (P,P)-5 in 80% yield.
Deracemization of 5 via Asymmetric Transformation of
the First Kind with 9. Racemic 5 (10.14 mg, 0.026 mmol) was
dissolved in 1.0 mL of CDCl3. Molecular sieves (4 Å, beads, 8ꢀ12 mesh)
were added and the mixture was stirred with 2 equiv of (R)-2-amino-1-
propanol (3.84 mg, 0.051 mmol) for 1 h at 25 °C. After the diimine
formation was complete, 1H NMR analysis indicated the presence of two
diastereomers—evidenced for example by the two doublets at 1.26 and
1.40 ppm (Figure 1). Upon heating to 58.0 °C, the signals of the
thermodynamically less favored diastereomer decreased in intensity.
In agreement with the amplification of asymmetric induction obser-
ved upon diimine formation of 1,8-bis(30-formyl-40-hydroxyphe-
nyl)naphthalene with (R)-2-amino-1-propanol, it is assumed that the
central chirality of amino alcohol controls the stereoselective outcome of
this atropisomerization process. The mixture is almost entirely con-
verted to the more stable diastereomer after 14 h (Figure 1).
Pure (P,P,R,R)-9 (43.2 mg, 0.08 mmol) was dissolved in 5 mL of 1 M
NaOH, and 1 mL of aqueous HCl (12.1 M) was added dropwise at 0 °C.
The mixture was allowed to stir for 10 min. The resulting suspension was
extracted with CH2Cl2 and the combined organic layers were dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatogra-
phy on silica gel (CH2Cl2) afforded enantiopure (P,P)-5 (28.5 mg, 0.07
mmol) in 85% yield, with no sign of the syn-diastereomer based on NMR
analysis. The enantiopurity of 5 was confirmed by derivatization to the
corresponding diimine, using (R)-2-amino-1-propanol. The NMR
1,8-Bis(20-methyl-40-methoxyphenyl)naphthalene (7). A
solution of 1,8-diiodonaphthalene (1.70 g, 4.5 mmol), 2-methyl-4-
methoxyphenylboronic acid, 2 (2.20 g, 13.4 mmol), Pd(PPh3)4 (0.78 g,
0.67 mmol), and K3PO4, (4.30 g, 20.1 mmol) in 50 mL of toluene was
stirred at 100 °C for 18 h. The resulting mixture was allowed to come to
room temperature, quenched with water, and extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and concentrated
in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:
hexanes 2:3) afforded 1.65 g (4.5 mmol, >99%) of off-white crystals
containing syn- and anti-isomers of 7 in a ratio of 1:3.
1H NMR: δ 1.76 (s, 4.6H), 1.83 (s, 1.4H), 3.69 (s, 4.4H), 3.71 (s,
1.4H), 6.28ꢀ6.39 (m, 4H), 6.66 (d, J = 8.2 Hz, 0.5H), 6.87 (d, J = 8.2 Hz,
1.5H), 7.16 (d, J = 6.8 Hz, 2H), 7.46 (dd, J = 7.2, 7.8 Hz, 2H), 7.89 (d, J =
8.0 Hz, 2H). 13C NMR: δ 20.9, 21.0, 55.1, 55.2, 109.9, 110.3, 114.3,
114.4, 124.8, 125.0, 128.5, 129.0, 130.2, 130.4, 131.0, 131.6, 132.3, 134.8,
134.9, 135.2, 135.4, 136.5, 136.9, 139.5, 157.6, 158.1. Anal. Calcd for
C26H24O2: C, 84.75; H, 6.57. Found: C, 84.74; H, 6.61.
1,8-Bis(20-methyl-40-methoxy-50-formylphenyl)naphthal-
ene (8). Phosphorus oxychloride (2.9 mL, 31.2 mmol) and dimethyl
formamide (2.4 mL, 31.2 mmol) were stirred in 10 mL of chloroform at
room temperature for 1 h. Then, 7 (0.60 g, 1.6 mmol) was added and the
mixture was refluxed at 90 °C for 48 h. It was then cooled to 0 °C,
carefully quenched with water, and extracted with CH2Cl2. The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography on silica gel (CH2Cl2:
EtOAc 25:1) afforded 0.69 g (1.6 mmol, 99%) of syn/anti-8 as a white
powder. The diastereomers of 8 can be separated by using flash
chromatography with gradient elution starting with dichloromethane
to collect the anti-isomer (73%), then increasing the polarity to DCM:
EtOAc 15:1 to recover the syn-diastereomer (27%).
1H NMR anti-8: δ 1.81 (s, 6H), 3.80 (s, 6H), 6.35 (s, 2H), 7.15 (d, J =
7.0 Hz, 2H), 7.38 (s, 2H), 7.50 (dd, J = 7.0, 8.2 Hz, 2H), 7.94 (d, J = 8.2
Hz, 2H), 10.28 (s, 2H). 13C NMR: δ 21.5, 55.5, 112.1, 121.6, 125.2,
127.8, 129.2, 130.1, 130.2, 134.8, 135.4, 137.4, 146.2, 160.3, 189.0. 1H
NMR syn-8: δ 1.90 (s, 6H), 3.85 (s, 6H), 6.42 (s, 2H), 7.14 (d, J = 8.2 Hz,
2H), 7.15 (s, 2H), 7.49 (dd, J = 7.0, 8.2 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H),
10.17 (s, 2H). 13C NMR: δ 21.6, 55.6, 112.0, 122.0, 125.0, 129.0, 130.3,
131.3, 131.8, 135.2, 137.5, 144.1, 159.5, 188.7. Anal. Calcd for
C28H24O4: C, 79.22; H, 5.70. Found: C, 78.99; H, 5.72.
1,8-Bis(20-methyl-40-hydroxy-50-formylphenyl)naphthal-
ene (5). To a solution of 1,8-bis(20-methyl-40-methoxy-50-formylphe-
nyl)naphthalene, 8 (0.78 g, 1.9 mmol), in 35 mL of anhydrous CH2Cl2
at 0 °C was added BBr3 (11.8 mL, 11.8 mmol) dropwise and the mixture
was stirred for 6 h. The reaction was carefully quenched with isopropyl
alcohol followed by addition of water, and extracted with CH2Cl2. The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography on silica gel (CH2Cl2:
hexanes 20:1) afforded 0.58 g of 5 (1.5 mmol, 77%) as a white solid. The
anti/syn-ratio was determined as 20:1 by 1H NMR spectroscopy.
Enantiopure anti-5 was obtained via formation of 9 or 10 as described
below and hydrolysis or by asymmetric transformation of the first kind
and subsequent hydrolysis (see the SI).
1H NMR (P,P)-5: δ 1.85 (s, 6H), 6.40 (s, 2H), 7.08 (s, 2H), 7.20 (d,
J = 7.1 Hz, 2H), 7.54 (dd, J = 7.0, 7.1 Hz, 2H), 7.99 (d, J = 7.0 Hz, 2H),
9.66 (s, 2H), 10.73 (s, 2H). 13C NMR: δ 21.7, 117.5, 118.0, 125.3, 125.4,
129.4, 129.5, 130.6, 132.9, 135.0, 136.9, 146.5, 160.5, 195.1. Anal. Calcd
for C26H20O4: C, 78.77; H, 5.09. Found: C, 78.69; H, 5.42.
Diimine (9). To racemic 5 (67.0 mg, 0.17 mmol) dissolved in 8 mL
of CHCl3 over molecular sieves (4 Å, beads, 8ꢀ12 mesh) was added 2
equiv of (R)-2-amino-1-propanol (25.4 mg, 0.34 mmol) and the mixture
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Figure 10. Change in the CD signal of (P,P,S,S)-10 as a result of
diastereomerization at 50.0 °C. The CD spectra were collected at 25.0 °C
with a concentration of 5.0 ꢁ 10ꢀ5 M in CHCl3.
Figure 9. CD spectra of (P,P)-5 (blue) and (P,P,R,R)-10 (red) at 5.0 ꢁ
10ꢀ5 M in CHCl3.
spectrum of the condensation product showed the presence of a single
diastereomer.
Deracemization of 5 via Asymmetric Transformation of
the First Kind with 10. The diimine (P,P,R,R)-10 was prepared in
quantitative yields from racemic 5 and (R)-2-amino-3-methyl-1-butanol,
using the same asymmetric transformation protocol as described above
for 9. The hydrolysis of (P,P,R,R)-10 to (P,P)-5 was conducted as
described above with (P,P,R,R)-9 and gave enantiopure (P,P)-5 in 80%
yield. The CD spectra of (P,P,R,R)-10 and (P,P)-5 are shown in Figure 9.
The unidirectional atropisomerization of (P,P,S,S)-10 to (M,M,S,S)-10
was monitored by CD spectroscopy and is in perfect agreement with the
results obtained with 9. Enantiopure (P,P)-5 (10.14 mg, 0.026 mmol) was
dissolved in 1.0 mL of CDCl3. Molecular sieves (4 Å, beads, 8ꢀ12 mesh)
were added and the mixture was stirred with 2 equiv of (S)-2-amino-3-
methyl-1-butanol (5.52 mg, 0.051 mmol) for 1 h at 25.0 °C. The mixture
was then heated to 50.0 °C. Aliquots were taken at 1 h intervals and diluted
to 5.0 ꢁ 10ꢀ5 M with anhydrous CHCl3 for CD analysis. After 24 h, the CD
signal indicated almost complete diasteriomerization (Figure 10).
Determination of the Initial Rate Constant for the Isomer-
ization of (P,P,S,S)-9. Enantiopure (P,P)-5 (10.14 mg, 0.026 mmol)
was dissolved in 1.0 mL of CDCl3. Molecular sieves (4 Å, beads, 8ꢀ12
mesh) were added and the mixture was stirred with 2 equiv of (S)-2-
amino-1-propanol (3.84 mg, 0.051 mmol) for 1 h at 25 °C. The mixture
was then heated to 58.0 °C and 1H NMR spectra were collected at short
intervals to follow the decay of (P,P,S,S)-9 (same signals as (M,M,R,R)-9,
Figure 1) before the appearance of any (M,M,S,S)-9 (same signals as (P,P,
R,R)-9, Figure 1). By plotting the mole fraction of (P,P,S,S)-9 versus time,
the initial rate of the reaction can be obtained from the slope of the fitted
line (Figure 11). Curve fitting to y = A1x þ B was performed with
OriginPro 8.1, with A1 = ꢀ0.00245 and B = 0.8634, A2 = 0.351, with R2 =
0.9929. The initial rate constant denoted k1 was determined as 4.083 ꢁ
10ꢀ5 sꢀ1, ΔGq(P,P,S,S)-9f(P,M,S,S)-9 = 109.2 kJ/mol.
Figure 11. Plot of the mole fraction of (P,P,S,S)-9 versus time (min).
Scheme 8. Kinetic Resolution of 2-Amino-1-propanol with
(P,P)-5
Determination of the Rate Constants for the Isomeriza-
tion of 920. As described above, enantiopure (P,P)-5 (10.12 mg, 0.026
mmol) was dissolved in 1.0 mL of CDCl3, treated with 2 equiv of
(S)-2-amino-1-propanol (3.84 mg, 0.051 mmol) for 1 h at 25 °C, and
58.0 °C. The individual rate constants were then calculated as described
in the SI.
1
then heated to 58.0 °C. H NMR spectra were collected at different
Kinetic Resolution. Enantiopure (P,P)-5 (15.89 mg, 0.040 mmol)
was dissolved in 1.0 mL of anhydrous CHCl3 (Scheme 8). Molecular
sieves (4 Å, beads, 8ꢀ12 mesh) were added and the mixture was stirred
with 4 equiv of racemic 2-amino-1-propanol (12.04 mg, 0.160 mmol) for
5 h at 25 °C. The mixture was then extracted with water, and the aqueous
layer was freeze-dried to recover the unreacted amino alcohol. The crude
material (6.02 mg, 0.080 mmol) was dissolved in 1.5 mL of chloroform
and treated with benzoyl chloride (117.8 mg, 0.801 mmol) in the
presence of triethylamine (162.2 mg, 1.60 mmol). The mixture was
intervals to monitor the change in the intensity of the resolved methyl
signals of (P,P,S,S)-9 (1.69 ppm), (M,P,S,S)-9 (1.81 ppm), and (M,M,S,S)-9
(1.66 ppm) until equilibrium was reached.
k3
k1
ðP, P, S, SÞ-9 aðP, M, S, SÞ-9 aðM, M, S, SÞ-9
k2
k4
The relative amounts of the three stereoisomers at equilibrium were
determined as 94.4:3.9:1.7 [(M,M,S,S):(P,P,S,S):(M,P,S,S)] in CDCl3 at
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allowed to stir for 16 h, then quenched with water and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography on silica gel
(CH2Cl2:EtOAc 9:1) afforded 11 (22.0 mg, 0.074 mmol) as a colorless
oil in 93%. The ee was determined as 54% by HPLC on Chiralpak AD,
using hexanes:ethanol (90:10) as the mobile phase. As expected,
formation of (P,P,R,R)-9 is favored and comparison of the HPLC
chromatogram with separately prepared enantiopure samples of 11
proved that 77% of the unreacted amino alcohol had (S)-configuration.
Crystallization and X-ray Diffraction. Single crystal X-ray
analysis was performed at 100 K using a Siemens platform diffractometer
with graphite monochromated Mo KR radiation (λ = 0.71073 Å). Data
were integrated and corrected with the Apex 2 program. The structures
were solved by direct methods and refined with full-matrix least-squares
analysis, using SHELX-97-2 software. Non-hydrogen atoms were re-
fined with anisotropic displacement parameters.
A crystal of enantiopure (P,P)-5 was obtained by slow evaporation of
a solution of 5.0 mg of (P,P)-5 in 3 mL of CHCl3. Crystal structure data
for (P,P)-5: formula C26H20O4, M = 396.43, crystal dimensions 0.15 ꢁ
0.10 ꢁ 0.05 mm3, tetragonal, space group P43, a = 11.7955(17) Å, b =
11.7955(17) Å, c = 28.4769(40) Å, V = 3962.10 Å3, Z = 1, Fcalcd = 1.3290
g cmꢀ3. Selected distances and angles: phenylꢀphenyl (centroid to
centroid), 3.470 Å; splaying angle between salicylidenimine planes,
20.51°; and torsion angle, 5.32°.
The slow evaporation of a solution of 5.0 mg of 5 and 2 equiv of (R)-2-
amino-1-propanol in 3 mL of CHCl3 afforded single crystals of syn-9.
Crystal structure data for syn-9: formula C32H34N2O4, M = 510.62, crystal
dimensions 0.120 ꢁ 0.10 ꢁ 0.07 mm3, monoclinic, space group P21/c, a =
22.3400(21) Å, b = 6.8469(6) Å, c = 17.6753(16) Å, β = 100.956(1), V =
2654.33 Å3, Z = 4, Fcalcd = 1.2726 g cmꢀ3. Selected distances and angles:
phenylꢀphenyl (centroid to centroid), 3.518 Å; splaying angle between
salicylidenimine planes, 21.09°; and torsion angle, 18.33°.
A crystal of (P,P,R,R)-10 was obtained by crystallization of 100.0 mg
of (P,P,R,R)-10 from 15 mL of hexanes. Crystal structure data for (P,P,R,R)-
10: formula C32H34N2O4, M = 566.73, crystal dimensions 0.10 ꢁ 0.10 ꢁ
0.05 mm3, orthorhombic, space group P21, a = 10.8469(44) Å, b =
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21.3655(86) Å, c = 13.6440(55) Å, V = 3161.99 Å3, Z = 2, Fcalcd
=
1.1903 g cmꢀ3. Selected distances and angles: CdN
HOCphenyl
OCphenyl hydrogen bond
3 3 3
hydrogen bond length, 1.861 Å; CaliphOH
3 3 3
length, 2.178 Å; phenylꢀphenyl (centroid to centroid), 3.326 Å;
splaying angle between salicylidenimine planes, 13.46°; and torsion
angle, 18.17°.
’ ASSOCIATED CONTENT
S
Supporting Information. Details of calculations of the
b
isomerization rate constants, thermal ellipsoid plots of the X-ray
structures, and CD and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: cw27@georgetown.edu.
’ ACKNOWLEDGMENT
This material is based upon work supported by the National
Science Foundation under CHE-0910604.
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(17) Please note that the (M,M)-scaffold in 1 corresponds to the
(P,P)-conformation in 5 and 9 because the presence of the o-methyl
groups in the latter results in a change in the CIP priorities.
(18) It is noteworthy that the CD amplitudes of the less stable (P,P,S,S)-
9 diastereomer are slightly diminished compared to (P,P,R,R)-9. This
is probably due to noticeable atropisomerization of (P,P,S,S)-9 to its
(M,M,S,S)-diastereomer, i.e. it is likely that the CD spectra obtained with
(P,P,S,S)-9 and (P,P,R,R)-9 only differ because the former was not
perfectly diastereomerically pure.
(19) Wolf, C., Ed. Dynamic Stereochemistry of Chiral Compounds;
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(20) The factor 2 in eq 1 accounts for the two enantiomeric anti-
isomers of 5.
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(22) See the Supporting Information for mathematical treatment of
the kinetics of consecutive, reversible, first-order reactions.
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