Synthesis and Comprehensive Structural and Chiroptical Characterization of Enones Derived from (-)-α-Santonin by Experiment and Theory

Article abstract of DOI:10.1021/acs.joc.6b00416

The aim of the present work is to explain the causes of the observed deviations from sector and helicity rules to determine the absolute configuration of optically active α,β-unsaturated ketones by means of electronic circular dichroism (ECD). To this end, a series of model compounds with a common decahydronaphthalene skeleton representing both cisoid and transoid enones were synthesized. In the framework of this work, detailed dichroic studies supported by single crystal X-ray analysis were performed where possible. To assist the achievement of the desired objectives the conformational flexibility of the selected cis-enones through the dependence of solvent and temperature on the ECD spectra were examined. All experimental studies were supplemented by detailed DFT calculations. A notable result of the study is assessing the applicability of the enone sector and helicity rules in dichroic studies and potential restrictions. To this end, a number of factors that could determine the signs of the individual Cotton effects has been considered. Among these nonminimum structure effects, i.e., twisting of the enone chromophore and nonplanarity of the enone double bond can be mentioned.

Full text of DOI:10.1021/acs.joc.6b00416

Article
pubs.acs.org/joc
Synthesis and Comprehensive Structural and Chiroptical
Characterization of Enones Derived from (−)-α-Santonin by
Experiment and Theory
†
†
†
‡
§
́
Marek Masnyk, Aleksandra Butkiewicz, Marcin Gorecki, Roman Luboradzki, Christoph Bannwarth,
,§
,†
Stefan Grimme,* and Jadwiga Frelek*
†
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Mulliken Center for Theoretical Chemistry, Institute of Physical and Theoretical Chemistry, University of Bonn, Beringstr. 4, 53115
‡
§
Bonn, Germany
*
S Supporting Information
ABSTRACT: The aim of the present work is to explain the causes of the
observed deviations from sector and helicity rules to determine the
absolute configuration of optically active α,β-unsaturated ketones by
means of electronic circular dichroism (ECD). To this end, a series of
model compounds with a common decahydronaphthalene skeleton
representing both cisoid and transoid enones were synthesized. In the
framework of this work, detailed dichroic studies supported by single
crystal X-ray analysis were performed where possible. To assist the
achievement of the desired objectives the conformational flexibility of the
selected cis-enones through the dependence of solvent and temperature on
the ECD spectra were examined. All experimental studies were
supplemented by detailed DFT calculations. A notable result of the
study is assessing the applicability of the enone sector and helicity rules in
dichroic studies and potential restrictions. To this end, a number of factors
that could determine the signs of the individual Cotton effects has been considered. Among these nonminimum structure effects,
i.e., twisting of the enone chromophore and nonplanarity of the enone double bond can be mentioned.
4
INTRODUCTION
and antibiotic properties produced by some mushrooms. In
■
5
Chart 1 this family is represented by (−)-illudin S. The
The cis-enone chromophore is one of the most ubiquitous
structural motifs in natural products. In particular, owing to
their wide variety of biological activities, an important group of
compounds is formed by α,β-unsaturated sesquiterpene
ketones possessing the decahydronaphthalene skeleton form.
Among them, eremophilane-type sesquiterpenes, represented
in Chart 1 by (−)-eremophilone and (+)-fukinone, manifest
selective antibacterial activity against Gram-positive organisms
which are causes of human disease. Moreover, the Eremophila
species are constantly being considered the “number one
medicine” by the Australian Aboriginal people due to their
decongestant, expectorant, and analgesic properties. The
illudins, in turn, are a family of sesquiterpenes with antitumor
essential oil of the liverwort Scapaniaundulata contains a large
variety of sesquiterpenes constituting important intermediates
in the biosynthesis of functionalized sesquiterpenes. This group
6
includes (−)-chiloscyphone (Chart 1) which is the main
component of the essential oil of the plant Chiloscyphus
polyanthus (L) corda.
Many natural products exhibit desired biological effects only
in one defined absolute configuration (AC). Therefore, the AC
determination calls for methods allowing the stereochemical
assignment in an unequivocal and straightforward way. For
enones, one such basic method was, and still is, the analysis of
their chiroptical properties. Extensive studies on this issue have
led to a formulation of several rules linking the signs of Cotton
effects (CEs) observed in the electronic circular dichroism
spectra (ECD) with the absolute configuration of enones. A7t
this point, the rules proposed in the 1960s by Djerassi et al.,
1
,2
3
Chart 1
8
9
Whalley, and Snatzke should be mentioned. These rules were
subsequently modified by Burgstahler and Barkhurst, Kirk,
10
11
Received: February 25, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00416
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Chart 2
Scheme 1. Synthesis of 1
1
2,13
14,15
Gawronski,
and most recently by Kwit and Gawronski,
material for our synthetic endeavor due to its significant
abundance and high functionality. Therefore, manipulating the
structure of santonin toward the desired structures should
proceed smoothly, efficiently, and according to the planned
synthetic strategy. Moreover, chemical and microbial trans-
formations of santonin into bioactive, potentially bioactive, or
synthetically interesting products may also be relevant due to its
relatively low price related to its abundance.
1
6
and Kuball et al. As it turns out, the analysis of chiroptical
properties of enones is quite complex due to many factors
13
affecting respective CEs signs. One of the most important of
them is the multiplicity of conformational structures and small
energy difference between them. Equally important is the
correct description of electronic transitions involved in
excitations that, particularly in a higher energy range, are not
pure but are composed of multiple excitations on different
chromophores present in the studied molecules. Recently, the
impact of nonplanarity of the enone double bond on signs of
The choice of dihydrosantonin derivatives 1−5 was addi-
tionally motivated by their conformational flexibility and
presence of substituents with their own interfering circular
dichroic activity. Although these terpene enones are computa-
tionally more challenging compared to the previously studied
15,17
particular CEs has additionally been demonstrated.
theless, for many enones the Kirk’s orbital helicity rule
correlating the n → π* CE sign with the helicity of the enone
Never-
11
16,18−20
steroidal enones,
their choice as models should enable a
11−13,18
unit is working well.
However, we should draw attention
close examination of the influence of substituents in proximity
to the chromophore on the conformation and thus their
chiroptical properties. Finally, this set of molecules has been
supplemented by representative trans-enones, i.e., dihydrosan-
tonin (6), epidihydrosantonin (7), and its reduction product 8.
The idea behind this is to examine the viability of the orbital
helicity rule based on the cis- and trans-enones that possess the
same carbon framework. This should help in the interpretation
of the obtained results and allow proper conclusions to be
drawn on their basis. In the present study, we have considered
substitution of cyclohexanone or cyclohexenone rings,
respectively, in cis- and trans-enones due to the likelihood of
opposing chiroptical effects.
to the fact that compared to trans-enones the cisoid enones have
rarely been studied. Moreover, the relation between the helicity
of the enone unit and its chiroptical properties appears to be
more complex compared with their trans counterparts. Our
preliminary study on this issue demonstrated derogations from
the Kirk rule for certain cis-enones.
these studies is that the nonsymmetrical conformation of the
cyclohexanone ring causes a breakdown of the working orbital
16,18−20
What results from
16,20
enone helicity rule.
These experimental observations,
however, are not yet supported by either extended studies of
other model compounds or an insightful theoretical examina-
tion.
Taking all this into consideration, we decided to carry out in-
depth studies on the relationship between chiroptical properties
and the structure of enones. To achieve this goal a number of
suitable model compounds were synthesized and their
geometries, structural parameters, and chiroptical properties
were analyzed experimentally and theoretically. As model
compounds for our chiroptical studies, a series of cisoid enones
based on the decahydronaphthalene skeleton were selected
We intend to achieve the planned goal by controlling the
influence of conformational changes of the cyclohexanone and
cyclohexenone rings on the diagnostic ECD bands. Our studies
are focused on the band attributed to the enone n → π*
transition, occurring at ∼320 nm, since this particular band is
subject to the enone helicity rule. Moreover, this ECD band is
clearly separated from the higher energy π → π* band so that
the risk of confusing overlap is minimized.
11
(
Chart 2). We recognized that (−)-α-santonin, a pharmaceuti-
We decided to use ECD spectroscopy in tandem with time-
dependent density functional theory (TDDFT) calculations.
cally important sesquiterpenoid, will be an excellent starting
B
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Scheme 2. Synthesis of 2 and 3
Scheme 3. Synthesis of 4 and 5
Scheme 4. Synthesis of 7 and 8
Currently, chiroptical methods combined with quantum
chemical calculations are considered as the most powerful
tools for elucidating stereochemistry and monitoring even the
smallest changes in the geometry of chiral molecules. A
combined experimental and theoretical analysis of ECD spectra
has already proven useful and reliable in the determination of
the absolute configuration of various classes of chiral
12. Finally, the alcohol 12 was oxidized with chromium trioxide
in pyridine yielding enone 1.
Enones 2 and 3 were synthesized according to Scheme 2.
Dihydrosantonin (6) was reduced with lithium tri-tert-
butoxyaluminum hydride producing an inseparable mixture of
stereomeric alcohols 13 in a ratio of 17:3 (equatorial:axial). The
hydroxyl group in 13 was then protected as tert-butyl-
dimethylsilyl ether in the reaction with tert-butyldimethyl-
chlorosilane. Crystallization of the crude reaction product gave
pure equatorial ether 14, which was subsequently reduced to
diol 15 with lithium aluminum hydride. The selective acylation
of 15 with pivalic anhydride in pyridine provided monohydroxy
alcohol 16, which was converted into enone 2 by oxidation with
chromium trioxide in pyridine. Cleavage of the silyl ether 2 with
tetrabutylammonium fluoride yielded enone 3.
2
1−29
molecules.
It should be stressed that only properly assigned electronic
transitions occurring within the enone chromophore and its
immediate surroundings allow for rational stereochemical
1
4,15
analysis.
Thus, we hope that the combined experimental
and theoretical analysis will enable an explanation of the origin
of discrepancy noted above in the working enone helicity rule.
Henceforth, it should be possible to find determinants which
influence both the sign and the magnitude of the Cotton effects
strongly.
Mother liquors remaining after crystallization of 14 were
taken for further elaboration. The same reaction sequence as
that for 16−3 (Scheme 2) yielded a separable mixture of
epimeric sillyl ethers 4 and 2. Deprotection of hydroxyl group
in 4 yielded the axial alcohol 5 (Scheme 3).
RESULTS AND DISCUSSION
■1
. Synthesis. Compound 1 was synthesized from natural
Dihydrosantonin (6) was converted into dihydro-6-epi-
santonin (7) by epimerization in DMF containing 5%
anhydrous HCl according to a commonly used procedure in
(
(
−)-α-santonin (9) according to Scheme 1. (−)-α-Santonin
9) was selectively hydrogenated over Wilkinson’s catalyst
30,31
producing dihydrosantonin
(6), in which the carbonyl
31−33
group was then subjected to a ketalization reaction with
ethylene glycol in the presence of p-toluene sulfonic acid. The
resulting ketal 10 was reduced with lithium aluminum hydride,
and then the yielded diol 11 was selectively acylated with the
pivalic anhydride in pyridine giving the monohydroxy alcohol
santonin chemistry (Scheme 4).
Treatment of compound
7 with zinc dust in methanol with glacial acetic acid caused
reductive cleavage of the cis-fused lactone ring with formation
of carboxylic acid which was then esterified with ethereal
32,33
diazomethane yielding methyl ester 8.
C
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4,35
3
Interestingly, when dihydrosantonin (6) was subjected to
rapid crystallization from a hot mixture of 1:1 methanol/water,
plate-like crystals were obtained. In contrast, slow evaporation
of methanol from the mother liquor that remained after
separation of the plate-like crystals yielded needle-like crystals.
In the asymmetric crystal unit of dihydrosantonin (6) there are
two homohelical molecules with an enone torsion angle ω
equal to −177.4° and −178.7° and a τ angle, defining the
nonplanarity of the enone double bond, of −4.6° and −6.7°,
respectively (for definition of angles ω and τ, see Chart 3).
technique to distinguish polymorphs of a compound.
As
can be seen in Figure 2, the spectra show significant differences,
especially in the enone n → π* transition spectral range. In this
region, the Cotton effect of the prism form of 7 is bisignate
while that of the needle form is monosignate and positive.
Based on the X-ray data the difference in the conformation of
the cyclohexanone ring in both polymorphic forms is also
clearly visible, as can be seen in Figure 2.
2
. Experimental and Calculated ECD Spectra of
Enones 1−8. The experimental electronic absorption (EA)
and ECD data of enones 1−8 are collected in Table 1.
The EA spectra of enones 1−8 display two well-resolved
bands arising at around 320 and 240 nm. The intensity of bands
occurring at ∼240 nm is much higher for trans-enones 6−8
Chart 3. Schematic Definition of Angles ω and τ
13
than for their cis counterparts, as expected. In turn, four bands
within the spectral range of 185−360 nm are present in the
ECD spectra, as can be seen in Table 1. The long-wavelength
band occurring at ∼325 nm is attributed to the enone n → π*
transition, and the one arising in the range of 230−250 nm is
assigned to the π → π* excitation of the same chromophoric
unit. The latter band corresponds to the EA band at ∼240 nm,
and the former, to the long-wavelength band near 320 nm. In
trans-enones 6−8, at least in acetonitrile solution, the 320 nm
ECD band exhibits a vibrational fine structure characteristic for
enone carbonyls. There exists an inconsistency in the literature
regarding the origin of the third band, appearing at ca. 200 nm
However, infrared spectra for both forms were identical in the
range of measurement error. Moreover, the single crystal X-ray
diffraction showed that despite the difference in morphology,
both forms had the same unit cell (Figure 1). In light of these
facts, the existence of two polymorphic forms is excluded.
For dihydroepisantonin (7), we were able to obtain two
distinct crystal forms by crystallization from a mixture of
methanol/water 1:1 and hexane. In the first case, needle-like
crystals were obtained, while the second, where hexane was
used as a solvent, yielded prismatic-shaped crystals (micro-
graphs of the forms are shown in the Supporting Information
which is practically undetectable in the UV spectra (see Table
12,15,36
1
).
However, the latest results seem to promote the
12
initial suggestion that the sign of this CE in cyclic enones is
controlled by the configuration of the saturated carbon−carbon
(
SI)). In the unit cell of the needle-like crystals of
15
chain. The fourth electronic transition usually observed in the
dihydroepisantonin (7) there are two molecules, one of
which is homohelical and the other heterohelical. The enone
torsion angle ω in the heterohelical molecule is equal to
1
85−195 nm range is considered to be an n → σ*
11−13,36
excitation.
Regarding the spectral shape and CEs signs, the ECD spectra
of compounds 1−6 and 8 show similar profiles with a negative
n → π* CE of comparable intensities of about Δε ≈ 1. The
second ECD band at ∼240 nm, characterized by moderate to
strong intensity (attributable to the π → π* transition), is
positive. The only exception in this regard is the enone 7
having both of these CEs of reverse signs with respect to
enones 1−6 and 8, including dihydrosantonin (6) and its
reduction product 8 both representing trans-enones. For trans-
enones 6 and 8, in agreement with working orbital helicity
−
169.0°, and the ene torsion angle τ, 3°. The ene torsion angle
τ is defined as C/H−CC−C(O), where C/H is syn to the
14,15
C−C(O) bond (see Chart 3).
In the homohelical
molecule the same angles are equal to +177.0° and +3.3°,
respectively. On the other hand, the prismatic-shaped form
contains only one molecule of dihydroepisantonin (7) in its
unit cell with ω and τ angles equal to −170.0° and −1.4°,
respectively.
These two forms of dihydroepisantonin (7) crystals differed
both in the infrared spectra as well as in elementary cells
11
rule, a sign reversal of CEs with respect to the cis-enones 1−5
(
Experimental Section, Figures 1 and 2), thus demonstrating
was expected to be the same as in the case of
the existence of two polymorphic forms of 7 (see Supporting
Information for X-ray details).
11,12,15
dihydroepisantonin (7).
Experimental solid-state ECD spectra of both polymorphic
forms of 7 recorded using integrating sphere attachment for a
regular ECD spectrometer once again demonstrated the utility
of diffuse transmittance CD (DTCD) using the pellet
The obtained result means that the Kirk rule anticipating
opposite signs for the two lowest-energy electronic transitions
for the cis- and trans-enones does not apply here. However, the
Kirk rule correlating a negative enone torsion angle with a
Figure 1. Molecular packing in crystals of the (a) dihydrosantonin (6, needles and plates), (b) dihydroepisantonin (7, needles), and (c)
dihydroepisantonin (7, prism). The displacement ellipsoids are drawn at the 50% probability level.
D
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Figure 2. Left: Comparison of experimental ECD (bottom) and EA (top) spectra of needle and prism forms of enone 7 recorded in the solid state
using KCl pellet technique in diffuse transmittance mode. Right-top: Overlay of enone 7 polymorphs crystallographic structures. Right-bottom:
Solid-state conformation of cyclohexanone ring in prisms and needle crystal of 7.
a
Table 1. EA and ECD Data for Enones 1−8 Recorded in Acetonitrile
enone
UV [ε (λmax)]
5020 (240.0)
ECD [Δε (λmax)]
−2.17 (202.5)
1
2
3
4
5
6
7
8
55 (318.0)
70 (317.5)
60 (315.0)
63 (314.0)
54 (314.0)
52 (319.5)
38 (330.0)
50 (315.5)
+1.50 (187.0)
+6.50 (185.0)
+9.20 (186.5)
+9.18 (191.0)
+7.00 (193.0)
−0.81 (196.0)
−6.63 (192.5)
−2.38 (194.0)
+11.93 (238.5)
+9.74 (244.5)
+8.91 (245.0)
+18.09 (241.0)
+13.12 (241.5)
+9.75 (241.0)
−4.75 (250.0)
+8.23 (244.0)
−1.12 (325.5)
−0.83 (325.5)
−0.61 (328.0)
−1.76 (323.5)
−0.95 (326.0)
−0.72 (321.0)
+0.90 (350.5)
−0.64 (317.0)
5530 (246.0)
9870 (242.5)
5880 (242.5)
4570 (243.0)
14880 (242.5)
14180 (243.5)
12980 (246.0)
−6.23 (206.0)
−5.80 (208.5)
−2.99 (210.0)
−2.51 (209.0)
+2.07 (209.5)
+4.90 (215.5)
+3.00 (212.0)
sh
#
†
a
EA and ECD values are given in M−1 cm−1 as ε (λmax/nm) and Δε (λmax/nm), respectively. sh: shoulder. #: an additional, very weak (Δε = +0.02) CE
present at 376.0 nm. †: an additional, very weak (Δε = +0.04) CE present at 367.0 nm.
Figure 3. EA (top) and ECD (bottom) spectra of enones 3 (a, b) and 5 (c, d) recorded in EPA (Et O/isopentane/EtOH, 5:5:2, v/v) and MI13
2
(
methylcyclohexane/isopentane, 1:3, v/v). The symbol ε denotes the molar decadic absorption coefficient; Δε, the difference of the molar decadic
absorption coefficients of left and right circularly polarized light; and λ, the wavelength. The lower temperature curves have been corrected for
solvent contraction.
negative sign of the n → π* CE and a positive sign of the π →
π* CE works perfectly for the examined cis-enones 1−5.
Clarification of the inconsistency observed for the trans-
enones 6 and 8 was expected in the evaluation of the
experimental ECD spectra with respect to those predicted using
reliable quantum chemical methods. A prerequisite of this task
is to determine all conformers contributing significantly to the
averaged spectra. Thus, the thorough conformational analysis
guaranteeing obtainment of a reliable conformer population
was conducted at the beginning. An in-depth analysis of the
combined experimental and theoretical results separately for cis-
and trans-enones is subject to the following considerations.
Details about the conformational analysis, optimization, and
reoptimization of results as well as simulation of EA and ECD
spectra are contained in the section “Computational Details”
directly following the “Experimental Section”.
E
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Figure 4. Comparison of computed ECD spectra of enones 6 (a), 7 (b), and 8 (c) obtained as a population weighted sum of the calculated spectra
of individual conformers with experimental spectra recorded in CH CN. Inserts show the range of n → π* transition.
3
2
.1. Chiroptical Properties of cis-Enones 1−5. Experimental
high-energy conformers from the equilibrium and shifts it
toward more stable conformers. With a decreasing temperature
shift in the λmax of the n → π* CEs, i.e., Δλmax, in MI13 is equal
to 16 nm for enone 3 and 19 nm for enone 5, thus approaching
a value close to the electronic absorption at room temperature,
and calculated electronic absorption spectra of cis-enones 1−5
are consistent regarding the position of absorption bands and
their intensity. The comparison shows that the position of the π
→
π* absorption bands in the calculated spectra required only
a slight red shift of about 3 nm or no adjustment at all (see SI).
After ensuring proper compatibility between experimental and
calculated EA spectra, we proceeded to compare their ECD
spectra. As seen in Figures S1−S5, the Boltzmann weighted
ECD spectra for all the cis-enones under question reflect the
experimental ECD features very well. The negative n → π* CE
is reproduced in the calculations for all five enones 1−5.
Consistently, the positive π → π* CE at ∼240 nm is also
reflected correctly as to the location and intensity. Similarly, the
good agreement applies to the short-wavelength part of the
spectrum regardless of the substituent type and the position of
substitution in the skeleton. The data indicate that the M
helicity of the enone chromophore in cis-enones 1−5 has a
decisive impact on their chiroptical properties. This statement
is confirmed by the same half-chair and chair conformation of
rings A and B, respectively, in all conformers found (see Table
S1 in Supporting Information). Also, the presence of a polar
substituent such as a hydroxyl group at the C3 carbon atom in
enones 3 and 5 affects neither the ECD curve shape nor the
signs of the respective CEs. The electronic transition associated
with the presence of this group in the experimental spectrum is
hidden within the adjacent bands and can be attributed to the
i.e. 316 and 319 nm, respectively. The same Δλ
in EPA
max
accounts to 3 and 2 nm respectively for enones 3 and 5. This
appears to be a case of the strong influence of the solvent,
which likely manifests itself in either stabilization or
destabilization of the investigated structures. Solvent polarity
affects the electronic structure of the solute by, e.g., enabling or
not the formation of intermolecular hydrogen bonds between
the OH group and carbonyl of the enone unit or ester group.
As a result, in the nonpolar solvent, the identity of the
chromophore is changed due to the creation of associates.
Thus, the presence of different molecular species leading to
various behaviors must be considered in nonpolar and polar
solvents.
To summarize this portion, it can be stated that the ECD
spectra of cis-enones in solution studied here show similar
profiles and all follow the Kirk enone helicity rule. This means
that the sign and magnitude of the n → π* CE are mainly
determined by the helicity of the enone unit, i.e., the sign of the
CC−CO (ω) angle. It implies that substituents at the C-3
position have a limited influence on ring conformation and thus
a negligible effect on the ECD curves within compounds 1−5.
2.2. Chiroptical Properties of trans-Enones 6−8. As already
nOH − π
* type. At this point it should be added that not all
CO
mentioned previously, the trans-enones 6−8 behave differently
with respect to their cis counterparts 1−5. In enone 7, the sign
of the n → π* CE is positive in agreement with the Kirk rule
while a negative sign of the same CE in enones 6 and 8 violates
this rule. On the other hand, simulated spectra of 6 and 8
calculated at the same level of theory as cis-enones 1−5 show
positive n → π* CEs, thus being in disagreement with the
experiment but consistent with the rule (Figure 4).
conformers of enones 2−5 fulfill the Beecham’s postulate of
compliance between the helical turn of the four-atom helix
containing allylic oxygen O−C−C(4)C(5) and the sign of
the π → π* band CE of the enone chromophore (see
37
Supporting Information).
To strengthen the conclusions regarding the conformational
homogeneity of the A and B rings in compounds 1−5, the
measurements of ECD spectra at variable temperatures were
recorded for the enones 3 and 5 serving as representative
model compounds (Figure 3). The results obtained in a
nonpolar solvent MI13 (methylcyclohexane/isopentane, 1:3, v/
v) at temperatures ranging from +25 °C to −180 °C show
more than a 2-fold increase in the intensity of the n → π* band
combined with its shift toward higher energies of 15 and 19 nm
for 3 and 5, respectively. In contrast, lowering the temperature
results in almost no changes in the band position and a barely
perceptible increase in the intensity in a polar solvent (EPA:
The lack of agreement between experimental and theoretical
spectra can be caused by multiple factors. One reason is the
small difference in energy between conformers strongly
associated with conformational flexibility. However, in the
case of the investigated trans-enones only compound 8 exhibits
a higher conformational flexibility closely related to mobility of
the side chain attached to the C7 carbon atom. In this case,
however, the 12 conformers found in the 3 kcal/mol window
showed no significant differences in the bicyclic skeleton
including the enone chromophoric unit. The other two trans-
enones, i.e., 6 and 7, are conformationally rigid as confirmed by
the presence of only two conformers in the 3 kcal/mol energy
range in both cases. Thus, the conformational flexibility cannot
be the primary cause of the observed discrepancies.
Et O/isopentane/EtOH, 5:5:2, v/v). The EPA result indicates
2
the conformational homogeneity of the rings containing the
enone chromophore without the need to stabilize them through
intermolecular hydrogen bonding. In the MI13 case, however,
lowering the temperature causes progressive elimination of
F
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Figure 5. Experimental and calculated VCD spectra of enones 6 (a), 7 (b), and 8 (c). The simulated spectra were averaged with the Boltzmann
distribution at PW6B95-D3/def2-QZVP+COSMO-RS level of theory (see computational details below).
Figure 6. ECD spectra of trans-enones 6, 7, and 8 (a, b, and c, respectively). The experimental spectra (dashed gray) are recorded in acetonitrile.
The computed spectra (blue solid lines) are obtained with sTD-DFT at the CAM-B3LYP/def2-TZVP+COSMO level on 100 MD “snap shots” (400
for compound 8). The corresponding spectra obtained on Boltzmann-weighted minimum structures at the same level of theory are given as well
(
black dashed lines). All computed spectra are red-shifted by 0.5 eV.
Another limiting factor that may cause the theory mismatch
very weak positive band on a long wavelength part of this band,
i.e. at 376 and 367 nm, respectively. This additional band,
present in many spectra of the enones, was first remarked on by
with the experiment can be linked to disregard in the
calculation of vibronic contributions, negligence of nonplanarity
of the enone double bond, or the presence of polar
38−40
Kuball et al. and termed the “preband”.
Based on the
1
4−16,20
substituents.
The presence of substituents in the
results of the extensive study of anisotropic circular dichroism
(ACD) with enones as model compounds, they concluded that
the sector and helicity rules can be used effectively provided
that vibronic progressions of all possible conformers will be
chromophore vicinity introduces additional complexity to the
geometric and electronic features of the compounds studied
thus increasing their conformational flexibility and finally
affecting their chiroptical properties. Such impact is seen in
the case of dihydrosantonin (6) and dihydroepisantonin (7),
i.e., molecules whose conformational mobility is very limited. In
these cases, the difference of the AC at the C6 carbon atom
induces a significant difference in the shape of the ECD curve.
The signs of the experimental n → π* and π →π* bands are
opposite although the geometry of the enone itself is the same.
To further ascertain the correctness of the conformational
analysis, for the same set of conformers, the VCD spectra were
18,19,40
considered.
Otherwise, a different vibronic coupling
caused by a variation in the surroundings of the chromophore
may even induce the CE sign change. They have also stated
that the enone helicity corresponds to the sign of the long
16,40
wavelength part of the n → π* CE.
Such compliance is
observed in enones 6 and 8 in which the preband CE is positive
thus being in agreement with the Kirk rule.
Among the limiting factors, one should also take into account
the impact of the applied level of theory on compliance with
the experiment. Significant deviations between the methods
used appear to be particularly common for inherently achiral
chromophores. It is already known that even moderate changes
in the calculation level may lead to a sign change, thus resulting
calculated at the B3LYP/aug-cc-pVDZ/PCM(CHCl ) level of
3
theory and compared with the experimental ones. As can be
seen in Figure 5, the agreement between simulated and
experimental spectra is excellent in all three cases. Thus, we
received further support for the correctness of our conforma-
tional analysis, namely selecting all conformers contributing to
the net ECD/VCD spectra.
In enones 6−8 the ECD bands within the n → π* transition
are highly structured, showing several identifiable bands
assigned to vibrational progressions in the carbonyl stretching
mode with the CE maxima at ∼320 nm for 6 and 8 and ∼350
nm for 7. The spectra of enones 6 and 8 additionally exhibit a
17,41,42
in unreliable theoretical predictions.
We, therefore, extended our computational study of the ECD
spectra to gain more insight. For this purpose, we reoptimized
the structures by the efficient, dispersion-inclusive PBEh-3c
level and recomputed the Boltzmann weights (for details see
Computational Details). Then the recently proposed simplified
time-dependent density functional (sTD-DFT) approach on a
CAM-B3LYP/def2-TZVP reference was used to compute the
G
DOI: 10.1021/acs.joc.6b00416
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The Journal of Organic Chemistry
Article
absorption and ECD spectra of all compounds. The calculation
has been conducted in the gas phase as well as by applying the
implicit conductor-like-screening solvation model COSMO in
the ground state. For the cis-enones, it can be seen that the
agreement between the experiment and the sTD-DFT results is
very good for both the EA and the ECD spectra (see SI).
Furthermore, we observed good mutual agreement with the
previous calculations at the B3LYP level. The influence of
COSMO is negligible for the cis-enones. In these cases, all
experimental ECD bands are computed with the correct sign.
From Figure 6 one can see that this does not hold for the trans-
enones. While the ECD signal of the π → π* transition (around
(see SI, p 185). This result strengthens the observation that the
ECD of the cis-enones is more robust than the one of the trans-
enones.
CONCLUSIONS
■
As a part of our ongoing research on the structure−chiroptical
properties relationship of α,β-unsaturated ketones, we describe
here a detailed stereochemical analysis of a set of model
compounds synthesized from (−)-α-santonin as a substrate.
The geometries, structural parameters, and chiroptical proper-
ties of all models were analyzed experimentally and
theoretically in detail by electronic circular dichroism (ECD)
partially supported by vibrational circular dichroism (VCD).
The structural characterization was assisted by nuclear magnetic
resonance (NMR) and single crystal X-ray analysis where
possible. In the case of dihydroepisantonin (7) we identified
and characterized the two polymorphic forms that are also
distinguishable by solid-state ECD.
250 nm) is the same in the gas phase and with COSMO, this
does not hold at all for the n → π*. In the gas phase, this band
is predicted to be negative in sign for all trans-enones 6−8.
When the solvation model COSMO is used, the sign of this
band is reversed in all these cases. This is in agreement with the
computed spectra mentioned above (Figure 4) where a
continuum solvation model (PCM in that case) was used as
well. One can infer that the implicit solvation leads to a
different stabilization of partial charges (and orbitals) which in
turn changes the coupling in the excited state. Although this
seems to be a realistic situation in solution, a positive sign for
this ECD band (as it is present when COSMO is used) is
experimentally observed only for dihydroepisantonin (7). It
was mentioned above that the ECD of the n → π* transitions
seems to feature some fine structure and, thus, might not
sufficiently be described solely by minimum geometries. For the
We have furthermore shown that the sign of the n → π*
ECD signals in trans-enones is not sufficiently described by a
minimum structure model. In such cases, it seems to be
necessary to go beyond this approach. We have achieved this by
computing ECD spectra on snap shots from a molecular
dynamics simulation. Thus, we demonstrated the remarkable
utility of the combined experimental and theoretical chiroptical
analysis to provide the complete three-dimensional solution
structures of chiral enones. Application of state-of-the-art
theoretical analysis allowed extraction of structural information
from the plethora of structure-sensitive bands in α,β-
unsaturated ketones.
“
problematic” trans-enones 6−8, we therefore chose to
compute ECD spectra on snap shots of a molecular dynamics
simulation (MD; see Computational Details). Thus, non-
minimum geometry effects on the ECD spectra can be taken
into account (Figure 6).
EXPERIMENTAL SECTION
■
General Techniques. Commercial reagents of the highest purity
available were used without further purification. All reactions were
monitored by thin-layer chromatography using aluminum backed silica
gel plates 60 F254; visualization was accomplished with UV light and/or
It is nicely observed that this improves the agreement with
the experimental spectra for all compounds. While the n → π*
turns out to be entirely negative for dihydrosantonin (6), it
remains (weakly) positive for dihydroepisantonin (7). The
corresponding ECD signal in compound 8 shows both a small
positive feature to lower energies and a stronger negative one to
those slightly above. It can be assumed that longer MD runs
will further improve the agreement between simulated and
measured spectra. At this moment, it is stated that by including
structures from MD runs (i.e., by going beyond the minimum
structure approach), the differences in the n → π* bands of the
trans-enones 6−8 are captured correctly. Note that averaging
UV or ECD spectra along MD trajectories does not yield the
vibronic fine structures of absorption and ECD bands, as these
staining with 50% H SO . Standard flash chromatography procedures
2 4
were followed (using silica gel with particle size 40−63 μm). The
melting points are given without correction. Optical rotation was
measured on a digital polarimeter at ambient temperature and are
−1
2
−1
quoted in units of 10 deg cm g . IR spectra were measured for
samples as KBr pellets or films or examined directly in the solid or
liquid state without further preparation with universal Attenuated
Total Reflectance (ATR) accessory in an FT-IR spectrophotometer.
1
13
H NMR and C NMR spectra were recorded in Fourier transform
mode at the field strength specified on a 400 or 500 MHz
spectrometer using CDCl as solvent and TMS as internal standard
3
and are reported as δ values (ppm) relative to residual CHCl signal
3
43
δH (7.26 ppm) and CDCl δC (77.16 ppm) as internal standards,
result from a quantum mechanical effect which is not properly
captured by computing vertical excitations obtained from a
classical MD.
3
respectively. Mass spectra were obtained at 70 eV. Electrospray
ionization (ESI) mass spectrometry (MS) experiments were
performed on a mass spectrometer under normal conditions. PFK
solution was used as a calibrant for HRMS measurements. UV spectra
were measured using acetonitrile as a solvent. The ECD spectra of 1−
While all minimum structure approaches were successful in
predicting the sign of the π → π* band, none of the considered
minimum geometry approaches can yield the right sign of the n
8
were recorded between 450 and 180 nm at room temperature in
→
π* band for all trans-enones. To achieve this, one has to go
spectroscopic grade acetonitrile with concentrations in the range from
−4
−4
beyond the minimum structure approximation in the
calculation of ECD spectra, as we have done by computing
ECD spectra on an MD trajectory. The agreement observed
with minimum structure based approaches (see, e.g., ECD
spectra of 6 and 8 in the SI) without an implicit solvation
model has to be interpreted as fortuitous error cancellation. It
has to be added at this point that a cross check calculation for
compound 5, used as a representative model of cis-enones,
shows no changes in sign compared to the minimum structures
3.0 × 10 to 7.47 × 10 M in a quartz cell with a path length of 0.1,
.2, 0.5, 1, or 2 cm. All spectra were recorded using a 100 nm/min
0
scanning speed, a step size of 0.2 nm, a bandwidth of 1 nm, a response
time of 0.5 s, and an accumulation of 5 scans. The spectra were
background corrected.
Low-temperature ECD measurements of 3 were performed in the
temperature range 298−93 K in a solution of MI13 (methylcyclohex-
ane/isopentane, 1:3, by vol.) and EPA (Et O/isopentane/EtOH,
2
5:5:2, by vol.) as solvents. The solutions with concentrations in the
−
3
−4
range from 1.82 × 10 to 1.87 × 10 M were measured between 450
H
DOI: 10.1021/acs.joc.6b00416
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The Journal of Organic Chemistry
Article
and 260 nm in a 1 cm quartz cell. Baseline correction was achieved by
subtracting the spectrum of a reference solvent obtained under the
same conditions. All spectra were normalized to Δε using volume
correction for EPA and MI13.
The ECD solid-state spectra of two polymorphic forms of 7 were
obtained using Diffused Transmission (DTCD) mode as the KCl
pellet was placed in the integrating sphere coated with barium sulfate
and introduced to the high sensitivity photomultiplier tube situated at
used for this purpose (employing the numerical quadrature grid m4).
Harmonic frequencies were computed at this level as well to verify
these structures as minima.
In order to obtain free energies for each conformer, electronic
energies (E , including nuclear repulsion and London dispersion)
el.
5
3
were computed with the D3(BJ) dispersion-corrected PW6B95
functional (grid m5) and Ahlrichs’ def2-QZVP basis set
54,55
on the
PBEh-3c geometries. The ro-vibrational contributions (GRRHO) to the
free energy (including the zero-point vibrational energy) were
computed according to ref 56 using the scaled (by a factor of 0.95)
harmonic frequencies at the PBEh-3c level of theory. Solvent effects to
the free energy (δGsolv.) were accounted for by the COSMO-RS
9
0°. ECD spectrum (0.164−1.006 mg/100 mg KCl) was recorded
between 400 and 200 nm at room temperature using the following
parameters: a 100 nm/min scanning speed, a step size of 0.2 nm, a
bandwidth of 5 nm, a response time of 0.5 s, and an accumulation of 5
scans. The resulting spectrum was background corrected. The KCl
pellet was mounted on a rotatable holder located just before
integrating sphere. The sample was measured upon rotation of the
disk around the incident axis direction at various rotation angles. The
spectra were almost identical, demonstrating the absence of detectable
spectral artifacts. Linear dichroism (LD) was also measured; the order
57−59
method employing the 2012 parametrization for acetonitrile.
The
resolution-of-identity approximation for the Coulomb integrals (RI-J)
was applied in all TURBOMOLE calculations using a matching default
6
0,61
auxiliary basis.
The relative free energies between the conformers
are then given as the sum of the individual contributions:
−3
ΔG = ΔEel. + ΔGRRHO + ΔδGsolv.
was less than 2 × 10 OD.
The VCD and IR spectra of 6−8 were measured at a resolution of 4
The Boltzmann weights were calculated using the free energies which
were computed as described above.
For each conformer, single-point calculations on the PBEh-3c
−1
cm in CDCl . The FT-VCD spectrometer was equipped with dual
3
sources and dual PEM (PhotoElastic Modulator). Solutions with
molar concentrations of 0.14 [6 (6.08 mg) in CDCl (180 μL)], 0.20
3
geometries were performed with the range-separated hybrid density
6
2−65
[
(
7 (8.39 mg) in CDCl (180 μL)], and 0.21 [8 (9.996 mg) in CDCl3
3
functional CAM-B3LYP
def2-TZVP
(numerical quadrature grid5) and the
basis set. Based on this ground state, all singly excited
states up to 10 eV were computed with the simplified time-dependent
5
5,66
180 μL)], were measured in a BaF cell with a path length of 99.8 μm.
2
−1
The ZnSe photoelastic modulator was set to 1400 cm . The spectra
6
7−69
were measured for 3 h 30 min (10240 scans). Baseline correction was
achieved by subtracting the spectrum of a reference sample of CDCl3
recorded under the same conditions as the enones samples. Single
density functional theory (sTD-DFT) approach.
A development
has been used for this purpose. The
same procedure was repeated but including the COSMO solvation
7
0,71
version of the ORCA program
7
2
crystal X-ray diffraction measurements for 1, 3, 6, and 7 (needles and
prism-like crystals) were carried out at 100 K with graphite
monochromated Cu Kα radiation (1.54184 Δ). All non-hydrogen
atoms were refined as anisotropic while hydrogen atoms were placed
in calculated positions and refined in riding mode. Crystallographic
data for 1, 3, 6, and 7 reported here have been deposited with the
Cambridge Crystallographic Data Centre (Deposition Nos. CCDC
426351 for 1, 1428736 for 3, 1428735 for 6, and 1428737 as well as
428889 for 7 (prism-like and needle-like crystals, respectively). These
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif.
model (ε = 35.688).
For the computations on an MD trajectory, a quantum mechanically
7
3
derived force field was parametrized using the PBEh-3c Hessian
(matrix elements scaled 0.95) of the most stable conformer of 6 and 7.
For compound 8, the four most stable conformers were considered.
With the resulting force fields, a molecular dynamics simulation
(NPT conditions) was performed of one molecule dissolved in a box
of 200 acetonitrile molecules at 300 K (periodic boundary conditions
were employed). After equilibrating for 0.5 ns, we ran the simulation
for another 0.5 ns with a time step of 1 fs. The X−H bonds were kept
1
1
7
4,75
76
fixed using the SHAKE
algorithm. The QMSIM program has
been used for this purpose. Every 5 ps, a structure was extracted (100
in total for each considered starting conformer) and an sTD-CAM-
B3LYP/def2-TZVP+COSMO calculation was performed on the
resulting solute geometry. For compound 8, the resulting spectra
were weighted by the Boltzmann weights of the respective starting
conformers.
The molar extinction (ε) and circular dichroism (Δε) spectra were
simulated by convoluting the oscillator and rotatory strengths,
respectively, with Gaussian functions with a full width at 1/e
maximum of 0.5 eV (0.3 eV for calculations on MD trajectories).
All spectra are shifted by −0.5 eV (i.e., red-shifted) to match the
experimental intense absorption band around 250 nm. The dipole
length formalism has been used for the oscillator strengths while the
origin-independent dipole velocity form was used for the rotatory
strengths.
COMPUTATIONAL DETAILS
■
In the case of cis-enones 1−5, a conformational search on the
molecular mechanics level was carried out within a 10 kcal/mol energy
44
window using CONFLEX 7 software with the MMFF94s force field
(
a static variant of MMFF94). Depending on the compound, we
obtained 237 to 535 conformers (detailed data in the Supporting
Information = SI). To reduce the number of conformers and to
remove conformers not fitting within the narrower 5 kcal/mol energy
window, the structures were optimized using the same force field. This
additional optimization resulted in a much-reduced number of
structures, namely 55 to 129 depending on the compound (see SI).
Next, the obtained geometries were subsequently reoptimized using
4
5
the density functional theory (DFT) employing Gaussian09 at the
B3LYP/TZVP/PCM(CH CN) level (see SI). As a result, 10 to 25
Preparation of Dihydrosantonin 6. Tris(triphenylphosphine)-
rhodium(I) chloride (280 mg, 0.3 mmol) was dissolved in acetone (50
mL) in a hydrogenation apparatus which was then flushed three times
with hydrogen. After stirring the solution in an atmosphere of
hydrogen for about 1 h the hydrogen uptake ceased and constant
pressure was attained. Then a solution of (−)-α-santonin (9, 600 mg,
2.4 mmol) in acetone (25 mL) was added, and the stirring was
continued until hydrogen consumption ceased. The solvent was
evaporated to dryness, and the residue was chromatographed (20%
ethyl acetate in hexanes) giving 6 (595 mg, 97%).
3
structures with a population of more than 1% were obtained and later
used to simulate chiroptical properties (see SI).The EA and ECD
spectra of all conformers were calculated by the TDDFT method with
the TZVP basis set and B3LYP functional by applying the PCM model
to reflect solvent influence. Next, before comparing the predicted and
experimental ECD spectra, the agreement of experimental and
calculated EA spectra was verified, as their conformity is a prerequisite
for analyzing the corresponding ECD spectra.
The geometries were reoptimized at the PBEh-3c level, i.e.,
employing a hybrid density functional in combination with a double-ζ
46
4
7
3
0
31
Colorless crystals, mp 100−101 °C (lit. 100−102, 102, 101−
48,49
77
24
77
1
basis set and the atom-pairwise D3(BJ) dispersion
and geometrical
102 °C); [α]D +72 (c 0.5, EtOH) [lit. [α] +79 (c 1.42)]; H
D
50
counterpoise (gCP) corrections. This composite method yields
NMR (500 MHz, CDCl ): δ = 4.69 (dd, J = 11.6, 1.3 Hz, 1H), 2.54
3
highly accurate geometries for organic compounds at comparably low
(ddd, J = 16.7, 14.1, 5.0 Hz, 1H), 2.44 (dt, J = 16.7, 4.3 Hz, 1H), 2.35
(dq, J = 12.2, 6.9 Hz, 1H), 2.02−1.97 (m, 1H), 2.00 (s, 3H), 1.96−
51,52
cost. The TURBOMOLE suite of programs (version 7.0)
has been
I
DOI: 10.1021/acs.joc.6b00416
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The Journal of Organic Chemistry
Article
1
(
.87 (m, 2H), 1.81 (dt, J = 13.4, 4.6 Hz, 1H), 1.77−1.63 (m, 2H), 1.56
td, J = 13.2, 4.4 Hz, 1H), 1.34 (s, 3H), 1.27 (d, J = 6.9 Hz, 3H); 13
NMR (125 MHz, CDCl ): δ = 198.8, 177.6, 152.5, 128.55, 81.9, 52.9,
38.8, 35.6, 30.8, 29.3, 27.2, 23.0, 22.7, 13.01, 12.97; IR (KBr): 2952,
−1
C
1721, 1681, 1479, 1287, 1173 cm ; Anal. Calcd for C H O : C,
2
2
34
5
69.81; H, 9.05. Found: C, 69.98; H, 9.13.
3
4
1
1.7, 41.2, 38.3, 38.2, 33.6, 24.6, 24.2, 12.4, 11.2; IR (CHCl ): 2937,
779, 1668, 1622, 1458, 1327, 1138, 1033 cm ; Anal. Calcd for
Preparation of 13. Dihydrosantonin (6, 580 mg, 2.3 mmol) was
dissolved in anhydrous THF (60 mL), and lithium tri-tert-butoxy-
aluminum hydride (1.2 g, 4.7 mmol) was added to the solution. After
the mixture stirred for 2 h at room temperature, a saturated aqueous
solution of sodium sulfate was added cautiously until a thick white
precipitate was formed. The precipitate was filtered off, and the solvent
was evaporated to dryness. The residue was chromatographed (15%
acetone in hexanes) yielding a mixture of stereomers 13 (equatorial/
axial = 17:3) (560 mg, 95%). An analytical sample of pure equatorial
isomer was prepared by crystallization from methanol.
3
−1
C H O : C, 72.55; H, 8.12. Found: C, 72.64; H, 8.03.
1
5
20
3
Fast crystallization of dihydrosantonin (6) from the hot mixture of
methanol/water 1:1 led to plate-like crystals, 100−101 °C, IR (KBr):
2
1
940, 1875, 1792, 1767, 1675, 1623, 1455, 1331, 1292, 1238, 1209,
185, 1138, 1099, 1028, 985 cm .
−1
Slow evaporation of the methanol from the mother liquor remained
after separation plate crystals gave needle-like crystals: mp 100−101
°
C; IR (KBr): 2940, 1874, 792, 1767, 1675, 1622, 1454, 1331, 1291,
−1
24
1
1
238, 1209, 1185, 1138, 1099, 1028, 985 cm .
Colorless crystals, mp 99−100 °C; [α]D −26 (c 0.5, EtOH); H
Preparation of Ketal 10. A boiling mixture of dihydrosantonin (6,
NMR (500 MHz, CDCl ): δ = 4.60 (d, J = 11.1 Hz, 1H), 4.01−3.95
3
7
10 mg, 2.9 mmol), benzene (50 mL), p-toluenesulfonic acid
(m, 1H), 2.28 (dq, J = 12.2, 6.9 Hz, 1H), 1.96 (s, 3H), 1.93−1.85 (m,
2H), 1.72 (qd, J = 11.8, 3.4 Hz, 1H), 1.67−1.59 (m, 4H), 1.52−1.49
(m, 1H), 1.48−139 (m, 2H), 1.23 (d, J = 6.9 Hz, 3H), 1.18 (s, 3H);
monohydrate (40 mg, 0.2 mmol), and ethylene glycol (1.5 mL) was
distilled slowly through a small Vigreux column for a period of 5 h (10
mL of distillate was collected). The cooled reaction mixture was
washed with aqueous sodium bicarbonate, and the organic layer was
dried over Na SO and evaporated to dryness. The main product of
13
C NMR (125 MHz, CDCl ): δ = 178.6, 133.8, 128.1, 82.7, 71.5,
3
53.6, 41.3, 40.6, 37.8, 36.4, 28.2, 26.2, 24.6, 15.5, 12.4; IR (CHCl ):
3
−1
2
4
3611, 2936, 1769, 1457, 1380, 1139, 1030 cm ; Anal. Calcd for
C H O : C, 71.97; H, 8.86. Found: C, 71.89; H, 8.93.
the reaction 10 (460 mg, 55%) was isolated by chromatography (5%
acetone in hexanes).
15
22
3
Preparation of 14. A mixture of 13 (500 mg, 2.5 mmol), tert-
2
4
1
Colorless crystals, mp 105−107 °C; [α] +34(c 0.5, EtOH); H
butyldimethylchlorosilane (450 mg, 3 mmol), dichloromethane (6
mL), triethylamine (0.6 mL), and DMAP (50 mg, 0.4 mmol) was kept
at room temperature for 20 h and then diluted with dichloromethane
(50 mL) and washed with water. The organic layer was dried over
Na SO , and the solvent was evaporated to dryness. The residue was
D
NMR (500 MHz, CDCl ): δ = 4.57 (dd, J = 11.3, 1.4 Hz, 1H), 3.90−
3
4
.10 (m, 4H), 2.27(dq, J = 12.2, 6.9 Hz, 1H), 1.94−1.88 (m, 1H), 1.84
(
d, J = 1.0 Hz, 3H), 1.86−1.80 (m, 1H), 1.79−1.73 (m, 2H), 1.72−
.65 (m, 1H), 1.62−1.42 (m, 4H), 1.22 (d, J = 6.9 Hz, 3H), 1.17 (s,
1
3
8
2
4
H); 13C NMR (125 MHz, CDCl ): δ = 178.5, 137.3, 127.1, 108.1,
3
chromatographed (5% ethyl acetate in hexanes) yielding 14 (610 mg,
84%) as a mixture of equatorial/axial isomers in a ratio of 17:3. The
mixture was crystallized from methanol/water affording pure
equatorial isomer 14 (480 mg, 66%).
2.5, 65.7, 64.7, 53.1, 41.2, 41.1, 37.4, 37.2, 29.3, 24.8, 24.6, 12.4, 11.4;
IR (KBr): 2940, 2870, 1773, 1659, 1457, 1380, 1308, 1244, 1172,
−1
1
143, 1087, 1065, 1023 cm ; Anal. Calcd for C H O : C, 69.84; H,
17 24 4
2
4
1
8
.27. Found: C, 69.78; H, 8.26.
Preparation of Ketal 12. Ketal 10 (234 mg, 0.8 mmol) was
dissolved in anhydrous THF (25 mL), and lithium aluminum hydride
30 mg, 0.8 mmol) was added to the solution. After the mixture stirred
Colorless crystals, mp 107−108 °C; [α] −7 (c 0.5, EtOH); H
D
NMR (500 MHz, CDCl ): δ = 4.56 (d, J = 11.2 Hz, 1H), 3.99−3.95
3
(m, 1H), 2.25 (dq, J = 12.1, 6.9 Hz, 1H), 1.91−1.85 (m, 1H), 1.87 (s,
3H), 1.80−1.47 (m, 6H), 1.44−1.33 (m, 2H), 1.21 (d, J = 6.9 Hz,
(
1
3
for 1 h at room temperature, a saturated aqueous solution of sodium
sulfate was added cautiously until a thick white precipitate was formed.
The precipitate was filtered off, and the solvent was evaporated to
dryness. The crude reduction product 11 was dissolved in dry pyridine
3H), 1.17 (s, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); C NMR
(125 MHz, CDCl ): δ = 178.7, 132.3, 129.4, 82.9, 72.3, 53.6, 41.3,
3
41.1, 37.7, 36.9, 28.8, 26.0, 25.9, 24.7, 18.1, 15.6, 12.4, −4.2, −4.7; IR
−1
(CHCl ): 2932, 1768, 1460, 1379, 1360, 1330, 1255, 1057, 1031 cm ;
3
(
6 mL), and pivalic anhydride (0.6 mL) was added. The mixture was
Anal. Calcd for C H O Si: C, 69.18; H, 9.95. Found: C, 69.08; H,
9.85.
21
36
3
kept at room temperature until all diol 11 disappeared (14 days) and
then was diluted with water and extracted with diethyl ether. The
organic layer was dried over Na SO , and the solvent was evaporated.
The residual pyridine was removed by evaporation with toluene. The
crude reaction mixture was chromatographed (13% ethyl acetate in
hexanes) yielding pivalate 12 (222 mg, 73% based on 10).
Preparation of 16. Sillyl ether 14 (400 mg, 1.1 mmol) was
dissolved in anhydrous THF (25 mL) and lithium aluminum hydride
(50 mg, 1.3 mmol) was added to the solution. After stirring for 1 h at
room temperature, saturated aqueous solution of sodium sulfate was
added cautiously until a thick white precipitate was formed. The
precipitate was filtered off and the solvent was evaporated to dryness.
The crude reduction product 15 was dissolved in dry pyridine (8 mL)
and pivalic anhydride (2 mL) was added. The mixture was kept at
room temperature until all diol 15 disappeared (14 days) and then
diluted with water and extracted with diethyl ether. The organic layer
was dried over Na SO and the solvent was evaporated. The residual
2
4
2
4
1
Colorless crystals, mp 127−128 °C; [α] +54 (c 0.5, EtOH); H
D
NMR (500 MHz, CDCl ): δ = 4.36 (dd, J = 11.0, 4.1 Hz, 1H), 4.10−
3
3
1
0
1
3
1
9
.92 (m, 6H), 2.49−2.41 (m, 1H), 1.91 (s, 3H), 1.82−1.70 (m, 4H),
.59−1.43 (m, 5H), 1.33−1.24 (m, 1H), 1.20 (s, 9H), 1.10 (s, 3H),
.92 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl ): δ = 178.6,
3
45.4, 126.3, 109.3, 72.8, 68.1, 65.5, 64.7, 46.6, 41.3, 38.8, 37.6, 36.8,
2
4
1.5, 29.3, 27.2, 23.6, 20.5, 12.2, 10.8. IR (CDCl ): 3623, 2959, 1718,
pyridine was removed by evaporation with toluene. The crude reaction
3
−1
459, 1288, 1157, 1074 cm ; Anal. Calcd for C H O : C, 69.44; H,
mixture was chromatographed (10% ethyl acetate and 0.1% Et N in
22
36
5
3
.53. Found: C, 69.45; H, 9.60.
Preparation of Enone 1. A solution of 12 (115 mg, 0.3 mmol) in
hexanes) yielding pivalate 16 (353 mg, 71% based on 14).
Colorless oil, [α]2 +14 (c 0.5, EtOH); 1H NMR (500 MHz,
4
D
pyridine (3 mL) was added to the complex prepared by the addition of
chromium trioxide (200 mg, 2 mmol) to pyridine (3 mL) at 0 °C. The
mixture was stirred at room temperature for 20 h, and then diethyl
ether was added (20 mL). The solids were filtered off, and the solvent
was evaporated. The residual pyridine was removed by evaporation
with toluene. The crude reaction mixture was chromatographed (10%
ethyl acetate in hexanes) yielding enone 1 (94 mg, 82%).
CDCl ): δ = 4.35 (d, J = 11.0 Hz, 1H), 4.02−3.91 (m, 3H), 2.50−2.41
3
(m, 1H), 1.95 (s, 3H), 1.83−1.67 (m, 3H), 1.58−1.39 (m, 6H), 1.25
(dt, J = 12.7, 2.3 Hz, 1H), 1.20 (s, 9H), 1.10 (s, 3H), 0.92 (d, J = 8.2
Hz, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (125
MHz, CDCl ): δ = 178.6, 140.3, 128.8, 74.4, 72.8, 68.2, 46.8, 41.6,
3
38.8, 37.8, 36.9, 31.5, 29.0, 27.2, 26.0, 24.6, 20.6, 18.2, 17.1, 10.8, −4.1,
−4.7; IR (CHCl ): 3620, 2933, 2857, 1718, 1461, 1288, 1156, 1080,
3
24
1
−1
+
Colorless crystals, mp 63−65 °C; [α] +59 (c 0.5, EtOH); H
1050 cm ; HRMS (ESI) m/z: [M + Na] Calcd for C H O NaSi
D
26 48 4
NMR (500 MHz, CDCl ): δ = 4.10−4.04 (m, 2H), 4.03−3.92 (m,
475.3220; Found: 475.3217.
3
4
1
0
H), 2.58−2.50 (m, 1H), 2.43−2.36 (m, 1H), 1.94−1.86 (m, 1H),
Preparation of 2. A solution of 16 (190 mg, 0.4 mmol) in pyridine
(4 mL) was added to the complex prepared by the addition of
chromium trioxide (300 mg, 3 mmol) to pyridine (6 mL) at 0 °C. The
mixture was stirred at room temperature for 20 h, and then diethyl
.83−1.69 (m, 6H), 1.63 (s, 3H), 1.62−1.56 (m, 1H), 1.19 (s, 9H),
.98 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl ):
3
δ = 206.5, 178.4, 145.2, 133.9, 107.2, 67.3, 65.9, 64.9, 53.2, 39.9, 38.9,
J
DOI: 10.1021/acs.joc.6b00416
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ether was added (30 mL). The solids were filtered off and washed with
diethyl ether, and the solvent was evaporated. The residual pyridine
was removed by evaporation with toluene. The crude reaction mixture
was chromatographed (2% ethyl acetate in hexanes) yielding enone 2
to dryness. The residue was chromatographed (20% ethyl acetate in
hexanes) yielding 7 (57 mg, 81%) as colorless crystals.
3
1
24
Colorless crystals, mp 123−124 °C (lit. 125 °C), [α]D −137 (c
1
0.4, EtOH); H NMR (500 MHz, CDCl ): δ = 5.45 (d, J = 5.3 Hz,
3
(
143 mg, 75%).
1H), 2.71 (ddd, J = 17.9, 14.9, 5.5 Hz, 1H), 2.53−2.48 (m, 2H), 2.21
(dt, J = 10.8, 5.8 Hz, 1H), 1.91 (s, 3H), 1.94−1.86 (m, 1H), 1.79−1.70
(m, 2H), 1.66−1.56 (m, 2H), 1.39 (d, J = 7.7 Hz, 3H), 1.41−1.37 (m,
2
4
1
Colorless crystals, mp 85−87 °C; [α] +9 (c 0.3, EtOH); H NMR
D
(
2
1
500 MHz, CDCl ): δ = 4.07 (dd, J = 9.1, 5.8 Hz, 1H), 4.01−3.94 (m,
3
1H), 1.26 (s, 3H); 13C NMR (125 MHz, CDCl ): δ = 198.8, 179.5,
H), 2.63−2.55 (m, 1H), 2.32 (ddd, J = 12.4, 6.4, 4.1 Hz, 1H), 1.90−
.73 (m, 3H), 1.67 (s, 3H), 1.72−1.56 (m, 4H), 1.53 (dd, J = 13.3, 2.6
3
151.2, 136.6, 75.8, 43.7, 43.1, 37.8, 37.7, 34.4, 34.0, 23.8, 23.1, 15.1,
Hz, 1H), 1.19 (s, 9H), 0.99 (s, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.89 (s,
10.8; IR (CHCl ): 2973, 2938, 2871, 1767, 1670, 1455, 1380, 1317,
3
H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl ): δ =
06.1, 178.4, 140.6, 138.7, 72.0, 67.4, 53.2, 40.3, 38.8, 38.7, 36.3, 30.8,
8.8, 27.2, 25.8, 24.7, 22.3, 18.1, 17.2, 12.9, −4.1, −4.9; IR (CHCl ):
957, 2930, 1717, 1689, 1623, 1604, 1461, 1286, 1164, 1092 cm ;
−1
9
2
2
2
1160, 957 cm ; Anal. Calcd for C15
C, 72.83; H, 8.03.
H O : C, 72.55; H, 8.12. Found:
20 3
3
Crystallization of dihydroepisantonin (7) from the mixture of
methanol/water 1:1 led to needle-like crystals: mp 96−98 °C; IR
(KBr): 2973, 2942, 2921, 2867,1773, 1669, 1645, 1590,1453, 1381,
3
−
1
Anal. Calcd for C H O Si: C, 69.28; H, 10.28. Found: C, 69.31; H,
26
46
4
−1
1
0.40.
Preparation of 3. Tetrabutylammonium fluoride trihydrate (190
1361, 1329, 1312, 1214, 1199, 1161, 1069, 1024, 953, 932 cm .
Crystallization of dihydroepisantonin (7) from hexane gave
prismatic crystals: mp 123−124 °C; IR (KBr): 2940, 1874, 792,
1767, 1675, 1622, 1454, 1331, 1291, 1238, 1209, 1185, 1138, 1099,
mg, 0.6 mmol) was added to a solution of 2 (84 mg, 0.19 mmol) in
THF (4 mL), and the mixture was stirred at 40 °C for 2 h. Then water
−
1
(
20 mL) was added, and the mixture was extracted with diethyl ether.
1028, 985 cm .
The organic layer was dried over Na SO and evaporated to dryness.
The residue was chromatographed (15% acetone in hexanes) yielding
2
4
pure 3 (59 mg, 94%).
2
4
1
Colorless crystals, mp 58−60 °C, [α] +59 (c 0.5, EtOH); H
D
NMR (500 MHz, CDCl ): δ = 4.10−3.95 (m, 3H), 2.62 (m, 1H), 2.34
3
(
1
1
ddd, J = 12.3, 6.5, 2.2 Hz, 1H), 2.03−1.95 (m, 1H), 1.93−1.86 (m,
H), 1.76 (s, 3H), 1.84−1.60 (m, 6H), 1.56 (qd, J = 13.6, 2.7 Hz, 1H),
.19 (s, 9H), 1.00 (s, 3H), 0.94 (d, J = 6.9 Hz, 3H). 13C NMR (125
MHz, CDCl ): δ = 206.3, 178.4, 141.8, 137.0, 71.3, 67.3, 53.2, 40.0,
3
[α]2
4
78
23
1
3
3
1
3
8.9, 38.8, 35.9, 30.8, 28.4, 27.2, 24.7, 22.4, 16.6, 12.9; IR (CHCl ):
3
596, 2968, 2937, 1720, 1688, 1626, 1480, 1457, 1381, 1286, 1164,
−1
+
032 cm ; HRMS (ESI) m/z: [M + Na] Calcd for C H O Na
2
0
32
4
59.2198; Found: 359.2204.
Preparation of 4. Mother liquors remaining after crystallization of
1
4 (120 mg, 0.26 mmol) were processed the same way as it was
applied for 15 and 16 affording a mixture of isomers 4 and 2. Pure
component 4 (44 mg) was isolated by preparative TLC chromatog-
raphy (10% diethyl ether in hexanes, three developments).
Colorless oil, [α]D +60 (c 0.5, EtOH); 1H NMR (500 MHz,
24
CDCl ): δ = 4.03−3.95 (m, 2H), 3.93−3.90 (m, 1H), 2.60−2.50 (m,
3
1
1
0
H), 2.44−2.37 (m, 1H), 1.92−1.84 (m, 1H), 1.82−1.70 (m, 3H),
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00416.
■
.69 (s, 3H), 1.68−1.60 (m, 3H), 1.39−1.34 (m, 1H), 1.18 (s, 9H),
*
S
.94 (d, J = 6.9 Hz, 3H), 0.91 (s, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 13
C
NMR (125 MHz, CDCl ): δ = 207.9, 178.4, 141.9, 135.6, 69.1, 67.5,
3
5
1
1
3.1, 39.9, 38.9, 38.8, 32.7, 30.8, 27.9, 27.2, 25.8, 23.4, 22.6, 22.3, 18.0,
7.7, 13.1, −4.4, −4.7; IR (CHCl ): 2956, 2932, 2857, 1731, 1693,
Crystallographic data for 1 (CIF)
Crystallographic data for 3 (CIF)
Crystallographic data for 6 (CIF)
3
−1
638, 1472, 1467, 1283, 1254, 1162, 1079, 1032 cm ; HRMS (ESI)
+
m/z: [M + Na] Calcd for C H O NaSi 473.3063; Found: 473.3066.
26
46
4
Preparation of 5. Tetrabutylammonium fluoride trihydrate (70
mg, 0.22 mmol) was added to a solution of 4 (28 mg, 0.06 mmol) in
THF (2 mL), and the mixture was stirred at room temperature for 2 h.
Then water (20 mL) was added, and the mixture was extracted with
diethyl ether. The organic layer was dried over Na SO and evaporated
Crystallographic data for 7, needle-like crystals (CIF)
Crystallographic data for 7, prism-like crystals (CIF)
1
13
H NMR, C NMR, and IR spectra for compounds 1−
2
4
15 and details of computational studies (PDF)
to dryness. The residue was chromatographed (15% acetone in
hexanes) yielding pure 5 (15 mg, 71%).
Pale yellow oil, [α]2 +96 (c 0.4, EtOH); H NMR (600 MHz,
4
1
AUTHOR INFORMATION
Corresponding Authors
E-mail: jadwiga.frelek@icho.edu.pl.
E-mail: grimme@thch.uni-bonn.de.
D
■
*
*
CDCl ): δ = 4.00−3.97 (m, 3H), 2.61−2.54 (m, 1H), 2.42−2.37 (m,
3
1
1
H), 1.81 (s, 3H), 1.93−1.61 (m, 8H), 1.46 (dt, J = 13.0, 3.5 Hz, 1H),
.19 (s, 9H), 0.95 (d, J = 6.9 Hz, 3H), 0.94 (s, 3H); 13C NMR (150
MHz, CDCl ): δ = 207.1, 178.5, 142. 8, 135.1, 68.5, 67.3, 53.1, 39.9,
3
Notes
3
3
1
8.9, 32.4, 30.7, 27.3, 27.23, 27.20, 23.1, 22.1, 18.0, 13.0; IR (CHCl ):
3
445, 2960, 2934, 2873, 1728, 1685, 1631, 1479, 1457, 1398, 1377,
The authors declare no competing financial interest.
−1
+
284, 1162, 1031 cm ; HRMS (ESI) m/z: [M + Na] Calcd for
C H O Na 359.2198; Found: 359.2195.
ACKNOWLEDGMENTS
2
0
32
4
■
Preparation of Dihydro-6-episantonin 7. Dihydrosantonin 6
70 mg, 0.28 mmol) was dissolved in anhydrous DMF containing 5%
This work was supported by Grant No. UMO-2011/01/B/
ST5/06413 from the National Science Centre of Poland. The
GAUSSIAN calculations were performed at the Interdiscipli-
nary Centre for Mathematical and Computational Modeling
(ICM) of University of Warsaw (Grant Nos. G34-15 and G36-
(
HCl (1 mL), and the solution was heated at 80 °C for 1 h. Then the
solution was diluted with water and extracted with diethyl ether. The
organic layer was washed with water, saturated sodium bicarbonate,
and brine. The organic portion was dried over Na SO and evaporated
2
4
K
DOI: 10.1021/acs.joc.6b00416
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
2). C.B. thanks Jakob Seibert for his help concerning the sTD-
Article
1
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́ ́
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