A new case of induced helical chirality in a bichromophoric system: Absolute configuration of transparent and flexible diols from the analysis of the electronic circular dichroism spectra of the corresponding di(1-naphthyl)ketals

Article abstract of DOI:10.1021/ol8012149

(Chemical Equation Presented) Di(1-naphthy)ketals of 1,n-diols show couplet effects allied to the ¹B naphthalene transition in their CD spectra. This means that they assume a conformation with a prevailing sense of twist of the naphthalene ring

Full text of DOI:10.1021/ol8012149

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3421-3424
A New Case of Induced Helical Chirality
in a Bichromophoric System: Absolute
Configuration of Transparent and
Flexible Diols from the Analysis of the
Electronic Circular Dichroism Spectra of
the Corresponding Di(1-naphthyl)ketals
Sabina Tartaglia, Francesca Pace, Patrizia Scafato, and Carlo Rosini*
Dipartimento di Chimica, UniVersita` della Basilicata, Via N. Sauro 85,
85100 Potenza, Italy
carlo.rosini@unibas.it
Received May 29, 2008
ABSTRACT
Di(1-naphthyl)ketals of 1,n-diols show couplet effects allied to the 1B naphthalene transition in their CD spectra. This means that they assume
a conformation with a prevailing sense of twist of the naphthalene rings, imposed by the absolute configuration (AC) of the starting diols and
by the nature of the R1 groups. A positive couplet for aliphatic diols is a probe of (R,R), AC while the opposite sign is found for (R,R) aromatic
diols.
Nowadays, the analysis of the chiroptical properties (optical
rotation (OR), electronic circular dichroism (ECD), vibra-
tional circular dicroism (VCD)) carried out by nonempirical
methods such as the exciton model1,2 or the use of ab initio
techniques2,3 can provide a safe assignment of the molecular
absolute configuration (AC). However, in spite of these
significant progresses, some problems still remain: in par-
ticular, the treatment of the electronic chiroptical properties
of all those compounds showing small [R]D and/or weak ECD
signals, such as aliphatic alcohols, diols, ethers, amines, and
so on. In fact, such compounds are species without typical
UV-vis chromophores which, in addition, present a large
conformational flexibility so that many conformers showing
different (even opposite) OR values and/or ECD spectra are
simultaneously present, leading to a weighted average value
which is small. This fact constitutes then the main obstacle
to a straightforward analysis of the chiroptical data and then
(1) (a) Nakanishi, K.; Berova, N. In Circular Dichroism: Principles and
Applications; Nakanishi, K., Berova, N., Woody, R. W., Eds.; Wiley-VCH
Publishers: New York, 2000; Chapter 12, pp 337-382. (b) DeVoe, H.
J. Chem. Phys. 1964, 41, 393–400. (c) ibidem 1965, 43, 3199-3208. (d)
Rosini, C; Salvadori, P.; Zandomeneghi, M. Tetrahedron: Asymmetry 1993,
4, 545–554. (e) Superchi, S.; Giorgio, E.; Rosini, C. Chirality 2004, 16,
(3) For a general discussion of the ab initio calculation of chiroptical
properties: (a) Polavarapu, P. L Chirality 2002, 14, 768–781. (b) Pecul,
M.; Ruud, K. AdV. Quantum Chem. 2006, 50, 185–227. (c) Crawford, T. D.
Theor. Chem. Acc. 2006, 115, 227–245. (d) Polavarapu, P. L. Chem Record
2007, 7, 125–136. (e) Crawford, T. D.; Tam, M. C.; Abrams, M. L. J. Phys.
Chem. A 2007, 111, 12057–12068. (f) Stephens, P. J. In Computational
Medicinal Chemistry for Drug DiscoVery; Bultinck, P.,; de Winter, H.,;
Langenaecker, W.,; Tollenaere, J., Eds.; Dekker: NY, 2003; Chapter 26,
pp 699-725.
422–451
.
(2) Koslowski, A.; Sreerama, N.; Woody, R. W. In Circular Dichroism:
Principles and Applications; Nakanishi, K., Berova, N., Woody, R. W.,
Eds.; Wiley-VCH Publishers: New York, 2000; Chapter 3, pp 55-95
.
10.1021/ol8012149 CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society

to a reliable AC determination. For a few years we have
been involved in a research project aimed at providing some
solutions to this difficult problem. Thus we decided to
transform the flexible, transparent compounds in chro-
mophoric, conformationally defined derivatives: the analysis
of the electronic chiroptical properties of these systems
should result as more simple and reliable, guaranteeing a
safe AC assignment.4 The same kind of approach has been
recently used by Stephens and co-workers5 to facilitate the
analysis of the VCD spectra of (-)-borneol. The flexible,
transparent aliphatic molecules we treated were mainly 1,n-
diols,4b and we present herein a new type of chemical
derivatization of some transparent 1,n-diols (compounds 1)
in the corresponding conformationally defined di(1-naphth-
yl)ketals, 2. The reasons of the above derivatization are as
follows: these compounds are easily synthesized from di(1-
naphthyl)ketone and the corresponding 1,n-diol. In this way,
on passing from the starting, acyclic 1,n-diols 1 to the cyclic
compounds 2, we certainly will have a reduction of the
conformational freedom. The introduction of the naphthyl
chromophore gives two remarkable advantages: (a) the
R-substitution provides derivatives characterized by reduced
conformational mobility owing to the presence of the steric
effect of the peri hydrogen in 1-naphthyl-substituted com-
pounds; (b) the naphthyl chromophore possesses the electri-
the AC of the starting diols by means of the Harada-
Nakanishi rule.1a
Ketals 2 were easily synthesized by reaction of dimethyl
acetal of di(1-naphthyl)ketone with the optically active diols
1a-h (Figure 1), traces of p-TsOH, and 4 Å activated
Figure 1. Structures of 1,n-diols 1a-h.
molecular sieves. Purification by chromatography column
afforded ketals 2a-h (Scheme 1), in 50-60% yield, as
Scheme 1. Preparation of Ketals 2a-h
1
cally allowed transition Bb at 220 nm, with high ε value
(90 000 ca.) and with known (long-axis) polarization direc-
tion.6 So, clear Cotton effects should appear in the ECD
spectra of 1. In particular, we expect that the derivatives 2
will assume a conformation where the two naphthyl chro-
mophores are twisted with respect each other, with a
preferential sense of twist dictated by the stereogenic center
of the optically active diol: i.e., we expect that in these
systems a transfer of chirality from the diol (central chirality)
to a preferential sense of twist of the two naphthyl rings
(helical chirality) will occur. It is noteworthy that, as reported
in some previous instances, the aryl rings were directly
linked,4b,7–9 while in the present case, they are linked to the
same carbon atom but not directly. From this point of View
the method should constitute a completely new example of
central to helical chirality transfer. Then, the presence of
two twisted naphthalene chromophores should guarantee, in
the ECD spectrum, the appearance of an exciton couplet,
linked to the naphthalene 1Bb transition at 220 nm. Then, by
knowing the molecular conformation and the polarization
direction of this transition, it should be possible to assign
foamy white solids. The experimental UV spectra of 2a-h
present similar features, typical of the naphthalene chro-
mophore:6 an absorption band at ∼283 nm (ε ∼ 12000) due
to 1La transition, followed by a more intense absorption band
1
at ∼224 nm (ε ∼ 79000) allied to Bb transition. The CD
spectra show weak Cotton effects at about 280 nm, followed
by clear couplet effects centered at 220 nm, with A values
between 45 and 650.
In Figure 2 are reported the spectra of 2b, while in Figure
3 are reported the data of 2f, as representative examples.
(4) (a) Rosini, C.; Spada, G. P.; Proni, G.; Masiero, S.; Scamuzzi, S.
J. Am. Chem. Soc. 1997, 119, 506–512. (b) Superchi, S.; Casarini, D.;
Laurita, A.; Bavoso, A.; Rosini, C. Angew. Chem., Int. Ed. 2001, 40, 451–
454. (c) Superchi, S.; Casarini, D.; Summa, C.; Rosini, C. J. Org. Chem.
2004, 69, 1685–1694. (d) Superchi, S.; Bisaccia, R.; Casarini, D.; Laurita,
A.; Rosini, C. J. Am. Chem. Soc. 2006, 128, 6893–6902.
(5) Devlin, F. J.; Stephens, P. J.; Besse, P. J. Org. Chem. 2005, 79,
2980–2993.
Figure 2. Absorption and ECD spectra of 2b in THF.
(6) Jaffe, H. H.; Orchin, M. The Theory and Application of UV
Spectroscopy; Wiley: New York (USA), 1962.
The analysis of the ECD spectra of ketals 2a-h reveals that
(7) Hosoi, S.; Kamiya, M.; Ohta, T. Org. Lett. 2001, 3, 3659–3662
.
we can indeed observe the expected exciton couplet allied
(8) Gawronski, J.; Kwit, M.; Gawronska, K. Org. Lett. 2002, 4, 4185–
1
4187
.
to the electrically allowed (intense) Bb transition.
(9) Dutot, L.; Wright, K.; Gaucher, A.; Wakselman, M.; Mazaleyrat,
J.-P.; De Zotti, M.; Peggion, C.; Formaggio, F.; Toniolo, C. J. Am. Chem.
We can then state that in these systems the aromatic
groups are twisted, making possible the degenerate exciton
Soc. 2008, 130, 5986–5992
.
3422
Org. Lett., Vol. 10, No. 16, 2008

in energy because in the (R,R,P) conformer repulsive
interactions between the aromatic rings and the axial
hydrogens linked to the stereogenic centers are completely
absent. Therefore the conformer (R,R,P) possessing positive
chirality is the most stable one; i.e., the above equilibrium
will be shifted toward the (R,R,P) diastereoisomer and hence
a positive couplet should be present in its ECD spectrum,
as experimentally found. This means that when a positiVe
couplet is obserVed in the ECD spectrum of a di(1-
naphthyl)ketal deriVed from an aliphatic diol, such a diol
will haVe (R) (or (R,R)) AC. As observed previously, in the
case of (R) (or (R,R)) aromatic diols, we have the opposite
correlation: the reason for that can be appreciated looking
at Figure 5 where the conformational diastereoisomers of
Figure 3
.
Absorption and ECD spectra of 2f in THF.
1
coupling between the naphthalene B transition (220 nm).
In other words, fixed, for example, the absolute configuration
(R) (or (R,R)) of optically active diols, the aromatic groups
of 2, in principle, can assume P or M torsion. In solution,
two diastereoisomers in equilibrium between them (R,M) a
(R,P) will be present. Since the couplet effect is clearly
observable, this means that one diastereoisomer (the most
stable one) is prevailing in solution: a transfer of chirality
from the stereogenic center(s) of optically active diols to the
sense of twist of the two naphthalene groups occurs. The
Figure 5. Conformational diastereoisomers of (R,R)-2h. The
rectangles linked to the stereogenic centers represent benzene
groups, while those linked to the same carbon atom of the dioxolane
ring represent naphthalene groups: the darker ones are placed above
the dioxolane ring, and the clearer ones are placed below the same
ring. In (R,R,M), stabilizing edge/face electronic interactions
between the aryl rings are possible: a couple (darker rectangles)
above the dioxolane ring and the others (clearer rectangles) below
the same ring.
1
sign of the couplet reflects the chirality defined by the B
transition dipole moments. Since the polarization direction
1
of the B transition within the naphthalene ring is known,
the AC of the stereogenic centers of the diols can be
determined, once the conformation of the most stable
diastereoisomer has been established.
It is also noteworthy that (R) (or (R,R)) aliphatic diols give
rise to positive couplets at 220 nm while (R) (or (R,R))
aromatic diols give rise to negative couplets at 220 nm. It is
known4a that the most stable conformation of dimethyl
dioxolanes derived from aliphatic or aromatic diols presents
the aliphatic (or aromatic) groups in a gauche disposition,
while the hydrogen atoms are in axial situation. We can use
this information to build the two possible conformers of a
generic (R) (or (R,R)) diol (Figure 4).
the di(1-naphthyl)ketal of (R,R)-1,2-diphenylethane-1,2-diol
are reported.
It results quite clearly from Figure 5 that for the (R,R,M)
conformer two possible face/edge electronic interactions are
possible: the former one between the rings above the
dioxolane plane and the latter one between the rings below
the same plane. It is generally accepted that interactions of
this type play an important role in some fundamental
chemical and biochemical processes,10 and a rough quantita-
tive estimate of this interaction is of the order of about 2
kcal/mol,10 i.e., a number sufficient to overcome steric
repulsions and so shift the (R,R,P)/(R,R,M) equilibrium
toward the (R,R,M) conformer. To put the above-described
results on a more quantitative basis, a conformational analysis
of compounds 2b and 2h, chosen as representative examples,
has been carried out by means of molecular mechanics
(MMFF94s force field of SPARTAN02),11 and the structures
so obtained were used to simulate the experimental ECD
spectra by means of DeVoe calculations.1b–e In the case of
2b, two different conformers having positive and negative
torsion of the naphthalene rings have been found with
populations of 88% and 12%, respectively. Using the
Figure 4. Conformational diastereoisomers of (R,R)-2b. The solid
square represents a hydrogen atom pointing above the dioxolane
ring, while the dashed square represents a hydrogen atom below
the same ring. The rectangles represent naphthalene rings: the dark
one is placed above the dioxolane ring, and the white one is placed
below the same ring.
(10) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K.
J. Am. Chem. Soc. 2001, 124, 104–112.
In these two structures, the two naphthalene rings place
the peri hydrogens in a free region of space, and they differ
(11) SPARTAN ’02Wavefunction Inc,: 18401 Von Karman Av. Suite
370, Irvine, CA 92612, 2002, http://www.wavefun.com/.
Org. Lett., Vol. 10, No. 16, 2008
3423

In the following Table 1 are collected observed and
predicted exciton couplet amplitudes and helical chirality of
2a-h: it results immediately that the true ACs of compounds
2 can be correctly obtained.
Table 1. Observed and Predicted Helicity of Ketals 2a-h
helicity and
exciton
chirality of the most stable
the most
stable
conformer
predicted
population of
observed
exciton
couplet
amplitude,
A
The main conclusions of this investigation are as follows:
first, the transformation of aliphatic 1,n-diols in the corre-
sponding di(1-naphthyl)ketals guarantees a strong reduction
of the number of conformers; i.e., the ketals exist as 1 or 2
conformers. These compounds present strong chromophoric
groups (the naphthalene rings), and owing to the presence
of the stereogenic centers of the diol moieties, the two
chromophores are twisted with respect to each other, with a
prevailing sense of twist leading to the observation, in the
ECD spectra of ketals 2, of significant couplet effects from
the analysis of which (even to a qualitative level) it is
possible to obtain the AC of the starting diols. Therefore,
conformer and
predicted (De predicted
Voe) A value
compd
AC
(S)-2a
(R,R)-2b
(S)-2c
(R,R)-2d
(R,R)-2e
(R)-2f
-45
+45
-55
M, negative
P, positive
M, negative
P, positive
P, positive
P, positive
M, negative
-
(S)
(R,R)
(S)
(R,R)
(R,R)
(R)
P (58%), +90
-
-
-
-
-
+70
+650
+650
-70
(R)-2g
(R)
(R,R)-2h
-600
M, negative M (100%), -500
(R,R)
geometrical parameters of these structures, the known
1
direction of the B transition dipole moment within the
chromophore, and standard spectroscopic parameters6 for this
transition (λmax 220 nm, D ) 40 D,2 Γ ) 3kK), a positive
couplet (in agreement with experiment but ten times more
intense than the experimental one) has been found. Optimiz-
ing the geometries at the DFT/B3LYP/6-31G* level,12 the
populations become 58% and 42%,13 respectively, and
therefore the weighted average ECD spectrum is still a
positive couplet but with intensity only twice the experi-
mental one, i.e., in good agreement with experiment and with
our previous qualitative predictions. In the case of 2h, the
molecular mechanics calculations provided only one con-
former where the edge-to-face disposition of the benzene
rings with respect to naphthalene groups is clearly present
and where the 1B transition dipoles define a negative chirality
(Figure 6), in total agreement with our qualitative predictions.
The ECD DeVoe calculations provide a negative couplet
having intensity very similar to that experimentally found
(Figure 15 of Supporting Information).
Figure 6. Only conformer of 2h, provided by molecular mechanics
calculations. Edge-to-face disposition of the benzene rings with
respect to the naphthalene ones is evident. The electric dipole
1
moments of the B transition define negative chirality.
we can state that a simple, new method for assigning the AC
of aliphatic diols has been set up. Interestingly, this method
has been tested also with diols where the two functional
groups are well far away (compound 1h); i.e., compounds
diffuse in natural product chemistry, and therefore it can find
several applications in this field. The method is based on
the observation of exciton couplet effects which, in turn, are
a consequence of the prevailing sense of twist of the
naphthalene planes. This represents a new case of helicity
induction in a bichromophoric system, different from those
described previously, because the two chromophores are not
linked directly.
(12) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
revision C.02; Gaussian, Inc.: Wallingford, CT, 2004, http://www.gauss-
ian.com/.
Acknowledgment. Financial support from MIUR (Roma)
and Universita` della Basilicata is gratefully acknowledged.
The authors are indebted to Professor Daniele Casarini of
our Department for the variable-temperature NMR measure-
ments on 2b.
Supporting Information Available: Experimental data:
NMR, absorption and CD spectra of compounds 2a-h. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) These populations have been obtained using the ∆G value of 0.18
kcal/mol, provided by the DFT calculations. With this energy difference,
the populations become 66 and 33% at -133° C, in excellent agreement
with some variable-temperature NMR measurements (see Figure 16 of
Supporting Information). The same analysis provides an energy of activation
for the P/M interconversion of about 9 kcal/mol (see Figure 16 of Supporting
Information).
OL8012149
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Org. Lett., Vol. 10, No. 16, 2008