The absolute configuration of simple aliphatic alcohols through a chemical/computational approach: triarylether derivatives of (+)-endo-2-norborneol as a case study

Article abstract of DOI:10.1016/j.tetasy.2009.10.028

The reliable determination of the absolute configuration of (+)-endo-2-norborneol 1, chosen as a representative case of simple aliphatic UV-vis transparent alcohols, was obtained by transforming this compound in its 1-naphthyl-diphenylmethyl ether 5 whose

Full text of DOI:10.1016/j.tetasy.2009.10.028

Tetrahedron: Asymmetry 20 (2009) 2435–2437
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The absolute configuration of simple aliphatic alcohols through
a chemical/computational approach: triarylether derivatives of
(+)-endo-2-norborneol as a case study
*
Giuseppe Mazzeo, Patrizia Scafato, Stefano Superchi, Carlo Rosini
Dipartimento di Chimica, Università della Basilicata, Via Nazario Sauro 85, 85100 Potenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The reliable determination of the absolute configuration of (+)-endo-2-norborneol 1, chosen as a repre-
sentative case of simple aliphatic UV–vis transparent alcohols, was obtained by transforming this com-
pound in its 1-naphthyl-diphenylmethyl ether 5 whose ECD spectrum displays several, low-lying,
intense Cotton effects, which can be satisfactorily simulated in position, sign, and intensity by TDDFT/
B3LYP/6-31G* calculations. This result represents a possible, general, new approach to the absolute con-
figuration of aliphatic alcohols.
Received 10 August 2009
Accepted 23 October 2009
Available online 24 November 2009
This paper is dedicated to Professor Antonio
M. Tamburro (1939–2009), an outstanding
researcher and an unforgettable colleague
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
tational efforts. Prompted by these data, we herein report our at-
tempts at extending the same chemical/computational approach
The recent progress in computational chemistry has made
available powerful ab initio methods for the simulation1 of elec-
tronic chiroptical properties such as specific rotation, and elec-
tronic circular dichroism (ECD)2 which, in principle, allows a
reliable assignment of the molecular absolute configuration. As a
matter of fact, these methods are increasingly used by experimen-
tal organic chemists to assign the absolute configuration of new
synthetic and natural compounds.3 However, some problems still
remain, such as the treatment of flexible and transparent mole-
cules. In fact, a large number of conformers and the presence of
only high-energy Cotton effects, require the intervention of high-
level calculations which, in turn, require powerful computational
resources. Such an approach can even become impracticable for
large molecules. To provide a solution to this problem, we devel-
oped a chemical/computational approach, which requires the
transformation of flexible and transparent compounds in chromo-
phoric, conformationally defined derivatives: the analysis of the
electronic chiroptical properties of the latter systems is then more
simple and reliable, guaranteeing a safe absolute configuration
assignment.4,5 Recently, we faced the absolute configuration deter-
mination of aliphatic diols through this approach.6 By chemical
transformation of these flexible and transparent molecules we ob-
tained more rigid derivatives with low-energy, intense Cotton ef-
fects, and then higher specific rotation values. This allowed us to
use computational methods at low-levels of theory, arriving to a
safe absolute configuration assignment with only modest compu-
to the case of flexible transparent monofunctional compounds such
as simple aliphatic alcohols, choosing (+)-endo-2-norborneol 1, as a
benchmark molecule. This task could also be achieved by trans-
forming the alcohol in a derivative bearing one or more chromoph-
ores and displaying, in principle, a low number of conformers. A
derivatization which, at first glance seemed to fulfill all the requi-
site was the triphenylmethylether (trityl) derivatization, one of the
most widely used protecting groups for alcohol functionalities.7,8
2. Results and discussion
The triphenylmethylether 3 of (+)-endo-2-norborneol9 was eas-
ily prepared by a standard procedure (Scheme 1)10 and its specific
rotation values were compared with those of the parent alcohol 1.
Alcohol 1 presents [a] numbers which are low in absolute value
D
but independent of the solvent: +1 (c 1, chloroform); +7 (c 0.97,
methanol); +2 (c 1.02, n-hexane). In the triphenylether 3, we ob-
served specific rotation values almost an order of magnitude high-
pyridine, 60ºC
O
OH
RPh2CCl
R
Ph
2 R = Ph
1
Ph
4 R = 1-Np
3 R = Ph
5 R = 1-Np
* Corresponding author. Tel.: +39 0971 202241; fax: +39 0971 202232.
E-mail address: carlo.rosini@unibas.it (C. Rosini).
Scheme 1.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.028

2436
G. Mazzeo et al. / Tetrahedron: Asymmetry 20 (2009) 2435–2437
er, but still quite small in absolute value, [
roform) and À14 (c 0.96, n-hexane).
a]
D = À14 (c 0.90, chlo-
The ECD11 spectrum of 3 (acetonitrile) is shown in Figure 1.
From this spectrum it can be seen that due to the introduction of
the trityl chromophoric system, Cotton effects can be measured
in the 250–200 nm spectral range whilst aliphatic alcohols absorb
below 200 nm.12 However, the ECD bands remain weak and we did
not observe a significant increase in the specific rotation values on
passing from 1 to 3. So the simulation of the chiroptical properties
of 3 with the aim at arriving at a safe assessment of the absolute
configuration of 1 remains a difficult task. These discouraging re-
sults could depend on the mobility of the trityl group, which can
present several conformers having different relative dispositions
of the three phenyl rings. Therefore, we decided to look for a less
mobile derivatizing agent and we thought to substitute one of
the phenyl rings of trityl chloride with a 1-naphthyl group, in order
to obtain alcohol derivatives as 1-naphthyl-diphenylmethyl ethers.
In fact, the introduction of the 1-naphthyl chromophore should
Figure 2. Absorption (UV curve) and ECD (exp. ECD curve) of 5 in acetonitrile.
Computed (TDDFT/B3LYP/6-31G* level, 50 states, velocity formalism) ECD spectrum
(theor. curve).
space, thus indicating that this particular geometrical parameter
plays an important role in determining the relative conformational
stability. In Figure 2, the experimental and calculated (TDDFT/
B3LYP/6-31G*, 50 states, velocity formalism, four most stable con-
formers, almost 90% of the overall population) ECD spectra are re-
ported. The theoretical curve reproduces more than satisfactorily
the experimental one: in fact, the sequence of negative, positive,
negative, negative, and positive Cotton effects at 265, 240, 220,
205 and 190 nm is correctly reproduced in the sign, position, and
intensity (only the intensity of the weak 205 nm band being over-
estimated18), showing that by calculating the ECD spectrum of 5
we can reliably determine the correct absolute configuration of
the alcohol 1. It is noteworthy that all the computational procedure
requires 596 h of CPU time on a standard desktop computer: in
other words, the possibility of using a low level of theory more
than compensates for the difficulty connected with the increase
of molecular size on passing from 1 to 5. Furthermore, the selected
chromophore leads to the presence of several Cotton effects, from
300 to 200 nm, their correct simulation of sign, intensity and posi-
tion is a clear evidence of the correct assignment of absolute con-
figuration. In this way ECD spectroscopy gains the same
advantages of VCD spectroscopy, that is, the need of reproducing
many CD bands and then a solid guarantee of a correct absolute
configuration assignment. Consequently, ECD spectroscopy can
be used even alone without a concerted use of the three chiroptical
spectroscopies.19
give rise to two advantages: (a) the a-substitution provides deriv-
atives characterized by reduced conformational mobility due to the
presence of the steric effect of the peri hydrogen in 1-naphthyl-
substituted compounds; (b) the naphthyl chromophore possesses
two intense electrically allowed transitions at 280 nm (1La,
e
4000 ca.) and at 220 nm (1Bb,
e 95000 ca.). Therefore clear Cotton
effects should appear in the ECD spectra of their alkyl ethers. The
new triaryl derivatizing agent 413 was prepared by reacting 1-
naphthylmagnesium bromide with benzophenone to give the cor-
responding alcohol, (87% yield), which was transformed in the re-
quired chloride by acetyl chloride14 in refluxing toluene (40%
yield). Reaction of 4 with alcohol 1 in the presence of pyridine pro-
vided derivative 515 in a satisfactory yield (60%) (Scheme 1). Com-
pound 5 shows [a]D = +26 (c 1, CHCl3) which is about thirty times
higher than that of 1, however its absolute value is still too small to
attempt a reliable DFT calculation of the specific rotation.16 On the
other hand, the ECD spectrum of 5 (Fig. 2) is much more intense
than that of 3, presenting at least four strong Cotton effects with
different signs. Such a spectrum can be safely reproduced, even
by our ‘approximate’ (i.e., TDDFT/B3LYP/6-31G* or smaller basis
sets) computational approach,6 thus allowing us to determine the
absolute configuration.
3. Conclusions
We believe that these results, even if preliminary, clearly show
that the transformation of aliphatic alcohol-triaryl ether could rep-
resent a very useful method to arrive at a reliable assessment of the
absolute configuration of non chromophoric chiral alcohols. The
introduction of such simple chromophoric moieties allows us to
observe higher specific rotation values and more intense ECD spec-
tra in the triaryl ethers, then allowing us to make the absolute con-
figuration assignments even employing a low level of theory. In
conclusion, coupling experimental organic chemistry with theoret-
ical calculations allows us to solve a problem which is very difficult
when using a computational approach only. Work is currently in
progress to extend this approach to other simple, more flexible, ali-
phatic alcohols, even designing new, tailor-made triaryl derivatiz-
ing agents. This and a previous paper6 clearly show how the
organic chemistry of the protecting groups can provide significant
help to design suitable new groups which are able to both reduce
the conformational mobility and introduce chromophoric moieties.
These groups can then act as sensitive probes of the absolute ste-
reochemistry of the original molecules, making the computational
Figure 1. Absorption (UV curve) and ECD (CD curve) spectra of 3 in acetonitrile.
The calculation of the ECD spectrum of 5 was then performed as
follows. The input structures were provided by some SPARTAN0217
calculations: using the MMFF94s force field, seven different con-
formers were found in the energy range 0–2 kcal/mol. Each of
these structures was optimized at the DFT/B3LYP/6-31G* level
obtaining the necessary input geometries for the calculations of
the chiroptical properties (TDDFT/B3LYP/6-31G* level). It is inter-
esting to note that the three most stable conformers (80% of the to-
tal population) present the peri hydrogen atom in a free zone of

G. Mazzeo et al. / Tetrahedron: Asymmetry 20 (2009) 2435–2437
2437
Superchi, S.; Casarini, D.; Summa, C.; Rosini, C. J. Org. Chem. 2004, 69, 1685–
1694; (h) Superchi, S.; Bisaccia, R.; Casarini, D.; Laurita, A.; Rosini, C. J. Am.
Chem. Soc. 2006, 128, 6893–6902.
efforts required for a reliable configurational determination much
simpler.
5. The same kind of approach has been also used by Stephens et al. to make the
analysis of the VCD spectra of (À)-borneol easier. See: Devlin, F. J.; Stephens, P.
J.; Besse, P. J. Org. Chem. 2005, 79, 2980–2993.
Acknowledgments
6. Tartaglia, S.; Padula, D.; Scafato, P.; Chiummiento, L.; Rosini, C. J. Org. Chem.
2008, 73, 4865–4873.
7. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley Interscience Publisher: New York, NY, 1999.
Financial support from MIUR (Roma) and Università della Basil-
icata (Potenza) is gratefully acknowledged.
8. Just after the submission of this manuscript we became aware of a paper from
Gawronski et al. on the same topic: Sciebura, J.; Skowronek, P.; Gawronski, J.
Angew. Chem., Int. Ed. 2009, 48, 7069–7072.
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