A chemical/computational approach to the determination of absolute configuration of flexible and transparent molecules: Aliphatic diols as a case study

Article abstract of DOI:10.1021/jo800516f

(Graph Presented) By reacting flexible and optically transparent in UV-vis molecules such as 1,2-, syn- and anti-1,3-diols, 1,3-sulfanylalcohols of known absolute configuration (AC) with fluorenone dimethyl acetal, the corresponding ketals are obtained. They are conformationally well-defined (only one conformer in most cases) compounds exhibiting medium-high optical rotation (OR) values, which are independent of the solvent, and electronic circular dichroism (ECD) spectra, which show several (up to five) Cotton effects in the 350-200 nm range due to valence shell π→π* transitions. These features allow simulation of the chiroptical properties of these compounds at the TDDFT/B3LYP/6-31G* level of theory to obtain, using the known ACs of these compounds, a satisfactory reproduction of the OR values (sign and order of magnitude; quantitatively, the predicted values are twice the experimental ones), and a more than satisfactory reproduction of the ECD spectra (sign, intensity, and position of the lowest-energy four Cotton effects) for all the compounds studied. Therefore, this approach can be used to assign the AC of such flexible molecules, in particular, syn-1,3-diols, which are important substrates in organic synthesis and for which nonempirical methods of AC assignment have not been devised so far. Furthermore, since the fluorene chromophore leads to the presence of several Cotton effects from, say, 350 to 200 nm, their correct simulation of sign, intensity, and position is a guarantee of the correct assignment of AC: in this way, ECD spectroscopy gains the same advantages of VCD spectroscopy, that is, the need of reproducing many ECD bands and then a solid guarantee of a correct AC assignment.

Full text of DOI:10.1021/jo800516f

A Chemical/Computational Approach to the Determination of
Absolute Configuration of Flexible and Transparent Molecules:
Aliphatic Diols As a Case Study
Sabina Tartaglia, Daniele Padula, Patrizia Scafato, Lucia Chiummiento, and Carlo Rosini*
Dipartimento di Chimica, UniVersita` degli Studi della Basilicata, Via N. Sauro, 85, 85100 Potenza, Italy
carlo.rosini@unibas.it
ReceiVed March 5, 2008
By reacting flexible and optically transparent in UV-vis molecules such as 1,2-, syn- and anti-1,3-diols,
1,3-sulfanylalcohols of known absolute configuration (AC) with fluorenone dimethyl acetal, the
corresponding ketals are obtained. They are conformationally well-defined (only one conformer in most
cases) compounds exhibiting medium-high optical rotation (OR) values, which are independent of the
solvent, and electronic circular dichroism (ECD) spectra, which show several (up to five) Cotton effects
in the 350-200 nm range due to valence shell πfπ* transitions. These features allow simulation of the
chiroptical properties of these compounds at the TDDFT/B3LYP/6-31G* level of theory to obtain, using
the known ACs of these compounds, a satisfactory reproduction of the OR values (sign and order of
magnitude; quantitatively, the predicted values are twice the experimental ones), and a more than
satisfactory reproduction of the ECD spectra (sign, intensity, and position of the lowest-energy four
Cotton effects) for all the compounds studied. Therefore, this approach can be used to assign the AC of
such flexible molecules, in particular, syn-1,3-diols, which are important substrates in organic synthesis
and for which nonempirical methods of AC assignment have not been devised so far. Furthermore, since
the fluorene chromophore leads to the presence of several Cotton effects from, say, 350 to 200 nm, their
correct simulation of sign, intensity, and position is a guarantee of the correct assignment of AC: in this
way, ECD spectroscopy gains the same advantages of VCD spectroscopy, that is, the need of reproducing
many ECD bands and then a solid guarantee of a correct AC assignment.
Introduction
techniques. However, in spite of these significant progresses,
some problems still remain: in particular, the treatment of the
electronic chiroptical properties of all those compounds showing
small [R]D and/or weak ECD signals, such as aliphatic alcohols,
The quantum-mechanical calculation of the chiroptical prop-
erties1 (optical rotation (OR)2 electronic circular dichroism
(ECD),3 and vibrational circular dichroism (VCD)4 spectra) can
allow a safe determination of the molecular absolute configu-
ration, as demonstrated in very recent years by several papers
where chiroptical data of molecules having known absolute
configuration (AC) have been correctly predicted,3,4 while, even
more recently, the absolute configuration of unknown molecules
has been assigned, in particular, by the concerted5 use of these
(2) The first ab initio calculation of [R]D has been carried out by Polavarapu: (a)
Polavarapu, P. L. Mol. Phys. 1997, 91, 551–554. (b) Polavarapu, P. L.
Tetrahedron: Asymmetry 1997, 8, 3397–3401. (c) Polavarapu, P. L.; Chakraborty,
D. K. J. Am. Chem. Soc. 1998, 120, 6160–6164. The method has been employed
to assign the AC of a natural product for the first time by Kondru et al. (d)
Kondru, R. K.; Wipf, P.; Beratan, D. N. J. Am. Chem. Soc. 1998, 120, 2204–
2205. (e) Kondru, R. K.; Wipf, P.; Beratan, D. N. Science 1998, 282, 2247–
2250. (f) Kondru, R. K.; Lim, S.; Wipf, P.; Beratan, D. N. Chirality 1997, 9,
469–477. For general discussion of the ab initio calculation of chiroptical
properties, see: (g) Polavarapu, P. L. Chirality 2002, 14, 768–781. (h) Pecul,
M.; Ruud, K. AdV. Quantum Chem. 2006, 50, 185–227. (i) Crawford, T. D.
Theor. Chem. Acc. 2006, 115, 227–245. (j) Polavarapu, P. L. Chem. Rec. 2007,
7, 125–136. (k) Crawford, T. D.; Tam, M. C.; Abrams, M. L. J. Phys. Chem. A
2007, 111, 12057–12068.
* To whom correspondence should be addressed. Telephone: +39 0971
202241. Fax: +39 0971 202223.
(1) The general theory of optical activity is given by: (a) Rosenfeld, L. Z.
Phys. 1928, 52, 161–174. (b) Condon, E. U. ReV. Mod. Phys. 1937, 9, 432–457.
(c) Buckingham, A. D. AdV. Chem. Phys. 1967, 12, 107–142.
10.1021/jo800516f CCC: $40.75
Published on Web 06/12/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4865–4873 4865

Tartaglia et al.
diols, ethers, amines, and so on. In fact, such compounds are
species without typical UV-vis chromophores and, in addition,
present a large conformational flexibility so that many conform-
ers showing different (even opposite) OR values and/or ECD
spectra are simultaneously present, leading to a weighted average
value which is small. For instance, for (2R,3R)-butanediol,
Polavarapu has recently6 pointed out that at least 10 conformers
are appreciably populated at room temperature and, as a matter
of fact, it shows a low OR, [R]D -17 (c 1, chloroform). It is
immediately clear that a case of this type presents many
formidable obstacles: a really accurate determination of the
conformers’ population is necessary, the calculation must be
repeated 10 times, and, considering the chemical nature of the
compound, a very large basis set is absolutely required. The
overall process is therefore quite long and arduous, without any
guarantee of obtaining the correct answer owing to the large
number of variables. It is to be noted that such an approach
can become even impracticable for larger molecules. Therefore,
in such cases, alternative methods are required to avoid all these
difficulties. From this point of view, it seems obvious to think
to some simple transformation of the original flexible compound
in order to remove (or at least reduce) its conformational
mobility. A further advantage of this simple derivatization could
be that the reduction of the conformational freedom could be
carried out introducing, at the same time, a chromophoric group.
So a derivative possessing more intense (and so more easily
measurable and possibly interpretable) chiroptical properties
might be obtained, where the newly derivatizing group intro-
duced would help in reducing the number of conformers and
work as a probe of the absolute stereochemistry of the starting
compound. We have been using this kind of reasoning for some
years7 when we first tackled the problem of the assignment of
the absolute configuration of optically active 1,2-diaryl-1,2-
ethanediols via the analysis of the ECD spectra of their suitable
derivatives. The approach was later extended to 1-arylethane-
1,2-diols and subsequently to aliphatic (transparent) 1,n-diols:
here their transformation into biphenyl ketals guarantees a strong
reduction of the number of the conformers, and the biphenyl
chromophore, with strong ECD signals easily correlated to the
AC of the original 1,2-diol, acts as a probe of the overall
molecular chirality. Interestingly, Stephens and co-workers have
recently employed8 the method of reducing the conformational
flexibility to make the analysis of the VCD spectra of (-)-
borneol easier. Therefore, we decided to verify further the
approach indicated above using a group of known diols and
sulfanylalcohol lj (Chart 1) as benchmark molecules, molecules
that play an important role in asymmetric catalysis9,10 and
natural product chemistry11,12 and exhibit high conformational
flexibility, low OR values, and weak ECD spectra.
(3) Calculation of OR values and ECD spectra: (a) Cheeseman, J. R.; Frisch,
M. J.; Devlin, F. J.; Stephens, P. J. J. Phys. Chem. A 2000, 104, 1039–1046. (b)
Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J.; Mennucci, B.;
Tomasi, J. Tetrahedron: Asymmetry 2000, 11, 2443–2448. (c) Stephens, P. J.;
Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J. J. Phys. Chem. A 2001, 105, 5356–
5371. (d) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J. Chirality
2002, 14, 288–296. (e) Mennucci, B.; Tomasi, J.; Cammi, J. R.; Cheeseman,
J. R.; Frisch, M. J.; Devlin, F. J.; Gabriel, S.; Stephens, P. J. J. Chem. Phys. A
2002, 106, 6102–6113. (f) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch,
M. J.; Rosini, C. Org. Lett. 2002, 4, 4595–4598. (g) Stephens, P. J.; Devlin,
F. J.; Cheeseman, J. R.; Frisch, M. J.; Bortolini, O.; Besse, P. Chirality 2003,
15, S57-S64. (h) McCann, D. M.; Stephens, P. J.; Cheeseman, J. R. J. Org.
Chem. 2004, 69, 8709–8717. (i) Stephens, P. J.; McCann, D. M.; Cheeseman,
J. R.; Frisch, M. J. Chirality 2005, 17 (Suppl), S52-S64. (j) McCann, D. M.;
Stephens, P. J. J. Org. Chem. 2006, 71, 6074–6098. (k) Autschbach, J.; Jensen,
L.; Schatz, G. C.; Electra Tse, Y. C.; Krykunov, M. J. Phys. Chem. A 2006,
110, 2461–2473. (l) da Silva, C.; Mennucci, B. J. Chem. Theory Comput. 2007,
3, 62–70.
(4) Theoretical prediction of VCD spectra: (a) Ashvar, C. S.; Stephens, P. J.;
Eggimann, T.; Wieser, H. Tetrahedron: Asymmetry 1998, 9, 1107–1110. (b)
Aamouche, A.; Devlin, F. J.; Stephens, P. J. Chem. Commun. 1999, 361–362.
(c) Stephens, P. J.; Devlin, F. J. Chirality 2000, 12, 172–179. (d) Aamouche,
A.; Devlin, F. J.; Stephens, P. J. J. Am. Chem. Soc. 2000, 122, 2346–2354. (e)
Aamouche, A.; Devlin, F. J.; Stephens, P. J.; Drabowicz, J.; Bujnicki, B.;
Mikolajczyk, M. Chem.—Eur. J. 2000, 6, 4479–4486. (f) Stephens, P. J.;
Aamouche, A.; Devlin, F. J.; Superchi, S.; Donnoli, M. I.; Rosini, C. J. Org.
Chem. 2001, 66, 3671–3677. (g) Devlin, F. J.; Stephens, P. J.; Scafato, P.;
Superchi, S.; Rosini, C. Tetrahedron: Asymmetry 2001, 12, 1551–1558. (h)
Stephens, P. J.; Devlin, F. J.; Aamouche, A. In Chirality: Physical Chemistry;
Hicks, J. M., Eds.; ACS Symposium Series, 2002; Vol. 810, Chapter 2, pp 18-
33. (i) Devlin, F. J.; Stephens, P. J.; Scafato, P.; Superchi, S.; Rosini, C. Chirality
2002, 14, 400–406. (j) Devlin, F. J.; Stephens, P. J.; Oesterle, C.; Wiberg, K. B.;
Cheeseman, J. R.; Frisch, M. J. J. Org. Chem. 2002, 67, 8090–8096. (k) Stephens,
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They will be transformed in the corresponding cyclic ketals
2 (Chart 2) using the commercially available ketone 9-fluorenone
3. In this way, on passing from the acyclic compounds 1 to the
cyclic ones 2, the conformational freedom will certainly be
reduced.
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J. R.; Frisch, M. J. J. Org. Chem. 2004, 69, 1948–1958. (b) Stephens, P. J.;
McCann, D. M.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J. J. Am. Chem.
Soc. 2004, 126, 7514–7521. (c) Stephens, P. J.; McCann, D. M.; Devlin, F. J.;
Flood, T. C.; Butkus, E.; Stoncius, S.; Cheeseman, J. R. J. Org. Chem. 2005,
70, 3903–3913. (d) Stephens, P. J.; McCann, D. M.; Devlin, F. J.; Smith, A. B.,
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F. J.; Krohn, K.; Kurtan, T. J. Org. Chem. 2007, 72, 3521–3536. (f) Stephens,
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Furthermore, the introduction of the biphenyl chromophore
of 2 with electronically allowed transitions at 260 and 210 nm
should guarantee the existence of Cotton effects in the near-
UV region which, in turn, should contribute at increasing the
value of [R]D of 2 with respect to the corresponding values of
compounds 1. In our opinion, these facts should allow a reliable
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4866 J. Org. Chem. Vol. 73, No. 13, 2008

Absolute Configuration of Flexible and Transparent Molecules
CHART 1
SCHEME 1
reason, the correct simulation of the ECD bands could constitute
an independent tool by which the AC of compounds 2 (and
therefore of compounds 1) can be reliably assigned.
Results and Discussion
Synthesis. Compounds 1 are representative of several classes
of diols: 1,2-aliphatic diols (1a-f), 1,3-anti- and syn-aliphatic
diols (1g, 1h, and 1i, respectively), 1,2-aromatic diols (1k and
1l). In addition, there is the sulfur-containing compound 1j. All
these substrates will be used to verify the applicability of our
ideas to systems having different structures. Compounds 1a,
1b, 1d, 1e, 1f, 1g, and 1l are commercially available, 1c has
been prepared by addition of methylmagnesium bromide to ethyl
lactate,13 1k has been prepared by asymmetric dihydroxylation
of the corresponding olefin.9 Diols 1h and 1i have been prepared
starting from the commercially available ester 4, protected as
its silylether 5.14 On adding excess ethynylmagnesium chloride
to a mixture of Me(MeO)NH·HCl and methyl ester 5, complete
conversion to ketone 6 has been observed, without the formation
of the Weinreb amide intermediate.15 Then ketone 6 was reduced
with NaBH4 in methanol to a mixture of compounds 7 and 8,
monoprotected anti- and syn-1,3-diols, respectively, which were
separated by column chromatography. Deprotection of the silyl
group with TBAF gave diols 1h and 1i in high yield (90 and
91%, respectively)16 (Scheme 1).
CHART 2
The sulfanylalcohol 1j has been prepared, in optically active
form, by the reported procedure.17
Ketals 2 have been prepared by reaction of diols with the
corresponding dimethylacetal 9 of 9-fluorenone 3, as reported
below (Scheme 2). Compounds 2 (Chart 2) have been character-
ized by NMR and mass spectrometry.
Chiroptical Properties. Table 1 collects the experimental
rotatory powers of compounds 2 compared to those of the
corresponding compounds 1. In several cases, on passing from
1 to 2, we have a remarkable increase of the OR, in the cases
of a, d, g, and h, this passage guarantees a variation of the [R]D
of about +80 units, while in the cases of c, e, and f, the increase
is even larger (an order of magnitude). This fact is really
(13) Dube´, D.; Brideau, C.; Descheˆnes, D.; Fortin, R.; Friesen, R. W.; Gordon,
R.; Girard, Y.; Riendeau, D.; Savoie, C.; Chan, C.-C. Bioorg. Med. Chem. Lett.
1999, 9, 1715–1720.
(14) Baktharaman, S.; Selvakumar, S.; Singh, V. K. Tetrahedron Lett. 2005,
46, 7527–7529.
(15) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.
(16) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528–2533.
(17) (a) Pickenhagen, M.; Bronner-Schindler, H. HelV. Chim. Acta 1984, 67,
947–952. (b) Weckerle, B.; Schreier, P.; Humpf, H.-U. J. Org. Chem. 2001, 66,
8160–8164.
simulation of [R]D by computational methods and then a safe
AC assignment. In addition, compounds 2, owing to the presence
of the biphenyl group, should show intense Cotton effects in
the UV-vis region, in contrast to compounds 1 and, for this
J. Org. Chem. Vol. 73, No. 13, 2008 4867

Tartaglia et al.
SCHEME 2
TABLE 1. [r]D Values of the Compounds 1a-l and of the Corresponding Derivatives 2a-l
a
a
diol 1
[R]D (c (g/100 mL), solvent)
ketal 2
[R]D (c (g/100 mL), solvent)
1a
1b
1c
1d
1e
1f
1g
1h
1i
-29 (c 0.78, CHCl3) -30 (c 0.81, MeOH)
+23 (c 1, CHCl3)
2a
2b
2c
2d
2e
2f
2g
2h
2i
+51 (c 0.6, CHCl3) +50 (c 0.78, hexane) +54 (c 0.74, MeOH)
-9 (c 0.61, CHCl3)
+4 (c 1.02, CHCl3)
-50 (c 1.25, CHCl3)
-17 (c 1, CHCl3) -5 (c 1, MeOH)
-1 (c 0.78, CHCl3)
+52 (c 1, CHCl3) +58 (c 1, hexane)
+61 (c 2.08, CHCl3)
-2 (c 1.2, CHCl3)
-35 (c 1, CHCl3) -38 (c 1, hexane)
+41 (c 1, CHCl3)
-36 (c 1, CHCl3)
-32 (c 0.8, CHCl3)
+41 (c 1, CHCl3)
+6 (c 1, CHCl3)
-4 (c 0.95, CHCl3)
1j
1k
1l
-8 (c 0.8, CHCl3)b
2j
2k
2l
+216 (c 1, CHCl3)
+73 (c 0.57, CHCl3) +71 (c 0.61, CH3CN) +84 (c 1, EtOH)
-64 (c 0.82, CHCl3) -38 (c 3, EtOH)
+247 (c 0.63, CHCl3)
+63 (c 1.04, CHCl3)
a deg [dm g/cm3]-1 b Pickenhagen, M.; Bronner-Schindler, H. HelV. Chim. Acta, 1984, 67, 947-952.
.
noteworthy because in the case of 1c, 1e, and 1f a direct
calculation of such a low value of OR on these flexible
molecules (they exist as a mixture of several conformers, vide
infra) cannot lead to a reliable result as basis of a safe
configurational assignment.
By contrast, [R]D values of the order of 50-60 deg [dm
g/cm3]-1 constitute a figure which can be reasonably reproduced
by the present calculations, especially considering that the
number of conformers of compounds 2 is much smaller than
for compounds 1. It is particularly interesting to note a very
strong increase of OR on passing from 1j to 2j: from -8 to
216! We cannot provide a reasonable explanation for this
observation, yet. In fact, in the case of other 1,3-diols (1g, 1h),
we do not have a relevant change in the absolute value of OR,
while here on passing from 1j to 2j, the OR value becomes 25
times larger. Only in the cases of 2b and 2i we do not observe
an increase of OR. However, it is interesting to note that even
when the [R]D value remains small (cf. 1b and 2b: from +23
to -9) we have a variation of 32 units, in absolute value.
Another important observation is that the [R]D values of
compounds 2 are independent of the solvent: the OR of 2a does
not change on passing from hexane to chloroform to methanol,
that is, over three very different solvents (see Table 1).
Therefore, we can compare the experimental results obtained
in a solvent with predicted figures obtained in the gas phase;
this means that we can avoid the use of solvation models,18
saving a great amount of computational effort. The absorption
and ECD spectra of 2a (acetonitrile), as representative example
of compounds 2, are reported in Figure 1.
FIGURE 1. Absorption (black line) and ECD spectrum (blue line) of
2a in acetonitrile.
present in 2a is the fluorene group, it is reasonable to assign
the observed bands to π-π* transitions localized on such a
chromophore and then polarized in the fluorene plane along the
C2 axis or perpendicular to it, as suggested by Sagiv and co-
workers.19 In the ECD spectrum, it is possible to observe Cotton
effects centered at 280 nm (∆ꢀ +3), 235 nm (∆ꢀ -4), 205 nm
(∆ꢀ +4), a weak, negative CD band followed by the onset of a
fifth, positive CD band. Clearly these bands are related to the
π-π* transitions discussed above. The presence of these Cotton
effects in the ECD spectra is of paramount importance. From a
completely ECD transparent compound, where it is possible to
measure with the commercial instruments, only a tail showing
very low ECD intensity (Figure 9 of Supporting Information)
and which is useless for a reliable configurational assignment,
the diol f ketal transformation allows one to obtain a simple
derivative which shows a spectrum with many intense Cotton
effects having differing signs. In this way, if the computational
procedure is able to simulate the correct sequence of Cotton
effects (sign, position, intensity), we shall have a reliable
configurational assignment based on the simulation of seVeral
Cotton effects. In other words, we have introduced to electronic
chiroptical spectroscopy the main advantage of vibrational CD
The absorption and ECD spectra of compounds 2b-2l, which
are entirely similar to that reported in Figure 1, are reported in
the Figures 1-8 of Supporting Information. In the UV spectrum
of 2a, several different regions of absorption can be easily
pointed out: a broadband with absorption maximum at about
280 nm (ꢀ ∼10 000), a couple of bands at 240 nm (ꢀ ∼30 000)
and 230 nm (ꢀ ∼30 000), and a last broadband centered at 205
nm (ꢀ ∼30 000). Taking into account that the only chromophore
(18) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. ReV. 2005, 105, 2999–
3093.
(19) Sagiv, J.; Yogev, A.; Mazur, Y. J. Am. Chem. Soc. 1977, 99, 6861–
6869.
4868 J. Org. Chem. Vol. 73, No. 13, 2008

Absolute Configuration of Flexible and Transparent Molecules
TABLE 2. [r]D Values and Number of Conformers of the Compounds 1a-l and of the Corresponding Derivatives 2a-l
predicted [R]D
6-31++G**
diol
[R]D
No. of conformersa
ketal
[R]D
No. of conformersa
6-31G*
1a
1b
1c
1d
1e
1f
1g
1h
1i
-29
+23
+4
-17
-2
-2
-36
-32
+6
-8
+73
-64
4
21
10
10
32
3
22
12
6
2a
2b
2c
2d
2e
2f
2g
2h
2i
+51
-9
1
2
1
1
3
1
1
2
1
1
1
1
+107
-52
+126
-59
-50
+52
+61
-35
+41
+41
-4
+216
+247
+63
-107
+122
+141
-76
-73
+134
+68
+50
+76
-4
-7
408
1j
1k
1l
22
6
12
2j
2k
2l
+402
+632
+355
+286
a Number of conformers obtained by molecular mechanics calculations, retaining the structures within 4 kcal/mol above the most stable one.
spectroscopy,4c,k,20 that is, the presence of several Cotton effects
and the need to reproduce all of them as a guarantee of a safe
configurational assignment. A last observation, for each com-
pound 2, [R]D and the lowest-energy Cotton effect have the same
sign, and this band provides the largest contribution to the OR
at 589 nm. This suggests that the calculation of the chiroptical
properties of 2 could be carried out21 at a relatively low level
of theory (e.g., TDDFT/B3LYP/6-31G*) without reducing the
reliability of the results but reducing the computational effort.
This is an important point. In fact, one might argue that on
passing from 1b to 2b, for instance, there is a significant increase
of the molecular complexity (from 42 to 120 electrons) with a
consequent increase of the computational effort. However, as
will be shown later, the large reduction in the number of
conformers and the use of the above-mentioned low level of
FIGURE 2. Structure (DFT/B3LYP/6-31G*) of 2a.
theory provide an easy and reliable simulation of the chiroptical
appreciably populated at room temperature.) Compounds 1
properties with a reduced computational effort (when compared
having a fewer number of conformers are 1a (4) and 1f (3).
to that required to treat compounds 1).
Compound 1j and its derivative 2j present some difficulties due
Computational Analysis of the Chiroptical Properties.
to the presence of the n-propyl tail linked to the stereogenic
Following the procedure described in the Computational Details,
center. In order to simplify the treatment, we substituted the
the first step of the computational analysis of the chiroptical
n-propyl group with a methyl group. Although this substitution
properties of compounds 2 is the determination of number and
might affect the predicted OR value, it should not affect the
structure of the conformers of compounds 2. The results of such
simulated ECD spectrum, taking into account that the observed
an analysis are collected in Table 2.
ECD bands are due to electronic transitions localized on the
An important comparison concerns the reduction of the
fluorene chromophore. However, in this case, we found two
conformational flexibility of the compounds 1 by transforming
different conformers with populations of 97 and 3%, respec-
them in the derivatives 2. For each of the compounds 1, a simple
tively. So, the calculations on this compound were carried out
molecular mechanics analysis (Spartan02,22 MMFF94s force
for the most stable conformer only. In summary, it is important
field, retaining only the structures having a total energy of 4
to note that, on passing to 2, we found that these derivatives
kcal/mol or less with respect to that of the most stable one)
possess only one conformer with the sole exceptions of 2b (2),
provides a very large number of conformers: for example, 21
2e (3), and 2h (2). Gratifyingly, the derivatization of 1 to 2
conformers for 1b, 32 for 1e, 22 for 1g, and 12 for 1h.
exerts the effect we expected: a very strong reduction of the
(Polavarapu established6 that for 1d at least 10 conformers are
number of conformers.
The structure of 2a is reported in Figure 2, as representative
(20) Nafie, L. A.; Freedman, T. B. In Circular Dichroism, Theory and
Practice; Nakanishi, K., Berova, N., Woody, W. Eds.; Wiley: New York, 2000;
example, while Tables 1-17 of Supporting Information report
p 97.
the geometries of the compounds 2a-l as obtained at the DFT/
(21) (a) Giorgio, E.; Minichino, C.; Viglione, R. G.; Zanasi, R.; Rosini, C.
B3LYP/6-31G*23 level of theory.
J. Org. Chem. 2003, 68, 5186–5192. (b) Giorgio, E.; Viglione, R. G.; Zanasi,
R.; Rosini, C. Chem. Phys. Lett. 2003, 376, 452–456. (c) Giorgio, E.; Viglione,
R. G.; Rosini, C. Tetrahedron: Asymmetry 2004, 15, 1979–1786. (d) Giorgio,
E.; Viglione, R. G.; Zanasi, R.; Rosini, C. J. Am. Chem. Soc. 2004, 126, 12968–
12976. (e) Giorgio, E.; Tanaka, K.; Ding, W.; Krishnamurthy, G.; Pitts, K.;
Ellestad, G. A.; Rosini, C.; Berova, N. Bioorg. Med. Chem. 2005, 13, 5072–
5079. (f) Giorgio, E.; Roje, M.; Tanaka, K.; Hamersak, Z.; Sunjic, V.; Nakanishi,
K.; Rosini, C.; Berova, N. J. Org. Chem. 2005, 70, 6557–6563. (g) Giorgio, E.;
Tanaka, K.; Verotta, L.; Nakanishi, K.; Berova, N.; Rosini, C. Chirality 2007,
19, 434–445. (h) Mennucci, B.; Claps, M.; Evidente, A.; Rosini, C. J. Org. Chem.
2007, 72, 6680–6691.
OR values have then been calculated, for compounds 2, at
the TDDFT/B3LYP/6-31G* level of theory, and the results are
reported in Table 2.
We call attention to five points. (1) The calculations reproduce
the experimental OR values in sign and order of magnitude for
all compounds 2. This means that the present method constitutes
a simple technique by which it is possible to carry out a safe
configurational assignment even in the particularly difficult cases
of compounds having a large number of conformers and very
(22) SPARTAN ′02; Wavefunction Inc.: Irvine, CA; http://www.wavefunc-
tion.com.
J. Org. Chem. Vol. 73, No. 13, 2008 4869

Tartaglia et al.
TABLE 3. Conformer Population, TDDFT/B3LYP/6-31G*
Calculated OR Value for Each Conformer, and the Boltzmann
Average Compared with the Experimental Rotatory Power for 2e
energy
difference
(kcal/mol)
population
(%)
calcd
[R]D
Boltzmann
average
exptl
[R]D
conformer
1
2
3
0
0.95
1.12
74
15
11
+131
+167
+145
+141
+61
low ORs. The examples of 1c, 1e, and 1f are particularly
representative because one cannot imagine arriving at a safe
configurational assignment with an approach where calculation
of the OR of the diol is directly attempted.
In summary, only by coupling the computational analysis with
some simple organic chemistry logic can we arrive at a fully
reliable configurational assignment. In the case of 2e with three
different conformers, the energies and populations of each are
given in Table 3. This table indicates that all the conformers
are dextrorotatory, with similar values of OR, so the average
rotation is clearly positive, in satisfactory agreement with
experiment.
FIGURE 3. Optical rotation of 2a, calculated with the method of sum-
over-states, at the TDFT/B3LYP/6-31G* level, as a function of the
number of states. The horizontal line corresponds to the figure obtained
with linear response theory at the same level of theory.
It may be seen that, even if this number of states does not
suffice to achieve convergence with the linear response theory
predictions, the sum-over-states prediction oscillates around the
limit value. This is because here, as we noticed above, [R]D
and the lowest-energy Cotton effect have the same sign, and
this band provides the largest contribution to the OR at 589
nm. In fact, an SOS calculation employing only the first excited
state gives an OR value which is correct in sign and order of
magnitude, and the inclusion of other states simply modifies
the numerical value from +91 (only the lowest-energy state)
to +107 (linear response theory). (Wiberg and co-workers say
that all the states coming from the excitation of valence electrons
have to be included in the sum.)25
This behavior can be found for other compounds 2 (2d, 2k,
2l in Figures 19-21 of Supporting Information). For example,
the predicted ORD curve (between 589 and 405 nm) of 2a is
monosignate and positive (λ 589 nm, +107, λ 577 nm, +114;
λ 546 nm, +132; λ 435 nm, +274; λ 405 nm, +364).
Furthermore, the predicted ORD curve, taking into account only
the rotational strength of the lowest-energy Cotton effect, is
essentially the same (λ 589 nm, +91; λ 577, +96; λ 546, +112;
λ 435 nm, 228; λ 405, 300) as that obtained above by means of
the linear response theory. This shows clearly that the OR values
in the long wavelength region, where no electronic transitions
appear, are dominated by the lowest-energy Cotton effect, that
is, the same behavior found26 by Polavarapu in the case of (R)-
3-chloro-1-butyne, (R)-3-methylcyclohexanone, and (R)-3-me-
thylcyclopentanone (5). From a quantitative point of view, the
agreement between experimental and predicted values cannot
be considered as perfect. In fact, the predicted [R]D values are
larger than the experimental ones: they are 2-3 times larger
for 2a and 2c-k and much larger (6 times) for 2b and for 2l.
The use of a larger basis set (6-31++G**) does not improve
the results much, with the exceptions of 2c, 2g, and 2l, where
the predicted [R]D value of 2l is significantly reduced (from
+355 to +286) toward better agreement with the experiment.
Since it is now generally recognized that the TDDFT/B3LYP
method tends to overestimate the OR figures (sometimes of a
factor of 2),5f,26,27 the behavior of 2a and 2c-k can be explained
on this basis. Obviously, the larger difference observed in the
(2) In the case of 2i, the experimental OR value (-4) is
exactly reproduced by our TDDFT/B3LYP/6-31G* calculation.
This almost perfect experiment/theory agreement is fortuitous.
Using the larger (6-31++G**) basis set, we obtain -7, that is,
a number which simulates the experimental value in sign and
order of magnitude. The observation that by increasing the
quality of the calculation for 2i we still obtain a negative OR
value of the correct order of magnitude indicates that we can
reproduce correctly even low OR values, even if the TDDFT/
B3LYP/6-31G* result was fortuitous. Thus we can assign the
AC of syn-1,3-diols, which are substrates for which no reliable
methods of configurational assignment based on analysis of
chiroptical properties are yet reported24a and only the empirical
method of the dimolybdenum tetracetate has been used to
date.24b,c This result is fully confirmed by the ECD calculations
(vide infra). (3) The case of 2j deserves more comment. Here,
in fact, we contracted the n-propyl tail to a simple methyl group.
It is interesting to note that this approximation does not much
affect the final result of the calculation. In fact, here too, we
predict an OR value twice the experimental, as in all the other
cases. (4) We have also attempted a calculation of [R]D using
the method of the sum-over-states (SOS),1 following an ap-
proach recently introduced by Wiberg and co-workers.25 In
Figure 3, the OR value of 2a, calculated as sum over the first
35 states, is reported together with the value corresponding to
that from the linear response theory prediction.
(23) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson,
G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez,
C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.;
Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 03;
Gaussian, Inc.; Pittsburgh, PA, 2003; http://www.gaussian.com/.
(24) (a) Harada, N.; Saito, A.; Ono, H.; Gawronski, J.; Gawronska, K.;
Sugioka, T.; Uda, H.; Kuriki, T. J. Am. Chem. Soc. 1991, 113, 3842–3850. (b)
Frelek, J.; Geiger, M.; Voelter, W. Curr. Org. Chem. 1999, 3, 145–174. (c)
Frelek, J.; Klimek, A.; Ruskowska, P. Curr. Org. Chem. 2003, 7, 1081–1104.
(25) Wiberg, K. B.; Wang, Y.; Wilson, S. M.; Vaccaro, P. H.; Cheeseman,
J. R. J. Phys. Chem. A 2006, 110, 13995–14002.
(26) (a) Polavarapu, P. L. J. Phys. Chem. A 2005, 109, 7013–7023. (b)
Polavarapu, P. L. Chirality 2006, 18, 348–356.
(27) (a) Mort, B. C.; Autschbach, J. J. Phys. Chem A 2006, 110, 11381–
11383. (b) Kowalczyk, T. D.; Abrams, M. L.; Crawford, T. D. J. Phys. Chem.
A 2006, 110, 7649–7654. (c) Tam, M. C.; Abrams, M. L.; Crawford, T. D. J.
Phys. Chem. A 2007, 111, 11232–11241.
4870 J. Org. Chem. Vol. 73, No. 13, 2008

Absolute Configuration of Flexible and Transparent Molecules
FIGURE 4. Comparison of the experimental (acetonitrile, blue line)
and predicted (TDDFT/B3LYP/6-31G*, velocity formalism, red line)
ECD spectra of 2a.
FIGURE 5. Comparison of the experimental (acetonitrile, red line)
and predicted (TDDFT/B3LYP/6-31G*, velocity formalism, blue line)
ECD spectra of 2i.
cases of 2b and 2l deserves more attention: (i) In the case of
2b, we have an equilibrium between two conformers (equatorial
methyl group, 86% and axial methyl group 14%), and the OR
values of the two conformers are -62 and +7, respectively.
An average value of -52 results. This figure depends on two
different parameters, that is, relative populations and values of
rotation of the two conformers. There are at least two sources
of error to be checked. (ii) In the case of 2l, we have evaluated
the role of the rotation of the benzene ring linked to the
dioxolane ring, following a known procedure28 by which, in
cases of this type, the optical rotation can be obtained by the
following equation:
the experimental and predicted spectra of 2b-l is collected in
the Figures 10-17 of the Supporting Information.
Examination of Figure 4 immediately reveals that the present
calculations are able to reproduce correctly a sequence of at
least four different Cotton effects in sign, position, and intensity
of the bands: this constitutes clear evidence that the absolute
configuration employed in the calculations is the right one; that
is, the absolute configuration has been safely assigned. This is
a consequence of the type of treatment for compounds 1. The
transformation 1f 2 guarantees the origin of a series of intense
and differently signed Cotton effects the theoretical reproduction
of all of which guarantees, in turn, the reliability of the
configurational assignment. In Figure 5, the comparison between
the experimental and simulated ECD spectra of the syn-1,3-
diol ketal 2i is reported.
In this case, as well, we note that the four Cotton effects
observed in the experimental spectrum are reproduced by the
calculations in sign, intensity, and position (the theoretical ECD
bands are red-shifted, 10-15 nm, with respect to the experi-
mental ones), thereby strongly indicating that the (R,R) AC
employed in the calculations corresponds to the real one.
Consequently, the computational analysis of the chiroptical
properties of the fluorenone ketals of syn-1,3-diols can constitute
a safe method for assigning the AC of these important substrates.
An examination of Figures 10-17 of the Supporting Infor-
mation reveals that the result above is valid for all the ketals
examined, and therefore, the method herein proposed is general
for aliphatic 1,n-diols. It is also important to comment on the
case of the derivative 2j. We already indicated (vide supra) our
attempts to further simplify the computational step by contract-
ing an n-propyl tail linked to a stereocenter down to a simple
methyl group, and this approximation did not affect the OR
calculation in a significant way. Thus the experimental value
was reproduced in sign and order of magnitude, with the
predicted value being twice the experimental one, as compared
to the other examples. Looking at Figure 6, we can see
immediately that all of the Cotton effects present in the
experimental spectrum are quite well simulated in sign, intensity,
and position, again confirming that the approximation above
could have general validity.
360 OR(θ) · e-ER(Tθ)dθ
∫
0
[R]D )
(1)
360 e-ER(θT)dθ
∫
0
where E(θ) is the function which gives the variation of the free
energy of the molecule varying the dihedral angle θ, which
describes the rotation of the benzene ring around the Car-C*
bond, and OR(θ) is the function linking the OR to the same
angle θ.
E(θ) and OR(θ) have been calculated at the DFT/B3LYP/6-
31G* and TDDFT/B3LYP/6-31G* levels of theory, respectively,
varying θ with a step of 20°. The corresponding curves are
reported in Figure 18 of the Supporting Information. They have
been interpolated by two eighth-order polynomial functions, so
obtaining E(θ) and OR(θ). The Boltzmann averaged [R]D value
was calculated at 298 K using the equation above, obtaining a
value of +278, which is still an overestimation of the experi-
mental one (+63) but represents a significant improvement with
respect to the value obtained with the single conformer (+355).
Combining reasonably the effect of the basis set and the effect
of the rotation of the benzene ring, which both lead to a
reduction of the calculated OR, one could arrive at a better
agreement with the experiment. It is noteworthy that assuming
free rotation around the above Ph-C* bond provides an OR
value of + 71, in excellent agreement with the experiment. ECD
spectra of the compounds 2 have been calculated, as well.
Details of these calculations are reported in the Computational
Details; the comparison between calculated and experimental
spectra of 2a is given in Figure 4, while comparison between
Conclusions
The main results of this work show clearly that computational
analysis of the chiroptical properties of flexible and transparent
(28) Wood, W. W.; Fickett, W.; Kirkwood, J. G. J. Chem. Phys. 1952, 20,
561–568.
J. Org. Chem. Vol. 73, No. 13, 2008 4871

Tartaglia et al.
theoretical values of optical rotation (to be compared with the
experimental ones) have been obtained as weighted averages on
the Boltzmann populations calculated in the gas phase. Rotational
strength calculations have been carried out at the TDDFT/B3LYP/
6-31G* level in the gas phase both in velocity and in length
formalism for the first 30 states. The simulated ECD spectra have
been obtained using overlapping Gaussian functions with a width
s ) 0.15 eV, according to ref 21e. All the QM calculations have
been carried out using the Gaussian03 package.
Preparation. All reactions were performed in flame-dried
glassware under nitrogen, unless noted. Chloroform was refluxed
over P2O5 and distilled under nitrogen atmosphere before its use.
THF was refluxed over sodium/benzophenone and distilled under
nitrogen atmosphere before use. Chromatography separations were
carried out on suitable dimension columns using silica gel 60
(70-230 mesh). Analytical thin-layer chromatography (TLC) was
performed on aluminum sheets precoated with silica gel (0.2 mm).
NMR spectra were recorded in CDCl3 on a 300 or 500 MHz NMR
spectrometer using TMS as the internal standard and are reported
in part per million (ppm) relative to TMS (0), with coupling
constants (J) in hertz. Optical rotatory powers at 589 nm have been
measured with a digital polarimeter, using standard cuvettes (l )
0.1 and 1 dm). Gas chromatographic analyses and mass spectra
(EI) were carried out on GC/MS chromatograph equipped with a
mass selective detector and a capillary column (30 m × 0.25 mm,
5% phenyl methyl siloxane as stationary phase) using helium as
carrier gas. Absorption and ECD spectra were recorded by a J-600
spectropolarimeter. Melting points were measured with a Scientific
SMP3 machine and are uncorrected. Unless otherwise noted,
commercially available diols, 1a, 1b, 1d, 1e, 1f, 1g, and 1n were
used without further purification. Compound 1c was prepared by
addition of MeMgBr to ethyl lactate,13 1j was prepared as
reported.17 Compounds 1h and 1i have been prepared as follows:
(-)-(R)-Methyl-3-(tert-butyldimethylsilanyloxy)butyrate (5): To
a cooled (0 °C) solution of the alcohol 4 (0.5 g, 2.1 mmol) in
CH2Cl2 (6 mL) were added imidazole (0.432 g, 6.35 mmol) and
TBSCl (0.477 g, 3.17 mmol). The mixture was stirred at room
temperature for 23 h, then hydrolyzed with a saturated aqueous
solution of NH4Cl and diluted with CH2Cl2. The aqueous layer was
extracted with CH2Cl2. The combined organic layers were washed
with brine and dried over Na2SO4 The concentrate was purified by
column chromatography on silica.gel (petroleum ether/EtOAc 9:1)
to provide 5 (0.453 g, 92%) as a colorless oil: [R]D ) -32 (c 1.3,
FIGURE 6. Comparison of the experimental (acetonitrile, red line)
and predicted (TDDFT/B3LYP/6-31G*, velocity formalism, blue line)
ECD spectra of 2j.
molecules can be made simpler by blocking conformational
flexibility and introducing a near UV-active chromophore.
Flexible systems, in principle, represent a problem requiring
an enormous computational effort because the calculation must
be repeated for each conformer and each single calculation must
be carried out at a high level of theory taking into account that
the Cotton effects are located in the far-UV region. In this way,
we have a smaller number of conformers (hopefully only one)
and, dealing with low-lying Cotton effects, a lower level of
theory can be used.
Furthermore, if the selected chromophore leads to several
Cotton effects in the near UV region (e.g., from 350 to 200
nm), the correct simulation of sign, intensity, and position is a
guarantee of the correct assignment of AC. In this way, ECD
spectroscopy gains the same advantages as VCD spectroscopy,
that is, the need for reproducing many CD bands as a solid
guarantee of a correct AC assignment.
Consequently, ECD spectroscopy can be used even alone
without a concerted use of the three chiroptical spectroscopies.
Other important conclusions of the present work include the
following: (i) with the fluorenone ketal method, we can safely
assign the AC of syn-1,3-diols, which are very difficult cases
for chiroptical spectroscopy; (ii) the method is also successful
in the case of sulfanylalcohols, important substrates in the field
of natural flavors; (iii) the present method could be extended
also to amino alcohols and diamines which are important
compounds to the field of synthetic intermediates in medicinal
chemistry, chiral ligands, and catalysts in asymmetric synthesis.
Work is now in progress on (iii).
1
CHCl3); H NMR (500 MHz, CDCl3) δ (ppm) 0.05 (s, 3H), 0.07
(s, 3H), 0.87 (s, 9H), 1.20 (d, J ) 6.0 Hz, 3H), 2.39 (dd, J ) 14.0
Hz, 5.0 Hz, 1H), 2.49 (dd, J ) 14.0 Hz, 8.0 Hz, 1H), 3.68 (s, 3H),
4.29 (m, 1H); 13C NMR (125 MHz, CDCl3) δ (ppm) -5.1, -4.5,
17.9, 23.9, 25.7, 44.7, 51.4, 65.8, 172.1; IR (cm-1) 2956, 2930,
2896, 2858, 1741. Anal. Calcd for C11H24O3Si: C, 56.85; H, 10.41.
Found: C, 56.91; H, 10.24.
(-)-(R)-5-(tert-Butyldimethylsilanyloxy)hex-1-yn-3-one (6): To
a slurry of ester 5 (0.864 g, 3.72 mmol) and Me(MeO)NH ·HCl
(0.473 g, 4.85 mmol) in THF (30 mL) at -40 °C under argon
atmosphere was added the solution of ethynylmagnesium chloride
(0.5 M in THF, 46.50 mL, 23.25 mmol) over 2 h. After 4 h at this
temperature, the reaction mixture was warmed to 25 °C, stirred
overnight, and then quenched with a saturated aqueous solution of
NH4Cl. The aqueous layer was extracted with Et2O. The combined
organic layers were washed with brine and dried over Na2SO4. The
concentrate was purified by column chromatography on silica gel
(petroleum ether/EtOAc 97:3) to provide 6 (0.555 g, 66%) as a
colorless oil: [R]D ) -21 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3)
δ (ppm) 0.06 (s, 3H), 0.08 (s 3H), 0.87 (s, 9H), 1.21 (d, J ) 6.0
Hz, 3H), 2.62 (dd, J ) 15.0 Hz, 5.0 Hz, 1H), 2.80 (dd, J ) 15.0
Hz, 7.0 Hz, 1H), 3.24 (s, 1H), 4.43 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ (ppm) -5.0, -4.4, 17.9, 23.9, 25.8, 55.1, 65.2, 78.6,
81.9, 185.65; IR (cm-1) 3302, 3257, 2957, 2930, 2896, 2858, 2360,
2342, 2094,1686; MS (EI) m/z 225 (M+ - 1, 1), 169 (100), 125
Experimental Section
Computational Details. The calculations of this investigation
have been carried out following the protocol described below. The
structures to be used as starting geometries in the QM optimizations
have been created by means of a conformational analysis with the
SPARTAN0222 software, using the methods of molecular mechan-
ics (MMFF94s force field) and retaining only the structures differing
by 2 kcal/mol in energy or less. All the resulting geometries have
been fully optimized at the DFT/B3LYP/6-31G*23 level in the gas
phase. All conformers are real minima; no imaginary vibrational
frequencies have been found. In all cases, the free energy values
at T ) 298 K have been employed to calculate the population of
each conformer, using the Boltzmann statistics. The calculations
of the optical rotatory power have been carried out at TDDFT/
B3LYP/6-31G* or 6-31++G** levels in the gas phase. The
4872 J. Org. Chem. Vol. 73, No. 13, 2008

Absolute Configuration of Flexible and Transparent Molecules
(73), 83 (100), 75 (49). Anal. Calcd for C12H22O2Si: C, 63.66; H,
9.80. Found: C, 63.91; H, 9.74.
Then, the reaction mixture was diluted with diethyl ether and treated
with an aqueous 1 M solution of NaOH. The separated organic
phases were washed with brine, dried over Na2SO4, and concen-
trated. The crude product was purified by crystallization from
methanol (72%): mp ) 82-84 °C; 1H NMR (500 MHz, CDCl3) δ
(ppm) 3.40 (s, 6H), 7.34 (t, J ) 7.5 Hz, 2H), 7.42 (t, J ) 7.5 Hz,
2H), 7.58 (d, J ) 7.5 Hz, 2H), 7.64 (d, J ) 7.5 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ (ppm) 50.6, 119.1, 123.5, 126.8, 128.9, 138.9,
140.5; MS (EI) m/z 226 (M+, 9), 195 (100), 180 (39) 152 (18).
Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found: C, 79.69; H,
6.18.
(-)-(3S,5R)-5-(tert-Butyldimethylsilanyloxy)-hex-1-yn-3-ol (7):
To a stirred solution of ketone 6 (0.486 g, 2.15 mmol) in methanol
(20 mL) was added NaBH4 (0.163 g, 4.3 mmol) at -40 °C. Then
the solution was stirred at that temperature for 24 h. To this solution
was added a solution of saturated aqueous solution of NH4Cl. The
organic phase was separated, dried over Na2SO4, and concentrated.
The residue was purified by column chromatography on silica gel
(petroleum ether/EtOAc 9:1) to give the title compound 7 (0.147
1
g) as clear oil (30% yield): [R]D ) -56 (c 1, CHCl3); H NMR
General Procedure for the Preparation of Ketals 2a-l: To a
solution of 113 mg (0.5 mmol) of dimethylacetal 9 in chloroform
(6.5 mL) were added diol 1 (0.5 mmol), activated molecular sieves
(4 Å), and traces of p-toluenesulfonic acid, and the reaction mixture
was stirred at room temperature for 16 h. Filtration and evaporation
of solvent at reduced pressure gave the crude product, which was
purified by chromatography column on silica gel (petroleum ether/
dichloromethane 6:4) and/or crystallization from methanol.
(+)-(3aR,7aR)-3a,4,5,6,7,7a-Hexahydrospiro[1,3-benzodioxole-
2,9′-fluorene] (2a): Yield 52%; mp ) 122-126 °C; [R]D ) +51 (c
0.6, CHCl3), +50 (c 0.78, hexane), +54 (c 0.74, CH3OH); 1H NMR
(500 MHz, CDCl3) δ (ppm) 1.37 (m, 2H), 1.58 (m, 2H), 1.85 (m,
2H), 2.21 (d, J ) 11.5 Hz, 2H), 3.73 (d, J ) 9.0 Hz, 2H), 7.18 (t,
J ) 6.7, 2H), 7.26 (t, J ) 7.2, 2H), 7.40 (d, J ) 6.5 Hz, 2H), 7.45
(d, J ) 7.0 Hz, 2H);13C NMR (125 MHz, CDCl3) δ (ppm) 22.9,
28.4, 80.7, 118.8, 123.0, 127.3, 129.1, 138.7, 143.8; MS (EI) m/z
278 (M+, 61), 180 (100), 165 (41), 152 (48). Anal. Calcd for
C19H18O2: C, 81.99; H, 6.52. Found: C, 81.90; H, 6.48.
(400 MHz, CDCl3) δ (ppm) 0.06 (s, 3H), 0.08 (s 3H), 0.87 (s, 9H),
1.21 (d, J ) 6.0 Hz, 3H), 2.62 (dd, J ) 15.0 Hz, 5.0 Hz, 1H), 2.80
(dd, J ) 15.0 Hz, 7.0 Hz, 1H), 3.24 (s, 1H), 4.43 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ (ppm) -4.8, -4.2, 17.9, 23.4, 25.8,
44.8, 60.1, 67.0, 72.5, 84.9; IR (cm-1) 3420, 3312, 2957, 2929,
2896, 2857, 2360, 2342; MS (EI) m/z 227 (M+ - 1, 1), 119 (100),
75 (75). Anal. Calcd for C12H24O2Si: C, 63.10; H, 10.59. Found:
C, 63.21; H, 10.70.
(-)-(3R,5R)-5-(tert-Butyldimethylsilanyloxy)-hex-1-yn-3-ol (8):
Further elution provided 8 (0.294 g) as clear oil (60%): [R]D
)
1
-42 (c 1, CHCl3); H NMR (500 MHz, CDCl3) δ (ppm) 0.10 (s,
6H), 0.91 (s, 9H), 1.22 (d, J ) 6.0 Hz, 3H), 1.82 (m, 1H),1.93 (m,
1H), 2.47 (s, 1H), 2.84 (br s, 1H), 4.09 (m, 1H), 4.55 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ (ppm) -4.9, -4.0, 17.9, 24.2, 25.7,
46.6, 61.3,67.7, 72.8, 84.7; IR (cm-1) 3420, 3312, 2957, 2929, 2896,
2857, 2360, 2342; MS (EI) m/z 227 (M+ - 1, 1), 119 (100), 75
(77). Anal. Calcd for C12H24O2Si: C, 63.10; H, 10.59. Found: C,
63.23; H, 10.67.
(-)-(2R,4S)-Hex-5-yne-2,4-diol (1h): To a stirred solution of
7 (99 mg, 0.43 mmol) in THF (0.66 mL) was added tetrabutylam-
monium floride (1 M solution in THF, 0.66 mL). Then the solution
was stirred at room temperature for 1 h. THF was evaporated, and
the crude mixture was purified by column chromatography on silica
gel (petroleum ether/EtOAc 2:1) without extractive workup to give
Acknowledgment. Financial support from Universita` della
Basilicata and MIUR (Roma) is gratefully acknowledged. We
are indebted to the reviewers of this paper for their constructive
criticism; in particular, we appreciated that one of them corrected
the language and the style of the manuscript.
the title compound 1h as a colorless oil (44 mg, 90%): [R]D
)
-33 (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3) δ (ppm) 1.27 (d,
J ) 6.0 Hz, 3H), 1.86 (m, 2H), 2.12 (br s, 1H), 2.51 (s, 1H), 3.20
(bs, 1H), 4.40 (m, 1H), 4.68 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ (ppm) 23.7, 43.9, 60.6, 65.7, 73.2, 84.4; IR (cm-1) 3344, 3294,
2967, 2923. Anal. Calcd for C6H10O2: C, 63.14; H, 8.83. Found:
C, 63.10; H, 8.70.
Supporting Information Available: Spectroscopic and
analytical data for ketals 2b-l. Absorption and ECD spectra
of 2b-l in acetonitrile. Absorption and ECD spectra of diol 1d
in acetonitrile. Comparison of the experimental (acetonitrile,
red line) and predicted (TDDFT/B3LYP/6-31G*, velocity
formalism, blue line) ECD spectra of 2b-l. Relative energies
(kcal/mol) and optical rotation at the sodium D line (deg [dm
g/cm3]-1) of ketal 2l with respect to the rotation of the Ph group
around the Ph-C* bond. All quantities have been obtained at
the B3LYP/6-31G* level, performing a relaxed scan of the Ph
rotation with a 20° step in the angle. Optical rotation at the
sodium D line of ketals 2d, 2k, and 2l calculated with the
method of sum-over-states. DFT/B3LYP/6-31G* optimized
geometries of all the conformers of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(+)-(2R,4R)-Hex-5-yne-2,4-diol (1i): Same procedure of com-
pound 7 was followed on compound 8 to afford 1i as a clear oil in
91% of yield: [R]D ) +6 (c 1, CHCl3); 1H NMR (500 MHz, CDCl3)
δ (ppm) 1.22 (d, J ) 6.0 Hz, 3H), 1.84 (m, 2H), 2.49 (s, 1H), 3.32
(br s, 1H), 4.00 (br s, 1H), 4.07 (m, 1H), 4.61 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ (ppm) 23.7, 45.4, 61.7, 67.4, 73.1, 84.4; IR
(cm-1) 3344, 3294, 2967, 2923. Anal. Calcd for C6H10O2: C, 63.14;
H, 8.83. Found: C, 63.09; H, 8.82.
9,9-Dimethoxyfluorene (9): To a solution of 9-fluorenone 9 (1.0
g, 5.55 mmol) in methanol (12 mL) were added trimethyl
orthoformate (1.21 mL, 11.1 mmol) and traces of p-toluenesulfonic
acid, and the solution was stirred at room temperature for 16 h.
JO800516F
J. Org. Chem. Vol. 73, No. 13, 2008 4873