Chiral 1, 2-Diols: The assignment of their absolute configuration by NMR made easy

Article abstract of DOI:10.1021/ol9021639

(Figure presented) The absolute configuration of a 1, 2-prlmary/secondary dlol can be easily determined by preparation of Its bls-(R)- and bls-(S)-9-AMA ester derivatives, followed by comparison of the NMR chemlcal shifts of the dlastereotoplc methylene protons In the two derivatives. Alternatively, the assignment can be carried out using only one derivative If the evolution with temperature of the signals corresponding to the CaH protons Is analyzed.

Full text of DOI:10.1021/ol9021639

ORGANIC
LETTERS
2010
Vol. 12, No. 2
208-211
Chiral 1,2-Diols: The Assignment of
Their Absolute Configuration by NMR
Made Easy
Fe´lix Freire, Jose´ Manuel Seco, Emilio Quin˜oa´, and Ricardo Riguera*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, and Unidad de RMN de
Biomole´culas Asociada al CSIC, UniVersidad de Santiago de Compostela,
15782, Santiago de Compostela, Spain
ricardo.riguera@usc.es
Received September 18, 2009
ABSTRACT
The absolute configuration of a 1,2-primary/secondary diol can be easily determined by preparation of its bis-(R)- and bis-(S)-9-AMA ester
derivatives, followed by comparison of the NMR chemical shifts of the diastereotopic methylene protons in the two derivatives. Alternatively,
the assignment can be carried out using only one derivative if the evolution with temperature of the signals corresponding to the CrH protons
is analyzed.
The assignment of the absolute configuration of a chiral
The full proton assignment in molecules with complex
structure (sugars, policyclic compounds, etc.) usually requires
the combination of multiple NMR techniques such as
TOCSY, COSY, NOESY, etc., a fact that can make tedious
the assignment of the absolute configuration by NMR. A
second limitation is the need to prepare two diastereomeric
derivatives from a sample that sometimes is very small.
Fortunately, for some functional groups, the configuration
can be determined by using only one derivative with an
appropriate CDA.3
1
substrate by H NMR using a chiral derivatizating agent
(CDA) is a well-established technique.1
The general method, derived from the pioneering
“Mosher-Trost Method”,1,2 consists of the derivatization
of the chiral substrate (i.e., alcohol, amine, thiol, etc.) with
the two enantiomers of a CDA (i.e., MPA: 2-methoxy-2-
phenylacetic acid; 9-AMA: 2-(anthracen-9-yl)-2-methoxy-
acetic acid; MTPA: 2-methoxy-2-trifluoromethyl-2-phenyl-
acetic acid), followed by the comparison of the chemical
shifts of the protons in the substrate moiety of the two
resulting derivatives.1
In this communication, we will demonstrate with the help
of theoretical and empirical studies that in the case of chiral
1,2-primary/secondary diols both limitations can be circum-
(1) (a) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17.
(b) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Tetrahedron: Asymmetry 2001,
12, 2915. (c) Wenzel, T. J. Discrimination of Chiral Compounds Using
NMR Spectroscopy; Wiley-Interscience: NJ, 2007.
(3) (a) Latypov, Sh.K.; Seco, J. M.; Quin˜o, a´, E.; Riguera, R. J. Am.
Chem. Soc. 1998, 120, 877. (b) Freire, F.; Seco, J. M.; Quin˜oa´, E.; Riguera,
R. Org. Lett. 2005, 7, 4855. (c) Freire, F.; Caldero´n, F.; Seco, J. M.;
Ferna´ndez-Mayorales, A.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 2007,
72, 2297. (d) Leiro, V.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. Org. Lett.
2008, 10, 2733.
(2) (a) Dale, A. J.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec,
J. M. J. Org. Chem. 1986, 51, 2370
.
10.1021/ol9021639  2010 American Chemical Society
Published on Web 11/18/2009

vented by using 9-AMA as the CDA of choice and just
looking at the chemical shifts of the diastereotopic methylene
protons (Figure 1).
the 9-AMA moieties adopt two possible orientations: an sp
orientation (the carbonyl and the OMe are synperiplanar)
or an ap orientation (the carbonyl and the OMe are
antiperiplanar).
With these results in hand, the orientation of the anthryl
and carbonyl groups toward the methylene protons can be
visualized, and therefore, the anisotropic effects over those
protons are predicted for each derivative.
Thus, in the bis-(R)-9-AMA ester of a type A diol, the
carbonyl group on the primary alcohol is oriented in such a
way that induces a deshielding effect over the pro-S proton
and a shielding effect over the pro-R proton. For its part,
the anthryl groups of the two auxiliary units are not well
oriented toward the methylene group, so their anisotropic
effects do not influence significantly those two protons
(Figure 2a).
In the case of the bis-(S)-9-AMA ester of the same diol,
the situation is more complex: the carbonyl group at C(1′)
is oriented to cause shielding on pro-R H and deshielding
on pro-S H in both conformers sp and ap, but the anthryl
groups of the two 9-AMA auxiliaries are also well oriented
to act on the methylene protons producing the following
effects: in the sp conformer, pro-R H is shielded by the two
anthryl units, while the pro-S H is shielded by only the
anthryl moiety of the 9-AMA at C(1′) (Figure 2b).
In this way, the methylene protons of a 1,2-diol are
subjected in every derivative to very different shielding/
deshielding effects that should produce very different spectral
patterns for the bis-(R)-9-AMA and the bis-(S)-9-AMA
derivatives (Figure 2c). These results are summarized as
follows: in a type A 1,2-diol, the methylene protons should
resonate at closer frequencies in the bis-(R)-9-AMA than in
the bis-(S)-9-AMA derivative (Figure 2c).
Figure 1. Structures of MPA, 9-AMA, and types A and B 1,2-
diols.
Thus, conformational analysis of the bis-(R)- and bis-(S)-
9-AMA esters of (S)-propane-1,2-diol (configuration type A,
Figure 2), using a combination of theoretical and experi-
Similar analysis on the relative orientation of the aniso-
tropic groups with respect to the methylene protons in the
enantiomeric 1,2-diol (configuration type B) shows the
reverse distribution of shielding/deshielding effects (Figure
2d). This means that in a type B diol the methylene protons
should resonate at closer frequencies in the bis-(S)-9-AMA
than in the bis-(R)-9-AMA derivative (Figure 2d). Figures
2c and 2d show the actual NMR spectra of the bis-9-AMA
esters of (S)- and (R)-propane-1,2-diol (types A and B,
respectively).
Figure 2. Representative conformers of the (a) bis-(R)- and (b)
Theoretical chemical shift calculations (GIAO)7 on the sp-
II and ap-II conformers of the bis-(R)- and bis-(S)-9-AMA
esters of (S)-propane-1,2-diol showed data in very good
agreement with the experimental chemical shifts.
bis-(S)-9-AMA esters of (S)-propane-1,2-diol. Partial 1H NMR
showing the methylene protons in the bis-9-AMA esters of (c) (S)-
and (d) (R)-propane-1,2-diol, types A and B, respectively.
Experimental demonstration of the general character of
this correlation between absolute configuration of the diol
and the spectra of the methylene protons was obtained with
a series of 1,2-diols of known absolute configuration (1-9,
mental data,4 indicated that in both the bis-(R)- and the bis-
(S)-9-AMA derivatives there is a conformational equilibrium
between two main conformers: II-sp and II-ap (Figure 2).
In these conformers, the O-C(1′) bond adopts a II confor-
mation with the carbonyl of the 9-AMA at C(1′) coplanar
to the pro-S-methylene proton5 at C(1), and the C(1′)-C(2′)
bond is in a gt (gauche-trans) conformation.6 For its part,
(5) The pro-R and pro-S-methylene protons have been assigned by means
of deuteration experiments (See Figure S5 in Supporting Information). Note
that in a type A 1,2-diol, the pro-S-proton resonates at lower field and the
pro-R at higher field, while in a type B 1,2-diol, the pro-S resonates at
higher field and the pro-R at lower field.
(6) H(2)-C(2)-C(1)-H proR in gauche and C(3)-C(2)-C(1)-O in
(4) For conformational studies by CD, structure calculations, coupling
constants analysis, and selective deuteration, see Supporting Information for
details.
trans conformations.
(7) Aromatic shielding effect calculations were performed using Gaussian
98. See Supporting Information.
Org. Lett., Vol. 12, No. 2, 2010
209

Figure 3
.
(a) Partial 1H NMR spectra showing the diastereotopic methylene protons of the bis-9-AMA esters 1-5 (type B) and 6-9 (type
1
A). (b) Partial H NMR spectra showing the diastereotopic methylene protons of the bis-MPA esters 10 and 11.
Figure 3). In all cases, the absolute configuration of the diol
correlates with the pattern of the methylene protons of Figure
2 for the bis-(R)- and bis-(S)-9-AMA derivatives, demon-
strating the usefulness of this correlation for the assignment
of the absolute configuration by NMR of the bis-9-AMA
derivatives.
It should be pointed out that when 9-AMA is replaced by
MPA the shielding/deshieldings observed for the methylenes
are so small that no useful differences are obtained (see
10-11 in Figure 3).8
Single Derivatization Method. In previous papers,3 we
have described the use of low-temperature NMR as a way
to obtain the absolute configuration using only one MPA
derivative. This requires the analysis of the evolution with
temperature of the chemical shift values for the L1/L2 groups.
It is based on the changes on relative populations of the main
conformers induced by temperature modification and its
translation to the NMR spectra via the anisotropic effects of
the phenyl ring of MPA on L1/L2.
These shifts with temperature can be explained by the
shieldings/deshieldings effect suffered by the CRH in each
conformer and the change of their relative populations with
temperature.
Thus, in the bis-(R)-9-AMA ester of the (S)-1,2-pro-
panediol (type A), we observe the following anisotropic
effects: (a) in the II-sp conformer, the 9-AMA unit on the
primary alcohol shields the CRH of the 9-AMA unit on the
secondary alcohol (Figure 4a); (b) in the II-ap conformer,
the opposite effect happens, and the 9-AMA on the secondary
alcohol shields the CRH of the 9-AMA on the primary
alcohol (Figure 4a).
As a consequence, a drop of the NMR probe temperature
compels the CRH protons of both 9-AMA units to move
upfield providing a positive ∆δT1T2 value9 (Figure 4c).
For its part, in the bis-(S)-9-AMA ester of the same diol
[(S)-propane-1,2-diol, Type A], the distribution of anisotropic
In the case of the bis-9-AMA ester derivatives of 1,2-
diols, the groups better oriented for this purpose are the
CRH protons on the 9-AMA moieties, and in fact, we
observed a perfect correlation between the evolution with
temperature of those signals and the absolute configuration
of the diol.
In this way, when the NMR spectra of the bis-(R)-9-AMA
ester of (S)-propane-1,2-diol (1, type A) are registered at
decreasing temperatures, both CRH protons are shifted to
higher field (Figure 4c and 4d). In the bis-(S)-9-AMA ester
of the same diol, the CRHs are shifted in opposite directions
(one to higher field and the other to lower field), and the
same pattern of evolution was observed for all the bis-9-
AMA esters of compounds 2-5 (type A, Figure 3).
Figure 4. Shielding effects over the CHR protons at the 9-AMA
(8) If MPA is the reagent of choice, the “classical” approximation is a
reliable alternative. For details, see: Freire, F.; Seco, J. M.; Quin˜oa, E.;
Riguera, R. Chem.sEur. J. 2005, 11, 5509, reference 3b.
(9) The ∆δT1T2 values are defined as δ at the higher temperature (T1)
minus δ at the lower temperature (T2).
moieties in the main conformers of (a) bis-(R)- and (b) bis-(S)-9-
AMA esters of (S)-propane-1,2-diol and evolution with the tem-
perature of their spectra (c,d).
210
Org. Lett., Vol. 12, No. 2, 2010

Figure 5. Evolution with the temperature of the CHR protons of the 9-AMA moieties of the bis-(R)- and bis-(S)-9-AMA 1-9.
effects is the following: (a) in the II-sp conformer, the
9-AMA unit on the secondary alcohol shields the CRH
proton of the other 9-AMA; (b) in the II-ap conformer, the
two 9-AMA units are oriented in such a way that they do
not affect any CRH proton.
When the NMR spectra are taken at lower temperatures, the
CRH of the 9-AMA on the primary alcohol (higher-field CRH
proton) moves upfield (positive ∆δT1T2), while the CRH proton
of the other 9-AMA (the one that resonates at lower field) moves
downfield (negative ∆δT1T2) (Figures 4b and 4d).
Similar analysis in the enantiomeric diol (type B) reveals
the opposite pattern in the NMR spectra for the shifts of the
CRH protons of the bis-9-AMA esters when the temperature
decreases. In this way, when the NMR spectra of the bis-
(R)-9-AMA ester of (R)-propane-1,2-diol (6, type B) are
registered at decreasing temperatures, the CRHs are shifted
in opposite directions (one to high-field and the other to low
field), while in the bis-(S)-9-AMA ester of the same diol,
both CRH protons are shifted to high field. The same pattern
of evolution was observed for all the bis-9-AMA esters of
compounds 6-9 (type B, Figure 3).
and complementary ways: (a) the comparison of the meth-
ylene protons in both derivatives, bis-(R)- and bis-(S)-9-AMA
esters, or (b) by using a single derivative, where the
movement of the CRH protons of the 9-AMA moieties in
the NMR spectra when the temperature decreases is related
to the absolute configuration of the diol. This is the first time
that the chiral auxiliary 9-AMA is applied in a single
derivatization method.
Acknowledgment. We thank Ministerio de Ciencia e
Innovacio´n (CTQ2009-08632/BQU, CTQ2008-01110), Xun-
ta de Galicia (PGIDIT06PXIB209029PR), Centro de Super-
computacio´n de Galicia (CESGA), and Bruker Espan˜ola
S.A. F. F. thanks MICINN for a postdoctoral Juan de la
Cierva fellowship. We are also grateful to Yamakawa
Chemical Industry Co. Ltd. (Japan) for their gift of (R)- and
(S)-MPA.
Supporting Information Available: Conformational analy-
sis (energy calculations, CD, selective deuteration, dynamic
NMR, experimental and theoretical chemical shifts), general
experimental procedures, synthesis of 9-AMA, and spectro-
scopic data of compounds 1-9. This material is available
free of charge via the Internet at http://pubs.acs.org.
Plots showing the evolution with temperature of the CRHs
of the bis-(R)- and bis-(S)-9-AMA esters of compounds 1-9
are shown in Figure 5.
In conclusion, the absolute configuration of 1,2-primary/
secondary diols can be easily determined by two different
OL9021639
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