Absolute configuration of ketone cyanohydrins by 1H nmr: The special case of polar substituted tertiary alcohols

Article abstract of DOI:10.1021/ol8023314

The absolute configuration of ketone cyanohydrins can be assigned from analysis of the ¹H NMR spectra of the corresponding (R)-and (S)-MPA ester derivatives and use of Δδ^RS signs. This is an application of the NMR methodology for ste

Full text of DOI:10.1021/ol8023314

ORGANIC
LETTERS
2009
Vol. 11, No. 1
53-56
Absolute Configuration of Ketone
1
Cyanohydrins by H NMR: The Special
Case of Polar Substituted Tertiary
Alcohols
Iria Louzao, Rosa Garc´ıa, Jose´ Manuel Seco, Emilio Quin˜oa´, and
Ricardo Riguera*
Departamento de Qu´ımica Orga´nica and Unidad de RMN de Biomole´culas Asociada al
CSIC, UniVersidad de Santiago de Compostela 15782, Santiago de Compostela, Spain
ricardo@usc.es
Received October 8, 2008
ABSTRACT
1
The absolute configuration of ketone cyanohydrins can be assigned from analysis of the H NMR spectra of the corresponding (R)- and
(S)-MPA ester derivatives and use of ∆δRS signs. This is an application of the NMR methodology for stereochemical assignment to tertiary
alcohols possessing polar groups as substituents.
Cyanohydrins are a versatile family of compounds that have
always attracted the interest of chemists due to their
importance both as industrial products and as reagents in
organic chemistry. For instance, they are key building blocks
for the synthesis of many biologically active compounds that
are otherwise only obtained with difficulty, such as hydroxy
aldehydes, amino alcohols, hydroxy amino acids and hydroxy
acids.1 Particularly, ketone cyanohydrins, are valuable in-
termediates in the preparation of compounds with a quater-
nary stereocenter.2 Additionally, cyanohydrins are exten-
sively found in nature (plants, insects) in the form of
glycosides that are believed to play important biological roles
(i.e., as antifeedants or insecticides).3
To date, only one attempt to disclose the absolute
configuration of cyanohydrins using NMR4 spectroscopy has
been described.5 It is useful only for aldehyde cyanohydrins
and relies on the preparation of diastereomeric CDA (chiral
1
derivatizing agent) derivatives and analysis of both H and
13C NMR data. 2-Methoxy-2-phenylacetic acid (MPA) was
found to be the CDA of choice for those compounds.
Despite their importance, there is not a parallel procedure
for ketone cyanohydrins. This is not surprising because these
compounds present an extra challenge when compared to
other hydroxylated compounds: they may be considered
tertiary alcohols with a polar substituent (CN), and tertiary
(3) (a) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555.
(b) Peterson, C. J.; Tsao, R.; Cotas, J. R. Pest Manag. Sci. 2000, 56, 615.
(4) For a recent review on NMR methods for configurational assignment,
see: Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17.
(5) Louzao, I.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. Commun.
2006, 1422.
(1) Kirsten, C. N.; Herm, M.; Schrader, T. H. J. Org. Chem. 1997, 62,
6882.
(2) Fessner, W.-D., Ed. Biocatalysis; Springer: Berlin, 1999.
10.1021/ol8023314 CCC: $40.75
Published on Web 12/03/2008
2009 American Chemical Society

Figure 1.
(a) ∆δRS values and signs for the MPA ester derivatives of ketone cyanohydrins 1-16 (CDCl3). (b) Spatial distribution of signs.
alcohols have been elusive in the past to stereochemical
assignment by NMR methods, due to the unsuitable confor-
mational characteristics of their CDA derivatives. Further-
more, they are notoriously difficult to derivatize. Few
attempts are registered in the literature and the examples are
limited to R-methyl-substituted tertiary alcohols.6
In this communication, we propose an NMR approach
based on theoretical and experimental evidence that allows
one to determine the absolute configuration of chiral ketone
cyanohydrins by comparison of the NMR spectra of their
(R) and (S)-MPA derivatives.
The MPA esters of 7 were chosen as model compounds
for theoretical calculations. Main conformations were gener-
ated around CR-C(O) (MPA moiety) and O-CR′ (cyano-
hydrin moiety). Rotation around the CR-C(O) bond provided
two conformers, sp and ap, while rotation around O-CR′
gave rise to three: g+, g- and a, in which the dihedral angle
formed by atoms C(O)-O-CR′-CN is ca. +60, -60 and 180°
respectively (see Figure 33S in the Supporting Information).
As summary, the calculations show (Table 1) that the
First, a representative collection of structurally varied
ketone cyanohydrins (including cyclic and acyclic ones) of
known absolute configuration (Figure 1) was selected for
this study. Next, the corresponding (R)- and (S)-MPA
derivatives were prepared, their NMR spectra analyzed with
special attention to the shifts of the substituents on the
asymmetric carbon, and the chemical shift differences (∆δRS)
for L1/L2 calculated. This parameter is obtained by subtract-
ing the chemical shifts observed for L1 and L2 in the (R)-
MPA ester minus the corresponding values in the (S)-MPA
ester.
Table 1. Relative Energies [B3LYP/6-31+G(d), kcal/mol] for
Significant Conformers of (R)- and (S)-MPA Derivatives of 7
conformer
ester
spg+
spg-
spa
apg+
apg-
apa
(R)-MPA
(S)-MPA
2.84
0.00
0.00
0.94
5.42
3.18
3.12
0.90
0.94
1.24
3.55
3.88
conformational equilibria are basically established by two
A homogeneous distribution of ∆δRS signs was found in
compounds 1-12, as shown in Figure 1: both substituents
of the stereogenic carbon (L1/L2) exhibit opposite signs. That
is, protons located at the same substituent (i.e., L1) present
the same ∆δRS sign and opposite to those of the other
substituent (i.e., L2). As a result, a correlation between the
∆δRS signs for L1 and for L2 and the spatial position around
the asymmetric carbon of these substituents is inferred, and
thus allowing the assignment of the cyanohydrin absolute
configuration.7
main sp conformers (spg+ and spg-, Figure 2), both having
In order to understand the origin of this correlation we
carried out studies to identify the most significant conformers,
using theoretical calculations [DFT (B3LYP)],8 circular
dichroism (CD) and variable temperature NMR experiments.
Figure 2. (a and b) Conformational equilibria for the (R)- and (S)-
MPA esters of 7; (c) NMR significant conformers.
(6) (a) Izumi, S.; Moriyoshi, H.; Hirata, T. Bull. Chem. Soc. Jpn. 1994,
67, 2600. (b) Takahashi, H.; Kato, N.; Iwashima, M.; Iguchi, K. Chem.
Lett. 1999, 1181. (c) Kobayashi, M. Tetrahedron 1998, 54, 10987.
(7) The 13C ∆δRS parameters of the CN groups of ketone cyanohydrins
1-16 are not diagnostic: the absolute values are small and the signs cannot
be correlated with the configurations. See Table 1S in the Supporting
Information and ref 9.
similar energies. The CN group is preferably placed in the
opposite side of phenyl group for both cases: so, in the
equilibrium of the (R)-MPA derivative, spg- is the most
54
Org. Lett., Vol. 11, No. 1, 2009

stable conformer (Figure 2a), while the most stable one in
the (S)-MPA derivative is spg+ (Figure 2b).9
According to this conformational scenario, the shielding
and deshielding effect of the phenyl ring of the auxiliary on
each conformation can now be analyzed. Thus, the butyl
group is effectively shielded in the spg- conformer of the
(R)-MPA ester, whereas the same group in the spg+
conformer is just slightly shielded (Figure 2a). Meanwhile
in the (S)-MPA ester, the butyl group is slightly shielded
only in spg+ conformer (Figure 2b). The neat result is that
the butyl group is more shielded in the (R) than in the (S)-
MPA derivative, leading to a ∆δRS negative difference.
Simultaneously, in the (S)-MPA ester, the methyl group
is strongly shielded in the spg+ conformation, and slightly
shielded in the spg- conformation (Figure 2b), while it is
slightly shielded only in spg- (Figure 2a) in the (R)-MPA
derivative. Consequently, the methyl group is more shielded
in the (S)- than in the (R)-MPA ester, leading to a ∆δRS
positive value.
1
Figure 3. Temperature evolution of the H NMR spectra of (R)-
and (S)-MPA derivatives of 1 (a and b) and ∆δT1T2 values (ppm).
The above conformational composition was experimentally
supported by CD studies, low-temperature NMR experiments
and exhaustive analyses of the collection of cyanohydrins
of known absolute configuration shown in Figure 1. Thus,
CD spectra (Figure 34S in Supporting Information) revealed
the conformational preference in the MPA fragment. Cotton
effects observed for the (R)- and (S)-MPA ester of (S)-2-
hydroxy-2-methylhexanonitrile 7 at 226 nm are negative and
positive respectively (∆ꢀ ) -2.42 and 4.34 cm-2 mol-1),
indicating that the most abundant conformer in the MPA
moiety is sp.10
Variable-temperature NMR experiments carried out on the
MPA derivatives of (1R,2S,5R)-1-hydroxy-2-isopropyl-5-
methylcyclohexanecarbonitrile (1), taken as model com-
pounds, exhibit in both cases a deshielding of the CRH signal
and a shielding of the OMe signal (Figure 3, MPA moiety),
when lowering the temperature of the NMR probe. Both
phenomena indicate an increase of the relative population
of the sp conformer around CR-C(O) bond,11 in agreement
with the theoretical calculations and CD experiments. As
temperature drops, a gradual shielding of Me(8′) and Me(9′)
signals (Figure 3a) is noticed in the NMR spectrum of the
(R)-MPA ester, whereas the signals from Me(10′) and H(6′)
are deshielded. These findings are due to the progressive
increase of the number of molecules in the most stable
conformations (spg- and spg+, according to the order of
stability) characterized by the shielding of Me(8′) and Me(9′),
along with a decrease in the number of molecules in the least
stable conformation (ap), where Me(10′) and H(6′) are
shielded.
sive shielding of Me(10′) and H(6′) when lowering the
temperature, meanwhile Me(8′) and Me(9′) get deshielded.
This outcome can be explained on the basis of an increase
of the population of the most stable conformers (spg+ and
spg-, according to the order of stability), in which Me(10′)
and H(6′) are shielded, and a decrease of least stable
conformer (ap), that produces a shielding of Me(8′) and
Me(9′) by the MPA phenyl group. These latter signals are
deshielded due to disappearance of molecules in the ap
conformation.
In practice, a simplified procedure for assignment relies
on the interpretation of the NMR shifts as if the conforma-
tional equilibria were summarized in just a single conformer,
the same for both MPA esters. This conformer is character-
ized by a synperiplanar situation between the CN and the
CdO groups (Figure 2c), which causes the shielding on one
of the substituents (L1 or L2, depending on the configuration).
Therefore, L1 substituent is clearly shielded in the (R)-MPA
derivative, while L2 is shielded in the (S)-MPA ester. This
simplified and representative (NMR standpoint) conformation
can be used in practice to rationalize the assignment of the
absolute configuration of ketone cyanohydrins by means of
their MPA derivatives: the substituent that presents a negative
∆δRS should occupy the location of L1 in Figure 1b,
meanwhile the other substituent, with a positive ∆δRS, should
be located in that of L2.12
Attention was paid to the scope and limitations of the
method. The ∆δRS sign distributions in R-arylsubstituted
cyanohydrins 13-16 showed anomalies at the protons placed
at the ꢀ′ position (methyl groups in 13-15 and methylene in
16). In those cases, ∆δRS presented very small values and
The analysis of the spectrum of the (S)-MPA derivative
(Figure 3b) leads to similar conclusions. It shows a progres-
(12) The MPA esters of aldehyde cyanohydrins [L1CH(OH)CN] adopt
a different preferred conformation where the C-H and CdO bonds are
synperiplanar, similar to the preferred form of the MPA derivatives of
secondary alcohols, amines and thiols [L1CH(Z)L2, Z ) OH, NH2, SH]. In
those cases, the presence of the hydrogen atom (small size and slight bond
polarity) as substituent at the asymmetric carbon plays a major role in
determining the main conformers. In ketone cyanohydrins, the asymmetric
carbon is substituted by the CN group, L1 and L2. The equilibria are now
more complex and the most favorable conformers (spg+, spg-, Figure 2)
do not place any of those substituents synperiplanar to the CdO.
(8) Frisch, M. J.; et al. Gaussian03, revision E.01; Gaussian, Inc.:
Wallingford, CT, 2004. For full reference see Supporting Information.
(9) In the most stable conformers, the CN group is not shielded by the
Ph and probably this contributes to the phenomenon depicted in ref 7.
(10) Garc´ıa, R.; Seco, J. M.; Va´zquez, S. A.; Quin˜oa´, E.; Riguera, R. J.
Org. Chem. 2006, 71, 1119.
(11) Latypov, S. K.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem.
1995, 60, 504.
Org. Lett., Vol. 11, No. 1, 2009
55

unexpected signs (i.e., +0.03 ppm, 14). For every mentioned
case, the aromatic system exhibited large values and the
expected signs of ∆δRS according to the model explained
previously (i.e., +0.25 ppm, 14).
The experimental procedure that allows assigning the
absolute configuration of a ketone cyanohydrin by NMR
follows the steps that are applied to (E)-2-hydroxy-2-methyl-
4-phenylbut-3-enenitrile in Figure 4.13 Special attention has
In order to clarify these facts, theoretical calculations were
performed, taking compound 15 as model. They revealed a
similar conformational preference concerning the rotation
around CR-C(O) (MPA) and O-CR′ (cyanohydrin) bonds
as in previous studies: spg- and spg+ for (R)- and (S)-MPA
derivatives respectively (see Figure 35S and Table 2S in
Supporting Information).
Thus, CD analysis corroborated those conformational
preferences (see Figure 36S in Supporting Information). Also,
1
in low-temperature H NMR experiments performed with
the (S)-MPA derivative, a strong shielding effect was
observed for the substrate phenyl protons (see Figure 37S
in Supporting Information) as expected according to the
increase in the number of molecules that adopt the most
stable conformation (spg+). However, in an analogous set
of experiments carried out with the (R)-MPA ester, the
expected shielding of the methyl group (due to the increase
in population of conformer spg-) did not take place.
The studies revealed that the observed behavior is due to
a third conformational process related to the rotation around
Ph-CR′ bond at the cyanohydrin fragment that induces
additional anisotropic effects on the methyl group in
competition with those from MPA, and therefore resulting
in an unpredictable ∆δRS sign for that substituent. As
expected, increasing the distance between the aryl group and
the proton considered attenuates this overlapping effect, as
observed in compound 16, where the methyl group at γ′
presents the expected sign.
The remainder of the studied cyanohydrins possessing
aromatic rings behaves in agreement to the previous model,
presenting opposite ∆δRS signs for both L1/L2 substituents.
The phenyl groups of compounds 3, 9 and 10 are further
from the asymmetric carbon and from the ꢀ′-methyls. In
compounds 11 and 12, the phenyl groups cannot rotate freely,
and therefore, the third conformational process does not take
place. In summary, when dealing with R-arylsubstituted
cyanohydrins (such as 13-16) the diagnostic signals are those
from the aromatic systems, which present large ∆δRS values
and correct signs.
Figure 4. Steps to follow to assign the absolute configuration of
ketone cyanohydrins using 9 as example.
to be paid to R-arylsubstituted cyanohydrins, where only the
aryl signs must be considered for assignment purposes.
Acknowledgment. We thank Ministerio de Educacio´n y
Ciencia (CTQ2005-05296/BQU), Xunta de Galicia (PGIDIT-
06PXIB209029PR), Bruker Espan˜ola S.A., Centro de Su-
percomputacio´n de Galicia, Yamakawa Chemical Industry
Co. Ltd., and Prof. Vicente Gotor (Universidad de Oviedo)
for providing samples of some ketone precursors. I.L. thanks
MEC for a FPU fellowship.
Supporting Information Available: Experimental Sec-
1
tion, Computational Methods, Spectroscopic Data, H and
1
13C NMR Spectra, H NMR Assignments, Tables 1S-2S,
Figures 33S-37S, Cartesian Coordinates and Total Energies.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8023314
(13) (1) Preparation of the corresponding (R)- and (S)-MPA derivatives
1
(Figure 4a). (2) Recording of their NMR spectra and calculation of the
chemical shifts differences (∆δRS) for L1/L2 (Figure 4b). (3) Situate the
substituent that presents negative signs in the position of L1 according to
Figure 1b [Me(1′)], and the substituent that shows positive signs in that of
L2 [H(3′) and H(4′)] (Figure 4c).
56
Org. Lett., Vol. 11, No. 1, 2009