Cross interaction between auxiliaries: The chirality of amino alcohols by NMR

Article abstract of DOI:10.1021/ol8008528

(Chemical Equation Presented) The absolute configuration of sec/prim- and prim/sec-1,2-amino alcohols is determined by comparison of the ¹H NMR chemical shifts of the auxiliary OMe or CαH groups at the corresponding bis-(R) and bis-(S)-MPA deri

Full text of DOI:10.1021/ol8008528

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2729-2732
Cross Interaction Between Auxiliaries:
The Chirality of Amino Alcohols by NMR
Victoria Leiro, Jose´ Manuel Seco, Emilio Quin˜oa´, and Ricardo Riguera*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica y Unidad de RMN de
Biomole´culas Asociada al CSIC, UniVersidad de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
ricardo@usc.es
Received April 14, 2008
ABSTRACT
1
The absolute configuration of sec/prim- and prim/sec-1,2-amino alcohols is determined by comparison of the H NMR chemical shifts of the
auxiliary OMe or CrH groups at the corresponding bis-(R) and bis-(S)-MPA derivatives. This is the first NMR method that allows the assignment
of absolute configuration without resorting to the shifts of hydrogens at the substrate and is based on the cross anisotropic interactions
between auxiliaries.
The use of NMR for the determination of the absolute
configuration of organic compounds in solution by deriva-
tization with auxiliary reagents is well established1 for
compounds having one derivatizable group (alcohols, amines,
carboxylic acids, cyanohydrins, thiols) or even two and three,
such as diols,2 triols,3 and some amino alcohols.4 In general,
the method consists on the derivatization of the chiral
substrate (unknown stereochemistry) with the two enanti-
omers of a chiral derivatizing agent [CDA, i.e., MPA:
2-methoxy-2-phenylacetic acid; 9-AMA: 2-(anthracen-9-yl)-
2-methoxyacetic acid; 2-NTBA 2-tert-butoxy-2-(2-
naphthyl)acetic acid...] followed by comparison of the NMR
spectra of the two resulting diastereomeric derivatives. The
assignment is based on the conformational composition and
different shielding/deshielding effects caused on L1/L2 sub-
stituents around the chiral center of the substrate by the
anisotropy generated by the auxiliary. The positive or
negative signs of the ∆δRS parameters on L1/L2 allow
inferring the absolute configuration.5
When the substrate is a polyfunctional compound, i.e.,
a diol with two asymmetric carbons, the same approach
works but one should have in mind two additional factors:
(a) the conformational composition around each one of
the derivatized groups, that may be different and (b) the
final chemical shifts and ∆δRS for L1/L2 result from the
combination of the aromatic effects of those two auxiliary
groups.2,4
* To whom correspondence should be addressed. Fax: +34 981591091.
(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.
(2) (a) Freire, F.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem.
2005, 70, 3778. (b) Freire, F.; Seco, J. M.; Quin˜oa´, E.; Riguera, R.
Chem.-Eur. J. 2005, 11, 5509. (c) Seco, J. M.; Martino, M.; Quin˜oa´, E.;
Riguera, R. Org. Lett. 2000, 2, 3261.
(3) Lallana, E.; Freire, F.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. Org.
Lett. 2006, 8, 4449.
(5) ∆δRS for a substituent is the difference between its chemical shift
in the (R)-CDA derivative minus its chemical shift in the (S)-CDA
derivative.
(4) Leiro, V.; Freire, F.; Quin˜oa´, E.; Riguera, R. Chem. Commun. 2005,
44, 5554.
10.1021/ol8008528 CCC: $40.75
Published on Web 06/04/2008
2008 American Chemical Society

In this communication, we present theoretical and experi-
mental evidence showing that the absolute configuration of
1,2-amino alcohols with secondary/primary and primary/
secondarystructures,6 (type 1 and 2 respectively, Figure 1)
Figure 1. Structures of (R)-MPA, sec/prim-, and prim/sec-1,2-amino
alcohols (1 and 2, respectively).
can be determined by comparison of the 1H NMR chemical
shifts of the auxiliary OMe or CRH groups at the corre-
sponding bis-(R) and bis-(S)-MPA derivatives, easily pre-
pared in a one-pot reaction.7
This constitutes the first case where the assignment of
configurations by NMR can be carried out by examination
of the auxiliary signals instead of those of the substrate due
to the cross anisotropic interactions between auxiliaries. An
additional merit is that the diagnostic signals are easily
identified singlets instead of the more complex signals due
to L1/L2 substituents.
Bis-(R) and bis-(S)-MPA derivatives of (S)-2-amino-
propan-1-ol (3) were selected as model compounds to
perform the conformational analysis8 of sec/prim-1,2-
amino alcohols with general structure 1 (Figure 1). Figure
2a shows the main processes and conformers (sp, ap) as
obtained from theoretical calculations9 (AM1, B3LYP),
dynamic and low-temperature NMR, selective deuteration,
and CD studies. Figure 2b-c shows the NMR significant
conformers10 and shielding effects for the bis-(R) and bis-
(S)-MPA derivatives of (S)-2-aminopropan-1-ol (3). These
Figure 2. (a) Generation of bis-MPA main conformers. Expected
shielding effect for bis-(R) and (S)-MPA derivatives of (S)-2-
aminopropan-1-ol (3) (b and c, respectively) and (S)-1-aminopropan-
2-ol (11) (d and e, respectively).
structures have a characteristic not present in any of the
polyfunctional substrates studied so far and that makes
this case special: in the bis-(R)-MPA derivative, the MPA
amide group shields the MPA ester moiety, whereas in
the bis-(S)-MPA derivative, the role between the two MPA
units is reversed and now the MPA amide unit is shielded
by the MPA ester.
A parallel situation takes place in the bis-MPA derivatives
of a prim/sec-1,2-amino alcohol with general structure 211
[i.e., (S)-1-aminopropan-2-ol (11), Figures 2d-e].
(6) The terms secondary/primary and primary/secondary refer only to
the carbons to which the amino/hydroxy groups are linked.
(7) The bis-MPA derivatives of amino alcohols 3-18 were prepared
(always introducing the two units of the auxiliary in a single reaction) by
treatment of the amino alcohol (1.0 equiv) with the corresponding (R) and
(S)-R-methoxy-R-phenylacetic acid (MPA; 2.2 equiv) in the presence of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 2.2
equiv) and DMAP (cat) in dry CH2Cl2, under a nitrogen atmosphere. The
reactions were stirred at rt for 3-8 h, followed by the usual purification
and isolation steps.
These results mean that in the bis-derivatives of 1,2-amino
alcohols of type 1 and 2, one of the MPA units is always
acting as “active reagent” and projecting its aromatic
shielding effect on the other MPA unit that therefore can be
considered as a “substrate”.
This “reagent-substrate” role of the two MPA units
exchanges both with the stereochemistries of the auxiliary
(the MPA unit acting as “reagent” in the bis-(R) is trans-
formed into the “substrate” in the bis-(S)-derivative of the
same amino alcohol) and with those of the amino alcohol
(for the same derivative, i.e., bis-(R)-MPA, the role of each
MPA unit is reversed with the absolute configuration of the
amino alcohol: the MPA unit acting as “reagent” in the (R)-
amino alcohol acts as “substrate” in the (S)-amino alcohol,
Figure 2). As a consequence, the chemical shifts of the
(8) See Supporting Information for conformational energy distribution
and a detailed conformer description.
(9) 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 98, revision A.7; Gaussian, Inc.:
Pittsburgh, PA, 1998.
(10) Only conformers generated by rotation around ω1 and ω2 bonds
[CR-CO, MPA] are of interest from the NMR point of view. They explain
the shielding effects and chemical shift differences experienced by CRH
and OMe MPA signals.
(11) The same conformational analysis (rotation around ω1-4 bonds,
AM1, B3LYP calculations, NMR and CD) performed on the bis-(R) and
(S)-MPA derivatives of (S)-1-aminopropan-2-ol leads to the same results.
See Supporting Information for detailed information.
2730
Org. Lett., Vol. 10, No. 13, 2008

signals due to the two MPA units sand particularly the easily
identified12 OMe and CRH singlets sshould reflect the
stereochemistry of the derivatives and, hence, the absolute
configuration of the aminoalcohol.
and MPA amide, respectively, when the NMR spectra are
compared (Figure 3a).
For its part, in the bis-MPA derivatives of (S)-1-amino-
propan-2-ol (11) (Figures 2d-e), OMe and CRH protons of
the MPA ester are more shielded in the bis-(R)-MPA
derivative (negative ∆δRS), while those of the MPA amide
are more shielded in the bis-(S)-MPA derivative (positive
∆δRS, Figure 3a).
Naturally, when the amino alcohols have the enantio-
meric structure, the opposite set of signs will be obtained
(Figure 3b).
Experimental demonstration of the rightness of these
predictions was obtained by comparison of the OMe and
CRH signals of the two MPA units in the bis-(R) and bis-
(S)-MPA derivatives of the series of amino alcohols of
known absolute configuration (3-18, Figure 4), belonging
to the structural types 1 and 2 and representing the (R) and
the (S) stereochemical possibilities. Table 1 shows the
experimental ∆δRS signs and values observed.
Figure 3.
∆δRS signs and ∆δR/∆δS ratios for sec/prim- and prim/
sec-1,2-amino alcohols.
Thus, the OMe and CRH protons of the MPA ester unit
are more shielded in the bis-(R) than in the bis-(S)-MPA
derivatives of (S)-2-aminopropan-1-ol (3) (Figure 2b), whereas
Table 1. ∆δRS, ∆δR, and ∆δS Values (ppm) for bis-MPA
Derivatives of Amino Alcohols 3-18
∆δRS CRH
∆δRS OMe
CRH
OMe
amino
alcohol ester amide ester amide ∆δR ∆δS ∆δR ∆δS
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
-0.12 +0.09 -0.06 +0.04 0.15 0.36 0.06 0.16
-0.13 +0.09 -0.08 +0.05 0.11 0.33 0.03 0.16
-0.11 +0.05 -0.05 +0.01 0.22 0.38 0.15 0.19
-0.11 +0.07 -0.06 +0.03 0.15 0.33 0.06 0.15
-0.19 +0.14 -0.09 +0.09 0.03 0.36 0.01 0.19
+0.12 -0.09 +0.06 -0.04 0.36 0.15 0.16 0.06
+0.19 -0.15 +0.08 -0.11 0.36 0.02 0.19 0.00
+0.15 -0.08 +0.07 -0.04 0.34 0.02 0.15 0.04
-0.04 +0.16 -0.02 +0.08 0.14 0.34 0.10 0.20
0.00 +0.18 -0.02 +0.10 0.15 0.33 0.08 0.20
+0.06 -0.20 -0.01 -0.11 0.44 0.18 0.20 0.10
+0.05 -0.20 -0.01 -0.10 0.43 0.18 0.19 0.10
+0.04 -0.20 -0.01 -0.11 0.41 0.17 0.19 0.09
+0.04 -0.16 +0.02 -0.08 0.34 0.14 0.20 0.10
0.00 -0.18 +0.02 -0.10 0.33 0.15 0.20 0.08
+0.08 -0.20 +0.03 -0.11 0.40 0.12 0.21 0.07
In this way, the absolute configuration of an amino alcohol
(structures 1 and 2), can be easily determined by preparation
of the bis-(R) and bis-(S)-MPA derivatives and comparison
of the ∆δRS signs for the OMe and CRH signals with those
in Figure 3.
In practice, it is not necessary to distinguish the signals
for the MPA ester and MPA amide units and calculate
the ∆δRS because the direct inspection of the separation
of the signals, in the bis-(R)-and the bis-(S)-MPA (∆δR
and ∆δS, respectively) is enough to establish the correla-
tion.13
Figure 4. Amino alcohols of type 1 and 2 employed in this study.
the OMe and CRH protons of the MPA amide are more
shielded in the bis-(S)- than in the bis-(R)-MPA derivatives
(Figure 2c). Consequently, negative and positive ∆δRS signs
will be obtained for the OMe and CRH of the MPA ester
(13) The separation between the two CRH signals (MPA ester/MPA
amide) in the bis-(R)-MPA derivatives is measured as ∆δR (absolute value,
ppm) and as ∆δS in the bis-(S)-MPA derivatives. The separation between
the OMe signals is calculated in the same manner.
(12) In all the substrates studied, the signals for the OMe and CRH of
the MPA ester unit are more deshielded than those due to the MPA amide
unit.
Org. Lett., Vol. 10, No. 13, 2008
2731

amino alcohols (type 1 or 2) with the absolute stereochem-
istry shown in Figure 2b and d, the CRH and OMe protons
of the MPA ester are more shielded than those of the MPA
amide, while in the bis-(S)-MPA derivatives, the CRH and
OMe protons of the MPA amide are more shielded than those
of the MPA ester. Thus, CRH and OMe singlets are less
separated in the bis-(R)-MPA derivative than in the bis-(S)-
MPA derivative (∆δR , ∆δS) as shown in Figures 5a and
b.
When the separation is greater in the bis-(R)-MPA
derivative than in the bis-(S)-MPA derivative (∆δR . ∆δS),
the amino alcohol has the enantiomeric spatial arrangement
and its absolute configuration is like those of Figures 5c and
d. Identical behavior and correlation between the separation
of the OMe and the CRH signals (∆δR, ∆δS) and the
stereochemistry was observed in all the amino alcohols
studied in this work (Figure 4 and Table 1).
This is the first NMR method that assigns configurations
without resorting to shifts from hydrogens at the substrate.
In some way, it resembles the exciton coupled CD14
approach: both describe how the mutual interaction between
auxiliaries (chromophores in CD, MPAs in NMR) allows
the determination of molecular chirality.
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2005-05296/BQU) and Xunta de Galicia
(PGIDIT06PXIB209029PR; PPIAI 2007/000028-0) for fi-
nancial support. V.L. thanks the MEC for a predoctoral FPU
fellowship. We are also grateful to the Centro de Super-
computacio´n de Galicia for their assistance with the com-
putational work, Yamakawa Chemical Industry Co. Ltd.
(Japan) for their gift of (R)- and (S)-MPA, and Bruker
Espan˜ola S.A. for its contribution as Observant Development
Entity (EPO).
Supporting Information Available: Conformational Analy-
1
sis; Experimental Section; Spectroscopic Data; H and 13C
NMR Spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
Figure 5. Partial H NMR spectra of bis-(R)- and bis-(S)-MPA
derivatives of sec/prim- and prim/sec-1,2- amino alcohols (a, c and
b, d, respectively).
OL8008528
(14) Nakanishi, K.; Berova, N.; Woody, R. W. Circular Dichroism;
Wiley-VCH, Inc.: New York, 2000.
In the bis-(R)-MPA derivatives of any of the two 1,2-
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Org. Lett., Vol. 10, No. 13, 2008