determination of the absolute configuration of chiral amines.
Unlike MTPA and MPA, compound 3 has C2 symmetry, and
the carboxylic acid and aromatic groups are constrained
through a [1,3]dioxolane ring (Figure 1). Once the dicar-
boxylic acid is linked to 2 equiv of a primary amine substrate
through amide bonds, the dioxolane oxygen and amide
hydrogen atoms will be located in close proximity, and
intramolecular hydrogen bonds are expected to be formed
between these atoms.5,6 Both the cyclic structure and the
intramolecular interaction might help to reduce the confor-
mational flexibility of the amide molecule and, as a result,
to induce large ∆δ values.
Figure 2.
∆δRS values (δ(R,R) - δ(S,S)) of DPD amides (3a, R )
A-D) of chiral amines.
side of the amide plane, and the anisotropic shielding is
expected for the R1 substituent. In (S,S)-DPD amides, on
the other hand, it is the R2 substituent that is on the same
side with the aryl group, and therefore the R2 substituent is
under the shielding effect. As a result, the ∆δRS value should
be negative for the R1 substituent and positive for the R2
substituent. This analysis is in good agreement with the
experimental data shown in Figure 2.
Figure 1. Structures of MTPA, MPA, DPD, and DND reagents (R
) OH).
To test the utility of compound 3 as a CDA, we first
synthesized (R,R)- and (S,S)-2,2-diphenyl-[1,3]dioxolane-4,5-
dicarboxylic acid (DPD, 3a) starting from dimethyl L- and
D-tartrate, respectively; the dioxolane ring was constructed
through an acid-catalyzed condensation reaction with ben-
zophenone dimethylketal, and the resulting dimethyl ester
was hydrolyzed under basic conditions.7 The dicarboxylic
acid 3a was then coupled with 2 equiv of R-chiral primary
1
amines of known absolute configuration. The H NMR
signals were assigned by using COSY and NOESY spec-
troscopy, and the chemical shift values were compared
between the diastereomeric amides to obtain ∆δRS values
(Figure 2). Because of molecular symmetry, only one set of
NMR signals were observed from the amine substrate.
All the tested compounds showed the same trend in their
∆δRS values. If the structure of amine substrates is repre-
sented as in Figure 3a, the ∆δRS values of DPD amides are
always negative for the R1 substituent and always positive
for the R2 substituent. These consistent ∆δRS values could
be explained on the basis of the conformational analysis
summarized in Figure 3. In the representative conformation
of DPD amides, the CdO bond and the ajacent C-O bond
are depicted in an anti conformation because this arrange-
ment could be stabilized by the intramolecular interaction
between the amide hydrogen and dioxolane oxygen atoms.
In (R,R)-DPD amides, the aryl group of the CDA and the
R1 substituent of the amine substrate are located on the same
Figure 3. (a) Representative conformations of (R,R)- and (S,S)-3
amides. In the Newman projection, the amide bond is omitted for
clarity. (b) The calculated structure of the (S,S)-DPD amide of
isopropylamine: a side view (left) and a front view (right with depth
cues) onto the [1,3]dioxolane ring. Atoms are colored following
the CPK color code (C, gray; H, white; O, red; N, blue).
The conformation preference of DPD amides was inves-
tigated further by computational modeling studies.8 In the
lowest-energy structure of the (S,S)-DPD amide of isopro-
pylamine(Figure3b),the(H-CR)-(N-H)and(OdC)-(C-O)
(5) For an example of a CDA using the intramolecular hydrogen bond
included in a five-membered quasi-ring, see ref 3e.
(6) (a) The role of an intramolecular hydrogen bond in determination
of molecular conformation has been well considered.6b (b) The Hydrogen
Bond; Schuster, P., Zundel, G., Sandorfy, C., Eds.; North-Holand: Amster-
(8) Spartan’06 (Wavefunction, Inc.) was used for the calculation. A
Monte Carlo conformation search was performed by using the MMFF force
field to find the lowest-energy conformation, which was then used as an
initial structure for the ab initio geometry optimization (RHF/6-31G**).
No symmetry contraints were used in the calculations.
dam, 1976
.
(7) The detailed synthesis and chracterization are described in the
Supporting Information.
Org. Lett., Vol. 12, No. 4, 2010
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