Most biologically active compounds including pharmaceuticals have chiral molecular structures with one or more stereogenic centers. The absolute configuration of pharmaceuticals is very important for biological activity. Generally one enantiomer has medicinal activity while the other enantiomer has no activity. In some cases the opposite enantiomer gives rise to adverse and harmful effects. For this reason it is of great significance to obtain enantiopure compounds and to develop chiral auxiliaries for the determination of their absolute configurations and enantiomeric excess.
Recently, Harada and co-workers have developed the MαNP acid method, which is useful for determining the absolute configuration of chiral alcohols and amines by the ¹H NMR anisotropy method.¹⁾ The MαNP acid moiety shows a strong anisotropy effect in ¹H NMR spectra, which enables one to determine the absolute configuration of chiral alcohols and amines. The following is an example of method applied to (+)-2-butanol. (+)-2-Butanol was allowed to react with (R)-(–)-MαNP and (S)-(+)-MαNP acid to yield (R)- and (S)-ester, respectively, whose ¹H NMR spectra were measured and all peaks were fully assigned. The Δδ values [Δδ = δ(R) - δ(S)] were determined for each proton, where δ(R) is the proton chemical shift of alcohol moiety of (R)-MαNP acid ester, and δ(S) is that of (S)-MαNP acid ester. The data are shown in Table 1.

According to the sector rule, when the MαNP ester group and methine proton of the secondary alcohol are fixed in the down/front and down/rear sides, respectively, as shown in Figure 1, protons with a positive Δδ value are placed on the right side and those with a negative Δδ value on the left side, leading to the conclusion that (+)-2-butanol has (S) absolute configuration.
Since the α-position of the carboxylic acid is fully substituted, the MαNP acid does not racemize. Futhermore, the naphthalene moiety has a strong anisotropy effect leading to larger Δδ values.

In addition, these diastereomers can be separated by HPLC with almost base-line separation on silica gel (hexane/EtOAc 20:1):α=1.15 and Rs=1.18. The MαNP acid has the ability to recognize the small difference between methyl and ethyl groups. It is well know that chiral discrimination between methyl and ethyl groups is the most difficult. Therefore, the MαNP acid would be a promising tool for enantioresolution.
Chiral DBD and NBD derivatives are also used as chiral derivatizing reagents for HPLC allowing for highly sensitive measurement of optical purity. Furthermore, Fujii and co-workers used 1-fluoro-2,4-dinitro-5-L-leucineamide as a chiral derivatizing reagent for amino acids. They have reported a non-empirical determination of the absolute configuration by HPLC.²⁾
The circular dichroic (CD) exciton chirality method has also been used for non-empirical assignments of absolute configurations on a wide variety of compounds. However, since exciton coupling requires two or more interacting chromophores in the same molecule, the method cannot be applied in a straightforward manner to molecules which have only a single site for derivatization. Recently, Nakanishi and co-workers reported that they have developed a bis-zinc porphyrin host to determine the absolute configuration of monoalcohols and monoamines.³⁾ A monoalcohol, e.g., (+)-isomenthol, is derivatized with 3-aminopropylglycine to generate a bidentate ligand as a guest, which is capable of forming the 1:1 host/guest complex with the chromophoric bis-zinc porphyrin host. At this time, the conformation of the two porphyrin moieties reflects the conformation of the ligand. The absolute configuration of (+)-isomenthol is determined from the observation of the interaction of excitons between these two porphyrin moieties.
As described above, excellent methods for the non-empirical determination of the absolute configuration and optical purity have been reported and put into use.

for NMR

for HPLC

for X-ray Crystallography

for Exciton Chirality CD Method

for NMR

M1339	M1103	B1720
M1104	B1721	C1021
D2176	D2459	A1657
N0713	D2460	D2175
A1658	N0714	N0482
P0794	M0831	I0334
B1143	I0336	T1520
M1366	P1219	M0830
D1852	D1853	B1161
B1144	I0398	T1521
M1367	P1220	M0829
N0481	P0793	M0832
I0335	B1343	C2184
M0662	M0661	S0473
S0474

for HPLC

A1657	N0713	A1658
N0714	I0334	A5565
A5566	I0336	M1366
A5561	A5568	A5563
A5577	I0398	M1367
A5560	A5569	A5562
A5578	I0335	A5564
A5567	A5524	D2259
A5523

for X-ray Crystallography

C1767	C1683	C1766
C1682

for Exciton Chirality CD Method

for Hydroxyl Groups

A1150	N0025	N0048
B0553	B0558	C0134
C0141	C0445	C1182
D0724	M0721	M0576
N0156	N0176	P0961
P1079	M1338	A0690
B0062	B0105	A0482

for Primary Amino Groups

N0530	D0645	D1495
D0648

for Monoalcohols, Monoamines

B2124	A1371	B1185
P1364