Assignment of the Absolute Configuration of β-Chiral Primary Alcohols by NMR:  Scope and Limitations

Abstract

The prediction of the absolute configuration of β-chiral primary alcohols from the 1H NMR spectra of their esters with (R)- and (S)-9-anthrylmethoxyacetic acids (9-AMA, 3) is discussed. Low-temperature NMR experiments, MM, semiempirical, ab initio, and aromatic shielding effect calculations allowed the identification of the main conformers and showed that, in all alcohols for which the calculated ΔE ag (CVff) is in the range of 0.7−1.5 kcal/mol, conformer a / a is the most stable. A simple model for the assignment of the absolute configuration from NMR data is presented and its reliability corroborated with alcohols (8−20) of known configuration. Nevertheless, cyclic alcohols 21−23 have much higher ΔE ag values (2.2−3.1 kcal/mol) due to their different conformational composition, and their absolute configuration cannot be reliably predicted by this method.

Application of Modified Mosher's Method for Primary Alcohols with a Methyl Group at C2 Position.

“…In the present study, we examined the relation between the absolute configuration and oxymethylene proton chemical shifts in the MTPA esters of simple primary alcohols (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) with a C2-branched methyl. Like the case of compounds 1-7, if the differences between Dd S and Dd R are relatively large (Ͼ0.10 ppm) they allow the assignment of the absolute configurations at the oxymethine carbons at C2.…”

“…Nevertheless, it is difficult to assign the absolute configurations of tertiary and primary alcohols since of the irregular arrangements of the Dd values. 1,4) Although attempts to assign the absolute stereochemistry of C2-chiral primary alcohols using its MTPA esters have been demonstrated, there is no conventional method applicable for a limited amount of natural products. 5) Minale and coworkers have applied a Mosher's method for determination of absolute stereochemistry of a methyl group at C25 of steroids with a primary hydroxyl group at C26, 6,7) and reported that the proton signals of the methylene (C26) attached to the ester linkage in the MTPA derivatives showed a unique split pattern as follows.…”

Pyrimidinone conjugates for the assignment of the absolute configuration of α-chiral carboxylic acids by 1H-NMR

“…Though several methods for asymmetric carboxylic acid preparations are highly reliable in effecting predictable stereochemical outcomes, each synthesis requires an independent confirmation of the product configuration and purity. Proton NMR, in particular, has been widely employed to provide dependable assignments for carboxylic acids, [3][4][5][6][7] alcohols, 8,9 and amines [10][11][12][13][14] covalently bound to chiral derivatizing agents (CDAs). In this report we describe the determination of the absolute configuration of chiral acids via proton NMR analysis of their conjugates with known dihydropyrimidinone 1.…”

“…A series of diastereomeric conjugates of 1 were prepared to examine the effect of carboxylic acid structure on the proton NMR shifts patterns ( Table 2). The analogs were designed to examine the influence of the size of the alkyl group (4 and 5), the presence of a heteroatom attached to the chiral center (6), and the size of the aryl group (7 and 8) or its absence (12)(13)(14). In addition, other samples were prepared to investigate combinations of structural influences (9) or commercially important applications (10 and 11).…”

Two New Phenylglycol Derivatives Isolated from Syringa reticulata var. mandshurica and Their Antifungal Activities

“…2). 5) Thus, the absolute stereochemistry of compound 2 was determined and was found to possess 2S configuration. The 2S configuration was confirmed by the fact that the specific optical rotation of compound 2 was ϩ38.5, whilst the specific optical rotation of (R)-phenyl-1,2-ethanediol was Ϫ58.0 under the same test condition.…”