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

Abstract

Modified Mosher's method using a-methoxy-a-trifluoromethylphenylacetyl (MTPA) esters has been recognized as a useful and reliable method for determination of absolute configurations of secondary alcohols and primary amines. [1][2][3] The absolute configurations at such methine carbons could be determined by the regular arrangement: positive and negative chemical shift differences [Dd(d S Ϫd R )] of the protons can be found on the right and left sides of the MTPA plane, respectively. 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. In the 1 H-NMR spectra of the (ϩ)-(R)-MTPA esters, two 26-methylene protons of the 25S isomer were much closer [Dd(d low Ϫd high ) ca. 0.04] to each other than those (Dd ca. 0.14) of the 25R isomer, whereas in the (Ϫ)-(S)-MTPA esters, the mutual relation was reverse. During our studies on stereochemistry of marine natural products, [8][9][10][11][12] we have applied this method for primary alcohols with a branched methyl at C2, and proposed the absolute configurations at chiral centers attached to the methyl group. For example, the absolute configuration at C14 of amphidinolide T1 was elucidated on the basis of chemical shift differences and signal patterns of the geminal protons at C13 of (S)-and (R)-MTPA esters of the C13-C21 segment 10) (Fig. 1). The methylene protons of C13 for the (R)-MTPA ester were observed as separated double doublet signals at d H 4.03 and 4.26 (Dd 0.23), while those for the (S)-MTPA ester appeared at d H 4.09 and 4.12 (Dd 0.03), indicating that absolute configuration at C14 was R. However, this methodology has not been substantiated by examination of compounds with known stereochemistry. Recently, we have applied this method for a series of primary alcohols with a C2-branched methyl whose stereochemistry is known. In this paper we describe the scope and limitation of this methodology on the basis of the present results. Results and DiscussionA series of primary alcohols (1-14) with a methyl group (Chart 1), whose absolute configurations are known, were synthesized or obtained commercially, and they were converted into the corresponding (S )-and (R)-MTPA esters. Chemical shifts of the oxymethylene protons in the (S)-and (R)-MTPA esters of each alcohol in CDCl 3 were shown in Table 1 The absolute configurations of a series of primary alcohols possessing a branched methyl group at C2 position were examined o...

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

“…52 The absolute configuration of the 3-position in 1,3-dihydroxy ketones can be assigned on the basis of its MTPA derivative. In this case, it is possible to almost exclusively derivatize the primary hydroxyl group and use data from known compounds to assign the configuration of the unknown.…”

Stereochemical analysis of α1, a mating hormone of the phytopathogen Phytophthora

“…On the other hand, the major isomer of (S)-MTPA ester (S)-2 (64:36 ratio) indicated overlapping methylene signals both for H-1 (d 4.34, Dd = 0) and Table 1). 7 Since the opposite phenomenon was observed for the oxymethylene protons (H-16) of (R)-2 (Dd = 0.17) and (S)-2 (Dd = 0.03) (Table 1), the (15R)-configuration of a1 1 was determined.…”

Isolation and Absolute Configuration Determination of Aliphatic Sulfates as the Daphnia Kairomones Inducing Morphological Defense of a Phytoplankton

“…The mixture was allowed to stand at room temperature for 30 min, diluted with pyridine-d 5 (400 ml), and the 1 H-NMR spectrum was recorded. The spectrum showed complete formation of the (R)-MTPA ester (5) 6 Hz, H-7, Me-6).…”

“…Hydrolysis of 7 and 8 afforded 2(S)-and 2(R)-2, 7) respectively, the absolute configuration of which was confirmed by the MTPA method: (R)-MTPA ester (9) of 2(S)-2 shows an overlapped AB pattern of H 2 -1, while (R)-MTPA ester (10) of 2(R)-2 shows a well-separated AB pattern (Experimental). Interestingly, the 6 Hz, Me-6). These chemical shifts are the same with those of the methyl protons of (1R,2R)-2ACyclo-COOH ester of 6(S)-methyloctan-1-ol, 10) leading to the 6(S)-configuration of 3.…”

“…[3][4][5] The absolute stereochemistry at C-2 of 1 was determined by the 1 H-NMR analysis of (R)-a-methoxy-a-(trifluoromethy)phenylacetic acid (MTPA) ester of 2, a hydrolysis product. It has been established that, 6) in the 1 H-NMR of an MTPA ester of a 2(S)-methyl aliphatic alcohol, the chemical shift difference of the methylene protons at C1 (appearing as an ABX pattern) is larger in the (S)-MTPA ester than in the (R)-MTPA ester. The reverse holds true for a 2(R)-methyl alcohol.…”