MTPA Amides Research Articles

Characteristic conformation of Mosher's amide elucidated using the cambridge structural database.

Conformations of the crystalline 3,3,3-trifluoro-2-methoxy-2-phenylpropanamide derivatives (MTPA amides) deposited in the Cambridge Structural Database (CSD) were examined statistically as Racid-enantiomers. The majority of dihedral angles (48/58, ca. 83%) of the amide carbonyl groups and the trifluoromethyl groups ranged from –30° to 0° with an average angle θ1 of −13°. The other conformational properties were also clarified: (1) one of the fluorine atoms was antiperiplanar (ap) to the amide carbonyl group, forming a staggered conformation; (2) the MTPA amides prepared from primary amines showed a Z form in amide moieties; (3) in the case of the MTPA amide prepared from a primary amine possessing secondary alkyl groups (i.e., Mosher-type MTPA amide), the dihedral angles between the methine groups and the carbonyl groups were syn and indicative of a moderate conformational flexibility; (4) the phenyl plane was inclined from the O–Cchiral bond of the methoxy moiety with an average dihedral angle θ2 of +21°; (5) the methyl group of the methoxy moiety was ap to the ipso-carbon atom of the phenyl group.

Alkaloids and styryllactones from the leaves of Goniothalamus tamirensis

Three new compounds, goniotamirine (1), goniotamiric acid (2), and 3,5-demethoxypiperolide (3) were isolated from the leaves of Goniothalamus tamirensis (Annonaceae), together with sixteen known compounds, (−)-N-nornuciferine (4), (−)-norisocorydine (5), (−)-isocorydine (6), (−)-3-hydroxynornuceferine (7), (−)-O-methylisopiline (8), (−)-anonaine (9), (−)-roemerine (10), (−)-roemeroline (11), (−)-boldine (12), glaunine (13), liriodenine (14), 9-deoxygoniopypyrone (15), 8-epi-9-deoxygoniopypyrone (16), 8-epi-9-deoxygoniopypyrone acetate (17), goniodiol (18) and goniothalamin (19). The structures were established from spectral analysis, including mass spectrometry and 2D-NMR. The absolute configuration of 1 was determined from analysis of its MTPA amide derivatives. The cytotoxicity of all isolates was evaluated against KB cells. Only compound 4 (N-nornuciferine) showed a moderate activity with an IC50 value of 12μg/mL.

The use of MPA amide for the assignment of absolute configuration of a sterically hindered cyclic secondary amine by ‘mix and shake’ NMR method

We present here a new method using methoxyphenylacetic acid (MPA) as the chiral derivatizing agent (CDA) for the assignment of absolute configuration of cyclic secondary amines. The MPA amides were prepared using the purification-free 'mix and shake' method. A detailed conformational analysis for the two diastereomeric amides was conducted by 2D NMR experiments and molecular mechanics calculations. We have established that, in the most stable conformation of each syn rotamer of MPA amides, the H-alpha in the MPA moiety is oriented toward the bulky substituent group at the asymmetric carbon in the chiral amine, presumably to avoid steric and/or electrostatic interactions. The observed NMR data were correlated with the conformational model to allow unambiguous assignment of absolute configuration of secondary amines. The results demonstrate that the MPA can be used as a useful CDA in the case of sterically crowded cyclic secondary amines from which the MTPA amides are usually difficult to make.

Synthesis of (R)- and (S)-3,3,3-trifluoro-2-phenylpropanoyl isocyanates and their use as reactive analogues of Mosher's acid

The title compounds have been prepared from the respective 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acids (MTPA) by a three-step synthesis with MTPA chloride and MTPA amide as reaction intermediates. The requested compounds were obtained in high chemical yields without any change in optical purity during the preparation. To ascertain the usefulness of this auxiliary agent in the chiral analysis, isomeric 3,3,3-trifluoro-2-phenylpropanoyl isocyanates were subjected in NMR tubes to noncatalyzed reactions with 16 different commercially available chiral alcohols. The steric arrangement of all diastereomers prepared correlated well with their NMR spectral nonequivalence data (Deltadelta), thus demonstrating the regular sign distribution of Deltadelta of particular groups according to the devised molecular model. The usefulness of the novel derivatization is discussed.

ChemInform Abstract: Practical Method for Chemoselective Formation of MTPA Amide Derivatives from Amino Alcohols and Phenols.

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Choosing the Right Reagent for the Determination of the Absolute Configuration of Amines by NMR: MTPA or MPA?

Molecular mechanics, semiempirical (AM1), aromatic shielding effect calculations, and dynamic NMR experiments demonstrate that MTPA amides are constituted by three main conformers, sp, ap3, and ap1 due to restricted rotation around the Cα−CO and the Cα−Ph bonds. Unlike MTPA esters, where the three rotamers have almost identical populations, in MTPA amides rotamer sp is more populated than the other two and has a shielding rather than deshielding character. This produces larger ΔδRS values for MTPA amides than for MTPA esters. Therefore, inference of absolute configuration with this reagent should be correspondingly more reliable for amines than for alcohols. Assignment of absolute configuration of chiral primary α-substituted amines with MTPA gives similar ΔδRS values than with MPA. A graphical description of the aromatic magnetic field distribution in MTPA and MPA amides, and its use to correlate the average chemical shifts with the absolute configuration of the amine, is presented.

Practical Method for Chemoselective Formation of MTPA Amide Derivatives from Amino Alcohols and Phenols

Practical Method for Chemoselective Formation of MTPA Amide Derivatives from Amino Alcohols and Phenols

MTPA (Mosher) Amides of Cyclic Secondary Amines: Conformational Aspects and a Useful Method for Assignment of Amine Configuration

Mosher's MTPA (methoxy(trifluoromethyl)phenylacetyl) technology is a well-known tool used to determine the absolute configuration of chiral alcohols and primary amines. The technique now has been extended to include secondary amines. A number of MTPA amide derivatives have been prepared from cyclic amines. Both piperidines and pyrrolidines have been studied. A detailed discussion of the conformational issues associated with both amide bond rotation and ring flipping is presented. The observed 1H NMR chemical shifts are correlated into a model that allows unambiguous determination of absolute configuration of cyclic secondary amines. While the presence of amide rotamers must be accounted for in the analysis, this is a relatively straightforward process that follows from detailed evaluation of coupling constant data and is often aided by COSY. The exceptionally large Δδ values observed for these MTPA amides make this a valuable and reliable method for assigning amine configuration.

Applications of MTPA (Mosher) Amides of Secondary Amines: Assignment of Absolute Configuration in Chiral Cyclic Amines

Mosher's MTPA (methoxy(trifluoromethyl)phenylacetyl) technology is applied to the assignment of absolute configuration of several synthetic and natural chiral amines. The substrates are cyclic, secondary amines. The resulting amides usually contain significant populations of two rotamers, readily distinguished by 1H NMR spectroscopy. Thus, two complementary sets of Δδ values are obtained from a single analysis, thereby enhancing the power of the method. A strategy for the MTPA derivatization of (the N-methyl tertiary amine in) the tropane alkaloid, cocaine, is also described. The exceptionally large Δδ values observed for these MTPA amides make this a valuable and reliable method for assignment of amine configuration (even in some cases where only one diastereomeric MTPA amide is readily available).