FULL PAPER DOI: 10.1002/ejoc.200600856 Conformational Analysis of MαNP Esters, Powerful Chiral Resolution and 1 H NMR Anisotropy Tools – Aromatic Geometry and Solvent Effects on Δδ Values Yusuke Kasai, [a] Akinori Sugio, [a] Satoshi Sekiguchi, [a] Shunsuke Kuwahara, [a] Takatoshi Matsumoto, [a] Masataka Watanabe, [a] Akio Ichikawa, [b] and Nobuyuki Harada* [a][‡] Keywords: Conformational analysis / 1 H NMR anisotropy effect / MαNP and related esters / Chirality / Aromatic geometry and solvent effects The MαNP acid method is very powerful for the preparation of enantiopure alcohols by resolution and the simultaneous determination of their absolute configurations by the 1 H NMR anisotropy effect, where the syn-syn conformation is taken as the preferred conformation of MαNP esters. How- ever, the syn-syn conformation of MαNP esters looks un- stable, because two electronegative oxygen atoms (CH 3 O and C=O) are close to each other. To solve the problem of why the MαNP esters take such a syn-syn conformation, the aromatic geometry and solvent effects on the 1 H NMR anisot- ropy data were studied, leading to the following conclusions: i) the hydrogen-bonding-like interaction among the H-8' of the naphthyl group, the ester carbonyl oxygen, and the Introduction It is well known that in 1951, J.M. Bijvoet and co- workers first succeeded in determining the absolute config- uration of a chiral compound, sodium rubidium tartrate, using the anomalous dispersion effect of heavy atoms in X- ray crystallography. [1] Since then, the absolute configura- tions of many compounds containing heavy atoms have been determined by the Bijvoet method. Once the absolute configuration of a compound has been determined by the Bijvoet method, the compound can be used as an internal reference of absolute configuration in the X-ray crystal- lography of derivatives of the compound. In our opinion, this relative method with the internal reference in X-ray crystallography is the most reliable, because the absolute configuration in question is automatically determined from the stereoview provided by X-ray crystallography. In ad- [a] Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan [b] National Institute of Agrobiological Sciences, 1-2 Owashi, Tsukuba, Ibaragi 305-8634, Japan [‡] Present address: Nobuyuki Harada, Department of Chemistry, Columbia University, 3000 Broadway, MC3114, New York, NY 10027, USA Fax: +1-212-932-8273 E-mail: nh2212@columbia.edu Eur. J. Org. Chem. 2007, 1811–1826 © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1811 methoxy oxygen supports a triangular intramolecular force to stabilize the syn-syn conformation; ii) triangular hydrogen bonding among a hydrogen atom of protic solvents, the ester carbonyl oxygen, and the methoxy oxygen also supports the syn-syn conformation. This hydrogen bonding, as the sol- vation effect implies, suggests that a similar hydrogen bond- ing between a MαNP ester and a hydroxy group of the silica gel surface would make a dominant contribution to the excel- lent discrimination of diastereomeric MαNP esters observed in the HPLC on silica gel. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) dition, this method does not need derivatives containing so- called heavy atoms. For example, the absolute configura- tions of chiral C 60 fullerene cis-3 bisadducts were first estab- lished by a combination of this X-ray method and CD spec- troscopy. [2] For such internal reference compounds, we have developed the chiral auxiliaries of camphorsultam-phthalic (CSP) and camphorsultam-dichlorophthalic (CSDP) ac- ids, [3–5] which are very powerful for the enantioresolution of racemic alcohols and for the simultaneous determination of their absolute configurations by X-ray crystallography. However, X-ray crystallography has a disadvantage in that it needs single crystals suitable for X-ray diffraction experi- ments, while such single crystals are not always available. For non-crystalline compounds, the relative and empiri- cal 1 H NMR anisotropy method is useful. For such chiral 1 H NMR anisotropy reagents, many chiral acids have been developed for determining the absolute configurations of alcohols and other chiral compounds: α-methoxy-α-(tri- fluoromethyl)phenylacetic acid (MTPA), [6] 2-methoxy-2- phenylacetic acid (MPA), [7] 2-methoxy-2-(1-naphthyl)acetic acid (1NMA), 2-methoxy-2-(2-naphthyl)acetic acid (2NMA), 2-(9-anthryl)-2-methoxyacetic acid (9AMA), [8,9] α-cyano-α-fluoro-p-tolylacetic acid (CFTA), [10] and other acids. [11] By using these chiral anisotropy reagents, the abso- lute configurations of many chiral alcohols and natural