Synthesis of Enantiopure 2-Aryl-2-methoxypropionic Acids and Determination of Their Absolute Configurations by X-Ray Crystallography SATOSHI SEKIGUCHI, 1 JUNPEI NAITO, 1 HIROMI TAJI, 1 YUSUKE KASAI, 1 AKINORI SUGIO, 1 SHUNSUKE KUWAHARA, 1 MASATAKA WATANABE, 1 AND NOBUYUKI HARADA 1,2 * 1 Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan 2 Department of Chemistry, Columbia University, New York, New York Dedicated to Professor Nina Berova on the occasion of her significant anniversary and her receiving the Chirality Medal 2007 ABSTRACT Racemic 2-aryl-2-methoxypropionic acids were enantioresolved by the use of (S)-()-phenylalaninol 4. For instance, racemic 2-methoxy-2-phenylpropionic acid (6)-7 was condensed with phenylalaninol (S)-()-4 yielding a diastereomeric mixture of amides, which was easily separated by HPLC on silica gel affording the first-eluted amide ()-13a and the second-eluted amide (þ)-13b: a ¼ 3.19, R s ¼ 3.49. The absolute configuration of amide ()-13a was determined to be (R;S) by X-ray crystallography by reference to the S configuration of the phenylalaninol moiety. Amide (R;S)-()-13a was converted to oxazoline (R;S)-()-14a, from which enantiopure 2-methoxy-2-phenylpro- pionic acid (R)-()-7 was recovered. Other 2-aryl-2-methoxypropionic acids, (R)-()-8, (R)-()-9,(R)-(þ)-10,(R)-()-11, and (R)-()-12, were similarly prepared in enantio- pure forms with the use of phenylalaninol (S)-()-4, and their absolute configurations were clearly determined by X-ray crystallography or by chemical correlation. Chirality 20:251–264, 2008. V V C 2007 Wiley-Liss, Inc. KEY WORDS: 2-methoxy-2-phenylpropionic acid; 2-aryl-2-methoxypropionic acids; phenylalaninol; diastereomeric amides; HPLC separation on silica gel; absolute configurations; X-ray crystallography; oxazolines INTRODUCTION The MaNP acid method 1–7 is very powerful for the prep- aration of enantiopure alcohols and the simultaneous determination of their absolute configurations by the 1 H NMR anisotropy effect. For example, racemic alcohol (6)- 2 is esterified with MaNP acid, 2-methoxy-2-(1-naphthyl)- propionic acid (R)-()-1 (Fig. 1a), yielding diastereomeric MaNP esters, which are easily separable by HPLC on silica gel. The 1 H NMR signals of the first-eluted ester (R;X)-3a and those of the second-eluted ester (R;X)-3b are assigned by 1 H- 1 H COSY, 13 C, HMQC, HMBC, and HSQC-TOCSY methods leading to the calculation of Dd values {Dd ¼ d(R;X)  d(S;X) ¼ d(R;X)  d(R;X) ¼ d(1st Fr.)  d(2nd Fr.)}, where R and S denote the absolute con- figurations of the MaNP acid parts, respectively, and X and X are those of the alcoholic parts of the first-eluted ester and the second-eluted ester, respectively. By apply- ing the MaNP sector rule, 1–7 the absolute configuration X of the first-eluted ester 3a can be determined. The solvoly- sis of the first-eluted ester (R;X)-3a yields enantiopure alcohol (X)-2 together with the recovery of MaNP acid (R)-()-1. From the second-eluted ester (R;X)-3b, enan- tiopure alcohol (X)-2 is obtained. MaNP acid 1 is thus useful for the preparation of enantiopure alcohols and the simultaneous determination of their absolute configura- tions as a chiral 1 H NMR anisotropy reagent (CAR) with resolving power. It should be noted that when MaNP acid (S)-(þ)-1 is used, Dd is defined as Dd ¼ d(R;X)– d(S;X) ¼ d(2nd Fr.) – d(1st Fr.). 1–7 To obtain enantiopure alcohol 2, it is necessary to use enantiopure MaNP acid 1. Recently we reported a large- scale preparation of enantiopure MaNP acid 1 by the use of (S)-()-phenylalaninol 4. 8 In this, racemic MaNP acid (6)-1 was condensed with amine (S)-()-4 yielding dia- stereomeric amides 5a and 5b (Fig. 1b). It was surprising to find that these diastereomeric amides were effectively separable by HPLC on silica gel with a large separation factor a ¼ 4.53. In addition, these amides have the advant- age of crystallizing as prisms, and the absolute configura- tion of the first-eluted amide ()-5a was determined to be R by X-ray crystallography by reference to the S absolute Contract grant sponsor: Japan Society for the Promotion of Science; Contract grant number: 16350069 Contract grant sponsors: Nissan Science Foundation, Mazda Foundation, Inamori Foundation *Correspondence to: Dr. Nobuyuki Harada, Department of Chemistry, Columbia University, 3000 Broadway, MC3114, New York, NY10027, USA. E-mail: nh2212@columbia.edu Received for publication 20 February 2007; Accepted 21 March 2007 DOI: 10.1002/chir.20416 Published online 8 June 2007 in Wiley InterScience (www.interscience.wiley.com). CHIRALITY 20:251–264 (2008) V V C 2007 Wiley-Liss, Inc.