Derivatization, Complexation, and Absolute Configurational Assignment of Chiral Primary Amines: Application of Exciton-Coupled Circular Dichroism JING ZHANG, 1 ANDREA E. HOLMES, 1 AKANKSHA SHARMA, 1 NEIL R. BROOKS, 2 RANDY S. RARIG, 3 JON ZUBIETA, 3 AND JAMES W. CANARY 1 * 1 Department of Chemistry, New York University, New York, New York 2 Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 3 Center for Science and Technology, Syracuse University, Syracuse, New York ABSTRACT We report here a sensitive method for the determination of the absolute configurations of primary amines using exciton-coupled circular dichroism (ECCD). The method works on a microgram scale by derivatization of chiral amines with quinoline chromophores. Complexation of the chiral ligands with metal ion fixes the geometry of the chromophores, resulting in a twist that is governed by the asymmetric carbon configuration and steric environment of the amine. The absolute configurations of the primary amines can be interpreted from the couplets of the ECCD spectra of the de- rivatized complexes. Crystal structures, 2D NMR studies, and semiempirical calculations provide structural evidence for our model. Chirality 15:180–189, 2003. © 2003 Wiley-Liss, Inc. KEY WORDS: chirality; configurational assignment; chiral primary amines; exciton- coupled circular dichroism; metal complexation Assignment of absolute configurations of molecules re- quires the knowledge of the molecular structure and an observable signal that can be assigned to one of two pos- sible enantiomers. The Bijvoet method, a procedure that can be applied in conjunction with the X-ray crystallo- graphic structural determination of a compound, was the first available such method. 1 More recently, chiroptical spectroscopic techniques have been used to assign abso- lute configurations in systems where the molecular struc- ture is known. 2 Among the most useful of these is exciton- coupled circular dichroism (ECCD) because of its nonem- pirical nature. 3–7 This method requires spatial proximity of two chromophores in a chiral environment. Dipole–dipole interactions between the electric transition moments of the chromophores can lead to splitting of the excited states (exciton coupling), which generates Cotton effects of mu- tually opposite signs. Several methods have been developed that relate the configuration of an analyte to that of another compound whose configuration is known by an absolute method such as the Bijvoet method or ECCD. For chiral amines, NMR methods are the most widely used. 8–11 Chiral chromatography, 12–14 optical rotatory dispersion, 15,16 and kinetic 17 methods have also been employed. Induced CD (ICD) spectra have been found to give useful correla- tions in several systems, including complexes formed be- tween gadolinium porphyrinate and amino acids, 18 lan- thanide tris( -diketonates) and amino alcohols or diols, 19,20 dirhodium tetraacetate and 1,2-amino alcohols, 21 and [poly(4-cayboxylphenyl)acetylene] or [poly(bis(4- carboxyphenoxy)phosphazene)] and primary amines, sec- ondary amines, and amino alcohols. 22–24 Some of the ICD methods are related to the classic Pfeiffer effect. 25 ECCD is potentially more sensitive than ICD, 2 but re- quires two or more chromophores on the same molecule. Absolute configurations of difunctional amines have been determined by ECCD when two chromophores were added to the two functional groups, and methods for mono- amines without a second functional group were also devel- oped recently. Watanabe et al. 26 made use of bis(2,3- naphthalenedicarboximido) derivatives of chiral 1,2- diamines and resolved their chirality by ECCD. Gawronski et al. 27 used phthalimide on amino groups and benzoate on hydroxyl or carboxyl groups to analyze the absolute con- figurations of diamines, amino alcohols and amino acids. Lo et al. 28,29 used 7-diethylaminocoumarin-3-carboxylate as a chromophore attached on both functional groups of the same analyte, such as amino, hydroxyl, and carboxyl Contract grant sponsor: the Petroleum Research Fund, administered by the American Chemical Society. *Correspondence to: J.W. Canary, Department of Chemistry, New York University, New York, New York 10003. E-mail: james.canary@nyu.edu This article includes Supplementary Material available via the Internet at http://www.interscience.wiley.com/jpages/0899-0042/suppmat/15/ v15.180.html Received for publication 25 June 2002; Accepted 16 August 2002 Published online 6 January 2003 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/chir.10158 CHIRALITY 15:180–189 (2003) © 2003 Wiley-Liss, Inc.