Sensing Remote Chirality: Stereochemical Determination of b-, g-, and d-Chiral Carboxylic Acids**

Determining the absolute stereochemisty of small molecules bearing remote nonfunctionalizable stereocenters is a challenging task. Presented is a solution in which appropriately substituted bis(porphyrin) tweezers are used. Complexation of a suitably derivatized b-, g-, or d-chiral carboxylic acid to the tweezer induces a predictable helicity of the bis(porphyrin), which is detected as a bisignate Cotton Effect (ECCD). The sign of the ECCD curve is correlated with the absolute stereochemistry of the substrate based on the derived working mnemonics in a predictable manner. Discoveries in enantioselective chemistry have outpaced the growth in methodologies for absolute stereochemical determination of asymmetric molecules. While conventional methods, such as nuclear magnetic resonance (NMR) spectroscopy and exciton coupled circular dichroism (ECCD), allow stereochemical characterization of chiral synthons, they are limited by the position of the stereocenter and are most often applicable to determining the chirality of carboxylic acids, amines, or alcohols bearing stereocenters at the site of functionality. Few reports address the determination of bchiral carboxylic acids or remote chirality, and among those, the scope of substrates is limited to carboxylic acids which bear either an aromatic moiety or a hydroxy or amino functionality at the stereocenter (the latter functionalities are used as handles for derivatization). Determining the absolute stereochemistry of b-substituted carboxylic acids in the absence of a chromophoric or a derivatizable site or more remote stereocenters remains a challenging task. We present herein a method for the absolute stereochemical determination of b-, g-, and d-chiral carboxylic acids by ECCD with the use of bulky porphyrin tweezers. Complexation of a chiral substrate (guest) with a zinc bis(porphyrin) tweezer (host) yields a conformationally rigid helical system, thus giving rise to exciton coupling (ECCD) between the two chromophores of the tweezer. The sign of the latter ECCD curve, detected as either a positive or a negative signal, reflects the chirality of the bound substrate and enables the direct assignment of the guestsÏ absolute stereochemistry by the use of mnemonics derived for that particular system. The subsequent correlation of the observed ECCD sign with the established geometry of the host–guest complex, which reflects the major ECCD-active conformation of the guest (i.e., mnemonic), enables a direct assignment of the guestsÏ absolute stereochemistry. The ECCD method has enabled the unambiguous absolute stereochemical assignment of a large number of substrates, such as alcohols, amines, diols, epoxides, and carboxylic acids, to name a few. We envisioned extending the use of porphyrin tweezers, which have been used successfully with a-substituted functionalities, for sensing remote stereocenters. Nonetheless, the conventional ZnTPP or ZnTPFP tweezers failed to yield observable ECCD spectra when complexed with guest molecules bearing chiral centers remote from the site of coordination with the host metalloporphyrin. We previously observed that the sensitivity of the tweezer can be modulated by the sterics of the porphyrins and the conformational flexibility of the linker. Based on the latter studies, and in pursuit of a molecular sensor for determining the absolute stereochemistry of stereogenic centers distal from the sites of binding, we synthesized the sterically demanding zinc 5-(4-carboxyphenyl)-10,50,20-tri-tert-butylphenyl porphyrin tweezers, ZnTBP-C5 (TBP5) and ZnTBPC3 (TBP3), which were derived from a pentanediol or propanediol linker, respectively. The 3,5-bis-tert-butyl-substituted phenyls of the ZnTBP tweezers (Figure 1) were expected to generate a more sterically sensitive binding cavity and facilitate steric interactions with remote stereocenters within the host–guest complex. Modelling studies of the ZnTPP and ZnTBP tweezer complexed with the carrier-derivatized (R)-(+)-citronellic acid 1, a representative substrate bearing a stereocenter at the b-carbon atom, were performed. It is noteworthy that substrate complexation to a bis(porphyrin) tweezer requires two sites of binding, and for carboxylic acids this binding is achieved with the use of a suitable carrier (here 1,4-phenylenediamine). Hence, 1 was modelled in the form represented in Table 1. The tweezer–amide complex was assembled by coordinating the amide carbonyl group and the free amine with the two porphyrins and the steric interactions within the complex were evaluated after geometry optimization (see the Supporting Information for details). The minimized structures revealed the potential for enhanced steric interactions within the ZnTBP tweezer, compared to the ZnTPP tweezer, as a result of the tert-butyl substituents which are directed into the binding pocket of the tweezer (Figure 1). A strong [*] Prof. Dr. B. Borhan Department of Chemistry, Michigan State University East-Lansing, MI 48824 (USA) E-mail: [email protected]