Angewandte
Chemie
DOI: 10.1002/anie.201410371
Host–Guest Systems
Sensing Remote Chirality: Stereochemical Determination of b-, g-, and
d-Chiral Carboxylic Acids**
Marina Tanasova, Mercy Anyika, and Babak Borhan*
Abstract: Determining the absolute stereochemisty of small
molecules bearing remote nonfunctionalizable stereocenters is
a challenging task. Presented is a solution in which appropri-
ately substituted bis(porphyrin) tweezers are used. Complex-
ation of a suitably derivatized b-, g-, or d-chiral carboxylic acid
to the tweezer induces a predictable helicity of the bis(por-
phyrin), 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.
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 guestsꢀ absolute stereo-
chemistry by the use of mnemonics derived for that particular
system.[5] 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
guestsꢀ absolute stereochemistry. The ECCD method has
enabled the unambiguous absolute stereochemical assign-
ment of a large number of substrates, such as alcohols, amines,
diols, epoxides, and carboxylic acids, to name a few.[2f,g,5] We
envisioned extending the use of porphyrin tweezers, which
have been used successfully with a-substituted functionalities,
for sensing remote stereocenters. Nonetheless, the conven-
tional ZnTPP[6] or ZnTPFP tweezers[7] 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[8] and the
conformational flexibility of the linker.[6b] 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-butyl-
phenyl porphyrin tweezers, ZnTBP-C5 (TBP5) and ZnTBP-
C3 (TBP3), which were derived from a pentanediol or
propanediol linker, respectively. The 3,5-bis-tert-butyl-substi-
tuted phenyls of the ZnTBP tweezers (Figure 1) were
expected to generate a more sterically sensitive binding
cavity and facilitate steric interactions with remote stereo-
centers within the host–guest complex.
Modelling studies of the ZnTPP and ZnTBP tweezer
complexed with the carrier-derivatized[9] (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-phenyl-
enediamine). 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 struc-
tures 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
D
iscoveries in enantioselective chemistry have outpaced the
growth in methodologies for absolute stereochemical deter-
mination of asymmetric molecules. While conventional meth-
ods, such as nuclear magnetic resonance (NMR) spectrosco-
py[1] and exciton coupled circular dichroism (ECCD),[2] 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 b-
chiral carboxylic acids or remote chirality, and among those,
the scope of substrates is limited to carboxylic acids which
bear either an aromatic moiety[3] or a hydroxy or amino
functionality at the stereocenter[4] (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 determina-
tion 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
[*] Prof. Dr. B. Borhan
Department of Chemistry, Michigan State University
East-Lansing, MI 48824 (USA)
E-mail: babak@chemistry.msu.edu
Dr. M. Anyika
Department of Medicinal Chemistry, University of Kansas
1251 Wescoe Hall drive, Lawrence, KS 66045 (USA)
Prof. Dr. M. Tanasova
Department of Chemistry, Michigan Technological University
1400 Townsend Dr, Houghton, MI 49931 (USA)
[**] We are grateful to the NSF (CHE-1213759) for funding.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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