A R T I C L E S
Figure 1. Formation of the 1:1 complex between an N-γ-propylamide conjugate and tweezer molecule Zn-T and schematic representation of the possible
conformations adopted by the complex and the subsequent intraporphyrin helicity in accordance to the substituent’s relative steric size.
assignments of R-chiral carboxylic acids.6-8 This protocol
requires derivatization of the substrate with both enantiomers
of an auxiliary reagent.6 1H NMR of the two diastereomeric
derivatives are compared, and the shielding effect values (∆δRS)
for the protons neighboring the chiral center are measured. The
scope of Mosher-like methods has been extended further by an
approach described by Riguera,7 but in general, the required
amount of sample is restrictive since milligram quantities of
the substrate are needed. Moreover, in some cases, the ∆δRS
are small, and extensive conformational analysis may be required
to interpret the results.
The development of a general protocol that easily allows
stereochemical determination of R-chiral carboxylic acids is of
great interest since many members of this class exhibit important
biological activities.9 In the past few years, a microscale protocol
to determine the absolute configuration of diamines, amino
acids, and amino alcohols has been developed.10 More recently,
the method has also been extended to monofunctional substrates
such as primary and secondary amines11,12 and secondary
monoalcohols13,14 that are devoid of further derivatization sites.
This microscale method is based on a host/guest complexation
mechanism in which the chiral substrate, linked to an achiral
trifunctional molecule to yield a suitable bisfunctional derivative
(the conjugate), is complexed to a dimeric Zn-porphyrin
molecule Zn-T to form a macrocyclic host-guest complex
(Figure 1); therein, the bis-porphyrin host is forced into a chiral
arrangement, with the intraporphyrin twist controlled by the
stereochemistry of the guest molecule. Exciton coupling of
porphyrin Soret transitions,15,16 whose effective polarization is
directed along the 5,15 and 5′,15′ directions (Figure 1),16,17 leads
to CD couplets, the sign of which correlates with the absolute
configuration of the substrates. A double nitrogen/zinc coordina-
tion is responsible for the binding in all of these previously
described cases.10-14
We have recently presented a protocol for the determination
of carboxylic acids’ configuration based on derivatization of
the substrates as N-γ-aminopropyl amides and complexation
to a Zn-porphyrin host tweezer Zn-T (Figure 1).18 The first
ligation responsible for the formation of the host-guest com-
plex occurs between the primary amino group and the Zn ion
in porphyrin P-1 (Figure 1), in a manner similar to that in
previous cases;10-14,19 the second nucleophilic site that ligates
the Zn in porphyrin P-2 is the amide oxygen. This carbonyl
originates from the substrate carboxylic group, which was
converted to the amide functionality. The carbonyl group of
this amide and the amino group of the aminopropyl moiety
together (see Figure 1) serve as the two ligating points to the
Zn-T. Besides being more straightforward, this procedure has
the merit of simplifying the chemical handling for the syntheses
of the conjugate molecules.11-13 A similar chiroptical protocol
to answer the same stereochemical question has recently been
proposed by Yang et al.20
In agreement with the previously described trend,10-14,19 the
relative steric sizes21 of the substituents at chiral centers give
rise to stereodifferentiation in the complex. As depicted in Figure
1, in the most favored conformation I adopted by the complex
shown, the large group L lies outside of the complex core, and
this leads to porphyrin moieties adopting a preferential positive
twist resulting in a positive CD exciton couplet.16,17
Intense CD couplets with the expected signs were observed
for substrates carrying aryl or alkyl substituents;18 however,
additional data in Table 1, measured with the same procedure
as that in ref 18, show that if N, O, or halogens are present at
the chiral center, inconsistent results are obtained. Electronic
(6) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12,
2915-2925.
(7) Ferreiro, M. J.; Latypov, S. K.; Quinoa, E.; Riguera, R. J. Org. Chem.
2000, 65, 2658-2666.
(8) Nagai, Y.; Kusumi, T. Tetrahedron Lett. 1995, 36, 1853-1856. Kusumi,
T.; Yabuuchi, T.; Ooi, T. Chirality 1997, 9, 550-555. Tyrrell, E.; Tsang,
M. W. H.; Skinner, G. A.; Fawcett, J. Tetrahedron 1996, 52, 9841-9852.
Fukushi, Y.; Shigematsu, K.; Mizutani, J.; Tahara, S. Tetrahedron Lett.
1996, 37, 4737-4740. Ferreiro, M. J.; Latypov, S. K.; Quinoa, E.; Riguera,
R. Tetrahedron: Asymmetry 1997, 8, 1015-1018.
(9) Terauchi, T.; Asai, N.; Yonaga, M.; Kume, T.; Akaike, A.; Sugimoto, H.
Tetrahedron Lett. 2002, 43, 3625-3628. Loiodice, F.; Longo, A.; Bianco,
P.; Tortorella, V. Tetrahedron: Asymmetry 1995, 6, 1001-1011. Ferorelli,
S.; Franchini, C.; Loiodice, F.; Perrone, M. G.; Scilimati, A.; Sinicropi,
M. S.; Tortorella, P. Tetrahedron: Asymmetry 2001, 12, 12853-12862.
Wehn, P. M.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 12950-12951.
Yokoya, M.; Masubuchi, K.; Kitajima, M.; Takayama, H.; Aimi, N.
Heterocycles 2003, 59, 521-526. van Klink, J. W.; Barlow, A. J.; Perry,
N. B.; Weavers, R. T. Tetrahedron Lett. 1999, 40, 1409-1412. Zidorn,
C.; Sturm, S.; Dawson, J. W.; van Klink, J. W.; Stuppner, H.; Perry, N. B.
Phytochemistry 2002, 59, 293-304.
(15) Huang, X.; Nakanishi, K.; Berova, N. Chirality 2000, 12, 237-255.
(16) Pescitelli, G.; Gabriel, S.; Wang, Y.; Fleischhauer, J.; Woody, R. W.;
Berova, N. J. Am. Chem. Soc. 2003, 125, 7613-7628.
(17) Matile, S.; Berova, N.; Nakanishi, K.; Fleischhauer, J.; Woody, R. W. J.
Am. Chem. Soc. 1996, 118, 5198-5206.
(10) Huang, X.; Rickman, B. H.; Borhan, B.; Berova, N.; Nakanishi, K. J. Am.
Chem. Soc. 1998, 120, 6185-6186.
(11) Huang, X.; Fujioka, N.; Pescitelli, G.; Koehn, F. E.; Williamson, R. T.;
Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2002, 124, 10320-10335.
(12) Huang, X.; Borhan, B.; Rickman, B. H.; Nakanishi, K.; Berova, N. Chem.s
Eur. J. 2000, 6, 216-224.
(18) Proni, G.; Pescitelli, G.; Huang, X.; Quraishi, N. Q.; Nakanishi, K.; Berova,
N. Chem. Commun. 2002, 1590-1591.
(19) Huang, X.; Borhan, B. H.; Berova, N.; Nakanishi, K. J. Indian Chem. Soc.
1998, 75, 725-728.
(13) Kurtan, T.; Nesnas, N.; Li, Y.-Q.; Huang, X.; Nakanishi, K.; Berova, N. J.
Am. Chem. Soc. 2001, 123, 5962-5973.
(20) Yang, Q.; Olmsted, C.; Borhan, B. Org. Lett. 2002, 4, 3423-3426.
(21) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley:
New York, 1994. Winstein, S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77,
5562-5578.
(14) Kurtan, T.; Nesnas, N.; Li, Y.-Q.; Koehn, F. E.; Nakanishi, K.; Berova, N.
J. Am. Chem. Soc. 2001, 123, 5974-5982.
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