Highly enantioselective fluorescent recognition of amino acid derivatives by unsymmetrical salan sensors

Tetrahedron Letters 52 (2011) 4611–4614

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Highly enantioselective fluorescent recognition of amino acid derivatives by unsymmetrical salan sensors Xia Yang a, Kang Shen a, Xuechao Liu a, Chengjian Zhu a,b,⇑, Yixiang Cheng a,⇑ a b

State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China

a r t i c l e

i n f o

Article history: Received 12 May 2011 Revised 12 June 2011 Accepted 21 June 2011 Available online 28 June 2011 Keywords: Chiral recognition Fluorescent sensor Unsymmetrical salan Amino acids PET

a b s t r a c t Novel unsymmetrical salan fluorescent sensors 2a and 2b have been designed and synthesized. The chiral recognition of N-Boc-protected amino acids by 2a and 2b has been investigated. Sensor 2a possesses higher sensitivity and enantioselectivity than sensor 2b does. Job analysis and nonlinear regression results show that 2a can form a 1:1 stoichiometric complex with a N-Boc-protected amino acid. The obtained response selectivities and the association constants indicate that 2a is a highly enantioselective and sensitive fluorescent sensor toward N-Boc-protected amino acids. Ó 2011 Elsevier Ltd. All rights reserved.

Introduction Since chiral recognition is a fundamental process of nature and plays important roles in various fields of science and technology,1 many efforts have been devoted to the design, synthesis and application of artificial chiral receptors.2 Among them, the fluorescent sensors using optically active 1,10 -bi-2-naphthols (BINOLs) as building blocks are very attractive due to their high enantioselectivities and sensitivities which benefit from the BINOL’s integration of chirality and fluorescence property.3 Chiral salen, salan, and their corresponding complexes have been widely applied in asymmetric catalysis.4 Recent studies demonstrate that unsymmetrical chiral salen and salan ligands possess important advantages,5 and their corresponding metal complexes could exhibit better enantioselectivities for several asymmetric reactions compared with their symmetrical counter-parts.5e,5f Moreover, significant progress has been made on the organocatalysis using unsymmetrical substituted trans-cyclo-hexane-1,2-diamine (trans-DACH) derivatives as catalysts.6 Realizing that the unsymmetrical salan ligand might establish a unique asymmetric recognition site with a high extent of chiral induction and considering BINOL’s integration of chirality and fluorescence property, we designed and synthesized unsymmetrical salan 2 as chiral fluorescent sensors.

⇑ Corresponding authors. Tel.: +86 25 8359 4886; fax: +86 25 8331 7761. E-mail addresses: [email protected] (C. Zhu), [email protected] (Y. Cheng). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.06.084

Since amino acids and their derivatives are fundamental molecules of life and being implicated in different biomolecular processes,7 the chiral recognition of amino acids and their derivatives is significant and related research is prosperous in recent years.3d,8 Herein, the N-Boc-protected amino acids are chosen as sensing substrates and the chiral recognition of sensors 2 toward them has been investigated.

Results and discussion Synthesis and optical spectroscopic studies of sensors 2 Sensors 2 were obtained by one pot reactions of 39 with 4 in which the intermediate products 1 were directly reduced with NaBH4 in situ without separation (Scheme 1). As shown in Figure 1, the fluorescence spectra of 2a and 2b are different. Sensor 2b mainly shows the emission of monomers, whereas 2a exhibits dual emission and bears a peak at ca. 440 nm indicating the possible formation of excimers.3h The concentration effect on the UV–vis and fluorescence spectra of 2a and 2b were studied (see Figs. S1–S4 in supporting information). When concentration ranges from 1  107 to 3  105 mol/L, the UV–vis spectra of 2a and 2b in toluene obey the Lambert–Beers Law well. Whereas, the fluorescence intensities of 2a and 2b reach maxima as the concentrations increase to ca. 1  105 mol/L, and then decline, which suggests that the suitable concentration of sensors should preferably be below 1  105 mol/L to avoid the violation of Lambert–Beer Law.

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Scheme 1. Synthesis routes of sensors 2.

Figure 2. (a) Fluorescence spectra of 2a (1  106 mol/L in toluene, kex = 331 nm) with Boc-(D or L)-Phg (1  104 mol/L) and (b) the plots of (I/I0) versus the concentration of acids during the titration of 2a with Boc-(D or L)-Phg (kex=331 nm, kem = 368 nm).

Figure 1. Fluorescence spectra of 2a and 2b (1  106 mol/L in toluene, kex = 331 nm).

The CD spectra of 2a and 2b (Fig. S5) are proximately mirrorimaged to each other. 2b exhibits intense positive Cotton effects at 254 and 241 nm, whereas 2a appears opposite Cotton effects at the corresponding wavelengths. Based on the CD studies on the 1,10 -binaphthyl compounds,3h,10 it can be suggested that 2a and 2b have a cisoid conformation, that is, the dihedral angle of the binaphthyl units is smaller than 90° (Fig. S6). Enantioselective fluorescent recognition of 2 toward amino acids First we investigated the recognition of 2a and 2b toward enantiomers of Boc-Phenylglycine (Boc-Phg) (Fig. 2, S7). Both 2a and 2b exhibit enhanced fluorescence responses toward Boc-Phg, which could be ascribed to the protonation of N atoms near the BINOL group suppressing the photoinduced electron transfer (PET) quenching.11 D-Enantiomers result in more enhancement responses than L-enantiomers do. The maximal fluorescence enhancement ratios IDmax/I0 of 2a and 2b are 13.7 and 1.7, respectively, and corresponding IR/IS reach 4.7 and 1.3, indicating that 2a

Figure 3. Fluorescence enhancement of 2a (1  106 mol/L) in the presence of the enantiomeric mixture of Boc-Phg at 5  106 mol/L in toluene.(kex = 331 nm).

possesses much higher sensitivity and enantioselectivity than 2b does. These results also suggest that, for sensors composed of BINOL and trans-DACH units, the chirality combination (S;S,S)12 or (R;R,R) might lead to higher sensitivity and enantioselectivity in comparison with (R;S,S) or (S;R,R). Unfortunately, until now, only (R;S,S) or (S;R,R) sensors have been reported.3h To the best of our knowledge, 2a is the first synthesized (R;R,R) sensor. To ascertain whether the different fluorescence responses of sensor 2a toward two enantiomers of Boc-Phg arise from chiral recognition, sensor 2c, the enantiomer of 2a, was synthesized. The fluorescence responses of 2c toward D- and L-Boc-Phg appear

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Figure 4. Job plot of receptor 2a with Boc-D-Phg obtained by using the 1H NMR signal change (Dd = d  d0) of the (a) a-H of Boc-D-Phg and (b) b-H of 2a and in CDCl3/C6D6, V/ V = 10% (the total concentration of 2a+Boc-D-Phg was maintained at 4.1  103 mol/L).

Table 1 Association constants and enantioselectivity for sensor 2a toward N-Boc-protected amino acids

Hosts 2b

Guests Boc-Phg

Conformation D L

2a

Boc-Phg

D L

Boc-Ala

D L

Boc-Val

D L

Boc-Phe

D L

a b

Ka (mol/L) 5

(1.53 ± 0.38)  10 (1.50 ± 0.21)  105 (2.03 ± 0.24)  105 (4.53 ± 0.65)  104 (3.05 ± 0.51)  104 (1.98 ± 0.41)  104 (1.89 ± 0.34)  104 (0.83 ± 0.31)  104 (1.33 ± 0.17)  105 (5.31 ± 0.43)  104

rsb

KD/KL

DDG (kJ/mol)

1.02

0.05

1.29

4.48

3.72

14.31

1.54

1.07

3.01

2.27

2.03

3.00

2.50

2.27

4.40

Obtained by performing nonlinear fitting according to Eq. 1; in most cases the determination coefficients r2 >0.98. Response selectivity15 rs = (KDFD)/(KL/FL), FD or L represents maximum fluorescence enhancement by D or L-N-Boc-protected amino acids.

as the mirror images of those of 2a (Fig. S8), which confirms that the observed fluorescence responses are indeed due to the enantioselective recognition. The influence of the enantiomeric composition of Boc-D-Phg on the fluorescence intensity was investigated (Fig. 3). A fair linear relationship (R >0.99) between the fluorescence intensity and the percent of the Boc-D-Phg component is observed, which indicates that 2a can be effectively applied for the enantiomer composition determination.

The NMR studies of the interaction of 2a with Boc-D-Phg (Fig. S9) indicate that all the hydroxyl and amino groups of 2a are engaged in the recognition process and remarkably interact with Boc-D-Phg. The obtained Job plot13 (Fig. 4, S9) reveals that 2a forms a 1:1 complex with Boc-D-Phg.The recognition of 2a toward enantiomers of three other N-Boc-protected amino acids, Boc-Alanine (Boc-Ala), Boc-Valine (Boc-Val), and Boc-Phenylalanine (Boc-Phe) was also studied (Figs. S10–S12). Sensor 2a shows remarkably enantioselective fluorescence responses to these acids

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as well. Assuming the acids form 1:1 complexes with 2a, Eq. 1 is applicable for the determination of association constants11a,14

I ¼ I0 þ 2

ðIlim  I0 Þ 2C H

1  4C H þ C G þ þ K

2.

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi3  2 1  4C H C G 5 CH þ CG þ K

ð1Þ

where K is the association constant, I represents the fluorescence intensity, CH and CG are the concentration of host and guest, respectively. The calculation results are summarized in Table 1. In most cases, plot fits Eq. 1 well (r2 >0.98) indicating the formation of a 1:1 stoichiometric complex, which is consistent with the result of 1H NMR Job plot. The comparison of the results of Boc-Val and Boc-Ala indicates that the increase of bulk of alkyl groups in a position of N-Boc-protected amino acids is conducive to the increase of enantioselectivity, but will lead to the decrease of associations. The association constants and enantioselectivities for sensor 2a toward aryl acids are higher than those of alkyl acids, suggesting that the aryl groups of guests might be engaged in the association process. Lower enantioselectivities of 2a toward Boc-Phe than Boc-Phg can be ascribed to the flexibility of the methylene unit between the benzene ring and the a position of Boc-Phe.3h The most outstanding enantioselectivity is corresponding to Boc-Phg, where the KD/KL is up to 4.48, that is, DDG values 3.72 kJ/mol, which is even higher than those of macrocyclic ligands,8i,16 and the response selectivity is up to 14.31 indicating that high enantioselectivity has been achieved.

3.

4.

5.

6.

Conclusions 7.

The unsymmetrical salan fluorescent sensors 2a and 2b have been designed and synthesized. The comparison of the recognition responses of 2a and 2b reveals that (S;S,S) or (R;R,R) sensors might have higher sensitivity and enantioselectivity than (R;S,S) or (S;R,R) sensors do. The Job analysis and nonlinear regression results indicate that 2a can form a 1:1 stoichiometric complex with a N-Bocprotected amino acid. The obtained response selectivities and the association constants indicate that 2a is a highly enantioselective and sensitive fluorescent sensor toward N-Boc-protected amino acids.

8.

Acknowledgments We are very grateful for the support of this work from National Natural Science Foundation of China (20832001, 20972065, 21074054) and the National Basic Research Program of China (2007CB925103, 2010CB92330) for their financial support. The Fundamental Research Funds for the Central Universities (1082020502) is also acknowledged.

9. 10.

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