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Optimization of the Synthesis of Flavone−Amino Acid and Flavone− Dipeptide Hybrids via Buchwald−Hartwig Reaction Dávid Pajtás,† Krisztina Kónya,*,† Attila Kiss-Szikszai,† Petr Džubák,‡ Zoltán Pethő,§ Zoltán Varga,§ György Panyi,§ and Tamás Patonay†,∥ †

Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 5, 779 00 Olomouc, Czech Republic § Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary ‡

S Supporting Information *

ABSTRACT: The article describes the development of Buchwald−Hartwig amination of different bromoflavones with amino acid and peptide derivatives as nitrogen source giving unique structures. The previously observed racemization, which occurred during the synthesis of flavone-amino acid hybrids, was successfully prevented in most cases. The biological assays of these novel structures showed cytotoxic effects on different cancer cell lines.

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INTRODUCTION Amino-functionalized benzopyrane derivatives represent a very important class of the oxygen-containing heterocycles; in many cases, versatile remarkable biological activity was observed. Flavone and chromone alkaloids without direct links between the amine nitrogen and the aromatic/heteoaromatic ring are natural molecules, and their occurrence and chemistry are reviewed.1 Rohitukine, a chromone alkaloid isolated from Amoora rohituka and Disoxylum binectifarum, has cyclindependent kinase (CDK) inhibitory properties.2 Its semisynthetic analogue flavopiridol (Alvocidib, L86-8275, NSC 649890, HMR 1275) is an antineoplastic agent that inhibits kinases. Clinical trials (phases I and II) have also been started (Figure 1).3 Nitrogen-containing flavones and chromones where the nitrogen is directly linked to the aromatic sp2 carbon represent another important subclass. It is noteworthy that many aminoflavone derivatives belonging to this second subclass showed considerable kinase inhibitory, antiprolifer-

ative, or cytotoxic effects. Antibacterial,4,5 α-glucosidase,6 and tyrosine-kinase inhibitor7 properties were also reported. While 5- or 6-amino-4′-dimethylaminoflavones as well as 5,4′diaminoflavone showed considerable antiproliferative effect against MCF-7 breast cancer cell-line,8 4′-amino-6- or 7fluoroisoflavones have moderate antitumor effects against various cell lines.9 Aminoflavone-based peptide derivative NSC 710464 (AFP 464)10 is being considered as an anticancer prodrug. It is in Phase I clinical investigation and appears to be useful against solid tumors (Figure 1).11 However, the synthesis of aminoflavones and aminochromones suffers from limitations, especially in the case of derivatives linked by their amine substituents to ring A (Figure 1). The most common synthetic methods based on the Baker− Venkataraman rearrangement12 or the Claisen−Schmidt condensation.13 The main problems of these methods are the nonregioselective nitration of the corresponding acetophenone and the sensitivity of other substituents to the harsh conditions of a nitration process. An alternative way is the nitration and reduction of a previously formed flavone moiety, but these possibilities are also limited by the regioselectivity and reactivity patterns of the nitration step.7a,14 Synthesizing derivatives with alkyl/arylamino or disubstituted amino functions represents a much greater challenge than the

Figure 1. Biologically active chiral flavonoids.

Received: January 18, 2017 Published: April 25, 2017

© 2017 American Chemical Society

4578

DOI: 10.1021/acs.joc.7b00124 J. Org. Chem. 2017, 82, 4578−4587

Article

The Journal of Organic Chemistry Scheme 2. Synthesis of 9a−ea

formation of the amino group. Due to the lack of selectivity, direct alkylation leads to low yields.8,15 Reductive alkylation was also reported,16 and further information about the synthesis of different aminoflavones is available in our previous publication.17 In the last decades, Buchwald−Hartwig amination of halosubstituted aromatic/heteroaromatic systems became useful method for synthesizing alkyl- and arylamino-substituted arenes.18 Nevertheless, in the field of oxygen heterocycles, only sporadic examples have been published. For instances, the synthesis of 4′-aminoisoflavone started from a bromide,19 while 7-amino-5-hydroxyflavone was prepared from the corresponding triflate.20 Caddick et al. used the Buchwald−Hartwig reaction for the amination of bromo- or triflyloxy-substituted flavones under microwave activation but only hexylamine was used as nitrogen source.21

a

Reagents and conditions: 2 (1.0 equiv), amino acid ester 7a−e (1.2 equiv), Pd(OAc)2 (5 mol %), BINAP (7.5 mol %), Cs2CO3 (2.6 equiv), xylene, 135 °C, 24 h.

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explained by the so-called “halogen dance”28 theory (Scheme 2), which is known in the case of haloheteroaromatic molecules, followed by the coupling reaction, or the migration of the palladium might proceed to provide 9a. As previously found,17 7-haloflavones react more readily; therefore, the investigation was continued by using 7bromoflavone (2). Applying the same conditions (Scheme 2) as in the case of 6-bromoflavone (1), 7-bromoflavone (2) was reacted with various amino acid methyl ester hydrochlorides (7) and the expected 9a−e products were obtained mostly in moderate or good yield.17 In these cases, the formation of regioisomers of 6-substituted products has not been detected. An additional drawback of the coupling of L-amino acid esters under basic condition is their possible racemization. In our reactions, enantiomerically pure L-amino acid esters were used, and the chiral HPLC measurements revealed poor enantiomeric excess of the isolated 9a−e products. This fact can be attributed to the deprotonation−reprotonation sequence at the stereogenic center of the amino acid unit leading to racemization (Scheme 3).

RESULTS AND DISCUSSION Recently, our group published the results of the amination of 6and 7-bromoflavone (1, 2) with different type of primary and secondary amines and aniline derivatives17 (Scheme 1). According to the isolated yields, 7-bromoflavone (2) proved to be more reactive in Buchwald-Hartwig coupling and this phenomenon was explained by electronic factors.17 Scheme 1

Considering the outstanding biological activity of aminoflavones, we planned to extend the Buchwald−Hartwig reaction of haloflavones with carboxyl-protected amino acids and even peptide derivatives. According to the literature, only two examples have been published so far that provide such derivatives, but neither of them utilized the Buchwald−Hartwig (or Ullmann) type reaction. Georg et al.22 coupled 8-amino-4′chloro-5-hydroxyflavone with N-Boc-protected amino acids, while Lee and co-workers23 prepared a conjugate by the alkylation of the previously formed 6-aminoflavone with an αbromo-α-phenylacetic acid thioester. To the best of our knowledge, amino acids were rarely used as a nitrogen source, not just in flavone chemistry but in any type of Buchwald−Hartwig24−27 reaction. Since the flavone− amino acid hybrids would be unique structures with potential pharmacological activity, our investigations in the field of the Buchwald−Hartwig reaction of haloflavones have been continued. Although 6-bromoflavone (1) was previously successfully reacted with different amines,17 under these optimized conditions in the case of amino acid methyl esters the desired coupled product could not be obtained (Scheme 2). After a long optimization procedure, we found a condition set that afforded the corresponding flavone−amino acid derivative (8a) using L-phenylalanine methyl ester (7a) as nitrogen source, palladium(II) acetate as catalyst, and BINAP as phosphane. Moreover, the originally applied base sodium tertbutoxide was replaced with cesium(I) carbonate. However, the expected product 8a was obtained but only in marginal yield (5%). In addition, the regioisomer 9a was also isolated in a similar yield (6%). The formation of regioisomer 9a might be

Scheme 3

It is also known that in palladium catalysis the racemization of the α-chiral amines can occur through β-hydride elimination during the catalytic cycle. Therefore, it is important to promote fast reductive elimination and inhibit β-hydride elimination. This unfavorable elimination might be suppressed by the combination of palladium catalysts with bulky ligands.24−28 Regarding the possibility of latter biological/pharmaceutical usage of these molecules, the preparation of enantiomerically pure products would be a requirement. Therefore, we decided to carry out a wide optimization on the Buchwald−Hartwig amination of 7-bromoflavone (2) with L-phenylalanine methyl ester (7a) (Table 1) in order to find a condition that provides higher yield and better enantiomeric excess (Scheme 4) for the synthesis of flavone−amino acid hybrid molecules. Since usually the racemization of amino acids is due to the applied basic conditions, we considered that cesium carbonate 4579


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The Journal of Organic Chemistry

Table 1. Optimization Reaction of 7-Bromoflavone (2) with L-Phenylalanine Methyl Ester Hydrochloride (7a) Yielding Compound 9a entry

a

Pd(OAc)2 (mol %)

phopsphane (mol %)

1 2 3 4 5

5 5 5 5 5

BINAP BINAP BINAP BINAP BINAP

(7.5) (7.5) (7.5) (7.5) (7.5)

6 7 8 9 10

5 5 5 5 5

BINAP BINAP BINAP BINAP BINAP

(7.5) (7.5) (7.5) (7.5) (7.5)

11 12 13

5 5 5

BINAP (7.5) BINAP (7.5) BINAP (7.5)

14 15 16 17

10 15 10 10

BINAP BINAP BINAP BINAP

18 19 20 21 22 23b 24b

10 10 10 10 10 10 10

Xphos (15) Sphos (15) DavePhos (15) XantPhos (15) XantPhos (15) BINAP (15) XantPhos (15)

(15) (22.5) (15) (15)

base (2.6 equiv)

solvent

base optimization Cs2CO3 xylene MeCOONa xylene K3PO4 xylene KHCO3 xylene KHCO3 xylene solvent optimization K3PO4 DMF K3PO4 iBuCOMe K3PO4 NMP K3PO4 C6H5Cl K3PO4 C6H4Cl2 time, temperature optimization Cs2CO3 toluene Cs2CO3 xylene Cs2CO3 toluene catalyst, ligand optimization Cs2CO3 toluene Cs2CO3 toluene Cs2CO3 toluene Cs2CO3 toluene phosphane optimization Cs2CO3 toluene Cs2CO3 toluene Cs2CO3 toluene Cs2CO3 toluene Cs2CO3 toluene Cs2CO3 toluene Cs2CO3 toluene

T (°C)

time (h)

yielda (%)

ee

135 135 135 135 90

24 24 24 24 24

64 0 11 24 6.1

7.0

135 115 135 135 135

24 24 24 24 24

0 0 0 9.5 8.0

58 74

110 135 110

24 3 3

44 21 7.6

17 36 93

110 110 95 85

3 3 3 3

46 53 38 6.4

71 63 92 97

110 110 110 110 110 110 110

3 3 3 3 1 3 3

35 51 32 85 20 74 61

11 5.6 7 21 49 98 62

66 2.7 67

Yields refer to pure isolated products. bUsing L-leucine methyl ester hydrochloride (7b) yield in compound 9b.

enantiomeric excess; unfortunately, the yield was dropped to 8.0% compared to xylene. The study of the effect of the temperature and reaction time showed that higher temperature or longer reaction time increases the yield but also decreases the enantiomeric excess. Within 3 h at 110 °C, even 93% of enantiomeric excess was gained (Table 1, entries 11−13) but the yield was still low. Since long reaction time and high temperature favor the racemization, our goal was to perform the reaction at lower temperature and as fast as possible. For this reason, double amount of catalyst and phosphane were added to the reaction mixture, and after 3 h reaction time and at lower temperature (135 °C → 110 °C), larger conversion occurred while the enantiomeric excess slightly changed. Under these conditions, product 9a was isolated in 46% yield and with 71% of enantiomeric excess (Table 1, entries 14−17). By keeping the higher concentration of the catalyst and phosphane, the effect of the modification of the phosphane ligands was also studied at low temperature over a short reaction time (Table 1, entries 18−24). Most of the used phosphane resulted similar yields, except Xantphos, which provided the best yield (85%) in this optimization procedure. The large conversion may be explained by the bidentate structure of Xantphos, which can form a more stable palladium complex during the catalytic cycle. Unfortunately, in every case, the racemization proceeded rapidly and resulted in lower enantiomeric excess in the end (Table 1, entries 18−24). Using Xantphos instead of BINAP for 1 h led to less enantiomeric

Scheme 4

is responsible for this disadvantageous process. In order to exclude the racemization of the flavone−amino acid hybrids, we started to change the base source. In the case of potassium phosphate and potassium bicarbonate, low yields were achieved at 135 °C, but potassium−phosphate provided much better enantiomeric excess (Table 1, entries 3 and 4). Applying potassium bicarbonate at lower temperature resulted in an equally good enantiomeric excess as at higher temperature (Table 1, entries 4 and 5), but the yield was decreased. A possible explanation may be the decomposition of the bicarbonate to its carbonate derivative29 that occurs above 100 °C; therefore, it behaves as cesium carbonate. Assuming the low solubility of potassium phosphate and potassium bicarbonate in xylene, some phase-transfer catalysts (e.g., tetrabutylammonium bromide, tetrabutylphosphonium bromide, 18-crown-6) were added to the reaction mixture, but none or just marginal transformation was achieved with very poor enantiomeric excess. The application of potassium phosphate in some polar solvent was also attempted (Table 1, entries 6−10), and in 1,2dichlorobenzene the product 9a was provided with 74% 4580


Article

The Journal of Organic Chemistry Scheme 6a

excess than using BINAP for 3 h. It appeared that BINAP, which is also a bidentate phosphane, prevents the base-induced racemization. In order to examine this effect, another amino acid derivative, namely L-leucine methyl ester hydrochloride (7b), was reacted using BINAP and Xantphos under the same conditions (Table 1, entries 23 and 24). Although, in the case of L-leucine (7b), the rate of the racemization is slower due to the carbanion destabilization effect of the side chain, the difference between the measured enantiomeric excess of 9b is significant (using BINAP ee = 98%, using Xantphos ee = 62%). Furthermore, in the case of L-leucine (7b) the application of Xantphos provided 9b in lower yield. This astonishing experience prompted us to examine the path of the racemization and study the effect of BINAP. We took two well-characterized amounts of the isolated 9a with known enantiomeric excess (81% and 63%, respectively), and these were treated with the same equivalent of reagents exactly under the same reaction conditions except that the amino acid and 7-bromoflavone (2) were not added to the mixture (110 °C, 3 h, Scheme 5). The experiment showed that when both

a Key: (i) 2 (1.0 equiv), Pd(OAc)2 (10 mol %) BINAP (15 mol %), Cs2CO3 (2.6 equiv), 7a−k (1.2 equiv), dry toluene, N2 atm, 3 h, 110 °C; (ii) 2 (1.0 equiv), Pd(OAc)2 (10 mol %) BINAP (15 mol %), Cs2CO3 (2.6 equiv), 10a−c (1.2 equiv), dry toluene, N2 atm., 3 h, 110 °C.

Table 3. Reaction of 7-Bromoflavone (2) with Amino Acid and Peptide Esters

Scheme 5

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14

palladium catalyst and BINAP were present the change of the enantiomeric excess was only marginal (Table 2, entries 1 and Table 2. Investigation of Racemization Experiments of 9a entry

Pd(OAc)2

BINAP

Cs2CO3

starting ee

final ee

Δee

1 2 3 4 5

+

+

+ + + + +

81

77 35 36 12 61

4 46 45 51 2

+ +

+ +

63

a

amino acid ester·HCl L-Phe-OMe

(7a) (7b) L-Ala-OMe (7c) L-Met-OMe (7d) L-Asp-OMe (7e) L-Val-OMe (7f) L-Ile-OMe (7g) L-Pro-OMe (7h) L-Cys-OMe (7i) L-phenylglycine-OMe (7j) L-Ala-OtBu (7k) L-Phe-L-Leu-OMe (10a) L-Phe-L-Trp-OMe (10b) L-Phe-L-Ser-OMe (10c) L-Leu-OMe

9, 11

yielda (%)

9a 9b 9c 9d 9e 9f 9g 9h 9i 9j 9k 11a 11b 11c

46 74 59 36 17 41 80 23 0 28 35 75 53 0

ee 71 98 96 85 73 99 98 97 0.9 41 nd nd

Yields refer to pure isolated products.

In the case of cysteine (7i), no successful transformation was accomplished. The reaction mixture also had strong hydrogen sulfide smell presuming the decomposition of the amino acid derivatives. The cross-coupling reaction was also carried out with L-alanine tert-butyl ester (7k), but the conversion occurred in lower yield with less enantiomeric excess compared to Lalanine methyl ester (7c) probably due to the steric hindrance of the tert-butyl group. The reaction was also extended to dipeptide derivatives 10a− c; in some cases, the product was isolated in good yield, but in the case of L-phenylalanyl-L-serine methyl ester (10c) the reaction did not show any conversion. We presume the protic hydroxyl group restrains the successful coupling in the case of 10c. In many cases, black solid material was observed on the side of the round-bottom flask, indicating the formation of some coagulated catalyst. The solubility of cesium carbonate is also low in toluene, so most of the base is in the solid phase, giving a heterogenic mixture. During the reaction, the solid powder settles on the side of the flask while the solution is stirred. This may allow the solid material to overheat, causing coagulation of the catalyst, and in our opinion, this is a serious drawback for the efficiency of the palladium catalyst. To prove our hypothesis, the

5). If only base or base with the catalyst was present, the racemization was significant (Table 2, entries 2 and 3). A similar observation was that when the base and BINAP without the catalyst were present (Table 2, entry 4) the ee difference was also large. The outcome of these experiments showed that both BINAP and palladium catalyst must be present to prevent the racemization of the flavone−amino acid hybrid. According to these optimization processes, the best experimental condition appears to utilizing 10 mol % palladium(II) acetate, 15 mol % of BINAP as phosphane, and 1.2 equiv of amino acid methyl ester in toluene at 110 °C for 3 h (9a yield: 46%, ee: 71%, 9b yield: 74%, ee: 98%, Table 1). As we think, the higher palladium amount facilitates a quicker reaction and the lower temperature decelerates the racemization. The Buchwald−Hartwig reaction of 7-bromoflavone (2) has been extended to other protected amino acid methyl esters (7c−j), and under these optimized conditions (Scheme 6, Table 3) 9c−j were isolated in moderate to high yields with high or excellent enantiomeric excess (Table 3). The increase of the carbanion-stabilizing effect of the side chains resulted in a decrease in the enantiomeric excess (Table 1, entries 1, 2, and 10). 4581


Article

The Journal of Organic Chemistry reactions were repeated under the same conditions but using a pressure tube instead of a round-bottom flask. The vertical wall of the pressure tube does not allow the solid phase to stop moving, thus avoiding the coagulation of the catalyst. In many cases, the isolated yields were increased while approximately the same enantiomeric excess was achieved (e.g., Table 4, entries 1 and 4).

Scheme 7

Table 4. Compared Yields Using Round-Bottom Flask and Pressure Tube in round-bottom flask entry 1 2 3 4 5 6 7 8 9 10 11 12 a

amino acid ester·HCl L-Phe-OMe

(7a) L-Leu-OMe (7b) L-Ala-OMe (7c) L-Met-OMe (7d) L-Asp-OMe (7e) L-Val-OMe (7f) L-Pro-OMe (7h) L-Phenylglycine-OMe (7j) L-Arg-OMe (7l) L-Lys-OMe (7m) L-Ala-OtBu (7k) L-Phe OtBu (7n)

trend. The aqueous solution of the formed salt was acidified with potassium bisulfate solution to afford carboxylic acids 12a−c in good yield. L-Alanine tert-butyl ester was reacted under classical peptide synthesis conditions to give the targeted products 13a−c in good yields (Scheme 7, Table 5). Under

in pressure tube

9

yielda (%)

ee

yielda (%)

ee

9a 9b 9c 9d 9e 9f 9h 9j

46 74 59 36 17 41 23 28

71 98 96 85 73 99 97 0.9

74 66 65 75 30 37 26 59

75 93 86 87 56 98 96 0.5

9l 9m 9k 9n

nd nd 35 nd

nd nd 41 nd

0 0 73 78

36 11

Table 5. Synthesis of Flavone−Dipeptide Hybrids 13 by Peptide Synthesis entry

9

ee of 9

1 2 3

9b 9d 9f

93 74 97

a

12

time of hydrolysis (h)

yield of 12a (%)

ee of 12

13

yield of 13a (%)

12a 12b 12c

2.5 1 3.5

83 79 73

82 46 81

13a 13b 13c

72 75 55


these conditions, the second stereogenic center retained its enantiomeric purity, leading us to only two diastereomers of 13a−c. The diastereomer excesses of the isolated products must be the same as the measured enantiomeric excess of the starting carboxylic acid, which can be increased by simple chromatography or recrystallization. We also tried to deprotect the flavone−amino acid tert-butyl ester instead of the methyl ester. The deprotection of the carboxylic acid was performed in acidic media, avoiding further racemization. The deprotected 14 molecule was reacted with Lserine methyl ester (7o) using a classic peptide synthesis method providing the flavone−peptide structure 15 in good yield (Scheme 8).


As a next step, the Buchwald−Hartwig reaction was extended to L-phenylalanine tert-butyl ester (7n) to provide 9n in very good yield as well. In the case of the methyl esters 7a,c, the enantiomeric excesses were much higher compared to the corresponding tert-butyl esters 7k,n. This may be explained by the greater steric hindrance of the bulky tert-butyl group, preventing the enantiomeric excess conservation effect of BINAP. Methyl esters of L-arginine (7l) and L-lysine (7m) were also tested under these optimized conditions, but besides flavone, which is the dehalogenated substrate, no other new compound was observed in the reaction mixture. Afterward, our attention was focused again on the synthesis of flavone dipeptide hybrids since these compounds represent new and pharmacologically potentially interesting derivatives of flavones. As we have already shown (Scheme 6, Table 3, entries 12 and 13), the synthesis of these unique compounds is possible directly from 7-bromoflavone (2) using protected dipeptides as a nitrogen source, but both stereogenic centers might go through racemization leading to a diastereomeric mixture. Furthermore, many amino acids have in the side chain protic functional groups (e.g., cysteine, serine, tyrosine, etc.) that could inhibit successful coupling. These amino acids must be protected before further application. These problems prompted us to examine different methods for synthesizing flavone−dipeptide structures. Three flavone− amino acid hybrids (9b,d,f) were prepared in a larger amount and then deprotected by basic hydrolysis in a dichloromethane−methanol mixture (Scheme 7). These reactions were monitored by thin-layer chromatography up to full conversion. The alkaline conditions caused more or less racemization where the rate is commensurable to the carbanion-stabilizing effect of the side chains and follows the previously observed

Scheme 8

Biological Activities. The antimicrobial and cytotoxic properties of the prepared compounds were evaluated in vitro. None of the tested compounds exhibited potent antimicrobial activity against (>200 μM) all the Gram-positive and Gramnegative bacteria tested. The tested compounds also have not showed antifungal activities (>200 μM). Cytotoxic Activity. The synthesized compounds were screened against cancer cell lines in vitro conditions for their cytotoxic activity: CCRF-CEM (T-lymphoblastic leukemia), CEM-DNR (T-lymphoblastic leukemia, daunorubicin resistant), K562 (acute myeloid leukemia) and K562-TAX (acute 4582


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The Journal of Organic Chemistry myeloid leukemia, paclitaxel resistant), A549 (human lung adenocarcinoma), HCT116 (human colorectal cancer), HCT116p53−/− (human colorectal cancer, p53 deficient), U2OS (human osteosarcoma), and two human noncancer fibroblast lines (BJ, MRC-5). Compound 11b showed less than 30 μM activities against most of the tested cell lines (see Table S1). It is worth noting that compound 12c was cytotoxic in 9.2 μM against CCRF-CEM (T-lymphoblastic leukemia). Glioblastoma is the most common primary brain tumor (U87) with the most dismal prognosis. It is characterized by extensive invasion, migration, and angiogenesis. Median survival is only 15 months due to this behavior, rendering focal surgical resection ineffective and adequate radiotherapy impossible. It must be highlighted that among the examined compounds 11a showed 95% killing rate in U87 cells lines (see Table S2).

7-{[2-Phenyl-1-(methoxycarbonyl)ethyl]amino}flavone (9a). 194 mg (74%), ee = 75%. Mp: 171.5−173.5 °C. Eluent: toluene/ethyl acetate = 2:1. 1H NMR (CDCl3) δ: 8.00 (d, J = 8.6 Hz, 1H, 5-H), 7.87 (m, 2H, 2′,6′-H), 7.50 (m, 3H, 3′,5′-H, 4′-H), 7.29 (m, 3H, 3‴,5‴-H, 4‴-H), 7.15 (m, 2H, 2‴,6‴-H), 6.70 (s, 1H, 3-H), 6.64 (dd, J = 1.8, 8.6 Hz 1H, 6-H), 6.53 (d, J = 2.2 Hz, 1H, 8-H), 4.93 (d, J = 7.9 Hz, 1H, NH), 4.49 (m, 1H, 1″-H), 3.75 (s, 3H, OCH3), 3.22 (m, 2H, 2″-H). 13 C NMR (CDCl3) δ: 177.6 (C-4), 172.4 (COOMe), 162.3 (C-2), 158.5 (C-8a), 151.1 (C-7), 135.5 (C-1‴), 132.1 (C-1′), 131.1 (C-4′), 129.2 (C-3‴,5‴), 128.9 (C-2‴,6‴), 128.7 (C-3′,5′), 127.3 (C-5), 127.0 (C-4‴), 126.0 (C-2′,6′), 115.3 (C-4a), 113.1 (C-6), 107.4 (C3), 97.7 (C-8), 56.9 (C-1″), 52.4 (OCH3), 38.1 (C-2″). IR (KBr) ν/ cm−1 3396, 3265, 3152, 3065, 3028, 2948, 1726, 1624, 1593, 1538, 1507, 1448, 1436, 1370, 1249, 1191, 1148, 906, 822, 766, 699. MS: 399 [M•+], 340, 308 (100), 248, 221, 165, 91. Anal. Calcd for C25H21NO4: C, 75.17; H, 5.30; N, 3.51. Found: C, 75.21; H, 5.32; N, 3.52.

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CONCLUSIONS In conclusion, we have demonstrated the Buchwald−Hartwig amination of bromoflavones using amino acid esters as nitrogen source to afford unique flavone−amino acid hybrid molecules. At the beginning of the study racemization of the stereogenic center occurred, but after an extensive screening of the reaction parameters we have found a way to preserve the configuration of the products. Under these new conditions, various amino acids were successfully coupled, providing our hybrid derivatives in higher yields and considerable enantiomeric excesses. Furthermore, the C−N bond formation was also extended to different peptide esters to give flavone−peptide hybrid molecules. The synthesis of these unique derivatives was also demonstrated by the deprotection of flavone−amino acid hybrids followed by classical peptide synthesis. The biological assays exhibited that these special structures are promising cytotoxic compounds on different cell lines.

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7-{[3-Methyl-1-(methoxycarbonyl)butyl]amino}flavone (9b). 159 mg (66%), ee = 93%. Mp: 152−156 °C. Eluent: toluene/ethyl acetate = 2:1. 1H NMR (CDCl3) δ: 8.01 (d, J = 8.6 Hz, 1H, 5-H), 7.89 (m, 2H, 2′,6′-H), 7.50 (m, 3H, 3′,5′-H, 4′-H), 6.71 (s, 1H, 3-H), 6.68 (dd, J = 2.1, 8.6 Hz, 1H, 6-H), 6.56 (d, 1H, J = 2.1 Hz, 8-H), 4.80 (d, J = 8.6 Hz, 1H, NH), 4.21 (m, 1H, 1″-H), 3.77 (s, 3H, OCH3), 1.78 (m, 3H, 2″,3″-H), 1.02 (d, J = 6.5 Hz, 3H, 4″a-H,), 0.97 (d, J = 6.1 Hz, 3H, 4″b-H). 13C NMR (CDCl3) δ: 177.7 (C-4), 173.9 (COOMe), 162.4 (C-2), 158.5 (C-8a), 151.8 (C-7), 132.0 (C-1′), 131.1 (C-4′), 128.9 (C-3′,5′), 127.0 (C-5), 126.1 (C-2′,6′), 115.5 (C-4a), 113.1 (C-6), 107.4 (C-3), 97.5 (C-8), 54.6 (OCH3), 52.4 (C-1″), 41.8 (C-2″), 24.9 (C-3″), 22.7 (C-4″a), 22.1 C-4″b). IR (KBr) ν/cm−1 3289, 3153, 3087, 2953, 1724, 1620, 1589, 1566, 1534, 1449, 1373, 1250, 1190, 1149, 1000, 9008, 824, 768, 686, 673. MS: 365 [M•+], 306 (100), 250, 91. Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.35; H, 6.36; N, 3.84.

EXPERIMENTAL SECTION

Column chromatography was performed on silica gel (Merck 60, 70− 230 mesh). Thin-layer chromatography was performed on aluminumbacked TLC plates of silica gel 60 F254 (Merck, 0.2 mm). The chiral HPLC was performed on a Chiralpack IB or Chiralpak IC column (250 × 4.6 mm, analytical column, Daicel Chemical Industries, Ltd.) with a JASCO HPLC system: JASCO PU-980 HPLC Pump, JASCO MD-910 multiwavelength detector. The purity of the compounds was established by GC-MS (Agilent 7890, Agilent 5975 MS detector) with positive EI at 70 eV. NMR spectra were recorded on a Bruker AM 360 (360.13 MHz for 1H, 90.03 MHz for 13C) spectrometer. Chemical shifts (δ) are given from internal CHCl3 (δ = 7.26 ppm) or TMS (δ = 0.00 ppm) signals for 1H NMR and CHCl3 (δ = 77.00 ppm) or DMSO (δ = 39.52 ppm) for 13C NMR. Melting point data were determined by using Büchi B-540 equipment. Elemental analyses (C, H) were conducted using the Elementar Vario MicroCube instrument. IR spectra were measured in KBr disc with JASCO FT-IR 4100A equipment. 6-Bromoflavone (1),30 7-bromoflavone (2),30 and amino acid methyl ester hydrochlorides31 were synthesized according to literature procedures. General Method for Coupling 7-Bromoflavone (2) with the Hydrochlorides of Carboxyl-Protected Amino Acids and Peptides. To a mixture of 7-bromoflavone (2) (200 mg, 0.66 mmol), cesium carbonate (557 mg, 1.71 mmol), BINAP (64 mg, 0.10 mmol), and amino acid ester hydrochloride (0.80 mmol) in dry toluene (6 mL) was added Pd(OAc)2 (14 mg, 0.064 mmol) in an oven-dried flask or pressure tube under nitrogen. The reaction mixture was stirred and refluxed at 110 °C for 3 h in oil bath. The crude reaction mixture was applied directly to a silica gel column to afford the purified cross-coupled product.

7-{[1-(Methoxycarbonyl)ethyl]amino}flavone (9c). 139 mg (65%), ee = 86%. Mp: 200.5−204.5 °C. Eluent: toluene/ethyl acetate = 1:1. 1 H NMR (CDCl3) δ: 8.01 (d, J = 9.0 Hz, 1H, 5-H), 7.88 (m, J = 3.6 Hz, 2H, 2′,6′-H,), 7.51 (m, 3H, 3′,5′-H, 4′-H), 6.71 (s, 1H, 3-H), 6.68 (dd, J = 1.4, 9.0 Hz, 1H, 6-H), 6.53 (d, J = 1.4 Hz 1H, 8-H), 4.95 (d, J = 7.2 Hz, 1H, NH), 4.26 (m, 1H, 1″-H), 3.80 (s, 3H, OCH3), 1.56 (d, J = 6.8 Hz, 3H, 2″-H). 13C NMR (CDCl3) δ: 177.6 (C-4), 173.8 (COOMe), 126.3 (C-2), 158.5 (C-8a), 151.2 (C-7), 132.1 (C-1′), 131.1 (C-4′), 128.9 (C-3′,5′), 127.0 (C-5), 126.1 (C-2′,6′), 115.4 (C4a), 113.1 (C-6), 107.4 (C-3), 97.4 (C-8), 52.6 (OCH3), 51.3 (C-1″), 18.6 (C-2″). IR (KBr) ν/cm−1 3299, 3067, 2951, 1740, 1631, 1586, 1449, 1436, 1379, 1188, 1162, 908, 770, 689. MS: 323 [M•+], 264 (100), 246, 162, 131, 91. Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.60; H, 5.32; N, 4.32. 4583


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acetate = 2:1. 1H NMR (CDCl3) δ: 8.01 (d, J = 8.6 Hz, 1H, 5-H), 7.88 (m, 2H, 2′,6′-H), 7.51 (m, 3H, 3′,5′-H, 4′-H), 6.70 (m, 2H, 3-H, 6-H), 6.56 (d, J = 1.8 Hz, 1H, 8-H), 4.92 (d, J = 7.2 Hz, 1H, N-H), 4.08 (m, 1H, 1″-H), 3.77 (s, 3H, OCH3), 1.96 (m, 1H, 2″-H), 1.65 (m, 1H, 3″a-H), 1.34 (m, 1H, 3″b-H), 0.99 (m, 6H, 4″-H, 1‴-H). 13C NMR (CDCl3) δ:177.6 (C-4), 172.8 (COOMe), 162.3 (C-2), 158.5 (C-8a), 151.8 (C-7), 132.1 (C-1′), 131.1 (C-4′), 128.9 (C-3′,5′), 127.0 (C-5), 126.0 (C-2′,6′), 115.4 (C-4a), 113.2 (C-6), 107.4 (C-3), 97.5 (C-8), 60.4 (C-1″), 52.2 (OCH3), 37.9 (C-2″) 25.6 (C-3″), 15.4 (C-1‴), 11.5 (C-4″). IR (KBr) ν/cm−1 3280, 3153, 3072, 2963, 2876, 1737, 1628, 1373, 908, 828, 769, 688. MS: 315 (100), 300, 194, 156, 115, 77. Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.34; H, 6.36; N, 3.84.

7-{[3-Methylthio-1-(methoxycarbonyl)propyl]amino}flavone (9d). 190 mg (75%), ee = 87%. Mp: 155.5−158 °C. Eluent: toluene/ ethyl acetate = 1:1. 1H NMR (CDCl3): δ: 7.81 (d, J = 8.6 Hz, 1H, 5H), 7.89 (m, 2H, 2′,6′-H), 7.51 (m, 3H, 3′,5′-H, 4′-H), 6.72 (m, 2H, 3-H, 6-H), 6.63 (d, J = 2.2 Hz, 1H, 8-H), 5.10 (d, J = 8.3 Hz, 1H, NH), 4.43 (m, 1H, 1″-H), 3.80 (s, 3H, OCH3), 2.65 (m, 2H, 3″-H), 2.18 (m, 2H, 2″-H), 2.13 (s, 3H, SCH3). 13 C NMR (CDCl3) δ: 177.6 (C-4), 173.1 (COOMe), 162.4 (C-2), 158.5 (C-8a), 151.5 (C-7), 132.0 (C-1′), 131.1 (C-4′), 128.9 (C3′,5′), 126.9 (C-5), 126.0 (C-2′,6′), 115.5 (C-4a), 113.2 (C-6), 107.3 (C-3), 97.7 (C-8), 54.6 (C-1″), 52.7 (OCH3), 31.6 (C-2″), 30.0 (C3″), 15.5 (SCH3). IR (KBr) ν/cm−1 3448, 3270, 1727, 1635, 1619, 1590, 1444, 1373, 1243, 1000, 824, 767, 675. MS: 383 [M•+], 324 (100), 264, 221, 165, 119, 91. Anal. Calcd for C21H21NO4S: C, 65.78; H, 5.52; N, 3.65. Found: C, 65.81; H, 5.54; N, 3.66.

7-[2-(Methoxycarbonyl)pyrrolidino]flavone (9h). 60 mg (26%), ee = 96%. Mp: 128.5−132 °C. Eluent: toluene/ethyl acetate = 2:1. 1H NMR (CDCl3) δ: 8.04 (d, J = 9.0 Hz, 1H, 5-H), 7.89 (m, 2H, 2′,6′H), 7.50 (m, 3H, 3′,5′-H, 4′-H), 6.71 (s, 1H, 3-H), 6.61 (dd, J = 9.0, 2.2 Hz, 1H, 6-H), 6.49 (d, J = 1.8 Hz, 1H, 8-H), 4.40 (dd, J = 1.8, 6.8 Hz, 1H, 1″-H), 3.76 (s, 3H, OCH3), 3.67 (m, 1H, 4″a-H), 3.49 (m, 1H, 4″b-H), 2.25 (m, 4H, 2″-H, 3″-H). 13C NMR (CDCl3) δ:177.7 (C-4), 173.5 (COOMe), 162.3 (C-2), 158.2 (C-8a), 150.8 (C-7), 132.2 (C-1′), 131.0 (C-4′), 128.9 (C-3′,5′), 126.9 (C-5), 126.1 (C2′,6′), 114.4 (C-4a), 111.2 (C-6), 107.3 (C-3), 97.8 (C-8), 60.7 (C2″), 52.4 (OCH3), 48.49 (C-5″), 30.8 (C-3″) 23.6 (C-4″). IR (KBr) ν/cm−1 3439, 3065, 2952, 2875, 1729, 1630, 1449, 1375, 1172, 818, 774, 691. MS: 279, 166, 149 (100), 112, 83, 70, 55. Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C, 72.22; H, 5.50; N, 4.02.

7-{[1,2-Bis(methoxycarbonyl)ethyl]amino}flavone (9e). 76 mg (30%), ee = 56%. Mp: 103.5−108 °C. Eluent: toluene/ethyl acetate = 1:1. 1H NMR (CDCl3) δ: 8.02 (d, J = 8.6 Hz, 1H, 5-H), 7.89 (m, 2H, 2′,6′-H), 7.51 (m, 3H, 3′,5′-H, 4′-H), 6.71 (m, 2H, 3-H, 6-H), 6.62 (d, J = 2.2 Hz, 1H, 8-H), 5.26 (d, J = 8.3 Hz, 1H, N-H), 4.56 (m, 1H, 1″-H), 3.81 (s, 3H, C-1″COOCH3), 3.73 (3H, s, C-2″COOCH3), 3.00 (m, 2H, 2″-H). 13C NMR (CDCl3) δ: 177.7 (C-4), 177.6 (C-1″C=O), 170.7 (C-2″-C=O), 162.4 (C-2), 158.5 (C-8a), 150.9 (C-7), 132.0 (C-1′), 131.2 (C-4′), 128.9 (C-3′,5′), 127.1 (C-5), 126.1 (C2′,6′), 115.8 (C-4a), 113.2 (C-6), 107.4 (C-3), 97.8 (C-8), 53.0 (C1″), 52.4 (C-1″COOCH3), 52.3 (C-2″COOCH3), 36.5 (C-2″). IR (KBr) ν/cm−1 3373, 3291, 3065, 2950, 2925, 2851, 1739, 1628, 1590, 1449, 1436, 1371, 1179, 908, 825, 771, 688, 675. MS: 381 [M+•], 322 (100), 248, 222, 91. Anal. Calcd for C21H19NO6: C, 66.13; H, 5.02; N, 3.67. Found: C, 66.17; H, 5.04; N, 3.68.

7-{[1-Phenyl-1-(methoxycarbonyl)methyl]amino}flavone (9j). 150 mg (59%). ee = 0.5%, Mp 193−196 °C. Eluent: toluene:ethyl acetate = 2:1. 1H NMR (CDCl3) δ: 7.97 (d, J = 9.0 Hz, 1H, 5-H), 7.82 (m, 2H, 2′,6′-H), 7.48 (m, 5H, 2‴, 6‴-H, 3‴,5‴-H, 4‴-H), 7.38 (m, 3H, 3′,5′-H, 4′-H), 6.69 (dd, J = 2.1, 6.5 Hz, 1H, 6-H), 6.67 (s, 1H, 3H), 6.41 (d, J = 2.2 Hz, 1H, 8-H), 5.72 (s, 1H, N-H), 5.17 (1H, s, 1″H), 3.78 (s, 3H, OCH3). 13C NMR (CDCl3) δ: 177.6 (C-4), 171.3 (COOMe), 162.3 (C-2), 158.3 (C-8a), 150.5 (C-7), 136.2 (C-1″), 132.0 (C-1′), 131.1 (C-4′), 129.1 (C-2‴,6‴), 128.8 (C-3′,5′), 128.7 (C-4‴), 127.0 (C-3‴,5‴), 126.8 (C-5), 126.0 (C-2′,6′), 115.4 (C-4a), 113.3 (C-6), 107.4 (C-3), 98.0 (C-8), 60.0 (C-1″), 53.2 (OCH3). IR (KBr) ν/cm−1 3399, 3307, 3056, 2952, 1740, 1592, 1379, 1254, 1189, 908, 771, 697. MS: 387 [M + H•+] (100). Anal. Calcd for C24H19NO4: C, 74.79; H, 4.97; N, 3.63. Found: C, 74.82; H, 4.99; N, 3.63.

7-{[2-Methyl-1-(methoxycarbonyl)propyl]amino}flavone (9f). 86 mg (37%), ee = 98%. Mp: 173−175 °C. Eluent: toluene/ethyl acetate = 2:1. 1H NMR (CDCl3) δ: 8.00 (d, J = 8.6 Hz, 1H, 5-H), 7.88 (m, 2H, 2′,6′-H), 7.50 (m, 3H, 3′,5′-H, 4′-H), 6.70 (m, 2H, 3-H, 6-H), 6.56 (d, J = 2.2 Hz, 1H, 8-H), 4.86 (s, 1H, N-H), 4.00 (s, 1H, 1″-H), 3.77 (s, 3H, OCH3), 2.21 (m, 1H, 2″-H), 1.08 (d, J = 6.8 Hz, 3H, 3″aH,), 1.04 (d, J = 6.8 Hz, 3H, 3″b-CH3). 13C NMR (CDCl3) δ:177.6 (C-4), 172.9 (COOMe), 162.3 (C-2), 158.5 (C-8a), 152.0 (C-7), 132.1 (C-1′), 131.1 (C-4′), 128.9 (C-3′,5′), 127.0 (C-5), 126.1 (C2′,6′), 115.4 (C-4a), 113.2 (C-6), 107.4 (C-3), 97.6 (C-8), 61.6 (C1″), 52.6 (OCH3), 31.5 (C-2″) 18.9 (C-3″a), 18.6 (C-3″b). IR (KBr) ν/cm−1 3281, 3156, 3078, 2965, 2885, 1732, 1629, 1374, 1245, 826, 771. MS: 315 (100), 300, 194, 156, 115, 77. Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99; Found: C, 71.80; H, 6.03; N, 4.00.

7-{[1-(tert-Butoxycarbonyl)ethyl]amino}flavone (9k). 176 mg (73%), ee = 36%. Mp: 185−193 °C. Eluent: toluene/ethyl acetate = 2:1. 1H NMR (DMSO-d6) δ: 8.00 (d, J = 9.0 Hz, 1H, 5-H), 7.87 (m, 2H, 2′,6′-H), 7.50 (m, 3H, 3′,5′-H, 4′-H), 6.71 (s, 1H, 3-H), 6.66 (d, J = 9.0 Hz, 1H, 6-H), 6.53 (s, 1H, 8-H), 7.98 (d, J = 7.2 Hz, 1H, N-H), 4.13 (m, 1H, 1″-H), 1.50 (m, 12H, 2″-H, OtBu). 13C NMR (DMSOd6) δ: 177.7 (C-4), 172.5 (COOtBu), 162.3 (C-2), 158.6 (C-8a), 151.4 (C-7), 132.1 (C-1′), 131.1 (C-4′), 128.9 (C-3′,5′), 126.9 (C-5), 126.0 (C-2′,6′), 115.2 (C-4a), 113.0 (C-6), 107.4 (C-3), 97.5 (C-8), 82.3

7-{[2-Methyl-1-(methoxycarbonyl)butyl]amino}flavone (9g). 193 mg (80%), ee = 98%. Mp: 158.5−160 °C. Eluent: toluene/ethyl 4584


Article

The Journal of Organic Chemistry (CMe3), 51.9 (C-1″), 27.9 (C(CH3)3), 18.4 (C-2″). IR (KBr) ν/cm−1 3400, 3291, 3070, 2978, 2933, 1735, 1627, 1590, 1377, 1150, 907, 770, 689. MS: 339 (100), 297, 239, 190, 162, 57. Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.35; H, 6.36; N, 3.84.

3H, OCH3), 3.71 (m, 2H, 2″″-H), 3.15 (m, 1H, 2″a-H), 3.04 (m, 1H, 2″b-H). 13C NMR (CDCl3) δ: 177.5 (C-4), 173.9 (COOMe), 170.3 (CONH), 163.6 (C-2), 157.0 (C-8a), 144.1 (C-7), 137.1 (C-3c), 135.4 (C-1‴), 131.7 (C-4′), 131.4 (C-1′), 129.6 (C-3‴,5‴), 129.0 (C3′,5′), 128.4 (C-2‴,6‴), 127.4 (C-4‴), 126.7 (C-2b), 126.2 (C-2′,6′), 123.4 (C-5), 121.4 (C-7c), 121.3 (C-5b), 120.3 (C-6b), 119.0 (C-7b), 115.3 (C-4a), 111.5 (C-6), 110.9 (C-4b), 109.9 (C-8), 107.4 (C-3), 58.8 (C-1″), 56.1 (C-1″″), 52.6 (OCH3), 37.1 (C-2″) 24.1 (C-2″″). IR (KBr) ν/cm−1 3360, 3058, 2948, 2853, 1742, 1645, 1451, 1370, 1188, 1026, 908, 743, 699. MS: 587 [M + H•+] (100), 294. Anal. Calcd for C36H31N3O5: C, 73.83; H, 5.34; N, 7.17. Found: C, 73.87; H, 5.36; N, 7.19. General Method for Hydrolysis of Methyl Ester. To the solution of the flavone-amino acid hybrid (9b,d,f) (1,00 mmol) in the mixture of 6 mL of dichloromethane and 0.2 mL of MeOH was added solid NaOH (48 mg, 1.2 mmol) and the mixture stirred until full conversion. The salt of the deprotected acid was filtered and washed with dichloromethane then dissolved into water. KHSO4 (10%) solution was added until the pH was slightly acidic. The protonated acid was filtered, washed with water, and dried at room temperature to give the deprotected flavone−amino acid hybrids.

7-{[2-Phenyl-1-(tert-butoxycarbonyl)ethyl]amino}flavone (9n). 227 mg (78%), ee = 11%. Mp: 174−177.5 °C. Eluent: toluene/ethyl acetate = 2:1. 1H NMR (DMSO-d6) δ: 8.00 (m, 2H, 2′,6′-H), 7.73 (d, J = 8.6 Hz, 1H, 5-H), 7.55 (m, 3H, 3′,5′-H, 4′-H), 7.27 (m, 6H, 2‴,6‴H, 3‴,5‴-H, 4‴-H, NH), 6.82 (dd, J = 8.9, 2.0 Hz, 1H, 6-H), 6.80 (s, 1H, 3-H), 6.69 (d, J = 1.6 Hz, 1H, 8-H), 4.34 (d, J = 7.8 Hz, 1H, 1″H), 3.36 (s, 3H, OCH3), 3.08 (d, J = 7.3 Hz, 1H, 2″-H), 1.29 (m, 9H, 2″-H, OtBu). 13C NMR (DMSO-d6) δ: 176.0 (C-4), 171.3 (COOtBu), 161.2 (C-2), 158.0 (C-8a), 152.8 (C-7), 137.0 (C-1‴), 131.5 (C-1′), 131.3 (C-4′), 129.3 (C-3‴,5‴), 129.1 (C-3′,5′), 128.1 (C-2‴,6‴), 126.6 (C-5), 125.9 (C-2′,6′), 125.7 (C-4‴), 113.6 (C-4a), 113.1 (C-6), 106.6 (C-3), 96.7 (C-8), 81.0 (CMe3), 57.6 (C-1″), 37.5 (C-2″), 27.5 (C(CH3)3). IR (KBr) ν/cm−1 3397, 3154, 3062, 2976, 2931, 1733, 1629, 1602, 1449, 1370, 1253, 1151, 908, 825, 771, 691, 503. MS: 401, 360 (100), 328, 281, 178, 157, 141, 78, 51. Anal. Calcd for C28H27NO4: C, 76.17; H, 6.16; N, 3.17. Found: C, 76.20; H, 6.18; N, 3.18.

7-{[1-Carboxyl-3-methylbutyl]amino}flavone (12a). 298 mg (83%), ee = 82. Mp: >280 °C. 1H NMR (CDCl3- DMSO-d6) δ: 7.93 (m, 3H, 5-H, 2′,6′-H), 7.53 (m, 3H, 3′,5′-H, 4′-H), 6.81 (dd, J = 2.2, 8.6 Hz 1H, 6-H), 6.68 (s, 1H, 3-H), 6.65 (d, J = 1.8 Hz 8-H), 5.78 (d, J = 8.3 Hz, 1H, NH), 4.20 (m, 1H, 1″-H), 1.93 (m, 1H, 3″H), 1.81 (m, 2H, 2″-H), 1.04 (d, J = 6.1 Hz, 1H, 4″a-H), 0.99 (d, J = 6.5 Hz, 1H, 4″b-H). IR (KBr) ν/cm−1 3370, 3071, 2953, 2868, 1630, 1586, 1379, 909, 820, 770, 674. MS: 352 [M + H•+] (100). Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.85; H, 5.99; N, 3.98. General Method for tert-Butyl Ester Deprotection. 7-{[1-(tertButoxycarbonyl)ethyl]amino}flavone (9k) (200 mg, 0.55 mmol) was added to a mixture of 15 mL of dichloromethane and 25 mL of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 24 h. The solvent was evaporated in vacuum; the solid residue was treated with 50 mL of 10% HCl solution and then filtered in vacuum to afford the pure deprotected compound 14.

N-(Flavon-7-yl)methoxy-L-leucyl-L-phenylalanine (11a). 253 mg (75%). Mp: 208.5−210.5 °C. Eluent: toluene/ethyl acetate = 1:1. 1H NMR (CDCl3) δ: 7.98 (d, J = 9.0 Hz, 1H, 5-H), 7.88 (m, 2H, 2′,6′H), 7.50 (m, 3H, 3′,5′-H, 4′-H), 7.30 (m, 5H, 2‴,6‴-H, 3‴,5‴-H, 4‴H), 6.74 (m, 2H, CONH, 3-H), 6.64 (m, 2H, 6-H, 8-H), 4.65 (m, 2H, 1″″-H, NH), 4.19 (s, 1H, 1″-H), 3.62 (s, 3H, OCH3), 3.35 (m, 1H, 2″a-H), 3.18 (m, 1H, 2″b-H), 1.55 (m, 3H, 2″″-H, 3″″-H), 0.91 (m, 6H, 4″″-H). 13C NMR (CDCl3) δ: 177.6 (C-4), 172.6 (COOMe), 171.4 (CONH), 162.6 (C-2), 162.6 (C-8a), 151.3 (C-7), 135.8 (C1‴), 131.8 (C-1′), 131.3 (C-4′), 129.1 (C-3′,5′), 129.0 (C-3‴,5‴), 128.9 (C-2‴,6‴), 127.5 (C-4‴), 126.9 (C-5), 126.1 (C-2′,6′), 116.3 (C-4a), 113.7 (C-6), 107.3 (C-3), 99.3 (C-8), 59.6 (C-1″), 52.2 (C1″″), 50.8 (OCH3), 41.1 (C-2″″), 38.5 (C-2″), 24.8 (C-3″″) 22.8 (C4″″a), 21.8 (C-4″″b). IR (KBr) ν/cm−1 3310, 3062, 2955, 2869, 1744, 1629, 1373, 1253, 1150, 909, 825, 772, 690. MS: 191, 175, 147, 121 (100), 92, 65. Anal. Calcd for C31H32N2O5: C, 72.64; H, 6.29; N, 5.47. Found: C, 72.70; H, 6.31; N, 5.49.

7-{[1-Carboxyl-3-methylbutyl]amino}flavone (14). 132 mg (70%), ee = 35%. Mp: 260−263 °C. 1H NMR (DMSO-d6) δ: 8.02 (m, 2H, 2′,6′-H), 7.73 (d, J = 8.6 Hz, 1H, 5-H), 7.57 (m, 3H, 3′,5′-H, 4′-H), 6.80 (m, 2H, 3-H, 6-H), 6.59 (s, 1H, 8-H), 4.17 (m, 1H, 1″-H), 1.44 (d, J = 6.8 Hz, 3H, 2″-H). IR (KBr) ν/cm−1 3409, 3331, 3067, 2981, 2933, 1716, 1627, 1451, 1379, 1190, 909, 826, 770, 687. MS: 310 [M + H•+] (100). Anal. Calcd for C18H16ClNO4: C, 62.52; H, 4.66; N, 4.05. Found: C, 62.60; H, 4.67; N, 4.06. General Method for Peptide Synthesis Starting from Flavone−Amino Acid Hybrids. To a flask containing a mixture of flavone−amino acid hybrid 12a−c (0.35 mmol), HOBt (47 mg, 0.35 mmol), EDC·HCl (74 mg, 0.385 mmol), and amino acid ester hydrochloride (0.35 mmol) were added triethylamine (0.12 mL, 0.84 mmol) and dichloromethane (35 mL). The reaction mixture was kept and stirred at 0 °C for 30 min thenallowed to warm to room temperature. The reaction was stirred for 24 h. The crude reaction mixture was applied directly to a silica gel column to afford flavone− peptide derivatives 13.

N-(Flavon-7-yl)-methoxy-L-triptophyl-L-phenylalanine (11b). 205 mg (53%). Mp: >280 °C. Eluent: hexane/acetone = 3:2. 1H NMR (CDCl3) δ: 8.33 (d, J = 8.6 Hz, 1H, 5-H), 7.94 (m, 2H, 2′,6′-H), 7.72 (m, 2H, 5b-H, 6b-H), 7.65 (s, 1H, 3b-H), 7.55 (m, 4H, 3′,5′-H, 4′-H, 4b-H), 7.36 (s, 1H, 8-H) 7.27 (m, 8H, 6-H, 2‴,6‴-H, 3‴,5‴-H, 4‴-H, 7b-H, CONH), 6.85 (s, 1H, 3-H), 4.01 (m, 2H, 1″-H, 1″″-H), 3.81 (s, 4585


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N-(Flavon-7-yl)methyl-L-seryl-L-alanine (15). 50 mg (81%). Mp: 232−239 °C. 1H NMR (DMSO-d6) δ: 8.40 (d, J = 8.0 Hz, 1H, 5-H), 8.00 (m, 2H, 2′,6′-H), 7.73 (m, 1H, OH), 7.56 (m, 3H, 3′,5′-H, 4′-H), 7.07 (d, J = 6.8 Hz, 1H, CONH), 6.81 (m, 2H, 3-H, 6-H), 6.61 (d, J = 2.0 Hz, 1H, 8-H), 5.15 (s, 1H, NH), 4.41 (m, 1H, 1‴-H), 4.19 (m, 1H, 1″-H), 3.72 (m, 2H, 2‴-H), 3.60 (s, 3H, 1.42, OCH3), 1.38 (d, J = 6.8 Hz, 3H, 2″-H). 13C NMR (DMSO-d6) δ: 176.0 (C-4), 173.2 (CONH), 170.8 (COOMe), 161.2 (C-2), 158.1 (C-8a), 152.9 (C7), 131.6 (C-1′), 131.3 (C-4′), 129.1 (C-3′,5′), 126.0 (C-2′,6′) 125.5 (C-5), 113.5 (C-4a) 113.4 (C-6), 106.7 (C-3), 96.6 (C-8), 61.2 (C2‴), 54.5 (C-1″), 51.9 (C-1‴), 51.7 (OCH3), 18.5 (C-2″). IR (KBr) ν/cm−1 3306, 3067, 2956, 1748, 1631, 1525, 1375, 1063, 908, 828, 772, 693. MS: 412 [M + H•+] (100). Anal. Calcd for C22H22N2O6: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.42; H, 5.42; N, 6.80.

N-(Flavon-7-yl)-tert-butyl-L-alanyl-L-leucine (13a). : 121 mg (72%). Mp: 199.5−204.5 °C. 1H NMR (CDCl3) δ: 8.01 (d, J = 8.6 Hz, 1H, 5-H), 7.88 (m, 2H, 2′,6′-H), 7.49 (m, 3H, 3′,5′-H, 4′-H), 7.15 (d, J = 6.5 Hz, 1H, CONH), 6.75 (d, J = 9.0 Hz, 1H, 6-H), 6.72 (s, 1H, 3-H), 6.65 (d, J = 1.4 Hz, 1H, 8-H), 6.65 (d, 1H, 8-H), 4.85 (d, J = 4.6 Hz, 1H, NH), 4.47 (m, 1H, 1‴-H), 3.94 (m, 1H, 1″-H), 1.79 (m, 3H, 2″-H, 3″-H), 1.36 (m, 12H, 2‴-H, tBu), 1.02 (d, J = 5.8 Hz, 3H, 4″aH), 0.95 (d, J = 6.1 Hz, 3H, 4″b-H). 13C NMR (CDCl3) δ: 177.7 (C4), 172.4 (COOtBu), 171.5 (CONH), 162.5 (C-2), 158.5 (C-8a), 151.9 (C-7), 131.9 (C-1′), 131.2 (C-4′), 128.9 (C-3′,5′), 126.8 (C-5), 126.1 (C-2′,6′) 115.9 (C-4a), 113.5 (C-6), 107.2 (C-3), 98.6 (C-8), 82.0 (C(CH3)3), 57.4 (C-1″), 48.4 (C-1‴), 42.4 (C-2″), 27.8 (C(CH3)3), 25.1 (C-3″), 23.0 (C-4″a), 21.7 (C-4″b), 18.4 (C-2‴). IR (KBr) ν/cm−1 3301, 3067, 2957, 2870, 1733, 1589, 1450, 1372, 1151, 908, 824, 770, 688. MS: 480 [M + H•+] (100). Anal. Calcd for C28H32N2O5: C, 70.27; H, 7.16; N, 5.85. Found: C, 70.30; H, 7.18; N, 5.87.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00124. 1 H and 13C spectra collection and results of biological assays (PDF)

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AUTHOR INFORMATION

Corresponding Author

N-(Flavon-7-yl)-tert-butyl-L-alanyl-L-methionine (13b): 130 mg (75%). Mp: 215.5−218 °C. 1H NMR (CDCl3) δ: 8.00 (d, J = 8.6 Hz, 1H, 5-H), 7.88 (m, 2H, 2′,6′-H), 7.50 (m, 3H, 3′,5′-H, 4′-H), 7.15 (d, J = 7.2 Hz, 1H, CONH), 6.74 (m, 2H, 3-H, 6-H), 6.65 (s, 1H, 8-H), 5.39 (d, J = 6.2 Hz, 1H, NH), 4.49 (m, 1H, 1‴-H), 4.17 (m, 1H, 1″-H) 2.71 (m, 2H, 3″-H), 2.20 (m, 5H, 2″-H, SCH3), 1.42 (m, 12H, 1‴-H, tBu). 13C NMR (CDCl3) δ: 177.7 (C-4), 171.5 (CONH), 171.2 (COOtBu), 162.5 (C-2), 158.5 (C-8a), 151.6 (C-7), 131.9 (C-1′), 131.2 (C-4′), 128.9 (C-3′,5′), 126.9 (C-5), 126.1 (C-2′,6′) 115.8 (C4a) 113.5 (C-6), 107.3 (C-3), 98.4 (C-8), 82.1 (C(CH3)3), 57.5 (C1″), 48.8 (C-1‴), 31.8 (C-2″), 30.6 (C-3″), 27.8 (C(CH3)3), 18.4 (C2‴), 15.5 (SCH3). IR (KBr) ν/cm−1 3294, 3067, 2977, 2931, 1735, 1627, 1589, 1371, 1150, 909, 823, 770, 688. MS: 498 [M + H+•] (100). Anal. Calcd for C27H32N2O5S: C, 65.30; H, 6.49; N, 5.64. Found: C, 65.34; H, 6.51; N, 5.65.

*E-mail: [email protected]. ORCID

Krisztina Kónya: 0000-0003-4490-1719 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Hungarian Scientific Research Fund (OTKA, Grant No. K75806) and from the New Hungary Development Plan, cofinanced by the European Social Fund and the European Regional Development Fund (project no. TÁ MOP-4.2.2/B-10/1-2010-0024), is greatly appreciated. Further support from the BAROSS REG_EA_09-1-20090028 (LCMS_TAN) project is gratefully acknowledged.

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N-(Flavon-7-yl)-tert-butyl-L-alanyl-L-valine (13c). 90 mg (55%). Mp: 231.5−233 °C. 1H NMR (CDCl3) δ: 8.00 (d, J = 8.0 Hz, 1H, 5H), 7.87 (m, 2H, 2′,6′-H), 7.49 (m, 3H, 3′,5′-H, 4′-H), 7.06 (d, 1H, J = 7.2 Hz, CONH), 6.75 (d, J = 8.6 Hz, 1H, 6-H), 6.71 (s, 1H, 3-H), 6.64 (1H, s, 8-H), 4.91 (d, J = 5.8 Hz, 1H, NH) 4.51 (m, 1H, 1‴-H), 3.80 (m, 1H, 1″-H), 2.38 (m, 1H, 2″-H), 1.38 (m, 12H, 1‴-H, tBu), 1.09 (d, J = 6.8 Hz, 6H, 3″-H). 13C NMR (CDCl3) δ: 177.7 (C-4), 171.6 (CONH), 170.9 (COOtBu), 162.5 (C-2), 158.5 (C-8a), 152.3 (C-7), 131.9 (C-1′), 131.2 (C-4′), 128.9 (C-3′,5′), 126.8 (C-5′), 126.0 (C-2′,6′) 115.8 (C-4a), 113.5 (C-6), 107.2 (C-3), 98.5 (C-8), 82.0 (C(CH3)3), 63.9 (C-1″), 48.7 (C-1‴), 31.4 (C-2″), 27.8 (C(CH3)3), 19.3 (C-3″a), 18.5 (C-3″b), 18.0 (C-2‴). IR (KBr) ν/cm−1 3335, 3272, 3068, 2971, 2934, 1736, 1628, 1450, 1372, 1150, 908, 826, 769, 687. MS: 466 [M + H•+] (100). Anal. Calcd for C27H32N2O5: C, 69.81; H, 6.94; N, 6.03. Found: C, 69.87; H, 6.96; N, 6.04.

DEDICATION Dedicated to the memory of Prof. Tamás Patonay. REFERENCES

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