Convergent Synthesis of N,S-bis Glycosylquinolin-2-ones via a Pd-G3-XantPhos Precatalyst Catalysis

Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or β-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of α- or β-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods.

Molecules 2018, 23, x FOR PEER REVIEW 2 of 14 quinolinone frameworks with the aim of identifying novel scaffolds of biological interest. Herein, we report our success in the development of such a strategy.

Synthesis of Starting Materials
To establish the appropriate conditions for the coupling of 3-halo-N-glycosyl quinolin-2-ones with various thiosugars, we initially started our chemistry by the synthesis of the appropriate α-or β-3-halo-N-glycosyl quinolin-2-ones 2a-g (Scheme 1). The compounds 2a-c were prepared by the electrophilic regioselective aromatic bromination of N-glycosyl quinolin-2-one 1a-c using N-bromosuccinimide in anhydrous dimethylformamide (DMF). Under these conditions, 3-bromo-N-glucopyranosylquinolin-2-ones 2a-c were isolated in good yields (Scheme 1). To compare the reactivity of brominated quinolinones 2a-c with its analogue, in which the bromine atom is replaced by the iodine one, derivatives 2d-f were synthesized from 2a-c through a halogen exchange by a Cu-catalyzed Finkelstein reaction [37]. Finally, compound β-2g bearing an unprotected sugar was also prepared in order to study the influence of a free hydroxyls group on the outcome of the coupling.

Synthesis of Starting Materials
To establish the appropriate conditions for the coupling of 3-halo-N-glycosyl quinolin-2-ones with various thiosugars, we initially started our chemistry by the synthesis of the appropriate αor β-3-halo-N-glycosyl quinolin-2-ones 2a-g (Scheme 1). The compounds 2a-c were prepared by the electrophilic regioselective aromatic bromination of N-glycosyl quinolin-2-one 1a-c using N-bromosuccinimide in anhydrous dimethylformamide (DMF). Under these conditions, 3-bromo-N-glucopyranosylquinolin-2-ones 2a-c were isolated in good yields (Scheme 1). To compare the reactivity of brominated quinolinones 2a-c with its analogue, in which the bromine atom is replaced by the iodine one, derivatives 2d-f were synthesized from 2a-c through a halogen exchange by a Cu-catalyzed Finkelstein reaction [37]. Finally, compound β-2g bearing an unprotected sugar was also prepared in order to study the influence of a free hydroxyls group on the outcome of the coupling.

Optimization of the Reaction Conditions on the Model Study
With these starting materials in hand, we turned our attention to explore the feasibility of the coupling of the quinolones β-2a and β-2d with tetra-O-acetylated 1-thio-β-D-galactopyranose 1a under various reaction conditions (Scheme 2). When β-2a and 1a were mixed under our previously reported conditions [38] (G3-XantPhos (5 mol %), Et3N (1.5 equiv.) in tetrahydrofuran (THF) at room temperature), only the starting material was recovered unchanged; however, when the reaction mixture was heated at 60 °C, product 3a was detected by NMR of the crude reaction mixture and the conversion rate was calculated to be around 35% (Table 1, entry 2). The conversion rate has never exceeded 50%, even when the amount of the thiogalactose 1a was increased until 2.5 equiv. and the reaction temperature was at 100 °C, probably due to the fact that the formation of disulfide dimer was faster than the coupling of product 3a. In the next set of experiences, we decided to use the iodinated quinolinone β-2d instead of β-2a. Delightfully, the coupling of β-2d with 1a in the presence of Pd-G3-XantPhos (5 mol %), with Et3N (1.2 equiv.) as the base in THF at room temperature, led to N-β-glycosyl S-β-galactosyl quinolin-2-one 3a (J1,2 = 9.9 Hz) in 70% yield (entry 3, Table 1). Decreasing the amount of thiogalactose 1a into 1.5 equiv. led to a lower conversion rate (40%, entry 4), indicating that the thiosugar concentration plays a critical role in the outcome of the reaction. It should be noted that the palladium catalyst is necessary to achieve this transformation, since no reaction occurs when the coupling is conducted in the absence of the Pd-G3-precatalyst.

Optimization of the Reaction Conditions on the Model Study
With these starting materials in hand, we turned our attention to explore the feasibility of the coupling of the quinolones β-2a and β-2d with tetra-O-acetylated 1-thio-β-D-galactopyranose 1a under various reaction conditions (Scheme 2). When β-2a and 1a were mixed under our previously reported conditions [38] (G3-XantPhos (5 mol %), Et 3 N (1.5 equiv.) in tetrahydrofuran (THF) at room temperature), only the starting material was recovered unchanged; however, when the reaction mixture was heated at 60 • C, product 3a was detected by NMR of the crude reaction mixture and the conversion rate was calculated to be around 35% (Table 1, entry 2). The conversion rate has never exceeded 50%, even when the amount of the thiogalactose 1a was increased until 2.5 equiv. and the reaction temperature was at 100 • C, probably due to the fact that the formation of disulfide dimer was faster than the coupling of product 3a. In the next set of experiences, we decided to use the iodinated quinolinone β-2d instead of β-2a. Delightfully, the coupling of β-2d with 1a in the presence of Pd-G3-XantPhos (5 mol %), with Et 3 N (1.2 equiv.) as the base in THF at room temperature, led to N-β-glycosyl S-β-galactosyl quinolin-2-one 3a (J 1,2 = 9.9 Hz) in 70% yield (entry 3, Table 1). Decreasing the amount of thiogalactose 1a into 1.5 equiv. led to a lower conversion rate (40%, entry 4), indicating that the thiosugar concentration plays a critical role in the outcome of the reaction. It should be noted that the palladium catalyst is necessary to achieve this transformation, since no reaction occurs when the coupling is conducted in the absence of the Pd-G3-precatalyst.

Optimization of the Reaction Conditions on the Model Study
With these starting materials in hand, we turned our attention to explore the feasibility of the coupling of the quinolones β-2a and β-2d with tetra-O-acetylated 1-thio-β-D-galactopyranose 1a under various reaction conditions (Scheme 2). When β-2a and 1a were mixed under our previously reported conditions [38] (G3-XantPhos (5 mol %), Et3N (1.5 equiv.) in tetrahydrofuran (THF) at room temperature), only the starting material was recovered unchanged; however, when the reaction mixture was heated at 60 °C, product 3a was detected by NMR of the crude reaction mixture and the conversion rate was calculated to be around 35% (Table 1, entry 2). The conversion rate has never exceeded 50%, even when the amount of the thiogalactose 1a was increased until 2.5 equiv. and the reaction temperature was at 100 °C, probably due to the fact that the formation of disulfide dimer was faster than the coupling of product 3a. In the next set of experiences, we decided to use the iodinated quinolinone β-2d instead of β-2a. Delightfully, the coupling of β-2d with 1a in the presence of Pd-G3-XantPhos (5 mol %), with Et3N (1.2 equiv.) as the base in THF at room temperature, led to N-β-glycosyl S-β-galactosyl quinolin-2-one 3a (J1,2 = 9.9 Hz) in 70% yield (entry 3, Table 1). Decreasing the amount of thiogalactose 1a into 1.5 equiv. led to a lower conversion rate (40%, entry 4), indicating that the thiosugar concentration plays a critical role in the outcome of the reaction. It should be noted that the palladium catalyst is necessary to achieve this transformation, since no reaction occurs when the coupling is conducted in the absence of the Pd-G3-precatalyst.

Scope and Limitation of the Cross-Coupling
Motivated by these results, we next explored the scope of the coupling reaction of structurally diverse mono-, di-, and tri-thiosugar derivatives 1a-f with various α-or β-N-glucosylquinolinones 2d-g (Scheme 3). Gratifyingly, all of the couplings proceeded in good yields as well as with a retention of the anomeric configuration. The nature of the N-β-glucosylquinolinone partner does not interfere with the outcome of the reaction, since both O-acetylated β-glucosylquinolinone β-2d and unprotected β-glucosylquinolinone β-2g were successfully coupled. Regarding the thio-nucleophilic partners, this coupling reaction tolerates a large variety of thiosugars 1a-f: and O-benzoylated 1-thio-β-D-glucopyranose 1d were coupled with both glucosylquinolinones β-2d and β-2g to give the β-N,S-bis-glycosyl quinolin-2-ones 3a-f without any loss of reactivity, except for the O-acetylated β-glucosylquinolinone β-2f due to the steric effects ( Figure 2).

Scope and Limitation of the Cross-Coupling
Motivated by these results, we next explored the scope of the coupling reaction of structurally diverse mono-, di-, and tri-thiosugar derivatives 1a-f with various α-or β-N-glucosylquinolinones 2d-g (Scheme 3). Gratifyingly, all of the couplings proceeded in good yields as well as with a retention of the anomeric configuration. The nature of the N-β-glucosylquinolinone partner does not interfere with the outcome of the reaction, since both O-acetylated β-glucosylquinolinone β-2d and unprotected β-glucosylquinolinone β-2g were successfully coupled. Regarding the thio-nucleophilic partners, this coupling reaction tolerates a large variety of thiosugars 1a-f: and O-benzoylated 1-thio-β-D-glucopyranose 1d were coupled with both glucosylquinolinones β-2d and β-2g to give the β-N,S-bis-glycosyl quinolin-2-ones 3a-f without any loss of reactivity, except for the O-acetylated β-glucosylquinolinone β-2f due to the steric effects ( Figure 2).   Importantly, this procedure is not limited to only β-glucosyl quinolin-2-ones, but it also worked successfully with 1-N-glucosylquinolin-2-one α-2e, which had an anomeric α-configuration. In this case, the corresponding α-N,S-bis-glycosyl quinolin-2-one 3j was obtained with a slightly lower yield of 35%. Finally, the efficiency of this C-S bond-forming reaction was well-demonstrated by the coupling of more complex di-and trisaccharide derivatives. Thus, 1-thio-β-D-cellobiose 1e as well as 1-thio-β-D-maltotriose 1f were readily reacted with β-2d and β-2g to give the corresponding thioglycosides 3g-i in 97%, 57% and 98% yields, respectively. More importantly, the stereochemistry of the β-1,4 -O-glycosidic bond in the di-saccharides 3g,h and the α-1,4 in β-tri-saccharide 3i remained intact. It is worth noting that all our attempts to react an unprotected thiogalactose with β-2d or β-2g under our optimized conditions failed. Alternatively, in order to produce completely unprotected β-N,S-bis-glycosyl quinolin-2-ones and show that their purification and characterization may be achieved easily, the deprotection of representative β-N,S-bis-glycosyl quinolin-2-one was performed (Scheme 4). Thus, acetyl protecting groups of 3b could be removed through the Zemplen reaction [39][40][41] by using a catalytic amount of potassium carbonate as the base in methanol. Under these conditions, unprotected β-N,S-bis-glycosyl quinolin-2-one 4a was isolated in a quantitative yield. Importantly, this procedure is not limited to only β-glucosyl quinolin-2-ones, but it also worked successfully with 1-N-glucosylquinolin-2-one α-2e, which had an anomeric α-configuration. In this case, the corresponding α-N,S-bis-glycosyl quinolin-2-one 3j was obtained with a slightly lower yield of 35%. Finally, the efficiency of this C-S bond-forming reaction was well-demonstrated by the coupling of more complex di-and trisaccharide derivatives. Thus, 1-thio-β-D-cellobiose 1e as well as 1-thio-β-D-maltotriose 1f were readily reacted with β-2d and β-2g to give the corresponding thioglycosides 3g-i in 97%, 57% and 98% yields, respectively. More importantly, the stereochemistry of the β-1,4′-O-glycosidic bond in the di-saccharides 3g,h and the α-1,4′ in β-tri-saccharide 3i remained intact. It is worth noting that all our attempts to react an unprotected thiogalactose with β-2d or β-2g under our optimized conditions failed. Alternatively, in order to produce completely unprotected β-N,S-bis-glycosyl quinolin-2-ones and show that their purification and characterization may be achieved easily, the deprotection of representative β-N,S-bis-glycosyl quinolin-2-one was performed (Scheme 4). Thus, acetyl protecting groups of 3b could be removed through the Zemplen reaction [39][40][41] by using a catalytic amount of potassium carbonate as the base in methanol. Under these conditions, unprotected β-N,S-bis-glycosyl quinolin-2-one 4a was isolated in a quantitative yield.

Typical Procedure A for the Synthesis of β or α 3-iodo N-glucosylquinolinones 2a-c
A 50-mL round tube flash was charged with 1a-c (1 equiv.), freshly crystallized N-bromosuccinimide (NBS) (2.5 equiv.). Under an argon atmosphere, anhydrous DMF was added. The mixture was heated to 70 °C and stirred until reaction completeness (72 h) ascertained by thin layer chromatography (TLC). The crude was diluted with EtOAc and extracted with saturated NH4Cl (50 mL × 3). The organic layer was washed with water, dried by MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography.

Typical Procedure A for the Synthesis of β or α 3-iodo N-glucosylquinolinones 2a-c
A 50-mL round tube flash was charged with 1a-c (1 equiv.), freshly crystallized N-bromosuccinimide (NBS) (2.5 equiv.). Under an argon atmosphere, anhydrous DMF was added. The mixture was heated to 70 • C and stirred until reaction completeness (72 h) ascertained by thin layer chromatography (TLC). The crude was diluted with EtOAc and extracted with saturated NH 4 Cl (50 mL × 3). The organic layer was washed with water, dried by MgSO 4 , and concentrated under vacuum. The residue was purified by silica gel column chromatography.