Synthesis of Benzomacrolactam by 11–endo Selective Aryl Radical Cyclization of 2–Iodobenzamide Derived from D–Galactose

Abstract

No âmbito de um programa de estudo de reações de macrociclização intramolecular de radicais arila de o-iodobenzamidas mediadas por hidreto de tri-n-butilestanho foi obtida a benzomacrolactama 2, proveniente de ciclização regiosseletiva 11-endo a partir de 4-O-alil-2,3-di-O-benzil-6-desoxi-6-(2-iodobenzoilamino)-α-D-galactopiranosídeo de metila (1). A benzamida 1 foi sintetizada a partir do α-D-galactopiranosídeo de metila em oito etapas. Da reação de 1 com hidreto de tri-n-butilestanho, além da macrolactama 2, foi isolado o produto de hidrogenólise 3. As estruturas das substâncias 1, 2 e 3 foram identificadas pelos seus espectros de RMN 1 H, RMN 13 C e DEPT e por experimentos de RMN bidimensional (COSY e HMQC).Encouraged by our previous studies of tri-n-butyltin-mediated radical cyclization reaction of oiodobenzamides, we applied this methodology to the synthesis of benzomacrolactam 2 from methyl 4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoylamino)-α-D-galactopyranoside 1. Apart from the macrolactam 2, resulting from regioselective 11-endo aryl radical cyclization, the hydrogenolysis produt 3 was obtained. The o-iodobenzamide 1 was prepared in eight conventional synthetic steps from methyl α-D-galactopyranoside. The unequivocal structures of 1, 2 and 3 were supported by 1 H, 13C and DEPT NMR spectroscopy and by COSY and HMQC experiments.

Tri-n-butyltin Hydride-Mediated radical reactions of ortho-and meta-Iodobenzamides to synthesize benzomacrolactams: surprising formation of biphenyl compounds from meta-regioisomers

“…[6][7][8][9][10][11] These precursors furnished benzomacrolactams with 11-, 12-and 20-membered ring by regioselective endo aryl radical carbocyclization. [6][7][8][9] The benzamides methyl 4-Oallyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoylamino)-α-D-galactopyranoside (1) and its gluco epimer 2 were found to furnish the benzomacrolactams 3 and 4 owing to 11-endo cyclization in 32% and 40% yield, respectively 6,7 ( Figure 1).Considering that (i) we have been stimulated to study the Bu 3 SnH-mediated radical reactions to construct Faraco et al 1505 Vol. 20, No.…”

“…20, No. 8, 2009 macrocycles, since there is a limited number of protocols available for the synthesis of large rings using free radical-mediated macrocyclizations, 13 (ii) the endomacrocyclization mode is favoured over the exo, [6][7][8][9]12,[14][15][16][17][18][19][20] (iii) the carbohydrate moiety impose conformational restriction to favour cyclization, [6][7][8][9]12 and (iv) although the majority of fused aromatic macrocycles have been obtained from ortho-halogenobenzene derivatives bearing an unsaturation in the side chain, [6][7][8][9][14][15][16][17][18][19] 3-halogenobenzene compounds have also been used as precursors of benzomacrolactams, 13 we selected to apply the Bu 3 SnHmediated radical reaction to the methyl 4-O-allyl-2,3- (Figure 2), the respective meta-isomers of 1 and 2 ( Figure 1), in an attempt to form the benzomacrolactams 7 and 8 ( Figure 2) by 12-endo carbocyclization. In view of the results of these radical reactions, we also carried out the Bu 3 SnH-mediated reaction with methyl 2,3-di-O-benzyl-6-deoxy-6-(3-iodobenzoylamino)-4-O-(1-pentenyl)-α-D-glucopyranoside (9) and methyl 2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoylamino)-4-O-(1-pentenyl)-α-Dglucopyranoside (10) to synthesize the respectively 14-and 13-membered lactams 11 and 12 (Figure 2).…”

“…O-allylation of C-4 hydroxy groups of 13a and 13b 6,7,23 gave 14a 7 and 14b, 6 also known compounds. The etherification of free hydroxy group of 13a with 5-bromo-1-pentene 6,7,23 furnished the new methyl 6-azido-6-deoxy-4-O-(1-pentenyl)-α-D-glucopyranoside (14c). Selective reduction of the azido groups of 14a, 14b and 14c 7,28 gave the known amines 15a 7 and 15b 6 and the new amine 15c.…”

“…Selective reduction of the azido groups of 14a, 14b and 14c 7,28 gave the known amines 15a 7 and 15b 6 and the new amine 15c. These amines upon treatment with the suitable iodobenzoyl chloride (3-iodobenzoyl chloride for 5, 6 and 9; 2-iodobenzoyl chloride for 10) 6,7,29 furnished the desired iodobenzamides 5, 6, 9 and 10 (Scheme 1).The radical reactions were performed in the usual way 20,30 with slow addition (1.5 to 5 h) of a solution mixture of Bu 3 SnH (1.5 molar equivalents) and catalytic amount of AIBN to a solution of 5, 6, 9 and 10 at concentrations ranging from 0.003 to 0.012 mol L -1 (Table 1). The products formed (16, 17, 18, 19, 20 and 21) and recovered (6) (Scheme 1) were isolated after solvent elimination and column chromatography.…”

“…5,13 In our previous papers we considered that the cyclization reactions were favoured by the conformational restriction present in the precursors due to the amide bond, the sugar moiety and the presence of a hydrogen bond formed between the hydrogen atom of the amide group and the oxygen atom of the allyloxy group. 6,7,9,35 The lack of cyclization products from radical reactions of 5 and 6 can indicate that the restricted rotation around the aryl-carbonyl bond present in 1 and 2 due to the iodine atom ortho to the amide group 36,37 also contributes to give a pre-organization to favour the ring closure. Despite this conformational restriction being absent in the aryl radicals, it is assumed that the relative amounts of Scheme 2.…”