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

Ildefonso Binatti , Maria Auxiliadôra F. Prado*, Ricardo J. Alves and José D. Souza Filho Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Olegário Maciel 2360, 30180-112 Belo Horizonte MG, Brazil Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, 31270-200 Belo Horizonte MG, Brazil


Introduction
Aryl radical cyclization reactions have become an important tool in the development of modern heterocyclic chemistry and the synthesis of natural products. 1Bu 3 SnHmediated aryl radical cyclizations are now widely used in organic synthesis for the construction of fused aromatic compounds. 2][3][4][5][6][7][8][9][10][11][12][13][14] To the best of our knowledge, there are few reports of Bu 3 SnH-mediated aryl radical cyclization to give fused aromatic compounds in which the rings have more than six members.[15][16][17][18][19][20][21] Until 1999, there were no benzolactams with lactam rings larger than six members obtained by the same method described in the literature.One possible explanation for this involves an assumption that, in the ortho-halogenobenzamides bearing a hydrogen in the saturated carbon at the 5-position relative to the aryl radical center, the generation of the aryl radical is followed by intramolecular hydrogen-atom transfer to the aryl group with formation of an amidoyl radical which undergoes a variety of new radical additions and cyclization reactions.22 Despite the knowledge about 1,5-hydrogen atom transfer, we decided to explore the possibility of using the Bu 3 SnH-mediated radical cyclization reaction to create benzomacrolactams from methyl 4-O-allyl-2,3-di-Obenzyl-6-deoxy-6-(2-iodobenzoylamino)-α-Dglucopyranoside 4 by 11-endo and/or 10-exo cyclization.We were somewhat encouraged by the possibility of the carbohydrate unit of the aryl radical precursor to favor a conformation in which the cyclization reaction would occur prior to 1,5-hydrogen atom transfer. Onlythe benzomacrolactam 5 resulting from 11-endo aryl radical cyclization and the hydrogenolysis product 6 were obtained in 40% and 42% yield, respectively.21 In view of this result we applied this methodology to the synthesis of benzomacrolactams by 11-endo and/or 10-exo cyclization from N-(3-allyloxypropyl)-2iodobenzamide (7) to examine whether or not the conformational restraint of 4 "imposed by the carbohydrate unit" aids the cyclization.We also intended to know whether or not the sugar unit affects the cyclization mode (endo or exo).In this case we have also obtained the benzomacrolactam 8, resulting from 11-endo aryl radical cyclization, and the hydrogenolysis product 9 in 14% and 85% yield, respectively.21 Comparison of the ratio lactam 5 : hydrogenolysis product 6 isolated from the Bu 3 SnH-mediated reaction of benzamide 4 (1:1) with the ratio lactam 8 : hydrogenolysis product 9 isolated from the reaction of benzamide 7 (1:6) suggests that our previous hypothesis might be correct: conformational restraint "imposed by the sugar unit" in the carbohydrate aryl radical precursor favored the cyclization.21 We have also concluded that the 11-endo cyclization mode is preferred over a 10-exo ring closure.21 In order to confirm the observation that conformational restraint "imposed by the carbohydrate unit" favors the cyclization and to examine the influence of the C-4 configuration of the sugar unit on the cyclization mode, the substrate methyl 4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(2-iodobenzoylamino)-α-D-galactopyranoside (1), C-4 epimer of 4, was synthesized and submitted to Bu 3 SnHmediated radical reaction.
The structures of precursor 1, lactam 2 and hydrogenolysis product 3 were established on the basis of their 1 H and 13 C NMR spectra.The unequivocal structures were also confirmed by DEPT, COSY and HMQC experiments.The selected 13 C NMR data for these compounds are listed in the Table 1.
The elemental analysis of iodobenzamide 1 is correct but attempts to obtain correct elemental analysis of compounds 2 and 3 were not successful due to the presence of tin impurities which could not be separated from the main products.The presence of tin compounds can be justified, since it is well known that a major drawback in employing the tri-n-butyltin reagent can be the poor separation of the products from the tin residues. 33he differences observed in the radical reactions of 1 and 4 (yields: 2 32%, 5 40%; ratios: 2:3 1.4:1, 5:6 1:1) are relatively small and could be attributed to the difficulties in the separation of the products from the tin residues.Comparison of these similar yields of macrolactams and ratios lactam:hydrogenolysis product with the yield of lactam 8 and the ratio lactam 8:hydrogenolysis product 9 isolated from benzamide 7 (15% and 1:6, respectively) Scheme 2. Reagents, conditions and yields: i, 13.4 equiv.benzaldehyde, 2 equiv.ZnCl 2 , rt, 71%; ii, 9 equiv.KOH, 25 equiv.BnCl, 100 o C, 77%; iii, acetone, aqueous HCl (cat.), reflux, 82%; iv, 2.5 equiv.triphenylphosphine, 2 equiv.imidazole, 1 equiv.iodine, toluene, reflux, 46%; v, 4.5 equiv.NaN  confirms that conformational restraint "imposed by the carbohydrate unit" favors the cyclization.The similarity of the results obtained with the epimeric iodobenzamides 2 and 4 suggests that the cyclization mode, the yields and the ratio of the products are not affected by C-4 configuration of the carbohydrate unit of iodobenzamide.
6][17][18][19][20][21] Our results have also confirmed that the presence of the sugar unit in the benzamide favors the aryl radical cyclization. 21This work allows to deduce that the C-4 configuration of the carbohydrate unit of oiodobenzamide does not interfere or has little effect on the formation of the products in Bu 3 SnH-mediated aryl radical reactions.

General procedures
All melting points were determined on a Kofler Sybron apparatus and are uncorrected.Optical rotations were determined at 25 o C with a Bellingham & Stanley P20 Polarimeter.The NMR spectra were measured in deuteriochloroform with TMS as the internal standard with a Bruker Avance DRX-400 or a Bruker Avance-200 instruments.Chemical shifts are given in δ scale and J values are given in Hz.Column chromatography was performed with silica gel 60, 70-230 mesh (Merck).The term "standard workup" means that the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure.4][25][26][27][28][29][30] The radical reaction was carried out using standard procedure. 32thyl 2,3-di-O-benzyl-6-deoxy-6-iodo-α-D-galactopyranoside (13)   To a solution of 12 (0.50 g, 1.3 mmol) in toluene (15 mL) were added imidazole (0.18 g, 2.7 mmol), triphenylphosphine (0.90 g, 3.4 mmol) and iodine (0.37 g, 1.4 mmol).The solution was stirred under reflux for 7 h.Saturated aqueous NaHCO 3 , iodine, and 1 mol L -1 aqueous sodium thiosulfate were added.The organic layer was separated and the aqueous layer was extracted with toluene.Standard work-up gave a residue, which was purified by column chromatography.The compound 13 (0.30 g, 0.62 mmol, 46%), eluted with hexane-ethyl acetate 8:2 (v/v), was obtained as a white crystal; mp 103.9-105.