Synthesis of Thiamacrocycles and Conformational Studies on Their Precursors Rudolph A. Abramovitch,* Xiaocong Ye, William T. Pennington, George Schimek, and Dariuz Bogdal Department of Chemistry, Clemson University, Clemson, South Carolina 29634-0973 Received July 16, 1999 1-(4-Nitrophenyl)-7-phenylthioheptane (1) and -9-phenylthiononane (2) have been synthesized and their conformations studied in solution and in the solid state. MMX calculations suggest that the global energy minimum structures are bent in the gas phase, probably owing to edge-to-face intramolecular attractive interaction between the electron rich and the electron poor terminal aryl groups. These conformations were confirmed in solution using 2D NOESY NMR. In the solid state, 1 and 2 exist in the staggered, linear conformation, stacked head-to-tail, with the plane of the nitro group being tilted above the plane of the benzene ring. It appears that the crystal lattice forces overcome the weak edge-to-face intramolecular aromatic interactions that dominate in the gas phase and in solution. The corresponding azides were treated with trifluoromethanesulfonic acid to generate the nitrenium ions, which underwent intramolecular ring-closure to give the corresponding 17- and 19-membered ring thiamacrocycles in modest yields. These results support the suggestion that MMX calculations on appropriate model compounds may be useful in predicting which precursors will lead to macrocycles and which will not. Introduction The synthesis of macrocyclic compounds has attracted extensive attention from synthetic chemists owing to the existence of a number of macrocyclic natural products that exhibit useful biological activities, e.g., vancomycin, 1a RA-VII, 1b arnabinol, 1c combretastatin D-2, 1d myricanone, 1e sinuloriolide, 1f to name but a few. Many effective methods have been developed during the past 20 years, especially for macrolide synthesis. Some involve high-dilution tech- niques to enhance intramolecular interaction. There was also some consideration of the effect of the conformation of the precursor in the process leading to macrocycle formation. For example, in the synthesis of macrolides, 2-4 intermediates were formed that brought the reacting sites close together, thus favoring lactonization. More recently, Marshall and co-workers 5 have synthesized a series of 12-16-membered propargylic alcohols in good yields through Lewis acid promoted electrophilic ring closure. Post facto molecular modeling calculations (MMX) on the corresponding formyl-O-protonated precursor 6a showed that the global MMXE minimum is the bent structure in which the reacting alkene site is right under the CdOH + group. Roussi, Beugelmans, and co-workers 7 formed a 15-membered ring biaryl ether intramolecularly in very good yield and attributed this to a favorable conformation of the cyclization precursor, indicated by molecular modeling to have the two interacting sites within 4.86 A of each other, resulting in a low activation energy (-187.5 kJ/mol) and a favorable entropy for cyclization. In 1989 we reported the formation (in 30% isolated yield) of a 16-membered ring involving intramolecular aromatic amination by an arylnitrenium ion under normal solution concentration (40 mM) conditions). 8 It was suggested that, in a long flexible chain bearing electron-acceptor and electron-donor end groups, these groups could “recognize” each other and get close enough such that, if this resulted in a lower activation energy for intramolecular cyclization compared with other pos- sible intermolecular pathways (thus satisfying the Cur- tin-Hammett hypothesis), intramolecular cyclization would take place. That this novel idea was plausible was first tested by computing the docking of benzene and nitrobenzene in several different approaches. 9 The two lowest energy orientations (nitrobenzene approaching benzene, and benzene approaching nitrobenzene) from MM were car- ried into MOPAC and minimized. The distance of nearest approach between a hydrogen of one molecule and a carbon of another was 2.8 Å. Nitrobenzene approaching benzene (the plane of the C 6 H 5 NO 2 is above, and orthogo- nal to that of benzene) had a computed MOPAC energy of 153.7 kJ/mol. The reverse approach (plane of C 6 H 6 above, and orthogonal to the plane of C 6 H 5 NO 2 ) had an energy of 157.9 kJ/mol. This suggested that edge-to-face aromatic interaction may account for the proposed mo- lecular recognition. (1) (a) Evans, D. A.; Dinsmore, C. J. Tetrahedron Lett. 1993, 43, 6029. (b) Itokawa, H.; Suzuki, J.; Hitoyanagi, Y.; Kondo, K.; Takaya, K. Chem. Lett. 1993, 695. 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(9) Abramovitch, R. A.; Boche, R. Unpublished results, 1993. 343 J. Org. Chem. 2000, 65, 343-351 10.1021/jo991139z CCC: $19.00 © 2000 American Chemical Society Published on Web 12/29/1999