Synthesis and reactivity of macrocyclic lactams and dynamic nmr studies of macrocyclic amines and a macrocyclic ketone
Creators: name: Lermer, Leonard
Publisher: name: University of British Columbia
Year: 2009

description: Conformationally controlled alkylations of lactams 65, 66, 67 and 68 were investigated. High stereoselectivity was obtained in the alkylation of the dianion of lactams 65, 66 and 67. The alkylation of 65 gave products 92 and 93 in a &gt;99:1 ratio. Alkylation of 66 gave 94 and 95 in a 62:1 ratio, and alkylation of 67 gave 96 and 97 in a 10:1 ratio. The relative stereochemistry of the products from the alkylation of 67 was determined by X-ray crystallography, and by chemical correlation for the alkylation products from 65, 66. [Figure.] The relative ratio of the products from the alkylation of the N-benzyl amide 68 was found to be solvent dependent. Alkylation of 68 in hexane resulted in a 5.7:1 ratio of 110 to 111, alkylation in THF resulted in a 2.3:1 ratio and in DMSO resulted in a 1:1.3 ratio. The relative stereochemistry of the two lactams 110 and 111 was determined by chemical correlation with the products 96 and 97 obtained from the dianion alkylation of lactam 67. [Figure.] The observation of selective proton NOE enhancements upon irradiation of the NH proton and analysis of coupling constant values indicated that the amide regions of lactams 65-67 and 92-97 are conformationally similar and rigid, in the syn-periplanar and Z-amide conformation. Molecular mechanics calculations were able to correctly model the conformational rigidity of the amide region of the lactams and the stereochemistry of the products from the alkylation of lactams 65-67. The conformational properties of 13-, 14- and 16-membered macrocyclic amines 120-122, N-methyl amines 123-125, N,N-dimethyl amines 126-128 and (2R*,12S*)-2,12-dimethylcyclododecanone (98) were investigated using dynamic NMR (DNMR). [Figure.] (2R*,12S*)-2)12-Dimethylcyclododecanone (98) was found to exist in two conformations from the 13C DNMR at -95 °C, a major unsymmetric conformation and a minor symmetric conformation. The major conformation was found to be 1.6 kcal/mol more stable than the minor conformation at -95 °C. Upon cooling to -115 °C, ketone 98 was found to exist only in the unsymmetric conformation. An energy barrier of ΔG‡ = 8.6 kcal/mol at -85 °C was measured for the process of ring inversion in the unsymmetric conformation. The observed chemical shift in the 1H and 13C DNMR were consistent with the unsymmetric [3333]-2-one and symmetric [2343] as the major and minor conformations respectively. The lowest energy conformation was found by molecular mechanics calculations to be the [3333]-2-one conformation (identical to the X-ray crystal structure) and the second lowest in energy was the [2343] conformation having a plane of symmetry, in agreement with the interpretation of the DNMR. [Figure.] Azacyclotetradecane (121) was found to exist in two conformations from the 1H DNMR at -130 °C in a mixture of CHCI2F and CHCIF2 (4:1), a major symmetric conformation and a minor unsymmetric conformation. The major conformation was found to be 0.21 kcal/mol more stable than the minor conformation at -130 °C. The barrier to ring inversion in the symmetric conformation was determined to be ΔG‡ = 8.7 kcal/mol at -90 °C. The barriers to ring inversion and pseudorotation in the unsymmetric [3434] conformation was determined to be ΔG‡ = 8.3-8.5 kcal/mol at -90 °C and the activation energy for the process of local inversion between the two conformations was estimated to be in this same energy range. Azacyclotetradecane (121) was also found to exist in a major symmetric conformation and a minor unsymmetric conformation from the 13C DNMR at - 110°C in d8-toluene:CHCI2F (1:3). The observed chemical shifts in the 1H and 13C DNMR were consistent with the symmetric [3434] conformer 121-A and an unsymmetric [3434] conformer 121-B as the major and minor conformations respectively. [Figure.] N-Methylazacyclotetradecane (124) was found to exist in two conformations from the 1H DNMR at -110 °C in d4-methanol:CHCl2F (1:4), a major symmetric conformation and a minor unsymmetric conformation. The major conformation was found to be 0.30 kcal/mol more stable than the minor conformation at -110 °C. The barrier to ring inversion in the symmetric conformation was found to be ΔG‡ = 8.6 kcal/mol at -90 °C. The barriers to ring inversion and pseudorotation in the unsymmetric conformation were measured to be ΔG‡ = 8.4 kcal/mol at -95 °C and ΔG‡ = 8.2 kcal/mol at -105 °C respectively. The observed chemical shifts in the 1H DNMR were consistent with the symmetric [3434] conformer 124-A and an unsymmetric [3434] confomer 124-B as the major and minor conformations respectively. [Figure.] N,N-Dimethyltrideca-1,13-diylammonium iodide (127) was found to have an energy barrier to ring inversion of ΔG‡ = 10.5 kcal/mol at -48 °C in d4-methanol. The lowest energy conformation was found by molecular mechanics calculations to be the [3434] conformation having the geminal dimethyl group at a corner position identical to the X-ray crystal structure. [Figure.] Azacyclohexadecane (122) was found to exist in two conformations from the 1H DNMR at -120 °C in d4-methanohCHCl2F (1:3), a major symmetric conformation and a minor unsymmetric conformation. The major conformation was found to be 0.43 kcal/mol more stable than the minor conformation at -120 °C. The barrier to inversion in the symmetric [4444] conformation was measured as ΔG‡ = 7.8 kcal/mol at -110 °C. The observed chemical shifts in the 1H DNMR spectra were consistent with the symmetric [4444] conformer 122-A and an unsymmetric [4444] conformer 122-B as the major and minor conformations respectively. [Figure.] N-Methylazacyclohexadecane (125) was found to exist in two conformations from the 1H DNMR at -120 °C in CHCI2F, a major unsymmetric conformation and a minor symmetric conformation. The major conformation was found to be 0.33 kcal/mol more stable than the minor conformation at -120 °C. The slowing on the NMR time scale of the process of ring inversion in N-methylazacyclohexadecane (125) was observed prior to the separation of the two conformations upon cooling. The barrier to ring inversion in N-methylazacyclohexadecane (125) was measured as ΔG‡ = 9.0 kcal/mol at -80 °C. The observed chemical shifts in the 1H DNMR were consistent with an unsymmetric [4444] conformer 125-C and the symmetric [4444] conformer 125-A as the major and minor conformations respectively. [Figure.] [Scientific formulae used in this abstract could not be reproduced.]