HETEROCYCLES

Note | Regular issue | Vol. 81, No. 1, 2010, pp. 149-161
Received, 20th September, 2009, Accepted, 26th October, 2009, Published online, 27th October, 2009.
DOI: 10.3987/COM-09-11835

■ A Synthetic Study of Dibenzo-Aromatic Macrolactams

David P. Brown* and Thomas Wong

Department of Chemistry, St. John’s College of Liberal Arts and Sciences, St. John's University, 8000 Utopia Parkway, Jamaica, New York 11439, U.S.A.

Abstract

Efforts to generate benzenoid macrolactams in the development of hybrid molecules as New Chemical Entities are described. The olefin metathesis protocol was adopted in facilitating the cyclization process.

Among the plethora of naturally occurring biologically active systems that have engaged the intellectual curiosity of synthetic chemists are those compounds containing an aromatic macrocyclic lactam skeleton.1 These compounds are known for their varied properties which include potent antibiotic and anti-tumor activities.2 An attractive feature of the macrocyclic skeletal system is the increased permeability of the macromolecules to membranous barriers. They are also less prone to standard routes of in vivo degradation. Accordingly, orally bioavailable macrocycles have been developed which include enzyme inhibitors of HIV protease, ACE, and matrix metalloproteinases.3
Current investigative efforts in the design and synthesis of novel natural product hybrids4 required that we explored the generation of macrolactams incorporating two or more independent benzenoid structural units. Of particular interest were the effects of atom connectivity across the aromatic rings, and ring size on product yields. Ibrahim and John have demonstrated the synthesis of some structurally related systems; specifically, a series of macrocyclic ployoxadi- and polyoxatetramides5 employing ring closing metathesis (RCM) methodology,6 Scheme 1. In a previous study, we have similarly applied the RCM protocol in the synthesis some novel macrolactones in good to excellent yields.7

Synthesis of the RCM substrates 1 through 12 were accomplished through nucleophilic acyl substitution reactions as were reported for the macrolactones previously synthesized.7 With the preliminary findings that, in addition to ring size, the macrocyclization process in the case of the lactones was affected by atom connectivity across the benzene rings, we initially explored the generality of this effect, observing the outcomes of dienes 1, 2 and 3. Table 1 summarizes the results from high dilution studies, employing the first generation Grubbs catalyst in CH2Cl2 under reflux for 8 h. The expected progressive increase in product yields was observed, with all three macrocycles isolated as inseparable mixtures of stereoisomers. For diene 2, extending the reaction time to about 20 h yielded the cyclic dimer 14a as the exclusive product in a low 5% yield, Scheme 2. The proton NMR spectrum of compound 14a gave distinct chemical shifts of δ 9.35 and 9.45 for the amide protons suggesting a head-to-tail dimerization outcome.

In the case of substrate 4, only the acyclic dimer 16, Scheme 3, and un-reacted starting material were isolated.

Attempted RCM cyclization of the mixed 1,2-di- and 1,3-disubstituted benzene derivatives 5 through 9 proved futile. Except for substrate 7, the starting diene and un-characterizable polymeric materials were recovered. For diene 7, trace amounts of the acyclic dimer 17 was isolated along with starting material.

The pentenyl esters 10, 11 and 12 were subjected to the RCM conditions with the expectation that increasing the ring size would assist in combating the apparent negative enthalpy factors during cyclization. Diene 10 afforded the expected product 18 along with the cyclic dimer 19, Scheme 5.

After about 3 h, the macrolactam 20 was isolated in about 15% yield from the RCM reaction on diene 11, Scheme 6. Extending the reaction time up to 20 h failed to improve on the product yield. As expected, the diene 12 failed to undergo cyclization under the reaction conditions investigated. Significant compound decomposition was observed on prolonged heating with the catalyst.

In summary, we have further elucidated the application of the first generation Grubbs catalyst in the synthesis of dibenzo-aromatic macrolactams, with our findings alluding to the necessity of using a more active catalyst system such as the second generation or the Schrock catalyst6 for mixed 1,2- and 1,3-disubstituted derivatives. Albeit, for the applied catalyst, the RCM approach appears to be more amenable to 1,2-disubstituted macrolactone and macrolactam precursors, with more encouraging yields resulting from substrates possessing four or more covalent bonds connecting the two aromatic rings.7

EXPERIMENTAL
Infrared spectra were obtained on a Perkin Elmer 1000 Spectrometer as neat samples or CCl4 solutions. 1H NMR and 13C NMR spectra were recorded using a Bruker DPX 400 MHz spectrometer, with chemical shifts reported as parts per million (δ ppm) downfield of the internal standard TMS. Gas Chromatography Mass Spectrometry (GC/MS) analyses were performed using the Shimadzu GCMS-QP5050A system. Elemental analyses were performed by Atlantic Microlab Inc., Norcross, GA. All required compounds for the outlined syntheses were obtained from Aldrich Chemical Company. High purity DMF was used without further purification. Dichloromethane (DCM) and THF were distilled from CaH2 and stored over 4 angstrom molecular sieves under nitrogen. Flash chromatographic purification was performed using silica gel, 200 – 400 mesh, purchased from Aldrich.

General Synthetic Procedure for the RCM Substrates 1 – 12.
A three-necked round-bottomed flask (RBF) fitted with a pressure-equalizing dropping funnel and a magnetic stir bar was flame-dried under a positive atmosphere of dry nitrogen for 5 min. After cooling to rt, a solution of the required amine (1.0 equiv.) in dichloromethane (DCM) was added via syringe through a pierced rubber septum. A separate RBF, equipped for magnetic stirring was similarly flame-dried, cooled to rt, and charged with the reacting acid (1.00 equiv.) and 5.0 equiv. SOCl2. The mixture was stirred for 2 h, after which the excess SOCl2 was evaporated in vacuo. The resulting acid chloride was re-dissolved in dry DCM and transferred via syringe to the dropping funnel, which was then added drop-wise with stirring to the amine solution at 0 oC. The mixture was stirred at the cooling temperature for 1 h after which the solvent was evaporated under reduced pressure. Ether was then added to extract the product, with the organic phase being washed with brine and dried over anhydrous MgSO4. Chromatographic purification was done with hexane-EtOAc (5:1 v/v) as eluent.

Allyl 2-[(2-allyloxybenzoyl)amino] benzoate, (1).
Compound 1 was isolated as a clear oil, (45%); IR: 754, 1074, 1123, 1253, 1297, 1446, 1518, 1583, 1667, 1703, 2939, 3070, 3268 cm-1; 1H NMR (CDCl3, ppm): δ 4.77 (d, J = 5.4 Hz, 2H), 4.82 (d, J = 4.0 Hz, 2H), 5.24 (d, J = 9.1 Hz, 1H), 5.26 (d, J = 9.1 Hz, 1H), 5.37 (d, J = 17.2 Hz, 2H), 6.04 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.1 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 8.94 (d, J = 8.3 Hz, 1H), 12.1 (s, 1H); 13C NMR (CDCl3, ppm): δ 65.9, 69.9, 113.4, 116.0, 118.4, 118.9, 121.5, 122.4, 123.0, 124.0, 131.2, 132.4, 132.6, 133.3, 134.6, 141.8, 156.8, 165.1, 167.8; MS: (EI, m/z): 337(M+), 279, 264, 234, 207, 177, 119, 105, 77, 51, 45. Anal. Calcd for C20H19NO4 (337.37): C, 71.20; H, 5.68; N, 4.14. Found: C, 71.31; H, 5.67; N, 4.08.

Allyl 2-([2-allyloxyphenyl]acetyl)amino benzoate, (2).
Compound 2 was obtained as a pale yellow oil, (38%); IR: 753, 1084, 1142, 1254, 1294, 1449, 1492, 1524, 1587, 1649, 1688, 2866, 2943, 2982, 3025, 3077, 3275, 3301 cm-1; 1H NMR (CDCl3, ppm): δ 3.79 (s, 2H), 4.56 (d, J = 3.7 Hz, 2H), 4.70 (d, J = 4.9 Hz, 2H), 5.16 (d, J = 10.6 Hz, 1H), 5.27 (d, J = 10.4 Hz, 1H), 5.33 (d, J = 17.0 Hz, 1H), 5.37 (d, J = 14.1 Hz, 1H), 5.98 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.95 (t, J = 7.3 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.3 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 8.73 (d, J = 8.4 Hz, 1H), 10.94 (s, 1H); 13C NMR (DMSO-d6, ppm): δ 66.2, 68.9, 112.9, 117.0, 117.4, 119.2, 121.3, 121.4, 123.7, 124.1, 129.5, 131.4, 132.2, 133.1, 134.4 (2C’s), 135.1, 141.2, 157.0, 167.5, 170.4; MS: (EI, m/z): 351(M+), 177, 160, 146, 119, 105, 91, 77, 65. Anal. Calcd for C21H21NO4 (351.40): C, 71.78; H, 6.02; N, 3.99. Found: C, 71.74; H, 6.08; N, 4.01.

Allyl 2-{3-[2-(allyloxy)phenyl]propanoyl}amino benzoate, (3).
Compound 3 was isolated as a clear oil, (45%); IR: 753, 930, 1162, 1253, 1526, 1588, 1602, 1688, 2846, 2917, 3010, 3076, 3312 cm-1; 1H NMR (CDCl3, ppm): δ 2.78 (t, J = 8.1 Hz, 2H), 3.13 (t, J = 7.5 Hz, 2H), 4.60 (d, J = 4.8 Hz, 2H), 4.83 (d, J = 5.5 Hz, 2H), 5.29 (dd, J = 0.6, 10.6 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H), 5.44 (d, J = 17.0 Hz, 1H), 5.46 (dd, J = 1.1, 17.3 Hz, 1H), 6.04 (ddt, J = 5.7, 10.6, 15.7 Hz, 1H), 6.13 (ddt, J = 5.1, 10.7, 16.9 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 8.3 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 8.77 (d, J = 8.5 Hz, 1H), 11.05 (s, 1H); 13C NMR (CDCl3, ppm): δ 27.1, 39.0, 66.1, 69.0, 111.9, 115.2, 117.5, 119.1, 120.8, 121.1, 122.7, 127.9, 129.6, 130.5, 131.2, 132.1, 133.9, 135.1, 142.2, 156.9, 168.2, 172.2; MS: (EI, m/z): 365(M+), 307, 288, 177, 161, 147, 131, 119, 105, 91, 77, 65, 55, 41. Anal. Calcd for C22H23NO4 (365.42): C, 72.31; H, 6.34; N, 3.83. Found: C, 72.29; H, 6.46; N, 4.00.

Allyl 2-[3-({2-methyl}allyloxyphenyl)propanoyl]amino benzoate, (4).
Subtrate 4 was obtained as a pale yellow oil, (56%); IR: 751, 935, 1158, 1532, 1587, 1600, 1687, 2845, 2920, 3011, 3079, 3316 cm-1; 1H NMR (CDCl3, ppm): δ 1.85 (s, 3H), 2.77 (t, J = 4.7 Hz, 2H), 3.11 (m, 2H), 4.45 (s, 2H), 4.79 (m, 2H), 4.98 (s, 1H), 5.13 (s, 1H), 5.29 (dd, J = 1.2, 10.4 Hz, 1H), 5.39 (dd, J = 1.5, 17.2 Hz, 1H), 6.02 (m, 1H), 6.84 (m, 2H), 7.05 (m, 1H), 7.20 (m, 2H), 7.53 (m, 1H), 8.04 (m, 1H), 8.76 (dd, J = 4.0, 8.3 Hz, 1H), 11.03 s, 1H); 13C NMR (CDCl3, ppm): δ 20.0, 27.1, 39.0, 65.2, 71.9, 111.8, 112.7, 115.2, 119.1, 120.8, 121.0, 122.7, 127.9, 129.5, 130.5, 131.2, 132.2, 135.1, 141.4, 142.2, 156.0, 168.2, 172.1; MS: (EI, m/z): 379(M+), 322, 218, 204, 177, 161, 105, 90, 77, 57. Anal. Calcd for C23H25NO4 (379.45): C, 72.80; H, 6.64; N, 3.69. Found: C, 72.69; H, 6.59; N, 3.71.

Allyl 3-[(2-allyloxybenzoyl)amino] benzoate, (5).
Substrate 5 was isolated as a yellow oil, (52%); IR: 751, 1069, 1124, 1258, 1460, 1520, 1588, 1667, 1706, 2939, 3071, 3265 cm-1; 1H NMR (CDCl3, ppm): δ 4.82 (m, 4H), 5.30 (dd, J = 1.1, 10.3 Hz, 1H), 5.42 (dd, J = 1.4, 17.2 Hz, 1H), 5.50 (d, J = 10.4 Hz, 1H), 5.56 (d, J = 17.2 Hz, 1H), 6.06 (m, 1H), 6.23 (m, 1H), 7.04 (t, J = 8.2 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.46 (m, 2H), 7.81 (dd, J = 0.9, 7.6 Hz, 1H), 8.14 (m, 2H), 8.30 (dd, J = 1.6, 7.8 Hz, 1H), 10.13 (s, 1H); 13C NMR (CDCl3, ppm): δ 66.1, 70.7, 113.3, 118.7, 120.9, 121.4, 122.1, 122.4, 125.1, 125.6, 129.6, 131.3, 132.1, 132.6, 133.0, 133.8, 139.2, 156.8, 163.7, 166.4; MS: (EI, m/z): 337(M+), 280, 204, 177, 162, 105, 77, 57. Anal. Calcd for C20H19NO4 (337.37): C, 71.20; H, 5.68; N, 4.15. Found: C, 71.21; H, 5.67; N, 4.16.

Allyl 2-[(3-allyloxybenzoyl)amino] benzoate, (6).
Compound 6 was obtained as a clear syrup, (42%); IR: 757, 1082, 1144, 1269, 1301, 1449, 1490, 1531, 1647, 1589, 1677, 2944, 3077, 3271, 3306 cm-1; 1H NMR (CDCl3, ppm): δ 4.61 (d, J = 5.0 Hz, 2H), 4.83 (d, J = 5.5 Hz, 2H), 5.31 (d, J = 10.2 Hz, 2H), 5.42 (d, J = 16.8 Hz, 1H), 5.44 (d, J = 16.8 Hz, 1H), 6.05 (ddt, J = 5.6, 10.5, 16.2 Hz, 2H), 7.10 (d, J = 6.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.58 (m, 3H), 8.09 (d, J = 7.8 Hz, 1H), 8.92 (d, J = 8.4 Hz, 1H), 11.94 (s, 1H); 13C NMR (CDCl3, ppm): δ 66.3, 69.3, 113.8, 115.5, 118.3, 119.2, 119.5, 119.8, 120.8, 123.0, 130.2, 131.4, 132.1, 133.4, 135.2, 136.7, 142.3, 159.4, 165.8, 168.5; MS: (EI, m/z): 337(M+), 177, 160, 133, 119, 105, 77, 55. Anal. Calcd for C20H19NO4 (337.37): C, 71.20; H, 5.68; N, 4.15. Found: C, 71.19; H, 5.64; N, 4.20.

Allyl 3-([2-allyloxyphenyl]acetyl)amino benzoate, (7).
Compound 7 was isolated as a clear syrup, (54%); IR: 753, 1084, 1142, 1254, 1298, 1492, 1524, 1587, 1649, 1688, 2943, 2982, 3025, 3078, 3275, 3307 cm-1; 1H NMR (CDCl3, ppm): δ 3.74 (s, 2H), 4.64 (m, 2H), 4.79 (m, 2H), 5.27 (d, J = 10.4 Hz, 1H), 5.35 (d, J = 11.1 Hz, 1H), 5.40 (dd, J = 1.4, 17.3 Hz, 1H), 5.48 (d, J = 17.3 Hz, 1H), 6.06 (m, 2H), 6.94 (m, 2H), 7.26 (m, 3H), 7.74 (d, J = 6.6 Hz, 1H), 7.90 (m, 2H), 8.12 (s, 1H); 13C NMR (CDCl3, ppm): δ 40.7, 66.1, 69.5, 112.4, 118.7, 119.0, 120.8, 122.0, 123.4, 123.8, 124.7, 125.4, 129.4, 129.5, 131.1, 131.9, 132.5, 133.1, 156.2, 166.3, 170.2; MS: (EI, m/z): 351(M+), 177, 160, 146, 119, 105, 91, 77, 65. Anal. Calcd for C21H21NO4 (351.40): C, 71.78; H, 6.02; N, 3.99. Found: C, 71.77; H, 6.01; N, 3.96.

Allyl 3-[3-((2-allyloxyphenyl)propanoyl)amino] benzoate, (8).
Compound 8 was isolated as a yellow syrup, (45%); IR: 750, 930, 1162, 1253, 1526, 1588, 1602, 1690, 2846, 2917, 3010, 3076, 3314 cm-1; 1H NMR (CDCl3, ppm): δ 2.73 (t, J = 7.6 Hz, 2H), 3.11 (t, J = 7.3 Hz, 2H), 4.60 (d, J = 4.3 Hz, 2H), 4.84 (d, J = 5.5 Hz, 2H), 5.32 (d, J = 10.4 Hz, 2H), 5.43 (dd, J = 1.4, 17.1 Hz, 1H), 5.46 (dd, J = 1.3, 13.0 Hz, 1H), 6.08 (ddt, J = 5.6, 10.5, 17.0 Hz, 2H), 6.89 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7.22 (m, 3H), 7.41 (t, J = 7.9 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.91 (s, 1H), 7.92 (d, J = 9.1 Hz, 1H); 13C NMR (CDCl3, ppm): δ 27.3, 39.5, 66.0, 69.1, 111.9, 115.2, 117.4, 119.1, 120.8, 121.1, 122.6, 127.8, 129.6, 130.4, 131.2, 132.1, 134.0, 135.1, 142.1, 156.9, 168.2, 172.3; MS: (EI, m/z): 365(M+), 307, 288, 177, 161, 147, 131, 119, 105, 91, 77, 65, 55. Anal. Calcd for C22H23NO4 (365.42): C, 72.31; H, 6.34; N, 3.83. Found: C, 72.33; H, 6.38; N, 3.89.

2-Methylallyl 3-[3-(({2-methyl}allyloxyphenyl)propanoyl)amino] benzoate, (9).
Substrate 9 was obtained as a pale yellow syrup, (52%); IR: 755, 930, 1162, 1255, 1526, 1588, 1608, 1697, 2845, 2917, 3010, 3076, 3328 cm-1; 1H NMR (CDCl3, ppm): δ 1.86 (s, 3H), 1.88 (s, 3H), 2.72 (t, J = 7.4 Hz, 2H), 3.11 (t, J = 7.5 Hz, 2H), 4.49 (s, 2H), 4.76 (s, 2H), 5.01 (s, 1H), 5.04 (s, 1H), 5.09 (s, 1H), 5.15 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.92 (t, J = 7.1 Hz, 1H), 7.22 (t, J = 7.3 Hz, 3H), 7.41 (t, J = 8.0 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.89 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, ppm): δ 19.7, 19.9, 27.3, 39.5, 66.0, 69.1, 111.7, 115.2, 117.3, 119.1, 120.8, 121.1, 122.6, 127.8, 129.6, 130.3, 131.2, 132.1, 134.1, 135.1, 142.3, 156.9, 168.1, 172.5; MS: (EI, m/z): 393(M+), 322, 232, 203, 177, 161, 105, 91, 77, 55. Anal. Calcd for C24H27NO4 (393.48): C, 73.26; H, 6.92; N, 3.56. Found: C, 73.31; H, 6.78; N, 3.58.

Pent-4-en-1-yl 2-{[3-(allyloxy)phenyl]carbonyl}amino benzoate, (10).
Compound 10 was obtained as a clear oil, (58%); IR: 757, 956, 1162, 1253, 1526, 1586, 1602, 1678, 2846, 2917, 3013, 3077, 3324 cm-1; 1H NMR (CDCl3, ppm): δ 1.89 (q, J = 6.7 Hz, 2H), 2.23 (dt, J = 7.0. 7.1 Hz, 2H), 4.36 (t, J = 6.6 Hz, 2H), 4.62 (d, J = 5.3 Hz, 2H), 5.03 (d, J = 10.2 Hz, 1H), 5.08 (dd, J = 1.6, 17.1 Hz, 1H), 5.31 (dd, J = 1.2, 10.5 Hz, 1H), 5.45 (dd, J = 1.5, 17.3 Hz, 1H), 5.84 (ddt, J = 6.6, 10.3, 17.0 Hz, 1H), 6.08 (ddt, J = 5.3, 10.5, 17.2 Hz, 1H), 7.11 (dt, J = 1.2, 8.4 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.61 (m, 3H), 8.08 (dd, J = 1.4, 8.0 Hz, 1H), 8.92 (d, J = 8.2 Hz, 1H), 12.07 (s, 1H); 13C NMR (CDCl3, ppm): δ 29.6, 38.7, 66.7, 69.1, 113.9, 115.7, 118.2, 119.2, 119.7, 119.9, 120.8, 123.1, 130.2, 131.4, 132.4, 133.4, 135.0, 136.7, 142.5, 159.4, 165.8, 168.7; MS: (EI, m/z): 365(M+), 280, 204, 177, 161, 113, 105, 85, 77, 41. Anal. Calcd for C22H23NO4 (365.42): C, 72.31; H, 6.34; N, 3.83. Found: C, 72.29; H, 6.28; N, 3.78.

Pent-4-en-1-yl 3-{3-[2-(allyloxy)phenyl]propanoyl}amino benzoate, (11).
Substrate 11 was isolated as a clear syrup, (56%); IR: 748, 928, 1256, 1529, 1588, 1602, 1690, 2849, 2918, 3013, 3077, 3321 cm-1; 1H NMR (CDCl3, ppm) δ 1.83 (q, J = 6.8 Hz, 2H), 2.18 (dt, J = 7.0. 7.2 Hz, 2H), 2.70 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.4 Hz, 2H), 4.29 (t, J = 6.6 Hz, 2H), 4.53 (d, J = 4.9 Hz, 2H), 5.00 (d, J = 10.2 Hz, 1H), 5.05 (dd, J = 1.3, 17.1 Hz, 1H), 5.26 (d, J = 10.5 Hz, 1H), 5.43 (d, J = 17.3 Hz, 1H), 5.83 (ddt, J = 6.6, 10.3, 17.0 Hz, 1H), 6.05 (ddt, J = 5.1, 10.7, 17.1 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 7.93 (s, 1H); 13C NMR (CDCl3, ppm): δ 26.6, 27.8, 30.1, 37.7, 64.6, 68.7, 111.7, 115.5, 117.4, 120.6, 120.9, 124.5, 125.1, 127.8, 129.0, 129.1, 130.2, 130.9, 133.3, 137.4, 138.3, 156.3, 166.4, 171.4; MS: (EI, m/z): 393(M+), 308, 246, 204, 190, 177, 147, 105, 91, 77. Anal. Calcd for C24H27NO4 (393.48): C, 73.26; H, 6.92; N, 3.56. Found: C, 73.29; H, 6.88; N, 3.58.

Pent-4-en-1-yl 2-{[4-(allyloxy)phenyl]carbonyl}amino benzoate, (12).
Compound 12 was obtained as a yellow oil, (57%); IR: 756, 956, 1163, 1253, 1526, 1586, 1607, 1678, 2849, 2920, 3013, 3075, 3326 cm-1; 1H NMR (CDCl3, ppm) δ 1.88 (q, J = 6.9 Hz, 2H), 2.21 (dt, J = 6.8, 7.7 Hz, 2H), 4.33 (t, J = 6.6 Hz, 2H), 4.56 (dd, J = 1.4, 5.3 Hz, 2H), 5.01 (dd, J = 1.7, 10.2 Hz, 1H), 5.07 (dd, J = 1.7, 15.4 Hz, 1H), 5.29 (dd, J = 1.4, 10.6 Hz, 1H), 5.42 (dd, J = 1.5, 17.3 Hz, 1H), 5.85 (ddt, J = 6.6, 10.3, 17.1 Hz, 1H), 6.03 (ddt, J = 5.2, 12.0, 17.3 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.06 (dt, J = 1.1, 6.9 Hz, 1H), 7.55 (dt, J = 1.3, 7.1 Hz, 1H), 7.98 (d, J = 8.9 Hz, 2H), 8.04 (dd, J = 1.5, 8.1 Hz, 1H), 8.93 (d, J = 8.5 Hz, 1H), 11.98 (s, 1H); 13C NMR (CDCl3, ppm): δ 27.7, 30.1, 64.8, 68.8, 114.7 (2 C’s), 115.1, 115.6, 118.0, 120.3, 122.3, 127.3, 129.3 (2 C’s), 130.8, 132.7, 134.7, 137.2, 142.2, 161.6, 165.1, 168.6; MS: (EI, m/z): 365(M+), 280, 204, 177, 161, 113, 105, 85, 77, 41. Anal. Calcd for C22H23NO4 (365.42): C, 72.31; H, 6.34; N, 3.83. Found: C, 72.30; H, 6.27; N, 3.81.

General Procedure for the RCM Reaction
A 100 mL round-bottomed flask fitted with a reflux condenser, a calcium chloride guard tube, and equipped for magnetic stirring, was flame dried under a positive atmosphere of dry nitrogen. After cooling to room temperature, the flask was charged with a solution of the RCM substrate in DCM (2 mM). To this solution was added the Grubbs catalyst (2 – 2.5 mol%) dissolved in 20 mL DCM with stirring. The reaction mixture was stirred under reflux (40 oC) for up to 20 h, cooled to rt, then filtered through a short silica gel column, after which the solvent was evaporated in vacuo. The desired product was then extracted by stirring with diethyl ether, evaporated to dryness, and the crude product purified by flash chromatography.

Dibenzo[b,f]-1,6,12-dioxazacyclotridec-3-en-7,13-dione, (13).
Compound 13 was obtained after 6 h as a clear syrup, (15%); IR: 746, 1049, 1122, 1137, 1243, 1312, 1359, 1453, 1533, 1585, 1600, 1666, 1718, 3025, 3068, 3340 cm-1; 1H NMR (CDCl3, ppm): δ 4.79 (d, J = 6.4 Hz, 2H), 4.94 (d, J = 7.6 Hz, 2H), 6.35 (m, 1H), 6.52 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 6.9 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.0 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 8.25 (d, J = 7.3 Hz, 1H), 8.90 (d, J = 8.4 Hz, 1H), 11.5 (s, 1H); 13C NMR (CDCl3, ppm): δ 59.4, 63.1, 110.0, 112.7, 118.6, 122.3, 122.4, 122.5, 123.7, 132.1, 132.6, 133.0, 133.5, 133.6, 134.5, 144.0, 161.0, 165.0; MS: (EI, m/z): 309(M+), 281, 239, 207, 189, 146, 119, 92, 65, 53, 45. Anal. Calcd for C18H15NO4 (309.32): C, 69.89; H, 4.89; N, 4.53. Found: C, 69.74; H, 4.91; N, 4.49.

Dibenzo[b,g]-1,6,12-dioxazacyclotetradec-3-en-7,13-dione, (14).
Macrolactam 14 was obtained after 8 hours as a yellow syrup, (20%); IR: 753, 1082, 1092, 1140, 1230, 1294, 1367, 1443, 1494, 1522, 1587, 1604, 1688, 1737, 3025, 3064, 3275 cm-1; 1H NMR (CDCl3, ppm): δ 3.74 (s, 2H), 4.32 (s, 2H), 4.81 (s, 2H), 5.74 (m, 1H), 5.90 (m, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.54 (t, J = 8.5 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 8.76 (d, J = 8.4 Hz, 1H), 10.93 (s, 1H); 13C NMR (CDCl3, ppm): δ 31.0, 65.6, 111.7, 112.1, 115.1, 118.5, 120.5, 121.7, 122.1, 122.4, 123.2, 128.9, 130.1, 131.3, 131.5, 133.2, 133.4, 167.5, 170.8; MS: (EI, m/z): 323(M+), 204, 119, 105, 90, 77. Anal. Calcd for C19H17NO4 (323.34): C, 70.58; H, 5.30; N, 4.33. Found: C, 70.60; H, 5.28; N, 4.39.

Macrocyclic Dilactam 14a
Compound 14a was obtained as a dark brown syrup (5%), IR: 763, 1082, 1140, 1230, 1294, 1367, 1443, 1494, 1522, 1587, 1610, 1688, 1743, 3025, 3064, 3280 cm-1; 1H NMR (CDCl3, ppm): δ 3.69 (s, 2H), 3.75 (s, 2H), 4.56 (d, J = 6.5 Hz, 2H), 4.72 (d, J = 7.2 Hz, 2H), 4.81 (s, 2H), 4.97 (d, J = 8.3 Hz, 2H), 5.84 (m, 2H), 6.27 (dt, J = 8.3, 16.9 Hz, 1H), 6.44 (dt, J = 7.0, 17.3 Hz, 1H), 7.06 (m, 6H), 7.40 (m, 6H), 7.68 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.44 (d, J = 8.2 Hz, 1H), 9.35 (s, 1H), 9.45 (s, 1H); 13C NMR (CDCl3, ppm): δ 66.2, 67.5, 68.9, 70.1, 112.7, 112.9, 117.0, 117.2, 117.4, 117.8, 119.2, 119.4, 121.3, 121.4, 121.5, 122.6, 123.7, 123.9, 124.1, 124.3, 129.5, 129.6, 131.4, 132.2, 133.1, 133.4, 134.2 (2C’s), 134.6, 134.9, 135.1, 141.2, 157.0, 157.1, 167.5, 168.0, 170.3, 170.6; MS: (EI, m/z): 646(M+), 323, 204, 188, 135, 119, 105, 90, 77. Anal. Calcd for C38H34N2O8 (646.23): C, 70.58; H, 5.30; N, 4.33. Found: C, 70.54; H, 5.29; N, 4.30.

Dibenzo[b,h]-1,6-12-dioxazacyclopentadec-3-en-7,13-dione, (15).
Macrolactam 15 was isolated as a clear solid, (70%); MP 92 oC; IR: 751, 973, 1244, 1447, 1552, 1583, 1604, 1668, 1681, 1714, 2846, 2919, 3021, 3060, 3335, 3384 cm-1; 1H NMR (CDCl3, ppm): δ 2.63 (dt, J = 3.5, 8.6 Hz, 2H), 3.04 (t, J = 8.0 Hz, 2H), 4.63 (d, J = 5.1 Hz, 2H), 4.94 (d, J = 6.0 Hz, 2H), 6.34 (m, 2H), 6.93 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 7.15 (dt, J = 1.0, 8.0 Hz, 1H), 7.25 (m 2H), 7.57 (dt, J = 1.5, 8.7 Hz, 1H), 8.04 (dd, J = 1.5, 7.9 Hz, 1H), 8.60 (d, J = 7.7 Hz, 1H), 9.60 (s, 1H); 13C NMR (CDCl3, ppm): δ 29.2, 40.0, 65.4, 67.3, 113.4, 118.3, 121.7, 122.1, 123.7, 128.4, 128.8, 130.0, 131.1, 132.4, 134.1, 134.5, 139.3, 157.1, 166.2, 171.6; MS: (EI, m/z): 337 (M+), 279, 264, 234, 207, 190, 175, 159, 145, 131, 120 (100%), 92, 77, 65, 55. Anal. Calcd for C20H19NO4 (337.37): C, 71.20; H, 5.68; N, 4.15. Found: C, 71.20; H, 5.61; N, 4.18.

Acyclic Dimer 16
Compound 16 was isolated as a brown syrup, (10%); IR: 759, 945, 1536, 1578, 1617, 1687, 2845, 2923, 3011, 3079, 3328 cm-1; 1H NMR (CDCl3, ppm): δ 1.18 (s, 6H), 2.77 (t, J = 7.9 Hz, 4H), 3.10 (t, J = 7.1 Hz, 4H), 4.45 (s, 4H), 4.84 (m, 2H), 4.97 (m, 4H), 5.12 (s, 2H), 6.06 (m, 2H), 6.83 (t, J = 8.2 Hz, 2H), 6.87 (d, J = 7.2 Hz, 2H), 7.15 (m, 6H), 7.54 (t, J = 7.0 Hz, 2H), 8.05 (d, J = 7.9 Hz, 2H), 8.75 (d, J = 8.1 Hz, 2H), 11.00 (s, 2H); 13C NMR (CDCl3, ppm, 2 C’s per signal): δ 20.0, 27.1, 32.5, 39.0, 64.8, 71.9, 111.8, 112.7, 115.0, 121.0, 122.7, 127.9, 128.5, 129.4, 130.5, 132.5, 135.3, 141.4, 142.2, 145.3, 156.8, 168.1, 172.2; MS: (EI, m/z): 730 (M+), 378, 322, 218, 204, 177, 161, 105, 90, 77, 57. Anal. Calcd for C44H46N2O8 (730.84): C, 72.31; H, 6.34; N, 3.83. Found: C, 72.28; H, 6.41; N, 3.78.

Acyclic Dimer 17
Compound 17 was obtained as a brown syrup, (5%); IR: 761, 1067, 1072, 1251, 1298, 1492, 1524, 1587, 1649, 1688, 2943, 2986, 3025, 3068, 3275, 3348 cm-1; 1H NMR (CDCl3, ppm): δ 3.75 (s, 4H), 4.74 (m, 8H), 5.36 (m, 4H), 6.12 (m, 4H), 6.95 (d, J = 7.2 Hz, 2H), 6.99 (d, J = 6.1 Hz, 2H), 7.29 (m, 6H), 7.80 (m, 6H), 8.00 (s, 1H), 8.04 (s, 1H); 13C NMR (CDCl3, ppm): δ 40.7, 66.1, 67.9, 69.5, 109.9, 111.1, 112.0, 112.4, 118.4, 118.7, 119.0, 120.8, 121.7, 122.0, 123.3, 123.4, 123.8, 124.1, 124.3, 124.7, 125.1, 125.4, 129.0, 129.1, 129.4, 129.5, 131.0, 131.1, 131.5, 131.9, 132.5, 132.6, 133.1, 138.5, 155.8, 156.7, 166.0, 166.3, 170.2, 179.3; MS: (EI, m/z): 674 (M+), 617, 498, 350, 294, 177, 160, 146, 119, 105, 91, 77, 65.

Macrolactam 18
Compound 18 was obtained as yellow syrup, (10%); IR: 760, 956, 1162, 1526, 1586, 1610, 1658, 2846, 2927, 3013, 3078, 3348 cm-1; 1H NMR (CDCl3, ppm): δ 1.97 (m, 2H), 2.23 (m, 2H), 4.56 (t, J = 5.6 Hz, 2H), 4.77 (d, J = 5.6 Hz, 2H), 5.71 (dt, J = 5.7, 15.7 Hz, 1H), 6.15 (dt, J = 6.7, 15.6 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.38 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.62 (dt, J = 1.6, 8.4 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 8.06 (dd, J = 1.4, 7.9 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H), 10.73 (s, 1H); 13C NMR (CDCl3, ppm): δ 29.7, 39.0, 66.7, 69.1, 113.9, 115.7, 119.2, 119.7, 120.7, 123.1, 130.1, 131.4, 132.9, 133.1, 134.9, 136.7, 142.5, 159.4, 166.3, 167.6; MS: (EI, m/z): 337 (M+), 293, 202, 177, 105, 91, 77. Anal. Calcd for C20H19NO4 (337.37): C, 71.20; H, 5.68; N, 4.15. Found: C, 71.18; H, 5.41; N, 4.28.

Macrocyclic Dilactam 19
Compound 19 was obtained as brown syrup, (5%); IR: 789, 948, 1202, 1536, 1634, 1639, 2843, 2930, 3015, 3067, 3337 cm-1; 1H NMR (CDCl3, ppm): δ 1.95 (q, J = 6.7 Hz, 4H), 2.80 (dt, J = 6.3, 6.6 Hz, 4H), 4.23 (t, J = 7.2 Hz, 4H), 4.67 (d, J = 5.6 Hz, 4H), 5.73 (dt, J = 5.9, 15.5 Hz, 2H), 5.91 (dt, J = 6.8, 15.5 Hz, 2H), 7.02 (dt, J = 1.0, 8.1 Hz, 2H), 7.09 (dd, J = 1.2, 8.8 Hz, 2H), 7.39 (t, J = 8.1 Hz, 2H), 7.43 (dt, J = 1.5, 8.6 Hz, 2H), 7.57 (m, 4H), 8.01 (dd, J = 1.4, 8.0 Hz, 2H), 8.73 (d, J = 7.9 Hz, 2H), 12.01 (s, 2H); 13C NMR (CDCl3, ppm): δ 21.1, 22.7, 23.7, 24.4, 28.1, 28.3, 28.5, 28.9, 31.6, 34.7, 60.4, 63.3, 63.6, 64.9, 68.7, 96.2, 104.9, 110.9, 113.4, 115.4, 116.2, 116.6, 119.2, 120.5, 122.6, 125.5, 129.7, 129.8, 130.2, 130.8, 131.1, 134.7, 136.4, 141.9, 150.5, 159.0, 165.5, 168.1, 168.6, 171.1; MS: (EI, m/z): 674 (M+), 532, 413, 294, 174, 120, 104, 91.

Macrolactam 20
Compound 20 was isolated as a yellow syrup, (15%); IR: 749, 975, 1244, 1452, 1552, 1583, 1604, 1668, 1681, 1714, 2846, 2925, 3032, 3060, 3335, 3378 cm-1; 1H NMR (CDCl3, ppm): δ 2.00 (m, 2H), 2.43 (m, 2H), 2.80 (m, 2H), 3.10 (m, 2H), 4.50 (m, 2H), 4.70 (m, 1H), 4.90 (m, 1H), 5.70 (m, 1H), 6.00 (m, 1H), 6.90 (m, 2H), 7.25 (m, 2H), 7.37 (m, 1H), 7.55 (s, 1H), 7.68 (m, 1H), 8.10 (s, 1H), 8.40 (m, 1H); 13C NMR (CDCl3, ppm): δ 24.1, 27.0, 28.2, 29.7, 30.1, 36.9, 66.1, 71.8, 113.7, 115.8, 118.1, 121.2, 124.4, 124.9, 126.6, 128.2, 130.3, 133.5, 136.0, 137.9, 156.5, 166.3; MS: (EI, m/z): 365 (M+), 202, 148, 119, 105, 91, 77. Anal. Calcd for C22H23NO4 (365.42): C, 72.31; H, 6.34; N, 3.83. Found: C, 72.36; H, 6.29; N, 3.76.

ACKNOWLEDGEMENTS
The authors thank the College of Liberal Arts and Sciences of St. John’s University for financial support.

References

1. B. Ruttens, P. Blom, S. Van Hoof, I. Hubrecht, and J. Van der Eycken, J. Org. Chem., 2007, 72, 5514; CrossRef A. Meyer, M. Brunjes, F. Taft, T. Frenzel, F. Sasse, and A. Kirschning, Org. Lett., 2007, 9, 1489; CrossRef F. Velazquez, S. Venkatraman, W. Wu, M. Blackman, A. Prongay, V. Girijavallabhan, N-Yang Shih, and F. George Njoroge, Org. Lett., 2007, 9, 3061.
2. W. Peng and B. S. J. Blagg, Org. Lett., 2006, 8, 975; CrossRef S. Funayama, K. Okada, K. Komiyama, and I. Umezawa, J. Antibiot., 1985, 38, 1107; K. Komiyama, Y. Hirokawa, H. Yamaguchi, S. Funayama, K. Masuda, Y. Anraku, I. Umezawa, and S. Omura, J. Antibiot., 1987, 40, 1768; W.-G Kim, N.-K Song, and L.-D Yoo, J. Antibiot., 2002, 55, 204; L. Ferrie, S. Reymond, P. Capdevielle, and J. Cossy, Org. Lett., 2006, 8, 3441; CrossRef A. Grassia, I. Bruno, C. Debitus, S. Marzocco, A. Pinto, L. Gomez-Paloma, and R. Riccio, Tetrahedron, 2001, 57, 6257; CrossRef R. Vidya, M. Eggen, S. K. Nair, G. I. Georg, and R. H. Himes, J. Org. Chem., 2003, 68, 9687; CrossRef A. K. Ghosh and L. Swanson, J. Org. Chem., 2003, 68, 9823. CrossRef
3. C. P. Decicco, Y. Song, and D. A. Evans, Org. Lett., 2001, 3, 1029; CrossRef J. D. A. Tyndall, R. C. Reid, D. P. Tyssen, D. K. Jardine, B. Todd, M. Passmore, D. R. March, L. K. Pattenden, D. A. Bergman, D. Alewood, S.-H. Hu, P. F. Alewood, C. J. Birch, J. L. Martin, and D. P. Fairlie, J. Med. Chem., 2000, 43, 3495; CrossRef G. M. Ksander, R. de Jesus, A. Yuan, R. D. Ghai, C. McMartin, and R. Bohacek, J. Med. Chem., 1997, 36, 506; CrossRef C.-B. Xue, X. He, J. Roderick, W. F. DeGrado, R. J. Cherney, K. D. Hardman, D. J. Nelson, R. A. Copeland, B. D. Jafee, and C. P. Decicco, J. Med. Chem., 1998, 41, 1745. CrossRef
4. B. Meunier, Acc. Chem. Res., 2008, 41, 69; CrossRef M. R. Barbachyn, 'Annual Reports in Medicinal Chemistry: Recent Advances in the Discovery of Hybrid Antibacterial Agents,' Vol. 43, ed. by J. E. Macor, Academic Press, Inc., New York, 2008, pp. 281-290; Y. Matsuya, T. Kawaguchi, K. Ishihara, K. Ahmed, Q.-L. Zhao, T. Kondo, and H. Nemoto, Org. Lett., 2006, 8, 4609; CrossRef T. Terasaka, T. Kinoshita, M. Kuno, and I. Nakanishi, J. Am. Chem. Soc., 2004, 126, 34; CrossRef L. F. Tietze, H. P. Bell, and S. Chandrasekhar, Angew. Chem. Int. Ed., 2003, 42, 3996; CrossRef G. Mehta and V. Singh, Chem. Soc. Rev., 2002, 31, 324. CrossRef
5. Y. A. Ibrahim and E. John, Tetrahedron, 2006, 62, 1001. CrossRef
6. A. Gradillas and J. Perez-Castells, Angew. Chem. Int. Ed., 2006, 45, 6086; CrossRef A. Deiters and S. F. Martin, Chem. Rev., 2004, 104, 2199; CrossRef I. Nakamura and Y. Yamamoto, Chem. Rev., 2004, 104, 2127. CrossRef
7. D. P. Brown and H. Q. Duong, J. Heterocycl. Chem., 2008, 45, 435. CrossRef