HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 10, 2014, pp. 2380-2391
Received, 8th September, 2014, Accepted, 24th September, 2014, Published online, 26th September, 2014.
DOI: 10.3987/COM-14-13085

■ Synthesis of Novel β-Lactam Hybrids of Phenstatin and Other Substituted Aromatics as New Bioactives

David P. Brown,* Haoran Zhao, Julkernine M. Khondoker, Jatin R. Bhavsar, and Cecil C. Sigamoney

Department of Chemistry, St. John's University, 8000 Utopia Parkway, Jamaica, New York 11439, U.S.A.

Abstract

Novel β-lactam hybrids have been synthesized as new chemical entities in the development of new antibiotic antineoplastic agents.

A persistent challenge in today’s society is the pressing need to develop new anticancer and antimicrobial agents in response to constantly emerging reports of drug resistance phenomena.1 Accordingly, investigative efforts have been refocused toward developing more potent systems, and with the evolving strategy of covalently linking two biologically significant species, new hybrids with very promising pharmacological properties have been developed and evaluated.2 Among these are new antibacterial, anti-malarial, anti-Alzheimer, and antitumor agents. In this context, our team recently reported on the synthesis and evaluation of new phenstatin-fatty acid conjugates as potential tubulin-binding agents.3 Kamal et al. similarly reported on the anticancer activities of hybrids possessing a cinnamide subunit linked to benzophenones.4 Furthermore, and in separate studies, D’hooghe et al. investigated the biological properties of novel purine-β-lactam and purine-aminopropanol hybrids,5 while the Tripodi team focused on developing 1,4-diaryl-2-azetidinones as specific anticancer agents.6 In the latter study, select systems were shown to induce inhibition of tubulin polymerization accompanied by activation of adenosine monophosphate activated protein kinase and apoptosis induction.
To further extend our work on hybridized systems, we embarked on the synthesis of some novel β-lactam hybrids of combretastatin-A4 (CA-4) and phenstatin (both tubulin polymerization inhibitors), and of estrone, in the hope of developing new potent antibiotic antineoplastic agents.7 By structurally incorporating the element fluorine, we envision these new entities to possess enhanced lipophilicity and metabolic stability.8 Herein we report on the synthesis of the hybrids represented in Figure 1.

All β-lactams were prepared either by the traditional Staudinger method or by the modified protocol mediated by triphosgene, Scheme 1, and obtained as racemates.9

For the two approaches, we found the product yields and purity to be comparable, affording the cis β-lactams exclusively; the proton NMR spectra revealing coupling constants of J = 4.5 Hz from the doublets of the two protons of the 2-azetidinone ring.10 Product yields for these systems range from 65% to 95%, Table 1, and all β-lactams were sufficiently stable under ambient conditions and accordingly were amenable to flash chromatographic purification on silica gel.
Combretastatin-A4 was prepared by the Wittig olefination approach reported in the literature.11 Likewise, phenstatin was synthesized according to the modified approach outlined in our previously published work.3
Generation of the β-lactam hybrids was accomplished by standard nucleophilic coupling in acetonitrile (MeCN), or by phase transfer catalysis in aqueous dichloromethane (DCM).12 In the former approach, a mixture of the phenol (0.500 g, 1.00 equiv), cesium carbonate (1.50 equiv), and the β-lactam (1.05 equiv) in MeCN (~40 mL) was stirred at room temperature before work-up. The biphasic approach involved combining a solution of the phenol (1.00 equiv in 5 mL DCM) with a stirred aqueous solution of KOH (1.50 equiv) and tetrabutylammonium hydrogensulfate (TBAHSO4, 0.250 equiv) in ~10 mL water.

A solution of the β-lactam (1.05 equiv) dissolved in 5 mL DCM was added portion-wise to this vigorously stirred solution at room temperature, with the reaction progress being monitored by TLC.
Shown in Table 2 are the hybrids of estrone with select β-lactam systems.

As expected, a 1:1 diastereomeric mixture was obtained in all instances from the coupling of the racemic β-lactams with enantiopure estrone.
Hybrids of phenstatin and CA-4 with representative β-lactams were similarly prepared with results summarized in Table 3. All hybrids were obtained as viscous oils, and in comparable yields for compounds 16, 17, 18, and 19 by either of the two coupling methods. Formation of compound 15 however, was somewhat sluggish yielding at best about 40% by the phase transfer catalytic approach, and 20 – 25% by the alternative method mediated by cesium carbonate. All attempts to improve on the intended reaction outcome proved unsuccessful. The use of stronger bases and/or elevated temperatures on these 2-chloroethyl systems resulted in competing eliminations to the N-vinyl substituted derivative (identified by proton NMR of the crude reaction mixture), Scheme 2.

As detailed below, all new compounds gave conclusive analytical data in support of their respective structures with the new hybrids currently being screened against various cell lines for their antiproliferative properties. The results of these investigations will be reported in a forthcoming manuscript.

EXPERIMENTAL
Infrared (IR) spectra were obtained on a Perkin-Elmer Spectrum 2 FT-IR spectrometer with the aid of a PIKE MIRacle ATR (Attenuated Total Reflectance) accessory. 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. Mass Spectrometry (GC/MS) analyses were performed using the Shimadzu GCMS-QP5050A system equipped with a direct insertion (DI) port. Elemental analyses were performed by Atlantic Microlab Inc., Norcross, GA. All required compounds for the outlined syntheses were obtained from Aldrich Chemical Company. Dichloromethane (DCM) and acetonitrile (MeCN) 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.

(+/-)-cis-1-(2-Chloroethyl)-4-(2-fluorophenyl)-3-methoxyazetidin-2-one, (1).
1H NMR (400 MHz, CDCl3): δ 3.20 (3H, s), 3.25 (1H, m), 3.55 (1H, m), 3.65 (1H, m), 3.88 (1H, m), 4.82 (1H, d, J = 4.5 Hz), 5.29 (1H, d, J = 4.5 Hz), 7.10 (1H, m), 7.21 (1H, m), 7.35 (2H, m). 13C NMR (100 MHz, CDCl3): δ 41.2, 42.2, 56.0, 58.5, 85.9, 115.5, 120.9, 124.2, 129.3, 130.1, 160.1, 167.4. IR (cm-1): 755, 1208, 1494, 1581, 1748, 2841, 2928, 2940, 2958, 3011. MS (EI, m/z): 257 (M+), 226, 186, 152 (100%), 137, 109, 95, 83, 72, 44, 41. Anal. Calcd for C12H13ClFNO2 (257.7): C, 55.93; H, 5.08; Cl, 13.76; F, 7.37; N, 5.44; O, 12.42. Found: C, 55.90; H, 5.04.

(+/-)-cis-1-(2-Chloroethyl)-4-(3-fluorophenyl)-3-methoxyazetidin-2-one, (2).
1H NMR (400 MHz, CDCl3): δ 3.19 (3H, s), 3.23 (1H, m), 3.57 (1H, m), 3.65 (1H, m), 3.84 (1H, m), 4.84 (1H, d, J = 4.5 Hz), 5.26 (1H, d, J = 4.5 Hz), 7.08 (1H, m), 7.25 (1H, m), 7.35 (2H, m). 13C NMR (100 MHz, CDCl3): δ 41.1, 42.2, 56.1, 58.5, 85.9, 115.4, 120.9, 124.3, 129.2, 130.3, 160.0, 167.3. IR (cm-1): 753, 1206, 1494, 1581, 1747, 2839, 2927, 2959, 3012. MS (EI, m/z): 257 (M+), 226, 186, 152 (100%), 137, 109, 95, 83, 72, 44, 41. Anal. Calcd for C12H13ClFNO2 (257.7): C, 55.93; H, 5.08; Cl, 13.76; F, 7.37; N, 5.44; O, 12.42. Found: C, 55.92; H, 5.10.

(+/-)-cis-1-(2-Chloroethyl)-4-(4-fluorophenyl)-3-methoxyazetidin-2-one, (3).
1H NMR (400 MHz, CDCl3): δ 3.09 (3H, s), 3.27 (1H, ddd, J = 5.2, 6.9, 14.7 Hz), 3.58 (2H, m), 3.80 (1H, ddd, J = 5.4, 6.5, 14.6 Hz), 4.78 (1H, d, J = 4.4 Hz), 4.96 (1H, d, J = 4.4 Hz), 7.10 (2H, t, J = 8.7 Hz), 7.40 (2H, dd, J = 5.4, 8.7 Hz). 13C NMR (100 MHz, CDCl3): δ 41.3, 41.9, 57.9, 61.8, 85.7, 115.2, 129.5, 130.2, 161.6, 164.0, 167.1. IR (cm-1): 913, 1032, 1225, 1462, 1764, 2850, 2921. MS: (EI, m/z): 257 (M+), 228, 206, 186, 169, 152, 137, 109, 85, 71, 57(100%), 43, 41. Anal. Calcd for C12H13ClFNO2 (257.7): C, 55.93; H, 5.08; Cl, 13.76; F, 7.37; N, 5.44; O, 12.42. Found: C, 55.97; H, 5.11.

(+/-)-cis-1-(3-Chloropropyl)-4-(2-fluorophenyl)-3-methoxyazetidin-2-one, (4).
1H NMR (400 MHz, CDCl3): δ 2.02 (2H, m), 3.12 (1H, dt, J = 6.4, 14.0 Hz), 3.17 (3H, s), 3.55 (2H, t, J = 6.3 Hz), 3.62 (1H, dt, J = 7.1, 14.3 Hz), 4.76 (1H, d, J = 4.5 Hz), 5.16 (1H, d, J = 4.5 Hz), 7.10 (1H, dt, J = 1.3, 9.8 Hz), 7.21 (1H, dt, J = 0.8, 8.3 Hz), 7.35 (2H, m). 13C NMR (100 MHz, CDCl3): δ 30.2, 38.3, 42.1, 58.2, 61.8, 85.7, 115.4, 115.9, 124.1, 130.2, 136.4, 164.1, 167.2. IR (cm-1): 1212, 1463, 1761, 2850, 2922. MS: (EI, m/z): 271 (M+), 228, 205, 176, 152(100%), 149, 120, 109, 87, 73, 57. Anal. Calcd for C13H15ClFNO2 (271.72): C, 57.46; H, 5.56; Cl, 13.05; F, 6.99; N, 5.15; O, 11.78. Found: C, 57.38; H, 5.73; Cl, 12.86; N, 5.20.

(+/-)-cis-1-(3-Chloropropyl)-4-(3-fluorophenyl)-3-methoxyazetidin-2-one, (5).
1H NMR (400 MHz, CDCl3): δ 2.00 (2H, m), 3.12 (1H, dt, J = 6.5, 14.0 Hz), 3.14 (3H, s), 3.53 (2H, t, J = 6.3 Hz), 3.60 (1H, dt, J = 7.1, 14.3 Hz), 4.72 (1H, d, J = 4.4 Hz), 4.77 (1H, d, J = 4.4 Hz), 7.07 (2H, m), 7.15 (1H, d, J = 7.7 Hz), 7.38 (1H, m). 13C NMR (100 MHz, CDCl3): δ 30.3, 38.3, 42.1, 58.3, 61.8, 85.6, 115.4, 115.9, 124.1, 130.2, 136.5, 164.0, 167.1. IR (cm-1): 1212, 1462, 1761, 2850, 2920. MS: (EI, m/z): 271 (M+), 228, 205, 176, 152(100%), 149, 120, 109, 87, 73, 57, 44. Anal. Calcd for C13H15ClFNO2 (271.72): C, 57.46; H, 5.56; Cl, 13.05; F, 6.99; N, 5.15; O, 11.78. Found: C, 57.55; H, 5.62.

(+/-)-cis-1-(3-Chloropropyl)-4-(4-fluorophenyl)-3-methoxyazetidin-2-one, (6).
1H NMR (400 MHz, CDCl3): δ 1.98 (2H, m), 3.08 (1H, m), 3.13 (3H, s), 3.51 (3H, m), 4.69 (1H, d, J = 4.3 Hz), 4.74 (1H, d, J = 4.3 Hz), 7.10 (2H, t, J = 8.6 Hz), 7.34 (2H, dd, J = 5.3, 8.6 Hz). 13C NMR (100 MHz, CDCl3): δ 30.5, 38.4, 42.3, 58.4, 61.9, 85.7, 115.7, 115.9, 129.5, 130.3, 130.4, 164.5, 167.4. IR (cm-1) 550, 843, 1008, 1100, 1159, 1223, 1355, 1400, 1511, 1605, 1760, 2319, 2922. MS: (EI, m/z): 271 (M+), 256, 240, 200, 177, 152(100%), 137, 122, 109, 95, 83, 72, 56, 51. Anal. Calcd for C13H15ClFNO2 (271.72): C, 57.46; H, 5.56; Cl, 13.05; F, 6.99; N, 5.15; O, 11.78. Found: C, 57.38; H, 5.73; F, 6.84; N, 5.23.

(+/-)-cis-1-(3-Chloropropyl)-3-methoxy-4-(4-nitrophenyl)azetidin-2-one, (7).
1H NMR (400 MHz, CDCl3): δ 2.02 (2H, m), 3.12 (1H, dt, J = 6.9, 13.9 Hz), 3.17 (3H, s), 3.55 (2H, t, J = 6.3 Hz), 3.59 (1H, dt, J = 7.0, 14.1 Hz), 4.77 (1H, d, J = 4.5 Hz), 4.88 (1H, d, J = 4.5 Hz), 7.54 (2H, d, J = 8.6 Hz), 8.28 (2H, d, J = 8.7 Hz). IR (cm-1): 1033, 1462, 1763, 2850, 2920. MS: (EI, m/z): 299 (M+), 268, 236, 204, 179, 164, 152(100%), 137, 109, 85, 71, 57, 43. Anal. Calcd for C13H15ClN2O4 (298.7): C, 52.27; H, 5.06; Cl, 11.87; N, 9.38; ), 21.42. Found: C, 52.36; H, 5.11; Cl, 11.72; N, 9.37.

(+/-)-cis-1-(2-Chloroethyl)-3-methoxy-4-(3,4,5-trimethoxyphenyl)azetidin-2-one, (8).
1H NMR (400 MHz, CDCl3): δ 3.18 (3H, s), 3.35 (1H, ddd, J = 5.3, 5.8, 14.4 Hz), 3.57 (2H, m), 3.78 (1H, ddd, J = 5.7, 5.7, 14.5 Hz); 3.86 (3H, s), 3.88(6H, s); 4.76 (1H, d, J = 4.4 Hz), 4.83 (1H, d, J = 4.4 Hz), 6.60 (2H, s). 13C NMR (100 MHz, CDCl3): δ 41.2, 42.1, 56.0( 2C’s), 58.2, 60.6, 62.7, 88.7, 105.1 (2C’s), 128.9, 138.0, 153.1( 2C’s), 167.2. IR (cm-1): 743, 913, 1005, 1129, 1239, 1328, 1427, 1464, 1508, 1591, 1757, 2838, 2929. MS: (EI, m/z): 329 (M+), 224, 209,72, 63(100%), 45. Anal. Calcd for C15H20ClNO5 (329.8): C, 54.63; H, 6.11; Cl, 10.75; N, 4.25; O, 24.26. Found: C, 54.60; H, 6.14; N, 4.27.

(+/-)-cis-4-(3-(tert-Butyldimethylsilyloxy)-4-methoxyphenyl)-1-(2-chloroethyl)-3-methoxyazetidin-2-one, (10).
1H NMR (400 MHz, CDCl3): δ 0.13 (6H, s); 0.97 (9H, s); 3.07 (3H, s); 3.57 (4H, m); 3.79 (3H, s); 4.32 (1H, s); 4.51 (1H, d, J = 1.0 Hz); 6.87 (3H, m). 13C NMR (100 MHz, CDCl3): δ -4.67, 18.42 25.68, 41.22, 41.34, 55.38, 55.43, 62.20, 85.70, 111.7 (2 C’s), 118.8 (2 C’s), 120.9 (2 C’s), 125.6, 144.9, 151.5, 167.2. IR (cm-1): 663, 784, 840, 1002, 1137, 1281, 1444, 1513, 1585, 1606, 1764, 2856, 2928. Anal. Calcd for C19H30ClNO4Si (257.7): C, 57.05; H, 7.56; Cl, 8.86; N, 3.50; O, 16.00; Si, 7.02. Found: C, 57.12; H, 7.49; Cl, 8.91.

Estrone Conjugate 11, diastereomer with Rf = 0.39: silica gel, hexanes:EtOAc, 2:1.
1H NMR (400 MHz, CDCl3): δ 0.91 (3H, s), 1.46 (5H, m), 2.05 (5H, m), 2.25 (1H, m), 2.38 (1H, d, J = 9.5 Hz), 2.51 (1H, dd, J = 8.8, 19.1 Hz), 2.87 (2H, m), 3.12 (3H, s), 3.29 (1H, ddd, J = 3.5, 7.8, 14.7 Hz), 3.80 (1H, m), 4.00 (2H, m), 4.68 (1H, d, J = 4.4 Hz), 4.87 (1H, d, J = 4.4 Hz), 6.50 (1H, s), 6.59 (1H, dd, J = 2.5, 8.5 Hz), 7.07 (2H, t, J = 8.6 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.34 (2H, dd, J = 5.5, 8.5 Hz). 13C NMR (100 MHz, CDCl3): δ 13.9, 21.6, 25.9, 26.5, 29.6, 31.6, 35.9, 38.3, 39.6, 44.0, 48.0, 50.4, 58.2, 62.4, 85.8, 112.0, 114.4, 115.3 (2C’s), 115.5, 126.4, 129.6 (2C’s), 130.1, 130.2, 132.7, 137.9, 156.0 (2C’s), 167.2. IR (cm-1): 1247, 1382, 1469, 1608, 1753, 1793, 2838, 2948, 3155. MS: (EI, m/z): 491 (M+), 460, 421, 390, 340, 324, 296, 253, 214, 186, 152(100%), 131, 109, 67, 40. Anal. Calcd for C30H34FNO4 (491.6): C, 73.30; H, 6.91; F, 3.85; N, 2.85; O, 13.02. Found: C, 73.16; H, 7.06.

Estrone Conjugate 12, diastereomer with Rf = 0.43: silica gel, hexanes:EtOAc, 2:1.
1H NMR (400 MHz, CDCl3): δ 0.91 (3H, s), 1.53 (5H, m), 2.05 (8H, m), 2.40 (1H, m), 2.50 (1H, dd, J = 8.3, 18.6 Hz), 2.87 (2H, m), 3.13 (1H, dt, J = 6.7, 13.9 Hz), 3.17 (3H, s), 3.69 (1H, dt, J = 7.4, 14.5 Hz), 3.94 (2H, m), 4.73 (1H, d, J = 4.5 Hz), 5.18 (1H, d, J = 4.5 Hz), 6.58 (1H, d, J = 1.9 Hz), 6.65 (1H, dd, J = 2.3, 8.6 Hz), 7.09 (1H, dd, J = 8.5, 10.0 Hz), 7.17 (1H, d, J = 8.1 Hz), 7.19 (1H, d, J = 6.7 Hz), 7.34 (2H, m). 13C NMR (100 MHz, CDCl3): δ 13.9, 21.6, 25.9, 26.5, 27.3, 29.6, 31.6, 35.9, 38.1, 38.3, 44.0, 48.0, 50.4, 55.2, 58.4, 65.3, 85.5, 112.1, 114.5, 115.3, 121.2, 124.2, 126.4, 129.3, 129.9, 132.3, 137.8, 156.6, 160.0, 162.5, 167.3. IR (cm-1): 710, 1096, 1201, 1512, 1608, 1758, 1892, 2834, 2930, 3145. MS: (EI, m/z): 505 (M+), 474, 434, 419, 377, 353, 325, 298, 268, 255, 238, 204, 164, 152(100%), 136, 109, 72, 58. Anal. Calcd for C31H36FNO4 (505.6): C, 73.64; H, 7.18; F, 3.76; N, 2.77; O, 12.66. Found: C, 73.51; H, 7.21; N, 2.68.


Estrone Conjugate 13, diastereomer with Rf = 0.37: silica gel, hexanes:EtOAc, 2:1.
1H NMR (400 MHz, CDCl3): δ 0.91 (3H, s), 1.55 (4H, m), 2.08 (8H, m), 2.38 (1H, m), 2.50 (2H, dd, J = 8.8, 18.6 Hz), 2.87 (2H, m), 3.11 (1H, m), 3.13 (3H, s), 3.64 (1H, dt, J = 7.2, 14.3 Hz), 3.92 (2H, t, J = 5.8 Hz), 4.69 (1H, d, J = 4.4 Hz), 4.76 (1H, d, J = 4.3 Hz), 6.57(1H, s), 6.64 (1H, dd, J = 2.4, 8.5 Hz), 7.06 (2H, m), 7.12 (1H, d, J = 7.7 Hz), 7.18 (1H, d, J = 8.6 Hz), 7.35 (1H, m). 13C NMR (100 MHz, CDCl3): δ 13.9, 21.6, 25.9, 26.5, 27.4, 29.7, 31.6, 35.9, 37.9, 38.3, 44.0, 48.0, 50.4, 58.3, 61.7, 65.3, 85.6, 112.1, 114.5, 115.5, 115.6, 115.8, 124.1, 126.4, 130.1, 132.4, 136.6, 137.8, 156.6, 167.1. IR (cm-1): 913, 1096, 1248, 1382, 1471, 1606, 1755, 1793, 2931, 2982, 3155. MS: (EI, m/z): 505 (M+), 353, 268, 236, 204, 164, 152(100%), 136, 109, 97, 71, 57, 43, 41. Anal. Calcd for C31H36FNO4 (505.6): C, 73.64; H, 7.18; F, 3.76; N, 2.77; O, 12.66. Found: C, 73.78; H, 7.21; F, 3.27; N, 2.69.

Estrone Conjugate 14, diastereomer with Rf = 0.46: silica gel, hexanes:EtOAc, 2:1.
1H NMR (400 MHz, CDCl3): δ 0.90 (3H, s), 1.56 (5H, m), 1.97 (5H, m), 2.23 (1H, t, J = 9.8 Hz), 2.37 (1H, d, J = 9.6 Hz), 2.48 (1H, dd, J = 9.2, 18.9 Hz), 2.87 (2H, m), 3.08 (3H, s), 3.11 (1H, m), 3.55 (3H, m), 3.92 (2H, t, J = 5.8 Hz), 4.68 (1H, d, J = 4.3 Hz), 4.79 (1H, d, J = 4.1 Hz), 6.57 (1H, s), 6.64 (1H, d, J = 8.6 Hz), 7.07 (2H, m), 7.17 (1H, d, J = 8.6 Hz), 7.35 (2H, m). 13C NMR (100 MHz, CDCl3): δ 13.8, 21.6, 25.9, 26.5, 27.4, 29.6, 31.6, 35.8, 37.7, 38.3, 42.2, 43.9, 47.9, 50.3, 58.0, 61.5, 65.2, 85.5, 112.1, 114.5, 115.4, 115.6, 126.3, 129.7, 130.2, 132.3, 137.7, 156.6, 161.7, 164.1, 167.1. IR (cm-1): 712, 1099, 1221, 1512, 1608, 1753, 1892, 2837, 2934, 3155. MS: (EI, m/z): 505 (M+), 353, 271, 200, 164, 152(100%), 138, 120, 109, 86, 84, 68, 47. Anal. Calcd for C31H36FNO4 (505.6): C, 73.64; H, 7.18; F, 3.76; N, 2.77; O, 12.66. Found: C, 73.51; H, 7.60; F, 3.22; N, 2.78.

Phenstatin-β-lactam Hybrid 15:
1H NMR (400 MHz, CDCl3): δ 3.14 (3H, s), 3.35 (1H, m), 3.87 (7H, m), 3.94 (3H, s), 3.96 (3H, s), 4.13 (2H, m), 4.71 (1H, d, J = 4.4 Hz), 5.00 (1H, d, J = 4.4 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.00 (2H, s), 7.04 (2H, m), 7.32 (1H, d, J = 1.9 Hz), 7.36 (2H, m), 7.42 (1H, dd, J = 2.0, 8.4 Hz). 13C NMR (100 MHz, CDCl3): δ 39.4, 56.0, 56.4, 58.2, 61.0, 62.5, 66.8, 85.9, 107.5, 110.3, 114.3, 115.2, 115.4, 125.8, 129.6, 130.2, 130.3, 130.4, 133.2, 141.8, 147.6, 152.9, 153.3, 161.7, 167.2, 194.4. IR (cm-1): 766, 1022, 1129, 1266, 1332, 1512, 1582, 1646, 1755, 2839, 2938, 3007. MS (EI, m/z): 539 (M+), 387, 372, 344, 318, 303, 287, 220, 190, 152 (100%), 109, 95, 72, 44, 41. Anal. Calcd for C29H30FNO8 (539.6): C, 64.56; H, 5.60; F, 3.52; N, 2.60; O, 23.72. Found: C, 64.58; H, 5.58.

Phenstatin-β-lactam Hybrid 16:
1H NMR (400 MHz, CDCl3): δ 2.12 (2H, m), 3.18 (4H, m), 3.79 (1H, m), 3.91 (6H, s), 3.93 (3H, s), 3.96 (3H, s), 4.11 (2H, t, J = 5.2 Hz), 4.75 (1H, d, J = 4.5 Hz), 5.29 (1H, d, J = 4.5 Hz), 6.91 (1H, d, J = 8.8 Hz), 7.04 (2H, s), 7.09 (1H, m), 7.20 (1H, m), 7.35 (2H, m), 7.42 (2H, m). 13C NMR (100 MHz, CDCl3): δ 27.1, 38.1, 55.1, 55.9, 56.3, 58.3, 60.9, 66.8, 85.6, 107.4, 110.1, 114.0, 115.3, 121.4, 124.1, 125.4, 129.2, 129.8, 130.3, 133.3, 141.6, 148.0, 152.9, 153.3, 160.0, 167.3, 194.6. IR (cm-1): 759, 1019, 1124, 1264, 1329, 1512, 1580, 1645, 1755, 2837, 2938, 3005. MS (EI, m/z): 553 (M+), 401 (100%), 386, 358, 318, 303, 287, 236, 195, 152, 109, 84, 72, 44, 41. Anal. Calcd for C30H32FNO8 (553.6): C, 65.09; H, 5.83; F, 3.43; N, 2.53; O, 23.12. Found: C, 65.11; H, 5.86.

Phenstatin-β-lactam Hybrid 17:
1H NMR (400 MHz, CDCl3): δ 2.06 (2H, q, J = 6.4 Hz), 3.14 (4H, m), 3.72 (1H, m), 3.89 (6H, s), 3.91 (3H, s), 3.94 (3H, s), 4.07 (2H, t, J = 5.8 Hz), 4.70 (1H, d, J = 4.4 Hz), 4.84 (1H, d, J = 4.4 Hz), 6.89 (1H, d, J = 8.1 Hz), 7.04 (4H, m), 7.12 (1H, d, J = 7.7 Hz), 7.36 (3H, m). 13C NMR (100 MHz, CDCl3): δ 27.1, 37.9, 55.9, 56.3, 58.3, 61.0, 61.6, 66.7, 85.7, 107.5, 110.1, 114.0, 115.2, 115.5, 124.1, 125.4, 130.0, 130.3, 133.3, 136.7, 141.6, 148.0, 152.9, 153.3, 161.6, 167.1, 194.6. IR (cm-1): 764, 1022, 1128, 1265, 1332, 1513, 1582, 1645, 1754, 2838, 2938, 3007. MS (EI, m/z): 553 (M+), 401 (100%), 386, 358, 318, 303, 287, 236, 195, 152, 109, 84, 72, 44, 41. Anal. Calcd for C30H32FNO8 (553.6): C, 65.09; H, 5.83; F, 3.43; N, 2.53; O, 23.12. Found: C, 65.04; H, 5.79.

Phenstatin-β-lactam Hybrid 18:
1H NMR (400 MHz, CDCl3): δ 2.05 (2H, m), 3.12 (3H, s), 3.16 (1H, m), 3.67 (1H, q, J = 7.1 Hz), 3.89 (6H, s), 3.91 (3H, s), 3.94 (3H, s), 4.07 (2H, t, J = 5.9 Hz), 4.68 (1H, d, J = 4.4 Hz), 4.84 (1H, d, J = 4.4 Hz), 6.90 (1H, d, J = 8.1 Hz), 7.06 (4H, m), 7.32 (2H, m), 7.40 (1H, s), 7.42 (1H, d, J = 1.9 Hz). 13C NMR (100 MHz, CDCl3): δ 27.1, 37.7, 55.9, 56.3, 58.1, 60.9, 61.3, 66.7, 85.5, 107.5, 110.1, 113.9, 115.3, 115.5, 125.4, 129.6, 130.1, 130.2, 130.3, 133.2, 141.6, 148.0, 152.8, 153.3, 161.7, 167.2, 194.5. IR (cm-1): 761, 1020, 1126, 1264, 1330, 1510, 1580, 1646, 1752, 2838, 2937, 3008. MS (EI, m/z): 553 (M+), 401 (100%), 386, 358, 318, 303, 287, 236, 195, 152, 109, 84, 72, 44, 41. Anal. Calcd for C30H32FNO8 (553.6): C, 65.09; H, 5.83; F, 3.43; N, 2.53; O, 23.12. Found: C, 65.07; H, 5.80.

CA4-β-Lactam Hybrid 19:
1H NMR (400 MHz, CDCl3): δ 1.91 (2H, q, J = 6.3 Hz), 3.03 (1H, dt, J = 6.4, 14.0 Hz), 3.11 (3H, s), 3.60 (1H, dt, J = 7.2, 14.3 Hz), 3.69 (6H, s), 3.79 (3H, s), 3.80 (2H, dt, J = 6.0, 15.6 Hz), 3.82 (3H, s), 4.66 (1H, d, J = 4.4 Hz), 4.77 (1H, d, J = 4.3 Hz), 6.45 (1H, d, J = 12.2 Hz), 6.49 (1H, d, J = 12.2 Hz), 6.51 (2H, s), 6.75 (2H, m), 6.88 (1H, dd, J = 1.8, 8.4 Hz), 7.05 (3H, m), 7.28 (1H, m). 13C NMR (100 MHz, CDCl3) δ 27.1, 29.7, 37.7, 52.3, 55.8, 56.0, 58.1, 60.9, 61.4, 84.0, 105.9, 111.2, 114.7, 115.6, 118.9, 122.4, 129.6, 131.4, 133.0, 135.6, 141.7, 151.2, 153.0, 160.2, 161.0, 163.3, 165.9. MS: (EI, m/z): 551 (M+). Anal. Calcd for C31H34FNO7 (551.6): C, 67.50; H, 6.21; F, 3.44; N, 2.54; O, 20.30. Found: C, 67.28; H, 6.46.

ACKNOWLEDGEMENTS
The authors thank the Department of Chemistry of St. John's University for financial support of this project.

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