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. Author manuscript; available in PMC: 2017 Dec 15.
Published in final edited form as: J Photochem Photobiol A Chem. 2016 Jul 7;329:182–188. doi: 10.1016/j.jphotochem.2016.07.004

Photoassisted access to complex polyheterocycles containing a β-lactam moiety

Weston J Umstead 1, Olga A Mukhina 1, Andrei G Kutateladze 1,✉
PMCID: PMC5731649  NIHMSID: NIHMS901721  PMID: 29249888

Abstract

Intramolecular cycloadditions of aza-o-xylylenes generated via excited state intramolecular proton transfer (ESIPT) to furanacetic acid-based unsaturated pendants was shown to overcome the unfavorable energetics of the azetidinone ring formation, offering rapid access to β-lactams as primary photoproducts. These 2,3- and 3,4-dihydrofuran-containing reactive intermediates are suitable for a broad spectrum of postphotochemical transformations yielding complex polyheterocyclic molecular architectures possessing the β-lactam moiety.

1. Introduction

During the past decade β-lactam chemistry has been enjoying a renaissance (Figure 1):1 there are on average three new publications containing “β-lactam” as a keyword appearing daily worldwide, one of which deals with the synthetic approaches to β-lactams. Despite such a remarkable activity in this field2 most of the existing synthetic methods including several photochemical ones3 are limited to mono- or bicyclic lactams, and there are relatively few methods applicable to the synthesis of complex polycyclic structures. Very few of such structures are known even though they may be of substantial interest from the medicinal chemistry standpoint.

Figure 1.

Figure 1

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Number of publications (A) mentioning “β-lactam” according to Scifinder database statistics (B) referring to the synthesis of β-lactams

Previously we have demonstrated that aza-o-xylylenes generated via excited state intramolecular proton transfer (ESIPT) in aromatic o-aminoketones and aldehydes readily undergo intramolecular [4+4] or [4+2] cycloaddition reactions to tethered unsaturated moieties to yield complex polyheterocyclic structures (Figure 2). 4 The synthesis of photoprecursors for such cycloadditions is facile and straightforward, and also is congruent with the philosophy of Diversity-Oriented Synthesis.5 The photoproducts can be successfully engaged in experimentally simple postphotochemical ground state reactions6 resulting in further growth of complexity and generation of novel molecular architectures. We now extend this method to the synthesis of β-lactams.

Figure 2.

Figure 2

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Photoassisted access to polyheterocycles via the azaxylylene strategy

2. Experimental Section

Common solvents were purchased from Pharmco or Fisher Scientific and used as is, except for THF, which was refluxed over and distilled from sodium benzophenone ketyl prior to use. Common reagents were purchased from Aldrich and used without additional purification, unless indicated otherwise. NMR spectra were recorded at 25°C on a Bruker Avance III 500 MHz in CDCl3 (unless noted otherwise). High resolution mass spectra were obtained on the Waters Synapt G2 ESI-MS mass spectrometer from the University of Colorado at Boulder. Flash column chromatography was performed using Teledyne Ultra Pure Silica Gel (230–400 mesh) on a Teledyne Isco Combiflash Rf using Hexanes/EtOAc as an eluent.

Dibromoformaldoxime6c, N-hydroxy-benzenecarboximidoyl bromide7, (1E)-N-phenyl-1-pyridin-2-ylmethanimine8, N-oxide-N-(phenylmethylene)-methanamine9 were prepared according to the published procedures.

N-(2-formylphenyl)-2-(furan-2-yl)acetamide (3). (i) 2-(furan-2-yl)-N-(2-{[(trimethylsilyl) oxy]methyl}phenyl)acetamide

1.0 g of 2-furanacetic acid (8.5 mmol, 1 eq) was dissolved in 10 mL of anh. DCM along with 1.6 g of CDI (9.8 mmol, 1.15 eq). The reaction was stirred at ambient temperature for 15 min. Upon full consumption of the starting 2-furanacetic acid as monitored by TLC, 1.6 g of 2-{[(trimethylsilyl)oxy]methyl}aniline4a (8.5 mmol, 1 eq) was added and the reaction was stirred for an additional 6 h, before quenching with 20 mL of water. The organic layer was separated, washed with brine, dried over anhydr. Na2SO4, filtered, and concentrated in vacuo to yield 1.6 g of a 10:1 mixture of crude 2-(furan-2-yl)-N-(2-{[(trimethylsilyl)oxy]methyl}phenyl) acetamide, which was used in the next step without separation or purification.10 (ii) N-(2-formylphenyl)-2-(furan-2-yl)acetamide: 0.49 mL of oxalyl chloride (5.7 mmol, 1.1 eq) dissolved in 6.4 mL of anhydr. DCM (0.9 M solution) was cooled to -78°C before 0.82 mL of dry DMSO (11.5 mmol, 2.2 eq) was slowly added. Upon complete addition, the mixture stirred for 2 min till the evolution of gas stopped. Then, 1.6 g of crude 2-(furan-2-yl)-N-(2-{[(trimethylsilyl)oxy] methyl}phenyl)acetamide (5.2 mmol, 1 eq) dissolved in 10.0 mL of anhydrous DCM (0.5 M solution) was slowly added. Upon complete addition, the mixture was stirred for 15 min, followed by the addition of 3.6 mL of NEt3 (26.1 mmol, 5 eq). The mixture was then allowed to warm to the ambient temperature at which it was stirred overnight. The reaction was quenched with water and extracted with DCM. The organic layer was separated, washed with brine, dried over anhydr. Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography with hexanes/EtOAc as eluent yielding 1.0 g of N-(2-formylphenyl)-2-(furan-2-yl)acetamide (57% over two steps). 1H NMR (500 MHz, CDCl3) δ 11.17 (s, 1H), 9.85 (s, 1H), 8.75 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 7.6, 1.6 Hz, 1H), 7.61 (ddd, J = 8.5, 7.6, 1.6 Hz, 1H), 7.47 (dd, J = 2.0, 0.8 Hz, 1H), 7.23 (td, J = 7.5, 1.0 Hz, 1H), 6.45 (dd, J = 3.3, 2.0 Hz, 1H), 6.39 (dd, J = 3.3, 0.6 Hz, 1H), 3.85 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 195.2, 168.3, 147.5, 142.9, 140.5, 136.1, 135.9, 123.2, 122.0, 120.0, 110.8, 109.4, 38.1.

Irradiation of N-(2-formylphenyl)-2-(furan-2-yl)acetamide

A solution with ca. 3.0 mM of N-(2-formylphenyl)-2-(furan-2-yl)acetamide in 3:1 ethanol/H2O was degassed and irradiated in a Pyrex or borosilicate glass reaction vessel in a Rayonet reactor equipped with RPR-3500 UV lamps (broadband 300–400 nm UV source with peak emission at 350 nm) until the reaction was complete, as determined by 1H NMR. The solution was concentrated and the mixture was purified by flash chromatography.

11-hydroxy-15-oxa-4-azatetracyclo[10.2.1.01,4.05,10]pentadeca-5,7,9,13-tetraen-3-one (5)

From 1.0 g of 3 was obtained 0.39 g (39%) of the title compound and 0.41 g (41%) of 4. 1H NMR (500 MHz, CDCl3) δ 7.79 (dd, J = 8.0, 1.3 Hz, 1H), 7.76 (dt, J = 8.0. 1.2 Hz, 1H), 7.32 (td, J = 7.6, 1.6 Hz, 1H), 7.20 (td, J = 7.7, 1.3 Hz, 1H), 6.71 (dd, J = 5.8, 1.9 Hz, 1H), 6.10 (dd, J = 5.8, 0.9 Hz, 1H), 5.26 (t, J = 4.7 Hz, 1H), 4.99 (dt, J = 3.9, 1.4 Hz, 1H), 3.51 (d, J = 15.5 Hz, 1H), 3.46 (d, J = 15.5 Hz, 1H), 2.33 (d, J = 7.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 160.6, 135.0, 131.2, 129.9, 128.6, 128.4, 128.3, 124.9, 121.3, 94.0, 84.4, 76.2, 45.7. HRMS (ESI) calcd for C13H11NO3+ (MH)+ 230.0817 found 230.0816.

10-hydroxy-6-oxa-2-azatetracyclo[9.4.0.02,5.05,9]pentadeca-1(15),7,11,13-tetraen-3-one (4)

From 1.0 g of 3 was obtained 0.41 g (41%) of the title compound and 0.39 g (39%) of 5. 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 1H), 7.32 (m, 3H), 6.39 (t, J = 2.8 Hz, 1H), 5.03 (dd, J = 3.0, 2.4 Hz, 1H), 4.95 (d, J = 6.4 Hz, 1H), 4.22 (dt, J = 6.4, 2.4 Hz, 1H), 3.61 (d, J = 15.7 Hz, 1H), 3.46 (d, J = 15.7 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.7, 147.3, 132.4, 132.3, 128.1, 127.2, 124.9, 122.7, 99.3, 91.5, 67.6, 52.0, 50.3. HRMS (ESI) calcd for C13H11NO3+ (MH)+ 230.0817 found 230.0821.

Postphotochemical Transformations

Addition of nitrile oxide, general procedure I6d

1 eq of photoproduct was dissolved in EtOAc. To this was added 3 eq of N-hydroxy-benzenecarboximidoyl bromide or dibromoformaldoxime and 6 eq of KHCO3. An additional 3 eq of N-hydroxy-benzenecarboximidoyl bromide or dibromoformaldoxime and 6 eq of KHCO3 were added after stirring for 12 h. The reaction was monitored by NMR until the starting photoproduct was consumed. The resulting mixture was diluted with water, extracted with 3×20 mL of EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The mixture was then purified by flash chromatography.

Nitrone Cycloaddition

1 eq of photoproduct was dissolved in 1 mL of anhyd. toluene along with 4 eq of nitrone. The reaction was sealed in a high pressure reaction vessel and heated to completion as shown by 1H NMR. The toluene was removed in vacuo and the residue purified by flash chromatography.

Povarov Cycloaddition:11

A solution was prepared with 2 eq of the corresponding imine and 1 eq of corresponding photoproduct in 1.5 mL of 2,2,2-trifluoroethanol. This was warmed to 40°C until the reaction was complete as observed by 1H NMR. The resulting mixture was concentrated in vacuo and purified by flash chromatography.

Hetero Diels-Alder Cycloaddition:12

1 eq of photoproduct and 1 eq of 1,3-dicarbonyl compound were dissolved in 0.7 mL of dry acetonitrile. To this was added 0.08 eq of L-proline and 1.3 eq of 37% aq. formaldehyde solution. The reaction stirred at ambient temperature until full consumption of the photoproduct, as determined by 1H NMR. The reaction was diluted with water and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The mixture was then purified by flash chromatography.

14-bromo-11-hydroxy-16,18-dioxa-4,15-diazapentacyclo[10.6.0.01,4.05,10.013,17]octadeca-5,7,9,14-tetraen-3-one (6)

From 0.14 g of 4, 0.37 g of dibromoformaldoxime, and 0.36 g of KHCO3, was obtained 85 mg (40%) of the title compound. 1H NMR (500 MHz, DMSO) δ 7.44 (dd, J = 7.8, 1.2 Hz, 1H), 7.37 (m, 2H), 7.20 (ddd, J = 7.8, 6.7, 1.9 Hz, 1H), 6.04 (d, J = 6.0 Hz, 1H), 5.81 (d, J = 5.8 Hz, 1H), 4.82 (t, J = 5.4 Hz, 1H), 4.39 (dd, J = 5.9, 0.5 Hz, 1H), 3.28 (d, J = 15.5 Hz, 1H), 3.27 (d, J = 4.9, 1H), 3.14 (d, J = 15.5 Hz, 1H). 13C NMR (126 MHz, DMSO) δ 165.5, 142.4, 131.8, 131.0, 129.2, 127.6, 124.9, 118.5, 107.5, 88.5, 63.8, 59.0, 51.9, 43.9. HRMS (ESI) calcd for C14H12BrN2O4+ (MH)+ 350.9980 and 352.9960 found 350.9981 and 352.9962

11-hydroxy-14-phenyl-16,18-dioxa-4,15-diazapentacyclo[10.6.0.01,4.05,10.013,17]octadeca-5,7,9,14-tetraen-3-one (7)

From 150 mg of 4 (0.7 mmol) was obtained 0.11 g (47%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.75 (m, 2H), 7.56 (dd, J = 8.1, 1.1 Hz, 1H), 7.49 (m, 4H), 7.42 (td, J = 7.7, 1.4 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 6.36 (d, J = 6.3 Hz, 1H), 4.97 (dd, J = 8.9, 5.1 Hz, 1H), 4.69 (d, J = 6.3 Hz, 1H), 3.49 (d, J = 16.0 Hz, 1H), 2.96 (d, J = 16.0 Hz, 1H), 2.85 (d, J = 5.2 Hz, 1H), 1.83 (d, J = 8.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.5, 157.5, 131.3, 131.0, 130.5, 130.3, 129.4, 126.9, 125.1, 124.5, 123.3, 119.2, 107.7, 87.8, 66.0, 53.8, 52.2, 45.2. HRMS (ESI) calcd for C20H16N2O4+ (MH)+ 349.1183 found 349.1179

14-hydroxy-11-(phenyl)-2-oxa-10,21-diazahexacyclo[11.10.0.01,21.03,12.04,9.015,20]tricosa-4(9),5,7,15,17,19-hexaen-22-one (9)

From 0.10 g of 4 (0.43 mmol) was obtained 55 mg (56%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.64 (dd, J = 8.0, 0.5 Hz, 1H), 7.46 (td, J = 7.8, 1.4 Hz, 1H), 7.43 (dd, J = 7.7, 1.1 Hz, 1H), 7.19 (td, J = 7.6, 1.1 Hz, 1H), 5.49 (s, 1H), 5.04 (d, J = 2.2 Hz, 1H), 3.36 (d, J = 15.7 Hz, 1H), 3.32 (d, J = 15.7 Hz, 1H), 2.73 (q, J = 1.8 Hz, 1H), 2.27 (dt, J = 10.0, 1.0 Hz, 1H), 2.23 (dt, J = 10.0, 1.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 162.2, 131.3, 130.7, 130.5, 124.3, 122.2, 118.2, 98.7, 86.0, 74.2, 49.4, 38.2, 37.5. HRMS (ESI) calcd for C13H11NO3Na+ (MNa)+ 252.0638 found 252.0637.

14-hydroxy-6,8-dimethyl-2,4-dioxa-6,8,21-triazahexacyclo[11.10.0.01,21.03,12.05,10.015,20] tricosa- 5(10),15,17,19-tetraene-7,9,22-trione (8)

From 100.0 mg of 4 (0.42 mmol) and 65 mg of 1,3-dimethyl barbituric acid (0.42 mmol) was obtained 55 mg (33%) of the title compound. 1H NMR (500 MHz, DMSO) δ 7.65 (dt, J=7.4, 1.4 Hz 1H), 7.40 (td, J = 7.5, 1.3 Hz, 1H), 7.36 (tdd, J = 7.5, 1.7, 0.80 Hz, 1H), 7.19 (dd, J = 7.5, 1.2 Hz, 1H), 6.14 (d, J = 5.3 Hz, 1H), 5.80 (d, J = 4.0 Hz, 1H), 4.93 (t, J = 5.8 Hz, 1H), 3.74 (d, J = 15.8 Hz, 1H), 3.42 (d, J = 15.8 Hz, 1H), 3.24 (s, 3H), 3.20 (dd, J = 10.6, 6.3, 1H), 3.18 (s, 3H), 2.97 (d, J = 15.9 Hz, 1H), 2.40 (dd, J = 15.9, 6.3 Hz, 1H), 2.34 (m, 1H) 13C NMR (126 MHz, DMSO) δ 165.5, 162.7, 154.4, 151.0, 134.7, 132.2, 128.2, 127.6, 126.5, 123.1, 103.6, 93.2, 82.9, 66.7, 51.2, 46.8, 38.3,28.8, 28.0, 19.5,. HRMS (ESI) calcd for C20H20N3O6+ (MH)+ 398.1347 found 398.1342.

14-bromo-11-hydroxy-16,18-dioxa-4,15-diazapentacyclo[10.5.1.01,4.05,10.013,17]octadeca-5,7,9,14-tetraen-3-one (10) and 16-bromo-11-hydroxy-14,18-dioxa-4,15-diazapentacyclo[10.5.1.01,4.05,10.013,17]octadeca-5,7,9,14-tetraen-3-one (10′)

From 0.10 g of 5 (0.5 mmol) was obtained 0.12 g (68%) of a 1.2 : 1 mixture of regioisomers 10 and 10′ that were inseparable by chromatography. HRMS (ESI) calcd for C14H12BrN2O4+ (MH)+ 350.9980 and 352.9960 found 350.9969 and 352.9967 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, J = 8.0, 1.3 Hz, 10′, 1H), 7.80 (d, J = 7.9 Hz, 10,1H), 7.77 (m, 10, 1H), 7.25–7.42 (m, 10, 2H and 10′, 3H), 5.10 (d, J = 8.8 Hz, 10,1H), 4.97 (m, 10′, 1H), 4.90 (m, 10, 1H), 4.88 (d, J = 8.5 Hz, 10′,1H), 4.77 (d, J = 3.0 Hz, 10, 1H), 4.71 (d, J = 3.0 Hz, 10′,1H), 4.14 (d, J = 15.8 Hz, 10, 1H), 3.73 (dd, J = 8.6, 1.0 Hz, 10′, 1H), 3.69 (d, J = 8.7 Hz, 10,1H), 3.61 (d, J = 15.9 Hz, 10′, 1H), 3.51 (d, J = 15.8 Hz, 10, 1H), 3.49 (d, J = 15.8 Hz, 10′, 1H), 2.53 (d, J = 5.7 Hz, 10′, 1H), 2.49 (d, J = 5.6 Hz, 10, 1H).

11-hydroxy-14-phenyl-16,18-dioxa-4,15-diazapentacyclo[10.5.1.01,4.05,10.013,17]octadeca-5,7,9,14-tetraen-3-one (11)

From 200 mg of 5 (1.0 mmol) was obtained 91 mg (31%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.89 (m, 3H), 7.86 (dt, J = 8.0, 1.4 Hz, 1H), 7.47 (m, 3H), 7.39 (td, J = 7.4, 1.4 Hz, 1H), 7.31 (td, J = 7.9, 1.3 Hz, 1H), 4.99 (m, 1H), 4.94 (d, J = 8.5 Hz, 1H), 4.73 (dd, J = 3.0, 0.8 Hz, 1H), 4.09 (dd, J = 8.6, 1.0 Hz, 1H), 3.68 (d, J = 15.7 Hz, 1H), 3.52 (d, J = 15.7 Hz, 1H), 2.73 (d, J = 5.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 161.1, 157.0, 132.2, 130.6, 129.5, 129.0, 128.9, 128.0, 127.6, 127.2, 125.6, 120.9, 94.1, 87.2, 85.1, 73.8, 53.9, 44.0. HRMS (ESI) calcd for C20H16N2O4+ (MH)+ 349.1183 found 349.1183

anti-11-hydroxy-15-methyl-14-phenyl-16,18-dioxa-4,15-diazapentacyclo [10.5.1.01,4.05,10.013,17]octadeca-5,7,9-trien-3-one (12)

From 100 mg of 5 (0.44 mmol) was obtained 51 mg (32%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.80 (dt, J = 7.8, 1.4 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.39 (m, 3H), 7.33 (m, 3H), 7.26 (td, J = 7.6, 1.4 Hz, 1H), 4.92 (dd, J = 5.5, 3.5 Hz, 1H), 4.65 (d, J = 7.0 Hz, 1H), 4.52 (d, J = 3.2 Hz, 1H), 3.44 (d, J = 15.3 Hz, 1H), 3.30 (d, J = 8.5 Hz, 1H), 3.23 (d, J = 15.3 Hz, 1H), 3.03 (t, J = 7.7 Hz, 1H), 2.51 (s, 3H), 2.40 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 160.6, 136.3, 131.6, 131.0, 129.3, 129.0, 128.6, 128.5, 127.7, 125.6, 121.3, 93.1, 84.9, 81.5, 77.5, 72.4, 61.9, 43.3, 42.3. HRMS (ESI) calcd for C21H21N2O4+ (MH)+ 365.1496 found 365.1501

3. Results and Discussion

Photoprecursors 3 are easily accessible through the amide coupling of commercially available o-aminobenzyl alcohol and 2-furanacetic acid, with subsequent oxidation of the alcohol moiety to aldehyde. The photoprecursors were dissolved in 75% aqueous methanol, degassed by an argon purge, and irradiated in a Rayonet photoreactor equipped with 16W RPR-3500 UV lamps (broadband 300–400 nm UV source with peak emission at 350 nm) until the reaction was complete, as monitored by 1H NMR. This resulted in the formation of [4+2] and [4+4] cycloadducts with excellent diastereoselectivity: only anti-[4+4] and syn-[4+2] primary photoproducts were obtained, where syn- and anti- refers to the respective arrangement of the benzylic hydroxy-group in the quinolinol or benzoazacane ring, and furan’s oxygen. Compounds 4 and 5 represent an unprecedented topology for a polyheterocyclic scaffold possessing a β-lactam ring in which the lactam is fused to benzoquinoline and azacane rings which, in turn, are fused with reactive 4,5 or 2,5-dihydrofuran moieties.

The structure of the products was determined by comparing the experimental spin-spin coupling constants with those calculated using the relativistic force field (rff) approach developed in our laboratory (Figure 3).13 In the case of [4+2] cycloadduct the spin-spin coupling constant (SSCC) of benzylic proton on the neighboring CH served to distinguish between syn- and anti-diastereomers. For the syn-cycloadduct this SSCC is calculated at 6.4 Hz, whereas for anti-product SSCC the value is 9.2 Hz – almost a 3 Hz difference. In calculations of the proton spin-spin coupling constants, the rff DU8 method was shown to achieve ~0.3Hz accuracy (rmsd), so the 3 Hz difference is conclusive.

Figure 3.

Figure 3

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Experimental (and calculated) SSCCs in β-lactams 4, 5 and 9

The experimentally observed SSCC is 6.4 Hz, unambiguously pointing to the syn- arrangement of benzylic hydroxyl-group and dihydrofuran moiety. This conclusion is further confirmed by NOE data: excitation of one of the methylene protons at 3.61 ppm produced a 4.9% NOE enhancement on the benzylic proton. The proof of the structure of [4+4] cycloadduct was somewhat more challenging, because of the similarity in the calculated values of the CH(OH)-CH SSCC for syn- and anti-diastereomers. It was found, however, that the relative position of the hydroxy-group has a significant effect on the chemical shift and the SSCC of the adjacent aromatic proton in the ortho-position: for the anti-adduct it was calculated to be 8.1 Hz, whereas for syn – 7.6 Hz. The experimental value of 8.0 Hz provides support for the anti-arrangement of the hydroxy-group and the oxa-bridge.

It is peculiar that the diastereoselectivity in this reaction is opposite to the one observed for the reaction of furanpropanamide photoprecursor in Figure 2, which results in the formation of syn-[4+4] anti-[4+2] cycloadducts.

Both [4+2] and [4+4] adducts can be further introduced in postphotochemical cycloaddition reactions, which substantially increase the complexity of the frameworks formed. Expectedly, 2,3-dihydrofuran-containing [4+2] cycloadduct 4 proved to be more reactive than the [4+4] azacane 5. It reacted under the 1,3-dipolar or hetero-Diels-Alder conditions with bromonitrile oxide generated in situ from dibromoformaldoxime,14 N-benzylideneaniline11 and oxabutadiene formed from dimethylbarbiturate and formaldehyde.12 It is instructive that despite the known high reactivity of the β-lactam moiety we have not observed any significant degradation or side reactions and the yields of the products formed ranged from moderate to good. Cycloadditions to the [4+2] primary photoproduct (4), which possesses a 2,3-dihydrofuran moiety, are both stereo- and regioselective, Scheme 2. 1,3-Dipolar cycloaddition of bromonitrile oxide to 4 occurs from the exo-face and results in single diastereomer 6. Similar outcome was observed with another 1,3-dipole, benzonitrile oxide, generated from bromohydroxamic acid. The oxa-Diels-Alder reaction of the [4+2] cycloadduct with the barbiturate-derived oxadiene also resulted in the formation of 8 as the single product of exo-attack. In all the cases the reactions seem to proceed via charge-controlled transition state and yield only one cycloadduct. The structure of the products was confirmed by the calculation of the SSCC, Figure 4.

Scheme 2.

Scheme 2

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Postphotochemical transformations of [4+2] photoproduct

Figure 4.

Figure 4

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Comparison of experimental and calculated SSCC for products of postphotochemical transformations 6–8

Under the conditions of Povarov reaction,11 instead of isolation of the expected [4+2] cycloaddition product, we observed the formation of acetal 9. The structure of the product was elucidated using the rff calculations, Figure 3.

Two pairs of methylene protons were observed in the 1H NMR spectrum of acetal 9: one, at 3.36 and 3.32 ppm with the germinal SSCC of 15.7 Hz, belongs to the azetidinone ring, whereas the other, at 2.23 and 2.27 ppm with the germinal SSCC of 10.0 Hz – to the bridge methylene of the 2,6-dioxabicyclo[2.2.1]heptane moiety. The formation of the acetal results in the significant changes in the value of SSCC for the benzylic proton, which is now 2.2 Hz (compare with 6.4 Hz in the open form of 4) and its neighboring tetrahydrofuran proton (2.73 ppm). We previously reported15 a similar acetalization in the case of p-methoxy substituted benzoidal aromatics. The example reported here, however, is the first one involving furan moiety. Remarkably, this strained acetal moiety is forming in the structure, already strained by the β-lactam moiety installed during the photochemical step.

Expectedy, [4+4] cycloadduct 5 was somewhat less reactive than dihydrofuran 4. However, we were able to engage it in dipolar cycloadditions with the two nitrile oxides and the nitrone, N-benzylidenemethanamine oxide, derived from benzaldehyde and methylhydroxylamine.9 It should be noted that the [4+2] photoproduct does not tolerate the conditions required for the reaction with the nitrone. In contrast to the postphotochemical transformations of [4+2] cycloadduct, the reactions of [4+4] result in the formation of the mixture of regio- (compounds 10 and 11) and stereoisomers (compounds 12 and 12′). Interestingly, the substitution on formaldoximes influenced considerably the ratio of the regioisomers: 10 and 10′ are formed in a 1.5:1 ratio, whereas the ratio for 11 and 11′ was 6:1. The structures of the products were determined using (i) NOE experiments, (ii) the calculated and experimental SSCCs and (iii) the analogy with the previously studied examples.

The structures of the products were determined using comparison of the calculated and experimental SSCCs and by analogy with the previously studied examples. Elucidation of the structure of compound 12 required additional NOE experiments to ascertain the stereochemistry of the phenyl group. For this purpose the CHN proton at 3.30 ppm was irradiated, and NOE of 4% on the CHON proton at 4.65 ppm was observed, implying respective syn position of these two protons.

In conclusion, we developed a method for photoassisted access to fused polyheterocyclic molecular architectures containing the β-lactam moiety. The primary photoproducts are amenable to postphhotochemical transformations preserving the β-lactam moiety, while offering considerable increase of molecular complexity as a result of experimentally simple single step reactions. The resulting polyheterocyclic β-lactams possess a minimal number of rotatable bonds, and a high Lovering’s fsp3 factor.16

Figure 5.

Figure 5

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Comparison of experimental and calculated SSCC for compounds 10–12

Scheme 1.

Scheme 1

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Synthesis of the photoprecursor, and the photoinduced cyclization.

Scheme 3.

Scheme 3

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Formation of acetal 9 under the conditions of Povarov reaction.

Scheme 4.

Scheme 4

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Postphotochemical transformations of [4+4] photoproduct 5. Compounds 10 and 10′ were isolated as a mixture of regioisomers; minor regioisomer 11′ and diastereomer 12′ were observed by NMR but not isolated

Acknowledgments

This research is supported by the NIH, GM093930

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