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Article

Site-Selective Modification of a Porpholactone—Selective Synthesis of 12,13- and 17,18-Dihydroporpholactones

by
Ana F. R. Cerqueira
1,
Gustautas Snarskis
1,
Jonas Zurauskas
1,
Samuel Guieu
1,2,
Filipe A. Almeida Paz
2 and
Augusto C. Tomé
1,*
1
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
2
CICECO–Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(11), 2642; https://doi.org/10.3390/molecules25112642
Submission received: 20 May 2020 / Revised: 3 June 2020 / Accepted: 4 June 2020 / Published: 6 June 2020
(This article belongs to the Special Issue Exclusive Papers of the Editorial Board Members of the Organic Chemistry Section of Molecules)
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Abstract

:
The reaction of meso-tetrakis(pentafluorophenyl)porpholactone with azomethine ylides and nitrones affords pyrrolidine-fused and isoxazolidine-fused dihydroporpholactones that display, respectively, isobacteriochlorin- and chlorin-type UV–Vis spectra. These reactions are site-selective, yielding, respectively, 17,18- or 12,13-dihydroporpholactones. The crystal and molecular features of pyrrolidine-fused and isoxazolidine-fused dihydroporpholactones were unveiled from single-crystal X-ray diffraction studies.

Graphical Abstract

1. Introduction

Pyrrole-modified porphyrins have attracted considerable attention in recent years. This group of compounds comprises a large diversity of porphyrin analogues where one or more pyrrolic units of the porphyrin macrocycle are replaced by non-pyrrolic units. The synthesis, reactivity, structural features, optical properties, and applications of these compounds have been comprehensively reviewed [1,2,3,4,5,6]. In short, these compounds may be prepared by two complementary routes: by constructing the porphyrin macrocycle using adequate pyrrolic and non-pyrrolic building blocks or by chemical modification of already existing porphyrins. The latter route has been extensively used by the group of Brückner that, by using the “breaking and mending of porphyrins” approach [7], was able to produce a large diversity of pyrrole-modified porphyrins [2]. Focusing on their optical properties, these porphyrinoids may display porphyrin-, chlorin-, isobacteriochlorin-, or bacteriochlorin-like spectra, which is an important feature for a range of applications, including biological (photodynamic therapy (PDT) of cancer or multimodal imaging contrast agents) and technical ones (catalysis or optical sensors) [3,8,9,10,11,12].
Porpholactones, a class of pyrrole-modified porphyrins in which a pyrrolic unit is formally replaced by an oxazolone unit, can be conveniently obtained from meso-tetraarylporphyrins in a two-step procedure (osmium tetroxide-mediated dihydroxylation of the porphyrin followed by KMnO4-induced cleavage of 2,3-dihydroxychlorin) [13] or simply by oxidation of a meso-tetraarylporphyrin with Oxone® in the presence of a catalytic amount of RuCl3 [14].
In the late 1990s, the group of Cavaleiro reported that the porphyrin macrocycle can participate as a dienophile in Diels–Alder reactions (D–A) [15] or as a dipolarophile in 1,3-dipolar cycloadditions (1,3-DC) [16]. The resulting monoadducts are heterocycle-fused chlorins, while bisadducts are bacteriochlorins or isobacteriochlorins. Concerning the 1,3-DC, the reaction of porphyrins with various types of 1,3-dipoles [17], namely, azomethine ylides [16,18,19] and nitrones [20,21], just to refer to the two types used in this work, has been reported. This is, effectively, an excellent and selective route to porphyrin derivatives with adequate optical properties for biological applications. Considering that 1,3-DC have also been successfully used for the peripheral functionalization of other porphyrin-type macrocycles, namely, tetraazaporphyrins [22], N-confused porphyrins [23], octaphyrins [24], and triply linked diporphyrins [25], the rarity of studies concerning the use of pyrrole-modified porphyrins as dipolarophiles is surprising [26]. In this article, we report the reaction of a porpholactone with two azomethine ylides and two nitrones. Since the porpholactone macrocycle is not symmetric, some site selectivity in these 1,3-DC reactions governed by the lactone unit was expected.
Porpholactones display porphyrin-like UV–Vis spectra, which indicates that the lactone moiety mimics very well the electronic properties of a β–β’ bond [27]. However, the reactivity of the three remaining β–β’ bonds is influenced differently by the lactone unit. This influence is observed, for instance, when porpholactone 1 reacts with Woollins’ reagent and PhMe2SiH [28,29] to afford, selectively, a compound with a hydrogenated pyrrole unit adjacent to the lactone moiety (A, Figure 1) or when porpholactones react with hydrazine [30] (or tosylhydrazide) [31] to give compounds with a hydrogenated β–β’ bond opposite to the lactone moiety (B). The selective formation of opp-porphodilactones [32] and 12,13-dihydroxyporpholactone osmate esters (C) [11] from porpholactones are other examples of the orientation effect of the lactone unit. These observations prompted us to investigate the effect of the lactone unit on the reactivity of porpholactones with azomethine ylides and nitrones and, specifically, to find if it induces site selectivity and, eventually, regioselectivity. In these studies, we used meso-tetrakis(pentafluorophenyl)porpholactone (1) that was prepared by Zhang’s method [14].

2. Results and Discussion

The reaction of porpholactone 1 with azomethine ylide 2a (generated in situ from N-methylglycine and paraformaldehyde) was performed under the same reaction conditions applied to meso-tetrakis(pentafluorophenyl)porphyrin [16] (Scheme 1). Interestingly, a single monoadduct was formed, indicating clearly that the reaction was site-selective. A similar reaction with azomethine ylide 2b (generated in situ from N-benzylglycine and paraformaldehyde) also afforded a single monoadduct. Both cycloadducts displayed isobacteriochlorin-type UV–Vis spectra (Figure 2 and Supplementary Materials) similar to that reported for dihydroporpholactone A [28], signifying that the cycloadditions occurred selectively at one of the pyrrolic units adjacent to the lactone moiety (i.e., they should have structures 3 or 4). Their emission spectra were also similar to that of an isobacteriochlorin [28], with a main band around 580 nm and a shoulder around 630 nm. The quantum yields were determined to be 0.59 and 0.69 for 3a and 3b, respectively. These values also correlate well with the quantum yields reported for isobacteriochlorins. Their 1H NMR spectra revealed the signals of the NH protons at 3.58 and 4.50 ppm (for the N-methyl derivative) and at 3.58 and 4.60 ppm (for the N-benzyl derivative). These signals disappeared after shaking with D2O. 1H NMR spectra of porphyrin derivatives with NH signals at such low fields are typical of isobacteriochlorins [15,18,21,33,34], and the same pattern is also observed in isobacteriochlorin-type structures such as compound A [28].
The N-benzyl cycloadduct led to the isolation of poor crystals, which could be, nevertheless, investigated using single-crystal X-ray diffraction studies. The crystallographic studies performed revealed that the material crystallized in the centrosymmetric P-1 triclinic space group, with the asymmetric unit being composed of two disordered halves of two independent molecular units. A full disclosure of the structure of the cycloadduct was instead achieved by solving and refining the structure in the P1 triclinic space group (by discarding the center of inversion). With this procedure, it was possible to unequivocally confirm that the cycloadduct has structure 3b (and not 4b, see Scheme 1 and Figure 3). Though the X-ray diffraction reliability factors were high (due to the poor diffraction of the crystal), the disclosed structural features were in perfect agreement with those obtained from additional characterization techniques, namely, NMR and UV–Vis spectroscopy.
The reaction of porpholactone 1 with nitrone 5a (generated in situ from N-methylhydroxylamine hydrochloride and paraformaldehyde in the presence of potassium carbonate) was performed under the same reaction conditions applied to meso-tetrakis(pentafluorophenyl)porphyrin [21]. TLC analysis of the reaction mixture showed one spot corresponding to porpholactone 1 and two very close spots corresponding to new compounds. The unreacted porpholactone and the two products could be separated by preparative TLC (silica gel) using a 1:1 mixture of CH2Cl2/hexane as the eluent. Similarly, when nitrone 5b was used (generated in situ from N-benzylhydroxylamine hydrochloride and paraformaldehyde in the presence of potassium carbonate), two products with similar Rf were also obtained. The UV–Vis spectra of the new compounds were identical to that of 12,13-dihydroxyporpholactone osmate ester C,11 showing Q bands at λmax 682 nm (Figure 2). These spectra clearly indicate that the cycloadditions occurred selectively at the pyrrolic unit opposite to the lactone moiety. Consequently, the cycloadducts are regioisomers 6 and 7 [35]. The mass spectra of these products indicated that they are all monoadducts, showing the protonated molecular peaks (M + H)+ = 1052 for 6a and 7a and (M + H)+ = 1128 for 6b and 7b. Each pair of regioisomers was obtained in a ratio of ca. 2.4:1, indicating that cycloaddition, besides being site-selective, was also regioselective. A slow crystallization of the main cycloadduct formed in the reaction with nitrone 5a allowed obtaining crystals adequate for single-crystal X-ray diffraction studies. These studies revealed that it has structure 6a (Figure 4) and, therefore, the minor isomer has structure 7a.
The emission spectra of adducts 6 and 7 presented two bands around 650 nm and 690 nm and quantum yields between 0.14 and 0.23, which were much smaller than those for adducts 3 (Table S1, SM). The 1H NMR spectra of compounds 6 and 7 were markedly different from those of compounds 3a/3b, particularly at the chemical shifts of the signals of the NH protons: −1.53 and −1.19 ppm for 6a, −1.67 and −1.36 ppm for 7a, −1.68 and −1.31 ppm for 6b, and −1.73 and −1.43 ppm for 7b. The 13C and 19F NMR spectra of the cycloadducts discussed above are also compatible with the proposed structures, displaying various sets of peaks as expected for porpholactone derivatives with reduced symmetry. In contrast to azomethine adducts 3, nitrone cycloadducts 6 and 7 revealed to be unstable in solution at room temperature, affording, slowly, porpholactone 1. This transformation, probably via retrocycloaddition, was easily observed by TLC and was also detected in the 13C NMR spectra of the cycloadducts that showed a signal corresponding to the carbonyl group of the adduct and a small one due to the carbonyl group of porpholactone 1.
In a previous work [21], we have shown that the addition of an azomethine ylide to a chlorin results in the formation of an isobacteriochlorin, while the addition of a nitrone to a chlorin leads to the formation of a bacteriochlorin. Although being electronically related to porphyrins (and not to chlorins), porpholactones react with azomethine ylides and nitrones with site selectivity identical to that expected for a chlorin, and this is a noteworthy observation. The reason for the site selectivity observed in the reaction of 1,3-DC with chlorins was elucidated by a DFT study [36]: while the addition of an azomethine ylide is irreversible and kinetically controlled, the addition of a nitrone is reversible, pointing to a thermodynamic control of the reaction. Experimental observations in this work, namely, the retrocycloaddition observed with nitrone cycloadducts, suggest that a similar reaction control also operates with porpholactones.
In conclusion, this study showed that the reactions of meso-tetrakis(pentafluorophenyl)porpholactone with 1,3-dipoles are site-selective and, depending on the type of 1,3-dipole used, the resulting cycloadducts are 12,13- or 17,18-dihydroporpholactones, which display, respectively, chlorin- or isobacteriochlorin-type UV–Vis spectra. Considering that a large diversity of substituents may be linked to these cycloadducts by nucleophilic substitutions at the pentafluorophenyl groups [37,38], the reaction of porpholactone 1 with 1,3-dipoles may be an excellent route to a myriad of compounds for biological or technical applications.

3. Materials and Methods

3.1. Chemicals and Instrumentation

1H, 13C and 19F NMR spectra were recorded on Bruker AVANCE 300 or Bruker AVANCE 500 spectrometers. CDCl3 was used as solvent, and tetramethylsilane (TMS) as an internal reference. The chemical shifts are expressed in δ (ppm), and the coupling constants (J) in hertz (Hz). UV–Vis spectra were recorded on a Shimadzu UV-2501PC spectrophotometer using CHCl3 as the solvent. Fluorescence emission spectra were recorded with a Jobin Yvon FluoroMax-3 spectrofluorometer using CHCl3 as the solvent. Fluorescence quantum yields ΦF were determined using 5,10,15,20-tetraphenylporphyrin (TPP) in chloroform (ΦF = 0.11) as the fluorescence standard. Mass spectra were recorded using a Micromass Q-TOF-2TM mass spectrometer and CHCl3 as the solvent. Preparative thin-layer chromatography was carried out on 20 × 20 cm glass plates coated with silica gel (1 mm thick, Merck, Kenilworth, NJ, USA). Analytical TLC was carried out on sheets precoated with silica gel (Merck 60, 0.2 mm thick). Solvents were purified or dried according to the literature procedures. Compound 1 was prepared according to a published procedure [14].

3.2. Synthesis

3.2.1. General Procedure for the Synthesis of Cycloadducts 3.

A solution of porpholactone 1 (50.0 mg, 0.05 mmol), N-substituted glycine (0.45 mmol), and paraformaldehyde (33.8 mg, 1.1 mmol) in toluene (25 mL) was heated at reflux under a nitrogen atmosphere for 4 h. Then, new portions of the N-substituted glycine (0.45 mmol) and paraformaldehyde (33.8 mg, 1.1 mmol) were added, and the mixture was refluxed for additional 4 h. The solvent was evaporated, and the compounds were separated by preparative TLC using dichloromethane/hexane as the eluent. The compound with higher Rf corresponded to unreacted porpholactone (~10%), and the fraction running immediately below it corresponded to the expected cycloadduct. Isolated yields: 3a = 85%; 3b = 43%.
Adduct 3a: (45.2 mg, 85% yield), 1H NMR (300 MHz, CDCl3): δ 2.23 (s, 3H, CH3), 2.44–2.54 (m, 2H, pyrrolidine-H), 2.84–2.98 (m, 2H, pyrrolidine-H), 3.58 (s, 1H, NH), 4.48–4.71 (m, 3H, NH and β-H [C (sp3)]), 7.32 (dd, 1H, J = 4.8 and 1.4 Hz, β-H), 7.59 (d, 2H, J = 1.4 Hz, β-H), 7.77 (d, 1H, J = 4.8 Hz, β-H). 13C NMR (75 MHz, CDCl3): δ 40.9, 47.6, 48.8, 62.0, 62.2, 83.2, 95.7, 109.3, 110.2, 110.6, 112.5, 113.7, 114.1, 122.0, 123.3, 134.7, 135.6, 135.9, 137.0, 138.5, 139.0, 141.2, 143.2, 144.1, 144.8, 145.4, 146.1, 146.6, 147.3, 151.2, 154.1, 157.6, 159.1, 162.2, 164.6. 19F NMR (282 MHz, CDCl3): δ −158.0 to −155.9 (m, 8H, m-F), −148.3 to −147.2 (m, 4H, p-F), −135.6 to −132.0 (m, 8H, o-F). UV-Vis (CHCl3): λmax (log ε) 382 (5.23), 531 (4.38), 572 (4.60), 617 (3.93). MS (ESI): m/z 1050.5 [M + H]+.
Adduct 3b: (24.2 mg, 43% yield), 1H NMR (300 MHz, CDCl3): δ 2.53–2.60 (m, 2H, pyrrolidine-H), 2.84 (t, J = 8.7 Hz, 2H, pyrrolidine-H), 3.46 (s, 2H, PhCH2), 3.58 (s, 1H, NH), 4.45–4.63 (m, 3H, NH and β-H [C (sp3)]), 7.06–7.09 (m, 2H, Bn-H), 7.15–7.18 (m, 1H, Bn-H), 7.28–7.30 (m, 3H, Bn-H and β-H), 7.59 (d, 2H, J = 1.6 Hz, β-H), 7.77 (d, 1H, J = 4.8 Hz, β-H). 13C NMR (125 MHz, CDCl3): δ 47.0, 48.2, 59.1, 59.7, 59.9, 83.1, 95.7, 109.4, 110.2, 110.5, 112.5, 114.0, 122.0, 123.2, 125.3, 127.7, 128.2, 128.4, 128.8, 129.05, 129.11, 134.8, 135.6, 135.8, 136.8, 138.8, 141.0, 143.2, 144.0, 144.5, 145.2, 146.0, 146.4, 146.8, 147.3, 151.3, 154.1, 157.6, 159.1, 162.3, 164.6. 19F NMR (282 MHz, CDCl3): δ −158.0 to −155.9 (m, 8H, m-F), −148.3 to −147.3 (m, 4H, p-F), −135.7 to −131.8 (m, 8H, o-F). UV-Vis (CHCl3): λmax (log ε) 382 (5.21), 532 (4.34), 572 (4.59), 629 (3.56). MS (ESI): m/z 1126.1 [M + H]+.

3.2.2. General Procedure for the Synthesis of Cycloadducts 6 and 7.

To a solution of porpholactone 1 (50.0 mg, 0.05 mmol) in toluene (5 mL), N-substituted hydroxylamine hydrochloride (0.20 mmol), paraformaldehyde (15.1 mg, 0.50 mmol), and K2CO3 (55.7 mg, 0.40 mmol) were added. The mixture was heated at 60 °C under a nitrogen atmosphere for 12 h, and then additional portions of N-substituted hydroxylamine hydrochloride, paraformaldehyde, and K2CO3 were added to the reaction mixture, which was heated for a total of 30 h. The reaction mixture was washed with H2O and then was purified by preparative TLC using dichloromethane/hexane (1:1) as the eluent. The fraction with higher Rf corresponded to unreacted porpholactone (~60%), the following one was the major cycloadduct, and the third one the minor cycloadduct. Isolated yields: 6a = 19% (48% yield based on consumed porpholactone 1), 7a = 8% (19% yield based on consumed porpholactone 1); 6b = 22% (43% yield based on consumed porpholactone 1), 7b = 9% (18% yield based on consumed porpholactone 1).
Adduct 6a: 1H NMR (300 MHz, CDCl3): δ −1.53 (s, 1H, NH), −1.19 (s, 1H, NH), 2.57 (s, 3H, CH3), 2.86–2.95 (m, 1H, isoxazolidine-H), 3.35–3.43 (m, 1H, isoxazolidine-H), 5.14–5.19 (m, 1H, β-H [C (sp3)]), 6.65 (d, 1H, J = 6.8 Hz, β-H [C (sp3)]), 8.19 (s, 1H, β-H), 8.48–8.52 (m, 2H, β-H), 8.64 (d, 1H, J = 4.0 Hz, β-H). 13C NMR (75 MHz, CDCl3): δ 44.0, 55.4, 64.0, 85.0, 89.7, 98.7, 102.3; 105.5, 105.8, 110.7, 111.4, 114.5; 122.9, 125.3, 126.8, 127.9, 128.1, 128.2, 128.3, 134.7, 137.5, 138.2, 138.9, 140.9, 141.6, 143.5, 145.1, 147.1, 148.9, 152.6, 162.9, 165.8. 19F NMR (282 MHz, CDCl3): δ −158.2 to −155.7 (m, 8H, m-F), −148.3 to −146.7 (m, 4H, p-F), −136.0 to −131.1 (m, 8H, o-F). UV-vis (CHCl3): λmax (log ε) 404 (5.30), 497 (4.07), 530 (3.86), 625 (3.75), 684 (4.61). MS (ESI): m/z 1052.5 [M + H]+.
Adduct 7a: 1H NMR (300 MHz, CDCl3): δ −1.67 (s, 1H, NH), −1.36 (s, 1H, NH), 2.57 (s, 3H, CH3), 2.90–2.95 (m, 1H, isoxazolidine-H), 3.39–3.44 (m, 1H, isoxazolidine-H), 5.21–5.23 (m, 1H, β-H [C (sp3)]), 6.66 (d, 1H, J = 7.4 Hz, β-H [C (sp3)]), 8.33 (d, 1H, J = 4.5 Hz, β-H), 8.40 (d, 1H, J = 4.4 Hz, β-H), 8.56 (d, 1H, J = 4.4 Hz, β-H), 8.66 (d, 1H, J = 4.5 Hz, β-H). 19F NMR (282 MHz, CDCl3): δ −158.4 to −155.6 (m, 8H, m-F), −148.7 to −146.1 (m, 4H, p-F), −136.3 to −131.2 (m, 8H, o-F). UV-vis (CHCl3): λmax (log ε) 404 (5.44), 496 (4.20), 530 (3.97), 625 (3.90), 684 (4.83). MS (ESI): m/z 1052.2 [M + H]+.
Adduct 6b: 1H NMR (300 MHz, CDCl3): δ −1.68 (s, 1H, NH), −1.31 (s, 1H, NH), 3.25 (s, 2H, isoxazolidine-H), 3.81 (s, 2H, PhCH2), 5.24–5.25 (m, 1H, isoxazolidine-H), 6.65 (d, 1H, J = 7.4 Hz, β-H [C (sp3)]), 7.00–7.02 (m, 2H, Bn-H), 7.19–7.22 (m, 3H, Bn-H), 8.22 (d, 1H, J = 3.2 Hz, β-H), 8.46 (d, 1H, J = 4.1 Hz, β-H), 8.55 (d, 1H, J = 4.1 Hz, β-H), 8.66 (d, 1H, J = 3.2 Hz, β-H). 13C NMR (125 MHz, CDCl3): δ 44.0, 53.9, 64.6, 86.1, 89.3, 99.6, 101.0, 105.8, 110.7, 112.7, 113.7, 115.3, 122.3, 125.4, 127.3, 128.3, 136.8, 137.5, 138.9, 139.3, 139.4, 141.2, 141.6, 143.3, 143.7, 144.8, 145.2, 146.9, 152.9, 163.0, 165.8. 19F NMR (282 MHz, CDCl3): δ −158.2 to −155.8 (m, 8H, m-F), −148.2 to −146.7 (m, 4H, p-F), −135.7 to −130.1 (m, 8H, o-F). UV-vis (CHCl3): λmax (log ε) 404 (5.92), 496 (4.66), 529 (4.46), 623 (4.35), 646 (4.33), 682 (5.24). MS (ESI): m/z 1128.4 [M + H]+.
Adduct 7b: 1H NMR (300 MHz, CDCl3): δ −1.73 (s, 1H, NH), −1.43 (s, 1H, NH), 3.31 (s, 2H, isoxazolidine-H), 3.85 (s, 2H, PhCH2), 5.33–5.37 (m, 1H, isoxazolidine-H), 6.67 (d, 1H, J = 7.8 Hz, β-H [C (sp3)]), 7.02–7.06 (m, 2H, Bn-H), 7.19–7.23 (m, 3H, Bn-H), 8.30 (d, 1H, J = 5.10 Hz, β-H), 8.42 (d, 1H, J = 4.2 Hz, β-H), 8.57 (d, 1H, J = 4.2 Hz, β-H), 8.68 (d, 1H, J = 5.1 Hz, β-H). 19F NMR (282 MHz, CDCl3): δ −158.3 to 155.5 (m, 8H, m-F), −148.3 to −146.1 (m, 4H, p-F), −136.3 to −130.0 (m, 8H, o-F). UV-vis (CHCl3): λmax (log ε) 404 (5.57), 497 (4.30), 529 (4.06), 626 (3.97), 643 (4.05), 684 (4.87). MS (ESI): m/z 1128.3 [M + H]+.
CCDC 1832879, 1832880, and 1985131 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Supplementary Materials

The following are available online. 1H, 13C and 19F NMR spectra, mass spectra, absorption, and emission spectra for the new compounds. Details of the crystal data collection, solution, and refinement of compounds 3b and 6a. Crystal structures in CIF format (CIF).

Author Contributions

Conceptualization, A.C.T.; synthesis of the porpholactone derivatives, A.F.R.C., G.S., J.Z.; single-crystal X-ray diffraction studies, S.G., F.A.A.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Fundação para a Ciência e a Tecnologia (FCT), through project PTDC/QEQ-QOR/6160/2014 and research units UID/QUI/00062/2019, UIDB/50006/2020, and UIDB/50011/2020.

Acknowledgments

Thanks are due to Fundação para a Ciência e a Tecnologia (FCT) for the financial support to project PTDC/QEQ-QOR/6160/2014, QOPNA research unit (FCT UID/QUI/00062/2019), the LAQV-REQUIMTE (UIDB/50006/2020), and CICECO (UIDB/50011/2020), financed through national funds and where applicable co-financed by FEDER, within the PT2020 Partnership Agreement, and also to the Portuguese NMR Network. S. Guieu acknowledges financial support from the pAge project (Centro-01-0145-FEDER-000003). Ana Cerqueira thanks FCT for her doctoral grant (SFRH/BD/135597/2018).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Brückner, C.; Akhigbe, J.; Samankumara, L.P. Porphyrin analogs containing non-pyrrolic heterocycles. In Handbook of Porphyrin Science; Kadish, K.M., Smith, K.M., Guilard, R., Eds.; World Scientific: River Edge, NY, USA, 2014; Volume 31, pp. 1–276. [Google Scholar]
  2. Brückner, C. The breaking and mending of meso-tetraarylporphyrins: Transmuting the pyrrolic building blocks. Acc. Chem. Res. 2016, 49, 1080–1092. [Google Scholar] [CrossRef] [PubMed]
  3. Costa, L.D.; Costa, J.I.T.; Tomé, A.C. Porphyrin macrocycle modification: Pyrrole ring-contracted or -expanded porphyrinoids. Molecules 2016, 21, 320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Taniguchi, M.; Lindsey, J.S. Synthetic chlorins, possible surrogates for chlorophylls, prepared by derivatization of porphyrins. Chem. Rev. 2017, 117, 344–535. [Google Scholar] [CrossRef] [PubMed]
  5. Chatterjee, T.; Shetti, V.S.; Sharma, R.; Ravikanth, M. Heteroatom-containing porphyrin analogues. Chem. Rev. 2017, 117, 3254–3328. [Google Scholar] [CrossRef]
  6. Ning, Y.; Jin, G.-Q.; Zhang, J.-L. Porpholactone chemistry: An emerging approach to bioinspired photosensitizers with tunable near-infrared photophysical properties. Acc. Chem. Res. 2019, 52, 2620–2633. [Google Scholar] [CrossRef]
  7. Akhigbe, J.; Samankumara, L.P.; Brückner, C. The breaking and mending of porphyrins: Reductive coupling of secochlorin bisaldehydes. Tetrahedron Lett. 2012, 53, 3524–3526. [Google Scholar] [CrossRef]
  8. Ke, X.-S.; Ning, Y.; Tang, J.; Hu, J.-Y.; Yin, H.-Y.; Wang, G.-X.; Yang, Z.-S.; Jie, J.; Liu, K.; Meng, Z.-S.; et al. Gadolinium(III) porpholactones as efficient and robust singlet oxygen photosensitizers. Chem. Eur. J. 2016, 22, 9676–9686. [Google Scholar] [CrossRef]
  9. Ning, Y.; Tang, J.; Liu, Y.-W.; Jing, J.; Sun, Y.; Zhang, J.-L. Highly luminescent, biocompatible ytterbium (III) complexes as near-infrared fluorophores for living cell imaging. Chem. Sci. 2018, 9, 3742–3753. [Google Scholar] [CrossRef] [Green Version]
  10. Yang, Z.-S.; Ning, Y.; Yin, H.-Y.; Zhang, J.-L. Lutetium (III) porphyrinoids as effective triplet photosensitizers for photon upconversion based on triplet-triplet annihilation (TTA). Inorg. Chem. Front. 2018, 5, 2291–2299. [Google Scholar] [CrossRef]
  11. Hewage, N.; Daddario, P.; Lau, K.S.F.; Guberman-Pfeffer, M.J.; Gascón, J.A.; Zeller, M.; Lee, C.O.; Khalil, G.E.; Gouterman, M.; Brückner, C. Bacterio- and isobacteriodilactones by stepwise or direct oxidations of meso-tetrakis(pentafluorophenyl)porphyrin. J. Org. Chem. 2019, 84, 239–256. [Google Scholar] [CrossRef]
  12. Jin, G.-Q.; Ning, Y.; Geng, J.-X.; Jiang, Z.-F.; Wang, Y.; Zhang, J.-L. Joining the journey to near infrared (NIR) imaging: The emerging role of lanthanides in the designing of molecular probes. Inorg. Chem. Front. 2020, 7, 289–299. [Google Scholar] [CrossRef]
  13. McCarthy, J.R.; Jenkins, H.A.; Brückner, C. Free base meso-tetraaryl-morpholinochlorins and porpholactone from meso-tetraaryl-2,3-dihydroxy-chlorin. Org. Lett. 2003, 5, 19–22. [Google Scholar] [CrossRef] [PubMed]
  14. Yu, Y.; Lv, H.; Ke, X.; Yang, B.; Zhang, J.-L. Ruthenium-catalyzed oxidation of the porphyrin β,β’-pyrrolic ring: A general and efficient approach to porpholactones. Adv. Synth. Catal. 2012, 354, 3509–3516. [Google Scholar] [CrossRef]
  15. Tomé, A.C.; Lacerda, P.S.S.; Neves, M.G.P.M.S.; Cavaleiro, J.A.S. meso-Arylporphyrins as dienophiles in Diels–Alder reactions: A novel approach to the synthesis of chlorins, bacteriochlorins and naphthoporphyrins. Chem. Commun. 1997, 1199–1200. [Google Scholar] [CrossRef]
  16. Silva, A.M.G.; Tomé, A.C.; Neves, M.G.P.M.S.; Silva, A.M.S.; Cavaleiro, J.A.S. meso-Tetraarylporphyrins as dipolarophiles in 1,3-dipolar cycloaddition reactions. Chem. Commun. 1999, 1767–1768. [Google Scholar] [CrossRef]
  17. Tomé, A.C.; Neves, M.G.P.M.S.; Cavaleiro, J.A.S. Porphyrins and other pyrrolic macrocycles in cycloaddition reactions. J. Porphyrins Phthalocyanines 2009, 13, 408–414. [Google Scholar] [CrossRef]
  18. Silva, A.M.G.; Tomé, A.C.; Neves, M.G.P.M.S.; Silva, A.M.S.; Cavaleiro, J.A.S. 1,3-Dipolar cycloaddition reactions of porphyrins with azomethine ylides. J. Org. Chem. 2005, 70, 2306–2314. [Google Scholar] [CrossRef]
  19. Silva, A.M.G.; Tomé, A.C.; Neves, M.G.P.M.S.; Cavaleiro, J.A.S.; Perrone, D.; Dondoni, A. Porphyrins in 1,3-dipolar cycloadditions with sugar azomethine ylides. Synthesis of pyrrolidinoporphyrin glycoconjugates. Synlett 2005, 857–859. [Google Scholar] [CrossRef]
  20. Aguiar, A.; Leite, A.; Silva, A.M.N.; Tomé, A.C.; Cunha-Silva, L.; Castro, B.; Rangel, M.; Silva, A.M.G. Isoxazolidine-fused meso-tetraarylchlorins as key tools for the synthesis of mono- and bis-annulated chlorins. Org. Biomol. Chem. 2015, 13, 7131–7135. [Google Scholar] [CrossRef]
  21. Almeida, J.; Aguiar, A.; Leite, A.; Silva, A.M.N.; Cunha-Silva, L.; Castro, B.; Rangel, M.; Barone, G.; Tomé, A.C.; Silva, A.M.G. 1,3-Dipolar cycloadditions with meso-tetraarylchlorins – site selectivity and mixed bisadducts. Org. Chem. Front. 2017, 4, 534–544. [Google Scholar] [CrossRef]
  22. Silva, A.M.G.; Lacerda, P.S.S.; Tomé, A.C.; Neves, M.G.P.M.S.; Silva, A.M.S.; Cavaleiro, J.A.S.; Makarova, E.A.; Lukyanets, E.A. Porphyrins in 1,3-dipolar cycloaddition reactions. Synthesis of new porphyrin-chlorin and porphyrin-tetraazachlorin dyads. J. Org. Chem. 2006, 71, 8352–8356. [Google Scholar] [CrossRef] [PubMed]
  23. Li, X.; Liu, B.; Yu, X.; Yi, P.; Yi, R.; Chmielewski, P.J. 1,3-Dipolar cycloaddition of 2,6-dichlorobenzonitrile oxide to 2-methyl-N-confused porphyrin. Regio- and stereoselective synthesis and structural characterization of 2-aza-21-carbabacteriochlorin and resolution of 2-aza-21-carbachlorin enantiomers. J. Org. Chem. 2012, 77, 2431–2440. [Google Scholar] [CrossRef] [PubMed]
  24. Hata, H.; Kamimura, Y.; Shinokubo, H.; Osuka, A. Synthesis of pyrrolidine-fused [34]- and [36]octaphyrins via 1,3-dipolar cycloaddition. Org. Lett. 2006, 8, 1169−1172. [Google Scholar] [CrossRef] [PubMed]
  25. Tanaka, T.; Nakamura, Y.; Aratani, N.; Osuka, A. Regioselective [3+4] cycloaddition of an azomethine ylide to meso−meso, β−β, β’−β’ triply linked diporphyrins. Tetrahedron Lett. 2008, 49, 3308–3311. [Google Scholar] [CrossRef]
  26. Yao, Y.; Rao, Y.; Liu, Y.; Jiang, L.; Xiong, J.; Fan, Y.-J.; Shen, Z.; Sessler, J.L.; Zhang, J.-L. Aromaticity versus regioisomeric effect of β-substituents in porphyrinoids. Phys. Chem. Chem. Phys. 2019, 21, 10152–10162. [Google Scholar] [CrossRef] [PubMed]
  27. Brückner, C.; Ogikubo, J.; McCarthy, J.R.; Akhigbe, J.; Hyland, M.A.; Daddario, P.; Worlinsky, J.L.; Zeller, M.; Engle, J.T.; Ziegler, C.J.; et al. meso-Arylporpholactones and their reduction products. J. Org. Chem. 2012, 77, 6480–6494. [Google Scholar] [CrossRef] [Green Version]
  28. Yu, Y.; Furuyama, T.; Tang, J.; Wu, Z.-Y.; Chen, J.-Z.; Kobayashi, N.; Zhang, J.-L. Stable iso-bacteriochlorin mimics from porpholactone: Effect of a β-oxazolone moiety on the frontier π-molecular orbitals. Inorg. Chem. Front. 2015, 2, 671–677. [Google Scholar] [CrossRef]
  29. Wu, Z.-Y.; Wang, T.; Meng, Y.-S.; Rao, Y.; Wang, B.-W.; Zheng, J.; Gao, S.; Zhang, J.-L. Enhancing the reactivity of nickel(II) in hydrogen evolution reactions (HERs) by β-hydrogenation of porphyrinoid ligands. Chem. Sci. 2017, 8, 5953–5961. [Google Scholar] [CrossRef] [Green Version]
  30. Akhigbe, J.; Haskoor, J.; Zeller, M.; Brückner, C. Porpholactams and chlorolactams: Replacement of a β, β’-double bond in meso-tetraphenyl-porphyrin and -chlorin by a lactam moiety. Chem. Commun. 2011, 47, 8599–8601. [Google Scholar] [CrossRef]
  31. Akhigbe, J.; Haskoor, J.; Krause, J.A.; Zeller, M.; Brückner, C. Formation, structure, and reactivity of meso-tetraarylchlorolactones, -porpholactams, and -chlorolactams, porphyrin and chlorin analogues incorporating oxazolone or imidazolone moieties. Org. Biomol. Chem. 2013, 11, 3616–3628. [Google Scholar] [CrossRef]
  32. Ke, X.-S.; Chang, Y.; Chen, J.-Z.; Tian, J.; Mack, J.; Cheng, X.; Shen, Z.; Zhang, J.-L. Porphodilactones as synthetic chlorophylls: Relative orientation of β-substituents on a pyrrolic ring tunes NIR absorption. J. Am. Chem. Soc. 2014, 136, 9598–9607. [Google Scholar] [CrossRef] [PubMed]
  33. Chang, C.K. Synthesis and characterization of alkylated isobacteriochlorins, models of siroheme and sirohydrochlorin. Biochemistry 1980, 19, 1971–1976. [Google Scholar] [CrossRef] [PubMed]
  34. Stolzenberg, A.M.; Spreer, L.O.; Holm, R.H. Octaethylisobacteriochlorin, a model of the sirohydrochlorin ring-system of siroheme enzymes - preparation and spectroscopic and electrochemical properties of the free base and its Zn(II) complex. J. Am. Chem. Soc. 1980, 102, 364–370. [Google Scholar] [CrossRef]
  35. A mixture of isomers 6a/7a was analyzed by HPLC: The two compounds show retention times at 32.15 min (7a, minor isomer) and 33.62 min (6a, major isomer) (see Supp. mat.)
  36. Jimenez-Oses, G.; Garcia, J.I.; Silva, A.M.G.; Santos, A.R.N.; Tomé, A.C.; Neves, M.G.P.M.S.; Cavaleiro, J.A.S. Mechanistic insights on the site selectivity in successive 1,3-dipolar cycloadditions to meso-tetraarylporphyrins. Tetrahedron 2008, 64, 7937–7943. [Google Scholar] [CrossRef]
  37. Costa, J.I.T.; Tomé, A.C.; Neves, M.G.P.M.S.; Cavaleiro, J.A.S. 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin: A versatile platform to novel porphyrinic materials. J. Porphyrins Phthalocyanines 2011, 15, 1116–1133. [Google Scholar] [CrossRef]
  38. Worlinsky, J.L.; Halepas, S.; Brückner, C. PEGylated meso-arylporpholactone metal complexes as optical cyanide sensors in water. Org. Biomol. Chem. 2014, 12, 3991–4001. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
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Figure 1. Known dihydroporpholactones structurally related to cycloadducts 3 and 6/7 [11,28,30].
Figure 1. Known dihydroporpholactones structurally related to cycloadducts 3 and 6/7 [11,28,30].
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Figure 2. Absorption spectra of compounds 3a, 6a, and 7a in chloroform (c = ~2 × 10−6 mol.L−1).
Figure 2. Absorption spectra of compounds 3a, 6a, and 7a in chloroform (c = ~2 × 10−6 mol.L−1).
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Figure 3. Ball-and-stick representation of the pyrrolidine-fused porpholactone derivative 3b. The chiral centers are indicated by an asterisk. Hydrogen atoms were omitted for clarity reasons.
Figure 3. Ball-and-stick representation of the pyrrolidine-fused porpholactone derivative 3b. The chiral centers are indicated by an asterisk. Hydrogen atoms were omitted for clarity reasons.
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Molecules 25 02642 sch001 550
Scheme 1. Reaction of porpholactone 1 with azomethine ylides 2a, b and nitrones 5a, b.
Scheme 1. Reaction of porpholactone 1 with azomethine ylides 2a, b and nitrones 5a, b.
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Figure 4. Oak Ridge Thermal Ellipsoid Plot (ORTEP) representation of the nitrone cycloadduct 6a derivative. Non-hydrogen atoms are represented as thermal ellipsoids drawn at the 50% probability level, and hydrogen atoms as small spheres with arbitrary radii. The chiral centers are indicated by an asterisk.
Figure 4. Oak Ridge Thermal Ellipsoid Plot (ORTEP) representation of the nitrone cycloadduct 6a derivative. Non-hydrogen atoms are represented as thermal ellipsoids drawn at the 50% probability level, and hydrogen atoms as small spheres with arbitrary radii. The chiral centers are indicated by an asterisk.
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Cerqueira, A.F.R.; Snarskis, G.; Zurauskas, J.; Guieu, S.; Paz, F.A.A.; Tomé, A.C. Site-Selective Modification of a Porpholactone—Selective Synthesis of 12,13- and 17,18-Dihydroporpholactones. Molecules 2020, 25, 2642. https://doi.org/10.3390/molecules25112642

AMA Style

Cerqueira AFR, Snarskis G, Zurauskas J, Guieu S, Paz FAA, Tomé AC. Site-Selective Modification of a Porpholactone—Selective Synthesis of 12,13- and 17,18-Dihydroporpholactones. Molecules. 2020; 25(11):2642. https://doi.org/10.3390/molecules25112642

Chicago/Turabian Style

Cerqueira, Ana F. R., Gustautas Snarskis, Jonas Zurauskas, Samuel Guieu, Filipe A. Almeida Paz, and Augusto C. Tomé. 2020. "Site-Selective Modification of a Porpholactone—Selective Synthesis of 12,13- and 17,18-Dihydroporpholactones" Molecules 25, no. 11: 2642. https://doi.org/10.3390/molecules25112642

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