Development of a Visible Light Triggerable Traceless Staudinger

Oct 15, 2018 - A series of substituted 9-methylenylanthracene photo-cage for diphenylphosphinothioesters have been synthesized to explore their ...
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Article Cite This: J. Org. Chem. 2018, 83, 12998−13010

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Development of a Visible Light Triggerable Traceless Staudinger Ligation Reagent Peng Hu, Karsten Berning, Yun-Wah Lam, Isabel Hei-Ma Ng, Chi-Chung Yeung, and Michael Hon-Wah Lam* Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China

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S Supporting Information *

ABSTRACT: A series of substituted 9-methylenylanthracene photocages for diphenylphosphinothioesters have been synthesized to explore their photo-uncaging properties by visible light. Substituents such as phenyl, p-trifluoromethylphenyl, p-methoxyphenyl, ethyn-1-ylbenzene, and 3,3-dimethylbut-1-yn-1-yl have been introduced in order to extend the π-conjugation of the photocage and to shift the wavelength response of the uncaging process to the visible spectral range. Among these new photocages, the (10-(3,3-dimethylbut-1-yn-1-yl)anthracen-9-yl)methyl has been shown to have the best performance in terms of fast photo-uncaging and minimal byproduct formation. It is responsive to both UV and visible photoexcitation. Quantum yields of the photoinduced heterolytic anthracenylmethyl−phosphorus bond cleavage at 366 and 416 nm were found to be 0.08 and 0.025, respectively. This photocage enables traceless Staudinger ligation to be triggered by photoirradiation in the visible spectral range for bioconjugation applications. We demonstrate this with a series of visible-light-induced oligopeptide syntheses via the conjugation of amino acid/oligopeptide building blocks by the characteristic peptide linkage attained by traceless Staudinger ligation. Yields of the resultant conjugated oligopeptides ranged from 31 to 43%. This new photocage opens up the possibility of in situ synthesis of functional proteins/peptides mediated by visible-light-induced photoclick processes for the regulation of cellular/metabolic functions of life systems.

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INTRODUCTION The versatile, stereospecific, and high-yield chemical linking of molecular units, with minimal byproduct formation, under mild reaction conditions in benign solvents is the scope of “click chemistry”. Since the promotion of this concept in 2001, click chemistry has been extensively utilized in organic synthesis, bioconjugation, polymer fabrication, functional surface modification, and nanotechnology.1,2 The photoinducibility of some of the “spring-loaded” click reactions has further enabled precise spatial and temporal control of the molecular conjugation events.3 Numerous elegant processes, such as copperfree acetylene−azide cycloaddition,4−6 photoinduced nitrile imine tetrazole−ene cycloaddition (NITEC),7−9 azirine− alkene cycloaddition, 10 photoinduced thiol−ene/thiol− yne coupling,11−13 photoenol reaction,14 and photoinduced Diels−Alder cycloaddition,15 have been developed in recent years for “photoclick” conjugation. Yet, most of these processes require UV excitation (λexcitation < 400 nm), which seriously © 2018 American Chemical Society

hinders their use in in vitro/in vivo bioimaging and other bioconjugation applications. So far, few visible-light-activated photo-click reactions have been reported. For example, Lin and co-workers demonstrated the photoinduced fluoro-tagging of microtubules in living CHO cells by a terthiophene−tetrazole photoclick reagent at 405 nm16 and a naphthalene−tetrazole photoclick reagent at 700 nm via two-photon excitation.17 Fraser et al. used eosin-Y as the photoinitiator for the thiol− ene photoclick reaction at 400−700 nm.18 Arslan et al. reported the use of dibenzoyldiethylgermane as the visible-lightresponsive photoreducer/photoinitiator for copper-catalyzed azide−alkyne cycloaddition (CuAAC) click reactions.19 Zhang et al. reported a coumarin-caged tetramethylguanidine photobase generator at 400−500 nm for thiol-Michael addition reactions.20 Received: May 31, 2018 Published: October 15, 2018 12998

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

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The Journal of Organic Chemistry Photocaging of phosphines to bring about photoactivation of nontraceless and traceless Staudinger ligation has recently been explored by Carrico and co-workers21 and our research team,22 respectively. Both the 4,5-dimethoxy-2-nitrobenzyl and anthracenylmethyl photocages involved were only responsive to UV excitation. In the latter case, the most efficient λexcitation at 376 nm is attributable to the π(anthryl) → π*(anthryl) and π(anthryl) → π*(diarylphosphine) transitions.22 Therefore, it may be possible to extend the wavelength responses of the photo-uncaging process to the visible spectral range via the fine-tuning of the energy of these electronic transitions. In their study of the laser flash photolysis of benzhydryl phosphonium salts at 266 nm, Ammer et al. also reported that electronic effects due to substituents on the benzhydryl rings perturbed their quantum efficiency.23 In this context, we explored the photolytic reactivity of a series of anthracenylmethyl-based photocages with extended π-conjugation for phototriggered traceless Staudinger ligation (Scheme 1) via single-photon photoexcitation in the visible spectral range.

Scheme 2. Synthesis of Substituted Anthracenylmethyl Photocaged Diarylphosphinothioesters (2−6)a

Scheme 1. Visible-Light-Triggered Traceless Staudinger Ligation

a

Reagents and conditions: (a) substituted phenylboronic acid, Pd(OAc)2, BINAP, K2CO3, THF, reflux, 16 h; (b) pyridine, SOCl2, CH2Cl2, −10 °C for 7 h; (c) diphenylphosphinothioester, CHCl3, rt, 16−48 h.

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RESULTS AND DISCUSSION A series of new substituted anthracenylmethyl photocaged diphenylphosphinothioesters (2−6) have been synthesized via the nucleophilic substitution of the corresponding 9-(chloromethyl)anthracene by the phosphinothioester (with R2 = methyl) (Scheme 2). All the substituted anthracenylmethylphosphinothioesters (chloride salt) are soluble in common organic solvents, such as THF, DMF, DMSO, methanol, and their aqueous organic mixtures. They are also soluble in water. The purpose of introducing aryl substituents at the 10-position of the anthracenyl chromophore is to extend the π-conjugation of the photocage so as to lower the π(anthryl)−π*(anthryl) and π(anthryl)−π*(diarylphosphine) energy gaps. Figure 1 shows the UV−vis absorption spectra of the phosphonium compounds 1−6. All the substituted compounds show redshifted absorption bands compared to 1 with an unsubstituted anthracenylmethyl chromophore. The extent of such a red-shift in phosphonium compounds 2−4 was very similar despite the presence of electron-withdrawing or electron-donating groups at the para-position of the phenyl substituent. This is most probably caused by the orthogonal orientation of the phenyl substituent with respect to the anthracenyl ring due to their steric interaction, which limits π-conjugation. For 5 and 6, where such steric hindrance is removed because of the acetylene bridge, absorption bands of the anthracenylmethyl chromophores display ca. 30−40 nm of red-shift. Photolysis of the new phosphonium compounds at >400 nm broad band irradiation at room temperature was monitored by 31 P NMR (Figure 2). Complete uncaging was achieved in

Figure 1. Spectroscopic properties of the anthracenylmethyl photocaged diphenylphosphinothioesters 1−6: UV−vis absorption spectra (10−5 M) in 3:1 THF/H2O.

20−40 min, giving the diphenylphosphinothioester and its oxide, as well as other uncharacterized byproducts. Among the five new phosphonium compounds, 4 gave the best yield of diphenylphosphinothioester, while 3 produced the least. This may be due to the presence of the electron-donating methoxy group in 4 that favors heterolytic cleavage of the anthracenylmethyl−phosphine bond via the stabilization of the carbocation intermediate. The electron-withdrawing trifluoromethyl group in 3 renders it prone to the homolytic pathway.23 Both 5 and 6 underwent heterolytic photolysis with minimal uncharacterized byproduct formation. Compound 5 required the longest photoirradiation duration for photolysis, while 6 required the least. As compounds 4−6 showed cleaner photolysis with less byproduct formation, they were further examined with visible photoexcitation (λexcitation > 420 nm). Photolysis of 1 (R1 = −H) 12999

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

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The Journal of Organic Chemistry

Figure 2. 31P NMR monitoring of photolysis of the phosphonium compounds 2−6 in degassed 3:1 THF-d8/D2O. Broadband photoexcitation (λex > 400 nm) was administered by a 500 W Hg lamp equipped with proper optical filters. Spectra shown were obtained upon complete disappearance of the corresponding phosphonium compounds.

Figure 3. 31P NMR monitoring of the photolysis of phosphonium compounds 1 and 4−6 in degassed 3:1 THF-d8/D2O. Broadband photoexcitation (λex > 420 nm) was administered by a 500 W Hg lamp equipped with proper optical filters. Spectra shown were obtained upon complete disappearance of the corresponding phosphonium compounds.

photo-uncaging process of 6 at 366 and 416 nm were measured to be 0.08 and 0.025, respectively, via reference to the absolute ϕFeII at the corresponding λexcitation of ferrioxalate actinometry.32,33 Thus, the UV photo-uncaging responses of 6 are quite comparable to that of our previous UV-only phototriggered traceless Staudinger reagent 1 (ϕ ≈ 0.07), while it also possesses reasonable photo-uncaging efficiency in the visible spectral range. For comparison, the quantum efficiency of the photo-uncaging of the dimethoxy-substituted p-hydroxyphenacyl photocaged γ-amino acids L-glutamic acid and GABA at 400 nm was 0.03−0.04.24 The photo-uncaging of cyclic nucleotides from dialkylamino-substituted coumarinylmethyl

under a similar photoirradiation condition was also evaluated for comparison (Figure 3). Only a small amount of the diphenylphosphinothioester was produced by 1, even after 90 min of broadband irradiation by visible light. On the other hand, compounds 4−6 were able to produce the diphenylphosphinothioester in 40, 50, and 25 min, respectively. The (10-(3,3dimethylbut-1-yn-1-yl)anthracen-9-yl)methyl chromophore (in compound 6) gives the best performance in terms of fast photo-uncaging and yield of the traceless Staudinger reagent. A closer examination of the spectroscopic properties of 6 reveals its absorption bands at 350−450 nm, with the lowestenergy absorption maximum at 423 nm. Quantum yields of the 13000

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

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The Journal of Organic Chemistry Table 1. Visible-Light-Triggered Traceless Staudinger Ligation of 6 with Selected Aliphatic Azides*

*

N.D. = not detected. †Concentration of phosphinothioester 6 = 0.2 mmol. ‡Concentration of azide = 0.2 mmol.

reagents with the new 3,3-dimethylbutynyl-substituted anthracenylmethyl photocage, it becomes possible to regulate peptide and protein synthesis by visible light. This cannot be achieved by any other photoclick processes currently available. This concept is demonstrated by the phosphonium salts 7 and 8. Instead of a simple (acetylthio)methyl moiety in 6, compounds 7 and 8 contain R2 = Ac-Gly and Ac-Ala-Gly, respectively, as the “clickable” amino acid and dipeptide units, which tether to the phosphonium via a thiol group to their C-termini (Tables 2 and 3). Their solubility properties in organic and aqueous organic solvents are comparable to that of 6, despite of the larger nonpolar R2 that they possess. Both reagents underwent photoinduced traceless Staudinger ligation with six azidylated amino acids and dipeptides (9a−9f) at λexcitation > 420 nm to give the corresponding oligopeptides, which were isolated from the reaction mixtures and characterized by mass spectrometry and 1H and 13C NMR spectrometry. Yields of those oligopeptides ranged from 31 to 43%, which are consistent with those obtained with traditional traceless Staudinger ligation processes.28−30 In summary, we demonstrated that by extending the π-conjugation of the anthracenyl chromophore of the photocage of diarylphosphinothioester traceless Staudinger ligation reagents, the wavelength responses of the photo-uncaging process can be shifted into the visible spectral range. This should render the phototriggered traceless Staudinger ligation process more biocompatible. The new (10-(3,3-dimethylbut-1yn-1-yl)anthracen-9-yl)methyl photocage on phosphonium salts can be uncaged with λexcitation > 420 nm. Visible-lightinduced conjugation of amino acids and peptides by peptide linkages have been achieved with moderate yields. This opens up the possibility of in situ synthesis of functional proteins/ peptides mediated by photoclick processes for the regulation of cellular/metabolic functions of life systems.

photocages at 350−400 nm was found to proceed with quantum yields of 0.20−0.28.25 Olson et al. reported a 7-diethylaminocoumarin-4-ylmethyl photocage for the photorelease of cAMP at 450 nm with a quantum efficiency of 0.78.26 Recently, Slanina et al. reported a series of BODIPY-based photocages that showed remarkable photo-uncaging quantum efficiency, ranging from 0.01 to 0.95, for a variety of simple leaving groups at >500 nm.27 Despite its relatively lower photo-uncaging quantum efficiency by visible light (ϕ ≈ 0.025) compared to that by UV excitation, 6 offers the possibility for visible-light-triggered traceless Staudinger ligation. This is demonstrated by its photoinduced reactivity toward azidomethylbenzene and 2-azido-N-benzylacetamide (azido-Gly-NHBn) under broadband irradiation at λ > 420 nm (Table 1). Product yields were 52 and 49%, respectively, which is comparable to those obtained by our previous UV-only phototriggered traceless Staudinger reagent.22 Reactions of the uncaged diphenylphosphinothioester with the azide substrates have also been carried out. The yields of the corresponding conjugation products were ≈75% for both reactions. The reduction in product yield from the photocaged traceless Staudinger ligation reagent suggests that quantitative photo-uncaging of all the caged reagent was not achieved. In our previous study of the UV-only photocage, the overall photolytic yield of the corresponding uncaged product was found to be 58%.22 Interference of the subsequent ligation process by side products generated during photolysis may also be the cause of the lower phototriggered ligation yield. One of the advantageous features of the traceless Staudinger ligation reaction is its ability to conjugate molecule units by a simple peptide bond without any other residual atoms at the conjugation. Because of this, it has long been recognized as a tool for convergent synthesis of peptides and proteins.28−30 By caging the phosphinothioester traceless Staudinger ligation 13001

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

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The Journal of Organic Chemistry Table 2. Visible-Light-Triggered Traceless Staudinger Ligation of 7† with Azidylated Amino Acids and Peptides

*

Duration of photolysis = 120 min. †Concentration of phosphinothioester 7 = 0.2 mmol. ‡Concentration of azide = 0.2 mmol.

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Edmund). Quantum yield measurements at specific excitation wavelength were carried out using a Newport 77200 monochromator. Qualitative and quantitative determination of reaction products were characterized by 1H NMR and mass spectrometry. Synthesis of Photocaged Phosphinothioesters 2−6. Synthesis of (10-Phenylanthracen-9-yl)methanol.

EXPERIMENTAL SECTION

Methods. All reagents were purchased and used without further purification unless specified otherwise. Solvents for photolysis studies were degassed with nitrogen. S-((Diphenylphosphaneyl)methyl)ethanethioate was prepared according to literature methods.22 (10-Bromoanthracen-9-yl)methanol was prepared according to the literature method.31 1H NMR, 13C NMR, and 31P NMR spectra were recorded on 300 and 400 MHz Bruker nuclear resonance spectrometers. 31P NMR spectra were proton-decoupled. Mass spectra were measured by an PE SCIEX API 150EX mass spectrometer and an Applied Biosystems QSTAR Elite hybrid quadrupole time-of-flight mass spectrometer. UV−vis spectra were measured by an Agilent 8453 ultraviolet−visible spectrophotometer. The light source used for photolysis studies was a Newport 67005 500W Hg lamp equipped with a Newport 61945 IR reducer. Broadband irradiation was achieved using optical filters of appropriate cutoff wavelengths (Newport and

(10-Bromoanthracen-9-yl)methanol (2.01 g, 7 mmol) and phenylboronic acid (2.56 g, 21 mmol) were dissolved in 35 mL of degassed 13002

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

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The Journal of Organic Chemistry Table 3. Visible-Light-Triggered Traceless Staudinger Ligation of 8† with Azidylated Amino Acids and Peptides

*

Duration of photolysis = 120 min. †Concentration of phosphinothioester 8 = 0.2 mmol. ‡Concentration of azide = 0.2 mmol.

THF. Pd(OAc)2 (157 mg, 0.7 mmol), BINAP (436 mg, 0.7 mmol), and potassium carbonate (2.90 g, 21 mmol) were then added. The suspension was refluxed under N2 for 16 h. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel eluting with hexane/ethyl acetate (v/v 3/1) to give (10phenylanthracen-9-yl) methanol as a pale yellow amorphous solid (1.82 g, yield 92%). 1H NMR (300 MHz, CDCl3): δ 8.50 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.53−7.62 (m, 5H), 7.33−7.42 (m, 4H), 5.76 (d, J = 6.0 Hz, 2H), 1.82 (t, J = 6.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 138.9, 131.1, 130.9, 130.2, 129.9, 128.4, 127.9, 127.6, 126.2, 125.0, 123.9, 57.6 ppm. Synthesis of (10-(4-(Trifluoromethyl)phenyl)anthracen-9-yl)methanol.

BINAP (124 mg, 0.2 mmol), and potassium carbonate (829 mg, 6 mmol) were then added. The suspension was reflux under N2 for 48 h. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel eluting with hexane/ethyl acetate (v/v 3/1) to give (10-(4-(trifluoromethyl)phenyl)anthracen9-yl)methanol as a pale yellow amorphous solid (410 mg, yield 58%). 1 H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.51−7.62 (m, 6H), 7.39 (t, J = 8.0 Hz, 2 Hz), 5.76 (d, J = 4.0 Hz, 2H), 1.87 (t, J = 4.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 143.0, 136.9, 131.7, 131.6, 130.1, 129.9, 129.9, 127.2, 126.3, 125.5, 125.5, 124.1, 123.0, 57.5 ppm. Synthesis of (10-(4-Methoxyphenyl)anthracen-9-yl)methanol.

(10-Bromoanthracen-9-yl)methanol (2.01 g, 7 mmol) and 4-(methoxyphenyl)boronic acid (3.19 g, 21 mmol) were dissolved in 35 mL of degassed THF. Pd(OAc)2 (157 mg, 0.7 mmol), BINAP (436 mg, 0.7 mmol), and potassium carbonate (2.90 g, 21 mmol)

(10-Bromoanthracen-9-yl)methanol (574 mg, 2 mmol) and (4-(trifluoromethyl)phenyl)boronic acid (1.14 g, 6 mmol) were dissolved in 10 mL of degassed THF. Pd(OAc)2 (45 mg, 0.2 mmol), 13003

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

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The Journal of Organic Chemistry were then added. The suspension was reflux under N2 for 16 h. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel eluting with hexane/ethyl acetate (v/v 3/1) to give (10-(4-methoxyphenyl)anthracen-9-yl)methanol as a pale yellow amorphous solid (1.64 g, yield 85%). 1H NMR (300 MHz, CDCl3): δ 8.45 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.48− 7.56 (m, 2H), 7.31−7.39 (m, 2H), 7.23−7.31 (m, 2H), 7.07−7.13 (m, 2H), 5.68 (d, J = 3.0 Hz, 2H), 3.93 (s, 3 H), 1.99 (t, J = 3.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 159.1, 138.7, 132.2, 130.9, 130.8, 130.5, 130.0, 127.9, 126.2, 125.0, 123.9, 113.9, 57.5, 55.4 ppm. Synthesis of (10-(Phenylethynyl)anthracen-9-yl)methanol.

(10-Phenylanthracen-9-yl)methanol (1.14 g, 4 mmol) was dissolved in 200 mL of dry dichloromethane and cooled to −10 °C. Pyridine (338 μL, 4.2 mmol) and SOCl2 (305 μL, 4.2 mmol) were then added. The resulting solution was stirred in an ice bath for 7 h. The mixture was then concentrated and purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (v/v 1/1) to give 9-(chloromethyl)-10-phenylanthracene as a yellow amorphous solid (1.15 g, yield 95%). 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 12.0 Hz, 2H), 7.52−7.65 (m, 5H), 7.34−7.42 (m, 4H), 1.98 (d, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 139.8, 138.7, 131.1, 130.2, 129.7, 128.4, 128.1, 127.7, 127.6, 126.7, 125.1, 123.4, 39.3 ppm. 9-(Chloromethyl)-10-(4-(trifluoromethyl)phenyl)anthracene.

(10-Bromoanthracen-9-yl)methanol (1.15 g, 4 mmol) and ethynylbenzene (879 μL, 8 mmol) were dissolved in 15 mL of degassed THF. PdCl2(PPh3)2 (281 mg, 0.4 mmol), Pd(PPh3)4 (462 mg, 0.4 mmol), CuI (76 mg, 0.4 mmol), and 5 mL of trimethylamine were then added. The suspension was refluxed under N2 for 16 h. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel eluting with hexane/ethyl acetate (v/v 3/1) to give (10-(phenylethynyl)anthracen-9-yl)methanol as a yellow amorphous solid (699 mg, yield 79%). 1H NMR (400 MHz, CDCl3): δ 8.75 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 2H), 8.46 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.63 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 4H), 7.39−7.49 (m, 3H), 5.70 (d, J = 4.0 Hz, 2H), 1.80 (t, J = 4.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 132.4, 132.1, 131.7, 129.9, 128.7, 128.6, 127.7, 126.7, 126.3, 124.3, 123.5, 119.2, 86.3, 57.5 ppm. Synthesis of (10-(3,3-Dimethylbut-1-yn-1-yl)anthracen-9-yl)methanol.

(10-(4-(Trifluoromethyl)phenyl)anthracen-9-yl)-methanol (352 mg, 1 mmol) was dissolved in 50 mL of dry dichloromethane and cooled to −10 °C. Pyridine (85 μL, 1.05 mmol) and SOCl2 (76 μL, 1.05 mmol) were then added. The resulting solution was stirred in an ice bath for 7 h. The mixture was then concentrated and purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (v/v 1/1) to give 9-(chloromethyl)-10-(4-(trifluoromethyl)phenyl)anthracene as a yellow amorphous solid (330 mg, yield 89%). 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 8.0 Hz, 2 Hz), 7.58 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 5.70 (s, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 142.7, 137.8, 131.6, 130.2, 129.9, 129.6, 128.4, 127.4, 126.8, 125.6, 125.5, 125.5, 123.6, 123.0, 39.1 ppm. 9-(Chloromethyl)-10-(4-methoxyphenyl)anthracene.

(10-(4-Methoxyphenyl)anthracen-9-yl)methanol (943 mg, 3 mmol) was dissolved in 150 mL of dry dichloromethane and cooled to −10 °C. Pyridine (254 μL, 3.15 mmol) and SOCl2 (229 μL, 3.15 mmol) were then added. The resulting solution was stirred in an ice bath for 7 h. The mixture was then concentrated and purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (v/v 1/1) to give 9-(chloromethyl)-10-(4-methoxyphenyl)anthracene as a yellow amorphous solid (998 mg, yield 80%). 1H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.69 (s, 2H), 3.95 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.2, 139.7, 132.2, 130.7, 130.5, 129.7, 128.1, 127.4, 126.6, 125.1, 123.4, 113.9, 55.4, 39.4 ppm. 9-(Chloromethyl)-10-(phenylethynyl)anthracene.

(10-Bromoanthracen-9-yl)methanol (574 mg, 2 mmol) and 3,3dimethylbut-1-yne (709 μL, 6 mmol) were dissolved in 9 mL of degassed THF. PdCl2(PPh3)2 (140 mg, 0.2 mmol), Pd(PPh3)4 (231 mg, 0.2 mmol), CuI (38 mg, 0.2 mmol), and 3 mL of trimethylamine were then added. The suspension was reflux under N2 for 16 h. The reaction mixture was concentrated under vacuum and purified by chromatography on silica gel eluting with hexane/ethyl acetate (v/v 3/1) to give (10-(3,3-dimethylbut-1-yn-1-yl)anthracen-9-yl)methanol as an orange amorphous solid (495 mg, yield 86%). 1H NMR (400 MHz, CDCl3): δ 8.57−8.63 (m, 2H), 8.36−8.45 (m, 2H), 7.54−7.62 (m, 4H), 5.66 (d, J = 4.0 Hz, 2H), 1.76 (t, J = 4.0 Hz, 1H), 1.55 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 132.2, 131.0, 129.8, 127.8, 126.5, 125.9, 124.2, 120.2, 111.3, 75.8, 57.4, 31.4, 29.0 ppm. 9-(Chloromethyl)-10-phenylanthracene.

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DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

Article

The Journal of Organic Chemistry (10-(Phenylethynyl)anthracen-9-yl)methanol (617 mg, 2 mmol) was dissolved in 100 mL of dry dichloromethane and cooled to −10 °C. Pyridine (169 μL, 2.1 mmol) and SOCl2 (153 μL, 2.1 mmol) were then added. The resulting solution was stirred in an ice bath for 7 h. The mixture was then concentrated and purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (v/v 1/1) to give 9-(chloromethyl)-10-(phenylethynyl)anthracene as a yellow amorphous solid (595 mg, yield 91%). 1H NMR (400 MHz, CDCl3): δ 8.75 (d, J = 8.0 Hz, 2H), 8.36 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.61−7.70 (m, 4H), 7.40−7.50 (m, 3H), 5.63 (s, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 132.3, 131.7, 129.6, 128.8, 128.6, 127.9, 127.2, 126.4, 123.8, 123.3, 120.2, 102.1, 86.2, 38.9 ppm. 9-(Chloromethyl)-10-(3,3-dimethylbut-1-yn-1-yl)anthracene.

Diphenylphosphinothioester (137 mg, 0.5 mmol) and 9-(chloromethyl)-10-(4-(trifluoromethyl)phenyl)anthracene (204 mg, 0.55 mmol) were dissolved in 1 mL of chloroform. The resulting solution was stirred at ambient temperature under N2 for 16 h. The reaction mixture was added to 30 mL of diethyl ether, stirred for 2 h, and filtered to give the photocaged phosphinothioester 3 as a yellow amorphous solid (300 mg, yield 93%). 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.53−7.61 (m, 6H), 7.30−7.47 (m, 10H), 7.23−7.28 (m, 2H), 6.24 (d, J = 16.0 Hz, 2H), 5.25 (d, J = 8.0 Hz, 2H), 2.16 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 191.0 (d, J = 2.0 Hz), 142.4, 137.3 (d, J = 6.0 Hz), 134.8 (d, J = 3.0 Hz), 134.0 (d, J = 9.0 Hz), 131.5 (d, J = 2.0 Hz), 130.5 (d, J = 6.0 Hz), 130.2 (d, J = 32.0 Hz), 129.5 (d, J = 4.0 Hz), 129.3 (d, J = 12.0 Hz), 127.0, 126.8, 125.6, 125.5 (d, J = 3.0 Hz), 124.8 (d, J = 3.0 Hz), 122.9, 110.3 (d, J = 11.0 Hz), 115.9 (d, J = 84.0 Hz), 29.8, 26.0 (d, J = 43.0 Hz), 21.3 (d, J = 49.0 Hz) ppm. 31P NMR (400 MHz, CDCl3): δ 28.16 ppm. HRMS (ESI): m/z calcd for C37H29F3OPS [M − Cl−]+ 609.1629, found 609.1630. Photocaged Phosphinothioester 4.

(10-(3,3-Dimethylbut-1-yn-1-yl)anthracen-9-yl)methanol (432 mg, 1.5 mmol) was dissolved in 75 mL of dry dichloromethane and cooled to −10 °C. Pyridine (127 μL, 1.58 mmol) and SOCl2 (115 μL, 1.58 mmol) were then added. The resulting solution was stirred in an ice bath for 7 h. The mixture was then concentrated and purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate (v/v 1/1) to give 9-(chloromethyl)-10-(3,3-dimethylbut-1-yn1-yl)anthracene as an orange amorphous solid (311 mg, yield 85%). 1 H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 8.0 Hz, 2H), 8.31 (d, J = 4.0 Hz, 2H), 7.56−7.66 (m, 4H), 5.60 (s, 2H), 1.55 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 132.2, 129.5, 128.0, 127.6, 127.0, 126.0, 123.7, 121.2, 111.9, 75.8, 39.1, 31.3, 29.0 ppm. Photocaged Phosphinothioester 2.

Diphenylphosphinothioester (549 mg, 2 mmol) and 9-(chloromethyl)10-(4-methoxyphenyl)anthracene (204 mg, 2.2 mmol) were dissolved in 2 mL of chloroform. The resulting solution was stirred at ambient temperature under N2 for 48 h. The reaction mixture was added to 60 mL of diethyl ether, stirred for 2 h, and filtered to give the photocaged phosphinothioester 4 as a yellow amorphous solid (1.03 g, yield 85%). 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.0 Hz, 2H), 7.51−7.60 (m, 8H), 7.29−7.37 (m, 6H), 7.19−7.25 (m, 4H), 7.11 (d, J = 8.0 Hz, 2H), 6.18 (d, J = 16.0 Hz, 2H), 5.24 (d, J = 8.0 Hz, 2H), 3.95 (s, 3H), 2.15 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 191.1 (d, J = 2.0 Hz), 159.2, 139.2 (d, J = 6.0 Hz), 134.7 (d, J = 3.0 Hz), 134.0 (d, J = 9.0 Hz), 132.2 (d, J = 2.0 Hz), 130.6 (d, J = 6.0 Hz), 130.3 (d, J = 2.0 Hz), 120.1 (d, J = 5.0 Hz), 129.3 (d, J = 12.0 Hz), 127.8, 126.7 (d, J = 2.0 Hz), 125.0, 124.5 (d, J = 13.0 Hz), 119.0 (d, J = 11.0 Hz), 116.0 (d, J = 83.0 Hz), 113.9, 55.4, 29.8, 25.9 (d, J = 43.0 Hz), 21.3 (d, J = 49.0 Hz) ppm. 31P NMR (400 MHz, CDCl3): δ 27.93 ppm. HRMS (ESI): m/z calcd for C37H32O2PS [M − Cl−]+ 571.1861, found 571.1860. Photocaged Phosphinothioester 5.

Diphenylphosphinothioester (549 mg, 2 mmol) and 9-(chloromethyl)10-phenylanthracene (666 mg, 2.2 mmol) were dissolved in 2 mL of chloroform. The resulting solution was stirred at ambient temperature under N2 for 16 h. The reaction mixture was added to 60 mL of diethyl ether, stirred for 2 h, and filtered to give the photocaged phosphinothioester 2 as a yellow amorphous solid (1.14 g, yield 99%). 1 H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 12.0 Hz, 2H), 7.49−7.60 (m, 10H), 7.27−7.38 (m, 8H), 7.21 (t, J = 8.0 Hz, 2H), 6.19 (d, J = 16.0 Hz, 2H), 5.24 (d, J = 8.0 Hz, 2H), 2.15 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 191.0 (d, J = 2.0 Hz), 139.3 (d, J = 7.0 Hz), 138.3 (d, J = 2.0 Hz), 134.8 (d, J = 3.0 Hz), 133.9 (d, J = 9.0 Hz), 130.0 (d, J = 2.0 Hz), 130.5 (d, J = 6.0 Hz), 129.7 (d, J = 5.0 Hz), 129.3 (d, J = 12.0 Hz), 128.4, 127.8, 127.7, 126.7 (d, J = 2.0 Hz), 125.0, 124.5 (d, J = 3.0 Hz), 119.8 (d, J = 11.0 Hz), 115.8 (d, J = 83.0 Hz), 29.8, 25.9 (d, J = 43.0 Hz), 21.3 (d, J = 49.0 Hz) ppm. 31P NMR (400 MHz, CDCl3): δ 28.01 ppm. HRMS (ESI): m/z calcd for C36H30OPS [M − Cl−]+ 541.1755, found 541.1750. Photocaged Phosphinothioester 3.

Diphenylphosphinothioester (274 mg, 1 mmol) and 9-(chloromethyl)-10-(phenylethynyl)anthracene (360 mg, 1.1 mmol) were dissolved in 1 mL of chloroform. The resulting solution was stirred at ambient temperature under N2 for 16 h. The reaction mixture was added to 30 mL of diethyl ether, stirred for 2 h, and filtered to give the photocaged phosphinothioester 5 as a yellow amorphous solid (535 mg, yield 89%). 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 8.0 Hz, 2H), 8.27 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.49− 7.58 (m, 6H), 7.42−7.49 (m, 5H), 7.30−7.40 (m, 6H), 6.15 (d, J = 16.0 Hz, 2H), 5.12 (d, J = 8.0 Hz, 2H), 2.13 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 190.8 (d, J = 2.0 Hz), 134.8 (d, J = 2.0 Hz), 134 (d, J = 9.0 Hz), 131.7, 131.65, 130.5 (d, J = 6.0 Hz), 129.4 (d, J = 13.0 Hz), 128.8, 128.6, 127.4, 127.0, 126.3, 125.0 (d, J = 3.0 Hz), 123.2, 120.3 (d, J = 11.0 Hz), 119.5 (d, J = 7.0 Hz), 115.7 (d, J = 83.0 Hz), 102.2 (d, J = 2.0 Hz), 86.0 (d, J = 4.0 Hz), 29.8, 25.9 13005

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

Article

The Journal of Organic Chemistry

δ 196.2 (d, J = 3.75 Hz), 170.4, 136.5 (d, J = 13.5 Hz), 132.8 (d, J = 19.5 Hz), 129.3, 128.7 (d, J = 6.75 Hz), 49.1, 25.4 (d, J = 24.0 Hz), 23.0 ppm. 31P NMR (300 MHz, CDCl3): δ −15.24 ppm. MS (ESI): m/z calcd for C17H19NO2PS [M + H]+ 332.0, found 332.1. Synthesis of Photocaged Phosphinothioester 7.

(d, J = 43.0 Hz), 21.1 (d, J = 49.0 Hz) ppm. 31P NMR (400 MHz, CDCl3): δ 27.33 ppm. HRMS (ESI): m/z calcd for C38H30OPS [M − Cl−]+ 565.1755, found 565.1755. Photocaged Phosphinothioester 6.

Diphenylphosphinothioester (137 mg, 0.5 mmol) and 9-(chloromethyl)-10-(3,3-dimethylbut-1-yn-1-yl)anthracene (169 mg, 0.55 mmol) were dissolved in 1 mL of chloroform. The resulting solution was stirred at ambient temperature under N2 for 16 h. The reaction mixture was added to 30 mL of diethyl ether, stirred for 2 h, and filtered to give the photocaged phosphinothioester 6 as an orange amorphous solid (273 mg, yield 94%). 1H NMR (400 MHz, CDCl3): δ 8.50 (d, J = 8.0 Hz, 2H), 8.26 (d, J = 8.0 Hz, 2H), 7.51−7.60 (m, 6H), 7.45 (t, J = 8.0 Hz, 2H), 7.31−7.40 (m, 6H), 6.14 (d, J = 16.0 Hz, 2H), 5.16 (d, J = 8.0 Hz, 2H), 2.15 (s, 3H), 1.56 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ 190.9 (d, J = 2.0 Hz), 134.8 (d, J = 3.0 Hz), 134.1 (d, J = 9.0 Hz), 131.7 (d, J = 5.0 Hz), 130.6 (d, J = 6.0 Hz), 129.3 (d, J = 12.0 Hz), 127.6, 126.9 (d, J = 2.0 Hz), 126.0, 124.8 (d, J = 3.0 Hz), 120.7 (d, J = 7.0 Hz), 119.0 (d, J = 11.0 Hz), 115.7 (d, J = 83.0 Hz), 112.1 (d, J = 3.0 Hz), 75.6 (d, J = 4.0 Hz), 31.2, 29.8, 29.0, 25.9 (d, J = 43.0 Hz), 20.9 (d, J = 49.0 Hz) ppm. 31P NMR (400 MHz, CDCl3): δ 27.02 ppm. HRMS (ESI): m/z calcd for C36H34OPS [M − Cl−]+ 545.2068, found 545.2070. Synthesis of Photocaged Phosphinothioester 7 with an Ac-Gly Moiety as Clickable Amino Acid. Synthesis of (Diphenylphosphino)methanethiol.

S-((Diphenylphosphino)methyl)-2-acetamidoethanethioate (1.658 g, 5 mmol) and 9-(chloromethyl)-10-(3,3-dimethylbut-1-yn-1-yl)anthracene (1.606 g, 5.25 mmol) were dissolved in 8 mL of chloroform. The resulting solution was stirred at ambient temperature under N2 for 16 h. The reaction mixture was added to 100 mL of diethyl ether/hexane (v/v 1/1), stirred for 2 h, and filtered to give the product as a yellow amorphous solid (3.045 g, yield 91%). 1H NMR (300 MHz, CDCl3): δ 9.45 (t, J = 6.0 Hz, 1H), 8.40 (d, J = 9.0 Hz, 2H), 8.07 (d, J = 9.0 Hz, 2H), 7.41−7.53 (m, 6H), 7.21−7.40 (m, 8H), 5.76 (d, J = 15.0 Hz, 2H), 4.56 (d, J = 9.0 Hz, 2H), 3.95 (d, J = 6.0 Hz, 2H), 2.10 (s, 3H), 1.55 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): δ 195.9 (d, J = 1.5 Hz), 172.3, 135.0, 134.0 (d, J = 9.8 Hz), 131.4 (d, J = 4.5 Hz), 130.2 (d, J = 6.0 Hz), 129.4 (d, J = 12.0 Hz), 127.5, 126.8, 125.8, 124.3, 120.7 (d, J = 6.8 Hz), 118.2 (d, J = 11.3 Hz), 116.0, 114.9, 112.1 (d, J = 3.0 Hz), 75.4 (d, J = 3.8 Hz), 48.6, 31.2, 28.9, 24.3 (d, J = 44.3 Hz), 22.9, 20.6 (d, J = 50.3 Hz) ppm. 31P NMR (300 MHz, CDCl3): δ 24.22 ppm. HRMS (ESI): m/z calcd for C38H37NO2PS [M − Cl−]+ 602.2283, found 602.2285. Synthesis of Photocaged Phosphinothioester 8 with an Ac-AlaGly Moiety as Clickable Dipeptide. Synthesis of S((Diphenylphosphaneyl)methyl)-2-(2-((tert-butoxycarbonyl)amino)propanamido)ethanethioate.

Diphenylphosphine thioester (7.132 g, 26.0 mmol) was dissolved in anhydrous methanol (160 mL), and N2 was bubbled through the solution for 1 h. Sodium hydroxide (2.08 g, 52.0 mmol) was then added, and the mixture was stirred under N2 for 2 h. Solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride (200 mL). The resulting solution was washed with 2 N HCl (2 × 200 mL) and brine (200 mL). The organic layer was dried over anhydrous MgSO4 and filtered, and solvent was removed under reduced pressure. The residue was purified by flash chromatography (alumina, v/v 1/3) to give (diphenylphosphino)methanethiol as a clear oil (5.374 g, yield 89%). 1H NMR (400 MHz, CDCl3): δ 7.41−7.47 (m, 4H), 7.34−7.37 (m, 6H), 3.05 (d, J = 8.0 Hz, 2H), 1.38 (q, J = 8.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 137.1 (d, J = 19.0 Hz), 132.9 (d, J = 25.0 Hz), 129.2, 128.8 (d, J = 9.0 Hz), 21.0 (d, J = 32.0 Hz) ppm. 31P NMR (400 MHz, CDCl3): δ −7.93 ppm. Synthesis of S-((Diphenylphosphino)methyl)-2-acetamidoethanethioate.

(Diphenylphosphino)methanethiol (3.019 g, 13 mmol) and 2-((tertbutoxycarbonyl)amino)acetic acid (2.277 g, 13 mmol) were dissolved in 100 mL of dichloromethane. DCC (2.525 g, 13 mmol) was then added. The mixture was stirred at room temperature under N2 for 16 h. The resulting mixture was filtered. The filtrate was concentrated and purified by chromatography on silica gel eluting with n-hexane/ethyl acetate (v/v 3/1) to give the product as a white amorphous solid (4.06 g, yield 80%). 1H NMR (300 MHz, CDCl3): δ 7.30−7.43 (m, 10H), 5.02 (br, 1H), 3.99 (d, J = 6.0 Hz, 2H), 3.51 (d, J = 3.0 Hz, 2H), 1.42 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): δ 197.5, 155.5, 136.7 (d, J = 13.5 Hz), 132.8 (d, J = 18.8 Hz), 129.2, 128.6 (d, J = 6.8 Hz), 80.4, 50.2, 28.3, 25.3 (d, J = 24.0 Hz), 23.0 ppm. 31P NMR (300 MHz, CDCl3): δ −15.43 ppm. MS (ESI): m/z calcd for C20H25NO3PS [M + H]+ 390.1, found 390.2. Synthesis of S-((Diphenylphosphaneyl)methyl)-2-(2acetamidopropanamido)ethanethioate.

(Diphenylphosphino)methanethiol (2.323 g, 10 mmol) and 2-acetamidoacetic acid (1.171 g, 10 mmol) were dissolved in 100 mL of dichloromethane and 40 mL of DMF. DCC (1.942 g, 10 mmol) was then added. The mixture was stirred at room temperature under N2 for 16 h. The resulting mixture was filtered. The filtrate was concentrated and purified by chromatography on silica gel eluting with hexane/ethyl acetate (v/v 1/2) to give the product as a white amorphous solid (2.61 g, yield 79%). 1H NMR (300 MHz, CDCl3): δ 7.32−7.46 (m, 10H), 6.00 (br, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.52 (d, J = 3.0 Hz, 2H), 2.02 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3):

S-((Diphenylphosphaneyl)methyl)-2-(2-((tert-butoxycarbonyl)amino)propanamido)ethanethioate (3.89 g, 10 mmol) was dissolved in 20 mL of dichloromethane and 20 mL of trifluoroacetic acid. The solution was stirred at room temperature under N2 for 2 h. The mixture was then concentrated and used in the next step without further purification. The residue was dissolved in 75 mL of dichloromethane. (S)-2-Acetamidopropanoic acid (1.311 g, 10 mmol), HATU (4.562 g, 12 mmol), and DIPEA (10.45 mL, 60 mmol) were then added. The solution was stirred at room temperature under N2 for 16 h. The 13006

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

Article

The Journal of Organic Chemistry mixture was washed with NaHCO3 (2 × 75 mL), 1 N HCl solution (75 mL), and brine. The solution was dried with anhydrous MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (v/v 8/1) to give the product as a white amorphous solid (2.358 g, yield 59%). 1H NMR (300 MHz, CDCl3): δ 7.30−7.43 (m, 10H), 6.33−6.43 (m, 1H), 4.50−4.63 (m, 1H), 4.13 (d, J = 6.0 Hz, 2H), 3.52 (d, J = 3.0 Hz, 2H), 1.96 (s, 3H), 1.37 (d, J = 6.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 196.3 (d, J = 3.8 Hz), 173.0, 170.6, 136.6 (dd, J1 = 1.5 Hz, J2 = 13.5 Hz), 128.7 (dd, J1 = 3.0 Hz, J2 = 11.3 Hz), 129.3, 128.7 (d, J = 6.8 Hz), 49.0, 48.7, 25.4 (d, J = 24.0 Hz), 23.1, 17.9 ppm. 31P NMR (300 MHz, CDCl3): δ −15.68 ppm. MS (ESI): m/z calcd for C20H24N2O3PS [M + H]+ 403.1, found 403.1. Synthesis of Photocaged Phosphinothioester 8.

The synthesis was similar to that of 9a, except that azido-L-Phe34 was used instead, to give azido-L-Phe-NHBn as a white amorphous solid (1.73 g, yield 77%). 1H NMR (300 MHz, CDCl3): δ 7.25−7.39 (m, 8H), 7.13−7.20 (m, 2H), 6.54 (br, 1H), 4.35−4.50 (m, 2H), 4.28 (dd, J1 = 6.0 Hz, J2 = 3.0 Hz, 1H), 3.40 (dd, J1 = 12.0 Hz, J2 = 3.0 Hz, 1H), 3.11 (dd, J1 = 12.0 Hz, J2 = 3.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 168.5, 137.5, 129.6, 128.8, 128.7, 127.8, 127.7, 127.3, 65.4, 43.5, 38.5 ppm. HRMS (ESI): m/z calcd for C16H16N4NaO [M + Na]+ 303.1222, found 303.1221. Azido-L-Val-NHBn (9c).

The synthesis was similar to that of 9a, except that azido-L-Val35,36 was used instead, to give azido-L-Val-NHBn as a pale yellow oil (1.67 g, yield 84%). 1H NMR (300 MHz, CDCl3): δ 7.26−7.41 (m, 5H), 6.67 (br, 1H), 4.48 (d, J = 3.0 Hz, 2H), 4.04 (dd, J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 1.65−1.95 (m, 3H), 1.01 (dd, J1 = 6.0 Hz, J2 = 3.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 169.9, 137.7, 128.8, 127.8, 127.7, 43.5, 41.4, 25.0, 23.1, 21.5 ppm. HRMS (ESI): m/z calcd for C13H18N4NaO [M + Na]+ 269.1378, found 269.1378. Azido-Gly-L-Phe-OMe (9d).

S-((Diphenylphosphaneyl)methyl)-2-(2-acetamidopropanamido)ethanethioate (1.61 g, 4 mmol) and 9-(chloromethyl)-10-(4-(3,3dimethylbut-1-yn-1-yl)phenyl)anthracene (1.29 g, 4.2 mmol) were dissolved in 10 mL of chloroform. The resulting solution was stirred at ambient temperature under N2 for 16 h. The reaction mixture was added to 300 mL of diethyl ether, stirred for 2 h, and filtered to give the product as a yellow amorphous solid (2.53 g, yield 89%). 1H NMR (300 MHz, CDCl3): δ 9.15 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 9.0 Hz, 2H), 8.07 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 2H), 7.45−7.63 (m, 4H), 7.25−7.45 (m, 10H), 5.52−5.75 (m, 2H), 4.57−4.69 (m, 1H), 4.16 (d, J = 6.0 Hz, 2H), 3.80−4.12 (m, 2H), 2.10 (s, 3H), 1.56 (s, 9H), 1.48 (d, J = 6.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 195.6, 175.0, 171.0, 135.1, 133.9 (t, J = 9.0 Hz), 131.5 (d, J = 4.5 Hz), 130.3 (d, J = 6.0 Hz), 129.6 (d, J = 13.5 Hz), 127.6, 126.9, 125.9, 124.1, 120.9 (d, J = 6.8 Hz), 117.8 (d, J = 11.3 Hz), 116.0 (d, J = 11.3 Hz), 114.9 (d, J = 11.3 Hz), 112.3 (d, J = 2.3 Hz), 75.4 (d, J = 4.5 Hz), 49.9, 48.4, 31.2, 28.9, 23.4 (d, J = 45.8 Hz), 23.2, 20.4 (d, J = 51.0 Hz), 17.9 ppm. 31P NMR (300 MHz, CDCl3): δ 23.91 ppm. HRMS (ESI): m/z calcd for C41H42N2O3PS [M − Cl−]+ 673.2654, found 673.2654. Synthesis of Azidylated Amino Acids and Peptides. Azido-GlyNHBn (9a).

2-Azidoacetic acid (505 mg, 5 mmol), HOBt (743 mg, 5.5 mmol), and DIPEA (1.938 g, 2.61 mL, 15 mmol) were dissolved in 15 mL of DMF. EDCI (1.917 g, 10 mmol) was then added and the reaction was stirred for 5 min at room temperature. A solution of (S)-methyl 2-amino-3-phenylpropanoate hydrochloride (1.186 g, 5.5 mmol) and DIPEA (957 μL, 5.5 mmol) in 10 mL of DMF was added to the resulting reaction mixture and the reaction was stirred for a further 16 h at room temperature. The reaction mixture was then transferred to a separation funnel and rinsed with ethyl acetate (50 mL). The organic layer was washed with water (2 × 50 mL), NaHCO3 (2 × 50 mL), 1 N HCl solution (50 mL), and brine. The solution was dried over anhydrous MgSO4, filtered, and evaporated to dryness to give a white amorphous solid (916 mg, yield 70%). 1 H NMR (400 MHz, CDCl3): δ 7.25−7.37 (m, 3H), 7.10−7.16 (m, 2H), 6.72 (d, J = 6.0 Hz, 1H), 4.91 (dt, J1 = 6.0 Hz, J2 = 6.0 Hz, 1H), 3.98 (dd, J1 = 15.0 Hz, J2 = 3.0 Hz,2H), 3.77 (s, 3H), 3.09− 3.24 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ 171.4, 166.3, 135.5, 129.2, 128.7, 127.4, 53.0, 52.5, 52.5, 37.9 ppm. HRMS (ESI): m/z calcd for C12H14N4NaO3 [M + Na]+ 285.0964, found 285.0965. Azido-L-Phe-L-Val-NH2 (9e).

2-Azidoacetic acid (888 mg, 8.8 mmol) and HOBt (1.189 g, 8.8 mmol) were dissolved in 50 mL of DMF. DIC (1.11 g, 1.377 mL, 8.8 mmol) was then added and the reaction was stirred for 5 min at room temperature. Benzyl amine (857 mg, 874 μL, 8 mmol) was added to the resulting reaction mixture and the reaction was stirred for a further 16 h at room temperature. The reaction mixture was then transferred to a separation funnel and rinsed with EtOAc (75 mL). The organic layer was washed with water (2 × 125 mL), NaHCO3 (2 × 75 mL), and brine. The solution was dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was purified by flash column chromatography eluting with ethyl acetate/n-hexane (v/v 1/1) to give a white amorphous solid (1.216 g, yield 80%). 1H NMR (400 MHz, CDCl3): δ 7.25−7.37 (m, 5H), 6.63 (br, 1H), 4.46 (d, J = 8.0 Hz, 2H), 4.02 (d, J = 4.0 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 166.4, 137.4, 128.9, 127.9, 127.8, 52.7, 43.5 ppm. HRMS (ESI): m/z calcd for C9H10N4NaO [M + Na]+ 213.0752, found 213.0752. Azido-L-Phe-NHBn (9b).

The synthesis was similar to that of 9d, except that (S)-2-azido-3phenylpropanoic acid and (S)-2-amino-3-methylbutanamide hydrochloride were used instead, to give azido-L-Phe-L-Val-NH2 as a white amorphous solid (1.48 g, yield 65%). 1H NMR (300 MHz, CDCl3): δ 7.22−7.37 (m, 5H), 6.75 (d, J = 9.0 Hz, 1H), 5.55 (d, J = 66.0 Hz, 2H), 4.21−4.29 (m, 2H), 3.31 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 3.07 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 2.08−2.22 (m, 1H), 0.91 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 172.7, 169.0, 135.9, 129.5, 128.8, 127.4, 65.0, 58.0, 38.4, 30.6, 19.2, 17.9 ppm. HRMS (ESI): m/z calcd for C14H19N5NaO2 [M + Na]+ 312.1436, found 312.1436. 13007

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

Article

The Journal of Organic Chemistry Azido-L-Leu-L-Phe-OMe (9f).

J2 = 18.0 Hz, 1H), 3.70 (s, 3H), 3.18 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 3.03 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 2.03 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ 172.7, 171.9, 170.8, 170.0, 136.7, 128.9, 128.1, 126.5, 54.0, 51.3, 42.4, 41.7, 36.9, 21.1 ppm. HRMS (ESI): m/z calcd for C16H21N3NaO5 [M + Na]+ 358.1379, found 358.1378. Ac-Gly-Phe-Val-NH2 (10e).

The synthesis was similar to that of 9e, except that (S)-2-azido-4methylpentanoic acid was used instead, to give azido-L-Leu1 L-Phe-OMe as a white amorphous solid (2.30 g, yield 91%). H NMR (300 MHz, CDCl3): δ 7.25−7.37 (m, 3H), 7.10−7.16 (m, 2H), 6.68 (d, J = 9.0 Hz, 1H), 4.88 (dt, J1 = 6.0 Hz, J2 = 6.0 Hz, 1H), 3.92 (dd, J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 3.76 (s, 3H), 3.07−3.25 (m, 2H), 1.55−1.88 (m, 3H), 0.97 (dd, J1 = 6.0 Hz, J2 = 3.0 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 171.5, 169.8, 135.6, 129.2, 128.7, 127.3, 62.8, 53.0, 52.5, 41.1, 37.8, 24.9, 23.0, 21.5 ppm. HRMS (ESI): m/z calcd for C16H22N4NaO3 [M + Na]+ 341.1590, found 341.1589. Characterization of Oligopeptide Products. Ac-Gly-Gly-NHBn (10a).

Ac-Gly-Phe-Val-NH2 (10e) was obtained as a white amorphous solid (28 mg, 39% yield). 1H NMR (300 MHz, CDCl3): δ 7.17− 7.35 (m, 5H), 4.62−4.70 (m, 2H), 4.11 (d, J = 6.0 Hz, 1H), 3.83 (s, 2H), 3.10 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 2.99 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 2.02−2.16 (m, 1H), 2.00 (s, 3H), 0.77 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 174.9, 172.5, 172.4, 170.3, 136.4, 129.0, 128.3, 126.7, 58.6, 55.1, 42.3, 37.2, 29.6, 21.3, 18.4, 16.7 ppm. HRMS (ESI): m/z calcd for C18H26N4NaO4 [M + Na]+ 385.1852, found 385.1852. Ac-Gly-Leu-Phe-OMe (10f).

Ac-Gly-Gly-NHBn (10a) was obtained as a white amorphous solid (21 mg, 41% yield). 1H NMR (300 MHz, CDCl3): δ 7.18−7.37 (m, 5H), 4.40 (s, 2H), 3.90 (s, 2H), 3.86 (s, 2H), 1.99 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 172.9, 171.1, 170.2, 138.4, 128.1, 127.1, 126.8, 42.5, 42.1, 21.1 ppm. HRMS (ESI): m/z calcd for C13H17N3NaO3 [M + Na]+ 286.1168, found 286.1165. Ac-Gly-Phe-NHBn (10b).

Ac-Gly-Phe-NHBn (10b) was obtained as a white amorphous solid (27 mg, 38% yield). 1H NMR (300 MHz, CDCl3): δ 7.17− 7.31 (m, 8H), 7.11−7.17 (m, 2H), 4.63 (t, J = 6.0 Hz, 2H), 4.33 (dd, J1 = 24.0 Hz, J2 = 15.0 Hz, 2H), 3.79 (dd, J1 = 27.0 Hz, J2 = 15.0 Hz, 2H), 3.15 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 2.94 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 1.96 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 172.6, 171.8, 170.1, 138.1, 136.9, 129.0, 128.1, 128.1, 127.1, 126.7, 126.4, 54.8, 42.7, 42.2, 37.5, 21.0 ppm. HRMS (ESI): m/z calcd for C20H23N3NaO3 [M + Na]+ 376.1637, found 376.1637. Ac-Gly-Leu-NHBn (10c).

Ac-Gly-Leu-Phe-OMe (10f) was obtained as a white amorphous solid (24 mg, 31% yield). 1H NMR (300 MHz, CDCl3): δ 7.15−7.33 (m, 5H), 4.60−4.71 (m, 2H), 4.39 (dd, J1 = 9.0 Hz, J2 = 6.0 Hz, 1H), 3.83 (s, 2H), 3.70 (s, 3H), 3.20 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 2.96 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 2.00 (s, 3H), 1.27−1.50 (m, 3H), 0.77 (t, J = 6.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 173.2, 172.6, 171.9, 170.1, 136.8, 128.9, 128.1, 126.5, 53.7, 51.4, 51.4, 42.2, 40.7, 36.9, 24.3, 22.0, 21.0, 20.6 ppm. HRMS (ESI): m/z calcd for C20H29N3NaO5 [M + Na]+ 414.2005, found 414.2002. Ac-Ala-Gly-Phe-NHBn (11a).

Ac-Gly-Leu-NHBn (10c) was obtained as a white amorphous solid (21 mg, 32% yield). 1H NMR (300 MHz, CDCl3): δ 7.20−7.35 (m, 5H), 4.45 (t, J = 6.0 Hz, 1H), 4.39 (s, 2H), 3.87 (s, 2H), 2.00 (s, 3H), 1.58−1.73 (m, 3H), 0.95 (dd, J1 = 12.0 Hz, J2 = 6.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 173.4, 172.7, 170.4, 138.5, 128.1, 127.0, 126.7, 52.0, 42.6, 42.3, 40.5, 24.5, 22.1, 21.0, 20.4 ppm. HRMS (ESI): m/z calcd for C17H25N3NaO3 [M + Na]+ 342.1794, found 342.1794. Ac-Gly-Gly-Phe-OMe (10d).Ac-Gly-Gly-Phe-OMe (10d) was obtained as a white amorphous solid (29 mg, 43% yield). 1H NMR (300 MHz, CDCl3): δ 7.18−7.34 (m, 5H), 4.69 (dd, J1 = 9.0 Hz, J2 = 6.0 Hz, 1H), 3.87 (s, 2H), 3.86 (dd, J1 = 27.0 Hz,

Ac-Ala-Gly-Phe-NHBn (11a) was obtained as a white amorphous solid (30 mg, 35% yield). 1H NMR (300 MHz, CDCl3): δ 7.15−7.32 (m, 10H), 4.63 (s, 1H), 4.60 (dd, J1 = 9.0 Hz, J2 = 6.0 Hz, 1H), 4.35 (s, 2H), 4.20 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 3.77 (s, 2H), 3.20 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 3.02 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 1.91 (s, 3H), 1.33 (d, J = 6.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 175.1, 172.3, 172.1, 170.2, 138.2, 137.3, 128.3, 128.1, 127.1, 126.7, 126.4, 55.4, 49.9, 42.6, 42.3, 37.2, 21.0, 15.9 ppm. HRMS (ESI): m/z calcd for C23H28N4NaO4 [M + Na]+ 447.2008, found 447.2007. 13008

DOI: 10.1021/acs.joc.8b01370 J. Org. Chem. 2018, 83, 12998−13010

Article

The Journal of Organic Chemistry

General Procedure for the Visible-Light-Induced Traceless Staudinger Ligation. Preparative photolyses were conducted by irradiation of a solution of 0.2 mmol of phosphonium salt and 0.2 mmol of azide in 4 mL of 3:1 THF/buffer (0.5 M K2HPO4/ KH2PO4, pH 7.4) using a 500 W Hg lamp (Newport 67005) equipped with an IR reducer (Newport 61945) and convex lens. A longwave pass cut-on colored-glass alternative filter (25.4 mm, 420 nm) (Newport 10CGA-420) was used to give broadband visible light (>420 nm) for photolysis. In a typical run, the mixture of azide substrate and phosphonium salt was photolyzed for 120 min and was allowed to stand for another 16 h. The consumption of starting material was monitored with 31P NMR. After that, the solvent was removed in vacuo, the residue was purified by flash chromatography on silica gel to isolate the final amide product. Some peptide products were triturated with a small amount of dichloromethane and filtered to get the pure NMR spectra. The progress of the reactions was monitored by analytical thin-layer chromatography. Plates were visualized first with UV (254 nm) and then illuminated by PMA stain (10% phosphomolybdic acid in ethanol).

Ac-Ala-Gly-Leu-NHBn (11b).

Ac-Ala-Gly-Leu-NHBn (11b) was obtained as a white amorphous solid (23 mg, 30% yield). 1H NMR (300 MHz, CDCl3): δ 7.17−7.35 (m, 5H), 4.63 (s, 1H), 4.30−4.47 (m, 3H), 4.18 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 3.86 (s, 2H), 1.89 (s, 3H), 1.55−1.80 (m, 3H), 1.34 (d, J = 9.0 Hz, 3H), 0.93 (dd, J1 = 12.0 Hz, J2 = 6.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 175.1, 173.5, 172.3, 170.4, 138.5, 128.1, 127.0, 126.7, 52.2, 49.9, 42.5, 42.4, 40.2, 24.5, 22.1, 21.0, 20.2, 15.8 ppm. HRMS (ESI): m/z calcd for C20H30N4NaO4 [M + Na]+ 413.2165, found 413.2164. Ac-Ala-Gly-Phe-Val-NH2 (11c).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01370. 1 H and 13C NMR spectra of the substituted anthracen-9yl methanols, chloromethylanthracenes, photocaged phosphinothioesters, azidylated amino acids and peptides, and oligopeptide products of the phototriggered traceless Staudinger conjugation (PDF)

Ac-Ala-Gly-Phe-Val-NH2 (11c) was obtained as a white amorphous solid (29 mg, 33% yield). 1H NMR (300 MHz, CDCl3): δ 7.15−7.35 (m, 5H), 4.55−4.65 (m, 2H), 4.21 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 4.10 (d, J = 6.0 Hz, 1H), 3.80 (d, J = 3.0 Hz, 2H), 2.98−3.18 (m, 1H), 2.04−2.15 (m, 1H), 2.02 (s, 3H), 1.35 (d, J = 3.0 Hz, 3H), 0.78 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 175.0, 174.9, 172.6, 172.3, 170.4, 136.8, 129.0, 128.4, 126.7, 58.9, 55.6, 50.1, 42.60, 36.7, 29,9, 21.9, 18.8, 17.1, 16.4 ppm. HRMS (ESI): m/z calcd for C21H31N5NaO5 [M + Na]+ 456.2223, found 456.2222. Ac-Ala-Gly-Leu-Phe-OMe (11d).

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AUTHOR INFORMATION

Corresponding Author

*Tel: (852)-3442-7329. Fax: (852)-3442-0522. E-mail: [email protected]. ORCID

Michael Hon-Wah Lam: 0000-0003-1213-3874 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region, China (Reference No. CityU 11337716 & CityU 11301414).

Ac-Ala-Gly-Leu-Phe-OMe (11d) was obtained as a white amorphous solid (29 mg, 31% yield). 1H NMR (300 MHz, CDCl3): δ 7.17−7.32 (m, 5H), 4.58−4.68 (m, 2H), 4.35 (dd, J1 = 9.0 Hz, J2 = 6.0 Hz, 1H), 4.22 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 3.84 (s, 2H), 3.68 (s, 3H), 3.18 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H), 2.99 (dd, J1 = 15.0 Hz, J2 = 9.0 Hz, 1H), 2.00 (s, 3H), 1.21−1.67 (m, 3H), 1.36 (d, J = 6.0 Hz, 3H), 0.86 (dd, J1 = 9.0 Hz, J2 = 6.0 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 174.8, 173.4, 172.4, 171.9, 170.1, 136.8, 129.0, 128.1, 126.5, 53.9, 51.7, 51.3, 49.9, 42.4, 40.21, 36.9, 24.3, 22.1, 21.1, 20.4, 16.0 ppm. HRMS (ESI): m/z calcd for C23H34N4NaO6 [M + Na]+ 485.2376, found 485.2376. General Procedure for the Photolysis Studies and Quantum Yield Measurements. Photolysis studies were performed by irradiating degassed solutions of phosphonium compounds 1−6 in deuterated solvents in NMR tubes using a 500 W Hg lamp (Newport 67005) equipped with an IR reducer (Newport 61945), a convex lens, and a monochromator (Newport 77200). To determine the photochemical quantum yield, 25 mM phosphonium compound in 3:1 THF/H2O was prepared. Chemical actinometry was employed for the photochemical quantum yield determination. Incident light intensities were taken from the average values measured just before and after each photolysis experiment using ferrioxalate actinometry.32,33 Quantum yield was determined by monitoring the amount of diphenylphosphinothioester generated via 31P NMR.

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