Using the 3-Diethylaminobenzyl Group as a Photocage in Aqueous

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Using 3-diethylaminobenzyl group (DEABn) as a Photocage in Aqueous Solution Xiong Ding, and Pengfei Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00550 • Publication Date (Web): 17 May 2018 Downloaded from http://pubs.acs.org on May 18, 2018

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The Journal of Organic Chemistry

Using 3-diethylaminobenzyl group (DEABn) as a Photocage in Aqueous Solution Xiong Ding, and Pengfei Wang* Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294 [email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) TOC

ABSTRACT We have demonstrated that the 3-diethylaminobenzyl (DEABn) photolabile protecting group (PPG) is an effective and structurally simple PPG for releasing molecules in aqueous environment. In general, the photoreaction is clean, and the released substrate and the PPG product, i.e., 3-diethylaminobenzyl alcohol, are obtained in high yield. The clean photoreaction can also be achieved under mild ambient conditions with sunlight while the

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reactant is stable under indoor lighting. Release of two substrates from one PPG chromophore in aqueous solution has been demonstrated to be feasible. We have also compared the uncaging properties of the DEABn and the widely used ortho-nitrobenzyl (o-NB) group, given their comparable structural simplicity. With its clean and efficient photochemical reaction, DEABn should find wide applications, including in the basic and applied research areas where o-NB and its various derivatives are widely used.

INTRODUCTION Photolabile protecting groups (PPGs) are protecting groups to be removed with photo irradiation, which often occurs under mild conditions with precise temporal and spatial control over the reaction course.1-4 PPGs have been widely used in bio-related research as “photocages”, and photochemical release of biologically important organic molecules often takes place in aqueous environments. We have recently developed a series of structurally simple PPGs for releasing carbonyl,5-12 hydroxyl,12-17 diol,18 carboxyl,15 and amino groups.19-20 Their applications in organic synthesis,21 photoactivated prodrugs,8, 22 photorelease of perfumes in solid phase,23 photocleavage of polymers,12 light-controlled hydrogel formation,24 and surface patterning25 have been explored recently. These PPGs have advantageous features, including (1) their structural simplicity and chemical stability, (2) simple and cost-effective preparation, (3) high efficiency of protection/deprotection, (4) compatibility with ambient conditions (e.g., air and water) during irradiation, and (5) flexible structural modification without compromising photochemical properties, etc.5-11, 13-14, 16For applications of these PPGs in aqueous solution as photocages, we demonstrated that by incorporating poly(ethylene glycol)8 or carboxylate side chains,16 the PPGs can be converted to their corresponding water-soluble counterpart. For


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instance, the hydrophobic 3-dimethylaminotrityl group (DMATr) PPG for hydroxyl group was converted to its water-soluble version (as the one shown in 1, Scheme 1).16 Its release of OHcontaining molecules has been achieved in excellent yield in water and PPG product 2 can also be recovered in nearly quantitative yield. Scheme 1. Release Substrates in Water

More recently, we have shown that 3-diethylaminobenzyl group (DEABn) is a robust PPG (Scheme 2).15 Typically PPG reagent 3 can be conveniently installed onto various substrates possessing a hydroxyl, carboxyl, or amino group. Upon UV irradiation, the DEABn PPG is removed efficiently in methanol or MeCN/water. Since the structure of DEABn is less hydrophobic than DMATr, we infer that DEABn may be used for release of polar substrates without PPG’s structural modification.

Scheme 2. DEABn PPG for Protection of Different Functionalities

RESULTS AND DISCUSSION



We thus prepared a number of caged polar substrates 3a-3f (Scheme 3). In 3a-3c, the PPG is on the primary 6-OH of galactose, the secondary 3-OH of glucose, and the anomeric 1-OH of galactose, respectively. In 3d-3f, the PPG is on the hydroxyl group of serine, the carboxyl group of aspartic acid, and the phenolic hydroxyl group of tyrosine, respectively. Preparation of these DEABn-caged substrates is straightforward. For example, for 3a and 3b, the PPG was installed onto the commercially available monosaccharide building blocks 4a and 4b, respectively, by using PPG reagent 3-diethylaminobenzyl chloride15 and subsequent removal of the acetonide protecting groups under acidic condition. To prepare 3c, we first installed 3-diethylaminobenzyl alcohol to 4c and then removed all the acetyl groups under basic conditions. Preparation of 3d and 3f started with PPG installation onto Boc-L-serine and Boc-Tyr-OH, respectively, followed by removal of the Boc group under acidic conditions. Preparation of 3e started from commercially available Fmoc-Asp(OtBu)-OH, and the sequence of PPG installation and removal of the Fmoc and tBu groups led to 3e.

Scheme 3. Installation of DEABn to Different Substratesa


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a

Reagents and conditions: (a) NaH, 3-diethylaminobenzyl chloride, THF, -10 – 50 oC, 89%; (b)

TFA, 0 oC – r.t., 86%; (c) NaH, 3-diethylaminobenzyl chloride, DMF, -10 oC – r.t., 92%; (d) TFA, 0 oC – r.t., 77%; (e) BF3.OEt2, 3-diethylaminobenzyl alcohol, DCM, 0 – 40 oC, 34%; (f) K2CO3, MeOH/H2O, r.t., 82%; (g) NaH, 3-diethylaminobenzyl chloride, DMF, -5 oC – r.t., 35%; (h) TFA, DCM, r.t., 93%; (i) 3-diethylaminobenzyl alcohol, DCC, DMAP, DCM, r.t., 92%; (j) piperidine, DMF, r.t., 88%; (k) TFA, DCM, r.t., 83%; (l) NaH, 3-diethylaminobenzyl chloride, DMF, -5 oC – r.t., 56%; (b) TFA, DCM, r.t., 71%.



With 3a-3f in hand, we began to evaluate the deprotection (i.e., uncaging) reactions in aqueous solution. In its neutral aqueous solution, 3a (5.0 mM in D2O) is a mixture of two anomers (with a / ratio of ca.3:7). Irradiation of 3a (304nm (H2O) = 1000 M-1 cm-1, )26 for 15 min without deaeration led to 96% conversion, and for 20 min led to complete removal of the PPG to provide galactose 4a as a / mixture (ca.3:7) in 100% yield and the PPG alcohol, i.e., 3-diethylaminobenzyl alcohol, in 96% yield based on 1H NMR analysis (Table 1, entry 1). In comparison, conducting the same reaction of 3a under nitrogen atmosphere provided almost identical results, with the released substrate in 100% overall yield and the PPG alcohol in 98% yield (Table 1, entry 2). In a larger scale run (5.0 mM), galactose was isolated in 98% yield as a / mixture, consistent with the yield calculated from 1H NMR (Table 1, entry 3). Irradiation of 3b (5.0 mM in D2O, / ca. 4:6) provided similar results, but the reaction was slightly slower (Table 1, entry 4). Irradiation for 15 and 20 min led to 82% and 89% conversion, respectively. Based on the 89% conversion at 20 min of irradiation, glucose was released in 100% overall yield (/ ca. 4:6) and the PPG alcohol was in 98% yield. With a more dilute solution of 3b (i.e., 2.5 mM), 20 min irradiation led to a complete conversion, and quantitative release of glucose (/ ca. 4:6) and 96% yield of the trityl alcohol (Table 1, entry 5). Irradiation of 3c (5.0 mM in D2O,  only) (306nm (H2O) = 800 M-1 cm-1, )26 was less efficient than 3a and 3b under the same conditions. For example, irradiation for 15 min and 20 min resulted in 61% and 74% conversion, respectively. Based on the respective conversion, the overall yields of the released monosaccharides as a mixture of two anomers were 97% and 100%, respectively, and the ratio of  remained at ca. 1:2 (Table 1, entries 6 and 7). With a more dilute solution of 3c (2.5 mM), the yield of the released substrate improved to 100% and the PPG alcohol to 75% yield (Table 1, entry 8).


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Table 1. Release of ROH and RCOOH in Watera

Entry 1 2 3 4 5 6 7 8 9 10 11 12 a

conversion released caged (%) substrate substrate (%) 100 100 3a 3ab 100 100b c 3a 100 98c 89 100d 3b 3be 100 100e f 61 97d,f 3c 74 100d 3c 3ce 100 100e f f 3d 100 100f 92 100d 3e 92 100d,g 3f 100h 100g 3f

released PPGOH (%) 96 98b 98d 96e 75e 96f 95d -

A 5.0 mM solution in 5 mm NMR tubes was irradiated with a 450W medium pressure mercury lamp equipped with

a Pyrex filter sleeve (>300 nm) for 20 min without deaeration. The yields are determined by 1H NMR analysis. For 3a-3c, the released monosaccharides are a mixture of / anomers. bIrradiation under N2 protection. cIsolated yield. d

Yield calculated based on the corresponding conversion. eIrradiation of a 2.5 mM solution. fIrradiation for 15 min.

g

Combined yield of two distinct products. h35 min irradiation, pH>14.

Photochemical release of amino acids went smoothly with 3d and 3e. Thus, irradiation of 3d (5.0 mM) for 15 min released serine in quantitative yield and the PPG alcohol in 96% yield (Table 1, entry 9). The reaction of 3e was also straight forward (Table 1, entry 10), albeit being slightly less efficient, with 100% yield of aspartic acid and 95% yield of the PPG alcohol based



on 92% conversion after 20 min of irradiation. The difference in reactivity of releasing carboxylic acid and hydroxyl group is consistent with our earlier observations.15, 17 The photochemical reaction of 3f was less straightforward. At pH = 7, conversion of 3f was up to 92%; however, there were two distinct products in ca. 1:1 ratio. One of the products was the expected tyrosine (5) and the other was rearranged product 6. To facilitate its isolation, compound 6 was derivatized by protecting the amino group with a Boc group, and the derivative was fully characterized. Under more basic conditions, e.g., at pH > 14, the ratio of 5/6 changed to ca. 1:2. Presumably, at high pH, released tyrosine existed as phenolate 7, facilitating the illustrated recombination of the ion pair 7 and 8 through formation of a photochemically stable C-C bond (Scheme 4).

Scheme 4. Photochemical reaction of 3f

Since the photochemical cleavage of the benzylic C-O bond does not change the effective PPG chromophore, we can repeatedly use the PPG chromophore to release another substrate to


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improve the PPG’s atomic efficiency. Thus, we prepared compound 9 with two benzylic C-O bonds to be cleaved with assistance from the meta diethylamino group (Scheme 5). Preparation of 9 is similar to that of 3a,15 and its irradiation under the same conditions as that of 3a led to clean release of both substrates in quantitative yield and corresponding PPG alcohol 11 in 92% yield. Scheme 5. Photochemical reaction of 9

For less polar substrates, we can convert the PPG to its more hydrophilic version, the same approach that we used for modification of the trityl-type hydroxyl PPG as shown in Scheme 1.16 Thus, new PPG reagent 12 can be easily prepared and used to protected methanol to provide 13 (Scheme 6). Neutralization of diacid 13 with KOH led to more water-soluble dicarboxylate while the corresponding DEABn methyl ether is insoluble in water. Irradiation of the dicarboxylate (5.0 mM in D2O) derived from 13 for 20 min provided both PPG alcohol 14 and methanol in quantitative yield based on 1H NMR analysis. Scheme 6. Photochemical reaction with more water-soluble PPGa



a

Reagents and conditions: (a) Cs2CO3, MeOH, 70 oC, 61%; (b) KOH, D2O; (c) h On the other hand, for water-soluble substrates, using DEABn or its more hydrophilic version

as in 13 does not make perceptible difference. For example, similar to preparation of 3c, reaction of 4c and benzyl alcohol 15 installed the PPG onto 4c, and subsequent hydrolysis provided photoresponsive monosaccharide 16 (Scheme 7). Its irradiation under the same conditions as that of 3c for 20 min led to the same conversion, which also confirmed that photochemical removal of PPG from anomeric position of galactoside seemed to be less efficient than the release of hydroxyl group at other positions (Table 1, entries 1-8).

Scheme 7. Photochemical reaction with more water-soluble PPGa


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a

Reagents and conditions: (a) BF3.OEt2, DCM, 0 – 40 oC, 39%; (b) MeOH/AcCl (10:1), DCM,

r.t., 64%; (c) KOH (0.5 N); (d) h

In the literature, the ortho-nitrobenzyl (o-NB) family of PPGs are probably the most widely used PPGs; o-NB can also release polar substrates directly in aqueous solution. We thus compared photoreactions of DEABn and o-NB in releasing the same monosaccharide in water. Irradiation of o-NB-protected galactose 1727 for 15 min led to release of galactose as a mixture of / anomers (Figure 1). However, the PPG region in 1H NMR deteriorated to the complicated baseline peaks, indicating generation of a number of unrecognizable fragments. On the contrary, irradiation of 3a under the same conditions resulted in not only clean release of galactose but also PPG alcohol 18 exclusively. There was no perceptible decomposition of the PPG based on 1

H NMR analysis. This is a significant advantage of DEABn over o-NB, especially in biological

studies, where the unknown o-NB fragments could potentially interfere with the biological events under study. Moreover, cleavage of the benzylic C-O bond of DEABn PPG to release alcohol is probably taking place in the S1 state,28 the kinetics of DEABn should be much faster than that of o-NB, since it is known that removal of o-NB involves a mutli-step thermal process after initial photo excitation of the chromophore.29-31 Thus, the clean and presumed fast reaction of the DEABn PPG suggest that it can be an attractive alternative to o-NB for uncaging in aqueous solution. It is also worth mentioning that photochemical removal of DEABn can be carried out with sunlight under very mild conditions. For example, the sample of 3a (5.0 mM in D2O) was placed outdoor in sunlight with a local UV index of 5 and temperature of 21 oC during the reaction time.



After two hours, the reaction completed and the 1H NMR spectrum showed a clean reaction as the one conducted with the UV lamp (Table 1, entry 1).

Figure 1. Comparison of the photoreaction of 3a and 17 in water. (a) Solution of 17 (5.0 mM in D2O,  3:7) before irradiation; (b) after 15 min of irradiation of 17; (c) solution of 3a (5.0 mM in D2O,  3:7) before irradiation; (d) After 15 min of irradiation of 3a. CONCLUSION


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In summary, we demonstrated that the structurally simple DEABn could be used for molecule release in aqueous solution under ambient conditions. Its comparison against the widely used oNB PPG under the same reaction conditions showed that DEABn had a cleaner photoreaction than o-NB, which can avoid undesired interference of the unknown PPG fragments to the biological events under study in its uncaging applications. These advantages of DEABn, along with the facts of its installation (especially to secondary hydroxyl group) and highly efficient removal with sunlight, suggest that DEABn can be an attractive alternative to the widely used ortho-nitrobenzyl family of PPGs.



Experimental Section General. Organic solutions were concentrated by rotary evaporation at ca. 12 Torr. Flash column chromatography was performed employing 230-400 mesh silica gel. Thin-layer chromatography was performed using glass plates pre-coated to a depth of 0.25 mm with 230400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Infrared (IR) data are presented as frequency of absorption (cm-1). Proton and carbon-13 nuclear magnetic resonance (1H NMR or 13C NMR) spectra were recorded on 300, 400 and 700 MHz NMR spectrometers; Chemical shifts are expressed in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: δ 7.26). Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet and/or multiple resonances), coupling constant in Hertz (Hz), integration. HRMS was conducted with ESI ionization method and with TOF mass analyser. Materials. Anhydrous solvents Tetrahydrofuran (THF), dimethylformamide (DMF), and dichloromethane (DCM) were used without distillation. Solvents for workup and column chromatography, such as petroleum ether (PE), ethyl acetate (EA), methanol (MeOH), and triethylamine (TEA), and other chemicals such as trifluoroacetic acid (TFA) were obtained from commercial vendors and used without further purification. Synthesis of 6-O-(3-diethylamino)benzyl-D-galactopyranoside (3a): The PPG was installed onto commercially available 1,2:3,4-di-O-isopropylidene-D-galactopyranose by using the published procedure.15 To the obtained 1,2:3,4-di-O-isopropylidene-6-O-(3-diethylamino)-D-galactopyranose

(200.0 mg, 0.474 mmol) was added TFA aqueous solution (80%, 1.0 mL) at 0

o

C. The reaction mixture was stirred at room temperature overnight and then concentrated. The

residue was washed with diethyl ether (2 mL x 3), dried under vacuum, and then neutralized with


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KOH aqueous solution (0.5 N) to pH of 8. The aqueous solution was then concentrated through lyophilization, and purified with flash chromatography (DCM/MeOH 8:1, Rf = 0.15) to provide 3a (/ 3:7) as a white solid (140.0 m g, 86%). 1H NMR (700 MHz, D2O) δ 7.22 (t, J = 7.7 Hz, 1 H) (+), 6.86-6.84 (m, 2 H) (+), 6.77 (d, J = 7.4 Hz, 1 H) (+), 5.12 (d, J = 3.7 Hz, 0.3 H) (), 4.47 (t, J = 12.2 Hz, 1 H) (+), 4.44-4.41 (m, 1.5 H) (), 4.10 (t, J = 6.0 Hz, 0.3 H) (), 3.80 (d, J = 2.5 Hz, 0.3 H) (), 3.75 (d, J = 3.3 Hz, 0.6 H) (), 3.72-3.57 (m, 3 H) (+), 3.49 (dd, J = 9.9, 3.4 Hz, 0.6 H) (), 3.35 (dd, J = 9.9, 8.0 Hz, 0.6 H) (), 3.18 (q, J = 7.1 Hz, 4 H) (+), 0.95 (t, J = 7.1 Hz, 6 H) (+); 13C NMR (176 MHz, D2O) δ 148.6, 138.24, 138.20, 129.6, 118.9, 116.4, 116.3, 96.3, 92.2, 73.4, 73.3, 72.6, 71.7, 69.5, 69.3, 69.2, 69.0, 68.9, 68.7, 68.2, 45.1, 10.8; IR (neat) 3361, 2968, 2922, 2874, 1597; HRMS (ESI-TOF) m/e: calc for C17H28NO6 [M+H]+ 342.1917, found 342.1924. Synthesis of 3-O-(3-diethylamino)benzyl-D-glucopyranoside (3b): The same procedure as preparing 3a was used. The product (/ 2:3) was obtained as a white solid (45.0 m g, 77%). Rf = 0.15 (DCM/MeOH 10:1); 1H NMR (700 MHz, D2O) δ 7.19 (t, J = 7.8 Hz, 1 H) (+), 6.926.91 (m, 1 H) (+), 6.83-6.79 (m , 2 H) (+), 5.06 (d, J = 3.7 Hz, 0.4 H) (), 4.49 (d, J = 7.9 Hz, 0.6 H) (), 3.73 (dd, J = 12.2, 2.1 Hz, 0.6 H) (), 3.69-3.66 (m, 0.85 H) (), 3.61-3.54 (m, 1.8 H) (+), 3.47 (dd, J = 9.8, 3.7 Hz, 0.4 H) (), 3.37-3.33 (m, 1.5 H) (+), 3.31 (m, 0.6 H) (), 3.18 (m, 0.6 H) (), 3.14 (q, J = 7.1, 4 H) (+), 0.91 (t, J = 7.1 Hz, 6 H) (+); 13C NMR (176 MHz, D2O) δ 148.4, 138.9, 138.7, 119.5, 117.0, 116.9, 116.7, 95.9, 92.1, 83.9, 81.3, 75.8, 75.2, 75.0, 73.9, 71.5, 71.3, 69.5, 69.3, 60.6, 60.4, 45.3, 10.8; IR (neat) 3337, 2968, 2924, 2879, 1598; HRMS (ESI-TOF) m/e: calc for C17H28NO6 [M+H]+ 342.1917, found 342.1931.



Synthesis of 1-O-(3-diethylamino)benzyl-D-galactopyranoside (3c): To the mixture of D-galactose

pentaacetate (195.0 mg, 0.50 mmol) and 3-(diethylamino)phenylmethanol (134.0

mg, 0.75 mmol) in DCM (2.0 mL) was added BF3.Et2O (48%, 168.0 L, 1.50 mmol) at 0 oC. The reaction mixture was stirred at 40 oC for 5 h and quenched with ice water followed by TEA. The organic layer was separated, concentrated and purified with flash column chromatography (PE/EA 3:1, Rf = 0.25) to provide 2,3,4,6-O-tetraacetyl-1-O-(3-diethylamino)benzyl-Dgalactopyranoside as an oil (85.0 mg, 34%). The acetyl groups were then removed with K2CO3 (100 mg) in the mixture of CH3OH/H2O (10:1) at room temperature to provide 3c (34.0 mg, 82%) after flash column chromatography. Rf = 0.2 (CH3OH/DCM 5:1); 1H NMR (700 MHz, D2O) δ 7.21 (t, J = 7.6 Hz, 1 H), 6.93 (s, 1 H), 6.90-6.80 (m, 2 H), 4.75 (d, J = 11.7 Hz, 1 H), 4.57 (d, J = 11.9 Hz, 1 H), 4.28 (d, J = 7.8 Hz, 1 H), 3.76 (d, J = 2.6 Hz, 1 H), 3.65 (ABM1, J = 11.7, 8.0 Hz, 1 H), 3.60 (ABM1, J = 11.7, 4.3 Hz, 1H), 3.51 (m, 1 H), 3.45 (ABM2, J = 9.9, 3.3 Hz, 1 H), 3.39 (ABM2, J = 9.7, 7.9 Hz, 1H), 3.17 (m, 4 H), 0.92 (t, J = 7.1 Hz, 6 H); 13C NMR (176 MHz, D2O) δ 148.6, 137.8, 129.6, 119.1, 116.6, 116.5, 101.5, 75.1, 72.7, 71.3, 70.7, 68.6, 60.9, 45.1, 10.8; IR (neat) 3506,2284, 2961, 2922, 2871, 1598; HRMS (ESI-TOF) m/e: calc for C17H28NO6 [M+H]+ 342.1917, found 342.1917. Synthesis of DEABn-protected L-serine 3d: To the solution of Boc-L-serine (1.0 g, 4.87 mmol) in dry DMF (10.0 mL) was added NaH (60% in mineral oil, 0.429 g, 10.71 mmol) in portions at -5 oC under nitrogen. The reaction mixture was stirred at room temperature till no more gas was released, and 3-(chloromethyl)-N, N-diethylaniline (2.117 g, 10.71 mmol) was then added at 0 oC under nitrogen and stirred at room temperature for 20 h. The reaction was quenched with ice water and washed with EA (20 mL x 2). The aqueous layer was neutralized with HCl (1.0 N) followed by extraction with EA. The EA layer was dried and concentrated


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under vacuum. The crude reaction mixture was purified with flash column chromatography (DCM/MeOH 10:1 to 5:1) to afford the intermediate (615.0 mg, 35%). The Boc group in the intermediate (164.0 mg, 0.45 mmol) was removed in the solution of TFA/DCM (1:4), neutralized with KOH (0.5N in water), and concentrated. The resulting aqueous phase was lyophilized to a white powder which was purified by flash column chromatography (DCM/MeOH 5:1, Rf = 0.3) to provide 3d (111.0 mg, 93%) as a white foam. 1H NMR (700 MHz, MeOD) δ 7.16 (t, J = 7.8 Hz, 1 H), 6.72 (s, 1H), 6.66-6.64 (m, 2 H), 4.54 (AB, J = 11.8 Hz, 1 H), 4.50 (AB, J = 11.8 Hz, 1 H), 3.87 (d, J = 7.6 Hz, 1 H), 3.76-3.74 (m, 2 H), 3.39 (q, J = 7.1 Hz, 4 H), 1.15 (t, J = 7.1 Hz, 3 H); 13C NMR (176 MHz, MeOD) δ 170.7, 147.9, 138.2, 128.9, 115.2, 111.6, 111.5, 73.7, 68.1, 54.9, 44.0, 11.4; IR (neat) 2967, 2920, 2860, 1592; HRMS (ESI-TOF) m/e: calc for C14H23N2O3 [M+H]+ 267.1709, found 267.1709. Synthesis of DEABn-protected Asp 3e: To the mixture of Fmoc-Asp(OtBu)-OH (206.0 mg, 0.5 mmol), 3-(diethylamino)phenylmethanol (108.0 mg, 0.60 mmol), and DMAP (3.0 mg, 0.025 mmol) in DCM (4.0 mL) at 0oC was added DCC (124.0mg, 0.60 mmol). The reaction mixture was stirred at room temperature for 15 h before quenched with water. The separated DCM layer was dried over anhydrous Na2SO4, concentrated, and the crude product was purified with flash column chromatography (PE/EA 5:1) to provide the intermediate, Fmoc-Asp(OtBu)DEABn (264.0 mg, 92%) as a colorless oil. To the solution of the intermediate (195.0 mg, 0.33 mmol) in DMF (1.0 mL) was added piperidine (1.0 mL) and the reaction mixture was stirred for 1h at room temperature. The crude reaction mixture was purified with flash column chromatography (PE/EA 6:1 to DCM/MeOH 20:1) to provide the 2nd intermediate Asp(OtBu)DEABn (105.0 mg, 88%). To the solution of this intermediate (80.0 mg, 0.228 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction completed in 2.5 h, and



solvent was removed. The residue was washed with Et2O (1.0 mLx3) and its aqueous solution (0.5 mL) was neutralized with aqueous KOH (0.5N) to pH ~6. A white precipitate formed and was filtered. The solid was washed with water three times and dried under vacuum to provide 3e (56.0 mg 83%) as a white powder. 1H NMR (700 MHz, MeOD) δ 7.17 (t, J = 7.9 Hz, 1 H), 6.73 (s, 1 H), 6.69 (dd, J = 8.3, 2.4 Hz, 1 H), 6.65 (d, J = 7.5 Hz, 1H), 5.19 (s, 2 H), 4.17 (t, J = 5.7 Hz, 1 H), 3.39 (q, J = 7.0 Hz, 4 H), 2.77-2.75 (m, 2 H), 1.16 (t, J = 7.1 Hz, 6 H); 13C NMR (176 MHz, MeOD) δ 174.4; 169.2, 147.9, 135.9, 129.1, 115.3, 112.0, 111.9, 68.4, 50.5, 44.0, 35.5, 11.4; IR (neat) 3029, 2968, 2931, 2871, 1750, 1601, 1578; HRMS (ESI-TOF) m/e: calc for C15H23N2O4 [M+H]+ 295.1658, found 295.1664. Synthesis of DEABn-protected Tyrosine 3f: To the solution of Boc-Tyr-OH (422.0 mg, 1.5 mmol) in dry DMF (10.0 mL) was added NaH (60% in mineral oil, 240.0 mg, 6.0 mmol) in portions at -5oC under nitrogen. The reaction mixture was stirred at room temperature till no more gas was released, and 3-(chloromethyl)-N, N-diethylaniline (652.0 mg, 3.3 mmol) was then added at 0 oC under nitrogen and stirred at room temperature for 20 h. The reaction was quenched with ice water and washed with EA (20 mL x 2). The aqueous layer was neutralized with HCl (1.0 N) followed by extraction with EA. The EA layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The crude reaction mixture was purified with flash column chromatography (DCM/MeOH 20:1, Rf = 0.2) to afford the intermediate (372.0 mg, 56%) as a colorless oil. The Boc group in the intermediate was removed in the solution of TFA/DCM (1:4) at room temperature overnight. DCM was then evaporated and the residue was washed with diethyl ether (2.0 mLx2) to provide the slurry of the crude product (as TFA salt). The slurry was neutralized with KOH (0.5N in water) to pH 8 and a white precipitate formed. The white precipitate was washed with water and dried to provide 3f (205.0 mg, 71%) as a white


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powder. 1H NMR (700 MHz, MeOD/CDCl310:1) δ 7.20-7.17 (m, 3 H), 6.94 (d, J = 8.3 Hz, 2 H), 6.70 (s, 1 H), 6.66 (d, J = 7.4 Hz, 1 H), 6.63 (d, J = 8.3, 1.8 Hz, 1 H), 4.95 (s, 2 H), 3.34 (q, J = 7.0 Hz, 4 H), 3.26 (dd, J = 14.4, 3.0 Hz, 1 H), 2.86 (dd, J = 14.4, 9.8 Hz, 1 H), 1.14 (t, J = 7.0 Hz, 6 H); 13C NMR (176 MHz, MeOD/CDCl310:1) δ 173.1, 158.2, 147.9, 137.7, 130.2, 129.4, 127.8, 114.5, 111.6, 110.8, 70.6, 56.3, 44.3, 36.1, 12.3; IR (neat) 2967, 2924, 2874, 1593, 1502; HRMS (ESI-TOF) m/e: calc for C20H27N2O3 [M+H]+ 343.2022, found 343.2021. Preparation of 9: To the solution of the commercially available 1,2:3,4-di-Oisopropylidene-D-galactopyranose (141.0 mg, 0.542 mmol) and tetrabutylammonium bromide (7.5 mg, 0.024 mmol) in DMF (5.0 mL) was added NaH (60% in mineral oil, 43.0 mg, 1.084 mmol) at 0 oC. After 15 min at 0 oC, the mixture was warmed up to room temperature and stirred for 30 min. The mixture was then cooled back to 0 oC and 3,5-bis(chloromethyl)-N,Ndiethylaniline (58.0 mg, 0.236 mmol) was added. The mixture was stirred at room temperature for 16 h then quenched with NH4Cl (aq). The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (15 mL x 3). The combined ethyl acetate layers were concentrated and the crude product was purified with flash column chromatography (DCM/MeOH = 20:1, Rf = 0.5) to provide the desired intermediate. To the intermediate (20.0 mg, 0.029 mmol) was added TFA (aq.) (80%, 0.5 mL) at 0oC. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was washed with ether (1.0 mL x 3), dried under vacuum, and re-dissolved in water. The pH value of the aqueous solution was adjusted to 8 with KOH (aq. 0.5N), and the solution was lyophilized to white powder which was purified with flash column chromatography (DCM/MeOH 3:1, Rf = 0.10) to provide product 9 (13.0 mg, 84%) as a white solid. 1H NMR (700 MHz, D2O) δ 6.81 (s, 2H), 6.75 (s, 1H), 5.12 (d, J = 3.8 Hz, 0.8 H) (), 4.48 (t, J = 11.9 Hz, 2H), 4.44-4.42 (m, 3 H), 4.10 (t, J = 6.0 Hz, 0.8 H) (), 3.81 (d, J = 2.7 Hz,



0.8 H) (), 3.75 (d, J = 3.3 Hz, 1H), 3.72-3.66 (m, 2.7 H) (), 3.63-3.57 (m, 4 H), 3.49 (dd, J = 9.9, 3.3 Hz, 1H), 3.35 (dd, J = 9.8, 8.0 Hz, 1H), 3.21 (q, J = 7.1 Hz, 4H), 0.96 (t, J = 7 Hz, 6H); 13C NMR (176 MHz, D2O) δ148.8, 138.6,118.7, 117.1, 115.4, 113.7, 96.3, 92.2, 73.4, 73.1, 73.0, 72.6, 71.7, 69.5, 69.2, 68.9, 68.7, 68.2, 45.0, 10.9; IR (neat) 3299, 2922, 2873, 1675, 1601; HRMS (ESI-TOF) m/e: calc for C24H40NO12 [M+H]+ 534.2551, found 534.2543. Preparation of 12: To a stirred solution of 15 (6.060 g, 0.0188 mmol) in DCM (50 mL) at 0 oC under anhydrous conditions, thionyl chloride (2.899 g, 0.0244 mmol) was added. The reaction mixture was then stirred at room temperature for 3 h before quenched with water (50 mL) and neutralized with NaHCO3. The organic layer was separated, and the remaining aqueous layer was extracted with DCM (20 mLx3). The combined DCM layers were washed with water, brine, dried with anhydrous sodium sulfate, and concentrated. The crude product was purified with column chromatography (Hex/EA=10:1) to provide 12 (4.817 g, 75 %) as a yellow oil. Rf = 0.5 (Hex/EA 3:1); 1H NMR (700 MHz, CDCl3) δ 7.22 (t, J = 8.0 Hz, 1 H), 6.73 (s, 1 H), 6.71 (d, J = 7.5 Hz, 1 H), 6.68 (d, J = 8.3 Hz, 1 H), 4.57 (s, 2 H), 3.71 (s, 6 H), 3.35 (t, J = 7.5 Hz, 4 H), 2.39 (t, J = 7.1 Hz, 4 H), 1.93 (quint, J = 7.2 Hz, 4 H); 13C NMR (176 MHz, MeOD/CDCl3 10:1) δ 173.6, 148.0, 138.5, 129.7, 111.6, 112.2, 51.7, 50.2, 47.1, 31.2, 22.3; IR (neat) 2951, 2874, 1730, 1602, 1579; HRMS (ESI-TOF) m/e: calc for C17H25ClNO4 [M+H]+ 342.1472, found 342.1468. Preparation of 15: To a stirred solution of 3-aminobenzyl alcohol (3.696 g, 0.03 mmol) in DMF (30 mL) was added methyl 4-bromobutyrate (21.723 g, 0.120 mmol), NaI (1.799 g, 0.012 mmol), and Na2HPO4 (21.294 g, 0.150 mmol) at room temperature. The mixture was heated to 70-80 oC for 18 hours before quenched with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined EtOAc layers were washed with water, brine, dried with anhydrous sodium


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sulfate, and concentrated to provide the crude product which was purified with column chromatography (Hex/EA 5:1, Rf = 0.6) to afford 15 (7.762 g, 80%) as a yellow/brown oil. 1H NMR (700 MHz, CDCl3) δ 7.20 (t, J = 7.8 Hz, 1H), 6.75 (s, 1H), 6.66-6.63 (m, 2 H), 4.64 (d, J = 5.1 Hz, 1H), 3.68 (s, 6 H), 3.33 (t, J = 7.5 Hz, 4 H), 2.36 (t, J = 7.1 Hz, 4 H), 1.91 (quint, J = 7.3 Hz, 4 H); 13C NMR (176 MHz, CDCl3) δ 173.7, 148.0, 142.2, 129.6, 114.7, 111.5, 110.7, 65.9, 51.7, 50.2, 31.2, 22.3; IR (neat) 3454, 2951, 2874, 1729, 1602; HRMS (ESI-TOF) m/e: calc for C17H26NO5 [M+H]+ 324.1811 found 324.1804. Synthesis of 13: A solution of 12 (91.0 mg, 0.266 mmol) and Cs2CO3 (326.0 mg, 1.0 mmol) in CH3OH (0.5 mL) was refluxed in a sealed vial overnight. The solvent was removed and the reaction mixture was acidified to pH 5 with HCl (1.0 N) and extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was purified with column chromatography (DCM/MeOH 10:1, Rf = 0.3) to provide 13 (51.0 mg, 61%) as a colorless oil. 1

H NMR (700 MHz, CDCl3) δ 7.19 (t, J = 7.1 Hz, 1 H), 6.70 (s, 1 H), 6.66 (d, J = 7.4 Hz, 1 H),

6.64 (d, J = 8.3 Hz, 1 H), 4.41 (s, 2 H), 3.39-3.30 (m, 7 H), 2.42 (t, J = 6.3 Hz, 4H), 1.91 (quint, J = 6.3 Hz, 4H); 13C NMR (176 MHz, CDCl3) δ 179.5, 147.8, 139.3, 129.4, 116.2, 112.2, 112.0, 75.1, 58.1, 50.3, 31.2, 22.0; IR (neat) 2929, 1705, 1602; HRMS (ESI-TOF) m/e: calc for C16H24NO5 [M+H]+ 310.1654, found 310.1648. Synthesis of 16: To a solution of -D-galactose pentaacetate (230.0 mg, 0.590 mmol) and 15 (287.0 mg, 0.885 mmol) in DCM (2 mL) at 0 oC was added BF3.Et2O (48%, 199 L, 1.768 mmol). The reaction mixture was stirred at 40 oC overnight before quenched with ice water and triethylamine. Purification with column chromatography (PE/EA gradient 3:1 to 1:1) provided the desired -glycoside (150.0 mg, 39%), Rf = 0.30 (PE/EA 3:1). To a solution of the intermediate -glycoside (19.0 mg, 0.029 mmol) in DCM (1.0 mL) was added CH3OH/AcCl



(10:1, 160 L) and the reaction mixture was stirred at room temperature overnight before quenched with TEA and washed with water. The DCM layer was dried with Na2SO4 and the crude product was purified with column chromatography (DCM/Methanol 20:1) to provide the intermediate (9.0 mg, 64%). Rf = 0.2 (DCM/Methanol 20:1); 1H NMR (700 MHz, CDCl3) δ 7.15 (t, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.70-6.67 (m, 2H), 4.87 (d, J = 11.8 Hz, 1 H), 4.65 (d, J = 11.8 Hz, 1 H), 4.33 (d, J = 7.8 Hz, 1 H), 3.84 (d, J = 3.3 Hz, 1 H), 3.81 (ABX1, J = 11.3, 6.9 Hz, 1 H), 3.76 (ABX1, J = 1.3, 5.3 Hz, 1 H), 3.68 (s, 6H), 3.60 (ABX2, J = 9.7, 7.8 Hz, 1 H), 3.51 (td, J = 6.1, 1.0 Hz, 1 H), 3.47 (ABX2, J = 9.7, 3.4 Hz, 1 H), 3.35 (t, J = 7.5, 4 H), 2.39 (t, J = 7.1 Hz, 4 H), 1.88 (quint, J = 7.5 Hz, 4 H);

C NMR (176 MHz, CDCl3) δ 174.3, 148.0, 138.4,

13

128.7, 115.7, 112.0, 111.6, 102.1, 75.3, 73.6, 71.2, 70.6, 68.9, 61.2, 50.7, 49.7, 30.5, 22.1; IR (neat) 3402, 2950, 2877, 1730, 1603; HRMS (ESI-TOF) m/e: calc for C23H36NO10 [M+H]+ 486.2339, found 486.2333. The solution of 16 (5.0 mM) was prepared by treating intermediate with 0.5 N KOH (aq). Photoreaction of 3a: A D2O solution of 3a (31.0 mg, 0.091 mmol, 5.0 mM, 18.0 mL) was distributed evenly into 18 of 5 mm NMR tubes. The NMR tubes were sealed with PTFE tape and bound to the immersion well condenser of the photoreactor and irradiated for 20 min. The reaction solution in all NMR tubes was then combined, and washed with chloroform to remove the PPG alcohol. The aqueous layer was freeze dried to provide the galactose (16.0 mg, 98%). With the 450 W medium pressure mercury lamp, the 313 nm UV emission is measured to be ~1 mW/cm2 (at a distance of ~4 cm from the UV lamp) with a UVX radiometer. The radiometer with an attenuator is placed behind a quartz cuvette (1.0 cm) containing a solution of 2.0 mM K2CrO4 in a 5% K2CO3 aqueous solution.


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Photoreaction of 3a under sunlight: The 5 mm NMR tubes containing 3a (5.0 mM) in D2O were placed outdoor in sunlight (with a UV index of 5 and temperature of 21 oC during the reaction time). After two hours, the reaction completed. Photoreaction of 3f: A 5.0 mM solution of 3f was prepared by dissolving 3f (194.0 mg, 0.567 mmol) in 113.0 mL of KOH (0.5 N) solution. The resulting solution was distributed evenly into 76 5 mm NMR tubes. The NMR tubes were sealed with PTFE tape and bound to the immersion well condenser of the Hanovia photoreactor and irradiated for 45 min. The reaction solution in all NMR tubes was then combined, and washed with chloroform to remove the PPG alcohol. The aqueous layer was frozen dry. Half of this crude product was dissolved in 3.0 mL of H2O/Dioxane (1:2) and treated with Boc2O (74.0 mg, 0.340 mmol). The reaction solution was stirred overnight at room temperature and then washed with ether (3.0 mL x 3). The aqueous layer was neutralized with HCl (1.0 N) and extracted with EA. The EA layer was concentrated and the residue was purified with flash column chromatography (DCM/methanol 10:1, Rf = 0.3) to afford Boc-protected 6 (64.0 mg, 51%) as a colorless oil. 1H NMR (700 MHz, MeOD/CDCl3 5:1) δ 7.16 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 1.8, 1H), 6.88 (dd, J = 8.1, 2.1 Hz, 1H), 6.81 (s, 1H), 6.76 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 8.1 Hz, 2 H), 4.28 (t, J = 6.1 Hz, 1 H), 3.91 (AB, J = 15.0 Hz, 1 H), 3.80 (AB, J = 15.0 Hz, 1 H), 3.36 (q, J = 7.0 Hz, 4 H), 3.01 (ABX, J = 13.8, 5.2 Hz, 1 H), 2.88 (ABX, J = 13.8, 7.0 Hz, 1 H), 1.40 (s, 9 H), 1.11 (t, J = 7.1 Hz, 6 H); 13C NMR (176 MHz, MeOD/CDCl3=5/1) δ 175.0, 156.0, 153.7, 145.2, 142.7, 142.6, 131.5, 129.0, 127.9, 127.7, 127.1, 120.1, 115.8, 114.7, 112.2, 80.0, 79.1, 72.3, 70.0, 60.8, 56.9, 55.5, 46.5, 46.4, 37.6, 36.8, 35.6, 35.5, 27.6, 27.4, 11.2; IR (neat) 3304, 2929, 1686, 1596; HRMS (ESI-TOF) m/e: calc for C25H35N2O5 [M+H]+ 443.2546, found 443.2536.



Quantum yield determination: A 5.0 mM solution of the sample and a 5.0 mM solution of DEABn-protected 3-phenyl-1-propanol (with known quantum yield of 0.26) in NMR tube were placed behind a standard 1 cm quartz UV cuvette contain the filter solution. Filtered light centered at 312 nm was obtained by passing light from the 450 W medium pressure mercury lamp through a solution of 2.0 mM K2CrO4 in a 5% K2CO3 aqueous solution. The yields of photo reactions were determined by 1H NMR analysis.

Supporting Information Available: 1H and 13C NMR spectra of new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. ACKNOWLEDGMENT. We thank the NSF (CHE 1401063) for financial support. We also thank D. Rountree for help in preparing 12 and 15, and Dr. Michael J. Jablonsky for assistance with NMR spectroscopy.


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