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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Org Chem. Author manuscript; available in PMC 2010 December 18.
Published in final edited form as:
PMCID: PMC2852026
NIHMSID: NIHMS159459

Silver-Mediated Allylic Disulfide Rearrangement for Conjugation of Thiols in Protic Media

Abstract

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Alkyl and aryl allyl disulfides are induced to undergo the desulfurative allylic rearrangement by silver nitrate in protic solvents at room temperature, thereby removing the necessity for the use of phosphines as thiophilic reagents. The silver-mediated reaction functions at ambient temperature in protic solvents and in the absence of protecting groups

Introduction

Allylic disulfides, readily formed by the well-known reaction between a thiol and a sulfenyl transfer reagent,1 may be converted into the more permanent alkyl allyl thioethers by the desulfurative allylic disulfide rearrangement. We have studied this reaction extensively over the last several years, during the course of which we have demonstrated that it is accelerated in polar solvents and that it may be applied to the functionalization of peptidyl thiols in protic media at room temperature.2 This reaction proceeds through an unfavourable equilibrium, the result of a reversible 2,3-sigmatropic rearrangement, with a transient allylic thiosulfoxide from which an atom of sulfur is excised by triphenylphosphine and which drives the equilibrium in the forward direction (Scheme 1).3 Recent computational work has provided strong support for this mechanism, in particular for the rate determining step being the desulfurization of the transient thiosulfoxide by the phosphine, and, in line with our initial postulate, for the acceleration in protic media being due to the stabilization of the thiosulfoxide.4

Scheme 1
Phosphine-Mediated Allylic Disulfide Rearrangement

Although in this reaction the phosphine can be replaced by morpholine in some instances, typically with a reduction in the E:Z selectivity of the final product, and can be dispensed with altogether in methanol at reflux, the optimum conditions, which result in excellent E:Z selectivity for disubstituted olefin formation, require the use of stoichiometric phosphine,2 a common feature with the Staudinger ligation.5 The function of this phosphine is to desulfurize the transient allylic thiosulfoxide that is in equilibrium with the allylic disulfide itself. In our continuing study of this desulfurative allylic rearrangement we have investigated alternative means of promoting the desulfurization step, retaining the high E:Z selectivity featured by the original variant. We initially considered the development of water-soluble phosphines, as has been achieved for the traceless Staudinger ligation,6 so as to be able to accelerate the reaction in aqueous media, but ultimately opted to search for a completely phosphine-free system. Along these lines we conceived that thiophilic metal species would bind preferentially to, and excise sulfur from, the more nucleophilic thiosulfoxide rather than from the allylic disulfide (Scheme 2), and report here on the reduction of this concept to practice.7

Scheme 2
Proposed Metal-Mediated Allylic Disulfide Rearrangement

Results and Discussion

We set out to screen a number of commonly available, potentially thiophilic salts for the rearrangement of a model system under protic conditions at room temperature. To this end a model diallyl disulfide 5 was prepared as outlined in Scheme 3 beginning from 3,4-dihydroxybutene.8 Thus, the diol was readily converted to the cyclic thiocarbonate 1 with thiophosgene and this latter was subjected to the Newman-Kwart9 rearrangement to give the thiolcarbonate 2 in excellent yield. In contrast to the somewhat complex purely thermal process, the tetrakis(triphenylphosphino)palladium (0) catalyzed rearrangement took place efficiently and in high yield in ethanol at reflux.10,11,12,13 Cleavage of the cyclic thiolcarbonate 2 was best achieved by reduction with lithium aluminium hydride, and was followed by immediate conversion of the resulting mercapto alcohol to the requisite pyridyl disulfide 3 by exposure to 2,2′-dipyridyl disulfide. Finally, the sulfenyl donor 3 was allowed to react with a protected L-cysteine derivative 4 to give the model disulfide 5 in 55% yield (Scheme 3).

Scheme 3
Preparation of a Model System

With a model system in hand screening experiments were conducted in both deuterioacetonitrile and deuteriomethanol at room temperature with monitoring by NMR spectroscopy and final chromatographic isolation of the products, leading to the results outlined in Table 1.

Table 1
Screening of Potentially Thiophilic Metal Salts

Among the salts screened, silver nitrate was the clear favorite, bringing about the desired rearrangement of the model system in high yield, with excellent trans-selectivity, in a matter of hours at room temperature. Silver salts were therefore adopted as the reagents of choice and applied to the conjugation of a number of systems as set out in Table 2.14 Where available the yields for the same reactions previously obtained by the phosphine-mediated rearrangement are also presented in Table 2 for ease of comparison. While the yields presented for the silver nitrate-mediated rearrangement in Table 2 are, with one exception, slightly lower than their counterparts for the phosphine-mediated rearrangement, it must be realized that the latter, for the most part, required more forcing conditions. Thus, entries 1 and 2 of Table 2 report yields for reactions conducted with triphenylphosphine in benzene at reflux, as no rearrangement was observed at room temperature. In distinct contrast the same rearrangements were effected at room temperature with silver nitrate. With the siloxylated allylic disulfide 12[14]15 sulfenyl transfer to the anomeric thiol 7 with subsequent silver-mediated desulfurative rearrangement was again successful, albeit with concomitant cleavage of the silyl ether group (Table 2, entry 3). When this same reaction was attempted in methanol at room temperature in the presence of triphenylphosphine rather than silver nitrate, a complex mixture was observed that did not contain the anticipated product (Table 2, entry 3). The failure of Table 2, entry 3 under the phosphine-mediated conditions is likely due to reduced nucleophilicity of the sulfur bound to the anomeric carbon, on which we have previously remarked,2 and the electron-withdrawing silyl ether moiety which destabilizes the partial positive charge on the allylic framework in the thiosulfoxide. Both of these factors reduce the equilibrium concentration of the thiosulfoxide, and thereby retard the desulfurization step, and so permit the onset of other deleterious processes including disulfide scrambling. Clearly, in view of Table 2, entry 3, silver nitrate is a more effective desulfurization reagent than triphenylphosphine and enables the combination of these factors to be overcome. This same retarding effect of the homoallylic oxygen on the phosphine-mediated rearrangement is apparent from a comparison of the yields in entries 4 and 6 of Table 2 when both reactions were conducted in the methanol at room temperature.

Table 2
Silver-Promoted Desulfurative Allylic Disulfide Rearrangement in Methanol

Entry 7 of Table 2 is particularly interesting as we had previously found that allyl aryl disulfides do not undergo the phosphine-mediated desulfurative allylic rearrangement owing to the more facile nature of the direct attack of the phosphine on the disulfide bond itself. Indeed, the simple heating of the disulfide formed from 3 and 18 resulted in none of the desired product 19. Clearly, the silver-mediated protocol reported here overcomes this problem and results in a good yield of the rearranged allylic sulfide 19. As noted previously, the allyl aryl disulfides can also be inducted to undergo desulfurative allylic rearrangement by simple heating to reflux in methanol but the yields in such cases are only modest.2 Finally, Table 2, entry 8, is the preparative scale run of the initial screening reaction. The somewhat lower yield reported for the preparative scale reaction reflects the two step nature of the process as opposed to the use of an isolated disulfide in the screening reactions. In general, and with the exception of entries 2 and 5 in which trisubstituted olefins were formed, the silver-mediated reaction presented in Table 2 took place with excellent E-selectivity on a par with that obtained in the phosphine-mediated reactions.16

The applicability of the silver-mediated reaction under aqueous conditions is demonstrated by the examples of Table 3. In particular, entry 2 of Table 3 shows how this chemistry may be applied to the formation of glycoconjugates in the complete absence of protecting groups. Once again, excellent E-selectivity was observed under these conditions.16

Table 3
Silver-Promoted Desulfurative Allylic Disulfide Rearrangement in Aqueous Buffera

Conclusion

We demonstrate a new variant on the desulfurative allylic disulfide rearrangement in which the key desulfurization of the transient thiosulfoxide intermediate is achieved through the use of silver nitrate rather than a triarylphosphine. This metal-mediated process enables the desulfurative allylic rearrangement of aryl allyl disulfides, something that could not be achieved with phosphines owing to the more facile disulfide cleavage reaction. Reactions take place at room temperature, give excellent E-selectivity for the formation of disubstituted alkenes and are conducted in protic media, including aqueous mixtures with organic solvents.

Experimental Section

4-Vinyl-[1,3]dioxolane-2-thione (1)

To a stirred solution of but-3-ene-1,2-diol (10.0 g, 113.5 mmol) in dichloromethane (200 mL) under a nitrogen atmosphere was added pyridine (19.8 g, 250 mmol) followed by DMAP (1.39 g, 11.4 mmol) at 0 °C. Thiophosgene (14.4 g, 124.8 mmol) dissolved in dichloromethane (100 mL) then was added dropwise over a period of 2 h. The reaction mixture was stirred at room temperature for 3 h and then diluted with 1.0 M HCl (100 mL). The organic part was separated and washed with sat NaCl (100 mL), dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography using EtOAc/Hexanes as eluent to give 4-vinyl-[1,3]dioxolane-2-thione (1) as a dark yellow liquid (12.5 g, 85%). IR (neat): 1709 cm−1. 1H-NMR (500 MHz): 5.95 (ddd, J = 17.0, J = 10.5, J = 7.0 Hz, 1H), 5.56 (d, J = 17.0 Hz, 1H), 5.51 (d, J = 10.5 Hz, 1H), 5.34 (m, 1H), 4.78 (t, J = 8.5 Hz, 1H), 4.36 (t, J = 8.5 Hz, 1H). 13C-NMR (125 MHz): δ 191.7, 131.2, 122.8, 82.7, 73.1. HREIMS: calc. for C5H6O2S [M]+ 130.0089, found 130.0064.

4-Vinyl-1,3-oxathiolan-2-one (2)

To a stirred solution of 4-vinyl-[1,3]dioxolane-2-thione (1) (5.08 g, 39.1 mmol) in degassed ethanol (150 mL) (0.26 M) was added Pd(PPh3)4 (904 mg, 0.78 mmol). The reaction mixture was stirred at 75 °C for 1 h after which the dark brown mixture was cooled to room temperature, and solvents were evaporated and the product was purified by column chromatography using EtOAc/Hexanes as eluent to give 4-vinyl-1,3-oxathiolan-2-one (2) as a colorless oil (4.0 g, 80%). IR (neat): 1738 cm−1. 1H-NMR (500 MHz): δ 5.89 (ddd, J = 17.0, J = 10.0, J = 7.0 Hz, 1H), 5.41 (d, J = 17.0 Hz, 1H), 5.29 (d, J = 10.0 Hz, 1H), 4.55 (m, 2H), 4.20 (m, 1H). 13C-NMR (125 MHz): δ 172.8, 133.2, 120.4, 72.7, 51.6. HREIMS: calc. for C5H6O2S [M]+ 130.0089, found 130.0089.

2-(Pyridin-2-yldisulfanyl)-but-3-en-1-ol (3)

To a stirred solution of 4-vinyl-1,3-oxathiolan-2-one (2) (2.0 g, 15.4 mmol) in dry ether (15 mL) cooled to 0 °C was added LiAlH4 (584 mg, 15.4mmol). The reaction mixture was stirred at the same temperature for 30 min and then at room temperature for 2 h before ethyl acetate (5 mL) was added followed by the sequential addition of 1.0 M HCl (10.0 mL) and MeOH (10.0 mL). The reaction mixture was stirred at room temperature for 30 min and then filtered through a pad of Celite with washing of the filter pad with MeOH (10.0 mL) and 1.0 M HCl (5.0 mL). The filtrate and washings were transferred to a solution of 2,2′-dipyridyl disulfide (3.0 g, 13.6 mmol) in MeOH (10.0 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 h before the solvents were evaporated and the crude reaction mixture was dissolved in EtOAc (100 mL), and washed with sat bicarbonate solution (50 mL). The ethyl acetate portion was further washed with brine solution (50 mL), dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel using EtOAc/Toluene as eluent to give 2-(pyridin-2-yldisulfanyl)-but-3-en-1-ol (3) as a colorless liquid (1.47 g, 45% for two steps). 1H-NMR (400 MHz): δ 8.48 (dd, J = 1.5 Hz, J = 4.8 Hz, 1H), 7.56 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 7.2 Hz, J = 4.8 Hz, 1H), 5.94 (m, 1H), 5.88 (m, 1H), 5.24 (dd, J = 16.5 Hz, J = 9.3 Hz, 2H), 3.79 (m, 1H), 3.62 (m, 2H). 13C-NMR (125 MHz,): δ 159.2, 150.0, 137.1, 134.3, 122.2, 121.8, 118.6, 61.4, 56.6. ESIHRMS: calc. for C9H11NOS2Na [M+Na]+ 236.0180, found 236.0191.

Methyl 2-tert-Butoxycarbonylamino-3-(1-hydroxymethylallyldisulfanyl)propionate (5)

To a stirred solution of 2-(pyridin-2-yldisulfanyl)-but-3-en-1-ol (3) (160 mg, 0.75 mmol) in methanol (6.0 mL) was added a solution of N-Boc-L-Cys-OMe (4) (176 mg, 0.75 mmol) in methanol (1.5 mL). The reaction mixture was stirred at room temperature under N2 atmosphere for 4 h before the solvents were removed and the crude product was purified by column chromatography on silica gel using EtOAc/Hexanes as eluent to give methyl 2-tert-butoxycarbonylamino-3-(1-hydroxymethylallyldisulfanyl)propionate (5) as a thick oil (139 mg, 55%). 1H-NMR (500 MHz): δ 5.81 – 5.78 (m, 1H), 5.38 (d, J = 8.0 Hz, 1H), 5.35 – 5.26 (m, 2H), 4.64 – 4.62 (m, 1H), 3.94 (d, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.57 – 3.49 (m, 1H), 3.22 – 3.11 (m, 2H), 2.23 (brs, 1H), 1.42 (s, 9H), 13C-NMR (125 MHz): δ 171.7, 155.6, 134.8, 134.7, 119.7, 119.6, 80.9, 63.6, 57.2, 56.7, 53.5, 53.2, 42.0, 41.8, 28.8. ESIHRMS: calc. for C13H23NO5S2Na [M+Na]+ 360.0915, found 360.0933.

General procedure for the silver nitrate promoted rearrangement of allylic disulfides

Thiol (1.0 equiv) was added to a stirred solution of disulfide in methanol (0.05 M) at room temperature. The reaction mixture was stirred at room temperature under a nitrogen atmosphere until complete disulfide exchange was visible on TLC (usually less than an hour). The reaction mixture was then treated with silver nitrate (2.0 equiv) and stirred in the dark for 16 h. After the completion of reaction (monitored by ESI mass spectrometry), NaCl (10 equiv) was added and the reaction mixture was stirred for 3–4 h. The reaction mixture was diluted with methanol and centrifuged to remove the black precipitate. The solvent was then concentrated to afford the crude product which was purified by column chromatography on silica gel to give the rearranged product.

(E)-N-tert-Butoxycarbonyl-S-(4-hydroxybut-2-enyl)-L-cysteine methyl ester (6)

Following the general procedure for the silver nitrate promoted rearrangement of allylic disulfides compound 6 was prepared in 72% yield as an oil. [α]23D 23.5 (c = 1.0); 1H-NMR (500 MHz): δ 5.80 (dd, J = 15.0, J = 5.0 Hz, 1H), 5.68 (dd, J = 15.0, J = 6.0 Hz, 1H), 5.28 (d, J = 7.5 Hz, 1H), 4.51 (d, J = 8.0 Hz, 1H), 4.15 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H), 3.17 (d, J = 7.0 Hz, 2H), 2.84 (dd, J = 14.0, J = 5.5 Hz, 2H), 1.90 (brs, 1H), 1.46 (s, 9H). 13C-NMR (125 MHz): δ 172.0, 156.0, 133.3, 127.7, 80.7, 63.2, 53.6, 52.8, 34.3, 33.3, 28.5. ESIHRMS: calc. for C13H23NO5SNa [M+Na]+ 328.1195, found 328.1183.

2-(2-(Tridec-1-en-3-yl)disulfanyl)pyridine (8) was prepared according to literature procedure and had spectral data in agreement with the literature.2c

Tridec-2-enyl-(tetra-O-acetyl-1-thio-β-D-glucopyranoside) (9)

Following the general procedure for the silver nitrate promoted rearrangement of allylic disulfides compound 9 was prepared in 62% yield. Its spectral data was consistent with that reported in the literature.2c

3,7,11-Trimethyl-dodeca-2,6,10-trienyl tetra-O-acetyl-1-thio-β-D-glucopyranoside (11)

To a stirred solution of 2-(1,5,9-trimethyl-1-vinyldeca-4,8-dienyldisulfanyl)benzothiazole2b (10) (78 mg, 0.19 mmol) in methanol (3.0 mL) was added triethylamine (27 μL, 0.19 mmol) followed by 1-thio-β-D-glucose tetraacetate (7) (54 mg, 0.16 mmol). After 1 h, silver nitrate (58 mg, 0.34 mmol) was added and the reaction mixture was stirred under a N2 atmosphere in the dark for 36 h. After following the general work up procedure the crude product was purified by column chromatography to give the title product (11) in 50% yield with spectral data was consistent with that reported in the literature.2b

1-tert-Butyldimethylsilyloxy-2-(pyridin-2-yldisulfanyl)but-3-ene (12)

To a stirred solution of 2-(pyridin-2-yldisulfanyl)but-3-en-1-ol (3) (1.0 g, 4.69 mmol) in DMF (10.0 mL) under a nitrogen atmosphere was added imidazole (319 mg, 4.69 mmol) followed by tert-butyldimethylsilyl chloride (716 mg, 4.69 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic part was washed with saturated NaCl solution (50 mL), dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography on silica gel using EtOAc/Hexanes as eluent to give the title product (12) as an oil (1.20 g, 80%). 1H-NMR (500 MHz): δ 8.44 (ddd, J = 5.0, J = 2.0, J = 1.0 Hz, 1H), 7.56 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 7.2, J = 4.8 Hz, 1H), 5.94 (m, 1H), 5.88 (m, 1H), 5.24 (dd, J = 16.5, J = 9.3 Hz, 2H), 3.79 (m, 1H), 3.62 (m, 2H). 13C-NMR (125 MHz): δ 161.2, 149.5, 137.1, 134.5, 120.6, 119.8, 119.2, 64.7, 57.1, 26.1, 18.6, −5.1. ESIHRMS: calc. for C15H25NOS2SiNa [M+Na]+ 350.1045, found 350.1042.

S-4-Hydroxybut-2-enyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside (13)

To a stirred solution of 1-tert-butyldimethylsilyloxy-2-(pyridin-2-yldisulfanyl)-but-3-ene (12) (115 mg, 0.35 mmol) in MeOH (2.0 mL) was added 1-thio-β-D-glucose tetraacetate (100 mg, 0.29 mmol) under a nitrogen atmosphere. The yellow colored solution was stirred at room temperature for 1 h before the solvents were removed and the crude reaction mixture was purified by column chromatography on silica gel to give the mixed disulfide. The mixed disulfide (78 mg, 0.13 mmol) was dissolved in MeOH (2.0 mL) and silver nitrate (46 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature under a N2 atmosphere in the dark for 16 h before NaCl (75 mg, 1.3 mmol) was added and the solution was stirred for 3–4 h and then diluted with MeOH (10.0 mL), and centrifuged. The supernatant were evaporated to give the crude product which was purified by column chromatography on silica gel using EtOAc/Hexanes as eluent to give 13 (45 mg, 67%). [α]23D -49.5 (c = 1.0); 1H NMR (500 MHz) δ 5.78 (dt, J = 15.5, J = 5.0, 1H), 5.71 (dtd, J = 15.5, J = 6.5, J = 1.0 Hz, 1H), 5.22 (t, J = 9.6 Hz, 1H), 5.07 (t, J = 9.6, 1H), 5.06 (t, J = 9.6 Hz, 1H), 4.50 (d, J = 10.0 Hz,1H), 4.24 (dd, J = 12.0, J = 5.0 Hz,1H), 4.18-4.10 (m, 2H), 4.15 (dd, J = 12.0, J = 2.0 Hz,1H), 3.68 (ddd, J = 9.5, J = 5.0, J = 2.0, 1H), 3.38 (dd, J = 13.5, J = 7.5, 1H), 3.26 (ddd, J = 13.5, J = 6.0, J = 1.0 Hz, 1H), 2.09 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.77 (br s, 1H). 13C NMR (125 MHz) δ 170.9, 170.5, 169.7, 169.6, 133.0, 127.2, 82.2, 76.0, 74.1, 70.2, 68.6, 63.0, 62.4, 31.6, 20.9, 20.9, 20.8, 20.8 ESIHRMS: calc. for C18H26O10SNa [M+Na]+ 457.1144, found 457.1138.

N-tert-Butoxycarbonyl-S-(tridec-2-enyl)glutathione dimethyl ester (15)2b

Following the general procedure for the silver nitrate promoted rearrangement of allylic disulfides compound 15 was prepared in 61% yield. Its spectral data were consistent with that reported data in the literature.2b

N-tert-Butoxycarbonyl-S-(3,7,11-trimethyldodeca-2,6,10-trienyl)glutathione dimethyl ester (16)

To a stirred solution of 2-(1,5,9-trimethyl-1-vinyl-deca-4,8-dienyldisulfanyl)-benzothiazole (10) (120 mg, 0.30 mmol) in methanol (5.0 mL) was added triethylamine (38 μL, 0.27 mmol) followed by Boc-(α-OMe)-γ-L-Glu-L-Cys-Gly-OMe2a (14) (100 mg, 0.23 mmol). After 1 h, silver nitrate (78 mg, 0.46 mmol) was added and the reaction mixture was stirred under a N2 atmosphere in the dark for 16 h. After following the general work up procedure the crude product was purified by column chromatography on silica gel to give the title product in 60% yield with spectral data consistent with the literature.2b

N-tert-Butoxycarbonyl-S-(4-hydroxybut-2-enyl)glutathione dimethyl ester (17)

Following the general procedure for the silver nitrate promoted rearrangement of allylic disulfides, a stirred solution of 2-(pyridin-2-yldisulfanyl)-but-3-en-1-ol (3) (70 mg, 0.25 mmol) in methanol (5.0 mL) was treated with Boc-(α-OMe)-γ-L-Glu-L-Cys-Gly-OMe2a (14) (108 mg, 0.25 mmol). The reaction mixture was stirred under a N2 atmosphere for 12 h before silver nitrate (85 mg, 0.50 mmol) was added and the mixture stirred in the dark for 16 h before the general work up procedure was applied. The crude product was purified by column chromatography on silica gel using CHCl3/MeOH as eluent to give the title product (17) in 65% yield. [α]23D -2.0 (c 0.85); 1H NMR (400 MHz) δ 7.16 (br s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 5.87 – 5.80 (m, 1H), 5.72 -5.65 (m, 1H), 5.38 (d, J = 7.6 Hz, 1H), 4.64 – 4.59 (m, 1H), 4.37 (br s, 1H), 4.12 (br s, 2H), 4.03 (d, J = 5.6 Hz, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.27 (br s,1H), 3.19 (d, J = 7.2 Hz, 2H), 2.90 – 2.86 (m, 1H), 2.80-2.76 (m, 1H), 2.36 – 2.33 (m, 2H), 2.18 (m, 1H), 1.95 – 1.89 (m, 1H), 1.42 (s, 9H). 13C NMR (100 MHz) δ 173.1, 172.6, 170.9, 170.3, 156.1, 133.4, 128.4, 80.6, 63.1, 53.0, 52.9, 52.7, 41.5, 34.5, 33.0, 32.4, 29.0, 28.6. ESIHRMS: calc. for C21H35N3O9SNa [M+Na]+ 528.19920, found 528.2016.

(E)-4-(4-Chlorophenylsulfanyl)but-2-en-1-ol (19)

Following the general procedure for the silver nitrate promoted rearrangement of allylic disulfides, compound 19 was prepared in 51% yield. Its spectral data were consistent with that reported in the literature.2c

(E)-S-(4-hydroxybut-2-enyl)-glutathione (21)

Glutathione (20) (29 mg, 0.09 mmol) was dissolved in 2 mL Tris buffer (0.2M, pH 8) and the resulting solution was treated with 2-(pyridin-2-yldisulfanyl)but-3-en-1-ol (3) (75 mg, 0.28 mmol) dissolved in 2.0 mL CH3CN/THF (1:1). The reaction mixture was stirred at room temperature for 12 h after which excess disulfide and liberated benzothiazole were removed by washing with t-butyl methyl ether (5 mL). The residue was dissolved in water (3 mL) and treated with silver nitrate (2.2 equiv). The yellow suspension was allowed to stir for 24 h and then treated with 3 mL of 5% dil HCl and centrifuged. The supernatant was injected into a reversed-phase HPLC system for purification using a gradient of 100% B to 50% B developed over 50 min (A, 0.1% TFA/CH3CN; B, 0.1% TFA/H2O; column. Varian Microsorb C18 250 × 21.4 mm; flow rate. 10 mL/min; UV detection. 215 nm). Lyophilization of the fraction eluting at 19 min afforded the rearranged glutathione 21 in 85% yield as a white foam. [α]23D -23.2 (c 0.8, CH3OH); 1H NMR (500 MHz, CD3OD) δ 5.80 – 5.74 (m, 1H), 5.69 – 5.64 (m, 1H), 4.53 (dd, J = 11.5, J = 6.0Hz, 1H), 4.06 (d, J = 5.0 Hz, 2H), 3.97 (d, J = 8.0 Hz, 2H), 3.61 (t, J = 8.5 Hz, 1H), 3.18 (d, J = 8.0 Hz, 2H), 2.99 (dd, J = 17.5, J = 6.0 Hz, 1H), 2.70 (dd, J = 17.0, J = 11.5 Hz, 1H), 2.57 – 2.50 (m, 2H), 2.48 – 2.03 (m, 2H); 13C NMR (125 MHz, CD3OD) δ 173.9, 172.7, 172.4, 170.4, 132.8, 126.9, 61.8, 54.2, 53.2, 40.7, 33.2, 32.1, 31.7, 26.6 ESIHRMS: calc. for C14H23N3O7SNa [M+Na]+ 400.1154, found 400.1150.

S-[4-(β-D-Galactopyranosyloxy)but-2-enyl]glutathione (23)

Glutathione (11 mg, 0.03 mmol) was dissolved in 0.5 mL Tris buffer (0.2M, pH 8) to which 2-(2-pyridyldisulfanyl)-3-enyl β-D-galactopyranoside2d (22) (37.5 mg, 0.10 mmol) dissolved in 0.5 mL CH3CN was added. The reaction mixture was stirred at room temperature for 16 h before the excess disulfide and liberated benzothiazole were removed by washing with t-butyl methyl ether (5 mL). The residue was dissolved in water (3 mL) and treated with silver nitrate (2.2 equiv). The yellow suspension was allowed to stir for 24 h and then was treated with 3 mL of 5% dil HCl and centrifuged. The supernatant was injected into a reversed-phase HPLC system for purification to give the product in 65% yield whose spectral data were consistent with the literature.2d

Supplementary Material

1_si_001

Acknowledgments

We thank Wayne State University and the NIH (GM62160) for partial support of this work, and an anonymous reviewer for helpful suggestions regarding the mechanism of the reaction.

Footnotes

Supporting Information Available. Copies of the 1H and 13C NMR spectra of cmpds 1–3, 5, 6, 9, 11–13, 15–17, 19, 21, and 23. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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3. For the early work on this rearrangement see: a) Höfle G, Baldwin JE. J Am Chem Soc. 1971;93:6307–6308. b) Baechler RD, Hummel JD, Mislow K. J Am Chem Soc. 1973;95:4442–4444. c) Moore CG, Trego GR. Tetrahedron. 1962;18:205–218. d) Evans MB, Higgins GMC, Moore CG, Porter M, Saville B, Smith JF, Trego BR, Watson AA. Chem Ind. 1960:897. e) Pilgram K, Phillips DD, Korte F. J Org Chem. 1964;29:1844–1847. f) Block E, Iyer R, Grisoni S, Saha C, Belman S, Lossing FP. J Am Chem Soc. 1988;110:7813. g) Braverman S, Cherkinsky M. Top Curr Chem. 2007;275:67–102. [PubMed]
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7. We note that the analogous deselenative allylic selenosulfide rearrangement of S-alkyl Se-allyl seleno sulfides proceeds in some cases in the absence of phosphine2 and has been recently applied to the allylation of a protein. Chaulker JM, Lin YA, Boutureira O, Davis BG. Chem Commun. 2009:3714–3716. [PubMed]
8. Although 3,4-hydroxybutene is available commercially, it may be obtained more economically by hydrolysis of the much cheaper 4-vinyl-1,3-dioxolan-2-one.
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10. The metal-catalyzed [3,3]-sigmatropic rearrangements of a variety of allylic thionoesters have been described in the literature previously. See, for example, a) Overman LE, Roberts SW, Sneddon HF. Org Lett. 2008;10:1485–1488. [PubMed] b) Gais HJ, Böhme A. J Org Chem. 2002;67:1153–1161. [PubMed]and references therein cited.
11. No attempt was made to develop an asymmetric version of this reaction in view of the destruction of the stereogenic center in the subsequent application.
12. The photochemical [1,3]-rearrangement of allylic thiocarbamates is also a known reaction; Sakamoto M, Yoshiaki M, Takahashi M, Fujita T, Watanabe S. J Chem Soc, Perkin Trans 1. 1995:373–377.
13. For a recent palladium-catalyzed variant on the aromatic Newman-Kwart reaction see: Harvey JN, Jover J, Lloyd-Jones GC, Moseley JD, Murray P, Renny JS. Angew Chem Int Ed. 2009;48:7612–7615. [PubMed]
14. For a collection of reviews on reactions promoted and or catalyzed by the coinage metals see: Lipshutz BH, Yamamoto Y. Chem Rev. 2008;108:2793–2795. [PubMed]and the reviews immediately following this editorial.
15. Obtained by silylation of 3 under standard conditions with tert-butyldimethylsilyl chloride in 80% yield.
16. For all disubstituted alkenes only the E-isomers were observed and isolated.