From Transient Sulfenic Acids to Disulfide-Functionalized Tripodal Structures

Abstract

The condensation of transient polysulfenic acids with thiols, some of which containing privileged structures, has been applied to the synthesis of tripodal disulfides. The easy access to this new kind of conformationally constrained polyfunctionalized compounds opens the way to their application in supramolecular chemistry.

Key words

sulfoxides - thiols - condensation - carbohydrates - ­pyridines

References and Notes

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9

2,4,6-Triethyl-1,3,5-tri{[(2-methoxycarbonylethyl)-thio]methyl}benzene (5)
To a solution of thiol 1a (6.73 g, 22.40 mmol) in dry THF (109 mL) under argon atmosphere at -78 ˚C, 4.7 mL of a 40 wt% Triton B solution in MeOH (10.62 mmol) were added. After 5 min stirring at -78 ˚C, 18 mL of methyl acrylate (197.88 mmol) were added. The reaction, monitored by TLC every 5 min, appeared complete after 30 min. The reaction mixture, evaporated under reduced pressure, was submitted to flash column chromatography, giving 9.90 g (17.72 mmol) of 5 (79% yield). TLC: R _f = 0.42 (PE-EtOAc, 60:40). Low-melting solid. ^¹H NMR (300 MHz, CDCl₃): δ = 3.74 (s, 6 H, 3 × ArCH ₂S), 3.67 (s, 9 H, 3 × OCH₃), 2.83 (m, 12 H, 3 × CH ₂CH₃ and 3 × CH ₂CH₂CO₂CH₃), 2.63 (t, 6 H, ^³ J = 7.0 Hz, 3 × CH ₂CO₂CH₃), 1.26 (t, 9 H, ^³ J = 7.6 Hz, 3 × CH₂CH ₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 172.3 (3 × CO), 142.3 and 131.1 (C-1-6), 51.6 (3 × CH₃), 34.5 (3 × CH₂CO₂CH₃), 31.2 and 28.3 (3 × CH₂SCH₂), 22.7 (3 × CH₂CH₃), 16.0 (3 × CH₂ CH₃). Anal. Calcd for C₂₇H₄₂O₆S₃ (558.8): C, 58.03; H, 7.58. Found: C, 58.17; H, 7.45.

10

2,4,6-Triethyl-1,3,5-tri{[(2-methoxycarbonylethyl)-sulfinyl]methyl}benzene (6a)
To a CH₂Cl₂ solution of 5 (1.36 g, 2.43 mmol in 23 mL) at -78 ˚C under continous stirring, 1.57 g of MCPBA (80 wt%, 7.28 mmol) in 50 mL of CH₂Cl₂ were added slowly. The reaction, monitored by TLC, appeared complete at the end of the oxidant addition. The reaction was quenched by adding a 10 wt% aq solution of Na₂S₂O₃. The organic layers were separated and washed twice with a sat. NaHCO₃ solution and then twice with brine. After Na₂SO₄ dehydration, filtration, and evaporation under reduced pressure, 6a was obtained in an almost quantitative yield as a diastereomeric mixture. TLC: R _f = 0.30 (PE-acetone, 25:75). Low-melting solid. ^¹H NMR (300 MHz, CDCl₃): δ = 4.33 and 4.04 (two br AB d, 6 H, 3 × ArCH ₂SO), 3.71 (s, 9 H, 3 × OCH₃), 3.20-2.60 (m, 18 H, 3 × CH ₂CH₃ and 3 × CH₂CH₂), 1.24 (br t, 9 H, 3 × CH₂CH ₃). Anal. Calcd for C₂₇H₄₂O₉S₃ (606.8): C, 53.44; H, 6.98. Found: C, 53.70; H, 7.20.

12

General Procedure for Thermolysis of Trisulfoxides 6a-c and Their Coupling with Thiols 7-12
A solution of 1 mmol of sulfoxide 6 and an excess of thiol in 20 mL of solvent (see Table  [¹] ) was maintained under stirring at the reflux temperature. The reaction was monitored via TLC and ^¹H NMR. Except for 7, directly precipitated from 1,4-dioxane solution after simple cooling at r.t., the excess of thiols 8-12 and the purified disulfides 13-18 were recovered from the chromatographic column.
1,3,5-Tri{[(2,3,4,6-tetra- O -acetyl-β- d -glucopyranosyl)-dithio]methyl}-2,4,6-triethylbenzene (17a)
TLC: R _f = 0.32 (PE-EtOAc, 50:50). White solid, mp 84 ˚C. [α]_D ^²8 -95.9 (c 0.02, CHCl₃). ^¹H NMR (300 MHz, CDCl₃):
δ = 5.30-5.10 (m, 9 H, H-2′-4′,2′′-4′′,2′′′-4′′′), 4.66 (m, 3 H, H-1′,1′′,1′′′), 4.33 (AB dd, J _5,6A = 5.0 Hz, J _6A,6B = 12.3 Hz, 3 H, H_A-6′,6′′,6′′′), 4.19 (s and AB dd, 9 H, 3 × CH₂S and H_B-6′,6′′,6′′′), 3.83 (m, 3 H, H-5′,5′′,5′′′), 2.94 (m, 6 H, 3 × CH ₂CH₃), 2.09, 2.05, 2.04 and 2.03 [4 s, 36 H, 12 × C(O)CH₃], 1.30 (t, 9 H, 3 × CH₂CH ₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 170.6, 170.2, 169.4 and 169.1 (12 × CO), 144.0 (C-1,3,5), 130.5 (C-2,4,6), 88.2 (C-1′,1′′,1′′′), 76.3, 73.7, 69.3 and 68.1 (C-2′-5′,2′′-5′′,2′′′-5′′′), 62.3 (C-6′,6′′,6′′′), 40.5 (3 × CH₂S), 23.4 (3 × CH₂CH₃), 20.8 (12 × OCH₃), 16.3 (3 × CHCH₃). Anal. Calcd for C₅₇H₇₈O₂₇S₆ (1387.6): C, 49.34; H, 5.67. Found: C, 49.51; H, 5.34.
1,3,5-Tri({[( R )-2- tert -Butoxycarbonylamino-2-methoxycarbonylethyl]dithio}methyl)-2,4,6-triethylbenzene (18)
TLC: R _f = 0.60 (PE-EtOAc, 50:50). Transparent oil. ^¹H NMR (300 MHz, CDCl₃): δ = 5.35 (br d, ^³ J = 8.1 Hz, 3 H, 3 × NH), 4.61 (m, 3 H, H-2′,2′′,2′′′), 4.06 and 4.03 (two AB d, ^² J = 11.8 Hz, 6 H, 3 Ž ArCH₂S), 3.75 (s, 9 H, 3 × OCH₃), 3.11 and 3.06 (two AB dd, J _1A,1B = 13.4 Hz, J _1A,2 = J _1B,2 = 4.7 Hz, 6 H, H₂-1′,1′′,1′′′), 2.88 (q, ^³ J = 7.6 Hz, 6 H, 3 × CH ₂CH₃), 1.44 [s, 27 H, 3 Ž C(CH₃)₃], 1.26 (t, 9 H, 3 × CH₂CH ₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 171.2 (3 × CO₂CH₃),155.1 (3 × NHCO), 143.9 (C-1,3,5), 130.1 (C-2,4,6), 80.2 [3 × C(CH₃)₃], 52.9 (C-2′,2′′,2′′′), 52.7 (3 × OCH₃), 41.3 and 38.5 (3 × ArCH₂S, C-1′,1′′,1′′′), 28.3 [3 × C(CH₃)₃], 23.3 (3 × CH₂CH₃), 16.0 (3 × CH₂ CH₃). Anal. Calcd for C₄₂H₆₉N₃O₁₂S₆ (1000.4): C, 50.42; H, 6.95; N, 4.20. Found: C, 50.56; H, 6.75; N, 4.26.