Studies toward the Total Synthesis of Sorangicins: Asymmetric Synthesis of the Key Fragments

Abstract

Efficient synthesis of the key fragments of the complex antibiotics class of sorangicins (Scheme [1] ) is described. Starting from simple compounds fragments I, II, and IV can be synthesized. For fragment III we chose an approach via l-glucal.

sorangicin - asymmetric synthesis - tetrahydropyran - ­bicyclic ether - macrolide - antibiotic activity

References

1

Present address: Schering AG, Müllerstraße 170-178, 13353 Berlin, Germany.

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Procedure for the Preparation of (1 R ,3 R ,4 R ,5 R ,7 R )-7-Benzyloxymethyl-4-methyl-2,6-dioxa-5,1-bicyclo[3.2.1]oct-3-yl-methoxytriisopropylsilane ( 15): To a stirred solution of 13 (12 mg, 0.023 mmol) in 1.5 mL THF cooled to -78 °C was added dropwise KHMDS (0.52 µL of 0.5 M solution in hexane, 0.026 mmol). After stirring at this temperature for 2 h, 0.6 mL sat. NH₄Cl solution was added and the mixture was allowed to warm to r.t. The product was then extracted with Et₂O, and the organic layer washed with brine and dried. The solvent was removed on a rotary evaporator, and the residue was flash-chromatographed (pentane-methyl-tert-butylether, 3:1) to give 7 mg of 15 (93%) as a colorless oil. Analytical data for 15: ¹H NMR (400 MHz, CDCl₃): δ = 7.38-7.26 (m, 5 H, H-11), 4.65-4.57 (m, 2 H, H-10), 4.36-4.34 (m, 1 H, H-7), 4.22 (d, J = 6.5 Hz, 1 H, H-5), 4.08 (dt, J = 2.3, 6.5 Hz, 1 H, H-8), 3.84-3.76 (m, 2 H, H-9), 3.71 (dq, J = 3.2, 11 Hz, 2 H, H-1), 3.47 (dt, J = 3.2, 7.1 Hz, 1 H, H-2), 1.99-1.94 (m, 1 H, H-6), 1.81 (dd, J = 1.5, 11.5 Hz, 1 H, H-6), 1.76-1.68 (m, 1 H, H-3), 1.05 (s, 21 H, H-12), 0.94 (d, J = 6.7 Hz, 3 H, H-4). ¹³C NMR (100 MHz, CDCl₃): δ = 138.34 (s, C-11), 128.32 (d, C-11), 127.69 (d, C-11), 81.71 (d, C-8), 79.52 (d, C-5), 79.16 (d, C-2), 74.52 (d, C-7), 73.27 (t, C-10), 68.39 (t, C-9), 65.22 (t, C-10), 38.15 (t, C-6), 37.00 (d, C-3), 17.99 (dq, C-12), 16.04 (q, C-4), 12.02 (dq, C-12). IR (neat): 2927, 2866, 1496, 1463, 1380, 1258, 1129, 1100, 1066, 1017, 883, 661 cm^-1. MS (CI): m/z = 435.1 (100) [M + H]⁺, 391.2 (89), 357.2 (7), 309.2 (10), 261.2 (50), 243.2 (10), 191.1 (6), 119.1 (10), 91.1 (28). HRMS: m/z calcd for C₂₅H₄₂O₄Si [M]⁺: 434.2852. Found: 434.2853.

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Krug, O., planned thesis, University of Magdeburg, 2004.