A New Convergent Approach to Biphenomycin Antibiotics

Abstract

A new, convergent approach to the biaryl key intermediate of Schmidt’s biphenomycin B total synthesis has been accomplished via a palladacycle complex catalyzed Stille cross-coupling of two o-tyrosine building blocks.

Key words

biphenomycins - antibiotics - cyclopeptides - asymmetric synthesis - Stille coupling

References

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8

Benzylbromide 8 was prepared from 5-iodo-salicylic acid in 40% overall yield as indicated in Scheme [6] .

9

( S )-2-Amino-3-(2-benzyloxy-5-iodophenyl)propionic acid(11): Colourless crystals, mp 228-230 °C (decomp.). [α]_D ²⁰ = -11.8 (c 0.11, MeOH); ¹H NMR (500 MHz, CD₃OD): δ = 2.89 (dd, J = 9.2/14.3 Hz, 1 H, CH ₂CH), 3.41 (dd, J = 4.7/14.3 Hz, 1 H, CH ₂CH), 3.89 (dd, J = 4.7/9.2 Hz, 1 H, CH₂CH), 5.18 (s, 2 H, OCH₂), 6.86 (d, J = 8.6 Hz, 1 H, H_arom), 7.28-7.49 (m, 5 H, H_arom), 7.54 (dd, J = 2.2/8.6 Hz, 1 H, H_arom), 7.57 (d, J = 2.2 Hz, 1 H, H_arom); ¹³C NMR (125 MHz, CD₃OD): δ = 33.5, 56.2, 71.3, 83.9, 115.9, 128.7, 128.9, 129.2, 129.8, 138.2, 138.8, 141.0, 158.3, 173.6; MS (MALDI): m/z = 398 [M + 1]. HRMS (CI, CH₅ ⁺): Anal. Calcd for C₁₆H₁₆NO₃I (M + H⁺): 398.0253; Found: 398.0253.

18

In addition to 20, 21 and 22 small amounts of the respective aryl iodide homocoupling product i (1-7%) and in case of entries 1-4 product ii (3-6%), which arises from aryl transfer by the arsine, were also obtained (Figure [2] ).

21

Stille coupling of 5b and 6: A solution of 5b (29.5 mg, 37 mol) in degassed NMP (0.14 mL) was added to a stirred mixture of anhydrous LiCl (4.3 mg, 102 mol), 6 (20.0 mg, 34 mol) and 23 (1.6 mg, 1.7 mol) in degassed NMP (0.2 mL) at room temperature. The reaction mixture was heated at 90 °C for 14 h. After cooling to room temperature, the reaction mixture was diluted with CH₂Cl₂ and filtered through a pad of silica gel. The filtrate was washed with aqueous 1.3 M phosphate buffer pH 7.0 and water, dried (MgSO₄) and concentrated under reduced pressure. The resulting residue was purified by prep. HPLC (LiChrosorb^® Si 60 5 µm, n-heptane-EtOAc, 85:15) to give 20.9 mg (64%) 3 as a colourless solid.
3: [α]_D ²⁰ = +10.3 (c = 0.95, CHCl₃); lit. [5a] : [α]_D = +11.2. ¹H NMR (500 MHz, CDCl₃) δ = -0.03 [s, 9 H, Si(CH₃)₃], 0.85-0.91 (m, 2 H, CH₂CH ₂Si), 1.35 [s, 9 H, C(CH₃)₃], 3.06-3.14 (m, 2 H, CHCH ₂), 3.18-3.26 (m, 2 H, CHCH ₂), 4.05-4.21 (m, 2 H, CH ₂CH₂Si), 4.56-4.67 (m, 2 H, CHCH₂), 4.95-5.17 (m, 8 H, OCH₂Ph), 5.38 (d, 1 H, J = 7.8 Hz, NHBoc), 5.61 (d, 1 H, J = 7.7 Hz, NHZ), 6.91 (d, 1 H, J = 8.6 Hz, H_arom), 6.94 (d, 1 H, J = 8.6 Hz, H_arom), 7.19-7.38 (m, 20 H, H_arom.), 7.42-7.48 (m, 4 H, H_arom).