Total synthesis and study of 6-deoxyerythronolide B by late-stage C-H oxidation

Abstract

Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C-H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C-H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C-H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C-O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C-H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core.

Figure 1. Macrocyclization approaches to macrolide antibiotics

a, Structures and approaches towards the erythronolides. b, A general strategy for reducing the “oxygen load” in a linear sequence through the use of late-stage C—H oxidation. c, Possible π-allylPd(carboxylate) intermediates for C—H macrolactonization. d, Energy minimized structures of macrolides 1 and epi-1 using MMFF94s force field implemented in Molecular Operating Environment (MOE). FG, functional group; PMP, p-methoxyphenyl.

Figure 2. Synthesis of C—H macrolactonization precursor 2

(a) LDA (2.1 equiv), LiCl (6.0 equiv), allyl iodide (1.5 equiv), −78°C, >20:1 d.r., 96% (b) NH₃BH₃ (4.0 equiv), LDA (4.0 equiv), 0°C, 98% (c) oxalyl chloride (1.3 equiv), NEt₃ (5.0 equiv), DMSO (1.6 equiv), −78°C (d) 5 (1.0 equiv), Bu₂BOTf (1.2 equiv), i-Pr₂NEt (1.4 equiv), −78°C, >20:1 d.r., 55% (2-steps) (e) AlMe₃ (5.0 equiv), (MeO)NHMe-HCl (5.0 equiv), −10°C, 86% (f) PMBBr (1.8 equiv), NaH (1.8 equiv), 0°C, 96% (g) Dibal-H (2.0 equiv), −78°C, 91% (h) 7 (1.0 equiv), Bu₂BOTf (1.2 equiv), NEt₃ (1.2 equiv), −78°C, >20:1 d.r., 96% (i) DDQ (1.2 equiv), MgSO₄ (14.0 equiv), >20:1 d.r., 93% (j) LAH (3.0 equiv), −78°C, 96% (k) PPh₃ (1.2 equiv), I₂ (1.4 equiv), imidazole (1.5 equiv), 94% (l) 4 (2.1 equiv), LDA (4.0 equiv), LiCl (12.7 equiv), 0°C, >20:1 d.r., 94% (m) NH₃BH₃ (4.0 equiv), LDA (4.0 equiv), 0°C, 99% (n) DMP (1.6 equiv), 96% (o) 10 (1.5 equiv), TiCl₄ (1.2 equiv), Ti(Oi-Pr)₄ (0.4 equiv), NEt₃ (1.6 equiv), −78°C, 95:5 d.r., 88% (p) Zn(BH₄)₂ (1.6 equiv), −78°C, >20:1 d.r., 75–86% (q) CSA (cat.), 2,2-dimethoxypropane (9.8 equiv), 84% (r) LiOOH_(aq) (2.0 equiv), 0°C, 99%. A, auxiliary number one; PMB, p-methoxybenzyl; LDA, lithium diisopropylamide; LAB, lithium amidotrihydroborate; DMSO, dimethylsulfoxide; OTf, trifluoromethanesulfonate; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LAH, lithium aluminum hydride; DMP. Dess-Martin periodinane; CSA, camphorsulfonic acid.

Figure 3. Synthesis of macrolides 1 and epi-1

Reaction conditions: (a) 3 (0.3 equiv), BQ (2.0 equiv), 45°C, 72 h, >40:1 d.r., 34% + 45% r.s.m. (56% + 8% r.s.m., 2x recycle) (b) 3 (0.3 equiv), BQ (2.0 equiv), TBAF (0.3 equiv), 45°C, 72 h, 1:1.3 d.r., 20% + 75% r.s.m. (44% + 36% r.s.m., 2x recycle) (c) 3 (0.1 equiv), BQ (2.0 equiv), p-NO₂BzOH (1.5 equiv), 45°C, 72 h, 1:1 d.r., 73% (combined) (d) LiOOH_(aq) (2.0 equiv) (e) K₂CO₃ (3.0 equiv), MeOH, 97% (2-steps) (f) Cl₃C₆H₂COCl (15.0 equiv), i-Pr₂NEt (20.0 equiv), DMAP (40.0 equiv), Benzene, 87%. BQ, 1,4-benzoquinone; r.s.m., recovered starting material; TBAF, tetra-n-butylammonium fluoride; p-NO₂BzOH, p-nitrobenzoic acid; DMAP, N,N-4-dimethylaminopyridine.

Figure 4. Synthesis of 6-deoxyerythronolide B

Reaction conditions for completing the synthesis of 6-dEB and its triacetate derivative 13 (X-ray crystallographic analysis shown): (a) Pd(OH)₂/C (cat.), H₂ (1 atm), i-PrOH, 96% (b) TPAP (cat.), NMO (5.0 equiv), 0°C, 84% (c) 1M HCl_(aq) (11 equiv), 98% (d) Ac₂O (93.0 equiv), DMAP (cat.), Pyridine, 96%. TPAP, tetra-n-propylammonium perruthenate; NMO, N-methylmorpholine oxide.