Total Synthesis of Kibdelomycin

Abstract

A modular total synthesis of kibdelomycin is disclosed that should enable structure-activity relationship (SAR) studies of this interesting class of antibiotics. The route uses simple building blocks and addresses lingering questions about its structural assignment and relationship to amycolamicin, a recently described natural product reported to have a similar structure. Initial antibacterial assays reveal that both C-22 epimers (the N-glycosidic linkage) of the natural product have similar activity while structurally truncated analogs lose activity.

Keywords: Antibiotics; Glycosidation; Modular Synthesis; Total Synthesis.

Figure 1

Structure and retrosynthetic analysis of kibdelomycin.

Scheme 1

Synthesis of intermediates 14 and 23. Reagents and conditions: A) 1) BnOH (10.0 equiv), pTsOH (0.1 equiv), 80 °C, overnight; 2) 2,2‐dimethoxypropane (3.0 equiv), pTsOH (0.2 equiv), DMF, rt, overnight, 50 % (2 steps); 3) DMP (1.75 equiv), DCM, rt, 2 h; 4) DIBAL (2.5 equiv), THF, −78 °C to rt, overnight, 87 % (2 steps); 5) MeI (6.0 equiv), Ag₂O (3.0 equiv), CH₃CN, 75 °C, overnight, 83 %; 6) 80 % aq. AcOH, 80 °C, 1 h; 7) Ac₂O (1.05 equiv), Et₃N (1.1 equiv), DMAP (0.05 equiv), DCM, rt, overnight, 80 % (2 steps); 8) 12 (2.0 equiv), DCM, 0 °C to rt, 1 h, 95 %; 9) Pd/C (10 % w/w), EtOAc, rt, 3 h; 10) H₂N‐Val‐OMe (1.8 equiv), PPTS (0.2 equiv), DCM, rt, 6 h, 84 % (2 steps). B) 1) 16 (1.4 equiv), THF, 0 °C, 4 h, 93 %; 2) (S)‐CBS (2.0 equiv), BH₃⋅THF (2.2 equiv), THF, −78 °C, 5 h, 88 % yield, 99 % ee; 3) TBSCl (1.5 equiv), imidazole (3.0 equiv), DMF, 50 °C, overnight, 93 %; 4) 9‐BBN (1.4 equiv), THF, 0 °C to rt, 5 h, then NaBO₃⋅4H₂O (4.0 equiv), H₂O, 0 °C to rt, overnight, 96 %; 5) DMP (1.4 equiv), DCM, rt, 2.5 h, 78 %; 6) Bn₂NCH₂OMe (1.1 equiv), L‐proline (0.2 equiv), DMF, 0 °C to rt, 2 h, then SiO₂, DCM, rt, 5 h, 85 %; 7) 20 (1.8 equiv), DCM, 45 °C, 24 h, 97 %; 8) TBAF⋅3H₂O (2.0 equiv), THF, 0 °C to rt, 2 h, 99 %; 9) Me₂AlCl (1.0 equiv), DCM, −20 °C to rt, 18 h, 51 %. Bn=benzyl, pTsOH=p‐toluenesulfonic acid, DMF=N,N‐dimethylformamide, DMP=Dess–Martin periodinane, DCM=dichloromethane, DIBAL=diisobutylaluminum hydride, THF=tetrahydrofuran, Ac=acetyl, DMAP=N,N‐4‐dimethylaminopyridine, PPTS=pyridinium p‐toluenesulfonate, CBS=Corey–Bakshi–Shibata reagent, TBSCl=tert‐butyldimethylsilyl chloride, 9‐BBN=9‐borabicyclo[3.3.1]nonane, TBAF=tetra‐n‐butylammonium fluoride.

Scheme 2

Total Synthesis of kibdelomycin (1 b). Reagents and conditions: For the synthesis of compound 24, see step 1–3 in Supporting Information; 4) n‐BuLi (1.1 equiv), Et₂O, −40 °C, 1 h, then 25 (1.2 equiv), −78 °C to rt, 2 h, 78 % (d.r. 5.5 : 1); 5) TBAF⋅3H₂O (2.0 equiv), THF, rt, 0.5 h, 98 %; 6) MB (0.0014 equiv), O₂, DCM, −78 °C, 2.5 h, then Me₂S (5.0 equiv), −78 °C to rt, 2 h, 92 %; 7) pTsOH (0.2 equiv), TCEOH, rt, 1.5 h, then HCl (2.0 equiv), rt, 1.5 h, then HATU (2.0 equiv), 28 (2.0 equiv), DIPEA (5.5 equiv), DMF, rt, 8 h, 44 % (d.r. 6 : 1); 8) NaBH₄ (4.0 equiv), CeCl₃⋅7H₂O (0.4 equiv), MeOH, 0 °C, 20 min, 88 %; 9) CF₃CO₃H (1.36 equiv), DCM, −40 °C to rt, 2 h, 43 %; 10) LiBH₄ (6.0 equiv), toluene, 60 °C, 3 h, 53 % S9+16 % 30; 11) TBSOTf (6.0 equiv), Et₃N (10.0 equiv), DCE, 7 h, 56 %; 12) 23 (2.0 equiv), 4 A MS, TfOH (1.0 equiv), DCM, rt, 2.5 h, 65 % (1.6 : 1, β:α); 12′) 23 (2.0 equiv), TCEOH (1.0 equiv), 4 A MS, TfOH (2.0 equiv), DCM, rt, 2.5 h, 70 % (1.5 : 1, β:α); 13) LiHMDS (20.0 equiv), CO(SMe)₂ (12.0 equiv), THF, −78 to 30 °C, 6.5 h, 78 % 34+13 % 33; 14) 14 (3.0 equiv), 4 A MS, AgTFA (5.0 equiv), THF, rt, 2 h; 15) Et₃N (5.0 equiv), MeOH, rt, 10 min, then TBAF (8.0 equiv), THF, rt, 0.5 h, 41 % (2 steps); 16) 0.1 % HCO₂H (4.4 equiv) in MeCN/H₂O, rt, 24 h, 78 % (4 : 3, 35/1 b). Bu=butyl, MB=methylene blue, TCE=trichloroethyl, HATU=O‐(7‐azabenzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium hexafluorophosphate, DIPEA=diisopropylethylamine, AgTFA=silver trifluoroacetate, Tf=trifluoromethanesulfonyl, DCE=dichloroethane, LiHMDS=lithium bis(trimethylsilyl)amide.

Figure 2

¹H NMR comparison of kibdelomycin and amycolamicin at varying pH (spectra taken in CD₃OD).