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A platform for the discovery of new macrolide antibiotics

Abstract

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

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Figure 1: Summary of macrolide antibiotic development by semisynthesis.
Figure 2: A convergent, fully synthetic route to the 14-membered azaketolide 25.
Figure 3: A convergent, fully synthetic route to the 15-membered azaketolide 38.
Figure 4: A convergent, fully synthetic route to solithromycin.
Figure 5: Structures of selected fully synthetic macrolide antibiotics, and their MICs compared to those of natural and semisynthetic macrolide antibiotics.

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Data deposits

Atomic coordinates and structure factors for the crystal structure reported have been deposited with the Cambridge Crystallographic Database under accession number CCDC 1440650.

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Acknowledgements

We acknowledge funding from Alistair and Celine Mactaggart, from the Gustavus and Louise Pfeiffer Research Foundation, and from the Blavatnik Biomedical Accelerator Program at Harvard University. We thank NERCE (NIH project number U54 AI057159), W. Weiss (Univ. North Texas), and R. Alm and S. Lahiri (Macrolide Pharmaceuticals) for measuring MIC values, R. Alm and T. Dougherty (Harvard Medical School) for genetic characterization of a microbial resistance gene, and S.-L. Zheng (Harvard University) for conducting X-ray crystallographic analyses. I.B.S. acknowledges postdoctoral fellowship support from the National Institutes of Health (F32GM099233); Z.Z. is a Howard Hughes Medical Institute International Student Research fellow; A.L.-M. acknowledges postdoctoral fellowship support from the Swiss National Science Foundation (PBGEPE2-139864) and the Novartis Foundation; D.T.H. is indebted to the Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral fellowship (HO 5326/1-1); T.F. acknowledges Daiichi-Sankyo Co., Ltd, for financial support; and Y.K. acknowledges support from the Engineering Promotion Fund of Gifu University.

Author information

Authors and Affiliations

Authors

Contributions

I.B.S., Z.Z. and A.G.M. identified the targets and designed the synthetic routes; I.B.S. and Z.Z. executed and optimized the synthetic routes described in the main text; I.B.S., Z.Z., P.J., P.M.W., A.L.-M. and D.T.H. executed the synthetic routes shown in the Extended Data; I.B.S., Z.Z., P.J., P.M.W., A.L.-M., D.T.H., K.Y., T.F., P.N.C., X.Z., M.L.C., F.T.S. and W.D.G. synthesized individual macrolide analogues; I.B.S., Z.Z., Y.K. and S.R.A. synthesized and scaled the building blocks. I.B.S., Z.Z. and A.G.M. wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Andrew G. Myers.

Ethics declarations

Competing interests

I.B.S., Z.Z. and A.G.M. have filed three provisional patents and an international patent application: US 62/061571, ‘14-Membered Ketolides and Methods of Their Preparation and Use’; US 62/138198, ‘Macrolides with Modified Desosamine Sugars and Uses Thereof’; US 62/214774, ‘Right Half Synthesis of 14-Membered Azaketolides’; PCT/US2014/033025, ‘Macrolides and Methods of Their Preparation and Use’. A.G.M. declares that he is a founder, board member, and chairman of the scientific advisory board of Macrolide Pharmaceuticals, and Z.Z. and I.B.S. declare that they serve as scientific consultants to Macrolide Pharmaceuticals.

Extended data figures and tables

Extended Data Figure 1 Synthesis of a C2-fluoro 14-membered azaketolide by a late-stage fluorination reaction.

Subjection of β-keto lactone 25 (FSM-22367) to potassium tert-butoxide (1.0 equiv.) at −78 °C followed by N-fluorobenzenesulfonimide (1.0 equiv.) afforded 50 (FSM-22391) in 43% yield.

Extended Data Figure 2 Synthesis of a 15-membered azaketolide with a modified C2-substituent.

Thermolysis of a β-keto tert-butyl ester substrate (55) proceeded at a lower temperature (80 °C) than that for dioxolenone substrates (132 °C) and afforded a 15-membered macrocycle without substitution at C2 (56). (Here and elsewhere we omit mention of the intermediate compounds for clarity.) This macrocycle served as a nearly ideal intermediate for preparation of macrolides with diverse C2-substitutions. For example, an allyl group was introduced at C2 by treatment of 56 with sodium tert-butoxide (1.1 equiv.) and allyl iodide (1.1 equiv.) at −40 °C followed by warming the reaction solution to 23 °C. The product 57 (obtained in 62% yield) was then transformed to 59 (FSM-56156) in two steps (via 58; 72% yield).

Extended Data Figure 3 Synthesis of a 15-membered azacethromycin hybrid.

Macrolactone 63 was prepared from amine 60 and aldehyde 61 in two steps (via 62) by a reductive amination–macrocyclization sequence. Treatment of 63 with paraformaldehyde (6.0 equiv.) and acetic acid (10.0 equiv.) furnished adduct 64 as a crystalline solid (84% yield; X-ray structure shown). The imidazolidine group within 64 served to protect both the secondary amine and the cyclic carbamate functions, and permitted the introduction of a quinoline heterocycle via a Heck reaction. Methanolysis (TFA, CH3OH) cleaved the imidazolidine group, affording 65 (FSM-20919; 29%, two-step yield).

Extended Data Figure 4 Synthesis of a 15-membered azaketolide with a modified C10-substituent.

N-tert-butylsulfinyl imine 68 (prepared in five steps via 66 and 67 from amide 10) allowed for the stereocontrolled introduction of various C10-substituents. For example, addition of allylmagnesium bromide proceeded with >20:1 stereoselectively to establish the stereocentre at C10; subsequent cleavage of the sulfinyl (HCl, CH3OH) and tert-butyldiphenylsilyl (Bu4NF) groups within the adduct then furnished left-hand intermediate 69 (81% yield). Amine 69 and aldehyde 35 were coupled by a reductive amination reaction (NaBH3CN, 60%–75% yield). The product (70) was then transformed to 73 (FSM-11044) in a three-step sequence that consisted of a macrocyclization reaction (giving 71; 72% yield), a methanolysis reaction (giving 72 in quantitative yield) and lastly a [3 + 2] dipolar cycloaddition reaction (giving 73 in 92% yield).

Extended Data Figure 5 Synthesis of a 15-membered azaketolide with a modified C13-substituent.

Modification of position C13 was achieved by modification of a single component, in this case the ketone building block 74 depicted above. Reductive coupling of 78 and 35 united the left- and right-halves to give 79; subsequent thermal macrocyclization provided macrolactone 80. The allyl group within intermediate 80 was cleaved upon ozonolysis (O3, trifluoroacetic acid); reductive workup with sodium cyanoborohydride afforded alcohol 81. Subjection of 81 to bis(2-methoxyethyl)aminosulfur trifluoride afforded the fluoroethyl-substituted macrocycle 82 (30%, two-step yield), which was transformed to 83 (FSM-11453) by a [3 + 2] dipolar cycloaddition reaction.

Extended Data Figure 6 Synthesis of a 15-membered azaketolide with a modified desosamine sugar residue.

The 15-membered macrolactone 90 was synthesized using thioglycoside 84 and alkyne 89 as building blocks (in lieu of building blocks 28 and 8 used for the synthesis of 15-membered azaketolide FSM-20707). Treatment of 90 with tributyltin hydride (2.0 equiv.), acetic acid (5.0 equiv.), and tetrakis(triphenylphosphine)palladium (2 mol%) led to cleavage of the allyloxycarbonyl protective group, giving rise to amine 91 (92% yield). The latter intermediate has been transformed into a number of fully synthetic macrolides with modified desosamine sugar residues. For example, acylation of the primary amino group of intermediate 91 with pyridine-2-carbonyl chloride (2.0 equiv.) in the presence of trimethylamine (3.0 equiv.) followed by removal of the tert-butoxycarbonyl group afforded 92 (FSM-21887, 86%, two-step yield).

Extended Data Figure 7 Synthesis of a 16-membered azaketolide.

Homologation of aldehyde 35 was achieved by a Wittig olefination reaction (CH3OCH3PPh3+ Cl, NaHMDS) followed by hydrolysis of the resulting enol ether to afford aldehyde 93 in 65% yield. Reductive coupling of amine 15 and aldehyde 93 furnished macrocyclization precursor 94 (73% yield). The 16-membered macrolactone 95 was obtained in 78% yield upon thermolysis of 94 (1 mM, 132 °C). Two additional steps transformed 95 via 96 to the 16-membered azaketolide 97 (FSM-21397).

Extended Data Figure 8 Synthesis of a 14-membered macrolide with a trans-olefin linkage.

Mesylate 98 was prepared in quantitative yield by treatment of alcohol 34 with methanesulfonyl chloride (1.50 equiv.) and triethylamine (2.0 equiv.). Displacement of the mesylate group in 98 with sodium 1-phenyl-1H-tetrazole-5-thiolate (2.0 equiv.) followed by oxidation of the resulting thioether with ammonium molybdate (0.20 equiv.)–hydrogen peroxide (100 equiv.) afforded sulfone 100 in 70% yield. Aldehyde 101 and sulfone 100 were coupled in a Julia–Kocienski olefination reaction (NaHMDS, −78 → 23 °C) to provide a 4.8:1 mixture of E- and Z-olefin isomers. The E-isomer 102 was isolated and desilylated (Bu4NF, 79%). Thermolysis of the product 103 (1 mM, 132 °C) furnished the 14-membered macrocycle 104 in 83% yield. 104 was then transformed to 106 (FSM-21079) in two additional steps (methanolysis and [3 + 2] dipolar cycloaddition) via 105.

Extended Data Figure 9 Synthesis of a 15-membered macrolide with an amide linkage (C9-N9a).

Oxidation of aldehyde 35 with sodium chlorite (10.0 equiv.) in the presence of sodium dihydrogen phosphate (10.0 equiv.) and 2-methyl-2-butene (100 equiv.) afforded carboxylic acid 107 in 70% yield. Acid 107 and amine 15 were coupled in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.00 equiv.) to provide amide 108. Macrocyclization of 108 (1 mM, 132 °C) proceeded in 81% yield to afford macrolactam 109. Methanolysis and [3 + 2] dipolar cycloaddition then transformed 109 to 111 (FSM-21344) in two steps via 110.

Extended Data Figure 10 Synthesis of a 15-membered macrolide with an amide linkage (C10-N9a).

Amine 112 was prepared in 70% yield by displacement of the mesylate group in 98 with sodium azide followed by reduction of the resulting alkyl azide (H2, Pd). The coupling of amine 112 and acid 113 proceeded in 54% yield. The product, amide 114, was desilylated (Bu4NF, 80%) to afford the macrocyclization precursor 115. Thermal macrocyclization of 115 followed by cleavage of the methoxycarbonyl protective group afforded lactam 116 in 80% yield. Copper-catalysed [3 + 2] dipolar cycloaddition then provided 117 (FSM-21473) in 64% yield.

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Seiple, I., Zhang, Z., Jakubec, P. et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016). https://doi.org/10.1038/nature17967

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