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Synlett 2009(15): 2503-2507  
DOI: 10.1055/s-0029-1217742
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Improved Convergent Synthesis of 5′-epi-Analogues of Muraymycin Nucleoside Antibiotics

Anatol P. Spork, Stefan Koppermann, Christian Ducho*
Institute of Organic and Biomolecular Chemistry, Department of Chemistry, Georg-August-University Göttingen, Tammannstr. 2, 37077 Göttingen
Fax: +49(551)399660; e-Mail: cducho@gwdg.de;
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Publication History

Received 8 June 2009
Publication Date:
27 August 2009 (online)

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Abstract

Nucleoside antibiotics represent a promising class of natural products for the development of novel antibacterial agents, with particular respect to structurally simplified analogues maintaining biological activity. There are established truncated 5′-epi-derivatives of muraymycin nucleoside antibiotics with reported antibacterial properties, but the lengthy preparation of such compounds is a major hurdle in more detailed structure-activity relationship (SAR) studies. A concise, improved synthesis of truncated 5′-epi-muraymycins based on a previously reported approach using sulfur ylide chemistry is reported here. The highly convergent nature of this strategy will allow the efficient synthesis of novel muraymycin analogues for thorough SAR investigations.

Key words

antibiotics - medicinal chemistry - MraY inhibitors - natural products - nucleosides

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14

Synthesis of Ester-Derived Sulfonium Salts
A solution of the respective alkyl bromoacetate in degassed dimethylsulfide (tert-butyl, n-propyl and benzyl esters) or in acetone-dimethylsulfide (methyl ester) was stirred at r.t. for 2 d. The precipitated product was subsequently filtered off, washed with n-hexane or PE, and dried in vacuo. With exception of the tert-butyl ester derivative, the obtained sulfonium salts still contained significant amounts of trimethylsulfonium bromide, but could be used for sulfur ylide generation in crude form. The ethyl ester derivative was commercially available.

16

Synthesis of Epoxy Ester 17 via ‘Direct’ Sulfur Ylide Reaction
A solution of sulfonium salt 18 (430 mg, 1.67 mmol) in dry THF (10 mL) was stirred over 4 Å MS at r.t. for 2 h to remove any traces of H2O from the hygroscopic sulfonium salt. Sodium hydride (60% suspension in mineral oil, 68 mg, 1.7 mmol) was then added at 0 ˚C, and the mixture was stirred at r.t. for 4 h. After filtration and evaporation of the solvent under reduced pressure, the obtained sulfur ylide was dissolved in dry CH2Cl2 (2 mL). This solution of the sulfur ylide was added in aliquots (0.5 mL each) at 0 ˚C over a period of 4 h to a stirred solution of uridine aldehyde 13 (99 mg, 0.168 mmol, freshly prepared by IBX oxidation of protected uridine 9 in MeCN) in dry CH2Cl2 (2 mL). After addition of more CH2Cl2 (25 mL) and H2O (25 mL), the aqueous layer was extracted with EtOAc (25 mL). The combined organics were dried over Na2SO4, and the solvent was evaporated under reduced pressure. The resultant crude product was purified by column chromatography (PE-EtOAc, 9:1) to give 17 (93 mg, 79%) as a colourless solid; mp 71 ˚C. TLC: R f = 0.50 (PE-EtOAc, 7:3). [α]D ²0 +31.6 (c 1.3, CHCl3). ¹H NMR (300 MHz, C6D6): δ = -0.06 (s, 3 H, SiCH3), -0.01 (s, 3 H, SiCH3), 0.07 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 0.93 [s, 9 H, SiC(CH3)3], 1.33 [s, 9 H, OC(CH3)3], 3.24 (s, 3 H, OCH3), 3.39 (dd, J = 1.3, 1.3 Hz, 1 H, 5′-H), 3.65 (d, J = 1.3 Hz, 1 H, 6′-H), 3.97 (dd, J = 4.3, 4.3 Hz, 1 H, 3′-H), 4.06 (dd, J = 4.3, 1.3 Hz, 1 H, 4′-H), 4.10 (dd, J = 4.3, 4.3 Hz, 1 H, 2′-H), 5.04 (d, J = 13.3 Hz, 1 H, PMB-CH2-Ha), 5.12 (d, J = 13.3 Hz, 1 H, PMB-CH2-Hb), 5.46 (d, J = 8.1 Hz, 1 H, 5-H), 6.10 (d, J = 4.3 Hz, 1 H, 1′-H), 6.72 (d, J = 8.2 Hz, 2 H, PMB-3-H, PMB-5-H), 7.42 (d, J = 8.1 Hz, 1 H, 6-H), 7.67 (d, J = 8.2 Hz, 2 H, PMB-2-H, PMB-6-H). ¹³C NMR (75 MHz, C6D6): δ = -5.1 (SiCH3), -4.7 (SiCH3), -4.5 (SiCH3), -4.5 (SiCH3), 18.2 [SiC(CH3)3], 25.9 [SiC(CH3)3], 26.0 [SiC(CH3)3], 27.8 [OC(CH3)3], 43.7 (PMB-CH2), 51.2 (C-6′), 54.6 (OCH3), 56.9 (C-5′), 73.7 (C-3′), 75.6 (C-2′), 78.9 (C-4′), 82.5 [OC(CH3)3], 89.2 (C-1′), 102.7 (C-5), 114.0 (PMB-C-3, PMB-C-5), 129.8 (PMB-C-1), 131.5 (PMB-C-2, PMB-C-6), 136.5 (C-6), 151.4 (C-2), 159.7 (PMB-C-4), 161.8 (C-4), 167.1 (ester C=O). MS (ESI+): m/z = 727.4 [M + Na]+. HRMS (ESI+): m/z calcd. for C35H56N2O9Si2: 705.3597 [M + H]+; found: 705.3597 [M + H]+. IR (KBr): ν = 2932, 1671, 1514, 1456, 1392, 1250, 1162, 839, 778 cm-¹. UV (MeCN): λmax (lg ε) = 194 (4.69), 222 (4.13), 262 (3.96).

17

When a procedure similar to the one used for the synthesis of 15 via route A (Scheme  [²] ) with in situ generation of the sulfur ylide from 18 was applied, epoxy ester 17 could also be obtained, though in lower yield (60%).

18

Aldehyde 20 was also converted into the respective epoxy ester product using transformations according to route A in Scheme  [²] as reported previously.9