Total Synthesis And Chemical Modification Of The Aminoglycoside Antibiotics

A. 4-Substituted 2-Deoxystreptamine-Containing

Aminoglycosides: Paromamine, Neamine, Paromamine, Apramycin, and Related Compounds

1. Neamine

The quinic acid derived 2,5,6-trideoxystreptamine analogs 61 was used to prepare 5,6-dideoxyneamine (62) biosynthetically from Streptomyces fradiae [49]. The crucial intermediate for synthesis of 61 was the hydroxyketone 55, which is readily available from quinic acid. Treatment of 55 with p-toluenesulfonyl chloride in pyr-idine gave enone 56, which after catalytic hydrogenation generated the saturated ketone 57. Stereoselective reduction of 57, followed by tosylation, furnished deriv-

Compounds 53 and 54

ative 58, which underwent cyclohexylidene deprotection and selective tosylation to afford 59. Conversion of 59 to the diazo compound 60, followed by subsequent hydrogenation gave the streptamine derivative 61, which was employed to make the 5,6-dideoxyneamine 62. The intermediate 59 was also used to prepare the 3',5,6-trideoxykanamine analog 66 by a glycal coupling procedure; the glycal 63 was used for the glycosylation in the presence of a catalytic amount of boron trifluoride eth-erate to afford 64 and 65 as a mixture of a and 3 isomers, respectively, in a 7:3 ratio. The a isomer 64 was converted to 66 by sequential azide treatment, deacety-lation, and catalytic reduction (compounds 55-66 ).

Periodate oxidation has been used to prepare the sorbistin analog 68 from the appropriately protected neamine derivative 67 [50]. Likewise the acetal analog of 2-deoxystreptamine (69) was prepared by selective cleavage of the C3—C4 bond of the neosamine moiety by subsequent oxidation, followed by borohydride reduction and deprotection (compounds 67-69 ).

In an attempt to prepare potent analogs of neamine, Sitrin and colleagues [51] have synthesized a series of amino derivatives of neamine including 3'- and 4'-amino analogs, as well as their 3'- and 4'-epimers. However, all these amino neamine derivatives were found to be less active than the parent compound.

Reductive radical elimination (Barton deoxygenation) of the 3',4'-xanthate derivative of neamine (70) has been used to prepare the key intermediate 71 (compounds 70, 71) for the synthesis of the 3',4'-dideoxyneamine analog gentamine C1a [52]. In this synthesis, a precursor possessing free hydroxyl groups at positions 3' and 4' was treated with a mixture of carbon disulfide, aqueous sodium hydroxide, and methyl iodide in DMSO to afford compound 70. Subsequent reduction of 70 with tributyltin hydride furnished the olefin 71, which after catalytic hydrogenation and deprotection was converted to gentamine C1a.

The 2'-nitro-2'-deaminoneamine 73, together with a 2'-nitro derivative of kan-amycin B, have been synthesized as the first mechanism-based inactivators for ami-noglycoside phosphotransferases [27]. Compound 73 was prepared from an appropriately protected neamine derivative (72) (compounds 72, 73), using trimethylsilyl chloride for protection of 2'-amino and hydroxyl groups. Then, selective deprotection of the silyl-protected amino group followed by oxidation of the free amino group with m-chloroperoxybenzoic acid (mCPBA), and deprotection of all protective groups with trifluoroacetic acid gave the title compound 73.

Another report describes syntheses of 6'-N-substituted amino acid derivatives of neamine with alanine, phenylalanine, and lysine. These neamine analogs were

Compounds 55-66

prepared by using either an active ester method under controlled conditions, or a mixed anhydride method by blocking of all functional groups of neamine except the 6'-amino function, leaving it free for modification [53]. The same group has also reported the synthesis of 5'-epi-neamine by conversion of the C5'-aminomethyl moiety to the aldehyde function, followed by reductive amination [54].

Roestamadji et al. [24] synthesized a series of deaminated derivatives of neamine and kanamycin A to investigate the effect of electrostatic interactions in binding ability and activity of substrates bound to the active sites of aminoglycoside-modi-fying enzymes. The four deaminated analogs of neamine (compounds 74-77 ) were prepared by selective protection-deprotection of the amino groups to get tri-pro-tected derivatives (e.g., compound 78). Reductive deamination of the corresponding free amino group via an intermediary formylated derivative (e.g., compound 79) using the Barton procedure, followed by deprotection of the protecting groups, resulted in the title compounds.

Compounds 67-69
Compounds 70 and 71
Compounds 72 and 73

The neamine-derived aldehyde 81 has been prepared and used in combinatorial synthesis of a library of neomycin B mimetic aminoglycoside antibiotics, a strategy for the discovery of new inhibitors for binding to the Rev-responsive element of HIV mRNA [55]. The synthesis involves allylation of the selectively protected neamine derivative 80, followed by ozonolysis of the allylic double bond to generate the aldehyde functional group (compounds 80, 81).

Recently an azo derivative of neamine was used by the same group to prepare a series of ribostamycin and neomycin analogs [34].

The 4',4'-difluoroneamine (compound 82) was recently synthesized from an appropriately protected neamine derivative having the 3'-hydroxyl group free for

Compounds 74-79
Compounds 80 and 81
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