O Ho

326-333 ); the mechanism was selective degradation of the 1,2',3,6'-tetra-jV-acetyl-sisomicin (332) by periodate oxidation [162], and it was used, as well, for syntheses of sisomicins B and D and 5"-C-methylsisomicin B by the Koenigs-Knorr glyco-sylation method with appropriately protected glycosyl halides [163].

Aminoglycoside adenyltransferases were used by Coombe and George [126] to prepare adenylated sisomicin. In another report Kim-Wright and colleagues [164] described a glycosylation method used to prepare 2'-deoxy- and 2',3'-dideoxygenta-micin B, 2'-deaminogentamicin C1a, and 2'-deaminosisomicin from garamine and an appropriately protected glycal; all the products showed potent antibacterial activity against resistant strains. The same group has also prepared the 6"-aminogentamicin C2 (compound 336) by the intramolecular insertion reaction of the acyl nitrene group into the C-methyl group in compound 334 (partial structure). This thermal reaction

proceeds through the oxazolidinone intermediate 335, which after deprotection affords the title compound 336 [165] (compounds 334-337 ).

Philippe et al. [166] reported the use of a quinic acid derived cyclic y-amino-a-hydroxy acid related to the 1-jV-4-amino-2-hydroxybutyric acid (AHBA) to prepare a 1-N-acyl derivative of gentamicin C1a (compound 337). This new antibiotic showed less activity than gentamicin C1a against gentamicin-sensitive gram-negative organisms, but it was more active against gentamicin-resistant bacteria.

To probe the role of the 1-amino group in aminocyclitol antibiotics, the same group used the sequence of reactions outlined below to prepare the 1-deaminogen-tamicin C2 derivative 341. The free amino group of the protected gentamicin C2 derivative 338 at position 1 was formylated with ^-nitrophenyl formate to give 339 and dehydrated to isocyanide 340 in the presence of ^-toluenesulfonyl chloride, and then phosphorus oxychloride and triethylamine. This compound was finally converted to the deamino derivative 341 (compounds 338-341) by reduction with the tributyltin hydride-AIBN procedure, followed by deprotection. The deaminated analog was neither a substrate nor an inhibitor for resistance enzymes, indicating that the 1-amino group is both essential for antibacterial activity and binding to the ribosomes [167].

A 3',4'-dideoxy-3'-unsaturated derivative of neamine, made by Barton and coworkers [52], from its 3',4'-bisxanthate intermediate via radical elimination reaction, was used for the synthesis of gentamicin C1a. Streicher et al. [130] elsewhere described the synthesis of N-guanyl derivatives of gentamicins C1, C1a, and C2 at positions 2',3', and 6'. Also, metal complexion has been used by Nagabhushan and colleagues [168] to prepare 1-N-ethylsisomicin (netilmicin) from a selectively protected sisomicin derivative. Other investigators have recently reported the synthesis of 1-N-ethylsisomicin by selective protection of the 3-, 2'-, and 6'-amino groups;

Metal Ethylation
Compounds 338-341

Zn(OAc)2 • 2H2O was used in methanol for selective acetylation with Ac2O and Et3N in THF, followed by decomplexation with NH3-EtOH solution and ethylation with NaBH(OAc)3 in AcOH-CHCl3 [169].

E. Streptamine-Containing Aminoglycosides: Spectinomycins

The keto moiety of spectinomycin 342 has been converted to an amino group via a hydroxyl intermediate, leading to the (S) isomer 343 [170], or through reduction of its oxime, resulting in both (S) and (R) isomers 343 and 344 (compounds 342-344 ), respectively. The (R) epimer 344 exhibited activity comparable to that of spectinomycin, but the (S) epimer 343 showed no activity [171]. A number of 3'-N-acetylated and 3'-N-alkylated derivatives were prepared from the active isomer 344 and tested for antibacterial activity. Some of these analogs showed improved activity, and the most active analog, the V-ethyl derivative, was superior to spectinomycin in terms of activity and toxicity [172].

a-Keto rearrangement of the N-protected spectinomycin 345 to the a-hydroxyl lactone 346 in the presence of bis(tributyltin) oxide and bromine or mild acid was reported by Hanessian and Roy [173]. This product (compound 347), which is related to spectinoic acid, was further degraded to 6-deoxy-d-isosaccharino-1,4-lactone 348 (compounds 345-348 ) by methonolysis (3% MeOH-HCl).

Partially and fully N-demethylated spectinomycin analogs were also prepared by using oxygen on platinum black for catalytic N-demethylation. However, the resulting products showed reduced or no antibacterial activity [174].

A series of 6'-alkylated spectinomycin analogs (compound 349), synthesized by White et al. [175], showed an increase of activity with increasing of the lipo-philicity of the antibiotic.

Total synthesis of spectinomycin with stereocontrolled rearrangement of its analogs has been reported [176]. There are also reports of the preparation of modified spectinomycin at the 3'-position, including mono- and dihalogenated derivatives, as well as branched-chain analogues via diazoketone intermediates [177,178], and synthesis of racemic spectinomycin from a cyclohexylbutadienyl ether precursor [179]. Some of the 3'-modified derivatives showed improved activity relative to the parent antibiotic. 3' -Aminomethyldihydrospectinomycins have been synthesized via spec-tinomycin 3'-cyanohydrin intermediates [180], and the Tiffeneau-Demjanov diazo-nium ion rearrangement of the resulting 3'-aminomethyl derivative compound 350 has led to the preparation of a series of spectinomycin analogs (compounds 351,

Compounds 345-348
0 0

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