Negamycin synthesis

Naturally occurring chiral compounds provide an enormous range and diversity of possible starting materials. To be useful in asymmetric synthesis, they should be readily available in high enantiomeric purity. For many applications, the availability of both enantiomers is desirable. Many chiral molecules can be synthesized from natural carbohydrates or amino acids. The syntheses of (+)-exo-brevicomin (66) and negamycin (67) illustrate the application of such naturally occurring materials. 

The unsaturated ester-aldehyde 79 was also used for the synthesis of methyl 3,6-bis(acetamido)-2,3,4,6-tetradeoxy-a-DL-fhreo-hexo-pyranoside40 (87), an intermediate for the synthesis of negamycin and of methyl 3-N-acetyM-deoxy-a-DL-daunosaminide41 (88). 

The /rflm -/V-silylated tetrahydro-2//-l, 3-oxazin-2-one 27 (R = TBDMS) has been utilized in the synthesis of (+ )-negamycin (28)15, a compound which shows a strong inhibitory activity against Gram-negative bacteria. 

Recently, analogous nitrones have been used by others in the synthesis of (2S)-4-oxopipecolic acid [45] and (-l-)-negamycin [46]. Chiacchio et al. [47] applied the Vasella-type nitrone 53 in an enantioselective synthesis of isoxazolidinyl thymine 55 (Scheme 10.18). As illustrated, the A-furanosyl nitrone 53 reacted with vinyl acetate to give a 1 1 mixture of two isoxazolidines 54 epimeric at C-5. In contrast to the poor cw/tran -diastereoselectivity, the diastereofacial selectivity... 

Kasahara, K, lida, H, Kibayashi, Ch., Asyimnetric total synthesis of (+)-negamycin and (—)-3-epinegamycin via enantioselective 1,3-dipolar cycloaddition, J. Org. Chem., 54, 2225-2233, 1989. 

Furanomycin has been shown to have the structure (35) by a synthesis from 2,5-anhydro-L-idose, which is summarized in Scheme 5. The quino-glycosides (36), which are bacteriocides and fungicides, have been synthesized by condensation of 2-methyl quinolinuim salts with peracetylated aldoses. The synthesis of the aminohexonhydrazide antibiotic negamycin is covered in Chapter 8,... 

A similar approach was taken to the synthesis of (+)-Negamycin Palladium(ll) assisted alkylation of the optically active enamide 15 followed by carbonylation with CO, and a vinyl trimethyltin afforded the intermediate 19 (Scheme 13). 

Some alkylpaUadium species may withstand the /3-hydrogen elimination and provide the carbonylative cross-coupling product in a reasonable yield (Scheme 12). The product was used for the total synthesis of (+)-negamycin. 

Stoichiometric amount of palladium catalyst was used. The mixture was placed in a -30 °C bath and the reaction vessel was evacuated. The atmosphere was replaced with carbon monoxide (1 atm), and the solution was stirred for 1.5 h. The resulting black slnrry was treated with isobutenyltrimethylstannane, and the solution was allowed to stand at room temperature and was then stirred for 4 h to afford 130 in good yield (68-77%). This was then converted into (—)-5(5)-ep/-negamycin (125b) in overall yield of 20% from 126. On the other hand, 131 was converted into 135 via 134, and the total synthesis of (+)-negamycin (125a) was reahzed from 135. 

Several procedures have been explored for converting dihydropyran derivatives to the racemic 3,6-diamino-2,3,4,6-tetradeoxy-DL-/Aren-hexopyra-nose derivative (29) required as an intermediate for the synthesis of dl-negamycin (see Vol. 6, p. 135) the most efficient entailed the sequence shown in Scheme 13. ... 

The lactone moiety 6 found in mevinic acids has been synthesized from L-malic acid using a chiral sulfoxide reagent to control the stereochemistry at C-3. Synthesis of the negamycin lactone 7 has been reported, while a lactone precursor of L-acosamine and L-daunosamine is discussed in Chapter 9. 

Carbamates also participate in analogous cyclizations as demonstrated in Ohno s synthesis of the antibiotic (-t-)-negamycin (227, Scheme 9.30) [168]. Halocyclization of N-silylated carbamate 225 proceeded with higher trans selectivity dr =93 7) relative to the analogous cyclization of the corresponding unprotected carbamate. 

---