Nonactic acids

The ionophoric antibiotic nonactin is a 32-membered macrocycle that contains two units of (-)-nonactic acid and two units of (+)-nonactic acid in an alternating sequence. 

A six-step synthesis of nonactic acid with excellent stereocontrol via sultone intermediates has been published (Scheme 26) <1998EJO2073>. The tricyclic sultone 107 was synthesized by a tandem esterification/cycloaddition with vinylsulfonyl chloride whereby only the fvo-adduct with fvo-Me was obtained <1989AGE202>. Next, the tandem elimination/alkoxide-directed 1,6-addition first led to a mixture of sulfones, but equilibration with catalytic... 

As noted previously, the use of chiral sultam auxiliaries provides access to ena-ntiomerically enriched isoxazolines. These products can be elaborated to provide nonactic acid and 8-ep/-nonactic acid, the subunits of nonactin (Scheme 2.15) (141-143). Subsequent cleavage of the isoxazoline ring in the presence of Raney... 

The same mechanistic pathway was proposed to rationalize the formation of furan-2-ylidene malonate 64, a key intermediate in the synthesis of nonactic acid (119). Other examples that involve the replacement of a C=S group by an... 

R. E. Ireland and J. P. Vevert, A chiral total synthesis of (—) and (+) nonactic acids from carbohydrate precursors and the definition of the transition for the enolate Claisen rearrangement in heterocyclic systems, J. Org. Chem. 45 4259 (1980). 

The synthesis of natural products by chirality transfer from carbohydrates has been used for a total synthesis of (-)-(7S)-nonactic acid (199). The furanoid glycal (197) was prepared from D-mannose, which is the appropriate chiral precursor (Scheme 46) (80JOC4259). A [3,3]-sigmatropic rearrangement of the silylated ketene-acetal (198) led to the control of the C-2 configuration. The intermediate furanoid glycal was prepared in ten steps from the carbohydrate precursor. 

The popular approach to tetrahydrofurans involves an electrophilic process and the commonly used electrophiles for the cyclization are acids, oxygen, halogen, mercury (see Section 3.11.2.2.9) and selenium. The ionic hydrogenation of furans with excess triethyl-silane in trifluoroacetic acid affords high yields, e.g. 2-methylfuran is reduced to 2-methyl-tetrahydrofuran and 2-ethylfuran to 2-ethyltetrahydrofuran (see Section 3.11.2.5). The synthesis of several dihydro and tetrahydrofurans containing natural products by chirality transfer from carbohydrates has been used successfully for total synthesis, e.g. (-)-nonactic acid. A reasonable yield of 2-alkyltetrahydrofuran was prepared from 4-alkylbut-l-en-4-ol by hydroboration followed by cyclization with p-toluenesulfonic acid. 

Woo, A. J., Strohl, W. R., and Priestley, N. D. (1999) Nonactin biosynthesis the product of nonS catalyzes the formation of the furan ring of nonactic acid. Antimicrob. Agents Chemother. 43, 1662-1668. 

Dehydration of a y-hydroxy ketone. The synthesis of the antibiotic nonactin (1) presents an unusual problem in that the subunit, nonactic acid, occurs as both optical antipodes. In a recent synthesis, this problem was simplifed by synthesis of both antipodes... 

In contrast, cyclization of the carbonate derivative (5) of 2 with potassium hydride in THF/HMPT proceeds with inversion at C to provide ( —)-6, which on hydrogenation provides the methyl ester of (-I-)-nonactic acid (7). 

Assembly of nonactin involves coupling the potassium salt of (+ )-nonactic acid with the mesylate of (- )-4 with inversion of C to give methyl (+ )-nonactyl (- )-nonactate (8) in 86% yield. The corresponding free acid was simultaneously dimerized and cyclized via the mixed anhydride formed from diphenyl phosphorochloridate (11, 223) to give nonactin (1) in 15-20% yield. 

Nonactic Acid, Lilac Alcohol and Prelog-Djerassi Lactone... 

The cycloadduct (75d) has been utilized for the synthesis of nonactic acid (116) and lilac alcohol (119) via (118). The Prelog-Djerassi lactone (117), a pivotal intermediate in Masamune s methymycin synthesis, has been prepared tom the key compound (75e) (Scheme 21)J ... 

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