Nonactic acids synthesis

The Ireland contribution to nonactic acid synthesis, outlined in Scheme 4.32, involves a selective silyl ketene acetal formation and Claisen rearrangement in the key step. D-Mannose (209) was readily converted in a straightforward manner to dihydrofuran 212 via 210 and 211 in 36% overall yield. Esterification of the free alcohol with propionyl chloride followed by the an enolate Claisen rearrangement afforded a mixture (89 11) of tetrahydrofuryl propionates 213 after catalytic reduction. 

The Bartlett nonactic acid synthesis, outlined in Scheme 4.33, arose from this group s work in the area of acyclic stereocontrol. From a common intermediate constructed using the carbonate cyclization methodology, Bartlett was able to obtain either antipode of nonactic acid and thus nonactin To this end, dimethyl-(S)-(-)-malic acid 217 was converted by a series of routine chemical transformations to epoxy tosylate 218 in 75% overall yield. Cleavage... 

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... 

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. 

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... 

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 ... 

Takatori, K., Tanaka, K., Matsuoka, K., Morishita, K., and Kajiwara, M., An enantioselective synthesis of (-)-nonactic acid and (+)-8-cy -nonactic acid using microbial reduction, Synlett, 159, 1997. Ornstein, P.L., Bleisch, T.J., Arnold, M.B., Wright, R.A., Johnson, B.G., and Schoepp, D.D., 2-Substituted (2SJ )-2-amino-2-(15 J, 2SR)-2-carboxycycloprop-l-yl)glycmes as potent and selective antagonists of group II metabotropic glutamate receptors. Part 1. Effects of alkyl, arylalkyl, and diarylalkyl substitution, 7. Med. Chem., 41, 346, 1998. 

The early synthetic endeavors in this area focused mainly on the synthesis of various nonactic acid derivatives. The scenario utilized in almost all of these early studies involved the hydrogenation of a 2,5-disubstituted furan ring to give a cis-disubstituted tetrahydrofuran. 

The second Gerlach synthesis of nonactic acid, detailed in Scheme 4.27, controlled the stereochemistry of the C-8 alcohol center early on, and formed... 

Schmidt and co-workers reported the first stereoselective synthesis of both enantiomers of a nonactic acid derivative, as well as nonactin itself.As depicted in Scheme 4.30, 2-lithiofuran was reacted with (S)-propylene oxide to... 

Fig. 1 Asymmetric synthesis of (+)- and (-)-nonactic acid and cyclic (+)(-)(+)(-)-linkage of (+)-nonactic acid and (-)-nonactic acid in the synthesis of nonactin.

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