Methyl nonactate

As a strategy for the construction of cyclic ethers, the radical cyclization of jS-alkoxyacrylates was used for the preparation of czs-2,5-disubstituted tetrahy-drofurans and cis-2,6-disubstituted tetrahydropyrans. An example is given with S-alkoxymethacrylate 38 as precursor of the optically active benzyl ether of (+)-methyl nonactate, exclusively formed as the threo product (Reaction 44). ° ... 

Propose an enantioselective synthesis of (+) methyl nonactate from the aldehyde shown. 

Radical cylization of a P-alkoxymethacrylate leads to the stereoselective preparation of the benzylether of (+)-methyl nonactate, demonstrating 2J5-cis selectivity in the radical cydization step and threo selectivity in the hydrogen abstraction step <990L1127>. 

Scheme 4.25. Beck s and Henseleit s methyl nonactate synthesis.

Scheme 4.26, Gerlach s first methyl nonactate syntheses.

White has also completed two syntheses of racemic methyl nonactate (154). The first approach controlled the C-8 alcohol stereochemistry, and the second provided a rapid entry into the ring system. The first sequence, outlined in Scheme 4.28, began with the opening of propylene oxide by 2-lithiofuran. The Friedel-Crafts acylation that followed also resulted in protection of the alcohol as the acetate to give 175 in 81% overall yield. Hydrogenation of the furan ring over rhodium on charcoal gave a 96% yield of tetrahydrofuran diastereomers... 

Scheme 4.28. White s first methyl nonactate synthesis.

Scheme 4.29. White s second methyl nonactate synthesis.

The intermediate enolate in this key rearrangenient is presumably enolate isomer, which rearranges through a boat-like transition state, r in the observed 89 11 ratio of 213 to 2-epi-213 after reduction. Ester 213, purification, was converted to 214 by removal of the MOM ether and 0x1 Addition of methyl Grignard reagent to aldehyde 214 then afforded a 1.1 of (—)-methyl nonactate [(—)-204] and (—)-8-epi methyl nonactate [( r in 33 and 36% overall yield, respectively, from 213. 

A. similar set of transformations was also done in an antipodal series w c led to (-l-)-204. Thus D-gluconic acid y-lactone (215) was converted via a straightforward protection and reduction sequence to furanoside 216. Reductive deoxygenation via the intermediate DMF acetal gave l-210 in 11% overall yield from 215. Conversion of e r-210 to a mixture of (-l-)-methyl nonactate [(+ )-204] and ( + )-8-epi methyl nonactate [(-I-)-180] was then accomplished in a manner identical to that described for the (-)-enantiomer. 

Secondly they found that a Walden inversion sequence could be used to change the relative configuration at C-8. Still in the racemic series, they found that the 8-tosylates gave the C-8 diastereoisomeric acetates on Walden inversion, and hydrolysis gave the diastereoisomers 38, 39, 40 and 41 in a ratio of 36.9 32.7 9.6 20.8. The ratio of 8-normal to 8-epi i.e. 38+39 40+41 was about 7 3. The racemic methyl nonactate 38 could be separated from the other diastereoisomers by chromatography. Methyl 2-epinonactate 39 could be equilibrated with sodium methoxide to a mixture of methyl nonactate 38 and methyl 2-epinonactate 39 in a ratio of 60 40. 

Following this exploratory work, the Schmidt group (13) reported the first homochiral synthesis of methyl (-)- and (+)-nonactate using (S)-propylene oxide as the only enantiomerically pure starting material (Scheme 4). This gave the mixture of diastereoisomeric methyl nonactates 38, 39,40 and 41, all with the ( -configuration at C-8, and chromatographic separation provided 25% of the natural (-) ester 38. The mixture of the other three diastereoisomers (39+40+41) was converted by Walden inversion into a mixture of the same three compounds with C-8 inverted, from which (+)-methyl (25,35,6R,8/J)-nonactate 44 could be isolated in approximately the same amount as its enantiomer 38. 

In their first and racemic synthesis of methyl nonactate 75 (Scheme 8), Bartlett and Jernstedt (18) introduced the 1,3-relationship between C-6 and C-8 in a diastereoselective manner from the diene 68, which gave the analogous cyclic phosphate. Upon treatment with sodium methoxide, the phosphate gave the epoxide 69, which was converted into the syn-1,3-diol 70. Acetylation of the diol followed by ozonolysis gave the aldehyde 71. Aldol condensation of the aldehyde with the silyl... 

Hydrogenolysis using palladium on charcoal, followed by stereoselective hydrogenation of the double bond using Bartlett s conditions gave a 1 1 mixture of racemic methyl nonactate 105 and methyl 8-epinonactate 106, which were separated by chromatography. 

This aldehyde had already been converted (26) to methyl nonactate and methyl 8-epinonactate with high selectivity using titanium tetrachloride catalysed addition of dimethyl zinc and lithium dimethylcuprate, respectively. Lygo also found that dialkylzinc addition under different Lewis acid conditions gave different diastereoisomers with high selectivity (Scheme 15). 

Kim and Lee have developed syntheses of methyl (+)-nonactate 134 and of methyl (-)-8-epinonactate 135 by way of Bartlett s intermediate 133 (=82) (Scheme 17) (28). They used a... 

Batmangherlich and Davidson (35) also resolved racemic methyl nonactate by chromatographically separating its esters 167 and 168 with (S)-O-acetylmandelic acid (36). 

Honda and his co-workers synthesised methyl (+)-nonactate 179, setting up the C-6 to C-8 relationship by a chelation controlled allylsilane reaction on the aldehyde 169, and the C-3 centre by hydrogenation of the dehydro intermediate 176 carrying two methoxycarbonyl groups (37) (Scheme 24). The thiolactone 175 and dimethyl diazomalonate gave the dehydro intermediate 176 in the presence of dirhodium tetraacetate, by way of a sulfur-ylid rearrangement developed by these... 

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