A combined experimental and computational strategy in the assignment of absolute configurations of 4-methyl-5-oxo-tetrahydrofuran-3-carboxylic acids and their esters

Enantiopure cis- and trans-4-methylparaconic acids and their alkyl esters were synthesized by a procedure involving the kinetic enzymatic resolution of diastereomeric lactonic esters. Thus, ethyl cis- and trans-4-methyl-5-oxo-tetrahydrofuran-3-carboxylates were isolated, at high conversion values, with 99% ee from the hydrolyses with HLAP and α-CT, respectively. The corresponding enantiopure cis- and trans-lactonic acids were also obtained. The absolute configurations of the products were assigned by chemical correlation, by analysis of their circular dichroism spectra and by electronic structure calculations. All three methodologies lead to the same assignment for the species considered, another example of successful interplay between experiment and theory.

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Ethyl (3S,4R)-(−)-4-methyl-5-oxo-tetrahydrofuran-3-carboxylateC8H12O4Ee = >99% (by chiral HRGC)[α]D25=-18.5 (c 0.33, MeOH)[Θ]213 = −3021 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: 3S,4R

Ethyl (3R,4R)-(+)-4-methyl-5-oxo-tetrahydrofuran-3-carboxylateC8H12O4Ee = >99% (by chiral HRGC)[α]D25=+68.5 (c 0.87, MeOH)[Θ]218 = −5119 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: 3R,4R

(3S,4S)-(−)-4-Methyl-5-oxo-tetrahydrofuran-3-carboxylic acidC6H8O4Ee = 91% (by chiral HRGC)[α]D25=-66.2 (c 0.63, MeOH)[Θ]218 = +3439 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: 3S,4S

(3R,4S)-(−)-4-Acetyl-3-methyl-2(3H)-dihydrofuranoneC7H10O3Ee = 99% (by chiral HRGC)[α]D25=-8.8 (c 0.17, MeOH)[Θ]216 = −3678 (MeOH)[Θ]296 = +271 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: 3R,4S

(3S,4S)-(−)-4-Acetyl-3-methyl-2(3H)-dihydrofuranoneC7H10O3Ee = 90% (by chiral HRGC)[α]D25=-72.1 (c 0.58, MeOH)[Θ]214 = +6073 (MeOH)[Θ]281 = −479 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: 3S,4S

(3R,4S)-(−)-3-Methyl-4-(2-methyl-1,3-dithiolan-2-yl)-2(3H)-dihydrofuranoneC9H14O2S2Ee = 95% (by chiral HRGC)[α]D25=-10.0 (c 0.18, MeOH)[Θ]200 = +5776 (MeOH)[Θ]223 = −1427 (MeOH)[Θ]241 = −1506 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: 3R,4S

(3S,4S)-(−)-3-Methyl-4-(2-methyl-1,3-dithiolan-2-yl)-2(3H)-dihydrofuranoneC9H14O2S2Ee = 90% (by chiral HRGC)[α]D25=-51.7 (c 0.70, MeOH)[Θ]206 = −5013 (MeOH)[Θ]246 = −2285 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: 3S,4S