Absolute Configuration of Menthene Derivatives by Vibrational Circular Dichroism

The aerial parts of <i>Ageratina glabrata</i> afforded (−)-(3<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>S</i>)-3,5,6-trihydroxy-1-menthene 3-<i>O</i>-β-d-glucopyranoside (<b>1</b>) and (−)-(3<i>S</i>,4<i>S</i>,6<i>R</i>)-3,6-dihydroxy-1-menthene 3-<i>O</i>-β-d-glucopyranoside (<b>3</b>). Acid hydrolysis of <b>1</b> yielded (+)-(1<i>R</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)-1,5,6-trihydroxy-2<i>-</i>menthene (<b>5</b>) and (+)-(1<i>S</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)-1,5,6-trihydroxy-2-menthene (<b>6</b>), while hydrolysis of <b>3</b> yielded (+)-(3<i>S</i>,4<i>S</i>,6<i>R</i>)-3,6-dihydroxy-1<i>-</i>menthene (<b>10</b>), (+)-(1<i>R</i>,4<i>S</i>,6<i>R</i>)-1,6-dihydroxy-2<i>-</i>menthene (<b>11</b>), and (+)-(1<i>S</i>,4<i>S</i>,6<i>R</i>)-1,6-dihydroxy-2<i>-</i>menthene (<b>12</b>). The structures of the new compounds <b>1</b>, <b>2</b>, <b>5</b>–<b>9</b>, and <b>11</b> were defined by 1D and 2D NMR experiments, while the absolute configurations of the series of compounds were determined by comparison of the experimental vibrational circular dichroism (VCD) spectra of the 1,6-acetonide 5-acetate derived from <b>6</b> and of the 1,6-acetonide derived from <b>12</b> with their DFT-calculated spectra. In addition, Flack and Hooft X-ray parameters of <b>10</b> permitted the same conclusion. The results further led to the absolute configuration reassignment of <b>10</b> isolated from <i>Brickellia rosmarinifolia</i>, <i>Mikania saltensis</i>, <i>Ligularia muliensis</i>, <i>L. sagitta</i>, and <i>Lindera strychnifolia</i>, as well as of <b>11</b> from <i>Cacalia tangutica</i>, as <i>ent</i>-<b>11</b>

Methodology for the Absolute Configuration Determination of Epoxythymols Using the Constituents of <i>Ageratina glabrata</i>

A methodology to determine the enantiomeric excess and the absolute configuration (AC) of natural epoxythymols was developed and tested using five constituents of <i>Ageratina glabrata</i>. The methodology is based on enantiomeric purity determination employing 1,1′-bi-2-naphthol (BINOL) as a chiral solvating agent combined with vibrational circular dichroism (VCD) measurements and calculations. The conformational searching included an extensive Monte Carlo protocol that considered the rotational barriers to cover the whole conformational spaces. (+)-(8<i>S</i>)-10-Benzoyloxy-6-hydroxy-8,9-epoxythymol isobutyrate (<b>1</b>), (+)-(8<i>S</i>)-10-acetoxy-6-methoxy-8,9-epoxythymol isobutyrate (<b>4</b>), and (+)-(8<i>S</i>)-10-benzoyloxy-6-methoxy-8,9-epoxythymol isobutyrate (<b>5</b>) were isolated as enantiomerically pure constituents, while 10-isobutyryloxy-8,9-epoxythymol isobutyrate (<b>2</b>) was obtained as a 75:25 (8<i>S</i>)/(8<i>R</i>) scalemic mixture. In the case of 10-benzoyloxy-8,9-epoxythymol isobutyrate (<b>3</b>), the BINOL methodology revealed a 56:44 scalemic mixture and the VCD measurement was beyond the limit of sensitivity since the enantiomeric excess is only 12%. The racemization process of epoxythymol derivatives was studied using compound <b>1</b> and allowed the clarification of some stereochemical aspects of epoxythymol derivatives since their ACs have been scarcely analyzed and a particular behavior in their specific rotations was detected. In more than 30 oxygenated thymol derivatives, including some epoxythymols, the reported specific rotation values fluctuate from −1.6 to +1.4 passing through zero, suggesting the presence of scalemic and close to racemic mixtures, since enantiomerically pure natural constituents showed positive or negative specific rotations greater than 10 units

Absolute Configuration of (13<i>R</i>)- and (13<i>S</i>)‑Labdane Diterpenes Coexisting in <i>Ageratina jocotepecana</i>

Chemical investigation of the hexanes extracts of <i>Ageratina jocotepecana</i> afforded (−)-(5<i>S</i>,9<i>S</i>,10<i>S</i>,13<i>S</i>)-labd-7-en-15-oic acid (<b>1</b>), methyl (−)-(5<i>S</i>,9<i>S</i>,10<i>S</i>,13<i>S</i>)-labd-7-en-15-oate (<b>2</b>), (+)-(5<i>S</i>,8<i>R</i>,9<i>R</i>,10<i>S</i>,13<i>R</i>)-8-hydroxylabdan-15-oic acid (<b>3</b>), and (−)-(5<i>S</i>,9<i>S</i>,10<i>S</i>,13<i>Z</i>)-labda-7,13-dien-15-oic acid (<b>5</b>). The coexistence of (13<i>R</i>)- and (13<i>S</i>)-labdanes in this member of the Asteraceae family was demonstrated by vibration circular dichroism measurements of ester <b>2</b> and methyl (+)-(5<i>S</i>,8<i>R</i>,9<i>R</i>,10<i>S</i>,13<i>R</i>)-8-hydroxylabdan-15-oate (<b>4</b>) in comparison to the DFT B3LYP/DGDZVP-calculated spectra. In addition, transformation of <b>1</b> and <b>3</b> with HClO₄ in MeOH yielded epimeric methyl (+)-(5<i>S</i>,10<i>S</i>,13<i>S</i>)-labd-8-en-15-oate (<b>6</b>) and methyl (+)-(5<i>S</i>,10<i>S</i>,13<i>R</i>)-labd-8-en-15-oate (<b>7</b>), respectively, confirming the presence of C-13 epimers in this plant. Diterpene <b>1</b> showed remarkable antibacterial activity against <i>Bacillus subtilis</i> (MIC 0.15 mg/mL) and <i>Staphylococcus aureus</i> (MIC 0.78 mg/mL), while diterpene <b>3</b> exhibited moderate activities against the same organisms