Isotopic Enrichment by Asymmetric Deuteriation. An Investigation of the Synthesis of Deuteriated (S)-(−)-Methylsuccinic Acids from Itaconic Acid

Abstract

Two different asymmetric hydrogenation methodologies based on gaseous hydrogen at 1 atm pressure and transfer hydrogenation from the decomposition of formic acid, in the presence of a rhodium catalyst, have been used to prepare (S)-(-)-methylsuccinic acid enriched with the deuterium isotope. NMR and mass spectroscopic evidence indicates that complex labeling occurs. We interpret this labeling pattern as the result of an equilibrium which exists between the olefin and a catalyst-alkyl intermediate in a Wilkinson-type mechanism. This phenomenon has not been reported in similar experiments with (E)-phenylitaconic acid where the expected cis-addition of deuterium from either deuterium gas at 1 atm, or deuteriated formic acid under transfer hydrogenation conditions, was observed. In our studies reducing itaconic acid (methylenebutanedioic acid), there was no loss of asymmetric induction (above 90% ee), approximately 2.4 deuterons were incorporated into (S)-(-)-methylsuccinic acid, a ratio of 1.8:1 methyl: methine deuteriation was observed, and there was no evidence for olefin isomerization into conjugation with both carboxylic acid groups. Following these isotopic enrichment studies, we present the first evidence for reversible transfer addition of deuterium to methylsuccinic acid, either by gaseous or transfer hydrogenation at atmospheric pressure. Such a mechanism has recently been eliminated for reduction at elevated pressures. These results have general applicability to the synthesis of isotopically labeled homochiral substituted carboxylic acids and also in interpreting the 13 C NMR data which are generated by the simultaneous presence of several deuterium containing isotopomers.

Kinetic and Mechanistic Study of the H-Transfer Reduction of Dimethyl Itaconate by a Rh/TPPTS Catalyst under Biphasic Conditions: Evidence for a Rhodametallacycle Intermediate

“…It has been shown that in this type of rhodium hydride or dihydride intermediate, scrambling always occurs. [1,23] That explains very well the partial incorporation of deuterium (13%) at the C 1 position when the reduction is carried out with H 2 O/DCOO -. The exchange Rh-D/H 2 O must be quite slow, as the incorporation obtained in the C 1 position (31%) is close to the theoretical incorporation (33%) with D 2 O/HCOO -.…”

An autoradiographic study of the distribution of binding sites for the novel α7‐selective nicotinic radioligand [3H]‐methyllycaconitine in the mouse brain

“…[ 3 H]‐Methyllycaconitine ([ 3 H]‐MLA; 25 Ci/mmol) was synthesized in collaboration with Tocris Cookson (Bristol, UK). This was prepared essentially as described for the production of deuterated methylsuccinic acid by Hardick et al . (1996b) and fully characterized (Blagbrough et al .…”

Biosynthesis of scopoletin and scopolin in cassava roots during post-harvest physiological deterioration: The E-Z-isomerisation stage

“…HR MS gave m/z 148.0516 [M -H] -, and comparison of the peak heights at m/z 148 (E-cinnamic-2-d 1 acid) and m/z 147 (unlabelled E-cinnamic acid) showed a deuterium label incorporation of 88%. Correspondingly, the 13 C NMR spectra showed two key signals corresponding to C-2 for labelled and unlabelled cinnamic acid respectively: δ 119.1 (t, 1:1:1, 1 J CD = 25 Hz), shifted upfield by 0.2 ppm by α-substitution with deuterium, typically 0.25 ppm per α-deuterium atom (Tulloch and Mazurek, 1973;Wehrli and Wirthlin, 1983;Hardick et al, 1996), and a small singlet at 119.3 for C-2 attached to proton, the residual isotopomer. In the 1 H NMR spectrum, H-3 signals (integrating for 1) appear at 7.66 ppm as a slightly broadened singlet (with a small 3 J HD 2 Hz, integral 0.88) (Williams and Fleming, 2008) -cinnamic-2',3',4',5',6'-d 5 acid, (d) E-cinnamic-3,2',3',4',5',6'-d 6 acid, (e) E-cinnamic-2, 3,2',3',4',5',6'-d 7 acid showing the isotopic labelling patterns found in the product scopoletin (M + 1 H) and (M + 23 Na) (f-j, respectively).…”