1 Introduction
Dioxiranes generated in situ from oxone and chiral ketones have appeared to be efficient reagents for asymmetric epoxidations of trans-olefins [1–5]. During investigation of type-I substituted cyclohexanones as precursors of chiral dioxiranes for asymmetric epoxidation of trans-stilbene 1 and trans-methyl p-methoxycinnamate 2 (Fig. 1), we recently reported a 26 to 30% increase of the ee (40 to 66% ee and/or 60 to 90% ee) with ketones 3 and 4 compared with 5 (due to de-symmetrization of the axial face of the cyclohexanone). A contribution of the axial approaches of the olefin onto the dioxirane (in addition to the main equatorial approaches) was thus envisaged [6].
However, because approaches (equatorial and axial) on the inverted ring (conformation C2) of the dioxirane (Fig. 1) provide the other enantiomer [7] and could be responsible for lowering the enantioselectivity, a new rigid ketone 6 similarly substituted at C2 and C5 (compared to ketone 4) and having only conformation C1 has been designed and synthesized.
We present here a comparison between the efficiencies of flexible ketones 3, 4 and 7 already used by Shi [8] (in which ring inversion is possible) and that of 6 (which is rigid) for epoxidation of trans-stilbene 1 and trans-methyl p-methoxycinnamate 2 (Fig. 2). Moreover, different epoxidation conditions have been used.
2 Results
Ketone 6 was obtained (from commercially available (R)-(–)-hexahydro-4a-methyl-2-naphtalenone 90% ee) as one diastereomer and it has been shown by NMR (in C6D6) that the fluorine atom was axial [9], as in the most populated conformer (C1) of ketones 3, 4 and 6. Shi’s ketone 7 was prepared according to the described process [10]. The percentages of conversion have been determined by combining weights and 1H NMR (200 and 300 MHz) of solvent-free crude products; then the obtained and known epoxides were isolated by flash chromatography on silica gel. The ee% were determined by HPLC (Chiralcel OD), 1H NMR (400 MHz, Eu(hfc)3) and the absolute configuration through the signs of optical rotations.
The results are gathered in Table 1.
Epoxidation of olefins 1 and 2 using ketones 3, 4, 6 and 7.
| Ketone | 3 | 4 | 6* | 7 | |||||
| Olef. | cond. | conv.% | ee% | conv.% | ee% | conv.% | ee% | conv.% | ee% |
| 1 | A | 90 | 90, (–)-( SS ) | 95 | 90, (–)-( SS ) | 100 | 91*, (+)-( RR ) | 62 | 82, (+)-( RR ) |
| 1 | B | 100 | 90, (–)-( SS ) | 47 | 98, (+)-( RR )** | ||||
| 2 | A | 74 | 60, (–)-( RS ) | 90 | 66, (–)-( RS ) | 75 | 50*, (+)-( SR ) | 30 | 34, (+)-( SR ) |
| 2 | B | 100 | 76, (–)-( RS ) | 43 | 86, (+)-( SR ) |
In all cases, 0.3 equiv of ketone were used and the reaction conditions were either A (dioxane/H2O; K2CO3 0.1 M/AcOH, 0.5%; oxone (3 equiv)/H2O and K2CO3 (6 equiv) dropwise; addition ~6 h at room temperature) or B (acetonitrile; Na2B4O7·10 H2O, 0.05 M/Na2EDTA, 4 × 10–4M; HSO4NBu4 (0.05 equiv); oxone (1.4 equiv)/Na2EDTA, 4 × 10–4M and K2CO3 (5.8 equiv) dropwise); addition ~2 h at 0 °C).
It was found that conditions B have a tendency to give slightly higher yields and higher ee% (compare lines 1/2 and 3/4 in columns 1 and 4).
It appeared that, under conditions A and for epoxidation of stilbene 1, ketones 3, 4 and 6 are more efficient (90–100% yield and 90–91% ee) than Shi’s ketone 7 (62% yield and 82% ee); however, under conditions B, ketone 7 provides higher enantioselectivity (98%), but lower yield (47%).
It is worth noting that the absolute configuration of the major epoxide enantiomer obtained (Table 1) fits with the postulated model [6] of equatorial (and partly axial) approaches of the olefin on the most populated conformer C1 of the non-rigid ketones 3, 4 and 7 and on rigid ketone 6 (Fig. 3).
We could thus conclude that, although the Curtin–Hammett principle holds to non-rigid ketones, the contribution of the olefin’s approaches on the inverted ring C2 is not significant. Moreover, direct epoxidation of the olefin by the oxone has been checked and appeared to be negligible under conditions B (3% epoxide formed in absence of the ketone for stilbene and 1% for methyl cinnamate), but started to become slightly significant under condition A (14% for stilbene and 9% for methyl cinnamate).
It thus seems that the maximum efficiency of the chiral ketones is reached and that more efficient substituents must be found. However, adjustment of the epoxidation conditions is very important and depends on both the olefin and the ketone. It is worth noting that while ketone 7 is not recovered under both conditions (A and B) for an undetermined reason (no Baeyer–Villiger product has been isolated or identified), ketones 3, 4 and 6 are recovered (almost quantitatively during chromatography). Only 3 undergoes 3–5% of Baeyer–Villiger product under conditions B.