7575
Further examples of the epimerisation of thevinone-related ketones were investigated (Table
8
,10
1
, entries 8–10). The t-butyl ketone (3d)
with perchloric acid gave a 1:1 ratio of 3d with the
7
b-epimer (5d), and dihydronepenthone (3c) similarly was 44% converted to its epimer (5c). The
higher proportion of epimerisation in these cases is most likely due to the greater steric bulk of
the t-butyl and phenyl groups thus causing more unfavourable interaction with the 6,14-ethano
bridge in the 7a-epimers. Separation of epithevinone and dihydroepithevinone was achieved by
3
,5
literature methods. The epi-t-butyl ketone could be isolated by silica gel chromatography,
whereas the other examples reported were not separable by this method.
We confirmed the lack of epimerisation of the etheno-ketone, thevinone (1a) and the N-CPM
5
analogue (2a) in the Schmidt reaction and showed that epithevinone (7a) was converted into a
3
:1 mixture of 7a- and 7b-acetylamino derivatives (14b, 15b) (Table 1, entries 11–13). When
thevinone was treated with perchloric acid alone at 70°C, a small amount of conversion to
epithevinone (7a) was detected together with a second product identified as 6-O-
demethylthevinone (16a). Under these conditions epithevinone was converted largely to
thevinone, confirming the substantially greater stability of the 7a- over 7b-ketone (entries 14 and
1
5).
The mechanism of the Schmidt reaction involves initial protonation of the ketone, followed by
attack of hydrazoic acid. In the ethano series it appears that deprotonation of the 7a-protonated
ketone to give the enol and epimerisation can occur in competition with the hydrazoic acid
attack. In the etheno series the greater accessibility of the 7a-protonated ketone to hydrazoic
acid allows the Schmidt reaction to predominate and no epimerisation is observed. That in the
etheno series Schmidt reaction is faster than epimerisation was confirmed when the hydrazoic
acid was omitted from the reaction of thevinone (1a) and epithevinone (7a). In both cases more
epimerisation was observed than in the equivalent Schmidt reactions. In the ethano series, the
7
a-ketone was epimerised to the same extent in the Schmidt and non-hydrazoic acid conditions
†
showing that the Schmidt reaction was slower than epimerisation.
When the temperature of the perchloric acid conditions alone was raised to 90°C, both
thevinone (1a) and epithevinone (7a) were converted largely to 6-deoxythevinone (16a). The
reaction involves the opening of the bridged ring to give the 14-(3-oxoalkyl)codeinone (17a),
which can ring close again to give the 6-deoxy ketone (16a) in the more stable 7a-acyl
configuration (Scheme 2). It was difficult to isolate the codeinone intermediate (17a) since the
ring closure to 16a occurs so readily. In the expectation of increased stability of the codeinone
relative to the 6-O-demethylthevinone derivative, the action of perchloric acid on the t-butyl
ketone (1d) was investigated. The codeinone (17d) was isolated in 37% yield, as well as the
6
-deoxy ketone (16d) (42%). The equilibrium between the two products was demonstrated by
subjecting the isolated deoxy ketone (16d) to the perchloric acid conditions to give a 1:1 mixture
of starting material and codeinone (17d), effectively increasing the yield of the latter.
†
General procedure for Schmidt reaction. Perchloric acid (70%: 10 ml/g of ketone) was added dropwise to a
vigorously stirred suspension of ketone in water (10 ml/g of ketone). After dissolution, sodium azide (2.7 equiv.) was
added and the solution warmed to 70 or 90°C. After the required time the solution was cooled to rt, basified with
ammonia (pH 10) and the products were extracted with EtOAc (3×50 ml). The combined organics were dried
1
(
Na SO ), the solvent removed in vacuo and the H NMR spectrum recorded for the crude mixture.
2
4