Perchloric acid induced epimerisation of the thevinones: An improved synthesis of 7β-dihydrothevinones

Article abstract of DOI:10.1016/S0040-4039(00)01300-9

The region above and away from C7 in the orvinols is known to be of particular importance in determining the μ-opioid receptor profile of this important class of opioids. However it has been difficult to explore this site due to the relative inaccessibility of 7β-substituted compounds. Here we report that perchloric acid induced epimerisation of the 7α-ketones (dihydrothevinones) allows considerably improved access to a series of β-ketones (β-dihydrothevinones). The extent of epimerisation of the 7α-ketone is determined by the degree of steric bulk in both the 6,14-bridge and in the ketone side chain. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01300-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7571–7576
Perchloric acid induced epimerisation of the thevinones: an
improved synthesis of 7b-dihydrothevinones
Ian Derrick, Andrew Coop, Sali M. Al-Mousawi, Stephen M. Husbands and
John W. Lewis*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Received 6 June 2000; accepted 28 July 2000
Abstract
The region above and away from C7 in the orvinols is known to be of particular importance in
determining the m-opioid receptor profile of this important class of opioids. However it has been difficult
to explore this site due to the relative inaccessibility of 7b-substituted compounds. Here we report that
perchloric acid induced epimerisation of the 7a-ketones (dihydrothevinones) allows considerably improved
access to a series of b-ketones (b-dihydrothevinones). The extent of epimerisation of the 7a-ketone is
determined by the degree of steric bulk in both the 6,14-bridge and in the ketone side chain. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: opioids; thevinones; 7b-dihydrothevinones; epimerisation.
1
. Introduction
Derivatives of the opioid thevinone (1a), obtained from the Diels–Alder reaction of thebaine
with methyl vinyl ketone, have been extensively studied. Further elaboration of thevinone leads
®
to a series of compounds termed the orvinols, which include etorphine (Immobilon , 9),
®
®
diprenorphine (Revivon , 10a) and buprenorphine (Temgesic , 10b), the latter being an anal-
1
gesic of clinical utility more recently developed as a pharmacotherapy for opioid abuse. The
orvinols contain a tertiary alcohol unit attached to the 7a-position of the ring system. It has
become clear that the region above and away from C has in particular, a significant impact on
7
the m-opioid receptor profile of orvinols and related compounds. However the relative inaccessi-
bility of the epimeric ketones (5–8) has hindered direct exploration into the role and nature of
this site. The Diels–Alder reaction gave almost exclusively the 7a-adduct (thevinone, 1a),
although 0.5% of the b-epimer (7a) was isolated by fractional crystallisation of the product of
2
a large scale reaction. Following large scale hydrogenation of the Diels–Alder adduct, 1.3% of
*
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01300-9

7572
3
the dihydroepimer (5a) was obtained by fractional crystallisation of the bitartrates. The only
reported studies of 7al7b epimerisation in the thevinone series have used basic conditions.
2
,4
Bentley et al. attempted to establish 7a/7b-equilibrium mixtures by reversible enolisation of
the 7a-ketones using sodium hydroxide in methanol, but instead of conversion to the 7b-epimer
found that rearrangement occurred with the formation of ketals of 5,14-bridged thebainone
5
derivatives (11). Marton et al. achieved some success in converting the 7a-ketones (1a, 1b, 3a,
3
c) to the 7b-epimers (7a, 7b, 5a, 5c) using bases with weak nucleophilic character (e.g. DBU),
but in most cases rearrangement to 11 could not be prevented and often predominated. In every
case the conversion to the 7b-ketone was less than 20%. These basic conditions appeared not to
have achieved epimeric equilibrium since when they were applied to the epimeric 7b-ketones (7b,
5
5
a) only about 50% of the 7a-epimer was formed, interestingly without any rearrangement.
Here we report more effective acidic conditions for the epimeric conversion of the dihy-
drothevinones (3, 4) and compare this with the effects of similar conditions on the equivalent
thevinones.
2
. Results and discussion
As part of our investigation into the effects of substituents at C7, we wished to prepare the
7
a-acetylamino derivative (12a) using the Schmidt reaction with N-cyclopropylmethylnordihy-
1
1
drothevinone (4a). This procedure had been successfully used to give the etheno analogue (14d)
from thevinone (1a). When 4a was treated with 35% aqueous HClO and NaN at 70°C, a
6
,7
10
4
3
2
:1 mixture of 7a- and 7b-acetylamino derivatives (12a, 13a) was formed. It was deduced that
acid-catalysed epimerisation via the enol (18) leading to a mixture of ketones (4a, 6a) was
competing with Schmidt rearrangement (Scheme 1). This was confirmed by carrying out the
reaction under identical conditions but without NaN . The proportions of 7a- and 7b-ketones
3
(
4a, 6a) in the product were very similar to those of the acetylamino products (12a, 13a) of the
Schmidt reaction. The results are shown in Table 1, entries 1 and 2. The product ratios were
8,9
determined on the unseparated reaction mixtures using NMR analysis. The product ratio was
determined by the magnitude of the H-5b signal, which for the ketones show at higher field for
the 7a-epimer than for the 7b-epimer. Unusually, with the acetylamino derivatives the relative
positions of the H-5b signals were reversed. In Table 2, the chemical shift of the H-5b signal is

7573
1
recorded for those compounds whose H NMR data have not previously been reported. 3d is
included for comparison with 5d.
.
Scheme 1. Competing Schmidt and epimerisation reactions

7574
Table 1
Product ratios for epimerisation in the presence and absence of sodium azide
Entry
Starting material
Sodium azide
Temp. (°C)
Time (h)
Product ratio
7a
7b
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
4a
4a
3a
3a
3a
3a
5a
3d
3c
3c
1a
2a
7a
1a
7a
1d
Yes
No
Yes
No
No
No
Yes
No
No
No
Yes
Yes
Yes
No
No
No
70
70
70
70
70
90
70
90
70
70
70
70
70
70
70
90
16
16
2
12a (ꢀ67)
4a (ꢀ67)
12b (ꢀ75)
3a (58)
3a (58)
3a (58)
3a (ꢀ50)
3d (ꢀ50)
3c (ꢀ70)
3c (56)
14b (100)
12b (100)
14b (70)
1a (ꢀ67)
1a (ꢀ83)
16d (42)
13a (ꢀ33)
6a (ꢀ33)
13b (ꢀ25)
5a (42)
5a (42)
5a (42)
5a (ꢀ50)
5d (ꢀ50)
5c (ꢀ30)
5c (44)
–
1
16
16
4.5
18
1
4
5
5
4
1
1
1
1
1
1
1
–
15b (25)
7a (ꢀ17)
a
4.5
4
5
7a (ꢀ17)
b
17d (37)
a
ꢀ
17% of 6-demethylthevinone (16a) also formed.
b
Product is not a thevinone.
The epimerisation of dihydrothevinone derivatives in perchloric acid with and without
Schmidt reaction was further investigated in some detail (Table 1, entries 3–7). Although
dihydrothevinone (3a) gave less b-epimer than its N-CPM analogue (4a) in the Schmidt reaction,
the proportion of its epimer from perchloric acid treatment alone was higher than for the
N-CPM analogue. Equilibrium was attained within 1 h with about 40% of the b-epimer (5a)
being formed. When epidihydrothevinone (5a) was subjected to the Schmidt reaction, approxi-
mately equal amounts of the 7a- and 7b-acetylamino derivatives (12b, 13b) were formed. This
result was very similar to that obtained when 5a was epimerised under weakly nucleophilic basic
5
conditions.
Table 2
Chemical shift of H-5b proton
Starting material
7a (ppm)
7b (ppm)
4a
3a
7a
3d
12a (4.60)
12b (4.70)
14b (4.80)
13a (4.55)
13b (4.64)
15b (4.77)
5d (5.58)
7
1
0
3d (4.35)

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

7576
Scheme 2. Epimerisation via a 14-arylethylcodeinone (17)
3
. Conclusions
The use of perchloric acid has led to a considerably improved method for generating
b-thevinones. The extent of epimerisation has been shown to be controlled by the nature of the
,14-bridge with the more bulky ethano bridge leading to greater amounts of b-epimer.
7
6
Similarly, the ketone side chain also influences the outcome, with the bulky t-butyl ketone
providing a greater proportion of 7b-epimer at equilibrium.
Acknowledgements
This work was supported by NIDA (OTDP Medications Development Division) Grant DA
0
7315.
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