Cinnamoyl derivatives of 7a-amino- and 7a-(aminomethyl)- N-(cyclopropylmethyl)-6,14-endo-ethanotetrahydronororipavines are high-potency opioid antagonists

Article abstract of DOI:10.1002/1522-2675(20001220)83:12<3122::AID-HLCA3122>3.0.CO;2-2

Methods have been developed for the synthesis of 7a-amino- and 7a-(aminomethyl)-N-cyclopropylmethyl-6.14-endo-ethanotetrahydronororipavines and their cinnamoyl derivatives (Schemes 1 and 3). In displacement binding assays, the cinnamoyl derivatives 4c and

Full text of DOI:10.1002/1522-2675(20001220)83:12<3122::AID-HLCA3122>3.0.CO;2-2

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Helvetica Chimica Acta ± Vol. 83 (2000)
Cinnamoyl Derivatives of 7a-Amino- and 7a-(Aminomethyl)-
N-(cyclopropylmethyl)-6,14-endo-ethanotetrahydronororipavines
are High-Potency Opioid Antagonists
by Ian Derricka), Stephen M. Husbandsa), Jillian Broadbearb), John R. Traynorb), James H. Woodsb),
and John W. Lewis*a)
a) School of Chemistry, University of Bristol, Bristol, BS8 1TS, U.K.
b) Department of Pharmacology, University of Michigan, Ann Arbor, USA
Methods have been developed for the synthesis of 7a-amino- and 7a-(aminomethyl)-N-cyclopropylmeth-
yl-6,14-endo-ethanotetrahydronororipavines and their cinnamoyl derivatives (Schemes 1 and 3). In displace-
ment binding assays, the cinnamoyl derivatives 4c and 5c had high affinity for opioid receptors, but no particular
selectivity for any receptor type or differences in affinity between 4c and 5c (Table 1). In tissue assays for opioid
receptor function, in which both 4c and 5c were potent antagonists, the aminomethyl derivative 5c was 20- to 70-
fold more potent than the amino derivative 4c (Table 2). These data are in keeping with previously reported in
vivo data and confirm the major effect of the methylene spacer in 5c.
Introduction. ± Understanding of the function of receptor systems is dependent on
the availability of selective antagonists and enhanced by the availability of selective
irreversible antagonists or affinity ligands. The first selective irreversible m-opioid
antagonist was b-funaltrexamine (b-FNA; 1) [1 ± 3], which has been widely used but
suffers from short-lived k-agonist activity that must be allowed to wane before it can be
effectively used. More recently, a series of cinnamoyl derivatives of 14b-amino-N-
(cyclopropylmethyl)-4,5a-epoxy-3-hydroxymorphinan-6-one), including clocinnamox
(C-CAM; 2a) and methcinnamox (M-CAM; 2b), have been reported [2] to have
selective irreversible m-antagonist activity without any agonist activity. The ring-C-
bridged series of oripavine derivatives called orvinols, e.g. 3, have a variety of
opioid profiles including the antagonist diprenorphine (Revivonꢀ; 3a) and the partial
agonist buprenorphine (Temgesicꢀ; 3b), which is used clinically as an analgesic
and for the pharmacotherapy of opiate abuse [3]. In the orvinol series, the side chain
at C(7) critically determines the opioid profile. In the orvinol series 3, very few
pure opioid antagonists were discovered. Diprenorphine (3a) is a m antagonist but
also has partial k-agonist effects; only the primary and secondary alcohols 3c ± e had
no agonist effects in rodent antinociceptive tests [4]. It was thus of interest to introduce
at the 7a position the cinnamoylamino group present in C-CAM (2a) and M-CAM
(2b). We here report the synthesis of the precursor amines 4a and 5a1) and two
cinnamoylamino derivatives 4c and 5c in which this group is attached in a-position
at C(7) of the bridged oripavine structure directly or separated by a methylene
1
)
Preliminary accounts of this research were given at the ꢁInternational Narcotics Research Conferenceꢂ, St.
Andrews, Scotland, 1995, and ꢁCollege on Problems of Drug Dependenceꢂ, San Juan, Puerto Rico, 1996.

Helvetica Chimica Acta ± Vol. 83 (2000)
3123
spacer, respectively. For these derivatives, we also report in vitro pharmacological
evaluation.
Synthesis. ± The planned route to the 7a-amino precursor 4a involved initial
Schmidt reaction with N-(cyclopropylmethyl)nordihydrothevinone 6 to give the 7a-
(acetylamino) derivative 4d. The thevinone derivative 6 was prepared by Diels-Alder
reaction of N-(cyclopropylmethyl)northebaine 7 with methyl vinyl ketone and hydro-
genation of the adduct 8 (Scheme 1). However, the Schmidt reaction conditions
promoted epimerization of the ketone 6 and resulted in formation of a substantial
amount of the epimeric 7b-amino derivative 9 [5]. Since the Schmidt reaction with
thevinone (10) had not been reported to give any epimerization [6], the route to the

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Helvetica Chimica Acta ± Vol. 83 (2000)
amino-ethano derivative 4a was modified to delay hydrogenation of the etheno bridge
until after the Schmidt reaction and hydrolysis of the acetylamino group (Scheme 1).
The 7a-amino-etheno intermediate 11 had been previously reported [7] but was
prepared by a different route from thevinone (10) via the Schmidt reaction followed by
conversion of the N-methyl to the N-(cyclopropylmethyl) group. In our synthesis, 11
was obtained in 42% overall yield from 7. Hydrogenation and 3-O-demethylation with
KOH in digol (ˆdiethylene glycol) at 2108 afforded the oripavine derivative 4a, which
Scheme 1
i) HClO4, NaN3. ii) 5n HCl, 108. iii) H2, Pd/C, 30 psi. iv) KOH, digol, reflux. v) NaHCO3, cinnamoyl chloride,
DCM then MeOH/H2O 9 :1, K2CO3.

Helvetica Chimica Acta ± Vol. 83 (2000)
3125
was converted to the cinnamamide 4c via the 3-(cinnamoyloxy)-7a-(cinnamoylamino)
derivative followed by mild base hydrolysis in 57% overall yield from 11.
For the synthesis of the required 7a-(aminomethyl) precursor 5a, the direct route
from N-(cyclopropylmethyl)dihydronorthevinal (12), involving reductive amination or
reduction of the oxime, gave, in our hands, very poor yields of the 7a-(aminomethyl)
intermediate 5a. Furthermore, reduction of a primary amide, e.g. of 13b, could be ruled
out since, on treatment with LiAlH4, the N-methyl analogue 13a was shown to undergo
dehydration ( ! 14a) and rearrangement before reduction ( ! 15a; Scheme 2) [8].
Thus, an indirect route was chosen, taking advantage of the finding that secondary and
tertiary amides equivalent to 13 were reduced smoothly with LiAlH4 to the
corresponding amines [8]. This route is shown in Scheme 3.
Scheme 2
i) LiAlH4.
The ethyl 7a-carboxylate derivative 16 [9] was hydrolysed, and the acid converted
via its chloride to the benzylamide 17. The latter was reduced by LiAlH4 to the
corresponding 7a-[(benzylamino)methyl]-etheno derivative 18, which was hydro-
genated to reduce the etheno bridge and hydrogenolyse the benzylamino group. 3-O-
Demethylation gave the (aminomethyl)oripavine derivative 5a, which was acylated
with excess of the cinnamoyl chloride to give the 3-O, 7-N-biscinnamoyl derivative from
which the free phenol derivative 5c was generated under mildly basic conditions.
Pharmacology. ± The cinnamoyl derivatives 4c and 5c were evaluated in opioid
receptor displacement binding assays in guinea pig brain membranes in which the
displaced radioligands were [3H]DAMGO (m), [3H]DPDPE (d), and [3H]U69593 (k)
(Table 1) [10]. The new ligands displayed high affinity for all the opioid receptor types
with no selectivity. The order of affinity was m ˆ d ꢀ k, whereas for the standard m-
affinity ligand b-FNA (1), there was significant selectivity for m over d but not over k.

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Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme 3
i) 12n HCl, steam bath. ii) oxalyl chloride, DCM, DMF. iii) PhCH2NH2, DCM, NEt3. iv) LiAlH4, THF, reflux.
v) H2, 30 psi, 458, EtOH. vi) cinnamoyl chloride, DCM, NaHCO3 then MeOH/H2O 9 :1, K2CO3.
Table 1. Affinities of Ligands 4c, 5c, and 1 in Opioid Receptor Binding Assays in Guinea Pig Brain Membranes
Ki /nm
m: [3H]DAMGO
d: [3H]Cl-DPDPE
k: [3H]U69593
4c
5c
0.9 Æ 0.35
0.7 Æ 0.25
0.4 Æ 0.05
1.1 Æ 0.35
0.7 Æ 0.05
7.7 Æ 2.4
1.3 Æ 0.45
2.6 Æ 0.00
0.9 Æ 0.05
b-FNA (1)
The cinnamoylamino derivative 4c had no agonist activity in the mouse vas deferens
opioid functional assay [10] but was a potent antagonist, again without selectivity
(Table 2). Of particular interest was the extreme potency of the (cinnamoylamino)-
methyl analog 5c; as a m antagonist, it was 70-times more potent than the equivalent
cinnamoylamino derivative 4c. The potency of 5c as a d and a k antagonist was also 20-
fold greater than that of 4c. The (cinnamoylamino)methyl derivative 5c had no agonist
activity in the guinea pig ileum functional assay [10], but the cinnamoylamino
derivative 4c displayed partial agonist activity with 37% maximum inhibition at
Table 2. Opioid Antagonist Activity of 4c and 5c in Mouse Vas Deferens Preparation
Ke/nm
m: vs. DAMGO
d: vs. Cl-DPDPE
k: vs. U69593
4c
5c
0.56 Æ 0.15
0.94 Æ 0.14
1.24 Æ 0.12
0.008 Æ 0.0006
0.044 Æ 0.005
0.052 Æ 0.003

Helvetica Chimica Acta ± Vol. 83 (2000)
3127
12.5 nm. This activity could not be removed by repeated washing of the tissue nor
reversed by the selective opioid antagonists CTAP (m) and norBNI (k). This indicates
that opioid receptor binding in this tissue is noncompetitive.
These data are complementary to those from mouse antinociceptive tests reported
earlier [11]. In these in vivo assays, the (cinnamoylamino)methyl derivative 5c had very
little opioid agonist activity and was a powerful irreversible m-selective antagonist. In
contrast, the cinnamoylamino derivative 4c was a full agonist in the AcOH-induced
writhing assay and had very modest m-antagonist activity.
It can be concluded that irreversible binding and potent m-antagonist activity is
sensitive to the position of the cinnamoylamino group and requires a methylene spacer
to link it to C(7) in the a-position.
This work was supported by NIDA (OTDP, Division of Treatment Research & Development) Grants DA
00254 and DA 07315 and pharmacological evaluation carried out at SRI under NIDA contract NO1DA ± 8307.
Experimental Part
General. All reagents were used as supplied by Aldrich. Flash column chromatography (FC): silica gel 60
(Fluka). TLC: Al-sheets coated with silica gel F254. M.p.: Reicher hot-stage microscope; uncorrected. IR
Spectra: Perkin-Elmer 881 spectrophotometer. 1H- and 13C-NMR Spectra: at 300 and 75 MHz, resp.; Jeol-JNM-
GX-FT-300 spectrometer, at 208 in CDCl3 unless otherwise stated, with SiMe4 as internal standard; d in ppm, J in
Hz. Mass spectra: Fisons Autosampler instrument; electron-impact ionisation (70 eV). Elemental analyses were
obtained by means of a Perkin-Elmer-240C analyser.
1-[(5a,7a)-17-(Cyclopropylmethyl)-4,5-epoxy-3,6-dimethoxy-6,14-ethenomorphinan-7-yl]ethenone (8).
Methyl vinyl ketone (18.6 ml, 229 mmol) containing N-(cyclopropylmethyl)northebaine ˆ 17-cyclopropyl-
methyl)-6,7,8,14-tetradehydro-4,5a-epoxy-3,6-diepoxymorphinane, 7; 7.0 g, 19.9 mmol) and two crystals of
quinol were refluxed for 2 h. After cooling to r.t., the soln. was diluted with AcOEt (50 ml) and extracted with
1n HCl (2 Â 75 ml). The combined aq. phases were alkalinised to pH 10 with NH4OH, and the product was
extracted with AcOEt (3 Â 150 ml). The combined org. phase was dried (Na2SO4) and evaporated. FC (SiO2
1
(45 ml), Et2O yielded 8.4 g (100%) of 8. Off-white foam. IR: 1700 (CO). H-NMR: 6.62 (d, J ˆ 8, HꢁC(2));
6.51 (d, J ˆ 8, HꢁC(1)); 5.89 (d, J ˆ 9, HꢁC(18)); 5.59 (d, J ˆ 9, HꢁC(19)); 4.59 (d, J ˆ 1.4, HꢁC(5)); 3.81
(s, MeOꢁC(3)); 3.60 (s, MeOꢁC(6)); 2.14 (s, MeCO). 13C-NMR: 208.99, 147.97, 141.75, 136.10, 134.03, 128.05,
125.63, 119.15, 113.34, 95.21, 81.40, 59.82, 57.15, 56.73, 53.54, 50.64, 48.27, 43.99, 43.26, 33.67, 30.45, 29.91, 23.16,
‡
9.45, 4.12, 3.39. EI-MS: 421 (100, M ).
1-[(5a,7a)-17-(Cyclopropylmethyl)-4,5-epoxy-3,6-dimethoxy-6,14-ethanomorphinan-7-yl]ethenone (6). A
mixture of 8 (22.8 g, 54.2 mmol) and 10% Pd/C (1.05 g) in EtOH was hydrogenated at 608/50 psi for 122 h. The
catalyst was then removed by filtration through Celite and the filtrate evaporated to leave a foam.
Recrystallization from EtOH yielded 14.9 g (65%) of 6. White prisms. M.p. 111 ± 1128. IR: 1705 (CO).
1H-NMR: 6.71 (d, J ˆ 8, HꢁC(2)); 6.56 (d, J ˆ 8, HꢁC(1)); 4.51 (s, HꢁC(5)); 3.87 (s, MeOꢁC(3)); 3.44
(s, MeOꢁC(6)); 2.27 (s, MeCO). 13C-NMR: 211.1, 146.8, 141.7, 132.7, 128.8, 119.2, 113.9, 94.7, 76.6, 59.8, 58.4,
‡
56.7, 52.2, 49.7, 46.5, 43.8, 35.3, 33.8, 30.4, 28.7, 22.8, 17.5, 9.4, 4.1, 3.3. EI-MS: 423 (100, M ).
(5a,7a)-17-(Cyclopropylmethyl)-4,5-epoxy-3,6-dimethoxy-6,14-ethenomorphinan-7-amine (11). To a vigor-
ously stirred soln. of 8 (8.4 g, 20.0 mmol) in 35% aq. perchloric acid soln., NaN3 (0.35 g, 53.9 mmol) was added.
The mixture was then heated to 708 for 5 h. After cooling to r.t., conc. NH4OH soln. was added ( ! pH 10), the
mixture extracted with AcOEt (3 Â 100 ml), the combined extract dried (Na2SO4) and evaporated and the
residue submitted to FC (2.5% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.): 7.66 g (88.0%) of acetamide. IR:
1662. 1H-NMR: 6.62 (d, J ˆ 8, HꢁC(2)); 6.52 (d, J ˆ 8, HꢁC(1)); 5.65 (d, J ˆ 9, HꢁC(18)); 5.58 (d, J ˆ 9,
HꢁC(19)); 4.55 (d, J ˆ 6, NHCO); 4.72 (s, HꢁC(5)); 3.82 (s, MeOꢁC(3)); 3.48 (s, MeOꢁC(6)); 1.96
(s, MeCO). 13C-NMR: 169.8, 147.9, 141.9, 138.2, 134.2, 127.9, 126.7, 119.3, 113.0, 90.5, 80.1, 59.8, 57.1, 56.3,
‡
51.1, 47.8, 45.4, 43.8, 42.3, 36.0, 33.1, 23.3, 23.0, 9.4, 3.9, 3.5. EI-MS: 436 (89, M ).
A soln. of the acetamide (7.64 g, 17.5 mmol) in 5n HCl (25 ml) was stirred at 108 for 22 h. The mixture was
cooled to r.t. and then alkalinised with conc. NH4OH soln. ( ! pH 10). After extraction with AcOEt (3 Â
50 ml), the combined org. phase was dried (Na2SO4) and evaporated and the residue submitted to FC (5%
MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.). 4.12 g (60%) of 11. Rf (5% MeOH/CH2Cl2 ‡ 1% conc. NH4OH

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Helvetica Chimica Acta ± Vol. 83 (2000)
soln.) 0.40. IR: 3369 (NH2). 1H-NMR: 6.62 (d, J ˆ 8, HꢁC(2)); 6.52 (d, J ˆ 8, HꢁC(1)); 5.73 (d, J ˆ 10,
HꢁC(18)); 5.58 (d, J ˆ 10, HꢁC(19)); 4.52 (s, HꢁC(5)); 3.82 (s, MeOꢁC(3)); 3.62 (s, MeOꢁC(6)). 13C-NMR:
147.9, 141.9, 136.9, 134.6, 128.1, 119.2, 113.3, 94.4, 82.5, 59.7, 57.1, 49.1, 47.9, 44.0, 42.4, 35.3, 33.1, 23.0, 9.4, 4.1, 3.4.
‡
‡
EI-MS: 394 (82, M ). HR-MS: 394.225685 (C24H30N2O3 ; calc. 394.225643).
(5a,7a)-7-Amino-17-(cyclopropylmethyl)-4,5-epoxy-6-methoxy-6,14-ethanomorphinan-3-ol (4a). A soln.
of 11 (4.12 g, 10.4 mmol) in EtOH (100 ml) was hydrogenated over 10% Pd/C (0.5 g) for 13 h at 30 psi. The
catalyst was filtered off and the filtrate evaporated: 3.92 g (95%) of pure ethano-amine. Rf (5% MeOH/
CH2Cl2 ‡ 1% conc. NH4OH) 0.46. IR: 3409 (NH2). 1H-NMR: 6.70 (d, J ˆ 9, HꢁC(2)); 6.53 (d, J ˆ 9, HꢁC(1));
4.41 (s, HꢁC(5)); 3.89 (s, MeOꢁC(3)); 3.50 (s, NH2ꢁC(7)); 3.43 (s, MeOꢁC(3)). 13C-NMR: 146.9, 141.8,
132.7, 128.5, 119.0, 113.6, 92.4, 77.4, 59.8, 58.4, 56.6, 51.1, 48.1, 46.0, 43.7, 37.4, 35.5, 35.1, 28.8, 22.6, 16.5, 9.4, 3.9,
‡
‡
3.4. EI-MS: 396 (100, M ). HR-MS: 396.241249 (C24H32N2O3 ; calc. 396.241293).
KOH (23.7 g, 422 mmol) was added to the ethano-amine (3.32 g, 8.4 mmol) in digol (ˆdiethylene glycol;
50 ml), and the mixture was refluxed for 11 h before cooling to r.t. Orthophosphoric acid (1m, 534 ml) was added
and the soln. washed with Et2O (540 ml) before alkalinising the aq. layer with conc. NH4OH soln. and extracting
with CH2Cl2 (4 Â 350 ml). The combined extract was dried (Na2SO4) and evaporated and the crude product
purified by FC (5% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.): 2.21 g (69%) of 4a. Rf (10% MeOH/CH2Cl2 ‡
1% conc. NH4OH soln.) 0.41. 1H-NMR: 6.68 (d, J ˆ 8, HꢁC(2)); 6.52 (d, J ˆ 8, HꢁC(1)); 4.42 (s, HꢁC(5));
‡
‡
3.40 (s, MeOꢁC(6)). EI-MS: 382 (100, M ). HR-MS: 382.224571 (C23H32NO6 ; calc. 382.225643).
N-[(5a,7a)-17-(Cyclopropylmethyl)-4,5-epoxy-3-hydroxy-6-methoxy-6,14-ethanomorphinan-7-yl]-3-phen-
ylprop-2-enamide (4c). To a soln. of 4a (0.44 g, 1.15 mmol) in CH2Cl2 (15 ml), NaHCO3, (0.68 g, 8.05 mmol) was
added. To this suspension, a soln. of freshly prepared cinnamoyl chloride (0.42 g, 2.53 mmol) in CH2Cl2 (15 ml)
was added, and then, 5 min later, H2O (3 ml) was added. The mixture was agitated vigorously for 15 min. Then
the aq. layer was neutralized with 2n HCl and extracted with CH2Cl2 (3 Â 30 ml). The combined org. phase was
dried (Na2SO4) and evaporated. The residue was dissolved in MeOH/H2O 9 :1, K2CO3 (0.80 g, 5.75 mmol)
added, and this suspension stirred for 12 h. The MeOH was removed in vacuo, the crude product extracted with
CH2Cl2 (3 Â 20 ml), the combined extract dried (Na2SO4) and evaporated, and the residue purified by FC (5%
MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.): 0.51 g (87%) of 4c. M.p. 162 ± 1648. Rf (AcOEt ‡ 1% conc. NH4OH
soln.) 0.45. IR: 1666 (NHCO). 1H-NMR: 7.65 (d, J ˆ 16, CˆCH); 7.51 (m, 2 H of Ph); 7.36 (m, 3 H of Ph); 6.72
(d, J ˆ 8, HꢁC(2)); 6.53 (d, J ˆ 8, HꢁC(1)); 6.47 (d, J ˆ 16, CˆCH); 4.64 (s, HꢁC(5)); 3.38 (s, MeOꢁC(6)).
13C-NMR: 166.2, 145.5, 141.0, 137.8, 134.6, 132.1, 129.4, 128.7, 128.5, 127.9, 127.6, 127.3, 120.5, 119.5, 116.9, 88.3,
‡
76.0, 59.7, 58.2, 50.0, 45.7, 45.0, 43.4, 35.3, 34.9, 28.6, 22.5, 19.5, 9.2, 3.7, 3.5. EI-MS: 512 (97, M ). HR-MS:
‡
512.269058 (C32H36N2O4 ; calc. 512.267508). Anal. calc. for C32H36N2O4 ´ (CO2H)2 ´ 2.5 H2O: C 63.1, H 6.4, N 4.3;
found: C 63.1, H 6.1, N 4.0.
(5a,7a)-N-Benzyl-17-(cyclopropylmethyl)-4,5-epoxy-3,6-dimethoxy-6,14-ethenomorphinan-7-carboxamide
(17). A soln. of 16 (13.5 g, 29.9 mmol) in 2m HCl (65 ml) was heated on a steam bath for 3 h. The resulting soln.
was diluted with ice-water and the resulting precipitate filtered off and recrystallized (2Â) from EtOH. To this
solid (8.13 g, 17.7 mmol) in CH2Cl2 (120 ml), oxalyl chloride (3.08 ml, 35.4 mmol) was added under N2. DMF
(0.1 ml) was added and the resulting soln. stirred at r.t. for 1.5 h before evaporating the solvents to leave the
crude acid chloride as an off-white solid. This was dissolved, without purification, in CH2Cl2 (100 ml) under N2 at
08 before adding Et3N (5.4 ml, 38.9 mmol), followed by benzylamine (2.12 ml, 19.4 mmol). The temp. was
allowed to rise to r.t. within 1.5 h before filtration. The filtrate was evaporated and the crude product purified by
FC (1% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.): 5.72 g (63%) of 17. M.p. 94 ± 958. Rf (2.5% MeOH/CH2Cl2 ‡
1% conc. NH4OH soln.) 0.54. IR: 1663 (CONH). 1H-NMR: 7.4 ± 7.1 (m, PhCH2); 6.58 (d, J ˆ 8, HꢁC(2)); 6.50
(m, CONH); 6.45 (d, J ˆ 8, HꢁC(1)); 5.90 (d, J ˆ 9, HꢁC(18)); 5.55 (d, J ˆ 9, HꢁC(19)); 4.51 (s, HbꢁC(5));
4.41 (m, PhCH2); 3.79 (s, MeOꢁC(3)); 3.60 (s, MeOꢁC(6)). 13C-NMR: 172.37, 147.77, 141.66, 138.45, 136.88,
134.23, 128.34, 128.11, 127.27, 127.00, 125.51, 119.30, 113.31, 94.76, 80.53, 59.61, 56.86, 56.42, 52.94, 47.72, 44.65,
‡
43.80, 43.33, 42.79, 33.30, 30.64, 23.02, 9.30, 3.99, 3.26. EI-MS: 512 (94.5, M ). HR-MS: 512.268539
‡
(C32H36N2O4 ; calc. 512.267508).
(5a,7a)-N-Benzyl-17-(cyclopropylmethyl)-4,5-epoxy-3,6-dimethoxy-6,14-ethenomorphinan-7-methan-
amine (18). A soln. of 17 (5.72 g, 11.2 mmol) in THF (20 ml) was added dropwise to a refluxing soln. of LiAlH4
(0.95 g, 24.5 mmol) in THF (10 ml). The mixture was cooled to r.t. after 20 h, Na2SO4 ´ 10H2O (2 g) added, and
the mixture stirred for a further 1 h. The mixture was filtered through Celite; the filtrate evaporated, and the
residue submitted to FC (2.5% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.): 3.94 g of 18 (71%). Colorless foam.
Rf (10% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.) 0.59. IR: 3350 (NH2). NMR: complex due to rotamers. EI-
‡
‡
MS: 498 (84.7, M ). HR-MS: 498.286774 (C32H38N2O3 ; calc. 498.288243).

Helvetica Chimica Acta ± Vol. 83 (2000)
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(5a,7a)-7-(Aminomethyl)-17-(cyclopropylmethyl)-4,5-epoxy-6-methoxy-6,14-ethanomorphinan-3-ol (5a).
A soln. of 18 (2.25 g, 1.26 mmol) in EtOH was hydrogenated at 458/30 psi over 10% Pd/C (445 mg) for 2.5 h.
The mixture was then filtered through Celite, the filtrate evaporated, and the crude product purified by FC
(7.5% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.): 1.41 g of ethano-amine (76%). Rf (10% MeOH/CH2Cl2 ‡ 1%
conc. NH4OH soln.) 0.47. IR: 3383 (NH2). 1H-NMR: 6.65 (d, J ˆ 8, HꢁC(2)); 6.58 (d, J ˆ 8, HꢁC(1)); 4.53
(s, HꢁC(5)); 3.88 (s, MeOꢁC(3)); 3.41 (s, MeOꢁC(3)). 13C-NMR: 146.90, 141.70, 132.74, 128.61, 118.94,
113.37, 92.27, 76.90, 59.93, 58.53, 56.53, 50.73, 45.60, 43.93, 43.78, 38.42, 35.52, 35.40, 33.44, 29.30, 22.59, 19.25,
‡
‡
9.44, 4.07, 3.45. EI-MS: 410 (100, M ). HR-MS: 410.256607 (C25H34N2O3 ; calc. 410.256943).
To the ethano-amine (1.41 g, 3.43 mmol), digol (25 ml) was added, followed by freshly ground KOH (10 g,
178.2 mmol). The mixture was stirred under reflux for 8 h before cooling to r.t. and adding 1m orthophosphoric
acid (222 ml). The resulting soln. was washed with Et2O (250 ml) and then the aq. layer basified with conc.
NH4OH soln. and extracted with CH2Cl2 (4 Â 220 ml). The combined extract was washed with H2O (2 Â
100 ml), dried (Na2SO4), and evaporated. FC (10% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.) gave 0.96 g
(71%) of 5a. M.p. 116 ± 1198. Rf (10% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.) 0.24. IR: 3576 (NH2).
1H-NMR: 6.68 (d, J ˆ 8, HꢁC(2)); 6.48 (d, J ˆ 8, HꢁC(1)); 4.49 (s, HꢁC(5)); 3.38 (s, MeOꢁC(6)). 13C-NMR:
145.65, 137.90, 132.42, 127.58, 119.50, 116.85, 92.07, 77.14, 59.97, 58.68, 50.55, 45.87, 43.77, 43.68, 38.02, 35.70, 35.38,
‡
‡
33.50, 29.22, 22.75, 15.40, 9.45, 4.02, 3.47. EI-MS: 396 (100, M ). HR-MS: 396.240959 (C24H32N2O3 ; calc.
396.241293).
N-{[(5a,7a)-17-(Cyclopropylmethyl)-4,5-epoxy-3-hydroxy-6-methoxy-6,14-ethanomorphinan-7-yl]meth-
yl}-3-phenylprop-2-enamide (5c). As described for 4c, with 5a (0.22 g, 0.55 mmol), CH2Cl2 (10 ml), NaHCO3
(0.32 g, 3.85 mmol), cinnamoyl chloride (0.20 g, 1.2 mmol), CH2Cl2 (10 ml) and H2O (2 ml). Hydrolysis with
MeOH/H2O 9 :1 and K2CO3 (0.39 g, 2.8 mmol). FC (10% MeOH/CH2Cl2 ‡ 1% conc. NH4OH soln.) gave 0.21 g
(71%) of 5c. M.p. 1788. Rf (AcOEt ‡ 1% conc. NH4OH soln.) 0.34. IR: 1662 (CONH). 1H-NMR: 7.62 (d, J ˆ 15,
CˆCH); 7.49 (d, J ˆ 9, 2 H of Ph); 7.25 (m, 3 H of Ph); 6.73 (d, J ˆ 8, HꢁC(1)); 6.52 (d, J ˆ 8, HꢁC(2)); 6.48
(m, CONH); 6.38 (d, J ˆ 15, CˆCH); 4.47 (s, HꢁC(5)); 3.49 (s, MeOꢁC(6)). 13C-NMR: 166.07, 145.6, 140.9,
137.8, 134.9, 132.4, 129.6, 128.8, 127.8, 127.6, 121.0, 119.5, 116.9, 93.0, 77.7, 59.9, 58.5, 51.2, 46.0, 43.7, 41.8, 35.5, 35.1,
‡
‡
33.2, 29.0, 22.7, 18.4, 9.4, 3.5. EI-MS: 526 (85, M ). HR-MS: 526.282455 (C33H38N2O4 ; calc. 526.283158). Anal.
calc. for C33H38N2O4 ´ 2 H2O: C 64.4, H 6.8, N 4.3; found: C 64.9, H 6.4, N 4.0.
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Received June 9, 2000