Regio- and stereoselective derivatisation of an aporphine scaffold

Article abstract of DOI:10.3987/COM-13-S(S)39

Treatment of 10,11-dimethoxyaporphine with chromium hexacarbonyl was found to give two diastereoisomeric products on regioselective co-ordination of the chromium tricarbonyl fragment to the A ring. For one of the diastereoisomeric complexes, alkylation was found to proceed with high regio- and diastereoselectivity at C(4), whereas regio- and diastereoselective alkylation was observed at C(6a) for the other diastereoisomer. In the case of the C(4)- and C(6a)-methylated products, these substrates were decomplexed in high yield to give the corresponding enantiopure, C(4)- and C(6a)-methyl substituted aporphines.

Full text of DOI:10.3987/COM-13-S(S)39

HETEROCYCLES, Vol. 88, No. 1, 2014
765
HETEROCYCLES, Vol. 88, No. 1, 2014, pp. 765 - 777. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 20th June, 2013, Accepted, 29th July, 2013, Published online, 31st July, 2013
DOI: 10.3987/COM-13-S(S)39
REGIO- AND STEREOSELECTIVE DERIVATISATION OF AN
APORPHINE SCAFFOLD†
Jonathan D. M. Atkinson, Stephen G. Davies,* and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K.
Abstract – Treatment of 10,11-dimethoxyaporphine with chromium hexacarbonyl
was found to give two diastereoisomeric products on regioselective co-ordination
of the chromium tricarbonyl fragment to the A ring. For one of the
diastereoisomeric complexes, alkylation was found to proceed with high regio- and
diastereoselectivity at C(4), whereas regio- and diastereoselective alkylation was
observed at C(6a) for the other diastereoisomer. In the case of the C(4)- and
C(6a)-methylated products, these substrates were decomplexed in high yield to
give the corresponding enantiopure, C(4)- and C(6a)-methyl substituted
aporphines.
Interest in apomorphine is associated with its activity as a dopaminergic agonist and its consequential
1
anti-Parkinsonian activity. Clinical utility has been demonstrated for apomorphine alone, and in
2
combination with other agents such as levodopa. Additionally, potential uses of apomorphine in
ameliorating the symptoms of Huntingdon’s chorea, tardive dyskinesia Gilles de la Tourette’s syndrome
3
and schizophrenia have been indicated. (–)-(R)-Apomorphine, which is synthesised commercially by the
4
acid catalysed rearrangement of (–)-morphine, has been shown to display dopamine agonist activity, whilst
its antipode (+)-(S)-apomorphine, which is a known dopamine antagonist, is accessible via resolution of the
5
racemate. Molecular modelling studies have shown that the apomorphine-like spatial arrangement of the
catechol ring, the nitrogen atom and the nitrogen lone pair (or N–H atom in the case of the corresponding
6
ammonium ions) is required for dopamine agonist activity; these findings were consistent with observed
7
biological activities, and this has made the apomorphine ring system an attractive scaffold for studying the
effect of structure on dopamine receptor activity. Previous work concerning the modification of this ring
*
†
Corresponding Author. E-mail: steve.davies@chem.ox.ac.uk
Dedicated to Professor Victor Snieckus on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 88, No. 1, 2014
8
system has largely focused on manipulation of either the aromatic rings or nitrogen functionality. A unique
procedure for the regio- and stereoselective functionalisation of this scaffold at either the C(4)- or
C(6a)-benzylic positions by manipulation of the corresponding arene chromium tricarbonyl complexes is
reported herein.
As part of our extensive research programme concerning the utility of arene chromium tricarbonyl
9
complexes in stereoselective synthesis, we have previously investigated the regio- and stereoselective
1
0
6
functionalisation of N(2)-methyltetrahydroisoquinolines. For example, thermolysis of Cr(CO) with 1
generated the corresponding arene chromium tricarbonyl complex 2 in 78% yield. Regioselective
deprotonation of 2 at the C(4) position with BuLi, followed by treatment of the resultant chromium
stabilised benzylic anion 3 (deep red colour) with a range of electrophiles (e.g., MeI, EtI, BnBr, etc.)
proceeded with high diastereoselectivity, with reaction occurring on the uncomplexed face in all cases.
2
Oxidative decomplexation upon standing solutions of the substituted complexes 4 in Et O and exposing
them to air and sunlight generated the corresponding 4-substituted-N(2)-methyltetrahydroisoquinolines 5 in
high yield (Scheme 1).
Scheme 1. Reagents and conditions: (i) Cr(CO)
h; (iii) RX, THF, –78 °C, 2 h; (iv) O , hν, Et O.
6 2
, Bu O/THF (10:1), reflux, 29 h; (ii) BuLi, THF, –78 °C, 2
2
2
6 2
Attempted thermolysis of Cr(CO) with apomorphine 6 in a 10:1 mixture of Bu O and THF resulted in
degradation of the chromium reagent and no complexation to 6 was observed. The catechol functionality
within 6 was therefore masked by conversion to 10,11-dimethoxyaporphine 7 upon treatment with freshly
5
a,b
6
prepared diazomethane which gave 7 in 88% isolated yield. Thermolysis of Cr(CO) with 7, under our
standard complexation conditions, afforded only two of the possible four products which were both
attributable to binding of the chromium to the A ring within 7. After chromatographic purification both 8
and 9 were isolated as single diastereoisomers (>99:1 dr) in 30 and 33% yield, respectively (Scheme 2). The
1
regioselectivity of this reaction was initially assigned by H NMR spectroscopic analysis: in both cases the
1
H NMR spectra of 8 and 9 contained three aromatic resonances which had all been shifted upfield by ~2

HETEROCYCLES, Vol. 88, No. 1, 2014
767
ppm, indicating that 8 and 9 were related as diastereoisomers. The relative configurations within
1pS,6aR)-8 and (1pR,6aR)-9 were determined by a series of derivatisation experiments and these
(
assignments were subsequently confirmed unambiguously by single crystal X-ray diffraction analysis of a
derivative of (1pS,6aR)-8.
2 2 2 6 2
Scheme 2. Reagents and conditions: (i) CH N (in Et O), MeOH, rt, 26 h; (ii) Cr(CO) , Bu O/THF (10:1),
reflux, 15 h.
It was predicted that deprotonation of either 8 or 9 (both >99:1 dr) with BuLi would proceed to give the
corresponding chromium stabilised benzylic anions, resulting from deprotonation of either the C(4)H or
C(6a)H protons. Indeed, treatment of 8 and 9 with BuLi, followed by treatment of the deep red solutions of
4
the corresponding anionic species with MeOH-d generated the C(6a)- and C(4)-deuterio substituted
complexes 10 and 11, respectively, with high regio- and diastereoselectivity. Subsequent metalation of
either deuterated complex 10 or 11 with BuLi, followed by treatment with MeOH, liberated the parent
complexes 8 and 9, respectively, in quantitative yield (Scheme 3).
Scheme 3. Reagents and conditions: (i) BuLi, THF, –78 °C, 1 h then MeOH-d
h then MeOH.
4
; (ii) BuLi, THF, –78 °C,
1

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HETEROCYCLES, Vol. 88, No. 1, 2014
The regio- and diastereoselective alkylation of these complexes was investigated next. In the case of 8,
deprotonation with BuLi at –78 °C, followed by treatment with MeI produced C(6a)-methyl substituted
complex 12 in 58% yield and >99:1 dr. Analogous treatment of 9 produced C(4)-methyl substituted
complex 14 in 59% yield and >99:1 dr. A series of other regio- and diastereoselective alkylations also gave
1
9
3 and 15–17 as single diastereoisomers (>99:1 dr). The carbanions generated upon deprotonation of 8 and
with BuLi were next treated with aldehydes. In the case of the carbanion derived from 9 being reacted
with acetaldehyde, substitution occurred as expected at the C(4) position to give a 50:50 mixture of two
inseparable diastereoisomeric alcohols 19 which were isolated in 50% combined yield. Analogous reaction
of the anion derived from 9 with benzaldehyde produced a 67:33 mixture of epimeric alcohols 20 which
were isolated in 42 and 22% yield, respectively. However, reaction of the anion derived from 8 with
acetaldehyde produced a single diastereoisomeric product 18 which was isolated in 58% yield and >99:1 dr
(
Scheme 4). The relative configuration within 18 was unambiguously established by single crystal X-ray
11
12
diffraction analysis (Figure 1); furthermore, the determination of a Flack x parameter of 0.004(6) for the
crystal structure of 18 confirmed the absolute (1pS,6aR,1'S)-configuration within 18. This analysis
therefore also confirmed the assigned configurations within complexes 8 and 9. Representative
decomplexation reactions were carried out on the C(4)- and C(6a)-methyl substituted complexes 12 and 14:
2
in both cases, exposing solutions of these complexes in Et O to air and sunlight gave the corresponding
enantiopure, C(4)- and C(6a)-methyl substituted aporphines 21 and 22 in ≥91% yield (Scheme 4).
Scheme 4. Reagents and conditions: (i) BuLi, THF, –78 °C, 1 h then RX, –78 °C to rt, 2 h; (ii) BuLi, THF,
78 °C, 1 h then MeCHO, –78 °C, 1 h; (iii) BuLi, THF, –78 °C, 1 h then PhCHO, –78 °C, 1 h;
–
a
(
2 2
iv) O , hν, Et O. [ combined isolated yield].

HETEROCYCLES, Vol. 88, No. 1, 2014
769
2
Cr(CO)
3
3
OMe
1
1
1
MeO 10
9
4
6
N
5
7
8
Me
OH
Me
18
Figure 1. X-Ray crystal structure of (1pS,6aR,1'S)-18 (selected H atoms are omitted for clarity).
X-Ray crystal structure data for 18 [C H CrNO ]: M = 475.46, orthorhombic, P2 2 2 , a = 8.942(1) Å,
2
4
25
6
1 1 1
3
–1
b = 12.108(1) Å, c = 20.545(4) Å, V = 2224 Å , Z = 4, μ = 46.29 mm , colourless block, crystal dimensions
3
=
0.4 × 0.4 × 0.8 mm . A total of 1804 unique reflections were measured for 1 < θ < 24 and 1645 reflections
were used in the refinement. The final parameters were wR = 0.044 and R = 0.035
I > –3.0σ(I)], with Flack enantiopole = 0.004(6). CCDC 945389.
2
1
1
2
[
6
The formation of 8 and 9 as the only complexes observed upon thermolysis of Cr(CO) with 7 was initially
unexpected. Within 7 there are four possible sites for complexation: the A ring and the D ring are each able
to present two diastereotopic faces for complexation, giving rise to four possible products in which one
chromium tricarbonyl unit is bound to an arene. Despite the prediction that the rate of complexation to the
1
3,14
more electron rich D ring within 7 would be faster,
the regioselectivity observed upon thermolysis of
Cr(CO) with 7, where both products 8 and 9 are attributable to binding of the chromium to the electron
6
1
5
poor A ring, can be rationalised by inspection of crystallographic data for 18 and similar structures (all
containing a 3,4-dimethoxy-9,10-dihydrophenanthrene 23 sub unit). These data reveal that a dihedral angle
of ~25° for C(4)–C(4a)–C(4b)–C(5) (i.e., the angle of tilt about the biphenyl bond) is typically observed,
and that the C(4)-methoxy group is oriented out of the plane of the aromatic ring [the dihedral angle of the
3
C(4a)–C(4)–O–CH bond is normally between 80° and 100°]. In this sort of conformation the
C(11)-methoxy group within 7 cannot mesomerically donate electrons into the aromatic ring and exerts a
purely inductive electron withdrawing effect; the rate of complexation to the D ring is therefore slower than
might initially be expected (Figure 2). The relative configurations within the C(4)- and C(6a)-substituted
complexes 10–20 were initially assigned following the regioselective deprotonation of complexes 8 and 9:
for both 8 and 9, the increased acidity of the benzylic protons may be rationalised by considering the
configurations of these complexes, with deprotonation occurring from the uncomplexed face in each case.

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HETEROCYCLES, Vol. 88, No. 1, 2014
For 8, the exo-C(6a)–H bond lies antiperiplanar to the chromium arene-centroid axis giving rise to the
chromium stabilised conjugate base, whereas for 9 it is the exo-C(4)–H bond that lies antiperiplanar to the
chromium arene-centroid axis (Figure 2); these findings are consistent with the well known requirement for
exo-benzylic C–H bonds to be antiperiplanar to the chromium arene-centroid axis to achieve regio- and
1
6
diastereoselective deprotonation. These structural analyses are also consistent with the solid state
conformation of 18 and the experimentally determined outcomes observed upon deuteration of 8 and 9, and
dedeuteration of 10 and 11, in which regioselective (and, in the case of 9 and 11, diastereoselective)
deprotonation occurs to give the corresponding chromium stabilised benzylic anions. In all cases, retention
of configuration was observed upon reaction of the chromium stabilised benzylic anions with the requisite
electrophiles.
Figure 2. Conformational analyses of 10,11-dimethoxyaporphine 7 and arene chromium tricarbonyl
complexes 8 and 9.
3
In conclusion, the complexation of 10,11-dimethoxyaporphine with Cr(CO) enabled a series of
diastereoisoselective transformations to be carried out at either the C(4)- or C(6a)-positions with high levels
of regio- and diastereoselectivity, with alkylation occurring on the uncomplexed face in each case.
Following the decomplexation of two representative methyl substituted complexes, (R)-6a-methyl-10,11-
dimethoxyaporphine and (4S,6aR)-4-methyl-10,11-dimethoxyaporphine were isolated in high yield as
single stereoisomers.
EXPERIMENTAL
Reactions involving organometallic or other moisture-sensitive reagents were carried out under a nitrogen
or argon atmosphere using standard vacuum line techniques and glassware that was flame dried and cooled
under nitrogen before use. BuLi (as a solution in hexanes) was titrated against diphenylacetic acid before
use. Solvents were rigorously deoxydenated before use. THF was dried over sodium benzophenone ketyl
and freshly distilled before use. Bu O and CH Cl were dried over CaH and freshly distilled before use.
2
2
2
2

HETEROCYCLES, Vol. 88, No. 1, 2014
771
Cr(CO)
as supplied without prior purification. Organic layers were dried over MgSO
was performed on aluminium plates coated with 60 F254 silica. Plates were visualised using UV light (254
nm), iodine, 1% aq KMnO , or 10% ethanolic phosphomolybdic acid. Flash column chromatography was
performed on Kieselgel 60 silica. Optical rotations were recorded on a Perkin-Elmer 241 polarimeter with a
6
was steam distilled and sublimed under reduced pressure before use. All other reagents were used
4
. Thin layer chromatography
4
−
1
2
−1
water-jacketed 10 cm cell. Specific rotations are reported in 10 deg cm g and concentrations in g/100
mL. IR spectra were recorded on a Perkin-Elmer 781 spectrometer as solutions in CH Cl using 1.0 mm
2
2
–
1
cells. Selected characteristic peaks are reported in cm . NMR spectra were recorded in the deuterated
solvent stated. Spectra were recorded at rt. The field was locked by external referencing to the relevant
deuteron resonance. Mass spectra were recorded on a VG MicromassMM30F spectrometer.
(
R)-10,11-Dimethoxyaporphine 7: A freshly prepared solution of (R)-apomorphine 6 (1.01 g, 3.78 mmol)
in deoxygenated MeOH (40 mL) was treated with a solution of diazomethane in Et O, generated from
2
N-methyl-N-(p-tolylsulfonyl)nitrosamide (5.66 g, 26.4 mmol) and KOH (1.35 g, 24.1 mmol). The reaction
mixture was allowed to stand until all the unconsumed diazomethane had evapourated (~14 h), and the
reaction mixture was then concentrated in vacuo. The residue was dissolved in Et O (50 mL) and the
2
resultant solution was washed sequentially with 5.0 M aq KOH (50 mL), H
The organic layer was then dried and concentrated in vacuo to give 7 as an orange oil (990 mg, 88%);
400 MHz, CDCl ) 2.59 (3H, s, NMe), 2.53–2.63 (2H, m, C(5)H , C(7)H ), 2.78 (1H, dd, J 16.5, 3.6,
C(4)H ), 3.06–3.27 (4H, m, C(4)H , C(5)H , C(6a)H, C(7)H ), 3.71 (3H, s, OMe), 3.91 (3H, s, OMe), 6.83
1H, d, J 8.2, C(9)H), 7.00 (1H, d, J 8.2, C(8)H), 7.10 (1H, d, J 7.6, C(3)H), 7.26 (1H, dd, J 7.9, 7.6, C(2)H),
2
O (50 mL) and brine (50 mL).
5
a,b
δ
H
(
3
A
A
A
B
B
B
(
8
.24 (1H, d, J 7.9, C(1)H).
(
1pS,6aR)- and (1pR,6aR)-10,11-Dimethoxyaporphine[tricarbonylchromium(0)] 8 and 9: A solution
of 7 (845 mg, 2.86 mmol) and Cr(CO) (757 mg, 3.44 mmol) in a mixture of Bu O/THF (10:1, 50 mL) was
heated at reflux for 15 h in the dark. The reaction mixture was then allowed to cool to rt, filtered through a
pad of celite (eluent Et O), and concentrated in vacuo. Purification via flash column chromatography
6
2
2
(
eluent hexane/Et O, 1:1) and subsequent recrystallisation (hexane/Et O) gave (1pS,6aR)-8 as a yellow
2
2
2
5
crystalline solid (371 mg, 30%, >99:1 dr); []D 245.7 (c 1.3 in CH
MHz, CDCl ) 2.43 (1H, app dt, J 12.1, 4.0, C(5)H
), 2.82–2.89 (2H, m, C(6a)H, C(7)H ), 3.02 (1H, ddd, J 11.9, 5.7, 1.2, C(4)H
, C(7)H ), 3.79 (3H, s, OMe), 3.89 (3H, s, OMe), 5.12 (1H, d, J 6.1, C(3)H), 5.61 (1H, dd, J 6.9, 6.1,
2
Cl
2 H
); νmax 1959, 1882 (CO); δ (400
3
A
), 2.53 (3H, s, NMe), 2.54 (1H, ddd, J 12.1, 5.7, 2.9,
C(5)H
B
B
A
A
), 3.12–3.21 (2H, m,
C(4)H
B
+
C(2)H), 6.40 (1H, d, J 6.9, C(1)H), 6.88 (1H, d, J 8.2, C(9)H), 6.96 (1H, d, J 8.2, C(8)H); m/z (CI ) 431
+
+
+
+
(
(
[M] , 100%); HRMS (CI ) C22
H
21CrNO
5
([M] ) requires 431.0819; found 431.0820. Further elution
O) gave (1pR,6aR)-9 as a yellow
eluent Et O/MeOH, 19:1) and subsequent recrystallisation (hexane/Et
2
2

772
HETEROCYCLES, Vol. 88, No. 1, 2014
2
5
2 2 H
crystalline solid (408 mg, 33%, >99:1 dr); []D +260.0 (c 0.6 in CH Cl ); νmax 1958, 1881 (CO); δ (400
MHz, CDCl ) 2.53 (3H, s, NMe), 2.53–2.62 (3H, m, C(7)H , C(5)H ), 3.07–3.14 (2H, m, C(4)H , C(6a)H),
3
A
2
A
2
.96 (1H, ddd, J 11.6, 6.0, 2.2, C(4)H
B
), 3.22 (1H, dd, J 13.2, 4.0, C(7)H
B
), 3.90 (3H, s, OMe), 4.00 (3H, s,
OMe), 5.33 (1H, d, J 6.6, C(3)H), 5.41 (1H, dd, J 6.7, 6.6, C(2)H), 6.62 (1H, d, J 6.7, C(1)H), 6.87 (1H, d,
+
+
+
+
+
5
J 8.3, C(9)H), 6.93 (1H, d, J 8.3, C(8)H); m/z (CI ) 431 ([M] , 100%); HRMS (CI ) C22H21CrNO ([M] )
requires 431.0819; found 431.0820.
(
1pS,6aR)-6a-Deuterio-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 10: BuLi (1.64 M, 0.75
mL, 1.23 mmol) was added to a solution of 8 (110 mg, 0.26 mmol, >99:1 dr) in THF (30 mL) at –78 °C and
the resultant mixture was stirred at –78 °C for 1 h. MeOH-d (2 mL) was then added, the reaction mixture
was stirred at –78 °C for 1 h, and the resultant mixture was allowed to warm to rt. The reaction mixture was
then filtered through a pad of celite (eluent Et O) and concentrated in vacuo. Purification via flash column
chromatography (eluent Et O) gave 10 as a yellow solid (106 mg, 96%, >99:1 dr); Anal. Calcd for
4
2
2
C
22
H
20DCrNO
5
: C, 61.1; H, 5.1; N, 3.2%. Found C, 61.1; H, 4.8; N, 3.05%; νmax 1959, 1882 (CO); δ
H
(400
MHz, CDCl
C(5)H ), 2.85 (1H, d, J 14.2, C(7)H
.17 (1H, ddd, J 12.0, 7.4, 6.2, C(4)H
.62 (1H, dd, J 6.9, 5.6, C(2)H), 6.40 (1H, d, J 6.9, C(1)H), 6.88 (1H, d, J 8.3, C(9)H), 6.96 (1H, d, J 8.3,
3
A
) 2.44 (1H, app td, J 12.1, 3.9, C(5)H ), 2.52 (3H, s, NMe), 2.56 (1H, ddd, J 7.4, 3.9, 1.4,
B
A A B
), 3.02 (1H, ddd, J 12.0, 6.2, 1.4, C(4)H ), 3.16 (1H, d, J 14.2, C(7)H ),
3
5
B
), 3.79 (3H, s, OMe), 3.89 (3H, s, OMe), 5.13 (1H, d, J 5.6, C(3)H),
+
+
C(8)H); m/z (CI ) 433 ([M+H] , 100%).
1pR,4S,6aR)-4-Deuterio-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 11: BuLi (1.64 M, 1.1
mL, 1.80 mmol) was added to a solution of 9 (151 mg, 0.35 mmol, >99:1 dr) in THF (30 mL) at –78 °C and
the resultant mixture was stirred at –78 °C for 1 h. MeOH-d (2 mL) was then added, the reaction mixture
was stirred at –78 °C for 1 h, and the resultant mixture was allowed to warm to rt. The reaction mixture was
then filtered through a pad of celite (eluent Et O) and concentrated in vacuo. Purification via flash column
chromatography (eluent Et O) gave 11 as a yellow solid (148 mg, 98%, >99:1 dr); Anal. Calcd for
(
4
2
2
C H DCrNO : C, 61.1; H, 5.1; N, 3.2%. Found C, 61.4; H, 5.1; N, 3.4%; ν 1958, 1881 (CO); δ (400
2
2
20
5
max
H
MHz, CDCl
3
) 2.53 (3H, s, NMe), 2.55–2.62 (3H, m, C(5)H
2
, C(7)H
), 3.90 (3H, s, OMe), 4.00 (3H, s, OMe),
.33 (1H, d, J 6.5, C(3)H), 5.42 (1H, dd, J 6.6, 6.5, C(2)H), 6.61 (1H, d, J 6.6, C(1)H), 6.87 (1H, d, J 8.3,
A
), 2.96 (1H, dd, J 10.4, 5.3, C(4)H),
3
5
.11 (1H, dd, J 14.3, 4.0, C(6a)H), 3.22 (1H, dd, J 13.2, 4.0, C(7)H
B
+
+
C(9)H), 6.93 (1H, d, J 8.3, C(8)H); m/z (CI ) 433 ([M+H] , 100%).
1pS,6aR)-6a-Methyl-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 12: BuLi (1.4 M in
hexanes, 1.3 mL, 1.82 mmol) was added to a solution of 8 (95 mg, 0.22 mmol, >99:1 dr) in THF (30 mL) at
78 °C and the resultant mixture was stirred at –78 °C for 1 h. MeI (1.0 mL, 16.1 mmol) was then added, the
reaction mixture was stirred at –78 °C for 2 h, then MeOH (2 mL) was added and the resultant mixture was
(
–

HETEROCYCLES, Vol. 88, No. 1, 2014
773
allowed to warm to rt. The reaction mixture was then filtered through a pad of celite (eluent Et
2
O) and
concentrated in vacuo. Purification via flash column chromatography (eluent Et
solid (58 mg, 58%, >99:1 dr); Anal. Calcd for C23 : C, 62.0; H, 5.2; N, 3.1%. Found C, 62.0; H,
); νmax 1957, 1880 (CO); δ (400 MHz, CDCl ) 1.00 (3H, s,
C(6a)Me), 2.52 (3H, s, NMe), 2.40–3.20 (6H, m, C(4)H , C(5)H , C(7)H ), 3.78 (3H, s, OMe), 3.90 (3H, s,
OMe), 5.15 (1H, d, J 6.0, C(3)H), 5.62 (1H, dd, J 6.0, 5.8, C(2)H), 6.47 (1H, d, J 5.8, C(1)H), 6.86 (1H, d,
2
O) gave 12 as a yellow
H23CrNO
5
2
D
5
5
.6; N, 2.95%; [] 292.4 (c 0.7 in CH
2
Cl
2
H
3
2
2
2
+
+
+
J 8.4, C(9)H), 6.93 (1H, d, J 8.4, C(8)H); m/z (CI ) 446 ([M+H] , 100%), 445 ([M] , 80%).
1pS,6aR)-6a-Benzyl-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 13: BuLi (1.6 M in
(
hexanes, 0.90 mL, 1.44 mmol) was added to a solution of 8 (93 mg, 0.22 mmol, >99:1 dr) in THF (30 mL)
at –78 °C and the resultant mixture was stirred at –78 °C for 1 h. BnBr (1.0 mL, 8.41 mmol) was then added,
the reaction mixture was stirred at –78 °C for 1 h, then MeOH (2 mL) was added and the resultant mixture
was allowed to warm to rt. The reaction mixture was then filtered through a pad of celite (eluent Et
concentrated in vacuo. Purification via flash column chromatography (eluent hexane/Et O, 1:1) gave 13 as
); νmax 1957, 1882 (CO); δ (400 MHz,
), 2.63 (3H, s, NMe), 2.72 (2H, s, CH Ph), 2.94–3.06 (3H, m, C(4)H
), 3.38 (1H, d, J 14.9, C(7)H ), 3.87 (3H, s, OMe), 3.93 (3H, s, OMe), 5.00 (1H, d, J 6.6, C(3)H),
.56 (1H, dd, J 6.7, 6.6, C(2)H), 6.70–6.75 (2H, m, Ph), 6.80 (1H, d, J 6.7, C(1)H), 6.90 (1H, d, J 7.9,
2
O) and
2
2
D
0
a yellow solid (38 mg, 34%, >99:1 dr); [] –143.4 (c 0.4 in CHCl
3
H
CDCl
3
) 2.00–2.34 (2H, m, C(5)H
2
2
2
,
C(7)H
A
B
5
+
+
+
C(9)H), 6.99 (1H, d, J 7.9, C(8)H), 7.08–7.15 (3H, m, Ph); m/z (CI ) 552 ([M+H] , 100%); HRMS (CI )
+
+
C
29
H
27CrNO
5
([M] ) requires 521.1289; found 521.1294.
(
1pR,4S,6aR)-4-Methyl-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 14: BuLi (1.4 M in
hexanes, 0.30 mL, 0.42 mmol) was added to a solution of 9 (89 mg, 0.21 mmol, >99:1 dr) in THF (30 mL)
at –78 °C and the resultant mixture was stirred at –78 °C for 1 h. MeI (1.0 mL, 16.1 mmol) was then added,
the reaction mixture was stirred at –78 °C for 2 h, then MeOH (2 mL) was added and the resultant mixture
was allowed to warm to rt. The reaction mixture was then filtered through a pad of celite (eluent Et
concentrated in vacuo. Purification via flash column chromatography (eluent Et O) gave 14 as a yellow
solid (54 mg, 59%, >99:1 dr); Anal. Calcd for C23 : C, 62.0; H, 5.2; N, 3.1%. Found C, 61.7; H,
); νmax 1958, 1880 (CO); δ (400 MHz, CDCl ) 1.49 (3H, d, J
.0, C(4)Me), 2.48 (3H, s, NMe), 2.56 (1H, app t, J 4.1, C(6a)H), 2.68 (2H, app s, C(5)H ), 2.75 (1H, app q,
2
O) and
2
H23CrNO
5
2
D
5
5
7
.4; N, 3.2%; [] +211.2 (c 0.4 in CH
2
Cl
2
H
3
2
A B
J 7.0, C(4)H), 3.09 (1H, dd, J 13.0, 4.1, C(7)H ), 3.17 (1H, dd, J 13.0, 4.1, C(7)H ), 3.90 (3H, s, OMe),
4
6
.00 (3H, s, OMe), 5.33 (1H, d, J 6.5, C(3)H), 5.42 (1H, dd, J 6.6, 6.5, C(2)H), 6.61 (1H, d, J 6.6, C(1)H),
+
+
.86 (1H, d, J 8.3, C(9)H), 6.92 (1H, d, J 8.3, C(8)H); m/z (CI ) 446 ([M+H] , 100%).
(
1pR,4S,6aR)-4-Ethyl-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 15: BuLi (1.6 M in
hexanes, 0.50 mL, 0.80 mmol) was added to a solution of 9 (80 mg, 0.19 mmol, >99:1 dr) in THF (30 mL)

774
HETEROCYCLES, Vol. 88, No. 1, 2014
at –78 °C and the resultant mixture was stirred at –78 °C for 1 h. EtI (0.15 mL, 1.88 mmol) was then added,
the reaction mixture was stirred at –78 °C for 1 h, then MeOH (2 mL) was added and the resultant mixture
was allowed to warm to rt. The reaction mixture was then filtered through a pad of celite (eluent Et
concentrated in vacuo. Purification via flash column chromatography (eluent hexane/Et O, 1:1) gave 15 as
a yellow solid (39 mg, 46%, >99:1 dr); Anal. Calcd for C24 : C, 62.7; H, 5.5; N, 3.05%. Found C,
); νmax 1957, 1879 (CO); δ (400 MHz, CDCl ) 1.09
3H, t, J 7.4, C(2')H ), 1.67–2.02 (2H, qd, J 7.4, 6.2, C(1')H ), 2.49 (3H, s, NMe), 2.40–2.61 (2H, m),
2
O) and
2
H25CrNO
5
2
D
0
6
3.0; H, 5.7; N, 3.0%; [] +191.3 (c 0.5 in CH
2
Cl
2
H
3
(
3
2
2
.90–3.23 (4H, m), 3.91 (3H, s, OMe), 4.00 (3H, s, OMe), 5.36 (1H, d, J 6.6, C(3)H), 5.44 (1H, dd, J 6.6, 6.2,
+
C(2)H), 6.64 (1H, d, J 6.2, C(1)H), 6.86 (1H, d, J 8.2, C(9)H), 6.94 (1H, d, J 8.2, C(8)H); m/z (CI ) 460
+
(
[M+H] , 100%).
(
1pR,4S,6aR)-4-Allyl-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 16: BuLi (1.4 M in
hexanes, 0.50 mL, 0.70 mmol) was added to a solution of 9 (70 mg, 0.16 mmol, >99:1 dr) in THF (30 mL)
at –78 °C and the resultant mixture was stirred at –78 °C for 1 h. Allyl iodide (0.6 mL, 6.54 mmol) was then
added, the reaction mixture was stirred at –78 °C for 1 h, then MeOH (2 mL) was added and the resultant
mixture was allowed to warm to rt. The reaction mixture was then filtered through a pad of celite (eluent
Et
gave 16 as a yellow solid (63 mg, 82%, >99:1 dr); Anal. Calcd for C25
Found C, 63.4; H, 5.45; N, 2.8%; νmax 1958, 1880 (CO); δ (400 MHz, CDCl
C(1')H ), 2.47 (3H, s, NMe), 2.56–2.87 (4H, m), 3.06–3.25 (2H, m), 3.91 (3H, s, OMe), 4.00 (3H, s, OMe),
.10–5.17 (2H, m, C(3')H ), 5.36–5.39 (2H, m, C(2)H, C(3)H), 5.92–5.95 (1H, m, C(2')H), 6.64 (1H, d, J
.2, C(1)H), 6.87 (1H, d, J 8.2, C(9)H), 6.94 (1H, d, J 8.2, C(8)H); m/z (CI ) 471 ([M] , 100%).
2
O) and concentrated in vacuo. Purification via flash column chromatography (eluent hexane/Et
: C, 63.7; H, 5.3; N, 3.0%.
) 0.88 (2H, dd, J 10.5, 4.8,
2
O, 1:9)
H
25CrNO
5
H
3
2
5
5
2
+
+
(
1pR,4S,6aR)-4-Benzyl-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 17: BuLi (1.4 M in
hexanes, 0.60 mL, 0.84 mmol) was added to a solution of 9 (98 mg, 0.23 mmol, >99:1 dr) in THF (30 mL)
at –78 °C and the resultant mixture was stirred at –78 °C for 1 h. BnBr (1.0 mL, 16.1 mmol) was then added,
the reaction mixture was stirred at –78 °C for 1 h, then MeOH (2 mL) was added and the resultant mixture
was allowed to warm to rt. The reaction mixture was then filtered through a pad of celite (eluent Et O) and
2
concentrated in vacuo. Purification via flash column chromatography (eluent Et
solid (92 mg, 78%, >99:1 dr); Anal. Calcd for C29 : C, 66.8; H, 5.2; N, 2.7%. Found C, 67.1; H,
(400 MHz, CDCl ) 2.48 (3H, s, NMe), 2.54–2.81 (5H, m),
.95–2.31 (3H, m), 3.92 (3H, s, OMe), 4.01 (3H, s, OMe), 5.15 (1H, d, J 6.6, C(3)H), 5.36 (1H, app t, J 6.6,
2
O) gave 17 as a yellow
H27CrNO
5
5
2
.3; N, 2.6%; νmax 1960, 1886 (CO); δ
H
3
C(2)H), 6.64 (1H, d, J 6.6, C(1)H), 6.89 (1H, d, J 8.3, C(9)H), 6.97 (1H, d, J 8.3, C(8)H), 7.20–7.40 (5H, m,
+
+
Ph); m/z (CI ) 521 ([M] , 100%).

HETEROCYCLES, Vol. 88, No. 1, 2014
775
(
1pS,6aR,1'S)-6a-(1'-Hydroxyethyl)-10,11-dimethoxyaporphine[tricarbonylchromium(0)] 18: BuLi
(1.6 M in hexanes, 0.50 mL, 0.80 mmol) was added to a solution of 8 (162 mg, 0.38 mmol, >99:1 dr) in
THF (30 mL) at –78 °C and the resultant mixture was stirred at –78 °C for 1 h. MeCHO (0.40 mL, 7.16
mmol) was then added, the reaction mixture was stirred at –78 °C for 1 h, then MeOH (2 mL) was added
and the resultant mixture was allowed to warm to rt. The reaction mixture was then filtered through a pad of
celite (eluent Et
hexane/Et O, 1:1) gave 18 as a yellow solid (103 mg, 58%, >99:1 dr); []D 157.0 (c 1.0 in CH
500–2800 (O–H), 1957, 1880 (CO); δ (400 MHz, CDCl ) 0.82 (3H, d, J 6.3, C(2')H ), 2.50 (1H, dt, J 15.6,
.4, C(5)H ), 2.73 (3H, s, NMe), 2.86–3.15 (3H, m, C(4)H , C(5)H ), 3.20 (1H, d, J 15.2, C(7)H ), 3.44
2
O) and concentrated in vacuo. Purification via flash column chromatography (eluent
2
5
2
2 2
Cl ); νmax
3
3
H
3
3
A
2
B
A
B
(1H, d, J 15.2, C(7)H ), 3.68 (1H, q, J 6.3, C(1')H), 3.79 (3H, s, OMe), 3.89 (3H, s, OMe), 5.24 (1H, d, J 6.2,
C(3)H), 5.58 (1H, app t, J 6.5, C(2)H), 6.85 (1H, d, J 8.3, C(9)H), 6.86 (1H, d, J 6.8, C(1)H), 6.98 (1H, d, J
+
+
+
+
+
8
4
6
.3, C(8)H); m/z (CI ) 476 ([M+H] , 100%); HRMS (CI ) C24H25CrNO ([M] ) requires 475.1082; found
75.1087.
(
R)-6a-Methyl-10,11-dimethoxyaporphine 21: Asolution of 12 (58 mg, 0.13 mmol, >99:1 dr) in Et
mL) was exposed to air and sunlight until a colourless solution containing a green precipitate was evident.
The reaction mixture was then filtered through celite (eluent Et O) and concentrated in vacuo to give 21 as
a pale orange oil (37 mg, 92%, >99:1 er); []D 135.9 (c 0.3 in CH Cl ); δ (400 MHz, CDCl ) 1.03 (3H,
2
O (10
2
2
5
2
2
H
3
2 2 2
s, C(6a)Me), 2.51 (3H, s, NMe), 2.53–3.25 (6H, m, C(4)H , C(5)H , C(7)H ), 3.70 (3H, s, OMe), 3.91 (3H,
s, OMe), 6.82 (1H, d, J 8.2, C(9)H), 6.95 (1H, d, J 8.2, C(8)H), 7.07 (1H, d, J 7.6, C(3)H), 7.23 (1H, dd, J
+
+
+
+
+
7
.8, 7.6, C(2)H), 8.27 (1H, d, J 7.8, C(1)H); m/z (CI ) 309 ([M] , 100%); HRMS (CI ) C20
requires 309.1723; found 309.1726.
4S,6aR)-4-Methyl-10,11-dimethoxyaporphine 22: A solution of 14 (57 mg, 0.13 mmol, >99:1 dr) in
Et O (10 mL) was exposed to air and sunlight until a colourless solution containing a green precipitate was
evident. The reaction mixture was then filtered through celite (eluent Et O) and concentrated in vacuo to
2
H23NO ([M] )
(
2
2
2
5
give 22 as a pale orange oil (36 mg, 91%, >99:1 dr, >99:1 er); []D 123.2 (c 1.9 in CH
CDCl ) 1.48 (3H, d, J 7.1, C(4)Me), 3.32–2.58 (4H, m, C(4)H, NMe), 2.69 (1H, dd, J 11.3, 3.6, C(5)H
.79 (1H, d, J 11.3, C(5)H ), 2.92–2.98 (1H, m, C(7)H ), 3.04–3.13 (3H, m, C(6a)H, C(7)H ), 3.72 (3H, s,
OMe), 3.91 (3H, s, OMe), 6.83 (1H, d, J 8.2, C(9)H), 6.99 (1H, d, J 8.2, C(8)H), 7.14 (1H, d, J 7.5, C(3)H),
2
Cl
2
); δ
H
(400 MHz,
3
A
),
2
B
A
B
+
+
+
7
.28 (1H, dd, J 7.8, 7.5, C(2)H), 8.25 (1H, d, J 7.8, C(1)H); m/z (CI ) 309 ([M] , 100%); HRMS (CI )
+
+
C
20 2
H23NO ([M] ) requires 309.1723; found 309.1726.

776
HETEROCYCLES, Vol. 88, No. 1, 2014
ACKNOWLEDGEMENTS
The authors would like to thank David Watkin and Alison Edwards for assistance with X-ray crystal
structure determination.
REFERENCES AND NOTES
1
2
3
4
.
.
.
.
P. J. Davis, S. Seyhan, W. Soine, and R. V. Smith, J. Pharm. Sci., 1980, 69, 1056.
R. J. Borgman, R. J. Baldessarini, and K. G. Walton, J. Med. Chem., 1976, 19, 717.
C. A. Tamminga, M. H. Schaffer, R. C. Smith, and J. M. Davis, Science, 1978, 200, 567.
(a) S. G. Holtzman and G. F. Steinfels, Pharmacol. Biochem. Behavior, 1994, 47, 575; (b) C. K. Mak,
M. Avalos, P. K. Randall, S.-W. Kwan, C. W. Abell, J. L. Neumeyer, R. Whisennand, and R. Wilcox,
Neuropharmacol., 1996, 35, 549.
5
.
(a) J. L. Neumeyer, B. R. Neustadt, and K. K. Weinhardt, J. Pharm. Sci., 1970, 59, 1850; (b) J. L.
Neumeyer, B. Neustadt, K. Oh, K. Weinhardt, C. Boyce, F. Rosenberg, and D. Teiger, J. Med. Chem.,
1
973, 16, 1223; (c) Y. Gao, V. J. Ram, A. Campbell, N. S. Kula, R. J. Baldessarini, and J. L. Neumeyer,
J. Med. Chem., 1990, 33, 39; (d) W. S. Saari, S. W. King, and V. J. Lotti, J. Med. Chem., 1973, 16, 171.
I. Pettersson and T. Liljefors, Computer Aided Mol. Design, 1987, 1, 143.
6
7
.
.
(a) C. Kaiser and T. Jain, Med. Res., 1985, Q5, 145; (b) W. S. Saari, S. W. King, V. J. Lotti, and A.
Scriabine, J. Med. Chem., 1974, 17, 1086; (c) M. Froimowitz and R. J. Baldessarini, J. Pharm. Sci.,
1
987, 76, 557.
8
.
(a) J. G. Cannon, P. Mohan, J. Bojarski, J. P. Long, R. K. Bhatnagar, P. A. Leonard, J. R. Flynn, and T.
K. Chatterjee, J. Med. Chem., 1988, 31, 313; (b) R. A. Abramovitch, P. Chinnasamy, K. Evertz, and G.
Huttner, J. Chem. Soc., Chem. Commun., 1989, 3; (c) S. Ramsby, J. L. Neumeyer, D. Grigoriadis, and
P. Seeman, J. Med. Chem., 1989, 32, 1198; (d) J. G. Cannon, H. Jackson, J. P. Long, P. Leonard, and R.
K. Bhatnagar, J. Med. Chem., 1989, 32, 1959; (e) V. J. Ram and J. L. Neumeyer, J. Org. Chem., 1982,
4
7, 4372. See also: Refs. 5c, 7b.
9
.
For instance, see: (a) J. Blagg, S. G. Davies, N. J. Holman, C. A. Laughton, and B. E. Mobbs, J. Chem.
Soc., Perkin Trans. 1, 1986, 1581; (b) S. G. Davies and C. L. Goodfellow, J. Chem. Soc., Perkin Trans.
1
, 1990, 393; (c) L. A. Bromley, S. G. Davies, and C. L. Goodfellow, Tetrahedron: Asymmetry, 1991, 2,
39; (d) S. G. Davies, T. J. Donohoe, and M. A. Lister, Tetrahedron: Asymmertry, 1991, 2, 1089; (e) S.
1
G. Davies, T. J. Donohoe, and M. A. Lister, Tetrahedron: Asymmertry, 1991, 2, 1085; (f) S. G. Davies,
C. L. Goodfellow, and K. H. Sutton, Tetrahedron: Asymmetry, 1992, 3, 1303; (g) S. G. Davies and T. J.
Donohoe, Synlett, 1993, 323; (h) S. G. Davies and W. E. Hume, J. Chem. Soc., Chem. Commun., 1995,
2
51; (i) S. G. Davies, O. M. L. R. Furtado, D. Hepworth, and T. Loveridge, Synlett, 1995, 69; (j) S. J.
Coote, S. G. Davies, A. M. Fletcher, P. M. Roberts, and J. E. Thomson, Chem. Asian J., 2010, 5, 589;

HETEROCYCLES, Vol. 88, No. 1, 2014
777
(
k) S. G. Davies, E. W. Hume, P. M. Roberts, and J. E. Thomson, Tetrahedron, 2010, 66, 8076.
1
0. (a) J. Blagg, S. J. Coote, S. G. Davies, and B. E. Mobbs, J. Chem. Soc., Perkin Trans. 1, 1986, 2257;
b) S. G. Davies, Chem. & Ind., 1986, 506.
(
1
1. Crystallographic data (excluding structure factors) for the structure of (1pS,6aR,1'S)-18 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication number
CCDC 945389.
1
2. (a) H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 876; (b) H. D. Flack and G. Bernardinelli, Acta
Crystallogr., Sect. A, 1999, 55, 908; (c) H. D. Flack and G. Bernardinelli, J. Appl. Crystallogr., 2000,
3
3, 1143.
1
1
3. B. Nicholls and M. C. Whiting, J. Chem. Soc., 1959, 551.
4. (a) S. G. Davies, J. Organomet. Chem., 1990, 400, 223; (b) S. G. Davies, C. L. Goodfellow, J. M.
Peach, and A. Waller, J. Chem. Soc., Perkin Trans. 1, 1991, 1019.
1
5. (a) V. Zabel, W. H. Watson, A. Urzua, and B. K. Cassels, Acta Crystallogr., Sect. B, 1979, 35, 3126; (b)
L. Castedo, R. Riguera, J. Sardina, S. García-Blanco, and I. Fonseca, Heterocycles, 1982, 19, 1591; (c)
K. L. Wert, S. Chackalamannil, E. Miller, D. R. Dalton, D. E. Zacharias, and J. P. Glusker, J. Org.
Chem., 1982, 47, 5141; (d) M. D. Menachery, P. Carroll, and M. P. Cava, Tetrahedron Lett., 1983, 24,
1
67; (e) I. Fonseca and S. García-Blanco, Acta Crystallogr., Sect. C, 1984, 40, 176; (f) S. Touré, G.
Germain, and L. A. Djakoure, Acta Crystallogr., Sect. C, 1985, 41, 1827; (g) G. R. Pettit, S. B. Singh,
M. L. Niven, and J. M. Schmidt, Can. J. Chem., 1988, 66, 406; (h) B. Ribár, C. Mészáros, P. Engel, O.
Gasic, and I. Kanyó, Acta Crystallogr., Sect. C, 1991, 47, 2500; (i) B. Ribár, D. Lazar, O. Gasic, I.
Kanyó, and P. Engel, Acta Crystallogr., Sect. C, 1992, 48, 945; (j) O. Simonsen, S. K. Singh, J. Wengel,
and V. S. Parmar, Acta Crystallogr., Sect. C, 1996, 52, 3195.
1
6. S. J. Coote, S. G. Davies, and C. L. Goodfellow 'Advances in Metal-Organic Chemistry', Vol. 2, ed. by
L. S. Liebeskind, JAI Press, London, 1991, 2, pp. 1–57.