Chemoenzymatic synthesis of enantiomerically pure tricyclic benzomorphan analogues

Article abstract of DOI:10.1016/j.tetasy.2006.11.020

The key step in the synthesis of enantiomerically pure benzomorphan analogous tricyclic amines 2 is the kinetic resolution of secondary alcohol 7 using the lipase from Pseudomonas fluorescence. The (S)-configured alcohol (S)-7 and the (R)-configured ester

Full text of DOI:10.1016/j.tetasy.2006.11.020

Tetrahedron: Asymmetry 17 (2006) 3046–3050
Chemoenzymatic synthesis of enantiomerically pure
tricyclic benzomorphan analogues
Christian Ketterer,a Stefan Grimme,b Edgar Weckertc and Bernhard Wunscha,*
¨
aInstitut fu¨r Pharmazeutische und Medizinische Chemie der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster,
Hittorfstraße 58-62, 48149 Mu¨nster, Germany
bOrganisch-Chemisches Institut der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster, Corrensstr. 40, D-48149 Mu¨nster, Germany
cHasylab at Desy, Notkestr. 85, D-22607 Hamburg, Germany
Received 25 October 2006; accepted 10 November 2006
Abstract—The key step in the synthesis of enantiomerically pure benzomorphan analogous tricyclic amines 2 is the kinetic resolution of
secondary alcohol 7 using the lipase from Pseudomonas fluorescence. The (S)-configured alcohol (S)-7 and the (R)-configured ester (R)-8
were obtained in good yield (40% and 46%, respectively) and excellent enantiomeric excess (99% ee and 98.4% ee, respectively). A
diastereoselective oxa-Pictet-Spengler reaction of (S)-7 with ethyl glyoxalate (O@HC–CO2Et) followed by a Dieckmann cyclization
provided the tricyclic ring system 11, which allowed the diastereoselective introduction of an amino group at the 6-position. The
absolute configuration of alcohol (S)-7 was determined with the tricyclic alcohol 13. The quantum mechanically calculated specific
optical rotation of (S,S,S)-configured alcohol 13 is in accordance with the measured specific rotation of the synthesized compound.
Moreover, X-ray crystal structure analysis of the synthesized compound, determined with the three-beam interference method, proved
the (S,S,S)-configuration of 13. The enantiomerically pure dimethylamine 12 showed moderate affinity toward r2 receptors.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In order to find novel receptor ligands, the benzomorphan
analogous tricyclic amines 2 with a 2-phenylethylamine
substructure were envisaged.2 Since the stereochemistry
strongly influences pharmacological activity, tricyclic
amines 2 should be synthesized in enantiomerically pure
form. The plan for the synthesis of enantiomerically pure
amines 2 is outlined in Scheme 1.
Several pharmacologically active compounds including
benzomorphans 1, sympathomimetics, and dopamine
receptor agonists contain the 2-phenylethylamine substruc-
ture. Depending on the stereochemistry of the tricyclic ring
system and the N-substituent, benzomorphans 1 can inter-
act with Opioid receptors (l, j receptors), r receptors and
the phencyclidine binding site of the NMDA receptor
(Fig. 1).1
Tricyclic ketone 3 will allow the diastereoselective intro-
duction of axially or equatorially oriented amino substitu-
ents at the 6-position. Ketone 3 should be available by an
oxa-Pictet-Spengler reaction3 of the 2-phenylethanol deriv-
ative 4, followed by Dieckmann cyclization, hydrolysis and
decarboxylation. The required, enantiomerically pure, 2-
phenylethanol derivative 4 will be synthesized from 4-oxo-
pentanoic acid 5 by an enzymatic kinetic resolution, using a
lipase as a key step.
O
R
N
6
R2N
1
2
Figure 1. Structural comparison of benzomorphans with planned tricyclic
amines.
2. Results and discussion
4-Oxopentanoic acid 54 was reduced with NaBH4 and sub-
sequently treated with HCl to provide c-lactone 6 in 60%
*
Corresponding author. Tel.: +49 251 8333311; fax: +49 251 832144;
e-mail: wuensch@uni-muenster.de
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.020

C. Ketterer et al. / Tetrahedron: Asymmetry 17 (2006) 3046–3050
3047
enantioselectivity leading to both alcohol (S)-7 and acetate
(R)-8 in good yield and excellent enantiomeric excess:
(S)-7: yield 40%, 99% ee; (R)-8: yield 46%, 98.4% ee. The
enantioselectivity E6 of this transformation is greater than
100. In addition to the enantiomerically pure alcohol (S)-7
and acetate (R)-8, a small amount of the enantioenriched
c-lactone (S)-6 (yield 10%, 72% ee) was isolated, which
had been formed by non-lipase catalyzed intramolecular
attack of the hydroxy moiety on the amide group.
H
H
H
O
H
O
6
O
NR2
2
3
The enantiomerically pure c-hydroxypentanamide (S)-7
reacted in an oxa-Pictet-Spengler reaction3 with ethyl
glyoxalate (OHC–CO2Et) and BF3ÆEt2O to give diastereo-
selectively the cis-configured 2-benzopyran 9 (Scheme 3).
Attempts to perform a Dieckmann cyclization with amido-
ester 9 failed to afford tricyclic products. Therefore, amido-
ester 9 was first transformed into diester 10, which reacted
with NaH and ethanol to give the Dieckmann condensa-
tion product 11. According to the NMR spectra, tricyclic
product 11 consists of three components, which are in a
thermodynamic equilibrium: two diastereomeric b-ketoest-
ers 11a and 11b and enolester 11c (ratio 20:15:65). Mixture
11 was hydrolyzed with NaOH to provide a uniform prod-
uct, ketone 3, in more than 65% yield thus confirming the
existence of the tautomeric/diastereomeric mixture 11.
The reductive amination of the tricyclic ketone 3 was
performed with dimethylamine and NaBH4 employing
H
O
+
O
OH
CO2Et
CO2H
COR
4
5
Scheme 1. Plan for the synthesis of enantiomerically pure benzomorphan
analogous tricyclic amines.
yield. The direct synthesis of c-lactone 6 by oxidative coup-
ling of allylbenzene with acetic acid in the presence of
Mn(OAc)35 gave a lower yield (44%) of c-lactone 6. More-
over, the work-up procedure is much more complicated
due to separation of the Mn-salts. Aminolysis of c-lactone
6 with dimethylamine led to the racemic c-hydroxypen-
tanamide 7 in 94% yield (Scheme 2).
(a)
(b)
H
CO2Et
H
H
H
CO2Et
Kinetic resolution was performed by the enantioselective
acetylation of c-hydroxypentanamide 7 with isopropenyl
acetate using the lipase from Pseudomonas fluorescence
(Amano AK) as a catalyst. The P. fluorescence lipase
converted secondary alcohol 7 in extraordinarily high
(S)-7
O
O
CONMe2
CO2Et
9
10
(c)
(a)
(b)
5
H
H
H
O
H
O
OH
O
O
OH
CO2Et
CO2Et
CONMe2
O
11a,b
11c
6
7
(d)
1
4
(e)
(f)
(c)
+
+ (S)-6
9
5
H
H
H
H
H
O
O
6
H
OH
O
OH
AcO
N(CH3)2
6
O
6
Me2NOC
CONMe2
12
3
13
(S)-7
(R)-8
Scheme 3. Reagents and conditions: (a) OHCCO2Et, CH2Cl2, BF3ÆEt2O,
6 h, rt, 4 d, 40 ꢁC, 93%; (b) (F3CSO2)2O, EtOH, pyridine, 12 h, rt, 83%; (c)
NaH, EtOH, toluene, 2.5 h, 110 ꢁC, 62%; (d) NaOH, EtOH, 3 h, 78 ꢁC,
91%; (e) (H3C)2NH, Ti(OiPr)4, EtOH, 63 h, rt, then NaBH4, 23 h, rt, 72%;
(f) NaBH4, CH3OH, 90 min, rt, 86%.
Scheme 2. Reagents and conditions: (a) NaBH4, CH3OH, rt, then HCl,
30 min, rt, 60%; (b) (H3C)2NH, EtOH, rt, 94%; (c) Pseudomonas
fluorescence lipase, isopropenyl acetate, BuOCH3, 141 h, rt, (S)-7: 40%
t
(99% ee), (R)-8: 46% (98.4% ee), (S)-6: 10% (72% ee).

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C. Ketterer et al. / Tetrahedron: Asymmetry 17 (2006) 3046–3050
the Lewis acid Ti(OiPr)4 as a catalyst.7 Here, the reducing
agent reacted diastereoselectively from the Re face giving
only the tricyclic amine 12 with an equatorially oriented
amino group.
of the synthesized alcohol (ꢀ)-13 as (S,S,S) and thus the
(S)-configuration of the starting c-hydroxypentanamide 7.
Recrystallization of alcohol 13 from (iPr)2O provided col-
orless crystals19 (mp 158 ꢁC), which were suitable for X-
ray crystal structure analysis.20 Since the crystals were quite
small (15 lm · 15 lm · 100 lm) and due to the low oxygen
content, the determination of the absolute configuration by
exploiting the anomalous dispersion effects was not possi-
ble. However, despite the small crystal size the absolute
structure could be determined using the three-beam inter-
ference method.21,22 This method exploits interference
effects between two wave fields inside a crystal and is
independent of any anomalous dispersion effects. In Figure
2, a three-beam interference profile for the crystals of 13 is
given, indicating the derived absolute configuration. Figure
3 shows the X-ray crystal structure of 13 confirming unam-
biguously the (S)-configuration of all the three stereogenic
centers.
3. Absolute configuration
According to the rule of Kazlauskas,8 lipases preferentially
convert the (R)-configured enantiomer of the secondary
alcohols, provided that the larger substituent has priority
according to the CIP rules. However, the definition of the
larger substituent within the c-hydroxypentanamide 7 re-
mains uncertain. On the condition that the benzyl substitu-
ent is the large group, application of the Kazlauskas rule
would lead to the (R)-configured acetate (R)-8 and the
(S)-configured alcohol (S)-7.
In order to unambiguously prove the absolute configura-
tion of the products from the lipase catalyzed reaction,
the stereochemistry of tricyclic alcohol 13, which was syn-
thesized diastereoselectively by NaBH4 reduction of ketone
3 (Scheme 3), was thoroughly investigated by quantum
chemical calculation of the specific optical rotation and
X-ray crystal structure analysis.
Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with
All quantum chemical calculations were carried out with
9
the TURBOMOLE program package. The geometries were
optimized at the DFT level of theory using a polarized tri-
ple-f valence basis set on all atoms (TZV(d,p))10 and the
PBE11 density functional. The frequency dependent optical
rotation (OR) values (in the following given in the usual
units deg dmꢀ1(g/mL)ꢀ1) were obtained from time depen-
dent density functional theory (TDDFT12 calculations
using the BH-LYP13 and B3-LYP14 functionals and Dun-
ning’s aug-cc-pVDZ basis set).15 For a general overview
about chiroptical calculations, see Ref. 16. For the partic-
ular application of TDDFT methods for computations of
OR, see Ref. 17 and for examples that include also several
conformers and Boltzmann averaging, see Ref. 18. For
technical reasons, the TDDFT calculations of the OR
could be performed only in the coordinate origin-depen-
dent dipole-length representation for the rotatory
strengths. Test calculations employing pure functionals
such as PBE and the origin-independent velocity gauge rep-
resentation show, however, that the differences between the
two forms with the aug-cc-pVDZ basis set are only about
2 deg dmꢀ1(g/mL)ꢀ1
.
Figure 2. Centro-symmetrically related three-beam interference profiles of
the three-beam cases 131jꢀ1ꢀ11j240 and ꢀ1ꢀ3ꢀ1j11ꢀ1jꢀ2ꢀ40:
During such an experiment, for example, the 131 reflection is set into
its diffraction position, subsequently the reflection ꢀ1ꢀ11 is also brought
into its diffraction position by a w-rotation about the reciprocal lattice
vector of 131. In such a situation, the reflections (240) fulfill the
diffraction conditions for the interference between 131 and ꢀ1ꢀ11. The
three-beam interference profile depends on the triplet phase
For tricyclic alcohol 13 we initially considered a conformer
with an axially oriented OH-group which, however, was
found to be higher in energy by about 2 kcal/mol compared
to the equatorial minimum and thus not further investi-
gated. At the TDDFT/B3LYP level, we obtained, for the
equatorial form, an [a]D value of ꢀ13.2 and with the
BHLYP functional of ꢀ16.4 deg dmꢀ1(g/mL)ꢀ1. These dif-
ferences and also the difference to the experimental value of
ꢀ71.819 are typical for such computations when molecules
with only weakly perturbed but inherently achiral chro-
mophores (benzene ring in 13) are involved. In any case,
this allows the assignment of the absolute configuration
uT = u(ꢀ1ꢀ11) + u(240) ꢀ u(131) ꢁ 70ꢁ. For 90 (ꢀ90) deg a symmetric
decrease (increase) of the three-beam interference profile is expected. The
slight asymmetry in the measured profiles is consistent with the triplet
phase 70 (ꢀ70) of the two centro-symmetrically related three-beam cases.
The sign of the triplet phase is directly related to the hand of absolute
structure.

C. Ketterer et al. / Tetrahedron: Asymmetry 17 (2006) 3046–3050
3049
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Acknowledgements
Financial support by the Deutsche Forschungsgemein-
schaft and the Fonds der Chemischen Industrie is grate-
fully acknowledged. Thanks are also due to Degussa AG
for the donation of chemicals. We also thank Alke Meents
and Hermann Franz for support at the beamline PETRA 1
(HASYLAB/DESY, Hamburg) during the X-ray
measurements.

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C. Ketterer et al. / Tetrahedron: Asymmetry 17 (2006) 3046–3050
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10-Hpseudoax), 4.02 (td, J = 4.7/11.6 Hz, 1H, 6-H), 4.35 (dd,
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¨
˚
gonal space group P32, lattice parameters: a = b = 12.214 A,
3
3
˚
˚
c = 5.791 A, V = 748 A , Z = 3, Dx = 1.267 Mg/m , crystal
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