Thiazole constrained analogues of the thevinones: Synthesis and structure

Article abstract of DOI:10.1002/mrc.2447

A simple synthesis of ring-constrained endoethenomorphinans possessing 2'-substituted thiazole ring 4-6 has been achieved by regio- and stereoselective Diels-Alder reaction of thiazolomorphinandienes 1-3 and methyl vinyl ketone in high yield (72, 64 and 8

Full text of DOI:10.1002/mrc.2447

Spectral Assignments and Reference Data
Received: 5 March 2009
Revised: 4 April 2009
Accepted: 8 April 2009
Published online in Wiley Interscience: 8 May 2009
(www.interscience.com) DOI 10.1002/mrc.2447
Thiazole constrained analogues of the
thevinones: synthesis and structure†
a∗
a
a
a,b
´
´
´
Attila Sipos, Tímea Skaliczki, Sandor Berenyi and Sandor Antus
A simple synthesis of ring-constrained endoethenomorphinans possessing 2ꢀ-substituted thiazole ring 4–6 has been achieved
by regio- and stereoselective Diels–Alder reaction of thiazolomorphinandienes 1–3 and methyl vinyl ketone in high yield
(72, 64 and 87%, respectively). The structure of cycloaddition products was determined by high resolution mass spectrometry
(HRMS), IR, 1D and 2D NMR techniques. Double-pulsed field gradient spin-echo–nOe and HMBC were found to be particularly
powerful and indispensable tools in the exact structural elucidation of the presented new class of spatially constrained
c
thevinones. Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: NMR; thevinones; opioid activity; DFT study; nOe
Introduction
2), remarkable stereo- and regiospecificity have been observed in
past efforts aiming these rigidified ethenomorphinans.[5]
Even the TLC study of the crude reaction mixtures of the
Diels–Alder addition of methyl vinyl ketone (MVK) to dienes 1–3
was surprising because of the fact that only one product was
formed in all three cases. The structure of adducts produced was
determined by combination of different spectroscopic methods
(MS, IR, 1D and 2D NMR). It was found that in the case of 2ꢁ-methyl
1 and 2ꢁ-phenyl 2 derivatives, the cycloaddition proceeded as
expected: one MVK molecule, based on the high resolution mass
spectrometry (HRMS) and IR results, with β-face cycloaddition
resulted in thevinones 4 and 5, that is, the Diels–Alder reaction
concerns only the conjugated diene of the C-ring of morphinan
(Scheme 3).
In the case of 2ꢁ-aminothiazolo-morphinandiene (3), mass
spectrometric studies revealed that one molecule of 3 reacts
with three MVK molecules. The role of thiazole ring as the target
of cycloaddition might be taken into consideration; however, it
wouldnotexplaintheadditionof threeequivalentsof MVKinstead
of one and the difference in the behaviour of 1 and 2 derivatives
to the aminothiazolo compound 3.
Ring-constrainedendoethenomorphinansrepresentanimportant
groupofsemi-syntheticopioidanalgesicsasthestericallyrigidified
moiety in the proximity of ring C of the morphinan backbone
offers the opportunity to study the potent substitution patterns
responsible for superior opioid binding affinities. Since the
fundamental work of Bentley and co-workers synthesizing and
characterizing buprenorphine[1] in the 60s and 70s of the past
century, wide variety of ethenomorphinans have been prepared.
Although wide spectra of structure–activity relationships have
been revealed on the receptor-binding functions of the additional
moieties relative to the basic morphinan backbone, there are still
unknown details in connection with the optimal spatial position of
the substituents. One of the most powerful tools for the discovery
of these details is the synthesis and characterization of the
family of ring-constrained orvinols (6,14-endoethenooripavines).
There are different methodologies for the formation of these
rigidified structures. The most common approach is the furan
ring closure between substituents at positions 6 and 7 of
the endoethenomorphinan skeleton.[2] Another useful method
is the direct addition of cyclic dienophiles to the starting
morphinandienes (i.e. thebaine, oripavine, etc.).[3]
We found the solution in two steps, on one hand the thorough
studyoftheIRspectrumofmoleculeshowedthatbesidethetypical
thevinone carbonyl band at 1750 cm−1, there is another one at
1670 cm−1 that may refer to the fact that two of the carbonyl
groups resulting from the three bonded MVK molecules are
equivalent. Besides, we found an analogous phenomenon where
Recently, a convenient method was published by two of us
for the preparation of 2ꢁ-substituted thiazolomorphinandienes
1–3 from the readily available 14β-bromocodeinone (Scheme
1)[4] and it seemed to be a tempting choice to perform further
transformation opportunities of these valuable intermediates by
Diels–Alder reaction.
∗
Correspondence to: Attila Sipos, Department of Organic Chemistry, University
of Debrecen, H-4032 Debrecen, Hungary. E-mail: asipos@puma.unideb.hu
Results and Discussion
†
a
Dedicated to Professor Reija Jokela on the occasion of her significant
anniversary.
In the present paper, we describe a novel alternative route to
spatially rigidified morphinans using hetero-ring-fused morphi-
nandienes as the target species of the cycloaddition. Although the
Diels–Alder reaction of a morphinan-6,8-diene with a monosub-
stituted ethene can result in eight isomeric cycloadducts (Scheme
DepartmentofOrganicChemistry, UniversityofDebrecen, P. O. Box20, H-4010,
Debrecen, Hungary
b
Research Group for Carbohydrates of the Hungarian Academy of Sciences, P.
O. Box 55, H-4010, Debrecen, Hungary
c
Magn. Reson. Chem. 2009, 47, 801–807
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

A. Sipos et al.
R
N
S
7
O
O
6
8
S
CH3
CH3
R
Br
C
R
C
14
5
N
N
NBS
N
1
2
3
CH3
NH2
H3C
H3C
H3C
O
O
O
O
Ph
B
10
DMF, reflux
NH2
A
3
1
CH3
CH3
O
O
2
14β-bromocodeinone
thebine
1 - 3
Scheme 1. Formation of thiazolomorphinandienes 1–3.
Table 1. 1D and 2D NMR data of compound 4
Chemical shifta, δ
Carbon
Numbering (Cn)
Protons
13C showing COSY
Protons
showing HMBC
1H [multiplicity, J(H,H)(Hz)]
Significant nOes
1
6.51 (d) J1–2 8.4
116.2
113.7
147.8
56.4
H2
H1b; H2
H2; H10a; H10b
b
2
6.62 (d) J2–1 8.4
H1
H1; H2
H1
–
3
–
–
O-3-CH3
3-O-CH3
3.91 (s)
–
–
–
H5
–
4
–
4.33 (s)
145.0
80.2
–
b
5
–
–
H5
3-O-CH3; H7; H8a; H8b; H15a; H15b
6
–
77.4
H5; H7
–
7
3.24 (dd) J7–8a 8.1 J7–8b 6.0
1.34–2.21 (m)
46.4
H8a; H8b
H7
H7b; H8a; H8b
H5; H8a; H8b; H15a; H15b; H16a; H21
b
8
47.7
H7; H8ab; H8b
ND
ND
ND
9
2.71 (dd) J9–10a 6.1 J9–10b 3.0
62.3
H10a; H10b
H9
H9∗; H10a; H10b
b
10
H
10a 3.01 (d) J10a–10b 18.4;
24.8
H9; H10ab; H10b
H
10b 2.89 (d) J10a–10b 18.4
11
12
13
14
15
–
–
–
–
126.7
132.3
27.8
–
H1
–
–
–
–
–
–
H5
–
40.8
H
8a; H8b; H9; H19
H15ab; H15bb; H16a; H16b
–
H
15a 1.28 (ddd) J15a,15b;15a,16a 12.5, J15a,16b 5.1; 36.7
15b 1.34–2.21 (m)
H16a; H16b
ND
H
b
16
H
16a; H16b 1.34–2.21 (m)
47.0
45.2
H15a; H15b
H15a; H15b; H16ab; H16b
ND
17-N-CH3
2.37 (s)
–
–
–
–
–
–
–
–
–
ND
18
140.9
119.9
214.6
33.4
H19
–
b
19
5.43 (s)
–
H19
H8a; H8b; H9; H10a; H10b
20
H7; H21
–
–
–
–
∗
21
2ꢁ
2ꢁ-CH3
1.89 (s)
–
H21
2ꢁ-CH3
2ꢁ-CH3
158.5
29.1
b
1.21 (s)
a In ppm from TMS.
b Derived from 1JCH and used for assigning carbons bonded to protons.
ND, Not determined.
Russian researchers report the reaction of a compound containing
2ꢁ-aminobenzothiazole moiety with MVK. In this case, they found
that the product was the N,N-bis(but-3-one-1-yl) derivative of the
compound expected.[6]
The use of previously mentioned spectroscopic methods
verified that the cycloaddition also took place from the β-face
in this product molecule, and the 1D-nOe studies, as well as COSY
and HMBC techniques unambiguously verified the presence of
tertiary amine structure formed by double Michael additions.
IR and HRMS data provided significant primary information on
the structure of adducts as described previously. Special attention
was paid to the ionization technique of MS as it was previously
reported that electron ionization (EI) conditions may lead to
in situ retro-Diels–Alder reaction detaining exact identification.[7a]
Structure elucidation, however, was only possible by means of
1
1D and 2D NMR techniques. H-NMR and 13C-NMR assignations
were determined with the evaluation of COSY and HMBC data
(Tables 2–4). The identification of the structure of compounds
4–6 was facilitated by previously published NMR studies on
versatile endoethenomorphinan derivatives.[7]
In the case of all three products 4–6, it was the HMBC
experiment that revealed the acetyl group being connected
to position 7 of the backbone. The spectrum shows that the
C18 and C19 carbons of the endoetheno-bridge are coupled
with the H19 proton, and the C20 carbonyl is coupled with
the neighbouring H7 proton besides C20 –CH3 protons. Protons
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 801–807

Spectral Assignments and Reference Data
ß-face approach
α-face approach
Q
Q
7
R
O
R
R
8
6
18
19
Q
Q
C
A
14
N
5
N
N
9
H3C
H3C
H3C
O
O
O
B
10
3
CH3
CH
1
CH3
3
O
O
2
6α,14α-ethenomorphinan
6ß,14ß-ethenomorphinan
Scheme 2. Potential isomers in the cycloaddition to morphinan-6,8-dienes.
Q
1′
2′
O
S
21
20
18
H3C
N
3′
19
6
7
14
8
N
H3C
O
O
CH3
R
4, Q = CH3
5, Q = Ph
S
N
H3C
N
O
O
H3C
∆, 24h
2′′
O
O
N1′′
4′′
CH3
3′′
1′
5′′
2′
O
S
CH
21
H3C
3
20
O
N
18
3′
R
19
6
7
17
N
14
1
2
3
CH3
8
5
9
H C
3
Ph
O
16
10
15
NH2
CH3
1
3
O
2
6
Scheme 3. Diels–Alder reactions of thiazolomorphinandienes 1–3.
attached to position 7 of the newly formed ring are coupled with
C6, C7 and C20 that proved the position of 7-acetyl moiety. The
conformation of 7-acetyl function was done by the data from
double-pulsed field gradient spin-echo (DPFGSE)–nOe studies.
The estimated spatial hydrogen–hydrogen distances deduced
from these studies are in good correlation with the data obtained
from the density functional theory (DFT)-optimized geometry of
the 7α-stereoisomer of 6 at the B3LYP/6-31G∗ level of theory
(Table 4). It is of particular importance in support of this structure
that there is no nOe between H19 and H7 protons. The orientation
of the cycloaddition, i.e. the β-face approach, was confirmed by
the 1D-nOe data of H5, H7 and H19 protons (Fig. 1, panels A-
C, respectively) in comparison with data of the DFT-optimized
geometry, with special respect to the interactions of H7 with H15a
15b and H16a
The structural elucidation of the double Michael addition was
,
H
.
based on the COSY and HMBC data of the novel N-(but-3-one-1-yl)
moieties (Table 3). Furthermore, the DPFGSE–nOe spectra of
H5 and C3 –OCH3 protons of compound 6 include additional
interactions in comparison with the same spectra for compounds
4 and 5. On the basis of the 1H-NMR assignation and the distance
data obtained for the DFT-optimized geometry of 6 (Table 4), it
c
Magn. Reson. Chem. 2009, 47, 801–807
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/mrc

A. Sipos et al.
Table 2. 1D and 2D NMR data of compound 5
Chemical shifta, δ
Carbon
Numbering (Cn)
Protons
13C showing COSY
Protons
showing HMBC
1H [multiplicity, J(H,H)(Hz)]
Significant nOes
1
6.54 (d) J1–2 7.9
119.7
114.9
146.1
56.2
H2
H1b; H2
H2; H10a; H10b
b
2
6.63 (d) J2–1 7.9
H1
H1; H2
H1
3
–
–
O-3-CH3
–
3-O-CH3
3.87 (s)
–
–
–
H5
4
–
144.9
80.7
–
–
b
5
4.43 (s)
–
–
H5
3-O-CH3; H7; H8a; H8b; H15a; H15b
6
–
76.2
H5; H7
–
7
3.31 (dd) J7–8a 8.7 J7–8b 6.1
1.37–2.20 (m)
47.3
H8a; H8b
H7
H7b; H8a; H8b
H5; H8a; H8b; H15a; H15b; H16a; H21
b
8
48.7
H7; H8ab; H8b
ND
ND
ND
9
2.70 (dd) J9–10a 6.0 J9–10b 3.7
H10a 3.07 (d) J10a–10b 16.1;
60.4
H10a; H10b
H9
H9b; H10a; H10b
b
10
24.4
H9; H10ab; H10b
H
10b 2.91 (d) J10a–10b 16.2
11
12
13
14
15
–
–
–
–
127.6
133.1
28.7
–
H1
–
–
–
–
–
–
H5
–
42.1
H8a; H8b; H9; H19
H15ab; H15bb; H16a; H16b
–
H
15a 1.18 (ddd) J15a,15b;15a,16a 11.9, J15a,16b 5.4; 33.6
15b 1.37–2.20 (m)
H16a; H16b
ND
H
b
16
H
16a; H16b 1.37–2.20 (m)
45.5
44.4
H15a; H15b
H15a; H15b; H16ab; H16b
ND
17-N-CH3
2.34 (s)
–
–
–
–
–
–
–
ND
18
–
144.2
117.9
210.8
32.2
H19
–
b
19
5.42 (s)
H19
H8a; H8b; H9; H10a; H10b
20
–
1.95 (s)
–
H7; H21
–
–
b
21
2ꢁ
2ꢁ-Ph
H21
160.5
–
–
7.21–7.48 (m)
129.1; 2ꢁ-Ph protons
2ꢁ-Ph protons
ND
129.4;
132.4;
138.9
a In ppm from TMS.
b Derived from 1JCH and used for assigning carbons bonded to protons.
NA, Not determined.
is obvious that the C3 –OCH3 protons are in correlation with H2ꢁꢁ Experimental
and H5ꢁꢁ protons of the N-(but-3-one-1-yl) chain, and H5 proton
The 1D and 2D NMR spectra were recorded on a Bruker AMX-400
spectrometer in CDCl3. Chemical shifts are in ppm (δ), relative
to tetramethylsilane as an internal standard, and scalar coupling
reported in hertz. The pulse conditions were as follows: for the 1H
NMR spectra, observation frequency 400.13 MHz, acquisition time
(AQ) = 2.732 s, number of scans (NS) = 64, number of dummy
scans (DS) = 0, relaxation delay (RD) = 1.0 s, 90◦ pulse width
= 10 µs, spectral width SW = 5995.20 Hz, line broadening =
0.3 Hz and fourier transform (FT) size = 16 384; for the 13C-NMR
spectrum, observation frequency 100.613 MHz, AQ = 0.658 s, NS
= 3000, DS = 2, RD = 1.5 s, 90◦ pulse width 12.3 µs, SW =
24 875.64 Hz, FT size = 32 768, line broadening = 1.5 Hz; the
COSY 45◦ spectra were recorded at 400 MHz at spectral width of
3071 Hz in F2 and 3092 in the F1 domain. The AQ was 0.14 s,
and the spectra were acquired with 1 K data points in F2 with 32
transients, 8 DS and 256 experiments. The 1D nOe obtained by
selective excitation and gradient selection was acquired using the
DPFGSE–nOe experiment with constant mixing time of 500 ms, a
recycle delay of 2 s and 128 transients per spectrum for 4 and 5
and 256 transients for 6. The spectra were acquired with spectral
width of 6443.3 Hz (≈16 ppm) for 4, 6018.9 Hz (≈15 ppm) for 5,
is in spatial interaction with H2ꢁꢁ protons. It is assumed that these
correlations related to the hindrance of the rotation of the chains
connected to the tertiary amino function.
The observed region- and stereoselectivity of the Diels–Alder
addition to thiazolomorphinans 1–3 is explained by the
strong controlling effect of the additional thiazole ring of
morphinandienes.
Conclusions
We hereby report on a novel strategy for the formation of
ring-constrained endoethenomorphinans known as an important
group of semi-synthetic opioid analgesics for studying the exact
spatial requirements of superior opioid binding affinities. The
structure elucidation of primary products of Diels–Alder additions
to thiazolomorphinandienes was achieved by HRMS, IR, 1D and
2D NMR techniques. DPFGSE–nOe and HMBC experiments were
found to be particularly powerful and indispensable tools in the
exact structural elucidation of the presented new class of spatially
constrained thevinones.
c
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 801–807

Spectral Assignments and Reference Data
Table 3. 1D and 2D NMR data of compound 6
Chemical shifta, δ
Carbon
Numbering (Cn)
Protons
showing COSY
Protons
showing HMBC
1H [multiplicity, J(H,H)(Hz)]
13C
Significant nOes
H2; H10a; H10b
1
6.56 (d) J1–2 8.3
120.1
115.2
148.6
57.1
H2
H1
–
H1b; H2
b
2
6.62 (d) J2–1 8.3
H1; H2
H1
–
3
–
O-3-CH3
3-O-CH3
3.84 (s)
–
–
–
–
H5; H ; H
ꢁꢁ ꢁꢁ
2 5
4
5
142.8
85.7
–
–
∗
4.48 (s)
–
H5
3-O-CH3; H7; H8a; H8b; H15a
15b; H2
;
H
ꢁꢁ
6
7
–
77.2
47.0
–
H5; H7
–
3.24 (dd) J7–8a 8.9 J7–8b 7.4
H8a; H8b
H7b; H8a; H8b
H5; H8a; H8b; H15a; H15b; H16a
H21
;
b
8
1.27–2.52 (m)
50.7
60.8
23.2
H7
H10a; H10b
H9
H7; H8ab; H8b
H9b; H10a; H10b
H9; H10ab; H10b
ND
ND
ND
9
2.74 (dd) J9–10a 6.3 J9–10b 4.2
b
10
H
10a 3.19 (d) J10a–10b 16.1;
H
10b 3.10 (d) J10a–10b 16.1
11
12
13
14
15
–
–
–
–
129.1
135.1
28.3
–
H1
–
–
–
–
–
–
H5
–
42.4
H
8a; H8b; H9; H19
H15ab; H15bb; H16a; H16b
–
H
15a 1.21 (ddd) J15a,15b;15a,16a 11.7, J15a,16b 5.7;
15b 1.27–2.52 (m)
33.8
H16a; H16b
ND
H
b
16
H
16a; H16b 1.27–2.52 (m)
45.9
44.4
H15a; H15b
H15a; H15b; H16ab; H16b
ND
17-N-CH3
2.31 (s)
–
–
–
–
–
–
–
ND
18
19
20
2ꢁ1
2ꢁꢁ
2
3ꢁꢁ
4ꢁꢁ
5ꢁꢁ
–
5.32 (s)
–
137.2
121.9
209.3
32.2
H19
–
b
H19
H8a; H8b; H9; H10a; H10b
H7; H21
–
–
b
2.08 (s)
–
H21
161.8
44.9
–
–
2.83 (t) J2
a 11.9, J2
b 3.5
H3
ꢁꢁ
H2 b; H3
ND
ND
–
ꢁꢁ ꢁꢁ
ꢁꢁ ꢁꢁ
ꢁꢁ
ꢁꢁ
a,3
a,3
1.27–2.52 (m)
41.5
H2
ꢁꢁ
H2 ; H b; H5
ꢁꢁ ꢁꢁ ꢁꢁ
3
–
208.2
30.4
–
H2 ; H ; H
ꢁꢁ ꢁꢁ ꢁꢁ
3 5
H3 ; H
∗
2.13 (s)
–
ND
ꢁꢁ
ꢁꢁ
5
a In ppm from TMS.
b Derived from 1JCH and used for assigning carbons bonded to protons.
ND, Not determined,
65 ms (corresponding to an average 1/nJ (C,H) of 7.7 Hz) and the
recycle time was 1.44 s. FT was done on a 2 × 1 K data matrix.
Melting points were determined with a Kofler hot-stage
apparatus and are uncorrected. Thin-layer chromatography
was performed on precoated Merck 5554 Kieselgel 60 F254
foils using chloroform: methanol=8 : 2 mobile phase; the spots
were visualized with Dragendorff’s reagent. High-resolution
mass spectral measurements were performed on a Bruker
micrOTOF-Q instrument in the electrospray ionization (ESI) mode.
Optical rotation was determined with a Perkin–Elmer Model 241
polarimeter. IR spectra were recorded on Perkin–Elmer 283 B
spectrometer.
· · ·
Table 4.
H
H distances from geometry optimized structure of 6 at
B3LYP/6-31G∗ level of theory
· · ·
H
H distances for compound 6 (Å)
H5
H7
H8a
H8b
H2
ꢁꢁꢁ
H5
ꢁꢁꢁ
H5
–
2.27
4.87a
–
3.67
3.16
–
4.51a
4.18
–
4.29
6.77a
3.58
–
H19
5.01a
7.11a
C3 –OCH3
4.26
3.83
a No nOe was observed.
and 7267.44 Hz (≈18 ppm) for 6 and 32 K data points, giving a
spectral resolution of 0.20 for 4, 0.19 for 5, and 0.22 Hz for 6
and processed with zero filling to 32 K data points and by an
exponential multiplication of the FID by a factor of 1 Hz. The
long-range 1H–13C correlations (HMBC) spectra resulted from
1024 × 256 data matrix with 16 scans per t1 increments. Spectral
width of 23 236 Hz in F1 and 3212 Hz in F2 domain were used.
The AQ was 0.14 s, the delays were set to 3.45 ms (1/2J (C, H)) and
General procedure for Diels–Alder addition
Diene (8 mmol) was heated with MVK (2.5 g, 36 mmol) in the
presence of a small amount of hydroquinone at 100 ◦C for 4 h. The
excess of MVK was removed under reduced pressure, and the dark
viscous residue was dissolved in warm glacial acetic acid (4 ml).
This solution was diluted with water (30 ml) and extracted with
ether. The aqueous phase was freed from ether by boiling and
c
Magn. Reson. Chem. 2009, 47, 801–807
Copyright ꢀ 2009 John Wiley & Sons, Ltd.
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A. Sipos et al.
for C24H27N2O3S+: 423.1737 (M++ H); for 1D and 2D NMR data,
see Table 1.
2ꢁ-Phenyl-[6,18:4ꢁ,5ꢁ]-thiazolo-7α-acetyl-6-demethoxy-6,14-
endoethenothebaine (5)
Pale yellow, plate shape crystals; mp.: 187–189 ◦C; yield: 2.48 g
25
(64%); [α]D −22.6 (c 0.1, chloroform); Rf 0.69; νmax (KBr disc)
1711 (C O); HRMS (ESI) m/z (%) found: 485.1881 [(M + H)+, 100],
calculated for C29H29N2O3S+: 485.1893 (M++ H); for 1D and 2D
NMR data, see Table 2.
N,N-Bis-(but-3-one-1-yl)-2ꢁ-amino-[6,18:4ꢁ,5ꢁ]-thiazolo-7α-acetyl-6-
demethoxy-6,14-endoethenothebaine(6)
White, cubic crystals; mp.: 211–213 ◦C; yield: 3.92 g (87%);
25
[α]D +4.6 (c 0.1, chloroform); Rf 0.69; νmax (KBr disc) 1705
(C O), 1670 (C O); HRMS (ESI) m/z (%) found: 564.2590 [(M +
H)+, 100], calculated for C31H38N3O5S+: 564.2557 (M++ H); for 1D
and 2D NMR data, see Table 3.
Computational procedure
We have carried out the geometry optimization at Becke’s three
parameter hybrid (B3LYP)[8] levels in the DFT with the basis set
6-31G∗ using Gaussian98.[9] Thesolventeffectwasnotconsidered.
The model for (5R,6R,7R,9R,13R,14S)-21-cyclopropylmethyl-6,14-
endo-ethano-2ꢁ,3ꢁ,4ꢁ,5ꢁ,7,8-hexahydro-4ꢁ,4ꢁ,5ꢁ,5ꢁ-tetramethyl-
furano[2ꢁ,3ꢁ,6,7]normorphide hydrochloride, a structurally ana-
logue 6,14-bridged morphinan was obtained at the B3LYP/6-31G∗
level and compared to X-ray data[10] in order to test the perfor-
mance of this DFT method in the case of this group of morphinans.
Besidesthestructureofcompound6presentedinFig. 1(derived
from the ß-face approach of MVK to compound 3), the structure
of its hypothetic isomer originated from α-face approach was also
generated at the same level of theory in order to confirm the
energetic preference of ß-face approach vs. α-face approach.
The energetic difference of the two isomers of compound
6 was calculated at two different levels of theory and shows
significant gap in favour of the ß-face approach product.
Further information, structures and coordinates are presented
as Supporting Information.
Acknowledgement
The authors are grateful for the financial support to the Hungarian
National Science Foundation (Grant OTKA reg. No. NI61336).
Supporting information
Figure 1. Geometry optimized structure of 6 at B3LYP/6-31G∗ level of
theory; nOes of H5 (panel A), H19 (panel B) and C3 –OCH3 (panel C) were
highlighted with arrows.
Supporting information may be found in the online version of this
article.
basified (cc. ammonia solution), and the precipitate was collected,
washed with water and dried to give the adduct.
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Magn. Reson. Chem. 2009, 47, 801–807

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