Synthesis, NMR studies and conformational analysis of oxazolidine derivatives of the β-adrenoreceptor antagonists metoprolol, atenolol and timolol

Article abstract of DOI:10.1039/a706442j

Formaldehyde-derived oxazolidine derivatives 4-7 of the β-adrenoreceptor antagonists metoprolol 1, atenolol 2 and timolol 3 have been synthesised. Conformational analysis of 1-3 and the oxazolidine derivatives 4-7 has been performed using ¹H NM

Full text of DOI:10.1039/a706442j

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Synthesis, NMR studies and conformational analysis of oxazolidine
derivatives of the â-adrenoreceptor antagonists metoprolol, atenolol
and timolol
Gerard P. Moloney,*,a David J. Craik,b Magdy N. Iskandera and
Tracy L. Neroc
a Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, 381
Royal Parade, Parkville, Victoria, Australia, 3052. E-Mail: Gerard.Moloney@vcp.monash.edu.au
b Centre for Drug Design and Development, University of Queensland, Brisbane, Queensland,
Australia, 4072
c Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre,
Heidelberg, Victoria, Australia, 3084
Formaldehyde-derived oxazolidine derivatives 4–7 of the â-adrenoreceptor antagonists metoprolol 1,
atenolol 2 and timolol 3 have been synthesised. Conformational analysis of 1–3 and the oxazolidine
derivatives 4–7 has been performed using 1H NMR spectroscopy and computational methods. The
1H NMR studies show that for the aryloxypropanolamine â-adrenoreceptor antagonists there is a
predominance of the conformer in which the amine group is approximately antiperiplanar or trans
to the aryloxymethylene group. Both 1H NMR data and theoretical studies indicate that the oxazolidine
derivatives 4–7 and the aryloxypropanolamine â-adrenoreceptor antagonists 1–3 adopt similar
conformations around the â-amino alcohol moiety. Thus, oxazolidine ring formation does not
dramatically alter the preferred conformation adopted by the â-amino alcohol moiety of 1–3. Oxazolidine
derivatives of aryloxypropanolamine â-adrenoreceptor antagonists may therefore be appropriate as
prodrugs, or semi-rigid analogues, when greater lipophilicity is required for drug delivery.
cessfully applied in the past to a variety of drug classes, includ-
Introduction
ing β-blockers.8,9,17–23
β-Adrenoreceptor antagonists are a group of compounds
that competitively inhibit the effects of catecholamines at
β-adrenergic receptors.1 These agents are used widely in clinical
medicine for the treatment of various conditions including
hypertension,2,3 angina pectoris,4 cardiac arrhythmias,5,6 hypo-
thyroidism7 and glaucoma.8 As the β-adrenoreceptor antagon-
ists (β-blockers) have such a diverse range of clinical applic-
ations, the mode of delivery of these drugs becomes crucial. In
particular there has been great interest in the percutaneous
transport of β-blockers for hypertension and ocular delivery for
glaucoma.8–10
Ocular β-blockers are primary agents currently used in the
treatment of glaucoma. They reduce aqueous humour produc-
tion, thereby decreasing intraocular pressure and thus prevent-
ing the loss of visual fields.10 Direct ocular application of
many of these drugs causes severe irritation, presumably as a
result of alkalinity produced by the strongly basic amines in an
aqueous environment (e.g. pKa of propranolol is 9.5).11,12 The
therapeutic usefulness of these drugs in treating glaucoma is
also often limited by a relatively high incidence of cardio-
vascular and respiratory side effects.10.13 These side effects arise
as a result of the highly polar nature of the β-blockers and their
consequent low lipophilicity which, in turn, results in poor
absorption of the drugs into the eye upon topical administra-
tion. As such, large concentrations of the drugs have to be used,
which ultimately results in the topically applied drug being
absorbed into the systemic circulation via the nasolacrimal
duct.10,14,15 A potentially useful approach to decrease the sys-
temic absorption of topically applied β-blockers, thereby dimin-
ishing adverse effects, may be the development of transient
derivatives or prodrugs16 with appropriate moieties included
in their structures designed to improve corneal absorption
through increased lipophilicity. This approach has been suc-
In the aryloxypropanolamine class of β-blockers there are
two functional groups which are obvious candidates for
manipulation to produce prodrugs. They are the β-hydroxy and
the amino groups. A range of β-blocker prodrugs have previ-
ously been synthesised by converting the β-hydroxy group into
bioreversible derivatives such as esters.8,9,17–21 There has also
been considerable research on the conversion of the amino
functional group into prodrug forms, for example carbamates.12
As well as exhibiting chemical stability, these derivatives have
been shown to have favourable lipophilic properties.
Another approach involves combining both β-hydroxy and
amino functional groups into a cyclic group such as an oxazol-
idine ring. Oxazolidine derivatives of arylethanolamines have
been synthesised as potential β3-adrenoreceptor agonists.24 Pre-
vious studies have been carried out on oxazolidine derivatives
of (Ϫ)-ephedrine and a range of aldehydes and ketones.25,26
These studies proposed that oxazolidines may have potential as
prodrug forms for β-amino alcohols or carbonyl containing
compounds. The oxazolidines are much weaker bases than the
parent β-amino alcohols and this results in higher lipophilicity
at physiological pH. Such increased lipophilicity may become
advantageous in situations where delivery problems for the β-
amino alcohol-type drugs are due to low lipophilicity, for
example glaucoma.
Oxazolidines and their properties have been examined in
detail in our laboratories.27 They appear to be useful as pro-
drugs for β-blockers because the resulting ‘masked’ amines do
not ionise and hence are more compatible with organic and
lipophilic media. It has been demonstrated that an oxazolidine
can penetrate a biological membrane from water faster than a
β-amino alcohol at pH values around 7.28 Control over the
chemical stability of the oxazolidine systems can be enforced
by the choice of different aldehyde moieties. In addition,
J. Chem. Soc., Perkin Trans. 2, 1998
199

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3′
6′
4′α
analysis of the β-blockers 1–3 and the formaldehyde-derived
oxazolidine derivatives 4–7 (Fig. 1), using H NMR spectro-
scopy and computational methods.
O
4′
1
2′
1′
CH3
4′β
4
2
5′
5
6
1
3
O
NHCH(CH3)2
OH
Experimental
1
4′α
3′
6′
NMR Spectroscopy
NH2
4′β
4′
1H and 13C NMR spectra were recorded in 5 mm tubes at 300 K
on a Bruker AM 300 WB spectrometer. All solutions of the
β-blockers were 0.06–0.07  in D2O and CDCl3 while the
oxazolidine derivatives were 0.06–0.07  in CDCl3 unless
otherwise stated. The deuterium signal of the solvent was used
as the lock and tetramethylsilane (TMS) was the internal
standard. J values are in Hz. One-dimensional NMR experi-
ments were carried out with a spectral width of 3 kHz, a 45Њ
pulse angle, 16 384 data points and a repetition delay of 2.0 s.
32 scans were accumulated prior to Fourier transformation.
DQF–COSY spectra were recorded using a spectral width of
3 kHz, a 90Њ pulse of 7.8 µs and a repetition delay of 2.0 s. For
each FID, 32 scans were accumulated. The two-dimensional
data were collected as a 512 × 1024-word matrix and zero-filled
to 1024 × 2048 prior to Fourier transformation. A sine-bell
window function was applied in both dimensions.
2′
1′
4
2
O
5′
1
5
3
6
O
NHCH(CH3)2
OH
2
5′′
2′′
6′′
O
OH
1
3′′
N
O
NHC(CH3)3
4′ 3′
3
5
6
4
2
N
N
2′
5′
S
1′
3
O
CH3
6
4
3
5
N
CH(CH3)2
O
1
O
2
Chemistry
Mass spectra and high resolution mass spectra (HRMS) were
obtained on a JEOL JMS DX-300 double focussing instrument.
Infra-red spectra were run in KBr disks on a Bruker IFS66
FTIR spectrometer. Melting points were determined on a
Gallencamp melting point apparatus and are uncorrected.
Methanol was distilled from iodine and magnesium and stored
over 3 Å molecular sieves. Solutions were concentrated on a
Buchi rotary evaporator.
4
H
N
R1
O
N
CH(CH3)2
O
O
R1
H
5
6
CH2OH
Synthesis
All compounds were prepared as racemic mixtures and no
attempts were made to maximise yields. The oxazolidine deriv-
atives 4–7 were synthesised in a one step reaction by conden-
sation of the β-amino alcohol derivatives 1–3 with formalde-
hyde. Experimental details for the synthesis of 4 are outlined
below. For the oxazolidine derivatives 5 and 7 any variations on
this procedure are described. The cyclisation of 2 was initially
performed in methanol using 38% formalin solution resulting
in hydroxymethylation of the primary amide group in addition
to oxazolidine ring formation to form 6. The desired oxazol-
idine 5 was eventually synthesised employing the conditions
described for 4.
3-Isopropyl-5-[4-(2-methoxyethyl)phenoxymethyl]oxazolidine
4. A solution of the free base of metoprolol 1 (0.79 g, 3.0 mmol)
in super-dry methanol (20 ml) was added to a solution of
paraformaldehyde (0.45 g, 15.0 mmol) and potassium hydr-
oxide (50 mg) in super-dry methanol (50 ml). Sodium sulfate
(0.5 g) was added to the mixture and the resulting suspension
was refluxed for 8 h. The solution was filtered hot and the
methanol removed under reduced pressure. Radial chromato-
graphy (chloroform–methanol 8:2, Rf 0.65) afforded the
desired oxazolidine 4 (0.76 g, 91%) as a clear viscous oil
(Found: C, 67.1; H, 8.7; N, 4.6. C16H25NO3ؒ0.5H2O requires
C, 66.7; H, 9.1; N, 4.8%) (Found: Mϩ, 279.186. C16H25NO3
requires Mϩ, 279.184). MS m/z 279 (Mϩ, 60%). δH 1.09 [d, 6H,
CH(CH3)2, J 6.2], 2.57 [sept, 1H, CH(CH3)2, J 6.3], 2.74 (dd,
1H, H4B, J 6.6, 10.1), 2.80 (t, 2H, CH24Јα, J 7.1), 3.10 (dd, 1H,
H4A, J 6.9, 10.1), 3.33 (s, 3H, OCH3), 3.54 (t, 2H, CH24Јβ,
J 7.1), 3.93 (dd, 1H, H6B, J 5.4, 9.7), 4.00 (dd, 1H, H6A, J 5.7,
9.5), 4.34 (d, 1H, H2B, J 3.6), 4.36 (m, 1H, H5), 4.39 (d, 1H,
H2A, J 4.0), 6.83 (d, 2H, H2Ј, H6Ј, J 8.5), 7.11 (d, 2H, H3Ј,
H5Ј, J 8.5). δC(CD3OD) 21.9, CH(CH3)2; 36.1, C4Јα; 53.0, C4;
53.9, CH(CH3)2; 58.7, OCH3; 70.3, C4Јβ; 74.7, C6; 76.9, C5;
85.9, C2; 115.6, C2Ј, C6Ј; 130.8, C3Ј, C5Ј; 132.8, C4Ј; 158.7,
C1Ј.
S
N
N
N
O
O
N
O
C(CH3)3
7
Fig. 1 Structures for the β-blockers 1–3 and the oxazolidine deriv-
atives 4–7. The numbering system for the compounds is indicated.
oxazolidines can be regenerated easily to the parent drugs via
hydrolysis.25,27–30
Structural properties of arylethanolamines and aryloxy-
propanolamines possessing β-adrenergic agonistic and/or
antagonistic activity have been extensively studied using a var-
iety of methods.31–54 Data obtained from X-ray crystallography
and quantum mechanical calculations on several β-blockers
show, without exception, that the preferred conformation
around the β-amino alcohol group has the hydroxy and the
amino group located gauche to each other, irrespective of
whether the amino group is charged or uncharged.31,32,42–45,54
1H NMR spectroscopic studies on several arylethanolamines
support this conclusion, indicating that the main conformation
adopted in solution has a gauche arrangement for the β-
hydroxy and amino groups.46–48,54 The major interaction leading
to the predominance of this rotamer has been postulated to be
hydrogen bonding between the two groups.48,49 These NMR
studies agreed well with X-ray diffraction analysis.50,51 1H
NMR studies performed on a range of aryloxypropanolamine
compounds52–57 including propranolol,53 metoprolol,56 aten-
olol56 and timolol57 also supported the proposed conformation
in which the β-hydroxy and the amino group are gauche and the
amino group and the O-aryl substituent are antiperiplanar to
each other.
In this work we describe the results of conformational
200
J. Chem. Soc., Perkin Trans. 2, 1998

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1′
3-Isopropyl-5-[(4-acetamido)phenoxymethyl]oxazolidine 5.
White crystals from methanol (70.4%) mp 156–157 ЊC (Found:
C, 63.0; H, 7.8; N, 9.0. C15H22N2O3ؒ0.5H2O requires C, 62.8; H,
8.1; N, 9.7%) (Found: Mϩ, 278.164. C15H22N2O3 requires Mϩ,
278.187). MS m/z 278 (Mϩ, 47%). δH 1.10 [d, 6H, CH(CH3)2,
J 6.6], 2.59 [sept, 1H, CH(CH3)2, J 6.36], 2.76 (dd, 1H, H4B,
J 6.6, 10.2), 3.11 (dd, 1H, H4A, J 6.9, 10.1), 3.52 (s, 2H,
CH2CO), 3.95 (dd, 1H, H6B, J 5.2, 9.6), 4.02 (dd, 1H, H6A,
J 5.7, 9.6), 4.35 (d, 1H, H2B, J 3.7), 4.41 (d, 1H, H2A, J 3.6),
4.41 (m, 1H, H5), 5.39 (s, 2H, NH2), 6.90 (d, 2H, H2Ј, H6Ј,
J 8.5), 7.17 (d, 2H, H3Ј, H5Ј, J 8.6). δC(CD3OD) 21.9,
CH(CH3)2; 42.6, CH2CO; 52.9, CH(CH3)2; 53.9, C4; 70.5, C6;
76.8, C5; 85.9, C2; 115.9, C2Ј, C6Ј; 129.4, C4Ј; 131.2, C3Ј, C5Ј;
159.3, C1Ј; 177.3, CO.
S
5′
2′
N
N
CH3
2
4
6
1
5
3
4′ 3′
N
O
NH
C
CH3
τ5
τ1 τ2
τ3 τ4
OH
O
CH3
3
3′
4′
5′
2′
4
2
1
CH3
6
5
3
1′
O
NH CH
τ3 τ4
6′
τ5
τ1
τ
CH3
2 OH
8
Fig. 2 Fragments 3 and 8 used for theoretical calculations. The torsion
angles τ1–τ5 are defined in the text.
3-Isopropyl-5-[4-(N-hydroxymethylacetamido)phenoxy-
methyl]oxazolidine 6. Atenolol 2 (0.24 g, 0.9 mmol) in super-
dry methanol was added to a solution of formalin (38%) (600
µl, 7.27 mmol) and the resulting mixture was refluxed for 8 h.
The methanol was removed under reduced pressure to a volume
of approximately 1 ml. Radial chromatography (chloroform–
methanol 8:2, Rf 0.44) gave the oxazolidine 6 (0.17 g, 61%) as
white crystals. Mp 88–89 ЊC (Found: C, 62.1; H, 8.0; N, 9.0.
C16H24N2O4 requires C, 62.3; H, 7.8; N, 9.1%) (Found: Mϩ,
308.174. C16H24N2O4 requires Mϩ, 308.175). MS m/z 308
(Mϩ, 3%). δH 1.05 [d, 6H, CH(CH3)2, J 6.5], 2.54 [sept, 1H,
CH(CH3)2, J 6.4], 2.70 (dd, 1H, H4B, J 6.6, 10.2), 3.05 (dd, 1H,
H4A, J 6.9, 10.1), 3.46 (s, 2H, CH2CO), 3.88 (dd, 1H, H6B, J 5.3,
9.6), 3.96 (dd, 1H, H6A, J 5.6, 9.6), 4.30 (d, 1H, H2B, J 3.7), 4.32
(m, 1H, H5), 4.35 (d, 1H, H2A, J 3.6), 4.60 (d, 2H, CH2OH,
J 6.5), 6.40 (t, 1H, NH, J 6.5), 6.83 (d, 2H, H2Ј, H6Ј, J 8.5),
7.09 (d, 2H, H3Ј, H5Ј, J 8.6). δC(CDCl3) 21.7, CH(CH3)2; 42.6,
CH2CO; 52.4, CH(CH3)2; 52.5, C4; 64.3, C6; 69.4, CH2OH;
74.9, C5; 85.1, C2; 114.9, C2Ј, C6Ј; 126.6, C4Ј; 130.5, C3Ј, C5Ј;
157.9, C1Ј, 172.9, CO.
1′
S
N 2′
5′
τ10
3
N
N
N
6
4
τ9
3α
5
3′
4′
O
C(CH3)3
7
τ7 τ8
1O
τ6
τ11
2
τ12
O
7
3′
4′
5′
2′
1′
τ10
4
6
τ9
3
N
3α
5
CH(CH3)2
τ11
O
7
6′
τ6
τ
7 τ8
O
2
1
τ12
9
Fig. 3 Oxazolidine fragments 7 and 9 used in the theoretical calcu-
lations. Torsion angles τ6–τ12 are defined in the text.
3-tert-Butyl-5-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-
methyl]oxazolidine 7. Purification by radial chromatography
(chloroform–methanol, 8:2, Rf 0.46) gave the desired oxazolid-
ine 7 (84.0%) (Found: C, 50.2; H, 7.4; N, 16.5. C14H24N4O3Sؒ0.5
H2O requires C, 49.8; H, 7.4; N, 16.6%) (Found: Mϩ, 328.156.
C14H24N4O3Sؒ0.5H2O requires Mϩ, 328.280). MS m/z 328 (Mϩ,
17). δH 1.06 [s, 9H, C(CH3)3], 2.66 (dd, 1H, H4B, J 6.70, 9.89),
3.10 (dd, 1H, H4A, J 6.61, 9.87), 3.47 [t, 4H, CH2(3Љ, 5Љ), J 4.79],
3.74 [t, 4H, CH2(2Љ, 6Љ), J 4.74], 4.35 (d, 1H, H2B, J 3.37),
4.46 (d, 1H, H2A, J 3.65), 4.37 (m, 1H, H5), 4.40 [m, 2H,
CH2(6)]. δC(CDCl3) 26.6, C(CH3)3; 47.1, C4; 47.7, C3Љ, C5Љ;
52.3, C(CH3)3; 66.3, C2Љ, C6Љ; 71.2, C6; 74.8, C5; 81.1, C2;
149.7, C4Ј; 153.9, C3Ј.
torsion angles (defined in Fig. 2) were varied in 30Њ increments
over 360Њ. The default values were used for all other parameters.
The resulting structures were then minimised using the protocol
described above. All unique conformers within 10 kcal molϪ1 of
the lowest energy conformer found were reported.
The conformers of 7 and 9 were generated in a similar
manner to that of 3 and 8, with the addition of conformational
analysis of the oxazolidine ring. The acyclic torsion angles
(defined in Fig. 3) were varied in 30Њ increments over 360Њ.
The bond between atoms C5 and O1 was chosen as the ring
closure bond and torsion angles τ9–τ12 were varied in 5Њ steps
over the full 360Њ circle. A detailed description of ring confor-
mational analysis has been given by Lipton and Still64 and
therefore will not be included here. The default values were used
for all other parameters. The resulting structures were then min-
imised as previously described for 3 and 8. The torsion angle to
the morpholine group in 3 and 7 was not considered because 1H
NMR data indicated that the oxypropanolamine sidechain of
timolol 3 adopted a similar conformation to metoprolol 1 and
atenolol 2 indicating that the morpholine group has no effect
upon the conformation adopted by the oxypropanolamine
sidechain in solution.
Computational conformational analysis
Computer-aided conformational analyses were carried out to
further define the conformations of 1–7. The primary aim
of these conformational studies was to examine closely the
orientations of the β-amino alcohol group. The (S)-aryloxy-
propanolamine isomers were examined in the conformational
analysis since it is known that most of the pharmacological
activity resides with this isomer.58 As a consequence, only the
(S)-oxazolidine isomers were considered here. All molecules
were constructed using standard bond angles and bond lengths
within the sketch functionality of the program SYBYL.59 The
molecules were then minimised using the TRIPOS force field,60
Gasteiger–Hückel atom charges (an algorithm which incorpor-
ates Gasteiger–Marsili61 and Hückel62 charge calculations) and
the Powell optimisation method.63 Minimisation was termin-
ated for each structure when the gradient fell below 0.05 kcal
molϪ1 ÅϪ1 (1 cal = 4.184 J). The default values were used for all
other parameters.
Superimposition of the selected minimised structures was
performed using the linear least squares fitting algorithm within
SYBYL. All calculations were performed on a Silicon Graphics
Indigo 2 XZ Unix workstation.
Results and discussion
NMR studies
Investigation of the low energy conformations of the β-amino
alcohol moiety of 1–3 was undertaken to determine whether
constraining the β-blocker backbone into an oxazolidine ring
affected the orientation of the β-hydroxyl oxygen and the
amino group. If the oxazolidine ring constrains the molecule
Conformer generation
The conformers for 3 and 8 were generated using the systematic
search algorithm implemented within SYBYL. The acyclic
J. Chem. Soc., Perkin Trans. 2, 1998
201

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Table 1 1H NMR spectral data for the free base of metoprolol 1 in
CDCl3 and metroprolol tartrate in D2O
Table 2 1H NMR spectral data for the free base of atenolol 2 in
CDCl3 and in D2O
δH
J/Hz
δH
J/Hz
Proton
CDCl3
D2O
Multiplicity
CDCl3
D2O
Proton
CDCl3
D2O
Multiplicity
CDCl3
D2O
CH(CH3)2
CH(CH3)2
H4A
H4B
H3
H2A
H2B
H2Ј, H6Ј
H3Ј, H5Ј
H4Јα
1.05
2.83
2.83
2.65
4.01
3.88
3.86
6.80
7.07
2.79
3.52
3.31
1.32
3.47
3.35
3.20
4.29
4.10
4.05
6.95
7.22
2.82
3.67
3.29
d
6.5
6.5
6.6
6.6
CH(CH3)2
CH(CH3)2
H4A
1.09
2.86
2.85
2.66
4.04
3.94
—
1.05
2.86
2.82
2.72
4.08
—
4.06
3.97
6.96
7.22
3.51
d
6.2
6.3
3.8, 12.0
8.3, 12.0
—
4.4
—
—
8.6
6.3
6.3
4.0, 13.2
7.9, 12.8
—
sept
dd
dd
m
dd
dd
d
d
t
t
s
sept
dd
dd
m
d
dd
dd
d
3.2, 11.9
8.9, 11.9
—
4.4, 9.6
5.4, 10.4
8.5
8.6
7.5
7.1
—
3.3, 13.0
9.3, 13.1
—
4.2, 10.4
5.1, 10.5
8.6
8.6
6.5
6.6
—
H4B
H3
CH2-2a
—
b
H2Ab
3.4, 11.0
7.0, 11.0
8.6
8.6
—
H2B
—
H2Ј, H6Ј
H3Ј, H5Ј
H4Јα
6.90
7.22
3.44
d
s
8.6
—
H4Јβ
OCH3
a CH2-2 protons of 2 in CDCl3 are equivalent. b H2 protons are in-
equivalent in D2O appearing as doublets of doublets.
Table 3 1H NMR spectral data for the free base of timolol 3 in CDCl3
close to one of the β-blocker’s preferred conformations, then
the drug may have potential as a rigid analogue. On the other
hand, controlled oxazolidine ring hydrolysis could provide an
effective prodrug agent for the delivery of the β-blocker by
improving the lipophilic characteristics of the molecule.
Compounds 1 and 2 have the same atomic constitutions
around the oxypropanolamine moiety while 3 possesses an N-
tert-butyl group instead of an N-isopropyl group. The spectral
characteristics of these compounds were very similar and func-
tional groups within the structures were easily identified in the
1H NMR spectra. Bridging of the hydroxy and amino functions
of 1–3 with formaldehyde to form the oxazolidine derivatives
4–7 did not appreciably change the chemical shifts of the vari-
ous protons although changes in the coupling constants were
observed.
and timolol maleate in D2O
δH
J/Hz
Proton
CDCl3 D2O Multiplicity CDCl3
D2O
—
CH(CH3)3
H4A
1.09
2.71
2.52
3.88
1.36
3.28 dd
3.08 dd
s
—
3.9, 11.9 2.7, 12.8
8.2, 11.9 10.0, 12.7
3.7, 4.3
5.8, 8.2
—
H4B
H3a
—
dddd
—
—
—
H3b
H2A
H2B
—
4.31
m
4.38
4.30
4.51 dd
4.43 dd
4.4, 11.0 4.1, 10.9
5.7, 11.0 5.5, 11.1
CH2-2Љ, CH2-6Љ 3.71
CH2-3Љ, CH2-5Љ 3.44
3.82
3.46
t
t
4.6
4.6
4.5
4.5
a H3 protons of 3 in CDCl3 can be resolved as eight peaks coupled to
1H NMR analysis of â-blockers 1–3
H2 and H4. b H3 in D2O is not resolved.
A combination of 2D homonuclear double quantum filtered
1
phase sensitive H᎐1H correlated spectroscopy (DQF–COSY)
R
R
τ2
O
O
and selective homonuclear decoupling experiments was utilised
in the H NMR assignment of the β-blockers and their corre-
sponding oxazolidine derivatives. The H NMR spectral data
1
R1NHCH2
H2
OH
H2
HO
H2
H3
H2
1
for 1–3 are given in Tables 1–3. The three bond vicinal coupling
constants of the β-amino alcohol moiety in 3 and 8 (Fig. 2)
provide valuable information about the torsion angles τ1–τ5.
The non-equivalence of the protons in the methylene groups
CH2-2 and CH2-4 is easily observed. For compounds 1–3, H4A
exhibits couplings of J4A,3 2.7–4.0 with H3 and J4A,4B 11.9–13.2
with H4B. Proton H4B couples to H3 with a coupling constant
in the range J4B,3 7.9–10.0. The CH2-2 protons appear further
downfield, proton H2A displaying couplings of J2A,3 3.4–4.4
with H3 and J2A,2B 9.6–11.0 with H2B. Proton H2B shows coup-
lings of J2B,3 5.1–7.0 with H3. An exception to this was noted in
(A or B)
(A or B)
H3
CH2NHR1
(g +)
(t )
R
O
H3
H2
CH2NHR1
H2
OH
1
(g –)
the H NMR spectral data of 2 in CDCl3, Table 2. The CH2-2
protons were found to be equivalent and appeared as a doublet
at δ 3.94 (J 4.4).
Fig. 4 Newman projections depicting the conformations around
the C2᎐C3 bond (τ2) of the aryloxypropanolamine sidechain of the
β-blockers
Conformation around the C2᎐C3 bond (ô2)
angles were predicted using the Karplus equation.65 These
results indicate a predominance of conformation t, Fig. 5.
These findings are consistent with those of Kulkarni and co-
workers53,56,57 who examined their molecules in D2O and indi-
cate that the most likely conformer is an extended form with the
possibility of H-bonding between the NH and the OH groups
and that an interaction involving H-bonding between the ether
oxygen and the amino group is unlikely.53–57
The three classical conformers about the C2᎐C3 bond are
shown in Fig. 4. The observed coupling constants of J2B,3 5.1–
7.0 and J2A,3 3.4–4.4 do not correspond to any of the con-
formers gϩ, t or gϪ. This suggests a rapid equilibrium involv-
ing more than one rotational isomer. Kulkarni observed the co-
existence of the three staggered rotamers for atenolol, meto-
prolol and timolol with the equilibrium dominated by the gϩ
rotamer.54,56,57
Conformation around the C3᎐C4 bond (ô3)
1H NMR analysis of the oxazolidine derivatives 4–7
NMR data for the oxazolidine derivatives 4–7 are given in the
Experimental section. The DQF–COSY spectrum of the ox-
azolidine derivative 4 in CDCl3 at 300 K is shown in Fig. 6 with
An examination was made of the coupling constants observed
between H3 and the two H4 protons for 1–3 recorded in both
CDCl3 and D2O and from these values approximate torsion
202
J. Chem. Soc., Perkin Trans. 2, 1998

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OR
OR
R
O
130–140°
HA4
CH2
CH2
H
H2C
H4B
R1
(CH3)2CH
H
τ3
N
H4A
HA4
H3
H4B
OH
4 CH(CH3)2
5 CH(CH3)2
6 CH(CH3)2
7 C(CH3)3
+
O 1
H3
OH
H5
H
3
+ N
10–30°
N
H4B
2
R1
H
H
H
(g +)
CH(CH3)2
Fig. 7 Newman projection showing the proposed conformation of the
oxazolidine ring system of 4–7 about the C4᎐C5 bond (τ9)
OR
(t )
CH2
H
+ N
CH(CH3)2
H
HA4
H3
Conformation around the C4᎐C5 bond (ô9)
The coupling between H4A and H5 of J4A,5 6.6–7.0 is consider-
ably larger than the values of 2.7–4.0 recorded for the corre-
sponding protons (H4A and H3) of 1–3. The bridging of the
nitrogen and the oxygen atom changes the conformation, lead-
ing to a decreased torsion angle between these vicinal hydro-
gens which results in the observed larger coupling constant. An
approximate value of 10–30Њ for τ9 (depicted in Fig. 7) was
estimated from the Karplus equation. Conversely the coupling
between H4B and H5 (J4B,5 6.6–6.7) is smaller than that between
the corresponding protons (H4B and H3) in the linear β-blocker
(J3,4B 7.9–10.0). Thus in 4–7 the H4B and H5 protons are orien-
tated at approximately 130–140Њ to each other, compared to a
torsion angle of 140–165Њ between the corresponding protons
H4B and H3 of 1–3. Oxazolidine formation changes the con-
formation of the protons H3 and H4B of the acyclic β-blocker
from an essentially trans configuration to one shown in Fig. 7,
with the corresponding oxazolidine protons H4B and H5 in a
less gauche configuration.
OH
H4B
(g –)
Fig. 5 Newman projections depicting the likely conformers around
the C3᎐C4 bond (τ3)
Conformation around the C5᎐C6 bond (ô8)
Cyclisation to form the oxazolidine ring does not affect the
coupling constants between the H6 and H5 protons as dramat-
ically as it does the couplings between the H4 and H5 protons.
The couplings between H6A and H5 (J6A,5 5.6–5.7) for the
oxazolidine derivatives 4–7 are slightly larger than the corre-
sponding H2A–H3 coupling (of 1–3) of J2A,3 3.4–4.4. The H5–
H6B coupling of J5,6B 5.3–5.4 is slightly smaller than J2B,3 5.1–
7.0 observed for the coupling between H2B–H3 of the linear
parent β-blockers 1–3. Thus, the conformation about this part
of the molecule is only slightly affected by oxazolidine ring
formation. Considering that the most likely conformation of
the acyclic β-blockers around τ2 corresponds to gϩ in Fig. 4,
the most likely cause of conformational change as a result of
oxazolidine formation appears to be due to the loss of hydrogen
bonding between the ether oxygen and the 3-hydroxy group
which was shown to be likely given the proposed conformer gϩ
in Fig. 5. In the oxazolidine derivatives, the 3-hydroxy group
becomes involved in the five-membered ring and can no longer
contribute to hydrogen bonding.
Fig. 6 Contour plot of the 2D DQF–COSY spectrum of 4 in CDCl3
assignments and connections between cross peaks indicated. As
the assignments of 4–7 have not been reported previously, the
assignment procedure for 4 is described now in some detail. The
torsion angles of interest within the oxazolidine derivatives (τ6–
τ12) are shown in Fig. 3.
The high field doublet in the 1D spectrum of 4 (see Experi-
mental section for H NMR data) at δ 1.09 (J 6.2) is readily
1
Conclusion
1
The H NMR data indicate that the cyclic oxazolidine deriv-
atives 4–7 and the linear β-blockers 1–3 have similar conform-
ations around the β-amino alcohol moiety.
assigned to the isopropyl methyl protons. Examination of the
DQF–COSY spectrum reveals a connection to the septet for the
isopropyl methine proton at δ 2.57. The protons of the methoxy
group were easily assigned as the singlet at δ 3.33. The methyl-
ene protons of the methoxyethyl side chain were also assigned
as the two triplets at δ 2.80 (CH2-4Јα, J 7.1) and 3.54 (CH2-4Јβ,
J 7.1). As expected, the two H4 protons of the oxazolidine ring
are non-equivalent and appear as doublets of doublets at δ 2.74
(H4B: J4B,5 6.6; J4A,4B 10.1) and 3.10 (H4A: J4A,5 6.9; J4A,4B 10.1).
Connections from these two protons can be traced to the
multiplet centred at δ 4.36 which can be assigned as proton H5.
The H5 multiplet overlaps with the doublets for H2B (J2B,2A 3.6)
at δ 4.34 and H2A (J2A,2B 4.0) at δ 4.39. A connection can be
traced from H5 to the doublet of doublets at δ 3.93 (J5,6B 5.4,
9.7) and 4.00 (J5,6A 5.7, 9.5) assigned to H6B and H6A, respect-
ively. The four aromatic protons H2Ј, H6Ј at δ 6.83 (J 8.5) and
H3Ј, H5Ј at δ 7.11 (J 8.5) are clearly defined.
Computational analysis
1
The H NMR data are valuable for the determination of the
lowest energy conformer in solution or for establishing the
presence of several conformers in rapid equilibrium. To check
for the presence of other conformers which may be of slightly
higher energy, yet which might become populated at the recep-
tor site it was of interest to perform an extensive computational
analysis of the energy surface of these molecules.
Computational analysis of the linear â-blocker fragments 3
and 8. The inherent flexibility of β-blockers results in an enor-
mous range of possible conformations that these compounds
can adopt. Since our interest lay only in the conformation of
the oxypropanolamine backbone, the parent molecules 1 and
J. Chem. Soc., Perkin Trans. 2, 1998
203

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HB6 H4
2 were pruned to the 4Ј-unsubstituted aryloxypropanolamine
derivative 8, where conformational preferences are unlikely to
be significantly different from the whole structure. Analysis of
both 1 and 2 showed that the methoxyethyl group of 1 and the
amidomethyl substituent of 2 were unlikely to fold in a way that
would affect the conformation of the β-amino alcohol func-
tionality. The entire structure of timolol (3) was built up to
examine the conformation around the β-amino alcohol moiety
since it contains a different aromatic moiety than either meto-
prolol (1) or atenolol (2).
HA6
A H4B
HB2
HA4
HA2
HB4
H5
R1
CH3
R2
H3
CH3
R2
R1
3α
4
6
O
7
2
5
N3
C
4
O
1
NH
C
6
3
5
2
CH3
1 O
CH3
H2B
OH
HA2
3α
S
S
3 R1
=
7 R1
=
R
2 = CH3
R
2 = CH3
N
N
N
N
N
N
O
O
The torsion angles of the two β-amino alcohol fragments 3
and 8 (Fig. 2) considered were τ1–τ5 where τ1 is defined by the
atoms C3Ј, O1, C2, C3 for fragment 3 and C1Ј, O1, C2, C3 for
the fragment 8; τ2 by atoms O1, C2, C3, C4; τ3 by the atoms C2,
C3, C4, N5; τ4 by the atoms C3, C4, N5, C6 and τ5 by the atoms
N2Ј, C3Ј, O1, C2 for fragment 3 and C2Ј, C1Ј, O1, C2 for
fragment 8. The torsion angles were varied in 30Њ increments
over 360Њ and the resulting structures were minimised using
molecular mechanics. Application of this protocol to fragment
8 resulted in the generation of 8857 conformers which were
within 10 kcal molϪ1 of the lowest energy conformer found
(E = 5.9 kcal molϪ1), while 3 afforded 596 conformers within
10 kcal molϪ1 of the lowest energy conformer (E = 15.0 kcal
molϪ1).
9 R1 = C6H5, R2 = H
8 R1 = C6H5, R2 = H
Fig. 8 Fragments indicating the protons between which torsion angles
were measured in the β-amino alcohol and oxazolidine low energy
conformers
number of theoretically determined conformers to be discarded
as not all conformations around the bonds of interest were
compatible with the coupling constants observed.
For the β-blockers 1 and 2 the coupling constants recorded
between the protons H2A–H3 (τ13 defined by H2A, C2, C3, H3)
ranges from J2A,3 3.4–4.4 while the magnitude of coupling
between protons H2B–H3 (τ14 defined by H2B, C2, C3, H3) is
J2B,3 5.1–7.0, Tables 1–3. As such, theoretically determined con-
formers containing torsion angles about τ13 and τ14 of a very
large (160–180Њ) or small magnitude (0–20Њ) were not con-
sidered. The magnitude of coupling between H4A–H3 (τ15
defined by H4A, C4, C3, H3) and H4B–H3 (τ16 defined by H4B,
C4, C3, H3) was J4A,3 3.2–4.0 and J4B,3 7.9–9.3, respectively. As
such, torsion angles in the approximate range τ15 = 40–60Њ and
110–140Њ and τ16 = 0–20Њ and 135–180Њ were considered. A simi-
lar process was used when selecting conformers generated from
timolol (3) and the oxazolidine fragments 7 and 9.
Computational analysis of the oxazolidine derivatives 4–7. As
for the β-blockers 1 and 2, the oxazolidine derivatives 4–6 were
pruned back to the 4Ј-unsubstituted analogue 9. The entire
structure of 7 was used in the conformational analysis. The
torsion angles τ6 (defined by atoms N2Ј, C3Ј, O7, C6 for 7 and
C2Ј, C1Ј, O7, C6 for fragment 9), τ7 (defined by atoms C3Ј, O7,
C6, C5 for 7 and C1Ј, O7, C6, C5 for 9) and τ8 (defined by
atoms O7, C6, C5, C4) were varied in 30Њ increments. The
oxazolidine ring torsion angles τ9 (defined by atoms C6, C5, C4,
N3), τ10 (defined by atoms C5, C4, N3, C2), τ11 (defined by
atoms C4, N3, C2, O1) and τ12 (defined by atoms N3, C2, O1,
C5) were varied in 5Њ steps over 360Њ. The resulting structures
were then minimised using molecular mechanics. Using this
protocol there were 8195 conformers of 9 all within 10 kcal
Comparison of timolol 3 with the oxazolidine 7
Conformational analysis of 3 generated 15 conformers con-
1
sistent with those expected from the H NMR data. All 15
conformers were subjected to a rigid superimposition using
the atoms C2, C3, C4 and N5 in order to check that all the
conformers were unique. There were three distinct conform-
ational families evident. The lowest energy conformer from
each family was then used in the superimposition with the
oxazolidine 7.
Examination of the torsion angles around the protons H4A–
H5 (τ17 defined by the atoms H4A, C4, C5, H5), H4B–H5 (τ18
defined by the atoms H4B, C4, C5, H5), H5–H6A (τ19 defined
by the atoms H5, C5, C6, H6A) and H5–H6B (τ20 defined by
the atoms H5, C5, C6, H6B) (Fig. 8) showed that of the 1058
low energy conformers generated from 7, 20 were found to
resemble the conformations predicted from 1H NMR measure-
ments.
Superimposition of all 20 conformers via atoms C6, C5, C4
and N3 revealed three distinct conformational families; the
lowest energy conformer from each family was then used in the
superimpositions with 3.
Fig. 9 shows the result of rigid superimposition (RMS =
0.15) of the three representative conformers generated from 3
(via atoms C2, C3, C4, N5) and the three oxazolidine con-
formers of 7 (via atoms C6, C5, C4, N3). The distance between
the β-hydroxy oxygen atom and the oxazolidine oxygen atom
is 0.45 Å and the distance between C6 of 3 and C3α of 7 is
0.34 Å.
molϪ1 of the lowest energy conformer (E = 10.8 kcal molϪ1
)
while for 7, 1058 conformers were within 10 kcal molϪ1 of the
lowest energy conformer (E = 8.8 kcal molϪ1).
Superimposition of low energy conformers of the â-blocker
fragments 3 and 8 and the oxazolidine analogues 7 and 9
The purpose of this study was to see whether the incorporation
of the oxazolidine ring significantly altered the conformation
adopted by the β-amino alcohol moiety of 1–3. Therefore, a
comparison was carried out between the theoretically deter-
1
mined conformers and the conformers predicted by H NMR
analysis.
The torsion angles between the vicinal protons H2A–H3,
H2B–H3, H3–H4A and H3–H4B within each of the conformers
generated from fragment 8 (representative of 1 and 2), and
timolol (3) were examined. Torsion angles between the protons
H4A–H5, H4B–H5, H5–H6A and H5–H6B of all the conformers
generated from the two oxazolidine fragments 7 and 9 were also
determined, Fig. 8. A comparison was then carried out between
the torsion angles of all the theoretically determined con-
1
formers and those experimentally determined using H NMR
spectroscopy.
The chemical shifts and coupling constants obtained from
the 1H NMR spectra of a species which consists of a mixture of
rapidly interconverting forms are average values and this is cer-
tainly the case with the flexible β-blocker molecules 1–3. As
such, it is difficult to derive torsion angles for these molecules
from the Karplus rule.65 However, the torsion angles predic-
ted from the 1H NMR data of the semi-rigid oxazolidine
derivatives are more tractable. The torsion angles estimated
from 1H NMR studies were used to discount unlikely con-
formers generated by theoretical studies. This allowed a large
Comparison of fragment 8 (representative of 1 and 2) with the
oxazolidine 9
From the 8857 low energy conformers resulting from conform-
ational analysis of fragment 8, 205 different conformers were
shown to closely match the conformations predicted from the
1H NMR measurements of 1 and 2. The conformers were
superimposed using the atoms C2, C3, C4 and N5 and six dis-
204
J. Chem. Soc., Perkin Trans. 2, 1998

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Fig. 9 Stereoview of the superimposition of three low energy conformers of 3 (red) and three from 7 (blue) consistent with the 1H NMR data. For
clarity hydrogen atoms have not been displayed.
1
Fig. 10 Stereoview of the superimposition of six low energy conformers of fragment 8 (red) and six of fragment 9 (blue) consistent with the H
NMR data. For clarity hydrogen atoms have not been displayed.
tinct conformational families of fragment 8 were evident, the
variations within each family being due to different τ4 and τ5
values. The lowest energy conformer within each distinct con-
formational family was used in the superimposition with the
p. 289.
oxazolidine 9.
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Paper 7/06442J
Received 3rd September 1997
Accepted 14th October 1997
206
J. Chem. Soc., Perkin Trans. 2, 1998