NMR study of diastereoisomerism of 2-(1-aminoethyl)bicyclo[2.2.1]heptane and its hydrochloride (deitiforin)

Article abstract of DOI:10.1023/A:1011313117695

The assignment of the signals for the H and C atoms of four diastereomers (without their separation) of 2-(1-aminoethyl)bicyclo[2.2.1]heptane (1) and its hydrochloride (2) (the antiviral drug deitiforin) was performed for the first time by two-dimensional ¹H and ¹³C NMR spectroscopy. The effects of the substituent at position 2 of norbornane on the chemical shifts of the α-, β-, and γ-carbon atoms of the bicycle were examined using the increments for alkanes. The changes in the chemical shifts of the C(6) and C(7) atoms are substantially larger than those for the other C atoms, which made it possible to identify the exo and endo forms. Each of these forms exists as a mixture of two diastereomers. The effect of the positive charge of the N atom on the γ-protons, which are closely spaced, but separated by a number of covalent bonds, was considered on going from amine 1 to hydrochloride 2. Based on significant changes in shielding of these H atoms, the configurations of the asymmetric center in the CHMe(NH₂) substituent of the diastereomers were established.

Full text of DOI:10.1023/A:1011313117695

1
014
Russian Chemical Bulletin, International Edition, Vol. 50, No. 6, pp. 1014—1022, June, 2001
NMR study of diastereoisomerism of
-(1-aminoethyl)bicyclo[2.2.1]heptane
and its hydrochloride (deitiforin)
2
«
S. N. Tandura, A. N. Shumsky, E. F. Litvin, L. M. Kozlova,
E. V. Shuvalova, V. Z. Sharf, and S. P. Kolesnikov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. E-mail: stas@ioc.ac.ru
The assignment of the signals for the H and C atoms of four diastereomers (without their
separation) of 2-(1-aminoethyl)bicyclo[2.2.1]heptane (1) and its hydrochloride (2) (the
antiviral drug deitiforin) was performed for the first time by two-dimensional 1H and
13C NMR spectroscopy. The effects of the substituent at position 2 of norbornane on the
chemical shifts of the α-, β-, and γ-carbon atoms of the bicycle were examined using the
increments for alkanes. The changes in the chemical shifts of the C(6) and C(7) atoms are
substantially larger than those for the other C atoms, which made it possible to identify the
exo and endo forms. Each of these forms exists as a mixture of two diastereomers. The effect
of the positive charge of the N atom on the γ-protons, which are closely spaced, but separated
by a number of covalent bonds, was considered on going from amine 1 to hydrochloride 2.
Based on significant changes in shielding of these H atoms, the configurations of the
asymmetric center in the CHMe(NH ) substituent of the diastereomers were established.
2
Key words: 2-(1-aminoethyl)bicyclo[2.2.1]heptane, deitiforin, 1H and 13C NMR spectro-
scopy, diastereoisomerism, anti-influenza drug.
Chemotherapy is the most commonly used, simple,
The exo form of amine 1, which was prepared from
the exo isomer of 2-acetylbicyclo[2.2.1]heptane by
oximation of ketone followed by reduction with a Raney
nickel alloy, was proposed as an antiviral drug in 1969.11
More recently, it was demonstrated that catalytic hydro-
genation of 2-acetylbicyclo[2.2.1]hept-5-ene oxime af-
forded a mixture of the exo and endo isomers of amine
1, which is (in the form of hydrochloride) also an active
virus inhibitor.9,10
The antiviral activity of 2-substituted bicyc-
lo[2.2.1]heptanes, including the 1-aminoethyl deriva-
tive, has long been known11,12 and has been well stud-
ied for the drug deitiforin.13—26 As an anti-influenza
drug, deitiforin is equal to rimantadine from the stand-
point of the protective effect in the treatment of the
influenza infection,14 and it can not only efficiently
suppress virus-specific growth, but can also selectively
act on virus-infected cells.15
and inexpensive means for the prophylaxis and treat-
ment of influenza. An empirical search for virus inhibi-
tors exhibiting anti-influenza activity among different
classes of organic compounds demonstrated that amines
containing alicyclic skeleton fragments selectively sup-
press influenza virus reproduction without disturbance of
the vital functions in the organism as a whole.1—3 These
compounds are efficient at rather low concentrations,
weakly toxic, and highly selective. Drugs of this class,
viz., amantadine (1-aminoadamantane hydrochloride)4—6
(
USA, 1966) and rimantadine (USSR, 1974; later on, in
5
—8
USA),
are widely used in public-health practice.
2
-(1-Aminoethyl)bicyclo[2.2.1]heptane (1) whose hydro-
chloride 2 is known as the drug deitiforin7
—10
is a
promising anti-influenza drug of this class. Rimantadine
and deitiforin contain the identical side fragments with
the asymmetric center (R/S)-R* = CHMeNH , but
2
differ in the structure of the hydrocarbon skeleton.
Deitiforin possesses lower toxicity16 and exhibits
noticeable activity not only against influenza À vi-
ruses17,18 and parainfluenza,19 but also (unlike rimanta-
dine) against influenza  viruses.18 Deitiforin does not
affect extension of resistant strains among epidemic
influenza À viruses, i.e., it does not give rise to drug
resistance.19,20 In addition, the efficiency of deitiforin
was examined depending on the concentration (for the
influenza FPV virus) and it was demonstrated that the
use of this drug in the treatment of influenza does not
7
4
5
NH •HCl
3
2
*
1
C
Me
H
6
2
*
NH •HCl
C
2
8
H
Me
Rimantadine
Deitiforin (2)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 971—978, June, 2001.
066-5285/01/5006-1014 $25.00 © 2001 Plenum Publishing Corporation
1

NMR study of 2-(1-aminoethyl)bicyclo[2.2.1]heptane Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
1015
cause complications associated with acuteness of bacte-
rial infections.21
metric centers in the substituents and, consequently,
occur only as two diastereomers (exo and endo
forms). The exo and endo forms of the amine deriva-
tives (sulfonamides, ureas, and thioureas) of the bi-
cyclo[2.2.1]hept-5-ene series (norbornene) were also
identified by 13C NMR spectroscopy.32—34 However, in
the latter case, these diastereomers were preliminarily
isolated as individual compounds by fine fractional dis-
tillation.
If the molecule contains four asymmetric centers,
the number of theoretically possible stereoisomers is
equal to 2n = 16. However, only one-half of these
stereoisomers can exist in the case of amine 1 or
deitiforin 2, which have the framework structure with
the asymmetric C(1) and C(4) bridgehead atoms, be-
cause the rigid bicyclic structure allows for only two
groups of isomers in which the C(1) and C(4) atoms
should adopt consistent configurations, i.e., (1R,4S) or
(1S,4R). Therefore, eight stereoisomers of racemic amine
1 and deitiforin 2 represent four enantiomeric pairs
(diastereomers). One of these pairs is shown below.
However, the mechanism of antiviral activity of
deitiforin remains unknown.17,22—24 Thus, the question
of which biochemical reactions are affected by deitiforin
upon interactions of influenza virus with cells is still
open. The antiviral effect may result from the fact that
deitiforin inhibits activation of protein kinase C in the
corresponding lymphoidal cells.22 This effect can be
realized through hydrophobic bonds present in the non-
polar portion of the molecule in the membrane.25 The
protective action of deitiforin against toxicosis is prob-
ably associated with its ability to prevent penetration of
the M protein into the membrane.23 Most likely,
deitiforin has the virus-specific action because it does
not cause structural-morphological and functional
changes in cells.26
Anti-influenza chemodrugs possessing a rigid skel-
eton belong to a group of molecular hindrances, which
efficiently block penetration of virus proteins through
cell membranes.27 Using rimantadine and adapromine*
as examples, it has been demonstrated that this activity
is closely related to their molecular structures.28 The
establishment of the relationship between the pharma-
cological action and the chemical structure in the case
of deitiforin** can enable one not only to examine the
effect of the molecule as a whole, but also to reveal the
effect of the different mutual arrangement of the mo-
lecular fragments resulting from stereoisomerism.
Identification of the biologically active stereoisomer
and its directed synthesis are topical problems in the
pharmaceutical industry because the use of smaller
amounts of the active compound in a drug reduces the
cost of the production of the substance and leads to a
decrease in the drug dose, which, in turn, results in an
increase in the average therapeutic drug dose.
4
4
1
2
H
8
H
H
1
1
4
C
2
2
8
8
H
C
C
H N
2
NH2
Me
H N
Me
2
H
H
Me
(
1R,2S,4S,8S)-
endo-1
(1S,2R,4R,8R)-endo-1
These enantiomeric pairs can be divided into two
groups depending on the orientation of the CHMeNH2
substituent at the C(2) atom in the bicycle. Two pairs occur
as two racemic endo diastereomers (1R,2S,4S,8R/S) cor-
responding to the endo orientation of the substituent. The
remaining two pairs (1R,2R,4S,8R/S) form two other
diastereomers with the exo orientation of the substituent.
For simplicity, only the (1R,4S) enantiomers are
shown below.
The only attempt to obtain a quantitative estimate of
the ratio between the exo or endo isomers in deitiforin
has been reported.10 According to the data from H NMR
spectroscopy of derivatives of amine 1 (sulfonamides
and ureas), only two isomers were experimentally de-
tected.10 These isomers were formally assigned to the
exo or endo forms (the ratios were 55—60 and 40—45%,
respectively). It was assumed that this ratio is also
typical of the initial amine 1. It should be noted that,
strictly speaking, the observed isomers could be two
diastereomers of only one of the forms (exo or endo).
It is worthy of note that 2-R-norbornanes (R = Me,
1
*
R (R,S)
H
*
H
R (R,S)
(
1R,2R,4S,8R/S)-exo-1
(1R,2S,4S,8R/S)-endo-1
CH OH, etc.) studied previously31 do not contain asym-
R* = CH(Me)NH2
2
Experimental
*
These
C(1)-substituted
adamantane
derivatives,
C*H(Me)NH •HCl (rimantadine) and C*H(Et)NH •HCl
2
2
(
adapromine) containing one asymmetric C atom, exist as
racemic mixtures of enantiomers.
* It has been reported that the mechanism of action of deitiforin
on the influenza virus reproduction differs from that of
The 1H and 13C NMR spectra were recorded on a Bruker
DRX-500 spectrometer (500.13 MHz for 1H and 125.76 MHz
for 13C). The chemical shifts, which are given in the δ scale
*
relative to Me Si for the H atoms and relative to CDCl
4
3
2
9
rimantadine. If virus mutants resistant to rimantadine arise in
(δ = 77.0) for the C atoms, are listed in Tables 1 and 2,
respectively. We used standard two-dimensional NMR tech-
niques (HSQC, HMQC, HMBC, TOCSY, and ROESY).
3
0
the course of the influenza epidemy, the design of a new drug
becomes an urgent problem.

1
016
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
Tandura et al.
Table 1. The 13C chemical shifts for 2-(1-aminoethyl)bicyclo[2.2.1]heptane (1) and its hydrochloride (2)
R*
Diastereomer
δ
Ñ(1)
Ñ(2)
Ñ(3)
Ñ(4)
Ñ(5)
Ñ(6)
Ñ(7)
Ñ(8)
Me
CH(Me)NH2
exo (1R,2R,4S)
(8R)
8S)
endo (1R,2S,4S) (8R)
8S)
(8R)
8S)
endo (1R,2S,4S) (8R)
8S)
39.04
38.03
38.13
39.04
38.30
37.84
37.77
38.42
52.00
51.79
49.55
50.22
46.86
46.83
44.73
45.14
35.54
35.52
34.63
35.26
35.54
34.96
34.17
34.97
36.70
36.68
36.82
37.01
36.48
36.25
36.56
36.82
28.52
28.48
30.19
29.92
27.91
27.91
29.89
29.55
30.51
30.34
22.39
22.55
29.55
29.81
22.07
22.66
35.23
35.89
40.00
39.81
35.66
35.54
39.37
39.44
51.09
50.85
49.24
50.22
52.86
51.61
50.06
52.04
22.97
21.16
22.63
22.48
18.10
16.46
18.26
18.26
(
(
CH(Me)NH •HCl exo (1R,2R,4S)
2
(
(
Table 2. The 1H chemical shifts for 2-(1-aminoethyl)bicyclo[2.2.1]heptane (1) and its hydrochloride (2)
R*
Diastereomer
δ
H(1) H(2)
H(3)
H(4)
H(5)
H(6)
H(7)
H(8) Me
exo endo
exo endo exo endo syn anti
CH(Me)NH2
exo (1R,2R,4S) (8R) 2.07 1.08 1.18 1.36 2.22 1.43 1.01 1.43 1.01 1.23 1.03 2.45 1.10
8S) 2.20 1.11 0.98 1.31 2.18 1.41 1.07 1.45 1.05 1.22 1.03 2.42 0.95
endo (1R,2S,4S) (8R) 2.25 1.50 1.66 0.59 2.15 1.49 1.05 1.49 1.38 1.30 1.24 2.66 1.03
(
«
«
«
«
(
8S)
2.16 1.48 1.77 0.81 2.19 1.48 1.09 1.43 1.31 1.32 1.27 2.64 1.04
CH(Me)NH •HCl exo (1R,2R,4S) (8R) 2.15 1.62 1.39 1.51 2.40 1.45 1.10 1.45 1.18 1.20 1.09 2.88 1.42
2
(
8S)
2.55 1.65 1.03 1.40 2.25 1.45 1.10 1.49 1.20 1.20 1.12 2.85 1.27
«
«
endo (1R,2S,4S) (8R) 2.45 1.95 1.65 0.58 2.12 1.44 0.99 1.42 1.22 1.36 1.31 3.02 1.26
«
«
(
8S)
2.11 1.95 1.75 0.98 2.17 1.43 1.22 1.43 1.25 1.36 1.27 3.02 1.24
«
We failed to perform the assignment of the syn/anti signals for the H(7) protons.
2
-Acetylbicyclo[2.2.1]hept-5-ene oxime (a mixture of iso-
were no higher than 10%. The simpler NMR spectral
mers) was prepared by condensation of cyclopentadiene with
methyl vinyl ketone followed by oximation. Hydrogenation of
the resulting compound to form amine 1 (specimen 1) was
carried out in the presence of Raney nickel according to a
known procedure10 in a laboratory reactor equipped with a
patterns of specimens 2 made it possible to perform the
assignment of all signals in the 1H and 13C NMR
spectra for both diastereomers. As shown below, speci-
men 2 represents a mixture of two (1R,2R,4S,8R/S)
diastereomers of the exo form.
magnetic stirrer at 80 °C under a hydrogen pressure of 20 atm.
i
Based on the 1H and 13C NMR spectra of speci-
We used Pr OH as the solvent. Deitiforin (2) was obtained by
acidification of the amine with HCl followed by recrystalliza-
tion from Pr OH, m.p. 282—285 °C. According to the results of
men 1 (a mixture of four diastereomers), the assignment
of the remaining signals to two (1R,2S,4S,8R/S) diaste-
reomers of the endo form was carried out taking into
account the signals of the exo form identified previously
i
titration with perchloric acid (99.2%), the content of the major
compound (C H17N•HCl) corresponded to the requirements.35
9
Specimen 2 was isolated from specimen 1 by chromatography.
(
see Tables 1 and 2).
To a first approximation, the effect of particular
Results and Discussion
substituents on the chemical shifts of the α-, β-, γ-, and
δ-carbon atoms in alkanes is constant and additive,
which makes it possible to introduce increments of the
substituents ∆δ13C = δ13C(R) – δ13C(H). Since the
usual effect of the substituent through covalent bonds
depends insignificantly on the orientation of these bonds,
empirical correlations between the chemical shifts and
the molecular structure are of most use in analysis of
13C NMR spectra of alkanes.36 The possibility of the
employment of increments of the substituents for the
molecules of amine 1 and its hydrochloride 2 is sup-
ported by the fact that the chemical shifts of the C
atoms in the (8R) and (8S) diastereomers are similar
both for the exo and endo forms (the differences are at
The 13C NMR spectra of the specimens containing
four diastereomers* of amine 1 or deitiforin 2 (speci-
mens 1) have more than 30 signals out of 36 theoreti-
cally possible signals. For these specimens, attempts to
assign the signals to particular diastereomers failed even
with the use of 2D NMR spectroscopy.
The 13C NMR spectra of specimens 2 of amine 1
and the corresponding deitiforin 2 have only 18 intense
signals, whereas the intensities of the remaining 18 signals
*
Hereinafter, this term is taken to mean racemic diastere-
omers, i.e., 1 : 1 mixtures of enantiomers.

NMR study of 2-(1-aminoethyl)bicyclo[2.2.1]heptane Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
Table 3. Increments of the substituents for 2-R-bicyclo[2.2.1]heptanes ∆δ13C = δ13C(R) – δ13C(H)
1017
R
∆δ13
Ñ
Ñ(1)
Ñ(2)
Ñ(3)
Ñ(4)
Ñ(5)
Ñ(6)
Ñ(7)
Ñ(8)
exo
0.5
ÑÍ3 31
6.7
1.8
1.77
1.27
6.7
15.1
21.79
16.74
10.1
4.4
5.43
5.15
0.2
0.2
–1.57
–2.19
–1.1
–0.7
0.32
–3.7
–3.3
–3.14
–3.10
22.3
66.4
50.97
52.23
3
1
CH OH
–0.2
–0.11
–0.44
endo
1.4
2
CH(Me)NH2*
CH(Me)NH •HCl*
–0.42
2
ÑÍ3 31
5.4
1.7
4.5
12.8
10.6
4.0
0.5
0.2
–7.7
–7.2
0.2
1.4
17.4
64.3
3
1
CH OH
0.4
2
CH(Me)NH2*
1.76
1.29
19.57
14.83
4.84
4.47
0.13
–0.11
0.12
–0.38
–7.50
–7.74
1.16
0.70
49.16
51.05
CH(Me)NH •HCl*
2
*
Calculated from the average values for the (8R/S) diastereomers.
most 1.0 ppm, see Table 1). The effects of the substitu-
ents on the chemical shifts of the C atoms in 2-methyl-
bicyclo[2.2.1]heptanes are presented in Table 3.
acyclic hydrocarbons using the additive scheme, result,
most likely, from bond strain in norbornane (the energy
is ∼ 12 kJ mol–
1 38
)
and substantial steric interactions of
the substituent R in the amine and deitiforin molecules.
The α- and β-effects
The γ- and δ-effects
In the case of 2-methylbicyclo[2.2.1]heptane, the
presence of the CH3 group causes deshielding of the
α-C atom by 6.7 ppm and deshielding of the β-C atom
by 6.7 (for C(1)) and 10.1 ppm (C(3)) compared to
nonsubstituted norbornane31 (see Table 3). It is known
that the β-effect of the CH3 group in alkanes (the
In the case of aliphatic hydrocarbons, the classical
γ- and δ-effects are substantially weaker than the α- and
β-effects.36 In the case of alicyclic compounds in which
some H atoms are involved in van der Walls interac-
tions, the signals for the corresponding C atoms are
shifted upfield due to polarization of the C—H bonds
(steric compression). In this case, the γ-effect is of most
importance for sterically strained structures. The in-
crements of the 13C chemical shifts were analyzed for a
wide range of norbornane derivatives.39—41
For all isomers of four compounds, including amine
1 and deitiforin (2) (see Table 3), the substituent R has
insignificant effects on the C(4) (γ-effect) and C(5)
(δ-effect) atoms, which is also typical of other 2-substi-
tuted norbornanes.31 However, the γ-effect of this sub-
stituent on the C(6) and C(7) atoms is abnormally high.
For specimens 2 of the amine and its hydrochloride,
the changes in the chemical shifts of the C(7) atoms
with respect to the norbornane core (∆δ13C are –3.14
and –3.10, respectively) are substantially larger than the
increments for the C(6) atoms (∆δ13C are 0.32 and
–0.42, respectively; see Table 3). Previously, it has been
demonstrated that this is the distinguishing characteris-
tic feature of the exo isomers of all 2-substituted
norbornanes studied previously.31,39 Based on this fact,
we assigned the exo configuration to two diastereomers
prevailing in specimen 2. However, in the case of the
endo isomers of amine 1 and hydrochloride 2, the
increments for the C(6) atom are, on the contrary, more
significant (∆δ13C are –7.50 are –7.74, respectively),
the changes for C(7) being small (∆δ13C are 1.16 and
0.70, respectively; see Table 3).
increment is 9.4 ppm) is larger than the α-effect (the
increment is 9.1 ppm).3
7,38
The β-effect of the CH3
3
6
group decreases as the H atoms of the methyl group are
successively replaced. Hence, in the remaining three
compounds (see Table 3), the corresponding β-effects at
the C(1) (1.2—2.2 ppm) and C(3) (4.4—5.4 ppm) atoms
are substantially smaller than the α-effect at the C(2)
atom (6.6—15.1 ppm). The β-effect of the substituent at
the C(2) atom on the signal for the C(3) atom is always
more substantial than that on the signal for the C(1)
atom, as has also been observed previously for other
norbornanes.31 Therefore, the side groups at position 2
of the norbornane bicycle in amine 1 (R = CH(Me)NH2)
and its hydrochloride 2 (R = CH(Me)NH •HCl) ex-
2
hibit the usual α- and β-effects.
However, if 2-methylnorbornane (for which δC(2) is
3
6.8 and 34.6 for the exo and endo isomers, respec-
tively31) is considered for comparison and the incre-
ments of the effects of the substituents in alkanes on
β-C (9.4 for CH ,36 11.3 for NH2,36 and 7.5 for NH3+ 37)
3
are taken into account, the values for amine 1 (δC(2) 57.6
and 55.4) and deitiforin (2) (δC(2) 53.7 and 51.5) are
regularly larger than the corresponding experimental
values by more than 5.6 and 6.6 ppm, respectively (see
Table 1). Analogously, the calculated chemical shifts of
the C(8) atom are also larger than the experimental
values, on the average, by 7.6 (1) and 3.3 ppm (2). The
upfield shifts of the experimental values for 1 and 2
compared to the values, which were calculated for
Apparently, the signals for the C(6) or C(7) atoms
are shifted upfield due to the steric γ-gauche interaction

1
018
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
Tandura et al.
Table 4. Effect of the orientation of the substituent R on δ13C for 2-R-bicyclo[2.2.1]heptane ∆δ13C =
1
3
13
δ
C(endo) – δ C(exo)
R
∆δ
Ñ(1)
Ñ(2)
Ñ(3)
Ñ(4)
Ñ(5)
Ñ(6)
Ñ(7)
Ñ(8)
ÑÍ3 27
–1.3
–0.1
–0.01
0.02
–2.2
–2.3
–2.33
–1.91
0.5
–0.4
–0.59
–0.68
0.9
0.6
0.03
0.33
0.3
0
1.69
1.81
–6.6
–6.5
–7.82
–7.32
3.9
4.7
4.30
3.80
–4.9
–2.1
–1.80
–1.18
2
7
CH OH
2
CH(Me)NH2
CH(Me)NH •HCl
2
of the substituent R with one of the H atoms at
C(6) or C(7).
ference between the chemical shifts ∆δ13C is –4.9 for
the CH group (see Table 4). The replacement of one H
3
atom by the OH group leads to a decrease in this
difference to –2.1 ppm, this difference being decreased
to –1.37 and –1.18 when two H atoms are replaced.
This fact is in agreement with the above-mentioned
γ-effect of the substituent R exerted on the C(6) and
C(7) atoms, which is manifested in the stronger
nonbonded endo(2)—endo(6) contact in the endo-diaste-
reomers of amine 1 and hydrochloride 2. For the same
reason, the resonance signal for the C(8) atom of the
substituent R, which is involved in the interaction as the
second member, is also more substantially shifted upfield
in the spectra of the endo-diastereomers (see Table 2).
Ha
7
Hs
Ha
7
Hs
4
4
5
5
3
3
*
R
Hx
Hx
Hx
1
1
6
2
6
2
*
R
Hn
Hn
Hn
exo-R(2)—syn-H(7)
endo-R(2)—endo-H(6)
The shift of the signal for the C(7) atom in the exo
isomer is smaller than that for the C(6) atom in
the endo isomer (see Table 3), which suggests that
the exo(2)—syn(7) interaction is weaker than the
endo(2)—endo(6) interaction, i.e., in the case of steric
interactions, the substituent R is located more closely to
the C(6) atom than to the C(7) atom.
For the C(4) atom, the γ-effect is, evidenlty, insig-
nificant because its H atom is directed away from the
substituent R*.
Proton resonance
In amine 1, three hindered conformers, which differ
by the angle of rotation of the aminomethyl fragment
about the C(8)—C(2) bond, can occur for each diaste-
reomer.10 According to the results of molecular-me-
chanics calculations (the MMX method), the total steric
energy of one of these conformers is noticeably smaller
than those of the remaining two conformers.* Below are
shown the most stable conformers of each diastereomer.
Exo and endo orientations of the substituent R
For the exo and endo isomers of amine 1 and
deitiforin 2, the differences in the chemical shifts
δ13C = δ13C(endo) – δ13C(exo) for the C(6) (–7.82
∆
H(8)
H(8)
and –6.71) and C(7) atoms (4.30 and 3.80, see Table 4)
are noticeably larger in magnitude than those for all
other single-type C atoms. For four structurally similar
compounds presented in Table 4, the observed differ-
ences for the C(2) atoms (for which the α-effect is most
significant) in the exo and endo isomers are actually no
larger than 2.3 ppm. For the C(1), C(3) (β-effect), and
C(4) (γ-effect) atoms, the effect of the orientation of the
substituent at position 2 is at most 1.3 ppm. Therefore,
the differences in shielding of the C(6) (upfield) and
C(7) (downfield) atoms due to nonbonded steric inter-
actions, which are observed on going from the exo to
endo diastereomers, are noticeably larger than the changes
for the remaining C atoms and these differences are
typical not only of 2-substituted norbornanes,31 but also
of compounds 1 and 2.
C(1)
Me
C(3)
NH2
C(1)
C(3)
Me
H N
2
H(2)
H(2)
exo-(8R)
exo-(8S)
H(2)
H(2)
H N
Me
C(3)
Me
NH2
C(3)
2
C(1)
C(1)
H(8)
endo-(8R)
H(8)
endo-(8S)
* The authors concluded10 that the S diastereomeric forms of
the amine are thermodynamically more stable both for the exo
and endo isomers. Apparently, the authors meant the 8S con-
figuration of the asymmetric CHMeNH2 substituent for the
For all compounds under consideration, the signals
for the C atom of the substituent R adjacent to the
bicycle (C(8)) are observed at somewhat higher field in
the spectra of the endo-isomers compared to those of
(
1R,2R,4S,8S) and (1R,2S,4S,8S) enantiomers of the exo and
endo isomers, respectively. However, an analogous conclusion
is also true for the (1S,2S,4R,8R) and (1S,2R,4R,8R) enantio-
mers for which the R confuguartion rather than the S configu-
ration of the substituent at the C(2) atom is thermodynamically
more stable.
the exo isomers. For the CH group containing three H
3
atoms, this regularity is more pronounced and the dif-

NMR study of 2-(1-aminoethyl)bicyclo[2.2.1]heptane Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
1019
In all cases, the H(2) and H(8) protons are in trans
orientations. The most stable conformers of the (8R)
and (8S) diastereomers differ only in that the NH2 and
Me groups actually change places. Apparently, this rea-
soning is also true for the symmetrically similar diaste-
reomers of hydrochloride 2.
other two diastereomers both of the salt and the amine
due to the γ-effect (see Table 1).
H(2) and H(3). The H(2) atom in the exo diastereo-
mers of the amine has the endo orientation and its signal
(δH 1.08 and 1.11) is observed at substantially higher
field than the signal for the exo-oriented H(2) atom in
the endo isomers (δH 1.50 and 1.48, see Table 2). These
values are close to the signals for the H atoms in the
endo and exo positions of nonsubstituted norbornane
(δ 1.18 and 1.49, respectively).43 In both cases, larger
shielding of the endo-proton occurs due to anisotropy of
the C(1)—C(6) bond. For an analogous reason, the
shielding of the proton in the axial position in cyclohex-
ane (in the case of slow inversion) is 0.5 ppm larger
than that of the equatorial proton.36 An analogous
regularity was observed in the case of deitiforin; how-
ever, the higher electronegativity of the ammonium N
atom leads to an approximately equal increase in the
chemical shifts of the H(2) protons in the exo/endo
positions (by 0.4—0.5 ppm; see Table 2).
Evidently, there is free rotation between three pos-
sible conformers in solution. According to the results of
calculations,10 these conformers should differ in occu-
pancy, which introduces an additional uncertainty of the
effect of the substituent R on shielding of the protons.
Despite the uncertainty of the assignment of the signals
for the syn and anti H(7) atoms in the diastereomers of
the amine and deitiforin with the endo orientation of the
substituent R, analysis of the chemical shifts made it
possible to follow some regularities of their changes. Let
1
us consider the particular H chemical shifts.
H(1). The resonance of the bridgehead H(1) proton
in two of four diastereomers of hydrochloride 2 is
noticeably shifted downfield (δ 2.55 and 2.45) relative to
the H(1) protons in other diastereomers for which the
The electronic effects of the substituent R on the
chemical shifts of the more remote geminal H(3) protons
through the covalent bonds are insignificant, and shield-
ing of the latter is determined primarily by the anisotro-
pic effect of the C(2)—C(8) bond depending on the
cis,trans orientation in the eclipsed configuration of the
C(2)—C(3) atoms. In accordance with the cone of mag-
netic anisotropy,36 the presence of the C(2)—C(8) bond
leads to an upfield shift of the signal for the cis-proton
and to a downfield shift of the signal for the trans-proton.
For the endo diastereomers, the C(2)—C(8) and
C(1)—C(6) bonds are located on the same side of the
C(1)—C(2)—C(3)—C(4) plane. In this case, the aniso-
tropic effects of these bonds exerted on shielding of the
exo-,endo-H(3) protons are summed. The effect of the
CH(Me)NH2 substituent in the endo position is such
that the high-field signal for the endo-proton is shifted
upfield by –0.59 (8R) and –0.37 ppm (8S), whereas the
low-field signal for the exo-proton is shifted downfield
by 0.17 (8R) and 0.18 ppm (8S) (see Table 2). In this
case, the differences in their shielding are increased to
1.07 (8R) and 0.96 ppm (8S) relative to nonsubstituted
norbornane (1.49 – 1.18 = 0.31 ppm).36
chemical shifts (δ 2.25—2.07, see Table 2) are close to
that for nonsubstituted norbornane (δ 2.20).4
2,43
This
anomalous decrease in shielding observed in the spectra
of two diastereomers of hydrochloride 2 is, most likely,
due to the proximity of the positively charged ammo-
nium N atom in the most favorable conformers.
Along with the electronic and magnetic effects, the
positively charged NH3+ group, which substantially sur-
passes the NH2 and CH3 groups in polarity (σ = 0.60
I
as compared to 0.10 and 0 for the NH2 and CH3
groups, respectively) makes a purely electrostatic contri-
bution to shielding of the H(1) atom.43 Due to electro-
static forces, the NH + group distorts the charge cloud
3
on the adjacent C—H bonds resulting in a decrease in
the spherical symmetry of the electron distribution at
the proton. In this case, the diamagnetic contribution to
shielding decreases and the resonance is shifted
downfield, which is observed for virtually all H atoms in
molecules 2 (see below).
Based on this fact, we performed the assignment for
the (8R/S) diastereomers of deitiforin 2. Thus, the
signal at δ 2.55 was assigned to the exo diastereomer in
which the amino group is located in proximity to H(1),
i.e., the diastereomer has the (8S) configuration, whereas
the signal at δ 2.45 was assigned to the endo-diastere-
omer with the (8R) configuration.
In the case of the exo diastereomers, the C(2)—C(8)
and C(1)—C(6) bonds are located on opposite sides of
the C(1)—C(2)—C(3)—C(4) plane, and their effects on
the geminal H(3) protons compensate each other. Since
the atoms at the C(2)—C(3) bond in the exo and endo
forms of the bicycle adopt an eclipsed conformation,
The assignment of the diastereomers of amine 1 was
carried out using the same criterion. In the above-
considered diastereomers of the amine, the observed
decrease in shielding of the H(1) protons (δ 2.20 and
H(2)
H(3)x
H(3)x
C(1)
2
.25) is less pronounced due to the absence of the
C(8)
C(4)
C(4)
C(1)
positive charge on the N atom (see Table 2).
It should be noted that these arguments are consis-
tent with the 13C NMR spectra. In the above-consid-
ered two diastereomers, viz., in exo-(8S) and endo-(8R),
the signals for the C(1) atoms are observed at higher
field (by δ ∼ 1) compared to those in the spectra of the
C(8)
H(3)n
H(2)
H(3)n
exo
endo
the arrangement of the C(2)—C(8) bond relative to the
geminal H(3) protons remains virtually unchanged and,

1
020
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
Tandura et al.
Norbornane
Hx
Hn
endo-(8R)-1
H(3)x
H(3)x
H(3)n
endo-(8S)-1
H(3)n
Norbornane
Hx
Hn
exo-(8R)-1
H(3)n
H(3)x
exo-(8S)-1
H(3)n
H(3)x
1
.8
1.5
1.2
0.9
0.6
δ
Fig. 1. Shielding of the H(3) protons.
consequently, the anisotropic effect of this bond on the
H(3) protons in the cis and trans positions with respect
to the substituent R is similar to that in the endo isomer.
0.43 for the exo diastereomers; and 0.38 and 0.36 for the
endo diastereomers). This anomaly, i.e., the larger
changes for the more remote proton, may be due to the
higher stability of the most favorable conformers (see
the chart in the preceeding paragraph) in which the
amino group is always located in the cis position with
respect to the H(2) atom.
Therefore, shielding of the cis-H(3) and trans-H(3)n
x
protons in the exo diastereomer of the amine is in-
creased and decreased, respectively, i.e., the low-field
signal for the exo-H(3) proton is shifted upfield by 0.18
x
(
8R) and 0.13 ppm (8S), whereas the high-field signal
Since the effect of the positive charge in saturated
systems is rapidly damped out as the distance to the
charged center increases (see Ref. 36, p. 84), the change
for the endo-H(3) proton is shifted downfield by –0.31
(
only does the difference in their shielding decrease, but
n
8R) and –0.51 ppm (8S) (see Table 2). In this case, not
1
in shielding ∆δ H for the remote γ-protons observed on
it also changes sign (–0.18 (8R) and 0.33 ppm
going from amine 1 to its hydrochloride 2 occurs through
space due to the field effect and is determined by the
proximity of these protons to the N atom. For example,
for two pairs of the diastereomers with the asymmetric
(
8S); Fig. 1).
Analogous regularities are also observed for the exo
and endo diastereomers of deitiforin (2) (see Table 2).
H(7). Shielding of the H(7) proton in all endo
diastereomers of 1 and 2 is analogous to that in
nonsubstituted norbornane (δ 1.20)42 and their differ-
ences are at most 0.09 ppm (see Table 2). However, in
the spectra of the exo diastereomers in which the sub-
stituent R is located more closely to the bridge, the
signals for the protons (syn-H(7)) are shifted downfield
and the differences are increased to 0.20 ppm (see
Table 2). Shielding of the H(7)s protons is decreased
compared to that of the H(7)a protons due to the
proximity of the substituent R.
1
(8R) center, the ∆δ H value (0.35) for the H(1) proton
located in proximity to the N atom in the exo form and
1
∆δ H for the H(1) and H(6)n protons (0.20 and –0.16,
respectively) in the endo form are substantially larger
than the changes for the other H atoms, which have
close contacts with the CH group (δ 0.05 and –0.01 for
3
H(3)x and H(3) , respectively) (Table 5). At the same
n
time, the reverse situation is observed in the case of the
(8S) diastereomers in which the amine and methyl
groups formally change places: the changes, which are
maximum in the above-considered case, become mini-
mum and vice versa (see Table 5). It should be noted
Effect of the positive charge of N+
Table 5. Effect of the positive charge of the N atom in
hydrochloride 2 on the chemical shifts of selected protons
An additional information on the structures of the
diastereomers can be obtained from the analysis of the
effect exerted by the ammonium N atom on the chemi-
cal shifts of the protons. On going from amine 1 to
deitiforin (2), the signals for virtually all protons (in-
cluding H(5) and H(6)) are shifted downfield to a
greater or lesser extent. It should be noted that the ∆δH
values for the H(2) atom at the β position (0.54 and
1
1
1
Diastereomer
∆δ Í = δ Í(2) – δ Í(1)
H(1) H(3)x
exo-(1R,2R,4S) (8R) (N...H(3)x)
0.08
0.35
0.21
0.05
(
8S) (N...H(1))
H(1) H(6)n H(3)n
endo-(1R,2S,4S) (8R) (N...H(1), H(6) ) 0.20 –0.16 –0.01
0
.54 for the exo diastereomers; and 0.47 and 0.45 for the
n
endo diastereomers) are larger than the corresponding
values for the H(8) protons at the α position (0.43 and
(
8S) (N...H(3)n)
–0.05 –0.06
0.18

NMR study of 2-(1-aminoethyl)bicyclo[2.2.1]heptane Russ.Chem.Bull., Int.Ed., Vol. 50, No. 6, June, 2001
1021
that shielding of the remote H(3)x proton in the endo
isomers, which are characterized by the maximum
nonequivalence of the H(3) protons, remains unchanged
in both diastereomers (δ 1.66 and 1.65 in (8R); and
δ 1.77 and 1.75 in (8S)), i.e., it is independent of the
arrangement of the amine group.
15. V. I. Votyakov, E. I. Boreko, L. K. Zaporozhets, and
Yu. M. Sudnik, in Nukleozidy, proizvodnye bitsiklogeptana i
adamantana, drugie antivirusnye veshchestva [Nucleosides,
Bicycloheptane and Adamantane Derivatives, and Other Anti-
viral Drugs], NII Epidemiologii i Mikrobiologii, Minsk,
1
981, 3 (in Russian).
1
6. K. N. Kozeletskaya, in Problemy i perspektivy izucheniya
nukleozidov, bitsiklogeptana, adamantana i drugikh protivo-
virusnykh soedinenii v eksperimente i klinike [Problems and
Prospects of Investigation of Nucleosides, Bicycloheptane,
Adamantane, and Other Antiviral Drugs in Experiments and
Clinic], NII Epidemiologii i Mikrobiologii, Minsk, 1982, 54
For two endo diastereomers of amine 1, the signals
for the H(3)x (δ 1.66 and 1.77) and H(3)n (δ 0.59 and
0
.81) protons are located separately from all other sig-
nals, which made it possible to determine the vicinal
spin-spin coupling constants 3JH(2)—H(3)n = 5.3 Hz and
3JH(2)—H(3)x = 11.6 Hz. The large values of the latter
constant and the cross-peaks observed for the closely
spaced H(2) and H(3)x protons in the ROESY experi-
ment confirmed the exo position of the H(2) proton in
the endo-(8R/S) diastereomers (see Scheme 2).
(
in Russian).
17. V. I. Votyakov, N. V. Gribkova, N. F. Kazak, and I. A.
Podol´skaya, Voprosy Virusologii [Problems of Virology], 1982,
27, 169 (in Russian).
18. V. I. Il´enko, V. G. Platonov, A. V. Vetyasenin, and I. N.
Prozorova, in Problemy i perspektivy izucheniya nukleozidov,
bitsiklogeptana, adamantana
i drugikh protivovirusnykh
We thank A. S. Shashkov for help in performing
two-dimensional NMR spectral studies.
soedinenii v eksperimente i klinike [Problems and Prospects of
Investigation of Nucleosides, Bicycloheptane, Adamantane,
and Other Antiviral Drugs in Experiments and Clinic],
NII Epidemiologii i Mikrobiologii, Minsk, 1982, 49 (in
Russian).
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Received July 28, 2000;
in revised form February 28, 2001