Synthesis and α4β2 nicotinic affinity of 2- pyrrolidinylmethoxyimines and prolinal oxime ethers

Article abstract of DOI:10.1016/j.bmcl.2004.09.044

Homochiral E and Z isomers of N-methylprolinal O-isopropyloxime and (1-methyl-2-pyrrolidinyl)methoxyimines were synthesized as candidate bioisosteres of nicotine and its isoxazolic analogue ABT 418. Two of them, namely (S)-2-isopropylideneaminooxymethyl- and (Z)-(S)-2- ethylideneaminooxymethyl-1-methylpyrrolidine, proved to bind at α4β2 nicotinic acetylcholine receptor with submicromolar affinity and remarkable selectivity over α7 and muscarinic receptors thus supporting the hypothesized bioisosteric relationship between their methyloxyimino group and the aromatic heterocycles of the reference ligands.

Full text of DOI:10.1016/j.bmcl.2004.09.044

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5827–5830
Synthesis and a4b2 nicotinic affinity of
2-pyrrolidinylmethoxyimines and prolinal oxime ethers
Marco Pallavicini,a,* Barbara Moroni,a Cristiano Bolchi,a Francesco Clementi,b
Laura Fumagalli,a Cecilia Gotti,b Silvia Vailati,b Ermanno Valotia and Luigi Villaa
a
`
Istituto di Chimica Farmaceutica e Tossicologica, Universita di Milano, viale Abruzzi 42, I-20131 Milano, Italy
bCNR, Istituto di Neuroscienze, Sezione di Farmacologia Cellulare e Molecolare, Dipartimento di Farmacologia Medica,
`
Universita di Milano, via Vanvitelli 32, I-20129 Milano, Italy
Received 2 June 2004; revised 3 September 2004; accepted 17 September 2004
Available online 5 October 2004
Abstract—Homochiral E and Z isomers of N-methylprolinal O-isopropyloxime and (1-methyl-2-pyrrolidinyl)methoxyimines were
synthesized as candidate bioisosteres of nicotine and its isoxazolic analogue ABT 418. Two of them, namely (S)-2-isopropylidene-
aminooxymethyl- and (Z)-(S)-2-ethylideneaminooxymethyl-1-methylpyrrolidine, proved to bind at a4b2 nicotinic acetylcholine
receptor with submicromolar affinity and remarkable selectivity over a7 and muscarinic receptors thus supporting the hypothesized
bioisosteric relationship between their methyloxyimino group and the aromatic heterocycles of the reference ligands.
Ó 2004 Published by Elsevier Ltd.
The neuronal nicotinic acetylcholine receptors (nAC-
hRs) play an important role in several brain functions
and they are also involved in severe brain pathologies
such as Parkinsonꢀs and Alzheimerꢀs diseases, schizo-
phrenia, anxiety, some forms of epilepsy and tobacco
smoking addiction. nAChRs are a heterogeneous family
of pentameric subtypes and this subtype variety is
mainly due to the diversity of combinations of a and b
subunits encoded by at least 12 different genes (a2–
a10, b2–b4).1–3 In vertebrate brain, the most abundant
subtypes are the a4b2 subtype, which accounts for most
moiety (p) with a relative separation of cationic and
HBA/p groups of ca. 4–6A (Fig. 1). More subtle differ-
˚
ences between the proposed nicotinic pharmacophores
derive from the individuation of additional elements,
which can be a ring centroid (C) or an atom in the ligand
defining the direction of the ligand–receptor hydrogen
bond,7 a planar area on the receptor recognizing the
p-electron rich moiety of the ligand,8 one or two points
(a and b) on the receptor, with which HBA and N+
interact, and the angle between two distance vectors
chosen out of those joining the various pharmacophore
elements.5,9,10 From most of these models, the direction-
ality of the HBA moiety relative to the N+ ! HBA/p
vector emerges as a critical feature and the flat area pro-
posed by Barlow and Johnson8 or the ring centroid of
the Sheridan model7 would be different ways to make
the pharmacophore tridimensional implicitly acknow-
ledging the importance of such a directionality.
3
of the high affinity H-agonist binding sites, and the a7
subtype, which binds aBungarotoxin (aBgtx) with high
affinity.1–3 The generation of potent and selective a4b2
ligands has thus become an important objective of phar-
maceutical research, which has been intensively pursued
over the last decade leading to the formulation of relia-
ble a4b2 pharmacophores and QSAR models.4–6
Common elements of these pharmacophoric patterns,
based on the structures of nicotine and other nicotinic
agonists, are (i) a protonated nitrogen (N+) and (ii) a
hydrogen bond acceptor (HBA) and/or a p-electron rich
HBA/π
C
+
N
a
N
Keywords: Neuronal nicotinic acetylcholine receptor; nAChR;
Nicotine; Ligand; Affinity; Oxime ether; Bioisostere.
b
*
Figure 1. The proposed pharmacophoric elements illustrated with (S)-
nicotine.
Corresponding author. Tel.: +39 2 50317524; fax: +39 2 50317565;
e-mail: marco.pallavicini@unimi.it
0960-894X/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2004.09.044

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M. Pallavicini et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5827–5830
On the ground of these postulates, the oximethereal
function (C@N–O–R) should suitably act as HBA/p
group promoting the interaction with the receptor. In
fact, it presents p electrons and hydrogen bond acceptor
atoms, in particular the weakly basic sp2 hybridized
nitrogen. Due to its planarity, such a function could
favourably interact with that flat area suggested by Bar-
low. Furthermore, the presence of the double bond and
the consequent geometric isomerism give the opportu-
nity of restraining and differentiating the possible direc-
tions of the ligand–receptor hydrogen bond.
OH
O
Cl
O N
b
a
N
+
N
N
N
N
(S)-1
(R)-4
e
c
O
NH2
O
N
O
N
f
d
N
N
N
.
2 HCl
(Z)-(S)-2
(S)-2
O
N
O
N
g
CHO
+
The bioisosteric replacement of the ester function of acet-
ylcholine by an oxyimino group dates back to the
1960s, when O-(b-dimethylamino)ethyl acetaldoxime
iodomethylate was found to show both muscarinic and
nicotinic activity by Rossi and co-workers.11 More re-
cently, arylalkenyl ethers of seven- to nine-membered
azabicyclic ketone oximes and alkyliden hydroxylamines
etherified with seven- to nine-membered azabicyclic resi-
dues have been described as muscarinic agonists.12–14
Although nicotine has been known to chemists for dec-
ades, surprisingly enough such a bioisosteric replace-
ment of its HBA/p moiety, namely the pyridine ring,
has never been undertaken. This prompted us to design
the oxime ethers 1–3 with the intention of evaluating the
affinity for the a4b2 nAChR of all their optical and geo-
metric isomers. Acetone and acetaldehyde were chosen
to construct the oxyimino ethers 1 and 2 with the intent
to mimic the 3-methyl-5-isoxazolyl residue of ABT 418,
a potent and rather selective a4b2 nAChR agonist,15
while the formal inversion of the methyloxyimino group
(C–O–N@C) of 1 led to the methyleneaminoxy group
(C@N–O–C) of prolinal oxime isopropyl ether 3. This
latter modification was made on the basis of the hypothe-
sized bioisosteric relationship between the O–N@C and
C@N–O atomic sequences.
N
N
N
(E)-(S)-3
(Z)-(S)-3
Scheme 1. Synthesis of oxime ethers. Reagents and conditions: (a)
SOCl2, toluene, 70°C, 3h; (b) acetone oxime, (CH3)3COK, DMSO,
18h; (c) 10% aq HCl, reflux, 16h; (d) CH3CHO, EtOH and TEA
(pH4); (e) (Z)-acetaldoxime, (CH3)3COK, DMSO, 18h; (f) (COCl)2,
DMSO, DCM, À50°C, 30min, then TEA; (g) (CH3)2CHONH2ÆHCl,
DCM, 18h.
line hydrochloride, while (S)-1 was salified with picric
acid, because its salts with hydrochloric acid or other
commonly used acids were found too hygroscopic to
be isolated.18
In order to obtain (S)-2, (S)-1 was hydrolyzed to (S)-(1-
methyl-2-pyrrolidinyl)methoxylamine and reacted with
acetaldehyde yielding a mixture of (E)-(S)-2 and (Z)-
1
(S)-2, whose H NMR analysis indicated a nearly equi-
molar composition. Unfortunately, such a mixture
could not be resolved by chromatography, neither could
it be significantly enriched in one of the two isomer by
preferential crystallization of the respective picrates.
Therefore, we decided to directly assess the binding
affinity of the purified mixture of the two free amines.19
This notwithstanding, the challenge to isolate almost
one of the two geometric isomers of (S)-2 was not
dropped. Analogously to the preparation of (S)-1, (S)-
1-methyl-2-chloromethylpyrrolidine was reacted with
(Z)-acetaldoxime and potassium tert-butoxide in
DMSO. Under such reaction conditions, the oxime con-
figuration was preserved and, after chromatographic re-
moval of the piperidine substitution product, isolated
(Z)-(S)-O-(1-methyl-2-pyrrolidinyl)methyl acetaldoxime
[(Z)-(S)-2] contained only traces of (E)-(S)-2,17 which
disappeared upon conversion into picrate.20
O
N
O
N
O
N
*
*
*
N
N
N
1
2
3
O
N
ABT 418
N
The synthesis of the S isomers of oxime ethers 1–3 was
accomplished as outlined in Scheme 1. (S)-N-Methyl-
prolinol was converted into (S)-1-methyl-2-chlorometh-
ylpyrrolidine by treatment with thionyl chloride in
toluene. Successive nucleophilic displacement of chlo-
ride by acetone oximate anion was performed by react-
ing with acetone oxime and potassium tert-butoxide in
DMSO. As anticipated, on the basis of the known form-
ation of a bicyclic aziridinium ion intermediate,16 the
reaction gave two substitution products, the 2-pyr-
rolidinemethyloxime (S)-1 and its 3-piperidinyloxime
isomer (R)-4, in an approximately 2:1 ratio. Repeated
MPLC purifications on silica gel allowed (R)-4, which
exhibited a slightly higher mobility than (S)-1, to be
completely separated from this latter.17 Finally, (R)-4
was easily transformed into the corresponding crystal-
Finally, the inverted oxime ethers (E)-(S)-3 and (Z)-(S)-
3 were prepared from (S)-N-methylprolinal, in turn ob-
tained by Swern oxidation of (S)-N-methylprolinol.
Reaction of the aldehyde with isopropoxyamine hydro-
chloride afforded a mixture of the two oxyimine ethers
with an approximately 2:1 E/Z ratio. The two isomers
were separated by chromatography21 and subjected to
the biological tests as free amines like the E/Z mixture
of (S)-2.22
(S)-4 and the R isomers of 1, 2 (E/Z mixture), (Z)-2,
(E)-3 and (Z)-3 were prepared by the same strategy
illustrated in Scheme 1 but starting from (R)-N-methyl-
prolinol.23

M. Pallavicini et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5827–5830
5829
The geometric configuration of the methyleneaminoxy
molecular portion (C@N–O) of 2 and 3 was assigned
by 1H NMR spectroscopy. The syn relationship between
the oxime oxygen and the hydrogen linked to the iminic
carbon atom of the aldehyde in the E isomers resulted,
due to the paramagnetic effect of the spatially proximal
oxygen, in the resonance of such a proton at a lower
field with respect to the same proton of the correspond-
ing Z isomers. This assumption was consistent with the
literature spectral data for (E)- and (Z)-acetaldox-
ime24,25 and the corresponding methyl ethers26,27 and,
in the case of 3, led to the reasonable assignment of
the presumably more stable E configuration to the prev-
alent oxime isomer produced by the reaction of prolinal
with isopropoxyamine.
Apart from 4, whose S and R forms exhibit similarly low
a4b2 affinities, the S isomers are invariably more potent
than their R enantiomers. As expected, such a trend is
more evident for 1 and 2 (eudismic index > 1) than for
the less potent oximes 3 (eudismic index < 1).
Compared with ABT-418, (S)-1 and (S)-2 exhibit 15- to
30-fold lower a4b2 affinity, but higher selectivity over
the a7 nAChR. Analogous subtype selectivity is shown
by (E)-(S)-3.
Finally, we also determined whether the most potent
compounds of our series bind at muscarinic AchRs.
As shown in Table 1, (S)-1 and (S)-2 had very low affin-
ity towards muscarinic receptors thus displaying a good
a4b2 selectivity, whereas (E)-(S)-3, with only 11-fold
higher affinity to a4b2 subtype, did not exhibit such a
selectivity.
We evaluated the affinity towards the a4b2 subtype pre-
sent in rat cortex membranes by binding studies using,
as a ligand, [3H]-epibatidine and the results are shown
in Table 1. For the most interesting compounds, the
affinities towards the a7-containing receptors, that bind
In summary, this study shows that replacement of the
nicotine pyridine or the ABT 418 isoxazole by an isopro-
pyliden- or ethylideneaminooxymethyl group leads to
two new nicotinoids, (S)-1 and (Z)-(S)-2, with (i) a mod-
erate submicromolar affinity for a4b2 nAChR and com-
pared to those compounds, (ii) the same stereoselectivity
(the S isomers have higher affinity than their R enantio-
mer) and (iii) analogous or better a4b2 versus a7 sub-
type selectivity, thus supporting the initially
hypothesized bioisosterism.
[
125I]-aBgtx, and muscarinic receptors, that bind [3H]-N-
methylscopolamine, were also determined. Nicotine and
ABT 418 were included in the series for comparison.
We found that, as shown in Table 1, the S isomers of
oximes 1 and 2 are the most potent compounds in the
series with a moderate submicromolar affinity for a4b2
nAChR. For (S)-2, such an affinity seems imputable to
the Z isomer, which is twice more potent than the
respective 1:1 E/Z mixture. This is also suggested by
the a4b2 affinity of (Z)-(R)-2, which is the double of that
displayed by the respective E/Z mixture. Otherwise, a
micromolar affinity for the a4b2 receptor is shown by
both the E and Z isomers of the inverted oxime (S)-3.
Furthermore, the double bond geometry, which should
be more determinant for the direction of the ligand–
receptor hydrogen bond relatively to the N+ ! HBA/p
vector in the compounds 3 than in the compounds 2,
conversely affects the affinity of these latter in greater de-
gree. This some unexpected result is probably imputable
to the fact that the loss of affinity, due to the reduced
internitrogen distance in the inverted oximes 3, not only
makes their chirality little influential but also their dou-
ble bond configuration.
Table 1. Affinity of nicotine, ABT 418 and compounds 1–4 for native
receptor subtypes, present in rat cortex membranes, labeled by [3H]-
epibatidine, [125I]-aBungarotoxin and [3H]-N-methylscopolamine
[3H]-Epi
[
125I]-aBgtx
[3H]-NMS
Finally, it is noteworthy that the 3-piperidinyloximes 4,
in which the optimal internitrogen distance of four
bonds28 is realized like in 1 and 2, are virtually devoid
of nicotinic affinity. Conformational analysis29 of the
protonated form of the S enantiomers of 1, (E)-2, (Z)-
2 and of (R)-4 with both R and S configuration at the
ammonium nitrogen revealed two significant differences
between the lowest energy structures of the 2-pyrrolidine
and the 3-piperidine derivatives: (a) the ammonium pro-
ton is engaged in an intramolecular hydrogen bond with
the oxygen atom in 1 and 2 to form a five-membered cy-
cle, while the same interaction is obviously precluded in
Ki (lM)
Ki (lM)
Ki (lM)
(À)-Nicotine
ABT-418
(S)-1
0.002 (59)
0.469 (33)
1.20 (85)
49 (18)
ND
ND
>50
>50
ND
>50
ND
>50
ND
17 (23)
ND
ND
ND
ND
ND
0.020 (14)
0.52 (14)
16.0 (9)
(R)-1
(S)-2 (1:1 E/Z)
(R)-2 (1:1 E/Z)
(Z)-(S)-2
(Z)-(R)-2
(E)-(S)-3
(E)-(R)-3
(Z)-(S)-3
(Z)-(R)-3
(S)-4
0.68 (23)
10.5 (15)
0.33 (24)
5.79 (14)
1.52 (22)
5.5 (13)
>50
ND
>50
ND
>50
47 (19)
ND
ND
1.9 (23)
14.5 (16)
+
˚
4; (b) the N –N distance is around 4.2A in all the S
>50
>50
ND
ND
forms of the 2-pyrrolidine derivatives regardless of the
configuration of the protonated tetrahedral nitrogen,
whereas this stereolabile center sensibly influences the
(R)-4
Kd (nM)
0.026 (12)
661 (41)
0.076 (19)
˚
same distance in (R)-4 (4.3A in the more stable con-
The Kd and Ki values were derived from [3H]-epibatidine, [125I]-
aBungarotoxin and [3H]-N-methylscopolamine saturation and two
competition binding experiments on rat cortex membranes. The curves
were fitted using a nonlinear least squares analysis program and the F
test. The numbers in brackets represent the %CV (ND = not
determined).
former having N+ with S configuration and both the
piperidinyl ring substituents equatorially oriented and
+
only 3.8A in the less stable conformer with N in R con-
˚
figuration). These observations are consistent with the
already underlined importance of the directionality of

5830
M. Pallavicini et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5827–5830
25
½aꢀD +19.4 (c 2, EtOH); 1H NMR (D2O, 300MHz):
d 4.28 (br s, 1H), 3.52 (pseudo d, J = 12.1Hz, 1H), 3.30
(pseudo d, J = 12.1Hz, 1H), 3.06 (pseudo d, J = 13.2Hz,
1H), 2.85 (pseudo t, J = 11.7Hz, 1H), 2.68 (s, 3H), 1.79 (s,
the HBA moiety in addition to a suitable distance of this
latter from the charged nitrogen. Furthermore, they
draw attention to the fact that, in some cases, such a dis-
tance can conform to the nicotinic pharmacophore on
condition of a given ammonium nitrogen configuration,
which is another important, but often neglected determi-
nant of the affinity of ligands containing protonation-in-
duced stereocenters.
1
3H), 1.74 (s, 3H), 1.4–2.0 (m, 4H). H NMR spectrum of
(R)-4 hydrochloride in CDCl3 shows the presence of
comparable quantities of both the ammonium and the
oxyimmonium species.
19. MPLC on silica gel; eluent: DCM/MeOH/30% aq NH3 95/
1
5/1. (S)-2 (E/Z mixture): H NMR (CDCl3, 300MHz): d
7.43 (q, J = 6.2Hz, ꢁ0.5H), 6.74 (q, J = 5.5Hz, ꢁ0.5H),
4.14 (dd, J = 11.0, 6.2Hz, ꢁ0.5H), 4.08 (dd, J = 10.6,
5.5Hz, ꢁ0.5H), 4.04 (dd, J = 11.0, 5.5Hz, ꢁ0.5H), 3.98
(dd, J = 10.6, 5.5Hz, ꢁ0.5H), 3.08 (m, 1H), 2.48–2.60 (m,
1H), 2.43 (s, ꢁ1.5H), 2.41 (s, ꢁ1.5H), 2.25 (m, 1H), 1.84
(d, J = 6.2Hz, 3H), 2.00–1.56 (m, 4H).
References and notes
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20. (Z)-(S)-2: 1H NMR (CDCl3, 300MHz):
d 6.74 (q,
J = 5.5Hz, 1H), 4.14 (dd, J = 11.0, 6.2Hz, 1H), 4.04 (dd,
J = 11.0, 5.5Hz, 1H), 3.08 (m, 1H), 2.55 (m, 1H), 2.43 (s,
3H), 2.24 (m, 1H), 1.84 (d, J = 6.2Hz, 3H), 1.56–2.00 (m,
25
4H). (Z)-(S)-2 Picrate: mp 102–104°C; ½aꢀD +12.9 (c 1,
1
EtOH); H NMR (CDCl3, 300MHz): d 10.95 (br s, 1H),
8.89 (s, 2H), 6.79 (q, J = 5.5Hz, 1H), 4.66 (dd, J = 8.8,
13.0Hz, 1H), 4.34 (dd, J = 13.0, 2.9Hz, 1H), 3.98 (m, 1H),
3.62 (m, 1H), 3.06 (s, 3H), 2.99 (m, 1H), 2.29 (m, 2H), 2.12
(m, 2H), 1.80 (d, J = 5.5Hz, 3H).
21. MPLC on silica gel; eluent: DCM/MeOH/30% aq NH3 97/
3/0.5.
25
22. (E)-(S)-3: ½aꢀ À44.4 (c 2, EtOH); 1H NMR (CDCl3,
300MHz): dD 7.18 (d, J = 7.7Hz, 1H), 4.31 (septet,
J = 6.2Hz, 1H), 3.10 (m, 1H), 2.77 (dd, J = 15.8, 7.9Hz,
1H), 2.31 (s, 3H), 2.22 (dd, J = 17.2, 8.8, 1H), 1.99 (m,
1H), 1.67–1.96 (m, 3H), 1.22 (d, J = 6.2, 6H). (Z)-(S)-3:
25
1
½aꢀD À60.6 (c 2, EtOH); H NMR (CDCl3, 300MHz): d
6.71 (d, J = 5.9Hz, 1H), 4.30 (septet, J = 6.2Hz, 1H), 3.39
(dd, J = 15.1, 7.0Hz, 1H), 3.07 (m, 1H), 2.33 (s, 3H), 2.18
(dd, J = 18.6, 8.1Hz, 1H), 2.10–2.20 (m, 1H), 1.72–1.92
(m, 2H), 1.61 (m, 1H), 1.22 (d, J = 6.2Hz, 6H).
1
23. (R)-1: H NMR identical to that of (S)-1. (R)-1 Picrate:
25
1
mp 92–93°C; ½aꢀD À18.9 (c 2, EtOH); H NMR identical
to that of (S)-1 picrate. (S)-4 Hydrochloride: mp 128–
25
129°C; ½aꢀD À19.5 (c 2, EtOH); 1H NMR identical to that
of (R)-4 hydrochloride. (R)-2 (E/Z mixture): 1H NMR
identical to that of (S)-2 (E/Z mixture) with similar E/Z
ratio. (Z)-(R)-2: 1H NMR identical to that of (Z)-(S)-2.
13. Plate, R.; Plaum, J. M.; de Boer, Th.; Andrews, J. S.
Bioorg. Med. Chem. 1996, 4, 239.
25
14. Cereda, E.; Pellegrini, C.; Sagrada, A.; Schiavi, G. B. WO
94/00448, 1994; Chem. Abstr. 1994, 122, 290728.
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16. Hammer, C. F.; Heller, S. R.; Craig, J. H. Tetrahedron
1972, 28, 239–253.
17. MPLC on silica gel; eluent: DCM/MeOH/30% aq NH3 95/
5/1.
(Z)-(R)-2 Picrate: mp 104–105°C; ½aꢀD À13.1 (c, 1 EtOH);
1H NMR identical to that of (Z)-(S)-2 picrate. (E)-(R)-3:
25
1
½aꢀD +40.9 (c 2, EtOH); H NMR identical to that of (E)-
25
(S)-3. (Z)-(R)-3: ½aꢀD +55.5 (c 2, EtOH); 1H NMR
identical to that of (Z)-(S)-3.
24. Kleinspehn, G. C.; Jung, J. A.; Studniarz, S. A. J. Org.
Chem. 1967, 32, 460–462.
25. Holloway, C. E.; Vuik, C. P. J. Tetrahedron Lett. 1979,
1017–1020.
26. Karabatsos, G. J.; Taller, R. A.; Vane, F. M. J. Am.
Chem. Soc. 1963, 85, 2326–2327.
1
18. (S)-1: H NMR (CDCl3, 300MHz): d 4.05 (dd, J = 10.4,
6.2Hz, 1H), 3.94 (dd, J = 10.4, 5.3Hz, 1H), 3.06 (pseudo t,
J = 7.9Hz, 1H), 2.53 (m, 1H), 2.42 (s, 3H), 2.23 (dd,
J = 17.6, 8.2Hz, 1H), 1.86 (s, 3H), 1.84 (s, 3H), 1.51–1.99
27. Karabatsos, G. J.; His, N. Tetrahedron 1967, 23, 1079–
1095.
28. Li, L.; Zhong, W.; Zacharias, N.; Gibbs, C.; Lester, H. A.;
Dougherty, D. A. Chem. Biol. 2001, 8, 47.
29. The conformational analyses were performed using Monte
Carlo approach that produced 1000 conformers for each
molecule by rotating its flexible torsions. All the obtained
geometries were optimized and clustered according to
their similarity.
25
(m, 4H). (S)-1 Picrate: mp 94–95°C; ½aꢀD +20.8 (c 2,
1
EtOH); H NMR (CDCl3, 300MHz): d 10.83 (br s, 1H),
8.89 (s, 2H), 4.55 (dd, J = 13.2, 8.8Hz, 1H), 4.26 (dd,
J = 13.2, 3.3Hz, 1H), 3.97 (m, 1H), 3.63 (m, 1H), 3.05 (s,
3H), 2.99 (m, 1H), 2.27 (m, 2H), 2.03 (m, 2H), 1.82 (s, 3H),
1.79 (s, 3H). (R)-4 Hydrochloride: mp 130–131°C;