First asymmetric syntheses of 6-substituted nipecotic acid derivatives

Article abstract of DOI:10.1016/j.tet.2003.11.014

Various nipecotic acid derivatives are known to be potent GABA uptake inhibitors thus being useful in the treatment of a number of neurological and psychological disorders. In this paper, the first asymmetric syntheses of 6-substituted nipecotic acid deri

Full text of DOI:10.1016/j.tet.2003.11.014

Tetrahedron 60 (2004) 307–318
First asymmetric syntheses of 6-substituted nipecotic
acid derivatives
*
¨
Cornelia E. Hoesl, G. Hofner and Klaus T. Wanner
¨ ¨ ¨
Department Pharmazie-Zentrum fur Pharmaforschung, LMU Munchen, Butenandtstr. 5-13, D-81377 Munchen, Germany
Received 25 July 2003; revised 29 October 2003; accepted 7 November 2003
Dedicated with the very best wishes to Professor Wolfgang Steglich on the occasion of his 70th birthday
Abstract—Various nipecotic acid derivatives are known to be potent GABA uptake inhibitors thus being useful in the treatment of a number
of neurological and psychological disorders. In this paper, the first asymmetric syntheses of 6-substituted nipecotic acid derivatives are
presented. The synthetic strategy was designed to provide access to a large variety of enantiomerically pure 6-substituted nipecotic acid
derivatives. The synthesis starts from the chiral N-acyldihydropyridines 15 and 16 obtained via asymmetric electrophilic a-amidoalkylation
reaction of a chiral N-acylpyridinium ion. These were utilized for the preparation of enantiomerically pure 6-(4,4-diphenylbutyl)nipecotic
acids and 6-(4,4-diphenylbutenyl)nipecotic acids in a multistep synthesis, including the removal of the dimethylphenylsilyl blocking group
from the dihydropyridine ring, the reduction of the dihydropyridine heterocycle, a Horner–Wittig reaction and the removal of the chiral
auxiliary. The obtained target molecules, however, showed only negligible affinity to the GAT-1- and GAT-3 transport proteins.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
readily cross the blood brain barrier, but have been used as
the basis for the design of some lipophilic and highly potent
GABA uptake inhibitors, e.g. SK&F-89976-A5 (3) and
Tiagabine6 (5) with GAT-1-selectivity and (S)-SNAP-51147
(4) with GAT-3-selectivity. Using structure-activity data
and molecular modeling, Wermuth et al.8 developed a
pharmacophore model of GABA uptake inhibitors which
suggests that for binding the lipophilic side chain is located
in the vicinity of position 6 of the piperidine ring. He
successfully confirmed his model by synthesizing 6-[(3,3-
diphenyl)propyl]guvacine (6) which he found to be a potent
GABA uptake inhibitor. The biological evaluation of
compound 6 was performed, however, with a test system
not clearly distinguishing between GAT-1 and GAT-3
uptake. Dhar and coworkers9 synthesized quinolizidine
derivatives (e.g., 7) with a diphenylmethyl substituent in
position 8 as conformationally restricted analogues of the
nipecotic acid derivative 6. Although, these analogues were
in accordance with the pharmacophore model proposed by
Wermuth, their affinity for GAT-1 or GAT-3 was very low.
In the context with a study aimed at the development of new
GABA uptake inhibitors we were interested in 6-substituted
nipecotic acid derivatives. Since it is well known that (R)-
nipecotic acid derivatives are more potent for GAT-1 than
(S)-nipecotic acid derivatives and that the opposite is true
for (S)-nipecotic acid derivatives exhibiting higher affinity
to GAT-3 than compounds derived from (R)-nipecotic acid,
it seemed reasonable to evaluate the enantiopure com-
pounds. Thus, we performed the first asymmetric synthesis
of 6-substituted nipecotic acid derivatives, which we,
g-Aminobutyric acid (GABA) is recognized as the pre-
dominant inhibitory neurotransmitter in the mammalian
brain. Malfunctions in GABAergic neurotransmission are
likely to contribute to the development of certain psychiatric
and neurological disorders such as epilepsy, Huntington’s
Chorea and Parkinson’s disease.1 One of the various
pharmacological approaches to palliate GABA deficiency
in vivo is to inhibit the uptake of the neurotransmitter,
thereby increasing the synaptic level of GABA and
enhancing inhibitory neurotransmission. In contrast to the
direct enhancement of GABA neurotransmission by
GABAA agonists or benzodiazepines, GABA uptake
inhibition results in a selective potentiation of endogenously
released GABA and therefore is thought not to give rise to
the development of tolerance.2 Four different GABA
transporters have been identified so far (GAT-1, GAT-2,
GAT-3 and BGT-1), which differ in their cellular
distribution in the brain and in their sensitivity to
pharmacological agents.3 A number of cyclic amino acids
such as (RS)-piperidine-3-carboxylic acid (nipecotic acid, 1)
and 1,2,5,6-tetrahydropyridine-3-carboxylic acid (guvacine,
2), which may be considered as conformationally restricted
GABA analogues, display in vitro activity as inhibitors of
[3H]-GABA uptake.4 These cyclic amino acids do not
Keywords: GABA uptake; Nipecotic acid; Asymmetric synthesis.
*
Corresponding author. Tel.: þ49-89-2180-77249; fax: þ49-89-2180-
77247; e-mail address: klaus.wanner@cup.uni-muenchen.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.014

308
C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
method termed as asymmetric electrophilic a-amidoalkyl-
ation (AEaA).10 In this type of reaction the new
stereocenter is formed by stereoselectively adding a suitable
nucleophile to a chiral N-acyliminium ion. In former studies
of our group the carboxylic acid depicted as acid chloride 8
has proven to be a useful chiral auxiliary for the synthesis of
pyrrolidines, piperidines, 1,2,3,4-tetrahydroisoquinolines
and b-carbolines via AEaA.11 Previously, we reported the
successful generation of the chiral N-acylpyridinium ion 11
from acid chloride 8 and methyl (4-dimethylphenylsilyl)-
nicotinate (9)12 by means of trimethylsilyl triflate.13 The
dimethylphenylsilyl group, served as a blocking substituent
in subsequent trapping reactions preventing addition reac-
tions to position 4 of the pyridinium ring. Reaction of the
N-acyl-4-dimethylphenylsilylpyridinium salt 11 with
{[1,3]-dioxolan-2-ylethyl}magnesium bromide (13) led to
the N-acyl-1,6-dihydropyridines 15 as the main product (15/
16¼87.2/12.8).13 Meanwhile further experiments revealed
that the sense of asymmetric induction is switched and
compound 16 becomes the major diastereomer when the
higher order cyanocuprate 14 (Scheme 2) is employed (see
below). Having both diastereomers 15 and 16 available in
reasonable amounts we set out to utilize these compounds as
the basis for the synthesis of a series of 6-substituted
nipecotic acid derivates. With regard to the above
mentioned [6-(3,3-diphenylpropyl)]guvacine (6) and con-
sidering the structure of the GABA uptake inhibitor SK&F-
89976-A (3) with a diphenylbutenyl substituent bound to the
nitrogen atom we planned to transform the side chain
present in 15 and 16—via the respective aldehyde—to a
diphenylbutenyl residue by employing a Horner–Emmons-
reaction or to a diphenylbutyl substituent. Besides, the
[1,3]-dioxolan-2-ylethyl substituent may open the way to
various functional groups, e. g. alcohols or ethers, or to
bicyclic ring systems either by intramolecular Schiff-Base-
reaction or by a-aminonitrile formation according to the
method of Husson et al.14 The dimethylphenylsilyl
substituent, which serves as a blocking group in the
trapping reaction as described above, may either be
removed thereby providing access to nipecotic acid
derivatives unsubstituted in the 4-position or it may serve
as a masked hydroxyl group15 leading to 4-hydroxynipeco-
tic acid derivatives. Furthermore, elimination of the
generated hydroxyl group might afford guvacine deriva-
tives. Both, 4-hydroxynipecotic acid as well as guvacine,
are promising substructures for potential GABA uptake
inhibitors.
Scheme 1.
furthermore, investigated for their biological potential
(Scheme 1).
2. Synthetic strategy
The overall strategy used for the stereoselective preparation
of the 6-substituted nipecotic acid derivates is based on a
Scheme 2.

C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
309
Scheme 3.
Scheme 4.

310
C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
3. Results and discussion
yield, see Scheme 3). Following cleavage of the acetal group
in compound 19 (90%), the resulting aldehyde 22 was
successfully converted to the diphenylbutenyl derivative 25
carrying out a Wittig–Horner reaction. Deprotonation of
phosphonate 24 with nBuLi17 and reaction of the resulting
carbanion with the aldehyde 22 gave the desired product 25 in
82% yield. The removal of the chiral auxiliary was achieved
straightforwardly in a yield of 90% by heating compound 25
with NaOMe in methanol at 120 8C in a sealed tube
(Scheme 3).13,18 As the resulting enamino ester 27 was
unstable, it became necessary to immediately reduce the
doublebondof the enamino ester unit. Thus compound27was
treated with triethylsilane in trifluoroacetic acid at 50 8C using
a method developed by Rosentreter19 for the synthesis of
piperidine derivatives from 1,4-dihydropyridines. Employing
these reaction conditions, the enamine-double bond and the
double bond in the side chain were reduced yielding
diastereomers 28 and 29 (total yield for amide cleavage and
Diastereomer 15 was available from a trapping reaction of
11 employing the Grignard reagent 13,16 which yielded a
mixture of 15 and 16 in a ratio of 87.2 to 12.8. Interestingly,
the sense of asymmetric induction observed for the Grignard
reagent was inverted when the cyanocuprate 14 was used
(15/16¼34.0/66.0, total yield: 47%). Consequently, the
reaction mixture resulting from this addition reaction was
utilized to get access to diastereomer 16 in pure form which
became available upon chromatography in a yield of 31%.
Both diastereomers, 15 and 16, were separately converted to
the target molecules 32, 33, (ent)-32 and (ent)-33 in a multi-
step synthesis. Though in the following only one of the two
sequences, the one starting from 15 and leading to 32 and 33
is described, the synthesis of the enantiomers (ent)-32 and
(ent)-33 was performed accordingly starting with the
N-acyl-1,6-dihydropyridine 16. The dimethylphenylsilyl
group was removed by treating 15 with tetrabutyl-
ammonium fluoride leading to product 17 (46%). In the
next step compound 17 was subjected to catalytic
hydrogenation, which yielded the 1,4,5,6-tetrahydropyridine
derivative 19 in 70% yield, but only when Na2CO3 was
present. Otherwise, in the absence of Na2CO3, only alcohol 21
was obtained by hydrogenolysis of the acetal moiety (68%
1
reduction: 50%, d.s.¼83/17 determined by H NMR). The
reduction of both double bonds was not very surprising but
quite useful, as it provided an even easier access to the
desired nipecotic acid derivates with a saturated side chain.
Since we were not able to separate the diastereomers at this
stage, we decided to convert them to the Boc-protected
derivatives 30 and 31.20 Compounds 30 and 31 were then
Scheme 5.

C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
311
easily separable by chromatography. By refluxing in 2 M HCl
the methyl ester and the carbamate function were simul-
tanously cleaved yielding the target molecules 32 and 33, each
in 99% yield (Scheme 4).
The configuration of the nipecotic acid derivatives 37 and
1
38 was determined from the H NMR spectra of the Boc-
protected compounds 35 and 36. Analysis of the coupling
pattern of the 2-H and 6-H signal in the 1H NMR spectrum
leads to the configuration of 35. For 6-H (d¼4.15–
4.24 ppm) only small coupling constants (J¼2.0/8.1 Hz)
are observed for the hydrogen atoms in position 6
indicating, that the diphenylbutenyl substituent is positioned
axially. This orientation of the side chain is to be seen as a
result of the allylic strain arising from the carbamate
function.21 As the ester function at 3-C adopts an axial
position which becomes apparent from the coupling
constants between 2-H and 3-H (2-Hax: 2.93 ppm, J¼14.0/
4.1 Hz; 2-Heq: 4.41 ppm, J¼14.0/1.2 Hz) compound 35
must, consequently, be (3S,6S)-configurated. Finally com-
pound 36 by differing from the aforementioned diastereo-
mer 35 only in the configuration at 3-C exhibiting the ester
function must be the (3R,6S)-stereoisomer.
To access target molecules with a diphenylbutenyl side
chain, the enamino ester 27 was first protected with a Boc
group providing 34 (yield: 75%). Upon subsequent
reduction of the enamido ester double bond in 34 with
magnesium in methanol the piperidine derivatives 35 and 36
1
were obtained (yield: 65%, d.s.¼57/43, determined by H
NMR). Chromatographic separation of the diastereomers
followed by the concurrent cleavage of the amide and the
ester bond by HCl yielded 92% of the target molecule 37
and 97% of the target molecule 38. The enantiomers (ent)-
37 and (ent)-38 were synthesized accordingly starting from
compound (ent)-27 (Scheme 5).
The relative stereochemistry of the piperidine derivatives 28
1
and 29 became apparent from their H NMR spectra. The
absolute stereochemistry of the precursor 15 had been
established in a former study by X-ray analysis.13 Thus,
piperidine derivative 28 obtained from 15 must be of
(S)-configuration in position 6 of the heterocycle, as it is the
case for 15. In the 1H NMR spectrum of 28 the signal of 6-H
(d¼2.28–2.45 ppm) is a multiplet due to coupling with 5-H
and the hydrogen atoms of the alkyl chain. A large coupling
constant of J¼12.1 Hz was identified to the hydrogen atoms
in position 5. Thus, 6-H must adopt an axial orientation. The
signal of one hydrogen in position 2 (d¼2.60 ppm) of the
heterocycle is split to a doublet of doublets by a geminal
(J¼11.8 Hz) and by a vicinal coupling (J¼11.3 Hz).
Consequently, this proton (2-H) and the proton in position
3 of the piperidine ring must be in an axial position.
Therefore, the residues in position 3 and 6 must both occupy
equatorial positions and diastereomer 28, as the major
diastereomer of the reduction, must, consequently, be of
(3S,6S)-configuration. As the minor isomer 29 differs from
28 only with respect to the stereochemistry at 3-C of the ring
system, it must have the stereochemistry indicated
[(3R,6S)], which in further support of this assignment
could also be delineated from the 1H NMR spectrum of this
compound. (6-H: d¼2.30–2.45 ppm, J¼12.1 Hz in addition
to small coupling constants; 2-Hax: d¼2.71 ppm, J¼12.8/
3.5 Hz; 2-Heq: d¼3.31 ppm, J¼12.8/2.5 Hz) (Scheme 6).
4. Biological test results
The enantiomerically pure nipecotic acid derivates were
evaluated for their in vitro activity as GABA uptake
inhibitors by a radioligand-receptor binding assay.22 The
results are depicted in Table 1 and are given as percentage of
GABA uptake compared to the control experiment without
test substance. To determine IC50 values did not seem
appropriate as none of the 6-substituted nipecotic acid
derivatives 32, 33, (ent)-32, (ent)-33, 37, 38, (ent)-37 and
(ent)-38 displayed a reasonable potency neither at GAT-1
nor at GAT-3 (see Table 1). For comparison purposes in
Table 1 also the data for SK&F-89976A (3), 6-[(3,3,-
diphenylpropyl)]guvacine (6) and (S)-SNAP-5114 (4) from
the literature are included. The low potency of the herein
synthesized target molecules is surprising considering the
high affinity of 6-[(3,3-diphenylpropyl)]guvacine (6). How-
ever, our results are in accordance with biological test
results reported by Dhar9 for conformationally restricted
6-substituted nipecotic acid derivatives (e.g., 7) also having
low affinity for GAT-1 and GAT-3.
Table 1.
Compound
IC50^SEM
GAT-1
GAT-3
6
3
4
32
33
(ent)-32
(ent)-33
37
38
(ent)-37
(ent)-38
0.1 mMa8,23
0.13^0.03 mMb
388^92 mMb7
944^110 mMb
5^1 mMb7
100 mM: 96.5%c
100 mM: 75.3%c
100 mM: 98.3%c
100 mM: 86.0%c
100 mM: 91.6%c
100 mM: 77.7%c
100 mM: 89.7%c
100 mM: 93.4%c
100 mM: 97.6c
100 mM: 95.3%c
100 mM: 85.5%c
100 mM: 94.8%c
100 mM: 71.8%c
100 mM: 74.5%c
100 mM: 65.0%c
100 mM: 69.9%c
a
[3H]GABA-synaptosomal uptake in rat brain given as IC50
determined for hGAT-1 and hGAT-3 given as IC50 according to
Borden.24
% uptake compared to a control experiment without test substance, each
experiment performed as triplicate.22
.
b
c
Scheme 6.

312
C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
5. Conclusion
6.1.2. Methyl (S)-6-(2-[1,3]dioxolan-2-ylethyl)-1-
[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octyl-
carbonyl]-1,6-dihydropyridine-3-carboxylate (17).
In summary, the first asymmetric synthesis for 6-substituted
nipecotic acid derivatives was developed. The synthetic
strategy was designed to provide a flexible access to a wide
range of nipecotic acid derivatives. The educts 15 and 16
were prepared by asymmetric electrophilic a-amidoalkyl-
ation via the chiral N-acylpyridinium ion 11. In multistep
syntheses the four enantiomerically pure isomers of 6-(4,4-
diphenylbutyl)nipecotic acid and of 6-(4,4-diphenylbutyl)-
nipecotic acid were obtained. The synthesized nipecotic
acid derivatives were evaluated for their in vitro activity at
the GAT-1 and GAT-3 transport proteins, but did not show
any reasonable potency.
880 ml (0.880 mmol, 5 equiv.) of Bu4NF (1 M in THF)
were slowly added to a solution of 100 mg (0.176 mmol) of
15 in 1760 ml THF over a period of 3 h. Phosphate buffer
(pH¼7, c¼1.0 M) was added. The reaction mixture was
extracted with CH2Cl2. The combined organic layer were
dried (Na2SO4) and concentrated in vacuo. Purification by
CC (n-heptane/EtOAc)¼50:50) afforded 35 mg (46%) of
compound 17.
Compound 17. Colorless oil. TLC: Rf¼0.20 (n-heptane/
EtOAc¼50:50). [a]D20¼þ436.3 (c¼0.16, CH2Cl2). IR
1
(KBr): n¼2955 cm21, 1718, 1677, 1219. H NMR (nitro-
˜
benzene-d5, 140 8C): d¼0.90 ppm (s, 3H, CH3), 1.07 (s, 3H,
CH3), 1.42 (s, 3H, CH3), 1.77–2.00 (m, 6H, CH2CH2,
CH2CH2), 2.28–2.40 (m, 1H, CH2CH2), 2.50–2.60 (m, 1H,
CH2CH2), 3.77 (s, 3H, COOCH3), 3.74–3.80 (m, 2H,
OCH2CH2O), 3.86–3.93 (m, 2H, OCH2CH2O), 3.99 (d,
J¼10.9 Hz, 1H, OCH2), 4.19 (dd, J¼10.9/1.9 Hz, 1H,
OCH2), 4.87 (t, 1H, J¼4.8 Hz, OCHO), 5.13–5.16 (m,
1H, NCHCH2), 5.84 (dd, J¼9.9/5.6 Hz, 1H, NCHCHvCH),
6.53 (d, J¼9.9 Hz, 1H, NCHvCCH), 7.94 (s, 1H, NCHvC).
MS (70 eV); m/z (%): 433 [Mþ] (1), 332 (23), 195 (100), 167
(28), 139 (31). C23H31NO7 (433.50): calcd C 63.73, H 7.21, N
3.23; found C 63.90, H 7.26, N 2.96.
6. Experimental
6.1. General
All reactions were carried out in vacuum dried glassware
sealed with rubber septa under argon atmosphere whenever
necessary. All reagents were used as commercially
available. The solvents were dried and distilled. Mp
(uncorrected values): Bu¨chi melting point apparatus no.
510 (Dr. Tottoli). Optical rotations: Polarimeter 241 MC
(Perkin–Elmer). IR: Perkin–Elmer FT-IR spectropho-
1
tometer Paragon 1000. H NMR: JEOL JNMR-GX 400
6.1.3. Methyl (R)-6-(2-[1,3]dioxolan-2-ylethyl)-1-
[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octyl-
carbonyl]-1,6-dihydropyridine-3-carboxylate (18). Syn-
thesis as described for the preparation of 17 from 985 mg
(1.734 mmol) of 16 and 8.67 ml (8.670 mmol, 5 equiv.) of
Bu4NF (1 M in THF). Purification by CC (iso-hexane/
Et2O¼25:75) afforded 355 mg (47%) of 18.
spectrometer (400 MHz) with TMS as internal standard. MS
spectra: Hewlett Packard 5989 with 59980 B particle beam
LC/MS interface. Elemental analysis: CHN Rapid (Heraeus).
TLC: TLC plates Merck 60 F-254. Column chromatography
(CC): Flash chromatography on silica gel (Merck 60 F-254,
0.040–0.063 mm). Analytical HPLC: L-6000 pump, L-4000
UV/VIS detector, D-7500 Chromato Integrator (Merck–
Hitachi), column: LiChroCartw with Lichrospherw Si 60
cartridge (5 mm, 250£4 mm with precolumn 4£4 mm),
(Merck). Preparative HPLC: L-6000 pump, L-4000 UV/Vis,
D-2000 Chromato Integrator (Merck–Hitachi), column:
Hibar RT LiChrosorbw Si 60 (7 mm, 250£25 mm) (Merck).
Compound 18. Colorless oil. TLC: Rf¼0.20 (iso-hexane/
Et2O¼25:75). [a]2D0¼2357.6 (c¼0.88, CH2Cl2). IR (KBr):
n¼2958 cm21, 1718, 1676, 1578, 1210. 1H NMR (CD2Cl2,
˜
120 8C): d¼0.93 ppm (s, 3H, CH3), 0.97 (s, 3H, CH3), 1.22
(s, 3H, CH3), 1.62–1.81 (m, 4H, CH2CH2), 1.87–2.00 (m,
2H, CH2CH2), 2.31–2.44 (m, 1H, CH2CH2), 2.73–2.87 (m,
1H, CH2CH2), 3.78 (s, 3H, COOCH3), 3.80–3.85 (m, 2H,
OCH2CH2O), 3.92–3.96 (m, 2H, OCH2CH2O), 3.98 (d,
J¼11.0 Hz, 1H, OCH2), 4.20 (dd, J¼11.0/2.1 Hz, 1H,
OCH2), 4.88 (t, 1H, J¼4.7 Hz, OCHO), 5.25–5.33 (m,
1H, NCHCH2), 5.70 (dd, J¼9.9/5.6 Hz, 1H,
NCHCHvCH), 6.44 (d, J¼9.9 Hz, 1H, NCHvCCH),
7.66 (s, 1H, NCHvC). MS (70 eV); m/z (%): 433 [Mþ]
(2), 402 (2), 332 (29), 195 (100), 167 (27), 139 (30).
C23H31NO7 (433.50): calcd C 63.73, H 7.21, N 3.23; found
C 64.01, H 7.42, N 2.74.
6.1.1. Methyl (S)-(4-(dimethylphenylsilyl)-6-(2-
[1,3]dioxolan-2-ylethyl)-1-[(1S,5R)-5,8,8-trimethyl-2-
oxo-3-oxabicyclo[3.2.1]octylcarbonyl]-1,6-dihydropyri-
dine-3-carboxylate (15) and methyl (R)-(4-(dimethyl-
phenylsilyl)-6-(2-[1,3]dioxolan-2-ylethyl)-1-[(1S,5R)-
5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octylcarbonyl]-
1,6-dihydropyridine-3-carboxylate (16). The generation
of the N-acylpyridinium triflate 11 was performed according
to literature13 starting from 3.0 mmol of acylchloride 8,
816 mg (3.0 mmol) of pyridine 9 and 543 ml (3.0 mmol) of
trimethylsilyl triflate in 15 ml CH2Cl2. To this solution
another solution was added at 278 8C over 3 min, that had
been prepared by addition of 18 ml (18.0 mmol, 2.0 equiv.) of
2-([1,3]dioxolan-2-yl)ethylmagnesium bromide (1.0 M in
THF) to a suspension of 806 mg (9.0 mmol, 1.0 equiv.) of
CuCN in 35 ml THF at 278 8C and had been allowed to react
at 0 8C for 10 min. After 3 h at 230 8C the reaction mixture
was quenched at 230 8C with phosphate buffer (pH¼7,
c¼1.0 M). Work up, purification and separation of the
diastereomers according to literature13 afforded 272 mg
(16%) of 15 and 528 mg (31%) of 16, which were identical
in all respect with authentic samples.13
6.1.4. Methyl (R)-6-(2-[1,3]dioxolan-2-ylethyl)-1-
[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octyl-
carbonyl]-1,4,5,6-tetrahydropyridine-3-carboxylate
(19). 681 mg Pd/C (10% Pd) were added to a suspension of
681 mg (1.571 mmol) of compound 17 and 666 mg
(6.284 mmol, 4 equiv.) of Na2CO3 in 31 ml of CH3OH.
The resulting mixture was hydrogenated for 48 h under
normal pressure. Then the mixture was filtered and
concentrated in vacuo. Purification by CC (iso-hexane/
Et2O¼20:80) afforded 478 mg (70%) of 19.

C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
313
Compound 19. Colorless crystals, mp 68 8C. TLC: Rf¼0.22
(iso-hexane/Et2O¼20:80). [a]2D0¼þ195.1 (c¼0.61,
3H, COOCH3), 3.99 (d, J¼11.1 Hz, 1H, OCH2), 4.19 (d,
J¼11.1 Hz, 1H, OCH2), 4.39–4.47 (br, 1H, OH), 4.58–4.68
(m, 1H, NCHCH2), 8.07 (s, 1H, NCHvC). MS (70 eV); m/z
(%): 437 [Mþ] (3), 406 (100), 334 (6), 195 (16), 167 (9), 139
(8). C23H35NO7 (437.53): calcd C 63.14, H 8.06, N 3.20;
found C 63.48, H 8.00, N 3.16.
CH Cl ). IR (KBr): n¼2954 cm21, 1728, 1623, 1244,
˜
2
2
1187. 1H NMR (C2D2Cl4, 120 8C): d¼0.94 ppm (s, 3H,
CH3), 1.03 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.60 (m, 1H,
NCHCH2CH2Cv), 1.69–1.81 (m, 5H, CH2CH2, NCHCH2-
CH2Cv), 1.86–1.97 (m, 2H, CH2CH2), 2.01 (dd, J¼12.9/
5.6 Hz, 1H, NCHvCCH2), 2.32 (dd, J¼12.9/6.4 Hz, 1H,
NCHvCCH2), 2.38–2.47 (m, 2H, CH2CH2), 3.76 (s, 3H,
COOCH3), 3.81–3.86 (m, 2H, OCH2CH2O), 3.93–3.98 (m,
2H, OCH2CH2O), 3.97 (d, J¼11.0 Hz, 1H, OCH2), 4.18 (d,
J¼11.0 Hz, 1H, OCH2), 4.51–4.59 (m, 1H, NCHCH2), 4.92
(t, 1H, J¼4.0 Hz, OCHO), 7.76 (s, 1H, NCHvC). MS
(70 eV); m/z (%): 435 [Mþ] (1), 404 (4), 336 (100), 240
(13), 195 (81), 167 (25). C23H33NO7 (435.52): calcd C
63.43, H 7.63, N 3.22; found C 63.23, H 7.74, N 3.05.
6.1.7. Methyl (R)-6-(3-oxopropyl)-1-[(1S,5R)-5,8,8-tri-
methyl-2-oxo-3-oxabicyclo[3.2.1]octylcarbonyl]-1,4,5,6-
tetrahydropyridine-3-carboxylate (22). 3.6 ml of HCl
(5% in H2O) were added to a solution of 478 mg
(1.102 mmol) of 19 in 7.3 ml THF. The reaction mixture
was stirred for 18 h and was then quenched with phosphate
buffer (pH 7, c¼1.0 M). The reaction mixture was extracted
with CH2Cl2. The combined organic layers were dried
(MgSO4) and concentrated in vacuo. Purification by CC
(iso-hexane/Et2O¼25:75) afforded 389 mg (90%) of 22.
6.1.5. Methyl (S)-6-(2-[1,3]dioxolan-2-ylethyl)-1-
[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octyl-
carbonyl]-1,4,5,6-tetrahydropyridine-3-carboxylate
(20). Synthesis as described for the preparation of 19 from
129 mg (0.298 mmol) of 18, 129 mg of Pd/C (10% Pd) and
126 mg (1.192 mmol, 4 equiv.) of Na2CO3 in 6 ml CH3OH,
hydrogenation time: 24 h. Purification by CC (iso-hexane/
Et2O¼25:75) afforded 67 mg (51%) of 20.
Compound 22. Colorless crystals, mp 83 8C. TLC: Rf¼0.22
(iso-hexane/Et2O¼25:75). [a]2D0¼þ191.8 (c¼0.34,
CH Cl ). IR (KBr): n¼2954 cm21, 2724, 1723, 1673,
˜
2
2
1621, 1246, 1180. 1H NMR (C2D2Cl4, 120 8C):
d¼0.94 ppm (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.37 (s, 3H,
CH3), 1.71–1.84 (m, 2H, NCHCH2CH2Cv, CH2CH2-
CHO), 1.85–1.98 (m, 4H, CH2CH2, CH2CH2CHO,
NCHCH2CH2Cv), 2.27–2.40 (m, 2H, CH2CH2, CH2CH2-
CHO), 2.40–2.55 (m, 3H, NCHvCCH2, CH2CH2, CH2-
CH2CHO), 2.56–2.67 (m, 1H, NCHvCCH2), 3.78 (s, 3H,
COOCH3), 3.98 (d, J¼11.0 Hz, 1H, OCH2), 4.19 (dd,
J¼1.7, 11.0 Hz, 1H, OCH2), 4.57–4.63 (m, 1H,
NCH(CH2)), þ7.75 (s, 1H, NCHvC), 9.80 (s, 1H, CHO).
MS (CI, CH5 ); m/z (%): 392 [Mþþ1] (35), 360 (100), 305
(9), 195 (57), 167 (44), 139 (51). C21H29NO6 (391.46):
calcd C 64.43, H 7.47, N 3.58; found C 64.16, H 7.46, N
3.44.
Compound 20. Colorless crystals, mp 160–161 8C. TLC:
Rf¼0.24 (iso-hexane/Et2O¼25:75). [a]2D0¼236.1 (c¼0.51,
CH Cl ). IR (KBr): n¼2950 cm21, 1717, 1676, 1610, 1238,
˜
2
2
1173. 1H NMR (C2D2Cl4, 120 8C): d¼0.94 ppm (s, 3H,
CH3), 1.00 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.61 (m, 1H,
NCHCH2CH2Cv), 1.63–1.76 (m, 4H, CH2CH2), 1.92 (m,
1H, NCHCH2CH2Cv), 1.90–2.06 (m, 2H, CH2CH2), 2.26
(ddd, J¼18.3/7.4/5.9 Hz, 1H, NCHvCCH2), 2.31–2.43 (m,
1H, CH2CH2), 2.46 (dd, J¼18.3/5.9 Hz, 1H, NCHvCCH2),
2.57–2.80 (m, 1H, CH2CH2), 3.76 (s, 3H, COOCH3), 3.81–
3.86 (m, 2H, OCH2CH2O), 3.92–3.97 (m, 2H, OCH2CH2O),
3.97 (d, J¼11.0 Hz, 1H, OCH2), 4.20 (d, J¼11.0 Hz, 1H,
OCH2), 4.76–4.83 (m, 1H, NCHCH2), 4.90 (t, 1H, J¼4.2 Hz,
OCHO), 7.79 (s, 1H, NCHvC). MS (CI, CH5þ); m/z (%): 436
[Mþþ1] (6), 404 (4), 336 (100), 195 (89). C23H33NO7
(435.52): calcd C 63.43, H 7.63, N 3.22; found C 63.36, H
7.74, N 3.14.
6.1.8. Methyl (S)-6-(3-oxopropyl)-1-[(1S,5R)-5,8,8-tri-
methyl-2-oxo-3-oxabicyclo[3.2.1]octylcarbonyl]-1,4,5,6-
tetrahydropyridine-3-carboxylate (23). Synthesis as
described for the preparation of 22 from 132 mg
(0.302 mmol) of 20 in 2 ml THF with 1.0 ml of HCl (5%
in H2O). Purification by CC (iso-hexane/ethyl
acetate¼55:45) afforded 106 mg (90%) of 23.
6.1.6. Methyl (R)-6-[3-(1-hydroxyethoxy)propyl]-1-
[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octyl-
carbonyl]-1,4,5,6-tetrahydropyridine-3-carboxylate
(21). Synthesis as described for the preparation of 19 from
84 mg (0.194 mmol) of 17 in 3.8 ml CH3OH, 168 mg of Pd/
C (10% Pd) and without Na2CO3, hydrogenation time: 48 h.
Purification by CC (iso-hexane/Et2O¼20:80) afforded
57 mg (67%) of 21.
Compound 23. Colorless crystals, mp 52–55 8C. TLC:
Rf¼0.27 (iso-hexane/ethyl acetate¼55:45). [a]2D0¼240.2
(c¼0.53, CH Cl ). IR (KBr): n¼2958 cm21, 1725, 1670,
˜
2
2
1618, 1243, 1184. 1H NMR (C2D2Cl4, 120 8C):
d¼0.95 ppm (s, 3H, CH3), 0.98 (s, 3H, CH3), 1.29 (s, 3H,
CH3), 1.76–2.03 (m, 6H, NCHCH2CH2Cv, CH2CH2CHO,
CH2CH2), 2.20–2.39 (m, 2H, CH2CH2, CH2CH2CHO),
2.42–2.60 (m, 3H, CH2CH2, CH2CH2CHO, NCHvCCH2),
2.64–2.85 (m, 1H, NCHvCCH2), 3.77 (s, 3H, COOCH3),
3.98 (d, J¼11.1 Hz, 1H, OCH2), 4.22 (dd, J¼11.1/1.8 Hz,
1H, OCH2), 4.80–4.85 (m, 1H, NCHCH2), 7.78 (s, 1H,
NCHvC), 9.79 (s, 1H, CHO). MS (CI, CH5þ); m/z (%): 392
[Mþþ1] (22), 360 (31), 195 (536), 180 (100), 167 (26), 139
(14). C21H29NO6 (391.46): calcd C 64.43, H 7.47, N 3.58;
found C 64.11, H 7.75, N 3.22.
Compound 21. Colorless oil. TLC: Rf¼0.25 (iso-hexane/
Et2O¼20:80). [a]2D0¼þ170.1 (c¼0.64, CH2Cl2). IR (film):
n¼3532 cm21, 2953, 1730, 1676, 1624, 1244, 748, 706. 1H
˜
NMR (nitrobenzene-d5, 140 8C): d¼0.91 ppm (s, 3H, CH3),
1.09 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.59–1.84 (m, 4H,
CH2CH2), 1.87–1.94 (m, 1H, NCHvCCH2CH2), 1.89–
2.00 (m, 2H, CH2CH2), 2.01–2.11 (m, 1H, NCHvCCH2-
CH2), 2.29–2.47 (m, 2H, NCHvCCH2), 2.47–2.62 (m, 2H,
CH2CH2), 3.26–3.36 (m, 5H, NCHCH2CH2CH2O, OCH2-
CH2O), 3.36–3.45 (m, 1H, NCHCH2CH2CH2O), 3.74 (s,
6.1.9. Methyl (S)-6-(4,4-diphenylbut-3-enyl)-1-[(1S,5R)-
5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octylcarbo-
nyl]-1,4,5,6-tetrahydropyridine-3-carboxylate
(25).

314
C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
722 ml (1.156 mmol, 1.2 equiv.) of nBuLi (1.6 M in hexane)
were added to 700 ml of THF. After cooling to 0 8C 327 mg
(1.156 mmol, 1.2 equiv.) of ethyl benzhydrylphosphonate
(24) in 1.6 ml THF were added. The reaction mixture was
warmed to room temperature. After 2.5 h a solution of
377 mg (0.963 mmol) of 22 in 4.6 ml THF were added
dropwise and the reaction mixture was stirred for 18 h. The
reaction was quenched with phosphate buffer (pH 7,
c¼1.0 M). Then it was extracted with CH2Cl2 and the
combined organic layers were dried (MgSO4) and concen-
trated in vacuo. Purification by CC (iso-hexane/
Et2O¼40:60) afforded 429 mg (82%) of 25.
mixture was extracted with CH2Cl2. The combined organic
layers were dried (MgSO4) and concentrated in vacuo.
Purification by CC (CH2Cl2/CH3OH¼95:5) afforded 15 mg
(90%) of 27. As product 27 appeared to be labile, it could
not be fully characterized. It was immediately transformed
to either the compounds 28 and 29 or 34.
Compound 27. Colorless oil. TLC: Rf¼0.68 (CH2Cl2/
CH3OH¼95:5). 1H NMR (CD2Cl2): d¼1.53–1.62 ppm
(m, 3H, NCHCH2CH2Cv, NCHCH2CH2CH–CPh2),
1.70–1.78 (m, 1H, NCHCH2CH2Cv), 2.14–2.21 (m, 3H,
NCHvCCH2, NCHCH2CH2CHCPh2), 2.22–2.31 (m, 1H,
NCHvCCH2), 3.12–3.21 (m, 1H, NCHCH2), 3.58 (s, 3H,
COOCH3), 4.16 (br, 1H, NH), 6.07 (t, J¼6.8 Hz, 1H,
HCvCPh2), 7.12–7.29 (m, 7H, Harom., NCHvC), 7.29–
Compound 25. Colorless crystals, mp 185 8C. TLC:
Rf¼0.22 (iso-hexane/Et2O¼40:60). [a]2D0¼þ136.9
þ
(c¼0.49, CH Cl ). IR (KBr): n¼2951 cm21, 1731, 1707,
7.45 (m, 4H, Harom.). MS (CI, CH5 ); m/z (%): 348 [Mþþ1]
˜
2
2
1674, 1622, 1243, 1186, 810, 764, 702. 1H NMR
(nitrobenzene-d5, 140 8C): d¼0.92 ppm (s, 3H, CH3), 1.09
(s, 3H, CH3), 1.43 (s, 3H, CH3), 1.81–1.87 (m, 2H,
NCHCH2CH2Cv), 1.87–2.04 (m, 4H, CH2CH2), 2.22–
2.36 (m, 3H, NCHvCCH2, CH2CH2), 2.41 (dd, J¼17.3/
5.8 Hz, 1H, NCHvCCH2), 2.48–2.59 (m, 2H, CH2CH2),
3.76 (s, 3H, COOCH3), 3.99 (d, J¼11.1 Hz, 1H, OCH2),
4.21 (d, J¼11.1 Hz, 1H, OCH2), 4.56–4.64 (m, 1H,
NCHCH2), 6.19 (t, J¼6.8 Hz, 1H, HCvCPh2), 7.18–7.37
(m, 8H, Harom.), 7.37–7.45 (m, 2H, Harom.), 8.07 (s, 1H,
(100), 316 (13), 237 (1), 138 (12).
6.1.12. Methyl (R)-6-(4,4-diphenylbut-3-enyl)-1,4,5,6-
tetrahydropyridine-3-carboxylate [(ent)-27]. Synthesis
as described for the preparation of 27 from 37 mg
(0.067 mmol) of 26 in 340 ml THF with 1.2 ml of freshly
prepared NaOMe (0.5 M in CH3OHabs.). Purification by CC
(CH2Cl2/ CH3OH¼95:5) afforded 22 mg (90%) of (ent)-27.
As product (ent)-27 appeared to be labile, it could not be
fully characterized. It was immediately transformed to
either the compounds (ent)-28 and (ent)-29 or (ent)-34.
þ
NCHvC). MS (CI, CH5 ); m/z (%): 542 [Mþþ1] (27), 510
(37), 346 (37), 271 (12), 195 (100), 167 (40), 139 (38).
C34H39NO5 (541.69): calcd C 75.39, H 7.26, N 2.59; found
C 75.14, H 7.26, N 2.47.
Compound (ent)-27. Colorless oil. 1H NMR as described for
27. MS (CI, CHþ5 ); m/z (%): 348 [Mþþ1] (100), 316 (12),
237 (21), 138 (23).
6.1.10. Methyl (R)-6-(4,4-diphenylbut-3-enyl)-1-
[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octyl-
carbonyl]-1,4,5,6-tetrahydropyridine-3-carboxylate
(26). Synthesis as described for the preparation of 25 using
137 ml (0.218 mmol, 1.2 equiv.) of nBuLi (1.6 M in
hexane), 137 ml of THF, 66 mg (0.218 mmol, 1.2 equiv.)
of ethyl benzhydrylphosphonate (24) in 296 ml THF, 71 mg
(0.182 mmol) of 23 in 865 ml THF. Purification by CC (iso-
hexane/Et2O¼40:60) afforded 80 mg (81%) of 26.
6.1.13. Methyl (3S,6S)-6-(4,4-diphenylbutyl)piperidine-
3-carboxylate (28) and methyl (3R,6S)-6-(4,4-diphenyl-
butyl)piperidine-3-carboxylate (29). The starting material
27 was prepared as described above from 430 mg
(0.794 mmol) of 25 in 4 ml THF and 18 ml of freshly
prepared NaOMe (0.5 M in CH3OHabs.). Following purifi-
cation by CC (CH2Cl2/CH3OH¼95:5) the solvent was
removed in vacuo and the residue was dissolved in 1.8 ml of
CF3CO2H. 380 ml (278 mg, 2.392 mmol, 3 equiv.) of
Et3SiH were added dropwise and the reaction mixture was
stirred for 3 h at 50 8C. The reaction was quenched with
saturated NaHCO3 solution. The reaction mixture was
extracted with CH2Cl2 and the combined organic layers
were dried (MgSO4) and concentrated in vacuo. Purification
by CC (Et2O/EtMe2N¼98:2) afforded 140 mg (50%) of a
mixture of 28 and 29.
Compound 26. Colorless crystals, mp 75 8C. TLC: Rf¼0.30
(iso-hexane/Et2O¼40:60). [a]2D0¼223.9 (c¼0.93, CH2Cl2).
IR (KBr): n¼2952 cm21, 1729, 1682, 1235, 1178, 763, 701.
˜
1H NMR (C2D2Cl4, 120 8C): d¼0.93 ppm (s, 3H, CH3),
0.95 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.50–1.70 (m, 3H,
CH2CH2, NCHCH2CH2Cv), 1.80–1.97 (m, 3H, CH2CH2,
NCHCH2CH2Cv), 2.04–2.22 (m, 3H, NCHvCCH2,
CH2CH2), 2.28–2.56 (m, 3H, CH2CH2, NCHvCCH2),
3.76 (s, 3H, COOCH3), 3.96 (d, J¼11.0 Hz, 1H, OCH2),
4.18 (dd, J¼11.1/1.2 Hz, 1H, OCH2), 4.71–4.79 (m, 1H,
NCHCH2), 6.12 (t, J¼7.5 Hz, 1H, HCvCPh2), 7.14–7.44
(m, 10H, Harom.), 7.77 (s, 1H, NCHvC). MS (CI, CHþ5 ); m/z
(%): 542 [Mþþ1] (100), 510 (23), 195 (20), 167 (14), 139
(14). C34H39NO5 (541.69): calcd C 75.39, H 7.26, N 2.59;
found C 75.37, H 7.56, N 2.44.
Compounds 28 and 29. Colorless oil. TLC: Rf¼0.28 (Et2O/
EtMe2N¼98:2). 1H NMR (CD2Cl2): d¼0.93–1.05 ppm (m,
1H, NCHCH2 (28), NCHCH2 (29)), 1.22–1.40 (m, 4H,
CH2CH2), 1.40–1.52 (m, 0.8£1H, NCHCH2 (28)), 1.53–
1.61 (m, 0.2£1H, NCHCH2 (29)), 1.65–1.75 (m, 1H,
NCH2CHCH2 (28), NCH2CHCH2 (29)), 1.96–2.15 (m, 3H,
NCH2CHCH2 (28), NCH2CHCH2 (29), CH2CHPh2 (28),
CH2CHPh2 (29)), 2.28–2.37 (m, 1.8H, NHCHax (28) one
large coupling J¼12.1 Hz was identifiable, CHCOO (28),
CHCOO (29)), 2.38–2.43 (m, one large coupling
J¼12.1 Hz was identifiable, 0.2H, NHCHax (29)), 2.60
(dd, J¼11.8/11.3 Hz, 0.8£1H, NCH2ax (28)), 2.71 (dd,
J¼12.8/3.5 Hz, 0.2£1H, NCH2ax (29)), 3.20 (dd, J¼11.8/
4.1 Hz, 0.8£1H, NCH2eq (28)), 3.31 (dd, J¼12.8/2.5 Hz,
6.1.11. Methyl (S)-6-(4,4-diphenylbut-3-enyl)-1,4,5,6-
tetrahydropyridine-3-carboxylate (27). A mixture of
600 ml of freshly prepared NaOMe (0.5 M in CH3OHabs
)
and 25 mg (0.046 mmol) of 25 in 230 ml THF was reacted at
120 8C for 18 h in a sealed tube. The reaction was quenched
with phosphate buffer (pH 7, c¼1.0 M). The reaction

C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
315
0.2£1H, NCH2eq (29)), 3.61 (s, 0.8£3H, COOCH3 (28)),
3.66 (s, 0.2£3H, COOCH3 (29)), 3.89 (t, J¼7.7 Hz,
0.2£1H, Ph2CH (29)), 3.90 (t, J¼7.7 Hz, 0.8£1H, Ph2CH
(28)), 7.11–7.20 (m, 2H, Harom. para), 7.21–7.35 (m, 8H,
Harom. ortho, meta); 28/29¼83/17. MS (CI, CH5þ); m/z (%):
352 [Mþþ1] (100), 320 (3), 274 (3), 142 (20). HRM (70 eV)
for C23H29NO2: calcd 351.2198; found 351.2195 (Mþ).
C23H29NO2 (355.22): calcd C 78.65, H 8.31, N 3.99; found
C 77.36, H 8.66, N 3.68.
CHPh2), 1.79–1.88 (m, 1H, NCH2CHCH2), 1.97–2.16 (m,
2H, CH2CHPh2), 2.35 (dddd, J¼11.9/11.6/4.3/4.0 Hz, 1H,
CHCOO), 2.63–2.86 (brkoal, 1H, NCH2CHCOO), 3.66 (s,
3H, COOCH3), 3.88 (t, J¼7.7 Hz, 1H, Ph2CH), 3.96–4.34
(brkoal, 2H, NCHCH2, NCH2CHCOO), 7.11–7.40 (m, 10H,
1
Harom.). H NMR (CD2Cl2, 278 8C): 0.93–1.09 ppm (m,
2H, CH2CH2CHPh2), 1.15 (s, 0.65£9H, tBu), 1.30 (s,
0.35£9H, tBu), 1.41–1.67 (m, 4H, CH2CH2CH2CHPh2,
NCHCH2), 1.71–1.82 (m, 2H, CH2CHPh2), 1.82–1.94 (m,
1H, NCH2CHCH2), 1.95–2.06 (m, 1H, NCH2CHCH2),
2.23–2.35 (m, 1H, CHCOO), 2.65 (dd, J¼13.7/12.5 Hz,
0.65£1H, NCH2CHCOOax), 2.73 (dd, J¼13.7/12.5 Hz,
0.35£1H, NCH2CHCOOax), 3.57 (s, 0.65£3H, COOCH3),
3.58 (s, 0.35£3H, COOCH3), 3.79 (t, J¼6.4 Hz, 1H,
Ph2CH), 3.95 (dd, J¼13.7/2.9 Hz, 0.35£1H, NCH2-
CHCOOeq), 3.98–4.06 (m, 0.65£1H, NCHCH2), 4.05–
4.17 (m, 1H, NCHCH2, NCH2CHCOOeq), 7.04–7.16 (m,
2H, Harom. ortho), 7.15–7.30 (m, 8H, Harom. meta, para); ratio
of rotamers: 65/35. MS (CI, CHþ5 ); m/z (%): 452 [Mþþ1]
(1), 396 (86), 352 (100), 142 (75). HRM (70 eV) for
C28H37NO4: calcd 451.2723; found 451.2721 (Mþ).
6.1.14. Methyl (3R,6R)-6-(4,4-diphenylbutyl)piperidine-
3-carboxylate [(ent)-28] and methyl (3S,6R)-6-(4,4-
diphenylbutyl)piperidine-3-carboxylate [(ent)-29]. Syn-
thesis as described for the preparation of 28 and 29 from
203 mg (0.345 mmol) of 26 in 1.9 ml of THF with 6.7 ml of
freshly prepared NaOMe (0.5 M in CH3OHabs.), 950 ml of
CF3CO2H and 193 ml (141 mg, 1.214 mmol, 3.5 equiv.) of
Et3SiH. Purification by CC (Et2O/EtMe2N¼98:2) afforded
66 mg (50%) of a mixture of (ent)-28 and (ent)-29.
Compounds (ent)-28and (ent)-29.1H NMR and IR as described
for 28 and 29, respectively. Colorless oil. HRM (70 eV) for
C23H29NO2: calcd 351.2198; found 351.2193 (Mþ).
6.1.16. Methyl (3R,6R)-1-tert-butyloxycarbonyl-6-(4,4-
diphenylbutyl)piperidine-3-carboxylate [(ent)-30] and
methyl (3S,6R)-1-tert-butyloxycarbonyl-6-(4,4-diphenyl-
butyl)piperidine-3-carboxylate (32). Synthesis as
described for 30 and 31 from 59 mg (0.167 mmol) of a
mixture of (ent)-28 and (ent)-29 [(ent)-29/(ent)-28¼79/21]
in 290 ml of THF with 23 ml (17 mg, 0.167 mmol,
1.0 equiv.) of NEt3, 164 mg (0.751 mmol, 4.4 equiv.) of
6.1.15. Methyl (3S,6S)-1-tert-butyloxycarbonyl-6-(4,4-
diphenylbutyl)piperidine-3-carboxylate (30) and methyl
(3R,6S)-1-tert-butyloxycarbonyl-6-(4,4-diphenylbutyl)-
piperidine-3-carboxylate (31). 44 ml (32 mg, 0.313 mmol,
1.0 equiv.) of NEt3, 307 mg (1.407 mmol, 4.4 equiv.) of di-
tert-butyldicarbonate and 39 mg (0.319 mmol, 1.0 equiv.)
of DMAP were added to a solution of 110 mg (0.313 mmol)
of a mixture of 28 and 29 (28/29¼83/17) in 1.7 ml of THF.
The reaction mixture was stirred for 3 days at room
temperature. Phosphate buffer (pH 7, c¼1.0 M) was added.
The reaction mixture was extracted with CH2Cl2. The
combined organic layers were dried (MgSO4) and concen-
trated in vacuo. Purification by CC (iso-hexane/Et2O/
EtMe2N¼80:20:2) afforded 81 mg (70%) of 30 and 17 mg
(10%) of 31.
di-tert-butyldicarbonate
and
21 mg
(0.319 mmol,
1.9 equiv.) of DMAP, reaction time: 2 days. Purification
by CC (iso-hexane/Et2O/EtMe2N¼80:20:2) afforded 43 mg
(57%) of (ent)-30 and 17 mg (10%) of (ent)-31.
Compound (ent)-30. Colorless Oil. 1H NMR and IR as
described for 30. [a]2D0¼237.88 (c¼0.68, CH2Cl2).
C28H37NO4 (451.61): calcd C 74.47, H 8.26, N 3.10;
found C 74.07, H 8.23, N 3.08.
Compound 30. Colorless oil. TLC: Rf¼0.14 (iso-hexane/
Et2O/dimethylethyl amine¼80:20:2). [a]2D0¼þ38.7
Compound (ent)-31. Colorless Oil. 1H NMR and IR as
described for 31. [a]D20¼þ22.8 (c¼0.365, CH2Cl2). HRM
(70 eV) for C28H37NO4: calcd 451.2723; found 451.2721
(Mþ).
(c¼1.16, CH Cl ). IR: n¼2932 cm21, 1736, 1688, 1418,
˜
2
2
1365, 1162, 741, 702. 1H NMR (CD2Cl2): d¼1.10–
1.25 ppm (m, 2H, CH2CH2CHPh2), 1.29–1.36 (m, 1H,
NCHCH2), 1.34 (s, 9H, tBu), 1.36–1.44 (m, 1H, NCHCH2),
1.64–1.84 (m, 3H, NCH2CHCH2, CH2CH2CH2CHPh2),
1.89–1.92 (m, 1H, NCH2CHCH2), 1.98–2.14 (m, 2H,
CH2CHPh2), 2.47–2.53 (m, 1H, CHCOO), 2.89 (dd,
J¼14.0/4.0 Hz, 1H, NCH2CHCOO), 3.66 (s, 3H,
COOCH3), 3.87 (t, J¼7.7 Hz, 1H, Ph2CH), 4.06–4.16 (m,
1H, NCHCH2), 4.32 (d, J¼14.0 Hz, 1H, NCH2CHCOO),
7.09–7.20 (m, 2H, Harom. ortho), 7.21–7.30 (m, 8H,
6.1.17. (3S,6S)-6-(4,4-Diphenylbutyl)piperidine-3-car-
boxylic acid hydrochloride (32). 34 mg (0.075 mmol) of
30 in 9 ml of 2 M HCl were refluxed for 3 h. After cooling to
room temperature the solvent was removed in vacuo and the
residue was dried over P2O5. Yield: 28 mg (100%).
Compound 32. Colorless crystals, mp 249 8C. [a]2D0¼þ7.6
(c¼0.38, DMSO). IR: n¼3423 cm21, 2940, 2804, 2501,
˜
þ
Harom. meta, para). MS (CI, CH5 ); m/z (%): 452 [Mþþ1] (2),
1724, 1200, 1180, 765, 699. 1H NMR (DMSO-d6):
d¼1.15–1.29 ppm (m, 2H, Ph2CHCH2CH2), 1.28–1.40
(m, 1H, NCHCH2), 1.42–1.55 (m, 2H, NCHCH2, Ph2-
CH(CH2)2CH2), 1.60–1.71 (m, 1H, Ph2CH(CH2)2CH2),
1.74–1.84 (m, 1H, NCH2CHCH2), 1.93–2.09 (m, 3H,
Ph2CHCH2, NCH2CHCH2), 2.59–2.69 (m, 1H, CHCOOH),
2.86 (dd, J¼13.7/12.0 Hz, 1H, NCH2axCHCOO), 2.90–3.00
396 (91), 352 (100), 142 (89). C28H37NO4 (451.61): calcd C
74.47, H 8.26, N 3.10; found C 74.66, H 8.52, N 3.09.
Compound 31. Colorless oil. TLC: Rf¼0.26 (iso-hexane/
Et2O/EtMe2N¼80:20:2). [a]2D0¼222.6 (c¼0.73, CH2Cl2).
IR: n¼2933 cm21, 1731, 1682, 1420, 1265, 1161, 740, 706.
˜
1H NMR (CD2Cl2): d¼1.09–1.24 ppm (m, 2H, CH2CH2-
CHPh2), 1.33 (s, 9H, tBu), 1.30–1.45 (m, 1H, NCHCH2),
1.51–1.79 (m, 4H, NCHCH2, NCH2CHCH2, CH2CH2CH2-
(m, 1H, NCHCH2), 3.30 (d, J¼13.7 Hz, 1H, NCH2eq
-
CHCOO), 3.92 (t, J¼7.0 Hz, 1H, Ph2CH), 7.02–7.19 (m,
2H, Harom.), 7.20–7.35 (m, 8H, Harom.), 8.62–9.03 (br, 2H,

316
C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
NHþ2 ), 12.54–12.89 (br, 1H, COOH). MS (70 eV); m/z (%):
337 [Mþ2HCl] (5), 319 (4), 260 (1) 167 (12), 128 (100).
C22H28NO2Cl·0.5H2O (382.93): calcd C 69.00, H 7.63, N
3.66; found C 68.87, H 7.57, N 3.54.
Compound 34. Colorless oil. TLC: Rf¼0.24 (iso-hexane/
Et2O¼80:20)-[a]2D0¼þ48.5 (c¼0.46 in CH2Cl2). IR (Film):
n¼2946 cm21, 1634, 1455, 1416, 1028, 739, 700. 1H NMR
˜
(C2D2Cl4, 120 8C): d¼1.51 ppm (s, 9H, tBu), 1.57–1.75 (m,
3H, NCHCH2, Ph2CCHCH2CH2), 1.83 (ddt, J¼13.5/5.8/
2.3 Hz, 1H, NCHCH2), 2.06–2.27 (m, 3H, NCHCCH2,
Ph2CCHCH2), 2.40 (dd, J¼18.4/4.9 Hz, 1H, NCHCCH2),
3.76 (s, 3H, COOCH3), 4.21–4.28 (m, 1H, NCHCH2),
6.11 (t, J¼7.6 Hz, 1H, HCvCPh2), 7.17–7 44 (m,
10H, Harom.), 8.01 (s, 1H, NCHvC). MS (CI, CH5þ); m/z
(%): 448 [Mþþ1] (54), 416 (9), 392 (100), 348 (98),
182 (29), 142 (34), 138 (24). C28H33NO4 (447.57):
calcd C 75.14, H 7.45, N 3.13; found C 74.64, H 7.95, N
2.66.
6.1.18. (3R,6S)-6-(4,4-Diphenylbutyl)piperidine-3-car-
boxylic acid hydrochloride (33). Synthesis as described
for the preparation of 32 from 14 mg (0.031 mmol) of 31 in
3.8 ml of 2 M HCl. Yield: 12 mg (99%).
Compound 33. Colorless crystals, mp 215 8C. [a]2D0¼20.5
(c¼0.38, DMSO). [a]D20¼20.5 (c¼0.19, DMSO). IR:
n¼3423 cm21, 2928, 2862, 1710, 1223, 1107, 762, 701.
˜
1H NMR (DMSO-d6): d¼1.18–1.26 ppm (m, 2H, Ph2-
CHCH2CH2), 1.28–1.37 (m, 1H, NCHCH2), 1.51–1.65 (m,
2H, Ph2CH(CH2)2CH2), 1.67–1.77 (m, 2H, NCHCH2,
NCH2CHCH2), 1.87–1.98 (m, 1H, NCH2CHCH2), 1.98–
2.11 (m, 2H, Ph2CHCH2), 2.77–2.84 (m, 1H, CHCOOH),
3.00–3.12 (m, 2H, NCHCH2, NCH2axCHCOO), 3.30 (d,
J¼13.7 Hz, 1H, NCH2eqCHCOO), 3.93 (t, J¼7.6 Hz, 1H,
Ph2CH), 7.11–7.22 (m, 2H, Harom.), 7.21–7.37 (m, 8H,
Harom.), 7.88–8.06 (br, 1H, NH2þ), 8.84–9.05 (br, 1H,
NHþ2 ), 12.78–12.98 (br, 1H, COOH). MS (70 eV); m/z (%):
337 [Mþ2HCl] (10), 167 (11), 128 (100). HRM (70 eV) for
C22H27NO2: calcd 337.2035; found 337.2030 (Mþ).
6.1.22. (R)-Methyl [1-tert-butyloxycarbonyl-6-(4,4-
diphenylbut-3-enyl)-1,4,5,6-tetrahydropyridine-3-car-
boxylate] [(ent)-34]. The starting material (ent)-27 was
prepared as described above from 118 mg (0.218 mmol) of
26 in 1.2 ml of THF, 4.2 ml of freshly prepared NaOMe
(0.5 M in CH3OHabs.). The synthesis of (ent)-34 was
performed in analogy to the preparation of 34 from 71 mg
of (ent)-27 in 0.4 ml of THF with 101 ml (25 mg,
0.245 mmol, 1.12 equiv.) of NEt3, 241 mg (1.105 mmol,
5.05 equiv.) of di-tert-butyldicarbonate and 31 mg
(0.254 mmol, 1.16 equiv.) of DMAP. Purification by CC
(iso-hexane/Et2O¼80:20) afforded 51 mg (52%) of (ent)-
34.
6.1.19. (3R,6R)-6-(4,4-Diphenylbutyl)piperidine-3-car-
boxylic acid hydrochloride [(ent)-32]. Synthesis as
described for the preparation of 32 from 27 mg
(0.060 mmol) of (ent)-30 in 7 ml of 2 M HCl. Yield:
22 mg (100%).
Compound (ent)-34. Colorless oil. 1H NMR and IR as
described for 34. [a]2D0¼247.4 (c¼1.35, CH2Cl2).
C28H33NO4 (447.57): calcd C 75.14, H 7.45, N 3.13;
found C 74.84, H 7.56, N 3.04.
Compound (ent)-32. Colorless crystals. 1H NMR and IR as
described for 32. [a]2D0¼27.4 (c¼0.19, DMSO). C22H28-
NO2Cl·0.5H2O (382.93): calcd C 69.00, H 7.63, N 3.66;
found C 69.21, H 7.63, N 3.66.
6.1.23. (3S,6S)-Methyl [1-tert-butyloxycarbonyl-6-(4,4-
diphenylbut-3-enyl)piperidine-3-carboxylate] (35) and
(3R,6S)-methyl [1-tert-butyloxycarbonyl-6-(4,4-di-
6.1.20. (3S,6R)-6-(4,4-Diphenylbutyl)piperidine-3-car-
boxylic acid hydrochloride [(ent)-33]. Synthesis as
described for the preparation of 33 from 6.6 mg
(0.015 mmol) of (ent)-31 in 1.8 ml of 2 M HCl. Yield:
5.5 mg (100%).
phenylbut-3-enyl)piperidine-3-carboxylate]
(36).
428 mg of magnesium powder were added to 185 mg
(0.141 mmol) of 34 in 1.64 ml of CH3OH. After 20 min in a
sonicator 5 ml of CH3OH were added, followed by the
addition of 4 ml of CH3OH after 1 h. Following stirring for
18 h phosphate buffer (pH 7, c¼1.0 M) was added and the
reaction mixture was extracted with CH2Cl2. The combined
organic layers were dried (MgSO4) and concentrated in
vacuo. Purification by CC (iso-hexane/Et2O¼70:30) and
separation by prep. HPLC (iso-hexane/Et2O¼70:30; 9 ml/
min) yielded 69 mg (37%) of 35 (tR¼42.14 min) and 51 mg
(28%) of 36 (tR¼26.20 min). Analytical HPLC (iso-hexane/
Et2O¼70:30; 1.0 ml/min); 36: tR¼10.41 min, 42.4%; 35:
tR¼18.36 min, 57.6%.
Compound (ent)-33. Colorless crystals. 1H NMR and IR as
describedfor33. [a]2D0¼þ0.7(c¼0.08, DMSO). HRM(70 eV)
for C22H27NO2: calcd 337.2035; found 337.2031 (Mþ).
6.1.21. (S)-Methyl [1-tert-butyloxycarbonyl-6-(4,4-
diphenylbut-3-enyl)-1,4,5,6-tetrahydropyridine-3-car-
boxylate] (34). The starting material 27 was prepared as
described above from 352 mg (0.650 mmol) of 25 in 3.2 ml
of THF with 11.5 ml of freshly prepared NaOMe (0.5 M in
CH3OHabs.). After purification by CC (CH2Cl2/
CH3OH¼95:5) the solvent was removed in vacuo and the
residue was dissolved in 1.24 ml of THF. 101 ml (74 mg,
0.728 mmol, 1.12 equiv.) of NEt3, 716 mg (3.282 mmol,
5.05 equiv.) of di-tert-butyldicarbonate and 92 mg
(0.755 mmol, 1.16 equiv.) of DMAP were added. The
reaction mixture was stirred for 3 days. Phosphate buffer
(pH 7, c¼1.0 M) was added. The reaction mixture was
extracted with CH2Cl2. The combined organic layers were
dried (MgSO4) and concentrated in vacuo. Purification by
CC (iso-hexane/Et2O¼80:20) afforded 217 mg (75%) of 34.
Compound 35. Colorless oil. TLC: Rf¼0.21 (iso-hexane/
Et2O¼70:380)-[a]D20¼þ45.2 (c¼0.5, CH2Cl2). IR:
n¼2928 cm21, 1738, 1693, 1418, 1364, 1364, 1168, 764,
˜
1
701. H NMR (CD2Cl2): d¼1.41 ppm (s, 9H, tBu), 1.36–
1.45 (m, 2H, NCHCH2), 1.49–1.60 (m, 1H, CH2CH2-
CHCPh2), 1.67–1.90 (m, 2H, CH2CH2CHCPh2, NCH2-
CHCH2), 1.95–2.16 (m, 3H, NCH2CHCH2, CH2CHCPh2),
2.52–2.57 (m, 1H, CHCOO), 2.93 (dd, J¼14.0/4.1 Hz, 1H,
NCH2CHCOO), 3.66 (s, 3H, COOCH3), 4.15–4.24 (m, 1H,
NCHCH2), 4.41 (d, J¼14.0 Hz, 1H, NCH2CHCOO), 6.10
(t, J¼7.6 Hz, 1H, Ph2CvCH), 7.14–7.44 (m, 10H, Harom.).

C. E. Hoesl et al. / Tetrahedron 60 (2004) 307–318
317
þ
MS (CI, CH5 ); m/z (%): 450 [Mþþ1] (2), 350 (100), 142
6.1.26. (3R,6R)-6-(4,4-Diphenylbutyl)piperidine-3-car-
boxylic acid hydrochloride [(ent)-37]. Synthesis as
described for the preparation of 37 from 10 mg
(0.022 mmol) of (ent)-35 in 2.8 ml of 2 M HCl. Yield:
8 mg (100%).
(49). C28H35NO4 (449.59): calcd C 74.80, H 7.85, N 3.12;
found C 74.80, H 8.00, N 2.90.
Compound 36. Colorless oil. TLC: Rf¼0.31 (iso-hexane/
Et2O¼70:30). [a]D20¼212.8 (c¼0.5, CH2Cl2). IR:
n¼2924 cm21, 1734, 1691, 1416, 1164, 765, 701. 1H
Compound (ent)-37. Colorless crystals. H NMR and IR as
1
˜
NMR (CD2Cl2): d¼1.32–1.45 ppm (brkoal, 9H, tBu), 1.45–
1.75 (m, 4H, NCHCH2, CH2CH2CHCPh2), 1.75–1.93 (m,
2H, NCH2CHCH2), 1.96–2.15 (m, 2H, CH2CHCPh2),
2.30–2.48 (m, 1H, CHCOO), 2.66–2.86 (brkoal, 1H,
described for 37. [a]2D0¼214.38 (c¼0.37, DMSO). HRM
(70 eV) for C28H35NO4: calcd 335.1885; found 335.1884
(Mþ).
NCH2CHCOO), 3.68 (s, 3H, COOCH3), 3.97–4.35 (brkoal
,
6.1.27. (3R,6S)-6-(4,4-Diphenylbuty-3-enyl)piperidine-3-
carboxylic acid hydrochloride (38). Synthesis as described
for the preparation of 32 from 32 mg (0.071 mmol) of 36 in
8.7 ml of 2 M HCl. Yield: 28 mg (97%).
2H, NCHCH2, NCH2CHCOO), 6.09 ppm (t, J¼8.1 Hz, 1H,
Ph2CvCH), 7.11–7.40 (m, 10H, Harom.). MS (CI, CHþ5 );
m/z (%): 450 [Mþþ1] (2), 394 (15), 350 (100), 142 (43).
C28H35NO4 (449.59): calcd C 74.80, H 7.85, N 3.12; found
C 74.67, H 7.91, N 3.01.
Compound 38. Colorless crystals, mp 150 8C (decomp.).
[a]20¼þ12.78 (c¼0.48, DMSO). IR: n¼3425 cm21, 2926,
˜
D
6.1.24. (3R,6R)-Methyl [1-tert-butyloxycarbonyl-6-(4,4-
diphenylbut-3-enyl)piperidine-3-carboxylate] [(ent)-35]
and (3S,6R)-methyl [1-tert-butyloxycarbonyl-6-(4,4-
diphenylbut-3-enyl)piperidine-3-carboxylate] [(ent)-36].
Synthesis as described for 35 and 36 from 65 mg
(0.145 mmol) of (ent)-34 with 150 mg magnesium powder
and 0.6 ml of CH3OH. Purification by CC (iso-hexane/
Et2O¼70:30) and separation by prep. HPLC (iso-hexane/
Et2O¼70:30; 9 ml/min) yielded 10 mg (16%) of (ent)-35
(tR¼42.14 min) and 17 mg (26%) of (ent)-36 (tR¼
26.20 min). Analytical HPLC (iso-hexane/Et2O¼70:30;
1.0 ml/min); (ent)-36: tR¼10.41 min, 42.6%; (ent)-35:
tR¼18.36 min, 57.4%.
2360, 1733, 1445, 767, 698. 1H NMR (DMSO-d6):
d¼1.21–1.35 ppm (m, 1H, NCHCH2), 1.60–1.73 (m, 3H,
NCHCH2, NCH2CHCH2, Ph2CCHCH2CH2), 1.73–1.83 (m,
1H, Ph2CCHCH2CH2), 1.87–1.97 (m, 1H, NCH2CHCH2),
2.04–2.17 (m, 2H, Ph2CCHCH2), 2.78–2.85 (m, 1H,
CHCOOH), 3.03–3.14 (m, 2H, NCHCH2, NCH2-
CHCOOax), 3.29 (dd, J¼13.2, 4.8 Hz, 1H, NCH2-
CHCOOeq), 6.11 (t, J¼7.7 Hz, 1H, Ph2CCH), 7.06–7.57
(m, 10H, Harom.), 7.88–8.31 (br, 1H, NH2þ), 8.88–9.34 (þbr,
1H, NHþ2 ), 12.60–13.15 (br, 1H, COOH). MS (CI, CH5 );
m/z (%): 336 [Mþþ1-HCl] (72), 167 (11), 128 (100).
C22H28NO3Cl (389.92): calcd. C 67.76, H 6.97, N 3.59;
found C 67.70, H 6.93, N 3.77.
Compound (ent)-35. Colorless oil. 1H NMR and IR as
described for 35. [a]D20¼245.68 (c¼0.82, CH2Cl2). HRM
(70 eV) for C28H35NO4: calcd 449.2566; found 449.2614
(Mþ).
6.1.28. (3S,6R)-6-(4,4-Diphenylbutyl)piperidine-3-car-
boxylic acid hydrochloride [(ent)-38]. Synthesis as
described for the preparation of 32 from 13 mg
(0.028 mmol) of (ent)-36 in 4.2 ml of 2 M HCl. Yield:
10 mg (99%).
Compound (ent)-36. Colorless oil. 1H NMR and IR as
described for 36. [a]2D0¼þ10.2 (c¼0.50, CH2Cl2). HRM
(70 eV) for C28H35NO4: calcd 429.2566; found 449.2560
(Mþ).
1
Compound (ent)-38. Colorless crystals. H NMR and IR as
described for 38. [a]2D0¼211.28 (c¼0.37, DMSO). HRM
(70 eV) for C28H35NO4: calcd 335.1885; found 335.1871
(Mþ).
6.1.25. (3S,6S)-6-(4,4-Diphenylbutyl)piperidine-3-car-
boxylic acid hydrochloride (37). Synthesis as described
for the preparation of 32 from 48 mg (0.107 mmol) of 35 in
13 ml of 2 M HCl. Yield: 38 mg (92%).
Acknowledgements
Financial support of this work by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie and the
BMBF is gratefully acknowledged.
Compound 37. Colorless crystals, mp 234–236 8C
,
(decomp.). [a]20¼þ13.6 (c¼0.53, DMSO). n¼3445 cm21
˜
D
1
2930, 2730, 2361, 1734, 1162, 766, 703, 696. H NMR
(DMSO-d6): d¼1.26–1.40 ppm (m, one large coupling
J¼12.9 Hz was identifiable, 1H, NCHCH2), 1.40–1.55 (m,
1H, NCH2CHCH2), 1.55–1.67 (m, 1H, Ph2CCHCH2CH2),
1.67–1.77 (m, 1H, NCHCH2), 1.77–1.87 (m, 1H, Ph2-
CCHCH2CH2), 1.93–2.03 (m, 1H, NCH2CHCH2), 2.09–
2.15 (m, 2H, Ph2CCHCH2), 2.62–2.72 (m, 1H, CHCOOH),
2.90 (dd, J¼13.0/11.6 Hz, 1H, NCH2CHCOOax), 2.95–3.04
(m, 1H, NCHCH2), 3.39–3.44 (m, 1H, NCH2CHCOOeq),
6.10 (t, J¼7.0 Hz, 1H, Ph2CCH), 7.07–7.50 (m, 10H,
Harom.), 8.76–9.08 (brþ, 2H, NH2þ), 12.61–12.91 (br, 1H,
COOH). MS (CI, CH5 ); m/z (%): 336 [Mþþ1-HCl] (37).
C22H28NO3Cl (389.92): calcd C 67.77, H 7.24, N 3.59;
found C 67.97, H 7.02, N 3.59.
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