Stereoselective transformation of pyrazinones into substituted analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol

Article abstract of DOI:10.1016/S0040-4020(03)00741-5

Various analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol have been prepared via Diels-Alder reaction of substituted pyrazinones with ethene followed by acid methanolysis of the bridged lactam adducts. Further reduct

Full text of DOI:10.1016/S0040-4020(03)00741-5

Tetrahedron 59 (2003) 5047–5054
Stereoselective transformation of pyrazinones into substituted
analogues of cis-5-amino-6-oxo-2-piperidinemethanol and
cis-5-amino-2-piperidinemethanol
Joeri Rogiers, Wim M. De Borggraeve, Suzanne M. Toppet, Frans Compernolle
*
and Georges J. Hoornaert
Department of Organic Chemistry, Laboratorium voor Organische Synthese, K.U.Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 18 February 2003; accepted 7 May 2003
Abstract—Various analogues of cis-5-amino-6-oxo-2-piperidinemethanol and cis-5-amino-2-piperidinemethanol have been prepared via
Diels–Alder reaction of substituted pyrazinones with ethene followed by acid methanolysis of the bridged lactam adducts. Further reduction
of the resulting methyl 2-piperidinecarboxylate ester compounds led to the corresponding 2-piperidinemethanol products that were converted
into potential SP antagonists. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Substance P, an undecapeptide isolated from animal tissue
by von Euler and Gaddum in the early thirties,1 displays a
broad range of biological effects. During the past few
decades, several peptide and non-peptide antagonists of
Substance P have been developed. Researchers at Merck
have claimed Substance P antagonistic activity for the
b-hydroxypiperidine derivative 1 (Fig. 1).2 In a previous
communication we reported on the synthesis of 2,(2,)5,5-tri-
and tetrasubstituted piperidines 2 containing the same
bioactive moiety as 1 plus an additional OH and alkyl/aryl
substituents in position 5.3 In an ongoing effort to expand
the substitution pattern of model 1, we envisaged the
synthesis of compounds of type 3 and 4 having an amide and
aryl/alkyl (or H) substituents at position 5.
Figure 1. Proposed target compounds and retrosynthetic analysis.
Here we present a short, versatile and stereoselective route
towards these substituted piperidin(on)es, according to the
retrosynthetic analysis shown in Figure 1. The two key steps
relationship between the acetamide and benzyl ether
moieties is imposed by the cycoaddition step with ethene.
in our approach involve (i) Diels–Alder addition of ethene
on a 5-chloro-2(1H)-pyrazinone azadiene system followed
by hydrolysis to form the bridged bislactam product and (ii)
2. Results and discussion
selective acid-catalysed methanolysis of the secondary
amide group to produce the corresponding methyl 2-piperi-
dinecarboxylate esters.4 Further reduction and O-alkylation
steps provide access to the target compounds. A cis-
2.1. Functionalisation of pyrazinones
1-Benzyl-3,5-dichloro-6-phenyl-2(1H)-pyrazinone 5a
served as a starting material for both piperidinones 3 and
piperidines 4 (Scheme 1). It can be prepared on a multigram
scale (67%) by reaction of 2-(benzylamino)-phenylaceto-
nitrile 6 with oxalyl chloride and triethylammonium
chloride in chlorobenzene.5 The 3-functionalised
Keywords: substituted piperidines; substituted piperidinones; Diels–Alder
reaction; Substance P antagonists.
*
Corresponding author. Tel.: þ32-16-32-74-09; fax: þ32-16-32-79-90;
e-mail: georges.hoornaert@chem.kuleuven.ac.be
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00741-5

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Scheme 1. Reagents and conditions: (a) oxalyl chloride, Et3NHþCl2
(b) Ph4Sn, Pd(PPh3)4, toluene reflux (c) Me4Sn, Pd(PPh3)4, toluene reflux
(d) HCOONa, Pd(PPh3)4, DMF, 1108C.
compounds 5b,c and 5-H-compound 5d were prepared
using Pd0-catalysed Stille and hydrogen transfer reactions.6
2.2. Diels–Alder reaction with ethene
Pyrazinones 5b–d were converted into the corresponding
ethylene bridged intermediates 7b–d by heating at 1358C in
toluene under ethene pressure (35 atm) (Scheme 2). After
opening the steel bomb, compounds 7c and 7d underwent
hydrolysis by air moisture to form bislactams 8c and 8d.
Hydrolysis of the 1,4-diphenyl substituted adduct 7b was
found to be slow, probably due to steric factors, and efficient
conversion into bislactam product 8b required overnight
reaction in EtOAc containing a drop of aqueous HCl
solution. Compounds 8b–d were purified by column
chromatography and crystallisation.
Figure 2. NOE effects used in the assignment of protons H7 and H8.
2.3. Methanolysis of the adducts
Bislactam products 8b–d were cleaved selectively by acid-
catalysed methanolysis to produce only the primary amino
esters 9b–d (Scheme 3). In view of the near-symmetric
character of the 2,5-diphenyl bislactam structure 8b (except
for the presence of the CONBn vs. CONH amide group), the
selectivity for cleavage of the secondary amide clearly must
be ascribed to the higher steric requirements for attack of
methanol on the protonated tertiary amide group. The
conversion of 8 into 9b–d was effected by heating at 508C
with HCl in methanol until all starting material had
disappeared. However, to prevent back conversion of
amino esters 9 into starting bislactams as was observed
upon workup by alkaline extraction, the free amines were
subjected to in situ acetylation. Thus, following evaporation
of the HCl–methanol reagent, an excess of acetic anhydride
was added to the cooled (08C) oily residue followed by
addition of Et3N. Ammonium salts were removed by
filtration, the filtrate was evaporated, and the residue
purified by column chromatography to afford the N–Ac
products 10b–d in good yields.
The 1H NMR spectra of compounds 8b–d exhibit a
complex coupling pattern in the region 2–4 ppm, due to
two pairs of diastereotopic protons on the ethylene bridge.
In the spectrum of compound 8d, this pattern is complicated
further by additional coupling with the bridgehead proton.
For compound 8c complete assignment of the ethylene
1
bridge protons and carbon atoms was based on H coupled
13C NMR, XHCORR and NOESY spectra. In the C–H
coupled NMR-spectrum, the triplet pattern of C8 is
3
broadened due to J couplings with the methyl protons.
Protons H7–H70 and H8–H80 are differentiated by a NOE
observed between the ortho protons of the benzyl group and
both H7 and H8 (Fig. 2).
Scheme 2. Reagents and conditions: (a) ethene 35 atm, toluene, 1358C,
steel bomb, (b) air moisture or EtOAc containing a drop of HCl.
Scheme 3. Reagents and conditions: (a) MeOH–HCl, (b) Ac2O, Et3N.

J. Rogiers et al. / Tetrahedron 59 (2003) 5047–5054
5049
Scheme 4. Reagents and conditions: (a) 1.1 equiv. LiBH4, 0.1 equiv.
LiEt3BH, THF, reflux, (b) 1.5 equiv. LiBH4, 0.15 equiv. LiEt3BH, THF,
reflux.
Figure 3. NMR conformational analysis of compounds 10b–d.
increasing the recording temperature. This assignment was
confirmed by selective decoupling of the CH proton at
4.64 ppm, which converted the OH doublet into a singlet;
concurrently the broad txd signals observed at 1.47 and
1.55 ppm were converted into sharp signals. The broadening
of signals in the coupled spectrum is attributed to
unresolved 4J couplings of H7 with semi-axial protons
H5a and H6a (see W-patterns in Fig. 4).
The NMR spectra of 10b–d in each case reveal a preferred
half-chair conformation (Fig. 3). For 5-H compound 10d
this half-chair corresponds to an equatorial orientation of
two large groups, i.e. 2-Ph and 5-NHAc, and an axial
disposition of H5. In the 1H NMR spectrum of 10d, the axial
position of H5 is demonstrated by a dxt signal at 4.52 ppm
with one large (<12 Hz) and two smaller (<5 Hz) 3J
coupling constants. For compounds 10b–c lacking a proton
at the 5-position, conformational assignments are based on
the sum of the 3J(CPh-ipso, H) couplings measured in the 1H
coupled 13C NMR spectra. These data reveal a similar half-
chair form for 2,5-diphenyl compound 10b as for 10d while
the 2-Ph, 5-Me compound 10c exists as the opposite half-
A plausible mechanism accounting for the formation of 12
is presented in Scheme 5: after partial reduction of the ester
to form an aldehyde and abstraction of the acidic CONH
amide proton, equilibration may occur between the N- and
chair conformer. For 10b an equatorial disposition of 2-Ph is
apparent from the small value found for 3J (15 Hz) of the
2-Ph-ipso carbon atom, and an axial one for the 5-Ph group
P
P3
from the large value measured for
J5-Ph-ipso (25 Hz). For
P
10c the 3J of the Ph-ipso carbon atom is about 25 Hz: this
value is consistent with a pseudo-axial position of the
3
phenyl group characterised by a large J trans (ca. 7 Hz)
with H3ax. The methyl group of 10c is in a pseudo-
P
equatorial position ( 3J(CMe, H)<9.5 Hz). Clearly, in these
lactam half-chair structures a planar axial 5-phenyl group is
better tolerated than an axial 5-methyl group, possibly due
to alleviation of 1,3-diaxial repulsions.
Figure 4. Coupling constants observed for structure 12.
2.4. Reduction of the aminopiperidinecarboxylates
In a next step piperidinecarboxylate esters 10 must be
converted into primary alcohols 11. For 10b and 10c
selective reduction of the ester group was accomplished by
reaction with LiBH4 and a catalytic amount of lithium
triethylborohydride;7 this procedure furnished alcohols
11b,c in 62 and 53% yield (Scheme 4). By contrast, from
the analogous reaction of 10d the corresponding alcohol
11d was isolated only as a minor constituent (24%) besides
the major product (55%), to which the bridged secondary
alcohol structure 12 was assigned. The 1H NMR spectrum of
12 reveals two coupled protons absorbing at 4.64 and
5.76 ppm. The latter signal was attributed to an OH group
bound to CH since it was shifted to higher field when
Scheme 5. Mechanism proposed for the formation of compound 12.

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J. Rogiers et al. / Tetrahedron 59 (2003) 5047–5054
apparatus and an Electrothermal IA 9000 digital melting
point apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin–Elmer 1600 Fourier transform
spectrometer. Mass spectra were run using a Hewlett
Packard MS-Engine 5989A apparatus for EI and CI spectra,
and a Kratos MS50TC instrument for exact mass measure-
ments performed in the EI mode at a resolution of 10,000.
For the NMR spectra (d, ppm) a Bruker AMX 400 and a
Bruker Avance 300 spectrometer were used. Coupling
constants are rounded to the nearest 0.5 Hz. Analytical and
preparative thin layer chromatography was carried out using
Merck silica gel 60 PF-224; for column chromatography
70–230 mesh silica gel 60 (E.M. Merck) was used as the
stationary phase. HPLC separations were performed using a
HIBAR column [Merck, cat. 151435].
Scheme 6. Reagents and conditions: (a) 1.1 equiv. NaH, DMF, bis-3,5-
(trifluoromethyl)benzylbromide, 08C!rt.
4.2. Synthesis
C-based anions 14 and 15. Cyclisation probably proceeds
via internal attack of the C-anion on aldehyde conformer
15–A to give product 12.
For the synthesis of compound 5a we refer to Ref. 5.
4.3. General procedure for the Stille reaction
When compounds 10b,c were treated with 1.5 instead of
1.1 equiv. of LiBH4, further reduction of the lactam
carbonyl group also occurred, affording piperidines 13b,c
in ca. 50% yield besides some remaining piperidinones
11b,c and other unidentified byproducts (Scheme 4).
Addition of more reducing agent did not improve the
yield of piperidines 13 but led to a complex reaction mixture
that was not analysed further.
To a solution of 13.4 g (0.04 mol) of pyrazinone 5a in
120 mL of toluene is added 0.048 mol of tetraphenyltin or
tetramethyltin and 0.4 mmol of Pd(PPh3)4. The solution is
stirred under a nitrogen atmosphere for 0.5–5 days at 1208C
(temperature oil bath) until all starting material has
disappeared (TLC monitoring). After evaporation of the
solvent, 60 mL of ethyl acetate and an excess of KF is added
to the residue. The suspension is stirred at room temperature
for 4 h. Following removal of the precipitates by filtration,
the solution is evaporated. The crude product is purified by
column chromatography (silica gel, EtOAc–CH2Cl2 95–5)
and subsequently crystallised from EtOH.
2.5. Conversion of alcohols into target products
To convert 11b–d and 13b,c into functionalised analogues
of compound 1, the alcohol group must be transformed into
a bis(trifluoromethyl)benzyl ether. This was accomplished
in 50–65% yield by reacting 3b–d and 4b,c with NaH and
bis(trifluoromethyl)benzyl bromide in DMF (Scheme 6).
4.3.1. 1-Benzyl-5-chloro-3,6-diphenyl-2(1H)-pyrazinone
(5b). Yield: 83%; white crystals, mp: 1848C (EtOH); IR
1
(KBr, cm21): 1545 (CN), 1650 (CO); H NMR (400 MHz,
The target compounds were characterised by prominent
molecular ions (MHþ) in the CI-mass spectra, which also
revealed fragment ions due to loss of HF or elimination of
the side chain. In the 1H NMR spectra, the methylene
protons of the two benzyl groups show up as AB-patterns.
CDCl3, ppm): 7.48–6.89 (m, 15H, PhH), 5.15 (s, 2H,
PhCH2); 13C NMR (100 MHz, CDCl3, ppm): 155.0 (C2),
150.9 (C3), 137.4 (C6), 135.5–127.3 (PhC), 126.7 (C5),
50.2 (CH2Ph); EIMS [m/z (%)]: 372 (Mþ, 16), 91 (PhCH2þ,
100); HRMS: calcd for C23H17ClN2O: 372.1029, found
372.1029.
Spectral data for compound 5c can be found in Ref. 8.
3. Conclusion
4.3.2. 1-Benzyl-5-chloro-6-phenyl-2(1H)-pyrazinone
(5d). To a solution of 660 mg (2 mmol) of pyrazinone 5a
in 20 mL of DMF is added 204 mg (3 mmol) of sodium
formate and 115 mg of Pd(PPh3)4. The solution is stirred at
1108C under nitrogen atmosphere for 4 h. Following
evaporation of the solvent, the residue is treated with
50 mL of water and extracted with 3£50 mL of CH2Cl2. The
extract is evaporated and the residue purified by
column chromatography using a solvent gradient (silica
gel, CH2Cl2!CH2Cl2–EtOAc (80–20)).
Substituted analogues of cis-5-amino-6-oxo-2-piperidine-
methanol and cis-5-amino-2-piperidinemethanol are pre-
pared via intermolecular Diels–Alder reaction of
functionalised 2(1H)-pyrazinones with ethene followed by
hydrolysis of the imidoyl chloride adducts. Subsequent
acid-catalysed methanolysis of the resulting bridged
bislactam products followed by selective reduction and
alkylation steps provides target products 3b–d and 4b,c as
potential SP antagonists.
Yield: 92%; white crystals, mp: 1058C (EtOH); IR (KBr,
cm21): 1552 (CN), 1654 (CO); 1H NMR (400 MHz, CDCl3,
ppm): 8.12 (s, 1H, H3), 7.48–6.80 (m, 10H, PhH), 5.00 (s,
2H, PhCH2); 13C NMR (100 MHz, CDCl3, ppm): 155.8
(C2), 147.0 (C3), 138.6 (C6), 135.2–127.3 (PhC), 127.2
4. Experimental
4.1. Analytical instruments
Melting points were taken using a Reichert-Jung Thermovar

J. Rogiers et al. / Tetrahedron 59 (2003) 5047–5054
5051
(C5), 49.5 (CH2Ph); EIMS [m/z (%)]: 296 (Mþ, 61), 261
(Mþ2Cl, 10), 91 (PhCHþ2 , 100); HRMS: calcd for
C17H13ClN2O: 296.0716, found 296.0717.
CDCl3, ppm): 171.8 (CO), 171.6 (CO), 137.4–127.2 (PhC),
68.1 (C1), 54.4 (C4), 45.6 (CH2Ph), 28.2 (CH2), 25.8 (CH2);
EIMS [m/z (%)]: 306 (Mþ, 22), 91 (PhCHþ2 , 100); HRMS:
calcd for C19H18N2O2: 306.1368, found 306.1369.
4.4. General procedure for the synthesis of cycloadducts
8b–d
4.5. General procedure for methanolysis of 8b–d and
subsequent acetylation to form N–Ac compounds 10b–d
Pyrazinone 5b–d (1 mmol) is dissolved in 30 mL of toluene
and the solution is transferred to a steel bomb. The mixture
is heated at 1358C under ethene pressure (35 atm) for 5–10
days. After cooling and removal of ethene, the solvent is
evaporated under reduced pressure. The intermediate
adducts of 5c and 5d spontaneously hydrolyse at the air to
produce bislactams 8c and 8d, which are purified by column
chromatography (silica gel, CH2Cl2–EtOAc (95–5)). The
bicyclic imidoyl chloride 7b is treated with 50 mL of
moisturised EtOAc containing a drop of HCl solution for
one night. Following addition of 10 mL of water, the
solution is neutralised with K2CO3. The organic phase is
separated, dried over MgSO4, and evaporated under reduced
pressure. The crude product is further purified by column
chromatography (silica gel, CH2Cl2).
A solution of 1 mmol of adduct 8b–d in 15 mL of MeOH is
cooled to 08C. This solution is saturated with dry HCl gas
for 5 min. Alternatively, after cooling of the methanol
solution, 1 mL of SOCl2 is slowly added (CAUTION
vigorous reaction). After reaction at 508C overnight, the
solution is evaporated under reduced pressure and
the residue is dissolved in 8 mL of acetic anhydride. The
mixture is cooled in an ice bath and Et3N is added.
Formation of triethyl ammonium salts is observed. Follow-
ing removal of the ammonium salts by filtration, the solution
is evaporated and the residue is purified by column
chromatography (silicagel, EtOAc).
4.5.1. Methyl (2Sp,5Sp)-5-(acetylamino)-1-benzyl-6-oxo-
2,5-diphenyl-2-piperidinecarboxylate (10b). Yield: 94%;
white crystals, mp: 1578C (CH2Cl2/hexane); IR (KBr,
cm21): 1640 (CO), 1735 (CO); 1H NMR (400 MHz,
CDCl3, ppm): 7.50–6.82 (m, 14H, PhH and NH), 6.69 (d,
2H, BnHortho), 5.20 (d, 1H, J¼14.0 Hz, PhCH2), 3.95 (s,
3H, OCH3), 3.89 (d, 1H, J¼14.0 Hz, PhCH2), 3.05 (dt (ddd),
1H, J¼14, 1.4 Hz, H3eq), 2.76 (td (ddd), 1H, J¼14.0,
1.4 Hz, H3ax), 2.53 (dt (ddd), 1H, J¼14.0, 1.4 Hz, H4eq),
2.29 (td (ddd), 1H, J¼14.0, 1.4 Hz, H4ax), 1.97 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3, ppm): 172.6 (CO),
172.3 (CO), 169.8 (CO), 141.7 and 138.8 and 141.7 (PhC-
ipso), 126.6–128.8 (PhC), 74.6 (C2), 63.0 (C5), 53.0
(OCH3), 51.4 (CH2Ph), 33.1 and 30.0 (C3 and C4), 24.2
(CH3); EIMS [m/z (%)]: 456 (Mþ, 4), 397 (Mþ2NH2-
COCH3, 30), 351 (Mþ2NCH2Ph, 85), 91 (PhCHþ2 , 100);
HRMS: calcd for C28H28N2O4: 456.2049, found 456.2044.
4.4.1. (1Sp,4Sp)-2-Benzyl-1,4-diphenyl-2,5-diazabicyclo-
[2.2.2]octane-3,6-dione (8b). Yield: 92%; white crystals,
mp: 2188C (EtOH); IR (KBr, cm21): 1696 (CO), 1710 (CO);
1H NMR (400 MHz, CDCl3, ppm): 7.56–6.60 (m, 14H,
PhH and NH), 6.65 (d, 2H, BnHortho), 4.92 (d, 1H,
J¼15 Hz, PhCH2), 3.97 (d, 1H, J¼15 Hz, PhCH2), 2.32
(ddd, 1H, J¼14.0, 10.0, 5.0 Hz, H7), 2.22 (ddd, 1H, J¼14.0,
10.00, 5.0 Hz, H70), 2.14 (ddd, 1H, J¼14.5, 10.0, 5.0 Hz,
H8 ), 1.98 (ddd, 1H, J¼14.5, 10.0, 5.0 Hz, H8); 13C NMR
(100 MHz, CDCl3, ppm): 172.3 (CO), 171.3 (CO), 137.5–
127.3 (PhC), 68.0 (C1), 63.3 (C4), 46.4 (CH2Ph), 29.3
(CH2), 29.8 (CH2); EIMS [m/z (%)]: 382 (Mþ, 33), 249
(Mþ2CONCH2Ph, 97), 221 (Mþ2CONCH2Ph–CO, 100),
91 (PhCHþ2 , 93); HRMS: calcd for C25H22N2O2: 382.1682,
found 382.1686.
4.4.2. (1Sp,4Rp)-2-Benzyl-4-methyl-1-phenyl-2,5-diaza-
bicyclo[2.2.2]octane-3,6-dione (8c). Yield: 86%; white
crystals, mp: 2128C (CH2Cl2/hexane); IR (KBr, cm21):
1706 (CO), 1715 (CO); 1H NMR (400 MHz, CDCl3, ppm):
7.20–7.48 (m, 9H, PhH and NH), 6.57 (d, 2H, BnHortho),
4.82 (d, 1H, J¼16 Hz, PhCH2), 3.93 (d, 1H, J¼16 Hz,
PhCH2), 2.27 (ddd, 1H, J¼12.5, 10.5, 4.5 Hz, H7), 2.11
(ddd, 1H, J¼12.5, 10.5,0 4.0 Hz, H70), 2.00 (ddd, 1H,
J¼13.0, 10.5, 4.5 Hz, H8 ), 1.90 (ddd, 1H, J¼13.0, 10.5,
4.0 Hz, H8), 1.55 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3, ppm): 173.0 (CO), 171.5 (CO), 137.6–127.2 (PhC),
68.1 (C1), 57.2 (C4), 46.0 (CH2Ph), 32.9 (CH2), 29.2 (CH2,
18.7 (CH3); EIMS [m/z (%)]: 320 (Mþ, 54), 158 (Mþ2
CONCH2Ph–CO, 100), 91 (PhCHþ2 , 92); HRMS: calcd for
C20H20N2O2: 320.1525, found 320.1527.
4.5.2. Methyl (2Sp,5Rp)-5-(acetylamino)-1-benzyl-5-
methyl-6-oxo-2-phenyl-2-piperidinecarboxylate (10c).
Yield: 93%; white crystals, mp: 1098C (CH2Cl2/hexane);
IR (KBr, cm21): 1663 (CO), 1736 (CO); 1H NMR
(400 MHz, CDCl3, ppm): 7.15–6.71 (m, 9H, PhH and
NH), 6.51 (d, 2H, BnHortho), 5.20 (d, 1H, J¼15.8 Hz,
PhCH2), 3.91 (s, 3H, OCH3), 3.74 (d, 1H, J¼15.8 Hz,
PhCH2), 2.65–2.56 (m, 2H, H3eq and H4eq), 2.47 (td (ddd),
1H, J¼15.0, 4.0 Hz, H3ax), 2.26 (td (ddd), 1H, J¼15.0,
4.0 Hz, H4ax), 1.99 (s, 3H, NCOCH3), 1.76 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3, ppm): 175.0 (CO), 172.5
(CO), 169.8 (CO), 138.6 and 138.3 (PhC-ipso), 126.2–
128.5 (PhC), 74.6 (C2), 56.6 (C5), 53.0 (OCH3), 50.6
(CH2Ph), 33.4 and 30.8 (C3 and C4), 25.5 (CH3) and 24.1
(COCH3); EIMS [m/z (%)]: 394 (Mþ, 10), 335 (Mþ2NH2-
COCH3, 44), 289 (Mþ2NCH2Ph, 100); HRMS: calcd for
C23H26N2O4: 394.1893, found 394.1891.
4.4.3. (1Sp,4Rp)-2-Benzyl-1-phenyl-2,5-diazabicyclo-
[2.2.2]octane-3,6-dione (8d). Yield: 82%; white crystals,
mp: 1578C (CH2Cl2/hexane); IR (KBr, cm21): 1698 (CO);
1H NMR (400 MHz, CDCl3, ppm): 7.48–6.57 (m, 11H,
PhH and NH), 4.84 (d, 1H, J¼16 Hz, PhCH2), 3.92 (d, 1H,
J¼16.0 Hz, PhCH2), 2.28 (ddd, 1H, J¼14.0, 10.0, 5.0 Hz,
H7), 2.18 (ddd, 1H, J¼14.0, 10.0, 5.0 Hz, H70), 2.10–1.95
(m, 2H, H8 and H80), 1.61 (s, 1H, H4); 13C NMR (100 MHz,
4.5.3. Methyl (2Sp,5Rp)-5-(acetylamino)-1-benzyl-6-oxo-
2-phenyl-2-piperidinecarboxylate (10d). Yield: 84%;
white powder, mp: 1778C (CH2Cl2/hexane); IR (KBr,
cm21): 1645 (CO), 1656 (CO); 1H NMR (400 MHz,
CDCl3, ppm): 7.26–6.73 (m, 9H, PhH and NH), 6.51 (d,
2H, BnHortho), 5.10 (d, 1H, J¼15.4 Hz, PhCH2), 4.52 (dt

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J. Rogiers et al. / Tetrahedron 59 (2003) 5047–5054
(ddd), 1H, J¼12, 5 Hz, H5), 3.83 (s, 3H, OCH3), 3.79 (d,
1H, J¼15.4 Hz, PhCH2), 2.62–2.74 (m, 2H, CH2CH2), 2.60
(td (ddd), 1H, J¼15.4, 5.1 Hz, H3ax), 2.04 (s, 3H,
NCOCH3), 1.58–1.66 (m, 1H, CH2CH2); 13C NMR
(100 MHz, CDCl3, ppm): 172.2 (CO), 171.4 (CO), 170.6
(CO), 138.2 and 138.0 (PhC-ipso), 128.5–126.4 (PhC), 74.6
(C2), 53.0 (OCH3), 52.0 (C5), 50.5 (CH2Ph), 35.2 (CH2),
26.3 (CH2), 23.3 (CH3); EIMS [m/z (%)]: 380 (Mþ, 1), 321
(Mþ2NH2COCH3, 9), 275 (Mþ2NCH2Ph, 31), 91
(PhCHþ2 , 100); HRMS: calcd for C22H24N2O4: 380.1736,
found 380.1730.
24.1 (CH3); CIMS [m/z (%)]: 367 (MHþ, 100), 349
(MHþ2H2O, 7), 335 (MHþ2CH3OH, 7); HRMS: calcd
for C22H26N2O3: 366.1943, –CH2OH: 335.1760, found
335.1755.
4.6.3. (3Rp,6Sp)-N-[1-Benzyl-6-(hydroxymethyl)-2-oxo-6-
phenyl-3-piperidinyl]acetamide (11d). Yield: 24%; color-
1
less oil; H NMR (400 MHz, CDCl3, ppm): 7.31–7.18 (m,
9H, PhH and NH), 6.70 (d, 2H, BnHortho), 5.02 (d, 1H,
J¼15.4 Hz, PhCH2), 4.40 (dt (ddd), 1H, J¼11.0, 5.6 Hz,
H3), 4.02 (d, 1H, J¼15.4 Hz, PhCH2), 3.99 (d, 1H,
J¼12.1 Hz, CH2OH), 3.90 (d, 1H, J¼12.1 Hz, CH2OH),
2.42–2.28 (m, 2H, CH2), 2.24–2.10 (m, 1H, CH2), 2.09–
1.92 (m, 4H, CH2 and CH3); 13C NMR (100 MHz, CDCl3,
ppm): 172.8 (CO), 170.4 (CO), 143.1 and 139.2 (PhC-ipso),
127.0–129.1 (PhC), 67.9 (CH2OH), 67.0 (C6), 51.1 (C3),
48.2 (CH2Ph), 34.3 and 25.1 (C4 and C5), 23.3 (CH3);
EIMS [m/z (%)]: 353 (Mþ, 100); HRMS: calcd for
C21H24N2O3: 353.1865, –CH2OH: 321.1603, found
321.1603.
4.6. General procedure for reduction of compounds
10b–d
To a solution of 1 mmol of 10b–d in 15 mL of THF is
added a solution of 1.1 mmol of LiBH4 and 0.1 mmol of
LiEt3BH in 5 mL of THF with a syringe under an inert
atmosphere. The mixture is refluxed overnight. Upon
cooling (08C), 5 mL of MeOH is added and the mixture is
filtered over Celite. The filtrate is evaporated under reduced
pressure and the residue is purified by column chromato-
graphy (silica gel, CH2Cl2 –MeOH 95–5) to afford
compounds 11b–d and 12.
4.6.4. N-[(1Rp,4Sp,7S p)-(2-Benzyl-7-hydroxy-3-oxo-1-
phenyl-2-azabicyclo[2.2.1]hept-4-yl)]acetamide
(12).
Yield: 55%; white crystals, mp: 2048C (CH2Cl2/hexane);
1
IR (KBr, cm21): 1694 (CO), 3302 (NHCO and OH); H
For the synthesis of compounds 13b–d this procedure is
modified by using 1.5 mmol of LiBH4 and 0.15 mmol of
LiEt3BH.
NMR (400 MHz, DMSO-d6, ppm): 8.16 (broad s, 1H, NH),
7.32–7.34 (m, 3H, PhH), 7.21–7.23 (m, 2H, PhH), 7.15–
7.17 (m, 3H, PhH), 6.75–6.80 (m, 2H, PhH), 5.76 (d, 1H,
J¼4.4 Hz, OH), 4.64 (d, 1H, J¼4.4 Hz, H7), 4.19 (d, 1H,
J¼15.1 Hz, PhCH2), 3.84 (d, 1H, J¼15.1 Hz, PhCH2), 2.20
(td (ddd), 1H, J¼10.8, 3.7 Hz), H6b), 2.10 (td (ddd), 1H,
J¼10.8, 2.5 Hz, H5b), 1.91 (s, 3H, COCH3), 1.55 (broad td
(ddd), 1H, J¼9.5, 2.5 Hz, H6a), 1.47 (broad td (ddd), 1H,
J¼9.5, 3.7 Hz, H5a); 13C NMR (100 MHz, CDCl3, ppm):
172.4 (CO), 169.5 (CO), 138.1 and 134.5 (PhC-ipso),
126.8–128.9 (PhC), 77.8 (CHOH), 71.7 (C4), 67.0 (C1),
42.8 (CH2Ph), 27.4 and 27.0 (C5 and C6), 22.7 (CH3);
EIMS [m/z (%)]: 350 (Mþ, 42), 291 (Mþ2CH3CONH2, 15),
259 (Mþ2PhCH2, 27); HRMS: calcd for C21H22N2O3:
350.1630, found 350.1627.
4.6.1. (3Sp,6Sp)-N-[1-Benzyl-6-(hydroxymethyl)-2-oxo-
3,6-diphenyl-3-piperidinyl]acetamide (11b). Yield: 62%;
white crystals, mp: 968C (Et2O); IR (KBr, cm21): 1629
(CO), 3316 (OH and NHCO); 1H NMR (400 MHz, CDCl3,
ppm): 7.19–7.56 (m, 14H, PhH and NH), 6.48 (d, 2H,
BnHortho), 4.95 (d, 1H, J¼15.4 Hz, PhCH2), 4.19 (d, 1H,
J¼11.7 Hz, CH2OH), 4.10 (d, 1H, J¼11.7 Hz, CH2OH),
3.89 (d, 1H, J¼15.4 Hz, PhCH2), 3.42 (td (ddd), 1H,
J¼13.9, 3.3 Hz, H4ax), 2.92 (br s, 1H, OH), 2.48 (dt (ddd),
1H, J¼13.9, 3.3 Hz, H4eq), 2.20 (dt (ddd), 1H, J¼14.6,
3.3 Hz, H5eq), 2.02 (s, 3H, COCH3), 1.87 (td, 1H, J¼14.6,
3.3 Hz, H5ax); 13C NMR (100 MHz, CDCl3, ppm): 172.1
(CO), 170.6 (CO), 141.4 and 138.6 (PhC-ipso), 126.8–
128.9 (PhC), 68.2 (CH2OH), 65.5 (C6), 63.7 (C3), 49.0
(CH2Ph), 32.0 and 29.5 (C4 and C5), 23.9 (CH3); CIMS
[m/z (%)]: 429 (MHþ, 100), 397 (MHþ2CH3OH, 14), 370
(MHþ2NHCOCH3, 14); HRMS: calcd for C27H28N2O3:
428.2099, –CH2OH: 397.1916, found 397.1920.
4.6.5. (3Sp-6Sp)-N-[1-Benzyl-6-(hydroxymethyl)-3,6-
diphenyl-3-piperidinyl]acetamide (13b). Yield: 53%;
white powder, mp: 868C (CH2Cl2/hexane); IR (KBr,
1
cm21): 1659 (NHCO), 3374, 3317 (OH and NHCO); H
NMR (400 MHz, CDCl3, ppm): 7.14–7.45 (m, 15H, PhH),
5.91 (broad s, 1H, NH), 4.56 (d, 1H, J¼14.3 Hz, PhCH2),
4.06 (t (dd), 1H, J¼11.7 Hz, CH2OH), 3.94 (t (dd), 1H,
J¼11.7 Hz, CH2OH), 3.74 (d, 1H, J¼14.3 Hz, PhCH2), 2.96
(d, 1H, J¼12.4 Hz, H2), 2.74 (broad d, 2H, OH and H2),
1.90–2.24 (m, 4H, CH2CH2), 1.89 (s, 3H, COCH3); 13C
NMR (100 MHz, CDCl3, ppm): 169.0 (CO), 143.3 and
141.7 and 141.2 (PhC-ipso), 125.4–128.9 (PhC), 68.4
(CH2OH), 65.5 (C6), 57.7 (C3), 56.8 and 55.1 (NCH2, C2),
30.2 and 29.3 (C4 and C5), 23.9 (CH3); CIMS [m/z (%)]:
415 (MHþ, 100), 397 (MHþ2H2O, 8), 383 (MHþ2
CH3OH, 17); HRMS: calcd for C27H30N2O2: 414.2307,
–CH2OH: 383.2123, found: 383.2123.
4.6.2. (3Rp,6Sp)-N-[1-Benzyl-6-(hydroxymethyl)-3-
methyl-2-oxo-6-phenyl-3-piperidinyl]acetamide (11c).
Yield: 53%; white crystals, mp: 918C (Et2O); IR (KBr,
cm21): 1628 (CO), 3312 (OH and NHCO); 1H NMR
(400 MHz, CDCl3, ppm): 7.29–7.10 (m, 9H, PhH and NH),
6.65 (d, 2H, BnHortho), 4.73 (d, 1H, J¼15.4 Hz, PhCH2),
4.16 (d, 1H, J¼11.8 Hz, CH2OH), 4.08 (d, 1H, J¼11.8 Hz,
CH2OH), 4.00 (d, 1H, J¼15.4 Hz, PhCH2), 3.47 (br s, 1H,
OH), 2.87 (td (ddd), 1H, J¼13.5, 3.4 Hz, H4ax), 2.42 (dt
(ddd), 1H, J¼14.1, 3.6 Hz, H5eq), 2.10 (td (ddd), 1H,
J¼14.1, 3.6 Hz, H5ax), 1.98 (s, 3H, CH3), 1.84 (dt (ddd),
1H, J¼13.5, 3.4 Hz, H4eq), 1.65 (s, 3H, 5CH3); 13C NMR
(100 MHz, CDCl3, ppm):175.2 (CO), 170.0 (CO), 143.1 and
139.2 (PhC-ipso), 127.0–129.1 (PhC), 68.7 (CH2OH), 66.2
(C6), 53.9 (C3), 49.3 (CH2Ph), 33.1 and 30.4 (C4 and C5),
4.6.6. (3Rp-6Sp)-N-[1-Benzyl-6-(hydroxymethyl)-3-
methyl-6-phenyl-3-piperidinyl]acetamide (13c). Yield:
47%; viscous oil; 1H NMR (300 MHz, CDCl3, ppm):
7.25–7.38 (m, 10H, PhH), 5.44 (br s, 1H, NH), 4.35 (d, 1H,

J. Rogiers et al. / Tetrahedron 59 (2003) 5047–5054
5053
J¼13.9 Hz, PhCH2), 4.05 (d, 1H, J¼11.7 Hz, CH2OH), 3.92
(d, 1H, J¼11.7 Hz, CH2OH), 3.72 (d, 1H, J¼13.9 Hz,
PhCH2), 2.68 (d, 1H, J¼12.4 Hz, NCH2), 2.61 (dd, 1H,
J¼12.4, 1.5 Hz, NCH2), 2.38 (dddd, 1H, J¼13.5, 5.5, 4.0,
1.5 Hz, H4eq), 2.1 (ddd, 1H, J¼13.9, 11.5, 4.0 Hz, H5ax),
1.96 (ddd, 1H, J¼13.9, 5.5, 4.4 Hz, H5eq), 1.84 (s, 3H,
COCH3), 1.35 (ddd, 1H, J¼13.5, 11.5, 4.4 Hz, H4ax), 1.24
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3, ppm): 169.6
(CO), 142.3 and 141.3 (PhC-ipso), 128.7–127.0 (PhC), 67.2
(CH2OH), 64.5 (C6), 56.6 and 55.0 (NCH2, C2), 52.1 (C3),
30.7 and 29.5 (C4 and C5), 24.3 and 23.8 (2£CH3); EIMS
[m/z (%)]: 352 (Mþ, 1), 321 (Mþ2HOCHþ2 , 100), 262
PhH and NH), 6.26 (d, 2H, BnHortho), 4.70 (d, 1H,
J¼15.4 Hz, PhCH2), 4.44 (d, 1H, J¼12.6 Hz, CH2OCH2-
Ar), 4.30 (d, 1H, J¼12.6 Hz, CH2OCH2Ar), 4.13 (d, 1H,
J¼9.9 Hz, CH2OCH2Ar), 4.05 (d, 1H, J¼15.4 Hz, PhCH2),
3.95 (d, 1H, J¼9.9 Hz, CH2OCH2Ar), 2.70 (td (ddd), 1H,
J¼13.5, 4.4 Hz, H4ax), 2.41 (dt (ddd), 1H, J¼14.6, 4.4 Hz,
H5eq), 2.11 (td (ddd), 1H, J¼14.6, 4.4 Hz, H5ax), 2.06 (dt
(ddd), 1H, J¼13.5, 4.4 Hz, H4eq), 2.00 (s, 3H, COCH3),
1.70 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3, ppm):
174.6 (CO), 169.9 (CO), 142.2 and 140.5 and 138.8 (PhC-
ipso), 131.4 (q, J¼33 Hz, CF3), 126.9–129.1 (PhC), 124.1
(q, J¼273 Hz, CF3), 73.4 and 71.6 (2£CH2O), 67.3 (C6),
65.5 (C3), 48.9 (CH2Ph), 32.8 and 29.5 (C4 and C5), 25.9
(CH3), 23.9 (NCOCH3); CIMS [m/z (%)]: 593 (MHþ, 100),
573 (MHþ2HF, 31), 335 (MHþ2(CF3)2C6H3CH2OCH3,
30); HRMS: calcd for C31H30N2O3F6: 592.2165, found
592.2158.
(Mþ2HOCH2þ2NH2COCH3);
HRMS:
calcd
for
C22H28N2O2: 352.2151, –CH2OH: 321.1967, found
352.2140, 321.1978.
4.7. General procedure for the etherification of
compounds 11b–d and 13b,c
4.7.3. (3Rp-6Sp)-N-[1-benzyl-6-({[3,5-bis(trifluoro-
methyl)benzyl]oxy}methyl)-2-oxo-6-phenyl-3-piper-
idinyl]acetamide (3d). Yield: 51%; colorless oil; 1H NMR
(400 MHz, CDCl3, ppm): 7.76 (s, 1H, ArH4), 7.67 (s, 2H,
ArH2 and ArH6), 7.07–7.29 (m, 9H, PhH and NH), 6.59 (d,
2H, BnHortho), 5.02 (d, 1H, J¼15.4 Hz, PhCH2), 4.47 (d,
1H, J¼12.6 Hz, CH2OCH2Ar), 4.37 (ddd, 1H, J¼10.7,
5.1 Hz, H3ax), 4.28 (d, 1H, J¼12.6 Hz, CH2OCH2Ar), 4.12
(d, 1H, J¼9.9 Hz, CH2OCH2Ar), 4.02 (d, 1H, J¼15.4 Hz,
PhCH2), 3.91 (d, 1H, J¼9.9 Hz, CH2OCH2Ar), 2.02–2.39
(m, 7H, CH2CH2 and CH3); 13C NMR (100 MHz, CDCl3,
ppm): 173.2 (CO), 170.0 (CO), 143.1 and 139.3 and 138.4
(PhC-ipso), 131.1 (q, J¼30 Hz, CF3), 126.6–129.1 (PhC),
123.9 (q, J¼272 Hz, CF3), 73.1 and 71.4 (2£CH2O), 68.0
(C6), 51.4 (C3), 48.6 (CH2Ph), 33.1 and 31.2 (C4 and C5),
23.4 (CH3); CIMS [m/z (%)]: 579 (MHþ, 100), 559
(MHþ2HF, 27), 321 (MHþ2(CF3)2C6H3CH2OCH3, 21).
To a suspension of 1 mmol of NaH in 2 mL of dry DMF is
added a solution of 0.5 mmol of 11b,c,d or 13b,c in 2.5 mL
of DMF. This mixture is stirred at room temperature for 1 h
and then cooled in an ice bath. To the cooled mixture is
added 0.6 mmol of 3,5-bis(trifluoromethyl)benzyl bromide.
The ice bath is removed and the mixture is stirred at room
temperature for 1 h. Following addition of 2 mL of CH2Cl2,
2 mL of MeOH and 5 mL of water, the mixture is extracted
with CH2Cl2 (3£50 mL). The organic layers are collected
and dried over MgSO4, filtered and evaporated under
reduced pressure. The products are purified by column
chromatography (silica gel, CH2Cl2 for 3b, CH2Cl2–MeOH
(98–2) for 3c and 3d, CH2Cl2–MeOH (95–5) for 4b and
4c).
4.7.1. (3Sp-6Sp)-N-[1-Benzyl-6-({[3,5-bis(trifluoro-
methyl)benzyl]oxy}methyl)-2-oxo-3,6-diphenyl-3-piper-
idinyl]acetamide (3b). Yield: 65%; white crystals, mp:
588C (CH2Cl2/hexane); IR (KBr, cm21): 1662 (CO), 1670
(CO); 1H NMR (400 MHz, CDCl3, ppm): 7.79 (s, 1H,
ArH4), 7.68 (s, 2H, ArH2 and ArH6), 7.07–7.59 (m, 14H,
PhH and NH), 6.48 (d, 2H, BnHortho), 4.85 (d, 1H,
J¼15.1 Hz, PhCH2), 4.50 (d, 1H, J¼12.6 Hz, CH2OCH2-
Ar), 4.44 (d, 1H, J¼12.6 Hz, CH2OCH2Ar), 4.20 (d, 1H,
J¼10.0 Hz, CH2OCH2Ar), 3.95 (d, 1H, J¼15.1 Hz,
PhCH2), 3.93 (d, 1H, J¼10.0 Hz, CH2OCH2Ar), 3.23 (td
(ddd), 1H, J¼14.2, 2.9 Hz, H4ax), 2.62 (dt (ddd), 1H,
J¼14.2, 2.9 Hz, H5eq), 2.26 (dt (ddd), 1H, J¼14.6, 2.9 Hz,
H4eq), 2.01 (s, 3H, COCH3), 1.92 (td (ddd), 1H, J¼14.6,
2.9 Hz, H5ax); 13C NMR (100 MHz, CDCl3, ppm): 172.0
(CO), 170.2 (CO), 142.4 and 141.5 and 140.5 and 138.6
(PhC-ipso), 131.6 (q, J¼33 Hz, CF3), 126.8–128.9 (PhC),
123.3 (q, J¼273 Hz, CF3), 72.9 and 71.6 (2£CH2O), 67.4
(C6), 63.7(C3), 49.0(CH2Ph),31.8and29.0(C4andC5),24.0
(CH3); CIMS [m/z (%)]: 655 (MHþ, 100), 635 (MHþ2HF,
19), 397 (MHþ2(CF3)2C6H3CH2OCH3, 23); HRMS: calcd
for C36H32N2O3F6: 654.2317, found 654.2314.
4.7.4. (3Sp-6Sp)-N-[1-Benzyl-6-({[3,5-bis(trifluoro-
methyl)benzyl]oxy}methyl)-3,6-diphenyl-3-piperidinyl]-
acetamide (4b). Yield: 58%; white crystals, mp: 678C
(CH2Cl2/hexane); IR (KBr, cm21): 1669 (CO), 3061
1
(NHCO); H NMR (400 MHz, CDCl3, ppm): 7.79 (s, 1H,
ArH4), 7.73 (s, 2H, ArH2 and ArH6), 7.12–7.44 (m, 15H,
PhH), 5.84 (s, 1H, NH), 4.68 (d, 1H, J¼12.4 Hz, CH2-
OCH2Ar), 4.62 (d, 1H, J¼12.4 Hz, CH2OCH2Ar), 4.27 (d,
1H, J¼13.5 Hz, PhCH2), 4.07 (d, 1H, J¼9.9 Hz, CH2-
OCH2Ar), 3.87 (d, 1H, J¼9.9 Hz, CH2OCH2Ar), 3.76 (d,
1H, J¼13.5 Hz, PhCH2), 2.92 (d, 1H, J¼12.8 Hz, H2),
2.70–2.86 (m, 2H, CH2CH2 and H2), 2.27–2.38 (m, 1H,
CH2CH2), 1.86–2.10 (m, 2H, CH2CH2), 1.85 (s, 3H,
COCH3); 13C NMR (100 MHz, CDCl3, ppm): 169.5 (CO),
143.7 and 143.1 and 141.5 and 141.2 (PhC-ipso), 132.1 (q,
J¼33 Hz, CF3), 125.5–129.3 (PhC), 123.7 (q, J¼272 Hz,
CF3), 72.5 and 71.8 (2£CH2O), 65.2 (C6), 57.3 (C3), 56.5
and 55.6 (2£NCH2), 31.0 and 27.1 (C4 and C5), 24.3 (CH3);
CIMS [m/z (%)]: 641 (MHþ, 2), 581 (MHþ2NHCOCH3,
41), 383 (MHþ2(CF3)2C6H3CH2OCH3, 80), 324 (MHþ2
(CF3)2C6H3CH2OCH3–NHCOCH3, 41); HRMS: calcd for
C36H34N2O2F6: 640.2524, –NH2COCH3: 581.2153 found:
581.2151.
4.7.2. (3Rp-6Sp)-N-[1-Benzyl-6-({[3,5-bis(trifluoro-
methyl)benzyl]oxy}methyl)-3-methyl-2-oxo-6-phenyl-3-
piperidinyl]acetamide (3c). Yield: 63%; white powder,
mp: 698C (CH2Cl2); IR (KBr, cm21): 1667 (CO), 1673
(CO); 1H NMR (400 MHz, CDCl3, ppm): 7.78 (s, 1H,
ArH4), 7.64 (s, 2H, ArH2 and ArH6), 7.02–7.31 (m, 9H,
4.7.5. (3Rp-6Sp)N-[1-Benzyl-6-({[3,5-bis(trifluoro-
methyl)benzyl]oxy}methyl)-3-methyl-6-phenyl-3-piper-
idinyl]acetamide (4c). Yield: 50%; colorless oil; 1H NMR

5054
J. Rogiers et al. / Tetrahedron 59 (2003) 5047–5054
(300 MHz, CDCl3, ppm): 7.80 (s, 1H, ArH4), 7.75 (s, 2H,
ArH2 and ArH6), 7.54 (d, 2H, J¼7.3 Hz, PhH), 7.40–7.24
(m, 8H, PhH), 5.41 (br s, 1H, NH), 4.69 (d, 1H, J¼12.8 Hz,
CH2OCH2Ar), 4.62 (d, 1H, J¼12.8 Hz, CH2OCH2Ar),
4.01–4.10 (m, 2H, PhCH2 and CH2OCH2Ar), 3.94 (d, 1H,
J¼10.3 Hz, CH2OCH2Ar), 3.76 (d, 1H, J¼13.9 Hz,
PhCH2), 2.66 (d, 1H, J¼12.4 Hz, NCH2), 2.60 (d, 1H,
J¼12.4 Hz, NCH2), 2.44 (ddd, 1H, J¼13.4, 7.5, 4.0 Hz,
H4eq), 2.17 (ddd, 1H, J¼13.9, 9.2, 4.0 Hz, H5ax), 2.03
(ddd, 1H, J¼13.9, 7.5, 4.0 Hz, H5eq), 1.80 (s, 3H, COCH3),
1.39 (ddd, 1H, J¼13.4, 9.2, 4.0 Hz, H4ax), 1.26 (s, 3H,
CH3); 13C NMR (75 MHz, CDCl3, ppm): 169.6 (CO), 143.6
and 141.3 and 140.9 (PhC-ipso), 131.6 (q, J¼33 Hz, CF3),
126.9–128.4 (PhC), 123.3 (q, J¼272 Hz, CF3), 73.8 and
72.0 (2£CH2O), 63.8 (C6), 55.5 (PhCH2N), 55.1 (NCH2),
52.2 (C3), 31.6 and 29.7 (C4 and C5), 24.2 and 23.8
(2£CH3); EIMS [m/z (%)]: 578 (Mþ, 2), 519 (Mþ2NH2-
COCH3, 64), 321 (Mþ2(CF3)2C6H3CH2OCHþ2 , 100), 262
(Mþ2(CF3)2C6H3CH2OCH2þ–NH2COCH3, 69); HRMS:
calcd for C31H32F6N2O2: 578.2368, found 578.2367.
Research-Flanders (Belgium)) thanks the F.W.O. for
fellowships received.
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The authors thank the FWO (Fund for Scientific Research-
Flanders, Belgium) and the Janssen Pharmaceutica
company for funding. We are grateful to R. De Boer for
HRMS measurements. J. R. thanks the K.U. Leuven and
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