Synthesis and conformational analysis of Substance P antagonist analogues based on a 1,7-naphthyridine scaffold

Article abstract of DOI:10.1016/S0040-4020(03)00732-4

Two analogues of formerly described piperidine-based Substance P antagonists have been synthesised using an intramolecular Diels-Alder reaction of 1-(4-pentenyl)-3-phenyl-2(1H)-pyrazinones, followed by acidic methanolysis of the strained adducts to form t

Full text of DOI:10.1016/S0040-4020(03)00732-4

Tetrahedron 59 (2003) 4721–4731
Synthesis and conformational analysis of Substance P antagonist
analogues based on a 1,7-naphthyridine scaffold
Frederik J. R. Rombouts, Jeroen Van den Bossche, Suzanne M. Toppet, Frans Compernolle
*
and Georges J. Hoornaert
Department of Organic Chemistry, K.U. Leuven, Celestijnenlaan 200F, Leuven, B-3001, Belgium
Received 5 February 2003; revised 8 April 2003; accepted 2 May 2003
Abstract—Two analogues of formerly described piperidine-based Substance P antagonists have been synthesised using an intramolecular
Diels–Alder reaction of 1-(4-pentenyl)-3-phenyl-2(1H)-pyrazinones, followed by acidic methanolysis of the strained adducts to form the
8-oxo-6-phenyldecahydro [1,7]-naphthyridine-6-carboxylate esters and further conversion to the corresponding O-benzyl substituted
6-(hydroxymethyl) target compounds. Conformational analyses of intermediates and the final products are presented, based on 1H NMR and
modelling data. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Using screening techniques, Pfizer optimised lead-com-
pound CP96345 (Fig. 1, 1) in 1991, the first non-peptide SP
antagonist.7 Further optimisations led to the piperidine
CP99994 (2),8 which is in the clinical phase for emesis and
post-operational dental pain.9 In 1994, researchers of
Merck, Sharp and Dohme showed that the benzylamine
moiety of 2 could be replaced by a benzyl ether (3).10 Also,
it was found that high activity was preserved in the 2,2-
disubstituted piperidine 4.11,12
Substance P is a member of the tachykinins, a group of small
peptides characterised by the common C-terminus Phe-X-
Gly-Leu-Met-NH2 (X¼Phe or Val).1 There are five known
mammalian tachykinins: Substance P (SP), Neurokinin A
(NKA), Neurokinin B (NKB), Neuropeptide K (NPK),
Neuropeptide g (NPg). The two latter are related to NKA,
but have a prolonged N-terminus. Also, about a dozen of
tachykinins have been isolated from lower species.2
Mammalian tachykinins are called neurokinins. The
tachykinins have G-coupled receptors that possess seven
transmembrane segments linked by intra- and extracellular
loops.3 Three receptor subtypes (NK1, NK2 and NK3) have
been identified that preferably bind SP, NKA and NKB,
respectively. SP, NKA and NKB are found in the central and
peripheral nerve system, where they act as neurotransmitters
and neuromodulators. They have been related to various
biological effects, including pain transmission, neurogenic
inflammation, smooth muscle contraction, vasodilatation,
secretion and activation of the immune system. A multitude
of neurokinin receptor antagonists has been described and
has been used to confirm the physiological role of
tachykinins. For NK1 receptor antagonists that constitute
the most studied group, the primary sites of action have been
identified. In this way, it was found that SP is related to the
pathophysiology of asthma,4 Crohn’s disease, pain,5
psoriasis, migraine, cystitis, schizophrenia, emesis and
anxiety.6
In a previous communication,13 we reported a synthetic
route towards cis-fused 1,7-naphthyridine 7: this involved
Keywords: Substance P; tachykinins; antagonists; pyrazinone;
intramolecular Diels–Alder.
*
Corresponding author. Tel.: þ32-16-327372; fax: þ32-16-327990;
e-mail: georges.hoornaert@chem.kuleuven.ac.be
Figure 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00732-4

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F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
ated with non-peptide SP antagonists of the first generation
has been circumvented in later work of the Merck
researchers by appropriate N-substitution of piperidines of
type 3 and their morpholine analogues.16
2. Results and discussion
2.1. Synthesis
Scheme 1. (a) PhBr, reflux, 1 night; (b) EtOAc/H2O, room temperature, 1 h
(hydrolysis); (c) 2.5 equiv. CH3SO3H, MeOH, reflux, 1 night.
For the synthesis of 8 and 9, we envisioned three possible
pathways depicted in Scheme 2.
1. Reductive cleavage of the strained, ketone-like tertiary
amide group of bislactam 6 could afford primary alcohol
10. This may proceed via ring opening of the hemiaminal
intermediate and further reduction of the aldehyde
formed. Subsequent O-benzylation and reduction of the
secondary amide group finally would provide target
products 9 and 8.
Figure 2.
2. Following selective acidic methanolysis of bislactam 6 to
give methyl ester 7, the latter in turn can be submitted to
chemoselective reduction of the ester group: this would
again produce primary alcohol 10 as a key intermediate.
3. Intramolecular cycloaddition of 11, the 5-H analogue of
5-Cl-pyrazinone 5, would afford imine adduct 13 instead
of imidoyl chloride 12. Subsequent reduction of imine 13
then may yield amino lactam 14, which can be converted
to diamines 15 and 8 in a similar way as depicted in
pathways 1 and 2.
the intramolecular Diels–Alder reaction of 2(1H)-pyrazi-
none 5, followed by acidic methanolysis of the strained
hydrolysed adduct 6 (Scheme 1). This approach also has
been used by our group to prepare a type VI b-turn mimic.14
Inspired by the structural resemblance between Merck
piperidine 4 and 1,7-naphthyridine 7, we also envisaged
conversion of 7 to potential SP antagonists 8 and 9 (Fig. 2).
Conformational analysis of 4 indicates an axial position of
the phenyl group,11 while both aromatic rings presumably
are in an edge-on conformation.15 A preferred axial
orientation of the phenyl group also has been demonstrated
for 1,7-naphthyridine 7.13,14 For diamine 8, this confor-
mation could be stabilised at physiological pH by an internal
hydrogen bridge involving both nitrogen atoms of the
mono-ammonium salt. Such hydrogen bridge is not feasible
for the 8-oxo analogue 9 (X¼CO). The absence of a basic
nitrogen at the 7-position in 9 could lower the undesired
activity for L-type Ca2þ-channels. This drawback associ-
Pathway 1. In an attempt to convert bislactam 6 directly into
alcohol 10 via reductive cleavage of the tertiary amide
group, 6 was treated with NaBH4 under protic conditions
(THF/H2O). These conditions were chosen to allow
protonation of N3, thus facilitating expulsion of the amine
from the hemiaminal intermediate produced in the first
reduction step. However, both the desired alcohol 10 and
Scheme 2.

F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
4723
tertiary amine 16 were identified by chemical ionisation
mass spectral analysis (CIMS) (Scheme 3). Following
isolation by continuous extraction and preparative TLC,
alcohol 10 was isolated in only 29% yield. Presumably, the
formation of amine 16 (not isolated) is due to competitive
reduction of the strained iminium ion generated from the
hemiaminal. We therefore decided to attempt pathway 2.
Scheme 3. (a) 4 equiv. NaBH4, MeOH, 608C, 5 days.
Pathway 2. Reduction of electron-deficient ester groups
Scheme 4. (a) Ac2O, 408C, 1 h; (b) NaBH4, THF/H2O (4:1), 608C, 30 min; (c) (F3C)2C6H3CH2Br, NaH, DMF, room temperature, overnight; (d) HCl/MeOH,
608C, 2 days.
sometimes can be effected by NaBH4. Applying this method
should allow for selective conversion of ester 7 into alcohol
10, without reducing the amide function. However, no
reaction was observed when treating a methanolic solution
of 7 with 2 equiv. of NaBH4 at room temperature. Upon
addition of two extra equivalents of NaBH4 and heating to
608C, alcohol 10 was produced along with an appreciable
quantity of ring-closed bislactam 6. Hence, to avoid
competing ring closure of amino ester 7, the amino nitrogen
N1 was protected as the N-Ac amide 17 (Scheme 4).
Subsequent treatment of 17 with 5 equiv. of NaBH4 in THF/
H2O (4:1) at 608C afforded alcohol 18 in 80% yield. When
18 was submitted to benzylation using only 1 equiv. of NaH
Scheme 5. (a) 2 equiv. BH3·DMS, THF, reflux, 1 h; (b) HCl/MeOH, reflux,
30 min.
and 3,5-bis(trifluoromethyl)benzyl bromide, this inevitably
led to formation of both the mono- and bis-benzylated
product 19 and 20. Addition of another 0.5 equiv. of NaH
drove the reaction to completion, yielding 52 and 20% of
purified products 19 and 20. Final cleavage of the N-acetyl
group of 19 was accomplished by heating amide 19 with
HCl in methanol at 608C to furnish 9 in 64% yield.
The diamine target product 8 was prepared from amino
lactam 9 via reduction with 2 equiv. of BH3·DMS in THF at
reflux temperature (Scheme 5). CIMS analysis of the
reaction mixture indicated the formation of the borane-
bridged diamine complex 21 (MHþ ions observed at m/z
485 and 484 in the expected isotopic ratio of ca. 4:1). This
borane complex was destroyed by refluxing with HCl in
methanol to provide diamine 8 in 43% yield.
Pathway 3. In an attempt to find a shorter pathway leading
to diamine 8, we prepared pyrazinone 22 using the base-
catalysed condensation of 2-amino-2-phenylacetamide with
glyoxal described by Jones (Scheme 6).17 N-alkylation of 22
Scheme 6. (a) 5-Bromo-1-pentene, Cs2CO3, dioxane, 508C, 1 week;
(b) PhCl, reflux, 3 days; (c) H2, 10% Pd/C, 40 psi, 1 night; (d) 3.5 equiv.
CH3SO3H, MeOH, reflux, 1 night; (e) Ac2O, 2 equiv. DMAP, 408C, 2 h.

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F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
Table 1. Experimental 3J coupling values in the 1H NMR spectra of lactam 7 and diamine 15 compared to the values calculated18 for conformational structures
A and B
Conf.
3J4a,5eq
Theor.
3J4a,5ax
Theor.
3J4a,4ax
Theor.
3J4a,4eq
Theor.
3J8a,8ax
Theor.
3J8a,8eq
Theor.
Exp.
Exp.
Exp.
Exp.
Exp.
Exp.
7
A
B
3.0
1.9
3.1
10.0
12.2
3.8
5.0
4.7
6.0
2.1
3.5
–
–
–
–
–
–
–
–
(gauche)
–
(gauche)
(anti)
–
(gauche)
(gauche)
–
(anti)
(gauche)
–
(gauche)
12.3
a
a
15
A
B
4.0
2.6
2.0
14.0
12.4
5.2
–
4.6
–
2.1
3.6
3.0
3.4
2.0
2.4
3.9
(gauche)
–
(gauche)
(anti)
–
(gauche)
(gauche)
–
(anti)
(gauche)
–
(gauche)
(gauche)
–
(anti)
(gauche)
–
(gauche)
12.3
11.2
a
Not determined due to overlap.
by heating with 5-bromo-1-pentene and Cs2CO3 in dioxane
provided the corresponding N-pentenyl derivative 11. When
heated in chlorobenzene at reflux temperature for 3 days, 11
underwent intramolecular cycloaddition to form imine
adduct 13. After removal of the solvent, imine 13 was
redissolved in THF and immediately reduced to amine 14 by
hydrogenation (40 psi) over 10% Pd/C catalyst (yield:
47%). Similar to the conversion of 6 to amino ester 7, acidic
cleavage of 14 could be effected by heating with 3.5 equiv.
of CH3SO3H in methanol to produce diamino ester 15 in
97% yield. To prevent competing ring closure upon
reduction of the ester group with NaBH4, diamine 15 first
was converted to diamide 23 by heating in acetic anhydride
with 2 equiv. of DMAP at 608C; besides diamide 23 (73%)
this also yielded a small quantity of N-acetylated ring-
closed product 24. Unfortunately, no reduction of the ester
group occurred even when heating 23 with up to 10 equiv.
of NaBH4 in MeOH/H2O (4:1) at reflux temperature. When
compared to the easy reduction of 17, this remarkable result
may be due to the increased steric requirements in 23 for
accessing the equatorial ester group that is co-planar with
the N7–Ac group.
amongst the three routes proposed for preparing target
products 9 and 8.
2.2. Conformational analysis of the 1,7-naphthyridines
cis-Fused naphthyridines of lactam type 9 and diamine
type 8 can adopt two conformations A and B, in which both
rings have a (half)chair conformation (see heading of
Table 1).13 The assignment of structure A or B relies on the
3
specific relation between the J coupling patterns observed
1
in the H NMR spectra and the dihedral angles of vicinal
protons (gauche or anti). Table 1 lists relevant 3J values for
lactam ester 7 and the analogous diamine 15. In support of
the conformational assignments, the measured coupling
values are compared to theoretical values calculated by
applying the equations of Haasnoot et al.18 to geometry
optimised model structures of A and B (feature
implemented in Macromodel 5.0). In the case of diamine
15, additional support for the assignment comes from
the coupling values found between protons H8 and the
angular proton H8a. From the comparison between
measured and calculated coupling values it clearly follows
that structure A applies to both compounds 7 and 15, as
argued below.
In summary, pathway 2 proved to be the method of choice

F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
4725
The 1H NMR analysis of 7 was carried out in a 1:1 mixture
of CDCl3 and C6D6, resulting in optimal separation of
signals. The analysis started with the assignment of the
downfield angular proton H8a (d 3.17) that is flanked by N1
and the C8 carbonyl group. Other contiguous ring protons
H
4a (d 1.94), H5 (d 2.93 and 2.02) and H4 (d 1.43 and 1.22)
were identified by decoupling experiments involving
sequential irradiation of H8a and H4a. Due to coupling
with the adjacent proton H4a, H8a was observed as a doublet
(3J8a,4a¼4 Hz) while both geminal protons H5 appeared as a
doublet of doublets. The H5-signal at d 2.93 displayed a
coupling value of 10 Hz, indicating a trans-diaxial relation-
ship of H5ax and H4a with regard to the piperidinone ring.
The other H5-signal (d 2.02) corresponding to H5eq revealed
a small coupling (3 Hz) with H4a. The 3J values for coupling
between H4a and H4 were determined from the difference in
the sum of coupling constants measured for each proton H4
before and after irradiation of H4a. The values found (6 Hz
in each case)19 were consistent with their gauche relation-
Figure 3. NOE-correlations between (non-geminal) protons in 15.
3
ship to H4a. Hence, in view of the large J4a,5ax and small
are relevant for the conformational assignment of 15 are
summarised in Table 1.
3
3
3J4a,5eq, J4a,4ax, J4a,4eq values compound 7 clearly adopts
conformation A. For structure B, one rather expects a large
3J4a,4ax value corresponding to a trans-diaxial disposition of
Finally the conformational assignment of 15 was confirmed
by 2D 1H–1H NOESY analysis which revealed a correlation
of the ortho-protons of the phenyl group with H8ax, H5eq and
H4a. This only can apply to conformer A (Fig. 3).
H
4ax and H4a with respect to the piperidine ring.
The conformational analysis of diamine 15 largely relies on
the coupling values found between the angular proton H8a
and geminal protons H8. In structure A, H8a is gauche
relative to both H8 protons, whereas in form B proton H8a is
gauche to H8eq but anti to H8ax (trans-diaxial disposition of
H8a and H8ax). Both protons H8 in fact were observed as a
doublet of doublets at d 2.77 and 2.95, exhibiting a gauche-
coupling of 2 and 3 Hz with H8a (d 2.62). By irradiating the
multiplet of H8a, one can identify H4a as a hidden multiplet
at d 1.78. Further irradiation of H4a revealed protons H5.
The higher stability of 15-A compared to 15-B can be
rationalised as follows. Structure A shows two 1,3-diaxial
interactions of the axial phenyl group with H4a and H8a,
while B displays 1,3-diaxial repulsions of the ester group
with H8ax and the C4a–C4 linkage. Clearly, the latter is more
important. For lactam 7 a similar repulsion exists between
the ester group and the C4a–C4 linkage in conformer B.
H
5ax appears as a triplet at d 2.51, and H5eq as a doublet of
In contrast to amino lactam 7 that exists as conformational
structure A, the analogous N1–Ac compounds 17–20 were
shown to adopt conformation B as seen from the relevant
doublets at d 2.37. The large coupling between H5ax and H4a
again indicates a trans-diaxial relationship. By comparison
of measured and predicted coupling values in Table 1, one
may conclude that diamine 15 also has the A-conformation.
Further assignment of the signals was carried out as
described for 7. Coupling constants and shift values that
1
vicinal coupling constants in their H NMR spectra (see
Section 4). This preference for B can be ascribed to the
strong repulsion between the N–Ac group and the coplanar
C8a–C8 linkage in conformer A. The 1H NMR spectra of the
Figure 4.

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F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
Scheme 7.
H2NCH2CH2NH2 similarly results from the stabilisation
provided by the internal hydrogen bridge in the mono-
protonated form.21
The two NH absorptions became visible at d 9.8 and d 8.9
upon cooling of the CD2Cl2 solution of 8 to 198 K (Fig. 5).
Presumably, these downfield chemical shift values result
from intramolecular hydrogen bridge formation. Since both
NH protons display downfield shift values one may infer
that the ether oxygen is also involved in internal hydrogen
bond formation, as shown in Figure 5.
The conformational structure of 8 was further examined by
2D 1H–1H NOESY analysis. The spectrum revealed a
correlation between the phenyl ortho-protons and H5eq, H4a
and H8ax, confirming the axial position of the phenyl group,
and hence the A-conformation. A correlation also was
observed between the phenyl ortho-protons and one of the
diastereotopic C6CH2-protons. This indicates a restricted
conformational freedom, probably due to intramolecular
hydrogen bond formation involving the adjacent oxygen
atom. The C6CH2 group could be distinguished from
the benzyl methylene group by the correlation found for
the latter methylene protons with the ortho-protons of the
3,5-bis(trifluoromethyl)phenyl moiety. Correlations
relevant for the structure determination of 8 are shown in
Figure 6.
Figure 5.
N–Ac compounds were rather complex due to the Z/E-
rotamerism about the N1-acetyl linkage. The downfield shift
of H8a for the major rotamer (e.g. d 5.35 vs d 4.19 for the
minor rotamer of 17) indicates its proximity to the N–Ac
carbonyl group, and hence the existence of the Z-rotamer.
The 1H NMR spectrum of bis-acetylated compound 23
showed severe signal broadening owing to the Z/E-rotamer
exchange about the two N-acetyl linkages. After cooling to
223 K (400 MHz, CD2Cl2), two components were identified
in a 77:23 ratio. For both of these H8ax was observed as a
triplet corresponding to trans-diaxial coupling with H8a,
while H8eq was found as a doublet of doublets with a small
gauche coupling of 4 Hz. Both protons H5 appeared as a
doublet of doublets showing relatively large coupling values
of 11 and 7 Hz with H4a. The large trans-coupling of H8ax
supports conformation B, but the coupling values found for
H5 are not compatible with this structure. Molecular
modelling using MM3p suggested the existence of con-
former C, in which the N7 piperidine ring has a boat form
that minimises the repulsion experienced by the N7-acetyl
group. The coupling constants calculated for C (Haasnoot
et al.) are in good agreement with the experimental values
(Table 2). The orientation of the N–Ac groups can be
inferred from the chemical shifts of the coplanar equatorial
neighbouring protons. Thus H2eq and H8a are coplanar with
the N1–Ac linkage and absorb at d 3.59 and d 4.36 for the
major component of 23 while these values are reversed for
the minor component (d 4.36 and d 3.78). These data
respectively indicate the Z and E-configuration of the N1-
acetyl group. Proton H8eq absorbs at similar values for the
An NMR analysis reported for model 4 revealed the axial
orientation of the phenyl group (as is commonly observed
for gem-disubstituted six-membered ring compounds).11
Since antagonists (contrary to agonists) preferably bind to
the receptor in their ground state,20 the Ph-ax conformer
presumably represents the bioactive conformation. As
shown below, this Ph-ax conformation A also is preferred
for the 1,7-naphthyridine target products 8 and 9, and
increased activity (if any) of these compounds would
support the importance of this conformation (Fig. 4).
The 1H NMR spectra of 9 and 8 both revealed a large trans-
diaxial coupling of H5ax and the angular proton H4a, a small
eq,ax coupling of H5eq and H4a, and small (unresolved)
gauche-couplings of each geminal proton H8 with H8a.
These findings clearly support conformation A. For B one
expects a large trans-diaxial coupling for H8ax and H8a, a
small gauche coupling for H8eq and H8a, and two small
gauche couplings for each proton H5 and H4a. As already
postulated for diamine 8, an intramolecular hydrogen bridge
can exist between N1 and N7. The strongly broadened NH
signals (d 1–6 at 303 K) indicate a fast exchange of protons.
Presumably, this process involves the mono-protonated
form of the diamine produced by fast exchange with water
(Scheme 7). The increased basicity of diamines like

F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
4727
Figure 6.
Table 2. Experimental 3J coupling values in the 1H NMR spectra of 23 compared to coupling and torsion angle values calculated for conformational structures
B and C
Conformation
Angle (8)
3J8ax,8a
Angle (8)
3J8eq,8a
Angle (8)
3J5ax,4a
Angle (8)
3J5eq,4a
23-Ba
2173.3
170.3
–
11.1
10.9
12.2
260.4
275.2
–
4.0
2.3
3.9
248.1
153.1
–
4.8
10.2
10.6
64.6
39.9
–
2.4
6.5
7.4
23-Ca
23-experimentalb
Only the Z-N1-acetyl rotamers are shown.
a
Calculated with Macromodel 5.0.
400 MHz, CD3Cl3, 223 K.
b
major (d 3.52) and the minor rotamer (d 3.44), revealing a
common Z-configuration of the N7-acetyl group with
minimal repulsion from the 6-substituents.
molecular hydrogen bonding. Biological evaluation of 8
and 9 is currently in progress.
4. Experimental
4.1. General
3. Conclusion
Specifically substituted 1,7-naphthyridines, prepared via
intramolecular Diels–Alder reaction of 1-(4-pentenyl)-
2(1H)-pyrazinones followed by acidic methanolysis of the
hydrolysed adducts, can be converted into potential
Substance P antagonists. The conformational structure of
intermediates and final products was determined by 1H
NMR analysis. From examination of the coupling pattern it
appears that the cis-fused 1,7-naphthyridine scaffold adopts
a well-defined conformation, which in the case of the final
products resembles the presumed bioactive conformation of
known antagonists. For the diamine naphthyridines, this
conformation can additionally be stabilised by intra-
Melting points were taken using a Reichert–Jung
Thermovar 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
measurements performed in the EI mode at a resolution of
10,000. For the NMR spectra (d, ppm) a Bruker AMX 400
(8–11, 14, 15, 18–20, 23 and 24) and a Bruker Avance 300
(17) spectrometer were used. Analytical and preparative
thin layer chromatography was carried out using Merck

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F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
silica gel 60 PF-224; for column chromatography 70–230
mesh silica gel 60 (E.M. Merck) was used as the stationary
phase. Preparative TLC plates were prepared with silica gel
(Kiesgel 60, 70–230 mesh) of Macherey-Nagel and Fluka.
HPLC separations were carried out using a HIBAR column
[Merck, cat. 151435].
C8H10NOþ2 ), 96 (38, C6H10Nþ); exact mass calculated for
C18H22N2O4: 330.1580, found: 330.1583.
4.1.3. (4aR p,6S p,8aR p)-1-Acetyl-6-(hydroxymethyl)-6-
phenyloctahydro[1,7]naphthyridin-8(2H)-one 18. To an
ice-cooled solution of 193 mg (0.58 mmol) 17 in 20 mL
THF/H2O (4:1) was added 111 mg (5 equiv.) of NaBH4.
This mixture was stirred at 608C during 30 min. After
cooling, the unreacted NaBH4 was destroyed by adding
20 mL of 10% HCl/H2O. Next, THF was evaporated
followed by addition of water and CH2Cl2. After separation
of the organic phase, the water phase was extracted three
times with CH2Cl2 and the combined organic layers were
dried on anhydrous K2CO3. Filtration and evaporation of the
solvent yielded alcohol 18. Yield: 80%; transparent oil; IR
(NaCl, cm21): 3377.2, 3303.7 (NH, OH), 1676.5 (CvO);
1H NMR (400 MHz, CDCl3). Major rotamer (70%): 7.66 (s,
1H, H7), 7.42–7.27 (m, 5H, H-arom.), 5.01 (d, J¼7 Hz, 1H,
H8a), 3.72–3.60 (m, 2H, CH2OHþH2eq), 3.18 (broad t,
J¼12 Hz, 1H, H2ax), 3.00 (broad s, 1H, OH), 2.59 (dd,
J¼14, 8 Hz, 1H, H5eq), 2.14 (m, 1H, H4a), 2.09 (s, 3H,
COCH3), 1.93 (dd, J¼14, 5 Hz, 1H, H5ax), 1.83, 1.67, 1.39,
1.30 (m, 4H, H3þH4). Minor rotamer (30%): 7.75 (s, 1H,
H7), 7.42–7.27 (m, 5H, H-arom.), 4.43 (d, J¼13 Hz, 1H,
For the synthesis and spectral data of 5–7, see Refs. 13,14.
4.1.1. (4aR p,6S p,8aR p)-6-Hydroxymethyl-6-phenylocta-
hydro [1,7]naphthyridin-8(2H)-one 10. To a solution of
100 mg (0.4 mmol) of 7 in a 4:1 mixture of MeOH/H2O was
added an excess of NaBH4 (747 mg, 20 mmol). This
solution was stirred during 5 days at room temperature.
Next, a saturated solution of NH4Cl was added. After
evaporation of MeOH, a continuous extraction was carried
out with CH2Cl2 for 1 night. Evaporation of the solvent
yielded crude 10 that was further purified using column
chromatography (silica gel, 10% MeOH/CH2Cl2), and
crystallised from Et2O. Yield: 29 %; colourless crystals,
1
mp 1238C (Et2O); IR (KBr, cm21): 1652.0 (CvO); H
NMR (400 MHz, DMSO-d6): 8.12 (s, 1H, H7), 7.40–7.24
(m, 5H, H-arom.), 4.5–3.5 (s, very broad, NHþOHþH2O),
3.59 (d, J¼11 Hz, 1H, CH2OH), 3.52 (d, J¼11 Hz, 1H,
CH2OH), 3.35 (d, J¼5 Hz, H8a), 2.99 (m, 1H, H2eq), 2.72
(m, 1H, H2ax), 2.35 (dd, J¼14, 11 Hz, 1H, H5ax), 1.95 (dd,
J¼14, 4 Hz, 1H, H5eq), 1.85 (m, 1H, H4a), 1.60–1.35 (m,
4H, H3þH4); 13C NMR (100 MHz, DMSO-d6): 168.9 (C8),
143.9 (C-ipso), 128.2, 126.7, 126.1 (C-orthoþC-metaþC-
para), 69.1 (CH2OH), 62.2 (C6), 55.1 (C8a), 40.1 (C2), 31.7
(C5), 27.4 (C4a), 27.2, 20.0 (C4þC3); m/z (E.I., %): 260 (4,
Mzþ), 229 (13, Mzþ2CH2OH), 217 (100, Mzþ2C2H5N), 96
(82, C6H10Nþ); exact mass calculated for C15H20N2O2:
260.1525, found: 260.1522.
H
H
H
2eq), 3.99 (d, J¼7 Hz, H8a), 3.72–3.55 (m, 2H, CH2OHþ
2ax), 3.24 (broad s, 1H, OH), 2.71 (dd, J¼14, 9 Hz, 1H,
5eq), 2.24 (m, 1H, H4a), 1.63 (s, 3H, COCH3), H5ax, H3 and
H4 are hidden; 13C NMR (100 MHz, CDCl3). Major rotamer:
171.3, 171.1 (CO), 142.5 (C-ipso), 129.1, 127.7, 125.5 (C-
orthoþC-metaþC-para), 70.7 (CH2OH), 61.6 (C6), 51.8
(C8a), 43.8 (C2), 36.9 (C5), 31.6 (C4a), 30.3, 24.9 (C3þC4),
21.6 (COCH3). Minor rotamer: CO not resolved, 142.4 (C-
ipso), 129.2, 127.9, 125.5 (C-orthoþC-metaþC-para), 70.3
(CH2OH), C6 not resolved, 56.2 (C8a), 38.9 (C2), 36.3 (C5),
31.8 (C4a), 31.1, 24.1 (C3þC4), 21.2 (COCH3); m/z (E.I., %):
302 (9, Mzþ), 271 (100, Mzþ2CH2OH), 259 (51, Mzþ2Ac),
229 (29, Mzþ2CH2OH–CH2CO), 212 (60, C14H14NOþ), 186
(C12H12NOþ), 152 (46, C8H10NOþ2 ); exact mass calculated
for C17H22N2O3: 302.1630, found: 302.1627.
4.1.2. Methyl (4aR p,6S p,8aR p)-1-acetyl-8-oxo-6-phenyl
decahydro[1,7]naphthyridine-6-carboxylate 17. A sol-
ution of 200 mg of 7 in 50 mL acetic anhydride was stirred
at 408C during 1 h. Removal of reagent and acetic acid
formed afforded 17 in quantitative yield. Transparent oil; IR
(NaCl, cm21): 1735.3 (CvO-ester), 1675.6 (CvO-lactam),
1636.4 (CvO-acetyl); 1H NMR (300 MHz, CDCl3). Major
rotamer (74%): 7.43–7.32 (m, 5H, H-arom.), 6.79 (s, 1H,
H7), 5.36 (d, J¼5 Hz, 1H, H8a), 3.76 (s, 3H, CO2CH3), 3.70
(broad d, J¼13 Hz, 1H, H2eq), 3.07 (td, J¼13, 3 Hz, 1H,
4.1.4. (4aR p,6S p,8aR p)-1-Acetyl-6-({[3,5-bis(trifluor-
methyl) benzyl]oxy}methyl)-6-phenyloctahydro[1,7]
naphthyridin-8(2H)-one 19 and bis-benzylated com-
pound 20. To a suspension of 24 mg (1 mmol) of NaH in
5 mL of dry THF was added 312 mg (1.0 mmol) of 18 in
20 mL of dry THF. This mixture was stirred for 30 min at
458C. After cooling, 195 mL (1 equiv.) of 3,5-bis(trifluor-
methyl)benzyl bromide was added, and the reaction mixture
was stirred at room temperature for 2 h. When the reaction
was found to be incomplete (TLC monitoring: silica gel, 5%
MeOH/CH2Cl2, rf: 0.07 (18), 0.22 (19), 0.89 (side product
20), another 12 mg (0.5 equiv.) of NaH was added, and
stirring was continued for 2 h. Next, the reaction mixture
was worked up with 50 mL of H2O. The mixture was
extracted three times with CH2Cl2. The combined organic
layers were dried on anhydrous K2CO3, filtered, and
concentrated. The residue was purified by preparative
TLC (silica gel, 5% MeOH/CH2Cl2) to yield two fractions:
Fraction 1. 20: yield: 20%; white solid, mp 188–1918C
(MeOH/CH2Cl2); IR (KBr, cm21): 1675.1 (CvO); 1H
NMR (400 MHz, CDCl3). Major rotamer: 7.77–7.24 (m,
11H, H-arom.), 5.51 (d, J¼16 Hz, 1H, NCH2Ar), 5.23 (d,
J¼7 Hz, 1H, H8a), 4.44 (d, J¼16 Hz, 1H, NCH2Ar), 4.32 (d,
H
2ax), 2.98 (ddd, J¼15, 3, 2 Hz, 1H, H5eq), 2.28 (dd, J¼15,
5 Hz, 1H, H5ax), 2.17 (s, 3H, COCH3), 2.10 (m, 1H, H4a),
1.83 (m, 1H, H3eq), 1.74 (dt, J¼13, 3 Hz, 1H, H4eq), 1.44 (qt,
J¼13, 4 Hz, 1H, H3ax), 1.67 (qd, J¼13, 3 Hz, 1H, H4ax).
Minor rotamer (26%): 7.43–7.32 (m, 5H, H-arom.), 6.98 (s,
1H, H7), 4.52 (broad d, J¼13 Hz, 1H, H2eq), 4.19 (d,
J¼6 Hz, 1H, H8a), 3.76 (s, 3H, CO2CH3), 2.89 (m, 1H,
H
5eq), 2.48 (td, J¼13, 3 Hz, 1H, H2ax), 2.41 (dd, J¼15,
3eq, H4eq en H3ax are hidden, 0.84 (m, 1H, H4ax); 13C NMR
5 Hz, 1H, H5ax), 2.14 (m, 1H, H4a), 1.96 (s, 3H, COCH3),
H
(75 MHz, CDCl3). Major rotamer: 171.6, 170.7, 168.9
(CO), 141.3 (C-ipso), 129.1, 128.4, 124.2 (C-orthoþC-
metaþC-para), 64.4 (C6), 52.3 (CO2CH3þC8a), 43.5 (C2),
38.2 (C5), 33.4 (C4a), 26.9, 25.5 (C3þC4), 21.5 (COCH3).
Minor rotamer: most signals are not resolved; m/z (E.I., %):
330 (27, Mzþ), 287 (69, Mzþ2Ac), 271 (100, Mzþ2
CO2CH3), 229 (20, Mzþ2CH2CO–CO2Me), 212 (42,
C14H14NOþ), 186 (26, C12H12NOþ), 152 (33,

F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
4729
J¼12 Hz, 1H, OCH2Ar), 4.03 (d, J¼12 Hz, 1H, OCH2Ar),
3.71–3.61 (m, 3H, C6CH2OþH2eq), 3.20 (t, J¼12 Hz, 1H,
(s, 2H, H-ortho (Ar)), 7.41–7.29 (m, 5H, Ph-H), 6.67 (s, 1H,
H7), 4.63 (d, J¼13 Hz, 1H, OCH2Ph), 4.39 (d, J¼13 Hz, 1H,
OCH2Ph), 3.87 (d, J¼9 Hz, 1H, C6CH2O), 3.74 (d, J¼9 Hz,
1H, C6CH2O), 3.28 (d, J¼4 Hz, 1H, H8a), 3.06 (broad d,
J¼11 Hz, 1H, H2eq), 2.64 (td, partially hidden, 1H, H2ax), 2.62
(t, J¼13 Hz, 1H, H5ax), 2.48 (s, 1H, H1), 1.84 (m, 1H, H4a),
1.70 (broad d, J¼13 Hz, 1H, H5eq), 1.66–1.41 (m, 4H,
H3þH4); 13C NMR (100 MHz, CDCl3): 172.9 (C8), 143.0
(C-ipso (Ph)), 131.7 (q, J¼33 Hz, CCF3), 128.6, 127.4, 125.6
(C-orthoþC-metaþC-para (Ph)), 127.0 (broad s, C-ortho
(Ar)), 123.2 (q, J¼271 Hz, CF3), 121.6 (m, C-para (Ar)), 78.8
(C6CH2O), 71.7 (OCH2Ph), 61.9 (C6), 57.8 (C8a), 46.7 (C2),
32.5 (C5), 28.3 (C4), 27.7 (C4a), 21.4 (C3); m/z (E.I., %): 486
(10, Mzþ), 443 (100, Mzþ2C2H5N), 259 (6, Mzþ2C9H5F6),
229 (25, Mzþ2CH2OC9H5F6), 227 (20, C9H5Fþ6 ), 186 (59,
C12H12NOþ), 96 (94, C6H10Nþ); exact mass calculated for
C24H24N2O2F6: 486.1742, found: 486.1734.
H
2ax), 2.76 (dd, J¼14, 9 Hz, 1H, H5eq), 2.19 (m, 1H, H4a),
2.10 (s, 3H, COCH3), 2.08 (dd (hidden), 1H, H5ax), 1.94–
1.26 (m, 4H, H3þH4). Minor rotamer: most signals are
hidden under the major rotamer; 13C NMR (100 MHz,
CDCl3). Major rotamer: 171.073, 171.047 (C8þCOCH3
(lb¼0.5 Hz)), 142.4, 141.4 (C-ipso (Ar)), 139.2 (C-ipso
(Ph)), 131.8 (q, J¼34 Hz, CCF3), 131.4 (q, J¼32 Hz,
CCF3), 129.5, 128.2, 125.3 (C-orthoþC-metaþC-para
(Ph)), 127.0 (broad s, 2£C-ortho), 123.2 (q, J¼271 Hz,
CF3), 123.0 (q, J¼271 Hz, CF3), 121.9 (m, C-para (Ar)),
120.5 (m, C-para (Ar)), 76.3 (C6CH2O), 71.6 (OCH2Ar),
66.2 (C6), 52.1 (C8a), 47.9 (NCH2Ar), 43.6 (C2), 39.2 (C5),
30.9 (C4), 30.5 (C4a), 25.0 (C3), 21.4 (COCH3). Minor
rotamer: most signals are not resolved; m/z (E.I., %): 754 (9,
Mzþ), 735 (15, Mzþ2F), 711 (45, Mzþ2Ac), 527 (15,
Mzþ2C9H5F6), 497 (100, Mzþ2CH2OC9H5F6), 455 (13,
Mzþ2CH2CO–CH2OC9H5F6), 438 (49, C23H18NOFþ6 ), 227
(32, C9H5Fþ6 ), 152 (45, C8H10NOþ2 ); exact mass calculated
for C35H30F12N2O3: 754.2065, found: 754.2070. Fraction 2.
19: yield: 52%; white crystals, mp 103–1058C (MeOH/
CH2Cl2); IR (KBr, cm21): 1681.3 (CvO), 1629.8 (CvO);
1H NMR (400 MHz, CDCl3). Major rotamer (67%): 7.77 (s,
1H, H-para (Ar)), 7.51 (s, 2H, H-ortho (Ar)), 7.41–7.30 (m,
5H, Ph-H), 6.70 (s, 1H, H7), 5.17 (d, J¼6 Hz, 1H, H8a), 4.58
(d, J¼13 Hz, 1H, CH2Ph), 4.41 (d, J¼13 Hz, 1H, CH2Ph),
3.70–3.61 (m, 3H, C6CH2OþH2eq), 3.24 (broad t, J¼12 Hz,
1H, H2ax), 2.58 (dd, J¼14, 8 Hz, 1H, H5eq), 2.11 (s, 3H,
COCH3), 1.90 (dd, J¼14, 4 Hz, 1H, H5ax), 1.87 (m, 1H,
H4a), 1.79, 1.51–1.33 (m, 4H, H3þH4. Minor rotamer
(33%): 7.77 (s, 1H, H-para (Ar)), 7.51 (s, 2H, H-ortho (Ar)),
7.41–7.30 (m, 5H, Ph-H), 7.02 (s, 1H, H7), 4.58 (d,
J¼13 Hz, 1H, CH2Ph), 4.47 (broad d, J¼12 Hz, 1H, H2eq),
4.35 (d, J¼13 Hz, 1H, CH2Ph), 4.04 (d, J¼6 Hz, H8a), H2ax
is hidden, 2.74 (dd, J¼14, 9 Hz, 1H, H5eq), 2.24 (m, 1H,
4.1.6. (4aRp,6Sp,8aRp)-6-{[3,5-Bis(trifluormethyl)benzyl]-
oxy} methyl-6-phenyloctahydro[1,7]naphthyridine 8. To
a solution of 28.5 mg (0.59 mmol) of 9 in 10 mL of dry THF
was added 59 mL (2 equiv.) of a 2 M solution of BH3·DMS in
THF. This mixture was stirred under reflux during 1 h. Next,
the solvent was evaporated and the residue was redissolved in
HCl-saturated MeOH. The mixture was refluxed for 30 min to
destroy the intermediate complex 21. After cooling, a 10%
solution of K2CO3 in H2O was added, and the mixture
extracted three times with CH2Cl2. The organic phase was
dried on anhydrous K2CO3 and the residue was purified by
preparative TLC (silica gel, 10% MeOH/CH2Cl2) to yield 8,22
which was crystallised from Et2O/heptane. Yield: 43%, white
crystals, mp 163–1658C (Et2O/heptane); IR (cm21, KBr):
3429.0 (NH), 1626.1; 1H NMR (400 MHz, CDCl3):23 7.71 (s,
1H, H-para (Ar)), 7.48 (s, 2H, H-ortho (Ar)), 7.45 (d, J¼7 Hz,
2H, H-ortho (Ph)), 7.35 (t, J¼7 Hz, 2H, H-meta), 7.28 (t,
J¼7 Hz, 1H, H-para), 4.42 (s, 2H, OCH2Ph), 3.64 (2£d (AB),
J¼9 Hz, 2H, C6CH2O), 3.56 (broad d, J¼11 Hz, 1H, H2eq),
3.36 (d, J¼14 Hz, 1H, H8eq), 2.92 (broad s, 1H, H8a), 2.89 (d,
J¼14 Hz, 1H, H8ax), 2.83 (t, J¼12 Hz, 1H, H2ax), 2.35 (t,
J¼14 Hz, 1H, H5ax), 2.16 (dd, J¼14 Hz, 1H, H5eq), 2.11 (m,
1H, H3ax), 1.94 (m, 1H, H4a), 1.70–1.65 (m, 3H, H3eqþH4);
13C NMR (100 MHz, CDCl3): 141.2, 140.5 (C-ipso (Ph)þC-
ipso (Ar)), 131.5 (q, J¼33 Hz, CCF3), 128.5, 127.1 (C-arom.
(Ph), one signal is hidden), 127.0 (broad s, C-ortho (Ar)),
123.2 (q, J¼273 Hz, CF3), 80.9 (C6CH2O), 71.7 (OCH2Ph),
59.8 (C6), 54.3 (C8a), 44.8 (C2), 43.8 (C8), 29.8 (C5), 28.4 (C4),
28.3 (C4a), 17.8 (C3); m/z (E.I., %): Mzþ-signal was not
detected, 376 (12, Mzþ2C6H10N), 227 (9, C9H5Fz6þ), 215 (100,
Mzþ2CH2OCH2C9H5F6); exact mass calculated for
C24H26N2OF6: 472.1949, found: Mzþ not detected; exact
mass calculated for C18H16NOF6: 376.1136, found: 376.1133;
exact mass calculated for C14H19N2: 215.1555, found:
215.1548.
H4a), 1.69 (s, 3H, COCH3), H5ax, H3 and H4 are hidden; 13
C
NMR (100 MHz, CDCl3). Major rotamer: 170.5, 169.7
(CO), 143.5 (C-ipso (Ar)), 140.1 (C-ipso (Ph)), 131.8 (q,
J¼33 Hz, CCF3), 129.0, 127.7, 125.0 (C-orthoþC-
metaþC-para (Ph)), 127.1 (broad s, C-ortho, (Ar)), 123.2
(q, J¼271 Hz, CF3), 121.7 (m, C-para (Ar)), 78.6
(OCH2Ph), 71.8 (C6CH2O), 60.1 (C6), 51.8 (C8a), 43.5
(C2), 37.8 (C5), 32.4 (C4a), 29.9, 25.3 (C3þC4), 21.5
(COCH3). Minor rotamer: most signals are not resolved; m/z
(E.I., %): 528 (6, Mzþ), 509 (6, Mzþ2F), 485 (34, Mzþ2Ac),
301 (7, Mzþ2C9H5F6), 271 (100, Mzþ2CH2OC9H5F6), 229
(18, Mzþ2CH2CO–CH2OC9H5F6), 227 (11, C9H5Fþ6 ), 212
(41, C14H14NOþ), 152 (30, C8H10NOþ2 ); exact mass
calculated for C26H26F6N2O3: 528.1848, found: 528.1847.
4.1.5. (4aRp,6Sp,8aRp)-6-{[3,5-Bis(trifluormethyl)benzyl]-
oxy} methyl-6-phenyloctahydro[1,7]naphthyridin-8(2H)-
one 9. A solution of 50 mg (0.1 mmol) of 19 in HCl-saturated
methanol was stirred at 608C for 2 days. Next, the solvent and
HCl were evaporated. After addition of 10% K2CO3/H2O to
the residue, the aqueous mixture was extracted three times
with CH2Cl2. The combined organic phases were dried on
anhydrous K2CO3, filtered and evaporated. The residue was
purified by preparative TLC (silica gel, 10% MeOH/CH2Cl2)
to afford 9. Yield: 64% (81% with recovery of starting
material); transparent oil; IR (NaCl, cm21): 1662.7 (CvO);
1H NMR (400 MHz, CDCl3): 7.75 (s, 1H, H-para (Ar)), 7.47
4.1.7. 1-(4-Pentenyl)-3-phenyl-2(1H)-pyrazinone 11. To a
solution of 3.5 g (19.4 mmol) of 3-phenyl-2(1H)-pyrazi-
none 22 (see Ref. 17) in 150 mL dioxane was added 8.0 g of
Cs2CO3 (1.2 equiv.). After stirring this mixture at 508C for
30 min, 3.0 mL of 5-bromo-1-pentene (1.5 equiv.) was
added, and stirring at 508C was continued for 1 week.
Following filtration of unreacted Cs2CO3 and CsBr formed
and removal of the solvent, the residue was purified by
column chromatography (silica gel, CH2Cl2) to give two

4730
F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
fractions consisting of O- and N-alkenylated product,
respectively. Only the N-alkenylated product (11) was
isolated. Yield: 96%; yellow oil; IR (NaCl, cm21): 1650.3
(CvO), 1591.3 (CvN); 1H NMR (400 MHz, CDCl3): 8.3–
96 (66, C6H10Nþ), 83 (38, C5H9Nþ); exact mass calculated
for C16H20N2O2: 274.1681, found: 274.1677.
4.1.10. Methyl (4aR p,6S p,8aR p)-1,7-diacetyl-6-phenyl-
decahydro[1,7]naphthyridine-6-carboxylate 23 and tri-
cyclic compound 24. A solution of 250 mg of 15 and
252 mg (2 equiv.) DMAP in 50 mL acetic anhydride was
stirred at 608C for 2 h. Next, Ac2O and the acetic acid
formed were evaporated, and the residue was purified by
preparative TLC (silica gel, 5% MeOH/CH2Cl2), which
afforded two fractions. Fraction 1. 24: yield: 13%; brown
crystals, mp 125–1278C (MeOH/CH2Cl2); IR (KBr, cm21):
1694.4 (CvO), 1662.7 (CvO); 1H NMR (400 MHz,
7.4 (m, 6H, H-arom.þH6), 7.08 (d, J¼4 Hz, 1H,0 H5), 5.80
0
(ddt, J¼18, 10, 7 Hz, 1H, H4 ), 5.06 (m, 2H, H5 ), 03.95 (t,
0
J¼7 Hz, 2H, H1 ), 2.14 (quart, J¼7 Hz, 2H, H3 ), 1.91
0
(quint, J¼7 Hz, 2H, H2 ); 13C NMR (100 MHz, CDCl3):
0
155.4 (C2), 153.4 (C3), 136.7 (C4 ), 136.0 (C-ipso), 129.8
(C-para),0128.9 (C-meta), 127.9 (C6þC-ortho), 123.2 (C5),
0
0
0
115.9 (C5 ), 49.6 (C1 ), 30.5 (C3 ), 27.5 (C2 ); m/z (E.I., %):
240 (46, Mzþ), 186 (40, Mzþ2C4H6), 172 (35, Mzþ2C5H8),
105 (100, PhCOþ), 77 (32, Phþ); exact mass calculated for
C15H16N2O: 240.1263, found: 240.1258.
CDCl3, 318 K): 7.39–7.31 (m, 5H, H-arom.), 4.16 (dd,
0
J¼13, 5 Hz, 1H, H4eq), 3.91 (dd, J¼12, 3 Hz, 1H, H9 ), 3.72
(dd, J¼12, 2.5 Hz, 1H, H9), 3.47 (m, 1H, H8), 2.92 (t0d,
J¼13, 2 Hz, 1H, H4ax), 2.83 (dd, J¼14, 10 Hz, 1H, H11 ),
2.43 (m, 1H, H7), 1.94 (dd, J¼14, 3 Hz, 1H, H11), 1.89 (m,
1H, H6ax), 1.72 (m, 1H, H5ax), 1.68 (m, 1H, H6eq), 1.49
(broad s, 3H, COCH3), 1.35 (m, 1H, H5eq); 13C NMR
(100 MHz, CDCl3, 318 K): 177.1 (C2), 171.9 (COCH3),
137.5 (C-ipso), 130.6, 126.1 (broad, 2£C-ortho), 128.1
(C-meta), 127.9 (C-para), 67.4 (C1), 57.3 (C8), 50.5 (C9),
49.8 (C4), 36.1 (C11), 32.9 (C7), 29.5 (C6), 24.9 (broad,
COCH3), 17.6 (C5); m/z (E.I., %): 284 (54, Mzþ), 256 (14,
Mzþ2CO), 242 (100, Mzþ2CH2CO), 241 (25, Mzþ2Ac),
213 (88, Mzþ2Ac–CO), 158 (22, Mzþ2Ac–(CH2)3NCO),
156 (34, C11H10Nþ); exact mass calculated for
C17H14N2O2: 284.1525, found: 284.1521. Fraction 2. 23:
yield: 73%; white crystals, mp 1668C (MeOH/CH2Cl2); IR
(KBr, cm21): 1742.5 (CvO-ester), 1644.0 (CvO-lactam)
1H NMR (400 MHz, CD2Cl2, 223 K). Major rotamer (77%):
7.36–7.25 (m, 5H, H-arom.), 4.37 (m, 1H, H8a), 3.60 (t,
J¼11 Hz, 1H, H8ax), 3.59 (d (hidden), 1H, H2eq), 3.56 (s,
3H, CO2CH3), 3.52 (dd, J¼11, 4 Hz, 1H, H8eq), 2.87 (broad
t, J¼11 Hz, 1H, H2ax), 2.63 (dd, J¼14.5, 7 Hz, 1H, H5eq),
2.19 (s, 3H, COCH3), 2.10 (dd, J¼13.5, 11 Hz, 1H, H5ax),
1.98 (s, 3H, COCH3), 1.80 (m, 1H, H4eq), 1.60 (m, 1H,
4.1.8. 1-Phenyl-3,10-diazatricyclo[5.3.1.03,8]undecan-2-
one 14. A solution of 335 mg (1.4 mmol) of 11 in dry
PhCl was refluxed for 3 days. Next, the solvent was
evaporated and the residue was redissolved in dry THF. To
this solution was added 50 mg of 10% Pd/C. After
degassing, the mixture was hydrogenated at 40 psi (Parr-
apparatus) during 1 night. The mixture was filtered and
evaporated. The residue was purified by column chroma-
tography (silica gel, 5% MeOH/CH2Cl2) followed by HPLC
(silica gel, 5% MeOH/CH2Cl2). Yield: 57%; white crystals;
mp 160–1638C (MeOH/CH2Cl2); IR (KBr, cm21): 3438.2
(broad, NH), 1647.2 (CvO); 1H NMR (400 MHz, CDCl3):
7.53–7.25 (m, 5H, H-arom.), 4.25 (dd, J¼13, 5 Hz, 1H,
0
H
4eq), 3.38 (m, 1H, H8), 3.27 (dd, J¼11, 4 Hz, 1H, H9 ), 3.14
(dd, J¼11, 1 Hz, 1H, H9), 2.87 (td, J¼13, 3 Hz, 1H, H4ax),
0
2.46 (dd, J¼13, 10 Hz, 1H, H11 ), 2.35 (broad d, J¼10 Hz,
0
1H, H7 ), 1.86 (dd, J¼13, 2 Hz, 1H, H11), 1.92–1.80 (m, 3H,
H5þH6þH10), 1.62 (m, 1H, H6), 1.36 (m, 1H, H5); 13C
NMR (75 MHz, CDCl3): 182.5 (C2), 139.2 (C-ipso), 127.8,
127.4; 127.1 (C-orthoþC-metaþC-para), 61.4 (C1), 57.9
(C8), 49.9 (C4), 46.0 (C9), 39.7 (C11), 33.8 (C7), 30.0, 18.5
(C5þC6); m/z (E.I., %): 242 (100, Mzþ), 214 (72, Mzþ2CO),
158 (55, Mzþ–(CH2)3NCO); exact mass calculated for
C15H18N2O: 242.1419, found: 242.1424.
H
3eq), 1.54 (m, 1H, H4a), 1.23 (m, 2H, H4axþH3ax). Minor
rotamer (23%): 7.36–7.25 (m, 5H, H-arom.), 4.4 (hidden,
1H, H2eq), 3.93 (t, J¼12 Hz, 1H, H8ax), 3.77 (m, 1H, H8a),
3.6 (hidden, 3H, CO2CH3), 3.44 (dd, J¼11.5, 2.5 Hz, 1H,
4.1.9. Methyl (4aR p,6S p,8aR p)-6-phenyldecahydro[1,7]
naphthyridine-6-carboxylate 15. To a solution of 94 mg
(0.39 mmol) of 14 in 20 mL MeOH was added 131 mL
(3.5 equiv.) CH3SO3H. This solution was stirred at reflux
temperature for 1 night. Next, the solvent was evaporated,
and the residue was distributed between CH2Cl2 and 10%
K2CO3 in H2O. After separation of the organic phase, the
aqueous phase was extracted three times with CH2Cl2. The
combined organic phases were dried on anhydrous K2CO3,
filtered and evaporated to afford pure 15. Yield: 97 %;
transparent oil; IR (NaCl, cm21): 1732.5 (CvO); 1H NMR
(400 MHz, CDCl3): 7.56 (d, J¼7 Hz, 2H, H-ortho), 7.37 (t,
J¼7 Hz, 2H, H-meta), 7.27 (t, J¼7 Hz, 1H, H-para), 3.62
(s, 3H, CO2CH3), 3.20 (broad d, J¼12 Hz, 1H, H2eq), 2.94
(dd, J¼14, 2 Hz, 1H, H8eq), 2.77 (dd, J¼14, 3 Hz, 1H, H8ax),
2.70 (td, J¼12, 3 Hz, 1H, H2ax), 2.61 (m, 1H, H8a), 2.51 (t,
J¼14 Hz, 1H, H5ax), 2.37 (dd, J¼14, 4 Hz, 1H, H5eq), 1.77
(m, 1H, H4a), 1.76 (m, 1H, H3ax), 1.64 (m, 2H, H4), 1.42 (dt,
J¼13, 3 Hz, 1H, H3eq); 13C NMR (100 MHz, CDCl3): 174.4
(CO2CH3), 138.3 (C-ipso), 128.5, 127.3, 127.2 (C-orthoþ
C-metaþC-para), 63.8 (C6), 53.2 (C8a), 52.4 (CO2CH3),
46.2 (C2), 46.0 (C8), 30.7 (C5), 29.4 (C4), 29.3 (C4a), 20.3
(C3); m/z (E.I., %): 275 (1, Mzþ), 215 (100, Mzþ2C2H4O2),
H
8eq), 2.72 (dd, J¼15, 8 Hz, 1H, H5eq), 2.38 (broad t,
J¼13 Hz, 1H, H2ax), 2.22 (s, 3H, COCH3), 2.1 (hidden, 1H,
H
5ax), 1.79 (s, 3H, COCH3), H3 and H4 are hidden, 1.70 (m,
1H, H4a); 13C NMR (100 MHz, CD2Cl2, 233 K), Major
rotamer: 172.4 (CO2CH3), 170.6, 169.7 (2£COCH3), 137.3
(C-ipso), 127.44, 127.36, 127.1 (C-orthoþC-metaþC-para),
65.3 (C6), 52.6 (CO2CH3), 44.4 (C8a), 43.4 (C2), 41.7 (C8), 39.7
(C5), 27.7 (C4), 26.2 (C4a), 23.4 (C3), 22.44, 22.39 (2£COCH3).
Minor rotamer: CvO, C-arom. and C6 are not resolved/hidden,
52.7 (CO2CH3), 48.9 (C8a), 43.8 (C8), 39.4 (C5), 37.6 (C2), 27.8
(C4), 27.0 (C4a), 23.1 (C3), 21.6, 21.8 (2£COCH3); m/z (E.I.,
%): 358 (17, Mzþ), 326 (45, Mzþ2CH3OH), 315 (44, Mzþ2Ac),
299 (16, Mzþ2CO2Me), 284 (17, Mzþ2CH3OH–Ac), 257
(100, Mzþ2CH2CO–CO2Me), 181 (27, C14H1þ3), 138 (11,
C8H12NOþ); exact mass calculated for C20H26N2O4: 358.1893,
found: 358.1894.
Acknowledgements
The authors thank the FWO (Fund for Scientific

F. J. R. Rombouts et al. / Tetrahedron 59 (2003) 4721–4731
4731
(d) Leroy, V.; Mauser, P.; Gao, Z.; Peet, N. P. Exp. Opin.
Investig. Drugs 2000, 9(4), 735.
Research-Flanders, Belgium) and Janssen Pharmaceutica
for financial support. We are grateful to R. De Boer for
HRMS measurements. F. R. thanks the K. U. Leuven for
the fellowships received.
13. Rombouts, F. J. R.; De Borggraeve, W.; Toppet, S.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett. 2001,
42, 7397–7399.
14. Rombouts, F. J. R.; De Borggraeve, W. M.; Delaere, D.;
Froeyen, M.; Toppet, S. M.; Compernolle, F.; Hoornaert, G. J.
Eur. J. Org. Chem. 2003, 10, 1868–1878.
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