Generation of cyclopenta[c]piperidines and pyrrolo[3,4-c]piperidines-Potential substance P antagonists - From adducts of cyclic dienophiles and 5-chloro-6-methyl-3-phenyl-2H-1,4-oxazin-2-one

Article abstract of DOI:10.1016/S0040-4020(00)00559-7

1,1,4,4-Tetrasubstituted cyclopenta[c]piperidines and the corresponding 4,4,7,7-pyrrolo[3,4-c]piperidines have been synthesised via cycloaddition of 5-chloro-6-methyl-3-phenyl-2H-1,4-oxazin-2-one with cyclopentene and 3-pyrroline derivatives, respectively, followed by reductive opening of the lactone-bridged adducts. The axial-equatorial conformational preferences of the substituents in these cis-fused bicyclic systems were opposite to those for the monocyclic piperidine analogues. The specific array of functional groups in the bicyclic aminoalcohols was used to accommodate, in stereocontrolled fashion, variable pharmacophoric groups that are of interest for substance P antagonist activity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00559-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6279±6290
Generation of Cyclopenta[c]piperidines and
Pyrrolo[3,4-c]piperidinesÐPotential Substance P
AntagonistsÐfrom Adducts of Cyclic Dienophiles
and 5-Chloro-6-methyl-3-phenyl-2H-1,4-oxazin-2-one
*
Xiujuan Wu, Suzanne Toppet, Frans Compernolle and Georges J. Hoornaert
Laboratorium voor Organische Synthese, Departement Scheikunde, K.U. Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium
Received 15 March 2000; revised 24 May 2000; accepted 8 June 2000
AbstractÐ1,1,4,4-Tetrasubstituted cyclopenta[c]piperidines and the corresponding 4,4,7,7-pyrrolo[3,4-c]piperidines have been synthesised
via cycloaddition of 5-chloro-6-methyl-3-phenyl-2H-1,4-oxazin-2-one with cyclopentene and 3-pyrroline derivatives, respectively, followed
by reductive opening of the lactone-bridged adducts. The axial-equatorial conformational preferences of the substituents in these cis-fused
bicyclic systems were opposite to those for the monocyclic piperidine analogues. The speci®c array of functional groups in the bicyclic
aminoalcohols was used to accommodate, in stereocontrolled fashion, variable pharmacophoric groups that are of interest for substance P
antagonist activity. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
based non-peptide substance P antagonists, we synthesised
bicyclic piperidine derivatives 1±2 mimicking the model
compounds III and IV (Fig. 1). Speci®c pharmacophoric
groups comprised in target products 1±2 are like those for
the previously reported monocyclic analogues,8 but now
accommodated in cis-fused bicyclic systems. Interestingly,
target product 2 incorporates both the 3,5-bis(tri¯uoro-
methyl)phenyl substitution favoured in the aminoether
series (III) and the o-methoxyphenylacetyl substituent
found in the perhydroisoindole-based series (IV). The
spatial orientation of substituents in these cis-decaline-like
fused bicyclic systems was studied by NMR compared to
conformational model calculations and was found to be
opposite to those reported for the monocyclic tetrasubsti-
tuted piperidine analogues8 and the related model
compound III.4
Substance P acts as a neurotransmitter and is the most abun-
dant neurokinin in the mammalian central nervous system
(CNS). Mediated by the NK1 receptor, substance P is postu-
lated to play an important role in a number of biological
processes including pain transmission, anxiety, asthma and
neurogenic in¯ammation.1 This pro®le has stimulated a
search for highly potent and selective antagonists of the
neurokinin-1 (NK1) receptor; many non-peptide NK1
antagonists have been developed, notable examples inclu-
ding the quinuclidine-based CP-96, 345 (I),2 aminopiperidine
CP-99, 994 (II),3 bis(tri¯uoromethyl)benzyloxypiperidine
(III),4 and the perhydroisoindole-based series related to
RPR-100, 893 (IV).5 However, many of the early non-
peptide NK1 antagonists suffered from poor brain penetra-
tion, low oral bioavailability, signi®cant ion channel
af®nity, or poor duration of action.6 Thus patent activity in
the area of NK1 antagonists remains high, and the emphasis
has shifted toward the ®ne-tuning of in vivo properties.
Results and Discussion
Synthesis of compounds 1 and 2
Structure activity relationship studies1b,6b,c,7 have estab-
lished that in many potent NK1 antagonists, common
pharmacophoric features are a piperidine ring, and phenyl
and 3,5-bis(tri¯uoromethyl)phenyl groups. As part of an
ongoing project aimed at developing novel piperidine-
Recently we described an ef®cient and general approach to
2,2,5,5-substituted piperidines proceeding via cycloaddition
of 3-alkyl or 3-phenyl-2H-1,4-oxazin-2-ones with ethene
and further conversions of the adducts.8 This methodology
now is extended to cyclic dienophiles. Cycloaddition of
cyclopentene with 5-chloro-6-methyl-3-phenyl-2H-1,4-
oxazin-2-one 3 was carried out in re¯uxing chloroform,
yielding predominantly endo-adduct 4 (see below for the
structural characterisation of 4 and other adducts derived
Keywords: bicyclic heterocyclic compounds; piperidines; Diels±Alder
reactions; conformation.
* Corresponding author. Tel.: 132-16-32-74-09; fax: 132-16-32-79-90;
e-mail: georges.hoornaert@chem.kuleuven.ac.be
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00559-7

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X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
Figure 1.
from 3 and cyclic dienophiles). This adduct was converted
to compound 1 in ca. 42% overall yield based on starting
oxazinone 3, by applying the previously described
sequence,8 i.e. reduction of the imidoyl chloride and lactone
groups of adduct 4 with lithium aluminium hydride
followed by selective O-alkylation of the primary alcohol
function of aminodiol 5 (Scheme 1).
products, from which the desired compound 10 could not be
isolated.
In a second approach, N-carbobenzyloxy(Cbz)-3-pyrroline,
prepared from cis-1,4-dichloro-2-butene according to the
literature procedure,9 was used as dienophile to give again
exclusively the endo-adduct 6b. Not unexpectedly, reduc-
tion of the sterically hindered imidoyl chloride and lactone
functions of 6b with LiAlH4 also led to the concurrent
conversion of the N-Cbz protecting group to a N-methyl
group. To avoid this unwanted reaction, NaBH4 in DMF/
THF was used as a more selective reducing agent, able to
reduce ester or lactone carbonyl groups in preference to
amide or carbamate functions.10 Under these conditions,
which involved heating at 758C (oil bath temperature)
for 2 days, the desired bicyclic alcohol 8 (PvCbz) was
obtained in low yield only. Finally, the commercially
In our ®rst approach to construct the tetrasubstituted
pyrrolo[3,4-c]piperidine ring system of compound 2,
cycloaddition of 3 was carried out using maleimide as
dienophile to form the endo-adduct 6a. Following conver-
sion of the imidoyl chloride function to a stable lactam
group by heating 6a with methanol, the endo-con®guration
of lactam 7 and its precursor was ascertained by NMR
analysis (see Fig. 2 and discussion below). Unfortunately,
reduction of 7 or 6a with LiAlH4 gave a complex mixture of
Scheme 1. (i): (1) NaH (2 equiv.), DMF; (2) 3,5-bis(tri¯uoromethyl)benzylbromide (1.1 equiv.), THF, rt, 1d.

X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
6281
available N-benzyl 3-pyrroline was selected as a dienophile
for Diels±Alder reaction with oxazinone 3. The inter-
mediate endo-adduct 6c was isolated (92%) by ¯ash chro-
matography and reduced with LiAlH4 to give the N-benzyl
protected pyrrolo[3.4-c]piperidinediol 9 in an excellent
overall yield.
13. The N-tri¯uoroacetyl compound 12b in turn was
subjected to the same O-benzylation conditions, since the
expected product 14 could also serve as an intermediate in
the synthesis of the end product 2. Indeed, because of its
ready cleavage under variable mild conditions,12 the N-
tri¯uoroacetyl group has been widely used as a protecting
function. However, the desired benzyl ether 14 was isolated
in small yield only (6%), besides the N, O-dibenzylated
product 15 (15%). Presumably, partial loss of the amide
protecting group results from intermolecular (N!O) acyl
migration.
To convert 9 to the end product 2, two alternative routes can
be used starting with: (a) N-debenzylation followed by
chemoselective acylation of the pyrrolidine N-atom; or (b)
initial introduction of the desired O-benzyl group which
then requires selective N- versus O-debenzylation. Both
sequences may be concluded with a second functionalisa-
tion step that allows for a broad variation of pharmacophoric
groups on either the hydroxymethyl side chain or the pyrro-
lidine moiety.
In our second approach we started with O-benzylation of 9
affording the benzyl ether derivative 16 in good yield
(Scheme 3). The next two steps consisted of selective
N-debenzylation followed by N-acylation with o-methoxy-
phenylacetyl chloride. Although O-debenzylation normally
proceeds more readily than removal of a N-benzyl group,
Czech and Bartsch13 reported that hydrogenolysis of the
O-benzyl group was inhibited when aliphatic amines were
added to the hydrogenation medium (Pd/C in ethanol), or
even when an aliphatic N-benzylamino group was present in
the same molecule. This ®nding was used to develop selec-
tive procedures for N-debenzylation and hydrogenation of a
double bond with retention of the O-benzyl group. We
further explored conditions for selective N-debenzylation
by subjecting N,N-dibenzyl-2-(benzyloxy)-1-ethanamine
(DBBEA) to catalytic transfer hydrogenation. Under the
conditions already described for N-debenzylation of 9,
both N-benzyl groups of DBBEA were removed and
(benzyloxy)ethylamine was isolated as the formate salt.14
In a similar way application of this procedure to the
O-bis(tri¯uoromethyl)benzyl ether 16 gave the selectively
N-debenzylated amine 17, again obtained as the formate salt
and characterised by spectral and CHN-analysis. Final
N-Debenzylation of 9 was carried out by catalytic transfer
hydrogenation11 using ammonium formate as the H-transfer
agent to produce 10 in excellent yield as the formate salt
(Scheme 1). In a preliminary experiment using o-methoxy-
phenylacetyl chloride, a poor selectivity was observed
between acylation of the pyrrolidine NH and the primary
OH group. When using 1 equiv. of both o-methoxyphenyl-
acetic acid and the coupling reagent 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide
hydrochloride
(EDCI),
together with triethylamine to liberate the free amine 10
from its formate salt, 10 was converted to the corresponding
N-acyl derivative 11 in 32% yield (Scheme 2). With an
excess of reagents, the acylation reaction again was not
selective. However, the N-formyl and N-tri¯uoroacetyl
derivatives 12a, b were obtained quantitatively by reaction
of the formate salt 10 with methyl formate or ethyl tri¯uoro-
acetate in methanol in the presence of triethylamine. Further
O-benzylation of 12a yielded the N-formylated end product
Scheme 2. (a): o-methoxyphenylacetic acid (1.0 equiv.), Et3N (2.2 equiv.), DMAP (0.2 equiv.), EDCI (1.0 equiv.), CH2Cl2/DMF, rt, overnight. (i): HCOOMe
(for 12a) (1.5 equiv.) or CF3COOEt (for 12b) (1.5 equiv.), Et3N (1.5 equiv.), MeOH, rt. (ii): (1) NaH (2 equiv.), DMF; (2) 3,5 bis(tri¯uoromethyl)benzyl-
bromide (1.1 equiv.), THF, rt, 1d.

6282
X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
Scheme 3. (i): (1) NaH (2 equiv.), DMF; (2) 3,5 bis(tri¯uoromethyl)benzylbromide (1.1 equiv.), THF, rt, 1d. (ii): HCOONH4, Pd/C, MeOH, re¯ux. (iii): (1)
o-methoxyphenylacetic acid, PPh3, CCl4, re¯ux; (2) pyridine, THF, 2158C.
acylation of the pyrrolidine N-atom was effected with
o-methoxyphenylacetyl chloride and pyridine, affording
compound 2 as white crystals; the overall yield for the
puri®ed product was ca. 50%, calculated over three steps
starting from 9.
clear long range coupling (4Jˆ2.0 Hz) was observed
between the pseudoaxial proton H-11 (18a dˆ2.98, 18b
dˆ3.02) and the exo proton H-6, showing the all-trans
bond connectivity (see W-pattern in Fig. 2). No general
explanation can be offered for the exclusive formation of
endo adducts in the reaction of 3 with cyclic dienophiles.
Although similar results have been reported for other
dienes,15 diverse arguments have been invoked: these can
be related to a favourable geometry for overlap in the endo
transition state for cyclopentene adduct 4,16 increased elec-
trostatic repulsions in the exo transition state for 3-pyrroline
adducts 6b, c,17 or secondary orbital interactions for the
maleimide adduct 6a.15c
Con®guration of cycloadducts 4 and 6 and conformation
of the bicyclic piperidine analogues
The stereochemical structure of cycloadducts 4 and 6,
including that of the lactam product 7 derived from 6a,
was assigned on basis of their 1H coupled 13C NMR spectra
(Fig. 2). For compounds 4, 6b and 6c, the endo con®gura-
tion was demonstrated by characteristic coupling constant
values of the angular protons H-2 and H-6 with, respec-
tively, the gauche-oriented lactone carbon atom C-9
(3Jˆca. 2 Hz) and the anti-oriented imidoyl carbon atom
C-11 (3Jˆca. 8 Hz). The latter carbon C-11 easily could
be distinguished from C-9 by a lower chemical shift value
and by the coupling observed with the protons of the bridge-
head methyl group. The structure of lactam 7 was attributed
The well-de®ned geometry and conformational structure of
the novel cis-fused bicyclic systems, exempli®ed by the
intermediate aminodiols 5, 9, and 10, and the functionalised
products 1 and 2, offer an excellent opportunity to de®ne
more exactly the spatial orientation of the pharmacophoric
groups required for bioactivity. From the endo mode of
cycloaddition, it follows that the cis-fused cyclopentane
(pyrrolidine) ring and the 1(4)-phenyl and 4(7)-methyl
substituents are located at the same side of the piperidine
ring. Two conformational structures, APheq and BPhax having
an equatorial and axial orientation of the phenyl group, may
apply to these cis-decaline-like bicyclic systems (Fig. 3).
From model calculations using Hyperchem it was
concluded that, in contrast to the analogous monocyclic
2,2,5,5-substituted piperidines which have the 2-phenyl
3
in a similar way on basis of J values corresponding to
coupling of H-2 and H-6 with, respectively, the lactone
and lactam carbon atoms C-9 (3Jˆ1 Hz) and C-11
(3Jˆ7 Hz). Further con®rmation for the endo mode of
cycloaddition was obtained from the tricyclic compounds
18. These were derived from adducts 4 and 6c via selective
reduction of the imidoyl chloride function with NaCNBH3
at pH 5. In the 1H NMR spectra of the reduced compounds, a
Figure 2.

X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
6283
Figure 3.
(alkyl, H) axially oriented,8 form APheq is largely favoured
over BPhax. Apparently, repulsive interactions between the
axial phenyl group and both cis-disposed methylene groups
of the ®ve-membered ring are more severe than those
experienced by the axial methyl group in the preferred
conformation.
As a consequence of the steric constraint imposed by the
axial methyl group in the favoured conformation APheq, rota-
tion of the amide bond is severely hindered for the
N-acylated end products 2 and 13. This resulted in the
separation of two rotameric forms on HPLC or TLC.
However, reinjection of two fractions of compound 13 sepa-
rated by HPLC revealed that an equilibrium mixture of the
two rotameric forms had been formed again. Reduction of
separate HPLC fractions of 13 with BH3zSMe2 gave only
one N-methyl product, appearing as a single spot on TLC.
1
Both H coupled 13C NMR spectra and NOE observations
con®rmed that APheq is the preferred conformer for the
bicyclic piperidine derivatives 1, 2, 5, 9, and 10 and related
compounds, as predicted by the conformational calcula-
1
tions. In the H coupled 13C NMR spectrum of 1, the ipso
The conformational features discussed so far for the bicyclic
systems may affect their biological activities. A striking
difference, as compared to the monocyclic piperidine ana-
logues, is the inversed orientation of the phenyl and benzyl-
oxymethyl substituents. However, this should not
necessarily lead to a decreased activity, as the conforma-
tional situation may be compared to that for the analogous
2,3- and 2,2-substituted substance P antagonists III and V.18
While a similar high af®nity (1 nM) for the NK1 receptor has
been determined for these compounds, an opposite orienta-
tion has been established for the phenyl and benzyloxy
substituents in their preferred conformations (Fig. 3).
carbon of the 1-phenyl group appeared as a quartet with
3JC±Hˆ6 Hz, which changed to a triplet when decoupled at
d
4.28 ppm. This coupling pattern was veri®ed by
`COLOC' (two dimensional long-range correlation of 13C
1
2
3
and H, J and J). In the spectra of compounds 1 and 10,
cross peaks revealed coupling of the Ph-ipso carbon with
both meta protons and one of the hydroxymethylene protons
(d 4.28 for 1, d 4.12 for 10), and of the methyl carbon with
two axial protons (d 2.10/2.80 for 1, d 2.05/2.78 for 10).
These observations demonstrate the axial and equatorial
orientation of the methyl and Ph-ipso carbon, respectively.
The latter couples not only with the meta protons but also
with the anti proton from the benzyloxymethyl side chain (d
4.28), and not with an angular axial proton H-7a, as could be
expected for conformation BPhax. On the other hand, a qtd
coupling pattern observed in the spectrum of 1 for the
Another important difference between compounds of type
III and V relates to the conformational freedom of the
b-aminoether moiety. Model compound V necessarily has
a gauche relationship between the N-atom of the piperidine
ring and the axial ether O-atom, whereas for type III
compounds including the bicyclic analogues, the hetero-
atoms of the b-aminoether moiety also might adopt an
anti orientation. However, from the anti-relationship
observed for one of the methylene H-atoms and the Ph-
ipso carbon in the NMR spectra of the bicyclic compounds,
it appears that the CH2 of the oxymethyl sidechain is locked
as a single conformer. According to the model calculations,
this may correspond to the O-atom being anti-oriented
relative to the largest group, i.e. the angular carbon C-7a,
again implying a favoured gauche orientation for the O- and
N-heteroatoms as required for V.
3
methyl carbon at C-4 (1Jˆ125.8 Hz, Jˆ5.0, 5.0, 3.5 Hz),
indicated coupling with two axial protons H-3ax and H-4a.
NOESY and NOE difference spectra of 1 revealed that the
1-phenyl group is close in space to H-7a (d 2.05) and that
the anti-H (d 4.28) in the benzyloxymethyl sidechain is near
to both axial protons H-3ax (d 2.80) and H-4a (d 2.10). This
is in agreement with the conformation APheq, but not BPhax
1
(Fig. 3). Conformation APheq also was supported by the H
NMR spectrum as compared to the model analysis. For all
bicyclic compounds studied, the vicinal coupling between
H-4a (for 1 and 5) or H-7a (for 2, 9 and related compounds)
and one of the two protons H-5 or H-1 was not resolved or
the 3J value was less than 1 Hz. This small vicinal coupling
correlated with a dihedral angle of 868 calculated for the
corresponding pair of protons in the model of the preferred
conformer. Also in agreement with this model was the
up®eld shift (,1 ppm) observed for one of the protons
H-7 (H-3), which apparently is located in the shielding
®eld of the 1(4)-phenyl group.
Conclusion
In this work we have developed an ef®cient route to cis-
fused bicyclic systems of type 1 and 2, which can be substi-
tuted with variable pharmacophoric groups of interest for
substance P antagonist activity. In our conformational study

6284
X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
of these bicyclic systems, it was established that the phenyl
group alpha to the piperidine N-atom assumes an equatorial
orientation, in contrast to the previously described 2,2,5,5-
substituted piperidines. The well-de®ned geometry and
conformational structure of these novel bicyclic systems
offer an excellent opportunity to de®ne further the `bio-
active conformation' of these non-peptide substance P
antagonists.
(CDCl3): 1.24 (m, 2H), 1.40 (m, 1H), 1.42 (m, 1H), 1.65
(m, 1H), 1.94 (m, 1H) [(CH2)3], 1.73 (s, 3H, CH3), 2.86 (q,
1H, 3Jˆ8.8 Hz, H-2 or H6), 3.07 (q, 1H, 3Jˆ8.8 Hz, H-6 or
H-2), 7.35±7.73 (m, 5H, Ph±H); 13C NMR (CDCl3): 19.36
(CH3), 26.8, 27.7, 28.8 [(CH2)3], 47.1, 50.6 (C-2 and C-6),
73.0 (C-1), 84.9 (C-7), 127.7, 127.8, 128.1 (Ph±C), 135.5
3
3
(C-ipso), 165.2 (q£d, JC±Hˆ5 Hz, JC±Hˆ8 Hz, C-11),
3
170.4 (d, JC±Hˆ2.2 Hz, C-9); m/z (%): 290 (1, MH1),
245 (72, M1z±CO2), 210 (100, M1z±CO2±Cl); exact mass
for C16H16O2N1: 289.0869, for C15H16N1: 245.0971; found:
289.0865, 245.0970.
Experimental
General methods
1a-(Hydroxymethyl)-4b-methyl-1b-phenyl-4aa,7aa-octa-
hydro-1H-cyclopenta[c]pyridin-4a-ol (5). To a stirred
ice-cooled slurry of LiAlH4 (285 mg, 7.5 mmol) in 25 ml
dry THF under nitrogen atmosphere was added dropwise a
solution of adduct 4 (722 mg, 2.5 mmol) in 25 ml dry THF.
The ice bath was removed and the reaction mixture was
stirred ®rst at room temperature for 2 h and then at re¯ux
temperature for 8 h. After the reduction was completed, the
mixture was cooled down and the excess of hydride was
decomposed by careful addition of a saturated NH4Cl solu-
tion to form a white granular precipitate. The organic layer
was decanted and the precipitate washed three times with
diethyl ether. The combined organic layers were dried over
MgSO4, ®ltered, and concentrated to afford crude compound
5, which was puri®ed by column chromatography (silica
gel, 1:9 MeOH/CH2Cl2) and crystallisation from dichloro-
methane/n-hexane. Yield: 535 mg, 82%; white crystals, mp:
Melting points were taken using a Reichert±Jung Thermo-
var apparatus and an Electrothermal IA 9000 digital melting
point apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin±Elmer 297 grating IR spectrophoto-
meter and a Perkin±Elmer 1720 Fourier transform spectro-
meter.1H NMR spectra were recorded on a Bruker WM 250
or on a Bruker AMX 400 instrument. The 1H and 13C chemi-
cal shifts are reported in ppm relative to tetramethylsilane or
the deuterated solvent as an internal reference. Mass spectra
were run using a Hewlett±Packard MS-Engine 5989A appa-
ratus for EI and CI spectra, and a Kratos MS50TC instru-
ment for exact mass measurements performed in the EI
mode at a resolution of 10,000. For the chromatography,
analytical TLC plates (Alugram Sil G/UV254) and 70±230
mesh silica gel 60 (E.M. Merck) were used. Microanalyses
were performed by Janssen Pharmaceutica. The preparation
and the spectroscopic data of 5-chloro-6-methyl-3-phenyl-
2H-1,4-oxazin-2-one 3 were described previously.19
1
162.5±165.58C; IR (KBr) cm21: 3393, 3341 (OH, NH); H
NMR (DMSO-d6): 0.76 (m, 1H, H-7), 1.07 (m, 1H, H-7),
1.11 (s, 3H, CH3), 1.35 (m, 2H, H-6), 1.50 (m, 1H, H-5),
1.81 (m, 1H, H-5), 1.95 (m, 1H, H-7a), 2.04 (t, 1H,
3Jˆ7.0 Hz, H-4a), 2.19 (s, br., 1H, NH), 2.50 (d, 1H,
Model calculations
2
2Jˆ11.4 Hz, H-3), 2.76 (d, 1H, Jˆ11.4 Hz, H-3), 3.60
2
3
These were carried out for the cis-fused cyclopentene
derivative 1 using the molecular mechanics method of
HyperCheme: Release 4.5, Hypercube, Inc. Two main
groups of conformers corresponding to APheq and BPhax
were created by imposing the appropriate torsion angles
for the bond sequence PhipsoC±C1±C7a±C4a. In addition,
the torsion angle O±CH2±C1±N2 was varied to create anti
and gauche conformers. Each of the conformers was then
energetically optimised. A difference of ca. 2.3 kcal/mol
favouring conformer APheq over BPhax (both with the favour-
able antiO±CH2±C1±C7a orientation) was observed. For
the APheq conformers a difference of ca. 1.5 kcal/mol
favoured the gauche O±CH2±C1±N2 (antiO±CH2±C1±
C7a) over the antiO±CH2±C1±N2 orientation.
(dd, 1H, Jˆ11.0 Hz, Jˆ6.0 Hz, CH2OH), 4.09 (s, 1H,
2
3
OH), 4.15 (dd, 1H, Jˆ11 Hz, Jˆ4.4 Hz, CH2OH), 4.34
3
3
(dd, 1H, Jˆ6.0 Hz, Jˆ4.4 Hz, CH2OH), 7.13 (td, 1H,
4
3
3Jˆ8 Hz, Jˆ1.2 Hz, H-para), 7.24 (t, 2H, Jˆ8 Hz, H-
meta), 7.43 (dd, 2H, Jˆ8 Hz, Jˆ1.2 Hz, H-ortho); 13C
NMR (DMSO-d6): 23.7 (CH3), 21.2, 26.4, 27.3 (C-5, C-6
and C-7), 45.6, 46.9 (C-4a and C-7a), 52.9 (C-3), 59.3 (C-1),
62.5 (CH2OH), 68.8 (C-4), 125.2, 126.0, 127.3 (Ph±C),
146.7 (C-ipso); m/z(%) (CI): 262 (77, MH1), 244 (100,
MH1±H2O), 230 (24, MH1±CH3OH); exact mass for
C16H23NO2: 261.1729; found: 261.1723; anal. calcd for
C16H23NO2: C 73.53, H 8.87, N 5.36; found: 73.48, H
8.91, N 5.40.
3
4
1a-({[3,5-Bis(tri¯uoromethyl)benzyl]oxy}-4b-methyl)-
1b-phenyl-4aa,7aa-octahydro-1H-cyclopenta[c] pyridin-
4a-ol (1). To a solution of 470 mg (1.8 mmol) of compound
5 in 18 ml DMF was added sodium hydride (91 mg,
3.8 mmol) in a single portion at room temperature. The
mixture was stirred for 30 min followed by the addition of
610 mg (2.0 mmol) 3,5 bis(tri¯uoromethyl)benzyl bromide
in 10 ml dry THF during 15 min. The reaction mixture was
stirred at rt for one day followed by careful addition of a
saturated ammonium chloride solution (up to pH 8.5±9.0),
and 40 ml of water. The aqueous layer was extracted with
three 40 ml portions of dichloromethane, and the combined
organic layers were dried (MgSO4), and concentrated in
vacuo. The residual yellow oil was chromatographed over
Synthesis of compound 1 via Diels±Alder reaction of
oxazinone 3 with cyclopentene
endo 11-Chloro-7-methyl-1-phenyl-8-oxa-10-azatricyclo-
[5.2.2.02,6]undec-10-en-9-one (4). Cyclopentene (0.8 ml,
9 mmol) was added to a stirred solution of 5-chloro-6-methyl-
3-phenyl-2H-1,4-oxazin-2-one 3 (663 mg, 3 mmol) in
chloroform (15 ml) at room temperature under nitrogen
atmosphere. After reaction for one day at re¯ux temperature
the solvent was removed under reduced pressure. The
residue was puri®ed by crystallisation to give 4 (824 mg,
95%). Slightly yellow crystals, mp: 1528C (decomposition);
IR (KBr) cm21: 1762 (CO), 1624 (CvN); 1H NMR

X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
6285
silica gel (1:4 EtOAc/CH2Cl2) to give 3, 5 bis(tri¯uoro-
methyl)benzyl ether 1.Yield: 490 mg, 56%; colourless oil;
NMR (CDCl3): 1.69 (s, 3H, CH3), 2.39 (m, 2H, H-3 or
3
2
H-5), 2.47 (dd, 1H, Jˆ4.6 Hz, Jˆ10 Hz, H-5 or H-3),
1
3
2
IR (NaCl, ®lm) cm21: 3404 (OH, NH); H NMR(CDCl3):
2.70 (dd, 1H, Jˆ7.6 Hz, Jˆ10 Hz, H-5 or H-3), 3.02 (m,
1H, H-6 or H-2), 3.25 (m, 1H, H-2 or H-6), 3.40, 3.44 (2£d,
0.98 (m, 1H, H-7), 1.24 (m, 1H, H-7), 1.33 (s, 3H, CH3),
1.46 (m, 2H, H-6), 1.62 (m, 1H, H-5), 1.84 (m, 1H, H-5),
2H, 2Jˆ13.2 Hz, PhCH2N), 7.22±7.71 (m, 10H, 2£Ph); 13
C
3
2.05 (m, 1H, H-7a), 2.10 (t, 1H, Jˆ7.0 Hz, H-4a), 2.80,
NMR (CDCl3): 19.50 (CH3), 45.7, 50.4 (C-2 and C-6), 54.7,
54.8 (C-3 and C-5), 59.4 (PhCH2N), 72.5 (C-1), 84.1 (C-7),
127.1±128.3 (Ph±C), 135.4, 138.1 (2£C-ipso), 165.7 (q£d,
3JC±Hˆ5 Hz, 3JC±Hˆ8 Hz, C-11), 169.8 (C-9); m/z (%): 380
(2, M1), 336 (18, M1z±CO2), 300 (13, M1z±CO2±HCl), 245
(41, M1z±CO2-Bn), 91 (100, Bn1z); exact mass calcd for
C22H21ClO2N2: 380.1292, found: 380.1290.
2
2.88 (2£d, 2H, Jˆ11.5 Hz, H-3), 3.68, 4.28 (2£d, 2H,
2Jˆ9.5 Hz, CH2OCH2Ar), 4.42, 4.60 (2£d, 2H, 2Jˆ
13.2 Hz, CH2OCH2Ar), 7.23 (m, 1H), 7.32 (m, 2H), 7.45
(m, 2H), 7.50 (s, 2H), 7.74 (s, 1H) (Ar±H); 13C
NMR(CDCl3): 21.5 (C-6), 24.1 (CH3), 26.5, 27.2 (C-5 and
C-7), 46.3, 47.9 (C-4a and C-7a), 53.1 (C-3), 59.2 (C-1),
70.6 (C-4), 71.7, 72.4 (CH2OCH2), 121.4 (Ar±C), 123.3
(CF3) 125.5 (Ph±C), 126.2 (Ph±C), 127.2 (Ar±C), 127.9
(Ph±C), 131.4 (q, Ar±C), 141.1 (Ar±C-ipso), 145.3 (Ph±
C-ipso); m/z (%) (CI): 488 (65, MH1), 470 (47, MH1±
H2O), 468 (39, MH1±HF), 230 (100, MH1±
CH2OCH2C6H3(CF3)2); exact mass for C25H27F6NO2:
endo 7-Methyl-1-phenyl-8-oxa-4,10-diazatricyclo-[5.2.2.02,6]-
undecane-3,5,9,11-tetraone (7). Maleimide (582 mg,
6 mmol) was added to a stirred solution of 5-chloro-6-meth-
yl-3-phenyl-2H-1,4-oxazin-2-one 3 (442 mg, 2 mmol) in
toluene (15 ml) at room temperature under nitrogen atmos-
phere. After reaction for one day at re¯ux temperature the
solvent was removed under reduced pressure. The residue
was dissolved in CH2Cl2 and following addition of methanol
(5 ml) the solution was heated at re¯ux temperature for one
day. The solvent was removed and the residue was puri®ed
by chromatography (silica gel, 1:1 EtOAc/ CH2Cl2) to give
pure compound 7. Yield: 444 mg, 74%; white crystals, mp:
2908C (decomp.); IR (KBr) cm21: 3187 (NHCO), 1775±
487.1946;
found:
487.1930;
anal.
calcd
for:
C25H27F6NO2: C 61.06, H 5.58, N 2.87, found: C 60.79,
H5.52, N 2.71.
Generation of adducts 6b±c and conversion of 6a to the
corresponding hydrolysed compound 7
endo 4-Benzyloxycarbonyl-11-chloro-7-methyl-1-phen-
yl-8-oxa-4,10-diazatricyclo[5.2.2.02,6]undec-10-ene-9-one
(6b). 3-Pyrroline prepared from cis-1,4-dichloro-2-butene
according to the literature procedure9 was treated with ben-
zyl chloroformate in CH2Cl2 in the presence of triethyl-
amine. N-Cbz-3-pyrroline was obtained as a colourless oil
1
1682 (CONH); H NMR (DMSO-d6): 1.71 (s, 3H, CH3),
3
3.38 and 4.39 (2£d, 2H, Jˆ8 Hz, H-2 and H-6), 7.44 (m,
5H, Ph±H), 10.0 (br.s, 1H, NHCO), 11.70 (br.s, 1H,
CONHCO); 13C NMR (DMSO-d6): 16.8 (CH3), 43.0, 51.2
(C-2, C-6), 63.5 (C-1), 81.5 (C-7), 127.7, 128.1 and 128.4
(Ph±C), 131.5 (Ph±Cipso), 167.8 (C-9), 168.1 (C-11), 173.5
and 173.8 (C-3 and C-5); m/z (%): 301 (1, MH1), 256
(48, M1±CO2), 185 (16, M1±CO2±CONHCO); exact
mass for C14H12N2O3 (M1±CO2): 256.0848; found:
256.0849.
1
in 91% yield; m/z (%): 203 (3, M1), 112 (14, M12Bn; H
NMR (CDCl3): 4.2 (s, 4H, CH2NCH2), 5.2 (s, 2H, CH2Ph),
5.8 (s, 2H, CHvCH), 7.4 (m, 5H, Ph±H). The N-Cbz-3-
pyrroline (2.38g, 15 mmol) was made to react with 10 mmol
oxazinone 3 under the same conditions as described for
adduct 4. Adduct 6b was puri®ed by ¯ash column chroma-
tography (silica gel, gradient elution: 100% CHCl3 to 5%
EtOAc/CHCl3) and/or crystallisation (CH2Cl2/Et2O).Yield:
3.81 g, 90%; slightly yellow crystals; mp: 1588C (decom-
position); IR (KBr) cm21: 1764, 1711 (COO, NCOO), 1618
Synthesis of octahydro-1H-pyrrolo[3,4-c]pyridin-7a-ol
10
2-Benzyloxycarbonyl-4a-(hydroxymethyl)-7b-methyl-
4b-phenyl-3aa, 7aa-octahydro-1H-pyrrolo[3,4-c] pyridin-
7a-ol (8). To a stirred solution of 1.70 g (4 mmol) adduct 6b
in 40 ml dry THF was added 1.51 g (40 mmol) NaBH4.
After stirring for 15 min. at 08C 10 ml dry DMF was
added slowly via a syringe. The reaction mixture was
warmed up slowly to a bath temperature of 758C and heated
for two days. The excess of hydride was decomposed by
careful addition of a saturated NH4Cl solution at 08C.
Following extraction (CH2Cl2), drying, ®ltration, and
evaporation, the crude product was puri®ed by column
chromatography (silica gel, 1:9 MeOH/CH2Cl2) to yield
compound 8 (396 mg, 25%). White crystals, mp: 1958C;
IR (KBr) cm21: 3485, 3395 (OH, NH), 1670 (CO); rotamer
1
(CvN); H NMR (CDCl3, 608C): 1.77 (s, 3H, CH3), 3.15
3
3
(td, 1H, Jˆ3Jˆ9.0 Hz, Jˆ4.5 Hz, H-6 or H-2), 3.25 (m,
2H, H5), 3.35 (m, 1H, H-2 or H-6), 3.45 (m, 1H, H-3 or H-
5), 3.69 (dd, 1H, 2Jˆ12.7 Hz, 3Jˆ9.0 Hz, H-5 or H-3), 5.06
(s, 2H, PhCH2), 7.27±7.69 (m, 10H, 2£Ph); 13C NMR
(CDCl3, 358C): 19.50 (CH3), 45.7, 46.6, 47.1, 49.4 (C-2,
C-3, C-5 and C-6), 67.2 (PhCH2), 72.3 (C-1), 83.6 (C-7),
127.8±128.5 (Ph±C), 134.4, 136.2 (2£C-ipso), 153.8
3
(NCOO), 165.1 (C-11), 168.8 (C-9, J is not resolved);
m/z (%) (CI): 425 (52, MH1), 381 (17, MH1±CO2), 345
(7, MH1±CO2±HCl), 91 (100, Bn1z); exact mass for
C23H21ClO4N2: 424.1190, found: 424.1191.
1
endo 4-Benzyl-11-chloro-7-methyl-1-phenyl-8-oxa-4, 10-
diazatricyclo[5.2.2.02,6]undec-10-ene-9-one (6c). Under
the conditions described for adduct 4, N-benzyl 3-pyrroline
(913 mg, 4.5 mmol) was made to react with 3 mmol oxazi-
none 3. Adduct 6c was puri®ed by ¯ash column chroma-
tography (silica gel, gradient elution: 100% CHCl3 to 5%
EtOAc/CHCl3) and/or crystallisation (CH2Cl2/Et2O). Yield:
1.05 g, 92%; slightly yellow crystals; mp 1668C (decompo-
a (55%): H NMR (CD3OD): 1.20 (s, 3H, CH3), 2.29 (m,
1H, H-7a), 2.60 (m, 1H, H-3a), 2.70, 2.93 (2d, 2H,
2Jˆ11.9 Hz, H-6), 2.78 (m, 2H, H-3), 3.33 (m, 1H, H-1),
3.76 (m, 1H, H-1), 3.79, 4.27 (2d, 2H, 2Jˆ11.4 Hz,
CH2OH), 5.02, 5.08 (2d, 2H, 2Jˆ12.5 Hz, OCH2Ph),
7.15±7.52 (m, 10H, Ph±H); 13C NMR (CD3OD): 22.9
(CH3), 44.0, 46.8 (C-3a and C-7a), 48.9, 49.2 (C-1 and
C-3), 53.0 (C-6) 59.5 (C-4), 63.9 (CH2OH), 67.9
(NCOOCH2Ph), 70.2 (C-7), 127.0±129.5 (C±Ph), 138.2
1
sition); IR (KBr) cm21: 1761 (COO), 1620 (CvN); H

6286
X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
(C-ipsoPh±Cbz), 145.4 (C-ipso Ph-4), 156.5 (NCO);
rotamer b (45%): H NMR (CD3OD): 1.19 (s, 3H, CH3),
146.1 (C-ipso), 168.9 (HCOO2); m/z (%): 231 (100, M1±
CH2OH); exact mass for C14H19N2O (M1±CH2OH):
231.1497, found: 231.1498.
1
2.29 (m, 1H, H-7a), 2.60 (m, 1H, H-3a), 2.70, 2.93 (2d, 2H,
2Jˆ11.9 Hz, H-6), 2.78 (m, 2H, H-3), 3.33 (m, 1H, H-1),
3.76 (m, 1H, H-1), 3.79, 4.27 (2d, 2H, 2Jˆ11.4 Hz,
CH2OH), 4.98, 4.99 (2d, 2H, 2Jˆ12.5 Hz, OCH2Ph),
7.15±7.52 (m, 10H, Ph±H); 13C NMR (CD3OD): 22.9
(CH3), 44.8, 46.1 (C-3a and C-7a), 48.4, 49.5 (C-1 and
C-3), 53.0 (C-6) 59.6 (C-4), 64.0 (CH2OH), 67.7
(NCOOCH2Ph), 70.1 (C-7), 127.0±129.5 (C±Ph), 138.3
(C-ipsoPh±Cbz), 145.3 (C-ipso), 156.6 (NCO); m/z (%):
397 (0.1, MH1), 365 (MH1±CH2OH, 100), 91 (68,
CH2Ph); exact mass for C23H28N2O4: 396.2049; for
C22H25N2O3: 365.1865; found: 396.2051, 365.1897; anal.
calcd for C23H28N2O4: C 69.68, H 7.12, N 7.07, found: C
69.77, H 7.13, N 7.10.
N-Acylation of 10: formation of compounds 11 and 12a±
b and conversion of 12a±b into 3,5-bis(tri¯uoromethyl)-
benzyl ethers 13±15
4a-(Hydroxymethyl)-2-[o-methoxyphenylacetyl)-7b-
methyl-4b-phenyl-3aa, 7aa-octahydro-1H-pyrrolo[3,4-c]-
pyridin-7a-ol (11). o-Methoxyphenylacetic acid (166 mg,
1.0 mmol), formate salt 10 (308 mg, 1.0 mmol), DMAP
(25 mg, 0.2 mmol), and Et3N (0.30 ml, 2.2 mmol) were
dissolved in a mixture of 10 ml of methylene chloride and
2 ml of DMF. The solution was cooled to 08C and 192 mg
(1.0 mmol) EDCI (1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide hydrochloride) was added. After 30 min, the
cooling bath was removed and the reaction was allowed to
proceed at room temperature overnight. Water (10 ml) was
added and the aqueous layer was extracted with methylene
chloride (3£10 ml). The combined organic layers were
dried and evaporated. Column chromatography (silica gel,
10 MeOH/90 CH2Cl2) gave 132 mg (32%) pure compound
11 as a white solid. Mp: 1258C; IR (KBr, cm21): 3397(OH,
NH), 1614, 1445 (CON); rotamer a (60%): 1H NMR
(CDCl3): 1.12 (s, 3H, CH3), 1.60- 2.04 (br., 3H, NH, OH),
2-Benzyl-4a-(hydroxymethyl)-7b-methyl-4b-phenyl-3aa,
7aa-octahydro-1H-pyrrolo[3,4-c]pyridin-7a-ol
(9).
Reduction of adduct 6c (950 mg, 2.5 mmol) was carried
out as described for the conversion of 4 to 5. Compound 9
was puri®ed by column chromatography (silica gel, 90/8/2
AcOEt/MeOH/Et3N). Yield: 818 mg, 93%; white powder;
1
mp: 1188C; IR (KBr) cm21: 3412 (OH, NH); H NMR
2
(CD3OD): 1.40 (s, 3H, CH3), 2.02 (dd, 1H, Jˆ10.0 Hz,
3
3
3Jˆ8.6 Hz, H-3), 2.28 (td, 1H, Jˆ3Jˆ6.5 Hz, Jˆ0.9 Hz,
3
2
3
H-7a), 2.34 (dd, 1H, Jˆ11.0 Hz, Jˆ10.0 Hz, H-3), 2.48
2.24 (t, 1H, Jˆ6.5 Hz, H-7a), 2.56 (m, 1H, H-3a), 2.72,
(m, 1H, H-3a), 2.72 (d, 1H, 2Jˆ12.0 Hz, H-6), 2.78 (dd, 1H,
2
2.90 (2£d, 2H, Jˆ11.5 Hz, H-6), 2.76 (m, 1H, H-3), 2.89
3Jˆ6.5 Hz, Jˆ10.0 Hz, H-1), 2.91 (d, 1H, Jˆ12.0 Hz,
2
2
2
3
(m, 1H, H-3), 3.26 (dd, 1H, Jˆ12.8 Hz, Jˆ6.5 Hz, H-1),
2
3
2
H-6), 2.98 (dd, 1H, Jˆ10.0 Hz, Jˆ0.9 Hz, H-1), 3.57,
3.30, 3.36 (2d, 2H, Jˆ15 Hz, NCOCH2Ar), 3.52 (s, 3H,
2
2
3.58 (2£d, 2H, NCH2Ph), 3.74, 4.25 (2£d, 2H, Jˆ11 Hz,
CH3O), 4.0 (d, 1H, Jˆ12.8 Hz, H-1), 3.70, 4.25 (2£d,
2H, 2Jˆ9.4 Hz, CH2OH), 6.72 (dd, 1H, 3Jˆ8.2 Hz,
CH2OD), 7.1±7.3 (m, 8H, Ph±H), 7.42 (d, 2H, Ph±Hortho);
13C NMR (CD3OD): 24.9 (CH3), 44.6, 47.9 (C-3a and C-7a),
53.2, 55.9, 61.4 (C-1, C-3 and C-6), 59.4 (C-4), 64.7
(CH2OD), 70.5 (C-7), 127.1, 127.2, 127.8, 128.8, 129.1,
129.5 (Ph±C), 140.6 (C-ipso of Bn), 146.0 (C-ipso); m/z
(%): 353.3 (2, MH1), 321 (100, M1±CH2OH), 91 (61,
PhCH2); exact mass for C22H28N2O2: 352.2151, found:
352.2151.
3
4
4Jˆ1.0 Hz, H-ortho), 6.83 (td, 1H, Jˆ7.6 Hz, Jˆ1.0 Hz,
H-para), 7.09±7.40 (m, 7H, Ph±H, Ar±H); 13C NMR
(CDCl3): 22.8 (CH3), 35.4 (COCH2Ar), 44.0, 44.4 (C-3a
and C-7a), 47.6, 47.9 (C-1 and C-3), 52.0 (C-6), 55.1
(OCH3), 58.6 (C-4), 63.9 (CH2OH), 69.1 (C-7), 110±157
(C±Ar), 170.1 (CO); rotamer b (40%): 1H NMR (CDCl3):
1.16 (s, 3H, CH3), 1.60- 2.04 (br., 3H, , NH, OH), 2.30 (t,
1H, 3Jˆ6.0 Hz, H-7a), 2.48 (m, 1H, H-3a), 2.72, 2.90 (2£d,
2
4a-Hydroxymethyl-7b-methyl-4b-phenyl-3aa,7aa-octa-
hydro-1H-pyrrolo[3,4-c]pyridin-7a-ol (formate salt of
10). To a stirred suspension of compound 9 (1.06 g,
3 mmol) and 530 mg 10% Pd/C in absolute methanol
(20 ml) under nitrogen atmosphere was added anhydrous
ammonium formate (945 mg, 15 mmol) in a single portion.
The reaction mixture was heated to re¯ux temperature and
reaction progress was monitored by TLC. When the reaction
was completed, the catalyst was removed by ®ltration
through a celite pad. After washing with 20 ml of chloro-
form, the combined organic ®ltrates were evaporated to
afford formate salt 10 (814 mg) in a yield of 98%. Slightly
yellow crystals; mp: 1558C; IR (KBr) cm21: 3332 (br., OH,
NH); 1H NMR (DMSO-d6): 1.18 (s, 3H, CH3), 1.99 (m, 1H,
H-3), 2.05 (t, 1H, 3Jˆ6.0 Hz, H-7a), 2.11±2.16 (m, 2H, H-3
and H-3a), 2.51, 2.78 (2£d, 2H, 2Jˆ12.0 Hz, H-6), 2.80 (dd,
1H, 2Jˆ11.0 Hz, 3Jˆ6.0 Hz, H-1), 2.99 (d, 1H, 2Jˆ11.0 Hz,
2H, Jˆ12.0 Hz, H-6), 2.88 (m, 1H, H-3), 3.11 (m, 1H,
2
3
H-3), 3.40 (dd, 1H, Jˆ11.2 Hz, Jˆ6.0 Hz, H-1), 3.50,
3.61 (2d, 2H, 2Jˆ15 Hz, NCOCH2Ar), 3.79 (s, 3H,
2
CH3O), 3.75 (d, 1H, Jˆ11.2 Hz, H-1), 3.67, 4.20 (2£d,
2H, 2Jˆ9.4 Hz, CH2OH), 6.83 (dd, 1H, 3Jˆ8.2 Hz,
3
4
4Jˆ1.0 Hz, H-ortho), 6.87 (td, 1H, Jˆ7.6 Hz, Jˆ1.0 Hz,
H-para), 7.09±7.40 (m, 7H, Ph±H, Ar±H); 13C NMR
(CDCl3): 22.9 (CH3), 35.4 (COCH2Ar), 42.4, 46.1 (C-3a
and C-7a), 47.3, 48.6 (C-1 and C-3), 55.4 (OCH3), 52.4
(C-6), 58.6 (C-4), 64.2 (CH2OH), 69.2 (C-7), 110±157
(C-Ar), 169.8 (CO); m/z (%): 411 (1, MH1), 379 (100,
MH1±CH2OH); exact mass for C24H30N2O4: 410.2206,
found: 410.2208.
2-Formyl-4a-(hydroxymethyl)-7b-methyl-4b-phenyl-
3aa,7aa-octahydro-1H-pyrrolo[3,4-c]pyridin-7a-ol (12a).
To a solution of compound 10 (786 mg, 3 mmol) in metha-
nol was added 456 mg (4.5 mmol) triethylamine and
270 mg (4.5 mmol) methyl formate at room temperature
under nitrogen. After stirring overnight the solvent and the
excess of reagents were removed under reduced pressure.
The residue was puri®ed by crystallisation to give pure
N-formyl derivative 12a. Yield: 835 mg, 96%; white
2
H-1), 3.62, 4.12 (2£d, 2H, Jˆ11.0 Hz, CH2OH), 7.13 (t,
3
3
1H, Jˆ7.5 Hz, Ph±Hpara), 7.24 (t, 2H, Jˆ7.4 Hz, Ph±
3
Hmeta), 7.46 (d, 2H, Jˆ7.6 Hz, Ph±Hortho), 8.34 (s, 1H,
HCOO2); 13C NMR: 23.6 (CH3), 44.6 (C-3a), 46.6 (C-7a),
47.8, 47.9 (C-1 and C-3), 52.6 (C-6), 58.2 (C-4), 62.6
(CH2OH), 68.2 (C-7), 125.4, 125.9 and 127.2 (Ph±C),

X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
6287
crystals, mp:1048C; IR (KBr) cm21: 3380 (OH, NH), 1650
(NCHO); rotamer a (60%): 1H NMR (DMSO-d6): 1.08 (s,
3H, CH3), 2.23 (m, 1H, H-3a or H-7a), 2.43 (s, 1H, NH or
OH), 2.56 (m, 1H, H-7a or H-3a), 2.81 (m, 1H, H-3), 3.07
(m, 1H, H-3), 3.17 (s, 2H, H-6), 3.65 (m, 1H, H-1), 3.82 (m,
1H, H-1), 4.10 (s, br. 1H, OH), 4.48 (s, 2H, CH2OH), 7.29 -
7.49 (m, 5H, Ph±H), 8.10 (s, 1H, HCON); 13C NMR
(DMSO-d6): 22.8 (CH3), 41.8, 44.4 (C-3a and C-7a), 45.0,
47.5 (C-1 and C-3), 52.3 (C-6) 58.2 (C-4), 62.3 (CH2OH),
67.9 (C-7), 125.8±127.6 (C±Ph), 145.2 (C-ipso), 160.9
928 mg, 60%; white crystals, mp: 133.0±1358C; IR (KBr)
cm21: 3435 (OH, NH), 1657 (NCHO); rotamer a (56%): 1H
NMR (CDCl3): 1.32 (s, 3H, CH3), 2.21 (s, 1H, OH or NH),
3
2.16 (br. s, 1H, NH or OH), 2.34 (t, 1H, Jˆ6.2 Hz, H-7a),
2.50 (m, 1H, H-3a), 2.79, 2.94 (2£d, 2H, 2Jˆ12.0 Hz, H-6),
3
2.80 (m, 1H, H-3), 3.03 (t, 1H, Jˆ2Jˆ10.6 Hz, H-3), 3.46
(dd, 1H, 2Jˆ13.0 Hz, 3Jˆ6.2 Hz, H-1), 3.72, 4.28 (2£d, 2H,
2
2Jˆ9.4 Hz, CH2OCH2Ar), 3.84 (d, 1H, Jˆ13.0 Hz, H-1),
4.44, 4.58 (2£d, 2H, 2Jˆ13.2 Hz, CH2OCH2Ar), 7.24 -7.46
(m, 5H, Ph±H), 7.48 (s, 2H, Ar±H-ortho), 7.75 (s, 1H, Ar±
H-para), 7.96 (s, 1H, HCON); 13C NMR (CDCl3): 23.3
(CH3), 43.3, 44.5 (C-3a and C-7a), 45.7, 46.7(C-1 and C-
3), 52.4 (C-6) 57.8 (C-4), 69.5 (C-7), 71.2, 71.8
(CH2OCH2), 121.6 (Ar±C), 123.2 (q, CF3)125.1 (Ph±C),
127.1 (Ar±C), 127.2 (Ph±C), 128.4 (Ph±C), 131.4 (q, Ar±
C), 140.7 (C-ipso Ar), 143.5 (C-ipsoPh), 161.2 (HCON);
1
(HCON); rotamer b (40%): H NMR (DMSO-d6): 1.09
(s, 3H, CH3), 2.23 (m, 1H, H-3a or H-7a), 2.43 (s, 1H,
NH or OH), 2.56 (m, 1H, H-7a or H-3a), 2.86 (m, 1H,
H-3), 2.83 (s, 2H, H-6), 3.40 (m, 1H, H-3), 3.65 (m, 1H,
H-1), 4.10 (s, br., OH), 4.15 (m, 1H, H-1), 4.48 (s, 2H,
CH2OH), 7.29±7.49 (m, 5H, Ph±H), 7.90 (s, 1H, HCON);
13C NMR (DMSO-d6): 22.7 (CH3), 42.1, 44.0 (C-3a and
C-7a), 45.2, 46.5 (C-1 and C-3), 52.1 (C-6), 58.0 (C-4),
62.2 (CH2OH) 68.1 (C-7), 125.8±127.6 (Ph±C), 145.1
(C-ipso), 161.1 (HCON); m/z (%): 259 (100, MH1±
CH2OH); exact mass for C16H22N2O3: 290.1630; for
C15H19N2O2: 259.1447; found: 259.1451; anal. calcd for
C16H22N2O3.H2O: C 62.30, H 7.85, N 9.09; found: C
62.09, H 7.69, N 8.83.
1
rotamer b (44%): H NMR (CDCl3):1.31 (s, 3H, CH3),
1.97 (s, 1H, OH or NH), 2.16 (br. s, 1H, NH or OH), 2.29
3
(t, 1H, Jˆ6.2 Hz, H-7a), 2.46 (m, 1H, H-3a), 2.79, 2.94
2
(2£d, 2H, Jˆ12.0 Hz, H-6), 2.80 (m, 1H, H-3), 2.84 (m,
1H, H-3), 3.25 (dd, 1H, 2Jˆ13.0 Hz, 3Jˆ6.2 Hz, H-1), 3.69,
4.25 (2£d, 2H, 2Jˆ9.4 Hz, CH2OCH2Ar), 3.88 (d, 1H,
2Jˆ13.0 Hz, H-1), 4.42, 4.62 (2£d, 2H, 2Jˆ13.2 Hz,
CH2OCH2Ar), 7.24 -7.46 (m, 5H, Ph±H), 7.48 (s, 2H,
Ar±H-ortho), 7.75 (s, 1H, Ar±H-para), 8.12 (s, 1H,
HCON); 13C NMR (CDCl3): 23.5 (CH3), 42.9, 44.8 (C-3a
and C-7a), 44.9, 47.9 (C-1 and C-3), 52.8 (C-6), 57.9 (C-4),
69.4 (C-7), 71.2, 71.6 (CH2OCH2), 121.6 (Ar±C), 123.2 (q,
CF3)125.1 (Ph±C), 127.1 (Ar±C), 127.2 (Ph±C), 128.5
(Ph±C), 131.4 (q, Ar±C), 140.6 (C-ipso Ar), 143.1 (C-
ipso Ph), 161.0 (HCON); m/z (%): 259 (100, MH1±
CH2OCH2C6H3(CF3)2); 227 (22, 1CH2C6H3(CF3)2); exact
mass for C25H26F6N2O3: 516.1848; found: 516.1826; anal.
calcd for C25H26F6N2O3: C 58.14, H 5.07, N 5.42, found: C
57.90, H 5.01, N 5.41.
2-Tri¯uoroacetyl-4a-(hydroxymethyl)-7b-methyl-4b-
phenyl-3aa,7aa-octahydro-1H-pyrrolo[3,4-c]-pyridin-
7a-ol (12b). The same procedure was applied as for the
preparation of 12a, using ethyl tri¯uoroacetate instead of
methyl formate for N-acylation of compound 10 (1.57 g,
6 mmol). Yield: 2.10 g, 98%; white crystals, mp: 988C; IR
(KBr, cm21): 3424 (OH, NH), 1681 (NCHO); rotamer a
(60%): 1H NMR (CDCl3): 1.24 (s, 3H, CH3), 1.93 (s, br., 3H,
3
NH, OH), 2.37 (t, 1H, Jˆ6.4 Hz, H-7a), 2.52 (m, 1H,
2
H-3a), 2.78, 2.91 (2d, 2H, Jˆ12.0 Hz, H-6), 2.98 (m, 1H,
H-3), 3.10 (m, 1H, H-3), 3.56 (dd, 1H, 2Jˆ13.0 Hz,
3Jˆ6.4 Hz, H-1), 3.73, 4.23 (2£d, 2H, 2Jˆ11.4 Hz,
2-Tri¯uoroacetyl-4a-({[3,5-bis(tri¯uoromethyl)benzyl]-
oxy}methyl)-7b-methyl-4b-phenyl-3aa,7aa-octa hydro-
1H-pyrrolo[3,4-c]pyridin-7a-ol (14) and 2-[3,5-bis(tri-
¯uoromethyl)benzyl]-4a-({[3,5-bis(tri¯uoromethyl)ben-
zyl]oxy}methyl)-7b-methyl-4b-phenyl-3aa,7aa-octahy-
dro-1H-pyrrolo[3,4-c]pyridin-7a-ol (15). Compound 12b
(1.79 g, 5 mmol) was subjected to the same procedure as for
the conversion of 12a to 13, to give a mixture from which
compounds 14 and 15 were isolated by column chromato-
graphy (silica gel, 6:94 MeOH/CH2Cl2). Yield of 14:
175 mg, 6%; colourless oil; IR (NaCl, ®lm) cm21: 3445
2
CH2OH), 4.00 (d, 1H, Jˆ13.0 Hz, H-1), 7.26±7.43 (m,
5H, Ph±H); 13C NMR (CDCl3): 22.9 (CH3), 41.6, 45.9 (C-
3a and C-7a), 48.7 (C-1 and C-3), 52.2 (C-6) 58.4 (C-4),
63.9 (CH2OH), 69.0 (C-7), 117.4 (q, CF3), 125.4±128.8 (C±
Ph), 142.2 (C-ipso), 155.3 (q, NCO); rotamer b (40%): 1H
NMR (CDCl3): 1.23 (s, 3H, CH3), 1.93 (s, br., 3H, NH, OH),
3
2.32 (t, 1H, Jˆ6.4 Hz, H-7a), 2.62 (m, 1H, H-3a), 2.78,
2
2.91 (2d, 2H, Jˆ12.0 Hz, H-6), 2.98 (m, 1H, H-3), 3.10
2
3
(m, 1H, H-3), 3.40 (dd, 1H, Jˆ13.0 Hz, Jˆ6.0 Hz, H-1),
2
3.77, 4.26 (2£d, 2H, Jˆ11.4 Hz, CH2OH), 4.00 (d, 1H,
2Jˆ13.0 Hz, H-1), 7.26±7.43 (m, 5H, Ph±H); 13C NMR
(CDCl3): 23.0 (CH3), 43.5, 44.2 (C-3a and C-7a), 47.3,
49.7 (C-1 and C-3), 52.0 (C-6), 58.5 (C-4), 63.5
(CH2OH), 69.1 (C-7), 117.4 (q, CF3), 125.4±128.8 (Ph±
C), 142.1 (C-ipso), 155.8 (q, NCO); m/z (%): 327 (100,
MH1±CH2OH); exact mass for C17H21F3N2O3: 358.1504;
for C16H18F3N2O2: 327.1320; found: 327.1321; anal.
clacd. for C17H21F3N2O3: C 56.98, H 5.91, N 7.82, found:
C 56.74, H 6.16, N 7.56.
(OH, NH), 1682 (NCHO); rotamer a (56%): H NMR
1
(CDCl3): 1.29 (s, 3H, CH3), 2.03 (br. s, 1H, NH or OH),
2.20 (s, 1H, OH or NH), 2.36 (t, 1H, 3Jˆ6.5 Hz, H-7a), 2.50
(m, 1H, H-3a), 2.78, 2.94 (2£d, 2H, 2Jˆ12.0 Hz, H-6), 3.00
3
(m, 1H, H-3), 3.03 (t, 1H, Jˆ2Jˆ11.5 Hz, H-3), 3.55 (dd,
2
3
1H, Jˆ13.0 Hz, Jˆ6.5 Hz, H-1), 3.70, 4.24 (2£d, 2H,
2
2Jˆ9.4 Hz, CH2OCH2Ar), 4.03 (d, 1H, Jˆ13.0 Hz, H-1),
4.42, 4.59 (2£d, 2H, 2Jˆ13.2 Hz, CH2OCH2Ar), 7.15 -7.45
(m, 5H, Ph±H), 7.48 (s, 2H, Ar±H-ortho), 7.75 (s, 1H, Ar±
H-para); 13C NMR (CDCl3): 23.1 (CH3), 41.8, 46.1 (C-3a
and C-7a), 48.7, 49.7(C-1 and C-3), 52.6 (C-6) 57.7 (C-4),
69.3 (C-7), 71.5, 71.8 (CH2OCH2), 116.2 (q, COCF3),
121.8±128.9 (C±Ar, Ph), 123.1 (CF3) 131.6 (q, Ar±C),
140.7 (C-ipso Ar), 142.9 (C-ipsoPh), 155.3 (q, COCF3);
2-Formyl-4a-({[3,5-bis(tri¯uoromethyl)benzyl]oxy}meth-
yl)-7b-methyl-4b-phenyl-3aa, 7aa-octahydro-1H-pyrrolo-
[3,4-c]pyridin-7a-ol (13). O-Benzylation of 12a (777 mg,
3 mmol) was carried out using the same procedure as for the
preparation of 1. Compound 13 was puri®ed by column
chromatography (silica gel, 6:94 MeOH/CH2Cl2). Yield:
1
rotamer b (44%): H NMR (CDCl3): 1.28 (s, 3H, CH3),
2.18 (br. s, 1H, OH), 2.20 (s, 1H, OH), 2.32 (t, 1H,

6288
X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
3Jˆ6.2 Hz, H-7a), 2.58 (m, 1H, H-3a), 2.78, 2.94 (2£d, 2H,
2Jˆ12.0 Hz, H-6), 3.00 (m, 1H, H-3), 3.15 (t, 1H,
2Jˆ3Jˆ11.5 Hz, H-3), 3.38 (dd, 1H, 2Jˆ13.0 Hz, 3Jˆ
6.2 Hz, H-1), 3.72, 4.28 (2£d, 2H, 2Jˆ9.4 Hz,
4a-({[3,5-bis(tri¯uoromethyl)benzyl]oxy}methyl)-7b-
methyl-4b-phenyl-3aa, 7aa-octahydro-1H-pyrrolo [3,4-c]-
pyridin-7a-ol (formate salt of 17). Prepared by N-deben-
zylation of 16 (867 mg, 1.5 mmol) using the same procedure
as for 10. Yield: 786 mg, 98%; white crystals, mp: 82.5±
85.08C; IR (KBr) cm21: 3394 (OH, NH); 1H NMR
(CDCl3):1.33 (s, 3H, CH3), 2.41 (m, 3H), 2.63 (m, 1H),
2
CH2OCH2Ar), 4.02 (d, br. 1H, Jˆ13.0 Hz, H-1), 4.44,
2
4.62 (2£d, 2H, Jˆ13.2 Hz, CH2OCH2Ar), 7.15 -7.45 (m,
5H, Ph±H), 7.48 (s, 2H, Ar±H-ortho), 7.75 (s, 1H, Ar±H-
para); 13C NMR (CDCl3): 23.1 (CH3), 43.6, 44.4 (C-3a and
C-7a), 47.2, 48.7 (C-1 and C-3), 52.3 (C-6), 57.8 (C-4), 69.3
(C-7), 71.1, 71.8 (CH2OCH2), 116.0 (q, COCF3), 121.8±
128.9 (C±Ar and Ph±C), 123.1 (CF3), 131.6 (q, Ar±C),
140.6 (Ar±C-ipso), 142.8 (Ph±C-ipso), 155.7 (q, COCF3);
m/z (%): 585 (13, MH1), 259 (100, MH1±
CH2OCH2C6H3(CF3)2); 227 (35, 1CH2C6H3(CF3)2); exact
mass for C26H25F8N2O3(M12F.): 565.1737; found:
565.1706.
2
2.72, 2.88 (2£d, 2H, Jˆ11.6 Hz, H-6), 3.20 (m, 1H), 3.54
2
(m, 1H), 3.67, 4.23 (2£d, 2H, Jˆ9.4 Hz, CH2OCH2Ar),
2
4.40, 4.60 (2£d, 2H, Jˆ13.0 Hz, CH2OCH2Ar), 7.24 (t,
3
3
1H, Jˆ7.2 Hz, H-para), 7.31 (t, 2H, Jˆ7.3 Hz, H-meta),
3
7.39 (d, 2H, Jˆ7.4 Hz, H-ortho), 7.46 (s, 2H, H-ortho),
7.74 (s, 1H, H-para), 8.35 (s, 1H, HCOO); 13C NMR
(CDCl3): 23.7 (CH3), 44.3, 45.9 (2£CH), 45.9, 46.5, 51.9
(3£CH2N), 57.6 (C-4), 68.6 (C-7), 71.1, 71.8 (CH2OCH2),
121.6 (Ar±C), 123.2 (q, CF3), 125.0 (Ph±C), 127.1 (Ar±C),
127.2 (Ph±C), 128.6 (Ph±C), 131.4 (q, Ar±C), 140.6 (Ar±
C-ipso), 143.2 (Ph±C-ipso), 169.0 (HCOO); m/z (%): 489
(1, MH1), 469 (1, MH1±HF), 231 (100, MH1±
CH2OCH2C6H3(CF3)2); exact mass for C24H26F6N2O2:
488.1898; found: 488.1902; anal. calcd for C24H26F6N2O2.-
CH2O2: C 56.18, H 5.28, N 5.24, found: C 55.94, H 5.23, N
5.15.
Yield of 15: 556 mg, 15%; colourless oil; IR (NaCl, ®lm)
cm21: 3383 (OH, NH); 1H NMR(CDCl3): 1.48 (s, 3H, CH3),
2.07 (t, 1H, H-3), 2.28 (t, 1H, 3Jˆ5.6 Hz, H-7a), 2.35 (br. s,
1H, NH, OH), 2.55 (m, 1H, H-3), 2.53 (m, 1H, H-3a), 2.72
(dd, 1H, 3Jˆ5.6 Hz, 2Jˆ10.0 Hz, H-1), 2.84, 2.93 (2£d, 2H,
2
2Jˆ11.8 Hz, H-6), 2.96 (d, br. 1H, Jˆ10.0 Hz, H-1), 3.70
(s, 2H, NCH2Ar), 3.68, 4.24 (2£d, 2H, 2Jˆ9.4 Hz,
CH2OCH2Ar), 4.43, 4.58 (2£d, 2H, 2Jˆ13.2 Hz,
CH2OCH2Ar), 7.21±7. 74 (m, 11H, Ph±H, Ar); 13C NMR
(CDCl3): 24.8 (CH3), 43.6, 47.3 (C-3a and C-7a), 52.8
(C-6), 54.8, 55.3 (C-1 and C-3), 58.4 (C-4), 59.5
(NCH2Ar), 69.9 (C-7), 71.8 (CH2OCH2Ar), 72.7
(CH2OCH2Ar), 121.4- 128.1 (Ph±C and Ar±C), 140.9,
142.9 (Ar±C-ipso), 144.3 (Ph±C-ipso); m/z (%): 715 (8,
MH1), 457 (100, MH1±CH2OCH2C6H3(CF3)2); exact
mass for C33H30F12N2O2: 714.2116; found: 714.2109.
2-[o-Methoxyphenylacetyl)-4a-({[3,5-bis(tri¯uoromethyl)-
benzyl]oxy}methyl)-7b-methyl-4b-phenyl-3aa, 7aa-octa-
hydro-1H-pyrrolo[3,4-c]pyridin-7a-ol (2). To a solution
of 498 mg (3 mmol) o-methoxy-phenylacetic acid in 30 ml
CCl4 was added 943 mg (3.6 mmol) PPh3 in a single portion.
The suspension was stirred at re¯ux temperature until
completion of the reaction (overnight). The mixture was
cooled and the white deposit was ®ltered off. The ®ltrate
was concentrated under reduced pressure to give 496 mg of
(o-methoxyphenyl)acetyl chloride as a colourless oil (yield,
90%). This acid chloride (256 mg, 1.4 mmol) was added
dropwise to a solution of formate salt 17 (641 mg,
1.2 mmol) and pyridine (0.32 ml, 4 mmol) in dry THF at
±158C. After being stirred at this temperature for 2 h the
reaction mixture was worked up in the usual way. Puri®-
cation by chromatography (silica gel, 4:96 MeOH/CH2Cl2)
and recrystallisation gave pure compound 2. Yield: 496 mg,
65%; white crystals; mp: 175.4±175.88C; IR (KBr, cm21):
3403 (shoulder, OH, NH), 1622.8 (s, CON); rotamer a
Synthesis of compound 2: O-benzylation of 9 followed by
N-debenzylation and N-acylation
2-[Benzyl]-4a-({[3,5-bis(tri¯uoromethyl)benzyl]oxy}meth-
yl)-7b-methyl-4b-phenyl-3aa, 7aa-octahydro-1H-pyrrolo-
[3,4-c]pyridin-7a-ol (16). This was prepared from
compound 9 (704 mg, 2 mmol) using the same procedure
as for 1. Compound 16 was puri®ed by column chroma-
tography (silica gel, 6:94 MeOH/CH2Cl2). Yield: 902 mg,
78%; colourless oil; IR (NaCl, ®lm) cm21: 3414 (OH, NH);
1H NMR (CDCl3): 1.46 (s, 3H, CH3), 2.00 (br. s, 1H, NH,
OH), 2.08 (t, 1H, H-3), 2.22 (t, 1H, 3Jˆ6.0 Hz, H-7a), 2.46
(m, 1H, H-3), 2.50 (m, 1H, H-3a), 2.70 (dd, 1H, 3Jˆ6.0 Hz,
1
(65%): H NMR (CDCl3): 1.18 (s, 3H, CH3), 2.20 (s, 1H,
3
OH), 2.24 (t, 1H, Jˆ6.5 Hz, H-7a), 2.49 (m, 1H, H-3a),
2
2.73, 2.90 (2£d, 2H, Jˆ11.5 Hz, H-6), 2.77 (m, 1H, H-
3), 2.88 (m, 1H, H-3), 3.26 (dd, 1H, 2Jˆ12.8 Hz, 3Jˆ
2
6.5 Hz, H-1), 3.30, 3.36 (2d, 2H, Jˆ15 Hz, NCOCH2Ar),
2
2Jˆ10.0 Hz, H-1), 2.81, 2.87 (2£d, 2H, Jˆ11.8 Hz, H-6),
3.53 (s, 3H, CH3O), 4.0 (d, 1H, 2Jˆ12.8 Hz, H-1), 3.65, 4.25
2
3
2
2.90 (dd, 1H, Jˆ10.0 Hz, Jˆ0.8 Hz, H-1), 3.59 (s, 2H,
(2£d, 2H, Jˆ9.4 Hz, CH2OCH2Ar0), 4.40, 4.58 (2£d, 2H,
2
CH2Ph), 3.63, 4.20 (2£d, 2H, Jˆ9.4 Hz, CH2OCH2Ar),
2Jˆ13.0 Hz, CH2OCH2Ar0), 6.72 (dd, 1H, 3Jˆ8.2 Hz,
4.42, 4.56 (2£d, 2H, 2Jˆ13.2 Hz, CH2OCH2Ar), 7.17±
7.31 (m, 8H), 7.44 (m, 2H) (Ph±H), 7.48 (s, 2H), 7.74 (s,
1H) (Ar±H); 13C NMR (CDCl3): 25.0 (CH3), 43.4, 47.2 (C-
3a and C-7a), 52.8, 54.7, 55.1, 60.4 (4£CH2N), 58.4 (C-4),
70.1 (C-7), 71.8, 73.0 (CH2OCH2), 121.5 (Ar±C), 125.5,
126.6, 126.7 (Ph±C), 127.2 (Ar±C), 127.9, 131.4 (q, Ar±
C), 140.0 (Ar±C-ipso), 141.9, 144.5 (Ph±C-ipso); m/z (%):
579 (1, MH1), 561 (2, MH1±H2O), 559 (1, MH1±HF), 321
(100, MH1±CH2OCH2C6H3(CF3)2); exact mass for
C31H32F6N2O2: 578.2368; found: 578.2360; anal. calcd for
C31H32F6N2O2:C 64.35, H 5.57, N 4.84, found: C 64.11, H
5.82, N 4.79.
4Jˆ1.0 Hz, H-ortho), 6.82 (td, 1H, Jˆ7.6 Hz, Jˆ1.0 Hz,
H-para), 7.09 -7.40 (m, 7H, Ph±H, Ar±H), 7.45 (s, 2H,
H-ortho Ar0), 7.74 (s, 1H, H-para Ar0); 13C NMR (CDCl3):
23.2 (CH3), 35.4 (COCH2Ar), 44.2, 44.5 (C-3a and C-7a),
47.5, 47.9 (C-1 and C-3), 55.1 (OCH3), 52.3 (C-6), 57.9
(C-4), 69.4 (C-7), 71.4, 71.8 (CH2OCH2), 110±157 (C-
Ar), 170.1 (CO); rotamer b (35%): 1H NMR (CDCl3):
1.23 (s, 3H, CH3), 2.32 (s, 1H, OH), 2.27 (t, 1H,
3Jˆ6.0 Hz, H-7a), 2.40 (m, 1H, H-3a), 2.73, 2.90 (2£d,
3
4
2
2H, Jˆ12.0 Hz, H-6), 3.00 (m, 1H, H-3), 2.88 (m, 1H,
2
3
H-3), 3.38 (dd, 1H, Jˆ11.2 Hz, Jˆ6.0 Hz, H-1), 3.50,
3.61 (2d, 2H, 2Jˆ15 Hz, NCOCH2Ar), 3.79 (s, 3H,

X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
6289
CH3O), 3.75 (d, 1H, 2Jˆ11.2 Hz, H-1), 3.67, 4.20 (2£d, 2H,
Acknowledgements
2Jˆ9.4 Hz, CH2OCH2Ar0), 4.42, 4.54 (2£d, 2H,
2Jˆ13.0 Hz, CH2OCH2Ar0), 6.83 (dd, 1H, 3Jˆ8.2 Hz,
The authors wish to thank the FWO (Fund for Scienti®c
Research Ð Flanders (Belgium)) and the `Ministerie voor
Wetenschapsbeleid', IUAP and the Janssen Pharmaceutica
company for ®nancial support to the lab. They are also
grateful to R. De Boer for mass spectral analysis. X. Wu
wishes to thank the K.U. Leuven for the fellowships
received.
3
4
4Jˆ1.0 Hz, H-ortho), 6.87 (td, 1H, Jˆ7.6 Hz, Jˆ1.0 Hz,
H-para), 7.09 -7.40 (m, 7H, Ph±H, Ar±H), 7.48 (s, 2H,
H-ortho Ar0), 7.74 (s, 1H, H-para Ar0); 13C NMR (CDCl3):
23.3 (CH3), 35.4 (COCH2Ar), 42.6, 46.2 (C-3a and C-7a),
47.2, 48.7 (C-1 and C-3), 55.4 (OCH3), 52.8 (C-6), 57.9 (C-
4), 69.7 (C-7), 71.4, 71.8 (CH2OCH2), 110±157 (C-Ar),
169.8 (CO); m/z (%): 637 (1, MH1), 617 (2, MH1±HF),
379 (100, MH1±CH2OCH2C6H3(CF3)2); exact mass for
C33H34N2O4F6: 636.2423, found: 636.2427; anal. calcd for
C33H34N2O4F6: C 62.26, H 5.38, N 4.40, found: C 62.31,
H5.29, N 4.33.
References
1. (a) Regoli, D.; Boudon, A.; Fauchere, J. L. Pharmacol. Rev.
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General procedure for reduction of adducts 4 and 6c
with NaCNBH3 to give tricyclic lactones 18
2. Snider, R. M.; Constantine, J. W.; Lowe, J. A.; Longo, K. P.;
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F. J.; Spencer, R. W.; Hess, H. Science 1991, 251, 435±437.
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Snider, R. M. J. Med. Chem. 1992, 35, 4911±4913.
4. Harrison, T.; Williams, B. J.; Swain, C. J. Bioorg. Med. Chem.
Lett. 1994, 4, 2733±2734.
To a clear solution of 502 mg NaCNBH3 (8 mmol) in a
mixture of 16 ml of THF and 4 ml acetate buffer (1 M
NaOAc/HOAc, pHˆ5.0) was added 2 mmol of adduct 4
or 6c. The reaction mixture was heated at a bath temperature
of 758C for one day. After concentration in vacuo 10 ml of
saturated NaHCO3 solution was added. The aqueous
suspension was extracted with three 20-ml portions of
dichloromethane. The combined extracts were dried
(MgSO4) and evaporated to give the crude product 18.
Further puri®cation was carried out by chromatography
(silica gel, 4:96 MeOH/CH2Cl2) and crystallisation.
5. Tabart, M.; Peyronel, J. F. Bioorg. Med. Chem. Lett. 1994, 4,
673±676.
6. (a) Elliott, J.; Seward, E. M. Exp. Opin. Ther. Patents 1997, 7,
43±54 and references therein. (b) Stevenson, G. I.; Huscroft, I. et
al. J. Med. Chem. 1998, 41, 4623±4635 and references therein. (c)
Hale, J. J.; Mills, S. G. et al. J. Med. Chem. 1998, 41, 4607±4614
and references therein. (d) Ward, P.; Armour, D. R. et al. J. Med.
Chem. 1995, 38, 4985±4992.
endo 7-Methyl-1-phenyl-8-oxa-4,10-diazatricyclo-[5.2.2.02,6]-
undecan-9-one (18a). Yield: 431 mg, 84%; slightly yellow
powder; mp: 123.0±124.58C; IR (KBr) cm21: 3290 (NH),
1
7. (a) Seward, E. M.; Swain, C. J.; Merchant, K. J.; Owen, S. N.;
Sabin, V.; Cascier, M. A.; Sadowski, S.; Strader, C.; Baker, R.
Bioorg. Med. Chem. Lett. 1993, 3, 1361±1364. (b) Stevenson, G.
I.; Macleod, A. M.; Huscroft, I.; Gascieri, M. A.; Sadowski, S.;
Baker, R. J. Med. Chem. 1995, 38, 1264±1271.
1738 (CO); H NMR(CDCl3): 1.36 (s, 3H, CH3), 1.1±1.5,
1.65±1.95 (7H, CH2CH2CH21NH), 2.48 (dtd, 1H,
3Jˆ12.0 Hz, 3Jˆ3Jˆ8.0 Hz, 4Jˆ2.0 Hz, H-6), 2.60 (dt,
1H, 3Jˆ12.0 Hz, 3Jˆ3Jˆ8.0 Hz, H-2), 2.98 (dd, 1H,
2Jˆ12.0 Hz, 4Jˆ2.0 Hz, H-11ax), 3.34 (d, 1H,
2Jˆ12.0 Hz, H-11eq), 7.27±7.49 (m, 5H, Ph±H); 13C
NMR (CDCl3): 21.9 (CH3), 25.6, 27.3, 28.4 (3£CH2), 45.8
and 47.2 (C-2 and C-6), 46.9 (C-11), 59.9 (C-1), 82.4 (C-7),
126.6, 127.3, 127.8 (Ph±C), 137.7 (C-ipso), 174.2 (C-9);
m/z (%): 258 (15, MH1), 213 (100, M1z±CO2); exact mass
for C16H20N1O2: 258.1494, found: 358.1494.
8. Wu, X.; Dubois, K.; Rogiers, J.; Toppet, S.; Compernolle, F.;
Hoornaert, G. J. Tetrahedron 2000, 56, 3043±3051.
9. Warmus, J. S.; Dilley, G. J.; Meyers, A. I. J. Org. Chem. 1993,
58, 270±271.
10. Volpin, M.; Dvolaitzky, M.; Levitin, I. Bull. Soc. Chim. Fr.
1970, 1526±1528.
11. (a) Anwer, M. K.; Spatola, A. F. Synthesis 1980, 929±932. (b)
Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515±516.
12. (a) Newman, H. J. Org. Chem. 1964, 30, 1287±1288. (b)
Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1988, 53, 3108±
3111. (c) Curphey, T. J. Org. Chem. 1979, 44, 2805±2807.
13. Czech, B. P.; Bartsch, R. A. J. Org. Chem. 1984, 49, 4076±
4076.
endo 4-Benzyloxycarbonyl-7-methyl-1-phenyl-8-oxa-4, 10-
diazatricyclo[5.2.2.02,6]undecan-9-one (18b). Yield:
633 mg, 91%; slightly yellow powder; mp: 142±1458C
1
(decomp.); IR (KBr) cm21: 3290 (NH), 1728 (CO); H
NMR(CDCl3): 1.35 (s, 3H, CH3), 2.17 (br. S, 1H, NH),
2
3
2.31 (dd, 1H, Jˆ10.0 Hz, Jˆ8.0 Hz, H-3), 2.51 (dd, 1H,
3
2
2Jˆ10.0 Hz, Jˆ4.0 Hz, H-5), 261 (dd, 1H, Jˆ10.0 Hz,
14. Commercially available 2-(benzylamino)-1-ethanol (BAE)
was converted to N,N-dibenzyl-2-(benzyloxy)-1-ethanamine
(DBBEA) by N,O-dibenzylation using NaH and benzyl bromide
3Jˆ8.0 Hz, H-5), 2.68 (m, 1H, H-6), 2.72 (dd, 1H,
3
3
2Jˆ10.0 Hz, Jˆ4.0 Hz, H-3), 2.94 (ddd, 1H, Jˆ4.3 Hz,
3Jˆ8.0 Hz, Jˆ10.0 Hz, H-2), 3.02 (dd, 1H, Jˆ11.6 Hz,
in THF; H NMR (DMSO-d6): 2.57 (t, 2H, Bn2NCH2CH2OBn),
3
2
1
4Jˆ2.0 Hz, H-11ax), 3.50 (d, 1H, Jˆ11.6 Hz, H-11eq),
3.51 (t, 2H, Bn2NCH2CH2OBn), 3.60 (s, 4H, [PhCH2]2N), 4.40 (s,
2H, OCH2Ph), 7.18±7.35 (m, 15H, Ph±H); m/z (%): 332 (100,
MH1), 210 (18, MH1±HCH2OBn). The pure DBBEA compound
was subjected to catalytic transfer hydrogenation under the con-
ditions described for the conversion of 9 to 10. On removal of
catalyst, excess of reagent, and solvent, (benzyloxy)ethylamine
2
2
3.49, 3.61 (2£d, 2£1H, Jˆ13.0 Hz, NCH2Ph), 7.27±7.49
(m, 10H, Ph±H); 13C NMR (CDCl3): 22.3 (CH3), 45.0 and
45.1 (C-2 and C-6), 48.1, 54.0, 55.4, 59.9 (4£CH2), 60.2
(C-1), 82.0 (C-7), 127.0, 127.1, 127.6, 128.0, and 128.4
(Ph±C), 137.6, 138.6 (2£C-ipso), 173.5 (C-9); m/z
(%):304 (33, M1z±CO2), 91 (78; Bn1); exact mass for
C22H24N2O2: 348.1838, found: 348.1836.
1
was isolated as the formate salt; H NMR (DMSO-d6): 2.84 (br.
t, NH2), 2.99 (t, 2H, CH2NH2), 3.61 (t, 2H, CH2CH2OBn), 4.48 (s,

6290
X. Wu et al. / Tetrahedron 56 (2000) 6279±6290
2H, OCH2Ph), 7.24±7.34 (m, 5H, Ph±H), 8.43 (s, 1H, HCOO2);
m/z (%): 152 (100, MH1), 91 (30, Bn1).
17. (a) Kakushima, M.; Scott, D. J. Can. Chem. 1979, 57, 1399±
1401. (b) Kakushima, M.; Scott, D. J. Can. Chem. 1979, 57, 2564±
2568.
15. (a) Fannes, C.; Meerpoel, L.; Toppet, S.; Hoornaert, G. J.
Synthesis 1992, 705±709. (b) Cristol, S. J.; Seifert, W. K.; Solo-
way, S. B. J. Am. Chem. Soc. 1960, 82, 2351±2352. (c) Houk, K. N.
Tetrahedron Lett. 1970, 2621±2624.
18. Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. J. Bioorg.
Med. Chem. Lett. 1994, 4, 2545±2550.
19. Van Aken, K. J.; Lux, G. M.; Deroover, G. G.; Meerpoel, L.;
Hoornaert, G. Tetrahedron 1994, 50, 5211±5224.
16. (a) Wassermann, A. Diels±Alder Reactions, Elsevier, Amster-
dam, 1965. (b) Herndo, W. C.; Hall, L. H. Tetrahedron Lett. 1967,
3095±3100.