The use of (-)-8-phenylisoneomenthol and (-)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2006.06.118

The asymmetric aza-Diels-Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH₄ afforded pure (-)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier-Wieland degradation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.

Full text of DOI:10.1016/j.tet.2006.06.118

Tetrahedron 62 (2006) 9475–9482
The use of (L)-8-phenylisoneomenthol and (L)-8-phenylmenthol
in the enantioselective synthesis of 3-functionalized
2-azabicyclo[2.2.1]heptane derivatives via
aza-Diels–Alder reaction
a
Maria Luısa Cardoso do Vale, Jose Enrique Rodrıguez-Borges, Olga Caaman˜o,
a,
b
*
´
´
Franco Fernandez and Xerardo Garcıa-Mera
ꢀ
b
b,
*
´
ꢀ
a
´
CIQ-Departamento de Quımica, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre, 687,
^
4169-007 Porto, Portugal
Departamento de Quımica Orgaꢀnica, Facultade de Farmacia, Universidade de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
b
´
Received 1 June 2006; accepted 23 June 2006
Available online 14 August 2006
Abstract—The asymmetric aza-Diels–Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived
N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicy-
clo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH4 afforded pure
(ꢀ)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier–Wieland degra-
dation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation
sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
intermediates in the synthesis of several compounds with
biological interest; among them are the four stereoisomers
of 4-aminocyclopent-2-ene carboxylic acid (4) and the cor-
responding saturated analogues,6 which show specific inhib-
itory activity toward some processes of the action and
metabolism of GABA (Fig. 1).7 On the other hand, isomer
(1R,3S)-3-aminocyclopentane carboxylic acid is the core
structure of the antibiotic amidomycin.8
Chiral nitrogen containing heterocycles are versatile struc-
tures, which often occur in natural products and frequently
show biological activity;1 therefore, the development of
efficient and stereoselective methods for their preparation
is of great interest for organic chemists. The aza-Diels–
Alder reaction is a well-known method for the preparation
of such nitrogen containing monocyclic and bicyclic mole-
cules,2 like 2-azabicyclo[2.2.1]heptane and its derivatives,
which can be transformed into a variety of compounds of
great interest. For example, [2-azabicyclo[2.2.1]hept-5-
ene]-3-carboxylates (1) are used in the preparation of the
corresponding bicyclic derivatives of [2-azabicyclo[2.2.1]-
hept-5-en-3-yl]methanol (2), which have been successfully
employed as chiral ligands in asymmetric synthesis or cata-
lysis (carbon–carbon bond formation,3 asymmetric transfer
hydrogenation of ketones4). Carboxylates of type 1 have
been used in the enantioselective synthesis of lactam 3 and
its enantiomer and of their saturated analogues,5 key
These bicyclic compounds containing the 2-azabicyclo-
[2.2.1]hept-5-ene system are, through cleavage of the N–
C3 bond, the precursors of an important group of synthons
useful in the preparation of chiral amino alcohols derived
from cyclopentene or cyclopentane, necessary for the syn-
thesis of carbocyclic nucleosides with antiviral and antineo-
plastic properties.9 On the other side, oxidation of the double
bond and reduction or hydrolysis of the ester functionality
would lead to a great number of chiral nonnatural amino
alcohols and a-aminoacids (pyrrolidine derivatives), which,
∗
HO2C
NH2
CO2R
OH
O
Keywords: Asymmetric synthesis; Aza-Diels–Alder reaction; Induction;
Chiral alcohols.
* Corresponding authors. Fax: +34 981 594912 (X.G.-M.); fax: +351 22
6082959 (J.E.R.-B.); e-mail addresses: qoxgmera@usc.es; jrborges@fc.
up.pt
N
N
NH
Ph
Ph
1
2
3
4
Figure 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.118

9476
M. L. Cardoso do Vale et al. / Tetrahedron 62 (2006) 9475–9482
in turn, are potential nonnucleosidic inhibitors of HIV repli-
cation.10
2. Results and discussion
The chiral auxiliaries (Fig. 2), (ꢀ)-8-phenylmenthol
[(1R,3R,4S)-8-phenylmenthan-3-ol; 5a] and (ꢀ)-8-phenyl-
isoneomenthol [(1R,3R,4R)-8-phenylmenthan-3-ol; 5b] were
prepared by Bouveault–Blanc reduction of (1R,4S)-8-phenyl-
p-menthan-3-one,11a which was easily obtained by conjugate
addition of phenylmagnesium bromide to (+)-(R)-pule-
gone.12 Alcohols 5a and 5b were straightforwardly sepa-
rated by flash chromatography on silica gel.
In what concerns the aza-Diels–Alder reaction, imines are
the most commonly used aza-dienophiles and generally
require activation by an electron-withdrawing group and
a Lewis acid to participate in these [4+2] cycloaddition
reactions.2c–g In order to perform the enantioselective syn-
thesis of the referred adducts (1), chiral imines must be
used. The use of glyoxylates as precursors of chiral electron
deficient imines allows the introduction of chirality either
through the use of chiral amines2e,g or chiral alcohols.
Among the latter, (ꢀ)-8-phenylmenthol (5a) is one of the
most widely employed, being used to achieve enantioselec-
tivity in numerous syntheses.11 Its popularity is due, both to
the good enantiomeric excesses it affords (specially in face
differentiation processes, in which its capacity for face se-
lective p-stacking interactions is decisive) and to its ready
availability (it can be prepared in good yields from the in-
expensive (R)-(+)-pulegone).12 Nevertheless, much less is
known about the chiral induction behavior of its isomers;
for example, its enantiomer, (+)-8-phenylmenthol,13 which
seems just as attractive as 5a as a chiral auxiliary from
a structural point of view, has rarely been used as such due
to its high cost.
Conversion of the alcohols into their glyoxylates16 was
achieved by reaction with excess oxalyl chloride in chloro-
form, followed by treatment of the resulting alkyloxy oxalyl
chlorides (6a, 6b)17 with excess tributyltin hydride in the
presence of a catalytic amount of tetrakis(triphenylphos-
phine)palladium(0), at room temperature (Scheme 1). Once
reaction was complete, the excess hydride was destroyed
by heating in anhydrous chloroform, yielding tributyltin
chloride as the only tin co-product. The glyoxylates (7a,
7b) were separated from the reaction mixture by column
chromatography on silica gel. Compounds 7a and 7b were
characterized by the determination of their spectroscopic
and physical properties and those of their 2,4-dinitrophenyl-
hydrazone derivatives (8a, 8b).16 Although, 7a and 7b were
each isolated initially as a mixture of the anhydrous glyoxy-
late and of its hydrate, this presented no problem since both
forms react with primary amines to give the desired imines.
Whitesell14 reported that the region C1–C2 in 8-phenyl-
menthol is the one responsible for chiral induction; this led
us to the conclusion that we could have similar induction re-
sults using diastereomers of (ꢀ)-8-phenylmenthol without
necessity to use (+)-8-phenylmenthol. Based on this hypoth-
esis, our group has been optimizing various methods of
synthesis of the isomers of (ꢀ)-8-phenylmenthol from inex-
pensive, readily available materials.11a–d In a recent work,15
we reported the use of (+)-8-phenylneomenthol and (+)-8-
phenylisomenthol in the synthesis of [2-azabicyclo[2.2.1]-
hept-5-ene]-3-carboxylates by an aza-Diels–Alder reaction,
where a high asymmetric (1R,3-exo) induction was observed.
Treatment of 7a or 7b with equimolar amounts of benzyl-
amine, trifluoroacetic acid, and boron trifluoride etherate
in dichloromethane generated the corresponding iminium
salt (protonated imine), which reacted in situ with excess cy-
clopentadiene at ꢀ78 ꢁC to give mixtures of diastereomeric
adducts. Chromatographic purification of each mixture of
We now report the high asymmetric (1S,3-exo) induction ob-
served in the same reaction using cyclopentadiene and the
iminium ions of the N-benzylimines of the glyoxylates of
the two diastereomeric alcohols (ꢀ)-8-phenylmenthol (5a)
and (ꢀ)-8-phenylisoneomenthol (5b).
OH
Ph
5b
OH
Ph
5a
Figure 2.
O
O
O
i
ii
iii
H
N
H
∗
Cl
∗
R O
R OH
5a, 5b
∗
R O
∗
R O
O
7a, 7b
N
H
O
6a, 6b
O2N
iv
OH
Ph
NO2
8a, 8b
N
v
∗
CO2R
Ph
2
∗
R OH
5a, 5b
N
1a, 1b
vi
O
N
Ph
9 O
Scheme 1. Reagents and conditions: (i) oxalyl chloride, CHCl3, 0 ꢁC, 1 h; (ii) Bu3SnH, Pd(PPh3)4, PhH, 85–89% (overall yield from 5a, 5b); (iii) 2,4-dinitro-
phenyl hydrazine, H2SO4, MeOH, 89–92%; (iv) PhCH2NH2, TFA, F3B$OEt2, cyclopentadiene, CH2Cl2, ꢀ78 ꢁC, 69–80%; (v) LiAlH4, Et2O, 5 h, rt, 96–97%;
(vi) See Scheme 2 (74–76% overall yield from 1a, 1b).

M. L. Cardoso do Vale et al. / Tetrahedron 62 (2006) 9475–9482
9477
O
adducts allowed isolation of the most abundant (1S,3-exo)-
diastereoisomer, 1a (80%yield) or 1b (69% yield).
Ph
NH
O
i
NH
O
ii
N
O
Both bicyclic adducts 1a and 1b were converted into the
same amino alcohol, (ꢀ)-[(1S,3-exo)-2-benzyl-2-azabicy-
clo[2.2.1]-hept-5-en-3-yl]-methanol (2), by treatment with
LiAlH4, and into the same lactam, (+)-(1R)-2-benzoyl-2-
azabicyclo[2.2.1]heptan-3-one (9), through a longer reaction
sequence based on Barbier–Wieland degradation (Scheme
1). The transformations into these two target compounds
were accomplished with a virtually quantitative recovery
of the chiral auxiliaries 5a (98%) and 5b (97%). Since the
absolute configuration of the bicyclic system of adduct 1a
had already been established by X-ray crystallography as
being (1S,3-exo),18 this outcome allowed to determine the
absolute configuration of adduct 1b (also 1S,3-exo).
3
14
ent-9
Scheme 3. Reagents and conditions: (i) H2, 10% Pd/C, AcOEt, 40 psi, rt,
1.5 h, 98%; (ii) (a) NaH, Et2O; (b) BzCl, Et2O, 14 h, 85%.
Me
Me
H
Me
H
O
O
Me
H
N
O
Me
Me
H
O
H
N
H
(1R)-8-phenylmenthol derivative
exo Si-face approach
(1R)-8-phenylisoneomenthol derivative
exo Si-face approach
Transformations of 1a and 1b into (1R)-2-benzoyl-2-aza-
bicyclo[2.2.1]heptan-3-one (9) began with their catalytic
hydrogenation to 10a and 10b, respectively, in order to
prevent rearrangements of the norbornene-type (Scheme 2).
Treatment of 10a or 10b with an excess phenylmagnesium
bromide,19 followed by hydrolysis of the crude product,
gave tertiary amino alcohol 11, with high recovery of the
chiral auxiliary (94–96%).
N
O
H
O
Me
H
H
O
N
H
Me
Me
Me
H
H
Me
O
Me
(1R)-8-phenylneomenthol derivative
exo Re-face approach
(1R)-8-phenylisomenthol derivative
exo Re-face approach
HO
Ph
∗
∗
CO2R
CO2R
Ph
Figure 3.
Ph
ii
i
N
N
N
* the iminium ion, which is the species that acts as dieno-
phile in the reaction, should have an E configuration,
more stable for both stereochemical (bulky groups far
apart) and polar (hydrogen bonding N+–H/O]C)
reasons.
Ph
Ph
5a, 5b
11
10a, 10b
1a, 1b
iii
Ph
* in the close vicinity of the C]N bond, the (Csp3) benzyl
group exerts a larger steric hindrance than the (Csp2
ester group.
O
O
iv
v
Ph
Ph
)
N
N
N
Ph
Ph
12
9 O
13
Consequently, in order to minimize stereochemical interac-
tions in the transition state between the (Csp3) methylene
group of the diene and the bulkier substituents of the dieno-
phile, the approach of diene/dienophile must occur in a man-
ner that places the (Csp3) benzyl group in an endo position
and therefore, given the E configuration of the dienophile,
the ester group in an exo position. That is, to say that the
stereochemical factors are more important than the second-
ary orbital interactions between the p systems of cyclo-
pentadiene and the ester group in the dienophile. The
configuration of the nitrogen atom in the final adduct is irrel-
evant, since it exists as a tertiary amine capable of undergo-
ing inversion of the lone pair of electrons to achieve the most
stable conformation.
Scheme 2. Reagents and conditions: (i) H2, 10% Pd/C, 99:1 EtOAc/AcOH,
40 psi, rt, 3 h, 95–97%; (ii) PhMgBr (10 equiv), THF, 12 h, 90–91%; (iii)
HMPA (2 equiv), 210 ꢁC, 2 h, 94–95%; (iv) O2 (air stream), Cu2Cl2 (cat.),
CHCl3, 0 ꢁC, 6 h, 92–93%; (v) KMnO4 (4 equiv), 18-crown-6 (cat.),
85:15 Me2CO/AcOH, 60 ꢁC, 15 h, 95–96%.
Amino alcohol 1120 was easily dehydrated to enamine 12 by
heating with HMPA;21 Cu(I)-catalyzed oxidation of 12 with
molecular oxygen22 gave a mixture of products from which
benzophenone and lactam 13 were easily separated by chro-
matography on silica gel. Finally, oxidation of 13 with potas-
sium permanganate afforded imide 9 (76 and 74% overall
yield from 1a and 1b, respectively). Imide 9 had identical
melting point and spectroscopic properties, differing only
in its [a]D, which was positive, as a sample of ent-9,18
prepared from authentic (1R)-2-azabicyclo[2.2.1]hept-5-
en-3-one (3)18,23 by catalytic hydrogenation to 14, followed
by reaction with benzoyl chloride (Scheme 3).
In what concerns the preference observed in the approach of
the diene to the diastereotopic faces (due to the presence of
the chiral auxiliary) of the dienophile, it is more difficult to
suggest a hypothesis, since the geometry of the fragment that
connects the chiral auxiliary to the reacting dienophilic site
(C]N) in the transition state (diene/dienophile) is not fully
known. This fragment consists of three single bonds a, b, and
c; for each one, two extreme conformations, syn and anti, are
depicted in Figure 4.
In an attempt to explain the stereochemical outcome of the
aza-Diels–Alder reaction, we present in Figure 3 a model
for the approach of diene and dienophile. The high exo-
selectivity observed in these cases may be explained con-
sidering that:

9478
M. L. Cardoso do Vale et al. / Tetrahedron 62 (2006) 9475–9482
a
b
c
asymmetric aza-Diels–Alder reaction between cyclopenta-
∗
CH=NH
R
O
C(O)
diene and the protonated imine formed from benzylamine
and the glyoxylates of these alcohols. It is noteworthy
that a common rationale may be advanced to explain this
outcome as well as the opposite asymmetric induction that
leads to the corresponding optically pure adducts with
(1R,3-exo) configuration observed when using as chiral
auxiliaries the diastereomeric alcohols (1R)-8-phenylneo-
menthol and (1R)-8-phenylisomenthol.15
H
C
O
O
O
CH NH
C
N
H
C(O)
∗
R
O
b-syn
O
H
a-syn
c-syn
H
N
C(O)
O
O
O
C
O
R*
C
H
CH NH
b-anti
O
H
a-anti
c-anti
From a practical point of view, it is of major importance that
the chiral auxiliaries used (isomers of 8-phenylmenthol) to
obtain the two enantiomeric families of these azabicyclic
compounds (1S,3-exo and 1R,3-exo) can be obtained from
the same inexpensive starting material, (R)-pulegone, with
no need to use (+)-(1S)-8-phenylmenthol (derived from the
prohibitively expensive (S)-pulegone).
Figure 4.
Some plausible qualitative considerations may be taken into
account to offer a rationale for the observed results:
* the –C(Me)2Ph group of the chiral auxiliary necessarily
has to lie in an equatorial position with regard to the
cyclohexane ring. Given the configurations of the dif-
ferent stereoisomers of the chiral auxiliary, this means
that the C(sp3)–O bond will be in an equatorial position
for 8-phenylmenthol and 8-phenylisomenthol deriva-
tives, and in an axial position for 8-phenylneomenthol
and 8-phenylisoneomenthol ones.
* p-stacking interactions are supposed to be established
between the phenyl group and the aza-diene system, in
order to account for the improved results obtained
with 8-phenylmenthol derivatives compared to the sim-
ple menthol derivatives in achieving better facial dia-
stereoselectivity, which is the base for their use as
chiral auxiliaries. This means that the C–Ph bond should
lie almost parallel to the C(sp3)–O bond, which deter-
mines the conformations of the C–C(Ph) and C(sp3)–O
bonds, as is shown in Figures 3 and 4 (a-syn bond).
4. Experimental
4.1. General
Silica gel was purchased from Merck. All other chemicals
used were of reagent grade and were obtained from Aldrich
Chemical Co. Flash column chromatography was performed
on silica gel (Merck 60, 230–240 mesh) and analytical thin-
layer chromatography (TLC) on pre-coated silica gel plates
(Merck 60 GF254) using iodine vapor and/or UV light for
visualization. Melting points were determined on a Reichert
€
Kofler Thermopan or in capillary tubes on a Buchi 510 appa-
ratus, and are uncorrected. Infrared spectra were recorded on
a Perkin–Elmer 1640-FT spectrophotometer and the main
1
bands are given in cmꢀ1. H NMR (300 MHz) and 13C
NMR spectra (75.47 MHz) were recorded on a Bruker
WM AMX spectrometer using TMS as an internal standard
(chemical shifts (d) in parts per million, J in hertz). Elemen-
tal analyses were obtained on a Perkin–Elmer 240B micro-
analyser by the Microanalysis Service of the University of
Santiago de Compostela. Mass spectra were performed on
a Hewlett–Packard HP5988A mass spectrometer by electron
impact (EI), or on a Finnigan Trace-MS mass spectrometer
by chemical ionization (CI). Optical rotations at the sodium
D-line were determined using a Perkin–Elmer 241 thermo-
stated polarimeter. GLC analyses were carried out on a
Hewlett–Packard 5890 II apparatus provided with a flame
ionization detector, using a semi-capillary column (5 mꢂ
0.53 mm i.d., film thickness 2.65 mm) and helium as carrier
gas. The hydrogenations were carried out using a Parr 3915
hydrogenator.
* On the other hand, eclipsing between C]O and C(sp3)
–
O bonds is the most favored conformation for esters
(b-syn bond), while preference for c-syn conformation
in the aza-diene system is justified by the establishment
of a stronger hydrogen bond in N+–H/O]C than in
N+–H/Oo.
In consequence, taking into account simultaneously all
polar, steric, and electronic prevailing interactions in the sys-
tem, which includes the syn-syn-syn-alignment of the C(sp3)
–
O–C(sp2)–C(sp2) fragment, the geometrical approaches
depicted in Figure 3 are the ones, which best explain the
stereochemical outcome of these reactions, i.e., formation
of the major adducts (1S,3-exo) as a result of the predomi-
nant attack on the si-face of the dienophile when using
(1R)-8-phenylmenthol and (1R)-8-phenylisoneomenthol de-
rivatives as chiral auxiliaries, and of the major adducts
(1R,3-exo) as a result of the predominant attack on the re-
face of the dienophile when using (1R)-8-phenylneomenthol
and (1R)-8-phenylisomenthol derivatives.
4.1.1. (L)-(1R)-8-Phenylmenthyl (1S,3-exo)-2-benzyl-2-
azabicyclo[2.2.1]hept-5-ene-3-carboxylate, 1a. A solution
of benzylamine (877 mg, 0.89 mL, 8.18 mmol) in dry
CH2Cl2 (16 mL) was added under argon to a stirred suspen-
sion of 7a16 (2.36 g, 8.18 mmol) and 3 A molecular sieves
˚
3. Conclusion
(6 g) in dry CH2Cl2 (48 mL) at 0 ꢁC. When the addition
was complete the reaction mixture was cooled to ꢀ78 ꢁC
and treated successively with TFA (933 mg, 0.63 mL,
8.18 mmol), BF3$OEt2 (1.16 g, 1.04 mL, 8.18 mmol), and
freshly distilled cyclopentadiene (ca. 2 equiv, 1.3 mL). After
6 h, a mixture of saturated aqueous NaHCO3 solution
(20 mL) and then solid NaHCO3 (2 g) were added. The
The results obtained illustrate the utility of (1R)-8-phenyl-
menthol (5a) and (1R)-8-phenylisoneomenthol (5b) as two
easily recoverable stereo controlling auxiliaries, affording
optically pure 3-functionalized 2-azabicyclo[2.2.1]hept-
5-enes with (1S,3-exo) configuration, by means of an

M. L. Cardoso do Vale et al. / Tetrahedron 62 (2006) 9475–9482
9479
reaction mixture was allowed to reach room temperature and
filtered. The organic layer was separated from the filtrate and
washed with H2O (50 mL) and CH2Cl2 (50 mL) on a Celite
pad; the organic layer of the resulting mixture was separated,
and the aqueous layer was extracted with CH2Cl2
(3ꢂ100 mL). The pooled organic layers were washed with
saturated NaHCO3 solution (128 mL) and brine (130 mL),
and were dried over Na2SO4. Removal of the solvent on a ro-
tary evaporator yielded an orange oil (ca. 3.7 g), which was
purified by chromatography on silica gel (105 g), using hex-
ane/EtOAc 7:1 as eluent affording a white solid identified as
the pure major adduct (1S,3-exo)-1a (2.90 g, 6.54 mmol;
yield 80%). Mp 125–126 ꢁC. [a]D25 ꢀ56.7 (c 1, CHCl3). IR
(neat): n¼2992, 2965, 2927, 2880, 2855, 2801, 1736,
1598, 1541, 1495, 1457, 1235, 1187, 1161, 1094, 1082,
4.1.3. (L)-[(1S,3-exo)-2-Benzyl-2-azabicyclo[2.2.1]hept-
5-en-3-yl]methanol, 2. A solution of adduct 1a (or 1b)
(1.20 g, 2.70 mmol) in dry Et2O (20 mL) was added drop-
wise under argon to a suspension of LiAlH4 (607 mg,
16 mmol) in dry Et2O (20 mL) at 0 ꢁC. The reaction mixture
was stirred for 12 h at room temperature and a mixture of
MeOH (30 mL) and H2O (100 mL) was added dropwise at
0 ꢁC; the resulting mixture was extracted with AcOEt
(4ꢂ100 mL) and the pooled organic layers were washed
with H2O (2ꢂ100 mL) and brine (100 mL), and dried with
Na2SO4. Removal of solvent in a rotary evaporator left a resi-
due that when chromatographed on silica gel with hexane/
EtOAc 3:1 as eluent afforded the chiral auxiliary 5a25
(615 mg, 98%) [or 5b24 (609 mg, 97%)] in the early frac-
tions and compound 2 (563 mg, 97% yield from 1a and
557 mg, 96% yield from 1b), as a colorless oil, in the later
fractions. [a]2D5 ꢀ71.3 (c 1, CHCl3). IR (neat): n¼3364,
3060, 2985, 2870, 1495, 1452, 1367, 1324, 1208, 1134,
1
1007, 736, 698 cmꢀ1. H NMR (CDCl3): d¼0.73–1.06 (m,
3H), 0.86 (d, J¼6.5 Hz, 3H, 10-CH3), 1.08 and 1.09 [2s,
6H, 80-(CH3)2], 1.28 (d, J¼8.3 Hz, 1H, 7anti-H), 1.39–1.60
(m, 3H), 1.79 (d, J¼8.3 Hz, 1H, 7syn-H), 1.87 (s, 1H),
1.84–1.97 (m, 2H), 2.79 (s, 1H, 4-H), 3.38–3.56 (AB system,
J¼13.1 Hz, 2H, NCH2Ph), 3.84 (br s, 1H, 1-H), 4.74 (td, Jt¼
10.7 Hz, Jd¼4.3 Hz, 1H, 30ax-H), 6.20 (dd, J¼5.6, 1.6 Hz,
1H, 5-H), 6.35 (dd, J¼5.6, 2.3 Hz, 1H, 6-H), 7.09–7.38
1028, 910, 717 cmꢀ1 1H NMR (CDCl3): 1.25–1.28 (d,
.
1H, J¼8.40 Hz, 7anti-H), 1.68–1.71 (d, 1H, J¼8.40 Hz,
7syn-H), 1.82–1.86 (t, 1H, J¼5.55 Hz, 3-H), 2.32 (br s, 1H,
OH), 2.69 (s, 1H, 4-H), 3.32–3.44 (m, 4H, CH2OH+CH2Ph),
3.69 (s, 1H, 1-H), 6.10–6.13 (dd, 1H, J¼5.65, 1.80 Hz, 5-H),
6.41–6.45 (dd, 1H, J¼5.65, 3.24 Hz, 6-H), 7.16–7.28 (m,
5H, C6H5). 13C NMR (CDCl3): 46.13 (C-7), 47.16 (C-4),
59.34 (NCH2Ph), 64.43 (C-1), 64.98 (C-3), 65.66
(CH2OH), 127.55 (C-40), 128.80 (C-20+C-60), 129.43
(C-30+C-50), 132.71 (C-5), 138.27 (C-6), 140.11 (C-10).
MS (EI, m/z): 215 (M+). Anal. Calcd for C14H17NO: C
78.10, H 7.96, N 6.51; found: C 77.99, H 8.11, N 6.38.
13
(m, 10H, 2ꢂC6H5). C NMR (CDCl3): 22.20 (10-CH3),
26.56 and 27.12 [80-(CH3)2], 27.20 (C-50), 31.63 (C-10),
35.00 (C-60), 40.20 (C-80), 41.88 (C-20), 46.68 (C-7), 49.18
(C-4), 50.78 (C-40), 59.43 (NCH2Ph), 64.91 (C-1), 65.53
(C-3), 75.02 (C-30), 125.39 [aromatic C-4 (Ph)], 125.88
[aromatic C-2+C-6 (Ph)], 127.37 [aromatic C-4 (Bn)],
128.28 [aromatic C-3+C-5 (Ph)], 128.61 [aromatic C-2+
C-6 (Bn)], 129.40 [aromatic C-3+C-5 (Bn)], 134.09 (C-5),
136.76 (C-6), 139.52 [aromatic C-1 (Bn)], 151.98 [aromatic
C-1 (Ph)], 173.11 [C(O)O]. MS (EI, m/z): 443 (M+). Anal.
Calcd for C30H37NO2: C 81.22, H 8.41, N 3.16; found: C
81.47, H 8.61, N 3.09.
4.1.4. (L)-(1R)-8-Phenylmenthyl [(1R,3-exo)-2-benzyl-
2-azabicyclo[2.2.1]heptane]-3-carboxylate, 10a. To a
solution of 1a (1.00 g, 2.25 mmol) and 99.5% AcOH
(0.13 mL, 2.30 mmol) in AcOEt (15 mL) was added 10%
Pd–C (ca. 34 mg). The reaction mixture was hydrogenated
at room temperature for 3 h under a hydrogen pressure
of 40 psi. Then a saturated aqueous NaHCO3 solution
(10 mL) was added, the reaction mixture was filtered, and
the organic solvents were removed in a rotary evaporator.
The resulting mixture (aqueous layer/oil) was extracted
with CH2Cl2 (3ꢂ20 mL), the pooled organic layers were
washed with 3% NaHCO3 solution (20 mL) and brine
(30 mL), and were then dried with Na2SO4. The solvent
was removed in a rotary evaporator yielding 10a as white
solid, which was crystallized from hexane (0.95 g; Yield
95%). Mp 121–122 ꢁC. [a]D22 ꢀ21.1 (c 1, CHCl3). IR
(KBr): n¼2971, 1734, 1600, 1540, 1496, 1304, 1195,
4.1.2. (L)-(1R)-8-Phenylisoneomenthyl (1S,3-exo)-2-
benzyl-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate, 1b.
Prepared from 7b16 by the same procedure used to prepare
1a from 7a. Yield: 69%. Mp 94–96 ꢁC. [a]D22 ꢀ60.4
(c 0.23, CHCl3). IR (KBr): n¼2974, 2935, 2897, 2843,
1735, 1601, 1495, 1456, 1150, 1116, 1003, 738, 702 cmꢀ1
.
1H NMR (CDCl3): d¼1.06 (d, J¼7.4 Hz, 3H, 10-CH3),
1.18 and 1.19 [2s, 6H, 80-(CH3)2], 1.23–1.28 (m, 1H), 1.39
(d, J¼8.2 Hz, 1H, 7anti-H), 1.46 (dt, Jd¼12.9 Hz, Jt¼4.3 Hz,
1H), 1.52–1.62 (m, 3H), 1.67–1.80 (m, 2H), 1.87–1.92 (m,
1H), 1.94 (d, J¼8.2 Hz, 1H, 7syn-H), 2.28 (s, 1H, 3endo-H),
3.20 (s, 1H, 4-H), 3.50 and 3.65 (AB system, J¼13.0 Hz,
2H, NCH2Ph), 3.88 (d, J¼1.2 Hz, 1H, 1-H), 5.04 (br s, w1/2
¼
1154, 1046, 993, 750, 699 cmꢀ1 1H NMR (CDCl3):
.
7.4 Hz, 1H, 30eq-H), 6.23 (dd, J¼5.6, 1.8 Hz, 1H, 5-H), 6.48
d¼0.85 (d, J¼6.5 Hz, 3H, 10-CH3), 1.10 and 1.13 [2s, 6H,
80-(CH3)2], 0.75–1.69 (m, 8H), 1.19–1.33 (m, 2H), 1.76
(dt, Jd¼9.5 Hz, Jt¼1.80 Hz, 1H), 1.82–1.99 (m, 3H), 2.14
(s, 1H, 3endo-H), 2.21 (d, J¼3.7 Hz, 1H, 4-H), 3.28 (s, 1H,
1-H), 3.67 and 3.70 (AB system, J¼13.0 Hz, 2H, NCH2Ph),
4.71 (td, Jt¼10.7 Hz, Jd¼4.3 Hz, 1H, 30ax-H), 7.12–7.42 (m,
(ddd, J¼5.6, 3.3, 1.0 Hz, 1H, 6-H), 7.15–7.42 (m, 10H,
13
2ꢂC6H5). C NMR (CDCl3): 17.75 (10-CH3), 21.49
(C-50), 25.90 (C-10), 26.61 and 26.84 [80-(CH3)2], 32.62
(C-60), 36.89 (C-80), 40.49 (C-20), 46.90 (C-7), 48.41
(C-4), 51.80 (C-40), 59.60 (NCH2Ph), 64.26 (C-1), 66.13
(C-3), 72.36 (C-30), 125.97 [aromatic C-4 (Ph)], 126.45 [aro-
matic C-2+C-6 (Ph)], 127.48 [aromatic C-4 (Bn)], 128.35
[aromatic C-3+C-5 (Ph)], 128.71 [aromatic C-2+C-6
(Bn)], 129.37 [aromatic C-3+C-5 (Bn)], 134.31 (C-5),
136.58 (C-6), 139.42 [aromatic C-1 (Bn)], 150.37 [aromatic
C-1 (Ph)], 173.23 [C(O)O]. MS (EI, m/z): 443 (M+). Anal.
Calcd for C30H37NO2: C 81.22, H 8.41, N 3.16; found: C
81.44, H 8.64, N 3.07.
13
10H, 2ꢂC6H5). C NMR (CDCl3): d¼22.23 (10-CH3),
22.79 (C-50), 26.67 and 27.02 [(80-(CH3)2], 27.14 (C-10),
29.56 (C-5), 31.62 (C-60), 35.02 (C-6), 36.62 (C-7), 40.14
(C-80), 41.88 (C-20), 42.95 (C-4), 50.67 (C-40), 55.94
(NCH2Ph), 60.11 (C-1), 70.01 (C-3), 74.62 (C-30), 125.38
[aromatic C-4 (Ph)], 125.87 [aromatic C-2+C-6 (Ph)],
127.29 [aromatic C-4 (Bn)], 128.31 [aromatic C-3+C-5
(Ph)], 128.58 [aromatic C-2+C-6 (Bn)], 129.45 [aromatic

9480
M. L. Cardoso do Vale et al. / Tetrahedron 62 (2006) 9475–9482
C-3+C-5 (Bn)], 139.78 [aromatic C-1 (Bn)], 152.17 [aro-
matic C-1 (Ph)], 172.91 [C(O)O]. MS (EI, m/z): 445 (M+).
Anal. Calcd for C30H39NO2 C 80.85, H 8.82, N 3.14, found
C 80.69, H 8.96, N 3.08.
(Bn)], 128.66 and 129.22 [aromatic, 2ꢂCmeta (Ph0 and Ph00)],
139.78 [aromatic C-1 (Bn)], 146.63 and 148.89 [aromatic,
2ꢂC-1 (Ph0 and Ph00)]. MS (CI, m/z): 370 (MH+). Anal. Calcd
for C26H27NO: C 84.51, H 7.36, N 3.79; found: C 84.28, H
7.51, N 3.84.
4.1.5. (L)-(1R)-8-Phenylisoneomenthyl [(1R,3-exo)-2-
benzyl-2-azabicyclo[2.2.1]heptane]-3-carboxylate, 10b.
Prepared from 1b by the same procedure used to prepare
10a from 1a. Yield: 96%. Mp 60–61 ꢁC. [a]D22 ꢀ25.0 (c
0.5, CHCl3). IR (KBr): n¼2971, 1734, 1654, 1636, 1559,
1496, 1457, 1172, 1115, 758, 694 cmꢀ1. 1H NMR (CDCl3):
d¼1.03 (d, J¼7.4 Hz, 3H, 10-CH3), 1.18 and 1.21 [2s, 6H, 80-
(CH3)2], 1.24–2.05 (m, 14H), 2.62 (br s, 2H, 3endo-H+4-H),
3.31 (s, 1H, 1-H), 3.71 and 3.99 (AB system, J¼13.2 Hz, 2H,
NCH2Ph), 4.97 (br s, w1/2¼8.6 Hz, 1H, 30eq-H), 7.14–7.45
(m, 10H, 2ꢂC6H5). 13C NMR (CDCl3): d¼17.80 (10-CH3),
21.44 (C-50), 22.80 (C-10), 26.04 (C-60), 26.59 and 26.85
[80-(CH3)2], 29.61 (C-5), 32.62 (C-6), 36.79 (C-7), 36.85
(C-80), 40.48 (C-20), 42.26 (C-4), 51.73 (C-40), 56.12
(NCH2Ph), 59.45 (C-1), 71.16 (C-3), 72.14 (C-30), 125.94
[aromatic C-4 (Ph)], 126.42 [aromatic C-2+C-6 (Ph)],
127.31 [aromatic C-4 (Bn)], 128.33 [aromatic C-3+C-5
(Ph)], 128.61 [aromatic C-2+C-6 (Bn)], 129.37 [aromatic
C-3+C-5 (Bn)], 129.68 [aromatic C-1 (Bn)], 150.32 [aro-
matic C-1 (Ph)], 172.83 [C(O)O]. MS (EI, m/z): 445 (M+).
Anal. Calcd for C30H39NO2: C 80.85, H 8.82, N 3.14; found:
C 80.64, H 8.94, N 3.04.
4.1.7. (D)-(1R)-2-Benzyl-3-(diphenylmethylidene)-2-aza-
bicyclo[2.2.1]heptane, 12. A solution of 11 (500 mg,
1.35 mmol) in HMPA (4.9 mL, 27.9 mmol) was heated at
215–220 ꢁC with stirring for 2 h. Then the mixture was
cooled to room temperature and chromatographed on silica
gel (170 g) using hexane/EtOAc 4:1 as eluent affording in
the early fractions compound 12 as a white solid, which
was crystallized from hexane. Yield 452 mg (95%). Mp
139–140 ꢁC. [a]D23 +938 (c 1, CHCl3). IR (KBr): n¼3021,
1H NMR (CDCl3): d¼1.26 (d, J¼9.0 Hz, 1H, 7-H), 1.48
(tdd, Jt¼11.7 Hz, Jd¼4.5 Hz, Jd¼2.4 Hz, 1H), 1.74–2.03
(m, 4H), 3.11 (d, J¼1.9 Hz, 1H), 3.35 (s, 1H), 3.50 (d,
J¼15.2 Hz, 1H, NCHHPh), 4.03 (d, J¼15.2 Hz, 1H,
NCHHPh), 6.98 (tt, J¼7.3, 1.3 Hz, 1H), 7.07–7.27 (m,
14H, arom.). 13C NMR (CDCl3): d¼24.86 (C-5), 28.75 (C-
6), 39.54 (C-7), 44.57 (C-4), 49.74 (C-1), 59.91 (NCH2Ph),
108.69 (CPh2), 124.98 and 125.53 [aromatic, 2ꢂCortho (Ph0
and Ph00)], 126.82 [aromatic Cpara (Bn)], 127.96 [aromatic,
2ꢂCpara (Ph0 and Ph00)], 128.00 [aromatic Cortho (Bn)],
128.20 [aromatic Cmeta (Bn)], 130.34 and 131.02 [aromatic,
2ꢂCmeta (Ph0 and Ph00)], 139.45 [aromatic C-1 (Bn)], 143.04
and 145.20 [aromatic, 2ꢂC-1 (Ph0 and Ph00)], 154.02 (C-3).
MS (CI, m/z): 352 (MH+). Anal. Calcd for C26H25N: C
88.85, H 7.17, N 3.98; found: C 88.73, H 7.28, N 4.14.
2961, 1609, 1593, 1492, 1350, 1219, 1148, 938, 731 cmꢀ1
.
4.1.6. (D)-(1R,3-exo)-2-Benzyl-3-[(hydroxy)diphenyl-
methyl]-2-azabicyclo[2.2.1]heptane, 11. A solution of
10a (or 10b) (800 mg, 1.80 mmol) in dry THF (5 mL) was
added dropwise under argon to a solution of PhMgBr [pre-
pared, under argon, from Mg (470 mg, 19.4 mmol) and
PhBr (1.9 mL, 18 mmol) in dry THF (25 mL)] at room tem-
perature. The reaction mixture was refluxed overnight. Then
the mixture was cooled to 0 ꢁC and saturated aqueous NH4Cl
solution (16 mL) was added dropwise, the resulting mixture
was filtered and the organic solvents were removed in a rotary
evaporator. The remaining mixture was then extracted with
CH2Cl2 (3ꢂ20 mL). The pooled organic layers were washed
with saturated aqueous NH4Cl solution (16 mL) and brine
(20 mL), and dried with Na2SO4. The solvent was removed
in a rotary evaporator and the resulting residue was treated
with MeOH (12 mL) yielding 11 as a white solid (591 mg,
89% from 10a and 578 mg, 87% from 10b).20 Removal of
the solvent from the mother liquor left an oil, which when
flash chromatographed on silica gel (75 g) using hexane/
EtOAc 3:1 as eluent afforded the chiral auxiliary (393 mg
of 5b,24 94% and 402 mg of 5a,25 96%). Mp 179–180 ꢁC.
[a]2D3 +51 (c 1, CHCl3). IR (KBr): n¼2992, 2910, 1426,
4.1.8. (D)-(1R)-2-Benzyl-2-azabicyclo[2.2.1]heptan-3-
one, 13. To a vigorously stirred solution of 12 (400 mg,
1.14 mmol) in CHCl3 (18 mL) was added Cu2Cl2 (ca.
14 mg) at 0 ꢁC and the resulting cooled suspension was bub-
bled for 6 h with O2 (air stream). The reaction mixture was
filtered. Removal of the solvent from the filtrate in a rotary
evaporator left an oil (438 mg) that upon chromatography
on silica gel (15 g) with hexane/AcOEt 2:1 as eluent af-
forded benzophenone (206 mg) in the early fractions and
13, as an oil, in the later fractions. Yield 208 mg (91%).
[a]2D2 +41 (c 0.56, CHCl3). IR (neat): n¼2954, 2930, 1693,
1
1409, 1227, 993, 751 cmꢀ1. H NMR (CDCl3): d¼1.33 (d,
J¼9.4 Hz, 1H, 7anti-H), 1.47–1.72 (m, 3H), 1.82 (dd, J¼
9.4, 1.5 Hz, 1H, 7syn-H), 1.82–1.90 (m, 1H), 2.85 (dd,
J¼3.8, 1.5 Hz, 1H, 4-H), 3.68 (s, 1H), 3.93 (d, J¼15.1 Hz,
1H, NCHHPh), 4.68 (d, J¼15.1 Hz, 1H, NCHHPh), 7.24–
7.35 (m, 5H, C6H5). 13C NMR (CDCl3): d¼24.94 (C-5),
27.30 (C-6), 40.30 (C-7), 44.35 (C-4), 45.90 (C-1), 59.00
(NCH2Ph), 127.66 [aromatic C-4 (Bn)], 128.17 [aromatic
C-2+C-6 (Bn)], 128.85 [aromatic C-3+C-5 (Bn)], 137.56
[aromatic C-1 (Bn)], 178.21 (C-3). MS (EI, m/z): 201
(M+). Anal. Calcd for C13H15NO: C 77.58, H 7.51, N
6.96; found: C 77.33, H 7.72, N 6.84.
1332, 1255, 1094, 966, 788 cmꢀ1 1H NMR (CDCl3):
.
d¼0.97 (d, J¼9.8 Hz, 1H, 7-H), 1.22–1.33 (m, 1H), 1.38–
1.61 (m, 2H), 1.94 (d, J¼9.8 Hz, 1H, 7-H), 1.98–2.07 (m,
1H), 2.22 (s, 1H), 2.98 (d, J¼13.0 Hz, 1H, NCHHPh), 3.11
(s, 1H), 3.25 (s, 1H), 3.32 (d, J¼13.0 Hz, 1H, NCHHPh),
5.17 (br s, 1H, D2O exch.), 7.08–7.36 (m, 11H, arom.),
7.60 [dd, J¼7.3, 1.2 Hz, 2H, Hortho-2 (Ph0)], 7.74 [dd,
J¼7.5, 1.2 Hz, 2H, Hortho-2 (Ph00)]. 13C NMR (CDCl3): d¼
22.14 (C-5), 30.73 (C-6), 36.06 (C-7), 41.21 (C-4), 53.86
(C-1), 58.00 (NCH2Ph), 75.49 (C-3), 77.34 [C(OH)Ph2],
126.12 [aromatic, Cpara (Ph0 and Ph00)], 126.67 and 126.84
[aromatic, 2ꢂCortho (Ph0 and Ph00)], 127.30 [aromatic Cpara
(Bn)], 128.52 [aromatic Cmeta (Bn)], 128.56 [aromatic Cortho
4.1.9. (D)-(1R)-2-Benzoyl-2-azabicyclo[2.2.1]heptan-
3-one, 9. To a solution of 13 (150 mg, 0.75 mmol) and
18-crown-6 (ca. 1 mg) in 10 mL of Me2CO/AcOH (85:15,
v/v) was added water (0.5 mL). The mixture was heated to
60 ꢁC, finely powdered KMnO4 (476 mg, 3 mmol) was
added in portions during 5 h, and heating was continued
for 10 h more. The reaction mixture was then cooled to

M. L. Cardoso do Vale et al. / Tetrahedron 62 (2006) 9475–9482
9481
room temperature, 1 M Na2S2O5 (8 mL) was added, and the
mixture was extracted with CH2Cl2 (4ꢂ20 mL). The pooled
organic layers were washed with 1 M Na2S2O5 solution
(8 mL) and brine (20 mL). The combined organic extracts
were dried over Na2SO4 and concentrated, affording a solid
residue. Purification of the resulting solid through a short
column of silica gel (6 g) using CHCl3 as eluent afforded 9
as a white solid. Yield 154 mg (96%). The purity of the com-
pound obtained was verified by GLC [99.9%; semi-capillary
column (5 mꢂ0.53 mm i.d., film thickness 2.65 mm); oven
temperature 150 ꢁC isothermal, helium as carrier gas]. Mp
180–181 ꢁC (hexane/CCl4). [a]D22 +286 (c 1, CHCl3). IR
(KBr): n¼2979, 2954, 2876, 1746, 1660, 1600, 1452,
1337, 1310, 1216, 1178, 1159, 1099, 1056, 1027, 952,
compound obtained was verified by GLC [99.9%, semi-cap-
illary column (5 mꢂ0.53 mm i.d., film thickness 2.65 mm),
oven temperature 150 ꢁC isothermal, helium as carrier
gas]. Mp 179–181 ꢁC (CCl4). [a]D22 ꢀ287 (c 1, CHCl3).
Spectroscopic data (IR, 1H NMR, 13C NMR) were identical
to those of compound (+)-9.
Acknowledgements
The authors thank the Xunta de Galicia for financial support
of this work under project PGIDIT05PXIB20301PR.
907, 804, 781, 732, 698, 675, 611 cmꢀ1 1H NMR
.
References and notes
(CDCl3): d¼1.59 (dt, Jd¼10.0 Hz, Jt¼1.1 Hz, 1H, 7anti-H),
1.73–1.80 (m, 1H), 1.95–2.03 (m, 3H), 2.06 (dt, Jd¼10.0 Hz,
Jt¼1.8 Hz, 1H, 7syn-H), 2.94 (t, J¼1.6 Hz, 1H, 4-H), 4.81 (s,
1H, 1-H), 7.37–7.42 [m, 2H, (30-H, 50-H)], 7.49–7.54 (m,
1H, 40-H), 7.61–7.65 [m, 2H, (20-H, 60-H)]. 13C NMR
(CDCl3): d¼24.99 (C-5), 28.24 (C-6), 37.64 (C-7), 47.36
(C-4), 59.24 (C-1), 127.90 [aromatic C-3+C-5 (Bz)],
129.57 [aromatic C-2+C-6 (Bz)], 132.38 [aromatic C-4
(Bz)], 134.22 [aromatic C-1 (Bz)], 169.56 [NC(O)Ph],
175.73 (C-3). MS (EI, m/z): 215 (M+). Anal. Calcd for
C13H13NO2: C 72.54, H 6.09, N 6.51; found: C 72.48, H
6.12, N 6.47.
1. (a) Kleemann, A.; Engel, J.; Kutscher, B.; Reischert, D.
Pharmaceutical Substances: Synthesis, Patents, Applications,
€
3rd ed.; Thieme: Wurtsburg, Germany, 1999; (b) Fleet,
G. W. J.; Witty, D. R. Tetrahedron: Asymmetry 1990, 1, 119.
2. (a) Weinreb, S. M. Comprehensive Organic Synthesis;
Paquette, L. A., Ed.; Pergamon: Oxford, 1991; Chapter 4.2;
(b) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Method-
ology in Organic Synthesis; Academic: Orlando, 1987;
Chapter 2; (c) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron
ꢀ
2001, 57, 6099; (d) Timen, A. S.; Somfai, P. J. Org. Chem.
2003, 68, 9958; (e) Rodrıguez-Borges, J. E.; Garcıa-Mera,
´
´
ꢀ
X.; Fernandez, F.; Lopes, V. H. C.; Magalhaes, A. L.;
4.1.10. (L)-(1S)-2-Azabicyclo[2.2.1]heptan-3-one, 14. To
a solution of 323 [(160 mg, 1.47 mmol), [a]D ꢀ563.4 (c 1,
CHCl3)] in AcOEt (50 mL) was added 10% Pd/C
(300 mg). The vigorously stirred black suspension was
hydrogenated under a hydrogen pressure of 40 psi at room
temperature. After the reaction was complete (1.5 h), the
reaction mixture was filtered and the filtrate was concen-
trated to give a white solid (161 mg, 98%). The purity of
the compound obtained was verified by GLC [99.5%,
semi-capillary column (5 mꢂ0.53 mm i.d., film thickness
2.65 mm), oven temperature 85 ꢁC isothermal, helium as car-
rier gas]. An analytical sample was obtained through crystal-
lization from cyclohexane and subsequent sublimation at
90–95 ꢁC (0.05–0.1 mmHg). Mp 96–98 ꢁC. [a]2D2 ꢀ160 (c
1, CHCl3).26 IR (KBr): n¼3219, 2946, 1684, 1507, 1398,
Cordeiro, M. N. D. S. Tetrahedron 2005, 61, 10951 and refer-
ences therein; (f) Ekegren, J. K.; Modin, S. A.; Alonso,
D. A.; Andersson, P. G. Tetrahedron: Asymmetry 2002, 13,
447; (g) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707.
3. Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998,
63, 2530.
4. Alonso, D.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson,
P. G. J. Org. Chem. 1998, 63, 2749.
5. Taylor, S. J. C.; Sutherland, A. G.; Lee, C.; Wisdom, R.;
Thomas, S.; Roberts, S. M.; Evans, C. J. J. Chem. Soc.,
Chem. Commun. 1990, 1120.
6. (a) Choi, S.; Storici, P.; Schirmer, T.; Silverman, R. B. J. Am.
Chem. Soc. 2002, 124, 1620; (b) Smith, M. E. B.; Lloyd,
M. C.; Derrien, N.; Lloyd, R. C.; Taylor, S. J. C.; Chaplin,
D. A.; Casy, G.; McCague, R. Tetrahedron: Asymmetry 2001,
12, 703.
1239, 1109, 954, 814, 754 cmꢀ1 1H NMR (CDCl3):
.
d¼1.31 (dq, J¼9.3, 1.3 Hz, 1H), 1.47–1.57 (m, 2H), 1.72–
1.80 (m, 2H), 1.83 (dquint, J¼9.3, 2.0 Hz, 1H), 2.73 (d,
J¼1.0 Hz, 1H), 3.88 (d, J¼0.8 Hz, 1H), 6.74 (br s, D2O
exch., 1H). 13C NMR (CDCl3): d¼23.93, 30.43, 41.73,
45.37, 55.70, 181.97. MS (EI, m/z): 111 (M+). Anal. Calcd
for C6H9NO: C 64.84, H 8.16, N 12.60; found: C 64.63, H
8.33, N 12.54.
7. (a) Ashby, C. R., Jr.; Paul, M.; Gardner, E. L.; Gerasimov,
M. R.; Dewey, S. L.; Lennon, I. C.; Taylor, S. J. C. Synapse
2002, 44, 61; (b) Allan, R. D.; Johnston, G. A. R. Med. Res.
Rev. 1983, 3, 91 and references therein.
8. Nakamura, S. Chem. Pharm. Bull. 1961, 9, 641.
9. (a) Zhu, X.-F. Nucleosides Nucleotides Nucleic Acids 2000, 19,
´
651; (b) Rodrıguez, J. B.; Comin, M. J. Mini-Rev. Med. Chem.
2003, 3, 95.
10. (a) Bickley, J. F.; Gilchrist, T. L.; Mendoc¸a, R. Arkivoc 2002,
192; (b) See Ref. 1b.
4.1.11. (L)-(1S)-2-Benzoyl-2-azabicyclo[2.2.1]heptan-3-
one, ent-9. A solution of 14 (85 mg, 0.765 mmol) in dry
Et2O (3 mL) was added under argon to a stirred suspension
of 60% NaH (46 mg, 1.15 mmol) in dry Et2O (5 mL) at 0 ꢁC.
The mixture was stirred for 20 min and then a solution of
benzoyl chloride (163 mg, 1.16 mmol) in dry Et2O (3 mL)
was added under argon. The reaction mixture was stirred
at room temperature overnight and then filtered through
a short column of silica gel using Et2O as eluent. The solvent
was removed in a rotary evaporator affording (ꢀ)-9 as
a white solid. Yield 140 mg (85%). The purity of the
ꢀ
´
11. (a) Fernandez, F.; Garcıa-Mera, X.; Lopez, C.; Rodrıguez, G.;
Rodrıguez-Borges, J. E. Tetrahedron: Asymmetry 2000, 11,
ꢀ
´
´
ꢀ
´
4805; (b) Caaman˜o, O.; Fernandez, F.; Garcıa-Mera, X.;
Rodrıguez-Borges, J. E. Tetrahedron Lett. 2000, 41, 4123; (c)
´
´
´
ꢀ
Fernandez, F.; Garcıa-Mera, X.; Rodrıguez-Borges, J. E.;
Blanco, J. M. Tetrahedron Lett. 2001, 42, 5239; (d) Jones,
G. B.; Chapman, B. J. Synthesis 1995, 475.
12. (a) Poyin, P.; Dumas, F.; Maddaluno, J. Synth. Commun. 1990,
20, 2805; (b) Ort, O. Org. Synth. 1987, 65, 203.

9482
M. L. Cardoso do Vale et al. / Tetrahedron 62 (2006) 9475–9482
13. Ensley, H. E.; Parnell, C. A.; Corey, E. J. J. Org. Chem. 1978,
43, 1610.
14. Whitesell, J. K.; Liu, C.-L.; Buchanan, C. M.; Chen, H.-H.;
Minton, M. A. J. Org. Chem. 1986, 51, 551.
21. Monson, R. S.; Priest, D. N. J. Org. Chem. 1971, 36, 3826.
22. Van Rheenen, V. J. Chem. Soc., Chem. Commun. 1969, 314.
23. (ꢀ)-(1R)-Azabicyclo[2.2.1]hept-5-en-3-one, 3. Professor P. M.
Cullis (from Leicester University) kindly supplied us with
a sample of 3 obtained by enzymatic resolution of racemic lac-
tam. See: Taylor, S. J. C.; McCague, R.; Wisdom, R.; Lee, C.;
Dickson, K.; Ruecroft, G.; O’Brien, F.; Littlechild, J.; Bevan,
J.; Roberts, S. M.; Evans, C. T. Tetrahedron: Asymmetry
1993, 4, 1117.
ꢀ
´
´
15. Fernandez, F.; Garcıa-Mera, X.; Vale, M. L. C.; Rodrıguez-
Borges, J. E. Synlett 2005, 319.
´
ꢀ
16. Blanco, J. M.; Caaman˜o, O.; Fernandez, F.; Garcıa-Mera, X.;
ꢀ
´
Lopez, C.; Rodrıguez-Borges, J. E.; Hergueta, A. R. Synthesis
1998, 1590.
17. Experiment showed that the overall yield of the sequence was
not improved by distilling the 8-phenylmenthoxy oxalyl chlo-
ride (bp 86–97 ꢁC/0.5 Torr) prior to reducing it.16
24. The recovered alcohol [[a]2D5 ꢀ4.3 (c 0.5, CHCl3)] was identi-
fied as (ꢀ)-8-phenylisoneomenthol by comparison of its spec-
troscopic and specific rotation data with those reported in
literature.11a
´
ꢀ
18. Blanco, J. M.; Caaman˜o, O.; Fernandez, F.; Garcıa-Mera, X.;
Lopez, C.; Rodrıguez-Borges, J. E.; Rodrıguez, G.; Hergueta,
25. The recovered alcohol [[a]2D5 ꢀ25.2 (c 0.5, CHCl3)] was iden-
tified as (ꢀ)-8-phenylmenthol by comparison of its spectro-
scopic and specific rotation data with those reported in
literature.11a
ꢀ
´
A. R. Tetrahedron Lett. 1998, 39, 5663.
19. Use of an excess of commercial 2 M phenyllithium in cyclo-
hexane/Et2O led to similar results.
´
20. From 1H and 13C NMR and specific rotation data we con-
cluded that both adducts 1a,b afforded the same chiral tertiary
alcohol 11.
26. Evans, C.; McCague, R.; Roberts, S. M.; Sutherland, A. G.
J. Chem. Soc., Perkin Trans. 1 1991, 656, where for compound
14 a [a]3D0 of ꢀ133 (c 0.26, MeOH) is reported.