Development of a new class of (1S,3R,4R)-2-azabicyclo[2.2.1]heptane- oxazoline ligands and their application in asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tet.2004.01.102

New 2-aza-norbornane-oxazoline compounds were synthesized and evaluated as ligands in the transfer hydrogenation of acetophenone. The best catalyst prepared in situ from [IrCl₂(COD)]₂ and a ligand afforded 1-(S)-phenylethanol in good yields and 79% ee.

Full text of DOI:10.1016/j.tet.2004.01.102

Tetrahedron 60 (2004) 3393–3403
Development of a new class of
(1S,3R,4R)-2-azabicyclo[2.2.1]heptane-oxazoline ligands
and their application in asymmetric transfer hydrogenation
*
¨ ¨
Anna Trifonova, Klas E. Kallstrom and Pher G. Andersson
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 599, SE-75124 Uppsala, Sweden
Received 10 November 2003; revised 9 January 2004; accepted 19 February 2004
Abstract—New 2-aza-norbornane-oxazoline compounds were synthesized and evaluated as ligands in the transfer hydrogenation of
acetophenone. The best catalyst prepared in situ from [IrCl2(COD)]2 and a ligand afforded 1-(S)-phenylethanol in good yields and 79% ee.
q 2004 Published by Elsevier Ltd.
1. Introduction
our research group8 as an efficient ligand in Ru(arene)-
catalyzed asymmetric transfer hydrogenation. Herein we
describe the synthesis of a new class of 2-aza-norbornane-
oxazoline ligands. We also show the importance of the
bulky aza-bicyclic group in the ligand molecule for
asymmetric transfer hydrogenation of acetophenone by
comparison of the results obtained using acyclic chiral
amine-oxazoline ligand complexes and initial results from a
series of aza-bicycle-oxazoline ligand complexes.
The development of new chiral ligands for catalytic
asymmetric transformations is one of the most important
issues in the research of asymmetric synthesis.1 Among the
nitrogen ligands1c oxazoline compounds have been used for
a long time in different asymmetric catalytic reactions.2
Chelating atoms could, in addition to the nitrogen in the
oxazoline ring, be phosphorus, amino nitrogen, aromatic
nitrogen or sulfur atoms present in the molecule.3
Bis(oxazolines) are widely employed as ligands4 as well.
2. Results and discussion
Enantioselective transfer hydrogenation represents a very
useful method for the preparation of optically active
alcohols.5 Recently Noyori and co-workers6 showed that
the NH function within the ligand molecule is crucial for the
asymmetric transformation of prochiral ketones into chiral
alcohols. Several C2 symmetric chiral bis(oxazolinyl-
methyl)amine ligands7a were found to be efficient in the
Ru(II) catalyzed asymmetric transfer hydrogenation.
Recently the use of ruthenium and iridium complexes
with bis(oxazoline) ligands in this asymmetric process was
also reported.7b However, there are few reports on the use of
C1 symmetric amine-oxazoline ligands in transfer hydro-
genation of prochiral ketones. The only example described
is the application of chiral 1,2,3,4-tetrahyroquinolinyl-
oxazoline ligands in complexes with Ru(II)7b (conversion
40–78%, ee 12–83%).
The syntheses of bicyclic amine-oxazoline ligands using a
Cbz-protecting group for cyclic secondary nitrogen are
shown in Scheme 1. The (1S,3R,4R)-2-azabicyclo[2.2.1]-
heptane-3-carboxylic acid (1) is easily available from a
stereoselective aza-Diels Alder reaction.9 The protection of
the amine was performed using benzyl chloroformate10 to
give 2 in 72% yield. The amide coupling11,12 of 2 with
appropriate L- and D-aminoalcohols lead to hydroxylamines
3a, 3b, 4a, 4b, 5a and 5b (yield 64–94%). These
compounds were converted into protected oxazolines 6a,
6b, 7a, 7b, 8a and 8b by treatment with mesyl chloride
under basic conditions11 in 65–95% yield after purification.
The cleavage of the benzyloxycarbonyl group from the
amine was accomplished by hydrogenolysis using palla-
dium on carbon as a catalyst13 to yield the ligands 9a, 9b,
10a, 10b, 11a and 11b in 55–74%.
Previously 2-aza-norbornan-3-ylmethanol has been used by
The syntheses of bicyclic amine-oxazoline ligands using
p-nitrobenzyloxycarbonyl protecting group are shown in
Scheme 2. First, the compounds having the secondary
amine protected by benzyloxycarbonyl were synthesized. It
turned out that the deprotection of these oxazolines by
Keywords: Azabicyclo[2.2.1]heptane; Oxazoline; Chiral ligands;
[IrCl2(COD)]2; Acetophenone; Catalysis; Asymmetric transfer
hydrogenation.
*
Corresponding author. Tel.: þ46-18-471-38-16; fax: þ46-18-471-38-18;
e-mail address: phera@kemi.uu.se
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.01.102

3394
A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
protected oxazolines 16, 17a, 17b, 18a and 18b in 63–
83% yield. The p-nitrobenzyloxycarbonyl group was readily
cleaved by hydrogenolysis using palladium on carbon as a
catalyst16b to yield the ligands 19, 20a, 20b, 21a and 21b in
55–59% yield. No considerable amounts of oxazoline
decomposition products were observed in the 1H NMR
spectra of the crude materials after deprotection.
2.1. Evaluation of the new oxazoline ligands in transfer
hydrogenation
As a starting point of our investigation, we screened a
number of different metal complexes as precatalysts for
transfer hydrogenation using isopropanol as a hydrogen
source and i-PrOK as a base. The following metal
complexes were tested together with ligand 10a: [RuCl2
(benzene)]2, RuCl2(PPh3)3, [IrCl(COD)]2, RhCl(PPh3)3,
[Rh(COD)Cl]2 and RuCl2(DMSO)4. The results are shown
in Table 1. Surprisingly, in our study we found that with the
complexes [RuCl2(benzene)]2, RuCl2(PPh3)3 and RuCl2
(DMSO)4, no 1-phenylethanol formation was observed at
all.7 Rh(I) complexes RhCl(PPh3)3 and [Rh(COD)Cl]2 were
also able to catalyze this asymmetric transformation, but the
catalyst was not as efficient as the one formed from
[IrCl2(COD)]2 and produced the 1-phenylethanol with
lower enantiomeric excess.
The presence of the bulky 2-aza-norbornanyl group in the
ligand molecule was found to be crucial. The acyclic amine-
oxazoline ligands 22a and 22b18 (Scheme 3) were tested in
transfer hydrogenation of acetophenone with [IrCl2(COD)]2
as the catalyst precursor. These catalysts turned out to be
unselective and produced racemic 1-phenylethanol with low
conversion (10%).
Scheme 1. Synthesis of ligands 9a, 9b, 10a, 10b, 11a and 11b. Conditions
and reagents: (i) CbzCl, sat. NaHCO3 in H2O, rt, 3 h; (ii) EDC, HOBt,
aminoalcohol, CH2Cl2, rt, overnight; (iii) MsCl, Et3N, CH2Cl2, 0 8C!rt,
overnight; (iv) Pd/C (10 wt%), H2 (1 atm.), EtOH, rt, overnight.
Next, the influence of the size and configuration of the
substituent on the oxazoline part of the ligand was studied
(Table 2). First, the Ir-complex was prepared from
compound 19, which has two methyl groups in the
oxazoline (entry 1). When we employed this catalyst,
acetophenone was reduced to 1-(R)-phenylethanol in 73%
conversion and moderate ee (53%). To investigate how the
configuration of the methyl substituent influences the
stereoselectivity, oxazolines 9a and 9b were tested. These
ligands gave 1-(R)-phenylethanol in 41% ee (20% conver-
sion) and 33% ee (40% conversion) respectively (entries 2
and 3). These results show that in the case of ligands with a
methyl substituent on the oxazoline ring the configuration of
the bicycle is mainly responsible for the stereoselectivity.
The diastereomeric pair of ligands 10a and 10b (entries 4
and 5) having a larger substituent on the oxazoline ring had
higher selectivity. Use of ligand 10a lead to the formation of
1-(R)-phenylethanol with 79% ee (32% conversion), while
ligand 10b resulted in formation of 1-(S)-phenylethanol
(27% ee, 58% conv.). A further increase of the substituent
steric size (t-butyl group) made the reaction more sluggish
and also decreased the ee significantly (ligands 11a and 11b,
entries 6 and 7). The ligands 20a and 20b prepared from L-
and D-phenylglycinol also formed less selective catalysts
with [IrCl2(COD)]2 (entries 8 and 9). This is in accordance
with the hypothesis that the steric bulk of the substituent is
crucial for asymmetric induction. The best conversion of
acetophenone to 1-(R)-phenylethanol (83%) was observed
hydrogenolysis using Pd/C as a catalyst resulted in
decomposition of the oxazoline ring. We then started a
search for a new protecting group, which could be removed
under basic conditions (oxazolines are highly unstable
under acidic conditions) or is more readily cleaved by
catalytic hydrogenation. It was found that a recently
reported method14 for the preparation of oxazolines using
a base-labile Fmoc protecting group did not work in the case
of bicyclic amine-oxazoline molecules. It was not possible
to cleave the Fmoc group by treatment of these compounds
with piperidine, diethyl amine or t-butyl ammonium
fluoride.15 Instead, p-nitrobenzyloxycarbonyl was chosen
because of its higher lability under mild catalytic hydro-
genation conditions as compared to benzyloxycarbonyl.
Alternatively, the deprotection can also be accomplished by
treatment of the substrate with sodium dithionite,16 but it
was found, that the oxazolines were not stable under these
conditions, even in the presence of a base.
The p-nitrobenzyl ester protected amino acid17 12 was
coupled11,12 with the appropriate L- and D-aminoalcohols to
produce hydroxylamines 13, 14a, 14b, 15a and 15b in 66–
87% yield. These compounds were cyclized by treatment
with mesyl chloride under basic conditions11 to give

A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
3395
Scheme 2. Synthesis of ligands 19, 20a, 20b, 21a and 21b. Conditions and reagents: (i) p-NO2-CbzCl, 2.0 M NaOH in dioxane/H2O, rt, overnight; (ii) EDC,
HOBt, aminoalcohol, CH2Cl2, rt, overnight; (iii) MsCl, Et3N, CH2Cl2, 0 8C!rt, overnight; (iv) Pd/C (10 wt%), H2 (1 atm.), EtOH, rt, overnight.
when ligand 21a (entry 10) was employed, but in this case
the selectivity was low (28%). The diastereomeric ligand
21b (entry 11) also afforded 1-(R)-phenylethanol (35% ee)
but with lower conversion (15%).
the rate of the reaction with ligands prepared from D-
aminoalcohol is usually higher, but the ee of the product is
lower.
Interestingly, it was found that the enantioselectivity
changes during the reaction time (Table 3). For example
the Ir-complex prepared from ligand 10a produced 1-(R)-
phenylethanol in 38% ee after 1 h. When the product was
analyzed after 16 h of reaction time its enantiomeric excess
unexpectedly increased up to 79% (entry 1). Compound 10b
gave 1-(S)-phenylethanol in 16% ee after 1 h and 27% ee
after 16 h (entry 2). Similar behaviour was recorded for the
Ir-complex of compound 20b. Using this ligand acetophe-
none was reduced to 1-(S)-phenylethanol in 14% ee in 1 h
and in 24% ee after 16 h (entry 3). In reaction with
oxazoline 21b the enantiomeric excess of 1-(R)-phenyletha-
nol significantly decreased during the reaction time (42% ee
in 1 h and 28% ee in 16 h, entry 4). In a recently published
computational study the mechanisms for transfer hydrogen-
ation reactions of ketones catalyzed by Ru- and Ir-amino
alcohol complexes were compared.19 The calculation
suggests that the Ru-catalysis proceeds via a concerted
These results show that in diastereomeric ligand pairs the
configuration of product strongly depends on the configur-
ation of a substituent on the oxazoline ring, except the
molecules where steric bulk is missing (ligands 9a, 9b, 21a
and 21b). Use of ligands produced from L-aminoalcohol
leads to 1-(R)-phenylethanol formation. 1-(S)-Phenyletha-
nol is obtained employing the Ir-complex with an oxazoline
synthesized from a D-aminoalcohol. It was also noticed, that
Table 1. Transfer hydrogenation of acetophenone using different metal
complexes and ligand 10aa
Entry Metal complexb Conv., 16 h (%)c ee (%)c Conf. of product
1
2
3
4
5
6
RhCl(PPh3)3
3
25
71
79
—
—
—
R
R
R
—
—
—
[RhCl(COD)]2
[IrCl(COD)]2
[RuCl2(benzene)]2
RuCl2(PPh)3
18
32
—
—
—
RuCl2(DMSO)4
a
b
c
See Section 4.1 for procedure.
Substrate/metal/ligand/base¼200:1:2:5.
Determined by chiral GC.
Scheme 3. Structure of ligands 22a and 22b.

3396
A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
Table 2. Transfer hydrogenation of acetophenone using ligands 9a, 9b,
10a, 10b, 11a, 11b, 19, 20a, 20b, 21a and 21ba
Table 3. Transfer hydrogenation of acetophenone using ligands 10a, 10b,
20b and 21ba
Entry
Ligandb
Conv., 16 h
(%)c
ee
(%)c
Conf. of
product
Entry
Ligandb
Time
(h)
Conv.
(%)c
ee
(%)c
Conf. of
product
1
73
20
40
32
58
10
43
16
48
15
83
53
41
33
79
27
18
23
48
24
35
28
R
R
R
R
S
1
1
3
38
79
R
S
16
32
19
10a
10b
20b
21b
2
2
3
1
9
16
27
16
58
9a
3
1
14
48
14
24
R
R
16
9b
4
4
1
13
83
42
28
10a
10b
11a
11b
20a
20b
21a
21b
16
a
5
See Section 4 for procedure.
Substrate/metal/ligand/base¼200:1:2:5.
b
c
Determined by chiral GC.
mechanism while the Ir-catalyzed reaction proceeds via
direct hydrogen transfer between simultaneously coordi-
nated ketone and alcohol. This difference in reaction
mechanisms might explain the change of the enantiomeric
excess in Ir-catalyzed transfer hydrogenation.
6
R
S
7
3. Conclusions
The synthesis of a new class of (1S,3R,4R)-2-aza-
bicyclo[2.2.1]heptane-oxazoline ligands has been
developed. This route can be used to prepare various
derivatives of these new ligands in enantiomerically pure
forms from commercially available starting materials.
8
R
S
9
The compounds were evaluated in the asymmetric
transfer hydrogenation of acetophenone. It was found that
[IrCl2(COD)]2 was the best catalyst precursor and use of the
oxazoline 10a as a ligand gave rise to a catalyst of good
selectivity, 79% ee. These C1 symmetric oxazolinyl aza-
bicyclic amine ligands are currently under investigation and
will be also tested in other asymmetric transformations.
10
R
R
4. Experimental
11
1H and 13C NMR spectra were recorded in CDCl3 solutions
at 399.95/100.57 MHz. The chemical shifts are reported
using the residual signal of CDCl3 as the internal reference.
Optical rotations were recorded on a thermostated polari-
meter using a 1.0 dm cell. GC analysis was performed using
a
See Section 4 for procedure.
Substrate/metal/ligand/base¼200:1:2:5.
b
c
Determined by chiral GC.

A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
3397
the chiral column CP-Chiralsil-Dex CB with N2 as the
carrier gas at 15 psi and using a FID detector. Flash
chromatography was performed on silica gel (37–70 mm).
The TLCs were performed on 0.25 mm precoated plates,
silica gel 60 UV254 and spots were visualized using UV light
and ethanolic phosphomolybdic acid followed by heating.
The chiral starting materials, amines, acids and other
reagents were used as received from commercial suppliers.
Dichloromethane and isopropanol were dried over CaH2
and distilled under nitrogen prior to use.
mixture was extracted with CH2Cl2 (2£500 mL). The water
phase was acidified with conc. HCl and extracted with
EtOAc (2£500 mL). The organic phase was dried over
MgSO4 and evaporated under reduced pressure. The crude
product was purified by column chromatography on silica
gel using 0–5%MeOH/CH2Cl2 as the eluent to give after
evaporation the title compound 12 as pale yellow crystals
(8.0 g, 24.9 mmol, yield 86%) mp¼198–199 8C. (NMR
spectra are reported for a mixture of two rotamers.) 1H NMR
(CDCl3) d 8.32–8.07 (m, 2H), 7.62–7.38 (m, 2H), 5.43–
4.18 (m, 2H), 4.52–4.30 (m, 1H), 4.00–3.86 (m, 1H), 2.98–
2.76 (m, 1H), 2.00–1.10 (m, 7H) ppm; 13C NMR (CDCl3) d
176.1, 174.1, 155.3, 153.2, 147.7, 147.4, 144.0, 143.6,
66.05, 65.4, 64.8, 64.0, 57.8, 57.35, 42.7, 41.1, 35.9, 34.7,
30.5, 30.1, 27.8, 27.15 ppm; IR (neat) nmax 3444, 2955,
1700, 1607, 1520, 1436, 1407, 1130, 859, 737 cm21; MS
(EI) m/z (rel. intensity) 321 (Mþ, 1%), 275 (20), 203 (69),
160 (20), 154 (47), 137 (100), 107 (90); HRMS (FABþ)
(MþHþ): calcd for C15H17N2O6: 321.1087. Found:
321.1084.
4.1. General procedure for transfer hydrogenation of
acetophenone
[IrCl(COD)]2 (3.35 mg, 5.0 mmol), ligand (20.0 mmol) and
i-PrOH (2 mL) were added to a dry 50 mL Schlenk flask
under argon. The solution was stirred for 1 h at 80 8C and
then cooled down to room temperature. i-PrOH (18 mL)
was added followed by acetophenone (235 mL, 2.0 mmol)
and 1.0 M i-PrOK in i-PrOH (50 mL, 50.0 mmol). The
reaction mixture was stirred for 16 h at room temperature
and quenched by addition of two drops of 1.0 M HCl.
Evaporation of solvent and flash chromatography (diethyl
ether/pentane) gave the pure 1-phenylethanol. The enantio-
meric excess was determined by chiral GC analysis.
4.2. General procedure for preparation of
hydroxylamides 3a, 3b, 4a, 4b, 5a, 5b, 13, 14a, 14b, 15a
and 15b
A mixture of protected acid 2 or 12 (1 equiv.), EDC
(2 equiv.) and HOBt (2 equiv.) was stirred in dry CH2Cl2
(4 mL/mmol of acid) at 0 8C for 5 min. The appropriate
aminoalcohol (1.5 equiv.) was dissolved in dry CH2Cl2
(2 mL/mmol) and added to the reaction mixture. The
resulting clear solution was warmed up to room temperature
and stirred overnight. The reaction mixture was washed
with 1.0 M HCl (aq.) and saturated NaHCO3 (aq.). The
organic phase was dried over MgSO4 and evaporated to give
the crude hydroxylamide, which was purified by column
chromatography using 0–2%MeOH/CH2Cl2 as the eluent to
yield pure compounds 3a, 3b, 4a, 4b, 5a, 5b, 13, 14a, 14b,
15a and 15b after removal of solvents.
4.1.1. (1S,3R,4R)-2-Aza-bicyclo-[2.2.1]-heptane-2,3-
dicarboxylic acid 2-benzyl ester (2). Compound 1 (7.0 g,
47.6 mmol) was dissolved in 476 mL of H2O (10 mL/
mmol). A solid NaHCO3 (10.0 g, 119.0 mmol) was added
and the mixture was stirred until a clear solution was
obtained. Benzyl chloroformate (7.5 mL, 52.4 mmol) was
added dropwise and the reaction mixture was stirred at room
temperature for 3 h. The water solution was extracted with
diethyl ether (2£200 mL), the phases were separated and the
aqueous phase was acidified with conc. HCl to pH,4. (A
milky white suspension was formed.) The suspension was
extracted with diethyl ether (2£300 mL), the organic phase
was dried over MgSO4 and evaporated to yield compound 2
(9.4 g, 34.3 mmol, yield 72%) as a colorless oil, which was
used in later steps without further purification. (NMR
spectra are reported for a mixture of two rotamers.) 1H NMR
(CDCl3) d 10.24 (brs, 1H); 7.39–7.26 (m, 5H); 5.23–5.08
(m, 2H); 4.44–4.34 (m, 1H); 3.96–3.90 (m, 1H); 2.90–2.79
(m, 1H); 2.00–1.30 (m, 6H) ppm; 13C NMR (CDCl3) d
175.1, 174.0, 155.5, 153.8, 136.2, 136.0, 128.2, 128.1,
127.8, 127.6, 127.5, 127.1, 67.2, 66.6, 64.45, 63.8, 57.4,
56.9, 42.35, 41.0, 35.4, 34.4, 30.2, 29.8, 27.5, 27.0 ppm; IR
(neat) nmax 2952, 1750, 1705, 1666, 1426, 1359, 1130,
1109 cm21; MS (EI) m/z (rel. intensity) 276 (Mþþ1, 40%),
232 (20), 186 (34), 158 (48), 141 (52), 112 (28), 92 (100), 68
(44); HRMS (FABþ) (MþHþ): calcd for C15H18NO4:
276.1236. Found: 276.1247.
4.3. General procedure for preparation of protected
oxazolines 6a, 6b, 7a, 7b, 8a, 8b, 16, 17a, 17b, 18a and 18b
The hydroxylamide (1 equiv.) was dissolved in CH2Cl2/
Et3N (3/1, v/v, 9 mL/mmol) under nitrogen atmosphere and
the solution was cooled to 0 8C. To this solution MsCl
(2 equiv.) was slowly added and the reaction mixture was
stirred at room temperature overnight. It was washed with
water; the organic phase was dried over MgSO4 and
evaporated to afford crude protected oxazoline. Purification
by column chromatography with 0–2%MeOH/CH2Cl2 as
the eluent and evaporation of solvents gave protected
oxazolines 6a, 6b, 7a, 7b, 8a, 8b, 16, 17a, 17b, 18a and 18b
as clear colorless oils.
4.1.2. (1S,3R,4R)-2-Aza-bicyclo-[2.2.1]-heptane-2,3-
dicarboxylic acid 2-p-nitrobenzyl ester (12). Compound
1 (4.1 g, 29.0 mmol) was dissolved in mixture of dioxane
(96 mL) and water (68 mL) followed by addition of 2.0 M
NaOH (16.6 mL). The solution was stirred for 5 min. Then
p-nitrobenzylchloroformate (8.1 g, 37.7 mmol) in dioxane
(58 mL) and 2.0 M NaOH (19.9 mL) were added simul-
taneously. The reaction was stirred at room temperature
overnight. Water (280 mL) was added and the reaction
4.4. General deprotection procedure for preparation of
oxazolines 9a, 9b, 10a, 10b, 11a, 11b, 19, 20a, 20b, 21a
and 21b
The protected oxazoline was dissolved in dry EtOH
(10 mL/mmol) and a solution of activated Pd/C in dry
EtOH (10 wt% of Pd/C related to oxazoline) was added. The
mixture was connected to the H2 source (1 atm.) and stirred
at room temperature overnight. The Pd/C was filtered off

3398
A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
and the solvent was evaporated to give crude deprotected
oxazoline. The crude compounds were purified on a
deactivated silica gel column. The deactivation was done
as follows: the column was packed with a suspension of
silica gel in 20%Et3N/CH2Cl2 and the silica was washed
with 1%Et3N/CH2Cl2. The chromatography was performed
using 0–2%MeOH/1%Et3N/CH2Cl2 as the eluent to
afford oxazolines 9a, 9b, 10a, 10b, 11a, 11b, 19, 20a,
20b, 21a and 21b after evaporation of solvents under
reduced pressure.
4.4.4. (1S,3R,4R)-3-(20-Hydroxy-10(R)-isopropyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (4b). (1.68 g, 4.69 mmol, yield
94%) (white crystals) mp¼129–132 8C; (NMR spectra are
reported for a mixture of two rotamers.) 1H NMR (CDCl3) d
7.41–7.26 (m, 5H); 6.77–6.65 (m, 0.6H); 6.33–6.23 (m,
0.4H); 5.30–4.97 (m, 2H); 4.34–4.25 (m, 1H); 3.86–3.35
(m, 4H); 2.96–2.81 (m, 1H); 1.79–1.30 (m, 7H); 0.94–0.78
(m, 6H) ppm; 13C NMR (CDCl3) d 171.1, 171.0, 156.7,
155.6, 136.1, 136.0, 128.4, 128.15, 127.8, 67.4, 67.2, 63.7,
63.3, 58.0, 57.3, 56.7, 42.05, 40.1, 36.1, 34.7, 30.0, 28.8,
28.7, 27.3, 26.7, 19.4, 18.6, 18.5 ppm; IR (neat) nmax 3408,
2960, 2873, 1687, 1530, 1414, 1353, 1301, 1167,
1100 cm21; MS (EI) m/z (rel. intensity) 361 (Mþþ1,
40%), 329 (33), 275 (20), 230 (26), 186 (100), 158 (70),
92 (88), 65 (18); HRMS (FABþ) (MþHþ): calcd for
C20H29N2O4: 361.2127. Found: 361.2125.
4.4.1. (1S,3R,4R)-3-(20-Hydroxy-10(S)-methyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-carboxylic
acid 2-benzyl ester (3a). (0.92 g, 2.86 mmol, yield 94%)
(white crystals) mp¼92–95 8C; (NMR spectra are reported
1
for a mixture of two rotamers.) H NMR (CDCl3) d 7.45–
7.22 (m, 5H); 6.82–6.68 (m, 0.55H); 6.28–6.18 (m, 0.45H);
5.30–4.93 (m, 2H); 4.34–4.19 (m, 1H); 4.08–3.90 (m, 1H);
3.81–3.72 (m, 1H); 3.64–3.37 (m, 2H); 3.19–2.78 (m, 2H);
1.91–0.86 (m, 9H) ppm; 13C NMR (CDCl3) d 171.1, 156.5,
155.7, 136.1, 135.9, 128.4, 128.1, 127.8, 67.3, 67.0, 66.9,
47.8, 47.5, 42.1, 40.3, 35.9, 34.55, 30.05, 29.0, 27.2, 26.6,
16.6, 16.5 ppm; IR (neat) nmax 3408, 3325, 2947, 2871,
1702, 1650, 1530, 1411, 1352, 1101, 1050 cm21; MS (EI)
m/z (rel. intensity) 333 (Mþþ1, 22%), 302 (24), 230 (32), 186
(84), 158 (82), 92 (100), 65 (20); HRMS (FABþ) (MþHþ):
calcd for C18H25N2O4: 333.1814. Found: 333.1817.
4.4.5. (1S,3R,4R)-3-(20-Hydroxy-10(S)-tert-butyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (5a). (0.68 g, 1.87 mmol, yield
64%) (white crystals) mp¼120–122 8C; (NMR spectra are
reported for a mixture of two rotamers.) 1H NMR (CDCl3) d
7.42–7.20 (m, 5H); 6.98–6.78 (m, 0.6H); 6.36–6.19 (m,
0.4H); 5.27–5.02 (m, 2H); 4.39–4.09 (m, 1H); 3.93–3.65
(m, 3H); 3.35–3.52 (m, 1H); 3.01–2.81 (m, 1H); 2.72–2.57
(m, 0.6H); 2.21–2.38 (m, 0.4H); 1.93–1.18 (m, 6H); 0.53–
1.01 (m, 9H) ppm; 13C NMR (CDCl3) d 171.8, 170.9,
156.65, 156.62, 136.4, 136.3, 128.4, 128.1, 127.8, 67.3,
66.9, 63.3, 62.7, 60.1, 59.3, 58.0, 42.3, 40.2, 36.1, 34.55,
33.2, 30.1, 29.0, 27.1, 26.6 ppm; IR (neat) nmax 3412, 3331,
2959, 2871, 1704, 1653, 1528, 1399, 1352, 1300, 1167,
1097, 1050 cm21; MS (EI) m/z (rel. intensity) 375 (Mþþ1,
5%), 343 (50), 255 (20), 230 (22), 186 (82), 158 (62), 91
(100), 65 (20); HRMS (FABþ) (MþHþ): calcd for
C21H31N2O4: 375.2284. Found: 375.2282.
4.4.2. (1S,3R,4R)-3-(20-Hydroxy-10(R)-methyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (3b). (0.96 g, 2.98 mmol, yield
87%) (white crystals) mp¼143–145 8C; (NMR spectra are
reported for a mixture of two rotamers.) 1H NMR (CDCl3) d
7.38–7.23 (m, 5H); 6.73–6.63 (m, 0.6H); 6.38–6.31 (m,
0.4H); 5.27–4.93 (m, 2H); 4.30–4.19 (m, 1H); 4.04–3.89
(m, 1H); 3.81–3.73 (m, 1H); 3.68–3.16 (m, 2.6H); 2.94–
2.63 (m, 1.4H); 1.82–0.98 (m, 9H) ppm; 13C NMR (CDCl3)
d 170.6, 156.5, 155.0, 136.0, 128.4, 128.05, 127.8, 67.3,
66.9, 66.2, 66.05, 57.9, 47.4, 47.1, 42.0, 40.2, 35.9, 34.5,
29.9, 29.0, 27.2, 26.7, 16.7 ppm; IR (neat) nmax 3408, 3330,
2952, 2874, 1691, 1661, 1536, 1414, 1354, 1167, 1102,
1050 cm21; MS (EI) m/z (rel. intensity) 333 (Mþþ1, 42%),
302 (14), 230 (30), 186 (90), 158 (80), 92 (100), 65 (16);
HRMS (FABþ) (MþHþ): calcd for C18H25N2O4: 333.1814.
Found: 333.1820.
4.4.6. (1S,3R,4R)-3-(20-Hydroxy-10(R)-tert-butyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (5b). (1.55 g, 4.15 mmol, yield
94%) (light-yellow oil) (NMR spectra are reported for a
1
mixture of two rotamers.) H NMR (CDCl3) d 7.41–7.25
(m, 5H); 6.78–6.65 (m, 0.7H); 6.38–6.27 (m, 0.3H); 5.30–
4.97 (m, 2H); 4.37–4.18 (m, 1H); 3.86–3.27 (m, 4H);
3.02–2.77 (m, 1.7H); 2.53–1.98 (m, 0.3H); 1.88–1.23 (m,
6H); 0.83 (s, 9H) ppm; 13C NMR (CDCl3) d 171.1, 156.6,
155.3, 136.05, 135.9, 128.4, 128.0, 127.7, 67.3, 67.1, 62.4,
59.7, 58.9, 57.9, 42.0, 39.9, 36.2, 34.7, 33.0, 29.9, 28.95,
26.6 ppm; IR (neat) nmax 3332, 2960, 2874, 1685, 1540,
1414, 1355, 1302, 1169, 1100, 1050 cm21; MS (EI) m/z (rel.
intensity) 375 (Mþþ1, 9%), 186 (24), 158 (22), 91 (100), 68
(19); HRMS (FABþ) (MþHþ): calcd for C21H31N2O4:
375.2284. Found: 375.2279.
4.4.3. (1S,3R,4R)-3-(20-Hydroxy-10(S)-isopropyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (4a). (1.10 g, 3.32 mmol, yield
73%) (light-yellow oil) (NMR spectra are reported for a
1
mixture of two rotamers.) H NMR (CDCl3) d 7.38–7.23
(m, 5H); 6.80–6.71 (m, 0.55H); 6.42–6.34 (m, 0.45H);
5.20–5.02 (m, 2H); 4.30–4.14 (m, 1H); 3.80–3.20 (m, 5H);
2.94–2.72 (m, 1H); 1.92–1.09 (m, 7H); 0.98–0.59 (m, 6H)
ppm; 13C NMR (CDCl3) d 171.0, 170.8, 156.2, 155.3, 136.0,
135.8, 128.3, 128.2, 128.0, 127.9, 127.7, 127.6, 67.1, 67.0,
66.7, 63.3, 62.8, 57.8, 56.8, 56.4, 42.0, 40.4, 35.6, 34.3,
29.9, 28.9, 28.5, 28.2, 27.0, 26.6, 19.4, 19.2, 18.3, 18.0 ppm;
IR (neat) nmax 3411, 2959, 2875, 1700, 1530, 1409, 1354,
1299, 1168, 1101, 1049, 912 cm21; MS (EI) m/z (rel.
intensity) 361 (Mþþ1, 18%), 344 (6), 159 (11), 92 (100);
HRMS (FABþ) (MþHþ): calcd for C20H29N2O4: 361.2127.
Found: 361.2125.
4.4.7. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-methyl-10,30-oxa-
zol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-carboxylic
acid benzyl ester (6a). (0.45 g, 1.42 mmol, yield 88%)
(light-yellow oil) (NMR spectra are reported for a mixture
1
of two rotamers.) H NMR (CDCl3) d 7.35–7.25 (m, 5H);
5.24 (d, J¼12.7 Hz, 0.45H); 5.21 (d, J¼12.7 Hz, 0.55H);
5.01 (d, J¼13.1 Hz, 0.55H); 4.98 (d, J¼13.1 Hz, 0.45H);
4.39–3.99 (m, 4H); 3.81–3.79 (m, 0.55H); 3.62–3.57 (m,
0.45H); 2.70–2.62 (m, 1H); 2.08–2.03 (m, 1H); 1.80–1.42

A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
3399
(m, 4H); 1.33–1.10 (m, 4H) ppm; 13C NMR (CDCl3) d
165.8, 165.6, 155.0, 153.9, 136.7, 136.6, 129.3, 128.15,
127.75, 127.73, 127.5, 127.3, 74.2, 74.05, 66.8, 66.3, 61.35,
61.30, 60.6, 60.3, 57.4, 56.9, 42.9, 41.6, 35.3, 34.7, 30.4,
29.9, 27.5, 27.1, 21.3, 21.05 ppm; IR (neat) nmax 3330,
2966, 2871, 1705, 1670, 1415, 1355, 1190, 1166,
1101 cm21; MS (EI) m/z (rel. intensity) 314 (Mþ, 16%),
208 (18), 179 (30), 164 (16), 91 (100), 65 (24); HRMS
(FABþ) (MþHþ): calcd for C18H23N2O3: 315.1709. Found:
315.1711.
nmax 3411, 3331, 3012, 2961, 2875, 1700, 1416, 1356, 1191,
1103 cm21; MS (EI) m/z (rel. intensity) 342 (Mþ, 100%),
255 (30), 236 (52), 208 (58), 192 (32), 158 (30); HRMS
(FABþ) (MþHþ): calcd for C20H27N2O3: 343.2022. Found:
343.2025.
4.4.11. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-tert-butyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (8a). (0.43 g, 1.22 mmol, yield
65%) (yellow oil) (NMR spectra are reported for a mixture
1
of two rotamers.) H NMR (CDCl3) d 7.37–7.26 (m, 5H);
4.4.8. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-methyl-10,30-oxa-
zol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-carboxylic
acid benzyl ester (6b). (0.82 g, 2.61 mmol, yield 87%)
(light-yellow oil) (NMR spectra are reported for a mixture
5.21–5.04 (m, 2H); 4.38–3.76 (m, 5H); 2.63–2.59 (m, 1H);
2.21–2.13 (m, 1H); 1.76–1.25 (m, 5H); 0.90–0.73 (m, 9H)
ppm; 13C NMR (CDCl3) d 165.7, 165.4, 154.1, 154.0, 136.8,
136.7, 128.3, 128.15, 127.72, 127.70, 127.5, 127.3, 75.63,
75.54, 68.73, 68.68, 60.6, 60.3, 57.3, 57.0, 43.3, 42.3, 35.5,
34.8, 33.7, 33.4, 30.5, 29.9, 27.5, 27.3, 25.7, 25.6 ppm; IR
(neat) nmax 2952, 1707, 1414, 1356, 1190, 1102 cm21; MS
(EI) m/z (rel. intensity) 357 (Mþþ1, 32%), 255 (30), 186
(16), 158 (18), 91 (100), 65 (26); HRMS (FABþ) (MþHþ):
calcd for C21H29N2O3: 357.2178. Found: 357.2175.
1
of two rotamers.) H NMR (CDCl3) d 7.37–7.26 (m, 5H);
5.25 (d, J¼12.6 Hz, 0.45H); 5.20 (d, J¼12.6 Hz, 0.55H);
5.06 (d, J¼12.6 Hz, 0.55H); 4.97 (d, J¼12.6 Hz, 0.45H);
4.40–3.96 (m, 4H); 3.85–3.69 (m, 1H); 2.68–2.62 (m, 1H);
2.08–2.02 (m, 1H); 1.82–1.45 (m, 4H); 1.33–1.11 (m, 4H)
ppm; 13C NMR (CDCl3) d 165.5, 165.4, 156.7, 155.6, 136.8,
136.6, 128.3, 128.2, 127.77, 127.75, 127.5, 127.3, 74.2,
74.1, 66.8, 66.3, 61.3, 61.2, 60.7, 60.3, 57.4, 56.9, 42.7,
41.9, 35.5, 34.7, 30.5, 29.9, 27.5, 27.2, 21.3, 21.2 ppm; IR
(neat) nmax 3336, 2967, 1705, 1671, 1416, 1356, 1190, 1164,
1101 cm21; MS (EI) m/z (rel. intensity) 315 (Mþþ1, 90%),
230 (12), 208 (24), 186 (50), 158 (44), 112 (18), 93 (100), 65
(18); HRMS (FABþ) (MþHþ): calcd for C18H23N2O3:
315.1709. Found: 315.1709.
4.4.12. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-tert-butyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (8b). (0.46 g, 1.25 mmol, yield
67%) (yellow oil) (NMR spectra are reported for a mixture
1
of two rotamers.) H NMR (CDCl3) d 7.37–7.24 (m, 5H);
5.20–4.98 (m, 2H); 4.38–4.30 (m, 1H); 4.18–3.7 (m, 4H);
2.70–2.60 (m, 1H); 2.01–1.96 (m, 1H); 1.78–1.21 (m, 5H);
0.93–0.73 (m, 9H) ppm; 13C NMR (CDCl3) d 165.5, 165.2,
154.6, 153.9, 136.6, 128.1, 128.0, 127.6, 127.5, 127.4,
127.3, 75.2, 68.7, 68.5, 66.5, 66.2, 60.6, 60.4, 57.3, 56.9,
43.2, 42.2, 35.5, 34.7, 33.6, 33.4, 30.4, 29.8, 27.3, 27.0,
25.4, 25.3 ppm; IR (neat) nmax 2953, 2871, 1706, 1415,
1357, 1305, 1190, 1164, 1128, 1102, 1050, 998 cm21; MS
(EI) m/z (rel. intensity) 357 (Mþþ1, 100%), 255 (25), 91
(70); HRMS (FABþ) (MþHþ): calcd for C21H29N2O3:
357.2178. Found: 357.2179.
4.4.9. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-isopropyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (7a). (0.99 g, 2.89 mmol, yield
87%) (light-yellow oil) (NMR spectra are reported for a
1
mixture of two rotamers.) H NMR (CDCl3) d 7.36–7.25
(m, 5H); 5.21 (d, J¼12.6 Hz, 0.55H); 5.19 (d, J¼12.6 Hz,
0.45H); 5.04 (d, J¼12.4 Hz, 0.55H); 5.02 (d, J¼12.4 Hz,
0.44H); 4.40–4.22 (m, 2H); 4.08–3.97 (m, 2H); 3.87–3.77
(m, 1H); 2.65–2.59 (m, 1H); 2.17–2.08 (m, 1H); 1.90–1.45
(m, 5H); 1.38–1.28 (m, 1H); 0.93–0.76 (m, 6H) ppm; 13C
NMR (CDCl3) d 165.7, 165.4, 154.85, 153.9, 136.7, 136.6,
128.4, 128.25, 128.1, 127.9, 127.7, 127.5, 127.3, 71.9, 71.6,
70.0, 69.6, 60.6, 60.3, 57.35, 56.9, 43.2, 42.0, 35.4, 34.8,
32.2, 31.9, 30.4, 29.9, 27.5, 27.2, 18.63, 18.59, 17.8,
17.2 ppm; IR (neat) nmax 3350, 2959, 2871, 1703, 1661,
1414, 1354, 1300, 1166, 1102 cm21; MS (EI) m/z (rel.
intensity) 343 (Mþþ1, 22%), 275 (15), 230 (30), 207 (16),
186 (96), 158 (72), 92 (100), 68 (20); HRMS (FABþ)
(MþHþ): calcd for C20H27N2O3: 343.2022. Found:
343.2018.
4.4.13. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-methyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (9a). (140 mg,
0.78 mmol, yield 55%) (yellow oil) [a]2D3¼263 (c¼0.55 in
1
CDCl3); H NMR (CDCl3) d 4.37 (dd, J¼8.0, 9.4 Hz, 1H);
4.17–4.11 (m, 1H); 3.82–3.78 (m, 1H); 3.56–3.49 (m, 1H);
3.41–3.36 (m, 1H); 2.60–2.53 (m, 1H); 1.82 (brs, 1H); 1.65–
1.57 (m, 3H); 1.48–1.43 (m, 2H); 1.45–1.23 (m, 4H) ppm;
13C NMR (CDCl3) d 168.55, 74.4, 60.95, 58.8, 55.9, 40.9,
35.4, 31.4, 28.2, 21.3 ppm; IR (neat) nmax 3304, 2968, 2871,
1665, 1360, 1203, 1055, 1033, 1002, 853 cm21; MS (EI) m/z
(rel. intensity) 181 (Mþþ1, 100%), 151 (26), 94 (22); HRMS
(FABþ) (MþHþ): calcd for C10H17N2O: 181.1341. Found:
181.1343.
4.4.10. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-isopropyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid benzyl ester (7b). (1.36 g, 3.97 mmol, yield
95%) (light-yellow oil) (NMR spectra are reported for a
4.4.14. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-methyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (9b). (272 mg,
1.51 mmol, yield 58%) (yellow oil) [a]2D3¼þ48 (c¼0.62 in
1
mixture of two rotamers.) H NMR (CDCl3) d 7.40–7.25
1
(m, 5H); 5.22–4.99 (m, 2H); 4.40–3.81 (m, 5H); 2.71–2.61
(m, 1H); 2.07–1.99 (m, 1H); 1.90–1.45 (m, 5H); 1.34–1.23
(m, 1H); 0.94–0.73 (m, 6H) ppm; 13C NMR (CDCl3) d
165.5, 165.3, 154.7, 153.9, 136.71, 136.66, 128.2, 128.1,
127.6, 127.5, 127.3, 71.5, 71.4, 69.7, 69.5, 66.6, 66.2, 60.6,
60.4, 57.4, 57.0, 43.1, 42.1, 35.5, 34.7, 32.0, 31.9, 30.4,
29.9, 27.4, 27.1, 18.34, 18.28, 17.4, 17.1 ppm; IR (neat)
CDCl3); H NMR (CDCl3) d 4.36 (dd, J¼8.0, 9.3 Hz, 1H);
4.18–4.10 (m, 1H); 3.84–3.80 (m, 1H); 3.53–3.48 (m, 1H);
3.40–3.35 (m, 1H); 2.57–2.52 (m, 1H); 1.90 (brs, 1H); 1.63–
1.58 (m, 3H); 1.47–1.42 (m, 2H); 1.26–1.21 (m, 4H) ppm;
13C NMR (CDCl3) d 168.5, 74.3, 60.9, 58.8, 55.8, 40.95, 35.4,
31.3, 28.2, 21.2 ppm; IR (neat) nmax 3305, 2968, 1664, 1357,
1199, 1054, 1033, 1002 cm21; MS (EI) m/z (rel. intensity) 181

3400
A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
(Mþþ1, 100%), 151 (52), 94 (38); HRMS (FABþ) (MþHþ):
4.4.19. (1S,3R,4R)-3-(20-Hydroxy-10,10-dimethyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (13). (0.62 g, 2.25 mmol,
yield 72%) (yellow oil) (NMR spectra are reported for a
calcd for C10H17N2O: 181.1341. Found: 181.1343.
4.4.15. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-isopropyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (10a). (420 mg,
2.02 mmol, yield 70%) (oily white crystals, melts at rt)
[a]2D3¼261 (c¼1.00 in CDCl3); 1H NMR (CDCl3) d 4.23 (dd,
J¼8.15, 9.6 Hz, 1H); 3.99–3.95 (m, 1H); 3.92–3.85 (m, 1H);
3.51–3.49 (m, 1H); 3.38–3.34 (m, 1H); 2.53–2.49 (m, 1H);
2.24 (brs, 1H); 1.79–1.69 (m, 1H); 1.61–1.55 (m, 3H); 1.47–
1.39 (m, 2H); 1.23–1.20 (m, 1H); 0.90 (d, J¼6.75 Hz, 3H);
0.84 (d, J¼6.75 Hz, 3H) ppm; 13C NMR (CDCl3) d 168.55,
71.3, 70.2, 58.9, 55.9, 41.15, 35.5, 32.2, 31.3, 28.3, 18.5,
17.7 ppm; IR (neat) nmax 3306, 2963, 2872, 1667, 1468, 1363,
1208, 1146, 1055, 1032, 945, 854 cm21; MS (EI) m/z (rel.
intensity) 208 (Mþ, 24%), 179 (100), 94 (22), 68 (20); HRMS
(FABþ) (MþHþ): calcd for C12H21N2O: 209.1654. Found:
209.1651.
1
mixture of two rotamers.) H NMR (CDCl3) d 8.21–8.08
(m, 2H), 7.49–7.38 (m, 2H), 6.69 and 6.15 (2 brs, 1H)
5.34–5.14 and 5.10–4.98 (m, 2H), 4.69–4.38 (m, 1H),
4.28–4.18 (m, 1H), 3.69 (s, 1H) 3.55–3.39 (m, 1H), 2.88–
2.69 (m, 1H), 1.86–1.05 (m, 12H) ppm; 13C NMR (CDCl3)
d 170.7, 155.9, 147.5, 143.5, 128.0, 123.6, 69.8, 67.2, 65.8,
65.6, 65.5, 59.2, 58.0, 55.7, 53.3, 42.4, 40.2, 39.0, 36.0,
34.5, 30.1, 29.5, 29.0, 27.4, 26.6, 24.3, 24.1, 22.8 ppm; IR
(neat) nmax 3383, 2973, 2872, 1707, 1607, 1522, 1403, 1344,
1165, 1107, 857, 736, 668 cm21; MS (EI) m/z (rel. intensity)
392 (Mþþ1, 5%), 360 (30), 275 (79), 203 (100), 140 (32),
136 (36), 106 (32), 89 (42), 78 (78), 68 (40); HRMS (FABþ)
(MþHþ): calcd for C19H26N3O6: 392.1822. Found:
392.1821.
4.4.16. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-isopropyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (10b). (562 mg,
2.70 mmol, yield 68%) (yellow oil) [a]2D3¼þ42 (c¼1.07 in
4.4.20. (1S,3R,4R)-3-(20-Hydroxy-10(S)-phenyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (14a). (0.82 g, 2.66 mmol,
yield 85%) (pale yellow semicrystals) (NMR spectra are
reported for a mixture of two rotamers.) 1H NMR (CDCl3) d
8.30–8.06 (m, 2H), 7.58–7.40 (m, 2H), 7.39–7.12 (m, 5H),
6.80 (brs, 1H), 5.40–4.96 (m, 3H), 4.38–4.16 (m, 1H),
4.00–3.66 (m, 3H), 3.06–2.22 (m, 1H), 1.89–1.18 (m, 7H)
ppm; 13C NMR (CDCl3) d 170.5, 143.4, 138.7, 128.8, 128.2,
127.8, 127.7, 126.6, 123.8, 67.2, 66.3, 66.0, 65.8, 58.3, 55.7,
40.2, 36.3, 30.2, 29.6, 26.7 ppm; IR (neat) nmax 3401, 2952,
1703, 1606, 1521, 1400, 1106, 458, 700 cm21; MS (EI) m/z
(rel. intensity) 441 (Mþþ1, 5%), 408 (50), 276 (61), 259
(100), 203 (40), 91(47), 77 (53), 68 (44); HRMS (FABþ)
(MþHþ): calcd for C23H26N3O6: 440.1822. Found:
440.1819.
1
CDCl3); H NMR (CDCl3) d 4.23 (dd, J¼9.9, 8.5 Hz, 1H);
3.99 (dd, J¼7.5, 8.5 Hz, 1H); 3.89–3.83 (m, 1H); 3.51–3.47
(m, 1H); 3.40–3.36 (m, 1H); 2.56–2.51 (m, 1H); 2.26 (brs,
1H); 1.78–1.65 (m, 1H); 1.62–1.53 (m, 3H); 1.50–1.39 (m,
2H); 1.24–1.21 (m, 1H); 0.91 (d, J¼6.75 Hz, 3H); 0.83 (d,
J¼6.35 Hz, 3H) ppm; 13C NMR (CDCl3) d 168.4, 71.3, 70.4,
58.95, 55.9, 41.1, 35.5, 32.3, 31.2, 28.3, 18.4, 17.7 ppm; IR
(neat) nmax 3387, 2961, 2872, 1666, 1471, 1361, 1203, 1055,
1033, 946, 853 cm21; MS (EI)m/z (rel. intensity)209 (Mþþ1,
100%), 179 (94), 96 (38), 68 (55); HRMS (FABþ) (MþHþ):
calcd for C12H21N2O: 209.1654. Found: 209.1650.
4.4.17. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-tert-butyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (11a). (200 mg,
0.90 mmol, yield 74%) (white crystals) mp¼105–108 8C;
[a]2D3¼254 (c¼0.61 in CDCl3); 1H NMR (CDCl3) d 4.21 (dd,
J¼8.75, 10.05 Hz, 1H); 4.08 (dd, J¼7.7, 8.75 Hz, 1H); 3.83
(ddd, J¼1.65, 7.7, 10.05 Hz, 1H); 3.55–3.48 (m, 1H); 3.41–
3.33 (m, 1H); 2.55–2.47 (m, 1H); 2.09 (brs, 1H); 1.66–1.42
(m, 5H); 1.30–1.23 (m, 1H); 0.88 (s, 9H) ppm; 13C NMR
(CDCl3) d 168.5, 75.2, 69.15, 59.1, 55.95, 41.3, 35.6, 33.5,
31.2, 28.4, 25.7 ppm; IR (neat) nmax 3256, 2954, 2900, 2869,
1656, 1361, 1346, 1248, 1218, 985 cm21; MS (EI) m/z (rel.
intensity) 223 (Mþþ1, 100%), 193 (40), 100 (26), 68 (16);
HRMS (FABþ) (MþHþ): calcd for C13H23N2O: 223.1810.
Found: 223.1805.
4.4.21. (1S,3R,4R)-3-(20-Hydroxy-10(R)-phenyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (14b). (0.85 g,
2.72 mmol, yield 87%) (pale yellow semicrystals) (NMR
spectra are reported for a mixture of two rotamers.) 1H NMR
(CDCl3) d 8.25–7.98 (m, 2H), 7.57–7.47 (m, 1H), 7.39–
7.10 (m, 6H), 6.70 (brs, 1H), 5.40–4.96 (m, 4H), 4.40–4.22
(m, 1H), 3.94–3.68 (m, 3H), 3.03–2.87 (m, 1H), 2.39–2.08
(m, 1H), 2.00–1.16 (m, 7H) ppm; 13C NMR (CDCl3) d
170.6, 165.2, 154.9, 147.6, 143.6, 143.0, 138.5, 128.8,
128.1, 127.8, 126.5, 123.8, 67.4, 67.1, 66.5, 66.3, 66.0, 58.2,
55.6, 55.4, 55.3, 42.5, 40.4, 36.2, 34.8, 30.3, 29.7, 29.2,
27.5, 26.7 ppm; IR (neat) nmax 3372, 2943, 1692, 1519,
1402, 1344, 1106, 747, 668 cm21; MS (EI) m/z (rel.
intensity) 441 (Mþþ1, 3%), 408 (47), 275 (72), 259
(100), 203 (60), 91(41), 77 (50), 68 (45); HRMS (FABþ)
(MþHþ): calcd for C23H26N3O6: 440.1822. Found:
440.1835.
4.4.18. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-tert-butyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (11b). (200 mg,
0.90 mmol, yield 72%) (white crystals) mp¼45–47 8C;
1
[a]2D3¼þ45 (c¼1.03 in CDCl3); H NMR (CDCl3) d 4.17
(dd, J¼10.0, 8.7 Hz, 1H); 4.09 (dd, J¼7.6, 8.7 Hz, 1H); 3.78
(ddd, J¼0.9, 7.6, 10.0 Hz, 1H);3.52–3.47(m, 1H);3.42–3.37
(m, 1H); 2.58–2.52 (m, 1H); 2.31 (brs, 1H); 1.62–1.52 (m,
3H); 1.48–1.40 (m, 2H); 1.25–1.20 (m, 1H); 0.85 (s, 9H)
ppm; 13C NMR (CDCl3) d 168.35, 75.0, 69.15, 59.05, 55.9,
41.2, 35.6, 33.5, 31.2, 28.3, 25.5 ppm; IR (neat) nmax 3306,
2955, 2904, 2870, 1669, 1479, 1359, 1199, 1055, 1027, 1004,
945, 853 cm21; MS (EI) m/z (rel. intensity) 223 (Mþþ1,
100%); HRMS (FABþ) (MþHþ): calcd for C13H23N2O:
223.1810. Found: 223.1803.
4.4.22. (1S,3R,4R)-3-(20-Hydroxy-10(S)-benzyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (15a). (0.75 g, 2.38 mmol,
yield 76%) (yellow foam) (NMR spectra are reported for a
1
mixture of two rotamers.) H NMR (CDCl3) d 8.29–8.17
(m, 2H), 7.59–7.43 (m, 2H), 7.34–7.11 (m, 5H), 6.63 (brs,
0.6H), 6.20 (brs, 0.4H), 5.31–5.05 (m, 2H), 4.26–4.11 (m,
1H), 3.81–3.44 (m, 2H), 2.98–2.30 (m, 5H), 1.82–1.06 (m,

A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
3401
7H) ppm; 13C NMR (CDCl3) d 170.3, 170.1, 155.6, 154.4,
147.2, 143.4, 137.5, 132.1, 131.8, 131.7, 131.6, 131.1,
128.8, 128.3, 128.2, 128.0, 127.8, 127.6, 126.1, 123.4, 66.8,
65.6, 65.3, 63.2, 63.0, 58.8, 57.8, 57.6, 53.3, 52.1, 52.0,
42.1, 40.3, 36.6, 35.4, 33.9, 29.9, 29.3, 29.0, 27.1, 26.5 ppm;
IR (neat) nmax 3396, 2952, 1703, 1656, 1606, 1521, 1401,
1344, 1107, 756, 747 cm21; MS (EI) m/z (rel. intensity) 454
(Mþ, 5%), 362 (10), 273 (100), 203 (34), 91 (29), 78 (19), 68
(12); HRMS (FABþ) (MþHþ): calcd for C24H28N3O6:
454.1978. Found: 454.1972.
285 (90), 275 (23), 241 (28), 226 (66), 225 (89), 203 (36),
106 (49), 91 (72), 78 (100); HRMS (FABþ) (MþHþ): calcd
for C23H24N3O5: 422.1716. Found: 422.1720.
4.4.26. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-phenyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (17b). (0.48 g,
1.13 mmol, yield 83%) (white semicrystals) (NMR spectra
are reported for a mixture of two rotamers.) 1H NMR
(CDCl3) d 8.21–7.98 (m, 2H), 7.54–7.36 (m, 2H), 7.34–
6.70 (m, 5H), 5.36–5.06 (m, 3H), 4.65–4.51 (m, 1H), 4.42–
4.35 (m, 1H), 4.17–4.06 (m, 2H), 2.81–2.72 (m, 1H), 2.27–
2.04 (m, 1H), 1.89–1.16 (m, 5H) ppm; 13C NMR (CDCl3) d
166.6, 166.5, 153.8, 153.3, 147.1, 156.9, 144.0, 144.0,
142.0, 141.7, 128.3, 128.2, 127.7, 127.3, 127.8, 127.0,
126.3, 126.2, 126.0, 123.3, 123.2, 69.2, 65.1, 64.8, 60.4,
60.3, 57.3, 57.1, 42.6, 41.7, 35.3, 34.5, 30.5, 29.3, 27.3,
27.1 ppm; IR (neat) nmax 3305, 2947, 1708, 1666, 1519,
1403, 1344, 1103, 747, 668 cm21; MS (EI) m/z (rel.
intensity) 423 (Mþþ1, 5%), 421 (23), 285 (83), 226 (60),
225 (24), 106 (26), 104 (48), 91 (58), 78 (100); HRMS
(FABþ) (MþHþ): calcd for C23H24N3O5: 422.1716. Found:
422.1714.
4.4.23. (1S,3R,4R)-3-(20-Hydroxy-10(R)-benzyl-ethyl-
carbomoyl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (15b). (0.63 g,
2.07 mmol, yield 66%) (pale yellow crystals) mp¼57–
60 8C; (NMR spectra are reported for a mixture of two
1
rotamers.) H NMR (CDCl3) d 8.16–8.01 (m, 1H), 7.60–
7.53 (m, 1H), 7.51–7.33 (m, 2H), 7.20–7.05 (m, 5H), 6.75
(brs, 0.7H), 6.66 (brs, 0.3H), 5.24–4.95 (m, 2H), 4.27–4.08
(m, 2H), 4.00–3.68 (m, 2H), 3.64–3.42 (m, 2H), 2.92–2.65
(m, 1H), 2.58 (brs, 1H), 1.73–1.00 (m, 7H) ppm; 13C NMR
(CDCl3) d 170.5, 170.2, 155.8, 154.5, 147.3, 143.4, 137.5,
128.9, 128.1, 127.9, 127.7, 126.2, 123.5, 66.9, 65.7, 65.4,
63.4, 57.9, 57.7, 52.2, 42.1, 40.3, 36.6, 35.4, 34.0, 30.0,
29.3, 29.0, 27.1, 26.5 ppm; IR (neat) nmax 3366, 2943, 1700,
1651, 1521, 1400, 1344, 1106, 756, 668 cm21; MS (EI) m/z
(rel. intensity) 274 (Mþ2p-Cbz-NO2, 19%), 273 (100), 203
(46), 91 (42), 78 (20), 68 (12); HRMS (FABþ) (MþHþ):
calcd for C24H28N3O6: 454.1978. Found: 454.1990.
4.4.27. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-benzyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (18a). (0.45 g, 1.03 mmol,
yield 78%) (colorless oil) (NMR spectra are reported for a
1
mixture of two rotamers.) H NMR (CDCl3) d 8.22–8.03
(m, 2H), 7.51–7.38 (m, 2H), 7.28–7.03 (m, 5H), 5.37–4.93
(m, 2H), 4.47–4.25 (m, 2H), 4.23–4.08 (m, 1H), 4.05–3.80
(m, 2H), 3.12–2.87 (m, 1H), 2.69–2.47 (m, 2H), 2.14–2.02
(m, 1H), 1.82–1.14 (m, 5H) ppm; 13C NMR (CDCl3) d
165.9, 165.7, 154.1, 153.2, 147.2, 147.1, 144.3, 143.9,
137.4, 137.2, 129.0, 128.9, 128.4, 128.21, 128.2, 127.8,
127.2, 126.3, 126.2, 123.4, 123.3, 71.8, 71.7, 69.3, 66.99,
66.96, 65.2, 64.7, 60.5, 60.2, 57.4, 57.0, 53.3, 49.5, 42.6,
41.5, 41.2, 41.1, 35.3, 34.6, 30.4, 29.8, 29.4, 27.3, 27.0 ppm;
IR (neat) nmax 3400, 2952, 1707, 1606, 1521, 1404, 1345,
1188, 1105, 747, 668 cm21; MS (EI) m/z (rel. intensity) 435
(Mþ, 5%), 344 (82), 299 (19), 203 (32), 191 (100), 148 (30),
117 (25), 91 (80), 78 (49); HRMS (FABþ) (MþHþ): calcd
for C24H26N3O5: 436.1872. Found: 436.1869.
4.4.24. (1S,3R,4R)-3-(40,50-Dihydro-50,50-dimethyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (16). (0.41 g, 1.09 mmol,
yield 74%) (yellow oil) (NMR spectra are reported for a
1
mixture of two rotamers.) H NMR (CDCl3) d 8.27–8.09
(m, 2H), 7.56–7.43 (m, 2H), 5.42–4.48 (m, 2H), 4.42–4.30
(m, 1H), 4.03–3.80 (m, 3H), 2.71–2.62 (m, 1H), 2.14–2.01
(m, 1H), 1.87–1.09 (m, 11H) ppm; 13C NMR (CDCl3) d
164.4, 164.2, 154.6, 153.9, 147.6, 144.7, 144.6, 138.4,
127.8, 124.0, 123.8, 79.64, 79.61, 67.5, 65.7, 65.3, 61.1,
60.9, 58.0, 57.6, 43.1, 42.1, 35.7, 35.0, 30.9, 30.1, 28.5,
28.4, 27.8, 27.5 ppm; IR (neat) nmax 2969, 1709, 1667,
1522, 1402, 1345, 1103, 736, 668 cm21; MS (EI) m/z (rel.
intensity) 374 (Mþ, 24%), 373 (36), 344 (25), 305 (27), 203
(18), 178 (100), 150 (26), 136 (25), 89 (38), 78 (68); HRMS
(FABþ) (MþHþ): calcd for C19H24N3O5: 374.1716. Found:
374.1720.
4.4.28. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-benzyl-10,30-
oxazol-20yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (18b). (0.42 g,
0.96 mmol, yield 73%) (colorless oil) (NMR spectra are
reported for a mixture of two rotamers.) 1H NMR (CDCl3) d
8.21–8.05 (m, 2H), 7.54–7.41 (m, 2H), 7.29–7.05 (m, 5H),
5.35–5.00 (m, 2H), 4.45–4.25 (m, 2H), 4.17–3.89 (m, 3H),
3.11–2.94 (m, 1H), 2.69–2.41 (m, 2H), 2.03–1.90 (m, 1H),
1.85–1.15 (m, 5H) ppm; 13C NMR (CDCl3) d 157.0, 156.7,
154.0, 153.3, 147.3, 147.2, 144.2, 144.1, 137.5, 137.2,
129.1, 128.9, 128.3, 128.2, 127.8, 127.3, 126.3, 126.2,
123.5, 123.3, 71.7, 66.9, 65.2, 64.9, 60.7, 60.4, 57.5, 57.1,
42.7, 41.7, 41.3, 41.2, 35.4, 34.7, 30.5, 29.8, 29.4, 27.3,
27.1 ppm; IR (neat) nmax 3400, 2923, 1708, 1605, 1521,
1403, 1345, 1106, 756, 668 cm21; MS (EI) m/z (rel.
intensity) 436 (Mþþ1, 4%) 344 (52), 299 (6), 203 (23),
191 (63), 117 (19), 91 (100), 78 (64); HRMS (FABþ)
(MþHþ): calcd for C24H26N3O5: 436.1872. Found:
436.1881.
4.4.25. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-phenyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane-2-N-car-
boxylic acid p-nitrobenzyl ester (17a). (0.45 g, 1.08 mmol,
yield 63%) (white semicrystals) (NMR spectra are reported
1
for a mixture of two rotamers.) H NMR (CDCl3) d 8.14–
7.95 (m, 2H), 7.50–7.32 (m, 2H), 7.30–7.03 (m, 5H), 5.34–
4.97 (m, 3H), 4.63–4.51 (m, 1H), 4.37–4.27 (m, 1H), 4.14–
3.90 (m, 2H), 2.77–2.65 (m, 1H), 3.20–2.05 (m, 1H), 1.86–
1.13 (m, 5H) ppm; 13C NMR (CDCl3) d 166.6, 166.3, 153.9,
153.1, 147.1, 146.9, 144.0, 143.9, 141.9, 141.5, 128.2,
128.1, 127.7, 127.2, 127.1, 126.2, 126.0, 123.3, 123.1, 74.9,
74.7, 69.3, 69.21, 69.20, 65.1, 54.8, 60.5, 60.2, 57.3, 57.0,
42.8, 41.6, 35.2, 34.6, 30.4, 29.7, 27.2, 27.0 ppm; IR (neat)
n
max 3400, 2952, 1708, 1519, 1402, 1344, 1104, 755 cm21
MS (EI) m/z (rel. intensity) 286 (Mþ2p-NO2-C7H7, 2%),
;

3402
A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
4.4.29. (1S,3R,4R)-3-(40,50-Dihydro-50,50-dimethyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (19). (32 mg,
0.17 mmol, yield 59%) (yellow oil) [a]2D0¼0 (c 4.25 in
1H), 3.55–3.51 (m, 1H), 3.40–3.37 (m, 1H), 3.08 (dd, J¼8.4,
7.0 Hz, 1H), 2.65 (dd, J¼13.6, 8.4 Hz, 1H), 2.57–2.53 (m,
1H), 2.15 (brs, 1H), 1.65–1.56 (m, 3H), 1.50–1.42 (m, 2H),
1.29–1.23 (m, 1H) ppm; 13C NMR (CDCl3) d 169.6, 137.7,
129.3, 128.5, 126.5, 66.8, 59.1, 56.0, 41.6, 41.2, 35.6, 31.5,
28.4 ppm; IR (neat) nmax 3300, 2967, 2871, 1663, 1493, 1452,
1361, 1198, 1054, 1028, 946, 771,701 cm21;MS(EI)m/z(rel.
intensity) 257 (Mþþ1, 48%). 256 (44), 227 (100), 117 (49), 94
(22), 91 (12), 69 (27); HRMS (FABþ) (MþHþ): calcd for
C16H21N2O: 257.1654. Found: 257.1658.
1
CHCl3); H NMR (CDCl3) d 3.90 (d, J¼8.1 Hz, 1H), 3.87
(d, J¼8.1 Hz, 1H), 3.48–3.43 (m, 1H), 3.30–3.29 (m, 1H),
2.53–2.48 (m, 1H), 2.08 (brs, 1H), 1.61–1.50 (m, 3H),
1.42–1.34 (m, 2H), 1.24–1.14 (m, 7H) ppm; 13C NMR
(CDCl3) d 167.2, 79.5, 66.6, 58.9, 55.9, 41.1, 35.4, 31.5,
28.31, 28.3, 28.1 ppm; IR (neat) nmax 3305, 2968, 2926,
2872, 1663, 1191, 1004, 909, 732, 642 cm21; MS (EI) m/z
(rel. intensity) 195 (Mþþ1, 98%), 194 (41), 165 (100), 94
(37), 72 (64), 68 (45); HRMS (FABþ) (MþHþ): calcd for
C11H19N2O: 195.1497. Found: 195.1501.
Acknowledgements
4.4.30. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-phenyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (20a). (64 mg,
0.26 mmol, yield 55%) (yellow oil) [a]2D0¼þ2 (c¼5.0 in
CHCl3); 1H NMR (CDCl3) d 7.39–7.14 (m, 5H), 5.19–5.09
(m, 1H) 4.66 (dd, J¼8.4, 1.7 Hz, 1H), 4.15–4.06 (m, 1H),
3.55–3.50 (m, 1H), 3.49–3.44 (m, 1H), 2.69–2.62 (m, 1H),
2.29 (brs, 1H), 1.73–1.57 (m, 3H), 1.54–1.40 (m, 2H), 1.33–
1.11 (m, 1H) ppm; 13C NMR (CDCl3) d 170.2, 142.2, 128.6,
127.5, 126.5, 76.7, 75.4, 69.2, 59.1, 56.1, 41.3, 35.7, 31.4,
28.4 ppm; IR (neat) nmax 3305, 2967, 1661, 1360, 1191, 1055,
1031, 755, 700 cm21; MS (EI) m/z (rel. intensity) 242 (Mþ,
37%), 213 (70), 120 (100), 94 (52), 91 (23); HRMS (FABþ)
(MþHþ): calcd for C15H19N2O: 243.1497. Found: 243.1498.
4.4.31. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-phenyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (20b). (63 mg,
0.26 mmol, yield 55%) (yellow oil) [a]2D0¼25 (c¼4.7 in
CHCl3); 1H NMR (CDCl3) d 7.39–7.18 (m, 5H), 5.23–5.12
(m, 1H), 4.66 (dd, J¼8.3, 1.8 Hz, 1H), 4.19–4.10 (m, 1H),
3.57–3.50 (m, 2H), 2.68–2.63 (m, 1H), 2.26 (brs, 1H), 1.74–
1.60(m, 3H), 1.54–1.44(m, 2H), 1.36–1.23(m, 1H)ppm;13C
NMR (CDCl3) d 170.2, 142.1, 128.6, 127.5, 126.5, 69.1, 59.2,
56.1, 41.4, 35.7, 31.5, 28.5 ppm; IR (neat) nmax 3304, 2967,
1661, 1453, 1358, 1189, 1054, 1033 cm21; MS (EI) m/z (rel.
intensity)242(Mþ 40%), 213(86), 120(100), 94(60), 91(26);
HRMS (FABþ) (MþHþ): calcd for C15H19N2O: 243.1497.
Found: 243.1486.
This work was supported by grants from The Swedish
Research Council. The authors are grateful to Dr. Ana Costa
Vicedo for the preparation of compounds 22a and 22b. We
also acknowledge Helen A. McManus and Professor Patrick
J. Guiry (University College Dublin, Ireland) for collabor-
ation during this project and COST for economic support.
References and notes
1. (a) Noyori, R. Asymmetric catalysis in organic synthesis;
Wiley: New York, 1994. (b) Ojima, I. Catalytic asymmetric
synthesis; VCH: New York, 1993. (c) Togni, A.; Venanzi,
L. M. Angew. Chem. 1994, 106, 517. Angew. Chem. Int. Ed.
Engl. 1994, 33, 497.
2. Braunstein, P.; Naud, F. Angew. Chem. Int. Ed. Engl. 2001, 40,
680.
3. (a) Hillgraf, R.; Pfaltz, A. Synlett 1999, 11, 1814.
(b) Bremberg, U.; Rahm, F.; Moberg, C. Tetrahedron:
Asymmetry 1998, 9, 3437. (c) Zhou, Q.; Pfaltz, A. Tetrahedron
Lett. 1993, 34, 7725.
4. Evans, D.; Woerpel, K.; Scott, M. Angew. Chem. 1992, 104,
439.
5. (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999,
10, 2045.
6. (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori,
R. Angew. Chem. Int. Ed. 1997, 36, 285. (b) Yamakawa, M.;
Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466.
7. (a) Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998,
120, 3817. (b) Zhou, Y.; Tang, F.; Xu, H.; Wu, X.; Ma, J.;
Zhou, Q. Tetrahedron: Asymmetry 2002, 13, 469. (c) Gomez,
M.; Jansat, S.; Muller, G.; Bonnet, M. C.; Breuzard, J. A. J.;
Lemaire, M. J. Organomet. Chem. 2002, 659, 186.
8. (a) Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.;
Andersson, P. G. J. Org. Chem. 1998, 63, 2749. (b) Alonso,
D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am.
Chem. Soc. 1999, 121, 9580. (c) Alonso, D. A.; Nordin, S. J.
M.; Roth, P.; Tarnai, T.; Andersson, P. G.; Thommen, M.;
Pittelkow, U. J. Org. Chem. 2000, 65, 3116. (d) Nordin, S. J.
M.; Roth, P.; Tarnai, T.; Alonso, D. A.; Brandt, P.; Andersson,
P. G. Chem. Eur. J. 2001, 7, 1431.
4.4.32. (1S,3R,4R)-3-(40,50-Dihydro-50(S)-benzyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (21a). (65 mg,
0.25 mmol, yield 55%) (yellow oil) [a]2D0¼22 (c¼7.62 in
CDCl3); 1H NMR (CDCl3) d 7.35–7.15 (m, 5H), 4.43–4.32
(m, 1H), 4.25–4.20 (m, 1H), 4.02 (dd, J¼13.7, 7.3 Hz, 1H),
3.56–3.52 (m, 1H), 3.40–3.36 (m, 1H), 3.10 (dd, J¼13.7,
5.1 Hz, 1H), 2.64 (dd, J¼13.7, 8.5 Hz, 1H), 2.56–2.52 (m,
1H), 2.16 (brs, 1H), 1.68–1.59 (m, 3H), 1.51–1.40 (m, 2H),
1.30–1.23 (m, 1H) ppm; 13C NMR (CDCl3) d 169.3, 137.5,
129.2, 128.5, 126.5, 66.8, 58.9, 56.0, 41.6, 41.1, 35.6, 31.5,
29.6, 28.4 ppm; IR (neat) nmax 3300, 2967, 2871, 1663, 1493,
1452, 1360, 1202, 1055, 1028, 946, 849, 757 cm21; MS (EI)
m/z(rel. intensity)256(Mþ 30%), 227(100),117(60),94(22),
91 (30), 68 (28); HRMS (FABþ) (MþHþ): calcd for
C16H21N2O: 257.1654. Found: 257.1650.
¨
9. (a) Sodergren, M. J.; Andersson, P. G. Tetrahedron Lett. 1996,
4.4.33. (1S,3R,4R)-3-(40,50-Dihydro-50(R)-benzyl-10,30-
oxazol-20-yl)-2-aza-bicyclo-[2.2.1]-heptane (21b). (67 mg,
0.26 mmol, yield 57%) (yellow oil) [a]2D0¼þ1 (c¼7.66 in
CDCl3); 1H NMR (CDCl3) d 7.34–7.17 (m, 5H), 4.43–4.32
(m, 1H),4.22(dd,J¼9.3,8.5 Hz, 1H),4.01(dd,J¼9.4,8.4 Hz,
¨
37, 7577. (b) Sodergren, M. J.; Bertilsson, S. K.; Andersson,
P. G. J. Am. Chem. Soc. 2000, 122, 6610.
10. Liang, B.; Richard, D. J.; Portonovo, P. S.; Joullie, M. M.
J. Am. Chem. Soc. 2001, 123, 4469.
11. Gilbertson, S. R.; Xie, D.; Fu, Z. J. Org. Chem. 2001, 66, 7240.

A. Trifonova et al. / Tetrahedron 60 (2004) 3393–3403
3403
12. Hall, S. E.; Han, W.-C.; Harris, D. N.; Goldenberg, H.; Michel,
I. M.; Monshizadegan, H.; Webb, M. L. Bio. Med. Chem. Lett.
1993, 3, 1263.
12, 219. (b) Qian, X.; Hindsgaul, O. Chem. Commun. 1997,
1059.
17. Baldwin, J. E.; Adlington, R. M.; Moss, N. Tetrahedron 1989,
45, 2841.
13. Husinec, S.; Savic, V. J. Serb. Chem. Soc. 1998, 63, 921.
14. Rajaram, S.; Sigman, M. S. Org. Lett. 2002, 4, 3399.
15. Ueki, M.; Amemiya, M. Tetrahedron Lett. 1987, 28, 6617.
16. (a) Guibe-Jampel, E.; Wakselman, M. Synth. Commun. 1982,
18. Costa Vicedo, A.; Andersson, P. G. Unpublished results.
19. Handgraaf, J.-W.; Reek, J. N. H.; Meijer, E. J. Organo-
metallics 2003, 22, 3150.