2-Azanorbornyl alcohols: Very efficient ligands for ruthenium-catalyzed asymmetric transfer hydrogenation of aromatic ketones

Article abstract of DOI:10.1021/jo991914a

2-Azanorbornyl-derived amino alcohols were prepared and evaluated as ligands in the Ru(II)-catalyzed asymmetric transfer hydrogenation of aromatic ketones. To improve selectivity and rate, the structure of the ligand was optimized. Acetophenone was reduced using 0.5 mol% catalyst in 40 min in 94% ee. This system was also able to reduce a wide range of aromatic ketones to the corresponding alcohols, while maintaining high enantioselectivities and yields. The effects of catalyst loading and the presence of cosolvents in the reaction vessel were examined, and a linearity study was also done.

Full text of DOI:10.1021/jo991914a

3116
J . Org. Chem. 2000, 65, 3116-3122
2-Aza n or bor n yl Alcoh ols: Ver y Efficien t Liga n d s for
Ru th en iu m -Ca ta lyzed Asym m etr ic Tr a n sfer Hyd r ogen a tion of
Ar om a tic Keton es
Diego A. Alonso, Sofia J . M. Nordin, Peter Roth, Tibor Tarnai, and Pher G. Andersson*
Department of Organic Chemistry, Uppsala University, Box 531, S-751 21 Uppsala, Sweden
Marc Thommen and Ulrich Pittelkow
Catalysis Research, Solvias AG, Postfach R-1055.6.17, 4002 Basel, Switzerland
Received December 14, 1999
2-Azanorbornyl-derived amino alcohols were prepared and evaluated as ligands in the Ru(II)-
catalyzed asymmetric transfer hydrogenation of aromatic ketones. To improve selectivity and rate,
the structure of the ligand was optimized. Acetophenone was reduced using 0.5 mol % catalyst in
40 min in 94% ee. This system was also able to reduce a wide range of aromatic ketones to the
corresponding alcohols, while maintaining high enantioselectivities and yields. The effects of catalyst
loading and the presence of cosolvents in the reaction vessel were examined, and a linearity study
was also done.
In tr od u ction
ruthenium catalyst using diamines as chiral ligands.9
Other types of chiral phosphorus and/or nitrogen ligands
have also been used with varying levels of rate, yield,
and selectivity.10 A drawback of this methodology is the
reversibility of the reaction. The equilibrium point de-
pends on the redox potentials of the substrate and the
hydrogen source.1a Consequently, long reaction times may
lead to a drop in the enantiomeric excess. In a study of
ligand acceleration effect in Ru(II)-catalyzed transfer
hydrogenation, it was found that â-amino alcohols showed
the highest reaction rate.1a,11a Despite these finding and
the recent progress in this catalytic enantioselective
Catalytic asymmetric reduction of ketones to form
chiral secondary alcohols is an important transformation
in organic synthesis.1 This enantioselective transforma-
tion can be accomplished by hydride reduction using the
oxazaborolidine catalyst,2 by hydrogenation with for
example BINAP and DuPHOS ligands,3 and by transfer
hydrogenation.4 The latter has been studied extensively
during recent years because of the low cost, operational
simplicity and favorable properties of the hydrogen
donorsusually secondary alcohols or formic acid.5 Ru-
thenium complexes are the most important catalysts in
the asymmetric transfer hydrogenation of ketones, al-
though other metal complexes of samarium,6 rhodium,7
and iridium8 have been used successfully. Recently,
Noyori developed an efficient and highly enantioselective
(8) (a) Zassinovich, G.; Bettella, R.; Mestroni, G.; Breciani-Pahor,
N.; Geremia, S., Randaccio, L. J . Organomet. Chem. 1989, 370, 187.
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G.; Peruzzini, M.; Rocchini, E.; Zanobini, F. Organometallics 1995, 14,
1489. (d) Inoue, S.; Nomura, K.; Hashiguchi, Sh.; Noyori, R.; Izawa,
Y. Chem. Lett. 1997, 957.
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10.1021/jo991914a CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000

2-Azanorbornyl Alcohols
J . Org. Chem., Vol. 65, No. 10, 2000 3117
F igu r e 2.
Sch em e 1
F igu r e 1.
process, there are only a few examples where simple
amino alcohols are used as chiral ligands.11 We recently
reported the use of Ru(II)-2-azanorbornyl-3-methanol
complexes as chiral ligands in this reaction.12 These
systems proved to be highly efficient for the reduction of
aromatic ketones, using 2-propanol as the hydrogen
source. The promising results regarding rates and enan-
tioselectivities encouraged us to further investigate the
limitations of this ligand and to optimize the 2-azanor-
bornyl structure in order to improve the catalytic activity
and selectivity.
ligands were compared to the unsubstituted derivative
2 (Scheme 1), which had previously shown very high
enantioselectivities and a large ligand acceleration ef-
fect.12
The already published synthesis of ligand 2 was
optimized in the LiAlH4 reduction step (Scheme 1) where
a excess of reducing agent (6 equiv) and shorter reaction
times were used in order to avoid the formation of a
byproduct, which was found to be dimer 3 (Figure 2). The
optimized synthesis and catalytic activity of 3 are cur-
rently being investigated in our group.15
In this paper, we present the synthesis of new bicyclic
â-amino alcohols and their use as chiral ligands in the
transfer hydrogenation of aromatic ketones.
Resu lts a n d Discu ssion
Ligands 4a -d were prepared16 following a literature
procedure and evaluated in the transfer hydrogenation
of acetophenone, using [RuCl2(p-cymene)]17 and isopro-
poxide as the base (acetophenone/Ru/chiral ligand/i-PrOK
200:1:4:5). The results are summarized in Table 1, entries
1-5.
As we expected, (R)-substitution in the carbinol carbon
led to higher rates and enantioselectivities than the
corresponding (S) forms (compare entries 2 and 4 with 3
and 5 in Table 1). In the case of phenyl-substituted
ligands 4c and 4d , the selectivity was lower when
compared with ligand 2, probably due to an increase in
the steric impediments that led to a less effective binding
of the chiral ligand to the metal center. Ligand 4a showed
the highest rate (TOF ) 1330 h-1, 40 min reaction time)
combined with a very good enantioselectivity (94% ee).
It is important to mention that when using any of the
ligands listed in Table 2, no decrease in optical purity of
the product was observed during the course of the
reaction.
Dien es: Diels-Ald er Mod ifica tion s. To investigate
the influence of the bicyclic skeleton on the stereoselec-
tivity, cyclopentadiene was replaced by 1,3-cyclohexadi-
ene in the aza-Diels-Alder reaction.13 Ligand 6 was then
synthesized following the same procedure as for ligand
4. Hydrogenation/hydrogenolysis of the Diels-Alder ad-
duct 5 followed by LAH reduction of the amino ester
intermediate afforded 6 in 90% yield (Scheme 2).
As shown in Table 1, entry 6, the ethylene-bridged
ligand 6 is also highly enantioselective. Acetophenone
Syn th esis of Ch ir a l Am in o Alcoh ol Liga n d s. An
important feature in the preparation of new chiral
ligands is their synthetic versatility, allowing a variety
of modifications of their structures. These modifications
can affect the performance of the ligand to a great extent.
In this context, the methyl (1S,3R,4R)-2-[(S)-1-phen-
ylethylamino]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxyl-
ate derivative, obtained in high yield via a highly exo-
and diastereoselective aza-Diels-Alder reaction between
cyclopentadiene and the iminium ion derived from methyl
glyoxylate and (S)-1-phenylethylamine,13 presents the
possibility of a wide variety of modifications in its
structure. Three different ligand modification strategies
were carried out and are shown in Figure 1.
Am in o Alcoh ol Su bstitu tion Effects. We recently
demonstrated that substitution of the carbinol carbon of
the bicyclic amino alcohol ligands affects both the selec-
tivity and the rate in the Ru(II)-catalyzed transfer
hydrogenation of acetophenone.14 It was shown that
merely by introducing a methyl substituent in R-position
to the alcohol the selectivity and the rate of the new
ligands changed from a very active catalytic species (for
the (R)-Me substitution) to a less active one ((S)-Me
substitution). This could be explained by steric interac-
tions between the substituent and the arene or between
the substituent and the Ru-hydride in the metal hydride
complex. To extend this study, not only were the (R)- and
(S)-methyl substituted ligands synthesized, but also the
bulkier phenyl-substituted analogues. These two new
(12) Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson,
P. G. J . Org. Chem. 1998, 63, 2749.
(13) (a) Stella, L.; Abraham, M.; Feneau-Dupont, J .; Tinant, B.;
Declercq, J . P. Tetrahedron Lett. 1990, 18, 2603. (b) Waldmann, H.;
Braun, M. Liebigs Ann. Chem. 1991, 1045. (c) Bailey, P. D.; Brown, G.
R.; Korber, F.; Reed, A.; Willson, R. D. Tetrahedron: Asymmetry 1991,
12, 1263.
(15) Alonso, D. A.; Nordin, S. J . M.; Andersson, P. G. Unpublished
results.
(16) Brandt, P.; Hedberg, Ch.; Lawonn, K.; Pinho, P.; Andersson,
P. G. Chem. Eur. J . 1999, 5, 1692.
(17) For the synthesis of the Ru complexes, see: (a) Bennett, M. A.;
Smith, A. K. J . Chem. Soc., Dalton Trans. 1974, 233. (b) Bennett, M.
A.; Matheson, T. W.; Robertson, G. B.; Smith, A. K.; Tucker, P. A. Inorg.
Chem. 1980, 19, 101.
(14) Alonso, D. A.; Brandt, P.; Nordin, S. J . M.; Andersson, P. G. J .
Am. Chem. Soc. 1999, 121, 9580.

3118 J . Org. Chem., Vol. 65, No. 10, 2000
Ta ble 1. Asym m etr ic Tr a n sfer Hyd r ogen a tion of Acetop h en on e Usin g Liga n d s 2, 4, 6 a n d 9a
Alonso et al.
a
b
Substrate to catalyst ratio 200 according to procedure 1 in the Experimental Section. Determined by 1H NMR spectroscopy.
c Determined by chiral HPLC analysis. Turnover frequencies [(mol product/mol catalyst)/h] were calculated at 50% conversion.
d
Sch em e 2
Sch em e 3
was reduced with 95% ee and in 95% yield, thus proving
to be just as selective as the methylene-bridged analogue
2. A drawback of this ligand is the decrease of the
reaction rate.
En ola te Mod ifica tion s. We were interested in how
a 3,3-disubstitution in the 2-azanorbornyl skeleton af-
fected the rate and the enantioselectivity in the transfer
hydrogenation of aromatic ketones. We recently reported
that a highly diastereoselective enolate alkylation of
2-azanorbornyl derivatives with different electrophiles
such as alkyl halides, aldehydes, and acyl chlorides gave
the corresponding exo addition products.18 These reac-
tions proceed with diastereoselectivities >98%. Taking
advantage of this new strategy, we synthesized amino
alcohol 9 (Scheme 3).
Hydrogenation/ hydrogenolysis followed by benzylation
of 1 afforded 7 in 80% yield. Addition of LDA at -20 °C
generated the enolate, which was diastereoselectively
alkylated with MeI to give 8. Reduction of the ester and
debenzylation with Pd(OH)2 under hydrogen atmosphere
(1 atm) afforded ligand 9 in 89% yield. However, this
transformation generated a poorly performing ligand that
produced 1-phenylethyl alcohol with low and reversed
enantioselectivity (R instead of S, entry 7, Table 1).
of substrate in 2-propanol was mixed with 2.5 mol %
i-PrOK used as cocatalyst before addition of the chiral
catalyst. The transfer hydrogenations were done at room
temperature, and the results are summarized in Table
2.
Due to the simple synthesis of ligand 2, it was chosen
for a more thorough study of the transfer hydrogenation
of various alkyl aryl ketones; see Table 2. Our ligand
shows a high capacity to hydrogenate most ketones with
good conversion and ee at a high rate. The enantiomeric
excess and the reaction rate in the reduction of alkyl aryl
ketones were found to be dependent on both steric and
electronic factors. Asymmetric transfer hydrogenation of
sterically hindered ketones are often associated with loss
of enantioselectivity and lower reaction rates. This is also
the case with our catalytic systems, but the decrease is
only moderate. The reduction of linear alkyl aryl ketones
(entries 1-5) proceeds rapidly to the corresponding chiral
alcohol with good ee’s, ranging from 92 to 95%. Ketones
with branched alkyl groups such as tert-butyl and iso-
propyl give lower yields of the reduced alcohol as well as
lower ee’s (entries 6 and 7).
Tr a n sfer H yd r ogen a t ion of Ar om a t ic Ket on es.
The reactions were run with a substrate-to-catalyst ratio
of (S/C) 200. The chiral catalysts were prepared by
refluxing 2 mol % ligand with 0.25 mol % [RuCl2(p-
cymene)]2 in 2-propanol for 30 min. The 0.10 M solution
The introduction of electron-withdrawing substituents,
such as -Br and -CF3 in the ortho, meta, and para
positions of the aryl ketone, resulted in higher rates but
(18) Alonso, D. A.; Nordin, S. J . M.; Andersson, P. G. Org. Lett. 1999,
1, 1595.

2-Azanorbornyl Alcohols
J . Org. Chem., Vol. 65, No. 10, 2000 3119
Ta ble 2. Asym m etr ic Tr a n sfer Hyd r ogen a tion of Acetop h en on es Ca ta lyzed by Liga n d 2a
a
b
Transfer hydrogenations were carried out using S/C 200 according to procedure 1 in the Experimental Section. Determined by 1H
NMR spectroscopy. c Determined by chiral GC analysis.
Ta ble 3. Asym m etr ic Tr a n sfer Hyd r ogen a tion of
1-In d a n on e a n d 1-Tetr a lon e Ca ta lyzed by Liga n d s
2 a n d 6a
slightly lower enantioselectivities (entries 10, 15, 20, and
22). The reaction rate was moderately decreased with
electron-donating substituents on the aromatic ring, but
the high enantioselectivity was maintained. The excep-
tion was the p-methoxy-substituted acetophenone that
gave a lower reaction rate and ee (entry 19). This sub-
strate has proven to be difficult to reduce efficiently with
other ligands as well; this is probably due to its lower
redox potential.11b
The results obtained with nitrogen substituents strongly
depend on their position in the aromatic ring. Neither
amino nor nitro groups can be present in the ortho
position for a successful hydrogenation to take place.
However, amino substituents in the meta position give
good yields and enantioselectivity (entry 16). Almost the
same result was obtained when a nitro group was
introduced in the para position (entry 23). Acetonaph-
thone and 2- and 3-acetylpyridine were reduced with good
to excellent ee. Acetonaphthone gave the highest enan-
tioselectivity reported in this paper (97%).
product
entry
ligand
ketone
t (h)
convnb (%)
eeb (%)
1
2
3
4
2
6
2
6
1-indanone
1-indanone
1-tetralone
1-tetralone
18
18
18
18
50
50
72
70
95
84
95
89
a
Transfer hydrogenations were carried out according to pro-
cedure 2 in the Experimental Section using S/C ) 50. b Determined
by HPLC analysis.
we were unable to reduce indanone and tetralone.
Changing the proton source to the more potent formic
acid/triethylamine failed. It is well-known that amino
alcohols are not compatible with this solvent system.4e
To overcome this problem, we developed an alternative
procedure where the substrateswere added to the catalyst
5 min after the base. In addition, the chiral ligand and
[RuCl2(p-cymene)]2 were not refluxed for 30 min but
simply stirred at room temperature for 5 min. Table 3
shows the optimized results with 1-indanone and 1-tet-
ralone using S/C 50. When this procedure was used,
ligand 2 induced high enantioselectivity, giving ee’s as
high as 95%. In all cases the reactions were substantially
slower (18 h) compared to the reduction of acetophenone
and the yields were low as well.
Generally, the best results were obtained when sub-
stituents were placed in the meta position. The yields
were increased, and the enantioselectivities remained
high. When reducing para-substituted acetophenone
derivatives a slight decrease in selectivity was observed.
Unfortunately, when using the described procedure in
the transfer hydrogenation reactions shown in Table 2

3120 J . Org. Chem., Vol. 65, No. 10, 2000
Alonso et al.
Ta ble 4. Solven t Effectsa
product
entry
solvent
t (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
THF (1 mol %)
6
6
2
20
2
2
95
73
95
27
95
85
92
93
93
92
94
91
THF/i-PrOH 1/1
DMF (1 mol %)
DMF/i-PrOH 1/1
toluene (1 mol %)
toluene//i-PrOH 1/1
a
The transfer hydrogenations were carried out using S/C ) 200
b
according to procedure 1 in the Experimental Section. Deter-
mined by 1H NMR spectroscopy. c Determined by chiral HPLC
analysis; see the Experimental Section.
Ta ble 5. Ca ta lyst Loa d in ga
product
entry
substrate/Ru/L*/base
t (h)
convnb (%)
% eec
1
2
3
200:1:4:5
400:1:4:5
800:1:4:5
1.5
2.5
18
91
94
81
94
94
94
F igu r e 3. Asymmetric transfer hydrogenation of acetophe-
none: ee of (S)-1-phenylethanol as a function of ee off ligand
2.
a
Transfer hydrogenations were carried out according to pro-
b
cedure 1 using 0.10 M solutions. Determined by 1H NMR
Exp er im en ta l Section
spectroscopy. c Determined by chiral HPLC analysis; see the
Experimental Section.
For general experimental information see ref 20. Reactions
were carried out under nitrogen using dried glassware. i-PrOH
was dried over CaH2 and freshly distilled under nitrogen prior
to use. Acetophenone was distilled and stored over activated
molecular sieves. i-PrOK (1 M) was prepared prior to use from
freshly distilled i-PrOH and potassium. Reactions in Tables 2
and 4 were carried out in a Quest 210 supplied by Argonaut
Technologies. Flash chromatography was performed on silica
gel (Matrex 60A, 37-70 µm). Deactivated silica gel means that
it was treated with 5% Et3N in pentane and the column was
eluted with the same solvent mixture until the eluent was
basic according to pH paper. HPLC analysis were carried out
using a chiral column (ChiralCel OD-H) and a diode-array
detector with a flow rate of 0.5 mL/min using 5% i-PrOH in
hexane as solvent. GC analysis was done on a Varian 3400
capillary gas chromatograph using a CP-Chirasil-Dex CB (25
m/0.25 mm i.d.) column with nitrogen as carrier gas and a
flame ionization detector.
Solven t Effect. Some substrates might not be soluble
in 2-propanol, and therefore, we were interested in how
an additional solvent (THF, DMF, and toluene) influ-
enced the enantioselectivity and reactivity. It was found
that all solvents when mixed 1:1 with 2-propanol slowed
the hydrogenation of acetophenone. In addition, a 1-4%
decrease in selectivity was generally observed.
Ca ta lyst Loa d in g. Reducing the catalyst loading did
not affect the enantioselectivity (Table 5, entries 1 and
2). (S)-1-Phenylethanol is obtained in 81% yield after 18
h reaction time with S/C ) 800 (entry 3); further increase
in S/C molar ratio is accompanied with low conversions.
Non lin ea r ity Stu d y. To examine the influence of
ligand purity on the ee, we carried out a series of
reactions with mixtures of the (R) and (S) enantiomers
of ligand 2 (using acetophenone/Ru/chiral ligand/base
molar ratio 200:1:1:5). When the ee of the (S)-1-phenyl
ethanol was plotted against the ee of ligand 2, a slight
nonlinear effect was revealed as can be seen in Figure 3.
The nonlinearity may in principle be caused by the
formation of dimeric precatalyst species consisting of a
mixture of so-called hetero- and homodimers.19 In our
case, the heterodimer seems to be more active, resulting
in (S)-1-phenylethanol of lower enantiomeric purity.
In conclusion, we have demonstrated that simple
amino alcohols can successfully be used as ligands in the
Ru(II)-catalyzed transfer hydrogenation of a wide variety
of aryl alkyl ketones. These chiral amino alcohols are
obtained in good yields after simple transformations of
an aza-Diels-Alder adduct derived from the highly
diastereoselective reaction between cyclopentadiene and
the iminium ion of methylglyoxylate and (S)-1-phenyl-
ethylamine. The reductions take place at a high rate,
with good yield and enantioselectivity. We have also
improved the performance of the system by altering the
general procedure. Further investigations of the 2-aza-
norbornane structure and its use in asymmetric transfer
hydrogenation are currently in progress.
Gen er a l P r oced u r es for Tr a n sfer Hyd r ogen a tion of
Ar om a tic Keton es. P r oced u r e 1. Amino alcohol ligand (20
µmol) and [RuCl2(p-cymene)]2 (1.53 mg, 2.5 µmol) were added
to a round bottle flask. Any moisture was azeotropically
removed via evaporation with benzene (3 × 4 mL) at reduced
pressure. Reflux under nitrogen for 30 min in 2 mL of i-PrOH
generated the precatalyst. The substrate (1 mmol) was dis-
solved in 8 mL of i-PrOH, and the base 1 M i-PrOK in i-PrOH
(25 µL, 40 mmol) was added at room temperature, followed
by the precatalyst. The resulting solution was stirred at room
1
temperature, and the reaction was monitored by H NMR.
P r oced u r e 2. Amino alcohol ligand (7.3 µmol) and [RuCl2-
(p-cymene)]2 (2.03 mg, 3.3 µmol) were dissolved in 2 mL
i-PrOH. After 5 min of stirring under nitrogen at room
temperature, the substrate (0.33 mol, 0.1 M in i-PrOH) was
added. Stirring was continued for 5 min, and NaOH (2.4 mL,
0.1 M in i-PrOH) was added.
Compounds 1,13 2,12 4a -d ,14,15 5,21 and 622 were carried out
following literature procedures.
(1S,3R,4R)-2-Ben zyl-2-a za b icyclo[2.2.1]h ep t -5-en e-3-
ca r boxylic Acid Meth yl Ester (7). Hydrogenation/deben-
zylation of compound 1 were performed according to a litera-
ture procedure.23 The resulting amino ester (3.0 g, 19.3 mmol)
was dissolved in acetonitrile (75 mL), and K2CO3 (5.3 g, 38.7
mmol) was added followed by benzylbromide (2.3 mL, 19.3
(20) Bedekar, A. V.; Koroleva, E. B.; Andersson, P. G. J . Org. Chem.
1997, 62, 2518.
(21) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707.
(22) Pinho, P.; Guijarro, D.; Andersson, P. G.Tetrahedron 1998, 54,
7897.
(19) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1998,
37, 2922.

2-Azanorbornyl Alcohols
J . Org. Chem., Vol. 65, No. 10, 2000 3121
Ta ble 6. An a lysis Meth od s a n d Reten tion Tim es for th e P r od u cts Obta in ed in th e Su bstr a te Stu d y
a
Program 1: hold 90 °C for 10 min, heat to 150 °C/min, hold min, heat to 220 °C, 40 °C/min. Program 2: heat from 110 °C to 180 °C,
1 °C/min, hold 180 °C for 10 min, heat to 220 °C, 40 °C/min.
mmol). The reaction mixture was stirred under nitrogen
overnight at room temperature. The solvent was removed in
vacuo, and the residue was dissolved in CH2Cl2 (60 mL) and
washed with brine (30 mL). Drying over MgSO4, concentration
under reduced pressure, and purification by flash chromatog-
raphy (deactivated silica, pentane/ EtOAc 20/1-5/1) afforded
MHz/CDCl3) δ 23.7, 26.2, 27.4, 35.5, 48.8, 51.3, 51.5, 60.0, 70.4,
126.6, 128.2, 128.4, 142.6, 177.3; MS (EI) m/z (rel intensity)
259 (M+, 6), 200 (100), 186 (11), 172 (40), 91 (41). Anal. Calcd
for C16H21NO2: C, 74.14; H, 8.16; N, 5.40. Found: C, 74.04;
H, 8.30; N, 5.40.
(1S,3S,4R)-2-Azabicyclo[2.2.1]h eptan e-3-m eth yl-3-m eth -
a n ol (9). Compound 8 (280 mg, 1.1 mmol) dissolved in THF
(7 mL) was slowly added to a suspension of LiAlH4 (42 mg,
1.1 mmol) in THF at 0 °C. The reaction mixture was stirred
for 1 h and then quenched by slow addition of water (0.3 mL),
5% NaOH (0.3 mL), and water (0.8 mL). The reaction mixture
was filtered and washed with THF, dried (MgSO4), and
concentrated under reduced pressure to afford the alcohol (239
pure 9 (4.0 g, 15.4 mmol) in 80% yield: [R]21 ) +71.8 (c )
D
0.11, CH2Cl2); IR (neat, cm-1) 2952, 1745, 1156; 1H NMR δ
1.25 (1H, d, J ) 9.6 Hz), 1.30-1.42 (2H, m), 1.62-1.71 (1H,
m), 1.91-2.03 (2H, m), 2.52 (1H, br s), 2.69 (1H, s), 3.33 (1H,
s), 3.53 (3H, s), 3.74 (1H, s), 3.64-3.77 (1H, m), 7.19-7.36 (5H,
m); 13C NMR δ 22.3, 29.2, 36.5, 42.3, 51.4, 55.4, 59.6, 66.7,
126.8, 128.0, 129.0, 139.1, 173.9; MS (EI) m/z (rel intensity)
245 (M+, 7), 186 (79), 158 (100), 92 (57).
1
mg) in 96% yield, pure by H NMR.
(1S,3S,4R)-2-Ben zyl-2-a za b icyclo[2.2.1]h ep t -5-en e-3-
m eth yl-3-ca r boxylic Acid Meth yl Ester (8). A solution of
compound 7 (100 mg, 0.41 mmol) in dry THF (1 mL) was slowly
added to freshly prepared LDA (0.45 mmol) in dry THF (5 mL)
at -20 °C. After 40 min, the reaction mixture was warmed to
5 °C, and MeI was added (0.43 mmol). The mixture was
allowed to reach room temperature overnight. The reaction
was quenched with brine and extracted with Et2O (3 × 20 mL).
The combined organic extracts were dried (MgSO4) and
evaporated, and the residue was purified by flash chromatog-
raphy (silica gel, pentane/ Et2O) to afford compound 8 in 80%
yield: [R]21D ) -30.9 (c ) 0.11, CH2Cl2); IR (neat, cm-1) 2966,
Without further purification the alcohol was debenzylated.
The alcohol was dissolved in MeOH and Pd(OH)2 (120 mg, 50
wt %) was added. The reaction mixture was put under
hydrogen pressure (1 atm), heated to 40-50 °C, and stirred
overnight. After the mixture was cooled to room temperature,
the Pd(OH)2 was filtered off through a pad of Celite and the
solvent was removed in vacuo. The residue was dissolved in
CH2Cl2 (30 mL), washed with brine (10 mL), dried with MgSO4,
and concentrated under reduced pressure to afford 9 (136 mg)
in 93% yield. The amino alcohol was recrystallized from ether/
pentane: [R]21 ) -2.7 (c ) 0.6, CH2Cl2); mp ) 194-197 °C;
D
IR (neat, cm-1) 3328, 2900, 2750, 1392, 1063, 1052; H NMR
1
1
1735, 1113; H NMR (400 MHz/CDCl3) δ 1.21 (1H, d, J ) 9.6
(400 MHz/CDCl3) δ 1.49-1.61 (1 H, m), 1.51(3H, s), 1.60 (1H,
d, J ) 12.0 Hz), 1.78 (1 H, m), 1.86-2.04 (2H, m), 2.24 (1H, d,
J ) 11.2 Hz), 2.32 (1H, br s) 3.51(1 H, d, J ) 12.8 Hz), 4.05
(1H, d, J ) 12.8 Hz), 4.12 (1H, br s); 13C NMR (100 MHz/
CDCl3) δ 22.30, 22.53, 25.09, 37.3, 44.29, 58.82, 64.91, 68.99;
MS (EI) m/z (rel intensity) 142 (M+, 10), 110 (66), 82 (100), 67
(17). Anal. Calcd for C8H15NO: C, 68.04; H, 10.71; N, 9.92.
Found: C, 68.00; H, 10.54; N, 9.80.
Hz), 1.30-1.49 (3H, m), 1.42 (3H, d, J ) 4.4 Hz), 1.70-1.76
(1H, m), 1.85-1.95 (1H, m), 2.41 (1H, br s), 3.06 (1H, br s),
3.73 (3H, d, J ) 4.4 Hz) 3.78 (1H, d, J ) 3.6 Hz), 4.05 (1H, dd,
J 1 ) 3.2 Hz, J 2 ) 14.4 Hz), 7.20-7.48 (5H, m); 13C NMR (100
(23) Guijarro, D.; Pinho, P.; Andersson, P. G. J . Org. Chem. 1998,
8, 2530.

3122 J . Org. Chem., Vol. 65, No. 10, 2000
Alonso et al.
Ack n ow led gm en t. We would like to thank the
Swedish Natural Science Research Council (NFR), the
Swedish Research Council for Engineering Science
(TFR), and The Swedish Foundation for Strategic
Research (SSF) for financial support. D.A.A. is also
grateful to the Wenner-Gren Foundation for grants.
J O991914A