The first enantioselective synthesis of chiral norbornane-type 1,4-diamine ligand

Article abstract of DOI:10.1016/S0957-4166(03)00161-7

The asymmetric synthesis of trans-2,3-bis(aminomethyl)norbornane was performed starting with endo-2,3-norbornene dicarboxylate anhydride. Desymmetrization of meso-anhydride 1 and following selective epimerization gave the trans-monoester (+)-3 with a high enantiomeric excess (98% e.e.). LiAlH₄ reduction of the trans-monoester to the 1,4-diol, which was then treated with phthalimide under Mitsunobu conditions and, following a Gabriel type amine synthesis with hydrazine hydrate, yielded a saturated and unsaturated diamine mixture. Hydrogenation of mixture finally afforded saturated diamine (+)-8 with a yield of 37%.

Full text of DOI:10.1016/S0957-4166(03)00161-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1167–1170
The first enantioselective synthesis of chiral norbornane-type
1,4-diamine ligand
8
Cihangir Tanyeli* and Salih Ozc¸ubukc¸u
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 6 January 2003; accepted 7 February 2003
Abstract—The asymmetric synthesis of trans-2,3-bis(aminomethyl)norbornane was performed starting with endo-2,3-norbornene
dicarboxylate anhydride. Desymmetrization of meso-anhydride 1 and following selective epimerization gave the trans-monoester
(+)-3 with a high enantiomeric excess (98% e.e.). LiAlH4 reduction of the trans-monoester to the 1,4-diol, which was then treated
with phthalimide under Mitsunobu conditions and, following a Gabriel type amine synthesis with hydrazine hydrate, yielded a
saturated and unsaturated diamine mixture. Hydrogenation of mixture finally afforded saturated diamine (+)-8 with a yield of
37%. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussions
In our synthetic strategy, cis-monoester (+)-2 was cho-
sen as the homochiral starting compound for the con-
struction of norbornane backbone. For this purpose,
desymmetrization of endo-2,3-methoxycarbonyl bicyclo-
[2.2.1]hept-5-ene via enzymatic hydrolysis with PLE
afforded cis-monoester (+)-2 with moderate yields and
enantiomeric excess,8 although it has been reported that
no hydrolysis of endo-2,3-methoxycarbonyl bicyclo-
[2.2.1]hept-5-ene was observed with PLE.9 On the other
hand, recently, Bolm et al.10 have reported a more
efficient method for highly enantioselective desym-
metrization of meso-anhydrides via alkaloid-mediated
opening with methanol. Quinine or quinidine are used
as chiral directing agents and both enantiomers of the
corresponding cis-monoester can be obtained with very
high enantiomeric excess values (up to 99% e.e.) and
chemical yield.
Nitrogen containing ligands are becoming very useful
for catalytic asymmetric synthesis. Diamine ligands are
one of the most common types of nitrogen containing
ligands1 which are becoming applicable for catalytic
asymmetric synthesis. Enantiomerically pure diamines
are constituents of many natural compounds and com-
monly used in various areas of organic chemistry, par-
ticularly in pharmaceutical and medicinal chemistry.2
Chiral diamine platinum complexes have advantages
over the well known cancer drug, cis-platin, by reduc-
ing toxicity and blocking drug resistance.3 Although
many studies have been performed in the enantioselec-
tive synthesis of 1,2-diamines,4 there are few examples
regarding the asymmetric synthesis of 1,4-diamines.5
Recently, chiral 1,4-diamines have served as key inter-
mediates in the synthesis of potent HIV protease
inhibitors.6 Despite numerous studies describing the
applications of 1,2-diamines in catalytic asymmetric
synthesis, no examples involving 1,4-diamines have
been reported in literature. In rigid backbones such as
the norbornane system, 1,4-diamines have some advan-
tages, since the existence of additional methylene units
gives more flexibility and facilitates the complexation
with various types of metals7 compared to 1,2-diamine
systems. This property prompted us towards the devel-
opment of a new chiral 1,4-diamine ligand, which can
be applicable to miscellaneous asymmetric reactions.
Scheme 1. Reagents and conditions: (a) Quinidine, MeOH,
−55°C; (b) (i) LiBHEt3, THF, (ii) 1N HCl.
Quinidine-mediated opening of anhydride
1 with
methanol resulted in cis-monoester (+)-2 with a high
* Corresponding author. Tel.: +90-312-210-3222; fax: +90-312-210-
1280; e-mail: tanyeli@metu.edu.tr
enantiomeric excess (98% e.e.) (Scheme 1). Monoester
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00161-7

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C. Tanyeli, S. Ozc¸ubukc¸u / Tetrahedron: Asymmetry 14 (2003) 1167–1170
1168
3. Conclusion
(+)-2 was then converted to lactone (+)-3 by selective
reduction of ester group with LiBHEt3, super hydride,
which was then analyzed by GC for enantiomeric
excess determination.11
In conclusion, 1,4-diamine 7 had been synthesized as a
racemic mixture in 196014 for the first time. Our study
is the first asymmetric synthesis of diamine 7 and 8. The
application of ligand (+)-8 in catalytic asymmetric syn-
thesis is currently in our focus area.
Selective epimerization12 of 2 with LDA at −78°C gave
trans-monoester (+)-4 with a yield of 81% after flash
column chromatography. Key intermediate 1,4-diol (+)-
5 was obtained by LiAlH4 reduction of trans-monoester
(+)-4 in THF with a yield of 74%. For the conversion of
the diol to the diamine several methods have been tried
and the Mitsunobu reaction was chosen as the best in
terms of the yields and simplicity. Substitution of diol 5
with phthalimide under Mitsunobu condition13 in the
presence of PPh3 and DEAD in THF gave diimide
(+)-6, which was then treated with hydrazine hydrate
for a Gabriel type amine synthesis to give surprisingly a
mixture of saturated and unsaturated diamines. Prob-
ably, diimine, NHꢀNH, was formed in the reaction
medium from hydrazine and it reduced the CꢁC double
bond of norbornene backbone. In order to overcome
this problem, full saturation of the mixture was done
via hydrogenation in the presence of Pd/C and diamine
(+)-8 was synthesized with a yield of 95% from the
diimide (Scheme 2).
4. Experimental
Nuclear magnetic resonance spectra were acquired on
Bruker Spectrospin Avance DPX 400 spectrometer at
400 MHz for 1H and 100 MHz for 13C, in CDCl3.
Chemical shifts are given in ppm from tetra-
methylsilane. IR spectra were obtained using a Perkin–
Elmer model 1600 series FT-IR spectrometer and are
reported in cm−1. Mass spectra were recorded with a
Varian MAT 212. Flash chromatography: Merck silica
gel 60 (230–400 mesh). Optical rotations were measured
in CHCl3 solution in a 1 dm cell using a Bellingham &
Stanley P20 polarimeter at 20°C.
4.1. Synthesis of (2R,3R)-3-methoxycarbonylbicy-
clo[2.2.1]hept-5-ene-2-carboxylic acid 2 via alkaloid-
mediated anhydride opening
The absolute configuration of (+)-5,6-bis(amino-
Methanol (3.66 mL, 0.090 mol) was added to a stirred
suspension of the anhydride 1 (4.92 g, 0.030 mol) and
quinidine/quinine (10.71 g, 0.033 mol) in a 1:1 mixture
of toluene and CCl4 (150 mL in the case of quinidine,
600 mL in the case of quinine) at −55°C under an argon
atmosphere. The reaction mixture was stirred at this
temperature for 60 h during which the material gradu-
ally dissolved. Subsequently, the resulting clear solution
was concentrated in vacuo to dryness, and the resulting
residue was than dissolved in ethyl acetate. The solu-
tion was washed with 2N HCl, and after phase separa-
tion, followed by extraction of the aqueous phases with
ethyl acetate, the organic layer was dried over MgSO4,
filtered and concentrated providing the corresponding
cis-monoester 2 as white solid (5.10 g, 87%); [h]D=+7.8
(c 4.23, CCl4), lit.15 [h]D20=+7.9 (c 4.8, CCl4); mp 75–
methyl)bicyclo[2.2.1]heptane
8
was determined as
(5R,6R) by comparing specific rotation signs deter-
mined at equal concentration in the same solvent given
in the literature for cis-monoester (+)-2,10 trans-
monoester (+)-412 and trans-diol (+)-5.16 Since transfor-
mation of trans-1,4-diol (+)-5 to trans-1,4-diamine (+)-8
has no effect on the stereocenters of the norbornene
backbone, the absolute configuration was not changed
during Mitsunobu and following Gabriel type amine
synthesis.
1
78°C, lit.1 74°C (racemic); H NMR: l 6.26 (dd, J=
3.02, 5.77 Hz, 1H), 6.15 (dd, J=3.02, 5.49 Hz, 1H),
3.53 (s, 3H), 3.27 (dd, J=3.30, 10.17 Hz, 1H), 3.22 (dd,
J=3.03, 10.17 Hz, 1H), 3.10 (m, 1H), 3.13 (m, 1H),
1.42 (dt, J=1.92, 8.51 Hz, 1H), 1.25–1.29 (m, 1H); 13C
NMR: l 177.8, 173.1, 135.6, 134.4, 51.6, 48.8, 48.2,
47.9, 46.6, 46.1. e.e.=98% [GC-analysis of the lactone:
Lipodex E, t1=80.7, t2=81.1. Lipodex E: 2,6-O-
Dipentyl-3-O-butyryl-g-CD. Column head pressure: 1.0
bar N2; 100°C (50 min), heating rate 3.0°C/min up to
180°C (60 min). Injector temperature 200°C, detector
temperature 250°C.
4.2. Synthesis of (2R,3R)-3-methoxycarbonylbicyclo-
[2.2.1]hept-5-ene-2-carboxylic acid 4
LDA preparation: i-Pr2NH (14.3 mL, 0.102 mol) was
dissolved in 75 mL of THF under an argon atmo-
sphere. It was cooled to 0°C in an ice-bath. n-BuLi
(0.096 mol, 1.6 M in hexane) was added carefully by the
Scheme 2. Reagents and conditions: (a) LDA, THF, −78°C;
(b) LiAlH4, THF; (c) phthalimide, PPh3, DEAD, THF; (d)
NH2NH2·H2O; (e) H2, Pd/C.

8
C. Tanyeli, S. Ozc¸ubukc¸u / Tetrahedron: Asymmetry 14 (2003) 1167–1170
1169
portions of 10 mL. After addition, it was stirred for 30
min. Then it stands to come to room temperature.
precipitated product was isolated by filtration and
washed with cold THF. After removing the solvent
from the filtrate by evaporation, additional product was
isolated which had to be recrystallized from methanol.
The combined crystals were chromatographed on a
silica gel column using ethyl acetate as an eluent, to
afford diphthalimide 6 as a white solid (3.35 g, 57%);
(2R,3S)-3-Methoxycarbonylbicyclo[2.2.1]hept-5-ene-2-
carboxylic acid 2 (6.1 g, 0.031 mol) was dissolved in 50
mL of THF. It was cooled to −78°C with acetone and
dry ice mixture. Under an argon atmosphere, the pre-
pared LDA was added drop wisely with the help of a
dropping funnel for 1.5 h. After the addition com-
pleted, it was stirred for 4 h. Then, 1N of HCl was
added until it became acidic and a clear solution. It was
extracted with 3×50 mL of CH2Cl2. It was evaporated
and purified by column chromatography (1:1 Et2O/pen-
tane+1% HOAc mixture) to give (2R,3R)-3-methoxy-
carbonylbicyclo[2.2.1]hept-5-ene-2-carboxylic acid 4 as
a white solid (4.94 g, 81%); [h]D=−152.44 (c 1.54,
1
[h]D=+31.2 (c 0.048, CHCl3); H NMR: l 7.65–7.70
(m, 4H), 6.18–6.23 (m, 2H), 3.91 (dd, J=7.71, 13.64
Hz, 1H), 3.84 (dd, J=7.93, 13.63 Hz, 1H), 3.59 (d,
J=7.61 Hz, 2H), 2.80 (s, 1H), 2.95 (s, 1H), 2.39–2.45
(m, 1H), 1.55 (d, J=9.05 Hz, 1H), 1.49 (bs, 2H); 13C
NMR: l 168.8, 168.6, 138.1, 135.1, 134.2, 134.1, 132.4,
123.5, 46.7, 46.0, 45.4, 44.4, 43.6, 42.9, 42.0. Exact mass
calcd for (C25H20N2O4) 412.1423, found 412.1430.
1
CHCl3); mp=73°C, 95.5°C (racemic); H NMR: l 6.29
4.5. Synthesis of (5R,6R)-5,6-bis(aminomethylbicyclo)-
[2.2.1]heptane 8
(dd, J=3.02, 5.50 Hz, 1H), 6.14 (dd, J=3.02, 5.62 Hz,
1H), 3.70 (s, 3H), 3.43 (dd, J=3.85, 4.40 Hz, 1 H), 3.30
(m, 1H), 3.08 (m, 1H), 2.66 (dd, J=1.65, 4.53 Hz, 1 H),
1.63 (dt, J=1.65, 8.79 Hz, 1H), 1.48 (dq, J=1.65, 8.79
Hz, 1H); 13C NMR: l 179.2, 174.5, 137.5, 135.0, 52.1,
47.9, 46.9, 45.6. MS (EI, 70 eV): m/z=196.0 (3), 131.0
(32), 119.1 (10), 91.1 (12), 67.1 (10), 66.1 (100). IR
(KBr): w˜=3002, 1731, 1685, 1434, 1315, 1277, 1182
cm−1.
Hydrazine hydrate (3.94 mL, 126 mmol) was added to
a stirred solution of diphthalimide 6 (3.39 g, 7.9 mmol),
and the solution was heated to reflux for eight hours. It
was then cooled to room temperature, and the solvent
was removed under reduced pressure. The residue was
dissolved in NaOH (30 mL, 20%), and the resulting two
layers were then extracted with CH2Cl2 (3×50 mL). The
combined organic solution was then dried over MgSO4.
The filtrate was evaporated to leave the diamine mix-
ture as pale yellow oil. The characterization of diamine
mixture was done by GC–MS and 1H NMR
spectroscopy.
4.3. Synthesis of (5R,6R)-5,6-bis(hydroxymethyl)bicyclo-
[2.2.1]hept-2-ene 5
LiAlH4 (2.09 g, 55 mmol) was dissolved in 25 mL of
dry THF under an argon atmosphere. (2R,3R)-3-
Methoxycarbonylbicyclo[2.2.1]hept-5-ene-2-carboxylic
acid 4 (4.6 g, 25 mmol) dissolved in 25 mL of dry THF
was added at a rate maintaining vigorous reflux, and
the reaction solution was refluxed an additional hour.
LiAlH4 was decomposed with cold water by cooling in
an ice bath. It was filtered off and filtrate is stored. The
solid residue part was dissolved in dilute H2SO4 and it
was extracted repeatedly with diethyl ether and all
extracts were combined, washed once with cold water
and, then dried over MgSO4. It was concentrated to
give diol 5. The filtrate, concentrated to a smaller
volume, yielded a second crop of diol 5 (2.85 g, 74%);
[h]D=+28.1 (c 0.018, CHCl3), lit.16 [h]D=−21.0 (in
The mixture was then dissolved in 25 mL THF and
Pd/C was added under an argon atmosphere. With a
balloon filled with H2, it was stirred overnight. It was
filtered through Celite and concentrated to give diamine
8 as pale yellow oil (1.15 g, 95%); [h]D=+3.2 (c 0.05,
1
CHCl3); H NMR (400 MHz, CDCl3): l 2.62–2.67 (m,
2H), 2.51 (dd, J=7.8, 12.0 Hz, 1H), 2.41 (dd, J=6.1,
11.6 Hz, 1H), 2.25 (bs, 4H), 2.18 (bs, 1H), 1.97 (bs,
1H), 1.48–1.54 (m, 1H), 1.27–1.34 (m, 4H), 1.00 (m,
2H), 0.84 (m, 1H); 13C NMR (400 MHz, CDCl3): l
52.0, 49.7, 47.4, 44.2, 40.0, 38.6, 37.1, 30.3, 22.3. Exact
mass calcd for (C9H18N2−NH3“C9H15N) 137.1205,
found 137.1207.
1
CHCl3, for other enantiomer); H NMR: l 6.23 (dd,
J=3.20, 5.47 Hz, 1H), 5.98 (dd, J=2.76, 5.54 Hz, 1H),
3.77 (dd, J=5.52, 9.75 Hz, 1H), 3.66 (dd, J=5.23, 9.72
Hz, 1H), 3.42 (t, J=9.95 Hz, 1H), 2.82 (s, 1H), 3.03 (t,
J=9.85 Hz, 1H), 2.59 (s, 1H), 1.91–1.96 (m, 1H), 1.45
(bs, 2H), 1.28–1.33 (m, 1H); 13C NMR: l 138.3, 133.8,
66.9, 66.4, 48.3, 47.5, 47.3, 45.0 44.9.
Acknowledgements
We thank the Middle East Technical University for a
grant (no. AFP-2001-01-03-04), the Turkish Scientific
and Technical Research Council for a grant [no.
TBAG-2244 (102T169)] and Turkish State Planning
Organization for a grant (no. BAP-07-02-DPT-2002
K120540-04).
4.4. Synthesis of (5R,6R)-5,6-bis[(1,3-dioxo-2,3-dihydro-
1H-2-isoindolyl)]methylbicyclo[2.2.1]hept-2-ene 6
Diethyl azodicarboxylate (5.3 mL, 34 mmol) was added
at 0°C to a solution of diol 5 (3.0 g, 14.3 mmol),
phthalimide (5.0 g, 34 mmol) and triphenylphosphine
(9.0 g, 34 mmol) in 100 mL anhydrous THF. The
mixture was stirred for 48 h at room temperature; the
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