Rapid access to enantiopure bicyclic diamines via aza-Diels-Alder reaction of iminoamides

Full text of DOI:10.1021/jo005508z

6736
J . Org. Chem. 2000, 65, 6736-6738
Notes
Sch em e 1a
Ra p id Access to En a n tiop u r e Bicyclic
Dia m in es via a za -Diels-Ald er Rea ction of
Im in oa m id es
Stefan A. Modin and Pher G. Andersson*
Department of Organic Chemistry, Uppsala University,
Box 531, SE-751 21 Uppsala, Sweden
phera@kemi.uu.se
Received April 25, 2000
In tr od u ction
Enantiopure diamine ligands have been widely used
over the last years.1 Diamines have, for example, been
used as lithium amide bases,2 resolving agents,3 and
chiral ligands,4 which clearly indicates considerable
interest for structures of this kind. In our group bicyclic
diamine ligands are currently being studied and applied
in the rearrangement of meso-epoxides into chiral allylic
alcohols.5 We have earlier reported on the synthesis of
these ligands using an aza-Diels-Alder reaction devel-
oped by Stella et al.6 The resulting cycloaddition product
was then modified into the desired ligand, and this
reaction sequence has been successfully adopted for
several other types of ligands by our group.7 However,
the synthesis of these diamines required six steps, and
it was therefore of interest to find a new, shorter
synthetic route to these ligands.
a
Reagents and conditions: (i) H5IO6, CH2Cl2 then (S)-phenyl-
ethylamine, then TFA, BF3‚Et2O, cyclopentadiene, -78 °C to rt.
(ii) H2 (1 atm), Pd(OH)2/C, ethanol. (iii) LiAlH4, THF.
Sch em e 2a
Resu lts a n d Discu ssion
a
Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, ethanol,
overnight. (ii) LiAlH4, THF. (iii) H2 (1 atm), Pd(OH)2/C, ethanol.
The synthesis of 1a -c origins from bisamido tartrates
and is outlined in Scheme 1.
by flash chromatography and recrystallized to afford
diastereomerically pure compounds 2a -c.
The first step in the synthesis of 1a -c is an aza-Diels-
Alder reaction involving the glyoxamide obtained from
the oxidative cleavage of 3a -c using periodic acid. The
amidoaldehyde was treated with (S)-phenylethylamine
in dry dichloromethane in the presence of molecular
sieves 4 Å. To the resulting imine was added trifluoro-
acetic acid, boron trifluoride ethyl etherate, and cyclo-
pentadiene at -78 °C, which led to the formation of 2a -c
as mixtures of diastereomers. This mixture was purified
We found that the order of the last two reactions was
important. Whereas amides 2a -c were easily depro-
tected by hydrogenolysis at 1 atm of H2, diamine 5 did
not give any debenzylated product, even after prolonged
reaction time of hydrogenation/hydrogenolysis at 1 atm
of H2 and Pd(OH)2; see Scheme 2.
The last step, reduction of the amide to the corre-
sponding amine, was performed using lithium aluminum
hydride as reductant. The synthesis described in this
paper gives enantiomerically pure 1a in 38% overall yield
in only three steps, whereas the original synthetic route
gives 1a in six steps. Furthermore, the methodology could
be extended to produce azanorbornane derivatives with
other N-substituents.8
(1) For a review of the chemistry of vicinal diamines see: Lucet,
D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580.
(2) (a) O’Brien, P. J . Chem. Soc., Perkin Trans. 1 1998, 1439. (b) de
Sousa, S. E.; O’Brien, P.; Steffens, H. C. Tetrahedron Lett. 1999, 40,
8423.
(3) Clayden, J .; Lai, L. W. Angew. Chem. Int. Ed. 1999, 38, 2556.
(4) (a) Pe´nicaud, V.; Maillet, C.; J anvier, P.; Pipelier, M.; Bujoli, B.
Eur. J . Org. Chem. 1999, 1745, 5. (b) Tommasino, M. L.; Thomazeau,
C.; Touchard, F.; Lemaire, M. Tetrahedron: Asymmetry 1999, 10, 1813.
(c) Murata, K.; Ikariya, T.; Noyori, R. J . Org. Chem. 1999, 64, 2186.
(5) (a) So¨dergren, M. J .; Andersson, P. G. J . Am. Chem. Soc. 1998,
120, 10760. (b) So¨dergren, M. J .; Bertilsson, S. K.; Andersson, P. G. J .
Am. Chem. Soc. 2000, 122, 6610.
(8) (a) von Seebach, D.; Do¨rr, H.; Bastani, B.; Ehrig, V. Angew.
Chem. 1969, 81, 1002. (b) Marx, M. A.; Grillot, A.-L.; Louer, C. T.;
Beaver, K. A.; Bartlett, P. A. J . Am. Chem. Soc. 1997, 119, 6153. (c)
Raczko, J .; Achmatowicz, M.; J ezewski, A.; Chapuis, C.; Urbanczyk-
Lipkowska, Z.; J urczak, J . Helv. Chim. Acta 1998, 81, 1264. (d)
Frankland, P. F.; Ormerod, E. J . Chem. Soc. 1903, 83, 1343. (e)
Frankland, P. F.; Twiss, D. F. J . Chem. Soc. 1910, 97, 154.
(6) (a) Stella, L.; Abraham, H.; Feneau-Dupont, J .; Tinant, B.;
Declercq, J . P. Tetrahedron Lett. 1990, 31, 2603. (b) Abraham, H.;
Stella, L. Tetrahedron 1992, 48, 9707.
(7) Brandt, P.; Andersson, P. G. Synlett 2000, 1092.
10.1021/jo005508z CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Notes
J . Org. Chem., Vol. 65, No. 20, 2000 6737
[(1R,3R,4S)-2-((S)-1-P h en yleth yl)-2-azabicyclo[2.2.1]h ept-
5-en -3-yl]-p yr r olid in -1-yl-m eth a n on e (2a ). In dry CH2Cl2 (40
mL) was dissolved 3a (5.15 g, 20.1 mmol). Periodic acid (4.86 g,
21.3 mmol) was added portionwise during 1 h. The mixture was
stirred for 1 h at room temperature and then poured onto
molecular sieves (MS) 4 Å to remove any water. After about 10
min., the solid was filtrated off and the solvent was evaporated.
To the crude glyoxylic acid pyrrolidide was added MS 4 Å, 100
mL of dry CH2Cl2, and (S)-phenylethylamine (5.27 mL, 40.7
mmol). After 1 h the reaction mixture was cooled to -78 °C, and
in 10 min intervals TFA (3.4 mL, 44.4 mmol), boron trifluoride
etherate (5.6 mL, 44.3 mmol), and cyclopentadiene (4.0 mL, 48.2
mmol) were added. The mixture was stirred overnight while
warming to room temperature and then neutralized with
NaHCO3 (saturated aqueous), and the mixture was filtrated. The
layers were separated, and the aqueous phase was extracted
with CH2Cl2 (4 × 50 mL). The combined organic phases were
dried (MgSO4), filtered, and evaporated. The crude 2a was
purified by flash chromatography (deactivated silica gel, pentane
to ethyl acetate 90/10) to give 2a (8.64 g, 72%) as a mixture of
diastereomers in a 9:1 ratio. Recrystallization from hot tert-butyl
methyl ether and washing of the crystals with 2,2,4-trimethyl-
pentane provided 4.81 g (40%) of the major isomer 2a as colorless
crystals: mp 137 °C; Rf 0.55 (ethyl acetate, deactivated silica
Sch em e 3
To determine their absolute configuration, ligands 1a
and c were tested in the rearrangement of cyclohex-
eneoxide to the corresponding allylic alcohol as outlined
in Scheme 3. The stereochemistry of the allylic alcohol
was the same as obtained with ligands made from the
aza-Diels-Alder of the ethylglyoxylate, implying that the
stereochemistry of the aminoamido aza-Diels-Alder ad-
duct 1a -c is as indicated in the figures.
gel); [R]25 ) +57.6° (c 0.97, CHCl3); IR (neat, cm-1) 1645; 1H
D
NMR (300 MHz, CDCl3) 1.37 (m, 6H), 1.57 (m, 2H); 2.09 (m,
1H), 2.17 (s, 1H), 2.53 (m, 1H), 2.73 (br s, 1H), 2.94 (m, 1H),
3.03-3.20 (m, 3H), 4.28 (br s, 1H), 6.26 (m, 1H), 6.38 (m, 1H),
7.10-7.20 (m, 3H), 7.28-7.32 (m, 2H); 13C NMR (75 MHz,
CDCl3) 23.3, 23.8, 25.9, 45.1, 45.4, 45.7, 48.6, 62.0, 62.8, 64.3,
126.8, 127.8, 127.9, 133.1, 136.6, 145.6, 172.1; MS (EI) m/z (rel
intensity) 297 (M+ + H, 100%), 231 (53), 230 (30), 105 (46), 94
(44). Anal. Calcd for C19H24N2O: C, 76.99; H, 8.16; N, 9.45.
Found: C, 77.03; H, 8.11; N, 9.50.
Con clu sion
The new dienophile derived from bisamido tartrates
has proven successful and results in a shorter and more
efficient synthesis of chiral diamine ligands based on the
aza-norbornyl skeleton. Further studies will be made to
broaden the usefulness of this modification of the Diels-
Alder reaction.
[(1R,3R,4S)-2-((S)-1-P h en yleth yl)-2-azabicyclo[2.2.1]h ept-
5-en -3-yl]-p ip er id in -1-yl-m eth a n on e (2b). Synthesized using
the same procedure as for 2a using 3b. Purification by flash
chromatography (deactivated silica gel, ethyl acetate) gave 2b
(1.35 g, 80%) as a mixture of diastereomers. Recrystallization
from hot tert-butyl methyl ether hot filtration and washing of
the crystals with 2,2,4-trimethylpentane provided 0.49 g (29%)
of the major isomer as colorless crystals: mp 134-135 °C; Rf
0.5 (ethyl acetate, deactivated silica gel); [R]25D ) +55.4° (c 0.99,
Exp er im en ta l Section
Gen er a l. For description of general experimental procedures
see ref 5 and references therein. The diamides 3 were prepared
using a literature procedure.9
(2R,3R)-2,3-Dih yd r oxy-1,4-d ip yr r olid in -1-yl-bu ta n e-1,4-
d ion e (3a ). The diamide 3a was synthesized using a literature
procedure.9 Purification by flash chromatography (silica gel,
ethyl acetate to ethyl acetate/methanol 90/10) gave 3a (10.6 g,
85%) as a white solid. All spectroscopic and physical data were
in accordance with those published.9
(2R,3R)-2,3-Dih yd r oxy-1,4-d ip ip er id in -1-yl-b u t a n e-1,4-
d ion e (3b). The diamide 3b was synthesized following a
literature procedure, except that the reaction mixture was kept
at 70 °C for 24 h.9 Purification by flash chromatography (silica
gel, ethyl acetate to ethyl acetate/methanol 90/10) gave 3b (866
mg, 60%) as a pale yellow solid: mp 58-59 °C; Rf 0.40 (ethyl
acetate/methanol 90/10, silica gel); [R]25D ) -5.0° (c 0.95, CHCl3);
IR (neat, cm-1) 3392, 2937, 1631; 1H NMR (200 MHz, CDCl3)
1.64 (m, 12H), 3.52 (m, 8H); 4.32 (m, 2H), 4.61 (m, 2H); 13C NMR
(50 MHz, CDCl3) 24.3, 25.4, 26.1, 44.0, 46.5, 69.9, 169.1; MS (EI)
m/z (rel intensity) 285 (M+ + H, 10%), 210 (12), 172 (49), 154
1
CHCl3); IR (neat, cm-1) 1641; H NMR (200 MHz, CDCl3) 0.67
(m, 1H), 1.00-1.44 (m, 9H), 2.35 (m, 1H), 2.45 (s, 1H), 2.71 (m,
1H), 2.80-3.12 (m, 4H), 3.59 (m, 1H), 4.34 (m, 1H), 6.31 (m, 1H),
6.42 (m, 1H), 7.10-7.35 (m, 5H); 13C NMR (50 MHz, CDCl3) 23.2,
24.4, 25.3, 25.6, 43.1, 45.3, 45.9, 49.0, 61.6, 62.5, 64.6, 126.8,
128.0, 133.7, 136.2, 145.4, 171.5; MS (EI) m/z (rel intensity) 311
(M+ + H, 89%), 245 (85), 159 (60), 131 (84), 105 (100), 94 (88).
Anal. Calcd for C19H24N2O: C, 77.38; H, 8.44; N, 9.02. Found:
C, 77.31; H, 8.41; N, 8.97.
Mor p h olin -4-yl-[(1R,3R,4S)-2-((S)-1-p h en yleth yl)-2-a za -
bicyclo[2.2.1]h ep t-5-en -3-yl]m eth a n on e (2c). Synthesized
using the same procedure as for 2a . Purification by flash
chromatography (deactivated silica gel, ethyl acetate) gave 2c
(332 mg, 29%) as a mixture of diastereomers. Recrystallization
from hot tert-butyl methyl ether and washing of the crystals with
2,2,4-trimethylpentane provided 0.16 g (14%) of the major isomer
2c as colorless crystals: mp 155-156 °C; Rf 0.55 (ethyl acetate,
deactivated silica gel); [R]25D ) +61.7° (c 0.81, CHCl3); IR (neat,
(23), 143 (30), 112 (100), 86 (26), 84 (44). Anal. Calcd for C14
24N2O4: C, 59.13; H, 8.51; N, 9.85. Found: C, 59.18; H, 8.58;
N, 10.02.
-
H
cm-1) 1646; H NMR (200 MHz, CDCl3) 1.39 (m, 4H), 2.38 (m,
(2R,3R)-2,3-Dih yd r oxy-1,4-d im or p h olin -4-yl-bu ta n e-1,4-
d ion e (3c). The diamide 3c was synthesized following a
literature procedure except that the reaction mixture was kept
at 70 °C for 48 h.9 Purification by flash chromatography (silica
gel, ethyl acetate to ethyl acetate/methanol 90/10) gave 3c (620
mg, 43%) as a white solid: mp 106-108 °C; Rf 0.10 (ethyl
acetate/methanol 95/5, silica gel); [R]25D ) + 7.6° (c 1.06, CHCl3);
IR (neat, cm-1) 3400, 1736, 1638; 1H NMR (200 MHz, CDCl3)
3.68 (m, 16H), 4.24 (m, 2H), 4.62 (m, 2H); 13C NMR (50 MHz,
CDCl3) 43.1, 46.3, 66.6, 70.0, 169.8; MS (EI) m/z (rel intensity)
289 (M+ + H, 45%), 70 (29), 83 (21), 88 (25), 114 (100), 145 (18),
174 (85), 202 (31), 271 (8). Anal. Calcd for C12H20N2O6: C, 49.99;
H, 6.99; N, 9.72. Found: C, 49.89; H, 7.04; N, 9.68.
1
2H); 2.70-3.49 (m, 10H), 4.34 (br s, 1H), 6.31 (m, 1H), 6.42 (m,
1H), 7.18-7.33 (m, 5H); 13C NMR (75 MHz, CDCl3) 23.1, 42.1,
45.3, 48.9, 61.1, 62.4, 64.6, 66.0, 66.7, 127.1, 128.1, 132.3, 133.7,
136.2, 145.4, 172.0; MS (EI) m/z (rel intensity) 313 (M+ + H,
100%), 247 (44), 159 (36) 131 (43), 105 (64), 94 (65). Anal. Calcd
for C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C, 73.16; H,
7.67; N, 9.05.
(1S,3R,4R)-3-P yr r olid in -1-ylm eth yl-2-a za bicyclo[2.2.1]-
h ep ta n e (1a ). To a 100-mL round-bottomed flask was added
Pd(OH)2 (1.0 g, 28 wt %), and the water content was removed
in vacuo and by heating. Under an Ar flow were added ethanol
(50 mL) and 2a (3.52 g, 11.9 mmol), and the atmosphere was
changed to H2. The reaction mixture was stirred at room
temperature overnight. Filtration through Celite and evapora-
tion of the solvent gave deprotected amine (2.56 g), which was
(9) Suzuki, M.; Kimura, Y.; Terashima, S. Bull. Chem. Soc. J pn.
1986, 59, 3559.

6738 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
used as is in the following reduction. To a suspension of lithium
aluminum hydride (2.07 g, 54.5 mmol) in THF (80 mL) at 0 °C
was added the deprotected amine (2.56 g, 13.2 mmol). The
mixture was allowed to slowly reach room temperature and was
then refluxed overnight. The reaction was cooled to 0 °C, diethyl
ether (50 mL) was added, and the reaction quenched with water
(2.1 mL), 2 M NaOH (aqueous) (2.1 mL), and water (6.3 mL).
The mixture was filtered and evaporated to give pure 1a (1.97
g, 92%). All spectroscopic and physical data were in accordance
with those published.5a
(1S,3R,4R)-3-P iper idin -1-ylm eth yl-2-azabicyclo[2.2.1]h ep-
ta n e (1b). Compound 1b was synthesized using the same
procedure as for 1a . All spectroscopic and physical data were in
accordance with those published.5a
(1S,3R,4R)-3-Mor p h olin -4-ylm eth yl-2-a za bicyclo[2.2.1]-
h ep ta n e (1c). Compound 1c was synthesized using the same
procedure as for 1a : [R]25 ) -37.6° (c 0.33, CHCl3); IR (neat,
D
cm-1) 3401; 1H NMR (200 MHz, CDCl3) 1.00-1.80 (m, 7H), 2.00-
3.88 (m, 8H), 3.18 (br s, 1H), 3.54-3.75 (m, 4H); 13C NMR (75
MHz, CDCl3) 28.7, 30.2, 31.7, 35.2, 39.9, 53.9, 55.8, 58.4, 62.2,
64.6, 66.9. Anal. Calcd for C11H20N2O: C, 67.31; H, 10.27; N,
14.27. Found: C, 67.40; H, 10.21; N, 14.33.
Ack n ow led gm en t. We thank the Swedish Natural
Research Council (NFR), The Swedish Foundation for
Strategic Research (SSF), and The Swedish Research
Council for Engineering Sciences (TFR) for generous
financial support.
J O005508Z