Stereospecific synthesis of new 4-amino-1,2,3-cyclohexanetricarboxylic acids and 4-amino-1,3-cyclohexanedicarboxylic acids

Article abstract of DOI:10.1248/cpb.53.81

Diels-Alder adducts of 1,2-dihydropyridine with maleic and acrylic acid derivatives were stereospecifically converted by way of RuO₄ oxidation into new 4-amino-1,2,3-cyclohexanetricarboxylic acids and 4-amino-1,3-eyclohexanedicarboxylic acids.

Full text of DOI:10.1248/cpb.53.81

January 2005
Chem. Pharm. Bull. 53(1) 81—85 (2005)
81
Stereospecific Synthesis of New 4-Amino-1,2,3-cyclohexanetricarboxylic
Acids and 4-Amino-1,3-cyclohexanedicarboxylic Acids
Yasushi ARAKAWA,* Manabu TAJIMA, Yukimi ARAKAWA, and Shigeyuki YOSHIFUJI
Faculty of Pharmaceutical Sciences, Hokuriku University; Kanagawa-machi Ho-3, Kanazawa 920–1181, Japan.
Received September 13, 2004; accepted October 27, 2004
Diels–Alder adducts of 1,2-dihydropyridine with maleic and acrylic acid derivatives were stereospecifically
converted by way of RuO4 oxidation into new 4-amino-1,2,3-cyclohexanetricarboxylic acids and 4-amino-1,3-cy-
clohexanedicarboxylic acids.
Key words 1,2-dihydropyridine; Diels–Alder adduct; ruthenium tetroxide; 4-amino-1,2,3-cyclohexanetricarboxylic acid;
4-amino-1,3-cyclohexanedicarboxylic acid
We recently reported the stereospecific synthesis of tained hydroiodides of amino acids were esterified with
2,3,4,5-piperidinetetracarboxylic acids and 2,3,5-piperidine- SOCl2–MeOH, and introductions of a Boc group were
tricarboxylic acids with a cis-2,5-dicarboxy configuration achieved by treatments with Boc2O in CHCl3, giving 14—17
from N-methoxycarbonyl-1,2-dihydropyridine (1), as a study in 87, 90, 84, and 85% yields, respectively. In the case of 12
of the synthesis of amino acids using Diels–Alder (D–A) and 13, as these carboxylic acids were sparingly soluble in
adducts of dienophiles and N-containing dienes.1) The inter- CCl4, CHCl3 was used as a solvent for removal of the Moc
mediate products, isoquinuclidines 2—7,1) seemed to be con- group. Similar treatments of the corresponding amino acids
vertible to other amino acids. In the present paper, we would gave 16 and 17 in 85% yields, respectively. No epimerization
like to report the synthesis of new 4-amino-1,2,3-cyclohexa- was observed in the above cases, although when 10 and 11
netricarboxylic acids and 4-amino-1,3-cyclohexanedicar- were similarly treated with trimethylsilyl iodide in CHCl3,
boxylic acids with a 1,4-cis-configuration. Aminocyclohexa- the epimerizations occurred and the resultant products
necarboxylic acid derivatives have been examined for bioac- became mixtures of 16 and 17, respectively.
tive compounds such as the inhibitor of the g-aminobutyric
Conversion of the methylene groups adjacent to N-atoms
acid (GABA) receptor.2) Although ethyl esters of 4-amino- into carbonyl groups was achieved by ruthenium tetroxide
1,3-cyclohexanedicarboxylic acids were synthesized by (RuO4) oxidation.9—13) Under similar conditions employing
3)
ˇ
Skaric´ et al., free amino acids have not yet been synthesized AcOEt as a reaction solvent, compounds 14—17 disappeared
and isolated.
after 2, 3.5, 1.5, and 3 h and gave lactams 18—21 in 92, 95,
First, D–A adducts 2—7 were hydrogenated in the pres- 96, and 97% yields, respectively. Although the yields of the
ence of 10% Pd/C under ordinary pressure to give com- resultant lactams were almost quantitative, the longer reac-
pounds 8—13 (Fig. 2) quantitatively, respectively. Although tion times were required when the ester groups were situated
no effective data regarding the stereochemistry of compound near to the methylene groups that would be oxidized. The
3 in comparison with that of compound 2 were obtained by a reaction rates of the oxidations seemed to be influenced by
nuclear Overhauser effect (NOE) experiment in the 1H-NMR the steric hindrances of the ester groups, and/or by the elec-
analysis, in the analysis of 9, ꢀNOEs were observed between trostatic repulsions between the ester groups and RuO4.
H5 and H8b between H6 and H7b, and ꢁNOE was observed
Finally, hydrolyses of lactams 18—21 were attempted.
between H6 and H7a (Fig. 3). Therefore, the stereochemistry Treatments of 18 and 19 with 6 M HCl–AcOH at 50 °C for
of 3 simultaneously became clear.
Next, as removal of the N-methoxycarbonyl (Moc) group
seemed to be difficult in the later steps, Moc groups of 8—13
were converted into tert-butoxycarbonyl (Boc) groups (Chart
1). Compounds 8—11 were treated with trimethylsilyl
iodide4—8) in CCl4 followed by treatments with water, respec-
tively, to cause removal of the N-Moc groups as well as
dealkylation and hydrolysis of the ester groups. Thus ob-
Fig. 2
Fig. 3. Selected Decisive NOE Relationships of Compound 9
Fig. 1
∗ To whom correspondence should be addressed. e-mail: ya-arakawa@hokuriku-u.ac.jp
© 2005 Pharmaceutical Society of Japan

82
Vol. 53, No. 1
Fig. 4. Selected Decisive Coupling Constants and NOE Relationships of the Target Amino Acids 22, 23, 24, and 25 in 2 M DCl (22ꢂ, 23ꢂ, 24ꢂ, 25ꢂ)
Fig. 5. The Acceleration Effect by the Carboxy Group in the Hydrolysis of
Compound 21
21 d quantitatively gave the expected hydrochlorides of
amino acids 22 and 23, respectively. These hydrochlorides
were dissolved in small amounts of water and the solutions
were adjusted to pH 4 with 2 M NaOH, giving free amino
acids 22 and 23 as crystals in 86 and 84% yields, respec-
tively. When the hydrolyses of 18 and 19 were executed at
100 °C, the reaction intermediates, which were observed by
monitoring with 1H-NMR spectra in the cases of the hydroly-
ses at 50 °C, disappeared within 7 d, but the NMR analysis
showed that the expected amino acids seemed to be contami-
nated with considerable amounts of the stereoisomers.
The stereochemistries of compounds 22 and 23 were con-
firmed by NMR spectroscopy (NOE analysis after assign-
ment of the signals with H–H COSY and C–H COSY spec-
tra) as shown in Fig. 4. In the case of 22, as the coupling con-
stant between H3 and H4 was 9.9 Hz and NOEs were
Chart 1. Conversion of D–A Adducts into the Amino Acids
observed between H3 and H5a and between H4 and H6b, the
relative configuration of H3 and H4 proved to be trans- HCl–AcOH at 50 °C for 1 d, respectively, the 1H-NMR analy-
diaxial. As an NOE was observed between H1 and H6b, the sis of the reaction intermediates showed the complete
relative configuration of H1 and H4 proved to be cis. As an removal of Boc groups and the complete hydrolysis of
NOE was observed between H2 and H3 and no NOE was methyl ester groups. These results imply that hydrolysis of
observed between H2 and H4, the relative configuration of H2 the lactam group in this reaction is the rate-determining step.
and H3 proved to be cis. These data support our hypothesis We therefore believe that the faster rate of hydrolysis of 21
that 22 is c-4-amino-r-1,t-2,t-3-cyclohexanetricarboxylic can be attributed to the acceleration by the carboxy group, as
acid. In the case of 23, as the coupling constant between H3 shown in Fig. 5.
and H4 was 2.2 Hz, the relative configuration of H3 and H4
The stereochemistries of 24 and 25 were analyzed simi-
proved to be cis. As NOEs were observed between H1 and larly to 22 and 23. In the case of 24, as the coupling constant
H5a and between H3 and H5a and no NOE was observed be- between H3 and H4 was 11.0 Hz and NOEs were observed
tween H2 and H6b, the relative configurations between H1, H2 between H3 and H5a, between H2b and H4, and between H4
and H3 proved to be all cis. Thus compound 23 was identified and H6b, the relative configuration of H3 and H4 proved to be
as c-4-amino-r-1,c-2,c-3-cyclohexanetricarboxylic acid.
trans-diaxial. As NOEs were also observed between H1 and
Hydrolysis of 20 with 6 M HCl–AcOH at 50 °C was com- H2b and between H1 and H6b, the relative configuration of H1
pleted in 14 d and that of 21 under similar conditions was and H4 proved to be cis. Thus compound 24 was identified as
completed in 7 d, producing the expected hydrochlorides of c-4-amino-r-1,t-3-cyclohexanedicarboxylic acid. In the case
amino acids 24 and 25 quantitatively, respectively. These hy- of 25, as the coupling constant between H3 and H4 was
drochlorides were also dissolved in small amounts of water, 3.9 Hz, the relative configuration of H3 and H4 proved to be
and the solutions were adjusted to pH 4 with 2 M NaOH, giv- cis. As NOEs were observed between H1, H2a, and H3, the
ing free amino acids 22 and 23 as crystals in 85 and 82% relative configuration between H1 and H3 proved to be cis.
yields, respectively. When 20 and 21 were treated with 1 M Thus compound 25 was identified as c-4-amino-r-1,c-3-cy-

January 2005
83
Hb), 3.57 and 3.62 (3H, each s, OCH3), 4.11—4.20 and 4.39—4.44 (5H, m,
1-H and –CH2CH2–), 6.90—6.97 and 7.26—7.30 (5H, m, aromatic H). 13C-
NMR14) (CDCl3) d: 23.37 (t), 23.48 (t), 25.26 (d), 25.38 (d), 26.52 (t), 26.75
(t), 43.28 (d), 43.32 (d), 46.00 (d), 46.50 (d), 48.89 (t), 52.25 (q), 63.14 (t),
65.75 (t), 65.84 (t), 114.63 (d), 114.69 (d), 121.02 (d), 121.18 (d), 129.46
clohexanedicarboxylic acid.
In conclusion, we succeeded in stereospecifically synthe-
sizing new 4-amino-1,2,3-cyclohexanetricarboxylic acids 22
and 23 as well as 4-amino-1,3-cyclohexanedicarboxylic acids
24 and 25 from Diels–Alder adducts.
(d), 129.53 (d), 155.91 (s), 156.18 (s), 158.52 (s), 158.56 (s), 173.80 (s),
KBr
174.17 (s). IR n
cmꢁ1: 1735 (CꢃO), 1697 (CꢃO). HR-MS m/z: Calcd
max
for C18H23NO5: 333.1576 (Mꢀ). Found: 333.1575.
Experimental
Melting points were measured with a Yanagimoto micromelting point
apparatus and are uncorrected. NMR spectra, except for the amino acids,
were recorded in chloroform-d (CDCl3) on a JEOL GSX-400 spectrometer
using tetramethylsilane as an internal standard. For the amino acids, analysis
was performed in 2 M deuterium chloride (DCl) using 1,4-dioxane as an
(1R*,4S*,6R*)-2-Methoxycarbonyl-2-azabicyclo[2.2.2]octane-6-car-
boxylic Acid (12) Compound 6 (8.25 g, 27.4 mmol) was hydrogenated in
MeOH (83 ml) in the presence of 10% Pd/C (825 mg) under atmospheric
pressure for 1.5 h. The catalyst was filtered off, and the filtrate was concen-
trated under reduced pressure to give 12 (5.84 g, 100%) as a white solid. It
was recrystallized from i-Pr2O to give a white powder, mp 114—115 °C. 1H-
NMR14) (CDCl3) d: 1.58—1.68 (2H, m, 8-H), 1.75—1.87 (3H, m, 5-Ha, 7-
H), 1.97—2.04 (1H, m, 4-H), 2.08—2.14 (1H, m, 5-Hb), 2.96—3.02 (1H,
m, 6-H), 3.35—3.40 (2H, m, 3-H), 3.73 (3H, m, OCH3), 4.33 and 4.46 (1H,
each dd, Jꢃ5.7, 3.2 Hz, 1-H), 10.00 (1H, br s, COOH). 13C-NMR14) (CDCl3)
d: 22.94 (t), 23.12 (t), 23.66 (t), 23.72 (t), 25.59 (d), 25.75 (d), 26.46 (t),
26.53 (t), 42.71 (d), 42.85 (d), 45.17 (d), 45.69 (d), 48.61 (t), 52.60 (q),
52.66 (q), 155.90 (s), 156.08 (s), 177.99 (s), 178.16 (s). IR nmKaBxr cmꢁ1: 3150
(OH), 1739 (CꢃO), 1654 (CꢃO). MS m/z: 213 (Mꢀ). Anal. Calcd for
C10H15NO4: C, 56.33; H, 7.09; N, 6.57. Found: C, 56.30; H, 6.93; N, 6.55.
(1R*,4S*,6S*)-2-Methoxycarbonyl-2-azabicyclo[2.2.2]octane-6-car-
boxylic Acid (13) Compound 7 (1.07 g, 3.55 mmol) was hydrogenated in
MeOH (11 ml) in the presence of 10% Pd/C (107 mg) under atmospheric
pressure for 1.5 h. The catalyst was filtered off, and the filtrate was concen-
trated under reduced pressure to give 13 (755 mg, 100%) as a white solid. It
was recrystallized from i-Pr2O to give a white powder, mp 111—112 °C. 1H-
NMR14) (CDCl3) d: 1.57—1.67 (2H, m, 8-H), 1.72—1.80 (2H, m, 5-Ha,
7-Ha), 1.89—2.03 (2H, m, 4-H, 7-Hb), 2.12—2.15 (1H, m, 5-Hb), 2.69—
2.76 (1H, m, 6-H), 3.25—3.35 (1H, m, 3-Ha), 3.41—3.43 (1H, m, 3-Hb),
3.65 and 3.70 (3H, each s, OCH3), 4.36 and 4.50 (1H, each br s, 1-H) 10.16
(1H, br s, COOH). 13C-NMR14) (CDCl3) d: 23.31 (t), 23.38 (t), 25.26 (d),
25.34 (d), 26.55 (t), 26.61 (t), 26.72 (t), 42.97 (d), 43.13 (d), 43.25 (d), 46.06
1
internal standard (d 3.7 for H-NMR and d 67.4 for 13C-NMR). NOE spec-
tra were measured in the differential modes. Infrared (IR) spectra were
recorded on a Hitachi 270-30 spectrophotometer. Mass spectra (MS) were
obtained with a JEOL JMS-DX300 instrument. Column chromatography
was performed on silica gel (Kieselgel 60, 70—230 mesh, Merck).
Trimethyl (1R*,4S*,5R*,6R*)-2-Azabicyclo[2.2.2]octane-2,5,6-tricar-
boxylate (8) Compound 2 (870 mg, 3.07 mmol) was hydrogenated in
MeOH (9 ml) in the presence of 10% Pd/C (87 mg) under atmospheric pres-
sure for 1 h. The catalyst was filtered off, and the filtrate was concentrated
under reduced pressure to give 8 (873 mg, 100%) as a white solid. It was re-
crystallized from i-Pr2O to give colorless prisms, mp 78.5—79 °C.
1H-NMR14) (CDCl3) d: 1.50—1.55 (1H, m, 8-Ha), 1.75—1.82 (1H, m,
7-Ha), 1.88—1.97 (2H, m, 7-Hb, 8-Hb), 2.33 and 2.38 (1H, m, Jꢃ4.8,
2.4 Hz, 4-H), 3.00—3.07 (1H, m, 5-H), 3.17—3.20 and 3.25—3.28 (1H, m,
6-H), 3.39—3.44 (2H, m, 3-H), 3.65 and 3.67 (6H, each s, 2ꢄOCH3), 3.72
(3H, m, NCOOCH3), 4.30 and 4.33 (1H, each dd, Jꢃ4.0, 2.0 Hz, 1-H). 13C-
NMR14) (CDCl3) d: 20.04 (t), 20.13 (t), 22.73 (t), 28.77 (d), 28.86 (d), 42.91
(d), 44.94 (d), 45.25 (d), 45.63 (d), 49.11 (t), 49.19 (t), 51.80 (q), 52.48 (q),
52.54 (q), 155.59 (s), 155.63 (s), 171.71 (s), 172.84 (s). IR nmKaBxr cmꢁ1: 1747
(CꢃO), 1698 (CꢃO). MS m/z: 285 (Mꢀ). Anal. Calcd for C13H19NO6: C,
54.73; H, 6.71; N, 4.91. Found: C, 54.88; H, 6.61; N, 4.93.
Trimethyl (1R*,4S*,5S*,6S*)-2-Azabicyclo[2.2.2]octane-2,5,6-tricar-
boxylate (9) Compound 3 (870 mg, 3.07 mmol) was hydrogenated in
MeOH (9 ml) in the presence of 10% Pd/C (87 mg) under atmospheric pres-
sure for 1 h. The catalyst was filtered off, and the filtrate was concentrated
under reduced pressure to give 9 (872 mg, 100%) as a white solid. It was re-
crystallized from i-Pr2O to give colorless needles, mp 97—98 °C. 1H-
NMR14) (CDCl3) d: 1.54—1.60 (2H, m, 8-H), 1.70—1.79 (1H, m, 7-Hb),
1.84—1.95 (1H, m, 7-Ha), 2.41 and 2.46 (1H, each dd, Jꢃ5.6, 2.8 Hz, 4-H),
3.20—3.25 (1H, m, 6-H), 3.30—3.35 (2H, m, 3-Ha, 5-H), 3.46—3.49 (1H,
m, 3-Hb), 3.67, 3.70, 3.71 and 3.73 (9H, each s, 3ꢄOCH3), 4.41 and 4.52
(1H, each dd, Jꢃ4.0, 2.0 Hz, 1-H). 13C-NMR14) (CDCl3) d: 19.85 (t), 19.92
(t), 22.06 (t), 26.27 (t), 28.93 (d), 28.97 (d), 42.78 (d), 42.83 (d), 45.63 (d),
(d), 46.41 (d), 48.92 (t), 48.97 (t), 52.43 (q), 52.73 (q), 156.40 (s), 156.81
KBr
(s), 177.10 (s), 178.66 (s). IR n
cmꢁ1: 3160 (OH), 1745 (CꢃO), 1671
max
(CꢃO). MS m/z: 213 (Mꢀ). Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09;
N, 6.57. Found: C, 56.48; H, 7.03; N, 6.55.
2-tert-Butyl 5,6-Dimethyl (1R*,4S*,5R*,6R*)-2-Azabicyclo[2.2.2]oc-
tane-2,5,6-tricarboxylate (14) Under an argon atmosphere, trimethylsilyl
iodide (10.6 g, 53.0 mmol) was added to a solution of 8 (4.68 g, 16.4 mmol)
in CCl4 (170 ml) at 0 °C, and the mixture was stirred in the dark at room
temperature for 4 d. After the reaction mixture was cooled in an ice bath,
water was added (100 ml) and the mixture was vigorously stirred for 1 h.
The aqueous layer was separated, washed with CHCl3 (100 mlꢄ5) and ben-
zene (100 ml), and concentrated under reduced pressure, giving a yellowish-
brown oil. Thionyl chloride (8.20 g, 68.9 mmol) was added dropwise to
MeOH (300 ml) at ꢁ10 °C, and the mixture was stirred at room temperature
for 10 min. The yellowish-brown oil obtained previously was dissolved in
MeOH (30 ml), which was added to the SOCl2–MeOH solution, and the
whole was stirred for 2 d. The reaction mixture was concentrated under re-
duced pressure. MeOH (100 ml) was added to the residue, and the solution
was concentrated under reduced pressure; this operation was then repeated
three times. After the residue was dissolved in CHCl3 (200 ml), triethyl-
amine (2.68 g, 26.5 mmol) was added dropwise at 0 °C, then Boc2O (6.00 g,
27.5 mmol) was added. The mixture was stirred in the dark at room tempera-
ture for 4 d, and concentrated under reduced pressure. CHCl3 (200 ml) and
water (100 ml) were added to the residue, and the whole was stirred for a
few minutes, after which the insoluble material was filtered out using Hyflo
Super-Cel®. The organic layer was washed with water (100 mlꢄ3), dried
over anhydrous Na2SO4, and concentrated under reduced pressure to give a
yellowish-brown oil. The oil was subjected to column chromatography on
silica gel [hexane–AcOEt (8 : 1)] to give 14 (4.68 g, 87%) as a colorless oil.
1H-NMR14) (CDCl3) d: 1.47 (s, 9H, C(CH3)3), 1.52—1.55 (1H, m, 8-Ha),
1.70—1.80 (1H, m, 7-Ha), 1.85—1.95 (2H, m, 7-Hb, 8-Hb), 2.31 and 2.35
(1H, each dd, Jꢃ5.2, 2.4 Hz, 4-H), 2.97—3.06 (1H, m, 5-H), 3.15—3.20 and
3.25—3.28 (1H, m, 6-H), 3.36—3.40 (2H, m, 3-H), 3.66 and 3.68 (6H, each
s, 2ꢄOCH3), 4.24 and 4.40 (1H, each dd, Jꢃ4.0, 2.0 Hz, 1-H). 13C-NMR14)
(CDCl3) d: 20.07 (t), 20.16 (t), 22.75 (t), 22.84 (t), 28.53 (q), 28.88 (d),
45.71 (d), 46.23 (d), 46.71 (d), 48.69 (t), 52.24 (q), 52.31 (q), 52.46 (q),
155.76 (s), 155.95 (s), 173.04 (s), 173.51 (s), 173.84 (s), 173.88 (s). IR n
KBr
max
cmꢁ1: 1733 (CꢃO), 1693 (CꢃO). MS m/z: 285 (Mꢀ). Anal. Calcd for
C13H19NO6: C, 54.73; H, 6.71; N, 4.91. Found: C, 54.63; H, 6.82; N, 4.90.
2-Methyl 6-(2-Phenoxyethyl) (1R*,4S*,6R*)-2-Azabicyclo[2.2.2]oc-
tane-2,6-dicarboxylate (10) Compound 4 (2.23 g, 6.37 mmol) was hydro-
genated in MeOH (22 ml) in the presence of 10% Pd/C (223 mg) under
atmospheric pressure for 1 h. The catalyst was filtered off, and the filtrate
was concentrated under reduced pressure to give 10 (2.25 g, 100%) as a col-
orless oil. 1H-NMR14) (CDCl3) d: 1.55—1.58 (1H, m, 8-Ha), 1.70—1.81
(4H, m, 5-Ha, 7-H, 8-Hb), 1.93—1.97 (1H, m, 4-H), 2.11—2.14 (1H, m,
5-Hb), 2.92—2.99 (1H, m, 6-H), 3.23—3.33 (2H, m, 3-H), 3.68 (3H, m,
OCH3), 4.14—4.18 and 4.39—4.50 (5H, m, 1-H and –CH2CH2–), 6.88—
6.97 and 7.25—7.30 (5H, m, aromatic H). 13C-NMR14) (CDCl3) d: 22.94 (t),
23.13 (t), 23.60 (t), 23.67 (t), 25.60 (d), 25.78 (d), 26.64 (t), 42.76 (d), 42.91
(d), 45.16 (d), 45.68 (d), 48.59 (t), 48.62 (t), 52.35 (q), 63.01 (t), 63.12 (t),
65.66 (t), 65.78 (t), 114.63 (d), 121.16 (d), 121.26 (d), 129.49 (d), 129.53
(d), 155.64 (s), 155.79 (s), 158.40 (s), 158.43 (s), 173.30 (s), 173.38 (s). IR
KBr
n
cmꢁ1: 1735 (CꢃO), 1693 (CꢃO). HR-MS m/z: Calcd for C18H23NO5:
max
333.1576 (Mꢀ). Found: 333.1574.
2-Methyl 6-(2-Phenoxyethyl) (1R*,4S*,6S*)-2-Azabicyclo[2.2.2]oc-
tane-2,6-dicarboxylate (11) Compound 5 (3.68 g, 11.1 mmol) was hydro-
genated in MeOH (37 ml) in the presence of 10% Pd/C (368 mg) under at-
mospheric pressure for 1 h. The catalyst was filtered off, and the filtrate was
concentrated under reduced pressure to give 11 (3.69 g, 100%) as a colorless
oil. 1H-NMR14) (CDCl3) d: 1.57—1.63 (2H, m, 8-H), 1.68—1.74 (2H, m, 5- 29.06 (d), 42.94 (d), 43.03 (d), 44.62 (d), 44.92 (d), 45.07 (d), 45.76 (d),
Ha, 7-Ha), 1.91—2.00 (2H, m, 4-H, 7-Hb), 2.14—2.17 (1H, m, 5-Hb),
48.68 (t), 49.54 (t), 51.73 (q), 51.76 (q), 79.68 (s), 79.88 (s), 154.53 (s),
KBr
max
2.65—2.80 (1H, m, 6-H), 3.26—3.31 (1H, m, 3-Ha), 3.40—3.43 (1H, m, 3- 171.87 (s), 172.97 (s). IR n
cmꢁ1: 1747 (CꢃO), 1693 (CꢃO). HR-MS

84
Vol. 53, No. 1
m/z: Calcd for C16H25NO6: 327.1682 (Mꢀ). Found: 327.1684.
14.2 mmol) in AcOEt (48 ml), RuO2·xH2O (142 mg), and a 10% NaIO4
aqueous solution (142 ml) were mixed and then vigorously stirred at room
temperature for 2 h. The AcOEt layer was separated, and the aqueous layer
was extracted with AcOEt (25 mlꢄ3). Isopropyl alcohol (1 ml) was added to
the combined AcOEt layers, and the solution was left to stand for 1 h. The
precipitated RuO2 was filtered off, and the solution was dried over anhydrous
Na2SO4, then concentrated under reduced pressure. The residual solid was
recrystallized from i-Pr2O to give 18 (4.49 g, 92%) as colorless needles, mp
130—132 °C. 1H-NMR14) (CDCl3) d: 1.53 (s, 9H, C(CH3)3), 1.76—1.81
(2H, m, 7-Ha, 8-Ha), 1.70—1.80 (1H, m, 7-Ha), 2.03—2.19 (2H, m, 7-Hb,
8-Hb), 2.93 (1H, m, 4-H), 3.15 (1H, ddd, Jꢃ11.3, 2.9, 1.5 Hz, 5-H), 3.32
(1H, ddd, Jꢃ11.3, 3.3, 1.1 Hz, 6-H), 3.69 and 3.70 (6H, each s, 2ꢄOCH3),
4.90 (1H, dd, m, 1-H). 13C-NMR14) (CDCl3) d: 18.43 (t), 21.57 (t), 27.92 (q),
27.99 (q), 28.02 (q), 28.13 (q), 40.25 (d), 42.47 (d), 44.73 (d), 51.29 (d),
51.35 (d), 51.40 (d), 51.84 (q), 51.94 (q), 51.97 (q), 52.03 (q), 52.13 (q),
2-tert-Butyl 5,6-Dimethyl (1R*,4S*,5S*,6S*)-2-Azabicyclo[2.2.2]oc-
tane-2,5,6-tricarboxylate (15) This compound (2.42 g, 90%) was ob-
tained as a colorless oil from 9 (2.34 g, 8.20 mmol) in a manner similar to
1
that described for 14. H-NMR14) (CDCl3) d: 1.43 (9H, s, C(CH3)3), 1.54—
1.58 (2H, m, 8-H), 1.69—1.77 (1H, m, 7-Ha), 1.84—1.90 (1H, m, 7-Hb),
2.38 and 2.45 (1H, each dd, Jꢃ5.6, 2.8 Hz, 4-H), 3.16—3.36 (3H, m, 3-Ha,
5-, 6-H), 3.42—3.47 (1H, m, 3-Hb), 3.69, 3.72, and 3.73 (9H, each s,
3ꢄOCH3), 4.34 and 4.48 (1H, each m, 1-H). 13C-NMR14) (CDCl3) d: 19.91
(t), 20.01 (t), 25.98 (t), 26.53 (t), 28.39 (q), 28.45 (q), 29.07 (d), 29.13 (d),
42.72 (d), 42.90 (d), 45.64 (d), 45.80 (d), 45.87 (d), 46.78 (d), 48.18 (t),
48.95 (t), 52.22 (q), 52.27 (q), 52.37 (q), 79.43 (s), 154.39 (s), 154.81 (s),
KBr
173.13 (s), 173.70 (s), 174.00 (s), 174.06 (s). IR n
cmꢁ1: 1736 (CꢃO),
max
1697 (CꢃO). HR-MS m/z: Calcd for C16H25NO6: 327.1682 (Mꢀ). Found:
327.1683.
52.18 (q), 52.24 (q), 52.32 (q), 83.82 (s), 149.92 (s), 170.76 (s), 171.14 (s),
2-tert-Butyl 6-Methyl (1R*,4S*,6R*)-2-Azabicyclo[2.2.2]octane-2,6-di-
carboxylate (16) From 10: Under an argon atmosphere, trimethylsilyl io-
dide (7.07 g, 35.3 mmol) was added to a solution of 10 (5.47 g, 16.4 mmol)
in CCl4 (170 ml) at 0 °C, and the mixture was stirred in the dark at room
temperature for 4 d. After the reaction mixture was cooled in an ice bath,
water was added (100 ml) and the mixture was vigorously stirred for 1 h.
The aqueous layer was separated, washed with CHCl3 (100 mlꢄ5) and ben-
zene (100 ml), and concentrated under reduced pressure, giving a yellowish-
brown oil. Thionyl chloride (8.20 g, 68.9 mmol) was added dropwise to
MeOH (300 ml) at ꢁ10 °C, and the mixture was stirred at room temperature
for 10 min. The yellowish-brown oil obtained previously was dissolved in
MeOH (30 ml), which was added to the SOCl2–MeOH solution, and the
whole was stirred for 2 d. The reaction mixture was concentrated under re-
duced pressure. MeOH (100 ml) was added to the residue, and the solution
was concentrated under reduced pressure; this operation was then repeated
three times. After the residue was dissolved in CHCl3 (200 ml), triethyl-
amine (2.68 g, 26.5 mmol) was added dropwise at 0 °C, then Boc2O (6.00 g,
27.5 mmol) was added. The mixture was stirred in the dark at room tempera-
ture for 4 d, and concentrated under reduced pressure. CHCl3 (200 ml) and
water (100 ml) were added to the residue, and the whole was stirred for a
few minutes, after which the insoluble material was filtered out using Hyflo
Super-Cel®. The organic layer was washed with water (100 mlꢄ3), dried
over anhydrous Na2SO4, and concentrated under reduced pressure to give a
yellowish-brown oil. The oil was subjected to column chromatography on
silica gel [hexane–AcOEt (8 : 1)] to give a white solid. It was recrystallized
from i-Pr2O, giving 16 (3.71 g, 84%) as colorless needles, mp 74.5—
75.5 °C.
KBr
171.99 (s). IR n
cmꢁ1: 1741 (CꢃO), 1733 (CꢃO), 1710 (CꢃO). MS m/z:
max
341 (Mꢀ). Anal. Calcd for C16H23NO7: C, 56.30; H, 4.10; N, 6.79. Found: C,
56.29; H, 4.07; N, 6.60.
2-tert-Butyl 5,6-Dimethyl (1R*,4S*,5S*,6S*)-3-Oxo-2-azabicyclo-
[2.2.2]octane-2,5,6-tricarboxylate (19)
A
solution of 15 (2.33 g,
7.12 mmol) in AcOEt (24 ml), RuO2·xH2O (71 mg), and a 10% NaIO4 aque-
ous solution (71 ml) were mixed and then vigorously stirred at room temper-
ature for 3.5 h. The AcOEt layer was separated, and the aqueous layer was
extracted with AcOEt (13 mlꢄ3). Isopropyl alcohol (0.5 ml) was added to
the combined AcOEt layers, and the solution was left to stand for 1 h. The
precipitated RuO2 was filtered off, and the solution was dried over anhydrous
Na2SO4, then concentrated under reduced pressure. The residual oil was sub-
jected to column chromatography on silica gel (AcOEt), giving 19 (2.31 g,
95%) as a colorless oil. 1H-NMR14) (CDCl3) d: 1.52 (s, 9H, C(CH3)3),
1.67—1.91 (4H, m, 7-H, 8-H), 3.05 (1H, dd, Jꢃ5.1, 2.6 Hz, 4-H), 3.29 (1H,
dd, Jꢃ5.5, 1.8 Hz, 5-H), 3.50 (1H, m, 6-H), 3.71 and 3.76 (6H, each s,
2ꢄOCH3), 5.05 (1H, dd, Jꢃ3.3, 1.5 Hz, 1-H). 13C-NMR14) (CDCl3) d: 18.43
(t), 21.56 (t), 27.78 (q), 27.96 (q), 41.71 (d), 42.30 (d), 44.91 (d), 52.34 (q),
52.37 (q), 52.51 (q), 52.56 (q), 52.76 (q), 83.46 (s), 150.10 (s), 171.26 (s),
KBr
171.98 (s), 172.17 (s). IR n
cmꢁ1: 1747 (CꢃO), 1714 (CꢃO). HR-MS
max
m/z: Calcd for C16H23NO7: 341.1475 (Mꢀ). Found: 341.1477.
2-tert-Butyl 6-Methyl (1R*,4S*,6R*)-3-Oxo-2-azabicyclo[2.2.2]octane-
2,6-dicarboxylate (20) This compound (3.86 g, 96%) was obtained as col-
orless prisms, mp 79—80.5 °C, from 16 (3.83 g, 14.2 mmol) in a manner
similar to that described for 18, except that the reaction (stirring) time was
1
1.5 h. H-NMR14) (CDCl3) d: 1.55 (s, 9H, C(CH3)3), 1.74—1.91 (4H, m, 7-,
8-H), 2.04—2.12 (1H, m, 5-Ha), 2.20—2.26 (1H, m, 5-Hb), 2.69 (1H, m, 4-
H), 2.93—2.99 (1H, m, 6-H), 3.75 (3H, s, OCH3), 4.97 (1H, dd, Jꢃ3.4,
1.6 Hz, 1-H). 13C-NMR14) (CDCl3) d: 22.40 (t), 22.56 (t), 25.56 (t), 28.07
From 12: Compound 12 (3.50 g, 16.4 mmol) was treated in a manner simi-
lar to the conversion of 10 into 16, except that CHCl3 was used as a reaction
solvent of the first step instead of CCl4, giving 16 (3.75 g, 85%). 1H-NMR14)
(CDCl3) d: 1.47 (9H, s, C(CH3)3), 1.54—1.68 (3H, m, 7-Ha, 8-H), 1.72—
1.84 (2H, m, 5-Ha, 7-Hb), 1.93—2.01 (1H, m, 4-H), 2.07—2.15 (1H, m, 5-
Hb), 2.88—2.97 (1H, m, 6-H), 3.28—3.34 (2H, m, 3-H), 3.71 (3H, m,
OCH3), 4.19—4.22 and 4.36—4.39 (1H, each m, 1-H). 13C-NMR14) (CDCl3)
d: 23.11 (t), 23.23 (t), 23.76 (t), 23.86 (t), 25.82 (d), 26.01 (d), 26.66 (t),
26.78 (t), 28.55 (q), 42.90 (d), 42.92 (d), 44.46 (d), 45.88 (d), 48.20 (t),
(q), 39.80 (d), 42.81 (d), 51.73 (d), 52.33 (q), 83.50 (s), 150.26 (s), 172.71
KBr
(s), 173.83 (s). IR n
cmꢁ1: 1735 (CꢃO), 1710 (CꢃO). MS m/z: 283
max
(Mꢀ). Anal. Calcd for C14H21NO5: C, 59.35; H, 7.47; N, 4.94. Found: C,
59.30; H, 7.31; N, 5.11.
2-tert-Butyl 6-Methyl (1R*,4S*,6S*)-3-Oxo-2-azabicyclo[2.2.2]octane-
2,6-dicarboxylate (21) This compound (3.89 g, 97%) was obtained as col-
orless prisms, mp 71—73 °C, from 17 (3.83 g, 14.2 mmol) in a manner simi-
lar to that described for 18, except that the reaction (stirring) time was 3 h.
1H-NMR14) (CDCl3) d: 1.52 (s, 9H, C(CH3)3), 1.70—2.00 (5H, m, 5-Ha,
7-H, 8-H), 2.28—2.34 (1H, m, 5-Hb), 2.69 (1H, m, 4-H), 2.74—2.79 (1H,
m, 6-H), 3.69 (3H, s, OCH3), 4.97 (1H, m, 1-H). 13C-NMR14) (CDCl3)
48.94 (t), 51.85 (q), 51.97 (q), 79.32 (s), 79.50 (s), 154.68 (s), 154.74 (s),
KBr
174.06 (s), 174.12 (s). IR n
cmꢁ1: 1735 (CꢃO), 1689 (CꢃO). MS m/z:
max
269 (Mꢀ). Anal. Calcd for C14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C,
62.51; H, 8.33; N, 5.22.
2-tert-Butyl 6-Methyl (1R*,4S*,6S*)-2-Azabicyclo[2.2.2]octane-2,6-di-
carboxylate (17) From 11: Compound 11 (5.47 g, 16.4 mmol) was treated
in a manner similar to the conversion of 10 into 16 without recrystallization,
giving 17 (3.76 g, 85%) as a colorless oil.
From 13: Compound 13 (1.75 g, 8.21 mmol) was treated in a manner simi-
lar to the conversion of 10 into 16 without recrystallization, except that
CHCl3 was used as a reaction solvent of the first step instead of CCl4, giving
17 (1.88 g, 85%). 1H-NMR14) (CDCl3) d: 1.43 (9H, s, C(CH3)3), 1.52—1.77
(4H, m, 5-Ha, 7-Ha, 8-H), 1.85—2.02 (2H, m, 5-Ha, 7-Ha), 2.10—2.20 (1H,
m, 5-Hb), 2.62—2.73 (1H, m, 6-H), 3.18—3.28 (1H, m, 3-Ha), 3.33—3.43
(1H, m, 3-Hb), 3.57 and 3.62 (3H, each s, OCH3), 4.27—4.30 and 4.35—
4.38 (1H, m, 1-H). 13C-NMR14) (CDCl3) d: 23.45 (t), 23.66 (t), 25.34 (d),
25.55 (d), 26.51 (t), 26.53 (t), 26.62 (t), 27.01 (t), 43.43 (d), 43.47 (d), 45.36
d: 22.30 (t), 26.10 (t), 26.13 (t), 27.97 (q), 39.57 (d), 42.05 (d), 52.22 (q),
KBr
82.98 (s), 150.28 (s), 173.10 (s), 173.39 (s). IR n
cmꢁ1: 1746 (CꢃO),
max
1712 (CꢃO). MS m/z: 283 (Mꢀ). Anal. Calcd for C14H21NO5: C, 59.35; H,
7.47; N, 4.94. Found: C, 59.46; H, 7.40; N, 4.91.
c-4-Amino-r-1,t-2,t-3-cyclohexanetricarboxylic Acid (22) Compound
18 (617 mg, 1.81 mmol) was heated in AcOH (20 ml) and 6 M HCl at 50 °C
for 21 d. The reaction mixture was concentrated under reduced pressure, and
the residue was dissolved in a small amount of water. The aqueous solution
was adjusted to pH 4 with 2 M NaOH, giving a white powder, which was
recrystallized from water to give 22·2H2O (416 mg, 86%) as a white pow-
der, mp 214 °C (dec.). 1H-NMR (2 M DCl) d: 1.48—1.61 (1H, m, 5-Ha),
1.61—1.73 (1H, m, 6-Hb), 1.98—2.14 (2H, m, 5-Hb, 6-Ha), 3.11 (1H, dd,
Jꢃ9.9, 4.8 Hz, 3-H), 3.27 (1H, q, Jꢃ3.7 Hz, 1-H), 3.77 (1H, dd, Jꢃ4.8,
3.7 Hz, 2-H), 3.86 (1H, dt, Jꢃ9.9, 4.0 Hz, 4-H). 13C-NMR (2 M DCl)
(d), 46.61 (d), 48.40 (t), 49.20 (t), 51.87 (q), 52.02 (q), 79.00 (s), 79.02 (s),
KBr
154.60 (s), 155.05 (s), 174.38 (s), 174.87 (s). IR n
cmꢁ1: 1735 (CꢃO),
max
1693 (CꢃO). HRMS m/z: Calcd for C14H23NO4: 269.1627 (Mꢀ). Found:
269.1624.
d: 22.81 (t), 26.60 (t), 41.23 (d), 43.02 (d), 43.74 (d), 48.59 (d), 175.62 (s),
KBr
175.81 (s), 176.98 (s). IR n
cmꢁ1: 3581, 3496, 3409, 3248 (NH, OH),
max
1720 (CꢃO), 1697 (CꢃO). MS (FAB) m/z: 232 (Mꢀꢀ1). Anal. Calcd for
2-tert-Butyl 5,6-Dimethyl (1R*,4S*,5R*,6R*)-3-Oxo-2-azabicyclo-
C9H13NO6·2H2O: C, 40.45; H, 6.41; N, 5.24. Found: C, 40.32; H, 6.13; N,
[2.2.2]octane-2,5,6-tricarboxylate (18)
A
solution of 14 (4.66 g,

January 2005
85
KBr
max
176.35 (s), 179.03 (s). IR n
cmꢁ1: 3567, 3373, 3234 (NH, OH), 1712
5.19.
(CꢃO), 1685 (CꢃO). MS (FAB) m/z: 188 (Mꢀꢀ1). Anal. Calcd for
C8H13NO4·2/3H2O: C, 48.24; H, 7.25; N, 7.03. Found: C, 48.29; H, 7.09; N,
6.93.
c-4-Amino-r-1,c-2,c-3-cyclohexanetricarboxylic Acid (23) Compound
19 (617 mg, 1.81 mmol) was treated in a manner similar to the conversion of
18 into 22, giving 23·1/2H2O (365 mg, 84%) as a white powder, mp 214 °C
1
(dec.). H-NMR (2 M DCl) d: 1.72 (1H, dq, Jꢃ3.7, 10.9 Hz, 6-Hb), 1.86—
1.94 (1H, m, 5-Ha), 1.92—2.13 (2H, m, 5-Hb, 6-Ha), 2.77—2.84 (1H, m,
Acknowledgement This work was supported in part by the Special Re-
search Fund of Hokuriku University.
1-H), 3.19—3.21 (2H, m, 2-, 3-H), 3.98 (1H, d, Jꢃ2.2 Hz, 4-H). 13C-NMR
(2 M DCl) d: 22.17 (t), 26.94 (t), 42.88 (d), 44.31 (d), 45.25 (d), 48.18 (d),
KBr
174.56 (s), 176.34 (s), 177.29 (s). IR n
cmꢁ1: 3448, 3412, 3112 (NH,
References and Notes
1) Arakawa Ya., Murakami T., Ozawa F., Arakawa Yu., Yoshifuji S.,
Tetrahedron, 59, 7555—7563 (2003).
max
OH), 1735 (CꢃO), 1700 (CꢃO). MS (FAB) m/z: 232 (Mꢀꢀ1). Anal. Calcd
for C9H13NO6·1/2H2O: C, 45.00; H, 5.87; N, 5.83. Found: C, 45.20; H, 5.68;
N, 5.85.
2) Segal M., Sims K., Smissman S., Br. J. Pharmac., 54, 181—188
(1975).
c-4-Amino-r-1,t-3-cyclohexanedicarboxylic Acid (24) Compound 20
(512 mg, 1.81 mmol) was treated in a manner similar to the conversion of 18
ˇ
3) Skaric´ V., Djuras B., Turjak-Zebi´c V., J. Chem. Soc. Perkin Trans. 1,
1
into 22, giving 24 (288 mg, 85%) as a white powder, mp 215 °C (dec.). H-
1975, 1959—1961 (1975).
NMR (2 M DCl) d: 1.55 (1H, dq, Jꢃ3.9, 12.1 Hz, 5-Ha), 1.64—1.67 (1H, m,
6-Hb), 1.69—1.74 (1H, m, 2-Hb), 2.01 (1H, dq, Jꢃ12.4, 3.7 Hz, 5-Hb),
2.06—2.16 (1H, m, 6-Ha), 2.41 (1H, dq, Jꢃ14.2, 2.9 Hz, 2-Ha), 2.80—2.84
(1H, m, 3-H), 2.85—2.87 (1H, m, 1-H), 3.48 (1H, dt, Jꢃ4.1, 11.0 Hz, 4-H).
4) Ho T.-L., Olah A., Angew. Chem. Int. Ed. Engl., 15, 774—775 (1976).
5) Jung M. E., Lyster M. A., J. Am. Chem. Soc., 99, 968—969 (1977).
6) Jung M. E., Lyster M. A., J. Org. Chem., 42, 3761—3764 (1977).
7) Jung M. E., Andrus W. A., Ornstein P. L., Tetrahedron Lett., 18,
4175—4178 (1977).
8) Olah G. A., Narang S. C., Gupta B. G. B., Malhotra R., J. Org. Chem.,
44, 1247—1251 (1979).
9) Sheehan J. C., Tulis R. W., J. Org. Chem., 39, 2264—2267 (1974).
10) Tangari N., Tortorella V., J. Chem. Soc., Chem. Commun., 1975, 71—
72 (1975).
11) Yoshifuji S., Matsumoto H., Tanaka K., Nitta Y., Tetrahedron Lett., 21,
2963—2964 (1980).
12) Carlsen P. H. J., Katsuki T., Martin V. S., Sharpless K. B., J. Org.
Chem., 46, 3936—3938 (1981).
13) Yoshifuji S., Tanaka K., Kawai T., Nitta Y., Chem. Pharm. Bull., 33,
5515—5521 (1985).
14) Some signals split or broaden due to the rotamers or the conformers.
13C-NMR14) (2 M DCl) d: 25.13 (t), 26.82 (t), 28.83 (t), 29.00 (t), 38.09 (d),
KBr
38.13 (d), 42.94 (d), 50.10 (d), 50.93 (d), 176.56 (s), 178.71 (s). IR n
max
cmꢁ1: 3518, 3135, 3112 (NH, OH), 1739 (CꢃO), 1700 (CꢃO). MS (FAB)
m/z: 188 (Mꢀꢀ1). Anal. Calcd for C8H13NO4: C, 51.33; H, 7.00; N, 7.48.
Found: C, 51.33; H, 6.75; N, 7.41.
c-4-Amino-r-1,c-3-cyclohexanedicarboxylic Acid (25) Compound 21
(512 mg, 1.81 mmol) was treated in a manner similar to the conversion of 18
into 22, giving 25·2/3H2O (296 mg, 82%) as a white powder, mp 240 °C
1
(dec.). H-NMR (2 M DCl) d: 1.62 (1H, dq, Jꢃ3.9, 12.1 Hz, 6-Hb), 1.79—
1.93 (3H, m, 5-Ha, 2-Hb, 6-Ha), 2.07 (1H, dq, Jꢃ10.6, 3.9 Hz, 5-Hb), 2.24
(1H, dt, Jꢃ10.6, 3.6 Hz, 2-Ha), 2.57—2.63 (1H, m, 1-H), 2.99 (1H, dt,
Jꢃ11.9, 4.0 Hz, 3-H), 3.85 (1H, d, Jꢃ3.9 Hz, 4-H). 13C-NMR14) (2 M DCl)
d: 22.35 (t), 25.61 (t), 27.30 (t), 40.80 (d), 42.38 (d), 42.48 (d), 48.23 (d),