SCHEME 4. Synthesis of
endo-1-Azabicyclo[2.2.1]heptane-2-carboxylicAcid(1b),1-Azabicyclo-
[2.2.1]heptane-7-carboxylic Acid (2), and 1-Azabicyclo[3.2.2]-
nonane-2-carboxylic Acid (3). R-Substituted amino acid ester is
taken up in 48% aq HBr. HBr gas was passed through the solution
until full saturation. The contents were heated at 110-120 °C for
8 h in a sealed tube. The contents were taken up in a round-bottom
flask and the acid was removed in vacuo by azeotroping with EtOH.
The resultant solid was dissolved in 28% NH4OH (∼10 mL for
each 1 g) and heated at 60 °C for 4 h. The solid obtained after
removal of NH4OH was taken up in EtOH to which concd H2SO4
was added and heated at reflux for 8 h. The reaction mixture was
cooled, basified with saturated aq NaHCO3 solution, and extracted
with CHCl3 (4 × 10 mL). Combined organic extracts were dried
over Na2SO4 and filtered and solvent was removed in vacuo. Ethyl
ester was heated at reflux with concd HCl to give the hydrochloride
salt.
1-Azabicyclo[3.2.2]nonane-2-carboxylic Acida
a Reagents and conditions: (a) NaH, (EtO)2POCH2CO2Et, benzene, 25
°C, (b) H2, EtOH, Pd/C, (c) LiAlH4, THF, 0 °C, (d) (i) MsCl, Et3N, CH2Cl2,
0 °C, (ii) LiBr, acetone, reflux, (e) 4, KOtBu, DMF/toluene (1:1), 0 °C, (f)
(i) 2 N HCl, (ii) NaHCO3, and (g) (i) 48% HBr, HBr(g), 120 °C sealed
tube, 8 h, (ii) NH4OH, 60 °C, (iii) H2SO4, EtOH, reflux, (iv) concd HCl,
reflux.
(a) exo-1-Azabicyclo[2.2.1]heptane-2-carboxylic Acid (1a). 1H
NMR (300 MHz, D2O) δ 4.13-4.18 (t, J ) 15.6 Hz, 1H), 3.26-
3.32 (m, 1H), 3.13-3.22 (m, 3H), 2.89 (br s, 1H), 1.98-2.14 (m,
3H), 1.63-1.66 (m, 1H); 13C NMR (75 MHz, D2O) δ 171.5, 64.8,
58.9, 52.4, 35.1, 33.4, 26.2. Anal. Calcd for C7H11NO2‚HCl: C,
47.33; H, 6.81; N, 7.89; Cl, 19.96. Found: C, 47.28; H, 6.87; N,
7.78; Cl, 19.82.
(b) endo-1-Azabicyclo[2.2.1]heptane-2-carboxylic Acid (1b).
1H NMR (300 MHz, D2O) δ 4.43-4.50 (dddd, J ) 20.8 Hz, 1H),
3.42-3.56 (m, 1H), 3.32-3.34 (m, 1H), 3.27-3.30 (br d, J ) 9.3
Hz, 1H), 3.18-3.21 (br d, J ) 9.3 Hz, 1H), 2.90-2.93 (t, J ) 8.8
Hz, 1H), 2.24-2.36 (m, 1H), 1.94-2.06 (m, 1H), 1.76-1.83 (dddd,
J ) 21.0 Hz, 1H), 1.59-1.69 (m, 1H); 13C NMR (75 MHz, D2O)
δ 169.8, 64.8, 60.7, 49.0, 36.4, 29.5, 27.5. Anal. Calcd for C7H11-
NO2‚HCl: C, 47.33; H, 6.81; N, 7.89; Cl, 19.96. Found: C, 46.87;
H, 6.84; N, 7.82; Cl, 20.04.
condensation, employing TiCl4 in the presence of N-methyl-
morpholine in THF.10 With use of these conditions, tertrahy-
dropyran-4-one and ethyl nitroacetate gave a mixture of isomers
12 (nonconjugated, major) and 13 (conjugated, minor) that were
not separated (70%). Hydrogenation of this mixture of isomers
with Raney Ni gave amino acid ethyl ester 11 in quantitative
yield. Bicyclic tertiary R-amino acid 2 was obtained in 90%
yield, in racemic form, as the HCl salt from 11 via a sealed
tube reaction with a 48% solution of HBr saturated with HBr(g),
followed by cyclization in NH4OH, esterification to the ethyl
ester, and subsequent hydrolysis with concd HCl. This procedure
removed ammonium or hydrobromide salts.
Bicyclic R-amino acid 3 (racemic mixture) was synthesized
in nine steps from tetrahydropyran-4-one (Scheme 4). Alkylation
of imine 4 with 4-(2-bromoethyl)tetrahydropyran16 14 gave 15
in good yield (70%). Sealed tube reaction with HBr opened the
pyran ring to the dibromo intermediate which was cyclized in
NH4OH, esterified to the ethyl ester, and subsequently hydro-
lyzed with concd HCl to give the desired amino acid 3 (85%).
In conclusion, the syntheses of three non-natural bicyclic
R-amino acids have been accomplished from readily available
starting materials. Currently, we are investigating the nonracemic
synthesis of these tertiary bicyclic R-amino acids, and the results
of these efforts will be reported in due course. We will also
report the transformation of these amino acids into biologically
active NNR ligands.
(c) 1-Azabicyclo[2.2.1]heptane-7-carboxylic Acid (2). Crystal-
lized from IPA and ether as a light brown solid (961 mg, 85%).
1
m.p. ) turned brown at 231 °C and melted at 254 °C. H NMR
(300 MHz, D2O) δ 4.15-4.16 (d, J ) 1.2 Hz, 1H), 3.56-3.67 (m,
1H), 3.24-3.36 (m, 1H), 3.04-3.16 (m, 2H), 2.92-2.97 (t, J )
8.1 Hz, 1H), 2.01-2.14 (m, 1H), 1.84-1.97 (m, 1H), 1.59-1.76
(m, 2H); 13C NMR (75 MHz, D2O) δ 168.8, 71.4, 53.4, 51.6, 37.8,
27.2, 26.5; MS (FD) m/z 142 (M + H). Anal. Calcd for C7H11-
NO2‚HCl: C, 47.33; H, 6.81; N, 7.89; Cl, 19.96. Found: C, 47.07;
H, 6.73; N, 7.92; Cl, 19.76.
(d) 1-Azabicyclo[3.2.2]nonane-2-carboxylic Acid (3). 1H NMR
(300 MHz, D2O) δ 4.11-4.17 (dd, J ) 16.6 Hz, 1H), 3.19-3.42
(m, 4H), 2.19-2.30 (m, 2H), 1.78-2.08 (m, 6H), 1.58-1.72 (m,
1H); 13C NMR (75 MHz, D2O) δ 171.9, 67.5, 49.1, 44.1, 32.3,
24.6, 24.4, 23.6, 20.5. Anal. Calcd for C8H13NO2‚HCl: C, 50.14;
H, 7.36; N, 7.31; Cl, 18.50. Found: C, 52.37; H, 9.00; N, 6.63; Cl,
17.42.
Experimental Section
General Experimental Procedures. See the Supporting Infor-
mation.
General Procedure for the Synthesis of Bicyclic r-Amino
Supporting Information Available: Experimental details,
synthetic methods for starting material preparation, characterization
data, and 1H NMR and 13C NMR spectra of compounds 1a, 1b, 2,
and 3. This material is available free of charge via the Internet at
Acids: exo-1-Azabicyclo[2.2.1]heptane-2-carboxylic Acid (1a),
(16) Kolbach, D.; Rill, M.; Cerkovnikov, E. Acta Pharm. Jugosl. 1956,
6, 65. (b) Prelog, V.; Kohlbach, D.; Cerkovnikov, E.; Rezek, A.; Piantanida,
M. Liebigs Ann. Chim. 1957, 532, 69. (c) Radzisewski, J. G.; Kaszynski,
P.; Littmann, D.; Balaji, V.; Hess, B. A.; Michl, J. J. Am. Chem. Soc. 1993,
115 (18), 8401-8408.
JO061977A
J. Org. Chem, Vol. 71, No. 26, 2006 9911