Synthesis of Functionalized Azabicycloalkane Amino Acids
to 0 °C over 1 h, and then pH 7 phosphate buffer (10 mL) was
added. The aqueous phase was extracted with CH2Cl2 (3 × 10
mL), the combined organic layers were dried with Na2SO4, and
the solvent was evaporated under reduced pressure. The crude
was used for the next reaction without further purification.
7.43-7.45 (m, 2H, aromatic protons); 13C NMR (HETCOR, 400
MHz, CDCl3) δ 129.7, 128.4, 127.3, 71.3, 65.0, 63.0, 59.3, 59.1,
42.4, 32.8, 32.9, 33.0, 28.5, 28.4; MS (FAB+) m/z 373 [M + H]+.
Anal. Calcd for C21H28N2O4: C, 67.72; H, 7.58; N, 7.52.
Found: C, 67.87; H, 7.66; N, 7.28.
To a solution of aldehyde 18 (0.780 mmol) and N-benzyl-
hydroxylamine hydrochloride (374 mg, 2.34 mmol) in toluene
(20 mL) was added a solution of NaHCO3 (330 mg, 3.90 mmol)
in H2O (10 mL), and the resulting mixture was refluxed for
20 h. After reaction completion, the solvent was evaporated
under reduced pressure, and the residue was dissolved in CH2-
Cl2 and washed with a saturated solution of NH4Cl. The
organic phase was dried with Na2SO4, and the solvent was
evaporated under reduced pressure. To remove the excess of
N-benzylhydroxylamine, the crude was dissolved in CH2Cl2
and Amberlyst A21 was added until pH ) 8, then at -20 °C,
tert-butylacetyl chloride (680 µL, 4.68 mmol) was added. The
reaction was stirred at room temperature for 15 min, and then
the mixture was filtered and washed with CH2Cl2. Finally, the
solvent was evaporated under reduce pressure, and the crude
was purified by flash chromatography to give the desired
product 22a.
(3aR,5R,7aR,9aR)-1-Benzyl-4-oxodecahydro-2-oxa-3,4a-
diazacyclopenta[f]azulene-5-carboxylic Acid tert-Butyl
Ester 22a. Compound 22a was prepared following the general
procedure D. The crude was purified by flash chromatography
(hexane/EtOAc 4:6) affording pure 22a (55% over two steps)
as a white solid: mp ) 123 °C; [R]22D ) +70.6 (c ) 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H, C(CH3)3), 1.54 (m,
1H, H-8), 1.65-1.75 (m, 3H, H-9, H-8, H-7), 1.95 (m, 1H, H-6),
2.06 (m, 1H, H-9), 2.17 (m, 1H, H-6), 2.35 (m, 1H, H-7), 2.63
(m, 1H, H-9a), 3.26 (d, 1H, J ) 10.19 Hz, H-3a), 3.47 (dd, 1H,
J1 ) J2 ) 6.4 Hz, H-1), 3.69 (d, 1H, J ) 13.88, HCHPh), 4.00
(m, 1H, H-7a), 4.10 (dd, 1H, J1 ) J2 ) 6.4 Hz, H-1), 4.50 (d,
1H, J ) 13.88, HCHPh), 4.54 (dd, 1H, J ) 10,23 Hz, J ) 2.34
Hz, H-5), 7.22-7.41 (m, 3H, aromatic protons), 7.42-7.5 (m,
2H, aromatic protons); 13C NMR (50.3 MHz, CDCl3) δ 171.3,
168.9, 137.4, 129.5, 129.4, 128.3, 127.3, 81.5, 73.0, 71.6, 61.2,
58.6, 45.1, 34.8, 32.7, 32.2, 29.8, 28.1, 27.2; MS (FAB+) m/z
387 [M + H]+. Anal. Calcd for C22H30N2O4: C, 68.37; H, 7.82;
N, 7.25. Found: C, 68.45; H, 7.99; N, 7.06.
General Procedure E. Hydrogenolysis. A solution of 19,
20, 21, or 22 (0.10 mmol) in MeOH (1.0 mL) containing a
catalytic amount of 10% Pd-C was stirred under hydrogen
for ca. 2 h. After reaction completion, the mixture was filtered
through a Celite pad and washed with MeOH. The collected
organic phase was evaporated under reduced pressure afford-
ing the corresponding amino alcohols 23-26.
(3S,4S,6R,9S)-3-Amino-1-aza-2-oxo-4-hydroxymethyl-
bicyclo[4.3.0]nonanecarboxylic Acid tert-Butyl Ester 23.
Compound 23 was prepared following the general procedure
E. The crude was purified by flash chromatography (CH2Cl2/
MeOH 9:1, EtOAc/MeOH 9:1) affording the pure product (99%)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.42 (m, 1H,
H-5), 1.48 (s, 9H, C(CH3)3), 1.7 (m, 1H, H-7), 1.9-2.25 (m, 4H,
H-5, H-7, CH2-8), 2.39 (m, 1H, H-4), 3.6 (m, 1H, H-6), 3.67 (m,
H, H-3), 3.72-3.78 (m, 2H, CH2OH), 4.38 (m, 1H, H-9); 13C
NMR (50.3 MHz, CDCl3) δ 171.0, 169.9, 82.0, 65.5, 59.3, 56.9,
53.3, 38.0, 32.0, 30.7, 29.8, 29.1, 28.1; MS (FAB+) m/z 285 [M
+ H]+. Anal. Calcd for C14H24N2O4: C, 59.20; H, 8.52; N 9.85.
Found: C, 59.13; H, 8.51; N, 9.85.
(3S,4S,7S,10S)-3-Benzyalmino-1-aza-2-oxo-4-hydroxy-
methylbicyclo[5.3.0]decanecarboxylic Acid tert-Butyl
Ester 24. Compound 24 was prepared following the general
procedure E. The crude was purified by flash chromatography
(CH2Cl2/MeOH 9:1, EtOAc/MeOH 9:1) affording the pure
product (90%) as a colorless oil: 1H NMR (200 MHz, CDCl3) δ
1.38-1.4 (m, 1H, H-5), 1.46 (s, 9H, C(CH3)3), 1.60-1.93 (m,
5H, H-4, H-5, CH2-6, H-8), 1.93-2.17 (m, 2H, CH2-9), 2.23 (m,
1H, H-8), 3.50 (d, 1H, J ) 9.5 Hz, H-3), 3.66 (d, 2H, J ) 5.5
Hz, CH2OH), 3.75 (m, 1H, H-7), 4.54 (dd, 1H, J ) 6 Hz, J )
5.4 Hz, H-10); 13C NMR (50.3 MHz, CDCl3) δ 173.0, 171.1, 81.4,
68.0, 61.6, 58.3, 58.0, 40.8, 33.5, 32.9, 32.7, 32.0, 29.6, 27.9,
27.7; MS (FAB+) m/z 299 [M + H]+. Anal. Calcd for
C15H26N2O4: C, 60.40; H, 8.77; N, 9.40. Found: C, 60.38; H,
8.77; N, 9.39.
(3R,4R,6S,9S)-3-Benzylamino-1-aza-2-oxo-4-hydroxy-
methylbicyclo[4.3.0]nonanecarboxylic Acid tert-Butyl
Ester 25. Compound 25 was prepared following the general
procedure E. The crude was purified by flash chromatography
(CH2Cl2/MeOH 9:1, EtOAc/MeOH 9:1) affording the pure
product (98%) as a colorless oil: [R]22D ) -79 (c ) 0.64, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.3 (m, 1H, H-5), 1.48 (s, 9H,
C(CH3)3), 1.53 (m, 1H, H-7), 1.85 (m, 1H, H-8), 2.06 (m, 1H,
H-5), 2.21 (m, 1H, H-7), 2.26-2.38 (m, 2H, H-8, H-4), 3.62-
3.8 (m, 4 H, CH2OH, H-3, H-6), 4.43 (m, 1 H, H-9); 13C NMR
(100.6 MHz, CDCl3) δ 171.2, 170.7, 81.7, 65.3, 59.0, 57.5, 52.9,
38.4, 32.7, 29.4, 28.0, 27.9; MS (FAB+) m/z 285 [M + H]+. Anal.
(3aS,4aR,7R,8aS)-1-Benzyl-8-oxo-octahydro-2-oxa-1,7a-
diaza-s-indacene-7-carboxylic Acid tert-Butyl Ester 19.
Compound 19 was prepared following procedure C. The crude
was purified by flash chromatography (hexane/EtOAc 65:35)
affording the pure product (74% over two steps) as colorless
oil: [R]22 ) -123.1 (c ) 1.03, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 1.49 (s, 9H, C(CH3)3), 1.62 (m, 1H, H-4), 1.88 (m, 1H,
H-5), 2.0-2.2 (m, 4H, CH2-6, H-4, H-5), 2.95 (m, 1H, H-3a),
3.22 (d, 1H, J ) 9.0 Hz, H-8a), 3.58 (dd, 1H, J ) 8.0 Hz, J )
6.1 Hz, H-3), 3.66 (m, 1H, H-4a), 3.92 (d, 1H, J ) 14.3 Hz,
CHHPh), 4.17 (dd, 1H, J ) 8.0 Hz, J ) 8.0 Hz, H-3), 4.34 (dd,
1H, J ) 8.6 Hz, J < 1 Hz, H-7), 4.90 (d, 1H, J ) 14.3 Hz,
CHHPh), 7.21-7.35 (m, 3H, aromatic protons), 7.4-7.46 (m,
2H, aromatic protons); 13C NMR (75.4 MHz, CDCl3) δ 170.8,
166.3, 137.8, 129.3, 128.0, 126.9, 81.5, 64.1, 62.0, 59.7, 59.1,
42.6, 33.0, 31.2, 29.7, 28.5, 27.9; MS (FAB+) m/z 373 [M + H]+.
Anal. Calcd for C21H28N2O4: C, 67.72; H, 7.58; N, 7.52.
Found: C, 67.89; H, 7.56; N, 7.44.
(3aS,5R,7aS,9aS)-1-Benzyl-4-oxodecahydro-2-oxa-3,4a-
diazacyclopenta[f]azulene-5-carboxylic Acid tert-Butyl
Ester 20. Compound 20 was prepared following the general
procedure C. The crude was purified by flash chromatography
(hexane/EtOAc 7:3) affording the pure product (75% over two
steps) as a white solid: mp ) 140-142 °C; [R]22D ) -146.0 (c
) 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H,
C(CH3)3), 1.63-1.94 (m, 4H, CH2-9, H-7, H-8), 1.98-2.12 (m,
3H, CH2-6, H-8), 2.27 (m, 1H, H-7), 2.79 (m, 1H, H-9a), 3.17
(d, 1H, J ) 10.1 Hz, H-3a), 3.52 (dd, 1H, J ) 7.6 Hz, J ) 6.6
Hz, H-1), 3.67 (d, 1H, J ) 13.6 Hz, CHHPh), 3.85 (m, 1H,
H-7a), 4.14 (dd, 1H, J ) 8.5 Hz, J ) 7.6 Hz, H-1), 4.47 (d, 1H,
J ) 13.6 Hz, CHHPh), 4.65 (dd, 1H, J ) 7.4 Hz, J ) 3.6 Hz,
H-5), 7.21-7.35 (m, 3H, aromatic protons), 7.41-7.44 (m, 2H,
aromatic protons); 13C NMR (75.4 MHz, CDCl3) δ 171.2, 168.5,
137.3, 129.3, 128.1, 127.1, 81.4, 73.2, 71.4, 61.4, 60.7, 58.8, 44.9,
34.0, 33.2, 32.2, 29.7, 28.0, 27.6; MS (FAB+) m/z 387 [M + H]+.
Anal. Calcd for C22H30N2O4: C, 68.37; H, 7.82; N, 7.25.
Found: C, 68.45; H, 7.84; N, 7.06.
(3aR,4aS,7R,8aR)-1-Benzyl-8-oxooctahydro-2-oxa-1,7a-
diaza-s-indacene-7-carboxylic Acid tert-Butyl Ester 21.
Compound 21 was prepared following the general procedure
C. The crude was purified by flash chromatography (hexane/
EtOAc 7:3) affording the pure product (85% over two steps)
as a white solid: mp ) 175 °C; [R]22D ) +9.4 (c ) 1.00, CHCl3);
1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H, C(CH3)3), 1.50-1.65
(m, 2H, H-4, H-5), 1.83 (m, 1H, H-6), 2.12 (m, 1H, H-4), 2.20
(m, 1H, H-5), 2.40 (m, 1H, H-6), 2.98 (m, 1H, H-3a), 3.36 (d,
1H, J ) 8 Hz, H-8a), 3.62 (m, 1H, H-3), 3.78 (m, 1H, H-4a),
3.93 (d, 1H, J ) 14.3, HCHPh), 4.15 (dd, 1H, J1 ) J2 ) 7.7
Hz, H-3), 4.48 (dd, 1H, J1 ) J2 ) 8.64 Hz, H-7), 4.82 (d, 1H,
J ) 14.3, NCH2Ph), 7.23-7.34 (m, 3H, aromatic protons),
J. Org. Chem, Vol. 70, No. 10, 2005 4131