200
P. Dalla Croce, C. La Rosa / Tetrahedron: Asymmetry 13 (2002) 197–201
starting from trans-4-hydroxy-
L
-prolines. The forma-
4.3. General procedure for the preparation of (2R,4R)-
N-acyl-4-hydroxy-prolines 3a and 3b
tion of the intermediate mesoionic compounds leads to
inversion of configuration at C(2) of the proline ring,
and thus affords the (1R,4R)-lactones. In this way, it is
possible to synthesize both enantiomers from the same
available compound by changing the synthetic scheme.
Subsequent hydrolysis makes it possible to obtain cis-4-
hydroxy-D-proline or its N-acyl derivatives in better
yields than those previously reported, depending on the
experimental conditions.
To a solution of 2a or 2b (5 mmol) in water/acetone=
1/1 (20 mL) Dowex 50×8 resin (1.5 g) was added in
portions and the mixture was stirred at room tempera-
ture until reaction was complete (about 48 h). The
mixture was filtered and the filtrate concentrated. The
products were recrystallized and identified by means of
analytical and spectroscopic data.
4.3.1. Compound 3a. White solid, mp 142–143°C
(iPrOH); [h]2D0=+88.2 (c 1.00, H2O); [lit.:11b mp 145.5–
4. Experimental
1
147°C; [h]2D2=+91.00 (c 9.70, H2O)]; H NMR (D2O): l
2.1 (s, 3H, CH3), 2.15–2.58 (m, 2H, 2H-3), 3.42–3.89
(m, 2H, H-5), 4.49–4.64 (m, 1H, H-2), 4.7–4.87 (m, 1H,
H-4). Anal. calcd for C7H11NO4: C, 48.55; H, 6.36; N,
8.09. Found: C, 48.45; H, 6.30; N, 8.01%.
4.1. General methods
Melting points were determined using a Bu¨chi appara-
tus and are uncorrected. All the H NMR spectra were
1
recorded by means of a Bruker AC 300 spectrometer.
Chemical shifts (l) are given in ppm relative to TMS
and the coupling constants (J) are reported in Hz.
Optical rotations were measured using a Perkin–Elmer
241 spectropolarimeter. Compounds 1a and 1c were
commercial products; 1b was prepared according to the
method of Portoghese.7a
4.3.2. Compound 3b. White solid, mp 138–140°C
(CHCl3); [h]2D0=+71.25 (c 1.00, EtOH); 1H NMR
(CDCl3): l 2.27 (m, 2H, 2H-3), 3.62 (m, 2H, H-5), 4.35
(broad s, 1H, H-2), 4.69 (dd, J=8.62, 2.81, 1H, H-4),
7.25–7.51 (m, 5H, arom.). Anal. calcd for C12H13NO4:
C, 61.28; H, 5.53; N, 5.96. Found: C, 61.23; H, 5.45; N,
5.87%.
4.2. General procedure for the preparation of (1R,4R)-
4.4. Hydrolysis of 2a to cis-4-hydroxy-D-proline 4
N-acyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-ones 2a and
2b
A stirred mixture of 2a (0.775 g, 5 mmol) and 2N
aqueous HCl (3 mL) was heated under gentle reflux
temperature for 2 h. The solution was decolorized with
charcoal while hot, filtered through Celite, and then
neutralized to pH 6 with 5N NaOH (1 mL). The
product was purified by adsorption on Dowex 50×8
ion-exchange resin: the resin was washed with distilled
water until chloride ions disappear, then eluted with 5
M NH4OH. Product 4 was obtained as a white solid in
75% yield. Mp 254–255°C (decomp.) (EtOH/H2O=2/
1); [h]2D0=+58.27 (c 2.00, H2O); [lit.:11b mp 252–257°C;
A mixture of 1a or 1b (15 mmol) and acetic anhydride
(25 mL) was stirred and heated at 90°C for 7 h, under
nitrogen. After evaporation of the solvent, the residue
was taken up in dichloromethane (50 mL) and the
solution was washed with cold water. The organic
phase was dried (Na2SO4) and the solvent evaporated
off. The products were recrystallized and identified by
means of analytical and spectroscopic data.
1
[h]2D2=+60.3 (c 2.60, H2O)]; H NMR (D2O): l 2.08,
4.2.1. Compound 2a. White solid, mp 95–98°C (iPrOH);
1
[h]2D0=−60.5 (c 1.00, CHCl3); H NMR (CDCl3): l 1.97
2.13 (2m, 1H, H-3), 2.37 (ddd, J=14.4, 10.2, 4.6, 1H,
H-3), 3.20 (dd, J=12.46, 3.95, 1H, H-5), 3.30 (dd,
J=12.48, 1.54, 1H, H-5), 4.10 (dd, J=10.41, 388, 1H,
H-2), 4.40 (m, 1H, H-4). Anal. calcd for C5H9NO3: C,
45.80; H, 6.87; N, 10.69. Found: C, 45.65; H, 6.70; N,
10.51%.
(dd, J=11.45, 1.72, 0.35H, H-7), 2.05 (s, 1.05H, CH3),
2.11 (dd, J=10.82, 1.79, 0.65H, H-7), 2.19 (s, 1.95H,
CH3), 2.26 (d, J=10.5, 0.35H, H-7), 2.32 (dd, J=10.85,
1.10, 0.65H, H-7), 3.53 (d, J=10.08, 0.35H, H-6),
3.60,3.62 (2s, 1.3H, H-6+H-6), 3.69 (d, J=10.06, 0.35H,
H-6), 4.45 (s, 0.65H, H-4), 5.09 (s, 0.35H, H-4), 5.16 (s,
1H, H-1). IR (KBr): 1786, 1650 cm−1. Anal. calcd for
C7H9NO3: C, 54.19; H, 5.81; N, 9.03. Found: C, 54.03;
H, 5.75; N, 8.92%.
4.5. Synthesis of cis-4-hydroxy-
D
-proline 4 from trans-
4-hydroxy- -proline 1c
L
A stirred mixture of 1c (6.55 g, 50 mmol) and acetic
anhydride (40 mL) was heated at 90°C for 16 h under
nitrogen. The solution was evaporated under reduced
pressure to give a thick oil that was dissolved in 2N
aqueous HCl (30 mL). The solution was heated under
reflux for 2 h, then decolorized with charcoal while hot,
filtered through Celite and neutralized to pH 6 with 5N
NaOH (10 mL). Product 4 was purified as described
above and was obtained with the same purity in a total
yield of 76%.
4.2.2. Compound 2b. White solid, mp 134–135°C
(iPrOH); [h]2D0=−92.75 (c 1.00, EtOH); 1H NMR
(CDCl3): l 2.03 (dd, J=10.88, 1.29, 1H, H-7), 2.22 (d,
J=10.92, 1H, H-7), 3.63 (d, J=9.93, 1H, H-6), 3.81 (d,
J=10.68, 1H, H-6), 4.51 (s, 1H, H-4), 5.16 (s, 1H, H-1),
7.37–7.48 (m, 3H, arom.), 7.57 (d, J=7.64, 2H, arom.).
IR (KBr): 1796, 1628 cm−1. Anal. calcd for C12H11NO3:
C, 66.36; H, 5.07; N, 6.45. Found: C, 66.23; H, 5.05; N,
6.37%.