2230 J . Org. Chem., Vol. 61, No. 6, 1996
Notes
72.65; H, 7.46; N, 5.98. RP-HPLC (Symmetry C8; 10-80%
CH3CN in 20 mM Na2HPO4 (pH 7.4) in 25 min; 0.8 mL/min): tR
20.7 min (>99.5% de).
g, 80.2 mmol). After stirring 5 min, additional H2O (40 mL) was
added to dissolve all solids. The organic layer was separated
and the aqueous phase extracted with TBME (100 mL). The
combined extracts were washed with 10% NH4OH (100 mL), H2O
(2 × 100 mL), and brine (100 mL). After drying (MgSO4) and
concentration, a colorless oil was obtained which solidified on
standing (18.40 g, 99% yield). The material was identical to
(2S,4R)-4b isolated previously by flash chromatography: mp
(2S,4R)-4b (m a jor d ia ster eom er ): Rf 0.62 (1:1 hexane/
EtOAc). Mp 83-84 °C. [R]25D -94.7° (c 1.01, CHCl3). IR (KBr)
ν 1765 cm-1 1H NMR (CDCl3) δ 7.42-7.37 (m, 2H), 7.35-7.29
.
(m, 2H), 7.28-7.22 (m, 1H), 4.77 (t, J ) 5.1 Hz, 1H), 3.70 (q, J
) 6.7 Hz, 1H), 3.33 (dd, J ) 11.8, 6.7 Hz, 1H), 3.18 (d, J ) 5.1
Hz. 1H), 2.48 (dt, J ) 11.8, 5.1 Hz, 1H), 2.12-2.02 (m, 2H),
1.95-1.86 (m, 1H), 1.82 (d, J ) 11.8 Hz, 1H), 1.33 (d, J ) 6.7
Hz, 3H). 13C NMR (CDCl3) δ 174.0, 144.5, 128.5, 127.4, 127.1,
76.4, 62.3, 57.1, 44.0, 37.2, 29.2, 21.3. MS m/ z 232 (MH+). Anal.
Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C,
72.85; H, 7.50; N, 6.00. RP-HPLC (Symmetry C8; 10-80%
CH3CN in 20 mM Na2HPO4 (pH 7.4) in 25 min; 0.8 mL/min): tR
19.6 min (>99.5% de).
81-84 °C. [R]25 -99.4° (c 1, CHCl3). Anal. Calcd for C14H17
-
D
NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.84; H, 7.52; N,
6.00. RP-HPLC (symmetry C8; 10-80% CH3CN in 20 mM Na2-
HPO4 (pH 7.4) in 25 min; 0.8 mL/min): tR 19.65 min (2S,4R)-4b
(96.9%, 93.9% de); tR 20.7 min, (2R,4S)-4b (3.1%).
(1R,5S)-2-[(S)-2-P h en yleth yl]-6-oxa -2-a za bicyclo[3.2.1]-
octa n -7-on e, (2R,4S)-4b. Following the procedure described
above for (2S,4R)-4b, (2R,4S)-7b (25.13 g, 46.32 mmol) was
neutralized to the free base which was obtained as a white solid
(10.57 g, 99% yield) identical to (2R,4S)-4b isolated previously
(2S,4R)-7b. Crude diastereomeric lactones 4b (50.01 g, 216.5
mmol) were dissolved in MeOH (150 mL). A solution of (S)-6 in
EtOAc (44% w/w, prepared from the ammonium salt as described
previously for the resolution of 4a , 99.5 g, 140.7 mmol, 0.65
equiv) was added dropwise with stirring. Absolute EtOH (150
mL) was added and the slurry stirred 16 h at room temperature.
The salt was collected by filtration, washed with EtOH (2 × 100
mL), and dried (48.74 g, 41.5% yield). Mother liquor and
washings were combined and concentrated to a viscous oil which
was saved for isolation of (2R,4S)-4b. Mp 233-236 °C dec.
by flash chromatography: mp 46-47 °C. [R]25 -15.9° (c 1,
D
CHCl3). Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06.
Found: C, 72.80; H, 7.51; N, 6.00. RP-HPLC (symmetry C8;
10-80% CH3CN in 20 mM Na2HPO4 (pH 7.4) in 25 min; 0.8
mL/min): tR 19.6 min (2S,4R)-4b (0.5%); tR 20.65 min, (2R,4S)-
4b (99.5%, 99% de).
(2S,4R)-4-Hyd r oxyp ip ecolic a cid , (2S,4R)-1 fr om (2S,4R)-
4b. The procedure described previously for the conversion of
(2S,4R)-4a into (2S,4R)-1 was used. cis-4-Hydroxypipecolic acid
was obtained in 88% yield and was identical in all respect to
the material described in the literature:7e,18 mp 270.5-271.5 °C
dec, lit.7e mp 265 °C dec. [R]25D -23.5° (c 1, H2O), [R]25365 -56.3°
[R]25 -63.9° (c 1, CHCl3). IR (KBr) ν 3450, 2500, 1775, 1755
D
cm-1
.
1H NMR (CDCl3) δ 11.95 (broad s, 1H), 7.70 (m, 2H), 7.50
(m, 3H), 5.10 (broad t, J ) 4.9 Hz, 1H), 4.66 (broad d, J ) 4.8
Hz, 1H), 4.42 (broad m, 1H), 4.28 (broad m, J ) 7.2 Hz. 1H),
3.75 (broad d, J ) 4.8 Hz, 1H), 3.31 (d, J ) 14.3 Hz, 1H, AB
system), 3.25 (t, J ) 4.1 Hz, 1H), 3.15-3.04 (m, 1H), 3.06 (d, J
) 14.0 Hz, 1H), 2.99-2.9 (m, 1H), 2.91 (d, J ) 14.0 Hz, 1H, AB
system), 2.4-2.17 (m, 4H), 1.86 (d, J ) 7.0 Hz, 3H), 1.74 (m,
1H), 1.51 (ddd, J ) 14.3, 8.6, 6.0 Hz, 1H), 1.32 (s, 3H), 1.02 (s,
3H). 13C NMR (DMSO-d6) δ 211.8, 169.5 (broad), 137 (broad),
129.3, 128.3, 76.0, 65.2 (broad), 59.0, 57.0, 54.5, 53.9, 47.2, 46.3,
33.7 (broad), 29.6, 26.9 (broad), 21.8, 18.0 (broad), 17.2, 9.5. MS
(c 1, H2O), lit.7e [R]23 -17° (1.1% in H2O). Anal. Calcd for
D
C6H11NO3 (1.14% w/w water): C, 49.08; H, 7.69; N, 9.54.
Found: C, 49.30; H, 7.81; N, 9.47. The enantiomeric purity of
the amino acid was determined by RP-HPLC analysis after
conversion to the (+)-1-(9-fluorenyl)ethyl carbamate:19 RP-HPLC
(CHIREX-(S)-Val and DNAn; 10 mM NH4OAc/MeOH isocratic;
1 mL/min): tR 13.2 min (2R,4S)-1 (0.1%); tR 15.2 min (2S,4R)-1
(99.9%, 99.8% ee).
m/ z 232 (MH+ of free base lactone). Anal. Calcd for C24H32
-
(2S,4R)-4-Hyd r oxyp ip ecolic Acid Meth yl Ester Hyd r o-
ch lor id e, (2S,4R)-9. Lactone (2S,4R)-4b (0.750 g, 3.24 mmol)
was dissolved in a mixture of 4 N HCl in dioxane (890 µL; 3.57
mmol) and MeOH (20 mL). 20% Pd(OH)2/C (75 mg) was added
and the suspension stirred under 1 atm of H2 gas for 18 h. The
catalyst was removed by filtration and the solvent removed
under reduced pressure to give a beige solid. The material was
triturated with 10% MeOH in ether (10 mL), filtered, washed
with a small amount of the same solvent, and dried overnight
at 60 °C under vacuum over P2O5 (0.604 g, 95% yield): mp
BrNO6S: C, 53.14; H, 5.95; N, 2.58. Found: C, 52.83; H, 5.94;
N, 2.53. RP-HPLC (Symmetry C8; 10-80% CH3CN in 20 mM
Na2HPO4 (pH 7.4) in 25 min; 0.8 mL/min): tR 19.6 min, (2S,4R)-
4b (98.2%, 96.4% de); tR 20.6 min, (2R,4S)-4b (1.8%).
(2R,4S)-7b. The mother liquors from the crystallization of
(2S,4R)-7b (see above) were stirred with a mixture of TBME
(300 mL), H2O (80 mL), and concd NH4OH (20 mL). The organic
layer was separated and the aqueous phase again extracted with
TBME (100 mL). The combined extracts were washed with 10%
NH4OH (100 mL), H2O (2 × 100 mL), and brine (100 mL). After
drying (MgSO4) and evaporation of the solvent, a dark brown
oil was obtained. The oil was dissolved in EtOAc (30 mL), and
a solution of (R)-6 in EtOAc (33% w/w, 118 g, 1 equiv based on
estimated lactone content) was added. The mixture was stirred
overnight at room temperature. The precipitated solids were
collected by filtration, washed with EtOAc (3 × 75 mL), and
dried (31.35 g, 26.7% yield, 98.8% de by RP-HPLC). The
material was stirred overnight in EtOAc (300 mL), collected,
washed with EtOAc (2 × 50 mL), and dried to give (2R,4S)-7b
as an off-white solid (30.37 g, 25.8% yield): mp 229-230 °C dec.
172.5-174.5 °C dec. [R]25 +9.9° (c 1.01, MeOH). IR (KBr) ν
D
3200, 1740 cm-1
.
1H NMR (DMSO-d6) δ 9.66 (broad s, 2H), 5.28
(broad s, 1H), 4.14 (dd, J ) 11.4, 3.3 Hz, 1H), 3.8-3.73 (m, 1H),
3.72 (s, 3H), 3.25 (dt, J ) 12.9, 4.0 Hz, 1H), 2.90 (dt, J ) 12.4,
3.0 Hz, 1H), 2.19 (m, 1H), 1.87 (m, 1H), 1.67-1.55 (m, 2H). 13C
NMR (DMSO-d6) δ 168.9, 63.5, 54.0, 52.8, 40.9, 34.1, 30.1. MS
m/ z 160 (MH+). Anal. Calcd for C7H14ClNO3 (0.6% w/w
water): C, 42.17; H, 7.25; N, 7.12. Found: C, 42.32; H, 7.29; N,
7.06. The enantiomeric purity of (2S,4R)-9 was determined by
RP-HPLC analysis after conversion to the (+)-1-(9-fluorenyl)-
ethyl carbamate:19 RP-HPLC (Chiralpak AS; 5% EtOH/hexane
isocratic; 0.5 mL/min): tR 26.4 min (2R,4S)-9 (2.1%); tR 28.5 min
(2S,4R)-9 (97.9%, 95.8% ee).
[R]25 +53.9° (c 1, CHCl3). IR (KBr) ν 3460, 2590, 2500, 1785,
D
1750 cm-1
.
1H NMR (CDCl3) δ 11.95 (broad s, 1H), 7.60 (m,
2H), 7.47 (m, 3H), 5.10 (broad t, J ) 4.9 Hz, 1H), 4.66 (broad d,
J ) 4.8 Hz, 1H), 4.4 (m, 2H), 3.41 (broad d, J ) 14.0 Hz, 1H),
3.30 (d, J ) 14.3 Hz, 1H), 3.24 (t, J ) 4.1 Hz, 1H), 3.21 (m, 1H),
2.89 (d, J ) 14.0 Hz, 1H), 2.85-2.72 (m, 1H), 2.68-2.52 (m, 2H),
2.3-2.08 (m, 3H), 1.94 (d, J ) 7.0 Hz, 3H), 1.72 (m, 1H), 1.51
(ddd, J ) 14.5, 8.7, 6.0 Hz, 1H), 1.31 (s, 3H), 1.01 (s, 3H). 13C
NMR (DMSO-d6) δ 212.7, 170.6, 136.8, 129.8, 129.5, 128.7, 76.6,
65.0, 59.5, 57.3, 54.8, 54.2, 47.5, 47.2, 46.7, 34.2, 30.0, 27.2, 22.2,
18.8, 17.7, 9.9. MS m/ z 232 (MH+ of free base lactone). Anal.
Calcd for C24H32BrNO6S: C, 53.14; H, 5.95; N, 2.58. Found: C,
52.85; H, 5.97; N, 2.51. RP-HPLC (symmetry C8; 10-80%
CH3CN in 20 mM Na2HPO4 (pH 7.4) in 25 min; 0.8 mL/min): tR
19.6 min, (2S,4R)-4b (0.4%); tR 20.6 min, (2R,4S)-4b (99.6%,
99.1% de).
(1S,5R)-2-(ter t-bu toxycar bon yl)-6-oxa-2-azabicyclo[3.2.1]-
octa n -7-on e, (2S,4R)-10. Lactone (2S,4R)-4b (0.750 g, 3.24
mmol) and di-tert-butyl dicarbonate (0.780 g, 3.57 mmol) were
dissolved in EtOAc (20 mL). 20% Pd(OH)2/C (75 mg) was added
and the mixture stirred under 1 atm of H2 gas for 18 h. The
catalyst was removed by filtration, and volatiles were removed
under reduced pressure to give a white solid. Pure (2S,4R)-10
was obtained after trituration with 10% ether in hexanes (10
mL) and drying overnight at 60 °C under vacuum over P2O5
(0.695 g, 94% yield): Rf 0.77 (1:3 hexane/EtOAc). Mp 144-145.5
°C. [R]25D -136.9° (c 1.075, CHCl3). IR (KBr) ν 1775, 1685 cm-1
.
1H NMR (CDCl3) δ 4.98 (t, J ) 5.1 Hz, 1H), 4.74 (broad m, 1H),
4.07 (broad m, 1H), 3.19 (broad m, 1H), 2.31 (m, 1H), 2.05 (m,
1H), 1.96 (d, J ) 12.1 Hz, 1H), 1.95-1.85 (m, 1H), 1.48 (s, 9H).
13C NMR (CDCl3) δ 173.2, 153.6, 80.9, 76.9, 53.7 (broad), 38.0
(broad), 36.5, 28.5, 28.1. MS m/ z 228 (MH+). Anal. Calcd for
(1S,5R)-2-[(S)-2-P h en yleth yl]-6-oxa -2-a za bicyclo[3.2.1]-
octa n -7-on e, (2S,4R)-4b. To a mixture of TBME (300 mL), H2O
(90 mL) and concd NH4OH (10 mL) was added (2S,4R)-7b (43.49
C
11H17NO4: C, 58.14; H, 7.54; N, 6.16. Found: C, 57.94; H, 7.61;