Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3495
acetate was converted, in a straighforward two-step reaction
sequence [H2/Pd(C), EtOAc, then BnBr, K2CO3, dioxane, rt,
(77%)], into its congener 8a (vide infra) from which the ee could
be determined as described above.
4.7 Hz), 4.02 (dd, 1 H, J ) 11.0, 5.1 Hz), 3.92 (dd, 1H, J ) 11.0,
7.2 Hz), 3.86 (br d, J ) 13.0 Hz), 3.41 (dd, J ) 13.0, 4.0 Hz),
2.93 (br dd, J ) 13.0, 8.2 Hz), 2.73 (br t, J ) 12.2 Hz), 2.51 (m),
2.49 (br t, J ) 12.2 Hz), 2.20-2.05 (m), 2.03 (s), 2.01 (s), 1.92
(m), 1.54 (ddd, J ) 13.2, 10.0, 5.2 Hz), 1.21 (q, J ) 12.3 Hz);
EIMS m/z (relative intensity) 319 (87, M+), 291 (100), 274 (48),
216 (88). Anal. Calcd for C17H21N1O5: C, 63.94; H, 6.63; N, 4.39.
Found: C, 63.79; H, 6.61; N, 4.28.
(3S,5R)-N-Ben zyl-3-(a cetoxym eth yl)-5-(h yd r oxym eth yl)-
p ip er id in e (8a ) was obtained by reaction of 6a with PFL in
vinyl acetate after 5 h (Table 1, entry 5). Purification of the
crude product by flash chromatography (9:1 CHCl3/MeOH) gave
74% yield of 8a (>98% ee) as an oil: Rf (9:1 CHCl3/MeOH) 0.40;
(3S)-Ben zyl 3-(Acetoxym eth yl)-1-p ip er id in eca r boxyla te
(11). To a stirred solution of 9 and 10 (200 mg, 0.63 mmol) in
dry toluene (6 mL) was added the complex RhCl(PPh3)3 (530 mg,
0.63 mmol). After heating at reflux for 24 h, the solvent was
evaporated, Et2O was added, and the solid was filtered off; after
evaporation of Et2O, the residue was purified by FC (2:1 hexane/
AcOEt) to give 11 (147 mg, 80% yield), as an oil: Rf (2:1 hexane/
1
[R]365 ) +5.3 (c 1, MeOH); H NMR(300 MHz, CDCl3, 50 °C) δ
7.32 (m, 5 H), 3.93 (dd, 1 H, J ) 11.7, 6.0 Hz), 3.86 (dd, 1 H, J
) 11.7, 7.0 Hz), 3.58 and 3.50 (AB system, 2 H, J ) 12.5 Hz),
3.48 (dd, 1 H, J ) 10.5, 6.1 Hz), 3.42 (dd, 1 H, J ) 10.5, 6.1 Hz),
2.99 (br d, 1 H, J ) 11.8 Hz), 2.93 (br d, 1 H, J ) 11.8 Hz), 2.04
(m, 1 H), 2.00 (s, 3 H), 1.90 (m, 1 H), 1.81 (br d, 1 H, J ) 12.4
Hz), 1.69 (t, 1 H, J ) 11.8 Hz), 1.65 (t, 1 H, J ) 11.8 Hz), 1.45
(m, 1 H), 0.73 (q, 1 H, J ) 12.4 Hz); HRMS calcd for C16H23N1O3
277.1678, found 277.1688. Anal. Calcd for C16H23NO3: C, 69.29;
H, 8.36; N, 5.05. Found: C, 69.11; H, 8.42; N, 5.01.
1
AcOEt) 0.37; [R]365 ) + 47.6 (c 1, CHCl3); H NMR (300 MHz,
CDCl3, 50 °C) δ 7.36 (m, 5 H), 5.12 (s, 2 H), 4.05 (br d, 1 H, J )
12.6 Hz), 4.01-3.85 (m, 3 H), 2.90 (ddd, 1 H, J ) 13.5, 10.7, 3.5
Hz), 2.72 (br t, 1 H, J ) 12.6 Hz), 2.01 (s, 3 H), 1.92-1.74 (m, 2
H), 1.68 (m, 1 H), 1.47 (m, 1 H), 1.22 (m, 1 H); EIMS m/z (relative
intensity) 291 (7, M+), 246 (13), 140 (80), 91 (100). Anal. Calcd
for C16H21N1O4: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.11;
H, 7.38; N, 4.99.
(3S,5R)-Ben zyl 3-(a cetoxym eth yl)-5-(h yd r oxym eth yl)-1-
p ip er id in eca r boxyla te (8b) was obtained by reaction of 6b
with PFL in vinyl acetate after 6 h (Table 1, entry 10).
Purification of the crude product by FC (EtOAc as an eluent)
gave 78% yield of 8b (>98% ee) as an oil: Rf (EtOAc) 0.33; [R]365
) + 25.4 (c 1, MeOH); IR (neat) 3635, 1725, 1690 cm-1; 1H NMR-
(300 MHz, CDCl3, 50 °C) δ 7.32 (m, 5 H), 5.12 (m, 2 H), 4.39-
4.17 (m, 2 H), 3.99 (dd, 1 H, J ) 10.5, 5.9 Hz), 3.86 (dd, 1 H, J
) 10.5, 7.2 Hz), 3.51 (m, 2 H), 2.51-2.30 (m, 2 H), 2.03 (s, 3 H),
1.95-1.80 (m, 2 H), 1.80-1.55 (m, 2 H), 0.92 (q, 1 H, J ) 11.6
Hz); HRMS calcd for C17H23NO5 321.1576, found 321.1569.
Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found:
C, 63.31; H, 7.06; N, 4.41.
Con ver sion of 8b to 8a . A solution of 8b (>98% ee; 0.8 g,
2.5 mmol) in EtOAc (9 mL) including 10% palladium on carbon
(80 mg) was shaken under a hydrogen atmosphere for 12 h. The
catalyst was filtered off, and the solution was concentrated to
dryness. The residue was dissolved in 10 mL of dioxane, and
K2CO3 (206 mg, 1.5 mmol) followed by BnBr (470 mg, 2.75 mmol)
were added. After being stirred at room temperature for 15 h,
the reaction mixture was concentrated in vacuo, the residue was
poured into water and extracted with EtOAc, and the combined
organic fractions were dried and evaporated. Flash chromatog-
raphy of the residue gave 8a (530 mg, 77% yield) which was
found identical in all respects to that isolated from the PFL-
catalyzed acetylation of 6a .
Gen er a l P r oced u r e for En zym a tic Hyd r olysis of N-
P r ot ect ed cis-3,5-Bis(a cet oxym et h yl)p ip er id in es 7a a n d
7b. A suspension of substrate (1 mmol) and an appropriate
enzyme [(PPL, 17040 units/mmol substrate), (CCL, 270 units/
mmol substrate), (PFL, 315 units/mmol substrate), (PLE, 390
units/mmol substrate)] in an appropriate solvent system (10 mL)
was shaken at room temperature, and the pH was kept at 7.0-
7.2 by adding 0.1 M NaOH solution with an automatic pH
starter. After an appropriate time, the reaction was stopped
by addition of AcOEt. The aqueous solution was repeatedly
extracted with AcOEt, and the collected organic layers were
evaporated in vacuo affording a crude mixture which was
purified by FC. The optical purity of the acetate en t-8a and
en t-8b thus obtained was determined as described for the
enantiomers 8a and 8b.
(3S)-ter t-Bu tyl 3-(Hyd r oxym eth yl)-1-p ip er id in eca r box-
yla te (12). A solution of 11 (728 mg, 2.5 mmol) in EtOAc (10
mL) including 10% palladium on carbon (440 mg) was shaken
under a hydrogen atmosphere for 12 h. The catalyst was filtered
off, and the solution was concentrated to dryness to give a
residue, which was subjected to the next reaction without
purification.
To a stirred solution of the above product in t-BuOH (5 mL)
and NaOH 1 N (10 mL) was added (Boc)2O (675 mg, 3 mmol).
After 6 h at rt, the reaction mixture was poured into water and
extracted with Et2O; the organic phase was washed with brine,
dried, and concentrated to give pure 12 (430 mg, 81% yield), as
an oil: Rf (1:1 AcOEt/hexane) 0.23; [R]365 ) +60.5 (c 1, EtOH)
{lit.7 [R]365 ) +60.7 (c 1, EtOH)}. Compound 12 had IR, 1H
NMR, and MS spectra identical with those reported.7
(1R ,5S )-7-Ca r b ob e n zyloxy-3-oxo-7-a za -b icyclo[3.3.1]-
n on a n -2-ol (13) (m ixtu r e 1.6:1 of C-2 ep im er s). To a room-
temperature solution of the above-described mixture of alde-
hydes 9 and 10 (1.80 g, 5.64 mmol) in THF (40 mL) was added
0.25 N aqueous NaOH (45 mL), and the mixture was stirred at
room temperature for 3 h. The reaction was then acidified with
5% aqueous H3PO4, and THF was evaporated. After partition
between 50 mL of CH2Cl2 and 20 mL of brine, the aqueous phase
was extracted three times with CH2Cl2, and the combined
organic fractions were dried and evaporated. FC (EtOAc) of the
residue afforded the lactol 13 (1.56 g, 95%) as an inseparable
mixture of C-2 epimers (1.6:1 ratio from 300 MHz 1H NMR):
oil; Rf (EtOAc) 0.32; [R]365 ) + 77.9 (c 1, CHCl3); IR (CHCl3)
3690, 3605, 3450, 1090 cm-1; 1H NMR (300 MHz, CDCl3, 50 °C)
δ 7.30 (m, 5 H), 5.20 (s), 5.12 (m, 2 H), 5.10 (s), 4.88 (br s), 4.85
(br s), 4.55 (br d, J ) 13.5 Hz), 4.48 (br d, J ) 13.5 Hz), 4.39 (br
d, J ) 13.5 Hz), 4.40-4.14 (m), 4.08 (br d, J ) 10.5 Hz), 3.96 (br
d, J ) 10.5 Hz), 3.80 (m), 3.74 (br d, J ) 10.5 Hz), 3.66 (br d, J
) 10.5 Hz), 3.21-2.95 (m), 2.91 (br d, J ) 13.5 Hz), 2.39 (br d,
J ) 12.8 Hz), 1.96 (br s), 1.91 (br s), 1.88-1.48 (m); EIMS m/z
(relative intensity) 277 (17, M+), 259 (27), 186 (24), 142 (100).
Anal. Calcd for C15H19N1O4: C, 64.97; H, 6.91; N, 5.05. Found:
C, 65.15; H, 6.97; N, 4.91.
(3R,5S)- a n d (3S,5S)-Ben zyl 3-(F or m yl)-5-(a cet oxy-
m eth yl)-1-p ip er id in eca r boxyla te (9 a n d 10) (Mixtu r e of
Dia ster eom er s 2.3:1). To a magnetically stirred solution of
8b (>98% ee; 2.50 g, 7.80 mmol) in dry DMSO (20 mL) under
nitrogen was added triethylamine (2.40 g, 23.5 mmol) followed
by dropwise addition of a solution of sulfur trioxide-pyridine
complex (3.75 g, 23.5 mmol) in dry DMSO (16 mL). After 2 h,
the reaction was quenched by addition of saturated NaHCO3
(aqueous) and extracted with CH2Cl2. The combined organic
extracts were washed with water, dried, and concentrated. FC
(1:1 EtOAc/hexane) of the residue gave 1.80 g (72%) of an
inseparable mixture of cis- and trans-aldehydes 9 and 10 (2.3:1
(3S,5S)-Ben zyl 3-(Hydr oxym eth yl)-5-(2-m eth oxyeth en yl)-
1-p ip er id in eca r boxyla te (14) (m ixtu r e 2.5:1 of E a n d Z
isom er s). To a stirred mixture of 13 (400 mg, 1.44 mmol) and
Ph3P(CH2OMe)(Cl) (738 mg, 2.15 mmol) in anhydrous toluene
(15 mL) under N2 was added t-BuOK (242 mg, 2.15 mmol) in
four portions over a period of 1 h. After additional stirring
during 2 h at room temperature, the reaction mixture was
partitioned between 30 mL of EtOAc and 20 mL of water, and
the aqueous phase was extracted twice with EtOAc. The organic
fractions were dried and evaporated, and the residue was
purified by FC (7:3 EtOAc/hexane) to give 14 (390 mg, 88%) as
an inseparable mixture of E and Z isomers (2.5:1 ratio from 300
1
ratio from 300 MHz H NMR): oil; Rf (1:1 EtOAc/hexane) 0.43;
[R]365 ) +34.5 (c 1, CHCl3); IR (CHCl3) 1725, 1650 cm-1
;
1H
MHz H NMR): colorless oil; Rf (EtOAc) 0.44; [R]365 ) - 69.1 (c
1
NMR(300 MHz, CDCl3, 50 °C) δ 9.69 (br, s), 9.65 (br, s), 7.32
(m, 5 H), 5.14 (s), 5.17 and 5.11 (AB system, J ) 11.8 Hz), 4.47
(br d, J ) 12.2 Hz), 4.27 (br d, J ) 12.2 Hz), 4.20 (dd, J ) 13.0,
1, CHCl3); 1H NMR (300 MHz, CDCl3, 50 °C) δ 7.35 (m, 5 H),
6.35 (d, J ) 12.7 Hz), 5.87 (d, J ) 6.5 Hz), 5.13 (m, 2 H), 4.56
(dd, J ) 12.7, 7.5 Hz), 4.29 (br d, 1 H, J ) 12.1 Hz), 4.13 (m, 1