Stephens and Liu
was immediately immersed in an oil bath preheated to 80 °C, and
DIEA (2 equiv) was added to the mixture. After 3 h of vigorous
stirring, heating was ceased, and once cooled to room temperature,
the mixture was filtered. The residue was extracted with CHCl3
and saturated aqueous NaHCO3. After phase separation of the
combined filtrates, the aqueous layer was further extracted with
CHCl3 (2 ×), and the combined organic layers were dried over
MgSO4, filtered, and evaporated under reduced pressure. The crude
isoxazolidine obtained was purified by flash column chromatog-
raphy (SiO2, 20-70% EtOAc in petroleum ether, 10% increments).
rac-(5R,6R)-Ethyl 7-Oxa-1-azabicyclo[3.2.1]octane-6-carboxy-
late (trans-3a). Obtained as a yellow oil (664 mg, 90%): IR (CHCl3)
The reversibility of the cycloaddition was found to be general
for aliphatic and aromatic nitrones, with those derived from
cyclohexanecarboxaldehyde (entries 8 and 9) and pyridine-3-
carboxaldehyde (entries 10 and 11) forming the corresponding
azepane-isoxazolidines in good isolated yields within 40 h at
180 °C. Relatively hindered isoxazolidines such as the ortho-
CF3 substituted 18j, which gave a high piperidine-azepane ratio
of 86:14 at 110 °C in toluene, required longer periods at 180
°C for isomerization (entry 12-15). In this case, the low isolated
yield appeared to result from decomposition of the nitrone at
180 °C when initially heated with base, as a dark, insoluble
residue was formed on the K2CO3 and MS3Å. When the
piperidine- and azepane-isoxazolidine cycloadducts 18j and
19j recovered after filtration were subsequently heated at 180
°C with MS3Å in the absence of base, no further decomposition
was observed.
1
νmax (cm-1) 2951, 2869, 1741, 1458, 1374, 1294, 1109, 920; H
NMR (400 MHz, CDCl3) δ 4.58 (s, 1H), 4.19 (m, 2H), 3.33 (dd,
J ) 14.2, 6.0 Hz, 1H), 3.26 (br. dt, J ) 11.3, 2.9 Hz, 1H), 2.97 (d,
J ) 11.4 Hz, 1H), 2.82 (br s, 1H), 2.76 (ddd, J ) 14.1, 12.0, 5.3
Hz, 1H), 1.93 (m, 1H), 1.85-1.68 (m, 2H), 1.55 (dt, J ) 14.0, 5.4
Hz, 1H), 1.27 (t, J ) 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
171.4, 81.4, 61.2, 59.1, 55.8, 43.2, 27.9, 19.2, 14.1; HRMS (ESI)
m/z calcd for C9H16NO3 [M + H]+ 186.1130, found 186.1127.
General Procedure for the Preparation of cis-Isoxazo-
lidines (Tables 2 and 3). TFA (70 equiv) was added to a mixture
of cis-6 (1 equiv) and aldehyde (2 equiv) at room temperature. After
15-45 min of stirring (15 min for (CH2O)n, 45 min for other
aldehydes), excess TFA was removed in vacuo (35 °C, 10 Torr),
and the residue was further dried under high vacuum (rt, 5 × 10-3
Torr). After 30 min, the crude nitrone was put under an atmosphere
of dry argon and dissolved in anhydrous solvent for cycloaddition
(20 mL mmol-1). The solution was immediately mixed with MS3Å
(3.1 g mmol-1) and K2CO3 (30 equiv) and subjected to the specified
reaction conditions (Tables 2 and 3). Once cooled to room
N-O Bond Reduction. With a regio- and diastereoselective
route to the piperidine-isoxazolidines developed, the final step,
N-O bond reduction, was investigated. When the ethyl ester
isoxazolidines trans-3a and cis-3a were reduced as their free
bases using Pd/C and hydrogen gas in t-BuOH-H2O,28 methanol,
or ethanol, reproducible results could not be obtained, with
varying amounts of decomposition observed (data not shown).
In contrast, the benzyl ester isoxazolidines trans-3b and cis-
3b, which form zwitterionic γ-amino acids, with the nitrogen
center protonated, on reduction, were reproducibly obtained in
excellent yield (Table 5, entries 2 and 3). On the assumption
that the basicity of the ethyl ester piperidines might be causing
their decomposition, trans-3a and cis-3a were reduced as their
HCl salts. This procedure was reproducible and gave 20a and
21a in 97% and 86% yield, respectively (entries 1 and 4).
These conditions were used for reduction of the disubstituted
piperidine-isoxazolidines 18a-j (entries 5-14) and gave the
corresponding piperidines in generally excellent yields. The
p-bromoisoxazolidine 18f underwent debromination as well as
temperature, the mixture was diluted with CH2Cl2 (50 mL mmol-1
)
and filtered. The residue was washed with CH2Cl2, and the
combined filtrates were evaporated under reduced pressure to afford
crude isoxazolidine, which was further purified according to the
methods specified below.
rac-(5R,6S)-Ethyl 7-Oxa-1-azabicyclo[3.2.1]octane-6-carboxy-
late (cis-3a). Purified by flash column chromatography (SiO2,
20-50% EtOAc in petroleum ether, 10% increments) and obtained
as a yellow oil (106 mg, 69%): IR (CHCl3/NaCl) νmax (cm-1) 2976,
1
N-O bond cleavage to form 22b in quantitative yield by H
NMR spectroscopy. In this case, selectivity was achieved by
using Zn in HCl (10%) instead, allowing the formation of 22f
in 98% yield (entry 10). The 3-pyridinylisoxazolidine 18d was
unstable as its HCl salt in the presence of Pd or Zn, with
decomposition observed by TLC. However, Zn in acetic acid
proved sufficiently mild, giving 22d in 88% yield (entry 8).
In conclusion, a novel route for the diastereoselective
synthesis of diversely substituted piperidines is presented. This
sequence offers an efficient and rapid entry from readily
available synthons using a new regio- and diastereoselective
intramolecular nitrone cycloaddition with suppression of the
competing Michael addition.
1
2873, 1744, 1458, 1373, 1284, 1116, 902; H NMR (400 MHz,
CDCl3) δ 4.59 (d, J ) 4.8 Hz, 1H), 4.30 (m, 2H), 3.46 (dd, J )
14.3, 6.7 Hz, 1H), 3.38 (m, 1H), 3.18 (d, J ) 11.3 Hz, 1H), 2.89-
2.79 (m, 2H), 2.13 (m, 1H), 1.87-1.69 (m, 2H), 1.42 (m, 1H), 1.32
(t, J ) 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.6, 81.9,
61.4, 61.1, 56.2, 41.0, 25.1, 18.3, 14.3; MS (ESI) m/z 186 [M +
H]+; HRMS (ESI) m/z calcd for C9H16NO3 [M + H]+ 186.1130,
found 186.1129.
rac-(5S,6R,8S)-Ethyl8-Cyclohexyl-7-oxa-1-azabicyclo[3.2.1]octane-
6-carboxylate (18a). Purified by flash column chromatography
(SiO2, 10-25% EtOAc in petroleum ether, 5% increments) and
obtained as a colorless solid (33.6 mg, 85%): IR (CH2Cl2/NaCl)
1
Vmax (cm-1) 2929, 2854, 1747, 1450, 1373, 1278, 1207, 1038; H
NMR (400 MHz, CDCl3) δ 4.51 (d, J ) 4.9 Hz, 1H), 4.26 (m,
2H), 3.52 (dd, J ) 14.1, 6.8 Hz, 1H), 2.87-2.78 (m, 2H), 2.60 (d,
J ) 10.0 Hz, 1H), 2.18 (m, 1H), 2.06 (m, 1H), 1.86 (m, 1H), 1.78-
1.58 (m, 5H), 1.40-1.06 (m, 8H), 0.94-0.77 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 170.2, 80.4, 77.6, 61.0, 57.1, 41.6, 37.7, 30.8,
29.4, 26.9, 26.4, 26.0, 25.7, 17.9, 14.2; HRMS (MALDI-TOF) m/z
calcd for C15H26NO3 [M + H]+ 268.1913, found 268.1930.
General Procedure for Reversibility Studies (Table 4). The
nitrone-TFA salt, prepared as described above, was put under an
atmosphere of dry argon and dissolved in anhydrous 1,2-dichlo-
robenzene (20 mL mmol-1). The solution was immediately mixed
with MS3Å (3.1 g mmol-1) and K2CO3 (30 equiv) and heated at
180 °C for 15 min. Once cooled to room temperature, the mixture
was filtered and the residue extracted with CH2Cl2. The combined
filtrates were concentrated in vacuo (50 °C, 10 Torr), and 1,2-
dichlorobenzene was removed by Kugelrohr distillation (50 °C, 0.1
Experimental Section
General Procedure for the Preparation of trans-Isoxazo-
lidines (Table 1). TFA (70 equiv) was added to the Boc-protected
hydroxylamine (1 equiv) at 0 °C. The solution was stirred at room
temperature for 30 min. Most TFA was then removed in vacuo
(35 °C, 10 Torr), and the resulting oil was further dried under high
vacuum (rt, 5 × 10-3 Torr). After 30 min, the oil was brought to
atmospheric pressure and, under an atmosphere of dry argon, mixed
with MS3Å powder (1.1 g mmol-1) and (CH2O)n (2 equiv) and
then suspended in toluene (20 mL mmol-1). The reaction vessel
(28) This solvent system was previously used in N-O bond reduction during
the synthesis of hydroxylated aminocycloheptanes: Shing, T. K. M.; Wong, W. F.;
Ikeno, T.; Yamada, T Org. Lett. 2007, 9, 207–209.
262 J. Org. Chem. Vol. 74, No. 1, 2009