From amino acids to enantiopure bicyclic isoxazolidinylpyridin-4(1H)-ones through intramolecular nitrone cycloadditions

Article abstract of DOI:10.1002/ejoc.200400847

Homochiral bicyclic isoxazolidinylpyridin-4(1H)-ones have been synthesised by an intramolecular nitrone cycloaddition process, starting from homochiral β-amino acids. Stereoselection at C² or C³ of the acyclic substrate appears to give the best results in the control of the stereochemistry of the new formed chiral centres. The synthetic approach has been further directed towards functionalised piperidones. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400847

FULL PAPER
From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin-4(1H)-ones
through Intramolecular Nitrone Cycloadditions
Roberto Romeo,*[a] Daniela Iannazzo,[a] Anna Piperno,[a] Maria A. Chiacchio,[b] and
Antonino Corsaro,[b] and Antonio Rescifina
Keywords: Intramolecular 1,3-dipolar cycloadditions / Nitrones / δ-Lactams / Functionalised piperidones / PM3 semiem-
pirical calculations
Homochiral bicyclic isoxazolidinylpyridin-4(1H)-ones have
been synthesised by an intramolecular nitrone cycloaddition
process, starting from homochiral β-amino acids. Stereoselec-
tion at C2 or C3 of the acyclic substrate appears to give the
best results in the control of the stereochemistry of the new
formed chiral centres. The synthetic approach has been fur-
ther directed towards functionalised piperidones.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Intramolecular nitrone–alkene cycloadditions have re-
ceived a great deal of attention as a useful methodology
for the formation of the intriguing frameworks occurring in
natural products and biologically interesting com-
pounds.[1–8] The key feature of the approach is that suitable
elaboration of the primary cycloadducts has proved to be a
practical strategy for different heterocyclic ring systems:[9,10]
in particular, the nitrogen–oxygen bond can readily be
cleaved to yield variously functionalised amino alcohols. In
this context, the insertion of an amido group in the tether
connecting the nitrone moiety to the dipolarophilic double
bond has allowed a valuable route to functionalised me-
dium-sized lactams, and in this way functionalised γ- and
δ-lactams have been synthesised by starting from 5-hexenyl-
Scheme 1.
ing from 5, which exclusively affords compound 6 with si-
multaneous introduction of three stereocentres (Scheme 1).
In this paper we have extended the intramolecular
nitrone cycloaddition process to a series of intermediate N-
oxides 12 generated from compounds 11, each containing a
stereocenter outside the tether, on the amide nitrogen atom
or in the chain connecting the alkene and the dipole moie-
ties, in the α or β position with respect to the nitrone func-
tionality. Stereoselection at C2 or C3 of the acyclic substrate
appears to give the best results in the control of the stereo-
chemistry of the newly formed chiral centres.
Our interest in this reaction is further stimulated by the
potential for useful functionalisation of the fused system by
cleavage of the isoxazolidine ring and formation of substi-
tuted piperidones. As reported, δ-lactams have been evalu-
ated as good substrates for the development of new classes
of antiinfectives and other inhibitors of serine protease such
as elastases.[15] Elastases are current targets for medicinal
chemistry; δ-lactams act by acylating a serine hydroxy
group in the catalytic centre of a bacterial protease, with
the same reactivity as β-lactam antibiotics.[16]
(1)[11]
and
6-heptenylnitrones
(2),[12]
respectively
(Scheme 1). The reaction showed complete diastereoselec-
tivity, with fused hexahydro-4H-pyrrolo[3,4-c]isoxazol-4-
ones (3) and hexahydroisoxazolo[4,3-c]pyridin-4(1H)-ones
(4) being formed, each possessing a cis junction between
the isoxazolidine and the lactam rings.
The insertion of a chiral centre into the starting substrate
could cause asymmetric induction, giving rise to the forma-
tion of new chiral centres with definite configurations in
the cycloadducts.[13,14] In fact, a stereocentre located in the
position α to the nitrone functionality completely controls
the stereochemical outcome of the pericyclic process start-
[a] Dipartimento Farmaco-Chimico, Università di Messina,
Viale SS. Annunziata, 98168 Messina, Italy
Fax: +39-090-355613
E-mail: gromeo@unime.it
[b] Dipartimento di Scienze Chimiche, Università di Catania,
Viale Andrea Doria 6, 95125 Catania, Italy
Fax: +39-06-233208980
E-mail: arescifina@unict.it
2368
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400847
Eur. J. Org. Chem. 2005, 2368–2373

From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin-4(1H)-ones
FULL PAPER
Results and Discussion
The β-amino acid 7a, containing a chiral centre attached
to the nitrogen atom, was synthesised by standard pro-
cedures.[17] Compound 7a was then reduced to 3-[((1S)-1-
phenylethyl)amino]propan-1-ol (8a), and further treatment
with (E)-but-2-enoyl chloride gave (after selective hydrolysis
of the intermediate ester 9a with K2CO3 in aqueous meth-
anol) the corresponding amido alcohol 10a. Attempts to
introduce the but-2-enoyl group selectively at the nitrogen
atom resulted in lower yields. Swern-like oxidation of 10a
afforded the aldehyde 11a, which was transformed by treat-
ment with N-methylhydroxylamine into the corresponding
hexahydroisoxazolo[4,3-c]pyridin-4(1H)-ones 13a and 14a,
in a 1:1 relative ratio, via the not isolated nitrone 12a
(Scheme 2).
The obtained compounds were characterised by analyti-
cal and spectroscopic data. High-resolution mass spectra
showed the correct molecular ions, and the IR absorptions
of the carbonyl groups are at 1680–1670 cm–1, consistently
1
with δ-lactams. The H NMR spectrum of compound 13a
shows the H3 proton at δ = 4.01 as a doublet of quartets,
the H3a proton resonates as a doublet of doublets at δ =
2.86, while H7a gives rise to a doublet of doublets at δ =
3.40. The methylene protons at C7 appear as an indistinct
multiplet centred at δ = 1.60, while the H6 protons resonate
as multiplets at δ = 3.01 and 2.80. Furthermore, the 1H
NMR spectrum shows the methyl group at C3 as a doublet
at δ = 1.53.
Diagnostic resonances for the diastereoisomer 14a are
only slightly different from the above values, except for H3,
which resonates as a multiplet at δ = 4.30, and for H3a,
which resonates as a doublet of doublets at δ = 2.72.
The investigated 1,3-dipolar cycloaddition showed com-
plete regioselectivity: no bridged products were detected in
the crude reaction mixture. Moreover, the process was
found to be stereospecific, but lacking in any diastereofacial
selectivity. The stereochemical information present in the
dipolarophile moiety is completely retained in the obtained
cycloadducts and the relative stereochemistry at C3 and C3a
in the formed isoxazolidine ring is trans, as predetermined
by the alkene geometry. Furthermore, the ring junction be-
tween the isoxazolidine ring and the lactam five-membered
Scheme 2. a) LiAlH4, THF, 0 °C to reflux, 12 h; b) (E)-but-2-enoyl
chloride, Et3N, DCM, 0 °C, 1 h and then room temp., 6 h; c) 6%
aqueous K2CO3, MeOH, room temp., 3 h; d) bis(trichloromethyl)
carbonate, DCM, DMSO, Et3N, –78 °C to room temp. 1 h;
ring is always cis, as evidenced by NOE experiments. Irradi-
ation of the H3a resonance in compounds 13 and 14 thus
gives rise to strong positive NOE effects on H7a and the
methyl substituent at C3, indicating a cis topological rela- e) MeNHOH·HCl, Et3N, EtOH, reflux, 24 h.
tionship. Straightforwardly, the configurations of com-
pounds 13 and 14 are interchangeable.
The effects of the introduction of a stereocentre into the by NOE measurements: the positive NOE effects observed
β position with respect to the nitrone functionality were for H7a and methyl groups at C3 and C6 when H3a was
investigated, starting from (3S)-3-methyl-3-[((1S)-1-pheny- irradiated are clearly indicative of their cis relationship.
lethyl)amino]propan-1-ol (8b), prepared from amino acid
The cycloaddition process was found to proceed with
7b.[18] Treatment of the β-amido aldehyde 11b, prepared by complete stereochemical control, furnishing homochiral
the above procedure, with methylhydroxylamine gave rise to compound 13b from homochiral starting material. Thus, in
nitrone intermediate 12b, which spontaneously cyclised to this reaction, the stereocentre at the α position with respect
the bicyclic compound 13b as the only obtained cycload- to the amido group can effectively control the formation of
duct (Scheme 2). The stereochemistry of 13b was assigned the new contiguous stereocentres and one of the eight pos-
Eur. J. Org. Chem. 2005, 2368–2373
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R. Romeo et al.
FULL PAPER
sible stereoisomers is produced in a highly selective fashion.
Analogous results were obtained when the chiral centre
was located in the α position with respect to the nitrone
group. The intramolecular cycloaddition process starting
from (2S)-2-methyl-3-[((1S)-1-phenylethyl)amino]propan-1-
ol (8c)[19] exclusively afforded the cycloadduct 14c
(Scheme 2).
The stereochemical outcomes of the investigated intra-
molecular cycloaddition processes clearly indicate that the
presence of the chiral centre in the α or β position promotes
a total diastereofacial selectivity: the obtained enantiomer-
ically pure cycloadducts 13b and 14c each show a cis rela-
tionship for H3a, H7a and methyl groups at C3 and C6.
As a further confirmation, changes of the configurations
Figure 1. Transition state structures for compounds 13 and 14; in
at C2 and C3, as in compounds 11d and 11e, respectively the case of compounds d and e all stereocentres, except for the N-
auxiliary, must be inverted.
[derived from the (2R)- and (3R)-propan-1-ols 8d and 8e],
resulted exclusively in the compounds 13d and 14e
(Scheme 3).
Thus, only the values for the (E)-TSs are reported (Table 1)
together with the calculated 13:14 ratio, obtained in accord
with the Boltzmann equation.
Table 1. PM3 formation enthalpies for transition states (E)-13 and
(E)-14.
ΔHf (E)-13-TS
ΔHf (E)-14-TS Calculated 13:14 ratio
a
b
c
d
e
30.79[a]
26.32
30.47
27.05
30.06
30.67
30.61
25.17
29.09
25.18
45:55
99.93:0.07
0.01:99.99
96.84:3.16
0.03:99.97
[a] All values are in kcalmol–1.
The data reported in Table 1 are fully in agreement with
the experimental results.
The selective ring cleavage of the isoxazolidine nucleus
allows an easy synthetic route to homochiral functionalised
piperidones. Thus, compound 16 was obtained by treatment
of 13d with methyl trifluoromethanesulfonate, in dry CCl4
at 0 °C, followed by hydrogenolysis with 5% palladium on
CaCO3 in dry MeOH at 60 °C for 12 h (yields 90%)
(Scheme 4).
Scheme 3.
The observed results were also confirmed by semiempir-
ical calculations. From inspection of Dreiding models, two
different transition state conformers—in the E or in the Z
configurations—are possible. These should produce com-
pounds 13 if the alkene moiety attacks the Re face of the
nitrone or compounds 14 if the attack takes place from the
Si face (Figure 1).
Scheme 4. (a) Methyl triflate, CCl4, 0 °C, 2 h; (b) 5% Pd/CaCO3,
gaseous H2, MeOH, 60 °C, 12 h.
In order to achieve quantitative information, three-di-
mensional models of all the possible TSs were full geometri-
cally optimised by use of the PM3 semiempirical Hamilto-
Conclusions
In conclusion, the reported intramolecular nitrone cyclo-
nian as implemented in the Chem3D graphic interface to addition process, starting from β-amino acids, affords
MOPAC. In all cases the (E)-TSs proved to be more stable homochiral
bicyclic
isoxazolidinylpyridin-4(1H)-ones,
(3–6 kcalmol–1) than the corresponding (Z)-ones,[20] due to which could be usefully manipulated towards functionalised
the steric hindrance of the two methyl groups at C1 and C3. piperidones.
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin-4(1H)-ones
FULL PAPER
5.05 (q, J = 6.5 Hz, 1 H), 6.40 (d, J = 14.7 Hz, 1 H), 6.85 (dq, J =
6.2, 14.7 Hz, 1 H), 7.35 (m, 5 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 13.7, 16.9, 21.2, 35.0, 47.9, 50.7, 67.4, 128.4, 128.9,
It has been reported that medium-sized lactams are the
least susceptible lactams to hydrolysis,[21] so the synthesised
compounds could be valuable candidates as potential elas-
tase inhibitors through the formation of stable acyl–enzyme
complexes.
129.6, 130.8, 132.9, 133.0, 141.0, 141.5, 170.2 ppm. IR (KBr): ν =
˜
3600, 3200, 1680, 1565, 1420, 1425, 1370, 1060, 980, 700 cm–1
.
Anal. Calcd. for C16H23NO2: C 73.52, H 8.87, N 5.35; found C
73.60, H 8.90, N 5.30. Exact mass calculated for C16H23NO2:
261.3594; found 261.3589.
Experimental Section
(2E)-N-((1R)-3-Hydroxy-1-methylpropyl)-N-((1S)-1-phenylethyl)-
but-2-enamide (10d): 4.44 g, 85% yield; white oil. 1H NMR (CDCl3,
300 MHz): δ = 1.34 (d, J = 6.8 Hz, 3 H), 1.62 (d, J = 6.9 Hz, 3 H),
1.81 (d, J = 6.5 Hz, 3 H), 1.88 (m, 2 H), 3.25 (m, 2 H), 5.05 (q, J
= 6.9 Hz, 1 H), 5.25 (m, 1 H), 5.98 (d, J = 14.3 Hz, 1 H), 6.83 (dq,
J = 6.5, 14.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 18.2,
19.0, 19.9, 41.5, 60.0, 76.5, 78.1, 127.4, 128.1, 129.4, 129.8, 129.9,
General Remarks: All melting points are uncorrected. Elemental
analyses were carried out on a C. Erba 1106 elemental analyzer.
IR spectra were recorded on a Perkin–Elmer Paragon 500 FT-IR
1
Spectrometer in potassium bromide discs. H and 13C NMR spec-
tra were recorded on a Varian Unity Inova 300 instrument in deu-
terated DMSO. Chemical shifts are expressed in ppm from CDCl3
1
(δ =7.26 ppm for H and 77.0 ppm for 13C). Thin-layer chromato-
132.1, 140.1, 140.6, 170.7 ppm. IR (KBr): ν = 3600, 3200, 1680,
˜
1565, 1420, 1370, 1060, 980, 700 cm–1. C16H23NO2: C 73.52, H
8.87, N 5.35; found C 73.46, H 8.85, N 5.31. Exact mass calculated
for C16H23NO2: 261.3594; found 261.3589.
graphic separations were performed on Merck silica gel 60-F254
precoated aluminium plates. Preparative separations were carried
out by flash column chromatography with Merck silica gel (0.035–
0.070 mm, eluent CHCl3/MeOH, 95:5).
(2E)-N-((2R)-3-Hydroxy-2-methylpropyl)-N-((1S)-1-phenylethyl)-
but-2-enamide (10e): 4.55 g, 87% yield; white oil. 1H NMR (CDCl3,
300 MHz): mixture of rotamers, δ = 0.95 (d, J = 6.9 Hz, 3 H), 1.55
(d, J = 5.8 Hz, 3 H), 1.90 (d, J = 6.9 Hz, 3 H), 2.58 (m, 1 H), 3.17
(m, 1 H), 3.43 (m, 1 H), 3.63 (m, 1 H), 5.10 (q, J = 5.8 Hz, 1 H),
6.35 (d, J = 14.7 Hz, 1 H), 6.95 (dq, J = 6.9, 14.7 Hz, 1 H), 7.35
(m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 15.6, 19.3, 19.5,
36.7, 45.6, 56.0, 63.2, 122.0, 126.0, 126.2, 127.6, 128.8, 131.4, 141.3,
General Procedure for the Preparation of Compounds 10a–e: A solu-
tion of (E)-but-2-enoyl chloride (3.93 mL, 41 mmol) in dry CH2Cl2
(20 mL) was added dropwise at 0 °C to a stirred solution contain-
ing compounds 8a–e (20.0 mmol) and triethylamine (5.71 mL,
41 mmol). The reaction mixture was stirred at 0 °C for 1 h and then
at room temperature for 6 h. At the end of this time, the mixture
was extracted with dichloromethane, washed with 10% aqueous
NaHCO3, dried (Na2CO3) and evaporated under reduced pressure.
Aqueous K2CO3 (6%, 25 mL) was added to a solution of the crude
amido ester 9a–e in MeOH (50 mL). The mixture was left stirring
until TLC showed the disappearance of the starting material. After
removal of the solvent under reduced pressure, the residue was sub-
jected to silica gel flash chromatography (eluent MeOH/CHCl3,
5:95).
142.6, 169.2 ppm. IR (KBr): ν = 3600, 3200, 1685, 1570, 1420,
˜
1370, 1060, 980, 700 cm–1. Anal. Calcd. for C16H23NO2: C 73.52,
H 8.87, N 5.35; found C 73.50, H 8.84, N 5.31. Exact mass calcu-
lated for C16H23NO2: 261.3594; found 261.3590.
General Procedure for the Preparation of Aldehydes 11a–e: Anhy-
drous DMSO (1.7 mL, 24 mmol) was added at –78 °C to a stirred
solution of bis(trichloromethyl) carbonate (1.19 g, 4 mmol) in dry
dichloromethane (12 mL). The reaction mixture was stirred for
15 min and then a solution of 10a–e (4 mmol) in dichloromethane
(8 mL) was slowly added at the same temperature. After the mix-
ture had been stirred for 15 min, triethylamine (3.90 mL, 28 mmol)
in dichloromethane (16 mL) was added dropwise, the temperature
being maintained below –70 °C. After the addition, the resulting
suspension was stirred at –78 °C for 5 min and then the acetone/
dry ice bath was removed. The reaction mixture was stirred at room
temp. for 1 h and the solvent was removed under reduced pressure.
The obtained residue was extracted with dichloromethane, washed
with water, dried with sodium sulfate and flash chromatographed
on silica gel (eluent CHCl3/MeOH, 97:3).
(2E)-N-(3-Hydroxypropyl)-N-((1S)-1-phenylethyl)but-2-enamide
1
(10a): 4.20 g, 85% yield; white oil. H NMR (CHCl3, 300 MHz): δ
= 1.60 (d, J = 6.9 Hz, 3 H), 1.80 (d, J = 6.6 Hz, 3 H), 1.85 (m, 2
H), 3.32 (m, 2 H), 4.87 (m, 3 H), 6.09 (d, J = 15.0 Hz, 1 H), 6.40
(dq, J = 6.6, 15.0 Hz, 1 H), 7.17–7.30 (m, 5 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 19.0, 20.0, 30.5, 47.2, 60.1, 73.5, 127.4,
128.2, 129.5, 129.8, 130.0, 132.0, 140.3, 140.6, 171.8 ppm. IR
(KBr): ν = 3600, 3200, 1675, 1560, 1420, 1370, 1060, 980, 700 cm–1.
˜
C15H21NO2: C 72.84, H 8.56, N 5.66%; found C 72.61, H 5.34,
N 5.35%. Exact mass calculated for C15H21NO2: 247.3308; found
247.3302.
(2E)-N-((1S)-3-Hydroxy-1-methylpropyl)-N-((1S)-1-phenylethyl)-
but-2-enamide (10b): 4.60 g, 88% yield; white oil. 1H NMR (CDCl3,
300 MHz): δ = 1.15 (d, J = 6.4 Hz, 3 H), 1.65 (d, J = 6.5 Hz, 3 H),
1.70 (d, J = 6.4 Hz, 3 H), 1.95 (m, 2 H), 3.02 (br.s, 1 H), 3.55 (m,
2 H), 4.95 (q, J = 6.5 Hz, 1 H), 5.05 (d, J = 14.7 Hz, 1 H), 6.95
(m, 1 H), 6.85 (dq, J = 6.4, 14.7 Hz, 1 H), 7.35 (m, 5 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 18.3, 19.2, 19.5, 42.0, 61.2, 74.3, 78.4,
127.4, 128.9, 130.6, 130.8, 132.9, 133.0, 141.0, 141.6, 170.9. IR
(2E)-N-(3-Oxopropyl)-N-((1S)-1-phenylethyl)but-2-enamide (11a):
1
755 mg, 77% yield; yellow oil. H NMR (CDCl3, 300 MHz): δ =
1.64 (d, J = 6.4 Hz, 3 H) 1.93 (d, J = 6.6 Hz, 3 H), 2.98 (m, 2 H),
3.98 (m, 2 H), 5.35 (q, J = 6.4 Hz, 1 H), 6.40 (d, J = 14.5 Hz, 1
H), 6.45 (dq, J = 6.6, 14.5 Hz, 1 H), 7.35 (m, 5 H), 9.63 (s, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 17.3, 18.3, 36.6, 51.5,
55.8, 121.8, 126.9, 127.3, 128.0, 128.7, 139.5, 142.3, 168.0,
(KBr): ν = 3600, 3200, 1680, 1565, 1420, 1425, 1370, 1060, 980,
˜
195.1 ppm. IR (KBr): ν = 3060, 2980, 2960, 1735, 1665, 1600, 1400,
˜
700 cm–1. Anal. Calcd. for C16H23NO2: C 73.52, H 8.87, N 5.35;
found C 73.60, H 8.90, N 5.30. Exact mass calculated for
C16H23NO2: 261.3594; found 261.3589.
1200, 970, 760, 700, 680 cm–1. C15H19NO2: C 73.44, H 7.81, N
5.70; found C 73.35, H 7.76, N 5.74. Exact mass calculated for
C15H19NO2: 245.3214; found 245.3250.
(2E)-N-((2S)-3-Hydroxy-2-methylpropyl)-N-((1S)-1-phenylethyl)-
(2E)-N-((1S)-1-Methyl-3-oxopropyl)-N-((1S)-1-phenylethyl)but-2-en-
but-2-enamide (10c): 4.44 g, 85% yield; white oil, 1H NMR (CDCl3, amide (11b): 716 mg, 69 % yield; yellow oil. 1H NMR (CDCl3,
300 MHz): mixture of rotamers, δ = 0.95 (d, J = 6.3 Hz, 3 H), 1.60
(d, J = 6.5 Hz, 3 H), 1.90 (d, J = 6.2 Hz, 3 H), 2.01 (br.s, 1 H),
300 MHz): δ = 1.24 (d, J = 6.5 Hz, 3 H), 1.69 (d, J = 6.4 Hz, 3 H),
1.95 (d, J = 6.4 Hz, 3 H), 2.85 (ddd, J = 1.4, 7.5, 9.2 Hz, 1 H), 3.33
2.17 (m, 1 H), 2.92 (m, 1 H), 3.10 (m, 1 H), 3.49–3.56 (m, 2 H), (ddd, J = 1.4, 7.5, 9.1 Hz, 1 H), 5.07 (q, J = 6.4 Hz, 1 H), 5.10
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R. Romeo et al.
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(ddq, J = 6.5, 9.1, 9.2 Hz, 1 H), 6.40 (d, J = 15.1 Hz, 1 H), 6.95
(dq, J = 6.4, 15.1 Hz, 1 H), 7.40 (m, 5 H), 9.77 (t, J = 1.4 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 17.5, 17.7, 18.1, 40.5,
45.8, 62.1, 123.8, 127.8, 127.8, 128.0, 129.5, 132.4, 139.6, 142.0,
N 10.10. Exact mass calculated for C16H22N2O2: 274.3630; found
274.3624.
(3R,3aS,7aR)-1,3-Dimethyl-5-((1S)-1-phenylethyl)hexahydroisoxa-
zolo[4,3-c]pyridin-4(1H)-one (14a): 112 mg, 41% yield; white oil,
172.3, 200.0 ppm. IR (KBr): ν = 3060, 2980, 2960, 1735, 1645,
˜
1
[α]2D5 = –20.76 (c = 0.62; CHCl3). H NMR (CDCl3, 500 MHz): δ
1600, 1400, 1200, 970, 760, 700, 680 cm–1. C16H21NO2: C 74.09, H
8.16, N 5.40; found C 74.13, H 8.13, N 5.35. Exact mass calculated
for C16H21NO2: 259.3435; found 259.3433.
= 1.55 (d, J = 5.7 Hz, 3 H), 1.57 (d, J = 5.8 Hz, 3 H), 1.59 (m, 2
H, H7), 2.71 (s, 3 H, N–CH3), 2.72 (dd, J = 7.3, 12.4 Hz, 1 H, H3a),
2.82 (m, 1 H, H6), 3.12 (m, 1 H, H6), 3.41(dt, J = 6.2, 12.4 Hz, 1
(2E)-N-((2S)-2-Methyl-3-oxopropyl)-N-((1S)-1-phenylethyl)but-2-en- H, H7a), 4.30 (dq, J = 5.7, 7.3 Hz, 1 H, H3), 6.04 (q, J = 5.9 Hz, 1
amide (11c): 695 mg, 67 % yield; yellow oil. 1H NMR (CDCl3,
300 MHz): δ = 0.95 (d, J = 6.2 Hz, 3 H), 1.40 (d, J = 6.1 Hz, 3 H),
1.90 (d, J = 6.5 Hz, 3 H), 3.40 (m, 1 H), 3.97 (m, 2 H), 5.35 (q, J
= 10.0 Hz, 1 H), 6.40 (d, J = 13.5 Hz, 1 H), 6.95 (dq, J = 6.5,
13.5 Hz, 1 H), 7.40 (m, 5 H), 9.45 (d, J = 0.9 Hz, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 19.4, 19.8, 211, 40.0, 56.2, 57.1, 121.5,
H, H5Ј), 7.35 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 15.5,
16.4, 26.4, 27.9, 37.7, 44.5, 51.1, 67.0, 78.6, 128.3, 128.4, 129.6,
130.8, 136.8, 141.3, 169.9 ppm. IR (KBr): ν = 1671 cm–1
.
˜
C16H22N2O2: C 70.04, H 8.08, N 10.21; found C 70.01, H 8.20,
N 10.25. Exact mass calculated for C16H22N2O2: 274.3630; found
274.3620. The configurations of compounds 13a and 14a are inter-
123.9, 127.7, 127.9, 128.0, 129.5, 132.3, 139.5, 141.9, 167.5, changeable.
200.0 ppm. IR (KBr): ν = 3060, 2980, 2960,1735, 1685, 1600, 1400,
˜
(3S,3aR,6S,7aS)-1,3,6-Trimethyl-5-((1S)-1-phenylethyl)hexahydrois-
oxazolo[4,3-c]pyridin-4(1H)-one (13b): 236 mg, 82% yield; white oil,
1200, 970, 760, 700, 680 cm–1. C16H21NO2: C 74.09, H 8.16, N
5.40; found C 74.10, H 8.09, N 5.35. Exact mass calculated for
C16H21NO2: 259.3435; found 259.3432.
[α]2D5 = –54.96 (c = 0.74; CHCl3). H NMR (CDCl3, 500 MHz): δ
1
= 0.53 (d, J = 6.9 Hz, 3 H), 1.43 (d, J = 7.2 Hz, 3 H), 1.48 (d, J =
(2E)-N-((1R)-1-Methyl-3-oxopropyl)-N-((1S)-1-phenylethyl)but-2-en- 6.3 Hz, 3 H), 1.70 (m, 1 H, H7), 1.75 (ddd, J = 0.8, 7.2, 12.6 Hz, 1
amide (11d): 674 mg, 65 % yield; yellow oil. 1H NMR (CDCl3,
300 MHz): δ = 1.43 (d, J = 6.5 Hz, 3 H), 1.67 (d, J = 6.7 Hz, 3 H),
1.93 (d, J = 6.6 Hz, 3 H), 3.21 (m, 2 H), 5.02 (m, 1 H), 5.07 (q, J
= 6.7 Hz, 1 H), 5.10 (m, 1 H), 6.23 (d, J = 15.1 Hz, 1 H), 6.95 (dq,
H, H7), 2.59 (s, 3 H, N–CH3), 2.68 (dd, J = 7.8, 10.5 Hz, 1 H, H3a),
2.91 (ddd, J = 7.2, 7.5, 10.5 Hz, 1 H, H7a), 3.56 (m, 1 H, H6), 4.25
(dq, J = 7.2, 7.8 Hz, 1 H, H3), 5.94 (q, J = 6.3 Hz, 1 H, H5Ј), 7.35
(m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 15.6, 17.4, 19.6,
J = 6.6, 15.1 Hz, 1 H), 7.35 (m, 5 H), 9.25 (dd, J = 1.3, 1.2 Hz, 1 29.7, 47.2, 50.6, 53.4, 64.8, 76.2, 127.7, 128.2, 128.3, 128.4, 128.4,
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 17.7, 18.5, 19.9, 40.0,
140.1, 169.3 ppm. IR (KBr): ν = 1675 cm–1. C H N O : C 70.80,
˜
17 24 2 2
45.9, 66.0, 123.9, 127.7, 127.9, 128.0, 129.5, 132.3, 139.5, 141.9,
H 8.38, N 9.71; found C 80.74, H 8.35, N 9.46. Exact mass calcu-
lated for C17H24N2O2: 288.3847; found 288.3841.
167.5, 200.0 ppm. IR (KBr): ν = 3060, 2980, 2960, 1735, 1645,
˜
1600, 1400, 1200, 970, 760, 700, 680 cm–1. C16H21NO2: C 74.09, H
8.16, N 5.40; found C 74.10, H 8.14, N 5.33. Exact mass calculated
for C16H21NO2: 259.3435; found 259.3437.
(3S,3aR,7S,7aS)-1,3,7-Trimethyl-5-((1S)-1-phenylethyl)hexahydrois-
oxazolo[4,3-c]pyridin-4(1H)-one (14c): 225 mg, 78% yield; white oil.
[α]2D5 = –65.12 (c = 0.43; CHCl3). H NMR (CDCl3, 500 MHz): δ
1
(2E)-N-((2S)-2-Methyl-3-oxopropyl)-N-((1S)-1-phenylethyl)but-2-en- = 0.62 (d, J = 7.1 Hz, 3 H), 1.48 (d, J = 7.1 Hz, 3 H), 1.50 (d, J =
amide (11e): 622 mg, 60 % yield; yellow oil. 1H NMR (CDCl3,
300 MHz): δ = 0.97 (d, J = 6.8 Hz, 3 H), 1.62 (d, J = 6.1 Hz, 3 H),
1.82 (d, J = 6.5 Hz, 3 H), 3.20 (m, 1 H), 4.10 (m, 2 H), 5.15 (q, J
6.0 Hz, 3 H), 1.71 (dddq, J = 2.3, 3.3, 7.1, 7.5 Hz, 1 H, H7), 2.51
(dd, J = 2.3, 8.8 Hz, 1 H, H7a), 2.61 (dd, J = 3.4, 12.0 Hz, 1 H,
H6), 2.66 (s, 3 H, N–CH3), 2.86 (dd, J = 7.2, 8.8 Hz, 1 H, H3a),
= 6.1 Hz, 1 H), 6.22 (d, J = 13.5 Hz, 1 H), 6.95 (dq, 1 H, J = 6.5, 3.50 (dd, J = 3.3, 12.0 Hz, 1 H, H6), 3.96 (dq, J = 6.2, 7.2 Hz, 1
13.5 Hz), 7.20 (m, 5 H), 9.45 (d, J = 1.0 Hz, 1 H) ppm. 13C NMR H, H3), 6.10 (q, J = 7.0 Hz, 1 H, H5Ј), 7.32 (m, 5 H) ppm. 13C
(CDCl3, 75 MHz): δ = 19.3, 19.5, 19.6, 39.5, 55.8, 56.0, 122.0,
NMR (CDCl3, 75 MHz): δ = 15.3, 15.8, 19.3, 29.0, 42.1, 43.6, 49.7,
126.0, 127.6, 128.8, 131.4, 140.3, 142.6, 169.6, 193.9 ppm. IR
54.0, 72.2, 77.5, 127.2, 127.6, 127.8, 128.3, 128.5, 139.8, 168.4 ppm.
(KBr): ν = 3060, 2980, 2965, 1735, 1680, 1600, 1400, 1200, 970, IR (KBr): ν = 1674 cm–1. C H N O : C 70.80, H 8.38, N 9.71;
˜
˜
17 24
2
2
760, 700, 680 cm–1. C16H21NO2: C 74.09, H 8.16, N 5.40; found C
found C 70.77, H 8.40, N 9.75. Exact mass calculated for
74.14, H 8.13; N,.5.43. Exact mass calculated for C16H2O2: C17H24N2O2: 288.3847; found 288.3845.
259.3435; found 259.3428.
(3R,3aS,6R,7aR)-1,3,6-Trimethyl-5-((1S)-1-phenylethyl)hexahydro-
General Procedure for the Preparation of 13a, 13b, 13d, 14a and 14e: isoxazolo[4,3-c]pyridin-4(1H)-one (13d): 233 mg, 81% yield; white
A mixture containing the aldehyde 11a–e (1.0 mmol), triethylamine
(1,5 mL, 1.1 mmol) and methylhydroxylamine hydrochloride
(92 mg, 1.1 mmol) in absolute ethanol (20 mL), was heated at re-
flux for 24 h. At the end of this time the solvent was evaporated
under reduced pressure and the residue was subjected to silica flash
chromatography (eluent MeOH/CHCl3, 2:8).
oil, [α]2D5 = –15.11 (c = 1.50; CHCl3). 1H NMR (CDCl3, 500 MHz):
δ = 1.27 (d, J = 6.5 Hz, 3 H), 1.53 (d, J = 6.3 Hz, 3 H), 1.58 (d, J
= 6.6 Hz, 3 H), 2.70 (m, 2 H, H7), 2.63(s, 3 H, N–CH3), 2.83 (dd,
J = 7.5, 9.9 Hz, 1 H, H3a), 3.02 (ddd, J = 7.8, 7.5, 9.9 Hz, 1 H,
H7a), 3.40 (ddq, J = 5.9, 6.5, 6.8 Hz, 1 H, H6), 3.98 (dq, J = 6.3,
7.5 Hz, 1 H, H3), 6.06 (q, J = 6.6 Hz, 1 H, H5Ј), 7.32 (m, 5 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 17.5, 19.8, 19.9, 21.5, 33.0, 47,3,
49.8, 52.9, 64.8, 76.8, 127.3, 127.9, 128.0, 129.4, 140.0, 169.8 ppm.
(3S,3aR,7aS)-1,3-Dimethyl-5-((1S)-1-phenylethyl)hexahydroisox-
azolo[4,3-c]pyridin-4(1H)-one (13a): 112 mg, 41% yield; white oil,
IR (KBr): ν = 1675 cm–1. C H N O : C 70.80, H 8.38, N 9.71;
˜
1
[α]2D5 = –30.26 (c = 0.53; CHCl3). H NMR (CDCl3, 500 MHz): δ
17 24
2
2
found C 70.75, H 8.57, N 9.75. Exact mass calculated for
C17H24N2O2: 288.3845; found 288.3860.
= 1.53 (d, J = 5.7 Hz, 3 H), 1.55 (d, J = 5.9 Hz, 3 H), 1.60 (m, 2
H, H7), 2.68 (s, 3 H, N–CH3), 2.80 (m, 1 H, H6), 2.86 (dd, J = 7.5,
12.6 Hz, 1 H, H3a), 3.01 (m, 1 H, H6), 3.40 (dt, J = 6.1, 12.6 Hz, 1
H, H7a), 4.01 (dq, J = 5.7, 7.5 Hz, 1 H, H3), 6.06 (q, J = 5.9 Hz, 1
H, H5Ј), 7.35 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 15.7,
16.6, 20.1, 27.0, 38.7, 44.3, 56.6, 67.1, 79.0, 128.3, 128.7, 129.5,
(3R,3aS,7R,7aR)-1,3,7-Trimethyl-5-((1S)-1-phenylethyl)hexahydro-
isoxazolo[4,3-c]pyridin-4(1H)-one (14e): 231 mg, 80% yield; white
oil, [α]2D5 = –79.11 (c = 3.16; CHCl3). 1H NMR (CDCl3, 500 MHz):
δ = 1.01 (d, J = 7.0 Hz, 3 H), 1.48 (d, J = 7.0 Hz, 3 H), 1.51 (d, J
= 5.9 Hz, 3 H), 1.75 (dddq, J = 2.9, 3.3, 4.3, 7.0 Hz, 1 H, H7), 2.58
(ddd, J = 1.1, 2.9, 9.3 Hz, 1 H, H7a), 2.66 (s, 3 H, N–CH3), 2.70
129.6, 130.8, 142.9, 169.8 ppm. IR (KBr): ν = 1672 cm–1
.
˜
C16H22N2O2: C 70.04, H 8.08, N 10.21; found C 70.14, H 8.15,
2372
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2368–2373

From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin-4(1H)-ones
FULL PAPER
(ddd, J = 1.1, 4.3, 12.8 Hz, 1 H, H6), 2.89 (dd, J = 7.9, 9.3 Hz, 1
H, H3a), 3.12 (dd, J = 3.3, 12.8 Hz, 1 H, H6), 3.98 (dq, J = 5.9,
7.9 Hz, 1 H, H3), 6.05 (q, J = 7.0 Hz, 1 H, H5Ј), 7.52 (m, 5 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 15.0, 16.3, 19.2, 29.7, 43.7, 43.8,
49.6, 54.1, 72.4, 77.6, 127.2, 127.3, 128.5, 128.8, 130.8, 139.9,
Mulzer, E. Schaumann), George Thieme, Stuttgart, New York,
1995, vol. E21c, chapter 1.6.1.2.
U. Chiacchio, A. Corsaro, V. Pistarà, A. Rescifina, G. Romeo,
R. Romeo, Tetrahedron 1996, 52, 7875–7884.
U. Chiacchio, A. Corsaro, V. Librando, A. Rescifina, R. Ro-
meo, G. Romeo, Tetrahedron 1996, 52, 14323–14334.
U. Chiacchio, A. Corsaro, A. Rescifina, M. Bkaithan, G.
Grassi, A. Piperno, G. Romeo, T. Privitera, Tethrahedron 2001,
57, 3425–3433.
U. Chiacchio, A. Corsaro, D. Iannazzo, A. Piperno, A. Proco-
pio, A. Rescifina, G. Romeo, R. Romeo, J. Org. Chem. 2002,
67, 4380–4383.
U. Chiacchio, A. Corsaro, G. Gambera, A. Rescifina, A. Pip-
erno, R. Romeo, G. Romeo, Tetrahedron: Asymmetry 2002, 13,
1915–1921.
P. Merino, in Science of Synthesis. Houben–Weyl Methods of
Molecular Transformations (Ed.: D. Bellus, A. Padwa), George
Thieme, Stuttgart, New York, 2004, vol. 27, chapter 13,
pp. 511–580.
A. Hassner, in Heterocycles in Bio-Organic Chemistry (Ed.: J.
Pergamon), Royal Soc. of Chem., Cambridge, 1991.
U. Chiacchio, A. Rescifina, G. Romeo, in Targets in Heterocy-
clic Systems. Chemistry and Properties (Eds.: O. A. Attanasi,
D. Spinelli), Italian Society of Chemistry: Italy, 1997, vol. 1,
pp. 225–276.
U. Chiacchio, G. Buemi, F. Casuscelli, A. Procopio, A. Rescif-
ina, R. Romeo, Tetrahedron 1994, 50, 5503–5514.
U. Chiacchio, A. Rescifina, F. Casuscelli, A. Piperno, V. Pisani,
R. Romeo, Tetrahedron 1996, 52, 14311–14322.
[3]
[4]
[5]
168.4 ppm. IR (KBr): ν = 1678 cm–1. C H N O : C 70.80, H 8.37,
˜
17 24
2
2
N 9.75; found C 70.84, H 8.44, N 9.68. Exact mass calculated for
C17H24N2O2: 288.3845; found 288.3852.
Preparation of Piperidone 16[22]
[6]
[7]
[8]
(3R,3aS,6R,7aR)-1,1,3,6-Tetramethyl-4-oxo-5-((1S)-1-phenylethyl)-
octahydroisoxazolo[4,3-c]pyridin-1-ium Trifluoromethanesulfonate
(15): This was prepared from compound 13d (0.5 mmol): 226 mg,
1
100% yield; sticky oil. H NMR (CDCl3/CD3OD, 300 MHz): δ =
1.45 (d, J = 6.8 Hz, 3 H), 1.65 (d, J = 7.4 Hz, 3 H), 1.75 (d, J =
5.1 Hz, 3 H), 2.47 (m, 2 H), 2.58 (m, 1 H), 3.35 (s, 3 H, N–CH3),
3.65 (m, 2 H), 3.72 (s, 3 H, N–CH3), 4.83 (dq, J = 5.1, 7.3 Hz, 1
H, H3), 5.15 (m, 1 H, H7a), 5.95 (q, J = 7.4 Hz, 1 H, H5Ј), 7.52 (m,
5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 16.9, 17.0, 20.0, 20.1,
20.6, 29.5, 50.6, 52.0, 73.7, 82.8, 121.31 (q, J = 311.2 Hz), 127.0,
127.2, 128.3, 129.0, 139.3, 168.3 ppm.
[9]
[10]
(3S,4R,6R)-4-(Dimethylamino)-3-((1R)-1-hydroxyethyl)-6-methyl-1-
((1S)-1-phenylethyl)piperidin-2-one (16): 137 mg, 90% yield; colour-
less oil, [α]2D5 = –48.79 (c = 1.10; CHCl3). 1H NMR (CDCl3/
CD3OD, 300 MHz): δ = 1.35 (d, J = 6.9 Hz, 3 H), 1.51 (d, J =
5.7 Hz, 3 H), 1.59 (d, J = 7.1 Hz, 3 H), 1.61 (dddd, J = 6.8, 7.5,
14.1 Hz, 1 H, H5a), 2.05 (ddd, J = 7.1, 8.3, 14.1 Hz, 1 H, H5b), 2.63
(s, 6 H, N–CH3), 3.93 (dd, J = 6.3, 7.5 Hz, 1 H, H3), 3.75 (ddd, J
= 6.9, 7.1, 7.5 Hz, 1 H, H6), 4.21 (ddd, J = 6.3, 6.8, 8.3 Hz,1 H,
H4), 4.35 (dq, 1 H, J = 5.7, 7.5 Hz, H3Ј), 5.85 (q, 1 H, J = 7.1 Hz,
H1Ј), 7.32 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.5,
20.8, 21.7, 38.9, 39.3, 42.9, 47.6, 51.8, 52.9, 62.0, 128.2, 128.2,
[11]
[12]
[13] U. Chiacchio, F. Casuscelli, A. Corsaro, V. Librando, A. Resci-
fina, G. Romeo, Tetrahedron 1995, 51, 5689–5700.
[14] U. Chiacchio, A. Corsaro, A. Piperno, A. Rescifina, G. Romeo,
R. Romeo, Heterocycles 1999, 51, 37–49.
[15] J. Seibel, D. Brown, A. Amour, S. J. F. Macdonald, N. J. Old-
ham, C. J. Schofield, Bioorg. Med. Chem. Lett. 2003, 13, 387–
389.
128.30, 128.31, 126.5, 137.0, 175.9 ppm. IR (KBr): ν = 1670 cm–1.
˜
[16] N. O. Sykes, S. J. F. Macdonald, M. I. Page, J. Med. Chem.
2002, 45, 2850–2856.
[17] K. Pankiewiz, R. Kinas, W. J. Stec, A. B. Foster, M. Jarman,
J. M. S. Van Maanen, J. Am. Chem. Soc. 1979, 101, 7712–7718.
[18] R. Kinas, K. Pankiewicz, W. J. Stec, J. Org. Chem. 1977, 42,
1650–1652.
C18H28N2O2: C 71.02, H 9.27, N 9.20; found C 70.83, H 9.25, N
9.21. Exact mass calculated for C18H28N2O2: 304.2151; found
304.2152.
Acknowledgments
[19] G. V. Shustov, A. Rauk, Tetrahedron: Asymmetry 1996, 7, 699–
708.
This work was supported by the M.I.U.R. (project P.R.I.N. 2002
and F.I.R.B.).
[20] This direct comparison is permitted because all nitrones ap-
pear, from PM3 calculations, as nearly equimolar mixtures of
(E) and (Z) isomers.
[1] R. Annunziata, N. Cinquini, F. Cozzi, L. Raimondi, Gazz.
Chim. Ital. 1989, 119, 253–269.
[2] N. Cinquini, F. Cozzi, in Methods in Organic Chemistry: Ster-
eoselective Synthesis (Eds.: G. Helmchen, R. W. Hoffman, J.
[21] P. Imming, B. Klar, D. Dix, J. Med. Chem. 2000, 43, 4328–
4331.
[22] For general procedures see ref.[14]
Received: November 29, 2004
Eur. J. Org. Chem. 2005, 2368–2373
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2373