Stereoselective amination of 5-substituted γ-lactones and γ-lactams - A convenient route for the preparation of 5-substituted (3S,5S)-3- acetylaminotetrahydrofuran-2-ones and (3S,5S)-3-acetylaminopyrrolidin-2-ones

Article abstract of DOI:10.1002/(SICI)1099-0690(199907)1999:7<1581::AID-EJOC1581>3.0.CO;2-2

5-Substituted (S)-tetrahydrofuran-2-ones (1a,b) and (S)pyrrolidin-2- ones (1c,d) were transformed in three steps, by treatment with tert- butoxybis(dimethylamino)methane (Bredereck's reagent), followed by nitrosation and stereoselective catalytic hydrogenation, into the corresponding 5-substituted (3S,5S)-3-acetylaminotetrahydrofuran-2-ones (4a,b) and (3S,5S)-3-acetylaminopyrrolidin-2-ones (4c,d).

Full text of DOI:10.1002/(SICI)1099-0690(199907)1999:7<1581::AID-EJOC1581>3.0.CO;2-2

FULL PAPER
Stereoselective Amination of 5-Substituted γ-Lactones and γ-Lactams –
A Convenient Route for the Preparation of 5-Substituted
(3S,5S)-3-Acetylaminotetrahydrofuran-2-ones and
(3S,5S)-3-Acetylaminopyrrolidin-2-ones
[a]
[a]
[a]
[b]
ˇ
ˇ
ˇ
Marko Skof, Jurij Svete,* Matej Kmetic, Simona Golic-Grdadolnik,
and Branko Stanovnik*[a]
Keywords: Tetrahydrofuran-2-ones / Pyrrolidin-2-ones / Aminations / Nitrosations / Asymmetric synthesis
5-Substituted (S)-tetrahydrofuran-2-ones (1a,b) and (S)-
catalytic hydrogenation, into the corresponding 5-substituted
pyrrolidin-2-ones (1c,d) were transformed in three steps, by (3S,5S)-3-acetylaminotetrahydrofuran-2-ones (4a,b) and
treatment with tert-butoxybis(dimethylamino)methane (Bre- (3S,5S)-3-acetylaminopyrrolidin-2-ones (4c,d).
dereck’s reagent), followed by nitrosation and stereoselective
Nitrosation of “active” methylene groups followed by re- as a useful synthetic tool in the synthesis of various biologi-
duction of the resulting oxime is one of the most common cally active compounds.[10]
methods for amination at the position adjacent to an elec-
tron-withdrawing group.[1] The advantage of this meth-
odology is the use of cheap reagents and mild reaction con-
ditions. The scope of this method, however, is usually lim-
ited to methylene groups bearing a strong electron-with-
drawing substituent, e.g. nitroalkanes, ketones, 1,3-
dicarbonyl compounds, and their analogs. Nitrosation of
aliphatic carboxylic acid derivatives, such as lactones and
lactams, is therefore hard to achieve. On the other hand,
such compounds are sufficiently nucleophilic to react with
tert-butoxybis(dimethylamino)methane (BredereckЈs re-
agent) to give the corresponding α-dimethylaminometh-
ylene-substituted compounds.[2Ϫ5] 2-Substituted 3-dimeth-
ylaminopropenoates and their analogs react with various
mono- and dinucleophiles and hence represent a useful syn-
thetic tool for the preparation of a variety of heterocyclic
systems.[6][7] 2-Substituted 3-dimethylaminopropenoates
also react with electrophiles and, in this context, we have
previously shown that nitrosation of α-dimethylaminometh-
ylene-substituted carbonyl compounds leads to the forma-
tion of oximes and 1,2,4-oxadiazoles.[8][9] As a continuation
of our work in this field, we report on the stereoselective
amination of lactones 1a,b and lactams 1c,d. In this man-
ner, 5-substituted (3S,5S)-3-acetylaminotetrahydrofuran-2-
ones 4a,b and (3S,5S)-3-acetylaminopyrrolidin-2-ones 4c,d
were prepared in 3 steps from easily accessible precursors.
Since α-amino-γ-hydroxy and α,γ-diamino acid structural
elements are both widely found in nature, a convenient ster-
eoselective α-amination of lactones and lactams can serve
Starting from (S)-2-oxotetrahydrofuran-5-carboxylic
acid, (S)-5-hydroxymethyltetrahydrofuran-2-one, and (S)-5-
methoxycarbonylpyrrolidin-2-one,[6] suitably protected lac-
tones 1a,b and lactams 1c,d were prepared according to the
procedures described in the literature.[11Ϫ13] Reactions of
1aϪd with tert-butoxybis(dimethylamino)methane (Bre-
dereckЈs reagent) gave 3-dimethylaminomethylene deriva-
tives 2aϪd, which, after treatment with nitrous acid, af-
forded the corresponding oximes 3aϪd. Finally, catalytic
hydrogenation of 3aϪd in the presence of acetic anhydride
furnished 5-substituted (3S,5S)-3-acetylaminotetrahydrofu-
ran-2-ones 4a,b, (3S,5S)-3-acetylaminopyrrolidin-2-ones
4c,d and their (3R,5S) epimers 5aϪd. Isomerically pure
compounds 4aϪd were prepared either by crystallisation of
crude isomeric mixtures (4aϪc), or by chromatographic
purification (4d). NMR spectra and elemental analyses for
compounds 4aϪd are in agreement with the proposed struc-
tures (Scheme 1).
The stereoselectivity of the catalytic hydrogenation of
oximes 3aϪd was generally high and was influenced by the
substituent at position 5, as well as by the N-acyl group in
the case of lactams 3c,d. Hydrogenation of lactones 3a,b
and N-Boc-protected lactam 3d proceeded with 82Ϫ86%
d.e., thus indicating that the stereodirecting effect of the
substituent at position 5 may not be particularly dependent
on its bulkiness. On the other hand, when the stereoselectiv-
ities obtained in the hydrogenation of lactams 3c,d are com-
pared, it could be presumed that the choice of N-acyl group
plays an important role, since d.e. values were significantly
lower in the hydrogenation of N-benzoyl lactam 4c with re-
spect to N-Boc-lactam 4d (Scheme 2).
[a]
Faculty of Chemistry and Chemical Technology, University of
Ljubljana,
The configurations of (3S,5S)-3-acetylamino-5-meth-
oxycarbonyltetrahydrofuran-2-one (4a) and (3S,5S)-3-
acetylamino-1-benzoyl-5-methoxycarbonylpyrrolidin-2-one
(4c) were confirmed by NMR (NOE) experiments. A strong
NOE effect was observed between 4-Hb and 3-H or 5-H, as
ˇ
Askerceva 5, 1000 Ljubljana, Slovenia
Fax: (internat.) ϩ 386-61/125-8220
E-mail: branko.stanovnik@uni-lj.si
jurij.svete@uni-lj.si
National Institute of Chemistry,
Hajdrihova 19, 1000 Ljubljana, Slovenia
[b]
Eur. J. Org. Chem. 1999, 1581Ϫ1584
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0707Ϫ1581 $ 17.50ϩ.50/0
1581

ˇ
M. Skof, J. Svete, M. Kmetic, S. Golic-Grdadolnik, B. Stanovnik
FULL PAPER
Compounds
1؊4
R
X
Yield
2
3
4
a
b
c
CO2Me
O
58 78 58
43 81 56
74 79 45
87 79 44
Scheme 3. Determination of the configurations of compounds 4a
and 4c by NMR (NOE) experiments
PhCO2CH2
CO2Me
O
NϪCOPh
NϪBoc
d
CO2Me
group in the lactone and lactam moiety by 3-dimethyl-
aminomethylene-substituted lactones and lactams as chiral
3-dimethylaminopropenoate analogs.
Scheme 1. Reagents and conditions: i: tert-butoxybis(dimethylami-
no)methane (BredereckЈs reagent), toluene, 90Ϫ100°C, 2 h; ii: HCl,
NaNO2, H2O, 0°C, 2 h; iii: H2, Pd/C, AcOH/Ac2O, 20Ϫ60°C, 1
bar, 10 h; iv: crystallisation (4a؊c) or chromatographic separation
(4d)
Experimental Section
General Remarks: Melting points were determined with a Kofler
1
micro hot stage. Ϫ The H-NMR spectra, 13C-NMR spectra, and
NOE measurements were obtained with a Bruker Avance DPX 300
(300 MHz) spectrometer with [D6]DMSO and CDCl3 as solvents
and Me4Si as internal standard. Ϫ The microanalyses for C, H,
and N were obtained with a PerkinϪElmer CHN Analyser 2400.
Ϫ The optical rotations were measured with a PerkinϪElmer 241
MC Polarimeter. Ϫ D.e. values were determined by examining the
1H-NMR spectra of crude products. Ϫ TLC: Merck, Alufolien Kie-
selgel 60 F 254, 0.2 mm. Ϫ Flash chromatography (FC) was per-
formed on a silica gel (FLUKA, Kieselgel 60, 0.04Ϫ0.063 mm).
Crude products 4aϪd were obtained as mixtures of two isomers:
major isomers 4aϪd and the corresponding minor isomers 5aϪd.
Major isomers 4aϪd were isolated, purified and fully characterised,
while minor isomers 5aϪd were detected and partially character-
Compounds
R
X
d. r. 4 (3S,5S)/ 4, d.e. (%)
5 (3R,5S)
1
ised by taking H-NMR spectra of crude products.
Starting Materials: The following starting compounds were pre-
pared according to the procedures described in the literature: (S)-
4a/5a
4b/5b
4c/5c
4d/5d
CO2Me
O
O
91:9
93:7
82
86
50
86
PhCO2CH2
CO2Me
5-methoxycarbonylpyrrolidin-2-one,[11]
(S)-5-methoxycarbonyl-
NϪCOPh 75:25
tetrahydrofuran-2-one (1a),[12] (S)-5-benzoyloxymethyltetrahydro-
furan-2-one (1b),[13] and (S)-1-benzoyl-5-methoxycarbonylpyrrol-
idin-2-one (1c).[7f]
CO2Me
NϪBoc
93:7
Scheme 2. Stereoselectivity of the catalytic hydrogenation of
oximes 3aϪd
Methyl (S)-1-Benzoyl-2-oxopyrrolidine-5-carboxylate (1c):[7f] Ben-
zoyl chloride (7.27 g, 52 mmol) was added to a solution of (S)-5-
methoxycarbonylpyrrolidin-2-one (7.30 g, 50 mmol) in pyridine (75
mL) and the mixture was stirred at room temperature for 2 h. Vol-
atile components were evaporated in vacuo, n-hexane (150 mL) was
added to the residue, the precipitate collected by filtration, and
well as between NH and 4-Ha, while only a weak NOE
effect was observed between 4-Ha and 3-H or 5-H. The
structures of 4a and 4c are therefore in accordance with
the proposed structures, indicating that hydrogenation of
oximes 3aϪd takes place preferentially from the less hin-
dered side of the CϭN double bond (Scheme 3).
Since direct nitrosation of lactones and lactams is usually
difficultly to achieve, these transformations represent a no-
vel, convenient, and stereoselective introduction of the am-
washed with methanol (100 mL) to give 1c. Yield: 10.39 g (84%),
23
colorless crystals. Ϫ M.p. 150Ϫ152°C (methanol). Ϫ [α]D
ϭ
ϩ30.1 (c ϭ 1.1, CH2Cl2). Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ
2.00Ϫ2.04 (m, 1 H, 4-Ha), 2.41Ϫ2.47 (m, 1 H, 4-Hb), 2.57Ϫ2.62
(m, 2 H, 3-CH2), 3.72 (s, 3 H, OMe), 4.84 (dd, 1 H, J ϭ 3.9, 8.7 Hz,
5-H), 7.42Ϫ7.47 (m, 2 H, Ph), 7.54Ϫ7.61 (m, 3 H, Ph). Ϫ 13C
ino group to the position adjacent to the ring carbonyl NMR (75.5 MHz, CDCl3): δ ϭ 22.2, 32.1, 53.1, 59.1, 128.3, 129.5,
1582 Eur. J. Org. Chem. 1999, 1581Ϫ1584

Stereoselective Amination of 5-Substituted γ-Lactones and γ-Lactams
FULL PAPER
132.7, 134.1, 170.8, 172.0, 173.8. Ϫ C13H13NO4 (247.3): calcd. C
63.15, H 5.30, N 5.66; found C 62.96, H 5.20, N 5.58.
C16H18N2O4 (302.3): calcd. C 63.56, H 6.00, N 9.27; found C 63.34,
H 6.35, N 9.13.
5-Methyl (S)-1-tert-Butoxycarbonyl-3-dimethylaminomethylene-2-
oxopyrrolidine-5-carboxylate (2d): Yield: 2.60 g (87%), colorless
crystals. Ϫ M.p. 131Ϫ133°C (ethyl acetate). Ϫ [α]D23 ϭ Ϫ55.9 (c ϭ
1-tert-Butyl 5-Methyl (S)-2-Oxopyrrolidine-1,5-dicarboxylate (1d):
Di-tert-butyl dicarbonate (29.5 g, 135 mmol) was added to a solu-
tion of (S)-5-methoxycarbonylpyrrolidin-2-one (10.0 g, 67 mmol)
and 4-dimethylaminopyridine (0.56 g, 5 mmol) in acetonitrile (150
mL) and triethylamine (50 mL) and the mixture was stirred at room
temperature for 3 h. Ethyl acetate (200 mL) was then added and the
solution was washed with 3% hydrochloric acid (200 mL), aqueous
sodium bicarbonate (200 mL), and brine (100 mL). The organic
phase was dried with anhydrous sodium sulfate, filtered, and the
filtrate concentrated in vacuo. The residue was triturated with n-
hexane/ethyl acetate (1:1, 150 mL) and the precipitate collected by
filtration to give 1d. Ϫ Yield: 11.25 g (69%), colorless crystals. Ϫ
M.p. 68Ϫ70°C (ethyl acetate/hexane). Ϫ [α]D23 ϭ Ϫ30.7 (c ϭ 1.16,
1
1.15, CH2Cl2). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.49 (s, 9 H,
tBu), 2.89 (ddd, 1 H, J ϭ 1.5, 2.5, 14.8 Hz, 4-Ha), 3.01 (s, 6 H,
NMe2), 3.25 (ddd, 1 H, J ϭ 1.5, 11.1, 14.8 Hz, 4-Hb), 3.75 (s, 3 H,
OMe), 4.55 (dd, 1 H, J ϭ 3.7, 10.6 Hz, 5-H), 7.13 (t, 1 H, J ϭ
1.5 Hz, 3Ј-H). Ϫ 13C NMR (75.5 MHz, [D6]DMSO): δ ϭ 26.0,
28.5, 42.5, 53.0, 56.1, 81.7, 91.1, 146.8, 150.5, 169.1, 173.3. Ϫ
C14H22N2O5 (298.3): calcd. C 56.36, H 7.43, N 9.39; found C 56.15,
H 7.41, N 9.44
General Procedure for the Preparation of 3-Oximino-Substituted
Tetrahydrofuran-2-ones and Pyrrolidin-2-ones 3a؊d: A stirred sus-
pension of 3-dimethylaminomethylene compound 2 (1 mmol) in
water (3 mL) was cooled to 0°C, hydrochloric acid (4%, 2 mL,
precooled to 0°C) was then added, followed by dropwise addition
of aqueous sodium nitrite (a solution of 90 mg of NaNO2 in 3 mL
of water). Stirring at 0°C was continued for 2 h and the precipitate
collected by filtration to give 3.
1
CH2Cl2). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.50 (s, 9 H, tBu),
2.03 (ddt, 1 H, J ϭ 3.6, 9.5, 13.2 Hz, 4-Ha), 2.32 (dq, 1 H, J ϭ 9.4,
13.3 Hz, 4-Hb), 2.49 (ddd, 1 H, J ϭ 3.7, 9.2, 17.4 Hz, 3-Ha), 2.64
(dt, 1 H, J ϭ 9.8, 17.5 Hz, 3-Hb), 3.79 (s, 3 H, OMe), 4.62 (dd, 1
H, J ϭ 3.1, 9.3 Hz, 5-H). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ
21.8, 28.2, 31.5, 52.9, 59.2, 83.9, 149.6, 172.2, 173.6. Ϫ C11H17NO5
(243.3): calcd. C 54.31, H 7.04, N 5.76; found C 54.21, H 7.11,
N 5.74.
5-Methyl (S)-3-Oximino-2-oxotetrahydrofuran-5-carboxylate (3a):
135 mg (78%), colorless crystals. Ϫ M.p. 106Ϫ109°C (ethyl acetate/
23
cyclohexane). Ϫ [α]D ϭ ϩ4.9 (c ϭ 0.92, CH2Cl2). Ϫ 1H NMR
General Procedure for the Preparation of 3-Dimethylaminomethy-
lene-Substituted Tetrahydrofuran-2-ones and Pyrrolidin-2-ones
2a؊d: A mixture of compound 1 (10 mmol), toluene (20 mL), and
tert-butoxybis(dimethylamino)methane (2.61 g, 15 mmol) was
heated at 90Ϫ100°C for 2 h, volatile components were evaporated
in vacuo, and the solid residue crystallised from the appropriate
solvent. The precipitate was collected by filtration to give 2.
(300 MHz, CDCl3): δ ϭ 3.16 (dd, 1 H, J ϭ 4.5, 19.6 Hz, 4-Ha),
3.36 (dd, 1 H, J ϭ 9.4, 19.6 Hz, 4-Hb), 3.84 (s, 3 H, OMe), 5.15
(dd, 1 H, J ϭ 4.5, 9.4 Hz, 5-H), 10.39 (br. s, 1 H, OH). Ϫ 13C
NMR (75.5 MHz, [D6]DMSO): δ ϭ 28.6, 53.5, 73.3, 145.8, 165.6,
170.5. Ϫ C6H7NO5 (173.1) calcd: C 41.63, H 4.08, N 8.09; found
C 41.40, H 3.94, N 7.90.
5-Methyl (S)-3-Dimethylaminomethylene-2-oxotetrahydrofuran-5-
carboxylate (2a): Yield: 1.16 g (58%), colorless crystals. Ϫ M.p.
(S)-5-Benzoyloxymethyl-3-oximinotetrahydrofuran-2-one
(3b):
Yield: 202 mg (81%), colorless crystals. Ϫ M.p. 166Ϫ168°C (etha-
23
23
nol/water). Ϫ [α]D ϭ ϩ148.5 (c ϭ 0.96, CH2Cl2). Ϫ 1H NMR
113Ϫ115°C (ethyl acetate). Ϫ [α]D ϭ ϩ2.3 (c ϭ 1.10, CH2Cl2).
Ϫ
1H NMR (300 MHz, CHCl3): δ ϭ 3.04 (s, 6 H, NMe2), 3.20
(300 MHz, CDCl3): δ ϭ 2.99 (dd, 1 H, J ϭ 4.5, 19.2 Hz, 4-Ha),
3.22 (dd, 1 H, J ϭ 8.7, 19.2 Hz, 4-Hb), 4.47 (dd, 1 H, J ϭ 4.7,
12.3 Hz, 5Ј-Ha), 4.59 (dd, 1 H, J ϭ 3.2, 12.2 Hz, 5Ј-Hb), 5.03Ϫ5.09
(ddt, 1 H, J ϭ 3.0, 4.5, 8.7 Hz, 5-H), 7.41Ϫ7.46 (m, 2 H, Ph),
7.54Ϫ7.60 (m, 1 H, Ph), 7.96Ϫ8.00 (m, 2 H, Ph), 11.40 (br. s, 1 H,
OH). Ϫ 13C NMR (75.5 MHz, [D6]DMSO): δ ϭ 27.4, 66.7, 75.3,
129.7, 129.9, 131.0, 134.5, 147.6, 166.2, 166.3. Ϫ C12H11NO5
(249.2): calcd. C 57.83, H 4.45, N 5.62; found C 58.11, H 4.55,
N 5.38.
(ddd, 1 H, J ϭ 1.3, 4.7, 14.3 Hz, 4-Ha), 3.43 (ddd, 1 H, J ϭ 1.1,
10.0, 14.1 Hz, 4-Hb), 3.79 (s, 3 H, OMe), 4.86 (dd, 1 H, J ϭ 5.0,
10.0 Hz, 5-H), 7.13 (t, 1 H, J ϭ 1.5 Hz, 3Ј-H). Ϫ 13C NMR
(75.5 MHz, CDCl3): δ ϭ 30.2, 42.1, 52.8, 72.6, 84.8, 148.4, 171.8,
174.2. Ϫ C9H13NO4 (199.2) calcd. C 54.26, H 6.58, N 7.03; found
C 54.31, H 6.79, N 7.14.
(S)-5-Benzoyloxymethyl-3-dimethylaminomethylenetetrahydrofuran-
2-one (2b): Yield: 1.18 g (43%), colorless crystals.
Ϫ M.p.
23
109Ϫ111°C (ethyl acetate/cyclohexane). Ϫ [α]D ϭ ϩ252.5 (c ϭ
5-Methyl (S)-1-Benzoyl-3-oximino-2-oxopyrrolidine-5-carboxylate
(3c): Yield: 218 mg (79%), colorless crystals. Ϫ M.p. 170Ϫ173°C
1
1.00, ethanol). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 2.93 (ddd, 1
25
(water). Ϫ [α]D ϭ ϩ7.35 (c ϭ 1.02, CH2Cl2). Ϫ 1H NMR
H, J ϭ 1.3, 5.5, 14.3 Hz, 4-Ha), 3.03 (s, 6 H, NMe2), 3.28 (ddd, 1
H, J ϭ 1.4, 9.0, 14.3 Hz, 4-Hb), 4.41 (dd, 1 H, J ϭ 5.8, 11.9 Hz,
5Ј-Ha), 4.47 (dd, 1 H, J ϭ 4.0, 11.9 Hz, 5Ј-Hb), 4.77 (ddt, 1 H, J ϭ
3.8, 5.7, 9.4 Hz, 5-H), 7.17 (t, 1 H, J ϭ 1.7 Hz, 3Ј-H), 7.41Ϫ7.47
(m, 2 H, Ph), 7.54Ϫ7.60 (m, 1 H, Ph), 8.03Ϫ8.07 (m, 2 H, Ph). Ϫ
13C NMR (75.5 MHz, CDCl3): δ ϭ 28.5, 41.7, 66.5, 73.3, 86.4,
128.4, 129.7, 129.8, 133.2, 147.6, 166.4, 174.7. Ϫ C15H17NO4
(275.3): calcd. C 65.44, H 6.22, N 5.09; found C 65.06, H 6.05,
N 5.08.
(300 MHz, [D6]DMSO): δ ϭ 2.89 (dd, 1 H, J ϭ 3.2, 19.0 Hz, 4-
Ha), 3.21 (dd, 1 H, J ϭ 9.9, 19.0 Hz, 4-Hb), 3.72 (s, 3 H, OMe),
4.96 (dd, 1 H, J ϭ 3.2, 9.9 Hz, 5-H), 7.45Ϫ7.50 (m, 2 H, Ph),
7.58Ϫ7.66 (m, 3 H, Ph), 12.79 (s, 1 H, OH). Ϫ 13C NMR
(75.5 MHz, [D6]DMSO): δ ϭ 25.7, 53.6, 55.1, 128.8, 129.7, 133.1,
134.5, 150.1, 162.8, 170.7, 171.9. Ϫ C13H12N2O5 (276.3): calcd. C
56.52, H 4.38, N 10.14; found C 56.44, H 4.37, N 10.16.
5-Methyl (S)-1-tert-Butoxycarbonyl-3-oximino-2-oxopyrrolidine-5-
carboxylate (3d): Yield: 215 mg (79%), colorless crystals. Ϫ M.p.
(S)-1-Benzoyl-3-dimethylaminomethylene-5-methoxycarbonyl-
25
pyrrolidin-2-one (2c): Yield: 2.24 g (74%), colorless crystals. Ϫ M.p.
145Ϫ147°C (methanol). Ϫ [α]D ϭ ϩ6.6 (c ϭ 0.82, CH2Cl2). Ϫ
23
133Ϫ134°C (ethyl acetate). Ϫ [α]D ϭ Ϫ36.0 (c ϭ 1.25, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.51 (s, 9 H, tBu), 2.87 (dd, 1
1
Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ 2.94 (dd, 1 H, J ϭ 3.1, H, J ϭ 3.2, 19.8 Hz, 4-Ha), 3.16 (dd, 1 H, J ϭ 10.0, 19.8 Hz, 4-
14.8 Hz, 4-Ha), 3.02 (s, 6 H, NMe2 ), 3.37 (dd, 1 H, J ϭ 10.7,
Hb), 3.79 (s, 3 H, OMe), 4.74 (dd, 1 H, J ϭ 3.2, 10.0 Hz, 5-H),
14.6 Hz, 4-Hb), 3.69 (s, 3 H, OMe); 4.73 (dd, 1 H, J ϭ 3.7, 10.2 Hz, 10.50 (br. s, 1 H, OH). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 24.9,
5-H), 7.02 (s, 1 H, 3Ј-H), 7.35Ϫ7.40 (m, 2 H, Ph), 7.45Ϫ7.51 (m,
28.2, 53.3, 55.2, 85.1, 149.3, 149.6, 161.8, 171.4. Ϫ C11H16N2O6
3 H, Ph). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 27.3, 43.0, 53.3, (272.3): calcd. C 48.52, H 5.92, N 10.29; found C 48.24, H 5.84,
56.6, 91.7, 128.3, 129.5, 131.9, 136.1, 148.1, 170.2, 171.7, 172.8. Ϫ N 10.24.
Eur. J. Org. Chem. 1999, 1581Ϫ1584
1583

ˇ
M. Skof, J. Svete, M. Kmetic, S. Golic-Grdadolnik, B. Stanovnik
FULL PAPER
General Procedure for the Preparation of 5-Substituted (3S,5S)-3-
Acetylaminotetrahydrofuran-2-ones 4a,b and (3S,5S)-3-Acetyl-
less solid. Ϫ M.p. 48Ϫ56°C (FC, ether/petroleum ether, 2:1). Ϫ [α]
23
1
ϭ Ϫ5.8 (c ϭ 1.00, CH2Cl2). Ϫ H NMR (300 MHz, CDCl3):
D
aminopyrrolidin-2-ones 4c,d: A mixture of oxime 3 (1 mmol), acetic δ ϭ 1.48 (s, 9 H, tBu), 1.82 (ddd, 1 H, J ϭ 9.4, 10.1, 12.5 Hz, 4-
acid (5 mL), acetic anhydride (2 mL), and palladium on charcoal
(10% Pd/C, 80 mg) was hydrogenated (1 bar, 3a,c,d: 20°C, 3b:
60°C) for 10 h. The catalyst was removed by filtration, washed with
methanol, and the filtrate concentrated in vacuo. The residue was
purified by flash chromatography (FC) using ethyl acetate/n-hexane
(1:1) as eluant. Fractions containing the product were combined
and evaporated in vacuo to give a mixture of 4 and its epimer
5. Isomerically pure compounds 4aϪd were obtained either upon
crystallisation (4aϪc), or upon chromatographic separation (FC,
4d).
Ha), 2.04 (s, 3 H, MeCO), 2.92 (ddd, 1 H, J ϭ 7.5, 8.7, 12.8 Hz, 4-
Hb), 3.79 (s, 3 H, OMe), 4.49 (dd, 1 H, J ϭ 7.5, 9.0 Hz 5-H), 4.63
(ddd, 1 H, J ϭ 6.4, 9.0, 10.2 Hz, 3-H), 6.79 (d, 1 H, J ϭ 6.4 Hz,
NH). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 22.8, 27.8, 29.8, 51.3,
52.7, 56.1, 84.5, 148.9, 170.9, 171.3, 171.5. Ϫ C13H22N2O7 (318.3):
calcd. C 49.05, H 6.97, N 8.80; found C 49.16, H 6.88, N 8.43. Ϫ
HRMS (FAB, MHϩ); C13H21N2O6: calcd. 301.1400; found
301.1410.
1
Minor Isomer 5d: H NMR (300 MHz, CDCl3): δ ϭ 1.51 (s, 9 H,
tBu), 2.03 (s, 3 H, MeCO), 3.05Ϫ3.14 (m, 1 H, 4-Hb), 3.80 (s, 3 H,
OMe), 4.26 (dd, 1 H, J ϭ 7.2, 9.0 Hz, 5-H), 6.52 (d, 1 H, J ϭ
7.5 Hz, NH).
5-Methyl (3S,5S)-3-Acetylamino-2-oxotetrahydrofuran-5-carboxyl-
ate (4a): Yield: 117 mg (58%), colorless crystals.
Ϫ
M.p.
122Ϫ124°C (ethyl acetate). Ϫ [α]D ϭ Ϫ5.7 (c ϭ 0.65, CH2Cl2).
1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.85 (s, 3 H, MeCO),
23
Ϫ
2.16 (ddd, 1 H, J ϭ 10.4, 11.1, 12.1 Hz, 4-Ha), 2.71 (ddd, 1 H, J ϭ
7.0, 9.2, 12.1 Hz, 4-Hb), 3.73 (s, 3 H, COOMe), 4.67 (ddd, 1 H,
J ϭ 7.9, 9.0, 10.9 Hz, 3-H), 5.04 (dd, 1 H, J ϭ 7.0, 10.4 Hz, 5-H),
8.42 (d, 1 H, J ϭ 7.9 Hz, NH). Ϫ 13C NMR (75.5 MHz,
[D6]DMSO): δ ϭ 23.1, 31.9, 49.0, 53.2, 73.3, 170.1, 170.2, 174.6.
Ϫ C8H11NO5 (201.2): calcd. C 47.76, H 5.51, N 6.96; found C
47.44, H 5.42, N 7.25.
Acknowledgments
The authors wish to express their gratitude to the Ministry of
Science and Technology, Slovenia, for financial support.
[1]
O. Touster, Org. React. 1953, 7, 327Ϫ377.
[2]
H. Bredereck, G. Simchen, Angew. Chem. 1963, 75, 1102.
[3]
H. Bredereck, G. Simchen, G. Beck, Liebigs Ann. Chem. 1972,
1
Minor Isomer 5a: H NMR (300 MHz, [D6]DMSO): δ ϭ 1.99 (s, 3
762, 62Ϫ72.
[4]
H. Bredereck, G. Simchen, W. Griebenow, Chem. Ber. 1974,
H, MeCO), 3.71 (s, 3 H, COOMe), 4.92 (dd, 1 H, J ϭ 6.8, 10.5
Hz, 5-H).
107, 1545Ϫ1554.
[5]
R. F. Abdulla, E. S. Brinkmeyer, Tetrahedron 1979, 35,
1675Ϫ1735.
(3S,5S)-3-Acetylamino-5-benzoyloxymethyltetrahydrofuran-2-one
(4b): Yield: 155 mg (56%), colorless crystals. Ϫ M.p. 153Ϫ156°C
[6]
[7]
[6a]
For short reviews see:
B. Stanovnik, “Methyl 2-Benzoyl-
amino-3-dimethylaminopropenoate in the Synthesis of Hetero-
cyclic Systems” in Progress in Heterocyclic Chemistry (Eds.: H.
Suschitzky, E. F.V. Scriven), Pergamon Press, Oxford, 1993, vol.
23
(toluene). Ϫ [α]D ϭ ϩ104.0 (c ϭ 1.16, CH2Cl2). Ϫ 1H NMR
(300 MHz, CDCl3): δ ϭ 1.98 (dt, 1 H, J ϭ 11.5, 12.4 Hz, 4-Ha),
2.05 (s, 3 H, MeCO), 2.96 (ddd, 1 H, J ϭ 5.7, 8.7, 12.4 Hz, 4-Hb),
4.47 (dd, 1 H, J ϭ 6.0, 12.4 Hz, 5Ј-Ha), 4.61 (dd, 1 H, J ϭ 3.0,
12.4 Hz, 5Ј-Hb), 4.69 (ddd, 1 H, J ϭ 6.0, 8.7, 11.7 Hz, 3-H), 4.82
(ddt, 1 H, J ϭ 3.0, 5.8, 11.7 Hz, 5-H), 6.10 (d, 1 H, J ϭ 5.6 Hz,
NH), 7.43Ϫ7.48 (m, 2 H, Ph), 7.56Ϫ7.62 (m, 1 H, Ph), 8.03Ϫ8.06
(m, 2 H, Ph). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 22.8, 32.4,
50.1, 64.8, 75.4, 128.5, 129.2, 129.8, 133.5, 166.0, 170.5, 174.3. Ϫ
C14H15NO5 (277.3): calcd. C 60.64, H 5.45, N 5.05; found C 60.29,
H 5.42, N 5.10.
5, pp. 34Ϫ53. Ϫ [6b] B. Stanovnik, Molecules 1996, 1, 123Ϫ127.
[7a]
ˇ ˇ
L. Selic, S. Golic-Grdadolnik,
[7b]
For recent publications see:
B. Stanovnik, Helv. Chim. Acta 1997, 80, 2418Ϫ2425. Ϫ
J.
ˇ
Smodis, B. Stanovnik, Tetrahedron 1998, 54, 9799Ϫ9810. Ϫ
[7c]
L. Pizzioli, B. Ornik, J. Svete, B. Stanovnik, Helv. Chim.
[7d]
ˇ
L. Selic, B. Stanovnik, Helv.
[7e]
Acta 1998, 81, 231Ϫ235. Ϫ
ˇ
L. Selic, S. Strah, R.
[7f]
Chim. Acta 1998, 81, 1634Ϫ1639. Ϫ
Toplak, B. Stanovnik, Heterocycles 1998, 47, 1017Ϫ1022. Ϫ
ˇ
ˇ
ˇ
M. Skof, J. Svete, B. Stanovnik, L. Golic, S. Golic-Grdadolnik,
ˇ
L. Selic, Helv. Chim. Acta 1998, 81, 2332Ϫ2340.
[8]
[9]
ˇ
M. Kmetic, B. Stanovnik, J. Heterocycl. Chem. 1995, 32,
1563Ϫ1565.
Minor Isomer 5b: 1H NMR (300 MHz, CDCl3): δ ϭ 1.61Ϫ1.73 (m,
1 H, 4-Ha), 1.93 (s, 3 H, MeCO), 4.91Ϫ4.98 (m, 1 H, 5-H).
M. Kmetic, B. Stanovnik, J. Heterocycl. Chem. 1997, 34,
ˇ
1705Ϫ1708.
[10]
For the synthesis of some α-amino-γ-hydroxy and α,γ-diamino
[10a]
5-Methyl (3S,5S)-3-Acetylamino-1-benzoyl-2-oxopyrrolidine-5-car-
boxylate (4c): Yield: 137 mg (45%), colorless crystals. Ϫ M.p.
compounds see:
H. Hahn, H. Heitsch, R. Rathmann, G.
Zimmermann, C. Bormann, H. Zähner, W. A. König, Liebigs
[10b]
Ann. Chem. 1987, 803Ϫ807. Ϫ
N. G. Park, S. Lee, H.
23
188Ϫ191°C (ethyl acetate). Ϫ [α]D ϭ Ϫ87.1 (c ϭ 0.76, CH2Cl2).
Maeda, H. Aoyagi, T. Kato, Bull. Chem. Soc. Jpn. 1989, 62,
2315Ϫ2319. Ϫ [10c] B. J. Williams, P. D. Leeson, G. Hannah, R.
Baker, J. Chem. Soc., Chem. Commun. 1989, 1740Ϫ1742. Ϫ
Ϫ
1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.86 (s, 3 H, MeCO),
1.99 (dd, 1 H, J ϭ 10.7, 12.4 Hz, 4-Ha), 2.65 (ddd, 1 H, J ϭ 7.3,
8.9, 11.9 Hz, 4-Hb), 3.68 (s, 3 H, OMe), 4.50 (dt, 1 H, J ϭ 8.5,
10.9 Hz, 3-H), 4.78 (dd, 1 H, J ϭ 7.2, 10.5 Hz, 5-H), 7.44Ϫ7.49
(m, 2 H, Ph), 7.56Ϫ7.62 (m, 1 H, Ph), 7.66Ϫ7.69 (m, 2 H, Ph),
8.46 (d, 1 H, J ϭ 7.9 Hz, NH). Ϫ 13C NMR (75.5 MHz,
[D6]DMSO): δ ϭ 22.2, 27.8, 50.7, 52.3, 54.9, 127.7, 129.2, 132.3,
133.6, 169.4, 170.1, 170.4, 171.4. Ϫ C15H16N2O5 (304.3): calcd. C
59.21, H 5.30, N 9.21; found C 59.07, H 5.37, N 9.17.
[10d]
J. Ariza, J. Font, R. M. Ortun˜o, Tetrahedron 1990, 46,
1931Ϫ1942. Ϫ [10e] A. G. M. Barrett, D. Dhanak, S. A. Lebold,
M. A. Russell, J. Org. Chem. 1991, 56, 1894Ϫ1901. Ϫ [10f] R. F.
W. Jackson, A. B. Rettie, Tetrahedron Lett. 1993, 34,
2985Ϫ2986. Ϫ [10g] C. Schmeck, L. Hegedus, J. Am. Chem. Soc.
[10h]
1994, 116, 9927Ϫ9934. Ϫ
V. Jäger, R. Müller, T. Leibold,
M. Hein, M. Schwarz, M. Fengler, L. Jaroskova, M. Pätzel, P.-
Y. LeRoy, Bull. Soc. Chim. Belg. 1994, 103, 491Ϫ507.
S. Saijo, M. Wada, J.-I. Himizu, A. Ishida, Chem. Pharm. Bull.
1980, 28, 1449Ϫ1458.
[11]
[12]
[13]
1
Minor Isomer 5c: H NMR (300 MHz, [D6]DMSO): δ ϭ 1.88 (s, 3
ˇ
O. Cervinka, L. Hub, Coll. Czech. Chem. Commun. 1968, 33,
H, MeCO), 3.75 (s, 3 H, OMe), 4.30Ϫ4.39 (m, 1 H, 3-H), 4.88 (dd,
1 H, J ϭ 2.8, 8.1 Hz, 5-H), 8.52 (d, 1 H, J ϭ 7.5 Hz, NH).
2927Ϫ2932.
M. Taniguchi, K. Koga, S. Yamada, Tetrahedron 1974, 30,
3547Ϫ3552.
5-Methyl (3S,5S)-3-Acetylamino-1-tert-butoxycarbonyl-2-oxopyrrol-
idine-5-carboxylate Monohydrate (4d): Yield: 140 mg (44%), color-
Received December 11, 1998
[O98553]
1584
Eur. J. Org. Chem. 1999, 1581Ϫ1584