Synthesis of optically pure 2-azetidinones having N-dehydroamino acid side-chains

Article abstract of DOI:10.1055/s-1998-1667

An efficient, three step synthesis of optically pure N-vinyl-2-azetidinones 1 starting from α- or β-amino ester imines has been developed. Stau?dinger reaction between amino ester derived imines and ketene precursors gave 2-azetidinones 2. Enolate formati

Full text of DOI:10.1055/s-1998-1667

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SYNLETT
Synthesis of Optically Pure 2-Azetidinones Having N-Dehydroamino Acid Side-Chains
Benito Alcaide,* Concepción Polanco, and Miguel A. Sierra*
Departamento de Química Orgánica I. Facultad de Química. Universidad Complutense. 28040-Madrid, Spain
Received 8 November 1997
Abstract. An efficient, three step synthesis of optically pure N-vinyl-2-
azetidinones 1 starting from α- or β-amino ester imines has been
developed. Staüdinger reaction between amino ester derived imines and
ketene precursors gave 2-azetidinones 2. Enolate formation on the
amino ester moiety of the optically pure 2-azetidinones 2, selenylation
and, finally, MCPBA treatment afforded N-vinyl-2-azetidinones 1 in
good to excellent yields, with total retention of the stereochemistry of
the starting material. Compounds 2 bear the functionality needed to
place a carboxy group contiguous to the lactam nitrogen, a structural
feature common to all the active β-lactam antibiotics.
2-Azetidinones having a vinyl moiety attached to the lactam nitrogen
have been used several times as intermediates in the preparation of
1
different types of β-lactam antibiotics. The main approach to these
compounds rests mainly in penicillin derivatives to produce, by ring
fission and basic isomerization of the double bond, the N-vinyl
2,3
moiety. Alternatively, this structural feature can be incorporated by
the Staüdinger reaction of 2-aza-1,3-diene derivatives and a ketene
precursor. The reported routes to prepare N-vinyl-2-azetidinone
corresponding ester enolates, which were quenched with BrSePh to
produce the α-seleno derivatives 3, as diastereomeric mixtures.
Although compounds 3 can be isolated, purified, and characterized, they
were submitted to oxidation as obtained. Thus, reaction of compounds 3
with MCPBA at -78 °C gave N-vinyl-2-azetidinones 1 in nearly
quantitative yields. The overall yields for the synthesis of compounds 1,
range from good to excellent (Table 1). 2-Azetidinone 1a derived from
β-alanine was obtained as a single E-isomer at the newly formed double
bond, while L-aspartic acid derivative 1e was obtained as an E/Z
mixture without selectivity. In this case, the stereochemistry of the
4
derivatives are, either, designed to accomplish the synthesis of a
particular product, or lack the necessary versatility, specially in the
introduction of the carboxy group contiguous to the lactam nitrogen,
5
which is always present on active β-lactam antibiotics. We report
herein a three step synthesis of N-vinyl-2-azetidinones 1 in optically
pure form, starting from α- or β-amino ester-derived imines. Our
approach is based on the sequential Staüdinger reaction between a
ketene and a β-amino ester derived imine to yield 2-azetidinones 2,
followed by α-selenylation of the amino ester moiety, and, finally,
double bond was determined by n.O.e. experiments, and by comparison
6
oxidative selenoxide elimination to produce the desired compounds 1.
12
with related compounds.
The stereochemical integrity of the
It should be noted that compounds 2 bear the functionality needed to
place a carboxy group contiguous to the lactam nitrogen, a structural
feature common to all the active β-lactam antibiotics. Compounds 2 are,
in turn, α,β-dehydroaminoacids having a 2-azetidinone-1-yl substituent.
The role of α,β-dehydroaminoacids as key intermediates in amino acid
and peptide synthesis, and as constituents of naturally occurring
stereogenic centers at the four membered ring remains unaltered during
13
the transformation of compounds 2 to products 1.
In conclusion,
a three step synthesis of optically pure α,β-
dehydroaminoacid esters having an N-2-azetidinone-1-yl substituent has
been developed. Efforts to develop efficient synthesis of diverse
polycyclic β-lactam systems, using the methodology reported here, are
now in progress.
7
antibiotics and phytotoxic peptide is well documented.
A series of imines derived from β-alanine, L-alanine, and L-aspartic
acid methyl esters, prepared in quantitative yield by condensation of
different aldehydes and the corresponding amino ester in CH Cl
/
2
2
8
14
MgSO , were reacted, without further purification, with the
4
Experimental Procedures. General Method for the Synthesis of 2-
9
corresponding acid chloride in the presence of Et N, except for
compound 2d where the acid/ Cl P(O)OPh/Et N modification of the
3
Azetidinones, 2a-e. Method A (Compounds 2a-b,2e): The acid chloride
(7.5 mmol) in anhydrous benzene (25 mL) was added dropwise via
10
2
3
Staüdinger reaction was used (Figure 1). 2-Azetidinones 2 were always
obtained as cis-diastereomers. A single cis-diastereomer was obtained,
except for compound 2b, when either a chiral ketene precursor or an
imine derived from D-glyceraldehyde acetonide, were used. The
assignment of a 3S,4R stereochemistry for 2-azetidinones derived from
Evans' ketene (2c and 2d), and 3R,4S to those derived from D-
glyceraldehyde acetonide (2a, and 2b major isomer) is based on the
syringe to a solution of the imine (5 mmol) and Et N (10 mmol) in
3
benzene (25 mL). The resulting mixture was stirred until complete
disappearance of the imine (TLC). The crude mixture was diluted with
CH Cl (25 mL) and successively washed with aqueous NaHCO (2 x
2
2
3
40 mL, saturated solution) and brine (20 mL). The organic layer was
dried (MgSO ) and the solvent removed under vacuum. Residues were
4
purified by crystallization from the indicated solvent, or by flash
chromatography (EtOAc/hexanes mixtures). Method B (Compound 2c):
11
current model for the asymmetric induction in the Staüdinger reaction.
When diastereomeric mixtures were obtained, both diastereoisomers
were easily obtained, as optically pure compounds, by flash
chromatography.
A solution of Et N (6 mmol) in CH Cl (5 mL) was added dropwise to a
3
2
2
solution of (S)-(4-phenyl-2-oxooxazolidinyl)acetyl chloride (0.71 g, 3
o
mmol) in CH Cl (10 mL) at -78 C under argon. The mixture was
2
2
With a variety of compounds 2 in hand, their transformation to the
desired N-vinyl-2-azetidinones was studied. Treatment of diast-
ereomerically pure β-lactams 2 with LHMDS at -78 °C, generated the
stirred for 30 min, and a solution of the imine (2 mmol) in CH Cl (5
2 2
mL) was added. The reaction was allowed to reach room temperature
and stirred for 12 h. Then, MeOH (2 mL) and CH Cl (20 mL) were
2
2

April 1998
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417
References and Notes
1.
Kant, J.; Walker, D. G. in The Organic Chemistry of β-Lactams,
Georg, G. I. ed.; VCH Publishers, Inc. New York 1992. Chapter 3.
2.
This chemistry has been carefully reviewed, see: Morin, R. B.;
Gorman, M., Eds. Chemistry and Biology of β-Lactam Antibiotics,
Academic Press, New York 1982-1983. Vol 1-3.
3.
For other, less general methods, to prepare N-vinyl-β-lactams,
see: (a) Hrytsak, M.; Durst, T. Heterocycles 1987, 26, 2393.
(b) Mastalerz, H.; Vinet, V. J. Chem. Commun. 1987, 1283.
(c) Just, G.; Liak, T.-J. Can. J. Chem. 1978, 56, 211. (d) Niu, Ch.;
Miller, M. J. Tetrahedron Lett. 1995, 36, 497. (e) Manhas, M. S.;
Van der Veen, J. M.; Wagle, D. R.; Hegde, V. R.; Bari, S. S.;
Kosarych, Z.; Ghosh, M.; Krishnan, L. Ind. J. Chem., Sect. B
1986, 25B, 1095. (f) Gunda, T. E.; Vieth, S.; Kover, K. E.;
Sztaricskai, F. Tetrahedron Lett. 1990, 31, 6707. (g) Fukuyama,
T.; Laird, A. A.; Schmidt, C. A. Tetrahedron Lett. 1984, 25, 4709.
(9) Cossio, F. P.; Palomo, C. Tetrahedron Lett. 1985, 26, 4235.
4.
(a) Georg, G. I.; He, P.; Kant, J.; Wu, Z.-J. J. Org. Chem. 1993,
58, 5771. (b) Georg, G. I.; Kant, J.; He, P.; Ly, A. M.; Lampe, L.
Tetrahedron Lett. 1988, 29, 2409. (c) Georg, G. I.; He, P.; Kant,
J.; Mudd, J. Tetrahedron Lett. 1990, 31, 451.
5.
6.
Dürckheimer, W.; Blumbach, J.; Latrell, R.; Sheunemann, K. H.
Angew. Chem., Int. Ed. Eng. 1985, 24, 180.
successively added. The mixture was washed with water and brine. The
organic layer was dried (MgSO ) and the solvent eliminated under
4
reduced pressure. The crude product was purified by column
chromatography (EtOAc/hexane 1/2)
To the best of our knowledge, the sole precedent in the use of a
seleno derivative to prepare a N-vinyl-2-azetidinone, is the
treatment of a β-lactam having a N-β-(phenylselenyl)ethyl moiety
General Method for the Synthesis of Compounds, 1a-e. Method A
with MCPBA/i-Pr NH to afford the exocyclic double bond. See,
Heck, J. V.; Christensen, B. G. Tetrahedron Lett. 1981, 22, 5027.
(Compounds 1a and 1e). BuLi (1.3 mmol, 1.6 M in hexanes) was added
2
o
dropwise via syringe to
a
cooled (-78 C) solution of
hexamethyldisilazane (1.35 mmol) in anhydrous THF (5 mL) under
7.
8.
Reviews: (a) Stammer, C. H. in Chemistry and Biochemistry of
Amino Acids, Peptides, and Proteins, Vol. 6, Weinstein, B., Ed.;
Marcel Dekker: New York, 1982. (b) Schmidt, U.; Hausler, J.;
Ohler, E.; Poisel, H. Progress in the Chemistry of Organic
Natural Products 1979, 37, 251.
argon. After 30 minutes, the resulting solution was transferred via
o
cannula to a cooled solution (-78 C) of the corresponding β-lactam (1
mmol) in anhydrous THF (5 mL) by using argon pressure. After stirring
o
o
1 h from -78 C to -60 C, PhSeBr (1.3 mmol) in THF (5 mL) was added
rapidly to the enolate solution, which causes an instantaneous
decolourization of the solution. After stirring for 1 h, the reaction
Racemization of imines derived from amino esters is a problem
found in the use of these compounds as substrates for the
Staüdinger reaction. For a recent example, see: Niu, C.; Petterson,
T.; Miller, M. J. J. Org. Chem. 1996, 61, 1014. In fact, when the
imine was prepared in boiling benzene total racemization was
observed. Conditions used through this work ensured that the
imine was obtained and used without racemization.
mixture was quenched with saturated aqueous NH Cl solution (7 mL)
4
and extracted with ethyl acetate (10 x 3 mL). The organic layer was
washed with saturated NaHCO solution (15 mL), brine (15 mL), and
3
dried (MgSO ). The solvent was removed under reduced pressure and
4
the obtained compound 3 was used in the next step without further
purification. Method B (Compounds 1b-d). This method was identical
to method A except for that the corresponding β-lactam was added
dropwise over the solution of LHMDS .
9.
Staüdinger, H. Liebigs Ann. Chem. 1907, 356, 51.
10. Arrieta, A.; Lecea, B.; Cossio, F. P.; Palomo, C. J. Org. Chem.
1988, 53, 3784, and references therein.
To a solution of the corresponding seleno-β-lactam 3 (1 mmol) in
11. (a) Cossio, F. P.; Arrieta, A.; Lecea, B.; Ugalde, J. M. J. Am.
Chem. Soc. 1994, 116, 2085. (b) Hegedus, L. S.; Montgomery, J.;
Narukawa, Y.; Snustad, D. C. J. Am. Chem. Soc. 1991, 113, 5784.
(c) Palomo, C.; Aizpurua, J. M.; Mielgo, A.; Linden, A. J. Org.
Chem. 1996, 61, 9186. Ojima, in a seminal series of papers, has
unambiguously established the configuration of 2-azetidinones
derived from chiral amino ester imines and Evans ketene
experimentally: (d) Ojima, I.; Chen, H.-J. C.; Qiu, X. Tetrahedron
1988, 44, 5307, and pertinent references therein. For 2-
azetidinones derived from D- and L-glyceraldehyde acetonide
imines, see: (e) Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone,
M. G.; Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas,
M. S.; Bose, A. K. J. Org. Chem. 1988, 53, 4227.
o
CH Cl (5 mL), cooled to -78 C, was added dropwise a solution of m-
2
2
chloroperbenzoic acid (1.1 mmol, 55%) in
5 mL of CH Cl .
2 2
Immediately after the end of the addition, TLC analysis showed the
complete transformation of the starting material. The cold reaction
mixture was poured into a separatory funnel containing 30 mL of Et O
2
and 30 mL of 10% aqueous Na SO The organic layer was separated,
2
3.
washed twice with saturated aqueous NaHCO solution, dried (MgSO )
3
4
and concentrated under reduced pressure. The crude product was
purified by crystallization or flash chromatography.
Acknowledgment. Support for this work under Grant PB93-0442
(DGICYT - MEC, Spain) is acknowledged. C. P. thanks the UCM for
the receipt of a pre-doctoral grant.
12. Hwu, J. R.; Lai, L.-L.; Hakimelahi, G. H.; Davari, H. Helv. Chim.
Acta 1994, 77, 1037.
1
13.
H NMR analysis of the reaction mixtures showed a single
diastereoisomer in all cases.

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SYNLETT
1
13
14. All new compounds were fully characterized by H NMR,
C
(m, 1 H), 3.73 (s, 3 H), 3.97 (dd, J = 9.0 Hz, J = 5.7 Hz, 1 H),
1 2
NMR, and IR and gave correct elemental analyses. Represent-
ative data are given for compound 1a.
4.21 (dd, J = 9.0 Hz, J = 6.9 Hz, 1 H), 4.31-4.42 (m, 1 H), 4.66
1 2
(d, J = 11.5 Hz, 1 H), 4.75 (d, J = 5.7 Hz, 1 H), 4.90 (d, J = 11.5
Hz, 1 H), 6.05 (d, J = 14.1 Hz, 1 H), 7.22-7.40 (m, 5 H), 7.48 (d, J
(+)-(3R,4S)-cis-3-Benzyloxy-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-1-[E-(2-methoxycarbonylethenyl)]-2-azetidinone, 1a. Method
A. From 0.18 (0.5 mmol) of β-lactam 2a, was obtained 0.17 g
(91%) of compound 1a as a pale green oil, after purification by
13
= 14.1 Hz, 1 H). C NMR: δ 167.6, 165.7, 136.8, 134.4, 128.7,
128.3, 128.4, 128.0, 110.1, 104.3, 80.5, 73.3, 66.7, 62.3, 51.5,
26.7, 25.0. IR (CHCl ): ν 1780, 1710, 1640. Anal. Calcd for
3
flash chromatography (EtOAc/hexane 1/6). [α] = +116.3 (c =
C H NO : C, 63.15; H, 6.41; N, 3.88. Found: C, 63.36; H, 6.67;
19 23 6
N, 4.04.
D
1
1.16, CHCl ). H NMR: δ 1.35 (s, 3 H), 1.50 (s, 3 H), 3.62-3.73
3