Asymmetric synthesis of trans-3-amino-4-alkylazetidin-2-ones from chiral N,N-dialkylhydrazones

Article abstract of DOI:10.1021/ol0490328

Enantiopure N,N-dialkylhydrazones 3 smoothly react with N-benzyloxycarbonyl-N-benzyl glycine as an aminoketene precursor to afford trans-3-amino-4-alkylazetidin-2-ones 4 as single diasteromers. As an exception, hydrazone 3f (R = OBn) affords cis-(3R,4R)-4

Full text of DOI:10.1021/ol0490328

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2749-2752
Asymmetric Synthesis of
trans-3-Amino-4-alkylazetidin-2-ones
from Chiral N,N-Dialkylhydrazones
,‡
Elena D´ıez,‡ Rosario Ferna´ndez,* Eugenia Marque´s-Lo´pez,‡
,†
Elo´ısa Mart´ın-Zamora,‡ and Jose´ M. Lassaletta*
Instituto de InVestigaciones Qu´ımicas, CSIC-USe, c/Ame´rico Vespucio s/n,
Isla de la Cartuja, E-41092 SeVille, Spain, and Departamento de Qu´ımica Orga´nica,
Facultad de Qu´ımica, UniVersidad de SeVilla, Apdo. de Correos No. 553,
E-41071, SeVille, Spain
jmlassa@iiq.csic.es
Received May 25, 2004
ABSTRACT
Enantiopure N,N-dialkylhydrazones 3 smoothly react with N-benzyloxycarbonyl-N-benzyl glycine as an aminoketene precursor to afford trans-
3-amino-4-alkylazetidin-2-ones 4 as single diasteromers. As an exception, hydrazone 3f (R ) OBn) affords cis-(3R,4R)-4f under modified conditions.
N−N Bond cleavage of cycloadducts 4 afforded free azetidinones 5 in high yields.
The discovery of monocyclic â-lactam antibiotics,1 named
and classified as monobactams, and the introduction of drugs
such as aztreonam and carumonam (Figure 1) have stimulated
considerable activity focused on the development of stereo-
selective routes for the key 3-aminoazetidin-2-one substruc-
ture.2 One of the most powerful methods for the preparation
of these compounds is the [2 + 2] cycloaddition reaction of
ketenes to imines (the Staudinger reaction), but the method
is in general limited by the poor stability of some imines, in
particular, the easily tautomerizable imines derived from
aliphatic aldehydes. On the basis of our previous experience
with N,N-dialkylhydrazones,3 we recently started a project
based on exploiting the higher stability of these compounds
relative to N-alkyl(aryl) imines in the Staudinger reaction.
It was discovered that formaldehyde derivatives behave as
a stable class of monomeric methanimines in their reaction
with functionalized (alkoxy and amino) ketenes4 and that
the stability of aliphatic N,N-dialkylhydrazones is key for a
† Instituto de Investigaciones Qu´ımicas.
‡ Departamento de Qu´ımica Orga´nica.
(1) (a) Imada, A.; Kitano, K.; Kintaka, K.; Muroi, M.; Asai, M. Nature
1981, 289, 590. (b) Sykes, R. B.; Cimarusti, C. M.; Bonner, D. P.; Bush,
K.; Floyd, D. M.; Georgopadakou, N. H.; Koster, W. H.; Liu, W. C.; Parker,
W. L.; Principe, P. A.; Rathnum. M. L.; Slusarchick, W. A.; Trejo W. H.;
Wells, T. S. Nature 1981, 291, 489.
(2) Review: Ternansky, R. J.; Morin, J. M., Jr. In The Organic Chemistry
of â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; p 257.
Figure 1. Clinically used monobactams.
10.1021/ol0490328 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/08/2004

straightforward synthesis of 3-alkoxy-4-alkyl(aryl)-azetidin-
2-ones and of the corresponding isoserines5 (Scheme 1).
50%). On the other hand, the analysis of the reaction mixtures
indicated the formation of a single stereoisomer.
Fortunately, a screening of different reaction conditions
revealed the key importance of the base used for the
generation of the ketene. Thus, replacement of Et3N by the
more hindered (i-Pr)2EtN resulted in a significant improve-
ment of the results, leading to the isolation of the corre-
sponding products 4a-f in moderate-to-good yields (Table
1).
Scheme 1. N,N-Dialkylhydrazones as Imine Component in the
Staudinger Reaction
Table 1. Synthesis of 3-Amino-4-alkylazetidin-2-ones 4a-f
entry educt
R
T (h) product yield (%)a trans:cisb
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Me
i-Pr
i-Bu
6
4a
74
66
72
70
58
66
>99:1
>99:1
>99:1
>99:1
92:8
53 4b
26 4c
PhCH2CH2 20 4d
n-C5H11
BnOCH2
10 4e
38 4f
54:46c
a Yield of isolated product. Reactions were performed at 1 mmol scale
We wish to report herein our results in the Staudinger-
like [2 + 2] cycloaddition of chiral, aliphatic N,N-dialkyl-
hydrazones 3 to R-aminoketenes 2 for the synthesis of
3-amino-4-alkylazetidin-2-ones 4 and derivatives therefrom.
We chose as reagents hydrazones 3a-f,6 containing C2-
symmetric (2R,5R)-2,5-dimethylpyrrolidine as the auxiliary,
bearing in mind the excellent stereocontrol and high reactivity
observed in their cycloadditions to benzyloxyketene.5 On the
basis of our previous experience with 4-unsubstituted deriva-
tives,4 we decided to use N-benzyloxycarbonyl-N-benzyl-
glycine 1 as the source of aminoketene 2 and 2-chloro-N-
methyl pyridinium iodide as activating agent (Scheme 2).
in toluene at 80 °C. b Determined by 1H and 13C NMR analysis of the crude
reaction mixtures. The (3R,4R)/(3S/4S) diasteromeric ratio was >99:1 in
all cases. c Separable by column chromatography.
Surprisingly, most reactions afforded products 4 as single
trans (3R,4R)-isomers,7 in sharp contrast with the reported
cis-selective cycloaddition with benzyloxyketene.5 This dif-
ferent behavior was interpreted as result of the more
demanding steric interactions at the conrotatory ring-closing
step. A possible cis f trans base-catalyzed isomerization
was experimentally ruled out,8 thereby confirming that
kinetically controlled products are obtained. According to
the commonly accepted mechanism for the Staudinger
reaction, the analysis of the results collected in Table 1 and
comparison with those observed for the cycloaddition to
benzyloxyketene (cis (3R,4S)-products) suggests a uniform
path (outward approach of the ketene) for the formation of
the zwitterionic intermediate, which in the absence of severe
steric interactions may directly suffer ring closing to afford
cis products. Alternatively, it may also undergo a CdN bond
isomerization prior to ring closing, this last process presum-
ably being favored if the barrier for the conrotatory ring
closure to cis products is relatively high as a result of steric
interactions, as apparently happens between the bulky
N-benzyloxycarbonyl-N-benzylamino group and the hydra-
zone alkyl group R (Scheme 3).
Scheme 2. Synthesis of 3-Amino-4-alkylazetidin-2-ones 4
(4) Ferna´ndez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Monge,
A. Angew. Chem., Int. Ed. 2000, 39, 2893.
(5) Ferna´ndez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Mart´ın-
Zamora, E. Angew. Chem., Int. Ed. 2002, 41, 831.
(6) Prepared from commercially available (S,S)-2,5-hexanediol (alter-
nativelly available from 2,5-hexanedione: Lieser, J. K. Synth. Commun.
1983, 13a, 765) by dimesylation followed by reaction with hydrazine
monohydrate and condensation with aldehydes.
(7) The relative trans stereochemistry was assigned after comparison of
the 2JH3,H4 coupling constants (2.2-2.5 Hz) with the reported typical values
[Jcis ) 4-6 Hz; Jtrans ) 0-3 Hz]: Kagan, H. B.; Basselier, J. J.; Luche, J.
L. Tetrahedron Lett. 1964, 941.
Experiments carried out under the conditions (Et3N, toluene,
∆) previously optimized for formaldehyde derivatives,4
however, afforded cycloadducts 4a-f in low yields (25-
(3) (a) Ferna´ndez, R.; Lassaletta, J. M. Synlett 2000, 1228. (b) Ferna´ndez,
R.; Mart´ın-Zamora, E.; Pareja, C.; Lassaletta, J. M. J. Org. Chem. 2001,
66, 5201. (c) Va´zquez, J.; Prieto, A.; Ferna´ndez, R.; Enders, D.; Lassaletta,
J. M. Chem. Commun. 2002, 498.
(8) Pure cis-4f was heated at 80 °C under the reaction conditions (6 equiv
of 1, 12 equiv of (i-Pr)2EtN, and 6.5 equiv of 2-chloro-N-methyl pyridinium
iodide). After 24 h no traces of trans-4f were observed.
2750
Org. Lett., Vol. 6, No. 16, 2004

The recently reported methodology for the oxidative
deamination of hydrazides10 was applied for the N-N bond
cleavage of compounds 4a-f. Treatment of these cycload-
ducts with methanolic magnesium monoperoxyphthalate
(MMPP) afforded enantiomerically pure free â-lactams 5a-f
in high yields (72-90%) (Table 3).
Scheme 3. Steric Effects in Conrotatory Ring Closing from
Zwitterionic Intermediates
Table 3. Oxidative Cleavage of N-N Bonds
Nevertheless, the initially unexpected trans selectivity can
be considered as an added value from the synthetic point of
view, as the above results complement the only existing
method available for the stereocontrolled ketene-aliphatic
imine cycloaddition leading to cis derivatives.9
As a remarkable exception, the reaction of R-benzyloxy-
acetaldehyde hydrazone 3f with 2 under the same conditions
afforded product 4f as a 54:46 trans/cis mixture. To improve
this particular result, the effect of the reaction temperature
in the product distribution was analyzed. Experiments
conducted at 100 and 120 °C (Table 2) afforded much lower
educt 4
R
product 5
yield (%)a
(3R,4R)-4a
(3R,4R)-4b
(3R,4R)-4c
(3R,4R)-4d
(3R,4R)-4e
(3R,4R)-4fb
Me
i-Pr
i-Bu
(3R,4R)-5a
(3R,4R)-5b
(3R,4R)-5c
(3R,4R)-5d
(3R,4R)-5e
(3R,4R)-5f
90
72
85
73
74
74
PhCH2CH2
n-C5H11
BnOCH2
a Yield of isolated product. b The cleavage reaction was performed using
the enantiomerically pure cis-(3R,4R)-4f adduct.
Products 5 are direct precursors for the synthesis of several
bioactive compounds, including R,â-diamino acids and
monobactams. As illustrative examples, compounds 5a and
5f were transformed into free 3-aminoazetidinones 6 and 8
(Scheme 4), enantiomers of the key components of the
Table 2. Effect of Reaction Temperature in the Product
Distribution of 4f
Scheme 4
entry
T (°C)
t (h)
yield (%)a
trans:cisb
1
2
3
4
5
6
rt
40
60
80
100
120
96
29
35
38
21
13
81
95
79
66
17
14
<1:99
<1:99
37:63
54:46
69:31
97:3
a Combined yield of separated cis and trans adducts after column
chromatography. b Determined by 13C and 1H NMR spectroscopy in the
crude reaction mixture.
yields of product (entries 5 and 6), but the observed trans/
cis ratios were markedly higher. However, the relatively high
reactivity of hydrazone 3f allowed the reactions to be carried
out at lower temperatures, leading to much higher yields of
product and increasing dramatically the cis:trans ratio. An
optimum reaction temperature of 40 °C resulted in the
formation of pure cis (3R,4R)-4f in an excellent 95% yield
while maintaining a reasonable reaction rate (entry 2).
antibiotics aztreonam and carumonam, respectively. The
availability of both enantiomers of the used auxiliary11 allows
(9) Palomo, C.; Aizpurua, J. M.; Legido, M.; Mielgo, A.; Galarza, R.
Chem. Eur. J. 1997, 3, 1432.
Org. Lett., Vol. 6, No. 16, 2004
2751

the obtention of the products with the desired absolute
configuration. It is worth mentioning also that acetaldehyde
and benzyloxyacetaldehyde derivatives 3a and 3f, used for
the above syntheses, are particularly prone to enolization, a
fact that highlights the stabilizing effect of the N-dialkyl-
amino group in hydrazones.
Finally, we used chemical correlation to confirm the
absolute stereochemistry assigned to these compounds.
Standard protection of compound 6 afforded the known
N-Boc-derivative 7. The absolute configuration of (3R,4R)-7
was determined by comparison of its optical rotation with
literature data.12 The absolute stereochemistry of the cis
adduct (3R,4R)-5f was also assigned after chemical correla-
tion. Thus, transfer hydrogenation of 5f by HCOONH4 and
Pd/C afforded deprotected (3R,4R)-8, and this material was
transformed into known N-Cbz derivative (3R,4R)-9.13
Summarizing, the unexpected trans selectivity and high
inductions achieved in the Staudinger-like cycloaddition of
N,N-dialkylhydrazones 3 to R-aminoketene 2 are key for the
development of a short route to bioactive R-amino-â-lactams.
Acknowledgment. We thank the Spanish “Ministerio de
Ciencia y Tecnolog´ıa” (Grant BQU2001-2376, predoctoral
fellowship to E.M.-L. and “Ramon y Cajal” grant to E.D.M.),
the European Commission (HPRN-CT-2001-00172 and
HPMT-CT-2001-00248), and the “Junta de Andaluc´ıa” for
financial support.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0490328
(12) Compound 7 had [R]22 +59.0 (c 1.9, CH3OH). Literature data of
D
(3S,4S)-7: [R]D -64.2 (c 0.85, CH3OH); Hegedus, L. S.; Imwinkelried,
R.; Alarid-Sargent, M.; Dvorak, D.; Satoh, Y. J. Am. Chem. Soc. 1990,
112, 9.
(10) Ferna´ndez, R.; Ferrete, A.; Llera, J. M.; Magriz, A.; Mart´ın-Zamora,
E.; D´ıez, E.; Lassaletta, J. M. Chem. Eur. J. 2004, 10, 737.
(11) Ikeda, H.; Sato, E.; Sugai, T.; Ohta, H. Tetrahedron 1996, 52, 8113.
(13) Compound 9 had [R]22 -7.4 (c 1, CHCl3). Literature data of
D
(3S,4S)-9: [R]D +8.6 (c 0.9, CHCl3); Evans, D. A.; Sjogren, E. B.
Tetrahedron Lett. 1985, 26, 3783.
2752
Org. Lett., Vol. 6, No. 16, 2004