Stereoselective, temperature-dependent [2+2] cycloaddition of N,N-dialkylhydrazones to N-benzyl-N-(benzyloxycarbonyl)aminoketene

Article abstract of DOI:10.1002/ejoc.200800194

The Staudinger-like [2+2] cycloaddition of aliphatic hydrazones derived from (2R,5R)-1-amino-2,5-dimethylpyrrolidine to N-benzyl-N-(benzyloxycarbonyl) aminoketene takes place to afford the corresponding β-lactams in good yields when iPr₂EtN is

Full text of DOI:10.1002/ejoc.200800194

FULL PAPER
DOI: 10.1002/ejoc.200800194
Stereoselective, Temperature-Dependent [2+2] Cycloaddition of
N,N-Dialkylhydrazones to N-Benzyl-N-(benzyloxycarbonyl)aminoketene
Eugenia Marqués-López,[a] Eloísa Martín-Zamora,[a] Elena Díez,[a] Rosario Fernández,*[a]
and José M. Lassaletta*[b]
Keywords: Asymmetric synthesis / Cycloaddition / Hydrazones / Lactams / Antibiotics
The Staudinger-like [2+2] cycloaddition of aliphatic hydra- pothesis that the observed stereochemistry is the result of
zones derived from (2R,5R)-1-amino-2,5-dimethylpyrrolidine
to N-benzyl-N-(benzyloxycarbonyl)aminoketene takes place
to afford the corresponding β-lactams in good yields when
iPr2EtN is used as the base. The reaction proceeds in all cases
with excellent stereocontrol to afford exclusively products
having the (3R) configuration. Temperature was observed to
exert a strong influence on the cis/trans selectivity, allowing
in most cases the obtention of single trans or cis cycloadducts
simply by performing the reactions at 80 °C or room tempera-
ture, respectively. Additional experiments support the hy-
C=N isomerization in the zwitterionic intermediate, which
takes place by a nucleophilic additionϪrotationϪelimination
mechanism effected by the nucleophiles present in the reac-
tion medium. Release of the dialkylamino group by oxidative
cleavage of the N–N bond affords valuable compounds such
as α,β-diamino acids and the azetidinone cores of monobac-
tam antibiotics such as aztreonam and carumonam.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
and co-workers have demonstrated the utility of synthetic
β-lactams as the key structures in the synthesis of confor-
mationally restricted peptidomimetics of biological signifi-
cance.[14] Moreover, β-lactams can be considered as pro-
tected β-amino acids and have been used as chiral building
blocks in synthetic organic chemistry.[15]
Introduction
β-Lactam antibiotics have been key drugs for over 70
years in man’s fight against infectious diseases. They are
the most widely employed type of antibacterial agents and,
therefore, constitute one of the major cornerstones in me-
dicinal chemistry.[1] The discovery[2] and structural elucida-
tion of the first isolated members of this family of anti-
biotics (penicillin G[3] and cephalosporin C[4]) boosted the
activity of synthetic chemists towards the development of
methodologies for the stereoselective construction of the β-
lactam skeleton.[5] Nowadays, the interest in these com-
pounds is sustained because of the constant need for new
drugs displaying broader antibacterial activity and/or dif-
ferent biological profiles to combat bacteria that have built
up resistance against most traditional compounds. Ad-
ditionally, the use of β-lactams for other purposes is at-
tracting attention. For instance, recent reports have de-
scribed the development of inhibitors such as serine prote-
ase,[6] human leukocyte elastase,[7] cytomegalovirus prote-
ase,[8] thrombin,[9] prostate specific antigen,[10] cholesterol
absorption,[11] and tryptase.[12] Some β-lactams have also
shown anticancer activity,[13] and recent studies by Palomo
Within the large family of β-lactams, the 3-amino-substi-
tuted derivatives have a specific importance owing to their
bioactivity. The discovery of monocyclic β-lactam antibiot-
ics,[16] named and classified as monobactams, and the intro-
duction of drugs such as aztreonam (Azactam®) and caru-
monam on the one hand, and the additional interest in 3-
amino-β-lactams as valuable precursors to biologically
active α,β-diamino acid derivatives[17] on the other, have
stimulated considerable efforts towards the development of
stereoselective routes to the key 3-aminoazetidin-2-one sub-
structure.[18] Among the methods available for the ste-
reocontrolled synthesis of the azetidinone skeleton and
their open-chain β-amino acid analogues, the [2+2] ketene–
imine cycloaddition,[19] known as the Staudinger reac-
tion,[20] appears as one of the most widely used strategies
due to its simplicity and the availability of the starting ma-
terials (Scheme 1).
One of the strategies used involves the cycloaddition of
imines and ketenes substituted by an oxygenated function-
ality that is later used as the leaving group in the introduc-
tion of nitrogen nucleophiles. For instance, the cyclo-
addition of sulfonylketenes to chiral imines has been used
for the stereoselective construction of 3-sulfonyl-β-lactams.
Ensuing substitution by azide enabled the synthesis of bio-
[a] Departamento de Química Orgánica, Facultad de Química,
Universidad de Sevilla,
Apdo. de Correos No. 1203, 41071 Seville, Spain
E-mail: ffernan@us.es
[b] Instituto de Investigaciones Químicas, CSIC-US,
c/ Américo Vespucio 49, Isla de la Cartuja, 41092 Seville, Spain
E-mail: jmlassa@iiq.csic.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
2960
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2960–2972

Cycloaddition of N,N-Dialkylhydrazones to Aminoketene
timization study of the cycloaddition of N,N-dialkylhydra-
zones to benzyloxyketene,[29] was used as the hydrazone chi-
ral auxiliary assuming in principle that similar interactions
should govern the stereochemical outcome of the reaction
with the nitrogenated ketene 2. Thus, aliphatic hydrazones
3a–e were synthesized and allowed to react with 1 under
the previously established conditions (toluene, 80 °C,
Et3N)[29b] to afford the corresponding cycloadducts 4a–e as
single diastereomers. Disappointingly, though, products 4
were obtained in low yields (25–50%) under these condi-
tions. Therefore, different reaction parameters were scre-
ened to improve the chemical efficiency of the cycload-
dition. From this study, a remarkable influence of the base
used for the generation of the ketene was identified. Thus,
when iPr2EtN was used as the base, the corresponding β-
lactams 4a–e were obtained in much better yields (59–74%,
Table 1, entries 1–5), and again as single diastereomers. In
sharp contrast, other bases tested (Bn3N, proton sponge,
di-tert-butylpyridine, etc.) gave no reaction under these con-
ditions.
Scheme 1. The ketene–imine [2+2] cycloaddition approach to 3-
amino-β-lactams.
logically important carbohydrates[21] and of the taxol amino
side-chain.[22]
[2+2] cycloaddition to 3-azidoketenes followed by re-
duction of the azido group has also been used for the syn-
thesis of 3-amino-β-lactams.[23] Another versatile method
that affords enantiopure 3-amino-β-lactams and α,β-di-
amino acids makes use of the [2+2] cycloaddition of N-acyl-
protected aminoketenes to imines, a reaction that has been
accomplished by introducing chiral auxiliaries into the im-
ine or ketene components.[24] Additionally, α-branched α-
amino-β-lactams and peptides derived therefrom have been
obtained by diastereoselective alkylation of 4-unsubstituted
derivatives.[25]
These methodologies, however, in general suffer some
limitations mainly imposed by the poor stability of the re-
quired imines. With very few exceptions,[26] enolizable, sim-
ple aliphatic aldimines cannot be used in this type of cyclo-
addition because of their low thermal stability and the com-
petitive deprotonation by the base required for the in situ
generation of the ketene. Based on our previous experiences
with N,N-dialkylhydrazones,[27] we recently started a project
based on 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)ketenes[28] and that the
stability of aliphatic N,N-dialkylhydrazones is key to the
straightforward synthesis of 3-alkoxy-4-alkyl(aryl)azetidin-
2-ones and that of the corresponding isoserines.[29]
We now wish to present the results of our study of the
use of chiral, aliphatic N,N-dialkylhydrazones as imine sur-
rogates in the Staudinger-like [2+2] cycloaddition to α-ami-
noketenes in the synthesis of 3-amino-4-alkylazetidin-2-
ones[30] and α,β-diamino acids, and of the marked influence
of the base and the reaction temperature on the course of
the reaction.
Scheme 2. Synthesis of 3-amino-4-alkylazetidin-2-ones 4.
Anomalous behavior was observed in the reaction of
benzyloxyacetaldehyde-derived hydrazone 3f with 2. Under
the same conditions, the expected cycloadduct 4f was also
obtained in 66% yield, but in this case as a 54:46 trans/cis
separable mixture of (3R,4S) and (3R,4R) diastereomers
Results and Discussion
The preliminary experiments were conducted using N- (Table 1, entry 6).
benzyl-N-(benzyloxycarbonyl)glycine (1) as the precursor to
The unexpected trans selectivity observed in the forma-
aminoketene 2 and 2-chloro-1-methylpyridinium iodide as tion of cycloadducts 4a–e contrasts the excellent cis selectiv-
the activating agent. This choice was made on the basis of ity observed with the same auxiliary in the cycloaddition of
previous results from the synthesis of 4-unsubstituted azeti- hydrazones 3 with benzyloxyketene,[29] which suggests that
din-2-ones[28] (Scheme 2). On the other hand, the C2-sym- a different mechanism operates in this case. A cis/trans
metric (2R,5R)-2,5-dimethylpyrrolidine, identified in an op- base-catalyzed epimerization at C-3 was eventually pro-
Eur. J. Org. Chem. 2008, 2960–2972
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2961

R. Fernández, J. M. Lassaletta et al.
FULL PAPER
Table 1. Synthesis of 4-alkyl-3-aminoazetidin-2-ones 4.
[b]
[b]
Entry
Starting material
R
Product
% Yield[a]
(3R)/(3S)trans
trans/cis[b]
(3R)/(3S)cis
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Me
iPr
iBu
PhCH2CH2
n-C5H11
BnOCH2
trans-crotyl
(3R,4R)-4a
(3R,4R)-4b
(3R,4R)-4c
(3R,4R)-4d
(3R,4R)-4e
(3R,4S/R)-4f
(3R,4S)-4g
74
66
70
70
59
66
67
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
–
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
54:46[c]
Ͻ1:99
–
–
–
–
–
Ͼ99:1
Ͼ99:1
3g
1
[a] Yield of isolated product 4. Reactions were performed on a 1 mmol scale in toluene at 80 °C. [b] Determined by H and 13C NMR
analysis of the crude reaction mixtures. [c] Separable by column chromatography.
posed to explain the anomalous trans selectivity observed. interactions (X = OBn) the intermediate directly undergoes
This possibility, however, was considered unconvincing be- ring-closure to afford the cis product, but for hindered sub-
cause such an epimerization to the observed (3R,4R)-4 re- strates this intermediate may also undergo C–N bond isom-
quires the initial formation of the (3S,4R) isomer, that is, a erization to the less hindered zwitterion (Z)-ZW and subse-
product that holds the opposite configuration at C-3 with quent ring-closure to the observed trans β-lactam.[34]
respect to that observed regularly in related systems of the
The zwitterion (E)-ZW isomerization mechanism re-
used auxiliary. Moreover, unsuccessful attempts to epimer- mains unknown, but there is evidence from the Staudinger
ize available cis compounds ruled out this possibility,[31] reaction between ketenes and imines that is not consistent
confirming that kinetically controlled products are obtained with a direct isomerization by C–N bond rotation.[35] On
under the reaction conditions. This is in agreement with the other hand, a multi-step (E)-ZW/(Z)-ZW isomerization
previous reports on the absence of epimerization of related process initiated by attack of a nucleophile on the azome-
cis-β-lactams in the presence of triethylamine.[32]
thine carbon of E-(ZW) followed by rotation of the re-
The trans selectivity observed could alternatively be ex- sulting C–N single bond and finally elimination of the nu-
plained as being the result of an “inward” approach of the cleophile to the Z-(ZW) intermediate seems to be a more
aminoketene to the hydrazone, leading to a zwitterionic in- plausible pathway.
termediate (E)-ZWЈ, which, upon direct conrotatory ring-
In addition to the above-mentioned steric effect, the dif-
closure, leads to the observed (3R,4S) configuration ferent stereochemical outcomes for benzyloxy- and amino-
(Scheme 3). However, previous studies have revealed that ketene 2 may also be partly affected by the experimental
cycloaddition via “inward” intermediates is more energy- conditions. The benzyloxyketene is generated in situ by eli-
demanding than via the “outward” intermediates when mination of benzyloxyacetyl chloride in the presence of tri-
electron-rich ketenes are involved.[33] Therefore, the ob- ethylamine, but the aminoketene derivative 2 is obtained by
served stereochemistry and a comparison with the stereo- reaction of the corresponding α-amino acid precursor 1 and
chemistry observed in the cycloaddition to benzyloxyketene 2-chloro-1-methylpyridinium iodide in the presence of
[cis (3R,4R) products] suggest a consistent path (outward iPr2EtN. It is clear that there is a marked difference in reac-
approach of the ketene) for the formation of the zwitter- tion conditions, such as the nature and concentration of the
ionic intermediates (E)-ZW. In the absence of severe steric nucleophiles (Et3N, iPr2EtN, iodide, chloride). We propose
Scheme 3. Suggested model for the relative stereochemistry of the cycloaddition.
2962
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2960–2972

Cycloaddition of N,N-Dialkylhydrazones to Aminoketene
that the trans configuration observed when the aminoketene observed byproduct 9 by hydrogen abstraction by bases, as
is generated from N-benzyl-N-(benzyloxycarbonyl)glycine is illustrated in Scheme 5. Interestingly, an experiment carried
the result of two factors: a) The inhibition of the direct out using Bn3N instead of the more basic iPr2EtN and
ring-closure of the (E)-ZW intermediate due to consider- Et3N afforded enamide 9 (92:8 mixture of isomers) as the
able steric interactions and b) a favored isomerization pro- sole reaction product in 74% yield; no traces of cyclo-
cess assisted by the presence of suitable nucleophiles and addition products were detected.
the high temperatures applied.
Experiments were carried out in order to support this
hypothesis. First, when 2-chloro-1-methylpyridinium triflate
was used to generate the aminoketene 2, the reaction with
hydrazone 3d (Scheme 4) afforded the corresponding β-lac-
tam 4d in an 80:20 trans/cis ratio, in sharp contrast to the
exclusive formation of the trans isomer observed when the
2-chloro-1-methylpyridinium iodide was used as the activa-
ting agent. The decrease in the trans-β-lactam product is
consistent with the use of triflate, a less nucleophilic anion
than iodide. The substantial amount of trans product ob-
served even in these conditions can be explained by the
presence of the chloride anion (also able to behave as a
nucleophile),[36] liberated in the activation of N-benzyl-N-
(benzyloxycarbonyl)glycine (1) by 2-chloro-1-methylpyridi-
nium triflate in the presence of iPr2EtN.
Scheme 5. Reaction of hydrazone 3d with benzyloxyacetyl chloride
5.
In order to help clarify the role of the base in the initial
ketene formation step, the reactions of 5 with Et3N,
Scheme 4. Effect of nucleophiles on the trans/cis ratio of the cyclo-
addition.
iPr2EtN, and Bn3N were performed in C6D6 solution under
1
argon and monitored by H NMR spectroscopy. The for-
We next investigated the reaction of benzyloxyacetyl mation of the ketene was complete at room temp. within
chloride 5 with hydrazone 3d (Scheme 5). The reaction was 2 h in the Et3N case, whereas unreacted 5 was observed
performed using the same conditions as those applied in the with iPr2EtN, and the transformation was even slower with
experiments with the aminoketene precursor 1 (12 equiv. of Bn3N. We conclude that there is competition between ke-
iPr2EtN, 6.5 equiv. of 2-chloro-1-methylpyridinium iodide, tene formation (favored by using iPr2EtN and Et3N) and
dry toluene, 80 °C). Under these conditions, the corre- the acylation of hydrazone (favored by Bn3N); the first
sponding β-lactam 7 was obtained in 85% yield as a 44:56 pathway leads mainly to β-lactam products, whereas the
trans/cis mixture, in contrast to the 9:91 trans/cis ratio ob- second produces only enamide derivative 9.
served under previously optimized conditions (dry toluene,
Finally, it was reasoned that any additional stabilization
80 °C, 8 equiv. of Et3N).[29] Again, the increase in the of the C=N bond in the initially formed (E)-ZW intermedi-
trans/cis β-lactam product ratio supports the hypothesis of ate should slow down the addition of nucleophiles, thereby
a marked influence by nucleophiles (iodide anions intro- making the isomerization process more difficult. Although
duced) on the stereoselectivity of the reaction. Note also the synthetic interest in aromatic derivatives of 4 (R = Ar)
the formation under these conditions of enamide 9 as a by- is not so high due to the availability of suitable alterna-
product in 14% yield. The formation of this byproduct is tives,[24] we decided to study the effect of stabilization of the
interpreted as being the result of an acylation of the hydra- C=N bond by its conjugation with an aromatic group in
zone 3d by the acyl chloride 5 to form the corresponding the zwitterionic intermediate, presuming that a higher
acyliminium chloride 8. This intermediate directly yields the amount of the cis product would be observed in these cases.
Eur. J. Org. Chem. 2008, 2960–2972
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2963

R. Fernández, J. M. Lassaletta et al.
FULL PAPER
Scheme 6. Reaction of crotonaldehyde derivative 3g with N-benzyl-N-(benzyloxycarbonyl)glycine (1).
Unfortunately, hydrazones 3 derived from benzaldehyde (R of 40 °C was established in this case, affording pure cis-
= Ph) or even p-methoxybenzaldehyde (R = p-MeOC6H4) (3R,4R)-4f in an excellent 95% yield (entry 5).
were found to be unreactive; no cycloaddition product was
Release of the 2,5-dimethylpyrrolidine auxiliary was re-
formed under any of the conditions attempted. As an alter- quired to afford the target β-lactams. Taking into account
native, crotonaldehyde hydrazone 3g was chosen as a model the poor results observed when the known reduction pro-
substrate to investigate the effect of stabilization by conju- cedures were applied to the required N–N bond cleavage in
gation. Interestingly, the cycloaddition of this substrate pro- the related 3-(benzyloxy)azetidinones,[29] compounds 4a–g
ceeded to afford the expected product 4g as a single cis- were deprotected by applying the recently reported method-
(3R,4S) isomer in 67% yield (Scheme 6, Table 1, entry 7). ology for the oxidative deamination of hydrazides
This result is consistent with the proposed nucleophile-as- (Scheme 7).[38] Accordingly, treatment of compounds 4 with
sisted isomerization hypothesis, as it leads to the conclusion methanolic magnesium monoperoxyphthalate hexahydrate
that the addition of nucleophiles to the corresponding (E)-
ZW intermediate is inhibited, in this case by the additional
stabilization of the allylic cation, thereby preventing the
isomerization of the C=N bond.
Further investigations showed a marked influence of
temperature on the stereoselectivity of the reaction.[37]
When reactions of aminoketene 2 with hydrazones 3c–f
were conducted at room temperature the corresponding cis-
(3R,4S)-4c–e and cis-(3R,4R)-4f compounds were obtained
in moderate-to-good yields and with good-to-excellent
cis/trans selectivities. Moreover, no cycloadducts having the
(3S) configuration were detected (Table 2). The formation
of small amounts of the trans-(3R,4R)-4c,e isomers were
observed in some cases (entries 1 and 3), but a simple sepa-
ration by flash chromatography allowed the isolation of the
major cis isomers (3R,4S)-4c and (3R,4S)-4e in pure form.
When hydrazone 3f was used, the reaction at room tem-
perature also led to the desired cis product (3R,4R)-4f in
Scheme 7. Release of the chiral auxiliary: oxidative cleavage of the
high yield (entry 4), but an optimum reaction temperature N–N bond.
Table 2. Effect of temperature on the trans/cis ratio of the cycloaddition.
Entry
Starting material
R
T [°C]
t
Major product
% Yield[a]
trans/cis[b]
(3R)/(3S)cis
1
2
3
4
5
3c
3d
3e
3f
3f
iBu
r.t.
r.t.
r.t.
r.t.
40
5 d
4 d
4 d
4 d
29 h
cis-(3R,4S)-4c
cis-(3R,4S)-4d
cis-(3R,4S)-4e
cis-(3R,4R)-4f
cis-(3R,4R)-4f
40
72
41
81
95
8:92 (Ͻ1: 99)[c]
Ͻ1:99
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
PhCH2CH2
n-C5H11
BnOCH2
BnOCH2
13:87 (Ͻ1: 99)[c]
Ͻ1:99
Ͻ1:99
[a] Yield of isolated cis product. Reactions were performed on the 1 mmol scale in toluene. [b] Determined by 1H and 13C NMR analysis
of the crude reaction mixtures. [c] Separable by column chromatography.
2964
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2960–2972

Cycloaddition of N,N-Dialkylhydrazones to Aminoketene
(MMPP·6H2O) readily afforded cis or trans free β-lactams
10a–f in high yields (72–93%) and in enantiomerically pure
form (Table 3). The presence of the C=C double bond in 4g
made the selective N-oxidation of the amino nitrogen diffi-
cult. Nevertheless, the desired product 10g could be ob-
tained in 60% yield by performing the reaction at a lower
temperature (0 °C). Under these conditions, epoxide 11 was
obtained as a byproduct in 33% yield. This compound was
obtained as the major product in 61% yield when an excess
of 2.6 equiv. of MMPP was employed at room temperature.
Table 3. Synthesis of the azetidin-2-ones 10a–g by oxidative N–N
bond cleavage of β-lactams 4a–g.[a]
Starting material
R
Product
% Yield[b]
trans-(3R,4R)-4a
trans-(3R,4R)-4b
trans-(3R,4R)-4c
cis-(3R,4S)-4c
trans-(3R,4R)-4d
cis-(3R,4S)-4d
trans-(3R,4R)-4e
cis-(3R,4S)-4e
cis-(3R,4R)-4f
cis-(3R,4S)-4g
cis-(3R,4S)-4g
Me
iPr
iBu
iBu
PhCH2CH2
PhCH2CH2
n-C5H11
n-C5H11
BnOCH2
trans-crotyl
trans-crotyl
trans-(3R,4R)-10a
trans-(3R,4R)-10b
trans-(3R,4R)-10c
cis-(3R,4S)-10c
trans-(3R,4R)-10d
cis-(3R,4S)-10d
trans-(3R,4R)-10e
cis-(3R,4S)-10e
cis-(3R,4R)-10f
cis-(3R,4S)-10g
cis-(3R,4R)-11
90
72
85
93
73
91
74
84
74
60[c]
61[d]
[a] Reactions were performed in MeOH on the 1 mmol scale using
1.25 equiv. of MMPP at room temp., unless indicated otherwise. [b]
Isolated yield. [c] The reaction was performed at 0 °C. [d] The reac-
tion was performed with 2.6 equiv. of MMPP.
Scheme 8. Chemical correlations used for the determination of the
absolute configurations.
The absolute configuration of these compounds was as-
signed by chemical correlation with the transformations
shown in Scheme 8. Compound trans-(3R,4R)-10a was
transformed into the corresponding free amine 12 in 75%
yield by hydrogenation with Pearlman’s catalyst [Pd(OH)2/
C] in 20:1 dioxane/H2O.[39] Ensuing protection using
Boc2O/Et3N in MeOH led to the known N-Boc derivative
13 in 72% yield.[40] The absolute stereochemistry of the cis
adduct (3R,4R)-10f was also assigned after chemical corre-
lation. Transfer hydrogenation of cis-(3R,4R)-10f with
HCO2NH4 and Pd/C followed by protection with ClCO2Bn
were performed to afford the known N-Cbz derivative
(3R,4R)-14 in 55% overall yield.[41] Compound cis-(3R,4S)-
10d was also transformed into the known N-Boc derivative
15[42] in 42% overall yield by again using transfer hydrogen-
ation with HCO2NH4 and Pd/C and ensuing protection by
Boc2O/Et3N in MeOH. Finally, the absolute configuration
of cis-(3R,4S)-4g was also assigned by chemical correlation.
In this case, transformation into cis-(3R,4R)-4f was ac-
complished by ozonolysis of the C=C bond, reduction of
the resulting aldehyde, and protection with benzyl bromide.
The absolute configurations of all other compounds were
assigned by analogy.
configuration. Note, the acetaldehyde and benzyloxyacetal-
dehyde imine derivatives required for the above syntheses
are particularly prone to enolization. This fact highlights
the stabilizing properties of the dialkylamino group in pri-
mary aliphatic hydrazones.
Figure 1. Antibiotics aztreonam and carumonam.
Finally, compounds 10 can also be considered as direct
precursors to valuable α,β-diamino acids. As an illustrative
example, standard transformations from compound
(3R,4R)-10c were applied to the synthesis of the corre-
sponding free diamino acid (2R,3R)-17, which was obtained
in good overall yield (Scheme 9).
The products 10 are direct synthetic precursors of several
bioactive compounds, including α,β-diamino acids and
monobactams. For instance, compounds 13 and 14 are
enantiomers of the key β-lactam components of the antibi-
Conclusions
The multiple roles played by the dialkylamino group of
otics aztreonam and carumonam, respectively (Figure 1). hydrazones 3 are key to the successful synthesis of target 3-
The availability of both enantiomers of the used auxiliary amino-β-lactams. First, the nǞπ conjugation of the N lone-
allows the obtention of products with the desired absolute pair with the C=N bond stabilizes these compounds, in par-
Eur. J. Org. Chem. 2008, 2960–2972
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2965

R. Fernández, J. M. Lassaletta et al.
FULL PAPER
saturated NaHCO3, dried (Na2SO4), filtered, and concentrated.
The resulting residue was cooled to 0 °C and hydrazine monohy-
drate (9.7 mL, 200 mmol) was added. The reaction was stirred at
room temp. overnight and then saturated NaHCO3 was added. The
aqueous layer was extracted with Et2O and the combined organic
layers were dried (Na2SO4) and filtered. Na2SO4 and the corre-
sponding aldehyde (1.2–1.5 equiv.) were added to the ethereal solu-
tion. The mixture was stirred until consumption of the starting
material (1–3 d), then filtered and concentrated. The purification
method, yields, and spectral and analytical data for compounds 3a
and 3e–g are as follows.
(2R,5R)-1-(Ethylideneamino)-2,5-dimethylpyrrolidine (3a): From
acetaldehyde (0.85 mL, 15 mmol), after 3 d purification by distil-
lation (65 °C, 15–20 mbar), 300 mg (25% over three steps) of 3a
was obtained as a colorless liquid: [α]2D5 = –6.7 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.06 (d, J = 6.2 Hz, 6 H), 1.41–
1.52 (m, 2 H), 1.92 (d, J = 5.1 Hz, 3 H), 2.04–2.17 (m, 2 H), 3.57–
3.65 (m, 2 H), 6.68 (q, J = 5.1 Hz, 1 H) ppm. 13C NMR (75 MHz,
Scheme 9. Synthesis of α,β-diamino acid (2R,3R)-17.
ticular against the otherwise favored enolization to enehyd-
razine tautomers. Secondly, the 2,5-dimethylpyrrolidine
moiety efficiently controls the approach of the hydrazone
to the aminoketene 2, always very selectively leading to
products with the (3R) configuration. Thirdly, the dialk-
ylamino chiral auxiliary simultaneously behaves as a pro-
tecting group that can be efficiently released under mild
conditions to afford the target 3-amino-β-lactams. These
properties, combined with the tunable, temperature-con-
trolled cis/trans selectivity results in a short and versatile
route to α-amino-β-lactams 10, which can be obtained with
the desired absolute and relative configurations. In particu-
lar, the a priori unexpected trans selectivity observed at high
CDCl ): δ = 17.6, 19.1, 29.1, 55.1, 133.6 ppm. IR (film): ν = 2965,
˜
3
2926, 2875, 1722, 1607, 1448, 1378, 1327, 1218, 1174, 1123 cm–1.
HRMS: calcd. for C8H15N2 139.1235; found 139.1231.
(2R,5R)-1-(Hexylideneamino)-2,5-dimethylpyrrolidine (3e): From
hexanal (1.82 mL, 15 mmol), after 1 d flash chromatography (1:16
Et2O/hexane), 1.32 g (67% over three steps) of 3e was obtained as
an oil: [α]2D5 = –16.3 (c = 1.1, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 0.88 (t, J = 6.9 Hz, 3 H), 1.06 (d, J = 6.2 Hz, 6 H),
1.26–1.37 (m, 4 H), 1.39–1.53 (m, 4 H), 2.02–2.17 (m, 2 H), 2.18–
2.25 (m, 2 H), 3.56–3.65 (m, 2 H), 6.62 (t, J = 5.6 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 14.2, 17.8, 22.7, 27.8, 29.3, 31.6,
temperatures can be considered as a particularly valuable 33.5, 55.3, 138.9 ppm. IR (film): ν = 2964, 2927, 2866, 1610, 1460,
˜
1371, 1319, 1208, 1171 cm–1. HRMS: calcd. for C12H23N2
195.1861; found 195.1868.
circumstance from the synthetic point of view as the avail-
able methods for the stereocontrolled ketene–aliphatic im-
ine cycloaddition lead to cis cycloadducts. Finally, the syn-
thetic value of this methodology is demonstrated by the
synthesis of α,β-diamino acid 17 and those of compounds
13 and 14, the β-lactam cores of monobactam antibiotics
such as aztreonam and carumonam.
(2R,5R)-1-[2-(Benzyloxy)ethylideneamino]-2,5-dimethylpyrrolidine
(3f): From benzyloxyacetaldehyde (1.74 mL, 12 mmol), after 3 d
flash chromatography (1:20 Ǟ 1:8 Et2O/hexane), 1.77 g (72%, over
three steps) of 3f was obtained as an oil: [α]2D2 = –42.8 (c = 1.0,
1
CH2Cl2). H NMR (300 MHz, CDCl3): δ = 1.10 (d, J = 6.3 Hz, 6
H), 1.43–1.55 (m, 2 H), 2.05–2.19 (m, 2 H), 3.64–3.72 (m, 2 H),
4.12 (dd, J = 11.7, 5.4 Hz, 1 H), 4.17 (dd, J = 11.7, 5.4 Hz, 1 H),
4.53 (s, 2 H), 6.54 (t, J = 5.5 Hz, 1 H), 7.24–7.38 (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 18.1, 29.4, 55.2, 71.3, 71.9, 127.6,
Experimental Section
128.1, 128.5, 128.7, 138.6 ppm. IR (film): ν = 3023, 2967, 2928,
General Methods: Toluene was distilled from sodium benzophe-
none ketyl and CH2Cl2 from CaH2 immediately prior use; Et3N
from Na and iPr2EtN from KOH. All other reagents and solvents
were purified by standard procedures or were used as obtained
from commercial sources as appropriate. Aqueous solutions were
all saturated, unless otherwise stated. Flash column chromatog-
raphy was carried out using silica gel (Merck, 0.063–0.200 mm or
0.040–0.063 mm) or prepacked silica columns (FLASH biotage).
1H NMR spectra were recorded at 300 or 500 MHz and are re-
ported as follows: δ values in ppm (multiplicity, coupling constant
J in Hz, number of protons). Residual protic solvent was used as
the internal reference. 13C NMR spectra were recorded at 75 or
125 MHz. Chemical shifts are quoted in ppm and referenced to
the appropriate solvent peak. Hydrazones 3b–d were synthesized
according to previously described procedures.[29b]
˜
2872, 1593, 1458, 1371, 1315, 1212, 1077, 846, 735, 703 cm–1
HRMS: calcd. for C15H22N2O 246.1732; found 246.1736.
.
(2R,5R)-1-(But-2-enylideneamino)-2,5-dimethylpyrrolidine (3g):
From but-2-enal (1.2 mL, 14 mmol), after 1 d flash chromatog-
raphy (1:9 Et2O/hexane), 815 mg (49% over three steps) of 3g was
obtained as a 90:10 mixture of E/Z isomers (oil): [α]2D0 = +63.4 (c
1
= 1.3, CHCl3). NMR spectroscopic data for the major isomer: H
NMR (300 MHz, CDCl3): δ = 1.08 (d, J = 6.3 Hz, 6 H), 1.44–1.54
(m, 2 H), 1.79 (dd, J = 6.7, 1.6 Hz, 3 H), 2.08–2.15 (m, 2 H), 3.67–
3.70 (m, 2 H), 5.69 (dq, J = 15.4, 6.7 Hz, 1 H), 6.20 (ddq, J = 15.4,
8.9, 1.6 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 18.0, 18.1, 29.2, 54.9, 127.3, 131.0,
134.7 ppm. NMR spectroscopic data for the minor isomer: 1H
NMR (300 MHz, CDCl3): δ = 1.14 (d, J = 6.3 Hz, 6 H), 1.44–1.54
(m, 2 H), 1.79 (dd, J = 6.7, 1.7 Hz, 3 H), 2.08–2.15 (m, 2 H), 3.67–
3.70 (m, 2 H), 5.46–5.57 (m, 1 H), 6.15 (ddq, J = 11.1, 9.3, 1.7 Hz,
1 H), 7.20 (d, J = 9.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
General Procedure for the Synthesis of Hydrazones 3a and 3e–g:
Et3N (3.5 mL, 25 mmol) was added to a solution of (2S,5S)-hex-
ane-2,5-diol (1.2 g, 10 mmol) in dry CH2Cl2 (20 mL) under argon.
The mixture was cooled to –30 °C and MsCl (2 mL, 25 mmol) was
added dropwise. The reaction was stirred at 0 °C for 3 h and then
1  HCl (20 mL) was added. The organic layer was washed with
δ = 18.1, 21.3, 30.9, 55.0, 123.4, 128.5, 129.8 ppm. IR (film): ν =
˜
2963, 1558, 1448, 1366, 1322, 1214, 1075, 967, 756 cm–1. HRMS:
calcd. for C10H19N2 167.1546; found 167.1548.
2966
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2960–2972

Cycloaddition of N,N-Dialkylhydrazones to Aminoketene
General Procedure for the Synthesis of 4-Alkyl-3-aminoazetidin-2-
ones 4a–g: iPr2EtN (2.1 mL, 12 mmol) was added to a solution of
hydrazones 3a–g (1 mmol) in dry toluene (5 mL) under argon. The
mixture was heated at the appropriate temperature and a solution
of 1 (1.8 g, 6 mmol) in dry toluene (15 mL) was added portionwise
(six portions of 1 mmol each over 5 h). Simultaneously, six portions
of 2-chloro-1-methylpyridinium iodide (281 mg each, 1.1 mmol)
were added over the same period of time. The reaction was stirred
at the appropriate temperature until TLC indicated total consump-
tion of the starting material. The mixture was then diluted with
EtOAc, washed with brine, dried (Na2SO4), filtered, concentrated,
and the residue purified by flash chromatography. The eluents,
yields, and spectral and analytical data for compounds 4a–g are as
follows.
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-di-
methylpyrrolidin-1-yl]-4-isobutylazetidin-2-one [(3R,4S)-4c]: From
3c (182 mg, 1 mmol), carrying out the reaction at room temp., after
5 d flash chromatography of the crude product (dr = 98:2) using
silica gel (Merck, 0.040–0.063 mm, 1:4 Et2O/hexane), 184 mg
(40%) of cis-(3R,4S)-4c was obtained as an oil: [α]2D5 = –36.4 (c =
1.0, CHCl3). 1H NMR (300 MHz, [D6]DMSO, 90 °C): δ = 0.78 (d,
J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3 H), 1.04 (d, J = 6.3 Hz, 6
H), 1.09–1.17 (m, 1 H), 1.24–1.39 (m, 3 H), 1.48–1.62 (m, 1 H),
1.84–1.98 (m, 2 H), 3.55–3.66 (m, 2 H), 3.67–3.73 (m, 1 H), 4.51
(s, 2 H), 4.91 (d, J = 5.4 Hz, 1 H), 5.12 (s, 2 H), 7.25–7.36 (m, 10
H) ppm. 13C NMR (75 MHz, [D6]DMSO, 90 °C): δ = 18.3, 21.6,
22.3, 24.4, 29.5, 37.3, 50.9, 55.5, 62.4, 62.9, 66.4, 126.5, 127.1,
127.2, 127.3, 127.6, 127.7, 136.0, 137.6, 154.9, 164.6 ppm. IR (film):
ν = 2959, 1755, 1708, 1456, 1371, 1238, 1121, 739, 700 cm–1
.
˜
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-
dimethylpyrrolidin-1-yl]-4-methylazetidin-2-one [(3R,4R)-4a]: From
3a (142 mg, 1 mmol), carrying out the reaction at 80 °C, after 6 h
flash chromatography (1:1:12 Ǟ 1:1:5 Et2O/CH2Cl2/hexane),
HRMS: calcd. for C28H38N3O3 464.2913; found 464.2918.
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-
dimethylpyrrolidin-1-yl]-4-(2-phenylethyl)azetidin-2-one [(3R,4R)-
4d]: From 3d (230 mg, 1 mmol), carrying out the reaction at 80 °C,
after 20 h flash chromatography (1:1:15 Ǟ 1:1:5 Et2O/CH2Cl2/hex-
312 mg (74%) of trans-(3R,4R)-4a was obtained as an oil: [α]2D4
=
1
–62.8 (c = 1.0, CHCl3). H NMR (300 MHz, [D6]DMSO, 90 °C):
δ = 0.97 (d, J = 6.3 Hz, 6 H), 1.05 (d, J = 6.1 Hz, 3 H), 1.26–1.34
ane), 358 mg (70%) of trans-(3R,4R)-4d was obtained as an oil:
(m, 2 H), 1.87–1.94 (m, 2 H), 3.52–3.58 (m, 3 H), 4.23 (d, J = [α]2D2 = –28.0 (c = 1.1, CHCl3). H NMR (500 MHz, [D6]DMSO,
1
2.2 Hz, 1 H), 4.50 (d, J = 16.0 Hz, 1 H), 4.60 (d, J = 16.0 Hz, 1
100 °C): δ = 1.00 (d, J = 6.3 Hz, 6 H), 1.23–1.35 (m, 2 H), 1.67–
H), 5.15 (s, 2 H), 7.21–7.34 (m, 10 H) ppm. 13C NMR (75 MHz, 1.73 (m, 1 H), 1.89–1.98 (m, 3 H), 2.57–2.61 (m, 2 H), 3.55–3.59
[D6]DMSO, 90 °C): δ = 14.8, 18.0, 29.4, 50.0, 54.9, 56.9, 66.4, 66.9,
(m, 3 H), 4.42 (d, J = 16.1 Hz, 1 H), 4.45 (d, J = 2.3 Hz, 1 H), 4.56
(d, J = 16.1 Hz, 1 H), 5.13 (d, J = 12.6 Hz, 1 H), 5.17 (d, J =
12.6 Hz, 1 H), 7.03–7.38 (m, 15 H) ppm. 13C NMR (125 MHz,
[D6]DMSO, 100 °C): δ = 18.4, 29.8, 31.2, 32.2, 50.4, 55.4, 61.0,
66.3, 67.0, 125.7, 126.9, 127.0, 127.5, 127.8, 128.0, 128.2, 128.2,
126.5, 126.6, 127.0, 127.3, 127.8, 136.0, 137.7, 154.7, 163.5 ppm.
IR (film): ν = 2965, 2928, 1755, 1707, 1450, 1421, 1371 cm–1
.
˜
C25H31N3O3 (421.53): calcd. C 71.23, H 7.41, N 9.97; found C
71.44, H 7.83, N 9.89.
136.5, 138.0, 141.2, 155.1, 164.1 ppm. IR (film): ν = 2960, 2926,
˜
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-
dimethylpyrrolidin-1-yl]-4-isopropylazetidin-2-one [(3R,4R)-4b]:
From 3b (168 mg, 1 mmol), carrying out the reaction at 80 °C, after
53 h flash chromatography (1:1:6 Et2O/CH2Cl2/hexane), 297 mg
(66%) of trans-(3R,4R)-4b was obtained as an oil: [α]2D2 = –18.4 (c
= 0.9, CH2Cl2). H NMR (500 MHz, [D6]DMSO, 95 °C): δ = 0.83
(d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 1.03 (d, J = 5.7 Hz,
6 H), 1.31–1.32 (m, 2 H), 1.76 (m, J = 6.8 Hz, 1 H), 1.91–1.94 (m,
1755, 1707, 1454, 1417 cm–1. C32H37N3O3 (511.65): calcd. C 75.12,
H 7.29, N 8.21; found C 75.26, H 7.63, N 8.04.
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-di-
methylpyrrolidin-1-yl]-4-(2-phenylethyl)azetidin-2-one [(3R,4S)-4d]:
From 3d (230 mg, 1 mmol), carrying out the reaction at room
temp., after 4 d flash chromatography (1:6 Ǟ 1:2 Et2O/hexane),
1
368 mg (72%) of cis-(3R,4S)-4d was obtained as an oil: [α]2D6
2 H), 3.35 (dd, J = 6.8, 2.5 Hz, 1 H), 3.60–3.67 (m, 2 H), 4.33 (d, –33.7 (c = 1.2, CHCl3); H NMR (300 MHz, [D6]DMSO, 90 °C):
J = 16.4 Hz, 1 H), 4.57 (d, J = 2.5 Hz, 1 H), 4.68 (d, J = 16.4 Hz, δ = 1.04 (d, J = 6.3 Hz, 6 H), 1.24–1.40 (m, 2 H), 1.55–1.67 (m, 1
=
1
1 H), 5.12 (d, J = 12.7 Hz, 1 H), 5.16 (d, J = 12.7 Hz, 1 H), 7.14–
H), 1.72–1.87 (m, 1 H), 1.89–2.01 (m, 2 H), 2.45–2.55 (m, 1 H),
2.58–2.68 (m, 1 H), 3.60–3.70 (m, 3 H), 4.49 (d, J = 15.6 Hz, 1 H),
7.31 (m, 10 H) ppm. 13C NMR (75 MHz, [D6]DMSO, 95 °C): δ =
17.7, 17.8, 18.5, 28.5, 29.3, 49.4, 54.9, 63.1, 66.1, 66.5, 126.2, 126.4, 4.55 (d, J = 15.6 Hz, 1 H), 4.91 (d, J = 5.1 Hz, 1 H), 5.12 (s, 2 H),
126.6, 127.3, 127.5, 127.7, 127.8, 128.4, 135.9, 137.5, 154.6, 7.05–7.35 (m, 15 H) ppm. 13C NMR (125 MHz, [D6]DMSO,
163.8 ppm. IR (film): ν = 2961, 1753, 1707, 1454, 1240, 1137 cm–1.
90 °C): δ = 18.3, 29.5, 30.2, 31.4, 51.0, 55.6, 62.3, 63.9, 66.5, 125.3,
˜
HRMS: calcd. for C27H35N3O3 449.2678; found 449.2658.
126.6, 127.0, 127.1, 127.3, 127.7, 127.8, 136.0, 137.6, 140.8, 155.0,
164.5 ppm. IR (film): ν = 2967, 1760, 1712, 1458, 1243, 1140,
˜
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-
dimethylpyrrolidin-1-yl]-4-isobutylazetidin-2-one [(3R,4R)-4c]: From
3c (182 mg, 1 mmol), carrying out the reaction at 80 °C, after 37 h
flash chromatography (1:1:8 Ǟ 1:1:6 Et2O/CH2Cl2/hexane), 335 mg
(70%) of trans-(3R,4R)-4c was obtained as a solid: m.p. 88–90 °C;
703 cm–1. HRMS: calcd. for C32H38N3O3 512.2913; found
512.2879.
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-
dimethylpyrrolidin-1-yl]-4-pentylazetidin-2-one [(3R,4R)-4e]: From
3e (196 mg, 1 mmol), carrying out the reaction at 80 °C, after 10 h
flash chromatography (1:8 Ǟ 1:2 Et2O/hexane), 282 mg (59%) of
1
[α]2D2 = –36.6 (c = 1.1, CH2Cl2). H NMR (500 MHz, [D6]DMSO,
95 °C): δ = 0.74 (d, J = 6.5 Hz, 3 H), 0.77 (d, J = 6.5 Hz, 3 H),
0.99 (d, J = 6.3 Hz, 6 H), 1.21–1.23 (m, 1 H), 1.29–1.31 (m, 2 H), trans-(3R,4R)-4e was obtained as an oil: [α]2D2 = –39.7 (c = 1.0,
1
1.54–1.61 (m, 2 H), 1.90–1.92 (m, 2 H), 3.53–3.58 (m, 3 H), 4.40
(d, J = 16.2 Hz, 1 H), 4.44 (d, J = 2.3 Hz, 1 H), 4.64 (d, J =
16.2 Hz, 1 H), 5.13 (d, J = 12.6 Hz, 1 H), 5.18 (d, J = 12.6 Hz, 1
H), 7.13–7.31 (m, 10 H) ppm. 13C NMR (125 MHz, [D6]DMSO,
95 °C): δ = 18.5, 22.3, 22.4, 24.7, 29.8, 50.2, 55.4, 59.8, 66.9, 67.0,
126.9, 127.1, 127.6, 127.9, 128.1, 128.3, 128.9, 136.5, 138.1, 155.2,
CHCl3). H NMR (300 MHz, [D6]DMSO, 90 °C): δ = 0.82 (t, J =
7.0 Hz, 3 H), 0.99 (d, J = 6.3 Hz, 6 H), 1.13–1.39 (m, 9 H), 1.59–
1.66 (m, 1 H), 1.87–1.97 (m, 2 H), 3.46–3.51 (m, 1 H), 3.54–3.60
(m, 2 H), 4.42 (d, J = 2.3 Hz, 1 H), 4.44 (d, J = 15.9 Hz, 1 H), 4.61
(d, J = 15.9 Hz, 1 H), 5.13 (d, J = 12.6 Hz, 1 H), 5.18 (d, J =
12.6 Hz, 1 H), 7.21–7.35 (m, 10 H) ppm. 13C NMR (75 MHz,
[D6]DMSO, 90 °C): δ = 12.9, 17.8, 21.1, 23.9, 29.3, 29.8, 30.5, 49.6,
54.9, 60.8, 65.7, 66.4, 126.3, 126.4, 127.0, 127.2, 127.6, 135.9, 137.5,
164.3 ppm. IR (film): ν = 2968, 1758, 1701, 1453, 1421 cm–1
.
˜
C28H37N3O3 (463.61): calcd. C 72.54, H 8.04, N 9.06; found C
72.25, H 8.07, N 9.32.
154.6, 163.6 ppm. IR (film): ν = 2961, 1753, 1707 cm–1
.
˜
Eur. J. Org. Chem. 2008, 2960–2972
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2967

R. Fernández, J. M. Lassaletta et al.
FULL PAPER
C29H39N3O3 (477.64): calcd. C 72.92, H 8.23, N 8.80; found C
73.05, H 8.38, N 8.68.
1.94 (m, 2 H), 3.51–3.57 (m, 2 H), 4.15 (dd, J = 8.5, 5.2 Hz, 1 H),
4.44 (d, J = 15.6 Hz, 1 H), 4.51 (d, J = 15.6 Hz, 1 H), 4.86 (d, J =
5.2 Hz, 1 H), 5.11 (s, 2 H), 5.22–5.30 (m, 1 H), 5.47–5.59 (m, 1 H),
7.23–7.32 (m, 10 H) ppm. 13C NMR (125 MHz, [D6]DMSO,
90 °C): δ = 16.9, 18.0, 29.1, 50.7, 55.2, 63.3, 66.2, 66.6, 125.5, 126.5,
127.0, 127.1, 127.2, 127.5, 127.6, 127.7, 131.2, 136.0, 137.3, 154.7,
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-di-
methylpyrrolidin-1-yl]-4-pentylazetidin-2-one [(3R,4S)-4e]: From 3e
(196 mg, 1 mmol), carrying out the reaction at room temp., after
4 d flash chromatography (1:4 Et2O/hexane) of the crude product
(dr = 87:13), 196 mg (41%) of cis-(3R,4S)-4e was obtained as an
oil: [α]2D5 = –37.0 (c = 1.4, CHCl3). 1H NMR (300 MHz, [D6]-
DMSO, 90 °C): δ = 0.84 (t, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.3 Hz,
6 H), 1.19–1.49 (m, 10 H), 1.85–1.97 (m, 2 H), 3.58–3.65 (m, 3 H),
4.48 (d, J = 15.9 Hz, 1 H), 4.54 (d, J = 15.9 Hz, 1 H), 4.90 (d, J =
5.1 Hz, 1 H), 5.12 (s, 2 H), 7.23–7.31 (m, 10 H) ppm. 13C NMR
(75 MHz, [D6]DMSO, 90 °C): δ = 13.1, 18.3, 21.1, 24.7, 28.2, 29.4,
30.7, 50.9, 55.5, 62.3, 64.7, 66.4, 126.5, 127.0, 127.1, 127.3, 127.6,
164.1 ppm. IR (film): ν = 2963, 1756, 1707, 1657, 1453, 1233 cm–1.
˜
HRMS: calcd. for C27H33N3O3 447.2522; found 447.2539.
2-(Benzyloxy)-N-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-N-(3-phen-
ylprop-1-enyl)acetamide (9): Bn3N (1.1 g, 4 mmol) was added to a
solution of 3d (115 mg, 0.5 mmol) in dry toluene (2.5 mL) under
argon. The mixture was heated to 60 °C and a solution of 5
(0.33 mL, 2 mmol) in dry toluene (5 mL) was added over 4 h (sy-
ringe pump). The mixture was then washed with H2O and the or-
ganic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated. Purification of the residue by flash chromatography
(1:1:6 Et2O/CH2Cl2/hexane) gave 140 mg (74%) of 9 as a 92:8 mix-
ture of E/Z isomers (oil): NMR spectroscopic data for the major
isomer: 1H NMR (500 MHz, CDCl3): δ = 0.94 (d, J = 6.0 Hz, 3
H), 1.04 (d, J = 6.0 Hz, 3 H), 1.30–1.44 (m, 2 H), 1.94–2.00 (m, 2
H), 3.43 (d, J = 7.5 Hz, 2 H), 3.36–3.50 (m, 1 H), 3.58–3.65 (m, 1
H), 4.19 (d, J = 17.0 Hz, 1 H), 4.64 (d, J = 17.0 Hz, 1 H), 4.68 (s,
2 H), 5.60 (dt, J = 14.5, 7.0 Hz, 1 H), 6.68 (d, J = 14.5 Hz, 1 H),
7.19–7.41 (m, 10 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 18.3,
19.3, 31.5, 32.5, 37.1, 53.0, 57.3, 68.2, 73.2, 115.4, 125.2, 126.2,
127.9, 128.1, 128.4, 128.5, 128.6, 138.0, 140.7, 173.0 ppm. IR (film):
127.7, 136.0, 137.6, 154.9, 164.4 ppm. IR (film): ν = 2967, 2869,
˜
1755, 1707, 1232, 748, 700 cm–1. HRMS: calcd. for C29H40N3O3
478.3070; found 478.3066.
trans-(3R,4S)- and cis-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)-
amino]-4-(benzyloxymethyl)-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-
azetidin-2-one [(3R,4S)-4f and (3R,4R)-4f]: From 3f (246 mg,
1 mmol), carrying out the reaction at 80 °C, after 38 h flash
chromatography (10:1 toluene/EtOAc), 348 mg (66%) of 4f was ob-
tained as a mixture of trans-(3R,4S)-4f and cis-(3R,4R)-4f in a
54:46 ratio. Medium-pressure liquid chromatography (6:1 toluene/
EtOAc) allowed the isolation of both pure isomers as oils.
trans-(3R,4S)-4f: [α]2D5 = –41.1 (c = 0.9, CH2Cl2). 1H NMR
(300 MHz, [D6]DMSO, 90 °C): δ = 0.99 (d, J = 6.4 Hz, 6 H), 1.25–
1.37 (m, 2 H), 1.87–1.98 (m, 2 H), 3.42 (dd, J = 10.8, 3.3 Hz, 1 H),
3.53–3.64 (m, 2 H), 3.62 (dd, J = 10.8, 3.3 Hz, 1 H), 3.75–3.78 (m,
1 H), 4.36 (d, J = 12.0 Hz, 1 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.48–
4.59 (m, 2 H), 4.68 (d, J = 2.4 Hz, 1 H), 5.15 (s, 2 H), 7.23–7.35
(m, 15 H) ppm. 13C NMR (125 MHz, [D6]DMSO, 95 °C): δ = 17.9,
29.6, 50.3, 55.6, 60.5, 61.5, 65.5, 66.6, 72.1, 126.6, 126.7, 126.9,
127.0, 127.1, 127.4, 127.8, 127.9, 128.0, 136.1, 137.5, 137.7, 154.8,
ν = 2961, 1692, 1658, 1259, 1128, 738, 698 cm–1. HRMS: calcd. for
˜
C24H31N2O2 379.2386; found 379.2370.
General Procedure for the Oxidative Cleavage of N–N Bonds. Syn-
thesis of Compounds 10a–f: MMPP·6H2O (730 mg, 1.25 mmol) was
added to a solution of 4a–f (1 mmol) in CH3OH (0.4 mL) and the
mixture was stirred at room temp. for 1 h. The mixture was then
diluted with CH2Cl2, washed with saturated NaHCO3 and H2O,
dried (Na2SO4), filtered, concentrated, and the residue purified by
flash chromatography. The eluents, yields, and spectral and analyti-
cal data for compounds 10a–f are as follows.
164.1 ppm. IR (film): ν = 1757, 1718, 1376, 1241, 1114, 748,
˜
709 cm–1. HRMS: calcd. for C32H37N3O4 527.2784; found
527.2795.
cis-(3R,4R)-4f: [α]2D6
=
–32.3 (c
=
1.0, CH2Cl2). 1H NMR
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-methylazet-
(300 MHz, [D6]DMSO, 95 °C): δ = 1.01 (d, J = 6.3 Hz, 6 H), 1.21– idin-2-one [(3R,4R)-10a]: From trans-(3R,4R)-4a, flash chromatog-
1.36 (m, 2 H), 1.83–1.97 (m, 2 H), 3.45 (dd, J = 10.7, 5.3 Hz, 1 H),
raphy (1:1:1 Et2O/CH2Cl2/hexane) and further purification using
3.51–3.66 (m, 3 H), 3.90 (q, J = 5.3 Hz, 1 H), 4.37 (s, 2 H), 4.41 medium-pressure liquid chromatography (1:1 toluene/AcOEt) gave
(d, J = 15.9 Hz, 1 H), 4.51 (d, J = 15.9 Hz, 1 H), 4.93 (d, J =
292 mg (90%) of trans-(3R,4R)-10a as an oil: [α]2D4 = +18.4 (c =
5.3 Hz, 1 H), 5.08 (s, 2 H), 7.14–7.37 (m, 15 H) ppm. 13C NMR 1.0, CHCl3). 1H NMR (500 MHz, [D6]DMSO, 90 °C): δ = 1.06 (d,
(125 MHz, [D6]DMSO, 95 °C): δ = 18.1, 29.2, 50.8, 55.1, 61.5, 63.5,
J = 6.1 Hz, 3 H), 3.51–3.53 (m, 1 H), 4.25 (d, J = 2.3 Hz, 1 H),
4.49 (d, J = 15.8 Hz, 1 H), 4.56 (d, J = 15.8 Hz, 1 H), 5.13 (s, 2
66.4, 67.6, 72.2, 126.5, 126.9, 127.1, 127.3, 127.6, 127.7, 136.0,
137.5, 137.6, 154.8, 164.1 ppm. IR (film): ν = 1759, 1704, 1379, H), 7.23–7.35 (m, 10 H), 7.82 (br. s, 1 H) ppm. 13C NMR
˜
1244, 1101, 708 cm–1. C32H37N3O4 (527.65): calcd. C 72.84, H 7.07,
N 7.96; found C 73.06, H 6.88, N 7.58.
(125 MHz, [D6]DMSO, 90 °C): δ = 18.3, 50.1, 66.5, 70.3, 126.6,
126.7, 127.0, 127.3, 127.8, 127.8, 136.0, 137.8, 154.7, 164.8 ppm.
IR (film): ν = 3255 (br), 1767, 1701, 1454, 1417, 1369 cm–1. HRMS:
˜
cis-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-(benzyloxy-
methyl)-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]azetidin-2-one
[(3R,4R)-4f]: From 3f (246 mg, 1 mmol), carrying out the reaction
at 40 °C, after 29 h flash chromatography (10:1 toluene/EtOAc),
501 mg (95%) of cis-(3R,4R)-4f was obtained, identical to the prod-
uct described above.
calcd. for C19H20N2O3 324.1474; found 324.1457.
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-isopropylazet-
idin-2-one [(3R,4R)-10b]: From trans-(3R,4R)-4b, flash chromatog-
raphy (1:1 Ǟ 5:1 Et2O/hexane) gave 253 mg (72 %) of trans-
1
(3R,4R)-10b as an oil: [α]2D2 = +24.4 (c = 1.1, CH2Cl2). H NMR
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-1-[(2R,5R)-2,5-di-
methylpyrrolidin-1-yl]-4-(prop-1-enyl)azetidin-2-one [(3R,4S)-4g]:
From 3g (166 mg, 1 mmol), carrying out the reaction at 80 °C, after
55 h flash chromatography (1:4 Ǟ 1:1 Et2O/hexane), 301 mg (67%)
of cis-(3R,4S)-4g was obtained as an oil: [α]2D6 = –7.8 (c = 1.2,
(300 MHz, [D6]DMSO, 95 °C): δ = 0.77 (d, J = 7.2 Hz, 3 H), 0.79
(d, J = 7.2 Hz, 3 H), 1.53–1.65 (m, 1 H), 3.21 (dd, J = 7.5, 2.7 Hz,
1 H), 4.36 (d, J = 16.2 Hz, 1 H), 4.52 (d, J = 2.7 Hz, 1 H), 4.65 (d,
J = 16.2 Hz, 1 H), 5.13 (s, 2 H), 7.23–7.32 (m, 10 H), 8.02 (br. s, 1
H) ppm. 13C NMR (75 MHz, [D6]DMSO, 95 °C): δ = 17.5, 17.8,
CHCl3). 1H NMR (300 MHz, [D6]DMSO, 90 °C): δ = 1.01 (d, J = 30.4, 49.6, 59.9, 66.5, 67.0, 126.6, 127.0, 127.3, 127.3, 127.8, 135.9,
6.3 Hz, 6 H), 1.26–1.31 (m, 2 H), 1.53 (d, J = 6.3 Hz, 3 H), 1.84– 137.7, 154.7, 165.4 ppm. IR (film): ν = 3277, 2967, 1776, 1704,
˜
2968
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2960–2972

Cycloaddition of N,N-Dialkylhydrazones to Aminoketene
1426, 1100, 743 cm–1. HRMS: calcd. for C21H25N2O3 353.1865;
found 353.1865.
13C NMR (125 MHz, [D6]DMSO, 90 °C): δ = 14.0, 22.2, 25.4, 31.3,
33.6, 50.8, 55.1, 67.5, 69.8, 127.6, 127.6, 128.0, 128.3, 128.6, 128.7,
136.9, 138.7, 155.6, 166.2 ppm. IR (film): ν = 3293 (br), 2930, 1767,
˜
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-isobutylazet-
idin-2-one [(3R,4R)-10c]: From trans-(3R,4R)-4c, flash chromatog-
raphy (1:1 Ǟ 4:1 Et2O/hexane) gave 311 mg (85 %) of trans-
1705, 1456, 1421 cm–1. HRMS: calcd. for C23H28N2O3 380.2100;
found 380.2103.
(3R,4R)-10c as an oil: [α]2D2 = +32.5 (c = 1.3, CH2Cl2). H NMR
1
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-4-pentylazetidin-2-
one [(3R,4S)-10e]: From cis-(3R,4S)-4e, flash chromatography
(1:1:2 Et2O/CH2Cl2/hexane) gave 320 mg (84%) of cis-(3R,4S)-10e
as an oil: [α]2D5 = –26.5 (c = 1.2, CHCl3). 1H NMR (300 MHz, [D6]-
DMSO, 90 °C): δ = 0.83 (t, J = 6.6 Hz, 3 H), 1.13–1.39 (m, 8 H),
3.49–3.58 (m, 1 H), 4.53 (s, 2 H), 4.89 (dd, J = 4.8, 1.2 Hz, 1 H),
5.11 (s, 2 H), 7.22–7.36 (m, 10 H), 8.08 (br. s, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO, 90 °C): δ = 13.1, 21.2, 24.7, 29.3, 30.5, 50.6,
53.9, 66.2, 66.4, 126.5, 127.1, 127.3, 127.6, 127.7, 136.0, 137.9,
(300 MHz, [D6]DMSO, 95 °C): δ = 0.73 (d, J = 7.0 Hz, 3 H), 0.75
(d, J = 7.0 Hz, 3 H), 1.13–1.36 (m, 2 H), 1.42–1.51 (m, 1 H), 3.42–
3.47 (m, 1 H), 4.38 (d, J = 2.5 Hz, 1 H), 4.44 (d, J = 15.9 Hz, 1
H), 4.59 (d, J = 15.9 Hz, 1 H), 5.12 (d, J = 12.6 Hz, 1 H), 5.16 (d,
J = 12.6 Hz, 1 H), 7.21–7.37 (m, 10 H), 7.93 (br. s, 1 H) ppm. 13C
NMR (75 MHz, [D6]DMSO, 95 °C): δ = 21.9, 22.6, 25.2, 42.6, 50.4,
53.2, 67.0, 69.9, 127.1, 127.6, 127.8, 128.3, 136.5, 138.3, 155.2,
165.8 ppm. IR (film): ν = 3293, 2959, 1776, 1704, 1458, 1428, 1243,
˜
743, 703 cm–1. C22H26N2O3 (366.45): calcd. C 72.11, H 7.15, N
7.64; found C 72.32, H 7.02, N 7.45.
154.9, 164.9 ppm. IR (film): ν = 3293 (br), 2925, 1765, 1704, 1455,
˜
1409, 1230 cm–1. HRMS: calcd. for C23H29N2O3 381.2178; found
381.2169.
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-4-isobutylazetidin-
2-one [(3R,4S)-10c]: From cis-(3R,4S)-4c, flash chromatography
(1:1 Et2O/hexane) gave 341 mg (93%) of cis-(3R,4S)-10c as an oil:
cis-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-(benzyloxy-
methyl)azetidin-2-one [(3R,4R)-10f]: From cis-(3R,4R)-4f, flash
chromatography (1:1 Ǟ 4:1 Et2O/hexane) gave 318 mg (74%) of
cis-(3R,4R)-10f as an oil: [α]2D7 = –29.5 (c = 0.9, CH2Cl2). 1H NMR
(300 MHz, [D6]DMSO, 95 °C): δ = 3.33–3.42 (m, 2 H), 3.83 (dt, J
= 6.2, 5.2 Hz, 1 H), 4.35 (s, 2 H), 4.45 (d, J = 15.6 Hz, 1 H), 4.52
(d, J = 15.6 Hz, 1 H), 4.93 (dd, J = 5.2, 1.3 Hz, 1 H), 5.07 (s, 2 H),
7.21–7.37 (m, 15 H), 8.12 (br. s, 1 H) ppm. 13C NMR (125 MHz,
[D6]DMSO, 95 °C): δ = 50.6, 52.8, 65.5, 66.4, 69.3, 72.1, 126.5,
126.8, 126.9, 127.1, 127.3, 127.6, 127.6, 127.7, 135.9, 137.7, 154.8,
1
[α]2D2 = –28.5 (c = 1.0, CHCl3). H NMR (500 MHz, [D6]DMSO,
90 °C): δ = 0.74–0.77 (m, 6 H), 0.96–1.15 (m, 2 H), 1.45–1.50 (m,
1 H), 3.62–3.65 (m, 1 H), 4.50 (d, J = 15.3 Hz, 1 H), 4.55 (d, J =
15.3 Hz, 1 H), 4.91 (dd, J = 5.0, 1.5 Hz, 1 H), 5.10 (d, J = 13.0 Hz,
1 H), 5.12 (d, J = 13.0 Hz, 1 H), 7.23–7.35 (m, 10 H), 8.07 (br. s,
1 H) ppm. 13C NMR (125 MHz, [D6]DMSO, 90 °C): δ = 21.3, 22.4,
24.5, 38.3, 50.6, 52.2, 66.4, 126.5, 127.2, 127.3, 127.4, 127.6, 127.7,
136.0, 137.8, 154.9, 165.0 ppm. IR (film): ν = 3291 (br), 2955, 1764,
˜
1703, 1455, 740, 697 cm–1. HRMS: calcd. for C22H27N2O3
367.2022; found 367.2015.
164.9 ppm. IR (film): ν = 1767, 1701, 1370, 1251, 1094 cm–1
.
˜
HRMS: calcd. for C26H27N2O4 431.1971; found 431.1971.
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-(2-phenyl-
ethyl)azetidin-2-one [(3R,4R)-10d]: From trans-(3R,4R)-4d, flash
chromatography (1:1:2 Et2O/CH2Cl2/hexane) gave 302 mg (73%) of
trans-(3R,4R)-10d as an oil: [α]2D2 = +26.4 (c = 0.9, CHCl3). 1H
NMR (300 MHz, [D6]DMSO, 90 °C): δ = 1.66–1.73 (m, 2 H), 2.41–
2.58 (m, 2 H), 3.45 (td, J = 6.3, 2.3 Hz, 1 H), 4.42 (d, J = 2.3 Hz,
1 H), 4.45 (d, J = 15.9 Hz, 1 H), 4.55 (d, J = 15.9 Hz, 1 H), 5.13
(s, 2 H), 7.04–7.35 (m, 15 H), 7.98 (br. s, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO, 90 °C): δ = 31.0, 34.4, 50.0, 53.7, 66.5, 68.9,
125.2, 126.6, 126.7, 127.0, 127.3, 127.5, 127.7, 127.8, 135.9, 137.6,
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-4-(prop-1-enyl)-
azetidin-2-one [(3R,4S)-10g]: From cis-(3R,4S)-4g, following the ge-
neral procedure but carrying out the reaction at 0 °C. Flash
chromatography (4:1 Et2O/hexane) gave 210 mg (60 %) of cis-
(3R,4S)-10g as an oil. cis-(3R,4R)-11 (115 mg, 33%) was also iso-
lated as an oil.
cis-(3R,4S)-10g: [α]2D0 = +11.9 (c = 1.3, CHCl3). 1H NMR
(500 MHz, [D6]DMSO, 90 °C): δ = 1.51 (d, J = 6.5 Hz, 3 H), 4.10
(t, J = 5.5 Hz, 1 H), 4.44 (d, J = 15.5 Hz, 1 H), 4.49 (d, J = 15.5 Hz,
1 H), 4.95 (d, J = 5.5 Hz, 1 H), 5.10 (s, 2 H), 5.11–5.19 (m, 1 H),
140.6, 154.6, 165.1 ppm. IR (film): ν = 3240 (br), 1767, 1699, 1454,
˜
5.42–5.49 (m, 1 H), 7.14–7.35 (m, 10 H), 8.10 (br. s, 1 H) ppm. 13
C
1420 cm–1. HRMS: calcd. for C26H26N2O3 414.1943; found
414.1947.
NMR (125 MHz, [D6]DMSO, 90 °C): δ = 16.8, 50.6, 55.1, 66.3,
67.8, 126.5, 127.1, 127.3, 127.4, 127.5, 127.7, 129.1, 136.1, 137.8,
cis-(3R,4S)-3-[Benzyl(benzyloxycarbonyl)amino]-4-(2-phenylethyl)-
azetidin-2-one [(3R,4S)-10d]: From cis-(3R,4S)-4d, flash
chromatography (1:1 Et2O/hexane) gave 377 mg (91 %) of cis-
(3R,4S)-10d as an oil: [α]2D4 = –40.6 (c = 1.5, CHCl3). 1H NMR
(300 MHz, [D6]DMSO, 90 °C): δ = 1.49–1.56 (m, 2 H), 2.37–2.61
(m, 2 H), 3.56–3.62 (m, 1 H), 4.54 (s, 2 H), 4.91 (dd, J = 5.1,
1.5 Hz, 1 H), 5.10 (s, 2 H), 7.02–7.35 (m, 15 H), 8.15 (br. s, 1
H) ppm. 13C NMR (75 MHz, [D6]DMSO, 90 °C): δ = 31.2, 31.2,
50.7, 53.3, 66.2, 66.4, 125.2, 126.5, 127.1, 127.3, 127.5, 127.6, 127.7,
154.8, 164.9 ppm. IR (film): ν = 3292 (br), 3031, 2919, 1766, 1703,
˜
1450, 1363, 969, 698 cm–1. HRMS: calcd. for C21H23N2O3
351.1709; found 351.1710.
cis-(3R,4R)-11: [α]2D0 = –23.7 (c = 0.7, CHCl3). 1H NMR (500 MHz,
[D6]DMSO, 90 °C): δ = 0.99 (d, J = 5.0 Hz, 3 H), 2.46–2.48 (m, 2
H), 3.38 (t, J = 5.5 Hz, 1 H), 4.50 (d, J = 15.5 Hz, 1 H), 4.59 (d, J
= 15.5 Hz, 1 H), 5.00 (d, J = 5.5 Hz, 1 H), 5.14 (s, 2 H), 7.25–7.40
(m, 10 H), 8.30 (br. s, 1 H) ppm. 13C NMR (125 MHz, [D6]DMSO,
90 °C): δ = 16.2, 50.4, 50.7, 55.6, 56.8, 66.2, 66.6, 126.6, 127.1,
127.3, 127.4, 127.7, 127.8, 135.9, 137.7, 154.7, 164.9 ppm. IR (film):
135.9, 137.8, 140.7, 154.9, 164.9 ppm. IR (film): ν = 3301 (br),
˜
1767, 1705, 1454, 1412, 1235, 745, 700 cm–1. HRMS: calcd. for
C26H27N2O3 415.2022; found 415.2018.
ν = 3295, 2924, 1771, 1703, 1455, 1257, 1025, 700 cm–1. HRMS:
˜
calcd. for C21H23N2O4 367.1658; found 367.1648.
trans-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-pentylazet-
idin-2-one [(3R,4R)-10e]: From trans-(3R,4R)-4e, flash chromatog-
raphy (1:1:2 Et2O/CH2Cl2/hexane) gave 281 mg (74 %) of trans-
(3R,4R)-10e as an oil: [α]2D2 = +27.6 (c = 0.9, CHCl3). 1H NMR
(500 MHz, [D6]DMSO, 90 °C): δ = 0.82 (t, J = 7.1 Hz, 3 H), 1.13–
1.23 (m, 6 H), 1.34–1.37 (m, 2 H), 3.39–3.41 (m, 1 H), 4.37 (d, J
cis-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-(1,2-epoxy-
propyl)azetidin-2-one (11): From cis-(3R,4S)-4g, following the gene-
ral procedure but adding 1.5 g (2.6 mmol) of MMPP. Flash
chromatography (4:1Ǟ8:1 Et2O/hexane) gave 224 mg (61%) of 11,
identical to the product described above.
= 2.4 Hz, 1 H), 4.47 (d, J = 15.9 Hz, 1 H), 4.57 (d, J = 15.9 Hz, 1 trans-(3R,4R)-3-Amino-4-methylazetidin-2-one (12): 20% Pd(OH)2/
H), 5.09–5.16 (m, 2 H), 7.23–7.34 (m, 10 H), 7.94 (br. s, 1 H) ppm. C (10 mg) was added to a solution of trans-(3R,4R)-10a (324 mg,
Eur. J. Org. Chem. 2008, 2960–2972
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2969

R. Fernández, J. M. Lassaletta et al.
FULL PAPER
1 mmol) in 20:1 dioxane/H2O (25 mL). The mixture was stirred un-
der H2 (6 bar) for 6 h at room temp., filtered through a Celite pad,
and concentrated. Purification of the residue by flash chromatog-
raphy (15:1Ǟ8:1 CH2Cl2/CH3OH) gave 75 mg (75 %) of trans-
(3R,4R)-12 as an oil: [α]2D2 = +63.5 (c = 0.7, CHCl3). 1H NMR
(300 MHz, CD3OD): δ = 1.33 (d, J = 6.1 Hz, 3 H), 3.42 (qd, J =
6.0, 2.0 Hz, 1 H), 3.55 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR
(c = 1.0, CH2Cl2)]. 1H NMR (300 MHz, CDCl3): δ = 1.45 (s, 9 H),
1.70–1.82 (m, 1 H), 1.87–1.98 (m, 1 H), 2.57–2.77 (m, 2 H), 3.76–
3.83 (m, 1 H), 5.06 (dd, J = 8.3, 4.5 Hz, 1 H), 5.17 (d, J = 8.3 Hz,
1 H), 5.82 (br. s, 1 H), 7.64–7.32 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.4, 32.6, 32.7, 55.0, 60.6, 80.7, 126.5,
128.5, 128.8, 140.9, 155.3, 167.7 ppm. HRMS: calcd. for
C16H23N2O3 291.1709; found 291.1705.
(75 MHz, CD OD): δ = 19.2, 55.9, 67.5, 172.9 ppm. IR (film): ν =
˜
3
cis-(3R,4R)-3-[Benzyl(benzyloxycarbonyl)amino]-4-(benzyloxy-
methyl)-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]azetidin-2-one
[(3R,4R)-4f] from (3R,4S)-4g: Compound cis-(3R,4S)-4g (144 mg,
0.32 mmol) was treated with ozone in CH2Cl2 (3 mL) at –78 °C
until a permanent blue color appeared. SMe2 (0.42 mL, 3.2 mmol)
was added, the solvent was evaporated, and the crude aldehyde was
dissolved in MeOH (2 mL). NaBH4 (25 mg, 0.64 mmol) was added,
the mixture was stirred at room temp. until TLC indicated total
consumption of the starting material, and concentrated. The resi-
due was diluted with EtOAc and washed with H2O. The organic
layer was dried (Na2SO4) and concentrated. The residue was dis-
solved in THF (3 mL) and NaH (33 mg, 0.8 mmol) and BnBr
(0.12 mL, 0.96 mmol) were added. The mixture was stirred at room
temp. for 3 h and then MeOH (3 mL) was added. The mixture was
partitioned between H2O and CH2Cl2 and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
(Na2SO4) and concentrated. Purification of the residue by flash
chromatography (1:1 Et2O/hexane) gave 71 mg of (3R,4R)-4f (43%,
three steps). The spectral and analytical data for this compound
are identical to those of cis-(3R,4R)-4f obtained directly by cyclo-
addition of 3f with N-benzyl-N-(benzyloxycarbonyl)aminoketene
as described above.
3283 (br), 2874, 1748, 1377, 1352 cm–1.
trans-(3R,4R)-3-[(tert-Butoxycarbonyl)amino]-4-methylazetidin-2-
one (13): Et3N (0.28 mL, 2 mmol) was added to a solution of trans-
(3R,4R)-12 (100 mg, 1 mmol) in CH3OH (2 mL). A solution of
Boc2O (436 mg, 2 mmol) in CH3OH (2 mL) was added dropwise
and the mixture was stirred at room temp. for 2 h. The mixture was
concentrated, diluted with CH2Cl2, and washed with H2O and
brine. The organic layer was dried (Na2SO4) and concentrated. Pu-
rification of the residue by flash chromatography (15:1 CH2Cl2/
MeOH) gave 144 mg (72%) of trans-(3R,4R)-13 as a white solid:
m.p. 132–134 °C. [α]2D2 = +59.0 (c = 1.9, CH3OH) [literature value
for (3S,4S)-13:[40] [α]2D2 = –64.2 (c = 0.85, CH3OH)]. 1H NMR
(300 MHz, CDCl3): δ = 1.38 (d, J = 6.1 Hz, 3 H), 1.41 (s, 9 H),
3.67 (qd, J = 6.1, 2.1 Hz, 1 H), 4.23 (d, J = 7.0 Hz, 1 H), 5.50 (d,
J = 7.0 Hz, 1 H), 6.59 (br. s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.2, 28.2, 54.1, 64.6, 80.2, 155.0, 167.4 ppm. IR (film):
ν = 3260 (br), 2982, 2920, 1726, 1695, 1530, 1449, 1385, 1371, 1072,
˜
880 cm–1. HRMS: calcd. for C9H17N2O3 201.1239; found 201.1249.
cis-(3R,4R)-3-[(Benzyloxycarbonyl)amino]-4-(hydroxymethyl)-
azetidin-2-one (14): Ammonium formate (780 mg, 12 mmol) and
10 % Pd/C (1.5 g) were added to a solution of cis-(3R,4R)-10f
(430 mg, 1 mmol) in CH3OH (20 mL). The reaction mixture was
stirred under reflux for 1 h, filtered through a Celite pad, and con-
centrated. The residue was dissolved in CH3OH (2 mL) and Et3N
(280 µL, 2 mmol) and benzyl chloroformate (300 µL, 2 mmol) were
added. The mixture was stirred at room temp. for 5 h and then
concentrated. The residue was dissolved in EtOAc and washed with
H2O. The organic layer was dried (Na2SO4) and concentrated. Pu-
rification of the residue by flash chromatography (EtOAc) gave
138 mg (55%, two steps) of cis-(3R,4R)-14 as a white solid: m.p.
124–126 °C; [α]2D5 = –7.4 (c = 1.0, CHCl3) [literature value for
(3S,4S)-14:[41] [α]2D2 = +8.6 (c = 0.9, CHCl3); for (3S,4S)-14:[43]
[α]2D2 = +8.7 (c = 0.55, CHCl3); for (3S,4S)-14:[44] [α]2D2 = +9.0 (c =
trans-(3R,4R)-3-Amino-4-isobutylazetidin-2-one (16): Ammonium
formate (520 mg, 8 mmol) and 10% Pd/C (0.5 g) were added to a
solution of trans-(3R,4R)-10c (366 mg, 1 mmol) in CH3OH
(20 mL). The reaction mixture was stirred under reflux for 1 h, fil-
tered through a Celite pad, and concentrated. Purification of the
residue by flash chromatography (13:1 CH2Cl2/CH3OH) gave
102 mg (72%) of trans-(3R,4R)-16 as an oil: [α]2D2 = +57.3 (c = 1.3,
1
CHCl3). H NMR (300 MHz, CD3OD): δ = 0.97 (d, J = 6.6 Hz, 3
H), 0.97 (d, J = 6.6 Hz, 3 H), 1.47–1.60 (m, 2 H), 1.61–1.75 (m, 1
H), 3.37–3.42 (m, 1 H), 3.59 (d, J = 2.1 Hz, 1 H) ppm. 13C NMR
(75 MHz, CD3OD):
δ = 22.5, 23.5, 27.2, 44.2, 58.9, 66.8,
173.2 ppm. IR (film): ν = 3279 (br), 2955, 2929, 2871, 1753, 1467,
˜
1
1368 cm–1. HRMS: calcd. for C7H15N2O 143.1184; found 143.1178.
0.93, CHCl3)]. H NMR (300 MHz, [D6]DMSO, 90 °C): δ = 3.49–
3.64 (m, 2 H), 3.69 (ddd, J = 6.1, 5.1, 4.4 Hz, 1 H), 4.49 (t, J =
5.1 Hz, 1 H), 4.88 (ddd, J = 6.2, 5.1, 1.1 Hz, 1 H), 5.06 (d, J =
12.6 Hz, 1 H), 5.10 (d, J = 12.6 Hz, 1 H), 7.28–7.40 (m, 5 H), 7.87
(br. s, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO, 90 °C): δ = 53.7,
59.1, 60.3, 65.4, 127.1, 127.3, 127.8, 136.5, 155.2, 167.0 ppm.
HRMS: calcd. for C12H14N2O4 250.0954; found 250.0954.
(2R,3R)-2,3-Diamino-5-methylhexanoic Acid (17): A solution of
trans-(3R,4R)-16 (43 mg, 0.3 mmol) in 6  HCl (1.2 mL) was stirred
at room temp. for 4 h. The solvent was then removed to give crude
(2R,3R)-2,3-diamino-5-methylhexanoic acid hydrochloride, which
was used in the next step without further purification. 1H NMR
(300 MHz, CD3OD): δ = 0.99 (d, J = 6.3 Hz, 3 H), 1.03 (d, J =
6.3 Hz, 3 H), 1.52–1.64 (m, 1 H), 1.76–1.87 (m, 2 H), 3.98–4.03
(m, 1 H), 4.48 (dd, J = 3.0, 1.2 Hz, 1 H) ppm. HRMS: calcd. for
C7H17N2O2 161.1290; found 161.1279. Treatment of crude hydro-
chloride with acid resin DOWEX 50WX8 gave 48 mg (quant.) of
(2R,3R)-17 as a white solid; m.p. 180–182 °C; [α]2D2 = +22.0 (c =
1.0, CH3OH). 1H NMR (300 MHz, CD3OD): δ = 0.94 (d, J =
6.6 Hz, 3 H), 0.98 (d, J = 6.6 Hz, 3 H), 1.41–1.45 (m, 2 H), 1.71–
1.80 (m, 1 H), 3.33–3.38 (m, 1 H), 3.42–3.43 (m, 1 H) ppm. 13C
NMR (75 MHz, CD3OD): δ = 21.8, 23.9, 25.4, 40.8, 52.4, 59.2,
cis-(3R,4S)-3-[(tert-Butoxycarbonylamino)]-4-(2-phenylethyl)-
azetidin-2-one (15): Ammonium formate (520 mg, 8 mmol) and
10 % Pd/C (1.0 g) were added to a solution of cis-(3R,4S)-10d
(414 mg, 1 mmol) in CH3OH (20 mL). The reaction mixture was
stirred under reflux for 1 h, filtered through a Celite pad, and con-
centrated. The crude residue was solved in CH3OH (2.6 mL) and
Et3N (280 µL, 2 mmol) was added. Then a solution of Boc2O
(436 mg, 2 mmol) in CH3OH (1 mL) was added dropwise and the
mixture stirred at room temp. for 4 h. The mixture was concen-
trated, diluted with CH2Cl2, washed with H2O and brine, dried
(Na2SO4), and concentrated. Purification of the residue by flash
chromatography (1:1 toluene/AcOEt) gave 122 mg (42%, two steps)
of cis-(3R,4S)-15 as a white solid: m.p. 134–136 °C; [α]2D6 = –56.5
(c = 1.1, CH2Cl2) [literature value for (3S,4R)-15:[42] [α]2D5 = +62.1
175.8 ppm. IR (film): ν = 3610–3140 (br), 2954, 1640 cm–1. HRMS:
˜
calcd. for C7H17N2O2 161.1290; found 161.1292.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for new compounds.
2970
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2960–2972

Cycloaddition of N,N-Dialkylhydrazones to Aminoketene
R. M. Fratila, A. Jimenez, I. Loinaz, J. I. Miranda, K. R.
Pytlewska, A. Micle, A. Linden, Org. Lett. 2004, 6, 4443–4446.
a) I. Ojima, F. Delaloge, Chem. Soc. Rev. 1997, 26, 377–386;
b) C. Palomo, J. M. Aizpurua, I. Ganboa in Enantioselective
Synthesis of β-Amino acids (Ed.: E. Juaristi), Wiley-VCH, New
York, 1997, chapter 14, pp. 279–372; c) C. Palomo, J. M.
Aizpurua, I. Ganboa, M. Oiarbide, Synlett 2001, 1813–1826.
Acknowledgments
[15]
We thank the Spanish Ministerio de Ciencia y Tecnología (MCYT)
(CTQ2007-61915, CTQ2007-600244, and CTQ2004-00241) and the
Junta de Andalucía (2005/FQM-658) for financial support. E. M.-
L. thanks the Ministerio de Educación y Ciencia (MEC) for a pre-
doctoral fellowship.
[16] a) A. Imada, K. Kitano, K. Kintaka, M. Muroi, M. Asai, Na-
ture 1981, 289, 590–591; b) R. B. Sykes, C. M. Cimarusti, D. P.
Bonner, K. Bush, D. M. Floyd, N. H. Georgopadakou, W. H.
Koster, W. C. Liu, W. L. Parker, P. A. Principe, M. L. Rathnum,
W. A. Slusarchick, W. H. Trejo, T. S. Wells, Nature 1981, 291,
489–491.
[1] a) W. Dürkheimer, J. Blumbach, R. Lattrell, K. H. Scheunem-
ann, Angew. Chem. Int. Ed. Engl. 1985, 24, 180–202; b) R. B.
Morin, M. Gorman (Eds.), Chemistry and Biology of β-lactam
Antibiotics, Academic Press, New York, 1982, vols. 1–3; c) S.
Coulton, E. Hunt in Recent Progress in the Chemical Synthesis
of Antibiotics and Related Microbial Products (Ed.: G. Lukacs),
Springer, Berlin, 1993, vol. 2; d) G. Burton, N. F. Osborne,
M. J. Pearson, R. Southgate in Burger’s Medicinal Chemistry
and Drug Discovery (Ed.: M. W. Wolff), Wiley, New York, 1997,
vol. 4, chapter 52.
[2] A. Fleming, Br. J. Exp. Path. 1929, 10, 226–236.
[3] E. P. Abraham, E. Chain, W. Baker, R. Robinson, PEN Report
No 103, 1943.
[4] G. G. F. Newton, E. P. Abraham, Biochem. J. 1956, 62, 651–
658.
[5] a) G. I. Georg (Ed.), The Organic Chemistry of β-Lactams,
VCH, New York, 1993; b) Recent Aspects of the Chemistry of
β-Lactams-II, M. J. Miller (Ed.), Tetrahedron Symposia-in-
Print 80, Tetrahedron 2000, 56, 5553–5742.
[6] a) T. M. Haley, S. J. Angier, A. D. Borthwick, R. Singh, R. G.
Micetich, Drugs 2000, 3, 512–517; b) O. A. Mascaretti, C. E.
Boschetti, G. O. Danelon, E. G. Meta, O. A. Roveri, Curr.
Med. Chem. 1995, 1, 441–470.
[7] a) P. E. Finke, S. K. Shah, D. S. Fletcher, B. M. Ashe, K. A.
Brause, G. O. Chandler, P. S. Dellea, K. M. Hand, A. L. May-
cock, D. G. Osinga, D. J. Underwood, H. Weston, P. Davis,
J. B. Doherty, J. Med. Chem. 1995, 38, 2449–2462; b) J. D. Buy-
nack, A. S. Rao, G. P. Fod, C. Carver, G. Adam, B. Geng, B.
Bachmann, S. Shobassy, S. Lackey, J. Med. Chem. 1997, 40,
3423–3433.
[17]
A. Viso, R. Fernández de la Pradilla, A. García, A. Flores,
Chem. Rev. 2005, 105, 3167–3196.
For a review, see: R. J. Ternansky, J. M. Morin Jr, in The Or-
ganic Chemistry of β-Lactams (Ed.: G. I. Georg), VCH, New
York, 1993, pp. 257–293.
a) A. E. Taggi, A. M. Hafez, H. Wack, B. Young, D. Ferraris,
T. Lectka, J. Am. Chem. Soc. 2002, 124, 6626–6635; b) B. L.
Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578–1579.
H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356, 51–123.
T. Storz, B. Bernet, A. Vasella, Helv. Chim. Acta 1999, 82,
2380–2412.
[18]
[19]
[20]
[21]
[22]
[23]
G. Moyna, H. J. Williams, A. I. Scott, Synth. Commun. 1997,
27, 1561–1567.
a) T. Fukuyama, R. K. Frank, C. F. Jewell Jr, J. Am. Chem.
Soc. 1980, 102, 2122–2123; b) D. R. Wagle, C. Garai, J. Chiang,
M. G. Monteleone, B. E. Kurys, T. W. Strohmeyer, V. R.
Hegde, M. S. Manhas, A. K. Bose, J. Org. Chem. 1988, 53,
4227–4236; c) A. K. Bose, M. S. Manhas, J. M. Van der Veen,
S. S. Bari, D. R. Wagle, Tetrahedron 1992, 48, 4831–4844.
a) G. I. Georg, V. T. Ravikumar in The Organic Chemistry of
β-Lactams (Ed.: G. I. Georg), VCH, New York, 1993, chapter
6, pp. 295–368; b) C. Palomo, J. M. Aizpurua, I. Ganboa, M.
Oiarbide, Eur. J. Org. Chem. 1999, 3223–3235.
a) C. Palomo, J. M. Aizpurua, A. Benito, R. Galarza, U. K.
Khamrai, J. Vázquez, B. de Pascual-Teresa, P. M. Nieto, A.
Linden, Angew. Chem. Int. Ed. 1999, 38, 3056–3058; b) C. Pal-
omo, J. M. Aizpurua, R. Galarza, A. Benito, U. K. Khamrai,
U. Eikeseth, A. Linden, Tetrahedron 2000, 56, 5563–5570.
C. Palomo, J. M. Aizpurua, M. Legido, A. Mielgo, R. Galarza,
Chem. Eur. J. 1997, 3, 1432–1441.
For reviews, see: a) R. Fernández, J. M. Lassaletta, Synlett
2000, 1228–1240; b) R. Brehme, D. Enders, R. Fernández,
J. M. Lassaletta, Eur. J. Org. Chem. 2007, 5629–5660.
R. Fernández, A. Ferrete, J. M. Lassaletta, J. M. Llera, A.
Monge, Angew. Chem. Int. Ed. 2000, 39, 2893–2897.
a) R. Fernández, A. Ferrete, J. M. Lassaletta, J. M. Llera, E.
Martín-Zamora, Angew. Chem. Int. Ed. 2002, 41, 831–833; b)
E. Martín-Zamora, A. Ferrete, J. M. Llera, J. M. Muñoz, R. R.
Pappalardo, R. Fernández, J. M. Lassaletta, Chem. Eur. J.
2004, 10, 6111–6129.
Previous communication: E. Díez, R. Fernández, E. Marqués-
López, E. Martín-Zamora, J. M. Lassaletta, Org. Lett. 2004, 6,
2749–2752.
For instance, pure cis-(3R,4R)-4f was heated at 80 °C under the
reaction conditions (6 equiv. of 1, 12 equiv. of iPr2EtN, and
6.5 equiv. of 2-chloro-1-methylpyridinium iodide in toluene).
After 24 h no traces of trans-4f were observed.
W. T. Brady, Y. Q. Gu, J. Org. Chem. 1989, 54, 2838–2842.
a) W. Kirmse, N. G. Rondan, K. N. Houk, J. Am. Chem. Soc.
1984, 106, 7989–7991; b) N. G. Rondan, K. N. Houk, J. Am.
Chem. Soc. 1985, 107, 2099–2111; c) R. López, T. L. Sordo,
J. A. Sordo, J. González, J. Org. Chem. 1993, 58, 7036–7037;
d) R. López, D. Suárez, M. F. Ruiz-López, J. A. Sordo, T. L.
Sordo, J. Chem. Soc., Chem. Commun. 1995, 1677–1678.
The stereochemistry of the Staudinger reaction has been corre-
lated with steric effects: G. I. Georg, P. He, J. Kant, Z. J. Wu,
J. Org. Chem. 1993, 58, 5771–5778. See also ref.[24a]
[24]
[25]
[8] a) W. W. Ogilvie, C. Yoakin, F. Do, B. Hache, L. Lagace, J.
´
Naud, J. A. OMeara, R. Deziel, Bioorg. Med. Chem. 1999, 7,
[26]
[27]
1521–1531; b) A. D. Borthwick, G. Weingarten, T. M. Haley,
M. Tomaszewski, W. Wang, Z. Hu, J. Bedard, H. Jin, L. Yuen,
T. S. Mansour, Bioorg. Med. Chem. Lett. 1988, 8, 365–370; c)
P. R. Bonneau, F. Hasani, C. Plouffe, E. Malenfant, S. R. La-
Plante, I. Guse, W. W. Ogilvie, R. Plante, W. C. Davidson, J. L.
Hopkins, M. M. Morelock, M. G. Cordingley, R. Deziel, J.
Am. Chem. Soc. 1999, 121, 2965–2973.
[28]
[29]
[9] W. T. Han, A. K. Trehan, J. J. K. Write, M. E. Federico, S. M.
Seiller, N. A. Meanwell, Bioorg. Med. Chem. 1995, 3, 1123–
1143.
[10] R. M. Adlington, J. E. Baldwin, B. Chen, S. L. Cooper, W.
McCoull, G. J. Pritchard, T. J. Howe, Bioorg. Med. Chem. Lett.
1995, 5, 2037–2040.
[11] a) D. A. Burnett, Tetrahedron Lett. 1994, 35, 7339–7342; b)
W. D. Vaccaro, H. R. Davis, Bioorg. Med. Chem. Lett. 1998,
8, 313–318; c) S. B. Rosenblum, T. Huynh, A. Afonso, H. R.
Davis Jr, N. Yumibe, J. W. Clader, D. A. Burnett, J. Med.
Chem. 1998, 41, 973–980; d) J. W. Clader, D. A. Burnett, M. A.
Caplen, M. S. Domalski, S. Dugar, W. Vaccaro, R. Sher, M. E.
Browne, H. Zhao, R. E. Burrier, B. Salisbury, H. R. Davis, J.
Med. Chem. 1996, 39, 3684–3693.
[12] X. Quian, B. Zheng, B. Burke, M. T. Saindane, D. R. Kro-
nenthal, J. Org. Chem. 2002, 67, 3595–3600.
[13] I. Banik, F. F. Becker, B. K. Banik, J. Med. Chem. 2003, 46,
12–15.
[14] a) C. Palomo, J. M. Aizpurua, A. Benito, J. I. Miranda, R. M.
Fratila, C. Matute, M. Domercq, F. Gago, S. Martin-Santama-
ria, A. Linden, J. Am. Chem. Soc. 2003, 125, 16243–16260; b)
C. Palomo, J. M. Aizpurua, I. Ganboa, A. Benito, L. Cuerdo,
[30]
[31]
[32]
[33]
[34]
Eur. J. Org. Chem. 2008, 2960–2972
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2971

R. Fernández, J. M. Lassaletta et al.
FULL PAPER
[35] a) L. Jiao, Y. Liang, J. Xu, J. Am. Chem. Soc. 2006, 128, 6060–
6069; b) Y. Wang, Y. Liang, L. Jiao, D.-M. Du, J. Xu, J. Org.
Chem. 2006, 71, 6983–6990.
[36] a) A. K. Bose, G. Spiegelman, M. S. Manhas, Tetrahedron Lett.
1971, 12, 3167–3170; b) A. Arrieta, B. Lecea, F. P. Cossio, J.
Org. Chem. 1998, 63, 5869–5876; c) L. S. Hegedus, J. Mont-
gomery, Y. Narukawa, D. C. Snustad, J. Am. Chem. Soc. 1991,
113, 5784–5791.
[37] For a recent article on the effect of temperature on the stereose-
lectivity of the Staudinger reaction, see: B. Li, Y. Wang, D.-M.
Du, J. Xu, J. Org. Chem. 2007, 72, 990–997.
[38] R. Fernández, A. Ferrete, J. M. Llera, A. Magriz, E. Martín-
Zamora, E. Díez, J. M. Lassaletta, Chem. Eur. J. 2004, 10, 737–
745.
[39] When hydrogenation was carried out using MeOH as the sol-
vent, the corresponding 1-(dimethylamino) derivative was the
main product isolated.
22
[40]
Compound (3R,4R)-13 gave [α]D = +59.0 (c = 1.85, CH3OH).
Literature value for (3S,4S)-13: [α]D = –64.2 (c = 0.85,
CH3OH): L. S. Hegedus, R. Imwinkelried, M. Alari-Sargent,
D. Dvorak, Y. Satoh, J. Am. Chem. Soc. 1990, 112, 1109–1117.
Compound (3R,4R)-14 gave [α]2D5 = –7.4 (c = 1, CHCl3). Litera-
ture value for (3S,4S)-14: [α]D = +8.6 (c = 0.9, CHCl3): D. A.
Evans, E. B. Sjogren, Tetrahedron Lett. 1985, 26, 3783–3786.
[41]
[42]
25
Compound (3R,4S)-15 gave [α]D = –56.5 (c = 1.1, CH2Cl2).
Literature value for (3S,4R)-15: [α]D = +62.1 (c = 1, CH2Cl2):
C. Palomo, I. Ganboa, A. Kot, L. Dembkowski, J. Org. Chem.
1998, 63, 6398–6400.
[43]
[44]
T. Kawabata, T. Minami, T. Hiyama, J. Org. Chem. 1992, 57,
1864–1873.
R. C. Thomas, Tetrahedron Lett. 1989, 30, 5239–5242.
Received: February 18, 2008
Published Online: April 29, 2008
2972
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2960–2972