Studies on stereoselective [2+2] cycloadditions between N,N-dialkylhydrazones and ketenes

Article abstract of DOI:10.1002/chem.200400452

Staudinger-like cycloadditions between chiral, non-racemic N,N-dialkylhydrazones 1 and functionalized ketenes constitute an efficient methodology for the stereoselective construction of the β-lactam ring. The potential for fine tuning of the dialkylamino

Full text of DOI:10.1002/chem.200400452

FULL PAPER
Studies on Stereoselective [2+2] Cycloadditions between
N,N-Dialkylhydrazones and Ketenes
Eloísa Martín-Zamora,[b] Ana Ferrete,[b] JosØ M. Llera,[c] Jesffls M. MuÇoz,[b]
Rafael R. Pappalardo,[d] Rosario Fernµndez,*[b] and JosØ M. Lassaletta*[a]
Abstract: Staudinger-like cycloaddi-
tions between chiral, non-racemic N,N-
dialkylhydrazones 1 and functionalized
ketenes constitute an efficient method-
ology for the stereoselective construc-
tion of the b-lactam ring. The potential
for fine tuning of the dialkylamino aux-
iliary structure, the availability of a
high-yielding deprotection method for
the release of the free azetidinones,
and the high thermal and chemical sta-
bility of hydrazones as N-dialkylamino
imines are highlighted as the key ele-
ments for the success of the strategy.
This last aspect is of particular impor-
tance concerning generality: even hy-
drazones from easily enolizable alde-
hydes or from formaldehyde reacted to
afford the corresponding cycloadducts
with high chemical and stereochemical
yields. The syntheses of the b-amino-a-
hydroxyacids (2R,3S)-phenylisoserine
(42) and (2R,3S)-norstatin (45) were
accomplished as illustrative examples
of the synthetic utility of this proce-
dure. A model system for the cycload-
dition of g series auxiliaries was studied
by ab initio computational methods.
The collected results support a two-
step mechanism through zwitterionic
intermediates, and explain the ob-
served absolute and relative stereo-
chemistry in terms of the preferred out-
ward cycloaddition to the Re face of
the hydrazone.
Keywords: [2+2] cycloadditions
·
b-lactams · asymmetric synthesis ·
hydrazones · synthetic methods
Introduction
(penicillin G[3] and cephalosporin C[4]), synthetic chemists
have intensively investigated the development of methodol-
ogies for the construction of the b-lactam skeleton.[5] This
activity has sustained its interest because of the constant
need for new drugs displaying broader antibacterial activity
and/or different biological profiles, while the indiscriminate
and massive use of classic antibiotics (both in humans and
in livestock) now necessitates the preparation of new b-
lactam antibiotics to combat bacteria that have built up re-
sistance against most traditional compounds.
Thanks to their high efficacy and extremely safe toxicologi-
cal profiles, b-lactam antibiotics have for over 60 years been
crucial drugs in the war against infectious diseases, being the
most widely employed type of antibacterial agents and thus
constituting one of the major cornerstones in medicinal
chemistry.[1] Since the discovery[2] and structural elucidation
of the first isolated members of this family of antibiotics
Apart from their clinical use as antibacterial agents,
recent reports on the use of b-lactams (especially non-natu-
ral ones) for other purposes are also gaining attention.
Some of the most notable advances deal with the develop-
ment of inhibitors, such as those of serine protease,[6] of
human leukocyte elastase,[7] of cytomegalovirus protease,[8]
of thrombin,[9] of prostate-specific antigen,[10] of cholesterol
absorption,[11] and of tryptase.[12] Some b-lactams have also
shown anti-cancer activity,[13] and recent studies have dem-
onstrated the utility of synthetic b-lactams as key structures
for the synthesis of conformationally restricted peptidomi-
metics of biological significance.[14] In addition to their im-
portance as bioactive compounds, b-lactams can also be
viewed as protected b-amino acids, and enantiopure deriva-
tives have hence been used as chiral building blocks in syn-
thetic organic chemistry.[15]
[a] Dr. J. M. Lassaletta
Instituto de Investigaciones Químicas (CSIC-US)
c/Americo Vespucio s/n, Isla de la Cartuja
41092 Sevilla (Spain)
Fax : (+34)95-446-0565
E-mail: jmlassa@iiq.csic.es
[b] Dr. E. Martín-Zamora, Dr. A. Ferrete, J. M. MuÇoz,
Dr. R. Fernµndez
Dpto. de Química Orgµnica
Universidad de Sevilla (Spain)
[c] Dr. J. M. Llera
Dpto. de Química Orgµnica y FarmacØutica
Universidad de Sevilla (Spain)
[d] Dr. R. R. Pappalardo
Dpto. de Química Física
Universidad de Sevilla (Spain)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2004, 10, 6111 – 6129
DOI: 10.1002/chem.200400452
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
Among the available methods for the stereocontrolled
synthesis of the azetidinone skeleton and their open-chain
b-amino acid analogues, catalytic enantioselective ap-
proaches such as the enolate–imine[16] and silyl ketene
acetal–imine[17] condensations, the Kinugasa reaction,[18] and
the [2+2] ketene–imine cycloaddition[19] have recently been
described for some derivatives. This last procedure, also
known as the Staudinger reaction,[20] is one of the most
widely used strategies, due to its simplicity and the availabil-
ity of the starting materials, and many approaches based on
the introduction of chiral auxiliaries in the ketene or in the
imine component in order to carry out cycloadditions in a
stereoselective way have also been examined.[21] These
methodologies, however, in general suffer some limitations,
mainly imposed by the poor stabilities of the required
imines. With very few exceptions,[22] enolizable aldimines
cannot be used in this type of cycloaddition because of their
low thermal stabilities and competitive deprotonation by the
base required for the generation of the ketene in situ. For-
maldimines constitute a second type of unstable imines, due
in this case to their tendency to tri- and oligomerize under
the conditions used in the Staudinger cycloaddition.[23,24] The
particular case of 4-unsubstituted b-lactams, however, de-
serves particular attention due to the presence of such moi-
eties in nocardicins, as well as in other bioactive compounds
such as tabtoxin[25] and the pachystermines,[26] and so indi-
rect, longer routes to these compounds have been devel-
oped.[27]
types of reactions.[28] During these studies, we have regularly
observed high stability of such hydrazones even at high tem-
peratures and in the presence of bases and some Lewis
acids. The higher stability of hydrazones in relation to
imines is most probably due to conjugation between the N-1
lone electron pair and the C=N double bond. Thanks to this,
reaction conditions (temperature, presence of acids or bases,
etc.) usually incompatible with simple imines can be success-
fully used with hydrazones, including aliphatic enolizable
ones or those derived from formaldehyde. Additionally, the
availability of several hydrazones containing tunable chiral
auxiliaries prompted us to explore the usefulness of these
compounds as imine components in Staudinger-like
[2+2] cycloaddition reactions with functionalized ketenes.[29]
Here we wish to report the results obtained on the basis of
this strategy, together with a theoretical study providing an
explanation for the high inductions achieved with the sim-
plest auxiliary and for the observed absolute and relative
configurations.
Results and Discussion
Cycloadditions between formaldehyde N,N-dialkylhydra-
zones and alkoxy- and aminoketenes: Preliminary reactivity
experiments were performed with a model system consisting
of benzyloxyketene (3; formed in situ from benzyloxyacetyl
chloride (2) and triethylamine as the base) and 1-(methyl-
eneamino)pyrrolidine (1a;[30] Scheme 1). The results collected
initially were discouraging: use of chloroform, THF, or Et2O
under a variety of conditions (several temperatures; 1.4 to
2.5 equivalents of triethylamine) resulted in the formation
of complex mixtures in which 1-benzyloxy-3-pyrrolidin-1-yli-
mino)-propan-2-one (5; 1,2-adduct to the ketene carbonyl)
was found as the major component along with smaller
amounts of the desired cycloadduct 4a. Indeed, when the re-
action between hydrazone 1a and ketene 3 was carried out
in CH2Cl2 as the solvent between 08C and room tempera-
ture, only the 1,2-adduct 5 was isolated, in 31% chemical
yield (Scheme 1). The formation of this compound is most
probably due to the nucleophilicity of the azomethine
carbon of 1a,[28] which is apparently able to attack the
ketene carbonyl of 3.
A marked improvement was observed for reactions car-
ried out in toluene at 508C; the desired product 4a could be
isolated in 67% yield without formation of significant
amounts of 5. Additional reactivity experiments were car-
ried out with formaldehyde N,N-dimethylhydrazone 1b.[31]
As would be expected, the lower nucleophilicity of the azo-
methine carbon of this reagent minimizes the side reaction
described above and results in the isolation of the corre-
sponding cycloadduct 4b in a better yield (84%) from the
reaction carried out in toluene at rt.
During the last few years, our research group has been in-
vestigating the chemical behavior of aldehyde N,N-dialkyl-
hydrazones and their use in asymmetric synthesis in several
Abstract in Spanish: La reacción de cicloadición [2+2] de
tipo Staudinger entre cetenas funcionalizadas y las hidrazo-
nas quirales 1 constituye un mØtodo eficiente para la cons-
trucción estereoselectiva del anillo de azetidinona. La modu-
lación de la estructura del grupo dialquilamino empleado
como auxiliar, la disponibilidad de un procedimiento eficien-
te para la desprotección de las b-lactamas libres y la alta esta-
bilidad química y tØrmica de las hidrazonas como N-dialqui-
lamino iminas son los puntos clave para el Øxito de la estrate-
gia. Este fflltimo aspecto es de particular importancia por su
implicación en la generalidad del mØtodo: hidrazonas deriva-
das de aldehídos fµcilmente enolizables o incluso las deriva-
das de formaldehído reaccionan para dar lugar a los corres-
pondientes cicloaductos con excelentes rendimientos quími-
cos y estereoquímicos. La síntesis de los b-amino-a-hidroxiµ-
cidos (2R,3S)-fenilisoserina (42) y (2R,3S)-norestatina (45)
se llevaron a cabo como ejemplos ilustrativos del potencial
sintØtico del mØtodo. Estudios computacionales ab initio rea-
lizados sobre una reacción modelo basada en los auxiliares
de la serie g sugieren un mecanismo en dos pasos a travØs de
intermedios zwitteriónicos. Los resultados obtenidos explican
la estereoquímica absoluta y relativa, así como el alto grado
de inducción observado para estos auxiliares, por la preferen-
cia de la aproximación “outward” de la cetena sobre la cara
Re de la hidrazona.
Once the desired reactivity was established, we started
studies to perform reactions in a stereoselective way. The
SAMP-derived formaldehyde hydrazone 1c[32] (Scheme 2; R
= H) exhibited a better reactivity than 1a, affording cyclo-
adduct 4c in 80 and 89% yields at room temperature and
808C, respectively, but the observed diastereoselectivities
6112
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Chem. Eur. J. 2004, 10, 6111 – 6129

Stereoselective Cycloadditions
6111 – 6129
pure major isomer (3R)-4e in
80% yield in
(entry 6).
a single step
We next investigated the be-
havior of C2-symmetric hydra-
zones, and started experiments
with the mannitol-derived re-
agent 1 f[33] (Scheme 3). The ini-
tial interest in this particular
compound was the result of
several singularities. Firstly,
better stereoselectivity could be
expected, due to the benefits
frequently observed for C2-sym-
metric auxiliaries.[34] Secondly,
the presence of two neighbor-
ing groups at either side (C-2
and C-5) of the C=N double
Scheme 1. Reactions between benzyloxyketene and formaldehyde N,N-dialkylhydrazones: preliminary experi-
ments.
were disappointing in both cases (Table 1, entries 1 and 2).
Different approaches to improve the chiral auxiliary were
therefore considered.
bond, together with the rigidity conferred by the condensed
1,3-dioxane rings, should hinder the planar conformation as-
sociated with the competing nucleophilic reactivity of the
azomethine carbon.[28] Finally,
hydrazone 1 f can be prepared
in bulk quantities and in a few
steps from inexpensive d-man-
nitol (Scheme 3). The prepara-
tion of the parent hydrazine 7
was carried out by modifying
the procedure described in the
literature.[35] In this way, the
known dimesylate 6[36] was
Scheme 2. Cycloadditions of proline-derived formaldehyde hydrazones 1c–e.
Table 1. Synthesis of 1-dialkylamino-3-azetidin-2-ones 4c–g, (R)-14e, (S)-14e, and 17e–g.
We first decided to investi-
gate the influence of the steric
bulk on other readily available
proline-derived hydrazones. Ac-
cordingly, hydrazones 1d[30]
(Scheme 2; R = Ph) and 1e[30]
Entry
Hydrazone
Ketene
R
T [8C]
t
Product
Yield [%][a]
dr[b]
Conf.[c]
[e]
1
2
3
4
5
6
7
8
1c
1c
1d
1d
1e
1e
1 f
1g
1e
1e
1e
1 f
1g
3[d]
3[d]
H
H
Ph
Ph
Et
Et
–
rt
80
rt
80
rt
80
80
80
80
80
80
60[k]
80
50 h
2.5 h
6 d
3.5 h
24 h
1.5 h
7 h
20 min
8 h
8 h
23 h
8 h
4c
4c
4d
4d
4e
4e
4 f
4g
(R)-14e
(S)-14e
17e
17 f
17g
80
89
85
96
89 (75)
96 (80)
89
58:42
58:42
85:15
81:19
85:15
84:16
>99:1
>99:1
>99:1
98:2
–
–
[e]
3[d]
R[e]
R[e]
R
R
S
R
R
S
3[d]
3[d]
3[d]
(Scheme 2;
R
=
Et), with
bigger (quaternary) residues at
position 2, were treated at room
temperature with benzyloxyace-
tyl chloride (2) to afford cyclo-
adducts 4d and 4e in good
3[d]
3[d]
–
88
94
9
(R)-13[f]
(S)-13[g]
16[i]
Et
Et
Et
–
10
11
12
13
80[h]
93 (76)
81
82:18
>99:1
>99:1
R
S
R
16[j]
16[i]
–
4 h
80
yields (85–96%) and with
a
marked improvement in dia-
stereoselectivity (Table 1, en-
tries 3–6). As in the preceding
cases, even better yields and
faster reaction times were ob-
served at 808C, while the dia-
[a] Isolated yield after column chromatography. In brackets: yield of isolated, pure major isomer (de >98%).
[b] Determined by 1H NMR in the crude reaction product. [c] At C3 of major isomer. [d] From 2 equiv 2.
[e] Inseparable mixture of diastereomers. [f] From 1.5 equiv (R)-12. [g] From 1.5 equiv (S)-12. [h] Isolated as
the pure mayor isomer; the minor isomer was lost during purification. [i] From 2.5 equiv 15. [j] From 6 equiv
15. [k] Extensive decomposition of 1 f was observed at 808C.
stereoselectivities were influenced very little by this change
(entries 4 and 6). The result obtained with hydrazone 1e
was particularly satisfactory, not only because of the better
induction observed, but also for the easy chromatographic
separation of the (3R)- and (3S)-4e diastereomers, the com-
bination of an excellent 96% chemical yield and a moderate
selectivity (dr 84:16) thus resulting in the isolation of the
treated with anhydrous hydrazine to yield 7, which gave 1 f
after condensation with paraformaldehyde in the presence
of Et3N (77% overall yield).
Interestingly, the reaction between hydrazone 1 f and ben-
zyloxyacetyl chloride (2) afforded a single isomer 4 f, which
was readily isolated in 89% yield under the optimized con-
ditions (toluene, 808C) found for proline derivatives. This
Chem. Eur. J. 2004, 10, 6111 – 6129
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R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
Scheme 3. Cycloadditions of C2-symmetric hydrazones 1 f and 1g.
result revealed for the first time the appropriateness of C2-
symmetric auxiliaries for this reaction. As would be expect-
ed in view of the relative stereochemistry of 1e and 1 f,
adduct 4 f had the S configuration at C-3, opposite to that of
the major isomer of 4e, and so hydrazones 1e and 1 f in this
way complement each other from a stereochemical point of
view. However, it should be pointed out that the presumed
lack of effective conjugation in 1 f did not result in the ex-
pected enhancement of the imine-like reactivity for this
compound. In fact, it was found that 1 f is less reactive than
proline derivatives towards 3, as demonstrated by the ab-
sence of reactivity at room temperature, and by the longer
reaction times (7 h for 1 f versus 1.5 h for 1e) required for
completion at 808C.
late, phenyl dichlorophosphate), under a variety of condi-
tions, but no significant amounts of the desired cycloadducts
could be isolated from the complex reaction mixtures. As
one exception, though, N,N-dibenzylglycine 10[41] underwent
a clean reaction in the presence of 2-chloro-N-methylpyridi-
nium iodide to afford hydrazone 11 as the sole reaction
product in 90% yield (Scheme 4).[42]
Finally, for reasons fully explained in the next section, the
behavior of the C2-symmetric hydrazone 1g was also investi-
gated. This product was obtained from the parent hydrazine
(2R,5R)-1-amino-2,5-dimethylpyrrolidine (9), which can be
efficiently prepared from the commercially available (S,S)-
2,5-hexanediol (8).[37] The reaction between hydrazone 1g
and 2 afforded a single isomer 4g, isolated in 88% chemical
yield (Scheme 3, Table 1, entry 8). As in the case of the pro-
line derivatives, 4g had the R configuration at C-3. It should
be noted, however, that the enantiomer of 1g is also easily
available, enabling access to the product 4g with the desired
absolute configuration. Additionally, hydrazone 1g proved
to be more reactive than any of the other hydrazones 1a–f
previously employed, as revealed by the shorter reaction
times needed for completion (20 min, Table 1, entry 7).
Once the methodology for the preparation of 4-unsubsti-
tuted 3-alkoxy-b-lactams had been established, and with ac-
count being taken of the fact that many biologically impor-
tant b-lactam derivatives carry nitrogen functionalities at C-
3, cycloadditions between hydrazones 1e–g and a-aminoke-
Scheme 4. Reaction between hydrazone 1e and dibenzylglycine 10.
On the other hand, the desired cycloadduct was detected
in the reaction between phthaloylglycine and 1e under dif-
ferent conditions, but was always isolated in low yields and
contaminated with unknown impurities. The low thermal
stability of the aminoketene generated in the reaction
medium (808C in toluene) was advanced as a possible ex-
planation for the poor results observed in this case. Since
Palomo et al. had described the Staudinger reaction of
Evans–Sjogren aminoketene 13 at high temperature,[22] we
studied the reactions between hydrazone 1e and the chiral
aminoketenes (R)- and (S)-13 (Scheme 5). The best results
were obtained by use of the corresponding a-amino acid
precursors (R)- and (S)-12 and 2-chloro-N-methylpyridinium
iodide as activating agent[43] for the generation of the amino-
ketene. A matched double induction experiment with (R)-13
and hydrazone 1e afforded the corresponding adduct (3R)-
14e as a single diastereoisomer in high yield (Table 1,
entry 9). The mismatched pair formed by hydrazone 1e and
aminoketene (S)-13 gave the corresponding b-lactam in a
slower and less clean reaction, although enantiomerically
pure (3S)-14e could be isolated in 80% yield after flash
chromatography (entry 10).
tene derivatives were also investigated.
A preliminary
screening was made with hydrazone 1e as the reagent and
many common combinations of aminoketene precursors
(azidoacetyl chloride,[38] phthalimidoacetyl chloride,[39]
Daneꢁs salt,[40] azidoacetic acid, and N-Boc-glycine) and acti-
vators (Et3N, 2-chloro-N-methylpyridinium iodide or tosy-
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Stereoselective Cycloadditions
6111 – 6129
effected by the chiral oxazo-
lidinone is clearly higher
than that of the dialkylami-
no auxiliary, suggesting
a
further improvement on the
latter. Again, C2-symmetric
dialkylamino groups proved
to be more efficient auxilia-
ries; an almost perfect par-
allel with the preceding
oxygen case was observed
in the cycloadditions be-
tween hydrazones 1 f and
1g and aminoketene 16,
with b-lactams 17 f and 17g
also being obtained in good
chemical yields and as
single diastereoisomers, the
two products having oppo-
Scheme 5. Cycloadditions between hydrazone 1e and aminoketenes (S)- and (R)-13.
site configurations at C3
(Scheme 7). Once more, hy-
Important conclusions were drawn from these experi-
ments, leading to the design of more efficient strategies:
drazone 1g proved to be much more reactive than 1 f
and 1e (Table 1, entries 12 and 13).
a) The stability of aminoketene derivatives in the reaction
conditions strongly depends on the nature of the sub-
stituents on nitrogen. Consequently, we prepared the gly-
cine derivative 15 (Scheme 6), which, carrying the same
functionality pattern on nitrogen as 12, should behave in
a similar way. Treatment of aminoketene 16—generated
from 15 under the above conditions—with 1e afforded
adduct 17e in 93% chemical yield and as an 82:18 mix-
ture of diastereoisomers (Table 1, entry 11). As also ob-
served for the oxygen analogues, the resolving properties
of the auxiliary of 1e allowed easy chromatographic sep-
aration of diastereomers (3R)- and (3S)-17e, isolated as
pure compounds in 76 and 16% yields, respectively.
Cycloadditions between higher hydrazones and benzyloxy-
ketene: In view of the above results, we started studies on
the extension of the methodology to cycloadditions of
higher hydrazones. Since the use of aliphatic, enolizable
imines is particularly restricted because of their limited sta-
bilities, we concentrated on cycloadditions of hydrazones de-
rived from easily enolizable aldehydes. In view also of the
lack of general approaches for the enantioselective synthesis
of 4-alkyl(aryl)-3-hydroxy-b-lactams and their potential as
precursors of bioactive b-amino-a-hydroxyacids (isoserines),
we focused on [2+2] cycloadditions between chiral aldehyde
hydrazones and a-benzyloxyketene 3.[44] Studies began with
treatment of the proline-derived hydrazones 18e–22e with
benzyloxyacetyl chloride (2), as in the preceding formalde-
hyde case. Under optimized re-
b) From the cycloaddition between the mistmatched pair of
reactants 1e/(S)-13, it can be deduced that the induction
action
conditions
(toluene,
Et3N, 80 8C for primary sub-
strates, 1008C for secondary or
aromatic hydrazones), the ex-
pected cycloadducts 23e–27e
were obtained in excellent
chemical yields (84–98%) and
with moderate to good (3R,4S)/
(3S,4R) selectivities (Scheme 8,
Table 2), with only traces of
trans isomers being detected in
some cases. Nevertheless, the
collected results were deemed
satisfactory because the major
diastereoisomers
could
be
easily separated by flash chro-
matography in all cases, thus al-
lowing the isolation of the opti-
cally pure major cis isomers
Scheme 6. Cycloaddition between 1e and aminoketene 16.
Chem. Eur. J. 2004, 10, 6111 – 6129
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R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
suggests that the higher steric
demand in these substrates hin-
ders the conrotatory ring-clo-
sure from the zwitterionic spe-
cies 29, a generally accepted in-
termediate in the Staudinger re-
action.[45] The formation of 28
can be then explained by as-
suming hydrolytic CN cleavage
of the alkylidene fragment
during workup.
The previously collected re-
sults from cycloadditions of
formaldehyde derivatives made
us consider the use of C2-sym-
metric auxiliaries in this case as
well. Surprisingly, however,
treatment of the d-mannitol-de-
rived hydrazone 19 f with 3 af-
forded only enamine 30 in high
yields (>90%) under a variety
of conditions (Scheme 9). The
observed gap in reactivity be-
tween 1 f and 1e may be associ-
ated with their structural differ-
ences. The small methylene
groups at C2 and C5 in 1 f donꢁt
appear to be much more de-
manding than the bigger side
chain at C2 in 1e. On the other
hand, the presence of the two
condensed dioxane rings in 1 f
strongly restricts the flexibility
of the pyrrolidine ring, hinder-
ing the ring planarity associated
with an effective n–p conjuga-
tion. Interestingly, a dramatic
difference in the reactivities of
1e and 1 f had previously been
observed in a different context:
the nucleophilicity of 1e allows 1,2-addition to trifluoro-
methyl ketones, while 1 f fails as reagent in the same reac-
tion.[33] The above considerations suggest that the f series hy-
drazones, due to less effective n–p conjugation, present
hybrid chemical behavior lying
between proline derivatives and
Scheme 7. Cycloadditions between C2-symmetric hydrazones 1 f and 1g and 15.
Scheme 8. Reactions between e-series hydrazones 18e–22e and 2.
(3R,4S)-23e to (3R,4S)-27e in yields ranging from 70 to
82%. The results collected in Table 2 indicate the generality
of the process, as applied both to aromatic and to primary
and secondary aliphatic substrates.
Table 2. Synthesis of 4-alkyl(aryl)-1-(N,N-dialkylamino)-3-benzyloxyazetidin-2-ones 23e–27e.
“normal” imines, possessing
high chemical stability as in the
former, but a tendency to tauto-
merize closer to the latter. The
formation of 30 was conse-
quently attributed to a tauto-
Hydrazone
T [8C]
Product
R
Yield [%][a]
dr[b,c]
cis/trans[c]
18e
19e
20e
21e
22e
80
80
80
100
100
23e
24e
25e
26e
27e
n-C5H11
iBu
Ph(CH2)2
iPr
85 (70)
84 (73)
97 (78)
90 (82)
98 (75)
82:18
87:13
80:20
91:9
98:2
98:2
>99:1
>99:1
>99:1
Ph
76:24
merization
path (Scheme 9, path a). The in-
itially proposed intramolecular
(!31)/acylation
[a] Isolated yield. Values in parentheses correspond to the pure (de 98%) major isomer. [b] (3R,4S)/(3S,4R).
1
[c] Determined by H and 13C NMR.
A high reaction temperature (80–1008C) proved to be
key for the cycloaddition: interestingly, reactions carried out
at room temperature afforded hydrazide 28 as the only iden-
tifiable product, in 70–75% yields (Scheme 8). This behavior
H-transfer[29b] in 32 (Scheme 9, path b) was later ruled out
because the calculated geometry of such intermediates (see
below) would prevent any significant contribution of n!p
conjugative effects, and there would therefore be no explan-
6116
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Chem. Eur. J. 2004, 10, 6111 – 6129

Stereoselective Cycloadditions
6111 – 6129
room temperature (entry 3), in
contrast with all other hydra-
zones tested. Secondary (21g)
and aromatic (22g) hydrazones
also reacted smoothly with 2 at
optimized temperatures of 80
and 1008C to give the corre-
sponding adducts 26g and 27g
in 80 and 96% yields, respec-
tively (entries 6 and 7).
Deprotection and synthesis of
b-amino-a-hydroxyacids: The
use of hydrazones as reagents
in Staudinger-like cycloaddi-
tions to ketenes appears to be a
successful strategy in view of
two key aspects: 1) the higher
stability of hydrazones derived
from formaldehyde or aliphatic
aldehydes provides an easy
route to the 4-unsubstituted
and 4-alkylated azetidin-2-one
Scheme 9. Reaction between 19 f and 2.
ation for the observed difference of behavior with proline
derivatives.
In order to gain further information, the non-enolizable
hydrazone 22 f (Scheme 10) was prepared and treated with
2. Under forcing conditions (1008C), the desired b-lactam
27 f was formed in a moderate 66% yield, but with excellent
stereoselectivity (deꢀ98%). Thus, the introduction of a C2-
symmetric auxiliary seems to be an appropriate strategy, but
the lower reactivity of d-mannitol derivatives prevents a
better result. The more flexible C2-symmetric hydrazone
19h was synthesized and treated with 2 to afford cycload-
duct 24h with complete (3R,4S)/(3S,4R) selectivity, support-
ing the validity of the starting hypothesis, but the yield
(53%) was disappointing and the product was contaminated
with ca. 10% of the undesired trans (3R,4R) diastereomer
(Scheme 10). The partial formation of trans products and
the moderate reactivity of 19h were now attributed to a
higher steric hindrance around the C=N bond.
A final attempt to improve the results obtained with hy-
drazones 18e–22e was therefore based on the strategy out-
lined above, but with use of substrates containing the steri-
cally less demanding (2R,5R)-dimethylpyrrolidine as the
auxiliary. As was to be expected, higher reactivities were ob-
served in the reactions between 19g–22g and 2, which pro-
ceeded smoothly to give the corresponding cycloadducts
24g–27g in high yields and, notably, with excellent (3R,4S)/
(3S,4R) selectivities (de ꢀ98%) in spite of the low steric
demand effected by the small methyl groups at C2 and C5
(Scheme 11, Table 3). In this case, an optimum reaction tem-
perature of 608C was applied for treatment of 2 with ali-
phatic primary hydrazones 19g and 20g (Table 3, entries 1
and 4), since significant amounts of trans isomers appeared
at 808C (entries 2 and 5). Interestingly, the high reactivities
of 19g–22g allow cycloadditions to be performed even at
Scheme 10. Cycloadditions of 22 f and 19h.
Scheme 11. Cycloadditions of 19g–22g.
rings, and 2) the potential for tuning of the structure of the
chiral dialkylamino auxiliary offers very efficient control
over the stereochemical course of the reaction, affording
enantiomerically pure compounds in all cases. The success
Chem. Eur. J. 2004, 10, 6111 – 6129
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6117

R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
Table 3. Synthesis of 1-(N,N-dialkylamino)-3-benzyloxyazetidin-2-ones 24g–27g.
Entry
Hydrazone
T [8C]
R
Product
Yield [%][a]
dr[b,c]
cis/trans[b]
[d]
1
2
3
4
5
6
7
19g
19g
20g
20g
20g
21g
22g
60
80
rt
60
80
80
100
iBu
iBu
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
iPr
24g
24g
25g
25g
25g
26g
27g
70
91
67
83
91
80
96
>99:195:5
>99:185:1
>99:1
>99:1
>99:191
>99:1
5
>99:1
>99:1
:9
>99:1
>99:1
Ph
>99:1
1
[a] Yield of isolated product. [b] Determined by 13C and H NMR. [c] (3R,4S)/(3S,4R) [d] Inseparable mixture. The pure cis isomer was obtained after re-
lease of the auxiliary (see Table 4, entry 14).
of the whole strategy, however,
relies on the availability of an
efficient method for the release
of the dialkylamino auxiliary to
obtain the desired deprotected
b-lactams. Unfortunately, the
attempted key cleavage of the
ꢁ
N N bonds in adducts 4e and
4 f by catalytic hydrogenolysis
with use of several catalysts
[Raney-Ni, Pd/C, and Pd(OH)2/
Scheme 13. Synthesis of Taxol side chain (2R,3S)-42 and norstatin (2R,3S)-45.
C] or by use of Li/NH3 under
several sets of conditions was
[46]
unsuccessful. Only large excesses of SmI2 in the presence
of HMPA as co-solvent afforded the desired products, but
this inconvenient procedure gave only low to moderate
yields of product in the investigated 4-unsubstituted cases
(33: 64–65% from 4e or 4 f; 34: 42% from 17e). We were
(R,R)-22g and (S)-22e, respectively, while (2R,3S)-norstatin
45 was obtained in 50 or 57% overall yields from (R,R)-19g
or (S)-19e, respectively. It is also worth stressing again that
the auxiliaries used (e and g series) are available in both
enantiomeric forms.[51] Thus, the same methodology but use
of the enantiomeric hydrazones (S,S)-19g or (R)-19e could
be applied to the synthesis of (2S,3R)-norstatin (ent-45), a
key component of amastatin, a nontoxic inhibitor of amino-
peptidase A and leucine aminopeptidase.[52]
ꢁ
therefore forced to develop a new procedure for the N N
bond cleavage, which was finally accomplished under oxida-
tive conditions[47] through the use of N-oxidation reagents
such as m-CBPA, magnesium monoperoxyphthalate
(MMPP), or Oxone. The best results were observed with
methanolic solutions of MMPP, which afforded high yields
of product 33–40 in all cases (Scheme 12, Table 4). The reac-
Determination of the absolute configurations: The absolute
3R configuration of (3R)-4e was determined by X-ray dif-
fraction analysis of its derivative (3R)-47.[29a] The absolute
configurations of (3S)-4 f and (3R)-4g were assigned by
chemical correlation according to the transformations shown
in Scheme 14.
The absolute configuration of (3S)-17 f was assigned by
chemical correlation with the known compound (3S)-48,[53]
while that (3R)-17e was assigned by comparison of the spe-
cific rotations of (3S)- and (3R)-35 as shown in Scheme 15.
The results of the double induction experiments per-
formed with (R)-13 and (S)-13 are in agreement with the R
configuration induced by (S)-1e: the latter forms a matched
pair with the R-inducing ketene (R)-13,[15a,24,44,54] while the S
product was formed from the mismatched pair (S)-1e/(S)-13
with predominant S induction by the ketene. This last state-
ment was deduced after cleavage of the cycloadducts (3R)-
14e and (3S)-14e, which afforded the enantiomeric products
(3R)-34 and (3S)-34, respectively (Table 4, entries 4 and 5).
The cis stereochemistry was established from the coupling
ꢁ
Scheme 12. Release of the chiral auxiliary: oxidative cleavage of N N
bonds.
tions were performed from single diastereomers except in
the case of (3R,4S)-24g (entry 14), which was contaminated
with 5% of the inseparable trans isomer (Table 3, entry 1).
The deprotected product (3R,4S)-37, however, was isolated
in 84% yield as the pure cis compound; the corresponding
deprotected trans derivative was presumably removed
during chromatographic purification.
Finally, standard transformations from 40 and 37 afforded
b-amino-a-hydroxy acids (2R,3S)-42, the side chain of
Taxol,[48] and (2R,3S)-45, a component of the renin inhibitor
KRI-1230[49] and of antitumoral drug ABT-271[50]
(Scheme 13).
3
constant JH3,H4, which can be easily distinguished from that
of trans isomers.[55] The absolute configuration of (3R,4S)-
27e was established by chemical correlation with the known
derivative (3R,4S)-41, obtained via (3R,4S)-40 (Scheme 13)
Overall, (2R,3S)-phenylisoserine (42) was synthesized in
four steps and in 66% and 52% yields from hydrazones
6118
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Chem. Eur. J. 2004, 10, 6111 – 6129

Stereoselective Cycloadditions
6111 – 6129
[a]
ꢁ
Table 4. Synthesis of azetidin-2-ones 33–40 by oxidative N N bond cleavage of N-dialkylamino-b-lactams.
Entry
Starting compound
X
R
NR1R2
t [h]
Product
Yield [%][b]
89
1(3
R)-4e
OBn
H
1
(3R)-33
(3S)-33
(3R)-33
2
3
(3S)-4 f
(3R)-4g
OBn
OBn
H
H
6
2
82
82
4
5
6
7
(3R)-14e
(3S)-14e
(3R)-17e
(3S)-17 f
H
H
H
H
2.5
1.75
1
(3R)-34
(3S)-34
(3R)-35
(3S)-35
75
71
83
82
6
8
9
(3R)-17g
H
2
3
(3R)-35
83
78
(3R,4S)-23e
OBn
n-C5H11
(3R,4S)-36
1
0
R,4S)-24e (3
(3R,4S)-25e
R,4S)-26e (3
R,4S)-27e (3
R,4S)-24g (3
R,4S)-25g (3
R,4S)-26g (3
R,4S)-27g (3
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
iBu
Ph(CH2)2
iPr
2.5
2
(3R,4S)-37
(3R,4S)-38
(3R,4S)-39
(3R,4S)-40
(3R,4S)-37
(3R,4S)-38
(3R,4S)-39
(3R,4S)-40
91
87
88
96
84[c]
84
91
95
11
1
2
3
4
5
7
8
4
1
Ph
2
1
iBu
2
1
Ph(CH2)2
iPr
2
1
2
1
Ph
2
[a] Substrate/MMPP 1:6. [Substrate] = 0.4m. [b] Of isolated product after column chromatography. [c] Of pure cis isomer.
Chem. Eur. J. 2004, 10, 6111 – 6129
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6119

R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
precursors (3R,4S)-24e and (3R,4S)-24g were assigned after
the synthesis of (2R,3S)-norstatin as described above.
Computational studies: Since there was no evident explana-
tion for the almost complete inductions achieved by the use
of the rather simple 2,5-dimethylpyrrolidine auxiliary, we
decided to perform a computational study in order to under-
stand the stereochemical outcome of the reaction better. Ab
initio calculations at the B3LYP6-31G* level were applied
to the cycloaddition of acetaldehyde hydrazone H and me-
thoxyketene K as the model system. In agreement with pre-
vious studies on the Staudinger reaction,[45] our results sup-
port a two-step mechanism consisting of: i) nucleophilic
attack of the imine nitrogen to the ketene carbonyl, leading
to a zwitterionic intermediate ZW trough a transition state
TS1, and ii) electrocyclic conrotatory ring-closure via TS2 to
the final product P. Four different paths can be considered
by combining two relative positions of the methoxy residue
of K (outward or inward) and the two diastereomeric faces
(Re,Si) of the C=N bond of H (Scheme 16).
The stationary points corresponding to the transition
states TS1 (first step) and TS2 (second step), the zwitterion-
ic intermediates ZW, and the final products P were located
for the paths described above and fully characterized by
computation of the vibrational frequencies. The relative en-
ergies calculated for these structures are collected in
Table 5.
Analysis of these data suggests that, as in related ketene-
imine systems,[45] the conrotatory ring-closure appears, in
general, to be the rate-determining step. A strong prefer-
ence for the outward ap-
Scheme 14. Determination of the absolute configurations of (3R)-4e,
(3S)-4 f, and (3R)-4g.
proaches can be deduced from
the different energies of the
TS2 and ZW structures. Thus,
the calculated energy barriers
for outward approaches are 5.1
and 6.3 kcalmolꢁ1 for the Re
and Si attacks, respectively. In
sharp contrast, the barriers cor-
responding to inward ap-
proaches are 16.9 and 17.6 kcal
molꢁ1. This tendency is also
consistent with previous studies
on related cycloadditions with
electron-rich ketenes, a fact an-
alyzed in terms of the so-called
torquoelectronic effect.[57]
In order to explain the pref-
Scheme 15. Determination of the absolute configurations of (3S)-17 f and (3R)-17e.
erence for the P-O/Re product,
it is therefore necessary to com-
([a]3D1 = +181.9 (c = 1.3, MeOH); lit. [a]D = 182–193
(MeOH)[56]). Compound (3R,4S)-40 ([a]2D5 = +97.3 (c = 1,
Table 5. Relative energies for the stationary points.
Pathway
Relative energies [kcalmolꢁ1
TS2
]
DMSO)) was also obtained from (3R,4S)-27g, which there-
fore had the same absolute configuration as (3R,4S)-27e at
C3 and C4. The obtaining of the enantiomer (3S,4R)-40
([a]3D1 = ꢁ102.4 (c = 0.3, DMSO)) from (3S,4R)-27 f con-
firmed the absolute configuration assigned to the latter. Fi-
nally, the absolute configurations of (3R,4S)-37 and their
TS1ZW
P
outward/Re
inward/Re
outward/Si
inward/Si
3.4
3.8
7.7
8.0
3.18.2
ꢁ36.4
ꢁ36.5
ꢁ35.8
ꢁ32.6
2.2
6.3
5.6
19.1
12.6
23.2
6120
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Chem. Eur. J. 2004, 10, 6111 – 6129

Stereoselective Cycloadditions
6111 – 6129
Scheme 16. Possible reaction paths between methoxyketene K and acetaldehyde g series hydrazone H according to a two-step mechanism via zwitterionic
intermediates.
pare the calculated relative energies for the stationary
points along the outward/Re and outward/Si paths
(Figure 1). Firstly, the most stable ZW-O/Re intermediate is
a) There are CH···O hydrogen bonds that contribute to the
stabilization of the proposed structures. However, there
is a considerable difference in the number and efficiency
of these interactions in the two paths: the outward/Re
transition states TS1-O/Re and TS2-O/Re (as well as the
zwitterionic intermediate ZW-O/Re) each exhibit two of
these hydrogen bonds, while the structures correspond-
ing to the outward/Si pathway present only the NCH···O
bond. The most significant difference appears through
comparison of the ring-closing transition states TS2-O/
Re, with H–O distances of 2.51and 2.49 Š, and TS2-O/
Si, which has only a weak CH···O bond with an H–O dis-
tance of 2.61Š.
b) The methyl groups at C2 and C5 in the pyrrolidine ring
arrange in almost perfect pseudoequatorial positions in
the calculated outward/Re stationary points. In the out-
ward/Si transition states and zwitterionic intermediate,
however, one of the methyl groups arranges in an almost
perfect pseudoaxial position. As a direct consequence,
there are considerable steric interactions that should
contribute to the higher relative energy calculated for
the latter. The short C(Me)–C(ketene carbonyl) distan-
ces in ZW-O/Si (3.11 Š) and TS2-O/Si (3.09 Š) are rep-
resentative examples of this effect.
Figure 1. Energy profiles for the outward/Re and outward/Si paths.
formed through a less energy-demanding addition step
(3.4 kcalmolꢁ1 for TS1-O/Re versus 7.7 kcalmolꢁ1 for TS1-
O/Si). Moreover, the second step operates in the same
sense: the barrier leading to product P-O/Re through the es-
sentially irreversible ring-closing step is also smaller (5.1
versus 6.3 kcalmolꢁ1 for P-O/Si).
A careful analysis of the relevant structures shown in
Figure 2 suggests a description of the data reported above in
terms of two significant interactions:
In summary, a model based on the computational study is
proposed. According to this model, the absolute and relative
absolute configurations are the result of a favored outward
cycloaddition involving the Re face of the hydrazone. This
Chem. Eur. J. 2004, 10, 6111 – 6129
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6121

R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
Figure 2. Transition states TS1 and TS2 and zwitterionic intermediates ZW for the outward/Re and outward/Si approaches.
products was carried out by chromatography (silica gel). The light petro-
approach is less energy-demanding than that resulting from
the attack to the Si face of the C=N bond, mainly due to the
contribution of stabilizing CH···O hydrogen bonds and the
absence of CO–Me repulsive interactions.
leum ether used had a boiling range of 40–658C. All the calculations
were performed by use of Gaussian98W[58] with the standard 6-31G**
basis set[59] and the B3-LYP[60] method; see Supporting Information for
further details.
General procedure for the synthesis of 1-dialkylamino-3-benzyloxyazeti-
din-2-ones 4a–g: A solution of benzyloxyacetyl chloride (2, 2 mmol,
0.33 mL) in toluene (5 mL) was added dropwise to a solution of the hy-
drazone 1a–g (1mmol) and TEA (4 mmol, 0.56 mL) in dry toluene
(10 mL). The mixture was heated until consumption of the starting hy-
drazone and washed with water, and the aqueous layer was extracted
with EA (2”15 mL). The combined organic layer was washed with brine,
dried (Na2SO4), and concentrated. Flash chromatography (Et2O/DCM/
PE) gave the corresponding 1-(dialkylamino)-3-benzyloxyazetidin-2-ones
4a–g. Starting materials, reaction times, and characterization data were
as follows:
Conclusion
The obtained results indicate that chiral N,N-dialkylhydra-
zones are advantageous reagents for use as imine compo-
nents in Staudinger [2+2] cycloadditions with functionalized
ketenes. The stability of formaldehyde and enolizable sub-
strates gives the method generality, while the potential for
fine tuning of the auxiliary offers efficient control over the
stereochemical course of the reaction. The method could be
applied to the synthesis of bioactive isoserines, which were
synthesized in a reduced number of steps thanks to the mul-
tiple roles played by the dialkylamino residue. In fact, the
optimized 2,5-dimethylpyrrolidine moiety was used simulta-
neously as stabilizing function, chiral auxiliary, and protect-
ing group.
3-Benzyloxy-1-pyrrolidin-1-yl-azetidin-2-one (4a): This compound was
prepared from hydrazone 1a,[30] the reaction being complete after 2.5 h
at 508C. Flash chromatography (Et2O/DCM/PE 1:1:2) gave 4a (165 mg,
67%) as an oil. 1H NMR (300 MHz, CDCl3): d = 1.81–1.85 (m, 4H),
2.90–2.96 (m, 4H), 3.27 (dd, J = 1.8, 5.2 Hz, 1H), 3.52 (t, J = 4.9 Hz, 1H),
4.57 (dd, J = 1.8, 4.8 Hz, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.85 (d, J =
11.5 Hz, 1H), 7.31–7.39 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d =
22.1 (2C), 45.0, 51.2 (2C), 72.3, 77.3, 128.0, 128.1, 128.4, 136.7, 166.2 ppm;
IR (KBr): n˜ = 1769, 1458, 1092, 1028 cmꢁ1; MS (EI): m/z (%): 246 (0.3)
[M]+, 127 (68), 91 (100), 56 (40); elemental analysis calcd (%) for
C14H18N2O2: C 68.27, H 7.37, N 11.37; found C 68.28, H 7.40, N 11.60.
Experimental Section
3-Benzyloxy-1-(dimethylamino)azetidin-2-one (4b): This compound was
prepared from hydrazone 1b, the reaction being complete after 48 h at
rt. Flash chromatography (Et2O/DCM/PE 1:1:1) gave 4b (185 mg, 84%)
as an oil. 1H NMR (300 MHz, CDCl3): d = 2.58 (s, 6H), 3.25 (dd, J =
1.9, 5.2 Hz, 1H), 3.50 (td, J = 4.7, 5.2 Hz, 1H), 4.56 (dd, J = 1.9, 4.7 Hz,
General methods: Melting points were determined on a metal block and
are uncorrected. Optical rotations were measured at room temperature.
FT-IR spectra were recorded on KBr pellets or films. EI-mass spectra
were recorded at 70 eV, with use of an ionizing current of 100 mA, an ac-
celerating voltage of 4 kV, and a resolution of 1000 or 10000 (10% valley
definition). The reactions were monitored by TLC. Purification of the
1H), 4.65 (d,
J = 11.5 Hz, 1H), 4.84 (d, J = 11.5 Hz, 1H), 7.30–
7.40 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d = 44.1, 44.4, 72.3, 77.6,
128.0, 128.1, 128.4, 136.7, 165.2 ppm; IR (KBr): n˜ = 1768, 1458, 1093,
6122
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Stereoselective Cycloadditions
6111 – 6129
1029 cmꢁ1; MS (EI): m/z (%): 220 (2) [M]+, 101 (100), 91 (65), 58 (22);
elemental analysis calcd (%) for C12H16N2O2: C 65.43, H 7.32, N 12.72;
found C 65.26, H 7.60, N 12.94.
(19), 91 (64); elemental analysis calcd (%) for C20H30N2O3: C 69.33, H
8.73, N 8.09; found C 69.34, H 8.54, N 8.06.
Compound [(3R)- and (3S)-4 f]: This compound was prepared from hy-
drazone 1 f, the reaction being complete after 7 h at 808C. Flash chroma-
tography (Et2O/PE 2:1) gave (3S)-4 f (460 mg, 89%) as a single crystal-
line diastereoisomer (dr >99:1). M.p. 77–808C; [a]2D1 = +88.5 (c = 1in
CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 3.39 (dd, J = 2.1, 5.0 Hz,
1H), 3.68 (brs, 2H), 3.86 (t, J = 5.0 Hz, 1H), 4.07 (dd, J = 2.6, 13.1 Hz,
2H), 4.23 (d, J = 13.1 Hz, 2H), 4.42 (d, J = 2.5 Hz, 2H), 4.66 (dd, J =
2.1, 4.8 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H),
5.45 (s, 2H), 7.29–7.45 ppm (m, 15H); 13C NMR (125 MHz, CDCl3): d =
48.7, 57.1(2C), 65.3, 72.5, 77.2, 78.1(2C), 99.5 (2C), 126.0–129.1(m),
136.9, 137.5, 169.2 ppm; IR (KBr): n˜ = 1771, 1395, 1111, 1018 cmꢁ1; MS
(EI): m/z (%): 514 (10) [M]+, 261 (40), 105 (100), 91 (83); elemental
analysis calcd (%) for C30H30N2O6: C 70.02, H 5.88, N 5.44; found C
69.82, H 5.86, N 5.46.
(3R)- and (3S)-3-Benzyloxy-1-[(2S)-2-methoxymethyl-pyrrolidin-1-yl]aze-
tidin-2-one [(3R)- and (3S)-4c]: These compounds were prepared from
hydrazone 1c, the reaction being complete after 2.5 h at 808C. Flash
chromatography (Et2O/DCM/PE 1:1:2!1:1:1) gave 4c (258 mg, 89%) as
an inseparable mixture of diastereoisomers (3R)- and (3S)-4c (dr 58:42).
1H NMR (500 MHz, CDCl3) (3R)-4c: d = 1.57–1.64 (m, 1H), 1.75–1.89
(m, 2H), 1.90–1.99 (m, 1H), 2.90 (q, J = 7.6 Hz, 1H), 3.10–3.24 (m, 2H),
3.25 (dd, J = 1.8, 5.0 Hz, 1H), 3.32 (s, 3H), 3.38–3.48 (m, 2H), 3.56 (t, J
= 5.0 Hz, 1H), 4.54 (dd, J = 1.8, 4.8 Hz, 1H), 4.64 (d, J = 11.6 Hz, 1H),
4.83 (d, J = 11.6 Hz, 1H), 7.29–7.38 ppm (m, 5H); (3S)-4c d = 1.57–
1.64 (m, 1H), 1.75–1.89 (m, 2H), 1.90–1.99 (m, 1H), 2.90 (q, J = 7.6 Hz,
1H), 3.10–3.24 (m, 2H), 3.33–3.35 (m, 1H), 3.34 (s, 3H), 3.38–3.48 (m,
2H), 3.50 (t, J = 4.9 Hz, 1H), 4.56 (dd, J = 1.9, 4.7 Hz, 1H), 4.65 (d, J
= 11.6 Hz, 1H), 4.83 (d, J = 11.6 Hz, 1H), 7.29–7.38 ppm (m, 5H); 13C
NMR (125 MHz, CDCl3) (3R)-4c: d = 20.9, 26.0, 45.7, 51.8, 59.0, 60.9,
72.1, 75.2, 77.4, 127.9, 128.0, 128.1, 128.4, 137.0, 166.7 ppm; (3S)-4c: d =
21.1, 26.1, 46.2, 51.9, 59.1, 61.1, 72.2, 75.0, 77.4, 127.9, 128.0, 128.1, 128.4,
137.0, 166.7 ppm; IR (KBr): n˜ = 1768, 1453, 1114, 1027 cmꢁ1; MS (CI):
m/z (%): 291(80) [ M+H]+, 129 (100), 91 (62); elemental analysis calcd
(%) for C16H22N2O3: C 66.18, H 7.64, N 9.65; found C 66.16, H 7.70, N
9.56.
(3R)-3-Benzyloxy-1-[(2R,5R)-2,5-dimethyl-pyrrolidin-1-yl]azetidin-2-one
(4g): This compound was prepared from hydrazone 1g, the reaction
being complete after 20 min at 808C. Flash chromatography (Et2O/DCM/
PE 1:1:3!1:1:2) gave (3R)-4g (241mg, 88%) as a single diastereomer
(dr >99:1). [a]2D8
= +2.1( c =
1in CH 2Cl2); 1H NMR (500 MHz,
CDCl3): d = 1.09 (d, J = 6.3 Hz, 6H), 1.32–1.48 (m, 2H), 1.95–2.06 (m,
2H), 3.40–3.44 (m, 2H), 3.54–3.60 (m, 2H), 4.65 (dd, J = 2.6, 4.0 Hz,
1H), 4.65 (d,
J = 11.6 Hz, 1H), 4.85 (d, J = 11.6 Hz, 1H), 7.32–
7.37 ppm (m, 5H); 13C NMR (125 MHz, CDCl3): d = 18.5 (2C), 30.0
(2C), 51.9 (2C), 56.2, 72.2, 77.4, 128.0, 128.1, 128.5, 137.0, 167.9 ppm; IR
(KBr): n˜ = 1768, 1458, 1093, 1032 cmꢁ1; MS (EI): m/z (%): 274 (11)
[M]+, 155 (32), 91 (100), 84 (47); HRMS: m/z: calcd for C16H22N2O:
274.1681; found: 274.1675.
(3R)- and (3S)-3-Benzyloxy-1-[(2S)-2-(methoxydiphenylmethyl-pyrroli-
din-1-yl]-azetidin-2-one [(3R)- and (3S)-4d]: These compounds were pre-
pared from hydrazone 1d, the reaction being complete after 3.5 h at
808C. Flash chromatography (Et2O/DCM/PE 1:1:4) gave 4d (424 mg,
96%) as an inseparable mixture of diastereoisomers (3R)- and (3S)-4d
(dr 81:19). 1H NMR (500 MHz, CDCl3) (3R)-4d: d = 0.21–0.33 (m, 1H),
1.22–1.34 (m, 1H), 1.58–1.65 (m, 1H), 1.93–2.18 (m, 1H), 2.61 (brs, 1H),
2.71–2.81 (m, 1H), 2.79 (s, 3H), 2.89–2.94 (m, 1H), 3.03 (dd, J = 1.6,
4.9 Hz, 1H), 4.16 (dd, J = 1.6, 4.5 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H),
4.44–4.49 (m, 1H), 4.65 (d, J = 11.5 Hz, 1H), 7.14–7.56 ppm (m, 15H);
(3S)-4d: d = 0.21–0.33 (m, 1H), 1.22–1.34 (m, 1H), 1.58–1.65 (m, 1H),
1.93–2.18 (m, 1H), 2.71–2.81 (m, 1H), 2.81 (s, 3H), 2.89–2.94 (m, 2H),
3.29 (t, J = 4.9 Hz, 1H), 4.09–4.10 (m, 1H), 4.21 (dd, J = 3.5, 10 Hz,
1H), 4.44–4.49 (m, 1H), 4.60–4.71 (m, 1H), 7.14–7.56 ppm (m, 15H); 13C
NMR (125 MHz, CDCl3) (3R)-4d: d = 22.7, 27.2, 49.6, 51.7, 54.0, 66.9,
72.1, 77.7, 85.9, 127.1–130.3 (m), 137.1, 138.0, 138.2, 140.0, 140.1,
165.9 ppm; (3S)-4d: d = 22.4, 27.0, 47.3, 51.7, 53.2, 66.4, 72.1, 77.7, 85.9,
127.1–130.3 (m), 137.1, 138.0, 138.2, 140.0, 140.1, 165.6 ppm; IR (KBr):
n˜ = 1762, 1452, 1093, 1038 cmꢁ1; MS (CI): m/z (%): 443 (5) [M+H]+,
411 (100), 245 (70), 91 (56); elemental analysis calcd (%) for
C28H30N2O3: C 76.00, H 6.83, N 6.33; found C 76.11, H 7.03, N 6.10.
Azetidin-2-ones (3R)- and (3S)-14e: 2-Chloro-N-methylpyridinium
iodide (219 mg, 0.83 mmol), dry TEA (0.21 mL, 1.5 mmol), and hydra-
zone 1e (0.5 mmol) were added to a solution of (S)- or (R)-12 (166 mg,
0.75 mmol) in dry toluene (7.5 mL). The reaction mixture was heated at
808C for 6 h and washed with water (2”8 mL), and the aqueous layer
was extracted with EA (2”15 mL). The combined organic layer was
washed with brine, dried (Na2SO4), filtered, and evaporated. Starting ma-
terial, reaction times, and purification conditions are as follows.
Compound (3R)-14e: Preparation from acid (R)-12 and, after 8 h, flash
chromatography (EA/PE 2:3) gave (3R)-14e (213 mg, 94%) as an oil (dr
>99:1). [a]2D2 = ꢁ112.8 (c = 1in CH 2Cl2); 1H NMR (500 MHz, CDCl3,
500 MHz): d = 0.76 (t, J = 7.5 Hz, 3H), 0.79 (t, J = 7.5 Hz, 3H), 1.31–
1.45 (m, 3H), 1.53–1.65 (m, 3H), 1.71–1.78 (m, 1H), 1.83–1.90 (m, 1H),
2.76 (t, J = 6.7 Hz, 2H), 2.86 (dd, J = 2.4, 5.2 Hz, 1H), 3.15 (s, 3H),
3.42 (t, J = 5.2 Hz, 1H), 3.47 (dd, J = 6.6, 8.3 Hz, 1H), 4.13 (dd, J =
6.7, 8.9 Hz, 1H), 4.65 (t, J = 8.9 Hz, 1H), 4.72 (dd, J = 2.4, 5.4 Hz, 1H),
J =
6.7, 9 Hz, 1H), 7.27–7.39 ppm (m, 5H); 13C NMR
(3R)- and (3S)-3-Benzyloxy-1-[(2S)-2-(1-ethyl-1-methoxypropyl) pyrroli-
din-1-yl]azetidin-2-one [(3R)- and (3S)-4e]: These compounds were pre-
pared from hydrazone 1e, the reaction being complete after 1.5 h at
808C. Flash chromatography (Et2O/DCM/PE 1:1:3) of the crude oil (dr
84:16) allowed separation of both diastereoisomers.
5.0 (dd,
(125 MHz, CDCl3): d = 7.8, 8.6, 24.0, 24.2, 25.9, 26.2, 48.5, 50.1, 54.5,
56.0, 59.0, 67.5, 70.8, 79.5, 127.3, 129.3, 129.4, 138.5, 157.7, 163.0 ppm; IR
(KBr): n˜ = 1760, 1090, 1034 cmꢁ1; MS (EI): m/z (%): 401(1) [ M]+, 300
(100), 101 (19), 91 (12); elemental analysis calcd(%) for C22H31N3O4: C
65.81, H 7.78, N 10.47; found C 65.83, H 7.94, N 10.41.
Diastereoisomer (3R)-4e: (266 mg, 80%); [a]D21
= +8.6 (c = 1in
CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 0.83–0.87 (m, 6H), 1.46–1.60
(m, 2H), 1.61–1.69 (m, 2H), 1.70–1.90 (m, 4H), 2.87–2.92 (m, 1H), 3.11–
3.15 (m, 1H), 3.26 (s, 3H), 3.26–3.31 (m, 2H), 3.47 (t, J = 4.9 Hz, 1H),
4.49 (dd, J = 1.8, 4.7 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 4.82 (d, J =
11.6 Hz, 1H), 7.26–7.34 ppm (m, 5H); 13C NMR (125 MHz, CDCl3): d =
8.0, 8.4, 23.5, 23.6, 25.6, 26.4, 46.1, 50.3, 54.2, 66.4, 72.2, 77.4, 79.6, 128.0,
Compound (3S)-14e: Preparation from acid (S)-12 and, after 8 h, flash
chromatography (EA/PE 2:3) gave (3S)-14e (160 mg, 80%) as an oil (dr
1
99:1). [a]2D2 = +38.3 (c = 1in CH Cl2); H NMR (500 MHz, CDCl3): d
2
= 0.76 (t, J = 7.5 Hz, 3H), 0.81(t, J = 7.5 Hz, 3H), 1.45–1.61 (m, 7H),
1.63–1.66 (m, 1H), 1.94–1.96 (m, 1H), 2.60 (dd, J = 2.4, 5.2 Hz, 1H),
2.61–2.64 (m, 1H), 2.77 (t, J = 8.1Hz, 1H), 3.17 (s, 3H), 3.40 (t, J =
5.2 Hz, 1H), 4.18 (dd, J = 6.7, 8.9 Hz, 1H), 4.66 (t, J = 9.0 Hz, 1H),
128.1, 128.5, 137.2, 165.8 ppm; IR (KBr): n˜
= 1762, 1458, 1088,
1030 cmꢁ1; MS (EI): m/z (%): 346 (3) [M]+, 245 (100), 101 (19), 91 (56);
elemental analysis calcd (%) for C2oH30N2O3: C 69.33, H 8.73, N 8.09;
found C 68.99, H 8.44, N 8.10.
4.77 (dd, J
= 2.4, 5.5 Hz, 1H), 5.05 (dd, J = 6.7, 9 Hz, 1H), 7.36–
7.42 ppm (m, 5H); 13C NMR (125 MHz, CDCl3): d = 7.7, 8.6, 21.9, 23.1,
24.7, 26.0, 41.8, 50.1, 52.8, 55.6, 58.6, 65.2, 70.5, 79.4, 127.6, 129.2, 129.3,
138.3, 157.6, 163.1 ppm; IR (KBr): n˜ = 1760, 1090, 1034 cmꢁ1; MS (EI):
m/z (%): 401(1) [ M]+, 300 (100), 109 (18), 91 (10); elemental analysis
calcd(%) for C22H31N3O4: C 65.81, H 7.78, N 10.47; found C 65.33, H
8.03, N 10.29.
Diastereoisomer (3S)-4e: (50 mg, 15%); [a]D21
=
ꢁ50.9 (c
= 1.3 in
CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 0.81(t, J = 7.5 Hz, 6H),
1.23–1.57 (m, 2H), 1.60–1.65 (m, 2H), 1.73–1.86 (m, 4H), 2.90–2.94 (m,
1H), 3.13–3.19 (m, 1H), 3.24–3.25 (m, 1H), 3.25 (s, 3H), 3.49 (t, J =
4.9 Hz, 1H), 4.45 (dd, J = 1.8, 4.8 Hz, 1H), 4.61 (d, J = 11.6 Hz, 1H),
4.80 (d, J = 11.6 Hz, 1H), 7.24–7.35 ppm (m, 5H); 13C NMR (125 MHz,
CDCl3): d = 7.9, 8.5, 23.1, 23.6, 25.5, 26.3, 45.8, 50.2, 53.9, 66.3, 72.3,
77.3, 79.6, 128.0, 128.2, 128.5, 137.1, 166.0 ppm; IR (KBr): n˜ = 1762,
1458, 1088, 1030 cmꢁ1; MS (EI): m/z (%): 346 (2) [M]+, 245 (100), 101
Synthesis of 1-dialkylamino-3-(N-benzyl-N-benzyloxycarbonylamino)aze-
tidin-2-ones 17e–g: 2-Chloro-N-methylpyridinium iodide (1.45 g,
5.5 mmol), dry TEA (1.4 mL, 10 mmol), and the hydrazone (2 mmol)
were added dropwise to a solution of N-benzyl-N-benzyloxycarbonylgly-
cine (15; 1.5 g, 5 mmol) in dry toluene (30 mL). The reaction mixture was
Chem. Eur. J. 2004, 10, 6111 – 6129
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6123

R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
heated at 808C until the hydrazone had been consumed and was then
washed with water (2”25 mL), and the aqueous layer was extracted with
EA (2”25 mL). The combined organic layer was washed with brine,
dried (Na2SO4), filtered, and evaporated. Flash chromatography (Et2O/
DCM/PE) gave compounds 17. Starting materials, reaction times, and
characterization data are as follows:
Synthesis of cis-4-alkyl(aryl)-1-(N,N-dialkylamino)-3-benzyloxy-azetidin-
2-ones 23e–27e: A solution of benzyloxyacetyl chloride (2; 0.4m, 1mL,
6 mmol) in dry toluene (15 mL) was added in small portions over 3 h to a
solution of the appropriate hydrazone (18e–22e, 1.5 mmol) and TEA
(1.7 mL, 12 mmol) in dry toluene (8 mL). The reaction mixture was
heated until the hydrazone had been consumed and washed with water
(2”25 mL), and the aqueous layer was extracted with EA (2”25 mL).
The combined organic layer was washed with brine, dried (Na2SO4), fil-
tered, and evaporated. Flash chromatography (Et2O/DCM/PE) gave the
b-lactams 23–27e. Starting materials, reaction times, and characterization
data are as follows:
(3R)- and (3S)-3-(N-Benzyl-N-benzyloxycarbonylamine)-1-[(2S)-2-(1-
ethyl-1-methoxypropyl)pyrrolidin-1-yl]azetidin-2-one (17e): The com-
pounds were obtained from hydrazone 1e, the reaction mixture being
heated for 23 h. Flash chromatography (Et2O/DCM/PE 1:1:2) of the
crude product (dr 82:18) gave (3R)-17e (720 mg, 76%) and (3S)-17e
(160 mg, 16%) as oils.
(3R,4S)- and (3R,4R)-3-Benzyloxy-1-[(2S)-2-(1-ethyl-1-methoxypropyl)-
pyrrolidin-1-yl]-4-pentylazetidin-2-one (23e): These compounds were
prepared from hydrazone 18e, the reaction mixture being heated at 808C
for 8 h. Flash chromatography (Et2O/DCM/PE 1:1:6) of the crude prod-
uct (dr 82:18 and cis/trans 98:2) gave (3R,4S)-23e (435 mg, 70%) and
(3S,4R)-23e (95 mg, 15%).
Compound (3R)-17e: [a]D21
=
ꢁ32.6 (c
=
1in CH 2Cl2); 1H NMR
(500 MHz, [D6]DMSO, 908C): d = 0.81(c, J = 7.3 Hz, 6H), 1.46–1.64
(m, 3H), 1.64–1.77 (m, 4H), 1.83–1.86 (m, 1H), 2.92–3.00 (m, 2H), 3.14
(s, 3H), 3.31(dd, J = 2.6, 5.1Hz, 1H), 3.37 (dd, J = 6.7, 8.7 Hz, 1H),
3.55 (t, J = 5.3 Hz, 1H), 4.47 (d, J = 16 Hz, 1H), 4.57 (d, J = 16 Hz,
1H), 4.72 (dd, J = 2.6, 5.3 Hz, 1H), 5.11 (d, J = 12.8 Hz, 1H), 5.13 (d, J
Compound (3R,4S)-23e: [a]D24
= +6.6 (c =
1in CH 2Cl2); 1H NMR
=
12.8 Hz, 1H), 7.22–7.33 ppm (m, 10H); 13C NMR (125 MHz,
(500 MHz, CDCl3): d = 0.84–0.91 (m, 9H), 1.29–1.37 (m, 4H), 1.41–1.53
(m, 4H), 1.53–1.59 (m, 2H), 1.68–1.75 (m, 2H), 1.68–1.78 (m, 2H), 1.96–
2.03 (m, 2H), 3.17–3.21 (m, 1H), 3.21 (s, 3H), 3.25–3.31 (m, 1H), 3.73–
3.78 (m, 2H), 4.38 (d, J = 4.8 Hz, 1H), 4.67 (d, J = 11.9 Hz, 1H), 4.85
[D6]DMSO, 908C): d = 7.0, 7.3, 22.8, 23.3, 25.0, 25.2, 43.8, 48.7, 49.2,
53.1, 59.1, 66.3, 66.7, 78.7, 126.2, 126.4, 127.1, 127.5, 135.9, 137.5, 154.6,
163.2 ppm; IR (KBr): n˜ = 1772, 1703, 1101, 1024 cmꢁ1; MS (CI): m/z
(%): 480 (56) [M+H]+, 448 (100), 378 (95), 91 (28); elemental analysis
calcd (%) for C28H37N3O4: C 70.12, H 7.78, N 8.76; found C 70.16, H
8.07, N 8.77.
(d, J
=
11.9 Hz, 1H), 7.28–7.36 ppm (m, 5H); 13C NMR (125 MHz,
CDCl3): d = 7.9, 8.5, 13.9, 22.5, 24.3 (2C), 25.8, 26.2, 26.4, 28.5, 31.9,
49.8, 56.7, 61.9, 67.7, 72.6, 79.1, 79.6, 127.6, 127.7, 128.3, 137.6, 166.4 ppm;
IR (KBr): n˜ = 1751, 1468, 1103 cmꢁ1; MS (EI): m/z (%): 416 (2) [M]+,
315 (41), 111 (100), 91 (30); elemental analysis calcd (%) for
C25H40N2O3: C 72.08, H 9.68, N 6.72; found C 72.12, H 9.25, N 6.92.
Compound (3S,4R)-23e: [a]2D4 = ꢁ96.3 (c = 1in CH 2Cl2); 1H NMR
(300 MHz, CDCl3): d = 0.83–0.91 (m, 9H), 1.25–1.50 (m, 4H), 1.52–1.67
(m, 4H), 1.71–1.96 (m, 8H), 2.92–3.0 (m, 1H), 3.26 (s, 3H), 3.27–3.32 (m,
1H), 3.39–3.44 (m, 1H), 3.93 (dt, J = 5.1, 8.6 Hz, 1H), 4.34 (d, J =
5.1Hz, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.92 (d, J = 11.9 Hz, 1H), 7.27–
7.37 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d = 7.8, 8.5, 13.9, 22.4,
23.3, 23.5, 25.6, 25.9, 26.2, 28.8, 31.8, 50.2, 55.7, 59.4, 65.3, 72.4, 78.4, 79.7,
Compound (3S)-17e: [a]D21
(500 MHz, [D6]DMSO, 908C): d
=
ꢁ28.9 (c
0.80–0.84 (m, 6H), 1.48–1.60 (m,
=
1in CH 2Cl2); 1H NMR
=
2H), 1.60–1.75 (m, 5H), 1.71–1.85 (m, 1H), 2.73–2.79 (m, 1H), 2.88–2.91
(m, 1H), 3.11–3.14 (m, 1H), 3.16 (s, 3H), 3.28 (dd, J = 2.7, 5.0 Hz, 1H),
3.51(t, J = 5.0 Hz, 1H), 4.50 (d, J = 16.0 Hz, 1H), 4.60 (d, J = 16.0 Hz,
1H), 4.59 (dd, J = 2.7, 5.4 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 5.15 (d, J
=
12.0 Hz, 1H), 7.24–7.33 ppm (m, 10H); 13C NMR (125 MHz,
[D6]DMSO, 908C): d = 7.0, 7.2, 22.4, 23.3, 24.7, 25.2, 43.2, 48.8, 49.6,
52.5, 59.0, 66.1, 66.4, 78.7, 126.3, 126.4, 126.9, 127.1, 127.5, 136.1, 137.5,
154.6, 163.4 ppm; IR (KBr): n˜ = 1772, 1703, 1101, 1024 cmꢁ1; MS (CI):
m/z (%): 480 (27) [M+H]+, 448 (100), 378 (77), 91 (37); elemental analy-
sis calcd (%) for C28H37N3O4: C 70.12, H 7.78, N 8.76; found C 69.61, H
7.89, N 8.73.
127.6, 127.8, 128.0, 137.6, 166.9 ppm; IR (KBr): n˜
= 1751, 1468,
1103 cmꢁ1; MS (CI): m/z (%): 417 (37) [M+H]+, 385 (100), 181 (98), 91
(76); elemental analysis calcd (%) for C25H40N2O3: C 72.08, H 9.68, N
6.72; found C 71.81, H 9.73, N 6.50.
Compound (3S)-17 f: This compound was prepared from 1 f with use of
different proportions of reactants: hydrazone (1mmol), acid 15
(6 mmol), 2-chloro-N-methylpyridinium iodide (6.6 mmol), TEA
(18 mmol), and dry toluene (15 mmol). The reaction mixture was heated
for 8 h at 608C. Flash chromatography (Et2O/DCM/PE 1:1:2) of the
crude product (dr >99:1) gave crystalline (3S)-17 f (524 mg, 81%). M.p.
(3R,4S)- and (3S,4R)-3-Benzyloxy-4-isobutyl-1-[(2S)-2-(1-ethyl-1-methoxy-
propyl)pyrrolidin-1-yl]azetidin-2-one (24e): These compounds were pre-
pared from 19e, the reaction mixture being heated at 808C for 8 h. Flash
chromatography (Et2O/DCM/PE 1:1:6) of the crude product (dr 87:13
and cis/trans 98:2) gave (3R,4S)-24e (441mg, 73%) and (3 S,4R)-24e
(66 mg, 11%).
67–708C; [a]2D1
= +84.3 (c =
1in CH 2Cl2); 1H NMR (500 MHz,
[D6]DMSO, 908C): d = 3.56 (m, 2H), 3.58 (dd, J = 2.9, 5.0 Hz, 1H),
3.73 (t, J = 5.0 Hz, 1H), 4.07 (dd, J = 2.7, 12.9 Hz, 2H), 4.23 (d, J =
12.9 Hz, 2H), 4.41 (d, J = 2.7 Hz, 2H), 4.56 (s, 2H), 4.74 (dd, J = 2.9,
5.5 Hz, 1H), 5.16 (s, 2H), 5.55 (s, 2H), 7.22–7.43 ppm (m, 20H); 13C
NMR (125 MHz, [D6]DMSO, 908C): d = 47.1, 52.1, 57.8 (2C), 60.7, 65.7
(2C), 67.8, 78.4 (2C), 99.4 (2C), 126.3–129.3 (m), 137.4, 138.9, 139.2,
155.9, 168.7 ppm; IR (KBr): n˜ = 1773, 1701, 1393, 1099 cmꢁ1; MS (EI):
m/z (%): 647 (0.5) [M]+, 556 (70), 105 (38), 91 (100); elemental analysis
calcd (%) for C38H37N3O7: C 70.46, H 5.76, N 6.49; found C 70.76, H
6.15, N 6.21.
Compound (3R,4S)-24e: [a]D26
=
+10.8 (c = 1.5 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d = 0.86 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz,
3H), 0.95 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.43–1.63 (m,
6H), 1.66–1.76 (m, 2H), 1.82 (q, J = 6.6 Hz, 1H), 1.95–2.02 (m, 2H),
3.14–3.22 (m, 1H), 3.21 (s, 3H), 3.25–3.31 (m, 1H), 3.73–3.78 (m, 1H),
3.86 (dt, J = 4.8, 6.6 Hz, 1H), 4.40 (d, J = 4.8 Hz, 1H), 4.67 (d, J =
11.9 Hz, 1H), 4.86 (d, J = 11.9 Hz, 1H), 7.27–7.36 ppm (m, 5H); 13C
NMR (75 MHz, CDCl3): d = 7.8, 8.3, 22.5, 23.0 (2C), 24.2, 25.1, 26.1
(2C), 36.9, 49.6, 56.6, 60.1, 67.6, 72.4, 78.9, 79.5, 127.5, 127.6, 128.2, 137.4,
166.2 ppm; IR (KBr): n˜ = 1751, 1467, 1094 cmꢁ1; MS (CI): m/z (%): 403
(72) [M+H]+, 371(64), 301(100), 91(24); elemental analysis calcd (%)
for C24H38N2O3: C 71.60, H 9.51, N 6.96; found C 71.53, H 9.87, N 7.13.
Compound (3S,4R)-24e: [a]2D6 = ꢁ106.8 (c = 1.2 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d = 0.86 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz,
3H), 0.94 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.3 Hz, 3H), 1.49–1.69 (m,
4H), 1.70–1.83 (m, 6H), 1.85–1.97 (m, 1H), 2.92–3.0 (m, 1H), 3.22–3.32
(m, 1H), 3.26 (s, 3H), 3.42–3.47 (m, 1H), 4.0–4.30 (m, 1H), 4.35 (d, J =
5.1Hz, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.90 (d, J = 11.9 Hz, 1H), 7.26–
7.38 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d = 7.6, 8.5, 22.4, 23.0,
23.3, 23.5 (2C), 25.7, 26.1, 37.0, 50.1, 55.8, 57.9, 65.2, 72.3, 78.5, 79.7,
Compound (3R)-17g: This compound was prepared from 1g, but with
use of the following proportions of reagents: hydrazone (1mmol),
acid 15 (2.5 mmol), 2-chloro-N-methylpyridinium iodide (2.8 mmol),
TEA (5 mmol), and dry toluene (13 mL). Flash chromatography (Et2O/
PE 1:1) of the crude product (dr >99:1) gave (3S)-17f (326 mg, 80%) as
an oil. [a]2D4
=
ꢁ38.0 (c
=
1in CH 2Cl2); 1H NMR (300 MHz,
[D6]DMSO, 908C): d = 0.99 (d, J = 6.3 Hz, 6H), 1.24–1.34 (m, 2H),
1.87–1.95 (m, 2H), 3.38–3.45 (m, 3H), 3.49 (dd, J = 2.8, 5.1Hz, 1H)),
4.48 (d, J = 16.1 Hz, 1H), 4.58 (d, J = 16.1 Hz, 1H), 4.84 (dd, J = 2.8,
5.4 Hz, 1H), 5.12 (d, J = 13.1 Hz, 1H), 5.16 (d, J = 13.1 Hz, 1H), 7.23–
7.31ppm (m, 10H); 13C NMR (125 MHz, [D6]DMSO, 908C): d = 17.8
(2C), 29.4 (2C), 49.9 (3C), 55.4, 59.3, 66.4, 126.4, 126.5, 126.9, 127.2,
127.7, 136.0, 137.5, 154.6, 164.9 ppm; IR (KBr): n˜ = 1776, 1712, 1458,
1100, 1024 cmꢁ1; MS (CI): m/z (%): 408 (100) [M+H]+, 316 (44), 91 (42);
HRMS: m/z: calcd for C24H30N3O3: 408.2287; found: 408.2287.
127.5, 127.9, 128.2, 137.5, 166.8 ppm; IR (KBr): n˜
= 1751, 1467,
1094 cmꢁ1; MS (CI): m/z (%): 403 (93) [M+H]+, 371(100), 301(84), 91
(55); elemental analysis calcd (%) for C24H38N2O3: C 71.60, H 9.51, N
6.96; found C 71.81, H 9.57, N 6.74.
6124
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6111 – 6129

Stereoselective Cycloadditions
6111 – 6129
(3R,4S)- and (3S,4R)-3-Benzyloxy-1-[(2S)-2-(1-ethyl-1-methoxypropyl)-
pyrrolidin-1-yl]-4-phenylethylazetidin-2-one (25e): These compounds
were prepared from 20e, the reaction mixture being heated at 808C for
9 h. Flash chromatography (EA/PE 1:6) of the crude product (dr 80:20
and cis/trans >99:1) gave (3R,4S)-25e (524 mg, 78%) and (3S,4R)-25e
(131 mg, 19%).
(m, 5H); 13C NMR (125 MHz, CDCl3): d = 7.6, 8.7, 23.6, 24.3, 25.8, 26.0,
49.6, 55.6, 65.6, 66.5, 72.1, 79.8, 80.1, 127.7–129.2 (m), 134.6, 136.3,
165.7 ppm; IR (KBr): n˜ = 1768, 1458, 1092 cmꢁ1; MS (CI): m/z (%): 423
(59) [M+H]+, 321 (41), 213 (53), 181 (100); elemental analysis calcd (%)
for C26H34N2O3: C 73.90, H 8.11, N 6.63; found C 73.83, H 8.17, N 6.74.
Compound (3S,4R)-27e: m.p. 74–768C; [a]D25
=
ꢁ159.8 (c
= 1in
Compound (3R,4S)-25e: [a]D28
=
+1 9 c( = 1in CH 2Cl2); 1H NMR
1
CH2Cl2); H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.5 Hz, 3H), 0.93
(t, J = 7.5 Hz, 3H), 1.24–1.33 (m, 1H), 1.45–1.61 (m, 2H), 1.63–1.77 (m,
5H), 2.46–2.55 (m, 1H), 3.0–3.07 (m, 1H), 3.17–3.20 (m, 1H), 3.22 (s,
3H), 4.09 (d, J = 11.2 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 4.53 (d, J =
4.8 Hz, 1H), 5.08 (d, J = 4.8 Hz, 1H), 6.92–6.98 (m, 5H), 7.18–7.54 ppm
(m, 5H); 13C NMR (75 MHz, CDCl3): d = 7.5, 9.1, 21.8, 23.3, 24.9, 26.0,
49.9, 54.9, 60.5, 64.9, 72.2, 80.1 (2C), 127.7–129.1 (m), 135.4, 136.3,
166.7 ppm; IR (KBr): n˜ = 1768, 1458, 1092 cmꢁ1; MS (CI): m/z (%): 423
(37) [M+H]+, 321 (36), 213 (61), 181 (100); elemental analysis calcd (%)
for C26H34N2O3: C 73.90, H 8.11, N 6.63; found C 73.90, H 8.29, N 6.46.
(500 MHz, CDCl3): d = 0.83 (q, J = 7.7 Hz, 6H), 1.41–1.55 (m, 4H),
1.66–1.73 (m, 2H), 1.95–2.06 (m, 4H), 2.72–2.77 (m, 2H), 3.17 (s, 3H),
3.18–3.23 (m, 1H), 3.28–3.37 (m, 1H), 3.72–3.75 (m, 1H), 3.78–3.82 (m,
1H), 4.41 (d, J = 4.8 Hz, 1H), 4.67 (d, J = 11.9 Hz, 1H), 4.89 (d, J =
11.9 Hz, 1H), 7.15–7.37 ppm (m, 10H); 13C NMR (125 MHz, CDCl3): d
= 7.9, 8.6, 24.3, 24.4, 26.3 (2C), 30.5, 32.3, 49.8, 56.8, 61.2, 67.9, 72.7, 78.9,
79.7, 126, 127.7–128.4 (m), 137.5, 141.8, 166.4 ppm; IR (KBr): n˜ = 1751,
1406, 1101 cmꢁ1; MS (CI): m/z (%): 451(98) [ M+H]+, 419 (100), 349
(77), 91(30); elemental analysis calcd (%) for C 28H38N2O3: C 74.63, H
8.50, N 6.22; found C 74.50, H 8.75, N 6.26.
Compound (3S,4R)-25e: [a]2D8 = ꢁ57.4 (c = 1.2 in CH2Cl2); 1H NMR
(500 MHz, CDCl3): d = 0.86 (q, J = 7.4 Hz, 6H), 1.51–1.64 (m, 4H),
1.73–1.82 (m, 3H), 1.89–1.94 (m, 1H), 2.11–2.22 (m, 2H), 2.60–2.66 (m,
1H), 2.72–2.84 (m, 1H), 2.93–2.98 (m, 1H), 3.24 (s, 3H), 3.26–3.30 (m,
1H), 3.40–3.42 (m, 1H), 3.98–4.01 (m, 1H), 4.40 (d, J = 5.1Hz, 1H),
4.74 (d, J = 11.9 Hz, 1H), 4.98 (d, J = 11.9 Hz, 1H), 7.16–7.41 ppm (m,
10H); 13C NMR (125 MHz, CDCl3): d = 7.8, 8.6, 23.5 (2C), 25.7, 26.2,
30.7, 32.3, 50.1, 55.8, 58.5, 65.4, 72.6, 78.4, 79.8, 125.9, 127.7–128.6 (m),
137.5, 141.5, 166.9 ppm; IR (KBr): n˜ = 1751, 1406, 1101 cmꢁ1; MS (CI):
m/z (%): 451(47) [ M+H]+, 419 (80), 349 (41), 138 (100), 91 (98);
HRMS: m/z: calcd for C28H39N2O3: 451.2961; found: 451.2954.
2-Benzyloxy-N-[(2S)-2-(1-ethyl-1-methoxypropyl)pyrrolin-1-yl]acetamide
(28): A solution of benzyloxyacetyl chloride (2, 0.4 mmol, 0.07 mL) in
dry toluene (1mL, 0.4 m) was added dropwise at rt to a solution of the
hydrazone 18e (0.2 mmol) and TEA (0.8 mmol, 0.12 mL) in dry toluene
(2 mL). The mixture was stirred at rt until TLC showed no change. The
reaction mixture was washed with water (2”25 mL), and the aqueous
layer was extracted with EA (2”25 mL). The combined organic layer
was washed with brine, dried (Na2SO4), filtered, and evaporated. Flash
chromatography (Et2O/DCM/PE 1:1:1) gave 28 (50 mg, 75%) as an oil.
1
[a]2D1 = ꢁ25.3 (c = 1in CH Cl2); H NMR (300 MHz, CDCl3): d = 0.87
2
(t, J = 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H), 1.49–1.66 (m, 4H), 1.77–
1.98 (m, 4H), 2.27–2.65 (m, 1H), 3.09–3.13 (m, 1H), 3.23 (s, 3H), 3.41–
3.49 (m, 1H), 3.98 (s, 2H), 4.56 (s, 2H), 7.32–7.38 (m, 5H), 7.9 ppm (brs,
1H); 13C NMR (75 MHz, CDCl3): d = 7.9, 8.4, 22.2, 24.2, 24.9, 26.2, 49.2,
56.3, 69.2, 69.5, 73.5, 79.8, 127.8, 128.1, 128.5, 136.8, 166.4 ppm; IR (KBr):
n˜ = 1683, 1412, 1022 cmꢁ1; MS (CI): m/z (%): 335 (17) [M+H]+, 305
(75), 303 (71), 287 (100); elemental analysis calcd (%) for C19H30N2O3: C
68.23, H 9.04, N 8.38; found C 68.27, H 9.39, N 8.43. From 20e, the same
product was obtained in 68% yield, and with identical characterization
data.
(3R,4S)- and (3S,4R)-3-Benzyloxy-1-[(2S)-2-(1-ethyl-1-methoxypropyl)-
pyrrolidin-1-yl]-4-isopropylazetidin-2-one (26e): These compounds were
prepared from 21e, the reaction mixture being heated at 1008C for 7.5 h.
Flash chromatography (Et2O/PE 1:3) of the crude product (dr 91:9 and
cis/trans >99:1) gave (3R,4S)-26e (477 mg, 82%) and (3S,4R)-26e
(47 mg, 8%).
Compound (3R,4S)-26e: [a]D23
=
+13.9 (c = 1.1 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d = 0.82–0.94 (m, 6H), 0.99 (d, J = 6.6 Hz, 3H),
1.13 (d, J = 6.6 Hz, 3H), 1.47–1.59 (m, 4H), 1.63–1.74 (m, 2H), 1.96–
2.09 (m, 3H), 3.18 (s, 3H), 3.21–3.31 (m, 1H), 3.32–3.38 (m, 1H), 3.51
(dd, J = 5.0, 8.8 Hz, 1H), 3.76–3.81 (m, 1H), 4.38 (d, J = 5.0 Hz, 1H),
4.69 (d, J = 11.9 Hz, 1H), 4.93 (d, J = 11.9 Hz, 1H), 7.27–7.32 ppm (m,
5H); 13C NMR (75 MHz, CDCl3): d = 7.6, 8.5, 19.5 (2C), 24.0, 24.1, 26.3,
26.4, 28.4, 49.5, 56.8, 67.3, 67.8, 72.4, 78.9, 79.6, 127.4, 127.5, 128.2, 137.6,
166.9 ppm; IR (KBr): n˜ = 1746, 1461, 1088, 1034 cmꢁ1; MS (CI): m/z
(%): 389 (82) [M+H]+, 357 (83), 287 (100), 91 (15); elemental analysis
calcd (%) for C23H36N2O3: C 71.10, H 9.34, N 7.21; found C 71.05, H
9.40, N 7.28.
Synthesis of 27 f, 30 f, and 19h—General procedure: A solution of benzyl-
oxyacetyl chloride (2, 0.4 mL, 2.4 mmol) in dry toluene (4.8 mL) was
added in 12 portions (each 0.4 mL, 0.2 mmol) at 30 min intervals to a so-
lution of hydrazones 22 f, 19 f, or 19h (0.4 mmol) and TEA (0.67 mL,
4.8 mmol) in dry toluene (1.7 mL). The reaction mixture was heated at
1008C until the hydrazone had been consumed (8.5 h) and washed with
water (2”25 mL), and the aqueous layer was extracted with EA (2”
25 mL). The combined organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated.
Compound 27 f: This compound was prepared from 22 f, flash chroma-
tography (EA/PE 1:2) providing crystalline (3S,4R)-27 f (151 mg, 66%,
Compound (3S,4R)-26e: [a]2D8 = ꢁ72.7 (c = 0.9 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d = 0.87 (t, J = 7.6 Hz, 3H), 0.90 (t, J = 7.6 Hz,
3H), 1.08 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H), 1.52–1.68 (m,
4H), 1.73–1.83 (m, 3H), 1.85–1.95 (m, 1H), 2.07–2.18 (m, 1H), 2.89–2.97
(m, 1H), 3.22 (s, 3H), 3.29–3.35 (m, 1H), 3.47 (dd, J = 5.7, 9.1Hz, 1H),
3.85 (t, J = 5.4 Hz, 1H), 4.33 (d, J = 5.4 Hz, 1H), 4.68 (d, J = 11.9 Hz,
dr >99:1). M.p. 78–808C; [a]D23
=
+4.4 (c = 1in CH 2Cl2); 1H NMR
(500 MHz, [D6]DMSO, 908C): d = 3.43 (brs, 2H), 3.95–3.98 (m, 2H),
4.04 (d, J = 11.4 Hz, 1H), 4.23–4.32 (m, 5H), 5.0 (d, J = 4.9 Hz, 1H),
5.35 (d, J = 4.9 Hz, 1H), 5.54 (s, 2H), 6.96–6.98 (m, 5H), 7.20–7.29 (m,
5H), 7.31–7.45 ppm (m, 10H); 13C NMR (125 MHz, [D6]DMSO, 908C):
d = 57.7 (2C), 65.4, 67.1, 72.6, 78.1 (2C), 80.9, 99.2, 126.9, 130.4, 137.8,
139.1, 168.9 ppm; IR (KBr): n˜ = 1776, 1394, 1092, 1021 cmꢁ1; MS (CI):
m/z (%): 591(18), [ M+H]+, 381 (92), 107 (71), 91 (100); HRMS: m/z:
calcd for C36H35N2O6: 591.2495; found: 591.2487; elemental analysis calcd
(%) for C36H34N2O6: C 73.20, H 5.80, N 4.74; found C 73.23, H 6.24, N
4.46.
1H), 4.94 (d,
J =
11.9 Hz, 1H), 7.27–7.38 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d = 7.7, 8.7, 18.7, 19.6 (2C), 22.8, 23.4, 28.2, 50.0, 55.2,
64.2, 64.5, 78.9, 80.0 (2C), 127.4, 127.5, 128.2, 137.6, 168.2 ppm; IR
(KBr): n˜ = 1746, 1461, 1088, 1034 cmꢁ1; MS (CI): m/z (%): 389 (60)
[M+H]+, 357 (75), 287 (100), 181 (71); HRMS: m/z: calcd for
C23H36N2O3: 388.2726; found: 388.2718.
(3R,4S)- and (3S,4R)-3-Benzyloxy-1-[(2S)-2-(1-ethyl-1-methoxypropyl)-
pyrrolidin-1-yl]-4-phenylazetidin-2-one (27e): These compounds were
prepared from 22e, the reaction mixture being heated at 1008C for 8 h.
Flash chromatography (EA/PE 1:4) of the crude product (dr 76:24 and
cis/trans >99:1) gave crystalline (3R,4S)-27e (472 mg, 75%) and crystal-
line (3S,4R)-27e (149 mg, 23%).
Compound 30: This compound was prepared from 19 f, flash chromatog-
raphy (Et2O/DCM/PE 1:1:4) providing 30 (196 mg, 86%) as an oil. [a]D25
= +50.6 (c = 1in CH 2Cl2); 1H NMR (300 MHz, CDCl3): d = 0.89 (d, J
= 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 2.20–2.33 (m, 1H), 3.55–3.57
(m, 1H), 3.89–3.91 (m, 1H), 3.97–4.03 (m, 3H), 4.20–4.26 (m, 1H), 4.23
(d, J = 16.1 Hz, 1H), 4.46–4.50 (m, 2H), 4.51 (d, J = 11.7 Hz, 1H), 4.67
(d, J = 11.7 Hz, 1H), 5.02 (d, J = 16.1Hz, 1H), 5.49 (s, 1H), 5.53 (s,
1H), 5.99 (dd, J = 7.1, 14.7 Hz, 1H), 6.73 (dd, J = 0.9, 14.7 Hz, 1H),
7.25–7.49 ppm (m, 15H); 13C NMR (75 MHz, CDCl3): d = 22.6, 22.7,
29.5, 52.6, 54.9, 63.9, 64.2, 68.3, 72.9, 77.2 (2C), 98.9, 99.6, 120.3, 125.4,
129.1, 137.4, 137.5, 137.7, 173.3 ppm; IR (KBr): n˜ = 1691, 1387, 1128,
1012 cmꢁ1; MS (EI): m/z (%): 570 (28), [M]+, 421(100), 338 (37), 91
Compound (3R,4S)-27e: m.p. 72–748C; [a]D25
= +76.7 (c = 1.1 in
1
CH2Cl2); H NMR (300 MHz, CDCl3): d = 0.78 (t, J = 7.5 Hz, 3H), 0.86
(t, J = 7.5 Hz, 3H), 1.40–1.55 (m, 2H), 1.58–1.70 (m, 4H), 1.80–2.0 (m,
2H), 3.10–3.36 (m, 1H), 3.21 (s, 3H), 3.35–3.43 (m, 1H), 3.73–3.78 (m,
1H), 4.09 (d, J = 11.1 Hz, 1H), 4.24 (d, J = 11.1 Hz, 1H), 4.62 (d, J =
4.5 Hz, 1H), 4.90 (d, J = 4.5 Hz, 1H), 6.93–7.23 (m, 5H), 7.36–7.49 ppm
Chem. Eur. J. 2004, 10, 6111 – 6129
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6125

R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
(64); elemental analysis calcd (%) for C34H38N2O6: C 71.56, H 6.71, N
4.91; found C 71.96, H 7.29, N 4.58.
tography (Et2O/DCM/PE 1:1:6) gave crystalline (3R,4S)-27g (168 mg,
96%). M.p. 90–928C; [a]D23
= +116.8 (c =
1in CH 2Cl2); 1H NMR
(300 MHz, CDCl3): d = 1.15 (d, J = 6.3 Hz, 6H), 1.26–1.36 (m, 2H),
1.83–1.95 (m, 2H), 3.60–3.70 (m, 2H), 4.14 (d, J = 11.2 Hz, 1H), 4.25 (d,
J = 11.2 Hz, 1H), 4.71 (d, J = 4.7 Hz, 1H), 4.78 (d, J = 4.7 Hz, 1H),
6.95–6.98 (m, 5H), 7.21–7.24 (m, 5H), 7.34–7.49 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d = 18.7 (2C), 28.8 (2C), 55.5 (2C), 68.7, 72.1, 79.9,
127.7, 128.1, 128.2, 128.3, 128.4, 134.5, 136.3, 167.0 ppm; IR (KBr): n˜ =
1752, 1593, 1442, 1371, 1108 cmꢁ1; MS (CI): m/z (%): 351(28) [ M+H]+,
231 (10), 141 (100), 91 (21); elemental analysis calcd (%) for
C22H26N2O2: C 75.40, H 7.48, N 7.99; found C 75.40, H 7.59, N 7.86.
Compound 24h: This compound was prepared from 19h, but with heat-
ing at 808C for 22 h. Flash chromatography (EA/PE 1:10) of the crude
product (de 98%, cis/trans 9:1) gave (3R,4S)-24h (96 mg, 53%, cis/trans
>99:1) as an oil; [a]D24
=
ꢁ80.7 (c
=
1.5 in CH2Cl2); 1H NMR
(300 MHz, CDCl3): d = 0.80 (t, J = 6.8 Hz, 6H), 1.03–1.23 (m, 2H),
1.55–1.65 (m, 1H), 2.04–2.15 (m, 2H), 2.38–2.48 (m, 2H), 2.95 (dt, J =
5.1, 6.8 Hz, 1H), 3.96 (d, J = 5.1Hz, 1H), 4.37 (d, J = 11.9 Hz, 1H),
4.51(d, J = 11.9 Hz, 1H), 4.87–4.92 (m, 2H), 7.13–7.60 ppm (m, 15H);
13C NMR (75 MHz, CDCl3): d = 22.3, 22.7, 25.1, 32.5 (2C), 36.7, 61.9,
65.8 (2C), 71.6, 78.1, 127.3, 128.5, 137.6, 141.3, 166.9 ppm; IR (KBr): n˜ =
1752, 1458, 1371, 1103 cmꢁ1; MS (CI): m/z (%): 455 (84), [M+H]+, 265
(100), 104 (32), 91 (55); HRMS: m/z: calcd for C30H35N2O2: 455.2699;
found: 455.2691.
Oxidative deamination—General procedure: MMPP·6H2O (524 mg,
0.9 mmol) was added to a solution of N-protected b-lactam (0.3 mmol) in
MeOH (0.4m, 0.75 mL). The reaction mixture was vigorously stirred until
the starting material had been consumed. The mixture was diluted with
H2O (10 mL) and extracted with CH2Cl2 (4”10 mL). The organic layer
was washed with saturated NaHCO3 solution, dried (MgSO4), and con-
centrated. The residue was purified by flash chromatography. Eluents,
yields, and spectral and analytical data for compounds (3R)-33, (3S)-33,
(3R)-34, (3S)-34, (3R)-35, (3S)-35, (3R,4S)-36, (3R,4S)-37, (3R,4S)-38,
(3R,4S)-39 and (3R,4S)-40 are as follows.
General procedure for compounds (3R,4S)-24–27g: Small amounts
(0.63 mL, 0.25 mmol) of
a solution of benzyloxyacetyl chloride (2,
0.33 mL, 2 mmol) in dry toluene (0.4m, 5 mL) were added every 30 min
over 4 h to a solution of hydrazone 19–22g (0.5 mmol) and TEA (0.6 mL,
4 mmol) in dry toluene (2.5 mL). The reaction mixture was heated until
the starting hydrazone had been consumed and then washed with water
(2”25 mL), and the aqueous layer was extracted with EA (2”25 mL).
The combined organic layer was washed with brine, dried (Na2SO4), fil-
tered, and evaporated. Flash chromatography (Et2O/DCM/PE 1:1:8)
gave b-lactams 24–27g: Starting materials, reaction times, and characteri-
zation data are as follows:
(3R)-3-Benzyloxyazetidin-2-one [(3R)-33]: This compound was prepared
from (3R)-4e, flash chromatography (toluene/EA 3:2) providing crystal-
line (3R)-33 (47 mg, 89%): M.p. 80–828C; [a]D22
= +54.9 (c = 1in
CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 3.28 (dd, J = 2.2, 4.9 Hz,
1H), 3.47 (t, J = 4.9 Hz, 1H), 4.67 (d, J = 11.6 Hz, 1H), 4.81–4.84 (m,
1H), 4.86 (d, J = 11.6 Hz, 1H), 5.93 (brs, 1H), 7.3–7.4 ppm (m, 5H); 13C
(3R,4S)-cis-3-Benzyloxy-4-isobutyl-1-[(2R,5R)-2,5-dimethyl-pyrrolidin-1-
yl]azetidin-2-one (24g): This compound was prepared from 19g, the reac-
tion mixture being heated for 8.5 h at 608C. Flash chromatography
NMR (125 MHz, CDCl3):
d = 44.1, 72.2, 82.5, 128.1, 128.5, 136.9,
168.3 ppm; IR (KBr): n˜ = 3311, 1731, 1461 cmꢁ1; MS (CI): m/z (%): 178
(100) [M+H]+, 150 (31), 91 (84); elemental analysis calcd (%) for
C10H11NO2: C 67.78, H 6.23, N 7.90; found C 67.45, H 6.25, N 7.90.
(Et2O/DCM/PE 1:1:8) gave (3R,4S)-24g (cis/trans 95:5, 116 mg, 70%) as
1
an oil. [a]2D3 = +28.1( c = 1in CH Cl2); H NMR (300 MHz, CDCl3): d
2
The same product was obtained, in 82% yield, from (3R)-4g, and
MMPP·6H2O (99 mg, 0.17 mmol), and had identical characterization
data.
= 0.94 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.08 (d, J =
6.3 Hz, 6H), 1.36–1.42 (m, 2H), 1.59–1.65 (m, 2H), 1.70–1.80 (m, 1H),
1.90–2.0 (m, 2H), 3.67–3.76 (m, 3H), 4.53 (d, J = 5.0 Hz, 1H), 4.71 (d, J
= 11.9 Hz, 1H), 4.89 (d, J = 11.9 Hz, 1H), 7.27–7.38 ppm (m, 5H); 13C
NMR (75 MHz, CDCl3): d = 18.8 (2C), 22.7, 22.8, 25.5, 30.3 (2C), 37.0,
56.3 (2C), 63.1, 72.3, 78.2, 127.5, 127.6, 128.2, 137.4, 167.8 ppm; IR
(KBr): n˜ = 1751, 1362, 1108 cmꢁ1; MS (CI): m/z (%): 331(27) [ M+H]+,
330 (10), 141 (100), 91 (63); elemental analysis calcd (%) for
C20H30N2O2: C 72.69, H 9.15, N 8.48; found C 72.81, H 9.52, N 8.47.
(3S)-3-Benzyloxyazetidin-2-one [(3S)-33]: This compound was prepared
from (3S)-4 f, flash chromatography (toluene/EA 3:2) providing crystal-
line (3S)-33 (44 mg, 82%). [a]2D2 = ꢁ55.9 (c = 0.9 in CH2Cl2); MS (CI):
m/z (%): 178 (56) [M+H]+, 150 (19), 91 (100); HRMS: m/z: calcd for
C10H11NO2: 178.068; found: 178.0866. The rest of spectral and analytical
data were in agreement with those described for (3R)-33.
(3R,4S)-cis-3-Benzyloxy-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-4-phe-
nylethylazetidin-2-one [(3R,4S)-25g]: This compound was prepared from
20g, the reaction mixture being heated for 6 h at 608C. Flash chromatog-
(3S)-3-[(S)-(5-Phenyloxazolidin-1-yl-2-one)]azetidin-2-one [(3S)-34]: This
compound was prepared from (3S)-14e, flash chromatography (DCM/
MeOH 20:1) providing crystalline (3S)-34 (50 mg, 71%). M.p. 156–
1
1588C; [a]2D2 = +76.3 (c = 1.1 in MeOH); H NMR (500 MHz, CDCl3):
raphy (Et2O/DCM/PE 1:1:6) gave (3R,4S)-25g (157 mg, 83%) as an oil.
1
[a]2D3 = +23.5 (c = 1in CH Cl2); H NMR (300 MHz, CDCl3): d = 1.10
d = 2.76 (dd, J = 2.8, 5.6 Hz, 1H), 3.32 (t, J = 5.6 Hz, 1H), 4.24 (dd, J
= 6.7, 9.0 Hz, 1H), 4.70 (t, J = 9.0 Hz, 1H), 5.01 (dd, J = 6.7, 9.0 Hz,
1H), 5.06 (ddd, J = 0.5, 2.8, 5.5 Hz, 1H), 5.63 (brs, 1H), 7.39–7.43 ppm
(m, 5H); 13C NMR (125 MHz, CDCl3): d = 42.0, 59.0, 60.9, 70.4, 127.4,
2
(d, J = 6.3 Hz, 6H), 1.93–2.12 (m, 4H), 2.63–2.80 (m, 4H), 3.60–3.80 (m,
3H), 4.58 (d, J = 5.0 Hz, 1H), 4.73 (d, J = 11.9 Hz, 1H), 4.93 (d, J =
11.9 Hz, 1H), 7.18–7.42 ppm (m, 10H); 13C NMR (75 MHz, CDCl3): d =
18.7 (2C), 29.9 (2C), 30.9, 32.0, 56.4 (2C), 63.7, 72.4, 78.1, 125.8, 127.6,
127.7, 128.3, 128.4, 137.4, 141.5, 167.7 ppm; IR (KBr): n˜ = 1746, 1456,
1355, 1112 cmꢁ1; MS (CI): m/z (%): 379 (100) [M+H]+, 378 (42), 141
(37), 91(23); elemental analysis calcd (%) for C 24H30N2O2: C 76.16, H
7.99, N 7.40; found C 76.04, H 8.26, N 7.37.
129.3, 129.5, 138.0, 157.0, 165.4 ppm; IR (KBr): n˜
= 3187, 1744,
1094 cmꢁ1; MS (CI): m/z (%): 233 (10) [M+H]+, 205 (100), 113 (11); ele-
mental analysis calcd (%) for C12H12N2O3: C 62.06, H 5.21, N 12.06;
found C 61.69, H 5.08, N 12.16.
(3R)-3-[(R)-(5-Phenyl-oxazolidin-1-yl-2-one)]azetidin-2-one
(3R)-34:
(3R,4S)-cis-3-Benzyloxy-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-4-iso-
propylazetidin-2-one [(3R,4S)-26g]: This compound was prepared from
21g, the reaction mixture being heated for 6.5 h at 808C. Flash chroma-
tography (Et2O/DCM/PE 1:1:12) gave (3R,4S)-26g (127 mg, 80%) as an
oil. [a]2D3 = +59.6 (c = 1.1 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d
= 0.98 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H), 1.09 (d, J =
6.7 Hz, 6H), 1.31–1.38 (m, 2H), 1.89–2.09 (m, 3H), 3.32 (dd, J = 5.3,
8.6 Hz, 1H), 3.69–3.80 (m, 2H), 4.54 (d, J = 5.3 Hz, 1H), 4.72 (d, J =
12.0 Hz, 1H), 4.93 (d, J = 12.0 Hz, 1H), 7.27–7.38 ppm (m, 5H); 13C
NMR (75 MHz, CDCl3): d = 19.0 (2C), 19.2 (2C), 28.3, 30.1 (2C), 56.0
(2C), 70.7, 72.3, 78.2, 127.4, 127.5, 128.2, 137.6, 169.9 ppm; IR (KBr): n˜ =
1752, 1355, 1108 cmꢁ1; MS (EI): m/z (%): 316 (6) [M]+, 225 (13), 140
(29), 91(100); elemental analysis calcd (%) for C 19H28N2O2: C 72.12, H
8.92, N 8.85; found C 72.51, H 9.23, N 8.87.
This compound was prepared from (3R)-14e, flash chromatography
(DCM/MeOH 30:1) providing crystalline (3R)-34 (52 mg, 75%). [a]D22
=
ꢁ77.8 (c = 1.1 in MeOH); MS (CI): m/z (%): 233 (8) [M+H]+, 205
(100), 113 (12); HRMS: m/z: calcd for C12H12N2O3: 233.0926; found:
233.0930. The rest of spectral and analytical data were in agreement with
those described before for (3S)-34.
(3S)-3-(N-Benzyl-N-benzyloxycarbonylamino)azetidin-2-one
[(3S)-35]:
This compound was prepared from (3S)-17 f, flash chromatography (tolu-
ene/acetone 7:1) providing (3S)-35 (76 mg, 82%) as an oil. The spectral
and analytical data were in agreement with literature data: [a]2D2 = ꢁ8.8
(c = 1in CH 2Cl2); 1H NMR (500 MHz, [D6]DMSO, 908C): d = 3.14
(dd, J = 2.9, 5.5 Hz, 1H), 3.31 (t, J = 5.5 Hz, 1H), 4.49 (d, J = 15.9 Hz,
1H), 4.61 (d, J = 15.9 Hz, 1H), 4.90 (dd, J = 2.9, 3.5 Hz, 1H), 5.12 (d, J
= 12.6 Hz, 1H), 5.16 (d, J = 12.6 Hz, 1H), 7.40 (brs, 1H), 7.22–7.34 ppm
(m, 10H); 13C NMR (125 MHz, [D6]DMSO, 908C): d = 47.0, 55.6, 70.2,
72.2, 132.2, 132.3, 132.7, 132.9, 133.4, 141.0, 143.5, 160.5, 172.0 ppm; IR
(KBr): n˜ = 3299, 1771, 1708 cmꢁ1; MS (CI): m/z (%): 311 (68) [M+H]+,
(3R,4S)-cis-3-Benzyloxy-1-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-4-
phenyl-azetidin-2-one [(3R,4S)-27g]: This compound was prepared from
22g, the reaction mixture being heated for 5.5 h at 1008C. Flash chroma-
6126
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6111 – 6129

Stereoselective Cycloadditions
6111 – 6129
283 (6), 239 (7), 221(5), 91(010); elemental analysis calcd (%) for
C18H18N2O3: C 69.66, H 5.85, N 9.03; found C 69.59, H 6.19, N 9.11.
(d, J = 11.1 Hz, 1H), 4.26 (d, J = 11.1 Hz, 1H), 4.87 (d, J = 4.5 Hz,
1H), 4.94 (dd, J = 2.3, 4.5 Hz, 1H), 8.65 (brs, 1H), 6.83–6.86 (m, 2H),
7.18–7.21 (m, 2H), 7.31–7.39 ppm (m, 6H); 13C NMR (75 MHz, CDCl3):
(3R)-3-(N-Benzyl-N-benzyloxycarbonylamino)azetidin-2-one [(3R)-35]:
This compound was prepared from (3R)-17e, flash chromatography (tolu-
ene/acetone 7:1) providing (3R)-35 (77 mg, 83%) as an oil. [a]2D2 = +8.0
(c = 1in CH 2Cl2). The rest of the spectral and analytical data were in
agreement with those described for (3S)-35. The same product was ob-
tained in 83% yield from (3R)-17g with use of MMPP·6H2O (99 mg,
0.17 mmol), and had identical characterization data.
d
= 56.7, 71.0, 81.7, 127.6, 127.8, 128.1, 136.9, 137.3, 167.3 ppm; IR
(KBr): n˜ = 1724, 1123, 1028 cmꢁ1; MS (CI): m/z (%): 254 (100), [M+H]+,
162 (29), 91 (91); elemental analysis calcd (%) for C16H15NO2: C 75.87,
H 5.97, N 5.53; found C 75.77, H 5.94, N 5.88.
Compound (3R,4S)-40 was also obtained, in 95% yield and with identical
characterization data, from (3R,4S)-27g, by use of MMPP·6H2O (99 mg,
0.17 mmol).
(3R,4S)-3-Benzyloxy-4-pentylazetidin-2-one [(3R,4S)-36]: This compound
was prepared from (3R,4S)-23e, flash chromatography (toluene/EA 3:1)
(3R,4S)-3-Hydroxy-4-phenylazetidin-2-one [(3R,4S)-41]:
A
catalytic
providing crystalline (3R,4S)-36 (58 mg, 78%). M.p. 38–408C; [a]D25
=
amount of Pd/C (10%) was added to a solution of b-lactam (3R,4S)-40
(126 mg, 0.5 mmol) in MeOH/dioxane (1:1, 8 mL) and the mixture was
hydrogenated at atmospheric pressure until the starting b-lactam had
been consumed (ca. 24 h). The catalyst was filtered off and washed with
MeOH, and the solution was evaporated. Flash chromatography (DCM/
MeOH 20:1) gave crystalline (3R,4S)-41 (59 mg, 72%); [a]2D5 = +181.9
(c = 1.5 in MeOH). Spectral and analytical data were in good agreement
with literature data.[56]
+28.9 (c = 1.1 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d = 0.89 (t,
J = 6.6 Hz, 3H), 1.25–1.57 (m, 6H), 1.60–1.71 (m, 2H), 3.38–3.74 (m,
1H), 4.67 (d,
J = 4.8 Hz, 1H), 4.68 (d, J = 11.9 Hz, 1H), 4.86 (d,
J = 11.9 Hz, 1H), 6.12 (brs, 1H), 7.27–7.38 ppm (m, 5H); 13C NMR
(75 MHz, CDCl3): d = 13.8, 22.3, 25.5, 29.8, 31.5, 55.0, 72.7, 82.3, 127.6,
127.7, 128.3, 137.1, 168.8 ppm; IR (KBr): n˜ = 1762, 1390, 1099 cmꢁ1; MS
(CI): m/z (%): 248 (100) [M+H]+, 220 (30), 91(74); elemental analysis
calcd (%) for C15H21NO2: C 72.84, H 8.55, N 5.66; found C 72.86, H 8.87,
N 5.58.
(3R,4S)-3-Hydroxy-4-isobutylazetidin-2-one [(3R,4S)-43]:
A catalytic
amount of Pd/C (10%) was added to a solution of b-lactam (3R,4S)-37
(117 mg, 0.5 mmol) in MeOH (4 mL) and the mixture was hydrogenated
at atmospheric pressure until the starting b-lactam had been consumed
(ca. 24 h). The catalyst was filtered and washed with MeOH, and the so-
lution was evaporated. Flash chromatography (DCM/MeOH 20:1) gave
crystalline (3R,4S)-43 (61 mg, 85%). M.p. 123–1278C; [a]2D0 = +28.0 (c
= 1in MeOH); 1H NMR (300 MHz, CD3OD): d = 0.94 (d, J = 6.7 Hz,
3H), 0.97 (d, J = 6.5 Hz, 3H), 1.40–1.54 (m, 2H), 1.64–1.75 (m, 1H),
3.75 (ddd, J = 4.8, 5.8, 8.0 Hz, 1H), 4.79 ppm (d, J = 4.8 Hz, 1H); 13C
(3R,4S)-3-Benzyloxy-4-isobutylazetidin-2-one [(3R,4S)-37]: This com-
pound was prepared from (3R,4S)-24e, flash chromatography (toluene/
EA 3:1) providing crystalline (3R,4S)-37 (63 mg, 91%). M.p. 73–75 8C;
[a]2D2
=
+33.4 (c = 0.9 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d =
0.92 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.50–1.57 (m, 2H),
1.59–1.74 (m, 1H), 3.81 (dt, J = 4.9, 8.2 Hz, 1H), 4.68 (dd, J = 2.6,
4.9 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 4.84 (d, J = 11.8 Hz, 1H), 6.35
(brs, 1H), 7.27–7.38 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d
=
21.9, 23.1, 25.4, 38.5, 53.4, 72.7, 82.4, 127.7, 127.8, 128.3, 137.1, 168.9 ppm;
IR (KBr): n˜ = 1759, 1100, 1027 cmꢁ1; MS (CI): m/z (%): 234 (100),
[M+H]+, 206 (48), 91(91); elemental analysis calcd (%) for C 14H19NO2:
C 72.07, H 8.21, N 6.00; found C 71.97, H 8.43, N 6.06.
NMR (75 MHz, CD3OD):
d = 25.0, 26.0, 28.9, 42.3, 57.8, 80.0,
175.6 ppm; IR (KBr): n˜ = 1681, 1418, 1097, 1033 cmꢁ1; MS (CI): m/z
(%): 144 (100), [M+H]+, 126 (16), 99 (16); elemental analysis calcd (%)
for C7H13NO2: C 58.72, H 9.15, N 9.78; found C 58.89, H 9.38, N 9.89.
Compound (3R,4S)-37 was also obtained, in 84% yield and with identical
characterization data, from (3R,4S)-24g, by use of MMPP·6H2O (99 mg,
0.17 mmol).
(2R,3S)-3-Amino-2-hydroxy-5-methylhexanoic acid [(2R,3S)-45]: Com-
pound (3R,4S)-43 (29 mg, 0.2 mmol) was dissolved in HCl (6n, 0.8 mL)
and stirred for 4 h. The reaction mixture was concentrated to give crystal-
line (2R,3S)-44 (39 mg, 99%). 1H NMR (300 MHz, CD3OD): d = 0.97
(d, J = 6.3 Hz, 3H), 0.98 (d, J = 6.3 Hz, 3H), 1.46–1.55 (m, 1H), 1.61–
(3R,4S)-3-Benzyloxy-4-phenylethylazetidin-2-one [(3R,4S)-38]: This com-
pound was prepared from (3R,4S)-25e, flash chromatography (toluene/
EA 3:1) providing crystalline (3R,4S)-38 (73 mg, 87%). M.p. 104–1068C;
1.80 (m, 2H), 3.51–3.58 (m, 1H), 4.23 ppm (d, J
=
3.1Hz, 1H); 1H
[a]2D5
=
+19.9 (c = 1.2 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d =
NMR (300 MHz, D2O): d = 0.87 (d, J = 6.1Hz, 3H), 0.88 (d, J =
6.1 Hz, 3H), 1.42–1.69 (m, 3H), 3.60–3.65 (m, 1H), 4.34 ppm (d, J =
3.2 Hz, 1H); 13C NMR (75 MHz, CD3OD): d = 20.8, 20.9, 23.6, 38.0,
51.1, 68.6, 172.7 ppm. Treatment of (2R,3S)-44 with Dowex 50W”8 gave
1.90–2.10 (m, 2H), 2.62–2.79 (m, 2H), 3.74 (td, J = 4.9, 8.1Hz, 1H), 4.69
(dd, J
= 2.6, 4.9 Hz, 1H), 4.69 (d, J = 11.8 Hz, 1H), 4.88 (d, J =
11.8 Hz, 1H), 5.96 (brs, 1H), 7.15–7.52 ppm (m, 10H); 13C NMR
b-amino-a-hydroxy acid (2R,3S)-45 in quantitative yield. [a]D25
= +25.2
(75 MHz, CDCl3): d = 31.7, 32.5, 54.4, 72.8, 82.4, 127.7, 127.8, 128.2,
128.3, 128.5, 137.1, 140.9, 168.5 ppm; IR (KBr): n˜
= 1725, 1101,
(c = 0.6 in AcOH). Spectral and analytical data were in good agreement
1034 cmꢁ1; MS (CI): m/z (%): 282 (100) [M+H]+, 254 (66), 91(81); ele-
mental analysis calcd (%) for C18H20NO2: C 76.84, H 6.81, N 4.98; found
C 76.75, H 6.95, N 5.08.
with literature data.[61]
(3R)-3-Hydroxy-1-[(2S)-2-(1-ethyl-1-methoxypropyl)pyrrolidin-1-yl]azeti-
din-2-one [(3R)-46]: A catalytic amount of Pd/C (10%) was added to a
solution of (3R)-4e (346 mg, 1mmol) in MeOH (13 mL), and the mixture
was hydrogenated at atmospheric pressure until the starting b-lactam had
been consumed (ca. 24 h). The catalyst was filtered and washed with
MeOH, and the solution was evaporated. Flash chromatography (Et2O/
PE 9:1) gave (3R)-46 (251mg, 98%) as an oil. [ a]3D0 = +19.6 (c = 1.1 in
Compound (3R,4S)-38 was also obtained, in 84% yield and with identical
characterization data, from (3R,4S)-25g, by use of MMPP·6H2O (99 mg,
0.17 mmol).
(3R,4S)-3-Benzyloxy-4-isopropylazetidin-2-one [(3R,4S)-39]: This com-
pound was prepared from (3R,4S)-26e, flash chromatography (toluene/
EA 3:1) providing crystalline (3R,4S)-39 (58 mg, 88%): M.p. 85–868C;
[a]2D6 = +120.4 (c = 1.1 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d =
0.94 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.9–2.1 (m, 1H), 3.35
(dd, J = 4.9, 9.2 Hz, 1H), 4.67 (dd, J = 2.9, 4.9 Hz, 1H), 4.72 (d, J =
11.9 Hz, 1H), 4.94 (d, J = 11.9 Hz, 1H), 6.41 (brs, 1H), 7.2–7.4 ppm (m,
5H); 13C NMR (75 MHz, CDCl3): d = 18.8, 18.9, 28.0, 60.8, 72.5, 81.9,
127.5, 127.6, 128.3, 137.3, 169.3 ppm; IR (film): n˜ = 3262, 1760 cmꢁ1; MS
(CI): m/z (%): 220 (60) [M+H]+, 192 (21), 91 (100); elemental analysis
calcd (%) for C13H17NO2: C 71.20, H 7.81, N 6.39; found C 71.16, H 8.00,
N 6.46.
1
CH2Cl2); H NMR (500 MHz, CDCl3): d = 0.86 (t, J = 7.5 Hz, 3H), 0.87
(t, J = 7.5 Hz, 3H), 1.47–1.60 (m, 2H), 1.62–1.72 (m, 2H), 1.75–1.93 (m,
4H), 2.89–2.94 (m, 1H), 3.13–3.18 (m, 1H), 3.28 (s, 3H), 3.28–3.30 (m,
1H), 3.33 (dd, J = 1.6, 5.0 Hz, 1H), 3.61 (t, J = 5.0 Hz, 1H), 4.45 (s,
1H), 4.69 ppm (dd, J = 1.6, 5.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d
=
7.9, 8.3, 23.3, 23.4, 25.5, 26.3, 48.3, 50.2, 54.1, 66.4, 71.3, 79.5,
168.0 ppm; IR (KBr): n˜ = 3300, 1760 cmꢁ1; MS (EI): m/z (%): 256 (2)
[M]+, 155 (100), 127 (25), 101 (27); elemental analysis calcd (%) for
C13H24N2O3: C 60.91, H 9.44, N 10.93; found C 61.05, H 9.68, N 10.69.
p-Nitrobenzoate [(3R)-47]: A solution of (3R)-46 (128 mg, 0.5 mmol), p-
nitrobenzoyl chloride (142 mg, 0.75 mmol), and TEA (0.42 mL, 3 mmol)
in DCM (5 mL) was stirred at rt for 3 h. The reaction mixture was
washed with water (1”7 mL), diluted HCl (2”7 mL), saturated NaHCO3
(1”7 mL), and brine (1”7 mL). The organic layer was dried (sodium sul-
fate), filtered, and evaporated. Flash chromatography (Et2O/PE 1:1) gave
crystalline (3R)-47 (193 mg, 95%). M.p. 89–918C; [a]2D4 = +0.6 (c = 1
in CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 0.89 (t, J = 7.6 Hz, 3H),
The same product was also obtained, in 91% yield and with identical
characterization data, from (3R,4S)-26g, by use of MMPP·6H2O (99 mg,
0.17 mmol).
(3R,4S)-3-Benzyloxy-4-phenylazetidin-2-one [(3R,4S)-40]: This com-
pound was prepared from (3R,4S)-27e, flash chromatography (toluene/
EA 3:1) providing crystalline (3R,4S)-40 (73 mg, 96%). M.p. 207–2108C;
[a]2D5 = +96.8 (c = 1in DMSO); 1H NMR (300 MHz, CDCl3): d = 4.09
Chem. Eur. J. 2004, 10, 6111 – 6129
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6127

R. Fernµndez, J. M. Lassaletta et al.
FULL PAPER
0.92 (t, J = 7.6 Hz, 3H), 1.57–1.67 (m, 2H), 1.69–1.75 (m, 2H), 1.76–1.86
(m, 3H), 1.88–1.98 (m, 1H), 2.96–3.04 (m, 1H), 3.22–3.24 (m, 1H), 3.26
(s, 3H), 3.34–3.39 (m, 1H), 3.48 (dd, J = 1.8, 5.8 Hz, 1H), 3.88 (dd, J =
4.8, 5.8 Hz, 1H), 5.63 (dd, J = 1.8, 4.7 Hz, 1H), 8.24 (d, J = 9 Hz, 2H),
8.30 ppm (d, J = 9 Hz, 2H); 13C NMR (125 MHz, CDCl3): d = 7.9, 8.7,
23.0, 24.0, 25.6, 26.2, 47.4, 50.0, 54.1, 66.6, 72.8, 123.0, 131.0, 134.0, 151.0,
163.0, 164.0 ppm; IR (KBr): n˜ = 1778, 1733, 1540, 1270 cmꢁ1; MS (EI):
m/z (%): 405 (1) [M]+, 304 (100), 101 (33); elemental analysis calcd (%)
for C20H27N3O6: C 59.25, H 6.71, N 10.36; found C 59.06, H 6.56, N 10.55.
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(3S)-3-tert-Butoxycarbonylaminoazetidin-2-one [(3S)-48]:
A catalytic
amount of Pd/C (10%) was added to a solution of (3S)-35 (93 mg,
0.3 mmol) in MeOH (10 mL), and the mixture was hydrogenated at
6 atm and rt. After 48 h, the catalyst was filtered off and washed with
MeOH, and the solution was evaporated. The residue was dissolved in
MeOH (3 mL), and Boc2O (169 mg, 0.75 mmol), TEA (0.12 mL,
0.9 mmol), and a catalytic amount of DMAP were added. Conventional
workup and flash chromatography (DCM/MeOH 15:1) gave crystalline
(3S)-48 (34 mg, 60%). [a]2D0 = ꢁ20.1( c = 0.8 in CH3OH). Spectral and
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Acknowledgment
We thank the Dirección General de Investigación Científica y TØcnica
(grant no. BQU2001-2376), the European Commission (RTN-2001–
00244), and the Junta de Andalucía for financial support. A.F. thanks the
Ministerio de Educación y Ciencia for a doctoral fellowship.
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Published online: October 29, 2004
Chem. Eur. J. 2004, 10, 6111 – 6129
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6129