Intramolecular opening of β-lactams with amines as a strategy toward enzymatically or photochemically triggered activation of lactenediyne prodrugs

Article abstract of DOI:10.1002/ejoc.200390188

In order to develop a general strategy for selective activation of designed enediyne prodrugs belonging to the "lactenediyne" family, we studied the scope of intramolecular transamidation of simple monocyclic β-lactams bearing a tethered amine. The effect of substituents, of reaction media, and of the type of tether, on the rate of transamidation is disclosed. The possibility of triggering the transamidation event under mild conditions by the action of suitable enzymes or UV light was demonstrated on model monocyclic β-lactams. Finally, the strategy of intramolecular opening of the β-lactam leading to a larger seven-membered ring was employed on a lactenediyne, demonstrating that ring enlargement could unleash the reactivity of the enediyne moiety. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390188

FULL PAPER
Intramolecular Opening of β-Lactams with Amines as a Strategy Toward
Enzymatically or Photochemically Triggered Activation of Lactenediyne
Prodrugs
Luca Banfi,*[a] Giuseppe Guanti,*[a] and Marcello Rasparini[a]
Keywords: Lactams / Nucleophilic substitution / Photolysis / Prodrugs / Ring expansion
In order to develop a general strategy for selective activation
was demonstrated on model monocyclic β-lactams. Finally,
of designed enediyne prodrugs belonging to the ‘‘lactene- the strategy of intramolecular opening of the β-lactam lead-
diyne’’ family, we studied the scope of intramolecular trans-
amidation of simple monocyclic β-lactams bearing a tethered
amine. The effect of substituents, of reaction media, and of
the type of tether, on the rate of transamidation is disclosed.
The possibility of triggering the transamidation event under
mild conditions by the action of suitable enzymes or UV light
ing to a larger seven-membered ring was employed on a lac-
tenediyne, demonstrating that ring enlargement could un-
leash the reactivity of the enediyne moiety.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
We have recently reported the synthesis of various mem-
bers of
a
new family of artificial enediynes
(lactenediynes)[1Ϫ3] characterized by the fusion of a β-lac-
tam with a ten-membered enediyne ring. These compounds
have been designed to be structurally simpler than natural
enediyne antibiotics,[4] and to be endowed with a triggering
mechanism amenable to selective control. The most useful
representatives of this family have the general formula 1
(Scheme 1). We have already proved that in these com-
pounds the β-lactam unit acts as a very efficient safety lock,
completely preventing Bergman cycloaromatization of the
enediyne. On the other hand, removing this constraint re-
sults in a reactive monocyclic enediyne, which cyclizes rap-
idly to a reactive diradical. Opening of the four-membered
ring may, therefore, represent the triggering event that con-
verts a stable prodrug into a reactive, cytotoxic drug.
In the absence of activating substituents, the β-lactam
unit is quite stable under physiological conditions. It is
necessary, therefore, to find a way to induce its opening
under mild conditions. Optimally, the triggering event
should be initiated by the action of a suitable enzyme or by
UV light. In this way, it would be possible, in principle, to
effect prodrug activation selectively within tumor cells.
There are three alternative strategies that exploit enzymes
for prodrug activation: prodrug monotherapy (PMT),[5,6]
antibody-directed enzyme prodrug therapy (ADEPT),[7]
Scheme 1
and gene-directed enzyme prodrug therapy (GDEPT). Pho-
tochemically directed prodrug therapy (PDPT) may also be
used to direct the cytotoxic effects with site selectivity. We
feel that designed enediynes can be ideal candidates for
these four strategies, although by now only a few examples
of artificial enediynes equipped with enzymatic[8] or photo-
chemical[9,10] triggers have been reported.
We thought that a good way to achieve our goals would
be to tether a nucleophile, in particular an amino group, to
the lactenediyne in order to make intramolecular opening
of the β-lactam unit feasible under mild conditions. Since
several enzymatically or photochemically removable amine
protecting groups are known, accomplishing such a strategy
definitely seems workable. Intramolecular opening of the β-
lactam unit in lactenediynes 1 does not lead to monocyclic
enediynes, but to ortho-fused or spiro-bicyclic systems. Be-
cause of the different nature of the newly formed fused het-
erocyclic rings, however, no longer are they expected to be
[a]
`
Dipartimento di Chimica e Chimica Industriale dell’Universita
di Genova
Via Dodecaneso 31, 16146 Genova, Italy
E-mail: banriv@chimica.unige.it
guanti@chimica.unige.it
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Eur. J. Org. Chem. 2003, 1319Ϫ1336  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1319 $ 20.00ϩ.50/0

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
stabilizing against cycloaromatization. Preliminary molecu- basic, provided that CaCl2 is used in slight excess, and thus
lar mechanics calculations, performed using the simplified intramolecular β-lactam opening by the alcohol is avoided.
approach proposed by Maier,[11] corroborated this hypoth- Compounds 9bϪd were prepared in a completely different
esis.
way, starting from the imine formed between cinnamal-
At the outset of this work very little was known on the dehyde and 2-[(tert-butyldimethylsilyl)oxy]ethanamine.[15]
intramolecular nucleophilic opening of simple monocyclic Staudinger condensations with methoxyacetyl and phen-
β-lactams.[12] For this reason, we decided to explore the oxyacetyl chlorides furnished azetidinones 10 and 13,
whole strategy on model compounds. In a preliminary com- respectively. Compound 10 was converted by desilylation to
munication we have already described some results concern- the 4-styrylazetidinone 9b or, through ozonolysis, protec-
ing the effect of the type of tether, of substituents, and of tion, and desilylation, to 9c. The synthesis of 9d from 13
reaction media, on the rate of transamidation.[13] We now was carried out similarly to that of 9c.
report in full the preparation of those and other model
compounds, the results of transamidation, and the conju-
gation of these model compounds with enzymatically or
photochemically removable protecting groups.
Finally, we report the first application of the strategy on
a simple lactenediyne, demonstrating that ring enlargement
removes all of the steric constraints that inhibit cycloaroma-
tization.
Preparation of Model Amines
To gain some insight on the influence that structural
changes have on the rate of transamidation reactions, we
prepared a series of model monocyclic β-lactams having an
amino group tethered either at N-1 (2aϪd) or at C-3. In
these compounds the amine is connected to the β-lactam
through either an oxygenated chain (3aϪc) or an alkyl
chain (4). All the compounds were prepared in racemic
form. They are depicted in Scheme 1 (BOM
ϭ
PhCH2OCH2). Although the amino group could be also
tethered, in principle, to C-4, we chose not to study this
type of compound for two reasons: a) We expected that
stereoselective synthesis of trans-lactenediynes, disubsti-
tuted at position 4 of the β-lactam unit, would be problem-
atic. b) The transition state for a transamidation reaction
in this case would be (again at the lactenediyne level) a
bridged tricyclic ring instead of an ortho-fused tricyclic ring
and, thus, we foresaw the intramolecular reaction as being
more difficult.
Amines 2aϪd were prepared in every case from the corre-
sponding alcohols 9aϪd through azides 14aϪd (Scheme 3).
The syntheses of alcohols 9aϪd are in turn described in
Scheme 2. Compound 9a was prepared from known azetidi-
none 5.[2] After protection of the hydroxy unit as a benzyl-
Scheme 2. a) BOMCl, EtNiPr2; b) nBu4NF, THF, Ϫ40 °C; c) KOH,
BrCH2CO2Et; d) Ca(BH4)2, THF/H2O, Ϫ20 °C; e)
HOCH2CH2NH2; f) Me2tBuSiCl, Et3N; g) MeOCH2COCl, Et3N,
CH2Cl2, Ϫ78 °C Ǟ room temp.; h) HF, H2O/CH3CN; i) O3, then
Me2S·NaBH4; l) PhOCH2COCl, Et3N, CH2Cl2, Ϫ78 °C Ǟ room
temp.
All of these alcohols were transformed into the corre-
oxymethoxy ether and N-desilylation, the required side sponding azides 16aϪd by substitution of their correspond-
chain was introduced by base-mediated alkylation of the ing mesylates (Scheme 3). Finally, reduction with tri-
nitrogen atom with ethyl bromoacetate. This reaction was phenylphosphane[16] gave the free amines 2aϪd, which were
carefully optimized by varying the bromoacetate and base purified by chromatography [CHCl3/MeOH/iPr2NH]. Inter-
employed. Good yields were obtained with either tBuOK, estingly, some of these amines (2a and 2d) tend to give two
NaN(SiMe3)2 or by the phase-transfer methodology de- spots by TLC, but they cannot be separated by column
scribed by Reuschling.[14] As for the ester, we found that chromatography. Treatment with an acylating agent (e.g.,
ethyl or tert-butyl bromoacetates definitely gave better Ac2O in pyridine) provokes the disappearance of both
yields than benzyl bromoacetate. In order to facilitate sub- spots, and affords the expected acetamides in high yields.
sequent reduction, we eventually chose the ethyl ester. Re- Therefore, we think that the presence of the two spots re-
duction of 8 with calcium borohydride gave 9a. This reagent flects an equilibrium between a free amine and its product
is ideal in this case because the reaction medium is not of addition to the β-lactam carbonyl group (a sort of hemi-
1320
Eur. J. Org. Chem. 2003, 1319Ϫ1336

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
aminal). This fact, however, could not be proved by 1H
NMR spectroscopy because the spectra were quite com-
plex. On standing, amines 2aϪd tended to afford less-polar
products, giving negative FluramTM tests,[17] identified as
the seven-membered azalactams 17aϪd. This trans-
formation is clearly faster for oxygenated compounds 2cϪd.
In the case of 2d in particular, 17d is already visible in the
crude mixture derived from azide reduction. After the intra-
molecular transamidation process was completed as de-
scribed below, the rearranged azalactams 17aϪd were easily
1
identified by IR, 13C NMR and H NMR spectroscopies.
In the IR spectrum, the β-lactam carbonyl signal that had
appeared at about 1740 cmϪ1 was replaced by a signal at
1660 cmϪ1. In the 13C NMR spectrum, the carbonyl group’s
signal was shifted downfield by about 8Ϫ9 ppm relative to
1
that of the β-lactam. In the H NMR spectrum, the coup-
ling constants between 3-H and 4-H (β-lactam numbering)
changed: the cis one went from 4Ϫ5 Hz to nearly 0 Hz,
while the trans one (present only in the case of 2aϪ17a)
went from 2.2 to 9.8 Hz. Moreover, the signal(s) of 3-H
proton(s) was (were) shifted upfield by about 0.5 ppm.
Scheme 4. a) p-Anisidine, mol. sieves; b) allyloxyacetyl chloride,
CH2Cl2, Et3N, Ϫ20 °C to room temp.; c) O3, CH2Cl2/MeOH, then
Me2S; d) BH3·THF; e) MsCl, Et3N, CH2Cl2, Ϫ30 °C; f) NaN3,
DMF, 50Ϫ60 °C; g) Ph3P, H2O/THF, room temp.; h)
Ce(NH4)2(NO3)6; i) tBuOK, BrCH2CO2tBu, nBu4NI
Scheme 3. a) MsCl, Et3N, CH2Cl2, Ϫ30 °C; b) NaN3, DMF, 50Ϫ60
°C; c) Ph3P, H2O/THF, room temp.
Amines 3a,b (Scheme 4) were prepared in racemic form
as shown in Scheme 4. Again, in this case the first step was
a Staudinger reaction[18] between an imine of glyceral-
dehyde acetonide and allyloxyacetyl chloride. As already re-
ported, this reaction afforded racemic 18 as a single dia-
stereoisomer from among the four possible ones. Ozonoly-
sis of 18, followed by in situ NaBH4 reduction, afforded
alcohol 19 in unsatisfactory yields, because intramolecular
opening of the lactam by the hydroxy group occurred, fol-
lowed by reduction of the resulting lactone. We then disco-
vered that an excellent yield of 19 could be achieved by
reduction of the ozonolysis product with Me2S to form the
aldehyde that then was reduced with BH3. Transformation
into the amine 3a was then realized as outlined above. To
evaluate the effect of an electron-withdrawing substituent
bonded to the nitrogen atom, we also replaced the anisyl
group with a tert-butoxycarbonylmethyl group to give 22.
Ozonolysis/reduction and the usual functional group trans-
formations gave 3b.
Scheme 5. a) O3, CH2Cl2/MeOH, then Me2S; b) p-anisidine, mol.
sieves; c) allyloxyacetyl chloride, CH2Cl2, Et3N, Ϫ20 °C to room
temp.; d) BH3·THF; e) MsCl, Et3N, CH2Cl2, Ϫ30 °C; f) NaN3,
DMF, 50Ϫ60 °C; g) Ph3P, H2O/THF, room temp.; h) crotonyl chlo-
ride, Et3N, CH2Cl2, reflux; i) Ca(BH4)2, THF/EtOH; l) BOMCl,
EtNiPr2; m) 9-BBN, THF, room temp.; then KHCO3, H2O2
The synthesis of amine 3c followed a very similar ap-
proach (Scheme 5). In this case the required imine was pre-
pared from benzyloxymethoxyacetaldehyde, in turn ob-
tained by ozonolysis of ether 26.
Eur. J. Org. Chem. 2003, 1319Ϫ1336
1321

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
Compounds 3aϪc also showed the same phenomenon of β-lactam (1740 cmϪ1) to 1692 cmϪ1, while in the 13C NMR
the double spot on TLC plates that was seen with 2a and spectrum, the signal of the carbonyl group was shifted
2d. On standing in solution, compounds 3aϪc were slowly downfield by about 10 ppm.
converted into morpholinones 25aϪc. The rearranged aza-
lactams 25aϪc could be easily identified by IR, 13C NMR
1
Studies on the Rate of Intramolecular
Transamidation of Model Amines
and H NMR spectroscopies. In the IR spectra, the β-lac-
tam carbonyl groups’ signals that had appeared at about
1740 cmϪ1 were replaced by signals at 1670 cmϪ1. In the
13C NMR spectra, the carbonyl groups’ peaks were shifted
The half-lives of amines 2aϪd, 3aϪc and 4 were exam-
downfield by about 4 ppm relative to those of the β-lactams. ined in 96% EtOH as solvent (Table 1) by taking aliquots of
In the 1H NMR spectra, the coupling constants between 3- the solutions and analysing them by 1H NMR spectroscopy.
H and 4-H (β-lactam numbering) went from 4Ϫ5 Hz to Although in aprotic solvents the reaction rate was in some
nearly 0 Hz. Finally, the 3-H protons were shifted upfield cases slightly higher,[13] we preferred a protic solvent be-
by about δ ϭ 0.4 ppm.
cause of its greater similarity to in vivo conditions. In all
For the synthesis of 4 (Scheme 5), we condensed crotonyl cases, the reactions were driven to completion after an ap-
chloride with imine 30. Although this reaction was reported propriate time, indicating that the equilibrium was shifted
to give a 60% yield,[19] in our hands the method was less to the right. The collected results show that the nature of
efficient. Nevertheless, the adduct 31 was reduced with cal- the substituent can be important in accelerating the reac-
cium borohydride in good yield to give the alcohol 32. It is tion. For example, in the case of lactams 2aϪd, where the
worth noting that the same reduction conditions failed amino group is tethered to the nitrogen atom, an OR group
when applied to the similar 3-(allyloxy)-4-(methoxycar- at C-3 causes an increase in the rate, with the phenoxy
bonyl)-1-(4-methoxyphenyl)-2-azetidinone, which led in- group being more activating than the methoxy one. An un-
stead to reduction also of the β-lactam unit. It seems that saturated substituent at C-4 also has an activating effect.
the 3-alkoxy substituent activates the β-lactam toward re- As for the lactams 3aϪc, with the amino unit tethered at C-
duction. Reduction of 31 with NaBH4 in THF/EtOH/H2O 3, the tert-butoxycarbonylmethyl group was more activating
produced a mixture of 32 and of the trans isomer, probably than an aryl group, despite the higher basicity of the leaving
because of enolization at the carbon atom α to the methyl group. This result suggests that the leaving group probably
ester. To avoid this isomerization, it is important to use a is not the amide anion, and that protonation of the lactam
slight excess of CaCl2 in the preparation of Ca(BH4)2.[20] nitrogen atom before opening of the ring may be required
After protection as the BOM ether, the double bond in 33 for a fast reaction rate.[21]
was smoothly hydroborated with 9-BBN to give the alcohol
34, which was finally converted into amine 4 through the 2bϪd is somewhat surprising, since they have an oxygenated
usual protocol. substituent at C-3 and an aryl group at the nitrogen atom
The lower reactivity of amines 3a and 3c compared to
Compound 4 also underwent rearrangement, albeit more (which is expected to be more activating than an alkyl
slowly, to the pyrrolidinone 36. In the IR spectrum, the car- group). This observation may depend on stereoelectronic
bonyl group’s signal moved from the position of a typical factors: if the activation by the oxygen atom in compounds
Table 1. Rate of intramolecular transamidation of amines 2aϪd, 3aϪc and 4 in 96% EtOH
Entry
Starting amine
Rearranged lactam
Additives
Conc.
[]
Temp.
[°C]
t1/2
[h][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
2b
2b
2c
2c
2d
2d
3a
3b
3c
4
2a
2a
2a
2a
2d
17a
17b
17b
17c
17c
17d
17d
25a
25b
25c
36
17a
17a
17a
17a
17d
none
none
none
none
none
none
none
none
none
none
none
none
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
10Ϫ1
60
60
40
60
40
60
40
60
60
60
60
60
60
60
40
40
136
8
55
25
90
8
50
130
22
120
204
130
130
8
0.1  Et3N
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
1.1·10Ϫ2
0.1  Et3N/0.05  AcOH
0.1  Et3N/0.05  AcOH
0.1  Et3N/0.05  AcOH
33
3
[a]
1
t1/2 was determined by H NMR spectroscopy (see Exp. Sect.).
1322
Eur. J. Org. Chem. 2003, 1319Ϫ1336

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
3 depends on the spatial arrangement of its nonbonding
electron pairs, intramolecular transamidation of amines
3aϪc may force the electron pairs into an unfavourable po-
sition. Another explanation is that the oxygen atom in the
β-position lower the basicity of the amine. To check this
hypothesis we prepared amine 4, in which the tether does
not contain an oxygen atom, but its reactivity was found to
be even lower than that of 3a and 3c.
As expected, the effect of concentration on rate was negli-
gible (compare Entry 12 with Entry 1). Also, a basic addi-
tive (Et3N) had no effect. On the contrary, we observed a
dramatic accelerating effect brought about by a near-neu-
tral buffer (compare Entry 14 with Entry 1 and Entry 16
with Entry 7). This observation indicates once again that
protonation of the leaving nitrogen atom is likely to be of
great importance in the mechanism. Surprisingly, the effect
of buffer on amine 3a was less significant than on other lac-
tams.[13]
In conclusion, the collected data allowed us to demon-
strate the possibility of intramolecular opening of the lac-
tam to give a larger ring under conditions similar to those
that may be present in the cell. Although the rate of trans-
amidation still seems too low in ethanol alone, the dramatic
effect of buffer is promising in view of in vivo applications.
Compounds with the amine tethered to the nitrogen atom
and having an alkoxyl group at C-3 have been singled out
as good candidates for implementing this strategy at the
lactenediyne level.
Control of Transamidation by Blocking the
Amines with an Enzymatically or
Photochemically Removable Protecting Group
Scheme 6
To induce selective intramolecular opening of the β-lac-
tam ring of the lactenediynes within the tumor cells or in
their neighbourhood, we planned to block the amino unit
with enzymatically or photochemically removable protect- At this point, TLC showed the presence of both amine 2b
ing groups. Again, in this case we first carried out a prelimi- and azalactam 17b. On stirring overnight at 37 °C, complete
nary study on a model compound lacking the enediyne conversion of 2b into 17b occurred and the latter was iso-
moiety, represented by amine 2b. It was converted, as shown lated in good yield.
in Scheme 6, into three protected derivatives: 37, 40 and 41.
Plasmin is a serine protease that has been found to be
The best yields of these compounds were obtained by not particularly abundant on the surface of tumor cells with
isolating the amine 2b chromatographically, but by directly high metastatic potential.[26] It was, therefore, suggested as
acylating the crude product of the reduction of azide 16b an ideal candidate for the development of a Prodrug Mono-
with PPh3.
therapy (PMT) approach to selective delivery of antitumor
Phenylacetamide 37 was prepared to exploit Penicillin G agents to cancer cells.[5,27] Plasmin is an endopeptidase that
acylase as the initiator of the cascade of events leading to is selective for breaking the peptide bond at a lysine site.
intramolecular β-lactam opening. This is a cheap, non-en- Tripeptide 38, therefore, is a well-suited protecting group to
dogenous enzyme that is perfectly suited for Antibody-Di- be cleaved by plasmin: the terminal -valine unit is import-
rected Enzyme Prodrug Therapy (ADEPT). The enzyme is ant to avoid the action of exopeptidases. The synthesis of
generally active in the hydrolysis of esters[22,23] and am- Boc-protected tripeptide 38 was carried out as described
ides[23,24] of phenylacetic acid, and has been used previously previously.[5] We also prepared the analogous Fmoc-pro-
in the activation of antitumor prodrugs.[25] The enzymatic tected derivative, but we had trouble coupling it with 2b
deprotection of 37 was carried out in aqueous TRIS buffer and in chromatographic purification (in part, because of the
(pH ϭ 7.5) containing 10% MeOH (used to partially solu- high insolubility of these Fmoc derivatives).
bilize the substrate). The hydrolysis reaction was complete
After coupling 2b with 38, the protecting groups were
in 5 h, indicating that 37 is a good substrate for the enzyme. smoothly removed by CF3CO2H. Reaction of the resulting
Eur. J. Org. Chem. 2003, 1319Ϫ1336
1323

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
salt 40 with plasmin took place at room temperature in likely azalactam 47, is always present in minimal quantities
buffer of pH ϭ 7.5. In this case the reaction was slower throughout the reaction; the main product is the cycloaro-
than that with Penicillin G acylase and, as a result, we iso- matized compound 48. The latter compound was isolated
lated the rearranged azalactam 17b directly.
in moderate yield (45%) after completion of the reaction (4
Finally, we also protected the amino group of 2b as the d). Its structure was easily identified, by H and 13C NMR
nitroveratryl urethane 41. This group is known to be remov- spectroscopy, by the absence of the ethylenic protons and
able by irradiation at 350 nm.[10,28] Compound 41 disap- carbon atoms and of the acetylenic carbon atoms typical of
peared after several hours (depending on the molar amount the enediyne moiety, and by the presence of aromatic pro-
and on the overall lamp power) when it was irradiated at tons and carbon atoms. The fact that intramolecular trans-
350 nm at room temperature in ethanol. The yields, how- amidation had occurred was demonstrated by: a) the car-
ever, of either the amine 2b or the azalactam 17b were poor. bonyl group’s appearance at 1663 cmϪ1 in the IR spectrum;
These low yields were probably due to reaction of the free b) the signal at δ ϭ 179.04 ppm in the 13C NMR spectrum
amine with the nitrosoaldehyde derived from the protecting for the carbonyl group; c) the presence of an amide NH
1
1
group. To circumvent this problem, we carried out the de- unit in both H NMR and IR spectra. The half-life of 46
blocking in the presence of semicarbazide or H2SO4.[29] The under these conditions was estimated to be about 24 h. At
yields in these cases turned out to be quite good, as deter- 40 °C the reaction was obviously slower. At this tempera-
mined by phenylacetylation of the resulting crude 2b to af- ture, however, 47 was only ever present in small quantities,
ford the corresponding phenylacetamide in 65Ϫ75% yield. indicating that cycloaromatization is faster than intramol-
The most convenient additive is H2SO4. The ammonium ecular transamidation. The reactivity of 46 towards trans-
salt of 2b is stable against transamidation and it can be amidation seems somewhat lower than that of the model
purified from the byproducts by simple extraction. On ad- compound 2a. Structural modifications, such as, for ex-
dition of a base, the amine 2b can be extracted into CHCl3. ample, the introduction of an alkoxy group at C-3, are ex-
Stirring of this solution at 40 °C led to complete conversion pected to increase its reactivity. We have recently completed
of 2b into azalactam 17b.
the total synthesis of lactenediynes endowed with this fea-
ture.[3,15]
First Application of the Intramolecular
Transamidation Reaction to Lactenediynes
The study described above on model compounds has
demonstrated the feasibility of triggering, with suitable en-
zymes or UV light, the intramolecular opening of a mono-
cyclic β-lactam under mild conditions (pH ϭ 7.5, tempera-
ture ca. 37 °C). We still had to check, however, that ring
enlargement to a more flexible seven-membered azalactam
really does remove the ‘‘safety lock’’ provided by the β-lac-
tam, thus allowing enediyne cycloaromatization to occur.
Preliminary force-field calculations had suggested that this
process was likely to happen, but we obviously needed
more solid experimental proof. Therefore, we prepared am-
ine 46, starting from the previously described lactenediyne
42 (Scheme 7). The first step of this synthesis is interesting.
On treating with a base such as KN(SiMe3)2 or NaH, a
fast, quantitative migration of the silyl group occurs from
the nitrogen atom to the oxygen atom. The resulting anion
at the nitrogen atom can be alkylated in situ with ethyl
bromoacetate. In just one step, therefore, we have succeeded
in protecting the hydroxy group, deblocking the nitrogen
atom, and then alkylating it. The following steps are similar
to those applied to the model compounds. Amine 46 was
purified by chromatography and can be stored in a freezer
as the stable hydrochloride salt. On warming the free amine
in THF at reflux in the presence of the hydrogen donor 1,4-
cyclohexadiene, the amine slowly disappears and gives rise
to two new spots (TLC). Small quantities (Ͻ 1 mg) of the
less-polar one were isolated by fast preparative TLC and
analyzed by 1H NMR spectroscopy. This compound, which
Scheme 7
Conclusions
A thorough study on the intramolecular transamidation
still possesses the enediyne group and, therefore, is most of model β-lactams bearing an amino group tethered at
1324
Eur. J. Org. Chem. 2003, 1319Ϫ1336

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
C 64.44, H 8.71, N 4.17; found C 64.5, H 8.75, N 4.1. GC-MS:
Rt ϭ 9.55, m/z ϭ 278 [Mϩ· Ϫ 57] (2.3), 248 (3.3), 206 (16.7), 158
(4.5), 100 (10.0), 91 (100.0), 75 (3.9), 73 (10.1), 65 (4.4), 57 (6.8),
either N-1 or C-3 has been carried out, showing interesting
structureϪreactivity relationships and the important effects
of solvent and buffer. Protection of this amine with enzy-
matically or photochemically removable groups allows the
selective triggering of intramolecular β-lactam opening. Fi-
nally, applying the same concepts to a lactenediyne, we have
demonstrated that, upon ring enlargement, the heterocycle
trans-fused with the enediyne ring is no longer able to act
as a ‘‘safety lock’’ (i.e., it no longer prevents cycloaromatiz-
ation).
These results open the way to the implementation of
these concepts in the development of new lactenediyne pro-
drugs whose activity against DNA may be triggered by a
suitable enzyme or by UV light. Studies towards this im-
portant goal are in progress.
1
41 (7.3). H NMR: δ ϭ 0.23 and 0.24 (2 s, 2 ϫ 3 H, CH3Si), 0.96
[s, 9 H, (CH3)3C], 2.78 (dd, J ϭ 2.0, 15.2 Hz, 1 H, CHHCϭO),
3.13 (dd, J ϭ 5.4, 15.2 Hz, 1 H, CHHCϭO), 3.56Ϫ3.76 (m, 3 H,
CHN and CH2O), 4.61 (s, 2 H, PhCH2), 4.77 (s, 2 H, OCH2O),
7.30Ϫ7.43 (m, 5 H, aromatics) ppm.
rac-4-[(Benzyloxymethoxy)methyl]azetidin-2-one (7): A solution of
alcohol 6 (2.620 g, 7.81 mmol) in dry THF (40 mL) was cooled to
Ϫ40 °C and treated with a solution of nBu4NF·3H2O in THF (1
, 23.4 mL, 23.4 mmol). After 1 h, the reaction was complete and
was quenched at Ϫ40 °C with saturated aqueous NH4Cl. Extrac-
tion with Et2O gave, after concentration and chromatography (PE/
EtOAc, 30:70 to 20:80), pure 7 as a slightly yellow oil (1.708 g,
99%). Rf ϭ 0.27 (PE/EtOAc, 30:70). C12H15NO3 (221.25): calcd. C
65.14, H 6.83, N 6.33; found C 65.3, H 7.05, N 6.2. GC-MS: Rt ϭ
7.93, m/z ϭ 190 [Mϩ· Ϫ 31] (0.2), 120 (29.5), 119 (9.8), 108 (12.0),
91 (100.0), 72 (8.4), 70 (12.8), 65 (10.4), 43 (19.7), 41 (7.6), 39 (5.3).
1H NMR: δ ϭ 2.65 (ddd, J ϭ 1.5, 2.4, 14.8 Hz, 1 H, CHHCϭO),
3.04 (ddd, J ϭ 1.9, 4.9, 14.8 Hz, 1 H, CHHCϭO), 3.56 (dd, J ϭ
8.5, 11.2 Hz, 1 H CHHO), 3.75Ϫ3.86 (m, 2 H, CHN and CHHO),
4.61 (s, 2 H, PhCH2), 4.79 (s, 2 H, OCH2O), 5.99 (br. s, 1 H, NH),
7.30Ϫ7.43 (m, 5 H, aromatics) ppm. 13C NMR (20 MHz): δ ϭ
40.52 (CH2), 46.92 (CH), 69.92 (CH2O), 70.80 (CH2O), 95.17
(OCH2O), 127.84, 128.53 (aromatics), 137.51 (quat. aromatic),
167.50 (CϭO) ppm. IR: ν˜max ϭ 3416, 3003, 2950, 2890, 2870, 1762
Experimental Section
1
General Remarks: H and 13C NMR spectra were taken in CDCl3
at 200 MHz and 50 (or 20) MHz, respectively. Chemical shifts are
reported in ppm (δ scale), using TMS as an internal standard.
Coupling constants are reported in Hz. In ABX systems, the proton
A is considered downfield and B upfield. Peak assignment in the
13C NMR spectra was also made on the basis of DEPT or off-
resonance experiments. GC-MS was carried out with an HP-5971A
instrument, with an HP-1 column (12 m long, 0.2 mm diameter),
electron impact at 70 eV, a mass temperature of about 167 °C, and
starting the spectral range from m/z ϭ 33. Analyses were performed
with a constant He flow of 0.9 mL/min, starting at 100 °C for 2 min
(unless otherwise noted) and then raising the temperature by 20
°C/min. Values of Rt were measured in minutes from injection. IR
spectra were measured as CHCl3 solutions. TLC analyses were car-
ried out on silica gel plates, which were scrutinized by UV or by
(s), 1604, 1494, 1453, 1412, 1361, 1337, 1167, 1109, 1037 cmϪ1
.
Ethyl rac-{2-[(Benzyloxymethoxy)methyl]-4-oxoazetidin-1-yl}acetate
(8): A solution of azetidinone 7 (1.00 g, 4.52 mmol) in dry THF
(30 mL) was cooled to 0 °C and treated with nBu4NBr (154 mg,
0.48 mmol), powdered KOH (85%, 348 mg, 5.27 mmol) and ethyl
bromoacetate (0.60 mL, 5.41 mmol). After 75 min, the reaction was
complete and was quenched with saturated aqueous NH4Cl. Ex-
traction with Et2O (2 ϫ) and EtOAc gave, after concentration and
chromatography (PE/EtOAc, 50:50 to 40:60), pure 8 as an oil
(1.171 g, 84%). Rf ϭ 0.41 (PE/EtOAc, 50:50). C16H21NO5 (307.34):
calcd. C 62.53, H 6.89, N 4.56; found C 62.35, H 6.9, N 4.5. GC-
MS: Rt ϭ 9.55; m/z ϭ 307 [Mϩ·] (0.1), 234 (0.5), 200 (9.3), 174
(5.7), 156 (9.7), 129 (6.6), 120 (13.2), 114 (7.5), 91 (100.0), 86 (11.3),
65 (5.6), 56 (5.6), 55 (4.5), 41 (7.2). 1H NMR: δ ϭ 1.28 (t, J ϭ
7.1 Hz, 3 H, CH3), 2.71 (dd, J ϭ 2.6, 14.6 Hz, 1 H, CHHCϭO),
3.08 (dd, J ϭ 5.2, 14.6 Hz, 1 H, CHHCϭO), 3.68 and 3.83 (AB
part of ABX system, JAB ϭ 10.4 Hz, JAX ϭ 3.4 Hz, JBX ϭ 7.6 Hz,
2 H, CH2O), 3.86 (d, J ϭ 18.0 Hz, 1 H, CHHCO2Et), 4.00 (mc, 1
H, CHN), 4.18 (d, J ϭ 18.0 Hz, 1 H, CHHCO2Et), 4.19 (q, J ϭ
7.2 Hz, 2 H, CH2CH3), 4.59 (s, 2 H, PhCH2), 4.75 (s, 2 H, OCH2O),
7.30Ϫ7.43 (m, 5 H, aromatics) ppm.
dipping into
a solution of (NH4)4MoO4·4H2O (21 g) and
Ce(SO4)2·4H2O (1 g) in H2SO4 (31 mL) and H2O (469 mL) and
warming. In the case of primary amines, the spots were also devel-
oped with the FluramTM reagent.[17] Values of Rf were measured
after an elution of 7Ϫ9 cm. Column chromatographies were carried
out on 220Ϫ400 mesh silica gel by using the ‘‘flash’’ methodology.
All reactions employing dry solvents were carried out under nitro-
gen (or argon, where indicated). During extractions, the aqueous
phases were always reextracted twice with the indicated organic
solvent. Organic extracts were always dehydrated with Na2SO4 and
filtered before concentration to dryness. Abbreviations used: PE ϭ
petroleum ether, boiling range 40Ϫ60 °C; THF ϭ tetrahydrofuran;
DMF ϭ dimethylformamide; BOM ϭ benzyloxymethyl; pyBOP ϭ
(benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluoro-
phosphate.
rac-4-[(Benzyloxymethoxy)methyl]-1-(2-hydroxyethyl)azetidin-2-one
(9a): A suspension of finely ground CaCl2 (388 mg, 3.48 mmol) in
dry THF (20 mL) and dry EtOH (10 mL) was cooled to Ϫ20 °C
and treated with NaBH4 (240 mg, 6.40 mmol). After 15 min, a
rac-4-[(Benzyloxymethoxy)methyl]-1-(tert-butyldimethylsilyl)-
azetidin-2-one (6): A solution of alcohol 5[2] (2.510 g, 11.65 mmol)
in dry CH2Cl2 (40 mL) was cooled to 0 °C and treated in sequence solution of ester 8 (357 mg, 1.16 mmol) in dry THF (10 mL) was
with N-ethyldiisopropylamine (3.00 mL, 17.52 mmol) and freshly added. After 3.5 h, the reaction was complete and was quenched
distilled benzyl chloromethyl ether (2.5 mL, 18.0 mmol). After by the slow addition of saturated aqueous NH4Cl. Most of the
10 min, the cooling bath was removed and the solution stirred for
5 h at room temp. After addition of diethylamine (1.21 mL,
THF and EtOH were evaporated and the mixture was extracted
three times with EtOAc. After concentration and chromatography
11.65 mmol) and stirring for 15 min, the mixture was poured into (PE/EtOAc, 30:70 to EtOAc/MeOH, 95:5) pure 9a was obtained as
saturated aqueous NH4Cl and extracted with Et2O. Concentration
and chromatography of the crude product (PE/EtOAc, 70:30 to
50:50 ϩ 1% Et3N) gave pure 6 as a slightly yellow oil (2.894 g,
an oil (281 mg, 91%). Rf ϭ 0.27 (PE/EtOAc, 30:70). C14H19NO4
(265.31): calcd. C 63.38, H 7.22, N 5.28; found C 63.6, H 7.4, N
5.0. GC-MS: Rt ϭ 9.31; m/z ϭ 234 [Mϩ· Ϫ 31] (1.5), 204 (2.1), 144
74%). Rf ϭ 0.55 (PE/EtOAc, 70:30). C18H29NO3Si (335.51): calcd. (2.4), 132 (5.6), 120 (7.9), 114 (14.8), 91 (100.0), 72 (20.4), 65 (5.4),
Eur. J. Org. Chem. 2003, 1319Ϫ1336 1325

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
45 (10.2), 41 (6.8). H NMR: δ ϭ 1.80 (br. s, 1 H, OH), 2.70 (dd,
1
0.746 mmol) was dissolved in dry DMF (3 mL), and treated in se-
J ϭ 2.2, 14.6 Hz, 1 H, CHHCϭO), 2.99 (dd, J ϭ 4.6, 14.6 Hz, 1 quence with nBu4NI (27 mg, 74 µmol), EtNiPr2 (188 µL,
H, CHHCϭO), 3.30Ϫ3.42 (m, 2 H, CH2N), 3.64Ϫ3.90 (m, 5 H, 1.11 mmol) and freshly distilled benzyloxymethyl chloromethyl
CH2O and CHN), 4.61 (s, 2 H, PhCH2), 4.79 (s, 2 H, OCH2O), ether (134 µL, 0.96 mmol). The solution was stirred for 6 h at 60
7.30Ϫ7.43 (m, 5 H, aromatics) ppm. 13C NMR (20 MHz): δ ϭ
°C. After cooling, Et2NH (115 µL, 1.11 mmol) was added. The
38.65 and 46.71 (CH2), 51.35 (CHN), 60.44, 68.43, 69.96 (CH2), solution stirred for 1 h at room temp. and then poured into satu-
94.98 (OCH2O), 127.69, 128.42 (aromatic CH), 137.33 (quat. aro- rated aqueous NH4Cl. Extraction with Et2O followed by concen-
matic), 167.66 (CϭO) ppm. IR: ν˜max ϭ 3668, 3603, 3430, 3085, tration and chromatography (PE/Et2O, 30:70 ϩ 1% Et3N) gave
3036, 2995, 2943, 2888, 1741 (s), 1602, 1453, 1402, 1379, 1344,
pure 12 as a yellowish oil (223 mg, 73%). Rf ϭ 0.47 (PE/Et2O,
1331, 1193, 1168, 1147, 1113, 1050, 944 cmϪ1
.
30:70). C21H35NO5Si (409.59): calcd. C 61.58, H 8.61, N 3.42;
1
found C 61.75, H 8.7, N 3.35. H NMR: δ ϭ 0.06 (s, 6 H, CH3Si),
(3R*,4S*)-1-(2-Hydroxyethyl)-3-methoxy-4-(2-phenylethenyl)-
azetidin-2-one (9b):
solution of silyl ether 10[15] (4.50 g,
0.89 [s, 9 H, (CH3)3C], 3.19 (dt, J ϭ 14.1, 5.7 Hz, 1 H, CHHN),
3.52 (dt, J ϭ 14.1, 5.5 Hz, 1 H, CHHN), 3.53 (s, 3 H, OCH3),
3.69Ϫ3.86 (m, 4 H, CH2O), 3.87Ϫ4.02 (m, 1 H, CHN), 4.52 (d,
J ϭ 4.6 Hz, 1 H, CHOMe), 4.61 (s, 2 H, CH2Ph), 4.78 (s, 2 H,
OCH2O), 7.35 (s, 5 H, aromatics) ppm. IR: ν˜max ϭ 2995, 2933,
2884, 2859, 1754 (s), 1602, 1453, 1405, 1358, 1191, 1113, 1046,
A
12.45 mmol) in CH3CN (40 mL) was cooled to Ϫ20 °C and treated
with 40% aqueous HF (2 mL, 45.18 mmol). The solution was
stirred at Ϫ20 °C for 1 h, at Ϫ10 °C for 5 h, and at 0 °C for 3 h.
Then the mixture was poured cautiously into a suspension of
NaHCO3 (12.6 g, 150 mmol) in 100 mL of H2O. Extraction with
EtOAc, followed by washing with saturated aqueous NaCl, concen-
tration, and chromatography (EtOAc to EtOAc/MeOH, 95:5) gave
pure 9b as a white solid (2.31 g, 75%). An analytical pure sample
was obtained by trituration with Et2O/PE. Rf ϭ 0.31 (EtOAc). M.p.
958 cmϪ1
.
(3R*,4S*)-4-[(Benzyloxymethoxy)methyl]-1-(2-hydroxyethyl)-3-
methoxyazetidin-2-one (9c): This compound was prepared in 92%
yield from 12 according to the same procedure employed for 9b.
78.2Ϫ79.4 °C. C14H17NO3 (247.29): calcd. C 68.00, H 6.93, N 5.66; Chromatography (EtOAc) gave pure 9c as a white solid. Rf ϭ 0.26
found C 67.9, H 7.0, N 5.6. GC-MS: Rt ϭ 8.98; m/z ϭ 247 [Mϩ·
(3.3), 216 (28.9), 215 (6.7), 188 (7.5), 176 (21.2), 172 (5.3), 163
]
(PE/EtOAc, 10:90). C15H21NO5 (295.33): calcd. C 61.00, H 7.17,
N 4.74; found C 61.4, H 7.3, N 4.6. GC-MS: Rt ϭ 9.54; m/z ϭ 295
(23.4), 160 (58.5), 159 (45.7), 156 (26.4), 145 (18.3), 144 (21.7), 140 [Mϩ·] (0.2), 173 (0.9), 130 (2.0), 120 (1.5), 119 (1.8), 107 (8.1), 102
(13.7), 129 (38.8), 128 (33.3), 127 (16.3), 121 (5.9), 117 (46.1), 116
(11.4), 101 (20.8), 100 (7.0), 91 (100.0), 87 (76.9), 72 (58.2), 71
(19.4), 115 (100.0), 91 (37.5), 85 (7.3), 77 (13.6), 72 (11.6), 65 (9.1), (56.9), 70 (77.3), 69 (21.5), 65 (10.0), 59 (39.0), 45 (10.7), 41 (14.8).
1
51 (13.0), 45 (34.8), 44 (12.0), 42 (12.0), 39 (15.7). H NMR: δ ϭ 1H NMR: δ ϭ 3.26Ϫ3.48 (m, 2 H, CH2N), 3.53 (s, 3 H, OCH3),
3.10Ϫ3.45 (m, 2 H, CH2N), 3.46 (s, 3 H, OCH3), 3.74Ϫ3.90 (m, 3
3.58Ϫ3.96 (m, 5 H, CH2O and CHN), 4.53 (d, J ϭ 4.3 Hz, 1 H,
H, CH2OH), 4.35 (dd, J ϭ 4.4, 9.1 Hz, 1 H, CHN), 4.64 (d, J ϭ CHOMe), 4.62 (s, 2 H, CH2Ph), 4.79 (s, 2 H, OCH2O), 7.35 (s, 5
4.4 Hz, 1 H, CHOMe), 6.24 (dd, J ϭ 9.1, 16.0 Hz, 1 H, CHϭ
H, aromatics) ppm. IR: ν˜max ϭ 3417, 3006, 2937, 2892, 2778, 1738
CHPh), 6.75 (d, J ϭ 16.0 Hz, 1 H, PhCH), 7.20Ϫ7.50 (m, 5 H, (s), 1604, 1513, 1404, 1351, 1189, 1107, 1046, 920 cmϪ1
aromatics) ppm. 13C NMR: δ ϭ 45.41 (CH2N), 58.62 (CH3O),
.
(3R*,4S*)-1-[2-(tert-Butyldimethylsilyloxy)ethyl]-3-phenoxy-4-(2-
phenylethenyl)azetidin-2-one (13): A solution of phenoxyacetyl
chloride (730 µL, 3.52 mmol) in dry CH2Cl2 (40 mL) was cooled
to Ϫ78 °C and treated dropwise with Et3N (1.47 mL, 10.4 mmol).
The temperature was allowed to rise to Ϫ40 °C during 30 min
and the solution was treated with a solution of [2-(tert-butyldi-
59.90 (CHN), 61.65 (CH2OH), 84.70 (CHOMe), 122.61 (Cϭ
CHPh), 126.72, 128.46, 128.68 (aromatic CH), 135.78 (aromatic
quat.), 137.07 (PhCHϭ), 167.66 (CϭO) ppm. IR: ν˜max ϭ 3402
(broad), 2994, 2928, 2832, 1739 (s), 1599, 1403, 1346, 1250, 1145,
1052, 995, 968 cmϪ1
.
(3R*,4S*)-1-[2-(tert-Butyldimethylsilyloxy)ethyl]-4-(hydroxy- methylsilyloxy)ethyl][(E)-3-phenylpropenylidene]amine[15] (1.020 g,
methyl)-3-methoxyazetidin-2-one (11): A solution of azetidinone 3.52 mmol) in dry CH2Cl2 (18 mL). The mixture was stirred at Ϫ20
10[15] (700 mg, 1.94 mmol) in dry CH2Cl2 (9 mL) and dry MeOH °C for 48 h and at room temp. for 1 h. After treating with MeOH
(13.4 mL) was ozonized at Ϫ78 °C until a grey-blue color persisted. (6 mL) and stirring for 30 min, the mixture was poured into satu-
The solution was treated with Me2S (0.50 mL) and, after 10 min, rated aqueous NaCl and extracted with CH2Cl2. Concentration
with NaBH4 (300 mg, 7.93 mmol). The temperature was allowed to and chromatography (PE/EtOAc, 8:2 to 7:3) afforded pure 13 as a
rise to 0 °C during 2 h. The mixture was quenched with saturated
aqueous NH4Cl. After evaporation of most of the MeOH, extrac-
tion with EtOAc, concentration and chromatography (PE/EtOAc, 3.2. H NMR: δ ϭ 0.08 [s, 6 H, Si(CH3)2], 0.92 [s, 9 H, C(CH3)3],
30:70 to 20:80) gave pure 11 as an oil (432 mg, 77%). Rf ϭ 0.39 3.14 (ddd, J ϭ 4.8, 7.4, 14.0 Hz, 1 H, CHHN), 3.52Ϫ3.87 (m, 3 H,
yellow oil (1.02 g, 68%). Rf ϭ 0.29 (PE/Et2O, 60:40). C25H33NO3Si
(423.62): calcd. C 70.88, H 7.85, N 3.31; found C 70.55, H 7.9, N
1
(PE/EtOAc, 30:70). C13H27NO4Si (289.44): calcd. C 53.94, H 9.40,
CH2OSi, CHHN), 4.64 (dd, J ϭ 4.4, 8.9 Hz, 1 H, CHN), 5.36 (d,
N 4.84; found C 54.3, H 9.2, N 4.7. GC-MS: Rt ϭ 7.42; m/z ϭ 274 J ϭ 4.4 Hz, 1 H, CHOPh), 6.21 (dd, J ϭ 8.9 Hz, 1 H, CHϭCHPh),
[Mϩ· Ϫ 15] (2.9), 232 (75.4) [Mϩ Ϫ 57], 204 (10.6), 202 (6.4), 174 6.71 (d, J ϭ 15.9 Hz, 1 H, CHϭCHPh), 6.98 (d, J ϭ 8.0 Hz, 2 H,
(11.8), 144 (36.7), 130 (6.8), 100 (78.6), 88 (100.0), 75 (49.8), 73 aromatics ortho to O), 7.18Ϫ7.40 (m, 3 H, other aromatics) ppm.
(46.1), 71 (64.8), 61 (8.0), 60 (29.2), 59 (26.2), 58 (25.3), 57 (29.2),
56 (26.2), 45 (23.9), 41 (12.7). H NMR: δ ϭ 0.09 (s, 6 H, CH3Si),
13C NMR (20 MHz): δ ϭ Ϫ5.38 [Si(CH3)2], 18.19 [C(CH3)3], 25.82
[C(CH3)3], 42.60 (CH2N), 60.92 (CH2O), 62.02 (CHN), 82.22
1
0.90 [s, 9 H, (CH3)3C], 3.08 (t, J ϭ 6.6 Hz, 1 H, OH), 3.40 (t, J ϭ (CHOPh), 115.61, 122.75, 126.59, 128.13, 128.49, 129.34 (aromatic
5.0 Hz, CH2N), 3.58 (s, 3 H, OCH3), 3.65Ϫ3.95 (m, 5 H, CH2O, CH), 122.01 (CHϭCHPh), 135.94 (aromatic quat.), 136.73 (CHϭ
CHN), 4.54 (d, J ϭ 4.4 Hz, 1 H, CHOMe) ppm. 13C NMR
CHPh), 157.37 (aromatic quat.), 165.49 (CϭO) ppm. IR: ν˜max ϭ
(20 MHz): δ ϭ Ϫ5.4 (CH3Si), 18.34 [C(CH3)3], 25.91 [C(CH3)3], 3009, 2954, 2930, 1756 (s), 1598, 1490, 1407, 1362, 1193, 1108,
43.30 (CH2N), 59.37, 59.73, 60.47, 62.05 (CH3O ϩ CHN ϩ 967 cmϪ1
CH2O), 167.49 (CϭO) ppm.
.
(3R*,4S*)-1-[2-(tert-Butyldimethylsilyloxy)ethyl]-4-(hydroxy-
(3R*,4S*)-4-[(Benzyloxymethoxy)methyl]-1-[2-(tert-butyldimethyl- methyl)-3-phenoxyazetidin-2-one (14): This compound was pre-
silyloxy)ethyl]-3-methoxyazetidin-2-one (12): Alcohol 11 (216 mg,
pared from 13 in 78% yield using the same procedure employed for
Eur. J. Org. Chem. 2003, 1319Ϫ1336
1326

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
11. M.p. 53.9Ϫ54.5 °C. Rf ϭ 0.47 (PE/EtOAc, 60:40). C18H29NO4Si rac-1-(2-Azidoethyl)-4-[(benzyloxymethoxy)methyl]azetidin-2-one
(351.51): calcd. C 61.50, H 8.32, N 3.98; found C 61.6, H 8.4, N (16a): A solution of alcohol 9a (191.9 mg, 0.72 mmol) in dry
3.85. 1H NMR: δ ϭ 0.12 [s, 6 H, Si(CH3)2], 0.93 [s, 9 H, C(CH3)3],
CH2Cl2 (10 mL) was cooled to Ϫ30 °C, and treated with triethyl-
3.26 (dd, J ϭ 6.3, 7.6 Hz, 1 H, OH), 3.41 (ddd, J ϭ 3.6, 7.7, amine (300 µL, 2.17 mmol) and methanesulfonyl chloride (84.0 µL,
14.5 Hz, 1 H, CHHN), 3.58 (ddd, J ϭ 3.3, 5.0, 14.5 Hz, 1 H, 1.08 mmol). After 1 h at the same temperature, the reaction was
CHHN), 3.72Ϫ4.15 (m, 5 H, CH2OSi, CH2OH, CHN), 5.27 (d, quenched by addition of saturated aqueous NH4Cl (10 mL). Ex-
J ϭ 4.4 Hz, 1 H, CHOPh), 6.98Ϫ7.12 (m, 3 H, aromatics), traction with EtOAc, and concentration to dryness, gave crude me-
7.25Ϫ7.42 (m, 2 H, aromatics) ppm. 13C NMR (20 MHz): δ ϭ
Ϫ5.41 [Si(CH3)2], 18.46 [C(CH3)3], 25.96 [C(CH3)3], 44.0 (CH2N),
sylate (Rf ϭ 0.49, EtOAc/MeOH, 90:10), which was taken up in
dry DMF (2 mL), treated with NaN3 (181 mg, 2.80 mmol) and
60.53 (CHN), 60.96 (CH2O), 62.23 (CH2O), 80.72 (CHOPh), heated at 50 °C for 5 h. After cooling to room temp., the mixture
115.63, 122.47, 129.67 (aromatic CH), 157.44 (aromatic quat.), was diluted with saturated aqueous NH4Cl, and extracted with
166.05 (CϭO) ppm. IR: ν˜max ϭ 3408, 3005, 2952, 2929, 2859, 1759 EtOAc. The organic extracts were washed with H2O, saturated
(s), 1600, 1492, 1407, 1358, 1193, 1097, 1027 cmϪ1
.
NaCl, concentrated and chromatographed (PE/EtOAc, 30:70 to
10:90) to give pure azide 16a as an oil (162.3 mg, 78%). Rf ϭ 0.74
(EtOAc/MeOH, 90:10). C14H18N4O3 (290.32): calcd. C 57.92, H
6.25, N 19.30; found C 58.25, H 6.5, N 18.8. GC-MS: Rt ϭ 9.55;
m/z ϭ 262 [Mϩ· Ϫ 28] (1.2), 234 (0.9), 204 (5.3), 141 (6.5), 120
(3.3), 91 (100.0), 84 (2.9), 69 (5.4), 65 (5.2), 56 (4.3), 55 (4.0), 42
(7.7), 41 (6.5). 1H NMR: δ ϭ 2.68 and 3.01 (AB part of ABX
system, JAB ϭ 14.6 Hz, JAX ϭ 5.0 Hz, JBX ϭ 2.3 Hz, 2 H, CH2Cϭ
O), 3.26 (ddd, J ϭ 2.6, 9.5, 15.4 Hz, 1 H, CHHN), 3.42Ϫ3.74 (m,
4 H), 3.78Ϫ3.90 (m, 2 H), 4.61 (s, 2 H, CH2Ph), 4.80 (s, 2 H,
OCH2O), 7.35 (s, 5 H, aromatics) ppm. IR: ν˜max ϭ 3001, 2937,
2889, 2107 (s), 1745 (s), 1603, 1453, 1400, 1348, 1331, 1286, 1148,
(3R*,4S*)-4-[(Benzyloxymethoxy)methyl]-1-[2-(tert-butyldimethyl-
silyloxy)ethyl]-3-phenoxyazetidin-2-one (15): A solution of alcohol
14 (260 mg, 0.74 mmol) in dry DMF (3 mL) was treated with
nBu4NI (27.4 mg, 0.074 mmol), EtNiPr2 (188 µL, 1.11 mmol) and
freshly distilled benzyloxymethyl chloride (134 µL, 0.96 mmol).
After 30 min, the solution was heated at 60 °C overnight. After
cooling to room temp., the reaction was quenched with diethyl-
amine (115 µL, 1.11 mmol). After stirring for 1 h, the mixture was
poured into saturated aqueous NH4Cl and extracted with Et2O.
Chromatography (PE/Et2O, 55:45 to 60:40) gave pure 15 as a yel-
1110, 1043 cmϪ1
.
lowish oil (258 mg, 74%). Rf
ϭ 0.53 (PE/Et2O, 60:40).
C26H37NO5Si (471.66): calcd. C 66.21, H 7.91, N 2.97; found C
66.5, H 8.1, N 2.75. GC-MS: Rt ϭ 13.92; m/z ϭ 456 [Mϩ· Ϫ 15]
(1.0), 414 (30.7) [Mϩ Ϫ 57], 200 (2.5), 184 (8.7), 164 (31.8), 149
(20.0), 144 (5.2), 133 (15.6), 121 (8.4), 105 (7.9), 100 (13.4), 94
(22.0), 91 (100.0), 77 (11.3), 75 (8.3), 73 (18.3), 71 (37.1), 70 (20.6).
1H NMR: δ ϭ 0.08 [s, 6 H, Si(CH3)2], 0.91 [s, 9 H, C(CH3)3], 3.26
(dt, J ϭ 14.0, 5.7 Hz, 1 H, CHHN), 3.61 (dt, J ϭ 14.0, 5.4 Hz, 1
H, CHHN), 3.74Ϫ3.98 (m, 4 H, CH2OSi, CH2OBOM), 4.17 (dt,
J ϭ 6.6, 4.8 Hz, 1 H, CHN), 4.51 (s, 2 H, CH2Ph), 4.71 (s, 2 H,
OCH2O), 5.26 (d, J ϭ 4.8 Hz, 1 H, CHOPh), 6.98Ϫ7.12 (m, 3 H,
aromatics), 7.20Ϫ7.40 (m, 6 H, aromatics) ppm. 13C NMR
(20 MHz): δ ϭ Ϫ5.32 [Si(CH3)2], 18.25 [C(CH3)3], 25.94 [C(CH3)3],
43.71 (CH2N), 58.24, 60.62, 66.72, 69.59 (CHN and CH2O), 80.28
(CHOPh), 95.05 (OCH2O), 115.63, 122.22, 127.84, 128.45, 129.54
(aromatic CH), 137.66, 157.69 (aromatic quat.), 166.05 (CϭO)
ppm. IR: ν˜max ϭ 3005, 2953, 2931, 2885, 2858, 1757 (s), 1598, 1491,
(3R*,4S*)-1-(2-Azidoethyl)-3-methoxy-4-(2-phenylethenyl)azetidin-
2-one (16b): This compound was prepared (oil) in 86% yield from
9b according to the same procedure used for 16a. Reaction time
of azide substitution: 5 h at 50 °C. Rf ϭ 0.46 (PE/EtOAc, 40:60).
C14H16N4O2 (272.30): calcd. C 61.75, H 5.92, N 20.58, found C
61.7, H 5.9, N 20.5. GC-MS: decomposition during analysis giving
two peaks at 8.10 and 8.82 min. 1H NMR: δ ϭ 3.10Ϫ3.34 (m, 2
H), 3.40Ϫ3.62 (m, 2 H), 3.47 (s, 3 H, OCH3), 4.40 (dd, J ϭ 4.4,
9.0 Hz, 1 H, CHN), 4.66 (d, J ϭ 4.4 Hz, CHOMe), 6.25 (dd, J ϭ
9.2, 15.9 Hz, 1 H, CHϭCHPh), 6.76 (d, J ϭ 16.2 Hz, 1 H, CHPh),
7.25Ϫ7.50 (m, 5 H, aromatics) ppm. 13C NMR: δ ϭ 39.46 and
49.30 (CH2N), 58.70 (CH3), 61.73 (CHN), 85.62 (CHOMe), 122.71
(CHϭCHPh), 126.74, 128.47, 128.70 (aromatic CH), 135.79 (aro-
matic quat.), 137.03 (CHϭCHPh), 167.02 (CϭO) ppm. IR: ν˜max ϭ
3037, 2996, 2926, 2833, 2106 (s), 1750 (s), 1399, 1347, 1132, 1058,
999, 968 cmϪ1
.
1405, 1358, 1236, 1111, 1049, 920 cmϪ1
.
(3R*,4S*)-1-(2-Azidoethyl)-4-[(benzyloxymethoxy)methyl]-3-meth-
oxyazetidin-2-one (16c): This compound was prepared (oil) in 85%
yield from 9c according to the same procedure employed for 16a.
Reaction time of azide substitution: overnight at 40 °C. Rf ϭ 0.73
(PE/EtOAc, 30:70). C15H20N4O4 (320.34): calcd. C 56.24, H 6.29,
N 17.49; found C 56.3, H 6.35, N 17.4. GC-MS: Rt ϭ 9.79; m/z ϭ
292 [Mϩ· Ϫ 28] (2.8), 171 (16.0), 160 (11.7), 113 (8.5), 107 (6.5),
102 (7.3), 101 (13.5), 91 (100.0), 87 (48.9), 84 (8.2), 81 (6.8), 72
(35.0), 71 (38.6), 70 (52.3), 69 (21.5), 65 (9.3), 59 (25.2), 42 (9.1),
(3R*,4S*)-4-[(Benzyloxymethoxy)methyl]-1-(2-hydroxyethyl)-3-
phenoxyazetidin-2-one (9d): This compound was prepared in 96%
yield from 15 according to the same procedure employed for 9b.
Chromatography (PE/EtOAc, 3:7 to 2:8) gave pure 9d as a white
solid. Rf ϭ 0.32 (PE/EtOAc, 3:7). C20H23NO5 (357.40): calcd. C
67.21, H 6.49, N 3.92; found C 67.4, H 6.6, N 3.8. GC-MS: Rt ϭ
11.92 (during GC analysis, partial transformation into the re-
arranged lactone, Rt ϭ 11.49, took place); m/z ϭ 357 [Mϩ·] (0.7),
177 (1.3), 176 (1.2), 164 (34.5), 149 (22.1), 134 (8.2), 133 (17.8), 131
(8.0), 121 (14.9), 119 (5.8), 105 (14.1), 95 (13.0), 94 (28.3), 92 (21.0),
91 (100.0), 77 (21.6), 71 (37.0), 70 (20.0), 69 (10.4), 65 (9.5), 39
(7.7). 1H NMR: δ ϭ 3.43 and 3.50 (AB part of ABX2 system,
JAB ϭ 14.6 Hz, JAX ϭ JBX ϭ 4.8 Hz, 2 H, CH2N), 3.80Ϫ4.00 (m,
4 H, CH2O), 4.12 (dt, J ϭ 7.6, 4.4 Hz, 1 H, CHN), 4.56 (s, 2 H,
CH2Ph), 4.76 (s, 2 H, OCH2O), 5.29 (d, J ϭ 4.7 Hz, 1 H, CHOPh),
6.95Ϫ7.08 (m, 3 H, aromatics), 7.20Ϫ7.40 (m, 7 H, aromatics)
ppm. 13C NMR (20 MHz): δ ϭ 46.86 (CH2N), 58.40, 60.35, 67.24,
1
41 (13.2). H NMR: δ ϭ 3.26Ϫ3.40 (m, 1 H), 3.42Ϫ3.64 (m, 3 H),
3.53 (s, 3 H, OCH3), 3.70Ϫ4.0 (m, 3 H), 4.54 (d, J ϭ 4.7 Hz,
CHOMe), 4.62 (s, 2 H, CH2Ph), 4.80 (s, 2 H, OCH2O), 7.36 (s, 5
H, aromatics) ppm. 13C NMR (50 MHz): δ ϭ 40.54 (CH2N), 49.00
(CH2N), 57.81 (CHN), 59.23 (OCH3), 67.23, 69.89 (CH2O), 83.51
(COMe), 95.19 (OCH2O), 127.70, 127.77, 128.43 (aromatic CH),
137.67 (aromatic quat.), 167.64 (CϭO) ppm.
(3R*,4S*)-1-(2-Azidoethyl)-4-[(benzyloxymethoxy)methyl]-3-
69.99 (CHN and CH2O), 79.51 (CHOPh), 95.19 (OCH2O), 115.51, phenoxyazetidin-2-one (16d): This compound was prepared (oil) in
122.40, 127.77, 128.44, 129.60 (aromatic CH), 137.48, 157.43 (aro- 91% yield from 9d according to the same procedure employed for
matic quat.), 166.70 (CϭO) ppm. IR: ν˜max ϭ 3442, 3002, 2945, 16a. Reaction time of azide substitution: overnight at 40 °C. Rf ϭ
2890, 1747 (s), 1599, 1492, 1408, 1348, 1194, 1115, 1041 cmϪ1
.
0.43 (PE/EtOAc, 60:40). C20H22N4O4 (382.41): calcd. C 62.82, H
1327
Eur. J. Org. Chem. 2003, 1319Ϫ1336

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
5.80, N 14.65; found C 62.55, H 6.55, N 14.5. 1H NMR: δ ϭ (3R*,4R*,4ЈS*)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(2-propenyl-
3.32Ϫ3.72 (m, 4 H, CH2CH2N3), 3.85 and 3.93 (AB part of ABX oxy)azetidin-2-one (21): A solution of compound 18 (304 mg, 912
system, JAB ϭ 10.7 Hz, JAX ϭ 3.5 Hz, JBX ϭ 8.3 Hz, 2 H, CH2O),
µmol) in CH3CN (10 mL) was cooled to Ϫ20 °C and treated with
4.14 (dt, J ϭ 8.4, 4.2 Hz, 1 H, CHN), 4.56 (s, 2 H, CH2Ph), 4.76 a solution of Ce(NH4)2(NO3)6 (CAN) (1.513 g, 2.76 mmol) in H2O
(s, 2 H, OCH2O), 5.29 (d, J ϭ 4.8 Hz, CHOPh), 6.95Ϫ7.10 (m, 3 H, (6 mL). After 30 min, the mixture was diluted with 60 mL of ice-
aromatics), 7.20Ϫ7.40 (m, 7 H, other aromatics) ppm. 13C NMR cold water, and rapidly extracted with EtOAc. The organic extracts
(50 MHz): δ ϭ 41.03 (CH2N), 49.19 (CH2N), 58.27 (CHN), 67.48, were washed with a mixture of saturated aqueous NaHCO3
70.12 (CH2O), 80.32 (COMe), 95.42 (OCH2O), 115.71, 122.54, (30 mL) and aqueous Na2SO3 (10%, 15 mL). After a final washing
127.89, 127.98, 128.62, 129.75 (aromatic CH), 137.80, 157.69 (aro-
with saturated NaCl, the organic phase was concentrated and chro-
matic quat.), 166.26 (CϭO) ppm. IR: ν˜max ϭ 3008, 2932, 2106 (s), matographed (PE/EtOAc, 70:30 to 50:50) to give pure 21 as a white
1761 (s), 1599, 1492, 1405, 1349, 1241, 1109, 1044 cmϪ1
C14H18N4O3 (290.32): calcd. C 57.92, H 6.25, N 19.30; found C
58.25, H 6.5, N 18.8.
.
solid (173 mg, 84%). Rf ϭ 0.12 (PE/EtOAc, 70:30). C11H17NO4
(227.26): calcd. C 58.14, H 7.54, N 6.16; found C 58.1, H 7.45, N
6.05. GC-MS: Rt ϭ 6.09; m/z ϭ 212 [Mϩ· Ϫ 15] (10.5), 169 (4.0),
154 (5.1), 143 (11.7), 126 (38.8), 113 (21.5), 101 (13.1), 85 (39.6),
84 (9.3), 83 (6.0), 82 (5.5), 72 (96.5), 71 (11.8), 70 (9.1), 69 (36.0),
68 (7.1), 59 (15.2), 57 (9.7), 56 (10.3), 55 (8.5), 43 (88.0), 42 (32.7),
(3R*,4R*,4ЈS*)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(2-hydroxy-
ethoxy)-1-(4-methoxyphenyl)azetidin-2-one (19): Racemic β-lactam
18 was obtained in 51% yield from racemic isopropylideneglyceral-
dehyde according to the procedure already described for the op-
tically active compound.[18] M.p. 94.0Ϫ94.2 °C. A solution of 18
(400 mg, 1.2 mmol) in dry CH2Cl2 (30 mL) and dry MeOH
(20 mL) was cooled to Ϫ78 °C and ozonized until the grey-blue
color persisted. Me2S (2 mL) was added. The temperature was al-
lowed to rise to room temp. and the solution stirred for 3 h at this
temperature. The solvent was evaporated to dryness and the residue
taken up in dry THF (10 mL) and cooled to 0 °C. A solution of
BH3·THF in THF (1 , 2.4 mL, 2.4 mmol) was added. After
30 min at 0 °C, the reaction was complete and was quenched with
saturated aqueous NH4Cl. Extraction with EtOAc, concentration
and chromatography (PE/EtOAc, 40:60 to 30:70) gave pure alcohol
19 as a white solid (360 mg, 90%). Rf ϭ 0.35 (PE/EtOAc, 30:70).
C17H23NO6 (337.37): calcd. C 60.52, H 6.87, N 4.15; found C 60.8,
H 7.0, N 4.05. GC-MS: Rt ϭ 10.36; m/z ϭ 337 [Mϩ·] (15.8), 322
(4.4), 279 (16.7), 234 (6.0), 209 (5.4), 164 (10.2), 160 (6.8), 150
(10.6), 149 (100.0), 136 (7.5), 135 (10.7), 134 (23.1), 117 (5.2), 101
(9.4), 77 (7.3), 73 (25.2), 72 (15.7), 69 (9.8), 45 (12.9), 43 (35.0). 1H
NMR: δ ϭ 1.34 and 1.53 [2 s, 2 ϫ 3 H, (CH3)2C], 3.70Ϫ4.00 (m,
5 H), 3.80 (s, 3 H, OCH3), 4.22Ϫ4.32 (m, 2 H), 4.39 (dt, J ϭ 8.7,
6.4 Hz, 1 H, CHO), 4.75 (d, J ϭ 5.4 Hz, CHOCH2), 6.87 (d, J ϭ
9.1 Hz, 2 H, aromatics), 7.65 (d, J ϭ 9.1 Hz, 2 H, aromatics) ppm.
IR: ν˜max ϭ 3402, 2990, 2936, 2838, 1731 (s), 1601, 1505, 1441, 1383,
1
41 (100.0), 39 (24.4). H NMR: δ ϭ 1.36 and 1.43 [2 s, 2 ϫ 3 H,
(CH3)2C], 3.66 [dd, J ϭ 5.7, 8.6 Hz, 1 H, CHHOC(CH3)2], 3.71
(dd, J ϭ 5.1, 8.9 Hz, 1 H, CHN), 4.05Ϫ4.40 [m, 4 H, CHO, CH2ϭ
CHCH2O, CHHOC(CH3)2], 4.65 (dd, J ϭ 5.1, 2.2 Hz, 1 H,
CHOallyl), 5.23 (dq, J ϭ 10.2, 1.4 Hz, 1 H, CHHϭCH), 5.30 (dq,
J ϭ 17.2, 1.6 Hz, 1 H, CHHϭCH), 5.88 (dddd, J ϭ 5.1, 5.9, 10.3,
17.3 Hz, 1 H, CHϭCH2), 6.44 (br. s, 1 H, NH) ppm.
(3R*,4R*,4ЈS*)-1-(tert-Butoxycarbonylmethyl)-4-(2,2-dimethyl-1,3-
dioxolan-4-yl)-3-(2-propenyloxy)azetidin-2-one (22): A solution of
azetidinone 21 (130.5 mg, 0.574 mmol) in dry THF (10 mL) was
˚
treated with freshly activated powdered molecular sieves (4 A,
100 mg) and with nBu4NI (84.3 mg, 0.228 mmol). The mixture was
cooled to Ϫ20 °C, and treated in rapid sequence with tBuOK
(77 mg, 0.69 mmol) and tert-butyl bromoacetate (102 µL,
0.69 mmol). After 30 min, the reaction was quenched with satu-
rated aqueous NH4Cl, and extracted with EtOAc. Concentration
and chromatography afforded pure 22 as an oil (125 mg, 64%).
Rf ϭ 0.27 (PE/EtOAc, 70:30). C17H27NO6 (341.40): calcd. C 59.81,
H 7.97, N 4.10; found C 60.0, H 8.05, N 4.0. GC-MS: Rt ϭ 8.09;
m/z ϭ 326 [Mϩ· Ϫ 15] (3.1), 268 (4.4), 184 (7.0), 182 (22.1), 169
(6.4), 154 (9.3), 143 (24.6), 126 (63.3), 113 (33.1), 112 (8.5), 101
(16.5), 85 (65.7), 84 (9.0), 83 (7.6), 82 (7.1), 72 (100.0), 71 (10.8),
70 (12.3), 69 (39.9), 68 (11.7), 59 (9.6), 57 (48.9), 56 (11.1), 55
(10.9), 43 (68.1), 42 (27.0), 41 (93.9), 39 (16.1). 1H NMR: δ ϭ 1.33
and 1.40 [2 s, 2 ϫ 3 H, (CH3)2C], 1.46 [s, 9 H, (CH3)3C], 3.68 [dd,
J ϭ 5.4, 8.8 Hz, 1 H, CHHOC(CH3)2], 3.87 (d, J ϭ 17.7 Hz, 1 H,
CHCO2tBu), 3.89 (dd, J ϭ 5.1, 9.3 Hz, 1 H, CHN), 4.04Ϫ4.18 (m,
2 H), 4.18 (d, J ϭ 17.7 Hz, 1 H, CHHCO2tBu), 4.26Ϫ4.44 (m, 2
H), 4.67 (d, J ϭ 5.1 Hz, 1 H, CHOallyl), 5.18Ϫ5.36 (m, 2 H, CH2ϭ
CH), 5.87 (ddt, J ϭ 10.6, 16.6, 5.3 Hz, 1 H, CHϭCH2) ppm. 13C
NMR (50 MHz): δ ϭ 25.24 and 26.93 [(CH3)2C], 28.06 [(CH3)3C],
43.03 (CH2N), 60.50 (CHN), 66.70 and 72.018 (CH2O), 76.79
(CHϪO), 81.14 (CHϪO), 82.18 [C(CH3)3], 109.50 (OCO), 117.75
(CHϭCH2), 133.38 (CHϭCH2), 167.03 and 167.62 (CϭO) ppm.
IR: ν˜max ϭ 2984, 2935, 1759 (s), 1597, 1453, 1410, 1394, 1383, 1371,
1298, 1192, 1136, 1069, 1031 cmϪ1
.
(3R*,4R*,4ЈS*)-3-(2-Azidoethoxy)-4-(2,2-dimethyl-1,3-dioxolan-4-
yl)-1-(4-methoxyphenyl)azetidin-2-one (20): This compound was
prepared (solid) in 76% yield from 19 according to the same pro-
cedure employed for 16a. Reaction time of azide substitution: 3 h
at 50 °C. Rf ϭ 0.60 (PE/EtOAc, 50:50). C17H22N4O5 (362.38):
calcd. C 56.34, H 6.12, N 15.46; found C 56.6, H 6.1, N 15.0. GC-
MS: Rt ϭ 10.73; m/z ϭ 362 [Mϩ·] (6.1), 334 [Mϩ· Ϫ 28] (13.6), 306
(7.0), 304 (6.1), 236 (11.0), 233 (10.5), 205 (46.3), 190 (8.8), 185
(8.3), 178 (15.5), 176 (17.7), 175 (8.3), 160 (19.5), 149 (100.0), 136
(17.4), 135 (20.6), 134 (59.8), 123 (17.7), 114 (27.5), 107 (9.1), 107
(8.9), 101 (19.3), 92 (9.0), 77 (16.9), 72 (32.6), 59 (11.9), 44 (16.9),
1334, 1194, 1152, 1067, 1045 990, 930 cmϪ1
.
1
43 (81.3), 42 (16.2), 41 (15.1). H NMR: δ ϭ 1.34 and 1.54 [2 s, 2
(3R*,4R*,4ЈS*)-1-(tert-Butoxycarbonylmethyl)-4-(2,2-dimethyl-1,3-
dioxolan-4-yl)-3-(2-hydroxyethyloxy)azetidin-2-one (23): This com-
pound was prepared from ester 22 (96 mg, 0.280 mmol) according
ϫ 3 H, (CH3)2C], 3.41 and 3.52 (AB part of ABXY system, JAB
ϭ
13.5 Hz, JAX ϭ 3.4 Hz, JAY ϭ 7.2 Hz, JBX ϭ 3.6 Hz, JBY ϭ 5.2 Hz,
2 H, CH2N3), 3.70Ϫ3.90 (m, 2 H), 3.80 (s, 3 H, OCH3), 4.15 (ddd, to the same procedure described for conversion of 18 into 19. Yield:
J ϭ 3.3, 5.3, 10.5 Hz, CHHO), 4.22 (dd, J ϭ 5.6, 8.7 Hz, 1 H, 70 mg (72%) (also 11 mg of the corresponding aldehyde were reco-
CHN), 4.29 (dd, J ϭ 6.8, 8.8 Hz, 1 H, CHHO), 4.39 (dt, J ϭ 8.7, vered). Rf ϭ 0.20 (PE/EtOAc, 30:70). C16H27NO7 (345.39): calcd.
6.4 Hz, 1 H, CHO), 4.69 (d, J ϭ 5.6 Hz, 1 H, CHOCH2), 6.87 (d, C 55.64, H 7.88, N 4.06; found C 55.9, H 8.05, N 3.95. GC-MS:
J ϭ 9.0 Hz, 2 H, aromatics), 7.65 (d, J ϭ 9.1 Hz, 2 H, aromatics)
Rt ϭ 8.78; m/z ϭ 330 [Mϩ·Ϫ15] (3.9), 272 (3.7), 244 (7.0), 214 (7.2),
ppm. IR: ν˜max ϭ 2988, 2934, 2835, 2108 (s), 1742 (s), 1602, 1506, 188 (10.4), 186 (19.8), 158 (10.5), 130 (62.4), 117 (34.5), 113 (7.4),
1463, 1440, 1382, 1338, 1298, 1134, 1061, cmϪ1
.
101 (14.2), 99 (7.6), 87 (19.7), 85 (6.5), 82 (5.6), 73 (100.0), 72
1328
Eur. J. Org. Chem. 2003, 1319Ϫ1336

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
(99.2), 71 (18.2), 70 (13.1), 69 (59.0), 68 (9.9), 59 (10.0), 57 (45.5), aldehyde was taken up in CH2Cl2 (20 mL) and treated with freshly
45 (26.4), 43 (66.6), 42 (19.4), 41 (32.2) 1H NMR: δ ϭ 1.33 and activated powdered molecular sieves (4 A, 1.8 g) and p-anisidine
˚
1.41 [2 s, 2 ϫ 3 H, (CH3)2C], 1.47 [s, 9 H, (CH3)3C], 3.69 [dd, J ϭ (807 mg, 6.56 mmol). After stirring at room temp. for 2.5 h, the
5.2, 8.9 Hz, 1 H, CHHOC(CH3)2], 3.62Ϫ3.94 (m, 3 H), 3.90 (d,
J ϭ 17.8 Hz, 1 H, CHCO2tBu), 3.96 (dd, J ϭ 5.2, 9.4 Hz, 1 H,
suspension was filtered and the filtrate concentrated to give crude
imine (1.94 g) as an oil. This imine was taken up in dry CH2Cl2
(35 mL), cooled to 0 °C, and treated with Et3N (3.93 mL,
CHN), 4.05Ϫ4.20 (m,
2 H), 4.17 (d, J ϭ 17.7 Hz, 1 H,
CHHCO2tBu), 4.37 (ddd, J ϭ 5.2, 6.5, 9.2 Hz, 1 H, CHOC(CH3)2], 28.21 mmol) and then (through a dropping funnel during 1 h) with
4.71 (d, J ϭ 5.2 Hz, 1 H, CHOCH2) ppm.
a solution of allyloxyacetyl chloride (1.84 g, 13.70 mmol) in dry
CH2Cl2 (25 mL). After stirring at room temp. overnight, the mix-
ture was poured into aqueous (NH4)H2PO4 (5%, 70 mL) and ex-
tracted with CH2Cl2. The organic extracts were washed with satu-
rated aqueous NaCl, concentrated and chromatographed twice
(PE/EtOAc, 50:50) to give 27 (1.578 g, 63%), about 80% pure by
NMR (real yield 51%). Rf ϭ 0.56 (PE/EtOAc, 50:50). GC-MS:
Rt ϭ 12.23; m/z ϭ 383 [Mϩ·] (6.0), 312 (14.9), 149 (93.2), 148 (8.2),
134 (22.8), 91 (100.0), 77 (6.0), 71 (8.5), 65 (5.7), 41 (21.9). 1H
NMR: δ ϭ 3.78 (OCH3), 3.93 and 3.99 (AB part of ABX system,
JAB ϭ 10.9 Hz, JAX ϭ 4.7 Hz, JBX ϭ 6.0 Hz, 2 H, CH2O),
4.15Ϫ4.50 (m, 3 H), 4.53 (s, 2 H, CH2Ph), 4.78 (s, 2 H, OCH2O),
4.79 (d, J ϭ not determined, 1 H, CHOallyl), 6.86 (d, J ϭ 9.1 Hz,
2 H, aromatics), 7.20Ϫ7.40 (m, 5 H, aromatics), 7.48 (d, J ϭ
9.1 Hz, 2 H, aromatics) ppm.
(3R*,4R*,4ЈS*)-3-(2-Azidoethyloxy)-1-(tert-butoxycarbonylmethyl)-
4-(2,2-dimethyl-1,3-dioxolan-4-yl)azetidin-2-one (24): This com-
pound was prepared in 67% yield from alcohol 23 following the
same procedure employed for 16a. Reaction time of azide substi-
tution: 4 h at 50 °C and overnight at room temp. Rf ϭ 0.58 (PE/
EtOAc, 30:70). C16H26N4O6 (370.40): calcd. C 51.88, H 7.08, N
1
15.13; found C 52.1, H 7.2, N 14.75. H NMR: δ ϭ 1.32 and 1.41
[2 s, 2 ϫ 3 H, (CH3)2C], 1.47 [s, 9 H, (CH3)3C], 3.32 (ddd, J ϭ 3.3,
5.2, 13.5 Hz, 1 H, CHHN3), 3.48 (ddd, J ϭ 3.2, 7.6, 13.5 Hz, 1 H,
CHHN3), 3.71 [dd, J ϭ 4.9, 9.0 Hz, 1 H, CHHOC(CH3)2], 3.77
(ddd, J ϭ 3.2, 7.6, 10.5 Hz, 1 H, N3CH2CHH), 3.89 (d, J ϭ
17.8 Hz, 1 H, CHCO2tBu), 3.92 (dd, J ϭ 5.2, 9.4 Hz, 1 H, CHN),
4.08 (ddd, J ϭ 3.2, 5.2, 10.5 Hz, 1 H, N3CH2CHH), 4.13 [dd, J ϭ
6.6, 9.0 Hz, 1 H, CHHOC(CH3)2], 4.18 (d, J ϭ 17.8 Hz, 1 H,
CHCO2tBu) 4.38 [ddd, J ϭ 4.9, 6.6, 9.4 Hz, 1 H, CHOC(CH3)2],
4.66 (d, J ϭ 5.2 Hz, 1 H, CHOCH2) ppm. 13C NMR (50 MHz):
δ ϭ 25.11 and 26.94 [(CH3)2C], 28.04 [(CH3)3C], 43.11 (CH2N),
50.73 (CH2N), 60.17 (CHN), 66.66 and 70.29 (CH2O), 76.57
(CHO), 82.08 [C(CH3)3], 82.28 (CHO), 109.59 (OCO), 166.99 and
167.04 (CϭO) ppm. IR: ν˜max ϭ 2983, 2934, 2109 (s), 1757 (s), 1601,
1408, 1394, 1383, 1371, 1337, 1286, 1246, 1151, 1113, 1062, 951
(3R*,4S*)-4-[(Benzyloxymethoxy)methyl]-3-(2-hydroxyethyloxy)-1-
(4-methoxyphenyl)azetidin-2-one (28): This compound was pre-
pared from 80% pure 27 in 62% yield (77% taking into account
the purity of starting material) using the same procedure already
described for the synthesis of 19. Rf ϭ 0.40 (EtOAc). C21H25NO6
(387.43): calcd. C 65.10, H 6.50, N 3.62; found C 64.65, H 6.8, N
3.3. GC-MS: Rt ϭ 13.23; m/z ϭ 387 [Mϩ·] (8.3), 357 (6.5), 286
(6.3), 178 (6.1), 149 (100.0), 148 (11.9), 134 (21.0), 91 (97.1), 77
(8.3), 73 (39.4), 70 (8.5), 65 (6.5), 57 (9.3), 45 (17.9). 1H NMR: δ ϭ
3.62 (broad s, 1 H, OH), 3.78 (s, 3 H, OCH3), 3.70Ϫ3.90 (m, 4 H,
cmϪ1
.
Allyloxymethyl Benzyl Ether (26): A solution of Et3N (8.02 mL,
57.52 mmol) in dry CH3CN (50 mL) was cooled to 0 °C and
treated, by addition through a dropping funnel, with freshly dis-
tilled benzyl chloromethyl ether (8.0 mL, 57.52 mmol). Then the
mixture was stirred for 2 h at room temp. Allyl alcohol (4.89 mL,
71.9 mmol) was added and the mixture heated under reflux for 5 h.
On cooling an abundant white precipitate was formed. The suspen-
sion was filtered and the precipitate washed with Et2O/PE (1:1,
120 mL). The filtrate was diluted with aqueous (NH4)H2PO4 (5%,
65 mL). The phases were separated and the organic one washed
with (NH4)H2PO4 (5%), and the solvents evaporated to dryness.
The crude oil was distilled at 6 ϫ 10Ϫ2 mbar to give pure 26 (6.73 g,
67%). B.p. 65Ϫ70 °C. C11H14O2 (178.23): calcd. C 74.13, H 7.92;
found C 74.2, H 7.9. GC-MS: Rt ϭ 4.07; m/z ϭ 177 [Mϩ·] (0.02),
148 (4.1), 120 (5.7), 119 (6.7), 107 (14.3), 92 (53.3), 91 (100), 79
(9.1), 77 (8.4), 65 (14.5), 51 (6.7), 41 (31.6), 39 (15.8). 1H NMR:
δ ϭ 4.13 (dt, J ϭ 5.6, 1.4 Hz), 4.63 (CH2Ph), 4.79 (OCH2O), 5.20
(dq, J ϭ 10.4, 1.4 Hz, 1 H, CHHϭCH), 5.31 (dq, J ϭ 17.2, 1.6 Hz,
1 H, CHHϭCH), 5.94 (ddt, J ϭ 10.4, 17.2, 5.7 Hz, 1 H, CHϭ
CH2), 7.25Ϫ7.40 (m, 5 H, aromatics) ppm. 13C NMR (20 MHz):
δ ϭ 68.51 and 69.48 (CH2O), 93.89 (OϪCϪO), 117.14 (CH2ϭCH),
127.69, 127.87, 128.42 (aromatic CH), 134.35 (CHϭCH2), 137.89
(aromatic quat.) ppm.
HOCH2CH2O), 3.95 and 4.02 (AB part of ABX system, JAB
ϭ
11.0 Hz, JAX ϭ 5.0 Hz, JBX ϭ 5.5 Hz, 2 H, CH2OBOM), 4.40 (q,
J ϭ 5.3 Hz, 1 H, CHϪN), 4.54 (s, 2 H, CH2Ph), 4.78 (s, 2 H,
OCH2O), 4.81 (d, J ϭ 5.2 Hz, 1 H, CHO), 6.87 (d, J ϭ 9.0 Hz, 2
H, aromatics), 7.25Ϫ7.36 (m, 5 H, aromatics), 7.46 (d, J ϭ 9.0 Hz,
2 H, aromatics) ppm. 13C NMR (50 MHz): δ ϭ 55.48 (OCH3),
58.13 (CHϪN), 62.22 (CH2O), 65.40 (CH2O), 69.73 (CH2O), 74.80
(CH2O), 82.12 (CHO), 94.89 (OCH2O), 114.35, 119.05, 127.85,
128.46 (aromatic CH), 130.40, 137.44, 156.62 (aromatic quat.),
165.59 (CϭO) ppm. IR: ν˜max ϭ 3433 (broad), 2998, 2938, 1742 (s),
1613, 1504, 1454, 1395, 1299, 1196, 1138, 1113, 1040 cmϪ1
.
(3R*,4S*)-3-(2-Azidoethyloxy)-4-[(benzyloxymethoxy)methyl]-1-(4-
methoxyphenyl)azetidin-2-one (29): This compound was prepared in
58% yield from alcohol 28 according to the same procedure em-
ployed for 16a. Reaction time of azide substitution: 4 h at 50 °C
and overnight at room temp. Rf ϭ 0.37 (PE/EtOAc, 60:40).
C21H24N4O5 (412.44): calcd. C 61.15, H 5.87, N 13.58; found C
61.5, H 6.0, N 13.05. 1H NMR: δ ϭ 3.37 (ddd, J ϭ 3.5, 5.1,
13.3 Hz, 1 H, CHHN3), 3.54 (ddd, J ϭ 3.5, 7.4, 13.3 Hz, 1 H,
CHHN3), 3.78 (s, 3 H, OCH3), 3.80Ϫ4.10 (m, 4 H, CH2O), 4.38
(q, J ϭ 5.3 Hz, 1 H, CHN), 4.53 (s, 2 H, CH2Ph), 4.77 (d, J not
determined, 1 H, CHO), 4.78 (s, 2 H, OCH2O), 6.86 (d, J ϭ 9.1 Hz,
2 H, aromatics), 7.25Ϫ7.40 (m, 5 H, aromatics), 7.48 (d, J ϭ
(3R*,4S*)-4-[(Benzyloxymethoxy)methyl]-1-(4-methoxyphenyl)-3-
(2-propenyloxy)azetidin-2-one (27): A solution of ether 26 (1.17 g,
6.56 mmol) in dry CH2Cl2 (14 mL) and dry MeOH (21 mL) was 9.0 Hz, 2 H, aromatics) ppm. 13C NMR (50 MHz): δ ϭ 50.71
cooled to Ϫ78 °C and ozonized until the grey-blue color persisted.
At this point, Me2S (1.5 mL) was added. The solution was stirred
at room temp. for 5 h and then concentrated to dryness and chrom-
atographed (PE/Et2O, 20:80 to 0:100) to give the aldehyde (1.268 g)
as an oil. The weight higher than expected is due to the presence
of mixed hemiacetal adducts with formaldehyde. In any case, this
(CH2N3), 55.48 (OCH3), 57.46 (CHN), 65.81 (CH2O), 69.64
(CH2O), 70.60 (CH2O), 81.50 (CHO), 94.94 (OCH2O), 114.28,
119.04, 127.76, 127.82, 128.43 (aromatic CH), 130.65, 137.60,
156.52 (aromatic quat.), 163.99 (CϭO) ppm. IR: ν˜max ϭ 2999,
2935, 2887, 2837, 2107 (s), 1745 (s), 1609, 1503, 1463, 1441, 1386,
1341, 1298, 1191, 1135, 1113, 1042 cmϪ1
.
Eur. J. Org. Chem. 2003, 1319Ϫ1336
1329

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
(3R*,4R*)-4-(Hydroxymethyl)-1-(4-methoxyphenyl)-3-vinylazetidin-
2-one (32): A suspension of finely ground anhydrous CaCl2
(536 mg, 4.83 mmol) in dry THF (15 mL) and absolute EtOH
(7.5 mL) was cooled to Ϫ20 °C, and treated with NaBH4 (308 mg,
8.14 mmol). After stirring for 15 min, a solution of racemic β-lac-
tam 31[19] (397 mg, 1.52 mmol) in dry THF (15 mL) was slowly
added during 5 min. The suspension was stirred at Ϫ20 °C for
15 min, and at 0 °C for 6 h. The reaction was quenched with satu-
rated aqueous NH4Cl and extracted with EtOAc. The organic
phase was washed with saturated NaCl, concentrated and chroma-
tographed (PE/EtOAc, 50:50) to give pure 32 as an oil (276 mg,
76%). Rf ϭ 0.32 (PE/EtOAc, 50:50). C13H15NO3 (233.26): calcd. C
66.94, H 6.48, N 6.00; found C 66.7, H 6.5, N 5.8. GC-MS: Rt ϭ
8.62; m/z ϭ 233 [Mϩ·] (6.1), 174 (1.5), 165 (1.7), 149 (100.0), 136
(10.5), 134 (38.7), 106 (5.1), 92 (6.2), 78 (4.8), 77 (10.2), 64 (5.4),
55 (4.5), 41 (4.6), 39 (7.6). 1H NMR: δ ϭ 3.78 (s, 3 H, OCH3), 3.97
(d, J ϭ 4.8 Hz, 2 H, CH2OH), 4.06 (mc) (m, 1 H, CHCHϭCH2,
on decoupling at 6.02 ppm, it becomes a d, J ϭ 5.5 Hz), 4.28 (q,
J ϭ 5.2 Hz, 1 H, CHN), 5.38 (dt, J ϭ 10.3, 1.0 Hz, 1 H, CHHϭ
CH), 5.48 (dt, J ϭ 17.2, 1.0 Hz, 1 H, CHHϭCH), 6.02 (ddd, J ϭ
8.0, 10.3, 17.2 Hz, 1 H, CHϭCH2), 6.86 (d, J ϭ 9.0 Hz, 2 H, aro-
matics), 7.42 (d, J ϭ 9.0 Hz, 2 H, aromatics) ppm.
ν˜max ϭ 3442 (broad), 3046, 2997, 2936, 1726 (s), 1603, 1504, 1454,
1440, 1396, 1298, 1193, 1111, 1046, 961 cmϪ1
.
(3R*,4R*)-3-(2-Azidoethyl)-4-[(benzyloxymethoxy)methyl]-1-(4-
methoxyphenyl)azetidin-2-one (35): This compound was prepared in
94% yield from alcohol 34 according to the same procedure em-
ployed for 16a. Reaction time of azide substitution: 3 h at 50 °C
and overnight at room temp. Rf ϭ 0.71 (PE/EtOAc, 30:70).
C21H24N4O4 (396.44): calcd. C 63.62, H 6.10, N 14.13; found C
63.95, H 6.3, N 13.8. GC-MS: Rt ϭ 13.50 (it decomposes in part);
m/z ϭ 368 [Mϩ· Ϫ 28] (3.2), 286 (8.5), 256 (4.7), 245 (5.3), 164
(7.3), 149 (28.3), 148 (7.9), 134 (24.4), 113 (14.4), 108 (7.4), 107
(6.9), 98 (17.0), 96 (9.6), 91 (100.0), 83 (9.9), 82 (17.1), 77 (11.3),
65 (7.4) 1H NMR: δ ϭ 1.87Ϫ2.24 (m, 2 H, CH2CH2N3), 3.40Ϫ3.70
(m, 3 H, CH2N3 and CHCϭO), 3.77 (s, 3 H, OCH3), 3.91 (d, J ϭ
5.0 Hz, 2 H, CH2OBOM), 4.28 (q, J ϭ 5.2 Hz, 1 H, CHN), 4.45
(s, 2 H, CH2Ph), 4.71 and 4.75 (AB system, J ϭ6.9 Hz, 2 H,
OCH2O), 6.85 (d, J ϭ 9.1 Hz, 2 H, aromatics), 7.20Ϫ7.38 (m, 5 H,
aromatics), 7.39 (d, J ϭ 9.1 Hz, 2 H, aromatics) ppm. 13C NMR
(20 MHz): δ ϭ 24.65 (CH2CH2N3), 48.64, 49.79 and 53.95 (CH2N,
CHCϭO, and CHN), 55.47 (OCH3), 65.36, 69.88 (CH2O), 94.90
(OCH2O), 114.31, 118.70, 127.74, 128.35 (aromatic CH), 130.91,
137.38, 156.12 (aromatic quat.), 166.25 (CϭO) ppm. IR: ν˜max
3005, 2938, 2100 (s), 1739 (s), 1506, 1454, 1394, 1297, 1192, 1111,
1045, 907 cmϪ1
ϭ
(3R*,4R*)-4-{[(Benzyloxy)methoxy]methyl}-1-(4-methoxyphenyl)-3-
vinylazetidin-2-one (33): This compound was prepared in 85% yield
from 32 according to the same procedure reported for 15. Rf ϭ
0.55 (PE/EtOAc, 50:50). C21H23NO4 (353.41): calcd. C 71.37, H
.
General Procedure for Reduction of Azides 16a؊d, 20, 24, 29 and
35 to Amines 2a؊d, 3a؊c and 4: A solution of azide (0.2 mmol) in
THF (5 mL) was treated at room temp. with Ph3P (0.4 mmol) and,
after 10 min, with H2O (250 µL). After stirring for 15 h, the solu-
tion was diluted with CH2Cl2, dried (Na2SO4), concentrated to dry-
ness, and chromatographed [CHCl3 to CHCl3/MeOH, 9:1 ϩ 2%
iPr2NH]. The amines always contained small percentages of the
corresponding transamidated products. Therefore elemental analy-
ses were not performed on these products. They were used at once
for the following reactions or else kept in a freezer for a minimum
amount of time. They were characterized by transformation into
acetamides or phenylacetamides.
1
6.56, N 3.96; found C 71.0, H 6.7, N 3.75. H NMR: δ ϭ 3.77 (s,
3 H, OCH3), 3.84 and 3.88 (AB part of ABX system, JAB
ϭ
11.0 Hz, JAX ϭ 4.6 Hz, JBX ϭ 5.7 Hz, 2 H, CH2OBOM), 4.07 (mc)
(m, 1 H, CHCHϭCH2), 4.32 (q, J ϭ 5.4 Hz, 1 H, CHN), 5.35 (dt,
J ϭ 10.3, 1.3 Hz, 1 H, CHHϭCH), 5.48 (dt, J ϭ 17.2, 1.4 Hz, 1
H, CHHϭCH), 5.94 (ddd, J ϭ 8.0, 10.3, 17.2 Hz, 1 H, CHϭCH2),
6.86 (d, J ϭ 9.1 Hz, 2 H, aromatics), 7.18Ϫ7.40 (m, 5 H, aro-
matics), 7.45 (d, J ϭ 9.1 Hz, 2 H, aromatics) ppm. IR: ν˜max ϭ 3085,
2999, 2937, 2890, 2837, 1738 (s), 1500, 1454, 1441, 1382, 1297,
1193, 1169, 1112, 1043, 989, 928 cmϪ1
.
(3R*,4R*)-4-[(Benzyloxymethoxy)methyl]-3-(2-hydroxyethyl)-1-(4-
methoxyphenyl)azetidin-2-one (34): A solution of compound 33
(176 mg, 0.497 mmol) in dry THF (8 mL) was cooled to 0 °C and
treated with solid 9-borabicyclononane (186 mg, 1.52 mmol). The
resulting solution was stirred at room temp. for 5 h and then cooled
again to 0 °C and treated with a solution of KHCO3 (1.5 g) and
35% H2O2 (2.1 mL) in H2O (2.1 mL). After stirring for 1 h at room
temp., the mixture was diluted with H2O and extracted with
EtOAc. The organic phase was washed with saturated NaCl, con-
centrated and chromatographed (PE/EtOAc, 30:70 to 10:90) to give
pure 34 (134 mg, 72%). Rf ϭ 0.41 (EtOAc). C21H25NO5 (371.43):
calcd. C 67.91, H 6.78, N 3.77; found C 68.2, H 6.7, N 3.5. GC-MS:
Rt ϭ 13.38 (during GC, 34 in part isomerizes to the corresponding
lactone, Rt ϭ 12.74); m/z ϭ 371 [Mϩ·] (16.8), 341 (17.2), 310 (12.5),
232 (5.8), 220 (45.6), 186 (5.7), 164 (5.3), 149 (28.9), 148 (7.0), 134
General Procedure for Rearrangement of Amines 2a؊d, 3a؊c and
4: The amines were dissolved in the solvent indicated in Table 1,
and stirred at the appropriate temperature. Small aliquots of the
crude reaction mixtures were taken from time to time, rapidly con-
centrated, taken up in CDCl3 and examined by 1H NMR spec-
troscopy. Integration of the developing amide NH unit allowed the
conversion to be estimated in all cases . In most cases other signals
could also be used for integration. For a control, a spectrum was
taken also of the starting amine at the beginning of the reaction,
in order to evaluate the amount of transamidated product already
present. At the end of reaction, the solvent was evaporated and the
transamidated product purified by chromatography (CHCl3/
MeOH).
rac-1-(2-Aminoethyl)-4-[(benzyloxymethoxy)methyl]azetidin-2-one
(32.2), 107 (6.1), 91 (100.0), 77 (9.7), 65 (7.1). 1H NMR: δ ϭ (2a): Rf ϭ 0.22 and 0.29 (CHCl3/MeOH, 95:5). 1H NMR: δ ϭ 2.70
1.84Ϫ2.20 (m, 2 H, CH2CH2OH), 3.46 (dt, J ϭ 10.4, 5.8 Hz, 1 H,
CHCϭO), 3.78 (s, 3 H, OCH3), 3.75Ϫ3.90 (m, 2 H, CH2OH), 3.91
(dd, J ϭ 1.8, 14.4 Hz, 1 H, CHHCϭO), 2.90 (t, J ϭ 6.0 Hz, 2 H,
CH2NH2), 2.99 (dd, J ϭ 4.7, 14.4 Hz, 1 H, CHHCϭO), 3.15Ϫ3.50
(d, J ϭ 5.4 Hz, 2 H, CH2OBOM), 4.31 (q, J ϭ 5.4 Hz, 1 H, CHN), (m, 2 H), 3.56Ϫ3.86 (m, 3 H), 4.61 (s, 2 H, CH2Ph), 4.79 (s, 2
4.46 (s, 2 H, CH2Ph), 4.72 and 4.75 (AB system, J ϭ 6.9 Hz, 2 H, H, OCH2O), 7.34 (s, 5 H, aromatics) ppm. This amine was better
OCH2O), 6.86 (d, J ϭ 9.1 Hz, 2 H, aromatics), 7.20Ϫ7.38 (m, 5 H,
characterized as the corresponding acetamide, which was obtained
in 90% yield by reaction with Et3N (3.3 equiv.) and Ac2O (2 equiv.)
aromatics), 7.41 (d, J ϭ 9.1 Hz, 2 H, aromatics) ppm. 13C NMR
(50 MHz): δ ϭ 27.85 (CH2CH2OH), 50.06 (CHCϭO), 53.95 in dry CH2Cl2 at 0 °C. The reaction was complete in 4 h. Workup
(CHϪN), 55.49 (OCH3), 61.47, 65.75, 69.85 (CH2O), 94.93 with saturated aqueous NH4Cl followed by extraction with EtOAc,
(OCH2O), 114.38, 118.96, 127.80, 127.84, 128.45 (aromatic CH),
130.94, 137.48, 156.41 (aromatic quat.), 167.91 (CϭO) ppm. IR:
concentration and chromatography (EtOAc/MeOH, 80:20), gave
the acetamide of 2a. Rf 0.55 (EtOAc/MeOH, 80:20).
ϭ
1330
Eur. J. Org. Chem. 2003, 1319Ϫ1336

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
C16H22N2O4 (306.36): calcd. C 62.73, H 7.24, N 9.14; found C 63.0,
9.3. GC-MS: Rt ϭ 9.98; m/z ϭ 294 [Mϩ·] (11.2), 279 (5.0), 249 (4.7),
H 7.4, N 8.95. GC-MS: Rt ϭ 10.49; m/z ϭ 278 [Mϩ· Ϫ 28] (0.1), 173 (7.0), 171 (5.9), 157 (5.4), 143 (14.7), 100 (11.4), 91 (100.0), 86
247 (0.1), 235 (0.2), 217 (1.3), 155 (1.8), 141 (8.7), 132 (3.6), 114 (7.6), 85 (6.4), 72 (7.8), 71 (7.9), 65 (6.1), 56 (6.8), 44 (8.8), 42 (5.3),
1
(5.1), 113 (4.1), 91 (100.0), 86 (7.9), 72 (6.4), 65 (5.2), 44 (8.9), 43 41 (5.1). H NMR: δ ϭ 2.75Ϫ2.90 (m, 1 H), 2.90Ϫ3.07 (m, 1 H),
1
(14.0), 41 (6.8). H NMR: δ ϭ 1.97 (s, 3 H, CH3CϭO), 2.67 (dd, 3.09Ϫ3.23(m, 2 H), 3.47 (s, 3 H, OCH3), 3.60 (d, J ϭ 7.0 Hz, 2 H,
J ϭ 2.2, 14.5 Hz, 1 H, CHHCϭO), 2.96 (dd, J ϭ 4.8, 14.5 Hz, 1
H, CHHCϭO), 3.18Ϫ3.46 (m, 3 H), 3.46Ϫ3.72 (m, 2 H),
CH2OBOM), 3.54Ϫ3.80 (m, 1 H), 3.85 (d, J ϭ 1.5 Hz, 1 H,
CHOMe), 4.60 (s, 2 H, CH2Ph), 4.78 (s, 2 H, OCH2O), 6.55 (br. s,
3.76Ϫ3.88 (m, 2 H), 4.61 (s, 2 H, CH2Ph), 4.79 (s, 2 H, OCH2O), 1 H, CONH), 7.34 (s, 5 H, aromatics) ppm. 13C NMR (50 MHz):
6.54 (br. s, 1 H, NH), 7.34 (s, 5 H, aromatics) ppm. IR: ν˜max
3442, 3357, 2997, 2932, 1737 (s), 1665 (s), 1513, 1402, 1376, 1331,
1240, 1168, 1111, 1040 cmϪ1
ϭ
δ ϭ 43.77 (CH2N), 49.48 (CH2N), 56.42 (CHN), 57.90 (OCH3),
68.83, 69.60 (CH2O), 84.46 (CHOMe), 94.94 (OCH2O), 127.71,
127.83, 128.42 (aromatic CH), 137.76 (aromatic quat.), 174.81 (Cϭ
O) ppm. IR: ν˜max ϭ 3409, 2998, 2941, 1663 (s), 1467, 1424, 1350,
.
rac-7-[(Benzyloxymethoxy)methyl]-1,4-diazepan-5-one (17a): Rf
ϭ
1249, 1192, 1102, 1042 cmϪ1
.
0.63 (CHCl3/MeOH, 95:5). C14H20N2O3 (264.32): calcd. C 63.62,
H 7.63, N 10.60; found C 63.95, H 7.9, N 10.35. 1H NMR: δ ϭ
2.40 (dt, J ϭ 14.2, 1.6 Hz, 1 H, CHHCϭO), 2.59 (dd, J ϭ 9.8,
14.2 Hz, 1 H, CHHCϭO), 2.84 (dd, J ϭ 9.9, 11.8 Hz, 1 H,
CHHN), 2.98Ϫ3.28 (m, 3 H), 3.34Ϫ3.52 (m, 1 H), 3.44 (dd, J ϭ
8.6, 9.6 Hz, 1 H, CHHOBOM), 3.61 (dd, J ϭ 3.9, 9.6 Hz, CHHO-
BOM), 4.60 (s, 2 H, CH2Ph), 4.76 and 4.79 (AB system, J ϭ 6.7 Hz,
2 H, OCH2O), 6.01 (br. s, 1 H, NH), 7.35 (s, 5 H, aromatics) ppm.
13C NMR (50 MHz): δ ϭ 42.43, 44.68, 49.60 (CH2), 53.37 (CHN),
69.69 and 71.80 (CH2O), 94.89 (OCH2O), 127.80, 127.84, 128.45
(aromatic CH), 137.48 (aromatic quat.), 176.34 (CϭO) ppm. IR:
ν˜max ϭ 3416, 2998, 2926, 2891, 2824, 1660 (s), 1601, 1466, 1438,
(3R*,4S*)-1-(2-Aminoethyl)-4-[(benzyloxymethoxy)methyl]-3-phen-
oxyazetidin-2-one (2d): Rf ϭ 0.36 and 0.40 (CHCl3/MeOH, 95:5 ϩ
1% Et3N). 1H NMR: δ ϭ 2.80Ϫ3.14 (m, 2 H), 3.20Ϫ3.55 (m, 2 H),
3.85, 3.93 (AB part of ABX system, JAB ϭ 10.8 Hz, JAX ϭ 3.8 Hz,
JBX ϭ 7.7 Hz, 2 H, CH2OBOM), 4.11 (dt, J ϭ 7.4, 4.4 Hz, 1 H,
CHN), 4.55 (s, 2 H, CH2Ph), 4.74 (s, 2 H, OCH2O), 5.31 (d, J ϭ
4.8 Hz, 1 H, CHOPh), 6.90Ϫ7.05 (m, 3 H), 7.20Ϫ7.35 (m, 7 H).
(6R*,7S*)-7-[(Benzyloxymethoxy)methyl]-6-phenoxy-1,4-diazepan-
5-one (17d): Rf
ϭ 0.50 (CHCl3/MeOH, 90:10). C20H24N2O4
(356.42): calcd. C 67.40, H 6.79, N 7.86; found C 67.7, H 6.6, N
7.8. GC-MS: Rt ϭ 12.35; m/z ϭ 356 [Mϩ·] (9.3), 235 (5.4), 188
(5.3), 141 (4.0), 129 (6.1), 119 (5.5), 112 (27.3), 107 (4.4), 105 (6.1),
99 (60.0), 91 (100.0), 85 (7.7), 84 (8.0), 83 (5.5), 77 (11.2), 71 (18.0),
1375, 1351, 1326, 1240, 1167, 1116, 1040, 963, 907 cmϪ1
.
(3R*,4S*)-1-(2-Aminoethyl)-3-methoxy-4-(2-phenylethenyl)azetidin-
2-one (2b): Rf ϭ 0.10 (CHCl3/MeOH, 95:5). 1H NMR: δ ϭ
2.70Ϫ3.30 (m, 4 H, CH2CH2), 3.45 (s, 3 H, OCH3), 4.37 (dd, J ϭ
4.3, 9.2 Hz, 1 H, CHCHϭCH), 4.67 (d, J ϭ 4.3 Hz, 1 H, CHOMe),
6.24 (dd, J ϭ 9.2, 16.0 Hz, 1 H, CHϭCHPh), 6.75 (d, J ϭ 16.0 Hz,
1 H, CHϭCHPh), 7.22Ϫ7.50 (m, 5 H, aromatics) ppm. This amine
was better characterized as the corresponding phenylacetamide 37
(see below), which was prepared in 92% yield by treating 2b, iso-
lated soon after chromatography, with phenylacetyl chloride and
Et3N in CH2Cl2.
1
65 (9.2), 56 (9.4), 55 (8.4), 44 (10.5), 43 (4.7), 42 (5.1), 39 (5.1). H
NMR: δ ϭ 2.83Ϫ3.06 (m, 2 H), 3.18Ϫ3.50 (m, 2 H), 3.54Ϫ3.88
(m, 3 H), 4.49 (s, 2 H, CH2Ph), 4.74 (s, 2 H, OCH2O), 4.79 (d, J ϭ
1.5 Hz, 1 H, CHOPh), 6.20 (br. s, 1 H, NH), 6.95Ϫ7.15 (m, 3 H),
7.18Ϫ7.36 (m, 7 H) ppm. 13C NMR (50 MHz): δ ϭ 44.09 (CH2N),
49.50 (CH2N), 56.42 (CHN), 68.39, 69.64 (CH2O), 80.23
(CHOMe), 94.89 (OCH2O), 115.75, 122.14, 127.67, 127.84, 128.39,
129.76 (aromatic CH), 137.75, 157.58 (aromatic quat.), 173.97 (Cϭ
O) ppm. IR: ν˜max ϭ 3410, 2998, 2940, 1666 (s), 1597, 1468, 1349,
1240, 1169, 1115, 1042 cmϪ1
.
(6R*,7S*)-Methoxy-7-(2-phenylethenyl)-1,4-diazepan-5-one (17b):
Rf ϭ 0.39 (CHCl3/MeOH, 95:5). C14H18N2O2 (246.30): calcd. C
68.27, H 7.37, N 11.37; found C 68.0, H 7.4, N 11.1. GC-MS: Rt ϭ
8.88; m/z ϭ 246 [Mϩ·] (3.8), 231 (43.0), 217 (18.6), 204 (26.2), 203
(8.4), 185 (24.3), 172 (18.6), 160 (94.7), 159 (67.7), 157 (32.9), 156
(51.7), 145 (25.3), 144 (31.2), 132 (31.3), 129 (63.2), 128 (39.7), 127
(3R*,4R*,4ЈS*)-3-(2-Aminoethoxy)-4-(2,2-dimethyl-1,3-dioxolan-4-
yl)-1-(4-methoxyphenyl)azetidin-2-one (3a): Rf ϭ 0.21 and 0.33
(CHCl3/MeOH, 75:25). 1H NMR: δ ϭ 1.34, 1.53 [2 s, 2 ϫ 3 H,
(CH3)2CO], 2.80Ϫ3.07 (m, 2 H, CH2NH2), 3.64Ϫ3.80 (m, 1 H,
CH2CHHO), 3.76 (dd, J ϭ 6.2, 8.6 Hz, 1 H, CHCHHO), 3.79 (s,
3 H, OCH3), 3.84Ϫ3.96 (m, 1 H, CH2CHHO), 4.21 (dd, J ϭ 5.5,
8.7 Hz, 1 H, CHN), 4.26 (dd, J ϭ 6.7, 8.6 Hz, 1 H, CHCHHO),
4.40 (dt, J ϭ 8.6, 6.5 Hz, 1 H, CHO), 4.68 (d, J ϭ 5.5 Hz, 1 H,
CHOCH2), 6.86 (d, J ϭ 9.1 Hz, 2 H, aromatics ortho to OCH3),
7.65 (d, J ϭ 9.1 Hz, 2 H, aromatics meta to OCH3). This com-
pound was best characterized as the acetamide, which was obtained
in quantitative yield by reaction with Et3N (3.3 equiv.) and Ac2O
(2 equiv.) in dry CH2Cl2 at 0 °C. C19H26N2O6 (378.42): calcd. C
60.30, H 6.93, N 7.40; found C 60.55, H 7.05, N 7.2. GC-MS: Rt ϭ
11.80; m/z ϭ 378 [Mϩ·] (21.7), 320 (7.7), 165 (11.8), 160 (5.7), 149
(74.6), 136 (7.1), 135 (7.1), 134 (12.7), 101 (6.5), 86 (100.0), 72
1
(25.4), 117 (58.3), 115 (100.0), 91 (45.4), 44 (33.2). H NMR: δ ϭ
2.84Ϫ3.10 (m, 3 H), 3.24 (dd, J ϭ 4.8, 14.2 Hz, 1 H), 3.51 (s, 3 H,
OCH3), 3.62Ϫ3.84 (m, 1 H), 3.71 (d, J ϭ 6.5 Hz, 1 H, CHN), 3.90
(s, 1 H, CHOMe), 6.10 (br. s, 1 H, CONH), 6.27 (dd, J ϭ 6.4,
16.0 Hz, 1 H, CHϭCHPh), 6.63 (d, J ϭ 16.0 Hz, 1 H, CHϭ
CHPh), 7.22Ϫ7.50 (m, 5 H, aromatics) ppm. 13C NMR (50 MHz):
δ ϭ 43.74 (CH2N), 49.39 (CH2N), 58.16 (OCH3), 58.60 (CHN),
87.75 (CHOMe), 126.48, 127.68, 128.54 (aromatic CH), 129.28,
131.46 (CHϭCH), 136.69 (aromatic quat.), 174.70 (CϭO) ppm.
IR: ν˜max ϭ 3410, 2927, 2852, 1665 (s), 1600, 1464, 1376, 1351, 1260,
1167, 1110, 967, 905 cmϪ1
.
1
(14.4), 44 (31.6), 43 (35.6). H NMR: δ ϭ 1.34, 1.53 [2 s, 2 ϫ 3 H,
(3R*,4S*)-1-(2-Aminoethyl)-4-[(benzyloxymethoxy)methyl]-3-
methoxyazetidin-2-one (2c): Rf ϭ 0.30 (CHCl3/MeOH, 80:20). 1H
NMR: δ ϭ 2.90 (t, J ϭ 6.2 Hz, 2 H, CH2N), 3.12Ϫ3.45 (m, 2 H,
CH2N), 3.53 (s, 3 H, OCH3), 3.70Ϫ3.95 (m, 3 H, CH2O, CHN),
4.53 (d, J ϭ 4.4 Hz, 1 H, CHOMe), 4.62 (s, 2 H, CH2Ph), 4.79 (s,
2 H, OCH2O), 7.35 (s, 5 H, aromatics) ppm.
(CH3)2CO], 2.02 (s, 3 H, CH3CO), 3.30Ϫ3.50 (m, 1 H, CHHNH2),
3.50Ϫ3.80 (m, 3 H, CH2CHHO, CHHNH2, CHCHHO), 3.80 (s, 3
H, OCH3), 3.95 (ddd, J ϭ 3.0, 6.0, 11.2 Hz, 1 H, CH2CHHO), 4.22
(dd, J ϭ 6.8, 8.8 Hz, 1 H, CHCHHO), 4.26 (dd, J ϭ 5.5, 8.5 Hz,
1 H, CHN), 4.37 (dt, J ϭ 9.0, 6.4 Hz, 1 H, CHO), 4.65 (d, J ϭ
5.5 Hz, 1 H, CHOCH2), 6.87 (d, J ϭ 9.1 Hz, 2 H, aromatics ortho
(6R*,7S*)-7-[(Benzyloxymethoxy)methyl]-6-methoxy-1,4-diazepan- to OCH3), 7.64 (d, J ϭ 9.1 Hz, 2 H, aromatics meta to OCH3)
5-one (17c): Rf ϭ 0.72 (CHCl3/MeOH, 80:20). C15H22N2O4
ppm. 13C NMR (50 MHz): δ ϭ 23.21, 24.88, 26.67 (CH3), 40.04
(294.35): calcd. C 61.21, H 7.53, N 9.52; found C 61.4, H 7.6, N (CH2N), 55.49 (OCH3), 62.55 (CHN), 66.89 (CH2O), 72.21
Eur. J. Org. Chem. 2003, 1319Ϫ1336
1331

L. Banfi, G. Guanti, M. Rasparini
MeOH, 75:25). H NMR: δ ϭ 2.88 (ddd, J ϭ 4.3, 5.5, 13.8 Hz, 1
FULL PAPER
(CH2O), 76.92, 81.96 (CHO), 109.92 (OCO), 114.10, 119.76 (aro-
1
matic CH), 130.82, 156.81 (aromatic quat.), 165.77 (CϭO lactam), H, CHHNH2), 2.96 (ddd, J ϭ 4.2, 6.7, 13.8 Hz, 1 H, CHHNH2),
170.48 (H3CϪCϭO) ppm. IR: ν˜max ϭ 3449, 3333, 2991, 2934, 3.63Ϫ3.86 (m, 2 H, OCH2CH2N), 3.78 (s, 3 H, OCH3), 3.93, 3.99
2837, 1734 (s), 1662 (s), 1504, 1455, 1440, 1382, 1297, 1222, 1134,
(AB part of ABX system, JAB ϭ 11.4 Hz, JAX ϭ 5.3, JBX ϭ 6.1, 2
H, CH2OBOM), 4.36 (q, J ϭ 5.4 Hz, 1 H, CHN), 4.53 (s, 2 H,
CH2Ph), 4.75 (d, J ϭ 5.2 Hz, 1 H, CHO), 4.77 (s, 2 H, OCH2O),
6.86 (d, J ϭ 9.1 Hz, 2 H, H ortho to OCH3), 7.23Ϫ7.40 (m, 5 H,
aromatics), 7.48 (d, J ϭ 9.1 Hz, 2 H, H meta to OCH3) ppm.
1066, 905 cmϪ1
.
(3R*,1ЈR*)-2-{[(4S*)-2,2-Dimethyl-1,3-dioxolan-4-yl][4-(methoxy-
phenyl)amino]methyl}morpholin-3-one (25a): Rf ϭ 0.44 (EtOAc/
MeOH, 95:5). C17H24N2O5 (336.38): calcd. C 60.70, H 7.19, N
8.33; found C 60.9, H 6.95, N 8.0. GC-MS: Rt ϭ 11.05; m/z ϭ 336
[Mϩ·] (28.1), 321 (8.6), 236 (100.0), 235 (68.6), 178 (87.9), 174
(12.0), 164 (5.1), 162 (5.4), 161 (8.7), 160 (41.5), 150 (14.4), 149
(10.6), 148 (28.1), 136 (23.4), 134 (26.3), 133 (11.9), 123 (8.5), 122
(17.5), 121 (15.8), 108 (9.4), 107 (6.4), 102 (6.1), 101 (9.9), 77 (11.1),
(2R*,1ЈS*)-2-{2-(Benzyloxymethoxy)-1-[(4-methoxyphenyl)amino]-
ethyl}morpholin-3-one (25c): Rf ϭ 0.75 (CHCl3/MeOH, 75:25).
C21H26N2O5 (386.44): calcd. C 65.27, H 6.78, N 7.25; found C
65.55, H 6.6, N 7.2. GC-MS: Rt ϭ 15.09; m/z ϭ 386 [Mϩ·] (7.5),
286 (35.2), 235 (13.9), 180 (4.4), 178 (9.4), 165 (9.0), 148 (20.6), 136
1
1
72 (12.4), 44 (16.1), 43 (33.5). H NMR: δ ϭ 1.37, 1.41 (2 s, 2 ϫ 3
(6.7), 134 (9.3), 133 (7.1), 122 (5.9), 91 (100.0), 44 (6.1). H NMR:
H, CH3), 3.15 (br. dt, J ϭ 11.9, 2.9 Hz, 1 H, CHHN), 3.50 (dt, J ϭ
4.0, 11.7 Hz, 1 H, CHHN), 3.72 (s, 3 H, CH3O), 3.73 (dt, J ϭ 2.9,
11.3 Hz, CH2ϪCHHO), 3.86 (t, J ϭ 7.9 Hz, 1 H, CHCHHO), 4.00
(dd, J ϭ 6.4, 8.2 Hz, 1 H, CHCHHO), 4.04Ϫ4.20 (m, 2 H,
CH2CHHO, CHN), 4.27 (s, 1 H, CHOCH2), 4.36 (dt, J ϭ 3.2,
7.3 Hz, CH2CHO), 6.55 (br. d, J ϭ 4.0 Hz, 1 H, NH), 6.71 (s, 4 H,
aromatics) ppm. 13C NMR (50 MHz): δ ϭ 25.62, 26.48 (CH3),
41.72 (CH2N), 55.76 (OCH3), 56.83 (CHN), 63.27, 66.70 (CH2O),
76.93, 78.06 (CHO), 109.50 (OCO), 114.80, 115.75 (aromatic CH),
δ ϭ 3.12Ϫ3.24 (m, 1 H, CHHN), 3.50Ϫ3.85 (m, 4 H, CHHN,
CHHOBOM, NCH2CH2O), 3.72 (s, 3 H, CH3O), 4.05 (dd, J ϭ
3.7, 11.1 Hz, 1 H, CHHOBOM), 4.28 (mc, 1 H, CHN), 4.43 (d,
J ϭ 1.7 Hz, 1 H, CHO), 4.58 (s, 2 H, CH2Ph), 4.76 (s, 2 H,
OCH2O), 6.51 (br. d, J ϭ 4.0 Hz, 1 H, NH), 6.68, 6.73 (AB system,
J ϭ 9.3 Hz, 4 H, anisyl aromatic), 7.32 (s, 5 H, other aromatics)
ppm. 13C NMR (50 MHz): δ ϭ 41.91 (CH2N), 55.41 (CHN), 55.79
(OCH3), 63.24, 66.16, 69.46 (CH2O), 76.82 (CHO), 94.75
(OCH2O), 114.92, 115.77, 127.69, 127.96, 128.41 (aromatic CH),
137.85, 140.91, 152.69 (aromatic quat.), 169.75 (CϭO) ppm. IR:
ν˜max ϭ 3406, 2996, 2946, 2877, 1675 (s), 1506, 1478, 1454, 1390,
141.54, 152.57 (aromatic quat.), 169.49 (CϭO) ppm. IR: ν˜max
3405, 2998, 2834, 1673 (s), 1504, 1477, 1383, 1373, 1345, 1190,
1155, 1123, 1071, 1035, 962 cmϪ1
ϭ
1345, 1332, 1238, 1112, 1039 cmϪ1
.
.
(3R*,4R*,4ЈS*)-3-(2-Aminoethoxy)-1-(tert-butoxycarbonylmethyl)-
4-(2,2-dimethyl-1,3-dioxolan-4-yl)azetidin-2-one (3b): Rf 0.40
(3R*,4R*)-3-(2-Aminoethyl)-4-[(benzyloxymethoxy)methyl]-1-(4-
ϭ
methoxyphenyl)azetidin-2-one (4): Rf 0.19 (CHCl3/MeOH,
ϭ
(CHCl3/MeOH, 80:20). 1H NMR: δ ϭ 1.33, 1.40 (2 s, 2 ϫ 3 H,
CH3), 1.46 [s, 9 H, (CH3)3C], 2.84 (ddd, J ϭ 4.2, 5.6, 13.6 Hz, 1
H, CHHNH2), 2.94 (ddd, J ϭ 4.1, 6.8, 13.6 Hz, 1 H, CHHNH2),
3.63 (ddd, J ϭ 4.2, 6.8, 9.9 Hz, 1 H, CH2CHHO), 3.68 (dd, J ϭ
5.2, 8.7 Hz, 1 H, CHCHHO), 3.83 (ddd, J ϭ 4.1, 5.6, 9.9 Hz, 1 H,
CH2CHHO), 3.88 (d, J ϭ 17.7 Hz, 1 H, CHHCO2tBu), 3.90 (dd,
J ϭ 5.1, 9.3 Hz, 1 H, CHN), 4.11 (dd, J ϭ 6.5, 8.7 Hz, 1 H,
CHCHHO), 4.17 (d, J ϭ 17.7 Hz, 1 H, CHHCO2tBu), 4.37 (ddd,
J ϭ 5.2, 6.5, 9.3 Hz, 1 H, CH2CHO), 4.65 (d, J ϭ 5.1 Hz, 1 H,
CHOCH2) ppm. 13C NMR (50 MHz): δ ϭ 25.21, 26.90 (CH3),
28.06 [C(CH3)3], 41.83, 43.09 (CH2), 60.67 (CHN), 66.72, 74.03
(CH2O), 76.72, 82.24 (CHO), 109.61 (OCO), 167.05, 167.67 (Cϭ
O) ppm.
75:25). 1H NMR: δ ϭ 1.75Ϫ2.05 (m, 2 H, CH2CH2NH2),
2.80Ϫ3.05 (m, 2 H, CH2NH2), 3.45 (dt, J ϭ 9.2, 6.1 Hz, 1 H,
CHCϭO), 3.77 (s, 3 H, OCH3), 3.90 (d, J ϭ 5.3 Hz, 2 H, CH2O-
BOM), 4.27 (q, J ϭ 5.5 Hz, 1 H, CHN), 4.46 (s, 2 H, CH2Ph),
4.72, 4.75 (AB system, J ϭ 6.9 Hz, 2 H, OCH2O), 6.85 (d, J ϭ
9.0 Hz, 2 H, H ortho to OCH3), 7.18Ϫ7.40 (m, 5 H, aromatics),
7.42 (d, J ϭ 9.0 Hz, H meta to OCH3) ppm. 13C NMR (50 MHz):
δ ϭ 28.86 (CH2CH2NH2), 40.77 (CH2N), 49.69, 54.05 (CHCϭO
and CHN), 55.48 (CH3O), 65.95, 69.75 (CH2O), 94.89 (OCH2O),
114.31, 118.84, 127.80, 128.44 (aromatic CH), 131.27, 137.51,
156.15 (aromatic quat.), 167.42 (CϭO) ppm.
(3R*,1ЈR*)-3-{2-(Benzyloxymethoxy)-1-[(4-methoxyphenyl)amino]-
ethyl}pyrrolidin-2-one (36): Rf ϭ 0.71 (CHCl3/MeOH, 75:25).
C21H26N2O4 (370.44): calcd. C 68.09, H 7.07, N 7.56; found C
67.65, H 7.3, N 7.25. 1H NMR: δ ϭ 2.12Ϫ2.32 (m, 2 H,
CH2CH2N), 2.73 (dt, J ϭ 4.0, 9.2 Hz, 1 H, CHHN), 3.25Ϫ3.40
(m, 2 H, CHHN, CHCϭO), 3.67Ϫ3.84 (m, 2 H, CH2OBOM), 3.74
(s, 3 H, OCH3), 3.87Ϫ3.98 (m, 1 H, CHN), 4.58 (s, 3 H, CH2Ph),
4.75, 4.77 (AB system, J ϭ 6.5 Hz, OCH2O), 6.72, 6.75 (AB system,
J ϭ 9.6 Hz, 4 H, aromatics), 7.20Ϫ7.40 (m, 5 H, aromatics) ppm.
13C NMR (50 MHz): δ ϭ 23.77 (CH2CH2N), 40.41 (CH2N), 42.80
(CHCϭO), 54.86 (CHN), 55.80 (OCH3), 69.02, 69.75 (CH2O),
95.14 (OCH2O), 115.08, 116.14, 127.75, 127.87, 128.45 (aromatic
CH), 137.81, 141.42, 152.77 (aromatic quat.), 178.57 (CϭO) ppm.
IR: ν˜max ϭ 3437, 3003, 2949, 2887, 1692 (s), 1505, 1452, 1193, 1113,
tert-Butyl (3R*,1ЈR*)-{[(4S*)-(2,2-Dimethyl-1,3-dioxolan-4-yl)-(3-
oxomorpholin-2-yl)methyl]amino}acetate (25b): Rf ϭ 0.53 (CHCl3/
MeOH, 90:10). C16H28N2O6 (344.40): calcd. C 55.80, H 8.19, N
8.13; found C 55.85, H 8.3, N 8.05. GC-MS: Rt ϭ 9.64; m/z ϭ 329
[Mϩ· Ϫ 15] (1.0), 273 (2.3), 244 (15.9), 243 (26.5), 187 (100.0), 185
(10.5), 141 (21.0), 130 (24.8), 113 (20.6), 101 (9.0), 84 (5.8), 72
(14.8), 70 (11.0), 68 (5.0), 57 (18.9), 56 (7.4), 44 (15.5), 43 (23.3),
1
42 (12.6), 41 (18.3). H NMR: δ ϭ 1.35, 1.42 (2 s, 2 ϫ 3 H, CH3),
1.45 [s, 9 H, C(CH3)3], 3.17Ϫ3.30 (m, 1 H, CHHNCϭO), 3.35 (dd,
J ϭ 1.8, 7.4 Hz, 1 H, CHN), 3.42, 3.51 (AB system, J ϭ 17.5 Hz,
2 H, CH2CO2tBu), 3.60Ϫ3.82 (m, 2 H, CH2CHHO, CHHNCϭO),
3.81 (t, J ϭ 7.8 Hz, 1 H, CHCHHO), 3.98Ϫ4.15 (m, 3 H,
CHCHHO, CHOCH2, CH2CHHO), 4.28 (q, J ϭ 7.1 Hz, 1 H,
CHCHO), 6.42 (br. s, 1 H, NH) ppm. 13C NMR (50 MHz): δ ϭ
25.63, 26.71 (CH3), 28.18 [C(CH3)3], 41.90, 50.88 (CH2), 60.67
(CHN), 63.25, 66.93 (CH2O), 77.77, 80.75 (CHO), 109.29 (OCO),
169.55, 171.89 (CϭO) ppm. IR: ν˜max ϭ 3406, 2981, 2932, 2871,
1726 (s), 1674 (s), 1477, 1451, 1380, 1370, 1343, 1235, 1152, 1120,
1042, 907 cmϪ1
.
(3R*,4S*,E)-3-Methoxy-1-[2-(phenylacetylamino)ethyl]-4-(2-phenyl-
ethenyl)azetidin-2-one (37): A solution of azide 16b (141 mg,
0.518 mmol) in THF (5 mL) was treated at room temp. with PPh3
(204 mg, 0.777 mmol) and H2O (250 µL). After stirring at room
temp. for 6 h, Et3N (289 µL, 2.07 mmol) and phenylacetyl chloride
(137 µL, 1.04 mmol) were added in sequence. After 2 h, the mixture
was quenched with saturated aqueous NH4Cl (15 mL) and NaOH
1069, 968, 907, 844 cmϪ1
.
(3R*,4S*)-3-(2-Aminoethoxy)-4-[(benzyloxymethoxy)methyl]-1-(4-
methoxyphenyl)azetidin-2-one (3c): Rf ϭ 0.10 and 0.15 (CHCl3/
1332
Eur. J. Org. Chem. 2003, 1319Ϫ1336

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
(1 , 4 mL). After further stirring for 15 min, the mixture was ex-
tracted with Et2O (1 ϫ) and EtOAc (2 ϫ). The combined organic
extracts were washed with saturated aqueous NaHCO3, concen-
7.0 Hz, 1 H, CHNH), 4.02Ϫ4.20 (m, 1 H, CHNH), 4.20Ϫ4.38 (m,
1 H, CHNH), 4.39Ϫ4.53 (m, 1 H, CHϭCHCHN), 4.58 and 4.63
(2 d, J ϭ 4.1 and 4.4 Hz, 1 H, CHOMe), 6.22 (dd, J ϭ 8.1, 16.1 Hz,
trated, and immediately chromatographed (CH2Cl2/EtOAc, 50:50 1 H, CHϭCHPh), 6.71 (br. s, 2 H, NH), 6.79 (d, J ϭ 16.1 Hz, 1 H,
to 30:70), to give 37 containing a slight impurity of triphenylphos-
phane oxide. A second chromatography afforded pure 37 as a foam
CHϭCHPh), 7.22Ϫ7.44 (m, 3 H, aromatics), 7.50 (d, J ϭ 7.7 Hz, 2
H, aromatics), 7.70Ϫ8.20 (m,
3
H, NH) ppm. 13C NMR
(161 mg, 85%). Rf ϭ 0.21 (CH2Cl2/EtOAc, 50:50). C22H24N2O3 ([D6]DMSO, 50 MHz): δ ϭ 18.32, 19.02, 20.96 (CH3), 22.85 (CH2),
(364.44): calcd. C 72.50, H 6.64, N 7.69; found C 72.55, H 6.6, N 23.17 (CH3), 23.99 (CH), 28.04 and 28.19 [C(CH3)2], 29.18 (CH2),
7.4. GC-MS: Rt ϭ 12.47; m/z ϭ 332 [Mϩ· Ϫ 32] (4.7), 241 (9.8),
198 (9.4), 197 (12.9), 172 (88.0), 171 (8.8), 162 (37.0), 161 (10.7),
30.08 (CH), 31.25, 36.23, 36.65, 39.69, 40.06 (CH2), 50.92, 50.97,
52.72 (CHN), 57.65 (OCH3), 59.67, 59.90, 59.99 (CHN), 77.25,
160 (57.5), 159 (29.5), 156 (19.7), 145 (13.1), 144 (24.6), 142 (12.2), 78.10 [C(CH3)3], 85.03, 85.12 (CHOCH3), 124.06, 124.17 (CHϭ
130 (9.6), 129 (28.4), 127 (24.3), 126 (10.5), 117 (31.1), 116 (13.9),
CHPh), 126.51, 127.99, 128.60 (aromatic CH), 135.12, 135.24
115 (59.4), 91 (100.0), 70 (9.2), 65 (16.3), 44 (10.1), 42 (9.8). 1H (CHϭCHPh), 135.96, 135.99 (aromatic quat.), 155.44, 155.55 (ure-
NMR: δ ϭ 3.00Ϫ3.45 (m, 3 H), 3.42 (s, 3 H, OCH3), 3.54 (s, 2 H, thane carbonyls), 165.95, 166.07 (β-lactam carbonyls), 171.48,
CH2Ph), 3.50Ϫ3.70 (m, 1 H), 4.29 (dd, J ϭ 4.4, 9.0 Hz, 1 H,
CHϪN), 4.45 (d, J ϭ 4.4 Hz, 1 H, CHϪOMe), 6.15 (dd, J ϭ 9.0,
15.7 Hz, 1 H, CHϭCHPh), 6.70 (d, J ϭ 16.2 Hz, 1 H, CHϭ
CHPh), 7.25Ϫ7.45 (m, 10 H, aromatics) ppm. 13C NMR (50 MHz):
δ ϭ 37.42, 41.02, 43.84 (CH2), 58.63 (OCH3), 61.09 (CHϪN), 85.15
(CHϪOMe), 122.70 (CHϭCHPh), 126.75, 127.27, 128.46, 128.70,
128.94, 129.45 (aromatic CH), 134.83, 135.82 (aromatic quat.),
171.53, 171.84, 171.89 (amidic carbonyls) ppm.
Transformation of Compound 39 into (3R,4S,E)- and (3S,4R,E)-1-
{2-[(D-Valyl-L-leucyl-L-lysyl)amino]ethyl}-3-methoxy-4-(2-phenyl-
ethenyl)azetidin-2-ones (40) and Their Hydrolysis with Plasmin:
Plasmin (from porcine blood, Sigma cat. P-8644, 3.2 units/mg;
2.6 mg) was dissolved in buffer [pH ϭ 7.5, 12.8 mL; prepared by
dissolving aminotris(hydroxymethyl)methane (10 mmol) in distilled
water (10 mL), adjusting the pH to 7.5 with 1  HCl, and diluting
to 50 mL]. The resulting solution contains 0.65 U/mL of active en-
zyme. A solution of compound 39 (42.3 mg) in dry CH2Cl2 (750
µL) was cooled to 0 °C and treated with CF3CO2H (250 µL). After
stirring at 0 °C for 40 min and at room temp. for 2 h, the solvents
were evaporated to dryness. The residue was taken up twice with
n-heptane and the solvents were evaporated again to give a white
foam (42.1 mg). This material was taken up in MeOH (0.9 mL).
One third of this solution (300 µL) was added to the above-pre-
pared Plasmin solution. The mixture was stirred at room temp. for
30 h. At this point TLC (CHCl3/MeOH, 75:25) showed complete
conversion of 40 into 2b and (mostly) 17b. After a further 18 h, the
pH was raised to 12 by addition of 1  NaOH. The mixture was
extracted with EtOAc and the organic phase washed with saturated
aqueous NaCl. Concentration and preparative TLC (CHCl3/
MeOH, 90:10) afforded pure 17b (2.9 mg, 68% from 39).
137.00 (CHϭCHPh), 167.60 and 171.48 (CϭO) ppm. IR: ν˜max
3421, 3039, 2990, 2931, 2833, 1746 (s), 1664 (s), 1600, 1524, 1400,
1349, 1143, 1063, 998, 969 cmϪ1
ϭ
.
Hydrolysis of Phenylacetamide 37 with Penicillin G Acylase: Penicil-
lin G acylase [activity: 450 U/g dry basis; supported on polyacrylic
resin and suspended in glycerol (80%) and 0.02  phosphate buffer
`
pH ϭ 7.8 (20%); a gift of Unita Biochimici De. Bi. Recordati] was
washed with distilled water and dried by suction just before use. A
buffer solution (pH ϭ 7.5) was prepared by dissolving 10 mmol of
aminotris(hydroxymethyl)methane in distilled water (10 mL), ad-
justing the pH to 7.5 with 1  HCl, and then diluting to 50 mL.
The washed and dried enzyme (70 mg) was dissolved in the buffer
solution (5 mL). A solution of 37 (18.8 mg, 51.6 µmol) in MeOH
(500 µL) was added. The solution became cloudy and was stirred
at room temp. for 6 h. At this point TLC (CHCl3/MeOH, 95:5)
showed the complete conversion of 37 into 2b and 17b. The mixture
was stirred at 37 °C overnight. The pH was raised to 12 by addition
of 1  NaOH. The mixture was extracted with EtOAc and the
organic phase washed with saturated aqueous NaCl. Concentration
and preparative TLC (CHCl3/MeOH, 90:10) furnished azalactam
17b (9.5 mg, 75%).
(3R*,4S*,E)-1-{2-{[(4,5-Dimethoxy-2-nitrophenyl)methoxy]-
carbonylamino}ethyl}-3-methoxy-4-(2-phenylethenyl)-
azetidin-2-one (41): A solution of freshly prepared amine 2b
(53.3 mg, 202 µmol) in dry CH2Cl2 (1 mL) was kept in the dark,
cooled to 0 °C, and treated with Et3N (181 µL, 1.30 mmol) and 6-
nitroveratryl chloroformate (179 mg, 650 µmol). After stirring at 0
°C for 3 h, the reaction was quenched with saturated aqueous
NH4Cl (3 mL) and stirred at room temp. for 15 min. The mixture
was diluted with NaHCO3 (5%, 20 mL) and extracted with EtOAc.
The organic phase was washed with aqueous (NH4)H2PO4 (5%)
and saturated aqueous NaCl. Concentration and chromatography
(Et2O/CH2Cl2/EtOH, 49:49:2) gave pure 41 as a yellow foam
(3R,4S,E)- and (3S,4R,E)-1-(2-{[(N-tert-Butoxycarbonyl-
D-valyl)-L-
leucyl-(N-ε-tert-butoxycarbonyl)- -lysyl]amino}ethyl)-3-methoxy-4-
L
(2-phenylethenyl)azetidin-2-ones (39): A solution of freshly prepared
amine 2b (51.6 mg, 210 µmol) in dry CH2Cl2 (1 mL) was cooled to
0 °C and treated in sequence with [(N-tert-butoxycarbonyl--valyl)-
-leucyl]-N-ε-tert-butoxycarbonyl--lysine (38)[5] (117.2 mg, 210
µmol), PyBOP (163.4 mg, 314 µmol), and a solution of Et3N in
CH2Cl2 (0.5 , 628 µL, 314 µmol). After stirring at 0 °C for 1 h
and at room temp. for 1 h, the solution was diluted with EtOAc
(20 mL), MeOH (2 mL) and aqueous (NH4)H2PO4 (5%, 30 mL);
the phases were separated and the aqueous one was extracted twice
again with EtOAc. Concentration and chromatography (CH2Cl2/
MeOH, 98:2) gave a slightly impure product that was further puri-
fied by preparative TLC (EtOAc/MeOH, 8:2) to give pure 39
(80.3 mg, 82%). Rf
ϭ 0.26 (Et2O/CH2Cl2/EtOH, 49:49:2).
C24H27N3O8 (485.49): calcd. C 59.37, H 5.61, N 8.66; found C 59.4,
H 5.75, N 8.7. 1H NMR: δ ϭ 3.10Ϫ3.65 (m, 4 H, CH2CH2N), 3.43
(s, 3 H, OCH3), 3.95, 4.00 (2 s, 2 ϫ 3 H, OCH3), 4.37 (dd, J ϭ 4.4,
9.2 Hz, 1 H, CHN), 4.56 (d, J ϭ 4.4 Hz, 1 H, CHOMe), 5.45, 5.53
(AB system, J ϭ 15.3 Hz, 2 H, CH2Ar), 5.73 (br. s, 1 H, NH), 6.22
(dd, J ϭ 9.2, 15.9 Hz, 1 H, CHϭCHPh), 6.74 (d, J ϭ 15.9 Hz, 1
H, CHϭCHPh), 7.05 (s, 1 H, veratryl aromatic), 7.20Ϫ7.46 (m, 5
H, aromatics), 7.71 (s, 1 H, veratryl aromatic) ppm.
(107 mg, 65%) as
a diastereoisomeric mixture. C41H66N6O9
(787.00): calcd. C 62.57, H 8.45, N 10.68; found C 62.2, H 8.2, N
10.8. 1H NMR ([D6]DMSO): δ ϭ 0.75Ϫ0.95 [m, 12 H, (CH3)2CH], Photochemical Cleavage of Compound 41 To Give Amine 2b: In a
1.10Ϫ1.80 [m, 9 H, CH2CH2CH2CH2N, CH2CH(CH3)2], 1.37 [s, 18 quartz test tube, a solution of 41 (20.3 mg, 41.8 µmol) in ethanol
H, (CH3)3C], 1.93 (sept, J ϭ 6.5 Hz), 2.80Ϫ3.05 (m, 2 H, CH2N),
(96%, 1 mL) was treated with H2SO4 (11 µL, 200 µmol). The solu-
3.07Ϫ3.42 (m, 2 H, CH2N), 3.32 (s, 3 H, OCH3), (3.78 (t, J ϭ tion was placed in a Rayonet ‘‘merry-go-round’’ apparatus and ir-
Eur. J. Org. Chem. 2003, 1319Ϫ1336
1333

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
radiated with 12 lamps (4.5 W, 350 nm) for 24 h. After this time,
TLC showed complete disappearance of the starting material. The
δ ϭ 0.14, 0.20 [2 s, 2 ϫ 3 H, (CH3)2Si], 0.90 [s, 9 H, (CH3)3C], 2.63
(dd, J ϭ 12.6, 17.9 Hz, 1 H, CHHCϵ), 2.90 (ddd, J ϭ 1.5, 4.0,
solution was diluted with CH2Cl2 (10 mL) and water (10 mL). The 17.9 Hz, 1 H, CHHCϵ), 3.18, 3.30 (AB part of ABX system, JAB ϭ
phases were separated and the aqueous one was extracted again 14.4 Hz, JAX ϭ 4.5 Hz, JBX ϭ 5.0 Hz, 2 H, CH2N), 3.62Ϫ3.90 (m,
with CH2Cl2. The combined organic phases were extracted with 5 H, CH2OH, OH, CHN, CHCϭO), 4.79 (t, J ϭ 1.8 Hz, 1 H,
(NH4)H2PO4 (5%). The combined aqueous phases were brought to
pH ϭ 13 by addition of aqueous NaOH (1 ) and extracted with
CHOSi), 5.89, 5.95 (AB part of ABX2 system, JAB ϭ 9.5 Hz, JAX ϭ
JBX ϭ 0.7 Hz, 2 H, CHϭCH) ppm. IR: ν˜max ϭ 3371, 2998, 2954,
CH2Cl2. The solvent was evaporated, and the residue taken up 2929, 2884, 2856, 1729, 1462, 1406, 1360, 1350, 1314, 1194, 1160,
again in THF (500 µL) and treated with Et3N (35 µL, 251 µmol)
and phenylacetyl chloride (17 µL, 125 µmol). After 2 h, the reaction
was complete. It was worked up as described for the preparation of
37. Chromatography gave pure phenylacetamide 37 (10 mg, 65%).
1138, 1114, 1062, 1028, 1001, 977 cmϪ1
.
(1R*,9R*,10S*,Z)-11-(2-Azidoethyl)-9-(tert-butyldimethylsilyloxy)-
11-azabicyclo[8.2.0]dodec-5-ene-3,7-diyn-12-one (45): A solution of
alcohol 44 (116.9 mg, 0.338 mmol) in dry CH2Cl2 (2 mL) was co-
oled to Ϫ30 °C and treated sequentially with Et3N (188 µL,
1.352 mmol) and methanesulfonyl chloride (52 µL, 0.676 mmol).
Ethyl (1R*,9R*,10S*,Z)-{9-(tert-Butyldimethylsilyloxy)-12-oxo-11-
azabicyclo[8.2.0]dodec-5-ene-3,7-diyn-11-yl}acetate (43): A solution
of alcohol 42[2] (150.2 mg. 0.498 mmol) in dry THF (3 mL) was After 50 min, the mixture was poured into saturated aqueous
cooled to 0 °C and treated with a solution of KN(SiMe3)2 in tolu-
ene (0.39 , 1.40 mL, 0.548 mmol). After 15 min, ethyl bromoacet-
ate (66 µL, 0.598 mmol) was added. After 75 min, the solution was
NH4Cl and extracted with Et2O. After concentration to dryness,
the crude mesylate was taken up in dry DMF (1.0 mL), treated
with NaN3 (66 mg, 1.1014 mmol) and heated at 50 °C for 2 h and
poured into saturated aqueous NH4Cl. Extraction with Et2O gave, 15 min. After cooling, the solution was poured into a mixture of
after concentration and chromatography (PE/Et2O, 60:40 ϩ 1%
Et3N, to PE/Et2O, 50:50), pure 43 as a solid (156.3 mg, 81%). Rf ϭ
0.48 (PE/Et2O, 50:50). M.p. 147.8Ϫ148.5 °C. C21H29NO4Si
saturated aqueous NH4Cl and H2O (2:1), and extracted with Et2O.
Chromatography (PE/EtOAc, 70:30) gave pure 45 as a white solid
(105.3 mg, 84%). Rf ϭ 0.74 (PE/EtOAc, 50:50). M.p. 87.5Ϫ88.4 °C.
(387.54): calcd. C 65.08, H 7.54, N 3.61; found C 64.95, H 7.65, N C19H26N4O2Si (370.52): calcd. C 61.59, H 7.07, N 15.12; found C
3.55. GC-MS: Rt ϭ 10.19; m/z ϭ 330 [Mϩ· Ϫ 57] (100), 284 (6.7), 61.8, H 7.25, N 14.95. GC-MS: Rt ϭ 10.21; m/z ϭ 342 [Mϩ· Ϫ 28]
256 (7.8), 228 (7.8), 217 (6.3), 201 (8.4), 182 (5.1), 177 (28.6), 156
(6.5), 155 (6.5), 154 (18.6), 128 (6.8), 127 (11.6), 126 (7.6), 125 (5.3), (5.4), 184 (6.0), 183 (14.9), 182 (6.7), 181 (6.8), 169 (5.4), 156 (7.6),
115 (9.9), 105 (6.8), 104 (7.2), 103 (10.8), 77 (8.1), 75 (57.9), 73 154 (8.6), 143 (6.1), 128 (7.6), 127 (13.5), 126 (6.3), 115 (11.5), 101
(30.3), 313 [Mϩ· Ϫ 57] (8.8), 285 (13.8), 257 (6.3), 211 (7.6), 185
1
(72.4), 59 (13.1), 45 (8.9), 41 (7.6). H NMR: δ ϭ 0.17 and 0.12 [2 (6.0), 84 (9.3), 77 (14.0), 76 (9.1), 75 (100), 74 (13.8), 73 (83.5), 69
s, 2 ϫ 3 H, (CH3)2Si], 0.89 [s, 9 H, (CH3)3C], 2.73 (dd, J ϭ 12.5, (13.7), 59 (15.0), 57 (9.0), 47 (9.6), 45 (14.4), 42 (13.5), 41 (12.1).
17.9 Hz, 1 H, CHHCϵC), 1.30 (t, J ϭ 7.1 Hz, 3 h, CH3CH2), 2.90
(ddd, J ϭ 1.5, 4.4, 17.9 Hz, 1 H, CHHCϵC), 3.44 (d, J ϭ18.0, 1 (CH3)3C], 2.65 (dd, J ϭ 12.6, 17.9 Hz, 1 H, CHHCϵC), 2.90 (ddd,
H, CHHCO2Et), 3.75 (ddd, J ϭ 2.2, 4.3, 12.3 Hz, 1 H, CHCϭO), J ϭ 1.5, 4.0, 17.9 Hz, 1 H, CHCϵC), 2.97 (ddd, J ϭ 4.4, 8.1,
4.05 (t, J ϭ 2.1 Hz, 1 H, CHN), 4.21 (mc)(m, 2 H, CH2CH3), 4.41 13.6 Hz, 1 H, CHHNCϭO), 3.40Ϫ3.77 (m, 4 H, CHCϭO, CH2N3,
1H NMR: δ ϭ 0.14, 0.19 [2 s, 2 ϫ 3 H, (CH3)2Si], 0.89 [s, 9 H,
(d, J ϭ 18.0 Hz, 1 H, CHHCO2Et), 4.72 (t, J ϭ 1.8 Hz, 1 H,
CHOSi), 5.94 and 5.88 (AB part of an ABX2 system, JAB
10.0 Hz, JAX ϭ JBX ϭ 0.7 Hz, 2 H, CHϭCH) ppm. 13C NMR
(50 MHz): ϭ 14.19 (CH2CH3), 18.05 [C(CH3)3], 19.29 [(CH3)2Si], 18.02 [C(CH3)3], 19.25 (CH2CϵC), 25.64 [C(CH3)3],
CHCϭO), 3.87 (t, J ϭ 2.1 Hz, 1 H, CHN), 4.81 (t, J ϭ 1.8 Hz, 1
ϭ
H, CHOSi), 5.89, 5.94 (AB part of ABX2 system, JAB ϭ 9.5 Hz,
J
AX ϭ JBX ϭ 0.7 Hz) ppm. 13C NMR (50 MHz): δ ϭ Ϫ4.16, Ϫ5.04
δ
(CH2CϵC), 25.64 [(CH3)3C], 41.28 (CH2CO2Et), 51.83 (CHCϭO), 39.65, 50.05 (CH2N), 51.67 (CHCϭO), 64.16 and 59.49 (CHOSi
59.49 (CHN), 61.73 (CH2O), 63.57 (CHOSi), 83.68, 86.52, 97.52, and CHN), 83.78, 86.68, 97.58, 100.54 (CϵC), 122.20, 125.85
100.60 (CϵC), 122.16, 125.82 (CHϭCH), 167.94, 168.33 (CϭO) (CHϭCH), 168.06 (CϭO) ppm. IR: ν˜max ϭ 3014, 2955, 2929, 2857,
ppm. IR: ν˜max ϭ 2954, 2930, 2857, 1756, 1740, 1462, 1410, 1375,
1363, 1350, 1316, 1191, 1132, 1115, 1094, 1014, 979, 936, 863, 1037, 907 cmϪ1
836 cmϪ1
2105, 1745, 1462, 1400, 1361, 1344, 1315, 1294, 1255, 1160, 116,
.
.
( 1R* , 9R* , 1 0S* , Z) -1 1 - (2 - Am in oethyl)-9-(t er t-butyl-
(1R*,9R*,10S*,Z)-9-(tert-Butyldimethylsilyloxy)-11-(2-hydroxy- dimethylsilyloxy)-11-azabicyclo[8.2.0]dodec-5-ene-3,7-diyn-12-one
ethyl)-11-azabicyclo[8.2.0]dodec-5-ene-3,7-diyn-12-one (44): Pow-
dered anhydrous CaCl2 (140 mg, 1.26 mmol) was suspended in
THF (7 mL) and absolute EtOH (4 mL). The mixture was cooled
Hydrochloride (46): A solution of azide 45 (30.0 mg, 81.0 µmol) in
THF (1.5 mL) was treated with H2O (250 µL) and with Ph3P
(62.0 mg, 236.4 µmol). The mixture was stirred at room temp. for
to Ϫ20 °C and treated with NaBH4 (75 mg, 1.99 mmol). After 14 h. The solvent was evaporated and the residue chromatographed
30 min, a solution of lactenediyne 43 (153 mg, 0.394 mmol) in THF
(4 mL) was added. The temperature was allowed to rise to 0 °C
during 2 h and 30 min. At this point TLC showed complete conver-
sion of the starting material. The mixture was poured into a cooled
(ice) saturated aqueous NH4Cl solution and extracted with Et2O.
(CHCl3 to CHCl3/MeOH, 85:15, to CHCl3/MeOH/iPrNH2,
82.5:15:2.5) to give pure amine 46. This amine was taken up in
CH2Cl2 (1 mL) and treated with a solution of HCl in Et2O (1 ,
75 µL). After concentration, the pure hydrochloride (26.1 mg, 85%)
was obtained as a white solid, which was stable in a freezer for
Immediate chromatography (CH2Cl2/EtOAc, 50:50) gave pure 44 several weeks. Rf (of free amine) ϭ 0.59 (CHCl3/MeOH, 85:15).
as a solid (120.1 mg, 88%). Rf ϭ 0.47 (CH2Cl2/EtOAc, 1:1), Rf ϭ
0.68 (EtOAc). M.p. 122.6Ϫ123.8 °C. C19H27NO3Si (345.51): calcd.
GC-MS: Rt ϭ 10.08; m/z ϭ 344 [Mϩ·] (1.2), 343 [Mϩ· Ϫ 1] (5.1),
287 [Mϩ· Ϫ 57], (85.9), 269 (6.6), 259 (7.9), 233 (14.8), 228 (5.0),
C 66.05, H 7.88, N 4.05; found C 66.15, H 7.9, N 3.95. GC-MS: 216 (7.8), 215 (5.2), 214 (18.9), 213 (11.5), 212 (5.2), 202 (5.1), 201
Rt ϭ 10.04; m/z ϭ 345 [Mϩ·] (0.11), 288 [Mϩ· Ϫ 57] (19.3), 287 (6.4), 186 (10.5), 185 (17.8), 184 (9.2), 183 (12.0), 160 (10.6), 156
(10.9), 272 (5.1), 271 (15.8), 270 (69.2), 216 (11.4), 186 (7.7), 168
(15.0), 156 (6.7), 143 (7.0), 142 (9.5), 135 (13.1), 127 (12.3), 126 (15.1), 126 (8.1), 115 (10.2), 77 (7.6), 75 (51.3), 73 (100), 59 (11.3),
(6.6), 119 (8.1), 115 (11.2), 77 (10.9), 76 (8.9), 75 (100), 73 (76.7),
45 (8.8), 44 (19.5). 1H NMR: δ ϭ 0.14, 0.19 [2 s, 2 ϫ 3 H,
59 (12.4), 57 (8.1), 47 (7.2), 45 (30.5), 43 (7.0), 41 (9.6). H NMR: (CH3)2Si], 0.90 [s, 9 H, C(CH3)3], 2.64 (dd, J ϭ 12.6, 17.8 Hz, 1 H,
(9.0), 154 (12.7), 143 (10.4), 142 (10.6), 141 (7.0), 128 (11.1), 127
1
1334
Eur. J. Org. Chem. 2003, 1319Ϫ1336

Intramolecular Opening of β-Lactams with Amines
FULL PAPER
2027Ϫ2046; Y. Pei, R. A. Houghten, J. S. Kiely, Tetrahedron
Lett. 1997, 38, 3349Ϫ3352; H. H. Wasserman, G. D. Berger,
Tetrahedron 1983, 39, 2459Ϫ2464.
L. Banfi, G. Guanti, M. Rasparini, Tetrahedron Lett. 1998,
39, 9539Ϫ9542.
D. Reuschling, H. Pietsch, A. Linkies, Tetrahedron Lett. 1978,
19, 615Ϫ618.
CHHCϵC), 2.80Ϫ3.10 (m, 3 H, CHHNCϭO and CHHCϵC),
3.43 (dt, J ϭ 10.4, 6.0 Hz, 1 H CHHNCϭO), 3.70 (ddd, J ϭ 2.0,
4.0, 12.7 Hz, 1 H, CHCϭO), 3.80 (t, J ϭ 3.9 Hz, 1 H, CHN), 4.79
(t, J ϭ 1.8 Hz, 1 H, CHOSi), 5.89, 5.94 (AB system, J ϭ 10.2 Hz,
2 H, CHϭCH) ppm.
[13]
[14]
(5aR*,11R*,11aS*)-11-(tert-Butyldimethylsilyloxy)-1,2,3,4,5a,6,
11,11a-octahydronaphtho[2,3-e]-1,4-diazepin-5-one (48): The hydro-
chloride salt of amine 46 (23.8 mg, 62.5 µmol) was taken up in
THF (2 mL) and treated with Et3N (100 µL) and 1,4-cyclohexadi-
ene (100 µL). The solution was heated under reflux for 4 d. The
solvent was evaporated. A preparative TLC (CHCl3/MeOH, 95:5)
gave pure 48 (9.7 mg, 45%). Rf ϭ 0.35 (CHCl3/MeOH, 95:5). GC-
MS: Rt ϭ 10.50; m/z ϭ 289 [Mϩ· Ϫ 57] (66.3), 234 (71.5), 227
(80.2), 214 (57.0), 163 (100), 129 (77.6), 115 (23.9), 91 (6.9), 75
(99.4), 44 (45.8). 1H NMR: δ ϭ 0.04, 0.17 [2 s, 2 ϫ 3 H, (CH3)2Si],
0.98 [s, 9 H, C(CH3)3], 2.80Ϫ2.95 (m, 2 H), 2.97Ϫ3.10 (m, 3 H),
3.10Ϫ3.35 (m, 2 H), 3.50Ϫ3.65 (m, 1 H), 4.81 (d, J ϭ 5.1 Hz, 1 H,
CHOSi), 5.96 (br. s, NH), 7.31 (s, 5 H, aromatics) ppm. 13C NMR
(50 MHz): δ ϭ Ϫ4.80 [(CH3)2Si], 18.25 [C(CH3)3], 25.86 [C(CH3)3],
27.45 (benzylic CH2), 45.00, 46.64, 49.95 (CH2N and CHCϭO),
60.0 (CHN), 72.27 (CHOSi), 124.79, 126.28, 127.36, 127.73 (aro-
matic CH), 136.62, 138.18 (aromatic quat.), 179.04 (CϭO) ppm.
IR: ν˜max ϭ 3416, 3062, 3020, 2997, 2927, 2856, 1663, 1461, 1237,
[15]
[16]
L. Banfi, G. Guanti, Eur. J. Org. Chem., in press.
H. Staudinger, J. Meyer, Helv. Chim. Acta 1919, 2, 635; A. Koz-
iara, K. Osowska-Pacewicka, S. Zawadski, A. Zwierzak, Syn-
thesis 1985, 202.
[17]
[18]
A. M. Felix, M. H. Jimenez, J. Chromatogr. 1974, 89, 361Ϫ364.
A. K. Bose, V. R. Hegde, D. R. Wagle, S. S. Bari, M. S.
Manhas, J. Chem. Soc., Chem. Commun. 1986, 161Ϫ162; D. R.
Wagle, C. Garai, J. Chiang, M. G. Monteleone, B. E. Kurys, T.
W. Strohmeyer, V. R. Hegde, M. S. Manhas, A. K. Bose, J. Org.
Chem. 1988, 53, 4227Ϫ4236; D. R. Wagle, C. Garai, M. G.
Monteleone, A. K. Bose, Tetrahedron Lett. 1988, 29,
1649Ϫ1652; D. R. Wagle, M. G. Monteleone, L. Krishnan, M.
S. Manhas, A. K. Bose, J. Chem. Soc., Chem. Commun. 1989,
915Ϫ916.
M. S. Manhas, M. Ghosh, A. K. Bose, J. Org. Chem. 1990,
55, 575Ϫ580.
G. Guanti, L. Banfi, E. Narisano, Tetrahedron Lett. 1989, 30,
5511Ϫ5514.
[19]
[20]
[21]
[22]
M. I. Page, Adv. Phys. Org. Chem. 1987, 23, 165Ϫ270; M. I.
Page, Acc. Chem. Res. 1984, 17, 144Ϫ151.
1105 cmϪ1
.
C. Fuganti, P. Grasselli, S. Servi, A. Lazzarini, P. Casati, J.
Chem. Soc., Chem. Commun. 1987, 538Ϫ539; C. Fuganti, P.
Grasselli, S. Servi, A. Lazzarini, P. Casati, Tetrahedron 1988,
44, 2575Ϫ2582; E. Baldaro, P. DЈArrigo, G. Pedrocchi-Fantoni,
C. M. Rosell, S. Servi, A. Tagliani, M. Terreni, Tetrahedron:
Asymmetry 1993, 4, 1031Ϫ1034; T. Pohl, H. Waldmann, Tetra-
hedron Lett. 1995, 36, 2963Ϫ2966; T. Pohl, H. Waldmann, An-
gew. Chem. Int. Ed. Engl. 1996, 35, 1720Ϫ1723; Angew. Chem.
1996, 108, 1829Ϫ1832.
Acknowledgments
We wish to thank Dr. Katharine Powles and Dr. Giulio Nervi for
their collaboration to this work, MIUR (COFIN 98 and COFIN
00), C.N.R., and the University of Genova for financial support,
`
and Recordati (Unita Biochimici De. Bi.) for a kind gift of penicil-
lin G acylase.
[23]
[24]
H. Waldmann, A. Heuser, A. Reidel, Synlett 1994, 65Ϫ67.
D. Rossi, A. Calcagni, A. Romeo, J. Org. Chem. 1979, 44,
2222Ϫ2225; D. Rossi, A. Romeo, G. Lucente, J. Org. Chem.
1978, 43, 2576Ϫ2581; C. Fuganti, P. Grasselli, P. Casati, Tetra-
hedron Lett. 1986, 27, 3191Ϫ3194; C. Fuganti, P. Grasselli, P.
F. Seneci, S. Servi, P. Casati, Tetrahedron Lett. 1986, 27,
2061Ϫ2062; A. Romeo, G. Lucente, D. Rossi, G. Zanotti,
Tetrahedron Lett. 1971, 21, 1799Ϫ1802; M. J. Zmijewski Jr., B.
S. Briggs, A. R. Thompson, I. G. Wright, Tetrahedron Lett.
1991, 32, 1621Ϫ1622; I. B. Stoineva, B. P. Galunsky, V. S. Loz-
anov, I. P. Ivanov, D. D. Petkov, Tetrahedron 1992, 48,
1115Ϫ1122; R. S. Topgi, J. S. Ng, B. Landis, P. Wang, J. R.
Behling, Bioorg. Med. Chem. Lett. 1999, 7, 2221Ϫ2229; G. Cai-
nelli, D. Giacomini, P. Galletti, M. DaCol, Tetrahedron: Asym-
metry 1997, 8, 3231Ϫ3235; A. L. Margolin, Tetrahedron Lett.
1993, 34, 1239Ϫ1242; S. Grabowski, J. Armbruster, H.
Prinzbach, Tetrahedron Lett. 1997, 38, 5485Ϫ5488; V. A. Solo-
shonok, N. A. Fokina, A. V. Rybakova, I. P. Shishkina, S. V.
Galushko, A. E. Sorochinsky, V. P. Kukhar, Tetrahedron: Asym-
metry 1995, 6, 1601Ϫ1610; H. Waldmann, Justus Liebigs Ann.
Chem. 1988, 1175Ϫ1180; M. Nettekoven, M. Psiorz, H. Wald-
mann, Tetrahedron Lett. 1995, 36, 1425Ϫ1428; H. Waldmann,
A. Heuser, S. Schulze, Tetrahedron Lett. 1996, 37, 8725Ϫ8728;
H. Waldmann, A. Reidel, Angew. Chem. Int. Ed. Engl. 1997,
36, 647Ϫ649.
[1]
L. Banfi, G. Guanti, Angew. Chem. Int. Ed. Engl. 1995, 34,
2393Ϫ2395; L. Banfi, G. Guanti, Eur. J. Org. Chem. 1998,
1543Ϫ1548; L. Banfi, G. Guanti, A. Basso, Eur. J. Org. Chem.
2000, 939Ϫ946; L. Banfi, G. Guanti, Tetrahedron Lett., submit-
ted.
L. Banfi, A. Basso, G. Guanti, Tetrahedron 1997, 53,
3249Ϫ3268.
[2]
[3]
L. Banfi, G. Guanti, Tetrahedron Lett. 2000, 41, 6523Ϫ6526.
K. C. Nicolaou, Angew. Chem. Int. Ed. Engl. 1991, 30,
[4]
1387Ϫ1530; K. C. Nicolaou, A. L. Smith, in Modern Acetylene
Chemistry (Eds.: P. J. Stang, F. Diederich), Wiley-VCH,
Weinheim, 1995, pp. 203Ϫ283; A. L. Smith, K. C. Nicolaou,
J. Med. Chem. 1996, 39, 2103Ϫ2117.
[5]
G. Eisenbrand, S. Lauck-Birkel, W. C. Tang, Synthesis 1996,
1246Ϫ1258.
[6]
A. M. Rauth, T. Melo, V. Misra, Int. J. Radiat. Oncol., Biol.,
Phys. 1998, 42, 755Ϫ762; B. G. Siim, W. A. Denny, W. R. Wil-
son, Oncol. Res. 1997, 9, 357Ϫ369.
I. Niculescu-Duvaz, C. J. Springer, Adv. Drug Delivery Rev.
[7]
1997, 26, 151Ϫ172; L. N. Jungheim, T. T. Shepherd, Chem.
Rev. 1994, 94, 1553Ϫ1566.
W. A. Denny, W. R. Wilson, J. Pharm. Pharmacol. 1998, 50,
[8]
387Ϫ394; M. P. Hay, W. R. Wilson, W. A. Denny, Bioorg. Med.
Chem. Lett. 1995, 5, 2829Ϫ2834; M. P. Hay, W. R. Wilson, W.
A. Denny, Bioorg. Med. Chem. Lett. 1999, 9, 3417Ϫ3422.
[25]
[26]
[27]
V. M. Vrudhula, P. D. Senter, K. J. Fischer, P. M. Wallace, J.
Med. Chem. 1993, 36, 919Ϫ923; G. S. Bignami, P. D. Senter, P.
G. Grothaus, K. J. Fischer, T. Humphreys, P. M. Wallace, Can-
cer Res. 1992, 52, 5759Ϫ5764.
P. A. Andreasen, R. Egelund, H. H. Petersen, Cell. Mol. Life
Sci. 2000, 57, 25Ϫ40; U. Reuning, V. Magdolen, O. Wilhelm,
K. Eischer, V. Lutz, H. Graeff, M. Schmitt, Int. J. Oncol.
1998, 893Ϫ906.
[9]
P. A. Wender, C. K. Zercher, S. Beckham, E.-M. Haubold, J.
Org. Chem. 1993, 58, 5867Ϫ5869; K. Nakatani, S. Isoe, S. Mae-
kawa, I. Saito, Tetrahedron Lett. 1994, 35, 605Ϫ608.
[10]
P. A. Wender, S. Beckham, J. C. O’Leary, Synthesis 1994,
1278Ϫ1282.
M. E. Maier, Synlett 1995, 13Ϫ26.
M. J. Begley, L. Crombie, D. Haigh, R. C. F. Jones, S. Osborne,
[11]
[12]
P. K. Chakravarty, P. L. Carl, M. J. Weber, J. A. Katzenellen-
bogen, J. Med. Chem. 1983, 26, 633Ϫ638; P. K. Chakravarty,
R. A. B. Webster, J. Chem. Soc., Perkin Trans. 1 1993,
Eur. J. Org. Chem. 2003, 1319Ϫ1336
1335

L. Banfi, G. Guanti, M. Rasparini
FULL PAPER
P. L. Carl, M. J. Weber, J. A. Katzenellenbogen, J. Med. Chem.
1983, 26, 638Ϫ644; F. M. H. de Groot, A. C. W. de Bart, J. H.
Verheijen, H. Scheeren, J. Med. Chem. 1999, 42, 5277Ϫ5283;
F. M. H. de Groot, L. W. A. van Berkom, H. W. Scheeren, J.
Med. Chem. 2000, 43, 3093Ϫ3102; F. M. H. de Groot, W. J.
Loos, R. Koekkoek, L. W. A. van Berkom, G. F. Busscher, A.
E. Seelen, C. Albrecht, P. de Bruijn, H. W. Scheeren, J. Org.
Chem. 2001, 66, 8815Ϫ8830; F. M. H. de Groot, E. W. P. Da-
men, H. W. Scheeren, Curr. Med. Chem. 2001, 8, 1093Ϫ1122;
A. Trouet, A. Passioukov, K. Van Derpoorten, A. M. Fernan-
dez, J. Abarca Quinones, R. Baurain, T. J. Lobl, C. Oliyai, D.
Shochat, V. Dubois, Cancer Res. 2001, 61, 2843Ϫ2846; G. Cav-
allaro, C. Pitarresi, M. Licciardi, G. Giammona, Bioconjugate
Chem. 2001, 12, 143Ϫ151; A. M. Fernandez, K. Van
Derpoorten, L. Dasnois, K. Lebtahi, V. Dubois, T. J. Lobl, S.
Gangwar, C. Oliyai, E. R. Lewis, D. Shochat, A. Trouet, J.
Med. Chem. 2001, 44, 3750Ϫ3753.
R. T. Cummings, G. A. Krafft, Tetrahedron Lett. 1988, 29,
65Ϫ68.
[28]
[29]
B. Amit, U. Zehavi, A. Patchornik, J. Org. Chem. 1974, 39,
192Ϫ196; A. Patchornik, B. Amit, R. B. Woodward, J. Am.
Chem. Soc. 1970, 92, 6333Ϫ6335.
Received November 5, 2002
[O02614]
1336
Eur. J. Org. Chem. 2003, 1319Ϫ1336