Synthesis and rearrangement of N-organyloxy β-lactams derived from a (4+2)/(3+2) sequential cycloaddition reaction involving enol ethers and nitro alkenes

Article abstract of DOI:10.1002/ejoc.200400371

The synthesis of N-organyloxy β-lactams 2 by treatment of nitroso acetals 1 with a base is discussed. Based on the formation of a by-product, a mechanism for the rearrangement to N-organyloxy β-lactams is proposed. This mechanism is supported by trapping of the intermediate acyl nitro compound 8 with dimethylamine. Furthermore, it was discovered that upon more forcing basic conditions these N-organyloxy β-lactams can rearrange further to 3-organyloxy β-lactams. By using a series of structurally diverse N-organyloxy β-lactams the generality of this novel rearrangement is demonstrated. A mechanism for the conversion of N-organyloxy β-lactams to 3-organyloxy β-lactams is proposed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400371

FULL PAPER
Synthesis and Rearrangement of N-Organyloxy β-Lactams Derived from a
(4؉2)/(3؉2) Sequential Cycloaddition Reaction Involving Enol Ethers and
Nitro Alkenes
[a]
[a]
[b]
´
Leon W. A. van Berkom, George J. T. Kuster, Rene de Gelder, and
Hans W. Scheeren*[a]
Keywords: β-Lactams / Cycloaddition / High-pressure chemistry / Rearrangement / Multicomponent reactions
The synthesis of N-organyloxy β-lactams 2 by treatment of
nitroso acetals 1 with a base is discussed. Based on the
ganyloxy β-lactams. By using a series of structurally diverse
N-organyloxy β-lactams the generality of this novel re-
formation of a by-product, a mechanism for the rearrange- arrangement is demonstrated. A mechanism for the conver-
ment to N-organyloxy β-lactams is proposed. This mechan- sion of N-organyloxy β-lactams to 3-organyloxy β-lactams is
ism is supported by trapping of the intermediate acyl nitro proposed.
compound with dimethylamine. Furthermore, it was
8
discovered that upon more forcing basic conditions these
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
N-organyloxy β-lactams can rearrange further to 3-or-
Germany, 2004)
Introduction
Key feature of the synthetic methodology was a high
pressure promoted (4ϩ2)/(3ϩ2) cycloaddition reaction of
an enol ether with two equivalents of a nitro alkene to give
a mixture of nitroso acetals (Scheme 2).[3Ϫ4]
Because of the important role in the treatment of bac-
terial infections, β-lactams have received much scientific at-
tention. Due to the developed resistance of bacteria against
β-lactams antibiotics, the search for novel antibiotics re-
mains a challenging problem.[1] Though organic chemists
have succeeded to develop numerous successful synthetic
methodologies towards this class of compounds, the dis-
covery of novel synthetic strategies remains an important
endeavor.
Recently we reported on a stereoselective route towards
bicyclic N-organyloxy β-lactams 2 via a base-induced re-
arrangement of nitroso acetals 1 (Scheme 1).[2]
Scheme 2. Formation of nitroso acetals
During a study to get more insight in the mechanism of
N-organyloxy β-lactam formation, we have found that un-
der slightly more forcing basic conditions these N-or-
ganyloxy β-lactams rearrange further to another lactam. In
this paper, the result of the mechanistic study towards the
formation of N-organyloxy β-lactams is presented. Further-
more, the scope and mechanism of the novel base-initiated
rearrangement of N-organyloxy β-lactams to 3-organyloxy
β-lactams will be discussed.
Scheme 1. Rearrangement to give N-organyloxy β-lactams
[a]
Department of Organic Chemistry, University of Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
E-mail: jsch@sci.kun.nl
[b]
Department of Inorganic Chemistry, University of Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Eur. J. Org. Chem. 2004, 4397Ϫ4404
DOI: 10.1002/ejoc.200400371
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4397

L. W. A. van Berkom, G. J. T. Kuster, R. de Gelder, H. W. Scheeren
FULL PAPER
Results and Discussion
nitro acyl anion 8 as intermediate (Scheme 4).[8] After for-
mation of 8 via deprotonation and NϪO bond cleavage,[9]
intramolecular substitution at the carbonyl group affords
N-organyloxy β-lactam 6 with loss of a NO2 anion (path-
way a).[10] Otherwise compound 8 reacts via pathway b
which involves elimination of 1-nitro-2-phenylethan-1-one
and formation of oxime O-ether 7.[11]
Formation of N-Organyloxy β-Lactams
As part of a study to investigate the scope of N-or-
ganyloxy β-lactam formation and as continuation of pre-
vious work,[2,3] 1-methoxycyclopent-1-ene was reacted with
two equivalents of β-nitrostyrene at 1.5 GPa to give the
nitroso acetals 3, 4 and 5 in a yield of 64% and in a ratio
of 15:9:1 respectively (Scheme 3). The stereochemistry of
the three isomers was assigned by using 2D-NOESY experi-
ments. The stereochemistry of nitroso acetal 3 was con-
firmed by using X-ray analysis (Figure 1).[5]
Scheme 4. Formation of N-organyloxy β-lactam 6 and trapping of
intermediate 8
Scheme 3. (4ϩ2)/(3ϩ2) cycloaddition of β-nitrostyrene and 1-meth-
oxycyclopent-1-ene
It was attempted to support this mechanism by trapping
of compound 8 with a nucleophile. Treatment of the nitroso
acetal 3 with an excess of dimethylamine at Ϫ50 °C for 2 h
gave the amide 9 in a yield of 63% (Scheme 4). To exclude
the possibility that amide 9 is formed by ring opening of
lactam 6 with dimethylamine, compound 6 was reacted un-
der the same conditions. This resulted only in partial epi-
merization of the starting material.[12]
Rearrangement of N-Organyloxy β-Lactams
Next, the base-promoted transformation of N-or-
ganyloxy β-lactam 6 was investigated in further detail
(Scheme 5). A solution of the lactam 6 and 1.0 equivalent
of triethylamine in CDCl3 was stirred at room temp. and
1
Figure 1. X-ray structure of nitroso acetal 3[6]
the reaction was studied with H NMR spectroscopy. After
24 h the conversion was 94% and two new compounds were
formed in a ratio of 2:1. After another 24 h the conversion
was complete and the ratio of products changed to 1.3:1
and after 4 days this ratio was 1:1.6. At this point the reac-
tion was stopped and epimer 10 and 3-organyloxy β-lactam
11 were isolated from the reaction in a yield of 34% and
Unexpectedly, nitroso acetal 3 did not give a clean and
quantitative conversion into N-organyloxy β-lactam 6 upon
treatment with triethylamine (Scheme 4). When nitroso ace-
tal 3 was reacted with a stoichiometric amount[7] of triethyl-
amine, N-organyloxy β-lactam 6 was initially formed but
under the reaction conditions this β-lactam slowly reacted
to give two new products. To prevent N-organyloxy β-lac-
tam 6 to react further, the reaction was performed at 0 °C
for 90 minutes. Interestingly, examination of the reaction
mixture indicated that not only lactam 6 was formed but
also the oxime O-ether 7. Although a concerted mechanism
for N-organyloxy β-lactam formation had been proposed
previously,[2] this result suggested that the reaction involves Scheme 5. Base-initiated rearrangement of N-organyloxy β-lactam
4398  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 4397Ϫ4404

Synthesis and Rearrangement of N-Organyloxy β-Lactams
FULL PAPER
O-ether 16 was obtained as by-product in 2% (Scheme 6,
Table 1. Results of base-induced rearrangement of N-organyloxy
β-lactams.
Figure 3).[13Ϫ14]
Entry
N-Organyloxy
β-lactam
Conditions[a]
Yield[b]
Product[c]
1
2
3
4
5
6
7
8
9
10
6
A
A
A
A
B
B
B
C
C
D
95 %
0
0
11/10, 1.6:1
12
13
14
12
13
14
12
14
14
0
92 %
91 %
0
78 %
n.d.
53 %
17/18, 3.3:1
19
Scheme 6. Synthesis of N-organyloxy β-lactam 14 and 15
17
20
21[d]
[a]
Conditions A: Et3N, CHCl3, room temp.. B: Et3N, reflux C:
[b]
NaOMe, THF, room temp.. D: LDA, THF, Ϫ78 °C.
Isolated
yield. [c] Product ratio based on 1H NMR analysis of crude reaction
[d]
mixture. pMBOH was isolated as by-product in 25% yield.
Figure 3. X-ray structure of compound 14[6]
The rearrangement of the N-organyloxy β-lactams 12Ϫ14
was studied by using a series of different conditions
(Table 1). Unexpectedly, the lactams 12Ϫ14 did not re-
arrange at room temperature with triethylamine (Entry
2Ϫ4). However, when the lactams 12 and 13 were heated at
reflux in the presence of triethylamine, rearrangement did
occur (Entry 5Ϫ6). Whereas the lactam 13 gave a clean and
near quantitative yield of the lactam 19, the lactam 12 gave
in good yield both the epimer 18 and the lactam 17. Lactam
14 did not rearrange under these conditions (Entry 7).
Upon treatment with sodium methoxide, the N-or-
ganyloxy β-lactam 12 gave the rearranged lactam 17 in 15
minutes in good yield (Entry 8). However, when these con-
ditions were applied to lactam 14, the main product of the
reaction was the ester 20 (Entry 9). It was reasoned that
ring opening is caused by the nucleophilicity of sodium
methoxide, and that application of a strong non-nucleo-
philic base should circumvent this problem. To our delight,
treatment of lactam 14 with LDA gave the lactam 21 in a
yield of 53% (Entry 10). In addition to the desired lactam,
p-methoxybenzyl alcohol was isolated as by-product in a
yield of 25%.
61% respectively (Entry 1, Table 1). The stereochemistry of
the rearranged lactam 11 was determined by X-ray crystal-
lography (Figure 2).[5]
Mechanistic Consideration
To explain the base-induced rearrangement, the mecha-
nism must involve cleavage of the NϪO bond (Scheme 7).
Since it was observed that the rate of the reaction depends
on the base that is employed, it is likely that the rearrange-
ment of the N-organyloxy β-lactam starts by deprotonation
Figure 2. X-ray structure of lactam 11[6]
To demonstrate the generality and the scope of this re- to give enolate I. After deprotonation, cleavage of the NϪO
arrangement, it was decided to investigate the lactams 12 bond can occur by formation of intermediate II, or via a
and 13 (Table 1).[2] To examine the effect of the acidity of SN1Ј-type pathway to give III.[15Ϫ16] Since it is unlikely that
the proton next to the lactam carbonyl, N-organyloxy β- the highly strained azabicyclobutanone II is formed, re-
lactam 14 was prepared. The lactams 14 and 15 were ob- arrangement most likely involves the zwitterionic intermedi-
tained in a yield of 53% and 13% respectively by reacting ate III. After formation of the intermediate III, ring closure
p-methoxybenzyl vinyl ether with two equivalents of nitro- followed by protonation gives 3-organyloxy β-lactam V.
ethene followed by treatment with triethylamine. The oxime Alternatively, intermediate III might give an elimination re-
Eur. J. Org. Chem. 2004, 4397Ϫ4404
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L. W. A. van Berkom, G. J. T. Kuster, R. de Gelder, H. W. Scheeren
FULL PAPER
per million (ppm) and coupling constants (J) are given in Hertz
(Hz). Mass spectra were recorded with a VG7070E double-focusing
mass spectrometer with EI and CI modes. IR spectra were recorded
with a Anadis Thermo Mattson IR300 spectrometer. Elemental
analysis were carried out with a CarloϪErba Instruments CHNSO
EA 1108 element analyzer. Thin layer chromatography (TLC) was
carried out on Merck precoated silica gel 60 F-254 plates. Spots
were visualised with UV or by dipping the TLC plate into a 6.2%
aqueous sulfuric acid solution containing ammonium molybdate
(42g/L) and ceric ammonium sulfate (3.6g/L) followed by charring.
Column chromatography was carried out with Baker silica gel
(63Ϫ200 mesh) and flash chromatography was carried out with
Acros silica gel (0.035Ϫ0.070mm). Melting points were determined
on a Buchi B-545 melting point apparatus and are uncorrected.
High pressure reactions were performed with the equipment de-
scribed by Aben et al.[18] When necessary, reactions were performed
under standard Schlenk conditions. Ethyl acetate and heptane were
distilled prior to use. Tetrahydrofuran was dried by distillation from
Scheme 7. Proposed mechanism for rearrangement of N-or-
ganyloxy β-lactam
action yielding an aldehyde IV. This is supported by the sodium/benzophenone ketyl.
observation that p-methoxybenzyl alcohol was formed as
Literature Preparations: The following compounds were prepared
side product in the rearrangement of the N-organyloxy β-
lactam 14. Unfortunately, we did not succeed to isolate or
detect the formation of an aldehyde IV.[17]
according to literature procedures: nitroethene,[19] 1-methoxycyclo-
pent-1-ene,[20] β-nitrostyrene,[21] p-methoxybenzyl vinyl ether[3d]
.
Preparation of Compounds 3, 4, and 5: 1-Methoxycyclopent-1-ene
(1.00 g, 10.2 mmol), β-nitrostyrene (3.12 g, 20.9 mmol, 2.05 equiv.)
and a spoontip of 5-tert-butyl-4-hydroxy-2-methylphenyl sulfide
were dissolved in CH2Cl2 in a 15-mL TeflonR tube. The reaction
mixture was pressurized at 1.5 GPa and room temperature for 36
h. After depressurizing the reaction, the solvent was evaporated in
vacuo. From NMR analysis of the crude reaction mixture it was
determined that the reaction gave 81% conversion into a mixture
of the compounds 3, 4, and 5 in a ratio of 16:9:1. The crude prod-
uct was purified by column chromatography (EtOAc/heptane, 1:8)
after which the nitroso acetals were isolated in a total yield of 64%.
Analytical samples were obtained from crystallization from
CH2Cl2/heptane.
Though this mechanism explains the formation of the
products, the influence of base, and the lower reactivity of
compound 14 compared with 6, 12, and 13, it is still not
clear to what extent the reactivity is influenced by structural
factors of the N-organyloxy β-lactams.
Conclusions
This work has confirmed the general applicability of the
(4ϩ2)/(3ϩ2) cycloaddition reaction of enol ethers and nitro
alkenes as a means to prepare N-organyloxy β-lactams. It
has been demonstrated that the rearrangement to these lac-
tams occurs via formation of an acyl nitro intermediate.
Furthermore, it has been discovered that these N-or-
ganyloxy β-lactams can give another base-induced re-
arrangement yielding 3-organyloxy β-lactams. It was dem-
onstrated with a series of structurally diverse substrates that
this novel rearrangement has a broad scope. The reaction
rate strongly correlates with the acidity of proton on the α
position of the carbonyl group and therefore depends on
the strength of the base that is used. It is believed that the
reaction is initiated by enolization, followed by a SN1Ј type
cleavage of the NϪO bond and cyclisation.
(؎)-(2S,3S,3aR,4S,4aR,7aR)-7a-Methoxy-2-nitro-3,4-diphenylper-
hydrocyclopenta[e]isoxazolo[2,3-b][1,2]oxazine (3): M.p. (CH2Cl2/
heptane) 151 °C (dec). 1H NMR (300 MHz, CDCl3): δ ϭ
0.84Ϫ0.97 (m, 1 H), 1.25Ϫ1.62 (m, 4 H), 1.94Ϫ2.05 (m, 1 H), 2.18
(dd, J ϭ 8.7 Hz, 12.9 Hz, 1 H), 2.30Ϫ2.39 (m, 1 H), 3.46 (s, 3 H),
3.96 (dd, J ϭ 1.2 Hz, 8.1 Hz, 1 H), 4.29 (dd, J ϭ 8.1 Hz, 8.7 Hz,
1 H), 6.29 (d, J ϭ 1.2 Hz, 1 H), 6.92Ϫ6.96 (m, 2 H), 7.22Ϫ7.46
(m, 8 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 21.9, 28.0, 31.2,
44.7, 47.6, 49.6, 56.6, 72.9, 112.8, 113.8, 127.6, 128.6, 128.7, 128.8,
128.9, 129.8, 134.8, 139.2 ppm. HRMS calcd. for [M]ϩ
(C22H24N2O5): 396.1685 found 396.1692. C22H24N2O5 (396.5):
calcd. C 66.65, H 6.10, N 7.07; found C 66.99, H 5.87, N 7.07.
(؎)-(2R,3S,3aR,4S,4aR,7aR)-7a-Methoxy-3-nitro-2,4-diphenylper-
hydrocyclopenta[e]isoxazolo[2,3-b][1,2]oxazine (4): M.p. (CH2Cl2/
heptane) 178 °C (dec). 1H NMR (300 MHz, CDCl3): δ ϭ
1.11Ϫ1.23 (m, 1 H), 1.59Ϫ1.78 (m, 4 H), 2.09Ϫ2.19 (m, 1 H),
2.39Ϫ2.49 (m, 1 H), 2.56 (dd, J ϭ 8.0 Hz, 12.6 Hz, 1 H), 3.45 (s,
3 H), 4.38 (dd, J ϭ 8.0 Hz, 9.3 Hz, 1 H), 5.17 (dd, J ϭ 6.6 Hz, 9.3
Hz, 1 H), 6.41 (d, J ϭ 6.6 Hz, 1 H), 7.22Ϫ7.39 (m, 10 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 21.8, 28.1, 30.9, 45.0, 47.0, 49.4,
76.4, 88.0, 94.3, 112.6, 126.5, 127.8, 128.6, 129.0, 129.1, 129.5,
134.7, 139.4 ppm. HRMS: calcd. for [M]ϩ (C22H24N2O5): 396.1685
found 396.1678. C22H24N2O5 (396.5): calcd. C 66.65, H 6.10, N
7.07; found C 66.79, H 5.89, N 7.02.
Because of the possibility to perform the (4ϩ2)/(3ϩ2)
cycloaddition reaction in a highly stereoselective and en-
antioselective manner,[4] this methodology has opened a
new route towards new β-lactam antibiotics.
Experimental Section
1
General Remarks: H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded with a Bruker AC-300 spectrometer in
CDCl3 with tetramethylsilane as internal standard. 2D NMR
experiments (NOESY, COSY) were performed with a Bruker AM-
400 spectrometer in CDCl3. Chemical shifts are reported in parts
(؎)-(2S,3R,3aR,4S,4aR,7aR)-7a-Methoxy-3-nitro-2,4-diphenylper-
hydrocyclopenta[e]isoxazolo[2,3-b][1,2]oxazine (5): M.p. (CH2Cl2/
4400
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Eur. J. Org. Chem. 2004, 4397Ϫ4404

Synthesis and Rearrangement of N-Organyloxy β-Lactams
FULL PAPER
heptane) 125 °C (dec). 1H NMR (300 MHz, CDCl3): δ ϭ
1.16Ϫ1.28 (m, 1 H), 1.58Ϫ1.81 (m, 4 H), 2.06Ϫ2.19 (m, 1 H),
1 H), 7.18Ϫ7.34 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
22.7, 30.6, 32.8, 36.1, 37.5, 46.0, 49.1, 50.0, 51.5, 62.1, 112.1, 126.7,
2.42Ϫ2.51 (m, 1 H), 2.79 (dd, J ϭ 7.0 Hz, 12.3 Hz, 1 H), 3.45 (s, 127.0, 128.2, 128.4, 129.0, 130.0, 136.0, 142.2, 172.3 ppm. HRMS
3 H), 4.41 (dd, J ϭ 7.0 Hz, 8.4 Hz, 1 H), 5.31 (dd, J ϭ 7.2 Hz, 8.4
Hz, 1 H), 5.79 (d, J ϭ 7.2 Hz, 1 H), 7.16Ϫ7.50 (m, 10 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 22.4, 28.7, 32.2, 47.8, 49.8, 49.9,
78.6, 90.2, 98.5, 113.2, 126.7, 127.8, 128.2, 128.8, 129.06, 129.08,
136.9, 139.2 ppm. HRMS: calcd. for [M]ϩ (C22H24N2O5): 396.1685
found 396.1687. C22H24N2O5 (396.5): calcd. C 66.65, H 6.10, N
7.07; found C 66.25, H 5.93, N 6.84.
calcd. for [M]ϩ (C24H30N2O3): 394.2257 found 394.2261.
Preparation of Compounds 10 and 11: The N-organyloxy β-lactam
6 (39.1 mg, 0.112 mmol) was dissolved in chloroform (1.5 mL).
Triethylamine (12.6 mg) was added and the reaction mixture was
stirred at room temperature. The reaction mixture was monitored
1
by H NMR spectroscopy. After 4 days the reaction solvents were
evaporated to dryness and the crude product was purified with col-
umn chromatography (EtOAc/heptane, 1:2). N-Organyloxy β-lac-
tam 10 (13.3 mg, 34%) was obtained as a white solid and lactam
11 (23.7 mg, 61%) was obtained as an oil. Lactam 10 was crys-
tallized from CH2Cl2/heptane to give white crystals. The lactam
11 was crystallized from CH2Cl2/diisopropyl ether yielding small
white crystals.
Preparation of Compounds 6 and 7: Nitroso acetal 3 (154 mg, 0.388
mmol) was dissolved in chloroform (3 mL). The solution was co-
oled to 0 °C and dropwise a solution of triethylamine (42 mg, 0.415
mmol) in chloroform (2 mL) was added. After 90 minutes the reac-
tion mixture was quenched with an excess of 1  ammonium chlo-
ride/water and extracted three times with dichloromethane. The
combined organic layers were dried (sodium sulfate), filtered, and
the solvents evaporated to dryness. The crude product was purified
by column chromatography (EtOAc/heptane, 1:8). The starting ma-
terial was recovered in 7% yield. The lactam 6 (100 mg, 74%) was
obtained as an oil. The imine 7 (7.8 mg, 9%) was also obtained as
a clear oil. An analytical sample of the lactam 6 was obtained by
crystallisation from CH2Cl2/heptane which yielded very small
white crystals.
(؎)-(1R,4aR,7aR,8S,8aR)-4a-Methoxy-1,8-diphenylperhydroazeto-
[1,2-b]cyclopenta[e][1,2]oxazin-2-one (10): M.p. (CH2Cl2/heptane)
149 °C. 1H NMR (300 MHz, CDCl3): δ ϭ 1.36Ϫ1.50 (m, 1 H),
1.51Ϫ1.65 (m, 1 H), 1.71Ϫ1.98 (m, 3 H), 2.01Ϫ2.12 (m, 1 H), 2.22
(td, J ϭ 7.2 Hz, 10.8 Hz, 1 H), 2.64 (t, J ϭ 10.8 Hz, 1 H), 3.86
(dd, J ϭ 2.1 Hz, 10.8 Hz, 1 H), 3.98 (d, J ϭ 2.1 Hz, 1 H), 6.96Ϫ7.03
(m, 2 H), 7.14Ϫ7.38 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 22.4, 30.6, 33.1, 49.6, 49.7, 51.1, 58.1, 62.2, 114.3, 127.0, 127.5,
127.7, 127.8, 128.7, 129.1, 134.1, 138.5, 167.3 ppm. HRMS calcd.
for [M]ϩ (C22H23NO3): 349.1678 found 349.1681. IR (film): ν˜ ϭ
(؎)-(1S,4aR,7aR,8S,8aR)-4a-Methoxy-1,8-diphenylperhydroazeto-
[1,2-b]cyclopenta[e][1,2]oxazin-2-one (6): M.p. (CH2Cl2/heptane) 99
°C. 1H NMR (300 MHz, CDCl3): δ ϭ 1.21Ϫ1.34 (m, 1 H),
1.51Ϫ1.78 (m, 3 H), 1.93Ϫ2.14 (m, 3 H), 2.32 (t, J ϭ 10.8 Hz, 1
H), 3.44 (s, 3 H), 4.20 (dd, J ϭ 5.1 Hz, 10.8 Hz, 1 H), 4.50 (d, J ϭ
5.1 Hz, 1 H), 6.47Ϫ6.53 (m, 2 H), 6.95Ϫ7.27 (m, 8 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 20.7, 28.5, 31.1, 45.0, 48.4, 50.7,
53.8, 58.1, 113.9, 126.7, 127.5, 127.9, 128.1, 128.2, 129.2, 131.3,
138.7, 166.9 ppm. HRMS calcd. for [M]ϩ (C22H23NO3): 349.1680
found 349.1672. IR (film): ν˜ ϭ 2952, 1774, 1496, 1452, 1328, 1192,
1133, 1084, 871, 751, 699 cmϪ1. C22H23NO3 (349.4): calcd. C 75.62,
H 6.63, N 4.01; found C 75.27, H 6.55, N 3.89.
2957, 1772, 1496, 1452, 1326, 1192, 1124, 1099, 873, 747, 699 cmϪ1
.
(؎)-(2aS,3aR,6aR,7S,7aR)-3a-Methoxy-2a,7-diphenylperhydro-
cyclopenta[5,6]pyrano[3,2-b]azet-2-one (11): M.p. (CH2Cl2/diisopro-
pyl ether) 169 °C. 1H NMR (300 MHz, CDCl3): δ ϭ 1.22Ϫ1.37
(m, 1 H), 1.51Ϫ1.75 (m, 2 H), 1.79Ϫ1.96 (m, 2 H), 2.18Ϫ2.27 (m,
1 H), 2.70Ϫ2.84 (m, 2 H), 3.38 (s, 3 H), 3.89 (d, J ϭ 2.1 Hz, 1 H),
6.36 (br. s, 1 H), 7.21Ϫ7.44 (m, 8 H), 7.55Ϫ7.62 (m, 2 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ ϭ 22.7, 30.8, 36.2, 42.1, 46.4, 49.6,
61.8, 86.8, 111.8, 125.6, 127.2, 128.0, 128.3, 128.6, 129.0, 136.8,
139.8, 170.5 ppm. HRMS: calcd. for [M ϩ H]ϩ (C22H24NO3):
350.1756 found 350.1750. IR (film): ν˜ ϭ 1759, 1493, 1448, 1329,
1171, 1090, 1011, 756, 735 cmϪ1. C22H23NO3 (349.4): calcd. C
75.62, H 6.63, N 4.01; found C 75.45, H 6.58, N 3.64.
(؎)-(4S,4aR,7aR)-7a-Methoxy-4-phenyl-4,4a,5,6,7,7a-hexahydro-
cyclopenta[e][1,2]oxazine (7): 1H NMR (300 MHz, CDCl3): δ ϭ
1.47Ϫ2.12 (m, 6 H), 2.25 (ddd, J ϭ 7.7 Hz, 7.7 Hz, 7.7 Hz, 1 H),
3.06 (dd, J ϭ 2.3 Hz, 7.7 Hz, 1 H), 3.56 (s, 3 H), 7.18Ϫ7.36 (m, 5
H), 7.77 (d, J ϭ 2.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 22.0, 31.3, 34.3, 43.1, 50.8, 51.2, 110.0, 127.1, 128.2, 128.7,
139.9, 161.1 ppm. HRMS calcd. for [M ϩ H]ϩ (C14H18NO2):
232.1338 found 232.1328. IR (film): ν˜ ϭ 2958, 1494, 1452, 1327,
(؎)-(2R,4S,4aR,5S)-2-[(4-Methoxybenzyl)oxy]-4,5-diphenylper-
hydroazeto[1,2-b][1,2]oxazin-6-one (12): Preparation according to
procedure in ref.[2]. Analytical sample was obtained by crystalliza-
tion from CH2Cl2/hexane. Rf ϭ 0.22 (EtOAc/hexane, 1:4 ϩ 1%
Et3N). M.p. (CH2Cl2/hexane) 143 °C. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.96Ϫ2.12 (m, 2 H), 2.64Ϫ2.72 (m, 1 H), 3.82 (s, 3
H), 3.99 (dd, J ϭ 4.8 Hz, 9.9 Hz, 1 H), 4.47 (d, J ϭ 4.8 Hz, 1 H),
4.77 (d, J ϭ 11.6 Hz, 1 H), 5.00 (d, J ϭ 11.6 Hz, 1 H), 5.02 (dd,
J ϭ 2.4 Hz, 10.8 Hz, 1 H), 6.42Ϫ6.49 (m, 2 H), 6.84Ϫ6.94 (m, 2
H), 7.02Ϫ7.17 (m, 5 H), 7.20Ϫ7.35 (m, 5 H) ppm. 13C NMR (75
MHz, CDCl3): δ ϭ 36.2, 41.4, 53.4, 55.3, 59.4, 71.5, 104.1, 113.9,
127.2, 130.0, 131.5, 138.8, 159.6, 163.7 ppm. IR (film): ν˜ ϭ 1771,
1614, 1587, 1515, 1454, 1250, 1149, 1035, 702 cmϪ1. C26H25NO4
(415.5): calcd. C 75.16, H 6.06, N 3.37; found C 75.23, H 6.00,
N 3.05.
1189, 1144, 1093, 842, 762, 701 cmϪ1
.
(؎)-2-[(3R,4S,4aR,7aR)-7a-Methoxy-4-phenylperhydrocyclo-
penta[e][1,2]oxazin-3-yl]-N,N-dimethyl-2-phenylacetamide (9): To a
2  solution of dimethylamine in tetrahydrofuran (5 mL) was ad-
ded dropwise at Ϫ70 °C a solution of nitroso acetal 3 (70 mg, 0.177
mmol) in dichloromethane (1.5 mL). The reaction mixture was
slowly warmed to Ϫ50 °C. After 2 h the reaction was quenched
with acetic acid (600 µL). The reaction mixture was diluted with 1
 ammonium chloride/water and extracted two times with di-
chloromethane. The organic layers were dried (sodium sulfate), fil-
tered and the solvents evaporated to dryness. The crude product (؎)-(1S,4aS,7aS,8S,8aR)-1,8-Diphenylperhydroazeto[1,2-b]cyclo-
was purified with column chromatography (EtOAc/heptane, 1:1).
penta[e][1,2]oxazin-2-one (13): Preparation according to procedure
1
The amide 9 (44.1 mg, 63%) was obtained as a clear oil. H NMR in ref.[2]. Rf ϭ 0.30 (EtOAc/hexane, 1:2 ϩ 1% Et3N). M.p. (EtOAc/
1
(300 MHz, CDCl3): δ ϭ 1.13Ϫ1.28 (m, 1 H), 1.39Ϫ1.68 (m, 4 H), hexane) 145 °C. H NMR (300 MHz, CDCl3): δ ϭ 1.63Ϫ1.70 (m,
1.80Ϫ1.93 (m, 1 H), 2.03Ϫ2.14 (m, 1 H), 2.37 (dd, J ϭ 9.3 Hz,
10.8 Hz, 1 H), 2.62 (s, 3 H), 2.72 (s, 3 H), 3.23 (s, 3 H), 3.77 (d, 3.94 (ddd, J ϭ 7.5 Hz, 9.2 Hz, 16.5 Hz, 1 H), 4.28 (dt, J ϭ 1.6 Hz,
J ϭ 4.8 Hz, 1 H), 3.97 (dd, J ϭ 4.8 Hz, 9.3 Hz, 1 H), 6.25 (br. s, 10.2 Hz, 1 H), 4.36 (dd, J ϭ 4.8 Hz, 10.4 Hz, 1 H), 4.54 (d, J ϭ
1 H), 2.19Ϫ2.52 (m, 2 H), 2.97 (dd, J ϭ 4.8 Hz, 10.4 Hz, 1 H),
Eur. J. Org. Chem. 2004, 4397Ϫ4404
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L. W. A. van Berkom, G. J. T. Kuster, R. de Gelder, H. W. Scheeren
FULL PAPER
4.8 Hz, 1 H), 5.53 (d, J ϭ 2.9 Hz, 1 H), 6.67Ϫ6.82 (m, 2 H),
Preparation of 17, Conditions c: Under argon, a solution of the
6.98Ϫ7.26 (m, 8 H) ppm. HRMS calcd. for [M]ϩ (C20H19NO3): lactam 12 (48.8 mg, 0.118 mmol) and sodium methoxide (9.5 mg,
321.1365 found 321.1365. C20H19NO3 (321.4): calcd. C 74.75, H
5.96, N 4.36; found C 74.75, H 5.81, N 4.39.
0.176 mmol) in dry tetrahydrofuran (1 mL) was stirred at room
temperature. After 15 minutes the reaction was quenched with an
excess of 1  ammonium chloride/water. The resulting mixture was
extracted three times with dichloromethane. The organic layer was
dried (sodium sulfate), filtered and the solvents evaporated to dry-
ness. The crude product was purified by using column chromatog-
raphy (EtOAc/heptane, 1:2) to give 17 (38.5 mg, 78%).
Preparation of 14, 15, and 16: A solution of p-methoxybenzyl vinyl
ether (497 mg, 3.03 mmol) and nitroethene (470 mg, 6.43 mmol)
in 1.5 mL chloroform was stirred at room temperature for 17 h. To
the reaction mixture was added triethylamine (400 mg, 3.95 mmol)
and the reaction mixture was stirred for 35 minutes. The reaction
mixture was diluted with dichloromethane and washed with satu-
rated sodium hydrogen carbonate. The aqueous layer was extracted
twice with dichloromethane. The combined organic layers were
dried (sodium sulfate), filtered, and the solvents evaporated to dry-
ness. The crude product was purified by column chromatography
(EtOAc/heptane, 2:5, 1% triethylamine) to obtain lactam 14 (423
mg, 53%) as a white solid, lactam 15 (101 mg, 13%) as an oil, and
the oxime O-ether 16 (16.1 mg, 2%) as an oil. An analytical sample
of N-organyloxy β-lactam 14 was obtained by crystallization from
EtOAc/heptane.
(؎)-(2aS,4R,6R,6aR)-4-[(4-Methoxybenzyl)oxy]-2a,6-diphenylper-
hydropyrano[3,2-b]azet-2-one (17): M.p. (CH2Cl2/diisopropyl ether)
154 °C. 1H NMR (300 MHz, CDCl3): δ ϭ 2.25 (dddd, J ϭ 0.9 Hz,
4.2 Hz, 7.2 Hz, 14.1 Hz, 1 H), 2.48 (dt, J ϭ 6.6 Hz, 14.1 Hz, 1 H),
3.21 (ddd, J ϭ 2.7 Hz, 4.2 Hz, 13.8 Hz, 1 H), 3.78 (s, 3 H), 4.03
(dd, J ϭ 0.9 Hz, 2.7 Hz, 1 H), 4.52 (d, J ϭ 11.4 Hz, 1 H), 4.95 (d,
J ϭ 11.4 Hz, 1 H), 5.32 (dd, J ϭ 6.6 Hz, 7.2 Hz, 1 H), 5.90 (s, 1
H), 6.83Ϫ6.88 (m, 2 H), 7.15Ϫ7.43 (m, 10 H), 7.56Ϫ7.61 (m, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 28.6, 38.8, 55.5, 62.0, 69.3,
87.0, 97.7, 113.8, 125.5, 127.2, 127.3, 128.5, 128.7, 129.0, 129.6,
130.1, 137.0, 139.8, 159.1, 170.0 ppm. HRMS: calcd. for [M ϩ H]ϩ
(C26H26NO4): 416.1862 found 416.1862. IR (film): ν˜ ϭ 2941, 1761,
(؎)-(2R,4aR)-2-[(4-Methoxybenzyl)oxy]perhydroazeto[1,2-b][1,2]-
oxazin-6-one (14): M.p. (EtOAc/heptane) 86 °C. 1H NMR (300
MHz, CDCl3): δ ϭ 1.50Ϫ1.65 (m, 1 H), 1.67Ϫ1.81 (m, 1 H), 1.88
(dtd, J ϭ 1.8 Hz, 3.9 Hz, 13.8 Hz, 1 H), 2.24Ϫ2.33 (m, 1 H), 2.34
(dd, J ϭ 1.5 Hz, 13.8 Hz, 1 H), 2.94 (dd, J ϭ 4.2 Hz, 13.8 Hz, 1
H), 3.59 (dtd, J ϭ 1.5 Hz, 4.2 Hz, 10.1 Hz, 1 H), 3.79 (s, 3 H),
4.65 (d, J ϭ 11.4 Hz, 1 H), 4.84 (dd, J ϭ 1.8 Hz, 9.0 Hz, 1 H),
4.89 (d, J ϭ 11.4 Hz, 1 H), 6.83Ϫ6.89 (m, 2 H), 7.23Ϫ7.31 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 28.0, 28.5, 40.2, 48.7,
55.3, 71.2, 103.5, 113.8, 128.3, 129.8, 159.2, 164.0 ppm. HRMS
calcd. for [M]ϩ (C14H17NO4): 263.1158 found 263.1159. IR (film):
ν˜ ϭ 2958, 1771, 1613, 1514, 1249, 1158, 1028, 952, 908, 832, 749
cmϪ1. C14H17NO4 (263.3): calcd. C 63.87, H 6.51, N 5.32; found
C 63.78, H 6.50, N 5.29.
1610, 1506, 1243, 1174, 1104, 1031, 970, 906, 828, 728, 694 cmϪ1
.
C26H25NO4 (415.5): calcd. C 75.16, H 6.06, N 3.37; found C 75.01,
H 5.91, N 3.08.
(؎)-(2R,4S,4aR,5R)-2-[(4-Methoxybenzyl)oxy]-4,5-diphenylper-
hydroazeto[1,2-b][1,2]oxazin-6-one (18): 1H NMR (300 MHz,
CDCl3): δ ϭ 2.08 (ddd, J ϭ 9.0 Hz, 12.6 Hz, 13.8 Hz, 1 H), 2.18
(ddd, J ϭ 1.9 Hz, 4.2 Hz, 13.8 Hz, 1 H), 3.01 (ddd, J ϭ 4.2 Hz,
9.6 Hz, 12.6 Hz, 1 H), 3.61 (dd, J ϭ 1.2 Hz, 9.6 Hz, 1 H), 3.80 (s,
3 H), 3.93 (d, J ϭ 1.2 Hz, 1 H), 4.75 (d, J ϭ 11.4 Hz, 1 H), 4.98
(d, J ϭ 11.4 Hz, 1 H), 5.10 (dd, J ϭ 1.9 Hz, 9.0 Hz, 1 H), 6.86Ϫ6.92
(m, 2 H), 7.11Ϫ7.45 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 35.4, 46.5, 55.5, 58.9, 63.7, 71.7, 104.0, 114.0, 126.9, 127.2,
127.73, 127.74, 128.3, 128.8, 129.1, 130.1, 133.8, 138.9, 159.5, 163.4
ppm. HRMS calcd. for [M]ϩ (C26H25NO4): 415.1784 found
415.1789. IR (film): ν˜ ϭ 2928, 1776, 1513, 1249, 1157, 1034, 811,
(؎)-(2S,4aR)-2-[(4-Methoxybenzyl)oxy]perhydroazeto[1,2-b][1,2]-
oxazin-6-one (15): 1H NMR (300 MHz, CDCl3): δ ϭ 1.80Ϫ2.00
(m, 4 H), 2.49 (dd, J ϭ 1.5 Hz, 13.5 Hz, 1 H), 2.99 (dd, J ϭ 4.2
Hz, 13.5 Hz, 1 H), 3.63Ϫ3.72 (m, 1 H), 3.79 (s, 3 H), 4.55 (d, J ϭ
11.1 Hz, 1 H), 4.92 (pseudo d, J ϭ 2.4 Hz, 1 H), 5.00 (d, J ϭ 11.1
Hz, 1 H), 6.78Ϫ6.89 (m, 2 H), 7.26Ϫ7.33 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 22.0, 26.4, 41.9, 49.7, 55.5, 70.1, 98.7, 113.8,
129.0, 130.3, 159.3, 166.0 ppm. HRMS calcd. for [M]ϩ
(C14H17NO4): 263.1158 found 263.1156.
737, 699 cmϪ1
.
(؎)-(2aS,3aR,6aS,7S,7aR)-2a,7-Diphenylperhydrofuro[3Ј,2Ј:5,6]-
pyrano[3,2-b]azet-2-one (19): A solution of the nitroso acetal 13
(40.2 mg, 0.125 mmol) and triethylamine (13.2 mg, 0.130 mmol) in
chloroform (1 mL) was heated at reflux for 4 days. The reaction
solvents were evaporated to dryness and the crude product was
purified by column chromatography (EtOAc/heptane, 1:1) to ob-
tain the lactam 19 (36.5 mg, 91%) as a white solid. An analytical
sample was obtained by crystallization from CH2Cl2/diisopropyl
ether. M.p. (CH2Cl2/diisopropyl ether) 187 °C. 1H NMR (300
MHz, CDCl3): δ ϭ 1.74 (dddd, J ϭ 3.3 Hz, 7.7 Hz, 10.7 Hz, 12.9
Hz, 1 H), 2.22 (qd, J ϭ 8.6 Hz, 12.9 Hz, 1 H), 2.93Ϫ3.06 (m, 1
H), 3.40 (dd, J ϭ 2.4 Hz, 6.0 Hz, 1 H), 3.61 (dt, J ϭ 8.1 Hz, 8.7
Hz, 1 H), 4.11 (dt, J ϭ 3.2 Hz, 8.7 Hz, 1 H), 4.28 (dd, J ϭ 0.9 Hz,
2.4 Hz, 1 H), 5.82 (d, J ϭ 7.8 Hz, 1 H), 7.20Ϫ7.39 (m, 8 H), 7.46
(br. s, 1 H), 7.55Ϫ7.64 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 28.1, 38.6, 40.2, 58.1, 66.0, 86.8, 102.4, 125.8, 127.1, 127.5,
128.6, 129.0, 136.5, 139.7, 170.9 ppm. HRMS: calcd. for [M ϩ H]ϩ
(C20H20NO3): 322.1443 found 322.1435. IR (film): ν˜ ϭ 2937, 1757,
1493, 1446, 1174, 1053, 1035, 906, 724, 698 cmϪ1. C20H19NO3
(321.4): calcd. C 74.75, H 5.96, N 4.36; found C 74.48, H 5.80,
N 4.06.
(؎)-6-[(4-Methoxybenzyl)oxy]-5,6-dihydro-4H-1,2-oxazine (16): 1H
NMR (300 MHz, CDCl3): δ ϭ 1.87Ϫ2.07 (m, 3 H), 2.25Ϫ2.40 (m,
1 H), 3.79 (s, 3 H), 4.54 (d, J ϭ 11.4 Hz, 1 H), 4.75 (d, J ϭ 11.4
Hz, 1 H), 5.14 (bd, J ϭ 5.1 Hz, 1 H), 6.83Ϫ6.89 (m, 2 H),
7.23Ϫ7.29 (m, 2 H), 7.33 (bd, J ϭ 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 16.9, 22.3, 55.5, 69.2, 94.4, 113.8, 129.7,
150.4, 159.1 ppm. HRMS calcd. for [M]ϩ (C12H15NO3): 221.1052
found 221.1052.
Preparation of 17 and 18, Conditions b: A solution of the lactam 12
(71 mg, 0.171 mmol) and triethylamine (20.2 mg, 0.200 mmol) in
chloroform (1.5 mL) was heated at reflux for 4 days. The reaction
was diluted with dichloromethane and the organic layer was
washed with 1  ammonium chloride/water. The aqueous layers
were extracted twice with dichloromethane. The combined organic
layers were dried (sodium sulfate), filtered, and the solvents evapo-
rated to dryness. The crude products were separated by using col-
umn chromatography (EtOAc/heptane, 1:2) to obtain the lactam (؎)-Methyl 2-{(3R,6R)-6-[(4-Methoxybenzyl)oxy]-1,2-oxazinan-3-
17 (49.9 mg, 70%) as a white solid and the epimer 18 (15.5 mg, yl}acetate (20): To a solution of the lactam 14 (48.8 mg, 0.185
22%) as a clear oil.
mmol) in dry tetrahydrofuran (1 mL) was added sodium methoxide
4402
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4397Ϫ4404

Synthesis and Rearrangement of N-Organyloxy β-Lactams
FULL PAPER
Table 2. Crystallographic data and parameters for the compounds 3, 11, and 14
Compound
3
11
14
Empirical formula
Molecular mass
Temperature (K)
Wavelength (A)
Crystal system
Space group
C22H24N2O5
396.43
293(2)
0.71073
monoclinic
P21/c
C22H23NO3
349.41
293(2)
0.71073
triclinic
¯
P1
C14H17NO4
263.29
208(2)
0.71073
orthorhombic
P212121
˚
˚
Unit cell dimension (A, °)
a
b
c
21.719(6)
9.2550(13)
21.821(4)
90
111.139(19)
90
4091.2(15)
8
10.939(2)
10.847(6)
17.982(6)
83.02(4)
76.50(2)
63.10(2)
1849.9(13)
4
6.2622(4)
13.6803(16)
15.5130(17)
90
90
90
1329.0(2)
4
1.316
α
β
γ
3
˚
Volume (A )
Z
Density (calculated, mg/m3)
1.287
0.092
1680
1.255
0.083
744
µ (mmϪ1
F(000)
)
0.097
560
Crystal size (mm)
θ Range (°)
Reflections collected
Independent reflections [Rint
Refinement method
Data/restraint/parameters
Goodness-of-fit on F2
R1, wR2 indices [I Ͼ 2σ(I)]
R1, wR2 indices (all data)
0.31 ϫ 0.16 ϫ 0.07
2.75Ϫ25.00
7364
7164 [0.0592]
Full-matrix least-squares on F2
7164/937/535
0.971
0.1066, 0.1468
0.3562, 0.2209
0.248 and Ϫ0.215
0.40 ϫ 0.36 ϫ 0.14
3.11Ϫ21.98
4681
0.25 ϫ 0.15 ϫ 0.08
3.51Ϫ27.52
17409
]
4503 [0.1644]
3016 [0.0428]
4503/824/471
0.986
0.1211, 0.1242
0.4309, 0.1986
0.249 and Ϫ0.245
3017/0/240
1.055
0.0473, 0.0793
0.0760, 0.0863
0.127 and Ϫ0.174
Ϫ3
˚
Largest diff. peak and hole (e·A
)
(15.3 mg, 0.283 mmol). The reaction mixture was stirred at room
temperature for 45 minutes and then quenched with an excess of 1
 ammonium chloride/water. The resulting mixture was extracted
2 H), 7.26Ϫ7.33 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
22.2, 23.7, 47.3, 55.5, 69.0, 76.6, 96.8, 113.7, 129.8, 129.9, 159.0,
170.2 ppm. HRMS: calcd. for [M]ϩ (C14H17NO4): 263.1158 found
three times with dichloromethane. The combined organic layers 263.1155. IR (film): ν˜ ϭ 2941, 1753, 1610, 1511, 1455, 1364, 1303,
were dried (sodium sulfate), filtered and the solvents evaporated to
dryness. Ester 20 was purified by using column chromatography
(EtOAc/heptane, 1:2). 1H NMR (300 MHz, CDCl3): δ ϭ 1.37Ϫ1.47
(m, 1 H), 1.55Ϫ1.69 (m, 1 H), 1.86Ϫ2.04 (m, 2 H), 2.49 (dd, J ϭ
5.4 Hz, 15.9 Hz, 1 H), 2.68 (dd, J ϭ 8.4 Hz, 15.9 Hz, 1 H),
3.34Ϫ3.45 (m, 1 H), 3.69 (s, 3 H), 3.79 (s, 3 H), 4.51 (d, J ϭ 11.4
Hz, 1 H), 4.71Ϫ4.75 (m, 2 H), 6.78Ϫ6.88 (m, 2 H), 7.23Ϫ7.29 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 25.4, 27.1, 36.5, 52.0,
52.7, 55.5, 69.9, 99.0, 113.9, 129.5, 129.7, 159.2, 172.1 ppm. HRMS
calcd. for [M]ϩ (C15H21NO5): 295.1420 found 295.1420. IR (film):
1242, 1178, 1152, 1100, 1070, 1035, 945, 910, 824, 728, 646, 564
cmϪ1
.
Crystal Structure Determinations:[5] Crystals suitable for X-ray dif-
fraction studies were grown by slow evaporation from CH2Cl2/
heptane for 3, CH2Cl2/diisopropyl ether for 11, and EtOAc/heptane
for 14. Single crystals were mounted in air on glass fibres. Intensity
data were collected at room temperature for 3 and 11 and at Ϫ65
°C for 14. An EnrafϪNonius CAD4 single-crystal diffractometer
was used for 3 and 11 (ω-2θ scan mode) and a Nonius KappaCCD
diffractometer for 14, (π and ω scan mode), all using graphite-
monochromated Mo-Kα radiation. The structures were solved by
the program CRUNCH[22] and were refined with standard methods
using SHELXL-97[23] with anisotropic parameters for the non-hy-
drogen atoms. For 3 and 11 all hydrogens were placed at calculated
positions and were refined riding on the parent atoms. For 14 the
hydrogens were initially placed at calculated positions and were
freely refined subsequently. Crystallographic data and parameters
of the refinements are listed in Table 2.
ν˜ ϭ 2950, 1731, 1610, 1515, 1437, 1299, 1256, 1035, 824 cmϪ1
.
(؎)-(2aS,4R,6aR)-4-[(4-Methoxybenzyl)oxy]perhydropyrano[3,2-b]-
azet-2-one (21): Under argon, a solution of the lactam 14 (56.9 mg,
0.216 mmol) in dry tetrahydrofuran (1 mL) was cooled to Ϫ78 °C
and a solution of LDA (0.4 mL 0.661  LDA/THF, 0.264 mmol)
was added dropwise over a period of 5 minutes. The reaction mix-
ture was stirred for 90 minutes and then quenched with an excess
of saturated sodium hydrogen carbonate. The resulting mixture was
extracted three times with dichloromethane. The combined organic
layers were dried (sodium sulfate), filtered and the solvents evapo-
rated to dryness. The crude products were separated by using col-
umn chromatography (EtOAc/heptane, 2:1) to yield p-meth-
oxybenzyl alcohol (7.6 mg, 25%) and the lactam 21 (30.4 mg, 53%)
Acknowledgments
We are grateful to Daniel Blanco Ania for his careful reading of
the manuscript.
1
as a clear oil. H NMR (300 MHz, CDCl3): δ ϭ 1.73Ϫ1.98 (m, 4
[1]
H), 3.77 (s, 3 H), 3.81Ϫ3.86 (m, 1 H), 4.43 (d, J ϭ 11.4 Hz, 1 H),
4.73 (dd, J ϭ 1.8 Hz, 5.4 Hz, 1 H), 4.85 (d, J ϭ 11.4 Hz, 1 H),
4.92 (dd, J ϭ 5.7 Hz, 5.7 Hz, 1 H), 6.33 (br. s, 1 H), 6.80Ϫ6.87 (m,
J. Davies, Science 1994, 264, 375Ϫ381.
[2]
G. J. Kuster, F. Kalmoua, R. de Gelder, H. W. Scheeren, Chem.
Commun. 1999, 855Ϫ856.
Eur. J. Org. Chem. 2004, 4397Ϫ4404
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4403

L. W. A. van Berkom, G. J. T. Kuster, R. de Gelder, H. W. Scheeren
FULL PAPER
[3] [3a]
[13]
R. M. Uittenbogaard, J.-P. G. Seerden, H. W. Scheeren,
Unfortunately all attempts to isolate the intermediate nitroso
[3b]
Tetrahedron 1997, 53, 11929Ϫ11936.
G. J. Kuster, H. W.
acetals failed, because evaporation of solvent in vacuo caused
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in the 1,3-dipolarcycloaddition step was quite surprising, since
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Crystallographic data for the structures 3, 11, and 14 have been
deposited with the Cambridge Crystallography Data Centre as
supplementary publication numbers CCDC-239386, CCDC-
239387, and CCDC-239388 respectively. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Fax: (internat.) ϩ44(0)-
1223Ϫ336033 or E-mail: deposit@ccdc.cam.ac.uk).
A. L. Spek (2004) PLATON, A Multipurpose Crystallographic
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Using a catalytic amount of base the reaction did not go to
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Under the basic reaction conditions the aldehyde probably re-
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In the presence of the weak base triethylamine the formation
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[11]
[12]
[23]
M. Joucla, J. Hamelin, R. Carrie, Tetrahedron 1974, 30,
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Treatment of the lactam 6 with dimethylamine for 2 h gave
56% conversion into the lactam 10 (Scheme 5).
4404
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4397Ϫ4404