Synthesis of enantiomerically pure α-amino-β-hydroxy- cyclobutanone derivatives and their transformations into polyfunctional three- and five-membered ring compounds

Article abstract of DOI:10.1016/j.tet.2004.06.085

Ketenes readily cycloadded to (R)-tert-butyldihydrooxazole 2a-d to yield enantiomerically pure bicyclic cyclobutanones. The cycloadditions proceeded with unusual regiochemistry giving predominantly or exclusively protected α-amino-β-hydroxycyclobutanone derivatives. The adducts could be converted into a variety of interesting enantiopure intermediates equipped with many functional groups: α-amino-β-hydroxy cyclopropane carboxylic acid derivatives, α-amino-β-hydroxy succinic acid derivatives, α-amino-β-hydroxy lactones and lactams derivatives.

Full text of DOI:10.1016/j.tet.2004.06.085

Tetrahedron 60 (2004) 7591–7606
Synthesis of enantiomerically pure a-amino-b-hydroxy-
cyclobutanone derivatives and their transformations into
polyfunctional three- and five-membered ring compounds
a,b
a
a
a
,
*
´
Leon Ghosez,
´
Gaoqiang Yang, Jose Renato Cagnon, Franck Le Bideau
and Jacqueline Marchand-Brynaerta
aDepartment of Chemistry, University of Louvain, Place L. Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
´
Institut Europeen de Chimie et Biologie, 2 rue Robert Escarpit, F-33607 Pessac Cedex, France
b
Received 17 May 2004; revised 8 June 2004; accepted 11 June 2004
Dedicated to Professor Dieter Seebach in recognition of his seminal contributions to organic chemistry
Abstract—Ketenes readily cycloadded to (R)-tert-butyldihydrooxazole 2a–d to yield enantiomerically pure bicyclic cyclobutanones. The
cycloadditions proceeded with unusual regiochemistry giving predominantly or exclusively protected a-amino-b-hydroxycyclobutanone
derivatives. The adducts could be converted into a variety of interesting enantiopure intermediates equipped with many functional groups:
a-amino-b-hydroxy cyclopropane carboxylic acid derivatives, a-amino-b-hydroxy succinic acid derivatives, a-amino-b-hydroxy lactones
and lactams derivatives.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The growing resistance of bacterial strains to antibiotics is a
major concern of our society.1 b-Lactam antibiotics are the
most often prescribed class of antibacterial agents and, as a
Figure 1.
result, bacteria have developed efficient resistance mecha-
nisms to these antibiotics. For instance the microorganisms
produce b-lactamases which are able to cleave the ester
linkage formed by acylation of D,D-peptidases by the
antibiotics, thus regenerating the free enzyme which can
again exercise its biological function.2 For several years, we
have been interested in the design, synthesis and biological
evaluation of new inhibitors of penicillin binding pro-
teins.3–5 Our approach was to design molecules which
would make an ether link with the serine protease, thus
suppressing the regeneration of the free enzyme by a
hydrolytic mechanism. In this context, the replacement of
the acylating lactam function of penicillins or cephalo-
sporins by a reactive hydroxyalkylating carbonyl group
could lead to stable adducts with bacterial serine proteases.
General structure 1 (Fig. 1) or its stereoisomers were
regarded as potential alkylating inhibitors of these enzymes:
(a) the carbonyl group is part of a strained ring and more
susceptible to undergo addition reactions; (b) the X atom
(H, F, Cl) could be used to modulate the electrophilic
reactivity of the neighbouring carbonyl group; (c) the
carboxyl and acylamino groups are properly placed to
mimic the b-lactam antibiotics.
Clearly such an endeavour required an easy access to
enantiomerically pure 2-aminocyclobutanones with appro-
priate functional groups at C-3 and C-4. Methyl (2R)-2-tert-
butyldihydrooxazole 2a first studied in Seebach’s group6
Keywords: Asymmetric synthesis; (2þ2) Cycloaddition; Ketene;
Cyclobutanone; Cyclopropane; Amino acid; Serine protease.
*
Corresponding author. Tel: þ33-5-4000-2217; fax: þ33-5-4000-2222;
e-mail address: l.ghosez@iecb.u-bordeaux.fr
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.085

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L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
was regarded as an interesting olefinic building-block which
should selectively cycloadd with ketenes from the face
opposite to the tert-butyl substituent (Scheme 1). However
Seebach et al. had shown that electrophilic additions to 2a
always occurred at C-5 as a result of the lower energy of an
acyl iminium intermediate relative to that of an oxonium
ion.7 Thus ketenes were expected to react with 2 to yield an
adduct with the carbonyl group a to the oxygen. Additional
steps would then be needed to move the carbonyl group to
the right position. Gratifyingly our initial studies showed
that the theoretical predictions were not fulfilled: the
cycloaddition of 2a with diphenylketene led to the
unpredicted, yet desired cycloadduct.8 We now report
the full details of the cycloaddition of ketenes to (2H)oxa-
zoles as well as illustrative examples of the synthetic
potential of the cycloadducts.
2. Results and discussion
2.1. Synthesis of (2H)oxazoles
Methyl (2R)-2-(tert-butyl)-1,3-oxazole-3(2H)-carboxylate
2a,b were prepared from l-serine following the procedure
described by Seebach6 except for the electrochemical
oxidative decarboxylation step (Scheme 2). We found that
a thermal oxidative decarboxylation with lead tetraacetate
was more practical and gave better yields (84 and 82%) than
the described electrochemical method (33%). The new
(2H)oxazoles 2c and 2d (enantiomer of 2b, prepared from
d-serine) were also synthesized by this modified procedure.
These optimized sequences of reactions allowed us to
prepare up to 50 g of enantiopure (2H)oxazoles in 35–45%
overall yield.
2.2. Synthesis of acyl chlorides
Ketenes were conveniently generated by dehydrochlori-
nation of the corresponding acid chlorides. a-Chloroacyl
chlorides 3a–h were readily prepared following literature
procedures (Fig. 2).9
Scheme 2. Reagents and conditions: (i) MeOCOCl, Et3N (4a), (Boc)2O,
NaHCO3, MeOH (4b), AllylOCOCl, NaHCO3, MeOH (4c); (ii) KOH,
MeOH–H2O, RT; (iii) Pb(OAc)4, benzene, reflux, (iv) NH4Br, 1,2-dichloro-
ethane, reflux.
Acyl chlorides 3i–n was synthesized by the sequences of
reaction shown in Scheme 3.
2.3. Cycloaddition reactions
2.3.1. Cycloadditions to a-haloketenes. a-Haloketenes
were generated in situ from the corresponding acid chlorides
3 and triethylamine. In most cases cycloadditions were
performed in cyclohexane at 60 8C to give high yields of
adducts (Scheme 4, Table 1). No cycloadduct was obtained
Figure 2.
Scheme 3. Reagents and conditions: (i) SOCl2, 70 8C, then NCS, SOCl2, HCl, 85 8C; (ii) (COCl)2, DMF, DCM; (iii) LDA, 278 8C, then CCl4; (iv) LiOH,
THF–H2O, H2O2; (v) O3, DCM; (vi) ethylene glycol, TsOH, benzene; (vii) H2, Pd/C.

L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
7593
Scheme 4.
Table 1. Cycloadditions of oxazolines 2a–c to haloketenes
exclusively the isomer with the carbonyl group a to the
nitrogen substituent.
Entry
R1
R2
X
Adduct Yield (%)
A/B
The cycloadditions were remarkably stereoselective. In all
cases, the addition took place from the face opposite to the
t-butyl group and the halogen atom was always exo. Thus
the reaction produced enantiomerically pure adducts. The
configuration of the stereogenic centers of the adducts
results from the selection of the serine enantiomer (here
l-serine) and the stereochemical course of the reaction.
1
2
3
4
5
6
7
8
Me Me
t-Bu Me
Allyl Me
Cl 13
Cl 14
Cl 15
Cl 16
Cl 17
Cl 18
Cl 19
Cl 20
Cl 21
Cl 22
Cl 23
Cl 24
Cl 25
Cl 26
Cl 27
Cl 28
Cl 29
Cl 30
Cl 31
Cl 32
80a
75a
78
.98:2
.98:2
Only A
Only A
10:1
4:1
10:1
6:1
Only A
Only A
6:1
8:1
20:1
8:1
8/1
19:1
20:1
Me
Me
Et
iPr
80
62a
65b
87a
60a
86
t-Bu iPr
Me Ph
t-Bu Ph
9
Me
CH2TMS
t-Bu CH2TMS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
82
(2H)Oxazole 2d, the enantiomer of 2b was prepared from
d-serine. It also reacted with ketenes derived from acid
chlorides 3a and 3c to give good yields of adducts 35 and
36a-b (Scheme 5).
Me CH2CH2Br
t-Bu CH2CH2Br
Allyl CH2CH2Br
80b
72b
77a
76b
54a
80a
75a
77b
72b
56
Me
Me
Me
CH2CH2OMe
CH2CH2OSitBuMe2
CH2CH2OSitBuPh2
The cycloaddition of 2b with dichloroketene was less
successful as a result of the instability of the adduct 37
which was therefore dechlorinated in situ to give a modest
30% yield of 38. The best conditions are described in
Scheme 6.
t-Bu CH2CH2OSitBuPh2
Allyl CH2CH2OSitBuPh2
10:1
6:1
Only A
10:1
Me
CH2CH2OBn
t-Bu CH2CH2OBn
Me
Me
Me
Me
Me
CH2CH(OCH2CH2O) Cl 33
CH2CO2CH3
iPr
Me
Ph
62b
0
Cl
Br 34
F
F
74b
0
4:1
The structure and configuration of adducts were established
by a detailed analysis of their 1H and 13C NMR spectra and
the use of NOE effects (Section 4). The assignments were
confirmed by X-ray diffraction analyses of a ‘minor’ adduct
20B and a ‘major’ adduct 29A.10 The regioselectivity of
the cycloaddition excluded a two-step pathway involving a
zwitterionic intermediate since an electrophilic addition to
(2H)oxazoles should predominantly lead to isomer B in
agreement with the earlier observations of Seebach’s
group.6 Both the regio- and stereoselectivity of the
cycloaddition can be accounted for by a concerted
cycloaddition involving an orthogonal approach of the
ketene to the less-hindered face (away from the t-butyl
substituent) of the (2H)oxazole and with the larger
0
a
Pure isomer A.
Purified mixture of A and B.
b
with the acid chloride derived from methyl monochloro-
succinate (entry 22). In this case, the ketene was probably
not formed since a facile competitive b-elimination of HCl
could occur. Also we did not get any adduct from the
a-fluoroacyl chlorides (entries 24 and 25). It is also highly
probable that the corresponding fluoroketenes were not
formed. As in the model reaction with diphenylketene, the
cycloaddition was regioselective, yielding predominantly or
Scheme 5.
Scheme 6.

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L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
interesting enantiopure synthetic intermediates. It was out
of the scope of this work to investigate in detail the synthetic
potential of these cyclobutanones. We just performed a
selected number of transformations showing that the four-
membered ring could readily be transformed into three-
and five-membered rings or be cleaved to generate
functionalized a-amino acid derivatives.
2.4.1. Synthesis of enantiopure a-aminocyclopropane
carboxylic acid derivatives. In the course of our studies on
the total synthesis of bacterial peptidase inhibitors, we
observed that the treatment of cyclobutanone 23 with NaI in
DMSO containing potassium carbonate did not yield the
desired iodide but rather led to a cyclopropane carboxylic
acid derivative 44 resulting from a Favorskii rearrangement
(Scheme 9). The same ring contraction could be more
classically effected by sodium hydroxide in methanol.13
Figure 3.
substituent R away from the double bond (Fig. 3). It can be
readily seen that rotation b which is favoured by electronic
factors would create an interaction between R and the
nitrogen substituent. No such steric repulsion results from
rotation a which places the carbonyl group a to the nitrogen
atom. Thus, in all cases, steric effects superseded electronic
effects.
Scheme 7.
2.3.2. Cycloadditions to other ketenes. Scheme 7
describes the [2þ2] cycloadditions of (2H)oxazoles 2a
and 2b with N-methyl-N-tosyl- or methoxyketene.11 Sur-
prisingly we could not isolate the cyclobutanone adducts
which were acylated in situ to give enol esters 39 and 40.
The high temperature (110 8C) required for these cyclo-
additions probably accounted for the acylation of the
adducts. Of special interest to us was the cycloaddition of
2b to dithiolanoketene 41, a synthetic equivalent of the
unknown dimer of CO (Scheme 8).12 In this case, the
cycloaddition did not occur when the ketene was generated
from the acid chloride. However the thermolysis of 42 in
refluxing toluene slowly generated ketene 41 which was
trapped by olefin 2b to give adduct 43 in moderate yields.
Scheme 9.
Thus the sequential cycloaddition-Favorskii rearrangement
represents a potentially useful route towards highly
functionalized enantiopure a-aminocyclopropane car-
boxylic acid derivatives.
2.4.2. Synthesis of enantiopure bicyclic g-lactones and
g-lactams. A number of cyclobutanones could be readily
oxidized to the corresponding g-butyrolactones 46a–h
(Scheme 10, Table 2). The reaction was totally regiospecific
giving the expected isomer resulting from the insertion of
the oxygen atom into the carbon–carbon bond adjacent to
the acylamino substituent. Yields were excellent.
Scheme 10.
Similarly treatment of cyclobutanones 13 and 21 by an
excess of o-mesitylsulfonylhydroxylamine,14 followed by
absorption on basic alumina and elution with methanol gave
a moderate yield of bicyclic g-lactam 47a–b and but in
moderate yields (Scheme 11).
Scheme 8.
2.4. Selected transformations of the cycloadducts
The concatenation of many functional groups in these
readily accessible cyclobutane derivatives make them
2.4.3. Synthesis of enantiomerically pure a-amino-b-
hydroxysuccinic acid derivatives. Based on previous

L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
7595
Table 2. Bayer–Villiger oxidations
Substrates
Products
Yield (%)
46a
46b
90
85
46c
46d
46e
92
90
88
Scheme 12.
followed by nucleophilic attack of the resulting alkoxide ion
on the carbamate group.
3. Conclusions
In conclusion, we have described the unique capacity of
(2H)oxazole to react with ketenes to yield enantiopure
a-amino-cyclobutanone derivatives. The stereochemistry of
the cycloadditions is controlled by the large t-butyl group.
Steric factors in an orthogonal transition state readily
account for the unusual regiochemistry of these reactions.
The rich functionality of the adducts should make them very
useful for further transformations. These intermediates thus
appeared to be well suited for the synthesis of our target
inhibitors 1 of bacterial peptidases (Fig. 1). We have also
shown in selected experiments that the four-membered ring
could be contracted or expanded to generate enantiopure
three- or five-membered ring derivatives. They could also
be used for the preparation of new a-amino acids.
46f
46g
46h
86
85
80
4. Experimental
4.1. General
NMR spectra were recorded on a Varian Gemini 300BB
1
(300 MHz for H and 75 MHz for 13C). High resolution
spectra were recorded on a Brucker AM-500 (500 MHz for
1H and 125 MHz for 13C). Chemical shifts are given in ppm
relative to the internal reference. Coupling constants
(J values) are reported in Hertz (Hz), and multiplicities
are indicated by the following symbols: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), b (broad).
The MS spectra were recorded on a Varian MAT-44 or
FINNIGAN MAT-TSQ 70 apparatus. Infrared spectra were
recorded on a BIORAD FTS-135. The optical rotation
values were measured on a PERKIN–ELMER 241
polarimeter. Concentrations are given in g/100 ml. Melting
points were measured with a BUCHI apparatus (oil bath)
and are uncorrected. Flash chromatography separations
were performed using MERCK 60 40–63 mm silica
and pre-distilled technical grade solvents. Triethyl-
amine, CH2Cl2 and ClCH2CH2Cl were distilled on CaH2.
Scheme 11.
observations, it was anticipated that cyclobutanone 43
should be readily cleaved by nucleophilic reagents. Indeed
treatment of 43 with sodium hydroxide in methanol–water
or with sodium methoxide at room temperature led to the
selective cleavage of the four-membered ring in very high
yield (Scheme 12). Compound 48 corresponds to a product
of vicinal acylation of (2H)oxazole 2b.
Interestingly the reaction of cyclobutanone 43 with tolyl
magnesium bromide yielded the tricyclic structure 50
resulting from a stereoselective addition of the Grignard
reagent from the exo-face of the bicyclic cyclobutanone

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L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
Cyclohexane and toluene were distilled on Na
with benzophenone as indicator. DMF was dried over
˚
3 A MS.
97.5 (NCHO), 81.8 (OtBu), 68.3 (CH2O), 59.7 (CHN), 52.4
(OMe), 37.5 (tBu), 28.3 (OtBu), 25.8 (tBu).
4.2. General procedure for the preparation of 5a–5d
4.1.1. 3-(tert-Butyl)4-methyl (2R,4S)-2-(tert-butyl)-1,3-
oxazolane-3,4-dicarboxylate 4b. Into a 1 l three-necked
flask equipped with a condenser, methyl (2R,4S)-2-(t-
butyl)-1,3-oxazolane-4-carboxylate (38.0 g, 0.2 mol),
sodium bicarbonate (41.72 g, 0.5 mol), di-t-butyl dicarbo-
nate (44.7 g, 0.2 mol,) and methanol (550 ml) were added,
the mixture was allowed to stay in an ultrasonic bath at
50 8C for 5 h. After cooling, the mixture was filtered, and
the filtrate was concentrated under the reduced pressure.
The resulting residue was diluted with diethyl ether, and
washed with brine, dried over MgSO4 and concentrated to
Into a 500 ml three-necked flask equipped with an
additional funnel, 4a–4d (1 equiv.) and methanol (2 ml/
mmol) was added, the mixture was cooled to 0 8C and then
3 N KOH (1.5 equiv.) was added dropwise. The mixture
was allowed to warm to room temperature and stirred
overnight. The solvent was removed, and the residue was
diluted with ether, then acidified with 3 N HCl till pH 1–2,
and then extracted with ether. The combined organic layers
were washed with 2 N NaCl, dried and concentrated to give
the product 5a–5d.
1
give 4b as a colourless oil (86%). H NMR (300 MHz,
CDCl3) d 5.03 (s, 1H, NCHO), 4.70 (dd, J¼8.3, 6.1 Hz, 1H,
CH2O), 4.30 (dd, J¼8.4, 6.0 Hz, 1H, CH2O), 4.12 (t, J¼
8.4 Hz, 1H, CHN), 3.75 (s, 3H, MeO), 1.47 (s, 9H, OtBu),
0.94 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d 171.0
(CvO), 155.2 (CvO), 97.8 (NCHO), 81.4 (OtBu), 68.7
(CH2O), 59.6 (CHN), 52.4 (OMe), 37.5 (tBu), 28.4 (OtBu),
25.6 (tBu). IR (neat) n 2976, 1764, 1709. [a]2D0¼233.1 (c
1.14 CHCl3). MS (CI) m/z 287 (Mþ), 230, 174, 130, 57.
Anal. Calcd for C14H25NO5 C 58.52, H 8.76, N 4.87; found
C 58.85, H 8.53, N 4.25.
4.2.1. (2R,4S)-4-(tert-Butoxycarbonyl)-2-(tert-butyl)-1,3-
oxazolane-4-carboxylic acid 5b. White solid, yield 94%,
mp 106–109 8C. 1H NMR (300 MHz, CDCl3) d 10.6 (b, 1H,
OH), 5.06 (s, 1H, NCHO), 4.69 (dd, J¼9.0, 6.4 Hz, 1H,
CH2O), 4.40 (dd, J¼9.0, 6.4 Hz, 1H, CH2O), 4.23 (t, J¼
9.0 Hz, 1H, CHN), 1.49 (s, 9H, OtBu), 0.93 (s, 9H, tBu). 13C
NMR (75 MHz, CDCl3) d 173.0 (CvO), 155.8 (CvO),
97.6 (NCHO), 82.4 (OtBu), 67.8 (CH2O), 59.4 (CHN),
37.8 (tBu), 28.2 (OtBu), 25.6 (tBu). IR (neat) n (cm21
)
3180, 2979, 1765, 1681. [a]2D0¼264 (c 1.0 CHCl3). MS
(CI) m/z 216 (Mþ), 160, 116, 57. Anal. Calcd for
C14H25NO5 C 57.12, H 8.48, N 5.12; found C 57.56, H
8.20, N 5.68.
4.1.2. 3-Allyl 4-methyl (2R,4S)-2-(tert-butyl)-1,3-oxazo-
lane-3,4-dicarboxylate 4c. Into a 500 ml three-necked flask
equipped with an additional funnel, methyl (2R,4S)-2-(t-
butyl)-1,3-oxazolane-4-carboxylate (38 g, 0.2 mol) and
dichloromethane (250 ml) were added, the mixture was
cooled to 0 8C, and then allyl chloroformate (25 g, 0.21 mol)
was added dropwise. The mixture was allowed to warm to
room temperature and stirred overnight. After filtration, the
filtrate was washed with 1 N HCl and brine, then dried over
MgSO4 and concentrated to give the product as a colourless
oil, yield 91%. 1H NMR (300 MHz, CDCl3) d 5.93 (m, 1H,
vCH), 5.32 (ddd, J¼17.2, 3.1, 1.5 Hz, 1H, CH2v), 5.24
(ddd, J¼10.4, 2.7, 1.3 Hz, 1H, CH2v), 5.1 (s, 1H, NCHO),
4.77 (dd, J¼8.0, 4.9 Hz, 1H, CH2O), 4.64 (dd, J¼5.4,
1.4 Hz, 2H, CH2OCO), 4.35 (dd, J¼8.6, 4.9 Hz, 1H, CH2O),
4.12 (t, J¼8.4 Hz, 1H, CHN), 3.72 (s, 3H, MeO), 0.94 (s,
9H, tBu). 13C NMR (75 MHz, CDCl3) d 170.6 (CvO),
155.8 (CvO), 132.2 (CHv), 117.9 (CH2v), 97.8 (NCHO),
68.2 (CH2OCO), 66.7 (CH2O), 59.6 (CHN), 52.4 (OMe),
37.5 (tBu), 25.6 (tBu).
4.2.2. (2R,4S)-4-(Allyloxycarbonyl)-2-(tert-butyl)-1,3-
oxazolane-4-carboxylic acid 5c. White solid, yield 96%,
1
mp 118–120 8C. H NMR (300 MHz, CDCl3) d 5.92 (m,
1H, vCH), 5.34 (ddd, J¼17.2, 3.0, 1.5 Hz, 1H, CH2v),
5.25 (ddd, J¼10.5, 2.7, 1.3 Hz, 1H, CH2v), 5.12 (s, 1H,
NCHO), 4.78 (dd, J¼8.5, 5.5 Hz, 1H, CH2O), 4.66 (ddd,
J¼15.7, 2.7, 1.4 Hz, 2H, CH2OCO), 4.41 (dd, J¼8.8,
5.5 Hz, 1H, CH2O), 4.2 (t, J¼8.6 Hz, 1H, CHN), 0.94 (s,
9H, tBu). 13C NMR (75 MHz, CDCl3) d 173.9 (CvO),
156.5 (CvO), 131.8 (CHv), 118.6 (CH2v), 97.9 (NCHO),
68.0 (CH2OCO), 67.2 (CH2O), 59.6 (CHN), 37.5 (tBu), 25.6
(tBu).
4.2.3. tert-Butyl (2S,4R)-4-hydroxycarbonyl-2-(tert-
butyl)-1,3-oxazolane-3-carboxylate (5d). White solid,
1
yield 89%, mp 103–105 8C. H NMR (300 MHz, CDCl3)
d 11.2 (s, 1H, OH), 5.07 (s, 1H, NCHO), 4.65 (dd, J¼8.7,
6.4 Hz, 1H, CH2O), 4.47 (dd, J¼8.7, 6.3 Hz, 1H, CH2O),
4.24 (t, J¼8.8 Hz, 1H, CHN), 1.50 (s, 9H, OtBu), 0.94 (s,
9H, tBu). 13C NMR (75 MHz, CDCl3) d 172.6 (CvO),
155.9 (CvO), 97.4 (NCHO), 83.5 (OtBu), 67.7 (CH2O),
59.4 (CHN), 37.8 (tBu), 28.1 (OtBu), 26.7 (tBu).
4.1.3. tert-Butyl (2S,4R)-4-methoxycarbonyl-2-(tert-
butyl)-1,3-oxazolane-3-carboxylate (4d). Into a 250 ml
flask equipped with a condenser, methyl (2S,4R)-2-(t-
butyl)-1,3-oxazolane-4-carboxylate (15.7 g, 83.85 mmol),
sodium bicarbonate (17.6 g, 209.6 mmol) and di-t-butyl
dicarbonate (18.86 g, 83.85 mmol) in methanol (234 ml)
were added. The mixture was stirred at 50 8C in an
ultrasonic bath for 5 h. The solution was filtered and the
MeOH was evaporated. The residue was diluted with ether
and washed with brine, dried over MgSO4 and concentrated
4.3. General procedure for the preparation of 6a–6d
Into a 1 l three-necked flask equipped with an additional
funnel, lead tetraacetate (1.5 equiv.) and benzene
(3 ml/mmol) were added. After stirring for 30 min, 5a–5d
(1 equiv.) in benzene (1 ml/mmol) was added dropwise. The
mixture was allowed to heat to reflux for 8 h. After cooling,
the mixture was filtered through a small column of 6–7 cm
celite, washed with cyclohexane. The solvent was removed
under the reduced pressure; the residue was diluted with
1
to give the product (22.6 g, 94%). H NMR (300 MHz,
CDCl3) d 5.03 (s, 1H, NCHO), 4.7 (m, 1H, CH2O), 4.28 (dd,
J¼8.6, 5.75 Hz, 1H, CH2O), 4.14 (t, J¼8.6 Hz, 1H, CHN),
3.76 (s, 3H, MeO), 1.48 (s, 9H, OtBu), 0.94 (s, 9H, tBu). 13C
NMR (75 MHz, CDCl3) d 170.9 (CvO), 155.9 (CvO),

L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
7597
pentane, then filtered through a pad of silica gel. The filtrate
was concentrated to give the product 6a–6d.
4.4.2. Allyl (2R)-2-(tert-butyl)-1,3-oxazole-3(2H)-carb-
oxylate 2c. White solid, yield 85%, mp 38–40 8C. 1H
NMR (300 MHz, CDCl3) d 6.20 (d, J¼13.7 Hz, 2H, CHO,
CHN), 5.93 (m, 1H, vCH), 5.62 (s, 1H, NCHO), 5.33 (ddd,
J¼17.2, 3.1, 1.5 Hz, 1H, CH2v), 5.26 (ddd, J¼10.4, 2.7,
1.4 Hz, 1H, CH2v), 4.64 (dd, J¼5.7, 1.4 Hz, 2H, CH2),
0.97 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d 154.1
(CvO), 133.7 (CHO), 132.3 (CHv), 118.1 (CH2v), 109.5
(CHN), 98.2 (NCHO), 66.4 (CH2O), 38.3 (tBu), 24.1 (tBu).
[a]2D0¼þ432 (c 1.05, CHCl3). MS (EI) m/z (%) 211 (Mþ1,
74), 154 (M2tBu, 100), 110 (74), 70 (19). Anal. Calcd for
C11H17NO3 C 62.86, H 8.08, N 6.42; found C 62.54, H 8.11,
N 6.63.
4.3.1. tert-Butyl (2R,4R)-4-acetyloxy-2-(tert-butyl)-1,3-
1
oxazolane-3-carboxylate 6b. Colorless oil, yield 78%. H
NMR (300 MHz, CDCl3) d 6.56 (dd, J¼5.2, 2.2 Hz, 1H,
CHOAc), 5.08 (s, 1H, NCHO), 4.15 (dd, J¼10.2, 5.2 Hz,
1H, CH2O), 3.98 (dd, J¼10.0, 2.2 Hz, 1H, CH2O), 2.08 (s,
3H, CH3CO), 1.48 (s, 9H, OtBu), 0.98 (s, 9H, tBu). 13C
NMR (75 MHz, CDCl3) d 170.3 (CvO), 154.5 (CvO),
97.7 (NCHO), 82.9 (CHOAc), 81.4 (OtBu), 66.8 (CH2O),
38.0 (tBu), 28.4 (OtBu), 25.2 (tBu), 21.2 (Me). IR (film) n
2978, 1719, 1480, 1360. [a]2D0¼þ25.7 (c 1.07 CHCl3). MS
(EI) m/z 287 (Mþz), 230 (M2tBu)þ, 130. Anal. Calcd for
C14H25NO5 C 58.51, H 8.76, N 4.87; found C 58.75, H 8.87,
N 4.97.
4.4.3. tert-Butyl (2S)-2-(tert-butyl)-1,3-oxazole-3-carb-
oxylate 2d. White solid, yield 74%, mp 45–47 8C. 1H
NMR (300 MHz, CDCl3) d 6.14 (se, 2H, NCHO, CHv),
5.56 (s, 1H, CHv), 1.49 (s, 9H, OtBu), 0.92 (s, 9H, tBu).
13C NMR (75 MHz, CDCl3) d 153.9 (CvO), 133.1 (CHv),
101.0 (CHv), 97.9 (NCHO), 81.0 (OtBu), 38.2 (tBu), 28.2
(OtBu), 24.1 (tBu). MS (APCI) m/z (%) 172 (M2tBu, 10),
126 (M2Boc, 80). [a]D20¼23.6 (c 1.3, CHCl3), Anal. Calcd
for C12H21NO3 C 63.41, H 9.31, N 6.16; found C 63.72, H
9.08, N 6.29.
4.3.2. Allyl (2R,4R)-4-acetyloxy-2-(tert-butyl)-1,3-oxazo-
lane-3-carboxylate 6c. Colourless oil, yield 68%. 1H NMR
(300 MHz, CDCl3) d 6.59 (dd, J¼4.94, 1.92 Hz, 1H,
CHOAc), 5.93 (m, 1H, vCH), 5.33 (ddd, J¼17.2, 3.0,
1.5 Hz, 1H, CH2v), 5.26 (ddd, J¼10.6, 2.7, 1.4 Hz, 1H,
CH2v), 5.12 (s, 1H, NCHO), 4.64 (dt, J¼15.7, 1.4 Hz, 2H,
CH2OCO), 4.13 (dd, J¼10.0, 5.0 Hz, 1H, CH2O), 4.01 (dd,
J¼10.0, 1.9 Hz, 1H, CH2O), 2.01 (s, 3H, CH3CO), 0.98 (s,
9H, tBu). 13C NMR (75 MHz, CDCl3) d 170.3 (CvO),
154.5 (CvO), 131.8 (CHv), 118.4 (CH2v), 97.7 (NCHO),
82.9 (CHOAc), 72.65 (CH2OCO), 66.8 (CH2O), 37.2 (tBu),
25.6 (tBu).
4.4.4. 2-Chloro-3-methoxycarbonylpropanoyl chloride
3i. Mono-methyl succinate (6.23 g, 44.79 mmol) and
thionyl chloride (13.1 ml, 179.1 mmol) were placed in a
50 ml flask equipped with a magnetic bar and a condenser
with a drying tube. The reaction mixture was stirred and
heated in a 70 8C oil bath. After 0.5 h, the flask was removed
from the oil bath and cooled to room temperature. The finely
powdered N-chlorosuccinimide (12 g, 89.6 mmol), thionyl
chloride (9 ml, 122.9 mmol) and hydrochloric acid (conc.
270 ml) were added consecutively. The flask was heated
again to 85 8C for 3 h. The solvent was removed under the
reduced pressure and the solid (succinimide) was washed
with CCl4. The filtrate was fractionally distilled to give the
4.3.3. tert-Butyl (2S,4R)-4-acetoxy-2-(tert-butyl)-1,3-oxa-
zolane-3-carboxylate 6d. Yield 76%. 1H NMR (300 MHz,
CDCl3) d 6.55 (dd, J¼5.3, 1.9 Hz, 1H, CHOCO), 5.08 (s,
1H, NCHO), 4.15 (dd, J¼10.0, 5.3 Hz, 1H, CH2O), 3.97
(dd, J¼10.0, 2.4 Hz, 1H, CH2O), 2.1 (s, 3H, Me), 1.48
(s, 9H, OtBu), 0.97 (s, 9H, tBu). 13C NMR (75 MHz,
CDCl3) d 170.4 (CvO), 153.6 (CvO), 97.4 (NCHO), 83.3
(CHOCO), 81.8 (OtBu), 72.7 (CH2O), 37.1 (tBu), 28.1
(OtBu), 25.6 (tBu), 21.0 (Me).
1
product (2.5 g, 30%), bp 30–32 8C/0.1 mm Hg. H NMR
(300 MHz, CDCl3) d 4.90 (dd, J¼7.1, 6.5 Hz, 1H, CHCl),
3.76 (s, 3H, OCH3), 3.04–3.29 (m, 2H, CH2). 13C NMR
(75 MHz, CDCl3) d 172.2 (CvO), 167.8 (CvO), 66.4
(CHCl), 52.2 (OCH3), 35.2 (CH2).
4.4. General procedure for the preparation of 2a–2d
Into a 500 ml three-necked flask equipped with an extractor
connected with a condenser, 6a–6d (1 equiv.), ammonium
bromide (2.5 equiv.) and toluene (2 ml/mmol) were
added. In the extractor toluene (150 ml) and 3 N KOH
(150 ml) were added. The mixture was allowed to warm
to reflux for 6 h. After cooling, the mixture was filtered
and the filtrate was washed with a solution of saturated
NaHCO3 and brine, then dried and concentrated.
The residue was flash chromatographied to give the product
2a–2d.
4.5. General procedure for a-chlorination of ester
Methyl 4-benzyloxybutanoate (10 g, 48.0 mmol) in THF
(25 ml) was added dropwise at 278 8C to a LDA solution
that was prepared by adding n-butyllithium (2.4 M in
hexane, 20 ml, 48.0 mmol) to diisopropylamine (7.1 ml,
50.4 mmol) in THF (250 ml) at 0 8C and stirring for 30 min.
After stirring for a further 20 min, CCl4 (5.0 ml, 52.8 mmol)
was added rapidly and the resulting solution was stirred
for 5 min at 278 8C, then a solution of saturated NH4Cl
(160 ml) was added and the mixture was extracted with
ether. The combined organic layers were washed with brine,
dried over MgSO4 and evaporated to give the product.
Purification by flash chromatography gave pure product.
4.4.1. tert-Butyl (2R)-2-(tert-butyl)-1,3-oxazole-3(2H)-
carboxylate 2b. White solid, yield 68%, mp 45–46 8C.
1H NMR (300 MHz, CDCl3) d 6.16 (d, J¼13.7 Hz, 2H,
CHO, CHN), 5.60 (s, 1H, NCHO), 1.44 (s, 9H, OtBu), 0.97
(s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d 153.8 (CvO),
133.5 (CHO), 109.5 (CHN), 98.2 (NCHO), 81.2 (OtBu),
38.3 (tBu), 28.2 (OtBu), 26.1 (tBu). [a]2D0¼þ352 (c 1.01,
CHCl3). MS (CI) m/z 227 (Mþ), 170, 114, 70. Anal. Calcd
for C12H21NO3 C 63.40, H 9.31, N 6.16; found C 63.10, H
9.22, N 5.91.
4.5.1. Methyl 4-benzyloxy-2-chlorobutanoate 7a. Colour-
less oil, yield 77%, Rf¼0.3 (PE/AcOEt¼9/1,) 1H NMR
(300 MHz, CDCl3) d 7.27–7.34 (m, 5H, Ph), 4.55 (dd,
J¼8.35, 5.55 Hz, 1H, CHCl), 4.50 (s, 2H, PhCH2), 3.71 (s,

7598
L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
3H, OMe), 3.65 (m, 2H, OCH2), 2.16–2.37 (m, 2H, CH2).
13C NMR (75 MHz, CDCl3) d 170.2 (CvO), 138.0 (Carom),
128.4, 128.3, 127.6 (CHarom), 73.1 (PhCH2), 65.7 (OCH2),
54.3 (CHCl), 52.7 (OMe), 35.1 (CH2). MS (APCI) m/z (%)
243 (Mþ1, 5), 91 (100). Anal. Calcd for C12H15ClO3 C
59.39, H 6.23, Cl 14.60; found C 59.68, H 6.14, Cl 15.39.
19.1 (CH2). MS (APCI) m/z (%) 377 (Mþ1, 100), 299
(M2Ph, 30), 209 (30). Anal. Calcd for C20H25ClO3Si C
63.72, H 6.68, Cl 9.41; found C 63.02, H 6.69, Cl 9.62.
4.6. General procedure for the preparation 3j–n
Into a 100 ml flask, 4-methoxy-2-chloro-3-butanoic acid
(1 equiv.), catalytical amount of DMF and CH2Cl2
(10 ml/mmol) were added, the mixture was cooled to
0 8C, then oxalyl chloride (5 equiv.) was added dropwise.
The mixture was allowed to warm slowly to 15 8C for
30 min. The solvent was removed under the reduced
pressure, and the residue was diluted with benzene and
concentrated one more time to give the product.
4.5.2. Methyl 2-chloro-4-tert-butyldimethylsilyloxy
butanoate 7b. Colorless oil, yield 58%, Rf¼0.42 (PE/
AcOEt¼16/1) 1H NMR (300 MHz, CDCl3) d 4.52 (dd,
J¼9.0, 5.1 Hz, 1H, CHCl), 3.78 (s, 3H, OMe), 3.76 (m, 2H,
OCH2), 2.0–2.3 (m, 2H, CH2), 0.89 (s, 9H, tBu), 0.05 (s,
6H, 2Me). 13C NMR (75 MHz, CDCl3) d 170.3 (CvO),
58.7 (OCH2), 54.1 (CHCl), 52.9 (OMe), 37.5 (CH2), 25.8
(tBu), 18.2 (tBu), 25.5 (SiMe).
4.6.1. 4-Methoxy-2-chloro-3-butanoyl chloride 3j. Yield
90%. 1H NMR (300 MHz, CDCl3) d 4.78 (dd, J¼8.0,
5.0 Hz, 1H, CH), 3.60 (m, 2H, OCH2), 3.35 (s, 3H, OMe),
2.2–2.48 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3) d
170.6 (CvO), 67.3 (OCH2), 62.4 (CH), 58.8 (OMe), 34.7
(CH2).
4.5.3. Methyl 2-chloro-4-tert-butyldiphenylsilyloxy
butanoate 7c. Yield 68%, Rf¼0.3 (PE/Et2O¼16/1), 1H
NMR (300 MHz, CDCl3) d 7.48–7.76 (m, 10H, 2Ph), 4.77
(dd, J¼8.8, 4.94 Hz, 1H, CHCl), 3.9 (m, 2H, OCH2), 3.8 (s,
3H, OMe), 2.15–2.45 (m, 2H, CH2), 1.15 (s, 9H, tBu). 13
C
NMR (75 MHz, CDCl3) d 170.5 (CvO), 133.5 (Carom),
135.5, 129.6, 127.6 (CHarom), 59.7 (OCH2), 54.1 (CHCl),
52.8 (OMe), 37.3 (tBu), 26.7 (tBu), 19.2 (CH2). MS (APCI)
m/z (%) 391 (Mþ1, 5), 313 (M2Ph, 100). Anal. Calcd for
C21H27ClO3Si C 64.51, H 6.96, Cl 9.07; found C 65.19, H
6.86, Cl 9.24.
4.6.2. 4-Benzyloxy-2-chlorobutanoylchloride 3k. Yield
90%. 1H NMR (300 MHz, CDCl3) d 7.29–7.38 (m, 5H, Ph),
4.81 (dd, J¼8.0, 5.2 Hz, 1H, CHCl), 4.50 (s, 2H, PhCH2),
3.66 (m, 2H, OCH2), 2.22–2.51 (m, 2H, CH2). 13C NMR
(75 MHz, CDCl3) d 170.3 (CvO), 137.8 (Carom), 128.4,
127.8, 127.6 (CHarom), 73.3 (PhCH2), 64.9 (OCH2), 62.5
(CHCl), 34.9 (CH2).
4.5.4. General procedure for the hydrolysis of methyl
esters. Into a 100 ml flask, methyl 2-chloro-4-benzyloxy-
butanoate (3.65 g, 15.0 mmol) was dissloved in THF
(90 ml), then a solution of lithium hydroxide monohydrate
(947 mg, 22.55 mmol) in water (40 ml) was added at 0 8C.
The mixture was stirred overnight, acidified with H2SO4 to
pH 3, and then extracted with CH2Cl2. The combined
dichloromethane was dried and evaporated to afford the
product.
4.6.3. 2-Chloro-4-tert-butyldimethylsilyloxybutanoyl
1
chloride 3l. Yield 79%, H NMR (300 MHz, CDCl3) d
4.91 (dd, J¼8.0, 4.9 Hz, 1H, CHCl), 3.84 (m, 2H, OCH2),
2.17–2.46 (m, 2H, CH2), 0.89 (s, 9H, tBu), 0.05 (s, 6H,
2Me). 13C NMR (75 MHz, CDCl3) d 170.9 (CvO), 62.5
(OCH2), 58.0 (CHCl), 38.5 (CH2), 25.9 (tBu), 18.3 (tBu),
25.5 (SiMe).
4.5.5. 4-Benzyloxy-2-chlorobutanoic acid 8a. Yield 93%.
1H NMR (300 MHz, CDCl3) d 9.7 (s, 1H, OH), 7.27–7.37
(m, 5H, Ph), 4.56 (dd, J¼8.6, 5.2 Hz, 1H, CHCl), 4.51 (s,
2H, PhCH2), 3.65 (m, 2H, OCH2), 2.12–2.41 (m, 2H, CH2).
13C NMR (75 MHz, CDCl3) d 173.2 (CvO), 137.8 (Carom),
128.4, 128.3, 127.6 (CHarom), 73.1 (PhCH2), 65.7 (OCH2),
54.4 (CHCl), 34.8 (CH2). MS (APCI) m/z (%) 229 (Mþ1,
45), 136 (10), 91 (100). Anal. Calcd for C11H13ClO3 C
57.78, H 5.73, Cl 15.50; found C 58.10, H 5.89, Cl 16.75.
4.6.4. 2-Chloro-4-tert-butyldiphenylsilyloxybutanoyl
1
chloride 3m. Yield 95%. H NMR (300 MHz, CDCl3) d
7.38–7.70 (m, 10H, 2Ph), 4.90 (dd, J¼8.0, 4.9 Hz, 1H,
CHCl), 3.84 (m, 2H, OCH2), 2.17–2.46 (m, 2H, CH2), 1.06
(s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d 170.8 (CvO),
133.0 (Carom), 135.5, 129.6, 127.7 (CHarom), 62.5 (OCH2),
59.0 (CHCl), 37.3 (tBu), 26.7 (tBu), 19.2 (CH2).
4.6.5. 2-Chloro-3-(1,3-dioxolan-2-yl)propanoyl chloride
1
3n. Yield 90%. H NMR (300 MHz, CDCl3) d 5.1 (dd,
4.5.6. 2-Chloro-4-tert-butyldimethylsilyloxybutanoic
1
acid 8b. Yield 88%. H NMR (300 MHz, CDCl3) d 9.95
J¼4.65, 3.3 Hz, 1H CHCl), 4.72 (dd, J¼7.5, 6.15 Hz, 1H,
OCHO), 3.89–4.04 (m, 4H, OCH2CH2O), 2.34–2.61 (m,
2H, CH2). 13C NMR (75 MHz, CDCl3) d 170.2 (CvO),
100.5 (OCHO), 65.1 (OCH2CH2O), 60.1 (CHCl), 38.7
(CH2).
(s, 1H, OH), 4.50 (dd, J¼8.5, 5.1 Hz, 1H, CHCl), 3.80 (m,
2H, OCH2), 2.0–2.3 (m, 2H, CH2), 0.89 (s, 9H, tBu), 0.05
(s, 6H, 2Me). 13C NMR (75 MHz, CDCl3) d 174.7 (CvO),
58.7 (OCH2), 54.3 (CHCl), 37.5 (CH2), 25.8 (tBu), 18.3
(tBu), 25.5 (SiMe).
4.6.6. 4-Oxo-butyric acid benzyl ester 9. Ozone was
passed through a solution of benzyl 4-pentenoate (21 g,
110.3 mmol) in dichloromethane (160 ml) in a 250 ml
three-necked flask at 278 8C until the solution became blue.
Then triethylamine (30.7 ml, 220.7 mmol) was added and
the mixture was warmed gradually to room temperature.
The mixture was washed with 1N HCl (100 ml), then 5%
NaHCO3 (50 ml). The organic layer was dried and
evaporated. The residue was flash chromatographied (PE/
4.5.7. 2-Chloro-4-tert-butyldiphenylsilyloxybutanoic
acid 8c. White solid, yield 94%. 1H NMR (300 MHz,
CDCl3) d 10.45 (s, 1H, OH), 7.38–7.72 (m, 10H, 2Ph), 4.68
(dd, J¼8.7, 5.0 Hz, 1H, CHCl), 3.8 (m, 2H, OCH2), 2.07–
2.36 (m, 2H, CH2), 1.05 (s, 9H, tBu). 13C NMR (75 MHz,
CDCl3) d 174.3 (CvO), 133.2 (Carom), 135.5, 129.6, 127.6
(CHarom), 59.6 (OCH2), 54.3 (CHCl), 37.3 (tBu), 26.7 (tBu),

L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
7599
AcOEt¼6/1) to give pure product as a colourless oil, yield
4.7.1. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-methyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
oxylate 13. White solid, yield 77%, mp 103–105 8C,
1
90%, Rf¼0.4. H NMR (300 MHz, CDCl3) d 9.8 (s, 1H,
CHO), 7.31–7.37 (m, 5H, Ph), 5.12 (s, 2H, OCH2), 2.61–
2.8 (m, 4H, CH2CH2). 13C NMR (75 MHz, CDCl3) d 199.5
(CvO), 171.6 (CvO), 135.8 (Carom), 128.6, 128.2, 127.9
(CHarom), 68.6 (OCH2), 37.5 (CH2CHO), 26.5 (CH2).
1
Rf¼0.27 (3% isopropanol in petroleum ether). H NMR
(500 MHz, CDCl3) d 5.36 (s, 1H, NCHO), 5.34 (d, J¼
5.5 Hz, 1H, CHN), 4.90 (d, J¼5.5 Hz, 1H, CHO), 3.76
(s, 3H, OMe), 1.62 (s, 3H, Me), 0.93 (s, 9H, tBu). 13C
NMR (125 MHz, CDCl3) d 195.9 (CvO), 154.6 (CvO),
102.1 (NCHO), 81.3 (CHO), 75.0 (CCl), 74.2 (CHN), 52.8
(OMe), 39.0 (tBu), 25.2 (tBu), 17.3 (Me). [a]2D0¼þ0.97
4.6.7. Benzyl 3-(1,3-dioxolan-2-yl)propanoate 10. Into a
500 ml flask equipped with a Dean-Stark dried with flame
under argon, benzyl 4-oxobutanoate (23 g, 119.6 mmol),
ethylene glycol (13.3 ml, 239.3 mmol), anhydrous para-
toluenesulfonic acid (2.06 g, 11.96 mmol) and benzene
(690 ml) were mixed and heated to reflux until 2 ml water
was collected. After cooling, the mixture was diluted with
ether and washed with saturated aqueous NaHCO3, then
dried and evaporated to give the product which is pure
enough for the next reaction, yield 95%. 1H NMR
(300 MHz, CDCl3) d 7.32–7.37 (m, 5H, Ph), 5.12 (s, 2H,
OCH2), 4.95 (t, J¼4.1 Hz, 1H, OCHO), 3.80–3.95 (m, 4H,
OCH2CH2O), 2.49 (t, J¼7.36 Hz, 2H, CH2CO), 2.04 (m,
2H, CH2). 13C NMR (75 MHz, CDCl3) d 171.5 (CvO),
135.8 (Carom), 128.6, 128.2, 127.9 (CHarom), 110.1 (OCHO),
68.2 (OCH2), 367.5 (OCH2CH2O), 26.4 (CH2CO), 25.9
(CH2).
(1.03, CHCl3). IR (KBr)
n
1802 (CvO), 1714
(CvOcarbamate). MS (EI) m/z (%) 276 (Mþz, 6), 248 (27),
246 (66), 220 (24), 218 (74), 164 (36), 162 (93), 128
(88), 126 (100). Anal. Calcd for C12H18ClNO4 C 52.27, H
6.58, Cl 12.86, N 4.77; found C 51.87, H 6.46, Cl 13.03, N
4.77.
4.7.2. tert-Butyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-methyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
oxylate 14. Yield 75%, Rf¼0.28 (3% isopropanol in
1
petroleum ether). H NMR (200 MHz, CDCl3) d 5.34 (s,
1H, NCHO), 5.23 (d, J¼5.5 Hz, 1H, CHN), 4.88 (d, J¼
5.5 Hz, 1H, CHO), 1.62 (s, 3H, Me), 1.47 (s, 9H, OtBu),
0.93 (s, 9H, tBu). 13C NMR (50 MHz, CDCl3) d 196.0
(CvO), 153.2 (CvO), 101.8 (NCHO), 81.6 (OtBu), 81.5
(CHO), 75.3 (CCl), 74.4 (CHN), 39.1 (tBu), 28.1 (OtBu),
25.3 (tBu), 17.5 (Me). [a]2D0¼þ1.0 (c 1.1, CHCl3). IR
(KBr) n 1803 (CvO), 1715 (CvOcarbamate). MS (EI) m/z
(%) 318 (Mþz, 7), 290 (24), 288 (60), 262 (20), 224
(69), 168 (100). Anal. Calcd for C15H24ClNO4 C 56.7, H
7.61, Cl 11.16, N 4.40; found C 57.77, H 7.70, Cl 10.27, N
4.27.
4.6.8. Benzyl 2-chloro-3-(1,3-dioxolan-2-yl)propanoate
11. Colourless oil, yield 68%, Rf¼0.3 (PE/AcOEt¼8/1).
1H NMR (300 MHz, CDCl3) d 7.32–7.37 (m, 5H, Ph), 5.21
(s, 2H, OCH2), 5.04 (dd, J¼5.22, 3.4 Hz, 1H CHCl), 4.51 (t,
J¼7.1 Hz, 1H, OCHO), 3.81–3.95 (m, 4H, OCH2CH2O),
2.27–2.50 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3) d
169.1 (CvO), 135.8 (Carom), 128.6, 128.2, 128.0 (CHarom),
110.1 (OCHO), 67.6 (OCH2), 65.1 (OCH2CH2O), 52.4
(CHCl), 38.9 (CH2).
4.7.3. Allyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-oxo-
7-methyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxyl-
ate 15. Yield 78%, Rf¼0.27 (petroleum ether/AcOEt¼4/1).
1H NMR (300 MHz, CDCl3) d 5.94 (m, 1H, CHv), 5.39 (s,
1H, NCHO), 5.37 (d, J¼5.5 Hz, 1H, CHN), 5.36 (ddd, J¼
17.2, 3.2, 1.5 Hz, 1H, CH2v), 5.26 (ddd, J¼10.3, 2.8,
1.4 Hz, 1H, CH2v), 4.92 (d, J¼5.5 Hz, 1H, CHO), 4.63 (dt,
J¼5.8, 1.4 Hz, 2H, CH2O), 1.64 (s, 3H, Me), 0.91 (s, 9H,
tBu). 13C NMR (75 MHz, CDCl3) d 196.0 (CvO), 154.1
(CvO), 132.2 (CHv), 118.5 (vCH2), 102.1 (NCHO), 81.3
(CHO), 75.0 (CH2O), 74.2 (CHN), 66.8 (CCl), 39.0 (tBu),
25.3 (tBu), 17.3 (Me). IR (film) n 1802 (CvO), 1714
(CvOcarbamate). MS (CI) m/z (%) 302 (Mþ1, 5), 244
(M2tBu, 69), 216 (M2Alloc, 44), 188 (100), 152 (88), 108
(71).
4.6.9. 2-Chloro-3-(1,3-dioxolan-2-yl)propanoic acid 12.
Benzyl 2-chloro-3-(1,3-dioxolan-2-yl) propanoate (3.65 g,
13.48 mmol), palladium on activated carbon (10% Pd,
1.3 g; 1.2 mmol) and ethyl acetate (110 ml) were added to a
250 ml flask at room temperature, then hydrogen was
flushed through a balloon. After 12 h, the mixture was
passed through a pad of celite, washed with ether, dried
over MgSO4 and evaporated to give the product as a white
solid, yield 95%. 1H NMR (300 MHz, CDCl3) d 10.1 (s, 1H,
OH), 5.1 (dd, J¼5.2, 3.4 Hz, 1H CHCl), 4.51 (t, J¼7.1 Hz,
1H, OCHO), 3.89–4.0 (m, 4H, OCH2CH2O), 2.29–2.51 (m,
2H, CH2). 13C NMR (75 MHz, CDCl3) d 174.5 (CvO),
101.1 (OCHO), 65.1 (OCH2CH2O), 52.4 (CHCl), 38.7
(CH2).
4.7.4. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-ethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
oxylate 16. Yield 82%, Rf¼0.29 (3% isopropanol in
4.7. General procedure for the [212] cycloaddition of
oxazolines to haloketenes
1
petroleum ether). H NMR (300 MHz, CDCl3) d 5.39 (s,
Into a 250 ml three-necked flask dried by flame under the
argon, oxazoline 2 (1 equiv.), triethylamine (1.2 equiv.) and
cyclohexane (5 ml/mmol) were added, then acyl chloride
(1.0–1.2 equiv.) in cyclohexane (2 ml/mmol) was added
dropwise by a syringe pump at 60 8C. After the addition, the
mixture was stirred at 60 8C for another 4 h, then cooled to
room temperature. The mixture was allowed to stay at room
temperature overnight, then filtered. The filtrate was
evaporated to give the crude cycloadduct, which was
purified by flash chromatography.
1H, NCHO), 5.31 (d, J¼5.56 Hz, 1H, CHO), 4.90 (d, J¼
5.56 Hz, 1H, CHN), 3.76 (s, 3H, OMe), 1.97 (q, J¼7.3 Hz,
2H, CH2), 1.10 (t, J¼7.3 Hz, 3H, CH3), 0.93 (s, 9H, tBu).
13C NMR (75 MHz, CDCl3) d 195.4 (CvO), 154.2 (CvO),
102.0 (NCHO), 81.1 (CHO), 80.0 (CCl), 73.6 (CHN), 62.8
(OMe), 39.0 (tBu), 25.4 (tBu), 23.5 (CH2), 8.1 (Me). IR
(KBr) n 1802 (CvO), 1714 (CvOcarbamate). MS (APCI) m/z
(%) 290 (Mþ1, 66), 251 (M2COOMe, 16), 222 (16), 186
(20), 144 (30). HRMS (ESI) Calcd for C13H20ClNO4
290.1159, found 290.1148.

7600
L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
4.7.5. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-isopropyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-
carboxylate 17. Colorless oil, yield 68%, Rf¼0.20 (PE/
J¼6.1 Hz, 1H, CHN), 5.55 (d, J¼5.9 Hz, 1H, CHN), 5.44 (s,
1H, NCHO), 5.17 (s, 1H, NCHO), 4.91 (d, J¼5.9 Hz, 1H,
CHO), 4.79 (d, J¼6.1 Hz, 1H, CHO), 1.11 (s, 9H, OtBu),
1.09 (s, 9H, OtBu), 0.93 (s, 9H, tBu). 13C NMR (75 MHz,
CDCl3) d 196.0 (CvO), 152.2 (CvO), 129.1, 128.8
(Carom), 128.6, 128.4, 128.3, 128.2, 128.1, 127.9 (CHarom),
102.1, 101.3 (NCHO), 91.9, 90.7, 66.5, 66.1, 40.0, 39.9,
27.7, 27.5, 25.7. 82.0 (CHO), 81.5 (OtBu), 77.6 (CCl), 74.3
(CHN), 39.0 (tBu), 28.8 (OtBu), 25.4 (tBu).
1
Et2O¼10/1). H NMR (300 MHz, CDCl3) d 5.35 (s, 1H,
NCHO), 5.31 (d, J¼5.26 Hz, 1H, CHO), 4.90 (d, J¼
5.26 Hz, 1H, CHN), 3.76 (s, 3H, OMe), 2.50 (m, 1H,
CHMe2), 1.10 (d, J¼6.75 Hz, 3H, CH3), 1.0 (d, J¼6.75 Hz,
3H, CH3), 0.93 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d
196.1 (CvO), 154.3 (CvO), 101.9 (NCHO), 84.3 (CCl),
81.3 (CHO), 73.3 (CHN), 52.8 (OMe), 39.0 (tBu), 28.1
(CHMe2), 25.4 (tBu), 16.8 (Me), 16.7 (Me). IR (KBr) n
1800 (CvO), 1716 (CvOcarbamate). MS (ESI) m/z (%) 304
(Mþ1, 16).
4.7.10. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-trimethylsilylmethyl-2-oxa-4-azabicyclo[3.2.0]-
heptane-4-carboxylate 21. White solid, yield 86%, mp
127–129 8C, Rf¼0.30 (3% isopropanol in petroleum ether).
1H NMR (300 MHz, CDCl3) d 5.34 (d, J¼5.5 Hz, 1H,
CHO), 5.33 (s, 1H, NCHO), 4.87 (d, J¼5.5 Hz, 1H, CHN),
3.76 (s, 3H, OMe), 1.36 (d, J¼1.5 Hz, 2H, CH2), 0.93 (s,
9H, tBu), 0.14 (s, 9H, 3Me). 13C NMR (75 MHz, CDCl3) d
196.7 (CvO), 154.8 (CvO), 102.0 (NCHO), 81.9 (CHO),
79.0 (CCl), 73.9 (CHN), 52.8 (OMe), 39.0 (tBu), 25.5 (tBu),
18.6 (CH2), 20.04 (SiMe3). [a]2D0¼þ1.16 (c 1.09, CHCl3).
IR (KBr) n 2959, 1804 (CvO), 1716 (CvOcarbamate), 1367,
844. MS (CI) m/z (%) 348 (Mþ1, 19), 312 (12), 262 (19),
240 (24), 208 (12), 144 (39), 112 (35), 73 (100). Anal. Calcd
for C15H26ClNO4Si C 51.78, H 7.53, N 4.03; found C 51.26,
H 7.66, N 4.64.
4.7.6. tert-Butyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-isopropyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-
carboxylate 18. White solid, yield 58%, mp 114–116 8C,
1
Rf¼0.30 (PE/Et2O¼20/1). H NMR (300 MHz, CDCl3) d
5.31 (s, 1H, NCHO), 5.20 (d, J¼5.7 Hz, 1H, CHO), 4.86 (d,
J¼5.7 Hz, 1H, CHN), 2.50 (m, 1H, CHMe2), 1.49 (s, 9H,
OtBu), 1.10 (d, J¼6.6 Hz, 3H, CH3), 1.0 (d, J¼6.6 Hz, 3H,
CH3), 0.92 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d 196.0
(CvO), 154.3 (CvO), 101.6 (NCHO), 84.7 (OtBu), 81.5
(CHO), 77.9 (CCl), 73.6 (CHN), 39.1 (tBu), 28.6 (OtBu),
28.1 (CHMe2), 25.4 (tBu), 16.9 (Me), 16.8 (Me). [a]2D0¼
þ1.25 (c 0.62, CHCl3). IR (KBr) n 1800 (CvO), 1716
(CvOcarbamate). MS (APCI) m/z (%) 290 (M2tBu, 60), 126
(100). Anal. Calcd for C17H28ClNO4 C 59.04, H 8.15, Cl
10.25, N 4.05; found C 59.08, H 7.92, Cl 10.03, N 3.93.
4.7.11. tert-Butyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-
6-oxo-7-trimethylsilylmethyl-2-oxa-4-azabicyclo[3.2.0]-
heptane-4-carboxylate 22. Yield 82%, Rf¼0.29 (PE/Et2O/
iPrOH¼100/3/3), mp 135–138 8C, 1H NMR (300 MHz,
CDCl3) d 5.31 (s, 1H, NCHO), 5.26 (d, J¼5.5 Hz, 1H,
CHO), 4.85 (d, J¼5.5 Hz, 1H, CHN), 1.49 (s, 9H, OtBu),
1.36 (d, J¼1.5 Hz, 2H, CH2), 0.93 (s, 9H, tBu), 0.14 (s, 9H,
3Me). 13C NMR (75 MHz, CDCl3) d 196.7 (CvO), 153.4
(CvO), 101.6 (NCHO), 82.0 (CHO), 81.4 (OtBu), 79.1
(CCl), 74.1 (CHN), 39.0 (tBu), 28.3 (OtBu), 25.7 (tBu), 18.8
(CH2), 20.05 (SiMe3). IR (KBr) n 2960, 1805 (CvO), 1715
(CvOcarbamate), 1367, 845.
4.7.7. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-phenyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
oxylate 19A. White solid, yield 76%, mp 159–162 8C.
1
Rf¼0.27 (PE/Et2O¼95/5), H NMR (300 MHz, CDCl3) d
7.48–7.30 (m, 5H, Ph), 5.41 (d, J¼5.3 Hz, 1H, CHN), 5.23
(d, J¼5.4 Hz, 1H, CHO), 5.08 (s, 1H, NCHO), 3.76 (s, 3H,
OMe), 0.90 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d
197.9 (CvO), 154.2 (CvO), 132.7 (Carom.), 129.4, 128.7,
128.2 (CHarom), 102.0 (NCHO), 82.0 (CHO), 81.0 (CCl),
74.1 (CHN), 52.8 (OMe), 39.0 (tBu), 25.4 (tBu). [a]D20¼
þ1.90 (c 0.5, CHCl3). IR (KBr) n 2990, 1800 (CvO), 1720
(CvOcarbamate), 1360. MS (CI) m/z 337 (Mþ1), 306, 280,
188. Anal. Calcd for C17H20ClNO4 C 60.44, H 5.96, N 4.14;
found C 59.96, H 6.32, N 3.88.
4.7.12. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-(2-bromo)ethyl-2-oxa-4-azabicyclo[3.2.0]heptane-
4-carboxylate 23. Yield 80%, Rf¼0.26 (PE/Et2O/
1
iPrOH¼100/4/3). H NMR (500 MHz, CDCl3) d 5.36 (d,
J¼5.5 Hz, 1H, CHO), 5.35 (s, 1H, NCHO), 4.92 (d, J¼
5.5 Hz, 1H, CHN), 3.72 (s, 3H, OMe), 3.51 (m, 2H, CH2Br),
2.50 (m, 2H, CH2), 0.91 (s, 9H, tBu). 13C NMR (125 MHz,
CDCl3) d 194.4 (CvO), 154.3 (CvO), 102.2 (NCHO), 80.8
(CHO), 77.0 (CCl), 74.3 (CHN), 52.9 (OMe), 39.0 (tBu),
33.1 (CH2Br), 25.2 (tBu), 25.2 (CH2). IR (film) n 2972,
1804 (CvO), 1715 (CvOcarbamate), 1366, 1223. MS (EI)
m/z (%) 368 (Mþz, 5), 254 (11), 144 (15), 87 (100). Anal.
Calcd for C13H19BrClNO4 C 42.35, H 5.19, N 3.79; found C
41.87, H 4.97, N 3.59.
4.7.8. tert-Butyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-phenyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
1
oxylate 20A. White solid, yield 76%, mp 101–103 8C. H
NMR (300 MHz, CDCl3) d 7.48–7.30 (m, 5H, Ph), 5.30 (d,
J¼5.2 Hz, 1H, CHN), 5.21 (d, J¼5.2 Hz, 1H, CHO), 5.01 (s,
1H, NCHO), 1.49 (s, 9H, OtBu), 0.90 (s, 9H, tBu). 13C NMR
(75 MHz, CDCl3) d 193.0 (CvO), 153.2 (CvO), 133.0
(Carom), 129.2, 128.5, 128.3 (CHarom), 101.3 (NCHO), 82.0
(CHO), 81.5 (OtBu), 77.6 (CCl), 74.3 (CHN), 39.0 (tBu),
28.8 (OtBu), 25.4 (tBu). IR (neat) n 2920, 1810 (CvO),
1720 (CvOcarbamate), 1364. MS (CI) m/z 351 (Mþ2CO),
295, 251, 222, 164. Anal. Calcd for C20H26ClNO4 C 63.23,
H 6.89, N 3.68; found C 63.39, H 7.00, N 3.19.
4.7.13. tert-Butyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-
6-oxo-7-(2-bromoethyl)-2-oxa-4-aza bicyclo[3.2.0]hep-
tane-4-carboxylate 24A. Yield 72%, two inseparable
regioisomers with a ratio of 8/1. Rf¼0.30 (PE/AcOEt/
1
4.7.9. tert-Butyl (1S,3R,5R,6S)-3-(tert-butyl)-6-chloro-6-
phenyl-7-oxo-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
iPrOH¼100/5/3). H NMR (200 MHz, CDCl3) d 5.36 (s,
1H, NCHO), 5.29 (d, J¼5.46 Hz, 1H, CHO), 4.92 (d, J¼
5.46 Hz, 1H, CHN), 3.55 (m, 2H, CH2Br), 2.52 (m, 2H,
CH2), 1.49 (s, 9H, OtBu), 0.92 (s, 9H, tBu). 13C NMR
1
oxylate 20B. White solid, yield 76%, mp 121–125 8C. H
NMR (300 MHz, CDCl3) d 7.6–7.30 (m, 5H, Ph), 5.63 (d,

L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
7601
(50 MHz, CDCl3) d 195.8 (CvO), 153.1 (CvO), 101.2
(NCHO), 83.4 (CHO), 82.6 (OtBu), 77.4 (CCl), 74.5
(CHN), 39.1 (tBu), 37.5 (CH2Br), 28.5 (OtBu), 26.1
(CH2), 25.6 (tBu). IR (film) n 2982, 1800 (CvO), 1698
(CvOcabamate), 1362, 1172. MS (FAB) m/z (%) 412 (Mþ1,
4), 356 (27), 154 (89), 136 (64).
4.7.18. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-(2-tert-butyldimethylsilyloxy)ethyl-2-oxa-4-aza-
bicyclo[3.2.0]heptane-4-carboxylate 27. Yield 54%, Rf¼
0.29 (PE/AcOEt/iPrOH¼100/4/3). 1H NMR (300 MHz,
CDCl3) d 5.40 (d, J¼5.2 Hz, 1H, CHN), 5.35 (s, 1H,
NCHO), 4.88 (d, J¼5.2 Hz, 1H, CHO), 3.85 (m, 2H,
CH2O), 3.74 (s, 3H, OMe), 2.37 (m, 1H, 1/2CH2), 1.96 (m,
1H, 1/2CH2), 0.98 (s, 9H, SitBu), 0.89 (s, 9H, tBu), 0.05 (s,
6H, SiMe2). 13C NMR (75 MHz, CDCl3) d 195.9 (CvO),
154.2 (CvO), 102.0 (NCHO), 81.4 (CHO), 77.4 (CCl), 74.7
(CHN), 66.3 (CH2O), 52.9 (OMe), 38.9 (tBu), 30.6 (CH2),
26.8 (SitBu), 25.2 (tBu), 19.1 (SitBu), 25.4 (SiMe). IR
(film) n 2959, 1803 (CvO), 1733 (CvOcarbamate), 1363,
1112. MS (FAB) m/z (%) 420 (Mþ1, 14), 384 (8), 280 (20),
154 (39), 73 (100). Anal. Calcd for C19H34ClNO5Si C
54.33, H 8.16, N 3.33; found C 52.63, H 8.14, N 2.87.
4.7.14. tert-Butyl (1S,3R,5R,6S)-3-(tert-butyl)-6-chloro-6-
(2-bromoethyl)-7-oxo-2-oxa-4-aza bicyclo[3.2.0]hep-
1
tane-4-carboxylate 24B. H NMR (200 MHz, CDCl3) d
5.36 (s, 1H, NCHO), 4.65 (d, J¼6.7 Hz, 1H, CHN), 4.41 (d,
J¼6.7 Hz, 1H, CHO), 3.55 (m, 2H, CH2Br), 2.52 (m, 2H,
CH2), 1.50 (s, 9H, OtBu), 0.91 (s, 9H, tBu). 13C NMR
(50 MHz, CDCl3) d 194.8 (CvO), 153.1 (CvO), 101.2
(NCHO), 90.3 (CHO), 82.2 (OtBu), 77.4 (CCl), 63.5
(CHN), 39.1 (tBu), 37.5 (CH2Br), 28.5 (OtBu), 26.1
(CH2), 25.6 (tBu).
4.7.19. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-(2-tert-butyldiphenylsilyloxy)ethyl-2-oxa-4-azabi-
cyclo[3.2.0]heptane-4-carboxylate 28. Yield 80%, Rf¼
0.28 (PE/AcOEt/iPrOH¼100/4/3), 1H NMR (300 MHz,
CDCl3) d 7.32–7.71 (m, 10H, 2Ph), 5.41 (d, J¼5.2 Hz,
1H, CHN), 5.32 (s, 1H, NCHO), 4.92 (d, J¼5.2 Hz, 1H,
CHO), 3.78–3.97 (m, 2H, CH2O), 3.73 (s, 3H, OMe), 2.42
(ddd, J¼15.0, 7.3, 7.3 Hz, 1H, 1/2CH2), 2.0 (ddd, J¼15.0,
6.4, 4.6 Hz, 1H, 1/2CH2), 1.04 (s, 9H, SitBu), 0.89 (s, 9H,
tBu). 13C NMR (125 MHz, CDCl3) d 195.9 (CvO), 154.2
(CvO), 133.3 (Carom), 135.6, 130.0, 129.7, 127.8, 127.7
(CHarom), 102.1 (NCHO), 81.4 (CHO), 77.4 (CCl), 74.8
(CHN), 59.2 (CH2O), 52.9 (OMe), 38.9 (tBu), 30.6 (CH2),
26.8 (SitBu), 25.2 (tBu), 19.1 (SitBu). IR (film) n 2958,
1803 (CvO), 1733 (CvOcarbamate), 1363, 1112. MS (FAB)
m/z (%) 544 (Mþ1, 6), 486 (10), 217 (15), 197 (41), 135
(100). Anal. Calcd for C29H38ClNO5Si C 64.01, H 7.04, N
2.43; found C 63.85, H 7.05, N 2.43.
4.7.15. Allyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-oxo-
7-(2-bromo)ethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-
carboxylate 25. Yield 77%, Rf¼0.3 (PE/AcOEt/iPrOH¼
100/5/3). 1H NMR (300 MHz, CDCl3) d 5.94 (m, 1H,
CHv), 5.42 (d, J¼5.4 Hz, 1H, CHN), 5.40 (s, 1H, NCHO),
5.37 (ddd, J¼17.1, 3.1, 1.5 Hz, 1H, CH2v), 5.26 (ddd,
J¼10.3, 2.9, 1.4 Hz, 1H, CH2v), 4.96 (d, J¼5.5 Hz, 1H,
CHO), 4.63 (dt, J¼5.8, 1.4 Hz, 2H, CH2O), 3.57 (m, 2H,
CH2Br), 2.50 (m, 2H, CH2), 0.91 (s, 9H, tBu). 13C NMR
(75 MHz, CDCl3)
d 194.6 (CvO), 154.0 (CvO),
132.2 (CHv), 118.6 (vCH2), 102.2 (NCHO), 80.9
(CHO), 77.0 (CH2O), 74.2 (CHN), 66.9 (CCl), 39.6
(CH2Br), 39.0 (tBu), 25.5 (tBu), 25.3 (CH2). IR (film) n
2942, 1792 (CvO), 1711 (CvO), 1140. MS (APCI) m/z
(%) 394 (Mþ1, 3), 338 (5), 282 (100). Anal. Calcd for
C15H21BrClNO4 C 45.64, H 5.36, N 3.55; found C 43.97, H
5.17, N 3.45.
4.7.16. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-(2-methoxy)ethyl-2-oxa-4-azabicyclo[3.2.0]hep-
tane-4-carboxylate 26A. Yield 76%, Rf¼0.24 (3% iso-
propanol in petroleum ether), two regioisomers inseparable
with a proportion of 6/1. 1H NMR (300 MHz, CDCl3) d 5.38
(s, 1H, NCHO), 5.35 (d, J¼5.45 Hz, 1H, CHN), 4.90 (d,
J¼5.45 Hz, 1H, CHO), 3.75 (s, 3H, OMe), 3.62 (m, 2H,
CH2O), 3.32 (s, 3H, OMe), 2.25 (m, 2H, CH2), 0.92 (s, 9H,
tBu). 13C NMR (75 MHz, CDCl3) d 195.1 (CvO), 154.5
(CvO), 102.0 (NCHO), 81.3 (CHO), 77.2 (CCl), 74.4
(CHN), 67.5 (CH2O), 58.6 (OMe), 52.8 (OMe), 39.0 (tBu),
29.7 (CH2), 25.4 (tBu). IR (KBr) n 1804 (CvO), 1715
(CvOcarbamate). MS (EI) m/z (%) 320 (Mþz, 22), 284 (31),
210 (30), 208 (100), 176 (72), 88 (76). Anal. Calcd for
C14H22ClNO5 C 52.58, H 6.93, N 4.38; found C 49.34, H
6.84, N 4.29.
4.7.20. tert-Butyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-
6-oxo-7-(2-tert-butyldiphenylsilyloxy)ethyl-2-oxa-4-aza-
bicyclo[3.2.0]heptane-4-carboxylate 29. Yield 80%,
Rf¼0.25, (PE/Et2O/iPrOH¼100/3/3), mp129–131 8C, 1H
NMR (500 MHz, CDCl3) d 7.38–7.72 (m, 10H, 2Ph), 5.34
(d, J¼5.1 Hz, 1H, CHN), 5.32 (s, 1H, NCHO), 4.91 (d,
J¼5.1 Hz, 1H, CHO), 3.78–3.97 (m, 2H, CH2O), 2.45 (ddd,
J¼14.8, 8.2, 6.3 Hz, 1H, 1/2CH2), 1.97 (ddd, J¼14.8, 6.3,
3.6 Hz, 1H, 1/2CH2), 1.49 (s, 9H, OtBu), 1.06 (s, 9H,
SitBu), 0.89 (s, 9H, tBu). 13C NMR (125 MHz, CDCl3) d
196.3 (CvO), 153.2 (CvO), 133.4 (Carom), 135.6, 130.0,
129.7, 127.8, 127.7 (CHarom), 101.7 (NCHO), 81.7 (CHO),
81.4 (OtBu), 75.0 (CHN), 74.5 (CCl), 59.2 (CH2O), 39.0
(tBu), 30.8 (CH2), 28.0 (OtBu), 26.8 (SitBu), 25.2 (tBu),
19.1 (SitBu). IR (KBr) n 2959, 1804 (CvO), 1726
(CvOcarbamate), 1363, 1112. MS (FAB) m/z (%) 586
(Mþ1). Anal. Calcd for C32H44BrClNO5S C 65.56, H
7.57, N 2.38, Cl 6.04; found C 65.85, H 7.68, N 2.31, Cl
5.70. [a]D20¼þ0.99 (c 1.06, CHCl3), X-Ray diffraction
4.7.17. Methyl (1S,3R,5R,6S)-3-(tert-butyl)-6-chloro-6-
(2-methoxy)ethyl-7-oxo-2-oxa-4-azabicyclo[3.2.0]hep-
1
˚
tane-4-carboxylate 26B. H NMR (300 MHz, CDCl3) d
analysis wavelength: 0.71069 A, Crystal system: orthor-
˚
5.38 (s, 1H, NCHO), 5.0 (d, J¼6.7 Hz, 1H, CHN), 4.95 (d,
J¼6.7 Hz, 1H, CHO), 3.75 (s, 3H, OMe), 3.62 (m, 2H,
CH2O), 3.32 (s, 3H, OMe), 2.25 (m, 2H, CH2), 0.92 (s, 9H,
tBu). 13C NMR (75 MHz, CDCl3) d 195.0 (CvO), 154.5
(CvO), 102.0 (NCHO), 94.0 (CHO), 77.3 (CCl), 67.1
(CH2O), 65.2 (CHN), 58.6 (OMe), 52.8 (OMe), 39.0 (tBu),
29.7 (CH2), 25.4 (tBu).
hombic unit cell dimensions, a¼9.738 (3) A, a¼908,
˚
˚
b¼10.205 (4) A, b¼908, c¼33.446 (8) A, g¼908.
4.7.21. Allyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-oxo-
7-(2-tert-butyldiphenylsilyloxy)ethyl-2-oxa-4-azabi-
cyclo[3.2.0]heptane-4-carboxylate 30. Yield 77%, two
inseparable regioisomers with a ratio of 10/1. Rf¼0.27 (3%

7602
L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
isopropanol in petroleum ether). 1H NMR (500 MHz,
CDCl3) d 7.37–7.69 (m, 10H, 2Ph), 5.98 (m, 1H, CHv),
5.43 (d, J¼5.5 Hz, 1H, CHN), 5.37 (s, 1H, NCHO), 5.35
(ddd, J¼17.4, 3.0, 1.5 Hz, 1H, CH2v), 5.25 (ddd, J¼10.3,
3.0, 1.5 Hz, 1H, CH2v), 4.93 (d, J¼5.5 Hz, 1H, CHO), 4.64
(dt, J¼6.1, 1.5 Hz, 2H, CH2OCO), 3.95 (ddd, J¼10.1, 8.2,
6.7 Hz, 1H, CH2OSi), 3.87 (ddd, J¼10.1, 7.6, 4.0 Hz, 1H,
CH2OSi), 2.43 (ddd, J¼14.6, 8.2, 7.6 Hz, 1H, CH2), 2.03
(CHN), 72.8 (CH2Ph), 65.1 (CH2O), 39.0 (tBu), 29.6
(CH2), 28.6 (OtBu), 25.2 (tBu). IR (film) n 1792 (CvO),
1706 (CvOcarbamate), 1368. MS (APCI) m/z (%) 438 (Mþ1,
12), 380, 316, 184 (11), 91 (51).
4.7.25. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-(1,3-dioxolan-2-ylmethyl)-2-oxa-4-azabicyclo-
[3.2.0]heptane-4-carboxylate 33. Yield 62%, Rf¼0.26
1
(ddd, J¼14.6, 6.7, 4.0 Hz, 1H, CH2), 0.90 (s, 9H, tBu). 13
C
(PE/AcOEt/iPrOH¼100/5/3). H NMR (200 MHz, CDCl3)
NMR (125 MHz, CDCl3) d 195.3 (CvO), 156.1 (CvO),
133.6 (Carom), 132.3 (CHv), 135.5, 129.5, 127.7 (CHarom),
118.3 (vCH2), 102.1 (NCHO), 81.5 (CHO), 77.3
(CH2OCO), 74.8 (CHN), 66.7 (CCl), 59.3 (CH2OSi), 39.0
(tBu), 31.2 (CH2), 25.3 (tBu). IR (film) n 2962, 1800
(CvO), 1709 (CvO). MS (APCI) m/z (%) 570 (Mþ1, 18),
534 (80), 492 (62), 314 (24). Anal. Calcd for
C31H40ClNO4Si C 65.30, H 7.07, N 2.45; found C 63.95,
H 7.49, N 2.20.
d 5.36 (s, 1H, NCHO), 5.32 (d, J¼5.4 Hz, 1H, CHN), 4.95
(d, J¼5.4 Hz, 1H, CHO), 4.45 (dd, J¼5.9, 4.5 Hz, 1H,
OCHO), 3.86–3.98 (m, 4H, OCH2CH2O), 3.76 (s, 3H,
OMe), 2.32 (m, 2H, CH2), 0.92 (s, 9H, tBu). 13C NMR
(50 MHz, CDCl3) d 194.2 (CvO), 153.6 (CvO), 101.9
(NCHO), 101.2 (OCHO), 81.6 (CHO), 75.8 (CCl), 74.5
(CHN), 65.0 (OCH2CH2O), 52.6 (OMe), 38.9 (tBu), 34.5
(CH2), 27.2 (tBu). IR (film) n 2960, 1803 (CvO), 1724
(CvOcarbamate), 1363, 1115. MS (APCI) m/z (%) 348
(Mþ1, 23), 312 (17).
4.7.22. Allyl (1S,3R,5R,7R)-3-(tert-butyl)-6-chloro-7-oxo-
6-(2-{[tert-butyl (diphenyl)silyl]oxy}ethyl)-2-oxa-4-aza-
bicyclo[3.2.0]heptane-4-carboxylate 30B. 1H NMR
(500 MHz, CDCl3) d 7.39–7.7 (m, 10H, 2Ph), 5.98 (m,
1H, CHv), 5.37 (s, 1H, NCHO), 5.38 (ddd, J¼17.5, 3.0,
1.5 Hz, 1H, CH2v), 5.22 (ddd, J¼10.3, 3.0, 1.5 Hz, 1H,
CH2v), 4.68 (dt, J¼6.1, 1.5 Hz, 2H, CH2OCO), 4.64 (d,
J¼6.1 Hz, 1H, CHN), 4.48 (d, J¼6.1 Hz, 1H, CHO), 3.65–
3.97 (m, 2H, CH2OSi), 1.70–2.79 (m, 2H, CH2), 0.92 (s,
9H, tBu). 13C NMR (75 MHz, CDCl3) d 195.3 (CvO),
156.1 (CvO), 133.6 (Carom), 132.3 (CHv), 135.5, 129.5,
127.7 (CHarom), 118.3 (vCH2), 102.1 (NCHO), 81.5
(CHO), 77.3 (CH2OCO), 74.8 (CHN), 66.7 (CCl), 59.3
(CH2OSi), 39.0 (tBu), 31.2 (CH2), 25.3 (tBu).
4.7.26. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-bromo-6-
oxo-7-isopropyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-
carboxylate 34A. Yield 76%, Rf¼0.27 (3% isopropanol in
petroleum ether), two regioisomers inseparable with a ratio
of 4/1. 1H NMR (300 MHz, CDCl3) d 5.32 (s, 1H, NCHO),
5.31 (d, J¼5.3 Hz, 1H, CHN), 5.0 (d, J¼5.3 Hz, 1H, CHO),
2.24 (m, 1H, CHMe2), 1.47 (s, 9H, OtBu), 1.09 (d, J¼
6.6 Hz, 3H, Me), 0.99 (d, J¼6.5 Hz, 3H, Me), 0.89 (s, 9H,
tBu). 13C NMR (75 MHz, CDCl3) d 195.6 (CvO), 153.6
(CvO), 101.6 (NCHO), 81.4 (CHO), 80.7 (OtBu), 77.3
(CBr), 73.3 (CHN), 39.1 (tBu), 28.2 (OtBu), 25.4 (CHMe2),
25.2 (tBu), 18.2 (Me). IR (film) n 2942, 1793 (CvO), 1696
(CvOcarbamate), 1368. MS (CI) m/z (%) 390 (Mþ1, 5), 334
(100), 290 (51), 256 (24).
4.7.23. Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-
oxo-7-(2-benzyloxyethyl)-2-oxa-4-aza bicycle[3.2.0]hep-
tane-4-carboxylate 31. Yield 72%, two inseparable regio-
isomers with a ratio of 6/1. Rf¼0.26 (PE/Et2O/iPrOH¼100/
3/3). 1H NMR (500 MHz, CDCl3, 47 8C) d 7.2–7.4 (m, 5H,
Ph), 5.36 (s, 1H, NCHO), 5.35 (d, J¼5.2 Hz, 1H, CHN),
4.90 (d, J¼5.2 Hz, 1H, CHO), 4.45–4.55 (ab, J¼12.2 Hz,
2H, CH2Ph), 3.75 (m, 2H, CH2O), 3.73 (s, 3H, OMe), 2.42
(ddd, J¼15.0, 7.3, 7.3 Hz, 1H, 1/2CH2), 2.14 (ddd, J¼15.0,
6.4, 4.6 Hz, 1H, 1/2CH2), 0.91 (s, 9H, tBu). 13C NMR
(125 MHz, CDCl3, 47 8C) d 195.1 (CvO), 154.6 (CvO),
138.3 (Carom), 128.2, 127.4, 127.3 (CHarom), 102.0 (NCHO),
81.4 (CHO), 77.4 (CCl), 74.6 (CHN), 72.8 (CH2Ph), 65.1
(CH2O), 52.7 (OMe), 38.9 (tBu), 29.6 (CH2), 25.2 (tBu). IR
(film) n 1804 (CvO), 1715 (CvOcarbamate). MS (CI) m/z
(%) 396 (Mþ1, 4), 362 (5), 306 (9), 288 (15), 254 (11), 211
(100), 184 (11), 91 (51).
4.7.27. Methyl (1S,3R,5R,6S)-3-(tert-butyl)-6-bromo-6-
isopropyl-7-oxo-2-oxa-4-azabicyclo[3.2.0]heptane-4-
carboxylate 34B. H NMR (300 MHz, CDCl3) d 5.32 (s,
1H, NCHO), 4.84 (d, J¼6.2 Hz, 1H, CHN), 4.1 (d, J¼
6.2 Hz, 1H, CHO), 2.25 (m, 1H, CHMe2), 1.47 (s, 9H,
OtBu), 1.09 (d, J¼6.6 Hz, 3H, Me), 0.99 (d, J¼6.5 Hz, 3H,
Me), 0.90 (s, 9H, tBu).
1
4.7.28. tert-Butyl (1R,3S,5S,7S)-3-(tert-butyl)-7-chloro-6-
oxo-7-methyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
oxylate 35. White solid, yield 72%, Rf¼0.16 (EP/Et2O¼20/
1), 1H NMR (300 MHz, CDCl3) d 5.34 (s, 1H, NCHO), 5.23
(d, J¼5.26 Hz, 1H, CHO), 4.88 (d, J¼5.26 Hz, 1H, CHN),
1.63 (s, 3H, Me), 1.49 (s, 9H, OtBu), 0.92 (s, 9H, tBu). 13C
NMR (75 MHz, CDCl3) d 190.2 (CvO), 153.6 (CvO),
101.7 (NCHO), 82.2 (OtBu), 81.2 (CCl), 81.0 (CHO), 74.4
(CHN), 39.1 (tBu), 28.3 (OtBu), 25.3 (tBu), 24.2 (Me).
[a]2D0¼20.95 (c 0.44, CHCl3). MS (APCI) m/z (%) 318
(Mþ1, 7), 260 (M2tBu, 6), 218 (100). Anal. Calcd for
C15H24ClNO4 C 56.68, H 7.61, N 4.41; found C 55.69, H
7.37, N 4.34.
4.7.24. tert-Butyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-
6-oxo-7-(2-benzyloxy)ethyl-2-oxa-4-azabicyclo[3.2.0]-
heptane-4-carboxylate 32. Yield 56%, Rf¼0.26 (PE/
AcOEt/iPrOH¼100/4/3). 1H NMR (300 MHz, CDCl3) d
1
7.22–7.37 (m, 5H, Ph), 5.33 (s, H, NCHO), 5.29 (d, J¼
5.2 Hz, 1H, CHO), 4.87 (d, J¼5.2 Hz, 1H, CHN), 4.47–
4.59 (ab, J¼12.2 Hz, 2H, CH2Ph), 3.75 (m, 2H, CH2O),
2.14–2.42 (m, 2H, CH2), 1.48 (s, 9H, OtBu), 0.91 (s, 9H,
tBu). 13C NMR (75 MHz, CDCl3) d 195.3 (CvO), 154.3
(CvO), 138.3 (Carom), 128.2, 127.4, 127.3 (CHarom), 102.0
(NCHO), 82.4 (OtBu), 81.6 (CHO), 77.4 (CCl), 74.3
4.7.29. tert-Butyl (1R,3S,5S,7S)-3-(tert-butyl)-7-chloro-6-
oxo-7-isopropyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-
carboxylate 36A. White solid, yield 66%, mp 110–113 8C,
1
Rf¼0.40 (PE/Et2O¼20/1). H NMR (300 MHz, CDCl3) d
5.32 (s, 1H, NCHO), 5.20 (d, J¼5.5 Hz, 1H, CHO), 4.87 (d,
J¼5.5 Hz, 1H, CHN), 2.48 (m, 1H, CHMe2), 1.49 (s, 9H,

L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
7603
OtBu), 1.09 (d, J¼6.7 Hz, 3H, CH3), 1.0 (d, J¼6.7 Hz, 3H,
CH3), 0.92 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d 190.2
(CvO), 153.6 (CvO), 101.5 (NCHO), 84.2 (OtBu), 81.0
(CHO), 76.9 (CCl), 73.5 (CHN), 39.1 (tBu), 28.4 (OtBu),
28.0 (CHMe2), 25.3 (tBu), 16.9 (Me), 16.8 (Me). [a]2D0¼
21.14 (c 1.25, CHCl3). MS (APCI) m/z (%) 290 (M2tBu,
46), 246 (100). Anal. Calcd for C17H28ClNO4 C 59.03, H
8.16, Cl 10.25, N 4.05; found C 58.77, H 8.00, Cl 9.46, N
4.28.
for C30H39N3O9S2 C 55.45, H 6.04, N 6.46; found C 53.85,
H 5.69, N 6.37.
4.8.2. Methyl (3R)-3-(tert-butyl)-7-methoxy-6-[(2-meth-
oxy acetyl)oxy]-2-oxa-4-azabicyclo[3.2.0]hept-6ene-4-
carboxylate 40a. Yield 72%, Rf¼0.33 (hexane/MeOH/
1
AcOEt¼100/7/20). H NMR (500 MHz, CDCl3) d 5.46 (s,
1H, NCHO), 5.07 (d, J¼4.4 Hz, 1H, CHO), 4.96 (d,
J¼4.4 Hz, 1H, CHN), 4.11 (s, 2H, CH2), 3.79 (s, 3H,
OMe), 3.64 (s, 3H, OMecarbamate), 3.48 (s, 3H, MeOCH2),
0.86 (s, 9H, tBu). 13C NMR (125 MHz, CDCl3) d 167.3
(CvO), 155.3 (CvO), 142.4 (OCv), 120.7 (vCOMe),
104.5 (NCHO), 77.7 (CHO), 69.0 (OCH2), 59.6 (CHN),
59.4 (MeOCH2), 58.0 (OCH3), 52.3 (OMecarbamate), 38.7
(tBu), 24.8 (tBu). IR (KBr) n 2959, 2931, 1780 (CvO),
1716 (CvOcarbamate), 1447, 1367, 1117. MS (CI) m/z (%) 330
(Mþ1, 16), 272 (M2tBu, 32), 240 (M2OCOCH2OCH3,
54), 216 (38), 202 (22), 172 (100), 144 (75). Anal. Calcd for
C15H23NO7 C 54.7, H 7.03, N 4.25; found C 54.29, H 6.77,
N 4.35.
4.7.30. tert-Butyl (1R,3S,5S,6R)-3-(tert-butyl)-6-chloro-6-
isopropyl-7-oxo-2-oxa-4-aza bicyclo[3.2.0]heptane-4-
carboxylate 36b. Rf¼0.34 (PE/E2O¼20/1). 1H NMR
(300 MHz, CDCl3) d 5.41 (d, J¼6.0 Hz, 1H, CHO), 5.29
(s, 1H, NCHO), 4.66 (d, J¼6.0 Hz, 1H, CHN), 2.32 (m, 1H,
CHMe2), 1.50 (s, 9H, OtBu), 1.15 (d, J¼6.7 Hz, 3H, CH3),
1.12 (d, J¼6.7 Hz, 3H, CH3), 0.94 (s, 9H, tBu).
4.7.31. (1R,3R,5R)-4-(tert-Butoxycarbonyl)-6-(tert-
butyl)-2-oxa-4-azabicyclo[3.2.0]heptane-6-one 38. Mp
1
90–91 8C, H NMR (300 MHz, CDCl3) d 5.38 (s, 1H),
5.07 (ddd, J¼5.0, 5.0, 2.3 Hz, 1H), 4.92–4.85 (m, 1H), 3.18
(ddd, J¼17.5, 5.0, 3.5 Hz, 1H), 3.08 (ddd, J¼17.5, 2.3,
2.3 Hz), 1H), 1.48 (s, 9H), 0.92 (s, 9H). 13C NMR (75 MHz,
CDCl3) d 199.9, 153.1, 101.1, 81.2, 76.2, 71.3, 52.6, 39.0,
28.0, 25.5; [a]2D0¼þ116 (c 1.00, CHCl3). IR (KBr) n 2960,
1790, 1700. MS (CI) m/z (%) 227, 170, 57. Anal. Calcd for
C14H23NO4 C 62.03, H 8.60, N 5.2; found C 61.72, H 8.57,
N 4.95.
4.8.3. tert-Butyl (3R)-3-(tert-butyl)-7-methoxy-6-[(2-
methoxyacetyl)oxy]-2-oxa-4-azabicyclo[3.2.0]hept-6ene-
4-carboxylate 40b. Yield 56%, Rf¼0.27 (hexane/iPrOH/
1
AcOEt¼100/8/8). H NMR (500 MHz, CDCl3) d 5.46 (s,
1H, NCHO), 5.41 (d, J¼4.12 Hz, 1H, CHN), 4.63 (d, J¼
4.12 Hz, 1H, CHO), 4.13 (s, 2H, CH2), 3.83 (s, 3H, OMe),
3.48 (s, 3H, MeOCH2), 1.46 (s, 9H, OtBu), 0.88 (s, 9H, tBu).
13C NMR (125 MHz, CDCl3) d 167.3 (CvO), 153.8
(CvO), 142.4 (OCv), 120.8 (vCOMe), 103.1 (NCHO),
80.2 (CHO), 79.3 (OtBu), 69.2 (OCH2), 59.8 (CHN), 59.5
(MeOCH2), 58.0 (OCH3), 39.0 (tBu), 28.2 (OtBu), 25.1
(tBu). IR (KBr) n 2959, 2931, 1780 (CvO), 1716
(CvOcarbamate), 1447, 1367, 1117. MS (CI) m/z (%) 372
(Mþ1, 12), 314 (M2tBu, 25), 282 (M2OCOCH2OCH3,
23), 270 (M2CO2tBu, 5), 258 (15), 187 (67), 83 (100).
HRMS (CI) Calcd for C18H29NO7 372.20235, found
372.20223.
4.8. General procedure for the [212] cycloaddition of
oxazolines to methoxyketene and N-methyl-N-tosyl-
aminoketene
Into a 25 ml three-necked flask dried by flame under the
argon, (2H)oxazole 2 (1 equiv.), triethylamine (1.2–
2.2 equiv.) and toluene (10 ml/mmol) were added, then
acetyl chloride (1.2–2.2 equiv.) in toluene (2 ml/mmol) was
added dropwise by a syringe pump at 110 8C. After the
addition (2 h), the mixture was stirred at 110 8C for 8 h then
10 h at room temperature and filtered. The filtrate was
evaporated to give crude product. Flash chromatography
gave the pure product.
4.8.4. tert-Butyl (1S,3R,5R)-3-(tert-butyl)-6-oxo-7,7-(eth-
ylene dithio)-2-oxa-4-azabicyclo[3.2.0]heptane-4-carb-
oxylate 43. Into a 25 ml three-necked flask dried by flame
under the argon, oxazoline 2b (0.37 g, 1.6 mmol) and
toluene (3 ml) were added and heated to reflux. 2,2-
dimethyl-1-(N-methylphenylanilino)vinyl-1,3-dithiolane-2-
carboxylate (1.34 g, 4.3 mmol) in toluene (2 ml) was added
dropwise by a syringe pump during a period of 6 h. After the
addition, the mixture was stirred for another 1 h. The solvent
was evaporated, and the resulting residue was flash
chromatographied to give product 0.23 g, 40%, Rf¼0.47
4.8.1. Methyl (3R)-3-(tert-butyl)-7-{methyl[(4-methyl-
phenyl) sulfonyl]amino}-6-[(2-{methyl[(4-methylphenyl)
sulfonyl]amino}acetyl)oxy]-2-oxa-4-azabicyclo[3.2.0]-
hept-6ene-4-carboxylate 39. White solid, yield 29%, mp
127–129 8C, Rf¼0.35 (hexane/iPrOH/AcOEt¼100/8/8). 1H
NMR (500 MHz, CDCl3) d 7.27–7.81 (m, 8H, 2Ph), 5.35 (s,
1H, NCHO), 5.31 (d, J¼4.12 Hz, 1H, CHN), 5.03 (d, J¼
4.12 Hz, 1H, CHO), 4.05 (d, J¼4.67 Hz, 2H, CH2), 3.67 (s,
3H, OMe), 3.05 (s, 3H, NMe), 2.89 (s, 3H, NMe), 2.45 (s,
3H, Me), 2.43 (s, 3H, Me), 0.89 (s, 9H, tBu). 13C NMR
(125 MHz, CDCl3) d 165.6 (CvO), 155.3 (CvO), 144.3,
143.8, 134.9, 134.7 (Carom), 129.8, 129.7, 127.8, 127.7,
127.4 (CHarom), 128.3 (OCv), 127.7 (vCN), 104.0
(NCHO), 74.3 (CHO), 61.5 (CHN), 52.7 (OMe), 50.6
(CH2), 38.8 (tBu), 35.5 (NMe), 34.7 (NMe), 25.0 (tBu), 21.6
(Me), 21.5 (Me). [a]2D0¼þ0.98 (c 0.62, CHCl3). IR (KBr) n
2959, 1726 (CvO), 1710 (CvOcarbamate), 1654, 1259,
1172. MS (CI) m/z (%) 635 (M2Me, 17), 480 (18), 410
(36), 298 (20), 242 (59), 190 (86), 155 (100). Anal. Calcd
1
(cyclohexane/AcOEt¼4/1). H NMR (200 MHz, CDCl3) d
5.28 (s, 1H, NCHO), 5.03 (d, J¼5.4 Hz, 1H, CHO), 4.96 (d,
J¼5.4 Hz, 1H, CHN), 3.38 (m, 4H, CH2CH2), 1.49 (s, 9H,
OtBu), 0.92 (s, 9H, tBu). 13C NMR (50 MHz, CDCl3) d
196.8 (CvO), 153.02 (CvO), 101.5 (NCHO), 81.4 (CHO),
80.9 (OtBu), 78.6 (CS), 74.4 (CHN), 39.7 (CH2), 39.4
(CH2), 28.1 (OtBu), 25.3 (tBu). IR (KBr) n 1796 (CvO),
1714 (CvOcabamate). MS (EI) m/z (%) 359 (Mþ), 331, 230,
174, 57. Anal. Calcd For C16H25NO4S2 C 53.45, H 7.0, N
3.89, S 17.83; found C 53.45, H 7.01, N 3.82, S 18.08.
4.8.5. Favorskii rearrangement of 23. Into a 25 ml two-
necked flask dried by flame under argon, sodium iodide

7604
L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
(56.9 mg, 0.38 mmol), potassium carbonate (53 mg,
0.38 mmol) and methyl sulfoxide (4 ml) were heated to
120 8C under argon, then methyl (1S,3R,5R,7R)-3-(tert-
butyl)-7-chloro-6-oxo-7-(2-bromoethyl)-2-oxa-4-aza bicyclo
[3.2.0]heptane-4carboxylate 23 (140 mg, 0.38 mmol) in
DMSO (1 ml) was added. After stirring for an additional
1 h, the mixture was rapidly cooled and then poured into
ice-cold brine (5 ml). The mixture was extracted with ether
(2£5 ml). The combined extracts were washed with water,
brine, 5% NaHCO3 and brine, then dried and evaporated.
The residue was chromatographied (PE/AcOEt¼6/1, Rf¼
0.3) to give a Favorskii rearrangement product 44 (70 mg,
68%), mp 95–97 8C. 1H NMR (500 MHz, CDCl3) d 5.14 (s,
1H, NCHO), 4.49 (d, J¼6.8 Hz, 1H, CHO), 4.46 (t, J¼
7.62 Hz, 2H, CH2O), 3.78 (d, J¼6.8 Hz, 1H, CHN), 3.77 (s,
3H, OMe), 2.12 (m, 2H, CH2), 0.92 (s, 9H, tBu). 13C NMR
(125 MHz, CDCl3, APT) d 174.1 (CvO), 156.1 (CvO),
104.6 (NCHO), 66.3 (CH2O), 66.0 (CHO), 53.2 (OMe),
42.4 (CHN), 38.0 (tBu), 37.1 (CCO), 24.3 (tBu), 20.8 (CH2).
IR (film) n 2971, 1754 (CvO), 1718 (CvOcarbamate), 1351,
1021. MS (CI) m/z (%) 270 (Mþ1, 29), 211 (M2tBu, 17),
144 (15), 184 (100), 144 (32), 89 (33). Anal. Calcd for
C13H19NO5 C 57.98, H 7.11, N 5.20; found C 57.74, 6.92, N
4.95.
6.21 (d, J¼3.02 Hz, 1H, CHN), 5.29 (s, 1H, NCHO), 4.82
(d, J¼3.02 Hz, 1H, CHO), 3.81 (s, 3H, OMe), 1.8 (s, 3H,
CH3), 0.96 (s, 9H, tBu). 13C NMR (75 MHz, CDCl3) d 170.8
(CvO), 154.3 (CvO), 99.5 (NCHO), 88.7 (CHN), 85.0
(CHO), 66.0 (CCl), 53.5 (OMe), 38.9 (tBu), 25.6 (tBu), 18.9
(CH3). IR (film) n 2960, 1800 (CvOlactone), 1740 (CvO),
1359, 1112. MS (APCI) m/z (%) 292 (Mþ1, 14).
4.9.2. Methyl (2R,6R)-6-(2-bromoethyl)-2-(tert-butyl)-6-
chloro-5-oxotetrahydrofuro[2,3-d][1,3]oxazole-3(2H)-
1
carboxylate 46b. 85% yield, Rf¼0.34. H NMR (CDCl3,
300 MHz) d 6.22 (d, J¼3.02 Hz, 1H, CHN), 5.29 (s, 1H,
NCHO), 5.0 (d, J¼3.02 Hz, 1H, CHO), 3.81 (s, 3H, OMe),
3.65 (m, 2H, CH2Br), 2.67 (m, 2H, CH2), 0.95 (s, 9H, tBu).
13C NMR (CDCl3, 75 MHz) d 169.9 (CvO), 154.2 (CvO),
99.5 (NCHO), 89.2 (CHN), 83.6 (CHO), 66.0 (CCl), 53.5
(OMe), 39.1 (tBu), 33.5 (CH2Br), 25.7 (CH2), 25.6 (tBu). IR
(film) n 2958, 1799 (CvOlactone), 1742 (CvO), 1365, 1124.
MS (FAB) m/z (%) 384 (Mþ1, 8), 307 (21), 154 (100), 136
(82).
4.9.3. Methyl (2R,6R)-6-(trimethylsilyl)methyl-2-(tert-
butyl)-6-chloro-5-oxotetrahydrofuro[2,3-d][1,3]oxazole-
3(2H)-carboxylate 46c. 96% yield, Rf¼0.37. 1H NMR
(CDCl3, 300 MHz) d 6.18 (d, J¼3.02 Hz, 1H, CHN), 5.28
(s, 1H, NCHO), 4.86 (d, J¼3.02 Hz, 1H, CHO), 3.81 (s, 3H,
OMe), 1.56 (ab, J¼15.3 Hz, 2H, CH2), 0.96 (s, 9H, tBu),
0.18 (s, 9H, SiMe3). 13C NMR (75 MHz) d 171.6 (CvO),
154.3 (CvO), 99.5 (NCHO), 88.4 (CHN), 84.7 (CHO), 67.3
(CCl), 53.5 (OMe), 39.1 (tBu), 25.6 (tBu), 20.2 (CH2), 20.1
(SiMe3). IR (film) n 2959, 1798 (CvOlactone), 1743 (CvO),
1360, 1160. MS (APCI) m/z (%) 364 (Mþ1, 32), 328
(44), 282 (88), 256 (100), 196 (19). Anal. Calcd for
C15H26ClNO5Si C 49.51, H 7.20, N 3.82; found C 48.80, H
7.24, N 4.19.
4.8.6. Dimethyl (1R,3R,5S,6R)-3-(tert-butyl)-6-methyl-2-
45.
oxo-4-azabicyclo[3.1.0]hexane-4,6-dicarboxylate
Methyl (1S,3R,5R,7R)-3-(tert-butyl)-7-chloro-6-oxo-7-[2-
(benzyloxy)ethyl]-2-oxa-4-azabicyclo[3.2.0]heptane-4-car-
boxylate 13 (280 mg, 1.0 mmol) and sodium hydroxide
(426 mg, 1.1 mmol) in MeOH/H2O (5:1, 5 ml) were mixed
and stirred at room temperature for 4 h, then solvent was
removed under reduced pressure. The residue was diluted
with ether (20 ml), washed with 1 N HCl (2 ml) and water
(5 ml), dried over MgSO4 and evaporated. Flash chroma-
tography (PE/AcOEt/iPrOH¼100/5/5, Rf¼0.45) gave the
1
product (0.16 g, 58%). H NMR (300 MHz, CDCl3) d 5.15
4.9.4. Methyl (2R,6R)-6-(2-{[tert-butyl(diphenyl)silyl]-
oxy}ethyl)-2-(tert-butyl)-6-chloro-5-oxotetrahydro-
furo[2,3-d][1,3]oxazole-3(2H)-carboxylate 46d. 92%
yield. Rf¼0.3 (PE/Et2O¼10/1), 1H NMR (CDCl3,
300 MHz) d 7.37–7.70 (m, 10H, 2Ph), 6.18 (d, J¼3.0 Hz,
1H, CHN), 5.23 (s, 1H, NCHO), 4.82 (d, J¼3.0 Hz, 1H,
CHO), 3.98 (m, 2H, OCH2), 3.80 (s, 3H, OMe), 2.44 (m, 2H,
CH2), 1.07 (s, 9H, SitBu), 0.86 (s, 9H, tBu). 13C NMR
(75 MHz) d 170.6 (CvO), 154.3 (CvO), 133.4 (Carom),
135.5, 129.8, 127.8 (CHarom), 99.5 (NCHO), 89.3 (CHN),
84.1 (CHO), 65.4 (CCl), 59.7 (CH2O), 53.5 (OMe), 39.0
(tBu), 32.8 (SitBu), 26.9 (CH2), 25.6 (tBu), 19.2 (SitBu). IR
(film) n 2960, 1798 (CvOlactone), 1735 (CvO), 1360, 1168,
760. MS (APCI) m/z (%) 560 (Mþ1, 12), 446 (17).
(s, 1H, NCHO), 4.37 (d, J¼5.8 Hz, 1H, CHO), 3.73 (s, 3H,
OMe), 3.68 (s, 3H, OMe), 3.62 (d, J¼5.8 Hz, 1H, CHN),
1.16 (s, 3H, CH3), 0.95 (s, 9H, tBu). 13C NMR (75 MHz,
CDCl3) d 170.7 (CvO), 157.1 (CvO), 105.0 (NCHO), 67.8
(CHO), 53.0 (OMe), 52.0 (OMe), 44.5 (CHN), 38.0 (tBu),
35.5 (CCO), 24.5 (tBu), 6.3 (CH3). IR (film) n 2957, 1734
(CvO), 1708 (CvOcarbamate), 1361, 1121. MS (FABþ) m/z
(%) 272 (Mþ1, 25), 214 (M2tBu, 28), 154 (100), 136 (67),
89 (30).
4.9. General procedure for the Baeyer–Villiger
oxidation
Into a 25 ml two-necked flask dried by flame under the
argon, cyclobutanones (1 equiv.) and chloroform
(5 ml/mmol) were added, then 3-chloroperoxybenzoic acid
(1 equiv.) and sodium bicarbonate (1 equiv.) were added
consecutively. The mixture was stirred at room temperature
under argon overnight, then washed with sodium sulphite
solution (10%) and saturated NaHCO3 solution. The organic
fraction was dried and evaporated. Flash chromatography
(PE/Et2O¼8/1) gave pure product (46a–h).
4.9.5. Methyl (2R,6R)-6-(2-[benzyloxy]ethyl)-2-(tert-
butyl)-6-chloro-5-oxotetrahydrofuro[2,3-d][1,3]oxazole-
3(2H)-carboxylate 46e. 88% yield, Rf¼0.33. 1H NMR
(CDCl3, 300 MHz) d 7.28–7.35 (m, 5H, Ph), 6.17 (d, J¼
2.8 Hz, 1H, CHN), 5.21 (s, 1H, NCHO), 4.88 (d, J¼2.8 Hz,
1H, CHO), 4.52 (s, 2H, CH2Ph), 3.82 (m, 2H, CH2O), 3.79
(s, 3H, OMe), 2.23–2.54 (m, 2H, CH2), 0.84 (s, 9H, tBu).
13C NMR (CDCl3, 75 MHz): d 170.8 (CvO), 154.3
(CvO), 137.8 (Carom), 128.5, 128.2, 127.8 (CHarom), 99.2
(NCHO), 89.3 (CHN), 84.4 (CHO), 73.4 (CH2Ph), 66.2
(CCl), 65.1 (CH2O), 53.3 (OMe), 38.8 (tBu), 31.9 (CH2),
25.5 (tBu). IR (film) n 2927, 1796 (CvOlactone), 1738
4.9.1. Methyl (2R,6R)-6-methyl-2-(tert-butyl)-6-chloro-5-
oxotetrahydrofuro[2,3-d][1,3]oxazole-3(2H)-carboxylate
1
46a. 95% yield, Rf¼0.34. H NMR (300 MHz, CDCl3) d

L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
7605
(CvO), 1360, 1109. MS (APCI) m/z (%) 412 (Mþ1, 12),
with methanol. The combined methanolic solution was
concentrated. The residue was dissloved in CHCl3
(2 ml/mmol) and the insoluble material was removed.
After evaporation of the solvent, the residue was chromato-
graphied on silica gel to give the product (47a–b).
394 (74), 326 (63), 304 (100), 246 (72).
4.9.6. tert-Butyl (2R,6R)-6-(2-[benzyloxy]ethyl)-2-(tert-
butyl)-6-chloro-5-oxotetrahydrofuro[2,3-d][1,3]oxazole-
3(2H)-carboxylate 46f. 89% yield, Rf¼0.36. 1H NMR
(CDCl3, 300 MHz) d 7.31–7.37 (m, 5H, Ph), 6.11 (d, J¼
2.8 Hz, 1H, CHN), 5.21 (s, 1H, NCHO), 4.84 (d, J¼2.8 Hz,
1H, CHO), 4.54 (ab, J¼15.4 Hz, 2H, CH2Ph), 3.81 (m, 2H,
CH2O), 2.54 (ddd, J¼15.1, 9.6, 6.1 Hz, 1H, CH2), 2.23
(ddd, J¼15.1, 4.7, 3.3 Hz, 1H, CH2), 1.47 (s, 9H, OtBu),
0.85 (s, 9H, tBu). 13C NMR (CDCl3, 75 MHz) d 171.6
(CvO), 156.0 (CvO), 137.5 (Carom), 128.7, 128.2, 128.0
(CHarom), 99.1 (NCHO), 90.2 (CHN), 84.7 (CHO), 82.2
(OtBu), 73.6 (CH2Ph), 69.2 (CCl), 65.5 (CH2O), 39.2 (tBu),
30.3 (CH2), 28.4 (OtBu), 25.9 (tBu). IR (KBr) n 2977, 1799
(CvOlactone), 1734 (CvO), 1361, 1163. MS (APCI) m/z
(%) 454 (Mþ1, 14), 282 (100), 144 (12). Anal. Calcd for
C23H32ClNO6 C 60.85, H 7.10, N 3.08, Cl 7.81; found C
60.68, H 6.95, N 2.97, Cl 8.01. X-ray diffraction analysis
4.10.1. Methyl (2R,3aR,6R,6aR)-2-(tert-butyl)-6-chloro-
6-methyl-5-oxotetrahydro-2H-pyrrolo[2,3-d][1,3]oxa-
zole-3(3aH)-carboxylate 47a. 38% yield, Rf¼0.25 (PE/
Et2O¼5/1). 1H NMR (CDCl3, 300 MHz) d 6.96 (s, 1H, NH),
6.21 (d, J¼3.0 Hz, 1H, CHN), 5.28 (s, 1H, NCHO), 4.81 (d,
J¼3.0 Hz, 1H, CHN), 3.81 (s, 3H, OMe), 1.76 (s, 3H, CH3),
0.96 (s, 9H, tBu). 13C NMR (CDCl3, 75 MHz) d 173.2
(CvO), 153.4 (CvO), 100.2 (NCHO), 85.7 (CHN), 75.9
(CHO), 69.5 (CCl), 54.6 (OMe), 39.1 (tBu), 25.3 (tBu), 17.6
(CH3). IR (KBr) n 2964, 1741 (CvOlactam), 1728 (CvO),
1361, 1112. MS (CI) m/z (%) 291 (Mþ1, 12), 253 (10), 199
(86), 183 (100).
4.10.2. Methyl (2R,3aR,6R,6aR)-2-(tert-butyl)-6-chloro-
6-(trimethylsilylmethyl)-5-oxotetrahydro-2H-pyrrolo
[2,3-d][1,3]oxazole-3(3aH)-carboxylate 47b. 40% yield,
˚
Wavelength: 0.71069 A, Crystal system: orthorhombic; unit
˚
cell dimensions: a¼9.560 (3) A, a¼908; b¼10.468 (3), b¼
1
908; c¼23.952 (9), g¼908.
Rf¼0.25 (PE/Et2O¼6/1). H NMR (CDCl3, 300 MHz) d
6.76 (s, 1H, NH), 5.36 (d, J¼4.8 Hz, 1H, CHN), 5.01 (s, 1H,
NCHO), 4.48 (d, J¼4.8 Hz, 1H, CHN), 3.66 (s, 3H, OMe),
0.86 (s, 9H, tBu), 0.14 (SiMe3). 13C NMR (CDCl3, 75 MHz)
d 172.3 (CvO), 154.5 (CvO), 98.6 (NCHO), 84.7 (CHN),
69.3 (CCl), 68.5 (CHO), 53.2 (OMe), 39.2 (tBu), 25.6 (tBu),
19.6 (CH2), 0.1 (SiMe3). IR (film) n 3237, 2942, 1744
(CvO), 1723 (CvO), 976. MS (CIþQ1MS) m/z (%): 363
(Mþ1, 35), 347 (100), 327 (32), 313 (14), 89 (10). MS
(CI2Q1MS) m/z (%) 361 (M21, 22), 240 (24), 168 (100).
Anal. Calcd for C15H27ClN2O4Si C 49.64, H 7.50, N 7.71;
found C 50.27, H 7.60, N 6.76.
4.9.7. Methyl (2R,6R)-6-(3-bromopropyl)-2-(tert-butyl)-
6-chloro-5-oxotetrahydrofuro[2,3-d][1,3]oxazole-3(2H)-
1
carboxylate 46g. 90% yield, Rf¼0.3. H NMR (CDCl3,
300 MHz) d 6.22 (d, J¼3.0 Hz, 1H, CHN), 5.29 (s, 1H,
NCHO), 4.82 (d, J¼3.0 Hz, 1H, CHO), 3.80 (s, 3H, OMe),
3.47 (m, 2H, CH2Br), 2.21–2.33 (m, 4H, CH2CH2), 0.95 (s,
9H, tBu). 13C NMR (CDCl3, 75 MHz) d 170.2 (CvO),
154.1 (CvO), 99.5 (NCHO), 88.9 (CHN), 83.9 (CHO), 66.4
(CCl), 53.5 (OMe), 39.0 (tBu), 32.2 (CH2Br), 30.2 (CH2),
27.2 (CH2), 25.6 (tBu). IR (film) n 2960, 1798 (CvOlactone),
1738 (CvO), 1360, 1143. MS (APCI) m/z (%) 398
(Mþ1, 9), 282 (100), 220 (32), 144 (12). Anal. Calcd for
C14H21BrClNO5 C 42.17, H 5.31, N 3.51, Cl 8.89; found C
42.07, H 5.44, N 3.58, Cl 9.29.
4.10.3. (2R,4R,5S)-2-tert-Butyl-5-[1,3]dithiolan-2-yl-oxa-
zolidine-3,4-dicarboxylic acid 3-tert-butyl ester 48. Into a
suspension of 43 (0.3 g, 0.83 mmol) and NaOH (60 mg,
1.5 mmol) in H2O (10 ml) was added acetone until a clear
solution was formed. The mixture was stirred overnight,
then diluted phosphoric acid was added to pH 1. The
mixture was extracted with ether (4£10 ml). The combined
ether was evaporated to give crude product which was
recrystallized in n-hexane–CH2Cl2 to afford pure product
0.29 g, 92%, mp 148.7–151 8C. 1H NMR (300 MHz,
CDCl3) d 5.14 (s, 1H, NCHO), 4.48–4.35 (m, 3H), 3.22–
3.19 (m, 4H), 1.43 (s, 9H, OtBu), 0.92 (s, 9H, tBu). 13C
NMR (75 MHz, CDCl3) d 175.5 (CvO), 154.5 (CvO),
97.1 (NCHO), 84.6 (CHN), 81.7 (OtBu), 64.3 (CH2O), 51.9
(SCHS), 39.1 (CH2), 38.5 (CH2), 28.1 (OtBu), 26.5 (tBu).
IR (film) n 3340, 2960, 1720 (CvO). MS (EI) m/z (%) 334
(M2CO2)þ, 320 (M2tBu), 264, 220, 175 (100). Anal.
Calcd for C16H27NO5S2 C 50.80, H 7.20, N 3.71, S 16.98;
found C 50.45, H 7.18, N 3.47, S 16.70.
4.9.8. Methyl (2R,6R)-6-methyl-2-(tert-butyl)-6-bromo-
5-oxotetrahydrofuro[2,3-d][1,3]oxazole-3(2H)-carboxyl-
ate 46h. 91% yield, Rf¼0.34. 1H NMR (CDCl3, 300 MHz) d
6.21 (d, J¼2.9 Hz, 1H, CHN), 5.29 (s, 1H, NCHO), 4.97 (d,
J¼2.9 Hz, 1H, CHO), 3.81 (s, 3H, OMe), 1.94 (s, 3H, CH3),
0.95 (s, 9H, tBu). 13C NMR (CDCl3, 75 MHz) d 171.5
(CvO), 154.3 (CvO), 99.5 (NCHO), 88.6 (CHN), 85.2
(CHO), 62.8 (CBr), 53.5 (OMe), 39.0 (tBu), 25.6 (tBu), 19.8
(CH3). IR (film) n 2960, 1797 (CvOlactone), 1739 (CvO),
1360, 1110. MS (APCI) m/z (%) 336 (Mþ1, 9), 282 (100).
4.10. General procedure for the Beckmann
rearrangement
To a solution of cyclobutanones (1 equiv.) in dichloro-
methane (1 ml/mmol) was added with stirring O-mesityl-
enesulfonylhydroxylamine (1.2 equiv.) in dichloromethane
(1 ml/mmol) dropwise at room temperature. After stirring
for another 70 min, the solvent was removed under reduced
pressure to yield a colourless oil which was then dissolved
in benzene–methanol (3:1, 1 ml/mmol) and the resulting
mixture was added dropwise to a stirring suspension of
alumina (5 g/mmol) in methanol (5 ml/mmol). The mixture
was stirred for 4 h and filtered. The alumina was washed
4.10.4. (2R,4R,5S)-2-tert-Butyl-5-[1,3]dithiolan-2-yl-oxa-
zolidine-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl
ester 49. Into a solution of 48 (91 mg, 0.24 mmol) in ether
(15 ml) was added CH2N2 in ether at 0 8C. After stirring for
15 min, acetic acid was added to neutralize excess CH2N2.
The organic phase was washed with saturated aqueous
NaHCO3 (2 ml), dried over MgSO4 and concentrated.
Recrystallization in n-hexane gave pure product 0.31 g,

7606
L. Ghosez et al. / Tetrahedron 60 (2004) 7591–7606
1
1989; Vol. 70. (b) Marchand-Brynaert, J.; Ghosez, L. In
Recent Progress in Chemical Synthesis of Antibiotics; Ohno,
M., Lukacs, G., Eds.; Springer Verlag Inc: Berlin, Heidelberg,
1990.
94%, mp 118.9–119.4 8C. H NMR (300 MHz, CDCl3) d
5.20 (s, 1H, NCHO), 4.56–4.37 (m, 2H), 4.15 (m, 1H), 3.77
(s, 3H), 3.27–3.12 (m, 4H), 1.40 (s, 9H, OtBu), 0.96 (s, 9H,
tBu). 13C NMR (75 MHz, CDCl3) d 170.1 (CvO), 154.3
(CvO), 96.7 (NCHO), 84.6 (CHN), 81.4 (OtBu), 64.4
(CH2O), 52.1 (OMe), 51.9 (SCHS), 39.0 (CH2), 38.8 (CH2),
28.1 (OtBu), 26.5 (tBu). IR (film) n 3055, 2987, 1747
(CvO), 1719 (CvO). MS (EI) m/z 335 (M2C4H8)þ, 278,
234, 189 (100%). Anal. Calcd for C17H29NO5S2 C 52.14, H
7.46, N 3.57, S 16.37; found C 51.99, H 7.48, N 3.36, S
15.74.
4. (a) Marchand-Brynaert, J.; Bounkhala-Krouz, Z.; Van Keulen,
B. J.; Vanlierde, H.; Ghosez, L. Isr. J. Chem. 1989, 29, 247.
(b) Carretero, J. C.; Davies, J.; Marchand-Brynaert, J.; Ghosez,
L. Bull. Soc. Chim. Fr. 1990, 127, 835. (c) Dive, G.; Dumas,
´
S.; Genicot, Ch.; Kumli, F.; Love, Ch.; Marchand-Brynaert, J.;
Ghosez, L. Antibiotics and Antiviral Compounds; VCH:
Weinheim, 1993; pp 177–186. (d) Durand, T.; Marchand-
Brynaert, J.; Ghosez, L. Bioorg. Med. Chem. Lett. 1993, 3,
2309. (e) Marchand-Brynaert, J.; Mougenot, P.; Combret, Y.;
Belotti, D.; Guillot, N.; Ghosez, L. Il Farmaco 1995, 50, 455.
(f) Mougenot, P.; Marchand-Brynaert, J.; Ghosez, L.
J. Pharmacie Belg. 1995, L2-3, 237. (g) Marchand-Brynaert,
J.; Durand, T.; Ghosez, L. J. Pharmacie Belg. 1995, L2-3, 249.
(h) Payne, D. J.; Bateson, J. H.; Gasson, B. C.; Proctor, D.;
Khushi, T.; Farmer, T. H.; Tolson, D. A.; Bell, D.; Skett, P. W.;
Marshall, A. C.; Reid, R.; Ghosez, L.; Combret, Y.; Marchand-
Brynaert, J. Antimicrobial Agents and Chemotherapy 1997,
41, 135.
4.10.5. 5-tert-Butyl-1a-(p-tolyl)1a,6b-dihydrospiro{1H,
3H,5H-cyclobuta[gh]oxazolo[3,4-c]oxazole-1,20-[1,3]-
dithiolan}-3-one 50. Into a solution of 43 (100 mg,
0.29 mmol) in THF (3 ml) was added 1 M para-tolylmag-
nesium bromide in ether at room temperature. After stirring
for 2 h, saturated aqueous NH4Cl (1 ml) was added. The
mixture was extracted with ether (3£5 ml). The combined
organic layers were washed with brine, dried over MgSO4
and concentrated. Flash chromatography (c-hexane/AcOEt¼
1
4/1) gave pure product 86 mg, 79%, mp 168–169 8C. H
5. See also (a) Lowe, G.; Swain, S. J. Chem. Soc., Chem.
Commun. 1983, 1279. (b) Lowe, G.; Swain, S. J. Chem. Soc.,
Perkin Trans. 1 1985, 391. (c) Cocuzza, A. J.; Boswell, G. A.
Tetrahedron Lett. 1985, 26, 1631. (d) Agathocleous, D.; Cox,
G.; Page, M. I. Tetrahedron Lett. 1986, 27, 1631. (e) Martyres,
D. C.; Baldwin, J. E. Tetrahedron 2001, 57, 4999.
NMR (300 MHz, CDCl3) d 7.26 (s, 4H), 5.36 (s, 1H), 4.85
(d, 1H, J¼4.6 Hz), 4.79 (d, 1H, J¼4.6 Hz), 2.40 (s, 3H),
0.98 (s, 9H). 13C NMR (75 MHz, CDCl3) d 162.7, 139.1,
131.8, 129.1, 125.8, 105.0, 87.9, 83.6, 77.4, 66.2, 39.9, 39.5,
36.3, 24.9, 21.3. IR (film) n 2990, 1760 (CvO), 1610, 1486,
1455, 1320. MS (EI) m/z 377 (M)þ, 321, 277, 91, 57; HRMS
Calcd for C19H23NO3S2 377.111, found 377.113.
6. (a) Renaud, P.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1986, 25, 843. (b) Seebach, D.; Stucky, G. Angew.Chem., Int.
Ed. Engl. 1988, 27, 1351. (c) Seebach, D.; Stucky, G.; Renaud,
P. Chimia 1988, 176. (d) Stucky, G.; Seebach, D. Chem. Ber.
1989, 122, 2365. (e) Seebach, D.; Srucky, G.; Pfammater, E.
Chem. Ber. 1989, 122, 2377. (f) Seebach, D.; Lamatsch, B.;
Amstutz, R.; Beck, A. K.; Dobler, M.; Egli, M.; Fitzi, R.;
Gautschi, M.; Herradon, B.; Stucky, G.; Petter, W.; Escalante,
J.; Molins, E. Helv. Chim. Acta 1992, 75, 913. (g) Lamatsch,
B.; Seebach, D.; Ha, T. K. Helv. Chim. Acta 1992, 75, 1095.
7. See for example: Speckamp, W. N.; Hiemstra, H. Tetrahedron
1985, 41, 4367.
Acknowledgements
This work was generously supported by grants from CNPq
´ ´
and CAPES (Brazil), Services federaux des Affaires
Scientifiques, Techniques et Culturelles (P.A.I. no 19), the
Fonds National de la Recherche Scientifique and UCL. We
would also like to thank Dr. B.Tinant and Prof. J. P. Declecq
for X-ray structure determinations, Prof. E. De Hoffmann
for the mass spectra and Dr. R. Touillaux for high field
NMR studies
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`
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Coyette, J.; Leyh-Bouille, M.; Ghuysen, J. M.; Dideberg, O.;
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(b) Bellus, D. J. Org. Chem. 1979, 44, 1208. (c) Matsui, S.;
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(d) See also Kumli, F. Dissertation, University of Louvain,
1996.
`
Frere, J. M.; Dive, G.; Lamotte-Brasseur, J.; Dideberg, O.;
Charlier, P. Biochem. J. 1991, 279, 213. (c) Page, M. I.
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´
12. (a) Ghosez, L.; Cossement, E.; Biname, R. Tetrahedron Lett.
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