Preparation of (3S,4S)-1-benzhydryl-3-[(5R)-1'-hydroxyethyl]-4-acyl-2- azetidinones from (2R,3R)-epoxybutyramide precursors

Article abstract of DOI:10.1016/S0040-4020(00)00196-4

The N-(phenacyl)-8a and N-(pivaloylmethyl)-8b derivatives of N- (benzhydryl)-(2R,3R)-cis-2,3-epoxybutyramide were prepared from sodium (2R,3R)-cis-2,3-epoxybutanoate 4. Under basic conditions they gave S(N)i reactions leading to the formation of four-, si

Full text of DOI:10.1016/S0040-4020(00)00196-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3209±3217
Preparation of (3S,4S)-1-Benzhydryl-3-[(5R)-10-hydroxyethyl]-4-
acyl-2-azetidinones from (2R,3R)-Epoxybutyramide Precursors
Bo-Liang Deng,a Marc Demillequand,a Mathieu Laurent,a Roland Touillaux,b Marc Belmans,c
c
 Â
Luc Kemps, Marcel Ceresiat and Jacqueline Marchand-Brynaert
c
a,
*
a
 Á Ã
Universite Catholique de Louvain, Laboratoire de Chimie Organique de Synthese, Batiment Lavoisier, Place Louis Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
Universite Catholique de Louvain, Laboratoire de Chimie Physique et Cristallographie, Batiment Lavoisier, Place Louis Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
b
Â
Ã
c
Ã
Tessenderlo Chemie, rue du Trone 130, B-1050 Bruxelles, Belgium
Received 21 December 1999; revised 14 February 2000; accepted 2 March 2000
AbstractÐThe N-(phenacyl)-8a and N-(pivaloylmethyl)-8b derivatives of N-(benzhydryl)-(2R,3R)-cis-2,3-epoxybutyramide were
prepared from sodium (2R,3R)-cis-2,3-epoxybutanoate 4. Under basic conditions they gave SNi reactions leading to the formation of
four-, six- and seven-membered heterocycles, namely the azetidin-2-ones 9a, b (C-alkylation), the 2,3-dehydro-morpholin-5-ones 10a, b
(O-alkylation), and the 4,5,6,7-tetrahydro-4-aza-oxepin-5-ones 12a, b (O-alkylation). The structures were con®rmed by NMR analysis.
Other rearrangement products, 13a and 14b, were also isolated. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
oxidation with ceric ammonium nitrate, i.e. 4-methoxy-
benzyl-, 2,4-dimethoxybenzyl-, or most usually, 4-methoxy-
phenyl-(ˆp-anisyl) groups. This method, starting from a
low cost, naturally occurring chiron,12,13 generates the
three chiral centres of the b-lactam precursors 2 in the
required absolute con®guration.
The pharmaceutical development of carbapenems, an
important class of b-lactam antibiotics,1 is connected to
the availability of appropriate synthetic precursors, such
as the chiral azetidinone 1: (3R,4R)-4-acetoxy-3-[(5R)-10-
(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone.2
In our laboratory, we became interested in a modi®cation of
the previous strategy making use of a nitrogen-protecting
group cleavable by hydrogenolysis. Our previous experi-
ence in the related b-lactamiminium derivatives led us to
consider the benzhydryl group.14 Accordingly, we prepared
the precursors 8 (Scheme 2) and examined their transforma-
tion into the corresponding b-lactams. During this work, we
found unexpected cyclization- and rearrangement products
described in this article.
Amongst the various strategies explored for the construction
of this versatile building block,3 one is based on the C-3/C-4
ring closure via an intramolecular nucleophilic substitution
of (2R,3R)-epoxy-butyramide precursors 3 derived from
l-threonine (Scheme 1).4±11 The structures 3 are equipped
with an electron-withdrawing group (EWG) able to stabilise
a carbanionic intermediate, and with a nitrogen-protecting
group (PG) that could be cleaved from the b-lactams 2 by
Scheme 1.
Keywords: epoxide ring-opening; intramolecular nucleophilic substitution; O/C-alkylation; b-lactam.
* Corresponding author. Tel.: 132-10-472740; fax: 132-10-474168; e-mail: marchand@chor.ucl.ac.be
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00196-4

3210
B.-L. Deng et al. / Tetrahedron 56 (2000) 3209±3217
Scheme 2. Reagents and conditions: (i) t-BuCOCl, CH3CN, 208C; (ii) HCl´H2NCH2COPh, Et3N, CH3CN, 208C; (iii) HCl´H2NCHPh2, Et3N, CH3CN, 208C; (iv)
(COCl)2, THF, 2158C; (v) 7, pyridine, THF, 215 to 208C.
of 4 has been established by chiral GC analysis, after
derivatization into the corresponding isopropyl ester.13
From the examination of several conditions for direct acti-
vation of the salt 4 (SOCl2/THF; SOCl21pyridine/benzene;
(COCl)21pyridine/THF; 2,3,5-trichlorobenzoyl chloride/
DMF; i-butyl chloroformate/DMF or CH3CN; pivaloyl
chloride1pyridine/CH3CN), we selected two methods
allowing the further coupling of amines in good yields,
i.e. the in situ formation of an acid chloride with oxalyl
Scheme 3.
chloride, or a mixed anhydride with pivaloyl chloride.
Thus, after appropriate activation, 4 was reacted with
2-aminoacetophenone or benzhydrylamine to furnish,
respectively, the epoxybutyramides 5a or 6 in good yields
(Scheme 2). All attempts to transform either 5a or 6 into the
Results
(2R,3R)-cis-2,3-Epoxybutanoate 4 was prepared from
l-threonine according to known procedures,12,13 adapted
for large quantities (100 g scale). The enantiomeric purity
Scheme 4.

B.-L. Deng et al. / Tetrahedron 56 (2000) 3209±3217
3211
Table 1. Ratio of products from 1H NMR analysis of the crude mixtures (%)
(examination of the 5.0±6.5 d spectral domain)
treatment of similar precursors 3 (Scheme 1) equipped
with a benzoyl group (EWGˆCOPh), i.e. K2CO3 in DMF
with heating (PGˆp-anisyl; 75% yield of 28,11) and
LiHMDS (lithium hexamethyldisilazide), at low tempera-
ture, in benzene (PGˆCH(OEt)Ph; 71% yield of 210) or in
THF (PGˆp-anisyl; 67% yield of 211). Our results, collected
in Table 1, showed that the treatment of 8a with K2CO3 led
to the formation of b-lactam 9a as a minor product (16%
yield), while the use of Li2CO3 slightly improved the forma-
tion of the desired product 9a (34% yield). The best results
were obtained with LiHMDS as the base, giving 57% of 9a.
In all cases, the b-lactam 9a was accompanied with a
mixture of three side-products (HPLC and NMR analyses
of the crude mixtures), which could be separated and
isolated as pure materials by careful column-chromato-
graphy (see Rf values in Experimental).
Entry
R1 (8); conditions
9
10 12 13 14
1
2
3
4
5
6
a, Ph; K2CO3, DMF, 1008C, 17 h
a, Ph; Li2CO3, DMF, 1008C, 17 h
a, Ph; LiHMDS, THF, 08C, 2 h
b, t-Bu; K2CO3, DMF, 1008C, 17 h
b, t-Bu; Li2CO3, DMF, 1008C, 17 h 62
b, t-Bu; LiHMDS, THF, 08C, 2 h
16
34
57
55
56 21 7
38 18 10
±
±
±
,2
5
±
21 20
2
±
±
±
35
24
8
9
.90 ,2 .2
required precursor 8a by the appropriate N-alkylation reac-
tion (R±X/base/DMF) failed. Also, the treatment of 5a
under various basic conditions (LiHMDS, LiOH, Li2CO3,
basic Al2O3) did not lead to the formation of the correspond-
ing N-unprotected b-lactam. Therefore, we developed a
convergent synthesis towards the N-protected precursors 8
using N-(benzhydryl) aminoketones 7 (Scheme 3).
The structure of 9a (single stereoisomer) was fully
con®rmed by the spectroscopic data in good agreement
with the literature;7,10 in particular, the trans b-lactam
protons appeared at 3.11 d (H-3, dd) and 5.07 d (H-4, d)
Compounds 7a and 7b were easily prepared by reaction of
diphenylaminomethane with 2-bromoacetophenone and
1-bromopinacolone, respectively, in methanol solution.
Activation of 4 with oxalyl chloride in THF at 2158C,
followed by addition of pyridine and 7a, b led to the
recovery of 8a, b in 80% yield (Scheme 2). Compounds
8a, b showed the presence of two rotamers in the NMR
spectra recorded in CDCl3, splitting practically all the
signals. This could be due to a restricted rotation around
the C(O)±N amide bond. As a matter of fact, recording
the 1H NMR spectrum of 8a in DMSO-d6 at 998C
(300 MHz) gave one singlet at 6.8 d attributed to the
benzhydryl proton H-8; after cooling to 198C, splitting of
the signal occurred, giving two distinct singlets at 6.73 and
6.88 d.
1
in the H NMR spectrum, with a typical coupling constant
value of 2.3 Hz. Two carbonyl stretches were found in the
IR spectrum, at 1741 cm21 (b-lactam) and 1685 cm21
(PhCO). The structures of the three side-products, eluted
1
before the b-lactam 9a, were attributed on the basis of H
and 13C NMR data (see Experimental): 10a (Scheme 4) and
12a (Scheme 5) correspond to intramolecular O-alkylation
products of the C-2 and C-3 carbon atoms, respectively, of
the epoxide ring, while 13a (Scheme 6) results from an
intramolecular transesteri®cation followed by N-alkylation
of the C-2 carbon atom of the epoxide ring. As a matter of
fact, in these three structures, the benzoyl group (PhCO) was
absent, i.e. a doublet near 7.7 d (2H, J,8 Hz) for the ortho-
1
aromatic protons in the H NMR spectra, and a quaternary
We ®rst examined the cyclization of 8a (R1ˆPh) into the
corresponding b-lactam 9a (Scheme 4) by using the experi-
mental conditions recommended in the literature for the
carbon near 200 ppm for the carbonyl in the 13C NMR spec-
tra. On the other hand, a vinylic proton (s, H-3 or H-5) was
clearly visible in the 1H NMR spectra at 6.07 d in compound
Scheme 5.

3212
B.-L. Deng et al. / Tetrahedron 56 (2000) 3209±3217
Scheme 6.
10a, 5.72 d in compound 12a, and 6.24 d in compound 13a.
Moreover, the structures showed in 13C NMR only one
carbonyl function corresponding to an amide (C-5 at
163.6 ppm in 10a and 172 ppm in 12a) or an ester (C-2 at
164 ppm in 13a), and two vinylic carbons corresponding to
an a,b-hetero-substituted double bond (C-2 at 140 ppm in
10a and 145 ppm in 12a and C-3 at 104 ppm; C-5 and C-6 at
104 ppm and 140 ppm in 13a). The typical features of the
10-hydroxyethyl side-chain were found in 10a and 13a, but
not in 12a. Accordingly, in the 1H NMR spectra, H-7 of 13a
appeared as a quartet of doublets of doublets (4.4 d,
coupling with Me-8, H-3 and OH) and H-7 of 12a appeared
as a quartet of doublets (4.8 d, coupling with Me-8 and
H-6). Consistent with the previous assignments, H-3 in
13a was a doublet (4.5 d, coupling with H-7), while H-6
in 12a was a doublet of doublets (4.7 d, coupling with H-7
and OH).
The structural assignments of 9b, 10b and 12b were made,
on the basis of NMR data, by analogy with the related
compounds 9a, 10a and 12a. Moreover, the structure of
12b was unambiguously con®rmed by the X-ray diffraction
analysis of a single crystal; the compound is one stereo-
isomer with the (6R,7S) con®guration.15 Compound 14b
(Scheme 7), isolated in the ®rst elution fractions from
chromatography in less than 5% yield, is devoid of a
1
hydroxyl function; in the H NMR spectrum, it shows a
typical AB pattern corresponding to two protons of a CH2
group adjacent to a nitrogen atom (H-4 at 2.9 d and H-40 at
3.3 d with Jˆ11.8 Hz). Since these protons appear less
deshielded than the related H-6 and H-60 protons of the
precursor 8b (4.2±4.9 d, Jˆ17.3 Hz), we concluded that
they are not adjacent to a carbonyl function (CO±t-Bu).
Accordingly, in the 13C NMR, only one carbonyl function
was found at 167 ppm corresponding to an amide. The
bridged tricyclic structure 14b was fully con®rmed by selec-
tive H/C decoupling experiments; the ketal-type carbon C-5
appeared at 110 ppm.
The spectral characteristics of 10a were similar to those of
13a. At this stage, the structure of 10a could be de®nitively
con®rmed by the X-ray diffraction analysis of a single crys-
tal; the compound is one stereoisomer with the (6S, 7R)
con®guration.15
Discussion
Assuming that the O-alkylation processes (direct attack of
the epoxide, or transesteri®cation) should be less favourable
in the case of the precursor 8b (R1ˆt-Bu) for electronic and
steric reasons, we treated this non-conjugated and hindered
ketone as above, with K2CO3, Li2CO3, or LiHMDS (Table
1). As expected, the b-lactam 9b resulting from the C-alkyl-
ation of the C-2 carbon atom of the epoxide ring was the
major product in all cases (Scheme 4). In the presence of
K2CO3 and Li2CO3, the O-alkylation products 10b (Scheme
4) and 12b (Scheme 5) were also formed, but under treat-
ment with LiHMDS, 8b was transformed into the b-lactam
9b in more than 90% yield. The products were separated and
isolated as pure compounds by careful column-chromato-
graphy (see Rf values in Experimental). A weakly polar
rearrangement product 14b (Scheme 7), not found during
the basic treatment of 8a, was isolated in a few percent
yield. No product resulting from a transesteri®cation
process (like 13 in Scheme 6) could be detected.
The intramolecular ring-opening of chiral expoxides is
a stereochemically controlled SNi process useful for
the preparation of various carbocycles16±18 and hetero-
cycles.19±24 The epoxide function behaves as an ambident
electrophile that can be attacked by nucleophiles on the C-2
or C-3 position of the small ring. In our case, the internal
nucleophile is an enolate, thus also an ambident function,
that could attack with either its carbon- or oxygen atom,
leading theoretically to the possible formation of four
products allowed by Baldwin's rules,25 as illustrated in
Schemes 4 and 5. In our hands, three products were isolated,
9, 10 and 12, corresponding, respectively, to C-nucleophilic
attack on the epoxide C-2 position, O-nucleophilic attack on
the epoxide C-2 position, and O-nucleophilic attack on the
epoxide C-3 position. Compounds 11 resulting fom
C-nucleophilic attack on the epoxide C-3 position were
never isolated nor detected in the crude reaction mixtures
1
from the H NMR analyses. If formed, they must only be

B.-L. Deng et al. / Tetrahedron 56 (2000) 3209±3217
3213
Scheme 7.
present in less than 2% yield (limit of detection of the
analytical method). The precursor 8a (R1ˆPh) also under-
went a base-catalysed intramolecular transesteri®cation,
leading to the ®nal rearrangement product 13a (Scheme 6)
in low yield. The same reaction did not occur with the
precursor 8b (R1ˆt-Bu), most probably for steric reasons.
On the other hand, this compound 8b displayed a reactive
unconjugated carbonyl function susceptible to intramolecu-
lar nucleophilic attack of the epoxide oxygen atom (Scheme
7), leading to the bridged rearrangement product 14b. Since
8b was thermally stable in pure hot DMF, we speculated
that the rearrangement could be catalysed by lithium cations
present in the basic reactive medium.
desired azetidinone (9a) (C-alkylation). Replacing the
benzoyl substituent (R1ˆPh) with the pivaloyl group
(R1ˆt-Bu) reversed the O/C chemoselectivity, allowing
the formation of azetidinone 9b as the major product. In
this case, the non-conjugated enolate reacts preferentially
with its C-nucleophilic site on the oxirane C-2 position.
However, the absence of C-alkylation on the oxirane C-3
position (product 11, Scheme 5), in all cases, remains
surprising. A recent study26 devoted to the intramolecular
cyclization of enolate derived from 1-phenyl-5,6-epoxy-
hexan-1-one reported similar observations: only the O-
alkylation products (6-phenyl-2-hydroxymethyl-3,4-di-
hydro-2H-pyran and 7-phenyl-3-hydroxy-2,3,4,5-tetrahydro-
oxepine) were formed, while the C-alkylation products were
not found (1-benzoyl-2-hydroxymethyl-cyclobutane and
1-hydroxy-3-benzoylcyclopentane). Dianions of acetoacetic
esters reacted with epibromohydrin derivatives at the
g-position to form enolate intermediates27 which subse-
quently cyclize, affording exclusively the O-alkylation
products of the epoxide moiety. In the previous examples,
the product selectivity remains unexplained by the authors.
Most of the previous syntheses of b-lactams 2 based on the
cyclization of precursors 3 (Scheme 1) made use of anion-
stabilising groups favouring C-nucleophilic attack
(EWGˆCO2±t-Bu;7 CN;6 SO2Ph);4 the corresponding
b-lactams 2 were isolated in relatively good yields (60±
80%), and the authors did not mention the formation of
any 5-, 6- or 7-membered heterocyclic side-products. At
low temperature of cyclization, some (3S,4R)-cis stereo-
isomer of b-lactam 2 could be a minor product (kinetic
control instead of thermodynamic control). Also, the course
of the reaction seemed to be independent on the nature of the
N-protecting group (PGˆaryl- or benzyl type). Reactions
making use of the benzoyl group (EWGˆCOPh) were
scarcely described in the literature;8,10,11 precursors 3
equipped with p-anisyl8,11 or phenylethoxymethyl protect-
ing groups10 gave similar yields of b-lactams 2 (67±75%).
The only reported side-product, isolated in about 10% yield,
was a bicyclic hemiketal derived from the (3S,4R)-cis
stereoisomer of 2.11
Both the reactivity and C/O-selectivity of enolates depend
on the nature of the solvent and the counter-ion in¯uencing
the degree of ion-pair dissociation.28,29 The formation of a
strong ion-pair with the lithium counter-ion tends to
increase the C-versus the O-enolate reactivity in weakly
polar solvents such as THF.29 The use of DMF as a polar
solvent reduces this counter-ion effect. In this case, the
nature of the leaving group of the alkylating reagent (i.e.
the epoxide) will exercise the major in¯uence on the C/O-
selectivity; generally, soft electrophiles favour the C-alkyl-
ation process, and hard electrophiles the O-alkylation one.28
Our observations are in good agreement with the hard
character of the epoxide reagent. Accordingly, the best
conditions to obtain high yield of azetidinone 9 (C-alkyl-
ation) from precursor 8 make use of lithium hexamethyl-
disilazide as the base, in THF solution. However, steric (low
We found that the N-benzhydryl bulky protecting group
dramatically changed the course of the cyclization reaction
of 8a, favouring the formation of O-alkylation products
(10a, 12a) and transesteri®cation product (13a) over the

3214
B.-L. Deng et al. / Tetrahedron 56 (2000) 3209±3217
hindrance) and electronic factors (conjugated carbonyl) still
allow the occurrence of side-reactions (O-alkylation and
transesteri®cation) in the case of precursor 8a (R1ˆPh;
Table 1, entry 3), but not with precursor 8b (R1ˆt-Bu:
Table 1, entry 6).
(25 mL). The aqueous solution was extracted with ethyl
acetate (3£30 mL). The organic phases were gathered,
washed with brine (3£30 mL), and concentrated under
reduced pressure to give crude 5a (1.558 g, 81% yield).
Pure product was recovered by crystallisation from t-butyl
methyl ether/ethyl acetate (0.96 g, 50% yield): mp 135±
1
1368C (white crystals);[a]Dˆ123.3 (cˆ0.242, CHCl3); H
NMR (500 MHz, CDCl3) d 1.41 (d, 3H, Jˆ5.8 Hz, H-4),
3.32 (qd, 1H, Jˆ5.8, 4.4 Hz, H-3), 3.56 (d, 1H, Jˆ4.4 Hz,
H-2), 4.69 (dd, 1H, Jˆ19.4, 4.4 Hz, H-6), 4.91 (dd, 1H,
Jˆ19.4, 5.5 Hz, H-60), 7.11 (br s, 1H, NH), 7.49 (t, 2H,
Jˆ7.7 Hz), 7.62 (t, 1H, Jˆ7.7 Hz), 7.96 (d, 2H, Jˆ
7.7 Hz); 13C NMR (125 MHz, CDCl3) d 13.01 (C-4),
45.41 (C-6), 54.33 (C-3), 55.23 (C-2), 127.78, 128.81,
134.06, 134.18, 167.67 (C-5), 193.29 (C-7). Anal. Calcd
for C12H13NO3 (219.24): C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.61; H, 5.85; N, 6.37%.
Experimental
The melting points were determined with an Electrothermal
microscope and are uncorrected. The speci®c rotations
(^0.5) were determined on a Perkin±Elmer 241 MC polari-
meter (concentration in g/100 mL). The IR spectra were
taken with a Bio-Rad FTS 135 instrument, and calibrated
with polystyrene (1601 cm21). The 1H and 13C NMR spectra
were recorded on Varian Gemini 300 (at 300 MHz for
proton and 75 MHz for carbon), or Bruker AM-500 spectro-
meters (at 500 MHz for proton and 125 MHz for carbon);
the chemical shifts are reported in ppm down®eld from
tetramethylsilane (internal standard); the attributions were
®rmly established by selective decoupling experiments. The
mass spectra were obtained on a Finnigan-MAT TSQ-70
instrument at 70 eV (electronic impact (EI) mode), or with
a Xenon ION TECH 8 KV (fast atom bombardment (FAB)
mode). The microanalyses were performed at the
Christopher Ingold Laboratories of the University College
London. The HRMS were performed at the University of
N-(Benzhydryl) (2R,3R)-cis-2,3-epoxybutyramide (6).
Amide 6 was prepared following the procedure described
for 5a, starting from 4 (10 g, 44 mmol) and aminodiphenyl-
methane hydrochloride (9.15 g, 45 mmol). Precipitation
from t-butyl methyl ether gave 6 as an amorphous white
1
solid (6.4 g, 54% yield): H NMR (300 MHz, CDCl3) d
1.25 (d, 3H, Jˆ5.5 Hz, H-4), 3.31 (dq, 1H, Jˆ5.5, 5.4 Hz,
H-3), 3.58 (d, 1H, Jˆ5.4 Hz, H-2), 6.32 (d, 1H, Jˆ8.7 Hz,
H-6), 6.84 (d, 1H, NH), 7.15±7.40 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 13.0 (C-4), 54.8 (C-3), 55.2 (C-2),
56.2 (C-6), 125±130 (CH Ar), 140.8, 141, 166.7 (C-5).
Á
Liege (Belgium) on a VG-AutoSpec-Q equipment (Fisons
Instruments, Manchester).
N-(Benzhydryl)-N-(phenacyl)amine (7a). To a suspension
of 2-bromoacetophenone (5 g, 25.12 mmol) in dry methanol
(35 mL), stirred under argon atmosphere, was added
benzhydrylamine (8.66 mL, 50.24 mmol). The mixture
was stirred during 5 h at 208C. The formed solid (86%
yield) was ®ltered, and recrystallised from ethanol
(50 mL) to give pure 7a (5.29 g, 70% yield); mp 130.78C
(white crystals); 1H NMR (300 MHz, CDCl3) d 4.11 (s, 2H),
2.74 (s, 1H), 7.2±7.6 (m, 13H); 7.87 (d, 2H, Jˆ 7.5 Hz); 13C
NMR (75 MHz, CdCl3) d 54.2, 67.2, 127.2±128.6, 133.4,
143.6, 198.0. Anal. Calcd for C21H19NO (301.38); C, 83.69;
H, 6.35; N, 4.65. Found: C, 83.64; H, 6.10; N, 4.61%.
Thin-layer chromatography was carried out on silica gel 60
plates F254 (Merck, 0.2 mm thick); visualisation was
effected with UV light, iodine vapour, or a spray of potas-
sium permanganate (3 g) and potassium carbonate (20 g) in
aqueous acetic acid (1%, 300 mL). Column-chromato-
graphy (under medium pressure) was carried out with
Merck silica gel 60 of 230±240 mesh ASTM. The HPLC
analyses were performed with a Beckman equipment,
System Gold, 126P Solvent module, 168 Detector, from
Analis (Belgium). We used a Hypersil Elite C18 Column
2
Ê
(100 A, 5 mm; 250£4.6 mm ) thermostatised at 258C and
eluted with a gradient of acetonitrile/water, from 50:50 to
0:100 during 30 min (detection at 254 nm). The following
retention times were recorded (min): 8a: 9.53; 8b: 10.38;
9a: 8.35; 9b: 8.75; 10a: 11.80; 10b: 13.18; 12a: 13.53; 12b:
15.58.
N-(Benzhydryl)-N-(pivaloylmethyl)amine (7b). This com-
pound (amorphous white solid) was similarly prepared from
1-bromopinacolone, and puri®ed by ¯ash-chromatography
1
on silica gel (CH2Cl2/EtOAc, 90:10); H NMR (300 MHz,
CDCl3) d 1.09 (s, 9H), 3.59 (s, 2H), 4.75 (s, 1H), 7.15±7.45
(m, 10H); 13C NMR (75 MHz, CDCl3) d 26.96, 43.77,
52.95, 67.73, 127.8, 127.98, 129.18, 144.2, 214.71. Anal.
Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C,
81.34; H, 8.28; N, 4.94%. HRMS: 281.1776 (calcd:
281.1780).
(2R,3R)-cis-2,3-Epoxybutanoate (4). This compound
(sodium salt) was prepared according to the known pro-
cedures12,13 and used without puri®cation: 1H NMR
(200 MHz, D2O) d 1.37 (d, 3H, Jˆ5.6 Hz), 3.36 (dq, 1H),
3.55 (d, 1H, Jˆ4.5 Hz).
N-(Phenacyl) (2R,3R)-cis-2,3-epoxybutyramide (5a). To
a suspension of 4 (2.0 g, 8.81 mmol) in dry CH3CN
(17 mL), stirred at 188C under argon atmosphere, was
added dropwise pivaloyl chloride (1.085 mL, 8.81 mmol).
After 5 h 45 min of stirring, the mixture was successively
treated with 2-aminoacetophenone hydrochloride (1.19 g,
8.81 mmol) (the temperature was maintained below 208C)
and with triethylamine (2.58 mL, 18.5 mmol) added drop-
wise during 30 min. After 3 h of stirring, the mixture was
®ltered and the ®ltrate was poured into ice-cold water
N-(Benzhydryl)-N-(phenacyl) (2R,3R)-cis-2,3-epoxybu-
tyramide (8a). To a suspension of 4 (2 g, 8.81 mmol) in
dry THF (25 mL), stirred at 2158C (bath with ice1NaCl)
under argon atmosphere, was added dropwise (with a
syringe, through a septum) oxalyl chloride (1.6 mL,
17.5 mmol). The mixture was stirred for 50 min at 2128C.
Pyridine (2.2 mL, 27.5 mmol) was added dropwise (with a
syringe, through a septum), followed by 7a (2.65 g,
8.81 mmol). The mixture was stirred for 30 min at 2128C,

B.-L. Deng et al. / Tetrahedron 56 (2000) 3209±3217
3215
then allowed to warm up slowly to room temperature within
50 min. The crude solution was poured into a 50:50 mixture
of ethyl acetate and 5% aqueous NaHCO3 (80 mL), and the
organic layer was separated. The aqueous phase was
extracted with ethyl acetate (3£25 mL). The organic phases
were gathered, washed with saturated aqueous ammonium
chloride (3£15 mL), dried over MgSO4 and concentrated
under vacuum (2.68 g, 79% crude yield). Pure 8a was
obtained by crystallisation from H2O/EtOH (5:2) (1.87 g,
55% yield): mp 161±1628C (white crystals); [a]Dˆ19.19
(cˆ0.96, CHCl3); 1H NMR (500 MHz, CDCl3; two rotamers
in a 53:47 ratio) d 1.36 and 1.48 (two d, 3H, Jˆ5.8 Hz,
H-4), 3.23 and 3.26 (two dq, 1H, Jˆ5.8, 4.4 Hz, H-3),
3.62 and 3.63 (two d, 1H, Jˆ4.4 Hz, H-2), 4.68 and 4.72
(two d, 1H, Jˆ17.3 Hz, H-6), 4.86 and 5.28 (two d, 1H,
Jˆ17.3 Hz, H-60), 6.71 and 7.18 (two s, 1H, H-8), 7.10±
7.50 (m, 13H); 7.58 and 7.66 (two d, 2H, Jˆ7.7 Hz) 13C
NMR (125 MHz, CDCl3; two rotamers in a 53:47 ratio) d
13.97 and 14.66 (C-4), 50.42 and 50.62 (C-6), 53.85
and 54.08 (C-3), 54.66 and 55.60 (C-2), 61.14 and
64.19 (C-8), 167.81 and 168.42 (C-5), 191.99 and 193.3
(C-7), 6 quaternary aromatic carbon signals (138.85,
138.60, 138.56, 138.28, 135.22, 134.5) 18 aromatic CH
signals (133.29, 132.91, 129.47, 128.85, 128.63, 128.57,
128.48, 128.44, 128.34, 128.31, 128.27, 128.15, 128.05,
128.03, 127.67, 127.47, 127.40, 127.31). Anal. Calcd for
C25H23NO3´0.1H2O: C, 77.56; H, 5.99; N, 3.62. Found: C,
77.61; H, 5.87; N, 3.59%. HRMS: 385.1678 (calcd:
385.1678).
concentrated under vacuum. Flash chromatography on silica
gel with a 20:1 mixture of CH2Cl2 and EtOAc furnished the
azetidinone 9a in the last fractions as a white gum (0.32 g,
30% yield): Rfˆ0.20 (CH2Cl2/EtOAc, 10:1); [a]Dˆ2 13.5
(cˆ0.222, CHCl3); IR (KBr) n 3400 (br), 1741, 1685, 1450,
1230, 600 cm21; 1H NMR (500 MHz, CDCl3) d 1.20 (d, 3H,
Jˆ6.3 Hz, H-6), 2.10 (br s, 1H, OH), 3.11 (dd, 1H, Jˆ2.3,
5.2 Hz, H-3), 4.31 (dq, 1H, Jˆ5.2, 6.3 Hz, H-5), 5.07 (d, 1H,
Jˆ2.3 Hz, H-4), 5.59 (s, 1H, H-8), 7.15±7.40 (m, 12H), 7.50
(t, 1H, Jˆ7.7 Hz), 7.70 (d, 2H, Jˆ7.7 Hz); 13C NMR
(75 MHz, CDCl3) d 22.0 (C-6), 55.3 (C-4), 62.3 (C-3),
62.5 (C-8), 65.2 (C-5), 127.6±133.7 (CHAr), 135.3, 138.4,
138.6, 167.1 (C-2), 197.6 (C-7). Mass (D-APCI/LCQ) m/e
386 (M1H1, 100%). Anal. Calcd for C25H23NO3´0.3H2O:
C, 76.84; H, 6.04; N, 3.59. Found: C, 76.85; H, 5.94; N,
3.57%.
(3S,4S,5R)-1-Benzhydryl-3-(10-hydroxyethyl)-4-pivaloyl-
2-azetidinone (9b). This compound was obtained as above
from 8b (0.214, 2 g, 0.58 mmol) (Table 1, entry 5). The last
fractions from the ¯ash-chromatography (SiO2; CH2Cl2/
EtOAc, 20:1) gave 9b (0.11 g, 58% yield) which crystal-
lised in ethanol: mp 168±1708C (white crystals); Rfˆ0.15
(CH2Cl2/EtOAc, 10:1); [a]Dˆ141.3 (cˆ0.995, CHCl3); IR
(KBr) n 3500 (br), 1759, 1704, 1457, 1367, 1115, 899,
1
703 cm21; H NMR (500 MHz, CDCl3) d 0.90 (s, 9H),
1.38 (d, 3H, Jˆ6.4 Hz, H-6), 2.04 (br, s, 1H, OH), 2.89
(dd, 1H, Jˆ2.1, 6.4 Hz, H-3), 4.21 (dq, 1H, Jˆ6.4,
6.4 Hz, H-5), 4.52 (d, 1H, Jˆ2.1 Hz, H-4), 5.69 (s, 1H,
H-8), 7.20±7.40 (m, 10H); 13C NMR (125 MHz, CDCl3)
d 21.92 (C-6), 25.80, 43.69, 55.26 (C-4), 61.86 (C-3),
66.23 (C-5), 127.61, 127.72, 128.01, 128.37, 128.55,
138.19, 138.54, 166.93 (C-2), 212.66 (C-7). Anal. Calcd
for C23H27NO3´0.2H2O: C, 74.88; H, 7.43; N, 3.80. Found:
C, 74.85; H, 7.53; N, 3.81%. HRMS: 365.1988 (calcd:
365.1991). Higher yield could be obtained as follows
(Table 1, entry 6): to a solution of 8b (0.111 g, 0.3 mmol)
in dry THF (5 mL), cooled at 08C under argon atmosphere,
was added in 5 min a 0.5 M solution of LiHMDS in THF
(1.3 mL, 0.6 mmol). The mixture was stirred for 2 h at 08C
and 1 h at 208C, then poured into 1 N HCl (10 mL). Extrac-
tion with ethyl acetate (3£15 mL), washing of the organic
phase with 5% NaHCO3 (2£10 mL) and brine (10 mL),
drying over MgSO4, and concentration gave crude 9b
(100% yield) which could be puri®ed (86% yield) by ¯ash
column-chromatography (SiO2; CH2Cl2/ethyl acetate, 10:1).
N-(Benzhydryl)-N-(pivaloylmethyl) (2R,3R)-cis-2,3-epoxy-
butyramide (8b). This compound was prepared as above
from 4 (2 g, 8.81 mmol) and 7b (2.48 g, 8.81 mmol).
Crystallisation of the crude material from H2O/EtOH (5:2)
gave pure 8b (1.48 g, 46% yield): mp 157±1588C (white
crystals); [a]Dˆ110.8 (cˆ1.03, CHCl3); 1H NMR
(500 MHz, CDCl3; two rotamers in a 60:40 ratio) d 0.89
and 0.85 (two, s, 9H), 1.46 and 1.29 (two d; 3H, Jˆ5.8 Hz,
H-4), 3.20 and 3.26 (two dq, 1H, Jˆ5.8, 4.4 Hz, H-3), 3.47
and 3.52 (two, d, 1H, Jˆ4.4 Hz, H-2), 4.23 (d, 1H,
Jˆ17.3 Hz, H-6), 4.44 and 4.97 (two, d, 1H, Jˆ17.3 Hz,
H-60), 6.61 and 7.2 (two, s, 1H, H-8), 7.10±7.40 (m,
10H); 13C NMR (125 MHz, CDCl3; two rotamers in a
60:40 ratio) d 13.97 and 14.74 (C-4), 26.16 and 26.25,
42.66 and 42.46, 48.82 and 49.36 (C-6), 53.73 and 53.81
(C-3), 54.60 and 55.70 (C-2), 61.02 and 63.96 (C-8), 167.48
and 168.27 (C-5), 206.58 and 208.56 (C-7), 4 quaternary
aromatic carbon signals (139.07, 138.75, 138.62, 138.50),
12 aromatic CH signals (129.90, 129.04, 128.60, 128.45,
128.38, 128.36, 128.17, 128.01, 127.96, 127.78, 127.71,
127.24). Anal. Calcd for C23H27NO3 (365.2): C, 75.62; H,
7.43; N, 3.80. Found: C, 75.59; H, 7.57; N, 3.85.
(6S,7R)-N-Benzhydryl-6-(10-hydroxyethyl)-2-phenyl-2,3-
dehydromorpholin-5-one (10a). This compound, formed
together with the azetidinone 9a, was isolated by chromato-
graphy, just before the b-lactam fraction, in about 35%
yield: mp 124.5±125.58C (white crystals); Rfˆ0.35
(CH2Cl2/EtOAc, 10:1); [a]Dˆ158 (cˆ0.4, CH2Cl2); IR
(®lm) n 3423, 1676, 1600, 1496, 1448, 1411, 1370, 1196,
(3S,4S,5R)-1-Benzhydryl-3-(10-hydroxyethyl)-4-benzoyl-
2-azetidinone (9a). Epoxide 8a (1.04 g, 2.7 mmol)
dissolved in dry DMF (15 mL) was heated at 1008C,
under argon atmosphere, in the presence of powdered
Li2CO3 (1.9 g, 26 mmol) (Table 1, entry 2). After 24 h (stir-
ring), the mixture was poured into a 50:50 solution of ethyl
acetate and brine (200 mL), and ®ltered. The organic layer
was separated and washed with brine (3£50 mL). The
aqueous layer was extracted with ethyl acetate (3£50 mL).
The organic phases were gathered, dried over MgSO4 and
1
1077 cm21; H NMR (500 MHz, CDCl3) d 1.46 (d, 3H,
Jˆ6.2 Hz, H-8), 2.90 (br s, OH), 4.50 (sharp m, 2H,
H-61H-7), 6.07 (s, 1H, H-3), 7.10 (s, 1H, H-9), 7.22±
7.42 (m, 15H); 13C NMR (125 MHz, CDCl3) d 18.2 (C-8),
59.7 (C-9), 66.65 (C-6), 79.27 (C-7), 103.73 (C-3), 123.58,
127.8, 128.1, 128.4, 128.66, 128.73, 128.77, 132.07, 137.95,
138.17, 139.7 (C-2), 163.6 (C-5); Mass (EI) m/e 385.1
(C25H23O3N), 367 (M2H2O), 167, 165; HRMS: 385.1690
(calcd: 385.1678). Anal. Calcd for C25H23NO3: C, 77.92; H,

3216
B.-L. Deng et al. / Tetrahedron 56 (2000) 3209±3217
5.97; N, 3.63. Found: C, 77.76; H, 5.91; N, 3.62%. The
structure of 10a has been fully con®rmed by X-ray diffrac-
tion analysis of a single crystal.15
gel (CH2Cl2/EtOAc, 20:1) in about 9% yield: mp 169±
1708C (white crystals); Rfˆ0.50 (CH2Cl2/EtOAc, 10:1);
[a]Dˆ122.4 (cˆ0.334, CHCl3);1H NMR (500 MHz,
acetone-d6) d 1.39 (d, 3H, Jˆ6.7 Hz, H-8), 4.05 (d, 1H,
Jˆ6.7 Hz, OH), 4.41 (ddq, 1H, Jˆ6.7, 6.7, 4.0 Hz, H-7),
4.54 (d, 1H, Jˆ4.0 Hz, H-3), 6.24 (s, 1H, H-5), 7.12 (s,
1H, H-9), 7.20±7.50 (m, 15H); 13C NMR (125 MHz,
acetone-d6) d 19.69 (C-8), 60.30 (C-9), 67.05 (C-7), 81.73
(C-3), 104.38 (C-5), 124.54, 128.52, 128.55, 128.73,
129.16, 129.40, 129.45, 129.54, 129.64, 133.90, 139.72
(C-6), 139.57, 139.85, 164.05 (C-2); Mass (D-APCI/LCQ)
m/e 386 (M1H1, 27%), 282 (20%), 167 (100%). HRMS:
385.1692 (calcd: 385.1678).
(6S,7R)-N-Benzhydryl-6-(10-hydroxyethyl)-2-tert-butyl-
2,3-dehydromorpholin-5-one (10b). This compound,
formed together with the azetidinone 9b, was isolated
from the medium fractions of the ¯ash-chromatography
on silica gel (CH2Cl2/EtOAc, 20:1) in about 20% yield.
Recrystallisation from ethanol gave pure 10b: mp 161±
1658C (white crystals): Rfˆ0.47 (CH2Cl2/EtOAc, 10:1);
[a]Dˆ111.5 (cˆ0.310, CHCl3);1H NMR (300 MHz,
CDCl3) d 1.02 (s, 9H), 1.37 (d, 3H, Jˆ6.6 Hz, H-8), 3.06
(d, 1H, Jˆ6.4 Hz, OH), 4.21 (d, 1H, Jˆ4.1 Hz, H-6), 4.35
(m, 1H, H-7), 5.3 (s, 1H, H-3), 7.0 (s, 1H, H-9), 7.15±7.40
(m, 10H); 13C NMR (75 MHz, CdCl3) d 18.68 (C-8), 28.14,
34.78, 60.16 (C-9), 67.32 (C-7), 79.93 (C-6), 101.77 (C-3),
128.36, 128.63, 128.89, 129.24, 129.33, 129.59, 139.06,
139.27, 151.07 (C-2), 164.18 (C-5). Anal. Calcd for
C23H27NO3´0.8H2O; C, 72.75; H, 7.54; N, 3.69. Found: C,
72.89; H, 7.31; N, 3.66%. HRMS: 365.1985 (calcd:
365.1991).
(1R,5S,7R)-3-Benzhydryl-5-tert-butyl-7-methyl-6,8-dioxa-
3-azabicyclo [3.2.1] octan-2-one (14b). This compound,
formed together with 9b, 10b and 12b, was isolated from
the ®rst fractions of the ¯ash-chromatography on silica gel
(CH2Cl2/EtOAc, 20:1) in about 5% yield: (still contami-
nated with 12b): Rfˆ0.80 (CH2Cl2/EtOAc, 10:1); 1H
NMR (500 MHz, CDCl3) d 0.95 (s, 9H), 1.30 (d, 3H,
Jˆ6.6 Hz, H-9), 2.93 (d, 1H, Jˆ11.8 Hz, H-4), 3.26 (d,
1H, Jˆ11.8 Hz, H-40), 4.15 (dq, 1H, Jˆ6.6, 4.6 Hz, H-7),
4.61 (d, 1H, Jˆ4.6 Hz, H-1), 7.13 (s, 1H, H-10); 7.15±7.40
(m, 10H); 13C NMR (125 MHz, CDCl3) d 14.77 (C-9),
24.38, 36.37, 47.95 (C-4), 58.45 (C-10), 76.35 (C-7),
79.45 (C-1), 109.87 (C-5), 127.46, 127.54, 128.42, 128.45,
128.55, 128.81, 137.79, 138.17, 166.57 (C-2). HRMS:
365.1982 (calcd: 365.1991).
(6R,7S)-N-Benzhydryl-6-hydroxy-7-methyl-2-phenyl-4,5,
6,7-tetrahydro-4-aza-oxepin-5-one (12a). This compound,
formed together with 9a and 10a, was isolated from the ®rst
fractions of the ¯ash-chromatography on silica gel (CH2Cl2/
EtoAc, 20:1) in about 15% yield: mp 113±1148C (white
crystals); Rfˆ0.70 (CH2Cl2/EtOAc, 10:1); [a]Dˆ152.5
1
(cˆ0.310, CHCl3); H NMR (300 MHz, CDCl3) d 1.25
(d, 3H, Jˆ6.5 Hz, H-8), 3.95 (d, 1H, Jˆ4.6 Hz, OH), 4.70
(dd, 1H, Jˆ4.6, 4.3 Hz, H-6), 4.85 (dq, 1H, Jˆ6.5, 4.3 Hz,
H-7), 5.72 (s, 1H, H-3), 7.19 (s, 1H, H-9), 7.20±7.40
(m, 15H); 13C NMR (75 MHz, CdCl3) d 15.5 (C-8), 62.0
(C-9), 71.5 (C-6), 81.0 (C-7), 104.5 (C-3), 125±129 (CH
Ar), 136, 138, 139, 145 (C-2), 172 (C-5). Anal. Calcd for
C25H23NO3´0.3H2O: C, 76.84; H, 6.04; N, 3.59. Found: C,
76.93; H, 5.80; N, 3.61%. HRMS: 365.1695 (calcd:
365.1678).
Acknowledgements
We thank Dr B. Tinant for the X-ray diffraction
analyses15 and V. Durieu for technical assistance. This
work was supported by the Fonds National de la Recherche
Scienti®que (FNRS, Belgium) and by Tessenderlo Chemie
(Belgium).
(6R,7S)-N-Benzhydryl-6-hydroxy-7-methyl-2-tert-butyl-
4,5,6,7-tetrahydro-4-aza-oxepin-5-one (12b). This com-
pound, formed together with 9b and 10b, was isolated
from the ®rst fractions of the ¯ash-chromatography on silica
gel (CH2Cl2/EtOAc, 20:1) in about 8% yield: mp 105±
106.58C (white crystals); Rfˆ0.75 (CH2Cl2/EtOAc, 10:1);
[a]Dˆ129.8 (cˆ0.276, CHCl3);1H NMR (500 MHz,
CDCl3) d 0.96 (s, 9H), 1.77 (d, 3H, Jˆ6.3 Hz, H-8), 3.87
(d, 1H, Jˆ5.2 Hz, OH), 4.57 (dd, 1H, Jˆ5.2, 4.6 Hz, H-6),
4.69 (dq, 1H, Jˆ4.6, 6.3 Hz, H-7), 5.05 (s, 1H, H-3), 7.09 (s,
1H, H-9), 7.14±7.40 (m, 10H); 13C NMR (125 MHz,
CDCl3) d 15.27 (C-8), 28.0, 36.41, 61.61 (C-9), 70.35
(C-6), 81.52 (C-7), 102.03 (C-3), 127.50, 127.81, 128.24,
128.34, 128.51, 128.81, 137.79, 138.86, 155.83 (C-2),
171.39 (C-5). Anal. Calcd for C23H27NO3´0.2H2O: C,
74.88; H, 7.43; N, 3.80. Found: C, 74.82; H, 7.34; N,
3.83%. The structure of 12b has been fully conformed by
X-ray diffraction analysis of a single crystal.15
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