Protecting group migration in the chemistry of 1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone

Article abstract of DOI:10.1016/S0040-4039(03)01525-9

The alkoxide anion derived from 1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone (1) rearranged at -78°C into amide anion by N-O migration of the silyl protecting group. The occurrence of this intermediate was proved by quenching with benzyl bromide and phenethyl chloroformate, giving respectively N-benzyl (4) and N-(phenethyloxycarbonyl) (6) derivatives of 4-(t-butyldimethylsilyloxy)methyl-2-azetidinone.

Full text of DOI:10.1016/S0040-4039(03)01525-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6339–6342
Protecting group migration in the chemistry of
1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone
Ste´phane Ge´rard and Jacqueline Marchand-Brynaert*
Unite´ de Chimie Organique et Me´dicinale, Universite´ catholique de Louvain, Baˆtiment Lavoisier, place Louis Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
Received 15 March 2003; accepted 12 June 2003
Abstract—The alkoxide anion derived from 1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone (1) rearranged at −78°C into
amide anion by N–O migration of the silyl protecting group. The occurrence of this intermediate was proved by quenching with
benzyl bromide and phenethyl chloroformate, giving respectively N-benzyl (4) and N-(phenethyloxycarbonyl) (6) derivatives of
4-(t-butyldimethylsilyloxy)methyl-2-azetidinone.
© 2003 Elsevier Ltd. All rights reserved.
1-t-Butyldimethylsilyl-4-hydroxymethyl-2-azetidinone
(1) has been used as key-intermediate for the synthesis
of b-lactam antibiotics such as carbapenems, iso-
clavams and isocephems.1,2 This compound (racemic or
enantiomerically pure) was obtained by reduction of
related 4-alkyloxycarbonyl-2-azetidinones,3,4 or by oxi-
dative cleavage of the corresponding p-methoxyphenyl
ether.2 Further transformations of the hydroxymethyl
residue were described by mesylation followed by nucle-
ophilic substitution,1 reaction with vinyl alkyl ether
under acidic catalysis,3 and silylation.5 The unstability
of 1 under strongly basic conditions was evoked by
Banfi et al.3 and Cundi et al.,4 and attributed to the
possible N–O migration of the silyl group. Neverthe-
less, selective C3 methylation of 1 could be realized by
treatment with two equivalents of nBuli or LDA at
−78°C followed by addition of three equivalents of
methyl iodide;4 concomitant O-methylation was not
reported (nor N-methylation, in the case of silyl group
migration occurrence).
Our interest in 1-alkyloxycarbonyl-2-azetidinone
derivatives as elastase inhibitors6,7 led us to consider 1
as starting material for the synthesis of various C4
substituted compounds. During this work, we unam-
biguously identified rearrangement products arising
from the silyl group migration.
4-Benzyloxycarbonyl-2-azetidinone8 was first N-
silylated9 (diisopropylethylamine, t-butyldimethylsilyl
chloride, CH2Cl2, 20°C, 24 h), then reduced with
lithium borohydride (THF, 0°C to 20°C, 1h) to furnish
1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone
(1) in about 95% overall yield. The alcohol function of
1 could be readily acylated, without trouble due to silyl
group migration. For instance, reaction with benzoyl
chloride, in the presence of triethylamine and dimethyl-
aminopyridine (DMAP) as catalyst,10 gave the ester 2
(Scheme 1) in 82% yield.11 N-Deprotection of 2 with
cesium fluoride followed by N-acylation with phenethyl
chloroformate, according to a previously described pro-
Scheme 1.
Keywords: N-silylation; O-silylation; silyl migration; b-lactam.
* Corresponding author: Tel.: + 32-10 47 27 40; fax + 32-10 47 41 68; e-mail: marchand@chim.ucl.ac.be
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01525-9

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cedure,6 afforded azetidinone 3 in 38% yield after chro-
matographic purification.12 This compound was inac-
tive against PPE (porcine pancreatic elastase).
silyl ether function of 6 (CsF, Bu4NF or LiOH–H2O)
without degradation of the four-membered ring most
probably due to an intramolecular O-nucleophilic
attack on the activated b-lactam carbonyl.
On the other hand, all attempts to alkylate the alcohol
function of 1, under Williamson-type conditions, failed.
Treatment of 1 with one equivalent of a strong base at
low temperature (NaH, LiHMDS, LDA or nBuli,
THF, −78°C) followed by quenching with benzyl bro-
mide gave 1-benzyl-2-(t-butyldimethylsilyloxy)methyl-
2-azetidinone (4) as the unique product. Silyl
deprotection and acylation as before finally furnished
compound 5 (Scheme 2) in 61% overall yield.13 The
presence of a carbonate function (resulting from O-
acylation) was inferred from the 13C NMR signal at 154
ppm; the carbamate function of 3 (resulting from N-
acylation) showed a characteristic signal at 148 ppm.
We further unambiguously demonstrated the occur-
rence of the N–O migration of the silyl group by
reacting 1 with one equivalent of BuLi and quenching
the anion with phenethyl chloroformate (Scheme 3).
After chromatography, 1-phenethyloxycarbonyl-4-(t-
butyldimethylsilyloxy)methyl-2-azetidinone (6) was
recovered in 52% yield;14 the carbamate function of 6
was characterized by a typical signal at 149 ppm in the
13C NMR spectrum. We were unable to deprotect the
Thus, in our hands, the mono-anion 8 derived from 1
was unstable, even at −78°C, and rearranged rapidly
into the amide anion 9 which could be trapped with
electrophiles (RX=PhCH2Br, PhCH2CH2OCOCl) to
furnish N-derivatized b-lactams 10 with the alcohol
function protected as silyl ether (Scheme 4). In the
previous literature,4 the precursor 1 was treated with an
excess of base to furnish the bis-anion 11; this interme-
diate is obviously less prone to silyl migration. Quench-
ing with a soft electrophile (RX=CH3I) gave thus
C3-substituted b-lactam 12, still N-protected with the
silyl group. Accordingly, azetidinone 1 appears to be a
good precursor for selective substitution of either posi-
tion C3 or position N1, depending on the amount of
base used for the initial deprotonation step. Thus,
under strongly basic conditions the hydroxyl group of 1
could not be further functionalized. On the other hand,
this OH group could selectively react, without migra-
tion of the N-silyl protecting group, under smoothly
acidic and electrophilic conditions, such as in acylation
reactions, or via nucleophilic substitutions of the corre-
Scheme 2.
Scheme 3.
Scheme 4.

S. Ge´rard, J. Marchand-Brynaert / Tetrahedron Letters 44 (2003) 6339–6342
6341
sponding mesylate.1 Our contribution has now defined
better the scope and limitation of the reactivity of
1-t-butyldimethylsilyl-4-hydroxymethyl-2-azetidinone, a
key intermediate for antibiotic synthesis.
(CH2O), 128.4 129.5 and 129.6 (CHAr), 133.1 (CAr), 166.1
and 171.8 (2×CꢀO); m/z (EI) 319 (3), 121 (69), 105 (100)
and 77 (66).
12. Synthesis and characterization of 1-phenethyloxycar-
bonyl-4-benzoyloxymethyl-2-azetidinone (3). A solution
of 2 (169 mg; 0.5 mmol) and cesium fluoride (114 mg;
0.75 mmol) in dry DMF (3 mL) was stirred for 2 h at
room temperature. The crude mixture was concentrated
and after addition of EtOAc, the organic layer was
washed twice with water, dried over MgSO4, filtered and
concentrated under vacuum. A solution of the depro-
tected b-lactam in THF (5 mL), cooled at −78°C under
argon atmosphere, was dropwise added to a solution of
LiHMDS (1 equiv.) in dry THF (3 mL). The mixture was
stirred for 30 min at −78°C, then phenethyl chlorofor-
mate (46 mg; 0.25 mmol) was added with a syringe
through a rubber stopper. Stirring was continued for 1 h
at this temperature and the mixture was allowed to reach
room temperature and stirred for 3 h at 20°C. After
addition of 10% NH4Cl (10 mL) and extraction with
CH2Cl2, the organic layer was dried over MgSO4, filtered
and concentrated under vacuum. The resulting b-lactam
was purified by column chromatography on silica gel
(CH2Cl2:EtOAc, 90/10) to yield 3 (33 mg, 38%) as a
colorless oil; (Found HRMS: 354.1341. C20H20NO5
requires 354.1341); wmax/cm−1 1817 and 1726; lH (500
MHz; CDCl3; Me4Si) 3.00 (2H, t, J 7.3, CH2CH2Ph),
3.05 (1H, dd, J 16.0 and 6.2, H-3), 3.19 (1H, dd, J 16.0
and 3.5, H-3%), 4.33 (1H, m, H-4), 4.43 (2H, t, J 7.3,
CH2CH2Ph), 4.56 (1H, dd, J 12.1 and 3.8, CH2O), 4.69
(1H, dd, J 12.1 and 3.1, CH2O), 7.15–7.69 (8H, m, Ar),
8.01–8.05 (2H, m, Ar); lC (100 MHz; CDCl3; Me4Si) 34.9
(CH2CH2Ph), 39.6 (C-3), 49.4 (C-4), 61.2 (CH2O), 67.0
(CH2CH2Ph), 126.7 128.4 129.2 129.5 and 129.6 (CHAr),
133.3 and 136.8 (CAr), 148.7 (CO carbamate), 163.1 and
165.9 (CO azetidinone and CO amide); m/z (CI) 354
(M+1, 4), 105 (100), 91 (12) and 77 (66).
13. Synthesis and characterization of 1-benzyl-4-(2%,4%-dioxa-
3%-oxy-6%-phenylhexyl)-2-azetidinone (5). A solution of
nBuLi (600 mL; 2M in hexane; 1.2 mmol) was added to a
solution of 1 (216 mg; 1 mmol) in dry THF (10 mL),
cooled at −78°C under argon atmosphere. Benzyl bro-
mide (130 mL; 1.1 mmol) was added dropwise and the
mixture was stirred for 3 h at −78°C. The solution was
then washed with water (10 mL), dried over MgSO4,
filtered and concentrated under vacuum. A solution of
the resulting b-lactam 4 (169 mg; 0.5 mmol) and cesium
fluoride (114 mg; 0.75 mmol) in dry DMF (3 mL) was
stirred for 2 h at room temperature. The crude mixture
was concentrated and after addition of EtOAc, the
organic layer was washed twice with water, dried over
MgSO4, filtered and concentrated under vacuum. A solu-
tion of the deprotected b-lactam in THF (5 mL), cooled
at −78°C under argon atmosphere, was added dropwise
to a solution of LiHMDS (1 equiv.) in dry THF (5 mL).
The mixture was stirred for 30 min at −78°C, then
phenethyl chloroformate (46 mg; 0.25 mmol) was added
with a syringe through a rubber stopper. Stirring was
continued for 30 min at this temperature and the mixture
was allowed to reach room temperature and stirred for 3
h at 20°C. After addition of 10% NH4Cl (5 mL) and
extraction with CH2Cl2, the organic layer was dried over
MgSO4, filtered and concentrated under vacuum. The
Acknowledgements
This work was supported by UCL (Universite´
catholique de Louvain), FNRS (Fonds National de la
Recherche Scientifique) and PAI (Poˆle d’Attraction
Inter-universitaire). J. M.-B. is senior research associate
of FNRS.
References
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11. Synthesis and characterization of 4-benzoyloxymethyl-N-
(tert-butyldimethylsilyl)-2-azetidinone (2). A solution of 1
(216 mg; 1 mmol) and DMAP (catalytic amount) in dry
CH2Cl2 (10 mL) was stirred at room temperature. Tri-
ethylamine (140 mL; 1 mmol) and benzoyl chloride (120
mL; 1 mmol) were added and stirring was continued for
20 h. Then, excess of triethylamine (28 mL; 0.2 mmol) and
benzoyl chloride (23 mL; 0.2 mmol) were added to the
solution and the mixture was stirred for an additional 20
h. The solution was washed three times with water (10
mL) and dried over MgSO4. After filtration and concen-
tration under vacuum, the resulting b-lactam was purified
by column chromatography on silica gel (CH2Cl2) to
yield 2 (261 mg, 82%) as a colorless oil. (Found: C, 63.96;
H, 7.87; N, 4.38%. C17H25O3NSi requires C, 63.91; H,
7.89; N, 4.38%); wmax/cm−1 1791, 1718 and 1180; dH (300
MHz; CDCl3; Me4Si) 0.27 (6H, s, 2×SiCH3), 0.95 (9H, s,
C(CH3)3), 2.98 (1H, dd, J 15.9 and 6.3, H-3), 3.25 (1H,
dd, J 15.9 and 3.4, H-3%), 3.95 (1H, m, H-4), 4.38 (1H, dd,
J 11.1 and 2.5, CH2O), 4.52 (1H, dd, J 11.1 and 2.4,
CH2O), 7.45–7.54 (3H, m, Ar), 8.01–8.09 (2H, m, Ar); lC
(75 MHz; CDCl3; Me4Si) −5.6 and −5.5 (SiCH3), 18.0
(C(CH3)3), 26.1 (C(CH3)3), 41.7 (C-4), 47.3 (C-3), 65.9

6342
S. Ge´rard, J. Marchand-Brynaert / Tetrahedron Letters 44 (2003) 6339–6342
resulting b-lactam was purified by column chromatogra-
atmosphere. The mixture was stirred for 1 h at −78°C,
then phenethylchloroformate (184 mg; 1 mmol) was
added with a syringe through a rubber stopper. Stirring
was continued for 1 h at this temperature and the mixture
was allowed to reach room temperature and stirred for 45
min at 20°C. After addition of water and extraction with
CH2Cl2, the organic layer was washed with brine, dried
over MgSO4, filtered and concentrated under vacuum.
The resulting b-lactam was purified by column chro-
matography on silica gel (CH2Cl2) to yield 6 (189 mg,
52%) as a colorless oil; wmax/cm−1 1813 and 1750; lH (300
MHz; CDCl3; Me4Si) 0.15 (6H, s, 2×SiCH3), 0.87 (9H, s,
C(CH3)3), 2.98–3.05 (4H, m, H-3 and CH2Ph), 3.75 (1H,
m, H-4), 4.05 (2H, m, CH2O), 4.39 and 4.40 (2×1H, 2×t,
J 5.9, OCH2CH2), 7.21–7.38 (5H, m, Ar); lC (75 MHz;
CDCl3; Me4Si) −5.6 and −5.5 (SiCH3), 18.2 (C(CH3)3),
25.7 (C(CH3)3), 35.2 (CH2Ph), 38.7 (C-4), 51.8 (C-3), 60.1
(CH2O), 66.9 (CH2CH2O), 126.8 128.6 and 129.1 (CHAr),
137.2 (CAr), 149.1 (CO carbamate), 164.0 (CO azetidi-
none); m/z (CI) 364 (M+1, 12), 105 (83), 91 (100).
phy on silica gel (CH2Cl2:EtOAc, 95/5) to yield 5 (142
mg, 61%) as a colorless oil; (Found HRMS: 340.1542.
C20H22NO4 requires 340.1549); wmax/cm−1 3031 and 1750;
lH (500 MHz; CDCl3; Me4Si) 2.76 (1H, dd, J 14.5 and
2.8, H-3), 2.97 (2H, t, J 6.8, CH2CH2Ph), 3.01 (1H, dd, J
14.5 and 5.2, H-3%), 3.69 (1H, m, H-4), 4.03 (1H, dd, J
15.1 and 6.4, CH2O), 4.16 (1H, d, J 15.1, CH2Ph), 4.28
(1H, dd, J 15.1 and 3.6, CH2O), 4.31 (2H, t, J 6.8,
CH2CH2Ph), 4.61 (1H, d, J 15.1, CH2Ph), 7.15–7.35
(10H, m, Ar); lC (125 MHz; CDCl3; Me4Si) 34.9
(CH2CH2Ph), 39.3 (C-3), 45.1 (NCH2Ph), 48.8 (C-4),
67.5 (CH2O), 68.6 (CH2CH2Ph), 126.7 127.6 128.4 128.5
128.6 and 128.7 (CHAr), 135.6 and 136.9 (CAr), 154.4 (CO
carbonate), 166.1 (CO azetidinone); m/z (CI) 340 (M+1,
12), 298 (51) and 105 (100).
14. Synthesis and characterization of 1-phenethyloxycar-
bonyl-4-(t-butyldimethylsilyloxy) methyl-2-azetidinone
(6). A solution of nBuLi (2.1 M in hexane, 476 mL; 1
mmol) was dropwise added to a solution of 1 (215 mg; 1
mmol) in dry THF (5 mL), cooled at −78°C under argon