N-Heterocyclic carbene catalysed β-lactam synthesis

Article abstract of DOI:10.1039/b800857b

N-Heterocyclic carbenes promote the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give the corresponding β-lactams in good to excellent isolated yields; chiral NHCs give β-lactams in high e.e. after crystallisation.

Full text of DOI:10.1039/b800857b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
N-Heterocyclic carbene catalysed b-lactam synthesis†
Nicolas Duguet, Craig D. Campbell, Alexandra M. Z. Slawin and Andrew D. Smith*
Received 21st December 2007, Accepted 22nd January 2008
First published as an Advance Article on the web 12th February 2008
DOI: 10.1039/b800857b
N-Heterocyclic carbenes promote the formal [2+2] cycloaddition of ketenes with N-tosyl imines to give
the corresponding b-lactams in good to excellent isolated yields; chiral NHCs give b-lactams in high e.e.
after crystallisation.
Introduction
Results and discussion
N-Heterocyclic carbenes (NHCs) readily promote a range of
organocatalytic reactions.1 The majority of these transformations
are initiated by nucleophilic attack of the NHC upon an aldehyde
or acylsilane to generate the corresponding acyl anion equivalent.
Alternatively, the reaction of an NHC with a-functionalised
aldehydes can generate homoenolates2 for use in redox reactions,3
a reaction sequence that has been utilised to promote formal
[4+2]4 and [3+3]5 cycloaddition processes. As part of a research
programme directed towards developing alternative uses of NHCs
as organocatalysts,6 their ability to promote the formal [2+2]
cycloaddition of ketenes and imines for the synthesis of b-lactams
was investigated (Fig. 1).
Developing an NHC mediated b-lactam synthesis
At the onset of these studies, a reliable working procedure for b-
lactam formation from diphenylketene and N-tosyl imine 4 using
triazolinylidene NHC 2 was sought. Deprotonation of azolium
salt 1 (20 mol%) with KHMDS (19 mol%) in toluene was used
to pre-generate NHC 2, with the order of addition of reactants
critical to the successful generation of b-lactam 5. Addition of
NHC 2 to an equimolar solution of diphenylketene and imine
4, or the inverse addition, gave 25% and 75% conversion to 5
respectively after 24 hours. Addition of imine 4 to NHC 2 followed
by diphenylketene gave no conversion to 5 even after 5 days, con-
sistent with reports of N-tosyl imine inhibition of catalyst turnover
in NHC reactions through irreversible nucleophilic addition.18
However, addition of diphenylketene to NHC 2, followed by imine
4, gave >95% conversion to product, giving 5 in 59% isolated
yield, implying that NHC activation of the ketene is necessary
to allow catalytic turnover in this reaction (Table 1, entry 1). To
further test this hypothesis, addition of diphenylketene (0.2 eq) to
NHC 2, followed by imine 4 (1.0 eq) and then a further portion of
diphenylketene (0.8 eq) gave 90% conversion to 5. Further reaction
optimisation showed that the initial addition of 1.3 eq of ketene 3
to NHC 2 in this procedure allowed full consumption of imine 4,
giving 5 in 84% isolated yield (entry 2). With a working protocol
in hand, the effect of solvent upon the catalytic efficiency of this
process was investigated. As a standard, using 19 mol% of NHC
2 in toluene gave 66% conversion to 5 after 1 hour, while the
corresponding reactions in THF or Et2O gave 83% and >95%
conversion respectively. Progressively lowering the catalyst loading
in Et2O showed that 4.5 mol% of NHC 2 gave >95% conversion to
5 within 1 hour, giving 5 in 93% isolated yield (entries 6–8). Lower
catalyst loadings (<1 mol%) of NHC 2 can be used to generate
moderate levels of conversion to b-lactam 5 but require extended
reaction times (entry 9).
Fig. 1 Proposed NHC catalysed b-lactam formation.
The b-lactam skeleton is a widely recognised pharmacophore
that has received extensive biological and synthetic investigation.
A number of methodologies exist for the preparation of b-
lactams,7,8 with asymmetric routes including the ring expansion
of aziridines9 and chiral auxiliary methods,10 amongst others.11
The Staudinger reaction12 is perhaps the most widely recognised
procedure for the synthesis of b-lactams,13 and Lectka et al.14 and
Fu et al.15 have elegantly shown that chiral amines can catalyse this
reaction asymmetrically. Although the addition of nucleophiles to
ketenes has been utilised for a number of synthetic applications,16
only limited studies concerning the activation of a ketene with
an NHC have been reported.17 We delineate herein that NHCs
catalyse the formation of b-lactams from ketenes and imines and
show that enantiomerically pure NHCs provide an important
platform for a catalytic enantioselective variant of this reaction.
Wilhelm and Sereda have recently shown that metal amides such
as KHMDS can catalyse directly the [2+2] cycloaddition of ketenes
and N-nosyl imines.19 To confirm that NHC 2 is the catalytic
species in this reaction manifold, control experiments indicated
that using KHMDS (5 mol%) alone gave <10% conversion to b-
lactam 5 after 24 hours in Et2O. Further experiments showed that
treatment of 3 and 4 with HMDS, or simply mixing 3 and 4 in
Et2O, returned only starting material. Using this information, a
simplistic mechanistic rationale for this process can be proposed.
Deprotonation of azolium salt 1 with KHMDS generates NHC
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh,
St Andrews, UK KY16 9ST. E-mail: ads10@st-andrews.ac.uk
† Electronic supplementary information (ESI) available: Further experi-
mental details and spectroscopic data (1H and 13C NMR) for all products.
See DOI: 10.1039/b800857b
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Table 1 Racemic b-lactam synthesis: reaction optimisation
Entry
1 (mol%)
KHMDS (mol%)
3 (eq)
Solvent
Time/h
Product conversiona
1
2
3
4
5
6
7
8
9
20
20
20
20
20
20
10
5
19
19
19
19
19
19
9
1
Toluene
Toluene
Toluene
CH2Cl2
THF
Et2O
Et2O
24
24
1
1
1
1
1
1
24
>95% (59%)b
>95% (84%)b
66%
0
83%
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
>95%
>95%
4.5
0.9
Et2O
Et2O
>95% (93%)b
60%
1
1
a All reaction conversions and product distributions were judged by H NMR spectroscopic analysis of the crude reaction product. b Isolated yield of
homogeneous product after chromatographic purification.
Table 2 Probing the generality of NHC catalysed b-lactam synthesis
2, that adds to diphenylketene to generate azolium enolate 6.
Enolate addition to N-tosyl imine 4 gives the b-amido carbonyl
7, which upon intramolecular cyclisation produces the b-lactam
5 and regenerates the NHC 2 (Fig. 2). While this mechanism
remains our current hypothesis, Fu et al. have proposed an
alternative mechanism when employing N-triflyl imines in this
reaction manifold that involves initial nucleophilic activation
of the imine.15b Preliminary mechanistic studies cannot, as yet,
unambiguously rule out this alternative pathway when employing
NHC mediated catalysis, and further investigations to delineate
conclusively the mechanism of this transformation are underway.
Entry
2 (mol%)
R
Time/h
Product
Yielda
1
2
3
4
5
6
4.5
4.5
4.5
9
9
9
Ph
1
1
1
24
1
1
5
8
93%
92%
85%
59%
89%
94%
2-Naphthyl
2-Furyl
4-MeOC6H4
4-BrC6H4
9
10
11
12
=
(E)–CH CHPh
a Isolated yield of homogeneous product after chromatographic purifica-
tion.
although with an electron rich 4-MeOC6H4 substituent (entry 4),
9 mol% of NHC 2 and a longer reaction time of 24 hours was
required, giving 10 in 59% isolated yield (Table 2).
The ability of NHC 2 to catalyse the formation of b-lactams
from unsymmetrical ketenes was next investigated. Addition of
isobutylphenylketene 13 to NHC 2 (9 mol%) followed by addition
of N-tosyl imine 4 gave full conversion after one hour to the desired
b-lactam 14 as a 68 : 32 mixture of syn : anti diastereoisomers in
89% isolated yield (entry 1).20 Lower catalyst loadings could be
used to achieve reasonable levels of conversion in this reaction
without altering the diastereoselectivity of this process (4.5 mol%
of NHC 2, 16 hours, 87% conversion). This protocol proved
general as a range of imines are readily tolerated, proceeding
to completion using 9 mol% of NHC 2 within one hour. The
desired b-lactams 14–17 are readily isolated in good yield (72–
94%) as a mixture of diastereoisomers, with a preference for the
syn-diastereoisomer observed in each case (Table 3).21
Fig. 2 Proposed mechanism of b-lactam synthesis using NHC 2.
Probing reaction scope
The generality of this catalytic process was next examined. Using
diphenylketene, a range of N-tosyl substituted imines derived
from aryl (entries 1 and 2), heteroaryl (entry 3), substituted aryl
(entries 4 and5) and a,b-unsaturated aldehydes (entry 6)are readily
tolerated. High levels of conversion to the desired b-lactams were
readily achieved with <10 mol% of NHC 2 within one hour,
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Table 3 Diastereoselective NHC catalysed b-lactam synthesis
Entry
R
Time/h
Product
d.r. (syn:anti)a
Yieldb
1
2
3
4
5
Ph
1
1
1
16
1
14
15
16
17
18
68 : 32
63 : 37
81 : 19
57 : 43
76 : 24
89%
89%
86%
94%
72%
2-Naphthyl
2-Furyl
4-BrC6H4
=
(E)–CH CHPh
a As shown by 1H NMR spectroscopic analysis of the crude reaction product. b Isolated yield of diastereoisomeric product mixture after purification.
Catalytic asymmetric b-lactam synthesis employing NHCs
Initial results showed that NHCs 21 and 22, prepared by
deprotonation of 19 and the popular triazolium salt 20 (10
mol%) with KHMDS (9 mol%) respectively, promote readily
the formal cycloaddition of diphenylketene and N-tosyl imine
4, giving complete conversion to b-lactam 5 in 58% and 64%
e.e. respectively and in good isolated yields (Table 4, entries 1
and 2). Preferential crystallisation of the racemate from the 64%
e.e. sample, and concentration of the mother liquor, gave access
to b-lactam (R)-5 in >98% e.e. The absolute configuration of 5
was proven unambiguously by X-ray crystallographic analysis
(Fig. 3).‡ This procedure was subsequently applied to a number
of N-tosyl imines, giving access to enantiomerically enriched b-
lactams (R)-8, (S)-9 and (R)-11 in 56–75% e.e. and in good isolated
yields (79–96%).24 In each case, crystallisation and re-isolation of
the b-lactam from the mother liquor was used to enhance the e.e.
of the b-lactam to >92% e.e. (entries 4, 5 and 8, Table 4).
Subsequent investigations probed the ability of enantiomerically
pure NHCs to catalyse an enantioselective version of this reac-
tion. As C2-symmetry has proven a useful tool in asymmetric
catalysis,22 a C2-symmetric tetrafluoroborate NHC precatalyst
19 was prepared from (1R,2R)-cyclohexane-1,2-diammonium
mono-(+)-tartrate23 via bis-reductive amination and subsequent
cyclisation, giving 19 in good yield over three steps (Scheme 1).
‡ CCDC reference number 671783. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b800857b
Scheme 1 Preparation of C2-symmetric imidazolinium salt 19.
Table 4 Asymmetric NHC catalysed b-lactam synthesis
Entry
Salt
R
Time/h
Product
Yielda
e.e.b
e.e.c
1
2
3
4
5
6
7
8
19
20
19
20
19
20
19
20
Ph
Ph
1
3
1
3
1
3
2
3
(R)-5
(R)-5
(R)-8
(R)-8
(S)-9
(S)-9
(R)-11
(R)-11
90%
96%
95%
92%
85%
93%
79%
96%
58%
64%
73%
75%
61%
55%
56%
57%
>98%
2-Naphthyl
2-Naphthyl
2-Furyl
2-Furyl
4-BrC6H4
4-BrC6H4
>99%
92%
>99%
a Isolated yield of homogeneous product after chromatographic purification. b e.e. of isolated b-lactam after chromatography as shown by HPLC analysis.
c e.e. of b-lactam after crystallisation and re-isolation of the mother liquor as shown by HPLC analysis.
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Andrews Mass Spectrometry facility or from the EPSRC National
Mass Spectrometry Service Centre, Swansea. At the University of
St Andrews, low and high resolution ESI MS was carried out on a
Micromass LCT spectrometer and low and high resolution CI MS
was carried out on a Micromass GCT. At the EPSRC National
Mass Spectrometry Service Centre, low and high resolution EI
MS was carried out on a Micromass Quattro II spectrometer.
General procedure 1 for the synthesis of b-lactams ( )-5 and ( )-8
to ( )-12
A 0.45 M solution of KHMDS in toluene (0.04 mL, 0.0174 mmol,
4.5 mol% or 0.08 mL, 0.0347 mmol, 9 mol%) was added to a
suspension of triazolium salt 1 (5.3 mg, 0.0193 mmol, 5 mol% or
10.5 mg, 0.0386 mmol, 10 mol%) in Et2O (1.5 mL) under a nitrogen
atmosphere and the mixture was stirred for 30 minutes at room
temperature. A solution of diphenylketene 3 (97.4 mg, 0.501 mmol,
1.3 equiv) in Et2O (1.5 mL) was added, followed immediately by
the imine (0.386 mmol, 1.0 equiv) as a solid, then the reaction
mixture was stirred at room temperature before concentration in
vacuo.
Fig. 3 Molecular representation of the X-ray crystal structure of (R)-5.
In conclusion, we have shown that NHCs can catalyse effectively
the formal [2+2] cycloaddition of ketenes and imines to generate
b-lactams, and that chiral NHCs show promising levels of
enantioselectivity in this reaction manifold. Current investigations
are focused upon expanding the reactions of chiral NHCs to a
variety of catalytic enantioselective processes.
Preparation of ( )-3,3,4-triphenyl-1-tosylazetidin-2-one ( )-5
Following general procedure 1, b-lactam ( )-5 was obtained
using diphenylketene 3 (97.4 mg, 0.501 mmol, 1.3 equiv)
and N-benzylidene-4-methylbenzenesulfonamide 4 (100.0 mg,
0.386 mmol, 1.0 equiv). The reaction mixture was concentrated
after stirring for 1 hour at room temperature and the residue was
purified by column chromatography (EtOAc–petroleum ether 20 :
80 then CH2Cl2–petroleum ether–EtOAc 50 : 45 : 5) to give b-
lactam ( )-5 (162.6 mg, 93% yield) as a white solid (mp = 184–
Experimental
General experimental
All reactions involving moisture sensitive reagents were performed
under an atmosphere of nitrogen via standard vacuum line
techniques and with freshly dried solvents. All glassware was flame
dried and allowed to cool under vacuum. Toluene, tetrahydrofuran
(THF), diethyl ether (Et2O) and dichloromethane were obtained
dry from a solvent purification system (MBraun, SPS-800). Potas-
sium hexamethyldisilazide (KHMDS) was supplied as a 0.5 M
solution in toluene (Aldrich), titrated before use,25 and used as a
0.45 M solution. Petrol is defined as petroleum ether 40–60 ◦C. All
solvents and commercial reagents were used as supplied without
further purification unless stated otherwise. Room temperature
refers to 20–25 ◦C. Reflux conditions were obtained using an
oil bath equipped with a contact thermometer. In vacuo refers
to the use of a Bu¨chi Rotavapor R-2000 rotary evaporator with
a Vacubrand CVC2 vacuum controller or a Heidolph Laborota
4001 rotary evaporator with a vacuum controller. Analytical
thin layer chromatography was performed on aluminium sheets
coated with 60 F254 silica. TLC visualisation was carried out
with ultraviolet light (254 nm). Column chromatography was
performed on Kieselgel 60 silica in the solvent system stated.
1H and 13C nuclear magnetic resonance (NMR) spectra were
185 ◦C). IR (KBr disk) mmax 3063, 3037, 2928, 1776 (C O), 1597,
=
1495, 1452, 1447, 1383, 1370, 1262, 1210, 1188, 1172, 1141, 1090,
1070, 1028; 1H NMR d 2.32 (3H, s), 5.70 (1H, s), 6.77–6.94 (7H,
m), 6.98 (2H, t, J = 7.6), 7.05 (1H, t, J = 7.2), 7.11–7.27 (5H, m),
7.31 (2H, d, J = 7.2), 7.65 (2H, d, J = 8.0); 13C NMR d 21.8 (CH3),
69.3 (CH), 72.9 (C), 127.0 (2 CH), 127.3 (CH), 127.7 (2 CH), 127.9
(3 CH), 128.0 (2 CH), 128.1 (2 CH), 128.4 (2 CH), 128.5 (CH),
129.0 (2 CH), 129.9 (2 CH), 134.0 (C), 135.4 (C), 135.9 (C), 139.0
+
(C), 145.4 (C), 166.9 (C); CIMS (NH3) m/z 471 (M + NH4 , 4),
+
+
=
= =
257 (67), 256 (Ph2C CH –Ph, 29), 212 (Ph2C C O + NH4 , 27),
+
=
106 (O C–N–SO2, 100), 91 (C6H5 –CH3, 77); HRMS (CI, NH3)
[M + NH4 ] C28H27N2O3S requires 471.1737, found, 471.1738;
+
Anal. Calcd. for C28H23NO3S: C 74.15, H 5.11, N 3.09%, Found:
C 73.84, H 4.97, N 3.12%.
Preparation of ( )-3,3-diphenyl-4-(2-naphthyl)-
1-tosylazetidin-2-one ( )-8
1
acquired on a Bruker Avance II 400 (400 MHz H, 100 MHz
Following general procedure 1, b-lactam ( )-8 was obtained
using diphenylketene 3 (97.4 mg, 0.501 mmol, 1.3 equiv) and
N-(2-naphthylidene)-4-methylbenzenesulfonamide (119.3 mg,
0.386 mmol, 1.0 equiv). The reaction mixture was concentrated
after stirring for 1 hour at room temperature and the residue was
purified by column chromatography (EtOAc–petroleum ether 20 :
80 then CH2Cl2–petroleum ether–EtOAc 50 : 45 : 5) to give b-
lactam ( )-8 (177.9 mg, 92% yield) as a white solid (mp = 182–
13C) spectrometer and in CDCl3 unless stated otherwise. Coupling
constants (J) are reported in Hz. Infrared spectra (mmax) were
recorded on a Perkin-Elmer Spectrum GX FT-IR Spectrometer
using KBr discs as stated. Only the characteristic peaks are
quoted. Microanalyses were carried out on a Carlo Erba CHNS
analyser. Melting points were recorded on an Electrothermal
apparatus and are uncorrected. Mass spectrometric (m/z) data
were acquired by electrospray ionisation (ESI), electron impact
(EI) or chemical ionisation (CI), either at the University of St
183 ◦C). IR (KBr disk) mmax 3054, 1792 (C O), 1595, 1496, 1449,
=
1374, 1361, 1167, 1128, 1121, 1088; 1H NMR d 2.39 (3H, s), 5.94
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(1H, s), 6.81 (1H, dd, J = 8.4, 1.2), 6.83–7.03 (5H, m), 7.18 (2H, d,
J = 8.0), 7.22–7.39 (4H, m), 7.39–7.51 (5H, m), 7.56 (1H, s), 7.63
(1H, dd, J = 5.6, 3.2), 7.69 (3H, d, J = 8.0); 13C NMR d 27.7 (CH3),
69.7 (CH), 72.8 (C), 124.8 (CH), 126.3 (CH), 126.5 (CH), 127.0 (2
CH), 127.3 (CH), 127.7 (4 CH), 128.0 (4 CH), 128.1 (CH), 128.2 (2
CH), 129.0 (2 CH), 129.8 (2 CH), 131.5 (C), 132.7 (C), 133.1 (C),
1.3 equiv) and N-(2-naphthylidene)-4-methylbenzenesulfonamide
(119.3 mg, 0.386 mmol, 1.0 equiv). The reaction mixture was
concentrated after stirring for 1 hour at room temperature (d.r. =
63 : 37 syn : anti) and the residue was purified by column
chromatography (EtOAc–petroleum ether 10 : 90 then CH2Cl2–
petroleum ether–EtOAc 50 : 45 : 5) to give b-lactam ( )-15
(165.8 mg, 89% yield). Trituration in Et2O gave a white solid (mp =
146–148 ◦C, d.r. = 90 : 10 syn : anti). IR (KBr disk) mmax 3060, 2956,
135.5 (C), 135.7 (C), 139.2 (C), 145.4 (C), 166.8 (C); CIMS m/z
+
= =
504 (M + H , 18), 308 (M − Ph2C C O, 13), 307 (100), 306 (40),
=
=
= =
=
198 (O C–N SO2–tol, 38), 194 (Ph2C C O, 18), 155 (SO2–tol,
16), 141 (C11H9, 5); HRMS (CI) [M + H+] C32H26NO3S requires
504.1633, found 504.1631.
2927, 2870, 2358, 1784 (C O), 1597, 1496, 1467, 1448, 1368, 1187,
1172, 1088; 1H NMR syn: d 0.72 (3H, d, J = 6.8), 0.91 (3H, d, J =
6.8), 1.51–1.65 (1H, m), 2.00 (1H, dd, J = 14.4, 6.0), 2.11 (1H, dd,
J = 14.0, 6.4), 2.38 (3H, s), 5.18 (1H, s), 6.62 (1H, dd, J = 8.4, 1.2),
6.88–7.00 (5H, m), 7.16 (2H, d, J = 8.0), 7.32 (1H, d, J = 8.8),
7.38–7.48 (3H, m), 7.60 (1H, dd, J = 6.0, 3.2), 7.60–7.69 (3H, m);
anti (visible peaks): d 0.33 (3H, d, J = 6.4), 2.45 (3H, s), 5.21 (1H,
s); 13C NMR syn: d 21.7 (CH3), 23.7 (CH3), 23.8 (CH3), 24.9 (CH),
47.8 (CH2), 69.2 (C), 70.0 (CH), 124.9 (CH), 126.2 (CH), 126.4
(CH), 127.0 (CH), 127.4 (2 CH), 127.5 (CH), 127.6 (2 CH), 127.9
(CH), 128.0 (2 CH), 128.2 (CH), 129.7 (2 CH), 131.7 (C), 132.6
(C), 133.1 (C), 134.8 (C), 135.6 (C), 145.1 (C), 168.0 (C); CIMS
General procedure 2 for the synthesis of b-lactams ( )-14 to ( )-18
A 0.45 M solution of KHMDS in toluene (0.08 mL, 0.0347 mmol,
9 mol%) was added to a suspension of triazolium salt 1 (10.5 mg,
0.0386 mmol, 10 mol%) in Et2O (1.5 mL) under a nitrogen
atmosphere and the mixture was stirred for 30 minutes at room
temperature. A solution of isobutylphenylketene 13 (87.3 mg,
0.501 mmol, 1.3 equiv) in Et2O (1.5 mL) was added, followed
by the imine (0.386 mmol, 1.0 equiv) as a solid, then the reaction
mixture was stirred at room temperature before concentration in
vacuo. The initial diastereoselectivity was measured by 1H NMR
on the crude product and can be improved (after purification by
column chromatography) by trituration of the product in Et2O
and filtration. This procedure allowed the characterisation of the
major syn diastereoisomer.
+
+
= =
m/z 484 (M + H , 100), 287 (MH –O C N–SO2tol, 37), 198
= =
= =
(O C N–SO2–tol, 40), 174 (Ph(i-Bu)C C O, 75), 154 (SO2tol,
29); HRMS (ESI+) [M + Na+] C30H29NNaO3S requires 506.1766,
found, 506.1768.
General procedure 3 for the enantioselective synthesis of b-lactams
(R)-5, (R)-8, (S)-9 and (R)-11
Preparation of syn-3,4-diphenyl-3-isobutyl-1-tosylazetidin-2-one
( )-1415
A 0.45 M solution of KHMDS in toluene (0.08 mL, 0.0347 mmol,
9 mol%) was added to a suspension of chiral imidazolinium salt
19 (15.2 mg, 0.0386 mmol, 10 mol%) or chiral triazolium salt
20 (14.5 mg, 0.0386 mmol, 10 mol%) in Et2O (1.5 mL) under a
nitrogen atmosphere and the mixture was stirred for 30 minutes
at room temperature. A solution of diphenylketene 3 (97.4 mg,
0.501 mmol, 1.3 equiv) in Et2O (1.5 mL) was added, followed
immediately by the imine (0.386 mmol, 1.0 equiv) as a solid,
then the reaction mixture was stirred at room temperature before
concentration in vacuo.
Following general procedure 2, b-lactam ( )-14 was obtained
using isobutylphenylketene 13 (87.3 mg, 0.501 mmol, 1.3 equiv)
and N-benzylidene-4-methylbenzenesulfonamide 4 (100.0 mg,
0.386 mmol, 1.0 equiv). The reaction mixture was concentrated
after stirring for 1 hour at room temperature (d.r. = 68 : 32 syn :
anti) and the residue was purified by column chromatography
(EtOAc–petroleum ether 10 : 90 then CH2Cl2–petroleum ether–
EtOAc 50 : 45 : 5) to give b-lactam ( )-14 (148.7 mg, 89% yield).
◦
Trituration in Et2O gave a white solid (mp = 156–158 C, d.r. =
89 : 11 syn : anti). IR (KBr disk) mmax 3064, 3034, 2958, 2927, 2868,
=
2360, 1770 (C O), 1597, 1496, 1447, 1364, 1241, 1188, 1170, 1145,
Preparation of (R)-3,3,4-triphenyl-1-tosylazetidin-2-one 5
1090; 1H NMR syn: d 0.69 (3H, d, J = 6.8), 0.87 (3H, d, J = 6.4),
1.48–1.61 (1H, m), 1.92 (1H, dd, J = 14.6, 6.0), 2.04 (1H, dd, J =
14.0, 6.4), 2.43 (3H, s), 5.00 (1H, s), 6.77 (2H, d, J = 7.6), 6.85–
6.92 (2H, m), 6.95–7.05 (5H, m), 7.10 (1H, t, J = 7.4), 7.15–7.30
(2H, m), 7.71 (2H, d, J = 8.4); anti (visible peaks): d 0.37 (3H, d,
J = 6.4), 2.43 (3H, s), 5.05 (1H, s), 7.80 (2H, d, J = 8.4); 13C NMR
syn: d 21.7 (CH3), 23.7 (CH3), 23.8 (CH3), 24.9 (CH), 47.5 (CH2),
69.3 (C), 69.8 (CH), 127.0 (CH), 127.4 (2 CH), 127.6 (2 CH), 127.9
(2 CH), 127.95 (2 CH), 128.0 (2 CH), 128.4 (CH), 129.7 (2 CH),
134.2 (C), 134.9 (C), 135.7 (C), 145.2 (C), 168.1 (C); anti (visible
peaks): d 23.0, 24.0, 24.5, 42.1, 69.9, 126.1, 127.4, 127.8, 128.6,
128.8, 128.9, 129.8, 168.5.
Following general procedure 3, the b-lactam (R)-5 was obtained
using diphenylketene 3 (97.4 mg, 0.501 mmol, 1.3 equiv) and N-
benzylidene-4-methylbenzenesulfonamide 4 (100 mg, 0.386 mmol,
1.0 equiv). The reaction mixture was concentrated after stirring for
1 hour (using the NHC from 19) or 3 hours (using the NHC from
20) at room temperature and the residue was purified by column
chromatography (EtOAc–petroleum ether 10 : 90 then CH2Cl2–
petroleum ether–EtOAc 50 : 45 : 5) to give b-lactam (R)-5 as a
yellow solid (158.0 mg, 90% yield, from chiral imidazolinium salt
19 and 167.2 mg, 96% yield from chiral triazolium salt 20). HPLC
analysis: 64% e.e. (Daicel CHIRALCEL OD-H column, eluent:
hexane–i-PrOH 90 : 10, flow: 1 mL min−1, wavelengh: 254 nm,
retention times: 9.4 min (major, R) and 16.5 min (minor, S)). [a]D20
+17.7 (c 1.00, CHCl3, 64% e.e.). The initial e.e. can be improved by
crystallisation (CH2Cl2–hexane) and re-isolation of the b-lactam
from the mother liquor, giving (R)-5 in 98% e.e. (mp = 152–154 ◦C,
98% e.e.). [a]2D0 +22.0 (c 0.63, CHCl3, 98% e.e.).
Preparation of syn-3-isobutyl-4-(2-naphthyl)-3-phenyl-
1-tosylazetidin-2-one ( )-15
Following general procedure 2, b-lactam ( )-15 was ob-
tained using isobutylphenylketene 13 (87.3 mg, 0.501 mmol,
1112 | Org. Biomol. Chem., 2008, 6, 1108–1113
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Preparation of (R)-3,3-diphenyl-4-(2-naphthyl)-1-
tosylazetidin-2-one 8
4 M. He, G. J. Uc and J. W. Bode, J. Am. Chem. Soc., 2006, 128, 15088;
M. He, J. R. Struble and J. W. Bode, J. Am. Chem. Soc., 2006, 128,
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5 A. Chan and K. A. Scheidt, J. Am. Chem. Soc., 2007, 129, 5334.
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Following general procedure 3, b-lactam (R)-8 was obtained
using diphenylketene 3 (97.4 mg, 0.501 mmol, 1.3 equiv) and
N-(2-naphthylidene)-4-methylbenzenesulfonamide (119.3 mg,
0.386 mmol, 1.0 equiv). The reaction mixture was concentrated
after stirring for 1 hour (using the NHC from 19) or 3 hours
(using the NHC from 20) at room temperature and the residue
was purified by column chromatography (EtOAc–petroleum ether
10 : 90 then CH2Cl2–petroleum ether–EtOAc 50 : 45 : 5) to give
b-lactam (R)-8 as a pale yellow solid (184.1 mg, 95% yield, from
chiral imidazolinium salt 19 and 178.5 mg, 92% yield from chiral
triazolium salt 20). HPLC analysis: 75% e.e. (Daicel CHIRALCEL
OD-H column, eluent: hexane–i-PrOH 90 : 10, flow: 1 mL min−1,
wavelengh: 254 nm, retention times: 10.0 min (major, R) and
20.5 min (minor, S)). [a]D20 −5.0 (c 1.00, CHCl3, 75% e.e.). The
initial e.e. can be improved by crystallisation (CH2Cl2–hexane)
and re-isolation of the b-lactam fro◦m the mother liquor, giving
(R)-8 in >99% e.e. (mp = 136–138 C, >99% e.e.). [a]2D0 −5.9 (c
0.69, CHCl3, >99% e.e.).
16 For reviews see: T. T. Tidwell, Angew. Chem., Int. Ed., 2005, 44, 6812;
J. Gonda, Angew. Chem., Int. Ed., 2004, 43, 3516.
Acknowledgements
17 During the preparation of this manuscript a related protocol for the
asymmetric synthesis of b-lactams from unsymmetrical ketenes and N-
Boc imines was reported; Y.-R. Zhang, L. He, X. Wu, P.-L. Shao and
S. Ye, Org. Lett., 2008, 10, 277. Bode et al. have also reported a related
b-lactam synthesis using NHCs; M. He and J. W. Bode, J. Am. Chem.
Soc., 2008, 130, 418.
The authors would like to thank the Royal Society for a University
Research Fellowship (ADS), The Leverhulme Trust (ND) and
the Carnegie Trust for the Universities of Scotland (CDC) for
funding, and the EPSRC National Mass Spectrometry Service
Centre (Swansea).
18 M. He and J. W. Bode, Org. Lett., 2005, 7, 3131.
19 O. Sereda and R. Wilhelm, Synlett, 2007, 3032.
20 The syn-configuration within b-lactam 14 (and 16 and 18) was
determined by comparison with the literature data;15 15 and 17 were
assigned by analogy.
21 Trituration of the isolated mixture of diastereoisomers with Et2O
resulted in an enhancement of the d.r. of the product, typically giving
a ∼90 : 10 syn : anti ratio of diastereoisomers; see ESI for full details†.
22 T. P. Dang and H. B. Kagan, J. Chem. Soc. D, 1971, 481.
23 J. F. Larrow and E. N. Jacobsen, Organic Syntheses, Coll. Vol. 10, 2004,
96; J. F. Larrow, E. N. Jacobsen, Y. Gao, Y. Hong, X. Nie and C. M.
Zepp, J. Org. Chem., 1994, 59, 1939.
24 The configuration within (R)-8, (S)-9 and (R)-11 was assigned by
analogy to that of (R)-5.
25 L. Duhamel and J.-C. Plaquevent, J. Organomet. Chem., 1993,
448, 1.
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