Chiral relay in NHC-mediated asymmetric β-lactam synthesis II; asymmetry from NHCs derived from acyclic 1,2-diamines

Article abstract of DOI:10.1016/j.tetasy.2010.03.002

The synthesis of a range of imidazolinium salts derived from acyclic 1,2-diamines, and an evaluation of the reactivity and asymmetric induction of the corresponding NHCs as catalysts for the asymmetric synthesis of β-lactams, is reported. An N-methyl-substituted NHC derived from (1R,2R)-1,2-diphenylethanediamine shows optimal reactivity and enantioselectivity in this series, in contrast to that observed with NHCs derived from (1R,2R)-cyclohexane-1,2-diamine.

Full text of DOI:10.1016/j.tetasy.2010.03.002

Tetrahedron: Asymmetry 21 (2010) 601–616
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral relay in NHC-mediated asymmetric b-lactam synthesis II; asymmetry
from NHCs derived from acyclic 1,2-diamines
Nicolas Duguet a, Adele Donaldson a, Stuart M. Leckie a, Eddy A. Kallström a, Craig D. Campbell a,
Peter Shapland b, Thomas B. Brown c, Alexandra M. Z. Slawin a, Andrew D. Smith a,
*
a EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
b GlaxoSmithKline, Research and Development Ltd, Medicine’s Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
c Pfizer Global Research and Development, 388 Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a range of imidazolinium salts derived from acyclic 1,2-diamines, and an evaluation of
the reactivity and asymmetric induction of the corresponding NHCs as catalysts for the asymmetric syn-
thesis of b-lactams, is reported. An N-methyl-substituted NHC derived from (1R,2R)-1,2-diphenylethan-
ediamine shows optimal reactivity and enantioselectivity in this series, in contrast to that observed with
NHCs derived from (1R,2R)-cyclohexane-1,2-diamine.
Received 18 February 2010
Accepted 23 February 2010
Available online 13 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Previous work:
optimal
ee
low
ee
The ability of Lewis bases to promote numerous catalytic asym-
metric processes has been investigated extensively over the last
decade.1 Within this area, an array of molecular catalysts have
been designed and utilised, with the development of stereochem-
ical models that rationalise the preferred configuration of a given
product central to the development of our mechanistic under-
standing of these reactions. As part of our ongoing studies with
regards to the development and understanding of the use of Lewis
base catalysts in asymmetric catalysis,2 in a previous manuscript
we reported that N-heterocyclic carbenes (NHCs)3 derived from
(1R,2R)-cyclohexane-1,2-diamine promote the formal [2+2] cyclo-
addition of diphenylketene and N-tosyl imines,4,5 with the nature
of the N-substituent key to maximising asymmetry in this series
due to a chiral relay effect (Fig. 1).6,7
BF4
N
N
BF4
Me
BF4
R
N
N
N
N
Me
R
10% ee
up to 70% ee
Relay
of chiral
information
H
O
Ts
Ar'
Ts
N
O
N
Ar
N
N
O
N
N
H
Ph
Ph
Ar
H
Ph
Ar'
Ph
chiral
relay
Ph
observed
Building upon this knowledge, this manuscript explores the
consequence of altering the catalyst architecture within this sys-
tem through the preparation of a range of imidazolinium precata-
Ph
Figure 1. Proposed chiral relay in C2-symmetric imidazolinium NHC promoted
lysts derived from acyclic 1,2-diamines and
a-amino acids rather
catalysis.
than (1R,2R)-cyclohexane-1,2-diamine. The trend in enantioselec-
tivity through variation of the N-substituents from N-methyl to
N-benzyl, as well as the consequence of incorporating stereogenic
N-a-methylbenzyl substituents, is assessed through evaluating
their catalytic activity in the formal [2+2] cycloaddition of ketenes
and their studies upon the enantioselectivity of a series of metal-
salen complexes being representative.8 In this study, the use of
(1R,2R)-cyclohexane-1,2-diamine 1 to form the catalyst backbone
allowed the Cu-salen complex 3 to only adopt the ‘gauche’ confor-
mation 5 due to the constraints of the cyclohexane ring, giving 8 in
high ee in the enantioselective phase transfer benzylation of 7.
However, the Cu-salen complex 4 prepared from (1R,2R)-1,2-
diphenylethane-1,2-diamine 2 preferred the ‘anti’ conformation
6, resulting in markedly reduced reactivity and enantioselectivity
in the benzylation of 7 (Fig. 3).
and N-tosyl imines (Fig. 2).
The conformational effects of ligands derived from both cyclic
and acyclic 1,2-diamines and their stereochemical influence on
reactions have been widely probed, with the work of North et al.
* Corresponding author.
E-mail address: ads10@st-andrews.ac.uk (A.D. Smith).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.002

602
N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
rived from commercially available (1R,2R)-1,2-diphenylethanedi-
acyclic
This work:
backbone
amine. N-Methyl-substituted precatalyst 10 was prepared
following modified literature procedures,9 while the N-benzyl-
substituted precatalyst 12 was prepared by sequential imine for-
mation, reduction and cyclisation (Scheme 1).
R
R
R
R
R
R
BF4 Ph
Ph
Me
BF4
R'
BF4
R'
N
N
N
N
N
N
R'
R'
R'
Me
NH4BF4
CH(OEt)3
MeOH, Δ
Ph
Ph
R = Ph, t-Bu
R' = Me, Bn
R = Ph, allyl
stereogenic N-α-methylbenzyl
Ph
Ph
Ph
Ph
ref 9
BF4
Me
substituents
R
N
N
H2N
NH2
NH HN
Me
Me
Me
R
R
84%
2
9
10
BF4
Bn
BF4
R"
BF4
(i). PhCHO
(ii). NaBH4
72% (2 steps)
N
N
N
N
N
N
R'
Ar
Bn
R = Bn, i-Pr
R' = Me, Bn
R = Bn
Ph
Ph
Ph
Ph
NH4BF4
CH(OEt)3
MeOH, Δ
BF4
Figure 2. C2-Symmetric and C1-symmetric imidazolinium precatalysts derived
NH HN
N
N
from acylic 1,2-diamines.
83%
Ph
Ph
Ph
Ph
11
12
Cyclic
Acyclic
Ph
Scheme 1. Preparation of (4R,5R)-diphenyl N-methyl and N-benzyl imidazolinium
salts 10 and 12.
Ph
H2N
NH2
2
1
H2N
NH2
To prepare the analogous N-methyl- and N-benzyl- substituted
4,5-di-tert-butyl imidazolinium salts 14 and 15, the method of
Mangeney et al.10 was followed from 13,11 with ion exchange of
the bromide salt to the tetrafluoroborate salt generating 16
(Scheme 2). Consistent with the observations of Nolan12 and Mov-
assaghi,13 the C(2) proton of imidazolium salt 15 with a coordinating
halide counterion shows a C(2)–H resonance at 11.0 ppm in CDCl3,
whereas upon ion exchange to a non-coordinating tetrafluoroborate
anion 16 the C(2)–H resonance appears at 9.1 ppm in CDCl3.
Ph
N
Ph
N
N
O
N
O
Cu
Cu
O
O
4
3
H
Ph
Ph
O
O
O
O
N
N
N
H
H
Cu
Cu
ref 10
N
I
Ph
Ph
H
NH HN
N
N
N
Me
Me
"gauche" 5
"anti" 6
13
14
ref 10
complex 3 or 4
(2 mol%)
Me
Ph
Me
Ph
N
CO2Me
Ph
N
CO2Me
NaOH (solid)/ BnBr
KBF4
acetone, rt
7
8
complex 3
Br
BF4
Ph
N
N
91% yield, 81% ee
N
87%
complex 4
Ph
Ph
Ph
15
16
21% yield, 25% ee
Figure 3. North’s proposed ‘gauche’ and ‘anti’ conformations of metal-Salen
complexes and their effect upon enantioselective phase transfer catalysis.
Scheme 2. Preparation of (4R,5R)-di-tert-butyl N-methyl and N-benzyl imidazolin-
ium salts 14, 15 and 16.
Given this precedent for conformational effects in complexes
derived from acyclic and cyclic 1,2-diamines resulting in markedly
different reaction enantioselectivities, we were intrigued to
discover the effect that such constraints would impose upon the
proposed chiral relay mechanism in the NHC-mediated synthesis
of b-lactams. We herein report our studies within this area.
The solid state structures of N-methyl precatalyst 10 and N-
benzyl precatalyst 15 were verified by X-ray crystallographic anal-
ysis (Figs. 4 and 5). Notably, in the solid state, the incorporation of
diphenyl substituents at C(4) and C(5) within 10 results in a H–
C(4)–C(5)–H dihedral angle of 143.1°, while the incorporation of
di-tert-butyl substituents at C(4) and C(5) results in a H–C(4)–
C(5)–H dihedral angle of 113.2°, both markedly different to the
approximately antiperiplanar array observed crystallographically
in the imidazolinium salts derived from (1R,2R)-cyclohexane-1,2-
diamine that were reported in the previous manuscript. While this
large difference in dihedral angle may be partly due to packing ef-
fects in the solid state, it also presumably reflects the minimisation
of the 1,2-strain between the acyclic skeletal substituents. These
effects result in the C(4)- and C(5)-aryl or alkyl substituents of imi-
dazolinium salts derived from acyclic 1,2-diamines disfavouring
the ‘gauche’ conformation found in the imidazolinium salts derived
from (1R,2R)-cyclohexane-1,2-diamine.
2. Results and discussion
2.1. C2-Symmetric precatalyst synthesis from acyclic 1,2-
diamines
2.1.1. C2-Symmetric N-Me and N-Bn substituted imidazolinium
salts with 4,5-diphenyl and 4,5-di-tert-butyl substituents
Initial studies focused upon the preparation of C2-symmetric N-
methyl and N-benzyl-substituted imidazolinium precatalysts de-

N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
603
2.1.2. C2-Symmetric N-a-methylbenzyl substituted
imidazolinium salts
N-a-Methylbenzyl imidazolinium salts 18 and 20 were next
prepared following standard methods from the corresponding acy-
clic diamines 17 and 19 (Scheme 3).14,15
2.2. Probing structure–enantioselectivity relationships in b-
lactam formation
These C2-symmetric imidazolinium salts were subsequently
used as precatalysts under standardised conditions (10% precata-
lyst, 9 mol % KHMDS) to promote the formal [2+2] cycloaddition
of diphenylketene and N-tosyl imine 21 to generate b-lactam (S)-
22. Their reactivity and enantioselectivity in comparison with
those of the N-methyl and N-benzyl imidazolinium precatalysts
23 and 24 prepared from (1R,2R)-cyclohexane-1,2-diamine are
shown (Table 1). Distinctive trends in reactivity observed within
this series indicate that the (4R,5R)-di-tert-butyl-substituted cata-
lysts 14–16 lead to only moderate reaction conversion (30–55%),
presumably reflecting poor reactivity due to steric encumbrance.
Notably, when using precatalysts 10 and 12 containing a (4R,5R)-
diphenyl backbone, good levels of reaction conversion were
observed independent of the N-substituent, although optimal
enantioselectivity was observed with N-methyl substituents
Ph
Ph
BF4
N
N
Me
Me
10
Figure 4. Molecular representation of the X-ray crystal structure of (4R,5R)-
diphenyl N-methyl precatalyst 10 (tetrafluoroborate counterion and selected H
atoms omitted for clarity).
(N-methyl, 58% ee, N-benzyl, 9% ee). The introduction of N-a-
methylbenzylsubstituents led to only moderate enantioselectivity.
Table 1
Asymmetric formal [2+2] cycloadditions using C2-symmetric imidazolinium
precatalysts
(i). KHMDS
R'
R'
R'
R'
(9 mol%)
rt, Et2O
O
Ts
(1 eq)
N
X
R
N
N
N
R
R
N
N
R
O
Ph
(ii).
Ts
H
Ph
Ph
Ph
O
(10 mol%)
Ph
O
O
(S)-22
Ph
(1.3 eq)
Ph
21
Br
N
N
Ph
Ph
Ph
BF4
Me
BF4
Me
BF4
15
N
N
N
N
N
N
Me
Me
Me
Me
10
14
23
quant conv; 79%, 58% ee 40% conv; 30%, 55% ee 94% conv; 68%, 10% ee
Ph
Ph
Figure 5. Molecular representation of the X-ray crystal structure of (4R,5R)-di-tert-
butyl N-benzyl precatalyst 15 (bromide counterion and selected H atoms omitted
for clarity).
X
BF4
Ph
BF4
Ph
N
N
N
N
N
N
Ph
Ph
Ph
Ph
12
84% conv; 76%, 9% ee
24
quant conv; 85%, 61% ee
15, X = Br
60% conv; 55%, 48% ee
16, X = BF4
NH4BF4
CH(OEt)3
MeOH, Δ
Ph
Ph
BF4 Ph
Ph
Ph
Ph
Me
Ph
Me
Ph
Me
58% conv; 51%, 47% ee
N
N
NH HN
92%
Me
Ph
Ph
17
18
20
BF4
Ph
BF4
Ph
N
Ph
Me
NH4BF4
CH(OEt)3
MeOH, Δ
Ph
N
N
N
BF4 Ph
Me
Me
Me
Ph
Me
Ph
Me
Ph
Me
Me
N
N
NH HN
18
20
93% conv; 89%, 20% ee
59%
19
63% conv; 60%, 1% ee
All conversions determined by 1H NMR spectroscopic analysis of the crude reaction
product. All ees determined by HPLC analysis.
Scheme 3. Synthesis of C2 symmetric imidazolinium salts bearing N-a-methyl-
benzyl substituents.

604
N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
"anti"
"gauche"
3. Trends in asymmetric induction
no chiral
relay
In the previous manuscript we described the results consistent
with a chiral relay mechanism operating within NHCs derived from
(1R,2R)-cyclohexanediamine, with N-benzyl or N-1-naphthyl-
methyl substitution leading to optimal enantioselectivity in b-lac-
tam formation. With C2-symmetric precatalysts derived from
acyclic 1,2-diamines, however, optimal (albeit modest) enantiose-
lectivity and reactivity in the b-lactam formation were observed
with 4,5-diphenyl substitution and N-methyl substituents. This
stereochemical dichotomy presumably reflects a change in the pre-
ferred conformation of the stereogenic units within these systems
in the intermediate azolium enolate. Using precatalysts derived
from (1R,2R)-1,2-cyclohexanediamine, the C(4)H and C(5)H imi-
dazolidinium substituents are held approximately antiperiplanar,
forcing the stereogenic cyclohexane ring substituents to adopt a
‘gauche’ conformation due to the conformational constraints of
the ring system, and therefore requiring a chiral relay mechanism
in order to operate to generate optimal ee. However, with NHC
precatalysts derived from acyclic diamines such as (1R,2R)-1,2-
diphenylethanediamine, the stereogenic substituents preferen-
tially adopt an alternative ‘anti’ conformation in order to minimise
1,2-steric interactions. This leads to the opposite trend in enanti-
oselectivity within these series, with N-methyl substituents lead-
ing to optimal ee and reactivity as schematically indicated in
Figure 6.
Given these results, a further comparison between the N-
methyl- and N-benzyl-substituted precatalysts in the cyclohex-
ane-fused and diphenyl series was probed, through their use in
the formal [2+2] cycloaddition of ethylphenylketene and imine
21 (Scheme 4). Analogous trends to those observed in the formal
[2+2] reaction with diphenylketene were observed, with (4R,5R)-
diphenyl N-methyl 10 giving the optimal, although only modest,
enantioselectivity (33% ee for the major syn-diastereoisomer).16
However, within this series, the use of precatalyst 10 also resulted
in a reversal in the absolute configuration of the major syn-diaste-
reoisomer 25, consistent with the sense and levels of asymmetric
induction in these reactions being dependent upon both the con-
formational flexibility of the stereogenic backbone and the nature
of the N-substituents.
Ph
Ph
chiral
relay
Ph
optimal
ee
N
N
O
N
N
Me
Ph
Me
Ph
Ph
O
Ph
Ph
chiral
relay
"anti"
"gauche"
no chiral
relay
Ph
Ph
low
ee
Ph
N
N
N
N
O
Me
Ph
Me
Ph
Ph
O
Ph
Ph
Figure 6. Schematic representations of conformational factors leading to enantio-
control in C2-symmetric imidazolidinium promoted b-lactam synthesis.
ven the modest reactivity of the NHC derived from precatalyst 10 in
this system, its reaction generality was not pursued further.
(i). KHMDS (9 mol%)
rt, Et2O
Ph
Ph
O
Ts
N
BF4
Me
(ii). diphenylketene
N
N
Ph
Me
(1.3 eq)
Ts
Ph
10
(10 mol%)
Br
N
27
28
76% conversiona
31%, 47% eeb
H
(1 eq)
Br
Scheme 5. C2-symmetric imidazolinium precatalyst 10 in asymmetric b-lactam
a
synthesis. As shown by 1H NMR spectroscopic analysis of the crude reaction
b
product. Determined by chiral HPLC analysis.
3.1. Asymmetric imidazolinium precatalyst synthesis from
amino acids
From all of these results, the NHC derived from N-Me precatalyst
10 showed the optimal compromise between reactivity and enanti-
oselectivity, with comparable reactivity and enantioselectivity in the
model system to that employing precatalyst 24. The use of N-Me pre-
catalyst 10 to generate b-lactam 28 fromdiphenylketene and N-tosyl
imine 27 was also evaluated, requiring high catalyst loadings
(20 mol %) to generate 28 in 47% ee at 76%conversion (Scheme 5). Gi-
As alternative precatalysts for asymmetric b-lactam formation,
we developed a flexible route to imidazolinium salts derived from
amino acids. This route was designed to allow both selective and
differential incorporation of N-substituents within the imidazolin-
ium framework, as well as allowing the level of asymmetry from a
R'
R'
(i). KHMDS
(9 mol%)
rt, Et2O
R'
R'
O
Ts
N
BF4
R
N
N
O
(1 eq)
N
R
R
O
N
N
Et
R
Ph
(ii).
Et
Ts
H
Et
10, 12, 23 and 24
O
syn-25 / anti-26
O
(10 mol%)
Ph
Ph
N
(1.3 eq)
21
Ph
Ph
Precatalyst Conversiona
dr (syn:anti)a ee (syn)c
Yieldb
49%
48%
27%
55%
BF4
N
BF4
R
10
12
23
24
quant
75%
64%
quant
68:32
60:40
74:26
65:35
33% (ent)
19%
N
N
R
R
R
1%
26%
10, R = Me
12, R = Bn
23, R = Me
24, R = Bn
Scheme 4. Comparison of C2-symmetric imidazolinium precatalysts in asymmetric b-lactam synthesis. a Determined by 1H NMR spectroscopic analysis of the crude reaction
b
c
product. Isolated yield of diastereoisomeric product mixture after purification. Determined by chiral HPLC analysis.

N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
605
(i). EtOCOCl, NMM, CH2Cl2
then 2-tert-butylaniline, 87%
(i). EtOCOCl, NMM, CH2Cl2
then benzylamine, 91%
Ph
H2N
Ph
H2N
O
Ph
CO2H
(ii). TFA, CH2Cl2, 92%
(iii). LiAlH4, 88%
HN
(ii). TFA, CH2Cl2, 99%
HN
BocHN
Ar
Ph
33, Ar = 2-tert-butylC6H4
30
29
(i). HC(OEt)3
(i). NaBH(OAc)3,
toluene, NH4BF4, Δ
then NaOH (aq)
62%
PhCHO, THF, 96%
(iii). LiAlH4, THF, 51%
(i).HC(OEt)3
toluene, NH4BF4
Δ, 95%
Ph
Ph
Ph
(i). PhCH2Br,
Ph
Ph
acetone, then
BF4
BF4
Ar
N
N
N
N
N
N
NH HN
(ii). KBF4
45%
Ar
Ph
Ph
35, Ar = 2-tert-butylC6H4
Ph
Ph
34, Ar = 2-tert-butylC6H4
31
32
Scheme 6. Synthesis of imidazolinium salts 32 and 35 from N-Boc-phenylalanine.
(i). Boc2O, NaOH
H2O, t-BuOH, 81%
(i).PhCOCl, NaOH (aq), 83%
O
O
(ii). EtOCOCl, NMM,
CH2Cl2 then
2-tert-butylaniline, 57%
CO2H
(ii). EtOCOCl, NMM,
CH2Cl2 then
2,5-dimethylaniline, 91%
BocHN
HN
BzHN
HN
H2N
Ar
Ar
37, Ar = 2-tert-butylC6H4
40, Ar = 2,5-dimethylC6H3
36
(iii). LiAlH4, 60%
(iii). LiAlH4, 95%
(i). HC(OEt)3
(i). HC(OEt)3
MeOH, NH4BF4
Δ, 93%
MeOH, NH4BF4
Δ, 48%
BF4
Ar
BF4
Ar
NH HN
N
N
N
N
NH HN
Ar
Me
Ar
Me
Ph
Ph
39, Ar = 2-tert-butylC6H4
38, Ar = 2-tert-butylC6H4
42, Ar = 2,5-dimethylC6H3
41, Ar = 2,5-dimethylC6H3
Scheme 7. Synthesis of imidazolinium salts 39 and 42 from valine.
single stereogenic centre within the catalyst framework to be eval-
uated. With this hypothesis in mind, N-Boc phenylalanine was
readily transformed into N,N-dibenzyl-substituted imidazolinium
32 through sequential amide formation, N-Boc deprotection,
reductive amination, LiAlH4 reduction and ring closure. Imidazolin-
ium salt 35 containing mixed N-aryl-N-benzyl substitution was
also prepared via a related route, through amide formation, N-
Boc deprotection, reduction and cyclisation to imidazoline 34
which was N-benzylated to give 35 after anion exchange
(Scheme 6).
In a similar fashion, imidazolinium salts 39 and 42 were pre-
pared from valine by sequential N-benzoylation or N-Boc forma-
tion, followed by amide formation, exhaustive reduction to the
corresponding N-benzyl and N-methyl diamines 38 and 41, respec-
tively, followed by cyclisation under standard conditions
(Scheme 7).
results are consistent with catalyst reactivity and reaction stere-
oselectivity being markedly dependent upon the nature of the N-
substituents of the catalyst, with a single stereogenic centre within
the imidazolinium catalyst architecture leading to only modest
enantioselectivity.
4. Conclusion
In conclusion, a range of imidazolinium precatalysts have been
prepared from acyclic 1,2-diamines and amino acids and subse-
quently evaluated in the formal [2+2] cycloaddition of ketenes with
N-tosyl imines. Optimal enantioselectivity for b-lactam formation in
this series was observed when using N-methyl-substituted salts de-
rived from (1R,2R)-1,2-diphenylethanediamine (up to 58% ee). Cur-
rent studies are focused upon fully probing the mechanisms of this
transformation and developing alternative applications of enantio-
merically pure NHCs in asymmetric catalysis.
3.2. Catalytic evaluation of imidazolinium precatalysts derived
from amino acids
5. Experimental
Imidazolinium precatalysts 32, 35, 39 and 42 were subse-
quently evaluated in model b-lactam syntheses using diphenylke-
tene and ethylphenylketene with N-tosyl imine 21. In both series,
the incorporation of an N-2-tert-butylphenyl substituent proved
detrimental to both the catalyst activity and enantioselectivity. Va-
line-derived precatalyst 42 bearing N-aryl-N-methyl substituents
and phenylalanine-derived N-benzyl-substituted 32 proved rea-
sonably catalytically active in both cases, although only modest
enantio- and diastereoselectivity were observed (Scheme 8). These
5.1. General experimental procedures
All reactions involving moisture sensitive reagents were per-
formed under an atmosphere of argon using standard vacuum line
techniques and with freshly distilled solvents. All glasswares were
flame dried and allowed to cool under vacuum.
Solvents were dried and purified either by distillation (under an
atmosphere of nitrogen as described below) or obtained from a sol-

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N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
doublet of doublets, doublet of triplets, triplet of doublets, quartet
and multiplet, respectively. The abbreviation Ar is used to denote
aromatic.
Precatalyst Conversiona Yieldb ee (22)c
32
35
39
42
65%
<10%
<10%
49%
21%
--
23%
--
--
--
Mass spectrometric (m/z) data were acquired by electrospray
ionisation (ESI) or chemical ionisation (CI), either at the University
of St Andrews Mass Spectrometry facility ([M+Na] quoted) or at the
EPSRC National Mass Spectrometry Service Centre, Swansea
([M+H]+, [2M+H]+, [M+Na]+ or [2M+Na]+ quoted). At the University
of St. Andrews, low and high resolution ESI MS was carried out on a
Micromass LCT spectrometer. At the EPSRC National Mass Spec-
trometry Service Centre, CI MS was carried out on a Micromass
Quattro II spectrometer. High resolution ESI was carried out on a
Finnigan MAT 900 XLT; a Thermofisher LTQ Orbitrap XL spectrom-
eter was used to obtain high resolution ESI MS for accurate mass
determination but also provided fragmentation data for the char-
acterisation of samples. Values are quoted as a ratio of mass to
charge in Daltons.
Temperatures of 0 °C were obtained using an ice/water bath and
of ꢀ78 °C were obtained using a dry ice/acetone bath.
Crystallographic data (excluding structure factors) for com-
pounds 10 and 15 have been deposited with the Cambridge Crys-
tallographic Data Centre and allocated the deposition numbers
CCDC 761457 and 761458, respectively. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
37% 31% (ent)
R
Ts
O
Ts
N
N
N
N
O
R'
R"
H
(1 eq)
Ar
O
Ph
Ph
Ph
22
21
Ph
Ph
O
(1.3 eq)
Ph
(i). KHMDS
(9 mol%)
rt, Et2O
R
R
BF4
R"
N
N
N
N
R'
R'
R"
(10 mol%)
32 R, R', R"=Bn
Ph
35 R, R'=Bn, R"=2-t-BuC6H4
39 R=i-Pr, R'=Bn, R"=2-t-BuC6H4
42 R=i-Pr, R'=Me, R"=2,5-(CH3)2C6H3
O
Et
R
(1.3 eq)
Ts
N
O
Ts
N
N
N
R'
Et
R"
H
(1 eq)
Ar
An authentic sample of diamine 17 was kindly provided by Pro-
fessor Nigel Simpkins.
O
Et
Ph
O
21
syn-25
Ph
5.2. Synthesis of NHC precatalysts 10, 12, 14, 15, 16, 18 and 20
Precatalyst Conversiona Yieldd dr (syn:anti)a ee (syn-25)c
5.2.1. (1R,2R)-N,N0-Dimethyl-1,2-diphenylethane-1,2-diamine 9
32
35
39
42
quant
70%
84%
53%
46%
76%
70:30
65:35
70:30
68:32
30%
4%
0%
3%
68%
quant
Me
Me
H
Ph
Ph
Ph
Ph
Ph
Ph
NH2
NH2
Ph
Ph
NH
N
N
O
O
P
P
Scheme 8. Catalytic evaluation of imidazolinium precatalysts derived from valine
and phenylalanine.
Ph
Ph
N
H
N
NH
Me
Me
Following the procedure outlined by Wills et al.,9 (R,R)-1,2-
diphenylethane-1,2-diamine 2 (0.500 g, 2.36 mmol) was dissolved
in CH2Cl2 (25 mL) and triethylamine (0.660 mL, 4.71 mmol) was
added and the mixture was cooled to 0 °C. Phenylphosphonic dichlo-
ride (0.330 mL, 2.36 mmol) was added dropwise over 30 min before
being left to stir overnight. The reaction was quenched by the addi-
tion of H2O (15 mL) and the separated organics were dried (MgSO4),
filtered and concentrated in vacuo to furnish the phosphacycle as a
vent purification system (MBraun, SPS-800). MeOH was distilled
from CaH2. Petrol refers to the fraction of petroleum ether boiling
between 40 °C and 60 °C. All other reagents were used directly as
supplied without further purification.
Silica chromatography was carried out using Silica Gel 60
(0.043–0.060 mm) (Merck) in the solvent system stated.
Analytical thin layer chromatography was performed on
commercially available pre-coated aluminium-backed plates
(Merck silica Kieselgel 60 F254). TLCs were visualised either by
UV fluorescence (254 nm) or by staining with basic KMnO4
solution.
colourless solid (0.647 g, 82%); mp 186–187 °C; ½a D20
¼ þ74:4 (c
ꢁ
1.0, CHCl3); mmax (KBr disc)/cmꢀ1 3199 (N–H), 3029 (N–H), 2888
(C–H), 1171 (P@O), 1124 (C–N), 748 and 696; dH (300 MHz, CDCl3)
8.07–8.00 (2H, m, ArH), 7.53–7.44 (3H, m, ArH), 7.28–7.23 (7H, m,
ArH), 7.19-7.15 (3H, m, ArH), 4.65 (1H, dd, J 8.8, 1.9, C6H5CH), 4.51
(1H, app d, J 8.8, C6H5CH), 3.36 (1H, d, J 15.0, NH) and 3.26 (1H, d, J
8.9, NH); dC (75 MHz, CDCl3) 139.7 (JPC 11.1), 139.6 (JPC 7.3), 134.0
(JPC 160.4), 132.4 (JPC 10.3), 131.8 (JPC 2.9), 127.3 (JPC 23.4), 128.6,
128.5, 128.4, 128.3, 68.7 (JPC 3.6) and 65.8 (JPC 4.5); dP (121 MHz,
CDCl3) 26.8 (s); m/z (ESI+) 367.2 (100, M+H++MeOH+), 335.1 (72,
M+H+); HRMS (ESI+) C20H20N2OP requires 335.1308, found
335.1312 (+1.3 ppm).
Melting points were recorded on an Electrothermal apparatus
and are uncorrected. Microanalyses were carried out on a Carlo
Erba CHNS analyser. Infrared spectra were recorded on a Perkin–
Elmer Spectrum GX FT-IR spectrometer and analysed either as thin
films between NaCl plates (thin film) or KBrs (KBr) as stated.
Absorption maxima (
and only structurally significant peaks are quoted.
m )
max) are quoted in wavenumbers (cmꢀ1
1H and 13C nuclear magnetic resonance (NMR) spectra were ac-
quired on either a Bruker Avance 300 (300 MHz 1H, 75.4 MHz 13C),
a Bruker Avance 400 (400 MHz 1H, 100 MHz 13C) or a Bruker
Avance 500 (500 MHz 1H, 125 MHz 13C) spectrometer in the deu-
terated solvent stated. 13C NMR spectra were recorded with proton
decoupling. Chemical shifts (d) are quoted in parts per million
(ppm) and referenced to residual solvent peaks or to SiMe4 as an
internal standard (d = 0.00). Coupling constants, J, are quoted in.
The abbreviations s, d, dd, dt, td, q and m denote singlet, doublet,
The phosphacycle (0.619 g, 1.85 mmol) was dissolved in THF
(25 mL) and cooled to 0 °C. nBuLi (2.5 M solution in hexanes,
1.49 mL, 3.73 mmol) was added dropwise and the resultant orange
solution was stirred for 1 h before dropwise addition of methyl io-
dide (0.230 mL, 3.73 mmol). After 1.5 h at room temperature, the
reaction was quenched by the addition of H2O (15 mL). The aque-
ous layer was extracted with CH2Cl2 (3 ꢂ 25 mL) and the combined

N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
607
organics were dried (MgSO4) and concentrated in vacuo to give the
methylated phosphacycle as a colourless sticky foam (0.610 g,
91%); ½a 2D0
ꢁ
¼ þ27:2 (c 1.0, CHCl3); mmax (film)/cmꢀ1 3061, 2925,
I
N
N
2855 (C–H), 1151 (P@O), 741 and 697; dH (400 MHz, CDCl3)
7.94–7.85 (2H, m, ArH), 7.50–7.41 (3H, m, ArH), 7.23–7.16 (6H,
m, ArH), 7.15–7.06 (2H, m, ArH), 7.05–7.00 (2H, m, ArH), 4.16
(1H, d, J 8.7, C6H5CH), 4.02 (1H, d, J 8.5, C6H5CH), 2.34 (3H, d, J
10.6, NCH3) and 2.10 (3H, d, J 9.8, NCH3); dC (100 MHz, CDCl3)
137.8, 137.1, 132.8, 131.8, 130.9, 128.6, 128.5, 128.5, 128.2,
128.2, 128.0, 127.6, 73.4, 71.8, 29.9 and 29.8; dP (121 MHz, CDCl3)
32.3 (s).
Me
Me
5.2.4. (4R,5R)-4,5-Di-tert-butyl-1,3-dimethyl-4,5-dihydro-1H-
imidazol-3-ium iodide 14
Compound 14 was prepared according to the protocols of
Mangeney et al.10 Mp 258–262 °C; {lit.10 mp 270–271 °C},
½
a 2D0
ꢁ
¼ ꢀ63:1 (c 0.42, CHCl3); {lit.10
½
a 2D0
ꢁ
¼ ꢀ54:4 (c 2.0, CHCl3);
dH (400 MHz, CDCl3) 9.97 (1H, s, NCHN), 3.43 (6H, s, CH3), 3.39
To a solution of methylated phosphacycle (0.649 g, 1.79 mmol)
in methanol (6.5 mL) was added 4 M HCl in dioxane (1.02 mL) and
the mixture was stirred at reflux for 24 h. The pale orange solution
was cooled to room temperature and concentrated in vacuo to give
a light brown solid which was recrystallised from iso-propyl alco-
hol to give the diamine hydrochloride salt as a colourless solid. The
solid was dissolved in saturated aqueous K2CO3 solution and ex-
tracted with CH2Cl2 (3 ꢂ 20 mL). The combined organics were
dried over K2CO3, filtered and concentrated in vacuo to give 9 as
a colourless solid (0.25 g, 59%) with spectroscopic data in accor-
dance with the literature.17 Mp 48–49 °C; {lit.17 mp 50–51 °C};
(2H, s, NCH) and 1.00 (18H, s, C(CH3)3).
Br
N
N
Ph
Ph
5.2.5. (4R,5R)-1,3-Dibenzyl-4,5-di-tert-butyl-4,5-dihydro-1H-
imidazol-3-ium bromide 15
Compound 15 was prepared according to the protocols of Mange-
½
a 2D0
ꢁ
¼ þ19:3 (c 1.0, CHCl3); {lit.17 = +20.0 (c 0.01, CHCl3)}; dH
ney et al.10 Mp 235–240 °C; {lit.10 mp 249–250 °C}; ½a 2D0
ꢁ
¼ ꢀ82:8 (c
1.09 in CHCl3); {lit.10
CDCl3) 11.12 (1H, s, N@CH–N), 7.55–7.52 (4H, m, ArH) 7.40–7.37
(6H, m, ArH), 5.52 (2H, d, J 14.3 Hz, CH2), 4.45 (2H, d, J 14.3 Hz,
CH2), 3.36 (2H, s, NCH) and 0.69 (18H, s, C(CH3)3).
½
a 2D0
ꢁ
¼ ꢀ114:3 (c 1.6 in CHCl3); dH (300 MHz,
(300 MHz, CDCl3) 7.28–7.17 (6H, m, ArH), 7.14–7.08 (4H, m,
ArH), 3.62 (2H, s, C6H5CH), and 2.33 (6H, s, NCH3).
Ph
Ph
BF4
N
N
Me
Me
BF4
5.2.2. (4R,5R)-1,3-Dimethyl-4,5-diphenyl-4,5-dihydro-1H-
imidazol-3-ium tetrafluoroborate 10
N
N
Ph
Ph
A mixture of diamine 9 (0.252 g, 1.05 mmol), triethyl orthofor-
mate (0.87 mL, 5.24 mmol), ammonium tetrafluoroborate (0.110 g,
1.05 mmol) and methanol (0.44 mL) was stirred at 110 °C for 16 h.
Upon cooling to room temperature, the residue was redissolved in
methanol and diethyl ether was added dropwise to induce precip-
itation of 10 as a pale yellow solid (0.298 g, 84%) with spectro-
scopic data in accordance with the literature.18 Mp 204–206 °C;
5.2.6. (4R,5R)-1,3-Dibenzyl-4,5-di-tert-butyl-4,5-dihydro-1H-
imidazol-3-ium tetrafluoroborate 16
To a suspension of bromide salt 15 (60.0 mg, 0.135 mmol) in ace-
tone (1 mL) was added potassium tetrafluoroborate (500 mg). The
resultant suspension was stirred at room temperature for 1 h and
concentrated in vacuo. The salt was reconstituted in CH2Cl2 (5 mL),
washed with a saturated solution of potassium tetrafluoroborate
(3 ꢂ 5 mL) and concentrated in vacuo to yield tetrafluoroborate salt
{lit.18 mp 223–224 °C}; ½a 2D0
ꢁ
¼ þ251 (c 0.6, CHCl3); {lit.18 +253 (c
0.59, CHCl3)}; dH (300 MHz, CDCl3) 8.62 (1H, s, NCHN), 7.50–7.44
(6H, m, ArH), 7.32–7.27 (4H, m, ArH), 4.87 (2H, C6H5CH) and 3.12
(6H, NCH3).
16 as
a
colourless solid (53.1 mg, 87%); mp 127–130 °C;
½
a 2D0
ꢁ
¼ ꢀ155:2 (c 0.53, CHCl3);
m
max (KBr disk)/cmꢀ1 2960 (N–CH2),
Ph
Ph
1632 (N@C), 1474 (CH3), 1375 (C(CH3)3), 1207 (C–N), 765 and 705;
dH (300 MHz, CDCl3) 9.05 (1H, s, NCHN), 7.44–7.37 (10H, m, ArH),
5.18 (2H, d, J 14.4, CH2), 4.50 (2H, d, J 14.4, CH2), 3.41 (2H, s, CH)
and 0.72 (18H, s, C(CH3)3); dC (75 MHz, CDCl3) 158.9, 132.6, 130.0,
BF4
N
N
Ph
Ph
129.5, 129.5, 70.0, 54.0, 35.8 and 26.5; m/z HRMS (ESIꢀ): C25H35N2
þ
5.2.3. (4R,5R)-1,3-Dibenzyl-4,5-diphenyl-4,5-dihydro-1H-imida
zol-3-ium tetrafluoroborate 12
requires 363.2795, found 363.2784 (ꢀ3.0 ppm).
A mixture of (1R,2R)-N,N0-dibenzyl-1,2-diphenylethane-1,2-dia-
mine 11 (prepared according to the protocols of Kobayashi et al.,19
1.05 g, 2.68 mmol), triethyl orthoformate (0.89 mL, 5.35 mmol)
and ammonium tetrafluoroborate (0.28 g, 2.7 mmol) in methanol
(10 mL) was heated at 110 °C for 5 h before concentration in vacuo
gave tetrafluoroborate salt 12 as a colourless solid (1.09 g, 83%).
Ph
Ph
BF4
Ph
Me
Ph
Me
N
N
5.2.7. (4S,5S)-4,5-Diphenyl-1,3-bis((R)-1-phenylethyl)-4,5-
dihydro-1H-imidazol-3-ium tetrafluoroborate 18
Mp 147–149 °C; ½a D20
¼ þ147 (c 0.25 in CHCl3); mmax (KBr disk)/
ꢁ
cmꢀ1 3422, 3033, 1638 (C@N), 1456, 1196, 1084 (C–N), 1030 (C–
N) and 702; dH (300 MHz, CDCl3) 9.27 (1H, s, NCHN), 7.40–7.33
(6H, m, ArH), 7.30–7.22 (6H, m, ArH), 7.20–7.14 (4H, m, ArH),
7.07–6.99 (4H, m, ArH), 5.13 (2H, d, J 14.6, PhCHAHB), 4.53 (2H, s,
PHCHN) and 4.12 (2H, d, J 14.6, PhCHAHB); dC (75 MHz, CDCl3)
158.1, 134.7, 131.9, 130.0, 129.9, 129.2, 129.1, 129.0, 127.3, 72.0
A suspension of diamine 17 (500 mg, 1.19 mmol) and ammo-
nium tetrafluoroborate (125 mg, 1.19 mmol) in neat triethyl ortho-
formate (0.99 mL, 5.94 mmol) was stirred at 80 °C for 2 days before
cooling to room temperature. Upon addition of a small volume of
diethyl ether, the crude product precipitated, which was purified
via recrystallisation (EtOAc/MeOH/hexane) to yield 18 as a colour-
less solid (567 mg, 92%) with spectroscopic data in accordance
and 50.6; m/z HRMS (ESI+): C29H27N2 requires 403.2169, found
þ
with the literature.20 Mp 196–197 °C; ½a 2D0
¼ ꢀ216 (c 0.98, CHCl3);
ꢁ
403.2159 (ꢀ2.4 ppm).

608
N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
{lit.20
½
a 2D0
ꢁ
¼ ꢀ174 (c 0.54, CHCl3)}; dH (400 MHz, CDCl3) 9.18 (1H,
eral procedure. The crude product was purified by silica
chromatography (EtOAc/petrol 10:90 then CH2Cl2/petrol/EtOAc
50:45:5) to give b-lactam (S)-22 as a pale yellow solid (140 mg,
79%) with spectroscopic data in accordance with the literature.5
s, NCHN), 7.38–7.31 (12H, m, ArH), 7.21–7.19 (4H, m, ArH), 6.95–
6.93 (4H, m, ArH), 4.45 (2H, s, PhCHN), 4.38 (2H, q, J 6.8, PhCHMe)
and 1.99 (6H, d, J 6.8, CH3).
Mp 160 °C; {lit.5 mp 160 °C}; ½a D20
¼ þ31:2 (c 1.00, CHCl3, 58%
ꢁ
ee); {lit.5
½
a 2D0
ꢁ
¼ þ32:6 (c 1.00, CHCl3, 61% ee); HPLC analysis:
58% ee (Daicel CHIRALCEL OD-H column, eluent: hexane/i-PrOH
90:10, flow 1 mL minꢀ1, wavelength 254 nm, retention times:
9.29 min (major, S) and 12.21 min (minor, R)); dH (300 MHz,
CDCl3); 7.72 (2H, d, J 8.4, SO2ArH), 7.44–7.23 (8H, m, ArH), 7.17–
7.03 (4H, m, ArH), 7.00–6.98 (1H, m, furylH), 6.18–6.13 (2H, m, fur-
ylH), 5.76 (1H, s, NTsCH) and 2.42 (3H, s, CH3).
Ph
Me
Ph
Me
NH HN
5.2.8. (4R,5R)-N4,N5-Bis((S)-1-phenylethyl)octa-1,7-diene-4,5-
diamine 19
Compound 19 was prepared according to the protocols of Sa-
voia et al.14
5.3.2. Table 1 entry 2: (S)-3,3-diphenyl-4-(2-furanyl)-1-
tosylazetidin-2-one (S)-22
BF4
The b-lactam (S)-22 was obtained using diphenylketene
(101 mg, 0.521 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (100 mg, 0.401 mmol) with chiral imidazolinium salt
14 (13.6 mg, 0.040 mmol) and a 0.50 M solution of KHMDS in
toluene (0.07 mL, 0.036 mmol) following the above-mentioned
general procedure. The crude product was purified by silica chro-
matography (EtOAc/petrol 10:90 then CH2Cl2/petrol/EtOAc
50:45:5) to give b-lactam (S)-22 as a pale yellow solid (53.4 mg,
30%) with spectroscopic data in accordance with the literature5
and as described above. HPLC analysis: 55% ee.
Ph
Me
Ph
Me
N
N
5.2.9. (4R,5R)-4,5-Diallyl-1,3-bis((S)-1-phenylethyl)-4,5-dihydro-
1H-imidazol-3-ium tetrafluoroborate 20
A mixture of diamine 19 (100 mg, 0.287 mol), triethyl orthofor-
mate (213 mg, 1.43 mol) and ammonium tetrafluoroborate
(30.1 mg, 0.287 mol) was heated to 80 °C and stirred for 4.5 h.
The reaction mixture was concentrated in vacuo and the remaining
triethyl orthoformate was removed via silica chromatography
(MeOH/CH2Cl2 1:9) to yield the pure product 20 as a dark brown
5.3.3. Table 1 entry 3: (S)-3,3-diphenyl-4-(2-furanyl)-1-tosylazetidin-
2-one (S)-22
oil (76.5 mg, 59%); ½a D20
¼ ꢀ33:1 (c 1.1, CHCl3); mmax (thin film)
ꢁ
Prepared from imidazolinium salt 23 as described in a previous
publication.6
2982, 1634 (N@C), 1456, 1386, 1271 and 705; dH (400 MHz, CDCl3)
9.04 (1H, s, NCHN), 7.46–7.33 (10H, m, ArH), 5.28 (2H, ddt, J 17.1,
10.1, 7.1, 2 ꢂ CH2CH@CH2), 5.06 (2H, dd, J 10.1, 1.1, CH@CHAHB),
4.87 (2H, dd, J 17.1, 1.1, CH@HAHB), 4.81 (2H, q, J 7.1, CHCH3),
3.48 (2H, q, J 7.1, NCHCH2), 2.20–2.14 (4H, m, NCHCH2) and 1.96
(6H, d, J 6.8, CH3); dC (75 MHz, CDCl3) 152.7, 138.5, 130.0, 129.8,
129.5, 126.6, 121.9, 63.0, 57.4, 35.7 and 20.7; m/z HRMS (ESIꢀ)
C25H35N2þ, requires 359.2482, found 359.2472 (ꢀ2.7 ppm).
5.3.4. Table 1 entry 4: (S)-3,3-diphenyl-4-(2-furanyl)-1-tosylazetidin-
2-one (S)-22
The b-lactam (S)-22 was obtained using diphenylketene
(97.4 mg, 0.501 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (96.1 mg, 0.386 mmol) with chiral imidazolinium salt
12 (18.9 mg, 0.039 mmol) and a 0.50 M solution of KHMDS in
toluene (0.07 mL, 0.035 mmol) following the above-mentioned
general procedure. The crude product was purified by silica chro-
matography (EtOAc/petrol 10:90 then CH2Cl2/petrol/EtOAc
50:45:5) to give b-lactam (S)-22 as a pale yellow solid (130 mg,
76%) with spectroscopic data in accordance with the literature5
and as described above. HPLC analysis: 9% ee.
5.3. Enantioselective synthesis of b-lactam (S)-22 by NHC precatalysts
10, 14, 12, 14, 16, 18 and 20
General procedure: A 0.50 M solution of KHMDS in toluene
(9 mol %) was added to a suspension of chiral imidazolinium salt
(10 mol %) in Et2O (1.5 mL) under a nitrogen atmosphere and the
mixture was stirred for 30 min at room temperature. A solution
of diphenylketene (1.3 equiv) in Et2O (1.5 mL) was added, fol-
lowed by the imine (1.0 equiv) as a solid, and the reaction mix-
ture was stirred at room temperature for 16 h before
concentration in vacuo. The residue was dissolved in CH2Cl2
(5 mL) and washed with 0.1 M HCl(aq) (5 mL). The aqueous
phase was extracted with CH2Cl2 (3 ꢂ 10 mL) and the combined
organic fractions were dried (MgSO4) and concentrated in vacuo
to yield the crude product as an orange oil.
5.3.5. Table 1 entry 5: (S)-3,3-diphenyl-4-(2-furanyl)-1-tosylazetidin-
2-one (S)-22
The b-lactam (S)-22 was obtained using diphenylketene
(101 mg, 0.521 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (100 mg, 0.401 mmol) with chiral imidazolinium salt
15 (17.8 mg, 0.040 mmol) and a 0.50 M solution of KHMDS in
toluene (0.07 mL, 0.036 mmol) following the above-mentioned
general procedure. The crude product was purified by silica chro-
matography (EtOAc/petrol 10:90 then CH2Cl2/petrol/EtOAc
50:45:5) to give b-lactam (S)-22 as a pale yellow solid (97.9 mg,
55%) with spectroscopic data in accordance with the literature5
and as described above. HPLC analysis: 48% ee.
O
Ts
N
O
Ph
Ph
5.3.6. Table 1 entry 6: (S)-3,3-diphenyl-4-(2-furanyl)-1-tosylazetidin-
2-one (S)-22
5.3.1. Table 1 entry 1: (S)-3,3-diphenyl-4-(2-furanyl)-1-
tosylazetidin-2-one (S)-22
The b-lactam (S)-22 was obtained using diphenylketene
(101 mg, 0.521 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (100 mg, 0.401 mmol) with chiral imidazolinium salt
16 (18.1 mg, 0.040 mmol) and a 0.50 M solution of KHMDS in
toluene (0.07 mL, 0.036 mmol) following the above-mentioned
general procedure. The crude product was purified by silica
The b-lactam (S)-22 was obtained using diphenylketene
(101 mg, 0.521 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (100 mg, 0.401 mmol) with chiral imidazolinium salt
10 (13.6 mg, 0.040 mmol) and a 0.50 M solution of KHMDS in tol-
uene (0.07 mL, 0.036 mmol) following the above-mentioned gen-

N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
609
chromatography (EtOAc/petrol 10:90 then CH2Cl2/petrol/EtOAc
5.4.1. Scheme 4: entry 1: (3S,4S)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3S,4S)-25
50:45:5) to give b-lactam (S)-22 as a pale yellow solid (90.1 mg,
51%) with spectroscopic data in accordance with the literature5
and as described above. HPLC analysis: 47% ee.
The b-lactam (3S,4S)-25 was prepared according to the above-
mentioned general procedure using chiral imidazolinium salt 10
(13.5 mg, 0.040 mmol) to give (3S,4S)-25 as a colourless solid
(77.8 mg, 49%) and as a diastereomeric mixture (dr syn:anti 68:32)
with spectroscopic data in accordance with the literature.4
5.3.7. Table 1 entry 7: (S)-3,3-diphenyl-4-(2-furanyl)-1-tosylazetidin-
2-one (S)-22
(3R,4R)-60 mp 158-162 °C; {lit.4 mp 117–118 °C}; ½a 2D0
¼ ꢀ30:0 (c
ꢁ
This compound was prepared from imidazolinium salt 24 as de-
scribed in a previous publication.6
0.1, CH2Cl2, 33% ee); {lit.4 ½a D20
¼ ꢀ45:2 (c 0.5, CH2Cl2, 83% ee}; HPLC
ꢁ
analysis: 33% ee (Daicel CHIRALCEL AD-H column, eluent: hex-
ane/iPrOH 90:10, flow 1 mL minꢀ1, wavelength 254 nm, retention
times: 13.6 min (minor, R,R) and 15.3 min (major, S,S)); dH
(300 MHz, CDCl3); 7.68 (2H, d, J 8.4, ArH), 7.19–7.15 (5H, m, ArH),
7.04–6.99 (3H, m, 2 ꢂ ArH, 1 ꢂ furylH), 6.13–6.10 (2H, m, furylH),
5.12 (1H, s, TsNCH), 2.43 (3H, s, ArCH3), 2.11 (2H, q, J 7.4, CH2) and
0.90 (3H, t, J 7.4, CH2CH3).
5.3.8. Table 1 entry 8: (S)-3,3-diphenyl-4-(2-furanyl)-1-tosylazetidin-
2-one (S)-22
The b-lactam (S)-22 was obtained using diphenylketene
(101 mg, 0.521 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (100 mg, 0.401 mmol) with chiral imidazolinium salt
18 (20.8 mg, 0.040 mmol) and a 0.50 M solution of KHMDS in
toluene (0.07 mL, 0.036 mmol) following the above-mentioned
general procedure. The crude product was purified by silica chro-
matography (EtOAc/petrol 10:90 then CH2Cl2/petrol/EtOAc
50:45:5) to give b-lactam (S)-22 as a pale yellow solid (106 mg,
60%) with spectroscopic data in accordance with the literature5
and as described above. HPLC analysis: 1% ee.
Me
O
O
S
N
O
Et
O
Ph
5.3.9. Table 1 entry 9: (S)-3,3-diphenyl-4-(2-furanyl)-1-tosylazetidin-
2-one (S)-22
(3R,4R) syn-25
The b-lactam (S)-22 was obtained using diphenylketene
(101 mg, 0.521 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (100 mg, 0.401 mmol) with chiral imidazolinium salt
20 (17.9 mg, 0.040 mmol) and a 0.50 M solution of KHMDS in
toluene (0.07 mL, 0.036 mmol) following the above-mentioned
general procedure. The crude product was purified by silica chro-
matography (EtOAc/petrol 10:90 then CH2Cl2/petrol/EtOAc
50:45:5) to give b-lactam (S)-22 as a pale yellow solid (159 mg,
89%) with spectroscopic data in accordance with the literature5
and as described above. HPLC analysis: 20% ee.
5.4.2. Scheme 4: entry 2: (3R,4R)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3R,4R)-25
The b-lactam (3R,4R)-25 was prepared according to the above-
mentioned general procedure using chiral imidazolinium salt 12
(19.6 mg, 0.040 mmol) to give (3S,4S)-25 as a colourless solid
(76.2 mg, 48%) and as a diastereomeric mixture (dr syn:anti
60:40) with spectroscopic data in accordance with the literature4
and as described above. HPLC analysis: 19% ee.
Me
5.4. General procedures for the synthesis of b-lactams 58–65 by
NHC precatalyst 10
O
O
S
N
O
A 0.50 M solution of KHMDS in toluene (0.07 mL, 0.036 mmol,
9 mol %) was added to a suspension of chiral imidazolinium salt
(10 mol %) in Et2O (1.5 mL) under nitrogen atmosphere and the
mixture was stirred for 30 min at room temperature. A solution
of ethylphenylketene (76 mg, 0.521 mmol, 1.3 equiv) in Et2O
(1.5 mL) was added, followed by the imine (100 mg, 0.401 mmol,
1.0 equiv) as a solid, and the reaction mixture was stirred at room
temperature for 16 h before concentration in vacuo. The residue
was dissolved in CH2Cl2 (5 mL) and washed with 0.1 M HCl(aq)
(5 mL). The aqueous phase was extracted with CH2Cl2
(3 ꢂ 10 mL) and the combined organic fractions were dried
(MgSO4) and concentrated in vacuo to yield the crude product as
an orange oil. The crude product was purified by silica chromatog-
raphy, (Et2O/petrol 10:90 then Et2O/petrol 30:70) to give syn-25 as
a colourless solid.
Et
O
Ph
(3R,4R) syn-25
5.4.3. Scheme 4: entry 3: (3R,4R)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3R,4R)-25
The b-lactam (3R,4R)-25 was prepared according to the above-
mentioned general procedure using chiral imidazolinium salt 23
(9.6 mg, 0.040 mmol) to give (3S,4S)-25 as a colourless solid
(42.0 mg, 48%) and as a diastereomeric mixture (dr syn:anti
74:26) with spectroscopic data in accordance with the literature4
and as described above. HPLC analysis: 1% ee.
Me
Me
O
O
O
S
O
S
N
O
N
O
Et
Et
O
Ph
O
Ph
(3R,4R) syn-25
(3S,4S) syn-25

610
N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
CH2Cl2. The organic extracts were washed in 1 M NaOH(aq), sat-
urated NaCl(aq), and dried (MgSO4), filtered and concentrated in
vacuo.
5.4.4. Scheme 4: entry 4: (3R,4R)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3R,4R)-25
The b-lactam (3R,4R)-25 was prepared as described in a previ-
ous manuscript.6
5.6.3. General procedure C: amide reduction
A solution of LiAlH4 in THF (2.5 equiv) was added dropwise to a
stirred solution of the amide (1 equiv) in THF at ambient tempera-
ture under nitrogen atmosphere. The reaction mixture was re-
fluxed at 80 °C for 96 h and then the reaction was quenched with
Et2O followed by sequential dropwise addition of water (1 mL gꢀ1
of LiAlH4), 40% KOH solution (1 mL gꢀ1 of LiAlH4) and water
(3 mL gꢀ1 LiAlH4). The reaction mixture was allowed to stir for a
few min before the addition of excess MgSO4 and then left to stir
for 1 h. The reaction mixture was filtered through Celite and the fil-
trate was washed with Et2O. The organic extracts were combined
and concentrated in vacuo.
5.5. Reaction generality with NHC precatalyst 10
Me
O
O
S
N
O
Ph
Ph
Br
A 0.50 M solution of KHMDS in toluene (0.11 mL, 0.056 mmol)
was added to a suspension of chiral imidazolinium salt 10
(20.0 mg, 0.059 mmol) in Et2O (1.5 mL) under a nitrogen atmo-
sphere and the mixture was stirred for 30 min at room temper-
ature. A solution of ethylphenylketene (104 mg, 0.384 mmol) in
Et2O (1.5 mL) was added, followed by the imine (100 mg,
0.296 mmol) as a solid, and the reaction mixture was stirred at
room temperature for 16 h before concentration in vacuo. The
residue was dissolved in CH2Cl2 (5 mL) and washed with 0.1 M
HCl(aq) (5 mL). The aqueous phase was extracted with CH2Cl2
(3 ꢂ 10 mL) and the combined organic fractions were dried
(MgSO4) and concentrated in vacuo to yield the crude product
as an orange oil. The crude product was purified by silica chro-
matography, (EtOAc/petrol 10:90 then CH2Cl2/EtOAc/petrol
50:5:45) to give syn-25 as a colourless solid (49 mg, 31%) with
spectroscopic data in accordance with the literature.5 Mp 170–
5.6.4. General procedure D: diamine cyclisation
A
suspension of the diamine (1 equiv), NH4BF4 (1 equiv),
CH(OEt)3 (5 equiv) in toluene was heated to 80 °C for 12 h. The
reaction mixture was concentrated in vacuo and the residue was
dissolved in CH2Cl2. The organics were washed in 0.1 M NaOH(aq),
saturated NaCl(aq), and dried (MgSO4), filtered and concentrated in
vacuo.
5.6.5. General procedure E: alkylation of amidine
Benzyl bromide (1 equiv) was added to a solution of amidine
(1 equiv) in acetone at ambient temperature under a nitrogen
atmosphere. The reaction mixture was refluxed at 75 °C for 12 h
and then concentrated in vacuo. The residue was redissolved in
acetone. Next, KBF4 (1.2 equiv) was added and the mixture was
stirred for 1 h at ambient temperature and thereafter concentrated
in vacuo. The residue was taken into CH2Cl2, washed with satu-
rated NaCl(aq), dried (MgSO4), filtered and concentrated in vacuo.
174 °C; {lit.5 mp 214–215 °C}; ½a 2D0
¼ þ17:6 (c 1.0, CHCl3, 57%
ꢁ
ee); {lit.5
½
a 2D0
ꢁ
¼ þ21:8 (c 1.0, CHCl3, 57% ee)}; HPLC analysis:
47% ee (Daicel CHIRALCEL OD-H column, eluent: hexane/iPrOH
90:10, flow: 1 mL/min, wavelength: 254 nm, retention times:
10.1 min (major, R) and 26.5 min (minor, S)); dH (300 MHz,
CDCl3); 7.80–7.69 (2H, m, ArH), 7.35–7.28 (7H, m, ArH), 7.26–
7.20 (2H, m, ArH), 7.17–7.02 (3H, m, ArH), 6.90–6.82 (2H, m,
ArH), 6.79 (2H, d, J 7.9, ArH), 5.69 (1H, s, NCH) and 2.43 (3H,
s, ArCH3).
5.6.6. General procedure F: reductive amination
NaBH(OAc)3 (1.5 equiv) was added to a solution of amine
(1 equiv) and aldehyde (1 equiv) in THF. The reaction mixture
was stirred at ambient temperature under a nitrogen atmosphere
for 12 h and thereafter washed in 1 M NaOH(aq), saturated Na-
Cl(aq), and dried (MgSO4), filtered and concentrated in vacuo.
5.6.7. (S)-tert-Butyl 1-(benzylamino)-1-oxo-3-phenylpropan-2-
5.6. Synthesis of NHC precatalysts 32, 35, 39 and 42
ylcarbamate
5.6.1. General procedure A: amide coupling via mixed
anhydride
N-Methylmorpholine (1 equiv) and ethyl chloroformate
(1 equiv) were added to a solution of carboxylic acid (1 equiv) in
CH2Cl2 over 10 min at 0 °C followed by the dropwise addition of
amine (1 equiv) over 10 min. The reaction mixture was stirred at
ambient temperature for 12 h and the reaction was then quenched
with water and the mixture was extracted with CH2Cl2 (ꢂ3). The
organic extracts were combined, washed with 1 M HCl, saturated
NaHCO3(aq), and dried (MgSO4), filtered and concentrated in va-
cuo. Further purification was achieved by trituration with ice-cold
pentane.
O
N
H
BocHN
Following general procedure A, N-methylmorpholine (4.00 mL,
37.7 mmol), ethyl chloroformate (3.79 g, 37.7 mmol), benzylamine
(4.04 g, 37.7 mmol), Boc-L-phenylalanine (10.0 g, 37.7 mmol) in
CH2Cl2 (145 mL), gave, after trituration with pentane, the amide
product (12.1 g, 91%) as a colourless solid with spectroscopic data
in accordance with the literature.21 Mp 129–130 °C; {lit.21 136–
5.6.2. General procedure B: deprotection of BOC protecting
group
At first TFA (9.5 equiv) was added dropwise to a solution of
the carbamate (1 equiv) in CH2Cl2 at ambient temperature and
the mixture was allowed to stir for 12 h. The reaction mixture
was concentrated in vacuo and the residue was dissolved in
137 °C}; ½a 2D0
ꢁ
¼ ꢀ2:3 (c 1.05, MeOH); {lit.21
½
a 2D0
ꢁ
¼ ꢀ1:8 (c 1.00,
MeOH); dH (400 MHz; CDCl3) 7.23–7.17 (8H, m, ArH), 7.05–7.00
(2H, m, ArH), 5.98–5.87 (1H, m, CHNHCO2), 5.02–4.86 (1H, m,
CONHCH2), 4.33–4.23 (3H, m, CH2CH(CO)NH, ArCH2NH), 3.08–
2.96 (2H, m, ArCH2), 1.48 (6H, s, O-t-Bu) and 1.33 (3H, s, O-t-Bu).

N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
611
5.6.8. (S)-2-Amino-N-benzyl-3-phenylpropanamide 30
5.6.11. (S)-1,3,4-Tribenzyl-4,5-dihydro-1H-imidazol-3-ium
tetrafluoroborate 32
O
N
N
N
H
NH2
BF4
To a solution of (S)-tert-butyl-1-(benzylamino)-1-oxo-3-phe-
nylpropan-2-ylcarbamate (8.00 g, 22.6 mmol) in CH2Cl2 (16 mL)
was added TFA (16 mL, 0.23 mol) to give amide 41 (5.75 g, 99%)
as a colourless solid with spectroscopic data in accordance with
Following general procedure D, (S)-N1,N2-dibenzyl-3-phenylpro-
pane-1,2-diamine 31 (1.53 g, 4.66 mmol), NH4BF4 (0.49 g,
4.66 mmol), CH(OEt)3 (3.45 g, 23.3 mmol) in toluene (25 mL), gave
after trituration with petrol, the imidazolinium salt 32 (2.08 g,
the literature.22 Mp 62–64 °C; {lit.22 61–68 °C); ½a 2D0
¼ ꢀ76:2 (c
ꢁ
1.05, CHCl3); {lit.22
½
a 2D0
ꢁ
¼ ꢀ69:0 (c 1.00, CHCl3); dH (400 MHz;
95%) as a yellow oil. ½a D20
ꢁ
¼ þ16:8 (c 0.53, MeOH);
mmax (thin film)/
CDCl3) 7.51 (1H, br s, CONHCH2), 7.27–7.14 (10H, m, ArH), 4.43–
4.33 (2H, m, PhCH2NH), 3.59 (1H, dd, J 9.2, 4.1, COCH(NH2)CH2),
3.23 (1H, dd, J 13.7, 4.1, PhCH2), 2.68 (1H, dd, J 13.7, 9.2, PhCH2)
and 1.27 (2H, br s, NH2).
cmꢀ1 3398, 3066, 2931, 1650, 1456, 1207, 1060, 744 and 703; dH
(400 MHz, CDCl3) 8.53 (1H, s, NCHN), 7.44–7.20 (13H, m, PhH),
6.96 (2H, dd, J 6.4, 2.8, PhH), 5.00 (1H, ABq, J 14.8, PhCHAHBNH),
4.69–4.61 (1H, m, PhCHAHBNH), 4.53 (1H, ABq, J 14.8, PhCHAHBNH)
5.6.9. (S)-N-Benzyl-2-(benzylamino)-3-phenylpropanamide
4.27–4.19 (1H, m, PhCHAHBCH–), 3.61 (1H, ABX t,
J 11.5,
PhCHAHBCH), 3.45–3.40 (1H, m, PhCHAHBCH), 3.15 (1H, ABX, JAB
13.9, JAX 4.8, NCHAHBCH) and 2.85 (1H, ABX, JBA 13.9, JBX 8.9,
NCHAHBCH); dC (100 MHz, CDCl3); 157.7, 134.3, 132.4 (2C), 129.5,
129.4, 129.2 (2C), 129.1, 128.9, 128.8, 128.7, 127.5, 60.4, 52.4, 52.2,
50.4, and 37.4; m/z ES(+) 251.15 (8, [MꢀPhCH2ꢀBF4]+), 341.20
O
NH HN
(100, [MꢀBF4]+), 460.27 (2, [M+MeOH]+; HRMS (ES+) C24H25N2 re-
þ
quires 341.2012, found 341.2006 (ꢀ1.8 ppm).
Following general procedure F, NaBH(OAc)3 (2.09 g, 9.84 mmol),
(S)-2-amino-N-benzyl-3-phenylpropanamide 30 and benzalde-
hyde (1.04 g, 9.84 mmol) in THF gave the amino amide (3.25 g,
96%) as a yellow oil with spectroscopic data in accordance with
O
N
H
the literature.23
½
a 2D0
ꢁ
¼ ꢀ73:7 (c 0.54, CHCl3); {lit.23
½
a 2D0
ꢁ
¼ ꢀ69:4
BocHN
(c 0.50, CHCl3)} dH (400 MHz; CDCl3) 7.61–7.57 (1H, m, CONHCH2),
7.35–7.10 (13H, m, PhH), 7.01–6.98 (2H, m, PhH), 4.50–4.40 (2H,
m, PhCH2NHCO), 3.67 (1H, ABq, J 13.3, PhCHAHBNH), 3.54 (1H,
ABq, J 13.3, PhCHAHBNH), 3.44 (1H, dd, J 9.4, 4.2, PhCH2CH), 3.25
(1H, ABX, JAB 13.8, JAX 4.2, PhCHAHBCH-), 2.78 (1H, ABX, JBA 13.8,
JBX 9.4, PhCHAHBCH) and 1.58 (1H, s, NH).
5.6.12. (S)-tert-Butyl 1-(2-tert-butylphenylamino)-1-oxo-3-
phenylpropan-2-yl-carbamate
Following general procedure A, N-methylmorpholine (4.00 mL,
37.7 mmol), ethyl chloroformate (3.79 g, 37.7 mmol), 2-tert-butyl-
5.6.10. (S)-N1,N2-Dibenzyl-3-phenylpropane-1,2-diamine 31
aniline (5.63 g, 37.7 mmol), Boc-L-phenylalanine (10.0 g,
37.7 mmol) and CH2Cl2 (145 mL), gave after trituration with pen-
tane, the amide product as a colourless solid (9.76 g, 87%). Mp
98-100 °C; ½a 2D0
ꢁ
¼ ꢀ21:6 (c 0.99, MeOH); mmax (KBr)/cmꢀ1 3300
(N–H), 3249, 2969, 1685 (C@O), 1655 (aryl C@C), 1528, 1366,
1250 (C–O), 1173 and 757; dH (300 MHz, DMSO-d6) 9.21 (1H, s,
ArNH), 7.40–7.26 (5H, m, PhH), 7.26–7.15 (4H, m, ArH), 7.00–6.96
(1H, m, CO2NH), 4.40 (1H, td, J 9.7, 4.5, BzCH), 3.10 (1H, ABX,
JAB13.8, JAX 4.5, PhCHAHB), 2.85 (1H, ABX, JBA13.8, JBX 9.7,
PhCHAHB–), 1.32 (9H, s, OC(CH3)3) and 1.29 (9H, C(CH3)3); dC
(100 MHz; DMSO-d6) 171.5, 155.3, 145.8, 138.1, 135.8, 130.5,
129.2, 128.0, 126.6, 126.4, 126.3, 126.2, 78.1, 56.1, 36.9, 34.5,
30.6 and 28.0; m/z ES(+) 297.20 (18, [Mꢀt-BuOCO+H]+), 341.19
(47, [Mꢀt-Bu+H]+), 397.25 (100, [M+H]+) and 419.23 (10,
NH
HN
Following general procedure C, LiAlH4 (14 mL, 28.3 mmol) and
(S)-N-benzyl-2-(benzylamino)-3-phenylpropanamide in THF gave
after chromatography (2% MeOH/CH2Cl2) the diamine 31 (1.57 g,
51%) as a yellow oil. ½a D20
¼ þ14:1 (c 1.07, CH2Cl2); mmax (thin
ꢁ
[M+Na]+); HRMS (ES+) C24H33O3N2 requires 397.2486, found
þ
film)/cmꢀ1 3310 (N–H), 3026, 2923, 2852, 1603, 1494, 1453,
1122 and 741; dH (400 MHz, CDCl3) 7.33–7.15 (15H, m, PhH),
3.81–3.65 (4H, m, PhCH2NH), 2.97–2.85 (2H, m, PhCH2, PhCH2CH),
2.74–2.68 (2H, m, PhCH2, BnNHCH2), 2.52 (1H, dd, J 11.9, 7.1,
BnNHCH2) and 1.70 (2H, s, NH); dC (100 MHz, CDCl3) 141.1,
141.0, 139.7, 129.8, 128.8, 128.8 (2C), 128.5, 127.3, 126.6, 58.5,
54.3, 52.4, 51.7 and 39.8; m/z ES(+) 224.11 (44, [MꢀPhCH2NH]+)
and 331.13 (100, [M+H]+); HRMS (ES+) C23H27N2 requires
331.2174, found 331.2166 (ꢀ2.4 ppm).
397.2487 (+0.3 ppm).
O
N
H
NH2

612
N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
mmax (thin film)/cmꢀ1 2961, 2869, 1677, 1602, 1489, 1442, 1091,
1055, 759 and 701; dH (400 MHz; CDCl3) 7.38 (1H, dd, J 7.9, 1.6,
ArH), 7.27–7.12 (7H, m, ArH), 6.90 (1H, d, J 1.5, N@CH), 6.80 (1H,
dd, J 7.6, 1.6, NHArC(6)H), 4.47 (1H, dtdd, J 9.5, 8.3, 5.6, 1.6,
PhCH2CH), 3.61 (1H, t, J 9.5, PhCH2–), 3.30 (1H, dd, J 9.5, 8.3,
PhCHAHB), 3.13 (1H, ABX, JAB 13.7, JAX 5.6, NCHAHB), 2.81 (1H,
ABX, JBA 13.7, JBX 8.3, NCHAHB) and 1.32 (9H, s, C(CH3)3); dC (100
MHz; CDCl3) 158.0, 149.0, 139.9, 137.9, 130.1, 130.0, 129.7,
129.1, 128.2, 128.1, 127.0, 66.0, 59.6, 41.9, 36.0 and 32.0; m/z
ES(+) 293.20 (100, [M+H]+) and 311.21 (5, [M+H2O+H]+); HRMS
5.6.13. (S)-2-Amino-N-(2-tert-butylphenyl)-3-
phenylpropanamide
At first, TFA (10.0 mL, 0.131 mol) was added to a mixture
of (S)-tert-butyl-1-(2-tert-butylphenylamino)-1-oxo-3-phenylpro-
pan-2-ylcarbamate (5.00 g, 12.6 mmol) in CH2Cl2 (40 mL) and
the mixture was stirred for 12 h. The mixture was concentrated
in vacuo, the residue was redissolved in CH2Cl2, then the organic
fraction was washed sequentially with 1 M NaOH(aq) (100 mL)
and brine (100 mL) then dried (MgSO4) to afford the deprotected
monoamide as an amber oil (3.83 g, 92%). The product was used
þ
(ES+) C20H25N2 requires 293.2012, found 293.2005 (ꢀ2.5 ppm).
without further purification. ½a D20
¼ ꢀ113:4 (c 1.29, CHCl3); mmax
ꢁ
(thin film)/cmꢀ1 3778, 3313 (N–H), 2966, 2874, 1681 (C@O),
1515, 1296 and 755; dH (400 MHz; CDCl3) 9.65 (1H, s, CONH),
7.88 (1H, dd, J 8.0, 1.4, ArH), 7.30–7.14 (8H, m, ArH), 7.04–7.00
(1H, m, ArH), 3.71 (1H, dd, J 9.4, 3.8, COCH), 3.31 (1H, dd, J
13.8, 3.8, PhCHAHB), 2.78 (1H, dd, J 13.8, 9.4, PhCHAHB), 1.43
(2H, s, NH2) and 1.30 (9H, s, C(CH3)3); dC (100 MHz; CDCl3)
171.9, 140.6, 137.7, 135.5, 129.4, 128.8, 127.0, 126.8, 126.4,
125.1, 125.0, 56.8, 40.6, 34.4 and 30.4; m/z ES(+) 297.20 (35,
5.6.16. Bis((S)-3,4-dibenzyl-1-(2-tert-butylphenyl)-4,5-dihydro-
1H-imidazol-3-ium) tetrafluoroborate 35
BF4
N
N
[M+H]+), 319.18 (2, [M+Na]+), 593.38 (100, [2 M+H]+) and
615.36 (22, [2M+H]+); HRMS (ES+) C19H23ON2
requires
þ
297.1961, found 297.1958 (ꢀ1.1 ppm).
Following general procedure E, benzyl bromide (0.117 g,
0.683 mmol), (S)-4-benzyl-1-(2-tert-butylphenyl)-4,5-dihydro-
5.6.14. (S)-N1-(2-tert-Butylphenyl)-3-phenylpropane-1,2-
diamine 33
1H-imidazole 34 (0.200 g, 0.683 mmol) in acetone (0.4 mL) gave
the crude product 35. The product mixture was treated with
KBF4 (0.103 g, 0.982 mmol) and gave after chromatography
(EtOAc/petrol, 1:1) the imidazolinium salt 35 (0.144 g, 45%) as a
pale brown solid. Mp 129–130 °C; ½a D20
¼ þ3:9 (c 1.03, CHCl3); mmax
ꢁ
(KBr)/cmꢀ1 2967, 1637, 1498, 1256, 1084, 765 and 703; dH
(400 MHz, CDCl3) 7.85 (1H, s, NCHN), 7.47–7.29 (12H, m, Ar-H),
7.19–7.17 (2H, m, ArC(6)H, NArC(5)H), 5.01 (1H, ABq, J 14.3,
PhCHAHBN), 4.80 (1H, ABq, J 14.3 PhCHAHBN), 4.75–4.69 (1H, m,
PhCH2CH), 4.23 (1H, ABX t, J 11.2, PhCHAHB), 4.00 (1H, ABX, JBA
11.2, JBX 8.5, PhCHAHB), 3.43 (1H, ABX, JAB 13.6, JAX 5.3, NCHAHBCH),
3.14 (1H, ABX, JBA 13.6, JBX 9.5, NCHAHBCH) and 1.33 (9H, s,
C(CH3)3); dC (100 MHz; CDCl3) 158.6, 146.8, 134.4, 134.0, 132.3,
130.5, 130.2, 129.5, 129.4, 129.3, 129.2, 129.1, 128.5, 128.3,
127.7, 61.5, 59.5, 50.7, 37.3, 35.7 and 32.0; m/z ES(+) 383.25
(100, [M]+); HRMS (ES+) C27H31N2 requires 383.2482, found
383.2479 (ꢀ0.7 ppm).
N
H
NH2
Following general procedure C, LiAlH4 (20.3 mL, 40.5 mmol) and
(S)-2-amino-N-(2-tert-butylphenyl)-3-phenylpropanamide (2.00 g,
6.75 mmol) in THF gave the diamine 34 (1.83 g, 88%) as a pale yel-
low solid. Mp 55–57 °C; ½a D20
¼ þ19:8 (c 1.06, CHCl3); mmax (KBr)/
ꢁ
cmꢀ1 3415 (N–H), 3384, 2962 (C–H), 2929, 2902, 1598, 1573,
1507, 1449, 752 and 704; dH (400 MHz; CDCl3) 7.35–7.22 (6H, m,
ArH), 7.12 (1H, ddd, J 8.1, 7.4, 1.3, NHArC(5)H), 6.69 (1H, td, 7.4,
1.3, NHArC(3)H), 6.63 (1H, dd, J 8.1, 1.3, NHArC(6)H), 4.67 (1H, br
s, ArNH), 3.40–3.32 (2H, m, CH(NH2), ArNHCHAHB), 3.02–2.96
(1H, m, ArNHCHAHB), 2.97 (1H, dd, J 13.4, 5.2, PhCHAHB), 2.64
(1H, dd, J 13.4, 5.2, PhCHAHB), 1.45 (9H, s, –C(CH3)3) and 1.23
(2H, br s –NH2); dC (100 MHz; CDCl3) 146.7, 138.9, 133.6, 129.3,
128.6, 127.1, 126.5, 126.2, 116.9, 111.7, 52.3, 50.1, 43.3, 34.3 and
29.9; m/z ES(+) 283.13 (100%, [M+H]+); HRMS (ES+) C19H27N2 re-
quires 283.2174, found 283.2181 (+2.4 ppm).
5.6.17. (S)-N2-Benzyl-N1-(2-tert-butylphenyl)-3-methylbutane-
1,2-diamine 38
O
H2N
OH
5.6.15. (S)-4-Benzyl-1-(2-tert-butylphenyl)-4,5-dihydro-1H-
imidazole 34
O
N
N
Ph
Ph
HN
HN
NH
NH
O
Following general procedure D, (S)-N1-(2-tert-butylphenyl)-3-
phenylpropane-1,2-diamine 33 (0.800 g, 2.83 mmol), NH4BF4
(0.297 g, 2.83 mmol), CH(OEt)3 (2.4 mL, 14.2 mmol) in toluene
(8.5 mL) gave after chromatography (2% MeOH/CH2Cl2) the ami-
37
38
L
-Valine (6.57 g, 56.1 mmol) and NaOH (2.34 g) were dissolved
in H2O (17 mL). Next, Et2O (90 mL) was added, and the mixture
was cooled to 0 °C and stirred rapidly. Benzoyl chloride (6.58 mL,
dine 34 (0.513 g, 62%) as a yellow oil. ½a D20
ꢁ
¼ ꢀ30:6 (c 1.01, CHCl3);

N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
613
56.6 mmol) and a solution of NaOH (2.34 g) in H2O (6 mL) were
added alternatively portionwise over 90 min, then the mixture
was warmed to ambient temperature over 16 h. The mixture was
then concentrated to half volume in vacuo before concd HCl
(5 mL) was added to induce precipitation of the product. The prod-
uct was collected by filtration and washed with Et2O (100 mL) and
dried. The product was obtained as a colourless solid (10.3 g, 83%),
which was used without further purification. A suspension of N-
benzoylvaline (1.50 g, 6.78 mmol) in CH2Cl2 (20 mL) was cooled
to 0 °C and N-methylmorpholine (0.75 mL, 6.78 mmol) was added
before the dropwise addition of ethyl chloroformate (0.67 mL,
6.78 mmol). After 20 min, 2-tert-butylaniline (1.06 mL, 6.78 mmol)
was added to the suspension. The mixture was warmed to ambient
temperature over 16 h then the reaction was quenched with H2O
(30 mL). The mixture was diluted with CH2Cl2 (20 mL) and ex-
tracted with CH2Cl2 (3 ꢂ 30 mL). The combined organics were
washed successively with 4% NaHCO3(aq) (30 mL) and 1 M HCl(aq)
(30 mL), then dried (MgSO4), filtered and concentrated in vacuo.
The product was triturated with pentane (20 mL) to obtain the
product 37 as a colourless solid (1.36 g, 53%) which was used with-
out further purification. To a suspension of diamide 37 (1.00 g,
4.06 mmol) in THF (10 mL) was added a solution of LiAlH4
(9.13 mL, 18.3 mmol) and the mixture was heated at reflux for
72 h, then quenched at 0 °C with H2O (0.69 mL), 40% KOH(aq)
(0.69 mL) and further H2O (2.07 mL), before drying with excess
MgSO4 and filtration through Celite. The product was obtained as
a clear colourless oil (790 mg) after chromatographic purification
1.21 (9H, s, C(CH3)3), 0.93 (3H, d, J 6.8, CH3), and 0.80 (3H, d, J 7.0,
CH3); dC (100 MHz, CDCl3): 158.8, 147.0, 134.0, 132.2, 130.6, 130.0,
129.5, 129.3, 129.0, 128.8, 128.3, 65.0, 54.9, 50.2, 35.7, 32.0, 26.6,
18.0 and 14.4; m/z (ES+) 335.07 (100, M); HRMS(ES+) C23H31N2 re-
quires 335.2487, found 335.2479, (ꢀ2.4 ppm).
5.6.19. (S)-tert-Butyl 1-(2,5-dimethylphenylamino)-3-methyl-
1-oxobutan-2-ylcarbamate 40
O
O
O
HN
BocHN
OH
OH
H2N
BocHN
36
40
To a solution of
L-valine (35.1 g, 300 mmol) in NaOH(aq) (12.0 g
in 300 mL) was added tert-butanol (200 mL) followed by the slow
addition of di-tert-butyl dicarbonate (75.2 g, 360 mmol), with vig-
orous stirring. The mixture was stirred for 48 h at ambient temper-
ature then the reaction was quenched with 1 M KHSO4(aq) to pH
ꢃ1. The mixture was saturated with NaCl, and then extracted with
Et2O (3 ꢂ 300 mL). The organics were combined, dried (MgSO4), fil-
tered and concentrated in vacuo to afford the crude Boc-L-valine
product as a colourless oil which partly solidified on standing
(52.6 g, 81%). The product was used without further purification.
½
a 2D0
ꢁ
¼ ꢀ4:7 (c 1.00, MeOH). The product was obtained as a mixture
(10% EtOAc/petrol). ½a D20
¼ þ0:3 (c 1.6, CHCl3). mmax (thin film)/
ꢁ
of rotamers. Data for the major rotamer: dH (400 MHz, CDCl3) 7.94
(1H, br s, COOH), 5.06 (1H, d, J 8.9, NHCH), 4.28 (1H, dd, J 8.9, 4.5,
NHCH), 2.27–2.19 (1H, m, CHMe2), 1.02 (3H, d, J 6.8, CH3) and 0.96
(3H, d, J 6.8, CH3).
cmꢀ1: 3425 (br, N–H), 2958, 2930, 1644, 1504, 1443, 1055, 834,
741 and 697; dH (400 MHz, CDCl3) 7.27–7.22 (4H, m, ArH), 7.20–
7.16 (2H, m, ArH), 7.07 (1H, td, J 7.6, 1.4, N-ArH-4), 6.63–6.58
(2H, m, ArH), 4.76 (1H, t, J 4.4, ArNH), 3.74 (1H, d, J 12.8, PhCHAHB),
3.71 (1H, d, J 12.8, PhCHAHB), 3.20 (1H, dt, J 11.5, 4.4, ArNHCHAHB),
2.95 (1H, ddd, J 11.4, 6.6, 4.4, ArNHCHAHB), 2.65 (1H, td, J 6.6, 4.0,
BnNHCH), 2.03–1.91 (1H, m, CH(CH3)2), 1.37 (9H, s, C(CH3)3), 0.97
(3H, d, J 6.8, CH3) and 0.90 (3H, d, J 6.8, CH3). dC (100 MHz, CDCl3):
147.1, 140.5, 133.5, 128.5, 128.4, 127.2, 127.1, 126.2, 116.5, 111.5,
61.9, 51.1, 43.3, 34.4, 29.9, 29.3, 20.0 and 18.4; m/z 325.05 (79,
M+H), 347.02 (M+Na); HRMS(ES+) C22H33N2 requires 325.2644,
found 325.2639 (ꢀ1.3 ppm).
A solution of Boc-L-valine (6.74 g, 31.0 mmol) in CH2Cl2 (80 mL)
was cooled to 0 °C, followed by addition of N-methylmorpholine
(3.41 mL, 31.0 mmol) and dropwise addition of ethyl chloroformate
(2.97 mL, 31.0 mmol) and then the mixture was stirred for 20 min.
2,5-Dimethylaniline (3.82 mL, 31.0 mmol) was added slowly, then
warmed to ambient temperature over 16 h, then the reaction was
quenched with H2O (100 mL) and the mixture was extracted with
CH2Cl2 (100 mL ꢂ 3). The organic fractions were combined and
washed sequentially with 4% NaHCO3(aq) (100 mL) and 1 M HCl(aq)
(100 mL), then dried (MgSO4), filtered and concentrated in vacuo.
The crude product was then triturated with ice-cold pentane to ob-
tain the purified product as a very pale green solid (9.01 g, 91%). Mp
5.6.18. (S)-1-Benzyl-3-(2-tert-butylphenyl)-5-isopropyl-4,5-
dihydro-1H-imidazolium tetrafluoroborate 39
155–156 °C; ½a 2D0
ꢁ
¼ ꢀ54:4 (c 1.00, MeOH); mmax (KBr)/cmꢀ1: 3316
(NH), 2973, 2963, 1691 (C@O), 1660 (C@O), 1579, 1524, 1491,
1457, 1379, 1368, 1298, 1283, 1247, 1171, 1048, 1024, 887, 814
and 684; dH (DMSO-d6, 400 MHz) 9.22 (1H, s, amide NH), 7.14 (1H,
s, ArH-3), 7.07 (1H, d, J 8.0, carbamate NH), 6.90–6.88 (1H, m, ArH-
6), 6.85 (1H, d, J 8.5, ArH-4), 3.93 (1H, t, J 8.0, BocNHCH), 2.23 (3H,
s, 5-ArCH3), 2.12 (3H, s, 2-ArCH3), 2.06–1.95 (1H, m, CHMe2), 1.39
(9H, s, C(CH3)3), 0.93 (3H, d, J 6.8, CH3) and 0.90 (3H, d, J 6.8, CH3);
dC (DMSO-d6, 100 MHz) 170.5, 156.1, 135.9, 135.5, 130.5, 130.3,
126.1, 125.8, 78.4, 60.4, 30.5, 28.4, 20.7, 19.6, 18.5 and 17.5; m/z
BF4
N
N
Amixtureof diamine38(186 mg, 0.573 mmol), NH4BF4 (61.0 mg,
0.573 mmol), triethyl orthoformate (0.23 mL) and MeOH (1.6 mL)
was heated at 80 °C for 16 h then concentrated in vacuo before dis-
solution in CH2Cl2 and filtration to remove excess NH4BF4. The prod-
uct was obtained as a clear colourless oil (225 mg, 93%) after
(ES+) 321.2174 (100, M+H+) 265.1549 (Mꢀt-Bu, 69), 221.1649 (M-
þ
Boc, 17). HRMS(ES+) C18H29O3N2
321.2174 (+0.4 ppm).
, requires 321.2173, found
5.6.20. (S)-N1-(2,5-Dimethylphenyl)-N2,3-dimethylbutane-1,2-
diamine 41
chromatographic purification (10% MeOH/CH2Cl2). ½a D20
¼ ꢀ0:7 (c
ꢁ
1.4, CHCl3); mmax (thin film)/cmꢀ1: 3389, 3069, 2957, 2924, 2850,
1635 (C@N), 1457, 1366, 1259, 1086, 1057, 1036, 753 and 703; dH
(400 MHz, CDCl3) 8.01 (1H, s, NCHN), 7.36 (1H, dd, J 8.1, 1.3,
ArCH(6)), 7.27–7.21 (6H, m, ArCH), 7.17–7.13 (2H, m, ArCH), 4.87
(1H, ABq, J 14.6, PhCHAHB), 4.44 (1H, ABq, J 14.6, PhCHAHB), 4.32–
4.26 (1H, m, Me2CHCH), 4.11 (1H, app t, J 11.6, ArNCHAHB), 3.81
(1H, ABX, JBA 11.6, JBX 9.9, ArNCHAHB), 2.34–2.23 (1H, m, CHMe2),
HN
NH
Me

614
N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
To a solution of Boc-protected amide 40 (958 mg, 3.00 mmol) in
Me
THF (10 mL) was cautiously added LiAlH4 (9.00 mL of a 2 M solu-
tion in THF, 18.0 mmol), then the mixture was heated at reflux
for 24 h. The mixture was then cooled (0 °C) and H2O (0.68 mL)
was added cautiously (with vigorous effervescence), followed by
40% KOH(aq) (0.68 mL) and H2O (2.04 mL). To the mixture was
added an excess of MgSO4 and stirred for 1 h, then the mixture
was filtered through Celite, washing with THF (30 mL). The solu-
tion was concentrated in vacuo to afford the desired diamine
(630 mg, 95%) as a pink/purple oil. Product was used without fur-
O
N
O
S
O
Ph
O
Ph
5.7.1. Scheme 8 entry 1: (S)-3,3-diphenyl-4-(2-furanyl)-1-
tosylazetidin-2-one (S)-22
ther purification. ½a D20
ꢁ
¼ þ5:0 (c 1.73, CHCl3);
m
max (thin film)/cmꢀ1
3370 (NH), 3015, 2958, 2927, 2871, 2796, 1715, 1615, 1582, 1520,
1455, 1387, 1368, 1313, 1298, 1155, 1137, 1100, 1035, 1001, 840,
792 and 716; dH (400 MHz, CDCl3) 6.94 (1H, d, J 7.4, ArH-3), 6.48
(1H, s, ArH-4), 6.44 (1H, s, ArH-6), 4.15 (1H, br s, ArNH), 3.22
(1H, dt, J 11.8, 4.2, ArNHCHAHB), 2.96 (1H, ddd, J 11.8, 7.5, 4.2,
ArNHCHAHB), 2.51 (1H, ddd, J 7.5, 6.4, 4.2, MeNHCH), 2.41 (3H, s,
NCH3), 2.31 (3H, s, 5-ArCH3), 2.12 (3H, s, 2-ArCH3), 1.96 (1H, dt, J
13.2, 6.8, CHMe2), 1.02 (3H, d, J 6.8, CHCH3) and 0.96 (3H, d, J
6.8, CHCH3); dC (100 MHz, CDCl3) 146.9, 136.8, 130.0, 119.5,
117.3, 110.9, 64.2, 43.3, 33.9, 29.0, 21.4, 19.6, 18.5 and 17.2; m/z
(ES+) C14H25N2 requires 221.2012, found 221.2017 (+2.1 ppm).
The b-lactam (S)-22 was obtained using diphenylketene
(82.5 mg, 0.31 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (81.5 mg, 0.33 mmol) with chiral imidazolinium salt
32 (14.0 mg, 0.033 mmol) and a 0.50 M solution of KHMDS in
toluene (0.06 mL, 0.029 mmol) following the above-mentioned
general procedure. The crude product was purified by silica
chromatography (Et2O/petrol 20:80) to give b-lactam (S)-22 as
a pale yellow solid (3.00 mg, 21%) with spectroscopic data in
accordance with the literature5 and as described above. HPLC
analysis: 23% ee.
Me
5.6.21. (S)-1-(2,5-Dimethylphenyl)-4-isopropyl-3-methyl-4,5-
dihydro-1H-imidazol-3-ium tetrafluoroborate
O
O
S
N
O
BF4
Ph
O
Ph
N
N
Me
5.7.2. Scheme 8 entry 4: (R)-3,3-diphenyl-4-(2-furanyl)-1-
tosylazetidin-2-one (R)-22
A mixture of diamine 41 (200 mg, 0.908 mmol), triethyl orthofor-
mate (0.37 mL, 2.27 mmol), MeOH (2.5 mL) and NH4BF4 (96 mg,
0.916 mmol) was heated at 100 °C for 6 h, then concentrated in va-
cuo. The mixture was triturated with Et2O (ꢂ3) and EtOAc (ꢂ1).
The mixture was redissolved in CH2Cl2 and loaded onto a short silica
plug (ꢃ2 cm depth). The product was eluted with CH2Cl2 then
ramped to 2.5% MeOH/CH2Cl2 to affordthe productas a green/brown
The b-lactam (R)-22 was obtained using diphenylketene
(50.7 mg, 0.261 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (50.1 mg, 0.201 mmol) with chiral imidazolinium salt
42 (4.7 mg, 0.020 mmol) and a 0.50 M solution of KHMDS in tolu-
ene (0.04 mL, 0.018 mmol) following the above-mentioned general
procedure. The crude product was purified by silica chromatogra-
phy (Et2O/petrol 10:90 then Et2O/petrol 30:70) to give b-lactam
(R)-22 as a pale yellow solid (33.0 mg, 37%) with spectroscopic
data in accordance with the literature5 and as described above.
HPLC analysis: 31% ee.
oil (140 mg, 48%). ½a D20
ꢁ
¼ þ38:7 (c 0.5, CHCl3);
m :
max (thin film)/cmꢀ1
3636, 3089, 2969, 2880, 1715 (C@N), 1652, 1619, 1576, 1515, 1509,
1464, 1428, 1397, 1377, 1315, 1270, 1215, 1161, 1134, 1058, 910,
823, 765, 719 and 675; dH (400 MHz, CDCl3) 8.12 (1H, s, NCHN),
7.13 (1H, s, ArH-6), 7.10 (2H, d, J 3.3, ArH), 4.50–4.44 (1H, m,
CHMe2CH), 4.33 (1H, app t, J 11.7, NCHAHB), 3.80 (1H, dd, J 11.1,
7.8, NCHAHB), 3.26 (3H, s, N+CH3), 2.33–2.26 (4H, m, N+CH and
ArCH3), 2.26 (3H, s, ArCH3) and 0.97 (6H, app t, J 6.5, CH(CH3)2); dC
(100 MHz, CDCl3) 157.8, 137.9, 134.6, 131.7, 130.6, 130.5, 126.5,
67.0, 52.0, 33.1, 27.0, 20.7, 17.8, 17.4 and 14.2; m/z HRMS(ES+)
Me
O
O
S
N
O
Et
þ
C15H23N2 requires 231.1856, found 231.1856 (+0.1 ppm).
O
Ph
5.7. Synthesis of b-lactam 22 by NHC precatalysts 32 and 42
5.7.3. Scheme 8 entry 5: (3S,4S)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3S,4S)-25
General procedure: A 0.50 M solution of KHMDS in toluene
(9 mol %) was added to a suspension of chiral imidazolinium salt
(10 mol %) in Et2O (1.5 mL) under a nitrogen atmosphere and the
mixture was stirred for 30 min at room temperature. A solution of
ketene (1.3 equiv) in Et2O (1.5 mL) was added, followed by the imine
(1.0 equiv) as a solid, and the reaction mixture was stirred at room
temperature for 16 h before concentration in vacuo. The residue
was dissolved in CH2Cl2 (5 mL) and washed with 0.1 M HCl(aq)
(5 mL). The aqueous phase was extracted with CH2Cl2 (3 ꢂ 10 mL)
and the combined organic fractions were dried (MgSO4) and concen-
trated in vacuo to yield the crude product as an orange oil.
The b-lactam (3S,4S)-25 was prepared using ethylphenylketene
(71.8 mg, 0.49 mmol) and N-(2-furfurylidene)-4-methylbenzenesulf-
onamide (94.3 mg, 0.38 mmol) with chiral imidazolinium salt 32
(16.2 mg, 0.038 mmol) and a 0.50 M solution of KHMDS in toluene
(0.07 mL, 0.034 mmol) following the above-mentioned general proce-
dure. The crude product was purified by silica chromatography (EtOAc/
petrol 5:95 then EtOAc/petrol 10:90) to give b-lactam (3S,4S)-25 as a
pale yellow solid (126 mg, 84%) and as a diastereomeric mixture (dr sy-
n:anti 70:30) with spectroscopic data in accordance with the literature4
and as described above. HPLC analysis: 30% ee.

N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
615
dance with the literature4 and as described above. HPLC analysis:
3% ee.
Me
O
N
Acknowledgements
O
S
O
The authors would like to thank the Royal Society for a Univer-
sity Research Fellowship (ADS), The Leverhulme Trust (ND), Pfizer
(CASE award to SML), GlaxoSmithKline (CASE award to AD), and
The Carnegie Trust for the Universities of Scotland (CDC) for fund-
ing. Prof. Nigel Simpkins is gratefully acknowledged for the gener-
ous gift of an authentic sample of diamine 17. The EPSRC mass
spectrometry facility is also acknowledged.
Et
O
Ph
5.7.4. Scheme 8 entry 6: (3R,4R)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3R,4R)-25
The b-lactam (3R,4R)-25 was prepared using ethylphenylketene
(45.2 mg, 0.309 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (59.4 mg, 0.238 mmol) with chiral imidazolinium salt
35 (11.2 mg, 0.0238 mmol) and a 0.50 M solution of KHMDS in
toluene (0.04 mL, 0.0214 mmol) following the above-mentioned
general procedure. The crude product was purified by silica chro-
matography (EtOAc/petrol 5:95 then EtOAc/petrol 10:90) to give
b-lactam (3R,4R)-25 as a pale yellow solid (31.9 mg, 34%) and as
a diastereomeric mixture (dr syn:anti 65:35) with spectroscopic
data in accordance with the literature4 and as described above.
HPLC analysis: 4% ee.
References
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Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638.
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Me
3. For recent reviews of the ability of NHCs to catalyse organocatalytic processes
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O
O
S
N
O
4. For elegant studies by the Ye group utilising NHCs in asymmetric catalysis using
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Et
O
Ph
5.7.5. Scheme 8 entry 7: (3R,4R)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3R,4R)-25
The b-lactam (3R,4R)-25 was prepared using ethylphenylketene
(38.2 mg, 0.261 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (50.1 mg, 0.201 mmol) with chiral imidazolinium salt
42 (6.7 mg, 0.020 mmol) and a 0.50 M solution of KHMDS in tolu-
ene (0.04 mL, 0.018 mmol) following the above-mentioned general
procedure. The crude product was purified by silica chromatogra-
phy (EtOAc/petrol 10:90 then EtOAc/petrol 30:70) to give b-lactam
(3R,4R)-25 as a pale yellow solid (41.0 mg, 46%) and as a diastereo-
meric mixture (dr syn:anti 70:30) with spectroscopic data in accor-
dance with the literature4 and as described above. HPLC analysis:
0% ee.
6. Duguet, N.; Donaldson, A.; Leckie, S. M.; Douglas, J.; Shapland, P.; Churchill, G.;
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Me
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N
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5.7.6. Scheme 8 entry 8: (3R,4R)-3-ethyl-4-(furan-2-yl)-3-
phenyl-1-tosylazetidin-2-one (3R,4R)-25
The b-lactam (3R,4R)-25 was prepared using ethylphenylketene
(38.2 mg, 0.261 mmol) and N-(2-furfurylidene)-4-methylbenzene-
sulfonamide (50.1 mg, 0.201 mmol) with chiral imidazolinium salt
39 (4.7 mg, 0.020 mmol) and a 0.50 M solution of KHMDS in tolu-
ene (0.04 mL, 0.018 mmol) following the above-mentioned general
procedure. The crude product was purified by silica chromatogra-
phy (EtOAc/petrol 10:90 then EtOAc/petrol 30:70) to give b-lactam
(3R,4R)-25 as a pale yellow solid (67.8 mg, 76%) and as a diastereo-
meric mixture (dr syn:anti 68:32) with spectroscopic data in accor-
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established by comparison of the sign of its specific rotation ½a D20
¼ ꢀ30 (c
ꢁ
0.1, CH2Cl2) to the literature,4a a 2D5
½ ꢁ ¼ ꢀ45:2 (c 0.5, CH2Cl2).

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N. Duguet et al. / Tetrahedron: Asymmetry 21 (2010) 601–616
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