Tertiary amine-promoted enone aziridination: Investigations into factors influencing enantioselective induction

Article abstract of DOI:10.1016/j.tetasy.2013.11.008

trans-N-Unsubstituted aziridines were synthesised (up to 77% ee) via a chiral tertiary amine-promoted nucleophilic aziridination of a,b-unsaturated ketones utilising in situ generated N-N ylides (aminimines). A wide range of chiral tertiary amines were sy

Full text of DOI:10.1016/j.tetasy.2013.11.008

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Tertiary amine-promoted enone aziridination: investigations
into factors influencing enantioselective induction
a
a
a
a
Alan Armstrong a, , Robert D. C. Pullin , Chloe R. Jenner , Klement Foo , Andrew J. P. White ,
⇑
James N. Scutt b
a Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
b Syngenta Ltd, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
trans-N-Unsubstituted aziridines were synthesised (up to 77% ee) via a chiral tertiary amine-promoted
nucleophilic aziridination of a,b-unsaturated ketones utilising in situ generated N–N ylides (aminimines).
A wide range of chiral tertiary amines were synthesised and evaluated, allowing structure–activity rela-
tionships to be drawn. The most efficient promoter for asymmetric aziridination, quinine, was assessed
with several enones to ascertain the effect of substrate structure on product ee, while the intermediate
hydrazinium salt was characterised by X-ray crystallography.
Received 12 September 2013
Accepted 8 November 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
N–N ylides (referred to in the literature as aminimines or aminimides)
as nucleophilic nitrene equivalents. This type of aziridination was
Aziridines are present in several biologically active natural
products1 as well as representing versatile building blocks for syn-
thetic manipulation,2–4 and their enantioselective preparation is
therefore an important challenge.2 Whilst several strategies for
aziridine synthesis are in principle available, a potentially powerful
approach involves the direct enantioselective transfer of a nitrene
equivalent to an alkene precursor. Indeed, the addition of electro-
philic metal nitrenoids to alkenes has been well documented.2
These reactions have proved applicable to the enantioselective
first reported by Ikeda in 1980,10 and subsequent studies by both
ourselves11 and Xu12 have shown that aminimines generated by
the deprotonation of pre-formed hydrazinium salts can effect the
aziridination of a variety of aromatic
a,b-unsaturated ketones
(chalcones) in high yields. The co-product of these aziridination
reactions is a tertiary amine. A significant development came when
it was demonstrated independently by both Shi13 and ourselves14
that aziridination can be effected via the in situ amination of ter-
tiary amines in the presence of a base. The tertiary amine promoter
is typically N-methylmorpholine (NMM) (25–100 mol %) and in
our work, the electrophilic nitrogen source is O-diphenylphos-
phinyl hydroxylamine 1 (DppONH2). This is suggested to form
the reactive N–N ylide in situ, delivering the aziridine via a conju-
gate addition-ring-closure process (Scheme 1). We have shown
aziridinations of styrenes,3
a,b-unsaturated compounds including
cinnamate esters,4 chalcones5 and more recently vinyl ketones.6
On the other hand, the direct enantioselective preparation of azir-
idines from alkenes via the use of nucleophilic nitrene equivalents
has, until relatively recently, received less attention. Phase-transfer
catalysts have been employed with nucleophilic nitrene equiva-
lents for the aziridination of certain electron-deficient alkenes
but, in general, only moderate levels of asymmetric induction have
thus far been realised.7 More recently, the use of both primary and
secondary aminocatalysts, via presumed iminium activation, has
led to the enantioselective preparation of aziridines from
that a variety of a,b-unsaturated carbonyl compounds can be azir-
idinated to give trans-N-unsubstituted aziridines diastereoselec-
tively.14–16 Developing enantioselective versions of these
processes by replacing NMM with a chiral amine is of great poten-
tial interest and importance. We initially reported14 a preliminary
result with a single chiral amine, quinine: (E)-chalcone 2a was
aziridinated with a promising level of asymmetric induction (56%
ee). This prompted the further studies described herein, in which
a wider range of chiral tertiary amines and substrates was
evaluated.
a
,b-unsaturated aldehydes8 and -ketones,9 and notably excellent
levels of enantioselectivity can be observed. However, the
previously reported methods usually deliver N-protected aziridines;
in the case of metal nitrenoids, this commonly means N-sulfonyl-
aziridines, protecting groups that can be difficult to remove. In
contrast, racemic N-unsubstituted aziridines can be prepared using
2. Results and discussion
Our previous studies of (E)-chalcone aziridination with
DppONH2 showed that aziridination does not take place in the
⇑
Corresponding author. Tel.: +44 02075945876.
E-mail address: A.Armstrong@imperial.ac.uk (A. Armstrong).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.008
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2
A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Proposed mechanism:
Previous work:
R3N = quinine
O
P
H
N
O
O
H
O
NH2
N
R3N
(25-100 mol%)
Ph
O
Ph
Ph
Ph
Ph
Ph
DppONH2
R1
R2
1
64% yield, 56% ee
This work:
2a
+
-
R3N NH2
Ph2PO2
H
N
O
O
*R3N
R1
R2
R1
R2
O
R1
base
R2
-
+
· investigation of
substrate scope
· investigation of
catalyst SARs
R3N-NH
aminimine
Scheme 1. Organocatalytic alkene aziridination using N-N ylides.
Table 1
Initial screening of chiral tertiary amines as promoters for the asymmetric aziridination of chalcone 2a
NMP framework:
NMM framework:
OR
quinuclidine framework:
TsN
OMe
Ph
Ph
N
N
O
Quinine,
N
14a
OH
7, R = TBDPS
8, R = H
N
4
OH
N
N
N
RO
11
O
MeO
OMe
6
N
O
N
H
N
9, R = Ph
(-)-Sparteine,
N
N
10, R = CH2OH
13
Ph
12
5
R
H
H
N
O
O
R3N (1.05 eq.), DppONH2 (1.05 eq.), MeCN, 0.5 h
Ph
Ph
Ph
Ph
then NaOH (2 eq.), chalcone, 16 h
3a
2a
Entrya
R3N
Yieldb (%)
eec (%)
Aziridine enantiomerd
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
11
12
75
<5
81
<5
5
<5
12
67
<5
23
59
64
4
—
6
—
14
—
<5
23
—
37
46
56
(2S,3R) (+)
—
(2S,3R) (+)
—
(2S,3R) (+)
—
(2S,3R) (+)
(2R,3S) (ꢀ)
—
9
10
11
12e
(ꢀ)-Sparteine, 13
(2S,3R) (+)
(2R,3S) (ꢀ)
(2R,3S) (ꢀ)
Quinine, 14a
Quinine, 14a
a
b
c
Reactions performed on a 0.12–0.24 mmol scale.
Isolated yield after purification by column chromatography.
Enantiomeric excess (ee) measured by HPLC analysis (conditions: 93:7 hexane:IPA, 0.8 mL/min, 254 nm, AD-H) (2S,3R, tR = 13.1 min, 2R,3S, tR = 15.0 min).
d
e
Configuration of the major enantiomer was determined by comparison to the literature.17
NaH/i-PrOH was used as the base, CH2Cl2 as the reaction solvent.14
absence of the tertiary amine promoter and that cyclic (aliphatic)
tertiary amines generally provided higher yields of aziridine than
acyclic tertiary amines.14 Thus we identified the N-methylmorpho-
line (NMM), N-methylpyrrolidine (NMP) and quinuclidine frame-
works as effective tertiary amines promoters for aziridination
(Scheme 1).14 In our search for a chiral tertiary amine capable of
delivering asymmetric aziridination, we began by surveying read-
ily accessible chiral derivatives of these frameworks, selecting (E)-
chalcone 2a as our model substrate (Table 1).
Based on the NMP framework, various pyrrolidine derivatives
were screened, which included 4, C2-symmetric derivative 5 and
diamine 6.18 However, only low levels of asymmetric induction
were observed in all cases (<10% ee) and with varying levels of
reactivity (entries 1–3). Switching to the NMM framework, a di-
verse range of chiral NMM derivatives were synthesised, including
C2-symmetric NMMs19 7 and 8, chiral N-pendant morpholines20
9
and 10, 3-substituted NMM21 12 and chiral piperazine 11. How-
ever, with the exception of piperazine 11, the reactivities of these
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A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
1,4-heterocycles were low, which we found to be closely related to
steric hindrance around the N-centre. In all cases, levels of asym-
metric induction were also low (up to 23% ee) (entries 4–9). The
commercially available alkaloid (ꢀ)-sparteine 13 was also
screened but again provided a low yield of aziridine (23%) and only
moderate levels of asymmetric induction (37% ee) (entry 10). The
cinchona alkaloid quinine 14a however, based upon the reactive
quinuclidine framework, showed promising levels of both reactiv-
ity (59%) and asymmetric induction (46% ee) (entry 11). As indi-
cated in our initial report, this could be improved upon by using
NaH/i-PrOH as the base with CH2Cl2 as the reaction solvent (entry
12).14 In light of this promising result and the ready access to sev-
eral cinchona alkaloid derivatives either commercially or via syn-
thetic modification, we decided to continue our investigations
with this class of tertiary amine, seeking to explore the effects of
structural modification on the enantioselectivity (Table 2).
Pseudoenantiomeric quinidine 14b was found to promote azir-
idination in a lower yield but comparable ee (50% ee) to quinine
14a and, as expected, was selective for the opposite aziridine enan-
tiomer (entry 2 vs 1). Cinchonidine 15a and cinchonine 15b, devoid
of the 6-methoxy group on the quinoline ring, gave lower levels of
ee (42% and 41% ee, respectively) (entries 3 and 4). Hydro-quinine
16a and –quinidine 16b were also less effective promoters in terms
of both yield and ee compared to their parent vinyl derivatives
(entries 5 and 6 vs 1 and 2). Quincorine 17a and quincoridine
17b, devoid of the C9-stereocentre and quinoline moiety, both gave
racemic aziridines indicating the importance of these groups in
terms of asymmetric induction (entries 7 and 8).
In light of the apparent importance of the C9-substituent, we
decided to screen a range of C9-modified quinine derivatives. Sev-
eral of these were prepared (Scheme 2).
Following reported procedures, we initially prepared O-Me
derivative 18,22 alkylated derivative 19,23 oxidised quininone
2024 and the fluorinated cinchona alkaloids 21a and its 9-epimer
21b.25 To allow testing of the importance of the C9-configuration,
we also prepared 9-epi-quinine 22 by hydrolysis of the mesylate
of the quinine according to conditions reported by Hoffmann.26
Similarly, the 9-epi primary amine 23b was obtained from quinine
following literature procedures reported by Brunner,27 via inver-
sion with diphenylphosphoryl azide (DPPA), followed by an
in situ Staudinger reduction. Amine 23b then served as precursor
to the corresponding C9-epi acetamide 24b, sulfonamide 25b and
thiourea derivative 26.28,29 In order to complement this C9-epi ser-
ies of hydrogen bond donor alkaloids, the corresponding members
of the natural C9-series were also synthesised. The required substi-
tution of 9-epi-quinine 22 with inversion to give amine 23a proved
challenging; indeed, attempted synthesis by following the proto-
cols adopted for the corresponding 9-epi-amino-derivative 23b
failed to afford any detectable traces of the desired compound
but instead yielded the elimination product 27 (single geometric
isomer; configuration not assigned). Modified reaction conditions
involving prolonged heating after addition of DPPA did afford
amine 23a, although in low yield (22%). Further functionalisation
then provided the novel N-acyl 24a and N-tosyl 25a derivatives.
These cinchona alkaloid derivatives were screened for the azir-
idination of chalcone (Table 3). The two compounds with sp2-
hybridisation at C9, ketone 20 and alkene 27, did not significantly
promote aziridination (entries 1 and 2). All of the C9-epi-deriva-
tives, irrespective of the C9-substituent, afforded very low enanti-
oselectivities (<14% ee, entries 3–8). Yields were also generally
very low, with the exception of the C9-epi-amino compound
23b.30,31 In this particular case, a possible explanation for the
low enantioselectivity could be that amination with DppONH2 pro-
ceeded on the primary amine; however, 1H NMR experiments in
the absence of enone suggested that only the tertiary amine was
being aminated. Overall, these poor results with C9-epi-derivatives
suggest that the natural cinchona alkaloid C8–C9 relative configu-
ration is essential for the reactivity and enantioselectivity.
Table 2
Screening of commercially available cinchona alkaloids for the asymmetric aziridin-
ation of chalcone
3
R
2
4
R
7
5
OH
)
(8S)
(9R)
N
1
6
(
9S
N
(8R)
OH
N
N
quinidine, R = OMe, 14b
cinchonine, R = H,15b
quinine, R = OMe, 14a
cinchonidine, R = H, 15a
Returning to derivatives with the natural C9-configuration, we
were disappointed that a very low conversion was observed with
the C9-fluoride 21a (entry 9). The C9-amine 23a was more encour-
aging (entry 10): a moderate yield (42%) and enantioselectivity
(35% ee) was observed. Interestingly, the major aziridine configu-
ration was the opposite to that observed with quinine itself, which
may indicate a role for the quinine 9-hydroxyl as a hydrogen bond
donor to the enone substrate (see later for discussion). However,
the acetamide 24a and sulfonamide 25a derivatives, also bearing
potential hydrogen bond donors, were essentially inactive, sug-
gesting that steric hindrance at C9 is detrimental to reactivity (en-
tries 11 and 12). In order to further probe the role of the C9
hydroxyl, we tested the C9-OMe derivative 18, which has previ-
ously been employed in an organocatalytic cyclopropanation reac-
tion involving C–N ylides.22 The introduction of the methyl group
at the 2-position of the quinoline ring was suggested to lower
the nucleophilicity of the quinoline nitrogen, thus favouring reac-
tion at the quinuclidine nitrogen. Conceivably, the incomplete con-
version in our aziridination chemistry using quinine could also be
due in part to competing amination at the quinoline nitrogen (not-
withstanding the observation, noted earlier, that amine 23b
appeared to be aminated selectively at the quinuclidine centre).
However, 18 displayed both poor reactivity and also poor levels
of asymmetric induction as a promoter for aziridination (entry
N
N
HO
HO
17b
quincoridine,
quincorine, 17a
O
H
N
O
R3N (1.05 eq.), DppONH2 (1.05 eq.), CH2Cl2, 0.5 h
Ph
Ph
Ph
Ph
then NaH/i-PrOH (2 eq.), chalcone, rt, 16 h
2a
Entrya R3N
3a
Yieldb (%) eec (%) Aziridine enantiomerd
1
2
3
4
5
6
7
8
Quinine, 14a
64 56
31 50
38 42
42 41
49 50
32 30
(2R,3S) (ꢀ)
(2S,3R) (+)
(2R,3S) (ꢀ)
(2S,3R) (+)
(2R,3S) (ꢀ)
(2S,3R) (+)
—
Quinidine, 14b
Cinchonidine, 15a
Cinchonine, 15b
Hydroquinine, 16a
Hydroquinidine, 16b
Quincorine, 17a
Quincoridine, 17b
44
85
0
0
—
a
b
c
Reactions performed on a 0.12 mmol scale.
Isolated yield after purification by column chromatography.
Enantiomeric excess (ee) measured by HPLC analysis.
d
Configuration of major enantiomer determined by comparison to the
literature.17
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4
A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
OMe
N
OMe
N
OMe
N
OMe
N
OMe
N
N
N
N
O
N
N
F
OH
OMe
F
18
19
20
21a
21b
ref. 22
ref. 23
ref. 24
ref. 25
ref. 25
OMe
N
(vi)
N
27
OMe
N
OMe
N
OMe
N
OH
N
N
N
(viii)
(vii)
9-epiquinine, 22
NHR
NH2
or (ix)
24a, R = Ac
25a, R = Ts
23a
(v)
ref. 29
OMe
OMe
OMe
N
N
N
N
(i)
ref. 32
(ii), (iii)
or (iv)
NHR
OH
NH2
N
24b, R = Ac
25b, R = Ts
N
23b
quinine, 14a
26
NHAr
, R =
S
-
(Ar = 3,5 (CF3)2C6H3)
Scheme 2. Synthesis of C9-functionalised cinchona alkaloids. Reagents and conditions: (i) PPh3, DIAD, (PhO)2P(O)N3, THF, rt, 3 h; PPh3, 50 °C, 1 h; H2O, rt, 16 h, 55%; (ii) AcCl,
Et3N, CH2Cl2, 0 °C to rt, 18 h, 78%; (iii) K2CO3, TsCl, CH2Cl2, rt, 16 h, 69%; (iv) 3,5-(CF3)2C6H3NCS, THF, rt, 18 h, 62%; (v) MsCl, Et3N, THF, 70 °C, 4 h, 98%; -tartaric acid, H2O,
L
100 °C, 1 h, 79%; (vi) PPh3, DIAD, (PhO)2P(O)N3, THF, rt, 3 h; PPh3, 50 °C, 1 h; H2O, rt, 16 h, 47%; (vii) PPh3, DIAD, (PhO)2P(O)N3, THF, rt to 45 °C 5 h; PPh3, 45 °C, 1 h; H2O, rt,
16 h, 22%; (viii) AcCl, Et3N, CH2Cl2, 0 °C to rt, 18 h, 83%; (ix) K2CO3, TsCl, CH2Cl2, rt, 16 h, 71%.
Table 3
Asymmetric aziridination of chalcone with C9-modified quinine derivatives
Entrya
R3N
C9-substituent
C9 config.b
Yieldc (%)
eed (%)
Aziridine enantiomere
1
2
3
4
5
6
7
8
20
27
22
—
—
Epi
Epi
Epi
Epi
Epi
Epi
Natural
Natural
Natural
Natural
Natural
Natural
16
<5
28
62
8
<5
<5
8
<5
42
<5
<5
8
<5
—
11
<5
14
—
—
10
—
35
—
—
7
37
(2S,3R) (+)
—
(2S,3R) (+)
(2S,3R) (+)
(2S,3R) (+)
—
OH
23b
24b
25b
26
21b
21a
23a
24a
25a
18
NH2
NHAc
NHTs
C(S)NHAr
F
—
(2S,3R) (+)
—
(2S,3R) (+)
—
9
F
10
11
12
13f
14
NH2
NHAc
NHTs
OMe
OH
—
(2R,3S) (ꢀ)
19
38
(2R,3S) (ꢀ)
a
b
c
d
e
f
Reactions performed on a 0.12–0.14 mmol scale using the conditions shown in Table 2.
Relative to quinine.
Isolated yield after purification by column chromatography.
Enantiomeric excess (ee) measured by HPLC analysis.
Configuration of major enantiomer determined by comparison to the literature.17
NaOH was used as the base.
13). The related derivative 19, also bearing a 2-alkyl substituent on
the quinoline but now possessing the free C9 hydroxyl functional-
ity, showed greater activity and selectivity as a promoter for the
aziridination (38%, 37% ee) (entry 14), although surprisingly its
performance was worse than that of its parent, quinine (compare
Table 2, entry 1).
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A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
Considering further modification of the cinchona alkaloid motif,
we were interested in derivatives that may be less conformational-
ly flexible, yet without presenting undue steric hindrance around
the reacting quinuclidine N-centre, which we believed to be a
problem with many C9-functionalised derivatives. b-Isocupreidine
(b-ICD) 28a, which possesses a rigid tricyclic structure, was an
attractive option and it and its derivatives have been shown to
be effective catalysts for enantioselective Morita-Baylis-Hillman
reactions.32 b-ICD 28a was obtained from quinidine 14b via proce-
dures described by Hatakeyama.33 Since this process not only pro-
motes cyclisation but also demethylates the quinoline methoxy
group, methyl ether 28b and the novel benzyl ether 28c were also
prepared (Scheme 3). All were then screened for the aziridination
of chalcone (Table 4).
deprotonated and this competing consumption of base may affect
the desired deprotonation of the in situ generated hydrazinium salt
required for the ylide formation (see Scheme 1). The methyl ether
28b circumvents this problem and showed a substantial increase
in both yield (54%) and ee (37% ee) of the aziridine product (entry
2). The sterically bulkier aromatic O-benzyl ether 28c again pro-
vided a moderate yield (47%) with a slight increase in ee (43%
ee) (entry 3). Interestingly, the configuration of the major aziridine
afforded with the amines 28b and 28c was the opposite of that
afforded by their parent, quinidine. This may again support the
possible role of the quinine/quinidine C9-hydroxyl as a hydrogen
bond donor (vide infra).
After extensive screening of chiral tertiary amines, quinine re-
mained the most favourable promoter in terms of asymmetric
induction in the aziridination reaction and so we were keen to
investigate potential relationships between the substrate structure
and product enantioselectivity. Quinine was therefore screened
b-ICD 28a promoted aziridination with low yield (28%) and ex-
tremely poor ee (5% ee) (entry 1). However, under the basic reac-
tion conditions, the phenolic moiety of b-ICD is likely to be
with
a range of electron-rich and electron-poor chalcones
(Table 5).
Asymmetric induction was found to be lowered for substrates
with electron withdrawing substituents (entries 4, 5 and 8). How-
ever, higher enantiomeric excesses were observed when electron
donating groups were present at the ketone aromatic (entries 6
and 7), with 4-methoxyphenyl aziridine 3f being obtained in 66%
ee. To probe this effect further, a variety of enones possessing elec-
tron rich heteroaromatics at the ketone were also screened with
quinine (Table 6).
O
O
(i)
(ii)
N
N
quinidine,
15b
or (iii)
ref. 37
N
N
OH
OR
28b, R = Me
28c, R = Bn
β-Isocupreidine (β-ICD)
28a
Scheme 3. Synthesis of b-isocupreidine 28a and derivatives 28b–c. Reagents and
conditions: (i) KBr, 85% H3PO4, 100 °C, 10 d, 54%; (ii) TMSCHN2, C6H6/MeOH (3:2),
rt, 3 h, 43%; (iii) NaH, THF, 0 °C, 10 min, BnBr, TBAI, 0 °C to 40 °C, 16 h, 20%.
Table 6
Asymmetric aziridination of heteroaromatic-substituted enones with quinine
O
R3N (1.05 eq.), DppONH2 (1.05 eq.)
CH2Cl2, 0.5 h
H
N
O
X
X
Table 4
Ph
Ph
then NaH/i-PrOH (2.0 eq.)
substrate, 16 h
Asymmetric aziridination of chalcone with b-isocupreidine 28a and derivatives 28b–c
R
R
2j-m
3j-m
Entrya
R3N
Yieldb (%)
ee (%)c
Aziridine enantiomerd
14a
R3N = quinine,
1
2
3
28a
28b
28c
28
54
38
5
37
43
(2R,3S) (ꢀ)
(2R,3S) (ꢀ)
(2R,3S) (ꢀ)
Entrya
R
Aziridine
Yieldb (%)
eec,d (%)
1
2
3
4
2-Furyl
2-Thiophenyl
4-Methyl-2-Thiophenyl
5-Chloro-2-thiophenyl
3j
3k
3l
41
47
46
27
71 (ꢀ)
72 (ꢀ)
77 (ꢀ)
64 (ꢀ)
a
Reaction performed on
Table 2.
a 0.12 mmol scale using the conditions shown in
3m
b
Isolated yield after purification by column chromatography.
Enantiomeric excess (ee) measured by HPLC.
c
a
b
c
Reaction performed on a 0.11–0.22 mmol scale.
Isolated yield after purification by column chromatography.
Enantiomeric excess (ee) measured by HPLC.
d
Configuration of major enantiomer determined by comparison to the
literature.17
d
The configuration of the major enantiomer assigned as (2R,3S) by analogy to the
aziridination of chalcone with quinine.
Table 5
Asymmetric aziridination of electron-rich and electron-poor chalcones with quinine
O
H
N
O
quinine (1.05 eq.), DppONH2 (1.05 eq.),
CH2Cl2, 0.5 h
then NaH/i-PrOH (2.0 eq.),
R1
R2
substrate, 16 h
R1
R2
3a-h
2a-h
Entrya
R1
R2
Aziridine
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
3a
3b
3c
3d
3e
3f
64
35
55
54
43
48
68
62
56 (2R,3S) (ꢀ)
55 (ꢀ)
MeO
Me
Cl
NO2
H
52 (ꢀ)
48 (ꢀ)
H
37 (ꢀ)
MeO
Me
Cl
66 (ꢀ)
H
H
3g
3h
59 (ꢀ)
46 (ꢀ)
a
b
c
Reaction performed on a 0.12–0.13 mmol scale.
Isolated yield after purification by column chromatography.
Enantiomeric excess (ee) measured by HPLC.
d
The configuration of the major enantiomer assigned as (2R,3S) in analogy to the aziridination of chalcone with quinine.
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6
A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
With heteroaromatic enones 2j–m, the observed levels of asym-
Pathway A (favoured)
metric induction (64–77% ee) were found to be consistently higher
than that of chalcone 2a (56% ee) in the aziridination. The more
electron rich aromatics (entries 1–3) afforded products with higher
ee than the 5-chloro-2-thiphenyl system (entry 4). The 4-methyl-
2-thiophenyl derivative 3l afforded the highest ee to date (77%
ee) (entry 3). These results indicate that varying the ketone aro-
matic substituent is a productive approach to improving the
enantioselectivity.
+
N
OH
H
N
O
(S)
NH
O
Ph
Ph
H
(R)
N
Ph
OMe
(2R, 3S)-major enantiomer
Figure 2. Proposed model for asymmetric aziridination with quinine.
Despite screening a range of tertiary amine promoters, none of
these afforded a higher enantioselectivity than quinine itself.
Rational improvement requires a more detailed study of the mech-
anism of the reaction. While this is presumed to involve a stepwise
conjugate addition of the aminimine intermediate to the enone
followed by ring closure, we currently do not know which of
these steps is rate/product determining. The addition step may
be irreversible and enantiomer determining; alternatively, it may
be reversible, with the enantioselectivity being controlled by the
relative rates of ring closure of diastereomeric intermediates. The
observation that electron poor enones are generally more reac-
tive11 suggests that the addition step is more likely to be rate-
and enantiomer determining. Consideration of the ground state
conformation of the aminimine may therefore be relevant. The pre-
ferred conformation of quinine itself is the so called anti-open con-
formation, both in solution34 and the solid state35 (where anti
denotes a C40a–C40–C9–C8 torsion angle of +90 deg, and open indi-
cates an N1–C8–C9–C40 torsion angle of 180 deg). We were pleased
to be able to isolate the precursor to our likely aminimine interme-
diate, the N-aminated quinine 29, as its tetraphenylborate salt,
crystals of which were suitable for analysis by X-ray crystallogra-
phy.36 The conformation of N-aminoquininium 29 was found to
be similar to that of the parent quinine, that is, anti-open (Fig. 1).
While the conformation of the aminimine intermediate may differ,
particularly in the transition state, this information may prove use-
ful in future catalyst design. In constructing a TS-model based on
this structure, a key question is whether the C9-hydroxy group acts
as a hydrogen bond donor towards the enone substrate. Jørgensen
has postulated this mode of hydrogen bonding in the transition
state of aza-Michael additions of hydrazones to cyclic enones pro-
moted by various cinchona alkaloids.37 In attempting to gain evi-
dence for this interaction from our own results, unfortunately
the most direct hydroxyl replacements, the 9-fluorocompound
21a and the dimethylated quinine 18, both afforded very low
yields (Table 3). However, tentative support for the H-bond comes
from the results with the 9-amino derivative 23a, where a steri-
cally comparable but much weaker H-bond donating C9-substitu-
ent than the hydroxyl afforded the opposite major aziridine
enantiomer to the quinine itself. The observation that b-ICD deriv-
atives 28, which are conformationally locked in the ‘open’ confor-
mation, but devoid of the C9-hydroxyl, give the opposite major
aziridine enantiomer relative to their parent, quinidine, is also con-
sistent with this idea. On this basis, we propose a tentative TS-
model to account for the observed major aziridine enantiomer
(Fig. 2). This model places the substrate C1-aromatic group in close
proximity to the quinoline ring, which is consistent with the ob-
served importance of this substrate substituent (as seen in
Table 6).
3. Conclusion
In conclusion, a detailed examination of the factors affecting the
enantioselective tertiary amine-promoted nucleophilic aziridin-
ation of
a,b-unsaturated ketones utilising in situ generated N–N
ylides (aminimines) has been conducted. We have prepared and
screened a wide range of structurally diverse chiral tertiary amines
and evaluated them as enantioselective organocatalysts. Quinine was
the most favourable promoter examined in terms of asymmetric
induction. Through structural derivatisation, correlations between
substrate structure and observed levels of enantioselectivity and
analysis of the preferred conformation of a reaction intermediate
we have been able to propose a preliminary transition state
model for enantioselective aziridination. In terms of future catalyst
development, this TS-model suggests that variation of the
quinoline ring to optimise the interaction with enone substituents
may be
a fruitful endeavour. In addition, further structural
variation on the b-ICD framework merits future investigation.
4. Experimental
4.1. General
Anhydrous acetonitrile and benzene were used as commercially
supplied; methanol, CH2Cl2 and THF were purified by passage
through an alumina solvent purification column. DMF was dried
over MgSO4 before distillation under reduced pressure over 4 Å
molecular sieves. All commercial reagents were used as supplied
unless otherwise stated. Reactions were run under a positive pres-
sure of argon in oven dried glassware with magnetic stirring. Reac-
tion temperatures were recorded as bath temperatures. Flash
column chromatography was carried out using silica gel, particle
size 40–60 lm. Analytical thin layer chromatography (TLC) was
performed using glass backed plates pre-coated with silica gel 60
F254. Melting points were obtained using a hotplate microscope
and are uncorrected. Infrared analyses were recorded using ATR.
NMR analyses were recorded at 400 or 500 MHz in CDCl3 or
D4-MeOD as specified. Chemical shifts are quoted in ppm relative
to TMS (as referenced to residual solvent, for example, CHCl3 dH
7.26 or CDCl3 dC 77.0), with coupling constants quoted in Hz and
reported to the nearest 0.1 Hz (1H NMR). 13C assignments, where
given, are based on HSQC, HMBC and DEPT-135 experiments. Mass
spectrometry analyses were carried out using CI+ (NH3), ES+ or EI+.
Specific rotations (a0) were recorded on a polarimeter, cell path
length (l) 0.5 dm, at the stated temperature (°C) and concentration
(c) measured in units of g/100 mL; specific rotations were con-
-
+
N
. BPh4
OH
NH2
N
H
OMe
verted to optical rotations [a] via the equation: [a]
D = (100.a0)/
29
D
(l.c). The enantiomeric excesses (ee) of the aziridines prepared
were measured by HPLC analysis (conditions: 93:7 hexane/IPA;
0.8 mL/min; 254 nm; AD-H column).
Figure 1. X-ray crystal structure of the cation present in the crystals of N-
aminoquininium tetraphenylborate 29.36
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A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
7
4.2. Preparation of tertiary amine catalysts
1667, 1590, 1472, 1428, 1391, 1361, 1307, 1275, 1260, 1112 br,
1022, 1000, 937, 824, 739, 701, 614, 505; dH (400 MHz, CDCl3)
7.66–7.63 (8H, m, 8 ꢂ PhH), 7.45–7.34 (12H, m, 12 ꢂ PhH),
3.82–3.75 (4H, m, 2 ꢂ CH2OR), 3.69–3.63 (4H, m, 2 ꢂ CH2OR),
2.66 (2H, br, 2 ꢂ CHN), 2.13 (3H, s, NCH3), 1.03 (18H, s,
2 ꢂ SiC(CH3)3); dC (100 MHz, CDCl3) 135.5, 133.4, 129.7, 127.7,
69.0, 60.3, 59.5, 40.10, 26.8, 19.1; m/z (EI+) 637 (M+, 3%), 368
(100); HRMS (ES+) MH+ calculated for C39H52NO3Si2 638.3486, ob-
served 638.3488.
(ꢀ)-Sparteine and cinchona alkaloids 14–17a,b were obtained
commercially and used as supplied. Amines 4,38 9,20 alkaloids
18,22 19,23 20,24 22,26 23b,27 2628 and 28a33 were prepared accord-
ing to literature procedures, with data in agreement with those
reported. All other tertiary amines were prepared, according to
the following procedures.
4.2.1. (2S,5S)-2,5-Bis(methoxymethyl)-1-methylpyrrolidine 5
Formaldehyde (0.12 mL, 1.57 mmol, 37% aqueous) was added to
a solution of commercially available (2S,5S)-(+)-2,5-bis(methoxy-
methyl)pyrrolidine (50 mg, 0.31 mmol) in MeOH (5 mL) and stir-
red for 5 min. Next, Pd/C (10 mg, 10% wt.) was added in one
portion and the mixture was stirred under an atmosphere of H2
for 15 h. The reaction mixture was then filtered through Celite
and washed with CH2Cl2. The filtrate was then concentrated in va-
cuo and purified by flash column chromatography (CH2Cl2 to 10%
MeOH/CH2Cl2) to afford 5 (38.1 mg, 70%) as a pale yellow oil;
4.2.4. (3S,5S)-3,5-Bis(hydroxymethyl)-4-methylmorpholine 8
Tetra-n-butylammonium fluoride in THF (3.5 mL of a 1 M solu-
tion) was added to a stirred solution of morpholine 7 (310 mg,
0.48 mmol) in THF (1.5 mL) at 0 °C. The mixture was then allowed
to warm to room temperature and stirred overnight. The solution
was concentrated in vacuo and purified by flash column chroma-
tography (10% MeOH/EtOAc) to afford 8 (63 mg, 80%) as a colour-
less oil; Rf: (20% MeOH/EtOAc) 0.20;
½
a 2D2
ꢁ
¼ þ30:4 (c 1.25,
CHCl3); mmax (neat)/cmꢀ1 3312 br, 2958, 2886, 2861, 1574, 1457,
1365, 1270, 1125, 926, 883, 844, 774, 698; dH (400 MHz, CDCl3)
3.86 (2H, dd, J 10.8 and 5.7, CH2OR), 3.79 (2H, dd, J 11.6 and 6.1,
CH2OR), 3.73 (2H, dd, J 11.6 and 3.5, CH2OR), 3.64 (2H, dd, J 11.2
and 3.4, CH2OR), 3.12 (2H, br), 2.84 (2H, br), 2.51 (3H, s, CH3); dC
(100 MHz, CDCl3) 67.9, 58.8, 58.2, 38.5; m/z (EI+) 161 (M+, 2%),
130 (M+ –CH2OH, 100); HRMS (ES+) MH+ calculated for C7H16NO3
162.1130, observed 162.1129.
½
a 2D8
ꢁ
¼ ꢀ51:4 (c 0.55, CHCl3); mmax (neat)/cmꢀ1 3360, 2970, 2875,
1660, 1465, 1115, 900; dH (400 MHz, CDCl3) 3.52 (2H, dd, J 10.1
and 5.1, CH2OMe), 3.45 (2H, dd, J 10.1 and 4.3, CH2OMe), 3.38–
3.35 (2H, m, 2 ꢂ CHCH2OMe), 3.35 (6H, s, 2 ꢂ °CH3), 2.64 (3H, s,
NCH3), 2.10–2.05 (2H, m, CH2CH), 1.77–1.74 (2H, m, CHCH2); dC
(100 MHz, CDCl3) 72.9, 63.8, 59.2, 35.9, 26.8; m/z (CI+ (NH3)) 174
(MH+, 100%); HRMS (CI+ (NH3)) MH+ calculated for C9H20NO2
174.1494, observed 174.1494.
4.2.5. (S)-2-Morpholin-4-yl-propan-1-ol 10
4.2.2. (S)-2-((S)-1-Isopropylpyrrolidin-2-yl)-1-methylpyrrolidine 6
Prepared using (S)-2-aminopropanol by following the reported
Formaldehyde (0.12 mL, 1.57 mmol, 37% aqueous) was added to
procedure for the synthesis of 9 by Oda;20 yellow oil; Rf: (1%
a
solution of (2S,5S)-(+)-2,5-bis(methoxymethyl)pyrrolidine
MeOH/CH2Cl2) 0.50; ½a D22
¼ þ40:4 (c 0.94, CHCl3); mmax (ATR)/
ꢁ
(50.5 mg, 0.28 mmol) (prepared and donated by the laboratories
of Alexakis18) in MeOH (5 mL) and stirred for 5 min. Next, Pd/C
(10 mg, 10% wt.) was then added in one portion and the mixture
was stirred under an atmosphere of H2 for 15 h. The reaction mix-
ture was then filtered through Celite and washed with CH2Cl2. The
filtrate was then concentrated in vacuo and purified by flash col-
umn chromatography (CH2Cl2 to 10% MeOH/CH2Cl2) to afford 6
cmꢀ1 3436 br, 2968, 2860, 1453, 1265, 1156, 1114, 1038, 960,
916, 872, 849, 731; dH (400 MHz, CDCl3) 3.76–3.66 (4H, m, 2 ꢂ
CH2OR), 3.42 (1H, dd, J 10.4 and 5.0, CHHOH), 3.32 (1H, t, J 10.4,
CHHOH), 2.77 (1H, m, NCH(CH2OH)), 2.69–2.62 (2H, m, CH2NR2),
2.39–2.43 (2H, m, CH2NR2), 0.92 (3H, d, J 6.7, CH3); dC (100 MHz,
CDCl3) 67.3, 62.1, 60.3, 48.1, 9.5; m/z (EI+) 145 (M+, 2%), 114 (M+
–CH2OH, 100); HRMS (ES+) MH+ calculated for C7H16NO2
146.1181, observed 146.1186.
(35 mg, 65%) as a pale yellow oil; ½a D20
¼ ꢀ62:8 (c 0.51, CHCl3); mmax
ꢁ
(neat)/cmꢀ1 2962, 2854, 2812, 1452, 1365, 1330, 1260, 1177, 1116,
1068, 978, 917, 873; dH (400 MHz, CDCl3) 3.19–3.02 (4H, m, NCH2
and 2 ꢂ CHN), 2.60–2.53 (2H, m, NCH2), 2.42 (3H, s, NCH3), 2.22
(1H, m, CH(CH3)2), 1.85–1.61 (8H, m, 4 ꢂ CH2), 1.18 (3H, d, J 6.7,
CH(CH3)3), 1.18 (3H, d, J 6.7, CH(CH3)3); dC (100 MHz, CDCl3) 68.0,
61.3, 57.9, 50.6, 47.4, 41.7, 26.4, 26.2, 23.9, 23.1, 21.9, 15.5; m/z
(CI+ (NH3)) 197 (MH+, 25%), 285 (100); HRMS (CI+ (NH3)) MH+ cal-
culated for C12H25N2 197.2018, observed 197.2022.
4.2.6. (2S)-1,2-Dimethyl-4-(para-toluenesulfonyl)piperazine 11
Triethylamine (190 ll, 1.37 mmol) was added to a solution of
commercially available (S)-(+)-2-methylpiperazine (125 mg,
1.25 mmol) in CH2Cl2 (7 mL) at 0 °C and stirred for 5 min. p-Tolu-
enesulfonyl chloride (238 mg, 1.25 mmol) was then added and
the mixture was stirred for 1 h at 0 °C before being allowed to
warm to room temperature and stirred for a further 4 h. Water
was then added and the aqueous layer was separated and
extracted with CH2Cl2, before being washed sequentially with
1 M HCl (50 mL), water (50 mL), saturated aqueous NaHCO3 solu-
tion (50 mL) and saturated aqueous sodium chloride solution
(50 mL). The organic layer was separated, dried (Na2SO4), filtered
and concentrated in vacuo to afford tosyl piperazine, (3S)-3-
methyl-1-[(4-methylbenzene)sulfonyl]piperazine (310 mg, 97%)
as a white solid. The product could be used without further purifi-
4.2.3. 4-Methyl-(3R,5R)-3,5-bis(tert-butyldiphenylsiloxymethyl)
morpholine 7
At first, Pd(OH)2/C (20 mg, 20% wt.) was added to a solution of
(3R,5R)-3,5-bis(tert-butyldiphenylsiloxymethyl)morpholine (pre-
pared according to the procedures of Sasaki19
) (187 mg,
0.30 mmol), formaldehyde (0.1 mL, 3.6 mmol, 37% aqueous) and
acetic acid (0.1 mL, 1.8 mmol) in methanol (5 mL) and was stirred
under the presence of H2 at room temperature and atmospheric
pressure for 3 h. The catalyst was then filtered off and the filtrate
concentrated in vacuo before the addition of saturated aqueous
Na2CO3 solution (10 mL) and water (10 mL). The aqueous layer
was separated and extracted with CHCl3, washed with a saturated
aqueous sodium chloride solution (10 mL), dried (Na2SO4), filtered
and concentrated in vacuo. Purification by flash column chroma-
tography (5% EtOAc/hexane) afforded 7 (156 mg, 81%) as a colour-
cation; mp 138.5–141 °C (acetone); ½a D23
¼ þ38:9 (c 0.93, CHCl3);
ꢁ
mmax (ATR)/cmꢀ1 3352, 2971, 2922, 2863, 2821, 1605, 1452, 1325,
1165, 1133, 1121, 997, 914, 861, 811, 754s, 655; dH (500 MHz,
DMSO-d6) 7.61–7.59 (2H, m, 2 ꢂ ArH), 7.47–7.44 (2H, m, 2 ꢂ ArH),
3.41–3.37 (2H, m, CH2NTs), 2.85 (1H, dt, J 12.1 and 2.8, CH2NTs),
2.68–2.60 (2H, m, 3-H and CHHN(H)), 2.41 (3H, s, ArCH3), 2.06
(1H, td, J 11.3 and 3.1, CHHN(H)), 1.70 (1H, t, J 10.8, CHHN(H)),
0.90 (3H, d, J 6.4, 3-(CH3)); dC (126 MHz, DMSO-d6) 143.4, 131.9,
129.7, 127.5, 52.3, 49.5, 45.9, 44.3, 20.9, 18.8; m/z (CI+) 255
(MH+, 100%), 99 (M+ –Ts, 10); HRMS (CI+) MH+ calculated for
less oil; Rf: (5% EtOAc/hexane) 0.40; ½a D18
¼ þ37:2 (c 0.86, CHCl3);
ꢁ
mmax (neat)/cmꢀ1 3071, 2930, 2889, 1960, 1891, 1825, 1730,
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8
A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
C12H19N2O2S 255.1167, observed 255.1164. Pd(OH)2/C (50 mg, 20%
wt.) was added to a solution of the tosyl piperazine (123 mg,
0.48 mmol), formaldehyde (0.13 mL, 4.8 mmol, 37% aqueous) and
acetic acid (0.14 mL, 2.4 mmol) in methanol (5 mL) and was stirred
under the presence of hydrogen at room temperature and atmo-
spheric pressure for 4 h. Next, the solution was filtered and the fil-
trate concentrated in vacuo before the addition of a saturated
aqueous Na2CO3 solution (10 mL) and water (10 mL). The aqueous
layer was separated and extracted with CH2Cl2, washed with a sat-
urated aqueous sodium chloride solution (10 mL), dried (MgSO4),
filtered and concentrated in vacuo to afford 11 (99 mg, 77%) as a
white solid. The product could be used without further purifica-
4.2.8. 9-Fluoro(9-deoxy)-quinine 21a
The title compound was obtained by washing the correspond-
ing dihydrochloride salt (prepared and donated by the laboratories
Gilmour25) with 1 M aqueous NaOH. The solution was diluted with
CH2Cl2 and the organic layer was then separated, dried (Na2SO4),
filtered and concentrated in vacuo to afford amine 21a (14.7 mg)
as a colourless oil; ½a D23
ꢁ
¼ ꢀ31:1 (c 0.90 CHCl3); mmax (ATR)/cmꢀ1
3350, 2950, 2900, 1600, 1575, 1500, 1450, 1400, 1250, 1200,
1100, 1050, 1000, 900, 850, 800, 750, 600; dH (400 MHz, CDCl3)
8.77 (1H, d, J 4.5, ArH), 8.04 (1H, d, J 9.2, ArH), 7.46 (1H, d, J 4.5,
ArH), 7.39 (1H, dd, J 9.2 and 2.7, ArH), 7.16 (1H, br s, ArH), 6.50
(1H, br d, J 48.6, 9-CHF), 5.70 (1H, m, CH@CH2), 5.00–4.94 (2H,
m, C@CH2), 3.97 (3H, s, CH3), 3.49 (1H, m, CH), 3.32–3.21 (2H, m,
2 ꢂ CH), 2.86 (1H, m, CH), 2.78 (1H, m, CH), 2.39 (1H, m, CH),
1.90–1.78 (3H, m, 3 ꢂ CH), 1.63 (1H, m, CH), 1.50 (1H, m, CH); dC
(100 MHz, CDCl3) 158.3, 147.3, 144.3, 141.6, 140.7, 131.9, 125.4
tion; mp 106-108oC; ½a D23
¼ þ48:9 (c 0.45, CHCl3); mmax (ATR)/
ꢁ
cmꢀ1 2968, 2860, 2801, 1596, 1453, 1359, 1339, 1304, 1285,
1242, 1166, 1152, 1126, 1062, 1020, 992, 968, 925, 813, 802,
761, 710, 655; dH (400 MHz, CDCl3) 7.61 (2H, d, J 8.2, 2 ꢂ ArH),
7.31 (2H, d, J 7.9, 2 ꢂ ArH), 3.54 (1H, m, CHHX), 3.46 (1H, dt, J
11.0 and 2.5, 3-CH), 2.75 (1H, dt, J 11.4 and 2.9, CHHX0), 2.46 (1H,
td, J 11.1 and 2.7, CHHX), 2.41 (3H, s, CH3), 2.34 (1H, td, J 11.3
and 3.0, CHHX0), 2.23 (3H, s, ArCH3), 2.19 (1H, m, 2-H), 2.06 (1H,
t, J 10.8, 3-HH), 1.01 (3H, d, J 6.3, 2-(CH3)); dC (100 MHz, CDCl3)
143.6, 132.0, 129.6, 127.8, 56.8, 54.3, 52.1, 46.0, 42.0, 21.5, 16.6;
m/z (EI+) 268 (M+, 20%), 113 (M+ –Ts, 100); HRMS (EI+) M+ calcu-
lated for C13H20N2O2S 268.1245, observed 268.1239.
3
3
1
(d, JF,C 5.5), 122.2, 117.4 (d, JF,C 11.2), 115.1, 100.7, 92.5 (d, JF,C
2
3
174.0), 59.3 (d, JF,C 21.6), 56.5, 56.1, 43.4 (d, JF,H 5.6), 39.2, 27.6,
26.9, 20.0 (d, JF,C 5.5); dF (376 MHz, CDCl3) ꢀ198.1; HRMS (ES+)
3
MH+ calculated for C20H24N2OF 327.1868, observed 327.1873.
4.2.9. 9-Fluoro(9-deoxy)-epiquinine 21b
The title compound was obtained by washing the correspond-
ing dihydrochloride salt (prepared and donated by the laboratories
of Gilmour25) with 1 M aqueous NaOH. The solution was diluted
with CH2Cl2 and the organic layer was then separated, dried
(Na2SO4), filtered and concentrated in vacuo to afford amine 21b
4.2.7. (3S)-3-Phenyl-N-methylmorpholine 12
Phenol (360 mg, 3.82 mmol) and 45% HBr/AcOH (1.6 mL) were
added to a solution of (3S)-3-phenyl-4-(para-toluenesulfonyl)mor-
pholine (35 mg, 0.11 mmol) (prepared according to the procedures
of Aggarwal21) at 0 °C, before being warmed to room temperature
and stirred for 16 h. The reaction was cooled to 0 °C and 20% aque-
ous NaOH was cautiously added. The mixture was then diluted
with Et2O, the organic layer was separated and extracted, dried
(MgSO4), filtered and concentrated in vacuo. Purification by flash
column chromatography (15% MeOH/CH2Cl2) afforded the depro-
tected morpholine, (3S)-3-phenylmorpholine (19.4 mg, quant.) as
(15.6 mg) as a colourless oil; ½a D23
¼ þ25:3 (c 1.19, CHCl3); mmax
ꢁ
(ATR)/cmꢀ1 2936, 2865, 1621, 1508, 1475, 1455, 1433, 1361,
1227, 1081, 1029, 981, 911, 853, 748, 717, 635; dH (400 MHz,
CDCl3) 8.77 (1H, d, J 4.4, ArH), 8.05 (1H, d, J 9.1, ArH), 7.42–7.38
(3H, m, 3 ꢂ ArH), 5.86 (1H, dd, J 48.4 and 9.2, 9-CHF), 5.76 (1H,
m, CH@CH2), 5.04–4.95 (2H, m, C@CH2), 3.94 (3H, s, CH3), 3.53
(1H, m, CH), 3.35–3.25 (2H, m, 2 ꢂ CH), 2.89 (1H, m, CH), 2.79
(1H, m, CH), 2.31 (1H, m, CH), 1.72 (1H, m, CH), 1.63–1.59 (2H,
m, 2 ꢂ CH), 1.41 (1H, m, CH), 0.94 (1H, dd, J 13.6 and 7.7, CH); dC
a colourless oil; Rf: (15% MeOH/CH2Cl2) 0.35; ½a D24
ꢁ
¼ þ36:8 (c
(100 MHz, CDCl3) 157.8, 147.1, 144.7, 141.2, 140.2 (d, JF,C 18.5),
2
0.87, CHCl3); mmax (ATR)/cmꢀ1 3429, 2962, 2848, 2789, 1493,
1449, 1350, 1289, 1232, 1116, 1037, 984, 904, 880, 794, 756,
700, 650, 590; dH (400 MHz, CDCl3) 7.42–7.26 (5H, m, 5 ꢂ PhH),
3.94 (1H, dd, J 10.1 and 3.2), 3.88 (1H, dd, J 11.3 and 2.9), 3.84
(1H, dd, J 11.3 and 3.3), 3.69 (1H, td, J 11.3 and 2.7), 3.45 (1H, t, J
10.5), 3.12 (1H, td, J 11.6 and 3.3), 3.00 (1H, br dt, J 11.6); dC
(100 MHz, CDCl3) 139.8, 128.5, 127.9, 127.2, 73.2, 66.9, 60.4,
46.3; HRMS (ES+) M+ calculated for C10H14NO 164.1075, observed
164.1064. Next, Pd(OH)2/C (10 mg, 20% wt.) was added to a solu-
tion of the deprotected morpholine (18.5 mg, 0.11 mmol), formal-
dehyde (0.1 mL, 3.6 mmol, 37% aqueous) and acetic acid (0.1 mL,
1.8 mmol) and stirred under the presence of hydrogen at room
temperature and atmospheric pressure for 5 h. The solution was
then filtered and the filtrate concentrated in vacuo before the addi-
tion of a saturated aqueous Na2CO3 solution (10 mL). The aqueous
layer was separated and extracted with CH2Cl2, washed with a sat-
urated aqueous sodium chloride solution (10 mL), dried (MgSO4),
filtered and concentrated in vacuo. Purification by flash column
chromatography (30% EtOAc/hexane) afforded 12 (16.2 mg, 83%)
131.7, 126.8 (d, JF,C 1.3), 121.7, 120.0 (d, JF,C 6.8), 114.4, 101.6,
4
3
1
2
91.2 (d, JF,C 179.4), 59.0 (d, JF,C 19.5), 55.7, 55.4, 41.3, 39.2, 27.7,
3
2
27.0, 24.3 (d, JF,C 4.4); dF (376 MHz, CDCl3) ꢀ176.4 (dd, JF,H 48.9
and JF,H 11.3); HRMS (ES+) MH+ calculated for C20H24FN2O
3
326.1873, observed 327.1871.
4.2.10. 9-Amino-(9-deoxy)-quinine 23a
9-Epiquinine, 22, (1.03 g, 3.70 mmol) and PPh3 (1.16 g,
4.44 mmol) were dissolved in THF (23 mL) and the solution was
cooled to 0 °C and diisopropyl azodicarboxylate (1.10 mL,
5.55 mmol) was added dropwise. After 5 min, diphenyl phosphoryl
azide (1.20 mL, 5.55 mmol) was added dropwise and the mixture
was allowed to warm to room temperature and stirred for 1 h
and then at 45 °C for 2 h. Next, PPh3 (1.16 g, 4.44 mmol) was added
in one portion and the mixture was heated at 45 °C until the visible
evolution of nitrogen had ceased. Next, H2O (2 mL) was added and
the solution was stirred for a 16 h at room temperature. The sol-
vents were removed in vacuo and the residue was dissolved in CH2-
Cl2 and 1 M aqueous HCl (1:1, 100 mL). The aqueous phase was
washed with CH2Cl2 and basified with conc. aqueous NH3,
extracted with CH2Cl2, dried (MgSO4), filtered and concentrated
in vacuo to afford a yellow oil. The crude oil was then purified by
mass triggered reverse phase chromatography (0.05% NH3HOAc
in MeCN/H2O) and finally washed with saturated aqueous K2CO3
solution, extracted with CH2Cl2, dried (MgSO4), filtered and con-
centrated in vacuo to afford 23a (263 mg, 22%) as a pale orange
as a colourless oil; Rf: (30% EtOAc/hexane) 0.25; ½a D24
¼ þ31:9 (c
ꢁ
0.69, CHCl3); mmax (ATR)/cmꢀ1 3004, 2985, 2912, 2857, 2840,
1622, 1499, 1447,1274, 1255, 1219, 1202, 1108, 1079, 1004, 925,
848, 744; dH (400 MHz, CDCl3) 7.34–7.27 (5H, m, 5 ꢂ PhH), 3.92
(1H, 3-H), 3.80 (1H, td, J 11.5 and 1.4, 2-HH), 3.72 (1H, dd, J 11.6
and 3.3), 3.41 (1H, t, J 10.9, 2-HH), 3.08 (1H, dd, J 10.3 and 3.1),
2.85 (1H, d, J 11.8), 2.43 (1H, td, J 11.7 and 3.4), 2.08 (3H, s, CH3);
dC (100 MHz, CDCl3) 128.5, 128.1, 127.8, 127.4, 73.0, 69.3, 67.2,
55.5, 43.6; m/z (CI+) 178 (MH+, 100%); HRMS (CI+) MH+ calculated
for C11H16NO 178.1232, observed 178.1234.
oil; ½a 1D9
ꢁ
¼ ꢀ55:1 (c 0.65, CHCl3); mmax (ATR)/cmꢀ1 3275 br, 2937,
2863, 1620, 1589, 1508, 1472, 1431, 1358, 1226, 1028, 911, 827,
713; dH (400 MHz, CDCl3) 8.74 (1H, d, J 4.6, ArH), 8.01 (1H, d, J
Please cite this article in press as: Armstrong, A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.008

A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
9
9.2, ArH), 7.45 (1H, d, J 2.6, ArH), 7.37–7.34 (2H, m, 2 ꢂ ArH), 5.91
(1H, m, CH@CH2), 5.08–5.02 (2H, m, CH@CH2), 4.70 (1H, br d, J 6.3,
9-CHNH2), 3.97 (3H, s, CH3), 3.21 (1H, q, J 8.4), 3.08 (1H, br), 3.06
(1H, dd, J 13.7 and 10.0), 2.58 (1H, m), 2.30 (1H, br), 2.12 (1H,
m), 2.05–1.47 (2H, br, NH2), 1.91 (1H, m), 1.69 (1H, m), 1.58–1.49
(2H, m); dC (100 MHz, CDCl3); 157.8, 149.1, 147.9, 144.8, 141.7,
132.0, 127.6, 121.2, 118.3, 114.6, 101.2, 60.6, 56.2, 55.7, 53.6,
42.0, 39.6, 27.8, 27.7, 26.2; m/z HRMS (ES+) MH+ calculated for
and stirred for 18 h. The reaction mixture was diluted with CH2Cl2,
filtered to remove solid K2CO3 and washed with saturated aqueous
Na2CO3 solution. The organic layer was then separated, dried (Na2-
SO4), filtered and concentrated in vacuo to afford an orange resi-
due. Purification by flash column chromatography (5% MeOH/
CH2Cl2) afforded 25a (174 mg, 71%) as a white solid; Rf: (5%
MeOH/CH2Cl2) 0.30; mp 75–78 °C; ½a D22
¼ þ96:6 (c 0.58, CHCl3);
ꢁ
mmax (ATR)/cmꢀ1 3285, 3083, 2942, 2871, 1622, 1600, 1510, 1450,
1318, 1223, 1155, 1091, 1029, 912, 811, 664; dH (400 MHz, CDCl3)
8.47 (1H, d, J 4.6, ArH), 7.80 (1H, d, J 9.2, ArH), 7.25 (1H, dd, J 9.2
and 2.5 ArH), 7.22–7.18 (4H, m, 4 ꢂ ArH), 6.63 (2H, d, J 8.1,
2 ꢂ ArH), 5.85 (1H, m, CH@CH2), 5.16 (1H, br, 9-CHNTs), 5.04–
5.00 (2H, m, CH@CH2), 3.95 (3H, s, °CH3), 3.30 (1H, br, CH), 3.17–
2.88 (2H, br, 2 ꢂ CH), 2.68–2.47 (2H, br, 2 ꢂ CH), 2.27 (1H, br,
CH), 2.16 (1H, br, CH), 2.09 (3H, s, ArCH3), 1.89 (1H, br, CH),
1.81–1.60 (2H, br, 2 ꢂ CH), 1.51 (1H, br, CH); dC (126 MHz, CDCl3)
157.6, 147.0, 144.5, 144.1, 142.8, 140.9, 136.5, 131.1, 128.3,
127.2, 126.3, 121.4, 118.8, 114.8, 101.0, 60.1, 56.0, 55.8, 54.1,
41.8, 39.1, 27.4, 26.9, 25.8, 21.0; HRMS (ES+) MH+ calculated for
C20H26N3O 342.2076, observed 324.2065.
4.2.11. 9-N-Acetamido-(9-deoxy)-9-quinine 24a
Amine 23a (30 mg, 0.1 mmol) was dissolved in CH2Cl2 (1 mL)
and triethylamine (0.19 mL, 1.4 mmol) and the solution was cooled
to 0 °C. Acetyl chloride (10 lL) in CH2Cl2 (1 mL) was then added
dropwise over 10 min. The reaction was then stirred at room tem-
perature for 18 h. Next CH2Cl2 (1.5 mL) was added, the organic
solution washed with saturated aqueous Na2CO3 (3 ꢂ 10 mL), dried
over Na2SO4 and the solvent removed in vacuo. Purification by
flash column chromatography on silica gel (25% MeOH/EtOAc)
afforded 24a (30 mg, 83%) as a colourless oil; ½a D22
ꢁ
¼ ꢀ35:3 (c 1.4,
C27H32N3O3S 478.2164, observed 478.2157.
CHCl3);
m
max/cmꢀ1(ATR) 3566, 2926, 1652, 1558, 1373, 1228,
1028; dH (400 MHz, CDCl3) 8.67 (1H, d, J 4.6, ArH), 7.95 (1H, d, J
9.2, ArH), 7.63 (1H, d, J 2.7, ArH), 7.34 (1H, dd, J 9.2 and 2.7, ArH),
7.31 (1H, d, J 4.6, ArH), 6.01–5.87 (3H, m, CH@CH2, 9-CHNH and
NH), 5.14–5.10 (2H, m, CH@CH2), 3.97 (3H, s, CH3), 3.67 (1H, m,
8-H), 3.12 (1H, dd, J 13.7 and 10.0, 2-HH), 2.92–2.84 (1H, m, 6-
HH), 2.76 (1H, m, 2-HH), 2.58 (1H, m, 6-HH), 2.32 (1H, br, 3-H),
2.04 (1H, m, 7-HH), 1.94 (3H, s, COCH3), 1.88 (1H, m, 4-H), 1.76
(1H, m, 5-HH), 1.55–1.47 (2H, m, 7-HH and 5-HH); dC (100 MHz,
CDCl3) 169.7 (C), 158.2 (C), 147.5 (CH), 144.8 (C), 144.5 (C), 142.0
(CH), 131.5 (CH), 128.4 (C), 122.2 (CH), 119.1 (CH), 114.5 (CH2),
101.5 (CH), 57.5 (CH), 55.9 (CH), 55.8 (CH2), 49.4 (CH), 41.4
(CH2), 39.5 (CH), 27.5 (CH2), 27.5 (CH), 25.4 (CH2), 23.3 (CH); m/z
(EI+) 365 (M+, 2%) 136 (100%); HRMS (EI+) M+ calculated for
4.2.14. N-(p-Toluenesulfonyl)-9-amino(9-deoxy)-9-epiquinine
25b
p-Toluenesulfonyl chloride (77 mg, 0.41 mmol) was added in
one portion to a solution of amine 23b (88 mg, 0.27 mmol) and
K2CO3 (45 mg, 0.33 mmol) in CH2Cl2 (6 mL) at room temperature
and stirred for 16 h. The reaction mixture was diluted with CH2Cl2,
filtered, to remove solid K2CO3 and washed with saturated aqueous
Na2CO3 solution (3 ꢂ 10 mL). The organic layer was then separated,
dried (MgSO4), filtered and concentrated in vacuo to afford a white
residue. Purification by flash column chromatography (CH2Cl2 to
5% MeOH/CH2Cl2) afforded 25b (89 mg, 69%) as a white solid;
Rf: (5% MeOH/CH2Cl2) 0.30; mp 64.5–67 °C; ½a D22
¼ þ49:1 (c 1.43,
ꢁ
CHCl3); mmax (ATR)/cmꢀ1 3211, 2927, 2871, 1621, 1593, 1508,
1477, 1323, 1228, 1154, 1091, 1030, 987, 915, 854, 813, 728,
661; dH (400 MHz, C2D2Cl4, 403 K) 8.61 (1H, d, J 4.4, ArH), 8.01
(1H, d, J 9.0, ArH), 7.54 (1H, br, ArH), 7.41–7.33 (3H, m, 3 ꢂ ArH),
7.28 (1H, br, ArH), 6.92 (1H, br d, J 7.5, ArH), 5.73 (1H, m, CH@CH2),
5.05–5.00 (2H, m, CH@CH2), 4.84 (1H, br), 4.01 (3H, s, CH3), 3.35
(1H, dd, J 13.8 and 10.1), 3.20 (1H, br), 3.05 (1H, m), 2.88–2.76
(2H, m), 2.39 (1H, br), 2.29 (3H, s, ArCH3), 1.75 (1H, m), 1.69–
1.64 (2H, m), 1.42 (1H, m), 0.97 (1H, m); dC (126 MHz, C2D2Cl4,
403 K) 158.7, 146.7, 144.1, 142.4, 137.6, 136.7, 136.7, 131.4,
128.1, 127.4, 126.4, 121.9, 121.6, 117.0, 102.0, 58.6, 56.3, 54.2,
41.2, 36.4, 29.3, 27.2, 24.6, 24.1, 20.6; m/z (CI+) 478 (M+, 95%),
189 (100), 309 (98); HRMS (ES+) M+ calculated for C27H32N3O3S
478.2164, observed 478.2174.
C22H27N3O2 365.2103, observed 365.2105.
4.2.12. 9-N-Acetamido(9-deoxy)-9-epiquinine 24b
Amine 23b (35 mg, 0.1 mmol) was dissolved in CH2Cl2 (0.7 mL)
and triethylamine (0.22 mL, 1.6 mmol) and the solution was cooled
to 0 °C. Acetyl chloride (11 lL) in CH2Cl2 (0.3 mL) was then added
dropwise over 10 min. The reaction was then stirred at room tem-
perature for 18 h. Next, CH2Cl2 (1.5 mL) was added, the organic
solution washed with saturated aqueous Na2CO3 (3 ꢂ 10 mL), dried
over Na2SO4 and the solvent removed in vacuo. Purification by
flash column chromatography (5% MeOH/CH2Cl2) afforded 24b
(29 mg, 78%) as a yellow oil; ½a D22
ꢁ
¼ þ16:6 (c 0.7, CHCl3); mmax
/
cmꢀ1 (ATR) 3245, 2960, 2927, 1650, 1508, 1027, 800, 665; dH
(400 MHz, CDCl3) 8.73 (1H, d, J 4.5, ArH), 8.02 (1H, d, J 9.2, ArH),
7.69 (1H, d, J 2.1, ArH), 7.39 (1H, dd, J 9.2 and 2.1, ArH), 7.33 (1H,
d, J 4.5, ArH), 6.76 (1H, br, NH), 5.75 (1H, m, CH@CH2), 5.37 (1H,
br s, 9-CHNH), 5.02–4.97 (2H, m, CH@CH2), 3.99 (3H, s, CH3), 3.28
(1H, dd, J 13.7 and 10.2, 2-HH), 3.20–3.10 (2H, br m, 8-H and 6-
HH), 2.79–2.69 (2H, m, 6-HH and 2-HH), 2.31 (1H, br m, 3-H),
1.98 (3H, s, COCH3), 1.68–1.61 (3H, m, 2 ꢂ 5-H and 4-H), 1.47
(1H, br t, J 10.5, 7-HH), 0.92 (1H, br dd, J 13.5 and 6.2, 7-HH); dC
(100 MHz, CDCl3) 170.1 (C), 157.8 (C), 147.5 (CH), 145.1 (C),
144.8 (C), 141.1 (CH), 131.7 (CH), 128.3 (C), 121.7 (CH), 119.2
(CH), 114.6 (CH2), 101.9 (CH), 59.5 (CH), 56.0 (CH2), 55.6 (CH),
51.1 (CH), 40.9 (CH2), 39.4 (CH), 27.8 (CH2), 27.3 (CH), 26.2 (CH2),
23.2 (CH); m/z (EI+) 365 (M+, 2%), 136 (100); HRMS (EI+) M+ calcu-
lated for C22H27N3O2 365.2103, observed 365.2100.
4.2.15. (3R,4S)-8-[(6-Methoxyquinolin-4-yl)methylene]-5-vinyl-
quinuclidine 27
9-Epiquinine, 22, (150 mg, 0.46 mmol) and PPh3 (145.5 mg,
0.55 mmol) were dissolved in THF (3 mL) and the solution was
cooled to 0 °C. Diisopropyl azodicarboxylate (100
was then added in one portion before the dropwise addition of
diphenyl phosphoryl azide (119 L, 0.55 mmol) in THF (1 mL).
lL, 0.51 mmol)
l
The mixture was allowed to warm to room temperature and stirred
for 3 h before the addition of PPh3 (242 mg, 0.92 mmol) in one por-
tion and the mixture was heated at 50 °C for 3 h. Next, H2O (1 mL)
was added and the solution was stirred for 16 h at room tempera-
ture. The solvents were removed in vacuo and the residue was dis-
solved in CH2Cl2 and 1 M aqueous HCl (1:1, 10 mL). The aqueous
phase was washed with CH2Cl2 and basified with concentrated
aqueous NH3, extracted with CH2Cl2, dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column chromatogra-
phy (7% MeOH/EtOAc) afforded 27 (63.4 mg, 47%) as a colourless
4.2.13. N-(p-Toluenesulfonyl)-9-amino(9-deoxy)-quinine 25a
p-Toluenesulfonyl chloride (136 mg, 0.71 mmol) was added in
one portion to a solution of amine 23a (166 mg, 0.51 mmol) and
K2CO3 (138 mg, 0.61 mmol) in CH2Cl2 (4 mL) at room temperature
oil; Rf: (7% MeOH/EtOAc) 0.45; ½a D22
¼ þ55:2 (c 0.58, CHCl3); mmax
ꢁ
Please cite this article in press as: Armstrong, A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.008

10
A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
(ATR)/cmꢀ1 2933, 2865, 1619, 1579, 1506, 1468, 1430, 1357, 1257,
1227, 1106, 1084, 1031, 913, 840, 729, 713, 676; dH (400 MHz,
CDCl3) 8.70 (1H, d, J 4.6, ArH), 7.97 (1H, d, J 9.2, ArH), 7.82 (1H,
d, J 4.6, ArH), 7.33 (1H, dd, J 9.1 and 2.7, ArH), 7.27 (1H, s, ArH),
6.42 (1H, s, CH@CR2), 5.98–5.89 (1H, br m, CH@CH2), 5.10–5.05
(2H, m, CH@CH2), 3.95 (3H, s, CH3), 3.28 (1H, dd, J 13.8 and 9.5),
3.07–2.93 (2H, m), 2.80–2.71 (2H, m), 2.44–2.38 (2H, m), 2.02–
1.99 (1H, m), 1.73–1.65 (2H, m); dC (100 MHz, CDCl3) 157.3,
154.3, 147.9, 144.6, 140.8, 139.7, 131.5, 127.7, 121.5, 120.9,
114.8, 1114.4, 102.1, 55.5, 53.78, 47.8, 39.7, 30.5, 29.7, 27.2; m/z
(CI+) 307 (MH+, 100%); HRMS (CI+) MH+ calculated for C20H23N2O
402.1810, observed 402.1815.
being warmed to room temperature and stirred for 20 h. The reac-
tion was then diluted with water (10 mL), neutralised with HCl
(10% aqueous) and extracted with EtOAc. The organic extracts were
then washed with saturated aqueous NaCl (20 mL), dried (Na2SO4)
and concentrated in vacuo. Purification by column chromatogra-
phy (5% EtOAc/hexane) afforded enone 2j (0.86 g, 88%) as a colour-
less solid; mp 84–86 °C (lit.39, 81–83 °C); dH (400 MHz, CDCl3) 7.87
(1H, d, J 15.8, PhCH@CH), 7.63–7.61 (3H, m, 3 ꢂ ArH), 7.45 (1H, d, J
15.8, PhCH@CH), 7.40–7.38 (3H, m, 3 ꢂ ArH), 7.34 (1H, m, ArH),
6.57 (1H, m, ArH); m/z (CI+ (NH3)) 199 (MH+, 100%); HRMS (CI+
(NH3)) MH+ calculated for C13H11O2 199.0759, observed
199.0762. All data were in agreement with those previously
reported.39
4.2.16. O-Methyl-b-isocupreidine 28b33
(Trimethylsilyl)diazomethane (0.11 mL of a 2.0 M solution in
hexanes, 0.21 mmol) was added dropwise to a solution of 28a
(50 mg, 0.16 mmol) in benzene/MeOH (2 mL, 3:2) and stirred for
3 h at room temperature. After this time, the reaction was concen-
trated in vacuo and the residue purified by flash column chroma-
tography (5% MeOH/CH2Cl2) to afford 28b (22.4 mg, 43%) as a
4.3.2. (E)-1-(4-Methylthiophen-2-yl)-3-phenylprop-2-en-1-one
2l
Following the procedure for the synthesis of 2j; using 2-acetyl-
4-methylthiophene (0.5 mL, 4.4 mmol) and benzaldehyde
(0.45 mL, 4.4 mmol), with flash column chromatography purifica-
tion (2% EtOAc/hexane) afforded enone 2l (0.72 g, 72%) as an off-
colourless oil; Rf: (5% MeOH/CH2Cl2) 0.60; ½a D22
ꢁ
¼ ꢀ8:7 (c 0.69,
white solid; mp 96-98 °C; m
max/cmꢀ1(ATR) 1645, 1599, 1572,
MeOH) {lit.33
½
a 1D9
ꢁ
¼ ꢀ8:2 (c 1.02, MeOH)}; dH (400 MHz, CDCl3)
1424, 1230; dH (400 MHz, CDCl3) 7.85 (1H, d, J 15.6, PhCH@CH),
7.69 (1H, br s, ArH), 7.66–7.63 (2H, m, 2 ꢂ ArH), 7.43–7.41 (3H,
m, 3 ꢂ ArH), 7.42 (1H, d, J 15.6, PhCH@CH), 7.27 (1H, br s, ArH),
2.33 (3H, s, CH3); dC (100 MHz, CDCl3) 182.0 (C), 145.0 (C), 143.8
(CH), 139.1 (C), 134.8 (C), 134.0 (CH), 130.6 (CH), 130.0 (CH),
129.0 (CH), 128.5 (CH), 121.6 (CH), 15.7 (CH); m/z (CI+ (NH3))
229 (MH+, 100%); HRMS (CI+ (NH3)) MH+ calculated for C14H13OS
229.0687, observed 229.0685.
8.78 (1H, d, J 4.5, ArH), 8.01 (1H, d, J 9.2, ArH), 7.71 (1H, d, J 4.4,
ArH), 7.34 (1H, dd, J 9.2 and 2.6, ArH), 7.17 (1H, d, J 7.2, ArH),
5.96 (1H, s, CHOR), 3.97 (3H, s, OCH3), 3.62 (1H, d, J 13.5), 3.56
(1H, d, J 6.0), 3.06–3.03 (2H, m), 2.71 (1H, d, J 13.5), 2.17 (1H, m),
1.80 (1H, m), 1.73–1.62 (3H, m, CH2CH3 and 1 ꢂ CH), 1.55 (1H,
m), 1.28 (1H, dd, J 12.6 and 6.3), 1.03 (3H, t, J 7.4, –CH2CH3). All data
were in agreement with those reported.33
4.2.17. O-Benzyl-b-isocupreidine 28c
At first, NaH (7.7 mg, 60% dispersion in mineral oil, 0.19 mmol)
was added to a solution of 28a (40.0 mg, 0.13 mmol) in THF (1 mL)
4.3.3. (E)-1-(5-Chlorothiophen-2-yl)-3-phenylprop-2-en-1-one
2m
Following the procedure for the synthesis of 2j; using 2-acetyl-
5-chlorothiophene (0.5 g, 3.1 mmol) and benzaldehyde (0.32 mL,
3.1 mmol), with flash column chromatography purification (3%
EtOAc/hexane) afforded enone 2m (0.35 g, 45%) as a white solid;
at 0 °C and stirred for 10 min. Benzyl bromide (16.8 lL, 0.14 mmol)
was then added dropwise to the solution before the addition of
TBAI (7 mg, 0.02 mmol). The mixture was then heated to 40 °C
and stirred for 20 h. The reaction was quenched by the addition
of a saturated aqueous NH4Cl solution and diluted with EtOAc.
The aqueous layer was separated and extracted with EtOAc, dried
(Na2SO4), filtered and concentrated in vacuo. Purification by flash
column chromatography (5% MeOH/CH2Cl2) afforded 28c
(10.5 mg, 20%) as a colourless oil; Rf: (5% MeOH/CH2Cl2) 0.35;
mp 94-96 °C; m
max/cmꢀ1 (ATR) 1645, 1592, 1576, 1424, 1233; dH
(400 MHz, CDCl3) 7.78 (1H, d, J 15.6, PhCH@CH), 7.61 (1H, d, J
4.1, ArH), 7.58–7.56 (2H, m, 2 ꢂ ArH), 7.38–7.37 (3H, m, 3 ꢂ ArH),
7.30 (1H, d, J 15.6, PhCH@CH), 6.95 (1H, d, J 4.1, ArH); dC
(100 MHz, CDCl3) 180.9 (C), 144.4 (CH), 144.3 (C), 139.7 (C),
134.4 (C), 131.4 (CH), 130.8 (CH), 129.0 (CH), 128.6 (CH), 127.8
(CH), 120.2 (CH); m/z (CI+ (NH3)) 249 (MH+, 100%); HRMS (CI+
(NH3)) MH+ calculated for C13H10OSCl 249.0141, observed
249.0141.
½
a 2D2
ꢁ
¼ þ10:3 (c 0.58, CHCl3); mmax (ATR)/cmꢀ1 2942, 2878, 1619,
1597, 1509, 1456, 1225, 1010, 909, 853, 730; dH (400 MHz, CDCl3)
8.76 (1H, d, J 4.5, ArH), 8.04 (1H, d, J 9.2, ArH), 7.72 (1H, d, J 4.3,
ArH), 7.54–7.52 (2H, m, 2 ꢂ ArH), 7.45–7.30 (5H, m, 5 ꢂ ArH),
5.96 (1H, s, CHOR), 5.28 (1H, d, J 11.5, CHHPh), 5.22 (1H, d, J
11.5, CHHPh), 3.62 (1H, d, J 13.4), 3.52 (1H, d, J 5.6), 3.07–3.00
(2H, m), 2.72 (1H, d, J 13.5), 2.18 (1H, m), 1.81–1.50 (5H, m, CH2CH3
and 3 ꢂ CH), 1.27 (1H, dd, J 12.6 and 6.3), 1.05 (3H, t, J 7.4,
–CH2CH3); dC (126 MHz, CDCl3) 157.0, 147.7, 144.1, 142.7, 136.5,
131.9, 128.5, 128.0, 127.9, 126.4, 122.0, 119.4, 102.1, 77.0, 72.9,
70.6, 56.3, 54.6, 46.6, 32.9, 27.4, 24.0, 23.4, 7.3; HRMS (ES+) MH+
calculated for C26H29N2O2 401.2229, observed 401.2238.
4.3.4. General procedure for the aziridination
ketones with quinine
a,b-unsaturated
All reactions were performed on
a 0.11–0.24 mmol scale
according to the following procedure: DppONH2 (1.05 equiv)
was added to a solution of amine quinine (1.05 equiv) in CH2Cl2
(0.06 M in substrate) at room temperature and the mixture stir-
red for 0.5 h. Next, NaH (60% dispersion in mineral oil, 2 equiv),
i-PrOH (2 equiv) and enone (1 equiv) were added sequentially
and the mixture was allowed to stir at room temperature for
16 h. The reaction was quenched by the addition of saturated
aqueous NH4Cl solution and the aqueous layer separated and
extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated
in vacuo. Purification by flash column chromatography afforded
the desired aziridine. Enantiomeric excess (ee) was measured
by HPLC analysis (conditions: 93:7 hexane:IPA, 0.8 mL/min,
254 nm, AD-H).
4.3. Preparation of aromatic a,b-unsaturated ketones
All were obtained from commercial sources and used as sup-
plied with the exception of 2j,l,m which were prepared according
to the procedures outlined:
4.3.1. (E)-1-(Furan-2-yl)-3-phenylprop-2-en-1-one) 2j39
2-Acetyl furan (0.54 g, 4.9 mmol) in EtOH (5 mL) was added
slowly to KOH (15 mL, 10% aqueous) at 0 °C and stirred for
15 min. Benzaldehyde (0.50 mL, 4.9 mmol) was then added and
the mixture was allowed to stir for a further 15 min at 0 °C before
4.3.5. (2R,3S)-Phenyl-(3-phenylaziridin-2-yl)methanone 3a14
Using chalcone 2a (25 mg, 0.12 mmol) afforded aziridine 3a
(18.0 mg, 64%) as a white solid; Rf: (10% EtOAc/hexane) 0.50; mp
Please cite this article in press as: Armstrong, A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.008

A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
11
99–101 °C (lit.14 99–101 °C); ½a 2D2
ꢁ
¼ ꢀ139 (c 0.66, CHCl3); dH
4.3.10. ((2R,3S)-3-Phenylaziridin-2-yl)-4-methoxyphenyl metha-
none 3f14
(400 MHz, CDCl3) 8.00 (2H, d, J 8.8, 2 ꢂ PhH), 7.62 (2H, t, J 7.4,
2 ꢂ PhH), 7.49 (1H, t, J 7.6, PhH), 7.39–7.30 (5H, m, 5 ꢂ PhH),
3.52 (1H, dd, J 2.3, 2-CHN), 3.18 (1H, dd, J 2.5, 3-CHN), 2.68 (1H,
br, NH); m/z (EI+) 233 (M+, 80%), 206 (100), 105 (100); Assay of
enantiomeric excess: (tR (minor) = 13.1 min, tR (major) = 15.0 min)
56% ee. All data were in agreement with those reported for the
racemate.14
Using 40-methoxychalcone, 2f, (31 mg, 0.13 mmol) afforded
aziridine 3f (16 mg, 48%) as a white solid; mp 71–72 °C (lit.14
,
71–73 °C); ½a 2D2
¼ ꢀ138:9 (c 0.36, CHCl3); dH (400 MHz, CDCl3)
ꢁ
8.02–8.00 (2H, m, 2 ꢂ ArH), 7.39–7.28 (5H, m, 5 ꢂ ArH),
6.99–6.97 (2H, m, 2 ꢂ ArH), 3.90 (3H, s, OCH3), 3.48 (1H, dd, J 8.0
and 2.3, CHNH), 3.17 (1H, dd, J 9.3 and 2.3, CHNH), 2.66 (1H, dd,
J 9.3 and 8.0, NH); m/z (CI+ (NH3)) 254 (MH+, 100%); HRMS
(CI+ (NH3)) MH+ calculated for C16H16NO2 254.1181, observed
254.1185; Assay of enantiomeric excess: (tR (minor) = 32.2 min,
tR (major) = 42.2 min) 66% ee. All data were in agreement with
those previously reported for the racemate.14
4.3.6. ((2R,3S)-3-(4-Methoxyphenyl)aziridin-2-yl)phenyl metha-
none 3b14
Using 4-methoxychalcone 2b, (31 mg, 0.13 mmol), afforded azi-
ridine 3b (12 mg, 35%) as a viscous orange oil; ½a D22
¼ ꢀ379:3 (c
ꢁ
0.12, MeOH); dH (400 MHz, CDCl3) 8.02 (2H, d, J 7.4, 2 ꢂ ArH),
7.64 (1H, t, J 7.4, ArH), 7.52 (2H, t, J 7.9, 2 ꢂ ArH), 7.32 (2H, d, J
8.7, 2 ꢂ ArH), 6.92 (2H, d, J 8.7, 2 ꢂ ArH), 3.84 (3H, s, OCH3), 3.50
(1H, br, CHNH), 3.16 (1H, br, CHNH), 2.67 (1H, br, NH); m/z (CI+
(NH3)) 254 (MH+, 100%); HRMS (CI+ (NH3)) MH+ calculated for
4.3.11. ((2R,3S)-3-Phenylaziridin-2-yl)-4-methylphenyl metha-
none 3g14
Using 40-methylchalcone 2g, (29 mg, 0.13 mmol) afforded aziri-
dine 3g (21 mg, 68%) as an off-white solid; mp 87–89 °C (lit.14, 89–
90 °C); ½a 2D2
¼ ꢀ169:6 (c 0.63, CHCl3); dH (400 MHz, CDCl3) 7.93–
ꢁ
C16H16NO2 254.1181, observed 254.1185; Assay of enantiomeric
7.91 (2H, m, 2 ꢂ ArH), 7.39–7.28 (7H, m, 7 ꢂ ArH), 3.51 (1H, dd, J
8.0 and 2.3, CHNH), 3.18 (1H, dd, J 9.3 and 2.3, CHNH), 2.70–2.66
(1H, br, NH), 2.45 (3H, s, CH3); m/z (CI+ (NH3)) 238 (MH+, 100%);
HRMS (CI+ (NH3)) MH+ calculated for C16H16NO 238.1232, observed
238.1239; Assay of enantiomeric excess: (tR (minor) = 16.0 min, tR
(major) = 21.5 min) 59% ee. All data were in agreement with those
previously reported for the racemate.14
excess: (tR (minor) = 23.3 min, tR (major) = 26.7 min) 55% ee. All
data were in agreement with those previously reported for the
racemate.14
4.3.7. ((2R,3S)-3-(4-Methylphenyl)aziridin-2-yl)phenyl metha-
none 3c14
Using 4-methylchalcone 2c, (29 mg, 0.13 mmol), afforded aziri-
dine 3c (17 mg, 55%) as a cream solid; mp 106–108 °C (lit.14, 106–
4.3.12. ((2R,3S)-3-Phenylaziridin-2-yl)-4-chlorophenyl metha-
none 3h14
07 °C); ½a 2D2
¼ ꢀ99:4 (c 0.9, CHCl3); dH (400 MHz, CDCl3) 8.02–8.01
ꢁ
(2H, m, 2 ꢂ ArH), 7.63 (1H, m, ArH), 7.52–7.49 (2H, m, 2 ꢂ ArH),
7.30–7.28 (2H, m, 2 ꢂ ArH), 7.21–7.19 (2H, m, 2 ꢂ ArH), 3.51 (1H,
br, CHNH), 3.17 (1H, br, CHNH), 2.68 (1H, br, NH), 2.39 (3H, s,
CH3); m/z (CI+ (NH3)) 238 (MH+, 100%); HRMS (CI+ (NH3)) MH+ cal-
culated for C16H16NO 238.1232, observed 238.1241; Assay of enan-
tiomeric excess: (tR (minor) = 13.3 min, tR (major) = 16.0 min) 52%
ee. All data were in agreement with those previously reported for
the racemate.14
Using 40-chlorochalcone 2h, (32 mg, 0.13 mmol) afforded aziri-
dine 3h (20 mg, 62%) as a white solid; mp 76–78 °C (lit.14, 75–
77 °C); ½a 2D2
¼ ꢀ128:0 (c 0.63, CHCl3); dH (400 MHz, CDCl3) 7.97–
ꢁ
7.95 (2H, m, 2 ꢂ ArH), 7.50–7.49 (2H, m, 2 ꢂ ArH), 7.40–7.34 (5H,
m, 5 ꢂ ArH), 3.48 (1H, br, CHNH), 3.21 (1H, br, CHNH), 2.66 (1H,
br, NH); m/z (CI+ (NH3)) 258 (MH+, 100%); HRMS (CI+ (NH3)) MH+
calculated for C15H13NOCl 258.0686, found 258.0690; Assay of
enantiomeric excess: (tR (major) = 16.6 min, tR (minor) = 17.7 min)
46% ee. All data were in agreement with those previously reported
for the racemate.14
4.3.8. ((2R,3S)-3-(4-Chlorophenyl)aziridin-2-yl)phenyl metha-
none 3d13
Using 4-chlorochalcone 2d, (32 mg, 0.13 mmol), afforded aziri-
4.3.13. ((2R,3S)-3-Phenylaziridin-2-yl)(furan-2-yl) methanone
3j
dine 3d (18 mg, 54%) as a white solid; mp 88–90 °C (lit.13, 88–
90 °C); ½a 2D2
¼ ꢀ147:5 (c 0.8, MeOH); dH (400 MHz, CDCl3) 8.00
ꢁ
Using enone 2j, afforded aziridine 3j (10 mg, 41%) as a white
solid; mp 82–84 °C; ½a D22
ꢁ
¼ ꢀ395:3 (c 0.4, MeOH);
m
max/cmꢀ1(ATR)
(2H, d, J 7.1, 2 ꢂ ArH), 7.65 (1H, t, J 7.1, ArH), 7.52 (2H, t, J 7.9,
2 ꢂ ArH), 7.37–7.32 (4H, m, 4 ꢂ ArH), 3.47 (1H, dd, J 7.8 and 2.2
CHNH), 3.17 (1H, dd, J 9.3 and 2.2 CHNH), 2.70 (1H, br m, NH);
m/z (CI+ (NH3)) 258 (MH+, 100%); HRMS (CI+ (NH3)) calculated for
1648, 1565, 1468, 1399, 1282, 1002, 764; dH (400 MHz, CDCl3) 7.68
(1H, d, J 1.2, ArH), 7.38–7.33 (6H, m, 6 ꢂ ArH), 6.62 (1H, dd, J 3.5
and 1.6, ArH), 3.46 (1H, d, J 2.1, CHNH), 3.28 (1H, d, J 2.1, CHNH),
2.54 (1H, br, NH); dC (100 MHz, CDCl3) 184.4 (C), 152.2 (C), 147.5
(CH), 138.3 (C), 128.5 (CH), 127.8 (CH), 126.3 (CH), 118.5 (CH),
112.7 (CH), 43.6 (CH), 43.4 (CH); m/z (CI+ (NH3)) 214 (M+, 100%);
HRMS (CI+ (NH3)) M+ calculated for C13H12NO2 214.0868, observed
214.0871. Assay of enantiomeric excess: (tR (minor) = 18.3 min, tR
(major) = 34.2 min) 71% ee.
C
15H13NOCl 258.0686, observed 258.0689; Assay of enantiomeric
excess: (tR (minor) = 16.3 min, tR (major) = 27.9 min) 48% ee. All
data were in agreement with those previously reported for the
racemate.13
4.3.9. ((2R,3S)-3-(4-Nitrophenyl)aziridin-2-yl)phenyl methanone
3e13
Using 4-nitrochalcone, 2e, (33 mg, 0.13 mmol) afforded aziri-
4.3.14. ((2R,3S)-3-Phenylaziridin-2-yl)(thiophen-2-yl) metha-
none 3k
dine 3e (15 mg, 43%) as a yellow solid; mp 139–141 °C (lit.13
,
141-143 °C); ½a 2D2
¼ ꢀ103:3 (c 0.6, CHCl3); dH (400 MHz, CDCl3)
ꢁ
Using enone 2k, afforded aziridine 3k (23 mg, 47%) as a white
solid; mp 114–116 °C; ½a D26
ꢁ
¼ ꢀ319:0 (c 0.79, MeOH);
m
max/cmꢀ1
8.25–8.23 (2H, m, 2 ꢂ ArH), 8.02–8.00 (2H, m, 2 ꢂ ArH), 7.66 (1H,
m, ArH), 7.58–7.51 (4H, m, 4 ꢂ ArH), 3.53 (1H, dd, J 7.8 and 2.1,
CHNH), 3.28 (1H, dd, J 8.8 and 2.1, CHNH), 2.80 (1H, br, NH); m/z
(CI+ (NH3)) 269 (MH+, 100%); HRMS (CI+ (NH3)) MH+ calculated
for C15H13N2O3 269.0926, observed 269.0928; Assay of enantio-
meric excess: (tR (minor) = 37.2 min, tR (major) = 76.3 min) 37%
ee. All data were in agreement with those previously reported for
the racemate.13
(ATR) 1645, 1523, 1500, 1420, 1261, 960; dH (400 MHz, CDCl3)
7.87 (1H, dd, J 4.0 and 0.9, ArH), 7.76 (1H, dd, J 5.1 and 0.9, ArH),
7.39–7.31 (5H, m, 5 ꢂ ArH), 7.19 (1H, dd, J 5.1 and 4.0, ArH), 3.42
(1H, d, J 2.2, CHNH), 3.29 (1H, d, J 2.2, CHNH), 2.45 (1H, br, NH);
dC (125 MHz, CDCl3) 188.2 (C), 142.8 (C), 138.2 (C), 134.8 (CH),
132.9 (CH), 128.5 (CH), 128.5 (CH), 127.8 (CH), 126.2 (CH), 44.3
(CH), 43.2 (CH); m/z HRMS (ES+) MH+ calculated for C13H12NOS
Please cite this article in press as: Armstrong, A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.008

12
A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
230.0647, observed 230.0640. Assay of enantiomeric excess: (tR
(minor) = 22.8 min, tR (major) = 26.8 min) 72% ee.
derivatives 21a,b and Professor Alexandre Alexakis of the Univer-
sity of Geneva for the kind donation of the precursor to amine 6.
We acknowledge Emilia F. Kouroussis for initial screening of
21a,b; Maria Flores for the synthesis and testing of 19; and Drs.
Richard Wincewicz and Carl A. Baxter for preliminary work on
enantioselective aziridinations.
4.3.15. ((2R,3S)-3-Phenylaziridin-2-yl)(4-methylthiophen-2-yl)
methanone 3l
Using enone 2l, afforded aziridine 3l (12 mg, 46%) as a yellow
oil; ½a 2D3
ꢁ
¼ ꢀ536:4 (c 0.22, MeOH);
m
max/cmꢀ1 (ATR) 1644, 1421,
1266, 1213, 756; dH (400 MHz, CDCl3) 7.67 (1H, s, ArH), 7.38–
7.32 (6H, m, 6 ꢂ ArH), 3.37 (1H, d, J 2.0, CHNH), 3.26 (1H, d, J 2.0,
CHNH), 2.31 (3H, s, CH3); dC (100 MHz, CDCl3) 188.2 (C), 142.3
(C), 139.4 (C), 138.3 (C), 134.8 (CH), 130.8 (CH), 128.5 (CH), 127.9
(CH), 126.2 (CH), 44.3 (CH), 43.2 (CH), 15.6 (CH); m/z (CI+ (NH3))
244 (M+, 100%); HRMS (CI+ (NH3)) M+ calculated for C14H14NOS
244.0796, observed 244.0807. Assay of enantiomeric excess: (tR
(minor) = 18.5 min, tR (major) = 25.4 min) 77% ee.
References
1. For a review see: Lowden, P. A. S. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH: Weinheim, Germany, 2006; p 399.
2. For a review see: (a) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905; (b) Osborn,
H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693; (c) Pellissier, H.
Tetrahedron 2010, 66, 1509; (d) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33,
599.
3. For a review see: (a) Kawabata, H.; Omura, K.; Uchida, T.; Katsuki, T. Chem.
Asian J. 2007, 2, 248; (b) Nishikori, H.; Katsuki, T. Tetrahedron Lett. 1996, 37,
9245; (c) Nishimura, M.; Minakata, S.; Takahashi, T.; Oderaotoshi, Y.; Komatsu,
M. J. Org. Chem. 2002, 67, 2101; (d) Subbarayan, V.; Ruppel, J. V.; Zhu, S.;
Perman, J. A.; Zhang, X. P. Chem. Commun. 2009, 4266.
4. For selected examples see (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.;
Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328; (b) Gillespie, K.
M.; Sanders, C. J.; O’Shaughnessy, P.; Westmoreland, I.; Thickitt, C. P.; Scott, P. J.
Org. Chem. 2002, 67, 3450; (c) Wang, X.; Ding, K. Chem. Eur. J. 2006, 12, 4568.
5. Ma, L.; Du, D.-M.; Xu, J. J. Org. Chem. 2005, 70, 10155.
4.3.16. (2R,3S)-3-Phenylaziridin-2-yl)(5-chlorothiophen-2-yl)
methanone 3m
Using enone 2m, afforded aziridine 3m (16 mg, 27%) as a white
solid; mp 83–85 °C; ½a D22
ꢁ
¼ ꢀ311:1 (c 0.54, MeOH);
m
max/cmꢀ1
(ATR) 1634, 1427, 1271, 1019, 833; dH (400 MHz, CDCl3) 7.66
(1H, d, J 4.1, ArH), 7.40–7.33 (5H, m, 5 ꢂ ArH), 7.01 (1H, d, J 4.1,
ArH), 3.32 (1H, d, J 2.1, CHNH), 3.28 (1H, d, J 2.1, CHNH), 2.25
(1H, br, NH); dC (125 MHz, CDCl3) 187.3 (C), 141.3 (C), 141.1 (C),
138.0 (C), 132.5 (CH), 128.6 (CH), 128.0 (CH), 128.0 (CH), 126.2
(CH), 43.8 (CH), 43.4 (CH); m/z HRMS (ES+) MH+ calculated for
6. Fukunaga, Y.; Uchida, T.; Ito, Y.; Matsumoto, K.; Katsuki, T. Org. Lett. 2012, 14,
4658.
7. For examples see (a) Aires-de-Sousa, J.; Lobo, A. M.; Prabhakar, S. Tetrahedron
Lett. 1996, 37, 3183; (b) Aires-de-Sousa, J.; Prabhakar, S.; Lobo, A. M.; Rosa, A.
M.; Gomes, M. J. S.; Corvo, M. C.; Williams, D. J.; White, A. J. P. Tetrahedron:
Asymmetry 2002, 12, 3349; (c) Fioravanti, S.; Mascia, M. G.; Pellacani, L.;
Tardella, P. A. Tetrahedron 2004, 60, 8073; (d) Murugan, E.; Siva, A. Synthesis
2005, 2022; (e) Minakata, S.; Murakami, Y.; Tsuruoka, R.; Kitanaka, S.; Komatsu,
M. Chem. Commun. 2008, 6363.
C13H11NOSCl 264.0252, observed 264.0252. Assay of enantiomeric
excess: (tR (major) = 15.9 min, tR (minor) = 20.2 min) 64% ee.
8. For examples see: (a) Arai, H.; Sugaya, N.; Sasaki, N.; Makino, K.; Lectard, S.;
Hamada, Y. Tetrahedron Lett. 2009, 50, 3329; (b) Deiana, L.; Dziedzic, P.; Zhao,
G.-L.; Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J.; Córdova, A. Chem. Eur. J. 2011, 17,
7904; (c) Deiana, L.; Zhao, G.-L.; Lin, S.; Dziedzic, P.; Zhang, Q.; Leijonmarck, H.;
Córdova, A. Adv. Synth. Catal. 2010, 352, 3201; (d) Desmarchelier, A.; Pereira de
Sant’Ana, D.; Terrasson, V.; Campagne, J. M.; Moreau, X.; Greck, C.; Marcia de
Figueiredo, R. Eur. J. Org. Chem. 2011, 4046; (e) Vesely, J.; Ibrahem, I.; Zhao, G.
L.; Rios, R.; Córdova, A. Angew. Chem., Int. Ed. 2007, 46, 778.
9. (a) Menjo, Y.; Hamajima, A.; Sasaki, N.; Hamada, Y. Org. Lett. 2011, 13, 5744; (b)
Jiang, H.; Holub, N.; Anker Jørgensen, K. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20630; (c) De Vincentiis, F.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Bartoli,
G.; Galzerano, P.; Melchiorre, P. Chem. Asian J. 2010, 5, 1652; (d) Pesciaioli, F.;
De Vincentiis, F.; Galzerano, P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.;
Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8703.
4.4. Preparation of N-aminoquininium tetraphenylborate 29
At first, DppONH2 (180 mg, 0.77 mmol) was added in one por-
tion to a stirred solution of quinine (250 g, 0.77 mmol) in THF
(5 mL). A thick white precipitate formed after 5 min of stirring
and THF (10 mL) was added to the mixture and stirred for 2 h.
The mixture was then filtered and the residue was dried under
vacuum to afford N-aminoquininium diphenylphosphinate as a
white powder (0.19 g, 44%).
A portion of the phosphinate
(120 mg, 0.22 mmol) was dissolved in H2O (20 mL) and a solution
of NaBPh4 (81 mg, 0.24 mmol) in H2O (1.2 mL) was added to the
mixture and a white solid precipitated out immediately. The mix-
ture was left to stir for 40 min and then filtered and dried under
reduced pressure overnight to afford N-aminoquininium tetra-
phenylborate 29 (77 mg, 54%) as a white solid; mp 115–120 °C;
10. Ikeda, I.; Machii, Y.; Okahara, M. Synthesis 1980, 650.
11. Armstrong, A.; Carbery, D. R.; Lamont, S. G.; Pape, A. R.; Wincewicz, R. Synlett
2006, 2504.
12. Xu, J.; Jiao, P. J. Chem. Soc., Perkin Trans. 1 2002, 1491.
13. Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew. Chem. Int. Ed. 2006, 45, 8005.
14. Armstrong, A.; Baxter, C. A.; Lamont, S. G.; Pape, A. R.; Wincewicz, R. Org. Lett.
2007, 9, 351.
15. Armstrong, A.; Ferguson, A. Beilstein. J. Org. Chem. 2012, 8, 1747.
16. Armstrong, A.; Pullin, R. D. C.; Jenner, C. R.; Scutt, J. N. J. Org. Chem. 2010, 75,
3499.
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m
max/cmꢀ1 (ATR) 3200 br, 3055, 2961, 1621, 1589, 1509, 1472,
1429, 1242, 1137, 1073, 1031, 910, 859, 734, 707; dH (400 MHz;
CDCl3) 8.72 (1H, d, J 4.5, ArH), 8.05 (1H, d, J 9.3, ArH), 7.85 (1 h,
m, ArH), 7.55–7.65 (8H, m, 8 ꢂ PhH), 7.45–7.36 (2H, m, 2 ꢂ ArH),
7.12–7.20 (8H, m, 8 ꢂ PhH), 6.93–7.0 (4H, m, 4 ꢂ PhH), 5.63 (1H,
s, 9-CH), 5.38 (1H, m, CH@CH2), 5.07–4.98 (2H, m, CH@CH2), 4.34
(1H, m, –CH–), 3.93 (3H, s, OCH3), 3.56 (1H, m, –CH–), 3.28 (1H,
m, –CH–), 3.18 (1H, m, –CH–), 2.86 (1H, m, –CH–), 2.74 (1H, m,
–CH–), 2.17 (2H, m, 2 ꢂ –CH–), 2.02 (1H, m, –CH–), 1.88 (1H, m,
–CH–), 1.42 (1H, m –CH–); dC (100 MHz; CDCl3) 164.8, 158.6,
147.2, 143.6, 142.9, 136.1, 135.6, 131.7, 128.4, 126.3, 125.3,
122.4, 121.8, 119.0, 118.2, 100.7, 71.6, 67.1, 63.6, 58.2, 55.9,
38.8, 25.9, 25.6, 19.7, 18.6; m/z (ES+) 340 (MH+ -Ph4B, 100%);
HRMS (ES+) calculated for C20H26N3O2 340.2025, observed
340.2037.
Acknowledgements
We thank the EPSRC and Syngenta (CASE award to RDCP) for
their support of this work. We also thank Professor Ryan Gilmour
of the Swiss Federal Institute of Technology (ETH) Zurich for the
kind donation of the dihydrochloride salts of cinchona alkaloid
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A. Armstrong et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
13
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Please cite this article in press as: Armstrong, A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.11.008