Synthesis and use of a stable aminal derived from TsDPEN in asymmetric organocatalysis

Article abstract of DOI:10.1016/j.tetlet.2010.06.017

A stable aminal formed stereoselectively from (R,R)-N-tosyl-1,2-diphenyl-1, 2-ethylenediamine (TsDPEN) is capable of asymmetric organocatalysis of Diels-Alder and α-amination reactions of aldehydes.

Full text of DOI:10.1016/j.tetlet.2010.06.017

Tetrahedron Letters 51 (2010) 4214–4217
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Tetrahedron Letters
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Synthesis and use of a stable aminal derived from TsDPEN in asymmetric
organocatalysis
*
Silvia Gosiewska, Rina Soni, Guy J. Clarkson, Martin Wills
Department of Chemistry, The University of Warwick, Coventry CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A stable aminal formed stereoselectively from (R,R)-N-tosyl-1,2-diphenyl-1,2-ethylenediamine (TsDPEN)
Received 1 April 2010
Revised 27 May 2010
Accepted 4 June 2010
Available online 9 June 2010
is capable of asymmetric organocatalysis of Diels–Alder and
a
-amination reactions of aldehydes.
Ó 2010 Elsevier Ltd. All rights reserved.
The use of enantiomerically pure amines as catalysts for organic
reactions has proved to be a productive area of research.1–10 Follow-
ing initial reports on the use of proline,2 several derivatives based on
five-membered N-containing rings have been developed, notably
pyrrolidine derivatives such as 1–4.3–6 Closely related cyclic ami-
nals, such as 5–8, have also been successfully applied.7–10 Imidazo-
lidinones 5 and 6 generate high enantioselectivity in, for example,
phy without hydrolysis. Significantly, 11 was formed as a single
diastereoisomer in high yield upon acid-catalysed reaction of 9 with
10 (Scheme 1). X-ray crystallographic analysis of a purified sample
(Fig. 1) revealed the relative stereochemistry illustrated, that is,
with the TBDPS group trans to the phenyl adjacent to the basic
amine.
Given the structural similarity of 11 to related organocatalysts
such as 5–8,7–10 we chose to investigate its ability to act in this
capacity. In the Diels–Alder reaction (Scheme 2, Table 1) between
cyclohexadiene and acrolein,7a using 10 mol % of 11 as its hydro-
chloride salt, the predominant endo cycloaddition product was
formed in up to 72% ee. Full conversion was achieved under opti-
mised conditions (see Supplementary data for full details). The
use of the salt is important; the free base gave no conversion at
5% catalyst loading, although 23% of racemic product was formed
after 24 h using 10 mol % of 11.7a The presence of a small amount
of water in the solvent increases the rate of the reaction but does
not reduce the selectivity. The product was shown to be of S con-
figuration at the atom adjacent to the aldehyde group by reduction
of a sample of 72% ee to the corresponding alcohol and comparison
of the sign of the optical rotation to that reported for this com-
pound.12 This configuration would mirror that of close prece-
dents7a in the literature which indicates that the cycloaddition
takes place through an endo transition state to the E-iminium cat-
ion on the less hindered face (Fig. 2).
Diels–Alder additions,
a-chlorination of ketones, Michael additions,
conjugate hydride additions to enones and aldol reactions.7,8 Ami-
nals 7 and 8 have been employed in asymmetric a-amination and
bromination of ketones and nucleophilic additions to enones.9,10 In
this Letter, we describe the synthesis of a novel class of homochiral
aminal which shows activity in asymmetric organocatalytic
reactions.
H
OTMS
Ph
O
HN S CF3
O
COOH
N
N
N
H
N
H
N
H
N
H
46
Ph
N
Ph
35
HN
12,3
Me
24
O
Ph
Ph
Me
N
O
N
NH
NH
Me
Me
Ph
CO2H
N
tBu
N
N
H
N
Ph
H
Ph
H
H
57
68
810
79
During the course of studies on the functionalisation of (R,R)-N-
tosyl-1,2-diphenyl-1,2-ethylenediamine (TsDPEN) 9 via reductive
Encouraged by this result, we sought to establish whether ami-
nal 11 remained intact under the reaction conditions or degraded
(for example, by hydrolysis) to TsDPEN 9. The use of TsDPENÁHCl
(9ÁHCl) under the same conditions gave a cycloaddition product
alkylation,11 we found that its reaction with
a-trialkylsilyloxy-
substituted aldehyde 10 resulted in the formation of stable aminal
11. This was not reduced in situ under conditions which we had
typically used for reductive alkylation, for example, NaBH3CN,
MeOH.11 Although aminal 11 could be reduced to the required
product 12 (the TBDPS group was also removed in this process)
using LiAlH4, it could also be readily purified by flash chromatogra-
Ph
Ph
Ph
Ph
i)
O
NTs
NHTs
OTBDPS
OTBDPS
+
96%
N
H
NH2
11
9
10
* Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652 4112.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
Scheme 1. Reagents: (i) AcOH, reflux.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.017

S. Gosiewska et al. / Tetrahedron Letters 51 (2010) 4214–4217
4215
Ph
Ph
Ph
NTs
NTs
OTBDPS
OTBDPS
or
Ph
N
N
S
CHO
Figure 2. Control of selectivity of the Diels–Alder cycloaddition using 11. Cyclo-
hexadiene adds to the least hindered face of each conformer of the E-iminium
cation.
CO2Et
HN
N
O
O
EtO2C
+
N
N
i)
H
CO2Et
16
H
R
CO2Et
R
see Table 2
(excess)
R=iPr, Me, Et, CH2Ph
100% conversion
Figure 1. X-ray structure of 11 (CCDC 767194). (a) H atoms removed for clarity, (b)
with H atoms shown.
O
O
H
ii), iii)
N
up to 97.5% ee
isolated product
NHCO2Et
17
see Tables 2 and 3
R
O
i)
Scheme 3. Reagents and conditions: (i) 2–10 mol % 11, 9, 13–15 RCO2H, neat; (ii)
NaBH4; (iii) NaOH.
+
+
100% conversion
87% yield
CHO
S
CHO
(3 eq.)
(1 eq.)
exo
endo
Scheme 2. Reagents and conditions: (i) 10 mol % 11ÁHCl, 95:5 MeCN/H2O.
tion and reused. An attempt to prepare an aminal from TsDPEN and
benzaldehyde did not give the required product. This difference in
stability may be a result of the electron-withdrawing effect of the
alkoxy group. The benzyloxy catalyst 13 gave a cycloaddition prod-
uct of 45% ee and the hydroxy catalyst 15, one of 44% ee, indicating
that the bulkier TBDPS group is advantageous to the reaction selec-
tivity. An attempt was made to form an aminal from trans-N-tosyl-
1,2-cyclohexanediamine, however, this failed, possibly due to a
high level of strain in the bicyclic product.
The application of aminals 11 and 13–15 to a series of other
asymmetric organocatalytic reactions was investigated. Of these,
promising results were obtained in the asymmetric addition of
diethylazodicarboxylate (DEAD) (Scheme 3)3a,b,9a in which addi-
tion products of up to 97.5% ee were isolated using 10 mol % of
11. Using a relatively non-volatile aldehyde, that is, 3-methylbut-
anal, in initial studies (Table 2) and 11 as the catalyst, the addition
of a small amount of AcOH was found to be advantageous to the
reaction rate, although the ee was not affected.
of just 28% ee (endo:exo 10:1.5, 87% conversion in 22.5 h). The reac-
tion of 11 with excess acrolein gave no evidence of exchange of
aldehyde with the aminal. In order to establish the importance of
the silyloxy group, the analogues 13 and 14 were also prepared
from TsDPEN and the corresponding aldehydes. Desilylation of 11
gave 15 in 85% yield, which was also tested.
Ph
Ph
Ph
Ph
Ph
NHTs
NTs
NTs
NTs
OBn
Ph
Ph
OH
OH
Ph
Ph
N
H
N
H
14
N
H
N
H
12
13
15
Benzyloxy derivative 13 proved to be stable and was readily puri-
fied in single diastereoisomer form (relative configuration assigned
by analogy with 11). In contrast, the benzyl derivative 14 was pre-
pared in low yield as a mixture of diastereomers from which the
major (relative configuration unknown) was purified by chromatog-
raphy on silica gel.
The use of aminal 14 in the cycloaddition reaction (Scheme 2)
gave a product with an ee similar to that obtained with 9ÁHCl,
and could not be recovered after the reaction, thus suggesting that
it may be hydrolysed (9 was detected by TLC). In contrast, all the
alkoxy- and hydroxy-derivatives could be reisolated from the reac-
Whilst 100% conversion of DEAD (limiting reagent) to 16 was
observed by NMR, this product was not isolated because it was
prone to racemisation. Instead, 16 was reduced and cyclised to
the configurationally stable oxazolidinone 17 in order to establish
the ee.3b Since the reactions were followed by taking samples at
intervals (see Supplementary data for graphs), the isolated yields
of 16 and 17 were not recorded at this stage.
Table 1
Diels–Alder reaction of acrolein and 1,3-cyclohexadiene using catalysts 11, 9 and 13–15ÁHCl
Entry
Catalyst
mol %
Solvent
t (h)
Conv.a (%)
Yieldb (%)
endo:exo
eec (%) (endo)
1
2
3
4
5
6
7
8
9
11ÁHCl
11 (free base)
11ÁHCl
11ÁHCl
11ÁHCl
9ÁHCl
5
5
10
15
5
10
10
10
10
CH3CN/H2O (95:5)
CH3CN/H2O (95:5)
CH3CN/H2O (95:5)
CH3CN/H2O (95:5)
CH3CN (dry)
CH3CN/H2O (95:5)
CH3CN/H2O (95:5)
CH3CN/H2O (95:5)
CH3CN/H2O (95:5)
48
24
24
16
180
22.5
17
17
18.5
83
0
38
—
12:1
—
10:1
8:1
10:1
7:1
10:1
5:1
67
—
100d
93
87
80
65
28
35
35
36
72
71
67
28
45
29
44
83
87
13ÁHCl
14ÁHCl
15ÁHCl
100d
100d
100d
12:1
a
b
c
Conversion calculated from the 1H NMR spectrum of the reaction mixture.
Isolated yield by column chromatography.
%ee determined by chiral GC of the purified endo product [115 °C, tR 43.14 (minor) and 44.64 min (major)].
d
No 1,3-cyclohexadiene signals were detected by 1H NMR spectroscopy.

4216
S. Gosiewska et al. / Tetrahedron Letters 51 (2010) 4214–4217
Table 2
Ph
Ph
Reaction of DEAD with 3-methylbutanal catalysed by 11; variation of acid level,
NTs
NTs
catalyst loading and acida
OTBDPS
OTBDPS
Ph
Ph
N
N
N
N
Entry
mol % 11
mol % Acid
(AcOH unless stated)
Timeb (h)
Temp
eec
CO2Et
N
EtO2C
or
N
CO2Et
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
0
5
10
15
20
10
10
5
10.0
6.0
4.5
4.5
4.5
rt
rt
rt
rt
96.2 (R)
97.2 (R)
96.6 (R)
96.0 (R)
95.6 (R)
93.4 (R)
97.5 (R)
96.3 (R)
ndd
EtO2C
DEAD added
to upper face
DEAD added
to lower face
rt
CO2Et
CO2Et
HN
3.0
40 °C
0–5 °C
rt
rt
rt
O
24.0
23.5
30.0
3.0
N
R
2
10
2
10
CF3CO2H
10
PhCO2H
10
4-NO2C6H4CO2H
10
10
10
71.7 (R)
Figure 3. Addition of DEAD to an E-enamine with blocking of one face by
substituents on the heterocyclic ring of 11.
11
12
10
10
6.0
6.0
rt
rt
96.2 (R)
96.0 (R)
alysts were evaluated, this time with propanal as the aldehyde,
both with and without added acetic acid and with variation of
the dialkyldiazodicarboxylate (Table 3).
13e
14f
10
10
5/20/24
5/17/24
rt
rt
96.0 (R)
95.6 (R)
After completion of the reaction (Scheme 3) the aldehyde was
immediately reduced and cyclised to 17, for which isolated yields
are given. In each case, the addition of AcOH significantly reduced
the reaction time required for 100% conversion of DEAD to product.
Aminal 11 gave the best results, and TsDPEN 9 gave the product in
up to 49% ee. The use of the iPr and tBu versions of DEAD gave
products in good yields but after much longer reaction times.
Enantiomeric excesses were not determined in these cases. The
reaction was extended to alternative carbonyl substrates, which
gave mixed results. The addition of butanal and 3-phenylbutanal
worked well, giving products in 97% and 84% ee, respectively (R
enantiomers) (see Supplementary data).
a
Aldehyde = 3-methylbutanal, catalyst (R,R)-11, DEAD, no solvent, reactions
were all followed by 1H NMR (see Supplementary data for plots).
b
Time at which 100% conversion was observed by 1H NMR.
ee of cyclised product 17 after reduction of 16.
nd = not determined, decomposition of DEAD was observed.
Three cycles of aldehyde and DEAD addition, without extra AcOH; ee given for
c
d
e
last run.
f
Three cycles of aldehyde, DEAD and AcOH addition; ee given for last run.
Table 3
Comparison of catalysts with and without AcOH; propanal additiona
Entry
Catalyst
Diimide
AcOH (%)
Timeb
Yieldc
ee (17)
The formation of the product of R configuration using catalyst
11 suggests a reaction via an E-enamine, trans either to the OTBDPS
group or to the phenyl ring on the other side of the heterocyclic
ring, depending upon the conformation of the intermediate enam-
ine (Fig. 3). This would be consistent with the directing effects ob-
served using diarylprolinol catalysts in which the substituent on
the pyrrolidine ring acts as a blocking group to electrophile addi-
tion.13 The observation of the same sense of induction with catalyst
15 also suggests that the hydroxymethyl group is not directing the
addition, that is, via a hydrogen bond. Attempts to catalyse the
1
2
RR 11
RR 11
RR 9
RR 9
RR 13
RR 13
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
0
10
0
10
0
2 h
110 min
47 h
45 min
44 h
45 min
47%
55%
42%
66%
46%
66%
97% (R)
95% (R)
32% (R)
49% (R)
62% (R)
90% (R)
3e
4
5
6
10
7
8
9
10
11
RR 14
RR 15
RR 15
RR 11
RR 11
DEAD
DEAD
DEAD
DiPrAD
DtBuAD
10
0
10
0
115 min
5 d
31 h
22.5 h
70.5 h
84% (R)
0d
37%
99%
68%
ndf
61% (R)
ndf
0
ndf
a
addition of the
a-branched aldehydes formylcyclohexane and
Aldehyde = propanal, 10 mol % catalyst, rt in all cases, neat unless otherwise
stated.
2-methylpropanal (i.e., a non asymmetric addition) and ketones
(acetone and cyclohexanone) to DEAD were unsuccessful.
In conclusion, we have demonstrated that a stable aminal
derived from TsDPEN 9 can be used as a catalyst for asymmetric
C–C and C–N bond-forming reactions.
Time at which 100% conversion was observed by 1H NMR.
b
c
d
e
f
Isolated yield of cyclised product 17 after reduction of 16.
No reaction observed.
In CH2Cl2 solvent.
nd = not determined.
Acknowledgements
At rt (20–25 °C), using 10 mol % of 11, the reaction was com-
plete in 4.5 h, whilst at slightly elevated temperature the reaction
was faster but the ee was lower (entry 6). As anticipated, the re-
versed trend was seen at lower temperature (entry 7) which gave
the highest measured ee. The amount of catalyst 11 could be re-
duced to 5 mol % without loss of enantioselectivity, however, at
2 mol % the reaction was significantly slower and competing
decomposition of DEAD was observed. A number of alternative
acids were investigated (entries 10–12), with the strongest acid,
TFA giving the shortest reaction time, but products of lower ee
were formed. Finally, the repeated addition of substrate (both with
and without extra acid; entries 13 and 14) was tested and revealed
that the catalyst continued to promote the addition in high enanti-
oselectivity, although the reaction time increased with each addi-
tion. The lower reactivity, but retained high ee, suggests that
catalyst inhibition may be taking place, rather than hydrolysis,
since TsDPEN was found to give a product of much lower ee (see
below). Having established satisfactory conditions, a series of cat-
We thank Warwick University for financial support (Warwick
Postgraduate Research Studentship to R.S.) and EPSRC for financial
support (Grant No. EP/D031168/1 to S.G.). Dr. B. Stein and col-
leagues of the EPSRC National MS service (Swansea) are thanked
for HRMS analyses. We acknowledge the use of the EPSRC Chemical
Database Service.14 The Oxford Diffraction Gemini instrument was
obtained through the Science City Project with support from the
Advantage West Midlands (AWM) Advanced Materials Project and
part funded by the European Regional Development Fund (ERDF).
A. Supplementary data
Supplementary data (experimental details, X-ray data, NMR and
HPLC spectra, and graphs of experimental results) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.06.017.

S. Gosiewska et al. / Tetrahedron Letters 51 (2010) 4214–4217
4217
S.; Li, P.; Jin, M.; Xue, F.; Luo, G.; Zhang, H.; Song, L.; Duan, W.; Wang, W.
Tetrahedron Lett. 2008, 49, 2681–2684.
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