Chiral bicyclic guanidines: A concise and efficient aziridine-based synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.11.133

A series of chiral bicyclic guanidines, either symmetrical or non-symmetrical, was synthesized using a concise and efficient aziridine-based synthetic methodology. Starting from commercial amino alcohols, five synthetic steps were performed, with only thr

Full text of DOI:10.1016/j.tetlet.2005.11.133

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1007–1010
Chiral bicyclic guanidines: a concise and efficient
aziridine-based synthesis
Weiping Ye, Dasheng Leow, Serena Li Min Goh, Chin-Tong Tan,
Chee-Hoe Chian and Choon-Hong Tan*
Department of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543, Singapore
Received 21 October 2005; revised 16 November 2005; accepted 24 November 2005
Available online 9 December 2005
Abstract—A series of chiral bicyclic guanidines, either symmetrical or non-symmetrical, was synthesized using a concise and efficient
aziridine-based synthetic methodology. Starting from commercial amino alcohols, five synthetic steps were performed, with only
three requiring chromatographic purification, giving the desired guanidines in 43–71% overall yield. Preliminary studies using these
guanidines showed moderate enantioselectivity for several Michael reactions.
Ó 2005 Elsevier Ltd. All rights reserved.
Arginines are found in the active site of many enzymes
and it is likely that their guanidine side-chains are
involved in substrate recognition as well as in the cataly-
tic cycle.1 Guanidinium ions are known to interact with
phosphate- and carboxylate-containing biomolecules
and the synthesis of artificial bicyclic guanidinium ions
as selective anion receptors is of considerable interest
in bioorganic chemistry.2 The bicyclic guanidinium moi-
ety is also found in a large variety of structurally diverse
natural products isolated from marine organisms.3 These
natural products have received intense synthetic investi-
gations due to their interesting biological activities.
in several asymmetric reactions8 such as epoxidation,9
Michael addition using glycine imines,10,11 silylation of
secondary alcohols12 and the Strecker reaction of
imines.13
Base catalyzed reactions are ubiquitous in organic chem-
istry. However, there are relatively few examples of
organocatalytic reactions utilizing Brønsted bases.14
We are attracted to the possibility of using chiral bicyclic
guanidines as general organobases and are particularly
interested in the 1,4,6-triazabicyclo[3.3.0]oct-4-enes. It
is a challenge to develop these guanidines into a Ôprivi-
legedÕ class of catalysts that is capable of catalyzing a
variety of reactions.15 The current synthetic approaches
to these guanidines include the coupling of two amino
acid derivatives and reduction of the resulting amide
to obtain the triamine backbone.13,16 Another strategy
is to go through a thiourea intermediate, followed by
1,3-dimethylimidazolinium chloride induced step-wise
cyclization.17 However, a more efficient synthetic proto-
col is needed if this class of catalysts is to gain wide-
spread use. We envisioned that an effective synthesis
would take advantage of the C2-symmetric nature of
the catalyst.
We recently reported that 1,5,7-triazabicyclo[4.4.0]dec-
5-ene (TBD), a bicyclic guanidine base, is an excellent
catalyst for Michael and Michael-type reactions.4 The
C2-symmetrical derivatives of the core structures of
batzelladine and crambescidin alkaloids have been
found to accelerate the Michael addition reaction of
pyrrolidine to a,b-unsaturated lactones.5 These guanidi-
niums are also excellent phase transfer catalysts, partici-
pating in the highly enantioselective alkylation reaction
of tert-butyl glycinate.6 On the other hand, as free bases,
guanidines are known as superbases due to their high
pKa.7 Chiral guanidines have been shown to participate
Aziridines can undergo regio- and stereoselective ring
opening reactions, making them useful synthetic inter-
mediates.18 N-tosyl aziridines 2 (Scheme 1) were readily
prepared from their corresponding commercially
available amino alcohols.19 Triamines 3 were easily
obtained by treating 2 with 0.5 equiv of benzylamine.20
Keywords: Guanidine; Aziridine; Michael reaction; Enantioselectivity;
Regioselectivity.
*
Corresponding author. Tel.: +65 6874 2845; fax: +65 6779 1691;
e-mail: chmtanch@nus.edu.sg
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.133

1008
W. Ye et al. / Tetrahedron Letters 47 (2006) 1007–1010
R
equivalent of aziridine 2c, leading to the triamine back-
bone 7b in 84% yield (from 2c). Detosylation and cycli-
zation resulted in the guanidine 9b (overall yield of 50%
from amino alcohol 1c). A step-wise approach to con-
struct the triamine backbone provided an opportunity
to prepare non-symmetrical chiral bicyclic guanidines
such as 9a through the use of two different aziridines.
By stirring aziridine 2a in MeOH saturated with NH3
gas in a sealed vessel, a single ring-opening product 6a
was obtained. Diamine 6a was used as the nucleophile
for the ring-opening of a second aziridine, 2b, leading
to 7a in 80% yield (based on 2a). After removal of the
tosyl group and cyclization, guanidine 9a was obtained
in 71% yield (from 2a).
R
R
R
i
iii
OH
N
N
NH2
TsHN
Bn NHTs
Ts
1a, R=Bn
1b, R=iPr
1c, R=tBu
2a, R=Bn
2b, R=iPr
2c, R=tBu
3a, R=Bn
3b, R=iPr
ii
v
R
R
N
N
iv
R
R
H
N
N
NH2
NH2
H
5a, R=Bn
5b, R=iPr
4a, R=Bn
4b, R=iPr
Scheme 1. Reagents and conditions: (i) TsCl, Et3N, MeCN, 92% for
2a, 94% for 2b; (ii) TsCl, Et3N, MeCN, 4 A MS, 0 °C then MsCl, Et3N,
DMAP, CH2Cl2, rt, 80%; (iii) 0.5 equiv BnNH2, MeOH, 60 °C, 3 days,
92% for 3a, 75% for 3b; (iv) (a) Na, NH3(l), À78 °C, THF; (b) H2, Pd/
C, MeOH; (v) (MeS)2C@S then MeI/AcOH, MeNO2, reflux, 84% for
5a, 61% for 5b.
˚
With efficient syntheses of the chiral bicyclic guanidines
in hand, we embarked on a preliminary evaluation of
these catalysts in several Michael reactions. It is known
that amidine and guanidine bases can interact with
nitroalkanes in non-polar solvents and form tightly
bound ion pair complexes.21 Nitroalkanes are a valuable
source of stabilized carbanions and are widely used as
carbon nucleophiles for conjugate addition to enones.22
The Michael adducts retaining a nitro group can then
undergo a variety of transformations, making them ver-
satile building blocks for organic synthesis.22 Chiral
spirocyclic guanidines have been shown to catalyze the
Michael reaction of nitroalkanes to chalcone with mod-
est enantioselectivity.6a In general, there are relatively
few examples of catalytic Michael reactions of nitroalk-
anes to chalcone derivatives with satisfactory enantio-
selectivities.23 Thus, as a reasonable and reliable starting
point, the chiral bicyclic guanidines 5a, 5b, 9a and 9b
were tested as catalysts in the Michael reactions between
nitroalkanes and trans-chalcone 10 (Scheme 3).
Nucleophilic attack occurs preferentially at the sterically
least hindered carbon atom. Subsequent removal of the
tosyl group was achieved using sodium in liquid ammo-
nia and the crude product was immediately subjected to
catalytic hydrogenolysis without further purification.
The crude triamine 4 was subjected to the final cycliza-
tion step, leading to the expected guanidines 5a and 5b
in 71% and 43% overall yields, respectively, from their
amino alcohols. Out of the five synthetic steps used, only
three required chromatographic purification.
The formation of aziridine 2c (Scheme 1) did not pro-
ceed as expected via the usual protocol. Tosylation of
the hydroxyl group proceeded poorly after the forma-
tion of the N-sulfonamide intermediate. We found that
if methanesulfonyl chloride was added, the O-sulfonate
was formed more easily and it also facilitated the SN2
ring-closing reaction.
With 20 mol % TBD, a non-chiral guanidine base, the
conjugate addition of nitromethane 11a to chalcone 10
was complete within 1.5 h, giving 12a in 99% yield
(Table 1, entry 1). In the presence of 10–20 mol % of 5a,
5b and 9b, 13%, 32% and 56% ee (entries 2, 3 and 4) were
obtained, respectively. As the appendage of the catalyst
became bulkier, the enantioselectivity improved while
both the reaction rate and yield decreased. The enantio-
selectivity was also affected by the nature of the nitro-
alkanes. With 2-nitropropane 11b and 5b as catalyst
(entry 5), a higher enantioselectivity (61% ee) was
obtained than with nitromethane 11a (entry 3).
In our attempt to prepare guanidine 9b (Scheme 2), we
were faced with another obstacle; the aziridine double
ring-opening reaction of 2c with benzylamine turned
out to be slow and low yielding, giving mainly the
mono-opened product. The problem was circumvented
by treating aziridine 2c with NH3 to form the diamine
6c, which was used without purification to open another
R1
R2
2a
or
2c
i
R
ii
N
NH2
NHTs
Malonates and b-dicarbonyl compounds are another
important source of stabilized carbanions.22 In our
report on TBD-catalyzed Michael reactions, fumarate
H
TsHN
NHTs
6a, R=iPr
6c, R=tBu
7a, R1=Bn, R2=iPr
7b, R1=R2=tBu
R1
R2
NH2
N
iv
iii
N
H
R1
R2
R
R
NO2
N
N
NH2
O
O
H
R
R
catalyst
8a, R1=Bn, R2=iPr
8b, R1=R2=tBu
NO2
9a, R1=Bn, R2=iPr
9b, R1=R2=tBu
toluene, rt
11a, R=H
11b, R=Me
12a, R=H
12b, R=Me
10
Scheme 2. Reagents and conditions: (i) NH3/MeOH, 0 °C to rt; (ii)
MeCN, 95 °C, 3 days, 2b or 2c, 80% for 7a from 2a, 84% for 7b from
2c; (iii) Na, NH3(l), À78 °C, THF; (iv) (MeS)2C@S then MeI/AcOH,
MeNO2, reflux, 89% for 9a from 7a, 75% for 9b from 7b.
Scheme 3. Bicyclic guanidines-catalyzed Michael reaction of nitroalk-
anes with trans-chalcone 10.

W. Ye et al. / Tetrahedron Letters 47 (2006) 1007–1010
Table 1. The influence of different guanidine catalysts on the reaction in Scheme 3
1009
Entry
Donor
Catalyst/mol %
Time/h
Yielda/%
eeb/%
1
2
3
4
5
6
11a
11a
11a
11a
11b
11b
TBD (20)
5a (10)
5b (20)
9b (20)
5b (20)
9b (20)
1.5
168
90
168
96
99
NA
13
32
56
61
54
60c
42c
35c
23c
20c
120
a Isolated yield.
b Chiral HPLC.
c Reaction did not go to completion.
and fumaric derivatives were good substrates for the
reactions with dimethyl malonate.4 Using either 5a or
5b as catalyst, poor enantioselectivities (12% ee or less)
were observed when 1,2-dibenzoylethylene 13a or
dimethyl fumarate 13b were reacted with dimethyl
malonate (Scheme 4). It was observed that the reaction
of 13a gave a much higher yield and occurred at a much
faster rate than 13b. This implies that a,b-unsaturated
ketones are more electrophilic than a,b-unsaturated
esters.
NOE experiments confirmed the structures as 14c and
14d (see Supplementary data). The formation of the
product is directed by preferential attack of the malon-
ate towards the a,b-unsaturated ketone portion of the
substrates. To the best of our knowledge, this is the first
example of regioselective Michael reaction of such
unsymmetrical olefins.24 The enantioselectivity of this
reaction was determined to be 41%, 33% and 35% ee
when catalysts 5a, 5b and 9a (entries 2, 3 and 4, Table
2) were used, respectively. When substrate 13d was used,
the yield was improved to 86% but the enantioselectivity
decreased (entry 5).
The observed difference in reactivity prompted us to
investigate the regioselectivity of unsymmetrical conju-
gated compounds such as methyl trans-4-oxo-2-pent-
enoate 13c and ethyl trans-3-benzoylacrylate 13d
(Scheme 4). With various bicyclic guanidine catalysts,
only one regioisomer was observed for both substrates.
In summary, a concise and efficient aziridine-based
method has been developed for the preparation of a ser-
ies of chiral bicyclic guanidines. It consists of five chemi-
cal steps, with only three requiring chromatographic
purification. The overall yields were good, ranging from
43% to 71%. The synthesized guanidines catalyzed the
Michael addition of nitroalkanes to trans-chalcone with
moderate enantioselectivity. Similarly, they catalyzed
the Michael reactions of dimethyl malonate with fuma-
ric derivatives, providing excellent regioselectivity but
with only moderate enantioselectivity. Based on these
preliminary results, further work on asymmetric Michael
reactions catalyzed by the synthesized guanidines will be
carried out.
O
CO Me
2
catalyst
2
R
1
R
toluene, rt
CO Me
2
O
1
2
13a, R =R =Ph
1
2
13b, R =R =OMe
1
2
13c, R =Me, R =OMe
1
2
13d, R =Ph, R =OEt
MeO C
CO Me
MeO C
CO Me
2
2
2
2
O
O
2
1
R
R
+
1
2
R
R
Acknowledgements
O
O
14
15
1
2
14a, R =R =Ph
This work was supported by grants (R-143-000-196-101
and R-143-000-222-112) and a scholarship (to W.P.Y.)
from the National University of Singapore. We thank
the Medicinal Chemistry Program for their financial
support. We also thank Dr. Martin J. Lear for helpful
discussions.
1
2
14b, R =R =OMe
1
2
1
2
15c, R =Me, R =OMe
14c, R =Me, R =OMe
1
2
1
2
15d, R =Ph, R =OEt
14d, R =Ph, R =OEt
Scheme 4. Bicyclic guanidines-catalyzed Michael reaction of dimethyl
malonate with fumaric derivatives.
Table 2. The influence of different guanidine catalysts on the reaction in Scheme 4
Entry
Substrate
Catalyst/mol %
Time/h
14:15
Yielda/%
eeb/%
1
2
3
4
5
13c
13c
13c
13c
13d
TBD (20)
5a (20)
5b (10)
9a (10)
5b (20)
0.5
120
90
93
120
100:0
100:0
100:0
100:0
100:0
90
NA
41
33
35
23
40c
41c
46c
86
a Isolated yield.
b Chiral HPLC.
c Reaction did not go to completion.

1010
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