Acid-base dual-functional catalysis by axially chiral guanidine in enantioselective [3+2] cycloaddition of maleate to Schiff bases as a precursor of azomethine ylides

Article abstract of DOI:10.1055/s-0029-1217345

The enantioselective [3+2] cycloaddition reaction of dimethyl maleate with Schiff bases as the precursor of azomethine ylide was developed using axially chiral guanidine catalysts to provide optically active pyrrolidine derivatives. Acid-base dual-functio

Full text of DOI:10.1055/s-0029-1217345

1670
CLUSTER
Acid–Base Dual-Functional Catalysis by Axially Chiral Guanidine in
Enantioselective [3+2] Cycloaddition of Maleate to Schiff Bases as a Precursor
of Azomethine Ylides
E
nantioselective [3+2]
e
Cycloaddit
g
ion Catalyz
e
u
d
by
A
xially
m
C
hiral
G
uanidine i Nakano, Masahiro Terada*
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Fax +81(22)795-6602; E-mail: mterada@mail.tains.tohoku.ac.jp
Received 22 February 2009
catalyzed 1,3-dipolar cycloaddition reaction of azome-
Abstract: The enantioselective [3+2] cycloaddition reaction of
dimethyl maleate with Schiff bases as the precursor of azomethine
ylide was developed using axially chiral guanidine catalysts to pro-
vide optically active pyrrolidine derivatives. Acid–base dual-func-
thine ylides generated from Schiff bases 2. Our working
hypothesis is depicted in Scheme 1. Chiral guanidines 1
would give rise to ion pairs consisting of a guanidinium
tional catalysis by an axially chiral guanidine through double ion and an enolate of Schiff base 2 via deprotonation. As
hydrogen-bonding interaction is proposed to give the cycloaddition
shown in brackets, these ion pairs would have several res-
products in good yields.
onance structures generated by double hydrogen-bonding
Key words: asymmetric catalysis, cycloadditions, Schiff bases,
stereoselectivity, ylides
interaction. Among the structures speculated, it is consid-
ered that C would be a 1,3-dipole, where the nitrogen
atom of the imine moiety is protonated by the conjugate
acid, guanidinium ion, to form azomethine ylides C.
Guanidine is a ubiquitous element in natural products and Herein we report the enantioselective [3+2] cycloaddition
plays a key role in many biological activities.1 The guani- reaction of azomethine ylides catalyzed by axially chiral
dinium ion, the protonated form of guanidine, participates guanidine bases 1 (Equation 1).
in numerous biological transformations and functions as
an efficient recognition moiety of anionic substrates hav-
ing carboxylate or phosphate functionalities through elec-
O
G
Ar
N
OEt
trostatic interaction and the formation of two parallel
hydrogen bonds. In addition to their biological function,
guanidine derivatives are well known as strong bases from
the viewpoint of synthetic organic chemistry and have
been widely utilized as Brønsted base catalysts.2,3 By tak-
ing advantage of the strong basic character of guanidine
derivatives coupled with their biological function as rec-
ognition moieties, chiral guanidines have found use as ef-
ficient enantioselective catalysts for numerous organic
reactions to date.4,5 We recently developed guanidines 1
bearing the binaphthyl backbone as novel axially chiral
Brønsted base catalysts for enantioselective transforma-
tions.6
2
NH2
NH
N
(R)-1
G
(R)-1
•
N
NH
H
HN
•
•
H
Ar
N
O
N
N
Once the guanidine functions as a Brønsted base to accept
an acidic proton from a substrate, its conjugate acid, a
guanidinium ion, is generated. This cationic ion having an
acidic proton is expected to play the role of an acid cata-
lyst. In fact, the enantioselective catalysis by chiral guani-
dinium ion that acted as a Brønsted acid was reported
recently.7 Hence the acid–base dual function of a guani-
dine-derived monofunctional catalyst would be anticipat-
ed.8 We therefore have shifted our attention to the
potential of chiral guanidine as a dual functional catalyst
for enantioselective organic transformations, and have
envisioned the development of the chiral guanidine-
OEt
NH
H
NH
H
HN
H
HN
A
H
Ar
Ar
N
O
N
O
OEt
OEt
C
B
(azomethine ylide)
Scheme 1 Resonance structures of ion pairs generated by guanidine
catalysts 1 via deprotonation of Schiff base 2: formation of azometh-
ine ylides C
The enantioselective [3+2] cycloaddition reaction of
azomethine ylides is one of the most powerful methods
for the preparation of optically active pyrrolidine struc-
tures, which are the constituents of many natural products
SYNLETT 2009, No. 10, pp 1670–1674
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217345; Art ID: Y01109ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

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Enantioselective [3+2] Cycloaddition Catalyzed by Axially Chiral Guanidine
1671
O
albeit in moderate yield and enantiomeric excess (entry
1). The introduction of terphenyl (3,5-Ph2C6H3) substitu-
ents to the 3,3¢-position of the binaphthyl backbone to
give guanidine 1b increased the enantioselectivity slightly
but decreased the yield significantly (entry 1 vs. 2). In
contrast, modification at 3,5-positions of the terminal phe-
nyl ring of the p-biphenyl substituents, that is, catalysts
1c–e (entries 3–5), improved both chemical yield and
enantiomeric excess remarkably. Corresponding cyclic
product endo-4a was obtained in good yield with high
enantiomeric excess (88% ee) when guanidine 1e possess-
ing 4-(3,5-t-Bu2C6H3)C6H4 substituents was employed as
the catalyst (entry 5).6b Further screening for solvents in-
dicated that the enantioselectivities and the chemical
yields were markedly dependent on the solvent used (en-
tries 5–8). Diethyl ether was found to be the best among
the solvents examined (entry 5).
Ar
N
OEt
R
H
R
N
Ar
CO2Et
2: R = H, 2': R = CO2Et
(R)-1 (2 mol%)
+
CO2Me
MeO2C
CO2Me
4: R = H
MeO2C
3
Equation 1
and biologically active compounds. A number of efficient
enantioselective catalyses have been established using
chiral metal complexes.9.10 Recently, organocatalytic ap-
proaches to enantioselective [3+2] cycloaddition have
been reported.11 However, in most of those approaches, a
geminal diester moiety is introduced to Schiff bases 2¢ (ex.
R = CO2Et) to improve their reactivity. Monoesters of
Schiff bases 2 (R = H) are rarely applied to organocatalyt-
ic reactions presumably due to their insufficient reactivi-
ty.11c,e As axially chiral guanidines 1 were found to exhibit
extremely high catalytic activity compared with other or-
ganocatalysts reported,6 we attempted to use Schiff base
monoesters 2 as the precursor of azomethine ylides.
With the optimized reaction conditions in hand, we next
investigated the scope and limitations of the present enan-
tioselective [3+2] cycloaddition reaction catalyzed by
(R)-1e. As shown in Table 2, marked substituent effects of
the aromatic ring introduced to Schiff base 2 were ob-
served with respect to chemical yields and enantioselec-
tivities, even though endo-4 was formed exclusively in all
cases. In particular, enantioselectivity was highly depen-
dent not only on the electronic effect but also on the posi-
tion to which the substituent was introduced. Higher
enantioselectivity was achieved by introducing a more
electronically withdrawing group to the phenyl ring (en-
We started by investigating the substituent effects of the
Ar group of catalyst 1 (Table 1). An initial screening was
performed in the reaction of 2a with dimethyl maleate
(3a) using 2 mol% of 1a in diethyl ether. Delightfully, p-
biphenyl-substituted 1a afforded endo-4a12 exclusively,
Table 1 [3+2]-Cycloaddition Reaction of 2a with 3 Catalyzed by Various Axially Chiral Guanidines 1
G
NH2
NH
NC
N
O
N
NC
NC
OEt
H
H
N
G
2a
N
CO2Et
CO2Et
(R)-1 (2 mol%)
+
+
0 °C, 24 h
MeO2C
MeO2C
CO2Me
CO2Me
MeO2C
CO2Me
endo-4a
exo-4a
3a
Entry
Guanidine (1)
Solvent
Yield (%)a
endo/exob
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
ee (%)c for endo-4a
1
1a G = 4-PhC6H4
Et2O
Et2O
Et2O
Et2O
Et2O
THF
EtOAc
DME
64
37
87
85
90
35
79
51
57
63
72
69
88
39
86
20
2
1b G = 3,5-Ph2C6H3
3
1c G = 4-(3,5-Ph2C6H3)C6H4
4
1d G = 4-[3,5-(F3C)2C6H3]C6H4
5
1e G = 4-(3,5-t-Bu2C6H3)C6H4
6
1e
1e
1e
7
8
a Isolated yield.
b Determined by 1H NMR.
c Determined by chiral HPLC analysis; DAICEL Chiralpak AD-H.
Synlett 2009, No. 10, 1670–1674 © Thieme Stuttgart · New York

1672
M. Nakano, M. Terada
CLUSTER
tries 1–6) and enantiomeric excess reached 91% in the tions (in diethyl ether, 0 °C, 24 h) using guanidine (R)-1e
reaction of 2b bearing a methoxycarbonyl group at the as the catalyst (2 mol%),15 presumably because the unfa-
para position (entry 1). The positional effect also de- vorable 5-endo-trig cyclization mode was enforced on the
served attention: substitution at the para position with an intramolecular reaction of intermediate enolate D. Conse-
electron-donating methoxy group to give Schiff base 2g quently, cyclization product 4 would be obtained through
significantly decreased enantiomeric excess and chemical the concerted pathway. In fact, the stereospecific forma-
yield (entry 6), while meta-substituted product 4h was ob- tion of the 3,4-cis-isomer of 4 from the (Z)-dipolarophile,
tained in fairly good yield with the same enantiomeric ex- dimethyl maleate (3a), suggests that the reaction would
cess as that of unsubstituted product 4f (entry 7 vs. 5). In proceed via the concerted pathway. Moreover, as shown
addition, acyclic products, 1,4-addition products 5, were in Equation 2, the reaction of the (E)-dipolarophile, dime-
obtained in the reaction of unsubstituted 2f and Schiff thyl fumarate 3b, with Schiff base 2a yielded the 3,4-trans-
bases bearing an electron-donating methoxy group, 2g isomer of 4a exclusively, even if the reaction was accom-
and 2h (entries 5–7).
panied by the formation of 1,4-addition product 5a in 11%
yield. The specific formation of the 3,4-trans-isomer of 4a
from the (E)-dipolarophile strongly supports the proposed
reaction mechanism.
Table 2 [3+2]-Cycloaddition Reaction of Various Schiff Bases 2
with 3 Catalyzed by (R)-1e
O
Ar
N
NC
CO2Me (R)-1e
OEt
O
H
(2 mol%)
+
N
Ar
CO2Et
2
N
(R)-1e (2 mol%)
MeO2C
NC
Et2O
0 °C, 24 h
OEt
+
Et2O, 0 °C, 24 h
2a
3b
MeO2C
CO2Me
NC
MeO2C
CO2Me
endo-4
O
O
H
3a
N
CO2Et
N
+
Ar
MeO2C
N
OEt
OEt
MeO2C
4
3
CO2Me
CO2Me
MeO2C
CO2Me
5
3,4-trans-isomer of 4a
5a
11% yield
Entry
2 (Ar)
4
Yield (%)a ee (%)b
77% yield, 20% ee
Equation 2
1
2
3
4
5
6
7
8
9
2b 4-MeOCOC6H4
2c 4-F3CC6H4
2d 4-BrC6H4
2e 4-ClC6H4
2f Ph
4b
4c
4d
4e
4f
79
53
71
80
65d
21e
67f
78
80
91
86
81
77c
75
59
75
78
70
In order to gain further mechanistic insight into the
present catalytic reaction, we performed control experi-
ments using common achiral organic bases, N,N,N¢,N¢-tet-
ramethylguanidine (TMG) and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU). As shown in Equation 3, the
reaction of 2a with 3a catalyzed by these organic bases
provided cyclization product 4a accompanied by a signif-
icant amount of 1,4-addition product 5a.
2g 4-MeOC6H4
2h 3-MeOC6H4
2i 3-BrC6H4
2j 2-BrC6H4
4g
4h
4i
4j
organic base (2 mol%)
+
2a
MeO2C
CO2Me
a Isolated yield; endo-4 was obtained exclusively.
Et2O, 0 °C, 24 h
b Determined by chiral HPLC analysis; DAICEL Chiralpak AD-H.
c Absolute configuration of 4e was determined to be 2R,3S,4S,5S by
comparing with optical rotation reported in the literature.10h,13
d Diastereomeric mixture (2:1) of 1,4-addition product 5f was
obtained in 20% yield.
3a
NC
NC
O
H
N
CO2Et
N
+
OEt
e Diastereomeric mixture (2:1) of 1,4-addition product 5g was
obtained in 21% yield.
MeO2C
CO2Me
MeO2C
endo-4a
CO2Me
f Diastereomeric mixture (2:1) of 1,4-addition product 5h was
obtained in 15% yield.
5a
4a
5a
NH
N
It is considered that two reaction pathways might exist in
the present catalytic cycloaddition reaction, the concerted
and stepwise pathways (Scheme 2),14 because 1,4-addi-
tion products 5 were obtained in some cases. However,
the reaction of 1,4-addition product ( )-5a did not provide
any cyclization product 4a under the same reaction condi-
64% 35%
TMG :
DBU :
28% 66%
Me2N
NMe2
TMG
N
DBU
Equation 3
Synlett 2009, No. 10, 1670–1674 © Thieme Stuttgart · New York

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Enantioselective [3+2] Cycloaddition Catalyzed by Axially Chiral Guanidine
1673
N
N
O
NH
H
HN
H
Ar
N
NH
H
HN
H
3a
protonation
OEt
Ar
stepwise pathway
MeO2C
Ar
CO2Me
N
O
N
O
5
Ar
O
OEt
B
(R)-1
OEt
N
OMe CO2Me
(R)-1e (2 mol%)
(Ar = 4-NCC6H4)
5-endo-trig
D
O
OEt
2
N
N
H
NH
H
HN
H
N
Ar
CO2Et
3a
NH
H
HN
Ar
concerted pathway
4
H
3
Ar
MeO2C
N
O
CO2Me
N
O
3,4-cis-isomer of 4
(endo-4)
MeO2C
OEt
C
OEt
CO2Me
(azomethine ylide)
Scheme 2 Plausible reaction mechanisms of enantioselective [3+2]-cycloaddition reaction catalyzed by axially chiral guanidine 1
temperature. The resulting solution was quenched with sat. NH4Cl
aq (a few drops), and the solvents were removed. The residue was
purified by column chromatography (hexane–EtOAc = 4:1 to 1:2)
to afford 4. The ee was determined by chiral HPLC analysis.
The formation of 1,4-addition product 5a strikingly con-
trasts that observed in the enantioselective catalysis by ax-
ially chiral guanidines 1 where 5a was not formed at all.
The excellent selectivity of the reaction pathways under
the enantioselective catalysis could be ascribed to the fact
that the 1,3-dipole, azomethine ylide, is generated effi- Acknowledgment
ciently by chiral guanidines 1 as the acid–base dual-func-
tional catalyst through double hydrogen-bonding
interaction and hence [3+2] cycloaddition products 4 were
formed exclusively in most cases.
This work was supported by a Grant-in-Aid for Scientific Research
on Priority Areas ‘Advanced Molecular Transformation of Carbon
Resources’ (Grant No. 19020006) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. We also acknow-
ledge the JSPS Research Fellowship for Young Scientists (M.N.)
from the Japan Society for Promotion of Sciences.
In conclusion, we have developed the enantioselective
[3+2]-cycloaddition reaction of dimethyl maleate with
Schiff bases as the precursor of azomethine ylides using
axially chiral guanidines as catalyst. Optically active pyr-
rolidine derivatives were obtained in acceptable yields
with good enantioselectivities, except for Schiff bases
having an electron-donating substituent. Experimental
evidence suggests that the cycloaddition products were
obtained through the concerted pathway. It can be consid-
ered that the acid–base dual function of the axially chiral
guanidine through the double hydrogen-bonding interac-
tion is crucial to accelerate the present [3+2] cycloaddi-
tion reaction substantially, in comparison with the
catalysis by achiral organic bases. Further studies on the
enantioselective cycloaddition reaction of a series of dipo-
larophiles using axially chiral guanidine catalysts are on-
going in our laboratory.
References and Notes
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To a dry test tube was added 1.7 mg of catalyst 1e (0.02 equiv, 0.002
mmol), and the atmosphere was replaced with nitrogen. The catalyst
was dissolved in 0.5 mL of Et2O and cooled to 0 °C. Schiff base 2
(0.11 mmol) and dimethyl maleate (3a, 0.10 mmol, 12.5 mL) were
introduced at 0 °C. The resulting solution was stirred for 24 h at that
Synlett 2009, No. 10, 1670–1674 © Thieme Stuttgart · New York

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M. Nakano, M. Terada
CLUSTER
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(12) Compound 4a: white solid. HPLC analysis Chiralpak AD-H
(hexane–i-PrOH = 70:30, 1.0 mL/min, 210 nm, 30 °C):
tR = 16.5 (minor), 39.2 (major) min. 1H NMR (300 MHz,
CDCl3): d = 1.28 (3 H, t, J = 7.2 Hz), 3.24 (3 H, s), 3.57–
3.63 (1 H, m), 3.68 (3 H, s), 3.68–3.74 (1 H, m), 4.13 (1 H,
d, J = 8.4 Hz), 4.23 (2 H, q, J = 7.2 Hz), 4.52 (1 H, d, J = 7.2
Hz), 7.49 (2 H, d, J = 8.4 Hz), 7.61 (2 H, d, J = 8.4 Hz).
13C NMR (75.5 MHz, CDCl3): d = 14.0, 50.7, 51.5, 52.1,
61.5, 62.2, 64.6, 111.5, 118.5, 127.6, 132.0, 143.1, 170.2.
170.3, 170.5. ESI-HRMS: m/z calcd for C18H20N2O6 [M +
Na]+: 383.1214; found: 383.1213. [a]D22 –47.1 (c 0.99,
CHCl3).
(8) (a) Terada, M. Chem. Commun. 2008, 4097. (b) Also see:
Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett
2005, 1491.
(9) For reviews on asymmetric [3+2]-cycloaddition reactions of
azomethine ylides, see: (a) Gothelf, K. V.; Jørgensen, K. A.
Chem. Rev. 1998, 98, 863. (b) Nájera, C.; Sansano, J. M.
Angew. Chem. Int. Ed. 2005, 44, 6272. (c) Husinec, S.;
Savic, V. Tetrahedron: Asymmetry 2005, 16, 2047.
(d) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006,
106, 4484. (e) Bonin, M.; Chauveau, A.; Micouin, L. Synlett
2006, 2349. (f) Pellisier, H. Tetrahedron 2007, 63, 3235.
(g) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887.
(10) For selected examples, see: (a) Longmire, J. M.; Wang, B.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.
(13) Compound 4e: white solid. HPLC analysis Chiralpak AS-H
(hexane–i-PrOH = 70:30, 1.0 mL/min, 210 nm, 30 °C): tR =
8.7 (2S,3R,4R,5R), 23.6 (2R,3S,4S,5S) min. 1H NMR (300
MHz, CDCl3): d = 1.29 (3 H, t, J = 7.2 Hz), 3.26 (3 H, s),
3.52–3.57 (1 H, m), 3.65–3.72 (1 H, m), 3.68 (3 H, s), 4.12
(1 H, d, J = 8.4 Hz), 4.22 (2 H, q, J = 7.2 Hz), 4.46 (1 H, d,
J = 7.2 Hz), 7.29 (4 H, s). 13C NMR (75.5 MHz, CDCl3): d =
14.1, 50.7, 51.4, 52.0, 52.3, 61.5, 62.3, 64.6, 128.3, 128.4,
133.5, 135.9, 170.4. 170.6, 170.7. ESI-HRMS: m/z calcd for
(b) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen,
K. A. Angew. Chem. Int. Ed. 2002, 41, 4236.
(c) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.;
Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043.
(d) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003,
125, 10174. (e) Knöpfel, T. F.; Aschwanden, P.; Ichikawa,
T.; Watanabe, T.; Carreira, E. M. Angew. Chem. Int. Ed.
2004, 43, 5971. (f) Gao, W.; Zhang, X.; Raghunath, M. Org.
Lett. 2005, 7, 4241. (g) Alemparte, C.; Blay, G.; Jørgensen,
K. A. Org. Lett. 2005, 7, 4569. (h) Zeng, W.; Zhou, Y.-G.
Org. Lett. 2005, 7, 5055. (i) Cabrera, S.; Gómez Arrayás,
R.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394.
(j) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431.
(k) Nyerges, M.; Bendell, D.; Arany, A.; Hibbs, D. E.; Coles,
S. J.; Hursthouse, M. B.; Groundwater, P. W.; Meth-Cohn,
O. Tetrahedron 2005, 61, 3745. (l) Yan, X.-X.; Peng, Q.;
22
C17H20ClNO6 [M + Na]+: 392.0871; found: 392.0870. [a]D
–47.6 (c 1.0, CH2Cl2); lit.10h [a]D20 62.7 (c 1.0, CH2Cl2, 98%
ee).
(14) For stepwise [3+2]-type cycloaddition reaction of
azomethine ylide by base catalyst, see: Saito, S.; Tsubogo,
T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364.
(15) The intramolecular reaction of 1,4-addition product 5a using
TMG or DBU as organic base catalyst (2 mol%), instead of
chiral catalyst (R)-1e, did not provide cyclization product 4a
at all under the same reaction conditions.
Synlett 2009, No. 10, 1670–1674 © Thieme Stuttgart · New York

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