Organocatalytic enantioselective one-pot four-component Ugi-type multicomponent reaction for the synthesis of epoxy-tetrahydropyrrolo[3,4-b] pyridin-5-ones

Article abstract of DOI:10.1002/chem.201202174

Enantioselective multicomponent reaction: In the presence of a catalytic amount of chiral BINOL-derived phosphoric acid (TRIP), the reaction of an α-isocyanoacetate 1, an aldehyde 2, and an aniline 3, followed by addition of a toluene solution of α,β-unsaturated acyl chloride 4 afforded the oxa-bridged tricycle 5 in excellent yield, diastereoselectivity, and enantioselectivity. Six chemical bonds, five stereogenic centers, and three cycles were formed in this one-pot four-component reaction. Copyright

Full text of DOI:10.1002/chem.201202174

COMMUNICATION
DOI: 10.1002/chem.201202174
Organocatalytic Enantioselective One-Pot Four-Component Ugi-Type
Multicomponent Reaction for the Synthesis of
Epoxy-tetrahydropyrroloACTHNUGRTNEUNG[3,4-b]pyridin-5-ones
Yingpeng Su,[a] Marinus J. Bouma,[a] Lilian Alcaraz,[b] Mike Stocks,[b] Mark Furber,[b]
Gꢀraldine Masson,*[a] and Jieping Zhu*[a, c]
The development of catalytic asymmetric reactions has
been one of the major research activities for the past
twenty-five years and nowadays remains a mainstream
chemical technology. While many uni- or bimolecular reac-
tions can currently be performed under catalytic conditions
to provide products in high yields with excellent enantiose-
lectivities,[1] the development of asymmetric multicompo-
nent reactions (MCRs) is still in its infancy.[2] In this context,
the development of asymmetric isocyanide-based MCRs is
known to be particularly challenging. While intensive efforts
have led to the development of a catalytic asymmetric Pass-
erini-type reaction[3] for the synthesis of a-acetoxy (a-hy-
droxy) amides[4] and enantiomerically enriched chiral non-
racemic heterocycles,[5] enantioselective Ugi-4CR remains
unknown.[6]
Scheme 1. Enantioselective one-pot four-component synthesis of epoxy-
tetrahydropyrrolo[3,4-b]pyridin-5-ones.
AHCTUNGTRENNUNG
Recently, we demonstrated that isocyanoacetates[7] bear-
ing an additional electron-withdrawing group at the a posi-
tion (1) display a different reactivity profile relative to the
parent one[8] and developed a three-component synthesis of
5-alkoxyoxazoles (4) by its reaction with aldehydes 2 and
amines 3.[9] As a continuation of our work[10] on organocata-
lytic enantioselective MCRs,[11] we report herein a Brønsted
acid[12] catalyzed enantioselective Ugi-type three-component
synthesis of 4 and the one-pot four-component synthesis of
with good to excellent diastereoselectivity and enantioselec-
tivity.
Reasoning that the absolute configuration of 2-(1-amino-
alkyl)-5-alkoxyoxazoles 4 will dictate those of the remaining
stereogenic centers in 6, we initiated our studies on the
chiral phosphoric acid-catalyzed enantioselective synthesis
of 4 using ethyl a-(p-nitrophenyl)-a-isocyanoacetate (1a),
pivalaldehyde (2a), and aniline (3a) as test substrates. As
summarized in Table 1, the optimum conditions consisted of
performing the three-component reaction at À358C in
CH2Cl2 (c 0.25m) in the presence of a bulky chiral phosphor-
ic acid (R)-TRIP (7g, 0.1 equiv; see Figure 1). Under these
conditions, 4a was isolated in 83% yield with 87% ee
(Table 1, entry 10).
epoxy-tetrahydropyrroloACTHUNRGTNE[NUG 3,4-b]pyridin-5-ones 6 (Scheme 1).
À
À
À
Six chemical bonds (one C O, two C N, and three C C)
and five contiguous stereogenic centers including two qua-
ternary ones were created in this four-component reaction
The scope of the reaction was examined next (Table 2).
Anilines bearing electron-donating (Me, OMe) or electron-
[a] Dr. Y. Su, Dr. M. J. Bouma, Dr. G. Masson, Prof. Dr. J. Zhu
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)1-69077247
E-mail: masson@icsn.cnrs-gif.fr
[b] Dr. L. Alcaraz, Dr. M. Stocks, Dr. M. Furber
AstraZeneca R & D Mçlndal
431 83 Mçlndal (Sweden)
[c] Prof. Dr. J. Zhu
Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fꢀdꢀrale de Lausanne, EPFL-SB-ISIC-LSPN
1015 Lausanne (Switzerland)
Fax : (+41)21-6939740
E-mail: jieping.zhu@epfl.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202174.
Figure 1. Structure of phosphoric acids used for catalyzing the reaction of
1a, 2a, and 3a.
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Table 1. Optimization of the three-component reaction.[a]
yl)-a-isocyanoacetate (1b) participated equally well in this
reaction to afford 4o in good yield and excellent ee
(Table 2, entry 14). The (R)-absolute configuration of oxa-
zole 4 was assigned based on X-ray crystallographic analysis
of compound 4 f[17] bearing a bromine atom (see the Sup-
porting Information for details).
With the conditions for the enantioselective synthesis of
5-alkoxyoxazoles in hand, we next turned our attention to a
Entry
Cat (equiv)
Solvent
T
[8C]
Yield
[%][b]
ee
one-pot
four-component
synthesis
of
epoxy-
[%][c]
tetrahydropyrroloAHCTUNGTRE[NNNUG 3,4-b]pyridin-5-ones 6. Eventually, stirring
1
2
3
4
5
6
7
8
7a (0.2)
7b (0.05)
7c (0.05)
7d (0.05)
7e (0.1)
7 f (0.1)
7g (0.1)
7g (0.1)
7g (0.1)
7g (0.1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
À78
À78
À78
À78
À78
À78
À78
À30
À30
À35
61
53
49
47
53
57
21
72
81
83
0
18
0
12
6
a CH2Cl2 solution of 1a, 2a, and 3a in the presence of chiral
phosphoric acid 7g at À358C for 24 h followed by addition
of cinnamoyl chloride 5a (R=Ph) and refluxing the result-
ing solution for 5 h afforded adduct 6a as a single detectable
diastereomer in 94% yield with 89% ee (Table 3, entry 1).
6
31
60
76
87
9[d]
10[d]
Table 3. Enantioselective
four-component
synthesis
of
epoxy-
tetrahydropyrrolo[3,4-b]pyridin-5-ones.
AHCTUNGTRENNUNG
[a] Reaction conditions: 1a/2a/3a=1.0/1.1/1.1; c=0.10m; aldehyde 2a
and aniline 3a were stirred at room temperature for 1 h followed by ad-
dition of phosphoric acid 7 and isocyanoacetate 1a at À788C. Stirring
was continued for 24 h at given temperature. [b] Yield of isolated prod-
uct. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] c=0.25m.
Entry
R1
R2
R
6, Yield
ee
Table 2. Scope of the three-component synthesis of 4.[a]
[%][a]
[%][b]
1
2
3
4
5
6
7
8
4-MeO-Ph
4-MeO-Ph
4-Me-Ph
4-Me-Ph
Ph
Ph
4-F-Ph
4-F-Ph
3-Br-4-MeO-Ph
3-Br-4-MeO-Ph
Ph
Ph
4-F-Ph
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
chex
chex
chex
chex
Ph
COOEt
Ph
COOEt
Ph
COOEt
Ph
COOEt
Ph
COOEt
Ph
COOEt
Ph
COOEt
6a, 94
6b, 76
6c, 76
6d, 81
6e, 81
6 f, 75
6g, 59
6h, 41
6i, 69
6j, 35
6k, 84
6l, 81
6m, 80
6n, 87
89
91
87
86
94
92
94
93
Entry R1
Ar1
Ar2
4
Yield ee
[%][b] [%][c]
1
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
4-Me-C6H4
C6H5
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
3-OMe-C6H4
3-Me-C6H4
3-Cl-C6H4
3,4-(Me)2-C6H3
3,5-(Me)2-C6H3
4-NO2-C6H4 4b
4-NO2-C6H4 4c
4-NO2-C6H4 4d
4-NO2-C6H4 4e
4-NO2-C6H4 4 f
4-NO2-C6H4 4g
4-NO2-C6H4 4h
4-NO2-C6H4 4i
4-NO2-C6H4 4j
4-NO2-C6H4 4k
78
76
80
76
84
94
93
65
95
95
87
87
92
93
92
91
92
92
92
89
90
92
84
84
94
2[d]
3[d]
4[d]
5[d]
6[d]
7[d]
8[d]
9
9
94
93
10
11
12
13
14
94[c]
81[d]
84[e]
84[c]
4-F-Ph
[a] Yield of isolated product. [b] Determined by HPLC analysis on a
chiral stationary phase. [c] d.r.=9/1. [d] d.r.=6/1. [e] d.r.=12/1.
tBu
tBu
tBu
10[d]
11[d]
12
13
14
3-Br-4-OMe-C6H3 4-NO2-C6H4 4l
chex C6H5
chex 4-F-C6H4
tBu
4-NO2-C6H4 4m 83
4-NO2-C6H4 4n
4-CN-C6H4 4o
80
77
Similarly, using 3-chlorocarbonylacrylic acid ethyl ester 5b
(R=COOEt) as the fourth component, compound 6b was
isolated in 76% yield with 91% ee (Table 3, entry 2). A se-
quence involving oxazole formation followed by intermolec-
ular acylation of the resulting secondary amine and intramo-
lecular hetero Diels–Alder reaction could account for the
formation of the observed product.[13] Interestingly, in this
one-pot four-component reaction, five stereogenic centers
were created and 16 pairs of enantiomers can be expected
theoretically. However, only one stereoisomer was obtained
in excellent yield and enantiomeric excess. The relative ster-
eochemistry of 6b was confirmed by its X-ray crystallo-
graphic analysis[17] (see the Supporting Information). The
coupling constant between Ha and Hb (JHa–Hb =4.0 Hz) indi-
cated a gauche relationship between these two protons, in
C6H5
[a] Reaction conditions: 1/2/3=1.0/1.1/1.1; c=0.25m in dichloromethane;
aldehyde 2 and aniline 3 were stirred at room temperature for 1 h fol-
lowed by addition of phosphoric acid 7g and isocyanoacetate 1 at À788C.
Stirring was continued for 5 min at À788C, then 24 h at À358C. [b] Yield
of isolated product. [c] Determined by HPLC analysis on a chiral station-
ary phase. [d] Reaction time: 48 h.
withdrawing groups (F, Cl, Br) in both meta- and para-posi-
tion underwent the reaction smoothly to afford the three-
component adduct 4 in high yields with excellent ee values.
Cyclohexanecarboxaldehyde behaved well in this reaction
(Table 2, entries 12 and 13), but linear aldehydes afforded
adducts with lower ee values. Finally, ethyl a-(p-cyanophen-
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Enantioselective Multicomponent Reactions
COMMUNICATION
accordance with the X-ray structure determined. Since the
oxazole intermediate is R-configured, the absolute configu-
ration of 6 was therefore determined as shown in Table 3.
The scope of this novel four-component reaction is shown
in Table 3. Excellent yields and enantiomeric excesses are
obtained for most of the oxa-bridged tricyclic adducts. The
diastereoselectivity was slightly reduced when cyclohexane-
carboxaldehyde was used and the formation of a minor dia-
stereomer was detected (6k–6n). However, the major prod-
uct shown in Table 3 has the same relative stereochemistry
as proven by X-ray structure analysis of compound 6b and
6k[17] (see the Supporting Information) as well as the charac-
teristic JHa–Hb (4.0 Hz) throughout these examples. When
electron-poor anilines were used, the acylation reaction was
less effective leading to the low conversion of the oxazole
intermediate. However, this can be remedied by filtration of
the catalyst after the initial oxazole formation followed by
addition of a solution of acyl chloride 5 in toluene.
tetrahydropyrroloACTHNGUTERNNUG
[3,4-b]pyridin-5-ones 6.[15] From the stereo-
chemical outcome that we observed, it was assumed that the
cycloaddition went through a concerted amide-exo/R3-endo
mode and that the bulky R1 group adopted a pseudo-equa-
torial position to avoid the steric interference with both
oxygen and the N-R2 group.
In summary, we developed an organocatalytic enantio-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
highly efficient leading to products in high yields with high
ee values. While the use of a-isocyanoacetate in enantiose-
lective transformation has attracted much attention recently,
all these reported catalytic asymmetric reactions are initiat-
ed by the nucleophilic addition of its a-carbanion to the po-
larized C=C and C=X bonds leading to formal [3+2] cyclo-
adducts.[16] To the best of our knowledge, the present work
represents the first examples of the enantioselective trans-
formation of a-isocyanoacetates wherein the stereogenic
center was generated by the nucleophilic addition of the di-
valent isocyanide carbon atom to the electrophiles (imines).
Together with our previous report on the a-isocyano acet-
amides,[6b,13] we expect further development of this approach
for the synthesis of complex enantioenriched polyheterocy-
cles, which are among the most medicinally relevant com-
pounds.
A possible reaction sequence leading to the enantioselec-
tive formation of heterocycles 6 is shown in Scheme 2. Con-
densation of aldehydes 2 and amines 3 led to imines 8,
Experimental Section
Four-component synthesis of epoxy-tetrahydropyrroloACTHUNRTGNEUNG[3,4-b] pyridin-5-
ones: To a flame-dried round-bottom flask equipped with a stir bar were
added aniline (0.05 mmol), aldehyde (1.1 equiv), and dry CH2Cl2
(0.1 mL). The solution was stirred at room temperature for 1 h. The
phosphoric acid (0.1 equiv) was then introduced and the resulting mix-
ture was cooled to À788C.
A solution of ethyl a-isocyanoacetate
(1.1 equiv) in CH2Cl2 (0.1 mL) was injected slowly by using a syringe
pump (addition time 5 min), and the resulting reaction mixture was stir-
red at À358C for 24 h. Then, the reaction mixture was cooled to 08C and
was diluted with toluene (1.0 mL). Et3N (6.0 equiv) was added followed
by acyl chloride (2.5 equiv). The reaction mixture was then heated to
reflux until the complete consumption of the intermediate amide. Satu-
rated aqueous NaHCO3 was added and the mixture was extracted with
CH2Cl2. The combined organic phases were washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (heptane/EtOAc=6/1) to afford
the desired product.
Scheme 2. Proposed mechanism for the formation of epoxy-
tetrahydropyrroloACHTUNGTRENNUNG[3,4-b]pyridin-5-ones.
which would be protonated by the chiral Brønsted acid 7g
to form an ion pair 9.[14] Nucleophilic attack of the divalent
carbon atom of isonitrile to the si-face of iminium would
afford the nitrilium intermediates 10. Deprotonation of the
a-proton by phosphate followed by the attack of the result-
ing enolate oxygen atom at the nitrilium carbon atom would
afford oxazole 4 with the concurrent regeneration of the cat-
alyst 7g. Following addition of acyl chloride 5 and triethyla-
mine, acylation of the secondary amine would take place to
produce 11, which would undergo intramolecular Kondrat’e-
va type Diels–Alder reaction to afford epoxy-
Acknowledgements
We thank the CNRS (France), EPFL (Switzerland), and Astrazeneca for
financial support. Y.S. thanks AZ for a post-doctoral fellowship and M.B.
thanks ICSN for a doctoral fellowship.
Keywords: brønsted acid
·
multicomponent reactions
·
organocatalysis · Ugi reaction · a-isocyanoacetate
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These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
Received: June 19, 2012
Published online: && &&, 0000
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Enantioselective Multicomponent Reactions
COMMUNICATION
Multicomponent Reactions
Y. Su, M. J. Bouma, L. Alcaraz,
M. Stocks, M. Furber, G. Masson,*
J. Zhu* ......................... &&&& — &&&&
Organocatalytic Enantioselective One-
Pot Four-Component Ugi-Type Multi-
component Reaction for the Synthesis
of Epoxy-tetrahydropyrroloACTHNUTRGENUG[N 3,4-
b]pyridin-5-ones
Enantioselective multicomponent reac-
tion: In the presence of a catalytic
amount of chiral BINOL-derived phos-
phoric acid (TRIP), reaction of an a-
isocyanoacetate (1), an aldehyde (2),
and an aniline (3), followed by addi-
tion of a toluene solution of a,b-unsa-
turated acyl chloride 4 afforded the
oxa-bridged tricycle 5 in excellent
yield, diastereoselectivity, and enantio-
selectivity. Six chemical bonds, five
stereogenic centers, and three cycles
were formed in this one pot four-com-
ponent reaction.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!