Chiral phosphoric acid-catalyzed enantioselective three-component Povarov reaction using cyclic enethioureas as dienophiles: Stereocontrolled access to enantioenriched hexahydropyrroloquinolines

Article abstract of DOI:10.1002/chem.201200523

Three become one: Phosphoric acid-catalyzed enantioselective three-component Povarov reactions of aldehydes, anilines, and endocyclic enethioureas have been developed (see scheme). This process afforded hexahydropyrroloquinolines in high yields with excellent diastereo- and enantioselectivities. The presence of the thiourea functionality is crucial for the enantioselectivity of the reaction. Copyright

Full text of DOI:10.1002/chem.201200523

COMMUNICATION
DOI: 10.1002/chem.201200523
Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component
Povarov Reaction Using Cyclic Enethioureas as Dienophiles:
Stereocontrolled Access to Enantioenriched Hexahydropyrroloquinolines
Guillaume Dagousset,[a] Pascal Retailleau,[a] Gꢀraldine Masson,*[a] and Jieping Zhu*[b]
Hexahydropyrrolo
[3,2-c]quinolines constitute a class of
nent fashion[12a,e,g,h] by using anilines, aldehydes and 2-pyrro-
line derivatives as dienophiles,[12] has also been exploited to
efficiently construct the tricyclic core of martinelline and
martinellic acid.[12] However, despite the recent develop-
ment of enantioselective Povarov reactions,[12j,13,14] there is
only one single example of an enantioselective two-compo-
nent Povarov cycloaddition, developed by Jacobsen, involv-
ing the use of N-Cbz-2-pyrroline (4a) as dienophile.[12j] Al-
though the enantioselectivity was excellent, the diastereose-
lectivity remained moderate for N-arylimines deriving from
aniline and aromatic aldehydes.[12j] Consequently, there is
a need for additional enantioselective catalytic Povarov re-
unusual azaheterocycles that is found in natural products,
such as martinelline and martinellic acid (Figure 1).[1] These
alkaloids, isolated from the roots of Martinella iquitosensis,[2]
display antibiotic activities and are the first nonpeptide an-
actions for the direct construction of hexahydropyrroloACHTUNGTRENNUNG[3,2-
Figure 1. Martinelline and martinellic acid with a hexahydropyrroloquino-
line core.
c]quinoline skeletons.[15,16]
We recently described a chiral phosphoric acid 5a cata-
lyzed three-component Povarov reaction using acyclic ene-
carbamates 4 as dienophiles (Scheme 1),[14] thereby allowing
tagonists for bradykinin B1 and B2 receptors.[1–3] The unusu-
al heterocyclic array contained in this family of pyrroloqui-
noline alkaloids, coupled with the interesting biological ac-
tivity, has made them attractive synthetic targets.
In this context, numerous elegant approaches for the con-
struction of hexahydropyrroloACTHNUGRTNEUNG[3,2-c]quinolines have been
developed, including, for example, 1) a [3+2] cycloaddition
between azomethine ylides and olefins,[4] 2) a silicon-teth-
ered RCM reaction/allylic amination,[5] 3) a cycloaddition
reaction of imines with 3-thiosuccinic anhydrides,[6] 4) an or-
ganocatalytic tandem Michael–aldol reaction,[7] 5) a tandem
Mukaiyama–Mannich reaction/aminal cyclization,[8] 6) a radi-
cal addition/cyclization/elimination sequence,[9] and 7) using
2-substituted 4-quinolinones as a key intermediate.[10] In ad-
dition, the Povarov reaction,[11] performed in a multicompo-
Scheme 1. Previous multicomponent Povarov reaction and its limitation
in the case of cyclic enecarbamate 4a.
[a] G. Dagousset, Dr. P. Retailleau, Dr. G. Masson
Centre de Recherche de Gif
direct access to highly substituted 4-aminotetrahydroquino-
lines 1[17] in high yields with excellent diastereo- and enan-
tioselectivities (87–99% ee).[18–20] However, with the five-
membered endocyclic enecarbamate N-Cbz-2,3-dihydropyr-
role (4a), lacking the NH function, the endo-hexahydropyr-
roloquinolone 1 was isolated in low yield and enantiomeric
excess.[11d,14] Nevertheless, these contrary results are in ac-
cordance with our mechanistic assumption that dual activa-
tion by hydrogen-bonding interactions between the bifunc-
tional phosphoric acid and both substrates (imine and ene-
carbamate) is crucial to achieve high enantioselectivity.[14]
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)169077247
E-mail: masson@icsn.cnrs-gif.fr
[b] Prof. Dr. J. Zhu
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
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.201200523.
Chem. Eur. J. 2012, 18, 5869 – 5873
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5869

Following this strategy, we en-
visioned that cyclic ene-
AHCTUNGTRENGN(UN thio)ureas 6, incorporating an
the backbone 3,3’-substituents on catalyst 5 and the NH
function of 6a are essential for the success of the process.
To reinforce the hydrogen-bonding network and the enan-
tioselectivity of the reaction, enethiourea 6b, having a more
acidic NH proton, was engaged in the Povarov reaction. To
our delight, the reaction of 6b with 3a and 2a in the pres-
ence of 0.1 equivalents of phosphoric acid 5g afforded the
endo-diastereomer 7b as a single detectable stereoisomer in
high yield (81%) and excellent enantioselectivity (92% ee,
entry 2).
NH donor group, might re-
store the missing hydrogen
bond with the catalyst 5,
therefore reestablishing the
high enantioselectivity in the
Povarov reaction via the tran-
sition state shown in the
Figure 2. In addition, we ex-
pected a better diastereoselec-
Figure 2. Hypothesized
dual
activation of an eneurea (ene-
thiourea) and an imine by
a phosphoric acid.
Having established the optimal conditions, we next exam-
ined the scope of this three-component Povarov reaction.
As shown in Table 2, aliphatic aldehydes were appropriate
substrates for this enantioselective three-component synthe-
sis of hexahydropyrroloquinolines 7. Indeed, linear and a-
or b-branched aliphatic aldehydes provided the desired cy-
cloadducts 7 in good yields with high diastereo- and enantio-
selectivities (entries 1–4 and 12–16). It is worth noting that
the competitive isomerization of the in situ formed aliphatic
N-arylimines to the corresponding enamines and/or the par-
tial isomerization of 6b were never observed.[22,23] This cata-
lytic process was also compatible with a,b-unsaturated alde-
hydes (entry 5), electron-neutral, -rich, and -poor aromatic
aldehydes (entries 6–10), and heteroaromatic aldehydes
(entry 11), affording the corresponding products 7g–7m in
similarly good yields (57–83%), high diastereoselectivities
(d.r.>9:1), and excellent enantioselectivities (84–98% ee).
Furthermore, a wide range of diversely functionalized ani-
lines (entries 12–16) were suitable partners for this reaction,
the best enantioselectivity being obtained for electron-poor
substrates (R2 =4-CF3, 96% ee, entry 15). When a meta-sub-
stituted aniline, such as 3-iodoaniline (entry 16), was used,
only the regioisomer 7-iodo-7s was isolated in 89% yield,
without a trace of the sterically more congested 5-iodo
isomer.[14] As expected, the R3 group of the thiourea 6 can
also influence the enantioselectivity of the reaction. While
the reaction with N-3,5-bis(trifluoromethyl)phenyl ene-
thiourea 6c afforded the product with a slightly reduced
enantiomeric excess (entries 2 vs. 1), no reaction occurred
with the bulky N-tert-butyl enethiourea 6d (result not
shown).
The absolute configuration of 7i was unambiguously as-
signed to (2S,3S,4S) by X-ray crystal structure analysis (see
the Supporting Information).[24] Mechanistically, the Povarov
reaction can proceed through either a concerted or a step-
wise process.[25] When using deactivated anilines as reaction
partners, the uncyclized Mannich adduct, in which the inter-
mediate iminium ions are trapped by water, has been isolat-
ed.[26] These results bore evidence of a stepwise mechanism
of the present Povarov reaction. Based on these observa-
tions, a simplistic mechanistic rationale that accounts for the
observed stereoselectivity was proposed (Scheme 2).[27] Ini-
tially, the bifunctional catalyst 5g activates both the imine
and the cyclic enethiourea by hydrogen bonding (compare
Figure 2). A pseudo-intramolecular Si-face attack of the
enethiourea to the iminium ion takes place via the transition
state 8, leading to the N-acyl iminium ion 9,[28] which then
tivity by using 6 instead of 4a, according to the seminal con-
tribution of Batey and co-workers.[12e]
Following this consideration, the three-component reac-
tion of 4-azidobutanal (2a), ethyl 4-aminobenzoate (3a),
and cyclic eneurea 6a in CH2Cl2 at À308C in the presence
of catalytic amounts of a phosphoric acid 5 (0.1 equiv) was
examined (Table 1). After having screened several diversely
Table 1. Survey of phosphoric acid catalysts 5 for the three-component
synthesis of hexahydropyrroloquinolines.[a]
Entry R1
6
Yield [%][b] endo/exo[c] ee [%][d]
1
2
3
4-ClC6H4 [H8] (5a)
6a
6a
6a
6a
6a
6a
48
34
61
41
56
56
72
6
5:1
4:1
5:1
4:1
5:1
27
5
9
42
29
20
88
43
92
4-OMeC6H4 (5b)
4-tBuC6H4 (5c)
SiPh3 (5d)
4
5
6
CH(Ph)2 (5e)
9-anthryl (5 f)
3.5:1
5:1
>95:5
>95:5
7
8
10
2,4,6-(iPr)3C6H2 (5g) 6a
2,4,6-(iPr)3C6H2 (5g) 4a
2,4,6-(iPr)3C6H2 (5g) 6b
81
[a] Reaction conditions: aldehyde 2a (0.1 mmol), aniline 3a (0.1 mmol),
ene(thio)urea (0.15 mmol), and catalyst (0.01 mmol) in CH2Cl2
A
6
5
(1.0 mL) at À308C. [b] Isolated yield after column chromatography.
[c] Ratio of endo/exo stereoisomers was determined by 1H NMR spec-
troscopy. [d] Enantiomeric excess was determined by HPLC analysis on
a chiral stationary phase.
substituted chiral phosphoric acids 5, we found that the
bulky (R)-TRIP catalyst (5g, TRIP=3,3’-bis(2,4,6-triisopro-
pylphenyl)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate) was
optimal in terms of both yield (72%) and enantiomeric
excess of the product 7a (88% ee), although the diastereose-
lectivity remained unsatisfactory (entry 7).[21] In a control
experiment using cyclic enecarbamate N-Cbz-2,3-dihydro-
pyrrole (4a) as dienophile, the corresponding cycloadduct
was obtained in a much lower yield (6%) and lower enan-
tiomeric excess (43% ee) under otherwise identical reaction
conditions (entry 8). These results clearly indicate that both
5870
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Chem. Eur. J. 2012, 18, 5869 – 5873

Chiral Phosphoric Acid Catalyzed Povarov Reaction
COMMUNICATION
Table 2. Enantioselective Povarov reaction using enethioureas as dieno-
phile.[a]
Table 2. (Continued)
Entry
Product
7
Yield
[%][a]
d.r.[c]
ee
[%][d]
10
7l
57
11:1
96
86
Entry
Product
7
Yield
[%][a]
d.r.[c]
ee
[%][d]
11
7m 83
9:1
1
7c
84
10:1
91
75
12
13
13
14
15
16
7n
7o
7p
7q
7r
82
78
80
83
90
89
8:1
18:1
85
85
86
92
96
88
2
7d
79
10:1
3
4
5
6
7e
7 f
7g
7h
64
93
68
72
11:1
7:1
98
93
91
84
10:1
20:1
9:1
>95:5
>95:5
>95:5
7s
[a] Reaction conditions: aldehyde 2 (0.1 mmol), aniline 3 (0.1 mmol),
enethiourea 6b (0.15 mmol), and catalyst 5g (0.01 mmol) in CH2Cl2
(1.0 mL) at À308C. [b] Isolated yield after column chromatography.
[c] Ratio of endo/exo stereoisomers was determined by 1H NMR spec-
troscopy. [d] Enantiomeric excess was determined by HPLC analysis on
a chiral stationary phase.
7
8
9
7i
81
77
81
14:1
>95:5
16:1
93
96
98
7j
7k
undergoes an intramolecular aza-Friedel–Crafts reaction to
give observed
the
(2S,3S,4S)-trisubstituted
hexahydropyrroloACHTUNGTERNN[UNG 3,2-c]quinolone 7 (Scheme 2).
Finally, the synthetic utility of these N-thiocarbamoyl aza-
heterocycles 7 was demonstrated by transformation of its
thiourea function into other functional groups.[29] According
to the procedure previously reported in literature,[12e,16] the
thiourea 7 f was converted to the corresponding guanidine
Chem. Eur. J. 2012, 18, 5869 – 5873
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5871

J. Zhu, G. Masson et al.
tive processes only worked with secondary enamides.[18b]
The current study revealed that both the nucleophilicity and
the enantioselectivity of tertiary enamides can be substan-
tially increased by their conversion to the corresponding
enethioureas. We believe that the approach delineated in
this paper could find application in designing other catalytic
enantioselective processes involving tertiary enamides as nu-
cleophiles.
Scheme 2. Proposed mechanism and stereochemical issue.
Experimental Section
General protocol: Aniline 3 (0.1 mmol) was added to a solution of alde-
hyde 2 (0.1 mmol) in dry CH2Cl2 (0.4 mL) at RT. After being stirred at
RT for 30 min, the reaction mixture was cooled to À308C and a solution
of phosphoric acid 5g (0.01 mmol) in CH2Cl2 (0.3 mL) and a solution of
the corresponding enethiourea 6b (0.15 mmol) in CH2Cl2 (0.3 mL) were
added. Then, the resulting solution was stirred under argon atmosphere
at À308C for 15 h. The solvent was removed in vacuo and the residue
was purified by flash chromatography on silica gel (n-heptane/EtOAc) to
afford the corresponding pure hexahydropyrroloACHTNUTRGNEUNG[3,2-c]quinoline 7.
Acknowledgements
Financial supports from CNRS are gratefully acknowledged. G.D. thanks
MESR for a doctoral fellowship, University of Paris XI.
Keywords: chiral Brønsted acids
·
enethioureas
·
Scheme 3. Transformations of the thiourea function.
multicomponent reactions
reaction
·
organocatalysis
·
Povarov
derivative 10 in 72% yield by a S-ethylation/nucleophilic ad-
dition of benzylamine sequence (Scheme 3a). Since the gua-
nidine-containing pyrroloquinoline is a core structural fea-
ture of martinelline and martinellic acid, 7 represents a new
entry to synthetic analogues of these biologically active nat-
ural products. Removal of the N-thiocarbamoyl group
turned out to be more challenging and, after a number of
unsuccessful trials, a two-step sequence was developed.
Thus, treatment of 7r with MeI in the presence of sodium
hydride, followed by TMSCN, afforded the imidoyl cyanide
11. Hydrolysis of 11 under acidic conditions (6n HCl,
EtOH, 758C) then provided the N-unprotected
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ACHTUNGTRENNUNG[3,2-c]quinoline 12 in 65% yield
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Chiral Phosphoric Acid Catalyzed Povarov Reaction
COMMUNICATION
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Received: February 27, 2012
Published online: March 29, 2012
Chem. Eur. J. 2012, 18, 5869 – 5873
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5873