Highly regio-, diastereo-, and enantioselective 1,6- and 1,8-additions of azlactones to Di- and trienyl N -acylpyrroles

Article abstract of DOI:10.1021/ja310209g

A vinylog of Michael addition (1,6-addition) of azlactones to η-substituted dienyl N-acylpyrroles has been developed with virtually complete 1,6-, diastereo-, and enantioselectivities by means of chiral P-spiro triaminoiminophosphorane as a catalyst. This system has been successfully extended to an unprecedented bis-vinylog of Michael addition (1,8-addition) of azlactones to ζ-substituted trienyl N-acylpyrroles with high levels of regio- and stereocontrol.

Full text of DOI:10.1021/ja310209g

Communication
pubs.acs.org/JACS
Highly Regio‑, Diastereo‑, and Enantioselective 1,6- and 1,8-
Additions of Azlactones to Di- and Trienyl N‑Acylpyrroles
Daisuke Uraguchi, Ken Yoshioka, Yusuke Ueki, and Takashi Ooi*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan
S
* Supporting Information
Table 1. Effect of the Structure of Catalyst 1 and Ar1 of
Azlactone 3 on the Stereoselectivity
a
ABSTRACT: A vinylog of Michael addition (1,6-
addition) of azlactones to δ-substituted dienyl N-
acylpyrroles has been developed with virtually complete
1,6-, diastereo-, and enantioselectivities by means of chiral
P-spiro triaminoiminophosphorane as a catalyst. This
system has been successfully extended to an unprece-
dented bis-vinylog of Michael addition (1,8-addition) of
azlactones to ζ-substituted trienyl N-acylpyrroles with high
levels of regio- and stereocontrol.
b
de
,
n contrast to the considerable progress in the field of
Icatalytic asymmetric Michael addition (1,4-addition) of
carbon nucleophiles to electron-deficient alkenes, research on
the development of the vinylog of Michael addition (1,6-
addition) to extended conjugated systems, such as dienyl
carbonyl compounds, has largely been sporadic, despite the
potential synthetic utility of the reaction.1 While the principle
of vinylogy states that the reactivity is, in theory, maintained by
the propagation of the electronic effect of the directing
functional group through a conjugated π system,2 it is well
recognized that 1,4-addition is generally favored over 1,6-
addition even with electron-deficient dienes.3 Several transition-
metal catalysts have been shown to be effective for overcoming
this regioselectivity issue, enabling the introduction of
carbanionic nucleophiles to the δ-carbon of δ-substituted
dienyl acceptors with high levels of enantiocontrol.4−7 On the
other hand, there is only one example of the catalytic
asymmetric 1,6-addition of enolates, in which δ-unsubstituted
dienyl carbonyl and sulfonyl compounds were employed to
appreciate the spatial accessibility of the terminal double bond
for governing the regioselectivity.8 This methodological
deficiency poses a formidable challenge associated with control
of not only the regiochemistry but also the stereochemistry in
the addition of prochiral enolates to δ-substituted, electron-
deficient dienes, where simultaneous discrimination of both
enantiofaces of the enolate and the vinylogous Michael
acceptor should be realized. Alexakis and Stephens recently
demonstrated the effectiveness of using 1,3-bis(sulfonyl)-
butadiene as an acceptor for guiding the initial 1,6-addition of
a chiral enamine intermediate in a catalytic stereoselective
formal [4+2] cycloaddition with aldehydes to give optically
active 1,3-bis(sulfonyl)cyclohexadienes.9,10 In conjunction with
our continuous efforts to explore the potential of P-spiro chiral
triaminoiminophosphorane11 of type 1 (see Table 1) as a
strong organic base catalyst,12−14 we disclose herein our
solution to this problem: the development of a highly diastereo-
catalyst
yield
(%)
ee
cd
,
entry
R, Ar (1)
3
dr
(%)
prod
1
2
3
4
5
6
7
8
iPr, Ph (1a)
Me, Ph (1b)
Bn, Ph (1c)
iBu, Ph (1d)
iBu, 4-MeC6H4 (1e)
iBu, 4-FC6H4 (1f)
1f
3a
3a
3a
3a
3a
3a
3b
3c
93
96
91
95
93
99
96
97
10:1
12:1
2:1
79
84
38
92
86
94
91
98
4a
4a
4a
4a
4a
4a
5a
6a
13:1
11:1
12:1
14:1
>20:1
1f
a
Reactions were performed with 0.11 mmol of 2a and 0.1 mmol of 3
in toluene (1.0 mL) in the presence of 1 (5 mol %) at 0 °C for 1−2 h.
Isolated yield. Diastereomeric ratios of 1,6-adducts were indicated,
which were determined by H NMR (400 MHz) analysis of crude
aliquot. Absolute configurations of 4a−6a were assigned by analogy
to that of 6d. Enantiomeric excesses of the major diastereomer were
b
c
1
d
e
indicated, which were analyzed by chiral stationary phase HPLC.
and enantioselective 1,6-addition of azlactones15 to simple δ-
monosubstituted dienyl N-acylpyrroles 23a,d,h by the utilization
of chiral iminophosphorane 1f as a requisite catalyst for total
yet rigorous selectivity control. Furthermore, this system can be
successfully extended to the hitherto unknown bis-vinylog of
Michael addition (1,8-addition) to ζ-substituted trienyl accept-
ors with high levels of regio- and stereocontrol.
As a vinylogous Michael acceptor, we employed dienyl N-
acylpyrrole 2 in consideration of its synthetic utility, i.e., the N-
acylpyrrole moiety can be easily converted into various
carbonyl functionalities with different oxidation states.16,17
The initial attempt was made by treating N-(2E,4E)-
hexadienoylpyrrole 2a with azlactone 3a in the presence of 5
mol % of L-valine-derived iminophosphorane 1a in toluene at 0
°C. The reaction proceeded to completion in 2 h, and
Received: October 16, 2012
Published: November 12, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
interestingly, 1H NMR (400 MHz) analysis of the crude aliquot
revealed the exclusive formation of the 1,6-adduct, β,γ-
unsaturated N-acylpyrrole 4a, with a diastereomeric ratio of
10:1 (Table 1, entry 1). Since no evidence for the concomitant
production of the isomeric, α,β-unsaturated analog of 4a was
detected, the intermediary generated vinylogous enolate was
thought to be protonated predominantly at the α-position of
the carbonyl group. After purification by standard silica gel
column chromatography, the diastereomeric mixture of 4a was
isolated in 93% yield with promising enantioselectivity for the
major diastereomer (79% ee). Encouraged by this prime finding
of the extraordinarily regioselective 1,6-addition, we next
investigated the effect of the catalyst structure on the
stereochemical outcome. In accordance with our anticipation,
appropriate choice of the alkyl group (R) originating from the
parent α-amino acid and the geminal aromatic substituents
(Ar) on the diazaphosphacycles of 1 turned out to be crucial for
improving the stereoselectivity. This scrutiny led to the
identification of L-leucine-derived iminophosphorane 1f bearing
4-fluorophenyl substituents as an optimal catalyst, and 4a was
isolated with good diastereoselectivity (dr = 12:1) and high
enantiomeric excess of 94% (entries 1−6). It should be noted
that the diastereo- and enantioselectivities were further
enhanced by the modification of the aromatic substituent at
the 2-position of azlactone 3. Introduction of a 2,6-
dimethoxyphenyl group (3c) allowed for the addition of 2a
to proceed with virtually complete selectivity control in the
presence of 1f to afford almost stereochemically pure 6a in 97%
yield (entries 7 and 8).
Having established the optimized conditions, we studied the
scope of this new catalytic, highly stereoselective 1,6-addition
protocol. The representative results are listed in Table 2.
Generally, the reaction reached completion within 3 h using 5
mol % of 1f to give 6 in nearly quantitative yield, and neither
the isomeric α,β-unsaturated 1,6-adducts nor the 1,4-adducts
were formed to a detectable extent. With respect to the
vinylogous Michael acceptor, the present system tolerated the
incorporation of various linear and branched terminal
substituents (R1, 2b−e), and excellent stereoselectivities were
uniformly observed (entries 1−4). Dienyl N-acylpyrroles 2f−h
bearing a functional group, such as olefin, ether, and ester, also
appeared to be good candidates for the reaction (entries 5−
7).18 In addition to the benzyl-substituted 3c, other azlactones
with different alkyl appendages at the 4-position (R2, 3d−f)
could be employed as donor substrates, and high levels of
stereochemical control were achieved regardless of their
structural features (entries 8−10).
Table 2. Substrate Scope of the 1,6-Addition of Azlactones 3
(Ar1 = 2,6-(MeO)2C6H3) to δ-Substituted Dienyl N-
a
Acylpyrroles 2
b
cd
,
time
(h)
yield
ee
entry
R1 (2)
3
(%)
(%)
6
1
2
Me(CH2)2 (2b)
Me(CH2)6 (2c)
Ph(CH2)2 (2d)
iBu (2e)
3c
3c
3c
3c
3c
3c
3c
3d
3e
3f
2
2
3
2
2
2
2
2
3
1
94
84
99
95
98
93
96
98
97
95
98
98
98
98
98
97
94
98
94
90
6b
6c
6d
6e
6f
3
4
5
CH2CH(CH2)3 (2f)
BnOCH2 (2g)
BzOCH2 (2h)
Me (2a)
6
6g
6h
6i
7
8
9
Me (2a)
6j
10
Me (2a)
6k
a
Reactions were performed with 0.11 mmol of 2 and 0.1 mmol of 3 in
toluene (1.0 mL) in the presence of 1f (5 mol %) at 0 °C.
Diastereomeric ratios of 6 were >20:1 as indicated, which were
determined by 1H NMR (400 MHz) analysis of crude aliquot.
b
c
Isolated yield. Absolute configuration of 6d was determined by X-ray
crystallographic analysis of its derivative 8, see Scheme 1 and the SI for
details. Absolute configurations of 6b,c, and 6e−k were assigned by
d
analogy to that of 6d. Enantiomeric excesses of the major
diastereomer of 6 were indicated, which were analyzed by chiral
stationary phase HPLC.
Scheme 1. Derivatization of 1,6-Adduct 6d (Ar1 = 2,6-
(MeO)2C6H3) for Determination of Absolute Configuration
The N-acylpyrrole and azlactone moieties of the 1,6-adducts
6 could be separately derivatized into various carbonyl
functionalities.15,16 For example, the N-acylpyrrole moiety
could be readily converted into the corresponding esters by
treatment with sodium methoxide, as shown by the illustrative
transformation from 6d to 7 in Scheme 1. Subsequent ring
opening of the azlactone component19 with 4-chloroaniline
afforded secondary amide 8, and its single-crystal X-ray
diffraction analysis allowed us to determine the absolute
configuration of 6d.20
The significant potential of our approach based on the
catalysis of P-spiro chiral triaminoiminophosphorane 1f was
amply demonstrated by applying it to the development of the
bis-vinylogous 1,8-addition of 3 to trienyl N-acylpyrroles 9
(Table 3).21 Reaction of 3c with (2E,4E,6E)-octatrienoylpyr-
role 9a under the same conditions as those for 1,6-addition,
except for the use of powdered 4A molecular sieves (MS4A),22
resulted in carbon−carbon bond formation at the ζ-position of
9a to afford the 1,8-adduct, β,γ,δ,ε-unsaturated N-acylpyrrole
10a, almost exclusively in 89% yield (1,8-/1,6-/1,4-adducts =
1
>20:<1:1) (entry 1). Further, H NMR (400 MHz) analysis
indicated that 10a was obtained virtually as a single
diastereomer (dr = >20:1), and the enantiomeric excess was
determined to be 99% by chiral HPLC measurement. A brief
survey of the possible variation in the structures of the pro-
nucleophile 3 and the bis-vinylogous Michael acceptor 9
showed the promising generality of this unprecedented,
regioselective 1,8-addition of enolates to electron-deficient
trienes efficiently catalyzed by 1f with remarkably high relative
and absolute stereocontrol (entries 2−5, Table 3).
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Journal of the American Chemical Society
Communication
Table 3. Catalytic, Regio- and Stereoselective 1,8-Addition of Azlactones 3 (Ar1 = 2,6-(MeO)2C6H3) to Trienyl N-Acylpyrroles
a
9
b
ef
,
yield
ee
c
de
,
entry
R3 (9)
R2 (3)
(%)
rr (1,8:1,6:1,4)
dr
(%)
prod
1
2
3
4
5
Me (9a)
Me(CH2)6 (9b)
BnOCH2 (9c)
9a
Bn (3c)
89
94
98
90
90
>20:<1:1
>20:<1:1
14:1:<1
>20:1
18:1
99
99
98
99
99
10a
10b
10c
10d
10e
3c
3c
>20:1
>20:1
8:1
4-MeOC6H4CH2 (3d)
iBu (3e)
>20:<1:1
>20:<1:1
9a
a
Reactions were performed with 1f (5 mol %), 0.11 mmol of 9, and 0.1 mmol of 3 in toluene (1.0 mL) containing 100 mg of MS4A at 0 °C for 10 h.
b
c
Isolated yield. Regioisomeric ratios (rr) were determined by 1H NMR (400 MHz for entries 1, 3, and 4, 700 MHz for entries 2 and 5) analysis of
d
1
crude aliquot. Diastereomeric ratios of 1,8-adduct 10 were indicated, which were determined by H NMR (400 MHz for entries 1, 3, and 4, 700
MHz for entries 2 and 5) analysis of crude aliquot. Absolute configurations of 10a−e were assigned by analogy to that of 6d. Enantiomeric excesses
of the major diastereomer of 10 were indicated, which were analyzed by chiral stationary phase HPLC.
e
f
(3) For recent, selected examples of asymmetric 1,4-additions to
electron-deficient dienes, see: (a) Park, S.-Y.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 2815.
(b) Agostinho, M.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 2430.
(c) Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org. Lett.
In conclusion, we have developed the 1,6-addition of
azlactones to δ-monosubstituted dienyl N-acylpyrroles with
essentially complete control of regio-, diastereo-, and
enantioselectivities by virtue of chiral P-spiro triaminoimino-
phosphorane as a strong organic base catalyst. This method-
ology has further been evolved into the highly regio- and
stereoselective 1,8-addition to ζ-substituted trienyl acceptors.
We believe that the present study would provide a new
perspective of coping with the selectivity issues associated with
the conjugate addition of prochiral enolates to prochiral
electron-deficient polyenes and of exploiting rich chemistry
involved in this type of selective carbon−carbon bond-forming
reactions.
́
2008, 10, 4557. (d) Vakulya, B.; Varga, S.; Soos, T. J. Org. Chem. 2008,
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(4) For chiral transition-metal complex-catalyzed enantioselective
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Hartog, T.; Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
́
L. Angew. Chem., Int. Ed. 2008, 47, 398. (e) Henon, H.; Mauduit, M.;
Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 9122. (f) Nishimura, T.;
Yasuhara, Y.; Sawano, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
7872. (g) Nishimura, T.; Noishiki, A.; Hayashi, T. Chem. Commun.
2012, 48, 973. (h) Magrez, M.; Wencel-Delord, J.; Alexakis, A.;
Corresponding Author
tooi@apchem.nagoya-u.ac.jp
Notes
The authors declare no competing financial interest.
́
Crevisy, C.; Mauduit, M. Org. Lett. 2012, 14, 3576. (i) Sawano, T.;
Ashouri, A.; Nishimura, T.; Hayashi, T. J. Am. Chem. Soc. 2012, 134,
DOI: 10.1021/ja309756k.
(5) For an enantioselective silyl 1,6-addition to a β-substituted cyclic
dienone, see: Lee, K.-s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132,
2898.
(6) Recently, an organocatalytic, 1,6-selective sulfa-Michael reaction
was reported. Tian, X.; Liu, Y.; Melchiorre, P. Angew. Chem., Int. Ed.
2012, 51, 6439.
(7) Sun, H.-W.; Liao, Y.-H.; Wu, Z.-J.; Wang, H.-Y.; Zhang, X.-M.;
Yuan, W.-C. Tetrahedron 2011, 67, 3991.
́
(8) Bernardi, L.; Lopez-Cantarero, J.; Niess, B.; Jørgensen, K. A. J.
Am. Chem. Soc. 2007, 129, 5772.
ACKNOWLEDGMENTS
■
Work was supported by NEXT program, a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT, Program for
Leading Graduate Schools “Integrative Graduate Education and
Research Program in Green Natural Sciences” in Nagoya
University, Grants of JSPS for Scientific Research, and the
Asahi Glass Foundation. Y.U. acknowledges JSPS for financial
support.
(9) For nonstereoselective examples, see: (a) Masuyama, Y.; Sato, H.;
Kurusu, Y. Tetrahedron Lett. 1985, 26, 67. (b) Padwa, A.; Gareau, Y.;
Harrison, B.; Norman, B. H. J. Org. Chem. 1991, 56, 2713. (c) Padwa,
A.; Gareau, Y.; Harrison, B.; Rodriguez, A. J. Org. Chem. 1992, 57,
3540.
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Journal of the American Chemical Society
Communication
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adduct 6 (R1 = Ph), diastereo- and enantioselectivity are rather
sensitive to the content of the water in the reaction media. So far, we
have found that the presence of an appropriate amount of water is
crucial for enhancing stereoselectivity, but establishment of a
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1,6-addition to 2a.
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