Highly stereoselective Michael addition of azlactones to electron-deficient triple bonds under P-spiro chiral iminophosphorane catalysis: Importance of protonation pathway

Article abstract of DOI:10.1039/c2sc22027j

A catalyst-controlled, geometrically divergent asymmetric Michael addition of azlactones to methyl propiolate has been achieved under the catalysis of P-spiro chiral triaminoiminophosphoranes. An uncommon O-protonation of the intermediary allenic enolate is proposed to rationalize geometric control and its validity is proven by the development of highly Z- and enantioselective Michael addition of azlactones to cyanoacetylene with broad substrate scope.

Full text of DOI:10.1039/c2sc22027j

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EDGE ARTICLE
Highly Stereoselective Michael Addition of Azlactones to Electron-
Deficient Triple Bonds under P-Spiro Chiral Iminophosphorane
Catalysis: Importance of Protonation Pathway†
Daisuke Uraguchi, Yusuke Ueki, Atsushi Sugiyama, and Takashi Ooi*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/c1sc00000x
A catalyst-controlled, geometrically divergent asymmetric Michael addition of azlactones to methyl
propiolate has been achieved under the catalysis of P-spiro chiral triaminoiminophosphoranes. An
uncommon O-protonation of the intermediary allenic enolate is proposed to rationalize geometric control
10 and its validity is proven by the development of highly Z- and enantioselective Michael addition of
azlactones to cyanoacetylene with broad substrate scope.
The Michael addition of carbon nucleophiles to α,β-
unsaturated carbonyl and related systems is one of the most
fundamental molecular transformations. Hence, extensive studies
15 have been made on the development of catalytic asymmetric
observed even in the highly enantioselective catalytic process.3
Recently, Misaki and Sugimura developed a highly Z- and
enantioselective addition of oxazol-4(5H)-ones to alkynyl
carbonyl compounds using a chiral bicyclic guanidine catalyst,4
protocols, rendering this methodology an extremely powerful tool 45 and Feng demonstrated the effectiveness of a chiral N,N’-dioxide-
for the construction of stereochemically defined, functionalized
organic molecules.1 When a Michael acceptor is an electron-
deficient olefin bearing a substituent at the α-position of electron-
20 withdrawing group, stereocontrol not only in the initial carbon-
scandium(III) complex in achieving high levels of Z- and
enantioselectivity in the reaction between pyrazol-5-ones and
alkynones.5 However, intrinsic problems associated with the
consistent yet rigorous facial discrimination of prochiral
carbon bond-forming step but also in the subsequent protonation 50 nucleophile and intermediary allenic enolate still remain to be
of the resulting enolate or its equivalent is essential for obtaining
a stereochemically pure product. In this context, several catalytic
Michael strategies that enable the stereoselective addition-
25 protonation sequence have been successfully introduced.2 On the
addressed.
Here, we describe a geometrically divergent
asymmetric Michael addition of azlactones7 to methyl propiolate
catalyzed by P-spiro chiral triaminoiminophosphorane 1 or 2
under proton transfer conditions.8-11 We propose that the
other hand, the catalytic asymmetric Michael addition to electron- 55 complete switch of the E/Z- selectivities originates from the
deficient triple bonds such as ynals, ynones, and ynoates, which
requires the geometric control of the newly formed olefin, has not
protonation of enolate
H
H
CO2R
RL
been explored as much despite its potential synthetic
30 importance.3-5 Since the intermediate of Michael addition of this
type is an allenic enolate having two orthogonal π planes, the
steric demand of the terminal substituents (RL: larger substituent,
RS: smaller substituent) would strongly affect the approaching
direction of the proton source in the protonation event, unlike the
35 case for a normal enolate (Figure 1). In fact, it has been reported
that the allenic enolate is protonated in the α,β-π plane with
preference trans to the RL under kinetic conditions.6 Although
this general notion suggests the preferable formation of a (Z)-
RS
RS
OR
RL
O
RL
CO2R
RS
H
H
protonation of allenic enolate
H
RS
CO2R
(Z)-isomer
RS
RL
RS
isomer in Michael addition to terminal alkynes (RS = H, RL
=
OR
40 nucleophile), moderate E-selectivity was actual tendency
O
RL
CO2R
(E)-isomer
RL
H
H
Department of Applied Chemistry, Graduate School of Engineering,
Nagoya University, Furo-cho B2-3(611), Chikusa, Nagoya 464-8603,
Japan
O-protonation
1,3-proton shift
RS
RL
E-mail: tooi@apchem.nagoya-u.ac.jp.
OR
OH
Fax: +81-(0)52-789-3338; Tel: +81-(0)52-789-4501
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data of 3-8. See DOI:
10.1039/c1sc00000x/
Figure 1. Possible protonation pathway of enolate and allenic enolate
Chem. Sci., 2012, 3, 00–00 | 1
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Chemical Science
Page 2 of 5
Table 1 E- and Z-Selective Asymmetric Michael Addition of Azlactones
difference in the protonation pathway depending on the structures
of the proton donors, conjugate acids of 1 and 2, and the
properties of the electrophile. Relevance of this hypothesis is
verified by the establishment of the first highly Z- and
enantioselective Michael addition of azlactones to cyanoacetylene.
Initially, we set out to evaluate the E/Z- and enantioselectivity
in the Michael addition of racemic azlactone 3a to methyl
propiolate in toluene at –60 °C under the influence of L-valine-
derived iminophosphorane 1a generated in situ by treatment of
60 3 and 5 to Methyl Propiolate Catalysed by Chiral Iminophosphoranes 1
and 2a
Me
N
Me
N
Cl
P
Ar
Ar
View Article Online
H
N
H
N
5
R
R
P
Ar
Ar
Ph
Ph
Ph
Ph
N
H
N
H
N
H
N
1a·HCl: Ar = Ph
1b·HCl: Ar = p-CF3-C6H4
2a: R = Me
2b: R = Et
10 aminophosphonium salt 1a·HCl having M-spirochirality with
KOtBu (Table 1). After 24 h of stirring, the desired Michael
adduct 4a was isolated in 78% yield with the E/Z ratio of 1:10
1·HCl/KOtBu
(5 mol%)
O
O
and 56% ee (S) for (Z)-isomer (entry 1).
The use of
R1
O
N
O
iminophosphorane 1b prepared from 1b·HCl possessing electron-
15 withdrawing p-trifluoromethyphenyl groups as aromatic
substituents (Ar) resulted in the almost exclusive formation of
(Z)-4a with 90% ee (entry 2). High Z-selectivity was generally
observed with other azlactones under the catalysis of 1b, though
enantioselectivity was sensitive to the features of the C4-
20 substituent (entries 3-5). These results suggested that the
structure of aminophosphonium ion 1b·H as a proton donor
would be suitable for solidifying inherently favorable C-
protonation from the less hindered side of the α,β-π plane of the
intermediary allenic enolate, whereas discrimination of the
25 enantiotopic faces of the azlactone enolate by 1b·H seemed
insufficient. Surprisingly, switching the catalyst to partially N-
methylated triaminoiminophosphorane 2 having opposite P-
spirochirality caused a dramatic reversal of E/Z-selectivity and, in
the presence of 2a, (E)-4a was formed preferentially with 76% ee
30 of (S)-isomer (entry 6).12,13 Furthermore, the parent amino acid
structure of the catalyst backbone was of critical importance in
improving the stereoselectivity as evident from the result with L-
isoleucine-derived iminophosphorane 2b (entry 7), and
combination with the electron-rich azlactone 5a led to the near
35 quantitative production of essentially pure (E)-6a with 93% ee
(entry 8). This intriguing phenomenon could not be rationalized
by the facial discrimination of the α,β-π plane of the allenic
enolate in the common C-protonation pathway because the spatial
MeO
R1
CO2Me
Ph
( )-
Z 4
O
toluene
–60 °C
O
N
O
Ar1
3 or 5
MeO
O
2
R1
N
(5 mol%)
Ar1
(E)-4 or 6
time yield
(h) (%)c
ee
entry cat.b
R1
Ar1
E/Zd
prod.
(%)e
1
2
Bn
Bn
Ph
Ph
Ph
24
12
24
12
30
24
13
10
12
12
8
78 1:10 56
92 1:>20 90
93 1:>20 85
95 1:>20 85
89 1:16 58
1a
1b
1b
1b
1b
2a
2b
2b
2b
2b
2b
3a
3a
3b
3c
3d
3a
3a
5a
5b
5c
5d
4a
4a
4b
4c
4d
4a
4a
6a
6b
6c
6d
3
p-Cl-C6H4CH2
4
p-MeO-C6H4CH2 Ph
5
Me2CHCH2
Ph
Ph
6
Bn
Bn
Bn
83
9:1 76
7
Ph
98 17:1 92
97 >20:1 93
98 18:1 90
92 >20:1 93
8
PMP
9
p-Cl-C6H4CH2 PMP
p-MeO-C6H4CH2 PMP
10
11
Me2CHCH2
PMP
92
7:1 87
a Reactions were performed on 0.2 mmol scale (entries 1-5) or 0.1 mmol
scale (entries 6-11) with 1.1 equiv of methyl propiolate in toluene (2.0 or
65 1.0 mL) at –60 °C. b Iminophosphoranes 1 were generated in situ from
corresponding phosphonium chloride 1·HCl and KOtBu and 2 were used
1
as isolated form.12 c Isolated yield. d The E/Z ratio was determined by H
e
environment
around
the
acidic
N-H
protons
of
NMR (400 MHz) analysis of crude aliquot. Enantiomeric excess of
40 aminophosphonium ion 2·H is more congested than that of
1·H.11a Rather, given the possible steric repulsion of 2·H even
with a smaller substituent (RS = H) and the ambident reactivity of
the allenic enolate, the catalyst-dependent selectivity profile with
2 could be accounted for by assuming an O-protonation pathway,
45 in which isomerization of the resulting allenol via 1,3-proton shift
would afford thermodynamically stable (E)-isomer as a major
product (Figure 1).14 Other selected examples included in Table
1 show that the significance of E-selectivity complies with the
structure of azlactone 5, but the stereocontrolling ability of 2b·H
50 in enantiofacial differentiation of the prochiral azlactone enolate
is superior to that of 1b·H (entries 9-11).15
In order to substantiate the hypothesis on the O-protonation
pathway, we turned our attention to employing cyanoacetylene as
a new Michael acceptor in view of the carbanionic character of
55 the α-cyano vinylic anion, an intermediate generated through the
addition of a nucleophile.16 At the protonation stage, the proton
donor could approach from the same plane of the vinylic
carbanion and the approaching direction would be affected by the
major isomer was indicated, which was analyzed by chiral HPLC.
70 Absolute configuration of (Z)- and (E)-4a was determined to be S by X-
ray crystallographic analysis of its derivative, see ESI for details.
Absolute configurations of (Z)-4b-d and (E)-6 were assigned by analogy
to 4a.
steric demands of RL and RS substituents (Figure 2). Importantly,
75 because the contribution of the N-protonation pathway would be
negligible in this case,16 the direction of proton transfer to the
anionic carbon (C-protonation) should be directly reflected in the
E/Z-selectivity of the Michael adduct, and thus the pathway
leading to the (Z)-isomer would be preferable. This assumption
80 was verified by conducting the Michael addition of azlactone 5a
to cyanoacetylene with iminophosphorane 2b as a catalyst in
toluene at –78 °C. The reaction indeed took place with complete
Z-selectivity to give (Z)-7a in 87% yield with 97% ee (entry 1),
even though 2b was an E-selective catalyst in the addition of 5a
85 to methyl propiolate.17 This observation in turn supports the
intervention of the O-protonation pathway in the 2b-catalyzed
stereoselective Michael addition of 5 to methyl propiolate.
Considering the previous deficiency in the utilization of
2
| Chem. Sci., 2012,
3, 00–00
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Page 3 of 5
Chemical Science
protonation of -cyano vinylic anion
H
RS
CN
RS
View Article Online
RL
RL
CN
H
RS
RS
CN
CN
RL
E-isomer
Figure 2. Protonation of α-cyano vinylic anion
RL
Z-isomer
30 Scheme 1 Derivatization of (Z)-7
cyanoacetylene to the development of catalytic asymmetric
reactions as well as the synthetic value of configurationally
defined α,β-unsaturated nitriles, the substrate scope of the present
system was extensively investigated. As summarized in Table 2,
not only benzylic (entries 2-5) but also alkyl groups including
linear (entries 6-9), β- and α-branched (entries 10 and 11) ones
were tolerated as a C4-substituent of azlactone 5 and (Z)-α,β-
10 unsaturated nitriles 7 were obtained in good chemical yields with
excellent stereoselectivities. It should be added that the reaction
of C4-phenyl-substituted azlactone 5l, which is a less reactive
nucleophile due to its low pKa and steric hindrance, with
cyanoacetylene under similar conditions proceeded smoothly to
15 exclusively afford (Z)-7l in 77% yield with 90% ee (entry 12).
These results clearly demonstrate the general applicability of this
unprecedented stereoselective Michael protocol and also cast
light on the potential utility of cyanoacetylene in catalytic
asymmetric synthesis.15
5
The olefin geometry of (Z)-7 can be cleanly reversed without
racemization by treatment with tributylphosphine in refluxing
35 toluene as exemplified in Scheme 1. In addition, the azlactone
moiety of 7 can behave as an effective acylating reagent.18 For
instance, the ring opening reaction of (Z)-7a with L-leucine tert-
butyl ester proceeded smoothly to give the stereochemically pure
dipeptide 8 in 89% yield.
40
In conclusion, we have achieved catalyst-controlled geometric
reversal in the development of the asymmetric Michael addition
of azlactones to methyl propiolate under the influence of P-spiro
chiral triaminoiminophosphoranes.
protonation pathway in the control of olefin geometry,
The importance of the
Table 2 Substrate Generality of Chiral Iminophosphorane 2b-Catalyzed
45 specifically the intervention of an O-protonation pathway, has
been proposed and its validity has been proven by employing
cyanoacetylene as a new yet useful Michael acceptor, where
excellent Z- and enantioselectivities have been attained for a wide
range of azlactones. We believe that the present study provides a
50 new axis for the rational development of still underutilized,
catalytic stereoselective Michael additions to electron-deficient
triple bonds.
Z- and Enantioselective Michael Addition of Azlactone
5 to
20 Cyanoacetylenea
time yieldb
eed
(%)
entry
R1
E/Zc
5
prod
(h)
(%)
87
85
88
76
82
76
73
72
80
87
73
77
Acknowledgements
1
2
Bn
p-Cl-C6H4CH2
p-MeO-C6H4CH2
o-F-C6H4CH2
3,5-(MeO)2-C6H3CH2
Et
4
1:>20 97
1:>20 96
1:>20 97
1:>20 95
1:>20 95
1:>20 91
1:>20 91
1:>20 93
1:>20 90
1:>20 92
1:>20 96
1:>20 90
5a
5b
5c
5e
5f
7a
7b
7c
7e
7f
This work was supported by NEXT program, a Grant-in-Aid for
55 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, and Grants of JSPS for Scientific Research. Y.U.
60 acknowledges JSPS for financial support.
9
3
3
4
5
5
24
10
24
24
9
6
5g
5h
5i
7g
7h
7i
7
Me(CH2)3
8
Me(CH2)5
9
MeS(CH2)2
Me2CHCH2
Me2CH
5j
7j
Notes and references
10
11
12
22
40
9
5d
5k
5l
7d
7k
7l
1
For reviews on asymmetric Michael reaction, see: a) S. B. Tsogoeva,
Eur. J. Org. Chem. 2007, 1701. b) D. Almaşi, D. A. Alonso, C.
Nájera, Tetrahedron: Asymmetry 2007, 18, 299. c) J. L. Vicario, D.
Badía, L. Carrillo, Synthesis 2007, 2065.
Ph
a
65
70
Reactions were performed on 0.1 mmol scale with 1.1 equiv of
cyanoacetylene in toluene (1.0 mL). b Isolated yield. c The E/Z ratio was
2
3
J. T. Mohr, A. Y. Hong, B. M. Stoltz, Nat. Chem. 2009, 1, 359.
a) M. Bella, K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126, 5672. b)
X. Wang, M. Kitamura, K. Maruoka, J. Am. Chem. Soc. 2007, 129,
1038. c) Q. Lan, X. Wang, K. Maruoka, Tetrahedron Lett. 2007, 48,
4675. d) Z. Chen, M. Furutachi, Y. Kato, S. Matsunaga, M. Shibasaki,
Angew. Chem. Int. Ed. 2009, 48, 2218. e) Q. Lan, X. Wang, S.
Shirakawa, K. Maruoka, Org. Proc. Res. Dev. 2010, 14, 684. f) T.
Misaki, N. Jin, K. Kawano, T. Sugimura, Chem. Lett. 2012, 41, 1675.
determined by 1H NMR (400 MHz) analysis of crude aliquot.
d
25 Enantiomeric excess of (Z)-isomer was indicated, which was analyzed by
chiral HPLC. Absolute configuration of (Z)-7a was determined to be S by
X-ray crystallographic analysis of its derivative, see ESI for details.
Absolute configurations of (Z)-7b-l were assigned by analogy to 7a.
This journal is © The Royal Society of Chemistry 2012
Chem. Sci., 2012, 3, 00–00 | 3

Chemical Science
Page 4 of 5
4
5
T. Misaki, K. Kawano, T. Sugimura, J. Am. Chem. Soc. 2011, 133,
5695.
Z. Wang, Z. Chen, S. Bai, W. Li, X. Liu, L. Lin, X. Feng, Angew.
Chem. Int. Ed. 2012, 51, 2776.
12 Iminophosphorane 1 is relatively unstable and thus in situ generation
procedure is usually used. On the other hand, 2 can be isolated in a
pure form and easily handled under ambient conditions probably due
to the steric effect of methyl substituents on nitrogen atoms.
30
35
40
45
50
5 6 a) H. E. Zimmerman, J. Org. Chem. 1955, 20, 549. b) H. E.
Zimmerman, A. Pushechnikov, Eur. J. Org. Chem. 2006, 3491.
7
13 When 4a (E/Z = 1:>20) was treated with 2a (5 mol%) in toluene at –
View Article Online
60 °C for 12 h in the presence of either 3a or methyl propiolate, no
isomerization of (Z)-4a to (E)-4a was observed. Therefore, (E)-4a
was the primary product of the reaction catalyzed by 2a.
a) J. S. Fisk, R. A. Mosey, J. J. Tepe, Chem. Soc. Rev. 2007, 36, 1432.
b) R. A. Mosey, J. S. Fisk, J. J. Tepe, Tetrahedron: Asymmetry 2008,
19, 2755. c) A.-N. R. Alba, R. Rios, Chem. Asian J. 2011, 6, 720.
14 The role of 2·H as a proton donor to the intermediary allenic enolate
was confirmed by the reaction with a stoichiometric amount of 2a
under otherwise similar conditions, providing comparable result to
that of the catalytic reaction. This protonation process was further
supported by the reaction with slow addition of azlactone 3a over a
period of 12 h. See ESI for details.
15 The present system was found to be ineffective for the reactions with
electron-deficient alkynes having terminal substituents as an acceptor.
16 a) H. M. Walborsky, L. M. Turner, J. Am. Chem. Soc. 1972, 94, 2273.
b) F. F. Fleming, V. Gudipati, O. W. Steward, Tetrahedron 2003, 59,
5585. See also: c) F. F. Fleming, Q. Wang, Chem. Rev. 2003, 103,
2035.
17 Although Z-selective Michael addition of 5a to cyanoacetylene was
catalyzed by 1b·HCl/KOtBu at –78 °C to give (Z)-7a (E/Z = 1:>20)
in 85% yield, its enantiomeric excess was only moderate (42% ee).
18 D. Uraguchi, Y. Asai, T. Ooi, Angew. Chem. Int. Ed. 2009, 48, 733
and references there in.
10 8 Triaminoiminophosphoranes are known as a P1-phosphazenes, which
was developed by Schwesinger, see: a) R. Schwesinger, H.
Schlemper, Angew. Chem. Int. Ed. Engl. 1987, 26, 1167. For a
review, see: b) T. Ishikawa, Superbases for Organic Synthesis:
Guanidines, Amidines, Phosphazenes and Related Organocatalysts;
15
20
25
John Wiley & Sons: West Sussex, U.K., 2009.
For a review on organic base catalysis, see: C. Palomo, M. Oiarbide,
R. López, Chem. Soc. Rev. 2009, 38, 632.
9
10 For reviews on phosphonium salt catalyses, see: a) T. Werner, Adv.
Synth. Catal. 2009, 351, 1469. b) D. Enders, T. V. Nguyen, Org.
Biomol. Chem. 2012, 10, 5327.
11 a) D. Uraguchi, T. Ooi, J. Synth. Org. Chem. Jpn. 2010, 68, 1185. b)
D. Uraguchi, S. Nakamura, T. Ooi, Angew. Chem. Int. Ed. 2010, 49,
7562. c) D. Uraguchi, Y. Ueki, T. Ooi, Angew. Chem. Int. Ed. 2011,
50, 3681. d) D. Uraguchi, Y. Ueki, T. Ooi, Chem. Sci. 2012, 3, 842.
e) M. T. Corbett, D. Uraguchi, T. Ooi, J. S. Johnson, Angew. Chem.
Int. Ed. 2012, 51, 4685. f) D. Uraguchi, K. Yoshioka, Y. Ueki, T. Ooi,
J. Am. Chem. Soc. 2012, 134, 19370.
Graphical Abstracts
Highly Stereoselective Michael Addition of Azlactones
to Electron-Deficient Triple Bonds under P-Spiro
Chiral Iminophosphorane Catalysis: Importance of
60 Protonation Pathway
Daisuke Uraguchi, Yusuke Ueki, Atsushi Sugiyama, and Takashi
Ooi*
The importance of the protonation pathway for controlling olefin
65 geometry of the products in the asymmetric Michael addition to
electron-deficient triple bonds was clarified.
55
4
| Chem. Sci., 2012,
3, 00–00
This journal is © The Royal Society of Chemistry 2012

Page 5 of 5
Chemical Science
View Article Online
Graphical Abstracts
Highly Stereoselective Michael Addition of Azlactones to Electron-Deficient Triple Bonds under
P-Spiro Chiral Iminophosphorane Catalysis: Importance of Protonation Pathway
Daisuke Uraguchi, Yusuke Ueki, Atsushi Sugiyama, and Takashi Ooi*
The importance of the protonation pathway for controlling olefin geometry of the products in the asymmetric Michael
addition to electron-deficient triple bonds was clarified.