Catalyst-Enabled Site-Divergent Stereoselective Michael Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors

Article abstract of DOI:10.1002/anie.201800057

A site-divergent stereoselective Michael reaction system is developed based on the identification of two distinct catalysts. Cinchonidine-derived thiourea catalyzes the 1,4-addition of prochiral azlactone enolates to enynyl N-acyl pyrazoles in a highly diastereo- and enantioselective manner to give stereochemically defined alkynes, while P-spiro chiral triaminoiminophosphorane catalytically controls the stereoselective 1,6-addition and the consecutive γ-protonation of the vinylogous enolate intermediate to afford Z,E-configured conjugated dienes. This 1,6-adduct serves as a valuable precursor for the synthesis of a 2-amino-2-deoxy sugar.

Full text of DOI:10.1002/anie.201800057

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Accepted Article
Title: Catalyst-Enabled Site-divergent Stereoselective Michael
Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl
Acceptors
Authors: Daisuke Uraguchi, Ryo Shibazaki, Naoya Tanaka, Kohei
Yamada, Ken Yoshioka, and Takashi Ooi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800057
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10.1002/anie.201800057
Angewandte Chemie International Edition
COMMUNICATION
Catalyst-Enabled Site-divergent Stereoselective Michael Reactions:
Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors
Daisuke Uraguchi,[a] Ryo Shibazaki,[a] Naoya Tanaka,[a] Kohei Yamada,[a] Ken Yoshioka,[a] and Takashi
Ooi*[a],[b]
Abstract: A site-divergent stereoselective Michael reaction system is
developed based on the identification of two distinct catalysts. Cinchonidine-
derived thiourea catalyzes the 1,4-addition of prochiral azlactone enolates to
enynyl N-acyl pyrazoles in a highly diastereo- and enantioselective manner
to give stereochemically defined alkynes, while P-spiro chiral
triaminoiminophosphorane catalytically controls the stereoselective 1,6-
addition and the consecutive γ-protonation of the vinylogous enolate
intermediate to afford Z,E-configured conjugated dienes. This 1,6-adduct
serves as a valuable precursor for the synthesis of a 2-amino-2-deoxy sugar.
However, site-selectivity primarily depends on the intrinsic reactivity
preference of the substrates, leading to the formation of a mixture of
isomers, especially when the molecule of interest has several similar
functional groups. This common trend causes an inherent difficulty in
not only enhancing the substrate-controlled selectivity but also
overriding it by a catalyst with recognition elements, capable of
differentiating the subtle steric and electronic differences between
potential reactive sites.
When this regiochemical consideration is coupled with
a
stereochemical issue in a general synthetic context, simultaneous
dictation of both the selectivities poses a more profound challenge,
particularly in catalytically directing the bond-forming reactions that
involve multiple stereoselectivity factors.[2-5] One of the synthetically
relevant carbon-carbon bond formations that are associated with this
innate selectivity problem is the Michael addition of prochiral enolates
to extended conjugate systems, such as dienyl carbonyl compounds.
Various different strategies have been introduced to control the reaction
site together with relative and absolute stereochemistry.[6,7] However,
elective modification of specific sites or functional groups of an
organic compound that has multiple sites of reactivity (site-selective
S
reaction) is a powerful tool for rapidly increasing molecular complexity,
thereby allowing the design of a straightforward synthetic route to access
complex targets.[1] This advantage stems from the fact that the site-
selective reaction leaves other reactive functional groups intact and the
product could be directly subjected to subsequent transformations.
O
G
Me Me
O
1,6-addition
R
R
-protonation
G
N
N



P
•
G

O
O
1,6--E,E
Ar
Ar
Ar
Ar
N
H
N
O
O
1,6--E,Z
(iii)
(iv)
O
2
O
G
regio- and facial-selectivity
at protonation
G
O
O
O

regio-selectivity
at C-C bond formation

1,6- -Z,E

+
1,6- -Z,Z
(v)

G
(vi)
O
O
derivatization
-protonation
CF3

HO
•
G
O

O
N
Me
S
O
O
1,6- -diastereomers


PHN
OH
F3C
N
H
N
H
(ii)

HO
OH
G
1,4-addition
N
formation of 8 isomers
and their enantiomers
2-amino-2-deoxy sugar
derivative
1,4-diastereomers
(i)
1
Figure 1. Site-divergence and Multiple Selectivity Control in Michael Addition of Prochiral Enolates to Enynyl Carbonyl Compounds.
catalyst-dependent switching of the reaction site with preservation of the
rigorous stereocontrol has to date proved elusive, despite offering an
expedient means to access structurally distinct yet stereochemically
homogeneous conjugate adducts from a single set of substrate
combination. This situation reflects that regiochemical control still
heavily relies on the exploitation of the intrinsic reactivity preference of
the employed substrates, especially in attaining selectivity at a remote
terminal site of the conjugated acceptor; hence, full synthetic potential
of this class of vinylogous Michael technologies remains to be realized.
Here, we report a complete site-divergence in the Michael addition of
[a]
Dr. D. Uraguchi, R. Shibazaki, N. Tanaka, K. Yamada, Dr. K.
Yoshioka, Prof. Dr. T. Ooi
Institute of Transformative Bio-Molecules (WPI-ITbM) and
Department of Molecular and Macromolecular Chemistry, Graduate
School of Engineering, Nagoya University, Nagoya 464-8601,
Japan.
E-mail: tooi@chembio.nagoya-u.ac.jp
Prof. Dr. T. Ooi
CREST, Japan Science and Technology Agency (JST), Nagoya
University, Nagoya 464-8601, Japan.
[b]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201800057
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of Catalyst Structure[a]
azlactone enolates to enynyl N-acyl pyrazoles enabled by the
identification of two requisite catalysts, cinchonidine-derived thiourea 1
and P-spiro chiral triaminoiminophosphorane 2, to afford 1,4- and 1,6-
adducts, respectively, with discrete structural and stereochemical
integrity. Furthermore, synthetic utility of the unprecedented 1,6-
addition system for enynyl carbonyl acceptors is clearly demonstrated
by the concise derivatization of the configurationally defined,
conjugated diene product to a novel 2-amino-2-deoxysugar, 2-amino-2-
deoxy-2-Me-
D-altrofuranose derivative, bearing a chiral tetrasubstituted
carbon.[8]
The Michael addition of prochiral enolates to enynyl carbonyl
compounds potentially produces eight isomers and their enantiomers
(total sixteen isomers) (Figure 1). The selective 1,4-addition with
discrimination of prochiral faces of both an enolate and the enynyl
acceptor gives stereochemically defined, functionalized alkynes (i).[9-11]
On the other hand, 1,6-addition involves the generation of a s-cis/trans-
vinylogous enolate; thus, regio- and facial-selectivity in the protonation
of this intermediate should be controlled in concert with regio- and
stereoselectivity of the initial carbon-carbon bond formation to obtain
enantioenriched allenes (ii) or conjugated dienes (iii)–(vi). The diversity
of regio- and stereochemical outcomes amplifies the complexity of the
possible product distribution, rendering the catalyst-directed multiple
selectivity control extremely challenging. In fact, no catalytic protocol
is available for the selective production of the stereochemically pure
Michael adduct out of the sixteen isomers, despite the significant
potential for the stereoselective construction of valuable organic
frameworks. Therefore, we decided to focus on this Michael reaction
system.
At the outset, we examined the intrinsic reactivity of enynyl N-acyl
pyrazole 4[12] as a Michael acceptor toward an enolate of alanine-derived
azlactone 3a[13] using several common achiral bases as catalysts (Table
1, entries 1–4). While the treatment of 4 with 3a under the influence of
KOtBu (1 equiv) in Et2O at 0 °C preferably gave a diastereomeric
mixture of the 1,4-adduct, 1,4-5a [type (ia) and (ib)], the use of a catalytic
quantity of relatively strong organic bases resulted in the formation of
complex mixtures containing all the expected adducts except for the
allene isomer, 1,6-α-diastereomers (ii). It is noteworthy that
representative chiral bases such as (−)-cinchonine and (+)-cinchonidine
were also totally ineffective in attaining an appreciable level of
regioselectivity (entries 5 and 6). These results clearly indicated the
difficulty in guiding the enolate nucleophile to a specific reactive site of
4. In marked contrast, however, when (+)-cinchonidine-derived thiourea
1 was employed as a bifunctional catalyst at ambient temperature, 1,4-
5a was obtained exclusively in high yield with nearly complete
diastereo- and enantioselectivity (entry 7).[14] Switching the solvent to
toluene allowed the reaction to proceed smoothly with 10 mol% of 1
without affecting the selectivity profile (Scheme 1).
entry
catalyst
yield
isomeric ratio[c]
ee
[%][b] (ia) (ib) (ii) (iii) (iv) (v) (vi) [%][d]
1
2
KOtBu[e]
TMG[f]
45 51 36
40 12 30
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1
1
–
2
1
–
–
–
–
–
–
–
–
–
–
–
6
2
6
9
8
25
37
9
–
–
–
–
29
46
39
3
DBU
84
60
47
2
9
8
8
35
6
4
TBD[g]
5
(−)-cinchonine[f,h]
(+)-cinchonidine[f,h]
1[f,h]
19 25 40 nd[i]
12 14 21 nd[i]
6
23 18 34
85
93 10
7
2
98
–
–
–
–
–
–
–
–
–
–
4
2
3
2
9
2
3
2
5
–
3
2
4
5
3
1
2
1
1
–
96[j]
8
2a (R = iPr, Ar = Ph)
2b ((S)-sBu, Ph)
2c (Me, Ph)
2d (iBu, Ph)
2e (Bn, Ph)
83 93
90 96
91 78
88 82
79 95
91 96
88 94
92 97
93 96
9
96
99
94
90
98
6
2
4
9
6
7
5
1
10
11
12
13
2f ((S)-sBu, 4-FC6H4)
14 2g ((S)-sBu, 4-MeC6H4) 99
15 2h ((S)-sBu, 3-FC6H4) 96
16 2i ((S)-sBu, 3-MeC6H4) 99
Ar1 = 2,6-(MeO)2C6H3
[a] Conditions: 0.10 mmol of 3a, 0.11 mmol of 4, 5 mol% of catalyst in Et2O
(1.0 mL) at 0 °C. [b] Isolated yields of the isomeric mixture of 5a. [c]
Determined by 1H NMR analysis of crude aliquot. See Fig. 1 for the general
structures of isomers (i)–(vi). [d] Enantiomeric excesses of 1,6-γ-Z,E-5a. [e]
100 mol% of catalyst. [f] 30 mol% of catalyst. [g] 50 mol% of catalyst. [h] At
RT for 24 h. [i] nd = not determined. [j] Enantiomeric excess of 1,4-5a (ib).
O
O
R1
+
O
1
O
O
N
(10 mol%)
N
N
O
N
N
This intriguing finding prompted us to investigate the substrate
generality of the 1-catalyzed 1,4- and stereoselective Michael addition
with respect to the structural feature of azlactone 3. The representative
results are summarized in Scheme 1. In general, 10 mol% of 1 was
sufficient for the bond formation to occur with high efficiency and
virtually complete regio-, diastereo-, and enantioselectivities. While
higher catalyst loading in Et2O was necessary to attain useful reactivity
in the reactions with 3 bearing a longer or branched alkyl group as the
C-4 substituent, phenylglycine-derived azlactone 3i, whose
nucleophilicity is known to be low due to the high stability of its enolate
ion, was found to react smoothly with rigorous selectivity control. The
relative and absolute stereochemistry of the Michael adduct was
Ar1
R1
toluene
N
3
4
1,4-5
Ar1
RT, 24 h
(Ar1 = 2,6-(MeO)2C6H3)
>95% regioselectivity
dr = >20:1
R1
=
5e
):
PhCH2
(
92%, 99% ee
5a
Me ( ):
84%, 99% ee 4-MeOC6H4CH2 (5f): 85%, 99% ee
):* 89%, 99% ee 4-ClC6H4CH2 (5g): 80%, 99% ee
5c
5b
(
Me(CH2)5
MeS(CH2)2 ( ): 73%, 99% ee N-Ts-3-IndolylCH2 (5h):84%, 99% ee
5d
88%, 96% ee
Me2CHCH2
(
):* 93%, 99% ee Ph (5i):
Scheme 1. 1,4-Selective Michael Addition to Enynyl N-Acyl Pyrazole 4. * With
30 mol% of 1 in Et2O.
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10.1002/anie.201800057
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Substrate Scope for 2i-catalyzed 1,6-Selective Michael Addition to
Enynyl N-Acyl Pyrazole 4[a]
unambiguously determined by single crystal X-ray diffraction analysis
of 1,4-5a (see SI).[15]
Having identified the catalyst capable of promoting 1,4-selective
reaction with rigorous control of stereoselectivity, we turned our
attention to search for a catalyst effective for overturning the
regiochemical preference to 1,6-selectivity while conserving
a
comparable level of stereocontrol, thereby establishing a site-divergent
stereoselective Michael reaction protocol. Toward this end, we applied
P-spiro chiral triaminoiminophosphorane 2[7,16] as a catalyst, considering
the unique ability of its conjugate acid 2ꞏH to recognize both a
nucleophile and an electrophile through hydrogen-bonding interactions
for providing them unusual mutual orientation in the transition state of
the subsequent bond formation.[7b,7c,17] Interestingly, the reaction of 3a
entry
R1 (3)
time yield 1,6-γ-Z,E-5 (ss) ee prod.
[h] [%][b]
[%][c]
[%][d]
1
2
Me (3a)
Et (3j)
1
4
99
>99
95
>99
98
98
98
92
97
99
99
99
91
88
93
95
96
97
95
95
94
90
98
92
90
93
94
94
92
94
5a
5j
with 4 in the presence of
L
-valine-derived 2a[18] in Et2O at 0 °C
3
Me(CH2)3 (3k)
Me(CH2)5 (3b)
MeS(CH2)2 (3c)
Me2CHCH2 (3d)
Me2CH (3l)
1
94
5k
5b
5c
5d
5l
selectively afforded 1,6-γ-Z,E-5a (vi) in high yield with excellent
enantioselectivity (Table 1, entry 8); this revealed that 2ꞏH indeed
diverted the site-selectivity by guiding the enolate of 3a to the terminal
carbon of 4 and also facilitated the γ-protonation of the intermediary
vinylogous enolate with precise control of the diene geometry.[19] This
initial observation encouraged us to evaluate the effect of catalyst
structure on the regio- and stereochemical outcomes (entries 9–12).
While satisfactory levels of isomeric ratios and enantiomeric excesses
were generally observed with 2 bearing different alkyl substituents of
4
4
94
5
2
94
6
2
>95
>95
94
7
2
8
PhCH2 (3e)
1
5e
5f
9
4-MeOC6H4CH2 (3f)
2-FC6H4CH2 (3m)
4-ClC6H4CH2 (3g)
2
>95
>95
>95
>95
>95
>95
amino acid origin (R),
L-isoleucine-derived iminophosphorane 2b
10
11
3
5m
5g
5n
5h
5i
exhibited the highest performance in regio- and enantiocontrol (entry 9).
The steric and electronic properties of the aromatic appendage of 2 (Ar)
slightly affected the selectivity profile and 2i possessing meta-tolyl
groups proved to be an optimal catalyst in terms of site-selectivity (93%
ss) (entries 13–16).
We then thoroughly explored the scope of azlactones 3 in the 2i-
catalyzed asymmetric 1,6-addition to 4. The results listed in Table 2
show that the incorporation of various alkyl and aryl groups onto the 4-
position of 3 was tolerated and 1,6-γ-Z,E-5 was predominantly obtained
with high stereoselectivity (entries 1–14). It should be noted that
lowering the temperature to −40 °C was crucial for the additions of N-
Ts-tryptophan- and phenylglycine-derived azlactones 3h and 3i to
proceed with rigorous enantiocontrol (entries 13 and 14).
3
12 3,4-(MeO)2C6H3CH2 (3n)
13[e] N-Ts-3-IndolylCH2 (3h)
2
12
12
14[e]
Ph (3i)
Ar1 = 2,6-(MeO)2C6H3
[a] Conditions: 0.10 mmol of 3, 0.11 mmol of 4, 5 mol% of 2i in Et2O (1.0 mL)
at 0 °C. [b] Isolated yields of the isomeric mixture of 5. [c] Site-selectivity (ss)
= percentage of 1,6-γ-Z,E-5 in the regio- and E/Z-isomeric mixture. [d]
Enantiomeric excesses of the major 1,6-γ-Z,E-5. See SI for X-ray diffraction
analysis of 1,6-γ-Z,E-5g.[15] [e] At −40 °C.
When an enynyl acceptor has a δ-substituent, the accessibility of the
δ-carbon would be considerably reduced, rendering the 1,6-addition
process more difficult.[5b] As we assumed, the attempted reaction of δ-
methyl enynyl N-acyl pyrazole 6a with azlactone 3e by the action of
DBU (30 mol%) furnished 1,4-adduct of type (i) predominantly with
concomitant formation of 1,6-γ-E,E-7a and 1,6-γ-Z,E-7a (94% ss).
Contrary to this profile, however, 1,6-γ-Z,E-7a was obtained as the
major isomer in the 2i-catalyzed reaction, and the site-selectivity was
improved to 86% when the reaction was conducted in tert-butyl methyl
ether (TBME) (Scheme 2).[20] This protocol appeared to be efficient and
applicable to a series of δ-substituted enynyl N-acyl pyrazoles 6 and 1,6-
γ-Z,E-7 was produced with good to high site-selectivity and excellent
enantioselectivity. These results emphasize the power of the catalysis of
2i in achieving multiply selective 1,6-addition by overriding the intrinsic
reactivity of the enynyl acceptor.
O
O
O
O
2i
Bn
+
N
N
O
(5 mol%)
Bn
N
N
O
N
Ar1
N
TBME
0 °C, 2 h
3e
6
1,6--Z,E-7
R2
1
Ar
R2
(Ar1 = 2,6-(MeO)2C6H3)
+ other isomers
R2 = Me ( ):
7a
99%, 86% ss, 98% ee
91%, 84% ss, 98% ee
7b
Et ( ):
Ph(CH2)2 (7c): 92%, 89% ss, 97% ee
BnOCH2 (7d): 98%, 93% ss, 96% ee
7a
7a
7a
cf. DBU (30 mol%): 1,4- /1,6--E,E- /1,6--Z,E- = 94:5:1
Scheme 2. 1,6-Selective Michael Addition to δ-Substituted Enynyl N-Acyl
Pyrazoles 6.
The synthetic utility of product 5 obtained in the site-selective
asymmetric 1,6-addition, which features two differentiated carbonyl
functionalities and Z,E-configured conjugated diene, was demonstrated
through straightforward derivatization to a 2-amino-2-deoxy sugar
(Scheme 3).[21] 2-Amino-2-deoxy sugar derivatives, such as
glucosamine, are biologically relevant molecules, yet their catalytic
asymmetric synthesis, particularly selective construction of non-natural
cores possessing tetrasubstituted stereogenic carbon centers, remains
challenging.[8] We anticipated that the geometrically defined diene
component of 5 would provide an ideal platform for the assembly of the
fully functionalized six-membered ring of the aza-sugar derivatives. The
actual synthesis was initiated by quantitative conversion of 1,6-γ-Z,E-5a
to hydroxy carboxylic acid 8 via a three-step sequence; i.e., azlactone
This article is protected by copyright. All rights reserved.

10.1002/anie.201800057
Angewandte Chemie International Edition
COMMUNICATION
ring-opening with methanol under mildly acidic conditions, reduction of
the N-acyl pyrazole group with NaBH4, and subsequent saponification
of the methyl ester. By taking advantage of the remaining diene moiety
in 8, δ-valerolactone 9[15] was produced by a diastereoselective
selenolactonization followed by the removal of the vicinal hydroxyl and
selenenyl groups.[22] Then, selective ozonolysis of the pendant vinyl
group was reductively quenched with NaBH4 and, after reduction of the
lactone carbonyl, diastereoselective syn-dihydroxylation of the
endocyclic olefin by the modified Baran’s procedure yielded aza-sugar
derivative 10.[23] Finally, acetylation of free hydroxyl groups of 10 with
concurrent isomerization of the pyranose core to the furanose form gave
Keywords: amino acid • Michael addition • iminophosphorane •
hexosamine • organocatalysis
[1]
[2]
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Acc. Chem. Res. 2017, 50, 465–471; d) F. D. Toste, M. S. Sigman, S. J.
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54, 9954–9957; Angew. Chem. 2015, 127, 10092–10095.
rise to a 2-amino-2-deoxy-2-Me-D-altrofuranose derivative 11 in good
yield. The relative stereochemistry of 11 was unequivocally assigned by
X-ray diffraction analysis of a single crystal of rac-11.[15]
[6]
[7]
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134, 19370–19373; b) M. Yamanaka, K. Sakata, K. Yoshioka, D.
Uraguchi, T. Ooi, J. Org. Chem. 2017, 82, 541–548; c) D. Uraguchi, K.
Yoshioka, T. Ooi, Nat. Commun. 2017, 14793; d) K. Yoshioka, K.
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Nature 2007, 446, 1017–1022; b) V. K. Jothivasan, C. J. Hamilton, Nat.
Prod. Rep. 2008, 25, 1091–1117; c) C. Slawson, G. W. Hart, Nat. Rev.
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9632–9665.
HO
O
O
a~c
d,e
f~h
HO2C
Me
Me
1,6--Z,E-5a
Ar1OCN
Ar1OCN
H
H
8
9
OAc
HO
Me
O
O
i
AcO
Ar1OCN
[8]
[9]
OAc
OH
Ar1OCN
H
H
HO
OAc
Me
11
OH
10
11
ORTEP of rac-
Scheme 3. Derivatization to 2-Amino-2-deoxy-2-Me-D
-altrofuranose (Ar1 = 2,6-
(MeO)2C6H3). Conditions: a) PPTS, MeOH, 0 °C; b) NaBH4, MeOH, –20 °C; c)
KOH, MeOH, 70 °C (>99% in three steps); d) (PhSe)2, (PhSO2)2NF, CH2Cl2, MS
4Å, –20 °C (60%); e) PBr3, CH2Cl2, 0 °C (70%); f) O3, MeOH/CH2Cl2, –78 °C,
then NaBH4, –78 °C (87%); g) DIBAH, CH2Cl2, –78 °C (>99%, dr = 2.5:1); h)
OsO4, NMO, citric acid, tBuOH/acetone/H2O, 50 °C; i) AcCl, Et3N, DMAP,
CH2Cl2, RT (67% in two steps).
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In conclusion, we established two distinct catalytic systems for
achieving a site-divergent, highly diastereo- and enantioselective
Michael addition of α-amino acid-derived, prochiral azlactone enolates
to enynyl N-acyl pyrazoles under mild conditions. The key is the ability
of the catalysts to override the intrinsic reactivity preference of the
substrates with precise control of multiple selectivity factors. The
synthetic value of the structurally and configurationally homogeneous
conjugated dienes was highlighted by the concise assembly of a 2-
amino-2-deoxy sugar, which substantiates the potential impact of the
stereoselective 1,6-addition protocol on the synthesis of complex targets.
We believe that the catalyst-directed site-divergent strategy significantly
expands the synthetic potential of the Michael reactions with extended
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Acknowledgements
Financial support was provided by CREST-JST (JPMJCR13L2:
13418441), 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. N.
Tanaka, K. Yamada, and K. Yoshioka acknowledge JSPS for financial
support.
[15] Crystallographic data (excluding structure factors) for 1,4-5a, 1,6-γ-Z,E-
5g, 9, and rac-11 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-
1813740, CCDC-1813741, CCDC-1813742, and CCDC-1813882,
respectively. Copies of the data can be obtained free of charge on
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application to CCDC, 12 Union Road, Cambridge CB2ꢀ1EZ, UK (fax:
(+44)ꢀ1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
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This article is protected by copyright. All rights reserved.

10.1002/anie.201800057
Angewandte Chemie International Edition
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Daisuke Uraguchi, Ryo Shibazaki,
Naoya Tanaka, Kohei Yamada, Ken
Yoshioka, Takashi Ooi*
Page No. – Page No.
Catalyst-Enabled Site-divergent
Stereoselective Michael Reactions:
Overriding Intrinsic Reactivity of
Enynyl Carbonyl Acceptors
A site-divergent stereoselective Michael reaction system is developed based on the
identification of two distinct catalysts. Cinchonidine-derived thiourea catalyzes the
1,4-addition of prochiral azlactone enolates to enynyl N-acyl pyrazoles in a highly
diastereo- and enantioselective manner to give stereochemically defined alkynes,
while P-spiro chiral triaminoiminophosphorane catalytically controls the
stereoselective 1,6-addition and the consecutive γ-protonation of the vinylogous
enolate intermediate to afford Z,E-configured conjugated dienes. This 1,6-adduct
serves as a valuable precursor for the synthesis of a 2-amino-2-deoxy sugar.
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