Controlling the α/γ-Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

Article abstract of DOI:10.1002/anie.201703764

The first regio-, diastereo-, and enantioselective direct Michael reaction of β,γ-unsaturated ketones with nitroolefins is enabled by Br?nsted base/hydrogen-bonding bifunctional catalysis. A squaramide-substituted tertiary amine catalyzes the reaction of a broad range of β,γ-unsaturated ketones to proceed at the α-site exclusively, giving rise to adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–98 % ee range.

Full text of DOI:10.1002/anie.201703764

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Accepted Article
Title: Controlling α- vs γ-Reactivity of Vinylogous Ketone Enolates in
Organocatalytic Enantioselective Michael Reactions
Authors: Igor Iriarte, Olatz Olaizola, Silvia Vera, Iñaki Gamboa, Mikel
Oiarbide, and Claudio Palomo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703764
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10.1002/anie.201703764
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Controlling - vs -Reactivity of Vinylogous Ketone Enolates in
Organocatalytic Enantioselective Michael Reactions
Igor Iriarte, Olatz Olaizola, Silvia Vera, Iñaki Gamboa, Mikel Oiarbide* and Claudio Palomo*
Abstract: The fully regio-, diastereo- and enantiocontrolled direct
Michael reaction of allyl ketones with nitroolefins is reported for the
first time under enabling Brønsted base/H-bond bifunctional catalysis.
It is shown that squaramide-tertiary amine catalysts induce the
reaction of a survey of allyl ketones to proceed at the -site
exclusively giving rise adducts with two consecutive tertiary carbon
stereocenters in diastereomeric ratios up to >20:1 and
enantioselectivities generally in the 90%-98% ee range.
bifunctional catalysis appeared.[11]
Catalyst-controlled reactions of in situ generated vinylogous
nucleophiles are of great synthetic value.[1] The overwhelming
majority of catalytic reactions involving vinylogous enolate
equivalents proceed from the -carbon of the unsaturated
carbonyl substrate, a process that preserves -conjugation along
the reaction coordinate (Scheme 1a). This reactivity pattern is
well illustrated in the literature for a broad range of enolizable
substrate families using either metallic catalysis[2] or different
aminocatalytic approaches.[3,4,5]
In contrast, the alternative -reaction pathway implies
disruption of the -conjugation at some point of the reaction
coordinate. Not surprisingly, switching the reactivity from the
most usual - to -carbon has resulted troublesome, with only
few direct enantioselective approaches reported. Shibasaki’s
group described a barium alkoxide-catalyzed Mannich reaction
of -unsaturated benzyl esters that upon C=C isomerisation
provides the corresponding Morita-Baylis-Hilmann type
adducts[6] (Scheme1b). On the other hand, -disubstituted
enals have been found to react through C of the dienamine
intermediate[7] because of the steric shielding of the disubstituted
-carbon (Scheme 1c).[8] A few Brønsted base-catalyzed -site
functionalizations of vinylogous enolic intermediates have also
appeared,[9] but the reported examples lead to moderate
enantioselectivity[9a] or apply to very restricted substrate
categories.[9b-d] Notably, the readily available allyl alkyl ketones,
with three potentially reactive sites (, , and ’) remain
undeveloped pronucleophiles in this context.[10] Here, we report
the first Brønsted base-catalyzed direct Michael reactions of allyl
alkyl ketones with nitroolefins that proceed through the ketone -
Scheme 1. Site-selectivity in catalyst-driven functionalization of ambivalent
vinylogous enolates.
While the C vs C selectivity problem appears to be
multivariable,[12] we hypothesized that a bifunctional Brønsted
base/H-bond catalyst,[13] might anchor both the dienolate and the
electrophilic reagent in a way favouring -reaction trajectory
(Scheme 1d). However, additional issues, namely (i) the - vs.
’-selectivity; (ii) the reaction diastereo- and enantioselectivity;
and (iii) the potential loss of -stereogenicity through C=C bond
isomerization, also needed to be addressed.
carbon
exclusively
and
with
high
diastereo-
and
For initial assessment of these aspects, the model reaction
of 1A with 7a in the presence of several bifunctional Brønsted
base catalysts[14] was investigated (Scheme 2). To our delight,
the -addition adducts were formed exclusively within a few
hours of reaction, although product diastereo- and
enantioselectivity were strongly catalyst-dependent (Table 1).
With cinchona alkaloid-derived thiourea C1[15] both the
diastereo- and the enantioselectivity were only moderate. The
enantioselectivity could be improved by using the squaramide
catalysts pioneered by Rawal,[16] such as catalyst C2[17] and,
especially, the cyclohexylamine-derived catalyst C4,[18]
enantioselectivity. During the preparation of this manuscript an
-selective functionalization of preformed silyl dienol ethers with
nitroolefins to give Rauhut-Currier type products under
[a]
Prof. C. Palomo, Prof. I. Gamboa, Prof. M. Oiarbide, Dr. S. Vera, O.
Olaizola, I. Iriarte
Departamento de Química Orgánica I
Universidad del País Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastián, Spain
Fax: (+34) 943015270
E-mail: claudio.palomo@ehu.es
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201703764
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Table 2. Scope of the reaction between ketones 1-6 and nitroalkenes 7 .[a]
Scheme 2. Catalyst-controlled enantioselective direct reaction of allyl ketones
with nitroalkenes.
although diastereoselectivity remained insufficient (dr <2:1).
Additional screening showed that the N-benzyl squaramide C5
performed best, affording upon reaction at 0 ºC product 8Aa in
high yield, 6.4:1 diastereomeric ratio and 96% ee for both
isomers.
Table 1. Screening of catalysts for the reaction of 1A with 7a to give 8Aa.[a]
[a] Unless otherwise stated, reactions carried out at 0.2 mmol scale using 1.5
equiv. of ketone and 10 mol% C5 at 0 °C in 0.4 mL CH2Cl2. Diastereomeric
ratios determined by HPLC. Yields of isolated product after chromatography.
ee determined by chiral HPLC. In brackets, ee´s of minor diastereomer. [b]
Reaction conducted at RT using 2 equiv. of ketone. [c] Isomerized by
treatment with Et3N overnight.
-enone during the reaction.[23] However, this circumstance
did not affect the reaction outcome provided that two equivalents
of the starting 5C and 6C were employed. If desired, adducts
from the above catalytic reactions, such as 12 and 13, could be
fully isomerized to the corresponding -enone product 14 and
15 almost quantitatively by exposure to 10 mol% DBU at RT in
CH2Cl2.
On the other hand, alkynyl allyl ketones also were competent
substrates. For example (Table 3), reaction of ketones 16–19
with nitroolefins 7 in the presence of quinine-derivative C2,
which was the best catalyst for these substrates, proceeded
smoothly and with good yields and excellent ee. However, unlike
in the previous cases, the evolved adducts proved to be quite
sensitive towards double bond isomerisation, and products 20–
28 were obtained directly. Once again, products from an
eventual -attack were not observed. It is worth of noting that the
otherwise difficult -alkyl nitroolefins 7h and 7i were competent
partners for this reaction, affording adducts 23, 25 and 28 in
good yields and excellent selectivity. The absolute configuration
[a] Reactions carried out at 0.2 mmol scale, using 1.5 equiv. of 1A and 10
mol% catalyst in 0.4 mL CH2Cl2. Diastereomeric ratios and ee determined by
chiral HPLC. Ee’s correspond to the major diastereomer.
Once conditions were optimized, the behavior of a survey of allyl
ketones and nitroolefins was examined.[19,20] As the results in
Table 2 show, the reaction tolerated well a variety of allyl
ketones with alkyl- and aryl- sidearm, and nitroolefins with either
electron-rich, electron-neutral or electron-poor aryl substituents
at C. The corresponding adducts 8–11 were produced in
diastereomeric ratios of 5:1 or higher and enantioselectivities up
to 98% for both the major and minor isomers.[21] For -
unsubstituted allyl ketones 5C and 6C, products 12C and 13C
were formed in poor diastereomeric ratios whilst the ee’s were
consistently good. In every case, the alkylation proceeded at
Cof the allyl ketone[22] and no isomerisation of the double bond
was observed. Incidentally, the starting ketones 5C and 6C
underwent partial (about 20%) isomerization to the respective
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of adducts was primarily established by X-ray analysis of
These results, especially the high dr, might be related to the
strong preference for Z-enolate formation from these bulky
ketols, as the corresponding E-enolate would present
destabilizing 1,3-allylic interactions. Adduct 36 was easily
transformed, via reduction and subsequent diol oxidation, into
aldehyde 43 which was later converted into ketone 8Aa thus
confirming the stereochemical assignment. Alternatively, 36 was
also correlated to thioester 30B through oxidative cleavage and
coupling of the resulting carboxylic acid 44 with thiophenol. In
each case, reactions occurred clean and without double bond
isomerization nor epimerization.
compound 8Aa and by assuming
a
uniform reaction
mechanism.[24,25]
Table 3. Catalytic reactions with allyl ynones 16–24.[a]
entry R’
R2
S.M./Product Yield [%][b] ee [%][c]
Table 4. Catalytic reactions with allylic ketols 32–35 and further elaboration.[a]
1
Ph
Ph
16 / 20
16 / 21
16 / 21
16 / 22
16 / 22
16 / 23
17 / 24
18 / 25
19 / 26
19 / 27
19 / 28
68
69
69
71
68
72
77
69
75
72
70
95
95
73
95
66
97
95
95
97
94
95
2
3[d]
Ph
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
(CH3)2CHCH2
Ph
Ph
4
Ph
5[d]
6
Ph
Ph
7
3-MeC6H4
8
4-MeOC6H4 CH3(CH2)4
9
nPr
nPr
nPr
Ph
10
11
4-MeOC6H4
iBu
[a] Reactions carried out at 0.2 mmol scale, using 2.0 equiv. of ynone. [b]
Yields of isolated product after chromatographic purification. [c] ee
determined by chiral HPLC. [d] Using catalyst C5.
Attempts to translate the present conditions to simple allyl esters
and equivalents, a substrate category that as far as we know
has neither been employed in enantioselective direct conjugate
additions,[26] revealed a divergent behavior. As data in equation
1 illustrate, the C5-catalyzed reaction of allyl esters/thioesters 29
with nitrostyrene produced a mixture of - and -addition
products 30 and 31, respectively. Thioesters resulted more
reactive and selective than the parent esters. However, while the
minor -adducts were obtained as essentially single isomer in
some cases,[27] the respective major -adduct was obtained with
diastereo- and enantioselectivities from low to moderate.
[a] Reactions carried out at 0.2 mmol scale, using 1.1 equiv. of nitroolefin
and 5 mol% C5 at r.t., unless otherwise stated, in 0.4 mL CH2Cl2.
Diastereomeric ratios determined by 1H NMR analysis of crude sample.
Yields of isolated product after chromatographic purification. ee determined
by chiral HPLC. [b] After 16 h of reaction. NDC: nicotinium dichromate.
In addition to these elaborations, the most obvious is the
selective reduction of the double bond that affords products
formally derived from the -alkylation of nonsymmetric aliphatic
ketones, which is difficult to achieve regioselectively. For
example (eq 2) exposure of 9Aa to H2 over Pd on charcoal
provided compound 45 almost quantitatively.
Given the observations noted above, and owing to the easy
conversion of the ketol moiety into diverse functionalities,[28] we
decided to examine the suitability of allyl ketols as allylester
equivalents. As the results in Table 4 show, it was very gratifying
to observe that the reaction of the allyl ketols 32–35[29] with
nitroolefins 7 in the presence of 5 mol% C5 led tothe
corresponding-addition adduct 36–42 in high yield, essentially
complete diastereoselectivity and ee’s typically higher than 95%.
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dienol ethers) c) V. Gupta, S. V. Sudhir, T. Mandal, C. Schneider,
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In conclusion, we have demonstrated that tertiary
amine/squaramide bifunctional catalysts are able to promote the
addition reaction of allyl ketones to nitroolefins not only with very
good enantio- and diastereocontrol, but also exclusive -site
selectivity. Different subsets of readily available allyl ketones,
including those with an alkyl-, aryl-, alkynyl- and hydroxyalkyl
sidearm, all participate well, giving access to a variety of -
branched ketone products with generally two vicinal tertiary
carbon stereocenters as essentially single isomer. Under similar
catalytic conditions, allyl(thio)esters showed inferior /-site as
well as stereo-selectivity, but the use of allyl ketols as superb
allylester equivalents can remediate this limitation. This study
complements previous efforts[9-11] to switch the innate -reactivity
of most vinylogous enolate equivalents (conjugation preserved)
into -reactivity (conjugation disrupted) and set the basis for
further developments.
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Acknowledgements
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Support has been provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
(GV grant No IT-628-13), and Ministerio de Economía y
Competitividad (MEC Grant CTQ2016-78487-C2), Spain. I.I. and
[7]
[8]
For pioneering work on dienamine-mediated asymmetric reactions, see:
S. Bertelsen, M. Marigo, S. Brandes, P. Dinér, K. A. Jørgensen, J. Am.
Chem. Soc. 2006, 128, 12973-12980.
O.O thank GV for
a fellowship. We also thank SGIker
(UPV/EHU) for providing NMR, HRMS, and X-Ray
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Keywords: allyl ketones • organocatalysis • regioselectivity •
Brønsted bases • conjugate additions.
[1]
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Cooperative Catalysis: Designing Efficient Catalysts for Synthesis (Ed.:
R. Peters), Wiley-VCH, Weinheim, 2015.
[21] Separation of diastereomers, while not systematic, was possible by
column chromatography in some instances. See the SI for details.
[22] Control experiments in which the bifunctional catalyst was replaced,
respectively, with Et3N, an achiral squaramide, or a combination of both
as catalyst, led to no reaction at all or variable amounts of - and -
addition adducts. See the SI for details.
[14] Reviews on Brønsted base catalysis: a) C. Palomo, M. Oiarbide, R.
López, Chem. Soc. Rev. 2009, 38, 632-653; b) Asymmetric
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[23] Conjugated enones resulted completely unreactive under the present
conditions.
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[24] CCDC-1542032 (compound 8Aa) contains the supplementary
crystallographic data for this paper. These data can be obtained from
the
Cambridge
Crystallographic
Data
Center
via
www.ccdc.cam.ac.uk/data_request/cif.
[25] Although configuration of the minor stereoisomer of compounds 8-13
(Table 2) was not determined, they should be epimeric at C
(stereolabile center) with respect to the major isomer. This assumption
would be in agreement with the essentially perfect nitroalkene facial
selectivity observed in all examples within Tables 3 and 4 and, most
important, the high ee of products 14 and 15 formed upon isomerization
of the diastereomeric mixtures of 12 and 13, respectively.
[18] W. Yang; D.-M. Du, Org. Lett. 2010, 12, 5450-5453.
[19] Selected reviews on asymmetric organocatalytic conjugate additions: a)
J. L. Vicario, D. Badía, L. Carrillo, E. Reyes, Organocatalytic
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Stereocontrolled Synthesis of Complex Molecules, RSC Publishing,
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[26] For use on direct -site amination and -Mannich reactions,
respectively, see: ref 5g and 9b.
[27] For full screen of allyl(thio)esters, see the Supporting Information.
[28] a) Palomo, C.; Oiarbide, M.; García, J. M. Chem. Soc. Rev. 2012, 41,
4150-4164; b . adiola, . iser, . G me -Bengoa, A. Mielgo, I.
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[29] These allyl ketones are readily prepared from commercial 3-hydroxy-3-
methylbutan-2-one in two steps. See the SI for details.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201703764
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Igor Iriarte, Olatz Olaizola, Silvia Vera,
Iñaki Gamboa, Mikel Oiarbide* and
Claudio Palomo*
Page No. – Page No.
Controlling - vs -Reactivity of
Vinylogous Ketone Enolates in
Organocatalytic Enantioselective
Michael Reactions
Direct with a switch: Most catalytic reactions involving in situ-generated
vinylogous enolate equivalents proceed through -carbon (conjugation preserved),
being the switch to -reactivity not obvious. Here a bifunctional tertiary amine/H-
bond catalyst-promoted highly diastereo- and enantioselective -addition of allyl
ketones to nitroolefins is presented for the first time.
This article is protected by copyright. All rights reserved.