Enantioselective organocatalytic Michael additions to acrylic acid derivatives: Generation of all-carbon quaternary stereocentres

Article abstract of DOI:10.1039/b805233f

Acrylic esters, thioesters and N-acryloyl pyrrole have been identified as effective electrophiles in the enantioselective Michael addition reaction with β-keto ester pro-nucleophiles catalysed by a cinchona alkaloid derived bifunctional organocatalyst; enantiomeric excesses of up to 98% and yields of up to 96% can be obtained for a range of Michael acceptors and pro-nucleophiles. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805233f

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Enantioselective organocatalytic Michael additions to acrylic acid
derivatives: generation of all-carbon quaternary stereocentresw
Caroline L. Rigby and Darren J. Dixon*
Received (in Cambridge, UK) 27th March 2008, Accepted 14th May 2008
First published as an Advance Article on the web 25th June 2008
DOI: 10.1039/b805233f
Acrylic esters, thioesters and N-acryloyl pyrrole have been
identified as effective electrophiles in the enantioselective Michael
addition reaction with b-keto ester pro-nucleophiles catalysed by
a cinchona alkaloid derived bifunctional organocatalyst; enantio-
meric excesses of up to 98% and yields of up to 96% can be
obtained for a range of Michael acceptors and pro-nucleophiles.
The asymmetric Michael addition of acidic methine pro-
nucleophiles to electron deficient alkenes is a direct and
Fig. 1 Bifunctional cinchona alkaloid-derived organocatalysts.
powerful method for the production of all-carbon quaternary
stereogenic centers bearing pendant functionality amenable to
With either ethyl acrylate 3a and ethyl thioacrylate 3b none
of the desired Michael adducts were observed after stirring in
further derivatisation. Since Wynberg’s description1 of the
cinchona alkaloid catalysed addition of cyclic b-keto esters to
methyl vinyl ketone, several examples of catalytic asymmetric
CH2Cl2 at room temperature for 7 days. However, with
1-naphthylthioacrylate 3c rapid and clean conversion to the
Michael additions of carbon acids to the simplest, b-unsub-
desired Michael adduct 4c was observed (entry 3, 495%
stituted Michael acceptors leading to adducts in high enantio-
conversion after 30 min). With suitable reactivity established,
meric excess have been reported. a,b-Unsaturated ketones,2,3
attention turned towards the development of the catalytic
asymmetric variant. An encouraging 40% ee was observed
acrolein,2,3 acrylonitrile4 vinyl sulfones4 and ethylidene bispho-
sphonate esters5 are all effective electrophiles using both
using 10 mol% catalyst 1b,8a–c however this could be increased
metal-2 and metal-free catalysis.3–5 Asymmetric Michael addi-
tions to acrylate derivatives leading to adducts with tertiary
significantly to 82% by the use of catalyst 1c4a,8f–i instead.
Optimisation of this result by examination of various reaction
stereogenic centres in moderate to high enantiomeric excesses
parameters resulted in a further increase of ee to 90%; finally,
are known through chiral phase transfer catalysis,6 however,
a change of catalyst to the slightly bulkier phenanthrene
the direct formation of acrylate Michael adducts bearing fully
substituted catalyst 1d4a,8f–i further increased the ee to 96%.
substituted quaternary stereogenic centres in high enantiomeric
excess under catalytic metal-free conditions has, to our knowl-
Table 1 Reactivity and optimisation studiesa
edge, yet to be reported, despite the synthetic potential of such
a methodology.6e,7 Through employment of cinchona alkaloid-
derived bifunctional organocatalysts developed in our, and
other, laboratories (Fig. 1),8–10 we believed the discovery of a
highly enantioselective variant was plausible and accordingly
began investigations.
Initial studies were required to assess the reactivity profile of
Entry E+ Cat. Solv.
cb/M T/1C Conv.c (%) eed (%)
various acrylate esters. Indanone-derived b-keto ester 2 was
chosen as the test pro-nucleophile on the basis of its high
reactivity in other Michael addition reactions. Ethyl acrylate
3a, ethyl thioacrylate 3b and 1-naphthylthioacrylate 3c were
then screened in the reaction using 3 equivalent of Michael
acceptor and DABCO (1,4-diazabicyclo[2.2.2]octane) at
10 mol% as catalyst. The results are presented in Table 1.
1
2
3
4
5
6
7
8
3a 1a
3b 1a
3c 1a
3c 1b
3c 1c
3c 1c
3c 1c
3c 1c
3c 1c
3c 1c
3c 1d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2 0.33
PhMe
THF
1
1
1
1
1
1
1
r.t.
r.t.
r.t. 495
r.t. 495
r.t. 495
0
0
—
—
—
40
82
86
88
90
82
74
96
0
À20
À20
À20
À20
À20
495
495
495
495
495
495
9
0.33
0.33
10
11
a
School of Chemistry, The University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: Darren.Dixon@man.ac.uk; Fax:
+44 (0)161 2754939; Tel: +44 (0)161 2751426
CH2Cl2 0.33
Reaction was carried out using 3 equivalents of Michael acceptor
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for compounds 3c, 3d, 3f, 3g, 11, 4c–4i,
12c–18c, 20 and 21. CCDC 683070. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b805233f
and 10 mol% catalyst: see ESIw for experimental details and full
b
c
optimisation table. Concentration of 2. Determined by 1H NMR
d
analysis. Determined by HPLC.
ꢀc
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3798 | Chem. Commun., 2008, 3798–3800

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The tolerance of these optimised reaction conditions to-
wards a variety of pro-nucleophiles was then investigated
(Table 2). Substituted indanone esters 5 and 6 gave compar-
able results to those obtained using indanone ester 2 (entries 2
and 3); regioisomeric 2-indanone derivative 7 gave a slightly
lower ee of 88% (entry 4). Cyclopentanone and cyclohexanone
derivatives 8 and 9 were also found to be good substrates
giving rise to the Michael adducts with high enantiocontrol,
albeit with a prolonged reaction time in the latter case (entries
5 and 6). Notably, the hexafluoroisopropyl esters were found
to be far superior to the tert-butyl ester analogues;3a cyclo-
pentanone derivative 10, bearing a tert-butyl ester moeity,
gave only 67% ee after 18 h (entry 7) and its cyclohexyl
analogue was found to be completely unreactive under the
reaction conditions. Acyclic b-keto ester 11 was also found to
react with 3c, albeit more slowly and with a reduced enantio-
selectivity; product 18c was obtained in 58% yield and 71% ee
(entry 8).11
Fig. 2 Determination of absolute stereochemistry.
Next, the scope of the reaction with respect to the Michael
acceptor was investigated. Comparable results were observed
using thioacrylates 3d and 3e (entries 9 and 10); the reaction
could also be extended to encompass the use of acrylate esters
Scheme 1 Manipulation of N-acryloyl pyrrole Michael adduct 4i.
such as 3f, 3g and 3h (entries 11, 12 and 13). Recrystallisation
of adduct 12c to enantiopurity followed by single-crystal X-
ray diffraction analysis allowed the S absolute stereochemical
configuration of the major enantiomer to be assigned (Fig. 2).
The absolute stereochemical configuration of all the other
products was assigned by analogy.
Table 2 Scope of the Michael addition reactiona
The success of N-acryloyl pyrrole 3i (entry 14) in this
reaction is significant as N-acylpyrroles are valuable synthetic
intermediates due to the unusual stability of the tetrahedral
intermediate formed upon addition of a nucleophile.12 To
demonstrate this utility, adduct 4i was treated sequentially
with Super-hydrides followed by sodium tert-butoxide to
generate lactol 19; Wadsworth–Horner–Emmons olefination
then afforded tetrahydropyran 20 (Scheme 1). The product
was isolated as a 5 : 1 mixture of diastereoisomers; the
stereochemistry of 20 as depicted in Scheme 1 was supported
by NOE experiments on 20 itself and partially reduced indanol
ester 21 (formed by treatment of 4i with one equivalent of
Super-hydrides).
To conclude, we have developed a highly enantioselective
organocatalytic Michael addition of methine carbon acids to
acrylic esters, thioesters and N-acryloyl pyrrole using a cinch-
ona alkaloid-derived bifunctional organocatalyst. This reac-
tion results in the formation of a quaternary stereogenic centre
and generates adducts in high yields and up to excellent
enantioselectivities. Further investigations in this field are
ongoing and the results will be reported in due course.
We gratefully acknowledge the EPSRC (EP/D04961X/1) for
funding (to C. L. R.) and Dr M. Helliwell for single-crystal
X-ray diffraction analysis.
Pro- Michael
Entry nucleophile acceptor t/h
Yield
(%)
eeb (%) Product
1
2
3
4
5
6
7
8
2
5
6
7
8
9
10
11
2
2
2
2
2
3c
3c
3c
3c
3c
3c
3c
3c
3d
3e
3f
2
83
78
90
95
75
52
64
58
75
83
83
76
78
96
96
93
94
88
95
98
67
71
95
95
94
94
94
95
4c
0.5
0.5
1
1
96
18
120
2
12c
13c
14c
15c
16c
17c
18c
4d
4e
4f
4g
4h
4i
9
10
11
12
13
14
a
2
72
72
72
3
3g
3h
3i
Notes and references
2
1 H. Wynberg and R. Helder, Tetrahedron Lett., 1975, 46, 4057.
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N. Yoshikawa, Chem. Rev., 2002, 102, 2187, and references
Reaction was carried out in CH2Cl2 at À20 1C using 3 equivalents of
Michael acceptor and 10 mol% catalyst: see ESIw for full experimental
details. Determined by HPLC.
b
ꢀc
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ꢀc
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3800 | Chem. Commun., 2008, 3798–3800