Unsaturated β-ketoesters as versatile electrophiles in organocatalysis

Article abstract of DOI:10.1039/c003296d

β-Ketoesters, which have widely been employed as nucleophiles, are also useful electrophiles in organocatalytic quinine mediated cascade reactions, leading to the formation of products bearing multiple stereocenters in high stereoselectivity. The Royal So

Full text of DOI:10.1039/c003296d

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Unsaturated b-ketoesters as versatile electrophiles in organocatalysisw
Susy Piovesana, Daniele M. Scarpino Schietroma, Ludovico G. Tulli,
Mattia R. Monaco and Marco Bella*
Received 17th February 2010, Accepted 20th May 2010
First published as an Advance Article on the web 7th June 2010
DOI: 10.1039/c003296d
b-Ketoesters, which have widely been employed as nucleophiles,
are also useful electrophiles in organocatalytic quinine mediated
cascade reactions, leading to the formation of products bearing
multiple stereocenters in high stereoselectivity.
Great advance has been achieved in the last few years in the field
of asymmetric organocatalyzed cascade reactions, where several
stereocenters are formed in one-pot operations and densely
functionalized molecules are cast at once with excellent control
of the relative and absolute stereochemistry.1 These fascinating
Scheme 1 b-Ketoesters as substrates for asymmetric catalysis.
and valuable transformations are mostly mediated by secondary
amines; a good number exploits as the catalyst proline or
Jørgensen–Hayashi TMS-prolinol,2 via the well known
enamine/iminium ion activation.3 The formation of multiple
stereocenters employing tertiary amines, such as the Cinchona
alkaloid derivatives, is less frequent; some examples are reported
by Deng and co-workers, who employed the bifunctional
cupreine catalyst derivatives, and by other authors.4 In these
works, the absolute and relative configuration of two stereo-
centers is controlled within a single reactive event.
Table 1 Screening of catalysts and solvents for the addition of
nitroalkanes 2a–b to a,b0-unsaturated b-ketoester 1a
b-Ketoesters, when employed as nucleophiles, can be
functionalized by organometal5 or organic6 catalysts, leading
to highly stereoselective reactions. The first example (proof of
concept) of an asymmetric reaction employing a new electro-
phile is often performed with b-ketoesters as nucleophiles and
they are among the mostly exploited substrates for the
asymmetric construction of quaternary stereocenters.7 Here
we show that a,b0-unsaturated b-ketoesters8 are also useful
electrophiles in a quinine mediated transformation, where
multiple stereocenters are formed in good stereoselectivity
(Scheme 1). Cyclic unsaturated b-ketoesters have been recently
employed in asymmetric metal catalyzed reactions by Shizuka
and Snapper in 20089a and Schotes and Mezzetti in 2010;9b
Scheidt et al. reported in 2007 the intramolecular ring closure
of phenols onto unsaturated b-ketoesters.9c
Our investigation commenced by reacting nitromethane 2a with
b-ketoester 1a. In the first attempt, conducted at rt, we isolated in
high yield the nitro Michael adduct 3a, with 79% ee under the
non-optimized conditions (Table 1, entry 1). The 1H-NMR
spectra showed the presence of both the enol and keto form of
3a, the keto form as a single diastereoisomer (trans relationship
between protons in the a and b0 positions, respectively).
Yb
eec
(%)
Entrya
R
Catalyst
Solvent T/1C (%) drc
1
2
3
4
5
6
7
8
H, 2a Quinine I
H, 2a Cinchonine II
H, 2a [DHQ]2PHAL III DCM Rt
H, 2a [DHQ]2PYR IV DCM Rt
DCM Rt
DCM Rt
92
91
86
90
92
82
92
94
—
—
—
—
—
—
—
—
—
—
—
—
—
—
79
67
32
32
78
30
80
80
85
81
80
85
89
ꢀ89d
H, 2a DHQ V
DCM Rt
MeOH Rt
H, 2a Quinine I
H, 2a Quinine I
H, 2a Quinine I
H, 2a Quinine I
H, 2a Quinine I
H, 2a Quinine I
H, 2a Quinine I
H, 2a Quinine I
H, 2a Thiourea VI
Et, 2b Quinine I
Et, 2b Quinine I
Et, 2b Quinine I
Et, 2b Quinine I
Et2O
EtOAc Rt
Rt
9
EtOAc ꢀ20 87
10
11
12
13
14
15
16
17
18
PhI
PhCH3 Rt
PhCH3
Rt
85
92
90
4
PhCH3 ꢀ20 92
PhCH3 ꢀ20 91
PhCH3 Rt
PhCH3
93 2 : 1 69/50
90 10 : 1 91/nd
4
EtOAc ꢀ20 91 20 : 1 92/nd
PhCH3 ꢀ20 93 70 : 1 94/nd
Dipartimento di Chimica, ‘‘Sapienza’’ University of Roma and Istituto
di Chimica Biomolecolare del CNR, P.le Aldo Moro 5, 00185 Roma,
Italy. E-mail: Marco.Bella@uniroma1.it; Fax: +39 06 490631
w Electronic supplementary information (ESI) available: Character-
ization of new compounds and chromatograms; details for the
determination of relative and absolute configuration. See DOI:
10.1039/c003296d
a
Reaction condition: 0.07 mmol 1a, 3 eq. 2a–b, 0.7 mL solvent;
10 mol% I–VI (structures: see ESIw); time: 12 h for reactions at rt
b
c
and up to 72 h for reactions at ꢀ20 1C. Isolated yield. ee and dr
determined by CSP-GC; see ESIw for stereochemistry determination.
Negative ee indicates the formation of the opposite enantiomer.
d
ꢁc
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The ratio between the two tautomers is influenced by the
sample concentration (low concentrations favor the enol form);
however, when these mixtures were analyzed by CSP-GC or
CSP HPLC, only the keto form of compound 3a could be
detected. A quick screening of other Cinchona alkaloid deri-
vatives did not lead to the identification of a better performing
catalyst (entries 2–5); compound 3a was obtained with similar
enantioselectivity in most of the solvents tested (entries 7–13),
with the exception of methanol (entry 6).10 The lowering of the
reaction temperature (entries 9, 12 and 13) resulted in the
increase of the enantiomeric excess of compound 3a to 89%.
Finally, we tested quinine-based thiourea VI, because it has
been recently reported by several authors as privileged catalyst
in several stereoselective asymmetric reactions.11 Under the
optimized conditions, catalyst VI performed well, affording
the nitro adduct 3a with similar enantioselectivity (89% ee,
entry 14), producing, however, the opposite enantiomer with
respect to the reaction mediated by quinine I. Since this
compound is obtained through a multistep synthetic sequence
from quinine I,11e we did not investigate further this catalyst.
Significant results were also achieved by employing in
the reaction other nitroalkanes as the nucleophile, such as
1-nitropropane 2b, where essentially only one of the eight
potential stereoisomers of 3b was isolated. Initially, when the
reaction was conducted at rt, the additional stereogenic center
formed in the g0-position (a-position with respect to the nitro
group) is obtained essentially in both configurations, while the
trans relationship between the protons in the a and b0-position
is kept (entry 15). Also in this case, the lowering of the
temperature to ꢀ20 1C resulted in the formation of adduct
Table 2 Quinine-mediated addition of nitrocompounds 2c–h to
a,b0-unsaturated b-dicarbonyl compounds 1a–c
Entrya n, R1
R2
Yb (%) drc
eec (%)
1
1, OEt, 1a Me, 2c
1, OEt, 1a nPr, 2d
1, OEt, 1a nPr, 2d
1, OEt, 1a Bn, 2e
1, OEt, 1a CH2OTIPS, 2f
1, OEt, 1a (CH2)2CO2Me, 2g 3g, 94
1, OEt, 1a Br, 2h
2, OEt, 1b H, 2a
2, OEt, 1b Me, 2c
3c, 92
3d, 93
3d, 96
3e, 94
3f, 90
40 : 1 94
30 : 1 94
2
3d
4
9 : 1
6 : 1
ꢀ93e
88
5
20 : 1 98
5 : 1 91
25 : 1 92
6
7f
8
3h, 45
3i, 87
3j, 84
3k, 90
—
2 : 1
—
87
79/76
52
9
10
1, Me, 1c
H, 2a
a
Reaction condition: 0.35 mmol 1, 3 eq. nitrocompund 2, 3.5 mL
b
toluene, 10 mol% quinine I, ꢀ20 1C, 3 days. Yield referred to pure
c
isolated compounds after FC. dr and ee determined by CSP-GC, or
by CSP-HPLC equipped with an IB chiralpack column, ee of the
d
major diastereoisomer. Quinidine VII employed as the catalyst.
e
Negative ee indicates the formation of the opposite enantiomer.
The isolated product is the cyclopropyl derivative 3h, see ref. 15 and
f
ESIw for details about the stereochemical determination.
(the pseudoenantiomer of quinine I) the major product is the
opposite enantiomer of compound 3d (entry 3). Nitro-
compounds bearing additional functional groups, such as an
aromatic moiety (nucleophile 2e, entry 4), protected alcohol or
ester (2f and 2g respectively, entries 5 and 6), perform well in
all cases, showing good control of diastereoselectivity (5 : 1 to
40 : 1) and enantioselectivity (up to 98% ee). Bromonitro-
methane 2h (entry 7) presents a similar reactivity; however, in
this case the isolated adduct is the cyclopropyl derivative 3h,
resulting from an internal SN2 process.15 The low yield
observed in this case depends upon the formation of
byproducts derived from the opening of the strained bicyclo-
[3.1.0]hexane system.
Finally, other a,b0-unsaturated b-dicarbonyl compounds as
the electrophile have been tested, such as 6-membered ring
a,b0-unsaturated b-ketoester 1b, which reacted with nitro-
methane 2a, affording the corresponding nitro Michael adduct
with an erosion of enantioselectivity (87% ee, Table 2, entry 8,
to be compared with 89% ee of the 5-membered ring 1a,
Table 1, entry 13). The reaction between 1b and nitroethane 2c
is less stereoselective (dr = 2 : 1 and ee = 79/76, entry 9).
The reaction gave the desired adduct in good yields also when
a,b0-unsaturated b-diketone 1c is employed as the electrophile,
however, in this case the enantioselectivity is only moderate
(52% ee, entry 10). Secondary (a,a0-disubstituted) nitro-
compounds employed as nucleophiles, or acyclic unsaturated
b-ketoesters as electrophiles, such as the ethyl ester of 2-acetyl-
3 phenyl acrylic acid, react significantly slower; only E/Z
isomerization is observed after 2 days in the reaction with
quinine I and nitromethane 2a.
3b with excellent control of diastereoselectivity (70
: 1,
mixture of epimers at the g0-position) and enantioselectivity
(92–94% ee, entries 17 and 18).
The nucleophilic addition of nitrocompounds is one of the
oldest organocatalyzed asymmetric reactions;12 a variety of
electrophiles have been employed as Michael acceptors.13 The
new chiral centers formed are generally present on the electro-
phile partner of the reaction; the control of the stereocenter
formed in the a-position with respect to the nitro group is
quite challenging, because of the acidity of this proton; the
corresponding stereocenter is therefore prone to epimerization.
Nevertheless, control of diastereoselectivity has been achieved
in the addition of nitroalkanes to aldehydes14a or imines;14b
furthermore, a few months ago Zhu and Lu described the
Michael addition of nitroalkanes to vinyl sulfones in 72–84%
ee, obtaining products that bear a stable tertiary stereocenter
without observing racemization.11a We believe that the success
of controlling the diastereoselection in our transformation is
possible thanks to the use of quinine I, which is not a strong
base, thus preventing the stereocenter epimerization in the
g0-position (a-position to the nitro group) of compounds 3,
which in these experimental condition is configurationally
stable.
Table 2 illustrates further examples where several nitro-
alkanes are added to b-dicarbonyl compounds 1 under the
optimized reaction conditions. All the transformations
proceed in high stereoselectivity. Examples include other
nitroalkanes such as nitroethane 2c or 1-nitrobutane 2d
(Table 2, entries 1 and 2). As expected, employing quinidine VII
We also achieved a tandem three component reaction with
an additional electrophile such as methyl vinyl ketone 4, added
directly once the Michael adducts 3 are formed. In this case,
ꢁc
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Table 3 Quinine-mediated tandem addition of nitrocompounds 2a–g
and methyl vinyl ketone 4 to 1a
H. Jiang, A. Milelli, P. Elsner, R. G. Hazell and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2007, 46, 9202; (f) D. Enders, M. R. M.
Huettl, C. Grondal and G. Raabe, Nature, 2006, 441, 861;
(g) Y. Huang, A. M. Walji, C. H. Larsen and D. W. C.
MacMillan, J. Am. Chem. Soc., 2005, 127, 15051.
3 (a) Enantioselective Organocatalysis, ed. P. I. Dalko, Wiley-VCH,
Weinheim, 2007; (b) A. Berkessel and H. Groger, Asymmetric
Organocatalysis, Wiley-VCH, Weinheim, 2004.
4 (a) B. Wang, F. Wu, Y. Wang, X. Liu and L. Deng, J. Am. Chem.
Soc., 2007, 129, 768; (b) P. S. Hynes, D. Stranges, P. A. Stupple,
A. Guarna and D. J. Dixon, Org. Lett., 2007, 9, 2107; (c) Y. Wang,
X. Liu and L. Deng, J. Am. Chem. Soc., 2006, 128, 3928;
(d) G. Bartoli, M. Bosco, A. Carlone, A. Cavalli, M. Locatelli,
A. Mazzanti, P. Ricci, L. Sambri and P. Melchiorre, Angew.
Chem., Int. Ed., 2006, 45, 4966.
5 For leading examples where asymmetric quaternary stereocenters
are built by metal catalysis see: (a) M. Marigo, K. Juhl and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2003, 42, 1367;
(b) Y. Hamashima, D. Hotta and M. Sodeoka, J. Am. Chem.
Soc., 2002, 124, 11240; (c) L. Hintermann and A. Togni, Angew.
Chem., Int. Ed., 2000, 39, 4359 and references cited therein.
6 M. Bella and T. Gasperi, Synthesis, 2009, 1583.
7 (a) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur. J. Org.
Chem., 2007, 5969; (b) B. M. Trost and C. Jiang, Synthesis, 2006,
369; (c) J. Christoffers and A. Baro, Adv. Synth. Catal., 2005, 347,
1473; (d) Quaternary Stereocenters—Challenges and Solutions for
Organic Synthesis, ed. J. Christoffers and A. Baro, Wiley-VCH,
Weinheim, 2005.
Entrya
R
Yb (%) 6 : 5
5–6a, 85 1 : 4
drc
eec (%)
1
2
3
4
5
6
H, 2a
Et, 2b
Me, 2c
Bn, 2e
CH2OTIPS, 2f
>10 : 1 >97
6b, 67
6c, 78
6d, 78
6e, 83
>10 : 1 >10 : 1 96
>10 : 1 >10 : 1 95
>10 : 1 >10 : 1 95
>10 : 1 >10 : 1 93
>10 : 1 >10 : 1 96
(CH2)2CO2Me, 2g 6f, 78
a
Reaction condition: 0.35 mmol 1a, 3 eq. nitrocompund 2, 1 mL
toluene, 10 mol% quinine I, ꢀ20 1C, 24 h, then 3 eq. methyl vinyl
b
ketone 4, 3 days. Yield referred to pure isolated compounds after
c
FC. dr and ee determined by CSP-HPLC equipped with an IB
d
chiralpack column. For 5a: ee of the more polar epimer; stereo-
chemistry determined via NOESY spectra, see ESIw for details; 5a as
1(more polar) : 1.5 (less polar) mixture of epimers. For the stereo-
chemical determination see ESI.w
8 For the preparation of these substrates see: H. J. Reich,
J. M. Renga and I. L. Reich, J. Am. Chem. Soc., 1975, 97, 5434.
9 (a) M. Shizuka and M. L. Snapper, Angew. Chem., Int. Ed., 2008,
47, 5049; (b) C. Schotes and A. Mezzetti, J. Am. Chem. Soc., 2010,
132, 3652; (c) M. M. Biddle, M. Lin and K. A. Scheidt, J. Am.
Chem. Soc., 2007, 129, 3830.
adduct 6a, derived from the addition of nitromethane to 1a,
cyclizes spontaneously to afford 5a (Table 3, entry 1)
differently from the other products derived from primary
nitroalkanes 2b, c and e–g (entries 2–6). The synthetic versa-
tility and usefulness of the functional nitro group is witnessed
by its several reported transformations.16
10 The stereoselectivity of Cinchona alkaloids mediated reaction is
generallydependent on the solvent; for the addition of nitroalkanes
a similar unusual behavior has been reported, see ref. 11b.
11 Cinchona alkaloids derived thiourea catalysts: (a) Q. Zhu and
Y. Lu, Org. Lett., 2009, 11, 1721; (b) H.-H. Lu, X.-F. Wang,
C.-J. Yao, J.-M. Zhang, H. Wu and W.-J. Xiao, Chem. Commun.,
2009, 4251; (c) P. Li, Y. Wang, X. Liang and J. Ye, Chem.
Commun., 2008, 3302; (d) B. Vakulya, S. Varga and T. Soos,
J. Org. Chem., 2008, 73, 3475; (e) B. Vakulya, S. Varga,
A. Csampai and T. Soos, Org. Lett., 2005, 7, 1967. Other chiral
thiourea catalysts see: (f) K. Mei, M. Jin, S. Zhang, P. Li, W. Liu,
X. Chen, F. Xue, W. Duan and W. Wang, Org. Lett., 2009, 11,
2864; (g) C. Rabalakos and W. D. Wulff, J. Am. Chem. Soc., 2008,
130, 13524. Review: (h) A. G. Doyle and E. N. Jacobsen, Chem.
Rev., 2007, 107, 5713.
12 (a) M. Yamaguchi, Y. Igarashi, R. S. Reddy, T. Shiraishi and
M. Hirama, Tetrahedron, 1997, 53, 11223; (b) M. Yamaguchi,
T. Shiraishi, Y. Igarashi and M. Hirama, Tetrahedron Lett., 1994,
35, 8233; (c) S. Hanessian and V. Pham, Org. Lett., 2000, 2, 2975;
(d) S. Hanessian, Z. Shao and J. S. Warrier, Org. Lett., 2006, 8,
4787.
13 Comprehensive review: R. Ballini, G. Bosica, D. Fiorini,
A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933.
14 Example of asymmetric reactions where a stable stereocenter in the
In conclusion, herein is presented the addition of nitro-
alkanes to a,b0-unsaturated b-ketoesters. The reactions
proceed with excellent stereoselectivity, affording Michael
adducts 3. A tandem reaction affords in good yields and
stereoselectivity densely functionalized compounds 5a or 6.
This control of multiple stereocenters is especially significant
in the field of Cinchona alkaloids catalysis or when nitro-
alkanes are employed as nucleophiles; we believe that
compounds 1 are attractive electrophiles whose synthetic potential
can be harvested in several other asymmetric transformations.
Authors thank Dr Fabio Sciubba and Mr Marco Pastore,
‘‘Sapienza’’ University of Roma, for the high-field spectra of
compounds 3h and 5a, and for invaluable technical help,
respectively. MB is also grateful to Prof. M. Antonietta Loreto
for the use of HPLC, and to Prof. Lelio Zoccolillo and
Dr Susanna Insogna, from the same institution, for the usage
of GC facilities and for very helpful discussions. Financial
support to this work was provided from ‘‘Sapienza’’ University
of Roma (‘‘Finanziamento di Ateneo’’ 2007–2008) and from
RSC with a Research Bursary to MB.
a-position to
a nitro group is obtained: (a) C. Palomo,
M. Oiarbide, A. Laso and R. Lopez, J. Am. Chem. Soc., 2005,
127, 17622; (b) T. P. Yoon and E. N. Jacobsen, Angew. Chem., Int.
Ed., 2005, 44, 466; (c) W. J. Nodes, D. R. Nutt, A. M. Chippindale
and J. A. Cobb, J. Am. Chem. Soc., 2005, 131, 16016 and ref. 11a.
15 The organocatalytic asymmetric cyclopropanation reaction of
enones employing bromonitromethane 2h is known; (a) J. Lv,
J. Zhang, Z. Lin and Y. Wang, Chem.–Eur. J., 2009, 15, 972;
(b) T. Inokuma, S. Sakemoto and Y. Takemoto, Synlett, 2009,
1627 and reference cited therein. The formation of the three
membered ring moiety in compound 3h0 allowed stereochemistry
determination of the stereocenter in the a-position to the nitro
group; see ESIw for details.
Notes and references
1 Overview: D. Enders, C. Grondal and M. R. M. Huettl, Angew.
Chem., Int. Ed., 2007, 46, 1570.
2 For recent examples of organocascade reactions employing these
and other catalysts see: (a) A. Michrowska and B. List, Nat. Chem.,
2009, 1, 225; (b) M. Rueping, A. Kuenkel, F. Tato and J. W. Bats,
Angew. Chem., Int. Ed., 2009, 121, 3699; (c) D. Enders, C. Wang
and J. W. Bats, Angew. Chem., Int. Ed., 2008, 47, 7539; (d) J. Zhou
and B. List, J. Am. Chem. Soc., 2007, 129, 7498; (e) E. Reyes,
16 (a) The Chemistry of Amino, Nitroso, Nitro and Related Groups,
ed. S. Patai, Wiley, Chichester, 1996; (b) The Nitro Group in
Organic Synthesis, ed. N. Ono, Wiley-VCH, New York, 2001.
ꢁc
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5162 | Chem. Commun., 2010, 46, 5160–5162