A catalytic and iterative route to β-substituted esters via highly enantioselective conjugate addition of dimethylzinc to unsaturated malonates

Article abstract of DOI:10.1039/b315871c

Using the chiral phosphoramidite ligand (S,R,R)-L1 in the conjugate addition of dimethylzinc to acyclic unsaturated malonates, enantioselectivities of up to 98% have been obtained for the first time. An iterative and stereodivergent route to 3,5-dimethyl esters that takes advantage of this asymmetric catalysis has been developed.

Full text of DOI:10.1039/b315871c

A catalytic and iterative route to b-substituted esters via highly
enantioselective conjugate addition of dimethylzinc to unsaturated
malonates†
Julia Schuppan, Adriaan J. Minnaard and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9749 AG Groningen, The Netherlands
Received (in Cambridge, UK) 5th December 2003, Accepted 28th January 2004
First published as an Advance Article on the web 24th February 2004
Using the chiral phosphoramidite ligand (S,R,R)-L1 in the
conjugate addition of dimethylzinc to acyclic unsaturated
malonates, enantioselectivities of up to 98% have been obtained
for the first time. An iterative and stereodivergent route to
3,5-dimethyl esters that takes advantage of this asymmetric
catalysis has been developed.
To further optimize the reaction conditions, L1 and L2 were
tested in different solvents (Table 2). In toluene, an ee of 95% was
obtained for both ligands. This could be improved to an excellent
value of 97% ee by using heptane as the solvent. Diethyl ether and
Among several methods for catalytic asymmetric carbon–carbon
bond formation, the copper-catalyzed conjugate addition of
organozinc reagents to unsaturated carbonyl compounds is a widely
used key transformation.1 To date, efficient protocols for the
conversion of both cyclic and acyclic enones, as well as
nitroalkenes, have been developed featuring excellent stereocon-
trol.1,2 Highly enantioselective additions have also been reported
for lactones.3,4 On the other hand, similar conjugate addition to
acyclic unsaturated esters remains a major challenge, in particular,
realizing the synthetic potential of optically active b-substituted
esters as chiral building blocks in organic synthesis. In earlier
studies, only moderate stereocontrol was achieved in the 1,4-addi-
tion of diethylzinc to nitro-substituted unsaturated esters4 and
malonates.5 Recently, Hird and Hoveyda described the addition of
diorganozinc reagents to N-acyloxazolidinones with excellent
enantioselectivity applying peptide-based phosphine ligands.6 We
wish to report the development of a highly enantioselective,
copper-catalyzed 1,4-addition to acyclic malonates employing
monodentate phosphoramidite ligands.7 Furthermore, an iterative
and stereodivergent route to 3,5-dimethyl esters is presented.
Since simple acyclic unsaturated esters are not reactive in the
conjugate addition of dialkylzincs, we focused on unsaturated
malonates 1 (Scheme 1).8 The products 2 can easily be converted
into the monoesters 3 by dealkoxycarbonylation.9 In view of the
prominent role of the resulting structural motif in numerous natural
products, the enantioselective introduction of a methyl substituent
using Me2Zn is considered the most important goal.
Diethyl isopentylidene malonate (1a) was chosen as a model
substrate and a variety of phosphoramidite ligands were screened
using 2 mol% of catalyst (Cu : L ratio 1 : 2; Scheme 2). The best
results were obtained with ligands L1, L2 and L3. Full conversion
was reached within 1–2 h, producing ees of up to 94% (Table 1).
These three ligands share the same amine part, but differ in the diol
backbone. Exchanging the phenylethyl substituent at nitrogen for
an alkyl group (L5–L7) decreased both conversion and ee (entries
5–7). Altering the configuration of the amine moiety from S,R,R in
L2 to S,S,S in L8 resulted in a significantly lower reaction rate and
reversed stereoselectivity, providing the R-enantiomer of 3a as the
major product.
Scheme 2 Conjugate addition of dimethylzinc to unsaturated malonic ester
1a.
Table 1 Effect of the ligand in asymmetric conjugate addition of Me2Zn to
1a at 240 °C in toluene
Conversion
(%)
eea
(%)
Entry
Ligand
Time/h
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
100
100
100
99
84
41
2
1
2
1
21
2
94
93
93
91
90
59
21
26b
22
92
21
21
a The configuration of the major product, (S)-2a, was determined by
comparison of the optical rotation with literature data (see ESI†). b R-
Enantiomer of 2a obtained.
Table 2 Effect of the solvent in asymmetric conjugate addition of Me2Zn to
1a at 260 °C
Entry
Ligand
Solvent
Timea/h
ee (%)
1
2
3
4
5
6
7
8
L1
L2
L1
L2
L1
L2
L1
L2
Toluene
Toluene
Heptane
Heptane
Diethyl ether
Diethyl ether
CH2Cl2
4
2
24
20
20
4
95
95
97
97
94
94
82
88
Scheme 1
20
4
† Electronic supplementary information (ESI) available: experimental
procedures and spectral data for all products. See http://www.rsc.org/
suppdata/cc/b3/b315871c/
CH2Cl2
a All conjugate additions were run to complete conversion.
792
C h e m . C o m m u n . , 2 0 0 4 , 7 9 2 – 7 9 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

dichloromethane also lead to full conversion within 20 h, but
somewhat lower ees were observed. As a general trend, it was
found that longer reaction times were required to reach full
conversion when using L1 as compared to L2, whereas the ees were
similar with both ligands.
Under the optimized conditions, a number of unsaturated
malonates were tested (Table 3). For linear alkyl substituents,
excellent ees of up to 96% and full conversion within 25 h were
achieved (entries 1–13). A second substituent at the g-position
lowers the reactivity of the system (entries 14–19); however, for the
isopropyl-substituted malonic ester 1e, an excellent ee of 98% was
obtained using ligand L1 in toluene. With the exception of substrate
1f, in general, L1 gave slightly higher ees than L2.
Table 3 Asymmetric conjugate addition of dimethylzinc to unsaturated
malonic esters 1b–1fa
Con-
Di-
version Time/ eeb
Entry ester
R
Ligand Solvent
(%)
h
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1b
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
1e
1f
Pr
Pr
Pr
Pr
Pr
Et
Et
Et
Et
L1
L2
L1
L2
L1
L1
L2
L1
L2
Toluene
Toluene
Heptane
Heptane
100
98
98
21
4
95
94
96
96
94
96
92
92
90
86
82
66
42
98
96
n.d.
n.d.
90
94
21
20
21
24
24
24
24
2
25
25
25
68
68
68
68
25
25
100
Diethyl ether 100
Scheme 4 Reagents and conditions: (a) 2 mol% Cu(OTf)2, 4 mol% L1, 1.5
eq. Me2Zn, toluene, 260 °C; (b) LiCl, H2O, DMF; (c) DiBAL-H; (d) Dess–
Martin oxidation; (e) diethyl malonate, pyridine, Ac2O; (f) 3 mol%
Cu(OTf)2, 6 mol% L1, 1.5 eq. Me2Zn, toluene, 260 °C; (g) 3 mol%
Cu(OTf)2, 6 mol% ent-L2, 1.5 eq. Me2Zn, toluene, 260 °C; (h) LiCl, H2O,
DMSO.
Toluene
Toluene
Heptane
Heptane
Toluene
Toluene
Heptane
Heptane
Toluene
Toluene
Heptane
Heptane
Toluene
Toluene
100
100
80
45
98
100
98
97
60
42
10
8
(CH2)2Ph L1
(CH2)2Ph L2
(CH2)2Ph L1
(CH2)2Ph L2
iPr
iPr
iPr
iPr
1-Furyl
1-Furyl
provides a powerful tool in the new iterative scheme to syn and anti
products (Scheme 4).
L1
L2
L1
L2
L1
L2
In summary, we have shown that excellent stereocontrol can be
achieved in the catalytic conjugate addition of dimethylzinc to
unsaturated malonic esters and that the methodology can be applied
iteratively, thus allowing the construction of either syn- or anti-
3,5-dimethyl carbonyl compounds.
80
57
1f
a All conjugate additions run at 260 °C. b The configuration of the major
product was determined by comparison of the optical rotation with literature
data (see ESI†). n.d.: not determined.
This project was financially supported by the European Network
COMBICAT (HPRN-CT-2000-00014).
Notes and references
An attractive aspect of the new methodology is that it provides
the basis for an iterative catalytic protocol (Scheme 3). In this way,
the stereoselective construction of 3,5-dimethyl carbonyl motifs
can be achieved, which are common in numerous naturally
occurring compounds.10
1 (a) N. Krause and A. Hoffmann-Roder, Synthesis, 2001, 171–196; (b) B.
L. Feringa, R. Naasz, R. Imbos and L. A. Arnold, in Modern
Organocopper Chemistry, ed. N. Krause, Wiley-VCH, Weinheim,
2002; (c) A. Alexakis and C. Benhaim, Eur. J. Org. Chem., 2002,
3221–3236.
2 (a) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos and A. H. M. de
Vries, Angew. Chem., Int. Ed. Engl., 1997, 36, 2620–2623; (b) I. H.
Escher and A. Pfaltz, Tetrahedron, 2000, 56, 2879–2888; (c) H.
Mizutani, S. J. Degrado and A. H. Hoveyda, J. Am. Chem. Soc., 2002,
124, 779–781; (d) A. Duursma, A. J. Minnaard and B. L. Feringa, J. Am.
Chem. Soc., 2003, 125, 3700–3701.
Scheme 3 Iterative 1,4-addition.
3 (a) M. Kanai, Y. Nakagawa and K. Tomioka, Tetrahedron, 1999, 55,
3843–3854; (b) M. Yan, L.-W. Yang, K.-Y. Wong and A. C. S. Chan,
Chem. Commun., 2000, 115–116; (c) M. T. Reetz, A. Gosberg and D.
Moulin, Tetrahedron Lett., 2002, 43, 1189–1191.
4 J. P. G. Versleijen, A. M. Leusen van and B. L. Feringa, Tetrahedron
Lett., 1999, 40, 5803–5806.
5 A. Alexakis and C. Benhaim, Tetrahedron: Asymmetry, 2001, 12,
1151–1157.
6 A. W. Hird and A. Hoveyda, Angew. Chem., Int. Ed., 2003, 42,
1276–1279.
Thus, diethyl propylidene malonate (1c) was subjected to an
asymmetric conjugate addition providing, after decarboxylation,
(S)-ethyl 3-methylpentanoate (3c) in excellent yield and enantiose-
lectivity (Scheme 4). A sequence involving reduction of the ester
moiety to the corresponding alcohol, oxidation to the aldehyde and
subsequent Knoevenagel condensation gave access to unsaturated
diester 4. Subjecting 4 to a second catalytic asymmetric conjugate
addition, again using ligand L1 (configuration S,R,R) resulted in the
syn-dimethylated product (S,S)-5, with an excellent selectivity of
97 : 3. With ligand ent-L2 (configuration R,S,S) in the second
conjugate addition, the other diastereomer, anti-(S,R)-6 was formed
and, again, very high selectivity (dr 97 : 3) was observed. The
diastereoisomers 5 and 6 can easily be distinguished by NMR, GC
and optical rotation (see ESI†). Apparently, the stereocenter present
in substrate 4 has no influence on the stereochemical outcome of the
second conjugate addition step. This nearly complete stereocontrol
governed by the chiral catalyst in subsequent 1,4-additions
7 B. L. Feringa, Acc. Chem. Res., 2000, 33, 346–353.
8 In accordance with observations by Alexakis et al. (see ref. 5), we found
modest ees for the addition of Et2Zn to malonates 1, attributed to a
significant uncatalyzed reaction.
9 A. P. Krapcho, Synthesis, 1982, 805–822.
10 See (a) A. Gambacorta, D. Tofani, P. Lupattelli and A. Tafi,
Tetrahedron Lett., 2002, 43, 2195–2198 and references therein; (b) N.
Tabata, Y. Ohyama, H. Tomoda, T. Abe, M. Namikoshi, Y. Yamaguchi,
R. Masuma and S. Omura, J. Antibiot., 1999, 52, 815–826; (c) M. A.
Calter and W. Liao, J. Am. Chem. Soc., 2002, 124, 127–129.
C h e m . C o m m u n . , 2 0 0 4 , 7 9 2 – 7 9 3
793