Asymmetric synthesis of carboxylic acid derivatives having an all-carbon α-quaternary center through Cu-catalyzed 1,4-addition of dialkylzinc reagents to 2-aryl acetate derivatives

Article abstract of DOI:10.1021/ol800923q

(Chemical Equation Presented) The asymmetric synthesis of carboxylic acid derivatives having an all-carbon α-quaternary center has been achieved via copper-catalyzed 1,4-addition of dialkylzinc reagents to aryl acetate derivatives in the presence of phosphoramidite ligand. High isolated yields and enantioselectivities were obtained. It was demonstrated that the Meldrum's acid and ester moieties present on the all-carbon quaternary center allow for a wide variety of subsequent transformations, leading to the expedient preparation of succinimides, succinate esters and succinic acids, γ-butyrolactones, and β-amino acid derivatives.

Full text of DOI:10.1021/ol800923q

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2801-2804
Asymmetric Synthesis of Carboxylic
Acid Derivatives Having an All-Carbon
r-Quaternary Center through
Cu-Catalyzed 1,4-Addition of Dialkylzinc
Reagents to 2-Aryl Acetate Derivatives
Ashraf Wilsily and Eric Fillion*
Department of Chemistry, UniVersity of Waterloo,
Waterloo, Ontario, Canada N2L 3G1
efillion@uwaterloo.ca
Received April 21, 2008
ABSTRACT
The asymmetric synthesis of carboxylic acid derivatives having an all-carbon r-quaternary center has been achieved via copper-catalyzed
1,4-addition of dialkylzinc reagents to aryl acetate derivatives in the presence of phosphoramidite ligand. High isolated yields and
enantioselectivities were obtained. It was demonstrated that the Meldrum’s acid and ester moieties present on the all-carbon quaternary
center allow for a wide variety of subsequent transformations, leading to the expedient preparation of succinimides, succinate esters and
succinic acids, γ-butyrolactones, and ꢀ-amino acid derivatives.
Asymmetric synthesis of carboxylic acid derivatives having
an all-carbon R-quaternary center is a long-standing challenge
in organic chemistry. At present, only a handful of catalytic
methods are available to access this structural motif.1,2 Our
recent success in the preparation of carboxylic acids having
an all-carbon ꢀ-quaternary center by enantioselective con-
jugate addition3,4 of dialkylzinc reagents to 5-(1-arylalkyl-
idene) Meldrum’s acids5 encouraged us to broaden the scope
and the synthetic versatility of this strategy. Consequently,
we hypothesized that acyclic, tetrasubstituted olefins 1 might
be suitable precursors to carboxylic acid derivatives bearing
an all-carbon R-quaternary center. To the best of our
knowledge, only two reports describe the synthesis of all-
carbon quaternary center R to carbonyl groups in the context
of asymmetric conjugate addition. Cu-catalyzed addition of
organozinc reagents to cyclic γ-keto esters6 and Rh-catalyzed
(1) For reviews on catalytic methods to all-carbon quaternary centers,
see: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396. (b) Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367
.
(2) For recent examples, see: (a) Fujimoto, T.; Endo, K.; Tsuji, H.;
Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 4492–4496.
(b) Capuzzi, M.; Perdicchia, D.; Jørgensen, K. A. Chem. Eur. J. 2008, 14,
128–135. (c) White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 810–811. (d) Wiedemann, S. H.; Noda, H.;
Harada, S.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 1661–1664.
(e) Denmark, S. E.; Wilson, T. W.; Burk, M. T.; Heemstra, J. R., Jr. J. Am.
Chem. Soc. 2007, 129, 14864–14865. (f) Trost, B. M.; Zhang, Y. J. Am.
Chem. Soc. 2007, 129, 14548–14549. (g) Doyle, A. G.; Jacobsen, E. N.
(3) For recent reviews on asymmetric conjugate addition, see: (a) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969–5994.
(b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007,
1279–1300.
Angew. Chem., Int. Ed. 2007, 46, 3701–3705
.
10.1021/ol800923q CCC: $40.75
Published on Web 05/30/2008
2008 American Chemical Society

reaction of arylboronic acids with 3-substituted maleimides
and 2-methyl-1,4-naphthoquinone7 were described. In both
these reports, excellent yields and selectivities were obtained
on cyclic, trisubstituted olefins.
In this paper, we describe a general approach to the
asymmetric construction of carboxylic acid derivatives
having an all-carbon R-quaternary center via copper-
catalyzed conjugate addition of dialkylzinc reagents to 2-(2,2-
dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)aryl acetates (1). As
depicted in Scheme 1, the proposed general strategy relies
Table 1. Survey of Phosphoramidites Ligands 3 on the Addition
of Et2Zn to Alkene 1a
entry
Ar
X
ligand
R
yield (%) er (S:R)
1
2
3
4
5
6
C6H5 MeO (1a)
C6H5 MeO (1a)
C6H5 MeO (1a)
C6H5 MeO (1a)
C6H5 MeO (1a)
C6H5 MeO (1a)
3a
3b
3c
3d
3e
3f
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
quant
quant
quant
85
85
85
94:6
95:5
96:4
94:6
85:15
42:58
chiral amine moiety was crucial for optimal selectivity; using
3e, 2a was obtained in a moderate 85:15 er (entry 5).
Furthermore, the binaphthyl moiety was necessary to achieve
high enantioselectivity as the biphenol based ligand 3f led
to a poor er (entry 6). On the basis of these results, 3a was
selected as the optimal ligand and used throughout this study.
Scheme 1. General Strategy
on the highly activated nature of these Michael acceptors to
induce umpolung of the position R to the non-Meldrum’s
acid carbonyl, and allow this center to act as an electrophile
toward organozinc reagents.
Readily prepared8 olefin 1a was subjected to 2 equiv of
Et2Zn, 10 mol % of phosphoramidite ligand 3a,9 and 5 mol
% of Cu(OTf)2 in 1,2-dimethoxyethane (DME); 2a was
isolated as a single regioisomer in quantitative yield and an
enantiomeric ratio of 94:6 (Table 1, entry 1). This result was
gratifying as it represents the first example of enantioselective
1,4-addition to electrophilic sp2-carbon centers flanked by
two sp2-hybridized carbons. In attempts to achieve higher
selectivities, phosphoramidites 3b-f were prepared (Figure
1).10 It was found that the replacement of the phenyl group
on 3a with 2-naphthyl or cyclohexyl had little effect (entries
2 and 3). Similarly, analogous ethyl-substituted ligand 3d
furnished identical er as 3a (entry 4). On the other hand, the
Figure 1. Phosphoramidite ligands 3a-f.
We then set out to define the scope of the methodology by
modifying the ester and aromatic moieties of 1 (Table 2). It
was shown that the nature of the ester had modest influence on
the enantioselectivity of the reaction (entries 1-6). Keeping
the ester moiety constant (X ) OMe), substitution at the para
and meta positions of the phenyl ring was determined to have
negligible influence on the enantioselectivity of the addition,
regardless of the substituent steric demand and electronic nature,
with er being highest in the para-substituted examples (entries
7-11 vs 12-14). Ortho substituents led to inconsistent results,
as competing, racemic conjugate reduction occurred (2, R )
H) and er fluctuated with the nature of the substituent (entries
15-18).11 Furyl and naphthyl substrates 1s and 1t provided
product 2s and 2t, respectively, in good yield and selectivity
(entries 19 and 20).
(4) For synthesis of all-carbon quaternary centers via 1,4-addition to
3-substituted cyclic enones, see: (a) Palais, L.; Mikhel, I. S.; Bournaud, C.;
Micouin, L.; Falciola, C. A.; Vuagnoux-d’Augustin, M.; Rosset, S.;
Bernardinelli, G.; Alexakis, A. Angew. Chem., Int. Ed. 2007, 46, 7462–
7465. (b) Vuagnoux-d’Augustin, M.; Kehrli, S.; Alexakis, A. Synlett 2007,
2057–2060. (c) Vuagnoux-d’Augustin, M.; Alexakis, A. Chem. Eur. J. 2007,
13, 9647–9662. (d) Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.;
Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417. (e)
Lee, K.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc.
2006, 128, 7182–7184. (f) Fuchs, N.; d’Augustin, M.; Humam, M.; Alexakis,
A.; Taras, R.; Gladiali, S. Tetrahedron: Asymmetry 2005, 16, 3143–3146.
(g) Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 14988–
14989. (h) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed.
2005, 44, 1376–1378. For 1,4-addition to 2,2-disubstituted nitroolefins, see:
(i) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
127, 4584–4585. For 1,4-addition to ꢀ,ꢀ-disubstituted R,ꢀ-unsaturated
pyridylsulfones, see: (j) Mauleo´n, P.; Carretero, J. C. Chem. Commun. 2005,
4961–4963.
(9) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353. (b) Feringa,
B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2620–2623.
(5) (a) Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774–2775.
(b) Fillion, E.; Wilsily, A.; Liao, E.-T. Tetrahedron: Asymmetry 2006, 17,
2957–2959.
(10) (a) Li, K.; Alexakis, A. Tetrahedron Lett. 2005, 46, 8019–8022.
(b) Watanabe, T.; Kno¨pfel, T. F.; Carreira, E. M. Org. Lett. 2003, 5, 4557–
4558. (c) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillet, F.;
Benhaim, C. Synlett 2001, 1375–1378. (d) Arnold, L. A.; Imbos, R.;
Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron
2000, 56, 2865–2878. (e) Hulst, R.; de Vries, N. K.; Feringa, B. L.
Tetrahedron: Asymmetry 1994, 5, 699–708.
(6) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 1097–1100.
(7) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc. 2006,
128, 5628–5629.
(8) Knoevenagel condensation of arylglyoxylates with Meldrum’s acid, see:
(a) Baxter, G. J.; Brown, R. F. C. Aust. J. Chem. 1975, 28, 1551–1557.
2802
Org. Lett., Vol. 10, No. 13, 2008

Table 2. Influence of the Ester and Aryl Moieties on the
Addition of Et2Zn to 1
entry
Ar
X
R
yield (%) er (S:R)
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
MeO (1a)
EtO (1b)
t-BuO (1c)
BnO (1d)
Et (2a)
Et (2b)
Et (2c)
Et (2d)
quant
94
quant
98
quant
90
91
97
98
82
quant
92
94:6
95:5
93:7
94:6
94:6
95:5
97:3
96:4
95:5
96:4
96:4
91:9
92:8
91:9
90:10
66:34
79:21
71:29
94:6
96:4
(allyl)O (1e) Et (2e)
t-BuS (1f)
MeO (1g)
MeO (1h)
MeO (1i)
Et (2f)
Et (2g)
Et (2h)
Et (2i)
Et (2j)
Et (2k)
Et (2l)
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-t-BuC6H4 MeO (1j)
4-MeOC6H4 MeO (1k)
3-ClC6H4
3-MeC6H4
3-MeOC6H4 MeO (1n)
2-ClC6H4
2-FC6H4
2-MeC6H4
2-MeOC6H4 MeO (1r)
2-furyl MeO (1s)
2-naphthyl MeO (1t)
9
Figure 2. X-ray structure of alkylidene 1t.
10
11
12
13
14
15
16
17
18
19
20
MeO (1l)
MeO (1m)
environment around the electrophilic carbon center created
by the ester group’s orientation might be key in the
enantiodifferentiating step.
Our hypothesis was corroborated with conformationally
locked and planar alkylidene 1u. As shown in Scheme 2,
Et (2m) quant
Et (2n)
Et (2o)
Et (2p)
Et (2q)
Et (2r)
Et (2s)
Et (2t)
87
MeO (1o)
MeO (1p)
MeO (1q)
41a
62b
quantc
79d
97
88
a Reduced product (R ) H) isolated in 53% yield. b Reduced product
(R ) H) isolated in 12% yield. c Isolated as a 84:16 mixture of 2p and
reduced product (R ) H). d Reduced product (R ) H) isolated in 21%
yield.
Scheme 2
.
Addition of Et2Zn to Conformationally Locked and
Planar Alkylidene 1u
The addition of n-Bu2Zn, i-Pr2Zn, and Me2Zn to alky-
lidenes 1g, 1k, and 1t led to Meldrum’s acids 2u-z in er’s
up to 96:4 (Table 3).12 n-Bu2Zn and i-Pr2Zn gave results
the addition of Et2Zn furnished nearly racemic 2aa, which
contrasts with the selectivity obtained with nonplanar ortho
substituted substrates 1o-r.
Table 3. Addition of Various Organozinc Reagents to
Alkylidene 1
The significance of preparing highly functionalized all-
carbon quaternary centers 2 lies in the variety of subsequent
transformations and diversity of chiral structures accessible
through these intermediates. Chiral succinimides 4a and 4b
were prepared in one step by treating 2b and 2t, respectively,
with BnNH2 (Scheme 3). This one-pot sequence allowed the
entry
Ar
X
R
yield (%) er (S:R)
1
2
3
4
5
6
4-MeOC6H4 MeO(1k) n-Bu (2u)
2-naphthyl MeO (1t) n-Bu (2v)
4-MeOC6H4 MeO(1k)
2-naphthyl MeO (1t)
4-ClC6H4 MeO(1g)
2-naphthyl MeO (1t)
91
95:5
96:4
92:8
94:6
80:20
81:19
88
86
i-Pr(2w)
i-Pr (2x)
Me (2y)
Me (2z)
79
quant
90
Scheme 3. Synthesis of Chiral Succinimides
comparable to Et2Zn, but Me2Zn furnished lower enantiose-
lectivity.13
Insights into factors determining the enantioselectivity of
the 1,4-addition were gained by solving the X-ray structure
of 1t. Figure 2 shows that the carbonyl group of the ester is
nearly perpendicular to the alkene (dihedral angle C3-C7-
C8-O5 ) 101.5°),14 which suggests that the nonplanar
(11) The use of 10 equiv of styrene as an additive had no influence on
the enantioselectivity or yield, see: Li, K.; Alexakis, A. Angew. Chem., Int.
Ed. 2006, 45, 7600–7603.
establishement of the absolute stereochemistry for conjugate
addition product 2 by comparison of known succinimides
4a and 4b.7
From compound 2d, 3,3- and 4,4-disubstituted γ-butyro-
lactones 6a and 6c were readily accessed (Scheme 4). The
(12) Addition of Ph2Zn led to complex mixtures, in which the reduced
product was major.
(13) A variety of reaction conditions were tested to improve the er for
Me2Zn addition. See the Supporting Information for details.
(14) Compared to 37.3° (C3-C7-C10-C11) for the naphthyl group.
Org. Lett., Vol. 10, No. 13, 2008
2803

Scheme 4
.
Synthesis of γ-Butyrolactones
Scheme 5. ꢀ-Amino Acid Derivative Synthesis
This method employs commercially available ligand 3a and
readily accessible Meldrum’s acids 1. The significance of
this method was established by the expedient preparation of
succinimides, γ-butyrolactones, and ꢀ-amino acid derivatives
from Meldrum’s acid 2. Further efforts to expand the
synthetic scope of alkylidene Meldrum’s acids in asymmetric
synthesis are underway.
more reactive Meldrum’s acid moiety found in 2d could be
transformed chemoselectively to provide 5a. From diester
5a, γ-butyrolactone 6a was synthesized in three high-yielding
steps. Disubstituted γ-butyrolactone 6c was obtained in only
two steps by hydrogenolysis of 2d to anhydride 6b, which
was selectively reduced with NaBH4 to give 6c/6a in an
excellent 18:1 ratio.
ꢀ-Amino acid derivative 7 was prepared through the
deprotection of 5a, followed by Curtius rearrangement of
succinic acid derivative 5c (Scheme 5).
Acknowledgment. This work was supported by Astra-
Zeneca Canada, Inc., the Merck Frosst Centre for Therapeutic
Research, Boehringer Ingelheim (Canada) Ltd., the Natural
Sciences and Engineering Research Council of Canada
(NSERC), the Canadian Foundation for Innovation, the
Ontario Innovation Trust, and the University of Waterloo.
A.W. is indebted to NSERC for CGS-M and CGS-D
scholarships. Dr. Alan Lough, University of Toronto, is
gratefully acknowledged for X-ray structure determination.
Supporting Information Available: Experimental pro-
cedures, NMR spectra, and CIF file for 1t. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have described a highly enantioselective
asymmetric synthesis of carboxylic acid derivatives having
an all-carbon R-quaternary center through Cu-catalyzed 1,4-
addition of dialkylzinc reagents to aryl acetate derivatives.
OL800923Q
2804
Org. Lett., Vol. 10, No. 13, 2008