Asymmetric synthesis of all-carbon benzylic quaternary stereocenters via Cu-catalyzed conjugate addition of dialkylzinc reagents to 5-(1-arylalkylidene) Meldrum's acids

Article abstract of DOI:10.1021/ja056692e

The asymmetric synthesis of all-carbon benzylic quaternary stereocenters has been successfully achieved through copper-catalyzed addition of dialkylzinc reagents to 5-(1-arylalkylidene) and 5-(dihydroindenylidene) Meldrum's acids in the presence of phosph

Full text of DOI:10.1021/ja056692e

Published on Web 02/14/2006
Asymmetric Synthesis of All-Carbon Benzylic Quaternary Stereocenters via
Cu-Catalyzed Conjugate Addition of Dialkylzinc Reagents to
5-(1-Arylalkylidene) Meldrum’s Acids
Eric Fillion* and Ashraf Wilsily
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received September 29, 2005; E-mail: efillion@uwaterloo.ca
Scheme 1
All-carbon benzylic quaternary centers are ubiquitous motifs in
natural products and pharmaceutical agents. Conjugate addition1
of carbon nucleophiles to electron-deficient olefins is a direct entry
into these structural elements.2 Surprisingly, the asymmetric
synthesis of all-carbon quaternary stereocenters through 1,4-
addition, under catalytic or stoichiometric conditions, has received
limited attention. The minimal number of literature examples may
be attributed to the intrinsic poor reactivity of tri- and tetrasubsti-
tuted alkene acceptors.3 Alexakis’ group reported the enantiose-
Table 1. Addition of R2′Zn to 5-(1-Arylalkylidene) Meldrum’s Acids
lective conjugate addition of trialkylaluminum reagents to 3-sub-
entry
Ar
R
R′
conv. (%)a
yield (%)
ee (%)b
stituted cyclohexen-2-ones in the presence of copper catalysts.4
Likewise, Hoveyda and co-workers described the synthesis of
nitroalkanes bearing all-carbon benzylic quaternary stereogenic
centers via Cu-catalyzed asymmetric conjugate addition of dialkyl-
zinc reagents to nitroalkenes.5
1
2
3
4
5
6
7
8
9
Ph (1a)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et (2a)
Et (2b)
Et (2c)
Et (2d)
Et (2e)
Et (2f)
Et (2g)
Et (2h)
Et (2i)
Et (2j)
Et (2k)
Et (2l)
Et (2m)
Et (2n)
Et (2o)
Et (2p)
Et (2q)
>99
>99
>99
>99
>99
>99
>99
>99
99
95
66
97
82
76
88
84
83
87
75
93
96
97
98
NR
NR
NR
78
NR
99
84
95
91
89
95
95
92
92
92
93
78
74
79
85
N/A
N/A
N/A
94
N/A
65
2-naphthyl (1b)
2-furyl (1c)
4-MePh (1d)
4-PhPh (1e)
4-ClPh (1f)
4-BrPh (1g)
4-FPh (1h)
4-(F3C)Ph (1i)
Aryl Grignard and organocopper reagents add in a conjugate
fashion to 5-(1-alkylalkylidene) Meldrum’s acids affording all-
carbon benzylic quaternary centers.6 Although a single case of this
strategy has been described, this element of structure has been
obtained alternatively by 1,4-addition of alkyl Grignard reagents
to 5-(1-arylalkylidene) Meldrum’s acids.7 Asymmetric versions of
either of these approaches have not been reported.8 5-(1-Substituted
alkylidene) Meldrum’s acids are conveniently prepared by Kno-
evenagel condensation of Meldrum’s acid with ketones, for which
typical problems associated with the preparation of geometrically
pure olefin acceptors are absent.9 Furthermore, benzyl Meldrum’s
acids resulting from conjugate addition are synthetically useful
intermediates that may be subsequently submitted to various
transformations.7,9,10 In this Communication, we disclose our results
on the asymmetric synthesis of all-carbon benzylic quaternary
stereocenters through Cu-catalyzed addition of dialkylzinc reagents
to 5-(1-arylalkylidene) Meldrum’s acids 1.
The ability of commercially available phosphoramidite ligand11
3 to promote the addition of Et2Zn to 1 was first examined (Scheme
1). 5-(1-Phenylethylidene) Meldrum’s acid (1a) was employed to
probe for optimum solvent and temperature. A >99% conversion12
and a 95% isolated yield of 2a were obtained when 1a was reacted
with 2 equiv of Et2Zn, 5 mol % of Cu(OTf)2, and 10 mol % of 3
in 1,2-dimethoxyethane (DME).13,14 The conjugate addition was
relatively slow and was carried out at room temperature for 48 h
(Table 1, entry 1).15
10 4-(BnO)Ph (1j)
11 3-MePh (1k)
12 3-ClPh (1l)
92
96c
99
13 3-(BnO)Ph (1m) Me
97
99
0
0
14 3,4-Cl2Ph (1n)
15 2-MePh (1o)
16 2-ClPh (1p)
17 2-(BnO)Ph (1q) Me
18 4-ClPh (1r)
19 Ph (1s)
20 4-ClPh (1f)
21 4-ClPh (1t)
22 4-ClPh (1f)
Me
Me
Me
0
n-Bu Et (2r)
>99
i-Pr
Me
Et
Et (2s)
0
i-Pr (2t)
Me (2f)
n-Bu (2u)
>99
35
99
N/A
87
N/A
87
Me
1
a Determined by analysis of the crude H NMR spectra. b Measured by
HPLC using a Chiralcel OD, OD-H, or AD-H column. c Reaction time is
72 h.
on the enantioselectivity of the addition (entries 4 and 5). This
observation was further confirmed with substrates 1f-i, substituted
with an electron-withdrawing group (entries 6-9), and substrate
1j, substituted with an electron-donating benzyloxy group (entry
10), with enantiomeric excesses ranging from 92 to 95%.
Contrariwise, substituting the 3-position of the arene with
electron-withdrawing or -donating groups had a detrimental effect
on the enantioselectivity of the process (entries 11-13), and
enantiomeric excesses of 74-79% were obtained. Of note, 5-(1-
(3,4-dichlorophenyl)ethylidene) Meldrum’s acid (1n) generated 2n
in 85% ee (entry 14). This result suggests that positions 3 and 4 of
the phenyl group apparently offset one another, leading to an
averaging of enantiomeric excess. Substrates bearing a substituent
at the 2-position of the aromatic moiety withstand conjugate addition
of Et2Zn (entries 15-17). The close proximity of the aromatic
substituent to the olefin electrophilic carbon likely blocks the
With this promising lead in hand, we proceeded to investigate
the scope of the catalytic conjugate addition reaction, and the results
are summarized in Table 1. The primary intent was to gain insights
on the steric and electronic properties of the tetrasubstituted olefin
substituents and their respective role on the enantioselectivity and
efficiency of the process. Replacing the phenyl group in 1 by
2-naphthyl or 2-furyl provided 2b and 2c in 95 and 91% ee,
respectively (entries 2 and 3). Substituting the 4-position of the
phenyl moiety seemed to have a significant and favorable impact
9
2774
J. AM. CHEM. SOC. 2006, 128, 2774-2775
10.1021/ja056692e CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Addition of R2′Zn to 5-(Dihydroindenylidene) Meldrum’s
Acids
Acknowledgment. This work was supported by NSERC, CFI,
OIT, and the University of Waterloo. We gratefully acknowledge
Boehringer Ingelheim (Canada) Ltd. (Young Investigator Award
to E.F.), and AstraZeneca Canada Inc. (AstraZeneca Award to E.F.)
for unrestricted support of this research. A.W. is indebted to NSERC
for a CGS-M scholarship.
Supporting Information Available: Experimental procedures and
NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
entry
R
R
′
conv. (%)a
yield (%)
ee (%)b
1
2
3
4
5
H (4a)
Cl (4b)
Cl (4b)
Cl (4b)
Cl (4b)
Et (5a)
Et (5b)
Me (5c)
n-Bu (5d)
i-Pr (5e)
>99
>99
>99c
>99
>99
96
94
98
97
99
96
99
99
97
57
References
(1) For reviews, see: (a) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A.
In Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
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Eur. J. Org. Chem. 2002, 67, 3221-3236. (c) Krause, N.; Hoffmann-
Ro¨der, A. Synthesis 2001, 171-196. (d) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033-8061.
(2) For an overview on catalytic asymmetric synthesis of all-carbon quaternary
carbon centers, see: Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363-5367.
a Determined by analysis of the crude H NMR spectra. b Measured by
HPLC using a Chiralcel OD, OD-H, or AD-H column. c Five equivalents
of Me2Zn were used.
1
(3) Enantioselective Michael additions in which the Michael donor is
transformed into an all-carbon benzylic quaternary stereocenter: (a) Li,
H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948-
8949. (b) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N.
J. Am. Chem. Soc. 2005, 127, 1313-1317. (c) Taylor, M. S.; Jacobsen,
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Scheme 2
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(5) (a) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
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lzinc reagents to 2,3-disubstituted enones was reported: Hird, A. W.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 14988-14989.
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(8) Asymmetric synthesis of tertiary carbon centers from alkylidene Meldrum’s
acids and dialkylzinc reagents: (a) Kno¨pfel, T. F.; Zarotti, P.; Ichikawa,
T.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 9682-9683. (b)
Watanabe, T.; Kno¨pfel, T. F.; Carreira, E. M. Org. Lett. 2003, 5, 4557-
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(11) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Feringa, B.
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(12) Typically, Rf values of the product and starting material were comparable,
thus the need for high % conversion to simplify purification.
(13) Meldrum’s acid 2a was formed in 86% yield (96% conversion) and 85%
ee when 1a was reacted with 2 equiv of Et2Zn, 6 mol % of 3, and 3 mol
% of Cu(OTf)2 in DME. Solvents typically used in Cu-catalyzed
enantioselective conjugate additions, such as Et2O (91%, 59% ee), THF
(59%, 63% ee), and toluene (99%, 57% ee), were inferior. MTBE (62%,
53% ee) and 1,4-dioxane (21%, 36% ee) also furnished poor results.
(14) Comparable results were obtained with 5 mol % of Cu(OAc)2‚H2O (90%,
88% ee), Cu(acac)2‚H2O (91%, 88% ee), and Cu(O2CCF3)2‚H2O (99%,
88% ee), but CuCN gave 1a in 80% yield and 48% ee.
trajectory for alkyl delivery, resulting in a lack of reactivity for
1o, 1p, and 1q.
Increasing the length of the alkyl chain on the electrophilic carbon
of the olefin acceptor did not affect enantioselectivity, as illustrated
with pentylidene Meldrum’s acid 1r that furnished the addition
product 2r in 94% ee (entry 18). Sterically demanding substrate
1s was unreactive toward Et2Zn (entry 19). On the other hand, i-Pr2-
Zn added efficiently to 1f, albeit with a modest 65% ee (entry 20).
Meldrum’s acid 1t displayed sluggish reactivity with Me2Zn (entry
21), but the addition of n-Bu2Zn to 1f afforded 2u in 87% yield
and 87% ee (entry 22).
The asymmetric synthesis of 1,1-disubstituted chiral indanes 5
from Meldrum’s acid derivatives 4 was also tackled (Table 2).16
In all cases, conversion was >99%. As for substrates 1, the
introduction of a chloride group in 4 para (5-position) to the benzylic
electrophilic site enhanced enantioselection (entries 1 and 2). A
variety of dialkylzinc reagents (Et2Zn, Me2Zn, n-Bu2Zn) added to
4b with equal enantioselectivity (97-99%) and efficiency (94-
99%) (entries 2-4), with the exception of i-Pr2Zn, which gave 5e
in 57% ee (entry 5).
The synthetic utility of benzyl Meldrum’s acids 2 was exempli-
fied, and the absolute stereochemistry of the addition products was
determined, by preparing known compounds 6 and 7 (Scheme 2).
Using a protocol previously developed in our group,10 2a was
transformed into (R)-3-ethyl-3-methyl-1-indanone (6).17 Hydrolysis
of 2a led to â,â-disubstituted pentanoic acid 7.
In conclusion, we have described the first highly enantioselective
synthesis of all-carbon benzylic quaternary stereocenters via
conjugate addition of dialkylzinc reagents to readily accessible 5-(1-
arylalkylidene) and 5-(dihydroindenylidene) Meldrum’s acids 1 and
4. This method employs commercially available ligand 3 and
dialkylzinc reagents. The significance of substituting the position
para, meta, and ortho to the electrophilic benzylic center was
highlighted. Current efforts are centered at broadening the scope
of enantioselective conjugate additions to 5-alkylidene Meldrum’s
acids.
(15) Adding various amounts of Zn(OTf)2 to the reaction mixture showed no
effect on either the enantioselectivity or the rate of the reaction; see ref
1b.
(16) Catalytic asymmetric synthesis of 1-substituted indanes: (a) Arp, F. O.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482-10483. (b) Troutman, M.
V.; Apella, D. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4916-
4917. Pd-catalyzed synthesis of 1-ethyl-1-methylindanes: (c) Fillion, E.;
Carson, R. J.; Tre´panier, V. E.; Goll, J. M.; Remorova, A. A. J. Am. Chem.
Soc. 2004, 126, 15354-15355. For reviews on the synthesis of indanes,
see: (d) Ferraz, H. M. C.; Aguilar, A. M.; Silva, L. F., Jr.; Craveiro, M.
V. Quim. NoVa 2005, 28, 703-712. (e) Hong, B.; Sarshar, S. Org. Prep.
Proc. Int. 1999, 31, 1-86.
(17) Hill, R. K.; Newkome, G. R. Tetrahedron 1969, 25, 1249-1260.
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