Asymmetric synthesis of all-carbon benzylic quaternary stereocenters via conjugate addition to alkylidene and indenylidene Meldrum's acids

Article abstract of DOI:10.1021/jo901559d

(Chemical Equation Presented) A systematic study outlining the enantioselective 1,4-addition of dialkylzinc reagents to 5-(1-arylalkylidene) and indenylidene Meldrum's acids is presented. Variation of the aryl and alkyl groups present on the alkylidene wa

Full text of DOI:10.1021/jo901559d

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Asymmetric Synthesis of All-Carbon Benzylic Quaternary Stereocenters
via Conjugate Addition to Alkylidene and Indenylidene Meldrum’s Acids
Ashraf Wilsily and Eric Fillion*
Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
efillion@uwaterloo.ca
Received July 22, 2009
A systematic study outlining the enantioselective 1,4-addition of dialkylzinc reagents to 5-(1-
arylalkylidene) and indenylidene Meldrum’s acids is presented. Variation of the aryl and alkyl
groups present on the alkylidene was thoroughly explored. The 1,4-addition displayed compatibility
with a wide range of heteroaromatics and functional groups, and the arene pattern of substitution
affected enantioselection, with a para-substituted aryl group consistently leading to high enantios-
electivities. The nature of the organozinc reagent on the efficiency and selectivity of the conjugate
addition was also investigated. The solid-state conformation was determined for a number of
alkylidene Meldrum’s acids and correlated with the observed enantioselectivity in relation to the
arene pattern of substitution.
Introduction
all-carbon quaternary stereocenters through conjugate addi-
tion a challenging task.2 Nevertheless, due to the fundamen-
tal importance of this structural element, the development of
enantioselective conjugate addition methods to access all-
carbon quaternary stereocenters has gained increasing atten-
tion over the last years.3,4
In the course of our total synthesis of (()-taiwaniaquinol
B (1) (Scheme 1), our group noted the ease of formation of
all-carbon benzylic quaternary centers through addition of
MeMgBr to alkylidene Meldrum’s acid 2 to form 3 in
excellent yield under mild reaction conditions.5 The con-
struction of this structural motif through conjugate addition
to 5-(1-arylalkylidene) Meldrum’s acids was unknown.
However, it had been obtained by 1,4-addition of aryl
The catalytic enantioselective conjugate addition of orga-
nometallic reagents to electron-deficient olefins ranks
among the most versatile C-C bond-forming transforma-
tions in synthetic organic chemistry.1 Despite the remarkable
achievements in the asymmetric formation of tertiary stereo-
centers, the intrinsic poor reactivity of tri- and tetrasubsti-
tuted alkene acceptors has rendered the construction of
(1) For reviews on conjugate addition, see: (a) Thaler, T.; Knochel, P.
Angew. Chem., Int. Ed. 2009, 48, 645–648. (b) Jerphagnon, T.; Pizzuti, M. G.;
Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039–1075. (c)
Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B.
€
L. Chem. Rev. 2008, 108, 2824–2852. (d) Alexakis, A.; Backvall, J. E.; Krause,
N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796–2823. (e) Alexakis,
ꢀ
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A.; Vuagnoux-d’Augustin, M.; Martin, D.; Kehrli, S.; Palais, L.; Henon, H.;
Hawner, C. Chimia 2008, 62, 461–464. (f) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2007, 5969–5994. (g) Christoffers, J.;
(2) For an overview on asymmetric synthesis of all-carbon quaternary
carbon centers, see: (a) Quaternary Stereocentres: Challenges and Solutions
for Organic Synthesis; Christophers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
2006. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396. (c) Christoffers, J.;
Baro, A. Adv. Synth. Catal. 2005, 347, 1473–1482. (d) Douglas, C. J.; Overman,
L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367. (e) Denissova, I.;
Barriault, L. Tetrahedron 2003, 59, 10105–10146. (f) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591–4597. (g) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388–401.
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Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279–1300. (h) Lopez,
F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179–188.
(i) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; pp 224-258.
(j) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–3236. (k) Krause,
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DOI: 10.1021/jo901559d
r
Published on Web 10/14/2009
J. Org. Chem. 2009, 74, 8583–8594 8583
2009 American Chemical Society

Wilsily and Fillion
JOCArticle
SCHEME 1. Formation of Benzylic All-Carbon Quaternary
Center toward the Total Synthesis of Taiwaniaquinol B
symmetry, which avoids difficult substrate preparation/se-
paration of Z/E isomers, (b) general means of preparation by
Knoevenagel condensation with a variety of ketones, and (c)
their crystalline nature, which permits purification by crys-
tallization/trituration.
Following the completion of the first total synthesis of
taiwaniaquinol B (1), we embarked on developing an asym-
metric version of the conjugate addition of organometallic
reagents to 5-(1-arylalkylidene) Meldrum’s acids. The cop-
per-catalyzed conjugate addition of dialkylzinc reagents to
alkylidene Meldrum’s acids was initiated using 5-(1-
phenylethylidene) derivative 4 to probe the reactivity of the
diactivated tetrasubstituted olefin. Treating Meldrum’s acid
4 with Et2Zn in the presence of catalytic amounts of copper-
(II) triflate and phosphoramidite ligand9 5 furnished desired
product 6 in >99% conversion, 95% yield, and 84% en-
antiomeric excess (eq 1).4d,10 This initial result illustrated the
superior electrophilicity of alkylidene Meldrum’s acids11 and
its value in the formation of all-carbon benzylic quaternary
centers via enantioselective conjugate addition.
Grignard and organocopper reagents to 5-(1-alkylalkylidene)
Meldrum’s acids.6 At the outset of this project, asymmetric
versions of either of these approaches were unprecedented.7
Meldrum’s acid derivatives8 are highly useful intermedi-
ates in a variety of chemical transformations, and alkylidene
Meldrum’s acids possess, from a practical viewpoint, a
number of advantageous features: (a) olefin geometrical
(3) Alexakis’ group: (a) Henon, H.; Mauduit, M.; Alexakis, A. Angew.
Chem., In. Ed. 2008, 47, 9122–9124. (b) Hawner, C.; Li, K.; Cirriez, V.;
Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 8211–8214. (c) 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. (d) Vuagnoux-d’Augustin, M.; Kehrli, S.;
Alexakis, A. Synlett 2007, 2057–2060. (e) Vuagnoux-d’Augustin, M.; Alex-
akis, A. Chem.;Eur. J. 2007, 13, 9647–9662. (f) Martin, D.; Kehrli, S.;
d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc.
2006, 128, 8416–8417. (g) Fuchs, N.; d’Augustin, M.; Humam, M.; Alexakis,
A.; Taras, R.; Gladiali, S. Tetrahedron: Asymmetry 2005, 16, 3143–3146.
(h) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed. 2005, 44,
1376–1378. Hoveyda’s group: (i) May, T. L.; Brown, M. K.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2008, 47, 7358–7362. (j) Brown, M. K.; Hoveyda, A.
H. J. Am. Chem. Soc. 2008, 130, 12904–12906. (k) Brown, M. K.; May, T. L.;
Baxter, C. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 1097–1100.
(l) Lee, K.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc.
2006, 128, 7182–7184. (m) Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc.
2005, 127, 14988–14989. (n) Wu, J.; Mampreian, D. M.; Hoveyda, A. H.
J. Am. Chem. Soc. 2005, 127, 4584–4585. Hayashi’s group: (o) Shintani, R.;
Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi, T. J. Am. Chem. Soc.
2009, 131, 13588–13589. (p) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am.
Herein, a systematic study outlining the enantioselective
1,4-addition of dialkylzinc reagents to 5-(1-arylalkylidene)
and indenylidene Meldrum’s acids is presented. Variation of
the aryl and alkyl groups present on the alkylidene was
explored thoroughly. The enantioselection was dependent
on the pattern of substitution of the arene, with para-
substituted aryl groups consistently leading to high enantios-
electivities. The nature of the organozinc reagent on the
efficiency and selectivity of the conjugate addition was also
investigated. The solid-state conformation was determined
for a number of alkylidene Meldrum’s acids and correlated
with the observed enantioselectivity in relation to the pattern
of substitution of the arene moiety.
ꢁ
Chem. Soc. 2006, 128, 5628–5629. Carretero’s group: (q) Mauleon, P.;
Carretero, J. C. Chem. Commun. 2005, 4961–4963. Tomioka’s group:
(r) Matsumoto, Y.; Yamada, K.; Tomioka, K. J. Org. Chem. 2008, 73,
4578–4581.
(4) (a) Wilsily, A.; Lou, T.; Fillion, E. Synthesis 2009, 2066–2072.
(b) Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801–2804. (c) Fillion, E.;
Wilsily, A.; Liao, E-T. Tetrahedron: Asymmetry 2006, 17, 2957–2959.
(d) Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774–2775.
(5) Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127, 13144–13145.
(6) For a recent example, see: (a) Limanto, J.; Shultz, C. S.; Dorner, B.;
Desmond, R. A.; Devine, P. N.; Krska, S. W. J. Org. Chem. 2008, 73, 1639–
1642. For all reports prior to our total synthesis, see: (b) Vogt, P. F.; Molino,
B. F.; Robichaud, A. J. Synth. Commun. 2001, 31, 679–684. (c) Davis, A. P.;
Egan, T. J.; Orchard, M. G. Tetrahedron 1992, 48, 8725–8738. (d) Fleming, I.;
Moses, R. C.; Tercel, M.; Ziv, J. J. Chem. Soc., Perkin Trans. 1 1991, 617–
626. (e) Huang, X.; Chan, C.; Wu, Q. Synth. React. Inorg. Met.-Org. Chem.
1982, 12, 549–556. (f) Huang, X.; Chan, C.; Wu, Q. Tetrahedron Lett. 1982,
23, 75–76. For Michael addition of nitromethane for the formation of
quaternary carbon, see: (g) Li, J.; Li, Z.; Chen, Q. J. Chem. Res. 2004, 758–
759. For the formation of 1,5-diionic phosphorous betaines, see: (h) Yavari,
I.; Anary-Abbasinejad, M.; Alizadeh, A.; Habibi, A. Phosphorus Sulfur
Silicon 2002, 177, 2523–2527.
Results and Discussion
Influence of the Substrate Structural Elements on the En-
antioselectivity of the Conjugate Addition. The scope of the
enantioselective 1,4-addition was initially examined by
studying the effect of the aromatic ring directly attached to
the electrophilic carbon of the alkylidene (Table 1). The
(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. (c) de Vries, A. H. M.; Meetsma, A.;
Feringa, B. L. Angew. Chem., Int. Ed. Engl. 1996, 35, 2374–2376.
(10) The absolute stereochemistry of Meldrum’s acid 6 was assigned by
derivatization to known compounds; see ref 4d.
(7) Asymmetric synthesis of tertiary carbon centers from alkylidene
€
Meldrum’s acids and dialkylzinc reagents: (a) Knopfel, T. F.; Zarotti, P.;
Ichikawa, T.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 9682–9683.
€
(b) Watanabe, T.; Knopfel, T. F.; Carreira, E. M. Org. Lett. 2003, 5, 4557–
4558.
(8) For reviews on Meldrum’s acid in synthesis, see: (a) Ivanov, A. S.
Chem. Soc. Rev. 2008, 37, 789–811. (b) Chen, B.-C. Heterocycles 1991, 32,
ꢁ
529–597. (c) Strozhev, M. F.; Lielbriedis, I. E.; Neiland, O. Ya. Khim.
Geterotsikl. Soedin. 1991, 579–599. (d) McNab, H. Chem. Soc. Rev. 1978,
7, 345–358.
(11) An interesting observation was made regarding the overall superior
electrophilicity of alkylidene Meldrum’s acids compared to their structurally
similar alkylidene dimethyl malonates. Under conditions in which alkylidene
Meldrum’s acid 4 is alkylated in >99% conversion, the analogous alkylidene
malonate was inert. For asymmetric 1,4-addition of organozinc or aluminum
reagents to alkylidene malonates for the formation of tertiary stereocentres,
see: (a) Schppan, J.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004,
792–793. (b) Alexakis, A.; Benhaim, C. Tetrahedron: Asymmetry 2001, 12,
1151–1157.
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TABLE 1. Enantioselective 1,4-Addition to Heteroaromatic-Substituted Alkylidene Meldrum’s Acids
aAverage of two experiments for the isolated yield and ee.
importance of heteroaromatic ring systems in medicinally
relevant compounds inspired us to examine these types of
arenes.
2-Thiophene- and 3-thiophene-substituted alkylidenes 7
and 9 furnished addition products 8 and 10 in 92 and 96% ee,
respectively (Table 1, entries 2 and 3). Tosylated pyrrole and
indole derivatives 11 and 13 gave excellent enantioselectiv-
ities and yields (Table 1, entries 4 and 5).12 Furyl-substituted
alkylidenes 15 and 17, when subjected to the reaction
conditions, provided products 16 and 18 in 91% and 84%
ee, respectively (Table 1, entries 6 and 7). On the other hand,
decreased enantioselectivities were observed for benzo- and
fused furyl derivatives (Table 1, entries 8 and 9). Although 1-
naphthyl-substituted alkylidene led to complete recovery of
starting material, possibly due to steric hindrance of the
electrophilic carbon center, 2-naphthyl-substituted alkyli-
dene 23 furnished 24 in an excellent 95% ee (entry 10).
The variation in heteroatoms, steric hindrance, and elec-
tron richness or poorness of the heteroatomics presented in
Table 1 prevented systematic comparison of the factors
affecting the enantioselectivity of the conjugate addition.
Therefore, additions to 1-arylalkylidene Meldrum’s acids
(12) It was necessary that the nitrogen substituent be electron-withdraw-
ing group to prevent decomposition of isolated products. Otherwise, elimi-
nation of the heteroaromatic ring generating 1-alkylalkylidenes Meldrum’s
acid was observed.
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TABLE 2. Para-Substituted 5-(1-Arylalkylidene) Meldrum’s Acids
aAverage of two experiments for the isolated yield and ee.
were investigated as this would provide control of both steric
and electronic properties by varying the substituent and its
position on the aromatic ring. We began our study with
examination of substituent at the para position, with the
expectation that conjugation to the electrophilic alkene
would reveal a strong electronic effect, while remoteness
from the site of the addition would make the steric contribu-
tion insignificant (Table 2).
Electron-withdrawing halogens and a trifluoromethyl
group at the para position of the aromatic moiety, when
subjected to the optimized reaction conditions using Et2Zn,
resulted in increased enantioselectivities when compared to
alkylidene 4, ranging from 92% to 95% (Table 2, entries
1-4). Similarly, phenol derivatives furnished products with
enantiomeric excesses between 93% and 96% in good iso-
lated yields (Table 2, entries 5-10). An array of phenol
protecting groups such as benzyl, alkyl, and silyl ethers and
acetyl esters were compatible with the mild reaction condi-
tions.
excellent enantioselectivity, although inferior to the tert-
butyl group (Table 2, entry 18).
The influence of the aromatic moiety on the enantioselec-
tive copper-catalyzed 1,4-addition was further probed with
ortho-substituted 1-arylalkylidene Meldrum’s acid deriva-
tives. Electron-donating benzyloxy group (61), electron-with-
drawing chloro group (62), and σ-donating methyl (63)
groups all had the same outcome; complete recovery of
starting material after 48 h (eq 2). It is interesting to note that
analogously substituted 2-methyl-3-furylalkylidene 17, where
the benzene ring has been replaced with a furan, gave Mel-
drum’s acid 18 in 92% yield and 84% ee (Table 1, entry 7).
Substituents bearing an sp2-hybridized carbon directly
attached to the aromatic moiety, including phenyl, vinyl,
and ester groups, gave the addition products in excellent
yields and up to 95% ee (Table 2, entries 11-13). Silyl-
protected alkyne derivative 51 furnished the conjugate addi-
tion product 52 in 97% ee (Table 2, entry 14).
Inductively donating alkyl groups showed a significant
increase in enantioselectivities with increasing size to yield
products with up to 99% ee and 91% yield (Table 2,
entries 15-17). The analogous but sterically less demanding
trimethylsilyl group furnished the addition product in
The effect of substituting the meta position of 1-arylalk-
ylidene Meldrum’s acids in the enantioselective conjugate
addition reaction was then examined. While meta-substi-
tuted arylalkylidene Meldrum’s acids did participate in the
reaction, the enantioselectivites of the observed products
were contrastingly and considerably lower than the ones
obtained with the analogous para-substituted arylalkylidene
Meldrum’s acids. Benzyloxy, chloro, and methyl derivatives
64, 66, and 68 furnished products containing an all-carbon
benzylic quaternary stereocenter in 74-79% ee (Table 3,
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TABLE 3. Meta-Substituted 5-(1-Arylalkylidene) Meldrum’s Acids
aAverage of two experiments for the isolated yield and ee. bThe catalyst loading and reaction time were increased: Cu(OTf)2 (8 mol %), ligand
5 (16 mol %) for 72 h.
entries 1-3),13 compared to 89-95% for the corresponding
para substrates (Table 2, entries 1, 5, and 15). Conversely,
i-Pr and t-Bu groups, which caused a substantial increase
in ee’s at the para position, led to identical results when
located at the meta position, to provide, from alkylidenes 70
and 72, Meldrum’s acids 71 and 73 in 97% and 98% ee,
respectively (Table 3, entries 4 and 5).
The combined influence of para and meta substituents on the
enantioselectivity of the addition was also of interest. When 3,4-
dimethylphenyl alkylidene Meldrum’s acid 74 was subjected to
the optimized conjugate addition conditions, 75 was obtained
in 91% ee (Table 3, entry 6). For comparison, p-methyl
derivative 53 gave 54 in 89% ee (Table 2, entry 15), while
(13) The absolute stereochemistry of 67 was assigned by X-ray crystal-
lography; see the Supporting Information.
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TABLE 4. Varying the Alkylidene Meldrum’s Acids and Dialkylzinc Reagents
aMe2Zn (2 equiv) was used with the 2-naphthyl derivative of ligand 5 (10 mol %). bAverage of two experiments for the isolated yield and ee.
m-methyl compound 68 furnished 69 in 78% ee (Table 3,
entry 3). A similar trend was observed with 3,4-dichloro-
phenyl alkylidene Meldrum’s acid 76, which led to 77 in
85% ee (Table 3, entry 7). Monosubstituted 3-chlorophenyl and
4-chlorophenylalkylidene Meldrum’s acids 66 and 25 furnished
1,4-addition products 67 and 26 in 74% and 95% ee, respec-
tively.
On the other hand, substituting the two meta positions was
adversely additive, and 3,5-dichloro derivative 78 yielded 79 in a
modest 50% ee (Table 3, entry 8). A similar result was obtained
with alkylidene 80 (Table 3, entry 9). When both meta positions
were substituted, a decrease in the level of conversion was also
noted. For the reactions to proceed to completion, higher
catalyst loadings and prolonged reaction times were required
(entries 8-10). The negative impact of substituting both meta
positions was further illustrated with alkylidene 82, which gave
Meldrum’s acid 83 in a low 26% ee and 31% yield.14 In contrast,
an exceptionally high enantiomeric excess of 98% was obtained
with mono-tert-butyl-substituted 72.
The reactions discussed above described the addition of
Et2Zn to 5-(1-arylalkylidene) Meldrum’s acids as an entry
into ethyl, methyl-substituted all-carbon benzylic stereocen-
ters. The nature of the alkyl substituents present on the all-
carbon stereocenter was broadened by either varying the
alkyl substituent on the alkylidene moiety or the diorgano-
zinc reagent. As depicted in Table 4, linear alkyl chains
gave slightly superior enantioselectivities in the conjugate
(14) Despite higher catalysts loading, a low 59% conversion was ob-
served.
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addition (entries 2-4) when compared to ethylidene 4. It is
important to note that terminal alkene and methyl ester were
compatible with the mild reaction conditions. In contrast,
alkyl chains branched at the 2-position of the alkylidene
hampered the addition, as illustrated with isopropyl deriva-
tive 90 (entry 5).15
provided indan 104 in an exceptionally high >99% ee, while
analogous Meldrum’s acid 105 yielded indan 106 in a modest
79% ee (Table 5, entries 6 and 7).18 Dichloro-substituted
indenylidene Meldrum’s acid 107 furnished 108 in excellent
yield and enantiomeric excess (Table 5, entry 8), which is in
contrast with the low selectivity obtained with dichlorophe-
nylalkylidene 78 (Table 3, entry 8).
Alternatively, the alkyl groups on the all-carbon benzylic
quaternary carbon center were varied by the addition of
dialkylzinc reagents other than Et2Zn. The enantiomers of
addition products 6 and 26, formed by addition of Et2Zn to 4
and 25 (Table 4, entry 1 and Table 2, entry 1), were
synthesized by the addition of Me2Zn to 92 and 93 in 76%
and 90% ee, respectively. Our efforts to overcome the poor
reactivity of alkylidene Meldrum’s acids toward the addition
of Me2Zn, and the associated low level of conversion, were
recently reported.4a These issues were successfully addressed
by conducting the conjugate addition at higher concentra-
tion with 2-fold excess of Me2Zn.16 Under these optimized
conditions, the addition of Me2Zn gave ent-6 and ent-26 in
good isolated yields (Table 4, entries 6 and 7). Furthermore,
the addition of n-Bu2Zn proceeded smoothly to give 94 in
87% ee (Table 4, entry 8). On the other hand, addition of
i-Pr2Zn gave a high yield but afforded product 95 in lower
ee than with other nucleophiles (Table 4, entry 9). How-
ever, this was the only mean of accessing sterically
hindered quaternary centers with R-branched substituents,
as alkylidene Meldrum’s acid 90 was unreactive (Table 4,
entry 5 vs 9).
An identical trend was observed with regioisomeric
indenylidene Meldrum’s acids 109 and 111, substituted
with a methoxy group (Table 5, entries 9 and 10). This
series of alkylidenes revealed that high enantioselectivities
were observed when the 6-position of the indenylidene
Meldrum’s acid was substituted, while substituting the
4-position substantially decreased the ee’s to the midse-
venties range, regardless of the electronic nature of the
group.
A last variant to explore on defining the factors influen-
cing the enantioselectivity of the conjugate addition onto
alkylidene Meldrum’s acid electrophiles was to use cyclic
malonates derived from the condensation of malonic acid
with ketones other than acetone. It was found that alkyli-
denes derived from cyclohexanone (113) and adamantone
(115) provided yields and ee’s similar to standard Meldrum’s
acid (eqs 3 and 4). Although adamantyl derivative 115 did
provide a slight improvement in ee over alkylidene 4, this
gain did not justify the use of a more expensive and non-
commercially available starting material.
Next, the reactivity of conformationally constrained in-
denylidene Meldrum’s acids, obtained via Knoevanagel
condensation of 1-indanones with Meldrum’s acid, was
explored (Table 5). Subjecting indenylidene Meldrum’s acid
96 to the optimized reaction conditions furnished indan17 97
in 96% ee, a substantial increase in enantioselectivity from
analogous 1-phenylethylidene 4, which yielded Meldrum’s
acid 6 in 84% ee (Table 5, entry 1, vs eq 1). Furthermore,
as observed previously with nonfused alkylidene Meldrum’s
acids, substitution at the para position on the aromatic
moiety relative to the electrophilic center enhanced the
enantioselection (Table 5, entry 2). Dialkylzinc reagents
Me2Zn and n-Bu2Zn reacted effectively with 98, yielding
100 and 101 in 99% and 97% ee, respectively (Table 5, entries
3 and 4). Similar to the addition of i-Pr2Zn to alkylidene 25
(Table 4, entry 9), low enantiomeric excess was obtained with
indenylidene 98 (Table 5, entry 5).
Indenylidene Meldrum’s acids possess two different meta
positions relative to the electrophilic carbon center. The
respective influence of the meta positions on the enantios-
electivity of the conjugate addition was then investigated
by preparing a series of indenylidene Meldrum’s acids
substituted with groups of various electronic properties.
Chloro-substituted indenylidene Meldrum’s acid 103
Rationalizing the Influence of the Substrate Structural
Elements on the Enantioselectivity of the Conjugate Addition.
In a recent review on enantioselective copper-catalyzed
conjugate addition, Alexakis and co-workers presented a
tentative catalytic cycle for the addition of dialkylzinc re-
agents to electron-deficient alkenes.19 The authors proposed
the formation of a [CuL2(alkyl)] olefin π-complex as the
3
enantiodetermining step in the conjugate addition. However,
the complexity of the mechanism and the fact that several
species are in equilibrium in solution20 render the stereo-
regulating step of this complex pathway difficult to ascertain.
Moreover, no three-dimensional model was advanced to
(15) The analogous cyclohexyl derivative was also unreactive toward
conjugate addition of Et2Zn.
(16) For the addition of Me2Zn, the 2-naphthyl derivative of ligand 5 was
used.
(17) Catalytic asymmetric synthesis of 1,1-disubstituted indanes: (a)
Garcıa-Fortanet, J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
´
8108–8111. Catalytic asymmetric synthesis of 1-substituted indans: (b)
Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482–10483. (c)
Troutman, M. V.; Apella, D. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 4916–4917. For reviews on the synthesis of indans, 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.
(18) The absolute stereochemistry of 106 was assigned by X-ray crystal-
lography; see the Supporting Information.
(19) See page 2809 in ref 1d.
(20) Zhang, H.; Gschwind, R. M. Angew. Chem., Int. Ed. 2006, 45, 6391–
6394.
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TABLE 5. Enantioselective Conjugate Addition to Indenylidene Meldrum’s Acids
bAverage of two experiments for the isolated yield and ee. bMe2Zn (5 equiv) was used.
rationalize stereoinduction in enantioselective 1,4-addition
using phosphoramidite ligands. We then applied Alexakis’
premise to arylalkylidene Meldrum’s acids, namely the for-
the para or meta position of the aromatic moiety led to
excellent conversions and yields of the desired products re-
gardless of the electronic nature of the substituent, with the
former consistently leading to high enantioselectivities. Steri-
cally demanding i-Pr and t-Bu, when positioned at the para or
meta position as depicted with substrates 55, 57, 70, and 72,
provided optimal selectivities (Table 2, entries 16 and 17,
and Table 3, entries 4 and 5). Additionally, conformationally
restricted indenylidene Meldrum’s acids furnished superior
mation of a [CuL2(alkyl)] olefin complex as the enantiode-
3
termining step, in an attempt to rationalize the observed
variations in enantioselectivity in relation to the pattern of
substitution of the aromatic moiety.
In the previous section, it was determined that, although
ortho substitution was detrimental to the reaction, substituting
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enantiomeric excesses when compared to analogous 1-arylalk-
ylidene Meldrum’s acids (Table 5). Similarly, the presence of a
substituent on the aromatic moiety para (5-position) to the
electrophilic carbon center was beneficial and resulted in
higher enantioselection (Table 5, entry 1 vs 2). Additional
information on the spatial arrangement of the meta group
relative to the electrophilic olefin and its effect on the enantios-
electivity of the 1,4-addition was obtained; substituting the
4-position furnished modest ee’s while substitution of the
6-position had a drastically opposite effect, leading to high
ee’s (Table 5, entries 6 and 9 versus entries 7 and 10). The
absolute configuration of compounds 6, 67, and 106 was
determined by derivatization or X-ray crystallography, and
the sense of induction was identical in all cases, suggesting a
similar enantiodetermining step.
The observations with 1-arylalkylidene and indenylidene
Meldrum’s acids presented above were opposite to our initial
postulate, expecting that conjugation of the arene with the
electrophilic alkene would reveal a strong electronic effect,
especially for the para- and meta-substituted substrates,
while remoteness from the site of the addition would make
the steric contribution insignificant. The enhanced results
obtained with the indenylidene derivatives suggest that the
conformation adopted by the planar bicyclic system led to
optimal interaction with the chiral copper species in the
enantiodetermining step for electronic and/or steric reasons.
Since experimental data suggested that the enantiodetermin-
ing step was strongly affected by steric factors, we then
attempted to draw a parallel between the conformation
adopted by the indenylidene Meldrum’s acids and the 1-
arylalkylidene Meldrum’s acids in the course of the conju-
gate nucleophilic addition by obtaining the X-ray structures
of Meldrum’s acids 4 and 96. A conformational similarity
was revealed; in both compounds, the Meldrum’s acid
moiety was in a boat conformation (Figure 1).21 The phenyl
ring and the olefin in 4 were out-of-plane, with a dihedral
angle C(5)-C(11)-C(12)-C(13) of -56.7°. On the contrary,
indenylidene 96 displayed a planar arrangement of the
aromatic moiety with the alkene, suggesting conjugation.
Examination of the cis-substituents around the olefin accep-
tor showed an out-of-plane arrangement of these groups.
For alkylidene 4, the dihedral angle C(4)-C(5)-C(11)-
C(12) was -10.8°, compared to a substantially more pro-
nounced C(4)-C(5)-C(11)-C(12) of 15.4° for indenyli-
dene 96. Also, a significant CdC bond length difference
was noted; 1.34 A for 4 versus 1.37 A for 96. The elongated
CdC bond may explain the superior electrophilicity of
the indenylidene systems. Furthermore, during the forma-
tion of the sp3-hybridized all-carbon quaternary center
from the sp2-hybridized electrophilic carbon, the aromatic
group in conjugation with the olefin might play a role in
FIGURE 1. X-ray structures of 5-(1-phenylethylidene) Meldrum
acid (4) and 5-(2,3-dihydro-1H-1-indenylidene)-2,2-dimethyl-1,3-
dioxane-4,6-dione (96).
facilitating the conjugate addition by stabilizing the transi-
tion state.
The effect of substituting the para position of the arene on
the conformation of alkylidene and indenylidene Meldrum’s
acids in the solid state was then studied by elucidating the
X-ray structures of compounds 25, 57, and 98. The confor-
mation of 5-[1-(4-chlorophenyl)ethylidene]-2,2-dimethyl-
1,3-dioxane-4,6-dione (25) and 5-(1-(4-tert-butylphenyl)-
ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (57) was
comparable to 4, with a boat conformation for the Mel-
drum’s acid moiety and the aromatic and olefin being out-of-
plane. The 4-chlorophenyl ring and the alkene in 25 were
almost perpendicular with a dihedral angle C(5)-C(11)-
C(12)-C(13) of -84.8°. Like 96, analogous chloroindenyli-
dene 98 was planar, with the aromatic ring in conjugation
with the olefin. An elongated CdC bond of 1.36 A was
observed for 98, compared to 1.34 A for 25. When compar-
ing 25 and 57, their conformations were practically indis-
tinguishable. Compound 57 displayed a dihedral angle
C(5)-C(11)-C(12)-C(17) of 99.2° and a CdC bond length
of 1.35 A.22
Despite the conformational discrepancies observed be-
tween alkylidene Meldrum’s acids 25 and 57 and indenyli-
dene Meldrum’s acid 96 and 98, comparable enantiomeric
excesses and identical sense of induction were obtained
with both systems. On the other hand, although displaying
identical conformations, a difference of 11-15% in enantio-
meric excess was noted when comparing Meldrum’s acids 4
to 25 and 57. This series of results seems to indicate that the
(21) This is consistent with published crystallographic data for alkylidene
Meldrum’s acids. (a) For a recent discussion on Meldrum’s acid’s boat
conformation, see: Chopra, D.; Zhurov, V. V.; Zhurova, E. A.; Pinkerton,
A. A. J. Org. Chem. 2009, 74, 2389–2395. (b) For the crystal structure of
5-(benzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (monosubstituted alkyli-
dene), see: Dong, N.; Cai, G.-Q.; Wu, N.-C.; Huang, X.; Hu, S.-Z.; Chen,
M.-D.; Mak, T. C. W Chin. Sci. Bull. 1989, 34, 1955–1960. (c) For a review on
the conformation of alkylidene Meldrum’s acids and similar derivatives, see:
Sato, M.; Sunami, S.; Kaneko, C. Heterocycles 1996, 42, 861–883. (d) For a
discussion of benzyl Meldrum’s acid conformation, see: Shengzhi, H.
J. Struct. Chem. 1985, 4, 107–114. (e) Original structure determination by
X-ray crystallography: Pfluger, C. E.; Boyle, P. D. J. Chem. Soc., Perkin
Trans. 2 1985, 1547–1549.
(22) The unit cell contains two molecules, thus two sets of data. The
dihedral angle C(27)-C(33)-C(34)-C(39) for the second molecule is
-100.4°. Bond length C(27)-C(33) is 1.35 A.
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Wilsily and Fillion
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solid-state conformation of 1-arylakylidene Meldrum’s acids
alone is not reflective of the enantiodetermining step.
Accordingly, the conformation adopted by the [CuL2(alkyl)]
3
alkene complex is likely similar to the one determined in the
solid state for constrained indenylidene Meldrum’s acids. That
key conformation is attained by the 1-arylakylidene Meldrum’s
acids through rotation of the C-C σ-bond linking the aromatic
moiety to the electrophilic carbon center. As judged by the
identical sense and level of induction, the introduction of a
substituent at the para position of the arene offers a superior
control in the enantiodetermining step by the catalyst through
steric interactions between the substrate’s remote substituents
and the ligands present on the Cu center.
As depicted in eq 2, 1-arylalkylidenes bearing a substituent
at the ortho position were subjected to the optimized 1,4-
conjugate addition reaction conditions but resulted in re-
covery of starting material, regardless of the electronic
nature of the substituent. At room temperature, the 1H
NMR spectrum of 2-benzyloxyphenylethylidene Meldrum’s
acid 61, 2-chlorophenylethylidene Meldrum’s acid 62, and 2-
methylphenylethylidene Meldrum’s acid 63 exhibited two
well-separated singlets, corresponding to the methyl groups
on the Meldrum’s acid moiety. The observation of diaster-
eotopic methyl groups for the Meldrum’s acid moiety sug-
gested that these molecules displayed hindered rotation
about the arylalkene C-C bond and exists as racemic
atropoisomers.23 X-ray analysis of alkylidene 62 and 2-
methoxyphenylethylidene Meldrum’s acid 117 (analogous
to 61) revealed identical three-dimensional structures, with a
boat conformation for the Meldrum’s acid moiety in both
cases, and absence of conjugation of the aryl moiety with the
olefin acceptor. In addition, the conformation adopted by
compounds 62 and 117 placed the ortho substituent endo to
the cup-shaped structure. The lack of reactivity for these
alkylidenes was rationalized by the close proximity of the
aromatic substituent to the olefin electrophilic carbon, ham-
FIGURE 2. X-ray structures of 5-[1-(3-chlorophenyl)ethylidene]-
2,2-dimethyl-1,3-dioxane-4,6-dione (66) and 5-(4-chloro-2,3-di-
hydro-1H-inden-1-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione
(105).
indenylidene Meldrum’s acid 105, which led to modest
enantioselection in the conjugate addition, similar to 66
and 68. As a working hypothesis, we postulated that the
least nuclear motion principle24 may be at play in the
nucleophilic attack of alkylidene 66. In the course of
the enantiodetermining π-complex formation between the
copper catalyst and olefin 66, rotation of the aromatic ring
would lead to a conformation similar to 4-substituted
indenylidene Meldrum’s acid 105 (Figure 2), which also
led to modest enantioselection.25 It is of note that low-
temperature 1H NMR studies could not detect the presence
of atropoisomers for 3-substituted arylalkylidene Mel-
drum’s acids. Therefore, when the meta substituent is
pointing away from the cup-shaped structure of the alky-
lidene and indenylidene Meldrum’s acids, the very large
nucleophilic CuL2(alkyl) complex coordinates with the
olefin with low discrimination for the enantiotopic faces,
resulting in modest enantiomeric excesses.
In contrast, 5-(1-(3-tert-butylphenyl)ethylidene)-2,2-di-
methyl-1,3-dioxane-4,6-dione (72), which yielded the qua-
ternary benzylic stereocenter in excellent enantioselectivity,
displayed an endo conformation relative to the cup-shaped
structure with a dihedral angle C(5)-C(11)-C(12)-C(13)
of -55.6° (Figure 3). Again, using the least nuclear motion
principle as a working hypothesis, in the course of the
nucleophilic attack, the tert-butyl group would end up at
the same spatial position as the 6-position of indenylidene
Meldrum’s acid following rotation of the aromatic ring,
pering the formation of the catalyst olefin complex, or
3
simply blocking the delivery of the alkyl group.
Substituents such as methyl, benzyloxy, or chloro at the
position meta to the electrophilic center were shown to have
detrimental effects on the enantioselectivity (Table 3). Ex-
ceptionally high enantioselectivites were observed, however,
when the meta position was substituted with large i-Pr and t-
Bu groups. To gain further insight on rationalizing the
enantioselectivity observed for meta-substituted alkylidenes
and indenylidenes, crystallographic data for 66, 68, 72, 76,
78, 103, and 105 were obtained.
5-[1-(3-Chlorophenyl)ethylidene]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (66) and 2,2-dimethyl-5-[1-(3-methylphenyl)-
ethylidene]-1,3-dioxane-4,6-dione (68) showed identical
conformations with the Meldrum’s acid moiety in a boat
conformation and a dihedral angle C(5)-C(11)-C(12)-
C(17) of 57.6° for 66 (Figure 2) and 57.8° for 68. Interest-
ingly, compounds 66 and 68, which gave similar enantios-
electivity in the conjugate addition reaction, also showed
a similar exo conformation of the meta substituent relative
to the boat, meaning that the substituent points away
from the cup-shaped structure. Comparison was made with
(24) (a) Sinnott, M. L. Adv. Phys. Org. Chem. 1988, 24, 113–204. (b) Hine,
J. Adv. Phys. Org. Chem. 1977, 15, 1–61.
(25) 4-Chloro-substituted indenylidene diplayed a much lower dihedral
angle than all the X-ray structures in this series, due to the presence of a
C-H O bond (2.16 A) between one of the carbonyl group carbonyl group
3 3 3
and a Csp2-H (7-position). A persistent, intramolecular C-H X (X = O,
3 3 3
(23) An example of atropoisomerism with alkylidene Meldrum’s acid was
reported; see: Huck, N. P. M.; Meetsma, A.; Zijlstra, R.; Feringa, B. L.
Tetrahedron Lett. 1995, 36, 9381–9384.
S, Br, Cl, and F) hydrogen bond in solution and solid states was previously
reported for benzyl Meldrum’s acid derivatives; see: Fillion, E.; Wilsily, A.;
Fishlock, D. J. Org. Chem. 2009, 74, 1259–1267.
8592 J. Org. Chem. Vol. 74, No. 22, 2009

Wilsily and Fillion
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structure of alkylidene Meldrum’s acid influence the
enantiodetermining step of the 1,4-addition. That is, an
exo-disposed group is detrimental to enantioselection
while an endo-oriented group is beneficial. This was further
validated by the reaction of Et2Zn with 3,5-disubstituted
arylalkylidene Meldrum’s acids 78, 80, and 82, in which
the exo and endo positions are filled, considering the
rotation of the aromatic ring during the carbon-carbon
bond-forming events. Not surprisingly, the products
formed in low conversions and ee’s (Table 3, entries 8-10)
as important steric interactions develop between the
chiral complex and the substrate in the formation of the
π-complex. The exception is the reaction of 5-(4,6-dichloro-
2,3-dihydro-1H-inden-1-ylidene)-2,2-dimethyl-1,3-dioxane-
4,6-dione (107), which furnished conjugate addition
product 108 in high enantioselectivity (Table 5, entry 8).
This is in striking contrast with the reactivity of analogous
dichloro compound 78. These results illustrates once again
that the locked conformation adopted by the planar bicyclic
system is most favorable in affecting reactivity and enantio-
selection.
In this section, evidence of a correlation between solid-
state conformation and enantioselection in solution have
been presented. However, to develop a reliable mnemonic
device for predicting the level of stereoselectivity in the
enantioselective conjugate addition reaction, the role of
packing effects in the solid-state conformation observed
for alkylidene and indenylidene Medrum’s acids remained
to be established, specially for meta-substituted 1-arylalk-
ylidene Meldrum’s acids. Nevertheless, from a practical
point of view, the predictable increase in enantioselectivity
by introduction of large substituents on the arene moiety
provides a simpler means of producing highly enantioen-
riched products.
Summary
The scope and limitation of the asymmetric synthesis of
all-carbon benzylic quaternary stereocenters via copper-
catalyzed conjugate addition of primary dialkylzinc reagents
to alkylidene and indenylidene Meldrum’s acids has been
studied. The reaction is tolerant to a wide range of hetero-
aromatic and functional groups. The significance of substi-
tuting the positions para, meta, and ortho to the electrophilic
center was also highlighted. Substituting the ortho position
leads to recovery of conjugate addition precursor, while
substituting the para position leads to increased enantios-
electivities. Small substituents at the meta position yield
lower ee while large groups provide a substantial increase
in facial selectivity. Steric interactions rather than electronic
factors related to the substitutents on the aryl group likely
cause the observed reactivity and enantioselectivity in the
conjugate addition of organozinc reagents to alkylidene
Meldrum’s acids. A correlation between the observed en-
antioselectivity and the alkylidene Meldrum’s acids solid-
state conformation, determined by the arene pattern of
substitution, was proposed.
FIGURE 3. X-ray structures of 5-(1-(3-tert-butylphenyl)ethyli-
dene)-2,2-dimethyl-1,3-dioxane-4,6-dione (72), 5-[1-(3,4-dichloro-
phenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (76), and
5-(6-chloro-2,3-dihydro-1H-inden-1-ylidene)-2,2-dimethyl-1,3-diox-
ane-4,6-dione (103).
leading to a conformation similar to Meldrum’s acid 103
(Figure 3), for which superior enantioselection was observed.
The correlation between solid-state conformation and en-
antioselection also applied to 5-[1-(3,4-dichlorophenyl)-
ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (76). A dihe-
dral angle C(5)-C(11)-C(12)-C(13) of -81.8° was
measured with a CdC bond length of 1.34 A (Figure 3). The
endo conformation was observed for Meldrum’s acid 76, and
accordingly, conjugate addition yielded a good enantiomeric
excess of 85% (Table 3, entry 7).
Experimental Section
The experimental data seem to indicate that the spatial
orientations of the meta substituents versus the cup-shaped
Preparation of Alkylidene Meldrum’s Acids: General Proce-
dure A. Alkylidene Meldrum’s acids were prepared by the
J. Org. Chem. Vol. 74, No. 22, 2009 8593

Wilsily and Fillion
JOCArticle
Knoevenagel condensation of Meldrum’s acid with ketones
using Brown and co-workers’ method.26 In a typical reaction,
a solution of TiCl4 (2.1 equiv) in CH2Cl2 (3 M relative to ketone)
was added dropwise under nitrogen to dry THF (0.3 M relative
to ketone), which was cooled at 0 °C, resulting in a yellow
suspension. A solution containing the ketone (1.0 equiv) and
Meldrum’s acid (1.0 equiv) in dry THF (0.7 M relative to ketone)
was cooled to 0 °C, and 5% HCl and EtOAc were added to the
reaction mixture. The layers were partitioned, and the aqueous
layer was extracted with EtOAc (3ꢀ). The combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated. The crude residue was purified by
flash column chromatography on silica gel using hexanes in
EtOAc to yield the desired product. HPLC using a chiral column
(OD-H or AD-H) was used to measure the enantiomeric ratio of
the products.
was added dropwise via a syringe to the TiCl4 THF complex.
3
The flask containing the solution of ketone and Meldrum’s acid
was rinsed with THF (2ꢀ) and added to the reaction mixture.
Subsequently, pyridine (5.0 equiv) was added to the reaction
mixture dropwise at 0 °C. The reaction was allowed to warm to
room temperature slowly and stirred until completion of the
reaction or for 24 h. The reaction was quenched by the addition
of water and diluted with either Et2O or EtOAc. After the solid
was dissolved, the layers were partitioned. The aqueous layer
was extracted with Et2O or EtOAc (2ꢀ), and the combined
organic layers were washed with a saturated solution of
NaHCO3 (2ꢀ) and brine (1ꢀ), dried over MgSO4, filtered,
and concentrated. Purification by either crystallization/tritura-
tion and/or flash chromatography provided the alkylidene
Meldrum’s acids.
(R)-4-(2-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)butan-2-yl)-
phenyl Acetate (44). Compound 44 was prepared according to
general procedure B with a reaction time of 29 h. Purification by
flash column chromatography on silica gel, eluting with 3:1
1
hexanes/EtOAc, afforded a white, waxy solid in 87% yield: H
NMR (CDCl3, 300 MHz) δ 7.28 (d, J = 8.7 Hz, 2H), 7.03
(d, J = 8.7 Hz, 2H), 3.54 (s, 1H), 2.26 (s, 3H), 2.15 (dq, J =
15.0, 7.3 Hz, 1H), 2.10 (dq, J= 14.4, 7.2 Hz, 1H), 1.61 (s, 3H), 1.58
(s, 3H), 1.19 (s, 3H), 0.78 (t, J = 7.3 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 169.2, 164.5, 164.1, 149.6, 139.6, 128.0,
121.4, 105.4, 57.1, 46.0, 32.6, 29.5, 27.1, 22.2, 21.1, 8.7; enantio-
meric excess of 93% (R) measured by chiral HPLC (AD-H,
5% i-PrOH/hexanes, 1.0 mL/min, tR1 = 13.2 min (S), tR2
=
4-(1-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)phe-
nyl Acetate (43). Prepared according to general procedure A.
Recrystallization from MeOH afforded a light yellow solid in
14.1 min (R)); [R]26.5D = þ5.9 (c 1.7, THF); absolute configura-
tion was assigned by analogy to 6, 67, and 106; HRMS(EI) m/z
calcd for C18H22O6 (Mþ) 334.1416, found 334.1414.
1
68% yield: mp 144-145 °C (MeOH); H NMR (CDCl3, 300
MHz) δ 7.19 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 2.68
(s, 3H), 2.27 (s, 3H), 1.79 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ
172.0, 168.9, 161.0, 160.2, 151.3, 138.8, 127.3, 121.6, 116.9,
103.8, 27.2, 26.2, 21.1; HRMS(EI) m/z calcd for C16H16O6
(Mþ) 304.0947, found 304.0943.
Acknowledgment. This work was supported by the Nat-
ural Sciences and Engineering Research Council of Canada
(NSERC), the Canadian Foundation for Innovation, the
Ontario Innovation Trust, and the University of Waterloo.
We gratefully acknowledge Boehringer Ingelheim (Canada)
Ltd., AstraZeneca Canada Inc., and the Merck Frosst Centre
for Therapeutic Research for unrestricted support of this
research. A.W. is indebted to NSERC for CGS-M and CGS-
D scholarships. Tim Rasmusson, University of Waterloo, is
acknowledged for preliminary experiments and thanks
NSERC for a USRA scholarship. The late Dr. Nicholas J.
Taylor, University of Waterloo, is acknowledged for
X-ray structure determination of 4, 25, 57, 62, 66, 68, 72,
76, 78, 96, 98, 103, 105, and 117 and Dr. Alan J. Lough,
University of Toronto, for X-ray structure determination of
67, and 106.
1,4-Addition of (Alkyl)2Zn to Alkylidene Meldrum’s Acids:
General Procedure B. Reactions were typically carried out using
0.12 mmol of substrate. In a glovebox, copper source (5 mol %)
and phosphoramidite chiral ligand (10 mol %) were charged in a
flame-dried resealable Schlenk tube. DME (0.5 mL) was then
added to the Schlenk tube to wash down any residual solids to
the bottom. The reaction mixture was allowed to stir at ambient
temperature for 30 min, outside the glovebox, and then cooled
to -40 °C. In the drybox, (alkyl)2Zn solution (2.0 equiv) was
transferred to a flask equipped with a septum. This solution was
added to the Schlenk tube dropwise via a syringe, and the
resulting solution was stirred for 5 min. A solution of alkylidene
Meldrum’s acid (1.0 equiv) in DME (0.5 mL) was then added
dropwise via a syringe. Finally, DME (0.2 mL) was added to
wash down the remaining solid on the sides of the Schlenk tube.
The reaction mixture was allowed to warm slowly to room
temperature. After being stirred for 48 h, the reaction mixture
Supporting Information Available: Experimental proce-
dures, NMR spectra, crytsallographic data, and CIF files for
4, 25, 57, 62, 66, 67, 68, 72, 76, 78, 96, 98, 103, 105, 106, and 117.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(26) Baxter, G. J.; Brown, R. F. C. Aust. J. Chem. 1975, 28, 1551–1557.
8594 J. Org. Chem. Vol. 74, No. 22, 2009