Enantioselective copper-catalyzed conjugate addition of dimethylzinc to 5-(1-arylalkylidene) Meldrum's acids

Article abstract of DOI:10.1055/s-0029-1216845

The asymmetric formation of all-carbon quaternary benzylic stereocenters containing a methyl substituent was realized by the enantioselective copper-catalyzed 1,4-addition of dimethylzinc to alkylidene Meldrum's acids in the presence of a chiral phosphora

Full text of DOI:10.1055/s-0029-1216845

2066
SPECIAL TOPIC
Enantioselective Copper-Catalyzed Conjugate Addition of Dimethylzinc
to 5-(1-Arylalkylidene) Meldrum’s Acids
Conjugate
A
dditio
s
n
of Me
Z
2 hn to 5-(1-Ar
r
ylalkylid
a
ene) Meldr
f
s
A
cids Wilsily, Tiantong Lou, Eric Fillion*
Department of Chemistry, University of Waterloo, Waterloo, ON, N2L 3G1, Canada
Fax +1(519)7460435; E-mail: efillion@uwaterloo.ca
Received 15 March 2009
R22Zn (2 equiv)
Cu(OTf)2 (5 mol%)
DME, –40 °C to r.t., 48 h
Abstract: The asymmetric formation of all-carbon quaternary ben-
zylic stereocenters containing a methyl substituent was realized by
the enantioselective copper-catalyzed 1,4-addition of dimethylzinc
to alkylidene Meldrum’s acids in the presence of a chiral phosphor-
amidite. Copper source and ligand optimization studies are present-
ed, as well as the scope and limitations of dimethylzinc addition to
various alkylidene Meldrum’s acids. Good to excellent yields and
enantioselectivities were obtained.
O
O
O
O
O
O
O
O
R1
Ar
R1
Ar
Ph
Ph
R2
O
P
N
O
1
2
Key words: Meldrum’s acid, all-carbon quaternary stereocenters,
enantioselective conjugate addition, copper catalysis, organozinc
reagents, phosphoramidite ligand
3a (10 mol%)
Scheme
1
Enantioselective copper-catalyzed 1,4-addition of
dialkylzinc reagents to alkylidene Meldrum’s acids 1
The catalytic asymmetric formation of all-carbon quater-
nary stereocenters remains an important goal in organic
chemistry.1 Conjugate addition of organometallic re-
agents to carbonyl-, nitro-, and sulfone-activated tri- and
tetrasubstituted alkenes, has become a general and effi-
cient method to access this structural motif.2 A number of
research groups,3 along with ours,4 have reported the
enantioselective copper-catalyzed addition of organoalu-
minum, organozinc, and Grignard reagents. The rhodium-
catalyzed addition of alkenyl- and arylboronic acids was
also described.5 From these synthetic strategies towards
the formation of all-carbon quaternary stereocenters, aryl,
alkenyl, and alkyl groups were introduced.
Our group4 has established that alkylidene Meldrum’s
acids 1 are excellent electrophiles6 to access all-carbon
benzylic quaternary stereocenters through enantioselec-
tive copper-catalyzed conjugate addition of organozinc
reagents in the presence of commercially available chiral
phosphoramidite7 ligand 3a. Excellent conversions,
yields, and enantioselectivities in the formation of 2 were
achieved (Scheme 1). We also demonstrated that the pat-
tern of substitution of the arene moiety impacted the effi-
ciency of the reaction as well as the enantioselectivity of
the conjugate addition.
O
O
O
O
O
O
Me2Zn (5 equiv)
Me
Cu(OTf)2 (5 mol%)
O
O
3a (10 mol%), DME
–40 °C to r.t., 48 h
Cl
Cl
1a
2a
>99% conversion
98% yield, 99% ee
O
O
O
O
Me2Zn (5 equiv)
Cu(OTf)2 (5 mol%)
O
O
O
O
3a (10 mol%), DME
–40 °C to r.t., 48 h
Et
Me
Et
Cl
Cl
1b
2b
35% conversion
Scheme 2 Dimethylzinc addition to alkylidene Meldrum’s acids
The commonality of methyl-containing all-carbon quater-
nary stereocenters in bioactive natural products prompted
us to optimize the enantioselective methyl delivery to
alkylidene Meldrum’s acids 1. A limited number of re-
ports have appeared in the literature regarding asymmetric
addition of methyl groups for the formation of all-carbon
quaternary carbons. Hoveyda showed that the poorly nu-
cleophilic dimethylzinc reacted with highly activated alk-
enes such as nitroalkenes,3n and cycloalkenones bearing a
carboxylate group at the 2- or 3-position,3m,k in the pres-
ence of a copper catalyst, to yield all-carbon quaternary
stereocenters in good yields and enantioselectivities. Our
group obtained limited success on the addition of
dimethylzinc to 2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-
ylidene)aryl acetates.4a The addition of methylmagnesium
bromide catalyzed by copper salts was also reported.3a,f,o
Despite the superior electrophilicity of alkylidene
Meldrum’s acids 1 towards organozinc reagents, the addi-
tion of dimethylzinc lacked generality. The conjugate ad-
dition of dimethylzinc to Meldrum’s acid indelydine 1a
gave >99% conversion, 98% isolated yield, and 99% ee.4c
However, less reactive alkylidene 1b led to a poor 35%
conversion (Scheme 2).4c
SYNTHESIS 2009, No. 12, pp 2066–2072
x
x.
x
x
.
2
0
0
9
Advanced online publication: 27.05.2009
DOI: 10.1055/s-0029-1216845; Art ID: C01109SS
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of Me2Zn to 5-(1-Arylalkylidene) Meldrum’s Acids
2067
To date, the copper-catalyzed addition of trimethylalumi- an axially chiral BINOL moiety as found in ligand 3a, led
num to cyclic enones has provided the best selectivity, as to complete inhibition of the conjugate addition
independently reported by the Alexakis3c–e,h and (Scheme 3). In contrast, leaving the BINOL moiety intact
Hoveyda3i,j groups. In this report, an optimized 1,4-conju- while replacing the chiral amine on the phosphorus atom
gate addition of dimethylzinc to tetrasubstituted alkenes 1 with a dimethylamino group (3c) gave 70% conversion
is outlined along with substrate scope and limitations.
and 50% ee after 48 hours. Increasing the steric hindrance
around the amine moiety by having a diisopropylamine
(3d) had a detrimental effect on both conversion and
enantioselectivity. The substitution of the phenyl moiety
on the chiral amine with the 2-napthyl moiety 3e gave
only slight improvement of conversion with an enantiose-
lectivity of 75% ee.
The asymmetric conjugate addition was optimized using
2,2-dimethyl-5-(1-phenylpropylidene)-1,3-dioxane-4,6-
dione (1c) (Table 1). Subjecting 1c under our previously
developed conditions, 2 equivalents of dimethylzinc (10
wt% solution in hexane) and 5 mol% of copper(II) triflate
in DME (final concentration of 0.08 M) from –40 °C to
room temperature, gave a 32% conversion to Meldrum’s From this survey of phosphoramidite ligands, decreasing
acid 2c after 48 hours (Table 1, entry 1). Strongly Lewis the size of the amine moiety increased the conversion,
acidic nucleophiles were then investigated to promote the while decreasing enantioselectivity. These results showed
addition to the alkylidenes with good conversions. Grig- that phosphoramidite ligand 3a and 2-naphthyl substitut-
nard reagents methylmagnesium iodide, methylmagne- ed ligand 3e led to optimal enantioselectivities despite
sium bromide, and methylmagnesium chloride gave lower conversions.
excellent conversions but nearly racemic product 2c
(Table 1, entries 2–4). The use of the (R,S)-Josiphos
O
O
ligand also gave excellent conversions with nearly racem-
ic products (not shown in Table 1). Conjugate addition in-
volving organoaluminum reagents led to improved
conversions in comparison to dimethylzinc. However,
poor enantioselectivities were observed (entries 5 and 6).
The nearly racemic product 2c observed for these reac-
tions suggested that the uncatalyzed addition of the nu-
cleophiles towards alkylidene Meldrum’s acid 1c was the
predominant pathway.
Me2Zn (2 equiv)
Cu(OTf)2 (5 mol%)
O
O
O
O
O
O
3 (10 mol%), DME
–40 °C to r.t.
Et
Me
2c
Ph
Ph
Et
1c
Ph
Ph
Ph
Ph
O
O
O
O
P
N
P
N
Table 1 Survey of Organometallic Reagents in the Conjugate Addi-
tion to Alkylidene Meldrum’s Acid 1c
3a: 32% conv, 48 h
3b: NR, 48 h
O
O
Me2Zn (2 equiv)
Cu(OTf)2 (5 mol%)
O
O
O
O
2-naphthyl
2-naphthyl
O
O
O
P
O
3a (10 mol%), DME
NR2
P
N
Et
Me
2c
–40 °C to r.t.
Ph
O
O
Ph
Et
1c
Entry
MenM
Time (h)
Conversion (%) ee (%)
3c (R = Me): 70% conv
3e: 37% conv, 75% ee, 48 h
50% ee, 48 h
1
2
3
4
5
6
Me2Zn
48
72
72
72
96
48
32
63
88
97
64
96
n/aa
<5
<5
<5
<5
<5
3d (R = i-Pr): 47% conv
<5% ee, 96 h
MeMgI
MeMgBr
MeMgCl
Me2AlCl
Me3Al
Scheme 3 Phosphoramidite ligands
To promote the addition of dimethylzinc to alkylidene
Meldrum’s acids 1, a bimolecular process, the concentra-
tion of the reaction mixture was increased. Two approach-
es were used to run the reaction at higher concentration;
either utilizing a more concentrated solution of dimethyl-
zinc, or diminishing the quantity of DME. The reactions
discussed above were carried out at a final concentration
of 0.08 M for 1c, considering for the total volume of sol-
vent DME and hexanes from the 10 wt% solution of di-
a Not applicable.
The tendancy of Grignard reagents and trimethylalumi-
num to give excellent conversion but racemic material led
us to reexamine the asymmetric conjugate addition of
dimethylzinc. We decided to systematically study the
phosphoramidite ligand and copper sources to improve
conversions. Ligand 3b, containing a biphenyl rather than
methylzinc.
Gratifying,
conversion
improved
substantially by decreasing the amount of DME used in
half, for a final concentration of 0.2 M. As depicted in
Table 2, when ligand 3a was used, conversion increased
from 32% to 78%, and 37% to 82% with ligand 3e. Of
Synthesis 2009, No. 12, 2066–2072 © Thieme Stuttgart · New York

2068
A. Wilsily et al.
SPECIAL TOPIC
to the best results (entry 7). This time, the final concentra-
tion was increased, by using a more concentrated solution
of dimethylzinc. The conversion was increased to near
completion by using a 2.0 M solution of dimethylzinc in
toluene (2 equiv) (Table 1, entry 8), for a final concentra-
tion of 0.33 M.
Table 2 Concentration Studies
O
O
Me2Zn (2 equiv)
Cu(OTf)2 (5 mol%)
O
O
O
O
O
O
3a or 3e (10 mol%), DME
Et
Me
–40 °C to r.t., 48 h
Ph
Ph
Et
final concentration
of 1c = 0.08 M or 0.2 M
Table 3 Optimization of the Copper Source
2c
1c
Entry
Ligand
Final concentration Conversion ee
O
O
Me2Zn (2 equiv)
copper source (5 mol%)
O
O
of 1c
(%)
32
78
37
82
(%)
n/aa
77
O
O
O
O
3a or 3e (10 mol%), DME
1
2
3
4
3a
3a
3e
3e
0.08 M
0.2 M
0.08 M
0.2 M
Et
Me
2c
–40 °C to r.t., 48 h
Ph
Ph
Et
final concentration of 1c = 0.2 M
1c
75
Entry
Ligand Copper source
Conversion (%) ee (%)
75
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3e
3e
3e
Cu(OTf)2
78
94
88
90
87
82
95
98b
77
75
75
74
73
75
77
76
a Not applicable.
Cu(OAc)2·H2O
Cu(acac)2
note, the decrease in the relative quantity of DME versus
hexane did not result in a loss in enantioselectivity.
CuTCa
Further ligands with modifications to the BINOL back-
bone were tested to increase the conversion and the enan-
tioselectivity (Scheme 4). Ligand 3f, with a hydrogenated
BINOL moiety, led to enantioselectivity similar to 3c. Fi-
nally, 6,6¢-dibrominated phosphoramidite ligand 3g gave
improved conversion but decreased enantioselectivity in
comparison to 3c. Based on these results, phosphoramid-
ite 3a and 3e were the best ligands in the dimethylzinc ad-
dition for obtaining high yield and enantioselectivity.
Cu(O2CCF3)2·ꢀH2O
Cu(OTf)2
Cu(O2CCF3)2·ꢀH2O
Cu(O2CCF3)2·ꢀH2O
a CuTC: copper(I) thiophene-2-carboxylate.
b Me2Zn (2.0 M in toluene) was used rather than Me2Zn (10 wt% in
hexane). Final concentration of 1c was 0.33 M.
Me2Zn (2 equiv)
Cu(OTf)2 (5 mol%)
O
O
O
With the optimal conditions in hand, the scope of the di-
methylzinc addition to alkylidene Meldrum’s acids was
investigated (Table 4).9 Electron-donating groups posi-
tioned para to the electrophilic site furnished products in
excellent yields and enantioselectivities (Table 4, entries
2–4, 7). Electron-withdrawing groups at the 4-position
also provided products with good yields and enantioselec-
tivities (Table 4, entries 5, 6). Substituting the meta posi-
tion yielded diminished selectivities, while ortho-
substitution led to fully recovery of starting material.
These results are consistent with our previously reported
diethylzinc addition to similar alkylidenes.4c Interestingly,
3-N-tosylpyrrole-substituted 1l gives product 2l in excel-
lent yield and enantioselectivity (Table 1, entry 11).
O
O
O
O
O
3f or 3g (10 mol%), DME
–40 °C to r.t., 48 h
Et
Me
Ph
Ph
Et
final concentration of 1c = 0.2 M
1c
2c
Br
O
O
O
P
N
P
N
O
Br
3f
78% conv, 48% ee
3g
89% conv, 35% ee
Scheme 4 Varying the phosphoramidite ligand
It is noteworthy to comment on the experimental proce-
dure. A typical reaction involves the addition of dimeth-
Copper sources were then explored to further optimize ylzinc to a precooled solution containing copper source
conversion and enantioselectivity.8 After testing a few and the chiral phosphoramidite ligand. After five minutes,
copper sources, it was shown that consistent enantioselec- a solution of the substrate in DME is added to the reaction
tivities were achieved regardless of the copper source for mixture. Although, this procedure works with a number of
both ligands 3a (Table 3, entries 1–5) and 3e (Table 3, en- these alkylidenes, it became a problem for some sub-
tries 6–8). However, the source of copper had a bigger in- strates insoluble in DME at high concentration. To over-
fluence on conversion. Copper(I) triflate gave the lowest come this problem, a solution of copper, phosphoramidite
conversion compared to all other copper sources tested ligand, and dimethylzinc was added onto a concentrated
(Table 3, entries 1 and 6), while Cu(O2CCF3)2·ꢀH2O led mixture of the substrate in DME. This ‘reverse’ addition
Synthesis 2009, No. 12, 2066–2072 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of Me2Zn to 5-(1-Arylalkylidene) Meldrum’s Acids
2069
mL, 32 mmol, 2.1 equiv) in CH2Cl2 (6 mL) was added dropwise
under N2 to anhyd THF (55 mL), which was cooled at 0 °C, result-
ing in a yellow suspension. A solution containing the ketone (15
mmol, 1.0 equiv) and Meldrum’s acid (15 mmol, 1.0 equiv) in an-
hyd THF (10 mL) was added dropwise via a syringe to the
TiCl4·THF complex. The flask containing the solution of ketone and
Meldrum’s acid was rinsed with THF (10 mL) and added to the mix-
ture. Subsequently, pyridine (75 mmol, 5.0 equiv) was added to the
reaction mixture dropwise at 0 °C. The reaction was allowed to
warm up slowly to r.t. and stirred until completion of reaction or for
24 h. The reaction was quenched by the addition of H2O (100 mL)
and diluted with either Et2O or EtOAc (100 mL). After the solid had
dissolved, the layers were partitioned. The aqueous layer was ex-
tracted with Et2O, or EtOAc (2 ꢀ 100 mL), and the combined organ-
ic layers were washed with aq sat. NaHCO3 (2 ꢀ 100 mL), brine (50
mL), dried (MgSO4), filtered, and concentrated. Purification by ei-
ther crystallization or trituration with MeOH provided the alkyl-
idene Meldrum’s acids. For data on 1a, see ref. 4c.
Table 4 Scope of the Conjugate Addition of Dimethylzinc
Me2Zn (2 equiv)
Cu(O2CCF3)2⋅xH2O (5 mol%)
O
O
O
O
O
O
O
O
3e (10 mol%), DME
–40 °C to r.t., 48 h
Et
Me
Ar
Et
Ar
final concentration of 1 = 0.33 M
1
2
Entry Ar
Product Conversion Yield
ee
(%)
2
(%)
98
99
99
99
98
96
99
97
0
(%)
93
85
99
84
68
68
93
79
n/a
82
93
1
2
Ph (1c)
2c
2d
2e
2f
2g
2b
2h
2i
76
83
94
97
91
90
85
69
n/a
79
97
4-MeC6H4 (1d)
4-i-PrC6H4 (1e)
4-t-BuC6H4 (1f)
4-BrC6H4 (1g)
4-ClC6H4 (1b)
4-MeOC6H4 (1h)
3-MeOC6H4 (1i)
2-MeOC6H4 (1j)
2-naphthyl (1k)
3
4
5-[1-(4-Chlorophenyl)propylidene]-2,2-dimethyl-1,3-dioxane-
4,6-dione (1b)
Yield: 15%; white solid; mp 120–122 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.36 (d, J = 8.4 Hz, 1 H), 7.08 (d,
J = 8.4 Hz, 1 H), 3.07 (q, J = 7.5 Hz, 2 H), 1.78 (s, 6 H), 1.05 (t,
J = 7.5 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d =176.6, 160.7, 160.1, 138.2, 135.2,
128.6, 127.6, 117.2, 103.9, 31.4, 27.3, 12.3.
HRMS (EI): m/z calcd for C15H15ClO4 (M+): 294.0659; found:
294.0668.
5
6
7
8
9
2j
2k
10
11
99
>99
3-(N-Ts)pyrrolyl (1l) 2l
2,2-Dimethyl-5-(1-phenylpropylidene)-1,3-dioxane-4,6-dione
(1c)
a Not applicable.
Yield: 43%; white solid; mp 98–100 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.40–7.38 (m, 3 H), 7.15–7.13 (m,
2 H), 3.12 (q, J = 7.4 Hz, 2 H), 1.80 (s, 6 H), 1.06 (t, J = 7.4 Hz, 3
allowed for better conversion and isolated yields while not
affecting the enantioselectivities.3d
H).
In summary, the asymmetric conjugate addition of di-
methylzinc to alkylidene Meldrum’s acids has been 13C NMR (CDCl3, 75 MHz): d = 178.0, 160.9, 160.3, 140.0, 129.1,
128.3, 126.1, 116.8, 103.8, 31.3, 27.2, 12.3.
HRMS (EI): m/z calcd for C15H16O4 (M+): 260.1049; found:
achieved in good to excellent yields and enantioselectivi-
ties. The application of this methodology to natural prod-
260.1040.
uct synthesis is in progress.
2,2-Dimethyl-5-(1-p-tolylpropylidene)-1,3-dioxane-4,6-dione
(1d)
Yield: 7% (unoptimized); white solid; mp 145–147 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.20 (d, J = 7.6 Hz, 2 H), 7.06 (d,
J = 7.7 Hz, 2 H), 3.12 (q, J = 7.4 Hz, 2 H), 2.37 (s, 3 H), 1.80 (s, 6
H), 1.05 (t, J = 7.4 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 178.4, 161.0, 160.6, 139.5, 137.1,
129.1, 126.3, 116.5, 103.7, 31.3, 27.3, 21.4, 12.5.
HRMS (EI): m/z calcd for C16H18O4 (M+): 274.1205; found:
274.1201.
All reactions were carried out in flame-dried glassware under a dry
argon atmosphere. 1,2-Dimethoxyethane (DME) was distilled from
sodium-benzophenone ketyl under N2 and degassed via freeze-
pump-thaw method. All copper sources were obtained from com-
mercial sources and used without further purification. Me2Zn (1.0
M in heptanes), and Me2Zn (2.0 M in toluene), were also obtained
from commercial sources and used without further purification.
Chiral phosphoramidite ligands were either obtained from commer-
cial sources or prepared according to literature procedures.10 1H
1
NMR spectra were referenced to residual H shift in CDCl3 (7.24
ppm). CDCl3 (77.0 ppm) was used as the internal reference for 13
C
NMR spectra. Flash chromatography was performed using 230–400
mesh silica gel. Melting points are uncorrected. Optical rotations
were recorded in cells with 1 dm path length. Chiral HPLC analyses
were performed using a Chiralcel OD-H or AD-H column. All col-
umns are 250 ꢀ 4.6 mm. High-resolution mass spectra were run at
the University of Waterloo with a source temperature of 200 °C,
mass resolution of 9000, and electron energy of 70 eV.
5-[1-(4-Isopropylphenyl)propylidene]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (1e)
Yield: 33%; light yellow solid; mp 106–108 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.24 (d, J = 7.5 Hz, 2 H), 7.10 (d,
J = 7.6 Hz, 2 H), 3.11 (q, J = 7.3 Hz, 2 H), 2.91 (sept, J = 6.8 Hz,
1 H), 1.80 (s, 6 H), 1.24 (d, J = 6.9 Hz, 2 H), 1.05 (t, J = 7.4 Hz, 3
H).
13C NMR (CDCl3, 75 MHz): d = 178.2, 160.9, 160.5, 150.1, 137.2,
126.4, 126.3, 116.3, 103.6, 33.7, 31.2, 27.1, 23.6, 12.5.
HRMS (EI): m/z calcd for C18H22O4 (M+): 302.1558; found:
302.1521.
Alkylidene Meldrum’s Acids 1; General Procedure A
Alkylidene Meldrum’s acids were prepared by the Knoevenagel
condensation of Meldrum’s acid with ketones using Brown and co-
workers’ method.11 In a typical reaction, a solution of TiCl4 (3.5
Synthesis 2009, No. 12, 2066–2072 © Thieme Stuttgart · New York

2070
A. Wilsily et al.
SPECIAL TOPIC
5-[1-(4-tert-Butylphenyl)propylidene]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (1f)
Yield: 26%; white solid; mp 110–112 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.87–7.82 (m, 3 H), 7.63 (s, 1 H),
7.52–7.49 (m, 2 H), 7.26 (d, J = 8.6 Hz, 1 H), 3.23 (q, J = 7.5 Hz,
2 H), 1.84 (s, 6 H), 1.09 (t, J = 7.4 Hz, 3 H).
1H NMR (CDCl3, 300 MHz): d = 7.39 (d, J = 7.9 Hz, 2 H), 7.11 (d,
J = 7.9 Hz, 2 H), 3.11 (q, J = 7.4 Hz, 2 H), 1.80 (s, 6 H), 1.31 (s, 9
H), 1.06 (t, J = 7.4 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 178.2, 161.0, 160.4, 137.5, 133.3,
132.7, 128.3, 128.0, 127.8, 126.9, 126.6, 125.3, 124.3, 116.9, 103.8,
31.6, 27.3, 12.5.
13C NMR (CDCl3, 75 MHz): d = 178.4, 161.0, 160.7, 152.5, 137.0,
HRMS (EI): m/z calcd for C19H18O4 (M+): 310.1205; found:
126.2, 125.2, 116.4, 103.7, 34.7, 31.3, 31.1, 27.2, 12.6.
310.1213.
HRMS (EI): m/z calcd for C16H18O5 (M+): 316.1675; found:
316.1673.
2,2-Dimethyl-5-[1-(1-tosyl-1H-pyrrol-3-yl)propylidene]-1,3-di-
oxane-4,6-dione (1l)
Yield: 39%; light yellow solid; mp 133–134 °C (MeOH).
5-[1-(4-Bromophenyl)propylidene]-2,2-dimethyl-1,3-dioxane-
4,6-dione (1g)
Yield: 25%; white solid; mp 124–125 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.51 (d, J = 8.1 Hz, 2 H), 7.01 (d,
J = 8.1 Hz, 2 H), 3.06 (q, J = 7.4 Hz, 2 H), 1.77 (s, 6 H), 1.03 (t,
J = 7.4 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 176.5, 160.6, 160.1, 138.7, 131.4,
127.7, 123.3, 117.0, 103.9, 31.2, 27.2, 12.2.
HRMS (EI): m/z calcd for C15H15BrO4 (M+): 338.0154; found:
338.0160.
1H NMR (CDCl3, 300 MHz): d = 7.77 (d, J = 8.3 Hz, 2 H), 7.64 (s,
1 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.11–7.09 (m, 1 H), 6.39–6.37 (m,
1 H), 2.99 (q, J = 7.4 Hz, 2 H), 2.39 (s, 3 H), 1.73 (s, 6 H), 1.12 (t,
J = 7.4 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 168.2, 161.2, 161.1, 145.8, 135.2,
130.3, 127.1, 125.6, 123.8, 120.9, 114.6, 114.0, 103.6, 30.8, 27.1,
21.7, 14.1.
HRMS (EI): m/z calcd for C20H21NO6S (M+): 403.1090; found:
403.1082.
Asymmetric 1,4-Conjugate Addition of Me2Zn to Alkylidene
Meldrum’s Acids 1; General Procedure B
5-[1-(4-Methoxyphenyl)propylidene]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (1h)
Reactions were typically carried out using 0.4 mmol of substrate. In
a glove box, copper source (5 mol%) and phosphoramidite chiral
ligand (10 mol%) were added to a flame-dried resealable Schlenk
tube. DME (0.3 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 r.t. for 30 min, outside the glove box, and then
cooled to –40 °C. In the dry box, Me2Zn solution (2.0 equiv) was
transferred to a round-bottom flask equipped with a septum. This
solution was added to the Schlenk tube dropwise via a syringe and
the resulting solution stirred for 5 min. A solution of alkylidene
Meldrum’s acid 1 (1.0 equiv) in DME (0.3 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 mix-
ture was allowed to warm up slowly to r.t. After stirring for 48 h, the
mixture was cooled to 0 °C, aq 5% HCl (5 mL) and EtOAc (20 mL)
were added to the mixture. The layers were partitioned and the
aqueous layer was extracted with EtOAc (3 ꢀ 20mL). The combined
organic layers were washed with brine (20 mL), dried (MgSO4), fil-
tered, and concentrated. The crude residue was purified by flash
column chromatography on silica gel using hexanes in EtOAc as
eluent 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. For data on 2a, see ref. 4c.
Yield: 29%; light yellow solid; mp 113–114 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.16 (d, J = 7.8 Hz, 2 H), 6.91 (d,
J = 7.8 Hz, 2 H), 3.82 (s, 3 H), 3.13 (q, J = 7.3 Hz, 2 H), 1.80 (s, 6
H), 1.05 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 178.2, 161.1, 161.0, 160.9, 132.0,
128.6, 115.8, 113.8, 103.6, 55.3, 31.3, 27.3, 12.9.
HRMS (EI): m/z calcd for C16H18O5 (M+): 290.1154; found:
290.1156.
5-[1-(3-Methoxyphenyl)propylidene]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (1i)
Yield: 26%; light yellow solid; mp 72–74 °C (MeOH).
1H NMR (CDCl3, 300 MHz): d = 7.32 (t, J = 7.9 Hz, 1 H), 6.91 (dd,
J = 8.3, 2.4 Hz, 1 H), 6.71–6.67 (m, 2 H), 3.80 (s, 3 H), 3.10 (q,
J = 7.5 Hz, 2 H), 1.79 (s, 3 H), 1.06 (t, J = 7.5 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 177.5, 160.9, 160.2, 159.4, 141.4,
129.5, 118.4, 117.0, 113.8, 112.3, 103.8, 55.2, 31.2, 27.3, 12.3.
HRMS (EI): m/z calcd for C16H18O5 (M+): 290.1154; found:
290.1159.
5-[1-(2-Methoxyphenyl)propylidene]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (1j)
Yield: 64%; light yellow solid; mp 105–107 °C (MeOH).
(S)-5-[1-(4-Chlorophenyl)-1-methylpropyl]-2,2-dimethyl-1,3-
dioxane-4,6-dione (2b)
Yield: 68%; white solid; mp 92–97 °C; [a]D30 –12.1 (c 2.8, CH2Cl2).
1H NMR (CDCl3, 300 MHz): d = 7.33 (dt, J = 7.7, 1.8 Hz, 1 H),
7.08–6.99 (m, 2 H), 6.88 (d, J = 8.3 Hz, 1 H), 3.74 (s, 3 H), 3.36 (dq,
J = 12.9, 7.4 Hz, 1 H), 2.85 (dq, J = 12.8, 7.6 Hz, 1 H), 1.86 (s, 3
H), 1.73 (s, 3 H), 1.02 (t, J = 7.5 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 174.0, 161.2, 160.4, 154.2, 130.0,
129.0, 127.3, 120.7, 118.0, 110.8, 103.9, 55.2, 30.7, 27.6, 26.4,
11.8.
An enantiomeric excess of 90% S was measured by chiral HPLC
[AD-H, 1% i-PrOH–hexanes with 0.1% TFA, 1.0 mL/min,
tR1 = 20.4 min (S), tR2 = 25.6 min (R)].
1H NMR (CDCl3, 300 MHz): d = 7.29 (d, J = 8.7 Hz, 2 H), 7.20 (d,
J = 8.7 Hz, 2 H), 3.60 (s, 1 H), 2.10 (q, J = 7.3 Hz, 2 H), 1.63 (s, 3
H), 1.58 (s, 3 H), 1.33 (s, 3 H), 0.72 (t, J = 7.3 Hz, 3 H).
HRMS (EI): m/z calcd for C16H18O5 (M+): 290.1154; found:
290.1163.
13C NMR (CDCl3, 75 MHz): d = 164.3, 163.8, 141.2, 132.8, 128.4,
128.3, 105.1, 57.0, 45.7, 32.7, 29.1, 27.4, 21.4, 8.6.
HRMS (EI): m/z calcd for C16H19ClO4 (M+): 310.0972; found:
310.0975.
2,2-Dimethyl-5-[1-(naphthalen-2-yl)propylidene]-1,3-dioxane-
4,6-dione (1k)
Yield: 14%; light yellow solid; mp 123–125 °C (MeOH).
Synthesis 2009, No. 12, 2066–2072 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conjugate Addition of Me2Zn to 5-(1-Arylalkylidene) Meldrum’s Acids
2071
(S)-2,2-Dimethyl-5-(2-phenylbutan-2-yl)-1,3-dioxane-4,6-dione
(2c)
(S)-5-[2-(4-Methoxyphenyl)butan-2-yl]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (2h)
Yield: 93%; white solid; mp 90–94 °C; [a]D25 –0.32 (c 4.8, CH2Cl2).
Yield: 93%; clear oil; [a]D23.5 +0.11 (c 5.5, CH2Cl2).
An enantiomeric excess of 76% S was measured by chiral HPLC
[AD-H, 1% i-PrOH–hexanes with 0.1% TFA, 1.0 mL/min,
tR1 = 15.5 min (S), tR2 = 20.3 min (R)].
An enantiomeric excess of 85% S was measured by chiral HPLC
[AD-H, 10% i-PrOH–hexanes, 1.0 mL/min, tR1 = 8.0 min (S),
t
R2 = 8.7 min (R)].
1H NMR (CDCl3, 300 MHz): d = 7.36–7.21 (m, 5 H), 3.64 (s, 1 H),
2.22 (dq, J = 7.2, 7.0, Hz 1 H), 2.11 (dq, J = 7.1, 7.0 Hz, 1 H), 1.64
(s, 3 H), 1.61 (s, 3 H), 1.19 (s, 3 H), 0.78 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 164.4, 163.9, 142.2, 128.2, 126.8,
126.7, 105.0, 57.0, 46.0, 32.5, 29.2, 27.0, 21.6, 8.6.
1H NMR (CDCl3, 300 MHz): d = 7.18 (d, J = 8.9 Hz, 2 H), 6.83 (d,
J = 8.9 Hz, 2 H), 3.76 (s, 3 H), 3.50 (s, 1 H), 2.15 (dq, J = 14.2, 7.3
Hz, 1 H), 2.05 (dq, J = 14.1, 7.2 Hz, 1 H), 1.57 (s, 3 H), 1.56 (s, 3
H), 1.16 (s, 3 H), 0.76 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 164.7, 164.2, 158.4, 133.9, 128.1,
113.6, 105.2, 57.3, 55.2, 46.0, 32.7, 29.6, 27.1, 22.3, 8.7.
HRMS (EI): m/z calcd for C17H22O5 (M+): 306.1467; found:
HRMS (EI): m/z calcd for C16H20O4 (M+): 276.1362; found:
276.1367.
306.1475.
(S)-2,2-Dimethyl-5-[1-methyl-1-(4-methylphenyl)propyl]-1,3-
dioxane-4,6-dione (2d)
Yield: 85%; white solid; mp 90–94 °C; [a]D
CH2Cl2).
(S)-5-[2-(3-Methoxyphenyl)butan-2-yl]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (2i)
26.5
+0.15 (c 4.4,
Yield: 79%; clear oil; [a]D25 –0.38 (c 4.8, CH2Cl2).
An enantiomeric excess of 83% S was measured by chiral HPLC
[AD-H, 1% i-PrOH–hexanes with 0.1% TFA, 1.0 mL/min,
tR1 = 15.3 min (S), tR2 = 19.1 min (R)].
An enantiomeric excess of 69% S was measured by chiral HPLC
[AD-H, 10% i-PrOH–hexanes, 1.0 mL/min, tR1 = 7.2 min (S),
tR2 = 8.4 min (R)].
1H NMR (CDCl3, 300 MHz): d = 7.17 (d, J = 13.8 Hz, 2 H), 7.12 (d,
J = 13.8 Hz, 2 H), 3.55 (s, 1 H), 2.29 (s, 3 H), 2.17 (dq, J = 14.2, 7.2
Hz, 1 H), 2.06 (dq, J = 14.1, 7.2 Hz, 1 H), 1.58 (s, 6 H), 1.17 (s, 3
H), 0.75 (t, J = 7.3 Hz, 3 H).
1H NMR (CDCl3, 300 MHz): d = 7.21 (t, J = 8.1 Hz, 1 H), 6.85 (d,
J = 8.0 Hz, 1 H), 6.80 (br s, 1 H), 6.74 (dd, J = 8.1, 2.1 Hz, 1 H),
3.75 (s, 3 H), 3.60 (s, 1 H), 2.09 (dq, J = 18.5, 7.1 Hz, 2 H), 1.59 (s,
3 H), 1.57 (s, 3 H), 1.23 (s, 3 H), 0.73 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 164.7, 164.2, 139.1, 136.5, 129.0,
126.8, 105.2, 57.2, 46.1, 32.7, 29.5, 27.1, 22.0, 20.8, 8.7.
HRMS (EI): m/z calcd for C17H22O4 (M+): 290.1518; found:
290.1515.
13C NMR (CDCl3, 75 MHz): d = 164.4, 163.8, 159.5, 144.1, 129.1,
119.1, 113.4, 111.4, 105.0, 56.9, 55.1, 46.0, 32.7, 29.1, 27.2, 21.5,
8.6.
HRMS (EI): m/z calcd for C17H22O5 (M+): 306.1467; found:
306.1471.
(S)-5-[2-(4-tert-Butylphenyl)butan-2-yl]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (2f)
Yield: 84%; white solid; mp 100–103 °C; [a]D +3.2 (c 2.8,
CH2Cl2).
‘Reverse’ Asymmetric 1,4-Conjugate Addition of Me2Zn to
Alkylidene Meldrum’s Acids 1e,k,l; General Procedure C
Reactions were typically carried out using 0.4 mmol of substrate. In
a glove box, copper source (5 mol%) and phosphoramidite chiral
ligand (10 mol%) were added to a flame-dried flask equipped with
a stir bar. DME (0.4 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 r.t. for 30 min, outside the glove box, and then
cooled to –40 °C. In the dry box, Me2Zn solution (2.0 equiv) was
transferred to a round-bottomed flask equipped with a septum.
Me2Zn solution was added to the mixture at –40 °C. After stirring
for 5 min, the resulting mixture was added to a –40 °C, pre-cooled
Schlenk tube charged with alkylidene Meldrum’s acid 1e,k,l (1.0
equiv) in DME (0.2 mL) dropwise via a syringe. DME (0.2 mL) was
used to wash the flask and transfer remaining residue into the
Schlenk tube. The mixture was allowed to warm up slowly to r.t.
After stirring for 48 h, the mixture was cooled to 0 °C, 5% aq HCl
(5 mL) and EtOAc (20 mL) were added to the mixture. The layers
were partitioned and the aqueous layer was extracted with EtOAc (3
ꢀ 20 mL). The combined organic layers were washed with brine (20
mL), dried (MgSO4), filtered, and concentrated. The crude residue
was purified by flash column chromatography on silica gel using
hexanes in EtOAc as eluent to yield the desired product. HPLC us-
ing a chiral column (OD-H or AD-H) was used to measure the enan-
tiomeric ratio of the products.
31
An enantiomeric excess of 97% S was measured by chiral HPLC
[AD-H, 1% i-PrOH–hexanes with 0.1% TFA, 1.0 mL/min,
tR1 = 11.7 min (S), tR2 = 14.3 min (R)].
1H NMR (CDCl3, 300 MHz): d = 7.32 (d, J = 8.6 Hz, 2 H), 7.20 (d,
J = 8.6 Hz, 2 H), 3.49 (s, 1 H), 2.25 (dq, J = 14.1, 7.2 Hz, 1 H), 2.13
(dq, J = 14.1, 7.1 Hz, 1 H), 1.61 (s, 3 H), 1.54 (s, 3 H), 1.26 (s, 9 H),
0.96 (s, 3 H), 0.82 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 164.7, 164.3, 150.0, 138.6, 126.7,
125.3, 105.4, 57.1, 46.2, 34.3, 32.4, 31.2, 29.8, 26.7, 22.5, 8.8.
HRMS (EI): m/z calcd for C20H28O4 (M+): 332.1988; found:
332.1996.
(S)-5-[1-(4-Bromophenyl)-1-methylpropyl]-2,2-dimethyl-1,3-
dioxane-4,6-dione (2g)
Yield: 68%; white solid; mp 84–85 °C; [a]D
CH2Cl2).
27.5
–10.8 (c 2.4,
An enantiomeric excess of 91% S was measured by chiral HPLC
[AD-H, 1% i-PrOH–hexanes with 0.1% TFA, 1.0 mL/min,
tR1 = 21.7 min (S), tR2 = 27.7 min (R)].
1H NMR (CDCl3, 300 MHz): d = 7.44 (d, J = 8.5 Hz, 2 H), 7.14 (d,
J = 8.5 Hz, 2 H), 3.60 (s, 1 H), 2.10 (q, J = 7.3 Hz, 2 H), 1.63 (s, 3
H), 1.57 (s, 3 H), 1.34 (s, 3 H), 0.72 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 164.2, 163.8, 141.8, 131.4, 128.6,
120.9, 105.1, 56.9, 45.7, 32.7, 29.0, 27.5, 21.3, 8.6.
HRMS (EI): m/z calcd for C16H19BrO4 (M+): 354.0467; found:
354.0470.
(S)-5-[2-(4-Isopropylphenyl)butan-2-yl]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (2e)
Yield: 99%; white solid; mp 80–82 °C; [a]D29 +5.8 (c 4.8, CH2Cl2).
An enantiomeric excess of 94% R was measured by chiral HPLC
[AD-H, 1% i-PrOH–hexanes with 0.1% TFA, 1.0 mL/min,
tR1 = 11.4 min (S), tR2 = 13.6 min (R)].
Synthesis 2009, No. 12, 2066–2072 © Thieme Stuttgart · New York

2072
A. Wilsily et al.
SPECIAL TOPIC
1H NMR (CDCl3, 300 MHz): d = 7.19 (d, J = 8.6 Hz, 2 H), 7.15 (d,
J = 8.7 Hz, 2 H), 3.50 (s, 1 H), 2.85 (sept, J = 6.9 Hz, 1 H), 2.24 (dq,
J = 14.3, 7.2 Hz, 1 H), 2.12 (dq, J = 14.1, 7.2 Hz, 1 H), 1.60 (s, 3 H),
1.54 (s, 3 H), 1.19 (d, J = 6.9 Hz, 6 H), 0.80 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 164.7, 164.2, 147.6, 139.0, 126.9,
126.4, 105.3, 57.1, 46.2, 33.5, 32.5, 29.7, 26.8, 23.8, 22.4, 8.8.
(2) For reviews, see: (a) Thaler, T.; Knochel, P. Angew. Chem.
Int. Ed. 2009, 48, 645. (b) Alexakis, A.; Vuagnoux-
d’Augustin, M.; Martin, D.; Kehrli, S.; Palais, L.; Hénon, H.;
Hawner, C. Chimia 2008, 62, 461. (c) Cozzi, P. G.; Hilgraf,
R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969.
(d) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle, M.
Synthesis 2007, 1279.
HRMS (EI): m/z calcd for C19H26O4 (M+): 318.1831; found:
(3) Alexakis’ group: (a) Henon, H.; Mauduit, M.; Alexakis, A.
Angew. Chem. Int. Ed. 2008, 47, 9122. (b) Hawner, C.; Li,
K.; Cirriez, V.; Alexakis, A. Angew. Chem. Int. Ed. 2008, 47,
8211. (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. (d) Vuagnoux-d’Augustin, M.; Kehrli, S.;
Alexakis, A. Synlett 2007, 2057. (e) Vuagnoux-d’Augustin,
M.; Alexakis, A. Chem. Eur. J. 2007, 13, 9647. (f) Martin,
D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.;
Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416. (g) Fuchs,
N.; d’Augustin, M.; Humam, M.; Alexakis, A.; Taras, R.;
Gladiali, S. Tetrahedron: Asymmetry 2005, 16, 3143.
(h) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem.
Int. Ed. 2005, 44, 1376. Hoveyda’s group: (i) May, T. L.;
Brown, M. K.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2008,
47, 7358. (j) Brown, M. K.; Hoveyda, A. H. J. Am. Chem.
Soc. 2008, 130, 12904. (k) Brown, M. K.; May, T. L.;
Baxter, C. A.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2007,
46, 1097. (l) Lee, K.; Brown, M. K.; Hird, A. W.; Hoveyda,
A. H. J. Am. Chem. Soc. 2006, 128, 7182. (m) Hird, A. W.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 14988.
(n) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem.
Soc. 2005, 127, 4584. Tomioka’s group: (o) Matsumoto,
Y.; Yamada, K.; Tomioka, K. J. Org. Chem. 2008, 73, 4578.
(4) (a) Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801.
(b) Fillion, E.; Wilsily, A.; Liao, E-T. Tetrahedron:
Asymmetry 2006, 17, 2957. (c) Fillion, E.; Wilsily, A. J. Am.
Chem. Soc. 2006, 128, 2774.
318.1832.
(S)-2,2-Dimethyl-5-[1-methyl-1-(2-naphthyl)propyl]-1,3-diox-
ane-4,6-dione (2k)
Yield: 82%; beige solid; mp 132–134 °C; [a]D –4.8 (c 2.7,
CH2Cl2).
31
An enantiomeric excess of 79% S was measured by chiral HPLC
[AD-H, 1% i-PrOH–hexanes with 0.1% TFA, 1.0 mL/min,
tR1 = 26.0 min (S), tR2 = 39.1 min (R)].
1H NMR (CDCl3, 300 MHz): d = 7.81–7.78 (m, 3 H), 7.70 (s, 1 H),
7.46–7.41 (m, 3 H), 3.71 (s, 1 H), 2.29 (dq, J = 14.2, 7.4 Hz, 1 H),
2.17 (dq, J = 14.1, 7.2 Hz, 1 H), 1.72 (s, 3 H), 1.59 (s, 3 H), 1.14 (s,
3 H), 0.75 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 125 MHz): d = 164.7, 164.1, 139.7, 133.1, 132.1,
128.2, 127.9, 127.3, 126.1 (2C), 126.0, 124.6, 105.2, 57.2, 46.5,
32.8, 29.4, 27.2, 21.7, 8.8.
HRMS (EI): m/z calcd for C20H22O4 (M+): 326.1518; found:
326.1519.
(S)-2,2-Dimethyl-5-[2-(1-tosyl-1H-pyrrol-3-yl)butan-2-yl]-1,3-
dioxane-4,6-dione (2l)
Yield: 93%; clear oil; [a]D30.5 +18.4 (c 1.5, CH2Cl2).
An enantiomeric excess of 97% S was measured by chiral HPLC
[AD-H, 10% i-PrOH–hexanes, 1.0 mL/min, tR1 = 16.7 min (S),
tR2 = 18.2 min (R)].
1H NMR (CDCl3, 300 MHz): d = 7.69 (d, J = 8.3 Hz, 2 H), 7.26 (d,
J = 8.2 Hz, 2 H), 7.05–7.03 (m, 1 H), 6.96 (t, J = 1.9 Hz, 1 H), 6.16
(dd, J = 3.2, 1.8 Hz, 1 H), 3.37 (s, 1 H), 2.37 (s, 3 H), 2.01 (dq,
J = 14.0, 7.2 Hz, 1 H), 1.85 (dq, J = 14.1, 7.2 Hz, 1 H), 1.52 (s, 3 H),
1.44 (s, 3 H), 1.01 (s, 3 H), 0.80 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 164.6, 164.2, 144.9, 136.0, 131.5,
129.9, 126.8, 120.8, 118.6, 113.1, 105.2, 55.9, 42.6, 32.8, 29.7,
26.8, 22.9, 21.5, 8.6.
HRMS (EI): m/z calcd for C21H25NO6S (M+): 419.1403; found:
419.1401.
(5) (a) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc.
2006, 128, 5628. (b) Mauleón, P.; Carretero, J. C. Chem.
Commun. 2005, 4961.
(6) For enantioselective conjugate additions to alkylidene
Meldrum’s acid acceptors leading to tertiary stereocenters,
see: (a) Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E.
M. J. Am. Chem. Soc. 2005, 127, 9682. (b) Watanabe, T.;
Knöpfel, T. F.; Carreira, E. M. Org. Lett. 2003, 5, 4557.
(7) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(b) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.;
de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36,
2620.
Acknowledgment
(8) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am.
Chem. Soc. 2002, 124, 5262.
This work was supported by the Merck Frosst Centre for Therapeu-
tic Research, the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Canadian Foundation for Innova-
tion, the Ontario Innovation Trust, and the University of Waterloo.
A.W. is indebted to NSERC for CGS-M and CGS-D scholarships.
T. L. thanks NSERC for NSERC-USRA.
(9) The absolute stereochemistry of 2 was opposite to the one
observed for the addition of Et2Zn to 2,2-dimethyl-5-(1-
arylethylidene)-1,3-dioxane-4,6-dione, see reference 4c.
(10) Rimkus, A.; Sewald, N. Org. Lett. 2003, 5, 79.
(11) (a) Brown, R. F. C.; Coulston, K. J.; Eastwood, F. W.;
Gatehouse, B. M.; Guddatt, L. W.; Pfenninger, M.;
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References
(1) For reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006,
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