Phase-transfer catalyzed glycolate conjugate addition

Article abstract of DOI:10.1016/j.tetlet.2007.11.071

Cinchonine based phase-transfer catalysts were developed for enantioselective conjugate additions to electron deficient alkenes, including acylates, acrylonitrile, and chalcone. N-Trifulorobenzyl cinchoninium bromide 6 catalyst (20 mol %) in THF at -40 °C promoted the conjugate addition of arylketone glycolate 1 generating S-product 2 in good yields and selectivities. Catalyst, solvent, and base variations are presented along with conditions to convert the products to intermediates useful for multistep applications.

Full text of DOI:10.1016/j.tetlet.2007.11.071

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Tetrahedron Letters 49 (2008) 534–537
Phase-transfer catalyzed glycolate conjugate addition
Merritt B. Andrus* and Zhifeng Ye
Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, UT 84602, United States
Received 10 October 2007; revised 8 November 2007; accepted 13 November 2007
Available online 19 November 2007
Abstract—Cinchonine based phase-transfer catalysts were developed for enantioselective conjugate additions to electron deficient
alkenes, including acylates, acrylonitrile, and chalcone. N-Trifulorobenzyl cinchoninium bromide 6 catalyst (20 mol %) in THF
at À40 °C promoted the conjugate addition of arylketone glycolate 1 generating S-product 2 in good yields and selectivities. Cata-
lyst, solvent, and base variations are presented along with conditions to convert the products to intermediates useful for multistep
applications.
Ó 2007 Published by Elsevier Ltd.
Phase-transfer catalysis (PTC) has become a practical
method for asymmetric synthesis.1 The process is partic-
ularly attractive using benzophenone protected glycine
for alkylation, conjugate addition, and epoxide forma-
tion.2 PTC provides numerous benefits including the
use of inexpensive cinchona-derived catalysts, which
are readily available in pseudo-enantiomeric antipodes,
the use of simple hydroxide bases, and mild conditions
performed in either liquid–liquid or liquid–solid mode
over an extended temperature range. The formation of
C–C bonds through a direct alkylation is a significant
synthetic challenge with only a few successes based on
catalytic methods.3 We previously reported PTC condi-
tions for alkylations using diphenylmethyl (DPM) aryl-
ketone 1 to give S-products 2 with alkyl halides (Scheme
1).3c,4 Optimal catalysts in this case proved to be the
cinchonidine (CD) derived ammonium bromides 3 and
4, previously developed by Corey, Lygo, and the group
of Park and Jew.5 The protected products 2 in this case
are readily transformed to the corresponding hydroxyes-
ter intermediate. The new glycolate approach was
applied to the synthesis of the diabetes drug ragaglitazar
and the farnesyltransferase inhibitor kurasoin A.4 This
substrate has also been developed for asymmetric PTC
aldol reactions where the cinchonine (CN) based cata-
lysts 5 and 6 were shown to be most effective to generate
protected 1,2-diol products.6 We now report the devel-
opment of a novel asymmetric PTC Michael-type conju-
gate addition with the substrate arylketone 1 to access
glutaric acid derivatives, 1,5-dicarbonyl-2-hydroxy
substituted products.
Diphenylmethyl (DPM) glycolate 2,5-dimethoxyphenyl
ketone 1 was produced as before in three steps beginning
with bromoacetic acid.4 Various catalysts were initially
OMe
O
O
R*4N+
O
O
Ph
Ph
Ar
base
E+
Ph
Ph
R*4N+=
E
1
2
OMe
CD
Br-
Ar
N+
H
3
4
Ar= 9-anthracenyl
9
2,3,4-trifluorophenyl
O
N
CN
O
5
6
Ar= 9-anthracenyl
9
N+
Br-
Ar
2,3,4-trifluorophenyl
N
H
F
F
F
F
7
8
*
Corresponding author. Tel./fax: +1 801 422 8171; e-mail:
mbandrus@chem.byu.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.071

M. B. Andrus, Z. Ye / Tetrahedron Letters 49 (2008) 534–537
535
Table 1. Conditions for acrylate conjugate PTC
Table 2. Substrate variations for conjugate PTC
R*4N+Br- 10 mol %
O
O
O
O
O
5 20 mol %
O
1
P
CsOH•H2O
CsOH•H2O
DPMO
PO
MeO
Ar
MeO
Ar
Ar
Ar
O
O
-40
˚
THF 0.3M
-40 °C
1
DPMO
PO
2
S-
2
S-
OMe
OMe
Ar=2,5-(MeO)2Ph
Entry
Ar
Ph
4-MeOPh
2-MeOPh
2,4-(MeO)2Ph
2,5-(MeO)2Ph
2,5-(MeO)2Ph
2,5-(MeO)2Ph
2,5-(MeO)2Ph
Time (h)
% Yield
% ee
Entry
Solvent
Cat.
Time (h)
% Yield
% ee
1
2
3
4
5
6
7
8
DPM
DPM
DPM
DPM
DPM
DPM
DPM
Bn
0.5
4.5
1.5
6
1.5
0.25
0.75
5.5
56
60
65
51
54
70
62
52
48
69
72
65
82
64a
78b
81
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
DCM/n-hex
Tol
PhCl
3
4
5
5
5
6
6
6
6
6
3
3
2
7.5
1.5
2.5
24
51
9
61
60
58
59
54
60
53
80
71
77
20
27
73
81a
82b
63
25
60
42
59
a Performed at 0 °C.
b At À20 °C.
10
THF/tol
16
a Using 20 mol % catalyst 5.
b With 20 mol % 5 at concentration of 0.3 M.
obtained, at the expense of selectivity, when the reaction
was performed at higher temperatures. When performed
at 0 °C, a yield of 70% (entry 6, 64% ee) was obtained.
After only 15 min, the starting material 1 was consumed.
At À20 °C, the reaction was complete in 45 min and a
yield of 62% (entry 7, 78% ee) was found. The influence
of the glycolate O-protecting groups was also explored.
Previous PTC alkylations with 1 showed that the com-
mon benzyl group (Bn) at this position lowered the
selectivity to 71% ee.4 In this case for conjugate addi-
tion, 1 with a Bn group in the place of DPM also gave
excellent selectivity at 81% ee (5.5 h, entry 8). Shorter
reaction times (1.5 h) prompted continued investigation
of the DPM substrate 1.
screened for reactivity using methacrylate (3.5 equiv) at
À40 °C with cesium hydroxide hydrate (5 equiv) as base
(0.2 M, Table 1). Cinchonidine (CD) derived catalysts 3,
4 proved to be highly reactive; however the selectivities
obtained were low at 20–27% ee (chiral HPLC, entries
1 and 2). THF was found to be the optimal solvent, pro-
viding for short reaction times. Cinchonine (CN) cata-
lysts 5 and 6 were found to give high selectivities, again
for S-isomer 2, used in THF. When the catalyst load
was increased to 20 mol %, N-anthracenylmethyl-5 gave
product with 82% ee and moderate yield of 54% after
only 1.5 h (entry 5). This combination of catalyst 5
proved to be optimal in this case. Other catalysts investi-
gated included C9-hydroxy and benzylated ethers, in
the place of the O-allyl substituent, in both the CD
and CN series. All were found to be inferior to CN-5
showing very low (0–10% ee) selectivities. The Maruoka
di-2-naphthylbisbinaphthyl ammonium bromide also
gave 2 with low (10% ee) selectivity.7 The more common,
less-polar PTC solvents, dichloromethane, toluene, chlo-
robenzene, and various solvent combinations required
much longer reaction times and gave product with lower
selectivities (entries 7–10). In some cases, however,
higher isolated yields of 2 were obtained.
Further improvements were found when conditions
were explored using 50% aqueous KOH as base mixed
with THF (Table 3). This combination allowed for
sub-zero temperatures, at À40 °C with improved yield
and selectivity. A 72% isolated yield was obtained with
83% ee with methacrylate (entry 1). Use of toluene or
THF/toluene (7:3) as solvent further improved the selec-
tivity to 86% ee (entries 2 and 3). Fluorinated anthr-
acenylmethyl-CN catalysts 7 and 88 were also shown
under these conditions to give high selectivities at 83%
and 79% ee (entries 4 and 5). Ethyl and t-butyl acrylate
(entries 6 and 7) gave high selectivities, 82% and 78% ee,
for conjugate addition using the THF/toluene mixture.
Acrylonitrile proved to be a problematic electrophile
giving low yields and high selectivity, as with CsOHÆ
H2O and using 50% KOH, 90% ee (entry 8). Chalcone,
with a b-phenyl substituent, also reacted to give PTC
conjugate addition products (entry 9). In this case a
2:3 mixture of syn:anti diastereomers was obtained with
73% and 27% ee, respectively. An X-ray crystal structure
was obtained in this case for the purified major anti
isomer.9
Catalyst 5 in THF was further explored with substrate
variations (Table 2). While 2,5-dimethoxyphenyl DPM
protected ketone 1 was the initial substrate, as optimized
previously for PTC alkylation, we needed to access the
effect of substrate variations on the new conjugate addi-
tion reaction. As seen previously,4 the simple phenyl
ketone 1 (entry 1) gave lower selectivity, 48% ee. The
addition of electron rich methoxy groups showed
improved yield and selectivity (entries 2–4). The more
electron rich enolate will form a tighter ion-pair with
the catalyst with accentuated van der Waals contacts
generating improved selectivity. The position of the
methoxyls in this case is also critical, as seen comparing
2,4-dimethoxy 1 (entry 4) at 65% ee for 6 h and 2,5-
dimethoxy 1 (entry 5) at 82% ee after only 1.5 h as
before shown in Table 1. Improved isolated yields were
The S-stereochemistry of the addition products 2 was
established by direct comparison to known material
(Scheme 2). The labile DPM group was removed and a
benzoate was attached to generate 9. Baeyer–Villiger
type oxidation conditions of Shibasaki,10 as employed

536
M. B. Andrus, Z. Ye / Tetrahedron Letters 49 (2008) 534–537
Table 3. Conjugate PTC with other electrophiles
O
O
1) TiCl4, DCM
-78 °C
O
O
O
O
MeO
Ar
5 20 mol %
2) BzCl, pyr.
MeO
Ar
FG
DPMO
50% KOH
DPMO
Ar
Ar
BzO
9
84%
2
E+ THF -40 °C
1
Ar=2,5-(MeO)2Ph
DPMO
2
S-
Ar=2,5-(MeO)2Ph
(TMSO)2
SnCl4, 4Å MS
Entry E+
FG
Time
%
%
O
O
1) NaOMe 76%
2) BOMCl, i-Pr2NEt
Yield ee
MeO
MeO
OAr
O
74%
BzO
72%
(+)
1
CO2Me
CO2Me
5
3
72
52
83
10
OMe
TsHN
NHTs
O
O
O
O
O
O
O
O
2
3
4
5
6
7
8
9
86a
OMe
11
OMe
OMe
OMe
OMe
OEt
BOMO
CO2Me
CO2Me
CO2Me
CO2Et
CO2t-Bu
CN
7
10
7
75
59
68
68
63
25
63f
86b
83c
79d
82b
78b
90e
73g
Scheme 2.
Acknowledgments
We are grateful for the support provided by the Ameri-
can Chemical Society Petroleum Research Fund—AC
(41552-AC1), Research Corporation, Research Oppor-
tunity Award, and Brigham Young University. We are
grateful to Professor John F. Cannon (BYU, Depart-
ment of Chemistry and Biochemistry) for X-ray data
of the anti-chalcone product 2.
6
Supplementary data
24
6
O
t-Bu
Supplementary data (NMR, HPLC, and optical rota-
tion data for all compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2007.11.071.
CN
O
PhCO, 3-Ph 19
Ph
Ph
References and notes
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d With 8 as catalyst.
e Using CsOHH2O.
f 2:3 ratio of syn, anti isomers.
g syn isomer, 27% ee for anti.
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