Novel Cinchona alkaloid derived ammonium salts as catalysts for the asymmetric synthesis of β-hydroxy α-amino acids via aldol reactions

Article abstract of DOI:10.1016/j.tetlet.2007.01.132

Using the cinchonidine-derived phase-transfer catalyst developed by Park and Jew as a lead structure, we have prepared novel chiral ammonium salts and investigated their efficacy for the preparation of β-hydroxy α-amino acids via asymmetric aldol reaction

Full text of DOI:10.1016/j.tetlet.2007.01.132

Tetrahedron Letters 48 (2007) 2083–2086
Novel Cinchona alkaloid derived ammonium salts as
catalysts for the asymmetric synthesis of b-hydroxy
a-amino acids via aldol reactions
Bing Ma, Jared L. Parkinson and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA
Received 7 December 2006; revised 18 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—Using the cinchonidine-derived phase-transfer catalyst developed by Park and Jew as a lead structure, we have prepared
novel chiral ammonium salts and investigated their efficacy for the preparation of b-hydroxy a-amino acids via asymmetric aldol
reactions. The modifications were performed at C3 of the cinchonidine nucleus and include dimers as well as catalysts possessing
electron-deficient alkyne and alkene moieties. Some of the new catalysts yielded improvements relative to the Park–Jew catalyst
in the aldol reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
Quaternary ammonium salts derived from inexpensive
and readily available Cinchona alkaloids have shown
great utility as chiral phase-transfer catalysts, particu-
larly in asymmetric alkylations.1 Recently, we examined
the viability of these catalysts for the synthesis of b-
hydroxy a-amino acids via aldol reactions, a topic first
explored by Miller and Gasparski.2,3 We discovered that
the N-2,3,4-trifluorobenzyl-substituted hydrocinchoni-
dine derivative of Park and Jew4 afforded protected
b-hydroxy a-amino acids in good yields under homo-
genous conditions in conjunction with the phospha-
zene base tert-butyliminotri(pyrrolidino)-phosphorane
(BTTP, Scheme 1).5 Although the syn diastereomers
were obtained in good ee, the reaction exhibited negli-
gible diastereoselectivity. In an attempt to improve the
selectivity of the aldol reaction, we designed novel
cinchonidine-based monomeric and dimeric quaternary
ammonium salts that retain the 2,3,4-trifluorobenzyl
group of the Park–Jew catalyst. In this Letter, we report
the synthesis of these catalysts as well as their perfor-
mance in the aldol reaction.
We viewed the C3-vinyl group of cinchonidine as a
potential handle for the construction of new catalysts.
Modifications of this functional group such as dehydro-
genation,6 hydroformylation,7 and oxidative cleavage8
are known; however, to the best of our knowledge, none
of these protocols have been incorporated into the syn-
thesis of quaternary ammonium salt catalysts. Hoffmann
and Frackenpohl recently reported that C3-ethynyl Cin-
chona alkaloids are significantly more basic and polar
than the parent compounds, thereby demonstrating that
this functional group, although remote from the nitro-
gen, has a profound effect on its properties.9 Accord-
ingly, we were optimistic that the catalytic abilities of
cinchonidine-derived ammonium salts could be tuned
via appropriate modifications of the C3-vinyl group. In
an attempt to develop catalysts capable of forming tight
ion pairs with enolates, we targeted ammonium salts
with electron-deficient substituents at this site.
1. Park–Jew catalyst
BTTP
OH
tol–CHCl3 7:3
–50 °C, 1 h
Ph
Ph
CO2
t
-Bu
R
+
N
HN
Ph
RCHO
2. 0.25 N HCl, THF
CO2t-Bu
3. NaHCO3, PhCOCl
O
34–78% over 3 steps syn: 50–83% ee
anti: 6–60% ee
syn:anti = 1–1.3:1
Scheme 1. Asymmetric aldol reaction mediated by Park–Jew catalyst.
Keywords: Cinchona alkaloids; b-Hydroxy a-amino acids; Sonogashira
coupling; Heck reaction; Asymmetric aldol reaction.
The preparation of C3-alkynyl ammonium salts 3a–d
possessing fluorinated and trifluoromethylated aryl
groups is summarized in Table 1. We employed
*
Corresponding author. Tel.: +1 801 422 1780; fax: +1 801 422
0153; e-mail: scastle@chem.byu.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.132

2084
B. Ma et al. / Tetrahedron Letters 48 (2007) 2083–2086
Table 1. Synthesis of C3-alkynyl ammonium salts 3a–d
coupling of 4 with nitroaryl iodides, we found that the
highest yields were obtained by employing TBAF as
base11 under aqueous conditions. We were unable to ob-
tain 3,4-dinitrophenyl-substituted salt 3g in good yield;
nevertheless, enough of this compound was produced
to examine its viability as a catalyst in the asymmetric
aldol reaction.
Ar
Ar-I, CuI (5 mol %)
Pd(PPh3)4 (2.5 mol %)
i
-Pr2NEt
N
N
H2O, 90 C, 3.5 h
°
OH
OH
N
N
1
2
C3-Alkenyl-substituted chiral ammonium salts 8 bear-
ing fluorinated aryl groups were assembled as illustrated
in Scheme 2, with a Heck reaction as the key step. Per-
forming the Heck reaction after the N-benzylation and
before the O-allylation delivered optimal results. The
previously developed conditions were satisfactory for
the benzylation and allylation steps, and PdCl2/Et3N
was found to be the best system for the Heck coupling
of ammonium salt 6 with fluorinated aryl iodides.
Ar
Br–
1. 2,3,4-trifluorobenzyl bromide
acetone–EtOH 1:1, rt, 16 h
N+
F
F
F
2. K2CO3, allyl bromide
acetone, rt, 16 h
O
N
3
Compound
Ar
Yield of 2 (%)
Yield of 3 (%)
In addition to the catalysts bearing electron-deficient
groups at C3, we were interested in constructing dimeric
catalysts linked through a C3 alkyne. Although dimeric
cinchonidine-derived chiral phase-transfer catalysts are
known, all previous examples of which we are aware in-
volve dimerization via an N-benzyl or N-alkyl group.12
Thus, we decided to prepare a novel class of dimeric chi-
ral ammonium salt catalysts. The synthesis of these cat-
alysts is shown in Scheme 3. The previously constructed
alkyne 4 could be dimerized in an Eglinton coupling,13
affording diyne 9 in good yield. We initially attempted
to prepare phenyl-linked dimer 10a and biphenyl-linked
dimer 10b in a single Sonogashira coupling employing
2 equiv of 4 and the appropriate aryl di-iodide. How-
ever, this approach was unsuccessful, so we performed
two sequential couplings instead. The second reaction
required increased loadings of the palladium and copper
catalysts, and the products were obtained in modest
yields. Each of the bis-ammonium salts 9 and 10 was
extremely polar, requiring pure CH3OH for elution
from a silica gel column.
3a
3b
3c
3d
p-CF3C6H4
p-FC6H4
3,4-F2C6H3
2,4-F2C6H3
96
93
92
87
52
15
64
71
10,11-didehydrocinchonidine (1)6a as our starting mate-
rial, and after considerable experimentation discovered
that the aqueous Sonogashira coupling conditions of
Bhattacharya and Sengupta10 were optimal for the prep-
aration of arylated compounds 2. Then, N-benzylation
followed by O-allylation afforded the target compounds
in good yield, with the exception of p-fluorophenyl-
substituted salt 3b. In all cases, benzylation provided
the quaternary ammonium salt in essentially quantita-
tive yield without the need for further purification.
Thus, the variability in the yields of 3 was a consequence
of the O-allylation. Attempts to optimize the allylation
in the synthesis of 3b were unsuccessful.
Unfortunately, despite examining numerous conditions,
we were unable to perform the O-allylation on sub-
strates possessing nitroaryl groups. Consequently, the
order of steps was changed, and the Sonogashira cou-
pling was performed last in the construction of nitro-
containing catalysts 3e–g (Table 2). Benzylation and
allylation of 1 proceeded under the same conditions
shown in Table 1 for Sonogashira adduct 2, affording
quaternary ammonium salt 4 in a 79% yield. For the
Catalysts 3a–g, 8a–b, 9, and 10a–b were evaluated in the
aldol reaction between hydrocinnamaldehyde (11) and
tert-butyl glycinate benzophenone imine (12). The re-
sults of this investigation are contained in Table 3. For
purposes of comparison, the Park–Jew catalyst mediates
Br–
N
-benzylation
96%
F
N
N+
Table 2. Synthesis of C3-alkynyl ammonium salts 3e–g
F
F
OH
OH
N
N
Ar-I, CuI
Pd(PPh3)4
Br–
5
6
Ar
N+
TBAF
1.
N
-benyzlation
F
3
1
Ar-I, Et3N
PdCl2 (8 mol %)
Br–
F
F
2.
79% overall
O-allylation
H2O, 90
3.5 h
°C
N+
O
a: Ar =
b: Ar = 2,4-F2C6H3
p
-FC6H4
F
N
F
F
DMF, 100 °C
63% for 7a
51% for 7b
OR
4
N
Compound
Ar
Yield of 3 (%)
O
-allylation
7a,b: R = H
8a,b: R = allyl
59% for 8a
38% for 8b
3e
3f
p-NO2C6H4
4-F-2-NO2C6H3
3,4-(NO2)2C6H3
54
60
22
3g
Scheme 2. Synthesis of C3-alkenyl ammonium salts 8a and 8b.

B. Ma et al. / Tetrahedron Letters 48 (2007) 2083–2086
2085
mers are obtained with 80% and 33% ee, respectively.5
Ammonium salt 3d possessing a 2,4-difluorophenyl-
substituted alkyne afforded the best ee’s of any of our
new catalysts; unfortunately, the diastereoselectivity
was both modest and reversed, with the major anti iso-
mer having low ee. In fact, anti-13 was produced in
low ee by all of the catalysts examined. p-Fluorophen-
yl-substituted alkyne catalyst 3b was able to improve
the diastereoselectivity of the reaction (2.6:1 dr in favor
of the syn isomer), but no enhancement of ee’s was ob-
served. Comparison of the results obtained with 3b and
3d shows that the presence or absence of an ortho fluoro
substituent exerts a significant effect on the aldol reac-
tion. While the underlying reasons for this effect are un-
clear, it is possible that aromatic F Á Á Á H interactions14
could be involved. Catalyst 3a, which bears a p-trifluo-
romethyl-substituted phenyl group on the alkyne, affor-
ded the aldol products in very good yield (86%);
however, the dr and ee’s were similar to those delivered
by the Park–Jew catalyst. Z-Alkene-containing catalysts
8a and 8b performed more poorly than did their alkyne
analogues 3b and 3d, indicating that the geometry of the
C3-substituent plays an important role in catalyst
efficiency.
F
F
N
F
O
N+
H
Br–
Cu(OAc)2
H
4
H
pyr, rt
89%
Br–
N+
H
O
N
F
F
F
9
F
F
N
F
O
N+
H
Br–
1. I-X-I (2 equiv), CuI (18 mol %)
Pd(PPh3)4 (9 mol %)
TBAF, THF, reflux, 30 min
H
X
4
H
2. 4 (2 equiv), CuI (40 mol %)
Pd(PPh3)4 (20 mol %)
TBAF, THF, reflux, 30 min
Br–
N+
H
Dimeric catalysts 9 and 10a–b were insoluble in the
toluene–chloroform solvent system used for most of
the aldol reactions.15 Thus, reactions employing these
compounds were performed in CH2Cl2. Inspection of
the results obtained with the dimers reveals that the phe-
nyl group serves as the optimal spacer between the two
catalyst units (cf. 10a vs 9 and 10b). Nevertheless, none
of the dimeric ammonium salts performed better than
the Park–Jew catalyst in the aldol reaction.
10a: X =
10b: X =
O
N
F
F
F
10a (35% for 1., 39% for 2.)
10b (56% for 1., 24% for 2.)
Scheme 3. Synthesis of dimeric ammonium salts 9 and 10.
Table 3. Survey of catalysts in asymmetric aldol reaction
In conclusion, we have synthesized novel monomeric
and dimeric cinchonidine-derived chiral ammonium
salts and examined their efficiency in the construction
of b-hydroxy a-amino acids via asymmetric aldol reac-
tions.16 We have discovered individual catalysts which
improve upon the performance of the Park–Jew catalyst
in terms of yield (3a), syn/anti ratio (3b), and ee (3d). We
have yet to find a single catalyst which performs well in
all three areas. Currently, the biggest limitation of this
method is the modest diastereoselectivity. Since asym-
metric alkylations of 12 mediated by cinchonidine-
derived phase-transfer catalysts typically proceed with
excellent ee, the problem is likely due to low facial selec-
tivity of the aldehyde. The methods developed in this
study for functionalization of the Cinchona alkaloid
scaffold (Sonogashira coupling, Heck reaction) should
prove useful to others interested in modifying this class
of alkaloids.
1. cat. (0.17 equiv)
BTTP (2.5 equiv)
tol–CHCl3 7:3
–50 °C, 1 h
Ph
Ph
Ph
O
OH
+
O
N
2. 0.25 N HCl, THF
CO2t-Bu
3. NaHCO3, PhCOCl
Ph
Ph
N
CO2t-Bu
H
11
12
13
Catalyst
Yield (%)
syn/anti
syn eeb (%)
anti eeb (%)
3a
3b
86
54
40
50
76
57
40
76
50
38
38
57
57
50
1.2:1
2.6:1
1.5:1
1:1.8
1.3:1
1:4.7
1:1.1
1:3.7
1:2.2
1:1.5
1.1:1
1:1.3
1.1:1
1:1.2
82
82
79
91
83
20
61
13
25
51
65
43
85
74
39
36
30
44
34
5
8
3
9
3
3c
3d
3e
3f
3fa
3g
3ga
8a
8b
9a
10aa
10ba
14
2
38
23
Acknowledgments
a CH2Cl2 was used as the solvent.
We thank the National Institutes of Health (GM70483)
and Brigham Young University (Graduate Studies Fel-
lowship to B.M., Undergraduate Research Awards to
J.L.P.) for financial support of this work. We also thank
Dr. Jens Frackenpohl for helpful comments concerning
the synthesis and purification of 1.
b Measured by HPLC (Chiralcel OD–H, 98:2 hexanes–i-PrOH, 1 mL/
min).
the reaction between 11 and 12 to afford a 64% yield of
13 with a syn/anti ratio of 1.3:1. The syn and anti iso-

2086
B. Ma et al. / Tetrahedron Letters 48 (2007) 2083–2086
Acta 2000, 83, 777; (b) Frackenpohl, J.; Braje, W. M.;
Supplementary data
Hoffmann, H. M. R. J. Chem. Soc., Perkin Trans. 1
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Tetrahedron Lett. 2004, 45, 4697.
Experimental procedures and characterization data for
compounds 3 and 8–10 are available. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.01.132.
9. Hoffman, H. M. R.; Frackenpohl, J. Eur. J. Org. Chem.
2004, 4293.
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phase-transfer-catalyzed alkylations, see Refs. 4,12b.
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a-amino acids, see: (a) Makino, K.; Iwasaki, M.;
Hamada, Y. Org. Lett. 2006, 8, 4573; (b) Crich, D.;
Banerjee, A. J. Org. Chem. 2006, 71, 7106. Please see
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strategies employed in the asymmetric synthesis of these
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