Asymmetric synthesis of β-hydroxy amino acids via aldol reactions catalyzed by chiral ammonium salts

Article abstract of DOI:10.1021/jo049283u

The Cinchona alkaloid derived chiral ammonium salt developed by Park and Jew functions as an effective catalyst for the synthesis of β-hydroxy α-amino acids via asymmetric aldol reactions under homogeneous conditions. The syn diastereomers are obtained in good ee, and aryl-substituted aliphatic aldehydes are the best substrates for the reaction. These results represent the highest ee's obtained to date in direct aldol reactions of glycine equivalents catalyzed by inexpensive, readily prepared chiral ammonium salts.

Full text of DOI:10.1021/jo049283u

aldehyde mediated by a chiral catalyst. In fact, Miller
has reported such a process, albeit with low ee values
(3-12%), that employs O’Donnell’s Cinchona alkaloid
derived phase-transfer catalyst.5 Furthermore, the asym-
metric synthesis of â-hydroxy amino acids via enzyme-
catalyzed aldol reactions has been disclosed; however,
these protocols suffer from limited substrate scope,
modest yields, and low diastereoselectivities in some
cases.6 Recently, Maruoka7 and Shibasaki8 have prepared
novel catalysts for direct aldol reactions of glycinate Schiff
bases with a variety of aliphatic aldehydes. Although the
Maruoka catalyst is particularly effective, providing anti-
â-hydroxy-R-amino acid derivatives in high ee (g90%),
we were intrigued with the idea of employing Cinchona
alkaloid based catalysts in these reactions due to their
low cost and ease of synthesis.9 Despite the fact that
Miller previously obtained poor enantioselectivities with
such a catalyst, we felt that the advent of newer, more
active catalysts of this type10 merited a reexamination
of this process. We now report that the trifluorobenzyl-
substituted Cinchona alkaloid derived catalyst reported
by Park and J ew (5, Figure 1)10b effectively catalyzes the
aldol reaction between a glycinate Schiff base and
aliphatic aldehydes under homogeneous conditions. Al-
though the diastereoselectivity is negligible, useful levels
of enantioselectivity (up to 83% ee) can be obtained for
the syn aldol product.
We selected hydrocinnamaldehyde (6a , Table 1) and
tert-butyl glycinate benzophenone imine (7) as the sub-
strates for testing the efficacy of catalysts 1-5 in the
asymmetric aldol reaction. In our hands, the reaction was
extremely sluggish under the biphasic conditions em-
ployed by Maruoka in the identical reaction catalyzed by
chiral ammonium salts derived from BINOL.7 Trace
amounts of aldol products were detected along with
several byproducts presumably formed by aldehyde self-
condensation.11 In contrast, use of the phosphazene base
tert-butyliminotri(pyrrolidino)phosphorane (BTTP) under
Asym m etr ic Syn th esis of â-Hyd r oxy Am in o
Acid s via Ald ol Rea ction s Ca ta lyzed by
Ch ir a l Am m on iu m Sa lts
Sashikumar Mettath, G. S. C. Srikanth,
Benjamin S. Dangerfield, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young
University, Provo, Utah 84602
scastle@chem.byu.edu
Received April 28, 2004
Abstr a ct: The Cinchona alkaloid derived chiral ammonium
salt developed by Park and J ew functions as an effective
catalyst for the synthesis of â-hydroxy R-amino acids via
asymmetric aldol reactions under homogeneous conditions.
The syn diastereomers are obtained in good ee, and aryl-
substituted aliphatic aldehydes are the best substrates for
the reaction. These results represent the highest ee’s
obtained to date in direct aldol reactions of glycine equiva-
lents catalyzed by inexpensive, readily prepared chiral
ammonium salts.
â-Hydroxy R-amino acids are constituents of several
complex bioactive peptide natural products.1 In addition,
they are useful chiral intermediates due to their ability
to undergo a variety of transformations.2 Accordingly,
several methods have been devised for their synthesis,
many of which require a stoichiometric amount of a chiral
auxiliary.3,4 A particularly attractive approach involves
the direct aldol reaction of a glycine equivalent with an
(1) (a) Boger, D. L. Med. Res. Rev. 2001, 21, 356. (b) Nicolaou, K.
C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed.
1999, 38, 2097. (c) Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.;
Wilkinson, S.; Luo, Y.; Lajoie G. A. J . Org. Chem. 1998, 63, 3631 and
references therein.
(2) (a) Misner, J . W.; Fisher, J . W.; Gardner, J . P.; Pedersen. S. W.;
Trinkle, K. L.; J ackson, B. G.; Zhang, T. Y. Tetrahedron Lett. 2003,
44, 5991. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
(c) Lotz, B. T.; Miller, M. J . J . Org. Chem. 1993, 58, 618. (d) Miller, M.
J . Acc. Chem. Res. 1986, 19, 49. (e) Pansare, S. V.; Vederas, J . C. J .
Org. Chem. 1987, 52, 4804. (f) Floyd, D. M.; Fritz, A. W.; Pluscec, J .;
Weaver, E. R.; Cimarusti, C. M. J . Org. Chem. 1982, 47, 5160.
(3) Recent chiral auxiliary or reagent-based syntheses: (a) Mac-
Millan, J . B.; Molinski, T. F. Org. Lett. 2002, 4, 1883. (b) Belokon, Y.
N.; Kochetkov, K. A.; Ikonnikov, N. S.; Strelkova, T. V.; Harutyunyan,
S. R.; Saghiyan, A. S. Tetrahedron: Asymmetry 2001, 12, 481. (c)
Caddick, S.; Parr, N. J .; Pritchard, M. C. Tetrahedron Lett. 2000, 41,
5963. (d) Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P. J . Org.
Chem. 2000, 65, 7663. (e) Avenoza, A.; Cativiela, C.; Corzana, F.;
Peregrina, J . M.; Zurbano, M. M. Tetrahedron: Asymmetry 2000, 11,
2195. (f) Di Felice, P.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry
1999, 10, 2191. (g) Hutton, C. A. Org. Lett. 1999, 1, 295. (h) Alker, D.;
Hamblett, G.; Harwood: L. M.; Robertson, S. M.; Watkin, D. J .;
Williams, C. E. Tetrahedron 1998, 54, 6089. (i) Iwanowicz, E. J .;
Blomgren, P.; Cheng, P. T. W.; Smith, K.; Lau, W. F.; Pan, Y. Y.; Gu,
H. H.; Malley, M. F.; Gougoutas, J . Z. Synlett 1998, 664.
(4) Recent syntheses employing a chiral catalyst: (a) Mordant, C.;
Du¨nkelmann, P.; Ratovelomanana-Vidal, V.; Genet, J .-P. Chem. Com-
mun. 2004, 1296. (b) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y.
Angew. Chem., Int. Ed. 2004, 43, 882. (c) Evans, D. A.; J aney, J . M.;
Magomedov, N.; Tedrow, J . S. Angew Chem., Int. Ed. 2001, 40, 1884.
(d) Park, H.; Cao, B.; J oullie´, M. M. J . Org. Chem. 2001, 66, 7223. (e)
Horikawa, M.; Busch-Petersen, J .; Corey, E. J . Tetrahedron Lett. 1999,
40, 3843. (f) Kuwano, R.; Okuda, S.; Ito, Y. J . Org. Chem. 1998, 63,
3499. (g) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett.
1998, 39, 2507. (h) Suga, H.; Ikai, K.; Ibata, T. Tetrahedron Lett. 1998,
39, 869.
(5) (a) Gasparski, C. M.; Miller, M. J . Tetrahedron 1991, 47, 5367.
(b) O’Donnell, M. J .; Wu, S.; Huffman, J . C. Tetrahedron 1994, 50,
4507.
(6) (a) J ackson, B. G.; Pedersen, S. W.; Fisher, J . W.; Misner, J . W.;
Gardner, J . P.; Staszak, M. A.; Doecke, C.; Rizzo, J .; Aikins, J .; Farkas,
E.; Trinkle, K. L.; Vicenzi, J .; Reinhard, M.; Kroeff, E. P.; Higgin-
botham, C. A.; Gazak, R. J .; Zhang, T. Y. Tetrahedron 2000, 56, 5667.
(b) Kimura, T.; Vassilev, V. P.; Shen, G.-J .; Wong, C.-H. J . Am. Chem.
Soc. 1997, 119, 11734. (c) Miller, M. J .; Richardson, S. K. J . Mol. Catal.
B: Enzym. 1996, 1, 161. (d) Lotz, B. T.; Gasparski, C. M.; Peterson,
K.; Miller, M. J . J . Chem. Soc., Chem. Commun. 1990, 1107.
(7) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem.,
Int. Ed. 2002, 41, 4542.
(8) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2002, 58, 8289.
(9) (-)-Cinchonidine can be purchased for $0.61/g (Aldrich); in
contrast, (S)-BINOL, the chiral component of the Maruoka and
Shibasaki, catalysts, costs $36/g (Aldrich). The catalysts used in this
study were synthesized from (-)-cinchonidine in two to three steps,
whereas Maruoka’s catalyst requires a longest linear sequence of 11
steps (see: Ooi, T.; Kameda, M.; Maruoka, K. J . Am. Chem. Soc. 2003,
125, 5139).
(10) (a) Park, H.-g.; J eong, B.-S.; Yoo, M.-S.; Lee, J .-H.; Park, B.-s.;
Kim, M. G.; J ew, S.-s. Tetrahedron Lett. 2003, 44, 3497. (b) J ew, S.-s.;
Yoo, M.-S.; J eong, B.-S.; Park, I.-Y.; Park, H.-g. Org. Lett. 2002, 4, 4245.
(c) Park, H.-g.; J eong, B.-S.; Yoo, M.-S.; Lee, J .-H.; Park, M.-k.; Lee,
Y.-J .; Kim, M.-J .; J ew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036. (d)
Corey, E. J .; Xu, F.; Noe, M. C. J . Am. Chem. Soc. 1997, 119, 12414.
(e) For a review on the use of phase-transfer catalysts in amino acid
synthesis, see: Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013.
10.1021/jo049283u CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004
J . Org. Chem. 2004, 69, 6489-6492
6489

TABLE 2. Op tim iza tion of Ald ol Rea ction s Ca ta lyzed by
5a
equiv of
yield of
anti ee syn ee
solvent
THF
tol/CHCl3
tol/CHCl3
tol/CHCl3
tol/CHCl3
BTTP equiv 5 8a (%) anti/syn
(%)
(%)
1.7
1.7
1.0
2.5
2.5
0.17
0.17
0.17
0.17
0.085
85
26
35
64
10
1.1:1
1:1.3
1.1:1
1:1.3
1:1
12
48
36
33
34
18
89
78
80
81
b
b
b
b
a
All aldol reactions were run with 4.0 equiv of aldehyde 6a at
b
-50 °C for 1 h. Toluene-CHCl3 7:3
useful levels of enantioselectivity. Notably, the complete
lack of selectivity in reactions catalyzed by free alcohols
2 and 4 indicates that alkylation of the (-)-cinchonidine
alcohol is necessary in order to obtain active catalysts
for this homogeneous aldol reaction. Finally, all of the
catalysts examined delivered 8a with low diastereose-
lectivity, although the Park-J ew catalyst 5 was alone
in displaying selectivity for the syn isomer. Accordingly,
we employed 5 in our attempts to optimize the reaction
conditions (Table 2).
F IGURE 1. Catalysts surveyed in this study.
TABLE 1. Asym m etr ic Ald ol Rea ction of 6a w ith 7a
Changing the solvent from CH2Cl2 to THF resulted in
a high yield of 8a ; however, the ee was negligible for both
diastereomers. Fortunately, syn-8a was delivered in 89%
ee when toluene-CHCl3 7:313 was used as the solvent. The
yield could be raised to acceptable levels by increasing
the amount of base from 1.7 equiv to 2.5 equiv, albeit
with a small drop in ee. Halving the catalyst loading did
not affect the enantioselectivity of the reaction, but the
yield dropped precipitously from 64% to 10%. Although
not investigated in detail, this result suggests that the
initially formed achiral enolate of 7 is consumed via
undesired competitive pathways when the catalyst is
employed at less than optimal levels.14 Additionally, the
lack of erosion in enantioselectivity indicates that the
achiral enolate is not reacting with aldehyde 6a at an
appreciable rate under these conditions. Unfortunately,
all of the conditions examined to date have provided 8a
in negligible diastereoselectivity.
Based on these studies, we selected 2.5 equiv of BTTP
and 0.17 equiv of catalyst 5 in toluene-CHCl3 7:3 as our
optimized reaction conditions and investigated the scope
of the aldol reaction with respect to the aldehyde struc-
ture (Table 3). Aliphatic aldehydes containing phenyl
groups, such as hydrocinnamaldehyde (6a ) and benzyl-
oxyacetaldehyde (6b), afforded adducts 8a and 8b in good
yields and syn ee’s of g80%. Interestingly, reactions
employing p-nitrohydrocinnamaldehyde (6c)15 delivered
the highest anti ee’s (60%) observed in this study;
however, syn-8c was obtained in slightly lower ee than
were syn-8a and syn-8b. Although adducts 8d were
obtained in good yield from p-methoxyhydrocinnamal-
catalyst
yield (%)
anti/syn
anti eeb (%)
syn eeb (%)
1
2
3
4
5
63
18
54
54
40
1.4:1
1.8:1
2:1
1.2:1
1:1.9
9
0
41
0
21
2
47
2
13
66
a
b
4.0 equiv of aldehyde was used in each reaction. Measured
by HPLC (Chiralcel OD-H, 97:3 hexanes/i-PrOH, 1 mL/min).
homogeneous conditions described by O’Donnell and
Schwesinger for alkylations of 712 resulted in a facile
reaction. The aldol adducts were not isolable due to
instability presumably derived from retro aldol reactions
during chromatography. Thus, the crude products were
subjected to a sequence of imine hydrolysis and acylation
to afford the stable, isolable benzoate 8a as a mixture of
diastereomers (Table 1).
The data summarized in Table 1 show that the tri-
fluorobenzyl-substituted catalyst 5 of Park and J ew10b
exhibited the highest levels of enantioselectivity for the
syn aldol product. Corey’s catalyst 310d provided both syn-
and anti-8a in moderate ee, whereas none of the other
catalysts examined afforded either diastereomer with
(11) In a footnote contained in ref 7, it is reported that reaction of
6 with 7 catalyzed by 3 under biphasic conditions yields aldol products
in 60% yield with a syn/anti ratio of 5.3:1 and 25% ee for the syn
diastereomer. In our hands, this reaction has been too sluggish to
provide any isolable aldol products. Maruoka has recently disclosed
new biphasic conditions for direct asymmetric aldol reactions of 7: Ooi,
T.; Kameda, M.; Taniguchi, M.; Maruoka, K. J . Am. Chem. Soc. 2004,
126, 9685.
(12) O’Donnell, M. J .; Delgado, F.; Hostettler, C.; Schwesinger, R.
Tetrahedron Lett. 1998, 39, 8775. The phosphazene base 2-tert-
butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphospho-
rine (BEMP) was equally effective in the aldol reaction; however, BTTP
was typically employed due to its lower cost.
(13) This solvent mixture was employed by Park and J ew as the
organic phase in phase-transfer-catalyzed alkylations of 7 with 1 or 5
as the catalyst: see ref 10b,c.
(14) Since all reactions in Table 2 were run for the same amount of
time (1 h), halving the catalyst loading should result in a decrease in
yield of no more than half if the rate is limited by catalyst turnover.
Since we observed a more dramatic decrease in yield, we believe that
the slower rate of chiral ammonium enolate formation with half of the
normal catalyst loading results in consumption of the initially formed
achiral enolate of 7 via undesired pathways.
(15) Griesgraber, G.; Kramer, M. J .; Elliott, R. L.; Nilius, A. M.;
Ewing, P. J .; Raney, P. M.; Bui, M.-H.; Flamm. R. K.; Chu, D. T. W.;
Plattner, J . J .; Or, Y. S. J . Med. Chem. 1998, 41, 1660.
6490 J . Org. Chem., Vol. 69, No. 19, 2004

TABLE 3. Ald ol Rea ction s of 7 w ith Selected
Ald eh yd esa
SCHEME 1. Asym m etr ic Ald ol Rea ction s w ith
Isobu tyr a ld eh yd e
yield
(%)
anti eeb
(%)
syn eeb
(%)
R
anti/syn
PhCH2CH2 (a )
BnOCH2 (b)
p-NO2PhCH2CH2 (c)
p-OMePhCH2CH2 (d )
CH2dCHCH2CH2 (e)
CH3(CH2)4CH2 (f)
64
70
74
78
46
34
1:1.3
1:1
1:1.3
1:1.2
1:1.2
1:1.2
33
45
60
10
19
6.5
80
83
75
50
60
52
a
Data are the average of two runs. 4.0 equiv of aldehyde was
b
used in each reaction. Measured by HPLC (Chiralcel OD-H, 90:
10 (8c), 96:4 (8d ), 97:3 (8a , 8e,f) or 98:2 hexanes/i-PrOH (8b), 1
mL/min).
dehyde (6d ),16 their ee’s were significantly lower than
those of 8a -c. The use of 4-pentenal (6e) and heptanal
(6f) also resulted in modest ee’s; additionally, the yields
of 8e and 8f were relatively poor. Finally, each adduct
except for 8b was obtained with a very slight preference
for the syn isomer.
10 met with failure, as syn-9 was unstable to chroma-
tography. In the end, we were able to obtain crude
benzoate anti-11 in poor yield (<16%) and enantiomeric
excess (12%).19 The low anti ee is consistent with the ee’s
obtained from aldehydes 6d -f. Thus, extension of this
method to R-branched aldehydes will require the devel-
opment of improved hydrolysis conditions.
Analysis of the data in Table 3 reveals that aldehydes
containing aromatic groups give the best yields in this
aldol reaction, followed by alkene-containing aldehydes
and saturated aldehydes, respectively. It is more difficult
to identify a trend in the ee’s with respect to aldehyde
structure, although it is clear that aldehydes possessing
either electronically neutral or electron-poor aromatic
rings give the best ee’s. Since the possibility exists for
multiple types of π-π interactions between aldehydes
6a -e, catalyst 5, and benzophenone imine 7, analysis of
potential transition states is a complex issue deserving
of further study. Although the observed ee’s are not as
high as those reported by Maruoka,7 they nevertheless
represent the highest ee’s obtained to date with readily
available Cinchona alkaloid derived catalysts in direct
aldol reactions.17
To probe the steric requirements of the aldehyde, we
performed the aldol reaction between 7 and isobutyral-
dehyde (Scheme 1). This reaction was more sluggish than
those of unbranched aldehydes and required 2 h for
complete consumption of 7. However, the aldol adduct
syn-9 did not undergo hydrolysis; prolonged reaction
times only led to decomposition. Surprisingly, retro aldol
scission also took place under the hydrolysis conditions
as evidenced by the generation of tert-butyl glycinate.18
Attempted separation of syn-9 and amino alcohol anti-
In an attempt to prepare â-hydroxyphenylalanine
derivatives such as those present in vancomycin and
related glycopeptide antibiotics,1a,b we examined the use
of benzaldehyde in this asymmetric aldol reaction. Al-
though we were able to observe the aldol adducts by
comparison of 1H NMR spectra of crude reaction mixtures
to published data,3a all attempts to purify or subject them
to further transformations resulted in rapid decomposi-
tion.20 We attribute the instability of the aldol products
to an extremely facile retro-aldol process, as copious
quantities of benzaldehyde were observed in the course
of purification attempts.21 Consequently, studies aimed
at derivatizing the free alcohol without promoting this
destructive pathway are in progress.
(19) We were unable to isolate anti-11 from the byproducts of
hydrolysis and the competing retro aldol reaction. Thus, the 16% yield
represents an upper limit. However, our sample was of sufficient purity
to determine the ee using chiral HPLC (Chiralcel OD-H, 98:2 hexanes/
i-PrOH, 1 mL/min).
(20) Our observations are consistent with those of Miller,5a who
reported an estimated crude yield for the aldol reaction of 7 and
benzaldehyde yet did not report the isolation or further derivatization
of the product. However, our observations contrast with those of
Molinski,3a who has reported isolation of the same aldol adduct from
a reaction mediated by n-BuLi and (-)-sparteine. Additionally, Mo-
linski has reported the isolation of anti-9 and syn-9 via SiO2 chroma-
tography; as detailed above, we were unable to perform this separation
(16) Amyes, T. L.; J encks, W. P. J . Am. Chem. Soc. 1989, 111, 7888.
(17) Corey4e has observed higher ee’s in Mukaiyama aldol reactions
employing a Cinchona alkaloid derived catalyst; however, this method
is limited by the fact that the silyl ketene acetal derived from 7 is
only stable in dry CH2Cl2 solutions at temperatures under -20 °C.
Kobayashi has recently utilized a more stable silyl ketene acetal glycine
equivalent in Mukaiyama aldol reactions: Kobayashi, J .; Nakamura,
M.; Mori, Y.; Yamashita, Y.; Kobayashi, S. J . Am. Chem. Soc. 2004,
126, 9192.
(18) Since 7 was completely consumed in the aldol reaction with
isobutyraldehyde, the tert-butyl glycinate must be formed via retro
aldol cleavage of 9 to return isobutyraldehyde and 7 followed by
hydrolysis of 7.
in our system. For
a discussion of the possible source of these
discrepancies, please see footnote 21.
(21) We speculate that the presence of the phosphazene base in the
crude reaction mixture may be initiating the retro aldol reaction on
silica gel. In the aldol reactions reported by Molinski,3a base is
presumably not present in the mixture at the time of chromatography
and therefore is unable to promote a retro aldol reaction. Thus, we
are currently examining the use of other bases that can be removed
prior to chromatography in order to extend the substrate scope to aryl
aldehydes.
J . Org. Chem, Vol. 69, No. 19, 2004 6491

SCHEME 2. Use of Cin ch on in e-Der ived Ca ta lyst
asymmetric reaction we have studied in which 5 is clearly
superior to closely related catalysts.22 Furthermore, An-
drus has recently disclosed the unique efficacy of 5 in
asymmetric glycolate alkylations.23 Together, these re-
ports suggest that 5 may be a useful catalyst in a wide
range of reactions and that efforts to design new and
improved chiral ammonium salt catalysts should make
use of the 2,3,4-trifluorobenzyl moiety.
Exp er im en ta l Section
Gen er a l P r oced u r e for Ald ol Rea ction , Hyd r olysis, a n d
Ben zoa te F or m a tion . To a solution of tert-butyl glycinate
benzophenone imine (7, 25 mg, 0.085 mmol) and chiral am-
monium salt 5 (8.0 mg, 0.014 mmol) in anhydrous toluene-
CHCl3 (7:3, 0.35 mL) at -50 °C was added tert-butyliminotri-
(pyrrolidino)phosphorane (64 µL, 65 mg, 0.21 mmol) dropwise
over 5 min. A solution of aldehyde (0.34 mmol) in anhydrous
toluene-CHCl3 (7:3, 0.10 mL) was then added via syringe pump
over 30 min. The resulting mixture was stirred at -50 °C under
N2 for 1 h, diluted with CH2Cl2 (1 mL), and treated with satd
aq NaHCO3 (0.5 mL) and H2O (1 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 3 mL), and the combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The crude
aldol product was then dissolved in THF (2 mL), cooled to 0 °C,
and treated with 0.25 N HCl (0.35 mL, 0.088 mmol). The
resulting mixture was stirred at 0 °C for 1 h, treated with satd
aq NaHCO3 (0.5 mL), and extracted with EtOAc (2 × 3 mL).
The combined organic layers were washed with brine (2 mL),
dried (Na2SO4), and concentrated in vacuo. The crude amine was
dissolved in dioxane-H2O (10:1, 1.5 mL) and treated with
NaHCO3 (16 mg, 0.19 mmol) followed by benzoyl chloride (24
µL, 29 mg, 0.21 mmol). The resulting mixture was stirred at rt
for 1 h, diluted with H2O (0.5 mL), and extracted with CH2Cl2
(2 × 5 mL). The organic layer was dried (Na2SO4) and concen-
trated in vacuo. Flash chromatography (SiO2, 2 × 10 cm, 5-10%
acetone in hexanes gradient elution) afforded the benzoates 8
as colorless oils that were mixtures of diastereomers.
We were curious to see how the pseudoenantiomeric
catalyst derived from (+)-cinchonine would behave in this
aldol reaction. Accordingly, we prepared chiral am-
monium salt 12 via a slight modification of the procedure
used by Park and J ew to synthesize 5.10b As expected,
catalysis by 12 of the aldol reaction between 6a and 7
resulted in opposite enantioselectivities relative to reac-
tions mediated by 5 (Scheme 2). The magnitude of the
anti ee was similar to that afforded by the cinchonidine-
derived catalyst; unfortunately, the syn ee dropped
significantly. O′Donnell has previously noted higher
enantioselectivities in alkylations of 7 that employ cin-
chonidine-based catalysts versus the psuedoenantiomeric
cinchonine derivatives.12 However, the differences in ee
were more modest (3-10%) than the differences we
observed for syn-8a .
In conclusion, we have found that glycinate Schiff base
7 undergoes asymmetric aldol reactions catalyzed by
Cinchona alkaloid derived ammonium salts under ho-
mogeneous conditions. The reaction is most useful for
aliphatic aldehydes containing either phenyl groups or
electron-poor aromatic rings. Studies to increase the
diastereoselectivity, enantioselectivity, and substrate
scope of the reaction are underway. Avenues under
exploration include the use of different bases, the devel-
opment of new hydrolysis conditions, and the preparation
of novel, potentially more active catalysts based on
cinchonidine. Despite the current limitations, this process
affords the highest enantioselectivities recorded to date
in a direct asymmetric aldol reaction catalyzed by an
inexpensive, easily synthesized Cinchona alkaloid de-
rived salt. Moreover, we note that this is the second
Ack n ow led gm en t. We thank Brigham Young Uni-
versity and the National Institutes of Health (GM70483)
for financial support.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details, spectral data for 8a -f, synthetic procedure and
spectral data for 12, and 1H and 13C NMR spectra for 8a -f
and 12. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O049283U
(22) Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
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