Atom economic and highly syn-selective prolinamide-catalyzed cross-aldol addition of hydroxyacetone to aromatic aldehydes

Article abstract of DOI:10.1080/00397910701863715

The highly selective cross-aldol addition of hydroxyacetone (HA) to p-nitro and m-nitrobenzaldehyde is reported; the reaction is catalyzed by three different di- or tripeptides all containing D-Pro in the N-terminal position and one or two residues of β3-

Full text of DOI:10.1080/00397910701863715

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Atom Economic and Highly Syn‐selective
Prolinamide‐Catalyzed Cross‐aldol Addition of
Hydroxyacetone to Aromatic Aldehydes
Gaetano Angelici a , Annamaria Falgiani a , Gianluigi Luppi a , Bernard
Kaptein b , Quirinus B. Broxterman b & Claudia Tomasini a
a Chemistry Department “G. Ciamician,” , Alma Mater Studiorum University
of Bologna , Bologna, Italy
b DSM Research, Pharmaceutical Products , Advanced Synthesis and
Catalysis , Geleen, The Netherlands
Published online: 12 Mar 2008.
To cite this article: Gaetano Angelici , Annamaria Falgiani , Gianluigi Luppi , Bernard Kaptein , Quirinus
B. Broxterman & Claudia Tomasini (2008) Atom Economic and Highly Syn‐selective Prolinamide‐Catalyzed
Cross‐aldol Addition of Hydroxyacetone to Aromatic Aldehydes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:7, 1137-1146, DOI:
10.1080/00397910701863715
To link to this article: http://dx.doi.org/10.1080/00397910701863715
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Synthetic Communicationsw, 38: 1137–1146, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701863715
Atom Economic and Highly Syn-selective
Prolinamide-Catalyzed Cross-aldol
Addition of Hydroxyacetone to Aromatic
Aldehydes
Gaetano Angelici,1 Annamaria Falgiani,1 Gianluigi Luppi,1
Bernard Kaptein,2 Quirinus B. Broxterman,2
and Claudia Tomasini1
1Chemistry Department “G. Ciamician,” Alma Mater Studiorum
University of Bologna, Bologna, Italy
2DSM Research, Pharmaceutical Products, Advanced Synthesis and
Catalysis, Geleen, The Netherlands
Abstract: The highly selective cross-aldol addition of hydroxyacetone (HA) to p-nitro
and m-nitrobenzaldehyde is reported; the reaction is catalyzed by three different di- or
tripeptides all containing D-Pro in the N-terminal position and one or two residues of
b3-homophenylglycine (b3-hPhg): H-D-Pro-(R)-b3-hPhg-OBn, H-D-Pro-(R)-b3-hPhg-
(S)-b3-hPhg-OBn and H-D-Pro-[(S)-b3-hPhg]2-OBn. Several reaction conditions have
been tested, always in the absence of a protecting group on the HA hydroxyl. This
reaction affords the desired compounds with complete regioselectivities being the
other regioisomer completely avoided. Furthermore high enantioselectivities and satis-
factory diastereoselectivities, always favouring the syn diastereoisomers, were
obtained. The stereochemistry of the diols was further confirmed by the analysis of
1
the H NMR spectrum of the corresponding carbonates, obtained by reaction of the
syn/anti mixtures with triphosgene in presence of dimethylamino-pyridine (DMAP).
Keywords: Cross-aldol addition, organocatalysis, b-peptides, hydroxyacetone,
diastereoselectivity
Received in the U.K. July 18, 2007
Address correspondence to Claudia Tomasini, Chemistry Department
“G. Ciamician,” Alma Mater Studiorum University of Bologna, Via Selmi 2, 40126
Bologna, Italy. E-mail: claudia.tomasini@unibo.it
1137

1138
G. Angelici et al.
Cross-aldol addition is one of the most important carbon–carbon bond-forming
reactions, both as a synthetic and as a biosynthetic reaction. Among the
approaches to control the regio- and stereochemistry of the adducts, organoca-
talysis is a very promising feature because it avoids the use of any metal.[1]
The regio- and stereochemistry of this reaction has been extensively
studied, and very interesting results have been obtained when more than
one stereogenic center is formed, both with aldolases as catalysts[2] and
with small molecules such as proline and proline derivatives.[3]
Among these interesting topics, the addition of hydroxyacetone (HA)[4] is
an important reaction that leads to the formation of polyfunctionalized
molecules, which can be used as precursors for more complex compounds,
such as carbohydrates.[5]
Although this reaction has been frequently investigated,[6] satisfactory
results in terms of enantio- and diastereoselectivity have not been obtained
for the cross-aldol addition of hydroxyacetone to aromatic aldehydes,
catalyzed by proline or prolinamides.
As a part of a program directed toward the study of b-amino-acid-
containing oligopeptides for organocatalytic reactions,[7] here we show our
results for the cross-aldol addition of hydroxyacetone (HA) to p-nitro and m-nitro-
benzaldehyde mediated by proline-containing oligopeptides 1, 2, and 3 (Fig. 1).[8]
The addition of HA (0.5 mL, 90 mmol) to p-nitrobenzaldehyde (45 mg,
0.3 mmol) catalyzed by peptides 1, 2, or 3 or D-Pro-OH was screened under
several reaction conditions, reported in Table 1.
Some interesting outcomes deserve mentioning: with D-Pro (10 mol%),
the products were formed only in tetrahydrofuran (THF) but not in DMSO.
This result could be ascribed to the effect of dimethyl sulfoxide (DMSO)
which coordinates the proline acidic hydrogen, thus reducing its availability
for the coordination of the aldehyde carbonyl. On the other hand, with
catalysts 1, 2, and 3, the desired compounds were obtained in good to quanti-
tative yields in every tested solvent, although with very different enantiomeric
excesses (ee’s) and diastereomeric ratios (dr’s). In any case, the formation of
the linear regioisomer is always completely avoided, and anti-adduct 5 is
obtained as a poor enantiomeric mixture (up to 30%).
On the other hand, excellent ee’s of the syn adduct 4 were obtained with
the three catalysts, the best diastereoselectivity being observed when the
reaction is catalyzed by 3 (entries 23 and 24). When these reactions are
Figure 1. Peptides evaluated in this study.

Cross-Aldol Addition of Hydroxyacetone to Aromatic Aldehydes
1139
Table 1. Catalyst screening and reaction conditions optimizationa
Entry
Catalyst
Aldehyde
Solvent Yield (%)b Ee 4 (%)c Dr 4/5c
1
2
D-Pro-OH
D-Pro-OH
pNO2-C6H5
mNO2-C6H5
THF
THF
76
70
94
92
78
62
95
96
50
53
31
27
77
97
98
5
58
69
47
58
63
70
58
57
57
64
60
66
39
33
53
—
—
89
86
83
85
88
85
60:40
68:32
60:40
69:31
64:36
71:29
74:26
69:31
69:31
69:31
78:22
64:36
65:35
64:36
65:35
—
3
1
pNO2-PhCHO
mNO2-PhCHO
pNO2-C6H5
THF
THF
4
1
5
2
THF
THF
6
2
mNO2-C6H5
7
3
pNO2-PhCHO
mNO2-PhCHO
pNO2-C6H5
THF
THF
8
3
9
1
DMF
DMF
10
11
12
13
14
15
16d
17d
19d
20d
21d
22d
23d
24d
1
mNO2-C6H5
2
pNO2-PhCHO
mNO2-PhCHO
mNO2-PhCHO
pNO2-C6H5
DMF
DMF
2
1
AcOEt
AcOEt
AcOEt
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
3
D-Pro-OH
D-Pro-OH
mNO2-C6H5
pNO2-PhCHO
mNO2-PhCHO
pNO2-C6H5
—
96
98
94
88
98
90
—
1
1
2
2
3
3
80:20
73:27
75:25
72:28
83:17
80:20
mNO2-C6H5
pNO2-PhCHO
mNO2-PhCHO
pNO2-PhCHO
mNO2-PhCHO
aUnless otherwise stated, the reaction was carried out with hydroxyacetone
(0.5 mL), the appropriate solvent (1.5 mL), the catalyst (0.03 mmol, 10 mol%), and
p-nitro or m-nitrobenzaldehyde (0.3 mmol) for 16 h at room temperature.
bYields of isolated products after flash chromatography.
cEe values and diastereomeric ratios were determined by HPLC.
dThe reaction time was 68 h.
performed in dry solvents under nitrogen conditions, the starting material is
recovered unchanged.[9]
The preferential formation of the syn adduct 4 is quite unexpected
although consistent with the addition of HA to aldehydes catalyzed by the
antibody 38C[2c] and by primary amine-containing amino acids[10] but has
never been reported for a proline-containing catalyst. In this field, conflicting
results have been described: Notz and List[6a] obtained the preferential
formation of the anti adduct in the proline-catalyzed cross-aldol addition of
HA to benzaldehyde, although with a very low diastereomeric excess,

1140
G. Angelici et al.
whereas Fernandez-Lopez et al.[6d] observed an inversion of diastereoselectiv-
ity for the addition of HA to 4-nitrobenzaldehyde catalyzed by Zn(Pro)2 from
a 2:1 syn/anti ratio in the presence of THF as co-solvent to a 1:8 syn/anti ratio
when the solvent is water.
The syn configuration of the major product 4 was determined by 1H NMR
analysis of a 4/5 diastereoisomeric mixture. The preferential conformations of
the two stereoisomers gathered from the 1H NMR data are reported in
Scheme 1. By nuclear overhauser exchange spectroscopy 1D (NOESY 1D)
analysis, we noticed a nuclear Overhauser effect between the methyl and
the aromatic hydrogens only for the more abundant compound, whereas in
both isomers the CaH hydrogen resonates on irradiating the ortho
hydrogens. Furthermore, the more abundant isomer has the methyl group
more shielded than the minor isomer (2.04 ppm versus 2.38 ppm), probably
because of its proximity with the phenyl group. Taking into account there
results, we can reasonably draw the conformation reported in Scheme 1 and
assign the syn configuration to the more abundant isomer. As this result is
not fully convincing, it was further confirmed by transformation of a syn/
anti mixture into the corresponding carbonates, by reaction with triphosgene
in the presence of dimethylaminopyridine (DMAP).
1
From the analysis of the H NMR spectrum of a 6a/7a mixture, we can
observe that the more abundant carbonate has an Ha–Hb coupling constant
Scheme 1. Preferential conformations of diastereoisomers 4 and 5 and synthesis of
carbonates 6 and 7. Reagents and conditions: i, triphosgene (1 equiv.), DMAP (2
equiv.), CH2Cl2, rt, 2 h.

Cross-Aldol Addition of Hydroxyacetone to Aromatic Aldehydes
1141
of 6.6 Hz, typical of a trans configuration, whereas the less abundant
compound shows a coupling constant of 9.0 Hz, in agreement with a cis
configuration.[11]
Furthermore, the methyl group is consistently more shielded in the cis
isomer 7a (1.86 ppm) than in the trans isomer 6a (2.43 ppm), because of
the shielding effect of the nearby phenyl group, as previously observed.[12]
1
Analogous results have been obtained for the carbonates 6b and 7b. The H
NMR and 13C spectra of syn-3,4-dihydroxy-4-(4-nitro-phenyl)-butan-2-one
4a and of anti-3,4-dihydroxy-4-(4-nitro-phenyl)-butan-2-one 5a have been
already reported as a mixture of diastereoisomers in Ref. (6d).
In conclusion, we have shown a practical approach to the metal-free
cross-aldol addition of hydroxyacetone (HA) to p-nitro and m-nitrobenzalde-
hyde catalyzed by three di- or tripeptides, all containing D-Pro in the
N-terminal position: H-D-Pro-(R)-b3-hPhg-OBn, H-D-Pro-(R)-b3-hPhg-(S)-
b3-hPhg-OBn, and H-D-Pro-[(S)-b3-hPhg]2-OBn, (b3-hPhg ¼ b3-homophe-
nylglycine). This reaction has been performed in the absence of a protecting
group on the HA hydroxyl group and affords the desired compounds with
high yields and enantioselectivities and with satisfactory diastereoselectiv-
ities, always favoring the syn diastereoisomers. Furthermore, a complete
regioselectivity was achieved and the other regioisomer completely avoided.
EXPERIMENTAL SECTION
General
Routine NMR spectra were recorded with spectrometers at 600, 300, or
200 MHz (1H NMR) and at 75 or 50 MHz (13C NMR). Chemical shifts are
reported in d values relative to the solvent peak of CHCl3, set at 7.27 ppm.
Measurements were carried out in CDCl3; proton signals were assigned by
COSY spectra. Data for conformational analysis are obtained with NOESY
1D spectra with typical mixing times of 1.5 s.
Infrared spectra were recorded with an FT-IR spectrometer. Melting points
were determined in open capillaries and are uncorrected. Analytical high-per-
formance liquid chromatography (HPLC) was performed on a HP 1090 liquid
chromatograph equipped with a variable-wavelength UV detector (deuterium
lamp 190–600 nm), using an AD column (0.46 cm i.d. ꢀ 25 cm) (Daicel
Inc.) for the analysis of ee’s and de’s. Hexane Chromasolvw and isopropanol
Chromasolvw for HPLC were used as the eluting solvents.
D-Proline is commercially available. b-Amino acids such as (R)-b3-
hPhg-OH (L-b3-homophenylglycine) and (S)-b3-hPhg-OH (D-b3-homophe-
nylglycine) are prepared at DSM Research as described in PCT Int. Pat.
Appl. WO 01/42173.[13] Peptide bond formation was accomplished via
standard solution-phase procedures, with HBTU [O-(benzotriazol-1-yl)-
N,N,N0,N0-tetramethyluronium hexafluorophosphate] and triethylamine in

1142
G. Angelici et al.
acetonitrile on Boc-protected prolines. The removal of the Boc group was
accomplished via reaction with trifluoroacetic acid in dichloromethane.
Data
H-D-Pro-R-b3-hPhg-OBn 1: Waxy solid; [a]D20 ¼ þ34.0 (c 1.0, CH2Cl2); IR
1
(neat): n ¼ 3298, 1740, 1669 cm21; H NMR (300 MHz, CDCl3): d 1.71–
1.81 (m, 2H), 1.88–1.98 (m, 1H), 2.16–2.24 (m, 1H), 2.84–3.13 (m, 4H),
3.93 (dd, J ¼ 5.4, 9.0 Hz), 5.07 (AB, 2H, J ¼ 12.0 Hz), 5.43 (dt, 1H,
J ¼ 6.9, 8.4 Hz), 7.26–7.36 (m, 10H), 8.52 (d, 1H, J ¼ 8.4 Hz); 13C
NMR (75 MHz, CDCl3): d 25.8, 30.5, 40.8, 47.0, 49.5, 60.3, 66.5,
126.3, 127.6, 128.1, 128.2, 128.5, 128.7, 135.5, 140.6, 170.6, 173.0.
C21H24N2O3 (352.43): calcd. C, 71.57; H, 6.86; N, 7.95. Found: C, 71.60;
H, 6.91; N, 7.91.
H-D-Pro-(R)-b3-hPhg-(S)-b3-hPhg-OBn 2: Mp 146–150 8C; [a]2D0 ¼ þ9.5
1
(c 0.4, CH2Cl2); IR (3 mM in CH2Cl2): n 3408, 1712, 1672 cm21; H NMR
(300 MHz, CDCl3): d 1.62–1.80 (m, 2H), 1.81–1.98 (m, 1H), 1.99–2.18
(m, 1H), 2.64–3.09 (m, 6H), 3.75 (dd, 1H, J ¼ 5.7, 8.6 Hz), 5.01 (AB, 2H,
J ¼ 12.0 Hz), 5.31 (q, 1H, J ¼ 6.6 Hz), 5.38 (q, 1H, J ¼ 7.8 Hz), 7.03–7.34
(m, 16H), 8.79 (d, 1H, J ¼ 8.4 Hz); 13C NMR (75 MHz, CDCl3): d 25.9,
30.5, 39.9, 42.9, 47.0, 49.4, 50.2, 60.5, 66.5, 126.2, 127.4, 128.2, 128.3,
128.5, 128.6, 128.7, 135.4, 140.0, 140.8, 169.4, 170.8, 173.9. C30H33N3O4
(499.60): calcd. C, 72.12; H, 6.66; N, 8.41. Found: C, 72.15; H, 6.63; N, 8.43.
H-D-Pro-[(S)-b3-hPhg]2-OBn 3: Mp 40–42 8C; [a]2D0 ¼ þ16.7 (c 0.4,
CH2Cl2); IR (3 mM in CH2Cl2): n 3410, 1712, 1674 cm21 1H NMR
;
(300 MHz, CDCl3): d 1.67–1.77 (m, 2H), 1.82–1.92 (m, 1H), 2.08–2.22
(m, 1H), 2.60–3.06 (m, 6H), 3.73 (dd, 1H, J ¼ 5.4, 9.0 Hz), 5.01 (AB, 2H,
J ¼ 12.0 Hz), 5.38 (dq, 2H, J ¼ 6.9, 7.8 Hz), 6.92 (d, 1H, J ¼ 8.4 Hz),
7.16–7.41 (m, 15H), 8.86 (d, 1H, J ¼ 9.0 Hz); 13C NMR (50 MHz, CDCl3):
d 26.0, 30.6, 39.6, 43.0, 44.1, 47.2, 49.3, 49.6, 52.6, 60.5, 66.3, 66.5, 126.0,
126.2, 126.3, 127.4, 127.5, 128.1, 128.3, 128.5, 128.6. C30H33N3O4
(499.60): calcd. C, 72.12; H, 6.66; N, 8.41. Found: C, 72.09; H, 6.70; N, 8.44.
General Method for the Cross-aldol Addition of Hydroxyacetone to
p-Nitro or m-Nitrobenzaldehyde
Catalyst 1, 2, or 3 (0.03 mmol) was stirred in a mixture of hydroxyacetone
(0.5 mL) and the appropriate solvent (1.5 mL) for 15 min at room tempera-
ture. Solid p-nitro or m-nitrobenzaldehyde (0.3 mmol, 45.3 mg) was added,
and the mixture was stirred for 16 hours at room temperature. Then the
liquids were removed under reduced pressure, and the mixture was purified

Cross-Aldol Addition of Hydroxyacetone to Aromatic Aldehydes
1143
by flash chromatography (cyclohexane–ethyl acetate 1:1), if required, to
afford a mixture of syn and anti stereoisomers. To remove DMSO; ethyl
acetate and water were added to the concentrated mixture; then the organic
layer was separated, dried, and concentrated under reduced pressure. The
enantiomeric and diastereomeric excesses were determined by chiral HPLC
1
prior to purification. (The H NMR and 13C spectra of syn-3,4-dihydroxy-4-
(4-nitro-phenyl)-butan-2-one 4a and of anti-3,4-dihydroxy-4-(4-nitro-
phenyl)-butan-2-one 5a have been already reported as a mixture of diastereoi-
somers in Ref. 6d.)
Data
1
Syn-3,4-dihydroxy-4-(4-nitro-phenyl)-butan-2-one 4a: H NMR (CDCl3,
600 MHz): d 2.04 (s, 3H, Me), 2.91 (bs, 1H, OH), 3.67 (bs, 1H, OH), 4.48
(d, J ¼ 4.8 Hz, 1H), 5.09 (d, J ¼ 4.8 Hz, 1H), 7.62 (dd, 2 H, J ¼ 1.8,
8.4 Hz, o-Ph), 8.27 (dd, 2 H, J ¼ 1.8, 8.4 Hz, m-Ph); 13C NMR (CDCl3,
50 MHz): d 27.8, 74.5, 80.7, 123.8, 127.2, 146.5, 207.3.
1
Anti-3,4-dihydroxy-4-(4-nitro-phenyl)-butan-2-one 5a: H NMR (CDCl3,
600 MHz): d 2.38 (s, 3H, Me), 2.74 (bs, 1H, OH), 3.74 (bs, 1H, OH), 4.42
(d, J ¼ 2.2 Hz, 1H), 5.22 (d, J ¼ 2.2 Hz, 1H), 7.62 (dd, 2H, J ¼ 1.8,
8.4 Hz, o-Ph), 8.27 (dd, 2H, J ¼ 1.8, 8.4 Hz, m-Ph); 13C NMR (CDCl3,
50 MHz): d 26.0, 73.0, 80.1, 123.8, 127.3, 147.9, 206.8.
1
Syn-3,4-dihydroxy-4-(3-nitro-phenyl)-butan-2-one 4b: H NMR (CDCl3,
200 MHz): d 2.10 (s, 3H, Me), 3.24 (bs, 1H, OH), 3.71 (bs, 1H, OH), 4.47
(d, J ¼ 4.8 Hz, 1H), 5.07 (d, J ¼ 4.8 Hz, 1H), 7.55 (t, 1H, J ¼ 7.8 Hz, Ph),
7.75 (t, 1H, J ¼ 7.8 Hz, Ph), 8.15 (d, 1H, J ¼ 7.8 Hz, Ph), 8.32 (s, 1H).
1
Anti-3,4-dihydroxy-4-(3-nitro-phenyl)-butan-2-one 5b: H NMR (CDCl3,
200 MHz): d 2.39 (s, 3H, Me), 3.03 (bs, 1H, OH), 3.80 (bs, 1H, OH), 4.43
(d, J ¼ 2.2 Hz, 1H), 5.24 (d, J ¼ 2.2 Hz, 1H), 7.55 (t, 1H, J ¼ 7.8 Hz, Ph),
7.75 (t, 1H, J ¼ 7.8 Hz, Ph), 8.15 (d, 1H, J ¼ 7.8 Hz, Ph), 8.32 (s, 1H).
General Method for the Synthesis of Carbonates
A mixture of 4 and 5 (11.2 mg, 0.05 mmol) and dimethylaminopyridine
(DMAP) (12.2 mg, 0.1 mmol) was stirred in dichloromethane (1 mL) at
0 8C; then solid triphosgene (15 mg, 0.05 mmol) was added, and the ice
bath was removed. The mixture was stirred at room temperature for 1 h and
30 min; then dichloromethane (10 mL) and a saturated solution of NH4Cl
(10 mL) were added. The organic layer was separated, washed with a 1 N
HCl aqueous solution and a saturated NaHCO3 aqueous solution, dried, and

1144
G. Angelici et al.
concentrated under reduced pressure. The residue was purified by flash chrom-
atography (cyclohexane–ethyl acetate 7:3). The mixture of 6 and 7 was
obtained pure in 90% yield.
Data
Trans-4-acetyl-5-(4-nitro-phenyl)-[1,3]dioxolan-2-one 6a: 1H NMR (600 MHz,
CDCl3): d 2.43 (s, 3H, Me), 4.63 (d, 1H, J ¼ 6.6 Hz), 5.76 (d, 1H, J ¼ 6.6 Hz),
7.57 (d, 2H, J ¼ 8.4 Hz, Ph), 8.27 (dd, 2H, J ¼ 8.4 Hz, Ph).
Cis-4-acetyl-5-(4-nitro-phenyl)-[1,3]dioxolan-2-one 7a: 1H NMR (600 MHz,
CDCl3): d 1.86 (s, 3H, Me), 5.23 (d, 1H, J ¼ 9.0 Hz), 5.96 (d, 1H,
J ¼ 9.0 Hz), 7.42 (d, 2H, J ¼ 8.4 Hz, Ph), 8.23 (dd, 2H, J ¼ 8.4 Hz, Ph).
Trans-4-acetyl-5-(4-nitro-phenyl)-[1,3]dioxolan-2-one 6b: 1H NMR (300 MHz,
CDCl3): d 2.49 (s, 3H, Me), 4.74 (d, 1H, J ¼ 6.6 Hz), 5.82 (d, 1H, J ¼ 6.6 Hz),
7.48–7.81 (m, 2H, Ph), 8.14–8.32 (m, 2H, Ph).
Cis-4-Acetyl-5-(4-nitro-phenyl)-[1,3]dioxolan-2-one 7b: 1H NMR (300 MHz,
CDCl3): d 1.94 (s, 3H, Me), 5.29 (d, 1H, J ¼ 9.0 Hz), 6.03 (d, 1H, J ¼ 9.0 Hz),
7.48–7.81 (m, 2H, Ph), 8.14–8.32 (m, 2H, Ph).
ACKNOWLEDGMENT
`
We thank Ministero dell’Universita e della Ricerca (Progetto di Rilevante
Interesse Nazionale 2006) (MIUR) (PRIN 2006), Consiglio Nazionale delle
`
Ricerche-Istituto per la Sintesi Organica e la Fotoreattivita (CNR-ISOF),
and the University of Bologna (funds for selected topics) for financial support.
REFERENCES
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Cross-Aldol Addition of Hydroxyacetone to Aromatic Aldehydes
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`
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