Stereoselective synthesis and characterization of new enantiomerically pure phosphoric acids

Article abstract of DOI:10.1002/chir.20754

Starting from (R)-6,6′-dimethyldiphenyl-2,2′-dicarboxylic acid, a novel class of enantiomerically pure cyclic dialkyl phosphates was synthesized and properly characterized. The absolute configuration was determined by 2D NOESY experiments. The catalytic behavior of the new chiral Bronsted acids was investigated in the stereoselective addition of a silyl keteneacetal to aldimines. The Mannich-type reaction was promoted in up to 94% yields and enantioselectivities up to 55%. On the basis of preliminary molecular mechanic calculations, a model of stereoselection was also proposed to explain the sense of the enantioselectivity observed in the reaction.

Full text of DOI:10.1002/chir.20754

CHIRALITY 22:369–378 (2010)
Stereoselective Synthesis and Characterization of New
Enantiomerically Pure Phosphoric Acids
*
CINZIA BIAGGI, MAURIZIO BENAGLIA, RITA ANNUNZIATA, AND SERGIO ROSSI
Dipartimento di Chimica Organica e Industriale, Universita’ di Milano, Milano, Italy
ABSTRACT
Starting from (R)-6,60-dimethyldiphenyl-2,20-dicarboxylic acid, a novel
class of enantiomerically pure cyclic dialkyl phosphates was synthesized and properly
characterized. The absolute configuration was determined by 2D NOESY experiments.
The catalytic behavior of the new chiral Bronsted acids was investigated in the stereo-
selective addition of a silyl keteneacetal to aldimines. The Mannich-type reaction was
promoted in up to 94% yields and enantioselectivities up to 55%. On the basis of prelimi-
nary molecular mechanic calculations, a model of stereoselection was also proposed to
explain the sense of the enantioselectivity observed in the reaction. Chirality 22:369–
C
VV
378, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: organocatalysis; Bronsted acids; enantioselectivity; phosphoric acids
INTRODUCTION
sterically hindering groups in 3 and 30 positions.10 The de-
velopment of new chiral phosphoric acids with different
scaffolds, alternative to the limited number of chiral biaryl-
derived backbones still represent an area of great interest
to further expand the number of organic transformations
promoted by chiral Bronsted acids.
To the best of our knowledge, only one example of not
binaphthol-derived phosphoric acid was reported14; 2 years
ago, Akiyama studied the catalytic behavior of chiral dia-
lkyl phosphates derived from TADDOL diols in the ketene
silyl acetal addition to imines.15
Demand for enantiomerically pure compounds is contin-
uously increasing, not only for use in pharmaceuticals but
also in other fields such as agrochemicals, flavor and
aroma chemicals, and specialty materials.1 A fundamental
reaction that enables stereoselective CꢀꢀC bonds is the
nucleophilic addition to imines,2,3 the reaction between an
ester derivative and an imine, or its analogs, represents a
powerful methodology to synthesize enantiomerically pure
b-amino esters,4 key intermediates for the preparation of
several different compounds, such as b-lactams.5
Here, we report the synthesis of a conceptually new
class of chiral phosphoric acid, derived from (R)-6,60-di-
methyldiphenyl-2,20-dicarboxylic acid, a chiral scaffold that
was already successfully used as chiral template to stereo-
control the synthesis of enantiopure double-helicates on
nanometer scale,16,17 to build macrocyclic phenanthroline-
based chiral ligands for Cu(I)-promoted enantioselective
cyclopropanations18 or chiral cyclic diamines as organoca-
talysts for Diels-Alder cycloadditions.19
Among all the synthetic strategies used to build com-
plex chiral molecules with high stereocontrol, the use of a
chiral catalyst represents in principle the most attractive
procedure. Therefore, it is not surprising that different
enantioselective catalytic organometallic systems have
been studied and developed for the Mannich-type reaction
between a silyl keteneacetal and imines.6 However, in the
last few years great attention has been devoted to the
exploration of new alternative catalytic methodologies that
involve the presence of organic catalysts.7 In this context
the use of ‘‘metal-free’’ chiral catalysts has offered a novel,
complimentary powerful approach that opened the way
toward new valuable chiral intermediates.8
MATERIALS AND METHODS
General
In the field of organocatalysis, chiral phosphoric acids
have rapidly emerged as one of the most important and
versatile class of organocatalysts, able to promote with
often high stereoselectivity a wide variety of reactions,
including nucleophilic addition to imines, aza Diels-Alder
reactions, transfer hydrogenation reductions9–13 and more
recently Friedel-Crafts and aza Friedel Crafts reactions,
three component Ugi reaction,1,3 dipolar cycloaddition,
epoxidation of enones, and vinylogous Mannich-type reac-
tions. However, most of the very successful chiral
Bronsted acids developed so far are derived from 1,10-
Melting points are uncorrected. NMR spectra were
recorded on a AMX 300 Bruker or a Bruker Avance
Contract grant sponsor: MIUR (project ‘‘Nuovi Metodi Catalitici Stereose-
lettivi e Sintesi Stereoselettiva di Molecole Funzionali’’).
*Correspondence to: Maurizio Benaglia, Dipartimento di Chimica
Organica e Industriale, via C. Golgi 19, I-20133 Milano, Italy.
E-mail: maurizo.benaglia@unimi.it
Received for publication 22 December 2008; Accepted 22 May 2009
DOI: 10.1002/chir.20754
Published online 7 July 2009 in Wiley InterScience
binaphthol scaffold, and require always the presence of (www.interscience.wiley.com).
C
VV
2009 Wiley-Liss, Inc.

370
BIAGGI ET AL.
2
500 MHz. 1H NMR spectra were recorded at 300 or (50-C), 129.7 (q, JC-F 5 30 Hz, 2 C, p,p0-aryl C), 128.4 (40-
500 MHz in chloroform-d (CDCl3) unless otherwise stated C), 128.3 (4-C), 127.6 (2 C, o’-aryl C), 127.1 (2 C, o-aryl C),
and were referenced to tetramethylsilane (TMS) at 125.9 (3-C), 125.1 (2 C, m-aryl C), 125.05 (2 C, m0-aryl C),
1
0.00 ppm. 13C spectra were recorded at 75 or 125 MHz 124.3 (30-C), 124 (q, JC-F 5 270 Hz, CF3, C0F3), 74.5
and were referenced to 77.0 ppm in CDCl3. 31P spectra (CHOH), 72.9 (C0HOH0), 19.9 (20-CH3), 19.45 (2-CH3) ppm.
were recorded at 121.4 or 202.4 MHz and were referenced 19F NMR (282.1 MHz, CDCl3): d 5 262.9 ppm.
to phosphoric acid (H3PO4) at 0.0 ppm. 19F spectra were
C2 isomer. Rf 5 0.29 (n-Hex/AcOEt 8:2). mp 94–968C.
recorded on a Bruker AC 300 at 282.1 MHz or on a Bruker 1H NMR (300 MHz, CDCl3): d 5 7.49 (d, 1J 5 8.2 Hz, 4 H,
Avance 500 MHz at 470.5 MHz and were referenced to m,m0-aryl H), 7.31 (m, 4 H, 4,40-H, 5,50-H), 7.29 (d, 1J 5 8.3
trichlorofluoromethane (CFCl3) at 0.0 ppm. Optical rota- Hz, 4 H, o,o0-aryl H), 7.04 (d, 1J 5 6.1 Hz, 2 H, 3,30-H), 5.36
tions were obtained on a Perkin-Elmer 241 polarimeter at (s, 2 H, CHOH, CH0OH0), 4.47 (sbr, 2 H, OH, OH0), 2.02
589 nm. IR spectra were obtained on a Jasco FT/IR-4100 (s, 6 H, 2,20-CH3) ppm. 13C NMR (75 MHz, CDCl3): d 5
type A instrument. Mass spectra were registered on a 146.7 (2 C, C aryl-CH, C aryl0-CH0), 141.2 (2 C, 2,20-C),
Thermo Finnigan LCQ Advantage instrument. HPLC anal- 137.9 (2 C, 1,10-C), 136.1 (2 C, 6,60-C), 129.9 (2 C, 5,50-C),
2
ysis was performed on a Agilent Instrument Series 1100 129.2 (q, JC-F 5 30 Hz, 2 C, p,p0-aryl C), 128.2 (2 C,
on chiral stationary phase. Purification of the products was 4,40-C), 126.4 (4 C, o,o0-aryl C), 126 (2 C, 3,30-C), 124.9 (q,
performed by column chromatography on silica gel (230– 3JC-F 5 10 Hz, 4 C, m,m0-aryl C), 71.5 (2 C, CHOH,
400 mesh ASTM, Merck). Reagents and solvents were C0HOH0), 20.2 (2 C, 2,20-CH3) ppm.
used as purchased.
Diol (7) and (8). The general procedure for the syn-
General Procedure for the Synthesis of Diols
thesis of diols is as follows. The Grignard reagent was
added to the solution of aldehyde at room temperature
and the resulting deep red solution was stirred at 608C for
18 h. Flash chromatography afforded two isomers C1 and
C2 in a 99% overall yield as yellowish-white low melting
point solids.
In a three-necked round-bottom flask equipped with a
reflux condenser and a dropping funnel, magnesium turn-
ings (5.0 mmol) were suspended under N2 in dry THF
(1.5 ml). The corresponding substituted bromobenzene
(5.0 mmol) dissolved in dry THF (1.5 ml) was slowly
added by the dropping funnel so that the reaction warmed
up. An oil bath was used to keep the temperature constant
(658C). When the magnesium disappeared, the reaction
was cooled to room temperature. In a two-necked round-
bottom flask, (R,R)-6,60-dimethyldiphenyl-2,20-dicarboxyal-
dehyde (1.0 mmol) was dissolved in dry THF (10 ml) and
cooled to –788C. The Grignard reagent previously pre-
pared was then added via a syringe. The solution became
dark red. The mixture was stirred at the same temperature
for 3 h and then allowed to warm to room temperature for
an additional 12 h. The reaction was quenched with H2O
(15 ml), diluted with AcOEt (ca. 20 ml), and filtered
through a pad of celite. The two phases were separated
and the aqueous phase was extracted twice with AcOEt
(10 ml). The combined organic phases were dried with
Na2SO4, filtered, and the solvent was removed in vacuo.
Flash chromatography (n-Hexane/AcOEt) afforded the
products.
C1 isomer. Rf 5 0.375 (n-Hex/AcOEt 8:2). mp 34–378C.
1H NMR (300 MHz, CDCl3): d 5 7.75 (s, 2 H, p,p0-aryl H),
7.55 (s, 4 H, o,o0-aryl H), 7.47–7.45 (m, 3 H, 3,30-H, 4-H),
1
7.36 (t, J 5 7.5 Hz, 1 H, 40-H), 7.32 (m, 1 H, 5-H), 7.06 (d,
1J 5 7.5 Hz, 1 H, 50-H), 5.85 (s, 1 H, CHOH), 5.28 (s, 1 H,
CH0OH0), 1.59 (s, 6 H, 2,20-CH3) ppm. 13C NMR (75 MHz,
CDCl3): d 5 145.6 (C aryl0-CH0), 144.7 (C aryl-CH), 140.7
(20-C), 138.8 (6-C), 137.9 (2-C), 137.3 (1-C), 136.4 (2 C, 10-
C, 20-C), 131.2 (5-C), 131 (4 C, m,m0-aryl C), 129.9 (50-C),
129 (40-C), 128.7 (4-C), 127.3 (3-C), 127.1 (2 C, o0-aril C),
126.3 (2 C, o-aryl C), 124.4 (30-C), 121.3 (2 C, p,p0-aryl C),
75.3 (CHOH), 72.3 (C0HOH0), 19.6 (2-CH3), 19.4 (20-CH3)
ppm.
C2 isomer. Rf 5 0.31 (n-Hex/AcOEt 8:2). mp 41–438C.
1H NMR (300 MHz, CDCl3): d 5 7.8 (s, 2 H, p,p0-aryl H),
1
7.69 (s, 4 H, o,o0-aryl H), 7.41 (t, J 5 7.6 Hz, 2 H, 4,40-H),
7.34 (d, 1J 5 6.9 Hz, 2 H, 5,50-H), 7.24 (d, 1J 5 7.5 Hz, 2 H,
3,30-H), 5.57 (s, 2 H, CHOH, CH0OH0), 1.93 (s, 6 H, 2,20-
CH3) ppm. 13C NMR (75 MHz, CDCl3): d 5 145.7 (2 C, C
aryl-CH, C aryl0-CH0), 140.6 (2 C, 2,20-C), 137.5 (2 C, 1,10-
Diol (1) and (2). Flash chromatography afforded two
isomers C1 and C2 in a 76:24 ratio and in a 99% overall
yield as white solids.
2
C), 136.7 (2 C, 6,60-C), 131.5 (q, J 5 37 Hz, 4 C, m,m0-aryl
C), 130.7 (2 C, 5,50-C), 129 (2 C, 4,40-C), 126.6 (4 C, o,o0-
aryl C), 125.4 (2 C, 3,30-C), 123 (q, 4 C, CF3, C0F3), 121.3
(2 C, p,p0-aryl C), 71.7 (2 C, CHOH, C0HOH0), 19.9 (2 C,
2,20-CH3) ppm.
C1 isomer. Rf 5 0.37 (n-Hex/AcOEt 8:2). mp 116–
1
1
1198C. H NMR (500 MHz, CDCl3): d 5 7.54 (d, J 5 8.2
Hz, 2 H, m-aryl H), 7.50 (d, 1J 5 7.8 Hz, 1 H, 30-H), 7.47 (d,
1J 5 7.8 Hz, 1 H, 3-H), 7.46 (d, J 5 8.2 Hz, 2 H, m0-aryl
1
H), 7.40 (t, 1J 5 7.6 Hz, 1 H, 4-H), 7.38 (t, 1J 5 7.6 Hz, 1 H,
General Procedure for the Synthesis of Phosphites
1
1
40-H), 7.29 (d, J 5 7.0 Hz, 2 H, o-aryl H), 7.21 (d, J 5
In a two-necked round-bottom flask under N2, TEA
1
7.6 Hz, 1 H, 5-H), 7.19 (d, J 5 7.5 Hz, 1 H, 50-H), 7.11 (d, (3.0 mmol) was dissolved in dry THF (6 ml) and cooled to
1J 5 8.1 Hz, 2 H, o0-aryl H), 5.65 (s, 1 H, CHOH), 5.0 (s, 1 08C by an ice bath. PCl3 (2.0 mmol) was added dropwise,
H, CH0OH0), 1.78 (s, 3 H, 20-CH3), 1.42 (s, 3 H, 2-CH3) followed by the corresponding diol (1.0 mmol) dissolved
ppm. 13C NMR (125 MHz, CDCl3): d 5 146.5 (C aryl-CH), in dry THF (6 ml). The formation of a white precipitate
146.4 (C aryl0-CH0), 141.2 (20-C), 139.7 (2-C), 137.7 (6-C), was observed. The reaction was stirred at 08C for 3 h and
137.3 (1-C), 136.8 (10-C), 136.5 (60-C), 130.3 (5-C), 129.7 at room temperature for 1 h. The reaction was quenched
Chirality DOI 10.1002/chir

NEW ENANTIOMERICALLY PURE PHOSPHORIC ACIDS
371
3
by the addition of TEA (1.5 mmol) and H2O (5.5 mmol) (125 MHz, CDCl3): d 5 142.4 (d, JC-P 5 11 Hz, C aryl-
3
and allowed to stir for an additional hour. The pale yellow CH), 141.2 (d, JC-P 5 11 Hz, C aryl0-CH0), 138.3 (2 C, 2,20-
solution was diluted with AcOEt/H2O (ca. 6 ml) and the C), 138.1 (6-C), 137.3 (10-C), 136.6 (60-C), 135.74 (1-C), 132
2
layers were separated. The aqueous layer was then (5-C), 131.9 (q, JC-F 5 32 Hz, 2 C, m-aryl C), 131.4 (50-C),
2
extracted 3 3 AcOEt (5 ml). The combined organic 131.3 (q, JC-F 5 32 Hz, 2 C, m0-aryl C), 129.2 (4-C), 129.1
phases were dried with Na2SO4, filtered, and the solvent (40-C), 128.5 (3-C), 126.6 (30-C), 126.1 (2 C, o0-aryl C), 125.6
1
was removed in vacuo. Flash chromatography (n-Hexane/ (2 C, o-aryl C), 123 (q, JC-F 5 250 Hz, 4 C, CF3, C0F3),
AcOEt) afforded the product.
121.8 (p0-aryl C), 121.4 (p-aryl C), 80.7 (CHOP), 73.6
(C0HOP0), 19.5 (2-CH3), 18.3 (20-CH3) ppm. 31P NMR
1
Phosphite (3). The general procedure was followed
to provide the title compound in a 28% yield as a white
foamy solid. Rf 5 0.42 (n-Hex/AcOEt 7:3). 1H NMR
(202.4 MHz, CDCl3): d 5 8 (d, JP-H 5 744 Hz, 1 P, PH)
ppm. 19F NMR (470.5 MHz, CDCl3): d 5 262.9 ppm.
1
Phosphite (10). The general procedure was followed
to provide the title compound in a 55% yield as a off-white
foamy solid. Rf 5 0.43 (n-Hex/AcOEt 8:2). 1H NMR
(500 MHz, CDCl3): d 5 7.92–6.45 (d, JP-H 5 735 Hz, 1 H,
PH), 7.61 (d, 1J 5 8.2 Hz, 3 H, 3-H, m0-aryl H), 7.48 (t, 1J 5
1
7.7 Hz, 1 H, 4-H), 7.43 (d, J 5 8.4 Hz, 2 H, m-aryl H),
1
1
7.41–7.39 (m, 4 H, 3-H, 5-H, o0-aryl H), 7.31 (t, J 5 7.7 Hz,
(500 MHz, CDCl3): d 5 7.88–6.4 (d, JP-H 5 740 Hz, 1 H,
PH), 7.88 (s, 1 H, p-aryl H), 7.85 (s, 1 H, p0-aryl H), 7.76
(s, 4 H, o,o0-aryl H), 7.52 (d, 1J 5 7.85 Hz, 2 H, 5,50-H), 7.47
1
1
1 H, 40-H), 7.09 (d, J 5 7.6 Hz, 1 H, 30-H), 7.03 (d, J 5
1
7.5 Hz, 1 H, 50-H), 6.97 (d, J 5 8.3 Hz, 2 H, o-aryl H), 6.57
1
1
(t, J 5 7.7 Hz, 1 H, 4-H), 7.41 (t, J 5 7.7 Hz, 1 H, 40-H),
3
3
(dbr, JH-P 5 3.9 Hz, 1 H, CHOP), 6.2 (d, JH-P 5 8.5 Hz, 1
H, CH0OP0), 2.0 (s, 3 H, 2-CH3), 0.99 (s, 3 H, 20-CH3) ppm.
13C NMR (125 MHz, CDCl3): d 5 143.75 (d, 3JC-P 5 10 Hz,
7.24 (d, 1J 5 7.1 Hz, 1 H, 3-H), 6.94 (d, 1J 5 7.7 Hz, 1 H, 30-
3
3
H), 6.42 (d, JH-P 5 10.7 Hz, 1 H, CHOP), 6.0 (d, JH-P
5
6.0 Hz, 1 H, CH0OP0), 2.18 (s, 3 H, 20CH3), 2.17 (s, 3 H,
2-CH3) ppm. 13C NMR (125 MHz, CDCl3): d 5 142.4
3
C aryl0-CH0), 142.5 (d, JC-P 5 10 Hz, C aryl-CH), 138.95
(2 C, 2,20-C), 138.2 (6-C), 137.8 (10-C), 137.15 (60-C), 136
(1-C), 131.3 (5-C), 130.6 (50-C), 129 (m, 2 C, p,p0-aryl C),
128.7 (4-C), 128.5 (40-C), 128.3 (3-C), 126.5 (30-C), 126.3
(2 C, o0-aryl C), 125.7 (2 C, o-aryl C), 125.2 (2 C, m0-aryl
3
(d, JC-P 5 11 Hz, C aryl-CH), 141.8 (C aryl0-CH0), 138.2
(10-C), 137.4 (2-C), 137.3 (6-C), 136.9 (20-C), 136.8 (60-C),
2
136.5 (1-C), 132.4 (5-C), 132.25 (50-C), 132 (q, JC-F
5
32 Hz, 4 C, m,m0-aryl C), 129.8 (4-C), 129.5 (40-C), 128.1 (3-
C), 127.3 (30-C), 126.1 (2 C, o0-aryl C), 125.8 (2 C, o-aryl C),
1
C), 124.7 (2 C, m-aryl C), 124 (q, JC-F 5 270 Hz, 2 C, CF3,
C0F3), 81 (CHOP), 74.3 (C0HOP0), 19.9 (2-CH3), 18.5 (20-
CH3) ppm. 31P NMR (202.4 MHz, CDCl3): d 5 7.33 ppm.
19F NMR (470.5 MHz, CDCl3): d 5 262.5 ppm.
1
123 (q, JC-F 5 270 Hz, 4 C, CF3, C0F3), 122.1 (p0-aryl C),
122 (p-aryl C), 76.8 (CHOP), 74.84 (C0HOP0), 20.4 (2-CH3),
20 (20-CH3) ppm. 31P (121.4 MHz, CDCl3): d 5 7.96 ppm.
Phosphite (4). The general procedure was followed
to provide the title compound in a 45% yield as a white
foamy solid. Rf 5 0.5 (n-Hex/AcOEt 7:3). 1H NMR
General Procedure for the Synthesis
of Phosphoric Acids
1
(300 MHz, CDCl3): d 5 8.24–5.28 (d, JP-H 5 721 Hz, 1 H,
In a round-bottom flask, the corresponding phosphite
(1.0 mmol) was dissolved in Pyridine/H2O (4.5 ml, 9:1
ratio). I2 (3.0 mmol) was added. The dark purple solution
was stirred at room temperature for 2 h and thereafter
quenched with a saturated solution of Na2SO3 until the
reaction became pale yellow. The reaction was diluted
with AcOEt (4 ml) and the layers were separated. The or-
ganic layer was acidified to pH 1 with a 1 M solution of
HCl. The organic phases were dried with Na2SO4, filtered,
and the solvent was removed in vacuo. The product was
obtained without further purification.
1
PH), 7.67 (d, J 5 8.3 Hz, 4 H, m,m0-aryl H), 7.47 (m, 6 H,
5,50-H, o,o0-aryl H), 7.44–7.40 (m, 2 H, 4,40-H), 7.25 (d, 1J 5
1
7.4 Hz, 1 H, 30-H), 7.08 (d, J 5 7.6 Hz, 1 H, 3-H), 6.33 (d,
3
3JH-P 5 9.8 Hz, 1 H, CHOP), 6.0 (d, JH-P 5 8.1 Hz, 1 H,
CH0OP0), 2.18 (s, 3 H, 20-CH3), 2.17 (s, 3 H, 2-CH3) ppm.
3
13C NMR (75 MHz, CDCl3): d 5 143.5 (d, JC-P 5 10 Hz,
3
C aryl0-CH0), 142.9 (d, JC-P 5 10 Hz, C aryl-CH), 138.1 (6-
C), 137.8 (10-C), 137.3 (1-C), 137 (60-C), 136.8 (2-C), 136.3
(20-C), 131.6 (50-C), 131.5 (5-C), 130.3 (m, 2 C, p,p0-aryl C),
129.1 (40-C), 129 (4-C), 127.8 (30-C), 127.2 (3-C), 126.2
(2 C, o-aryl C), 125.9 (2 C, o0-aryl C), 125.3 (4 C, m,m0-aryl
1
Phosphoric acid (5). The general procedure was fol-
lowed to provide the title compound in a 90% yield as a
white solid. mp 224–2258C. [a]2D5 5 269.07 (c 5 0.197,
CHCl3). IR (CH2Cl2): m 5 1621, 1413, 1325, 1264, 1008
C), 124 (q, JC-F 5 260 Hz, 2 C, CF3, C0F3), 77.4 (C0HOP0),
75.4 (CHOP), 20.2 (2 C, 2,20-CH3) ppm. 31P NMR (121.4
MHz, CDCl3): d 5 8.28 ppm.
Phosphite (9). The general procedure was followed cm21
.
1H NMR (300 MHz, CDCl3): d 5 7.75 (sbr, 1 H,
1
to provide the title compound in a 31% yield as a white OH), 7.47 (d, J 5 8.1 Hz, 2 H, m0-aryl H), 7.39 (m, 3 H,
1
foamy solid. Rf 5 0.33 (n-Hex/AcOEt 8:2). H NMR (500 3,4,5-H), 7.33 (m, 4 H, o0-aryl H, m-aryl H), 7.24 (t, 1J 5 7.7
1
1
MHz, CDCl3): d 5 7.99–6.49 (d, JP-H 5 745 Hz, 1 H, PH), Hz, 1 H, 40-H), 6.98 (m, 2 H, 30-H, 50-H), 6.82 (d, J 5 7.8
7.83 (s, 1 H, p0-aryl H), 7.76 (s, 1 H, p-aryl H), 7.71 (s, 2 H, Hz, 2 H, o-aryl H), 6.3 (d, 3JH-P 5 3.7 Hz, 1 H, CHOP), 5.81
1
1
o0-aryl H), 7.64 (d, J 5 7.5 Hz, 1 H, 3-H), 7.52 (t, J 5 (d, 3JH-P 5 7.9 Hz, 1 H, CH0OP0), 2 (s, 3 H, 2-CH3), 0.92 (s,
7.5 Hz, 1 H, 4-H), 7.46 (d, J 5 7.5 Hz, 1 H, 5-H), 7.36 (d, 3 H, 20-CH3) ppm. 13C NMR (75 MHz, CDCl3): d 5 144 (d,
1
1J 5 7.75 Hz, 1 H, 40-H), 7.25 (s, 2 H, o-aryl H), 7.06 (d, 3JC-P 5 15 Hz, C aryl0-CH0), 142.6 (d, JC-P 5 15 Hz, C aryl-
3
1J 5 7 Hz, 1 H, 30-H), 7.04 (d, J 5 7 Hz, 1 H, 50-H), 6.57 CH), 138.5 (2-C), 138.3 (20-C), 138.1 (6-C), 138 (10-C),
1
3
(sbr, 1 H, CHOP), 6.23 (d, JH-P 5 8.5 Hz, CH0OP0), 2.02 136.7 (60-C), 136.2 (1-C), 131 (5-C), 130.3 (50-C), 129 (m, 2
(s, 3 H, 2-CH3), 0.97 (s, 3 H, 20-CH3) ppm. 13C NMR C, p,p0-aryl C), 128.6 (4-C), 128.4 (40-C), 128.1 (3-C), 126.7
Chirality DOI 10.1002/chir

372
BIAGGI ET AL.
(30-C), 126.3 (2 C, o0-aryl C), 125.6 (2 C, o-aryl C), 125.1 (2 white solid. mp 1228C (with glassy transition). [a]2D5
5
C, m0-aryl C), 124.5 (2 C, m-aryl C), 124 (q, 1JC-F 5 270 Hz, 2153.12 (c 5 0.192, CH3OH). IR (CH2Cl2): m 5 1381,
1
2 C, CF3, C0F3), 82.4 (CHOP), 75.9 (C0HOP0), 19.7 (2-CH3), 1278, H NMR (300 MHz, CDCl3): d 5 7.84 (s, 2 H, p,p0-
1
18.3 (20-CH3) ppm. 31P NMR (121.4 MHz, CDCl3): d 5 aryl H), 7.71 (s, 4 H, o,o0-aryl H), 7.45 (d, J 5 7.5 Hz, 2 H,
1
21.42 ppm. MS (ESI–): m/z 5 595.5.
5,50-H), 7.34 (t, J 5 7.7 Hz, 2 H, 4,40-H), 7.0 (d, 1J 5
1
7.7 Hz, 3,30-H), 6.06 (d, J 5 8 Hz, 2 H, CHOP, CH0OP0),
5.6 (br, 1 H, OH), 2.17 (s, 6 H, 2,20-CH3) ppm. 13C NMR
Phosphoric acid (6). The general procedure was fol-
lowed to provide the title compound in a 88% yield as a
white solid. mp 2188C (dec.). [a]2D5 5 293.13 (c 5 0.35,
CHCl3). IR (CH2Cl2): m 5 1641, 1433, 1323, 1261,
3
(75 MHz, CDCl3): d 5 142.3 (d, JC-P 5 10 Hz, 2 C, C aryl-
CH, C aryl0-CH0), 137.5 (2 C, 1,10-C), 137.1 (2 C, 6,60-C),
136.8 (2 C, 2,20-C), 131.9 (2 C, 5,50-C), 131.7 (q, 4 C, m,m0-
aryl C), 129.4 (2 C, 4,40-C), 127.4 (2 C, 3,30-C), 125.9 (4 C,
1
1
1000 cm21. H NMR (500 MHz, CDCl3): d 5 7.56 (d, J 5
1
8 Hz, 4 H, m,m0-aryl H), 7.39 (d, J 5 8 Hz, 4 H, o,o0-aryl
1
o,o0-aryl C), 123 (q, JC-F 5 270 Hz, 4 C, CF3, C0F3), 121.7
1
1
H), 7.37 (d, J 5 8 Hz, 2 H, 5,50-H), 7.26 (t, J 5 6.5 Hz, 2
(2 C, p,p0-aryl C), 77.4 (2 C, CHOP, C0HOP0), 20.1 (2 C,
2,20-CH3) ppm. 31P NMR (121.4 MHz, CDCl3): d 5 1.36
ppm. MS (ESI–): m/z 5 727.2.
1
1
H, 4,40-H), 6.99 (d, J 5 7.5 Hz, 2 H, 3,30-H), 6.05 (d, J 5
8 Hz, 2 H, CHOP, CH0OP0), 2.13 (s, 6 H, 2,2-CH3) ppm.
13C NMR (125 MHz, CDCl3): d 5 143.7 (d, JC-P 5 10 Hz,
3
2 C, C aryl-CH, C aryl0-CH0), 137.9 (2 C, 1,10-C), 137.7 (2 C,
2,20-C), 136.5 (2 C, 6,60-C), 131.4 (2 C, 5,50-C), 130 (m, 2 C,
p,p0-aryl C), 129 (2 C, 4,40-C), 127.55 (2 C, 3,30-C), 126.2 (q,
4JC-F 5 35 Hz, 4 C, o,o0-aryl C), 125.3 (4 C, m,m0-aryl C),
General Procedure for the Mannich-Type Reaction
In a 2 ml vial, catalyst (0.017 mmol) and imine (0.17)
were introduced and the atmosphere was replaced with
N2. The solids were dissolved in dry toluene (2 ml), cooled
to –408C, and stirred for half an hour. SKA (0.34 mmol)
was added dropwise. The reaction was stirred at –408C for
40 h. The mixture was quenched by successive addition of
saturated NaHCO3 (5 ml), saturated KF solution (3 ml),
and MeOH/THF (4 ml) at –408C and was kept stirring for
further 30 min at room temperature. The mixture was
extracted 3 3 AcOEt (4 ml). The combined organic layers
were washed with brine, dried with Na2SO4, filtered, and
the solvent was removed in vacuo. Flash chromatography
(n-Hexane/AcOEt 8:2) afforded the product. The enantio-
meric excess was determined on a Daicel Chiralpak AD
column.
1
124 (q, JC-F 5 260 Hz, 2 C, CF3, C0F3), 77.9 (2 C, CHOP,
C0HOP0), 20.4 (2 C, 2,20-CH3) ppm. 31P NMR (202.4 MHz,
CDCl3): d 5 0.19 ppm. MS (ESI–): m/z 5 595.3.
Phosphoric acid (11). The general procedure was
followed to provide the title compound in a 98% yield as a
white solid. mp 2358C. [a]2D5 5 277.13 (c 5 0.25, CHCl3).
IR (CH2Cl2): m 5 1378, 1278, 1174, 1133, 1031 cm21. H
1
NMR (300 MHz, CDCl3): d 5 7.78 (s, 1 H, p0-aryl H), 7.70
(s, 1 H, p-aryl H), 7.69 (s, 2 H, o0-aryl H), 7.47 (sbr, 3 H,
1
3,4,5-H), 7.33 (t, J 5 7.7 Hz, 1 H, 40-H), 7.18 (s, 2 H, o-aryl
1
1
H), 7.04 (d, J 5 8.8 Hz, 1 H, 30-H), 7.0 (d, J 5 8 Hz, 1 H,
3
3
50-H), 6.40 (dbr, JH-P 5 3.15 Hz, 1 H, CHOP), 5.90 (d, JH-
P 5 7.7 Hz, 1 H, CH0OP0), 2.0 (s, 3 H, 2-CH3), 0.98 (s, 3 H,
20-CH3) ppm. 13C NMR (125 MHz, CDCl3): d 5 142.5 (d,
RESULTS AND DISCUSSION
3
3JC-P 5 11 Hz, C aryl-CH), 141.1 (d, JC-P 5 11 Hz, C aryl0-
CH0), 138.4 (6-C), 137.5 (20-C), 137.4 (2-C), 137.3 (10-C),
In designing a novel class of Bronsted acid, we decided
to take advantage of Akiyama’s work on TADDOL-derived
phosphoric acids, where it was demonstrated that cyclic
phosphates obtained from benzydryl diols were effective
organocatalysts for Mannich-type reaction; on this basis
we synthesized structurally new Bronsted acids, which
should control the stereochemical outcome of the reaction
through the action of two stereogenic centers really close
to phosphorous atom, in combination with a stereogenic
axis of well-defined absolute configuration19 (Fig. 1).
2
136.2 (60-C), 135.9 (1-C), 131.9 (5-C), 131.7 (q, JC-F 5 33
Hz, 4 C, m,m0-aryl C), 131.2 (50-C), 129.1 (4-C), 128.8 (40-
C), 128.7 (3-C), 126.7 (30-C), 126 (2 C, o0-aryl C), 125.5 (2
1
C, o-aryl C), 123 (q, JC-F 5 250 Hz, 4 C, CF3, C0F3), 121.6
(p0-aryl C), 121.3 (p-aryl C), 82.2 (CHOP), 75.6 (C0HOP0),
19.3 (2-CH3), 18.2 (20-CH3) ppm. 31P NMR (202.4 MHz,
CDCl3): d 5 23 ppm. 19F NMR (470.5 MHz, CDCl3): d 5
262.9 ppm. MS (ESI–): m/z 5 727.4.
Phosphoric acid (12). The general procedure was
The synthetic sequence adopted for the preparation of
followed to provide the title compound in a 99% yield as a such novel Bronsted acids is illustrated in Scheme 1: start-
Fig. 1. A new class of chiral phosphoric acids.
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Scheme 1. Synthetic plan for new chiral phosphoric acids.
ing from enantiomerically pure acid A the corresponding
The reaction of C1-symmetric compound 7 and of C2-
(R)-6,60-dimethyldiphenyl-2,20-dialdehyde B was easily pre- symmetric compound 8 with phosphorous trichloride to
pared in quantitative yield19 and reacted with an aryl Gri- afford phosphites 9 and 10, followed by oxidation led to
gnard reagent to afford corresponding diol C in yields the formation of chiral phosphoric acids 11 and 12 in 31%
higher than 98%, as mixtures of isomers; the diol was then and 55% overall yield, respectively (Scheme 3).
reacted with phosphorous trichloride and hydrolyzed to
afford the cyclic phosphite D, which was finally oxidized pounds to be used as organic catalysts, a complete confor-
to phosphoric acid E. mational analysis was performed on all the possible diaster-
To assign the absolute configuration to the new com-
For example, the addition to (R)-6,60-dimethyldiphenyl- eoisomers, with Monte Carlo metods and Merck Molecular
2,20-dialdehyde of 4-(trifluoromethyl)-phenyl magnesium Force Field as implemented in MacroModel 8.5 package.20
bromide afforded in 98% yield a mixture of only two dia- All calculations were performed in vacuum. All torsional
stereoisomers; by running the reaction at 08C a 76:24 ratio angles but the biphenylic one were included as variables in
between a C1 isomer (1) and a C2 isomer (2 or 20) was the stochastic searches; convergence was reached after
obtained (By running the reaction at 2788C, the ratio 5000 steps. Only conformers within 3 kcal/mol from the
between the two same isomers was modified to 85:15, the global minimum were considered in each case for the eval-
C1 isomer being always the major one.) The two isomers, uation of proton–proton distances to compare with experi-
easily separated by flash chromatography, were converted mental ones. The structure of two C2-symmetric (R,S,S)
into the dialkyl phosphites 3 and 4, in 28% and 45% yield and (R,R,R) global minima are reported in Figure 2.
for the C1 isomer 1 and C2 isomer 2, respectively (Only
As shown in Figure 2, the R,R,R isomer locates H-A pro-
˚
the diastereoisomers whose configuration was later estab- ton close to H-B (2.28 A) and it should evidence a marked
lished by NOE studies are showed in the picture; see in NOE effect between those two protons, while the R,S,S
the text for a discussion about the determination of abso- isomer shows H-A and H-B protons to be on the opposite
˚
lute configuration. Configurations of catalysts 6 and 12 side (3.79 A); indeed in the NOESY experiments per-
were established according the same NOESY experimen- formed on the chiral C2 symmetric phosphoric acid 12 a
tal technique.) (Scheme 2). Finally oxidation of 3 and 4 of clear correlation of H-A with H-B was found. Therefore,
with I2 in pyridine afforded the corresponding enantio- the absolute configuration of acid phosphoric 12 was
merically pure phosphoric acids 5 and 6 in 90% yield.
established to be R at stereogenic axis and R,R at the two
Analogously, the reaction with 3,5-bis-(trifluoromethyl)- benzhydrylic stereocenters.
phenyl magnesium bromide led to the isolation of two
The four novel enantiomerically pure phosphoric acids
diastereoisomeric diols 7 and 8 in 99% overall yield 5, 6, 11, and 12 were tested as organocatalysts in a
(Scheme 3). Also in this case, the C1 isomer was obtained nucleophilic addition to imines. The trimethylsilyl ketenea-
as major isomer in 70:30 ratio over the minor C2 isomer. cetal of methyl isobutyrate was chosen as model substrate
(By running the reaction at different temperatures, the that was reacted with differently substituted aldimines in
ratio between the two same isomers remained virtually the presence of a catalytic amount of chiral Bronsted acid
unchanged, the C1 isomer being always the major one.)
(Fig. 3).
Chirality DOI 10.1002/chir

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BIAGGI ET AL.
Scheme 2. Synthesis of enantiomerically pure acids 5 and 6.
In the reaction between the silyl ketene acetal 13 and alyst 12 a low enantioselectivity was obtained (17% ee,
N-4-methoxyphenyl imine of ethyl glyoxylate 14, all the entry 4). Better results were obtained with N-2-hydroxy-
four catalysts showed a good chemical activity but a mod- phenyl imine of benzaldehyde 15; also in this case all the
est ability to control the absolute stereochemistry of the four chiral catalysts exhibited a good chemical activity, but
addition (entries 1–4, Table 1) (the reaction did not occur only catalyst 12 was able to catalyze the reaction with ster-
in the absence of the catalyst); only with C2-symmetric cat- eoselection (entries 4–8, Table 1). By running the reaction
Chirality DOI 10.1002/chir

NEW ENANTIOMERICALLY PURE PHOSPHORIC ACIDS
375
Scheme 3. Synthesis of enantiomerically pure acids 11 and 12.
Fig. 2. Determination of the configuration of 12. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.
com.]
Chirality DOI 10.1002/chir

376
BIAGGI ET AL.
TABLE 2. Catalytic behavior of C2 symmetric catalyst 12 in
the addition of 13 to imine 15a
Temp.
(8C)
Time
(h)
Yield
%
ee
%
b
c
Entry
Additive
1d
2
–
–
240
278
240
240
240
240
240
40
72
40
40
40
40
40
77
61
75
77
56
56
53
37
37
43
55
36
36
37
3e
4
–
MeOH
t-Bu-OH
5
6
7
2,6-di t-Bu-4-Me-PhOH
i-Pr-OH
aThe reaction was run in dry toluene in the presence of 10 mol % amount
of catalyst, see experimental section for details.
Fig. 3. Organocatalytic Mannich reaction.
bYields of isolated products.
cAs determined by HPLC on a chiral stationary phase; yields and ee are
average of duplicate experiments.
dReaction was quenched by simple addition of NaHCO3 sat. sol.
eReaction was quenched with NaHCO3 sat. sol., followed by a treatment
with KF sat. sol. and methanol/THF 1:1 mixture.
at 2408C for 40 h in the presence of 10 mol % amount of
the C2 symmetric Bronsted acid 12 the expected b-amino
ester was obtained in 77% yield after chromatographic puri-
fication in 37% ee. The reaction with N-4-methoxyphenyl
imine of benzaldehyde 16 in the same experimental condi-
tions did not afford the condensation product (entry 9,
Table 1). (The reaction of silyl keteneacetal 13 with
N-BOC, N-CBz, or N-tosyl imines in the presence of
10 mol % amount of catalyst 12 did not lead to any conden-
sation product.)
Catalyst 12, bearing two 3,5-bis-trifluoromethyl phenyl
groups, was then selected as the catalyst of choice for fur-
ther experiments (Table 2). Lower reaction temperatures
did not have a beneficial effect on the enantioselectivity;
by running the addition of 13 to imine 15 at 2788C the
product was isolated with a virtually unchanged enantio-
meric excess (entries 1–2, Table 2). Different work up
might bring some difference in the level of enantioselectiv-
ity of the whole process; a simple quench of the reaction
with NaHCO3 sat. sol. allowed to isolate the product in
37% ee, while by quenching with NaHCO3 sat. sol., fol-
lowed by a treatment with KF sat. sol. and methanol/THF
1:1 mixture, the b-amino ester was obtained in 43% ee
(entry 3, Table 2).
The use of some additive was also briefly investigated;
Yamamoto has already shown that the addition of an achi-
ral stoichiometric proton source may have a beneficial
effect on the chemical and stereochemical yield in the
Mannich reaction of silyl keteneacetal with imines.21 With
our present catalytic system, the addition of methanol
showed some positive effect indeed on the stereochemis-
try of the process; the reaction between 13 and 15 in the
presence of a stoichiometric amount of methanol afforded
the product in 77% yield and 55% ee (entry 4, Table 2).
However, the use of other achiral proton source did not
bring any other further improvement (entries 5–7 of Table
2). (The addition of a stereogenic silyl ketene acetal such
as the trimethylsilyl keteneacetal of methyl propionate to
imine 15 afforded the product in low yield (23%) and low
stereoselectivity.)
The behavior of catalyst 12 was then studied by explor-
ing the Mannich reaction between the trimethylsilyl ke-
teneacetal of methyl isobutyrate and N-2-hydroxyphenyl
imine of different aromatic aldehydes 17–20 (Table 3).
Preliminary results seem to indicate that imine of aro-
matic aldehydes bearing electron withdrawing groups are
usually more reactive than aldehydes substituted with
electron donating groups; so reaction with imine 17
TABLE 1. Catalytic stereoselective Mannich reaction
promoted by chiral acids 5, 6, 11, and 12a
Entry Catalyst
R
R0
Time (h) Yield %b ee %c
TABLE 3. Catalytic stereoselective Mannich addition
to different imines promoted by 12a
1
2
3
4
5
6
7
8
9
5
6
11
12
5
COOEt
COOEt
COOEt
COOEt
Ph
Ph
Ph
Ph
Ph
PMP
PMP
PMP
20
20
20
20
40
40
40
40
40
68
61
94
65
63
45
77
77
–
<5%
7%
<5%
17
17
27
5
Entry
Imine
R
Yield %b
ee %c
PMP
2-OH-Ph
2-OH-Ph
2-OH-Ph
2-OH-Ph
PMP
1
2
3
4
5
15
17
18
19
20
Ph
75
82
–
42
23
43
37
–
38
37
6
4-CF3-C6H4
4-NO2-C6H4
2,4-diOMe-C6H3
2-naphthyl
11
12
12
37
–
aThe reaction was run at 2408C in dry toluene in the presence of 10 mol %
amount of catalyst, see experimental section for details.
bYields of isolated products.
aThe reaction was run at 2408C in dry toluene for 40 h in the presence of
10 mol % amount of catalyst, see experimental section for details.
bYields of isolated products.
cAs determined by HPLC on a chiral stationary phase; yields and ee are
average of duplicate experiments.
cAs determined by HPLC on a chiral stationary phase; yields and ee are
average of duplicate experiments.
Chirality DOI 10.1002/chir

NEW ENANTIOMERICALLY PURE PHOSPHORIC ACIDS
377
derived from 4-trifluoromethyl benzaldehyde afforded the face due to the steric hindrance of the 3,5-bis trifluorome-
product 21 in 82% yield, while 77% yield was obtained with thylphenyl groups of the catalyst, leading preferably to the
imine derived from benzaldehyde (entries 1–2, Table 3); formation of the (S) enantiomer, in full accordance with
with N-2-hydroxyphenyl imine 19 of 2,4-bis methoxy benz- the experimental results (Fig. 4).
aldehyde and imine 20 of 2-naphthyl carboxyaldehyde the
products 22 and 23 were isolated in 43% and 23% yield,
respectively (entries 4,5). Only exception was the case of
CONCLUSIONS
In conclusion, starting from (R)-6,60-dimethyldiphenyl-
2,20-dicarboxylic acid, the synthesis of novel enantiomeri-
cally pure phosphoric acids was successfully accomplished
and the determination of the absolute configuration of
structurally new Bronsted acids realized by NMR studies.
Such chiral acids were able to promote the stereoselective
addition of a silyl keteneacetal to aldimines in decent
yields and enantioselectivity up to 55%. The use of an addi-
tive as achiral proton source was also briefly investigated
and the addition of methanol was shown to have a moder-
ate positive effect on the stereoselectivity of the process.
On the basis of preliminary molecular mechanic cal-
culations, a tentative model of stereoselection was also
proposed to explain the sense of the enantioselectivity
observed in the reaction.
imine 18 of 4-nitrobenzaldehyde that did not afford the
corresponding b-amino ester, probably due to the interfer-
ence of the nitro group in the coordination action of the
chiral phosphoric acid to the nitrogen of the aldehydimine
(entry 3, Table 3).
When N-2-hydroxyphenyl imines are used in the Man-
nich reaction, generally the proposed transition state
involves the presence of two hydrogen bondings or tight
ion pairs, on a case-by-case basis11; however, recent den-
sity functional theory calculations seem to suggest that in
the case of binaphthol-derived phosphoric acids the reac-
tion proceeds through a nine-membered zwitterionic cyclic
transition state with a double coordination between the
phosphoric acid and the imine.22 On the basis of the ex-
perimental results obtained with our catalytic systems, a
possible reactants assembly for the nucleophilic attack to
imine 15 of benzaldehyde promoted by catalyst 12 is
shown in Figure 4. Key features of the proposed complexa-
tion mode are the coordination of the Bronsted acidic site
to the nitrogen of the aldimine and the binding of the phe-
nolic proton of the imine to the Lewis basic site of the chi-
ral phosphoric acid. The lack of reactivity of N-PMP imine
15 and the fact that stereoselectivity was observed only
in reactions with N-2-hydroxyphenyl substituted imines
seem to support this hypothesis. Preliminary molecular
mechanic calculations indicate that the adduct with imine
double coordinated to phosphoric acid offering Re face to
the silyl keteneacetal addition is more stable than the TS
where the Si face would react.
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Chirality DOI 10.1002/chir