Expeditious synthesis of TADDOL-derived phosphoramidite and phosphonite ligands

Article abstract of DOI:10.1016/j.tetasy.2010.03.010

A simple and reliable protocol for the synthesis of TADDOL-derived monodentate ligands is reported. The reaction of the requisite TADDOL with PCl₃ is immediately followed by the treatment of the crude intermediate with both nitrogen and carbon

Full text of DOI:10.1016/j.tetasy.2010.03.010

Tetrahedron: Asymmetry 21 (2010) 1232–1237
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Expeditious synthesis of TADDOL-derived phosphoramidite
and phosphonite ligands
*
Marius Mewald, Andreas Weickgenannt, Roland Fröhlich, Martin Oestreich
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and reliable protocol for the synthesis of TADDOL-derived monodentate ligands is reported. The
reaction of the requisite TADDOL with PCl3 is immediately followed by the treatment of the crude inter-
mediate with both nitrogen and carbon nucleophiles. Several previously unknown or difficult-to-make
phosphoramidite and phosphonite ligands L1–L3 and L4–L9 were accessed using this novel procedure.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 January 2010
Accepted 4 March 2010
Available online 13 April 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1. Introduction
2. Results and discussion
Chiral monodentate phosphorus ligands attracted considerable
interest in recent years.1 These ligands challenged the supremacy
of bidentate ligands in asymmetric transition metal catalysis.2
Privileged monodentate ligands are often based on chiral BINOL
or TADDOL backbones (Fig. 1), which are combined with a phos-
phorus(III) reagent and a carbon or heteroatom substituent in a
modular way.3–5 The modular assembly predestines these ligands
for systematic screenings, and that makes general protocols for
their rapid synthesis highly desirable.
There are many protocols in the literature describing the syn-
thesis of phosphorus ligands derived from TADDOL.7 A generally
applicable method is still missing though, and this is particularly
true for sterically congested ligands. Our aim was to find condi-
tions that would allow for the rapid assembly of both phospho-
ramidites and phosphonites decorated with electron-donating as
well as electron-withdrawing groups in addition to sterically
demanding substituents. The general procedure is shown in Ta-
ble 1. The TADDOLs I used in these syntheses were prepared
according to the literature.8
The synthesis began with the reaction of TADDOL I with PCl3
and N-methylmorpholine as base in toluene; N-methylmorpholine
appears to be superior to Et3N (often used in other protocols) as the
yields obtained were considerably higher in several cases. The
reaction mixture was filtered under argon at ꢀ78 °C to remove as
much of the salt as possible. After a solvent change from toluene
to THF, the resulting intermediate II was either added to a freshly
prepared solution of a lithium amide or treated with an organolith-
ium compound. The reaction mixture was usually kept at room
temperature for 2 h, before it was concentrated to a small volume
and submitted directly to flash column chromatography on deacti-
vated silica gel (cyclohexane/Et3N mixtures as eluent). The ligands
were obtained as white or pale-yellow solids. This protocol gives
the ligands in moderate to excellent yields in a few hours.
The ligands synthesized by this method are shown in Table 1.
Ligands L1 and L2 were substituted with a sterically demanding
2,2,6,6-tetramethylpiperidinyl (TMP) group at phosphorus (Table 1,
entries 1 and 2). To the best of our knowledge, no such TMP-substi-
tuted TADDOL-based phosphoramidite had been reported so far.9
We were able to obtain crystals of L1 suitable for X-ray analysis
(Fig. 2). Its molecular structure in the single crystal reveals that
the environment around the phosphorus atom is indeed sterically
crowded. The steric hindrance is even more pronounced in ligand
O
O
X = substituent = phosphonite
C
P
X
X = substituent = phosphite
O
*
X = substituent = phosphoramidite
N
Figure 1. Chiral monodentate phosphorus ligands.
We recently reported a kinetic resolution through catalytic
asymmetric, dehydrogenative Si–O coupling of donor-functional-
ized alcohols and achiral silanes.6 This enantioselective Si–O cou-
pling is catalyzed by a Cu–H complex decorated with a single
monodentate phosphorus ligand in the stereochemistry-determin-
ing step. The ligand identification required extensive screening for
which a straightforward protocol for the synthesis was needed.
Herein we report a robust and reliable procedure for the time-sav-
ing preparation of several TADDOL-derived phosphoramidites and
phosphonites. We have exclusively focused on new ligands in this
work, except for L5 (cf. entry 5, Table 1). Ligand L5 emerged as the
ideal ligand in the enantioselective Si–O coupling, and hence we
also report a gram scale synthesis herein.
* Corresponding author. Tel.: +49 (0) 251/83 33271; fax: +49 (0) 251/83 36501.
E-mail address: martin.oestreich@uni-muenster.de (M. Oestreich).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.010

M. Mewald et al. / Tetrahedron: Asymmetry 21 (2010) 1232–1237
1233
Table 1
Preparation of phosphoramidites and phosphonites with a TADDOL backbone
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
PCl3
OH
OH
O
P
O
O
P R'
O
O
O
O
O
O
O
Li-R'
N-methylmorpholine
R
R
R
R
R
R
Cl
tolu ene
0°C → rt, 30 min
THF
−78°C → rt, 2h
Ar
Ar
I
II
L1−L9
Entry
1
Compound
Ligand
Ar
Yield (%)
50
Ar
Ar
O
P
O
O
O
N
N
N
L1
Ar
Ar
Ar
Ar
O
P
O
O
O
2
3
4
5
6
7
8
9
L2
L3
L4
L5
L6
L7
L8
L9
20
Ar
Ar
Ar
Ar
O
O
O
73 (lit: 27%)7c
P
O
Ar
Ar
Ar
Ar
O
P
O
O
O
62 (lit: 45%)3a
Ar
Ar
Ar
Ar
O
O
O
78 (lit: 66%)6
P
O
Ar
Ar
Ar
Ar
O
O
O
P
69
22
86
26
O
Ar
Ar
Ar
Ar
CF3
O
O
O
P
O
CF3
Ar
Ar
Ar
Ar
O
O
O
Ar
Ar
P
O
Ar
Ar
Ar
Ar
O
O
O
P
O
N
Ar
Ar
L2, with xylyl instead of phenyl moieties in the TADDOL backbone.
This might also account for the rather poor chemical yield (20% as
compared to 50%).
Phosphoramidite L37b (Table 1, entry 3), phosphonites L43a, and
L56 (Table 1, entries 4 and 5) have been published previously, but
the yields obtained with our method are substantially higher. Li-

1234
M. Mewald et al. / Tetrahedron: Asymmetry 21 (2010) 1232–1237
gand L5 was prepared on a gram scale in 78% yield. Ligand L6 is the
first phosphonite derived from tetra-o-tolyl-substituted TADDOL
(Table 1, entry 6), and L7 is an unprecedented octa-CF3-substituted
TADDOL derivative (Table 1, entry 7). Ligand L8 is a hexaphenyl-
substituted TADDOL ligand (Table 1, entry 8) and L9 is substituted
with a picolyl moiety, providing another Lewis basic coordination site.
methylmorpholine (2.0 equiv) in toluene (0.2 M based on I). The
resulting suspension was stirred at rt for 30 min, cooled to
ꢀ78 °C, and filtered under argon. The solvent of the filtrate was re-
moved under reduced pressure and the pale-yellow residue was
dissolved in THF (0.3 M). The solution was cooled to ꢀ78 °C and
added dropwise to the lithium amide (1.0 equiv) in THF (for phos-
phoramidites) or the appropriate organolithium solution
(1.0 equiv) was added to the dissolved crude intermediate II (for
phosphonites). After stirring for an additional 2 h at rt, the mixture
was concentrated to a slurry and subjected directly to flash column
chromatography on silica gel using cyclohexane/Et3N mixtures as
eluent. Ligands L1–L9 were obtained as white or pale-yellow
solids.
3. Conclusion
In conclusion, we elaborated a general, time-saving method for
the preparation of TADDOL-derived phosphoramidites and phos-
phonites, easily applicable to almost any TADDOL.
4. Experimental
4.1. General
4.3. (1R,7R)-4-(2,2,6,6-Tetramethylpiperidin-1-yl)-9,9-dimethyl-
2,2,6,6-tetraphenyl-3,5,8,10-tetraoxa-4-phosphabicyclo[5.3.0]-
decane L1
Reagents were obtained from commercial sources and were
used without further purification unless otherwise noted. All reac-
tions were performed in flame-dried glassware under a static pres-
sure of argon. Liquids and solutions were transferred with syringes.
Solvents were dried prior to use following standard procedures
(tetrahydrofuran and toluene). Technical grade cyclohexane for
chromatography was distilled before use. Analytical thin layer
chromatography was performed on Silica Gel 60 F254 glass plates
by Merck using the indicated solvents. 1H, 13C, 31P and 19F NMR
spectra were recorded in C6D6 or toluene-d8 on Bruker AV 300
and AV 400 instruments. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, m = multiplet,
br = broad), coupling constants (Hz), and integration. Infrared spec-
tra were recorded on a Digilab Excalibur Series FTS 4000 spectro-
photometer. Optical rotations were measured on a Perkin–Elmer
341 polarimeter. Melting points (Mp) were measured with a
Thompson Scientific apparatus and are not corrected. High resolu-
tion mass spectrometry (HRMS) as well as elemental analysis was
performed by the analytical facility at the Organisch-Chemisches
Institut of the Universität Münster.
According to the general procedure, a solution of [(4R,5R)-2,2-
dimethyl-1,3-dioxolan-4,5-diyl]bis(diphenylmethanol)10 (250 mg,
0.536 mmol) and N-methylmorpholine (108 mg, 1.07 mmol) in tol-
uene (2 mL) was added to an ice-cold solution of PCl3 (73.6 mg,
0.536 mmol) in toluene (1 mL). The resulting suspension was stir-
red for 30 min at rt, cooled to ꢀ78 °C, and filtered under argon. The
solvents of the filtrate were removed under reduced pressure. The
pale-yellow residue was dissolved in THF (2 mL) and added drop-
wise to a solution of lithium tetramethylpiperidide in THF [pre-
pared by the addition of methyl lithium (1.6 M in Et2O, 0.335 mL,
0.536 mmol) to
a
solution of 2,2,6,6-tetramethylpiperidine
(75.7 mg, 0.536 mmol) in THF (2 mL) at ꢀ78 °C followed by warm-
ing to 0 °C] at ꢀ78 °C. The solution was maintained at rt for 2 h and
concentrated under reduced pressure. The residue was subjected
to flash column chromatography on silica gel (cyclohexane/Et3N
97:3), yielding L1 as a white solid (170 mg, 50%). Crystals suitable
for X-ray diffraction were obtained from a methanol/ethylacetate
(1:1) solution. Rf = 0.39 (cyclohexane–tert-butylmethylether
97:3). Mp 250–252 °C. 1H NMR (400 MHz, C6D6): d 0.33 (s, 3H),
0.85–2.25 (m, 18H), 1.39 (s, 3H), 5.28 (d, J = 8.6 Hz, 1H), 5.88 (dd,
J = 8.6, 4.2 Hz, 1H), 6.94–7.24 (m, 12H), 7.74–7.91 (m, 6H), 8.13–
8.18 (m, 2H) ppm. 13C NMR (100 MHz, C6D6): d 17.6, 25.2, 28.0,
32.5 (m), 42.6 (m), 56.7, 82.7 (d, JC–P = 27.8 Hz), 83.1 (d, JC–
P = 5.5 Hz), 83.5 (d, JC–P = 3.9 Hz), 83.8 (d, JC–P = 14.4 Hz), 111.6,
127.3–128.3 (m), 129.6, 129.7, 130.0, 142.9 (d, JC–P = 2.1 Hz),
143.7 (d, JC–P = 1.3 Hz), 147.3 (d, JC–P = 3.0 Hz), 148.0 ppm. 31P
NMR (121 MHz, C6D6) d 156.5 ppm. IR (ATR): 1447 (w), 1031 (s),
4.2. General procedure for the preparation of TADDOL-derived
phosphoramidites and phosphonites
To an ice-cold solution of PCl3 (1.0 equiv) in toluene (0.4 M) was
added a solution of TADDOL I (1.0 equiv) and freshly distilled N-
736 (s), 696 (s) cmꢀ1
. HRMS (ESI) calcd for C40H46NO4PNa
([M+Na]+): 658.3057. Found: 658.3067. Anal. Calcd for C40H46NO4P
(635.77): C, 75.57; H, 7.29; N, 2.20. Found: C, 75.44; H, 7.15; N,
2.09. ½a 2D0
¼ ꢀ102 (c 0.985, CHCl3).
ꢁ
4.4. (1R,7R)-4-(2,2,6,6-Tetramethylpiperidin-1-yl)-9,9-dimethyl-
2,2,6,6-tetrakis(3,5-dimethylphenyl)-3,5,8,10-tetraoxa-4-phos-
phabicyclo[5.3.0]decane L2
According to the general procedure, a solution of [(4R,5R)-
2,2-dimethyl-1,3-dioxolan-4,5-diyl]bis{bis[(3,5-dimethylphenyl)-
methanol]}11 (673 mg, 1.16 mmol) and N-methylmorpholine
(241 mg, 2.38 mmol) in toluene (5 mL) was added to an ice-cold
solution of PCl3 (159 mg, 1.16 mmol) in toluene (3 mL). The result-
ing suspension was stirred at rt for 30 min, cooled to ꢀ78 °C, and
filtered under argon. The solvents of the filtrate were removed un-
der reduced pressure. The pale-yellow residue was dissolved in
THF (4 mL) and then added dropwise to a solution of lithium
tetramethylpiperidide in THF [prepared by the addition of n-butyl
lithium (2.5 M in hexanes, 0.465 mL, 1.16 mmol) to a solution of
2,2,6,6-tetramethylpiperidine (164 mg, 1.16 mmol) in THF (4 mL)
Figure 2. Molecular structure of phosphoramidite L1.

M. Mewald et al. / Tetrahedron: Asymmetry 21 (2010) 1232–1237
1235
at ꢀ78 °C followed by warming to 0 °C] at ꢀ78 °C. The solution was
maintained at rt for 2 h and concentrated under reduced pressure.
The residue was subjected to flash column chromatography on sil-
ica gel (cyclohexane/Et3N 95:5), yielding an off-white solid, which
was recrystallized from a methanol/ethylacetate (1:1) solution to
obtain L2 as colorless crystals (175 mg, 20%). Rf = 0.18 (cyclohex-
ane–tert-butylmethylether 97:3). Mp 221 °C. 1H NMR (300 MHz,
C6D6): d 0.44 (s, 3H), 1.07–1.68 (m, 12H), 1.62 (s, 3H), 2.04 (s,
6H), 2.05–2.26 (m, 6H), 2.11 (s, 6H), 2.16 (s, 6H), 2.19 (s, 6H),
5.36 (d, J = 8.6 Hz, 1H), 5.93 (dd, J = 8.6, 4.1 Hz, 1H), 6.69 (m, 3H),
6.79 (m, 1H), 7.56 (m, 2H), 7.63 (m, 2H), 7.68 (m, 2H), 8.01 (m,
2H) ppm. 13C NMR (75 MHz, C6D6): d 17.8, 21.5, 21.6, 21.7, 21.7,
25.5, 28.3, 32.5 (m), 43.2 (m), 56.8, 82.8 (d, JC–P = 6.7 Hz), 83.4 (d,
JC–P = 27.8 Hz), 84.0 (d, JC–P = 13.8 Hz), 84.6 (d, JC–P = 3.6 Hz),
111.4, 126.1, 126.4, 127.4–128.4 (m), 129.0, 129.1, 129.4, 129.5,
gon. The solvents of the filtrate were removed under reduced pres-
sure. The pale-yellow residue was dissolved in THF (6 mL) and a
solution of 2-naphthyl lithium in THF [prepared by the addition
of n-butyl lithium (2.5 M in hexanes, 0.600 mL, 1.15 mmol) to a
solution of 2-naphthyl bromide (311 mg, 1.15 mmol) in THF
(6 mL) at ꢀ78 °C] was added dropwise at ꢀ78 °C. The solution
was maintained at rt for 2 h and concentrated under reduced pres-
sure. The residue was subjected to flash column chromatography
on silica gel (cyclohexane/Et3N 95:5), yielding L4 as a white solid
(765 mg, 62%). Rf = 0.18 (cyclohexane–tert-butylmethylether
97:3). Mp 180 °C (decomp.). 1H NMR (300 MHz, C6D6): d 0.28 (s,
3H), 1.65 (s, 3H), 5.81 (d, J = 8.6 Hz, 1H), 6.70 (dd, J = 8.6, 4.9 Hz,
1H), 7.00–7.30 (m, 9H), 7.39–7.69 (m, 14H), 7.78–7.82 (m, 1H),
7.86 (dd, J = 8.6, 1.5 Hz, 2H), 8.03 (dd, J = 8.7, 1.6 Hz, 1H), 8.17
(ddd, J = 8.8, 8.8, 1.8 Hz, 2H), 8.47–8.61 (m, 4H), 8.70 (d,
J = 1.3 Hz, 1H), 9.21 (d, J = 0.9 Hz, 1H). 13C NMR (75 MHz, C6D6): d
25.5, 27.2, 28.2, 83.7 (d, JC–P = 20.6 Hz), 83.8 (d, JC–P = 3.6 Hz), 84.6
(d, JC–P = 7.6 Hz), 85.0 (d, JC–P = 4.1 Hz), 112.5, 125.9–129.3 (m),
132.2, 132.6, 133.4–133.6 (m), 135.4, 139.2 (d, JC–P = 20.6 Hz),
136.6, 136.9, 137.0, 137.4, 143.1 (d, JC–P = 2.0 Hz), 143.4 (d, JC–P
=
1.2 Hz), 147.4 (d, JC–P = 3.2 Hz), 148.5. 31P NMR (121 MHz, C6D6) d
156.4 ppm. IR (ATR): 1458 (w), 1041 (s), 854 (s), 779 (s) cmꢀ1
.
HRMS (ESI) calcd for C48H62NO4PH ([M+H]+): 748.4489. Found:
748.4484. Anal. Calcd for C48H62NO4P (747.98): C, 77.08; H, 8.35;
139.5 (d, JC–P = 1.9 Hz), 139.9 (d, JC–P = 1.5 Hz), 143.9 (d, JC–P
=
N, 1.87. Found: C, 77.48; H, 8.62; N, 1.62. ½a D20
ꢁ
¼ ꢀ80:1 (c 1.03,
3.6 Hz), 144.6 ppm. 31P NMR (121 MHz, C6D6) d 159.1 ppm. IR
(ATR): 3055 (m), 2924 (m), 1506 (m), 1027 (s), 879 (s), 858 (s),
756 (s). HRMS (ESI) calcd for C57H43O4PNa ([M+Na]+): 845.2791.
CHCl3).
4.5. (1R,7R)-4-(Diisopropylamino)-9,9-dimethyl-2,2,6,6-tetra-
phenyl-3,5,8,10-tetraoxa-4-phosphabicyclo[5.3.0]decane L3
Found: 845.2794. ½a D20
¼ ꢀ109 (c 0.305, CHCl3).
ꢁ
4.7. (1R,7R)-4-tert-Butyl-9,9-dimethyl-2,2,6,6-tetra(naphthalen-
According to the general procedure, a solution of [(4R,5R)-2,2-
dimethyl-1,3-dioxolan-4,5-diyl]bis(diphenylmethanol)10 (600 mg,
1.29 mmol) and N-methylmorpholine (260 mg, 2.57 mmol) in tolu-
ene (5 mL) was added to an ice-cold solution of PCl3 (177 mg,
1.29 mmol) in toluene (3 mL). The resulting suspension was stirred
for 30 min at rt, cooled to ꢀ78 °C, and filtered under argon. The sol-
vents of the filtrate were removed under reduced pressure. The
pale-yellow residue was dissolved in THF (4 mL) and then added
dropwise to a solution of LDA in THF [prepared by the addition of
methyl lithium (1.6 M in Et2O, 0.804 mL, 1.29 mmol) to a solution
of diisopropylamine (143 mg, 1.41 mmol) in THF (4 mL) at ꢀ78 °C
followed by warming to 0 °C] at ꢀ78 °C. The solution was main-
tained at rt for 2 h and concentrated under reduced pressure. The
residue was subjected to flash column chromatography on silica
gel (cyclohexane/Et3N 95:5), yielding L3 as a white solid (479 mg,
73%). Rf = 0.29 (cyclohexane–tert-butylmethylether 97:3). Mp
173–175 °C. 1H NMR (300 MHz, C6D6): d 0.32 (s, 3H), 1.15 (d,
J = 6.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 6H), 1.40 (s, 3H), 3.96 (m, 2H),
5.11 (d, J = 8.6 Hz, 1H), 5.73 (dd, J = 8.6, 3.9 Hz, 1H), 6.93–7.25 (m,
12H), 7.72–7.78 (m, 2H), 7.82–7.92 (m, 4H), 8.11–8.17 (m, 2H)
ppm. 13C NMR (75 MHz, C6D6): d 24.2 (d, JC–P = 7.2 Hz), 24.4 (d,
JC–P = 6.9 Hz), 25.3, 27.9, 44.5 (d, JC–P = 14.3 Hz), 81.6 (d,
JC–P = 2.9 Hz), 81.8 (d, JC–P = 10.6 Hz), 83.1 (d, JC–P = 22.2 Hz), 83.8
(d, JC–P = 3.7 Hz), 111.5, 127.3–128.4 (m), 129.3, 129.4, 130.0,
2-yl)-3,5,8,10-tetraoxa-4-phosphabicyclo-[5.3.0]decane L5
According to the general procedure, a solution of [(4R,5R)-2,2-
dimethyl-1,3-dioxolan-4,5-diyl]bis(dinaphthalen-2-ylmethanol)12
(2.57 g, 3.85 mmol) and N-methylmorpholine (779 mg, 7.70 mmol)
in toluene (20 mL) was added to an ice-cold solution of PCl3
(529 mg, 3.85 mmol) in toluene (10 mL). The resulting suspension
was stirred for 30 min at rt, cooled to ꢀ78 °C, and filtered under ar-
gon. The solvents of the filtrate were removed under reduced pres-
sure. The pale-yellow residue was dissolved in THF (25 mL) and
tert-butyl lithium (1.9 M in n-pentane, 2.07 mL, 3.85 mmol) was
added dropwise at ꢀ78 °C. The solution was maintained at rt for
2 h and concentrated under reduced pressure. The residue was sub-
jected to flash column chromatography on silica gel (cyclohexane/
Et3N 4:1), yielding L5 as a pale-yellow solid (2.22 g, 78%). Rf = 0.15
(cyclohexane–tert-butylmethylether 97:3). Mp 130 °C (decomp.).
1H NMR (300 MHz, C6D6): d 0.18 (s, 3H), 1.38 (d, J = 12.8 Hz, 9H),
1.63 (s, 3H), 5.51 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 8.6, 4.9 Hz, 1H),
7.05–7.74 (m, 20H), 7.82–7.94 (m, 2H), 8.08 (m, 2H), 8.35 (m, 1H),
8.48 (s, 1H), 8.58 (m, 1H), 9.10 (m, 1H) ppm. 13C NMR (75 MHz,
C6D6): d 24.1 (d, JC–P = 16.4 Hz), 25.4, 28.2, 35.4 (d, JC–P = 13.2 Hz),
82.8 (d, JC–P = 2.2 Hz), 83.0 (d, JC–P = 23.5 Hz), 83.9 (d, JC–P
=
5.4 Hz), 84.9 (d, JC–P = 3.6 Hz), 112.0, 126.2, 126.3, 126.3, 126.4,
126.5, 126.5, 126.5, 126.6, 126.7, 127.1, 127.1, 127.7–128.5 (m),
128.9–129.3 (m), 133.1, 133.2, 133.3, 133.4, 133.6, 140.3 (m),
144.4, 144.4 ppm. 31P NMR (121 MHz, C6D6) d 172.0 ppm. IR
(ATR): 2926 (m), 1032 (m), 802 (s), 741 (s) cmꢀ1. HRMS (ESI) calcd
for C51H45O4PH ([M+H]+): 753.3131. Found: 753.3128. Anal. Calcd
for C51H45O4P (752.87): C, 81.36; H, 6.02. Found: C, 81.68; H, 5.99.
142.7 (d, JC–P = 1.8 Hz), 143.5 (d, JC–P = 1.3 Hz), 147.2 (d, JC–P
=
2.6 Hz), 148.2. 31P NMR (121 MHz, C6D6) d 141.1 ppm. IR (ATR):
1447 (w), 1049 (s), 733 (s), 696 (s) cmꢀ1. HRMS (ESI) calcd for
C
37H42NO4PH ([M+H]+): 596.2924. Found: 596.2922. Anal. Calcd
for C37H42NO4P (595.71): C, 74.60; H, 7.11; N, 2.35. Found: C,
74.53; H, 7.04; N, 2.10. ½a D20
ꢁ
¼ ꢀ96:2 (c 1.00, CHCl3).
½
a 2D0
ꢁ
¼ ꢀ95:2 (c 1.05, CHCl3).
4.6. (1R,7R)-9,9-Dimethyl-2,2,4,6,6-penta(naphthalen-2-yl)-
4.8. (1R,7R)-4-tert-Butyl-9,9-dimethyl-2,2,6,6-tetra-(o-tolyl)-
3,5,8,10-tetraoxa-4-phosphabicyclo[5.3.0]decane L4
3,5,8,10-tetraoxa-4-phosphabicyclo[5.3.0]decane L6
According to the general procedure, a solution of [(4R,5R)-2,2-
dimethyl-1,3-dioxolan-4,5-diyl]bis(dinaphthalen-2-ylmethanol)12
(1.00 g, 1.50 mmol) and N-methylmorpholine (303 mg, 3.00 mmol)
in toluene (6 mL) was added to an ice-cold solution of PCl3
(206 mg, 1.50 mmol) in toluene (6 mL). The resulting suspension
was stirred for 30 min at rt, cooled to ꢀ78 °C, and filtered under ar-
According to the general procedure, a solution of [(4R,5R)-2,
2-dimethyl-1,3-dioxolan-4,5-diyl]bis(o-tolylmethanol)13 (599 mg,
1.15 mmol) and N-methylmorpholine (232 mg, 2.29 mmol) in tol-
uene (4 mL) was added to an ice-cold solution of PCl3 (158 mg,
1.15 mmol) in toluene (4 mL). The resulting suspension was stirred
for 30 min at rt, cooled to ꢀ78 °C, and filtered under argon. The

1236
M. Mewald et al. / Tetrahedron: Asymmetry 21 (2010) 1232–1237
solvents of the filtrate were removed under reduced pressure. The
pale-yellow residue was dissolved in THF (8 mL) and tert-butyl
lithium (1.75 M in n-pentane, 0.66 mL, 1.15 mmol) was added
dropwise at ꢀ78 °C. The solution was maintained at rt for 2 h
and concentrated under reduced pressure. The residue was sub-
jected to flash column chromatography on silica gel (cyclohex-
ane/Et3N 95:5), yielding L6 as a white solid (484 mg, 69%).
Rf = 0.28 (cyclohexane–tert-butylmethylether 97:3). Mp 125 °C
(decomp.). Presumably due to hindered C–C bond rotation of the
four o-tolyl groups, the signals in the NMR spectra are broad-
ened.14 1H NMR (300 MHz, C6D6): d 0.15 (br s, 3H), 0.89–1.13 (m,
9H), 1.51 (br s, 3H), 1.79–2.14 (m, 12H), 5.02–6.33 (m, 1H), 6.71–
7.45 (m, 13H), 8.06–8.97 (m, 4H) ppm. 13C NMR (75 MHz, C6D6):
d 22.5, 22.7, 23.3, 23.6, 24.5 (d, JC–P = 17.3 Hz), 25.6, 28.6, 34.8 (d,
JC–P = 13.7 Hz), 82.2, 82.4, 82.6, 83.2, 83.3, 88.3 (d, JC–P = 3.8 Hz),
111.7, 125.4, 126.4, 126.5, 126.7, 127.2, 127.5, 127.8, 128.7,
129.2, 130.0, 132.9, 133.1, 133.4, 133.7, 137.7, 139.0, 139.8,
139.9, 140.4, 141.4, 144.0, 145.9 ppm. 31P NMR (121 MHz, C6D6)
0.820 mmol) and N-methylmorpholine (166 mg, 1.64 mmol) in tol-
uene (4 mL) was added to an ice-cold solution of PCl3 (113 mg,
0.820 mmol) in toluene (4 mL). The resulting suspension was stir-
red for 30 min at rt, cooled to ꢀ78 °C, and filtered under argon. The
solvents of the filtrate were removed under reduced pressure. The
pale-yellow residue was dissolved in THF (8 mL) and tert-butyl
lithium (1.9 M in n-pentane, 0.430 mL, 0.820 mmol) was added
dropwise at ꢀ78 °C. The solution was maintained at rt for 2 h
and concentrated under reduced pressure. The residue was sub-
jected to flash column chromatography on silica gel (cyclohex-
ane/Et3N 95:5), yielding L8 as a white solid (477 mg, 86%).
Rf = 0.18 (cyclohexane–tert-butylmethylether 97:3). Mp 115 °C.
1H NMR (300 MHz, C6D6): d 1.17 (d, J = 12.8 Hz, 9H), 5.35 (d,
J = 8.9 Hz, 1H), 6.36 (dd, J = 8.9, 4.3 Hz, 1H), 6.61–6.81 (m, 8H),
6.93–7.21 (m, 12H), 7.47 (m, 2H), 7.72 (m, 2H), 7.82–7.94 (m,
6H). 13C NMR (75 MHz, C6D6): d 24.0 (d, JC–P = 16.2 Hz), 35.2 (d,
JC–P = 12.9 Hz), 82.1 (d, JC–P = 3.7 Hz), 83.4 (d, JC–P = 5.4 Hz), 84.3
(d, JC–P = 22.6 Hz), 86.4 (d, JC–P = 4.0 Hz), 122.2, 125.5, 126.1,
127.2–129.5 (m), 141.9 (d, JC–P = 1.7 Hz), 142.4 (d, JC–P = 1.9 Hz),
144.4, 147.2 (d, JC–P = 3.4 Hz), 147.4 ppm. 31P NMR (121 MHz,
C6D6) d 171.5 ppm. IR (ATR): 2922 (m), 1447 (m), 1221 (m), 982
(s), 810 (s), 737 (s) cmꢀ1. Anal. Calcd for C45H41O4P (522.57): C,
d
167.6 ppm (two additional minor signals at 173.6 and
184.0 ppm that might be assigned to rotamers were detected). IR
(ATR): 2923 (m), 2360 (m), 1457 (s), 1215 (s), 998 (s) cmꢀ1. HRMS
(ESI) calcd for C39H45O4PH ([M+H]+): 609.3128. Found: 609.3137.
Anal. Calcd for C39H45O4P (608.75): C, 76.95; H, 7.45. Found: C,
79.86; H, 6.11. Found: C, 79.96; H, 6.14. ½a D20
¼ þ28:4 (c 0.295,
ꢁ
77.07; H, 7.71. ½a D20
ꢁ
¼ ꢀ89:7 (c 1.00, CHCl3).
CHCl3).
4.9. (1R,7R)-4-tert-Butyl-9,9-dimethyl-2,2,6,6-tetrakis[3,5-bis
(trifluoromethyl)phenyl]-3,5,8,10-tetraoxa-4-phosphabicyclo
[5.3.0]decane L7
4.11. (1R,7R)-9,9-Dimethyl-2,2,6,6-tetraphenyl-4-(7-picolyl)-
3,5,8,10-tetraoxa-4-phosphabicyclo[5.3.0]decane L9
According to the general procedure, a solution of [(4R,5R)-2,2-
dimethyl-1,3-dioxolan-4,5-diyl]bis(diphenylmethanol)10 (933 mg,
2.00 mmol) and N-methylmorpholine (405 mg, 4.00 mmol) in tolu-
ene (6 mL) was added to an ice-cold solution of PCl3 (275 mg,
2.00 mmol) in toluene (6 mL). The resulting suspension was stirred
for 30 min at rt, cooled to ꢀ78 °C, and filtered under argon. The sol-
vents of the filtrate were removed under reduced pressure. The
pale-yellow residue was dissolved in THF (6 mL) and a solution
of 7-picolyl lithium in THF [prepared by the addition of LDA
(1.0 M in THF, 2.00 mL, 2.00 mmol) to a solution of 2-picoline
(186 mg, 2.00 mmol) in THF (4 mL) at ꢀ78 °C] was added dropwise
at ꢀ78 °C. The solution was maintained at rt for 2 h and concen-
trated under reduced pressure. The residue was subjected to flash
column chromatography on silica gel (cyclohexane/Et3N 95:5),
yielding L9 as a white solid (306 mg, 26%). Rf = 0.18 (cyclohex-
ane–tert-butylmethylether 97:3). Mp 215 °C (decomp.). 1H NMR
(300 MHz, C6D6): d 0.23 (s, 3H), 1.42 (s, 3H), 3.53 (d, J = 5.9 Hz,
2H), 5.08 (d, J = 8.6 Hz, 1H), 5.87 (dd, J = 8.6, 4.3 Hz, 1H), 6.61 (m,
1H), 6.91–7.08 (m, 11H), 7.11–7.21 (m, 3H), 7.53–7.62 (m, 4H),
7.73–7.78 (m, 2H), 8.00–8.05 (m, 2H), 8.41–8.45 (m, 1H) ppm.
According to the general procedure, a solution of [(4R,5R)-2,2-
dimethyl-1,3-dioxolan-4,5-diyl]bis{bis[3,5-bis(trifluoro-
methyl)phenyl]methanol}15 (1.04 g, 1.03 mmol) and N-methyl-
morpholine (208 mg, 2.06 mmol) in toluene (15 mL) was added
to an ice-cold solution of PCl3 (141 mg, 1.03 mmol) in toluene
(10 mL). The resulting suspension was stirred for 30 min at rt,
cooled to ꢀ78 °C, and filtered under argon. The precipitate was
washed thoroughly with THF (3 ꢂ 10 mL). The solvents of the com-
bined filtrates were removed under reduced pressure. The residue
was dissolved in THF (30 mL) and tert-butyl lithium (1.75 M in n-
pentane, 0.590 mL, 1.03 mmol) was added dropwise at ꢀ78 °C.
The solution was maintained at rt for 2 h and concentrated under
reduced pressure. The residue was subjected to flash column chro-
matography on silica gel (cyclohexane/Et3N 95:5), yielding L7 as a
pale-yellow solid (246 mg, 22%). This phosphonite appeared to be
quite sensitive toward air and moisture as compared to the other
ligands. Rf = 0.58 (cyclohexane–tert-butylmethylether 97:3). Mp
68–70 °C. 1H NMR (300 MHz, toluene-d8): d 0.05 (s, 3H), 1.10 (d,
J = 12.6 Hz, 9H), 1.34 (s, 3H), 4.51 (d, J = 8.9 Hz, 1H), 5.50 (dd,
J = 8.9, 4.6 Hz, 1H), 7.60 (m, 2H), 7.64 (m, 2H), 8.04 (m, 2H), 8.09
(m, 2H), 8.25 (m, 2H), 8.50 (m, 2H) ppm. 13C NMR (75 MHz, tolu-
13C NMR (75 MHz, C6D6): d 25.0, 27.2, 27.9, 46.9 (d, JC–P
=
23.0 Hz), 82.0 (d, JC–P = 2.9 Hz), 83.3 (d, JC–P = 23.4 Hz), 83.5 (d,
JC–P = 7.2 Hz), 84.4 (d, JC–P = 4.2 Hz), 111.7, 120.9 (d, JC–P = 2.1 Hz),
124.7 (d, JC–P = 4.2 Hz), 127.4–128.5 (m), 129.1 (d, JC–P = 4.0 Hz),
129.9, 142.0 (d, JC–P = 1.5 Hz), 142.5 (d, JC–P = 1.1 Hz), 146.8,
147.3, 149.8 (d, JC–P = 1.0 Hz), 155.5 (d, JC–P = 5.2 Hz) ppm. 31P
NMR (121 MHz, C6D6) d 173.0 ppm. IR (ATR): 2361 (s), 2342 (s),
1448 (m), 1034 (s), 877 (s), 805 (s), 791 (s), 740 (s) cmꢀ1. HRMS
ene-d8):
d 23.0 (d, JC–P = 15.9 Hz), 24.3, 26.6, 35.5 (d, JC–P =
13.2 Hz), 80.5 (d, JC–P = 3.3 Hz), 82.0 (d, JC–P = 22.8 Hz), 82.4 (d,
JC–P = 4.6 Hz), 84.5 (d, JC–P = 3.9 Hz), 113.3, 121.5–123.3 (m),
125.2–125.3 (m), 127.1 (m), 127.5 (m), 128.9–129.4 (m), 131.4–
133.5 (m), 142.8, 142.8 (d, JC–P = 1.9 Hz), 146.7 (d, JC–P = 3.1 Hz),
147.2 ppm. 19F NMR (282 MHz, toluene-d8) d ꢀ63.3 (s, 6F), ꢀ63.3
(s, 6F), ꢀ63.2 (s, 6F), ꢀ63.1 (s, 6F) ppm. 31P NMR (121 MHz, tolu-
(ESI) calcd for
C
37H34NO4PH ([M+H]+): 588.2298. Found:
ene-d8) d 177.2 ppm. IR (ATR): 1373 (m), 1122 (s), 902 (s) cmꢀ1
.
588.2297. Anal. Calcd for C37H34NO4P (587.64): C, 75.62; H, 5.83;
HRMS (ESI) calcd for C43H29F24O4PH ([M+H]+): 1097.1493. Found:
N, 2.38. Found: C, 75.82; H, 5.84; N, 2.43. ½a D20
¼ ꢀ118 (c 0.430,
ꢁ
1097.1482. ½a 2D0
ꢁ
¼ ꢀ38:4 (c 0.645, CHCl3).
CHCl3).
4.10. (1R,7R)-4-tert-Butyl-2,2,6,6,9,9-hexaphenyl-3,5,8,10-
4.12. X-ray data
tetraoxa-4-phosphabicyclo[5.3.0]decane L8
4.12.1. General information
According to the general procedure, a solution of [(4R,5R)-2,2-
Data set was collected with a Nonius KappaCCD diffractometer.
Programs used: data collection COLLECT (Nonius B.V., 1998), data
diphenyl-1,3-dioxolan-4,5-diyl]bis(diphenylmethanol)16 (484 mg,

M. Mewald et al. / Tetrahedron: Asymmetry 21 (2010) 1232–1237
1237
17a
17b
Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.;
Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539–11540.
3. For seminal contributions, see: (a) Sakaki, J.-i.; Schweizer, W. B.; Seebach, D.
Helv. Chim. Acta 1993, 76, 2654–2665; (b) Alexakis, A.; Frutos, J.; Mangeney, P.
Tetrahedron: Asymmetry 1993, 4, 2427–2430; (c) de Vries, A. H. M.; Meetsma,
A.; Feringa, B. L. Angew. Chem., Int. Ed. 1996, 35, 2374–2376.
4. For authoritative reviews on asymmetric catalysis (allylic substitution,
conjugate addition and hydrogenation) using BINOL- or TADDOL-derived
monodentate phosphoramidites and phosphonites, see: (a) Alexakis, A.;
Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108,
2796–2823; (b) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353; (c) Minnaard,
A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267–1277;
(d) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486–2528.
5. For recent original publications, see: Hydrogenation: (a) Peña, D.; Minnaard, A.
J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552–14553; Allene
diboration: (b) Burks, H. E.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007, 129,
8766–8773; C–H bond activation/arylation: (c) Albicker, M. R.; Cramer, N.
Angew. Chem., Int. Ed. 2009, 48, 9139–9142.
reduction DENZO-SMN
,
absorption correction DENZO
,
structure
solution SHELXS-97,17c structure refinement SHELXL-97,17d graphics
SCHAKAL (E. Keller, Universität Freiburg, 1997).
CCDC 761360 L1 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: (internat.) +44(1223)336-033, E-mail:
deposit@ccdc.cam.ac.uk].
4.12.2. X-ray crystal structure analysis of L1
Formula
C
40H46NO4P, M = 635.75, colorless crystal 0.30 ꢂ
0.25 ꢂ 0.15 mm, a = 10.8981(5), b = 9.4572(4), c = 16.8058(9) Å,
b = 90.507(2), V = 1732.03(14) Å3,
q , l = 1.027
calcd = 1.219 g cmꢀ3
6. Weickgenannt, A.; Mewald, M.; Muesmann, T. W. T.; Oestreich, M. Angew.
Chem., Int. Ed. 2010, 49, 2223–2226.
mmꢀ1, empirical absorption correction (0.748 6 T 6 0.861), Z = 2,
monoclinic, space group P21 (No. 4), k = 1.54178 Å, T = 223(2) K,
7. (a) Seebach, D.; Hayakawa, M.; Sakaki, J.-i.; Schweizer, W. B. Tetrahedron 1993,
49, 1711–1724; (b) Keller, E.; Maurer, J.; Naasz, R.; Schader, T.; Meetsma, A.;
Feringa, B. L. Tetrahedron: Asymmetry 1998, 9, 2409–2413; (c) Alexakis, A.;
Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.; van den Heuvel, A.; Levêque, J.-
M.; Mazé, F.; Rosset, S. Eur. J. Org. Chem. 2000, 4011–4027.
8. Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92–138.
9. For the related BINOL-based, TMP-containing phosphoramidite, see: Du, H.;
Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688–11689.
10. Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A. Helv. Chim.
Acta 1987, 70, 954–974.
x
and u scans, 9157 reflections collected ( h, k, l), [(sin h)/
k] = 0.60 Åꢀ1, 4624 independent (Rint = 0.034) and 4528 observed
reflections [I P 2r(I)], 422 refined parameters, R = 0.036,
wR2 = 0.097, Flack parameter 0.04(2), max. (min.) residual electron
density 0.22 (ꢀ0.32) e Åꢀ3, hydrogen atoms calculated and refined
as riding atoms.
11. (a) Haase, C.; Sarko, C. R.; DiMare, M. J. Org. Chem. 1995, 60, 1777–1787; (b)
Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A.; Kuehnle, F. N.
M. J. Org. Chem. 1995, 60, 1788–1799.
12. Beck, A. K.; Gysi, P.; La Vecchia, L.; Seebach, D. Org. Synth. 1999, 76, 12–
22.
Acknowledgments
This research was supported by the Deutsche Forschungsgeme-
inschaft (Oe 249/4-1) and the Fonds der Chemischen Industrie
(predoctoral fellowship to A.W., 2008–2010).
13. Toda, F.; Tanaka, K.; Leung, C. W.; Meetsma, A.; Feringa, B. L. J. Chem. Soc., Chem.
Commun. 1994, 2371–2372.
14. A similar observation was made with a related phosphite: Linghu, X.; Potnick, J.
R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070–3071.
15. Seebach, D.; Beck, A. K.; Dahinden, R.; Hoffmann, M.; Kühnle, F. N. M. Croat.
Chem. Acta 1996, 69, 459–484.
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