TARTROL-derived chiral phosphine-phosphite ligands and their performance in enantioselective Cu-catalyzed 1,4-addition reactions

Article abstract of DOI:10.1016/j.tetasy.2013.04.008

By using (R,R,R,R)-2,3-dimethoxy-2,3-dimethyl-1,4-dioxane-5,6-bis- diphenylmethanol (TARTROL) as a chiral building block, a set of six modular phosphine-phosphite ligands (with a 1,2-phenylene backbone) were synthesized and evaluated in the Cu-catalyzed a

Full text of DOI:10.1016/j.tetasy.2013.04.008

Tetrahedron: Asymmetry 24 (2013) 657–662
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
TARTROL-derived chiral phosphine–phosphite ligands and their performance
in enantioselective Cu-catalyzed 1,4-addition reactions
Mehmet Dindarog˘lu a, Sema Akyol a, Hamza Sßimßsir a, Jörg-Martin Neudörfl a, Anthony Burke b,
Hans-Günther Schmalz a,
⇑
a Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln, Germany
b Department of Chemistry and Centro de Química de Evora, Universidade de Evora, Rua Romão Ramalho, 59 7000 Evora, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 March 2013
Accepted 12 April 2013
By using (R,R,R,R)-2,3-dimethoxy-2,3-dimethyl-1,4-dioxane-5,6-bis-diphenylmethanol (TARTROL) as a
chiral building block, a set of six modular phosphine–phosphite ligands (with a 1,2-phenylene backbone)
were synthesized and evaluated in the Cu-catalyzed asymmetric 1,4-addition of Grignard reagents to
cyclohexenone. Ligands with bulky substituents at the ortho- and para-positions to the chiral phosphite
moiety were found to be the most selective affording the 1,4-addition products with enantioselectivities
of up to 84% ee.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
gands containing phosphite moieties have also demonstrated
their usefulness in various applications.3
Over the past few decades, chiral bidentate phosphorous li-
gands have evolved as indispensable tools in asymmetric transition
metal catalysis.1 While C2-symmetric bis-phosphine ligands such
as BINAP2 are certainly most prominent, the electronic differentia-
tion of the two ligand teeth is an advantage in many cases.2 Li-
In this context, our group has introduced modular chiral phos-
phine–phosphite ligands (of type L⁄ (Fig. 1),4 some of which were
found to perform extremely well in a variety of transition metal-
catalyzed reactions.5–10
While the modular architecture of these ligands opens up a easy
structural variation, we had so far mainly focused on compounds
prepared from TADDOL11 or BINOL12 as chiral building blocks.
Herein we describe a new series of such ligands (of type 1) employ-
ing TARTROL13,14 2 as a chiral diol (Fig. 2). In contrast to TADDOL,
which contains a more flexible 1,3-dioxol ring, the two OH-substi-
tuted carbon atoms in 2 are pre-oriented in a defined 1,2-di-equa-
torial position at the central 1,4-dioxane ring.
variable chiral
phosphite unit
variable
O
O
backbone
*
R
O
P
PAr2
variable
phosphine unit
L*
2. Results and discussion
Figure 1. General structure of modular phosphine–phosphite ligands L⁄.
2.1. Ligand synthesis and characterization
Following slightly modified literature protocols, the preparation
of 2 was accomplished as shown in Scheme 1. According to Ley15
Ph Ph
Ph Ph
OMe
OMe
OMe
OMe
R1
O
O
O
O
O
the reaction of
L-(+)-dimethyl tartrate 3 with 2,3-butanedione
HO
HO
O
P
Ph Ph
O
OMe
OMe
O
O
MeO2C
MeO2C
O
MeO2C
MeO2C
OH
OH
R2
PPh2 Ph Ph
Ph Ph
a
b
HO
HO
ref.16
86%
ref.13
64%
1
TARTROL 2
O
OMe
OMe
Ph Ph
Figure 2. TARTROL-derived chiral phosphine–phosphite ligands of type 1.
3
2
4
⇑
Corresponding author.
E-mail address: Schmalz@uni-koeln.de (H.-G. Schmalz).
Scheme 1. Synthesis of TARTROL 2. Reagents: (a) 2,3-butanedione, HC(OMe)3,
camphorsulfonic acid, MeOH; (b) PhMgBr, THF.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.008

658
M. Dindarog˘lu et al. / Tetrahedron: Asymmetry 24 (2013) 657–662
R1
R1
and trimethyl orthoformate in methanol in the presence of cam-
phorsulfonic acid16 proceeded stereoselectively to afford the crys-
OH
OH
Br
(iPr)2NH, NBS
talline 1,4-dioxane derivative
4 in high yield. The relative
CH2Cl2, reflux
configuration of 4 was confirmed by X-ray crystal structure analy-
sis (Fig. 3).17 As expected for stereoelectronic reasons,15 both
methoxy groups are in an axial position at the 1,4-dioxane chair.
Treatment of diester 4 with an excess of phenylmagnesium bro-
mide then afforded 2, which crystallized as a 1:1 clathrate with
diethyl ether as proven by X-ray crystallography. This structure
(Fig. 4)18 also displays an intramolecular hydrogen bond between
the two OH-groups and, again, a 1,2-diaxial orientation of the
methoxy groups.
R2
R2
5a-f
6a-f
a: R11 = R2 = tert-butyl
: R1 = R2 = tert-pentyl
b
c R
tert-pentyl, R2 = H
=
1. DABCO
2. ClPPh2
3. BH3-THF
:
d: R1 = tert-butyl, R2 = H
1
: R = phenyl, R2 = H
e
f: R1 = methyl, R2 = H
CH2Cl2, 0 °C
R1
R1
BH3
O
OH
According to our general scheme,4 the ligand synthesis
(Scheme 2) commenced with the preparation of the air-stable
and crystalline borane-protected phosphanylphenols 8a–f. Starting
n-BuLi
PPh2
R2
PPh2
BH3
THF, 0 °C
R2
Br
8a-f
7a-f
Ph Ph
OMe
OMe
R1
1. DABCO
O
O
O
2. PCl3
O
P
3. TARTROL
O
CH2Cl2, 0 °C
R2
PPh2 Ph
Ph
1a-f
Scheme 2. Synthesis of TARTROL-derived chiral ligands 1a–f.
from different commercial phenols 5a–f, the building blocks 8
were obtained in only three preparative steps by ortho-bromina-
tion, O-phosphanylation, and n-BuLi-initiated migration of the
BH3-protected phosphanyl unit onto the adjacent carbon center.4
The final assembly of the ligands was then achieved by the reac-
tion of phenols 8a–f with PCl3 and subsequently with TARTROL 2 in
the presence of DABCO as a base. After chromatographic purifica-
tion, ligands 1a–f were obtained in 46–62% yields on a multigram
scale (for details see Section 4).
2.2. Cu-catalyzed 1,4-addition using ligands of type 1
As a first functional characterization of the TARTROL-based li-
gands 1a–f, we studied their performance in the asymmetric Cu-
catalyzed 1,4-addition of Grignard reagents to cyclohexenone 9
(Scheme 3).19 This reaction system was selected because the re-
lated TADDOL-derived ligands had given excellent enantio- and
regioselectivity in such transformations.5
Figure 3. Structure of 4 in the crystal.17
Using either ethyl- or phenyl-magnesium bromide, ligand
screening was performed under standard reaction conditions
(4 mol % of CuBr-SMe2, 6 mol % of L⁄, 2-Me-THF, ꢀ78 °C, slow addi-
tion of Grignard reagent, 2 h) on a 0.3 mmol scale. The yield and
the enantiomeric composition of the products were analyzed by
GC.20 The absolute configuration of the major enantiomer was as-
signed by correlating the relative retention times with reference
data.5a
As Table 1 indicates, the TARTROL-derived ligands 1a and 1b
carrying bulky tert-butyl or tert-pentyl substituents performed
O
O
R-MgBr
6 mol% L*
4 mol% Cu(I)
R
HO
+
2-Me-THF
C
*
R
9
10a (R = Et)
10b (R = Ph)
11
Scheme 3. Cu-catalyzed 1,4-addition of Grignard reagents to cyclohexenone 9 in
the presence of chiral ligands L⁄.
Figure 4. Structure of TARTROL 2 Et2O in the crystal.18

M. Dindarog˘lu et al. / Tetrahedron: Asymmetry 24 (2013) 657–662
659
Table 1
ceived. 1,4-Diazabicyclo-[2.2.2]octane (DABCO) was purchased
from Alfa Aesar (98%) and purified by sublimation (50 °C,
0.06 mmHg) before use. 2-Cyclohexenone (97%) was purchased
from Acros, distilled and stored under argon.
Performance of TARTROL-based chiral ligands L⁄ in the enantioselective 1,4-addition
of Grignard reagents to cyclohexenone 9
Entry
L⁄
R
Yielda (%)
10:11a
eeb
%
Config.c
1H, 13C and 31P NMR spectra were recorded at room tempera-
ture in CDCl3 on Bruker instruments (Avance DPX300 or Avance
AV300). Chemical shifts (d) are reported in parts per million
(ppm) from tetramethylsilane using the residual solvent resonance
as an internal standard (CDCl3: 7.24 ppm for 1H NMR, 77.0 ppm for
13C NMR). Multiplicities are abbreviated as follows: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet. Coupling con-
stants (J) are presented as absolute values in Hz. IR spectra were re-
corded on a Perkin–Elmer Paragon 1000 FT-IR spectrometer in ATR
mode at rt. Mass spectra (ESI) was recorded on a Finnigan instru-
ment MAT 900. Melting points were determined on a Büchi B-
545 instrument. Analytical TLC was carried out using precoated sil-
ica gel plates (Merck TLC plates, silica gel 60-F254). Flash column
chromatography was performed using Merck silica gel 60 (40–
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1f
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
61
55
57
63
65
52
73
75
82
68
78
46
85:15
80:20
82:18
84:16
92:08
83:17
86:14
89:11
90:10
86:14
92:08
67:33
84
80
60
78
30
76
14
10
8
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
9
10
11
12
4
4
10
a
b
c
Determined by GC.
Determined by GC on a chiral stationary phase (BGB 176 SE).
Assigned by comparison with reference samples.
63 lm). Optical rotations were determined on a Perkin–Elmer
343 polarimeter, concentrations (c) are given in g/100 mL.
quite well, at least when Et-MgBr was used as a reagent. In the best
case, the 1,4-addition product 10a was obtained with 84% ee and a
reasonable level of regioselectivity (85:15). The substitution pat-
tern on the aromatic ligand backbone had a pronounced influence
on the ligand performance. However, in contrast to the related
TADDOL-derived systems5 none of the TARTROL-based ligands
tested allowed the transfer of a phenyl group with a useful level
of enantioselectivity. It is interesting to note that in all of the cases
investigated, the TARTROL-based ligands 1a–f preferentially affor-
ded the opposite enantiomers of the 1,4-addition products com-
pared to the corresponding TADDOL-derived ligands [also
synthesized from the (R,R)-tartrate 3]. This once again demon-
strates the influence of ligand geometry (and conformational flex-
ibility) on the reactivity and selectivity of the resulting metal
complexes.
4.2. General procedure I: synthesis of chiral phosphine
phosphite ligands 1a–f
Under an argon atmosphere, a flame-dried Schlenk-flask was
charged with borane-protected phosphine 8a–f (1.0 equiv), DABCO
(8.0 equiv) and CH2Cl2. The resulting solution was stirred for
10 min at room temperature, then cooled to 0 °C before PCl3 (2 M
in CH2Cl2, 1.2 equiv) was added dropwise via syringe over
30 min. The resulting slurry was stirred for 30 min at this temper-
ature, then allowed to warm to room temperature and stirred for
another 3 h. The reaction mixture was cooled again to 0 °C and a
solution of TARTROL 2 (1.5 equiv) in CH2Cl2 was added dropwise
via syringe over 30 min. The resulting suspension was stirred for
30 min at 0 °C, then allowed to warm to room temperature and
stirred for another 20 h. The reaction mixture was filtered over sil-
ica gel. After concentration of the filtrate by rotary evaporation un-
der reduced pressure, the crude product was purified by flash
column chromatography on silica gel, eluting with cyclohexane/
CH2Cl2. The desired ligands were obtained as a white foam.
3. Conclusion
As an expansion of our library of modular chiral phosphine
phosphites, we have synthesized and characterized a set of six
new ligands of type 1 employing TARTROL 2 as a chiral diol build-
ing block. X-ray crystal structure analysis of 2 and of its precursor 4
confirmed that the 1,4-dioxane ring of this compound adopted a
chair conformation with the OMe groups in the axial position. In
contrast to their TADDOL-derived congeners, the new ligands did
not exhibit superior properties in the Cu-catalyzed 1,4-addition
of Grignard reagents to cyclohexenone. However, we are confident
that some of these ligands will prove useful in other transition me-
tal-catalyzed reactions in the future.
4.3. General procedure II: 1,4-addition reactions
Under an argon atmosphere, a chiral ligand (0.018 mmol,
0.06 equiv) and CuBr–SMe2 (0.012 mmol, 0.04 equiv) were dis-
solved in 1.5 mL of dry 2-Me-THF and the solution was stirred
for 15 min at room temperature. After addition of 2-cyclohexenone
(0.3 mmol, 1.0 equiv), the mixture was stirred for 15 min before it
was cooled to ꢀ78 °C. Then a dilute solution of the Grignard re-
agent (0.36 mmol, 1.2 equiv, in 1 mL 2-Me-THF) was added slowly
via syringe pump over 2 h. The mixture was stirred at ꢀ78 °C for
another 1 h and then quenched by the slow, successive addition
of MeOH (1 mL) and saturated aqueous NH4Cl solution (2 mL).
The layers were separated and the organic phase was analyzed
by GC on a chiral stationary phase.20
4. Experimental
4.1. General information
All reactions were carried out under an argon atmosphere in
flame-dried glassware using Schlenk techniques. Solvents were
dried as follows: THF and 2-Me-THF were distilled from sodium/
benzophenone under an argon atmosphere; CH2Cl2 was refluxed
over and distilled from CaH2 under an argon atmosphere; MeOH
was refluxed over and distilled from magnesium turnings/iodine
4.4. (2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-dioxane-
2,3-dicarboxylic acid dimethyl ester 4
under an argon atmosphere. L-(+)-Dimethyl tartrate (99%), 2,3-
Under an argon atmosphere 17.82 g (100 mmol, 1.0 equiv) of L-
butanedione (99%), DL-10-camphorsulfonic acid (98%), trimethyl
orthoformate (99%), phosphorus trichloride (PCl3) (2 m in CH2Cl2),
phenylmagnesium bromide (1.0 M in THF), phenylmagnesium bro-
mide (2.8 M in 2-Me-THF), ethylmagnesium bromide (3.2 M in 2-
Me-THF), and copper(I) bromide–dimethyl sulfide complex
(CuBr–SMe2) (99%) were purchased from Acros and used as re-
(+)-dimethyl tartrate 3 and 1.16 g (5 mmol, 0.05 equiv) of cam-
phorsulfonic acid were dissolved in 100 ml of dry methanol. To this
solution was added 10.33 ml (120 mmol, 1.2 equiv) of 2,3-butane-
dione and 44 ml (400 mmol, 4.0 equiv) of trimethyl orthoformate.
The reaction mixture was then heated at reflux for 24 h. After cool-
ing to room temperature, 16 g of NaHCO3 was added to the dark

660
M. Dindarog˘lu et al. / Tetrahedron: Asymmetry 24 (2013) 657–662
red solution and stirring was continued for 15 min. The mixture
was filtered and concentrated under reduced pressure by rotary
evaporation. The crude product was purified by flash column chro-
matography on silica gel with cyclohexane/EtOAc (5:1) to give
product 4 as a white solid (25.1 g, 86 mmol, 86%). A sample used
for X-ray analysis was re-crystallized from cyclohexane. Rf = 0.25
(cyclohexane/EtOAc, 5:1), mp = 108 °C, 1H NMR (300 MHz, CDCl3):
d = 4.51 (s, 2H, CH), 3.74 (s, 6H, CO2CH3), 3.30 (s, 6H, COCH3), 1.33
(s, 6H, CH3). 13C NMR (APT, 75 MHz, CDCl3): d = 168.4 (CO2CH3),
99.2 (Cq), 68.7 (CH), 52.5 (CO2CH3), 48.4 (COCH3), 17.3 (CH3). IR
(neat): 2992, 2951, 2835, 1742, 1437, 1377, 1359, 1285, 1200,
((CH3)3), 1.07 (s, 9H, ((CH3)3), 1.06 (s, 3H, CH3), 1.02 (s, 3H, CH3).
13C NMR (APT, 75 MHz, CDCl3): d = 147.6, 146.7, 146.6, 144.6,
141.1, 140.9, 140.8, 139.3, 139.2, 134.0, 133.7, 133.5, 131.4,
131.3, 130.7, 129.8, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8,
127.7, 127.5, 126.6, 126.4, 126.4, 125.7, 99.0, 98.7, 86.6, 86.3,
83.0, 82.9, 75.7, 75.1, 47.6, 46.9, 35.5, 34.4, 31.2, 30.8, 17.0. 31P
NMR {1H} (121 MHz, CDCl3): d = 138.2 (d, J = 115.8 Hz, P(OR)3),
ꢀ15.7 (d, J = 106.8 Hz, PR3). IR (neat): 3054, 2957, 2868, 2831,
1583, 1492, 1476, 1445, 1432, 1418, 1391, 1372, 1361, 1283,
1258, 1202, 1128, 1029, 983, 905, 856, 837, 810, 776, 732, 694,
671, 649 cmꢀ1. HRMS (ESI): m/z = [M+Na]+: 981.4015 (calcd: m/
20
20
1172, 1110, 1032, 950, 886, 853, 809, 773, 741 cmꢀ1. HRMS (ESI):
z = 981.4019). ½
a
ꢁ
¼ þ125:7 (c 0.5, CHCl3), ½
a
ꢁ
¼ þ153:5 (c
589
546
20
589
20
20
m/z = [M+Na]+: 315.1045 (calcd: m/z = 315.1050).: ½
a
ꢁ
¼ ꢀ140:6
0.5, CHCl3), ½
a
ꢁ
¼ þ450:2 (c 0.5, CHCl3), ½
aꢁ
¼ þ764:0 (c 0.5,
405
365
20
546
20
405
(c 1.0, CHCl3), ½
aꢁ
¼ ꢀ166:0 (c 1.0, CHCl3), ½
aꢁ
¼ ꢀ324:7 (c 1.0,
CHCl3).
20
CHCl3), ½
a
ꢁ
¼ ꢀ413:8 (c 1.0, CHCl3).
365
4.7. (2R,3R,4aR,9aR)-7-(2-Diphenylphosphino-4,6-di-tert-
pentyl-phenoxy)-2,3-dimethoxy-2,3-dimethyl-5,5,9,9-
tetraphenyl-hexahydro-[1,4]dioxino[2,3-e][1,3,2]-
dioxaphosphepine 1b
4.5. (2R,3R,5R,6R)-2,3-Bis(hydroxydiphenylmethyl)-5,6-
dimethoxy-5,6-dimethyl-1,4-dioxane 2 (TARTROL)
Under an argon atmosphere 90.2 ml (90.2 mmol, 4.4 equiv) of
phenylmagnesium bromide (1 M in THF) was placed in a 250 ml
Schlenk-flask and cooled to 0 °C. To this Grignard solution was
slowly added 6.0 g (20.5 mmol, 1.0 equiv) of diester 4 in 80 ml of
dry THF. After completion of the addition, the reaction mixture
was heated at reflux for 2 h and then stirred at room temperature
for 18 h. Then the mixture was hydrolyzed under cooling in an ice/
water bath by the careful addition of 200 ml of aqueous saturated
NH4Cl solution. A precipitate, initially formed during the hydroly-
sis, was re-dissolved under intense stirring. Next, 10% aqueous
HCl was added until the pH was in the range of 7–8. The orange or-
ganic layer was separated, and the aqueous layer was extracted
three times with 100 mL of EtOAc. The combined organic layers
were washed with brine and dried over MgSO4. The solvent was re-
moved by rotary evaporation and the resulting crude product was
purified by flash column chromatography on silica gel with cyclo-
hexane/EtOAc (20:1) to afford TARTROL 2 as a white foam (7.1 g,
13.1 mmol, 64%). A sample used for X-ray analysis was re-crystal-
lized from ether. Rf = 0.28 (cyclohexane/EtOAc, 10:1), mp = 96 °C,
1H NMR (300 MHz, CDCl3): d = 7.98–7.96 (m, 4H, CHAr), 7.44–7.22
(m, 6H, CHAr), 7.14–7.02 (m, 10H, CHAr), 4.38 (s, 2H, CH), 4.33 (s,
2H, OH), 2.57 (s, 6H, OCH3), 0.99 (s, 6H, CH3). 13C NMR (APT,
75 MHz, CDCl3): d = 146.0 (CqAr), 142.8 (CqAr), 127.9 (CHAr), 127.7
(CHAr), 127.2(CHAr), 127.1 (CHAr), 126.8 (CHAr), 98.5 (COCH3), 79.4
(COH), 75.9 (CH), 47.6 (COCH3), 17.1 (CH3). IR (neat): 3355, 3057,
3021, 2992, 2943, 2830, 2244, 1598, 1491, 1446, 1371, 1318,
According to general procedure I, phosphine 8b (1.97 g,
4.56 mmol) was reacted with DABCO (4.09 g, 36.48 mmol) and
PCl3 (2.8 ml, 5.47 mmol) in 25 mL of CH2Cl2 before diol 2 (3.70 g,
6.84 mmol) in 25 mL of CH2Cl2 was added. The crude product
was purified by flash column chromatography (cyclohexane/
CH2Cl2, 5:1) to afford 1b (2.26 g, 2.29 mmol, 50%) as a white foam.
Rf = 0.6 (cyclohexane/CH2Cl2, 2:1), mp = 118–125 °C, 1H NMR
(300 MHz, CDCl3): d = 7.91 (s, 2H, HAr), 7.59 (d, J = 7.6 Hz, 2H,
HAr), 7.35–6.98 (m, 23H, HAr), 6.92 (t, J = 7.2 Hz, 2H, HAr), 6.80 (t,
J = 7.4 Hz, 2H, HAr), 6.61 (s, 1H, HAr), 4.84 (d, J = 11.5 Hz, 1H, CH),
4.80 (d, J = 11.6 Hz, 1H, CH), 2.70 (s, 3H, OCH3), 2.37 (s, 3H,
OCH3), 1.86–1.63 (m, 2H, CH2), 1.42–1.40 (m, 2H, CH2), 1.25 (s,
6H, (CH3)2), 1.10 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.07 (s, 3H, CH3),
1.02 (s, 3H, CH3), 0.58 (t, J = 7.2 Hz, 3H, CH2CH3), 0.51 (t,
J = 7.1 Hz, 3H, CH2CH3). 13C NMR (APT, 75 MHz, CDCl3): d = 147.6,
147.5, 146.5, 146.4, 142.8, 141.0, 140.9, 139.5, 139.4, 139.2,
133.9, 133.6, 131.4, 131.3, 131.2, 129.5, 128.5, 128.4, 128.1,
128.0, 127.9, 127.8, 127.6, 127.5, 126.6, 126.5, 126.4, 99.0, 98.6,
86.3, 86.4, 83.0, 82.9, 75.7, 75.2, 47.7, 46.8, 39.0, 37.5, 36.8, 33.2,
29.3, 28.8, 28.2, 28.0, 17.0, 9.7, 9.0. 31P NMR {1H} (121 MHz, CDCl3):
d = 140.0 (d, J = 109.4 Hz, P(OR)3), ꢀ15.0 (d, J = 109.3 Hz, PR3). IR
(neat): 3054, 2958, 2872, 2831, 1583, 1492, 1445, 1432, 1419,
1373, 1360, 1297, 1263, 1204, 1128, 1030, 989, 924, 905, 834,
810, 783, 770, 739, 695, 671, 649 cmꢀ1
. HRMS (ESI): m/
20
z = [M+Na]+: 1009.4354 (calcd: m/z = 1009.4332). ½
aꢁ
¼ þ79:5 (c
589
20
20
405
1122, 1034, 908, 847 cmꢀ1. HRMS (ESI): m/z = [M+Na]+: 563.2400
0.5, CHCl3), ½
a
ꢁ
¼ þ99:8 (c 0.5, CHCl3), ½
aꢁ
¼ þ296:5 (c 0.5,
546
20
589
(calcd:
m/z = 563.2404).
½
a
ꢁ
¼ þ50:6
(c 1.0,
CHCl3),
CHCl3).
20
20
405
½
a
ꢁ
¼ þ62:0 (c 1.0, CHCl3),
½aꢁ
¼ þ154:1 (c 1.0, CHCl3),
546
20
½
aꢁ
¼ þ226:0 (c 1.0, CHCl3).
4.8. (2R,3R,4aR,9aR)-7-(2-Diphenylphosphino-6-tert-pentyl-
phenoxy)-2,3-dimethoxy-2,3-dimethyl-5,5,9,9-tetraphenyl-
hexahydro-[1,4]dioxino[2,3-e][1,3,2]-dioxaphosphepine 1c
365
4.6. (2R,3R,4aR,9aR)-7-(2,4-Di-tert-butyl-6-diphenyl-
phosphino-phenoxy)-2,3-dimethoxy-2,3-dimethyl-5,5,9,9-
tetraphenyl-hexahydro-[1,4]dioxino[2,3-e][1,3,2]-
dioxaphosphepine 1a
According to general procedure I, phosphine 8c (1.24 g,
3.43 mmol) was reacted with DABCO (3.08 g, 27.44 mmol) and
PCl3 (2.1 ml, 4.2 mmol) in 25 mL of CH2Cl2 before diol 2 (2.78 g,
5.14 mmol) in 25 mL of CH2Cl2 was added. The crude product
was purified by flash column chromatography (cyclohexane/
CH2Cl2, 4:1) to afford 1c (1.66 g, 1.8 mmol, 53%) as a white foam.
Rf = 0.45 (cyclohexane/CH2Cl2, 4:1), mp = 110–115 °C, 1H NMR
(300 MHz, CDCl3): d = 7.87 (s, 2H, HAr), 7.54 (d, J = 7.4 Hz, 2H,
According to general procedure I, phosphine 8a (2.02 g,
5.0 mmol) was reacted with DABCO (4.49 g, 40.0 mmol) and PCl3
(3.0 mL, 6.0 mmol) in 25 mL of CH2Cl2 before diol 2 (4.05 g,
7.5 mmol) in 25 mL of CH2Cl2 was added. The crude product was
purified by flash column chromatography (cyclohexane/CH2Cl2,
4:1) to afford 1a (2.97 g, 3.1 mmol, 62%) as a white foam. Rf = 0.4
(cyclohexane/CH2Cl2, 4:1), mp = 115–120 °C, 1H NMR (300 MHz,
CDCl3): d = 7.88 (s, 2H, HAr), 7.51 (d, J = 7.6 Hz, 2H, HAr), 7.33–
7.04 (m, 21H, HAr), 6.94–6.79 (m, 6H, HAr), 6.70 (dd, J = 3.6 Hz,
2.6 Hz, 1H, HAr), 4.86 (d, J = 10.8 Hz, 1H, CH), 4.75 (d, J = 10.8 Hz,
1H, CH), 2.60 (s, 3H, OCH3), 2.33 (s, 3H, OCH3), 1.20 (s, 9H,
HAr), 7.31–6.98 (m, 23H, HAr), 6.88 (t, J = 6.7 Hz, 3H, HAr), 6.76 (t,
J = 7.1 Hz, 2H, Ar), 6.65 (d, J = 6.6 Hz, 1H, HAr), 4.79 (d,
H
J = 11.9 Hz, 1H, CH), 4.76 (d, J = 11.7 Hz, 1H, CH), 2.67 (s, 3H,
OCH3), 2.32 (s, 3H, OCH3), 1.64–1.57 (m, 2H, CH2), 1.20 (s, 6H,
(CH3)2), 1.06 (s, 3H, CH3), 1.02 (s, 3H, CH3), 0.47 (t, J = 7.0 Hz, 3H,
CH2CH3). 13C NMR (APT, 75 MHz, CDCl3): d = 147.5, 146.3, 146.2,

M. Dindarog˘lu et al. / Tetrahedron: Asymmetry 24 (2013) 657–662
661
133.9, 133.7, 133.2, 131.4, 131.3, 129.9, 129.4, 128.5, 128.3, 128.2,
128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 126.6, 126.5, 126.4, 123.0,
1581, 1492, 1445, 1432, 1402, 1372, 1203, 1127, 1030, 982, 907,
843, 819, 765, 740, 696, 671 cmꢀ1. HRMS (ESI): m/z = [M+Ag]+:
20
589
98.9, 98.6, 75.7, 75.2, 47.7, 46.8, 38.9, 33.0, 29.5, 28.9, 17.0, 9.8. 31
P
1029.2230 (calcd: m/z = 1029.2239). ½
aꢁ
¼ þ219:1 (c 0.5, CHCl3),
20
546
NMR {1H} (121 MHz, CDCl3): d = 140.4 (d, J = 111.2 Hz, P(OR)3),
ꢀ15.5 (d, J = 111.2 Hz, PR3). IR (neat): 3053, 2953, 2872, 2830,
1583, 1492, 1445, 1432, 1400, 1373, 1301, 1264, 1203, 1140,
1128, 1030, 1014, 989, 924, 905, 837, 811, 739, 717, 696,
½aꢁ
¼ þ269:4 (c 0.5, CHCl3).
4.11. (2R,3R,4aR,9aR)-7-(2-Diphenylphosphino-6-methyl-
phenoxy)-2,3-dimethoxy-2,3-dimethyl-5,5,9,9-tetraphenyl-
hexahydro-[1,4]dioxino[2,3-e][1,3,2]-dioxaphosphepine 1f
671 cmꢀ1
z = 939.3550).
.
HRMS (ESI): m/z = [M+Na]+: 939.3551 (calcd: m/
20
20
½
a
ꢁ
¼ þ137:1 (c 0.5, CHCl3),
½aꢁ
¼ þ169:0 (c
589
546
20
405
20
365
0.5, CHCl3), ½
aꢁ
¼ þ470:0 (c 0.5, CHCl3), ½
aꢁ
¼ þ777:0 (c 0.5,
Accordingto generalprocedureI, phosphine8f (1.53 g, 5.0 mmol)
was reacted with DABCO (4.49 g, 40.0 mmol) and PCl3 (3.0 mL,
6.0 mmol) in 25 mL of CH2Cl2 before diol 2 (4.05 g, 7.5 mmol) in
25 mL of CH2Cl2 was added. The crude product was purified by flash
column chromatography (cyclohexane/CH2Cl2, 4:1) to afford 1f
(2.19 g, 2.54 mmol, 51%) as a white foam. Rf = 0.3 (cyclohex-
ane:CH2Cl2, 4:1), mp = 125–130 °C, 1H NMR (300 MHz, CDCl3):
d = 7.85 (d, J = 8.0 Hz, 2H, HAr), 7.66 (t, J = 7.9 Hz, 3H, HAr), 7.48–
7.39 (m, 2H, HAr), 7.33–7.26 (m, 7H, HAr), 7.19–7.16 (m, 6H, HAr),
7.12–6.99 (m, 11H, HAr), 6.85 (t, J = 7.5 Hz, 1H, HAr), 6.55 (ddd,
J = 7.3 Hz, 3.0 Hz, 1.3 Hz, 1H, HAr), 4.75 (d, J = 10.9 Hz, 1H, CH), 4.70
(d, J = 10.9 Hz, 1H, CH), 2.67 (s, 3H, OCH3), 2.33 (s, 3H, OCH3), 2.14
(s, 3H, Ph-CH3), 1.07 (s, 3H, CH3), 1.00 (s, 3H, CH3). 13C NMR (APT,
75 MHz, CDCl3): d = 146.1, 146.0, 140.9, 140.8, 134.4, 134.1, 133.8,
131.8, 131.7, 131.4, 131.2, 131.1, 129.8, 128.5, 128.3, 128.2, 128.1,
127.9, 127.7, 127.5, 127.2, 126.9, 126.7, 126.6, 126.4, 125.6, 123.8,
98.9, 98.6, 86.5, 82.6, 75.5, 75.0, 47.7, 46.9, 17.0. 31P NMR {1H}
(121 MHz, CDCl3): d = 139.3 (d, J = 69.4 Hz, P(OR)3), ꢀ16.6 (d,
J = 69.4 Hz, PR3). IR (neat): 3054, 2945, 2830, 1583, 1491, 1445,
1433, 1408, 1373, 1255, 1205, 1176, 1140, 1128, 1030, 984, 925,
CHCl3).
4.9. (2R,3R,4aR,9aR)-7-(2-tert-Butyl-6-diphenylphosphino-
phenoxy)-2,3-dimethoxy-2,3-dimethyl-5,5,9,9-tetraphenyl-
hexahydro-[1,4]dioxino[2,3-e][1,3,2]-dioxaphosphepine 1d
According to general procedure I, phosphine 8d (1.74 g,
5.0 mmol) was reacted with DABCO (4.49 g, 40.0 mmol) and PCl3
(3.0 mL, 6.0 mmol) in 25 mL of CH2Cl2 before diol 2 (4.05 g,
7.5 mmol) in 25 mL of CH2Cl2 was added. The crude product was
purified by flash column chromatography (cyclohexane/CH2Cl2,
4:1) to afford 1d (2.07 g, 2.30 mmol, 46%) as a white foam.
Rf = 0.4 (cyclohexane/CH2Cl2, 4:1), mp = 115–125 °C, 1H NMR
(300 MHz, CDCl3): d = 7.87 (s, 2H, HAr), 7.53 (d, J = 7.8 Hz, 2H,
HAr), 7.34–7.31 (m, 5H, HAr), 7.23–7.04 (m, 16H, HAr), 6.96–6.80
(m, 7H, HAr), 6.71 (ddd, J = 7.5 Hz, 3.0 Hz, 1.6 Hz, 1H, HAr), 4.86
(d, J = 10.8 Hz, 1H, CH), 4.75 (d, J = 10.8 Hz, 1H, CH), 2.61 (s, 3H,
OCH3), 2.33 (s, 3H, OCH3), 1.21 (s, 9H, ((CH3)3), 1.06 (s, 3H, CH3),
1.02 (s, 3H, CH3). 13C NMR (APT, 75 MHz, CDCl3): d = 147.4, 140.9,
139.1, 133.9, 133.8, 133.7, 133.6, 133.5, 131.4, 131.3, 129.7,
128.7, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7,
127.5, 126.6, 126.5, 126.4, 126.3, 123.0, 99.0, 98.7, 86.6, 86.4,
75.7, 75.1, 47.6, 46.9, 35.3, 30.7, 17.0. 31P NMR {1H} (121 MHz,
CDCl3): d = 138.5 (d, J = 118.2 Hz, P(OR)3), ꢀ16.5 (d, J = 118.2 Hz,
PR3). IR (neat): 3054, 2945, 2829, 1492, 1445, 1432, 1400, 1389,
1372, 1360, 1204, 1139, 1128, 1029, 1013, 981, 924, 904, 839,
906, 874, 840, 817, 740, 696, 671 cmꢀ1
. HRMS (ESI): m/
20
z = [M+Na]+: 883.2925 (calcd: m/z = 883.2924). ½
aꢁ
¼ þ113:3 (c
589
20
20
0.5, CHCl3), ½
a
ꢁ
¼ þ138:5 (c 0.5, CHCl3), ½
aꢁ
¼ þ375:1 (c 0.5,
546
405
20
CHCl3), ½
a
ꢁ
¼ þ598:2 (c 0.5, CHCl3).
365
References
814, 747, 695, 666, 650 cmꢀ1
.
HRMS (ESI): m/z = [M+Na]+:
1. (a)Privileged Chiral Ligands and Catalysts; Zhou, Qi-Lin, Ed.; WILEY-VCH, 2011;
(b)Phosphorus Ligands in Asymmetric Catalysis; Börner, Armin, Ed.; WILEY-VCH,
2008. Vols. 1–3.
2. (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345; (b) Shimizu, H.;
Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405–5432.
20
925.3391 (calcd: m/z = 925.3393). ½
a
ꢁ
¼ þ189:3 (c 0.5, CHCl3),
589
20
546
20
405
½
aꢁ
¼ þ230:7 (c 0.5, CHCl3), ½
aꢁ
¼ þ650:9 (c 0.5, CHCl3).
3. (a) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Claver, C.; Pamies, O.; Dieguez, M.
Chem. Rev. 2011, 111, 2077–2118; (b) Fernandez-Perez, H.; Etayo, P.; Panossian,
A.; Vidal-Ferran, A. Chem. Rev. 2011, 111, 2119–2176; (c) Löhr, S.; Holz, J.;
Börner, A. ChemCatChem 2011, 3, 1708–1730.
4. (a) Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.; Schmalz, H.-G. Adv. Synth. Catal.
2002, 344, 868–883; (b) Velder, J.; Robert, T.; Weidner, I.; Neudörfl, J.-M.; Lex,
J.; Schmalz, H.-G. Adv. Synth. Catal. 2008, 350, 1309–1315; (c) Dindarog˘lu, M.;
Falk, A.; Schmalz, H.-G. Synthesis 2013, 527–535.
5. Cu-catalyzed 1,4-addition of Grignard reagents: (a) Robert, T.; Velder, J.;
Schmalz, H.-G. Angew. Chem., Int. Ed. 2008, 47, 7718–7721; (b) Naeemi, Q.;
Robert, T.; Kranz, D. P.; Velder, J.; Schmalz, H.-G. Tetrahedron: Asymmetry 2011,
22, 887–892. see also Ref. 4c.
6. Cu-catalyzed allylic substitution of Grignard reagents: (a) Lölsberg, W.; Ye, S.;
Schmalz, H.-G. Adv. Synth. Catal. 2010, 2023–2031; (b) Lölsberg, W.; Werle, S.;
Neudörfl, J.-M.; Schmalz, H.-G. Org. Lett. 2012, 14, 5996–5999.
7. Rh-catalyzed hydroformylation: Robert, T.; Romanski, S.; Abiri, Z.; Wassenaar,
J.; Reek, J. N. H.; Schmalz, H.-G. Organometallics 2010, 29, 478–483.
8. Rh-catalyzed intramolecular [4+2]-cycloaddition: Falk, A.; Fiebig, L.; Neudörfl,
J.-M.; Adler, A.; Schmalz, H.-G. Adv. Synth. Catal. 2011, 353, 3357–3362.
9. Ni-catalyzed hydrocyanation: Falk, A.; Göderz, A.-L.; Schmalz, H.-G. Angew.
Chem., Int. Ed. 2013, 52, 1576–1580.
10. Co-catalyzed 1,4-hydrovinylation of dienes: (a) Bohn, M. A.; Schmidt, A.; Hilt,
G.; Dindarog˘lu, M.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2011, 50, 9689–9693;
(b) Arndt, M.; Dindarog˘lu, M.; Schmalz, H.-G.; Hilt, G. Org. Lett. 2011, 13, 6236–
6239.
4.10. (2R,3R,4aR,9aR)-7-(3-Diphenylphosphino-biphenyl-2-
yloxy)-2,3-dimethoxy-2,3-dimethyl-5,5,9,9-tetraphenyl-
hexahydro-[1,4]dioxino[2,3-e][1,3,2]-dioxaphosphepine 1e
According to general procedure I, phosphine 8e (1.84 g,
5.0 mmol) was reacted with DABCO (4.49 g, 40.0 mmol) and PCl3
(3.0 mL, 6.0 mmol) in 25 mL of CH2Cl2 before diol 2 (4.05 g,
7.5 mmol) in 25 mL of CH2Cl2 was added. The crude product was
purified under nitrogen by flash column chromatography (cyclo-
hexane/CH2Cl2, 4:1) to afford 1e (2.44 g, 2.64 mmol, 53%) as a
white foam. Rf = 0.3 (cyclohexane/CH2Cl2, 2:1), mp = 115–120 °C,
1H NMR (300 MHz, CDCl3): d = 7.70 (d, J = 7.1 Hz, 2H, HAr), 7.52
(d, J = 7.6 Hz, 2H, HAr), 7.30–7.28 (m, 4H, HAr), 7.25–7.19 (m, 8H,
HAr), 7.17–7.12 (m, 9H, HAr), 7.07–7.04 (m, 6H, HAr), 7.02–6.97
(m, 2H, HAr), 6.89 (t, J = 7.7 Hz, 2H, HAr), 6.77 (ddd, J = 7.6 Hz,
3.3 Hz, 1.7 Hz, 1H, HAr), 6.29 (d, J = 7.3 Hz, 2H, HAr), 4.64 (d,
J = 10.7 Hz, 1H, CH), 4.49 (d, J = 10.7 Hz, 1H, CH), 2.50 (s, 3H,
OCH3), 2.30 (s, 3H, OCH3), 1.03 (s, 3H, CH3), 1.02 (s, 3H, CH3). 13C
NMR (APT, 75 MHz, CDCl3): d = 152.7, 152.6, 152.5, 152.4, 147.0,
146.9, 141.1, 139.5, 139.4, 138.2, 138.1, 137.1, 137.0, 136.4,
136.3, 135.2, 135.1, 134.2, 134.1, 133.9, 133.8, 133.7, 132.3,
131.3, 131.2, 131.1, 130.9, 130.8, 130.4, 129.8, 128.6, 128.3,
128.2, 127.8, 127.5, 127.3, 126.7, 126.6, 126.4, 125.9, 124.0, 98.8,
98.6, 86.3, 86.2, 82.6, 82.5, 75.3, 74.7, 47.4, 46.9, 17.0, 16.9. 31P
NMR {1H} (121 MHz, CDCl3): d = 137.1 (d, J = 106.4 Hz, P(OR)3),
ꢀ15.9 (d, J = 106.4 Hz, PR3). IR (neat): 3053, 2945, 2830, 1599,
11. Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, 92–138.
12. Brunel, J. M. Chem. Rev. 2005, 105, 857–898.
13. (a) Berens, U.; Leckel, D.; Oepen, S. C. J. Org. Chem. 1995, 60, 8204–8208; (b)
Haag, D.; Runsink, J.; Scharf, H.-D. Organometallics 1998, 17, 398–409.
14. For the use of C2-symmetric diphosphane ligands containing the TARTROL core
unit, see: (a) Berens, U.; Selke, R. Tetrahedron: Asymmetry 1996, 7, 2055–2064;
(b) Li, W.; Waldkirch, J. P.; Zhang, X. J. Org. Chem. 2002, 67, 7618–7623; (c)
Marques, C. S.; Burke, A. J. Tetrahedron: Asymmetry 2007, 18, 1804–1808; (d)
Marques, C. S.; Burke, A. J. Eur. J. Org. Chem. 2012, 22, 4232–4239.

662
M. Dindarog˘lu et al. / Tetrahedron: Asymmetry 24 (2013) 657–662
15. (a) Ley, S. V.; Priepke, H. W. M.; Warriner, S. L. Angew. Chem., Int. Ed. 1994, 33,
2290–2292; (b) Ley, S. V.; Douglas, N. L.; Osborn, H. M. I.; Owen, D. R.; Priepke,
H. W. M.; Warriner, S. L. Synlett 1996, 793–795; (c) Ley, S. V.; Barlow, J. S.;
Dixon, D. J.; Foster, A. C.; Reynolds, D. J. J. Chem. Soc., Perkin Trans. 1 1999,
1627–1629.
Å; unit cell: a = 9.7760(5) Å, b = 11.4835(6) Å, c = 30.0220(15) Å; V = 3370.4(3)
Å3; Z = 4; d (calcd) = 1.212 g/cm3; F(0 0 0) 1320;
-range: 1.36°–27.00°; 4109
independent reflexes; R indices [I > 2 (I)]: R1 = 0.0394, wR2 = 0.0788; residual
H
r
electron density: 0.182 and -0.209 eÅ3. Structure determination with direct
methods (SHELXS). CCDC 911863 contains the Supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
16. Bellec, N.; Montalban, A. G.; Williams, D. B. G.; Cook, A. S.; Anderson, M. E.;
Feng, X.; Barrett, A. G. M.; Hoffman, B. M. J. Org. Chem. 2000, 65, 1774–1779.
17. X-ray crystal structure of 4: Formula: C12H20O8, crystal size: 0.3 ꢂ 0.2 ꢂ 0.1 mm;
orthorhombic; space group P21221; 100 K; k = 0.71073 Å; unit cell:
a = 7.5641(4) Å, b = 9.1334(6) Å, c = 10.3354(7) Å; V = 714.03(8) Å3; Z = 2; d
19. Reviews: (a) López, F.; Minaard, J. A.; Feringa, B. L. Acc. Chem. Res. 2007, 40,
179–188; (b) Harutyunyan, M. S.; den Hartog, T.; Geurts, K.; Minnard, A. J.;
Feringa, B. L. Chem. Rev. 2008, 108, 2824–2852.
(calcd) = 1.359 g/cm3; F(0 0 0) 312;
H-range: 2.23°–26.99°; 933 independent
reflexes; R indices [I > 2
r
(I)]: R1 = 0.0265, wR2 = 0.0680; residual electron
20. 1,4-Addition reactions were monitored by GC–MS using an Agilent GC 6890N
gas chromatograph equipped with a Hewlett Packard 5973N mass selective
detector. Enantiomeric ratios were determined by chiral GC analysis using an
density: 0.185 and ꢀ0.172 eÅ3. Structure determination with direct methods
(SHELXS). CCDC 911862 contains the Supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Agilent GC 6890N gas chromatograph and a BGB 176 SE column
(30 m ꢂ 0.25 mm).
18. X-ray crystal structure of
2
Et2O: Formula: C38H46O7, crystal size:
0.4 ꢂ 0.3 ꢂ 0.3 mm; orthorhombic; space group P212121; 100 K; k = 0.71073