Synthesis of chiral biphenol-based diphosphonite ligands and their application in palladium-catalyzed intermolecular asymmetric allylic amination reactions

Article abstract of DOI:10.1002/asia.201000697

A library of new 2,2'-bis(diphenylphosphinoyloxy)-1,1'-binaphthyl (binapo)-type chiral diphosphonite ligands was designed and synthesized based on chiral 3,3',5,5',6,6'-hexasubstituted biphenols. These bop ligands have exhibited excellent efficiency in a palladium-catalyzed intermolecular allylic amination reaction, which provides a key intermediate for the total synthesis of Strychnos indole alkaloids with enantiopurities of up to 96% ee. A library of chiral diphosphonite (bop) ligands was synthesized based on chiral hexasubstituted biphenols with fine-tuning capability. Their application for the synthesis of a key intermediate to indole alkaloids through a palladium-catalyzed intermolecular asymmetric allylic amination is reported (TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl, dba=dibenzylideneacetone). Copyright

Full text of DOI:10.1002/asia.201000697

FULL PAPERS
DOI: 10.1002/asia.201000697
Synthesis of Chiral Biphenol-Based Diphosphonite Ligands and Their
Application in Palladium-Catalyzed Intermolecular Asymmetric Allylic
Amination Reactions
Ce Shi, Chih-Wei Chien, and Iwao Ojima*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Abstract:
A library of new 2,2’-bis(diphenylphosphinoyloxy)-1,1’-binaphthyl
(binapo)-type chiral diphosphonite ligands was designed and synthesized based on
chiral 3,3’,5,5’,6,6’-hexasubstituted biphenols. These bop ligands have exhibited ex-
cellent efficiency in a palladium-catalyzed intermolecular allylic amination reac-
tion, which provides a key intermediate for the total synthesis of Strychnos indole
alkaloids with enantiopurities of up to 96% ee.
Keywords: amination · biphenols ·
chirality · ligands · palladium
Introduction
et al.[2,9] and a series of P–N ligands developed by Pfaltz,
Helmchen, and Williams independently[10] have been widely
used. However, these chiral ligands do not always achieve
high enantioselectivity and catalyst efficiency in different re-
action systems.[11] Thus, there is a continuous need for new
and efficacious chiral ligands for asymmetric allylic substitu-
tion reactions. A diphosphonite ligand 2,2’-bis(diphenyl-
phosphinoyloxy)-1,1’-binaphthyl (binapo), originally devel-
oped by Grubbs and DeVries for asymmetric hydrogena-
tion,[12] was found to be effective and better than 2,2’-bis(di-
phenylphosphino)-1,1’-binaphthyl (binap) in palladium-cata-
lyzed allylic substitution reactions.[13] The efficacy of binapo
has been demonstrated in several total syntheses of natural
products by Mori and co-workers[14] However, the highest
enantioselectivity reported for the palladium/(S)-binapo cat-
alyst is 84% ee and no systematic modifications of binapo
had been reported. Thus, the usage of binapo and chiral di-
phosphonite ligands has been limited.
We have designed and synthesized a series of new chiral
biphenol compounds (1) that contain various substituents at
the 3,3’-positions,[15] and used them to create the libraries of
novel monodentate phosphite and phosphoramidite ligands
with fine-tuning capabilities.[15–16] These novel monodentate
phosphorus ligands have demonstrated excellent efficiency
in various transition-metal-catalyzed asymmetric transfor-
mations.[15–16] We recognized that the enantiopure C2-sym-
metric biphenols 1 would also serve as the axial chirality
component of binapo-type novel diphosphonite (bop) li-
gands with wide bite angles (Scheme 1). We hypothesized
Metal-catalyzed asymmetric reactions have been playing an
important role in the synthesis of biologically active substan-
ces.[1] Among various transformations, transition-metal-cata-
lyzed allylic substitution reactions provide unique and pow-
erful methods for the regio- and stereocontrolled formation
of carbon–carbon bonds and carbon–heteroatom bonds.[2]
Whilst most enantioselective versions of these reactions are
using palladium complexes as the metal catalysts,[3] the use
of molybdenum,[4] tungsten,[5] ruthenium,[6] rhodium,[7] and
iridium catalysts[8] has been steadily increasing, albeit their
efficiencies are not as high as that of palladium catalysts.
Thus, chiral palladium catalysts have been used almost ex-
clusively for applications of asymmetric allylic substitutions
in the total synthesis of complex natural products and their
congeners.[2,9]
Extensive efforts have been made for the development of
efficient chiral ligands for palladium-catalyzed asymmetric
allylic substitution reactions.[2] Among the most successful li-
gands, “modular” diphosphine ligands developed by Trost
[a] C. Shi, C.-W. Chien, Prof. Dr. I. Ojima
Department of Chemistry
State University of New York at Stony Brook
Stony Brook, New York 11794-3400 (USA)
Fax : (+1)631-632-7942
E-mail: iojima@notes.cc.sunysb.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000697.
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Chem. Asian J. 2011, 6, 674 – 680

we selected this process as a showcase to examine the validi-
ty of our combinatorial approach to the optimization of the
process through fine-tuning of the novel bop ligands.
Herein, we report the design and synthesis of a series of
enantiopure BOP ligands and their application to the inter-
molecular asymmetric allylic amination process.
Scheme 1. Biphenol-based diphosphonite ligands (bops).
Results and Discussion
that a judicious choice of substituents at the 3,3’-positions of
the bop ligand would influence the conformational rigidity
of the bop/metal complex by controlling the orientation of
the aryl groups on the phosphorus atoms. The development
of chiral ligands bearing fine-tuning capability based on
easily modifiable core structures is crucial for a practical
combinatorial approach to the selection of the most-suitable
ligand for a specific catalytic asymmetric process. Thus, we
set out to develop a series of novel bop ligands with a varie-
ty of substituents at the 3,3’-positions.
Enantiopure biphenol (R)-1a was prepared by following our
previously reported procedure.[17] The tert-butyl groups at
the 3,3’-positions of (R)-1 were removed by treating with
AlCl3 in nitromethane/toluene in a transfer Friedel–Crafts
reaction to give biphenol (R)-1b without any loss of enan-
tiopurity.[15,18] The biphenols (R)-1c–e (R=Br, Me and Ph,
respectively) were prepared from (R)-1b by using our previ-
ously reported procedures.[15] Biphenols (R)-1 f–h bearing
benzyl or substituted benzyl groups (Ar=Ph, 4-MeC6H4,
and 3,5-Me2C6H3, respectively) were synthesized through a
copper(I)-mediated cross-coupling reaction[19] from (R)-3,3’-
bis(chloromethyl)biphenol, followed by removal of the
methyl groups in excellent overall yields (Scheme 3).
In 2003, Mori and co-workers reported the total synthesis
of Strychnos indole alkaloids using a palladium/binapo com-
plex to catalyze the key intermolecular allylic amination re-
action to construct the critical chiral center (Scheme 2).[14c]
The 3,3’-disubstituted-biphenol-based diphosphonite bop
ligands were synthesized according to the synthetic protocol
described for the binapo ligand (Scheme 4).[20] The coupling
reaction between biphenols (R)-1b–h and chlorodiarylphos-
phines (ClPAr2) proceeded smoothly, affording the corre-
sponding diphosphonites in good to excellent yields. By
using this protocol, we created a small bop ligand library,
(R)-5a–g, (R)-6a,b, and (R)-7, shown in Scheme 4 (only the
R series is shown for simplicity).
For initial bop-ligand screening, we employed only slightly
modified conditions for the palladium/binapo catalyst
system reported by Mori et al (Scheme 5).[14c] 2-TBSO-meth-
ylcyclohex-2-en-1-yl vinylcarbonate (8a; TBS=tert-butyldi-
methylsilyl) was used as the allylic component as it was the
best substrate in Moriꢁs reactions with a palladium/binapo
catalyst, and N-tosyl-2-bromoaniline (3) as the amine com-
ponent. As solvent, tetrahydrofuran and N,N-dimethylform-
amide were used with the concentration of 8a at 0.05m and
a palladium/ligand ratio of 1:1.5. Ligands (R)-5a–d were
screened first under these conditions (Table 1).
Scheme 2. Moriꢁs total synthesis of Strychnos indole alkaloids via key in-
termediate 4a obtained from Pd/binapo-catalyzed asymmetric allylic ami-
nation.
All reactions gave the desired product (R)-4a, but with
different conversion and enantioselectivities as the substitu-
ents at the 3,3’-positions of the biphenol moieties of bop li-
gands varied. We also observed the formation of 9a, which
was not reported previously.[14c] It is highly likely that the
ceiling of the chemical yield (64–80%) reported for the for-
mation of 4a by Mori et al. is attributed to the considerable
formation of 9a. The ratio of 4a to 9a was determined by
1H NMR spectroscopic analysis. Results from the reactions
in tetrahydrofuran indicate that the reaction slows down as
the size of the 3,3’-substituents increases (Table 1, entries 1–
4). When 5a (R=H) and 5c (R=Me) were used, the reac-
tions were complete in 48 hours (Table 1, entry 1) and
60 hours (Table 1, entry 3), respectively. However, when
The product (S)-4a from this key reaction was converted
into versatile key intermediate 5 through several steps,
which was used as a common intermediate in the total syn-
theses of (À)-tubifoline, (À)-dehydrotubifoline, and (À)-
strychnine (Scheme 2).[14c]
As shown in Scheme 2, the best result for the key step,
that is, the intermolecular asymmetric allylic amination, was
84% ee and 80% yield, when the reaction was performed at
08C. Recrystalization was required in the subsequent steps
to obtain enantiomerically pure key intermediate 5.[14c] Ac-
cordingly, this very useful process still needs substantial im-
provement in its enantioselectivity and chemical yield. Thus,
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I. Ojima et al.
FULL PAPERS
Scheme 3. Synthesis of enantiopure biphenols (1b–h; only the R series is shown for simplicity). a) Me2SO4, nBu4NI, KOH, CH2Cl2; b) Br2, CHCl3;
c) H3PO4, HCl, AcOH, (CH2O)n; d) LiAlH4, THF; e) BBr3, CH2Cl2; f) [Pd
AHCTUNGTRENNUNG
ArMgBr, THF, 0–508C. THF=tetrahydrofuran, DME=1,2-dimethoxyethane.
Scheme 5. Asymmetric allylic amination of 8a (initial screening of chiral
ligands).
bulkier ligands, 5b (R=Br; Table 1, entry 2) and 5d (R=
Ph; Table 1, entry 4), were employed, the reactions gave
little or low conversion after 72 hours. When the 3,3’-sub-
stituents were changed from H to Me, the enantioselectivi-
ties increases from 65 to 89% ee (Table 1, entries 1 and 3).
The use of larger 3,3’-substituents led to a decrease in the
enantioselectivity and poor catalytic activity (Table 1, en-
tries 2 and 4). When N,N-dimethylformamide was used as
the solvent, a clear acceleration of reaction rate as well as a
substantial increase in the 4a/9a ratio (up to 95:5) was ob-
served (Table 1, entries 5 and 6). Accordingly, the combina-
Scheme 4. Synthesis of novel diphosphonite bop ligands (only the R ser-
ies is shown for simplicity).
Table 1. Initial screening of chiral ligands.
Entry
Ligand (R)-5
Solvent
t [h]
Conv. [%][a,b]
ee 4a [%] (4a/9a)[a,b]
1
2
3
4
5
6
5a
5b
5c
5d
5a
5c
THF
THF
THF
THF
DMF
DMF
48
72
60
72
12
20
100
~30
100
<5
100
100
65 (70:30)
74 (50:50)
89 (65:35)
n.d.
67 (95:5)
88 (95:5)
1
[a] Product ratio was determined by H NMR spectroscopy. [b] The enantiopurity of 4a was determined by HPLC by using Chiralpak AD-RH, CH3CN/
H2O (80:20).
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Chem. Asian J. 2011, 6, 674 – 680

Synthesis of Chiral Biphenol-Based Diphosphonite Ligands
tion of 5c (R=Me) as the chiral ligand and N,N-dimethyl-
formamide as the solvent afforded the best result in this first
screening.
Next, we screened the allylic substrates (8a–e) by using
the optimized conditions: (R)-5c as the chiral ligand in N,N-
dimethylformamide (Scheme 6). The use of TBS or triiso-
We then carried out the optimization of the bop ligands
for the reaction of 8d (R=TIPS; R’=vinyl) under the stan-
dard conditions by using our library of bop ligands (see
Scheme 4). Excellently, ligand (R)-5e (Ar=Ar’=Ph) ach-
ieved 96% ee (4b/9b=93:7) with complete conversion in
24 hours (Table 3). The introduction of substituted phenyl
groups at the 3,3’-position, that is, (R)-5 f (Ar=4-MeC6H4;
Ar’=Ph) and (R)-5g (Ar=3,5-Me2C6H3; Ar’=Ph), did not
improve the enantioselectivity or product selectivity
(Table 3, entries 2 and 3 versus Table 3, entry 1). The intro-
duction of substituted phenyls to the diarylphosphorus moi-
eties, that is, (R)-6a (R=Me; Ar’=4-MeC6H4), (R)-6b (R=
Me; Ar’=4-MeC6H4), and (R)-7 (R=PhCH2; Ar’=4-
MeC6H4), slowed down the reaction, and also lowered the
enantioselectivity as well as the product selectivity (Table 3,
entries 4–6), especially when (R)-7 was used (Table 3,
entry 6).
Scheme 6. Screening for allylic substrates 8 for the asymmetric allylic
amination.
propylsilyl (TIPS) groups as the bulky silicon protecting
group for the allylic alcohol moiety did not make large dif-
ferences in the reaction rate, enantioselectivity, or product
selectivity (Table 2). There were recognizable differences in
the enantioselectivity when vinyl, trichloroethyl, and diethyl-
phosphonyl groups were used as the substituents of the car-
bonate moiety (Table 2, entries 1–3). Thus, 8d (R=TIPS;
R’=vinyl) appears to be the best allylic substrate of the
ones examined, and the reaction of 8d achieved 91% ee at
room temperature (258C).
In addition, the effects of reaction temperature and addi-
tives were examined, by using the optimal chiral ligand (R)-
5e and allylic substrate 8d (Table 4).
Although it was reported that the best results (84% ee,
64% yield or 84% ee, 80% yield) with the use of binapo
were obtained at 08C,[14c] no advantage was observed in our
reaction (Table 4). The addition of acetic acid to the system
was detrimental to the reaction (Table 4, entry 3). The addi-
tion of triethylamine to the system accelerated the reaction,
but the enantioselectivity decreased (Table 4, entry 4). A
Table 2. Screening of allylic substrates by using (R)-5c ligand at room temperature.
Entry
1
Allylic substrate
t [h]
Conv. [%][a,b]
100
ee 4a,b [%] (4/9)[a,b,c]
8a
R=TBS
R’=vinyl
8b
R=TBS
R’=CH2CCl3
8c
20
89 (95:5)
2
3
4
5
24
16
24
30
100
100
100
100
85 (90:10)
83 (97:3)
91 (95:5)
88 (90:10)
R=TBS
R’=P(O)ACTHNURGTNEUNG(OEt)2
8d
R=TIPS
R’=vinyl
8e
R=TIPS
R’=CH2CCl3
[a] Products of entries 1–3 are 4a and 9a and those of entries 4 and 5 are 4b and 9b. [b] Product ratio was determined by 1H NMR spectroscopy.
[c] Enantiopurity was determined by HPLC by using Chiralpak AD-RH with CH3CN/H2O (80:20) for O-TBS product 4a and Chiralcel OD-H with hex-
anes/iPrOH (98:2) for O-TIPS product 4b after desilylation with 4m HCl.
Table 3. Optimization of chiral ligands for the reaction of 8d at room temperature.
Entry
Ligand
t [h]
Conv. [%][a,b]
ee 4b [%] (4b/9b)[a,b]
1
2
3
4
5
6
(R)-5e
(R)-5 f
(R)-5g
(R)-6a
(R)-6b
(R)-7
24
24
24
50
50
50
100
100
100
100
100
100
96 (93:7)
94 (89:11)
91 (90:10)
89 (85:15)
89 (80:20)
43 (65:35)
[a] Product ratio was determined by 1H NMR spectroscopy. [b] Enantiopurity of 4b was determined by HPLC by using a Chiralcel OD-H column with
hexanes/iPrOH (98:2) after desilylation with 4m HCl.
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I. Ojima et al.
FULL PAPERS
Table 4. Effects of temperature and additive.
Entry
Additive
T [8C]
t [h]
Conv. [%][a,b]
ee 4b [%] (4b/9b)[a,b]
1
2
3
4
5
6
–
–
25
0
25
25
0
24
48
24
8
17
48
100
100
<5
100
100
~80
96 (93:7)
96 (90:10)
–
88 (92:8)
91 (80:20)
77 (80:20)
AcOH (1 equiv)
NEt3 (1.1 equiv)
NEt3 (1.1 equiv)
NEt3 (1.1 equiv)
À25
[a] Product ratio was determined by 1H NMR spectroscopy. [b] Enantiopurity of 4b was determined by HPLC by using Chiralcel OD-H column with
hexanes/iPrOH (98:2) after desilylation with 4m HCl.
modest increase in enantioselectivity (88 to 91% ee) was ob-
served for the reaction at 08C, but the enantioselectivity
substantially dropped (to 77% ee) at À258C (Table 4, en-
tries 5 and 6). The product selectivity was low at 08C and
À258C, compared to that at room temperature (258C). Ac-
cordingly, the reaction was found to be optimal at room
temperature.
Furthermore, we carried out the synthesis of (S)-4b,
which is the correct enantiomer for the naturally occurring
Strychnos indole alkaloids, by using the (S)-5e ligand under
the optimized reaction conditions mentioned above, except
for 36 hours reaction time (Scheme 7). The reaction of 8d
with 3 (1.0 mmol) was run by using a slight excess of 8d
(1.2 equiv) to maximize the product yield. Then, (S)-4b with
96% ee was isolated in 97% yield.
8e as the substrate, that is, formation of the p-allylic PdII/L*
species. A molecular modeling study of the complex re-
vealed that there were two possible conformational isomers,
arising from two possible orientations of the bulky TIPS-O-
methyl group. Both orientations led to the local-energy-
minimized structures A and B (Scheme 8). The energy dif-
ference between A and B was calculated to be 14.6 kJmolÀ1,
with A being the favorable conformer. The observed energy
Scheme 8. Proposed mechanism for enantioselection by a Pd/(S)-5e cata-
lyst, leading to the highly selective formation of (S)-4b.
Scheme 7. Synthesis of (S)-4b, a key intermediate for Synchonus indole
alkaloids.
difference can be attributed to the steric repulsion between
the TIPS group and one of the phenyl moieties of the
benzyl group at the 3,3’-positions of the backbone chiral bi-
phenyl (Scheme 8). Accordingly, the predominant pathway
for the nucleophilic attack of the anion of TsNH(bromo-
phenyl) (3) should be through the A complex. In the A
complex, the nucleophilic attack from the left side obviously
suffered from the steric hindrance of the bulky TIPS group.
Thus, the reaction should proceed through attack from the
right side, leading to the formation of (S)-4b.
It is reasonable to assume that the palladium/bop ratio is
1:1 in the active catalyst species. Thus, we carried out the
molecular modeling of a simplified active catalyst species
ACHTUNGTRENNUNG
[PdIIL*(p-allyl)]+ (L*=(R)-5e) by using the Spartan pro-
gram (MM2/PM3 for energy minimization). The result after
energy minimization clearly indicated a pseudo C2-symmet-
rical structure, in which the Ph groups on the PPh2 moieties
formed a C2-symmetric environment surrounding the allyl
moiety. As anticipated, this complex had a large bite angle
(P*-Pd-P*) of 1258, which should be beneficial in achieving
high enantioselectivity in the asymmetric allylic amination
reaction.
Conclusions
Next, we constructed a cationic palladium/(S)-5e complex
with the p-allylic 2-TIPS-O-methylcyclohexenyl group,
which was the most likely intermediate in the first step of
the asymmetric allylic amination process when using 8d or
A highly efficient palladium/bop catalyst system has been
developed for the intermolecular asymmetric allylic amina-
tion reaction of 8 and 3, giving the desired product 4 with
up to 96% ee, through systematic optimization of the chiral
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Synthesis of Chiral Biphenol-Based Diphosphonite Ligands
thylamine (0.8 mL, 6 mmol) in CH2Cl2 (10 mL) at 08C. The mixture was
stirred at the same temperature for an additional 2 h. The reaction mix-
ture was then concentrated in vacuo. The residue was redissolved in tolu-
ene (10 mL) and filtered through a pad of Celite. The filtrate was concen-
trated again and the crude product was purified on a silica gel column
pretreated with NEt3 by using hexanes/NEt3 (100:1) as the eluent to give
the corresponding diphosphnite ligand (BOP), 5, 6, and 7. The characteri-
zation data for (R)-5e and (S)-5e are shown below, and those for all
other BOP ligands are summarized in the Supporting Information.
ligand, allylic substrate, and reaction variables. The results
clearly show the highly beneficial feature of bop ligands
bearing fine-tuning capability with various substituents on
the chiral biphenyl core, especially those at the 3,3’-posi-
tions. Further study on the development of bop ligands and
their applications to various catalytic asymmetric reactions
are actively underway in our laboratory.
(R)-2,2’-Bis(diphenylphosphinyloxy)-3,3’-dibenzyl-5,5’,6,6’-tetramethyl-
1,1’-biphenyl ((R)-5e): White foam; yield: 74%; m.p. 75–778C; [a]D25
=
À101 (c=2.2 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.81 (s, 6H),
1.90 (s, 6H), 3.54 (d, J=16 Hz, 2H), 3.70 (d, J=16 Hz, 2H), 6.45 (s, 2H),
7.23 ppm (m, 30H); 31P NMR (162 Hz, CDCl3): d=110.9 ppm; HRMS
(EI): m/z: calcd for C54H48O2P2: 790.3130 [M]+; found: 790.3136 (D=
+0.8 ppm); (S)-5e was synthesized in the same manner from (S)-1 f;
yield: 73%; [a]2D0 =+101 (c=1.0 in CHCl3).
Experimental Section
Materials
Enantiopure biphenols (R)-1b–e were synthesized according to our pre-
viously reported procedures.[15] N-(4-methyl-benzenesulfonyl)-2-bromoa-
niline (3),[21] 2-(hydroxymethyl)cyclohex-2-en-1-ol, 2-tert-butyldimethylsi-
loxymethyl-2-cyclohexenol,[14c] 2-(1-tert-butyldimethylsiloxymethyl)cyclo-
hex-2-en-1-yl ethenyl carbonate (8a),[14c] and 2-(tert-butyldimethylsiloxy-
methyl)cyclohex-2-en-1-yl diethylphosphinate (8c)[14c] were prepared ac-
cording to the literature procedures.
General procedure for the preparation of 2-(siloxymethyl)cyclohex-2-en-1-
ols
A solution of 2-hydroxymethyl-2-cyclohexenol[14c] (60 mmol), tert-butyldi-
methylsilylchloride (TBSCl) or triisopropylchlorosilane (TIPSCl)
(60 mmol), and imidazole (182 mmol) in THF (100 mL) was stirred at
08C for 1.5 h. Then, EtOAc was added and the organic layer was washed
with water, dried over anhydrous Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel (hexanes/EtOAc
6:1) to give the corresponding 2-(siloxymethyl)cyclohexenol in high yield
as a colorless oil.
(R)-3,3’-Dibenzyl-2,2’-dimethoxy-5,5’,6,6’-tetramethyl-1,1’-biphenyl ((R)-
1 f): A solution of phenylmagnesium bromide in THF (1m, 1.5 mL,
3 equiv) was added at 08C to a solution of 3,3’-bis(chloromethyl)biphenyl
(183 mg, 0.5 mmol, 1 equiv) in THF (5 mL) containing CuI (24 mg,
0.125 mmol, 0.25 equiv) under nitrogen over 30 min. The mixture was
warmed up to room temperature and stirred for an additional 30 min and
then at 508C for 10 h. The reaction was quenched with aqueous NH4Cl
solution (10 mL) and the reaction mixture was extracted with CH2Cl2
(10 mLꢂ3). The combined organic layer was washed with water (20 mL)
and brine (20 mL), dried over anhydrous MgSO4, and concentrated in
vacuo. The crude product was purified by flash chromatography on silica
gel (hexanes/EtOAc=30:1 to 10:1) to afford (R)-3,3’-dibenzyl-2,2’-dime-
thoxy-5,5’,6,6’-tetramethyl-1,1’-biphenyl (209 mg, 93%) as a colorless oil.
Triisopropylsiloxymethyl-2-cyclohexenol (10): Colorless oil; yield: 83%;
1H NMR (300 MHz, CDCl3): d=1.03 (m, 21H), 1.53 (m, 1H), 1.80 (m,
3H), 1.95 (m, 1H), 2.01 (m, 1H), 2.92 (brs, 1H), 4.25 (m, 3H), 5.72 ppm
(brt, J=4.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d=11.8, 17.9, 25.1,
30.9, 66.3, 68.2, 126.5, 137.5 ppm; HRMS (EI): m/z: calcd for C13H25O2Si:
241.1624 [MÀiPr]+; found: 241.1622 (D=+0.2 ppm).
1
[a]2D0 =+14.0 (c=0.8 in CH2Cl2); H NMR (300 MHz, CDCl3): d=1.95 (s,
General procedure for the preparation of allylic substrates, 2-
(siloxymethyl)cyclohex-2-en-1-yl carbonates
6H), 2.27 (s, 6H), 3.27 (s, 6H), 4.08 (q, J=6.8 Hz, 4H), 7.23 (s, 2H),
7.30–7.35 (m, 2H), 7.41–7.45 (m, 4H), 7.58–7.61 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3): d=16.4, 19.8, 121.6, 125.6, 127.1, 128.4, 129.2, 129.3,
132.1, 136.4, 137.9, 148.4 ppm; HRMS (EI): m/z: calcd for C32H34O2
450.2559 [M]+; found: 450.2560 (D=+0.1 ppm); (S)-3,3’-dibenzyl-2,2’-di-
methoxy-5,5’,6,6’-tetramethyl-1,1’-biphenyl was prepared in the same
manner: yield: 92%; [a]2D2 =À14.0 (c=0.9 in CH2Cl2,).
Chloroformate (3.41 mmol) was added to a solution of 10 (3.39 mmol)
and pyridine (3 mL) in CH2Cl2 (10 mL) at 08C. The resulting solution
was stirred at 08C for 1 h. After removal of the solvent, the residue was
subjected to column chromatography on silica gel by using hexane as the
eluent to give 8 as a colorless oil. The characterization data for 8d is
shown below, and those for all other allylic substrates are summarized in
the Supporting Information.
BBr3 (1.1 mL, 1.0m solution in CH2Cl2) was added dropwise over 20 min
to
a stirred solution of (R)-3,3’-dibenzyl-2,2’-dimethoxy-5,5’,6,6’-tetra-
methyl-1,1’-biphenyl (225 mg, 0.5 mmol) in CH2Cl2 (20 mL) at 08C. The
mixture was stirred at 08C for 1.5 h. The reaction was quenched by the
slow addition of water. The layers were separated and the aqueous layer
was extracted with Et2O. The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. The solution was concentrated
under reduced pressure. The crude product was purified by flash chroma-
tography on silica gel (hexanes/EtOAc=15:1 to 5:1) to give (R)-1 f
2-(Triisopropylsiloxy)methylcyclohex-2-en-1-yl ethenyl carbonate (8d):
Colorless oil; yield: 87%; 1H NMR (400 MHz, CDCl3): d=1.06 (m,
21H), 1.69 (m, 3H), 2.04 (m, 3H), 4.12 (d, J=12.6 Hz, 1H), 4.23 (d, J=
12.6 Hz, 1H), 4.53 (dd, J=2, 6.4 Hz, 1H), 4.88 (dd, J=2, 14 Hz, 1H),
5.29 (brs, 1H), 6.01 (brs, 1H), 7.09 ppm (dd, J=6.4, 14 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=11.9, 17.9, 24.7, 28.3, 64.4, 71.9, 97.3,
128.5, 134.2, 142.7, 152.4 ppm; HRMS (EI): m/z: calcd for C16H27O4Si:
311.1679 [MÀiPr]+; found: 311.1675 (D=À1.3 ppm).
(186 mg, 88%) as
a
colorless oil. [a]2D2 =+9.0 (c=0.75 in CH2Cl2);
1H NMR (400 MHz, CDCl3): d=1.92 (s, 6H), 2.26 (s, 6H), 4.04 (q, J=
6.8 Hz, 4H), 4.69 (s, 2H), 7.00 (s, 2H), 7.24 (m, 4H), 7.33 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=16.1, 19.7, 35.8, 120.3, 124.7, 125.8,
128.3, 128.7, 128.8, 132.4, 134.7, 141.0, 149.5 ppm; HRMS (EI): m/z: calcd
for C30H30O2: 422.2246 [M]+; found: 422.2248 (D=+0.2 ppm); (S)-1 f was
synthesized in the same manner from (S)-3,3’-dibenzyl-2,2’-dimethoxy-
5,5’,6,6’-tetramethyl-1,1’-biphenyl: yield: 87%; [a]2D0 =À8.9 (c=1.1
inCH2Cl2).
General Procedure for the Asymmetric Allylic Substitution Reaction
A solution of a subtrate 8 (0.1 mmol) in THF or DMF (1.0 mL) was
added to
(2.5 mmol) and (R)-5 or (S)-5 (7.5 mmol) in THF or DMF (0.5 mL), which
was preincubated for 15 min before the addition. Sulfonamide
a
solution of [Pd2ACHTNGUTERNNU(G dba)3] (dba=dibenzylideneacetone)
3
(0.11 mmol) in THF or DMF (0.5 mL) was added to this solution and the
mixture was stirred at an appropriate temperature. Then, EtOAc was
added to quench the reaction. The reaction mixture was washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was passed through a short pad of silica gel by
using hexanes/EtOAc (5:1) as the eluent to remove the catalyst and
ligand. The filtrate was concentrated and subjected to HPLC analysis.
The corresponding product N-(2-bromophenyl)-N-(2-siloxymethyl-cyclo-
hex-2-en-1-yl)(4-methylbenzene)sulfonamide (4) was isolated by flash
chromatography on silica gel by using hexanes/EtOAc (20:1–5:1) as the
In the same manner, chiral biphenols, (R)-1g and (R)-1h were synthe-
sized. The characterization data for these biphenols are shown in the
Supporting Information.
General Procedure for the Preparation of the Diphosphonite Ligands
A solution of chlorodiarylphosphine (2.5 mmol) in CH2Cl2 (5 mL) was
added slowly over 20 min to a solution of an enantiopure biphenol 1
(1 mmol), 4-N,N-dimethylaminopyridine (DMAP) (10 mol%), and trie-
Chem. Asian J. 2011, 6, 674 – 680
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
679

I. Ojima et al.
FULL PAPERS
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R and +2.4 for S
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(400 MHz, CDCl3): d=0.71 (m, 0.2H), 1.11 (m, 21H), 1.72 (m, 4.3H),
2.22 (m, 1.5H), 3.12 (s, 0.75H), 3.21 (s, 2.25H), 4.62 (m, 2H), 5.92 (brs,
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Acknowledgements
This work was supported by a grant from the National Science Founda-
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Received: September 25, 2010
Published online: December 22, 2010
680
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 674 – 680