3,3′-Substituted BINAP derivatives containing C-bound substituents: Applications in asymmetric hydrogenation reactions

Article abstract of DOI:10.1016/j.tetasy.2012.04.022

The synthesis and resolution of the first 3,3′-disubstituted BINAP ligands containing C-bonded substituents are described. An ortho-metallation/ electrophile capture sequence was used to obtain the key trisubstituted naphthalene intermediate available and this intermediate was successfully converted into the desired ligands. Minor changes in the steric and stereoelectronic components of the 3,3′-substituents on the enantioselectivity and product enantiosense were also assessed in the context of the Rh-catalyzed asymmetric hydrogenation of enamides. A comparison of the absolute stereochemistry of the products derived from 3,3′-disubstituted BINAPs containing C-bonded substituents with their O-bound counterparts indicated that the product enantiosense could be dictated by increased steric bulk due to the 3 and 3′-substituents.

Full text of DOI:10.1016/j.tetasy.2012.04.022

Tetrahedron: Asymmetry 23 (2012) 754–763
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
3,30-Substituted BINAP derivatives containing C-bound substituents:
applications in asymmetric hydrogenation reactions
⇑
Danica A. Rankic, Masood Parvez, Brian A. Keay
Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4
a r t i c l e i n f o
a b s t r a c t
The synthesis and resolution of the first 3,30-disubstituted BINAP ligands containing C-bonded substitu-
ents are described. An ortho-metallation/electrophile capture sequence was used to obtain the key trisub-
stituted naphthalene intermediate available and this intermediate was successfully converted into the
desired ligands. Minor changes in the steric and stereoelectronic components of the 3,30-substituents
on the enantioselectivity and product enantiosense were also assessed in the context of the Rh-catalyzed
asymmetric hydrogenation of enamides. A comparison of the absolute stereochemistry of the products
derived from 3,30-disubstituted BINAPs containing C-bonded substituents with their O-bound counter-
parts indicated that the product enantiosense could be dictated by increased steric bulk due to the 3
and 30-substituents.
Article history:
Received 30 March 2012
Accepted 7 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
results, we questioned if the oxygen atoms at the 3- and 30-posi-
tions were responsible for the enantiosense reversals seen with
The substitution of BINAP to alter not only its size, but also the
stereoelectronic properties of the phosphine atoms has been well
documented.1 While elaboration of the 3,30-positions of BINAP
1a–d (Fig. 1) and related bisphosphines is challenging, it is highly
desirable due to the proximity of the P-atoms in the ligand and
therefore the metal center.1 Elaboration of these positions has an
impact on both enantioselectivity and product enantiosense in
Rh-catalyzed asymmetric hydrogenations 2 and Pd-catalyzed Heck
reactions. 3 Recently, we showed that the effect of 3,30-substitution
could be combined with the 3,5-dialkyl meta effect4 to afford 3,30-
disubstituted xylBINAP ligands 2, which were highly enantioselec-
tive in both Rh-catalyzed hydrogenations of methyl N-acetamido
cinnamate 3 (MAC)5 and the Pd-catalyzed arylation of 2,3-dihydro-
furan.6 With P-xylyl-containing BINAP derivatives 2, a reversal of
the enantiosense of the products was observed in both hydrogena-
tion and Heck chemistries.
In all cases of BINAP ligands that were observed to cause
enantiosense reversals, oxygen atoms were present at the 3- and
30-positions of the binaphthyl backbone. In an analogous study
with 3,30-disubstituted MeO-BIPHEP derivatives, we saw that the
enantiosense reversal could be suppressed by changing the atom
of attachment for the 3,30-substiutents.2e Specifically, going from
oxygen-bonded (O-bound) to carbon-bonded (C-bound) 3,30-
substituents resulted in a reversal of the product enantiosense
observed compared with the parent MeO-BIPHEP. Based on these
ligands 1 and 2. In order to test this hypothesis, we developed a
synthetic route to 3,30-disubstituted BINAP derivatives in which a
carbon atom was directly bonded to the naphthalene ring in the
ligands, rather than the oxygen atom currently present in 3,30-
disubstituted BINAP derivatives. Herein we report our synthetic
route for the preparation of these ligands and their use in the
Rh-catalyzed asymmetric hydrogenations of enamides.
2. Results and discussion
To date, the synthesis of both 3,30-disubstituted BINAP ligands 1
and xylBINAP derivatives 2 has been limited to ligands containing
oxygen-bonded (O-bound) groups at the 3- and 30-positions. The
synthesis of these ligands relies on the use of 1-bromo-2-diaryl-
phosphinoyl-3-hydroxy naphthalene 6 (Scheme 1). The free hydro-
xyl group in this key intermediate allows for covalent chiral
auxiliary attachment, essential for the resolution of the chiral axis
upon biaryl bond formation.2a,5 This reliance on naphthol 6 limits
the synthesis of BINAP derivatives containing O-bonded substitu-
ents. Attempts to derivatize 6 or related 3,30-dihydroxy BINAP via
the formation of their corresponding triflates with subsequent
cross-coupling reaction conditions have been unsuccessful.7 More-
over, some elegant work by Widhalm and Mereiter has demon-
strated that the direct metallation of the bisphosphine oxide of
BINAP leads to intramolecular cyclization products rather than
the desired 3,30-disubstituted BINAP derivatives.8
In order to access BINAP ligands containing C-bonded substitu-
⇑
Corresponding author. Tel.: +1 403 210 8434; fax: +1 403 282 9154.
E-mail address: keay@ucalgary.ca (B.A. Keay).
ents at the 3- and 30-positions, we sought a route to an Ullmann
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.022

D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
755
OR
OR
PPh2
PPh2
Pxyl2
Pxyl2
OR
OR
BINAP series
xylBINAP series
(Sax)-1a R = Me
(Sax)-1b R = iPr
(Sax)-1c R = Bn
(Sax)-1d R = Piv
(Sax)-2a R = iPr
(Sax)-2b R = Piv
(Sax)-2c
Me
(Rax)-2d
R =
OMe
Rh(nbd)2BF4 (1 mol%)
Ligand (1.1 mol%)
CO2Me
Ph
CO2Me
Ph
*
MeOH, H2 (2 atm)
r.t., 24 h
NHAc
NHAc
4
3
(S)-BINAP: 15% ee — (R)-configuration
1
2
(Sax)- or (Sax)- : up to >99% ee — (S)-configuration
Figure 1. 3,30-Disubstituted BINAP and xylBINAP ligands, 1 and 2 respectively, and their application in the hydrogenation of MAC (3).
R
OH
LDA
Ligand
1 or 2
P(O)Ar2
P(O)Ar2
Br
5a Ar = phenyl
5b
6a Ar = phenyl
6b
Ar = 3,5-xylyl
Ar = 3,5-xylyl
Scheme 1. The synthesis of 1-bromo-2-diarylphosphinoyl-3-hydroxy naphthalene 6, a key intermediate in the synthesis of 3,30-disubstituted BINAP and xylBINAP
derivatives 1 and 2.
coupling precursor that already possesses a C-bonded substituent.
In preliminary investigations, we examined the use of compounds
7, containing aryl groups, esters, and nitriles, as precursors to tri-
substituted naphthalenes 8 (Scheme 2). The ortho-metallation/ha-
lide capture sequences involving these substrates failed to yield
the desired products.9 It should be noted that while nitrile-substi-
tuted naphthalene 8 did provide us with some of the desired Ull-
mann precursor, a competitive lithiation was observed at the 4-
position, along with nucleophilic attack of LDA on the cyano group
to afford an amide by-product. We presumed that the successful
lithiation of cyano-containing naphthalene 8 was due to its small
size and linear projection away from the naphthalene ring. We
1. Li or Mg
amide base
R
R
2. "X+"
P(O)Ph2
P(O)Ph2
X
7
8
R = Ph, CO2R', COR', CN
Scheme 2. Attempted C-1 metallation of 2-diphenylphosphinoyl naphthalenes 7 to afford Ullman coupling precursors 8.

756
D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
Ph
phenyl acetylene
OTf
Pd(PPh3)4 (5 mol%)
CuI (10 mol%)
OTf
OTf
NEt3, MeCN, 18 h
9
then HP(O)Ph2
80 °C, 16 h
80% (one pot)
Ph
Ph
1. LDA, THF
– 78 °C, 30 min
2. I2, –78 °C to r.t.
P(O)Ph2
71%
P(O)Ph2
I
11
10
Cu, DMF
140 °C, 3h
86%
Ph
Ph
P(O)Ph2
P(O)Ph2
P(O)Ph2
P(O)Ph2
(–)-DTTA
CHCl3/EtOAc
47%
Ph
Ph
(Sax)-12
12
Pd/C, H2
24 h
quant.
Ph
Ph
Ph
PPh2
PPh2
P(O)Ph2
P(O)Ph2
HSiCl3, NBu3
xylenes, 140 °C
24 h, 67%
Ph
(Sax)-14
(Sax)-13
Scheme 3. Synthesis of (Sax)-3,30-(phenethyl)2-BINAP 14.
hypothesized that an alkyne, linear yet less susceptible to attack by
nucleophiles, might be able to undergo lithiation and successful
electrophile capture without the formation of by-products.
the best of our knowledge, this synthetic sequence represents the
first synthesis and resolution of a BINAP ligand containing carbon
bound substituents at the 3- and 30-positions.
With this goal in mind, we synthesized alkyne 10 via a one-pot,
sequential Sonogashira coupling/P–C bond formation reaction of
ditriflate 9 (Scheme 3). Compound 10 was ortho-lithiated using
LDA and then iodinated to furnish iodonaphthalene 11. Ullmann
coupling of 11 forged the biaryl bond in rac-12 which was resolved
by co-crystallization with (ꢀ)-DTTA to afford (Sax)-12 in 47%
yield.2a Hydrogenation of the alkynyl groups in (Sax)-12 followed
by phosphine oxide reduction afforded (Sax)-14 in 67% yield. To
We recognized that phenethyl-substituted BINAP 14 was
isostructural to benzyloxy-substituted BINAP 1c, the former
containing a methylene unit in place of the oxygen atom present
in the latter. In order to gain access to another analogue of BINAP
1c, we oxidatively cleaved the alkynyl groups in intermediate
(Sax)-12 using
a three-step procedure (Scheme 4). This was
accomplished by converting bis-alkyne (Sax)-12 to bis(diketone)
(Sax)-15 (Scheme 4).10 Reduction of (Sax)-15 to the corresponding

D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
757
Ph
O
Ph
O
P(O)Ph2
P(O)Ph2
P(O)Ph2
DMSO, I2
P(O)Ph2
O
140 °C, 12h
98%
Ph
O
Ph
12
(Sax)-
15
(Sax)-
1. NaBH4
2. Pb(OAc)4
3. NaBH4
70% over 3 steps
OPh
OH
1. MsCl, NEt3
CH2Cl2, 1 h
P(O)Ph2
P(O)Ph2
P(O)Ph2
P(O)Ph2
2. NaH, PhOH
DMF, 18 h
0 °C to r.t.
88%
OPh
OH
(Sax)-17
HSiCl3, NEt3
(Sax)-16
HSiCl3, NEt3
xylenes
140 °C, 24 h
87%
OPh
PPh2
PPh2
OPh
18
(Sax)-
Scheme 4. Synthesis of (Sax)-3,30-(phenoxymethyl)2-BINAP 18.
derivative (Sax)-14 displayed a 31P–77Se coupling constant nearly
identical to that of BINAP. This is important, since the change in
the steric properties between BINAP and 14 is quite drastic with
very little deviation in the electronic properties of the two ligands.
The absence, presence, and position of the oxygen atoms in the
3,30-substituents of 1c, 14, and 18 have subtle effects on the elec-
tronic properties of the ligands. The phosphorus atoms of the 3,30-
OBn-substituted ligand 1c were estimated to be the most electron
rich, while the phosphorus atoms in ligand 14 were found to be the
most electron deficient of the series. Interestingly, 18 had an inter-
mediate basicity, even though the phenoxymethyl-substituent was
anticipated to be inductively electron withdrawing.
Ligands 1c, 14, and 18 were tested along with BINAP in the Rh-
catalyzed hydrogenation of dehydroamino acids 19. When a Rh/
(S)-BINAP catalyst system was used for the hydrogenation of olefin
19a, alanine derivative (R)-20a was isolated in 21% ee (Table 2, en-
try 1). However, employing ligand (S)-14 in the same hydrogena-
tion resulted in (S)-20a being isolated in 98% ee, nearly a 5-fold
amplification of the enantiomeric excess and a reversal in product
Table 1
Summary of the 31P–77Se coupling constants obtained from diselenides of (S)-BINAP,
(S)-1c, (S)-14, and (S)-18
Entry
Ligand
3,30-Substituent
Diselenide
1J(31P–77Se) (Hz)
1
2
3
4
(S)-BINAP
(S)-1c
(S)-14
–H
(S)-BINAP(Se)2
(S)-1c(Se)2
(S)-14(Se)2
(S)-18(Se)2
739
722
738
727
–OCH2Ph
–CH2CH2Ph
–CH2OPh
(S)-18
bis(diol), followed by oxidative cleavage using Pb(OAc)4 and reduc-
tion of the resultant dialdehyde afforded diol (Sax)-16 in 70% over
three steps. Mesylation of (Sax)-16 and subsequent substitution
with NaOPh afforded (Sax)-17. Phosphine oxide reduction provided
BINAP analogue (Sax)-18 in 87% yield.
The electronic properties of BINAP and isostructural 3,30-ligands
were estimated by synthesizing their corresponding diselenides
and measuring their 1J(31P–77Se) values (Table 1).11 The BINAP

758
D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
Table 2
Rh-catalyzed hydrogenations of dehydroamino acids 19 using ligands (S)-(BINAP), (S)-1c, (S)-14, and (S)-18
Rh(cod)2OTf (1 mol%)
Ligand (1.1 mol%)
CO2R
NHAc
CO2R
*
MeOH, H2 (2 atm)
r.t., 24 h
NHAc
19a
19b
20a
20b
R = Me
R = H
R = Me
R = H
Entrya
Ligandb
3,30-Substituent
–H
Olefin
%ee (Config)c
1
2
3
4
(S)-BINAP
(S)-14
19a
19b
19a
19b
19a
19b
19a
19b
21 (R)
34 (R)d
98 (S)
95 (S)d
83 (S)
69 (S)d
96 (S)
92 (S)d
–CH2CH2Ph
–CH2OPh
–OCH2Ph
5
(S)-18
6
7e
8e
(S)-1c
a
Catalysts formed in situ by stirring Rh(cod)2OTf and the ligand in MeOH for 30 min at rt. All reactions proceeded with 100%
conversion as determined by 1H NMR.
b
The results in this table are ordered by increasing 31P–77Se coupling constant.
Measured by chiral GC.
c
d
Converted to methyl ester for ee determination
e
Obtained by comparison to the literature.2a
Table 3
Rh-catalyzed hydrogenations of methyl cinnamate 3 using ligands (S)-BINAP, (S)-1c, (S)-14, and (S)-18
Rh(nbd)2BF4 (1 mol%)
Ligand (1.1 mol%)
CO2Me
NHAc
CO2Me
Ph
Ph
*
MeOH, H2 (2 atm)
r.t., 24 h
NHAc
3
4
Entrya
Ligandb
3,30-Substituent
%ee (Config)c
1
2
(S)-BINAP
(S)-14
(S)-18
–H
15 (R)
78 (S)
65 (S)
45 (S)
–CH2CH2Ph
–CH2OPh
–OCH2Ph
3
4d
(S)-1c
a
Catalysts formed in situ by stirring Rh(nbd)BF4 and ligand in MeOH for 30 min at rt. All reactions proceeded with 100% conversion
as determined by 1H NMR.
b
The results in this table are ordered by increasing 31P–77Se coupling constant.
c
Measured by chiral HPLC.
d
Obtained from the literature2a for the sake of comparison.
enantiosense, when compared to the parent BINAP (entry 3). This
observation was not restricted to substrate 19a. When acid 19b
was hydrogenated, (S)-BINAP gave (R)-20b in 34% ee whereas
(S)-14 gave amino acid derivative (S)-20b in 95% ee (entries 2 vs.
4). It should be reiterated that ligand 14 is nearly electronically
identical to BINAP, yet sterically different due to the presence of
the 3,30-phenethyl substituents on its binaphthyl skeleton; this
suggests that increasing the steric bulk around the Rh center in-
duces both a marked increase in ee as well as a reversal of the
absolute configuration of products 20.
as the electron density of each ligand increased or decreased would
be expected.
In contrast, an apparent relationship between the ligand
sicity and ee was observed for the hydrogenation of olefin 3
(Table 3). As the ligand
-basicity (as estimated by 1J(31P–77Se)
r-ba-
r
values) was increased (i.e., 14 to 18 to 1c), the ee of product 4 de-
creased. This suggests that subtle electronic changes in the utilized
3,30-disubstituted BINAP ligand might influence the ee, even with
only minor changes in ligand structure.
The electronic effects of the ligand were assessed by analyzing
the results obtained for the hydrogenations of dehydroamino
acids 19 using isostructural 3,30-BINAP ligands 1c, 14, and 18. No
relationship was found between ligand electron density and the
ee of the products formed in the hydrogenation of N-acetyl alanine
19b or its methyl ester 19a. Ligands (S)-1c and (S)-14 afforded
higher ee0s than those obtained from (S)-18 (Table 2). If an elec-
tronic effect was present, an increase or decrease in product ee
3. Conclusion
In conclusion, we have demonstrated that the synthesis of 3,30-
disubstituted BINAP ligands containing C-bonded substituents
could be successfully accomplished using an appropriately trisub-
stituted naphthalene intermediate 11. This intermediate was ob-
tained by an ortho-lithiation/halide capture sequence. Two new
BINAP derivatives were synthesized and tested in Rh-catalyzed

D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
759
hydrogenation reactions. The ee0s of the hydrogenation products
derived from these ligands and 3,30-(OBn)2-BINAP 1c were com-
pared and this allowed us to study how subtle changes in the struc-
ture would influence the ee in the Rh-catalyzed hydrogenations of
enamides. It appears as though a reversal in the product enantio-
sense observed with 3,30-disubstituted BINAP ligands may arise
due to an increase in steric bulk at the 3- and 30-positions of the
ligand backbone. However, further studies are currently underway
in order to further supplement the results obtained herein and
these will be reported in a full account.
low resolution mass spectra were obtained on a Bruker Esquire
3000 mass spectrometer by either Ms. Q. Wu or Mr. W. White. High
resolution mass spectra were obtained by Ms. D. Fox on a Kratos
MS80 mass spectrometer (HRMS(EI) or HRMS(CI)) or by Ms. Q.
Wu on a Burker Autoflex III mass spectrometer (MALDI-TOF). Mass
spectral data are listed in the following format: mass (m/z),
(assignment). Elemental analyses were performed by Mr. J. Li on
a Perkin Elmer Model 2400 series II elemental analyzer. X-Ray
structure determination was performed by Dr. M. Parvez (Univer-
sity of Calgary) using either a Bruker APEX2 CCD installed on a
Nonius Kappa Goniometer diffractometer with graphite mono-
chromated Mo-Ka radiation. Flash column chromatography was
4. Experimental
4.1. General
performed using silica gel 60 (E. Merck, 0.04–0.063 mm, 230–400
mesh) using the method developed by Still et al.12 Analytical TLC
was carried out on aluminum sheets coated with a uniform thick-
ness of 0.2 mm of Merck silica gel 60 F254. Spots were visualized
under UV light or by dipping in a stain solution followed by heat
development.
All glassware used in anhydrous reactions were either flame-
dried or dried overnight in a 120 °C oven and subsequently cooled
under an argon atmosphere. Moisture or oxygen sensitive reac-
tions were performed under an argon atmosphere or through the
use of Schlenk techniques. All solvents and reagents were purified
via standard methods, when required. Tetrahydrofuran (THF) was
distilled from sodium benzophenone ketyl immediately prior to
use. Dichloromethane and toluene were freshly distilled from cal-
cium hydride. Other reagents/solvents including triethylamine,
diethylamine, diisopropylamine, benzene, acetonitrile, methanol,
dimethyl sulfoxide (DMSO), and xylenes were distilled from CaH2
and the stored over 4 Å molecular sieves in Sure/SealÒ bottles.
N,N-Dimethyl formamide was purchased as an anhydrous solvent
in a Sure/SealÒ bottle from the Aldrich Chemical Company. Lithium
diisopropylamide (LDA) was purchased as a 1.8 M solution in THF/
heptane/ethylbenzene from the Aldrich Chemical Company. n-
Butyllithium was titrated prior to use with N-benzylbenzamide
as the indicator. Solutions of NaCl, NaHCO3, and NH4Cl for washing
organic phases were saturated unless specified otherwise.
Chiral GC analyses were carried out on a Shimadzu GC-9A gas
chromatograph equipped with
a widebore column (30 m,
0.32 mm, 0.25 m I.D.) with a solid phase of b-cyclodextrin and a
l
flame ionization detector. HPLC analyses were carried out using a
Waters 1525 Binary HPLC pump equipped with a Daicel Chiralcel
OD column and a Waters 2487 detector (UV detection at 254 nm).
4.2. 2-(Diphenylphosphinoyl)-3-phenylethynyl naphthalene 10
Ditriflate 913 (3.796 g, 8.9465 mmol) was dissolved in acetoni-
trile (50 mL) under an atmosphere of argon. Phenyl acetylene
(0.88 mL, 8.0 mmol), Pd(PPh3)4 (514 mg, 0.445 mmol, 5 mol %),
CuI (172 mg, 0.903 mmol, 10 mol %), and NEt3 (15.5 mL, 108 mmol)
were added to the reaction vessel sequentially. The reaction was
stirred at ambient temperature for 15 h. TLC analysis revealed
complete consumption of the starting material. Diphenyl phos-
phine oxide (1.842 g, 9.110 mmol) and an additional 5 mol % of
Pd(PPh3)4 were added to the reaction vessel and the mixture was
heated to 80 °C. After 18 h, the reaction mixture was cooled to
room temperature prior to being poured into a saturated NH4Cl
solution (100 mL) and extracted with EtOAc (3 ꢁ 50 mL). The or-
ganic layers were combined and washed with NaCl(aq)
(1 ꢁ 75 mL), dried over MgSO4, filtered, and concentrated to afford
a bright yellow solid. Purification by silica gel chromatography (2:1
EtOAc/hexanes) provided a spectroscopically pure product as a yel-
low solid (2.74 g, 6.39 mmol, 80%). An analytical sample was ob-
tained by recrystallization from hot EtOAc to give pale gold
needles. mp 184–185 °C; IR (film) vmax 3043, 2204, 1957, 1891,
Melting points were determined using an ElectrothermalÒ
melting point apparatus in a sealed capillary tube. Optical rotations
were obtained using a Rudolph Research Autopole IV polarimeter
at 589 nm using a 1 dm path length cell. HPLC Grade CHCl3 stored
over K2CO3 was the solvent used for optical rotation measure-
ments. Infrared spectra were recorded on a Nicolet Nexus 470
FT-IR E.S.P spectrophotometer. Liquid samples were analyzed neat
between KBr plates while solid samples were handled as chloro-
form thin films. Characteristic absorptions are listed in wavenum-
bers followed by the assignment in parentheses.
Proton, carbon, and phosphorus NMR spectra were obtained on
a
Bruker DMX 300 (1H 300 MHz, 13C 75 MHz, 31P
1839, 1487, 1439, 1187, 1113, 1030 cmꢀ1 1H NMR (300 MHz) d
;
either
121.5 MHz), Bruker Avance DRX 400 (1H 400 MHz, 13C 100 MHz,
31P 162 MHz), Bruker Avance II DRY 400 (1H 400 MHz, 13C
100 MHz, 31P 162 MHz), or a Bruker Avance III RDQ 400 (1H
400 MHz, 13C 100 MHz, 31P 162 MHz). Unless otherwise noted,
CDCl3 was used as the NMR solvent. The residual chloroform signal
was used as an internal standard for chemical shift referencing in
the case of 1H NMR and 13C NMR spectra. A solution of H3PO4 in
D2O was used as an external reference when obtaining 31P NMR
spectra. 1H NMR spectra are listed in the following format:
chemical shift (in ppm), (multiplicity, coupling constant (Hz),
number of protons, assignment). For all 13C NMR spectra, the sig-
nals were assigned as C, CH, CH2, or CH3 by DEPT 135 experiments.
13C NMR spectra are listed in the following format: chemical shift
(in ppm), [multiplicity, coupling constant (Hz), methyl (CH3),
methylene (CH2), methane (CH), or quaternary (C) assignment].
GC-MS analyses were performed on an Agilent HP5975 gas
chromatograph. Low resolution mass spectra on non-volatile sam-
ples were obtained on a Thermo Finnigan SSQ7000 mass spectrom-
eter by Mr. J. Li [LRMS(EI) and LRMS(CI)]. Electrospray ionization
8.47 (d, J = 14.5 Hz, 1H), 8.12 (d, J = 3.9 Hz, 1H), 7.88–7.78 (m,
6H), 7.59–7.46 (m, 4H), 7.43–7.37 (m, 4H), 7.24–7.19 (m, 3H),
7.01 (dd, J = 7.9 Hz, 1.7 Hz, 2H); 13C NMR (75 MHz) 136.4 (d,
J = 8.6 Hz, CH), 134.3 (d, J = 2.1 Hz, C), 134.1 (d, J = 8.7 Hz, CH),
132.4 (d, J = 106 Hz, C), 132.3 (d, J = 10.0 Hz, CH), 131.8 (d,
J = 2.8 Hz, CH), 131.6 (d, J = 12.5 Hz, CH), 131.3 (CH), 130.2 (d,
J = 101 Hz, C), 129.1 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH),
128.1 (CH), 127.6 (CH), 127.4 (CH), 122.6 (C), 121.2 (d, J = 8.0 Hz,
C), 96.1 (C), 88.97 (d, J = 4.4 Hz, C); 31P{1H} NMR (162 MHz) 29.1;
LRMS(EI) 427.2 (base peak), 349.1, 302.1, 226.1; HRMS(TOF-EI)
calcd for C30H21OP 428.1330, found 428.1309.
4.3. 2-(Diphenylphosphinoyl)-1-iodo-3-phenylethynyl
naphthalene 11
Phenylethynyl naphthalene 10 (447 mg, 1.043 mmol) was dis-
solved in THF (7 mL), and cooled to ꢀ78 °C after which was added
dropwise a solution of lithium diisopropyl amide (0.7 mL in THF/
heptane/ethylbenzene, 1.26 mmol). A cherry red anion solution

760
D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
formed and was stirred for 0.5 h. A solution of iodine (336 mg,
1.32 mmol) in THF (1.3 mL) was prepared and added to the anion
solution dropwise. The reaction mixture was stirred at ꢀ78 °C for
30 min before being warmed to room temperature and quenched
with a 10% sodium thiosulfate solution. The reaction mixture was
extracted with EtOAc (3 ꢁ 20 mL). The combined organic layers
were washed with NaCl(aq) (1 ꢁ 20 mL), dried over Na2SO4, filtered,
and evaporated to afford an amber film. Purification by flash col-
umn chromatography (2:1 EtOAc/hexanes) afforded an off-white
solid (242 mg, 0.436 mmol, 42%). mp 230–231 °C; IR (film) vmax
10% NaOH(aq) (75 mL) for 1 h. The layers were separated and the
aqueous layers extracted with CH2Cl2 (2 ꢁ 50 mL). The combined
organic layers were washed with 10% NaOH(aq) (75 mL) and H2O
(75 mL), dried over MgSO4, filtered, and concentrated in vacuo to
afford (ꢀ)-12 as a white solid (1.270 g, 1.486 mmol, 30.5%):
½
a 2D0
ꢃ
¼ ꢀ137 (c 0.225, CHCl3)
The mother liquor of the crystals was also base extracted (vide
supra) to afford a scalemic mixture enriched in (+)-12 (2.888 g,
3.378 mmol, 69.5%). This mixture was dissolved in CHCl3
(145 mL) and heated to 60 °C. A preheated solution of (+)-DTTA
(1.305 g, 3.378 mmol) in EtOAc (97 mL) was added to the afore-
mentioned solution and the mixture was refluxed for 1 h. The reac-
tion was cooled to r.t. in the absence of stirring and allowed to sit
for 18 h. The formed crystals were washed with base and (+)-12
was isolated as a white solid by the procedure outlined above
3052, 2222, 1578, 1483, 1435, 1248, 1191, 1113 cmꢀ1 1H NMR
;
(400 MHz) d 8.56 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 3.2 Hz, 1H),
7.86–7.81 (m, 4H), 7.74 (d, J = 7.1 Hz, 1H), 7.66–7.60 (m, 2H),
7.50–7.34 (m, 6H), 7.00 (d, J = 7.9 Hz, 2H); 13C NMR (100 MHz) d
136.0 (d, J = 8.0 Hz, CH), 135.5 (d, J = 10.2 Hz, C), 134.7 (CH),
133.8 (d, J = 108 Hz, C), 133.62 (d, J = 102 Hz, C), 133.61 (C),
133.59 (C), 132.0 (d, J = 8.4 Hz, CH), 131.5 (d, J = 2.9 Hz, CH),
131.2 (CH), 129.3 (CH), 129.2 (CH), 128.4 (d, J = 12.4 Hz, CH),
127.9 (CH), 127.8 (CH), 124.1 (d, J = 9.1 Hz, C), 122.7 (C), 110.7 (d,
J = 5.2 Hz, C), 98.9 (C), 88.9 (d, J = 4.7 Hz, C); 31P{1H} NMR
(162 MHz) d 33.3; ESI-MS 593 (M+K)+, 577 (M + Na)+, 555
(M+H)+, MS/MS of 555: 477, 427, 323; Anal. calcd for C30H20IOP
C, 65.00; H, 3.64; found C, 64.90; H, 4.02.
(1.642 g, 1.920 mmol, 39%): ½a D20
¼ þ137 (c 0.22, CHCl3).
ꢃ
The mother liquor of these crystals was treated in a similar
fashion with the same relative proportions of CHCl3, EtOAc, and
(ꢀ)-DTTA to afford a second batch of (ꢀ)-12 (674 mg, 0.788 mmol,
16.2%): ½a 2D0
¼ ꢀ127 (c 0.220, CHCl3). It should be noted that in all
ꢃ
instances, the spectroscopic data of the resolved material matched
those reported for the racemic material (vide supra).
4.5. (Sax)-2,20-Bis-(diphenylphosphinoyl)-3,30-bis-
4.4. (Sax)-2,20-Bis-(diphenylphosphinoyl)-3,30-bis-
phenylethynyl-[1,10]binaphthyl 13
phenylethynyl-[1,10]binaphthyl 12
Bisalkyne (ꢀ)-13 (221 mg, 0.259 mmol) was dissolved in MeOH.
To this was added 10% Pd/C (222 mg) and the flask was evacuated
and purged with H2 gas three times. The reaction was placed under
an atmosphere of H2 gas (2 atm) for 24 h with adequate stirring.
The reaction mixture was filtered through a pad of Celite and the
Celite was washed with MeOH (3 ꢁ 5 mL). The filtrate was concen-
trated in vacuo and the residue was purified by silica gel chroma-
tography (2:1 EtOAc/hexanes) to afford the product as a white
Iodonaphthalene 11 (3.602 g, 6.497 mmol) was dissolved in
DMF (35 mL) under argon. To this solution was added Cu powder
(1.238 mg, 19.48 mmol) and the reaction mixture was immersed
in an oil bath preheated to 140 °C. The reaction was stirred for
3 h before cooling to rt, diluting with CHCl3 (50 mL), and stirring
for an additional 10 min. The reaction mixture was filtered and
the collected solids were washed with CHCl3 (2 ꢁ 25 mL). The
filtrate was concentrated under vacuum to afford a light brown so-
lid. This solid was suspended in CHCl3 and passed through a 3 ꢁ 1
inch plug of silica gel, eluting with 1:1 CH2Cl2/EtOAc, in order to re-
move any inorganic salts. Upon concentration, a light brown
residue was obtained and this solid was suspended in 1:1 EtOAc/
Et2O (ꢂ75 mL). After stirring for 10 min, the suspension was
filtered and the collected solids were washed with 1:1 EtOAc/
Et2O (5 mL) and then Et2O (5 mL). The filtrate was concentrated
to afford the product as a white solid (2.493 g, 2.916 mmol, 90%).
mp 318–319 °C; IR (film) vmax 3052, 2205, 1490, 1438, 1195,
foamy solid (223 mg, 0.259 mmol, 100%): ½a D20
¼ þ95:5 (c 0.225,
ꢃ
CHCl3); mp 138–139 °C; IR (film) vmax 3062, 1438, 1186, 1114,
1095 cmꢀ1 1H NMR (400 MHz) d 7.75–7.73 (m, 4H), 7.58 (dd,
;
J = 12.2, 7.0 Hz, 4H), 7.44–7.37 (m, 6H), 7.27–7.21 (m, 6H),
7.19–7.07 (m, 16H), 6.81 (d, J = 6.8 Hz), 3.02–2.90 (m, 4H),
2.68–2.60 (m, 2H), 2.46–2.39 (m, 2H); 13C NMR (100 MHz) d
145.6 (C), 141.6 (C), 140.14 (d, J = 10.7 Hz, C), 135.2 (d, J = 103 Hz,
C), 134.9 (d, J = 102 Hz, C), 134.1 (d, J = 2.3 Hz, C), 133.2 (d,
J = 11.5 Hz, CH), 132.3 (d, J = 10.0 Hz, CH), 131.7 (d, J = 10.0 Hz,
CH), 130.7 (d, J = 2.3 Hz, CH), 130.3 (d, J = 3.1 Hz, CH), 129.7 (d,
J = 10.0 Hz, CH), 128.2 (CH), 128.1 (d, J = 21.5 Hz, CH), 128.0 (CH),
127.8 (CH), 127.7 (CH), 127.7 (CH), 127.5 (CH), 127.4 (CH),
127.36 (CH), 127.28 (CH), 125.6 (CH), 125.4 (CH), 37.2 (CH2), 37.1
(CH2), 37.0 (CH2); 31P{1H} NMR (162 MHz) d 29.3; ESI-MS 901
(M+K+)+; 885 (M+Na+)+; 863 (M + H+)+; HRMS(MALDI-TOF) calcd
for (C60H48O2P2 + H+) 863.3208, found 863.3195.
1110 cmꢀ1 1H NMR (400 MHz) d 8.25 (d, J = 3.7 Hz, 2H), 7.88 (d,
;
J = 8.1 Hz, 2H), 7.81–7.73 (m, 4H), 7.68–7.62 (m, 4H), 7.49 (ddd,
J = 8.0, 6.9, 1.0 Hz, 2H), 7.37–7.33 (m, 2H), 7.26–7.12 (m, 14H),
7.11–7.01 (m, 6H), 6.82–6.75 (m, 4H); 13C NMR (100 MHz) d
147.2 (d, J = 4.8 Hz, C), 147.1 (d, J = 4.8 Hz, C), 135.3 (d, J = 9.0 Hz,
CH), 134.0 (d, J = 108 Hz, C), 133.8 (d, J = 11.0 Hz, C), 133.51 (C),
133.49 (C), 133.3 (d, J = 104 Hz, C), 132.8 (d, J = 9.7 Hz, CH), 132.4
(d, J = 11.0 Hz, CH), 131.1 (CH), 130.9 (d, J = 2.6 Hz, CH), 130.5 (d,
J = 2.6 Hz, CH), 128.3 (C), 128.1 (CH), 127.94 (CH), 127.8 (CH),
127.64 (CH), 127.61 (CH), 127.58 (CH), 127.5 (CH), 127.3 (CH),
127.2 (CH), 126.8 (CH), 123.0 (C), 121.4 (d, J = 10.0 Hz, C), 96.9
(C), 91.2 (d, J = 5.0 Hz, C); 31P NMR (162 MHz) d 30.4; ESI-MS 855
4.6. (Sax)-2,20-Bis-(diphenylphosphino)-3,3‘-bis-phenylethynyl-
[1,10]binaphthyl 14
Bisphosphine oxide (S)-(+)-13 (213 mg, 0.247 mmol) was com-
bined with xylenes (3.9 mL) and NBu3 (1.05 mL, 4.42 mmol). To
this was added HSiCl3 (0.37 mL, 3.67 mmol) dropwise and the reac-
tion mixture was heated at 140 °C for 22 h. The reaction was cooled
to 60 °C and aqueous NaOH (30%, 3.9 mL) was added dropwise.
After 1 h of stirring at 60 °C, the reaction was cooled to room tem-
perature, diluted with CHCl3 (10 mL) and the layers separated. The
aqueous layer was diluted with 30% NaOH (10 mL) and extracted
with CHCl3 (2 ꢁ 10 mL). The combined organic layers were washed
with H2O (2 ꢁ 10 mL) and were then dried over Na2SO4, filtered,
and the solvent removed in vacuo to afford a white semi-solid.
Purification by silica gel chromatography (20:1 hexanes/EtOAc)
(M+H)+;
HRMS(MALDI-TOF)
calcd
for
(C60H40O2P2 + H+)
855.25763, found 855.2578; Anal. calcd for C60H40O2P2 C, 84.29;
H, 4.72, found C, 83.79; H 4.95.
The racemic bisphosphine oxide 12 (4.158 g, 4.864 mmol) was
dissolved in CHCl3 (209 mL) and heated to 60 °C. To this was added
a pre-warmed solution of (ꢀ)-DTTA (1.879 mg, 4.863 mmol) in
EtOAc (139 mL). The solution was refluxed for 1 h before being al-
lowed to cool to room temperature and sit at room temperature for
24 h. An off-white crystalline solid was collected by vacuum filtra-
tion. The solid was suspended in CH2Cl2 (100 mL) and stirred with

D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
761
followed by trituration with MeOH afforded the product as an off-
and the final difference Fourier map was essentially featureless.
The figure was plotted with the aid of ORTEPII.18 The following
crystal parameters were obtained: monoclinic C2; a = 25.3676(9)
white powder (129 mg, 155 mmol, 63%): ½a D20
¼ ꢀ137.1 (0.275,
ꢃ
CHCl3); mp 196–197 °C; IR (film) vmax 3047, 2929, 1481, 1433,
742, 695 cmꢀ1
;
1H NMR (400 MHz) d 7.94 (s, 2H), 7.85 (d,
Å, b = 9.2100(5) Å, c = 12.8530(4) Å,
b = 117.724(2), V = 2658.18(19) Å3; Z = 2.
a
= 90°,
c = 90°,
J = 8.2 Hz, 2H), 7.43 (ddd, J = 1.6, 6.2, 8.1 Hz, 2H), 7.26–7.20 (m,
4H), 7.18–7.01 (m, 21H), 6.98–6.87 (m, 6H), 6.75–6.69 (m, 4H),
2.86–2.78 (m, 4H), 2.58–2.46 (m, 2H), 2.45–2.33 (m, 2H); 13C
NMR (100 MHz) d 151.1 (d, J = 10.7 Hz, C), 150.6 (d, J = 10.7 Hz,
C), 144.1 (s, 2H, C), 141.8 (C), 137.2 (d, J = 19.2 Hz, C), 135.6 (d,
J = 14.6 Hz, C), 134.1 (C), 133.5 (d, J = 4.6 Hz, C), 133.4 (d,
J = 4.6 Hz, C), 132.62 (d, J = 14.6 Hz, C), 131.9 (d, J = 19.9 Hz, CH),
131.4 (d, J = 19.2 Hz, CH), 129.1 (CH), 128.5 (CH), 128.3 (CH),
128.1 (d, J = 2.3 Hz, CH), 128.0 (CH), 127.9 (CH), 127.8 (d,
J = 2.3 Hz, CH), 127.4 (CH), 127.3 (CH), 127.1 (CH), 126.8 (CH),
125.5 (CH), 125.3 (CH), 36.8 (CH2), 36.7 (CH2); 31P{1H} NMR
(162 MHz)
d
ꢀ12.6; ESI-MS 831 (M
+
H)+; Anal. calcd for
C60H48P2 C, 86.72; H, 5.82, found C, 86.49; H, 5.81.
4.7. Bis(diketone) 15
Bisalkyne (S)-(ꢀ)-12 (1.235 g, 1.445 mmol) was dissolved in
DMSO (23 mL), after which I2 (367 mg, 1.446 mmol) was added
and the reaction was heated at 140 °C for 16 h. The reaction mix-
ture was cooled to rt, diluted with CH2Cl2 (100 mL), and washed
with 1% Na2S2O3 (100 mL). The layers were separated and the
aqueous portion was extracted with CH2Cl2 (3 ꢁ 30 mL). The com-
bined organic layers were washed with water (5 ꢁ 30 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to afford the prod-
uct as a yellow solid (1.297 g, 1.411 mmol, 98%): ½a D20
¼ ꢀ528 (c
ꢃ
0.195, CHCl3); mp 305–306 °C; 1H NMR (400 MHz) d 8.52 (d,
J = 3.7 Hz, 2H), 7.90–7.80 (m, 6H), 7.52 (dd, J = 12.6, 7.3 Hz, 6H),
7.42 (t, J = 7.4 Hz, 2H), 7.39–7.19 (m, 21H), 7.16 (dt, J = 7.7,
2.9 Hz, 4H), 7.09 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz) d 193.5
(C@O), 192.8 (C@O), 150.2 (C), 137.8 (d, J = 7.7 Hz, CH), 136.0 (d,
J = 11.5 Hz, C), 134.4 (CH), 132.8 (C), 132.7 (d, J = 10.0 Hz, CH),
132.4 (d, J = 1.5 Hz, C), 131.3 (d, J = 10.7 Hz, CH), 130.7 (d,
J = 2.3 Hz, CH), 130.0 (CH), 129.8 (CH), 129.5 (CH), 128.7 (CH),
128.6 (CH), 127.8 (CH), 127.7 (CH), 127.3 (d, J = 13.0 Hz, CH),
126.1 (d, J = 92.8 Hz, C); 31P{1H}NMR (162 MHz) d 35.9; ESI-MS
919 (M + H)+; HRMS(MALDI-TOF) calcd for (C68H40O6P2 + H)+
919.23729, found 919.23671.
4.8. (Sax)-2,20-Bis-(diphenylphosphinoyl)-3,30-bis-
(hydroxymethyl)-[1,10]binaphthyl 16
Bis(diketone) (ꢀ)-12 (1.297 g, 1.411 mmol) was suspended in
CH2Cl2 (4 mL) and 95% EtOH (16 mL). To this stirring yellow slurry
was added NaBH4 (107 mg, 2.828 mmol) and the reaction was stir-
red for 1 h to give a red solution. TLC analysis revealed that all of
the starting material had been consumed. The reaction was
quenched by adding 5% HCl(aq) dropwise at 0 °C until the color of
the solution went from red to pale yellow. This was diluted with
H2O (50 mL) and extracted with EtOAc (3 ꢁ 50 mL). The combined
organic fractions were washed with H2O (50 mL) and NaCl(aq)
(50 mL) before being dried over Na2SO4, filtered, and concentrated
in vacuo to afford an orange foam.
The crude orange foam was dissolved in CH2Cl2 (20 mL) and to
this was added Pb(OAc)4 (1.314 g, 2.964 mmol). The reaction was
stirred for 4 h at rt before being quenched with H2O (60 mL) and
extracted into CH2Cl2 (3 ꢁ 30 mL). The combined organic layers
were washed with H2O (30 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to afford an orange solid. This solid was sus-
pended in CH2Cl2 (4 mL) and EtOH (16 mL) and treated with NaBH4
(107 mg, 2.828 mmol) for 16 h at rt. The reaction was quenched by
adding 5% HCl(aq) dropwise at 0 °C until evolution of H2 gas ceased.
The mixture was diluted with H2O (50 mL) and extracted with
EtOAc (3 ꢁ 50 mL). The combined organic fractions were washed
with H2O (50 mL) and NaCl(aq) (50 mL) before being dried over
Na2SO4, filtered, and concentrated in vacuo to afford a yellow foam.
The crude material was purified by silica gel chromatography (9:1
EtOAc/MeOH) to afford the product as an off-white solid (704 mg,
4.7.1. Crystal structure of 15
The X-ray quality crystals were obtained by recrystallization
from a solution of 15 in 1:1 CH2Cl2/CHCl3 layered with EtOAc.
X-ray crystallographic analysis was performed by Dr. Masood
Parvez. A colorless prismatic crystal of C60H40O6P2ꢄCHCl3ꢄCH2Cl2
was coated with Paratone 8277 oil (Exxon) and mounted on a glass
fiber. All measurements were made on a Bruker APEX2 CCD
installed on a Nonius Kappa Goniometer diffractometer with
graphite monochromated Mo-K radiation. The data were col-
lected14 and were corrected for Lorentz and polarization effects
and for absorption using multi-scan method.15 The structure was
solved by direct methods using SHELXS.16 The asymmetric unit
contains half of the complex molecule and one half of each of the
solvent molecule occupying the same location exhibiting posi-
tional disorder. The H-atoms were included at geometrically
idealized positions and were not refined. The final cycle of full-
matrix least-squares refinement using SHELXL16 converged with
unweighted and weighted agreement factors, R = 0.0483 and
wR = 0.11732 (all data), respectively, and goodness of fit,
S = 1.027. The absolute structure was established by the Flack
method17 and is presented herein; the inverted structure gave a
Flack parameter of 0.80(8) and was therefore, rejected as the struc-
ture present in the crystal. The Friedel pairs of reflections were not
merged. The weighting scheme was based on counting statistics

762
D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
0.985 mmol, 70% over three steps): ½a D20
ꢃ
¼ þ759 (c 0.205, CHCl3);
d 27.8; ESI-MS 867 (M + Na)+; HRMS(MALDI-TOF) calcd for
mp 255–256 °C; IR (film) vmax 3324 (OꢀH), 3052, 2923, 1438,
(C58H42O4P2 + Na+) 889.2670, found 889.2598.
1157, 1105, 1095, 1019 cmꢀ1 1H NMR (400 MHz) d 7.64 (d,
;
J = 8.1 Hz, 2H), 7.53 (d, J = 3.5 Hz, 2H), 7.46 (t, J = 7.0 Hz, 2H),
7.42–7.30 (m, 6H), 7.29–7.20 (m, 8H), 7.13–7.09 (m, 2H),
7.02–6.85 (m, 8H), 5.18 (br d, J = 6.4 Hz, 2H), 4.68 (d, J = 11.9 Hz,
2H), 4.29 (dd, J = 13.3, 9.5 Hz, 2H); 13C NMR (100 MHz) d 141.3
(d, J = 9.2 Hz, C), 140.6 (d, J = 5.4 Hz, C), 140.5 (d, J = 5.4 Hz, C),
136.1 (d, J = 103 Hz, C), 134.3 (d, J = 2.3 Hz, C), 133.2 (d,
J = 10.0 Hz, CH), 133.0 (d, J = 12.3 Hz, C), 132.4 (d, J = 10.7 Hz, CH),
131.9 (C), 131.7 (C), 131.4 (d, J = 3.1 Hz, CH), 130.7 (d, J = 2.3 Hz,
CH), 130.6 (d, J = 9.2 Hz, CH), 128.3 (CH), 128.1 (CH), 128.0 (CH),
127.8 (CH), 127.6 (CH), 127.5 (CH), 127.0 (CH), 65.6 (d, J = 4.6 Hz,
CH2ꢀO); 31P{1H}NMR (162 MHz) d 31.8; ESI-MS 737 (M + Na)+;
HRMS(MALDI-TOF) calcd for (C46H36O4P2 + Na+) 737.1981, found
737.1989.
4.10. (Sax)-2,20-Bis-(diphenylphosphino)-3,30-bis-
(phenoxymethyl)-[1,10]binaphthyl 18
Bisphosphine oxide (+)-17 (571 mg, 0.659 mmol) was dissolved
in xylenes (11 mL). To this was added NBu3 (4.00 mL, 16.8 mmol)
and then HSiCl3 (1.40 mL, 13.9 mmol). The reaction was heated
to 140 °C in an oil bath over 15 minutes and this reaction temper-
ature was maintained for 21 h. The reaction was cooled to 60 °C
and 30% NaOH(aq) (11 mL) was added slowly. After 1 h of stirring
at 60 °C, the reaction was cooled to room temperature, diluted
with CHCl3 (10 mL), and the layers separated. The aqueous layer
was diluted with 30% NaOH(aq) (10 mL) and extracted with CHCl3
(2 ꢁ 10 mL). The combined organic layers were washed with dis-
tilled water (2 ꢁ 10 mL) and then dried over Na2SO4, filtered, and
the solvent removed in vacuo to afford a white semi-solid. Purifica-
tion by silica gel chromatography (20:1 hexanes/EtOAc) followed
by trituration with MeOH afforded the product as an off-white
4.9. (Sax)-2,20-Bis-(diphenylphosphinoyl)-3,30-bis-
(phenoxymethyl)-[1,10]binaphthyl 17
Diol (+)-16 (704 mg, 0.985 mmol) was dissolved in CH2Cl2
(7.5 mL). To this was added NEt3 (0.63 mL, 4.40 mmol) and the
solution was cooled to 0 °C. Next, MsCl (0.17 mL, 2.20 mmol) was
added dropwise and the reaction was stirred for 1 h. TLC analysis
indicated that all of the starting material had been consumed.
The reaction was quenched with saturated NaHCO3 (10 mL) and
the layers separated. The aqueous layer was extracted with CH2Cl2
(3 ꢁ 10 mL). The combined organic fractions were washed with
H2O (10 mL), dried over Na2SO4, filtered, and concentrated to
afford a yellow foam. This material was dissolved in DMF (5 mL)
and set aside.
powder (481 mg, 0.577 mmol, 87%): ½a D20
¼ þ129 (c 0.200, CHCl3);
ꢃ
mp 224–225 °C; IR (film) vmax 3048, 2917, 1602, 1579, 1492, 1429,
1237, 1028 cmꢀ1 1H NMR (400 MHz) d 8.38 (s, 2H), 7.91 (d,
;
J = 8.2 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.26–7.22 (m, 4H),
7.19–6.98 (m, 26H), 6.85 (t, J = 7.3 Hz, 2H), 6.54 (d, J = 7.9 Hz,
4H), 4.56 (d, J = 13.8 Hz, 2H), 4.52 (d, J = 13.8, 2H); 13C NMR
(100 MHz)
d 158.6 (C), 150.0 (d, J = 11.5 Hz, C), 149.6 (d,
J = 11.5 Hz, C), 139.0 (d, J = 4.6 Hz, C), 136.2 (d, J = 16.1 Hz, C),
135.7 (d, J = 17.6 Hz, C), 133.8 (C), 133.3 (d, J = 3.1 Hz, C), 133.3
(C), 133.2 (d, J = 3.1 Hz, C), 132.2 (d, J = 19.9 Hz, CH), 131.2 (d,
J = 1.5 Hz, CH), 131.1 (d, J = 2.3 Hz, CH), 130.9 (d, J = 4.1 Hz, C),
130.8 (d, J = 4.6 Hz, C), 129.2 (CH), 128.4 (CH), 128.3 (CH), 128.3
(CH), 128.20 (CH), 128.0 (d, J = 6.9 Hz, CH), 127.3 (d, J = 6.1 Hz,
CH), 127.1 (CH), 125.9 (CH), 120.5 (CH), 114.5 (CH), 69.5
(CH2–O); 31P{1H}NMR (162 MHz) d ꢀ14.4; ESI-MS 835 (M + H)+;
HRMS(MALDI-TOF) calcd for (C58H42O2P2 + H+) 835.28893, found
835.28657.
In another flask, phenol (927 mg, 9.85 mmol) was dissolved in
DMF (5 mL) and cooled to 0 °C. Next, NaH (355 mg, 60% dispersion
in mineral oil) was added to this solution portionwise. Once added,
the mixture was allowed to warm to rt over 30 min. The previously
prepared solution of 16 in DMF (vide supra) was added dropwise to
the solution of sodium phenoxide using a canula. The flask contain-
ing 16 was then rinsed with DMF (2 ꢁ 1 mL) and these washings
were added to the reaction mixture along with NaI (59 mg,
0.39 mmol, 20 mol% per hydroxyl group). The reaction was stirred
at rt for 18 h before being cooled to 0 °C and quenched with satu-
rated NH4Cl (5 mL) dropwise. The quenched reaction was diluted
with EtOAc (15 mL) and NaCl(aq) (15 mL) and the layers were sep-
arated. The aqueous layer was extracted with EtOAc (3 ꢁ 15 mL).
The combined organic layers were washed with NaCl(aq) (30 mL),
dried over Na2SO4, filtered, and concentrated to afford a thick yel-
low oil. The crude material was purified by silica gel chromatogra-
phy (100% EtOAc) to afford the product as a white foam (756 mg,
0.872 mmol, 88%). An analytical sample was obtained by recrystal-
lizing from Et2O to afford the product as a white, crystalline solid
4.11. General procedure for the synthesis of bisphosphine-
diselenides
Bisphosphine (20 mg) was dissolved in CHCl3 (2 mL). To this
solution was added elemental selenium (10 equiv). The reaction
was stirred at rt and monitored by TLC for the disappearance of bis-
phosphine. For sluggish reactions (>4 h at rt), the mixtures were
heated at 60 °C for 16 h. Once completed, the reaction was cooled
to rt and filtered through a plug of Celite. The Celite was washed
with CHCl3 (3 ꢁ 2 mL) and the filtrate was concentrated. The crude
material was then analyzed by 31P NMR spectroscopy without fur-
ther purification.
(580 mg, 0.669 mmol, 68%): ½a D20
¼ þ228 (c 0.265, CHCl3); mp
ꢃ
218–219 °C; IR (film) vmax 3057, 1590, 1581, 1495, 1433, 1238,
4.12. General procedure for Rh-catalyzed asymmetric
hydrogenations
1186, 1105 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.96 (d, J = 3.7 Hz,
;
2H), 7.72 (d, J = 8.2 Hz, 2H), 7.57 (dd, J = 12.0, 7.0 Hz, 4H),
7.47–7.39 (m, 2H), 7.35–7.29 (m, 2H), 7.28–7.07 (m, 20H), 6.96
(dt, J = 7.9, 3.1 Hz, 4H), 6.92–6.87 (m, 2H), 6.66–6.63 (m, 4H),
5.12 (d, J = 13.9 Hz, 2H), 4.95 (d, J = 13.9 Hz, 2H); 13C NMR
At first, Rh(nbd)2BF4 (3.7 mg, 0.01 mmol), ligand (0.011 mmol),
and MeOH (1 mL) were combined under an inert atmosphere and
stirred for 30 min at room temperature. Olefin (1 mmol) was added
with an additional volume of MeOH (1 mL). The reaction mixture
was then subjected to three consecutive freeze/pump/thaw cycles
on a double manifold (pump time = 10 min). Upon warming to
room temperature, the reaction was placed under a hydrogen
atmosphere (2 atm) for 24 h. Upon completion, the volatiles were
removed in vacuo and the remaining residue was passed through
a plug of silica gel (hexanes–EtOAc, 1:1). Upon solvent evaporation,
the isolated products were used directly for either chiral GC or
(100 MHz)
d 158.40 (C), 142.1 (d, J = 5.4 Hz, C), 142.0 (d,
J = 5.4 Hz, C), 136.6 (d, J = 13.0 Hz, C), 136.5 (C), 135.7 (C), 134.0
(d, J = 1.5 Hz, C), 133.2 (d, J = 104 Hz, C), 133.0 (d, J = 10.7 Hz, C),
132.5 (d, J = 10.0 Hz, CH), 131.2 (d, J = 2.3 Hz, CH), 130.9 (d,
J = 10.0 Hz, CH), 130.6 (d, J = 3.1 Hz, CH), 129.2 (CH), 128.9 (d,
J = 9.2 Hz, CH), 128.3 (CH), 128.1 (CH), 128.0 (CH), 127.95 (C),
127.8 (CH), 127.6 (CH), 127.1 (CH), 127.0 (CH), 126.4 (CH), 120.7
(CH), 114.6 (CH), 68.6 (d, J = 3.8 Hz, CH2); 31P{1H}NMR (162 MHz)

D. A. Rankic et al. / Tetrahedron: Asymmetry 23 (2012) 754–763
763
2177–2180; (e) Gorobets, E.; Wheatley, B. M. M.; Hopkins, J. M.; McDonald, R.;
Keay, B. A. Tetrahedron Lett. 2005, 46, 3843–3846.
chiral HPLC analysis. Chiral GC data for methyl 2-acetamidopro-
panoate 20a: Chiral GC, Cyclodex B, isothermal 90 °C,: tR1
[(R)-20a] = 31.8 min, tR2 [(S)-20a] = 32.8 min.
3. For BINAP see: (a) Hopkins, J. M.; Gorobets, E.; Wheatley, B. M. M.; Parvez, M.;
Keay, B. A. Synlett 2006, 3120–3124. For MeO-BIPHEP see Refs.2c,e.
4. (a) Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.; Pregosin, P. S.;
Tschoerner, M. J. Am. Chem. Soc. 1997, 119, 6315–6323; (b) Tschoerner, M.;
Pregosin, P. S.; Albinati, A. Organometallics 1999, 18, 670–678; (c) Selvakumar,
K.; Valentini, M.; Pregosin, P. S.; Albinati, A.; Eisentrager, F. Organometallics
2000, 19, 1299–1307; (d) Dotta, P.; Kumar, P. G. A.; Pregosin, P. S. Magn. Reson.
Chem. 2002, 40, 653–658; (e) Dotta, P.; Magistrato, A.; Rothlisberger, U.;
Pregosin, P. S.; Albinati, A. Organometallics 2002, 21, 3033–3041.
5. Rankic, D. A.; Hopkins, J. M.; Parvez, M.; Keay, B. A. Synlett 2009, 2513–2517.
6. Rankic, D. A.; Lucciola, D.; Keay, B. A. Tetrahedron Lett. 2010, 51, 5724–5727.
7. (a) S. Y. W. Lau, Ph. D. Thesis, University of Calgary 2001.; (b) J. M. Hopkins, M.
Sc. Thesis, University of Calgary 2003.; (c) J. M. Hopkins, Ph. D. Thesis,
University of Calgary 2006.; (d) D. A. Rankic, Ph. D. Thesis, University of Calgary
2010.
Chiral data for methyl
a-acetamide cinnamate 4: Chiral
HPLC, chiralcel OD; hexane–iPrOH, 9:1; 1.0 mL/min: tR1[(R)-4] =
12.4 min, tR2 [(S)-4] = 16.3 min.
Acknowledgments
Financial support for this work was provided by Merck Frosst
Canada and by the Natural Sciences and Engineering Research
Council of Canada through a CRD grant to B. A. K. and a NSERC
postgraduate scholarship to D. A. R. Alberta Ingenuity is also
thanked for a studentship to D. A. R. Thanks are also extended to
Prof. Warren Piers for the use of his chiral HPLC.
8. Widhalm, M.; Mereiter, K. Bull. Chem. Soc. Jpn. 2003, 76, 1233–1244.
9. For more information, see Ref.7c,d
10. Yusybov, M. S.; Filimonov, V. D. Synthesis 1991, 131–132.
11. Allen, D. W.; Taylor, B. F. J. Chem. Soc. Dalton Trans. 1982, 51–54.
12. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
13. Prepared by according to the following procedure: Nicolaou, K. C.; Dai, W. M.;
Hong, Y. P.; Baldridge, K. K.; Siegel, J. S.; Tsay, S. C. J. Am. Chem. Soc. 1993, 115,
7944.
14. Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307.
15. R. Hooft, COLLECT. 1998 Nonius BV, Delft. The Netherlands.
16. Sheldrick, G. M. Acta Cryst. 2008, A64, 112.
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