Stereoselective Synthesis of All Possible Phosferrox Ligand Diastereoisomers Displaying Three Elements of Chirality: Stereochemical Optimization for Asymmetric Catalysis

Article abstract of DOI:10.1021/acs.joc.9b03342

All four possible diastereoisomers of phosphinoferrocenyloxazoline (Phosferrox type) ligands containing three elements of chirality were synthesized as single enantiomers. The S_c configured oxazoline moiety (R = Me, i-Pr) was used to control th

Full text of DOI:10.1021/acs.joc.9b03342

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Article
Stereoselective Synthesis of all Possible Phosferrox Ligand
Diastereoisomers Displaying Three Elements of Chirality:
Stereochemical Optimization for Asymmetric Catalysis
Ross A Arthurs, David L. Hughes, and Christopher John Richards
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03342 • Publication Date (Web): 27 Feb 2020
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The Journal of Organic Chemistry
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Stereoselective Synthesis of all Possible Phosferrox Ligand
Diastereoisomers Displaying Three Elements of Chirality:
Stereochemical Optimization for Asymmetric Catalysis
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Ross A. Arthurs, David L. Hughes and Christopher J. Richards*
School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, U.K.
Supporting Information Placeholder
D
Ph
Ph
Stereochemical
optimization
O
O
P
P
Fe
Fe
o-Tol
o-Tol
N
N
for Pd-catalysed
allylic alkylation
R
R
O
(S,Rp,Rphos
)
(S,Sp,Sphos
)
R
N
Sphos
Rphos
Fe
Sp
Rp
D
(S)
GR-S
o-Tol
Ph
o-Tol
Ph
O
O
Rphos
Sphos
P
P
Fe
Fe
N
N
R
R
(S,Sp,Rphos
)
(S,Rp,Sphos
)
ABSTRACT: All four possible diastereoisomers of phosphinoferrocenyloxazoline (Phosferrox type) ligands containing three
elements of chirality were synthesized as single enantiomers. The Sc configured oxazoline moiety (R = Me, i-Pr) was used to
control the generation of planar chirality by lithiation, with the alternative diastereoisomer formed by use of a deuterium
blocking group. In each case subsequent addition of PhPCl2 followed by o-TolMgBr resulted in a single P-stereogenic
diastereoisomer (Sc,Sp,Sphos and Sc,Rp,Rphos respectively). The alternative diastereoisomers were formed selectively by addition
of o-TolPCl2 followed by PhMgBr ((Sc,Sp,Rphos and Sc,Rp,Sphos respectively). Preliminary application of these four ligand
diastereoisomers, together with (Sc,Sp) and (Sc,Rp) Phosferrox (PPh2), to palladium catalysed allylic alkylation of trans-1,3-
diphenylallyl acetate revealed a stepwise increase/decrease in ee, with the configuration of the matched/matched
diastereoisomer as Sc,Sp,Sphos (97% ee).
use. These frequently contain two elements of chirality (e.g.
Josiphos and Walphos) such that two diastereoisomers are
INTRODUCTION
Metal-based asymmetric catalysis is a major branch of
potentially available. Typically only one of the two is usually
organic chemistry that is exploited widely for the synthesis
explored, this being primarily a consequence of synthetic
of research-focused and economically important
availablity.8 In cases where both diastereomeric ligands are
compounds.1 To these ends the discovery of a new metal-
tested in a metal-catalysed reaction, the matched and
catalysed reaction is frequently followed by work aimed at
mismatched chirality pairings are usually identified
extending the reaction to the formation of enantioenriched
readily.9
chiral products. This process typically requires the
screening of many chiral non-racemic ligands to achieve the
R'
goal of high enantioselectivity.2 The choice of ligands
PR2
screened may be guided by the success of related chemistry,
PR'2
PR'2
PR2
PR2
R2P
and/or ligand availability, many of which may be sourced
commercially. Certain ligand types have proven to be
successful in a number of different reactions, and as a result
these have been described as ‘privileged’.3 Once identified
as such many analogous ligands, based on the same core
structure, are frequently synthesized by substituent
variation. In this way multiple ligands closely related to, for
example, BINAP,4 Josiphos5 and Walphos6 are known, and
many are commercially available (Figure 1).
Fe
Fe
(R,Sp)
(R,Rp)
R'
(Sa)
BINAP type
Josiphos type
Walphos type
Figure 1. Representative ‘privileged’ and commercially
available ligands for which multiple variation of the
substituents (R/R’) has been demonstrated.
Although specific advantages have been identified for the
use of C2-symmetric ligands in asymmetric catalysis (e.g.
BINAP),7 C1-symmetric ligands have also found widespread
This basis of ligand selection may potentially be
expanded to the use of all four possible diastereoisomers
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arising from a ligand containing three elements of chirality.
the literature of the reaction of chiral nucleophiles with
RPX2 (X = Cl, NEt2) where differential replacement of both
1
2
3
4
5
6
7
8
The configuration of each of the these will likely have a
significant influence on product enantioselectivity, and the
optimum relative configuration may well be reaction
dependent. This has the potential to provide an alternative
pathway to ligand optimization in asymmetric catalysis. To
the best of our knowledge such methodology has not been
described previously.10
leaving groups
X
leads to
a
product in high
diastereoselectivity.17 A further example is the use of
lithiated planar chiral Ugi’s amine as the nucleophile for the
first step, followed by addition of an aryl Grignard reagent,
to give P-stereogenic P-N ligands in high dr.18
Accordingly, diastereoselective lithiation at -78 oC of (S)-
1a (conditions A) was followed by addition of PPhCl2 and
warming of the reaction mixture to room temperature. After
RESULTS AND DISCUSSION
9
o
Our approach to achieving the selective synthesis of all four
possible enantiopure diastereoisomers of a chiral bidentate
ligand started with ferrocenyloxazoline (S)-1a (R = i-Pr).
This is known to undergo highly diastereoselective
lithiation (dr > 100 : 1),11 such that subsequent addition of
Ph2PCl results in bidentate ligand (S,Sp)-L1a (Scheme 1).12
This ligand has been applied extensively in metal-catalysed
asymmetric synthesis (Pd, Ru, Ir, Cu, Ag, Ni).13 We recently
reported the adaptation of this lithiation/Ph2PCl quench
procedure for the selective synthesis of the corresponding
diastereomeric ligand. Specifically, initial selective
lithiation is followed by introduction of deuterium to give
(S,Rp)-2-d-1a,14 such that a second lithiation, under non-
selective conditions, is instead controlled by the introduced
isotope (kH/kD ~ 20). Following addition of Ph2PCl the target
product (S,Rp-5-d-L2a) is obtained predominantly as one
diastereoisomer (dr = 10 : 1 – Scheme 1).15 Corresponding
ligands (S,Sp)-L1b and (S,Rp-5-d-L2b) have been obtained in
the same way from ferrocenyloxazoline (S)-1b (R =
Me).12c,15
re-cooling to -78 C, subsequent addition of o-TolMgBr,
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followed by warming of the reaction mixture to room
temperature and work-up, resulted in the isolation of a new
Phosferrox ligand. After purification by column
chromatography and recrystallisation, the product was
identified as (S,Sp,Sphos)-L3a following determination of the
X-ray crystal structure (Scheme 2, Figure 2).19 Use of the
same methodology, but instead with o-TolPCl2 and PhMgBr
as reagents, resulted in the formation of the alternative P-
stereogenic diastereoisomer (S,Sp,Rphos)-L4a, an outcome
again confirmed by determination of the X-ray crystal
structure (Figure 3).19 In both cases the new phosphorus-
based stereogenic center is formed with high
diastereoselectivity (vide infra). As lithiation of (S)-1b is
also known to proceed with high diastereselectivity,12c,15
this enabled the application of this methodology to the
synthesis of (S,Sp,Sphos)-L3b and (S,Sp,Rphos)-L4b, both
isolated as single diastereoisomers following column
chromatography.
Scheme 2. Stereoselective synthesis of P-stereogenic
diastereoisomers (S,Sp,Sphos)-L3a/b and (S,Sp,Rphos)-L4a/b.
Scheme 1. Oxazoline auxiliary mediated control of planar
chiral diastereoselectivity (S,Sp), and adaption by use of a
deuterium blocking group (S,Rp).
A
i) Conditions
O
O
ii) 1.4 equiv PPhCl2
-78 oC - rt, 1 h
Ph
O
R
R
P
N
PPh2
N
1a b
/
(S)-
Fe
A
i) Conditions
o-Tol
N
iii) 1.4 equiv o-TolMgBr
Fe
Fe
-78 oC - rt, 1 h
ii) 1.3 equiv Ph2PCl
0 oC - rt, 10 min
R
L3a
L3b
(S,Sp,Sphos)-
(S,Sp,Sphos)-
(R = i-Pr 63%)
(R = Me 39%)
1a
(S)- (R = i-Pr)
L1a
L1b
(S,Sp)-
(S,Sp)-
(64%)
(59%)
1b
(S)- (R = Me)
A
i) Conditions
Conditions B
Conditions A
A
i) Conditions
ii) 1.5 equiv
MeOH-d4
ii) 1.4 equiv o-TolPCl2
-78 oC - rt, 1 h
1.3 equiv n-BuLi
THF, -78 oC, 2 h
1.3 equiv s-BuLi
1.3 equiv TMEDA
Et2O, -78 oC, 2-3 h
o-Tol
O
P
1a b
/
(S)-
Fe
Ph
0 oC - rt, 10 min
N
iii) 1.4 equiv PhMgBr
-78 oC - rt, 1 h
R
PPh2
O
O
L4a
L4b
(S,Sp,Rphos)-
(S,Sp,Rphos)-
(R = i-Pr 54%)
(R = Me 49%)
R
N
R
N
B
i) Conditions
D
D
Fe
Fe
ii) 1.5 equiv Ph2PCl
0 oC - rt, 10 min
(*2 steps)
The extension of this methodology to the synthesis of the
remaining two planar chiral diastereoisomers started with
(S,Rp)-2-d-1a (>90% D incorporation).15 Use of lithiation
conditions B, followed by addition of o-TolPCl2 and then
PhMgBr as before, led to isolation of a single Phosferrox
derivative containing n-butyl and ortho-tolyl groups (14%
yield). The competitive and undesired reaction of n-BuLi led
us to evaluate s-BuLi/THF as an alternative base/solvent
combination for this reaction. These conditions (C) applied
previously to the lithiation of (S)-1a resulted in an 8 : 1 dr,11
therefore allowing the larger kinetic isotope effect
associated with lithiation20 to dominate planar chiral
1a b
/
L2a
L2b
(S,Rp)-2-d-
(S,Rp)-5-d-
(S,Rp)-5-d-
(49%*)
(39%*)
In order to extend this chemistry for the introduction of a
third element of chirality we considered procedures for the
selective creation of a phosphorus-based stereogenic
center. Although many methods are known for the
stereocontrolled synthesis of P-stereogenic compounds,16
in this instance efficiency would result if the lithiated planar
chiral precursor to phosphorus introduction could be used
to control diastereoselectivity. There are several reports in
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diastereoselectivity. To confirm this, application of
conditions C to the lithiation of (S,Rp)-2-d-1a followed by
1
2
3
4
5
6
7
8
addition of TMSCl resulted in a 5 : 1 ratio of the resulting
silylated (S,Rp) : (S, Sp) diastereoisomers (68% yield).
Furthermore, lithiation in the same way, followed by
addition of o-TolPCl2 and then BuMgCl, led to the
predominant formation of the same Phosferrox derivative
formed when using n-BuLi as base, assigned as (S,Rp,Sphos)-
2a by analogy to the chemistry described above (Scheme 3).
Scheme 3. Demonstration of deuterium mediated planar
chirality reversal with configurational control of
phosphorus based stereogenic center.
a
Conditions C
i)
1.3 equiv s-BuLi
THF, -78 oC, 3 h
9
D
10
11
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o-Tol
O
P
1a
(S,Rp)-2-d-
Fe
N
ii) 1.4 equiv o-TolPCl2
-78 oC - rt, 1 h
i-Pr
iii) 1.4 equiv BuMgCl
-78 oC - rt, 1 h
2a
(S,Rp,Sphos)- (59%)
Scheme 4. Stereoselective synthesis of P-stereogenic
‡
diastereoisomers (S,Rp,Rphos)-L5 and (S,Rp,Sphos)-L6, (dr =
15 : 1 for L5b).
C
i) Conditions
D
ii) 1.4 equiv PhPCl2
-78 oC - rt, 1 h
Ph
O
P
1a b
/
Fe
(S,Rp)-2-d-
o-Tol
N
iii) 1.4 equiv o-TolMgBr
-78 oC - rt, 1 h
i-Pr
Figure 2. Representation of the X-ray crystal structure of
(S,Sp,Sphos)-L3a (hydrogen atoms omitted for clarity). Principal
bond lengths [Å] include: C(1)-C(3) 1.460(2), C(2)-P(1)
1.8283(18). Principal torsions [°] include: C(2)-C(1)-C(3)-N(1)
-159.38(19), C(1)-C(2)-P(1)-C(6) 58.74(17), C(1)-C(2)-P(1)-
C(4) 162.54(16), C(2)-P(1)-C(6)-C(7) -154.48(15), C(2)-P(1)-
C(4)-C(5) 86.89(15). Thermal ellipsoids are drawn at the 50%
probability level.
L5a
L5b
(S,Rp,Rphos)-5-d-
(S,Rp,Rphos)-5-d-
(R = i-Pr 59%)
(R = Me 17%)
C
i) Conditions
D
ii) 1.4 equiv o-TolPCl2
-78 oC - rt, 1 h
o-Tol
O
P
1a b
(S,Rp)-2-d-
/
Fe
Ph
N
iii) 1.4 equiv PhMgBr
-78 oC - rt, 1 h
i-Pr
L6a
L6b
(S,Rp,Sphos)-5-d-
(S,Rp,Sphos)-5-d-
(R = i-Pr 58%)
(R = Me 29%)
Conditions C were then used for the synthesis of
(S,Rp,Rphos)-5-d-L5a and (S,Rp,Sphos)-5-d-L6a (Scheme 4). For
both reactions comparison of the 31P NMR spectra obtained
after work-up again revealed excellent configurational
control of the phosphorus-based stereogenic center.
Separation of the product from the alternative planar chiral
diastereoisomer was achieved readily by column
chromatography. This chemistry was extended to the
synthesis of (S,Rp,Rphos)-5-d-L5b and (S,Rp,Sphos)-5-d-L6b,
both isolated predominantly as a single diastereoisomer
following column chromatography, and in the case of
(S,Rp,Sphos)-L6b as a single isomer by a subsequent
recrystallisation. The configuration of (S,Rp,Sphos)-L6b was
established by an X-ray crystal structure determination
(Figure 4),19 confirming that it is the planar chirality, and
not the oxazoline-based stereogenic center, that exclusively
controls the configuration of the phosphorus based
stereogenic center.
Figure 3. Representation of the X-ray crystal structure of
(S,Sp,Rphos)-L4a (hydrogen atoms omitted for clarity). Principal
bond lengths [Å] include: C(1)-C(3) 1.458(4), C(2)-P(1)
1.826(3). Principal torsions [°] include: C(2)-C(1)-C(3)-N(1) -
175.6(3), C(1)-C(2)-P(1)-C(6) 83.7(3), C(1)-C(2)-P(1)-C(4) -
172.2(3), C(2)-P(1)-C(6)-C(7) 176.3(2), C(2)-P(1)-C(4)-C(5)
92.6(3). Thermal ellipsoids are drawn at the 50% probability
level.
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1
2
3
4
Scheme 5. Planar chiral stereocontrol in the synthesis of P-
stereogenic diastereoisomer (S,Sp,Rphos)-L4a.
5
O
O
6
7
8
i-Pr
i-Pr
N
N
-Cl
P
P
Fe
Fe
o-Tol
o-Tol
epimerisation
Cl
9
4
3
(S,Sp,Sphos)-
(S,Sp)-
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A
iii) PhMgBr
i) Conditions
SN2 (inversion)
ii) o-TolPCl2 (non-selective)
L4a
(S,Sp,Rphos)-
1a
(S)-
Attempts to isolate and further characterize the
intermediate were unsuccessful. There are three pointers to
the intermediate being (S,Sp,Sphos)-4,18 although these do not
rule out other possibilities. Firstly, aryl/lone-pair
differentiation, with the aryl group oriented away from
ferrocene in this cyclic structure, provides a basis for
epimerization selectivity. Thermodynamic control of this
sort has been used to explain the diastereoselective
formation of other auxiliary mediated P-stereogenic
derivatives.17,25 Secondly, stereospecific SN2 reaction with
PhMgBr accounts for the configuration of the phosphorus-
based stereogenic center in (S,Sp,Rphos)-L4a. Finally, the
observed 31P NMR chemical shift of 67.7 ppm is in
reasonable agreement with the value estimated for this
intermediate (ca. 72 ppm). This was determined starting
with the reported value of 88 ppm26 for (DMAP)Ph2P+TfO-
corrected for the replacement of both phenyls by a
ferrocenyl (-9.4 ppm) and an ortho-tolyl (-6.4 ppm) group.27
Figure 4. Representation of the X-ray crystal structure of
(S,Rp,Sphos)-L6b (hydrogen and deuterium atoms omitted for
clarity). Principal bond lengths [Å] include: C(1)-C(3) 1.460(5),
C(2)-P(1) 1.828(4). Principal torsions [°] include: C(2)-C(1)-
C(3)-N(1) 7.5(7), C(1)-C(2)-P(1)-C(6) -89.2(4), C(1)-C(2)-P(1)-
C(4) 169.7(3), C(2)-P(1)-C(6)-C(7) -173.0(3), C(2)-P(1)-C(4)-
C(5) -93.3(3). Thermal ellipsoids are drawn at the 50%
probability level.
All four P-stereogenic diastereoisomers (L3a/b-L6a/b)
were obtained by column chromatography on silica. In
some instances epimerization was noted, as has been
observed previously for other P-stereogenic compounds
containing a ferrocenyl substituent.18a,21,22 To investigate
this further, a 1 : 0.2 ratio of (S,Sp,Sphos)-L3a/(S,Sp,Rphos)-L4a
was heated for 24 h at 65 oC in hexane containing
chromatography grade SiO2 (40-65 μm). This resulted in a
change in ratio to 1 : 1, whereas the in the absence of SiO2,
or with added neutral Al2O3 (10-200 μm), no change was
observed. Similarly, heating initially pure (S,Rp,Rphos)-5-d-
Table 1. Palladium catalysed allylic alkylation with ligands
L1a-L6a.
o
L5a in silica doped hexane for 24 h at 65 C gave a 1 : 0.5
ratio of (S,Rp,Rphos)-5-d-L5a/(S,Rp,Sphos)-5-d-L6a. The
promotion of epimerization by SiO2 is likely related to its
acidity.23,24
1 mol% [Pd(3-allyl)Cl]2
2.5 mol% ligand
L1a L6a
-
(MeO2C)2CH
Ph Ph
OAc
Ph
3 equiv H2C(CO2Me)2
The excellent diastereoselectivity observed for the
formation of the P-stereogenic ligands could be a
consequence of highly selective differentiation, on
substitution, of the two enantiotopic chlorine components
of ArPCl2 to give 3 (kinetic control). Alternatively, this first
step in the reaction could proceed without selectivity,
requiring a subsequent epimerization step to produce a
single isomer (thermodynamic control). To investigate this
further the synthesis of (S,Sp,Rphos)-L4a was repeated, with
examination by 31P NMR spectroscopy of the reaction
mixture after addition o-TolPCl2 and warming to room
temperature (Scheme 5). This revealed a major signal at
67.7 ppm, and following addition of PhMgBr this signal
disappeared and was replaced by the 31P NMR signal for
(S,Sp,Rphos)-L4a (-23.9 ppm). No signal was observed for
Ph
3 equiv BSA, 2 mol% KOAc
CH2Cl2, rt
5
6
(S)-
rac-
Entry
Ligand
Time Conversion ee%[b]
(h)
(%)[a]
1
2
3
4
5
(S,Sp)-L1a
<1
24
5
100
92
95
71
97
95
84
(S,Rp)-5-d-L2a
(S,Sp,Sphos)-L3a
(S,Sp,Rphos)-L4a
100
100
90
7
(S,Rp,Rphos)-5-d-
24
L5a
6
(S,Rp,Sphos)-5-d-
24
86
63
(S,Sp,Sphos)-L3a
(ca. -28 ppm), from which the
L6a
diastereoselectivity is estimated as > 100 : 1.
[a] Determined by 1H NMR spectroscopy. [b] Determined
by chiral HPLC. (S)-6 was the major enantiomer in all cases.
The availability of all four ligand diastereoisomers
enabled a preliminary investigation into the influence of
ligand configuration on enantioselectivity. To this end we
chose as a model reaction palladium catalysed allylic
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lithiation reactions were carried out under an inert atmosphere of
alkylation of rac-5 as t-Bu substituted Phosferrox ligands
are known to work well in this chemistry.13a,28 In addition to
i-Pr substituted diastereomeric ligands L3a-L6a, precursor
ligands L1a and L2a were also employed. All ligands
resulted in the formation of (S)-6 as the major enantiomer,
and the ee values obtained (Table 1) revealed a clear
preference for the S,Sp diastereoisomers, with the S,Sp,Sphos
ligand L3a being the matched/matched diastereoisomer. A
pictorial representation of these ee values highlights the
additive/subtractive influence of the phosphorus-based
stereogenic center (Figure 5a). Assuming the availability of
only two diastereomeric transition states,29 an alternative
either nitrogen or argon. Alkyllithiums and Grignards were not
titrated prior to use. Silica gel (60 Å pore size, 40 - 63 µm technical
grade) was used for chromatography. All protons and carbons
were assigned using 2D NMR techniques including HSQC, HMBC,
NOESY and COESY.
1
2
3
4
5
6
7
8
Preparation
of
(S)-2-[(Sp)-2-((Sphos)-ortho-
tolylphenylphosphino)ferrocenyl]-4-(1-
methylethyl)oxazoline, (S,Sp,Sphos)-L3a. (S)-1a (0.100 g, 0.34
mmol) was added to a flame dried Schlenk tube under an inert
atmosphere and dissolved in dry diethyl ether (4 mL). TMEDA
(0.07 mL, 0.44 mmol) was added and solution was cooled to -78 °C
and stirred for 5 min after which s-butyllithium (1.4 M in hexanes)
(0.31 mL, 0.44 mmol) was slowly added. After stirring for 3 hours,
dichlorophenylphosphine (64 μl, 0.47 mmol) was added and the
reaction allowed to stir at room temperature for 1 h. The reaction
was re-cooled to -78 °C and o-tolylmagnesium bromide (2.0 M in
THF) (0.24 mL, 0.47 mmol) was added and the reaction allowed to
warm to room temperature and stir for an additional hour. The
reaction was cooled to 0 °C quenched with saturated sodium
carbonate solution and separated with diethyl ether, dried with
magnesium sulphate and the solvent removed in vacuo.
Purification by column chromatography (SiO2, 10%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
representation of these results is as ΔΔG‡
(calculated with rt = 22 C - Figure 5b). In both cases the
phosphine based stereogenic center adds to ΔΔG‡R-S a value
of ~2 kJ mol-1.
values
R-S
o
a) ee(%)
95 (S,Sp)
b) GR-S (kJ mol-1
8.8 (S,Sp)
)
10.3 (S,Sp,Sphos
)
97 (S,Sp,Sphos
95 (S,Sp,Rphos
)
)
8.7 (S,Sp,Rphos
)
84 (S,Rp,Rphos
)
EtOAc/hexane) yielded an orange solid (0.11 g, 63%). Rf 0.2 (10%
5.9 (S,Rp,Rphos
)
25.5°C
EtOAc/hexane). Mp 150 - 151 °C. [α]D
= +120 (c 0.20, CHCl3).
71 (S,Rp)
4.3 (S,Rp)
1
3.6 (S,Rp,Sphos
)
IR (film): 3053, 2955, 2926, 2873, 1656 (CN). H NMR (500 MHz,
CDCl3): 7.29 - 7.22 (2H, m, o-TolH), 7.23 - 7.15 (5H, m, PhH), 7.08 -
7.01 (2H, m, o-TolH), 5.09 (1H, brs, CpH), 4.40 (1H, brs, CpH), 4.27
63 (S,Rp,Sphos
)
Figure 5. Outcomes of palladium catalysed allylic alkylation
with ligands L1a-L6a.
(1H, apt, 2+3JHH = 8.9 Hz, CHH), 4.22 (5H, s, CpH), 3.85 (1H, td, 2JHH
=
= 8.5
3
2+3
9.0, JHH = 6.2 Hz, CH), 3.72 (1H, s, CpH), 3.41 (1H, apt,
Hz, CHH), 2.85 (3H, s, CH3), 1.62 (1H, apoct,
J
HH
3+3+3
J
HH
= 6.6 Hz, CH),
CONCLUSION
3
3
0.83 (3H, d, JHH = 6.8 Hz, CH3), 0.66 (3H, d, JHH = 6.8 Hz, CH3).
13C{1H} NMR (125 MHz, CDCl3): 166.4 (C=N), 143.5 (d, JCP = 27.4
2
We have demonstrated that sequential addition to a
lithiated planar chiral ferrocenyloxazoline of Ar1PCl2
Hz, o-TolC), 140.5 (d, 1JCP = 13.0 Hz, PhC), 136.8 (d, 1JCP = 15.4 Hz, o-
TolC), 136.0 (d, 2JCP = 3.7 Hz, o-TolC), 132.4 (d, 2JCP = 20.4 Hz, PhC),
followed by Ar2MgBr results in
a diarylferrocenyl
3
3
130.1 (d, JCP = 4.9 Hz, o-TolC), 129.2 (o-TolC), 128.2 (d, JCP = 6.8
phosphine with excellent control of diastereoselectivity.
Coupled with the high diastereoselectivity of lithiation, as
controlled by the (S)-valine or (S)-alanine derived oxazoline
auxiliary, and the use of a deuterium blocking group to
reverse lithiation diastereoselectivity, this enables the
selective synthesis of all possible Phosferrox ligand
diastereoisomers containing three elements of chirality. To
the best of our knowledge this is the first time four
Hz, PhC), 127.8 (PhC), 126.1 (d, 3JCP = 2.1 Hz, o-TolC), 79.8 (d, 2JCP
=
17.6 Hz, CpC), 74.5 (CpC), 74.2 (CpC), 71.9 (CpC), 71.6 (CH), 71.0
3
(2CpC), 70.1 (CH2), 32.0 (CH), 22.2 (d, JCP = 22.9 Hz, CH3), 19.1
(CH3), 17.7 (CH3). 31P{1H} NMR (202 MHz, CDCl3): -26.51 (PPho-
Tol). HRMS (ASAP-TOF) m/z: [M+H]+ Calcd for C29H31FeNOP
496.1493; Found 496.1493.
Preparation
of
dichloroortho-tolylphosphine.
Bis(diethylamino)chlorophosphine (5.00 g, 23.7 mmol) was added
to a flame dried Schlenk tube, dissolved in diethyl ether (25 mL)
and cooled to -78 °C. Ortho-tolylmagnesium bromide (2M in THF)
(17.80 mL 35.6 mmol) was then added slowly and the reaction
allowed to warm to room temperature and stirred vigorously for 1
h. The resulting suspension was allowed to settle and the mother
liquor transferred to a dry flask by cannula filtration, and the
remaining white solid washed with diethyl ether (3 x 10 mL). The
solvent was then removed in vacuo and the resulting oil re-
dissolved in fresh diethyl ether (10 mL). The flask was cooled to 0
°C and hydrogen chloride (2 M in Et2O) (59.33 mL, 118.7 mmol)
was added and the reaction allowed to stir vigorously at room
temperature for 1 hour. Again, the resulting suspension was
allowed to settle and the mother liquor transferred to a dry flask
by cannula filtration, and the remaining white solid washed with
diethyl ether (3 x 10 mL). The solvent was removed in vacuo and
the resulting oil purified by Kugelrohr distillation (130 - 140 °C @
7 mbar) to give a clear oil (2.53 g, 55 %): 1H NMR (500 MHz, CDCl3):
8.05 (1H, brd, 3JHH = 7.0 Hz, ArH), 7.44 (1H, apt, 3+3JHH = 7.4 Hz, ArH),
7.38 (1H, apt, 3+3JHH = 7.3 Hz, ArH), 7.23 (1H, brd, 3JHH = 7.2 Hz, ArH),
diastereoisomers of
a bidentate ligand have been
synthesized. On application to palladium-catalysed allylic
alkylation of trans-1,3-diphenylallyl acetate the
configuration of the matched/matched i-Pr substituted
ligand was identified as S,Sp,Sphos. Furthermore, comparison
in catalysis to the simpler diphenylphosphine containing
Phosferrox ligands reveals a positive and negative influence
of the phosphorus-based stereogenic center. The results of
this study concur with our previous literature analysis on
the addition of an element of chirality to a parent ferrocene-
based ligand to give both possible diastereomeric offspring
ligands.30 In nearly all cases this analysis revealed (in 20 out
of 23 examples), as in this work, a systematic increase and
decrease in ee, providing further support for the iterative
use of this approach in ligand optimization studies.
Application of the new ligands in this way is currently in
progress.
2.65 (3H, s, ArCH3). 13C{1H} NMR (125 MHz, CDCl3): 140.6 (d, 2JCP
=
1
35.5 Hz, ArC), 137.9 (d, JCP = 57.5 Hz, ArC), 132.7 (ArC), 130.9
(ArC), 130.4 (d, 2JCP = 11.1 Hz, ArC), 127.1 (ArC), 20.0 (d, 3JCP = 24.9
Hz, CH3). 31P{1H} NMR (202 MHz, CDCl3): 163.35 (ClPAr2). Matches
previously reported data.31
EXPERIMENTAL SECTION
General remarks. Diethyl ether and tetrahydrofuran were
distilled
over
sodium
and
benzophenone
ketyl.
Tetramethylethylenediamine (TMEDA) was dried with 4 Å MS. All
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
Preparation
tolylphenylphosphino)ferrocenyl]-4-(1-
of
(S)-2-[(Sp)-2-((Rphos)-ortho-
CH2), 71.2 (CpC), 70.9 (d, 3JCP = 0.8 Hz, CpC), 70.6 (CpC), 61.5 (CH),
3
22.2 (d, JCP = 22.7 Hz, CH3), 21.0 (CH3). 31P{1H} NMR (202 MHz,
CDCl3): -25.89 (PPho-Tol). HRMS (ASAP-TOF) m/z: [M+H]+ Calcd
for C27H27FeNOP 468.1180; Found = 468.1174.
1
2
3
4
5
6
7
8
methylethyl)oxazoline, (S,Sp,Rphos)-L4a. (S)-1a (0.100 g, 0.34
mmol) was added to a flame dried Schlenk tube under an inert
atmosphere and dissolved in dry diethyl ether (4 mL). TMEDA
(0.07 mL, 0.44 mmol) was added and solution was cooled to -78 °C
and stirred for 5 min after which s-butyllithium (1.4 M in hexanes)
(0.31 mL, 0.44 mmol) was slowly added. After stirring for 3 hours,
ortho-tolyldichlorophosphine (64 μl, 0.47 mmol) was added and
the reaction allowed to stir at room temperature for 1 h. The
reaction was re-cooled to -78 °C and phenylmagnesium bromide
(1.0 M in THF) (0.47 mL, 0.47 mmol) was added and the reaction
allowed to warm to room temperature and stir for an additional
hour. The reaction was cooled to 0 °C quenched with saturated
sodium carbonate solution and separated with diethyl ether, dried
with magnesium sulphate and the solvent removed in vacuo.
Purification by column chromatography (SiO2, 10%
EtOAc/hexane) yielded an orange solid (0.09 g, 54%). Rf 0.3 (10%
EtOAc/hexane). Mp 104 - 105 °C. [α]D25.5°C = +20 (c 0.20, CHCl3). IR
Preparation
of
(S)-2-[(Sp)-2-((Rphos)-ortho-
tolylphenylphosphino)ferrocenyl]-4-methyloxazoline,
(S,Sp,Rphos)-L4b. (S)-1b (0.120 g, 0.45 mmol) was added to a flame
dried Schlenk tube under an inert atmosphere and dissolved in dry
diethyl ether (5 mL). TMEDA (0.09 mL, 0.58 mmol) was added and
solution was cooled to -78 °C and stirred for 5 min after which s-
butyllithium (1.4 M in hexanes) (0.41 mL, 0.58 mmol) was slowly
added. After stirring for 2 hours, ortho-tolyldichlorophosphine (85
μl, 0.62 mmol) was added and the reaction allowed to stir at room
temperature for 1 h. The reaction was re-cooled to -78 °C and
phenylmagnesium bromide (1.0 M in THF) (0.62 mL, 0.62 mmol)
was added and the reaction allowed to warm to room temperature
and stir for an additional hour. The reaction was cooled to 0 °C
quenched with saturated sodium carbonate solution and separated
with diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. Purification by column chromatography (SiO2,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(film): 3053, 2959, 2902, 2869, 1660 (CN). H NMR (500 MHz,
CDCl3): 7.46 (2H, aptd, 3JHP = 7.3, 3JHH = 7.3, 4JHH = 2.2 Hz, PhH), 7.38
30% EtOAc/hexane) yielded an orange solid (0.10 g, 49%). Rf 0.3
- 7.34 (3H, m, PhH), 7.14 (1H, aptd, 3JHP = 7.4, 3JHH = 7.4, 4JHH =1.3 Hz,
22.2°C
(30% EtOAc/hexane). Mp 188 - 190 °C. [α]D
= +84 (c 0.27,
3+3
o-TolH), 7.10 - 7.05 (1H, m, o-TolH), 7.01 (1H, apt,
J
HH
= 7.4 Hz,
CHCl3). IR (film): 3049, 2961, 2904, 1642 (CN). 1H NMR (500 MHz,
o-TolH), 6.84 - 6.79 (1H, m, o-TolH), 5.13 (1H, brs, CpH), 4.42 (1H,
apt, 3+3JHH = 2.0 Hz, CpH), 4.30 (1H, apt, 2+3JHH = 8.9 Hz, CHH), 4.24
(5H, s, CpH), 3.92 - 3.86 (1H, m, CH), 3.74 (1H, apt, 2+3JHH = 8.1 Hz,
CDCl3): 7.49 - 7.44 (2H, m, PhH), 7.39 - 7.33 (3H, m, PhH), 7.16 (1H,
3
3
apt, JHH = 6.8, JHP = 6.8 Hz, o-TolH), 7.11 - 7.06 (1H, m, o-TolH),
3+3
3+3
7.04 (1H, apt,
J
HH
= 7.4 Hz, o-TolH), 6.84 (1H, apdd,
J
HH
= 6.7,
4
CHH), 3.59 (1H, s, CpH), 2.28 (3H, d, JHP = 1.5 Hz, CH3), 1.71 (1H,
4JHH = 4.3 Hz, o-TolH), 5.03 (1H, brs, CpH), 4.43 - 4.34 (2H, m, CpH
+ CHH), 4.23 (5H, s, CpH), 4.15 - 4.03 (1H, m, CH), 3.56 (1H, brs,
CpH), 3.39 (1H, apt, 2+3JHH = 8.3 Hz, CHH), 2.27 (3H, s, CH3), 1.13 (1H,
d, 3JHH = 6.6 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3): 166.1 (C=N),
3+3+3
3
3
apoct,
J
= 6.7 Hz, CH), 0.85 (3H, d, JHH = 6.8 Hz, CH3), 0.71
HH
(3H, d, JHH = 6.8 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3): 165.3
2
1
(C=N), 140.9 (d, JCP = 25.5 Hz, o-TolC), 138.3 (d, JCP = 14.2 Hz, o-
TolC), 137.3 (d, JCP = 12.5 Hz, PhC), 134.9 (d, JCP = 21.1 Hz, PhC),
1
2
2
1
141.0 (d, JCP = 25.3 Hz, o-TolC), 138.2 (d, JCP = 14.3 Hz, o-TolC),
3
131.9 (o-TolC), 129.7 (d, JCP = 4.5 Hz, o-TolC), 129.1 (PhC), 128.4
1
2
137.1 (d, JCP = 11.9 Hz, PhC), 134.8 (d, JCP = 21.0 Hz, PhC), 131.7
(d, 3JCP = 7.1 Hz, PhC), 128.1 (o-TolC), 125.7 (o-TolC), 78.9 (d, 2JCP
=
(o-TolC), 129.8 (d, 3JCP = 4.4 Hz, o-TolC), 129.1 (PhC), 128.4 (d, 3JCP
1
2
14.7 Hz, CpC), 75.8 (d, JCP = 16.6 Hz, CpC), 74.4 (d, JCP = 4.2 Hz,
2
= 7.3 Hz, PhC), 128.1 (o-TolC), 125.7 (o-TolC), 78.7 (d, JCP = 14.5
CpC), 72.4 (d, 3JCP = 1.9 Hz, CpC), 72.2 (CH), 71.0 (CpC), 70.9 (d, 3JCP
1
3
Hz, CpC), 75.4 (d, JCP = 16.3 Hz, CpC), 74.5 (d, JCP = 3.8 Hz, CpC),
74.2 (CH2), 72.4 (d, 3JCP = 1.8 Hz, CpC), 71.2 (CpC), 70.9 (d, 3JCP = 0.9
Hz, CpC), 61.7 (CH), 21.3 (CH3), 21.1 (CH3). 31P{1H} NMR (202 MHz,
CDCl3) -23.32 (Po-TolPh). HRMS (ASAP-TOF) m/z: [M+H]+ Calcd
for C27H27FeNOP 468.1180; Found 468.1181.
3
= 1.0 Hz, CpC), 69.8 (CH2), 32.4 (CH), 21.1 (d, JCP = 21.7 Hz, CH3),
’
18.8 (CH3 ), 17.8 (CH3). 31P{1H} NMR (202 MHz, CDCl3): -23.90 (Po-
TolPh). HRMS (ASAP-TOF) m/z: [M+H]+ Calcd for C29H31FeNOP
496.1493; Found 496.1497.
Preparation
of
(S)-2-[(Sp)-2-((Sphos)-ortho-
Preparation
tolylphosphino)-5-deuteroferrocenyl]-4-(1-
of
(S)-2-[(Rp)-2-((Sphos)-butylortho-
tolylphenylphosphino)ferrocenyl]-4-methyloxazoline,
(S,Sp,Sphos)-L3b. (S)-1b (0.120 g, 0.45 mmol) was added to a flame
dried Schlenk tube under an inert atmosphere and dissolved in dry
diethyl ether (5 mL). TMEDA (0.09 mL, 0.58 mmol) was added and
solution was cooled to -78 °C and stirred for 5 min after which s-
butyllithium (1.4 M in hexanes) (0.41 mL, 0.58 mmol) was slowly
added. After stirring for 2 hours, dichlorophenylphosphine (85 μl,
0.62 mmol) was added and the reaction allowed to stir at room
temperature for 1 h. The reaction was re-cooled to -78 °C and o-
tolylmagnesium bromide (2.0 M in THF) (0.31 mL, 0.62 mmol) was
added and the reaction allowed to warm to room temperature and
stir for an additional hour. The reaction was cooled to 0 °C
quenched with saturated sodium carbonate solution and separated
with diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. Purification by column chromatography (SiO2,
methylethyl)oxazoline, (S,Rp,Sphos)-2a. (S)-2-d-1a15 (0.040 g,
0.13 mmol) was added to a flame dried Schlenk tube under an inert
atmosphere and dissolved in dry THF (1 mL). The solution was
cooled to -78 °C and stirred for 5 min after which s-butyllithium
(1.4 M in hexanes) (0.13 mL, 0.17 mmol) was slowly added. After
stirring for 2 hours, ortho-tolyldichlorophosphine (27.5 μl, 0.19
mmol) was added and the reaction allowed to stir at room
temperature for 1 h. The reaction was re-cooled to -78 °C and
butylmagnesium chloride (2.0 M in THF) (0.09 mL, 0.19 mmol) was
added and the reaction allowed to warm to room temperature and
stir for an additional hour. The reaction was cooled to 0 °C
quenched with saturated sodium carbonate solution and separated
with diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. Purification by column chromatography (SiO2,
30% EtOAc/hexane) yielded an orange solid (0.08 g, 39%). Rf 0.2
10% EtOAc/hexane) yielded an orange oil (0.038 g, 59%). Rf 0.2
(10% EtOAc/hexane). [α]D
22.4°C
(30 % EtOAc/hexane). Mp 56 - 57 °C. [α]D
= +182 (c 0.20,
23.5°C
= -153 (c 0.16, CHCl3). IR (film):
CHCl3). IR (film): 3052, 3003, 2964, 2929, 2890, 1649 (CN). 1H NMR
1
3056, 2957, 2929, 2873, 1656 (CN). H NMR (500 MHz, CDCl3):
7.07 - 7.05 (2H, m, o-TolH), 6.97 - 6.89 (2H, m, o-TolH), 4.53 (1H, d,
3JHH = 2.5 Hz, CpH), 4.51 (1H, d, 3JHH = 2.4 Hz, CpH), 4.25 (5H, s, CpH),
(500 MHz, CDCl3): 7.29 - 7.17 (7H, m, PhH + o-TolH), 7.08 - 6.98
(2H, m, o-TolH), 4.95 (1H, ddd, JHH = 2.4, JHH = 1.5, 4JHP = 0.5 Hz,
CpH), 4.38 - 4.31 (2H, m, CpH + CHH), 4.23 (5H, s, CpH), 4.09 - 4.00
(1H, m, CH), 3.69 (1H, ddd, 3JHH = 2.4, 3JHP = 1.4, 4JHH = 0.8 Hz, CpH),
3.02 (1H, dd, 2JHH = 9.0, 3JHH = 8.1 Hz, CHH), 2.86 (3H, s, CH3), 1.03
3
4
4.01 (1H, dd, JHH = 9.7, 3JHH = 8.2 Hz, CHH), 3.95 (1H, apt,
J
HH
=
2
2+3
7.4 Hz, CHH), 3.89 - 3.84 (1H, m, CH), 2.63 (3H, d, 4JHP = 1.1 Hz, CH3),
2.04 - 1.96 (1H, m, CHH), 1.83 - 1.76 (1H, m, CHH), 1.66 - 1.56 (2H,
m, CH + CHH’), 0.51 - 1.42 (3H, m, CHH + CH2), 0.93 (3H, t, 3JHH = 7.2
Hz, CH3), 0.70 (3H, d, 3JHH = 6.8 Hz, CH3), 0.66 (3H, d, 3JHH = 6.8 Hz,
3
(3H, d, JHH = 6.5 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3): 166.1
(C=N), 143.5 (d, 2JCP = 27.4 Hz, o-TolC), 140.4 (d, 1JCP = 12.8 Hz, PhC),
1
2
136.9 (d, JCP = 15.4 Hz, o-TolC), 135.8 (d, JCP = 3.3 Hz, o-TolC),
CH3). 13C{1H} NMR (125 MHz, CDCl3): 165.1 (C=N), 142.1 (d, 2JCP
=
132.6 (d, 2JCP = 20.6 Hz, PhC), 130.1 (d, 3JCP = 4.9 Hz, o-TolC), 129.2
27.8 Hz, o-TolC), 140.5 (d, 1JCP = 17.3 Hz, o-TolC), 131.5 (d, 2JCP = 2.0
3
3
(o-TolC), 128.2 (d, JCP = 6.9 Hz, PhC), 127.9 (PhC), 126.1 (d, JCP
=
Hz, o-TolC), 129.3 (d, 3JCP = 5.4 Hz, o-TolC), 128.0 (o-TolC), 125.8 (o-
2.0 Hz, o-TolC), 79.7 (d, 2JCP = 15.5 Hz, CpC), 74.6 (CpC), 74.2 (CpC +
2
TolC), 79.9 (d, JCP = 16.7 Hz, CpC), 74.7 (CpC), 72.1 (CH), 71.5 (d,
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
2JCP = 3.4 Hz, CpC), 70.8 (CpC), 70.4 (CpC), 69.3 (CH2), 32.4 (CH),
29.0 (d, 2JCP = 1.8 Hz, CH2), 28.8 (d, 1JCP = 4.9 Hz, CH2), 24.7 (d, 3JCP
12.5 Hz, CH2), 21.9 (d, JCP = 23.1 Hz, CH3), 18.3 (CH3), 17.8 (CH3),
14.0 (CH3). 31P {1H} NMR (202 MHz, CDCl3): -40.38 (Po-TolBu).
HRMS (ASAP-TOF) m/z: [M+H]+ Calcd for C27H34DFeNOP
477.1869; Found 477.1866.
0.59 (3H, d, JHH = 6.8 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3):
3
=
164.7 (d, 3JCP = 3.6 Hz, C=N), 141.0 (d, 2JCP = 25.4 Hz, o-TolC), 138.1
1
2
3
4
5
6
7
8
3
1
1
(d, JCP = 12.8 Hz, o-TolC), 137.4 (d, JCP = 12.2 Hz, PhC), 135.0 (d,
2JCP = 20.8 Hz, PhC), 131.8 (o-TolC), 129.7 (d, 3JCP = 4.7 Hz, o-TolC),
129.0 (PhC), 128.3 (d, 3JCP = 7.2 Hz, PhC), 128.0 (o-TolC), 125.5 (o-
TolC), 78.6 (d, 2JCP = 13.5 Hz, CpC), 75.3 (d, 1JCP = 16.1 Hz, CpC), 74.6
(d, 2JCP = 4.4 Hz, CpC), 72.3 (CH), 70.8 (CpC), 70.6 (CpC), 69.8 (CH2),
Preparation
of
(S)-2-[(Rp)-2-((Rphos)-ortho-
3
32.8 (CH), 21.1 (d, JCP = 21.7 Hz, CH3), 18.2 (CH3), 17.9 (CH3).
tolylphenylphosphino)-5-deuteroferrocenyl]-4-(1-
31P{1H} NMR (202 MHz, CDCl3): -24.70 (Po-TolPh). HRMS (ASAP-
TOF) m/z: [M+H]+ Calcd for C29H30DFeNOP 497.1556; Found
497.1557.
methylethyl)oxazoline, (S,Rp,Rphos)-2-d-L5a. (S)-2-d-1a (0.073 g,
0.25 mmol) was added to a flame dried Schlenk tube under an inert
atmosphere and dissolved in dry THF (3 mL). The solution was
cooled to -78 °C and stirred for 5 min after which s-butyllithium
(1.4 M in hexanes) (0.23 mL, 0.32 mmol) was slowly added. After
stirring for 2 hours, dichlorophenylphosphine (47 μl, 0.34 mmol)
was added and the reaction allowed to stir at room temperature
for 1 h. The reaction was re-cooled to -78 °C and ortho-
tolylmagnesium bromide (2.0 M in THF) (0.17 mL, 0.34 mmol) was
added and the reaction allowed to warm to room temperature and
stir for an additional hour. The reaction was cooled to 0 °C
quenched with saturated sodium carbonate solution and separated
with diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. Purification by column chromatography (SiO2,
9
Preparation
tolylphenylphosphino)-5-deuteroferrocenyl]-4-
of
(S)-2-[(Rp)-2-((Rphos)-ortho-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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53
54
55
56
57
58
59
60
methyloxazoline, (S,Rp,Rphos)-2-d-L5b. (S)-2-d-1b15 (0.100 g,
0.37 mmol) was added to a flame dried Schlenk tube under an inert
atmosphere and dissolved in dry diethyl ether (5 mL). The solution
was cooled to -78 °C and stirred for 5 min after which s-
butyllithium (1.4 M in hexanes) (0.34 mL, 0.48 mmol) was slowly
added. After stirring for 2 hours, dichlorophenylphosphine (70 μl,
0.52mmol) was added and the reaction allowed to stir at room
temperature for 1 h. The reaction was re-cooled to -78 °C and o-
tolylmagnesium bromide (2.0 M in THF) (0.26 mL, 0.52 mmol) was
added and the reaction allowed to warm to room temperature and
stir for an additional hour. The reaction was cooled to 0 °C
quenched with saturated sodium carbonate solution and separated
with diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. Purification by column chromatography (SiO2,
10% EtOAc/hexane) yielded an orange solid (0.07 g, 59 %). Rf 0.2
22.5°C
(10% EtOAc/hexane). Mp 100 - 101 °C. [α]D
= -80 (c 0.22,
CHCl3). IR (film): 3052, 2957, 2873, 1656 (CN). 1H NMR (500 MHz,
CDCl3): 7.28 - 7.22 (2H, m, o-TolH), 7.21 - 7.13 (5H, m, PhH), 7.08 -
3
7.02 (2H, m, o-TolH), 4.37 (1H, d, JHH = 2.4 Hz, CpH), 4.20 (5H, s,
2
3
CpH), 3.99 (1H, dd, JHH = 7.0, JHH = 5.0 Hz, CHH), 3.87 - 3.75 (2H,
m, CH + CHH), 3.71 (1H, d, 3JHH = 2.3 Hz, CpH), 2.84 (3H, s, CH3), 1.57
(1H, apoct, 3+3+3J = 5.9 Hz, CH), 0.72 (3H, d, 3JHH = 6.8 Hz, CH3), 0.71
30% EtOAc/hexane) yielded an orange oil (0.04 g, 17%). Rf 0.2
(30% EtOAc/hexane). [α]D
23.5°C
= -67 (c 0.60, CHCl3). IR (film):
1
3052, 2962, 2923, 2873, 1652 (CN). H NMR (500 MHz, CDCl3):
7.27 - 7.22 (2H, m, o-TolH), 7.20 - 7.14 (5H, m, PhH), 7.07 - 7.04 (2H,
m, o-TolH), 4.37 (1H, d, 3JHH = 2.5 Hz, CpH), 4.20 (5H, s, CpH), 4.08 -
4.02 (1H, m, CH), 3.91 - 3.86 (1H, m, CHH), 3.79 (1H, dd, 2JHH = 8.0,
3JHH = 5.8 Hz, CHH), 3.70 (1H, dd, 3JHH = 2.5, 4JHH = 0.7 Hz, CpH), 2.85
(3H, s, CH3), 0.96 (3H, d, 3JHH = 6.6 Hz, CH3). 13C{1H} NMR (125 MHz,
CDCl3): 165.3 (d, 3JCP = 2.9 Hz, C=N), 143.6 (d, 2JCP = 27.0 Hz, o-TolC),
140.7 (d, 1JCP = 12.4 Hz, PhC), 136.9 (d, 1JCP = 15.4 Hz, o-TolC), 136.4
(d, 2JCP = 4.3 Hz, o-TolC), 132.3 (d, 2JCP = 20.2 Hz, PhC), 130.1 (d, 3JCP
= 4.7 Hz, o-TolC), 129.2 (o-TolC), 128.0 (d, 3JCP = 6.7 Hz, PhC), 127.5
(PhC), 126.0 (d, 3JCP = 2.2 Hz, o-TolC), 79.4 (d, 2JCP = 15.7 Hz, CpC),
74.4 (CpC), 74.3 (d, 1JCP = 10.3 Hz, CpC), 73.6 (CH2), 70.9 (CpC), 70.4
3
(3H, d, JHH = 6.8 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3): 165.1
(C=N), 143.7 (d, 2JCP = 26.6 Hz, o-TolC), 140.7 (d, 1JCP = 12.4 Hz, PhC),
1
2
137.0 (d, JCP = 15.5 Hz, o-TolC), 136.5 (d, JCP = 4.9 Hz, o-TolC),
132.3 (d, 2JCP = 20.0 Hz, PhC), 130.1 (d, 3JCP = 4.8 Hz, o-TolC), 129.2
(o-TolC), 128.0 (d, JCP = 6.7 Hz, PhC), 127.6 (PhC), 126.0 (d, JCP
3
3
=
2
2
2.5 Hz, o-TolC), 79.0 (d, JCP = 15.3 Hz, CpC), 74.4 (d, JCP = 2.8 Hz,
CpC), 72.1 (CH), 72.0 (d, 1JCP = 20.8 Hz, CpC), 70.8 (CpC), 70.3 (CpC),
69.5 (CH2), 32.5 (CH), 22.4 (d, 3JCP = 22.2 Hz, CH3), 18.3 (CH3), 17.9
(CH3). 31P{1H} NMR (202 MHz, CDCl3): -26.69 (PPho-Tol). HRMS
(ASAP-TOF) m/z: [M+H]+ Calcd for C29H30DFeNOP 497.1556;
Found 497.1556.
3
(CpC), 61.6 (CH), 22.3 (d, JCP = 22.4 Hz, CH3), 21.3 (CH3). 31P{1H}
Preparation
of
(S)-2-[(Rp)-2-((Sphos)-ortho-
NMR (202 MHz, CDCl3): -26.51 (PPho-Tol). HRMS (ASAP-TOF) m/z:
tolylphenylphosphino)-5-deuteroferrocenyl]-4-(1-
[M+H]+ Calcd for C27H26DFeNOP 469.1243; Found 469.1242.
methylethyl)oxazoline, (S,Rp,Sphos)-2-d-L6a. (S)-2-d-1a15 (0.100
g, 0.34 mmol) was added to a flame dried Schlenk tube under an
inert atmosphere and dissolved in dry THF (4 mL). The solution
was cooled to -78 °C and stirred for 5 min after which s-
butyllithium (1.4 M in hexanes) (0.31 mL, 0.44 mmol) was slowly
added. After stirring for 2 hours, ortho-tolyldichlorophosphine (63
μl, 0.47 mmol) was added and the reaction allowed to stir at room
temperature for 1 h. The reaction was re-cooled to -78 °C and
phenylmagnesium bromide (1.0 M in THF) (0.47 mL, 0.47 mmol)
was added and the reaction allowed to warm to room temperature
and stir for an additional hour. The reaction was cooled to 0 °C
quenched with saturated sodium carbonate solution and separated
with diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. Purification by column chromatography (SiO2,
Preparation
tolylphenylphosphino)-5-deuteroferrocenyl]-4-
of
(S)-2-[(Rp)-2-((Sphos)-ortho-
methyloxazoline, (S,Rp,Sphos)-2-d-L6b. (S)-2-d-1b15 (0.100 g, 0.37
mmol) was added to a flame dried Schlenk tube under an inert
atmosphere and dissolved in dry tetrahydrofuran (4 mL). The
solution was cooled to -78 °C and stirred for 5 min after which s-
butyllithium (1.4 M in hexanes) (0.34 mL, 0.48 mmol) was slowly
added. After stirring for 2 hours, ortho-tolyldichlorophosphine (76
μl, 0.52 mmol) was added and the reaction allowed to stir at room
temperature for 1 h. The reaction was re-cooled to -78 °C and
phenylmagnesium bromide (1.0 M in THF) (0.52 mL, 0.52 mmol)
was added and the reaction allowed to warm to room temperature
and stir for an additional hour. The reaction was cooled to 0 °C
quenched with saturated sodium carbonate solution and separated
with diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. Purification by column chromatography (SiO2,
30% EtOAc in Hexane) yielded an orange solid as a 16:1 ratio of
diastereoisomers (0.055 g, 32%). This was then recrystallized by
dissolving in a minimum amount of dichloromethane and layering
hexane on top and allowing to stand for 2 days in the freezer to give
orange crystals (0.05 g, 29%): Rf 0.3 (30% EtOAc/hexane). Mp 178
- 179 °C. [α]D24.3°C = -14 (c 0.56, CHCl3). IR (film): 3051, 2965, 2897,
10% EtOAc /hexane) yielded an orange solid (0.10 g, 58%). Rf 0.3
22.4°C
(10 % EtOAc/hexane). Mp 97 - 98 °C. [α]D
= +85.5 (c 0.22,
CHCl3). IR (film): 3052, 2954, 2873, 1656 (CN). 1H NMR (500 MHz,
CDCl3): 7.49 (2H, aptd, 3JHH = 7.3, 3JHP = 7.3, 4JHH = 2.2 Hz, PhH), 7.38
- 7.34 (3H, m, PhH), 7.13 (1H, aptd, JHH = 7.4, 3JHP = 7.4, 4JHH = 1.3
3
3+3
Hz, o-TolH), 7.08 - 7.04 (1H, m, o-TolH), 6.99 (1H, apt,
J
HH
= 7.7
3
4
5
Hz, o-TolH), 6.78 (1H, ddd, JHH = 7.6, JHH = 4.3, JHP = 1.1 Hz, o-
TolH), 4.37 (1H, d, 3JHH = 2.5 Hz, CpH), 4.23 (5H, s, CpH), 4.08 (1H,
dd, 3JHH = 9.6, 2JHH = 8.2 Hz, CHH), 3.98 (1H, dd, 2JHH = 8.2, 3JHH = 6.6
3+3
3
Hz, CHH), 3.90 (1H, apdt,
J
HH
= 9.6, JHH = 6.2 Hz, CH), 3.57 (1H,
1650 (CN). 1H NMR (500 MHz, CDCl3): 7.51 - 7.45 (2H, m, PhH), 7.38
3
2
4
3+3
dd, JHH = 2.5, JHH = 0.6 Hz, CpH), 2.29 (3H, d, JHP = 1.4 Hz, CH3),
- 7.33 (3H, m, PhH), 7.15 (1H, aptd,
J
= 7.4, 4JHH = 1.4 Hz, o-
HH
1.48 (1H, apoct, 3+3+3JHH = 6.3 Hz, CH), 0.64 (3H, d, 3JHH = 6.8 Hz, CH3),
TolH), 7.09 - 7.05 (1H, m, o-TolH), 7.01 (1H, apdd, 3+3JHH = 11.3, 4JHH
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The Journal of Organic Chemistry
Page 8 of 10
= 4.1 Hz, o-TolH), 6.80 (1H, ddd, 3JHH = 7.6, 3JHP = 4.3, 4JHH = 1.2 Hz,
Notes
3
4
o-TolH), 4.39 (1H, dd, JHH = 2.5, JHP = 0.5 Hz, CpH), 4.22 (5H, s,
CpH), 4.13 - 4.07 (2H, m, CH + CHH), 3.86 - 3.78 (1H, m, CHH), 3.57
(1H, dd, 3JHH = 2.5, 3JHP = 0.7 Hz, CpH), 2.28 (3H, d, 4JHP = 1.4 Hz, CH3),
1
2
3
4
5
6
7
8
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The EPSRC (EP/N019393/1) (R.A.A.) is thanked for financial
support. We also thank the EPSRC National Mass Spectrometry
Centre (University of Wales, Swansea).
3
1.04 (1H, d, JHH = 6.5 Hz, CH3). 13C{1H} NMR (125 MHz, CDCl3):
165.4 (d, 3JCP = 3.1 Hz, C=N), 141.0 (d, 2JCP = 25.2 Hz, o-TolC), 138.1
1
1
(d, JCP = 13.5 Hz, o-TolC), 137.3 (d, JCP = 12.0 Hz, PhC), 134.9 (d,
2JCP = 20.9 Hz, PhC), 131.8 (o-TolC), 129.7 (d, 3JCP = 4.6 Hz, o-TolC),
129.1 (PhC), 128.4 (d, 3JCP = 7.2 Hz, PhC), 128.0 (o-TolC), 125.5 (o-
TolC), 78.7 (d, 2JCP = 14.2 Hz, CpC), 75.0 (d, 1JCP = 16.4 Hz, CpC), 74.6
REFERENCES
2
3
(d, JCP = 4.2 Hz, CpC), 73.8 (CH2), 71.1 (d, JCP = 0.9 Hz, CpC), 61.7
9
(CH), 21.5 (CH3), 21.2 (d, JCP = 21.2 Hz, CH3). 31P{1H} NMR (202
3
(1) (a) New Frontiers in Asymmetric Catalysis (Eds.: Mikami, K.;
Lautens, M.) Wiley, Hoboken. New Jersey 2007. (b) Asymmetric
Catalysis on Industrial Scale: Challenges, Approaches and Solutions
(Eds: Blaser, H. U.; Federsel, H.-J.) Wiley,Weinheim 2010.
(2) For illustrative recent examples see: (a) Burns, A. R.; González,
J. S.; Lam, H. W. Enantioselective Copper(I)-Catalyzed Borylative
Aldol Cyclizations of Enone Diones. Angew. Chem. Int. Ed. 2012, 51,
10827-10831. (b) Huang, K.; Li, S.; Chang, M.; Zhang, X. Rhodium-
Catalyzed Enantioselective Hydrogenation of Oxime Acetates. Org.
Lett. 2013, 15, 484-487. (c) Meng, F.; Haeffner, F.; Hoveyda, A. H.
MHz, CDCl3): -24.02 (Po-TolPh). HRMS (ASAP-TOF) m/z: [M+H]+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Calcd for C27H25DFeNOP+H+ 469.1243; Found 469.1236.
General Procedure for Allylic Alkylation. Ligand (0.0125 mmol)
and [Pd(allyl)Cl]2 (0.0019 g, 0.005 mmol) were added to a flame
dried Schlenk tube, dissolved in dichloromethane (0.85 mL) and
allowed to stir for 30 min at room temperature. In a separate flask,
racemic 1,3-diphenylallyl acetate (0.126 g, 0.50 mmol) was
weighed out and subsequently dissolved in dichloromethane (0.85
mL). After 30 min, the acetate solution was added to the reaction
vessel followed by dimethyl malonate (0.17 mL, 1.5 mmol), N,O-
bis(trimethylsilyl)acetamide (0.37 mL, 1.5 mmol) and KOAc (0.001
g, 0.01 mmol) in that order. The reaction was stirred at room
temperature and monitored by TLC (SiO2, 5% EtOAc/hexane).
After completion or 24 h (whichever came first), the reaction was
quenched with saturated ammonium chloride, separated with
diethyl ether, dried with magnesium sulphate and the solvent
removed in vacuo. A crude 1H NMR was performed at this point to
determine the conversion. Purification by column chromatography
(SiO2, 5% EtOAc/hexane) gave the product as a colourless oil.
Enantiomeric excess measurements was determined by chiral
Diastereo-
and
Enantioselective
Reactions
of
Bis(pinacolato)diboron, 1,3-Enynes, and Aldehydes Catalyzed by
an Easily Accessible Bisphosphine-Cu Complex. J. Am. Chem. Soc.
2014, 136, 11304-11307. (d) Fan, L.; Takizawa, S.; Takeuchi, Y.;
Takenaka, K.; Sasai, H. Pd-catalyzed enantioselective
intramolecular α-arylation of α-substituted cyclic ketones: facile
synthesis of functionalized chiral spirobicycles. Org. Biomol. Chem.
2015, 13, 4837-4840. (e) Xu, K.; Wang, Y.-H.; Khakyzadeh, V.; Breit,
B. Asymmetric Synthesis of allylic amines via hydroamination of
allenes with benzophenone imine. Chem. Sci. 2016, 7, 3313-3316.
(f) Pujol, A.; Whiting, A. Double Diastereoselective Approach to
Chiral syn- and anti-1,3-Diol Analogues through Consecutive
Catalytic Asymmetric Borylations. J. Org, Chem. 2017, 82, 7265-
7279.
(3) (a) Yoon, T. P.; Jacobsen, E. N. Privileged Chiral Catalysts.
Science 2003, 299, 1691-1693. (b) Privileged Chiral Ligands and
Catalysts (Ed.: Zhou, Q.-L.) Wiley-VCH, Weinheim 2011.
(4) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
T.; Noyori, R. Synthesis of 2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl (BINAP), an atropisomeric chiral bis(triaryl)phosphine,
and its use in the rhodium(I)-catalyzed asymmetric hydrogenation
of α-(acylamino)acrylic acids. J. Am. Chem. Soc. 1980, 102, 7932-
7934.
HPLC analysis using
a CHIRALCEL OD-H; Eluent = 98:2
(Hexane:IPA); Flow rate = 0.5 mL min-1; Concentration = 0.0015 g
mL-1, Injection volume = 5 µl. Major enantiomer RT = 18.8 min,
Minor enantiomer RT = 17.3 min. 1H NMR (500 MHz, CDCl3) δ 7.34
- 7.27 (8H, m, PhH), 7.26 - 7.18 (2H, m, PhH), 6.48 (1H, d, 3JHH = 15.7
3
3
Hz, HC=CH), 6.33 (1H, dd, JHH = 15.7, JHH = 8.6 Hz, HC=CH), 4.27
3
3
(1H, dd, JHH = 10.8, 3JHH = 8.7 Hz, CH), 3.96 (1H, d, JHH = 10.9 Hz,
CH), 3.71 (3H, s, CH3), 3.52 (3H, s, CH3). 13C{1H}NMR (125 MHz,
CDCl3): 168.4 (C=O), 167.9 (C=O), 140.3 (PhC), 137.0 (PhC), 132.0
(HC=CH), 129.3 (HC=CH), 128.9 (PhC), 128.6 (PhC), 128.0 (PhC),
127.7 (PhC), 127.3 (PhC), 126.5 (PhC), 57.8 (CH), 52.8 (CH3), 52.6
(CH3), 49.3 (CH). Matches previously reported data.32
(5) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. A Novel Easily Accessible Chiral Ferrocenyldiphosphine
for Highly Enantioselective Hydrogenation, Allylic Alkylation, and
Hydroboration. J. Am. Chem. Soc. 1994, 116, 4062-4066.
(6) Sturm, T.; Weissensteiner, W.; Spindler, F. A Novel Class of
Ferrocenyl-Aryl-Based Diphosphine Ligands for Rh- and Ru-
Catalysed Enantioselective Hydrogenation. Adv. Synth. Cat. 2003,
345, 160-164.
(7) (a) Whitesell, J. K. C2 Symmetry and Asymmetric Induction.
Chem. Rev. 1989, 89, 1581-1590. (b) Pfaltz, A.; Drury III, W. J.
Design of chiral ligands for asymmetric catalysis: From C2-
symmetric P,P- and N,N-ligands to sterically and electronically
nonsymmetrical P,N-ligands. PNAS 2004, 101, 5723-5726.
(8) For example, the diastereoisomers of Josiphos and Walphos
used are a consequence of the highly diastereoselective lithiation
of Ugi’s amine, a precursor used in the synthesis of both ligands.
See: Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I.
Stereoselective syntheses. VI. Correlation of central and planar
chirality in ferrocene derivatives. J. Am. Chem. Soc. 1970, 92, 5389-
5393.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
1
13
31
Copies of the H, C, P NMR spectra, HPLC traces and details of
the X-ray crystal structure determinations (PDF), together
with the associated CIF files.
Accession Codes
CCDC 1916753, 1916752, and 1916751
supplementary crystallographic data for this paper. These data
can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
contain the
AUTHOR INFORMATION
(9) For example see: (a) Li, W.; Zhang, X. Synthesis of 3,4-O-
Isopropylidene-(3S,4S)-dihydroxy-(2R,5R)-
bis(diphenylphosphino)hexane and Its Application in Rh-
Catalyzed Highly Enantioselective Hydrogenation of Enamides. J.
Org. Chem. 2000, 65, 5871-5874. (b) Yan, Y.-Y.; RajanBabu, T. V.
Corresponding Author
*E-mail: chris.richards@uea.ac.uk.
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The Journal of Organic Chemistry
Ligand Substituent Effects on Asymmetric Induction. Effect of
Structural Variations of the DIOP Ligand on the Rh-Catalyzed
1963, 4, 1473. (b) Schlögl, K.; Fried, M.; Falk, H. Die relative
Konfiguration von optisch aktiven, α-disubstituierten
Ferrocenderivaten. Monatsh. Chem. 1964, 95, 576-597.
(15) Arthurs, R. A.; Richards, C. J. Deuterium as a Stereochemically
Invisible Blocking Group for Chiral Ligand Synthesis. Org. Lett.
2017, 19, 702-705.
1
2
3
4
5
6
7
8
Asymmetric Hydrogenation of Enamides. Org. Lett. 2000, 2, 4137-
4140. (c) Qiu, L.; Oi, J.; Pai, C.-C.; Chan, S.; Zhou, Z.; Choi, M. C. K.;
Chan, A. S. C. Synthesis of Novel Diastereomeric Diphosphine
Ligands and Their Applications in Asymmetric Hydrogenation
Reactions. Org. Lett. 2002, 4, 4599-4602. (d) Li, M.; Yuan. K.; Li, Y.-
Y.; Cao, B.-X.; Sun, J.; Hou, X.-L. On the role of planar chirality in
asymmetric catalysis: Improvement of enantioselectivity in the
addition of diethylzinc to aldehydes with planar chiral 1,1’-N,O-
ferrocenyl ligands. Tetrahedron: Asymmetry 2003, 14, 3347-3352.
(e) Hu, X.-P.; Zheng, Z. Unsymmetrical Hybrid Ferrocene-Based
Phosphine-Phosphoramidites: A New Class of Practical Ligands for
Rh-Catalyzed Asymmetric Hydrogenation. Org. Lett. 2004, 6, 3585-
3588. (f) Song, X.-G.; Zhu, S.-F.; Xie, X-L.; Zhou, Q.-L.
Enantioselective Copper-Catalyzed Intramolecular Phenolic O-H
(16) (a) Pietrusiewicz, K. M.; Zablocka, M. Preparation of Scalemic
P-Chiral Phosphines and Their Derivatives. Chem. Rev. 1994, 94,
1375-1411. (b) Grabulosa, A.; Granell, J.; Muller, G. Preparation of
optically pure P-stereogenic trivalent phosphorus compounds.
Coord. Chem. Rev. 2007, 251, 25-90. (c) Kolodiazhnyi, O. I. Recent
developments in the asymmetric synthesis of P-chiral phosphorus
compounds. Tetrahedron: Asymmetry 2012, 23, 1-46. (d) Dutartre,
M.; Bayardon, J.; Jugé, S. Applications and stereoselective syntheses
of P-chirogenic phosphorus compounds. Chem. Soc. Rev. 2016, 45,
5771-5794.
(17) (a) Segi, M.; Nakamura, Y.; Nakajima, T.; Suga, S. Preparation
of Optically Active Phosphine Oxides by Regioselective Cleavage of
Cyclic Phenylphosphonite with Alkyl Halides. Chem. Lett. 1983,
913-916. (b) Jugé, S.; Stephan, M.; Laffitte, J. A.; Genet, J. P. Efficient
Asymmetric Synthesis of Optically Pure Tertiary Mono and
Diphosphine Ligands. Tetrahedron Lett. 1990, 31, 6357-6360. (c)
Corey, E. J.; Chen, Z.; Tanoury, G. J. A New and Highly
Enantioselective Synthetic Route to P-Chiral Phosphines and
Diphosphines. J. Am. Chem. Soc. 1993, 115, 11000-11001. (d)
Kolodiazhnyi, O. I.; Grishkun, E. V. Simple Route to Chiral
Organophosphorus Compounds. Tetrahedron: Asymmetry 1996, 7,
967-970. (e) Rippert, A. J.; Linden, A.; Hansen, H. J. Formation of
Diastereomerically Pure Oxazaphospholes and Their Reaction to
Chiral Phosphane-Borane Adducts. Helv. Chim. Acta 2000, 83, 311-
321.
(18) (a) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. A Very
Simple, Highly Stereoselective and Modular Synthesis of
Ferrocene-Based P-Chiral Phosphine Ligands. J. Am. Chem. Soc.
2006, 18, 3922-3923. (b) See also: Chen, W.; Roberts, S. M.;
Whittall, J.; Steiner, A. An efficient and highly stereoselective
synthesis of new P-chiral 1,5-diphosphanylferrocene ligands and
their use in enantioselective hydrogenation. Chem. Commun. 2006,
2916-2918.
(19) CCDC 1916753, 1916752, and 1916751 (L3a, L4a, L6b)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
(20) Hoppe, D.; Paetow, M.; Hintze, F. Stereodivergent
Enantioselective Synthesis by Exploiting Unusually Large Kinetic
H/D Isotope Effects on Deprotonation. Angew. Chem., Int. Ed. Engl.
1993, 32, 394-396.
(21) Schwenk, R.; Togni, A. P-Trifluoromethyl ligands derived from
Josiphos in the Ir-catalysed hydrogenation of 3,4-
dihydroisoquinoline hydrochlorides. Dalton Trans. 2015, 44,
19566-19575.
(22) The electron-rich nature of the ferrocenyl substituent
increases the p-character of the lone pair orbital reducing the
energy required for rehybridization to the trigonal planar
transition state needed for epimerisation. This can be countered by
use of an electron-withdrawing substituent on phosphorus. See
reference 21.
(23) Kropp, P. J.; Breton, G. W.; Craig, S. L.; Crawford, S. D.; Durland,
Jr. W. F.; Jones, III, J. E.; Raleigh, J. S. Surface-Mediated Reactions. 6.
Effects of Silica Gel and Alumina on Acid-Catalyzed Reactions. J.
Org. Chem. 1995, 60, 4146-4152.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
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50
51
52
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57
58
59
60
Bond
Insertion:
Synthesis
of
Chiral
2-Carboxy
Dihydrobenzofurans,
Dihydrobenzopyrans,
and
Tetrahydrobenzooxepines. Angew. Chem. Int. Ed. 2013, 52, 2555-
2558.
(10) Three of the four possible diastereoisomers of a ferrocene-
based ligand containing three elements of chirality have been
synthesised and applied to ruthenium-catalysed hydrogenation
and transfer hydrogenation. See: a) Schuecker, R.; Zirakzadeh, A.;
Mereiter, K.; Spindler, F.; Weissensteiner, W. Synthesis,
Coordination Behavior, and Structural Features of Chiral Amino-,
Pyrazolyl-, and Phosphino-Substituted Ferrocenyloxazolines and
Their Application in Asymmetric Hydrogenations. Organometallics
2011, 30, 4711-4719. b) Zirakzadeh, A.; Schuecker, R.; Gorgas, N.;
Mereiter, K.; Spindler, F.; Weissensteiner, W. Ruthenium
Complexes of Phosphino-Substituted Ferrocenyloxazolines in the
Asymmetric Hydrogenation and Transfer Hydrogenation of
Ketones: A Comparison. Organometallics 2012, 31, 4241-4250.
(11) Sammakia, T.; Latham, H. A. Ligand effects on the
stereochemistry of the metalation of chiral ferrocenyloxazolines. J.
Org. Chem. 1995, 60, 6002-6003.
(12) (a) Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B.
Synthesis of
2-[2-(Diphenylphosphino)ferrocenyl]oxazoline
Ligands. Synlett 1995, 74-76. (b) Nishibayashi, Y.; Uemura, S.
Asymmetric Synthesis and Highly Diastereoselective ortho-
Lithiation of Oxazolinylferrocenes. Synlett 1995, 79-81. (c)
Richards,
C.
J.;
Mulvaney,
A.
W.
Synthesis
of
Phosphinoferrocenyloxazolines. New Ligands for Asymmetric
Catalysis. Tetrahedron: Asymmetry 1996, 7, 14191430.
(13) Examples for each metal include: (a) Pd: You, S.-I.; Hou, X.-L.;
Dai, L.-X.; Yu, Y.-H.; Xia, W. Role of Planar Chirality of S,N and P,N-
Ferrocene Ligands in Palladium-Catalyzed Allylic Substitutions. J.
Org. Chem. 2002, 67, 4684-4695. (b) Ru: Onodera, G.; Nishibayashi,
Y.; Uemura, S. Ir- and Ru-Catalyzed Sequential Reactions:
Asymmetric α-Alkylative Reduction of Ketones with Alcohols.
Angew. Chem. Int. Ed. 2006, 45, 3819-3822. (c) Ir: Lu, S.-M.; Han, X.-
W.; Zhou, Y.-G. Asymmetric Hydrogenation of Quinolines Catalyzed
by Iridium with Chiral Ferrocenyloxazoline Derived N,P Ligands.
Adv. Synth. Cat. 2004, 346, 909-912. (d) Ag: Liu, K.; Xiong, Y.; Wang,
Z.-F.; Tao, H.-Y.; Wang, C.-J. Ligand-controlled stereodivergent 1,3-
dipolar cycloaddition of azomethine ylides with 3-methyl-4-nitro-
5-styrylisoxazoles. Chem. Commun. 2016, 52, 9458-9461. (e) Cu:
Wei, L.; Zhu, Q.; Xu, S.-M.; Chang, X.; Wang, C.-J. Stereodivergent
Synthesis of α,α-Disubstituted α-Amino Acids via Synergistic Cu/Ir
Catalysis. J. Am. Chem. Soc. 2018, 140, 1508-1513. (f) Ni:
Hernandez, L. W.; Klöckner, U.; Pospech, J.; Hauss, L.; Sarlah, D.
Nickel-Catalyzed Dearomative trans-1,2-Carboamination. J. Am.
Chem. Soc. 2018, 140, 4503-4507.
(24) Epimerisation was not a problem during chromatography
provided the time taken was less than ca. 20 min (excepting
relatively polar ligand L5b which was not separated readily). Use
of alumina resulted in no separation.
(25) Carey, J. V.; Barker, M. D.; Brown, J. M.; Russell, M. J. H.
Preparation of enantiomerically pure phosphine oxides by
nucleophilic displacement chemistry using oxazaphospholidines.
J. Chem. Soc., Perkin 1 1993, 831-839.
(14) In this Letter compounds that differ only by the presence or
absence of deuterium have the same number. In all cases position
1 of the substituted cyclopentadienyl ring is attached to the
oxazoline substituent. Planar chiral configurations are assigned by
the Schlögl convention. See: (a) Schlögl, K.; Fried, M. Über Optisch
Aktive Kohlenwasserstoffe der Ferrocenreihe. Tetrahedron Lett.
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(26) Burford, N.; Losier, P.; Phillips, A. D.; Ragogna, P. J.; Cameron,
nucleophile to an η3-trans,trans-1,3-diphenylallyl palladium
T. S. Nitrogen Ligands on Phosphorus(III) Lewis Acceptors: A
Versatile New Synthetic Approach to Unusual N-P Structural
Arrangements. Inorg. Chem. 2003, 42, 1087-1091.
intermediate, for which the two possible endo/exo isomers result
in (S)- and (R)-6 respectively. See: Helmchen, G.; Pfaltz, A.
Phosphinooxazoline-A New Class of Versatile, Modular P,N-
Ligands for Asymmetric Catalysis. Acc. Chem. Res. 2000, 33, 336-
345.
(30) Richards, C. J.; Arthurs, R. A. Catalyst Optimisation for
Asymmetric Synthesis by Ligand Chirality Element Addition: A
Perspective on Stereochemical Cooperativity. Chem. Eur. J. 2017,
23, 11460-11478.
1
2
3
4
5
6
7
8
(27) Correction values determined from the comparison of the 31
P
NMR value for PPh3 (-6.0 ppm) with the values for FcPPh2 (-15.4)
and o-TolPPh2 (-12.4). On the same basis, starting with Ph2PCl (81),
the estimated value for (S,Sp)-3 is ca. 65, and thus also compatible
with the observed intermediate.
(28) Related phosphinooxazoline ligands containing
a
phosphorus-based stereogenic centre have been synthesised with
modest diastereocontrol. Distinct matched/mismatched outcomes
were observed for the palladium catalysed allylic alkylation of
cyclic substrates. See: (a) Peer, M.; de Jong, J. C.; Kiefer, M.; Langer,
T.; Rieck, H.; Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.;
Wiese, B.; Helmchen, G. Preparation of chiral phosphorus, sulfur
and selenium containing 2-aryloxazoline. Tetrahedron 1996, 52,
7547-7583. (b) Kudis, S.; Helmchen, G. Enantioselective Allylic
Substitution of Cyclic Substrates by Catalysis with Palladium
Complexes of P,N-Chelate Ligands with a Cymantrene Unit. Angew.
Chem. Int. Ed. 1998, 37, 3047-3050.
(31) Dailler, D.; Rocaboy, R.; Baudoin, O. Synthesis of β-Lactams by
Palladium(0)-Catalyzed C(sp3)-H Carbamoylation. Angew. Chem.
Int. Ed. 2017, 56, 7218-7222.
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57
58
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(32) (a) Tanaka, Y.; Mino, T.; Akita, K.; Sakamoto, M.; Fujita, T.
Development of Chiral (S)-Prolinol-Derived Ligands for Palladium-
Catalyzed Asymmetric Allylic Alkylation: Effect of a Siloxymethyl
Group on the Pyrrolidine Backbone. J. Org. Chem. 2004, 69, 6679-
6687. (b) Liu, D.; Xie, F.; Zhang, W. Novel C2-Symmetric Planar
Chiral Diphosphine Ligands and Their Application in Pd-Catalyzed
Asymmetric Allylic Substitutions. J. Org. Chem. 2007, 72, 6992-
6997.
(29)
A
reasonable assumption for this reaction as
enantioselectivity arises in the trans to phosphorus addition of the
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