Profiling the tuneable R-SMS-Phos structure in the rhodium(i)-catalyzed hydrogenation of olefins: The last stand?

Article abstract of DOI:10.1039/c1ob05364g

A diversified family of enantiopure P-stereogenic "R-SMS-Phos" {R-SMS-Phos = 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane} ligands wherein R = branched or heteroatom-substituted alkyl, aralkyl, silyl, acyl, sulfonyl, etc. was screened for the Rh(i)-catalyzed hydrogenation of a representative set of olefinic substrates. This systematic and detailed investigation revealed a marked beneficial impact on enantioselectivity and catalyst activity in comparison to Knowles' ultimate DiPAMP {DiPAMP = 1,2-bis[(o-anisyl)(phenyl) phosphino]ethane} design. Mutant ligands with highly enhanced properties possessing particular features wherein the DiPAMP structure is found embedded were identified. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05364g

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PAPER
Profiling the tuneable R-SMS-Phos structure in the rhodium(I)-catalyzed
hydrogenation of olefins: the last stand?†
a
a
a
Michel Stephan,*a,b Damjan Sterk, Borut Zupancˇicˇ and Barbara Mohar
ˇ
Received 8th March 2011, Accepted 21st April 2011
DOI: 10.1039/c1ob05364g
A diversified family of enantiopure P-stereogenic “R-SMS-Phos” {R-SMS-Phos =
1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane} ligands wherein R = branched or
heteroatom-substituted alkyl, aralkyl, silyl, acyl, sulfonyl, etc. was screened for the Rh(I)-catalyzed
hydrogenation of a representative set of olefinic substrates. This systematic and detailed investigation
revealed a marked beneficial impact on enantioselectivity and catalyst activity in comparison to
Knowles’ ultimate DiPAMP {DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]ethane} design. Mutant
ligands with highly enhanced properties possessing particular features wherein the DiPAMP structure
is found embedded were identified.
virtually preserved, as any radical departure from the model would
Introduction
probably lead to the loss of the essential features in the molecular
recognition process gained with the parent ligand. This was the
Despite milestone achievements in transition metal-catalyzed
asymmetric hydrogenations since the late 1960’s, a do-it-all catalyst
proved to be elusive due to the structurally diverse plethora
of prostereogenic olefinic targets to be reduced and to their
different possible interactions with the catalyst.1 Consequently,
for an increased chance of success in R&D efforts within the
constrained time-frames allocated to projects, broad ligand and
catalyst libraries are indispensable screening tools for a quick
evaluation of the technical feasibility of a catalyzed transformation
step within a devised synthetic strategy. An added impetus to
industrial production purposes is that bench-top results have
to concur: short reaction times (100% conversion in <12 h) at
maximum substrate-to-catalyst ratios (S/Cs) coupled with high
ee values. An extra vital advantage would be to operate with
high substrate concentrations and under mild conditions, i.e.
at technically convenient pressures (<10 bar H2) and around
room temperature.1d A number of enantiopure phosphorus-based
ligands were elaborated for those purposes but each is associated
with specific drawbacks.
R
case for instance with DIOP, BPPM, DEGUPHOS, catASiumꢀ
MN, and MeO-BIPHEP ligands wherein the peripheral remote
O- or N-substituents were varied, and with the ferrocene-based
diphosphines (ex. Josiphos, MandyPhosTM, and Walphos) and the
P-stereogenic BisP* where the P-substituents were exchanged.3,4
A comprehensive survey of the literature reveals several study-
cases whereby the diversification of a given diphosphine by
judicious alterations was undertaken.2 Variations were brought
forth by modifying the scaffold spanning the two phosphorus
atoms and/or by exchanging the P-substituents. These changes
were attained in such a way that the overall original structure was
In particular, during their ligand optimization in the mid-
1970’s, Knowles et al. prepared a set of P-stereogenic 1,2-bis[(o-
R-phenyl)(phenyl)phosphino]ethanes from which DiPAMP (with
R = MeO) exhibited in their hands the best performance in
the Rh(I)-hydrogenation of a-amidocinnamic acids.5 Of inter-
est, the 1,2-bis[(o-acetoxy-phenyl)(phenyl)phosphino]ethane lig-
and was prepared therein by acetylation of the corresponding
P-o-(hydroxy-phenyl) intermediate (R = HO) derived from the
demethylation of DiPAMP.6 However, “since it did not crystallize,
it was used without purification” and it furnished a much
lower enantioselectivity than DiPAMP.5 In 2004, Imamoto et
al. introduced congeners of such diphosphines with R = alkyl,
aNational Institute of Chemistry, Hajdrihova 19, SI-1001, Ljubljana, Slove-
nia; Fax: +386 1 4760300; Tel: +386 1 4760250
bPhosPhoenix SARL, rue de l’Abbe´ Groult, 75015, Paris, France. E-mail:
mstephan@phosphoenix.com; Fax: +33 1 48283011
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR, 31P NMR, HRMS,
GC) for all compounds. See DOI: 10.1039/c1ob05364g
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and demonstrated that the enantioselection in hydrogenation “is
induced by the spacial properties of the ligands”.7
Moreover, prepared by decomplexation of 1a (step b), SMS-
Phos (2a) was also prepared from DiPAMP (2b) using BBr3
(step e) and its complexation with borane (step c) retrieved
1a. The diastereomeric purity was maintained throughout these
transformations.
We have reported our in-depth and detailed study on the
beneficial effect gained from incorporating substituents into
DiPAMP’s P-o-anisyl rings.8 Herein, we present our extended
study on the alteration of DiPAMP’s methyl groups by switching
to branched or substituted/functionalized chains, and its impact
on the Rh(I)-catalyzed asymmetric hydrogenation of olefins.9
Hydrogenation screening results
The prepared R-SMS-Phos (2) were evaluated under mild
conditions (1 bar of H2 at room temperature in MeOH) in
the Rh(I)-catalyzed hydrogenation of a representative refer-
ence set of olefins: methyl a-acetamidoacrylate (S1), methyl
(Z)-a-acetamidocinnamate (S2), methyl (Z)-3-acetamidobut-
2-enoate (S3), methyl (E)-3-acetamidobut-2-enoate (S4), a-
acetamidostyrene (S5), dimethyl itaconate (S6), and atropic acid
(S7) (Table 1). Our adopted systematic transmutation of the
pendant R groups revealed significant variations in reactivity
and enantioselectivity of the Rh(I)-(R-SMS-Phos) catalysts with
a consistent sense of stereoselection per examined substrate. Both
steric bulk and coordinating ability of the R substituents proved
to markedly impact the catalysis, with the predominant majority
of the examined ligands displaying a superior performance than
that of the basic DiPAMP (2b).11
Results and discussion
Ligand synthesis
A representative spectrum of potential variety of 1,2-bis[(o-RO-
phenyl)(phenyl)phosphino]ethanes (2) was targeted. In this type
of series, which we have dubbed “R-SMS-Phos”, R represents a
branched or substituted/functionalized chain. Mutants modified
at the level of the RO groups were envisaged possessing branching
on the first or second carbon atom, heteroatom-substitution, or O
atom-borne heteroatoms (e.g. Si, P).
The bulk of the selected analogues 2 were readily obtained in
85–96% yield from the crystalline precursor 1,2-bis[(o-hydroxy-
phenyl)(phenyl)phosphino-P-borane]ethane (1a) (Scheme 1).10
The latter was easily prepared in enantiomerically pure form
with 57% overall yield via an adapted Juge´–Stephan asymmetric
route from the enantiopure 1,3,2-oxazaphospholidine-2-borane
complex (oxazaPB). Via this strategy, both enantiomers of the
diphosphine were equally easily accessible from the commercially
available (+)- and (-)-ephedrine.
The key intermediate 1a opens a general access within 2 steps
(step a followed by step b or step b followed by step d) to
a very large variety of enantiopure P-stereogenic R-SMS-Phos
ligands (2). This family of ligands includes the O-alkylated series
of the demethylated-DiPAMP 2a, as well as for instance the
(P-o-t-BuO2CCH2OPh)-substituted ligand 2q which would not
survive through the classical Juge´–Stephan route. Hence, this novel
approach offers an added flexibility in terms of synthesis of a
wide diversity of homochiral analogues and virtually unlimited
opportunities for fine-tuning the features of the ligands.
Hydrogenation of methyl a-acetamidoacrylate (S1) and methyl
(Z)-a-acetamidocinnamate (S2)
DiPAMP’s saga is partially attributable to its good performance
in the hydrogenation of dehydro-a-amido acids. In our initial
hydrogenation screening on these probe dehydro-a-amido acid
derivatives, even a subtle modification from R = Me (DiPAMP:
2b) to R = Et (2c) provided an improved catalysis furnishing 99.1%
ee vs. ~95% ee at ca. 3-fold reaction rate increase. The derived
MeOCH2CH2-substituted ligand (2p) also performed compara-
tively well. Shifting to branched R groups such as R = i-Pr (2d),
i-Bu (2e), t-Bu (2f), 3-Pen (2g), cPen (2h), Cy (2j), or TMSCH2 (2o),
further enhanced the overall result pushing the enantioselectivity
up to 99.9% ee at 9-fold faster rate. Noteworthy, even with i-Pr-
SMS-Phos (2d), which is the simplest higher branched DiPAMP
homolog, >99.4% ee was attained in few minutes. Within the
Scheme 1 Synthesis of the R-SMS-Phos series.10 Reagents and conditions: a) for 1b–e,g–i,k–m,o–t: RX (X = Br, I or OTs), K2CO3, acetone or DMF, r.t. to
60 ◦C; for 1u–z: RCl, NaH, THF, 0 ◦C to r.t.; 1j derives from hydrogenation (3 bar H2, PtO2, MeOH/CH2Cl2) of 1i (prepared from 3-bromocyclohexene);
b) Et2NH, 55–60 ◦C; c) Me2S·BH3, THF, r.t.; d) for 2t,u: RCl, NaH, THF, 0 ◦C to r.t.; e) for R = Me: BBr3, CH2Cl2, 0 ◦C.
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Table 1 [Rh((R,R)-R-SMS-Phos)(MeOH)2]BF4-catalyzed hydrogenation of selected representative classes of olefinsa
R-SMS-Phos (2) S1 S2 S3 S4 S5 S6
S7b
R =
t (min) ee (%) t (min) ee (%) Conv (%) t (min)ee (%)Conv (%) t (min) ee (%) t (min)ee (%) t (min) ee (%) Conv (%) t (min) ee (%)
a H
20c
15
6
6
6
4
5
6
5
12
20
6
6
6
94.5 70
93.6 18
97.8
2
24 h 17.0
5.5 h 65.8 100
0
24
5.5
2
1.5
1.5
1
1.5
0.3
0.75 97.8
21
24
1.5
16
2
2
3
16
20
24
16
16
16
—
—
87.0 11
91.3 10
93.0
93.4
97.3
94.9
97.6
35
84.7 30
84.0 10
64.2 17
85.4 100
96.6 70
98.1 100
98.5 78
99.8 100
98.6 100
99.3 100
99.3 100
96.9 100
91.2 100
98.7 100
91.7 53
99.1 59
95.0 88
84.6 72
93.3 93
98.7 39
86.2 13
86.3 63
91.2 76
86.6 60
3
3
2
2
2
2
2
2
2
3.3
3
3
3.3
2
2
3
3
3
15.1
48.6d
78.6
88.0
86.0
94.7e
92.9
96.4
97.1e
76.8
85.2
94.8
61.1
86.8
83.8
26.8
1.6
b Me11
c Et
94.9 100
99.1 100
99.7 100
99.7 100
99.8 100
99.4 100
99.9 100
99.9 100
99.6 100
99.1
99.4
99.4
99.9
99.8
99.9
99.8
99.2
6
4
4
2
4
3
3
5
90
20
30
7
66.7 100
82.1 100
70.2 100
80.1 100
84.4 100
84.8 100
88.2 100
63.9 77
92.1
97.8
96.9
99.3
98.5
99.9
99.9
9
5
5
2
4
3
3
d i-Pr
e i-Bu
f t-Bu
g 3-Pen
h cPen
3
5
2
4
3
3
5
7
4
7
8
4
7
4
9
6
9
5
5
15
10
15
4 h
24 h
15
90
30
50
45
60
j
Cy
k Bn
88.0
—
95.4 15
l
9-AnthCH2
99.5 10
99.7
0
—
0
95.3 30f
m C6F5CH2
n Ph
99.7
96.5
99.7
98.1
3
9
4
5
99.8 100
97.1 100
99.7 100
98.8 100
98.1 100
95.8 100
99.3 100
99.2 26
81.5 100
66.6 92
71.4 100
75.3 100
75.3 100
46.4 76
95.8
78.1
95.1
95.0
91.3
87.3
65.6
—
46.8
57.9
79.1
—
99.4
87.7
98.1
93.4
93.7
3
7
7
7
9
o TMSCH2
p MeOCH2CH2
6
q t-BuOC(O)CH2 4c
r t-BuNHC(O)CH2 5c
95.8 15
93.6 10
99.7 50
88.0 17
99.9 20
90.4 40
98.8 1 h
95.2 18
92.1 15
t TIPS
u Ac
v Piv
w Bz
x Ts
2c
5
5
6
5
2.5 h 12.2 70
24 h 50.2
90.2
71.1
90.6
87.6
80.7
—
98.0
99.6
99.0
99.2
—
4
6
3
3
0
3
3
3
3
99.7 84
99.3 100
99.3 100
6 h
90
90
—
33.7 45
57.5 33
70.1 69
y Ph2P(O)
—
150
98.5
—
—
—
4 hg 93.0 5 hh
40.0
—
—
a The catalysts were prepared in situ from [Rh(nbd)2]BF4. Runs were carried out under 1 bar of H2 (10 bar for S7) at room temperature in MeOH
(0.5 mmol of substrate in 7.5 mL MeOH) with a S/C = 100 (S/C = 1000 for S1) for the time indicated (100% conversion) if not stated otherwise and
are unoptimized. Typical isolated yields were >90%. Ee’s were determined by chiral GC (Lipodex-E column for hydrogenation products of S1 and S6,
Chiralsil-L-Val for S2 and CP-Chiralsil-DEX CB for S3, S4, S5 and S7; prior to analysis, the carboxylic group of hydrogenation product of S7 was
esterified with TMSCHN2); for this, see the ESI.† With (R,R)-R-SMS-Phos, S-configured products were obtained except with S6. b In the presence of
Et3N (1.1 equiv). c S/C = 100. For 2t with S/C = 1000, a 99.8% ee was obtained in 18 min. d 7% ee in the absence of Et3N. e Identical result was obtained
in the presence of 0.05 equiv. Et3N. In the presence of 0.05 equiv. Cy2NH, 95.6% ee obtained with 2f and 97.4% ee with 2j. f 60% conversion. g 35%
conversion. h 32% conversion.
R-SMS-Phos series wherein R = Bn (2k), 9-AnthCH2 (2l),
C6F5CH2 (2m), or Ph (2n), it is interesting to notice that 2n and 2l
exhibited the least good performance regarding enantioselectivity
and activity, respectively, and with the use of C6F5CH2-SMS-Phos
(2m) the situation got “renormalized” as with the other (branched
R)-based ligands. In this series’ case, this could stem from a
possible competitive secondary interaction of an aryl unit (of the
R groups) with the Rh center, particularly if taken with the Cy-
SMS-Phos (2j) results. The interplay of steric and electronic factors
is evident by the advantage of the isosteric C6F5CH2 group over
Bn due to its electron-poorer ring hence precluding the likelihood
of its coordinative deleterious interference with the metal. Also,
it seems that a borderline magnitude of the R substituent bulk
is required for an optimal performance, especially if one takes
into consideration the runs with the highly-hindered TIPS-SMS-
Phos (2t) and the other (branched R)-substituted ligands as
well.
our pure SMS-Phos (2a) and Ac-SMS-Phos (2u), respectively,
compared to the 84% ee and 63% ee respectively reported for
the reduction of (E/Z)-a-benzamidocinnamic acid by Knowles
and co-workers using the same ligands (vide supra).5 Regardless of
the bulk or nature of the ligand’s phenolic ester functionality (with
Ac (2u), Piv (2v), Bz (2w), or Ts (2x)) a >99% ee was maintained
with a fast reaction rate, however with the Ph2P(O)-substituted
ligand (2y) leading to
a dramatically protracted reaction
time.
Hydrogenation of methyl (Z)-3-acetamidobut-2-enoate (S3) and
methyl (E)-3-acetamidobut-2-enoate (S4)
Rh(I)-catalyzed hydrogenation of these substrates (the Z-isomer
in particular) proved to be somewhat more challenging using the
prepared R-SMS-Phos series under our standard test conditions
(reaction variables were not optimized in this study). Analyzed as
a whole in order to identify any trends in those two cases, the least
useful results were clearly obtained with the ligands possessing
pendant R groups having a good coordinating nature (e.g. H
(2a), t-BuNHC(O)CH2 (2r), Ac (2u), Piv (2v)) or with quite bulky
character (e.g. TIPS (2t), Piv (2v)), reflecting a special coordinative
binding of these substrates to the Rh center. In particular, the Ac-
SMS-Phos (2u) furnished a low ee (50.2%) and conversion (26%)
in the hydrogenation of the Z-isomer, while it was inactive against
Besides, the enantioselectivity and rate penalties derived from
the (carbonylmethyl fragment)-containing ligands 2q (R = t-
BuOC(O)CH2) and 2r (R = t-BuNHC(O)CH2), clearly demon-
strate a competitive coordination during catalysis to the Rh core
between these functionalities (amplified in the latter ligand’s case)
and the amide oxygen of the substrates.
Most surprisingly, we have obtained a 97.8% ee (within 70 min)
and 99.2% ee (within 4 min) for the reduction of S2 applying
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the E-isomer. An identical polar case was encountered with SMS-
Phos (2a). Noteworthy, the 9-AnthCH2-substituted ligand (2l) was
ineffective with both isomers.
ligands with R = t-BuOC(O)CH2 (2q) or t-BuNHC(O)CH2 (2r)
led to a pronounced attenuation of the enantioselectivity reflecting
a strong interference of such neighbouring substituents during
catalysis.
Nonetheless, recoursing to Cy-SMS-Phos ligand (2j), up to
88.2% ee (within 15 min) and 97.8% ee (within 45 min) were
attained for the Z- and E-geometric isomers, respectively, with
a convergent predominant preference for the (S)-product. Also,
there exist strong parallels together with cPen-SMS-Phos (2h) and
3-Pen-SMS-Phos (2g). Finally, comparison of the hydrogenation
outcome of the family members with R = Et (2c), i-Pr (2d), i-Bu
(2e), t-Bu (2f), and TMSCH2 (2o), implies that a close proximity
of the R branching is beneficial especially in the case of the Z-
isomer.
This investigation clearly demonstrates that under given reac-
tion conditions, the level of enantioselectivity and the reaction rate
continue to be intrinsically dependent on the nature (bulkiness,
electronic properties, coordination strength) of the various coor-
dinating groups present in the medium (i.e. pendant groups of the
ligand, functional groups of the olefinic substrate/hydrogenation
product and the solvent) and on the reactivity of the olefin.
Compared to relevant studies with Rh-DiPAMP, our published
X-ray crystal structure analysis of [Rh(i-Pr-SMS-Phos)(nbd)]BF4
revealed its pronounced dissymmetry and the 31P NMR study of
[Rh(i-Pr-SMS-Phos)(S2)]BF4 showed the occurrence of different
dynamics during hydrogenation.9b Here, coordinating functional
groups of the pendant R (R = H, Bn, t-BuOC(O)CH2, t-
BuNHC(O)CH2, Ph2P(O), etc.) proved to interfere with catalysis.
Thus, a correlation between the catalyst activity–enantioselectivity
and the various R groups of the R-SMS-Phos series is not straight-
forward to establish. However, projected mechanistic studies with
the R-SMS-Phos ligands wherein R represents branched alkyls,
may shed some light on the origin of influence of such variation
on the catalyst performance. Despite the need for rationally
modelling the optimum catalyst for a given substrate, still guess-
work and empirical design of ligands and catalysts are definitely
unavoidable.
In a broad sense, Rh-(R-SMS-Phos) catalytic profile as a
function of pendant R length or nature shows that spacial mapping
in proximity of the Rh center of catalysis through replacement
of DiPAMP’s suitably-placed methyl groups may further result
in catalysts with potentially improved efficiency for a given
substrate. The 1,2-bis[(o-hydroxy-phenyl)(phenyl)phosphino-P-
borane]ethane (1a) can be regarded as a user-adjustable precursor
of an assortment of do-it-yourself ethane-bridged diphosphines
which may be targeted for a special application in, inter alia,
biphasic- or supported-catalysis.
Hydrogenation of a-acetamidostyrene (S5) and dimethyl itaconate
(S6)
Inspection of the screening data transpires that essentially similar
trends can be drawn for these substrates as with dehydro-a-
amido acid derivatives S1 and S2. However, the hydrogenation
of S6 was overall more influenced by the nature of the R groups
compared to the hydrogenation of S5. This can be attributed to the
stronger binding affinity of enamides to the Rh. If one compares
on one hand the results obtained with the ligands where R = t-
BuOC(O)CH2 (2q), t-BuNHC(O)CH2 (2r), and DiPAMP (2b) in
the case of S5, and on the other hand the ones obtained with the
same ligands in the case of S6, the influence of the amide/ester
functionality of the ligand in presence of either the corresponding
amide or ester functionality of the substrate, is perceptible albeit
limited.
Apart from SMS-Phos (2a) and Ph2P(O)-SMS-Phos (2y),
virtually any changes to DiPAMP’s Me groups had a positive
effect on enantioselectivity culminating with the best performing
(with respect to enantioselectivity allied with kinetics) R-SMS-
Phos ligands wherein R = t-Bu (2f), 3-Pen (2g), cPen (2h), Cy (2j),
and C6F5CH2 (2m), followed closely (depending on the substrate)
by i-Pr (2d), TMSCH2 (2o), TIPS (2t), and Piv (2v). Up to 99.9%
ee was reached within 2–3 min (S/C = 100) in the hydrogenation
of both S5 and S6.
Conclusions
Hydrogenation of atropic acid (S7)
Since the early development of metal-catalyzed asymmetric hy-
drogenations, interest in non-steroidal anti-inflammatory drugs
and analgesics has incited research on S7 reduction which proved
to be a major challenging goal.12 Some mechanistic studies have
been conducted in order to elucidate the binding mode to the
Rh core of this substrate and its derivatives (ester, amide, salt,
etc.) which in turn profoundly affects the hydrogenation result.
The beneficial effect on its hydrogenation by an added base
(such as Et3N, Cy2NH) in equimolar or catalytic (~5 mol%)
amounts has been communicated.9 With this substrate, the best
enantioselectivity inducing R-SMS-Phos ligands possess R = t-
Bu (2f), cPen (2h), or Cy (2j), followed very closely by 3-Pen (2g)
and C6F5CH2 (2m). In fact, up to 97.1% ee was reached under
10 bar H2 within 2 h (S/C = 100) using Cy-SMS-Phos (2j) in the
presence of Et3N (0.05 equiv) at room temperature, and 97.4%
ee in the presence of Cy2NH (0.05 equiv).9d Apart from SMS-
Phos (2a), the hydrogenation outcome using the R-SMS-Phos
In summary, a very wide variety of enantiopure R-SMS-Phos-type
ligands of DiPAMP lineage was readily prepared and assessed in
the Rh(I)-catalyzed asymmetric hydrogenation of various classes
of olefins (dehydroamido acids, enamides, itaconates, and acry-
lates). Far from being a gimmick, this meticulous and exhaustive
alteration of the R groups was a rewarding enterprise culminating
in advantageous ligands which sharply boosted reaction rates by
several times and increased enantioselectivities. In hindsight, had
such a study been carried out at an early development stage of
asymmetric hydrogenation, it would have undoubtedly guided the
design of the ensuant phosphines.
Our library of non-exotic ligands with enhanced efficiency
over the DiPAMP archetype, possesses the prerequisite criterion
of compatibility for the elaboration of industrial processes. The
presented concept of modular structure is being extended in our
group to other phosphine skeletons and the advances will be
communicated in due course.
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[Rh((RP,RP)-R-SMS-Phos)(MeOH)2]BF4 complex in MeOH. A
vacuum was applied to this system then it was backfilled with
H2. The mixture was stirred at r.t. and H2 pressure as indicated.
Progress of the hydrogenation was monitored by the diminution of
the volume of the closed reaction system at 1 bar (until H2 uptake
ceased and a colour change of the solution occurred); for reactions
at 10 bar (S7) analyses were carried out at the indicated times.
The reaction mixture was analyzed by chiral GC (prior to
analysis carboxylic groups were esterified with TMSCHN2 in
hexanes). Absolute configurations were assigned by comparison
with the literature data of optical rotation of isolated products
(90–98% yield) and/or of the tR on chiral GC.
Experimental
General procedures for the preparation of 1b,c,l,p–z by
derivatization of 1a10a (Scheme 1, step a)13
(A) A mixture of 1a (458 mg, 1 mmol), K2CO3 (553 mg, 4 mmol),
and the appropriate (substituted)alkyl halide or tosylate (2.5–
3 mmol) in acetone (10 mL) was stirred at r.t. or refluxed until
TLC showed complete conversion. The mixture was concentrated,
filtered through a pad of silica gel eluting with CH2Cl2. The
product was recrystallized from hexane/CH2Cl2.
(B) A mixture of 1a (458 mg, 1 mmol), K2CO3 (553 mg,
4 mmol), and the appropriate (substituted)alkyl halide or tosylate
(2.5–3 mmol) in DMF (5 mL) was stirred at 40 ◦C until TLC
showed complete conversion. The mixture was concentrated,
filtered through a pad of silica gel eluting with CH2Cl2. The
product was recrystallized from hexane/CH2Cl2.
(C) To a stirred solution of 1a (458 mg, 1 mmol) in THF
(10 mL) was added NaH (60 mg, 2.5 mmol) at 0 ◦C. After 15
min the appropriate acid chloride (2.5 mmol) was added and
left to stir at r.t. for 1 h. The mixture was quenched with H2O
(0.1 mL), concentrated, and the residue was filtered through a pad
of silica gel eluting with CH2Cl2. The product was recrystallized
from hexane/CH2Cl2.
Acknowledgements
This work was supported by the Ministry of Higher Education,
Science, and Technology of the Republic of Slovenia (Grants
No. P1-242 and J1-9806). M. S. acknowledges the innovation
stimulation (No. 00P141 to PhosPhoenix SARL) by the Ministry
of National Education, Research, and Technology of France.
Notes and references
1 (a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, John Wiley
& Sons, New York, 1994; (b) Comprehensive Asymmetric Catalysis, Vol.
1–3 (ed., E. N. Jacobsen, A. Pfaltz and H. Yamamoto), Springer, Berlin,
1999; (c) Catalytic Asymmetric Synthesis, (Ed., I. Ojima), Wiley-VCH,
Weinheim, 2000; (d) Asymmetric Catalysis on Industrial Scale, (ed., (H.-
U. Blaser and E. Schmidt), Wiley-VCH, Weinheim, 2004; (e) Handbook
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Grabulosa, J. Granell and G. Muller, Coord. Chem. Rev., 2007, 251,
25–90; (c) Phosphorus Ligands in Asymmetric Catalysis, Vol. 1–3 (Ed.,
A. Bo¨rner), Wiley-VCH, Weinheim, 2008.
General procedures for the synthesis of (RP,RP)-1,2-bis[(o-RO-
phenyl)(phenyl)phosphino]ethane “(RP,RP)-R-SMS-Phos”
(2c,l,p–r,t–y) - Scheme 1, step b13
(RP ,RP )-1,2-Bis[(o-RO-phenyl)(phenyl)phosphino-P-borane]-
ethane in Et2NH (10 mL/1 mmol of (RP,RP)-1) was refluxed for
2–3 h under inert atmosphere. After concentration, purification
on silica gel and/or recrystallization under inert atmosphere, the
title compound (RP,RP)-2 was obtained.
3 For DIOP [2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenyl-
phosphino)butane], see: (a) C. F. Hobbs and W. S. Knowles, J. Org.
Chem., 1981, 46, 4422–4427; (b) K. Tamao, K. Nakamura, H. Ishii, S.
Yamaguchi and M. Shiro, J. Am. Chem. Soc., 1996, 118, 12469–12470.
For BPPM (N-tert-butoxycarbonyl-2-diphenylphosphinomethyl-4-
diphenylphosphino-pyrrolidine), see: (c) H. Takeda, T. Tachinami, S.
Hosokawa, M. Aburatani, K. Inoguchi and K. Achiwa, Chem. Pharm.
Bull., 1991, 39, 2706–2708; (d) K. Achiwa and T. Soga, Tetrahedron
Lett., 1978, 19, 1119–1120. For DEGUPHOS [DEGUPHOS =
“(RP,RP)-R-SMS-Phos” (2t,u) - Scheme 1, step d
To a stirred solution of (RP,RP)-SMS-Phos (2a) (1 mmol) in THF
(10 mL) was added NaH (60 mg, 2.5 mmol) at 0 ◦C. After 15 min,
TIPSCl or AcCl (2.5 mmol) was added and left to stir at r.t. for
1 h under inert atmosphere. The mixture was quenched with H2O
(0.1 mL), concentrated, and the residue was filtered through a
pad of silica gel and the product was recrystallized under inert
atmosphere.
catASiumꢀR D(R)
=
(3R,4R)-bis(diphenylphosphino)-N-benzyl-
pyrrolidine], see: (e) H. Jendralla, Synthesis, 1994, (05), 494–498; (f) U.
Nagel and E. Kinzel, Chem. Ber., 1986, 119, 3326–3343; (g) For
catASiumꢀR MN series [2,3-bis(2,5-dimethylphospholanyl)-pyrrole-
2,5-diones], see: A. Bo¨rner, J. Holz, A. Monsees, T. Riermeier, R.
Kadyrov, C. A. Schneider, U. Dingerdissen and K. Drauz, (Evonic
Degussa GmbH), US2005/0209455, 2005. For MeO-BIPHEP
In situ preparation of [Rh((RP,RP)-R-SMS-Phos)(MeOH)2]BF4
complex
[2,2¢-bis(diphenylphosphino)-6,6¢-dimethoxy-1,1¢-biphenyl],
see:
(h) R. Schmid, J. Foricher, M. Cereghetti and P. Scho¨nholzer,
Helv. Chim. Acta, 1991, 74, 370–389; (i) For SONIPHOS series
[2,2¢-bis(diphenylphosphino)-6,6¢-diacyloxy-1,1¢-biphenyls], see: M.
Bulliard, B. Laboue and S. Roussiasse, (PPG-SIPSY), WO2002012253,
To a solution of [Rh(nbd)2]BF4 (2.3 mg, 6.3 mmol) in MeOH
(0.5 mL), a solution of the (RP,RP)-R-SMS-Phos (2) ligand (0.8
equiv. to Rh-atom) in MeOH (0.5 mL) was added dropwise at r.t.
The resulting solution was hydrogenated under 1 bar of H2 for ca.
15 min. Elimination of metallic rhodium by filtration through a
No. 3 sintered-glass filter afforded a clear brown solution of the
title complex.
2002. For CnTunaPhos series and analogues {C3-TunaPhos
=
C3-TunePhos 1,13-bis(diphenylphosphino)-7,8-dihydro-6H-
=
dibenzo[f ,h][1,5]dioxonin}, see: (j) Z. Zhang, H. Qian, J. Longmire
and X. Zhang, J. Org. Chem., 2000, 65, 6223–6226; (k) L. Qiu, J. Wu,
S. Chan, T. T.-L. Au-Yeung, J.-X. Ji, R. Guo, C.-C. Pai, Z. Zhou,
X. Li, Q.-H. Fan and A. S. C. Chan, Proc. Natl. Acad. Sci. U. S. A.,
2004, 101, 5815–2820. For similarly modified group of atropoisomeric
diphosphines, see: for SEGPHOS [5,5¢-bis(diphenylphosphino)-
4,4¢-bi-1,3-benzodioxole]: (l) T. Saito, T. Yokozawa, T. Ishizaki, T.
Moroi, N. Sayo, T. Miura and H. Kumobayashi, Adv. Synth. Catal.,
Hydrogenation procedure for the substrates in Table 1
To a solution of the substrate in MeOH, three freeze-pump-thaw
cycles were applied and the system was filled with Ar. Then to
this solution was added under Ar a solution of the preformed
ꢀR
2001, 343, 264–267. For SYNPHOS [6,6¢-bis(diphenylphosphino)-
2,2¢,3,3¢-tetrahydro-5,5¢-bi-1,4-benzodioxin] and DIFLUORPHOS
5270 | Org. Biomol. Chem., 2011, 9, 5266–5271
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ꢀR
ˇ
[5,5¢-bis(diphenylphosphino)-2,2,2¢,2¢-tetrafluoro-4,4¢-bi-1,3-benzo-
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[Rh((R,R)-1,2-bis{(o-R-phenyl)(phenyl)phosphino}ethane)] catalysts
(conditions: S/C = 1000 under 3 atm of H2 in iPrOH (88%) at 50
◦C for 0.8–1 h): 96% ee (S) with o-R-Ph = o-MeO-Ph (DiPAMP),
84% ee with o-HO-Ph, 63% ee with o-AcO-Ph, 73% ee with o-
MeSO2-Ph, 60% ee with o-F-Ph, while no reaction occurred with o-
MeS-Ph.
6 Prepared via resolution of l-menthyl (RSP)-(o-anisyl)(methyl)phos-
phinate, (R,R)-DiPAMP was demethylated using Ph2PLi. For this, see
ref. 5.
7 Y. Wada, T. Imamoto, H. Tsuruta, K. Yamaguchi and I. D. Gridnev,
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9 (a) M. Stephan and B. Mohar, (PhosPhoenix SARL; Nat. Inst.
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(http://www.cas.org/spotlight/rlist1q07p/rlist1q07p.html); (b) M.
13 For the preparation of the rest of the (RP,RP)-series and some (SP,SP)-
enantiomers, see ref. 9 and the ESI†.
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