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Cite this: Chem. Soc. Rev., 2011, 40, 37443763
BINEPINES: chiral binaphthalene-core monophosphepine ligands
for multipurpose asymmetric catalysis
Serafino Gladiali,*a Elisabetta Alberico,b Kathrin Jungec and Matthias Beller*c
Received 2nd November 2010
DOI: 10.1039/c0cs00164c
The atropisomeric structure of 4,5-dihydro-3H-dinaphtho[2,1-c;10,20-e]phosphepine is the common
axially chiral scaffold of a library of monophosphine ligands nicknamed BINEPINES that have
shown a quite remarkable stereoselection efficiency in a broad variety of enantioselective reactions
involving the formation of new CH or CC or CX bonds. In this critical review the properties
and scope of this type of chiral ligands are illustrated (70 references).
Introduction
The last decade has witnessed the enormous success of
chiral monodentate phosphorus ligands in several metal- and
organo-catalyzed enantioselective reactions. The renaissance
of this class of chiral inducers has turned around the established
belief that only bidentate diphosphines could be the ligands of
choice for asymmetric catalysis. The breakthrough in the
field was achieved in 2000 when almost simultaneously three
independent groups pointed out the exceptional stereoselective
ability displayed in Rh-catalyzed asymmetric hydrogenation
of a-acyldehydroamino acid derivatives by the phosphor-
amidites 1,1 phosphites 22 and phosphonites 33 of binaphthol
(Fig. 1). Given the presence of polar Pheteroatom bonds
(heteroatom = O; N), these compounds are ligands of comparably
higher p-acidity than tertiary trialkyl or triaryl phosphines.
a Dipartimento di Chimica, Universita` di Sassari, via Vienna 2,07100 Sassari, Italy. E-mail: [email protected];Fax: +39 079 229559; Tel: +39 079 229546
b Istituto di Chimica Biomolecolare, CNR, trav. La Crucca 3,07040, Italy
c Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock,Albert-Einstein-Strae 29a, Rostock 18059, Germany.E-mail: [email protected]; Fax: +49 381 1281 51113;Tel: +49 381 1281 113
Serafino Gladiali
Prof. Serafino Gladiali was born
in Milano. He accomplished
his studies in Industrial
Chemistry at the University
of Milano where he received
the laurea in Industrial
Chemistry in 1968. After gaining
four years of experience in
industrial research on steroid
chemistry, in 1972 he moved to
the University of Sassari,
where he is full Professor of
Industrial Organic Chemistryat the Faculty of Sciences. His
main research interests are
centred on asymmetric homo-
geneous catalysis and ligand design. Stereoselective synthesis of
optically active organic compounds, mainly nitrogen hetero-
cycles and atropisomeric phosphorus and sulfur derivatives, is
a further subject of his research. He has co-authored over
250 papers, patents and communications covering the areas of
enantioselective hydroformylation and hydrogen transfer reduction;
synthesis and applications to asymmetric catalysis of chiral hetero-
cycles with pyridine nitrogen donors; preparation and catalytic
applications of atropisomeric phosphorus and sulfur donor ligands;
catalysis for energy production.
Elisabetta Alberico
Elisabetta Alberico obtained her
degree in Chemistry (Laurea)
from the University of Sassari
in 1993. From 1993 to 1996
she worked at the University
of Sassari in Prof. Gladialis
group and for the National
Research Council as research
assistant in the field of
asymmetric homogeneous cata-
lysis. After spending ten months
at the University of Ottawa in
1998 in the group of Prof.Howard Alper, she moved to
the Rheinisch-Westfalische
Technische Hochschule where
she obtained her PhD under the supervision of Prof. Albrecht
Salzer. Since 2001 she has held a permanent position as researcher
at the Institute of Biomolecular Chemistry of the National
Research Council in Sassari. Her research interests are in the
fields of organometallic chemistry, asymmetric homogeneous
catalysis and application of catalytic methods to the synthesis of
molecules endowed with biological activity.
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BINEPINES 5 are monodentate phosphines which retainthe basic structural features of these monodentate binaphthalene-
core ligands, i.e. a seven-membered phosphepine ring embedded
in a C2-symmetrical environment with an endocyclic P-donor
atom and a stereogenic axis as the unique chiral element, but
possess a P-donor of comparably higher electron density
(Scheme 1). This feature is expected to display a positive
effect in several catalytic processes like the hydrogenation of
enamides by Rhphosphine complexes where the turn-over
limiting step of the catalytic cycle is the oxidative addition of
hydrogen.4
Like the other chiral monophosphines, BINEPINES have
several advantages over the bidentate counterparts: they are
readily accessible from rather inexpensive starting materialsvia synthetic routes which enable the easy introduction of
structural diversity; they are amenable to combinatorialscreening of catalysts;5 they allow the design of catalysts built
up on metal complexes containing an unpaired number
of chiral ligands. The higher lability of monophosphines as
compared to chelating bidentate diphosphines may influence
the dissociation equilibria in favor of unsaturated species.
While this may have contrasting effects on the catalytic
process, an increase of the rate is anticipated in the case where
vacation of a coordination site is required in an early step of
the catalytic cycle. The main drawback in the use of mono-
phosphines as chiral ligands follows from the higher number
of regioisomers that, depending on the geometry of the complex,
can be obtained when two or more ligands are complexed to
the metal. The presence of a mixture of catalysts is normallydetrimental for the selectivity of the reaction.
Fig. 1 Selection of chiral monodentate biaryl phosphoramidites 1,
phosphites 2 and phosphonites 3 for asymmetric hydrogenations.Scheme 1 First synthesis ofBINEPINES 5 according to Gladiali et al.
Kathrin Junge
Dr Kathrin Junge, born in
1967 in northern Germany,
received her PhD degree in
Chemistry from the University
of Rostock in 1997 (Prof.
E. Popowski Laboratory).
After a postdoctoral position
in the Max-Planck group of
Prof. U. Rosenthal she joined
the group of Prof. M. Beller in2000. Since 2008 she is group
leader for homogeneous redox
catalysis at LIKAT. She has
been involved for years on
catalysis and has developed
efficient hydrogenations for
ketoesters and other carbonyl compounds. Moreover, new chiral
ligands based on the binaphthophosphepine structure were developed
by her. Her current main interest is the development of environ-
mentally benign and efficient catalytic reactions based on cheap
nonprecious metals.
Matthias Beller
Matthias Beller, born in 1962,
studied chemistry at the
University of Gottingen,
Germany, where he completed
his PhD thesis in 1989 in the
group of Prof. Tietze. As a
recipient of a Liebig scholar-
ship, he then spent one year in
the group of Prof. Sharpless at
the MIT. From 1991 to 1995,Beller was an employee of
Hoechst AG in Frankfurt, where
he directed the Homogeneous
Catalysis project in the
companys central research
unit. In 1996 he moved to the
Technical University of Munchen as Professor for Inorganic
Chemistry. In 1998, he relocated to the University of Rostock to
head the Institute for Organic Catalysis. Since 2006 Matthias
Beller is director of the newly formed Leibniz-Institute for
Catalysis. His scientific work has been published in around
450 original publications and review articles. In addition, ca.
100 patent applications have been filed.
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Synthesis and structure of BINEPINES
Synthesis
The first preparation of a 4,5-dihydro-3H-dinaphtho-
[2,1-c;10,20-e]phosphepine derivative 5 (BINEPINE) was reported
in 1994 (Scheme 1).6 A nickel-catalyzed Kumada coupling
of 1-bromo-2-methylnaphthalene with its Grignard reagent7
gave racemic 2,2
0
-dimethylbinaphthyl 4 which was selectivelydouble-lithiated on the methyl groups and subsequently
quenched with phenyldichlorophosphine to yield racemic
P-phenyl-4,5-dihydro-3H-dinaphtho[2,1-c;10,20-e]phosphepine 5a.
Resolution of the enantiomers was carried out by fractional
crystallization of the diastereomeric complexes with (+)-
di-m-chloro-bis[(S)-N,N-dimethyl-a-phenylethylamine-2C,-N]-
dipalladium 6.8 Finally, the enantiopure monodentate
phosphine 5a (PhBINEPINE) was liberated by reacting the
single diastereomeric complex with bidentate phosphines
(e.g. DPPE). Some years later the group of Stelzer reported
the synthesis of the secondary phosphepine 5 (R = H) (Scheme 2)
in good yields.9
Both these approaches were however unpractical withrespect to up-scaling due to the expensive auxiliaries and low
overall yields. A more convenient two step pathway starting
from enantiomerically pure 2,20-binaphthol (498% ee) was
established later when enantiopure 2,20-binaphthol became
commercially available on large scale.10,11 This material
can be efficiently converted into enantiopure 2,2 0-dimethyl-
binaphthyl 4 in more than 90% overall yield via a two step
sequence involving a Kumada coupling of the intermediate
ditriflate (Scheme 2).12,13 Two different methodologies were
developed for the conversion of 4 into 5. In the first procedure
double metallation of 2,20-dimethylbinaphthyl 4 with n-butyl-
lithium in the presence of TMEDA (N,N,N0,N0-tetramethyl-
ethylenediamine) followed by quenching with commercially
available dichlorophosphines gave ligands 5a (P-phenyl) and
5b (P-tert-butyl) in 6083% yield, which were both synthesised
on a scale greater than 10 g.10
In the second procedure the dilithiated 2,20-dimethyl-
binaphthyl 4 was quenched with diethylaminodichlorophosphine
to produce the amino BINEPINE 814 which, upon treatment
with gaseous HCl, was converted into the chloro BINEPINE9
in 80% yield. By coupling with various Grignard or lithium
reagents the chlorophosphine provides a broad selection of
ligands 5. The limited number of commercially available
dichlorophosphines and the large diversity of Grignard
reagents make the access through 4-chloro-4,5-dihydro-
3H-dinaphtho[2,1-c;1
0
,2
0
-e]phosphepine 9 the route of choicefor a library of ligands 5.11 Very recently, Wild and co-workers
have added one more member to the ligand family 5. The
2-(methoxymethyl)phenyl derivative 5t was exploited in the
enantioselective synthesis of arsenium and bis(arsenium)
salts.15
Scheme 2 Synthetic approach to 4,5-dihydro-3H-dinaphtho[2,1- c;10,20-e]phosphepines developed by Beller et al.
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A synthetic approach to monodentate BINEPINESanalogous
to the one devised by Beller et al. was reported at the same time
by the group of Zhang (Scheme 3).
13
The t-Bu derivative 5b wasexploited in the preparation of the bidentate ligand with the
phosphepine motif 1113 which adds to the bis-phosphepine
ligands 1016 and 1217 previously reported by the same group.
Structural diversity in the BINEPINElibrary can be generated
in different ways and nowadays a vast array of derivatives has
been reported. While the group of Beller has focused on the
variation of substituents on the P-centre, Widhalm et al. have
managed to introduce one or two substituents on the benzylic
carbons a- to the phosphorus (Scheme 4).18 The introduction
of new stereocentres in the proximity of the P-donor was
deemed to improve the transfer of chiral information. The
sulfide 13, prepared from 5a, was deprotonated with n-butyl-
lithium and then quenched with suitable electrophiles to provide
monosubstituted ligands. Monosubstitution at the benzylic
carbon destroys the C2-symmetry of the supporting scaffold
and generates, at the same time, two new stereogenic centres,at C and at P. The monoalkylated products 14 (Scheme 4) are
obtained as a mixture of two diastereoisomers with a relative
syn (Sax,S,SP)-14 or anti (Sax,S,RP)-14 arrangement of the
substituents on C and P. The latter stereochemistry is favoured
in all cases. Dialkylation of the phosphepine sulfide (S)-13 is
better achieved by a step-wise protocol involving two sequential
deprotonationalkylation reactions with the same alkylating
agent. t-BuLi is necessary in order to place the second
substituent on C(5). This step proceeds with complete diastereo-
selectivity providing the trans protected phosphepine
(Sax,S,S)-16 as the exclusive reaction product and restoring
the original C2-symmetry of the supporting scaffold. Ligands
15 and 17 are accessible also from the relevant phosphine
Scheme 3 Synthesis of 4,5-dihydro-3H-dinaphtho[2,1-c;10,20-e]phosphepines by a protocol established by Zhang et al.
Scheme 4 Synthesis ofa- and a,a0-substituted 4,5-dihydro-3H-dinaphtho[2,1-c;10,20-e]phosphepines.
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oxide following a similar deprotonation/alkylation protocol
followed by deoxygenation.19 The observed stereochemistry
was identical and again only one diastereomer is formed.
Dimethoxydibenzophosphepine (R)-23 is the unique example
of phosphepine where a diaryl template other than binaphthalene
has been used for the installation of the phosphepine ring
(Scheme 5). The enantiopure (R)-configured product is readily
accessible from the phenol 18 through the bisphenol 20 which
has been resolved with the aid of menthyl chlorocarbonate.20
Structural and electronic properties of BINEPINE derivatives
The 1H- and 13C-NMR spectra of PhBINEPINE 5a
(Scheme 1) show the non-equivalence of the methylene and
the naphthyl groups of the 1,1 0-binaphthyl-2,20-bis(methylene)
backbone. Accordingly, the diastereotopic CH2 groups show
in the 13C{1H} NMR spectrum two doublets with different
PC coupling constants. In the 1H-NMR spectrum, the
diastereotopic hydrogens of the CH2 groups give rise to four
sets of partially overlapping double doublets arising from
geminal 1H,1H and from 31P,1H couplings. The 31P{1H} NMR
spectra of ligands 5 show a single peak whose chemical shift
depends on the nature of the R substituent on the phosphorus
and varies within the range ofd 3 to +28 ppm.
These spectral data, which are common to ligands 5,
indicate that no atropisomerization of the dinaphthyl frame-
work occurs at room temperature and that the seven membered
phosphepine ring is locked in a single conformation which
does not undergo any significant dynamic process. A noticeable
feature of BINEPINES is that the phosphorus atom is not a
stereogenic centre since it is located on the C2-symmetry axis
of the dinaphthyl substituent. As a consequence, if pyramidal
inversion at phosphorus had to occur, which however is
not the case, this should not affect the chirality of the molecule
which is determined exclusively by the atropisomeric dinaphthyl
framework.
When the C2-symmetry of the dinaphthyl backbone is lost,
as it occurs upon introduction of one substituent at the
benzylic position (ligands 15ae, Scheme 4), the phosphorus
becomes a stereogenic centre. In ligands 17ae (Scheme 4),
where the two substituents R1 and R2 are identical and have a
mutual trans arrangement, the C2-symmetry of the binaphthyl
template is restored and the phosphorus is no longer stereogenic.
X-Ray structures have been obtained for ligands 5H R = H,9
(S)-5c and (S)-5k (Fig. 2),11 rac-14b and rac-16b (Fig. 3).18
Common features of the BINEPINE ligands resulting
from the comparison of these structures are the distorted skew-
boat conformation of the seven-membered phosphepine ring
containing the phosphorus atom and the large dihedral angle
(Table 1) existing between the average planes of the naphthalene
rings.
These torsional angles lie in the range 651701 for BINEPINES5,
lower values being associated to the presence of aryl substituents
at the P-centre. Since the amplitude of this angle is almost
unchanged in the relevant P-oxide (compare entries 3 and 4,
Table 1), it can be confidently assumed that the torsional angle
Scheme 5 Synthesis of diphenyl templated phosphepines.
Fig. 2 Crystal structures of (S)-5c (left hand side) and (S)-5k
(right hand side). For ligand 5c, only one of the two symmetry-
independent molecules of the asymmetric unit is depicted. H-atoms
are omitted for clarity.
Fig. 3 Crystal structures600 dpi in TIF format)??4 of rac-16b
(left hand side) and rac-14b (right hand side). In both cases, structures
having S configuration at the benzylic carbons are depicted. H-atoms
are omitted for clarity.
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of the parent ligand PhBINEPINE 5a should be very close to
that of the relevant P-oxide (631). Unlike the case ofP-oxides,
the introduction of sulfur in place of oxygen induces a signifi-
cant increase of the dihedral angle (compare entries 6 and 7,
Table 1) as to span over 711 in rac-14b and in rac-16b. In both
these last ligands the methyl substituents at the benzyliccarbons hold a pseudo-axial position.
A few transition metal complexes containing PhBINEPINE5a
have been isolated and characterized. Cationic [Rh(nbd)(5a)2]+X
derivatives, where nbd is norbornadiene and X is a non-
coordinating anion (CF3SO3; BF4
; PF6; SbF6; BaRF
)
show in solution a NMR pattern consistent with the presence
of two units of P-ligand coordinated to the metal and an
overall C2-symmetry of the complex.21 The same structural
features can be extracted from the NMR spectra of neutral
dichloro and cationic ditriflate Pt-complexes synthesized
by reacting Pt(cod)Cl2 (cod = 1,5-cycloctadiene) with two
equivalents of 5a followed by treatment of the dichloro
derivative with aqueous silver triflate.22
Crystals suitable for X-ray analysis have been obtained for two
metal complexes containing just one unit of (S)-PhBINEPINE
5a: the cyclopalladated complex with the (R)-phenethylamine
derivative 246 and the cycloplatinated complex 25a23 (Fig. 4).
The measure of the dihedral angle of the BINEPINE is
reported only for the cyclopalladated complex 24 and is very
close to that of the corresponding phosphepine oxide (compare
entries 5 and 9, Table 1). From this it follows that the binding of
a metal at the P-centre has only minor consequences on the
atropisomeric conformation of the ligand.
Tolmans cone angle y of PhBINEPINE as extracted from
the crystal structure of (S,R)-24 spans some 1511, slightly
larger than that of triphenylphosphine (1451
).24
The electron density at the P-donor of a range ofBINEPINES
has been evaluated by means of the 1JP,Se of the corresponding
selenides, prepared in situ by heating the phosphepine derivative
and selenium in CDCl3.25 This method is among the most
reliable ones for assessing the donating ability of the phosphorus
donors, smaller coupling constants corresponding to a higher
electron density at the phosphorus and vice versa.26
Fromthe data of Table 2 it is apparent that the electronic effect
of the substituents on the phenyl ring is effectively transmitted
to the P-donor of aryl substituted BINEPINES and that the
dimethoxydibenzophosphepine23 (1JP,Se = 725 Hz) is slightly
more basic than PhBINEPINE5a (1JP,Se = 728 Hz).3 For the
sake of comparison, the 1JP,Se of a typical phosphoramidite
such as Monophos (1; R1 = R2 = Me), a ligand much more
p-acidic than any BINEPINE 5, is as high as 971.1 Hz
(Table 2; entry 9).
Formation of CH bonds
Hydrogenation of CQC double bonds. Hydrogenation of
CQC double bonds is the benchmark reaction for assessing
the efficiency of a chiral ligand. Driven by the success of mono-
dentate phosphorus ligands based on the binaphthyl backbone
(Fig. 1), the ligand tool box 5 was assessed in the asymmetric
catalytic hydrogenation of a variety of substrates. A first set
of experiments was dedicated to the rhodium-catalyzed
asymmetric hydrogenation of a-aminoacid precursors.10,11
Here, methyl-(Z)-a-acetamidocinnamate 26 and methyl-
a-acetamidoacrylate 27 were chosen as model substrates
(Scheme 6). High enantioselectivities (up to 93% ee) and
activities (TOF 10006000 h1) were achieved in toluene and
in ethyl acetate with 26 as the substrate.11 The use of sodium
dodecyl sulfate (SDS) as an additive frequently led to improved
enantioselectivities (up to 95% ee in the case of 5a) for the
reaction in toluene.10 This result is rather unexpected because
aromatic hydrocarbons are known to induce the formation of
coordinatively saturated Rh-complexes which are less reactive
towards hydrogen.27 A negative effect on the kinetics of the
hydrogenation is the expected consequence and this may have
an unfavorable impact also on the stereoselectivity. In the
present case, however, the decrease in the reaction rate is
counterbalanced by a definite increase of the stereoselectivity.
The same happens in the hydrogenation in ethyl acetate when
the ligand to metal ratio is increased from 2 : 1 to 4 : 1.10 Both
these results are most probably related to the stabilization of
Table 1 Dihedral angles of BINEPINE derivatives
Entry Compound Torsion angle Reference
1 5H 67.6(5)1 92 5k 70.21(5)1 113 5c 65.11(10)1a 11
66.20(9)14 5c-oxide 65.05(7)1
a 1966.86(6)1
5 5a-oxide 63.01(7)1 196 17b-oxide 67.39(4)1 197 16b 71.361 188 14b 71.431 189 24 63.81 6
a The two values refer to the two symmetry independent molecules
present in the asymmetric unit.
Fig. 4 Crystal structures of cyclometalated Pd (24) and Pt (25a)
complexes with (S)-5a. H-atoms are omitted for clarity.
Table 2 31P-NMR chemical shifts for selected BINEPINES and1JP,Se coupling constants of the corresponding selenides measured inCDCl3 at room temperature
Entry Ligand d (31P)/ppm 1JP,Se/Hz
1 5d 2.3 711.42 5r 4.3 711.43 5c 5.7a 721.84 5l 7.8a 723.1
5 23 1.7 725.06 5a 7.8 728.37 5n 8.2a 739.98 5h 5.1a 761.79 1 148.7 971.1
a Values measured in CD2Cl2.
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the resting state of the catalyst and to the consequent decrease
in the rate of its decomposition.27
The best enantioselectivities were obtained with aryl substituted
BINEPINES, while alkyl derivatives led, in most cases, to
enantiomeric excesses lower than 50%. In the case of asymmetric
hydrogenation of methyl a-acetamidocinnamate 26 a detailed
study of various ligands with substituted aryl groups at the
phosphorus demonstrated no significant change in enantio-
selectivity, when electron-donating or electron-withdrawing
functionalities were situated in the para-position. Analogous
substitution in the ortho-position caused a decrease in the
enantioselectivity. The substituents on the P-phenyl group
display a significant influence on the activity of the catalyst
which is increased by electron donating substituents such as
p-OMe and reduced by electron-withdrawing ones such as p-F
and p-CF3. While the majority of the catalysts gave lower enantio-
selectivities in the reduction of methyl a-acetamidoacrylate 27
as compared with methyl a-acetamidocinnamate 26, in the
case of the best ligand, (S)-5o, the ee was practically the same
(9495%). With both substrates, ligand (S)-5o gives also rise
to the catalyst with the highest activity. As a general trend, with
BINEPINES 5 the handedness of the reaction is opposite
(the inducing ligand and the reaction product have opposite
configurations). The sole exception to this behavior has been
noticed in the reduction of 27 with t-BuBINEPINE 5b,
where the inducing ligand and the product have the same
configurations.
With C-substituted BINEPINES, the best results in the
reduction of a-acetamidocinnamic acid 28 (91% ee) and its
methyl ester 26 (73% ee) are achieved with ligands (Sax
,S,S)-
17b and (Sax,S,S)-17d respectively (Scheme 7).18 Interestingly,
with all these ligands the handedness of the reaction is reversed
as compared to the corresponding unsubstituted BINEPINES
5, indicating that axial- and central chiralities are mismatched
and that stereoselection is steered by the configuration of the
stereogenic centres rather than by that of the stereogenic axis.
The hydrogenation ofb-aminoacid precursors is attracting
increasing interest because the resulting products are useful
building blocks for various novel biologically active compounds.28
While investigating the application of ligand class 5 in the
rhodium-catalyzed asymmetric hydrogenation ofb-dehydroamino
acids derivatives, the necessity of different reaction conditions
for the E- and Z-isomers became soon apparent (Scheme 8).29
A good enantioselectivity (79% ee (R)) was obtained for
the reduction of (E)-methyl-3-acetamido butenoate E-29 in
2-propanol at 2.5 bar hydrogen pressure, while higher pressures(50 bar) and ethanol as the solvent turned out to be beneficial
for the Z-isomer Z-29 (92% ee (S)). Notably, a chiral switch in
the product configuration was noticed depending on the geometry
of the double bond, which had been scarcely reported before.30
Furthermore, a higher reaction rate was monitored for the
Z-isomer compared to the E-isomer, in spite of the opposite
behavior reported for most other catalysts.31
With Z-29 the highest enantioselectivity was reached with
ligand 5a while the tert-butyl-substituted derivative 5b was
completely inactive. Surprisingly, ligand 5b gave a good enantio-
selectivity in the hydrogenation ofE-29. Several b-dehydroamino
acids derivatives have been screened and in the best case 94%
ee was attained when the methyl ester of Z-29 was replacedby the ethyl ester. From the observation of a non-linear
dependence of the stereoselectivity of the reduction on the
enantiopurity of the used BINEPINES, it was inferred that
2 equiv. of ligand per metal were present in the active catalyst.32
This circumstance gave the chance for a combinatorial screening
of catalysts. Unfortunately no positive effect was observed upon
combining 5a with different achiral phosphorus ligands.29
Scheme 6 Asymmetric hydrogenation of 26 and 27 in the presence of
BINEPINE ligands 5.
Scheme 7 Hydrogenation of acetamidocinnamic acid 28 and its
methyl ester 26 catalyzed by Rh-complexes of PhBINEPINE 5a
and a,a0-disubstituted PhBINEPINES 17b and 17d.
Scheme 8 Hydrogenation ofE-29 and Z-29 with different BINEPINES5.
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The mechanistic details of the hydrogenation ofb-aminoacid
precursors are still to be clarified. This does not allow us to
draw any sound conclusion from the results obtained in the
RhBINEPINE catalyzed hydrogenation.
In the asymmetric hydrogenation of dimethyl itaconate 31
with BINEPINES 5 the best results (enantioselectivities up to
88% ee) were obtained in dichloromethane (Scheme 9).11
The hydrogenation of itaconic, acetamidocinnamic and
acetamidoacrylic acids and of the relevant methyl esters
proceeds at a fast rate and with a high ee, up 96%, even in
the presence of dimethoxydibenzophosphepine (R)-23 as the
chiral inducer. In this case dichloromethane is the solvent of
choice and a preformed cationic Rh-complex containing two
units of the ligand (R)-23 has been used as the catalyst.20
PhBINEPINE (S)-5a and related BINEPINES were
applied to the rhodium-catalyzed reduction of enamides, an
atom economic and straightforward route for the synthesis of
chiral amines (Scheme 10).33
As a general trend, with these substrates aryl-substituted
phosphepines are much better suited chiral inducers than the
alkyl-substituted ones and, among them, (S)-5a is the most
efficient. Electron-rich substrates such as 33 were hydrogenated
in somewhat higher enantioselectivity compared to N-(1-phenyl-
vinyl)acetamide, the opposite behaviour being observed with
electron-poor substrates. Under optimized conditions an
enantioselectivity as high as 93% has been obtained in the
reduction of N-(1-phenylvinyl)acetamide 32 (Scheme 10) with
ligand (S)-5a. This is the highest stereoselectivity obtained up
to now with monodentate phosphine ligands in this reaction.
The enantioselective reduction of enol carbamates offers an
alternative approach for the preparation of chiral benzylic
alcohols.19 Pioneering work in this field has been reported by
Feringa and co-workers who have obtained enantioselectivities
up to 98% ee with rhodium-catalysts containing monodentate
phosphoramidites (MonoPhos-family).34 Utilizing compound
34 as a model substrate, various reaction parameters were
investigated in detail and enantioselectivities up to 96% ee
were achieved with a catalyst made up in situ from
[Rh(cod)2]+BF4
and ligand 5a (Scheme 11).19 Notably, the
catalyst gave a similar enantioselectivity (9496% ee) over the
entire temperature range 1090 1C.
The influence of a,a0-substitution in the ligand was also
explored in a comparative study. Ligand (Sax,S,S)-17b was the
best chiral inducer for some enolcarbamates and caused in
most cases a switch of configuration compared to the parent
ligand 5a.19
Transfer hydrogenation of CQX bonds. Phenyl BINEPINE
5a is an excellent chiral inducer in the hydrogen transfer
reduction of the CQC double bond of a,b-unsaturated acid
derivatives, a reaction which had no other precedent for the
use of chiral monodentate P-donors. In the presence of preformed
and well-defined cationic [Rh(nbd)(5a)2]+X complexes
(X = non-coordinating anion) a range of a,b-unsaturated
acids and esters have been selectively reduced to the corres-
ponding saturated products using formic acid as the hydrogen
donor (Scheme 12).21 While with most substrates the stereo-
selectivities were moderate, an excellent enantioselectivity
(97% ee), definitely higher than that obtained in the reduction
with hydrogen, was attained in the reduction of itaconic acid
35 where 5a outperformed by far all the other monodentate
P-donors screened. Notably, while the corresponding a-methyl
monoester (R1 = H; R2 = Me) was quantitatively reduced
to the saturated derivative of the same configuration with
respectable ee (81%), under the same conditions the dimethyl 31
and the b-methyl monoester (R1 = Me; R2 = H) gave modest
yields of the opposite enantiomer in low ees (13% and 28%,
respectively). This chiral switch stresses the role played in the
catalytic process by the free b-COOH group in the substrate.
This structural feature not only dictates the configuration of
the reduction product, but is as well needed for high conversions
and stereoselectivities to be obtained.
We may speculate that the b-COOH can be involved in the
intramolecular oxidative addition to the metal centre facilitating
the formation of the first Rh(III)-intermediate of the catalytic
cycle. Replacement of the carboxylato ligand at the metal
centre by formate anion provides the conditions for carbon
dioxide extrusion, leading to a Rh(III)dihydride. Such a species
Scheme 9 Asymmetric hydrogenation of dimethyl itaconate 31 in the
presence of BINEPINE ligands 5.
Scheme 10 Asymmetric hydrogenation of N-acyl enamides.
Scheme 11 Hydrogenation of enolcarbamate 34 in the presence ofBINEPINE 5a.
Scheme 12 Transfer hydrogenation of itaconic acid derivatives.
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has been proposed as the intermediate in the highly enantio-
selective asymmetric hydrogenation of itaconic acid by chiral
Rhdiphosphine complexes.35
Ligands 5 in association with chiral pyridinebisimidazoline
ligands have been used in the Ru-catalyzed hydrogen transfer
reduction of ketones yielding enantioselectivities up to 95% ee
(Scheme 13).36 The role of the P-ligand in this reaction,
however, is of scarce significance since the ees obtained in
the presence of5 are equal or sometimes even lower than those
observed when the chiral pyridinebisimidazolines are associated
with triphenylphosphine. In the same reaction stereoselectivities
lower than 30% were obtained using a catalyst prepared in situ
from [Ru(cod)(methallyl)2] and PhBINEPINE 5a.
Hydroboration of CQC bonds. The rhodium-catalyzed hydro-
boration of styrene with catechol borane proceeds smoothly
with ligands 5a, 15, and 17 affording predominately the branched
product (Scheme 14).18 The stereoselectivities are rather modest
with a top value of 42% ee obtained with ligand 17b. A switch of
the product configuration may occur depending on the nature of
the substituents on the benzylic carbons of the phosphepine ring.
This may be indicative of a mismatched combination of the
stereogenic elements present in the ligands.
Hydrogenation of CQO bonds. The asymmetric hydrogenation
of carbonyl groups provides a straightforward route to chiral
alcohols and a number of Ru- or Rh-complexes modified with
chiral bidentate phosphine have been successfully employed in
the reduction of ketones. The first successful application of mono-
dentate phosphines to the catalytic asymmetric hydrogenation
ofb-ketoesters was described in 2004 when it was shown that
BINEPINES 5 in combination with [Ru(cod)(methallyl)2]
complexes give rise in situ to a catalytic system capable of hydro-
genating b-ketoesters 36 in a high stereoselectivity of up to 95%
(Scheme 15) even at fairly high temperatures (100120 1C).37
Interestingly, other monodentate ligands of excellence in hydro-
genation such as phosphites, phosphonites and phosphoramidites
were much less efficient than BINEPINES5 in this reaction.
When the enantioselective hydrogenation of b-ketoesters
was run in a homogeneous solution made up of ionic liquids
(IL) and methanol,38 the reaction rate was higher than in pure
ILs but the enantioselectivity was lower than that observed in
plain methanol.39 These differences have been attributed to the
concurrent formation of ketal and hemiketal that is suppressed
to a significant extent in the mixed system IL/methanol.
Nature and performance of the catalysts heavily depend on
the structure of the cationic part of IL.38 With bis(trifluoro-
methylsulfonyl)-imide anions [NTf2] hydroxyalkylammonium
salts display the best catalytic activity and the induction
time for the generation of the active species is short. In these
systems the enantioselectivities were found to be in the same
range as for pure methanol (9096% ee).
Very recently it has been reported that the asymmetric
hydrogenation of CQO double bonds can be efficiently performed
in the presence of a Cu-catalyst generated in situ from
Cu(OAc)2 and 5.40 A wide array of aryl- and alkyl-substituted
ketones including cyclic and heterocyclic ones were success-
fully hydrogenated with enantioselectivities of up to 89% eeunder optimized reaction conditions (50 bar H2, 1030 1C,
i-PrOH, KO-t-Bu) (Scheme 16). A base is essential for the
formation of an active copper catalyst, presumably a hydridic
species. Although the model reaction is run with a base in
i-PrOH, the transfer hydrogenation pathway is not operating
since without hydrogen no reaction at all is observed.
The same catalytic system is effective also in the hydrosilyl-
ation of ketones where slightly higher enantiomeric excesses
have been reported (next section).
Hydrosilylation of CQO bonds. Although asymmetric
hydrogenation shows excellent enantioselectivities and yields
for a wide range of ketones, high pressure and temperatures
Scheme 13 Transfer hydrogenation of acetophenone in the presence
of Pybim ligand and ligand 5a.
Scheme 14 Asymmetric hydroboration of styrene with catechol
borane.
Scheme 15 Ruthenium-catalyzed hydrogenation of b-ketoesters in
the presence of p-anisylBINEPINE 5c.
Scheme 16 Copper-catalyzed enantioselective hydrogenation of
ketones with BINEPINE 5n.
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and special equipment are often required. Asymmetric hydro-
silylation offers an attractive alternative due to smooth reac-
tion conditions and easy to handle starting materials. Various
copper-based catalysts have been investigated for the asymmetric
hydrosilylation of carbonyl compounds, but there was no report
on the use of copper complexes with chiral monodentate
phosphorus ligands until 2010 when the first copper-catalyzed
asymmetric hydrosilylation of carbonyl compounds using
monodentate BINEPINE ligands 5 has been described(Scheme 17).41
These CuBINEPINE catalysts have been successfully used
in the hydrosilylation of a broad range of carbonyl compounds
including aryl alkyl, cyclic, heterocyclic and aliphatic ketones.
The reaction proceeds under mild conditions without any
base providing, after desilylation with tetrabutylammonium
fluoride (TBAF), the expected carbinols in high yields and
enantioselectivities (up to 96% ee).
Formation of CC bonds
Addressing the stereochemistry in the formation of CC bonds
is frequently the most challenging task to be faced in the synthesisof an organic product of medium complexity. Asymmetric
transition metal catalysis provides one of the most powerful
instruments for driving the reaction towards the desired stereo-
isomer. Due to the huge number of CC bond-forming reactions,
chiral ligands of broad general scope are extremely helpful in
sorting out the best synthetic strategy and the sequence of CC
bonds to be formed.
Hydroformylation
The Rh-catalyzed hydroformylation of styrene was the first
asymmetric catalytic reaction where PhBINEPINE 5a was
screened as a chiral inducer.6 The catalyst, prepared in situ
from [Rh(CO)2(acac)] and 5a, displayed a good activity and
the reaction proceeded at a satisfactory rate even at tempera-
tures as low as 30 1C. Under standard conditions (benzene;
substrate/P/Rh, 500: 4 : 1, CO/H2, 1 : 1, 50 bars) the reaction
was completely chemoselective towards aldehydes and afforded
a 64% conversion in 3 h. The branched isomer accounted for
95% of the aldehydic product, but the enantioselectivity was
very poor, 20% ee.6
Several years later, a systematic screening of the potential of
BINEPINES in Rh-catalyzed asymmetric hydroformylation
of styrene was undertaken and the influence of the structure of
the substituent at the P-centre on catalytic activity and
selectivity of the reaction was investigated in some detail
(Scheme 18).25
This study confirmed that Rh/BINEPINE complexes
are quite active catalysts for this reaction and that they
show a pronounced preference towards the branched isomer
(8596%). The enantiomeric purity of 2-phenylpropanal improved
substantially from the first report (48% ee obtained with the
phosphepine 5r) but was still far away from an acceptable
threshold so as to make the process a viable tool for the
enantioselective synthesis of arylpropionic acids.25
Allylic alkylation of 1,3-diphenylallyl esters
The asymmetric allylic alkylation of 1,3-diphenylallyl esters by
dimethylmalonate anions has been performed in the presence
of palladium/BINEPINE complexes prepared in situ from
[Pd(allyl)Cl]2 and the appropriate ligand (Scheme 19).42
The outcome of the reaction is strongly affected by the solvent,
the base, the ligand and the temperature. In this reaction aryl
substituted BINEPINES are by far better chiral inducers than
the P-alkyl derivatives which leads to low stereoselectivities.
By proper choice of the reaction conditions and of the substi-
tuent on the phosphorus, stereoselectivities up to 92% have
been achieved in the alkylation of 1,3-diphenylprop-2-enyl-
1-acetate using the p-anisyl substituted ligand 5d, while phenyl
BINEPINE 5a ranked the second in efficiency (86% ee)
among the ligands tested. Similar enantioselectivities have
been recorded with 1,3-diphenylprop-2-enyl-1-carbonate as
the substrate. These results are among the best ones recorded
in this reaction with a monodentate P-donor.
Allylation of aldehydes by p-allyl Pd-complexes
(umpolung of reactivity)
The first ever documented example of catalytic asymmetric
aldehyde allylation by umpolung of a p-allyl palladium complex
Scheme 17 Copper-catalyzed enantioselective hydrosilylation of
ketones using PhBINEPINE 5a.
Scheme 18 Rhodium-catalyzed asymmetric hydroformylation of
styrene using ligands 5a and 5r.
Scheme 19 Allylic alkylation of 1,3-diphenylallyl esters catalyzed by
PdBINEPINE complexes.
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was accomplished in 2004 when it was demonstrated that upon
addition of an excess of diethylzinc, an electrophilic Pdallyl
complex undergoes transmetallation and is turned into
a nucleophilic metalallyl species, supposedly an allyl zinc
reagent, which can then deliver the allyl fragment to a
carbonyl electrophile.43 Preliminary evidence suggests that
transmetallation involves the transfer of an ethyl group from
zinc to palladium and that elimination of diethylpalladium
eventually occurs. The structure of the nucleophilic reagent
and its binding to the chiral ligand, however, have not been
determined. The net result is the addition of an allyl fragment
to the aldehyde group with formation of a homoallylic alcohol
(Scheme 20).
Remarkably chiral bidentate phosphines are not well suited
ligands for this catalysis as they fail to produce optically
active products. When the reaction of benzaldehyde with
cinnamyl acetate is performed in the presence of a catalytic
amount of [Pd(allyl)Cl]2 and 5a at 30 1C, the allylation
reaction is completely diastereoselective and affords only the
anti homoallylic alcohol in 77% yield and in 70% enantio-
selectivity. Even if this value can be hardly considered in
the range of excellence, this ee was by far the best one scored
in an extensive screening where some twenty different chiral
monodentate phosphorus donors were compared as chiral
inducers.
Addition of organoaluminium reagents to aldehydes
The 1,2-addition of AlMe3 or its air-stable analogue DABCO
(AlMe3) to aldehydes proceeds with high stereoselectivity in
the presence of Ni-complexes containing chiral P-donors. In
this catalysis monodentate phosphines enable the enantio-
selective preparation of secondary alcohols in high ee, whereas
chelating diphosphines afford very low enantioselectivities.
44
The complex prepared in situ by addition of a suitable
amount of phosphoramidite 1 to Ni(acaca)2 is the catalyst of
choice for this transformation: on a range of aromatic and a
few aliphatic aldehydes it enables high turnover numbers and
frequencies even at 25 1C with stereoselections in between
85% and 94%. Cinnamaldehyde, however, turned out to be a
poor substrate for the phosphoramidite complex, possibly due
to competition in CQC vs. CQO p-bonding to the metal
centre. In this case the BINEPINE ligand 5a was by far more
efficient, affording the relevant methyl carbinol in a gratifying80% ee (Scheme 21).
SuzukiMiyaura coupling of aryl boronic acids
PhBINEPINE 5a and its 3-mono- and 3,5-disubstituted
congeners (Sax,S,RP)-15b and (Sax,S,S)-17b respectively, have
been tested in the palladium-mediated SuzukiMiyaura coupling
of 1-iodo-2-methoxynaphthalene with o-tolyl boronic acid.18 A
good yield of the expected biaryl derivative (76%) was obtained
with ligand 17b (Scheme 22), but the stereoselectivities were
poor, lower than 20% ee whichever the ligand employed.
Conjugate addition
The Rh-complex [RhCl(Sax,S,Sp)-15f]2 containing the phosphepine
alkene ligand 15fhas proved to be an efficient chiral ligand for
the Rh-promoted conjugate addition of aryl boronic acids to
cyclohex-2-enone (Scheme 23).45
A range of aryl boronic acids, with either electron-rich
or electron-poor aryl substituents, were used and in all cases
the reactions proceeded in fair to good yields (6478%) and
excellent enantioselectivities (9298% ee). These results compare
favourably with the previous ones which have been obtained
with different chiral diolefin or phosphanealkene ligands. The
high efficiency displayed by the catalytic system supports the
view that, despite the comparably high degree of conformational
freedom of the ligand, the catalytic active species is quite robust
and endowed with an efficient chiral bias.
The conjugate addition to open chain a,b-unsaturated
ketones or to nitroolefins can be performed under completely
different conditions using copperphosphepine complexes as
catalysts and alkylzinc as a nucleophile.46a This reaction gives
good yields, but the enantioselectivities are not exceptional
and by far lower than those obtained with the analog
phosphoramidite-based catalysts.46b The best ee was obtained
with 5a as the ligand and was not higher than 74% (Scheme 24).
Scheme 20 Enantioselective catalytic allylation of aldehydes by
umpolung ofp-allyl palladium complexes.
Scheme 21 Ni-catalyzed 1,2-addition of AlMe3 to cinnamaldehyde.
Scheme 22 SuzukiMiyaura coupling catalyzed by palladiumBINE-
PINE complexes.
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Platinum catalyzed cycloisomerization and tandem
cycloisomerizationoxyaddition or hydroarylation
of 1,6-enynes
Noble metal complexes are able to promote the cycloisomeri-
zation of 1,6-enynes via a sequential multi-step reaction path
proceeding through a cyclopropylcarbene intermediate that, in
suitable conditions, may terminate in a bicyclic derivative
featuring a cyclopropane ring (Scheme 25). While in apolar
solvents and in the absence of nucleophiles, this species is the
terminal product, when the reaction is run in the presence of a
nucleophilic species, either a reactant or a solvent, ring
opening of the cyclopropane and reorganization of the
multiple bonds take place in such a way as to lead to the
incorporation of a unit of the nucleophile in the final product
(Scheme 25).
If the metal catalyst promoting this transformation is
capable of driving the reaction cascade with high selectivity
and in an enantioselective manner, the synthetic utility of such
atom-economic sequence of events is immediately apparent for
the preparation of cyclic compounds of significant molecular
complexity. Platinum complexes with P-donors are quite
active and chemoselective catalysts for this transformation
both in the presence and in the absence of nucleophiles. This
gives the choice to terminate the transformation at the stage of
the bicyclocyclopropane derivative or to push it further until
incorporation of the nucleophile occurs.
In a first paper on this topic, PhBINEPINE 5a was shown
to outperform by far any other mono- or bidentate chiral
inducer of the pool of P-donors screened for this process in the
Pt-catalyzed tandem cycloisomerizationoxyaddition, providing
the corresponding oxy-cycloadduct in high chemical yield
and in up to 85% ee (Scheme 26: i).47 In this reaction the
BINEPINEPt catalyst shows a remarkable substrate tolerance
Scheme 23 Rh-catalyzed conjugate addition of aryl boronic acids to
cyclohex-2-enone.
Scheme 24 Cu-catalyzed conjugate addition of diethylzinc totrans-chalcone.
Scheme 25 Platinum catalyzed cycloisomerization of 1,6-enynes: reaction
path.
Scheme 26 Platinum catalyzed cycloisomerization and tandem-
cycloisomerization of 1,6-enynes.
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and a range of diverse functionalities can be admitted in the
starting 1,6-enynes without compromising the outcome of the
reaction to a major extent. The specificity of PhBINEPINE5a
in this process is unique and, more important, is not limited to
this single case. More recent work has shown that very high
enantioselectivities, up to 96% ee, can be obtained when the
cycloisomerization is performed in the presence of electron rich
arenes or heterocycles such as indoles. In this case the final
product arises from a tandem cycloadditonhydroarylation
involving an electrophilic aromatic substitution as the terminal
step of the sequence (Scheme 26: ii).48 In this study evidence has
been provided that the Pt-catalyst might contain three P-donors
in the coordination sphere of the metal and that in principle one
equivalent of BINEPINE might suffice to enable high stereo-
selectivities to be obtained. This assumption is corroborated
by a report by Marinetti et al. who have performed the
Pt-catalyzed cycloisomerization of 1,6-enynes in apolar solvent
(toluene) using a preformed cyclometalated carbenePt
complex 25 containing one unit of PhBINEPINE 5a as
the sole chiral fragment.23 Under these conditions the reaction
stops at the stage of the bicyclic cyclopropane derivative
(Scheme 26: iii) that can be isolated in good chemical yields
and excellent enantioselectivity, up to 97% (absolute configuration
was not assigned).
Asymmetric platinum-catalyzed BayerVilliger oxidation
of cycloalkanones: regiodivergent kinetic resolution
of cyclobutanones
The ability of platinum complexes with chiral diphosphines to
catalyze the enantioselective BayerVilliger oxidation of ketones
with moderate to high stereoselectivities is well documented in
the literature.49 Monodentate phosphines are much less efficient
chiral inducers than the bidentate chelating counterparts whenused in the BV oxidation of achiral ketones. With tert-butyl-
cyclohexanone, for instance, the ee obtained with the preformed
bis-aquo cationic Pt-complex containing PhBINEPINE5a is as
low as 16% to be compared with 92% ee of the relevant BINAP
complex (Scheme 27).22
In the BV oxidation of unsymmetrical ketones two parallel
reaction paths are available for the substrate which lead either to
the normal or to the abnormal lactone (NL and AL,
respectively). In the presence of Pt-chiral phosphine catalysts,
chiral racemic substrates are expected to undergo kinetic resolu-
tion and rate differentiation may be convergent or divergent,
meaning that the same enantiomer of the substrate might react at
a faster rate in both the competitive reactions leading to NL andto AL (regioconvergent process) or vice versa (regiodivergent
process). In the case of Pt/5a complexes, the BV oxidation of two
racemic cyclobutanones does proceed through a regiodivergent
process, thus enabling very high stereoselectivities for both the
lactones to be attained. Notably, in this transformation mono-
dentate P-donors are better suited than bidentate derivatives and
PhBINEPINE5a is better than phosphoramidite 1 (Scheme 28).
Organocatalysis
The use of monophosphines as chiral organocatalysts has
become more and more frequent in recent years and the
subject has been recently reviewed.50
Scheme 27 Pt-catalyzed BayerVilliger oxidation of achiral ketones.
Scheme 28 Regiodivergent kinetic resolution in BayerVilliger oxidation of chiral racemic cyclobutanones catalyzed by Pt/PhBINEPINE
complexes.
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Cycloaddition reactions of activated allenes and alkynes
[3+2] cycloaddition. Phosphines are able to catalyze the
[3+2] cycloaddition of activated alkynes and allenes to suitable
dipolarophiles such as b-substituted a,b-unsaturated enones
and N-tosylimines. The reaction involves addition of the
phosphorus nucleophile to the central carbon atom of the
allene moiety or to the b-carbon of the alkyne as the key step,
followed by reaction of the resulting zwitterionic intermediate I(Scheme 29) with an electron-deficient unsaturated substrate.
The products of the annulation are, respectively, cyclo-
pentenes and 3-pyrrolines which, due to the presence of the
double bond, are prone to further, often highly stereoselective,
derivatization. Two regioisomers A and B are possible, which
arise from a Michael-type addition of the phosphine-adduct I
to the electrophilic partner through its g or a carbon respectively
(Scheme 29).
Synthesis of carbocycles. t-BuBINEPINE 5b catalyzes the
asymmetric [3+2] cycloaddition of ethyl-2,3-butadienoate
with a wide array ofb-substituted a,b-unsaturated enones to
give substituted cyclopentenes (Scheme 30).
51
These products are generated in good ee (7590%) from both
electron-rich and electron-poor chalcone derivatives. In line
with the known reactivity of allenes towards nucleophiles, with
electron rich-substrates (entries 3 and 5, Table 3) the reac-
tion is less efficient and two equivalents of allenes instead of
1.2 are required for the reaction to proceed. The prevailing
regioisomer A shows the opposite regioselectivity compared to
b-unsubstituted a,b-unsaturated enones for which the
prevailing regioisomer is B.51 This protocol can be applied to
trisubstituted olefins thus generating adjacent quaternary and
tertiary stereocentres.
t-BuBINEPINE 5b is as well efficient when 2-aryl-1,1-dicyanoethylenes are used as substrates.52 The corresponding
cyclopentenes are obtained as single regioisomers in high yield
and with over 70% enantioselectivity in most cases (Scheme 31).
Best substrates are olefins with heteroaromatic substituents: with-
in this class, 95% ee was scored when 1,1-dicyano-2(2-N-methyl-
indolyl)ethene was reacted with ethyl-2,3-butadienoate at 0 1C.52
Allenylphosphonates represent another class of substrates
suitable for the construction of carbocycles through t-Bu
BINEPINE5b promoted [3+2] cycloadditon witha,b-unsaturated
esters (Scheme 32).53 Even if the lower reactivity of allenyl-
phosphonates compared to allenic esters requires the application
of more drastic conditions, the expected products are obtained
with very good selectivity and in moderate yield.
53
Synthesis of heterocycles. When arylimines bearing electron-
withdrawing N-substituents are used in place of activated
olefines, the phosphine promoted [3+2] cycloaddition gives
access to functionalized 3-pyrrolines (Scheme 33). In this
process Ph and t-BuBINEPINES5a and 5b were by far more
effective in terms of conversion rates and enantioselectivities
than any other mono- or bidentate chiral inducer of the pool
of P-donors screened.54
The preferred regioisomer arises from electrophilic addition
of the imine to the a-position of the zwitterionic phosphonium
intermediate followed by cyclisation.55 By proper combination
Scheme 29 Reaction pathway of [3+2] cycloaddition promoted by
phosphine catalysts.
Scheme 30 t-BuBINEPINE 5b catalyzed asymmetric [3+2] annula-
tion of ethyl-2,3-butadienoate with b-substituted a,b-unsaturated enones.
Table 3 Selected results obtained in the t-Bu-BINEPINE 5b catalyzedasymmetric [3+2] annulation of ethyl-2,3-butadienoate with b-substituteda,b-unsaturated enones (see Scheme 30)
Entry R R0 Yielda (%) eeb (%) A : Bc
1 C6H5 C6H5 64 88 13 : 12 C6H5 4-ClC6H5 76 82 7 : 13 C6H5 4-OMeC6H5 54 88 42 0 :14 C6H5 2-Thienyl 74 90 6 : 1
5 C5H11 C6H5 39 75 42 0 :1a Yield of isolated A and B. b Enantiomeric excess of A. c Absolute
configuration of B not assigned.
Scheme 31 Asymmetric [3+2] cycloaddition of allenes with dicyano-
ethylenes (absolute configuration of product not assigned).
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of allenic ester, aryl-substituted tosylimines and BINEPINE,
3-pyrrolines can be obtained with ee up to 86%. The best ees
are obtained when the aryl substituent on the imine is either a
phenyl or an electron-rich aryl. High levels of asymmetric
induction (7392% ee), but at the expenses of reactivity, are
obtained by applying t-BuBINEPINE nucleophilic catalyst
5b to the cycloaddition of N-diphenylphosphino (DPP)
arylimines and 2-butynoates. The DPP protecting group offers
the advantage of being more easily removed than the Ts group
from the reaction product.56
3-Pyrrolines can be prepared also from allenylphosphonates
under t-BuBINEPINE catalysis 5b but with modest results
(2545% yield, 5768% ee).53
Synthesis of spirocyclic compounds. Electron-poor allenes
participate in the phosphine-catalyzed [3+2] cycloaddition
with 4-substituted 2,6-bis(benzylidene)cycloesanone 39 to
afford spirocyclic compounds. Upon reaction with an alkyl
allenoate in the presence of either (S,S)-FerroPHANE 41 or
t-BuBINEPINE (S)-5b, the substrate undergoes desymmetri-
zation providing the product 40 via a regio-, diastereo- and
enantioselective process (Scheme 34).57
The product 40 results from the formation of a new CC
bond at the b-olefinic carbon of the substrate and is obtained
as a mixture of two diastereomers. The stereoselectivity obtained
with BINEPINE (S)-5b compares well with those obtained with
FerroPHANE. The latter one, however, is a more efficient
catalyst and promotes higher yields (compare entries 3 and 4,
Table 4) probably in consequence of a higher electron-donating
ability and nucleophilicity.
As evinced from the X-ray structure, the major diastereomer
of 40a comes from the addition of the allenoate syn to the
R2 substituent. Likely, the latter group rests in the equatorial
position of the most stable conformer of the substrate and the
syn approach of the nucleophile minimizes steric interactions
with the axial H-substituent. This might explain the improved
enantioselectivities observed with FerroPHANE when increasing
the steric bulk of the R2 group from Me-, to i-Pr to t-Bu.
The phosphine-mediated [3+2] cycloaddition of alkyl
2,3-butadienoate to 3-alkylideneindolin-2-ones 42 is a valuable
procedure for the highly enantioselective synthesis of 3-spiro-
cyclopentane-2-oxindoles 43 (Scheme 35). This scaffold is
found in several natural alkaloid derivatives and bioactive
compounds.58
The stereochemistry of the quaternary carbon at position
3 is the main synthetic challenge in this reaction and the
Scheme 32 [3+2] cycloaddition of allenylphosphonates with
a,b-unsaturated esters.
Scheme 33 Asymmetric [3+2] cycloaddition of N-tosyl arylimines
with unsaturated esters.
Scheme 34 Synthesis of spirocyclic compound 40 via asymmetric
[3+2] cycloaddition of enones 39.
Table 4 Results obtained in the synthesis of spirocyclic compound 40via asymmetric [3+2] cycloaddition of enones 39 (see Scheme 34)
Entry Cat. Product R1 R2 Yield (%) dr eea (%)
1 (S)-5 b 40 a Et Me 75 85 : 15 822 (S)-5 b 40 b t-Bu Me 20 80 : 20 86
3 (S)-5 b 40 c Et t-Bu 50 495 : 5 924 (S,S)-4 1 40 c Et t-Bu 98 495 : 5 92
a The two catalysts display the same sense of chiral induction.
Scheme 35 Synthesis of spirocyclic compounds 43 via asymmetric
[3+2] cycloaddition of 3-alkylideneindolin-2-ones 42.
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BINEPINE (S)-5b stood out as the most effective catalyst
among all the other chiral P-donors screened in this task. The
low yields obtained with some of the substrates (entries 3, 8, 10,
Table 5) could be improved by the use of FerroPHANE
although at the expense of the enantioselectivity. From the
X-ray absolute configuration of product 43b it is established
that the substrate double bond retains the E-geometry during
the cycloaddition.
[4+2] cycloadditions
Heterocycles. BINEPINE 5b is an effective nucleophilic
catalyst for the synthesis of functionalized piperidine derivatives
through the Kwon [4+2] cycloaddition59 of imines with 2-allyl
substituted 2,3-butadienoate (Scheme 36).60 A range of aryl
imines with either electron-rich (Table 6, entry 2), electron-
poor (Table 6, entries 3 and 4) or ortho-substituted aromatic
groups have been successfully reacted (Table 6, entry 4).
Heteroaryl imines are also suitable substrates for this reac-
tion (Table 6, entries 6 and 7). The desired heterocycles
are obtained in good yield with excellent enantio- and
diastereoselectivity.
[2+2] cycloadditions. t-BuBINEPINE5b has been tested in
the catalytic asymmetric cycloaddition of phenyl ethyl
ketene to dimethyl azodicarboxylate and nitrosobenzene to
generate aza-b-lactams61 and 1,2-oxazetidin-3-ones62 respectively
(Scheme 37). The BINEPINE ligand is able to catalyze this
reaction, but in both cases the product is almost racemic. The
catalyst of choice for this process turned out to be a planar-chiral
ferrocene-based 4-dimethylaminopyridine derivative.
Additions of nucleophiles to the c-position of activated
alkynes and allenes. Phosphines can catalyze the addition of
some carbon, nitrogen and oxygen nucleophiles to the g-position
of 2-butynoates and 2,3-butadienoates.63 On suitable substrates
the formation of the new bond may generate a new stereogenic
centre (Scheme 38). The synthetic utility of these processes may
be impaired by the competitive phosphine-catalyzed isomeri-
zation of the substrates to the corresponding dienones.
C-Nucleophiles. Formation of CC bonds has been achieved
using nitromethane and 1,3-dicarbonyl compounds as C-based
nucleophiles.
Table 5 Selected results obtained in the synthesis of spirocycliccompounds 43 via asymmetric [3+2] cycloaddition of 3-alkylideneindolin-2-ones 42: variations of the olefin substituent R1 (see Scheme 35)
Entry Product R1 Yield (%) 43/44 43 ee (%)
1 43a C6H5 95 49 5 :5 4992 43b 1-naphthyl 98 49 5 :5 499a
3 43c 4-C6H4C6H4 20 (61) 90 : 10 99 (92)4 43d 4-CF3C6H4 62 85 : 15 99
5 43e 4-ClC6H4 80 92 : 8 4996 43f 3-BrC6H4 82 85 : 15 4997 43g 4-MeC6H4 99 88 : 12 4998 43h 2-Furyl 25 (80) 76 : 24 97 (90)9 43i 2-Quinolyl 75 90 : 10 9710 43l CRCC5H11 38 (56) 74 : 26 97 (86)
Values within parentheses refer to the use of FerroPHANE 41 under
otherwise identical reaction conditions.a (1S,5R) configuration according
to X-ray data.
Table 6 Selected results obtained in the t-Bu-BINEPINE 5bpromoted Kwon [4+2] annulation of imines with 2-allyl substituted2,3-butadienoate: scope with respect to the imines (see Scheme 36)
Entry Ar Yielda (%) cis : trans eeb (%)
1 C6H5 93 91 : 9 982 3-MeC6H4 98 93 : 7 983 4-ClC6H4 99 91 : 9 964 2-(NO2)C6H4 98 96 : 4 685 2-Naphthyl 96 93 : 7 996 2-Furyl 98 87 : 13 977 3-Pyridyl 76 91 : 9 97
a Isolated yields. b The ee-value is for the cis diastereomer.
Scheme 36 t-BuBINEPINE 5b promoted Kwon [4+2] annulation
of imines with 2-allyl substituted 2,3-butadienoate.
Scheme 37 Phosphepine catalyzed cycloaddition of phenyl ethyl
ketene to dimethyl azodicarboxylate and nitrosobenzene.
Scheme 38 BINEPINE-catalyzed addition of nucleophiles to theg-position of activated alkynes and allenes.
Scheme 39 Asymmetric g-addition of a nitromethane to allenes catalyzed
by chiral BINEPINES.
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3760 Chem. Soc. Rev., 2011, 40, 37443763 This journal is c The Royal Society of Chemistry 2011
In the addition of nitromethane to a variety of racemic
electron-poor allenes (Scheme 39), the amine-substituted
BINEPINE 8 afforded the best results in terms of enantio-
selectivity among several bis- and monophosphines tested as
catalysts.64 The reactions proceed with good to excellent yields
and stereoselectivities (7397%) under mild conditions. Several
functional groups in the R substituent of the allenamides are
tolerated and in all cases only the E isomer of the product
is observed. Since no kinetic resolution of the starting racemic
allene has been noticed in the course of the reaction, the
stereochemical bias is determined by enantioface selection.
PhBINEPINE5a turned out to be the catalyst of choice for the
asymmetric g-addition of malonate esters to g-substituted 2,3-
allenoate (Scheme 40) and 2,3-allenamides (Weinreb allenamides)
where very high yields (6598%) and enantioselectivities (8595%)
have been achieved.65
The formation of the CC bond is compatible with the
presence of diverse functional groups in the substrate such as
alkynes, halides, ethers, acetals, esters and alkenes (Table 7).
At variance with other phosphine catalyzed enantioselective
g-addition reactions, in this process kinetic resolution of the
allene is observed. From mechanistic investigations a reaction
path where addition of the phosphine catalyst to the substrate
is the turnover-limiting step can be proposed (Scheme 41).
O-Nucleophiles. Chiral tetrahydrofurans and tetrahydropyrans
are accessible from a variety of substrates possessing a hydroxy-
2-alkynoate motif through phosphine-catalyzed intramolecular
g-addition (Scheme 42).66
Substituents a, b or g to the hydroxygroup are tolerated in the reaction thus allowing for structural
diversity. In this transformation, t-Bu and PhBINEPINES
(S)-5b and (S)-5a are ranked the best effective ligands immediately
after the spirophosphocin (S)-45 among a range of mono- and
bisphosphines.
BINEPINE-promoted intramolecular Michael addition
Monophosphines have been exploited by Fu et al. as nucleo-
philic catalysts in the synthesis of diquinanes 50 from properly
functionalized alicyclic substrates through a double-cyclization
process (Scheme 43).67
Following a reactivity manifold discovered by Tomita,68
the synthesis is triggered by the conjugated addition of the
phosphine to the ynone subunit of the substrate to give inter-
mediate 46 (Scheme 43), which by cross-tautomerization turns
into the zwitterionic enolate 47. The latter undergoes intra-
molecular Michael addition to the unsaturated ester subunit to
generate the first ring as in 48. A second intramolecular
addition affords intermediate 49 and eventually, after catalyst
release, the desired diquinane 50. In optimal conditions and
using PBu3 as nucleophile, the products are obtained with
very high diastereoselectivity (dr 4 20: 1). By applying
t-BuBINEPINE 5b, a moderate but encouraging enantio-
selectivity, 60% ee, could be achieved.67 This is the sole
Scheme 40 PhBINEPINE 5a promoted asymmetric g-addition of
malonate esters to g-substituted 2,3-allenoate.
Table 7 Selected results obtained in the Ph-BINEPINE 5a promotedasymmetric g-addition of malonate esters to g-substituted 2,3-allenoate(see Scheme 40)
Entry R1 Yielda (%) ee (%)
1 Me 94 94
2 88 92
3 (CH2)3Cl 91 934 (CH2)4TLPS 78 875 (CH2)4OBn 78 90
6 71 94
7 (CH2)3CO2Me 77 94
8 71 86
a Yield of purified products. Only the E product is observed.
Scheme 41 Possible mechanism for the phosphine catalyzed asymmetric
g-addition of malonate ester to an activated allene.
Scheme 42 Asymmetric g-addition of an oxygenated nucleophile
catalyzed by chiral monophosphines.
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example of the enantioselective version of this reaction which
provides for the elaboration of fused-ring systems featuring
three vicinal stereocentres and one double bond.
Desymmetrization ofmeso-diols. PhBINEPINE5a has been
tested as organocatalyst in the enantiotoposelective mono-
acylation of cis-1,2-cyclohexane-diol and meso-hydrobenzoin
(Scheme 44).
In this transformation BINEPINE5a was a poor inducer and
much less efficient than (2S,5S)-dimethyl-1-phenyl-phospholane
(S,S)-51, which in this reaction gave the best conversion (up to
84%) and selectivity (up to 81% ee), outperforming the chiral
bidentate phosphines used in the screening test.69
Asymmetric phase-transfer catalysts. Quaternary tetraalkyl-
phosphonium salts 52 and 53, prepared by alkylation of the
corresponding phosphepines with butyl bromide, have been
used as phase transfer catalysts to mediate the asymmetricamination of cyclic b-keto esters and b-diketones with di-tert-
butyl azodicarboxylate (Scheme 45). Under optimized conditions,
the expected products have been obtained in quantitative yields
and ee ranging from 73 to 95%.70
Chiral auxiliary. The BINEPINE 5t has been exploited as
the chiral auxiliary to assist the generation of a stereogenic
arsenic centre in the chiral tertiary arsine 54 (Scheme 46).15
The key step in this preparation is the irreversible nucleophilic
addition of n-butyllithium to the corresponding diastereo-
meric phosphepine-stabilized methylphenylarsenium hexafluoro-
phosphate salts (Scheme 46). When the reaction is carried out
Scheme 43 Enantioselective phosphepine-promoted synthesis of
diquinanes 50.
Scheme 44 Enantiotopo-differentiating acylation ofmeso-diolspromoted
by monodentate phosphines.
Scheme 45 Asymmetric phase transfer catalyzed amination of
b-ketoesters.
Scheme 46 BINEPINE-assisted enantioselective synthesis of
As-stereogenic trisubstituted arsine.
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3762 Chem. Soc. Rev., 2011, 40, 37443763 This journal is c The Royal Society of Chemistry 2011
at 95 1C in dichloromethane, the chiral arsine 54 is obtained
with 70% enantioselectivity. The 2-methoxymethyl substituent
in 5t is crucial for a good selectivity to be achieved as with
PhBINEPINE 5a the diastereoselectivity in the complex
formation is only 16%.
Conclusions and outlook
More than fifteen years have passed since the first preparation
of PhBINEPINE 5a was reported in the literature. From that
first report, this fairly simple P-ligand has tremendously
expanded its fields of application which at present comprise
a wide variety of asymmetric reactions covering metal catalyzed,
organocatalyzed, phase transfer catalyzed and stoichiometric
asymmetric processes. The versatility displayed by the parent
ligand is further supported by the size and the diversity of the
library of BINEPINE derivatives built up in recent times and
that is still growing. The number of different asymmetric
processes where BINEPINES have demonstrated their
stereorecognitive efficiency is pretty wide and for this reason
BINEPINE can be considered a multipurpose chiral ligand.
Based on previous results, specific fields of transition metal
catalyzed reactions where the use of BINEPINES can be
recommended are the Rh-catalyzed hydrogenation and transfer
hydrogenation of CC double bond; the Pt-catalyzed cyclo-
addition of 1,6-enynes and the BayerVilliger oxidation of
strained ketones; the Pd-catalyzed allylation of aldehydes by
umpolung of reactivity. Due to the peculiar electronic properties
of these ligands which are characterized by a fairly high electron
density at the P-donor in these reactions BINEPINES are
expected to perform at the highest level of efficiency.
The second area where BINEPINES can be recommended
for their versatility and their efficiency in chiral recognition is
in organocatalysis. Their use as chiral catalysts has led to veryhigh yields/stereoselectivities in several cases, particularly in a
variety of [3+2] and [4+2] cycloaddition reactions, both in
the intra- and inter-molecular fashion. There is little doubt
that these good performances are strictly related to the basicity
of the P-centre that substantially increases the nucleophilicity
of BINEPINES as compared to other monodentate P-donors
derived from binaphthol 1, 2 and 3. We can reasonably expect
that good results will be achieved by the application of these
chiral ligands in similar reactions.
Acknowledgements
EA acknowledges financial support from the Regione Autonomadella Sardegna, L.R. 7 Agosto 2007, n. 7.
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