An efficient and highly stereoselective synthesis of new P-chiral 1,5-diphosphanylferrocene ligands and their use in enantioselective hydrogenation

Article abstract of DOI:10.1039/b601952h

An efficient and highly stereoselective synthesis of P-chiral 1,5-diphosphanylferrocene ligands has been developed, and the introduction of P-chirality in ferrocene-based phosphine ligands enhances the enantioselective discrimination produced by the corre

Full text of DOI:10.1039/b601952h

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An efficient and highly stereoselective synthesis of new P-chiral
1,5-diphosphanylferrocene ligands and their use in enantioselective
hydrogenation{
Weiping Chen,{* Stanley M. Roberts, John Whittall and Alexander Steiner
Received (in Cambridge, UK) 9th February 2006, Accepted 12th May 2006
First published as an Advance Article on the web 6th June 2006
DOI: 10.1039/b601952h
We focused our interest on the new range of phosphine ligands,
incorporating several elements of the Taniaphos skeleton but also
incorporating a stereogenic centre at phosphorus. In theory,
P-chiral phosphines are highly likely to provide a superior class of
ligands for asymmetric catalysis by virtue of bringing the chiral
environment into the closest possible proximity to the catalytic
centre. Thus, there are some examples of phosphines wherein the
configuration(s) of the stereogenic centre(s) at phosphorus (where
different steric and electronic properties are readily tunable) is (are)
critical for the attainment of high selectivity in asymmetric
catalysis.4 However, there is only one documented example of
P-chiral phosphines featuring ferrocenyl groups incorporating
carbon-centred stereogenicity,4(ii) despite their potential utility as
ligands in asymmetric catalysts, doubtless due to the previous
difficulties in their synthesis. Herein, we are pleased to describe the
efficient and highly stereoselective synthesis of novel P-chiral
ferrocene-based 1,5-diphosphines 2 (PingFer), and their unprece-
dented reactivity and selectivity in a portfolio of important
asymmetric transformations.
An efficient and highly stereoselective synthesis of P-chiral 1,5-
diphosphanylferrocene ligands has been developed, and the
introduction of P-chirality in ferrocene-based phosphine
ligands enhances the enantioselective discrimination produced
by the corresponding catalyst when matching of the planar
chirality, the chirality at carbon and the chirality at phosphorus
occurs.
Asymmetric catalysis is a powerful tool for producing enantio-
merically enriched compounds. In this area, the design and
synthesis of chiral phosphine ligands has played a significant role
in the development of efficient transition metal-catalysed reac-
tions.1 However, the search for more practical and efficient ligands
in terms of ease of preparation, air-stability, high enantioselectivity
and activity remains an important goal in asymmetric catalysis.
Since careful matching of the chiral ligand, the reaction type, the
catalyst, and the substrate is usually necessary, there is a demand
for highly efficient, flexible and modular syntheses of phosphines
to allow convenient modification of steric and electronic proper-
ties, and hence rapid optimisation of ligand–substrate matches.
Ferrocene-based phosphine ligands are well documented.2
Recently Knochel and co-workers reported a new type of
ferrocene-based 1,5-diphosphine 1a called Taniaphos,3 which gave
excellent enantioselectivities for various metal-catalysed asym-
metric reactions. The nature of the substituent at the a-position in
Taniaphos as well its absolute configuration proved to be very
important for achieving high degrees of stereocontrol. The second
generation of Taniaphos (type 1b), bearing a methoxy group with
the (aS)-configuration, proved to be superior for all of the
reactions under study.
UnlikethesynthesisoffirstgenerationTaniaphos1a, therouteto
second generation Taniaphos 1b is non-stereoselective. The key
step, namely the reaction of lithiated ferrocenyl sulfoxide with
2-diphenylphosphanylbenzaldehyde, furnished a mixture of two
diastereomeric alcohols in the ratio ca. 5:4, which were separated
only by tedious column chromatography.3c Key to our long-term
goal,intheinitialstagesofourworkwedevelopedtwonew,efficient
and highly stereoselective routes to Taniaphos 1b, generating
the required aS stereochemistry in a highly selective manner.
In the first route (Scheme 1A), reaction of (S)-a-(diphenylpho-
sphino)ferrocenecarboxaldehyde 45 with the Grignard reagent 3,
prepared from the readily available (2-bromophenyl)diphenylpho-
sphine,6 gave the product in 96% yield with a ratio of 9:1 for the
aS/aR diastereomers. Recrystallisation from hexane gave the pure
diastereomer (SFc,aS)-5 in 76% yield. Standard methylation of
(SFc,aS)-5 afforded 1b in 91% yield. The physical properties of the
sample of 1b prepared in this way were identical with those
reported previously.
In the second route (Scheme 1B), reaction of (S)-2-bromoferro-
cenecarboxaldehyde 65 with the Grignard reagent 3 gave the
desired (SFc,aS)-7 in 98% yield as a single diastereomer.
Methylation of alcohol (SFc,aS)-7 furnished the ether (SFc,aS)-8,
whereafter exchange of the bromine atom for the diphenylpho-
sphino moiety proceeded without incident to afford Taniaphos 1b
in 92% overall yield.
StylaCats Ltd. Chemistry Department, University of Liverpool,
Liverpool, UK L69 7ZD
{ Electronic supplementary information (ESI) available: Experimental
procedures and X-ray crystal structure data for compounds
(29S,49S,SFc,RP)-10a and (29S,49S,SFc,RP)-10b. See DOI: 10.1039/
b601952h
{ Present address: Solvias AG, WRO-1055.6.68B, 4002 Basel, Switzerland.
Fax: +41 61 68 66 311; Tel: +41 61 68 66 433; E-mail: weiping.chen@
solvias.com
The difference in the diastereoselectivity for the addition of
Grignard reagent 3 to (S)-2-bromoferrocenecarboxaldehyde 6 and
2916 | Chem. Commun., 2006, 2916–2918
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Scheme 2 Reagents and conditions: (a) t-BuLi, THF, 278 uC; (b)
PhPCl2, 278 uC–rt; (c) ArLi, 278 uC–rt.
Scheme 3
ring, quaternary phosphonium salt intermediate is formed and
then the organometallic compound ArM attacks from the front (as
portrayed) to give the products observed.
Scheme 1 Reagents and conditions: (a) THF, 278 uC–rt, 76% (A); (b)
30% KH, MeI, THF, 0 uC, 91% (A); (c) t-BuLi, THF, 278 uC; (d) Ph2PCl,
278 uC–rt, 94% (B).
Efforts to make suitable crystals of (SFc,aS,SP)-2a or
(SFc,aS,SP)-2b or (SFc,aS,RP)-2b for X-ray diffraction analysis
failed. However, the absolute configuration of (SFc,aS,RP)-2a was
confirmed by employing another synthetic route (Scheme 4). The
ferrocenyl dioxane derivative (2S,4S)-95 was lithiated with t-BuLi
(278 uC, 10 min, then rt, 1.5 h), and then reacted with PhPCl2
(278 uC, 10 min, then rt, 1.5 h) followed by the requisite
aryllithium (278 uC–rt, overnight) to afford a mixture of two
diastereomers in ca. 90% yield. The ratio of the two diastereomers
(S)-2-(diphenylphosphino)ferrocenecarboxaldehyde
4
can be
explained as follows. The lone electron pair on substituent X
(Fig. 1) and the oxygen atom of the carbonyl group repel each
other, so that the favoured conformation of the 2-substituted
ferrocenecarboxaldehyde has the carbonyl group oriented anti to
the substituent X. Addition of the Grignard reagent to the
carbonyl group occurs from the Si-face exclusively when X is small
(such as Br), while when X is the bulky diphenylphosphino entity,
one of the phenyl groups hinders attack by Grignard reagent on
the Si-face of the aldehyde unit to a minor extent.7
1
was determined by H NMR and 31P NMR spectroscopy to be
ca. 3.3:1. The major diastereomers (29S,49S,SFc,RP)-10a and
(29S,49S,SFc,RP)-10b can be easily separated by a single recrys-
tallization from hexane in about 50% yield; their absolute
configuration was confirmed by single-crystal X-ray diffraction
analysis.§ Acid hydrolysis of (29S,49S,SFc,RP)-10a afforded the
aldehyde (SFc,RP)-11a quantitatively. Reaction of (SFc,RP)-11a
with the Grignard reagent prepared from (2-bromophenyl)diphe-
nylphosphine gave the desired product in 96% yield as a mixture of
Utilising some of this new chemistry, we turned our attention to
the preparation of the new family of phosphine ligands 2.
Halogen–lithium exchange on compound (SFc,aS)-8 (278 uC,
15 min) and reaction with PhPCl2 (278 uC, 10 min, then rt, 1.5 h)
and then o-anisyllithium (278 uC–rt, overnight) gave a single
diastereomer (SFc,aS,SP)-2a in 91% yield (Scheme 2). Similarly,
replacement of o-anisyllithium with 1-naphthyllithium afforded 2b
as a mixture of two diastereomers in 90% yield. The ratio of
(SFc,aS,SP)-2b to (SFc,aS,RP)-2b was determined by 1H NMR and
31P NMR spectroscopy to be 9:1. The major diastereomer can be
purified very easily by recrystallisation from hexane.
The high diastereoselectivity of the transformation from
(SFc,aS)-8 to (SFc,aS,SP)-2 can be explained by a similar reaction
mechanism to that proposed in the synthesis of P-chiral phos-
phines from Ugi’s amine (Scheme 3),8 whereby a seven-membered
Scheme 4 Reagents and conditions: (a) t-BuLi, Et2O, 278 uC–rt; (b)
PhPCl2, 278 uC–rt; (c) ArLi, 278 uC–rt, (d) p-TsOH, H2O–CH2Cl2, rt,
100%; (e) 2-diphenylphosphinophenylmagnesium bromide, THF, 278 uC–
rt; (f) 30% KH, MeI, THF, 0 uC.
Fig. 1
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Table 1 Asymmetric hydrogenation of a-dehydroamino acid
derivativesa
Notes and references
§ Crystallographic data were recorded on Stoe IPDS (10a) and Bruker
˚
Smart Apex (10b) diffractometers using MoKa-radiation (l = 0.71073 A).
Structures were refined by full-matrix least squares against F2 using all data
(SHELX979). Apart from disordered atoms, non-hydrogen atoms were
refined anisotropically and hydrogen atoms were fixed geometrically. 10a:
C29H31FeO4P, M = 530.36, T = 213 K, orthorhombic, space group P212121
3
˚
˚
Runb Ligand
R1
R2
R3
Ee (%)
(No. 4), a = 8.2767(8), b = 10.7033(12), c = 29.205(3) A, V = 2587.2(5) A ,
Z = 4, m(MoKa) = 0.678, 4118 unique reflections (Rint = 0.0817), R1 [I >
2s(I)] = 0.0586, wR2 (all data) = 0.1319; 10b: C32H31FeO3P, M = 550.39,
1
2
3
1b
CO2Me
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2Me
CO2Me
Ph
Ph
Ph
Ph
90.5 (S)
99.6 (S)
69.3 (S)
10.8 (S)
T = 100 K, monoclinic, space group P21 (No. 19), a = 9.210(4), b =
(SFc,aS,SP)-2b CO2Me
(SFc,aS,RP)-2b CO2Me
(SFc,aS,RP)-2a CO2Me
3
˚
˚
7.142(3), c = 20.061(8) A, b = 94.636(7)u, V = 1315.4(9) A , Z = 2,
m(MoKa) = 0.667, 3385 independent reflections (Rint = 0.0595), R1 [I >
2s(I)] = 0.0455, wR2 (all data) = 0.1149. 10a contains a disordered dioxane
group and 10b a disordered phenyl ring. Disordered atoms were split on
two positions and refined isotropically with 0.5 occupancy factors using
similar-distance and similar-U restraints. CCDC 604420 and 604421. For
crystallographic data in CIF or other electronic format see DOI: 10.1039/
b601952h
4
5
1b
CO2Me
3-BrPh 97.3 (S)
3-BrPh .99.9 (S)
3-BrPh 17.1 (S)
3-BrPh 12.2 (S)
2-BrPh 91.4 (S)
2-BrPh .99.9 (S)
2-BrPh 52.4 (S)
H
H
H
H
6
7
8
(SFc,aS,SP)-2b CO2Me
(SFc,aS,RP)-2b CO2Me
(SFc,aS,RP)-2a CO2Me
9
1b
CO2Me
10
11
12
13
14c
15c
a
(SFc,aS,SP)-2b CO2Me
(SFc,aS,RP)-2b CO2Me
1b
(SFc,aS,SP)-2b Ph
1b Me
(SFc,aS,SP)-2b Me
Ph
86.4 (S)
96.3 (S)
92.4 (S)
96.1 (S)
1 (a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
New York, 1994; (b) T. Ohkuma, M. Kitamura and R. Noyori,
in Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH,
Weinheim, 2000, p. 1; (c) J. M. Brown, in Comprehensive
Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Springer, Berlin, 1999, p. 121; (d) G. Helmchen and
A. Pfaltz, Acc. Chem. Res., 2000, 33, 336; (e) A. Borner, Eur. J. Inorg.
Chem., 2001, 327; (f) W. Tang and X. Zhang, Chem. Rev., 2003, 103,
3029; (g) T. P. Clark and C. R. Landis, Tetrahedron: Asymmetry, 2004,
15, 2123.
b
(SFc,aS,SP)-2a is not active in this reaction. All reactions went to
completion under the conditions except for run 4 (55.4% conversion)
and run 8 (61.8% conversion). The hydrogenation reactions were
performed under 300 psi hydrogen for 12 h at room temperature.
c
two diastereomers (ratio of aS:aR = 9.5:1) whereupon recrystalli-
sation from hexane gave the pure diastereomer (SFc,aS,RP)-12a in
73% yield. Subsequent methylation of (SFc,aS,RP)-12a afforded
(SFc,aS,RP)-2a in 46% yield. Etherification of (SFc,aS,RP)-12b
failed under similar conditions, presumably due to interference by
the naphthyl moiety.
2 For reviews, see: (a) A. T. Hayashi, in Ferrocenes: Homogeneous
Catalysis, Organic Synthesis, Materials Science, ed. A. Togni and
T. Hayashi, VCH, Weinheim, 1995, pp. 105–142; (b) C. J. Richards
and A. J. Locke, Tetrahedron: Asymmetry, 1998, 9, 2377; (c) T. J. Colacot,
Chem. Rev., 2003, 103, 3101; (d) L. X. Dai, T. Tu, S. L. You, W. P. Deng
and X. L. Hou, Acc. Chem. Res., 2003, 36, 659; (e) P. Barbaro,
C. Bianchini, G. Giambastiani and S. L. Parisel, Coord. Chem. Rev.,
2004, 248, 2131.
The preliminary results of some asymmetric hydrogenation
reactions catalysed by PingFer-Rh complexes show that the
introduction of P-chirality into ferrocene-based phosphine ligands
enhances the enantioselective discrimination of the catalyst when
synergistic matching of the planar chirality, the chirality of carbon
and the chirality on phosphorus exists. Thus the matched new
ligand (SFc,aS,SP)-2b leads to higher enantioselectivities than
Taniaphos 1b in a wide range of asymmetric hydrogenations. First,
we compared the new ligands in the Rh-catalysed asymmetric
hydrogenation of a-dehydroamino acid derivatives (Table 1). The
ligand (SFc,aS,SP)-2b gives products in over 99% ee for the three
a-dehydroamino acid derivatives tested. In contrast, when the
mismatched (SFc,aS,RP)-2b is employed in the same reactions
much lower enantioselectivity is observed (17–69% ee).
3 (a) T. Ireland, G. Grossheimann, C. Wieser-Jeunesse and P. Knochel,
Angew. Chem., Int. Ed., 1999, 38, 3212; (b) T. Ireland, K. Tappe,
G. Grossheimann and P. Knochel, Chem.–Eur. J., 2002, 8, 843; (c)
M. Lotz, K. Polborn and P. Knochel, Angew. Chem., Int. Ed., 2002, 41,
4708; (d) K. Tappe and P. Knochel, Tetrahedron: Asymmetry, 2004, 15,
91–102.
4 Some ferrocene-based phosphines incorporating phosphorus chirality and
other chiralities are known: (i) for phosphines incorporating both planar
and phosphorus chirality, see: (a) U. Nettekoven, P. C. J. Kamer,
P. W. N. M. van Leeuwen, M. Widhalm, A. L. Spek and M. Lutz, J. Org.
Chem., 1999, 64, 3996; (b) F. Maienza, M. Wo¨rle, P. Steffanut and
A. Mezzetti, Organometallics, 1999, 18, 1041; (c) U. Nettekoven,
M. Widhalm, P. C. J. Kamer, P. W. N. M. van Leeuwen, K. Mereiter,
M. Lutz and A. L. Spek, Organometallics, 2000, 19, 2299; (d)
U. Nettekoven, P. C. J. Kamer, M. Widhalm and P. W. N. M. van
Leeuwen, Organometallics, 2000, 19, 4596; (e) U. Nettekoven,
M. Widhalm, H. Kalchhauser, P. C. J. Kamer, P. W. N. M. van
Leeuwen, M. Lutz and A. L. Spek, J. Org. Chem., 2001, 66, 759; (f)
E. A. Colby and T. F. Jamison, J. Org. Chem., 2003, 68, 156; (ii)
for phosphines combining carbon, planar and phosphorus chirality, see:
(g) P. Barbaro, C. Bianchini, G. Giambastiani and A. Togni, Chem.
Commun., 2002, 2672.
5 O. Riant, O. Samuel, T. Flessner, S. Taudien and H. B. Kagan, J. Org.
Chem., 1997, 62, 6733–6745.
6 P. Machnitzki, T. Nickel, O. Stelzer and C. Landgraf, Eur. J. Inorg.
Chem., 1998, 1029.
7 A very recent paper describes similar reasoning: C. J. Taylor, F. X. Roca
and C. J. Richards, Synlett, 2005, 2159.
8 W. Chen, W. Mbafor, S. M. Roberts and J. Whittall, J. Am. Chem. Soc.,
2006, 128, 3922.
Similarly, in the Rh-catalysed asymmetric hydrogenations of an
enamide (run 12 vs. run 13) and an (E)-b-dehydroamino acid
derivative (run 14 vs. run 15), the chiral ligand with matched
stereodirecting units (SFc,aS,SP)-2b again gave superior results to
Taniaphos 1b.
Insummary, wehavedevelopedahighlystereoselectivesynthesis
of P-chiral 1,5-diphosphanylferrocene ligands. The introduction of
P-chirality in ferrocene-based phosphine ligands enhances the
enantioselective discrimination produced by the corresponding
catalyst when matching of the different stereogenic components is
achieved. The highly stereoselective, modular synthesis of new
phosphine ligands and the excellent enantioselectivities obtained in
three important transformations, combine to signpost the potential
importance of this new family of chiral ligand.
9 G. M. Sheldrick, SHELXL-97, Program for refinement of crystal
structures, University of Go¨ttingen, Germany, 1997; G. M. Sheldrick,
SHELXS-97, Program for solution of crystal structures, University of
Go¨ttingen, Germany, 1997.
2918 | Chem. Commun., 2006, 2916–2918
This journal is ß The Royal Society of Chemistry 2006