Catalytic asymmetric synthesis of ferrocenes and P-stereogenic bisphosphines

Article abstract of DOI:10.1021/ja062616f

The catalytic asymmetric synthesis of planar chiral ferrocenes and P-stereogenic phosphines and bisphosphines (important classes of chiral ligands for metal-catalyzed asymmetric processes) is successfully demonstrated using n-BuLi or s-BuLi in combination

Full text of DOI:10.1021/ja062616f

Published on Web 06/28/2006
Catalytic Asymmetric Synthesis of Ferrocenes and P-Stereogenic
Bisphosphines
Ce´dric Genet,† Steven J. Canipa,† Peter O’Brien,*,† and Sven Taylor‡
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K., and F. Hoffmann-La Roche Ltd,
CH-4070 Basel, Switzerland
Received April 14, 2006; E-mail: paob1@york.ac.uk
Chiral ferrocenes1 and P-stereogenic bisphosphines2 are two of
Scheme 1
the most important classes of chiral ligands for transition metal-
catalyzed asymmetric processes. Surprisingly, however, almost all
of the methods used to prepare such chiral ligands use stoichiometric
quantities of a chiral reagent or auxiliary.3,4 Two recent reports on
catalytic asymmetric synthesis of P-stereogenic phosphines5,6 have
prompted us to disclose our results. In this paper, efficient
asymmetric deprotonation-electrophilic trapping reactions of a
ferrocene amide 1 (f 2)7 and a phosphine borane 3 (f 4)8,9 using
n-BuLi or s-BuLi in conjunction with substoichiometric quantities
(0.1-0.5 equiv) of chiral diamines are described (Scheme 1). We
were particularly attracted to developing catalytic asymmetric
variants of such reactions since they each deliver products that are
precursors to important chiral catalysts in their own right.10-12 In
addition, either enantiomer of the products 2 and 4 can be accessed
using (-)-sparteine or the (+)-sparteine surrogate 5.13
Table 1. Asymmetric Directed Ortho-Metalation of Ferrocene
Since the reactivity of n-BuLi or s-BuLi is increased by
complexation to (-)-sparteine, we reasoned that it should be
possible to successfully use substoichiometric amounts of the chiral
diamine in ligand-accelerated asymmetric deprotonation. We refer
to this as one-ligand catalysis14 to distinguish it from our recently
developed ligand-exchange approach to catalytic deprotonation
(two-ligand catalysis).15
Amide 1 (f 2) Using Substoichiometric Quantities of Chiral
Diamines
entry
diaminea
equiv of diamine
yield of 2 (%)b
er (S:R)c
1
2
3
4
5
6
7
8
(-)-sparteine
1.2
0.4
0.3
0.2
1.2
0.4
0.2
77
78
77
72
78
75
84
41d
98:2
92:8
84:16
75:25
4:96
(-)-sparteine
(-)-sparteine
(-)-sparteine
5
5
5
To start with, we confirmed that (-)-sparteine and (+)-sparteine
surrogate 5 gave enantiocomplementary results in the stoichiometric
conversion of ferrocene 1 into 2. Thus, ferrocene amide 1 was
lithiated using n-BuLi/(-)-sparteine and then reacted with methyl
iodide to deliver a 77% yield of adduct (S)-2 of 98:2 er (Table 1,
entry 1).7b Pleasingly, use of (+)-sparteine surrogate 5 led to the
formation of the antipode (R)-2 of 96:4 er (78% yield) (Table 1,
entry 5). Next, we examined the use of substoichiometric amounts
of the chiral diamines. With 0.4 equiv of (-)-sparteine, ferrocene
amide (S)-2 of 92:8 er was produced in 78% yield (entry 2). This
result is strikingly similar to that obtained using 1.2 equiv of (-)-
sparteine (77%, 98:2 er, Table 1, entry 1) and demonstrates that
(-)-sparteine is being recycled. Lower loadings of (-)-sparteine
led to reduced enantioselectivity (Table 1, entries 3 and 4),
presumably due to background deprotonation by n-BuLi alone
(which was verified by a 41% yield of rac-2 from a reaction in the
absence of diamine ligand, Table 1, entry 8). Notably, even better
results were obtained using the (+)-sparteine surrogate 5: with 0.4
equiv of diamine 5, a 75% yield of ferrocene amide (R)-2 of 94:6
er was generated (Table 1, entry 6), which is almost identical to
the stoichiometric result (78%, 96:4 er, Table 1, entry 5). In addition,
use of only 0.2 equiv of diamine 5 produced adduct (R)-2 with
high enantioselectivity (84%, 89:11 er, Table 1, entry 7).
6:94
11:89
a Reaction conditions: (i) 1.2 equiv of n-BuLi, 6:1 Et2O-toluene, -78
°C, 2 h; (ii) MeI, -78 °C, 1 h then to room temperature over 4 h and room
temperature, 12 h. b Isolated yield of 2 after chromatography. c Enantiomer
ratio (er) determined by chiral HPLC (Chiralcel OD) of the decumylated
ferrocene amide (see Supporting Information and ref 7b). d Reaction carried
out in the absence of diamine ligand; 25% of ferrocene amide 1 also
recovered.
and stoichiometric (-)-sparteine followed by reaction with air, we
isolated alcohol (R)-4 of 92:8 er (65% yield) (Table 2, entry 1), a
result that could be nearly matched using 0.5 equiv of (-)-sparteine
(61%, 87:13 er, Table 2, entry 2).16 With 0.2 equiv of (-)-sparteine,
the enantioselectivity was lower (77:23 er, Table 2, entry 4). In
contrast, and in line with the results obtained with ferrocene amide
1, the (+)-sparteine surrogate 5 proved to be a superior catalyst.
Thus, the enantioselectivity was essentially the same using 1.2 and
0.5 equiv of diamine 5 (Table 2, entries 4 and 5), and even using
0.2 equiv of (+)-sparteine surrogate 5, alcohol (S)-4 was generated
with high selectivity (54%, 86:14 er, Table 2, entry 6). We believe
that the higher enantioselectivity observed with the (+)-sparteine
surrogate 5 compared to (-)-sparteine is a result of a faster
deprotonation by the n-BuLi or s-BuLi/diamine 5 complex com-
pared to that with the (-)-sparteine complex.17
A similarly successful set of catalytic results was obtained in
the lithiation-oxygenation of phosphine borane 3.9b Using s-BuLi
To further demonstrate the usefulness of these catalytic reactions,
we carried out catalytic asymmetric lithiation-dimerization of
† University of York.
‡ F. Hoffmann-La Roche Ltd.
9
9336
J. AM. CHEM. SOC. 2006, 128, 9336-9337
10.1021/ja062616f CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Lithiation-Trapping of Phosphine Borane 3
(f 4) Using Substoichiometric Quantities of Chiral Diamines
Royal Society of Chemistry for the award of a J W T Jones
Travelling Fellowship (to P.O’B.) for a sabbatical stay at the
University of Geneva and Dr. M. J. McGrath for assistance.
entry
diaminea
equiv of diamine
yield of 4 (%)b
er (R:S)c
1
2
3
4
5
6
7
(-)-sparteine
1.2
0.5
0.2
1.2
0.5
0.2
65
61
57
63
60
54
57d
92:8
Supporting Information Available: Full experimental procedures
and characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(-)-sparteine
87:13
77:23
9:91
8:92
14:86
(-)-sparteine
5
5
5
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Scheme 2
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(R,R)-6 (each g99:1 er) were obtained using substoichiometric
amounts of the chiral diamine (Scheme 2). These dimerizations
benefit from asymmetric amplification18 (an under-utilized approach
to enantiopure compounds), and the isolated yield of (S,S)- or
(R,R)-6 compared to that of meso-7 is an indication of the efficiency
of the catalysis. Significantly, use of just 0.1 equiv of (+)-sparteine
surrogate 5 directly gave a 45% yield of (R,R)-6 of g99:1 er.
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stoichiometric amounts of (-)-sparteine or (+)-sparteine surrogate
5 in the asymmetric deprotonation of ferrocene amide 1 and
phosphine borane 3. Instead, one-ligand catalytic asymmetric
deprotonation is a viable and effective method for the synthesis of
planar chiral ferrocenes and P-stereogenic bisphosphines, two
important classes of chiral ligands for metal-catalyzed asymmetric
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Acknowledgment. We thank the EPSRC, F. Hoffmann-La
Roche Ltd, and the EU for financial support. We also thank The
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