Catalytic asymmetric deprotonation of phosphine boranes and sulfides as a route to P-stereogenic compounds

Article abstract of DOI:10.1039/b806864j

A comparison between phosphine boranes and sulfides in their catalytic asymmetric deprotonation using organolithiums and sub-stoichiometric amounts of (-)-sparteine has revealed superior catalytic efficiency in the phosphine sulfide deprotonation. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806864j

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Catalytic asymmetric deprotonation of phosphine boranes and sulfides
as a route to P-stereogenic compoundsw
Jonathan J. Gammon,a Steven J. Canipa,a Peter O’Brien,*a Brian Kellyb and
Sven Taylorc
Received (in Cambridge, UK) 23rd April 2008, Accepted 26th June 2008
First published as an Advance Article on the web 17th July 2008
DOI: 10.1039/b806864j
A comparison between phosphine boranes and sulfides in their
catalytic asymmetric deprotonation using organolithiums and
sub-stoichiometric amounts of (À)-sparteine has revealed super-
ior catalytic efficiency in the phosphine sulfide deprotonation.
The last five years have seen a significant increase in the use of
Fig. 1
P-stereogenic phosphines as ligands in metal-catalysed asym-
metric processes.1 One class of P-stereogenic ligand that has
1.2 equiv. (À)-sparteine (stoichiometric); (ii) 1.1 equiv. RLi and
been widely utilised is based on a diphosphine with at least one
0.2 equiv. (À)-sparteine (catalytic) and (iii) 1.1 equiv. RLi only
t-Bu substituent at each phosphorus atom. The original ligand in
(background). Three different organolithium bases (RLi) were
this class is BisP*,2 developed by Imamoto, and other represen-
investigated and the results are shown in Table 1.
tative members include Zhang’s Tangphos3 and Hoge’s affectio-
Using s-BuLi under stoichiometric conditions (1.2 equiv. (À)-
sparteine), lithiation of phosphine borane 1 proceeded with higher
enantioselectivity (92 : 8 er, entry 1) than that of phosphine sulfide
4 (84 : 16 er, entry 2). Both reactions gave the same sense of
induction.11 Under catalytic conditions (0.2 equiv. (À)-sparteine)
using s-BuLi, there was a dramatic reduction in enantioselectivity
with phosphine sulfide 4 (60 : 40 er, entry 4) which is a result of a
significant background lithiation by uncomplexed s-BuLi (as
demonstrated by the generation of an 83% yield of rac-6 using
s-BuLi alone, entry 6). In contrast, the relative reduction in er was
less using phosphine borane 1 (74 : 26 er, entry 3).
nately named tri-chickenfootphos4 (Fig. 1). Other closely related
ligands developed by Imamoto include MiniPHOS5 and
QuinoxP*.6 The popularity of such P-stereogenic ligands in
asymmetric catalysis stems not only from the high enantioselec-
tivity that they impart but also from the development of efficient
methodology for their synthesis. The synthetic route of choice to
this class of ligands is the asymmetric deprotonation of
phosphine boranes and sulfides using s-BuLi or n-BuLi and
(À)-sparteine, originally reported by Evans in 1995.7
Recently, our group8 disclosed a catalytic variant of the
Evans protocol in which the s-BuLi-mediated deprotonation
of phosphine borane 1 can be carried out with good enantio-
selectivity using sub-stoichiometric amounts of (À)-sparteine
or our (+)-sparteine surrogate.9,10 Thus, deprotonation of
phosphine borane 1 using 1.1 equiv. s-BuLi and 0.2 equiv. of
the chiral diamine was followed by CuCl2-promoted dimerisa-
tion to give either (S,S)-2 or (R,R)-2 (protected forms of
BisP*) in satisfactory yield and Z 99 : 1 er (Scheme 1).
In this paper, we report the first examples of the catalytic
asymmetric deprotonation of phosphine sulfides. In addition, by
comparing phosphine boranes and sulfides under the same
catalytic conditions, we have identified some fundamental and
unexpected differences. Finally, use of a phosphine sulfide
allowed us to complete the catalytic asymmetric synthesis of
either enantiomer of an analogue of Hoge’s tri-chickenfootphos.
To start with, we directly compared t-Bu-substituted
phosphine borane 1 with phosphine sulfide 4 using lithiation–
silylation under three sets of conditions: (i) 1.1 equiv. RLi and
With the less reactive n-BuLi as base, some unexpected results
were obtained. Under stoichiometric conditions, both phosphine
borane 1 and sulfide 4 were deprotonated with good yield and
enantioselectivity to give (R)-5 (76%, 89 : 11 er, entry 7) and
(S)-6 (88%, 88 : 12 er, entry 8), respectively. Despite several
attempts, we have been unable to lithiate phosphine borane 1
using n-BuLi alone at À78 1C12 (entry 11) and this suggested
that the catalytic conditions should work well. Unfortunately,
however, there was no turnover of the ligand using n-BuLi and
0.2 equiv. (À)-sparteine: (R)-5 of 84 : 16 er was obtained in
a Department of Chemistry, University of York, Heslington, York, UK
YO10 5DD. E-mail: paob1@york.ac.uk; Fax: +44-1904-432516;
Tel: +44-1904-432535
b Celtic Catalysts Ltd, Nova Centre, Belfield Innovation Park, Dublin
4, Ireland
c F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data. See DOI: 10.1039/b806864j
Scheme 1
ꢀc
This journal is The Royal Society of Chemistry 2008
3750 | Chem. Commun., 2008, 3750–3752

View Article Online
Table 1 Lithiation–silylation of phosphine borane 1 and phosphine
sulfide 4 using RLi–(À)-sparteine
Equiv.
(À)-sp
Yield
Product (%)b
Entry
RLia
Erc
1
2
3
4
5
6
7
8
s-BuLi
s-BuLi
s-BuLi
s-BuLi
s-BuLi
s-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
1.2
1.2
0.2
0.2
0
(R)-5
(S)-6
(R)-5
(S)-6
rac-5
rac-6
(R)-5
(S)-6
(R)-5
(S)-6
rac-5
rac-6
(R)-5
(S)-6
(S)-6
rac-6
74
74
76
75
70
83
76
88
21
82
0
45
0
88
79
18
92 : 8
84 : 16
74 : 26
60 : 40
—
Scheme 2
(À)-sparteine cannot be displaced from the lithiated intermediate 7
by n-BuLi (Step 2, Scheme 2). In contrast, lithiation of phosphine
sulfide 4 proceeds with the highest enantioselectivity (89 : 11 er)
using n-BuLi–(À)-sparteine. Significantly, high yield and good
enantioselectivity can be obtained in the lithiation of phosphine
sulfide 4 using n-BuLi and 0.2 equiv. (À)-sparteine (82% yield,
83 : 17 er) ((À)-sparteine is efficiently displaced in lithiated
intermediate 8, Scheme 2); s-BuLi gives inferior results to n-BuLi
due to a fast background deprotonation of 4 by uncomplexed s-
BuLi. These comparisons are summarised schematically in
Scheme 2.16
0
—
1.2
1.2
0.2
0.2
0
89 : 11
88 : 12
84 : 16
83 : 17
—
—
—
88 : 12
82 : 18
—
9
10
11
12
13
14
15
16
a
0
Me3SiCH2Li 1.2
Me3SiCH2Li 1.2
Me3SiCH2Li 0.2
Me3SiCH2Li
0
A solution of 1 or 4 in Et2O was added to a pre-mixed solution of the
Given the high catalytic efficiency observed with phosphine
sulfide 4, we briefly explored lower loadings and the use of
toluene (Table 2). In Et2O, it was possible to lower the amount
of (À)-sparteine to 0.1 equiv. whilst maintaining good enan-
tioselectivity (84 : 16 er, entry 3). Use of 0.05 equiv.
(À)-sparteine with phosphine sulfide 4 gave 74 : 26 er (entry
4). In toluene, the catalytic asymmetric deprotonation of
phosphine sulfide 4 was even more efficient: use of 1.1 equiv.
n-BuLi in conjunction with just 0.05 equiv. (À)-sparteine
generated adduct (S)-6 of 85 : 15 er in 88% yield (entry 8),
almost the same as the stoichiometric result (90% yield, 89 : 11
er, entry 6) and despite an appreciable background deproto-
nation reaction using n-BuLi alone (54% yield, entry 9).
The use of 1.1 equiv. n-BuLi and 0.05 equiv. (À)-sparteine in
toluene represents our optimised conditions for the deproto-
nation of phosphine sulfide 4. To illustrate the usefulness of
the catalytic phosphine sulfide methodology in ligand synth-
esis, we prepared each enantiomer of diphosphine 9, an
analogue of Hoge’s tri-chickenfootphos.4 Thus, catalytic
asymmetric deprotonation of 4 using n-BuLi and (À)-
sparteine, trapping with Ph2PCl and then borane protection
gave a 77% yield of (S)-9 of 85 : 15 er (Scheme 3). Alterna-
tively, use of the (+)-sparteine surrogate 3 under otherwise
identical conditions gave (R)-9 of 78 : 22 er in 86% yield. To
show that our methodology is useful for the synthesis of
P-stereogenic ligands, we converted phosphine sulfide (R)-9
into bisphosphine borane (S)-10 using a modified version of a
protocol used in Zhang’s Tangphos synthesis.3 Thus, with the
rigorous exclusion of oxygen throughout the procedure, reac-
tion of (R)-9 of 78 : 22 er with Si2Cl6 in toluene at 80 1C3,17
followed by treatment with aqueous NaOH and then BH3Á
Me2S gave (S)-1018 in 88% yield. Crucially, there was no loss
b
RLi and (À)-sparteine (where used) in Et2O at À78 1C. Isolated yield
c
after chromatography. Er determined by chiral HPLC (the sense of
induction is the same in each case11 but, due to a Cahn–Ingold–Prelog
priority change, (R)-5 is equivalent to (S)-6).
21% yield. Since we have already demonstrated turnover of
(À)-sparteine using s-BuLi at À78 1C, it can be concluded that
the organolithium base is not an innocent bystander in the
catalytic process.13 The turnover of (À)-sparteine with n-BuLi
could be improved by carrying out the reaction at À50 1C but
the enantioselectivity was lower (80 : 20 er).14 In contrast, with
phosphine sulfide 4, (À)-sparteine was efficiently recycled and
there was only a slight reduction in enantioselectivity using
n-BuLi–0.2 equiv. (À)-sparteine: (S)-6 of 83 : 17 er was generated
in 82% yield (entry 10). This is especially impressive given that
there is a significant background lithiation of 4 using n-BuLi
(45% yield, entry 12). Finally, we also compared the s-BuLi and
n-BuLi results with those obtained using Me3SiCH2Li. There
was no lithiation of phosphine borane 1 using stoichiometric
amounts of Me3SiCH2Li and (À)-sparteine at À78 1C15 (entry
13). However, the results with phosphine sulfide 4 (entries
14–16) mirrored those obtained using n-BuLi and there were
no obvious advantages in using Me3SiCH2Li.
From the results presented in Table 1, some important conclu-
sions can be drawn. For the lithiation of phosphine borane 1,
s-BuLi–(À)-sparteine gives the highest enantioselectivity (92 : 8 er)
and acceptable enantioselectivity can be obtained under catalytic
conditions (74 : 26 er). There is no turnover of (À)-sparteine in the
n-BuLi-mediated deprotonation of phosphine borane 1 using
0.2 equiv. (À)-sparteine at À78 1C (21% yield, 84 : 16 er) as
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3750–3752 | 3751

View Article Online
Table
n-BuLi–(À)-sparteine
2
Lithiation–silylation of phosphine sulfide
4
using
Notes and references
1 (a) W. Zhang, Y. Chi and X. Zhang, Acc. Chem. Res., 2007, 40,
1278; (b) A. Grabulosa, J. Granell and G. Muller, Coord. Chem.
Rev., 2007, 251, 25; (c) W. Tang and X. Zhang, Chem. Rev., 2003,
103, 3029; (d) K. V. L. Crepy and T. Imamoto, Top. Curr. Chem.,
2003, 229, 10; (e) K. V. L. Crepy and T. Imamoto, Adv. Synth.
Catal., 2003, 103, 3029.
2 T. Imamoto, J. Watanabe, Y. Wada, H. Masuda, H. Yamada, H.
Tsuruta, S. Matsukawa and K. Yamaguchi, J. Am. Chem. Soc.,
1998, 120, 1635.
3 W. Tang and X. Zhang, Angew. Chem., Int. Ed., 2002, 41, 1612.
4 (a) G. Hoge, H.-P. Wu, W. S. Kessel, D. A. Pflum, D. J. Greene
and J. Bao, J. Am. Chem. Soc., 2004, 126, 5966; (b) I. D. Gridnev,
T. Imamoto, G. Hoge, M. Kouchi and H. Takahashi, J. Am.
Chem. Soc., 2008, 130, 2560.
5 Y. Yamonoi and T. Imamoto, J. Org. Chem., 1999, 64, 2988.
6 T. Imamoto, K. Sugita and K. Yoshida, J. Am. Chem. Soc., 2005,
127, 11934.
7 A. R. Muci, K. R. Campos and D. A. Evans, J. Am. Chem. Soc.,
1995, 117, 9075.
Entry
Solvent
Equiv. (À)-sp
Yield (%)a
Erb
1
2
3
4
5
6
7
8
9
a
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
Toluene
Toluene
Toluene
1.2
0.2
0.1
0.05
0
1.2
0.2
0.05
0
88
82
74
88
45
90
89
88
54
88 : 12
83 : 17
84 : 16
74 : 26
—
89 : 11
83 : 17
85 : 15
—
b
Isolated yield after chromatography. Er determined by chiral HPLC.
8 C. Genet, S. J. Canipa, P. O’Brien and S. Taylor, J. Am. Chem.
Soc., 2006, 128, 9336.
9 M. J. Dearden, C. R. Firkin, J.-P. R. Hermet and P. O’Brien, J.
Am. Chem. Soc., 2002, 124, 11870.
10 (a) P. O’Brien, Chem. Commun., 2008, 655; (b) A. J. Dixon, M. J.
McGrath and P. O’Brien, Org. Synth., 2006, 83, 141.
11 The sense of induction in the asymmetric deprotonation of phos-
phine borane 1 and sulfide 4 using RLi–(À)-sparteine is the same in
each case. This was shown by converting borane (R)-5 of 75 : 25 er
into sulfide (S)-6 of 75 : 25 er (via reaction with DABCO and S8 in
refluxing toluene for 12 h, quantitative yield). Note that, due to a
Cahn–Ingold–Prelog priority change, (R)-5 is equivalent to (S)-6.
The sense of induction is consistent with that obtained by Evans
(ref. 7) and Imamoto (ref. 2).
12 Phosphine borane 1 can be lithiated using n-BuLi alone at tem-
peratures higher than À78 1C. The following results were obtained
by lithiating 1 using n-BuLi at the stated temperature for 3 h and
then trapping with benzophenone: À50 1C (11% yield); À42 1C
(29% yield); 0 1C (51% yield).
13 A. Ramirez, X. Sun and D. B. Collum, J. Am. Chem. Soc., 2006,
128, 10326.
14 Lithiation of 1 with n-BuLi–0.2 equiv. (À)-sparteine in Et2O at
À50 1C for 3 h and trapping with PhMe2SiCl gave a 49% yield of
(R)-5 of 80 : 20 er.
15 Lithiation of 1 with Me3SiCH2Li–(À)-sparteine in Et2O at À20 1C
for 3 h and trapping with PhMe2SiCl gave a 75% yield of (R)-5 of
75 : 25 er.
Scheme 3
of er during the process: (S)-10 was generated with 79 : 21 er.
Furthermore, unmasking of the free diphosphine from dipho-
sphine boranes like (S)-10 is well documented in similar
compounds.4,5 It was also important to demonstrate that
enantiomerically pure P-stereogenic ligands could be obtained
using our route. Thus, a sample of (R)-9 of 78 : 22 er was
recrystallised to give racemic crystals (52% recovery) and a
mother liquor that contained (R)-9 of 99 : 1 er (48% recovery).
In conclusion, we report the first examples of the catalytic
asymmetric deprotonation of phosphine sulfides and demonstrate
the potential in P-stereogenic ligand synthesis with the prepara-
tion of bisphosphines (S)- and (R)-9. The optimised deprotona-
tion conditions involved using n-BuLi and 0.05 equiv. chiral
diamine in toluene at À78 1C. Significant differences between
the results obtained with phosphine boranes and sulfides were
identified as part of our study. It seems likely that the efficiency of
the catalytic asymmetric deprotonation of phosphine sulfides
could prove useful in the synthesis of P-stereogenic chiral ligands.
We thank Celtic Catalysts and F. Hoffmann-La Roche Ltd
for funding.
16 The structures of the organolithium reagents (e.g. RLi and
RLiÁ(À)-sp) and the lithiated phosphine boranes and
sulfides (e.g. 7 and 8) in Scheme 2 are schematic representations
only and nothing is implied about their true solution structure
(e.g. C–Li contact, aggregation state). For reports on the solution
and solid-state structures of lithiated phosphine boranes
and sulfides, see: (a) K. Izod, C. Wills, W. Clegg and R. W.
Harrington, Organometallics, 2007, 26, 2861; (b) K. Izod,
C. Wills, W. Clegg and R. W. Harrington, Organometallics,
2006, 25, 338; (c) X.-M. Syn, K. Manabe, W. W.-L. Lam, N.
Shiraishi, J. Kobayashi, H. Utsumi and S. Kobayashi, Chem.–Eur.
J., 2005, 11, 361; (d) K. Izod, W. McFarlane, B. V. Tyson, W.
Clegg and R. W. Harrington, Chem. Commun., 2004, 570; (e) K.
Izod, Coord. Chem. Rev., 2002, 227, 153; (f) H. Schmidbauer, E.
Weiss and B. Zimmer-Gasse, Angew. Chem., Int. Ed. Engl., 1979,
18, 782.
17 (a) G. Zon, K. E. DeBruin, K. Naumann and K. Mislow, J. Am.
Chem. Soc., 1969, 81, 7012; (b) K. Naumann, G. Zon and K.
Mislow, J. Am. Chem. Soc., 1969, 81, 7023.
18 A sample of rac-10 was independently prepared from phosphine
borane 1 for conclusive proof that desulfurisation of (R)-9 had
occurred.
ꢀc
This journal is The Royal Society of Chemistry 2008
3752 | Chem. Commun., 2008, 3750–3752