Synthesis of P-stereogenic compounds via kinetic deprotonation and dynamic thermodynamic resolution of phosphine sulfides: Opposite sense of induction using (-)-sparteine

Article abstract of DOI:10.1021/ja1060966

A systematic study of the asymmetric deprotonation of a dimethyl-substituted phosphine sulfide using organolithium bases in the presence of (-)-sparteine has been carried out. Use of nBuLi and (-)-sparteine in Et₂O at -78 °C gave trapped adducts in ～88:12 er via a kinetically controlled process that was successfully predicted using a computational approach at the B3LYP/6-31+G(d) level. This initial kinetic enantioselectivity could be enhanced up to 97:3 er by trapping the lithiated intermediate with a prochiral electrophile (e.g., pivaldehyde or tBuPCl ₂). In addition, it was found that the R_P and S _P stereoisomers of the lithiated methylphosphine sulfide could interconvert at temperatures above 0 °C. Such interconversion is unprecedented and differs from the configurational instability of organolithiums that are stereogenic at a lithiated carbon atom. The major, thermodynamically preferred diastereomeric (-)-sparteine-complexed lithated phosphine sulfide was investigated by X-ray crystallography and computational methods at the B3LYP/6-31+G(d) level. Through the interconversion of the R_P and S_P stereoisomers of the lithiated methylphosphine sulfide, a novel dynamic thermodynamic resolution of a racemic lithiated phosphine sulfide has been developed. Thus, the phosphine sulfide was lithiated with nBuLi, and then (-)-sparteine was added. After equilibration at 0 °C for 3 h, electrophilic trapping generated an adduct in 81:19 er with the configuration opposite to that obtained under kinetic control. Thus, the methodology provides access to P-stereogenic compounds with the opposite sense of induction using (-)-sparteine as the ligand simply by changing the reaction conditions (kinetic or thermodynamic control).

Full text of DOI:10.1021/ja1060966

Published on Web 09/15/2010
Synthesis of P-Stereogenic Compounds via Kinetic
Deprotonation and Dynamic Thermodynamic Resolution of
Phosphine Sulfides: Opposite Sense of Induction Using
(-)-Sparteine
Jonathan J. Gammon,† Viktoria H. Gessner,‡ Greg R. Barker,† Johan Granander,†
Adrian C. Whitwood,† Carsten Strohmann,*,‡ Peter O’Brien,*,† and Brian Kelly§
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K., Anorganische
Chemie, Technische UniVersita¨t Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany,
and Celtic Catalysts Ltd., NoVa Centre, Belfield InnoVation Park, Dublin 4, Ireland
Received July 19, 2010; E-mail: paob1@york.ac.uk
Abstract: A systematic study of the asymmetric deprotonation of a dimethyl-substituted phosphine sulfide
using organolithium bases in the presence of (-)-sparteine has been carried out. Use of nBuLi and (-)-
sparteine in Et2O at -78 °C gave trapped adducts in ∼88:12 er via a kinetically controlled process that
was successfully predicted using a computational approach at the B3LYP/6-31+G(d) level. This initial kinetic
enantioselectivity could be enhanced up to 97:3 er by trapping the lithiated intermediate with a prochiral
electrophile (e.g., pivaldehyde or tBuPCl2). In addition, it was found that the RP and SP stereoisomers of
the lithiated methylphosphine sulfide could interconvert at temperatures above 0 °C. Such interconversion
is unprecedented and differs from the configurational instability of organolithiums that are stereogenic at a
lithiated carbon atom. The major, thermodynamically preferred diastereomeric (-)-sparteine-complexed
lithated phosphine sulfide was investigated by X-ray crystallography and computational methods at the
B3LYP/6-31+G(d) level. Through the interconversion of the RP and SP stereoisomers of the lithiated
methylphosphine sulfide, a novel dynamic thermodynamic resolution of a racemic lithiated phosphine sulfide
has been developed. Thus, the phosphine sulfide was lithiated with nBuLi, and then (-)-sparteine was
added. After equilibration at 0 °C for 3 h, electrophilic trapping generated an adduct in 81:19 er with the
configuration opposite to that obtained under kinetic control. Thus, the methodology provides access to
P-stereogenic compounds with the opposite sense of induction using (-)-sparteine as the ligand simply by
changing the reaction conditions (kinetic or thermodynamic control).
Introduction
P-Stereogenic bisphosphine ligands such as DIPAMP,1
BisP*,2 Mini-PHOS,3 QuinoxP*,4 and Tangphos5 (Figure 1)
have broad utility in transition-metal-catalyzed asymmetric
processes, of which asymmetric hydrogenation is the most
important.6 As a result, the development of new methodologies
for the asymmetric synthesis of either enantiomer of such
P-stereogenic compounds is still an important challenge. One
synthetic route that has gained popularity is the lithiation-trapping
reaction of phosphine boranes and sulfides mediated by org-
† University of York.
‡ Technische Universita¨t Dortmund.
Figure 1. Examples of P-stereogenic bisphosphine ligands.
§ Celtic Catalysts Ltd.
(1) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.;
Weinkauff, O. J. J. Am. Chem. Soc. 1977, 99, 5946.
(2) (a) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.;
Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998,
120, 1635. (b) Gridnev, I. D.; Yamanoi, Y.; Higashi, N.; Tsuruta, H.;
Yasutake, M.; Imamoto, T. AdV. Synth. Catal. 2001, 343, 118.
(3) (a) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988. (b)
Imamoto, T.; Tamura, K.; Ogura, T.; Ikematsu, Y.; Mayama, D.
Tetrahedron: Asymmetry 2010, 21, 1522.
anolithium bases in the presence of naturally occurring (-)-
sparteine. In this context, two distinct reaction manifolds have
previously been identified (Scheme 1): (i) Evans-style7 kineti-
cally controlled asymmetric deprotonation of dimethylphosphine
boranes (or sulfides) at low temperature (-78 °C) (1 f 2) and
(ii) Livinghouse’s8 dynamic thermodynamic resolution of a
(4) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127,
11934.
(7) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995,
117, 9075.
(5) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612.
(6) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(8) Wolfe, B.; Livinghouse, T. J. Am. Chem. Soc. 1998, 120, 5116.
9
13922 J. AM. CHEM. SOC. 2010, 132, 13922–13927
10.1021/ja1060966  2010 American Chemical Society

Synthesis of P-Stereogenic Compounds
A R T I C L E S
Scheme 1
Table 1. Asymmetric Lithiation-Trapping of Phosphine Sulfide 5
entry
RLi
ligand
solvent
product yield (%)a
er (S/R)b
1
2
3
4
5
6
7
8
nBuLi
sBuLi
MeLi
(-)-sp Et2O
(-)-sp Et2O
(-)-sp Et2O
6
6
6
6
6
6
7
8
6
6
6
6
88
74
17
92
90
100
18c
95f
59
87
79
88:12
84:16
79:21
88:12
89:11
55:45
lithiated phosphane borane (lithiated at phosphorus) (3 f 4).
Notably, high enantioselectivity was achieved in both processes
using the same ligand, (-)-sparteine.
Me3SiCH2Li (-)-sp Et2O
nBuLi
nBuLi
nBuLi
nBuLi
sBuLi
nBuLi
nBuLi
nBuLi
(-)-sp toluene
(-)-sp THF
(-)-sp Et2O
(-)-sp Et2O
9:91d e
13:87d
26:74
14:86
19:81
21:79
,
The Evans approach of desymmetrizing dimethyl-substituted
phosphines has become one of the most useful methods for the
synthesis of P-stereogenic bisphosphine ligands.2-5 Furthermore,
P-stereogenic compounds in the opposite enantiomeric series9
can now be accessed using a (+)-sparteine surrogate developed
in our group10 or via the regioselective lithiation of a silylphos-
phine sulfide.11 Since Evans’ seminal paper,7 the desymmetri-
zation of phosphine boranes has attracted the most interest,2-5,9
with only isolated reports on the asymmetric lithiation-trapping
of phosphine sulfides.5,11-13 In this paper, we report a systematic
study of the factors controlling the enantioselectivity of the
kinetically controlled asymmetric deprotonation of a phosphine
sulfide. Notably, we highlight the opportunity for enhancement
of enantioselectivity via the use of prochiral electrophiles, which
is an underdeveloped strategy in asymmetric synthesis. Fur-
thermore, a study of the effect of temperature on the lithiation
process revealed that the RP and SP stereoisomers of the lithiated
methylphosphine sulfide could interconvert at temperatures
above 0 °C. This unexpected result ultimately allowed us to
develop a synthetic route to P-stereogenic compounds via a
novel dynamic thermodynamic resolution process. Thus, the two
aspects of the methodology described herein provide access to
P-stereogenic compounds with opposite sense of induction using
(-)-sparteine as the ligand simply by changing the reaction
conditions (kinetic or thermodynamic control).
9
9
9
Et2O
Et2O
10
11
12
9
10
toluene
Et2O
76
a Yield after purification by column chromatography. b Enantiomer
ratio (er) determined by chiral-stationary-phase HPLC (CSP-HPLC).
c Lithiation time ) 10 min. d It should be noted that because of a
Cahn-Ingold-Prelog priority change, (S)-6, (R)-7, and (R)-8 have the
same configuration and are the major enantiomers generated using
(-)-sparteine. e Enantiomer ratio (er) determined by CSP-HPLC of the
corresponding alcohol obtained after reduction with NaBH4. f Lithiation
time ) 6 h.
of 1.2 equiv of (-)-sparteine [or (+)-sparteine surrogate 9 or
10] in Et2O, tetrahydrofuran (THF), or toluene at -78 °C. In
general, phosphine sulfide 5 was lithiated for 3 h before
electrophilic quenching with PhMe2SiCl, Ph2CO, or N,N-
dimethylformamide (DMF). The results of these experiments
are summarized in Table 1.
Four organolithium reagents (sBuLi, nBuLi, MeLi, and
Me3SiCH2Li) were compared in Et2O using PhMe2SiCl as the
electrophile (entries 1-4), and the highest enantioselectivity in
the formation of adduct (S)-6 was observed with nBuLi (88:12
er, entry 1) and Me3SiCH2Li (88:12 er, entry 4). Because of
the ready availability of nBuLi, it was selected as the optimum
base. Similar enantioselectivity (89:11 er) was observed in
toluene (entry 5), but as expected, poor enantioselectivity (55:
45 er) was noted in THF (entry 6), presumably because a more
reactive nBuLi/THF complex was formed in solution.14 A very
short lithiation time (10 min) and trapping with DMF delivered
aldehyde (R)-7 in only 18% yield (entry 7), indicating that an
extended lithiation time is required for high yield. The absolute
configuration of the major enantiomer obtained from lithiation
using (-)-sparteine was unequivocally established from the
X-ray crystal structure of (R)-8, the product of trapping with
Ph2CO (see the Supporting Information). In this case, adduct
(R)-8 with g99:1 er was isolated by recrystallization, and
crystals of suitable quality for the X-ray structure determination
were then grown. Finally, use of (+)-sparteine surrogates 9 and
10 gave the opposite sense of induction, and adduct (R)-6 was
formed in up to 86:14 er (entries 9-12).
Results and Discussion
Kinetically Controlled Asymmetric Deprotonation of a Phos-
phine Sulfide. Since some of the best P-stereogenic ligands (e.g.,
BisP*,2 Mini-PHOS,3 and QuinoxP*4) contain tBu and Me
groups on the phosphorus atom, lithiation-trapping of tert-
butyldimethylphosphine sulfide (5) was investigated. Lithiation
of 5 was carried out using 1.1 equiv of different organolithium
reagents (sBuLi, nBuLi, MeLi, and Me3SiCH2Li) in the presence
(9) (a) Johansson, M. J.; Schwartz, L. O.; Amedjkouh, M.; Kann, N. C.
Eur. J. Org. Chem. 2004, 1894. (b) McGrath, M. J.; O’Brien, P. J. Am.
Chem. Soc. 2005, 127, 16378. (c) Genet, C.; Canipa, S. J.; O’Brien,
P.; Taylor, S. J. Am. Chem. Soc. 2006, 128, 9336.
(10) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870. (b) O’Brien, P. Chem. Commun. 2008,
655.
(11) Gammon, J. J.; O’Brien, P.; Kelly, B. Org. Lett. 2009, 11, 5022.
(12) Tang, W.; Wang, W.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42,
943.
(14) (a) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2158. (b) Sott, R.; Håkansson, M.;
Hilmersson, G. Organometallics 2006, 25, 6047.
(13) Gammon, J. J.; Canipa, S. J.; O’Brien, P.; Kelly, B.; Taylor, S. Chem.
Commun. 2008, 3750.
9
J. AM. CHEM. SOC. VOL. 132, NO. 39, 2010 13923

A R T I C L E S
Gammon et al.
Scheme 2
Scheme 3
The experimental results in Table 1 indicate that asymmetric
deprotonation of phosphine sulfide 5 using nBuLi/(-)-sparteine
generates an 88:12 mixture of the (-)-sparteine-complexed
diastereomeric lithiated phosphine sulfides (RP)-11 and (SP)-11
(Scheme 2). This kinetic enantioselectivity was also predicted
from a density functional theory (DFT) study of the deproto-
nation at the B3LYP/6-31+G(d) level. For the calculations, we
explored the transition states for deprotonation of phosphine
sulfide 5 using EtLi (as a model for nBuLi) and (-)-sparteine;
13 different diastereomeric transition states were calculated.
Figure 2 depicts the most favored diastereomeric transition states
to (RP)-11 and (SP)-11. The difference in energy between RP-
TS and SP-TS is 4 kJ mol-1, which is consistent with the
enantioselectivity obtained via the kinetically controlled depro-
tonation (for detailed information on the DFT studies, see the
Supporting Information).
Scheme 4
As part of the study of the lithiation-trapping of phosphine
sulfide 5, we were interested in comparing the efficiency of
trapping of the lithiated phosphine sulfide with DMF and
PhMe2SiCl at -78 °C. Thus, phosphine sulfide 5 was lithiated
using nBuLi/(-)-sparteine in Et2O at -78 °C for 3 h. Next, the
electrophile was added, and after 10 min at -78 °C, MeOH
was added to quench any remaining lithiated intermediates. With
DMF, a 94% yield of aldehyde (R)-7 (91:9 er) was obtained,
indicating a high rate of trapping using this electrophile. In
contrast, with PhMe2SiCl, silylphosphine sulfide (S)-6 (94:6 er)
was formed in only 54% yield (together with a 38% yield of
recovered phosphine sulfide 5) (Scheme 3). Clearly, PhMe2SiCl
traps the lithiated phosphine sulfide more slowly than DMF at
-78 °C. Furthermore, this lower rate of trapping facilitated the
formation of silylphosphine sulfide (S)-6 with higher enanti-
oselectivity (94:6 er) than when the trapping was allowed to
proceed to completion (88:12 er; Table 1, entry 1). The
improved enantioselectivity indicated that the major diastere-
omeric lithiated phosphine sulfide (RP)-11 reacts with PhMe2SiCl
at a higher rate than lithiated phosphine sulfide (SP)-11. This
was confirmed by generating a 50:50 mixture of diastereomeric
lithiated phosphine sulfides (RP)-11 and (SP)-11 (via deproto-
nation of phosphine sulfide with nBuLi and subsequent addition
of (-)-sparteine) and trapping with a deficiency of PhMe2SiCl
(0.24 equiv). In this way, silylphosphine sulfide (S)-6 was
formed with 70:30 er (67% yield based on the electrophile)
(Scheme 3).
Finally, trapping of the diastereomeric lithiated phosphine
sulfides (RP)-11 and (SP)-11 obtained by nBuLi/(-)-sparteine-
mediated asymmetric deprotonation with prochiral electrophiles
was explored. With pivaldehyde, the two diastereomeric hy-
droxyphosphine sulfides (RP,RC)-12 (54% yield, 97:3 er) and
(RP,SC)-13 (19% yield, 76:24 er) were isolated (Scheme 4). The
configuration of hydroxyphosphine sulfide (RP,RC)-12 was
established by X-ray crystallography (see the Supporting
Information). The difference in the ers of the two diastereomeric
products can be explained by different rates of trapping of the
lithiated phosphine sulfides (RP)-11 and (SP)-11. Fortunately,
the major diastereomeric lithiated phosphine sulfide (RP)-11 traps
most efficiently with pivaldehyde to give hydroxyphosphine
sulfide (RP,RC)-12 in higher enantioselectivity (97:3 er) than
trapping with benzophenone (87:13 er; Table 1, entry 8). A
similar enhancement of enantioselectivity was noticed for
trapping with another prochiral electrophile, tBuPCl2. In this
case, trapping was followed by displacement of the remaining
chloride by MeMgBr (presumably with inversion) and then
treatment with sulfur. This delivered Mini-PHOS precursor
(S,S)-14 (41% yield, 94:6 er) and meso-15 (10% yield) (Scheme
4). Thus, high enantioselectivity in the lithiation-trapping of
phosphine sulfide 5 (up to 97:3 er) can be obtained using
prochiral electrophiles. Such a strategy for improving the initially
obtained kinetically controlled enantioselectivity may find more
widespread application in organolithium/diamine-mediated
lithiation-trapping reactions.
Figure 2. Most favored diastereomeric transition states for the kinetically
controlled deprotonation of 5 computed at the B3LYP/6-31+G(d) level.
9
13924 J. AM. CHEM. SOC. VOL. 132, NO. 39, 2010

Synthesis of P-Stereogenic Compounds
A R T I C L E S
Table 2. Effect of Temperature on the Asymmetric Lithiation-
Trapping of Phosphine Sulfide 5
entry
temperature (°C)
yield (%)a
er (S/R)b
1
2
3
4
5
-90
-78
-50
0
80
88
88
96
86
91:9
88:12
79:21
39:61
39:61
20
a Yield after purification by column chromatography. b Enantiomer
ratio (er) determined by CSP-HPLC.
Interconversion of the RP and SP Stereoisomers of the
Lithiated Methylphosphine Sulfide and Dynamic Thermody-
namic Resolution. During the course of our studies of the
kinetically controlled asymmetric deprotonation of phosphine
sulfide 5 described above, we investigated the effect of
temperature on the enantioselectivity using nBuLi/(-)-sparteine
(Table 2). The enantioselectivity of the obtained silyl adduct
(S)-6 decreased as the temperature increased from -90 °C (91:9
er, entry 1) to -78 °C (88:12 er, entry 2) to -50 °C (79:21 er,
entry 3), which is consistent with a kinetic deprotonation.
However, to our surprise, a reversal of the sense of induction
was observed at 0 and 20 °C: silyl adduct (R)-6 (with the
opposite configuration at phosphorus) was isolated in 61:39 er
in both cases (entries 4 and 5).
To further investigate this unexpected deprotonation
behavior of phosphine sulfide 5, X-ray crystallography of
the lithiated intermediate was attempted. Thus, phosphine
sulfide 5 was lithiated using nBuLi and (-)-sparteine in Et2O
between -90 and -78 °C. Intermediate warming (including
6 h at 25 °C) and subsequent cooling to -78 °C produced a
significant amount of crystalline lithiated phosphine sulfide
11. It was possible to refine the structure satisfactorily (see
the Supporting Information) only for an 83:17 ratio of
diastereomeric lithiated phosphine sulfides (SP)-11 and (RP)-
11, in which the major configuration at phosphorus is the
same as that in the major product (R)-6 obtained from the 0
and 20 °C deprotonation reactions (Table 2, entries 4 and
5). The results were confirmed by repeating the crystallization
experiments and structure analyses. The preference for (SP)-
11 was independent of the organolithium reagent: use of
nBuLi and tBuLi led to the same ratio. In the molecular
structure of 11 (orthorhombic crystal system, space group
P212121), the lithium atom exhibits fourfold coordination, with
two contacts to the (-)-sparteine ligand, one to the lithiated
carbon atom, and one to the sulfur atom (Figure 3). Structure
11 is the first isolated R-lithiated trialkylphosphine sulfide.15,16
To further confirm the uniformity of the crystals and exclude
trapping with inversion of configuration, the crystals of 11 were
redissolved in Et2O and trapped with Ph2CO to give (S)-8 in
Figure 3. Molecular structure of the major diastereomer of lithiated
phosphine sulfide (SP)-11 in the crystal. For bond lengths and angles and
detailed crystallographic data, see the Supporting Information.
Scheme 5
88:12 er. Hence, the major diastereomer (SP)-11 in the crystals
(which was generated via intermediate warming to 25 °C)
yielded (S)-8, in which the sense of induction is the same as
that observed in the 0 and 25 °C lithiations and opposite that
observed at -78 °C. Taken together, these results suggest that
the initially formed diastereomeric lithiated phosphine sulfide/
(-)-sparteine adducts (RP)-11 and (SP)-11 can interconvert at 0
°C or higher temperatures in a thermodynamic equilibration
process (Scheme 5). This accounts for the formation of (R)-6
in 61:39 er (Table 2, entries 4 and 5). By chance, the
configuration of the major diastereomer [(SP)-11] is the opposite
of that obtained [(RP)-11] using (-)-sparteine at -78 °C (kinetic
control). This interconversion of (RP)-11 and (SP)-11 is unprec-
edented and totally different from the configurational instability
of organolithiums that are stereogenic at a lithiated carbon
atom17 or a lithiated phosphorus atom (see Scheme 1).8
The thermodynamic preference for lithiated phosphine sulfide
(SP)-11 was predicted by a computational study of the relative
energies of (RP)-11 and (SP)-11 at the B3LYP/6-31+G(d) level.
Figure 4 depicts the lowest-energy structures for (RP)-11 and
(SP)-11. There is a difference in energy of 3 kJ mol-1 in favor
of (SP)-11, which is consistent with the 83:17 ratio of (SP)-11
and (RP)-11 observed by X-ray crystallography (for detailed
information on the DFT studies, see the Supporting Information).
Next, the effect of temperature on the interconversion of
lithiated phosphine sulfides (RP)-11 and (SP)-11 was investigated.
Thus, a presumed 88:12 ratio of (RP)-11 and (SP)-11 was
generated by kinetic deprotonation of phosphine sulfide 5 [1.1
equiv of nBuLi, 1.2 equiv of (-)-sparteine, -78 °C, 3 h], and
then the reaction mixture was incubated at different temperatures
for 1 or 3 h before trapping with Ph2CO at -78 °C to give
adduct 8 (Table 3). After incubation at -78, -20, and -10 °C
(entries 1, 3, and 5), high er (87:13) was maintained. However,
at 0 °C, a reduction in er to 79:21 was obtained after 3 h at 0
°C (entry 9).
(15) For an X-ray structure of a lithiated thiophosphonamide, see: Denmark,
S. E.; Swiss, K. A.; Wilson, S. R. J. Am. Chem. Soc. 1993, 115, 3826.
(16) For other examples of organolithium/(-)-sparteine structures, see: (a)
Strohmann, C.; Dilsky, S.; Strohfeldt, K. Organometallics 2006, 25,
41. (b) Strohmann, C.; Da¨schlein, C.; Auer, D. J. Am. Chem. Soc.
2006, 128, 704. (c) Strohmann, C.; Strohfeldt, K.; Schildbach, D.;
McGrath, M. J.; O’Brien, P. Organometallics 2004, 23, 5389. (d)
Strohmann, C.; Seibel, T.; Strohfeldt, K. Angew. Chem., Int. Ed. 2003,
42, 4531.
(17) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41, 716.
9
J. AM. CHEM. SOC. VOL. 132, NO. 39, 2010 13925

A R T I C L E S
Gammon et al.
Scheme 6
a After equilibration, the precipitate was allowed to settle (no stirring),
and the solvent was removed using a cannula; the remaining solid was
redissolved in Et2O and trapped with Ph2CO.
The results in Table 3 clearly indicate that the lithiated
phosphine sulfides (RP)-11 and (SP)-11 derived from 5 can
interconvert above -20 °C in the presence of nonlithiated
phosphine sulfide 5. With this in mind, we reasoned that it
should be possible to develop a dynamic thermodynamic
resolution of a racemic lithiated phosphine sulfide at 0 °C as a
means of generating nonracemic P-stereogenic compounds.
Dynamic thermodynamic resolution of organolithium intermedi-
ates that are stereogenic at carbon was pioneered by Hoppe and
Beak.20,21 However, there are only a few examples of crystal-
lization-induced dynamic thermodynamic resolution of lithiated
intermediates.8,21a-c
Figure 4. Optimized structures of the isomers (SP)-11 and (RP)-11 and
their relative energies.
Table 3. Effect of Temperature on the Interconversion of Lithiated
Phosphine Sulfides (SP)-11 and (RP)-11
In our process, phosphine sulfide 5 was lithiated in a racemic
fashion using 0.8 equiv of nBuLi in Et2O ([5] ) 1.00 mol dm-3)
at 0 °C for 1 h. Next, (-)-sparteine (0.8 equiv) was added, and
the mixture was allowed to equilibrate at 0 °C over 3 h. After
the reaction mixture was cooled to -78 °C to freeze the
equilibrium, Ph2CO was added to give (S)-8 in 73:27 er (79%
yield) (Scheme 6). This formation of enantioenriched 8 shows
that a dynamic resolution of the lithiated intermediates must
have occurred. There was a noticeable degree of precipitation
after the 3 h equilibration period, and better enantioselectivity
was obtained when the solvent was removed (via a cannula)
before trapping. Thus, after solvent removal, the remaining
crystals were redissolved in Et2O and trapped with Ph2CO to
give (S)-8 in 81:19 er in a satisfactory 55% yield (Scheme 6).
This result is consistent with the 83:17 ratio of (SP)-11 and (RP)-
11 observed by X-ray analysis.
entry
temperature (°C)a
time (h)a
equiv of nBuLi
yield (%)b
er (R/S)c
1
2
3
4
5
6
7
8
9
-78
-78
-20
-20
-10
-10
0
3
3
1
1
1
1
1
1
3
3
1.1
0.8
1.1
0.8
1.1
0.8
1.1
0.8
1.1
0.8
95
76
67
89
82
93
83
60
87
62
87:13
87:13
87:13
67:33
87:13
59:41
79:21
44:56
79:21
38:62
0
0
0
10
a Temperature/time for incubation of lithiated phosphine sulfide 11
generated using nBuLi/(-)-sp at -78 °C for 3 h ([5] ) 0.07 mol dm-3).
b Yield after purification by column chromatography. c Enantiomer ratio
(er) determined by CSP-HPLC.
Conclusion
A plausible mechanism for interconversion of lithiated
phosphine sulfides (RP)-11 and (SP)-11 involves nonselective
proton transfer from nonlithiated phosphine sulfide 5 to the
lithiated phosphine sulfide 11.18,19 Such a process could occur
as a result of incomplete lithiation or partial quenching of the
lithiated intermediate but appears not to operate at temperatures
below -20 °C. To evaluate this mechanistic conjecture further,
the incubation experiments were carried out in the presence of
excess 5 (obtained by lithiating 5 with only 0.8 equiv of nBuLi;
entries 2, 4, 6, 8, and 10). At -78 °C, there was no loss of er
(entry 2), but at higher temperatures, there was significant
erosion of er (entries 4 and 6). Indeed, after incubation for 3 h
at 0 °C, a 62% yield of adduct (S)-8 in 62:38 er was obtained
(entry 10). Thus, under these conditions, the initially formed
88:12 mixture of (RP)-11 and (SP)-11 was epimerized to a 62:
38 mixture of (SP)-11 and (RP)-11. The formation of (S)-8 is
consistent with the 0 and 25 °C lithiations of 5 (Table 2, entries
4 and 5) and the opposite of that obtained via kinetic lithiation
at -78 °C (Table 1, entry 8).
In summary, we have described the synthesis of P-stereogenic
compounds with the opposite sense of induction using (-)-
sparteine as the ligand simply by changing the reaction
conditions (kinetic or thermodynamic control). Lithiation of
(20) For reviews, see: (a) Gawley, R. E. Top. Stereochem. 2010, 26, 93.
(b) Coldham, I.; Sheikh, N. S. Top. Stereochem. 2010, 26, 253. (c)
Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.;
Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715.
(21) For examples, see: (a) Hoppe, D.; Zschage, O. Angew. Chem., Int.
Ed. Engl. 1989, 28, 69. (b) Hoppe, I.; Marsch, M.; Harms, K.; Boche,
G.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2158. (c) Bou
Chedid, R.; Bru¨mmer, M.; Wibbeling, B.; Fro¨hlich, R.; Hoppe, D.
Angew. Chem., Int. Ed. 2007, 46, 3131. (d) Otte, R.; Fro¨hlich, R.;
Wibbeling, B.; Hoppe, D. Angew. Chem., Int. Ed. 2005, 44, 5492. (e)
Heinl, T.; Retzow, S.; Hoppe, D.; Fraenkel, G.; Chow, A. Chem.sEur.
J. 1999, 5, 3464. (f) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118,
1575. (g) Coldham, I.; Dufour, S.; Haxell, T. F. N.; Howard, S.;
Vennall, G. P. Angew. Chem., Int. Ed. 2002, 41, 3887. (h) Wang, L.;
Nakamura, S.; Toru, T. Org. Biomol. Chem. 2004, 2, 2168. (i)
Coldham, I.; Dufour, S.; Haxell, T. F. N.; Patel, J. J.; Sanchez-Jimenez,
G. J. Am. Chem. Soc. 2006, 128, 10943. (j) Thayumanavan, S.; Basu,
A.; Beak, P. J. Am. Chem. Soc. 1997, 119, 8209. (k) Kessar, S. T.;
Singh, P.; Singh, K. N.; Venugopalan, P.; Kaur, A.; Bharatam, P. V.;
Sharma, A. K. J. Am. Chem. Soc. 2007, 129, 4506. (l) Coldham, I.;
Raimbault, S.; Chovatia, P. T.; Patel, J. J.; Leonori, D.; Sheikh, N. S.;
Whittaker, D. T. E. Chem. Commun. 2008, 4174. (m) Coldham, I.;
Raimbault, S.; Whittaker, D. T. E.; Chovatia, P. T.; Leonori, D.; Patel,
J. J.; Sheikh, N. S. Chem.sEur. J. 2010, 16, 4082.
(18) An intramolecular proton transfer process could also be envisaged.
(19) An alternative mechanism involving dianion formation could also be
considered. For dianion formation with phosphine boranes, see:
Gessner, V. H.; Dilsky, S.; Strohmann, C. Chem. Commun. 2010, 46,
4719.
9
13926 J. AM. CHEM. SOC. VOL. 132, NO. 39, 2010

Synthesis of P-Stereogenic Compounds
A R T I C L E S
phosphine sulfide 5 using nBuLi and (-)-sparteine in Et2O at
-78 °C gave trapped adducts in ∼88:12 er via a kinetically
controlled process. Notably, this initial kinetic enantioselectivity
was improved to 97:3 er by trapping of the lithiated intermediate
with prochiral electrophiles (e.g., pivaldehyde or tBuPCl2). In
addition, we have reported for the first time that lithiated
phosphine sulfides such as (RP)-11 and (SP)-11 can interconvert
at temperatures above -20 °C in the presence of nonlithiated
phosphine sulfide 5. This unexpected result accounts for the
fact that the configuration at phosphorus in the major diaster-
eomeric lithiated phosphine sulfide (SP)-11 observed by X-ray
crystallography is the opposite of that in the product formed
from the kinetic deprotonation of 5 using nBuLi/(-)-sparteine
(-78 °C), and these results are supported by DFT analysis. In
addition, such interconversion of (RP)-11 and (SP)-11 led to the
realization of a novel dynamic thermodynamic resolution of a
racemic lithiated phosphine sulfide. Although the enantioselec-
tivity is at present only moderate (81:19 er), the viability of
this novel route to P-stereogenic phosphine sulfides has been
demonstrated. Overall, through the use of different reaction
conditions with the same chiral ligand [(-)-sparteine], the
methodology reported herein provides selective access to
lithiated phosphine sulfide (RP)-11 (kinetic control) or (SP)-11
(thermodynamic control) and thus to P-stereogenic phosphines
enriched in either enantiomer.
Acknowledgment. We thank the Deutsche Forschungsgemein-
schaft, Fonds der Chemischen Industrie, EPSRC/Celtic Catalysts,
and the EU/Celtic Catalysts (Marie-Curie ToK Grant) for funding.
Supporting Information Available: Full experimental proce-
dures and data, 1H/13C NMR spectra of new compounds, details
of the X-ray crystal structure determinations, a summary of the
calculations, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA1060966
9
J. AM. CHEM. SOC. VOL. 132, NO. 39, 2010 13927