Asymmetric deprotonation using s -BuLi or i -PrLi and chiral diamines in THF: The diamine matters

Article abstract of DOI:10.1021/ja107672h

The solution structures of [⁶Li]-i-PrLi complexed to (-)-sparteine and the (+)-sparteine surrogate in Et₂O-d₁₀ and THF-d₈ at -80 °C have been determined using ⁶Li and ¹³C NMR spectroscopy. In Et₂O, i-PrLi/(-)-sparteine is a solvent-complexed heterodimer, whereas i-PrLi/(+)-sparteine surrogate is a head-to-tail homodimer. In THF, there was no complexation of (-)-sparteine to i-PrLi until ≥3.0 equiv (-)-sparteine and with 6.0 equiv (-)-sparteine, a monomer was characterized. In contrast, the (+)-sparteine surrogate readily complexed to i-PrLi in THF, and with 1.0 equiv (+)-sparteine surrogate, complete formation of a monomer was observed. The NMR spectroscopic study suggested that it should be possible to carry out highly enantioselective asymmetric deprotonation reactions using i-PrLi or s-BuLi/(+)-sparteine surrogate in THF. Hence, three different asymmetric deprotonation reactions (lithiation-trapping of N-Boc pyrrolidine, an O-alkyl carbamate, and a phosphine borane) were investigated; it was shown that reactions with (-)-sparteine in THF proceeded with low enantioselectivity, whereas the corresponding reactions with the (+)-sparteine surrogate occurred with high enantioselectivity. These are the first examples of highly enantioselective asymmetric deprotonation reactions using organolithium/diamine complexes in THF.

Full text of DOI:10.1021/ja107672h

Published on Web 10/11/2010
Asymmetric Deprotonation using s-BuLi or i-PrLi and Chiral
Diamines in THF: The Diamine Matters
Giorgio Carbone,† Peter O’Brien,*,† and Go¨ran Hilmersson*,‡
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K., and
Department of Chemistry, UniVersity of Gothenburg, SE-412 96 Go¨teborg, Sweden
Received August 25, 2010; E-mail: peter.obrien@york.ac.uk
Abstract: The solution structures of [6Li]-i-PrLi complexed to (-)-sparteine and the (+)-sparteine surrogate
6
in Et2O-d10 and THF-d8 at -80 °C have been determined using Li and 13C NMR spectroscopy. In Et2O,
i-PrLi/(-)-sparteine is a solvent-complexed heterodimer, whereas i-PrLi/(+)-sparteine surrogate is a head-
to-tail homodimer. In THF, there was no complexation of (-)-sparteine to i-PrLi until g3.0 equiv (-)-sparteine
and with 6.0 equiv (-)-sparteine, a monomer was characterized. In contrast, the (+)-sparteine surrogate
readily complexed to i-PrLi in THF, and with 1.0 equiv (+)-sparteine surrogate, complete formation of a
monomer was observed. The NMR spectroscopic study suggested that it should be possible to carry out
highly enantioselective asymmetric deprotonation reactions using i-PrLi or s-BuLi/(+)-sparteine surrogate
in THF. Hence, three different asymmetric deprotonation reactions (lithiation-trapping of N-Boc pyrrolidine,
an O-alkyl carbamate, and a phosphine borane) were investigated; it was shown that reactions with (-)-
sparteine in THF proceeded with low enantioselectivity, whereas the corresponding reactions with the (+)-
sparteine surrogate occurred with high enantioselectivity. These are the first examples of highly en-
antioselective asymmetric deprotonation reactions using organolithium/diamine complexes in THF.
Scheme 1
Introduction
It is well-known that asymmetric deprotonation reactions
using a chiral base derived from an organolithium reagent (e.g.,
s-BuLi or n-BuLi) and (-)-sparteine proceed with negligible
enantioselectivity if carried out in THF.1-8 This was first noted
by Hoppe et al. in 19951 and is usually rationalized by the THF
complexing preferentially to the organolithium.1,9 An example
from Beak’s work is illustrative: the s-BuLi/(-)-sparteine-
mediated asymmetric deprotonation-cyclization of N-Boc
amino chloride 1 to arylated pyrrolidine (S)-2 proceeds in a
racemic fashion in THF but in 98:2 er in toluene (Scheme 1).2
Hence, noncoordinating solvents such as Et2O, toluene, pentane,
or hexane must be employed for highly enantioselective
deprotonation processes using s-BuLi or n-BuLi and (-)-
sparteine.10 It is tempting to assume that similar behavior would
be observed with other chiral diamines such as the structurally
similar (+)-sparteine surrogate [(+)-(1R,2S,9S)-11-methyl-7,
11-diazatricyclo[7.3.1.02,7tridecane] (Scheme 1) developed in
our laboratory.11,12 However, in this contribution, we demon-
strate that such an assumption is not at all valid, and three
different examples of highly enantioselective asymmetric depro-
tonation processes using s-BuLi or i-PrLi/(+)-sparteine surrogate
in THF are presented. Our synthetic results were guided by
determination of the solution structures of [6Li]i-PrLi/chiral
† University of York.
‡ University of Gothenburg.
6
diamine complexes using Li and 13C NMR spectroscopy.
(1) Hoppe, I.; Marsch, M.; Harms, K.; Boche, G.; Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2158.
Results and Discussion
(2) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715.
(3) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757.
(4) Bertini Gross, K. M.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997, 62,
7679.
Investigation of the Solution Structure of i-PrLi Complexed
with (-)-Sparteine and the (+)-Sparteine Surrogate using NMR
Spectroscopy. The most commonly used reagents for asymmetric
deprotonations are complexes of (-)-sparteine and n-BuLi or
s-BuLi;10 however, despite their widespread use, very little is
known about their solution structure and aggregation states. In
(5) Pakulski, Z.; Koprowski, M.; Pietrusiewicz, K. M. Tetrahedron 2003,
59, 8219.
(6) Huang, J.; O’Brien, P. Chem. Commun. 2005, 5696.
(7) Kessar, S. V.; Singh, P.; Nain Singh, K.; Venugopalan, P.; Kaur, A.;
Bharatam, P. V.; Sharma, A. K. J. Am. Chem. Soc. 2007, 129, 4506.
(8) Hodgson, D. M.; Kloesges, J. Angew. Chem. Int. Ed. 2010, 49, 2900.
(9) Sott, R.; Håkansson, M.; Hilmersson, G. Organometallics 2006, 25,
6047.
(11) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870.
(10) (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
(b) Kizirian, J.-C. Top. Stereochem. 2010, 26, 189.
(12) O’Brien, P. Chem. Commun. 2008, 655.
9
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J. AM. CHEM. SOC. 2010, 132, 15445–15450 15445

A R T I C L E S
Carbone et al.
Figure 1. Structures for complexes of organolithium reagents and (-)-
sparteine.
1992, Beak and co-workers used 6Li, 13C, and 1H NMR
spectroscopy to characterize a complex of i-PrLi (a model for
s-BuLi) and (-)-sparteine in Et2O as heterodimer 3 (Figure 1).13
In contrast, using a similar spectroscopic approach, Collum et
al. identified homodimer 4 as the solution structure for the less
sterically demanding n-BuLi/(-)-sparteine complex in toluene.14
More recently, Strohmann and colleagues have characterized
heterodimer 3 (n ) 1) and homodimer 4 in the solid-state by
X-ray crystallography.15 Furthermore, Strohmann et al. have also
reported the X-ray crystal structure of monomer 5 for the t-BuLi/
(-)-sparteine complex.16 A comprehensive overview of the
solid-state and solution structures of organolithium reagents has
been published by Strohmann and co-workers.17
Due to the limited information on solution structures of or-
ganolithium/(-)-sparteine complexes, we embarked on a NMR
spectroscopic study of the solution structure of [6Li]-i-PrLi18
complexed to (-)-sparteine and the (+)-sparteine surrogate in
Et2O-d10 and THF-d8 at -80 °C (the usual temperature employed
for asymmetric deprotonation reactions). To start with, we
reproduced Beak’s characterization of heterodimer 3 for i-PrLi/
(-)-sparteine in Et2O. [6Li]-i-PrLi was prepared according to a
literature method.19 The Li NMR spectrum of [6Li]-i-PrLi in
6
Et2O-d10 has one signal at δ 2.60 ppm and was assigned to an
Et2O-solvated dimer (concentration of i-PrLi in Et2O-d10 ) 0.07
M). Addition of 2 equiv (-)-sparteine gave a complex that was
characterized as heterodimer 3 on the basis of the following
6
NMR spectroscopic data: the Li NMR spectrum showed two
signals at δ 2.83 and δ 2.63 ppm in a 1:1 ratio; the 13C NMR
spectrum showed two approximate quintets at δ 13.89 ppm
(1J(6Li,13C) ) 8.0 Hz) and δ 11.86 ppm (1J(6Li,13C) ) 8.5 Hz)
for the CH carbons of the i-Pr groups (the quintets indicate that
each CH couples to two lithium atoms) as well as signals due
Figure 2. 6Li NMR spectra of [6Li]-i-PrLi/(+)-sparteine surrogate in Et2O-
d10 at -80 °C: (a) No (+)-sparteine surrogate; (b) 1.0 equiv (+)-sparteine
surrogate; (c) 2.0 equiv (+)-sparteine surrogate.
to uncomplexed and complexed (-)-sparteine; the J(6Li,13C)
6Li cations directly connected to the observed 13C),20 and the
6Li,1H-HOESY spectrum21 showed NOEs from signals due to
1
values of 8.0 and 8.5 Hz suggest a dimeric aggregate based on
the empirical Bauer-Winchester-Schleyer rule for coupling
constants (J(6Li,13C) ) (17 ( 2)/nC where nC is the number of
6
the (-)-sparteine ligand to only one of the Li signals (2.63
ppm). Full details are provided in the Supporting Information.
Next, we established the solution structure of the i-PrLi/(+)-
sparteine surrogate complex in Et2O in a similar fashion. Starting
from the dimeric [6Li]-i-PrLi in Et2O-d10 at -80 °C, we added
0.5-equiv aliquots of the (+)-sparteine surrogate and recorded
(13) Gallagher, D. J.; Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1992,
114, 5872.
(14) Rutherford, J. L.; Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc.
2002, 124, 264.
6
the Li NMR spectrum. The results are shown in Figure 2. As
(15) Strohmann, C.; Strohfeldt, K.; Schildbach, D. J. Am. Chem. Soc. 2003,
125, 13672.
more (+)-sparteine surrogate was added, a new signal was
observed in the 6Li NMR spectrum, and this was the only signal
present after addition of g1.5 equiv (+)-sparteine surrogate.
Thus, the heterodimer similar to 3 observed for i-PrLi/(-)-
(16) Strohmann, C.; Seibel, T.; Strohfeldt, K. Angew. Chem., Int. Ed. 2003,
42, 4531.
(17) Gessner, V. H.; Da¨schlein, C.; Strohmann, C. Chem.sEur. J. 2009,
15, 3320.
(18) i-PrLi was used instead of the more commonly employed s-BuLi as
the NMR spectra of s-BuLi/chiral diamines would be more complicated
due to the presence of diastereomeric complexes.
(19) Morrison, R. C.; Hall, R. W.; Schwindeman, J. A.; Kamienski, C. W.;
Engel, J. F. Eur. Pat. Appl. EP 92-202236 A1 19930203, 1993.
(20) (a) Bauer, W.; Winchester, W. R.; Schleyer, P. v. R. Organometallics
1987, 6, 2371. (b) Bauer, W.; Schleyer, P. v. R. AdV. Carbanion Chem.
1992, 1, 89.
(21) Bauer, W.; Schleyer, P. v. R. Magn. Reson. Chem. 1988, 26, 827.
9
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Enantioselective Asymmetric Deprotonation Reactions
A R T I C L E S
6
(-)-sparteine, there was no change in the Li NMR spectrum
(Figure 5b and c). A new, minor signal (δ 1.27 ppm) was
observed only when an excess of (-)-sparteine was added (3.0
equiv) (see Supporting Information). In contrast, with the (+)-
sparteine surrogate, a new signal was observed in the 6Li NMR
spectrum at δ 1.43 ppm after 0.5 equiv (+)-sparteine surrogate
was added (Figure 5b), and this was the only signal present
after addition of 1.0 equiv (+)-sparteine surrogate (Figure 5c).
The 13C NMR spectrum of i-PrLi in the presence of 1.0 equiv
(+)-sparteine surrogate contained a 1:1:1 triplet (1J(6Li,13C) )
14.0 Hz) at δ 16.36 ppm (Figure 6), suggesting a monomeric
Figure 3. Head-to-tail homodimer 6 for i-PrLi/(+)-sparteine surrogate
complex in Et2O.
1
structure. The magnitude of the J(6Li,13C) coupling constant
(14.0 Hz) is slightly lower than expected for a monomeric
aggregate based on the Bauer-Winchester-Schleyer rule.20
Thus, we characterized monomer 7 (Figure 7) for i-PrLi/(+)-
sparteine surrogate in THF. This is the first example of
characterization of a simple organolithium/diamine monomer
in solution. A similar monomeric structure was observed for
i-PrLi and a large excess of (-)-sparteine (6.0 equiv) in THF
(see Supporting Information).
6
The most striking feature of the Li NMR spectra presented
in Figure 5 is that the (+)-sparteine surrogate complexes readily
to i-PrLi in THF (fully complexed with 1.0 equiv ligand present),
whereas complexation of i-PrLi with (-)-sparteine in THF is
much weaker: the i-PrLi/(-)-sparteine complex is only detected
with excess (g3.0 equiv) of (-)-sparteine (Figure 5c and
Supporting Information). Thus, through characterization of the
solution structure of i-PrLi in THF, the low enantioselectivity
of i-PrLi/(-)-sparteine reactions in THF can be rationalized.
However, of far more interest, the NMR spectroscopic studies
reveal that the (+)-sparteine surrogate does complex to the i-PrLi
even in THF, and this suggested to us that it might be possible
to carry out highly enantioselective asymmetric deprotonation
reactions using i-PrLi/(+)-sparteine surrogate in THF.
Investigation of Asymmetric Deprotonation Reactions Using
i-PrLi and s-BuLi with Chiral Diamines in Different Solvents.
From a mechanistic and synthetic point of view, arguably the
most widely studied asymmetric deprotonation reaction using
organolithium/diamine complexes is Beak’s lithiation-trapping
of N-Boc pyrrolidine 8.23 As a result, we selected the lithiation
and benzaldehyde trapping of N-Boc pyrrolidine 8 (f syn-9
and anti-924) as a suitable reaction to investigate the enanti-
oselectivity with different organolithium reagents (i-PrLi and
s-BuLi) and solvents (Et2O, TBME, THF, and 2-methyl-THF25).
The general procedure involved lithiation of N-Boc pyrrolidine
8 using 1.3 equiv organolithium/diamine complex in solvent at
-78 °C for 3 h (concentration of i-PrLi or s-BuLi in solvent )
0.4 M). Subsequent trapping with benzaldehyde gave two
diastereomeric hydroxy pyrrolidines syn-9 and anti-10 (formed
in ∼75:25 dr) which were separated by chromatography and
the enantioselectivity was determined using CSP-HPLC. To
start with, we investigated the use of (-)-sparteine as a ligand
(Table 1).
Figure 4. Part of the 13C NMR spectrum of [6Li]-i-PrLi/(+)-sparteine
surrogate (1.5 equiv) in Et2O-d10 at -80 °C.
sparteine in Et2O can be ruled out. Instead, the i-PrLi/(+)-
sparteine surrogate complex (1.5 equiv) in Et2O was charac-
terized as the head-to-tail homodimer 6 (Figure 3). Key
6
spectroscopic features are as follows. The Li NMR spectrum
contained one signal at δ 2.76 ppm, indicating only one lithium
environment. In contrast, the 13C NMR spectrum (Figure 4)
showed two approximate quintets at δ 13.75 ppm (1J(6Li,13C)
) 8.0 Hz) and δ 11.49 ppm (1J(6Li,13C) ) 8.0 Hz) for the CH
carbons of the i-Pr groups (as well as signals due to uncom-
plexed and complexed (+)-sparteine surrogate). The magnitudes
of the 1J(6Li,13C) coupling constants (8.0 Hz) suggest a dimeric
aggregate based on the empirical Bauer-Winchester-Schleyer
rule for coupling constants.20 The quintet multiplicity indicates
that each CH is bonded to two lithium atoms, and so the solution
structure must be dimeric. Only the head-to-tail homodimer 6
has equivalent lithium atoms and inequivalent carbon atoms (the
alternative head-to-head homodimer has equivalent lithium and
carbon atoms - see Supporting Information).22 Thus, under
identical conditions in Et2O-d10 at -80 °C, i-PrLi/(-)-sparteine
exists as heterodimer 3, whereas i-PrLi/(+)-sparteine surrogate
complex exists as homodimer 6. Presumably, the less sterically
hindered (+)-sparteine surrogate allows homodimer formation.
The corresponding NMR titration experiments were then
carried out using i-PrLi and (-)-sparteine or the (+)-sparteine
6
surrogate in THF-d8 at -80 °C. As shown by the Li NMR
As expected, using i-PrLi or s-BuLi in Et2O or TBME, high
enantioselectivity (95:5-98:2 er) in the formation of hydroxy
pyrrolidines syn-9 and anti-10 ensued (entries 1-3). In contrast,
spectra (Figure 5), there was a significant difference in behavior
with the two ligands. The 6Li NMR spectrum of [6Li]-i-PrLi in
THF-d8 shows one signal at δ 0.92 ppm and was assigned to a
THF-solvated dimer. In the presence of 0.5 equiv or 1.0 equiv
(23) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231.
(22) Interestingly, the less sterically hindered complexes of MeLi/(+)-
sparteine surrogate and MeLi/(-)-sparteine have both been charac-
terised in the solid-state as head-to-head homodimers. Strohmann, C.;
Strohfeldt, K.; Schildbach, D.; McGrath, M. J.; O’Brien, P. Organo-
metallics 2004, 23, 5389.
(24) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009, 11,
1935.
(25) 2-Methyl-THF is an attractive alternative solvent to THF since it is
produced from renewable resources. Aycock, D. F. Org. Process Res.
DeV. 2007, 11, 156.
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A R T I C L E S
Carbone et al.
Figure 5. 6Li NMR spectra of [6Li]-i-PrLi/(-)-sparteine and (+)-sparteine surrogate in THF-d8 at -80 °C: (a) No diamine; (b) 0.5 equiv diamine;
(c) 1.0 equiv diamine.
Figure 7. Monomer 7 for i-PrLi/(+)-sparteine surrogate complex in THF.
use of i-PrLi in THF gave syn-9 in 63:37 er (65% yield) and
anti-10 in 60:40 er (22% yield) (entry 4). This result is consistent
with the NMR spectroscopic study. Even lower enantioselec-
tivity (51:49 er) was observed using s-BuLi/(-)-sparteine in
THF (entry 5). Finally, we demonstrated that 2-methyl-THF was
“THF-like” since poor enantioselectivity resulted in using
s-BuLi/(-)-sparteine in 2-methyl-THF (entry 6).
Figure 6. Part of the 13C NMR spectrum of [6Li]-i-PrLi/(+)-sparteine
surrogate (1.0 equiv) in THF-d8 at -80 °C.
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Enantioselective Asymmetric Deprotonation Reactions
A R T I C L E S
Table 1. Asymmetric Lithiation-Trapping of N-Boc Pyrrolidine 8 Using (-)-Sparteine
entry
RLi
solvent
yield of syn-9 (%)a
er of syn-9b
yield of anti-10 (%)a
er of anti-10b
1
2
3
4
5
6
i-PrLi
Et2O
Et2O
TBME
THF
THF
64
63
51
65
50
50
97:3
97:3
97:3
63:37
51:49
59:41
22
23
24
22
14
29
95:5
97:3
98:2
60:40
51:49
55:45
s-BuLi
s-BuLi
i-PrLi
s-BuLi
s-BuLi
2-methyl-THF
a Yield after purification by column chromatography. b Enantiomer ratio (er) determined by CSP-HPLC.
Table 2. Asymmetric Lithiation-Trapping of N-Boc Pyrrolidine 8 Using the (+)-Sparteine Surrogate
entry
RLi
solvent
yield of syn-9 (%)a
er of syn-9b
yield of anti-10 (%)a
er of anti-10b
1
2
3
4
5
6
i-PrLi
Et2O
Et2O
TBME
THF
THF
68
58
56
66
45
53
98:2
95:5
94:6
97:3
95:5
93:7
23
23
31
21
20
22
95:5
94:6
93:7
97:3
95:5
93:7
s-BuLi
s-BuLi
i-PrLi
s-BuLi
s-BuLi
2-methyl-THF
a Yield after purification by column chromatography. b Enantiomer ratio (er) determined by CSP-HPLC.
Scheme 2
The same set of experiments was then carried out with the
(+)-sparteine surrogate (Table 2). In this case, high enantiose-
lectivity (93:7-98:2 er) in the opposite sense was obtained in
all cases (entries 1-6). Thus, using i-PrLi/(+)-sparteine sur-
rogate in THF gave syn-9 in 97:3 er (66% yield) and anti-10 in
97:3 er (21% yield) (entry 4). A similar result was obtained
using s-BuLi (entry 5), a more commonly used reagent. As
predicted by the NMR spectroscopic study, it is indeed possible
to carry out highly enantioselective asymmetric deprotonation
reactions using s-BuLi or i-PrLi/(+)-sparteine surrogate in THF
or 2-methyl-THF. Our results also show that i-PrLi (used in
the NMR spectroscopy study) and s-BuLi behave in a similar
isolated syn-9 in 59% yield and 50:50 er together with anti-10
in 24% yield and 53:47 er. Clearly, diamine (R,R)-11 does not
complex to s-BuLi in THF, resulting in low enantioselectivity,
and behaves in an analogous fashion to (-)-sparteine.
The results obtained with N-Boc pyrrolidine 8 and (-)-
sparteine and the (+)-sparteine surrogate were verified using
two other s-BuLi-mediated asymmetric deprotonation reactions.
First, we carried out Hoppe’s29 lithiation-MeO2CCl trapping
of O-alkyl carbamate 12 (f 13) using 1.2 equiv s-BuLi/chiral
diamine complex in Et2O and THF (concentration of s-BuLi in
solvent ) 0.3 M) (Table 3). Reactions using s-BuLi/(-)-
sparteine in THF proceeded with low enantioselectivity (61:39
er) (entries 2 and 3). Low enantioselectivity (61:39 er) was even
obtained using an excess of (-)-sparteine (3.3 equiv relative to
s-BuLi) in THF (entry 3). Significantly, use of s-BuLi/(+)-
sparteine surrogate in THF gave adduct (S)-13 in 72% yield
and 93:7 er (entry 5).
fashion.
Recently, we have shown that diamine (R,R)-11, originally
developed by Alexakis et al.,26 can be used as an effective
sparteine surrogate in the asymmetric lithiation-trapping of
N-Boc pyrrolidine 8.27,28 Hence, we attempted the asymmetric
deprotonation-benzaldehyde trapping with s-BuLi/diamine (R,R)-
11 in THF at -78 °C (Scheme 2). From this reaction, we
(26) Kizirian, J.-C.; Caille, J.-C.; Alexakis, A. Tetrahedron. Lett. 2003,
44, 8893. (b) Kizirian, J.-C.; Cabello, N.; Pinchard, L.; Caille, J.-C.;
Alexakis, A. Tetrahedron 2005, 61, 8939.
(27) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409.
(28) For other examples of the use of diamine 11 as a sparteine surrogate,
see: (a) Mealy, M. J.; Luderer, M. R.; Bailey, W. F.; Bech Sommer,
M. J. Org. Chem. 2004, 69, 6042. (b) Coldham, I.; O’Brien, P.; Patel,
J. J.; Raimbault, S.; Sanderson, A. J.; Stead, D.; Whittaker, D. T. E.
Tetrahedron: Asymmetry 2007, 18, 2113. (c) Kanda, K.; Endo, K.;
Shibata, T. Org. Lett. 2010, 12, 1980. (d) Hodgson, D. M.; Kloesges,
J. Angew. Chem., Int. Ed. 2010, 49, 2900. (e) Metallinos, C.; Zaifman,
J.; Dudding, T.; Van Belle, L.; Taban, K. AdV. Synth. Catal. 2010,
352, 1967.
(29) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl. 1990,
29, 1422.
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Carbone et al.
Table 3. Asymmetric Lithiation-Trapping of O-Alkyl Carbamate 12
Using (-)-Sparteine and the (+)-Sparteine Surrogate
using s-BuLi/chiral diamines in THF, provided that a suitable
diamine is selected. Thus, as previously noted by others1-8 and
confirmed by our studies, (-)-sparteine in THF is not suitable
and the reactions proceed with low enantioselectivity. The
Alexakis diamine (R,R)-11 in THF is also not suitable. However,
use of s-BuLi and the (+)-sparteine surrogate does facilitate
high enantioselectivity even in THF. These results are fully
supported by the NMR spectroscopic results which show that,
in contrast to (-)-sparteine, the (+)-sparteine surrogate readily
complexes to i-PrLi in THF. Fundamentally, our results
demonstrate that the diamine matters. This is particularly
surprising for (-)-sparteine and the (+)-sparteine surrogate as
they are structurally so closely matched. There are also potential
synthetic benefits of our results: THF is preferred to Et2O for
large-scale industrial applications due to the low flash point of
Et2O; there are substrates for deprotonation that will be insoluble
in Et2O at -78 °C but soluble in THF, and 2-methyl-THF is
becoming a more popular solvent in industry as it is derived
from a renewable resource.25 Our results can also explain
Fukuyama et al.’s successful use of s-BuLi and the (+)-sparteine
surrogate for the regioselective deprotonation of an unsym-
metrical substituted N-Boc pyrrolidine during their total syn-
theiss of (-)-kainic acid even though the reaction was carried
out in THF.31 Finally, it should also be highlighted that
significant differences were observed for the solution structures
of i-PrLi/(-)-sparteine and i-PrLi/(+)-sparteine surrogate in
Et2O and THF. In Et2O, i-PrLi/(-)-sparteine is an Et2O-
complexed heterodimer whereas i-PrLi/(+)-sparteine surrogate
is a head-to-tail homodimer. In THF, a 1:1 mixture of i-PrLi
and (-)-sparteine did not form a complex, whereas a 1:1 mixture
of i-PrLi and the (+)-sparteine surrogate gave a monomer. This
is the first time that a monomeric organolithium/diamine
complex has been characterized in solution by 6Li and 13C NMR
spectroscopy. Overall, the results presented in this study suggest
that, for diamines other than (-)-sparteine and (R,R)-11, THF
should be considered as a viable solvent since high enantiose-
lectivity can be obtained using s-BuLi/(+)-sparteine surrogate-
mediated asymmetric deprotonation reactions in THF.
entry
diamine
solvent
yield (%)a
er (R:S)b
1
2
3
4
5
(-)-sparteine
Et2O
THF
THF
Et2O
THF
84
68
24
67
72
97:3
(-)-sparteine
61:39
61:39
7:93
(-)-sparteinec
(+)-sparteine surrogate
(+)-sparteine surrogate
7:93
a Yield after purification by column chromatography. b Enantiomer
ratio (er) determined by CSP-HPLC. c 3.3 equiv (-)-sparteine relative to
s-BuLi was used.
Table 4. Asymmetric Lithiation-Trapping of Phosphine Borane 14
Using (-)-Sparteine and the (+)-Sparteine Surrogate
entry
diamine
solvent
yield (%)a
er (S:R)b
1
2
3
4
5
(-)-sparteine
Et2O
THF
Et2O
THF
THFc
88
30
89
44
78
95:5
50:50
5:95
12:88
9:91
(-)-sparteine
(+)-sparteine surrogate
(+)-sparteine surrogate
(+)-sparteine surrogate
a Yield after purification by column chromatography. b Enantiomer
ratio (er) determined by CSP-HPLC. c Concentration of s-BuLi in sol-
vent ) 0.3 M whereas concentration for entries 1-4 ) 0.1 M.
A similar set of results was obtained in Evans-style30
lithiation-trapping of phosphine borane 14 (f 15) (Table 4).
Use of s-BuLi/(-)-sparteine in THF (concentration of s-BuLi
in THF ) 0.1 M) gave a 30% yield of racemic adduct 14 (entry
2) whereas high enantioselectivity (88:12 er, 44% yield) was
maintained using s-BuLi/(+)-sparteine surrogate in THF at the
same concentration (entry 4). Due to the low solubility of
phosphine borane 14 in Et2O at -78 °C, these reactions are
typically carried out under dilute conditions (concentration of
s-BuLi in THF ) 0.1 M). However, due to the higher solubility
of 14 in THF at -78 °C, we were able to carry out the same
reaction at higher concentration (0.3 M) and obtained a better
result: adduct (R)-15 of 91:9 er was generated in 78% yield
(entry 5).
Acknowledgment. We thank the EPSRC for funding and
Richard Sott for carrying out important preliminary NMR spec-
troscopy experiments.
Supporting Information Available: Full experimental proce-
1
dures and data, H/13C NMR spectra of new compounds and
6
full details of the Li and 13C NMR spectroscopic study. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Conclusion
In conclusion, we demonstrate that it is possible to carry out
highly enantioselective asymmetric deprotonation reactions
JA107672H
(30) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995,
117, 9075.
(31) Morita, Y.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2005, 7, 4337.
9
15450 J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010