Dynamic kinetic and kinetic resolution of N-Boc-2-lithiopiperidine

Article abstract of DOI:10.1039/b710066c

Asymmetric substitution of 2-lithiopiperidines can be achieved by dynamic resolution; the organolithium is formed as a racemic mixture by proton abstraction (or tin-lithium exchange) and is resolved in the presence of a chiral ligand. The Royal Society of

Full text of DOI:10.1039/b710066c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Dynamic kinetic and kinetic resolution of N-Boc-2-lithiopiperidine{
Iain Coldham,*a Jignesh J. Patel,a Sophie Raimbaulta and David T. E. Whittakerb
Received (in Cambridge, UK) 3rd July 2007, Accepted 4th September 2007
First published as an Advance Article on the web 12th September 2007
DOI: 10.1039/b710066c
sec-butyllithium and the ligand tetramethylethylene diamine
(TMEDA), followed by quenching with tributyltin chloride
(Scheme 1).7 We tested a variety of chiral ligands to effect the
asymmetric substitution of the organolithiums 3, generated from
the racemic stannane 2 with n-butyllithium in Et2O at 210 uC.
Transmetalation was rapid at this temperature in the presence of
the chiral ligands 5 or 6, but TMEDA was added to enhance the
rate of transmetalation prior to addition of the ligands 7–9 (which
were pre-treated with n-butyllithium in Et2O).8
Asymmetric substitution of 2-lithiopiperidines can be achieved
by dynamic resolution; the organolithium is formed as a
racemic mixture by proton abstraction (or tin–lithium
exchange) and is resolved in the presence of a chiral ligand.
The formation and reaction of chiral organolithiums provides a
valuable and stereoselective method for asymmetric synthesis.1
Excellent selectivities have been achieved for the asymmetric
deprotonation of a variety of substrates, an important example
being N-(tert-butoxycarbonyl)pyrrolidine (N-Boc-pyrrolidine), in
which the pro-S hydrogen atom at C-2 is removed with almost
complete selectivity using sec-butyllithium and (2)-sparteine as the
chiral base.2 However, extension of this methodology even to the
next higher homologue (N-Boc-piperidine) is problematic and
occurs with low yields and low selectivities even after long reaction
times.3 Our recent success with the asymmetric substitution of
N-Boc-2-lithiopyrrolidine,4 in which the asymmetry arises not
from a deprotonation but from the faster reaction of one of the
diastereomeric chiral ligand complexes,5 prompted us to attempt
the resolution of the homologous 2-lithiopiperidine. Piperidines are
one of the most important ring systems in natural products and
medicinal compounds, and therefore selective and efficient
methods for their synthesis are of widespread interest. We report
the first highly enantioselective substitution of N-Boc-2-lithiopi-
peridine by a dynamic kinetic resolution.
To test for dynamic thermodynamic resolution, the organo-
lithium?ligand complexes were allowed 1 h at 210 uC before
cooling to 278 uC and electrophilic quench with trimethylsilyl
chloride (TMSCl) (conditions c). The results for the different
ligands are shown in Table 1. With the ligands (2)-sparteine (5) or
the diamine 6, the product 4 was formed essentially as a racemic
mixture. Some selectivity was achieved using the ligands 7–9,
although the enantiomer ratio (er) was low. This was not improved
by using longer reaction times or higher temperatures prior to
cooling and quenching. The er of the product 4 was determined by
chiral GC or by conversion of
4 to the corresponding
p-bromobenzamide, followed by chiral HPLC, as reported.3
We then studied the dynamic kinetic resolution of the
organolithiums 3 (Scheme 1, conditions d). The electrophile
TMSCl was added slowly (over 40–50 min) at 210 uC and the
results for the different ligands are shown in Table 1. The diamine
Dynamic resolution of organolithiums can occur in the presence
of a chiral ligand under either thermodynamic or kinetic control.6
For a dynamic thermodynamic resolution, the diastereomeric
organolithium complexes must be allowed sufficient time at an
appropriate temperature to equilibrate to their thermodynamic
ratio prior to quenching with the electrophile. If electrophilic
quench is fast in comparison with equilibration then the
enantiomer ratio (er) of the product is a reflection of the ratio of
the diastereomeric organolithium complexes. However, in dynamic
kinetic resolution, the electrophilic quench is slower than
interconversion of the organolithium complexes and the enantio-
mer ratio of the product arises from the faster reaction of one of
the complexes. Both possibilities should be explored for any
particular chiral organolithium that is complexed with a chiral
ligand.
Initially we began our study with the known racemic stannane 2,
prepared by proton abstraction of N-Boc-piperidine 1 using
Scheme 1 Dynamic resolution of N-Boc-2-lithiopiperidine. a) sec-BuLi
(1.2 equiv.), TMEDA (1.2 equiv.), Et2O, 278 uC, 3.5 h, then Bu3SnCl,
74%; b) n-BuLi (1.2 equiv.), Et2O, 210 uC, 10 min, chiral ligand L*
(1.5 equiv.) (ligands 7–9 were pre-treated with n-BuLi in Et2O and with
these ligands TMEDA was used to promote tin–lithium exchange); c)
210 uC, 1 h then 278 uC, 4.5 equiv. TMSCl; d) 210 uC, 2 min then
4.5 equiv. TMSCl in Et2O added slowly over 50 min at 210 uC; see
Table 1.
aDepartment of Chemistry, University of Sheffield, Sheffield, UK
S3 7HF. E-mail: i.coldham@sheffield.ac.uk; Fax: (+44) 114 222 9346;
Tel: (+44) 114 222 9428
bAstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK
SK10 4TG
{ Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data and GC and HPLC traces. See DOI:
10.1039/b710066c
4534 | Chem. Commun., 2007, 4534–4536
This journal is ß The Royal Society of Chemistry 2007

View Article Online
Table 1 Formation of 4 by dynamic resolution using ligands 5–9
Entry Ligand Yield, er (R : S)a (DTR)b Yield, er (R : S)a (DKR)c
1
2
3
4
5
a
5
6
7
8
9
86%, 55 : 45
88%, 50 : 50
46%, 23 : 77
39%, 59 : 41
41%, 58 : 42
55%, 53 : 47
86%, 51 : 49
45%, 72 : 28
60%, 11 : 89
62%, 7 : 93d
Scheme 3 Kinetic resolution with ligand 9 and sacrificial electrophile
TMSCl. a) sec-BuLi (1.2 equiv.), THF, TMEDA (1.2 equiv.), 278 uC, 3 h,
then 9 (1.5 equiv.) (pre-treated with n-BuLi in Et2O), then 2 equiv. TMSCl
added over 1 h at 278 uC, then after 1 h Bu3SnCl or Me2SO4; yield (S)-4
30–37%, er 75–80 : 20–25, yield (R)-2 12%, er 99 : 1 or yield (R)-10 19%, er
95 : 5, yield recovered 1 y30%.
The absolute configuration of the major enantiomer was
determined by comparison with an authentic sample prepared
according to ref. 3. Dynamic thermodynamic resolution using
b
c
conditions c) as described in Scheme 1. Dynamic kinetic resolution
d
using conditions d) as described in Scheme 1. Yield at 220 uC was
71%, er 6 : 94.
PhMe2SiCl gave N-Boc-2-(dimethylphenylsilyl)piperidine in rea-
sonable yield and enantiopurity (58% yield, er 88 : 12). These
results indicate that the enantioselectivity is dependent on the
electrophile, as would be expected for a kinetic resolution, and
more reactive electrophiles are less able to discriminate between the
diastereomeric complexes.
ligands 5 and 6 gave poor asymmetric induction. However the
ligands 7–9 gave higher levels of selectivity. The ligand 7 is known
to give good selectivity for the related dynamic kinetic resolution of
N-Boc-2-lithiopyrrolidine.4 By comparing entries 3–5 in Table 1, it
is apparent that ligand 7 is the mismatched diastereomer in the
resolution of N-Boc-2-lithiopiperidine. Excellent enantiomer ratios
of the product 4 were obtained using dynamic kinetic resolution
with the ligand 9 (a diastereomer of 7). In this case, the
diastereomeric organolithium complexes 3 can interconvert faster
than electrophilic quench and one complex (the minor diaster-
eomer based on the ratio obtained in the dynamic resolution under
thermodynamic control with ligand 9) reacts faster than the other.
An improvement to this procedure is to use direct proton
abstraction of N-Boc-piperidine 1 to form the racemic N-Boc-2-
lithiopiperidine. Using sec-BuLi, Et2O and TMEDA followed by
addition of the ligand 9 provides directly the diastereomeric
complexes 3. Addition of TMSCl then gave the desired product 4
(66%, er 92 : 8, S : R). We carried out some optimization of this
dynamic resolution and found that the solvent THF gave slightly
improved results (Scheme 2).{ With chiral ligand 9, the product
(S)-4 was formed with er 95 : 5. This is remarkable as THF often
results in reduced levels of enantioselectivity in reactions of chiral
organolithiums, and this has been ascribed to competition between
THF and the chiral ligand for complexation to the lithium atom.1
In our case, it is likely that the organolithium 3 complexed with the
ligand 9 is considerably more reactive (to TMSCl) than any
organolithium complexed with THF or TMEDA. As would be
expected, the use of the enantiomeric ligand ent-98 gave the
product (R)-4, with the opposite absolute configuration (Scheme 2).
We next probed the scope of the reaction with a variety of
electrophiles. To our disappointment, slow quench at 220 uC of
the organolithium 3 complexed with 9 using the electrophiles
Bu3SnCl, allyl bromide, DMF or Me2SO4 all resulted in products
with little or no enantioselectivity. However, quenching with
As the reaction of the organolithium is highly selective with
TMSCl, it is possible to use this as a sacrificial electrophile prior to
addition of the desired electrophile. After some experimentation, it
was found that best results were obtained by adding 2 equiv. of
TMSCl slowly at 278 uC and leaving to stir for about 1 h prior to
addition of the second electrophile (Scheme 3). This resulted in the
formation of the product (S)-4 (reduced amounts of TMSCl or
shorter reaction times gave lower yields of 4 with high er) together
with (R)-2 or (R)-10 (depending on the electrophile) and recovered
piperidine 1. As these reactions are conducted under kinetic (not
dynamic) control, it is necessary to consume (S)-3 prior to addition
of the second electrophile. This limits the yield of the desired
product (R)-2 or (R)-10, but allows its formation with excellent
levels of enantioselectivity (er up to 99 : 1).
Hence, high levels of enantioselectivity for either enantiomer of
N-Boc-2-trimethylsilylpiperidine can be obtained by dynamic
kinetic resolution of racemic N-Boc-2-lithiopiperidine in the
presence of the chiral ligand 9. This ligand does not, however,
promote enantioselective dynamic kinetic resolution with a range
of electrophiles, although TMSCl can be used as a sacrificial
electrophile to promote enantioselective kinetic resolution. This
chemistry could provide a solution to the poor levels of asymmetric
induction obtained for the asymmetric deprotonation of N-Boc-
piperidine, and could find use in the asymmetric synthesis of
biologically active piperidine-containing compounds.
Notes and references
{ General procedure: N-Boc-piperidine 1 (0.103 g, 0.55 mmol) and
TMEDA (0.1 mL, 0.67 mmol) in THF (0.55 mL) were treated with sec-
BuLi (0.51 mL, 0.67 mmol, 1.3 M in hexanes) at 278 uC. After 3 h, the
deprotonated ligand 9 [prepared by adding n-BuLi (0.37 mL, 0.89 mmol,
2.4 M in hexanes) to 9 (0.165 g, 0.83 mmol) in THF (0.55 mL) at 0 uC] was
added. The mixture was warmed to 220 uC and the electrophile TMSCl
(0.32 mL, 2.5 mmol) in THF (0.32 mL) was added slowly over
approximately 50 min. The mixture was quenched with MeOH (1.5 mL),
the solvent was evaporated and the residue was purified by column
chromatography on silica, eluting with light petroleum (b.p. 40–60 uC)–
EtOAc (98 : 2) to give the piperidine (S)-4 (85 mg, 60%), [a]D24 +36.4 (1.95,
CHCl3), lit.3 for (R)-4, er 73 : 27, [a]D 216.0 (1.16, CHCl3); other data as
reported;3 er 95 : 5 determined by GC [b-cyclodextrin-permethylated 120
fused silica capillary column 30 m 6 0.25 mm i.d., 20% permethylated
b-cyclodextrin in SPB-35 poly(35% diphenyl/65% dimethyl)siloxane,
nitrogen carrier at 14 psi, retention times 28.2 min (major) and 29.2 min
(minor) (at 85 uC)] or by removal of the N-Boc group and conversion to the
Scheme 2 Dynamic kinetic resolution with ligands 9 and ent-9. a) sec-
BuLi (1.2 equiv.), THF, TMEDA (1.2 equiv.), 278 uC, 3 h, then 9 (1.5
equiv.) (pre-treated with n-BuLi in Et2O), then 220 uC, 2 min then 3–4
equiv. TMSCl added over 40–50 min at 220 uC, 60%, er 95 : 5, S : R; b) as
a) but using ent-9, 58%, er 96 : 4, R : S.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 4534–4536 | 4535

View Article Online
p-bromobenzamide,3 followed by chiral HPLC (Chiracel OD column,
hexane–iPrOH 99.5 : 0.5, flow rate 0.5 mL min21, detection at 254 nm,
retention times: 26.8 min (major enantiomer (S)) and 27.9 min (minor
enantiomer (R) – absolute configuration as reported3)). The chiral ligand 9
can be recovered by column chromatography, eluting with CH2Cl2–MeOH
(5 : 1), followed by evaporation of the solvent, acid/base wash (acidify with
2 M HCl, wash with EtOAc, basify with NaOH pellets and extract with
EtOAc) and distillation under reduced pressure.
8% yield, er S : R 87 : 13, see (a) W. F. Bailey, P. Beak, S. T.
Kerrick, S. Ma and K. B. Wiberg, J. Am. Chem. Soc., 2002, 124, 1889; (b)
For two other chiral ligands that give compound 4 in yields of 28% (er 27
: 73) or 36% (er 45 : 55), see M. J. McGrath, J. L. Bilke and P. O’Brien,
Chem. Commun., 2006, 2607; (c) For a recent report with a larger number
of chiral ligands, see I. Coldham, P. O’Brien, J. J. Patel, S. Raimbault, A.
J. Sanderson, D. Stead and D. T. E. Whittaker, Tetrahedron: Asymmetry,
2007, DOI: 10.1016/j.tetasy.2007.09.001.
4 (a) I. Coldham, J. J. Patel and G. Sanchez-Jimenez, Chem. Commun.,
2005, 3083; (b) I. Coldham, S. Dufour, T. F. N. Haxell, J. J.
Patel and G. Sanchez-Jimenez, J. Am. Chem. Soc., 2006, 128,
10943.
5 For a review on kinetic resolution, see E. Vedejs and M. Jure, Angew.
Chem., Int. Ed., 2005, 44, 3974.
1 For reviews, see (a) A. Basu and S. Thayumanavan, Angew. Chem., Int.
Ed., 2002, 41, 716; (b) J. Clayden, Organolithiums: Selectivity for
Synthesis, Pergamon, Oxford, 2002; (c) Organolithiums in Enantioselective
Synthesis, ed. D. M. Hodgson, Springer-Verlag, Heidelberg, 2003; (d)
R. E. Gawley and I. Coldham, in The Chemistry of Organolithium
Compounds, ed. Z. Rappoport and I. Marek, Wiley, Chichester, 2004,
p. 997; (e) D. Hoppe and G. Christoph, in The Chemistry of
Organolithium Compounds, ed. Z. Rappoport and I. Marek, Wiley,
Chichester, 2004, p. 1055.
2 P. Beak, S. T. Kerrick, S. Wu and J. Chu, J. Am. Chem. Soc., 1994, 116,
3231.
3 Asymmetric deprotonation with sec-BuLi and (2)-sparteine in Et2O at
278 uC for 16 h, followed by quenching with TMSCl gives compound 4,
6 P. Beak, D. R. Anderson, M. D. Curtis, J. M. Laumer, D. J. Pippel and
G. A. Weisenburger, Acc. Chem. Res., 2000, 33, 715.
7 P. Beak and W. K. Lee, J. Org. Chem., 1993, 58, 1109.
8 Ligands 7–9 can be prepared readily in 2 steps (by coupling
proline methyl ester with N-Cbz-proline followed by reduction)
according to (a) T. Mukaiyama, Tetrahedron, 1981, 37, 4111; (b)
D. J. Gallagher, S. Wu, N. A. Nikolic and P. Beak, J. Org. Chem., 1995,
60, 8148.
4536 | Chem. Commun., 2007, 4534–4536
This journal is ß The Royal Society of Chemistry 2007